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Carbohydrate-based syntheses of C3-chirons

Citation for published version (APA):Emons, C. H. H. (1992). Carbohydrate-based syntheses of C3-chirons. Technische Universiteit Eindhoven.https://doi.org/10.6100/IR366605

DOI:10.6100/IR366605

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https://doi.org/10.6100/IR366605

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CARBOHYDRATE-BASED SYNTHESES OF C3-CHIRONS

CARRY EMONS

CARBOHYDRATE-BASED SYNTHESES OF

PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven. op gezag van de Rector Magniflcus. prof. dr. J. H. van Lint. voor een commissie aangewezen door het College van Dekanen In het openbaar te verdedigen op vrijdag 31 januari 1992 om 16.00 uur

door

Catharina Henrica Huberta Emons

geboren te Oploo

druk: wibro dissertatiedrukkeriL helmond.

Dit proefschrift is goedgekeurd door

de promotoren:

en de copromotor:

prof. dr. R.A. Sheldon

prof. dr. B. Zwanenburg

dr. J.A.J.M. Vekemans

The work described in this. thesis was supported by the Netherlands Foundation

for Technica! Research (STW) under the auspices of the NetherlandS Organization

for Scientific Research (NWO) and by Andeno BV.

A green little chemist On a green little day

Mixed some green little chemieals In a green little way

The green little grasses Now tenderly wave Over the green little chemisf s Green little grave

Morris Goran

Allen die aan het ·totstandkomen van dit proefschrift een bijdrage hebben geleverd, in welke vorm dan ook, ben ik erg erkentelijk en betuig ik mijn welgemeende dank.

Contents 5

1. INTRODUCTION 9 1.1 Chirality 9

1.2 Carbohydrates 15

1.3 ~-Chirons 20

1.4 Catalysis 27 1.5 Aim and outline of this thesis 30 1.6 Relerences and notes 31

2. ANALYSIS 35

2.1 Abstract 35

2.2 Introduetion 35

2.3 Reaction products 38

2.4 Resul.ts and discussion 39

2.4.1 HPLC-analysis 39

2.4.2 GC-analysis 42

2.5 Conc1usions 44

2.6 Experimental 44 2.6.1 HPLC-analysis 44

2.6.2 GC-analysis 46

2.7 References and notes 47

3. CATALYTIC OXIDATIVE CLEAVAGE OF D-MANNITOL

DERIV ATIVES 49

3.1 Abstract 49

3.2 Introduetion 50

3.3 Reactions 55 3.4 Results and discussion 55 3.4.1 Oxidative cleavage 55 3.4.2 Ruthenium catalyzed oxidative cleavage 59

3.5 Conclusions 74

3.6 Experiment al 75

6 Carbohydrate-based syntheses of Crchirons

3. 7 References and notes 76

4. SYNTHESIS OF C3-CIDRONS STARTING FROM

L-ASCORBIC AND D·ISOASCORBIC ACIDS 81 4.1 Abstract 81 4.2 Introduetion 81 4.3 Reactions 85 4.4 Results and discussion 86 4.4.1 Proteetion of L-ascorbic and D-isoascorbic acids 86 4.4.2 Synthesis of protected glyceraldehydes 89 4.4.3 Synthesis of protected glyceric acids 90 4.5 Conclusions 91 4.6 Experiment al 93 4.7 References and notes 97

5. REDUCTION OF PROTECTED GLYCERALDEHYDE AND

GLYCERIC ACID TO GLYCEROL DERIVATIVES 99 5.1 Abstract 99 5.2 Introduetion 99 5.3 Reactions .101 5.4 Results and discussion 102 5.4.1 Catalytic hydragenation of protected glyceraldehydes 102 5.4.2 Rednetion of protected glyceric acid and their esters 104 5.5 Conclusions 106 5.6 Experimental 107 5.7 References and notes 110

6. SELECTIVE DEGRADATION OF UNPROTECTED

SUGARS TO GLYCERALDEHYDE AND GLYCERIC ACID 111 6.1 Abstract 111 6.2 Introduetion 112 6.3 Reactions 117 6.4 Results and discussion 119 6.4.1 Selective degradation of aldoses with oxygen under alkaline

conditions using AMS and ltz02 in catalytic amounts 119 6.4.2 Selective degradation of aldonic acids with NaOCl 124

Contents 7

6.4.3 Selective degradation of D-fructose 141 6.4.4 Oxidative degradation of 2-ketoaldonic acids 147 6.4.5 Oxidation of ascorbic acids with ~02 153 6.5 Conclusions 154 6.6 Experimental 155 6.7 Refenmces and notes 157

7. GENERAL CONCLUSIONS AND ECONOMIC ASPECTS 161 7.1 References and notes 168

SUMMARY 169

SAMENVATTING 172

CURRICULUM VITAE 175

APPENDIX I: LIST OF ABBREVIATIONS AND SYMBOLS

APPENDIX 11: LIST OF STRUCTURES

APPENDIXill: OVERALL REACTION SCHEME

1. Introduetion 9

1.1 Cbirality

In 1893 Lord Kelvin defmed cbirality as follows: "I call any geometrical

figure or any group of points cbiral, and say it has cbirality, if its image in a plane

mirror, ideally realized, cannot be brought to coincide with itself'. This definition

still holds after almost one hondred years. An asymmetrie object is ebiral when

it is not superimposable upon its mi.rror image and it is acbiral when it is.

Examples of asynnnetry in the two dimensional case are the letters of the alphabet.

The letter T is synnnetric while the letter P is asymmetrie. Two commonplace

examples of asymmetrie objects in the three dimensional case are a clockwise and

counter clockwise threaded screw and a persons left and right hand. They are not

superimposable upon their mirror images and are therefore ebiral The term

cbirality refers to this last example of handedness and originates from the greek

word for hand: 'Xetp' 1• Cbirality and achirality also exist at a molecular level.

Molecules possessing at least one tetrabedral carbon atom with four different

substituents and not possessing one or more intemal mirror planes are not

superimposable upon their mirror images and are chiral. The oldest known

characteristic of molecular cbirality is the presence of optica! activity: rotation of

the plane of po1arized light. An examp1e of a ebiral molecule is the amino acid

serine. The L-enantiomer cannot be superimposed upon its mirror image the D

enantiomer (Fig. 1.1 ).

Louis Pasteur was the fli'St to recognize that optical activity is a result of

molecular asymmeuy-2. In 1848 heresolveda racemate, optically inactive sodium

ammonium tartrate, with a hand lens and a pair of tweezers in two different kinds

of crystals which were mirror images of each other. Later he also separated a

racemate by fractional crystallization with an optically active acid and base (1853)

and by the use of preferential mold growth (1860). In 1860 he proposed the

existence of two isomers, being mirror images of each other and differing in

structure only in the direction of rotation of polarized light. ln·1874 Van 't Hoff

10 Carbohydrate-based syntheses of C3-chirons

D-serine L-serine m

Figure 1.1: Examples of chiral molecules

and Ie Bel fully interpreted these results into chemical constitution by introducing

the tetrabedral carbon theory: optical isomers differ in the sequence of

arrangement of their four different tetrabedral groups on the central carbon

atom2.3•

In nature chirality plays an important role. Most natural organic products,

such as carbohydrates and proteins, occur in one of the two possible mirror image

fonns. If a molecule is both ebiral and biologically active its unique biological

activity and selectivity is generally caused by only one of the two possible

enantiomers. The other enantiomer is at best supertluous ballast but frequently

inhibits the desired biological effect or even shows unwanted effects. A few

examples are given in Table 1.1.

Table 1.1: Examples of enantiomer·pairs with different biological effects

u·······~··············./····.····· .. ·········<············· ~~ên~ti~ i<nt·········· ' )'~~ei•·•·············· Asparagine sweet bitter

Propanolol contraceptive 8-blQC.k:er

Limonene orange odour Iernon odour

Penicillamine extremely toxic antiarthritic

Ethambutol blindness (RR) tuberculostatic (SS)

I. Introduetion 11

The increasing awareness of this distinct difference in biologica! properties

of enantiomers, caused a growing interest in the synthesis of enantiomerically pure compounds especially in the phannaceutical and agrochemical industry4

• For

example, the artificial sweetener aspartame is one of the four stereoisomers of a

elipeptide derivative. Of those four stereoisoroers one is sweet, another bitter while

the remaining two are tasteless'. Another example is the drug thalidomide, better

k:nown as Softenon. lts R-enantiomer is active against morning sick:ness in

pregnant women, but the S-enantiomer caused fetal malformation6.1n the last two decades a tendency to market optically pure compounds rather than racemie

mixtures has developed, due to an increasing environmental pressure to reduce

unwanted side effects of the inactive enantiomer. Also regulatory authorities are increasingly aware of the potendal risks involved with the use of racemates. The

FDA (Food and Drug Administration) as well as the EC registration procedures require information of the biologica! activity of both enantiomers of a racemate

for approval. In the near future it is even believed that they will insist on

marketing all newly developed products as single enantiomers. At the moment

however, most synthetic drugs are still marketed as racemates. Of the 1327 synthetic drugs marketed world wide, 528 are chiral but only 61 are marketed as

the single enantiomer7• As a result of these trends, considerable effort has been

devoted to the development of economically viabie routes to optically pure enantiomers4.8• The different methods, subdivided according to the nature of their

substrates, are listed in Figure 1.2.

- preferential crystallization

- diastereomede crystallization

- kinetic resolution: · chemica! · enzymatic

- chromatography

·•·•p··.· ,nl<n.nin AL·· .. §~'1~ES - catalytic asymmetrie

synthesis:

· biocatalysis · chemocatalysis

- synthesis starting from readily available:

·carbohydrates terpenes ·aminoacids etc.

Figure 1.2: Methods for the preparation of optically pure compounds

12 Carbolrydrate-based syntheses of C,-chirons

Racemates. Racemate resolution is the oldest and still most important

metbod for the industrial production of pure enantiomers4• There are two major

types of racernatel: conglomerates, and racemie compounds, each of them

showinga characteristic melting point diagram (Fig. 1.3).

T T T T

D L D L

(a) Conglomerate (b) Racemie compound

Figure 1.3: Melting point diagrams of racemates

Conglomerates consist of a mechanica! mixture of the crystals of both

enantiomers and the melting point curve shows a minimum at the racemie

composition. This is the reason why a conglomerate can be resolved by

preferential crystallization. Seeding of a supersaturated solution with crystals of

one of the enantiomers causes crystallization of this enantiomer, due to the higher

solubility of the lower melting racemie mixture. The racemie mixture resolved by

Pasteur is a conglomerate but unfortunately more than 80 % of the racemates are

not. On industrial scale resolution by preferential crystallization is very attractive

and is e.g. used for the manufacture of a-methyl-L-dopa10•

Racemie compounds consist of a homogeneons solid phase, in which the

two enantiomers occur in the same unit cell. Therefore, in those cases the racemie

1. lntrod11ction 13

mixture cannot be resolved by preferendal crystallization, and then diastereomeric

crystallization is a widely applied technique. The racemie mixture is allowed to

react with an optically pure compound (resolving agent), often an acid or a base,

to form a diastereomeric mixture which can in principle be separated by

crystallization into both diastereomers. An example of this technique is the

Andeno process for the manufacture of D-phenylglycine in which optically pure

camphorsulphonic acid is used as the resolving agent11• The disadvantages of this

technique are the need for a stoichiometrie amount of the resolving agent and the

two extra steps in the synthetic routes. However, if the resolving agent can be

recycled, diastereomede crystallization bas a broad scope and gives access to both

enantiomers of a racemate.

A third metbod for the separation of enantiomers in a racemie mixture is

kinetic resolution. Via this technique one of the enantiomers reacts at a higher

reaction rate or reacts exclusively with an optically pure addend. This addend can

be an enzyme or another optically active compound which may be used in

stoichiometrie amounts but, from an economical point of view, preferably in

catalytic amounts. An example of a biocatalytic route is the enzymatic resolution

of amino acids based on the stereoselective hydrolysis of amino acid amides by

specific aminopeptidases 12•

During the last two decades chromatographic methods, initially only used

for analytica! purposes, have been developed for the resolution of racemates as

well. Nowadays also preparalive HPLC is available13• The chromatographic

techniques arebasedon separation of diastereomede mixtures (indirect method)

or on separation of the enantiomers using a ebiral column or an optically pure

eluent (direct method). An example of this last technique is the resolution of a

wide variety of racemates by HPLC on a multi-gram scale using an optically pure

phenylglycine dedved stationary phase14• At the moment, however,

chromatographic resolutions are only applicable on a limited scale.

The methods described above all have one disadvantage in common: when

only one enantiomer is needed, the maximum yield amounts to 50 %. This is not

really a problem when racemization of the undesired enantiomer is easy, thus

allowingin theory a 100% yield in a two-step process.


Proebiral substrates. Probably the most challenging metbod for preparing

optically pure compounds is asymmetrie synthesis and in particular catalytic

asymmetrie synthesis. With this technique a proebiral compound is converted into

an optically active one, using bio- or chemocatalysis. An example of this metbod

is the Monsanto process for the manufacture of L-dopa by catalytic asymmetrie

hydrogenation1'. Theoretically a 100% yield can be achieved with this metbod

compared to 50% for racemate resolutions. In practice, however, asymmetrie

syntheses tend to be more complicated processes and have significantly lower

volume yields than kinetic resolutions.

Chirality pool. The use of optically pure starting materials is very

attractive when they are available on an industrial scale. Optically active

compounds can thus be synthesized by conventional organic synthesis. The

primary souree of ebiral building blocks ( chirons) is nature. It produces

enantiomerically pure amino acids, carbohydrates, alkaloids, terpenes etc. A

number of review articles has been publisbed in this field, covering different kinds

of building blocks16• When racemization can be avoided, their use reduces the

risk of obtaining enantiomerically impure products. The major disadvantage is that

the number of readily accessible compounds is limited.

In summary, a number of methods is available for the synthesis of optically

pure compounds. In genera!, the metbod to be chosen is dependent on the distinct

advantages and disadvantages in each particular case. The enzymatic methods for

example, are highly stereoselective and can possibly shorten the total number of

steps in a reaction sequence. Major drawbacks are the operational instability of

enzymes, limited use in non aqueous media, low product concentrations, limited

availability of enzymes on a larger scale and cofactor dependent conversions

without easy cofactor regeneration8• On the other hand only a small part of the

existing enzymes is known at the moment17, leaving many opportunities for

future research and applications. Racemate resolution can be very efficient when

resolving agent and undesired enantiomer can easily be recycled, but this also can

result in the build-up of impurities, thus greatly affecting the crystallization

properties. Other important factors that have to be considered wheri choosing the

best metbod to synthesize optically pure products are: cost price of the resolving

agent, cost price of the ebiral synthon, chemica! and optica! yield, volume yield,

cost of manufacture, bulk availability, need for one or both enantiomers, simplicity

1. Introduetion 15

of synthesis, in situ racemization, timing of resolution step, new or old product,

investments etc. Due to the growing consciousness of the different biological

effects shown by enantiomers still much effort is devoted to the impravement and

expansion of the existing methods.

1.2 Carbohydrates

The most abundant class of optically pure compounds produced in living

matter is carbohydrates. They are mainly formed during the photochemical carbon

dioxide fixation in green plants, in which they generally appear as D-enantiomers.

They constitute three quarters of the dry material weight of plant world and are

widely distributed in other life forms. They serve as ~nergy stores of cells, as

structural elements and as human and animal food which gives them an important

role in metabolism. They are often called sugars, reflecting their relationship to

'sugar', the familiar sweetener sucrose. The term carbohydrate originates from the

belief that they are hydrates of carbon since elemental analysis of most common

carbohydrates leads to the empirical formula Cx(llzO)y. Many carbohydrates,

however, have compositions not fitting with this simplified generalization. The

scheme in Appendix m shows some examples of carbohydrates in relationship to

one another. More examples of sugar derivatives are given in the list of structures

(Appendix JI).

All mono- and some oligosaccharides are called sugars, of which the

monosaccharides are the simplest. They are polyhydroxy aldehydes or ketones or

can be hydrolyzed to them. Monosaccharides usually contain five or six carbon

atoms. Although glycolaldehyde (33) is structurally the smallest carbohydrate,

D(R)-glyceraldehyde (28), having one ebiral carbon atom, is considered as the

simplest biologically important aldose. Dihydroxy-acetone is the simplest ketose.

According to Fischer's convention a D-carbohydrate bas the hydroxyl group

attached to the highest numbered chiral carbon atom, orientated to the right. These

Rosanoff-descriptors (D,L)18 are still widely used in carbohydrate chemistry

instead of the more universa! Cahn-Ingold-Prelog-descriptors (R,S)19• The

nomendature in carbohydrate chemistry is quite confusing as a result of the by

IUP AC and IUB20 approved application of a mixture of trivial and systematic

names. Structures of the most common aldoses may be derived from the structure

Hr HO HO

OH OH

D-lyxose

H 0 H

HO HO HO HO HO

OH OH

H{O HO OH OH

D-threose

0 H OH HO

HO OH OH

HtO OH OH

D-glyceraldehyde

H{O OH HO

OH OH

H

10

HO OH OH OH

H

10

OH OH OH

D-erythrose H

10

OH OH OH OH

D-xylose D-arabinose D-ribose

0 H 0 H 0 H 0 H 0 H OH HO OH HO

OH OH HO HO OH HO OH OH OH

OH OH OH OH OH OH OH OH OH OH

0

OH OH OH OH OH

D-talose D-galactose D-idose D-gulose D-mannose D-glucose D-altrose o-allose

Figure L4: FiscMr-projection formulas of D-aldoses containing up to si:x carbon atoms

1. Introduetion 17

of D(R)-glyeeraldehyde (28), the stereochemical point of departure, simply by

ad.ding carbon atoms (Fig. 1.4).

In solution monosaccharides form five- or six-membered cyclic

hemiacetals, when allowed by their carbon skeleton. The relative stahilities of

these herniaeetals depend on the ring size but in genera!, six-membered rings

(pyranoses) are favoured. The formation of cyclic herniaeetals in solutions is a

dynamic process depending on pH, temperature, solvent and on the substituents

attached to the sugar moiety. This phenomenon greatly complicates the chemistry

of sugars and explains why one sugar often yields several reaction products.

Further common reaelions of carbohydrates are isomerisation, proteetion of the

hydroxyl functions, nucleophilic reactions on the carbonyl group, degradation to

shorter-ehaio monosaccharides, chain elongation, oxidation of the carbonyl group

and hydroxyl functions, reduction of the carbonyl group and glycoside formation.

In short, carbohydrates are unmatched in cbirality and functionality which makes

them ideally suitable for chemica! manipulations.

Sugars (Fig. 1.5) are industrially utilized to a considerable extenfla.b.

Sucrose, the familiar sweetener 'sugar', is the most important industrial sugar

foliowed by glucose, produced by hydralysis of starch. Sorbitol is manufactured

by catalytic hydragenation of glucose or as a mixture with rnannitol by catalytic

hydragenation of invert sugar (mixture of fructose and glucose obtained by

hydrolysis of sucrose or by isomerlzation of glucose with the enzyme isomerase ).

In this respect the combi-process developed by Mak:kee et al., is also of

interestztc.d. The main applications of these sugars are in food as a sweetener and

in pharmaceuticals. Oxidation of glucose by microbial processes, electrolytically

or via catalytic air oxidation, yields gluconic acid, that is mainly used as a

sequestering agent for calcium, iron and other metals. Also L-ascorbic acid, being

a vitamin and antioxidant simultaneously, is reckoned among the carbohydrates

and is manufactured from sorbitol. Finally fermentation of monosaccharides gives

rise to important chemicals, in particular ethanol.

Most of the naturally occurring sugars are inexpensive, compared to other

ebiral materials. The cheapest sugars are even in the priee range of the standard

organic solvents (Table 1.2).

In conclusion, carbohydrates are a relatively cheap replenishable souree of

ebiral carbon compounds, available in bulk quantities and in a variety of cyclic

18 Carbohydrate-based syntheses of C;rehirons

© ö {~ H H OH H OH 0 H OH HO

HO 0~ HO OH H OH OH H OH OH

OH H OH

sucrose D-glucose D-sorbitol

OrB {~H :~1 ~ OH

HO HO HO 0 OH OH OH 0 OH OH OH OH OH OH HO OH

D-gluconic acid D-fructose D-mannitol L-ascorbic acid

Figure 1.5: lndustrially important carbohydrates

Table 1.2: Marlcet-prlce of some carbohydrates in comparlson to other chemicals-

sucrose à 0.47 glueonic acid 1.04

aaetbaool 0.56 fmctoSeà 1.56

glucose 0.68 manoitot' 3.12

lactose a 0.75 pyridine 6.80

somitot' 0.75 isoascomic acid" 10.49

acetone 0.80 ascolbic acid 13.25

cldoroi'Oim 0.86

"Lowest price, Marcb 199112• 'World-market prices on bulk deHvery.

1. I ntroduction 19

and acyclic fonns, chain lengtbs and oxidation states. They possess a number of

functionalized carbon atoms with various stereochemical and conformational

features and are biodegradable. This explains the increasing interest in sugars as

ebiral starting materials for the synthesis of enantiomerically pure carbohydrate

and non-carbohydrate derivatives and as ebiral synthons for applications in the pharmaceutical and agrochemie al industry. A number of review articles has been

publisbed in which carbohydrates are used as ebiral templates16•23 and in which

their utility for application in ebiral synthesis is demonstrated. Especially, natorally occurring D-glucose appears to be useful as a souree of optica! activity1

6a.b.r.

Surprisingly, sugars generally are not utilized on a large scale as a raw material

for the chemica! industry and for the synthesis of enantiomerically pure

compounds. Convenient application implies inexpensive reagents and simple conversion into key intennediates. The majority of the routes described, however, is not of practical value due to the large number of steps with insufficient yields,

the use of expensive reagents and complex separations techniques and the

difficulties in developing reliable sealing-up procedures. Therefore, the number of industrially viabie routes is very limited1

6f. Another reason for the absence of more

practical routes is obviously the overfunctionalization of sugars with hydroxyl

groups of similar or identical reactivity and the large number of chiral centres, more than required for non-sugar target molecules. Nevertheless, sugars are the

cheapest and most abundant souree of renewable materials and therefore, it seems attractive to develop new, economically feasible reaction routes based on a number of practical criteria. Such criteria comprise selection of simple and inexpensive reagents, easy work-up procedures, simple protecting groups, reasonably high

overall yields and good sealing-up prospects. In this context it would be very

attractive to transform a sugar, into an enantiomerically pure building block, containing one or two ebiral eentres and suitable functional groups. One approach involving the shortening of the carbon chain, or more simply, its bisection, is examplified by the synthesis of 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a)

from 1,2:5,6-di-0-isopropylidene-D-mannitol (1)24 (Fig. 1.6). It may be argued

that despite the fact that nature generously providesus with six-carbon compounds

containing usually foor asymmetrie carbon atoms, they are not utilized very efficiently. However, due totheir large number of applications, the importance of.

small enantiomerically pure building blocks is very great, so this inefficient raw

material use may be overlooked, certainly from an economical point of view. In short, catalytic transformation of carbohydrates, employing cheap stoichiometrie

20 Carbohydrate-based syntheses of CJ·chirons

reagents such as 0 2, }\02, }\, is a potentially useful metbod for synthesizing

small ebiral synthons.

Pb(OAc) 4 ...

or Nai04

1,2:5,6-di-o-isopropylidene

D-mannitol (2a)

2

2,3-0-isopropylidene-D·

glyceraldehyde (4a)

Figure 1.6: Biseetion of 1 ,2:5,6-di-0-isopropylidene-D-mannitol (:Za) irrto 2.3-0-isopropylideneD(R)-glyceraldehyde (4af'

1.3 Cl'"Chirons

Recently there has been a growing interest in the synthesis of sma1l chira1 fragments which can be incorporated into opti.cally pure compounds of biological and synthetic importance•&:.e. Three carbon structural units showing chirality at the

central carbon atom are very important ebiral synthons ( chirons ). Examples of

these C3-chirons are protected glycerol derivatives and the conesponding

glyceraldehyde and glyceric acid derivatives (Fig. 1.7). They are widely used and

versatile building blocks susceptible to a variety of transfonnations:u. The most

widely used protective group in this field is the acetonide, in addition to the less

frequently encountered acetate, benzoyl, benzoate, cyclohexylidene, benzylidene

and carbonate functions. Other important small ebiral building blocks1&: are

epichlorohydrin4A.'Sc·26,. R-glycidylesters27

, L-2,3-diaminopropionic acid1Sc,

protected aldotetroses28, malie acid29

, threitols30, L(S)-erythrulose31

, D- and

L-tartaric acid and dimethyl tartrate32, and L-lactic acid1&:. Some of these small

synthons can be derived starting from glycerol, glyceraldehyde or glyceric acid

derivatives.

1. Introduetion

2,3-0-isopropylidene-D(R)-glyceric

acid (3a)

2,3-0-isopropylidene-L(S)-glyceric

acid (13a)

2,3-0-isopropylidene-D(R)-glycer

aldehyde (4a)

J:~xCHJ Ào CH3

H 0

2,3-0-isopropylidene-L(S)-glycer

aldehyde (lla)

Fipre 1.7: Examples of versatile c,-chirons

21

1,2-0-isopropylidene-L(S)-gly

cerol (Sa)

1,2-0-isopropylidene-D(R)-gly

cerol (14a)

The most widely recognized c3~synthons, appearing in an increasing

number of publications, are the 2,3~0~isopropylidene-D(R)-glyceraldehyde (4a)

and its reduction product, 1,2-0~isopropylidene-L(S)-glycerol (5a)33• In 1986 an

extensive review was published33b covering the numerous applications of protected

glyceraldehyde and glycerol derivatives. The most important ones are summarized

in Table 1.3. A potentially important application, for example, is the synthesis of

8-blockers.....,3•34 (S-aryloxypropanolamines, Fig. 1.8), used for the treatment of

angina and hypertension.

Due to their tendency to polymerize and racemize, the 2,3-0-

isopropylidene-D(R)- and L(S)~glyceraldehydes (4a, lla) should either be used

irnmediately after preparation or should be converted into the more stabie alcohols,

22 Carbohydrate-based syntheses of CJ-chirons

1,2-0-isopropylidene-L(S)- and D(R)-glycerols (Sa, 14a). If necessary they can be

stored in the freezer dissolved in toluene or benzene33b·", but distillation prior to

use is recommended.

Table 1.3: Applications of protected glyceraldehyde and glycerol derivativel'.»

- Otber ebiral C,-syntltons - 8-Adrenergi.c blocking agents (8-blockers) - Platelet activating factor (PAF) - y..amino-8-hydroxybutyric acid (GABOB) - Glycerides, phospbolipids - Dipbosphinel (cbiralligands) - Natural products e.g. ( + )-brefeldin A, Leukottiene LT~, prostaglandines (PGBt), insect

pberomones

The corresponding 2,3-0-isopropylideneglyceric acids (3a, 13a) are less

commonly used bqt they also are versatile optically active building blocks36•

They may for example be used for the synthesis of (24R)-24,25-dihydroxyvitamine 0 3

37, (S)-(L)-tulipalin B38 and ether phospholipids", or eventually as a

resolving agent. Moreover, rednetion with LAH, although industrially less attractive, gives the corresponding glycerol derivatives40

•

The above mentioned optically pure C3-chirons can be prepared by kinetic

resolution of the racemate, by asymmetrie synthesis and by the use of ebiral building blocks.

The îtrSt preparation of racemie 1,2-0-isopropylideneglycerol was reported by Fischer in 189541

• Recendy, some enzymatic methods were developed for the

resolution of this racemate using selective oxidation42 or selective hydrolysis43•

Via this technique both enantiomers of protected glycerol (5, 14) and the D(R)

enantiomer of 2,3-0-isopropylideneglyceric acid (3a) a:te available. Also asymmetrie synthesis is reported to be a successful metbod for the

synthesis of protected glycerol (5, 11). Starting from allyl alcohol (34) by

asymmetrie epoxidation44 and starting from glycerol (35) by acylation with an

optically active acid chloride4' 4a and lla have been prepared.

However, the majority of the reported rnethods make use of carbohydrates as optically pure building blocks. The fust effective preparation of 2,3-0-

1. Introduetion

ArO~~NHR H/'-~OH

General structure S-P-blocker

S-Penbutolol

Flgure 1.8: General structure of p.blockers and some examples

23

S-Propanolol

S-Timolol

isopropylidene-D(R)-glyceraldehyde (4a) was reported by Baer and Fischer in

193~. D-Mannitol (1), anaturally occurring inexpensive polyhydroxy compound,

was used as starting material. Proteetion of its 1,2- and 5,6-hydroxyl functions,

affording diol (2a) and subsequent oxidative cleavage by lead tetraacelate gave

two molecules of the 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a) (Fig. 1.9).

In later years several modiftcations of this classica! and still most frequendy

applied route were introduced e.g. other protecting methods46 and other diol

cleaving agents, such as sodium periodate47, bismuth derivatives48

, meta

iodoxybenzoate49.

Other suitable starting matenals for the synthesis of optically pure 2,3-0-

isopropylidene-D(R)-glyceraldehyde (4a) are D-arabinose (22)so, D-glucono-è>

lactone (36i11, dimethyl L-tartrate (37)3

2a and D-isoascorbic acid (16). The last

one is transfonned into glyceraldehyde 4a by perioclate cleavage of intermediate

24

HO

HO HO acetone ..

OH OH

OH

D-mannitol

(1)


HO Pb (0Ac) 4

1,2:5,6-di-0-isopro

pylidene-D-mannitol

(2&)

..

2,3-0-isopropyli

dene-D(R)-glycer

aldehyde (Ca)

Fipre 1.9: Synthesis of2,3-0-isopropylidene-D(R)-glyceraldehyde (44) startingfrom D-mannitol (I )U

1,2-0-isopropylidene-D-erythritol (38)30c or by electrochemical oxidation of

intennediate 3,4-0-isopropylidene-D-erythronic acid (18a)52•

In contrast to 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a) its Senantiomer (lla) became readily available when L-ascorbic acid {6) was recognized as a starting materia1:~3 • In 1984 Mizuno patented an inexpensive route, covering conversion of 5,6-0-isopropylidene-L-ascorbic acid (7a) into 2.3-0-isopropylidene-L(S)-glyceraldehyde (lla) by hydrogen peroxide oxidation and

subsequent sodium hypochlorite oxidation of the intermediate 3,4-0-

isopropylidene-L-threonic acid (9a)"' (Fig. 1.10). Other, more expensive routes,

involving sodium periodate or lead tetraacelate as cleaving agent, are based on Lmannitol (39)':~, L-ascorbic acid (6~.s2.56, L-arabinose (40f7, 2R,3R-dimethyl

tartrate (4li8, L-erythrulose {42i1

, L-galactono-ö-lactone (43)$9 or sorbitol (44)60.

The protected glycerol derivatives Sa and lla have been prepared starting from the corresponding aldehydes (4a, lla) and acids (3a, 13a) as optically pure

building blocks (Fig. 1.11 ). Previously L(S)- and D(R)-isopropylidene glycerols {Sa, lla) have been obtained from the corresponding aldehydes (4a, lla) by

catalytic rednetion using Raney-Ni as catalysf4·c51, and more recently by sodium

1. Introduetion

5,6-0-isopropy

lidene-L-ascorbic

acid (7a)

0 CH3

HO {

OXCH3

HO 0

3,4-0-isopropy

lidene-L-threonic

acid (9a)

25

2,3-0-isopropyli

dene-L(S)-glycer

aldehyde (lla)

Figure 1.10: Synthesis of 2,3-0-isopropylidene-L(S)-glycera/dehyde (lla) storting from 5,6-0-isopropylidene-L-ascorbic acid (7a)'4

bomhydride reduction53•62

• LAH rednetion of the corresponding acids (3a, l3a)40

gives the protected glycerols Sa and lla as well. Finally, the R-enantiomer (lla) has been obtained from the S-enantiomer (4a) by a six-step procedure in 7%

overall yield63•

The preparadon of optically pure 2,3-0-isopropylideneglyceric acids (3a, l3a) is less known. They can be synthesized by oxidation of the corresponding ebiral glycerol derivatives (Sa, lla) using potassium permanganate64 and by oxidation with Br2 36a or potassium permanganate65 of the corresponding

glyceraldehyde derivatives (4a, lla) as optically pure starting materials (Fig. 1.11 ).

Both enantiomers of the glyceric acid derivatives (3a, l3a) are accessible by

oxidative cleavage starting from D- or L-serine ( 45)40 and from protected Dmannitol (2a) and L-ascorbic acid (7a), respectively, at a nickel hydroxide

electrode66• Finally, the R-enantiomer can be obtained enzymatically starting from

dimethyl L-tartrate (37)67•

The most frequently applied methods in the synthesis of abovementioned C3-chirons start from D-mannitol (lt74 and L-ascorbic acid (7i3

, respectively, but

are industrially not attractive since expensive oxidizing agents such as sodium

periodate and lead tetraacelate are used. Most other methods are economically not attractive either. Exceptions are the synthesis of 2,3-0-isopropylidene-L(S)

glyceraldehyde (lla) starting from L-ascorbic acid (6), using hydrogen peroxide

26

Ra-Ni7. H224,61 or

NaBH4!13,62

2,3-0-isopropylidene-D/L-glyceric

acid (3a,13a)


u3cxo:J H3C OA.

H o ~ol' or

2,3-0-isopropyli- ~ Br2 dene-D/L-glycer-

aldehyde (4a,lla)

LAH40

1,2-0-isopropyli

dene-D/L-glycerol (!5a,14a)

Fipre 1.11: Conversion of C,-synthons into one another

and sodium hypochlorite as the oxidizing agents"* (Fig. 1.10), and the synthesis

of 1,2-0-isopropylidene-L(S)-glycerol (14a) and 2.3-0-isopropylidene-D(R)

glyceric acid (3a) starting from racemie 1,2-0-isopropylideneglycerol by

enantioselective enzymatic oxidation42 (see above). Presumably, the synlt,esis of

D(R)- and L(S)-glyceric acid derivatives (3a, 13a) starting from D-mannitol (1)

and L-ascorbic acid (6)66, respectively, and the synthesis of the D(R)- and L(S)-.

glyceraldehyde derivatives (4, 11) starring from L-ascorbic (6) and D-isoascorbic

(16) acids52, using electrochemical oxidation, are industrially acceptable as well.

Chemieals suppliers offer 1 ,2-0-isopropylidene-D(R)- and L(S)-glycerol

(Sa, 13a) at a relatively high price (Table 1.4), which makes these building blocks

at the moment too expensive for use on a large scale in contrast to·the racemate, which is cheap. Only 1,2-0-isopropylidene-D(R)-glycerol (13a) and 2,3-0-

isopropylidene-D(R)-glyceric acid (3a), which are produced simultaneously by

enantioselective enzymatic oxidation42, are available at an acceptable price. The

protected aldehydes (4,11) are not commercially available due totheir instability.

1. Introduetion 27

Table 1.4: Catalogue prices of commercial/y available C3-chirons".

Janssen 59 114 0.079 Chimica

Aldricb 37 113 0.086

Merck: 19 50 28

Huka 15 50 0.104

Sigma 6 22

miS' 0.4 0.33

"Lowest oost price mentioned in catalogs (8/g). "100: 1,2-0-isopropylideneglycerol. "'GA: 2.3-0-isopropylideneglyceric acid. "Fonner joint-venture of Gist-Brocades and SbeU.

Summarizing we can conclude that a plethora of methods is available,

especially for the synthesis of protected glyceraldehyde (4a, lla) and glycerol

(Sa,13a) derivatives. In most cases, however, expensive reagents and/or substrates

are used and only a limited number of routes are economically attractive. At the

moment the cost prices of most of the C3-chirons are too high for application on

an industrial scale. Exceptions are 1,2-0-isopropylidene-D(R)-glycerol (13a) and

2,3-0-isopropylidene-D(R)-glyceric acid (3a), obtained by stereoselective

enzymatic oxidation of racemie 1,2-0-isopropylideneglycerol42•

1.4 Catalysis

As compared with their non-catalytic counterparts catalytic reacrions

generally benefit from milder reaction conditions, higher selectivity and lower

energy costs and are, therefore, more efficient processes. The interest in catalytic

processes, chemocatalytic as well as biocatalytic, bas grown due to an increasing

environmental consciousness in recent years. Especially, the fine chemical industry

is under increasing pressure to develop cleaner processes, although the absolute

volumes are significantly less than in bulk chemical industry. The main reason for

this tendency is the large volume of by-products per kilogram of product in fine

chemical industry compared to bulk chemical industry68• The environmentally

unacceptable processes have already been replaced in the latter by cleaner ones.


Both chemo- and biocatalytic processes possess the capacities to replace

a large number of stoichiometrie oxidations, reductions, etc. In every

transformation occurring in vivo, enzymes are catalytically involved sbowing their

ability in catalyzing a broad spectrum of reactions. Sofar, the number of successful

applications in industry is limited, despite the well-known advantages of enzymes.

Bottlenecks are the commercial availability of biocatalysts, the operational stability

and the need for efficient coenzyme regeneration procedures in coenzyme

dependent bioconversions8• In addition, only a small fraction of enzymes present

in nature is identified17• However, a number of interesting applications using

biocatalysis is known. The oxidation of D-glucose to D-gluconic acid using

bromine water bas been replaced by a fennentation process69• Another example

is the selective oxidation of tbe S-enantiomer of 1 ,2-0-isopropylideneglycerol (Sa)

into 2,3-0-isopropylidene-D-(R)-glyceric acid (3a), teaving the R-enantiomer (14)

untouched"2• In conclusion, biocatalysis can be an excellent tool for conversion of

carbobydrates into enantiomerically pure building blocks providing the right

enzyme for the desired transfonnation is available.

Almost the same reasoning may be used for cberriocatalytic reactions when

achiral catalysts are applied. They are also generally more selective, produce less

side-products and proceed under mild reaction conditions in comparison to their

stoichiometrie counterparts. Catalytic oxidations are extremely important for

industrial conversions. They replace stoichiometrie reagents sucb as e.g. chromic

acid, potassium pennanganate, lead tetraacetate and sodium periodate, whicb have

a broad scope in oxidation cbemistry but are very expensive and produce an

enonnous amount of inorganic, often toxic, byproducts. The simplest and cleanest

oxidizing agent of all is molecular oxygen. It is used in bulk cbemical industry for

catalytic oxidations. However, in fme cbemical industry, wbere substrates are

generally more complex, multi-functional and thennally instable, as is certainly the

case for carbobydrates, its applications are limited. Here bydrogen peroxide and

organic peroxides, sodium bypochlorite or potassium persnipbate are acceptable

as. oxidizing agents. When used without catalysts, no reaction or a non-selective

reaction occurs. Hence, the use of catalysts like metals, beteropolyanions, zeolites

and pillared clays is necessary. These oxidation reactions are more expensive than tbe catalytic oxidations witb oxygen, but also have a broader scope and by

products sucb as water, sodium chloride and potassium sulphate are obviously

preferred over chromium, iodine, manganese and lead salts, produced in

stoichiometrie oxidations. Organic peroxides produce byproducts like

1. Introduetion 29

tert.butylalcohol (from tBHP) which can easily be recycled. They have the

advantage over the inorganic oxidizing agents that they are soluble in organic

media. Phase-transfer catalysis (PTC) can give ( catalytic) reactions a higher

synthetic utility because it allows performance in both organic and aqueous media.

For reactions with sugars PTC can also play an important role especially in

reactions with carbohydrates where protective groups are used in order to obtain

a high selectivity. Unprotected sugars are generally only soluble in water, whereas

protected sugars may show sufficient solubility in organic solvents. Depending on

the nature of the oxidizing agent, PTC can be necessary to obtain a reasonable

reaetion rate. Catalytic rednetion is a well known technique in carbohydrate

chemistry, e.g. the industrially applied catalytic reduction of D-glucose to sorbitol

using a Raney-Ni catalysr1• It is an attractive alternative for the expensive and

difficult to handle classica! stoichiometrie reagent, lithium aluminium hydride, or

the relatively expensive sodium borohydride. However, reaction conditions are

often extreme(> 200 °C, > 100 atm.). Other metal catalysts arealso known for

the catalytic rednetion of aldehydes and ketones e.g. Cu/silica, Pd/C, Ru/C.

Catalysis can be performed in a homogenons or heterogenons manner, both

possessing their own specifi.c advantages. The main advantage of a heterogenons

catalyst is the easy separation from the reaction mixture and reuse of the catalyst.

Homogenons catalysts are in general more reactive because substrate and catalyst

can more easily approach each other. In industrial applications immobilization of

homogeneons catalysts on a suitable carrier in order to obtain an easy product

purification is frequently applied. However, immobilization is generally

accompanied by some loss of reaetivity.

In conclusion, catalytic conversion of carbohydrates is potentially an

extremely good tooi to develop highly efficient, environmentally acceptable and

industrially attractive routes to optically active compounds. Reaction conditions are

mild, high selectivities and high overall yields, at least in principle, can be

obtained, relatively little inorganic by-products are formed and possibly a fewer

number of steps is needed. Other cost-affecting aspects that have to be considered

are energy efficiency, equipment needed, environmental acceptabillty, and volume

yield.


1.5 Aim and outline of tbis thesis

. Small enantiomerically pure building blocks can be incorporated into

optically pure natura! products and compounds of biologica! and synthetic interest.

1bey are increasingly important in phannaceutical and agrochemical industry from

an environmental point of view.

Carbohydrates are an extremely cheap, naturally occurring replenishable

souree of ebiral carbon atoms, nnmatched in chirality and functionality. 1bey

obviously are interesting starting materials for the synthesis of chiral building

blocks. This thesis concerns the exploration of carbohydrates as feedstock: for the

synthesis of C3-chirons using indnstrially and environmentally viabie synthetic

methods.

1be methods used for analysis of reaction mixtures and for detennination

of the optica! purity of the reaction products are described in Chapter 2.

Chapter 3 deals with D-mannitol (1), as a symmetrical C6-sugar derivative,

being the ideal starting material for the synthesis of C3-chirons. 1be main subject

is the ruthenium catalyzed oxidative cleavage of protected D-mannitol (2) to

protected glyceric acid derivatives (3) with the aid of sodium hypochlorite as the

stoichiometrie oxidizing agent. On the basis of the reaction kinetics, UV

measurements and available literature data, a reaction mechanism is proposed.

1be use of L-ascorbic (6) and D-isoascorbic (16) acid as starting materials

for the synthesis of protected glyceraldehyde (4, 11) and glyceric acid (3, 13)

derivatives is described in Chapter 4. 1be proteetion of the C-5 and C-6 hydroxyl

functions is studied and compared with existing methods. Other topics are the non

catalytic and the ruthenium-catalyzed oxidative cleavage of protected erythronic

(18) and threonic (9) acid derivatives.affording proteered glyceraldehyde (4, 11)

and glyceric acid (3, 13) derivatives, again nsing sodium hypochlorite as oxidizing

agent.

Chapter 5 deals with the catalytic rednetion of protected glyceraldehyde

derivatives (4, 11) and with rednetion of glyceric acid derivatives (3, 13) to the

cortesponding glycerol derivatives (5, 14).

In Chapter 6 unprotected sngars are considered as possible starting

materials for the synthesis of D(R)-glyceraldehyde (28) and D(R}-glyceric acid

(29). Attention is paid to the AMS- and H:z02-catalyzed alkaline oxidative

degradation of c .. -aldoses to c ... ,-aldonic acids with oxygen and to the degradation

of c .. -aldonic acids to C.,.caldoses nsing sodium hypochlorite as oxidizing agent.

I. Introduetion 31

Also D-fructose (15) is studied as starting material using the alkaline AMS-H:z02-

oxygen system and sodium hypochlorite as oxidizing agents.

Finally, in Chapter 7 the different reaction pathways studied are reviewed

and compared by way of a cost price analysis based on the use of multi-purpose

reactors.

1.6 Relerences and notes

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1987.

I. Introduetion 33

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(44) Kaog, S. K.; Shin, D. S. BuU. Korean Chem. Soc. 1986, 7, 159. (45) Mukaiyama. T.; Taoabe, Y.; Sbim.im, M. Chem. Lett. 1984, 401. (46) (a) Kierstead, R. W.; Raraone, A.; Mennona, A, Mullin, 1.; Gutbrie, R. W.; Crowley, H.;

Sinko, 8.; 8laber, L. C. J. Med. Chem. 1963, 26, 1561. (b) Chittendeo, G. 1. F. Carbohydr. Ru. 1980, 84, 350. (c) Debost, J.; Gelas, J.; Horton, D. J. Org. Chem. 1983, 48, 1381.

