Asymmetric Synthesis of Proline Derivatives Abdollah Javidan University of Wollongong

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1996 Asymmetric synthesis of proline derivatives Abdollah Javidan University of Wollongong

Recommended Citation Javidan, Abdollah, Asymmetric synthesis of proline derivatives, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 1996. http://ro.uow.edu.au/theses/1116

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ASYMMETRIC SYNTHESIS of PROLINE DERIVATIVES

A Thesis Submitted for The award of

The Degree of Doctor of Philosophy

from

The University of Wollongong pa mm W

Department of Chemistry

by

Abdollah Javidan (B.Sc, M.Sc.)

February 1996

UWVERSITYOF WOLLONGONG LIBRARY In the Name of God, the Compassionate and the Merciful

- -c.» 1

DECLARATION

The Thesis contains no material which has been accepted for the award of any other degree or diploma in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference is made in the text.

l Abdollah Javidan. ..D&te ...M:. ..??.3.!?.. 11

Publications

Some of the work described in this thesis has been reported in the following publications:

"Asymmetric Synthesis of Proline Derivatives.1 Abdollah Javidan and Stephen G.

Pyne, Proceedings of the 14th National Organic Conference (RACI), University of

Wollongong, 1994, p31.

"Asymmetric Synthesis of Proline Derivatives from (2R) and (2S)-2-tert-Buty\-3- benzoyl-4-methyleneoxazolidin-5-one.' Stephen G. Pyne« Abdollah Javidan, Brian W.

Skelton, and Allan H. White, Tetrahedron 1995, 51, 5157-5168.

"Asymmetric Synthesis of Proline Derivatives.1 Abdollah Javidan and Stephen G.

Pyne, Proceedings of the 6th Asian Chemical Congress '95, Manila, 1995, Syn-O-16.

"Diastereoselective 1,3-Dipolar Cycloadditions and Michael Addition Reactions of

Azomethine Ylides to (2R)- or (2S)3-Benzoyl-2. tert-butyI-4-methyleneoxazolidin-

5-one." Stephen G. Pyne and Abdollah Javidan, In preparation. iii

ACKNOWLEDGMENTS

'Man is a creature for Whom spirituality is the ultimate aim of his life.' "Imam Khommeni"

First and foremost, I would sincerely like to thank my supervisor Associate Professor

Stephen G. Pyne for his guidance, discussions and assistance over the last three and a

half years. His friendship has been very much appreciated. I am thankful for the time

that I have been able to spend in his research group.

I like to especially thank the past and present members of the Pyne group and all the

members and technical staff of the Chemistry Department for providing a pleasant

working environment.

I would like to thank Dorothy David and Karl Schafer for the time spent for proof

reading and Dr Garry Mockler for allowing me to use his computer.

I am very appreciative of the significant efforts of Professor Allan H. White and Brian

W. Skelton from The University of Western Australia for X-ray structural analysis.

I would also thank The University of Imam Hossein and The Ministry of Culture and

Higher Education of Islamic Republic of Iran for the Ph. D. scholarship.

I thank the Islamic association of Iranian students in Wollongong for providing a

suitable living environment for me and my family over the past few years.

Finally, I'm particularly grateful to my darling wife, thank you for your unfailing

support and understanding over these years. Without your contribution, the writing of

this thesis would of been much more arduous. And thank you to my daughters, Zahra,

Fatemeh and Maryam for their patience and encouragement. A warm thank you to my family, my brothers and my sisters, especially my parents and my mother in law and my father in law, for their love and interest, albeit from afar. ABBREVIATIONS

The following abbreviations have been used throughout this thesis.

[a] specific rotation Ac acetyl

ACE angiotensin converting enzyme

ALBN a ,a-azabisisobutyronitrile

AO atomic orbital Ar aryl

atm atmosphere

BrPhFI 9-Bromo-9-Phenylfluorene

Bn benzyl bz benzoyl bp boiling point Bu butyl Bu1 tert-butyl °C degrees Celsius

calcd calculated

CH2CI2 dichloromethane a chemical ionization CIPP Cis wopropyl proline cm centimetre COSY correlation spectroscopy 8 chemical shift in parts per million downfield from

tetramethylsilane

d doublet ID 1 dimensional 2D 2 dimensional DBTA dibenzoyl-D-tartaric acid monohydrate DBU l,8-diazabicyclo[5.4.0]undec-7-ene

de diastereomeric excess

dec decomposes

DJJ3AL-H diisobutylaluminum hydride

DMF dimethylform amide

DMSO dimethylsulfoxide

dr diastereoisomeric ratio

ee enantiomeric excess

EI electron impact

ent enantiomer

epi epimer

equiv. (molar) equivalents

ES electrospray

Et ethyl

FAB fast atom bombardment

FMO frontier molecular orbital

Fmoc 9-fluorenylmethoxycarbonyl

FT Fourier transform

g gram

HMPA hexamethylphosphoramide

HOMO highest occupied molecular orbital

HPLC high-performance liquid chromatography

hr hours

Hz hertz

IR infrared

J coupling constant k kilo

KHMDS potassium hexamethyldisilazide

L litre(s) LAH lithium aluminium hydride

LDA lithium diisopropylamide

LHMDS lithium hexamethyldisilazide lit. literature

LUMO lowest unoccupied molecular orbital m multiplet (spectral), milli

M mols per litre mCPBA m-chloroperoxybenzoic acid

Me methyl

MHz megahertz min minutes

MNDO modified neglect of differential overlap mol mole(s) mp melting point MTPA a-methoxy-a-trifluoromethylphenylacet

MS mass spectrometry m/z mass to charge ratio

ND not determined

NMR nuclear magnetic resonance

NOESY nuclear Overhauser effect spectroscopy

NR no reaction

OTHP O-tetrahydropyranyl

Ph phenyl

Phe phenylalanine ppm parts per million

Pr propyl

Pri wopropyl

Pro proline

PFP Polyfunctionalized Prolines Vll

PTLC preparative thin layer chromatograph q quartet RT room temperature s singlet SUMO second LUMO or Second HOMO t triplet TBAF tetrabutylammoniumfluoride TBDMC1 te/t-butyldimethylsilylchloride TEBAC triethylbenzylammonium chloride TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy tert tertiary THF tetrahydrofuran TIPS-Tf triiso-propylsilyl triflate TLC thin layer chromatography TMS tetramethylsilane Tos p- toluenesulfony 1 Voc vinyloxycarbonyl

Z or Cbz benzyloxycarbonyl viii

ABSTRACT

This thesis describes three new approaches to the asymmetric synthesis of chiral proline derivatives from (R) and (.S>ferf-butyl-3-benzoyl-4-methylene-2-oxazolidin-5- one. In the first Chapter, some important aspects of proline derivatives, specially the strategies used for the synthesis of these compounds was presented. It was found that for the preparation of proline derivatives in high enantiomeric purity, starting materials with a chiral auxiliary have generally been employed.

In Chapter Two, the Michael addition reactions of the pyrrolidine enamines (223-

225) to (.S>2-te/t-butyl-3-benzoyl-4-methylene-oxazolidin-5-one (222) and its enantiomer, (R)- (222), to give Michael addition adducts of the type (226) was examined. The Michael addition reactions of the pyrrolidine enamines (223) and (225) to the chiral oxazolidinones (S)-(222) or (R)-(222) favours cis 2,4-disubstituted oxazolidinone adducts while trans 2,4-disubstituted oxazolidinone adducts were favoured from the addition reactions of enamine (224). The diastereomeric adducts from the addition of (223) to (222) were readily separated and were converted to (5R,

2S) and (55, 2#>cw-5-w<>propylproline, efficiently in good overall yields and in high enantiomeric purities. The extension of this protocol to the synthesis of (2S, 3aS, 7aS)- perhydroindole carboxylic acid (3) suffered from poor overall stereochemical control and a mixture of two diastereoisomeric products reasulted.

In Chapter Three, the synthesis of polyfunctionalized proline derivatives via the asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides derived from N- alkylidene or AAarylidene imino esters (201), with the chiral oxazolidinone (222) as a dipolarophile, have been presented. The cycloadducts were obtained with a high degree of regio- and diastereoselectivity that resulted from addition of the dipole to the exo- cyclic methylene group of the oxazolidinone (222) from the less hindered side of the oxazolidinone ring. Good endo-diastereoselectivity and high yields were obtained from the reactions of the dipolarophile (222) and ethyl JV-benzylidene glycinate (201g) in the IX presence of AgOAc and DBU in CH3CN. While the cycloaddition reactions of (222) and the a-substituted imines (201b-g) proceeded with high gjcodiastereoselectiviy using LiBr / DBU in THF as solvent.

In Chapter Four, the synthesis of polyfunctionalized proline derivatives via the asymmetric Michael addition reactions of lithium enolates derived from N-alkylidene or arylidene imino esters (201), (212a,b) and (218a, c-e) with (S) or (R) -oxazolidinone

(222) as a Michael acceptor have been presented. High levels of diastereoselectivity and good yields were obtained from the reactions of the Michael acceptor (7?)-(222) with the bulky imines (212a) and (218a) in the presence of LiBr / DBU / THF or with the camphor imine (361) using ButOLi / THF. The stereochemical outcome of these reactions could be rationalized by invoking a ' endo' like transition state. The Michael reactions of the imino alanine derivative (212b) gave a mixture of two Michael adducts.

The Michael adducts were converted to optically active lactams upon acid hydrolysis.

