Institute of Pharmaceutical Chemistry

University of Szeged

REGIO- AND STEREOSELECTIVE SYNTHESES AND SOME

TRANSFORMATIONS OF 1,3-N,N- AND

1,3-O,N-HETEROCYCLES

PhD thesis

by Iván Kanizsai

Szeged

2007

2

Contents

page

List of publications and lectures related to the thesis 1

Abbreviations 4

1. Introduction and Aims 5

2. Literature Survey 6

2.1. γ- and δ-oxocarboxylic acids 6

2.2. Aminocarbohydrazides as tridentate reagents 7

2.3. Preparation from diamines with oxocarboxylic acids 11

2.4. Isocyanide-based multicomponent reactions; Ugi reactions 12

2.4.1. Ugi reactions in methanol 12

2.4.2. Water as solvent for Ugi and other multicomponent reactions 14

2.5. Syntheses and some tranformations of natural alkaloids 15

2.5.1. Syntheses of Sedum alkaloids and their analogues 15

2.5.2. Ephedra alkaloids; transformations of norephedrine 17

3. Results and Discussion 18

3.1. Syntheses of pyrazolo[3,4-d]pyrimidine derivatives 18

3.2. Syntheses and transformations of 5,6-dehydronorcantharidin derivatives 21

3.3. Multicomponent reactions with oxabicycloheptene-based β-amino acids 23

3.3.1. Use of methanol as solvent 24

3.3.2. Use of water as solvent 25

3.3.3. Transformations of the resulting β-lactam 17 26

3.4. Reactions of oxanorbornenediamine with γ- and δ-oxocarboxylic acids 27

3.4.1. Preparation of pyrrolo- and isoindoloquinazolines 27

3.4.2. Establishment of the structures 29

3.5. Syntheses of Sedum alkaloid analogues and transformations of norephedrines 30

3.5.1. Syntheses of Sedum alkaloid analogues 31

3.5.2. Transformations of chiral norephedrines 35

4. Summary 39

5. References 40

Acknowledgements

Appendix

3

List of publications and lectures related to the thesis

Full papers

I. Ferenc Miklós, Iván Kanizsai, Pál Sohár, Géza Stájer:

Preparation and structure of pyrazolo[3,4-d]pirimidinones

J. Mol. Struct. 610, 41-46 (2002) if: 1.44

II. Iván Kanizsai, Zsolt Szakonyi, Reijo Sillanpää, Ferenc Fülöp:

A comparative study of the multicomponent Ugi reactions of an oxabicycloheptene-based

β-amino acid in water and in methanol

Tetrahedron Lett. 47, 9113-9116 (2006) if: 2.484

III. Iván Kanizsai, Ferenc Miklós, Pál Sohár, Antal Csámpai, Reijo Sillanpää, Géza Stájer:

Preparation and structure of pyrrolo[2,1-b] and isoindolo[1,2-b]epoxyquinazolines

J. Mol. Struct. (2007) accepted for publication,

doi.: 10.1016/j.molstruc.2006.07.019 if: 1.44

IV. Zsolt Szakonyi, Matthias D’hooghe, Iván Kanizsai, Ferenc Fülöp, Norbert DeKimpe:

Synthesis of bicyclic carbamates as precursors of Sedum alkaloid derivatives

Tetrahedron 61, 1595-1602 (2005) if: 2.61

V. Iván Kanizsai, Zsolt Szakonyi, Reijo Silanpää, Matthias D’hooghe, Norbert DeKimpe

and Ferenc Fülöp:

Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclisation

of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Tetrahedron: Asymmetry 17, 2857-2863 (2006) if: 2.429

Other publications

1. Ferenc Miklós, Iván Kanizsai, Steven Thomas, Erich Kleinpeter, Reijo Sillanpää,

Géza Stájer:

Preparation and structure of diexo-oxanorbornane-fused 1,3-heterocycles

Heterocycles 63, 63-74 (2004)

2. Géza Stájer, Ferenc Miklós, Iván Kanizsai, Ferenc Csende, Reijo Sillanpää, Pál Sohár:

Application of furan as a diene: Preparation of condensed 1,3-oxazines by retro Diels-

Alder reactions

Eur. J. Org. Chem. 3701-3706 (2004)

4

3. Iván Kanizsai, Szilvia Gyónfalvi, Zsolt Szakonyi, Ferenc Fülöp, Reijo Sillanpää:

Synthesis of bi- and tricyclic β-lactam libraries in aqueous medium

Green Chem. (2007) accepted for publication

Scientific lectures

1. Iván Kanizsai, Matthias D’hooghe, Zsolt Szakonyi, Ferenc Fülöp, Norbert deKimpe:

Synthesis of bicyclic carbamates as precursors to Sedum alkaloid derivatives;

Bilateral Scientific and Technological Cooperation Workshop (BWTS)

19 September 2003, Ghent, Belgium, p. 22.

2. Szakonyi Zsolt, D’hooghe Matthias, Kanizsai Iván, Ferenc Fülöp, DeKimpe Norbert:

Pirrolidin- és piperidinvázas heterociklusok szintézise alkenil-imidátok és karbamátok

elektrofil ciklizációjával.

MTA Heterociklusos Kémiai Munkabizottság elıadóülése

Balatonszemes, 2004. május 20-21.

3. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:

Izoindol-kondenzált heterociklusok elıállítása retro Diels-Alder reakcióval

Clauder Ottó Emlékverseny

Visegrád, 2004. október 14-15. p 27.

4. Kanizsai Iván, Miklós Ferenc:

Izoindol-kondenzált O,N-heterociklusok elıállítása retro Diels-Alder reakcióval

XXVII. Kémiai Elıadói Napok

Szeged, 2004. október 25-27. pp 51-53.

5. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:

Izoindol-kondenzált O, N- és N, N-heterociklusok elıállítása retro Diels-Alder reakcióval

Szegedi Ifjú Kémikusok elıadóülés

Szeged, 2005. január 12.

6. Iván Kanizsai, Ferenc Miklós, Pál Sohár, Géza Stájer:

Preparation of isoindole-condensed heterocycles via retro Diels-Alder reactions

Joint Meeting on Medicinal Chemistry

20-23 June 2005, Vienna, Austria, PO-38, S-96.

5

7. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:

Heterociklusok elıállítása oxokarbonsavakból diaminokkal és hidrazidokkal

Vegyészkonferencia

2005. június 28-30, Hajdúszoboszló, P-40.

8. Kanizsai Iván, Szakonyi Zsolt, Fülöp Ferenc:

Ugi-reakció alkalmazása β-laktámok szintézisére vizes és metanolos közegben

Congressus Pharmaceuticus Hungaricus

2006. május 25-27, Budapest, P-12.

9. Gyónfalvi Szilvia, Kanizsai Iván, Szakonyi Zsolt, Fülöp Ferenc:

Vizes közegő Ugi-reakció alkalmazása β-laktámok elıállítására

Congressus Pharmaceuticus Hungaricus

2006. május 25-27, Budapest, P-11.

10. Kanizsai Iván, Gyónfalvi Szilvia, Szakonyi Zsolt, Fülöp Ferenc:

Bi- és triciklusos β-laktámok elıállítása metanolos és vizes közegben

Heterociklusos Munkabizottsági Ülés

Balatonszemes, 2006. június 7-9.

11. Iván Kanizsai, Szilvia Gyónfalvi, Zsolt Szakonyi, Ferenc Fülöp:

Synthesis of bi- and tricyclic β-lactams via Ugi-4C-3C reactions in water and organic

media

Bilateral Scientific and Technological Cooperation Workshop (BWTS)

10 July 2006, Ghent, Belgium; pp. 13-15.

6

Abbreviations

DIBAL: diisobutylaluminium hydride

DMAP: 4-methylaminopyridine

LDA: lithium diisopropylamide

MCC: multicomponent condensation

MCR: multicomponent reaction

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

NIS: N-iodosuccinimide

PP1: protein phosphatase 1

PP2A: protein phosphatase 2A

PP2B: protein phosphatase 2B

PTSA: p-tolylsulfonic acid

RCM: ring-closing metathesis

rDA: retro Diels-Alder

TBAF: tetra-n-butylammonium flouride

TEA: triethylamine

TFA: trifluoroacetic acid

TMSCl: trimethylsilyl chloride

TMSI: trimethylsilyl iodide

U-4CC: Ugi-4-component condensation

U-4C-3CR: Ugi-4-centre-3-component reaction

U-5C-4CR: Ugi-5-centre-4-component reaction

7

1. Introduction and Aims

One of the research topics at the Institute of Pharmaceutical Chemistry, University of

Szeged, has been the study of cyclocondensation with a view to obtaining saturated and par-

tially saturated condensed heterocycles. The reactions of bi- or trifunctional β-aminoacids and

derivatives, e.g. aminoalcohols, diamines, carboxamides or aminohydrazides, with γ- or δ-

oxoacids have afforded a great number of cis-, trans- and diexo- or diendo-fused 1,3-O,N- and

N,N-heterocycles, e.g. isoindolones, oxazines and quinazolines. The bi-, tri-, tetra- and penta-

cyclic compounds prepared are stereochemically interesting and pharmacologically active.1-3

In our laboratory, Stájer et al. developed a new method for the preparation of O,N-

heterocycles based on the retro Diels-Alder (rDA) reaction.4 Starting from diendo- or diexo-3-

aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acids or their derivatives, such as amides, hy-

drazides, etc., partially saturated parent heterocycles are built up on cyclopentadiene, which is

finally removed by heating to melting on a preparative scale. Earlier, similar heteromono- and

bicyclic structures were accessible only under more forceful reaction conditions, e.g. flash

vacuum pyrolysis. It is important to note that the closing step takes place under mild condi-

tions only when the target compound acquires a (hetero)aromatic or quasi(hetero)aromatic

character, e.g. oxazinone, thioxooxazinone, oxazinethione or pyrimidinones. Nevertheless,

only a few literature data describe similar rDA reactions, when the rDA products exhibit a

quasi-aromatic, e.g. a 1,3-oxazine character.5-8

The aim of this thesis was to extend the above cyclocondensations to new oxabi-

cyclonorbornene heterocycles, starting from β-amino acid and its derivatives, e.g. the dia-

mine. For furan, which was found to be a “good-leaving” moiety in our compounds, further

transformations via the rDA method were also attempted. As the pharmacological importance

of pyrazole-containing heterocycles was known, we prepared heterocycles, e.g. pyrazo-

lo[3,4-d]pyrimidines, via cyclocondensation, starting from oxocarboxylic acid derivatives, for

pharmacological tests.