(47) (a) Le Cocq, J.; 8allou, C. E. Biochem. 1968, 33, 128. (b) Golding, 8. T.; loannou, P. V. Synthesis 1!117, 423. (c) Bibl, H. Chem. Phys. Lipids 1981, 28, 1. (d) Jack:son, D. Y. Synth. Commun. 1988, 18, 337. (e) Daumas, M. Synthesis 1989, 64.

(48) (a) 8arton, D. H. R.; Kitcbin, J. P.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1978, 1099. (b) 8arton, D. H. R.; Lester, D. J.; Motherwell, W. 8.; 8arrospapoola, M. T. J. Chem. Soc., Chem. Commun. 1979, 705. (c) Barton, D. H. R. Tetrahetiron Suppl. 1981, 73. (d) 8arton, D. H. R.; Motherwell, W. B.; Stobie, A J. Chem. Soc., Chem. Commun. 1981, 1232.

(49) Barton, D. H. R.; Godfrey, C. R. A.; Morzycki, J. W.; Motherwell, W. B.; Stobie, A Tetrahedron Lett. 1982,23,957.

(50) Ba.lrer, S. B. J. Am. Chem. Soc. 1952, 74, 827. (51) Oü.ttenden, (3.1. F. Reel. Trav. Chim. Pays-Bas 1988, 107, 455. (52) Voeffray, R. EP 3259671989. (53) Jung. M B.; Shaw, T. 1. J. Am. Chem. Soc. 1980, 102, 6304. (54) Mizuno, Y.; Sugimoto, K. EP 143973 1984. (55) (a) 8aer, E.; Fischer, H. 0. L. J. Am. Chem. Soc. 1939, 61, 761. (b) Baer, E.; Flebmig,

H.-H. Can. J. Biochem. 1969, 47, 79. (56) (a)Takano,S.;Numata,H.; Ogasawara.K. Heterocyclu1982,19, 327. (b)Hubschwerlen,

C. Synth. 198fi, 962. (c) Marco, J. L. Tetrahedron Lett. 1988, 29, 1997. (57) Maloneybuss, K. B. Synth. Commun.1985, 15,273. (58) (a) Taoaka, A.; Otsuta, S.; Yamasbita, K. Agric. Biol. Chem. 1984, 48, 2135. (b) Al-

Baldm, AH.; Haines, AH.; Modey, C. Synthesis 1985,207. (59) Morgenlie, S. Carbohydr. Res. 1982,107, 137. (60) Pressman, 8. C.; Anderson, L.; Lardy, H. A. J. Am. Chem. Soc. 1950, 72, 2404. (61) Fischer, H. 0. L.; 8aer, B. Chem. Rev. 1941, 29, 287. (62) Baldwin, J. J.; Raab, A W.; Meosler, K.; Ari.soo, B. H.; McOure, D. B. J. Org. Chem.

1978,43,478. (63) Fischer, H. 0. L.; 8aer, B. J. Am. Chem. Soc. 1945, 67, 944. (64) (a) Reicbstein, T.; Pedotin, A.; Grüssner, A. Helv. Chim. Acta 1935,18, 598. (b) Tanaka,

A.; Yamasbita. K. Agric. Biol. Chem. 1980, 44, 199. (c) Dumont, R.; Pfandler, H. Helv. Chim. Acta 1983, 66, 814.

(65) (a) Iwadare, K. Bull. Chem. Soc. Jpn. 1939, 14, 131. (b) Tanaka, A.; Yamasbita, K. Agric. Biol. Chem. 1980, 44, 199.

(66) RuboU, H.; Scbäfer, H. J. Synth. Commun. 1988, 54. (67) Woog, C.-H.; Matos, J. R. J. Org. Chem. 1985, 50, 1992.

34 Carbohydratt-bastd syntheses of C1-chirons

(68) (a) Sbeldoo, R. A.; Kocbi, 1. K. Metal-Catalyred Oxidations ofOrganic Compounds 1981, Academie Pess inc., New York. (b) Sbeldon, R. A. Ntw Dtvelopm. Select. Oxid. 1990, 1.

(69) Hepoer, L. Carbohydrate Feedstock in the Pennentalion Intlustry 1987-1992 1988, London.

2. Analysis 35

2.1 1l~et

Methods are described for the HPLC- and GC-analysis of reaction mixtures

from the carbohydrate-based synthesis of C3-chirons. Pour different HPLC-columns

have been utilized, on which most carbohydrate derivatives could be analyzed. An

anion-exchange resin-based column in the er- or sol·-fonn was used for the analysis of ionic carbohydrate compounds, whereas a cation-exchange resin-based

column in the eau -fonn or a RP-18 column were applied for the analysis of non

ionic carbohydrate derivatives. After 1MS-derivatization, separation of C3- and C4-

acids was realized by GC, using a WCOT fused silica column with CP Sil 5 CB

as stationary phase. 11te cyclohexylidene derivatives of D-mannitol and D(R)

glyceraldehyde could be analyzed directly by this method. Por the detennination

of the optica! purity of proteeled ~-chirons, OC-analysis, using a commercial

capillary column fi11ed with 2,3,4-tri-0-methylated ~-cyclodextrin as stationary

phase, was appropriate. Separation factors of about 1.02 were obtained.

2.2 Introduetion

Por studying the various reacrions described in this thesis with respect to

selectivity and reaction netwotks, a fast and accurate analysis of all the reaction

products is required. 11te analysis ·of carbohydrates and related polyhydroxy

compounds is often performed by gas chromatography1 (OC) or high-performance

liquid chromatographyl (HPLC). A number of publications3 dealing with both

techniques, but especially with HPLC-analysis, have appeared from our

laboratories. A major disadvantage of OC is the need for time consuming

prepatation of stable, volatile derivatives. Moreover, many sugar compounds give


rise to multiple peaks, due to tbe existence of isomers.

Liquid chromatography (LC), in genera.I, requires no derivatization and can

be carried out at relatively low temperatures and has generally replaced the time

consuming OC metbods. Column packings used include polystyrene-based cation

and anion-exchange resins, propylaminosilane-modi:fied silica, and octadecylsilane

modifled silica (reversed phase). Refractive-index detectors (RI) are the most

commonly used detectors for HPLC analysis of sugars. UV detectors are useful

for tbose compounds having carboxyl or other UV absorbing groups. For example,

allphatic acids can be detected by UV -absOiption at 205 - 220 nm witb higher

sensitivity tban witb RI detection4• The molecular UV response depends on the

interaction of various functional groups within tbe molecule, whereas peak areas

generated by RI detection, are roughly correlated with mass quantity. Therefore,

tbe ratio of tbe UV and RI response gives additional information for identiflcation

of tbe peaks in the chromatogram. In HPLC, loop injection of samples can be

done with high reproducibility. This implies tbat pure compounds can be used as

external standards for quantiflcation.

Another important aspect of analysis in the synthesis of C3-chirons, is tbe

determination of optica! purity or enantiomeric excess (e.e.). Most quantitative

determinations have utilized polarimetric data measured on tbe isolated products.

This metbod indeed gives a good indication of tbe optical purity of compounds,

but tbe impact of impurities on the optica! rotation can be very large. Oas-liquid

chromatography witb ebiral stationary phases is a promising altemative, that has

becOine an efficient and sensitive technique for tbe stereochemical analysis of such

natura! compounds as pheromones, carbohydrates, amino acids, etc.'. Altbough

analytica! resolution using HPLC has been successfully applied6, \.it appears that

much less functionality is required for OC resolution tban for corresponding LC

enantiomeric separationsSc. The interest in enantiomer separations on ebiral

stationary phases is partly due to tbe development of commercially available

columns.

GC of volatile enantiomeric carbohydrate derivatives, has been initially

carried out on ebiral polysiloxane stationary p~ases7, where hydragen bonding

interaction is essential for enantiomer separation. This metbod is,· however, not

generally applicable, but is limited to functionalities as amide, carbonate and

oxime, which can eventually be introduced by derivatization. Recently, there have

been reports on derivatized cyclodextrins which are liquids and tberefore can be

2.Anolysis 37

used as stationary phase coatings'. The separation process is dominaled by

ioclusion complexation5b·8• This additional interaction will support ebiral

recognition and allows enantiomeric separation of compounds which eannot be

separated o~ ebiral diamide phases. Moreover, derivatized cyclodextrins exhibit

a wide operating temperature range and are stabie to above 200 ocs•. Analytieal resolution of racemie 1 ,2-0-isopropylideneglycerol (Sa, 14a) bas

been carried out by HPLC onswollen microcrystalline cellulose triacetate6c9 , but

only poor resolution has been achieved presumably due to the very weak.

hydrogen-bonding between the free hydroxyl group and the ester groups of the

stationary phase. Resolution of racemie 1,2-0-isopropylideneglycerol (Sa, 14a) by

oe on pennethyl-0-(S)-2-hydroxypropyl derivatives of P- and y-cyclodextrins

was realized successfully, however, for the latter stationary phase derivatization

with trifluoroacetie anhydride was necess~.

This ehapter describes the methods applied for the analysis of unproteeted

and protected carbohydrate derivatives reported in the subsequent chapters.

Generally, HPLC-analysis bas been used, but occasionally also GC-methods have

been applied. For the determination of the optical purity of protected ~-chirons

by oe a commercially available ebiral column was used.

38 Carbohydrate-based syntheses of C ,-chirons

1.3 Reaetion produels

a: isopropylidene (R = -CH3)

b: cyclohexylidene (R = -(CsH10)-)

CHO COOH COOH

I I I (CHOH) D (CHOH) 0

co I I I CH20H CH20H (CHOH) o-1

I CH20H

(10,19,22,26,28) (8,20,23,27,29,50) (21, 24, 51)

OH R 0 HCOOH (47) 0 RXO.

HO HO HOOCCOOH (46) OH OH

OH 0 R OH OXR

(15) (2a,b)

R R R R R R R R o)( o)( o)( 0~ H0~

0 000 000 HO~O

HO 0 H OH

(9a,b; 18a,b) (4a,b; 11a,b) (3a,b; 13a,b) (5a,b; 14a,b)

Figure 2.1: Reaction products analyzed lry HPLC and GC methods

2. ARalysis 39

2.4 Results

2.4.1 HPLC-analysis ·

Aldonic acid derivatives. Chromatography of unprotected aldonic acids

based on anion-exchange resins has been proven to proceed very satisfactorily in

our laboratories3• Both, a BA-X8 (0") column eluted with an aqueous solution of

NaO and MgC~ or just NaO and a BA-X8 (804 2") column eluted with an aqueous

solution of (NH4)2S04, have been applied for the analysis of unprotected aldonic

acids (8, 20, 23, 27, 29, 50), ketoaldonic acids (21, 51, 24), formic acid (47) and

oxalic acid (46). Detection was performed with both, UV and RI detectors. The

protected ~- and c,.-acids (3a,b; 9a,b; 13a,b; 18a,b) have also been analyzed on

both columns (see Table 2.1). Advantage ofthe BA-X8 (0")/NaCl-Mg~ system

is the possibility to intluence the elution time of diacids by the Mi+

concentration. Complex formation of diacids with Mi+ deminishes the adsorption

and hence the elution times. The intluence of the Mi+ -concentration on the

elution time of aldonic acids is relatively small. This enables one to shift the peaks

of diacids over great distances in.the chromatogram. Oxalic acid (46), often a side

product in oxidation reactions, normally needs a long elution time (40 min), but

by choosing the right Mt+ -concentration, its elution time has been reduced

substantially, which resulted in a fast analysis3c.

The separation of unprotected and protected ~- and C4-acids on the BA

X8 column in the o·-form was poor. The separation of these acids on the BA-X8

column in the so./--form was better, but still could not be used for quantification.

This problem was solved by application of OC, after trimethylsilyl (TMS)

derivatization (see Section 2.4.2).

Non-ionic carbohydrate derivatives. Chromatography on a column of a

cation-exchange resin in its Ca2+-form, with water as eluent, has proven to be

convenient for the separation of sugars and polyols and their derivatives10•

Analyses of aldoses (10, 19, 22, 28, with exception of D-erythrose (26)), D

fructose (15) and D-mannitol (1) were mainly carried out using a BC-X8 column

in the Ca2+ -form with water as eluent and using RI detection. Also the

isopropylidene derivatives of D-mannitol and D(R)-glyceraldehyde (2a and 4a,

respectively), could be analyzed by this method (see Table 2.2). However, analysis

of the corresponding cyclohexylidene derivatives (2b and 4b, respectively),

40 Carbohydrate-based syntheses of C,-chirons

Table l.l: Relative retention times of sugar acids analyzed by HPLC"

20

23

21

8

29

50

46

47

21

51

:!4

18a

9a

Ja, 13a

1

1.08

1.26

1.20

1.33

1.54

5.88

2.20

1.26

2.09

2.05

1.96

1 1

1.17 1.12

1.37 1.30

1.29 130

1.38 1.31

1.69 1.59

10.97 1.83

2.45 2.47

1.40 1.47

1.36 1.47

1.90 1.80

"Retention times are related to tbe elution dme of D-glucooic acid (20). "Eloent.

resulted in insuffi.ciently separated broad peaks, presumably due to the low solubility of the cyclohexylidene derivatives in water. The problern was solved by application of GC (see Section 2.4.2).

Quantitative analysis of D-e:rythrose (26) with the abovementioned BC-X8 column was not possible due to appearence of multiple peaks in the cbromatogram. Analysis on a reversed phase column (RP-18) with water as the eluent and using RI detection, yielded only one single peak: (see Table 2.3).

However, sometimes calculated selectivities to D-e:rythrose (26) exceeded 100 %,

thereby indicating that the analysis is not accurate. These results probably are

attributable to the complexity of D-e:rythrose (26) solutions. Conside'rable amounts of D-e:rythrose (26) in solution are in the aldehydrol form and, moreover, De:rythrose (26) forms readily dimers in solution11

• An external standard differing in composition, could induce different responses. Therefore, analysis of D-

2. Analysis

19

zz Z6

10, Z8

1

1.17

1.1, 1.32, 1.45

1.30

15

1

Za

4a

1.22

1.61

1.23

1.11

41

'The BCX8 (Ca2+) column witb water as eluent was used for analysis and tbe retennon times are related to tbe elunon time of D-glucose (19).

erythrose (26) should preferably be carried out by GC-analysis after TMS

derivatization36. Another possibility is to hydrogenate D-erythrose (26) to the

corresponding erythritol (52), and to analyze the latter by HPLC. Although the analysis of D-erythrose (26) by HPLC was obviously not very accurate, this

metbod bas been used occasionally to analyze reaction mixtures containing D

erythrose (26). The deviation bas proven to be relatively small (up to 5 %), as was

checked by comparison of the AMS-~02-catalyzed alkaline degradation of D

erythrose (26) to D(R)-glyceric acid (29), as well as that obtained from the NaOO-mediated degradation of D-fructose (15) and D-arabinonic acid (23) (see

Chapter 6).

Table 2.3: Relative relention times of non-ionic carbohydrates analyzed by HPI.C'

························~~~····················· .. · ~~(~)·?· •.•.... 15

Z6

Z8

1

1.15

0.93

'The RP-18 column witb water as eluent was used for analysis and tbe retennon times are related to D-fructose (15).


2.4.2 GC-analysis

(Un)protected C3• and C4-aldonic acids. The separation of protected and

unprotected C3- and C4-aldonic acids could not be realized satisfactorily by HPLC

analysis. GC-analysis of the 'IMS-derivatized compounds according to the reported method3a on a capillary column (WCOT fused silica with CP Sil 5B as stationary

phase) using tl.ame ionization detection (FID), appeared, however, to be successful

(see Table 2.4). Tridecane was used as internal standard. An important advantage

of this metbod is that the introduetion of the trimethylsilyl groups results in a

relatively large increase of the molecular weight per active hydrogen atom. The

d.ifferences in the physical properties between the corresponding ~- and C4-

moieties, therefore, increase, which results in a better separation by GC.

3a, 13a•

3.53d

1.14d

1.69"

1.78.

1.57"

8"

29'

tsb·

Jb•

2.3r

2.41•

1.29"

3.14.

1.93•

"WCOT -fused sllica column with CP Sil 5 CB as statiooary pbase. "TMS-derivatization according to metbod A 'TMS-derivatization according to metbod B (see Section 2.6.2). "Naphthalene was used as intemal standard with a temperature program of 20 oe/min at 50 oe to 250 oe. "Tridecane was used as intemal standard with a temperature program of 10 oe/min at 70 oe to 250 oe.

Cyclohexylidene derivatives. Analysis of the cyclohexylidene derivatives

of D-mannitol and D(R)-glyceraldehyde (lb, 4b) by HPLC was not feasible.

Therefore, GC-analysis on a capillary column (WCOT fused silica with CP Sil SB

as stationary phase) using FID detection was applied and it was found successful

(see Table 2.4). Derivatization of the substrates was not necessary. The intemal

standard used was naphthalene. Analysis of the corresponding isopropylidene

derivatives (la, 4a) by this metbod could, however, not be accomplished, probably

due to degradation of the compounds.

2. Analysis

Racemate resolution. For the detennination of the optical purity of protected c,-chirons (3a, 4a, Sa,b, lla, 13a, 14a,b) GC-analysis on a commercially available capillary column coated

with 2,3,4-trimethylated ~

cyclodextrin12, was found to be

successful (see Table 2.5). The protected glycerol and

glyceraldehyde derivatives ( 4a, Sa,b, lla, 14a,b) could be

resolved sufficiently without

43

7 111s Time lmin)

Figure 2.2: GC-chromatogram of a racemie mixture of I ,2-0-isopropylideneglycerol (511, 144) in CHC/3

(I wt%)

derivatization, but glyceric acid compounds (3a, 13a) had to be trimethylsilylated3•

in order to obtain volatile compounds. The separation factors (a) of the racemates achieved by GC analysis amounted to about 1.02. A typical chromatogram showing the resolution of racemie 1,2-0-isopropylideneglycerol (Sa, 14a) is presented in Figure 2.2.

Table 2.5: Retention times and separation factors of chiral C 3-synthons analyzed by Ge'

14a 15.99" 1.024

Sa 16.38" .. 14b 24.0'" 1.013

5b 24.3f "

4a 5.331 1.022

lla 5.441

3ad 16.23" 1.025

13ad 16.6311

"WCOT fused silica column with CP-cyclodextJin...P--236-M-19 as stationary phase. "Retentiou time. •Separation factor with respect to its enantiomer. ~S-derivatization according metbod B (see Sectioo 2.6.2). "Temperature program of 2 "C/min at 70 oe to 120 oe. "remperature program of 1 °C/m:in at 105 oe to 140 oe. 'Temperature program of 2 OC/min at 100 oe to 124 oe. "Temperature program of 3 oe/min at 80 oe to 170 oe.


2.5 Condusions

. For the analysis of protected as well as unprotected carbohydrate

derivatives, HPLC-analysis with extemal standardization, and without sample

derivatization, could be utilized in most cases. An anion-exchange resin-based

column in the er- or sot-form was used to separate ionic carbohydrate compounds, whereas a cation-exchange resin-based column in the Ca2+ -form was

applied for the analysis of non-ionic derivatives. D-Erythrose (26), however, had to be analyzed on a RP 18 column, due to multiple peak: formation on the cation

exchange column.

The separation of protected as well as unprotected c,- and c .. -acids by the abovementioned HPLC-methods, was not sufficient for quantification. Therefore,

a oe-method was developed using a WCOT fused silica column with CP Sil 5 CB

as stationary phase. After TMS-derivatization the C3- and C4-acids could be

analyzed quantitatively. Also the cyclohexylidene derivatives of D-mannitol and

D(R)-glyceraldehyde (2b and 4b, respectively), not appropriately analyzed by the

applied HPLC-methods, could be analyzed quantitatively with oe, without

derivatization. OC-analysis of the corresponding isopropylidene derivatives (2a and

4a, respectively), was not successful: apparently they degrade under the analysis

conditions.

Racemate resolution of protected C3-chirons could be accomplished

satisfactorily with oe, using a commercial capillary· column with 2,3,4-tri-0-methylated ~-cyclodextrin as stationary phase. TMS-derivatization was necessary for the protected C3-acids in order to obtain volatile compounds. Separation factors

for the different enantiomers amounted to about 1.02.

2.6 Experimental

2.6.1 HPLC-analysis

Apparatus and pr~edure. A Spectra Physics type SP 8800 liquid chromatograph in combination with a SP 88775 autosampler, a Rheodyne 7010

injection valve with a 20.10-3 mL sample loop, and a SP 8790 column heater were

used. Dual detection was realized with a Millipore Waters type R410 refractive

2. Analysis 45

index detector in series with a Spectra Physics SP 8450 variabie wavelength UV

VIS detector operated at 212 nm, and connected to a SP 4290 two channel digital

integrator.

The eluents were filtered over a Millipore type MA WP filter (0.45.10'3nun)

and degassed with helium, whereas the samples were filtered over a Schleicher &

Schuell OF 92/RC 55 filter combination. When necessary, the samples were

adjusted to pH= 8 with diluted HCl or with a NaOH solution before filtration.

Extemal standardization with pure compounds was used for quantification.

Column BA-X8 (Cl"). A 280 x 4.6 nun I.D. Lichroma SS column slurry

packed with BA-X8 anion-exchange resin (Benson), partiele size 7- 10.10·3 mm,

during the packing wasbed ovemight with 1 L of an aqueous 0.2 M Naa solution,

at a temperature of 85 OC, was used. The eluents used were an aqueous 0.16 M

Naa and 0.02 MA solution or a 0.2 M NaO solution, both with a flow rate of

1.15 mL/min, resulting in a pressure drop over the column of 4.5 MPa. The

relative retention times of the compounds analyzed are listed in Table 2.1.

Column BA-X8 (SOl"). As described for the BA-X8 (Cr) column but

wasbed with 1 Lof an aqueous 0.5 M (NH4hS04 solution. The pressure drop over

the column was 18 MPa. The eluent used was a 0.2 M (NH4hS04 solution. The

relative retention times of the compounds analyzed are listed in Table 2.1.

Column BC-X8 (Ca:z+). As described for the BA-X8 (0") column but

column size was 300 x 7.6 nun I.D. and the column was slurry packed with BC

X8 cation-exchange resin (Benson) and wasbed with 1 L of an aqueous 0.2 M

CaCI:z solution. The column temperature was 60 °C. The eluent was water with a

flow rate of 1 ml/min, resulting in a pressure drop over the column of 34 MPa.

The relative retention times of the compounds analyzed are reported in Table 2.2.

Column RP-18 (reversed phase). A 250 x 4.6 nun I.D. SS column

obtained from Chrompack, prepacked with CP Spher C18 (5.10"3 nun) was used.

The temperature of the column was - 0 °C. The eluent used was water with a flow

rate of 0.5 mL/min, resulting in a pressure drop over the column of 100 MPa. The

relative retendon times of the compounds analyzed are listed in Table 2.3.


2.6.2 GC-analysis

Apparatus and procedure. A Chrompack Pack:ard 438 A gas

chromatograph equipped with a Chrompack Pack:ard 910 autosampler and a

capillary column was used. 1he carrier gas, N2, had a flow rate of about

30 ml./min and the splitting ratio was 100:1, resulting in a pressure drop over the

column of 30 kPa. A hydrogen flame ionisation (FID) detector was used with a

hydrogen flow rate of about 30 mi..Imin and an air flow mte of about 300 ml../min. 1he temperature of both, the injection pon and the FID-detector was 250 oe and

the injection volume was 0.1 - 0.5.10"3 mL. The intemal standards used were

naphthalene or tridecane.

Samples were injected with or without TMS-derivatization. Derivatization

of the unprotected carbohydrates (method A) was canied out with approximately

200 mg of an aqueous sample in a 2 mL vial, containing - 10 mg of the

compound, to which 0.1 mLofan aqueous 6 M HO solution was added. 1he vial

was kept at 60 °C under vacuo for 2 - 3 h, until it contained nearly dry residue.

1he residue was then dissolved in about 0.3 mL DMSO and an accurate measured

volume of pyridine (about 1 mL), containing a known quantity of the intemal

standard and about 0.3 mL Trisil-concentrate (PIERCE) were added, whereas the

vial was sealed. This solution was shaken vigorously for 12 h at room temperature

and was then analyzed. Derivatization of the unprotected carbohydrates (method

B) was carried out as described above for the unprotected derivatives, but

acidification was omitted.

Column CP Sil S CB (WCOT fused silica). A Chrompack 10 m x

0.22 nun I.D. WCOT fused silica column with CP Sil 5 CB (0.12.10"3 mm) as

stationary phase was used. 1he relative retention times ·of the compounds analyzed

are listed in Table 2.4.

Column methylated p-cyclodextrin (WCOT fused silica). A Chrompack

25 m x 0.25 mm I.D. WCOT fused silica column with CP-cyclodextrin-fJ-236-M-

19 as stationary phase (0.25.10"3 nun) (Chrompack) was used. 1he retention times

of the compounds analyzed are listed in Table 2.5.

2. Analysis 47

2. 7 Relerences and notes

(1) (a) Sweeley, C. C.; Bently, R.; Makita, M.; Wells, W. W. J. Am. Chem. Soc. 1963, 85, 2497. (b) Bisbop, C. T. Adv. Carbohydr. Chem. 1964, 19, 95, ed. M. L. Wolftom, R. S. Tipson, Acad. Press, N.Y. (c) Berry, J. W. Adv. Chromatogr. 1966, 2, 271, ed. J. C. Giddings, R. A Keller, Marcel Dekker, N.Y. (d) Petersson, 0. Carbohydr. Res. 1974,33, 47.

(2) (a) Honda, S. Anal. Biochem. 1984, 140, 1. (b) Hicks, K. B. Adv. Carbohydr. Chem. & Biochem. 1988, 46, 17. (c) Lee, Y. C. Anal. Biochem. 1990, 189, 151. (d) Hicks, K. B. Carbohydr. Res. 1991, 215, vü .

(3) See for example: (a) Verhaar, L. A. Tb.; de Wilt. H. 0. I. J. Chromatogr. 1969, 41, 168. (b) Diikx, I. M. H.; Verhaar, L. A. Th. Carbohydr. Res. 1979, 73, 287. (c) Dijkgraaf, P. J. M.; Verhaar, L. A Th.; Groenland, W. P. T.; van der Wiele, K.. J. Chromatogr. 1985, 329, 371. (d) Verhaar, L.A. Th.; Hendtiks, H. E. J.; Groenland, W. P. Th.; Kuster, B. F. M. J. Chromatogr.1991, 549, 113.

(4) Verhaar, L. A Th; Db:kx, I. M.H. Carbohydr. Res. 1978, 62, 197. (5) (a) KOnig. W. A.; Miscbnit-LUbbecke, P.; Brassat, B.; Lutz. S. Carbohydr. Res. 1988,

183, 11. (b) KOnig, W. A. Carbohydr. Res. 1989, 192, 51. (c) Annstrong, D. W.; Li, W.; Cbang. C. D.; Pidla, I. Anal. Chem. 1990, 62, 914. (d) Bertbod, A; Li, W. Y.; Annstrong, D. W. Carbohydr. Res. 1990, 201, 175.

(6) (a) Morrison, J. D. Asymmetrie Synthesis 1983, 4. (b) Wainer, I. W. Trends Anal. Chem. 1987, 6, 125. (c) Aransson. E.; Micbelsen, P.; Oldbam, 0. Chem. Scripta 1988, 28, 313.

(7) (a) Frank, H.; Nicbolson, 0. J.; Bayer, E. J. Chromatogr. Sd. 1977, 15, 174. (b) Frank, H.; Nicbolson, 0. J.; Bayer, E. Angew. Chem. 1978, 90, 90.

(8) KOnig. W. A; Lutz, S.; Wentz, 0.; von der Bey, E. J. High Res. Chromatogr. & Chromatogr. Commun. 1988, 11, 506.

(9) lsaksson, R.; Lamm, B. J. Chromatogr. 1986, 362, 436. (10) (a) Verhaar, L. A. Th.; Kuster, B. F. M. J. Chromatogr. 1981, 210, 279. (b) Angyal, S.

I.; Bedtell, 0. S.; Beverldge, R. Carbohydr. Res. 1979, 73, 9. (11) Angyal, S. Adv. Carbohydr. Chem. & Biochem. 1986, 42, 15. (12) Cbrompack BV, Middelburg, tbe Nedtedands.

3. Catalytic oxidative cleavage of D-mannitol derivatives 49

3.1 Abstract

A plethora of mainly catalytic oxidizing systems has been tested for the

cleavage of 1,2:5,6-di~O-isopropylidene- and cyclohexylidene-D-mannitol to the

corresponding protected D(R)-glyceraldehydes and glyceric acids. Most systems

investigated are not able to cleave a.-diols in contrast to the RuC~-catalyzed a.-diol

cleavage with NaOCl as primary oxidant, that shows high selectivity and high rate

under mild reaction conditions. Also cleavage with NaOCl, with or without the

presence of Pb(N03)2 or F~(S04)3 , yields the protected glyceric acids as main

reaction product, however, with low rate and/or selectivity. Thus, Ru03-catalyzed

cleavage of 1,2:5,6-di-0-isopropylidene-D-mannitol (0.2 Min ~0 at pH= 8 and

room temperature) with 4 equivalentsof NaOCl per mole substrate, gave sodium

2,3-0-isopropylidene-D(R)-glycerate in 95 % yield within 30 min reaction.

Although the formation of 2,3-0-isopropylidene-D(R)-glyceraldehyde is observed,

the reaction could not be stopped at the aldehyde stage. Similarly, cleavage of the

corresponding cyclohexylidene derivative of D-mannitol in a two phase system

(~0/DCM/CH3CN) yields 64 % of sodium 2,3-0-cyclohexylidene-D(R)-glycerate.

Several ruthenium catalysts were effective, e.g. tetrapropylammonium

perruthenate (TPAP), Ru-Dowex, Ru/C, Pb[Ru1 .33Pb0.67"106.~ (pyrochlore oxide)

using NaOCl as the primary oxidant, but other oxidants are not active. The best

results with a heterogeneaus catalyst are obtained with the pyrochlore oxide,

Pb[Ru133Pb0•67 4+]06.5, which reacts with a comparable activity and selectivity as the

homogeneaus catalyst (RuC13), and which probably reacts at the surface of the

catalyst. Addition of active carbon to the RuC13-catalyzed cleavage has a positive

effect on the reaction rate. The homogeneously catalyzed reaction is flrst order

with respect to Ru03 and diol and the observed activation energy amounts to

55.8 kJ/mol. Presumably the reaction proceeds via Ru04 which adds to the a.-diol

function. Subsequent cleavage of the C-C bond gives Ru03 and two molecules of


protected C,-aldehyde which are forther oxidized to the corresponding C,-acid.

3.2 Introduetion

D-Mannitol (l) is a well-known, inexpensive, natorally occurring souree

for the preparation of optically pure C,-synthons (C3-chirons)'. Each molecule of

D-mannitol (1) affords, after proteetion of the 1,6- and/or 2,5-hydroxyl functions

and subsequent oxidative cleavage, without loss of carbon atoms, two molecules

of versatile C,-chirons. D-Mannitol (1) has a twofold axis of symmetty. When this

symmetry is preserved during chemical transformations, C-2 and C-5 will have

identical absolute conftgurations and the cleavage of the C-3 and C-4 bond will

lead to two identical chiral molecules with one chiral centre. The fust report of D

mannitol (1) as a starting material for the preparation of chiral C3-synthons dates

from 193!f, providing 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a) (Fig. 3.1).

All methods for the synthesis of C3-chirons starting from D-mannitol (l)

include two important steps: the proteetion of the 1,6- and/or 2,5-hydroxyl

functions and cleavage of the C-3 - C-4 bond.

Proteetion of the 1,6- and/or 2,5-hydroxyl functions is necessary in order

HO

HO HO

OH

OH

OH

acetone ..

D-mannitol

(1)

Pb(0Ac) 4

OH

OXCH3

0 CH3

1,2:5,6-di-O-isopro

pylidene-D-mannitol

(2a)

..

2,3-o-isopropyli

dene-D(R)-gl yceral

dehyde (4a)

Flgve 3.1: Synthesis of 2,3 -0-isopropylidene-D(R)-glyceraldehyde ( 44) storting from D-mannitol (lf

3. Catalytic oxidativ~ cl~avage of D-mannito/ derivatives 51

to realize selective cleavage of the C-3 and C-4 bond. Although the threo-3,4-

configuration in D-mannitol (1) is particularly vulnerable to cleavage via a cyclic

complex3, cleavage of unprotected D-mannitol (1) by e.g. Nalo: doesnotlead

to ~-fragments in high yield, but is accompanied by cleavage of other C-C honds, in the starring material as well as in primary cleavage products. 1be protective

group most widely used is the isopropylidene function, which tan proteet two hydroxyl functions simultaneously. Several methods are described for the

proteetion of D-mannitol (1) to 1,2:5,6-di-0-isopropylidene-D-mannitol (2a)

employing acetone and ~ 2.!1, 2,2-dimethoxypropane in the presence of catalytic

amounts of Sn~6 or pTsOH7, and 2-methoxypropene in the presence of catalytic

amounts of pTsOH'. Three of the methods mentioned above, were studied in

detail and compared with the aid of gas-liquid chromatographic techniques9• In

each reaction isomerie diaeetals and one tri-acetal were formed, but the metbod

using acetone and ZnClz gives 2a in the highest yield ( 63 % ). Very recently a

practical 'bulk' synthesis of 2a was developed, for which the procedure which

used catalytic amounts of Sn~ and 2,2-dimethoxypropane was selected for its combination of . high throughput, low catalyst loads, simple processing and reproducibility10

• Other less frequently encountered protective groups are cyclohexylidene11

, methyl12, benzyl13

, carbonate14, benzoyl15

, benzylidene14',

and anhydro17 functions. A general approach for the synthesis of three

representative protective groups, acetyl, tert-butyldimethylsilyl and diisopropylmethylene was reported recently18

• However, only proteetion as

isopropylidene and cyclohexylidene derivatives (2a,b) can be realized in one single step, whereas the other protecting groups are introduced in multi-step procedures.

1be majority of methods for cleavage of the 3,4-glyoollinkage of protected

D-mannitol (2) employs either lead tetraacetate2 or sodium periodate10•19

, but also

meta-iodoxybenzoate20, bismuth derivative~1 and electralysis at a nickel

hydroxide electrode22 were reported. Just one 'catalytic method' for the cleavage of protected D-mannitol (2a) is known, using catalytic amounts of

triphenylbismuth and N-bromosuccinimide as the primary oxidanr3• The reaelions

reported all yield protected glyceraldehyde (4) as the main cleavage product, except the electrolytic cleavage at a nickel hydroxide electrode, which yields the

conesponding glyceric acid derivative (3a). Abovementioned stoichiometrie and

catalytic oxidations are, however, too expensive and environmentally unacceptable

for industrial applications.


A large amount of a-glycol cleavage reactions bas been reported in

literature. Both, stoichiometrie as well as catalytic systems have been used with

different kinds of a-glycols to give aldehydes, acids or ketones as cleavage

products. Depending on the nature of the a-glycol, e.g. aromatic or aliphatic,

primary - primaiy, primary - secondary, secondary -secondary etc., trans or cis,

and on the nature of the oxidizing system, different glycols afford different

products. A summary of the stoichiometrie reagents and of the catalytic systems

for a-diol cleavage is given in Table 3.1 and 3.2 respectively, with the exception

of those already known for the cleavage of D-mannitol derivatives (2).

As can be seen from these tables, a variety of methods is,· in principle,

available for the catalytic oxidative cleavage of a-glycols using inexpensive and

non-polluting oxidants, e.g. 0 2, ~02, tBHP, Naoa or ~S208 in combination

with a metal catalyst. To our knowledge none of these industrially acceptable

methods bas been used for the oxidative cleavage of proteeled D-mannitol (2). In

this chapter we report our attempts to accomplish catalytic oxidative cleavage of

1,2:5,6-di-0-isopropylidene- (2a) and cyclohexylidene-D-mannitols (2b) using

inexpensive oxidizing agentsin combination with roetal catalysts. Tables 3.1 and

3.2, and especially the one with the catalytic systems, formed the starting point of

our search for a new industrially applicable cleavage route of proteeled D-mannitol

(2) to optically pure c,-chlrons. Although the commonly used stoichiometrie

methods are not industrially acceptable, if the expensive oxidant could be used in

catalytic amounts in combination with a suitable oxidant to regenerale the catalyst,

they might be interesting for the cleavage of proteeled D-mannitol (2). In fact

several catalytic methods from Table 3.2 have been developed in this manner.

aeavage of 2 to protected glyceraldehyde derivatives (4a,b) is preferred

over cleavage to protected glyceric acid derivatives (3a,b ). The aldehydes ( 4a,b)

have a broader range of applications and can be more easily reduced to the

corresponding alcohols (Sa,b )1*, which themselves are also very interesting ebiral

building blocks, and in principle oxidizable to the proteeled acids (3a,b). However,

when applying a strong oxidizing system, oxidation of the aldehyde to the acid

will be difficult to prevent.


Table 3.1: Survey of stoichiometrie reagents for the cleavage of a.-glycols

aJipbatic aldehyde NiOOH ether 24

aJipbatic acid NiOOH ~O,NaOH 24c

aromatic acid NaB03 MeOH.NaOH 2S

aJipbatic aldehyde Mn-based ~0 (acidic) or DCM 26

aromatic aldehyde Mn-based acetone 27

t,t-diol ketone Cr-based HO Ac 28

alipbatic aldehyde Cr-based acidic 29

aJipbatic aldehyde HgO,~ DCM 30

aJiphatic aldehyde Ag(ll) radiolytic 31

t,t-diol ketone Ce-salt acidic 32

aromatic aldehyde Ce-salt HO Ac 33

alipbatic aldehyde Ce-salt ~0 (acidic) 34

aromatic aldehyde Tb-salt HO Ac 35

aJipbatic aldehyde, acid xenic acid ~0 (basic or neutral) 36

alipbatic acid V-based acidic 37

t,t-diol ketone V-based acidic 38

alipbatic aldehyde anodic oxidation C-electrode 39

saccbaride aldehyde NaOCl ~O,pH=7 40

saccbari.de, acid Naoa ~o. pH=9 -ll 41

staich

alipbatic aldehyde Ca(OCI)2 HOAc, DCM, CllgCN 42

'Typical reaction conditions: ambient temperature and atmospheric pressure.


Table 3.2: Survey of methods for the catalytic cleavage of a.-glycols

aromatic

aromatic

aromatic

aromatic

aldehyde

aldehyde

aldehyde

ketone

Cr-pOtphyrin

Fe-porphyrin

Peel,

rat liver eozyme

N-oxide

NADPHgs

~CN

DCM

~CN

HzO, pH=7.4

43

44

45

46 -----------------------------------------------------------------------------------

aliphatic

aliphatic

alkene

aliphatic

aliphatic

aliphatic

aliphatic

aliphatic

aliphatic

aliphatic

aromatic

acid

acid

acid

acid

aldehyde

acid

acid

acid

acid

acid

acid

Pb,Ru,.O. or Bi,.Ru,.O.

Pb,Ru,.o. or Bi,.Ru,.O.

Ru02, PTC

Ru Cl,

RuC~

wottPot H,PMo(or W)12041lb

(NHJ~o10:u, PTC

H,PMo10V2041l or VO(acac)2

Mo02(acac)2

Mo(C0)6, PTC

02

e

NaOCI

NaOCI

~02

tB HP

tB HP

~O,pH> 13

~O,pH> 13

DCM,~o (basic)

~0

acetone

~0, H+, 90 °C

CHCI3 /~0

~0/THF

EtOH

chorobenzene

benzene

47

48

49

50

51

53

54

55

56

57

58

aromatic acid VO(acac)2, tBHP BuOH 59 mchloro-

pelbenzorc acid

-~p~~-------~~-----------Y.19L-----------~?! ________ !!tq!..~~-:~------~~--aliphatic

aliphatic

aliphatic

acid Co-salts, AcOOH

acid Co-,Mn-,Ni-,Fe-Pd"salts

aldehyde Co- or Mn-salt

AcOOH

~0 (basic)

benzene, 60 oe

100-200 °C, organic solvent

61

62

63

-----------------------------------------------------------------------------------aliphatic aldehyde AgN03 :KzS20a ~0 64

t,t-diol ketone AgN03 KzS20a ~0 65

aliphatic acid AgO/ Ag 02 ~o. pH> 13 66

starch acid AgO I Ag 02 or o3· ~O,pH> 13 67

'Typical reaction conditions: ambient temperature and atmospheric pressure, unless indicated otherwise. bAs cetylpyridinium salt. "With Co- or Pd-cocatalyst.

3. Catalytic oxidative cleavage of D-mannitol derivatives

3.3 Reactions

1,2:5,6-di-O-isopropylidene-Dmannitol (2a)

0~ HO

OH~

~>() 1,2:5,6-di-O-cyclo

hexylidene-Dmannitol (2b)

2,3-0-isopropylidene-D(R)-g 1 ycer

aldehyde ( 4a)

2,3-0-cyclohexylidene-D(R)-gl ycer

aldehyde (4b)

55

2,3-o-isopropylidene-D(R)-glyceric

acid (3a)

2,3-0-cyclohexylidene-D(R)-g lyceric

acid (3b)

Fipre 3.2: Oxidative cleavage of proteeled D-mannitols (2a,b) to C3-chirons

3.4 Results and discussion

3.4.1 O:xidative cleavage

Por the oxidative cleavage of protected D-mannitol (2) to C3-chirons with

cheap oxidizing systems, two substrates were used, i.e. 1,2:5,6-di-0-isopropylidene- (2a) and 1,2:5,6-di-0-cyclohexylidene-D-mannitols (2b). Bothare

available from D-mannitol (1) in one step6•11

• The low molecular weight and small


size of the isopropylidene group is of economical interest and is favourable for a

good accessibility of the remaining free diol function, but is atso responsible for

the relatively low boiling point of the protected aldehyde (4a). This boiling point

is too low for efficient GC analysis of the reaction mixture. On the other hand, the

cyclohexylidene derivatives cannot be easily anatyzed by HPLC (see Chapter 2).

Manipulation of the fliSt cleavage product, 2,3-0-isopropylidene-D(R)

glyceratdehyde (4a), is inconvenient due to its tendency to polymerize and racemize and its instability towards acids, which are expected to be less

pronounced for the corresponding cyclohexylidene derivative ( 4b )11• Therefore,

reacrions have to be carried out in a limited pH-range. At too high pH (>8) aldol

condensation and racemization of the aldehydes (4a,b) occur, due to the acidic

character of the proton at C-2, and at too low pH (<5) deprotection of substrate

(2a,b) as well as products (3a,b; 4a,b) occurs. Only when the corresponding

glyceric acid derivative (3a,b) is fonned in the cleavage reaction, either directly

or via rapid oxidation of the intermediale aldehyde (4a,b), higherpH-values are

allowed. Isopropylidene derivatives (2a, 3a, 4a) are soluble in water as wellas in

organic solvents, while the corresponding cyclohexylidene derivatives (lb, 3b, 4b)

show better solubility in organic solvents. This implies that reacrions with 1,2:5,6-

di-()..cyclohexylidene-D-mannitol (2b) have to be carried out in organic solvents

or in a two phase system, whereas reaelions with 1,2:5,6-di-0-isopropylidene-D

mannitol (2a) can, in principle, be carried out in both, water and in organic

systems. 2,3-0-Isopropylidene-D(R)-glyceraldehyde (4a) is very soluble in water,

which can make product isolation more difficult than for the corresponding

cyclohexylidene derivative (4b). As a consequence ofthe lower solubility in water,

it may also be easier to stop oxidative cleavage of cyclohexylidene diol (2b) at the

aldehyde stage. In conclusion, application of both protective groups is possible, but

each of them bas its own distinct advantages and disadvailtages. Both rnannitol

derivatives (2a,b) have been used to study the oxidative cleavage to the

careesponding ~-chirons, using inexpensive oxidizing agents.

Most systems were tested with pH-control at the lower (pH = 5) and upper

(pH= 8) pH-limit when carried out in an aqueous solution. In alkaline medium

the optimal pH was determined. The tested systems are summarized in Table 3.3.

Reaction mixtures were analyzed by OC for cyclohexylidene derivatives and by

HPLC for isopropylidene derivatives (see Chapter 2).