The stereochemistry of the products in each Chapter has been determined by a combination of single crystal X-ray structural analysis, ID and 2D NMR spectroscopy and computer aided molecular modelling. X

TABLE OF CONTENTS pages

Declaration l

Publications u

Acknowledgements m

Abbreviations 1V

Abstract viii

Table of contents x

Chapter One : Introduction : The Synthesis of Substituted Prolines 1

1.1 Introduction 2

1.2 Substituted Proline Derivatives -2

1.3 Synthesis of Monocyclic Substituted Prolines 4

1.4 Synthesis of Bicyclic Substituted Prolines 36

1.5 Synthesis of Polyfunctional Prolines (PFP) 45

1.6 Aims of The Research 50

Chapter Two : Asymmetric Synthesis of Prolines Derivatives via Michael

Addition Reactions of Enamines to Chiral Oxazolidinones 53

2-1 Introduction 54

2.2 Asymmetric Michael Addition Reactions 54

2.3 Michael Addition Reactions of Enamines to Electron Deficient Alkenes 56

2.4 Michael Addition Reactions of Oxazolidinones (S) and (R)-(222) with

Pyrrolidine Enamines. 66

2.5 Mechanistic Details of the Michael Addition Reaction of Enamines. 89

2.6 Asymmetric Synthesis of the Enantiomers of 5-Cis-/so-propylproline 94

2.7 Synthesis of (25, 3a5,7a5)-Perhydroindole-2-carboxylic acid (3) 107

2.8 Conclusion 112 xi

Chapter Three : Synthesis of Polyfunctionalized Prolines via Asymmetric 1,3-

Dipolar Cycloaddition Reactions 113

3.1 Introduction 114

3.2 Synthesis of Polyfunctionalized Prolines via Asymmetric 1,3-Dipolar

Cycloaddition Reactions 114

3.3 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides (348)

with Oxazolidinone (222). 126

3.4 Mechanistic Details of the 1,3-Dipolar Cycloaddition Reaction of Azomethine

Ylides 144

3.5 Synthesis of Polyfunctionalised Prolines

148

3.6 Conclusion 149

Chapter Four : Asymmetric Michael Addition Reactions of oc-Imino Esters

to Chiral Oxazolidinones 150

4.1 Introduction 151

4.2 Asymmetric Michael Addition Reactions of oc-Imino Esters 151

4.3 Double Asymmetric Induction in Michael Addition Reactions of Imines 155

4.4 Asymmetric Michael Addition Reactions of Imines of a-Amino Esters to

Chiral Oxazolidinone (222) 157

4.5 Michael Addition Verses Cycloaddition in Reactions of Bulky Imines with

Electron Deficient Alkenes. 195

4.6 Determination of the Optical Purity of the Michael Adducts. 799

4.7 Conclusion 201

Chapter Five : Experimental 202

5.1 General Procedures 203

5.2 Experimental Chapter Two 207

5.3 Experimental Chapter Three 223

5.4 Experimental Chapter Four 231

3 0009 03201114 5 1

CHAPTER ONE

INTRODUCTION : THE SYNTHESIS OF SUBSTITUTED PROLINES Chapter One 2

1-1 Introduction

The asymmetric synthesis of conformationally constrained a-amino acid analogues has gained considerable interest in recent years.la ~c This seems mainly due to the notion

that the introduction of conformational constraints into peptides may provide useful

information on their bioactive conformations and may result in beneficial physiological

effects such as optimisation of peptide-receptor binding and resistance to peptidases.2

Non-proteinogenic a-amino acids attract ever increasing interest as drugs or components

of many therapeutic agents.3a~d The specific activity is generally related to one enantiomer

of a particular a-amino acid. Since the usual methods of enzymic synthesis are often

inapplicable to the preparation of optically pure uncommon a-amino acids, enantioselective

chemical methods are required to solve the problem. This is the underlying reason for the

recent progress in the field of the asymmetric synthesis of uncommon a-amino acids.4

1.2 Substituted Proline Derivatives

Among all the known a-amino acids, L-proline possesses a unique position in

relation to its biological function in naturally occurring proteins and peptides.5 Theoretical

and experimental studies on peptides have shown that, in general, the peptide group is

more stable in the trans rather than in the cis conformation. However, peptides formed

from L-proline can exist in either a cis or a trans conformation about the amide bond

(Figure 7.7).6ac

C02H \ C02H Q

R (cw-amide) (trans-amide)

Figure 1.1. Cis and trans conformations of prolyl amides.

Studies of many globular proteins have revealed that cis peptide bonds are almost completely absent, and only in a sequence of Pro residues is the cis conformation Chapter One 3

occasionally observed.7 Because only proline amides have this conformational flexibility,

the cis-trans isomerisation of Pro residues is considered to be responsible for many

important biochemical roles, including controlling the rate of protein folding, triggering

receptor-mediated transmembrane signalling, providing a recognition element in peptide

antigens, and regulating both the activation and breakdown of peptide hormones.8a>b

Substituted prolines are rare naturally occurring amino acids. They are constituent

amino acids in antibiotics,9 and recently they have gained importance in the development of

novel angiotensin converting enzyme (ACE) inhibitors,10a"c such as perindopril (1),

which has (25, 3a5 , 7a5)-octahydroindole-2-carboxylic acid (3) as the C-terminal

portion. Substituted prolines have also attracted much attention as chiral ligands for

asymmetric synthesis.lla"c For example, the optically active pAamino alcohol (2), derived

from the bicyclic proline analogue (\R, 3R, 5#)-2-azabicyclo[3.3.0]octane-3-carboxylic

acid (4), catalyses the enantioselective addition of diethylzinc to various aldehydes.llb

OH

C02Et (D (2)

H H ''/COOH N H I H

(25,3a5, 7a5)-(3) (1R, 3R, 5R)-(4)

The non-proteinogenic proline derivatives, (5) and (6), have recently been detected in the novel cyclic peptide, scytonemine A, a metabolite of the cultured cyanophyte Scytonema sp., which possesses potent calcium antagonistic properties.12 Chapter One 4

HO ,xCH3 j.CH3

s ^r/^C0 H ^rr co2H 2 I H H (5) (6)

1.3 Synthesis of Monocyclic Substituted Prolines

1.3.1 Synthesis of 2-Substituted Prolines

1.3.1.1 2-Methylproline

A synthesis of 2-methyl-DL-proline, that exemplifies the general route to proline analogues via the Favorskii rearrangement of 3-chloro-2-piperidones, is shown in Scheme l.l.13 3-Methyl-2-piperidone (8) was obtained by reduction of ethyl 4-cyano-2- methylbutyrate (7) over Raney nickel in ethanol. When compound (8) was treated with phosphorus pentachloride and sulfuryl chloride then 3-chloro-3-methyl-2-piperidone (9) was produced, that was converted to 2-methylproline (10) via a Favorskii type rearrangement upon treatment with barium hydroxide.

Ni-H2(80 atm) CN COOEt O H (7) (8)

S02C12

Ba(OH);

Scheme 1.1

A general method for the asymmetric synthesis of a-branched amino acids, and the synthesis of (5)-2-methyl-proline (10a) in particular, starting from (5j-proline (11) was reported by Seebach and co-workers.14 This method involved the condensation of (5)- Chapter One 5 proline with pivaldehyde to give the oxazolidinone (12). (Scheme 1.2).

Deprotonation of (12) with LDA and then quenching of the resulting carbanion with Mel gave the methylated oxazolidinone product (13) as a single diastereoisomer. Methylation had occurred syn to the bulkyte/t-butyl grou p and from the less hindered convex-face of the l-aza-3-oxa-bicyclo[3.3.0]octane ring system in (12). Acid catalysed hydrolysis of the oxazolidine ring of (13) gave (S>2-methylproline (10a).

B^CHO, CF3COOH

C02H pentane, reflux, 144 hr

(ID (12)

1. LDA 2. Mel

A>-CH3 1. 3NHC1 .reflux, 1 hr C -*- + 2. Dowex 50W x 8(H ) H Y—O

(10a) (13)

Scheme 1.2

1.3.2 Synthesis of 3-Substituted Prolines:

The literature reports several different procedures15 for effecting conversion of the

Michael adducts (15), that can be prepared from the reaction of the a,p-unsaturated

aldehydes (14) and diethyl acetamidomalonate, to a mixture of cis and trans 3-substituted

prolines. For example, a mixture of cis and trans 3-phenylproline (17a) and 3- propylproline (17b) were prepared by first treatment of diethyl acetamidomalonate with the a,pAunsaturated aldehydes (14a) or (14b) in the presence of the sodium ethoxide to give the Michael adducts (15a) or (15b) respectively.16 Acid-catalyzed silane reduction Chapter One 6 of (15a) or (15b) provided the pyrrolidine diesters (16a) or (16b) respectively.

Saponification and then decarboxylation of (16a) or (16b) gave a 4:1 mixture of the cis and trans proline derivatives (17a) or (17b) in 89% and 80% yields respectively, as shown in Scheme 1.3.16

0 C02Et R

H C02Et / NaOEt C02Et H HO N C02Et O' R I Ac (14a); R = Ph (15a); R = Ph (14a); R = n-propyl (15b); R = n-propyl

Et3SiH TFA

R 1. NaOH y C02Et + ^C02H 2.H "C02Et 1 3. A 1 H Ac (17a); R = Ph (16a); R = Ph (17b); R = n-propyl (16b); R = n-propyl

Scheme 1.3

Moss et a/.17a~b recently described a new approach to the synthesis of five

membered ring cyclic amino acids that relied on the intramolecular 1,3-dipolar

cycloaddition of the co-azidoketene-5,5-acetal (18), followed by regioselective alkylation

of the resulting cycloadduct (Scheme 1.4). Hydrolysis of the alkylated cyclic 2-

aminoketene-5,5-acetal products (19) gave trans 3-substituted prolines as racemic

mixtures. Chapter One

1) heat S\^ LDA 2)R-X

(18) R'X

R' R' R' / 0 ^ MeO~ MeOH j ^ BF3.Et20 OMe - v x 1 >r K2C03 1 R R R S\^

NaOH, H20 CF3COOH X = S(CH2)3SH (19) R = COBu*

R

C02H

Scheme 1.4

1.3.2.1 3-Methylproline

3-Methylprohne is a highly potent inhibitor of actinomycin production when added to the culture medium of Streptomyces antibiotiicus. Inhibition of actinomycin was accompanied by acceleration of protein and cell synthesis. The cis isomer had more inhibitor activity than the trans isomer.13 Racemic 3-methylproline was first synthesised by Adams and Leonard18 from 4- methylpyridine (Scheme 1.5). 4-Methylpyridine (20) was catalytically reduced to 4- methylpiperidine (21), that was converted to l-m-nitrobenzoyl-4-methylpiperidine (22) by a Schotten-Baumann reaction with m-nitrobenzoyl chloride. Oxidation of compound (22) with potassium permanganate gave P-methyl-8-m-nitrobenzoylamino-valeric acid (23), by oxidative cleavage of a ring carbon-nitrogen bond. Bromination of this acid with Chapter One 8 phosphorus and bromine resulted in the a-bromo acid (24). Cyclisation of (24) with alkali and then subsequent hydrolysis with hydrochloric acid gave the carboxylic acid hydrochloride (25). Neutralisation of (25) with base gave the free amino acid (26).