Our cooperation with the Department of Organic Chemistry at the University of Ghent

allows research in the field of electrophile-induced cyclizations and the syntheses of recently

reported alkaloids. The aim was the preparation of Pomgranaceae alkaloid analogues, in spite

of their instability even under mild conditions, which meant a good synthetic challenge. Fur-

ther, regio- and diastereoselective cyclizations, starting from (+)- and (-)-norephedrines, were

also attempted.

In accordance, the present work deals with extension of the cyclocondensation of oxa-

bicyclo[2.2.1]heptene-β-amino acid, its derivative diamine and a pyrazolaminocarbohydrazide

8

to the preparation of heterocycles. The second part of my work relates to a new method for

the synthesis of Sedum alkaloid analogues, the transformation of γ-lactams derived from (+)-

and (-)-norephedrine and their preparation via electrophile-induced cyclization.

2. Literature Survey

2.1. γ- and δ-oxocarboxylic acids

The preparation and applications of the γ- and δ-oxocarboxylic acids are wellknown in

the literature.9-11 Although use of the Grignard reagent or organolithium compounds results in

oxocarboxylic acids, the most commonly applied method is the Friedel-Crafts reaction12,13

because of its simplicity and good to excellent yields. In our laboratory, a broad range of oxo-

carboxylic acids, e.g. aliphatic, alicyclic and bicyclic analogues, have been prepared by means

of the Friedel-Crafts reaction. The general preparation of these compounds is carried out by

the reaction of an alicyclic and bicyclic anhydride and an aryl component, e.g. toluene, ben-

zene or chlorobenzene, in the presence of 1 or 2 equivalents of AlCl3. A variation starts from

dicarboxylic acids or aroyl-substituted analogues which are transformed to anhydrides by the

use of acetic anhydride. The Friedel-Crafts reaction has led to diaryl-substituted alicyclic and

bicyclic oxocarboxylic acids.14,15 The stereochemistry of the mono- and disubstituted oxocar-

boxylic acids has been established by NMR measurements.16 To apply methanobenzocyclo-

octene oxoacids, morphine analogue pharmacophores were synthetized.17

The reactions of bi- or trifunctional compounds of β-aminoacids and their derivatives,

e.g. aminoalcohols, diamines or aminocarbohydrazides, with aldehydes or oxocarboxylic ac-

ids furnish O,N- or N,N-heterocycles. The configurations of the starting oxocarboxylic acids

can change during the reactions. Earlier studies have dealt with the epimerization of cis-2-

acylcyclohexane-1-carboxylic acid and diendo- or diexo-3-acyloxanorbornane and norbor-

nane-2-carboxylic acid derivatives.18 The cis→trans epimerization of cyclohexane analogues

occurs when they are reacted with diamines as basic reagents or boiled in EtOH and water on

the use of NaOH.19,20 Trans compounds can also be epimerized to cis compounds under simi-

lar conditions.21 The norbornane analogues, as bicyclic compounds, are rigid and hence the

configuration of the starting material usually remains during cyclization.21,22 On the other

hand, refluxing of diendo-3-toluylbicyclonorbornane-2-carboxylic acid or its 6-exo-phenyl

analogue in the presence of HCl or triethylamine (TEA), results in the exo-aroyl-endo-

carboxylic acid isomer. A similar endo→exo epimerization occurs during the esterification of

diendo-3-toluylbicyclonorbornane-2-carboxylic acid.23 Endo→exo aroyl isomerization on the

9

norbornene ring was already known21 when diexo starting materials were transformed into

diendo compounds in the presence of basic reagents.

Numerous publications have reported diastereoselective one-pot reactions of chiral

aminoalcohols and racemic oxocarboxylic acids. Meyers et al. applied the reactions of (R)-

phenylglycinol with oxoacids, e.g. levulinic acid, and from the bicyclic lactams generated

natural compounds.24 Amat et al. also studied the stereoselective cyclocondensations of chiral

aminoalcohols, e.g. (R)-phenylglycinol, when oxazolopiperidones were prepared from race-

mic or prochiral δ-oxoesters. These procedures involved the dynamic kinetic resolution of

racemic substrates and/or desymmetrization of a diastereotopic or enantiotopic ester chain and

provided a route to the synthesis of substituted chiral bicyclic lactams in high yields.25 A large

number of natural piperidine-based alkaloids and bioactive compounds have been prepared

from aminoalcohols.26

In our Institute, Stájer et al. made a systematic study of the syntheses and stereochem-

istry of saturated or partially saturated isoindolone-fused heterocycles. For the preparations,

aliphatic, alicyclic and bicyclic γ-oxocarboxylic acids were reacted with β-amino acids, ami-

noalcohols, carboxamides, diamines or aminocarbohydrazides.27

2.2. Aminocarbohydrazides as tridentate reagents

A systematic economical synthetic pathway to aminocarbohydrazides has been devel-

oped, starting from (bi)cyclic anhydrides: ammonolysis and then Hoffman degradation results

in a β-amino acid. Esterification of this with SOCl2 and EtOH or MeOH, followed by reflux-

ing with N2H4 affords the aminocarbohydrazide in good yields (~70%) (Scheme 1).

O

O

O

O

OH

NH2

O

NH2

O

OH

NH2

O

OEt

NH2

O

NHNH2

cc. NH4OH NaOCl

SOCl2/EtOH

H2N NH2

Scheme 1

Several publications have described the cyclocondensations of aliphatic, alicyclic or

aromatic aminocarbohydrazides with 2-aroyl and 2-alkyloxocarboxylic acids.9 Generally, two

processes occurred, the first step either involving the formation of a Schiff base from the pri-

10

mary amino group with the aroyl group (pathway A), resulting in pyridazino[6,1-b]quinazoli-

nes, or the formation of an imine by reaction of the hydrazide primary amino group with the

aroyl moiety (pathway B), furnishing phthalazino[1,2-b]quinazolines (Scheme 2).

-H2O

NH

N

O

NH2

Ar

OHO NH

N

O

NH2

Ar OHO

NH

N

O

Ar

HN O

NH

NH2

O

N

Ar

O

OH

N

O N

ONH2

Ar

N

NN

O

Ar

-H2O

NH

NH2

+OH

O

Ar

O

Ar = p-tolyl

O

NH2

pathway A

pathway B

pyridazino[6,1-b]quinazoline

: cis- or trans-cyclohexane or diendo-norbornane

phenylcis- or trans-cyclo-hexane, diendo- or diexo-norbornene

phthalazino[1,2-b]quinazoline

-H2O

:

-H2O -H2O

Scheme 2

In the past decade, many efforts have been made to synthetize different heterocyclic

rings. Recently, anthranilic hydrazides were reacted with 2-formylbenzoic acid, 2-acetylben-

zoic acid, 2-benzoylbenzoic acid28 or phthalic anhydride29 to obtain phthalazino[1,2-b]quina-

zolines. From succinic anhydride,30 pyridazino[6,1-b]quinazolines were obtained. The reac-

tions of anthranilic hydrazide, its saturated derivative or diexo bicyclic analogues with 4-

oxocarboxylic acids resulted in saturated or partially saturated pyridazino[6,1-b]- and phtha-

lazino[1,2-b]quinazolines.31 Tetra- and pentacyclic analogues were also prepared by applying

cyclohexane or diendo-norbornane oxocarboxylic derivatives. The saturated cis- and trans-2-

amino-1-cyclohexanecarbohydrazides reacted with 2-aroyl-1-cyclohexanecarboxylic acids or

3-(p-chlorobenzoyl)propionic acid to furnish pyridazino[6,1-b]quinazolines.31 From cis ami-

nocarbohydrazides, mixtures of cis and trans tetracyclic diastereoisomers were obtained and

this focused attention onto the stereochemical outcome of this cyclocondensation. The cis

starting configuration changed to trans during the ring closure. The resulting N,N-heterorings

are pharmacological potentially active compounds, e.g. the pyridazino[6,1-b]quinazolines

11

exhibit antiallergic32 and herbicidal activity33,34 and the phthalazino[1,2-b]quinazolines act as

anti-inflammatory35 and analgesic36 pharmacophores.

When diendo-3-aminobicyclo[2.2.1]hept-5-ene-2-carbohydrazide and its diexo ana-

logue were treated with a cis-cyclohexane oxoacid, phthalazino[1,2-b]quinazoline, penta-

cyclic heterocompounds were obtained. These compounds underwent transformation in rDA

reactions: the cyclopentadiene split off from the heterocycle on gentle heating and the reaction

yielded pyrimidino[2,1-a]phthalazines (Scheme 3).37

N

NN

O

Ar

phthalazino[1,2-b]quinazoline

N

NN

O

Ar

pyrimidino[2,1-a]phthalazine

∆

Scheme 3

In an extension of this cycloreversion to a double rDA process, when two molecules of

cyclopentadiene were removed, pyrimido[1,2-b]pyridazines were obtained in the reaction of

diexo or diendo carbohydrazides with the adduct from trans-p-toluoylacrylic acid and cyclo-

pentadiene (Scheme 4).38

N

NN

O

Ar

NH2

NHNH2

O

COOH

Ar

O

2 N

NN

O

Ar

Ar = p-tolyl

pyrimido[1,2-b]pyridazine

∆

Scheme 4

Pyrazole-fused pyrimido[2,1-a]phthalazines were also prepared from phthalic anhydride with

5-aminopyrazole-4-hydrazide.39

For a further extension of the method, oxoesters were applied. From the reactions of 2-

(2-oxocyclopentyl or -cyclohexyl)acetate with diexo or diendo aminocarbohydrazides, mix-

tures of pyridazino[6,1-b]-, isoindolo[2,1-a]quinazolines and cyclopenta- or hexane-fused

pyridazines were obtained. The products could be separated by column chromatography. As

mechanism A shows, the primary amino group on the bicyclic skeleton attacks the carbonyl

carbon and forms a Schiff base, which stabilizes in a spirocompound and converts into isoin-

dolo[2,1-a]- or pyridazino[6,1-b]quinazolines. When the nucleophilic attack occurs from the

12

secondary amine in the ring, isoindolo[2,1-a]quinazolines are obtained (pathway A, protocol

1). In the second variation, the primary amino group of the hydrazide takes part in the in-

tramolecular cyclization, affording pyridazino[6,1-b]quinazolines (pathway A, protocol 2). In

process B, the carbonyl and the primary amino group of the hydrazide react and afford pyri-

dazinones (Scheme 5).