3. Cata/ytic oxidative cleavage of D·mannitol derivatives 57

Table .3.3: Tested ( catalytic) oxidation systems for the cleavage of D-mannitol derivatives (Za,b)

~~tV D ~i: i•.·······••<\ >··.········· {··· >.~~.·.y.y·····•· i .. ~l:i."*t/······•·•·.·.········· lb CAN, NH,.V03 01' VO(acac)2 tBHP or 0,02 DCB 01' DCP.II\0, PTC

2b

la

2b

lb

la

la

NaVO, 01' H,[PMo10 V20 ..,].32H,O"

VO(acac)2 01' NH,.VO,

NaBiO,, BiO, 01' Bi(Ph),

Bu(Ph), 01' NaBi03

Co(acach. CoPc, or CoPc(NaS03)4

Co(NO,)z, Co(acac)2 01' Na,[Co(NOJJ

CoS04.7H,O, CoPc

CoS04.'7H,O ----------2b Na, W04.21fz0

la ( !tC,H,N(CH,)..,CH3 lPW 120.,;

2b MoNRzOc-2HzO or Mo(acac),

la lltC,H,N(CH,>.,al, JPMo,20 40 • -----------2b CuPc(SO,Na)4 01' Cu(ll)imidazole

BtOH, 75 oe

NaOCl H,O,pH •7

tBHP 01' H,02 DCB 01' DCPJH:P• PTC

NaOCl H,O, pH = 8

tBHP 01' H,02 DCB 01' DCP.II\0. PTC

NaB03 HOAc 01' DCM/MeOH

NaOCl 0,0, pH =8

AcOOH H,O,pH=S.S --------tBHPorH,02 DCB 01' DCPJH,O, PTC

H,O• DCM 01' DCFM.zO, pH=6

tBHP 01' H,02 DCB 01' DCP.II\0, PTC

a,o. DCM or DCP.II\0, pH=6 -------------------------tB HP DCB ----------·-------------------. ----------· lb

2b --------· la01'2b

tBHPorH,02

(Bu,SnO),Cr02

DCM or benzeDe

DCMorDCB --------------H,02 01' tBHP DCB 01' DCP.II\0, PTC ---------·--- ---·------

2b

--------·--------------------2a

la

la

AgN03, Ag-Sn/Si02 01' Ag~0,

AgNO,

As/ALO

AMS, Pb,Pt/C 01' Pt/C

a,o. 01' DCB 01' NaB03 DCM /Mf!OH,PTC

NaOCl H,O, pH = S - 11 ---------

02

H,O,pH =S

H,O, pH =8

H,O, 3 tr, NaOH

H,O, 3 tr, NaOH ---H,O, pH == 8 - 10

-----------------------------------------------------------------------------V -bromoperoxidase H,O, pH=6.4 01' DCM'

2a rat-liver-S9 NADPHgs H,O, pH = 7.4' -------------------------------------------------------------------28 Ft!,(SO)l. Pb(NO,)l 01' NaOCl H,O, pH= 8 Ni(N03) 2

Pb-anode and Nal04 01' Nal04

2a

e resp. NaOCl

NcOCfl

H,O,pH =S -8

H,O,pH .. 5- 8

"Typical reaction conditions: reftux temperature and atmospberic pressure, somelimes with tetrabutyl ammonium hydrog~n sulfate as PTC, unless stated otherwise. The pH-controlled reactions are usually canied out at 40 °C. "Pre~ared as described by Tsigd.ino68

• 'Prepared as described by Ishii"'69

• "Titanium-con~ zeolite . •camed out as descri6ed by de Boer71• rcanied out as

described by Laskowski46• 1Successful.

58

As may be concluded from Table 3.3 almost all oxidizing reagents

mentioned in Tables 3.1 and 3.2 have been tested in combination with one or more

primary oxidants. Only Mn-, Hg-, Th- and Xe-based systems were not tested. Very

few oxidizing systems were able to cleave protected D-mannitols (2a,b ). Most of

the systems leave the substrate unchanged. Others cause deprotection of the

1,2:5,6-acetals, due totheir acidic character, whereafter the formed D-mannitol (1)

undergoes further degradation to lower sugar acids and carbon dioxide. The

systems with Pb(N03h or Fe2(S04) 3 as catalysts and NaOCl as the primary

oxidant, cleave 1,2:5,6-di-0-isopropylidene-D-mannitol (2a) to 2,3-0-

isopropylidene-D(R)-glyceric acid (3a), although not very selectively (selectivity

according to HPLC-analysis is 30- 40 %). Without catalyst, at pH= 8, Naoa

also cleaves 2a to 3a rather selectivly (selectivity according to HPLC-analysis is

73 %) but the reaction is relatively slow, even at higher temperatures (60 °C), and

consumes large amounts of reagent (8 equivalents NaOCl per mole substrate

results in only 54% conversion). On the other hand, the Ru03-catalyzed reaction

with NaOCl, is extremely selective (sodium 2,3-0-isopropylidene-D(R)-glycerate

(sodium salt of 3a) can be isolated in 95 % yield), very fast, even at room

temperature, and needs 4 equivalent& of NaOCl per mole substrate in order to

achleve 100% conversion (theoretically 3 equivalents are needed). The oxidative

cleavage of protected D-mannitol (2a,b) with Ru-based oxidizing systems is

discussed in detail in the next section (Section 3.4.2).

Protected D-mannitol (2a,b) is an aliphatic, secondary - secondary a-diol,

containing acid sensitive protecting groups. lts reactivity towards electrophilic

oxidizing reagents is limited in comparison to aromatic a-glycols. Therefore

systems that are capable to cleave aromatic diols may cause difficulties in cleaving

2. Indeed, none of the systems previously known to induce cleavage of aromatic

a.-glycols was able to cleave 2a or 2b. Por steric reasons the reactivity of the D

mannitol derivatives 2a,b will be situated between that of primary - primary and tertiary - tertiary diols, whereas the reverse is expected from electtonic

considerations. Many oxidizing systems are effective only in acidic media where

they are strong electrophiles. In basic media they are often much less effective due

to formation of insoluble oxides or hydroxides, which also may be a limitation for

reactions with 2 (see above ). This problem is nicely illustrated by the AgN03-

catalyzed systems. In the presence of oxidants, the silver ion forms AgO, which

is only soluble in acidic media and that precipitates immediately after its formation


at higher pH. Also reacrions with ~02 and heteropolyacids or tungstic acid as

catalysts proceed well onder acidic conditions but the catalysts lose their reactivity

at increasing pH. Unfortunately, in none of the tested reaelions protected

glyceraldehyde ( 4a,b) is obtained. However, it was detected in small amounts in

the Ru03-catalyzed oxidation with NaOCl at low conversion, indicating that it is

an intermediale during the synthesis of the corresponding glyceric acid (3a).

In conclusion, it is not easy to find a suitable oxidizing system for the

cleavage of protected D-mannitol (2a,b) which is economically attractive as well.

Due tothefact that until now only Nal04 and Pb(0Ac)4 seem to be used for this

interesting reaction and due to the limitations in reaction-pH, it is not swprising

that many known a-diol cleavage systems are not suitable for the cleavage of 2.

The effectiveness of the Ru03-Na0Cl system for the selective cleavage of 2a to

3a presumably depends on in situ formation of the very powerful and versatile

oxidizing reagent, Ru04, at very mild reaction conditions in the right pH-range.

3.4.2 Ruthenium catalyzed oxidative cleavage

Since its introduetion in organic chemistry in 1953n, Ru04 bas been

recognized as a powerful and versatile oxidizing agent73• Although numerous

catalytic procedures have been developed74 because of the high costs of

ruthenium metal, only a few examples of mthenium-catalyzed oxidative cleavage

reactions are known (see Table 3.2). In 1970 Wolfe50 reported a RuC13-catalyzed

hypochlorite oxidation of various organic compounds. Thus, cyclohexane-1 ,2-diol

was cleaved to adipic acid using catalytic amounts of RuC13 and 6.2 equivalents

of sodium hypochlorite. Under these reaction conditions (low pH) our substrates

are fully deprotected and degraded, apparently due to the production of acids.

However, when the pH is controlled during the process at pH= 8, this

deprotection and subsequent degradation can be prevented, as already mentioned

above, without loss of the cleaving ability towards protected D-mannitol (2a). In

this section the Ru-catalyzed cleavage of 2a and 2b is discussed in detail.

The RuCl3-catalyzed oxidative cleavage of 2a with NaOCl at standard

reaction conditions (see Table 3.4) occurs very fast. At the applied substrate and


catalyst concentrations, NaOO has to be added in small portions in order to be

able to control the pH accurately with 5 M NaOH. The reaction mixture is dark

coloured during the entire experiment, indicating the presence of Ru(III - Vll)

species. When a dilute reaction mixture is treated with an excess of NaOCl, the

reaction mixture is clear and yellow, which points to the presence of Ru(VIII)04•

The nature of the active species in the catalytic cycle is therefore not clear. The

reaction is very selective (see also Fig. 3.3 and 3.4), but when an excess ofNaOCl

is used, further degradation to lower sugar acids and co2 occurs. The optima!

reaction pH is 8. At low conversions, small amounts of 2,3-0-isopropylidene

D(R)-glyceraldehyde (4a) are detected, suggesting its intermediacy in the cleavage

reaction. Product (3a), sodium 2,3-0-isopropylidene-D(R)-glycerate (sodium salt

of 3a), can be easily isolated in high yield (95 %) after concentration of the

reaction mixture to a solid residue, redissolving in hot ethanol, filtering insoluble

inorganics, and concentration of the flltrate. The homogeneous catalyst usually

remains in the solid residue together with inorganic salts, but can be completey

removed by treatment of the aqueous or ethanollayer with active carbon.

~

::::. 0 i-

! c 0 :;:; .. .. .. c "' Cl c 0 u

1.50 3.00 4.50 6.00 7.50

NaOCl (eq. per mole 2a)

Figure 3.3: Concentroti on profile (Q2a, +:3a, 0:4a, !J.:46) in the RuCI,-catalyzed cleavage of 2a with NaOCI. Conditions: [2a] = 0.2 mol/I, [RuC/3] = 5 mmol/1, pH = 8, T = 20 oe

Qj .,

> c 0 u

1.50 3.00 4.50 6.00 7.50

NaOCl (eq. per mole 2a)

Figure 3.4: Conversion (Q2a), selectivity (+:3a, !J.:4a, o:46), and yield (0:3a) in the RuCI,-catalyzed cleavage of 2a with NaOCI. Conditions: [2a] = 0.2 mol/I, [RuC/3] = 5 mmo/I/, pH = 8, T = 20 oe

Extraction of an acidic solution of Ja (pH = 2) with DCM and in vacuo

concentration of the organic layer gives the corresponding acid 2,3-0-


isopropylidene-D(R)-glyceric acid (3a) in 50- 70% yield. Due to its acidic

character, distillation of 3a leads to degradation of the product.

1. Alternative Ru-catalysts and primary oxidants. The Ru03-catalyzed

oxidative cleavage of 2a with NaOCl as the oxidizing agent is very selective and

proceeds fast under mild reaction conditions. The proteeled glycerate (sodium salt

of 3a) can relatively easy be separated from the homogeneons catalyst and the

inorganic by-product, NaCl. From economie point of view, possible improvements

of this procedure are the use of an oxidizing agent not producing inorganic salts

(e.g. 0 2, ~02, tBHP) and/or the use of a heterogeneons catalyst, that is easily

recovered from the reaction mixture for reuse. Moreover, the application of a less

strong oxidant (e.g. NMO, ~02) may allow the cleavage reaction to be stopped

at the aldehyde stage, due to the formation of a lower valent Ru-species. The

results of cleavage of 2a with alternative primary oxidants and Ru-catalysts are

summarized in Table 3.4.

The reactions with Naoa as primary oxidant and various Ru-catalysts,

homogeneons as well as heterogeneous, all show cleavage of 1,2:5,6-di-0-

isopropylidene-D-mannitol (2a) to 2,3-0-isopropylidene-D(R)-glyceric acid (3a)

in moderate to good yield (55 - 98 % ). Probably the same reactive intermediale

is formed in the homogeneons reactions, which show similar results ( entries 1 and

2). The Ru-Dowex catalyst shows a rather low selectivity and part of the

ruthenium dissolves (10- 20 %) during the reaction, which make this catalyst not

suitable for cleavage. The Ru/C catalyst shows high selectivety and activity,

although more NaOO is consumed than in the homogeneons reaction. Selectivity

and reactivity hardly decrease when the catalyst is reused, which makes this

catalyst a very interesting one for the cleavage reaction. However, immediate

ftltration of areaction mixture containing Ru/C and an excess of NaOO, yields

a Ru-containing ftltrate that reacts forther with some loss of selectivity and

reactivity. When an equimolar amount of RuC13 and active carbon are used,

similar results are obtained. This implies that Ru-metal dissolves during the

reaction under the influence of NaOCl and precipitates on carbon at the end of the

reaction, presumably as insoluble Ru02 and that the supposed heterogeneons

reaction is actually a homogeneons one 1s. The role of active carbon, which

enhances the reaction rate, is not very clear untill now. Abovementioned results


with the Ru/C catalyst are not unexpected when taking into account, the use of

NaOCl-solutions for cleaning glass-work polluted with ruthenium76 and for

extraction of ruthenium out of metal samples 77•

Table 3.4: Alternative Ru-catalysts and primary oxit:kmts for the cleavage of 2a•

1 NaOCI (4) 30 RuQ,.~O 97

2 NaOCI (4) 30 TPAP" 93

3 NaOCI (4.5) 120 Ru-Dowex W50-X8d 70

4 NaOCI (4.5) < 30 5% Rute 98

5 NaOCI (4.5) < 30 Pb2[Ru133Pb0•67 "106.s" 95

6 NaOCI (4.5) « 30 5% Pb2[RU133Pb0•67 "10,..,/C' 55

7 NaOCI (8•) lOOS 54•

8 02h 1200 Pb2[Ru133Pb0•67 "10,.s"

9 NMO (9.5) 1200 TPAP" 16

10 tBHP (5) 3oot RuQ,.xH20

11 ~02 (5) 1150' RuQ,.~O 2

12 Ac00H(4f 300 RuQ,.~O

13 Na:zS20s (5) 1700 RuQ,.~O

14 Nal04 200 RuQ,.~O 99

"Reactions carried out at room temperatule and pH = 8 (0.2 M la in H20) using 0.025 equilvalents of catalyst per mole 4a. bYie1d in solutions determined by HPLe (as described in Cbapter 2). "Tetrapropyl-ammonium perruthenate (TP AP)'4d. dPrepared by stirring a mixture ofRuQ,.~O and Dowex 50W-X8 durlog 16 b. "Prepared as described by Horowitz78

• 'Prepared as described by Horowitz75 in tbe presence of tbe calculated amount of active carbon. SReaction temperatule 60 oe and conversion is 54 %. hearried out at pH = 11 and pH > 13. 1Carried out under retlux in DeE with lb as substrate.lR.eaction temperatule 40 oe. tearried out at pH= 5.5.

Reactions with the pyrochlore oxide catalyst (Pb2[Ru1.33Pb0.670'*]06.5) on the contrary are truly heterogeneous. Ruthenium does not dissolve during the reaction and reuse of the catalyst is not accompanied by a deercase in selectivity or activity. The pyrochlore oxide catalyst is slightly more active than the

3. Catalytic oxidative clet1Vage of D-mannitol derivatives 63

homogeneous catalyst, althougil most probably only the surface of the catalyst

participates in the reaction. To test this assumption, the catalyst was prepared in

the presence of such a quantity of active carbon, that a 5% pytochlore oxide/C

catalyst would result, hoping that at the same time a finely divided ruthenium

pyrochlore oxide catalyst would develop. Indeed, the reactivity of the catalyst

increased enonnously, but unfortunately the selectivity decreased. The exact nature

of the catalyst is unknown however, and no effort bas been made to characterize

this catalyst. In view of the increased activity of this pyrochlore oxide catalyst, it

possibly can replace the conventional pyrochlore oxide catalysts. By fmely

dividing the pyrochlore oxide on active carbon the catalyst can be used more

efficiently.

Other oxidants in combination with RuCl3 either were unable to cleave 2a

or did not cleave 2a in good yield, except, of course, Nal04• The latter cleaves

1,2:5,6-di-0-isopropylidene-D-mannitol (2a) into 2,3-0-isopropylidene-D(R)

glyceraldehyde (4a), but also generates Ru04 in the presence ofRu03, in the same

way as does Naoa, thus explaining why the cortesponding acid (3a) is fonned.

The other oxidants are not known to fonn Ru(VTII)04, but they oxidize ruthenium

to rutheniumcompoundsof lower valency (V- Vll)7.w.79, which is probably the

reason fortheir unability to cleave 2a. A1so the pyrochlore catalyst, in combination

with 0 2 reported to cleave e.g. cyclohexanediol to adipic acid in alkaline

medium47, did not cleave la with 0 2•

In conclusion, the oxidative cleavage of 2a is best perfonned with NaOCl

as primary oxidant and with the aid of a homogeneons RuCl3-catalyst or a

heterogeneous pyrochlore oxide catalyst. Both catalysts very selectively produce

2,3-0-isopropylidene-D(R)-glyceric acid (2a) under mild reaction conditions at a

high reaction rate.

2. Attempts to stop the cleavage of diacetonide 2a at the aldehyde stage

and cleavage of 1,2:5,6-di-0-cyclohexylidene-D-mallllitol (lb). Because of the

observation of small amounts of 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a)

in the cleavage reaction at low conversion (see Fig. 3.3 and 3.4), it is assumed that 4a is an intennediate in the cleavage reaction at which the reaction possibly can

be stopped. However, it is reported that Ru04 cannot nonnally be used for the

oxidation of primary alcohols to aldehydes; with this oxidant further oxidation of


the incipient aldehyde to the carboxylic acid is rapid80• In order to stop the

reaction at the aldehyde stage different approaches were used. The cleavage was

canied out in either a two phase system or in DCM, using stoichiometrie amounts

of •organic• hypochlorite. The RuC13~catalyzed cleavage of 2a in DCM /l:lzO with

NaOCl using tetrabutyl ammonium hydrogen sulfate as PTC, gives protected acid

(3a) in low yield. The ruthenium catalyst precipitates during the reaction. probably

together with the reaction product (see later), and the appearance of aldehyde (4a)

was not observed. Reaction with Ca(OO)z as the primary oxidant in the presence

of traces water (see also Table 3.4), did not induce significant cleavage. Also

when 'organic' hypochlorite was used, HOCl in Et0Ac81 or t-BuOCl in DCE82,

the desired reaction was not observed.

Finally, attempts to stop the reaction at the aldehyde stage were canied out

with 1,2;5,6-di-0-cyclohexylidene-D-mannitol (2b) as starring material. Due to the

very low solubility of 2,3-0-cyclohexylidene-D(R)-glyceraldehyde (4b) in water,

it might be easier to stop the reaction at the aldehyde stage than with the

corresponding isopropylidene derivative (2a) as substrate. However, when the

reaction is carried out in a two phase system again a dark coloured ruthenium

containing precipitate is observed and the reaction stops at low conversion. This

problem of catalyst precipitation can be solved by addition of ~CN as co

solvent to the traditional DCM I llzO phases. In this way sodium 2,3-0-

cyclohexylidene~D(R~glycerate (sodium salt of 3b) can be isolated in 64 % yield,

using 6 equivalents of NaOCl per mole substrate. The reacrion-pH was adjusted

to pH = 10 in order to achleve a higher reaction rate. The corresponding

glyceraldehyde (4b) is not observed. Lower valent ruthenium carboxylate

complexes might be responsible for the loss of catalyst activity, which was first

reported by Cartsen and co-workers83• They noted that difficult cases of

ruthenium catalyzed reactions shared a common feature; carboxylic acids were

either present or being generated during the course of the oxidation. By addition

of CH3CN dissolution of the precipitated ruthenium catalyst and restoration of full

catalytic activity was observed. The choice of CH3CN was dictated by rudimentary

considerations of coordination chemistry suggesting the use of a good ligand for

the lower valent ruthenium species. Nitriles are unique in their ability to resist

oxidation and yet retain good ligating ability towards lower valent transition

metals. However, CH3CN and water alone are not effective, but the presence of

a third solvent, DCM or CH03, is essential.

In conclusion, we were not able to fmd a ruthenium~hypochlorite reagent


that was able to effect selective oxidation of 2a to the aldehyde without substantial

funher oxidation.

3. Mechanistic study of the ruthenium-catalyzed oxidative cleavage of

2a to 3a. Catalytic oxidative cleavage of a-diols by Nal04 and Pb(0Ac)4 is

generally accepted to proceed via a cyclic oxidant-diol complex, which

decomposes into the corresponding aldehydesM4• When it is not possible to fonn

such a cyclic complex Nal04 does not cleave the diol whereas Pb(0Ac)4 is

capable to cleave the diol via an acyclic mechanism. By analogy to the reactions

with Nal04 and Pb(OAc)4 it is assumed that glycol cleavage reactions with Ru04

also proceed via a cyclic complex4tl.85• However, not much research bas been

devoted to the mechanistic aspects of a-glycol cleavage with Ru04 or Ru

catalyzed systems. Moreover, whether the pedodate reaction proceeds indeed via

a cyclic intennediate seems to be doubtfu186• Our first interest was to identify the

exact nature of the active species inducing cleavage of 2. The second interest was

to clarify the reaction mechanism i.e. whether a cyclic or acyclic complex

intervenes and which intermediatea are essential for the course of the reaction.

With the aid of the Pourbaix-diagram of ruthenium87 · and the more simple,

experimentally-derived, potential- pH diagram of P. Eichner88 we can conclude

that RuO 4 is the most stabie ruthenium species under the conditions used in our

cleavage reactions (NaOCl as primary oxidant gives an equilibrium potendal of

1.24 V at pH= 8). To check this experimentally, UV-spectroscopy is very

suitable. The ruthenium species Ru(VIll), Ru(Vll) and Ru(VI) show a very

characteristic UV -absorption spectrum, which allows the identification of the

nature and measurement of the quantity of the ruthenium species in solution89•

Unfortunately, the high reactivity of the catalytic system prevented the

identification of the active ruthenium species under standard reaction conditions.

The reaction is too fast to generare a UV -absorption spectrum at a constant

reaction-pH. However, when workingin a diluted reaction mixture and applying

an excess of NaOCl, the 1JV -absorption can be measured at constant pH and under

these conditions only Ru04 was observed. The diluted reaction mixture is brightly

yellow, which already indicates the presence of Ru(VIll)O 4, whereas the standard

reaction mixture is darlc coloured, which indicates the presence of lower valent

Ru-species. In the diluted reaction mixture NaOCl is present in excess in contrast

Carbohydrate-based syntheses of Crchirons

to the standard reaction conditions. In the latter case the amount of NaOCl

available for the cleavage reaction is limited due to the rapid formation of acid,

which makes pH-adjustment at a constant level difficult. For that reason a limited

amount of NaOCl is present, explaining the presence of lower valent ruthenium

species and the dark coloor of the reaction mixture. We, therefore, conclude that

the active species in the reaction mixture bas to be Ru04• This is also supported

by the formation of a dark coloured, ruthenium containing precipitate at the neck

of the reactor. Ru04 is a volatile, low melting solid (mp 25.5 °C)90 that easily

sublimes at room temperature and will precipitate in a reduced fonn on solid

surf aces.

The rate of the cleavage reaction at defined acidity can be expressed as in Equation 3.1.

-<l[diol(la)]/dt = k. [la]'" • [RuOJ1 • [NaOO]z [3.1]

When NaOO is in excess, Equation 3.1 can be written as Equation 3.2.

[3.2]

To detennine the order of the reaction with respect to diol and catalyst, kinetic

experiments were carried out at 15 oe (to limit sublimation of Ru04) and pH = 8

in a diluted reaction mixture (to limit the reaction rate). The reaction rate is

measured on the basis of NaOH-consumption. This consumption corresponds to

the arnount of product (3a) formed and to half of the amount of reacted substrate

(2a), which was verified by HPLC-analysis. No aldehyde (4a) was observed. To

start the reaction a frxed portion of NaOCl (pH = 8) was added to a mixture

containing substrate and catalyst. The initial reaction rates are used to detennine

the order of the reaction. A plot of the concentration 2a versus the initial reaction

rate, at a constant catalyst concentration, and a plot of the concentration of RuC13

versus the initial reaction rate, with a constant substrate concentration, is given in

Figures 3.5 and 3.6, respectively. The plots are both linear showing the order in

la as well as RuCl3 to he unity. The reaction rate can than be expressed as in

Equation 3.3.

-d[diol(la)]/dt = k"... • [la] .. [Ru03] [3.3]

3. Catalytic oxidative cleavage of D·mannitol derivatives 67

Q ~

!l ä 0.50 E 0.50

' ' Cl «< N N

0 OAO ö 0.40

! ! .. 03:1 .. 0.30 ... lil ""M .,,

"'• "lil "lil 11 0.20 l'l 0.20 0 0 :; :;; (I ()

Cl 0.10 Cl 0.10 .. " " ... ] ë ... :;:;

0.05 0.20 0.25 :§ 0.20 0.<!0 O.fiO o.ao 1.00 ] O.tO 0.15 E-n E-21

Coneentratlon 2a (mol/I) Coneentratlon RuCI, (mol/I)

Fipre 3.5: Plot of the concentranon of 2a versus the initial reaction rate. Conditions: [RuCIJ = 1.2 mmolll, [NaOCI} = 01J91 moUI, pH= 8, T = l5°C

Figure 3.6: Plot of the concentranon of RuC/3

versus the initia/ reaction rate. Conditions: [26} = 0.045 moUI, [NaOCl} = 0.091 mol/I, pH = 8, T = l5°C

1he initial.reaction rates of the Ru/C, Ru03 - active carbon, pyrochlore oxide and

pyroclûore oxide/C catalysts were also measured and compared with those of the

homogeneons reaction (see Table 3.5) and the activation energies for the reaction

of 2a with Ru03, Ru/C and the pyroclûore oxide catalyst were calculated (see Fig. 3.7 and Table 3.5) on the basis of initial reaction rates at different temperatures.

The results reveal that the Ru/C catalyst or the RuO~ - active carbon system are

more active than the homogeneons catalyst, whereas the pyroclûore oxide catalyst

shows about the same activity under standard reaction conditions. On the other

hand, when the pyroclûore oxide catalyst was more fmely divided (pyroclûore

oxide/C), the reaction rate was strongly enhanced. This may also point to the

occurence of diffusion limitation in reactions with the pyroclûore oxide catalyst.

Moreover, the activation energies for the Ru/C and pyroclûore catalyzed reactions

are lower than that in the homogeneons reaction. These results prove that the

presence of active carbon is benificial and that ruthenium in the pyroclûore oxide

catalyst bas a favourable environment for a facile cleavage of la.

Based on the above results we conclude that the active species is

homogeneons Ru04 that reacts with diol 2a in the rate determining step, to afford

intermediate aldehyde 4a which is precursor for the acid 3a and Ru02 as the final

products. In order to test whether the reaction proceeds via a cyclic or acyclic Ru

diol complex, we compared the initial reaction rates of the cleavage of trans- and

cis-1,2-cyclohexanediol. Studies of the oxidative cleavage by lead tetraacetate'11,

68

Table 3.5: Initia/ reaction rates and Ea.obl

of different Ru-catalysts-

Ru~ 0.1475 55.8

5% Ru/C 0.3679 37.1

Ru~. C!' 0.2976

pyrocblore oxide 0.1492 44.8

pyrocblore oxide/C )) 0.4·

"Reactioos carried out at pH = 8 and l5°C with a substrate concentration of 0.0456 mol/I and a catalyst concenlralion of 1.2 mmol/1. b Active carbon. "Too fast for pH-adjustment at a constant value.


" -4.00 .. .. ..

1:: -5.20

0 :: " .. 4J .. ." 4J > .. 4J

"' .t:J ~ 1:: - -10.00 L....-_....__ _ _.__ _ __._ _ __._ _ __,

0.30 o.Jl 0.32 0.33 0.34 o.J5 E-21

1/T (1/K)

Figure 3.7: Plot for calculation of E. for different Ru-catalysts (+:RuC/3, A:5%Ru!C, o:pyrochlore oxide). Conditions: [2a] = 0.046 molll, [RuCIJ = 1.2 mmol/1, [NaOCI] = 0.091 mol/I

periodate92, chromic acid93 and vanadium pentoxide94 show that the cis isomer

is oxidized up to about 30 times faster than the trans isomer (23, 4 or 30

respectively (depending on the reaction conditions), 6 and 3.3 times as fast). The

higher rate observed for cis-I ,2-cyclohexanediol as compared with the trans-isomer

was fust attributed to differences in the ability of the isomers to form a chelated

intermediate91•

However, recent Chem-X molecular grapbics comparisons of cis- and trans

I ,2-diol substrates coordinated to a metal atom, show the 0 - 0 distance in the cis

(2.85 Á) and trans (2.81 Á) forms of cyclohexanediol to be practically the

same95• The differences in reaction rates are explained by steric interactions that

attribute to a faster rate of decomposition of the cis isomer transition state. The

trans-1,2-diol is seen to project the cyclohexane ring away from the coordinated

metal atom whereas the cis-1 ,2-diol causes the cyclohexane ring to project

perpendicular to the trans-I ,2-cyclohexanediol conformation. This perpendicular

C6-ring of the cis isomer produces unfavourable steric interactions with the metal.

Buisf12" calculated much earlier the inter-oxygen distances for cis- and trans-I ,2-

cyclohexanediol and found both to be about 2.86 Á. He also attributed the faster

cleavage of the cis- than of the trans-diol not to the ease of intermediate-complex

formation, but to the rapid breakdown of this complex. This part of Buist's report,


however, remained unnoticed and the explanation initially given by Criegee91 was

generally accepted3•85 until recently'. However, the differences in reaction rates of

cis- and trans-I ,2-cyclohexanediol can still be explained by the formation of a

cyclic oxidant - diol complex. Therefore, the initial reaction rates of the cleavage

of trans-1 ,2-cyclohexanediol and a mixture of trans- and cis-1 ,2-cyclohexanediol

have been measured under standani reaction conditions, whereby the initial

reaction rate in the cleavage of cis-1,2-cyclohexanediol was a factor 2.7 higher

than that of the trans isomer. These results suggest that the reaction path rather

proceeds via a cyclic Ru-diol intermediate than via an acyclic one. The 3,4-threo

configuration of protected D-mannitol (la) allows the easy formation of a cyclic

complex with Ru04, partly because the threo configuration can be compared with

a cis-diol and partly because an open chain molecule is involved. It will, therefore,

presumably be cleaved via the preferred cyclic intermediate to form aldehyde 4a (see Fig. 3.8).

However, although our results favour a cyclic reaction intermediate, the

trans-cis effect is not large and it cannot be excluded totally that part of the diol

is cleaved via an acyclic reaction intermediate. By oxidation of 2a to the a

hydroxy ketone ( 48) and subsequent oxidative cleavage, one molecule of aldehyde

(4a) and one molecule of acid (3a) should be formed (see Fig. 3.9), which also

could explain the presence of the aldehyde (4a) as a reaction intermediate.

Formation of an intermediale diketone of 2a is excluded since cleavage thereof

only gives rise to the acid (3a). Formation of a-hydroxy ketone (48) would then

be the rate determining step. Possible intermediate formation of a hydroxy ketone

was tested by oxidizing butane-2,3-diol, acetoine and butane-2,3-dione with NaOCl

and Ru03-catalysis under standard reaction conditions. However, the a-hydroxy

R R 0

~OH - H20 ~--~U-0 - Ru03 OYH + Ru04 ___.. ___.. 2

OH o<::i 11 R R R 0

2a Ru-diol complex 4a

Figure 3.8: Preferred reaction mechanism of tlle cleavage of protected D-mannitol (2a) to protected D(R)-glyceraldehyde (4a).


R R R fo ~: ~OH H OH 11 - H20 + Ru04 ---tllo-

H 0 ("Ru=O ____,..

OH - Ru03

R rl R R OH

2a 48

R R HO 0

~:H +Ru04 ~o-\( -Ru~ OYH OYOH ____,.. 0 1/ ~ 0 ____,..

+

0 R R

R R

48 .... 3a

Figure 3.9: Possible cleavage of protected D-mannitol (2aJ via the corresponding a.-hydroxy ketone (48)

ketone and diketone were oxidized 2.8 and 13 times faster, respectively, than the

corresponding diol. This did not allow any deflnite condusion to be drawn with

regard to the mechanism.

In the Ru03-catalyzed oxidative cleavage of cyclohexene, with less than

one equivalent of NaOCl per mole substrate, Wolfeso observed the formation of

both, adipaldehyde and adipic acid, thereby suggesting that the cleavage of the

double bond can proceed via a cyclic mechanism. On the other hand, he reported

for the cleavage of trans-cyclohexane-1,2-diol with less than one equivalent of

NaOO per mole substrate the formation of 2-hydroxycyclohexanone as the first

reaction product, thereby suggesting that cleavage of trans diol proceeds via an

acyclic mechanism. However, the a.-hydroxy ketone of protected D-mannitol ( 48)

was never observed in our reactions, although very small portions of NaOCl were

added, and also the results with the trans- and cis-1 ,2-cyclohexanediol favour the


reaction path proceeding via a cyclic Ru-diol complex (see Fig. 3.8).

In addition to Ru04 otber oxidants present in the reaction mixture can, in

principle, oxidize intennediate aldehyde 4a to tbe corresponding acid 3a. The fust

one is the primary oxidant NaOCI, from which it is already known that it oxidizes

aldehydes to acids, e.g. D-glucose (19) to D-gluconic acid (20) at pH= 1196•

Secondly, the ruthenate(VI) formed in the cleavage reaction can oxidize aldehyde

to acid. However, it is not stabie onder the reaction conditions37 and can

disproportionate or be reoxidized by NaOCl to Ru04• When ruthenate (Ru(VI))

solutions, which are only stabie at pH > 12, are acidified, different ruthenium

species are formed according Equations 3.4- 3.837•88

.97

•

3 RuO/· + 2 f110 -+ 2 Ru04" + Ru02J.. + 4 on· [3.5]

3 Ru04" + 3 W -+ 2 Ru04 + Ru(V)Ox.-. [3.7]

Solutions of pelTUthenate (Ru(VTI)) are more stabie onder the reaction conditions

than the ruthenate solutions and can also oxidize an aldehyde to the corresponding

acid, but in the presence of NaOO pelTUthenate (Ru(Vll)) can also be oxidized

forther to Ru04 or disproportionate toother ruthenium species (see Eq. 3.7 and

3.8). In order to determine the nature of the active species, aldehyde 4a bas been

oxidized using abovementioned reagents and the reaction rates have been

compared with the oxidation of 4a with NaOCI and Ru03 in catalytic amoonts.

Ru(Vlll)04, Ru(Vll)04 and Ru(VI)O/" were synthesizedll9b.98 and used in

stoichiometrie amounts. Unfortunately, it was not possible to measure the re action

rate accurately. Adjust4tg the pH of the oxidant solutions to' pH = 8 causes

formation of a dark coloured ruthenium containing precipitate, decreasing the

actual oxidant concentration. Therefore, the oxidants were not adjusted at the

reaction pH, but were added in small portions and the reaction rates were

compared qualitatively. The results are summarized in Table 3.6.


Table 3.6: Oxidation of 2,3-0-isopropylidene-D(R)-glyceraldehyde (4a} using different ~xidizing

1 Naoa, RuCI,d 2.5 times as fast 92

2 Ru04 sameorder 96

3 RuO,; sameorder 93

4 Ru042" slow 42

5 Naoa slow 54

"Reactions carried out at 15 °C and pH = 8 (0.00456 M 4a in ~0). "Reactioo rates compared with the catalytic oxidative cleavage of la using NaOO and Ruet,. "Yield in solutioo detennined by HPLC (as described in Cbapter 2). "Used in catalytic amooots.

From these results a few conclusions can he drawn. Oxidation of aldehyde

(4a) to acid (Ja) is not rate limiting (entry 1) and oxidation with NaOO alone

(entry 5) and Ru(VI)O/" (entry 4) proceeds at a low reaction rate and acid (Ja)

is formed in relatively low yield. The oxidizing agent therefore has to he

Ru(Vlll)04 or Ru(Vll)4" (entries 2 and 3). Ru(Vll)04·, however, is not very stabie

at the applied reaction conditions (see above) and will disproportionate according

to Equations 3.7 and 3.8. lt is, therefore, assumed that Ru(Vlli)04 also oxidizes

intermediate aldehyde (4a) to the corresponding acid (Ja). The completereaction

mechanism is depicted in Figure 3.10.

Conceming the oxidative cleavage of trans-1 ,2-cyclohexanediol with a

pyrochlore oxide catalyst two different mechanisms, involving a cyclic reaction

intermediate, are reported. Horowitz et al.48 suggest in an electrocatalytic reaction

with Pb- or Bi-Ru-pyrochlore oxide catalysts, the formation of a Ru-moiety on the

surface of the catalyst similar to Ru04• Pelthouse and cowoik:ers95 on the other

hand, suggest for the cleavage of trans-I ,2-cyclohexanediol over a Pb-Ru

pyrochlore oxide catalyst with 0 2 as the primary oxidant, the formation of a cyclic

Pb-diol complex. The ruthenium sites are thought to reoxidize the catalyst through

electron transfer to 0 2• These suggestions are among other things based on the

observation that the specific activity of Pb2+xR~.,.Ocs.s oxides increases approximately linearly with the expected increase in Pb(IV) present in the bulk

structure and in spite of the decreased surface area at higher Pb(IV) levels. Also


R R 0

~OH - 820 r~=O - Ruo3 OYH + Ru04 --+ --+ 2 OH o<:;i 11 R

R R 0

2a Ru-diol comple:J!i 4a

OYH +Ru04 OYOH and Ru03 + NaOCl --+ -Ru03

__.. Ru04 + NaCl R R

4a 3a

Figure 3.10: Proposed reaction mechonism for the Ru-catalyzed oxidative cleavage of 1.2:5 ,6-di-0-isopropylipene-D-mannitol (la; with NaOCI

cis-1,2-cyclohexanediol is oxidized aJmost two times faster than the trans isomer,

which is in support of the formation of a cyclic complex. In our reactions,

however, NaOa is used as oxidizing agent, whereas 0 2 is unable to cleave Za (see

Table 3.4), while all ruthenium-containing catalysts are able to cleave Za with

Naoa as the primary oxidant whereas Pb(N03h gives very poor results (see page

58). We, therefore, conclude that ruthenium, in the form of a 'RuO.,.-surface'

species, rather than lead complexes with the diol. From the results obtained with

pyrochlore oxide on carbon (see Table 3.4) we conclude that the reaction proceeds

at the surface of the catalyst, in contrast to the fmdings of Feithouse and

coworkers95 in the oxidation with 0 2 as primary oxidant. However, a more detailed

study to obtain better founded arguments to support the proposed mechanism is

desirable. One possibility is to test and compare other pyrochlore catálysts not

containing both Pb and Ru. This can give rise to other complications, which have

tobetaken into account. For example the replacement of Pb by Bi, implies at the

same time formation of a catalyst with a higher surface are~s. But since also Bi

is known to cleave a-diols, the conclusions drawn from these experiments must

be interpreted carefully.


J.S Conelusions

A large number of oxidizing systems, reported to cleave simple a-diols, is

not able to cleave 1,2:5,6-protected D-mannitol (2a,b). This is partly due to the

limited pH-range in which the cleavage reacrions have to be canied out in order

to avoid deprotection, racemization and polymerization of the reaction products

and/or substrates. Most of the systems tested leave the substrates unchanged or

cause deprotection, whereafter the D-mannitol (1) formed is usually further

degraded to lower sugar acids and carbon dioxide. Only NaOCl, withor without

Pb(N03h-, Fe2(S04k or RuC13-catalysis, is able to cleave protected D-mannitol

(2). However, only the RuC13-catalyzed reaction is both, fast and selective,

whereas the other reacrions proceed with low selectivities and at low reaction

rates. In the RuC13-catalyzed cleavage of 2a with 4 equivalents of NaOCI per mole

substrate at pH = 8 and room temperature, 95 % of the theoretica! amount of

sodium 2,3-0-isopropylidene-D(R)-glycerate (sodium salt of Ja) can be isolated

after 30 min of reaction. Cleavage of the corresponding cyclohexylidene derivative

(2b) can be effected in a two phase system (DCM I CH3CN I HzO) at pH= 10

and room temperature with 6 equivalents of NaOCl per mole substrate, yielding

64 % of sodium 2,3-0-cyclohexylidene-D(R)-glycerate (sodium salt of 2b ). The

use of C~CN as third solvent is necessary to prevent precipitation of the catalyst.

Other ruthenium catalysts that cleave 2a with NaOCI as primary oxidant

are e.g. TPAP74d, Ru-Dowex, Ru/C, Pb:z[Ru1•33Pbom ""]0~7' (pyrochlore oxide).

However, the Ru-Dowex catalyzed reaction proceeds with lower selectivities and

during the reaction, part of the ruthenium dissolves. The Ru/C catalyst is relatively

selective and fast, but addition of NaOCl dissolves Ru as expected and addition

of active carbon to the homogeneons system gives the same results. The supposed

heterogeneously catalyzed reaction is actually homogeneous, whereby the active

carbon enhances the reaction rate. On the contrary, the cleavage of 2a with the

pyrochlore catalyst, is truly heterogeneons and also yields Ja in high yield at a

high reaction rate. When this catalyst is precipitated on active carbon, the reaction

rate increases trernendously. Presumably, the reaction proceeds at the surface of

the catalyst, and the surface area is increased considerably when the catalyst is

precipitated on active carbon.

Both, homogeneons and heterogeneons Ru-catalysts cleave protected D

mannitol (2a) when NaOCl is used as the primary oxidant. Other oxidants, e.g. 0 2,

Hz02, tBHP, NazS20 8, are not active. In the RuC13-catalyzed cleavage of 2a with


Naoa as the primary oxidant, intennediate 2,3-0-isopropylidene-D(R)

glyceraldehyde (4a) is observed in small quantities. However, the cleavage

reaction could not be stopped at the aldehyde stage.

The homogeneously catalyzed cleavage is fJrSt order with respect to

substrate and catalyst and B..oo. amounts to 55.8 kJ/mol. The active oxidant is

Ru04, which complexes with the a-diol lunetion and subsequently cleaves the C-C

bond under formation of Ru03 and two molecules of aldehyde (4a). Finally,

aldehyde (4a) is further oxidized by Ru04 to the corresponding acid (Ja).

J.6 Experimental

General methods. 1H NMR spectra were recorded on a Hitachi Perkin

Elmer R 24B spectrometer (60 MHz) (Me4Si intemal standard). Optical rotations

were detennined on an Optical Activity AA-10 polarimeter.

Sodium 2,J-O-Isopropylidene·D(R)-glycerate (sodium salt of Ja). To a

well stirred solution of 1,2:5,6-di-0-isopropylidene-D-mannitol (2a, 22.8 g, 0.087

mol) and RuCl3.x~O (0.54 g, 0.002 mol) in water (400 mL, pH = 8, room

temperature), sodium hypochlorite (13 wt% in water, 230 mL, 0.4 mol) was added

dropwise over a period of 0.5 h. The pH was maintained at 8 by adding a 5 M

NaOH-solution. The reaction mixture wasthen concentrated in vacuo at 60 °C to

a solid residue, which was taken up in hot ethanol. Concentration of the fdtrate

gave the sodium salt of 3a (27.7 g, 0.165 mol, 95 %). 1H-NMR (020): ö 1.71 (s,

3H, C(CH3) 2), 1.76 (s, 3H, C(CH3) 2), 3.94.9 (m, 3H, H-2, H-3); [a]020 +32.6°

(c 0.98, ~0), lit.99 [a]020 = 30.1° (c 1.03, ~0), lit.22 [a]0

20 = 23.5° (c 2, H20).

Sodium 2,3·0-Cyclohexylidene-D(R)-glycerate (sodium salt of Jb). To

a well stirred solution of 1,2:5,6-di-0-cyclohexylidene-D-mannitol (2b, 10.3 g,

0.03 mol) in water (40 mL, pH = 10), CH3CN (30 mL) and DCE (30 mL) at room

temperature RuC13.x~O (0.41 g, 1.5 mmol) was added. In the following 3 h

NaOO (13 wt%, 100 mL, 0.176 mol) was added in 4 portions. The pH was

maintained at 10 by adding a 5 M NaOH-solution. After 4 h reaction the water

layer was separated from the organic layer and wasbed with DCM. The water

layer was then concentrated in vacuo at 60 oe to a solid residue, which was taken

up in hot ethanol. Concentration of the filtrate gave the sodium salt of 3b (8.0 g,

76 Carbohydrate-based syntheses of Crchirona

0.038 mol, 64 %). 1H-NMR (D20): 61.5 (m, 10H, C(C~)5), 3.4-4.8 (m, 3H, H-

2, H-3); [a]020 +34° (c 1, ~0).

Measurement of tbe Initial Resetion Rate at Standard Readion

Conditions. To a solution of substrate (7.5 nnnol) and catalyst (0.19 nnnol) in ~0 (150 mL, T = 15 °C, pH = 8) sodium bypocblorite (pH = 8, 15 mL,

15 nnnol, 7.5 wt% )100 is added. The pH is controlled by automatic titration witb

a lM NaOH-solution. The consumption of alkali is recorded as function of tbe

time.