CH3 CH3 CH3 CH3 m-nitrobenzoyl Ni chloride KMn04

H2 NaOH COOH NT NH R I R (21) (22) (23)

P/Br2

CH3 CH3 ,CH3 CH3 OH" . f OH" A C02H ^C02H \A C02H H H2cr R

(26) (25) (24) (R - m-nitrobenzoyl)

Scheme 1.5

An alternative synthesis of racemic 3-methylproline (26) from 3-chloro-4-methyl-

2-piperidone, is shown in Scheme 1.6.19 In this synthesis catalytic reduction of (27) over Raney nickel in EtOH gave 4-methyl-2-piperidone (28) that upon reaction with phosphorus pentachloride and sulfuryl chloride gave 3,3-dichloro-4-methyl-2-piperidone

(29). Catalytic reduction of (29) over Raney nickel in MeOH yielded 3-chloro-4-methyl-

2-piperidone (30). Compound (30) underwent a Favorskii rearrangement when heated in a solution of KOH and EtOH for 16 hr to give 3-methylproline (26), after passing the crude product mixture through an amberlite IRC-50 ion-exchange column. Chapter One 9

CH CH3 CH3 3

Ni-H2 100 °C, 120 atm CN COOEt H (27) (28)

Et3N

KOH -EtOH 130 °C

Scheme 1.6

Mauger20 described a synthetic route for the preparation of the racemic

diastereoisomers of cis and trans 3-methylproline in good yield. The known, crystalline

pyrrolidone (31), that was available in one step from Michael condensation of diethyl

acetamidomalonate with ethyl crotonate, was the starting point of this synthesis (Scheme

1.7). Partial saponification of (31), followed by decarboxylation, afforded a mixture of

the cis and trans isomers of ethyl 3-methylpyroglutamate (32a) and (32b) in good yield.

Separation of (32a) and (32b) followed by reduction of the individual diastereoisomers

(32a) and (32b) with lithium aluminium hydride and then in situ tosylation afforded the

corresponding AA(p-toluenesulfonyl)-3-methylprolinols (33a) and (33b) respectively.

Oxidation of these alcohols, using chromic acid, gave the two diastereoisomers of AA(p-

toluenesulfonyl)-3-methylproline, (34a) and (34b) respectively. Chapter One 10

/CH3 JCH3

/ \X02C2H5 /N /X 0^>T ^C02C2H5 0 N C02C2H5 of ^N^*C02C2H5 H H H (311 (32a) (32b)

CH3 *CH3

CH2OH CH2OH

Tos (33b) "J *CH3

C02H "N" ^C02H

'TOS TOS (34a) (34b)

Scheme 1.7

a) EtOH, 1 N NaOH, 16 hr, 24 °C; b) LAH, THF, reflux, 18 hr; c) Na2C03, TsCl, 1 hr; d) Cr03,

acetone.

1.3.2.2 3-CarboxyproIine

3-Carboxyproline is an amino acid which combines the properties of two other amino acids in one structure. Thus this compound can be thought of either as a conformationally constrained aspartic acid derivative, or as a proline analogue with modified acidity due to the incorporation of the 3-carboxyl group. A synthesis of racemic cis and trans 3-carboxyproline and an asymmetric synthesis of (25, 35)-3-carboxyproline was reported by Cotton et al.21 The asymmetric synthesis is outlined at Scheme 1.8.

Alkylation of the dianion of the protected aspartic acid (35) with 2 equivalents of LHMDS followed by allylbromide gave the diester (36) as a 3:1 mixture of diastereoisomers. Chapter One 11

Ozonolysis of (36) afforded (37) that upon catalytic hydrogenation gave the te/t-butyl ester (38). Exposure of (38) to acid gave frans-3-carboxyproline (39a).

,C02Me 1. 2xLHMDS V^N^C°2Me 2. allylbromide

l 1 ZHN^ C02Bu ZHN CO^u

(35) (36)

3:1 ratio of diastereoisomers

1. 03/MeOH 2. Me2S

C02H C02H C02H

H30" H2/Pd/C

l l C02H C02Bu MeO C02Bu I H (39a) (38) (37)

Scheme 1.8

Sasaki et al.22 described a new synthetic methodology for the asymmetric synthesis of (25, 3#)-/V-Boc-pyrrolidine-2,3-dicarboxylic acid (47) and its (25, 35) enantiomer ent-(47) as depicted in Scheme 1.9. The chiral synthon (R)-(40) was converted to the pyrrolidine sulfone (41) by treatment with 2 molar equivalents of n-butyllithium and then l-bromo-2-chloroethane at -78 °C. The target molecules were prepared from the key intermediate (41), and its enantiomer at C-2, by ethoxycarbonylation, desulfonylation and finally by standard functional group manipulations, as shown in Scheme 1.9. Chapter One 12

~S02Ph S02Ph

Boc(H)> s—OTHP H OTHP OTHP

(JCM40) (42)

C02Et

OTHP

I Boc (43)

0 C02H ^.C0 Et 2 NC02Et

OH + C0 H 2 C02H CO- Boc Boc Boc

(46) (45) (44)

C02H ^S02Ph

Boc(H)I

a) 2 equiv. n-BuLi, THF, 1.2 equiv. Br-(CH2)2CI, -78 °C to rt; b) 1.5 equiv. n-BuLi. THF, 3 eq HMPA, 1.2 eq Cl-C02Et, -78 °C to RT; c) 5 equiv. 6% Na-Hg, EtOH, -10 °C, 5 hr; d)

EtOH, 0.1 equiv. pyridinium p-toluenesulfonate, 60 °C, 3 hr; e) Jones oxidation, acetone, 0

°C, 1 hr; 0 IN NaOH, MeOH, rt, 1 hr.

Scheme 1.9

A diastereoselective and enantioselective synthesis of the four stereoisomers of 3- carboxyproline has been described by Humphrey et al.2^ as outlined in Scheme 1.10. Chapter One 13

PhFI 1. K2C03, C02CH3 I BrPhFI BnNVs^C02CH3

2.Pb(N03)2 C02CH3 k C02CH3 (48) (49)

1. KHMDS2. CH2CHCH2I

PhFI PhFI I I BnN ^C0 CH BnN ^C0 CH v 2 3 Vs 2 3 + <^\y\ *C02CH3 C02CH3 (50a) (50b) KHMDS. 10 : 1 1. 03, Me2S 1. 0 , Me S LHMDS. 1 : 23 3 2 2. H2 / Pd-C 2. H2 / Pd-C 3. H20, HC1 3. H20, HC1 4. Ion-exchange 4. Ion-exchange

X0 H >C02H 2

C02H C02H

(39b) (39a)

Scheme 1.10

This method is similar to the synthesis reported by Cotton and coworkers.21 The key step was a Rapoport type aspartate alkylation of the derivative (49) that gave a good yield of either diastereoisomer (50a) or (50b) depending upon the nature of the cation used.

Deprotonation of (49) with potassium hexamethyldisilazide (KHMDS) in THF followed by quenching with allyl iodide gave (50a) as the major component of a 10:1 mixture of the diastereoisomers (50a) and (50b). Interestingly, switching from KHMDS to LHMDS resulted in a reversal in diastereoselectivity and gave a 23:1 mixture of (50b) and (50a).

Ozonolysis and then removal of the N-protecting group of (50a) or (50b), followed by Chapter One 14

intramolecular reductive amination, under hydrogenation conditions at 53 psi using 10%

palladium on carbon, gave the cyclized proline diester derivatives. Acid hydrolysis and

then anion exchange chromatography afforded (39a) or (39b) respectively in ca. 25%

overall yields.

1.3.2.3 3-Hydroxyproline

Cis-(2S,3R) and *ra/w-(25,35)-3-hydroxy-proline occur naturally as components of

the antibiotic peptide telomycin, the trans isomer is also present in collagen and obtained

from the Mediterranean sponge.24 A preparation of (25, 3/?)-cw-3-hydroxyproline (53a)

has been reported by Cooper et ai25 that involved the baker's yeast reduction of 3-oxo-

proline (51) to the alcohol (52), that was obtained as a single diastereoisomer (Scheme

1.11). Removal of the N-Boc group of (52) followed by base hydrolysis and then ion-

exchange chromatography gave (+)-(25,3/?)-c/.y-3-hydroxy-proline (53a) in >90%

enantiomeric purity.

baker's yeast TFA C0 H 2 C02H CH2Q2 C02H

Scheme 1.11

Golebiowski et al.26 reported a new methodology for the highly stereoselective synthesis of (2R, 35)-c/s-3-hydroxyproline ent-(53a), a structural unit present in biological compounds, such as slaframine, castanospermine, and detoxinine. In this method, allyltrimethylsilane was reacted with N-carbobenzyloxy-O-te/t-butyldimethylsilyl-

L-serinal (54) to give the syn adduct (55), that was converted to cis-(2R,3S)-3- hydroxyproline ent-(53a) via the chemistry shown in Scheme 1.12. The proline ring Chapter One 15

of ent-(53a) was prepared by reduction cyclization of the aldehyde (56) that was

obtained from (55) via oxidative cleavage of the terminal alkene group.