NH2

NHNH2

O

+O

( )n

n = 1,2diexo, diendo

-H2O

N

NHNH2

O

NH

N

O

NH2

N

N

ONH2

O

1

2

NH

N

OHN O

NH2

NHN

O

NHN

O

21

isoindolo[2,1-a]quinazoline pyridazino[6,1-b]quinazoline

pyridazinone

( )

( )

n

n

( )n

( )n

( )n

( )n

-H2O(diexo)

+ +

O

EtO

OEtO

O

EtO

O

EtO

-norbornene-based

amino acid

-EtOH

-EtOH -EtOH

BA

n = 1 n =1, 2

n = 1, 2

Scheme 5

The isoindolo[2,1-a]quinazolines, as quasi-aromatic systems, can be transformed into pyrro-

lo[1,2-a]pyrimidine (n = 1) via a rDA process. However, thermolysis does not take place in

the case of bisacylhydrazide compounds because there conjugation can not arise in the elec-

tron system by splitting-off of the cyclopentadiene moiety (Scheme 6). 40,41

13

N

N

ONH2

O

NH

N

OHN O

N

N

ONH2

O

NH

N

OHN O

pyridazino[6,1-b]quinazolineisoindolo[2,1-a]quinazoline

pyrrolo[1,2-a]pyrimidine

Scheme 6

2.3. Preparation from diamines with oxocarboxylic acids

By variation of the diamines and oxocarboxylic acids, a broad range of heterocycles

can be synthetized. In a systematic study, Stájer et al. employed diamines with β-amino acids

or carboxamides and 4-aroyl-and 3-alkyloxocarboxylic acids in the reactions.9 Two primary

amino groups can attack the carbonyl carbon: the amino on the ring forms a Schiff base, and

the other amino group cyclizes with the iminocarbon when two intramolecular cyclizations

are possible stereochemically (Scheme 7).

NH2

NH2+

OH

O

R

O

NH2

N

R

HO O

N

NH R

O

N

NH R

ONH

N

NH

N

O O

RR

NH

NHR

OHONH

NH

R

O

HO

-H2O

++

: n = 0: o-phenylenediamine, n = 1: 1,3-diaminoalkanes or cis- or trans-cyclohexane diexo-norbornane and norbornenediamines

n

X

X XXX

X

X

X

propionic acid derivatives,

cis-cyclohexane

diendo-norbornane; X = CH2

diexo-norbornane; X = O, CH2

R = Me, p-tolyl or p-chlorophenyl

-H2O -H2O

Scheme 7

14

In an exceptional case, the extra acylation of the secondary amine takes place in the

reaction after the ring closure and a new heterocyclic system is formed. For instance, the reac-

tions between diexo-norbornane/enediamines and levulinic acid furnished methylene-bridged

pyrrole-condensed 1,4-benzodiazepinones besides the pyrrolo[2,1-b]quinazolinones.42 Gener-

ally, the diamines react with equimolar γ-oxocarboxylic acids during refluxing in the presence

of p-tolylsulfonic acid (PTSA), and N-heterorings with new chiral centres are formed. In these

reactions, the configurations of the starting oxocarboxylic acids, i.e. the cis, trans, diexo or

diendo structures, are retained during the cyclization.43-47 Via other synthetic routes, pyrrolidi-

none derivatives have been obtained by means of the action of microwaves or in the presence

of Al2O3, using ethyl levulinate and aliphatic diamines.48

In the reactions of cyclohexane γ-oxocarboxylic acid and alicyclic diamines, the satu-

rated isoindole-condensed pyrrolidine and piperidine derivatives are formed.49 On application

of the aroylcyclohexane- or aroylnorbornanecarboxylic acids and stereoisomeric cycloalkane-

1,3-diamines, polycyclic heterocycles with five or more new chiral centres are formed; stereo-

isomers have been isolated by means of column chromatography.50-52 The aryl-substituted

aroyloxocarboxylic acids condense with aliphatic diamines: 1,2- or 1,3-diaminoalkanes yield

isoindolone analogues.53-55 In other preparations, compounds with morphine-like structures

have been synthetized. The methanobenzocyclooctene oxoacid reacted with 1,2-, 1,3- and 1,4-

diamines to afford pentacyclic benzo[g]pyrimido[2,1-i]indolones and benzo[g][1,3]diazepi-

no[2,1-i]indolones. The products proved to be analgesic pharmacophores.56 Diexo-norbor-

nane- and oxabicyclonorbornane-fused 1,3-N,N-heterocyclic isoindol(on)es were also pre-

pared. From diexo-bicyclo[2.2.1]heptane oxoacids with diaminoalkanes, imidazo-, pyrimido-

and diazepino[2,1-a]isoindolones were synthetized.57 Starting from the diexo-3-aroyloxabi-

cyclonorbornane oxoacid, the imidazo- and diazepino[2,1-a]isoindolone analogues were pre-

pared.58 The reactions of o-phenylenediamine and aromatic 1,2-diamines yielded isoindo-

lo[2,1-a]benzimidazolones.57,58

2.4. Isocyanide-based multicomponent reactions; Ugi reactions

2.4.1. Ugi reactions in methanol

Combinatorial syntheses provide possibilities via which to generate diverse chemical

libraries which are available to multiply the range of potential pharmacologically active com-

pounds. Multicomponent condensation (MCC), in which several components are reacted in a

one-pot reaction, is one of the important strategies in combinatorial chemistry.59 The most

commonly used and cited MCC is the Ugi reaction.60 This reaction type can be divided into

15

three subtypes: the Ugi-4-component condensation (U-4CC), the Ugi-4-centre-3-component

reaction (U-4C-3CR) and the Ugi-5-centre-4-component reaction (U-5C-4CR). The reactions

are generally carried out in organic solvents, e.g. in MeOH, and can be aligned as isocyanide-

based multicomponent reactions (MCRs).

A traditional U-4CC incorporates a carboxylic acid, an amine, a carbonyl compound

and an isocyanide in a one-pot condensation. For example, α-acetocarboxamides are synthe-

tized in this way in good yields and with good diastereoselectivity (Scheme 8). This method

has been utilized for the preparation of peptidomimetics.61,62

O

OHR1R2 NH2+ +

R3 H

O

+ R4 NCO

R1

O

N

NH

R2

R3

R4

R1 N

OHNR4

R2

R3

O

Scheme 8

For the other types of Ugi reactions (U-4C-3CR and U-5C-4CR), α- or β-amino acids

can be used as starting materials, containing two functional groups on the same compound,

and afford α- or β-amino acid derivatives and β-lactams. Starting from α-amino acids, trans-

alicyclic or exo-endo bicyclic β-amino acids, Ugi adducts, e.g. α- and β-amino acid ester

derivatives, can be obtained via the U-5C-4CR. Through the generation of a Schiff base, an

oxazinone is formed. In the next step, this intermediate reacts with molecules of the solvent.

As the carbonyl and amino groups are situated relatively distant from each other, intramolecu-

lar cyclization (similarly to the U-4C-3CR) can not occur, and the reaction furnishes linear

products (Scheme 9).

COOH

NH2R1+

R2 H

O

-H2O

COO

NHR1

HR2

R3 NC

HN

O

O

NR3

R1

R2

R4 OH

NH

OHN

O

O

R4

R1R2

R3(MeOH)

Scheme 9

16

The N-methyl-substituted exo-endo-oxabicyclo[2.2.1]hept-5-ene-based β-amino acid has been

used as starting material for the U-5C-4CR protocol. The Ugi adducts generated have been

applied for the synthesis of chiral α-amino acid derivatives.63,64

The most commonly used and cited reaction type is the U-4C-3CR, in which N-

substituted β-lactams are generated from cis-cycloalkane/ene- and bicyclic, diexo- or diendo-

β-amino acids. The reaction mechanism proposed for the U-4C-3CR has been explained. In

the first step, the β-amino acid reacts with the appropriate aldehyde, resulting in a protonated

Schiff base. The next step is the addition of the isocyanide, affording the β-lactam via intra-

molecular cyclization and rearrangement (Scheme 10).

NH2

COOH

R1 H

O

+

-H2O

NH

R1

O

O C N R2

NH2

R1

O

O

NR2

NH

O

O

R1

N

R2N

O

R1

O

NH

R2

MeOH

: cis cyclopentane, cyclohexane, cyclohexene diexo norbornane or norbornene

R1 = Et, nPr, Ph, p-OMePh, etc.