3. 7 Keferences and notes

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3. Catalytic oxidative c/eavoge of D-mannitol derivatives 77

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Chem. Soc. 1975, 97, 2546. (40) Nevell, T. P.; Singb, 0. P. Textile Res. J. 1986, 56, 270. (41) (a) Wbisder, R. L.; Linke, E. G.; Kazeniac, S.J. Am. Chem. Soc. 1956, 78, 4707. (b)

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3. Catalytic o.xidatlve cleavage of D-mannitol derivatives 79

(86) de Wit, D., submitted for pubHeation in Carbohydr. Res. 1991. (87) Pourbaix, M.; de Zoubov, N.; van Muylder, J. Atlas d'équilibr~s ilectrochimique 1963,

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393,421. (96) Whistler, R. L.; Schweiger, R. J. Am. Chem. Soc. 1959, 5190. (97) Nowogrocki, G.; Tridot, G. Mem. Pres. Soc. Chim. 1964, 684, 688. (98) Larsen, R.P.; Ross, L E. Anal. Chem.1959, 31, 176. (99) Tanaka, A.; Yamashita, K. Agric. Biol. Chem. 1980, 44, 199. (100) By adjusting the pH of a commercia113 wt% Naoa solurioo with conc. Ha,~ escapes

from the mixture. Therefore the amount of NaOCJJHoa is detemûned iodometrically and the calculated amount of water is added to obtain a 7.5 wt% NaOC1/HOO solutioo.

4. Synthesia ofCrcllirona atarting from L-aacorbic and D-iaoaacorbic acida 81

'k':'~'-~l:~~~~~~~:~~~i~i~~m···· ·· ·········.·.···<•••·• ~t\$CQ~Utlç~nn;ts9J\SÇQJ{PI~ .4.tms······

4.1 Abstract

Routes are described for the preparation of enantiomerically pure 2,3-0-isopropylidene-L(S)- and D(R)-glyceraldehyde, and 2,3-0-cyclohexylidene-L(S)

and D(R)-glyceric acid derivatives in good yield. Consecutive proteetion of L

ascorbic and D-isoascorbic acids in almost quantitative yield and ~02-cleavage afforded 3.4-0-isopropylidene-L-threonic and D-erythronic acids and the corresponding cyclohexylidene derivatives. Subsequent NaOCl-mediated decarboxylation of these protected tetronic acids at pH= 5.5 in a two phase

system gave rise to the corresponding glyceraldehydes in moderate yield (36 -

74 % ). In contrast, RuC13-catalyzed oxidation with NaOO at pH = 8 led to the

corresponding glyceric acids in high yields (93 - 99 % ).

4.2 Introduetion

Although the chemistry of L-ascorbic acid (6, vitamin C) has been thoroughly studied\ that of its C-5-epirner, D-isoascorbic acid (16, isovitamin C or D-araboascorbic acid or D-erythorbic acid), remains relatively unexplored and has only recently found application as an intermediale in organic synthesis2

• The

presence oftwo asymmetrie eentres in L-ascorbic (6) and D-isoascorbic (16) acids

coupled with their low price and ready availability makes them both valuable

starting materials for the. synthesis of enantiomerically pure compounds.

For the preparation of protected D(R)-glyceraldehydes (4), cleavage of

proteeted D-mannitol (2) by lead tetraacetate3 or sodium periodate4 has been used most frequently. The L(S)-enantiomer (11), in contrast, bas commonly been made


by lead tetraacetate5 or sodium periodate6 oxidation of protected L-ascorbic acid

(7). By analogy, protected D-isoascorbic acid (17) would be expected to yield

protected D(R)-glyceraldehyde (4). More recently electrochemical oxidation2s of

D-isoascorbic acid (16) bas been used for the synthesis of the D(R)-enantiomer

(4).

D-Mannitol (1) is the preferred starting material for the synthesis of~

chirons by yielding, without loss of carbons, two identical ebiral C3-derivatives

(see Fig. 4.1 ). The cleavage of protected L-ascorbic acid (7) with lead tetraacetate5

or sodium periodate6 is more complex and affords just one molecule of the ~

chiron. In order to indoce cleavage, the carbon-carbon double bond of the

protected L-ascorbic acid (7) first bas to be reduced whereafter the proteeled L(S)

glyceraldehyde (11) is fonned by lead tetraacelate or sodium perioclate cleavage

of the intermediate tetrol. However, for the synthesis of protected L(S)

glyceraldehyde (11), this complex route is preferred because of the inaccessibility

of L-mannitol (L-enantiomer of 2). Both methods need, however, expensive and

environmentally unacceptable oxidizing agents and are therefore not attractive for

industrial application.

Recently, Mizuno7 patented a less expensive route for the preparation of

2,3-0-isopropylidene-L(S)-glyceraldehyde (lla) starting from 5,6-0-

isopropylidene-L-ascorbic acid (17a) and using ~02 and NaOCI as oxidizing

H3CXO H3C 0

HO

HO

HO acetone HO Pb (0AC)4

OH

OH

OH

D-mannitol

(1)

...

1,2:5,6-di-o-isopro

pylidene-D-mannitol

(2a)

...

2,3-o-isopropyli

dene-D(R)-gl yceral

dehyde (4a)

Figure 4.1: Synthesis of two identical Crcllirons, starting from D-mannitol (1)

4. Synthesis of C3-chirons starring from L·ascorbic and D-isoascorbic acids 83

agents (see Fig. 4.2). Also the electrochemical oxidation of the tetronic acids

(9a,b; 18a,b) obtained after ~02-oxidation of protected L-ascorbic (7a,b) and D

isoascorbic acids (17a,b) to the corresponding glyceraldehyde derlvatives (lla,b

and 4a,b, respectively), may be interesting for industrial application.

~ ~[x~ lox~ Hz~ NaOCl 3 0 CH3 0 CH3

0 ____....

HO ____....

CaC03 H 0 HO OH HO 0

5,6-o-isopropy- 3,4-0-isopropy- 2,3-0-isopropy-

lidene-L-ascorbic lidene-L-threonic lidene-L-qlycer-

acid (7a) acid (9a) aldehyde (11a)

Figure 4.2: Synthesis of proteeled L(S)-glyceraldehyde (I la) starring from 5 ,6.0-isopropylidene-Lascorbic acid (7a)

For the preparation of the D(R)-glyceric acid derivatives 3a and 3b we

recently reported8 a very attractive RuC~-catalyzed oxidative cleavage of

protected D-mannitol (2a,b) with NaOO at pH = 8 (see also Chapter 3). The

synthesis of protected L(S)-glyceric acids (13a,b) starting from expensive

unnatural L-mannitol (L-enantiomer of 1) by this metbod is not attractive.

Electrochemical oxidation of protected D-mannitol (2a) and L-ascorbic acid (7a)

at a nickel hydroxide electrode2e, yielding the corresponding glyceric acid

derivatives (3a and 13a, respectively). may be industrially acceptable as well.

In conclusion, D-mannitol (1) is the prefeered starting materlal for the

synthesis of protected D(R)-glyceraldehydes ( 4a,b) and D(R)-glyceric acids (3a,b ).

but the preparation of protected D(R)-glyceraldehydes ( 4a,b) necessitates

expensive and environmentally unacceptable oxidizing agents. Therefore, the

combined use of D-isoascorbic acid (16) and the inexpensive ~02-NaOCI couple

as described for the oxidation of protected L-ascorbic acid (17a)7, would be

preferred. For the synthesis of protected L(S)-glyceraldehydes (lla,b) and L(S)-

84 Carbohydrate-based syntheses of C.,-chirons

glyceric acids (13a,b ), L-ascorbic acid ( 6) is the starting material of choice.

In view of their low price and ready availability, L-ascorbic acid ( 6) and

D-isoascorbic acid (16) were investigated as starting materials for the synthesis of

<;-chirons. When using inexpensive and environmentally acceptable reagents, they

should give access to both, D(R)- and L(S)-enantiomers of C3-chirons in an

industrially acceptable way. This chapter deals with the synthesis of

enantiomerically pure L(S)- and D(R)-glyceraldehydes (lla,b and 4a,b,

respectively) and glyceric acids (13a,b and 3a,b, respectively), starting from L

ascorbic (6) and D-isoascorbic (16) acids. First a novel metbod for the high yield

proteetion of L-ascorbic (6) and D-isoascorbic (16) acidsis reported. The 5,6-0-

isopropylidene (7a and 17a) and 5,6-0-cyclohexylidene (7b and 17b) derivatives,

respectively, are subsequently oxidized to the threonic (9a,b) and erythronic

(18a,b) acid analogues with hydrogen peroxide as was described previously2d.'.s·9

(see Fig. 4.3). Finally, we shall focus on the decarboxylation ofthe threonic (9a,b)

and erythronic (18a,b) acid derivatives providing the corresponding glyceraldehyde

(lla,b; 4a,b) and glyceric acid (13a,b; 3a,b) derivatives.

o~6

R-f-- 4 0 t 0 R 0 -2

H03

OH

7a,b : 4(S), 5(S) 18a,b : 4(S), 5(R)

CaCO:J

R R 0~

Ho~.O Á~ 4

HO 1

2

0

+ HOOCCOOH

9a,b 2(S), 3(S) 18a,b 2(S), 3(R)

Figure 4.3: H:/)2-Mediated oxidation ofprotected ascorbic acids (7a,b; 17a,b) to corresponding tetronic adds (9a,b; 18a,bf4"'JJ (a:isopropylidene, b:cyclohexylidene)

4. Synthesis of CJ-chirons startins from L-ascorbic and D-isoascorbic acids 85

4.3 Reactions

a: isopropylidene derivative. R = -CH3

b: cyclohexylidene derivative, ~ = -(C5H10)-

6 HOÀC/;6 O

HO DMP/DMC

... +o~Oto R 0 4 + 2MeOH 2

HO 3

OH

6 : 4 (S), 5 (S) 16 : 4 ( S) , 5 (R)

R -2

HO 3

OH

7a,h 17a,b

4(S), 5(S)

4(S), 5(R)

Figure 4.4: Proteetion of L-ascorbic add (6) and D-isoascorbic acid (16) to the corresponding isopropylidene and cyclohexylidene derivatives (7a,b; 17a,b)

R R 0~

HOVO 3 4 l 2

HO 0

9a,b: 2(S),3(S) 18a,b: 2(S),3(R)

NaOCl,pH==5.5 R R 0~

o_ ;_/o (f2 3 H

lla,b: 2 (S)

4a,b : 2 (R)

+

Fipre 4.5: Oxidative decarboxylation of protected threonic (9a,b) and erythronic (18a,b) adds to the corresponding glyceraldehydes (lla,b; 411,b) using NaOCI in a two phase system


R R 0~ HOt!O 3 4

1 2

HO 0

9a,b : 2(S),3(S) 18a,b: 2 (S), 3 (R)

NaOCl,pH=8

Ru-cat.

R R 0~

o_ J.__/0 lf2 3 OH

13a,b: 2 (S) 3a,b : 2 (R)

+

Figure 4.6: Oxidative decarboxylation of protected threonic (9a,b) and erythronic (18a,b) acids to the corresponding glyceric acids (13a,b; 3a,b) with NaOCI at pH= 8 using RuC/3 as catalyst


4.4.1 Proteetion of L-ascorbic and D-isoascorbic acids

The saturated 5,6-diol of D-isoascorbic acid (16) was selectively and easily

converted into the con-esponding isopropylidene derivative l7a in nearly

quantitative yield by treatment with 2,2-dimethoxypropane (DMP) in acetone in

the presence of catalytic amounts of tin(ll)chloride. On similar treatment of L

ascorbic acid (6), isopropylidene derivative 7a was obtained in high yield (94 %)

in concentrated solutions and almost quantitatively under more dilute reaction

conditions. Similarly the cyclohexylidene derivatives 7b and 17b were obtained

in high yields (93 and 99 %, respectively) by using 1,1-dimethoxycyclohexane

(DMC) instead of DMP. The effectiveness of this kinetically controlled proteetion

metbod bas been demonstrated previously for the isopropylidenation of other

vicinal diols10 but was not known for cyclohexylidenation. The metbod is rapid

(t < lh), involves an easy work-up procedure, without the need for large quantities

of solvents and reagents and produces the 5,6-0-acetals (7a,b; 17a,b) in high

yields.

Several other methods have been reported for the proteetion of 6 and 16. For the synthesis of L-threo isopropylidene derivative 7a the use of acetone in

combination with CuS0/1, or HCI-gas12

, or catalytic amounts of p-

4. Synthesis of Crchirons storting from L-ascorbic and D-isoascorbic acids 87

toluenesulfonic acid13 or acetyl chloride14 have been recommended. Also DMP

in combination with HC1-gas15 afforded acetonide 7a in high yield (88 %). Until

recently the efficient proteetion of 16 seemed very difficult, as is illustrated by

Tanaka's24 failure to synthesize the isomerie acetonide 17a. In 1988, however,

Abushanab2r succeeded in synthesizing 17a with the aid of acetone and CuS04 in

quantitative yield. Also methods involving acetone and catalytic amounts of acetyl

chloride (41 % yieldi8 and DMP and HCl-gas (90% yield)211, respectively, were

reported recently. The cyclohexylidene derivatives 7b and 17b were obtained by

treatment of 128 and 224.8, respectively, with cyclohexanone and triethyl

orthoformate in ethyl acelate in the presence of catalytic amounts of p

toluenesulfonic acid in moderate yields (67 and 86 %, respectively).

However, most of these reported methods involve the use of large amounts

of solvent and/or CuS04 or triethyl orthoformate and are therefore less attractive

for industrial application. The preparadon of 7a with the aid of acetone in the presence of catalytic amounts of acetyl chloride13 is very simple and allows very

concentrated reaction conditions. Therefore, it constitutes probably the most

attractive way to obtain the acetonide of L-ascorbic acid (7a), although our metbod

proceeds in a higher yield (94 or 100 % in comparison to 80 % ). Por the synthesis

of the acetonide of D-isoascorbic acid (17a) the acetone-acetyl chloride metbod

is, however, not suitable (see later). Although the metbod using DMP and HC1-

gas15 is very attractive, the yield in our Sn~-catalyzed reaction is higher (neady

quantitative yield in comparison with 90 %). Finally, for the synthesis of the cyclohexylidene derivatives 7b and 17b, large amounts of triethyl orthoformate

have been used to remove the water produced2d.8• The latter is absent in our

reaction (see later). Moreover, we obtained cyclohexylidene derivatives in higher

yields (93 and 99 % in comparison to 67 and 86 % ).

The distinct difference encountered in the syntheses of the isopropylidene

derivatives of L-ascorbic acid (6) and its C-5-epimer D-isoascorbic acid (16),

respectively, is attributable to the difference in solubility in the reaction mixture

between acetonides 7a and 17a. Acetonide 7a is very poorly soluble in acetone

and therefore precipitates immediately after its formation thus allowing easy

isolation from the reaction mixture. The water produced, when using acetone, and

the acid catalyst do not need to be removed. Acetonide 17a on the contrary, is

soluble in the reaction mixture and bas to be isolated by evaporation of the

solvent. When using acetone the equilibrium involving acetonide 17a has to be

shifted by removal of the water formed. The acid catalyst bas to be removed or


neutralized in order to avoid partial deprotection during evaporation. When using

DMP instead of acetone, methanol is formed, which does not cause deprotection

during evaporation and affords, after removal or neutralization of the acid catalyst,

the isopropylidene derivatives 7a and 17a in quantitative yield. The

cyclohexylidene derivatives ofboth L-ascorbic (7b) and D-isoascorbic (17b) acids

are soluble in the reaction mixture and are, therefore, isolated by concentration.

When using cyclohexanone as reagent, the water formed also has to be removed

during reaction, e.g. by addition of triethyl orthoformate2d.8• In our metbod

however, DMC is used instead of cyclohexanone and methanol is fonned instead

of water. Consequently before work-up, the acid catalyst only bas to be

neutralized.

DMC can be easily prepared from cyclohexanone and methanol onder acidic catalysis (see Fig. 4.7). In order to shift the equilibrium from cyclohexanone

to DMC, in most reported methods water is removed during the reaction16•

However, we found that a mixture of DMC and cyclohexanone can be used as

such; cyclohexylidene derivatives (7b, 17b) are fonned selectively and

cyclohexanone remains unchanged. In this way the difficulties inherent to removal

of water and the separation of cyclohexanone and DMC (similar boiling points)

can be avoided.

Substrates 6 and 16 are not soluble in the reaction mixture in contrary to

their protected derivatives (7a,b; 17a,b). Thus, after proteetion of (iso)ascorbic

acid ((16),6), the reaction mixture becomes clear, the acid catalyst (Sn~) can be

neutralized with pyridine and the mother liquor can be concentraled to give 7a,b

0

+ 2 MeOH

cyclohexanone

Figure 4.7: Synthesis of 1,1-dimethoxycyclohexane

+ ~0

1,1-dimethoxy

cyclohexane (DMC)

4. Synthesis ofC3-chirons staning from L-ascorbic and D-isoascorbic acids 89

and 17a,b in high yields. The low solubility of 7a in the reaction mixture

necessitates its dilution ( 4 times) in order to obtain a clear solution. Thanks to the

low solubility of 7a, however, the work-op procedure in this particular reaction

could be simplified. By carrying out the reaction at higher concentration, careful

heating allows isolation of 7a by filtration after 5 minutes of reaction (72 %

yield). From the mother liquor another 22 % of 7a could be obtained in a second

erop. Reaction at room temperature during 24 h under the more concentrated

conditions, gave 76% of 7a after filtration of the reaction mixture and an

additional18 % by concentration of the mother liquor.

4.4.2 Synthesis of proteded glyceraldehydes

Oxidation of protected ascorbic acid derivatives 7a,b and 17a,b with

hydrogen peroxide leads to the L-threonic (9a,b) and D-erythronic (18a,b) acid

derivatives in high yiel~r.s.•s.t? (see Fig. 4.3). Subsequent decarboxylation (see

Fig. 4.5) of protected C4-acids (9a,b; 18a,b) with NaOCl in a two phase system

(~0/dichloroethane) using tetra-butylammonium hydrogen sulfate as a phase

transfer catalyst (PTC), gave the corresponding isopropylidene glyceraldehyde

derivatives lla and 4a in relatively low yield (39 and 36 %, respectively), but the

cyclohexylidene derivatives llb and 4b in fair yield (54 and 74 %, respectively).

The susceptibility to polymerization and racemization limits the stability

of the aldehydes (lla,b; 4a,b ). Therefore they should be used immediately after

preparation, e.g. through conversion into the cortesponding alcohols (14a,b; Sa,b ). When desired they may be stored in the freezer as a solution in toluene or

benzene18 but distillation before use is then recommended. Loss of product, due

to the inherent polymerization of lla,b; 4a,b during distillation, could be elegantly

circumvented by rednetion of the undistilled, crude aldehydes (lla,b; 4a,b ). Indeed, pure alcohols (14a,b; Sa,b) were obtained in higher yield (one reaction

step extra) than the pure aldehydes (lla,b; 4a,b ). Por isopropylidene derivatives

14a and Sa yields of .40 and 50 %, respectively, and for cyclohexylidene

derivatives 14b and Sb yields of 59 and 67 %, respectively, were accomplished

(see also Chapter 5).

Alternative but economically less attractive methods for the preparation of

protected glyceraldehyde derivatives lla,b and 4a,b, starting from 9a,b and 18a,b


(and hence from L-ascorbic (6) and D-isoascorbic (16) acids), include consecutive

LAH mediated reduction and either oxidative cleavage by sodium periodate2t·8•

19

or electrochernical decarboxylation2b. Our method is in fact an improvement and

generalization of Mizuno's7 method for the oxidation of 3,4-0-isopropylidene-L

threonic acid (9a) with NaOCl at pH= 5.5 in water (see also Fig. 4.2). In our

hands Mizuno's7 method yielded 20- 30 % of lla in contrast to the 60%

reported and oxidation of 3,4-0-isopropylidene-D-erythronic acid (18a) to 4a

occurred in the same poor yield. Some of the aldehyde formed, was oxidized

further to the corresponding acids 13a and 3a, and quantitative extraction of the

aldehyde from the water layer was difficult to achleve presumably due to

hydration. However, when applying a two phase system, part of the product was

extracted into the organic layer where it was apparently not further oxidized.

Saturation of the water layer with N aCl further pushed the partition equilibrium

in favour to the organic layer. Since reaction in the absence of PTC resulted in lower yield, it cannot be excluded that the oxidation proceeds primarily in the

organic layer. Especially for oxidation of the cyclohexylidene derivatives this two

phase system was very prornising. The larger preferenee of substrates 9b and 18b

and products llb and 4b for the organic layer, when compared with the

corresponding isopropylidene derivatives, apparently lirnited over-oxidation of

aldehydes llb and 4b to the corresponding acids 13b and 3b.

4.4.3 Synthesis of protected glyceric acids

RuCl3-catalyzed oxidation of protected L-threonic (9a,b) and D-erythronic

(18a,b) acid derivatives with NaOCl at pH = 8 gave the corresponding protected

glycerate derivatives (sodium saltsof 13a,b and 3a,b) in nearly quantitative yield

(93 - 99 % ). The reacrions proceed under very mild conditions and the use of a

cheap oxidizing agent makes the process industrially viable. Extraction of an

acidified aqueous solution of the salts of 13a,b and 3a,b with dichloromethane

gave the corresponding acids in modest yield (50 - 70 % for the isopropylidene

derivatives (13a, 3a) and 80 - 90 % for the cyclohexylidene derivatives (13b, 3b)).

Efforts to further purify the acids by distillation were hampered by degradation.

The ruthenium-catalyzed oxidative cleavage of a-diols by NaOCI was first

reported by Wolfe20 in 1970. Thus cyclohexane-1,2-diol was cleaved to adipic

4. Synthesis of Crchirons starting from L-ascorhic and D-isoascorbic acids 91

acid in the presence of catalytic amounts of RuC13 and 6.2 equivalents of sodiurn

hypochlorite. To our knowledge there is no application of this catalytic oxidative

cleavage in carbohydrate chemistry. Under Wolfe's reaction conditions without

pH-control, however, our substrates were fully deprotected and degraded, due to

the growing acidity of the reaction mixture. Subsequently we observed that at

higher pH (pH = 8) a highly selective reaction for the cleavage of the a.-hydroxy

acids 9a,b and 18a,b and also for some other carbohydrate derivatives8 occurs.

Cleavage of protected C4-a.-hydroxy acids, produces carbon dioxide and protected

C3-acids. Without buffering, the acetals are cleaved in the acidic medium thus

leaving deprotected sugars which are cleaved by the Naoa - RuCl3 system in a

non selective manner. It is essential to control the pH throughout the process not

only to avoid deprotection at lower pH but also to prevent racemization at a higher

pH. The highest selectivity was observed at pH= 8. Cyclohexylidene derivatives

9b and 18b are less susceptible to cleavage than the corresponding isopropylidene derivatives, but an increase of the reaction temperature to 35 oe is sufficient to

allow the complete conversion in a comparable reaction time.

The active species in the reaction is probably Ru04 , which is formed in a

catalytic cycle from RuCl3 when using an excessof NaOCl (UV-spectroscopy). A

possible reaction mechanism camprises the formation of a cyclic ruthenium - a.

hydroxy acid complex, which degrades to carbon dioxide and aldehyde. The latter

is oxidized further under the reaction conditions applied to produce the

corresponding acid (see Fig. 4.8).

4.5 Conclusions

Proteetion of L-ascorbic acid (6) and D-isoascorbic acid (16) to the

corresponding isopropylidene (7a and 17a, respectively) and cyclohexylidene (7b

and 17b, respectively) derivatives, was readily accomplished in nearly quantitative

yield by treatment with DMP or DMC, respectively, in the presence of catalytic

amounts of SnC12 • ~02-mediated oxidation of thus protected ascorbic acid

derivatives (7a,b; 17a,b) according to literature procedures, gave the L-threonic

(9a,b) and D-erythronic (18a,b) derivatives in high yields (85 % ). Subsequent

decarboxylation of protected C4-acids (9a,b; 18a,b) with NaOCl at pH = 5.5 in a

two phase system in the presence of a PTC, gave the corresponding isopropylidene


R

~OH +

OAOH

H20

L..

(9a,b; 18a,b)

(lla,b; 4a,b) (13a,b; 3a,b)

Figure 4.8: Suggested reaction mechanism for the Ru-catalyzed NaOCI-mediated decarboxylaûon ofprotected tetronic acids (!JlJ,b; 18a,b) to the corresponding glyceric acids (13a,b; 3a,b)

glyceraldehyde derivatives lla and 4a in relatively low yield (39 and 26 %,

respectively), but the cyclohexylidene derivatives llb and 4b in fair yield (54 and

74 %, respectively). The method is an improvement and generalization of the reponed oxidation of 3,4-0-isopropylidene-L-threonic acid (9a) with NaOCl at

pH = 5.5 in water. Application of the two phase system limited over-oxidation of

aldehydes lla,b and 4a,b to the corresponding glyceric acids (13a,b; 3a,b ). RuC13-catalyzed oxidation of protected C4-acids (9a,b; 18a,b) with NaOCl at

pH= 8, on the other hand, gave the corresponding protected glycerate derivatives

(sodium salts of 13a,b and 3a,b, respectively) in nearly quantitative yield (93 -

99 % ). It was essential to control the pH during the process especially to avoid

deprotection at lower pH. Extraction of an acidified solution of the salts of 13a,b

and 3a,b with DCM gave the free acids in modest yield (50- 70% for the

isopropylidene derivatives 13a and 3a and 80 - 90 % for the cyclohexylidene

derivatives 13b and 3b ). Attempted purification of the acids by distillation led to

degradation. The RuC13-catalyzed cleavage of protected a-hydroxy acids 9a,b and

18a,b, presumably comprises formation of a cyclic Ru04 - a-hydroxy acid

4. Synthesis of CJ·chirons starting from L-ascorbic and D-isoascorbic acids 93

complex, which degrades further to the reaction products.

The overall-yields for the synthesis of isopropylidene derivatives lla and

4a starting from L-ascorbic (6) and D-isoascorbic (16) acids, respectively, were

rather low (30 - 33 % ), but the corresponding cyclohexylidene derivatives llb and

4b were obtained in better overall yields (58 and 45 %, respectively). The overall

yields in the syntheses of the corresponding glyceric acid derivatives (13a,b; 3a,b ), on the other hand, all were very high (79 - 84 %) as a result of the highly

selective decarboxylation step. For the synthesis of protected glycerol derivatives

either protected glyceraldehydes (lla,b; 4a,b) or protected glyceric acids (13a,b; 3a,b ), can be used as substrates. In view of the high overall yields obtained for the

syntheses of protected glyceric acids (13a,b; 3a,b) they may be considered as the

preferred synthons. However, reduction of the protected glyceraldehydes (lla,b; 4a,b) is easier to achleve than that of the protected glyceric acids (13a,b; 3a,b) (see Chapter 5), and this may counterbalance the overall yields.

In conclusion, the syntheses of protected optically pure glyceraldehyde

(lla,b; 4a,b) and glyceric acid derivatives (13a,b; 3a,b) starting from L-ascorbic

(6) and D-isoascorbic (16) acids according to the reaction pathways described

above, are good alternatives to the previously reported methods. Especially the use

of a cheap oxidizing agent, i.e. sodium hypochlorite, and inexpensive carbohydrate

substrates is of interest for industrial application.

4.6 Experimental


Elrner R 24B spectrometer (60 MHz) (Me4Si intemal standard). Optica! rotations

were determined on an Optica! Activity AA-10 polarimeter. Optica! purity was

checked on aChrompack Packard 438 A gaschromatograph using a WCOT fused

silica 25 m x 0.25.10'3 mm capillary column coated withOP cyclodex B 236 m,

DF = 0.25.10'3 mm (Chrompack). Splitinjection (100 to 1) and flame ionization

detection were utilized. The injection port temperature was 250 °C and N2 was

used as the carrier gas. Melting points, recorded on a Fischer-Johns block, are

uncorrected.


5,6-0-Isopropylidene-D-isoascorbic Acid (17a). A stirred suspension of

D-isoascorbic acid (16, 160 g, 0.91 mol) and DMP (176 mL, 1.42 mol) in acetone (0.9 L) was heated to boiling. Then tin(ll)chloride (160 mg, 0.84 mmol) was

added and the mixture was heated under reflux for 40 min whereupon a clear solution fonned. The solution was cooled, treated with pyridine (0.8 mL),

concentrated in vacuo and the residue flusbed with ethyl acetate to yield 17a

(196 g, 99 %). 1H NMR (DMSO-~): ö 1.33 (s, 3H, e(eH3h), 1.40 (s, 3H, C(eH3h), 3.61 (dd, 1H, H-6), 3.97 (dd, 1H, H-6), 4.46 (dt, 1H, H-5), 4.90 (d, lH, H-4); mp 132- 135 oe; [«]n20 ~7.5° (c 2, MeOH). Anal. Calcd for CJI120 6 (MW

216.10): e, 49.98; H, 5.60. Found: e, 49.77; H, 5.63. 5,6-0-Isopropylidene-L-Ascorbic Acid (7a). a. The title compound was

obtained as described for the synthesis of 17a but in a four times more diluted

reaction mixture. On a 0.23 molar scale 7a was obtained almost quantitatively (48.6 g, 99 %).

b. A vigorously stirred suspension of L-ascorbic acid (6, 20 g, 0.114 mol) and DMP (22 mL, 0.179 mol) in acetone (115 mL) was carefully heated to boiling. Tin(II)chloride ( 40 mg, 0.21 mmol) was then added and suddenly, after

5 min heating under reflux, a solid reaction mixture was formed. The moist solid

was cooled and treated with pyridine (0.2 mL), filtered and wasbed with cold acetone to yield 7a (17.8 g, 72.3 %). The ftltrate was forther concentraled to yield another 5.4 g of 7a (21.9 %). Total yield: 23.2 g (94 %).

c. The title compound was obtained as described under b but stirred for 24 h at room temperatu.re instead of heating to boiling. Total yield: 22.95 g (93 %). 1H NMR (DMSO~): ö 1.30 (s, 6H, e(eH3) 2), 4.00 (dd, 1H, H-6), 4.24 (dd, 1H, H-6), 4.32 (dt, 1H, H-5), 4.72 (d, lH, H-4); mp 218 - 220 oe, lit.28 mp 223 -226 °C,lit.3 mp 214- 218 oe; [CX]n20 +12.0° (c 2,Me0H),lit.28 [CX]n20 +10.5° (c 5, MeOH). Anal. Calcd for ~H1206 (MW 216.10): C, 49.98; H, 5.60. Found: C, 50.14; H, 5.70.

1,1-Dimethoxycyclohexane (DMC). To a solution of cyclohexanone

(196 g, 2 mol) and methanol (1.2 L) were added 10 drops of concentrated sulfurie acid. The yellow reaction mixture was stirred during 16 h at room temperature and thereafter neutralized to pH = 8 by addition of sodium methoxide, which turned

the coloor to brown. In vacuo concentration and distillation (52 - 56 oe, 20 mmHg) gave a colourless oil (167 g, 73 w/w% DMC, 27 w/w% cyclohexanone). 1H NMR (CDC13): ö 1.70-1.18 (m, lOH, C(C~)5), 3.08 (s, 6H,-

4. Synthesis of C3-chirons storting from L-ascorbic and1D-isoascorbic acids 95

5,6-0-Cyclohexylidene-D-isoascorbic Add (17b). A stirred suspension of D-isoascorbic acid (16, 100 g, 0.57 mol) and OMe (166 g, 0.84 mol) in EtOAc (0.8 L) was heated to boiling. Tin(ll)chloride (400 mg, 2.1 mmol) was added and the mixture was heated under reflu:x for 40 min whereupon a clear solution appeared. The solution was cooled, treated with pyridine (0.4 mL) and

concentrared in vacuo. The residue was dissolved in acetone and hexane was added to induce precipitation of a crystalline product which was colleered by filtration; yield 144 g (99 %). 1H NMR (DMSO-dJ: ö 1.5 (m, 10H, C(e~)5), 3.62 (dd, 1H, H-6), 3.86 (dd, 1H, H-6), 4.29 (dt, 1H, H-5), 4.91 (d, 1H, H-4); mp 183 -184 oe,lit.2dmp 178- 180 oe; [<X]n20 -17.1° (C 1, acetone),lit.2d (<X]o20 -18.0° (C 1, acetone). Anal. ealcd for e 12H160 6 (MW 256.13): e, 56.24; H, 6.29. Found: e, 56.34; H, 6.82.

5,6-0-CyclohexyUdene-L-ascorbic Acid (7b). The title compound was obtained as described for 17b. Yield: 134.4 g (92 %). 1H NMR (DMSO~): ö 1.55 (m, 10H, e{eUz)s), 3.91-4.60 (m, 3H, H-5, H-6), 4.74 (d, lH, H-4); mp 186-

188 oe; [a]o20 +10.1° (c 1, acetone). Anal. ealcd for e.2Hl606 (MW 256.13): e, 56.24; H, 6.29. Found: e, 56.34; H, 6.26.

2,3-0-Isopropylidene-L(S)-glyceraldehyde (lla). To a stirred solution of calcium 3,4-0-isopropylidene-L-threonate.2~0 (calcium salt of 9a2d.t.g.ts,t1, 13.9 g,

0.06 mol) and Nael (7.5 g) in water (50 mL, pH = 5.5, 40 °C) were added dichloroethane (150 rnL) and tetrabutyl ammonium hydrogen sulfate (2 g, 6 mmol). Over a period of 1.5 h NaOel (13 w/w% in water, 38 rnL, 0.066 mol) was added dropwise while the pH was maintained at 5.5 by concomitant addition of concentrated HCl. After another 0.5 h of reaction the aqueous layer was separated from the organic layer and then consecutively extracted with dichloromethane (5 x 100 rnL) and EtOAc (4 x 100 rnL). The combined organic layers were driedover anhydrous MgS04 and concentrated in vacuo. Distillation of the residue (42 -44 oe, 10 mmHg, lit.6 64- 66 °C, 35 mmHg) gave lla in

39% yield (3.1 g). 1H NMR (eDC13): ö 1.41 (s, 3H, C(CH3) 2), 1.45 (s, 3H, C(CH3)2), 3.95-4.52 (m, 3H, H-2, H-3), 9.72 (d, lH, H-1); [a.]0

20 -70.0° (c 1.25, benzene), lit.6 [a.]0

20 -67.9° (c 8, benzene). 2,3·0-Isopropylidene-D(R)-glyceraldehyde (4a). The title compound was

obtained as described for the synthesis of lla, starring from calcium 3,4-0-isopropylidene-D-erythronate.2H20 (calcium salt of 18a2d.r.s.•s.t7

). Yield 36 %. 'H NMR (eDC13): ö 1.40 (s, 3H, C(eH3) 2), 1.44 (s, 3H, C(CH3)2), 4.0-4.61 (m,


3H, H-2, H-3), 9.78(d,lH,H-1); [CX]n20 +71.5° (c 1.25, benzene), lit.4 [CX]n20 +63.3°

(c 1.25, benzene).

2,3-0-Cyclobexylidene-L(S)-glyceraldehyde (llb). The title compound

was obtained as described for lla, but starring with calcium 3,4-0-

cyclohexylidene-L-threonate.2H2d8 (calcium salt of9b) forming a suspension with

the reaction mixture, and without any Nael. Yield: 54 %. 1H NMR (eDC13): 51.6

(m, lOH, C(eH2)5), 4.0-4.6 (m, 3H, H-2, H-3), 9.87 (d, 1H, H-1); [«1n 20 -55.1°

(c 3, eHC13); bp 98 -100 oe (1 mmHg).

2,3-0-Cyclobexylidene-D(R)-glyceraldehyde (4b). The title compound

was obtained as described for lla, but starting with calcium 3,4-0-

cyclohexylidene-D-erythronate.~028 (calcium salt of 18b) fomring a suspension

with the reaction mixture and without any NaCl. Yield 74 %. 1H NMR (CDel3):

() 1.5 (m, 10H, e(e:H:z)5), 4.0-4.5 (m, 3H, H-2, H-3), 9.81 (d, 1H, H-1);

[CX]n20 +53.6° (c 3, eHC13), lit.21 [a]n20 +61.2° (c 3.4, benzene); bp 98-100 oe (1 mmHg), lit.22 bp 90-93 oe 2 mmHg), lit.23 bp 102 oe (1 mmHg).

Sodium 2,3-0-lsopropylidene-L(S)-glycerate (sodium salt' of 13a). To

a well stirred solution of sodium 3,4-0-isopropylidene-L-threonate.2:H:z0 (sodium salt of 9a2d.f.s.ts,t7

, 15.0 g, 0.065 mol) and RuC13.3:H:zO (0.4 g, 1.53 mmol) in water

(100 mL, pH= 8, room temperature) NaOCl (13 w/w% in water, 100 mL,

0.176 mol) was added dropwise over a period of 0.5 h. The pH was maintained

at 8 by adding a 5 M NaOH-solution. The reaction mixture was then concentrated

in vacuo at 60 oe to a solid residue, which was taken up in hot ethanol.

eoncentration of the ftltrate gave the sodium salt of l3a (9 g, 95 % ). 1H NMR

(020): () 1.77 (s, 3H, C(eH3) 2), 1.83 (s, 3H, e(eH3)2), 3.9-4.9 (m, 3H, H-2, H-3);

[a]020 -29.1° (c 1, :~!zO). Extraction of an acidic solution of the sodium salt of 13a

(pH = 2) with dichloromethane and in vacuo concentration of the organic layer,

gave the corresponding acid 13a (6.9 g, 72.8 %). 1H NMR (eDC13): () 1.47 (s, 3H,

C(eH3h), 1.54 (s, 3H, e(eH3)2), 4.0-4.95 (m, 3H, H-2, H-3), 10.5 (s, 1H, OH);

[a]n 20 -21.0° (c 2, eHel3). Due to its acidic character distillation of 9a

(0.4 mmHg, 78 °C) leads to degradation of the product .

Sodium 2,3-0-Isopropylidene-D(R)-glycerate (sodium salt of 3a). As

described for 13a, starting from sodium 3,4-0-isopropylidene-D-erythronate.2H20 (sodium salt of 18au.r.a.ts.t7). Yield: 10.8 g (99 %). 1H NMR (D:P): 5 1.72 (s, 3H,

e(eH3) 2), 1.76 (s, 3H, C(eH3h), 3.9-4.8 (m, 3H, H-2, H-3); [«]020 +30.2° (c 1,

:1-lzO), lit.2e [a]020 +23.5° (c 2, :~!zO), lit.24 [cx]0

20 +30.1° (c 1.03, :~!zO). Extraction

of an acidified solution of the sodium salt of 3a (pH= 2) with dichloromethane

4. Synthesis ofC3-chirons storting from L-ascorbic and D-isoascorbic acids 97

and in vacuo concentranon of the organic layer, gave the corresponding acid 2,3-

0-isopropylidene-D(R}-glyceric acid (la} (5.6 g, 50 % ). 1H NMR (eDCl3): ö 1.42 (s, 3H, C(eH3h), 1.48 (s, 3H, C(CH3) 2), 3.90-4.75 (m, 3H, H-2, H-3), 9.6 (s, lH,

OH); [a]0 20 +20.0° (c 2, CHC13).

Sodium 2,3-0-Cyclohexylidene-L(S)·glycerate (sodium salt of llb). The

title compound bas been obtained as described for lla, but starting from sodium

3,4-0-cyclobexylidene-L-threonate.2H2021 (sodium salt of 13b, 13.5 g, 0.05 mol)

and performed at 35 oe. Yield: 10.9 g (99.5 %). 1H NMR (DMSO): ö 1.6 (m,

10H, C(CHz),), 3.9-4.8 (m, 3H, H-2, H-3); [a]020 -26.0° (c 1, HzO). Extraction of

an acidic solution of the sodium salt of 13b (pH= 2) with dichloromethane and

in vacuo concentranon of the organic layer, gave the corresponding acid llb (8.4 g, 90.3 %). 1H NMR (CDC13): ö 1.6 (m, lOH, C(CH2)5), 3.93-4.64 (m, 3H,

H-2, H-3), 7.95 (s, lH, OH); [a]020 -9.0° (c l, CHC13).

Sodium 2,3-0-Cyclohexylidene-D(R)-glycerate (sodium salt of 3b). The

ntle compound bas been obtained as described for lla, but starting from sodium

3,4-0-cyclobexylidene-D-erythronate.2Hz021 (sodium salt of 18b, 13.5 g, 0.05 mol) and tbe reaction performed at 35 oe. Yield: 10.2 g (93.1 %). 1H NMR

(DMSO): ö 1.5 (m, lOH, C(CHz)5), 3.5-4.9 (m, 3H, H-2, H-3); [a]0 20 +34.5° (c 1,

HzO). Extraction of an acidic solution of the sodium salt of 3b (pH= 2) with

dichloromethane and concentranon of the organic layer in vacuo, gave the

conesponding acid 3b (7.2 g, 77.4 %). 1H NMR (CDC13): ö 1.6 (m, lOH,

e(eHz)5), 3.94-4.81 (m, 3H, H-2, H-3), 8.7 (s, lH, OH); [a]0 20 +12.0° (c l,

CHC13).

4. 7 References and notes

(1) Andrews, G. C.; Crawfurd, T. Adv. Chem. Ser. 1982, 200, 59. (2) (a) Andrews, G. C.; Crawford, T. C.; Bacon, B. E.I. Org. Chem. 1981, 46, 2976. (b)

Cohen, N.; Baoner, B. L.; Lopresti, R. J.; Wong, F.; Rosenberger, M.; Liu, Y.; Thom, E.; Liebmann, A. A. I. Am. Chem. Soc. 1983, 105, 3661. (c) Ve.k:emans, J. A. J. M; Boerek:amp, J.; Godefroi; E. F.; Chittenden, G. J. F. Reel. Trav. Chim. Pays-Bas 1985, 266. (d) Tanaka, A;; Yamasbita, K. Synthesis 1987, 570. (e) Ruholl, H.; Schäfer, H. J. Synth. Commun. 1988, 54. (f) Abushanab, E.; Vemisbetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu, D. C.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598. (g) Voeffray, R. EP 3259671989. (h) Le Merrer, Y.; Gravier-Pelletier, C.; Dumas, J.; Depezay, J.C. Tetrahedron Lett. 1990, 31, 1003.

(3) Baer, E.; FIScher, H. 0. L.I. Biol. Chem. 1939,128,463, 472. (4) Jackson, D. Y. Synth. Commun. 1988, 18, 337.


(5) Jung, M. B.; Shaw, T. J. J. Am. Chem. Soc., 1980, 102, 6304. (6) Hubschwetlen, C. Synthesis 1986, 962. (7) Mizuno, Y.; Sugimoto, K. EP 143973 1934. (8) Emons, C. H. H.; Kuster, B. F. M.; Vekemans, J. A. J. M.; Sheldou, R. A. Tetrahedron

Asymm. 1991, 2, 359. (9) Mik:kilineni, A. B.; Kumar, P.; Abusbanab, B. J. Org. Chem. 1988, 53, 6005. (10) (a) Chittenden, G. J. F. Carbohydr. Res. 1980, 84, 350. (b) Vekemans, J. A. J. M.;

Boerekamp, J.; Godefroi, E. F., Chittenden, G. J. F. Reel. Trav. Chim. Pays-Bas 1985, 104, 266. (c) Chittenden, G. J. F. Reel. Trav. Chim. Pays-Bas 1988, 107, 455.

(11) Vargha von, L. Nature 1932, 130, 847. (12) Salomon, L. L. Experientia 1963, 19, 619. (13) Cutolo, E.; Larizza, A. Gazz. Chim. ltal. 1961,91, 964. (14) Jackson, K. G. A.; Jones, Z K. N. Can. J. Chem. 1969, 47, 2498. (15) (a) Wei, C.-C.; Mangele, M. EP 143973 1983. (b) Wei, C.-C.; Bemardo de, S.; Teogi, J.

P.; Boregese, J. J. Org. Chem. 1985, 50, 3462. (16) (a) Roelofsen, D. P.; Wtls, B. R. J.; Beldrom van, H. Reel. Trav. Chim. Pays-Bas 1971,

90, 1141. (b) Olah, G. A; Subbash, C. N., Meida:r, D.; Salem, G. F. Synthesis 1981, 282. (17) Abushaoab, E.; Bessodes, M.; Aotooalds, K. Tetrahedron Lett. 1934, 25, 3841. (18) (a) Lopez Aparicio, F. J.; lzquerdo Cubero, I.; Poral Olea, M.D. Carbohydr. Res. 1983,

115. 250. (b) Jurczak:, J.; Picul, S.; Bauer, T. Tetrahetiron 1986, 42, 447. (19) Abushaoab, E. US 4931575 1990. (20) Wolfe, S.; Hassao, S. K.; Campbell, J. R. J. Chem. Soc. D 1970, 1420. (21) Sugiyama, T; Sugawara, H.; Wataoabe, M.; Yamasbita, K. Agric. Biol. Chem. 1934,48,

1841. (22) De W:tlde, H.; De Cle~q, P.; Vaodewalle, M. Tetrahetiron Lett. 1987, 28, 4757. (23) Petersen, U.; Metzger, K.; :àiler, H. J.; Stadler, P.; Voss, B. Japan Kokai 55-1607791

1980. (24) Taoak:a, A; Yamashita, K. Agric. Biol. Chem. 1980, 44, 199.