OH OTIPS CHO TBSO TBSO OHC OTBS NHCbz HN NHCbz I Cbz (54) (55) (56)

e,f

^OH OTIPS JOTIPS h,i

>J*C02H C02H I I Cbz H Cbz

ent-(53a) (58) (57)

a) Allyltrimethylsilane, SnCL,, CH2CI2, -78 °C; b) TIPS-Tf, 2,6-lutidine, CH2CI2, 0 °C; c) Os04,

NMO, Me2CO-H20, rt; d) Silica gel, CH2CI2, rt; e) NaBH3CN, AcOH-MeOH, rt; f) AcOH-MeOH,

reflux, 1 hr; g) NaOCl, TEMPO, KBr, NaHC03, Et20-H20, 0 °C, then Me2C0, NaI04, RuCl(cat.), RT,

h) H2SiF6, MeCN-H20, 55 °C, 50 min; i) H2, Pd/C, MeOH,

Scheme 1.12

(25,35)-rran5,-3-hydroxyproline (53b) was found in naturally occurring peptides such as Mucrorine-D, Telomycine and in bovine achilles tendon collagen. Castanodiol,26

(L-fran.s-3-hydroxyprolinol (65)) the reduced form of (53b), was also isolated from

Castanospermum australe. Herdeis et al.21 presented a route to (53b) starting from the

enantiomerically pure bicyclic amide (59), that was readily prepared from 5-pyroglutamic

acid. The 3-hydroxy group of (53b) was introduced via a stereospecific and regiospecific

reductive ring opening of the epoxide (60) to give alcohol (61a). This compound was

converted to the target compounds (53b) and (65) via a series of protection, deprotection,

reduction and oxidation steps as shown in Scheme 1.13. Chapter One 16

b,c

(59) (61a); R = H (61b); R = TBDMS

..NOTBDMS .v^ OR vOR S\ « r-& e V C02H NT^CH^H ^JT CH2OH | Boc Bn (63a); R = H (62a); R = H (63b); R = TBDMS (62b); R = TBDMS h4 f

1 OH

C02H CH2OH

a) BukX)H, n-Bu4NF, K2CO3, DMF; b) Al/Hg, EtOH/acetone 2:1; c) TBDMC1, imidazole, DMF; d)

BH3.S(CH3)2, THF, 70 °C; e) Pd/C-H2, B0C2O, MeOH; f) 5M HC1; g) RUCI3, NaI04,

CH3CN/H2O; h) 6M HC1; i) Dowex 50Wx2, NH4OH.

Scheme 1.13

Hughes et al.2^ developed the enantiospeciflc synthesis of fran.y-3-hydroxyproline

(53b) starting with pure trans glycidic ester (68), that was prepared from allylic alcohol

(67) via a Sharpless asymmetric epoxidation reaction, as shown in Scheme 1.14. The glycidic epoxy ester (68) was saponified and then the epoxide ring was opened with aqueous ammonia to give the potassium salt of the {3-hydroxy-a-amino acid (69). The Chapter One 17

final product was formed by acid hydrolysis of the dimethoxy acetal group and then in situ

hydrogenation of the cyclic imine (70) over Pt02- Neutralising the reaction mixture and

desalting with ion exchange resins gave the free L-fran.y-3-hydroxyproline (53b) in 87%

yield.

Q. OCH CH302C 3 OCH3 a, b, c HO' OCH3 OCH3 (67) trans-(6S)

d, e

vOH OCH3

+ K " 02 C02H OCH I N C02H 3 H NH2 (53b) (70) (69)

a) ButOOH, Ti(OPri)4, L-(+)-diethyl tartarate; b) RUO4; c) CH2N2; d) K2CO3, CH3OH, H2O; e)

NH3, H2O; f) EtOH, H2O, CF3CO2H, Pt02, H2

Scheme 1.14

1.3.3 Synthesis of 4-Substituted Prolines

Rapoport et al.29 reported an efficient synthetic protocol for 4-substituted prolines based on diastereoselective transformations of glutamic acid. The glutamic acid derivative

(73) was first alkylated and then selective reduction of the y-ester functionality of the products (74) and (75) was achieved by the proper choice of ester protecting groups.

Finally ring closure to the prolines (76) and (77) completed the synthesis as shown in

Scheme 1.15. To introduce a phenyl group at the y-carbon of glutamic acid, and hence the 4-position of proline, benzene chromium tricarbonyl complex was used as the electrophilic arylation reagent in step c. Chapter One 18

t 1 H2N^ C02H PhFlHN^ C02R PhFlHN^ /C02Bu PhFlHN^ /CO^u

C02CH3 C02CH3 (72) R = H (75 a-d) , (73) R = Bu1

PhFlHN^ CO^u1 PhFlHN^ CO^u1

+ ..<* R

CH2OH CH2OH

R R

l C02Bu N 'C02Bu I PhFI PhFI I R

(a); R = CH3 (b); R = CH2CH3 N CO- (c); R = CH2CH2CH3 N tx (d); R = C6H5 H2 H2 (76) (77)

a) PhFI, CHCI3, NEt3, TMSC1, pH=2; b) O-tert-butyl-Af, N'-diisopropylisourea, CH2CI2; c)

KMHDS, RI or Cr(CO)3C6H6; d) DIBAL, THF, -40 °C, 2 hr; e) LAH, THF, -20 °C, 4 hr; f)

Triphenylphosphine, CBr4, PriEtN, THF; g) TFA, CH2CI2 or HOAc, MeOH.

Scheme 1.15

Recently Moody and Young30 reported a general and stereospecific synthesis of

(25, 45)-4-alkylproline derivatives from 4-alkylidinepyroglutamates (78) as described in

Scheme 1.16 . Hydrogenation of (78) gave the corresponding ds-alkyl derivatives

(79) that were converted to the 4-alkylproline derivatives (77) by reduction with borane- Chapter One 19 dimethylsulfide followed by deprotection. Access to the (25, 4/?)-epimer of (79a) [(81)] was gained by conjugate addition of organocuprates to the compound (78a), that gave the thermodynamically more stable trans product (81), via protonation of the intermediate lactam enolate anion from the more hindered face of the lactam ring.

H2, Pd-C

EtOAc

(78) (79) (a); R = H E=COOBut (b); R = CH3 BH3-SMe2 THF (c); R = CH2CH3 (d); R = Ph

R H//.,i_ 6NHC1 Ak H2CF I H (77a-d) E (80)

H H- \ Me2CuLi ». + O' C 2But l l ° Et20 - 78°C C02Bu o C02Bu Boc Boc Boc

(78a) (81) (79a)

Scheme 1.16 Chapter One 20

1.3.3.1 4-Methylproline

7>a«.s-4-methyl-L-proline was found in young apple fruits, while cis-4- methylproline was isolated from the hydrolysate of antibiotic I.C.I. 13,959, which occurred in a strain of Paecilomyces}1^ 4-Methyl-L-proline of unknown configuration at C-4 was found in the hydrolysate of an actinomycin complex from Streptomyces antibioticus, after racemic 4-methylproline had been administered to the culture medium.32 It was found to be a less potent inhibitor than 3-methylproline. Racemic 4-methylproline (85) and the amino acid (86) were obtained from acid hydrolysis of the crude condensate of sodio diethyl acetamidomalonate (83) and 1-chloro- 3-iodoisobutane (82) as shown in Scheme 1.17.33 The amino acids (85) and (86) could be readily separated due to their different solubilities in hot ethanol.

H3 Na CH3\ u ^C CH2I + ^N- C Et CH2C1 Ac °2 cr H C02H Ac (82) (83) (84) H+

H3C

C0 H I 2 H

(86) (85)

Scheme 1.17

Racemic 4-methylproline hydrochloride (85) was prepared by Michael condensation of diethyl acetamidomalonate (87) with methacrolein (88) to give the cyclic product (89), followed by hydrolysis and reduction by tin in boiling hydrochloric acid as outlined in Scheme /./#.34 Chapter One 21

CH3 H^ ,C02Et CH3 + ^CH, Ac C°2Et CHO

(87) (88)

Sn-HCl

CH3

C02H

Scheme 1.18

Cw-4-methyl-D-proline (85a) and fran.s-4-methyl-L-proline (85b) have been

prepared from (+)-5-acetoxy-4-methylpentanoic acid (90) of known absolute configuration

as outlined in Scheme 7.7P.35 Partial separation of the final product into the cis and

trans isomeric products [(85a) and (85b)] was achieved through fractionation of their

copper salts. Pure fran.y-4-methyl-L-proline (85b) could be obtained in this manner by

destruction of the D-cw-diastereoisomer (85a), by treatment of a mixture of (85a) and

(85b) with D-amino acid oxidase. Repeated recrystallization of the acid (94) gave a single

diastereoisomer. Acid hydrolysis of (94) to (95) and then cyclization with base gave pure

cw-4-methyl-L-proline (85a) with inversion of the stereochemistry at C-2. Chapter One 22

CH3 H CH3 H CH3 H HBr MeOH COOH COOH C02Me H2S04 OAc Br Br (90) (91) (92)

NK

CH3 H H Br H CH3H H30 P/Br2

C02H C02Me

NH3C1" NPhth NPhth (95) (94) (93)

OH

CH3 CH3. CHH separation

"'// C02H C0 H + N ^C02H 2 I H H H (85) (85a) (85b)

Scheme 1.19

1.3.3.2 4-MethyleneproIine

Proline dehydrogenase is an enzyme involved in the energetic processes required for flight in insects.36 4-Methyleneproline (100) is a natural product which has been isolated from the seeds of loquat (Eriobotyra japonica). Optically pure (5)-(100) is a potential enzyme inhibitor,36 particularly of the enzyme proline dehydrogenase. It has also been found to be useful as a structural element of peptides and drugs such as tomamycin analogues.37 Chapter One 23

Proline analogues such as 4-methylene-L-proline (100) and (ZO-and (Z)-4-

(fluoromethylene)-L-proline (101) were designed for the inhibition of the proline

dehydrogenase enzyme.38 The proline derivatives (100) and (101) were prepared from 4-

hydroxy-L-proline (96) through the sequence shown in Scheme 1.20.

HO,

C02H H (96)

C0 CH I 2 3 Boc (97)

CH2

C02CH3 + C02CH3 C02CH3 Boc (E)-(99) (Z)-(99)

CH2

C02H ^C02H N ^C02H H (100) (E)-(lOl) (Z)-(101) a) Methyl triphenylphosphonium bromide, KOBu1, ether; b) Huoromethyltriphenylphosphonium tetrafluoroborate, -78 °C; c) 2N NaOH, H2O, 0.1N HC1; d) TFA, CH2CI2.