R2 = tert-butyl, cyclohexyl, benzyl

Scheme 10

β-Lactams have proved to be enzyme inhibitors (serine and cysteine protease) and an-

tibiotics.65 Through the Ugi reaction, a large number of N-substituted β-lactams with very

diverse structures can be prepared. In our Institute, cis alicyclic (e.g. cyclopentane or cyclo-

hexane) and diexo-bicyclo[2.2.1]heptane and -5-ene β-amino acids have been utilized for the

U-4C-3CR in MeOH. The β-lactams obtained could be successfully applied for the synthesis

of β-amino acid derivatives, e.g. the corresponding free amino acids and their esters.66-68

2.4.2. Water as solvent for Ugi and other multicomponent reactions

Water has become a versatile solvent in recent years. It is inexpensive and environ-

mentally benign, and allows new reactivity. Water can accelerate reactions and even control

the diastereoselectivity of reactions. Moreover, most Ugi products are less soluble in water,

which facilitates precipitation of the target compound from the reaction mixture.69-71 The clas-

17

sical MCRs, such as the Mannich and Biginelli reactions, were carried out in water. β-

Aminocarbonyl compounds were synthetized in good to excellent yields, but with modest

diastereoselectivity via three-component Mannich reaction.72 Water could be also utilized as

solvent for the exothermic Biginelli reaction to obtain dihydropyrimidines.73 The most impor-

tant MCRs, such as the Passareni and Ugi reactions, have been accomplished in water. Pir-

rung and Mironov investigated the accelerating effect of water in the Passerini and Ugi reac-

tions.74,75 It was found that the significant acceleration effect was due to the hydrophobic ef-

fect and the large cohesive energy of water.76

Pirrung et al. focused on the U-4C-3CR of aliphatic β-amino acids in water, using 1 M

glucose solution to accelerate the reaction. β-Lactams were obtained in good purity in good to

excellent yields.75,77 Other strained β-lactams were also synthetized by means of β-keto ac-

ids.78 The reactions failed in organic media; this condensation was carried out in water with

only moderate yields in 3 days. Nevetheless, 1 M glucose solution was necessary or 5 v/v% of

CHCl3 or toluene as phase-transfer catalyst for the successful reactions. In contrast, a number

of literature data have revealed a considerable decrease in reaction rate, and in some cases the

Ugi reaction was not accelerated by water.79

2.5. Syntheses and some transformations of natural alkaloids

2.5.1. Syntheses of Sedum alkaloids and their analogues

The Sedum species, e.g. S. acre, S. bulbiferum and S. anglicum, contain 2- and 2,6-

disubstituted piperidines (Figure 1). These natural alkaloids possess a 1,3-aminoalcohol struc-

ture, e.g. sedamine, sedridine, allosedridine and halosine.80,81 The pharmacological reports in

recent years revealed that the aminoalcohol moiety and the subsituent at position 2 determine

memory-enhancing properties and lead to potential pharmacological application against Alz-

heimer disease.82

N

Me

OH

sedamine

N

Me

Me

OH

sedridine

NH

OH

Me

halosaline

Figure 1

A high number of synthetic pathways towards Sedum alkaloids are available in the lit-

erature.83 Most of the synthetic strategies can be divided into one or other of two groups. In

the first group, the preformed starting compounds possess a nitrogen heterocycle, e.g. a pyri-

18

dine or a piperidine moiety, and a side-chain is appended to the skeleton. These protocols

should be aligned as the reduction of ketopiperidine with Raney-Ni or LiAlH4,84 a Grignard

reaction85 or 1,3-dipolar cycloaddition, e.g. the reactions of (piperidine-based) nitrones with

alkenes (Scheme 112).86 Most of these reactions have been found not to be enantioselective: a

racemic mixture of aminoalcohols is obtained in almost all cases. However, the stereochemi-

cal outcome of 1,3-cycloadditions can be controlled.86 The regioisomer isoxazolidine formed

can be opened by reduction with Raney-Ni/H2 or LiAlH4, resulting in Sedum alkaloids. In the

other synthetic pathway, the piperidine ring is built up by a variety of techniques, such as Mi-

chael addition87 and ring-closing metathesis (RCM) reactions (Scheme 11).88

N

R1

R2

OH

N

O

N

1. LDA,

R2CHO

2. DIBAL

N

R1

R2

O

N

R1

CHO

1. R2MgBr

2. TFA

AcO OAc

(RCM)

NH R2

O

R1

(Michael addition)

N

OO R2

H2/Pt/C or

LiAlH4

DIBAL, etc. R1 = Me, H, COOEt, etc.

R2 = Me, Ph.

R1 = Boc

R2 = Me, Et

1. KOtBu

2. R2MgBr

3. LiAlH4R1 = COOEt, Me

R2 = Ph

1. Me2Si(Cl)CHCH=CH

2. DIBAL

3. Mitsunobu reaction

4. Grubbs' catalyst

5. TBAF then H2, Pd/C

6. Na/Hg, K2HPO4

R1 = H

R2 = nPr

R1 = H

R2 = Ph.

1. H2, Pd/C

2. KOH, HCl, NaOH

R21.2. (MeI then) LiAlH4

R1 = H, (Me)

R2 = Me, Ph, iPr

R1 = H,

R2 = Me, Ph

Scheme 11

The synthetic pathway includes the generation of bicyclic carbamates as precursors to the

synthesis of Sedum alkaloids. In this strategy, the final step is ring opening with either KOH

in EtOH or LiAlH4 to obtain the target alkaloid analogues.89-93 Bicyclic carbamates can be

reached by starting from N-Boc-subtituted piperidines, because of the features of the N-Boc

group. This protecting group is able to react intramolecularly as an electrophile or as a nucleo-

phile. The intramolecular reactivity generally stems from the presence of an electrophilic car-

bon atom, due to a good leaving group, a halonium ion or a carbenium ion attached to the

electrophilic centre. This centre is then attacked by the appreciable negative charge on the

19

carbonyl oxygen of the Boc group.94 The intramolecular cyclization of N-Boc compounds

occurs when adequately strong electrophilic reactants are used, e.g. N-iodosuccinimide (NIS),

N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS).95 In a special example, with an

N-Boc-2-piperidine alcohol derivative, CBr4/PPh3 must be used for successful cyclization.96

2.5.2. Ephedra alkaloids; transformations of norephedrine

Ephedra plants, including E. sinica, E. intermedia and E. equisetina, contain alkaloids

with a 1,2-aminoalcohol structure in quantities of from 0.5% up to 2.5%: mainly (-)-ephedrine

and pseudoephedrine. Some ephedrine derivatives can be identified as minor compounds, e.g.

D-methylephedrine, N-methyl-pseudoephedrine and norephedrine.97,98 The Ephedra alkaloids

exhibit general sympathomimetic behaviour activation of the α1-adrenergic receptor, similarly

to the catecholamines.99-102

(1R,2S)- and (1S,2R)-norephedrine and their derivatives are used extensively as start-

ing materials for asymmetric syntheses, components of chiral ligands, or catalysts and

resolution agents103 (Scheme 12).

Ph OH

NH2Me

(1R,2S)- or (1S,2R)-norephedrine

ON

O

PhMe

O

R

chiral auxiliary for exo double bond

transformation

N

N

NH

NH

Ph

OHMe

OHMe

Ph

PhP

O

chiral ligand with Cu(II)in asymmetric syntheses

NH

O

Me Ph

OH

PhMe

NH OH

Ru(III)-catalysed asymmetric hydrogenation

O NH

NHO

Me

Ph

OH

Me

Ph

OH

addition to Et2Zn

to aldehydes

O

N

NR

Ph

Me

O

aldol synthesis

N

N

OO

NPh

Me

Ph

Me

PYBOX catalyst

NH

Ph

O

Me

Li Li

epoxide openingto alcohol

N

Me

Ph

F3C

N

Li

Li

N

N

MeOBN R

H

Me Ph

enantioselective reduction of prochiral ketones

Scheme 12

20

(+)-Norephedrine has been used as intermediate for the synthesis of naturally occur-

ring alkaloids, e.g. (+)-Geldanamicin,104 (+)-Discodermolide105 and Rhizoxin.106 In this proc-

ess, syn or anti aldol intermediates are generated for further enantioselective transformations.

In other cases, the chiral alcohol is a moiety of the target compound, e.g. (+)-norephedrine-

based cyanoacetamide, which exhibits a scytalone dehydratase inhibitory effect.107

As ligands, norephedrine derivatives have been used for the enantioselective hydro-

genation of acetophenone.108 (1R,2S)-Norephedrine-based heterocyclic derivatives have

proved to be excellent catalysts in stereoselective aldol syntheses109 or the asymmetric addi-

tion of Et2Zn to a high number of aldehydes.110-112 The norephedrine derivatives can be

utilized for the stereoselective rearrangement of alicyclic or aliphatic epoxides to allylic alco-

hols. For this, the (di)lithiated norephedrine-based diamine catalysts furnish the best enan-

tioselectivity.113

1,3,2-Oxazaborolidines derived from chiral norephedrines are available for the enanti-

oselective reduction of oximethers and prochiral ketones.114 Other ring-closed compounds,

e.g. 1,2,3-oxathiazolidinones, may be applied to generate optically active sulfinamides and

sulfoxides.115 Other heterocycles, e.g. oxazolidines, are valuable in asymmetric syntheses, e.g.

as chiral auxiliaries in enantioselective domino reactions.116 1,3-N,O-Heterocycles e.g. oxa-

zoli(di)nes, can readily be formed by ring closure, using dehydrating agents under thermal

conditions,117 or condensation reactions with acetals118 or ketoacids.119 Other N-containing

heterocycles have also been synthetized. The N-alkylation of norephedrines allows the syn-

thesis of substituted piperidine derivatives.120 Moreover, polyhydroxylated piperidines pre-

pared from both norephedrine enantiomers have proved to be inhibitors of α-glucosidases.121

Starting from chiral norephedrines, tricyclic γ-lactams122 can be prepared, similarly to the

condensation of 1,2-aminoalcohols with γ-oxoacids.25,123 Further, thiolactams have been pre-

pared by thio-Claisen rearrangement.124

3. Results and Discussion

3.1. Syntheses of pyrazolo[3,4-d]pyrimidine derivativesI

The reactions of 5-amino-1-phenyl-4-pyrazolecarbohydrazide (1) with γ- or δ-oxo-

carboxylic acids were carried out. The starting 1, prepared from ethyl 2-cyano-3-ethoxy-

acrylate by treatment with phenylhydrazine and N2H4,125 was refluxed in chlorobenzene with

oxocarboxylic acids A, C-E and G, in the presence of PTSA and the products were purified

on an Al2O3 column. On application of levulinic acid (A), 1-phenyl-7-methyl-8,9-dihydro-

pyrazolo[3´,4´:4,5]pyrimido[5,6-b]pyridazin-4-one (2) was obtained (Scheme 13). When 3-p-

21

chlorobenzoylpropionic acid (C) and 4-p-tolylbutyric acid (D) were applied, the reactions

afforded 1-phenyl-7-p-chlorophenyl-8,9-dihydropyrazolo[3´,4´:4,5]pyrimido[5,6-b] pyri-

dazin-4-one (3) and 1-phenyl-7-p-tolyl-8,9-dihydro-10H-pyrazolo[3´,4´:4,5]pyrimi-

do[5,6-b][1,2]diazepin-4-one (4). The reaction of cis-2-toluoylcyclohexanecarboxylic acid (E)

resulted in the tetracyclic compound 1-phenyl-7-p-tolyl-7ar,8,9,10,11,11ac-hexahydropyrazo-

lo[3´,4´:4,5]pyrimido[5,6-b]phthalazin-4-one (5). With diendo-3-p-toluoylbicyclo[2.2.1]hept-

ane-3-carboxylic acid (F), the diendo-8,11-methano-1-phenyl-7-p-tolyl-7a,8,9,10,11,11a-

hexahydropyrazolo[3´,4´:4,5]pyrimido[5,6-b]phthalazin-4-one (6) was prepared.