5. Reduction of protected glyceraldehyde and glyceric acid to glyurol derivatives 99

.< s. üötr~~iö~öij~ö~~üötiir~~~mn~~~>'}' ··•····.· . .A"N» oL'Y<JÊRîèÄêî»•fo· atfdèB.otr :l'lttîûVi\TIVÊS(•···

5.1 Albstract

The preparations of enantiomerically pure 1,2-0-isopropylidene-L(S)- and

D(R)-glycerols, and of 1,2-0-cyclohexylidene-L(S)- and D(R)-glycerols starting

from the corresponding glyceraldehyde or glyceric acid derivatives are described.

Ru/C or Pd/C catalyzed hydragenation of the protected glyceraldehyde derivatives

gave the corresponding alcohols in 75 - 90% yield. Direct esterification of the

protected sodium glycerates with benzyl bromide in acetonitrile yielded the corresponding benzyl esters in up to 80 % yield. Altematively, esterification of the

protected glyceric acids with MeOH in the presence of catalytic amounts of

pTsOH, gave the deprotected methyl esters. Subsequent proteetion with DMP or

DMC in the presence of catalytic amounts of SnC~, then gave the protected

methyl esters in 65 - 70 % overall yield. Finally, NaBH4-reduction of the proteeled

methyl esters gave the protected glycerol derivatives in 60 - 80 % yield, in

contrast to direct rednetion of the protected glyceric acids, which was not

successful.

5.2 Introduetion

Protected glycerol derivatives (Sa,b; 14a,b) are versatile building blocks

with numerous applications1• They can be readily obtained by rednetion of the

corresponding glyceraldehyde derivatives (4a,b; lla,b) with hydrogen in the

presence of a nickel catalysf and with sodium borohydride3, or by rednetion of

the corresponding methyl esters of the glyceric acid derivatives (30a,b; 31a,b)

with NaBH/ or LAH5• Protected glyceraldehydes (4a,b; lla,b) and glyceric acid


derivatives (3a,b; 13a,b) are readlly available from cleavage of protected D

mannitol (2a,b), L-ascorbic acid (7a,b), and D-isoascorbic acid (17a,b), by

inexpensive oxidizing agents (see Chapters 3 and 4). Protected glyceraldehyde

derivatives ( 4a,b; lla,b) were obtained in rather low yield, when compared with

glyceric acid derivatives (3a,b; 13a,b ). Therefore, in principle, rednetion of

protected glyceric acids (3a,b; 13a,b) should be preferred for the synthesis of the

corresponding glycerol derivatives (5a,b; 14a,b).

The rednetion methods described above, however, employ expensive

reagents, NaBH4 or LAH, and especially, the latter is of little practical value.

Catalytic hydrogenation of protected glyceraldehydes in the presence of a nickel

catalysf is industrially more attractive, although relatively high pressores have to

be applied (80 atm).

In genera!, rednetion of aldehydes to primary alcohols is very easy and can

be accomplished by a number of reagents6• Saturated aliphatic aldehydes are

readlly reduced to alcohols by catalytic hydrogenation. Ruthenium is an excellent

catalyst for the hydrogenation of aliphatic aldehydes and has been used, for

example, to convert polysaccharides to polyhydric alcohols. In the past, these

reductions always have been carried out industrially. with nickel, but new plants

may fmd ruthenium more advantageous7• Also homogeneons hydrogenation

catalysts have been used7• In addition, aldehydes can be rednced with LAH and

with NaBH4 to yield primary alcoholsin high yields, but the latter reagentsare

less suitable for industrial application.

Rednetion of acids to primary alcohols is more complicated6.7• Catalytic

hydragenation requires special catalysts, high temperatures (140- 420 °C) and high pressores (150 - 990 atm) and is, therefore, oot suitable for the rednetion of

carbohydrate acid derivatives. Under mild reaetion conditions, the rednetion of free

acids is only possible with very reactive metal hydrides, e.g. LAH. NaBH4 is

unable to reduce the free carboxylic group, but borane, prepared from NaBH4 and

BF3-etherate in THF, couverts aliphatic acids to alcohols under mild reaction

conditions. Ester gronps are oot reduced with borane, but can be rednced by

hydrides and metal hydrides e.g. LAH and NaB~. Catalytic hydrogenation of

esters to alcohols is oot straightforward either.

In conclusion, rednetion of aldehydes is much easier to perform than

rednetion of acids or their corresponding esters. Catalytic hydrogenation is

5. Reduction of protected glyceraldehyde and glyceric acid to glycerol derivatives 101

industrially very attractive whilst NaBH4 is more expensive and LAH is both expensive and difficult to handle. On the other hand, formation of protected glyceric acids (13a,b; 3a,b) proceeds more selectively than that of the corresponding aldehydes (lla,b; 4a,b) (see Chapters 3 and 4). In addition, the stability of aldehydes 4a,b and lla,b is limited, since racemization and

polymerization occur on standing. Therefore, reduction of the acids or the conesponding esters with NaBH4 may, after all, be preferred over catalytic hydrogenation of the aldehydes. In this chapter, reduction of protected <;aldehydes (4a,b; lla,b) and the conesponding methyl esters (30a,b; 3la,b) are described. In addition, we describe attempts to reduce the C3-acids (13a,b; 3a,b).

5.3 Reactions

a: isopropylidene derivative (R = -CH3)

b: cyclohexylidene derivative (~ = -(C5H10)-)

R R 0~

0~ J._/0 11"' 2 3 H

lla,b: 2 (S)

4a,b: 2 (R.)

R R 0~

HO~O 3

2 1

14a,b: 2 (R)

Sa,b : 2 (S)

Figure 5.1: Catalytîc hydrogenation of protected glyceraldehydes (lla,b; 4a,b) to the corresponding alcohols (14a,b; Sa,b)

102 Carbohydrate·based syntheses of C;-chirons

R R R R R R

0~ ~~ 0~ NaBH4 0~ 0~0 • H0~0 ... 0~0

1 2 3 3 2 1 1 2 3 OH OCH3

13a,b: 2 (R) lla,b: 2 (S) 30a,b: 2 (S)

3a,b : 2 (S) 4a,b : 2 (R) 3la,b: 2 (R)

Figure 5.2: Reduction of protected glyceric acids (13a,b; 3a,b) to the corresponding glycerol derivatives (14a,b; So.,b) directly or via the corresponding methyl esters (30a,b; 3la,b)


5.4.1 Catalytic hydrogenation of protected glyceraldehydes

Ru- or Pd-mediated catalytic hydrogenation of pure 2,3-0-isopropylidene

D(R)-glyceraldehyde (4a) and of its cyclohexylidene analogue (4b) gave the

corresponding glycerol derivatives 12a,b in high yields (75 - 90 % ). Ruthenium

catalyzed hydrogenation of the undistilled aldehydes Ua,b and 4a,b derived from

the corresponding L-threonic (9a,b) and D-erythronic (18a,b) acid derivatives (see

Chapter 4), gave the conesponding glycerol derivatives (14a,b and 5a,b,

respectively) in good overall-yield (50, 59 and 40, 67 %, respectively). The results

of sevefal hydrogenations of 4a and 4b undef different feaction conditions are

collected in Table 5.1.

The methods reported fof the feduction of the protected glyceraldehyde

derivatives Ua,b and 4a,b necessitate eithef the use of relatively expensive

NaBH43 Of a Raney-Ni catalyst at high pressures (80 atm, 24 h at room

temperature)2• The reaction conditions applied in our Ru/C- Of Pd/C-catalyzed

hydrogenation, however, are very mild (3 atm, 3 - 18 h at room temperature).

We have used two different metal catalysts, Pd/C and Ru/C, of which the

5. Reduction of proteeled glyceraldehyde and glyceric acid to glycerol derivatives 103

Table 5.1: Catalytic hydragenation of proteeled glyceraldehydes (4tl,b) to the corresponding derivatives

4a Ru/C, 50% HzO BtOAc 80-90 100 18

4b 75 99.2 18

4a Pd/C, 50% HzO BtOAc 30-40 95 3

4a Pd/C, 50% H20 BtOAc NaHC03 75-80 99.7 3

4b " .. tl 65 99.3 3

4a Ru/C,dry BtOAc 20.9 > 48"

4a Pd/C, dry BtOAc 60 3 3

4a Ru/C, 50% HzO HzO 8 91.5 10

4a Ru/C, 50% lfzO lfzO NaHC03 30 95.8 10

4b .. 44" 97.6 >48

4a Ru/C, 50% HzO MeOH 30 92.3 10

4a Ru/C, 50% llzO MeOH NaHC03 60 95.5 10

4b .. " 66 98.9 10

4a Pd/C, 50% HzO HzO NaHC03 18 95.5 6

4a Pd/C, 50% H20 MeOH NaHC03 46 97.8 6

"Reacti.on conditi.ons: [substrate] = 1 M, [catalyst] = 0.025 M, p = 3 atm, room temperature. bAddition of 0.5- 1 g per 10 g substrate. 'Determined by GC-analysis. "Conversion 30 %. "Undistilled material.

Pd/C-catalyst was six times more active than the Ru/C-catalyst. When using the

Pd/C-catalyst, yields were relatively low (30 - 40 % ), but upon addition of sodium bicarbonate, the same high yields were obtained as with the Ru/C-catalyst.

Surprisingly, only wet catalysts (containing 50% moisture) led to optically pure product (GC-analysis, [a]0

20). Dry catalysts on the contrary, strongly indoeed

racemization. This is probably due to differences in the carrier material, i.e. the

active carbon, which can possess different surface groups, basic as well as acidic,

depending on the preparalive procedure. Under basic conditions the substrate

(aldehyde) is susceptible to racemization due to the acidic proton at C-2 and under acidic conditions the product (alcohol) can undergo trans-acetalization with

concomitant racemization. The activity of the dry Ru/C catalyst was very low:


after 48 h only 30 % conversion was observed. It is well known, indeed, that

water is a very strong and unique promotor for ruthenium~catalyzed

hydrogenations7• The surprising effect of water to inhibit the catalytic

racemization, was not further investigated.

Et0Ac2•8

, was used as solvent, but also MeOH and ~0 were suitable,

although the yields and e.e.'s were somewhat lower. When using MeOH or H20,

addition of sodium bicarbonate was necessary to obtain alcohols in high material

yields, as is the case when using the Pd/C~catalyst. Presumably acidic side~

products are formed in these reactions, which are neutralized by NaHC03•

Addition of CaC03 is reported in the catalytic hydrogenation of D~glucose and

invert sugar to D~mannitol to neutralize undesired acids9• In general, the activity

of the ruthenium catalyst increased when using MeOH or water as solvents (about

2 times), in contrast to the activity of the Pd/C~catalyst. This again may be

explained by the promoting effect of water for ruthenium~catalyzed

hydrogenations 7• Hydrogenation of the cyclohexylidene derivative 4b over Ru/C

in ~0, however, proceeded very slowly, probably due to the low solubility of this

derivative in water. The lower yields with water or MeOH as solvent may find its

origin in partial hydradon of the aldehyde function, which suppresses

hydrogenation. This hydradon can also explain why hydrogenations with Pd/C as

catalyst proceeded slower with ~0 and MeOH as solvents. Moreover, there is a

marked tendency of palladium-hydrogen to promote acetal formation in alcoholic

solvents Th.

Catalytic hydrogenation of undistilled aldehydes is also possible and even

prefeered provided the aldehydes are treated with active carbon in order to remove

the PTC which acts as a poison for the metal catalysts and hence inhibits

hydrogenation. Proteeled glycerol derivatives (14a,b; Sa,b) have been obtained in

an overall yield of 42, 46 and 34, 57 %10, respectively, starting from inexpensive

L~ascorbic (6) and D-isoascorbic (16) acids and employing cheap reagents. We

conclude, therefore, that this route to c3~synthons is industrially viable.

5.4.2 Rednetion of protected glyceric acids and their esters

Catalytic hydrogenation of carboxylic acids and esters to the corresponding

alcohols, requires elevated temperatures (140 ~ 420 °C) and pressores (150 ~


990 atmt·7•11 and is, therefore, not suitable for the reduction of carbohydrate

derivatives. LAH and borane, on the contrary, may well reduce acids to the

corresponding alcohols under mild reaction conditions, but are difficult to handle

due totheir water and/or air sensitivity. In situ generation of borane from BF3-

ethyl etherate and NaBH4u,u may circumvent these problems and is probably a

better choice for industrial applications. An attempt to reduce 2,3-0·

isopropylidene-D(R)·glyceric acid (3a) directly by in situ generated borane12 was,

however, not successful.

Esters on the other hand are reduced to the conesponding alcohols by the

safe reagent NaBH46

• Reduction of methyl 2,3·0·isopropylidene·L(S)· and D(R)·

glycerate (30a, 3la) with NaBH/ and LAHs has been reported to give the

conesponding alcohols 14a and Sa in high yields (80 - 90 % ). At the moment

NaBH4 appears to be the best option despite its higher costs in comparison to

catalytic hydrogenation. Therefore, for the synthesis of alcohols Sa,b NaBH4 was

used, after esterification of the corresponding acids 3a,b, according to the reported

method4• In this way, by inclusion of one additional step, i.e. conversion of the

glyceric acid derivatives (3a,b) to the conesponding methyl esters (3la,b ), and

subsequent reduction with NaBH4, the corresponding alcohols (Sa,b) were obtained

in 55 and 40% yield, respectively. lnitially, the yield of alcohol was very poor,

due to partial deprotection of the protected glyceric acid derivatives during

esterification. Esterification was carried out with MeOH in the presence of

catalytic amounts of pTsOH, and using DMP or DMC, respectively, as water

scavengers. However, also under mild reaction conditions protected glyceric acids

(3a,b) and/or the derived methyl glycerates (31a,b ), were deprotected to a large

extent (70 - 90 % ). Treatment of the latter reaction mixture with DMP or DMC,

respectively, in 1,2·dimethoxyethane using catalytic amounts of SnCI:z, yielded

protected methyl glycerates (31a,b) in 70 and 65 % yield, respectively.

Esterification of sodium glycerates (sodium salts of 3a,b) with benzyl chloride in

a two phase system under alkaline conditions was not successful. Probably the

carboxylate anion is too much stabilized, which makes it a weak nucleophile.

However, when the reaction was carried out in acetonitrile with benzyl bromide,

benzyl2,3.0·isopropylidene-D-glycerate (SSa) was isolated in high yield (81 %).

Similarly, the corresponding cyclohexylidene derivative (SSb) was obtained in

57 % yield. The reactions have, however, not yet been optimized. The

lastmentioned esterification metbod seems very attractive since sodium glycerates

3a,b are converted directly into the conesponding benzyl esters (SSa,b) in high

106 Carbohydrate·based syntheses of Crchirons

yield, without deprotection, and, therefore, can be carried out very efficiently.

Presumably these results also imply that methyl iodide and allyl chloride can be

used to prepare the corresponding esters.

In summary, synthesis of 1,2-0-isopropylidene-L(S)-glycerol (Sa) and 1,2-

0-cyclohexylidene-L(S)-glycerol (Sb) starting from the corresponding glyceric

acids (3a,b ), proceeded in reasonable yield, but two extra steps, esterification and

protection, were needed in comparison to the syntheses starting from the

corresponding glyceraldehyde derivatives ( 4a,b ). It is reasonable to assume that

the corresponding D(R)-glycerols (l4a,b) can be obtained similarly and in

comparable yield. Synthesis of benzyl glycerates probably is a better method for

obtaining protected glycerol derivatives.

S.S Conclusions

For the syntheses of protected glycerol derivatives 14a,b and Sa,b, two

routes have been investigated. In the first one protected glyceraldehydes lla,b and

4a,b are used as starting materials, which produced after catalytic hydragenation

the corresponding alcohols (14a,b; Sa,b) in 80- 90% yield. In this approach

cheap reducing agents were used, which yielded the alcohols in high yields, but

the yields of the products lla,b and 4a,b were rather low (see Chapter 4). The

second approach, invalving protected glyceric acids 3a,b as starting material,

afforded after subsequent esterification, proteetion and NaBH4-reduction, the

corresponding alcohols (Sa,b) in 40 and 55 % yield, respectively. Rednetion ofthe

L-enantiomers (13a,b) is believed to proceed similarly. In this approach the

relatively expensive NaBH4 was used as reducing agent; two extra steps were

needed, viz. esterification and protection, in comparison to the first approach. On

the other hand, preparation of starting glyceric acids 13a,b and 3a,b, proceeded

in high yields (see Chapters 3 and 4). This may counterbalance tosome extent the

need of two extra steps and the relatively high costs of the NaBH4-reduction.


S.6 Experimental


EhDer R 24B spectrometer (60 MHz) (Me4Si intemal standard). Optical rotations

were detennined on an Optical Activity AA-10 polarimeter. Optical purity was

checked on aChrompack Packard 438 A gascbromatograph using a WeOT fused

silica 25 m x 0.25.10"3 mm capillary column coated with OP cyclodex B 236 m,

DF = 0.25.10'3 mm (ehrompack). Split~ection (100 to 1) and flame ionization

detection were utilized. The ~ection port temperature was 250 oe and N2 was

used as the carrier gas. Melting points, recorded on a Fischer-Johns block, are

uncorrected. Hydrogenations were carried out in a commercial Parr-apparatus.

1,2-0-Isopropylidene-L(S)..glycerol (Sa) from 2,3-0-lsopropylidene

D(R)-glyceraldehyde (4a). A mixture of 2,3-0-isopropylidene-D(R)

glyceraldehyde (4a) (11.2 g, 0.085 mol) and Rute (5 %, Janssen ehimica, 50%

moisture) (8.6 g, 2.1 mmol) in EtOAc (85 mL) was hydrogenated for 18 h at room

temperature at 3 atm. Removal of the catalyst, concentration in vacuo and

subsequent distillation of the residue (50 oe, 2 mmHg, lit.4 82 oe, 13 mmHg)

afforded optically pure Sa (OC-analysis) (8.75 g, 78 %). 1H NMR (CDC13): ö 1.38

(s, 3H, e(eH3)2), 1.46 (s, 3H, e(eH3h), 2.58 (br.s, 1H, OH), 3.5-4.1 (m, 5, H-1,

H-2, H-3); [<x]020 +14.6° (neat), lit13

• [a]020 +14.0° (neat), lit.4 [a]0

20 +15.4°

(neat).

1,2-0-Cyclohexylidene-L(S)-glycerol (Sb) from 2,3-0-cyclohexylidene-D

glyceraldehyde (4b). The tide compound has been obtained as described for Sa from 4a. Yield: 75 %. 1H NMR (eDCl3): ö 1.5 (br.s, 10H, e(e~),), 2.55 (br.s,

1H, OH), 3.6-4.3 (m, 5, H-1, H-2, H-3); [a]020 +6.4° (c 1, MeOH), lit.14

[a]0 20 +7.3° (c 2, MeOH); bp 88 oe (0.75 mmHg), lit}4 bp 87-89 oe (1 mmHg).

1,2-0-Isopropylidene-D(R)-glycerol (14a) from calcium 3,4-0-

isopropylidene-L-threonate (calcium salt of 9a). To a stirred solution of calcium

3.4-0-isopropylidene-L-threonate.2~0 (calcium salt of 9a14•1', 13.9 g, 0.06 mol)

and Nael (7.5 g) in water (50 mL, pH= 5.5, 40 °C) were added dichloroethane

(150 mL) and tetrabutyl ammoniumhydrogen sulfate (2 g, 6 mmol). Over a period

of 1.5 h NaOO (13 w/w% in water, 38 mL, 0.066 mol) was added dropwise while

the pH was maintained at 5.5 by adding concentraled Hel. After another 0.5 h the

aqueous layer was separated from the organic layer and was consecutively

extracted with dichloromethane (5 x 100 mL) and EtOAc {4 x 100 mL). The


combined organic layers were driedover anhydrous MgS04 and concentr_ated in

vacuo toa residue which was dissolved in EtOAc (100 mL). To this solution was

added active carbon (2 g) and the latter was removed by futration after stirring for

0.5 h at room temperature. The ftltrate was then concentrared in vacuo to ± 40 mL

and after addition of Rute (5 %, Janssen Chimica, 50 % moisture) (4 g, 1 mmol)

was hydrogenated at room temperature and 3 atm for 18 h. Removal of the

catalyst, concentration in vacuo and subsequent distillation of the residue

(48-50 oe, 2 mmHg, lit.4 82-83 oe, 13 mmHg, lit.' 75.5-76 oe, 10 mmHg)

afforded optically pure 14a (GC-analysis) (3.93 g, 49.6 %). 1H NMR (eDC13): ö 1.37 (s, 3H, e(eH3h), 1.45 (s, 3H, e(eH3)2), 2.55 (br.s, 1H, OH), 3.5-4.2 (m, 5, H-1, H-2, H-3); [a]0

17 -14.5° (neat), lit.4 [a]020 -14.4° (neat), lit.5 [a]D 22 -13.2°

(neat).

1,2-0-Isopropylidene-L(S)-glycerol (Sa) from calcium 3,4-0-

isopropylidene-D-erytbronate (calcium salt of 18a). The title compound bas

been obtained as described for the synthesis of 14a from 9a but starting from

calcium 3,4-0-isopropylidene-D-erythronate.2Hz0 (calcium salt of 18a14•15

). Yield

40.4 %. 1H NMR (eD03): l> 1.38 (s, 3H, e(e~)2), 1.46 (s, 3H, e(eH3h), 2.58

(br.s, 1H, OH), 3.5-4.1 (m, 5, H-l, H-2, H-3); [a]D17 +14.6° (neat), lit13•

(a)D20 +14.0° (neat), lit.4 [a]D20 +15.4° (neat); bp 50 oe, 2 mmllg, lit.4 82 oe,

13 mmHg.

1,2-0-Cyclohexylidene-D(R)-glycerol (14b) from calcium 3,4-0-

cyclohexylidene-L-tbreooate (calcium salt of 9b). The title compound bas been

obtained as described for the synthesis of 14a from 9a but starting from calcium

3,4-0-cyclohexylidene-L-threonate.2HP14 (calcium salt of Sb) forming a

suspension with the reaction mixture, and without Nael. Yield: 59 %. 1H NMR

(eDCI3): ö 1.5 (br.s, 10H, e(eH2)5), 2.52 (br.s, 1H, OH), 3.7-4.4 (m, 5, H-1, H-2,

H-3); [a]017 -9.9° (neat); bp 87-88 oe (0.75 mmHg).

1,2-0-Cyclohexylidene-L(S)-glycerol (Sb) from calcium 3,4-0·

cyclohexylidene-D-erythronate (calcium salt of 18b). The title compound bas been obtained as described for the synthesis of 14a from 9a but starting from

calcium 3,4-0-cyclohexylidene-D-erythronate.2Hz014 (calcium salt of6b) forming

a suspension with the reaction mixture and without Nael. Yield: 67.2 %. 1H NMR

(eDCI3): l> 1.5 (br.s, !OH, C(eH2)5), 2.55 (br.s, 1H, OH), 3.6-4.3 (m, 5, H-1, H-2,

H-3); [a]017 +10.3° (neat), lit. 14 [a]0

20 +7.3° (c 2, MeOH); bp 87-88 oe

(0.75 mmHg),lit.14 bp 87-89 oe (1 mmHg).

5. Reduction of proteeled glyceraldehyde and glyceric acid to glycerol derivatives 109

Methyl 2,3-0-Isopropylidene-D(R)-glycerate (31a). A stirred so1ution of

2,3-0-isopropylidene-D(R)-glyceric acid (3a, 1.46 g, 10 mmol), pTsOH (17 mg,

0.1 mmol), and DMP (1 g, 10 mmol) in MeOH (10 mL) was heated under reflux

for 4 h. The so1ution was cooled, treated with NaHe03, filtered, and concentrated

in vacuo. The residue was taken up in 1,2-dimethoxyethane (10 mL), filtered and

treated with DMP (1 g, 10 mmol) and Sne~ (10 mg, 0.05 mmol) under reflux for

1 h. The solution wasthen cooled, treated with pyridine (1 drop), concentrated in

vacuo and distilled to yield 31a (1.12 g, 70% yield). 1H NMR (eDCI3): a 1.43

(s, 3H, C(eH3) 2), 1.52 (s, 3H, C(eH3) 2), 3.79 (s, 3H, -OCH3), 3.9-4.7 (m, 3, H-2,

H-3); [a]020 +18.3° (c = 0.97, eHel3), lit4

• [a]020 -18.6° (L-enantiomer, c = 1.52,

acetone), [a]020 +18.1° (c = 3.07, eHel3); bp 50-52 oe, 0.75 mmHg, lit4

• 73 oe,

23 mmHg.

Methyl2,3-0-Cyclohexy6dene-D-(R)-glycerate (3lb ). The title compound

has been obtained as described for 31a, however, DMe was used instead ofDMP.

Yield: 62.4 %. 1H NMR (eDel3): a 1.62 (br.s, 10H, e(e~)s), 3.75 (s, 3H, -

OeH3), 3.88-4.72 (m, 3, H-2, H-3).

Benzyi2,3-0-Isopropylidene-D(R)·glycerate (55a). A stirred so1ution of

sodium 2,3-0-isopropylidene-D(R)-g1ycerate (sodium salt of 3a, 16.8 g, 0.1 mol)

and benzyl bromide (34 g, 0.2 mol) in eH3eN (100 mL) was heated under reflux

for 48 h. The reaction mixture was then concentrated in vacuo and distilled to

yield 55a (9.52 g, 81 % yie1d). 1H NMR (eDel3): a 1.40 (s, 3H, e(eH3) 2), 1.51

(s, 3H, C(eH3) 2), 4.0-4.8 (m, 3H, H-2, H-3); 5.25 (s, 2H, e~-Ar); 7.40 (s, 5H,

H-Ar); [a]020 +12.3° (c = 1, eHCI3); bp 140 oe, 3.75 mmHg.

Benzyi2,3-0-Cyclohexy6dene-D-(R)-glycerate (55b). The title compound

has been obtained as described for 55a, but distillation was not possible due to the

high boiling point. Yield: 56.9 %. 1H NMR (eDel3): a 1.60 (br.s, 10H, C(eH2)s),

4.1-4.8 (m, 3, H-2, H-3); 5.25 (s, 2, e~-Ar); 7.43 (s, 5H, H-Ar).

1,2-0-Isopropylidene-L(S)-glycerol (Sa) from methyl 2,3-0-

isopropylidene-D(R)-glycerate (31a). To a stirred solution of methyl 2,3-0-

isopropylidene-D(R)-glycerate (31a, 3.2 g, 20 mmol) in MeOH (30 mL) NaBH4

(0.76 g, 20 mmol) was added in small portions. The reaction temperature was kept

below 30 oe. After addition of NaBH4 the reaction mixture was heated under

reflux for 1 h, cooled and treated with acetone (5 mL) and after 15 min with water

(5 mL). The reaction mixture was then concentrated in vacuo and the residue

dissolved in saturated aqueous Nael (20 mL). Extraction with eHel3, drying over

anhydrous MgS04, ftltration, concentration in vacuo and distillation yielded


enantiomerically pure Sa (2 g, 77 % yield). 1H .NM:R. (eDa3): ~ 1.37 {s, 3H,

C(eH3) 2), 1.46 (s, 3H, C(eH3)2), 2.51 (br.s, 1H, OH), 3.6-4.2 (m, 5, H-1, H-2, H-

3); [0:]020 +13.8° (neat), lit13

• [a]020 +14.0° (neat), lit.4 [0:]0

20 +15.4° (neat); bp

50 oe, 2 mmHg, lit.4 82 oe, 13 mmHg.

1,2-0-eyclohexylidene-L(S)-glycerol (Sb) from methyl 2,3..0· cyclohexyUdene-D(R)-glycerate (3lb). The title compound bas been obtained as

described for Sa from 3la. Yield: 60.5 %. 1H NMR (eDC13): ~ 1.5 (br.s, 10H, C(e~)5), 2.35 (br.s, 1H, OH), 3.6-4.2 (m, 5, H-1, H-2, H-3); [a]0

20 +9.7 o (neat), lit!" [0:]0

20 +7.3° (c 2, MeOH); bp 87-88 oe (0.75 mmHg), lit.14 bp 87-89 oe (1 mmHg).

S. 7 Relerences and notes

(1) -Jw:czak:, J.; Pllwi. S.; Baaer, T. Tetrahetiron 1986,42,447. (2) Fis<:her, H. 0. L.; Baer, E. Chem. Rev. 1941, 29, 287. (3) (a) Baldwin, J. J.; Raab, A. W.; Mensler, K.; Arison, B. H.; McClure, D.

E.I. Org. Chem. 1978, 43, 4876. (b) Jung, M. E.; Sbaw, T. J. I. Am. Chem. Soc. 1980, 102, 6304. (c) De W'llde, H.; De Oetq, P.; Vandewalle, M. Tetrahetiron Lett. 1987, 28, 4757.

(4) Hirth, 0.; Walther, W. Helv. Chim. Acta 1985, 68, 1863. (5) Lok, C. M.; Ward, J. P.; van Dorp, D.A. Chem. Phys. Lipids 1916, 16, 115. (6) Hudlickj, M. Reductions in Organic Chemistry 1984, Ellis Horwood

Limited, England (7) (a) Rylander, P. N. Catalytic Hydrogenation in Organic Syntheses 1919,

Academie Press, US. (b) Rylaader, P. N. Best Synthetic Methods: Hydrogenation Methods 1985, 66, Academie Press, US.

(8) Baer, E.; Fiscber, H. 0. L. I. Biol. Chem. 1939, 128, 463, 472. (9) FP 1377972 1964. (10} Assumption: all H:z02-reactions proceed in 85 % yield (average of literature

data and own experience). (11) Freifelder, M. Practical Catalytic Hydragenation 1971, Jobn W'tly & Sons,

loc., US. (12) Smith, F.; Stephen, A. M. Tetrahetiron Lett. 1960, 7, 17. (13) Mikk:ilineni, A. B.; Kumar, P.; Abusbanab, E. I. Org. Chem. 1988, 53,

6005. (14) Voeffray, R. EP 325967 1989. (15) (a) Wei, C.-C.; Mangele, M. EP 113261983. (b) Abusbanab, B.; Bessodes, M.; Antonakis,

K. Tetrahedron Lett.1984, 25, 3841. (c) Taaaka, A.; Yamasbita, K. Synthesis 1987, 570.

6. Selective degradation ofunprotected sugars to glyceraldehyde and glyceric acid 111

~: §~ótt1~ift~êii~ö~rióN ó~ tiN~äö~~# / ·•$'lJqAJl$···t~.•··~~~~~~~~~mî>I•••·R···<i~lrQI~~··I\.CW

6.1 Abstract

A number of selective degradation methods for unprotected sugars to low

molecular weight carbohydrates with practical value are presented. AMS-If:z02-

catalyzed alkaline oxidative cleavage of C6-, Cs- and C4-aldoses with oxygen

affords the next lower aldonic acids in good yields (70 % to 98 % in solution).

Also oxidation of D-fructose to D-arabinonic acid with oxygen in the presence of

AMS and lf:z02 proceeds with a remarkable selectivity (85 % yield). NaOCl

mediated degradation of C6-, Cs- and C4-aldonic acids at pH = 4.5 - 5.5 yields the

next lower aldoses with high selectlvities (up 90% at 80% conversion), but

unfortunately selectivity decreases at higher conversions. Selectivity seems to be

govemed by the amount of hypoclllorite present in the reaction mixture. An excess

of oxidant causes side-reactions and hence decreases selectivity. The reaction also

can be carried out with in situ generated hypochlorite by electrochemical oxidation

of NaCl. The active species probably is HOCl which is reflected in the mechanism

proposed. Degradation of D-fructose with hypochlorite at pH = 9 yields D

erythrose and glycolic acid in good yields (60 %). In this reaction oet· is thought

to be the active oxidant and a mechanism is suggested. Degradation of most C6-

and Cs-2-ketoaldonic acids with H20 2 at pH = 7 or NaOCl at pH = 5.5 yields the

next lower aldonic acid in high yields (up to 95 % ). However, degradation of 2-

keto-D-arabinonic acid with H20 2 is less selective (70% yield of D-erythronic

acid, besides 30% D(R)-glyceric acid). Cleavage of L-ascorbic acid and D

isoascorbic acid with lf:z02 affords the corresponding tetronic acids, together with

oxalic acid, in high yield (95 % ).

Sequentia! use of abovementioned oxidation methods yields L(S)

glyceraldehyde, D(R)-glyceraldehyde, and D(R)-glyceric acid in two or three

reaction steps from readily available C6-carbohydrates. Especially degradation of

D-fructose with hypochlorite and degradation of the ascorbic acids with H20 2,


involving cleavage of two carbon atoms in one reaction step, seem very promising.

The intermediate C,- and C4-derivatives, need not to be isolated but may be oxidized further in the reaction mixture without significant loss of selectivity, thereby reducing the number of expensive isolation procedures.

6.2 Introduetion

Low molecular weight carbohydrate derivatives containing less than six carbon atoms, are not available in large amounts at a reasonable price in contrast

toa number of C6-carbohydrates (see Chapter 1). Examples of interesting low

molecular weight carbohydrates are: D(R)- and L(S)-glyceraldehydes (28 and 10, respectively), D(R)- and L(S)-glyceric acids (29 and 12, respectively), D-erythrose (26), D-erythronic acid (27), and L-threonic acid (8) (see Fig. 6.1).

0

1H

OH OH

(10,28)

0

10H

OH OH

(12, 29)

0

1H

OH OH OH

(26)

0

10H

OH OH OH

(8,27)

Figure 6.1: Examples of interesting low molecular weight carbohydrates

They contain one or two ebiral eentres and can serve as versatile building blocks for the synthesis of optically pure compounds1

• However, at the moment they are

too expensive for large scale use. The syntheses of these low molecular weight

carbohydrates mostly comprise degradation of readily available monosaccharides, but methods being at the same time selective and inexpensive, have not been

developed. A Ïrrst fruitful, high yielding approach to small carbohydrates

constitutes degradation of cheap proteered monosaccharides, as is described in


Chapters 3 and 4 for the selective cleavage of D-mannitol (1) and D-iso- and Lascorbic acids (16 and 6, respectively), with the aid of cheap oxidizing agents. In

this way small, protected carbohydrates are obtained, easily deprotectable under

acidic conditions. However, selective proteetion of hydroxyl functions in most

carbohydrates is often very difficult, due to the large number of equally reactive

hydroxyl functions. A second approach to small carbohydrates consists in the

selective degradation of unprotected sugars. Selective proteetion of the low

molecular weight carbohydrates obtained via this route is attained more easily in

view of the lower number of functionalities.

Carbohydrate degradation reactions are among the most fundamental tools

of carbohydrate chemistrf. They have traditionally been used to unravel the

structure of higher sugars, e.g. by pedodie acid oxidation3• V aluable information

emerges from the exact nature and the amounts of products and from the quantity

of oxidant consumed. A number of oxidizing systems cleaves unprotected

carbohydrates into the lower sugar derivative and C02 • For example, alkaline

H20 2, in the presence or absence ofFe2+-catalysis (Fenton's reagent4), sequentially

degrades aldoses, aldonic acids and alditols nearly completely to formic acid and

water. Some selective methods are known, but in general the use of an excess

of oxidizing agents or extremereaction conditions (temperature and pH) causes

further degradation of the initia! reaction products. For example, when the

unprotected sugars D-glucose (19) and L-arabinose (L-enantiomer of 22) are

treated with an excessof Pb(0Ac)4, total degradation to formaldehyde and formic

acid occurs. However, application of two equivalents Pb(0Ac)4 per mole substrate,

allows the isolation of D-erythrose (26) and L(S)-glyceraldehyde (10) in fairly

good yields (80- 83 %)6•

One of the most widely used preparalive oxidative degradation methods is

the Ruff degradation2'8 (see Fig. 6.2). In this reaction an aldonic acid undergoes

oxidative decarboxylation by the action of ~02 in the presence of ferric ions, and

affords the next lower aldose. Although the reaction is fairly specific, ferrous ions

interfere by causing oxidation of the aldose formed. One of the major problems

in the Ruff degradation lies in the separation of the sugar from the large amount

of inorganic salts in the f"mal reaction mixture. Ion-exchange resins offered a

simple metbod of improving the isolation (up to 45 % yield9). The highest yield

(60 %10) of D-arabinose (22) basedon D-gluconic acid (20), was obtained when

114 Carbohydrate-bosed syntheses of C3-chirons

catalytic amounts of ferric gluconate (ferric salt of 20) were used instead of Fe03•

Other classica! degradation methods2•8 yielding the next lower aldose are the Wohl

degradation11, degradation of an intermediale nitrile by ammoniacal silver

hydroxide, the Weerman degradation12, alkaline hypochlorite oxidation of amides,

the disulfone method13, oxidation of diethyl dithioacetals by peroxypetpropionic

acid foliowed by base-catalyzed cleavage with dilute aqueous ammonia, and the

Hunsdiecker reaction14, bromine oxidation of silver saltsof poly-0-acetyl-aldonic

acids. Relatively new methods for the selective degradation of carbohydrate

derivatives to the next lower aldose are oxidation of aldoses by silver carbonale

on Celite, giving formic esters of the next lower aldose as major products15,

cerium(IV) oxidations of aldoses and aldonic acids to the next lower aldose16,

oxidation of aldoses by Fe03 upon irradiation under aerobic atmosphere 17, and

hypochlorite oxidations of aldonic acids at pH = 4.5 - 5.018 (see also Fig. 6.6).

COOH CHO

I H2027 I (CHOH) n (CHOH)n-1 + co2 I Fe3+ I CH20H CH20H

(20,23) (22, 26)

Figure 6.2: Rujf degradation of aldonic adds to, the next lower aldose7

However, in comparison with the Ruff degradation7, abovementioned

stoichiometrie oxidations are, with the exception of the hypochlorite degradation

of aldonic acids18, less attractive since they need expensive reagents and/or more

than one reaction step. Another classica!, useful preparalive degradation of aldoses

is the alkaline oxidative degradation with molecular oxygen19• lt affords the next

lower aldonic acid, even with ketoses. Although the reaction generally proceeds

in good yields (up to 84 % for the synthesis of sodium D-arabinonate (sodium salt

of 23) from D-glucose (19l0), a recent impravement by Hendriks et al.Z1

, viz.

addition of catalytic amounts of AMS (sodium anthraquinone-2-sulfonate) and

~02, increases the yield to nearly quantitative for the transformation of D-glucose

6. Selective degradation qJ unprotected sugars to glyceraldehyde and glyceric acid 115

(19) into D-arabinonic acid (23). Also degradation of a-keto-acids using

bromine22 or ~0/3 yielding the next lower aldonic acid, seems to be very promising (up to 93% yield in the ~02 oxidation of calcium 2-keto-D-gluconate (calcium salt of 21) to calcium D-arabinonate (calcium salt of 23)231>). In this

context degradations of D-iso- and L-ascorbic acids (16 and 6, respectively) with ~02 to D-erythronic acid (27)'-4 and L-threonic acid (8?', respectively, are also

of great interest. In these reactions two carbon atoms are removed from a C6-

carbohydrate derivative thus affording the corresponding tetronic acids and oxalic acid in high yield (94 %) (see Fig. 6.3).

K00:< 01

0K 0 0 H2o224,2S OH

HO ... OH + HOOCCOOH

HO OH OH

(16, 6) (27, 8)

Flgure 6.3: HP2-mediated cleavage of ascorbic acids (6, I6)'4:n

In conclusion, a number of methods is available for the selective degradation of carbohydrates to derivatives containing fewer carbon atoms. Especially, alkaline oxidative degradation of an aldose or ketose to the next lower aldonic acid19

'21

, NaOCl- or Ruff-degradation of an aldonic acid to the next lower

aldose7-10

, and ~02-degradation of a.-keto-acids and ascorbic acids to lower

aldonic acids23"25

, seem to be of practical value. D-Olucose (19), D-gluconic acid (21), D-fructose (15), D-iso- and L-ascorbic acids (16 and 6, respectively)

presumably are substrates for a sequentia! use of these methods for the synthesis of low molecular weight carbohydrates. Most of these methods degrade C6-

carbohydrates to C5-derivatives, although some are applied for the degradation of

C5-carbohydrates to C4-derivatives, usually in somewhat lower yield. Moreover,

oxidation of aldoses to their corresponding aldonic acids can be realized very efficiently by oxidation with bromine26

, NaOCl at pH= l1 18a.b or NaC102

27, 0 2

116 Carbohydrate-based syntheses of C;-chirons

in combination with catalytic amounts of some transition metals on carbon28, and

biochemica! oxidation29• 1bis completes the reaction scheme descrihing possible

syntheses of low molecular weight carbohydrates such as D(R)-glyceraldehyde

(28) and D(R)-glyceric acid (29), starting from readily available monosaccharides

(see Fig. 6.4 and alsothe reaction scheme in Appendix ID).

CHO COOH COOH

I a I c I (CHOH) n ... (CHOH) n ... co I I I CH20H CH20H (CHOH) n-1

x / I CH20H

CHO COOH COOH

I a I c I (CHOH) n-1 ... (CHOH) n-1 ... co I I I CH20H CH20H (CHOH) n-2 dx /te. I

CH20H

Figure 6.4: General strategy jor the stepwise oxidation and degradation of unprotected carbohydrate derivati~es to low molecular weight derivatives (a - e according to the overallreaction scheme in Appendix lil)

In this chapter the syntheses of D(R)- and L(S)-glyceraldehyde (28 and 10,

respectively) and of D(R)-glyceric acid (29) by sequentia! degradation of D

glucose (19), D-gluconic acid (20), D-fructose (15), 2-keto-D-gluconic acid (21),

and D-iso- and L-ascorbic acids (16 and 6, respectively) are described, using 0 2

in the presence of catalytic amounts of AMS and ~02, Naoa (also by in situ

electrochemical generation), and ~02•


6.3 Reaetions

We have studied the following selective oxidative cleavage reactions of

unprotected sugars:

CHO COOH

I 02, pH = 13 I (CHOH)n (CHOH) n-l + HCOOH

I AMS-H202-cat. I CH20H CH20H

(19, 22, 26) (23,27,29)

Figure 6.5: AMS·HP2-catalyzed allcaline oxidative degradation of a/doses to the next lower aldonic acid with 0 2

COOH CHO

I NaOCl I (CHOH) n (CHOH) n-1 + co2 I pH=4.5-5.5 I CH20H CH20H

(20,23,27,8) (22, 26, 28, 10)

Figure 6.6: Degradation of aldonic acids to the next lower aldose with NaOCI

118

0 OH

HO 0 2,pH=13

OH OH AMS-H20 2-cat •

OH

(23)


OH

0

HO OH OH OH

(15)

NaOCl ... pH=9

0

1H

OH OH OH

(26)

Figure 6. 7: De grOllation of D-fructose ( 15) with 0 2 using catalytic amounts of AMS and H20 2 and withNaOCl

COOH

I co

COOH

NaOCl or I I

(CHOH) 8

I

(CHOH) n + C02 H202 I

CH20H

CHzOH

(21, 24) (23, 27)

Figure 6.8: Degradation of 2-keto-aldonic acids to the next lower aldonic acid using HP2

orNaOCI

HO/-y 01

0H 0 0 Hz02 OH

HO ... OH + HOOCCOOH

HO OH OH

(16, 6) (27,8)

Figure 6.9: HP2-Mediated degradation of ascorbic acid derivatives to the corresponding tetronic acids

6. Selective degradation of unprotected sugars to glyceraldehyde and glyceric acid 119


6.4.1 Selecüve degradaüon of aldoses with oxygen onder alkaline conditions uslng AMS and ~02 in catalytic amounts

0 H OH

OrH 0 OH 021 pH=13 02 1 pH=13

HO HO HO OH ... OH

.,. OH

OH AMS-H2o2-cat .

OH AMS-H20 2-cat. OH OH OH OH

(19) (23) (15)

Figure 6.10: AMS-Hz(J2-catalyzed alkaline o.xidative cleavage ofD-glucose (19f1 and D-fructose (15).

The fust study of the alkaline oxidation of aldoses by oxygen dates from

the beginning of this century30 and deals with the synthesis of D-arabinonic acid

(23) from D-glucose (19). Thanks to later work. the reactivity and selectivity19.20.31

have been improved. The yields of D-arabinonic acid (23) obtainable upon alkaline

degradation of D-glucose (19) amounts to 75 - 85 %, although, Scholtz et al.32

claimed a 98 % yield. Reactions of pentoses with 0 2 in alkaline medium are less selective and afford the corresponding tetronic acids in up to 45 % yield1

9b,d.