Scheme 1.20

The Wittig reaction of ketone (97) with the ylide derived from methyltriphenylphosphonium bromide gave the methylene compound (98) in a yield of Chapter One 24

66%. Base hydrolysis of the methyl ester of (98) and removal of the AAprotecting group

with acid gave 4-methylene-L-proline (100). Using a similar procedure, the Wittig

reaction of (97) with the ylide derived from (fluoromethyl)triphenylphosphonium

tetrafluoroborate and butyllithium at -78 °C gave both geometric isomers (E)-(99) and

(Z)-(99) in a ratio of 4:5 respectively, in a total yield of 50%. These compounds were

then converted to (E)-(101) and (Z>(101) respectively, by removal of the ester and

Boc-protecting groups with acid.39

Recently Adington and Mantell40 reported the synthesis of (5)-4-methyleneproline

(100) from (5)-serine using a free radical cyclization to form the proline ring. N-

alkylation of the protected serine derivatives (102) with propargyl bromide provided

(103) that upon treatment with triphenylphosphorous dibromide gave the bromide

compound (104). A solution of (104) in benzene was heated under reflux in the presence

of tributylstannane and AIBN for 8 hr to give the proline derivative (105) as a single

diastereoisomer. Deprotection of (105) was achieved smoothly with buffered sodium

amalgam to give (5)-4-methyleneproline (100) as oudined in Scheme 1.21 H H2r PhSO- a,b, c \vv' w» OH OTHP PhS02 \^ H H H OTHP C02H C02Bn C02Bn

(102) (103)

PhS02 r .\< Br H C02H C0 Bn I 2 C02Bn H S02Ph

(105) (104)(100) a) PhS02Cl, Na2C03; b) BnBr, NaHC03; c) Dihydropyran, Pyridinium toluene-4-sulfonate; d) Propargyl bromide, CS2CO3; e) Triphenylphosphorous dibromide; f) AIBN, tri-n-butyltin hydride; g) K2HPO4,6% sodium amalgam

Scheme 1.21 Chapter One 25

More recently Panday et al.41 described a short synthesis of benzyl (5)-4- methyleneproline (111) starting from inexpensive (5j-pyroglutamic acid through a sequence of Mannich and Cope elimination reactions as shown in Scheme 1.22. In this synthesis the lithium enolate obtained from benzyl AAterf-butoxycarbonyl pyroglutamate

(106) and LHMDS, was alkylated in good yield at -78 °C with Eschenmoser's salt to give the 4-dimethylaminomethyl derivative (107). The pyrrolidone carbonyl group of the

Mannich product (107) was then reduced with DIBAL-H to the intermediate cc-hydroxy- carbamate (108). Compound (108) was then directly treated with an excess of sodium cyanoborohydride in acetic acid to afford compound (109) without deprotection of the pyrrolidine nitrogen. N-oxidation of (109) with m-CPBA (1.1 molar equiv, 98%) and subsequent heating of (110) at 85 °C in THF / toluene followed by deprotection gave the methylene compound (111).

\ \ .N .N

C02Bn O C02Bn HO C02Bn Boc Boc Boc

(106) (107) (108)

C02Bn C0 Bn I 2 H Boc

(HD (110) (109)

+ a) LHMDS, THF, CH2=NMe2 T; b) DIBAL-H; c) NaBH3CN, CH3CO2H d) m-CPBA, CH2C12; e) A, CF3CO2H CH2C12.

Scheme 1.22 Chapter One 26

1.3.3.3 4-(l-Hydroxy-l-methyl)ethylproline

Agami et al.42 explored a method for the asymmetric synthesis of (R, i?)-4-(l- hydroxy-l-methyl)ethylproline (116) as outlined in Scheme 1.23. The ene-iminium intermediate, that resulted from the condensation of amino alcohol (112) and glyoxal in formic acid solution, underwent an aza-Cope rearrangement and gave the bicyclic hemiacetal (113). Swern oxidation of (113) gave lactone (114) as a single diastereoisomer, that was treated with vinylchloroformate to give the N-vinyloxycarbonyl compound (115). Acid hydrolysis and then ion-exchange chromatography resulted in the desired (K)-proline derivative (116).

OHC-CHO, HC0 H,1.5hr 2 Ph* 76% OCHO

(112) (113)

1. (COCl)2,DMSO 53%

2. Et3N /°^0

OCHO

(114)

CH2=CH-OCOCl 66% reflux, 72 hr

1. 6N HC1, reflux, 3 hr 2. IRA- 68

C02H OCH2CHClPh 96%

(116) (115)

Scheme 1.23 Chapter One 27

1.3.3.4 4-CycIohexyIproline

7>a«s-4-cyclohexyl-L-proline (126) is an intermediate in the synthesis of

Fosenopril an ACE inhibitor. Thottathil et al.43 described a stereocontrolled route to (126) that is outlined in Scheme 1.24 and starts from inexpensive and readily available L- pyroglutamic acid (117).

1. ROH/H PhCHO ,wH -O^V>> - O C02H N "CH2OH T, N 2. NaBH4 H H O Plf u (117) (118) (119)

Br LDA

(120)

H2/Pd-C LAH

THF

CH2OH CH2OH

(123) (122)

Z-Cl / K2C03 H20-THF

Jones Oxidation H2/Pd-C

Scheme 1.24

In this synthesis use was made of the oxazolidine ring in (119), as a bidentate protecting group and as a control element, for the introduction of further stereochemical centres. The oxazolidinone (119) was obtained as a single diastereoisomer from L-pyroglutamic acid Chapter One 28 by first reduction and then condensation of the resulting amido-alcohol (118) with benzaldehyde. Reaction of the lithium enolate of (119) with 3-bromocyclohexene (120) gave (121), that was converted to (122) using LAH. Compound (122) on hydrogenation / hydrogenolysis produced the amino alcohol (123) in 65% yield.

Treatment of (123) with benzyloxycarbonyl chloride (Z-Cl) in the presence of K2CO3 gave (124). Jones oxidation of (124) followed by catalytic hydrogenolysis gave the desired compound (126) in 70-80% overall yield.

1.3.4 Synthesis of 5-Substituted Prolines

1.3.4.1 5-PhenyIproIine

In the synthesis by Gershon and Scala,44 the sodium salt of diethyl

acetylamidomalonate (83) and 3-bromo-l-phenylpropanone (127) were condensed under

the influence of an excess of sodium ethoxide. l-Phenyl-2-propen-l-one (128) was a

probable intermediate in this reaction. The condensation product (129) was converted to

the iminium salt (130) upon treatment with concentrated hydrochloric acid. Catalytic

hydrogenation of (130) gave 5-phenylproline (131) as a mixture of diastereoisomers (Scheme 1.25). 0 H

+ ( CRlBx Na C"(C02Et)2NHCOCH3 + Vh^~ ^~ M H (83) (127)

H NCOCH3 C02H- C02H^ C02Et HCI Et02(

(131) (130) (129)

a) NaOEt / EtOH; b) Cone. HCI; c) Catalytic hydrogenation

Scheme 1.25 Chapter One 29

An alternative synthesis of 5-phenylproline has been described by Kolk et al.45, that

is illustrated in the Scheme 1.26. The ketopiperidine (132), that was prepared from 5-

keto-5-phenyl-pentanoic acid by reductive amination, was chlorinated with phosphorus

pentachloride to give the trichloropiperidine (133). On hydrolysis with water this

compound was immediately converted to dichloro-2-ketopiperidine (134), that upon

further hydrolysis in boiling hydrochloric acid furnished the hydrochloride of 5-amino-2,2-

dichloro-5-phenyl-pentanoic acid (135). Cyclization and reduction of (135) gave a

racemic mixture of the two diastereoisomers of 5-phenylproline (131).

H Ph" A U (132H ) (133) (134)

Cl Cl H C02H Ph C02H Ph I NH2. HC1 H (131) (135)

a) PC15, Xylene, b) H2O; c) HC1, heat; d) Na/Hg

Scheme 1.26

1.3.4.2 5-Methylproline

5-Methylproline inhibited actinomycine production in streptomyces antibioticus less than either 3-methyl or 4-methylproline.13 Racemic 5-methylproline was first synthesised46 by ammonolyis of methyl a, y-dibromocaproate as outlined in Scheme

1.27. A^-dimethylproline was prepared using methylamine instead of ammonia Chapter One 30

H H3C- A NH3 H CHC02Me CH3' CONH2-^— CH3' C02H Br Br MeOH H H

(136) (137) (138)

Scheme 1.27

Racemic 5-methylproline (138) has also been synthesised47 from the catalytic hydrogenation and then acid catalysed decarboxylation of diethyl 2-methyl-A1-pyrrohdine-

5,5-dicarboxylate (142) as shown below in Scheme 1.28.

Ac A \/C02Et N C02Et A ^C02Et Ac J OHN C02Et NH I I Cbz Cbz (139) (140) (141)

H2-Pd

00 HC1 ^"k ^ XV CH3 / CO.Ei " CH3^% C02Et C02H- CH3 >f H H

(138) (143) (142)

Scheme 1.28

A synthetic route for the syntheses of cis- and frans-5-methylprolines has been reported by Overberger et al. 48 as shown in Scheme 1.29. In this method, catalytic hydrogenation of the hydrochloride of racemic A'-2-methylpyrroline-5-carboxylic acid

(147a, R = Me), that was prepared by cyclization of ethyl 2-acetamido-2-carboethoxy-5- Chapter One 31

oxohexanoate (145, R = Me) with hydrochloric acid, gave predominantly cis-5-

methylproline hydrochloride (148).

0 C02Et Na/C2H50H R 0 C0 Et + CH3^ N-C(C0 Et) 2 "> 2 O NH R HI H (144a); R = Me (87) (145)7= ° (144b); R = Et (144c); R = Pr' 6NHC1

H HnnJ V^H IR-45 H/'/^y , Vi,i\ H H2 S R'XJk R^^>T " C02H" N C02H H2cr Pt02 H 1 HCL (138a); R = Me (147); R = Me (146) (150); R = Et (148); R = Et (151); R = Pr1 (149); R = Pr1

(note: although only one diastereoisomer is shown all compounds are racemic.)

Scheme 1.29

A mixture of cis- and fran.s-5-methylproline was obtained from the sodium borohydride reduction of A'-2-methylpyrroline-5-carboxylic acid (146, R = Me). Trans-5- methylproline (138b) was separated from this mixture by reaction with p-toluenesulfonyl chloride in water-acetone solution for 24 hr (Scheme 1.30). Cw-(147a) reacted smoothly to give the sulfonamide (152) that was isolated by extraction into ethyl acetate.

7ran.y-(147b) did not react with /?-toluenesulfonyl chloride but gave the corresponding p- toluenesulfonate salt. The aqueous solution of the p-toluenesulfonate salt of trans (147b) was passed over a weakly basic ion-exchange resin to give pure trans (138b) (Scheme 1.30). Chapter One 32

«*H l.NaBH H/.„ %.+ 4 C0 H Me Me 2 C02H I 2.HC1 HC1" (146)

TosCl

H/^V \^H X / Me^ N ^C02H I H (138a)

Scheme 1.30

1.3.4.3 5-Ethylproline

Synthetic routes for the preparation of racemic fran^-5-ethylproline (150) were developed by Overberger et alA9a'b starting from ethyl vinyl ketone (144b) and N- acetamidomalonate diethyl ester (87), as shown above in Scheme 1.29.