N

N

Ph

NH2

O

NHNH2

NN

PhN

NN

O

Me

NN

PhN

NN

O

ArNN

PhN

N

O

5 6

1

GE

A B C

D

NN

PhN

NN

O

Ar

2

3

NN

PhN

N

O

NAr

COOH

Me

O

A

COOH

Ar

O

C

Ar = C6H4Cl(p)

4

COOH

O

ArD

COOH

Ar

O

Ar = C6H4Me(p) Ar = C6H4Me(p)

Ar = C6H4Me(p)

COOH

O

Ar

N Ar

Scheme 13

Via these reactions, pyrazole-based pyrimido[5,6-b]pyridazinones 2 and 3, pyrimi-

do[5,6-b][1,2]diazepinone 4 and pyrimido[5,6-b]phthalazinones 5 and 6 were synthetized.

The bisacyl hydrazide derivatives depicted in Scheme 2 (pathway A) were not generated

through this protocol. This can probably be explained in terms of the less basic character of

the aromatic primary amino group of 1, which does not furnish the Schiff base, the cyclocon-

densation passing through a hydrazone intermediate (Scheme 2, pathway B).

22

The structures of 2-4 were established by 2D NMR techniques. Ring D in 5 is cis, the

C(Ar)=N carbon is equatorial, and the C(N)=N carbon is axial to the ring D. The deshielding

is due to the anisotropy of the sp2 N atom. For product 6, the unaltered diendo annelation of

the starting norbornane was proved by DNOE measurements.

In the second part, the pyrazole-condensed pyrrolotriazepinone was prepared. Hy-

drazide 1 was acetylated with Ac2O, and then cyclized with levulinic acid. Instead of the ex-

pected triazepinone compound, the ring-closed derivatives 3-phenyl-8-methylpyrazo

lo[3,4-b]azepin-5(4H)-one 7 and 5-acetylamino-1-phenyl-5a-methyl-6,7-dihydropyrro

lo[1,2-g]pyrazolo[3,4-d]pyrimidin-4-one 8 were isolated on SiO2 by means of column chro-

matography. The possible ring closure can take place in two ways. The primary amino group

of 1a is acylated by levulinic acid, and the intermediate forms the pyrazoloazepine 7 by in-

tramolecular cyclization on the pyrazole carbon and elimination of the hydrazide. When the

Schiff base is formed from levulinic acid and the primary amino group and the NH next to the

CO in the carbohydrazide then cyclizes, the pyrrolopyrimidine 8 is obtained (Scheme 14).

NN

Ph

NH2

NHNHAc

O

NN

Ph

N

N

O NHAc

O

Me

8

NN

Ph

NH

Me

O

7

1a

NN

Ph

N

NHNHAc

O

Me

OHO

NN

Ph

NH

N

ONHAc

Me

O

HO

-H2O

NN

Ph

NH

NHNHAc

O

O

OMe

-H2O

NN

Ph

NH

Me OH H

O-H2O -H2O

COOH

Me

O

A

COOH

Me

O

A

AB

CA

B

Scheme 14

The non-planar structure of ring B in 7 and 8 hinders the electron delocalization,

which leads to a more pronounced polarization of the C=O bond. Consequently, the 13C NMR

line of the carbonyl carbon is downfield-shifted. For 7 and 8, an upfield shift of the C-9b line

was found as compared with compounds 2-6. Similarly, the olefinic carbon bound to C-3a in

7 significantly influences the chemical shift of this carbon, which has a higher value, relative

to the data measured for compounds 2-6 and 8, where the substituent on C-3a is a carbonyl

group.

23

The similar pyrazolo[3,4-d]pyrimidine compounds are found to be selective kinase in-

hibitors, inhibiting glycogen synthase kinase-3,126 tyrosine kinases127,128 and cyclin-dependent

kinase.129 When attached to nucleosides, they depress virus replication (HIV-1 and DNA

viruses).130 The derivatives with this structure are adenosine 1A receptor antagonists and

substitution on C-4 and C-6 increases the effect.131 The tricyclic pyrazolo[3,4-d]pyrimidi-

no[1,2-b][1,2,4]triazines show moderate pharmacological effects in vitro, as antiviral agents

against herpes simplex-1, and cytotoxicity.132

3.2. Syntheses and transformations of 5,6-dehydronorcantharidin derivatives

Cantharidin (Figure 1) was originally identified as a biologically active constituent of

the dried body of Chinese blister beetle (Mylabris phalerata or M. cichorii) and Spanish fly.

Cantharidin inhibits Ser/Thr protein phosphatases 1 (PP1) and 2A (PP2A), which control

many cellular processes, such as the regulation of cell proliferation and differentiation. Nu-

merous studies of cantharidin analogues have had the aim of the discovery of potent and se-

lective inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). The

syntetic pathway of cantharidin and its analogues involved the preparation of the Diels-Alder

adduct with furan and dimethylmaleic anhydride, followed by hydrogenation and transforma-

tion into different carboxylic acid derivatives, e.g. diesters or amides. Although several can-

tharidin derivatives have been synthetized, their inhibitory effects were in all cases re-

duced.133-136 The unsaturated analogue 5,6-dehydronorcantharidin (Figure 2) has also been

prepared and its pharmacological effect studied. These experiments proved that demethylation

of the cantharidin resulted in the same biological effect, but the products are less nephro-

toxic.137,138

O

O

O

O

1

5

2

34

6

O

O

O

O

cantharidin norcantharidin

Figure 2

The structure-activity relationship showed that the bridging ethereal oxygen is crucial

for activity. Moreover, a hydrophobic character, e.g. the saturated double bond at position

C5/C6 is beneficial for the inhibition of protein phosphatase 2B (PP2B). Although the anhy-

dride or dicarboxylate moiety and methyl groups at positions C2 and C3 are also beneficial

for depression of the activities of PP1 and PP2A, methyl substituents cause very toxic side-

effects, such as nephrosis and severe gastritis. Recent investigations have focused attention on

24

norcantharidin and its unsaturated analogue, which exhibit similar pharmacological effects,

with significant anticancer properties, but they are less toxic.139,140

As a continuation of the earlier research into the pharmacological features of 5,6-de-

hydronorcantharidin derivatives, and especially the antitumour activity found for N-acyl-3-

carbamoyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (10), some saturated and partially

saturated analogues, β-lactams and 1,3-N,N-heterocycles, were synthetized. The aim was the

ring closure of the β-amino acid 11 and diamine 14. An antibacterial, serine protease-inhibi-

tory effect and antitumour activity were supposed. Chemically, the rDA reactions of these

derivatives were of interest because it was known that, on thermolysis, furan is a “good-

leaving” group in the molecule.

Maleic anhydride was reacted with furan to give the Diels-Alder adduct 5,6-dehydro-

norcantharidin 9. Ammonolysis resulted in compound 10, and Hofmann degradation then fur-

nished diexo-3-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid 11. Esterification of

11 with SOCl2 in EtOH, followed by the ammonolysis of 12 and LiAlH4 reduction of the car-

boxamide 13, afforded the diamine 14 (Scheme 15). It should be emphasized that the final

step of LiAlH4-mediated reduction was carried out under very mild conditions because the

oxabicyclic compounds are sensitive to temperature. The reaction mixture must be cooled to

-15 ºC for successful transformation. Higher temperatures, even 0 ºC or room temperature,

resulted in a complex reaction mixture.

SOCl2/EtOH

LiAlH4

O

OOO

O

NH2

OEt

O

NH2OH

O

O

NH2

NH2

O

O

O

O

O

NH2NH2

O ONH3/MeOH

O

OH

ONaOCl

NH2

O NH4OH

9 10 11

121314

Scheme 15

The oxabicyclo β-amino acid 11 and diamine 14 prepared reacted in two ways. diexo-

3-Amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (11) was cyclized by means of

aldehydes and isonitriles in U-4C-3CRs, to give N-substituted β-lactams. Moreover, diexo-3-

amino-7-oxabicyclo[2.2.1]hept-5-ene-2-methanamine (14) with γ- and δ-oxocarboxylic acids

was cyclized to furnish isoindolone derivatives.

25

3.3. Multicomponent reactions with oxabicycloheptene-based β-amino acids II

The cis alicyclic, diexo and diendo bicyclic β-amino acids have been used for the U-

4C-3CR in organic solvent. The main conception was the extension of the U-4C-3CR for ox-

abicyclo[2.2.1]hept-5-ene-based β-amino acids, using MeOH and water as solvents, in order

to compare the obtained yields, reaction times and diastereoselectivities. On the other hand,

the possible further transformations of the β-lactams were also attempted.

The building blocks utilized in the Ugi reactions to construct the β-lactam library are depicted

in Figure 3.

O

NH2

O

OH

Cl

O

H

H3C

O

H

H3CO

O

H

O

H

O

H

NC

NC

11 A B C

D a bE

Figure 3

Generally, β-amino acid 11 was used in a small excess (1.1 equiv.) and was reacted with ali-

phatic (A or B) or aromatic aldehydes (C, D or E) and tert-butyl or cyclohexyl isocyanide (a

or b) in MeOH or in water. The proposed reaction mechanism is displayed in Scheme 16.

O

NH2

O

OH

O

HN

O

O

R2 N

O

HN

O

N

O

R2

R1

O

N

O

R1 HN

O

R2

-H2O

C

O

HN

O

O

R1

CNR2

15-24

11

MeOH or water

R1 CHO;

A-E a or b

A-E: a or b:

R1

Scheme 16

26

3.3.1. Use of methanol as solvent

At first, MeOH was used as solvent to carry out the U-4C-3CR. To a suspension of 1.1

equivalents of β-amino acid 11 in MeOH, the required aldehyde (1 equiv.) was added at room

temperature. After stirring for 45 min at room temperature, 1 equivalent of tert-butyl or

cyclohexyl isocyanide was added dropwise to the solution, which was next stirred for 3 days

at ambient temperature. The crude products 15-24 were obtained in yields of 43-76% and the

diastereomeric ratio ranged from 56:44 (16) up to 87:13 (17) (Table 1).

