CHAPTER I

NATURALLY OCCURRING MOLECULES BEARING CHIRAL y-BUTY ROLACTONE RING SYSTEMS

Introduction

ptically active chiral compounds are enjoying an unprecedented renaissance

in virtually all disciplines of biology, medicine, biochemistry and chemistry.

They are finding increasing utility in food industry, material sciences, in the

synthesis of pharmaceutically important compounds and agrochemicals. Hence

chirality and asymmetric synthesis imply piytal involvement in biological '-; b

activity. Hence the synthesis of chiral compounds becomes a special and brutally

challenging testing ground for methods in asymmetric synthesis1.

Transformations of optically active natural products such as arninoacids,

hydroxy acids, carbohydrates etc, optical resolution of an intermediate or final

products and chemical or biochemical synthesis are few of the methods to obtain

enantiomerically pure compounds. Out of thes chemical or biochemical synthesis 3 is clearly attractive since it offers a great variation of solutions as well as challenge

for the search of new methods2.

Chemists have long been fascinated by the remarkable rate acceleration and

high regio- and stereo selectivities obtained by asymmetric synthesis. The

successful application of chiral reagents to asymmetric synthesis requires their

ready availability. Of the available methods of obtaining various optically active

compounds of definite absolute configuration, asymmetric synthesis seems to have

the highest potential. Thus, the design of highly efficient methods for asymmetric

synthesis constitutes one of the most challenging and exciting fields in synthetic

organic chemistry . i

d .

,,.

Asymmetric synthesis implies the $e-novo synthesis of a chiral substance

from an achiral precursor such that one enantiomer predominates over the other.

Out of the several strategies for getting enantiomerically pure compounds, the one

using readily available chiral molecules obtained from the chiral pool, as starting

point for synthesising molecules with desired stereochemistry gains promin nce3. / 4' f Hence during the past two decades there has been a great deal of interest to find

. cheap and potential chiral molecules from chiral pool to accomplish synthetic

X., efforts with a high degree of asymmetric induction. Hence inexpensive naturally X.-- occurring molecules possessing numerous functional groups and stereogenic

centres are significant.

Since the quantity of optically active compounds isolated from natural

; -'.-.,,sources is often less than milligram, difficulties are encountered in stereochemical . , . .

studies. The best way to circumvent this difficulty is to execute an enantioselective

synthesis of the target molecule starting from a compound of known absolute

configuration2.

The ingenious synthetic methodologies that employ members of the "chiral

carbon pool" comprise a significant portion of this technology. To the organic

chemists, the chiral pool, which is composed mainly of naturally occurring amino 1 J

acids, teip nes, sugars and carbohydrates is an invaluable source of j stereochemically pure molecules. The majority of them are commercially available

and many are inexpensive4.

1% --. An effort towards this direction, this laboratory has recently identified

(2S,3 S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furmdicboxylic acid [(-)-hydroxycitric

acid lactonels and (2S,3R)-Tetrahydr0-3-hydroxy-5-0~0-2,3 -furandicarboxy lic

acid [(+)-hydroxycitric acid lactone] as potential chirons for the synthesis of

various optical1.y active intermediates and introduced a select group of molecules

with complete physical data. As the unique structure and stereochemistry of these

molecules rnatch$Gith the chiial y-butyralacionc moiety of a large number of

complex natural molecules, these molecules can judiciously be used for their

synthesis.

As this thesis concerns with the structural and synthetic investigations

of chiral (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid

[(+)-hydroxycitric acid lactone]- a molecule with chiral y-butyrolactone skeleton,

the present review deals with the strategies for the synthesis of chiral

y-butyrolactone skeleton of naturally occurring molecules which have interesting

synthetic as well as pharmaceutical applications6. Stereochemically defined

y-butyrolactones serve as key building blocks for the synthesis of alkaloids,

macrocyclic antibiotics, pheromones, antileukemics and flavour components.

Generally appropriately functionalised y-butyrolactones are obtained from

molecules such as amino acids, hydroxy acids, carbohydrates, chiral sulphoxides

2,9,10 or epoxides7**. Though already few reviews deal with these topics, an

exhaustive inventory of chiral y-butyrolactone bearing natural products and their

\ general synthetic approaches are lacking. In this background an inventory o f : ? G.'