1.3.4.4 Cis- and trans-5-iso-propylproline (5IPP)

Overberger et a/.50 also developed synthetic routes for the synthesis of the 5- isopropyl derivatives of proline (151) starting from iso-propyl vinyl ketone (144c), that was prepared in situ from l-chloro-4-methyl-3-pentanone, and diethyl acetamidomalonate

(87) as shown above in Scheme 1.29. Furthermore, (+) and (-) c/j-5-iso- Chapter One 33

propylproline ent-(151) and (151) respectively, were prepared by resolution with tartaric

acid as shown in Scheme 1.31.

H H 1 Pr C02H H rac-(151)

(+)-dibenzoyl-D-tartaric acid (-)-dibenzoyl-D-tartaric acid monohydrate (DBTA) monohydrate (DBTA)

(+)-salt CIPP:DBTA (-)-salt CIPP:DBTA

1. 3N HC1 2. IR -45 1. 3N HC1 2. IR -45

uC02H H. H Pr1

(151)

D(+)[a]D + 64.7 ° L(-)[a]D -65.3 ° in MeOH in MeOH yield = 69% yield = 77%

Scheme 1.31

1.3.5 Asymmetric Synthesis of 5-Substituted Prolines

Teresa et al. 51 have developed a versatile and convenient route for the asymmetric synthesis of cw-5-alkylprolineamides from the inexpensive and readily available L or D- glutamic acids as outlined in Scheme 1.32. Chapter One 34

H2CO 2H 0. HNZ-CH-C02H 0C1 * ? ° Vo Benzene 9 V0 CH2CH2C02H TsOH, Benzene \ 7 \ »- PC15 N N (153) Z Z (154) (155)

1. RCH=N2 2. HI

(a); R = H (b); R = Me RCH2OC (c); R = Pr (d); R = Ph

K2C03 / MeOH

RCH2

(161a-d) (159a-d) H ,Pd/C 2 H2,Pd/C

RCH2 C02H

(138a); R = H (160a-d) (150); R = Me (162); R = Pr (132); R = Ph

Scheme 1.32

A^-(Benzyloxycarbonyl)-L-glutamic acid (N-Z-L-Glu-OH) (153) was protected by reaction with formaldehyde to give the oxazolidinone (154). Compound (154) was converted to its acid chloride (155) with PCI5 that upon treatment with an excess of Chapter One 35

diazoalkane (RCH=N2) and HI gave the oxazolidinone ketones (156a-d). Ammonolysis

of the oxazolidinones (156a-d) in THF generated the corresponding keto-amides (157a-

d) that upon reduction gave the cyclized products (159a-d). Compounds (159a-d)

were converted to the desired (25,5/?)-cw-5-alkyl- or 5-aryl-prolineamides (160a-d) by

catalytic hydrogenation. The diastereoselectivity of the catalytic reduction was dependent

on the catalyst used, as shown in Table 1.1.

Table 1.1. Hydrogenation of compounds (159a-d) to (160a-d).

product R cis /trans ratio of (160a-d)

(160a) H 95:5a 95; 15b, 85:15^, 70:30d

a (160b) CH3 75:25 , 80:20^

(160c) 11-C3H7 90:10a,90:10b

(160d) Ph 90:10b

ent-(160a) H 92:8b

a: Pd(black) was used as catalyst. b:10% Pd/C was used as catalyst c: 10% Pd/C in EtOH/HOAc with cyclohexene as H2 source, d: Adams catalyst

Oxazolidinones (156a-d) upon saponification with potassium carbonate in methanol generated the keto-acids (158a-d), that upon catalytic hydrogenation gave only the desired

(25, 55j-c/.y-5-alkyl- or 5-aryl-proline derivatives (138a), (150), (162) and (143) as shown in Scheme 1.32. Chapter One 36

1.3.5.1 Terr-butyl (25, 5S)-cis-5-butyIproline

Ibrahim and Lubell52 reported a novel method for the asymmetric synthesis of (25,

55)-cw-5-butylproline terr-butyl ester (166) as shown in Scheme 1.33. Thus acylation

of the glutamate derivative (164) with valeryl chloride and subsequent decarboxylation

with LiOH in a THF / H2O / MeOH solution provided the S-keto a-amino nonanoate

(165) in 58% overall yield. Hydrogenation of (165) over palladium-on-carbon in the

presence of acetic acid resulted in cleavage of the phenylfluorenyl group, intramolecular

imine formation, protonation and addition of hydrogen from the less hindered face of the

iminium intermediate to selectively furnish (25, 55j-cw-5-butylproline terr-butyl ester

(166) in greater than 99% ee.

Bu 1. LiN(SiMe3)2, n-BuCOCl "" >- CO^u1 2.L10H, 58% NHPhFI (165)

H2,Pd/C 85% MeOH / HO Ac

n-Bu' CO^u1 N H (166)

Scheme 1.33 1.4 Synthesis ofBicyclic Proline Derivatives

In contrast to the large number of methods that have been reported for the synthesis of monocyclic proline derivatives there are only a few literature methods for the stereoselective synthesis of bicyclic proline derivatives. Much attention has been focused on the synthesis of the compounds (25, 3a5, 7a5)-perhydroindole-2-carboxylic acid Chapter One 37

54 (3)53a-e ana- (i£ i>S, 55)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (4) which are precursors to the highly potent angiotensin converting enzyme (ACE) inhibitors such as perindopril (1) and ramipril (167). Many antihypertensive drugs acting via inhibition of

ACE, have been designed from the peptide model:

-(5) Phe (5) ala (5) pro-OH

Many of these compounds contain a phenylethyl moiety at their A^-terminal end and most of them contain a proline moiety at their C-terminal end.

Me C02H Me C02H

perindopril-(l) Ramipril- (167)

Perindopril, an antihypertensive drug, was designed from the viper's venom peptide, with norvaline used in place of phenylalanine and the more lipophilic perhydroindole carboxylic acid (3) used in place of proline. Perindopril is a very potent and long acting ACE inhibitor. It was marketed in France in 1989 with success and has been the subject of numerous pharmacological and clinical studies.55

1.4.1 Synthesis of (2S, 3aS, 7aS; PerhydroindoIe-2-carboxylic acid (3)

Initial work on these compounds was first described by Blankley56 whom first reported the synthesis of racemic (3) by the method outlined in Scheme 1.34. Catalytic reduction of ethyl indole-2-carboxylate (168) over rhodium on carbon gave the racemic perhydroindole-2-carboxylic acid (3) as a single diastereoisomer. Chapter One 38

a, b H C02Et

Ccv •• - C°2H N H H H (168) rac-(2SR, 3aSR, 7aSR)-(3)

(a) H2, Rh / C, HO Ac. (b) Aqu. HC1

Scheme 1.34

More recently the eight stereoisomers of (3) were prepared and isolated as their

hydrochloride salts. The products could be divided into two groups depending on their cis

or trans ring junction at the C3a-C7a bond. In this work, which was reported by Vincent

and colleagues,57 each diastereoisomer was prepared using the stereospecific strategy

described below.

1.4.1.1 Synthesis of the cis-fused isomers of (3)

The method used for the preparation of c/5-fused isomers of (3) is shown in

Scheme 1.35 and follows a method described by Corey et a/.58 Ethyl indole-2-

carboxylate (168) was reduced to racemic ethyl indoline-2-carboxylic acid by Sn / HC1.

After saponification of the ester group, the racemic indoline-2-carboxylic acid (2SR)-(169)

was resolved into its enantiomers [(5)-(169) and (R)-(169)]. The ee for each

enantiomer was greater than 99%. The catalytic reduction of indoline-2-carboxylic acid to

perhydroindole-2-carboxylic acid was highly stereoselective with the carboxylic group

controlling the approach of hydrogen. Thus, in the reduction of (5)-(169), hydrogen was

delivered to the rc-face opposite that of carboxylic group leading to 90% (25, 3a5, 7a5)-

(3) and only 10% (2S, 3aR, 7aR )-(3) . Similarly, reduction of (R)-(169) lead to 90%

(2R, 3aR, 7aR >(3) and 10% (2R, 3aR, 7aR >(3). Chapter One 39

C0 Et DS"^ ^ rry-2 C02H

H 2)H20/OH"

(168) (2RS)-(169)

Resolution

C02H 'C02H

(S)-(169) (RH169)

Pd/C Pd/C

H N^^COOH H H H H

(2S, 3aS, 7aS)-(3) (2S, 3aR, 7aR)-(3) (2R, 3aR, 7aR)-(3) (2R, 3aS, 7aS)-(3)

Scheme 1.35

1.4.1.2 Synthesis of the trans -fused isomers of (3).

The synthesis of the trans fused isomers of (3) by Henning et a/.59 was based on a

Favorskii rearrangement of the chlorinated lactam (170) containing a trans ring junction.

The procedure furnished a mixture of two racemates [(2S, 3aR, 7aS)-(3) and (2R, 3aS,

7aR)-(3)] and [(2R, 3aR, 7aS)-(3) and (2S, 3aS, 7aR)-(3)] which were separated by crystallisation and resolution of their benzyl esters (171) as outlined in Scheme 1.36. Chapter One 40

* N COOH H rac-(3)

(2S, 3aR, 7aS)-(3) (2R, 3aR, 7aS)-(3) racemic- racemic. (2R, 3aS, 7aR)-(3) (2S, 3aS, 7aR)-(3)

S02C12 S02C12 BzOH BzOH

2S 3aR racemic < > > 7aS)-(l7l) racemic (2R, 3aR, 7aS)-(l7l) I (2R, 3aS, 7aR)-(171) (2S, 3aS, 7aR)-(l7l)

resolution resolution

C0 R H H H H H H 2 H H

(2S, 3aR, 7aS)-(3) (2R, 3aS, 7aR)-(3) (2R, 3aR, 7aS)-(3) (2R, 3aS, 7aR)-(3) (2S, 3aR, 7aS)-(171)(2R, 3aS, 7aR)-(17l) (2R, 3aR, 7aS)-(17l) (2R, 3aS, 7aR)-(171)

(3); R =H (171); R =Bz

Scheme 1.36

1.4.2 (75, 3S, 5S>2-Azabicyclo[3.3.0]octane-3-carboxylic acid (4).