Table 1

Compound R1 R2 dr Yield (%)

15 Et tBu 62:38 61 16 Et cyclohexyl 56:44 76 17 tBu tBu 87:13 71 18 tBu cyclohexyl 82:18 65 19 C6H4Cl(p) tBu 62:38 52 20 C6H4Cl(p) cyclohexyl 79:21 76 21 C6H4Me(p) tBu 78:22 55 22 C6H4Me(p) cyclohexyl 86:14 43 22 C6H4OMe(p) tBu 64:36 48 24 C6H4OMe(p) cyclohexyl 69:31 45

Compounds 15-20 had an average purity of over 90% without purification (based on 1H NMR

measurements). For compounds 21-24, further purification was necessary by means of flash

chromatography in order to remove the remaining aldehyde. On use of the aliphatic alde-

hydes, the intramolecular Ugi cyclization afforded higher yields, and for compound 17 the

highest diastereomeric ratio (87:13) was found. A high average diastereoselectivity, but de-

creased yields were obtained when the aromatic aldehydes were used.

Compounds 17 and 19 were prepared for X-ray crystallography so as to determine the

relative configurations of the major diastereoisomers (Figure 4). For the major isomers, the

configuration of the substituent at position C-2 remains the same position relative to the

annelation H-atoms.

27

17 19

Figure 4

3.3.2. Use of water as solvent

The Ugi reactions were carried out in water, starting from the same materials to allow

comparison with the results in MeOH (Table 2). To 1.1 equivalent of β-amino acid 11 in a

minimal amount of water (200 µL), aldehyde (1 equiv.) was added dropwise. Next, ap-

proximately 1 mL of water was added dropwise until the components had completely dis-

solved. After vigorous stirring for 30 min at room temperature, the corresponding isocyanide

(1 equiv.) was added to the mixture. Precipitation of products 16-22 and 24 started immedi-

ately. In the cases of compounds 15 and 23, some precipitation was detected, but extraction

was necessary for complete isolation. It was found that the cyclizations proceeded success-

fully in distilled water in from 3 h up to 1 day, and the precipitation depended greatly on the

concentrations besides the type of the starting materials. Precipitation occured when less wa-

ter-soluble amino acids (the bicyclic oxabicyclo- and bicyclo[2.2.1]heptane-based amino ac-

ids were found appropriate) were used.141

Table 2

Compound R1 R2 dr Yield (%)

15a Et tBu 67:33 71%

16b Et cyclohexyl 60:40 61%

17b tBu tBu 100:0 59%

18b tBu cyclohexyl 80:20 64%

19b C6H4Cl(p) tBu 52:48 69%

20b C6H4Cl(p) cyclohexyl 55:45 55%

21b C6H4Me(p) tBu 58:42 54%

22b C6H4Me(p) cyclohexyl 75:25 54%

23a C6H4OMe(p) tBu 57:43 51%

24b C6H4OMe(p) cyclohexyl 63:37 47%

a isolated by extraction b precipitated compound, isolated by filtration

28

The ideal concentrations were achieved when starting components had just dissolved.

After the addition of the isocyanide, the solution became slightly opalescent because of pre-

cipitation of the target molecules. We tested both concentrated and diluted mixtures in order

to investigate the precipitation process. When the components had only partially dissolved,

the yields were lower. In dilute solutions, the products were not precipitated, or only partially.

Organic solvent extraction was therefore necessary to isolate them. When the reaction time

was prolonged to 3 days, the yields were similar to those when the reaction mixture was satu-

rated with the starting materials. In accordance with these experiments, we assume that a

“personalized” amount of water is necessary to optimize acceleration of the reaction with pre-

cipitation in water.

The best result was observed for compound 17 containing the bulky tert-butyl sub-

stituents. The reaction time was only 3 h and the diastereomeric ratio was 100:0. Derivatives

15-12 and 24 were isolated in average purities of over 90% and further purification was not

necessary for NMR measurements. For product 23, chromatographic purification was neces-

sary because of the residual anisaldehyde. Table 3 presents NMR data on the H atom at posi-

tion 2, the melting point intervals for the mixtures of diastereoisomers and the reaction times.

Table 3

Com-pound

R1 R2 2-H (ppm) major/minor

M.p. (○C)

Time (h)

15a Et tBu 3.65 (t)/3.72 (m) 97-106 24

16b Et cyclohexyl 3.68-3.74 (m) 159-166 15

17b tBu tBu 3.75 (s) 176-178 3

18b tBu cyclohexyl 3.84 (br s) 160-164 6

19b C6H4Cl(p) tBu 3.96/3.95 (s) 165-169 15

20b C6H4Cl(p) cyclohexyl 3.93/3.92 (s) 155-176 15

21b C6H4Me(p) tBu 3.97/3.96 (s) 135-141 15

22b C6H4Me(p) cyclohexyl 3.94/3.93 (s) 122-138 15

23a C6H4OMe(p) tBu 3.96/3.95 (s) 120-134 24

24b C6H4OMe(p) cyclohexyl 3.93/3.92 (s) 129-141 24

3.3.3. Transformations of the resulting β-lactam 17

To demonstrate the possibility of further transformations of the resulting azetidinone

derivatives, compound 17 was converted into the corresponding carboxylic acid 25 or ethyl

ester 26 by means of acid-catalysed solvolysis in the presence of water or EtOH. A saturation

process with H2 at atmospheric pressure was carried out, catalysed by Pd on charcoal, to yield

derivative 27 (Scheme 17). Another conversion was performed with LiAlH4 or LDA in an

attempt to synthetize hydroxy-substituted amino acid derivatives 28a or 28b, but the target

29

compounds could not be isolated from the complex reaction mixture. To utilize the oxano-

rbornene moiety of compound 17, the rDA protocol was attempted by classical methods

(heating to the melting point, and refluxing in a high-boiling point solvent) and microwave-

assisted thermolysis (150-250 °C, 100-200 W, for from 10 min up to 1 h, in o-dichloro-

benzene or solvent-free, on SiO2 or AlCl3/toluene), but only the starting material could be

detected; the rDA product 29 was not formed.

O

N

O

NH

O

2526

27

HCl/H2OHCl/EtOH

H2/Pd

17

HH

O

NH

COOH

NH

O.HCl

HH

O

N

O

NH

O

HH

63%56%

90%

O

NH

COOEt

NH

O.HCl

HH

N

O

NH

O

NH

O

LDA or

LiAlH4

NH

OH

or

COOH

NH

OH

28a 28b

29

COOH

O

O

HN

Scheme 17

3.4. Reactions of oxanorbornenediamine with γ- and δ-oxocarboxylic acidsIII

The oxanorbornene diamine skeleton was cyclized with several oxoacids. This

protocol, which resulted in 1,3-N,N-heterocycles, followed the reaction route described earlier

(Scheme 7).

3.4.1. Preparation of pyrrolo- and isoindoloquinazolines

Diamine 14 was reacted with aliphatic (B and C), alicyclic (E), bicyclic (G, H and K)

and aromatic (I and J) γ-oxocarboxylic acids (Scheme 18). The cyclocondensation is illus-

trated here by the example of the reaction of diamine 14 and 3-p-tolylpropionic acid (B).

When diamine 14 was boiled with equimolar 3-p-tolylpropionic acid (B) in chlorobenzene,

30

the Schiff base was formed. This intermediate can cyclize into quinazolines by forming a C-N

bond between the primary amine of the metheneamine and the imine carbon. Next, the final

cyclization step resulted in a pyrrolo[2,1-b]quinazoline, compound 30. Potentially four iso-

mers (pyrrolo[2,1-b] and [1,2-b]quinazolines) could be formed in this protocol, but only one

isomer could be isolated from the reaction mixture (Scheme 7). A similar result was obtained

when 3-p-chlorobenzoylpropionic acid (D) was used; aryl diexo-5,8-epoxypyrrolo[2,1-

b]quinazolin-1-one derivative 31 was isolated. When cis-2-p-tolylcyclohexanecarboxylic acid

(E) was used, the reaction afforded the cis- and trans-condensed decahydro-5a-p-tolyl-1,4-

epoxy-diexo-5H,12H-isoindolo[1,2-b]quinazolin-10-one pentacyclic derivatives 32a and 32b

(Figure 4); in the latter case, the oxocyclohexane acid isomerized. The results showed that the

configuration of the starting aroylcarboxylic acid often changed in the reactions. With diendo-

3-benzoylbicyclo[2.2.1]heptane-2-carboxylic acid (G) or the diendo-6-phenyl-3-

benzoyl[2.2.1]heptane-2-carboxylic acid (H), 1,4-epoxy-diendo-6,9-methano-diexo-5H,12H-

isoindolo[1,2-b]quinazolin-10-ones 33 and 34 were obtained.

NH2

O

NH2

NO

NH

O

Ar

N

NH

O

Ar

O

N

O

Ar

NH

O

14

30 Ar = C6H4Me(p)

31 Ar = C6H4Cl(p)

32a: cis, 32b: trans

Ar = C6H4Me(p)

37a

37b

E G or H

K

J

N

O

Ar

NH

O

I

N

O

Ph

NH

OR

33 R = H34 R = Ph

H

H

H

H

H

H

H

HH

H

N

NH

O

Ar

O

37c

H

H

H

H

H

H

H

HH

H

H

H

NH

N OO

36

H

H

H

H H

N

O

N

O O

O

35

HH

H

H

COOH

Ar

O

B, C

COOH

Ar

OCOOH

OAr

COOH

H

O

COOH

O

H H

H

COOH

O

Ar

R

Ar = C6H4Me(p)

Scheme 18

31

When 2-formylbenzoic acid (I) was reacted, 6-(3-oxoisobenzofuran-1-yl)-1,4-epoxyhexa-

hydro-diexo-isoindolo[1,2-b]quinazolin-11-one (35) was obtained because I cyclized with the

diamine, but underwent partial lactonization and the NH group was substituted. The hepta-

cyclic octahydro-1,4-epoxy-8,10-ethanobenz[6,7]indolo[7a,1-b]quinazolin-7-one (36) was

formed in the reaction with methanobenzocyclooctenoxocarboxylic acid (J).17 The adduct K

of trans-3-p-tolylacrylic acid and cyclopentadiene, containing a mixture of the exo-aroylnor-

bornene-endo-carboxylic acid and endo-aroylnorbornene-exo-carboxylic acid, epimerizes to

diendo- and diexo-aroylnorbornenecarboxylic acids in the reaction. Hence, four isoindo-

lo[1,2-b]quinazolinone isomers were expected, and the isolation of three of these succeeded

on column chromatography: the two diexo diastereoisomers, 37a and 37b, and one diendo

isomer, 37c.