',, +-.:-A ),. i -

naturally occurring molecules bearing chiral y-butyrolactone moiety is listed at 1 first followed by the strategies for the synthesis of chiral y-butyrolactone moiety. I

,/ i

Inventory of naturally occurring molecules bearing chiral y-butyrolactone moiety

No.

1

2

3

4

5

6

7

8

Structure

0 0 v,::~~, B$-)

C5Hll

O e a H

0

~ ~ Z H 2 0 Ph,

r o 0

M& @ Me0 ++'

OMe

'. Me 0 OMe <IT OMe ,

0~ llb,,

R

Name

Analogue acetylcholine of.

y-nonalact one

y -caprolactone

y-Trityloxymethyl- y-butyrolactone

Podophyllotoxin

Podorhizon

'

Annonacea acetogenin

Murisolin

Reference

l l

12

12,21

13

14

15

16

17

Black-tailed deer pheromone

Japaneese beetlep herornone

Tu berolid e

Litsenilide Cl

Litsenilide C2

Valerolactone

P-hydroxy- valerolac tone

A B ring subunit of ~reinantholide A

Actinomy cete

Epianas trephin

Anastrephin

lsostegane

OMe

Oak lactone

Isoavenaciolide

Avenaciolide

44

47,5 1

52

5 3

53

Ethisolide

(+)-Dihydrocana- densolide

Muconin

Cinatrin C

Cinatrin c3

31

32

33

34

35

' . o+oc2b H2C H

oe: Me

H25q2vw AH t ; \ HOW

0 c1 $25

H~~, . , . 0' H 0

HZsC oyy&H I 21ab11,..

H0 "'* OH -P

36

37

38

Calcidiol lactone

HO .lc,T o

CH,

:W: OWIH H ~ N ~ CH3

Trilobacin

Qu arari b ea metabolite

5 5

56

O p m . ""H

" ' ' I rn3 Funebral

(+)S quamo t acin

Stemolide

43 i 0

OH

Corrossoline 59

Vernolep in

Vernomenin

Precursor of CGA 8000

Paeonilactone A

54

55

56

57

58

59

60

61

62

--i3 -

"B H 'i.

OTOY COOH "'CH~COOH

0

H0 H

& I Me

" p f H l

'"'COOH

"Q""" "'COOH

Rosigenin

Sapranthin

Intermediate of X-14547 A (Ionophore -antibiotic)

Hornocitric acid lactone

(+)-Digitoxigenin

Ancep senolide

(-)-Methylenolact- ocin

Protolichesterinic acid

(-)-Phaseolinic acid

68

69

70

71

72

73

74-78

76

7 5

r-c!

"'"H .-gym

[+)-Phaseolinic acid

Lissoclinolide

Steganone

Frullanolide

Arbusculin

MGO

OMe

Podophyllotoxin

Picropodophyllin

(+)-Dihydroactin- idiolide

Aeginetolide

Asteriscanolide

H0

OMe OMe

Paniculide A

Enterolactone

Arctigenin

Syringolide 1

Syringolide 2

Scobinolide

86

87

88

89

:A0 H l l ~ p ~ o ~ l l b . . d H0

H, ,c .~co~~~. . , .A0

d H0

='\ H O OCOC5H1 1

H 0 0C0C7Hl5

91

93

Secosyrin 1

Secosyrin 2

Suributin 1

Syributin 2 I

O V H ~IIIIH

~ ~ 5 C ~ f OAc

104

104

100, 104

100, 104

0

Lipid metabolites 106

Blastirnycinone 106

1.3 Synthesis of chiral y-butyrolactone ring systems of naturally occurring molecules

It is well established that ~lhtarnic acid (96) has been extensively used as a

starting point for the synthesis of a large number of natural products (1-10) with

desired chiral y-butyrolactone moiety (Scheme I. 1 ) ' "l9.

Scheme 1.1

Chiral y-caprolactone (3) and black-tailed deer pheromone (10) were

obtained in high optical purity from optically active propargylic carbinols (99)

prepared by the asymmetric reduction of a- acetylinic ketones with chiral complex

[LiAlh, N-methyl ephedrine-3,5-dimethyl phenol] (Scheme I. 2) 20p21.