Urbach et al.60 reported an enantioselective synthesis of (75,55,55j-(4) and (IS,

3S, 5R)-(4) by an intramolecular radical cyclization of an optically active olefmic a-amino acid derivative, with the correct configuration at C3 of the bicyclic system. Thus treatment of 3-bromocyclopentene (172) with L-serine methyl ester (173) gave a diastereomeric mixture of L-serine derivatives (174), which were acylated with benzyl Chapter One 41

H N 2 CH3CN OH K C0 2 3 C0 H a C02CH3 2 (172) Br (173) (174)

ClC02Bn

Bu3SnH C0 H PPh3 r 2 C02H C02H AIBN C0 Bn 2 C02Bn

(177) (175)

i H benzyl (Pr O)4Ti alcohol H

C02Bn ft\ C02Bn C02Bn

(IR, 3S, 5R)-(17S) (75, 35, 55>(178)

H2 Pd/C H2 Pd/C

H

+ C02H C02H H H (IR, 3S, 5R)-(4) (75, 35, 5S)-(4)

Scheme 1.37 chloroformate to give (175) in 90% yield. Treatment of compound (175) with iodine, triphenylphosphine and imidazole in benzene gave the iodo compound (176). A mixture of the two cis fused diastereoisomers, (IR, 3S, 5R)-(177) and (75, 3S, 55>(177), was obtained by radical cyclization of (176) with tri-n-butyltin hydride in benzene in the Chapter One 42 presence of AIBN. Esterification of this mixture with benzyl alcohol and titanium tetra-wo- propoxide gave benzyl esters (1R,3S,5R)-(178) and (IS, 3S, 5S>(178) which could be separated by column chromatography on silica gel. Hydrogenation of (IR, 3S, 5R)-(178) or (75, 3S, 55J-(178) over 10% palladium on carbon in ethanol gave proline derivatives

(IR, 3S, 5R)-(4) or (75, 3S, 5S)-(4) respectively as shown in Scheme 1.37.

A report from Henning61 described a new method for the synthesis ofthe bicyclic, racemic proline analogues (183) and (184) starting from the cyclopentanone (181), the condensation product of the morpholine enamine (180) and ethyl 3-bromo- hydroxyiminopropanoate (179) as outlined in Scheme 1.38. Reductive cyclization of

(181) over Raney Nickel in ethanol gave the amino ester (182) as a mixture of two diastereoisomers in a ratio of 1.5 : 1 and in 84% yield. The ratio of the two diastereoisomers was determined by converting (182) to the acetamides (183) and (184) by treatment with acetyl chloride in CH2CI2.

Na C0 B C02Et 2 3 + 40°C, 5 hr (I N0H NOH O

(179) (180) (181)

Raney nickel EtOH,50°C

H2 9hr

H H

^ H ' ^C0 Et Ct>™ N 2 C02Et H k O Y (184) 0 (182) (183) Scheme 1.38 Chapter One 43

Henning et al.62 reported an alternative method for the synthesis of the racemic,

bicyclic proline analogues (3) and (4) as outlined in Scheme 1.39. Reaction of

cyclopentene (185) or cyclohexene (186) with acetonitrile and mercuric nitrate followed

by ligand exchange with sodium chloride gave the organomercury compounds (187) or

(188), respectively. Treatment of (187) or (188) with a-chloro acrylonitrile gave the

nitriles (189) and (190) respectively. Base promoted cyclization of (189) or (190)

gave a separable 4 : 1 mixture of two bicyclic derivatives (191) and (192) or a 18 : 1

mixture of (193) and (194) respectively. Finally, the major diastereoisomer (191) or

(193) was hydrolysed to the bicyclic proline derivatives (3) or (4) respectively in 85 or

74% yield respectively, by refluxing with 5N HC1.

^^^NHCOCHs NHCOCH3 (CH,)n j ^ (CH2)n ^"'"HgCl CH2CHC1-CN

(185); n = 1 (187); n = 1 (189); n = 1 (186); n = 2 (188); n = 2 (190); n = 2

(CH2)n C02H- (CH2)n + (CH 'CN

(3); n = 1 (191); n = 1 (192); n = 1 (4); n = 2 (193); n = 2 (194); n = 2

a) CH3CN, HgN03, NaCl; b) EtOH, 4 equiv. oc-chloro-acrylonitrile, -15 °C, 1 equiv. NaOH, CH2CI2; c)

1.6 equiv. NaH, DMF, 0 °C; d) 5N HC1.

Scheme 1.39

A novel and efficient asymmetric synthetic route to proline derivatives (3) and (4) has been reported by Harwood et al.63 using enantiomerically pure 5-phenylmorpholine-2- Chapter One 44

one (195) as a chiral template. In this methodology, aldehydes possessing unsaturation at

C5 or C6, such as 5-hexenal (196) and 6-heptenal (197), were condensed with the chiral template (195) to generate the chiral stabilised azomethine ylides (198a) and (198b) respectively. These ylides underwent intramolecular [3+2] dipolar cycloaddition to form adducts (199) and (200), respectively. By removal of the chiral template (195), the compounds (199) and (200) were individually converted to the bicyclic proline derivatives (3) or (4) respectively by hydrogenolysis using palladium hydroxide on carbon, as shown in Scheme 1.40.

H tl

(5S)-(195) CHO vW "A (196) A, benzene A, toluene (5S)-(195)

Ph««J

(198a); X=CH2 (198b); X=(CH2)2

(200)

H2,Pd(OH)2/C MeOH/TFA

/> ks^-N C02H H H (IR, 3S, 5R)-(4) (2S,3aR,7aR)-(3)

Scheme 1.40 Chapter One 45

1.5 Synthesis of Polyfunctional Prolines (PFP)

A common and general method for the preparation of polyfunctional prolines is based on the 1,3-dipolar cycloaddition of azomethine ylides of a-amino esters with

alkenes.64 Azomethine ylides are 1,3-dipoles that undergo regio- and stereoselective

cycloadditions to alkene and alkyne dipolarophiles to give pyrrolidines, pyrrolines or

polyfunctional prolines.

1.5.1 Synthesis of (PFP) using 1,3-Dipolar Cycloaddition Reactions

The 1,3-dipolar cycloaddition reaction is one of the most efficient reactions for the

synthesis of polyfunctionalized heterocyclic rings containing a nitrogen atom. Kuffmann65

was the first to pioneer the use of 2-aza-allyl anions as a [4TC] component in [4n +2n]

anionic cycloadditions. A considerable amount of work has been developed by Grigg et

al 66a-e Grigg and co-workers have reported that the reaction of azomethine ylides with

several dipolarophiles gave a wide range of novel polyfunctionalized pyrrolidines or

prolines, via endo type transition states, as shown in Scheme 1.41. The azomethine

ylides were prepared from oc-imino esters by thermal 1,2-prototropy67 or by deprotonation

in the presence of a metal salt and a base.68a~c H R^ ^N+ .EWG Y R H R*,../N\,*EWG R\^N^ .EWG 0 M Y R ^ MX, Et3N, 25 ° C R^N+ EWG \= W l Ri Ri

Ti H k/'', / \ ,v^J 'Ri RT Y

M=Ag(I),Mg(II),Mn(II),Co(II)

EWG-CO2R, CN, P(0)(Et)2, 2-pyridyl, 2-thiazoyl; Y= CO2R

Scheme 1.41 Chapter One 46

For example, a-(arylideneamino)esters (201a, b) react with dimethyl maleate (202) in toluene at 110 °C for 24-48 hr to give about a 3:1 mixture of the endo (203a,b) and exo- cycloadducts (204a,b) respectively.660

Ph C02Me xv H Ri

Me02C C0 Me (202) 2 Ph-^N C0 R Me02C. .C02Me (203a) 2 2 (203b) toluene, 110 °C Ri

(201a); Ri = CH2Ph, R2 = Me Ph C02Me (201b); Rx = Me, R2 = Me Hv> l \^v> Me02C C02Me

(204a) (204b)

Scheme 1. 42

Tsuge 69a-b has also used this chemistry for the synthesis of novel polyfunctional prolines. For example, methyl iV-benzylidineglycinate (201c) reacted via its azomethine ylide (205) with methyl acrylate in the presence of lithium bromide and NEt3 to produce the endo cycloadduct (207a) as a single diastereoisomer in 82% yield. In contrast, the thermal cycloaddition gave a mixture of more than three diastereoisomers of the cycloadducts (207) in low yield as shown in Scheme 1.43. Thermal tautomerisation of imine (205) was thought to generate the iV-protonated azomethine ylide (206) which was captured by methyl acrylate. Chapter One 47

0 NEfr Ph Xyl e + N. .CQ2Me , !!.P\ j£ OMe LiBr 135 °C, OMe H 48 hr H H (205) (201c) (206)

CH2=CHCOOMe CH2=CHCOOMe

H H H Ph C02Me Plu .N NC02Me Ph .NL C02Me

C0 Me 2 C02Me xr

(207a) (207b) C02Me (207c) Scheme 1.43

In continuation of this work, Tsuge et a/.70a-b found that in contrast to AAprotonated azomethine ylides, which generate exclusively syn-endo cycloadducts, the N-substituent azomethine ylides derived from iminium salts (208a-b) underwent cycloaddition with alkene dipolarophiles, such as methyl acrylate, to give predominantly anti-endo cycloadducts (209a-b) as shown in Scheme 1.44.

R O v\VC0 2R' R CH2=CHCOOMe Ph. + OR' reflux C0 Me HV 2

(208a); R = Me , R*=Et (209a); R = Me , R'=Et (208b); R = Ph , R'=Me (209b); R = Ph , R'=Me

Scheme 1.44 Chapter One 48

1.5.2 Synthesis of (PFP) via Asymmetric 1,3-Dipolar Cycloadditions

A related approach for the asymmetric synthesis of chiral prolines involves the use

of either chiral nonracemic dipolarophiles7 la"f or dipoles^'f" as stereocontrol elements or

by utilising a chiral metal complex as catalyst,73a'b These methods will be reviewed in more

detail in Chapter Three of this thesis.

1.5.3 Synthesis of Polyfunctional Prolines from Michael Adducts of cc-Imino

Esters.