In an attempt to gain a rDA product, compounds 30–37 were heated under different

conditions, such as refluxing in chlorobenzene or o-dichlorobenzene, or by heating to the

melting point, but no transformations were detected. These large, high-melting molecules

appear to be thermostable and give no rDA products under such conditions.

3.4.2. Establishment of the structures

The constitutions of the compounds were proved via the IR and NMR spectra. For 30

and 31, similarly to 32a,b, 35, 36 and 37a,b,c the diexo annelation of the oxanorbornene to

perhydropyrimidine follows from the doublet structure of the H-1 signal. This also holds for

the norbornene ring in 37a,b. For 30 and 31, the endo position of the tolyl group was con-

firmed by DIFFNOE measurements. In the cases of 32a and 32b, the orientation of H-5’

changes from equatorial in 32a to axial in 32b. The stereostructures of 32a and 32b are de-

picted in Figure 5.

O

NH

N

O O

NH

N H

H

H

O

32a 32b

H

H

H

H

H

H

1

6

1'

6'

4'

7'

4'5'

5'

H

H

Figure 5

DIFFNOE experiments provided a direct evidence for the endo position of the phenyl group

and H-1 in 33 and 34. The H-1 and H-6 signals confirmed that the norbornane moiety in 33

32

and 34 (and also in norbornene 37c) is diendo. For 35, the constitution was proved by the IR

and NMR data. In the IR spectrum, the γ-lactone and γ-lactam carbonyl bands (at 1761 and

1694 cm–1) are observed in the expected intervals. NOE was not observed between H-1 (and

also H-6) and the diazaketoacetal-H (NCHN). These H atoms lie on opposite side of the mo-

lecular skeleton and the exo orientation of the former may be supposed; consequently, the two

chirality centres have opposite configurations. For 36, the NOE proves sterically close-lying

positions for H-5’ and H-1, together with diexo annelation of the norbornene moiety.

The structures of 37a-c were established by NOE experiments and X-ray crystallography.

37a 37b

37c

Figure 6

3.5. Syntheses of Sedum alkaloid analogues and transformations of norephedrine

The preparation and transformation of 1,3-O,N-heterocycles such as bicyclic oxazi-

nones and oxazolidines are among the main research topics at the Institute of Pharmaceutical

Chemistry. These compounds or their derivatives are frequently encountered in nature. Since

the syntheses of these materials are very often based on the transformation of five- or six-

membered heterocycles with an imine function, this research has led to collaboration with the

research group of Prof. Norbert De Kimpe at the Faculty of Bioscience Engineering, Univer-

33

sity of Ghent. Within that cooperation, I have participated in a project aimed at devising syn-

thetic pathways to produce or transform natural compound analogues.

3.5.1. Syntheses of Sedum alkaloid analoguesIV

The main research initially focused on the synthesis of Pomgranaceae alkaloids. The

original assumption was that the target compound was accessible following a known synthetic

procedure starting from piperidine. The retrosynthetic route is depicted in Scheme 19.

NH

N

N

N

NH

P

O

PhPh

N P

O

PhPh

Boc

N

Boc

N

Scheme 19

The phosphorylated carbamate 40 was prepared in three steps according to literature

methods.142-144 The piperidine was reacted with either tBuOCl or NCS and the resulting N-

chlorinated intermediate was treated with a strong base to furnish compound 38 in moderate

yields (Scheme 20). The 2,3,4,5-tetrahydropyridine (piperideine) trimer obtained was phos-

phorylated with Ph2PH(O), and the amine 39 was then protected by means of (Boc)2O

(Scheme 20).

A. tBuOCl NaOMe

B. NCS KOH/MeOH

45%

33%

75%Ph2PH(O)

Boc2O, TEA

DMAP

80%

N

H

N

N

N

N3

NH Ph

PhP

ON

Ph

PhP

O

38

3940

Boc

Scheme 20

The modified Horner reaction between the phosphorylated carbamate 40 and various

α,β-unsaturated aldehydes or benzaldehyde resulted in enamides 41a-f and 42 in good to ex-

cellent yields (Scheme 21 and Table 4).145 Deprotection of enamide 42 with trifluoroacetic

acid (TFA) in CH2Cl2 afforded 2-benzylpiperideine 43 in excellent yield.

34

N PPh

Ph

O

NPh

NR1

R2

nBuLi,

(R1)(R2)CH=CHCHO

-78°C rt

nBuLi, PhCHO

-78°C rt

40

NPh

43

TFA

81%

BocBoc Boc

41a-f 42 E/Z: 77/23

90%33-68%

Scheme 21

The deprotection method therefore seemed suitable for the preparation of piperideine alka-

loids bearing alkenyl substituents at position 2 [e.g. 2-(2’-propenyl)-1-piperideine (R1 = R2 =

H), an alkaloid in Punica granatum (see I) and related alkaloids (II-IV) (Figure 6)].146

N

I

N

II

NHIII

NH

IV

N Ph

OH

V

2-(2-Propenyl)-piperidine

Nigrifactin α-Conicein β-Conicein 1-Phenyl-2-(3,4,5,6-tetrahydropyridine-2-

yl)ethanol

Figure 7

The results of modified Horner reactions are presented in Table 4. In every case, predomi-

nantly the E isomers were formed. In the cases of 41c (R1 = methyl) and 41f (R1 = p-

methoxyphenyl), only the E isomer was obtained. The yields were established after flash

chromatography on silica.

Table 4

Compound R1 R2 Yield (%) E/Z

41a H H 47 67/33 41b Me H 54 86/14 41c Me Me 60 100/0 41d iPr H 53 92/8 41e Ph H 68 76/24 41f C6H4OMe(p) H 33 100/0

To obtain Pomgranaceae alkaloid analogues 44a-c, removal of the protecting group of

compounds 38a-c was first attempted with inorganic acids such as HCl or H2SO4. In all cases,

decomposition of the starting materials was detected. Deprotection was also unsuccessful ei-

ther when TFA was used in the presence of thioanisol or thiophenol, or microwave-assisted

solvent-free thermolysis on SiO2 was applied. In each case, only a complex reaction mixture

was observed. When mild condition and reagents were used, e.g. trimethylsilyl chloride

(TMSCl) or trimethylsilyl iodide (TMSI) itself or with phenol, conversion was detected

35

(Scheme 22). TMSCl and phenol (1:3) were first used as deprotecting agent, in accordance

with the literature reports.147 This method seemed effective and conversion was observed, but

the reaction time was 1 day, and instead of dienes 44a-c, unsaturated bicyclic carbamates 45a-

f were formed. To improve the efficiency of this protocol, enamides 41a-f were reacted with

TMSI and phenol in a ratio of 1:1 and the reaction time was reduced to 30 min; under these

conditions, acceptable yields (41-70%) were achieved (Scheme 22).

N

Boc

R1

R2N O

O

R1

R2

41a-f (E,E) and (Z,E)

NR1

R2

45a-f44a-c

deprotectiontechniques

1. TMSI/phenol2. NaOH

41-70%

Scheme 22

The possible reaction mechanism is shown in Scheme 23. The combination of TMSI

and phenol leads to the formation of trimethylsilyl phenoxide147 with the liberation of HI. In

this medium, the Boc group was cleaved with the expulsion of isobutene, and the resulting

oxygen anion underwent intramolecular trapping by an iminium species formed in situ due to

the presence of HI. It should be noted that the double bond shifts from its initial position in

the carbamate ring to the piperidine ring.

H+

H+N

R1

R2O

Me

O

OSi

NR1

R2O OMe

MeMe

SiMe

MeMe

NR1

R2O O

SiMe

Me

Me

NR1

R2O O

SiMe Me

Me

OH-

45a-f

N

OO

SiMeMe

R1

R2

Me

N

OOR1

R2

N

OOR1

R2

H

N

OOR1

R2

H

N

OOR1

R2

H+

Me

Me

Me

MeMe

Scheme 23

The obtained yields of derivatives 45a-f are listed in Table 5.

36

Table 5

Compounds R1 R2 Yield (%)

45a H H 41 45b Me H 52 45c Me Me 60 45d iPr H 48 45e Ph H 70 45f C6H4OMe(p) H 46

The first efforts to open unsaturated bicyclic carbamates 45a-e into 1,3-aminoalcohols

(analogues of V; Figure 7) were not successful. Neither N-methyl-substituted derivatives 46a-

e nor aminoalcohols 47A (a-e), 47B (a-e) could be synthetized (Scheme 24).

45a-e46

N

OOR1

R2

A. KOH/MeOH,EtOH or H2O

B. TFA

NH

OH

R1

R2N

OH

R1

R2Me

LiAlH4

47A (a-e)

N

OH

R1

R2

47B (a-e)

Scheme 24

When unsaturated bicyclic carbamates 45a and 45b were reduced either with NaCNBH3 or

with NaBH4, a mixture of diastereomers [48a (cis/trans = 86/14) and 48b (cis/trans = 88/12)]

was obtained. NOESY experiments demonstrated that the major component was the cis iso-

mer in each case. Reduction of 45c with NaBH4 in glacial AcOH resulted in only the cis com-

pound 48c. Afterwards, 48a and 48b were reduced by means of LiAlH4, resulting in racemic

Sedum alkaloids such as (2R*,2’S*)-N-methylallosedridine 49a and (2R

*,2’S*)-1-(1-methyl-

piperidin-2-yl)butan-2-ol 49b after purification by column chromatography (Scheme 25).148

N

OOR

N

Me

OH

RN

OOR

H

N

OOR

H

+

45a-c cis-48a-c trans-48a-c 49a,b

Na(CN)BH3/AcOH

LiAlH4

NaBH4/AcOH

80% (R = H)95% (R = Et)50% (R = Ph)

80% (R = Et)76% (R = Ph)

60-65%H H

Scheme 25

37

3.5.2. Transformations of chiral norephedrinesV

In this field of my research work, the electrophile-induced cyclization149 of alkenyl

1,3-oxazolidines derived from chiral norephedrines (natural 1,2-aminoalcohols) and transfor-

mation of the resulting γ-lactams were performed.