Scheme 1.2

Reports on the enantioselective synthesis of (2)-5-(l-deceny1)-

oxacyclopentan-Zone (Il) , the pheromone of the Japanese Beetle employing 20-23 99-101 as starting material are also available (Scheme 1.3) .

Scheme 1.3

B. Maurer and A. Hauser have successivel synthesis of .--'

several lactones of Polianthes family adopting different strategies (Schemes 1.4

and 1.5) 24.

Scheme L4

Scheme 1.5

Several synthetic approaches are available on Eldanolide (g), the wing

gland pheromone of the male African sugar-cane borer using different starting

materials (Scheme 1.6) 18.25-31

CH H 0 OH 107 106

108

OM:

H0 OH -OH + f

OM

Scheme 1.6

Traditionally carbohydrates such as D-ribonolactone has been employed as

chiral synthons for the synthesis of a large number of molecules containing

32-34 y-lactone moiety (Scheme 1.7) .

Scheme 1.7

Readily available y-butyrolactone precursor (110) from natural sources has

r 0 been used by R. K. Bfeckrnan Jr. et al. for the preparation of the AA3 ring system

of eremantholide A (21) (Scheme I. @ "," "-,

L

Scheme 1.8

L-lyxono-l,4-lactone (22), the chiral template of several aldonolactones

which are extensively used for the synthesis of enzyme inhibitors, antibiotics,

peptides and antimetabolites has been synthesised from D-gulono- l ,4-lactone 36 (Scheme 1.9) .

Scheme 1.9

Stereocontrolled aldol condensation between 6-methyl heptanal and lactone

(1 12) has lead to the synthesis of abutanolide (23), the fermentation product of an

actinomy.cete species CNB-228 (Scheme 1.1 o)'~.

Scheme 1.10

Synthesis of (+)-epianastrephin (24), pheromone of Caribbean fruit fly and

its antipode (25) using different starting materials has been demonstrated (Scheme

I. l 1 ) 3 8 y 3 9 .

Scheme 1.11

The first successful, highly specific asymmetric synthesis of (-)-isostegane

(26), a very important antileukaemic lignan starting from a chiral butenolide (115)

was reported by Koga et al. (Scheme I. 1 $3 4-i "

0 Mt:

Scheme 1.12

Several synthetic methodologies have been investigated to obtain 5- buty1,4-

methyl-tetrahydro-2-furanone (27), the ccquercus lactone" or "oak lactone"

(Scheme 1.1 3)30*41-44.

Scheme L13

Synthesis of (R)-enantiomer of 4-dodecanolide (28), a defensive secretion

of Rove Beetles via asymmetric reduction with immobilised Baker's yeast on

monoalkylated-3-0x0-glutarates (121) and from L-tartaric acid (122) has been

achieved (Scheme I. 1 4)42945.

Scheme L14

Routes for the synthesis of avenaciolide (30) and its diastereomer

isoavenaciolide (29), two naturally occurring secondary metabolites present in the /--- \

cultures of Aspergillus and Pencillium species have bee tarting with \

123-126 independently (Scheme I. 15) 43,47-49

Scheme 1.15

Synthesis of 30 from several other synthons were also reported. Another

natural product (3 aS,6aS)-ethisolide (3 1) was prepared from (1 19) (Scheme

1, 1 6)42.44,50

Scheme L16

Synthesis of (+)-dihy drocanadensolide (32) using Tungsten-K-ally l

complexes4' involving the diastereoselective Zwitterionic Aza-Claissen

rearrangement5' were reported (Scheme I. 17).

Scheme 1.17

An acetogenin, muconin (33) a potent and selective in vitro cytotoxic agent

against pancreatic and breast tumor cell lines has been synthesised

(Scheme I. l8)'2.

Scheme 1.18

Evans and coworkers reported the asymmetric synthesis of phospholipase

A2 inhibitors, Cinatrin C, and Cj (34 & 35) employing aldol reaction of ketal- 1'4

protected tartrate ester enolates (Scheme I. l& ,'

-+ O M -

BnO

0 I

Scheme 1.19

25-Hydroxy vitamin D3 26,234actone (calcidiol lactone) (36), one of the

major metabolites of vitamin Dj has been synthesised using C-22 steroid aldehyde

and citramalic acid (Scheme I. 20)'~.