Recently, a significant improvement of the classical oxidation reaction was

reported by Hendrik.s et al. from this laboratoryl1• Upon addition of catalytic

amounts of AMS and ~02 to the classical oxidation mixture, selectivity increased

up to 98 % for the synthesis of D-arabinonic acid (23) from D-glucose (19) (see

also Fig. 6.10). In contrast to the classical oxidation, even higher reaction

temperatures were allowed, thus deminishing the reaction time considerably. The

reaction is believed to proceed as is depicted in Figure 6.1121• The 1,2-enediol

anion derived from D-glucose (19) in alkaline medium is oxidized by AMS to the

corresponding aldosulose which in turn is cleaved selectively by ~02 into D

arabinonic acid (23) and formic acid (47). The reduced AMS is reoxidized in situ

120 Carbohydrate-based syntheses of C 3-chirons

by 0 2 thereby producing ~02, which completes the reaction cycle. This AMS~02:catalyzed alkaline oxidative degradation provides the most efficient route for the selective degradation of aldoses to the next lower aldonic acids.

or H): -a+ OH -+

HO ....,__

HO +W R R

(19)

HO~ 0~: 1-o· . -+ HO ~ + AMS ....,__ HO + AMSH"

R R

AMSH" + Oz .... AMS + aoo·

oA ~oo-

Ho-f"' + Hl

0 H

Ho-o.:Ïo- + HO~

R R

OH oÇ} HO-O.:rOH+OH· ~

HO~ ·

H

HOto· H0-0 OH

H~O-OH ' 0 +OH·

HO HO~

R R R

H HOf -~0 o o-o o- -H20

'!.%~_. OH -+

HOr + y ....,__

R H R (anion of 23)

Net reaction: 19 + Oz -+ 23 + HCOOH

OH

HtO-OH HO o· HO

R

H$OHO_foH HO o-HO ,._,

R

Figore 6.11: Simplified reaction scheme for the AMS-H10 2-catalyzed alkaline oxidative degradation of V-glucose (19f1


In our reaction scheme dealing with the degradation of unprotected

monosaccharides to D(R)- and L(S)-glyceraldehydes (28 and 10, respectively) and

D(R)- and L(S)-glyceric acids (29 and 12, respectively) (see Appendix ill), three

AMS-~02-catalyzed degradations of an aldose to the next lower aldonic acid can

be applied, namely degradation of D-glucose (19) to D-arabinonic acid (23) (step

bl), degradation of D-arabinose (22) to D-erythronic acid (27) (step b2), and

degradation of D-erythrose (26) to D(R)-glyceric acid (29) (step b3). Also the

degradation of D-fructose (15) to D-arabinonic acid (23) (step y, see also Fig.

6.10) is expected to proceed selectively, analogous to the classical alkaline

degradation19• It is generally accepted that the reaction proceeds via the 1,2-enediol

anion appearing in alkaline medium, which is the same for D-glucose (19) and D

fructose (15Y3 (and forD-mannose (32)).

The AMS-~02-catalyzed oxidative degradation of D-glucose (19) to D

arabinonic acid (23) already has been reported to proceed very selectively (max.

yield of 23 in solution is 98 %21). In order to isolate the product in high yield, the

degradation was carried out according to Hendriks et al.:Z1, with some minor

adjustments. The. concentradon of D-glucose (19) in the reaction mixture was

increased to 0.5 M, sodium hydroxide was used instead of potassium hydroxide,

and the reaction temperature was gradually increased from 40 oe at low

conversion to 55 oe at high conversion. Higher concentradons and reaction

ternperatures led to a decrease in selectivity. In this way the batch reaction time

necessary for complete conversion could be reduced from 24 to 1.5 h. Isolation of

sodium D-arabinonate (sodium salt of 23) was accomplished by crystallization of

a metbanolie oxidation product mixture, according to Dubourg et al. 1"". The

alkaline reaction mixture was acidified to pH = 7 and treated with active carbon

to remove AMS and other impurities, f.tltered and partly concentraled in vacuo.

Addition of methanol induced crystallization of sodium D-arabinonate (sodium salt

of 23), which subsequendy could be isolated by fUtration in 85 % yield. The

purity of crystalline sodium D-arabinonate was 96 - 97 %, with sodium formate

as the main impurity.

In order to determine the general applicability of the AMS-~02-catalyzed oxidative cleavage, the oxidation of two pentoses, one tetrose and one ketose (see

Fig. 6.12) was carried out on smaller scale. The results are collected in Table 6.1

and Figures 6.13 and 6.14 show the concentradon prof.tle and the selectivity and

conversion prof.tle, respectively, of the oxidation of tetrose D-erythrose (26).


or or OH OH or HO HO OH HO OH OH HO OH OH

(40) (49) (26)

~ AMS-H202-cat. ~ 02,pH=13

~ OrOH

0

10H

0

10H

HO HO HO OH OH HO OH OH

(54) (53) (29)

Figure 6.12: AMS-H20 2-Catalyzed alkaline oxidative c/eavage of some pentoses and a tetrose

The results shown in Table 6.1 reveal that the selectivities in all reacrions described are somewhat lower than in the degradation of D-glucose (19). The oxidative degradation of D-erythrose (26) seems to proceed with the lowest selectivity, but the reaction conditions in none of these oxidations have been optimized. For the degradation of pentoses to the next lower aldonic acid, the AMS-~02-catalyzed oxidative degradation is preferred over the classical alkaline

oxidative degradation (yield almost twice as high compared to the classical method1

9b,d). For the reaction with D-fmctose (15) no significant difference in

selectivity between the classicarw and the AMS-~02-catalyzed reaction is

observed. However, the AMS-~02-catalyzed oxidative degradation of D-fmctose (15) proceeds faster at higher reaction temperatures without loss of selectivity. The differences in selectivities between the reaction with D-glucose (19) and other substrates are presumably caused by differences in stability in the alkaline reaction


Table 6.1: Selectivity of the AMS-Hz02-catalyzed oxidative degradation of some a/doses and a ketose"

·.·.··.·.·.··.-................. ·.· .. · .. · .. ·.·: .. ··.:.:·.· ..... ·.· ··· .. · ... •.·. ··:.·.:. ·····. ···.··.·· .. ·· .· ....... •·,· ... ··,••,••,,,',,'.'',,' ............ ·.·.· .. ·

>~~try • ...• ~~~ti'ät~ ·.·•.. • •. .• c()ri\fè~~ (~)i; • ~~~~l:l (~)f i t(iÏatiy~ reäétim1 ratë" .

1 D-glucose (19) 100 95 1

2 L-arabinose (40) 86 83 1/3

3 D-xylose (49) 98 72 1/2

4 D-erythrose (26)d 99 62 10

5 D-fructose (15) 94 85 2

"Reactions carried out at 20 - 30 oe and r = 100 % (0.2 M substrate in 0.6 M aqueous NaOH) using 0.01 equivalents of AMS and ~02 per mole substrate. beooversion and selectivity in solutions determined by .HPLe (as described in Chapter 2). •Qualitative relative reaction mte compared with the degmdation of D-glucose (19). deoncentmtion of D-erythrose (26) is 0.045 M in 0.135 M aqueous NaOH andreaction tempemture is 25 oe.

medium of substrates and reaction intermediates and the possible side reactions

that may occur at different reaction rates e.g. ~-elimination, isomerization, retro

aldol condensation. The aldonic acids produced are, in general, stabie to further

degradation3s. In the reaction with D-fructose (15) the selectivity is lower than

in the reaction with D-glucose (19), due to simultaneous formation of 1 ,2-enediol

and 2,3-enediol anion. Both enediolates react further yielding different aldonic

acids. The principal enolization occurs between C-1 and C-2, and therefore leads

dominantly to D-arabinonic acid (23)33•3s. The relatively low selectivity in the

reaction of D-erythrose (26) may be caused by the considerable proportions of

aldehyde and aldehydrol forms of aldotetroses in aqueous solution. Moreover, they

readily form dimers in solution, which renders the reaction mixture very

complex36• Due to the different reaction conditions applied, the reaction rates have

not been compared.

No effort has been made to isolate the reaction products formed. This will

probably be more difficult than the isolation of sodium D-arabinonate (sodium salt

of 23) since precipitation with methanol did not yield crystalline materiaL Product

isolation at this stage is, however, not really necessary because all further reactions

are carried out in the same solvent and are not influenced substantially by side

products and impurities.

In conclusion, the AMS-~02-catalyzed alkaline oxidative degradation of

aldoses and ketoses to the next lower aldonic acids proceeds satisfactorily.

124 Carbohydrate-based syntheses of C rchirons

Especially the degradation of D-glucose (19) proceeds very selectively and the

reaction product, D-arabinonic acid (23), can be isolated easily in high yield

(85 %) as the sodium salt. Although yields in the reactions with the other

substrates are somewhat lower, they are equal to or higher than yields obtainedin

the classic al alkaline oxidative degradation. Moreover, the batch reaction time can

be reduced without loss of selectivity when the reaction is carried out at higher

temperatures, in contrast to the classica! reaction. This renders the AMS-~02-catalyzed oxidative degradation of high practical value for the selective

degradation of aldoses and ketoses to the next lower aldonic acids. The yields of

these reactions may possibly be further improved by optimization of the reaction

conditions.

1.1)0

"....

' OBO 0 ! g~

0.60

-I C:IY .. 0.40 .., A .. .. a 0.20 0 u

0.00 0.00 0.24 0.48 0.72 0.96 1.20

0, (eq. per mole 26)

Figure 6.13: Concentration profile (0:26, +:29, 0:47, ll:SO) in the AMS-Hz02-catalyzed alkaline oxidative degradation of 26. Conditions: pH>13, T=25 °C, r=JOO%, [26]=fJ.045 moliL, [AMS]= {H20J= 0.45 mmoliL

N' 1.00

0 ! .., Gl >. ~

il .. ~ r:: 0 u

0.24 0.48 0.72 0.96 1.20

o, (eq. per mole 26)

Figure 6.14: Conversion (0:26), selectivities (+:29, t..:47, o:SO), and yield (0:29) in the AMS-H20 2-catalyzed alkaline oxidative degradation of 26. Conditions: pH>13, T=25 °C, r=JOO%, [26]=0.045 mo/IL, [AMS]=[HzOJ=0.45 mmoliL

6.4.2 Selective degradation of aldonic acids with NaOCI

Decarboxylation of aldonic acids to the next lower aldose traditionally bas

been achieved by the Ruff degradation7, implying the action of ~02 on aldonic

acids in the presence of ferric salts. The isolated yields in the case of hexonic

acids are relatively low (up to 45 % for D-arabinose (22)9), probably due to the

6. Selective degradation ofunprotected sugars to glyceraldelryde and glyceric acid 125

ability of ferrous ions to induce formation of hydroxy radicals and hence forther

oxidation of the aldoses fonned. The yields starting from the conesponding

pentonic acids are even lower (20 %)7• The highest yield, 60 %, is claimed for the

synthesis of D-arabinose (22) from D-gluconic acid (20) with Hz02 in the presence

of catalytic amounts of ferric gluconate (ferric salt of 20) instead of Fe0310

•

Higher yields are obtained in the Na0Cl18- and Ce(IV)(S04) 2

16-mediated

degradation of aldonic acids to the next lower aldose (yields up to 73 and 90 %,

respectively), of which the NaOO-degradation is industrially the most attractive

one. We, therefore, applied this metbod for the degradation of aldonic acids to the

next lower aldose in the degradation of readily available monosaccharides to D(R)

and L(S)-glyceraldehydes (28 and 10, respectively) and D(R)-glyceric acid (29).

This reaction bas been applied 4 times (see Fig. 6.15 and overall scheme in

Appendix ill) i.e. in the degradation of D-gluconic acid (20) to D-arabinose (22)

(step dl), in the degradation of D-arabinonic acid (23) to D-erythrose (26) (step

d2), in the degradation of D-erythronic acid (27) to D(R)-glyceraldehyde (28) (step

d3), and in the degradation of L-threonic acid (8) to L(S)-glyceraldehyde (10)

(step d4).

Originally the NaOO-mediated degradation was reported by Whistier et

al. 1~~a, who prediered that varlation of oxidation potenrial and alteration in

composition of hypochlorite solution with pH might be useful for the production

of D-arabinose (22) from D-glucose (19). It is well established that D-glucose (19)

is readily converled to D-gluconic acid (20) by hypohalite oxidation in alkaline

solution8• lndeed, Whistier et al.1

Sa have shown that reaction of the sugar with 3

molar equivalents NaOCl afforded sodium D-gluconate (sodium salt of 20) in

80% yield. In conjunction herewith they found that D-arabinose (22) is also

present in the reaction mixture, especially in hypochlorite-mediated oxidations of

D-glucose (19) carried out at near-neutrality. Additionally, they established a

reaction pH between 4.5 and 5.0 to be optimal. This gave a 65- 70% yield of D

arabinose (22) when 2 moles Naoa were used per mole sodium D-gluconate

(sodium salt of 20). Combination of the two reactions ledtoa single-batch two

stage reaction for conversion of D-glucose (19) to D-arabinose (22) in 35 %

overall yield.

More recently improvements of the N aOO-degradation of D-gluconic acid

(20) to D-arabinose (22) have been reported more recently in patent literature 1~~c ....

Wolf et al. found that at higher substrate concentradons (0.6- 0.7 M) and at


0 OH

OH OrH HO HO O{OH OrH OH OH OH OH OH OH HO OH OH OH OH OH

(20) (23) (8) y (27)

~ pH=4. 5-5. 5 ~ NaOCl

or HO or 01H

OH OH OH OH OH OH OH OH

(22) (26) (10, 28)

Figure 6.15: Degradation of aldonic acids to the next lower aldose with NaOCl

higher reaction temperatures (60 oe) the relative amount of oxidant could be

reduced to 1.2 equivalents yielding up to 73 % crystalline D-arabinose (22)18c .. ,

while Whistier et al. kept substrate concentration and reaction temperature low

(0.05 M and 20 oe, respectively) to avoid hypochlorite degradation18a,b. Also the

reaction time needed for total conversion is much shotter at higher temperatures

and higher concentrations, and this also reduces the possibility of D-arabinose (22)

being oxidized forther under the reaction conditions. The selectivities obtained by

adjustment of the reaction conditions, however, do not differ substantially from the

original selectivities (73 % and 65 - 70 %, respectively).

The kinetics and the mechanism of this reaction have not yet been studied,

although Shilov et al.37 studied the oxidation of 0-gluconic acid (20) with

chlorine water at different pH's. They suggested for the oxidation of cx.-hydroxy

acids with chlorine water in the middle-range of pH the intermediacy of an alkyl


hypochlorite which decomposes, presumably catalyzed by hydroxide ion, to ~

cortesponding cx-keto acids. The active oxidizing agent is believed to be HOCl,

while e~ and OCl' are only weakly active. The rate of the oxidation of D-gluconic

acid (20) by active chlorine is very low in Hel, but readily rises with increase of

pH, reaching the maximum rate at pH = 7, after which it steadily declines.

In oxidations with hypochlorite it is not clear which reagent is the active

species. The composition of a hypochlorite solution is strongly dependent on the

pH of the reaction mixture, according to Equations 6.1 and 6.238• Since HOCl

and e1o· coexist over a wide pH-range, kinetic studies are necessary to establish

their respective roles.

HeiO • ao· + W ~8 = 3.4.10..s mol/I [6.1]

e~ + ~0 .,. HaO + a· + W ~ = 4.2.104 mofz/12 [6.2]

The molar fractions of ~. HOa and

Oei' versus pH at 25 oe for a solution

containing 0.2 M Naoa and 0.2 Ma·,

are given in Figure 6.16.

The chlorine compounds are

strong oxidants, although Shilov et al.37

have shown that action of~ and oer on D-gluconic acid (20) is relatively

weak:, compared with the action of

HOei. When the substrate is an aldose,

however, both, ~ and oer' will oxidize aldehyde to the cortesponding

acid8, which makes it very important to

control the reaction pH during

oxidations of carbohydrates. This also

explains the high selectivity in the degradation of aldonic acids to the next

1.00

0.90

~ 0.80

0.70 c cro-Q 0.60 ... 0 0.50 lil ... ...

0.40 ~

OJO ö E 0.20

0.10

0.00 0 2 4 6 6 10 12 14

pH

Figure 6.16: Molar fractions of C/1 ( .... ), HOC/ (-) and OCI' ( -.-) as function of the pH.

lower aldose at pH = 4.5- 5.0. In this pH-region the active chlorine compound is

almost exclusively HOei, while the concentrations of e~ and oer are negligibly

low. ehlorine compounds, however, exhibit lack of stability. Therefore, several

128 Carbohydrate-based syntheses of C,~-chirons

decomposition reactions (Eq. 6.3 - 6.6) have to be taken into account, all yielding

chlorine compounds with varying degrees of oxidizing power which may interfere

in any oxidation reaction38•39

• Dilute hypochlorous acid solutions are quite stabie

when pure, especially when kept cool and in the dark. For example, at 0 °C the

decomposition rate of a 1 M solution is only about 0.3 %per day, while at 20 °C

the decomposition rate is about ten times higher9•

2 HOCI • 2 H+ + Cl" + ClO; [6.3]

[6.4]

2 HOCl ~ 2 H+ + 2 er + 0 2 [6.5]

HOCI + HCl02 ~ HC103 + H+ + Cl' [6.6]

In conclusion, reactions of carbohydrates with hypochlorite are very

complex and may be greatly influenced by pH, temperature,light and composition.

Therefore all reactions have been carried out with pH and temperature controL The

influence of light at the chosen reaction conditions was found to be negligible.

Before reaction the sodium hypochlorite solutions (13 wt% active chlorine in

solution) were adjusted at the reaction pH with the aid of concentraled HCI.

However, during this pH-adjustment, C~ escapes from the oxidant solution

probably due to local high HCI-concentrations according Equation 6.4. Therefore,

the strength of the oxidant solution was determined iodometrically40• A drastic

decrease in oxidant concentradon is observed below pH = 8, as is depicted in

Figure 6.17. When NaOCl is adjusted to the reaction pH with concentrated HO,

a relatively large amount of oxidant is necessary, especially at low pH. No nuther

research was done to reduce the loss of oxidant, although neutralization by diluted

HCl-solutions is expected to minimize the loss. In that case, however, relatively

large volumes of HCl are necessary leading to a very diluted oxid.ant solution.

Also addition of alkaline NaOCl in small portions to the reaction mixture, kept at

constant pH by addition of 1 M HCI, reduces the amount of oxidant needed for

total conversion. In practice it is, however, easier to add pH-adjusted hypochlorite

solutions to the reaction mixture, and therefore we chose for this metbod and


* 15r---------------------~ l 5 12 f:; :J ö m 9

2 4 6 8 10 12 14

pH

accepted the loss of oxidant ..

1. Oxidation of aldonic acids witb NaOCL The de~on of

(

aldonic acids to the next lower aldose

by hypochlorite is intioeneed by pH,

temperature, and substrate

concentraûons. Presumably the amount

of oxidant present in the reacûon

mixtures also determines the

selectivity of the degradation. In order

to achleve a reasonable reaction rate a

reaction temperature of 40 oe was

chosen as standard condition which

resulted in batch reaction times of 2 -Figare 6.17: Oxidative strengthof pH-adjusted NaOCI solutions with concentrated HCI determined iodometrically. 3 h (substrate concentraûon usually

0.15 M). The oxidant, NaOCI adjusted

at the reaction pH, was added in small

portions every 15 min. The reaction mixtures were analyzed by HPLC, as

described in Chapter 2. The influence of pH, temperature, substrate concentration,

and the rate of NaOCl-addition on the oxidation of several aldonic acids was

studied.

Influence of temperature. The oxidations of D-gluconic acid (20) and D

arabinonic acid (23) to D-arabinose (22) and D-erythrose (26), respectively, were

studied onder standard reaction conditions at pH = 5 at temperatures ranging from

20 to 60 oe. When the reaction temperatures are kept between 40 and 60 oe, no

significant differences in selectivity are observed in both reactions. However, at

lower reaction temperatures (20 °C) selectivity decreases (see Fig. 6.18).

Presumably, at 40 oe and higher temperatures over-oxidation of the substrates and

fust reaction products is minimized, whereas at lower temperatures excess NaOCl

indoces side-reactions. Also, at lower reaction temperatures, more oxidant is needed fortotal conversion, presumably doe to side reactions that occur.

130

lnftuence of rate of addition

of NaOCI. Oxidations of D-gluconic

acid (20) and D-arabinonic acid (23)

tO) D-arabinose (22) and D-erythrose

(26), respectively, were studied under

standard reaction conditions at

pH= 5.5 with variation ofthe addition

time of NaOCl. When the oxidant is

added in small portions every 15 min

during 2 h 20 is obtained more

selectively (90 - 75 %) than when the oxidant is added in three portions each

30 min ( 60 - 70 %) or in one portion

at the beginning of the reaction

(40 %). These results again can be

explained by an unfavourable excess

of NaOC1 in the latter reactions and

are in agreement with the temperature

earbohydrote-based syntheses of eJ-chirons

1.00 t t

~ ö ! 1>. ... :E 0.40 ..... Cl .. 4i lil 0.20

0.00----~--~--~--~--~

0.00 0.20 0.40 MO O.BO 1.00

Conversion (mol%)

Figure 6.18: lnjluence of the temperature (0:20 oe, +:40 oe, 0:60 °C) on the oxidation of ZO with NaOel. eonditions: [20]=0.3 M, pH=5.5, 0.3 eq. NaOeltJO min

experiments. When sodium hypochlorite is added in small portions, se1ectivity is

usually high up to 70- 80% conversion and then decreases (see Fig. 6.20- 6.23).

This high se1ectivity presumab1y can be achieved also at higher conversions upon

reduction of the rate of addition of NaOCl.

Influence of pH. Oxidations of D-gluconic acid (20), D-arabinonic acid

(23), D-erythronic acid (27), and L-threonic acid (8) to D-arabinose (22), D

erythrose (26), D(R)-g1yceraldehyde (28), and L(S)-glyceraldehyde (10),

respectively, were studied under standard reaction conditions and at a pH-range

from 4 to 7. The maximum se1ectivities in all reactions are obtained at pH = 4.5 -

5.5 (see Fig. 6.19). These results indicate that HOCI is the active oxidant, which

is present in maxir?um amounts at pH = 5 (see Fig. 6.16). At lower or higher pH,

the percentages of ~ and oa· increases, causing oxidation of aldoses formed to

the corresponding aldonic acids, which then may undergo forther degradation by

HOCl etc.

Influence of substrates. At standard reaction conditions and pH = 4.5 - 5.5

maximum selectivity is achieved for all substrates. The selectivity and conversion


profdes of oxidations of D-gluconic acid (20), D-arabinonic acid (23), D-erythronic acid (27), and L-threonic

acid (8) are depicted in Figures 6.20 -

6.23. The selectivity of each reaction

is high up to 70 - 80 % conversion,

whereafter selectivity decreases presurnably due to the unfavourable excess of Naoa present at higher conversions. The amount of oxidant

needed for total conversion is about 2

equivalents per mole substrate at

40 °C. These results agree with the reported results for the oxidation of D

gluconic acid (20) with NaOCl at pH= 4.5- 5.018

• However, yields in solution in our reactions are somewhat

higher than the reported 73 % yield

"" ... :E ... " "' 'i I'Jl 0.20

000~--~--~--~--~--~

0.00 0.20 0.40 0.60 o.so 100

Conversion (mol~)

Figure 6.1.9: lnjluence of the pH (0:4, +:5, 0:6, IJ.:7) on the oxidation of 23 with NaOCI. Conditions: {23]=0.()6 M, · T=40 °C, 0.2 eq. NaOCI/15 min

for crystalline D-arabinose (22), due to losses during isolation. Probably the

product yield can be improved forther by controlled addition of the oxidant at high conversion. The highest selectivities (80 - 90 %) are obtained in the oxidation of

D-gluconic acid (20), whereas the selectivities in oxidations of the C,- and C4-

aldonic acitls (23, 27 and 8, respectively), are somewhat lower at higher

conversion (70 %).

The abovementioned results show that the oxidative degradation of aldonic acids to the next lower aldose with NaOCl at pH= 4.5 - 5.0 proceeds fairly

selectively. The hypochlorite concentration in solution is of crucial importance due to side reactions that occur when an excess of oxidant is present. The hypochlorite

concentration can be regulated directly by varying the rate of addition of the oxidant and indirectly by temperature variation. In the latter case, the reaction rate

can be influenced thereby causing variations in hypochlorite concentration. At

lower reaction temperatures more oxidant is needed for total conversion at

standard reaction conditions. By limiting the rate of addition of NaOCl, however, the lossof oxidant can be limited.

132

NaOCI (eq. per mole 20}

Figure 6.20: Conversion (0:20), selectivity (+:22), and yield (0:22) in the NaOCI degradation of 20. Conditions: [20]=0.3 M, T-42 °C, pH=5.5, 0.3 eq. NaOCI/30 min

NaOCI {eq. per mole 27)

Figure 6.22: Conversion (0:27), selectivity (+:28, o:SO, {:47), and yield (0:28) in the NoOCI degrodation of 27. Conditions: [27]=0.125 M, T=40 °C, pH=5.0, 03 eq. NoOCI/15 min

Carbohydrate-based syntheses of C;-chirons

1.00 ~ ö ! '0 öi ·;:. Jd

0..40 öi Ol

::: 020 t:l 0 u

NaOCI (eq. per mole 23)

Figure 6.Zl: Conversion (0:23), selectivity (+:26, 4:27,29, o:50,(:47), and yield (0:26) in the NaOCI degradation of 23. Conditions: [23]=0.15 M, T=40 °C, pH=5.0, 0.2 eq. NoOC/115 min

1.00 ~ t t t

ö ! '0

ti

"" Jd

-; Ol

> t:l 0 u

NaOCI (eq. per mole 8}

F'agure 6.23: Conversion (0:8), selectivity (+:10, ll:SO, o:47), and yield (0:10) in the NaOCI degradation of 8. Conditions: [8]=0.094 M, T-40 °C, pH=5.0, 0.2 eq. NaOCI/15 min

Mechanism. The mechanism of the degradation of a-hydroxy acids with aqueous chlorine in the middle pH-range suggested by Shilov et al.:n, involves formation of an intennediate alkyl hypochlorite ester and forther decomposition


into the corresponding a-keto acids. Oxidative degradation of 2-keto acids,

however, will not lead to the next lower aldose, as is suggested incorrectly in the

mechanism of the Ruff degradation41, but to the next lower aldonic acid (see

Section 6.4.3). The oxidations with aqueous chlorine canied out by Shilov et al.37,

leading to keto acids, therefore differ from our reactions. Aukett et al. 42

o o- o o-

H+OH ... H+O-CI + HOC! + HzO ... R R

o.f;;

~~ ... OYH + co2 + er H 0-Cl

R R

Figare 6.24: Suggested mechanism for the decarboxylation of aldonic acids to the next lower aldose by HOC/

suggested, however, a mechanism for the decarboxylation of mandetic acid with

hypobromous acid without formation of an intermediate tx-keto acid and in our

view this may be also applied to the decarboxylation of aldonic acids to the next

lower aldose with hypochlorite. The mechanism is given in Figure 6.24 and

involves formation of an intermediate alkyl hypochlorite ester, which decomposes

into the next lower aldose and carbon dioxide. The formation of alkyl hypochlorite

esters of alcohols in aqueous solutions of HOCI has been studied and is subject

to general acid-base catalysis. Alkyl hypochlorite esters are also formed readily

when an alcohol is treated with Na0Cl43• In reacrions with carbohydrates they

are suggested to function as intermediates in the oxidative cleavage of e.g. starch

with Na0Cl40, where the ester formation is fast and the decomposition reaction is

the rate limiting step. Indeed, this alkyl hypochlorite ester formation rationalizes

perfectly the degradation of aldonic acids to the next lower aldose, without forther


reaction of the latter with HOCl. The electtonic requirement for decarboxylation

is the presence of an electron-withdrawing substituent in the organic residue. In

the absence of hypochlorite, reaction cannot take place because H' cannot function

as teaving group under these conditions. The other hydroxy functions also may be replaced by hypochlorite in a fast equilibrium reaction, but do not induce

decarboxylation, which is also the reason why aldoses are not further degraded by

HOCl. Observed side reactions can be explained by oxidation of carbohydrates

with other chlorine species present in the reaction mixture. Since optimum selectivity is reached at pH= 4.5 - 5.5, HOClis the active species,~ and oa· being only present in very small amounts. At higher and lower pH the

concentrations of ~ en OCI' are higher. These oxidants will oxidize aldoses

fonned to the cortesponding acids, which then may be degraded further by HOCI

and accordingly causing lower selectivities in these pH-regions. NaOCl is also able

to fonn hypochlorite esters with alcohols, but at high pH (pH> 10) this formation of hypochlorite esters is not favoured and consequently the oxidation reaction can be stopped at the acid stage43

• At low pH, C~ is the main oxidizing agent, but it does not react significantly with alcohols to produce hypochlorite esters and

moreover, the substrates are fully protonated, which makes decarboxylation less favourable.

2. Indirect electrochemical HOCI·oxidation of aldonic acids. Usually NaOCl solutions (12- 15 wt% active chlorine) are prepared by chlorination of NaOH according to Equation 6.8.

C~ + 2 NaOH -+ NaOCl + NaCl + fl:tO [6.8]

However, because of transportation costs and for safety reasoos this production

process is not always preferred. Therefore, it is also prepared electrolytically onsite, using small diaphragmless or membrane cells, but only low concentradons of hypochlorite can be realized (Eq. 6.9- 6.11).

anode: 2cr • c~ + 2e· Eo = 1.35 V [6.8]

cathode: Eo=OV [6.9]


solution: c~:z + ou· "* oer + w + a· [6.10]

Recently, Czametzki44 studied the electrochemical production of hypochlorite to

optimize the NaOO-production and minimize energy losses. Application of a

divided cell by a cation-exchange membrane with a platinum anode and a catbode of perforated nickel plate, yielded current efficiencies for the synthesis of

hypochlorite of about 80 %. For the HOO-degradation of aldonic acids to the next

lower aldose, this electrochemical preparation of hypochlorite might be applied

favourably. By varying the current density the amount of HOO produced can be controlled efficiently during the reaction, which may be of great practical value. Moreover, if the carbohydrates used do not react significantly at the anode, HOCl can be produced electrochemically in situ, in principle, only with a catalytic amount of NaCl. We therefore, investigated the electrochemical HOCI-production

and its effect on the degradation of aldonic acids to the next lower aldose. The

equipment used is described by Czametzki44, but the standard reaction conditions

applied (see Table 6.2) were partly adjusted to the conditions of the chemica!

NaOCl-mediated reaction. According to Czametzki44, at standard reaction

conditions the current efficiency should be optimal ('lluoa = 80 % ), but especially at higher temperatures and lower NaCl-concentrations the current efficiency decreases. pH 5.5, was chosen as aresult of the optimalization of the chemica!

NaOO-degradation reaction and because no current efficiency data were available

at lower pH.

Table 6.2: Standard reaction condinons of the in situ electrochemical production of HOC/ and subsequent degradation of aldonic acids to the next lower aldose"

0.25M

3M

5.5

0.75 L

0.75 L 3 M NaCI

4 k.A/ml

0.075 m/s

*Reaction ca.nied out in tbe .anode oompartment of a divided membrane eeD as described by Czarnetzld44

•

Other side reactions (Eq. 6.12- 6.13) are possible at the anode than those occurring in solution (Eq. 6.3 and 6.6).


Eo = 1.23 V [6.12)

6Cl0- + 3~0 • 2003" + 4Cl" + 6H+ + 3/202 + 6e. Eo = 1.14 V [6.13]

Since production of oxygen (Eq. 6.12), bas a lower reversible potential than the evolution of chlorine, the oxygen evolution is favoured thennodynamically.

However, it is restrained kinetically under the applied electrolysis conditions.

Moreover, at standard reaction conditions the production of chlorate is also

minimal (fla03• < 2 %)44•

Indirect electrochemical oxidations of 0-gluconic acid (20), 0-arabinonic

acid (23), 0-erythronic acid (27), and L-threonic acid {8) to D-arabinose (22), D

erythrose (26), and D(R)- (28) and L(S)-glyceraldehydes (10), respectively, have

been studied. Unfortunately the quantitative analysis of 0-erythrose (26) was not

possible in these reactions, so these results are only of qualitative value. To study

the in:fluence of pH, temperature, substrate and NaCl concentration, D-gluconic

acid (20) was used as substrate.

Under standard reaction

conditions (Fig. 6.25), degradation of

D-gluconic acid (20) and 0-arabinonic

acid (23)., praeeed similarly to the

chemica! NaOCl-degradation. This

indicates that negligible little

carbohydrate oxidation occurs at the

anode and that the electrochemical

production of HOCI is not greatly

in:fluenced by carbohydrates. The

selectivities in the reactions with D

erythronic acid (27) and L-threonic

acid (8) are, however, significantly

lower (compare Fig 6.25 to Fig. 6.22

and 6.23). This is presumably due to

the high viscosity of the reaction

mixture that is formed ( dimerization or

polymerization of the glyceraldehydes

100r-------------------~

'N o.eo 0 ! >. .... E .... .. .. 'ij

0.60

(1) 0.20

0 -~-IJ l:r

000~--~--~--~--~--~ 0.00 0.20 0.40 0.60 0.80 1.00

Conversion (mol%)

Figure 6.25: Selectivity (0:20, +:27, 0:8) versus conversion of the indirect electrochemical oxidation of 20, 27, and 8 at standard conditions (see Tabie 6.2)

(28,10) ), which may in:fluence both, the production of HOCI and the degradation


reaction. Probably, the reaction will praeeed more selectively at a lower substrate

concentration, as is indicated by the results shown in Figures 6.22 and 6.23. The

current efficiencies of the indirect electrochernical oxidation of all aldonic acids

are collected in Table 6.3 at 50 % conversion and, when available, at 100 %

conversion. There is a slight difference in 111 at 50% conversion for all substrates,

and the C4-aldonic acids (27, 8) show the greatest differentiation especially at high

conversion. This again rnay be due to the high viscosity of the reaction mixture. The current efficiency for the production of HOCl at standard reaction conditions,

amounts to 80% according to Czarnetzki44• However, the infl.uence of

carbohydrates on the HOCI-production and side-reactions is unknown. Impurities

can cause decomposition of the oxidant and thereby deercase Tlooa· The current

efficiencies for the degradation of D-gluconic acid (20) under standard reaction

conditions are 60% at 50% conversion and 40% at 100 %. Their valnes seem

reasonable, but may theoretically be improved up to 80 % by optimalization of the

reaction conditions.

60% 40% [Na0]=0.5M 27%

50 oe 53% 37% [ZO]=O.lM 44% 32%

30°C 48% 27% [Z0]=0.5M 72% 38%

25 oe 44% 27% [20]=1M 53%

pH=4.5 67% 36% 23 53% 34%

pH= 6.5 44% 33% 28 59% 28%

pH= 7.5 32% 27% 8 44% 25%

[NaO]=lM 41%

"Reacûons canied out as described by Czametzki44 onder standard reacûon conditions, unless indicated otherwise.

lnftuence of temperature. The influence of temperature on the selectivity

of the indirect electrochemical oxidation of D-gluconic acid (20) to D-arabinose

138 Carbohydrate-based syntheses ofCrchirons

(22) is very small (Fig. 6.26), in comparison to that of the chemical NaOCl·

mediated degradation (Fig. 6.18). However, the temperature trajectstudiedis also

relatively small. In the chemical NaOCl-mediated degradation the reaction rate at

low temperatures is low, which is responsible for an excess of NaOCl during a

long period and therefore, will induce side-reactions. In the indirect

electrochemical oxidation the substrate concentration is higher and the HOCI

production is slower, which limits the HOCl concentration in comparison to the

chemical NaOCl-degradation, and thus diminishes influence of the temperature. On

the other hand, the HOCl concentration is influenced negatively by higher

temperatures, due to a greater instability of HOCl teading to an increase of the

production of Cl03• according to Bquations 6.6 and 6.12. This effect may

neutralize (partly} the positive effect of higher reaction rates on the selectivity at

higher temperatures. The current efficiency is, however, lower at lower

temperatures and high conversions (Table 6.3).

Inftuence of pH. The influence of pH on the selectivity of the indirect

electrochemical degradation of D-gluconic acid (20) (Fig. 6.27) is comparable to

that on the chemical NaOCl-degradation (Fig. 6.19). The maximum selectivity is

obtained at pH = 4.5 - 5.5, whereas at higher pH selectivity decreases, especially

at higher conversions. These results indicate that HOCl is the active oxidant,

which is present in maximum amounts at pH = 4.5- 5.5 (Fig. 6.16), while at

higher pH a higher percentage of oa· is present. This hypochlorite anion oxidizes

aldoses to the corresponding aldonic acids, which than can be oxidized forther by

HOCI and as a consequence, this decreases selectivity. The current efficiency

increases at higher pH, due to side-reactions also consuming hypochlorite.

loftuenee of substrate concentration. The selectivity of the indirect

electrochemical degradation of D-gluconic acid (20) under standard reaction

conditions is higher than at lower as well as higher substrate concentrations (Fig.

6.28). At lower substrate concentradons (0.1 M) the oxidant/substrate ratio is

higher, which indoces side-reactions. At higher substrate concentrations, especially

:2: 1 M, the viscosity of the reaction mixture increases significantly, thereby

negatively influencing both production of HOCl and oxidation of aldonic acid.

Also current efficiencies are intioeneed accordingly (Table 6.3).


Intluence of NaCI eoncentration. Decrease of the NaCl concentration

during the indirect elect:rochemical degradation of D-gluconic acid (20), increases

selectivity at low conversion but decreases selectivity at high conversions (Fig.

6.29). According to Czametzki44, cuerent efficiency for the production of HOCI

will be lower at lower NaO concentration. At low conversion the lower Tluoa has a positive effect, presumably caused by the smaller oxidant/substrate ratio, but at

higher conversion more side-reactions occur, probably due to chlorate and oxygen

formation according to Equations 6.12 and 6.13, that will both oxidize the

products formed. Also cuerent efficiencies are significantly lower (see Table 6.3),

due to side-reactions.

1.00 -....t::

N' 0.80 0 ! O.fiO

"' .. E 0.40 .. 0 4> 'i fll 0.20

0.00 0.00 020 O.«l 0.60 0.80 1.00

Conversion (mol%)

Figure6.26:Jnjluence ofT(0:50 oe, +:40 oe, 0:30 oe, !:.:25 oe) on the indirect e/ectrochemica/ oxidation of :10. eonditions: [20]=0.25 M, [Naei]=3M, pH=5.5, i=4kAJm2

1.00

N' 0.80

0 ! 0.60

"' :::: ! OAO .. 0 4>

'i fll 020

0.00 0.00 0.20 O.«l O.fiO o.ao 1.00

Conversion (mol~)

Figure 6.27: lnfluence of pH (0:4.5, +:5.5, 0:6.5, !:.:7 .5) on the indirect electrochemical oxidation of 20. eonditions: [20]=0.25 M, [Nael}=3M, T=40 oe, i=4kAJ~

In conclusion, indirect electrochemical degradation of aldonic acids to the

next lower aldose, proceeds analogously to the chemica! NaOCl-degradation. The

selectivities are good at standard reaction conditions and probably can be improved

further by optimalization of the reaction conditions. Also relatively good cuerent

efficiencies are obtained ( current efficiency of 20 (1120) is 60 % at 50 % conversion

and 40 % at 100 % conversion), which may be even higher when cuerent densities

are adjusted according to conversion. This adjustment of cuerent density with

conversion probably also increases selectivity at higher conversions as a result of

140

0

0.00 L._-~--'-----'--~--' 0.00 Cl.20 O.oiO 0.00 0.80 1.00

Conversion (mol%) a

Figure 6.28: lnfluence of [20] (0:0.25 M, +:0.5 M, 0:1 M, 1:!.:0.1 M (i=2kAI71f)) on the indirect electrochemical oxidation of 20. Conditions: [NaCl]=JM, T=40 °C, pH=5.5, i=4kAI71f

Carbohydrate-based syntheses of Crchirons

0.00 L...__...__ _ _.__----l. __ ..__ _ _, 0.00 0.20 O.oiO 0.60 OBO 1.00

Conversion (mol%)

Figore 6.2': ltlf/uence of [NaCI] (0:3 M, +:1 M, 0:0.5 M) on the indirect electrochemical oxidation of 20. Conditions: [20]=0.25 M, T=40 °C, pH=5.5, i=4W71f

optimal HOCl concentration controL In the indirect electrochemical oxidation,

control of the HOCl concentration can be achieved very efficiently by varying the

current density, which makes this metbod of great practical value. Optimization

of the current regulation with respect to maximum selectlvities and current

efficiencies in order to take maximum advantage of the positive aspects of the

indirect electrochemical oxidation, will require more detailed research. In principle,

the indirect electrochemical oxidation requires NaO in catalytic amounts.

However, in order to achleve high current efficiencies for the production of HOCI,

the use of a 3 M NaO solution bas proven to be necessary. Product isolation will

be more easy and effective at lower salt concentrations. Therefore, with respect

to product isolation and amount of inorganic salts, the chemical NaOCl

degradation is favoured.


6.4.3 Selective degradation of D-fructose.

Although D-fructose (15) is the second most abundant of the

monosaccharides, its chemistry bas not kept in pace with that of D-glucose (19).

11tis is partly due to the difficulties encountered in crystallizing the free sugar.

Only P..D-fructopyranose is available in a crystalline fonn. D-Fructose (15) also

exhibits a complex mutarotation resulting in mixtures that contain five tautomers

in different concentrations depending on solvent, time, temperature, and

concentmtion.

D-Fructose (15) is readily cleaved between C-l and C-2 in good yield

(85 %) to D-arabinonic acid (23) under alkaline conditions with the aid of

molecular oxygen19• The AMS-~02-catalyzed oxidative degradation gives the

same selectivity (see Section 6.4.1), but the reaction time can be reduced without

loss of selectivity by increasing the reaction tempemture. Selective cleavage

between C-2 and C-3 is also reported, either yielding D-erythrose (26) and

glycolic acid (50) or D-ecythronic acid (27) and oxalic acid (46). Oeavage

between C-2 and C-3 is very interesting because, in principle, it allows conversion

of a C6-carbohydrate into a C,-building blockin two steps (see also Fig. 6.30). However, the stoichiometrie reagents reported to cleave D-fructose (15) to D

erythrose (26), silver carbonate on Celite46 and Pb(0Ac)447

, are industrially not

very attractive. HOI-mediated48 oxidation of D-fructose (15) produces oxalic acid

( 46) and presumably D-erythronic acid (27). An attempt to separate the latter acid

from unoxdized D-fructose (15) was not successful. Oxidative degradation of D

fructose (15) to D-erythrose (26) was also achieved by photolytic oxygenation in

the presence of catalytic amounts of FeCl349

• The reaction proceeds very

selectively (selectivity up to 80 % ), but at conversions ;;;:: 30 % the reaction stops,

due to precipitation of Fe(ill)-hydroxide. Fe(ID) is only soluble in the reaction

mixture when a largeexcessof D-fructose (15) is present. In conclusion, only the

classical alkaline oxidation and the AMS-H20 2-catalyzed oxidation with oxygen

seem to be suitable for the selective degradation of D-fructose (15) to lower

carbohydrates.

In view of the reported HOI-mediated oxidation of D-fructose (15) at

pH = 9 to oxalic acid ( 46) and presumably D-erythronic acid (27)48, we assumed

that HOCl, would also induce degradation of D-fructose (15). For this reason we

studied the oxidation of D-fructose (15) with NaOCl as a function of pH (pH = 5 -


OrH HO OH + HCOOH

~ OH

OH OH 0 AMS H20 2 ca t .

HO (23) (47) OH or OH r0Ac)447

OH OH + HOCH2COOH HO OH

(15) OH

OrH (26) (50)

OH + HOOCCOOH OH OH

(27) (46)

Figure 6.30: Selective cleavage of D-fructose (15) between C-1 and C-2 and C-2 and C-3, respectively

12). In the reactions carried out at low pH, the main reaction products formed

were D-erythrose (26) and D(R)-glyceraldehyde (28), in almost equal amounts and

in addition glycolic acid (50) and formic acid (47). At higher pH the ratio D

erythrose (26) I D(R)-glyceraldehyde (28) increased and at pH = 9 D(R)

glyceraldehyde (28) was not observed anymore. Surprisingly the main reaction

product was D-erythrose (26) and not expected D-erythronic acid (27) (see

Fig.6.31 and 6.32). The high selectivity for D-erythrose (26) at low conversion

decreases at higher conversion probably due to over-oxidation by excess of

NaOCI. The selectivity at higher conversion presumably can be improved by

limiting the amount of NaOCl added per unit time. The results of óne attempt to

improve selectivity at higher conversion are depicted in Figure 6.33. The initial

rate of addition of NaOCI was twice as high as in the reacrions of Figures 6.31

and 6.32, but the last portions were added about twice as slow. These results


.-

' ö ! §':!