The syntheses of the chiral 3-(3-butenyl)-1,3-oxazolidines 54 and 55 were

accomplished by two methods. The starting materials (1R,2S)- (50) and (1S,2R)-norephedrine

(51) were acylated with 4-pentenoyl chloride150 in CH2Cl2 in the presence of TEA, resulting

in amides 52 and 53. The ring closure of the hydroxyamides 52 and 53 was performed by

reflux in toluene in the presence of a catalytic amount of PTSA, which afforded oxazoline

derivatives 54 and 55 in good yields. In an alternative method, chiral oxazolines 54 and 55

were obtained directly in one-step syntheses by the reaction of norephedrine and 3-butenoic

acid in toluene under reflux in the presence of a catalytic amount of PTSA. However, the

yields of the 2-oxazolines 54 and 55 were then much lower as compared with the two-step

procedure. Treatment of 2-oxazolines 54 and 55 with Br2 or with I2 resulted in pyrrolidinones

56-63 as a 50:50 (X = Br) or 57:43 (X = I) mixture of diastereomers (Schemes 26 and 27).

OHPh

NH2Me

OHPh

NH

Me

O

N

OPh

Me

OHPh

NMe

O

X OHPh

NMe

O

X

(R)

(S)

(R)

(S)

(S)

(R)

(R)+

52

545660

5761

X = BrX = I

50

N

OPh

Me

(R)

(S)N

OPh

Me

(R)

(S)

X

H2O

1.1. equiv. 4-pentenoyl chloride1.1.equiv. TEA

90%

1 equiv. 3-butenoic acid PTSA

43% ∆∆

86%

1.1 equiv. Br2, 56%

or 3 equiv. I2, 77%

X

Scheme 26

The 1S,2R-norephedrine 51 was also transformed into lactams 58, 59, 62 and 63 via a three-

step protocol (Scheme 27).

38

OHPh

NH2Me

(S) OHPh

(R) NH

Me

O

(S)

(R) N

OPh

Me

(S) OHPh

(R) NMe

O

X OHPh

NMe(S)

O

X

+

53

555862

5963

X = BrX = I

51

1.1. equiv. 4-pentenoyl chloride1.1.equiv. TEA

57%

1 equiv. 3-butenoic acid PTSA

45% ∆∆

83%

1.1 equiv. Br2, 53%

or 3 equiv. I2, 74%

Scheme 27

The electrophile-induced cyclization of 2-(3-butenyl)oxazolines 54 and 55 was highly regio-

selective, but less diastereoselective, and only the formation of five-membered ring products

was observed. The diastereoisomeric γ-lactams 56 and 57 were easily separated by column

chromatography, resulting in one isomer in a crystalline form which was suitable for X-ray

diffraction analysis. Accordingly, this X-ray diffraction analysis revealed the structure of γ-

lactam 56 as (R)-5-bromomethyl-1-[(1R,2S)-1-hydroxy-1-phenylpropan-2-yl]pyrrolidin-2-one

(Figure 8). The diastereomeric ratio was determined by 1H NMR, and the relative stereo-

chemistry of the oily product 57 was established by NOESY.

Figure 8

The cyclization of (4S,5R)-2-oxazoline 54 was also attempted with PhSeBr in CH2Cl2.

However, only an unseparable mixture of compounds was obtained. Under similar conditions,

the intermediate amide 52 underwent an electrophile-induced lactonization instead of the

expected lactamization.149 The iminolactone 64 obtained decomposed upon chromatographic

purification on silica gel. When 64 was stirred with SiO2 in CH2Cl2, the known151 racemic

lactone 65 was obtained in 95% yield (Scheme 28).

39

N

OPh

Me

(R)

(S)

54

OHPh

NMe (S)

(R)

O SePh OO

SePhPhSeBr

90%

64 65

SiO2

95%

Scheme 28

The synthesis of pyrrolo[2,1-c][1,4]oxazines 66 from γ-lactams 56 and 60 by cycliza-

tion with bases such as NaOMe or NaH failed. The latter bicyclic morpholines 66 could be

suitable precursors of stereodefined 2,3,5-trisubstituted morpholines. Such compounds have

received considerable interest in recent years.152 However, γ-lactams 56 and 60 underwent

ring closure to yield pyrrolo[2,1-b]oxazol-5-one 67 in a diastereoselective fashion instead of

the expected pyrrolo[2,1-c][1,4]oxazine 66 (Scheme 29).

OHPh

NMe

O

X

N

O

O

MePh

Me

HOHPh

NMe

O

OHPh

NMe

O

X

NaH

-HH

-X

N

O

O

Ph

Me

H

67

Scheme 29

Bicyclic compound 67 was also prepared in 80% yield by an alternative synthesis via

tandem cyclization of (1R,2S)-norephedrine 50 with levulinic acid (Scheme 30).

OHPh

NH2Me

OHPh

(S) NMe

O

X

56,60

50

N

OPh

Me

O

(R)

(S) N

O

O

MePh

Me

6766

COOH

O

Me

NH

O

Me

COOHPh

Me

OHPh

NMe

Me

COOH68a 68b

NH

OPh

Me

Me

COOH

68c

(R)

(R)

(S)(R)

(S)

(R)

(R)

(S)

Scheme 30

40

This reaction is highly stereoselective as only a single diastereomer was detected in

the crude reaction mixture. The stereochemical outcome of this cyclization was also corre-

lated with Meyer’s work.153 The first step of the cyclocondensation process is the reaction of

norephedrine with the γ-ketoacid, resulting in a three-component tautomeric mixture.154,155

From the tautomeric mixture, only intermediate 68c is a suitable participant for the second

cyclization step to result in (2R,3S,7aS)-3,7a-dimethyl-2-phenylpyrrolo[2,1-b]oxazol-5(6H)-

one (67) (Scheme 30).

41

4. Summary

The preparation of 62 new compounds has been discussed.

From the reactions of pyrazole aminocarboxylic hydrazides 1 and diexo-oxanorbornene-

diamine 14 with γ- and δ-oxocarboxylic acids, N,N-heterocycles such as pyrazolo[3,4-d]pyri-

midino[5,6-b]phthalazines, pyrazolo[3,4-d]pyrimido[5,6-b]pyridazinones 2-6, pyrrolo[2,1-b]-

and isoindolo[1,2-b]quinazolines 30-37 were synthetized. When the starting pyrazole amino-

carbohydrazide was modified by acylation, it underwent a special ring closure involving hy-

drazide elimination and resulted in a pyrazoloazepine 7. Starting from maleic anhydride and

furan, 5,6-dehydronorcantharidin was prepared. Ammonolysis and Hoffman degradation af-

forded diexo-oxabicyclo[2.2.1]hept-5-ene amino acid 11, from which the corresponding dia-

mine 14 was prepared. With oxoacids, isoindolone derivatives 30-37 were obtained by cyclo-

condensation. For 37a-c, diastereoisomers were separated: for 37a and 37b, X-ray examina-

tions revealed that the oxanorbornene and norbornene moieties are in the diexo position and

the diastereoisomers differ in the positions of the epoxy group and methylene bridge. In 37a,

the situation is the opposite and there is a “head-foot” structure, while in 37b, the epoxy and

methylene groups are in the same position and exhibit a “head-head” structure. In 37c, the

norbornene is diendo and the oxanorbornene is diexo, and there is a “head-foot” position. β-

Amino acid 11 was applied for the U-4C-3CR in pure water and MeOH, to study the solution

effect. In this, β-lactam derivatives 15-24 were obtained and the yields, diastereoselectivities

and reaction times were compared. With water as solvent, the yields were found to those in

MeOH. The diastereoselectivity was also similar or better in some cases, and excellent di-

astereoselectivity could be observed for 17. The advantage of water was that compounds 16-

22 and 24 were precipitated in good yields and good purities, and thus the use of organic sol-

vent was not necessary.

A new synthetic route was devised for the synthesis of bicyclic carbamates such as 1,3-O,N-

heterocycles 45a-f. In the final step, the intramolecular cyclization was carried out under mild

conditions instead of with strong electrophilic reactants such as NBS or NIS. The subsequent

hydrogenation of the unsaturated bicyclic carbamates and ring opening resulted in the racemic

Sedum alkaloids 49a and 49b, in good yields. The electrophile-induced cyclization was also

carried out from enantiopure (+)- or (-)-norephedrines. From the chiral oxazolines 54 and 55,

new chiral 1,5-disubstituted pyrrolidinones 56-63 were obtained. The cyclocondensation of 5-

halomethyl-γ-lactams resulted in good yields of bicyclic lactam 67, containing a tetrahydro-

pyrrolo[2,1-b]oxazole skeleton. This molecule was alternatively prepared in high yields via

the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.

42

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Acknowledgements

I am greatful to for Prof. Ferenc Fülöp, Head of the Institute of Pharmaceutical Chem-

istry, University of Szeged, for the possibility to work for my thesis in the Institute.

I would like to express my deepest thanks to Prof. Géza Stájer for his encouragement

and guidance of my work. As supervisor, his advice has greatly helped me during all stages of

my PhD work.

My thanks are due to Prof. Pál Sohár for the IR and NMR spectroscopic measurements

and valuable interpretations, and to Prof. Reijo Sillanpää for his help in the X-ray work.

I would also like to thank Prof. Norbert De Kimpe for providing me with working fa-

cilities in the University of Ghent.

I am likewise grateful to Dr. Zsolt Szakonyi and Dr. Ferenc Miklós for facilitating my

laboratory work with practical advice.