Scheme 1.20

The first total synthesis of Trilobasin (37), an excellent cytotoxic

(O/+nonaceous acetogenin, was described by Sinha by Kennedy oxidative-

cyclisation with rhenium oxide followed by the Mltsunobu inversion of alcohols

@ TL (Scheme 1.21) .

Scheme 1.21

Recently Le Quense et al. reported the synthesis of quararibea metabolite

(38), funebral (39) an 3 Tunebrine (40) having a wide range of physiological sg, r '3 activity (Scheme 1.221.- . ,)

Scheme 1.22'

Synthesis of Isotelekin (41), a sesquiterpene lactone, has been reported

(Scheme 1 . 2 3 ) ~ ~ .

Scheme 1.23

The total synthesis of (+)-squamotacin (42), an Annonaceous acetogenin,

adopting Sharpless asymmetric dihydroxylation and epoxidation reactions, was

reported by Sinha (Scheme 1.24)~'.

Scheme 1.24

4 6

Corrossolin (43), yet another member of t h e p o n a c e o u s family, has been

synthesised by Yu-Lin Wu et al. recently from an aldehyde (132) obtained from p 63 D-glucono lactone (Scheme 1.25 -/

Scheme 1.25

The first synthetic route to Stemolide (44), a diterpenoid having potent

60 '-3 cytotoxic activity, is demonstrated by vanTamelen et al. (Scheme 1.26) .

Scheme 1.26

d

Starting with (R)-lactic acid (133), (-)-yertinolide (45), a p-tetronic acid

derivative isolated from VerticiNium intertexturn, was synthesised adopting

Seebach's chiral self-reproduction method by Matsuo et al. (Scheme 1.27) '2'',

Scheme 1.27

Synthesis of natural adriadysiolide (46), a monoterpenoid from marine

sponge, starting from 3-methyl-2-cyclopenten- l -one (134) is also available

(Scheme 1 . 2 8 ) ~ ~ .

Scheme 1.28

The total synthesis of the bis-a-methylene lactonic sesquiterpenes,

vernolepin (47) and vernomenin (48), two potent tumor inhibitors were achieved

in several steps from dienone ester (135) (Scheme 1.29)".

Scheme 1.29

Yang et al. used Mn(OAc),-mediated oxidative free radical cyclization

method f o r the synthesis of (-)-triptolide (50), (-)-triptonide (49) and

(+)-triptophenolide (51) (Scheme 1.3 0 1 ~ ~ ~ ~ ~ . v

The unchlorinated precursor of CGA 8000 (52), the internal Ciba-Geigy

code number for a new phenylamide fungicide, was synthesised enantioselectively

by two conceptionally different routes: (a) by starting from L-malic acid (138) and

(b) by the enantioselective hydrogenation of an enarnide intermediate (139), using

chiral Rh- or Ru-pho sphine-comp lexes (Scheme I. 3 1 )65.

COOH

52

Scheme L31

Paeonilactone A (53), a compound having lot of pharmaceutical

applications, has been synthesised by Backvall et al. using palladium, copper

catalysed reactions of cy clohexadiene (140) (Scheme 1.32) 67.

53

Scheme 1.32

h- A biosynthesis of yosigenin (54), an unusual metabolite from

MycosphaereZZu rosigena, is reported by L. Camarda et al. (Scheme 1.33

Scheme 1.33

("\

A simple synthesis of Sapranthin (55), an alkaloid, is reported

Waterman (Scheme 1.34) 69.

Scheme L34

The synthetic intermediate (56), for ionophore antibiotic X - 14547A, was

resulted by the asymmetric alkylation of aldehydes using optically active SAMP

hydrazones (141) (Scheme 1.35) 70.

Scheme 1.35

Enantioselective syntheses of homocitric acid lactones (57a & 57b) were

described employing thermal Diels-Alder cycloaddition strategy (Scheme I. 3 6 ) 71.

57a 57b

Scheme 1.36

(+)-Digitoxigenin (S), a natural cardenolide, has been synthesised by

Stork ef al. (Scheme 1.37)'~.

Scheme 1.37

Larson el al. demonstrated the application of alkylidenation reaction for the

synthesis of ancepsenolide (59), a bisbutenolide of marine origin (Scheme 1.38)'~.