().fi()

-I til!l ... ... OAO 1'1

" Cl 1'1 0.20 0 u

().5() 1.!)0 1.50 2.00 2.50

NaOCI (eq. per mole U>)

Figure 6.31: eancentration profile (C1:15, +:16, 0:17,29, A:50, o:47) in the NaOC/ oxidation of 15. Conditions: [15}=0.15 M, T=40 oe, pH=9, 0.25 eq. NaOCI/20 min

tt 1.50

0 ! ." o; >.. ~

'ii .. > 1'1 0 u

0.!50 1.00 1.50 2.00 2.50

NaOCI {eq. per mole 15)

Figure 6.32: Conversion (0:15), selectivities (+:26, A:50, o:Z7,29, v.47}, and yield (0:26) in the NaOC/ oxidation of 15. Conditions: [15]=0.15 M, T=40 oe, pH=9, 0.25 eq. NaOel/20 min

indicate that also in the degradation of D-fmctose (15) to D-erythrose (26) the

amount of NaOCI present in the reaction mixture, bas a great intluence on the

selectivity of the reaction. 1be reaction, therefore, may presumably be intluenced

by the reaction temperature, analogously to the NaOCl-degradation of aldonic

acids to the next lower aldose (see Section 6.4.2). The influence of temperature

and addition rate ofNaOCl were not investigated further. At higher pH, selectivity

to D-erythrose (26) decreases, partly due to its further degradation to the

cortesponding acid (27) by OCI". The main side-products that are fonned in all reactions are formic acid ( 47) and D-erythronic acid (27) and/or D(R)-glyceric acid

(29). Glycolic acid (50) is always formed in large amounts (30- > 100 %), also

in the beginning of all reactions. However, when a large excess of NaOCl is

present, glycolic acid (50) is also oxidized further. In the reaction at pH= 12

relatively little glycolic acid (50) is observed, whereas relatively large amounts of

D-arabinonic acid (23) and D-erythronic acid (37) are formed. In this case clearly

a different reaction occurs. Glycolic acid (50) may not only be formed by the

cleavage of D-froctose (15) to D-erythrose (26), but also by other reactions, which

explains its presence in more than 100 mol%.

144

The abovementioned results for

the selective degradation of D-fructose (15) to D-erythrose (26) at pH = 9 and 40 °C were rather unexpected. Under alkalineconditions, most hypochlorite

is present as oa·' which is known to oxidize aldoses to the corresponding aldonic acids18a.b. Therefore, when

cleavage between C-2 and C-3 occurs, D-erythronic acid (27) was expected to

be the main reaction product. This is indeed the case at higher pH

(pH ~ 10), but at pH = 9, the cleavage reaction occurs considerably faster than the oxidation of aldoses to the conesponding aldonic acids. When an excess of Naoa is present (at high

conversion), however, selectivity to 26

decreases doe to over-oxidation.


l( 0 ! .., öl ·r;, .lil

öl ., .. 020 1::1 0 u

0.40 0.80 1.20 1.80 2.00

NaOCI (eq. mol 15)

Figure 6.33: Conversion (Q15), selectivities (+:26, 6.:50, o:Z7,29, v:47), and yield (0:26) in the NaOCI oxidation of 15. Conditions: [15]=0.15 M, T=4() °C, pH=9, 0.5-0.1 eq. NaOCU20min

In all reactions a large amount of D-glycolic acid (50) is formed,

irrespective of the degree of conversion, but only at pH = 9 selectivity is near 100

% during the entire reaction. This indicates that at pH = 9 D-fructose (15) is selectively cleaved between C-2 and C-3, whereas at other pH's alsoother carboncarbon bonds are cleaved and/or glycolic acid (50) is formed by oxidation of initial reaction products. At pH > 8, preferentially carboxylate side-products are formed, especially formate (anion of 47) and to a lower extenf,D-erythronate (anion of 27) and/or D(R)-glycerate (anion of 29), whereas at pH< 7 primarily

aldehyde products are observed. Indeed, onder acidic conditions aldonic acids are

degraded to the next lower aldose by HOO, but under alkaline conditions aldoses are oxidized to the conesponding aldonic acid by oa·. Under extreme1y alkaline

conditions (pH = 12) a special situation arises since now enolization of D-fructose (15) to the 1 ,2-enolate and in minor amounts to the 2,3-enolate anions occurs. In the oxidation of D-fructose (15) at lower pH (pH < 12), only · traces of D

arabinonate (anion of 23) are observed, but at pH= 12, D-arabinonate (anion of 23) is fonned in relatively large amounts, albeit not selectively, together with relatively large amounts of D-erythronate (anion of 27) and relatively little

6. Selective degradation of unprotected augars to glyceraldehyde and glyceric acid 145

glycolic acid (50).

Areaction mixture obtained from the oxidation of D-fructose (15) toD

erythrose (26) with 1.5 equivalents Naoa per mole substrate at pH= 9 and

40 oe, was consecutively oxidized with oxygen and catalytic amounts of AMS and

H20 2 at pH> 13. D-Erythrose (26) obtained from the NaOCl oxidation of D

fructose (15), gave exacdy the same result as authentic materiaL

In conclusion, for the synthesis of D-erythrose (26) from D-fructose (15)

with NaOel at pH = 9 and 40 oe, a special situation arises. At lower pH, D(R)

glyceraldehyde is formed in relatively large amounts, which indicates that HOCI

is not the active oxidant responsible for cleavage of D-fructose (15) between e-2

and e-3. At pH= 9 almost all hypochlorite exists as OCI". At still higher pH,

further oxidation to D-erythronic acid (27) is relatively fast, which deercases the

selectivity to D-erythrose (26). At pH= 12 again a different situation arises, due

to the formation of both the 1,2-enolate and 2,3-enolate anions. As mentioned

before, D-fructose (15) exists in solution as a complex isomerie mixture. At 40 oe

66 % is present as the P-pyranose structure, 23 % as the P-furanose, 7% as the

«-furanose and 4 % as the «-pyranose. Also traces of the acyclic form are

presenf<'. For the oxidative cleavage of D-fructose (15) to D-erythrose (26) and

glycolic acid (50) with lead tetraacetate47 and silver carbonare on eelite46, it is

assumed that P-furanose is cleaved. Indeed, an initial intermediate formed in these

reacrions is identified as a glycolic ester of D-erythrose (26), and this can only

arise from the cleavage of P-furanose (see Fig. 6.34). Why the cleavage does not

HO

~~Ü)(_OH p~OH

HO

Ot~~OH [OH 0

~-fructofuranose (15) glycolic ester of D-erythrose

Figure 6.34: Cleavage of ~-fructofuranose between C-2 and C-3


proceed in a manner analogues to (J-pyranose, is not k.nown. In our reaction,

however, glycolic ester is not observed and, even at low conversion, the selectivity

OH OH 0 0

HO ... Cl-0 + HOCl + H20 OH .. OH

OH OH OH OH

(15)

OH Cl-0 o-

... Cl-0 .. OH OH OH

OH 0

1H

-er OH ;;OH OH ...

OH Cl-0 0 OH OH OH

(26)

,(OH "(OH + H20 ... + HOCl .. Cl-0 0 HO 0

(50)

Figure 6.35: Suggested mechanism for the cleavage of Dfructose ( 15) to D-erythrose (26) with NaOCI at pH = 9


to glycolate (anion of 50) is nearly 1. Furthermore, the believed active oxidant,

oer, will react as a nucleophile with the carbonyl tunetion of acyclic D-fructose

(15). We, therefore, suggest the following mechanism (see Fig. 6.35). Under the

reaction conditions used, both, oer and HOCI, will form reversibly esters with

the alcohol functions of D-fructose (15) in a fast equilibrium reaction. After attack

of ao· to the carbonyl function, cleavage cao take place because a· is a good

leaving group. Presumably, cleavage does oot occur between C-1 aod C-2 due to

the neighbouring group participation of C-4-0H. Another possible mechanism

would be attack of Cto· at the carbonyl function, and cleavage without previous

ester formation. However, in this case cleavage cao occur between both C-1 aod C-2 aod C-2 and C-3, unless the cleavage between C-2 aod C~3 is sterically

favoured, but this is difficult to envisage. At lower pH, D~rythrose (26) aod

D(R)-glyceraldehyde (28) are formed as the main reaction products. Still part of

the hypochlorite is present as oct·, which explains formation of D-erythrose (26).

Hypochlorite is also known to cleave n~ols with a maximum rate at pH = 7s1•

Por example starch is cleaved between C-2 aod C-3 to the conesponding acids,

D-erythronic acid (26) and glyoxylic acid52• Cleavage of D-fructose (15) then

yields severallower carboxylic acids, which cao be forther oxidized by HOCl to

the next lower aldehydes. In such a reaction, both D(R)-glyceraldehyde (28) aod

D-erythrose (26) cao be formed, which explains the complex product distribution

at lower pH. The assumption by Bailey et al.48, that the degradation of D-fructose

(15) with HOI yields D~rythronic acid (27), seems very speculative. Because

-these authors isolated a large amount ( 60 mol%) of oxalic acid ( 46), they assumed

that D-fmctose (15) was cleaved by HOI to D-erythronic acid (27) aod oxalic acid

(46). However, oxalic acid (46) probably also cao be fonned by other degradation

reactions of D-fructose (15) with the aid of HOI.

6.4.4 Oxidative degradation of 2-ketoaldonic acids

2-Ketoaldonic acids are valuable substrates for selective degradation to

lower aldonic acids e.g. Rz02-degradation yields the next lower aldonic acid in up

to 93 % yield23• Also electrochemical oxidation in slightly acidic solution in the

presence of CaBr2 yields the next lower aldonic acid in high yield (85 %)22•

Moreover, oxidation of 2-keto-D-gluconic acid (21) by permangaoate bas been


described by Ohle et a1.'3, who found that a controlled reaction under acidic conditions yielded D-arabinonic acid (23), whereas under alkaline conditions they detected only the formation of oxalic acid ( 46) in 80 % yield. The latter was expected from a cleavage of the keto acid to oxalic acid ( 46) and D-erythronic acid (27), but 27 was not isolated (see Fig. 6.36).

0 OH 0 OH

OH OrH 0 KMn04,H+ HO 02 HO HO OH ---+- .. OH + co2 OH OH Pt,Pb/C OH

~ OH

OH OH OH

(20) (21) (23) os-

OrH . OH + HOOCCOOH OH OH

(27) (46)

Figure 6.36: Selective cleavage of 2-keto-D-gluconic acid between C-1 and C-2 or C-2 and C-35J

2-Ketoaldonic acidscan be synthesized from the corresponding aldonic acid by classica! chemica! oxidation, with chlorate in the presence of vanadium pentoxide and phosphoric acid54 or with chromic aci<f', and by biochemica! oxidation56

• The latter process requires long reaction times. A very attractive route for the synthesis of 2-ketoaldonic acids was recently reported and involves a lead-modified Pt/C-catalyzed oxidation of aldoses or aldonic acids with oxygen at pH= 8 and 55 °c!7

• Selectivities, obtained in these oxidation reactions, vary from 60 to 97 % yield in solution. When deactivation of the catalyst can be prevented, this metbod seems to be very promising for the synthesis of 2-ketoaldonic acids in high yields. Because of the attractiveness of the heterogeneously catalyzed preparation of 2-ketoaldonic acids and the possibility of removing two carbon atoms in one reaction step (see above ), 2-keto-D-gluconic

6. Selective degradation of unprotected sugars to glyceraldelryde and glyceric acid 149

acid (21), 2-keto-L-gulonic acid (51), and 2-keto-D-arabinonic acid (24) were

oxidized with 0 2, ~02 and NaOCI. The C6-2-ketoaldonic acids were available in

crystalline form, and 2-keto-D-arabinonic acid (24) was prepared according to

Smits et al.57•

Preparation of 2-keto-D-arabinonic acid. The oxidation of D-arabinonic

acid (23) to 2-keto-D-arabinonic acid (24) was carried out as reported by Smits

et al.57• Sodium 2-keto-D-arabinonate (sodium salt of 24) was isolated from an

ethanolic oxidation product mixture and yielded crystalline material in 43 % yield.

Analysis of the product (24) by HPLC indicated that the material did oot contain

significant impurities. The product obtained by crystallization was used as standard

compound for analyzing 2-keto-D-arabinonic acid (24) in reaction mixtures.

However, an analytical sample to check the purity of the crystalline material (24)

was oot available. We assumed that the purity of the crystalline material was

100 %, which is presumably an optimistic assumption. The concentradon of 24 in

reaction mixtures probably may be somewhat higher than calculated by this

method.

Oxidation of D-arabinonic acid (23) by oxygen in the presence of a lead

modifred Pt/C catalyst yielded the 2-keto-D-arabinonic acid (24) in up to 60%

yield. When the reaction is oot stopped at near 100 % convers ion, the initial

reaction product (24) is oxidized further to lower aldonic acids, co2, oxalic acid

(4()), glycolic acid (50), and formic acid (47). To study the oxidative degradation

of 2-ketoaldonic acids, a reaction mixture of near 100 % conversion was usually

used.

Oxidation of a crude reaction mixture from the AMS-H20 2-catalyzed

oxidative cleavage of D-glucose (19), containing D-arabinonic acid (23), was

initially not successful, as indicated by the very low oxygen conswnption.

However, when the reaction mixture was treated with active carbon before

oxidation, the rate of oxygen consumption increased enormously. Presumably,

traces · of AMS present in the reaction mixture poisoned the metal catalyst, but

were removed by precipitation on active carbon. The oxygen consumption after

this treatment was even higher than in the normal reaction, but decreased durlog

reaction and to stop fmally at relatively low conversion ( 40 - 60 %) of D

arabinonic acid (23). The difference in composition of the reaction mixture in the

normal oxidation of D-arabinonic acid (23) and in the reaction mixture obtained

from the AMS-H20 2-catalyzed oxidation of D-glucose (19) to D-arabinonic acid

150 Carbohydrate-based syntheses of C rchirons

(23) on the other hand, offer an explanation for this behaviour. In the latter case

D-arabinonic acid (23) is accompanied by equal amounts of fonnic acid (47),

which is oxidized faster to C02 than D-arabinonic acid (23) to 2-keto-D-arabinonic

acid (24). Since the reaction is carried out in a closed system, a large part of C02

will diffuse to the gas phase, thereby diluting the oxygen. At higher conversions

almost all 0 2 is replaced by C02, and oxygen consumption drops. When the

reaction is carried out in an open system, however, the direct oxidation of the

reaction mixture probably will give no difficulties. Acidification of the reaction

mixture and removal of fonnic acid ( 47) by e.g. N2-stripping, will solve the C02-

problem also and simultaneously lowers the amount of oxygen needed.

Oxidation of 2-ketoaldonic acfds with H20 2• In addition to the previously

high yield oxidation of 2-keto-D-gluconic acid (21) to D-arabinonic acid (23f3b,

the oxidation of 2-keto-D-arabinonic acid (24) with H20 2 has been studied (see

Fig. 6.37). lndeed, also in this reaction the major cleavage occurs between C-1 and

C-2 (70 % ). However, also a significant amount of oxalic acid. ( 46) is formed

(30 %). Cleavage of C6-2-ketoaldonic acids (21, 51) on the other hand, proceeds

very selectively (> 90 % ), probably as a result of a prefeered isomer in solution

(pyranose insteadof furanose).

Oxidation of 2-keto-D·gluconic acid with NaOCI. The good results

obtained in the oxidation of D-fructose (15) with NaOCl, prompted us to oxidize

2-keto-D-gluconic acid (21) with NaOCl, albeit, only at pH= 5.5. The reaction

proceeds very fast and selectively, but unlike the reaction with D-fructose (15), D

arabinonic acid (23) is formed in high yield (95 %) when 1.1 molar equivalents

of NaOCl are used. D-Arabinonic acid (23) is then forther oxidized to D-erythrose

(26), as is already described inSection 6.4.2. In the oxidation of D-fructose (15)

with NaOCI at pH = 5.5, D-erythrose (26) and D(R)-glyceraldehyde (28) are the

main reaction products, while in the oxidation of 2-keto-D-gluconic acid (21) with

NaOCl, decarboxylation to D-arabinonic acid (23) is favoured.

Oxidation of 2-ketoaldonic acids with 0 2 in alkali. Oxidation of 2-keto

D-gluconic acid (21) with permanganate under alkaline conditions is believed to

yield D-erythronic acid (27) and oxalic acid ( 46), whereas under acidic conditions

D-arabinonic acid (23) and formic acid (47} are the main reaction products53• We,

therefore, assumed that under alkaline reaction conditions oxidative degradation


COOH

I co NaOCl or COOH

I I + co2

(CHOH} n H2~

(CHOH)n

I I CH20H CH20H

:21, 24) (23, 27)

COOH

I (CHOH) n-1

I + HOOCCOOH

CH20H

(27,29} (46}

Figure 6.37: Cleavage of 2-ketoaldonic acids

with oxygen, would, irrespective of the presence of AMS and fl:z02 in catalytic

amounts, yield oxalic acid (46) and the conesponding aldonic acid. Totest this,

2-keto-L-gulonic acid (51) and 2-keto-D-arabinonic acid (24) were oxidized with

oxygen under various conditions. The results are collected in Table 6.4 (see also

Fig. 6.37).

From the results from Table 6.4 it is clear that 2-ketoaldonic acids (24; 51)

are not cleaved selectively between C-2 and C-3 with oxygen under alkaline

conditions. At high pH (pH> 13), the reaction is non-selective and 2-ketoaldonic

acids are degraded to lower aldonic acids, co2, oxalic acid ( 46), glycolic acid

(50), and formic acid (47). At pH= 12 reactions are limited to cleavage between

C-1 and C-2 and between C-2 and C-3, which proceed to the same extent.

Decrease of the pH only favours cleavage between C-l and C-2 and at pH < 10.5

152 Carbolrydrate-based syntheses of C"-chirons

enolization is very slow and oxygen consumption bas become negligible. Addition

of catalytic amounts of AMS and H20 2 did also not result in a selective cleavage

between C-2 and C-3.

••···.··········•·•••·•···•1f··.··•····· ·.•• .•. ·.·••.··•• .• ·•.·.·.•.·.·.··.···.·•.•·.········)?····· .. •··.··.· .. ·(·e.-··.·.i .. cr.A····.·.•~·.··•.lll •. · ... ·~.··.•·.•.· ... · •. · ... )···./ · ~~it 2D••··•·•··• .. ? <fç)/ ... w;Yf.' ••. • (~9.{%,} . 51 >13 AMS.~o2 40 < 25 < 25

12 50 38 38

11 " 44 50

10-10.5 .. 0 0

> 13 35 <25 <25

24 >13 .. < 25 <25

12 30 < 25

"Reacûon condiûons: [substrate] = 0.075 M, r = 100 %. 19Catalyûc amounts. "Yield deteonined by HPLC (see Cbapter 2).

In conclusion, cleavage of C6-2-ketoaldonic acids between C-1 and C-2 by

either ~02 or NaOO proceeds selectively, but selective cleavage between C-2 and

C-3 could not be realized. Cleavage of 2-keto-D-arabinonic acid (24) with ~02 is less selective (70 %) and cleavage between C-2 and C-3 bas only been achieved

with low selectivities. Cleavage between C-1 and C-2 of 2-ketoaldonic acids is,

bowever, less interesting in comparison to the AMS-~02-catalyzed oxidative

cleavage of aldoses and the NaOO-mediated degradation of aldonic acids, because

one extra step, oxidation of the aldonic acid to the conesponding 2-ketoaldonic

acid, is necessary. Oxidation with NaOCl on the other hand, cleaves two carbon

atoms from the 2-ketoaldonic acids in a one pot two-step reaction, which makes

this reaction more attractive.


6.4.5 O:ddation of aseorbic acids with H20 2

L-Ascorbic acid (6, vitamin C) and D-isoascorbic acid (16, isovitamin C)

are readily available C6-carbohydrate derivatives. The chemistry of L-ascorbic acid

(6) has been thoroughly studied in the past. However, that of its C-5-epimer, D

isoascorbic acid (16), remains relatively unexplored.

Of special interest and of great practical value is the oxidation of L

ascorbic (6) and D-isoascorbic (16) acids with H20 2, affording oxalic acid (46) and

L-threonic acid (8)2!1 and D-erythronic acid (27)'24, respectively (see Fig. 6.38). This

cleavage can also be realized with KMn0458 instead of ~02, but the latter is

obviously preferred. The reaction is carried out in water in the presence of two

molar equivalents of CaC03, while Ilz02 is added gradually. Calcium oxalate

(calcium salt of 46) precipitates immediately and, therefore, can be removed by

f:lltration, leaving a solution of calcium L-threonate (calcium salt of 8) or D

erythronate (calcium salt of 27) in water. The processis believed to take place in

two stages:zs. The flfSt stage is the oxidation to dehydro-ascorbic acids, the second

stage decomposition into the corresponding tetronic acids and oxalic acid (46) (see

also cleavage of the corresponding proteeled derivatives (7a,b; 17a,b) in Chapter 4).

Indeed, oxidation of L-ascorbic acid (6) and D-isoascorbic acid (16)

according to lsbell and cowork.ers:zs, yields the corresponding calcium tetronates

in high yields (90 %). We have subjected the crude reaction mixtures obtained by

this method directly to oxidation with NaOCl at pH= 4.5 - 5.5 (see Section 6.4.2).

HO~ 0

10H

0 0 H202 OH HO ...

OH + HOOCCOOH

HO OH OH

(16, 6) (27,8)

F'agure 6.38: H/)2-Mediated c/eavage of ascorbic acids (6, I6f4.2

5


In this way we obtained D(R)-glyceraldehyde (28) and L(S)-glyceraldehyde (10)

from C6-carbohydrate derivatives in two reaction steps in a one pot synthesis

(80 % . selectivity at 80 % conversion of D-erythronic acid (27), not optimized).

6.5 Cooclusions

The AMS-H20 2-catalyzed alkaline degradation of aldoses with oxygen

yields the next lower aldonic acids in high yields (from 70 % for the oxidation of

D-erythrose (26) to D(R)-glyceric acid (29) to 98 % for the oxidation of D-glucose

(19) to D-arabinonic acid (23)). The lower selectivity in the oxidation of D

erythrose (26) to D(R)-glyceric acid (29) may be ascribed to the formation of

considerable proportions of free aldehyde and aldehydrol forms and to the ready

formation of dimers of aldotetroses in aqueous solutions. Oxidation of D-fructose (15) to D-arabinonic acid (23) occurs also in high yield (85 % ), but is somewhat

inferior to that of D-glucose (19), probably due to formation of the 2,3--enolate

anion in addition to the 1 ,2-enolate anion.

Hypochlorite degradations of aldonic acids to the next lower aldoses at

pH= 4.5 - 5.5 proceed selectively, especially at low conversions. Although

selectivities up to 90 % can be achieved, the reaction products are oxidized further

at higher conversions, due to the high oxidant/substrate ratio in the reaction mixture. When the relative concentration of hypochlorite could be limited,

presurnably selectivity can be increased. The reactions also can be carried out with

the aid of indirect electrochemical oxidation, by which hypochlorite is produced

in situ from NaCl. By this method, the concentradon of hypochlorite can be

controlled very efficiently by adjusting the current density and thereby the

hypochlorite production. However, disadvantage of this metbod is the need for large quantities of NaCl (3 M solution) to obtain high current efficiencies. The

active species in the hypochlorite oxidation of aldonic acids to the next lower

aldoses probably is HOCl, which forms alkyl hypochlorite esters with hydroxyl

functions of the aldonic acid. The intermediate alkyl hypochlorite ester then

decomposes to the next lower aldose and co2 in the rate limiting step.

D-fructose (15) is cleaved selectively between C-2 and C-3 with alkaline

hypochlorite at pH= 9 to yield D-erythrose (26) and glycolic acid (50). Again selectivity is high (90 %) at low conversions, but when an excess of hypochlorite

6. Se/ective degradation ofunprotected sugars to glycera/dehyde and glyceric acid 155

is present, selectivity decreases. Higher selectivity at higher conversions

presumably necessitates limitation of the amount of hypochlorite present in the

reaction mixture. At lower pH also D(R)-glyceraldehyde (28) is fonned, while at

pH = 12 considerable amounts of D-arabinonic acid (23) and D-erythronic acid

(27) are fonned. The active species in the reaction probably is oer, which attacks

the carbonyl function of acyclic D-fructose (15). The emerging intennediate then

decomposes to glycolic acid (50) and D-erythrose (26).

2-Ketoaldonic acidscan be cleaved selectively to the next lower aldonic

acids with ~02 at pH= 7 or NaOCl at pH= 5.5. For the degradation of 2-keto

D-gluconic acid (21) to D-arabinonic acid (23), selectivity of the reaction with

NaOCl is 95 % and with ~02 even higher than 95 %. Degradation of 2-keto-D

arabinonic acid (24) to D-ecythronic acid (27) is less selective (70 % ). Oeavage

between C-2 and C-3 with oxygen under alkaline conditions could not be realized

in a selective manner. Oxidation ofL-ascorbic acid (6) and D-isoascorbic acid (16)

with ~02 to L-threonic acid (8) and D-erythronic acid (27), respectively, shows

cleavage of two carbon atoms from the substrate in one reaction step. Reaction

mixtures obtained in these reactions can be oxidized direcdy with hypochlorite at

pH = 4.5 - 5.5 to.produce L(S)-glyceraldehyde (10) and D(R)-glyceraldehyde (28),

respectively.

The abovementioned selective oxidations of unprotected carbohydrates to

carbohydrates containing less carbon atoms, can be used sequentially to prepare

L(S)-glyceraldehyde (8), or D(R)-glyceraldehyde (28), and D(R)-glyceric acid (29)

starting from readily available sugars. The oxidizing agents used are inexpensive

and the intennediate products not have to be isolated, but are oxidized further in

the crude reaction mixture.

6.6 Experimental

General. During all experiments the pH is adjusted at a constant value by

automated titration.

Sodium D·Arabinonate (sodium salt of 23)21• A stilred salution of D

glucose (19, 22.5 g, 0.125 mol) and AMS (0.2 g, 0.63 nunol) in water (300 mL,


T = 40 °C) was saturated with 0 2, while a solution of NaOH (17 .52 g, 0.438 mol)

in water (150 mL, T = 40 °C) was saturated with 0 2 in the reactant snpply vessel.

The reaction was started by adding the NaOH-solution to the reaction mixture,

whereafter ~02 (30 wt%, 0.1 mL, = 1 mmol) was added and 0 2-consumption

started. The 0 2-consumption was recorded as function of time and was kept

constant to higher conversions by gradually increasing the reaction temperature to

55 oe. After 1.5 h reaction the 0 2-consumption was negligible and the reaction

was stopped. The reaction mixture was acidified with conc. HC1 to pH = 7, treated

with active carbon, filtered, and concentrated in vacuo to = 150 mL. After addition

of MeOH ( 400 mL) 23 was collected by filtration. Yield: 20 g (85 % ). HPLC

analysis (see Chapter 2): purity is 96- 97 %.

Indirect electrochemical oxidation of aldonic acids at standard reaction

conditions44• The reservoir of the anode (Pt-electrode, 15 cm2

) campartment was

filled with a solution ofthe aldonic acid (0.1875 mol) and Nael (131 g, 2.25 mol)

in water (750 mL, T = 40 oe. pH= 5.5). The sugar salution was pumped

continuously with a volumetrie rate of 11 ml/s through the capillary into the

anodic compartment. The reservoir of the catbode (perforated nickel plate

electrode, 15 cm?) campartment was filled with a solution of NaCl (26.3 g,

0.45 mol) in water (150 mL, 40 °C), that was pumped continuously through the

catbode compartment. The pH of the sugar solution was kept at 5.5 by addition

of 5 M NaOH. Tostart the reaction the current density was adjusted to 4 kA/m2•

During the reaction samples are taken (5 mL) and analyzed by HPLe (see Chapter

2).

Sodium 2-Keto-D-arabinonate (sodium salt of 24)17• After saturation of

a stirred solution of the sodium salt of 23 (20.3 g, 0.108 mol) in water (300 mL,

pH = 8) with N2, a suspension of Ptte (5 wt%, 55 % water, 22.5 g, 2.6 mmol) in water (200 mL) and Pb(0Ac)z.2~0 (0.47 g, 1.3 mmol) were added and

subsequently the reaction mixture was heated to 55 oe under N2 atmosphere. The

pH was maintained at 8 by adding 4 M NaOH. Thereafter the stirrer and the N2

flow were stopped, the gas circulation system was quickly evacuated and refilled

with 0 2, and the experiment was started by switching on the stirrer. In order to

avoid catalyst deactivation, the 0 2 concentration in salution was kept near 0 % by

adjusting the stirrer speed. After 75 min 0 2-consumption nearly stopped and the

reaction was ended. The reaction mixture was filtered and concentrated in vacuo

to"" 200 mL, whereafter EtOH (1 L) was added and after precipitation the sodium

salt of 24 was collected by fdtration. Yield: 8.64 g (43 %). HPLC-analysis (see

6. Selective degradation tJ/ unprotected augars to glyceraldehyde and glyceric acid 157

Chapter 2) showed no side-products in significant amounts.

Oxidation of Sodium 2-Keto-D-gluconate (21) and 2-Keto-D

arabinonate (24) with H10 2• To a stirred solution of 2-ketoaldonic acid

(0.25 mol) in water (460 mL, T = 70 °C, pH = 7) ~02 (30 wt%, 34 mL, 0.3 mol)

was added dropwise to control C02-evolution. The pH was adjusted to 7 by

addition of 4 M NaOH. After 1.5 halmost 100% conversion was achieved and

the reaction mixture was analyzed by HPLC (see Chapter 2). Oxidation of 21

afforded D-arabinonic acid (23) in > 95 % yield in solution and oxidation of 24

afforded approximately 70 % D-erythronic acid (27) and 30 % D(R)-glyceric acid

(29) and oxalic acid (46) in solution.

Oxidation of Sodium 2-Keto-D-gluconate (21) with NaOCI. To a

solution of the sodium salt of 21 (4.36 g, 20 mmol) in water (75 mL, pH = 5.5,

T = 30 °C)Na0Cl(13 wt%,57 mL,O.l mol)wasaddeddropwiseduring3 h. The

pH was kept at 5.5 by addition of conc. HCI or 1 M NaOH. During the reaction

samples were taken (2 mL) and analyzed by HPLC (see Chapter 2). HPLC

analysis: After addition of 1.1 eq. NaOCl D-arabinonic acid (23) was formed in

95% yield. Forther addition of NaOCl, converted 23 to D-erythrose (26).

6. 7 Relerences and notes

(1) (a) Vasella, A. Modern Synth. Methods, Conf. Pap. Int. Semin. 1980, 173, 2nd ed., Otto Salie Verlag. (b) Morrison, J. D. Azymmetric Synthesis 1983, 4. (d) Inch, T. D. Tetrahedron 1984, 40, 3161.

(2) Hough. L.; Ricbardson, A. C. The Carbohydrates Chem. & Biochem. 1972, IA, 114, 2nd ed., W. Pigman and D. Horton eds., Academie Press, US.

(3) (a) Malaprade, M. L. Bull. Soc. Chim. France 1928, 43, 683. (b) Bobbitt, J. M. Advan. Carbohydr. Chem.1956, 11, 1. (c) Bunton, C.A. Oxidation in Organic Chemistry 1965, vol A, 367, U. Wiberg ed.

(4) (a) Fenton, H. J. H. J. Chem. Soc. 1894, 65, 899. (b) Fenton, H. J. H.; Jackson, H. J. Chem. Soc.1899, 75, L (c) Moody, G.J. Tetrahedron 1963, 19, 1105.

(5) (a) Isbell, H.S.; Fmsh, H.L.; Parks, E. W. Carbohydr. Res.1976, 51, C5. (b) Isbell, H.S.; Czubarow, P. Carbohydr. Res. 1990, 203, 287.

(6) Perting, A. S.; Brice, C. Can. J. Chem. 1955, 33, 1216. (7) (a) Ruff, 0. Ber. 1898,31, 1573. (b) Ruff, 0. Ber. 1899, 32, 3672. (c) Ruff, 0. Ber. 1901,,

33, 1362. (8) Green, J. W. The Carbohydrates Chem. & Biochem. 1980, TB, 1101. (9) Fletcber Jr., H.G.; Diehl, H. W.; Hudson, C. S. J. Am. Chem. Soc, 1950, 72, 4546. (10) Walon, R. G. P. US 3755294 1973. (11) Wohl, A. Ber. 1899, 22, 3666. (12) Weeunan, R. A. Rec. Trav. Chim. 1917, 37, 16.

158 Carbohydrate-based syntheses ofCrchirons

(13) (a) Ballou, C. E.; Fischer, H. 0. L.; MacDonald, D. L. J. Am. Chem. Soc. 1955, 77, 5967. (b) Hougb, L.; Taylor, T. J. J. Chem. Soc. 1955, 1213.

(14) Johnson, R. G.; Ingbam, R. K. Chem. Revs. 1956, 56, 219. (15) (a) Morgeolie, S. Acta Chem. Scand.1972, 26, 1709. (b) Morgelie, S. Acta Chem. Scand.

1973, 27, 2607. (16) (a) Pottenger, C. R.; Johnson, D. C. J. Pol. Science, Part A-1 1970, 8, 301. (b) Sala, L.

F.; Femandez Cirelli, A.; de Lederlcremer, R. M. J. Chem. Soc. Perkin 111971, 685. (c) Nogucbi lnstitute JP 58039695 1983.

(17) Araki, K.; Sakuma, M.; Sbiraisbi, S. Bull. Chem. Soc. Jpn. 1984, 57, 997. (18) (a) Wbistler, R. L.; Schweiger, R. J. Am. Chem. Soc. 1959,81, 5190. (b) Wbistler, R. L.;

Yagi, K. J. Org. Chem. 1961, 26, 1050. (c) Wolf, R. DE 2923267 1980. (d) Wolf, R.; Reiff, F.; Wittmann, R. DE 2923268 1980. (e) Wolf, R.; Reiff, F.; Wittmann, R.; Butzke, J. EP 801024861980.

(19) (a) Spengler, 0.; Pfannenstiel, A. Ztschr. Winschaftgruppe Zuckerind. 1935, 85, 546. (b) Isbell, H.S. J. Res. Nat. Bur. Stand. 1942, 29, 227. (c) Dubourg, J.; Naffa, P. Bull. Soc. Chem. France 1959, 1353. (d) Gleason, W. B.; Barker, R. Can. J. Chem. 1971,49, 1425.

(20) Vuorinen, T.; Hyppänen, T.; Sjöström, E. Starek 1991,43, 194. (21) Hendrlks, H.E. J.; Kuster, B. F. M.; Marin, G. B. Carbohydr. Res.1991, 214, 71. (22) (a) Mehltretter, C.L.; Dvonch, W. US 2502472 1950. (b) Mebltreuer, C.L.; Dvonch, W.;

Rist, C. E. J. Am. Chem. Soc.1950, 72,2294. (23) (a) Gardner, T. S.; Wenis, E. J. Am. Chem. Soc. 1951, 73, 1855. (b) Fujisawa, T.;

Yamazaki, M; Nishiyama, K. JP 156101963. (24) (a) Coheo, N.; Baooer, B. L.; Lopresti, R. J.; Woog, F.; Roseoberger, M.; Liu, Y.-Y.;

Thom, E.; Liebman, A A. J. Am. Chem. Soc. 1983,105, 3661. (b) Collen, N.; Banner, B. L.; Laurem.aoo, A. J.; C8rozza, L. Org. Syntheses 1985, 63, 127.

(25) Isbell, H. S.; Frusb, H.L. Carbohydr. Res. 1979, 72, 301. (26) (a) Kiliani, H. Ber.1896,19, 3029. (b) lsbell, H.S.; Frusb, H.L. Bur. Stand. J. Res.1931,

6, 1151. (c) Pink, C. F.; Summers, D. B. Trans. Electrochem. Soc. 1938, 74, 625. (27) Isbell, H. S.; Soiegoski, L. T. J. Res. Nat. Bur. Stand. A 1964, 68A, 301. (28) (a) Heyos, K.; Paulsen, H. Adv. Carbohydr. Chem. 1962, 17, 169. (b) de Wit, G.; de

Vlieger, J. J.; Koek van Dalen, A C.; Kieboom, A. P. G.; van Bekkum, H. Tetrahedron Len. 1978, 15, 1327. (c) Deller, K.; Krause, H.; Peldszus, E.; Despeyroux, B. DE 3823301C1 1989. (d) Despeyroux. B.; Deller, K.; Peldszus, B. Stud. Surf. Scienc. Cat. 1990, 55, 159. (e) Hendrlks, H. E. J.; Kuster, B. F. M.; Marin, G. B. Carbohydr. Res. 1990, 204, 121.

(29) (a) May, D. E.; Herrick, H.T.; Moyer, A. J.; Hellbach, R.1nd. Eng. Chem. 1928, 21, 1198. (b) Porges, N.; Clark, T. F.; Gastrock, G. A.1nd. Eng. Chem.1940, 32, 107. (c) van Gelder, D. W. US 2916515 1959. (d) Tramper, J.; Luybeo, K. C.A. M.; van der Tweel, W. J. J. Eur. J. Appl. Microbiol. Biotechnol. 1983,17, 13.

(30) Nef, J. U. Liebigs Ann. 1910, 376, 1. (31) Vuorinen, T.; Sjöström, E. J. Wood Chem. Techn. 1982, 2, 129. (32) Scholz, H.; Gotsmann, G. US 4125559 1978. (33) Isbell, H. S.; Frusb, H. L.; Wade, C. W. R.; Hunter, C. E. Carbohydr. Res. 1969, 9, 163. (34) K.irillova, N. 1.; Tul'chioskaya, L.S.; Shereshevskii, A. A.; Berezovskii; V.M. Zh. Prikt.

Khim. (Leningrad) 1916, 49, 2504. (35) Pigmao, W.; Aoet, E. F. L. J. The Carbohydrates Chem. & Biochem. 1972, IA, 165, 2nd

ed., W. Pigman and D. Horton eds., Academie Press, US. (36) Angyal, S. Adv. Carbohydr. Chem. & Biochem. 1984, 42, 15. (31) Shilov, E. A; Yasoik:ov, A. A. CA(49):1574h 1955.


(38) (a) Lister, M. W.; Can. J. Chem. 1956, 34, 465. (b) Chababartty, S. K. Oxidation in Organic Chemistry, Part C 1978, 343, W. S. Trabanovsky ed., Academie Press, US.

(39) Kirk.()thmer Encyclopedia ofChemic:al Technology 1981,5, 580, 31h ed., ]ohn Wiley & Sons.

(40) Patel, K. F.; Mehta, H. U.; Srivastava, H. C. Stiirke 1973, 25, 266. (41) Jsbell, H. S.; Salam, M. A Carbohydr. Res. 1981, 90, 123. (42) Aukett, P.; Batker, I. R. L. J. Chem. Soc. Perkin H 1973, 965. (43) Anbar, M.; Dostrovsk:y,l. J. Chem. Soc. 1954, 1094. (44) Czametzlri, L. R. Aspectsof Electrochemical Production of Hypochlorite and Chlorate

1989, PHD-thesis, Uuiversity of Technology Eindhoven. (45) Selectivity detennined qualitatively with lhe aid of lhe amounts of side-products fonned. (46) Morgenlie, S. Acta Chem. Scand. 1973, 27, 1557. (47) Pedin, A S.; Brice, C. Can. J. Chem. 1956, 34, 85, 541. (48) Bailey, K.; Hopkins, R. H. Biochem. J. 1933, 27, 1965. (49) Araki, K.; Shiraisbi, S. Bull. Chem. Soc. Jpn. 1986, 59, 229. (50) Scbneider, B; Lichtenthaler, F. W.; Steinle, G.; Schiweck, H. Liebigs Ann. Chem. 1985,

2443. (51) Wbistler, R. L.; Schweiger~ R. J. Am. Chem. Soc. 1957, 79, 6460. (52) Floor, M.; Kieboom, A. P. G.; van Bek:kum, H. Starch 1989, 41, 348. (53) Ohle, H.; Berend, G. Chem. Ber. 1927, 60, 1159. (54) (a) Pastemack, R.; Regna, P. P. US 2203923 1939. (b) Pastemack, R.; Regna, P. P. US

2188777 1940. (55) Pastemack, R.; Regna, P.P. US 2153311 1939. (56) (a) Stubbs, J. J.; Lockwood, L.B.; Roe, B. T.; Tabenkin, B.; Ward, G. B. lnd. Eng. Chem.

1940,32, 1626. (b) Lockwood, L.B.; Tabenkin, B.; Ward, G. B. J. Bacteriol. 1941,42, 51. (c) Kita, D. A. US 4155812 1979.

(57) (a) Smits, P.C. C. EPA 8520006371985. (b) Smits, P.C. C.; Kuster, B. F. M.; Wiele van der, K.; Baan van der, H.S. Carbohydr. Res. 1986,153, 227.

(58) Glltzi, K.; Reichstein, T. Helv. Chim. Acta 1937, 20, 1298.

7. General conclusions and economie aspects 161

Two approaches for the oxidative degradation of readily available

monosaccharides to <;-chirons have been presented in this thesis. The fJ.rSt one

includes proteetion of C6-carbohydrates and subsequent cleavage to the

corresponding protected <;-chirons in one or two steps. Selective proteetion of

hydroxyl functions in most carbohydrates is, however, often very difficult to

achleve due to the large number of equally reactive hydroxyl functions. The second approach, therefore, consists of the selective degradation of unprotected

sugars, which, after proteetion of the free hydroxyl functions of the cleavage

products, gives protected C3-chirons. Direct protections at 0-2 and 0-3 of

glyceraldehyde (10, 28) and glyceric acid (12, 29), however, have not been

studied. Proteetion of glyceric acids (12, 29) has been reported by Hirth et al.1 to

proceed in high yield, provided the glyceric acids (12, 29) were converted first to

the corresponding methyl esters (30a, 31a). The necessity of this extra step relies

on the incompatibility of the carboxylic acid function and the proteelive

isopropylidene and cyclohexylidene groups. The high yield proteetion of the free

hydroxyl functions of glyceraldehyde may also be difficult to achieve, because of

the tendency to dimerization and polymerization reactions of this aldehyde. Fischer

et al. 2 reported in 1930 the isopropylidenation with the aid of acetone and ZnC~

of racemie glyceraldehyde (10 + 28), affording 4a + Ua in 53 % yield.

The most promising reaction reported in this thesis (Chapter 3), is the Ru

catalyzed oxidative cleavage of protected D-mannitol (2a,b) to the corresponding

D(R)-glyceric acids (3a,b) with NaOCl. Until now, Nal04 and Pb(0Ac)4,

expensive and environmentally unacceptable oxidants, have been used to

accomplish cleavage of D-mannitol derivatives (2a,b ). Our Ru-catalyzed oxidative

cleavage, with inexpensive NaOCl is, however, very selective and fast and also

yields two identical C3-chirons (3a,b) and only NaO as byproduct. L-Enantiomers

(13a,b) are similarly obtained, starting from L-ascorbic acid (6), but one extra step


is needed and one C6-molecule results only in one C3-molecule. Preparation of the

conesponding protected glyceraldehydes (3a,b; lla,b) from D-isoascorbic acid

(16) and L-ascorbic acid (6), respectively, is less selective and again only one

mole C3-chiron is formed per mole substrate. Also in this method, however, cheap

oxidants are used. Moreover, catalytic hydragenation of protected glyceraldehydes

( 4a,b; lla,b) to the conesponding glycerol derivatives (5a,b; 14a,b) proceeds very

selectively, while reduction of protected glyceric acids (3a,b; 13a,b) to the

corresponding glycerol derivatives (5a,b; 14a,b) is somewhat cumbersome.

For the synthesis of unprotected ~-chirons, always a combination of

selective degradation methods is needed and only one C3-chiron is formed per

molecule of substrate. Without the use of protective groups, C6-carbohydrates

cannot be cleaved selectively between C-3 and C-4. The AMS-Hz02-catalyzed

alkaline oxidative cleavage of aldoses to the next lower aldonic acids is

remarkably because of its high selectivity and cheapness of the oxidant.

Furthermore, the efficient, selective cleavage ofL-ascorbic and D-isoascorbic acids

(6 and 16, respectively) into the conesponding tetronic acids ((27), 8) and oxalic

acid (46) and the cleavage of D-fructose (15) into D-erythrose (26) and glycolic

acid (50), should be mentioned: in these reaction two carbon atoms are split of in

one reaction step.