Scheme 1.38

Syntheses of (-)-methylenolactocin (60), a densely functionalized and

isomerization-prone antitumor antibiotic. isolated from the Penicilliunz sp. were .p

illustrated by a number of groups. (-) and (+)-Bhaseolinic acid (62, 63), metabolite

of a fungus Macrophomina phmeolina, have been prepared by Valentin el al. as

CO-products of 60. Roy et al. also reported the preparation of protolichesterinic 74-77 acid (61) along with methylenolactocin (Scheme 1.39) ,

Scheme 1.39

Two independent stereoselective syntheses of lissoclinolide (64), a

secondary metaboli te from the ternicate Lissoclznum patella, have been achieved

using (148) and (149) (Scheme 1 . 4 0 ) ~ ~ ~ ' ~ .

Scheme L40

2 -/ Depezay et al. reported the synthesis of (-)-bfuricatacin (65) , an

annonaceous acetogenin, from D-isoascorbic acid. Another simple procedure

involving TMSOF and an aldehyde is also described (Scheme 1.4 1)811X2.

Scheme L41

t- A novel synthesis of (+)-P'aeonolactone B (66) has been accomplished from

a tricyclic ketone (151) (Scheme 1.42) 83.

Scheme 1.42

Total synthesis of (-)-Steganone (67) utilizing a samarium (11) iodide

promoted 8-endoketyl-olefine cyclization has been reported by Molander et al.

(Scheme 1.43) 84.

(C0)3Cr I OMe

Scheme 1.43

5. .H--,

Ferraz el al. reported a short route to (-)-~:ntlactone (68) employing

thallium triacetate mediated cyclization of (-)-isopulegol (152) (Scheme 1-44) ".

Scheme 1.44

Two different routes to a-methylene-y-butyrolactones, [(-)-Frullanolide

(69) and (+)-Arbusculin B (70)], allergenic sesquiterpene lactones, have been

designed starting from a-methyl lactones (153) (Scheme 1.45)

Scheme 1.45

A stereocontrolled synthesis of (-)-picropodophyllone (71) was achieved by

the Michael addition of lithium salt of cyanohydrin to (R)-3-(2,2-dimethyl-1,3-

dioxolan-4-yl)-cis-2-propeonate (154) (Scheme 1.46) ".

Scheme L46

Recently Berkowitz et al. reported the synthesis of (-)-podophyllotoxin

(72) and i ts C-2 epimer, (-)-picropodophyllin (73) starting from 155 (Scheme

1 . 4 7 ) ~ ~ .

SENQ OTIPS SEMO OTPS

o o s i r o o 155

S EMQ I

SEMQ

Scheme 1.47

4 h Total syntheses of kkginetolide (76), (R)-dihydroactinidiolide (74) and

(R)-actinidiolide (75) have been reported involving asymmetric catalytic hetero-

Diels-Alder methodology (Scheme 1.48) 89?90.

Scheme L48

A recent successful synthetic effort depicting (+/-)-Asteriscanolide (77), a

cyclooctane sesquiterpene lactone from Asteriscus aqualieus, employing three

independent strategies have been reported (Scheme 1.49)

Scheme 1.49

*

A total synthesis of Paniculide A (78), a'highly oxygenated sesquiterpene

lactone, starting from D-glucose and methyl-4,6-0-benzylidine-a-D-

glucop yranoside involving Ferrier 'S car bocyclization and CIaisen rearrangement

was reported by Chida and coworkers (Scheme I. 50) 94.

D-glucose - 0

OMe

Methyl-4,6-0- benzylidine- a- 1==4 D-glucopyrano side OMOM

Scheme '1.50

Independent enantioselective syntheses of natural dibenzylbutyrolactone

lignans like (-)-enterolactone (79), (-)-pluviatolide (80) and (+)-arctigenin (U),

having antiturnor activity, platelet-activating factor (PAF), sodium selective

diuretic properties and inhibitory effects on microsomal monooxygenases in 95-98 insects, have been reported (Scheme L 5 1) ,

- OMe 162 7 9

Scheme 1.51

Syntheses of (-)-S-methoxyhinokinin (83) and (-)-hinokinin (82),

employing conjugate addition of benzylic dithioacetals to chiral dihydrofuran

ketones as the key step followed by appropriate reduction and oxidation reactions,

are known (Scheme 1.52) 96p".

Scheme L52

Non protein elicitors syringolide 1 and 2 (84 & 85), from bacterial plant

pathogen Pseuhnzonas syringaae pv. lonzalo which trigger a hypersensitive

defence response in resistant soybean plant, have been sytlthesised making use of

different synthons (Scheme I. 53) 100-103

OMOM

01-1

Scheme 1.53

First total synthesis of (+)-Secosyrins 1 and 2 (86, 87) using the spiro

skeleton prepared by taking advantage of an alkyne-cobalt complex using

diisopropyl tartrate (164) were achieved by Hanaoka et al. (Scheme 1.54) Io4.

BllO,,,, toys H0 --

BnO B U ~ 164 H 0

I

Scheme L54

Syributins 1 and 2 (88 & 89) from diisopropyl tartrate using alkyne-cobalt

complex were achieved by Hanaoka et al. Enantioselective synthesis of 88 and

89 through the Sharpless catalytic asymmetric dihydroxylation is also reported

(Scheme I. 55)"'.

Scheme 1.55

Synthesis of scobinolide (go), a monoterpene lactone, was carried out by

Thaller et al. (Scheme 1.56) l"'.

Scheme 1.56

Trisubstituted butyrolactones such as lipid metabolites (91,92) and

Blastimicinone (93) were synthesised by Sibi et al. following independent

106,107 strategies (Scheme 1.57) .

~~9~: HIII,~. -S=== -

'., R'O R

\ 9 1 R=Ci4Hs, R' = COCH, Ph 92 R= C1a33, R' = CH3C0

NHCHO

OH R OH

93

Scheme 1.57

Momose ef al. achieved the synthesis of NFX-2 (94) and NFX-4 (95)

employing stereoselective intrarnolecular lactonization of homochiral N-benzyl-N -

methyl-3-hydroxy-4-pentenamides (165) and 0-TBDMS (Scheme 1.58)"'.

-- - HI~,,, V""'"' +*, TBDMSO . H 0 R

Scheme 1.58

1.4 Scope and Objective of the Present Study

Asymmetric synthesis involves the use of chiral auxiliaries - catalytically

or stoichiometrically , chiral molecules as starting points for obtaining optically

active molecules. Usage of simple chiral molecules as chiral building blocks is an

important strategy in the synthesis of naturally occurring molecules especially

when they are derived from cheap and abundantly available small molecules such

as lactic acid, tartaric acid etc. Hence inexpensive natural products possessing

numerous functional groups and stereogenic centres are of great interest to organic

chemists.

Hence there is a great deal of interest prevailing in the synthesis of

naturally occurring molecules bearing chiral y-butyrolactone ring systems which

are widely distributed. It is clear from the review that most of these molecules

have potential biological as well as pharmacological applications.

In this background it is the objective of the present study to explore the . .

possibility of using ( 2 ~ , 3 R)-Tetrahydro-3 -hydroxy-5-0x0-2,3 -furandicarboxylic

acid, [(+)hydroxycitric acid lactone or hibiscus acid], a chiral molecule from the

chiral pool, as chiral synthon in the preparation of potential optically active

molecules bearing chiral y-butyrolactone moiety or their derivatives.

Garcinia acid, one of the optical isomers of hydroxycitric acid found

extensive application in the pharmacological as well as synthetic fronts. However

only very little information is available on Hibiscus acid. The potential of the

molecule is not yet explored due to the non-availability of the compound in the

market. This is due to the lack of any economically viable large-scale isolation

procedure and physical data of the compound. In spite of the ready accessibility in

the optically pure form from the chiral pool, no effort has been made towards the

use of hibiscus acid in the broad area of asymmetric synthesis. In this background,

a detailed reinvestigation on the isolation and structure of the title compound is

necessary .

The present investigation aims at the synthesis of novel chiral synthons,

ligands and catalysts starting from hibiscus acid and their application in

asymmetric synthesis. It is proposed to carry out various chemical modifications

on the acid, to obtain novel functionalised chiral synthons and ligands especially

useful for asymmetric catalysis. In general attempts will be focussed to project

! I, (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-fboxyli acid as yet another

choice for asymmetric synthesis from the chiral pool.