In summary, two approaches have been investigated, resulting in protected

and unprotected ~-chirons. Comparison of both approaches is difficult and fully

depends on the feasibility of the ultimate proteetion reactions.

Comparison of the different routes resulting in the same C3-chiron is

difficult. Some routes proceed in high overall-yields, but use expensive reagents

and/or need more reaction steps. Indeed, economie feasibility depends i.a. on yield,

raw material costs, reaction time, simplicity. In order to compare the different

routes a cost price analysis was carried out, based on the use of multi-purpose

equipment and on reaction procedures described in the experimental sections. Raw

material costs were based on prices in Chemica! Marketing Reporter, when

available, or on 20 % of the prices per kg listed by Janssen Chimica4• The results

are summarized in Table 7 .1. Column 3 gives information about the selectivities

in the reactions, column 4 about the equipment cost, column 5 about the man

hours needed and the last two columns give the cost prices per mole and per kg

product.


Table 7.1: Cost price analysis of protected carbohydrates based on reactions in multi-purpose equipment' ::.::".:":,:;=::::::::::.: .. <:' ·.:.·.:.:··; :::::·:: ··::,·:.:

$uM/ ~~îaw ~~~ ~( i~~~~; . ~tltt'Y ~······ ..

'" '" ···'"

··••· •..•..•.•. · .•.. ·• ••• .•••••••.• ••. .•. < (.P%.~l1l ·Jil~> ~~~{ .(~ f(~~ <AA~ .. · ... ············?·········> ..• •ti .. •· .. .(~~~ <

1 7a' 6 (1.02) 2.90 0.79 0.46 8.94 41.41

2 7a')> 6 (1.25) 0.98 1.11 0.22 7.80 36.10

3 17a' 16 (1.01) 2.80 0.38 0.71 8.16 37.77

4 7b' 6 (1.08) 5.47 1.69 0.74 12.97 50.71

5 17b' 16 (1.01) 5.11 1.58 0.70 l1.84 46.28

6 laf)> 1 (1.72) 9.24 1.3 0.55 14.17 54.08

7 lb')> 1 (1.52) 11.15 3.4 0.77 18.62 53.82 ---------------------------------------------------... 8 221 20 (1.18) 1.33 1.32 1.61 5.55 37.00

9 231 19 (1.03) 0.46 0.54 0.38 2.60 13.67 ---- ------------------------------10 9aP 7a (1.18) 1.11 2.02 0.75 15.72 67.13

11 18r" 17a (1.18) 1.11 2.02 0.75 14.78 63.13

12 9~ 7b (1.18) 1.01 5.79 2.15 25.57 94.34

13 18))1P 17b (1.01) 1.01 5.79 2.15 24.23 89.42

14 IJIP 6 (1.18) 1.44 1.57 0.57 8.65 54.07

15 271P 16 (1.18) 1.44 1.57 0.57 8.23 51.41

16 27' 22 (1.20) 0.54 0.64 0.45 9.12 57.02

17 w 23 (1.25) 1.41 1.40 1.71 8.39 69.64

18 lfiB 15 (1.43) 1.63 1.62 1.98 6.56 54.67 -------------------------------------------------------------------19 13ar 9a (1.05) 2.73 4.32 1.97 26.45 157.40

20 Ja' 18a (1.01) 2.59 4.09 1.86 24.02 142.93

21 Jar la (1.05) 2.50 4.13 1.88 16.79 99.94

22 13bf 9b (1.01) 2.44 5.16 2.33 35.11 168.86

23 Jb' 18b (1.07) 2.61 5.52 2.49 36.20 174.10

24 Jb' 2b (1.56) 4.38 7.26 3.38 30.58 147.02 ----------------------------------------------------, 25 29' 26 (1.61) 0.73 0.86 0.61 16.34 125.65

(23)

26 29' 26 (1.61) 0.73 0.86 0.61 13.29 102.19 (15)

-----------------------------------------------------------------------------------27 Jlar Ja (1.43) 7.64 1.84 1.01 35.31 220.69

164 Carbohydrate-based syntheses of C3-clurons

Table7.1 continued

28 31b' 3b (1.60) 13.01 2.06 1.13 66.13 330.65 ------------------------------------------------------------------------------------

29 nar 9a (2.56) 6.90 8.47 6.32 62.76 482.65

30 4a' 18a (2.77) 7.48 9.18 6.85 65.36 502.65

31 4af,lt la (1.11) 7.00 0.67 0.43 16.62 125.91

32 llb' 9b (1.85) 4.92 6.03 4.50 63.65 374.24

33 4b' 18b (1.35) 3.59 4.40 3.29 44.82 263.55

34 4b'.h lb (1.11) 13.92 3.15 1.89 30.15 175.29

35 U)' 8 (1.33) 1.50 1.49 1.82 16.75 186.06

36 1811 17 (1.33) 1.50 1.49 1.82 17.37 193.01 (11)

37 1811 27 (1.33) 1.50 1.49 1.82 16.38 179.78 (15)

----------------------------------------------------------------------------------~ 38 14a' 9a (2.00) 6.66 10.32 5.27 54.25 411.24

39 Sa' 18a (2.50) 8.26 12.80 6.53 64.80 491.21

40 Sa'.n 4a (1.15) 1.32 0.92 0.53 20.54 158.00

41 sar S3a (1.30) 5.44 2.08 1.18 53.91 409.72

42 14b' 9b (1.69) 5.60 8.96 4.43 63.21 367.24

43 Sb' 18b (1.49) 4.92 7.87 3.89 53.55 311.13

44 Sbf,lt 4b (1.15) 1.32 0.92 0.53 38.29 225.24

45 Sb' S3b (1.65) 6.72 2.20 1.26 130.92 772.45

"Volume of multi-pmpose reactor is 4 m'. "Raw material costs, witbout substrate costs, basedon chemical prices in Cbemical Marketing Reporter or on 20 % of the chemical prices (kg'1) of lanssen Chimica4

• "Prices for the use of multi-pmpose equipment based on the reaction procedures described in the experimental sections. "Prices of the Iabour costs to operate the multi-purpose equipment basedon tl 75,- per man-hour. "Cost prices of the produelS including tl 5,~/kg for storage costs etc. 'Isolated. 'In aqueous solution. l!f.iterature procedure.

All reacrions proceed fairly to very selectively (55 to near.lOO %). with

exception of entties 29 and 30 and toa lesser extent (two reaction steps) entties 38 and 39. In these reactions isopropylidenated glyceraldehydes (4a, lla) are produced by decarboxylation of the corresponding tetronic acids (9a, 18a). Decarboxylation of cyclohexylidene derivatives (9b, 18b) proceeds more

7. General conclusions anJ economie aspects 165

selectively (entries 32 and 33).

The raw material costs for the synthesis of all unprotected carbohydrates

mentioned are very low (entries 8,9, 14- 27, 25, 26, 35 -37), as result ofthe low

costs of the oxidants used, as is also the case for the oxidations of the protected

carbohydrates. In addition, all reactions are carried out in water without the need

of relatively expensive organic solvents.

As far as the equipment and Iabour costs are concerned, reaction time and

simplicity of the reaction procedure are very important. Again reactions yielding

unprotected carbohydrates are relatively attractive. However, this is partly due to

the fact that these products are not isolated, but remain in solution. Work-up

procedures, e.g. distillation, extraction etc., usually detennine a large part of the

equipment costs and rnan-hours needed. No further study is ondertaken to isolate

unprotected <;-derivatives, but probably ion-exchange or proteetion methods,

which makes them soluble in organic solvents, facilitate their easy isolation.

Finally, product prices increase of course with decreasing number of carbon

atoms, while unprotected derivatives are less expensive than the corresponding

proteeled carbohydrates. The cost prices of L(S)- and D(R)-glyceraldehydes (10,

28) and D(R)-glyceric acid (29) amount to fl 16,75, fl 16,38, and ft 14.24 per

mole, respectively. whereas those of the corresponding protected derivativeslla,b,

4a,b and 13a,b, 3a,b, amount to fl50,- to fl 60,- and fl 20,- to ft 30,- per mole,

respectively. The prices for the protected glycerol derivatives range from ft50,to fl 60,- per mole.

1. Proteetion of ascorbic acids. Proteetion of D-iso- and L-ascorbic acids

(16 and 6, respectively) with the aid of DMP or DMC and catalytic amounts of

SnC~ (entries I, 3 - 5), is competitive with the reported isopropylidenation of L

ascorbic acid (6) to 7a (entry 2). Raw material costs are higher, but selectivities

are higher as well.

2. Synthesis of proteeteel glyceraldehydes. Preparation of

isopropylidenated glyceraldehydes ( 4a; lla) from D-iso- and L-ascorbic acids (16

and 6, respectively) is rather expensive, due to the low selectivities in the

decarboxylation of the intermediale protected tetronic acids (9a; 18a) to lla and'

4a, respectively) (entries 29 and 30). Synthesis of the corresponding

cyclohexylidene derivative 4b (entry 33) is, however, more attractive. The last

cleavage step proceeds relatively selectively and presumably the L-enantiomer


(llb) can also be obtained in the same high yields by optimalization of the

reaction conditions. On the other hand, protected D(R)-glyceraldehydes (4a,b) still

can be obtained from D-mannitol (1) at a lower cost price, when using the

relatively expensive Nal04 according to the literature procedure. Here the

relatively high price of Nal04 is not counterbalancing by the simplicity and

efficiency of the reaction. In two reaction steps, proteetion and cleavage, two

identical protected C3-chirons are obtained from one C6-carbohydrate, without loss

of carbon atoms.

3. Synthesis of protected glyceric acids. Isopropylidene derivatives of

L(S)- and D(R)-glyceric acids (13a and 3a, respectively) can be producedat very

attractive cost prices starting from D-mannitol (1) as wellas from D-iso- and L

ascorbic acids (16 and 6, respectively) (entries 19- 21). However, for the

synthesis ofthe D-enantiomer (3a), D-mannitol (1) is preferred as starting material

(cost price fll6.79 in comparison to t1 24.02 per mole for 3a). Also the

corresponding cyclohexylidene derivatives can be produced against attractive cost

prices of fl 30.58,- to fl 36,- per mole (entries 22- 24). Again for the synthesis

of the D(R)-enantiomer (3b ), D-mannitol (1) is preferred as starting material. The

attractiveness of D-mannitol (1) for the synthesis of the D(R)-enantiomers 3a and

3b, relies on the symmetry of the C6-molecule, which yields two identical C3-

chirons upon cleavage. The difference in attractiveness with D-isoascorbic acid

(16) as starting material is, however, smaller than expected. This is caused by the

relatively low selectivities achieved in the preparation of protected D-mannitol

(2a,b), whereas the proteetion of D-isoascorbic acid (16) proceeds almost

quantitatively (entries 6,7 and 3,5, respectively). The higher costs of protective

groups is reflected by the fact that the cyclohexylidene derivatives (13b, 3b) are

more expensive per mole than the coeresponding isopropylidene derivatives (13a,

3a).

4. Synthesis of protected glycerols. Por the synthesis of protected

glycerols (14a,b; Sa,b ), catalytic hydragenation of protected glyceraldehydes

( 4a,b) is prefeered to rednetion of the coeresponding acids via intermediate ester

formation (entries 40, 44 and 41, 45, respectively). The synthesis' via the latter

route, employs expensive reagents and needs one extra reaction step. However,

when the protected glyceraldehydes are obtained from D-isoascorbic acid (16)

instead of D-mannitol (1), rednetion of the acid is prefeered in the isopropylidene


derivative case (Sa), but catalytic hydragenation ofthe protected aldehyde (4b) in

the cyclohexylidene derivative case (Sb) (entries 39,41 and 43, 45, respectively).

This again finds its origin in the low selectivity during the decarboxylation of

protected tetronic acids (18a,b ). In the case of isopropylidene derivative ( 4a) the

selectivity is so low, that rednetion of the corresponding acid (3a), produced very

selectively from D-mannitol (1), with one extra step and with the use of an

expensive reducing agent, is more attractive.

S. Synthesis of unprotected C3-ebirons. Synthesis of L(S)- and D(R)

glyceraldehyde (10 and 28, respectively) according to entries 35 - 37, is very

interesting and proceeds at lower cost price when performed in two instead of

three reaction steps (entries 36 and 37, respectively). When proteetion could be

carried out in an appropriate manner, this route presumably competes with the

reported cleavage of protected D-mannitol (Za,b) with Nal04, whereas

opportunities for the synthesis of the L-enantiomer are even better. D(R)-Glyceric

acid can also be produced against a reasonable cost price ( entties 25 and 26).

Again the two step procedure (entry 26) is more favourable than that invalving

three steps (entry 25). Proteetion presumably bas to be carried out alter

esterification, wbich makes it difficult to compete with the synthesis of protected

glyceric acid (3a,b) starting from D-mannitol (1). However, when the methyl ester

is used as intermediate for the synthesis of protected glycerol (Sa,b ), tbis metbod

is probably more attractive.

In conclusion, the synthesis of protected L(S)- and D(R)-glyceric acids

(13a,b; 3a,b) seems to be feasible for industrial application, whereas synthesis of

the corresponding glyceraldehyde derivatives (lla,b; 4a,b) is relatively expensive.

In the latter case, the use of an expensive stoichiometrie reagent is still more profitable than the use of cheap oxidizing agents following a more complicated

reaction pathway. Catalytic hydragenation of protected glyceraldehydes (lla,b; 4a,b) is more attractive for the synthesis of protected glycerols (14a,b; Sa,b) than

NaBH4-reduction via the corresponding methyl glycerates (30a,b; 31a,b). However, due to the bigh costs for the production of the protected aldehydes

(lla,b; 4a,b), the production of protected glycerol derivatives (14a,b; Sa,b) still remains relatively expensive. It is worth noting in tbis context that Janssen

Cbimica4 charges fl.lOO,- per gram for the protected optically pure glycerol

derivatives (14a,b; Sa,b). However, the latter bigh price is basedon a small scale


and market, and presumably will decrease when the product is sold in larger

amounts. Only the L(S)-enantiomer of the isopropylidene derivative of glyceric

acid (13a) is commercially available on a larger scale. Shell5 offers this derivative

(13a) at fl400,- per kg for large amounts. Even with this relatively low price,

compared with that of the glycerol derivatives (14a, Sa), our metbod looks

attractive.

Unprotected C3-chirons L(S)- and D(R)-glyceraldehydes (10, 28) and D(R)

glyceric acid (29) can be producedat very low cost prices (fl 110,- -fl 190,- per

kg). However, these prices are based on the derivatives in solution. They are

particularly attractive when the C3-chirons are obtained in a two-step procedure,

thereby reflecting the importance of a limited number of reaction steps. Especially

the synthesis of D-erythrose (26) from D-fructose (15) with Naoa is unique and

limits the cost price of D-erythrose (26) to fl55,- per kg product in solution.

Prices of abovementioned C3- and C4-chirons asked by chemieals suppliers are in

the range of fl 100,- per gram product! Again, the latter high prices are based on

a small scale and market, and probably will decrease when the products are sold

in larger amounts.

In this and the preceding chapters it has been demonstrated that carbohydrates are valuable starting materials for the preparation of a host of ebiral

building blocks. By taking advantage of this primary souree of chiral building

blocks from nature, enantiomerically pure products with high added value are

obtained. Several routes have been investigated for the synthesis of C3-chirons, and

this resulted in several potentially interesting and environmentally. acceptable

procedures. Sorne methods still have to be optimized, but the yields already

accomplished are promising.

7.1 Relerences and notes

(1) Hirth, 0.; Walther, W. Helv. Chim. Acta 1985,68, 1863. (2) Fischer, H. 0. L.; Baer, B. Ber. 1930, 63, 1749. (3) Chemica/ Marketing Reporter 1991, April 1, 32. (4) lanssen Chimica Catalogue 1991. (5) Originally developed by IBIS, the fonner joint-venture of Shell and Gist-Brocades.

Summary 169

Small enantiomerically pure building blocks can be incorporated into

optically pure natura! products and compounds of biologica! and synthetic interest.

They are increasingly important in the pharmaceutical and agrochemical industries

from an enviromnental point of view. Carbohydrates are an extremely cheap,

naturally occurring replenishable souree of chiral carbon compounds, unmatched

in chirality and functionality. They obviously are interesting starting matcrials for

the synthesis of ebiral building blocks. This thesis concerns the exploration of

carbohydrates as feedstock for the synthesis of C3-chirons using industrially and

environmentally viabie synthetic methods.

GC and HPLC methods were used to analyze the reaction mixtures and OC

was used todetermine the optica! purity (Chapter 2).

A plethora of mainly catalytic oxidizing systems has been tested for the

cleavage of 1,2:5,6-di-0-isopropylidene- and cyclohexylidene-D-mannitol to the

corresponding proteeled D(R)-glyceraldehydes and glyceric acids (Chapter 3).

Most systems investigated were not able to cleave a-diols, but fortunately the Ru03-catalyzed a-diol cleavage with NaOCl as primary oxidant showed high

selectivity and high reaction rate under mild conditions. Also cleavage with

NaOCl, with or without the presence of Pb(N03.h or Fe2(S04) 3, yielded protected

glyceric acid as main reaction product, however, with low rate and/or selectivity.

Thus, RuC~-catalyzed cleavage of 1,2:5,6-di-0-isopropylidene-D-mannitol with

NaOCl gave sodium 2,3-0-isopropylidene-D(R)-glycerate in 95 % yield within 30

min. Similarly, cleavage of the corresponding cyclohexylidene derivative of D

mannitol in a two phase system (~0/DCM/CH3CN) yielded 64 % of sodium 2,3-

0-cyclohexylidene-D(R)-glycerate. Several mthenium catalysts were effective, e.g.

tetrapropyl ammonium permthenate (TPAP), Ru-Dowex, Ru/C,

Pb[Ru1.33Pf>o.67 *]06..s (pyrochlore oxide), but only with NaOO as the primary

oxidant. The best results with a heterogeneous catalyst were obtained with · the

pyrochlore oxide, Pb[Ru133Pf>o.67 4+]06..s, which reacts with a comparable activity

and selectivity as the homogeneous catalyst (RuC13), and which presumably reacts

at the surface of the catalyst. The addition of active carbon has a positive effect

170 Carbohydrate-based syntheses of C,rchirons

on the reaction rate of the RuC13-catalyzed cleavage. The homogeneously catalyzed

reaction is first order with respect to RuC~ and diol and the observed activation

energy amounts to 55.8 kJ/mol. Presumably the reaction proceeds via Ru04 which

forms a complex with the cx.-diol function. Subsequent cleavage of the C-C bond

gives Ru03 and two molecules of protected C3-aldehyde which then are forther

oxidized to the conesponding C3-acid.

Preparadon of enantiomerically pure 2,3-0-isopropylidene-L(S)- and D(R)

glyceraldehyde and 2,3-0-cyclohexylidene-L(S)- and D(R)-glyceric acid

derivatives in good yield was achieved by selective degradation of D-iso- and L

ascorbic acids (Chapter 4). Consecutive proteetion of the ascorbic acidsin almost

quantitative yield and H20 2-cleavage afforded 3,4-0-isopropylidene-L-threonic and

D-erythronic acids or the conesponding cyclohexylidene derivatives. Subsequent

decarboxylation of these protected tetronic acids with NaOCl at pH = 5.5 in a two

phase system gave rise to the conesponding glyceraldehydes in moderate yields

(36 - 74 % ). In contrast, Ru03-catalyzed oxidation with NaOCl at pH = 8 led to

the corresponding glyceric acids in excellent yields (93 - 99 % ).

Enantiomerically pure 1 ,2-0-isopropylidene-L(S)- and D(R)-glycerols, and

1,2-0-cyclohexylidene-L(S)- and D(R)-glycerols were obtained by reduction of the

corresponding glyceraldehyde or glyceric acid derivatives (Chapter 5). Ru/C or

Pd/C catalyzed hydragenation of the protected glyceraldehyde derivatives gave the

conesponding alcohols in 75 - 90 % yield. Direct esterification of the protected

sodium glycerates with benzyl bromide in acetonitrile yielded up to 80 % of the

cortesponding benzyl esters. Alternatively, esterification of the protected glyceric

acids with MeOH in the presence of catalytic amounts of pTsOH, gave the methyl

esters, but deprotected. Subsequent proteetion with DMP or DMC in the presence

of catalytic amounts of Sn~ gave the protected methyl esters in 65 - 70 %

overall yield. Finally, NaBH4-reduction of the protected methyl esters gave the

proteeled glycerol derivatives in 60 - 80 % yield.

A number of selective degradation methods for unprotected sugars with

practical value led to low molecular weight carbohydrates (Chapter 6). AMS-H20 2-

catalyzed alkaline oxidative cleavage of C6-, Cs- and C4-aldoses with oxygen

afforded the next lower aldonic acids in good yields (70 - 98 % in solution). Also

oxidation of D-fructose to D-arabinonic acid with oxygen in the pre8ence of AMS

and ~02 proceeded with a remarkable selectivity (85 % yield). Degradation of C6-

• Cs- and C4-aldonic acids with NaOCl at pH= 4.5- 5.5 yielded the next lower

aldoses with high selectivities (up to 90% at 80% conversion), but unfortunately

Summary 171

selectivity decreases at higher conve:rsions. Selectivity seemed to be governed by

the amount of hypocblorite present in the reaction mixture. The reaction was also

carried out with in situ generated hypocblorite produced by electrochemical

oxidation of NaCl. The active species probably is HOCl as is reflected in the

mechanism proposed. Degradation of D-fructose with hypocblorite at pH= 9,

affording D-erythrose and glycolic acid in good yields (60 %), is believed to rely

on the intennediacy of oo· as the active oxidant. Degradation of most C6- and Cs-2-ketoaldonic acids with ~02 at pH= 7 or NaOCl at pH= 5.5 yielded the next

lower aldonic acid in high yields (up to 95 % ). However, degradation of 2-keto-D

arabinonic acid with ~02 was less selective (70 % yield of D-erythronic acid,

besides 30 % D(R)-glyceric acid). Cleavage of D-iso- and L-ascorbic acids with

~02 afforded the cortesponding tetronic acids, together with oxalic acid in high

yield (95 % ). Sequentia! use of abovementioned oxidation methods yielded L(S)

and D(R)-glyceraldehydes and D(R)-glyceric acid in two or three reaction steps

from readily available C6-carbohydrates. Especially degradation of D-fructose with

hypocblorite and degradation of the ascorbic acids with ~02, involving cleavage

of two carbon atoms in one reaction step, seem very promising. The intennediate

C5- and C4-derivatives, need not to be isolated but may be.oxidized further in the

reaction mixture without significant loss of selectivity, thereby reducing the

number of expensive isolation procedures.

A cost price analysis was carried out (Chapter 7), showing that our

synthetic methods are potentially interesting for industrial applications and are at

least competitive with existing methods.

Summarizing, two approaches for the degradation of readily available

monosaccharides to C3-chirons have been described. The ftrst one includes

proteetion of C6-carbohydrates and subsequent cleavage to the cortesponding

protected ~-chirons in one or two steps. The second approach consists in the

selective degradation of unprotected suga:rs in two or three steps to C3-chirons, which may be protected ultimately.

172 Carbohydrate-based syntheses of C;-chirons

~-chironen zijn veelzijdige bouwstenen voor de synthese van optisch

aktieve verbindingen zoals natuurprodokten en biologisch aktieve stoffen. Vanuit

milieu oogpunt gezien, worden ze van steeds groter belang in de fannaceutische

en agrochemische industrie. Koolhydraten zijn goedkope, veel in de natuur

voorkomende, optisch ak.tieve verbindingen en derhalve uitermate geschikt als

uitgangsmateriaal voor de synthese van chirale bouwstenen. Dit proefschrift

beschrijft het onderzoek naar het potentieel van koolhydraten als

uitgangsmaterialen voor de synthese van C3-chironen met behulp van industrieel

toepasbare en milieu technisch gezien aanvaardbare reagentia.

Voor de analyse van reaktiemengsels is gebruik gemaakt van HPLC en GC

en deze laatste techniek is ook gebruikt voor bepaling van de optische zuiverheid

van de verschillende eindprodokten (Hoofdstuk 2).

Een skala aan hoofdzakelijk katalytische oxidatie-systemen is getest voor

de splitsing van 1,2:5,6-di-0-isopropylideen- en cyclohexylideen-D-mannitol tot

de overeenkomstige glyceraldehyde of glycerinezuur derivaten (Hoofdstuk 3 ). De

meeste systemen bleken echter niet in staat de a.-diolen te splitsen in tegenstelling

tot NaOCl in aanwezigheid van katalytische hoeveelheden RuC4, waarmee de

splitsing zeer selektief en met hoge reaktiesnelheid onder milde omstandigheden

gerealiseerd kon worden. Ook de reaktie met alleen NaOCl of in aanwezigheid van

katalytische hoeveelheden Pb(N03) 2 of F~(S04)3 , leverde het beschermde

glycerinezuur als hoofdprodukt op, echter met een lagere aktiviteit en/of

selektiviteit dan de RuC13-gekatalyseerde reaktie. RuC13-gekatalyseerde splitsing

van 1,2:5,6-di-0-isopropylideen-D-mannitol met NaOCl, gaf in 30 min. natrium

2,3-0-isopropylideen-D(R)-glycerinaat in hoge opbrengst (95 % ). Splitsing van het

cyclohexylideen derivaat verliep analoog en gaf bij gebruik van een twee-fasen

systeem (~0/DCM/CH3CN) natrium 2,3-0-cyclohexylideen-D(R)-glyceraat in

64% opbrengst. Verschillende rutheenkatalysatoren waren aktief, o.a.

tetrapropylammonium perruthenaat (TP AP), Ru-Dowex, Ru/C, Pb[Rtiu~bo.67 *]06.5

(pyrochloor oxide), echter alleen bij gebruik van NaOCI als primair

oxidatiemiddeL De beste heterogene katalysator was het pyrochloor oxide, die

reageert met vergelijkbare aktiviteit en selektiviteit als de homogene katalysator

Samenvatting 173

(RuCl3), waarschijnlijk aan het oppervlak van de katalysator. Ak:tieve kool had een

positief effekt op de reaktiesnelheid van de RuCl3-gekatalyseerde reaktie. De homogeen gekatalyseerde reaktie is eerste orde in diol en RuC13 en de

waargenomen aktiveringsenergie bedraagt 55.8 kJ/mol. De reaktie verloopt

waarschijnlijk via Ru04 dat met de ardiol funktie komplexeen. Vervolgens breekt de C-C binding en worden Ru03 en twee molekulen beschermd glyceraldehyde

gevormd, die worden doorgeoxideerd tot het overeenkomstige zuur. De synthese van enantiomeerzuiver 2,3-0-isopropylideen-D(R)- and L(S)

glyceraldehyde en 2,3-0-cyclohexylideen-D(R)- en L(S)-glycerinezuur werd

gerealiseerd in goede opbrengst uitgaande van D-iso- en L-ascorbinezuur

(Hoofdstuk 4). Na bescherming van de ascorbinezuren en 1402-oxidatie, werden

calcium 3,4-0-isopropylideen-L-threonaat en D-erythronaat en de overeenkomsting

cyclohexylideen derivaten in hoge opbrengst verkregen. Decarboxylatie van de

beschermde telronzuren met NaOCl bij pH = 5.5 in een twee-fasen-systeem, gaf de beschermde glyceraldehyde derivaten in redelijke opbrengsten (36 - 74 % ). De

RuCl3-gekatalyseerde decarboxylatie met NaOCl bij pH= 8 daarentegen, gaf de

overeenkomstige glycerinezuur derivaten in zeer hoge opbrengst (93 - 99 % ).

Enantiomeerzuiver 1,2-0-isopropylideen-L(S)- and D(R)-glycerol en 1,2-0-

cyclohexylideen-L(S)- and D(R)-glycerol werden verkregen door reduktie van de

overeenkomstige glyceraldehyde en glycerinezuur derivaten (Hoofdstuk 5). De

Ru/C- of Pd/C-gekatalyseerde hydrogenering van de beschermde glyceraldehydes

gaf de overeenkomstige alkobolen in 75 - 90 % opbrengst. Direkte verestering van

de natriumzouten van beschermd glycerinezuur met benzylbromide in acetonitril

gaf de overeenkomstige benzylesters in 80% opbrengst. Verestering met MeOH

in aanwezigheid van katalytische hoeveelheden pTsOH leverde de overeenkomstige, maar gedeeltelijk ontschermde, methylesters op. Bescherming van deze esters met DMP of DMC in aanwezigheid van SnCl2, gaf de beschermde

methylesters in een totaalopbrengst van 65- 70 %. Tenslotte leverde NaBH4-

reduktie van de beschermde methylesters, de overeenkomstige glycerol derivaten

in 60 - 80 % opbrengst.

Een aantal praktische methoden voor de selektieve degradatie van

onbeschermde koolhydraten tot optisch aktieve C3-synthonen zijn beschreven

(Hoofdstuk 6). De AMS-1402-gekatalyseerde alkalische degradatie van C6-, Cs

en C4-aldoses met 0 2 gaf de overeenkomstige C5-, C4- en C3-aldonzuren in goede opbrengsten (70 - 98 % in oplossing). Ook de oxidatie van D-fructose met dit systeem verliep zeer selektief en gaf D-arabinonzuur in 85 % opbrengst. De

174 Carbokydrate-based syntheses of Crchirons

degradatie van C6-, C,- en C4-aldonzuren met NaOCl bij pH= 5.5 gaf de

overeenkomstige C,-, C4- en C3-aldoses met hoge selektiviteit (tot 90% bij 80%

konversie), maar bij hogere konversies daalde de selektiviteit. Deze lijkt voor een

belangrijk deel bepaald te worden door de hoeveelheid NaOCl die aanwezig is in

het reaktiemengseL De reakties werden ook uitgevoerd met in situ NaOCl-vorming

door elektrochemische oxidatie van NaCI. Het aktieve deeltje in de reaktie is

waarschijnlijk HOCI, zoals is weergegeven in het voorgestelde reaktiemechanisme.

De degradatie van D-fructose met NaOCl bij pH= 9 gaf D-erythrose en

glycolzuur in 60 % opbrengst, waarbij waarschijnlijk oei- het aktieve deeltje is.

Degradatie van C6- en C,-ketozuren met ~02 bij pH = 7 of NaOCI bij pH = 5.5,

gaf de overeenkomstige C5- en C4-aldonzuren in hoge opbrengst (tot 95 %). De

degradatie van 2-keto-D-arabinonzuur met ~02 was echter minder selektief: naast

D-erythronzuur (70 %) werden ook aanzienlijke hoeveelheden D(R)-glycerinezuur

gevormd (30 % ). Splitsing van D-iso- en L-ascorbinezuur met H20 2 tenslotte, gaf

respektievelijk D-erythronzuur en L-threonzuur en oxaalzuur in 95 % opbrengst.

Met name de degradatie van D-fructose met NaOCl en van D-iso- en L

ascorbinezuur met ~02 zijn in dit opzicht erg interessant omdat in één reaktiestap

twee koolstofatomen worden afgesplitst. Door kombinatie van bovenstaande

selektieve degradatiemethoden, kunnen L(S)- en D(R)-glyceraldehyde en D(R)

glycerinezuur in twee of drie reaktiestappen worden gesynthetiseerd uit goedkope

C6-koolhydraten. De tussenprodukten (C,- en C4-derivaten) hoeven niet geïsoleerd

te worden maar kunnen rechtstreeks ingezet worden voor de volgende reaktie

zonder substantieel verlies in selektiviteit. Hierdoor kan het aantal dure

isolatieprocedures tot het minimum beperkt worden.

Uit een kostprijsanalyse, die voor de diverse routes is uitgevoerd, bleek dat

de onderzochte methoden potentiële kandidaten voor industriële toepassing zijn

(Hoofdstuk 7).

Samengevat: twee benaderingen zijn beschreven voor de selektieve

degradatie van goedkope koolhydraten naar C3-synthonen. De eerste benadering

behelst de bescherming van C6-koolhydraten, waarna degradatie in één of twee

stappen tot beschermde C3-chironen leidt. De tweede benadering behelst de

selektieve degradatie, in twee of drie stappen, van onbeschermde C6-koolhydraten

naar C3-chironen, welke tenslotte beschermd kunnen worden.

Curriculum vitae 175

De schrijfster van dit proefschrift werd op 7 januari 1965 geboren te

Oploo. Na het behalen van het VWO diploma (ongedeeld) aan het

Elzendaalcollege te Boxmeer, begon ze in september 1983 met de studie Scheikundige Technologie aan de Technische Universiteit Eindhoven. Het

afstudeerwerk werd verricht onder leiding van prof. dr. E. F. Oodefroi en was

getiteld: Stereoselektleve addities aan beschermde 2,3-dideoxy-L-ascorbinezuur

derivaten. In december 1987 werd hiermee de ingenieurstitel (cum laude) behaald.

Van 1 januari 1988 tot 31 december 1991 was zij als onderzoeker in opleiding in

dienst van STW/NWO en werkzaam binnen de vakgroep Chemische Proceskunde van de Technische Universiteit Eindhoven. De resultaten van het in deze periode

o.l.v. Prof. dr. R. A. Sheldon verrichtte onderzoek, zi~ beschreven in dit proefschrift.

APPENDIX I: LIST OF ABBREVIATIONS a: acac: AcOOH:

AMS: BuOH:

CAN:

DCE:

DCM: DMC:

DMP:

DMSO:

e.e.:

EtOAc:

EtOH:

11= FDA: FID: GC: r: HPLC: HO Ac:

I.O.:

i: LAH: LC:

MeOH:

NMO: PTC:

pTsOH: RI: tB HP: t-BuOCl:

THF:

TMS: TPAP: [x]:

V:

separation factor

acetyl acetonate

peracetic acid

sodium anthraquinone-2-sulfonate

butanol

ceric ammonium nitrate

dichloroethane

dichloromethane 1,1-dimethoxycyclohexane 2,2-dimethoxypropane

dimethyl sulfoxide

enantiomeric excess (%)

ethyl acetate

ethanol current efficiency of i (%)

Food and Drug Administration

flame ionization detection

gas chromatography

degree of saturation (%) high-performance liquid chromatography

acetic acid

inside diameter current density (kAlm?)

lithium aluminium hydride liquid chromatography

methanol

4-methylmotpholine N-oxide phase-transfer catalysis ( catalyst)

p-toluenesulfonic acid refractive index tert-butyl hydroperoxide

tetrabutyl hypochlorite

tetrahydrofuran

trimethylsilyl tetrapropyl ammonium perruthenate

concentration of compound x (mol/L)

volume (L)

liquid flow velocity (m/s)

APPENDIX Il: LIST OF STRUCTURES a: isopropylidene (R • -CH,)

b: cyclobexylideoe <R = cyclohexylidene (R = -(c,H10)-)

H01 HO HÖ

1

OH OH OH

1: D-mannitol; 2a: 1,2:5,6-di-0-isopropyHdene-D-mannitol; lb: 1,2:5,6-di-0-cyclohexylidene-D-mannitol; 3a: 2,3-0-isopropyHdene-D(R)-glyceric acid; 3b: 2,3-0-cyclohexylidene-D(R)-glyceric acid;

7a,b 8

7a: 5,6-0-isopropylidene-L-ascorbic acid; 7b: 5,6-0-cyclohexyHdene-L-ascorbic acid; 8: L-thrconic acid; 98: 3,4-0-isopropylidene-L-threonic acid;

4a: 2,3-0-isopropylidene-D(R)-glyceraldehyde; 4b: 2,3-0-cyclohexyHdene-D(R.)-glyceraldehyde; Sa: 1,2-0-isopropylidene-L(S)-glycerol; Sb: 1,2-0-cyclohexylidene-L(S)-glycerol; 6: L-ascorbic acld; ·

OJOH O H

R 0 OH HOt' RxO HO]

9a,b 10

9b: 3,4-0-cyc1ohexylidene-L-thrconic acid; 10: L(S)-glyceraldehyde; ll.a: 2,3-0-isopropylidene-L(S)-glyceraldehyde: llb: 2,3-0-cyclohexylidene-L(S)-glyceraldehyde;

--rHHO · OjOH OrOH HOj HO OHO~

RXO OH 0

HO RXO OH -HO R 0 R 0 OH HO OH

12 13a,b 14a,b

12: L(S)-glyceric acid; 13a: 2,3-0-isopropylidene-L(S)-glyceric acid; 13b: 2,3-0-cyclohexylidene-L(S)-glyceric acid; 14a: 1,2-0-isopropylidene-D(R)-glycerol:

15 16

14b: 1,2-0-cyclohexylid,ene-D(R)-glycerol; 15: D-fructose; 16: D-isoascorbic acid;

RX0\4 o

10H

0

1~H R 0 0 0 OH HO

- 0 R OH HO OH OXR g~

OlOH OH HO

OH OH OH

~l~H H~lH OH OH OH OH OH OH

17a,b 18a,b

17a: 5,6-0-isopropylidene-D-isoascorbic acid; 17b: 5,6-0-cyclohexylidene-D-isoascorbic acid; 18a: 3,4-0-isopropylidene-D-erythronic acid; 18b: 3,4-0-cyclohexylidene-D-erytbronic acid;

HO

19 lO 21 22

19: D-glucose; 20: D-gluconic acid; :U: 2-keto-D-gluconic acid; 22: D-arabinose;

OlOH HO OH OH OH

~10H OH OH OH

'--};(0 HO OH

OlH OH OH OH

OlOH OH OH OH

OtH OtOH OH OH OH OH

13 Z4

23: D-arabinonic acid; 24: 2-k.eto-D-arabinonic acid; 25: D-araboascorbic acid; 26: D-erythrose:

Z5 26

HO HO OrOCH3

RXO

otocH, OXR

or OH OH

R 0 0 R OH 30a,b 3la,b 32

30a: methyl 2,3-0-isopropylidene-L(S)-glycerate; 30b: methyl 2,3-0-cyclohexylidene-L(S)-glycerate; 31a: methyl 2,3-0-isopropylidene-D(R)-glycerate; 31b: methyl 2,3-0-cyclohexylidene-D(R)-glycerate;

27 28 29

27: D-erythronic acid; :ZS: D(R)-glyceraldehyde; l9: D(R)-glyceric acid;

OLH OH

33

Hf=CH-CH20H

34

32: D-mannose; 33: glycolaldehyde; 34: allyl alcohol; 35: glycerol;

EOH OH OH

35

36: D-glucono-3-laetone; 37: dimethyl L-tartrate;

E

OxCH3 0 CH3HO OH HO OH HO

g~ O~H OH OH

HO HO HO

38 39 40

39: L-mannitol; 40: L-arabinose;

38: 1 ,2-0-isopropylldene-D-erythritol;

OIOCH, HO HO~ HO 0

HO 0 OCH3 HO

41

41: dimethyl tartrate; 42: L-erythndose;

42

43: L-galactono-&.laetone;

OH

f(lo~~0 Ho OH

OH OtOH 0~ OH H2N OH

OH OH OH

43 44 45

44: sorbitol; 45: D- or L-serine;

HOOCCOOH H3C x 0

H{:H ol~H H3C 0 46 0

OH HO HO HOLO OH HCOOH OXCH3 OH HO

47 0 CH3 OH OH OH

46: oxalic acid; 47: fonnic acid;

48

48: 1,2:5,6-di-0-isopropylidene-3-keto-D-mannitol;

49 50

49: D-xylose; 50: glycolic acid; 51: 2-keto-L-gulonic acid;

51

~OH OH OH OH

HO{O HO

OH OH

52 53

52: erytbritol; 53: D-threonic acid; 54: L-erythronic acid;

OrOH HO HO HO

54

55a: benzyl2,3-0-isopropylideM-D(R)-glycerate; 55b: benzy12,3-cyclohexylidene-D(R)-glycerate.

APPENDIX ill: OVERALL REACTION SCHEME

: known

: unknown

a x not investigated . d investigate a x

kl ~: o .•• , .,..___ :

nl

: HO OH l

1 ,,

OYH

HOj HO

10

OYOH

HOj HO

12

ml

. . . . . . . . . . . . . . . . . . . . . . . . . a bl :

. ael : .......... .:

H01 HO HO

OH OH OH

V

\

b HOj

R 0 xo R

HO {~H

OH OH OH

15

p

0

1H

OH HO

OH OH OH

al

o

10H

. OH

HO OH ~ 01:H OH

OH HO 1!1

Tbl OH ~~1 ------ OH

- ~ OH ~ .::lH ..... 21

d2

0

1H

OH OH OH

26

a2 OH •••• ••• OH ,.•' ~ ~ /

-----... .•• •• fl ... OH •••• .. x2

...___c20 010H 22 ••••

OH •• ••

• ~OH ~~10H · HO~ ,..., \\ i OH 110

0

HO \\ : o R 0 o \ \ e2 : XR _ . .

\ · ... \ •, \ •. . . . .

_ \ ; , z2 :: ••• .•' I f2 ' • 3:.---- " _..- /

1

/ H ........-.. •••• / k2 ag_ •• :/ , ••• •' 010 fj •··•·•• .... •' 3

.-'---.,.. OH 1: ,.••'ac2 • ...~ ............. ..._ OH : ;.... , ••. ......... . ... .. ~ ,• ••• •• OH , •••.•• : ; a b ?.··· RXO

/ •• • •• •• 27 ••••• :: j2 •• • • •• ae2 ... -: 3 : • ~~· R 0 0 0 •• •• •• ••• •• •• :d ;f ••• •• ... •' •' ······ ' . . .. -b3: ,.· •. ·· ••. ·· ········ ff,··

' ..- •• ••• H .. HO OH ,.. "~~.··· ······ ot U b

OH .......... , k-::~.2 •• ~ Ot OH ! f ,/ . . . OH OH_;; / 28 .~ /

OH ,,.: ~;·; .. •:•• •• /» 29 2 •••• .. ' : •• •

ot+ ":H ~1;x; /:~· --E-:H--R- I OXR x 0 R "·' 0 R 3a,~b-~~--==~--~-- -

_ m2

STELLINGEN

behorende bij het proefschrift

CARBOHYDRATE-BASED SYNTHESES OF C3-CHIRONS

van

Carry Emons

1. In tegenstelling tot hetgeen Tanaka et al. beweren, is 5,6-0-isopropylideen-D

isoascorbinezuur niet te watergevoelig voor oxidatieve splitsing met

waterstofperoxide. A. Tanaka, K. Yamashita, Synthesis 1987, 570; Dit proefschrift Hoofdstuk 4.

2. De door Pelthouse et al. beschreven oxidatieve splitsing van trans-I ,2-

cyclohexaandiol m.b.v. Ru-Pb-pyrochloor oxiden, berust niet noodzakelijk op

komplexatie van Pb met het a.-diol. T. R. Felthouse, P. B. Fraundorf, R. M. Friedman, C. L. Schosser, J. Cat. 1991, 127, 421; Dit

proefschrift Hoofdstuk 3.

3. De door Wolf et al. gerapporteerde opbrengstverbetering in de degradatie van

D-gluconzuur naar D-arabinose, is hoogstwaarschijnlijk niet te danken aan de

hogere substraatkoncentratie en reaktietemperatuur, maar aan de

doseringswijze van NaOCl. R. L. Wbistler, R. Schweiger, J. Am. Chem. Soc. 1959, 81, 5190; R. Wolf, F. Reiff, R.

Wittmann, J. Butzke, EP 80102486 1980; Dit proefschrift Hoofdstuk 6.

4. Interpretatie van reakties aan de hand van vermeende nevenprodukten, zoals

Bailey et al. beschrijven, is zeer spekulatief. K. Bailey, R. H. Hopkins, Biochem. J. 1933, 27, 1965; Dit proefschrift Hoofdstuk 6.

5. Het uitvoeren van het laatste experiment werkt vaak autokatalytisch.

6. Het gebruik van koolhydraten als goedkope chirale bouwstenen heeft, gezien

de hoge kosten van de overige grondstoffen, vaak weinig invloed op de

kostprijs van het eindprodukt.

7. Het toedienen van geneesmiddelen als racernaten is een vorm van

milieuvervuiling.

8. De kwantiteit van de tijdens een promotie-periode behaalde resultaten is veelal

omgekeerd evenredig met de kwaliteit van de in deze periode gebruikte

apparatuur.

9. Het feit dat de goede gezondheid van de Nederlanders, getuige de hoge

gemiddelde leeftijd, een extreem hoog percentage aan arbeidsongeschikten niet

heeft kunnen voorkomen, duidt op een chronische kwaal aan het gevoerde

beleid.

10. Gezien de gebruikte aanhefvan brieven, weet de maatschappij zich nog steeds

geen raad met vrouwelijke ingenieurs.

December, 1991

carbohydrate-based syntheses of c3-chirons · 6 carbohydrate-based syntheses of crchirons 3. 7...

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