Grigg et alJ4 reported that the Michael adduct (209) of a-imino esters (201a)

and methyl acrylate can be converted into a mixture of two diastereoisomeric cycloadducts

(210) and (211) upon treatment with a stoichiometric amount of potassium ferf-butoxide

in benzene at room temperature as shown in Scheme 1.45. This cyclization is an

example of a geometrically disfavoured 5-endo-trig cyclization.7^

H

;"Me C02Me Me02C, \= KOBu* (201a) benzene base Me C02Me H (209)

*"'C02Me Me

(211)

Scheme 1.45

A different approach to polyfunctional substituted proline derivatives using the

Michael products of sterically bulky ^-substituted a-imino esters and a,P-unsaturated carbonyl compounds has been reported.76a"d If the starting a-imino esters are derived from Chapter One 49

a sterically bulky carbonyl compound such as pivaldehyde, benzophenone or camphor,

then the Michael adducts rather than 1,3-dipolar cycloaddition products are obtained.

Kanemasa et alP"1 reported the stereoselective Michael addition reactions of the a-

imino ester (212a) as shown in Scheme 1.46. Lithiation of methyl 2-[(2,2-

dimethylpropylideneaminoj-propanoate (212a) was readily achieved with lithium bromide

/ DBU in THF at room temperature. The resulting enolate (213) was diastereoselectively

trapped with methyl crotonate (214) to give (215) as a single diastereoisomer. Treatment

of (215) with acetic acid in aqueous methanol at room temperature caused smooth

hydrolysis of the imine moiety to produce the corresponding cyclized product (216) in

high yield. Compound (216) could be converted to methyl 4,5-dimethyl prolinate by

catalytic hydrogenation.

Bii\ ^N. /C02Me LiBr/DBU Y* ^^ — BuDu1 \ ^-1N\ s*y\ H THF J^ ^^ OMe H (212a) (213)

(214) ^COMe Me

Me • Me MeOH But\^NL^A^^COMe

C02Me HOAc I I H C02Me

(216) (215)

Scheme 1.46

Recently Kellogg et al?% described an approach to form racemic 3,5-dialkyl proline derivatives (221). Michael addition of the Schiff base (218a), derived from the reaction of glycine alkyl ester with benzophenone imine, to a,P-unsaturated ketones (217) followed by hydrogenation of the products (219) gave 3,5-disubstituted prolines as outlined in Scheme 1.47. Chapter One 50

Ri Ph O C0 Alk + N 2 Ph r C02Et

R2 (217a); Rx = CH3, R2= H (218a) (219a-c) (217b); Rt = CH2CH3, R2= H (217c); Rx = CH3, R2= CH3

b, c

R2

R C02Alk C02Alk I H (221a-c) (220a-b)

a) 10 mol% CS2CO3, DBU; b) IN HC1 / Ether; c) Et3N / CH2CI2; d) Pd on C / H2 / ROH

Scheme 1.47

Wada et al?9 extended this methodology by using a-imino esters of camphor to achieved the asymmetric Michael addition of these a-imino esters to a,£ unsaturated esters. The details of this and related work will be discussed in Chapter Four of this thesis.

1.6 Aims of the Research

From the above overview it is clear that there are several methods for the synthesis of mono-substituted and polyfunctionalized proline derivatives. These routes have many advantages and disadvantages. Many of them gave a mixture of diastereoisomeric products which were also racemic in nature and had to resolved using either chemical or enzymatic methods. While some target molecules could be synthesised in enantiomerically pure form, a general asymmetric route to functionalized prolines has not been developed. The aim of this research project was to develop an asymmetric synthesis of functionalized prolines from (25)-3-terr-butyl-4-methylene-2-phenyloxazolidin-5-one (222) and its enantiomer Chapter One 51

(R)-(222). In particular, three methods for preparing functionalized prolines were to be developed. The first method to be examined was the asymmetric synthesis of proline derivatives from the Michael addition products of pyrrolidine enamines with compound

(222). Because of their biological interest, two molecules that were targeted for synthesis were (+) and (-)-c/5-5-wo-propylproline (151) and (25, 3a5, 7a5j perhydroindoie-2- carboxylic acid (3). The second method to be developed was the asymmetric synthesis of proline derivatives from the 1,3-dipolar cycloaddition reactions of azomethine ylides derived from A/-alkylidene or arylidene a-amino acid esters with compound (222). The third method to be developed for the asymmetric synthesis of polyfunctional substituted proline derivatives was via the Michael addition reactions of the chiral oxazolidinone (222) with imines of a-amino esters (Scheme 1.48). The diastereoselectivity and enantioselectivity of the products from these proposed reactions were to be studied using various analytical and spectroscopic methods, including one dimension and two dimension

^H-NMR spectroscopy, circular dichroism spectroscopy, single-crystal X-ray crystallography and computer based molecular modelling. Chapter One 52

Michael addition of' enamines H / R2 \ ~C02H Ri 4 H ~x

R2 Hd CH2 R! o O H'"..A / PhCON. O

R2> Bu1 H

Ri

H2C -/ Vr PhCONB,^/ H (S)-(222) EWG

C R R2 'R / °2 H EWG

Rr N O

PhCO O PhCON

Bu1 H

„ NHCOPh Ri •a, / Lu NHCOPh

..„«C02R

Et0 C^ H 2 1 R H Michael addition of imines Cycloaddition of azomethine ylides

Scheme 1.48 53

CHAPTER TWO

ASYMMETRIC SYNTHESIS OF PROLINE DERIVATIVES VIA MICHAEL ADDITION REACTIONS OF ENAMINES TO CHIRAL OXAZOLIDINONES Chapter Two 54

2-1. Introduction

As outlined in the Introduction (Chapter One), one of our aims was to develop an asymmetric synthesis of the biologically interesting compounds (+) and (-)-cis-5-iso- propylproline (151) and (25, 3a5, 7a5j perhydroindole-2-carboxylic acid (3) from the chiral oxazolidinone (5j-(222). In the first part of this study, the Michael addition reactions of the pyrrolidine enamines (223-225) to (2S)-2-tert butyl-3-benzoyl-4- methylene-oxazolidin-5-one (5j-(222) and its enantiomer, (R)-(222), to give adducts of type (226) was examined. In the second part of this study the hydrolysis of (226) to give the cyclised iminium ions (227) was addressed. Finally the reduction of (227) to give chiral prolines of the type (228) was investigated (Scheme 2.1).

,-R2 CH2 Vf R2 H 'RI^N^V * A '<

(225); R!,R2 = (CH2)3 H3O* |

R2 '• N* Reduction y^

Ri-^N^COOH Ri^l/^COOO H COOH

H H NH2

(228) (227)

Scheme 2.1

2.2. Asymmetric Michael Addition Reactions

The Michael addition reaction is a powerful and widely used method of synthesis.80"82 Although the reaction was discovered more than 100 years ago,83 the stereochemistry of this reaction has been investigated only recently.84 Stereoselective Chapter Two 55 carbon-carbon formation is an important goal as it expands the number of potentially synthetic routes to desired target molecules.

The use of the Michael addition reaction in a complex synthesis was nicely illustrated by Corey and Magriotis85 in their synthesis of 20-diisocyanoadociane (234).

The key step of this synthesis was a kinetically controlled Michael addition of the menthol ester (229) to methyl crotonate as outlined in Scheme 2.2. An 89 : 11 (syn I anti,

(230+231) /(232+233)) mixture of diastereoisomeric pairs was formed; the major syn diastereoisomer was obtained as an 80 : 20 (230 : 231) mixture. J3N "xyy :> (229) (234) LDA, THF, -78 °C MeO

OMe OMe

(230) (231)

OMe OMe

230 +231 = 89:11 232 + 233 230 = 80:20 231

Scheme 2.2 Chapter Two 56

2.3 Michael Addition Reactions of Enamines to Electron

Deficient Alkenes

2.3.1 Introduction

The term "enamine" was first introduced by Wittig and Blumenthal86 as the nitrogen analogue of the term "enol". -ffr -trm

(enamine) (enol)

Since the electron pair on the nitrogen atom can overlap with the % electrons of the double bond, enamines are capable of existing in two mesomeric forms, (I) and (II) (Figure

2.1). This type of mesoisomerism is much more important in enamines possessing a tertiary nitrogen atom than in those possessing a secondary nitrogen atom since the latter exist largely in the tautomeric imino form.

Enamines derived from pyrrolidine have been found to be most generally useful in

Michael addition reactions to activated alkenes.87'88 The rate of these Michael reactions has been found to be higher than that for the related morpholine-enamines or piperidine- enamines. This difference in reactivity between pyrrolidine-enamines and morpholine- enamines may be attributed to the basicity of the amino group. Because of the difference in the strength of the parent bases, pyrrolidine-enamines give a higher reaction rate than the more weakly basic morphline-enamines. The extent of overlap of the electron pair on the nitrogen atom and the n electrons of the double bond in these enamines can be measured by *H NMR analysis. It was found that the chemical shifts of the vinylic protons of the pyrrolidine enamines were at a higher field than those of the corresponding morpholine and piperidine enamines by 20-27 Hz. On the other hand, the greater amount of electron delocalisation, in the case of pyrrolidine enamine, would be expected since a double bond exo to a five membered ring is more favoured than the double bond exo to a six-membered ring.8^ Chapter Two 57

> ON H relative rate of reactivity of the related enamine

0 0

> > > H3C CH3

relative rate of reactivity of the related pyrrolidine-enamines

The effect of the ring size in the case of cyclic ketones such as cyclohexanone and cyclopentanone is also notable; thus the pyrrolidine-enamine of cyclopentanone reacted more rapidly than that of cyclohexanone and both of these reacted more rapidly than the pyrrolidine-enamines of acyclic ketones. The relative rates of reactivity are shown above.90

Electrophilic attack on enamines may occur either at the nitrogen atom of the enamine to give an enammonium cation (III) or at the pVcarbon atom of the enamine to give an iminium cation (IV) (Figure 2.1).

r>=C—N? - -rrf a) ai) E+

E + I + T ^=C— N— —C—C=N—

(in) (IV)

Figure 2.1 Chapter Two 58

Stork et al.91 reported that the alkylation of the pyrrolidine-enamine of cyclohexanone (224) with methyl iodide followed by acid hydrolysis led to the monoalkylated ketone (237). Thus the protonated alkylated enamine (236), that formed by prototropic rearrangment of the intermediate methylated iminium cation

(235), is unable to undergo any further alkylation, as shown in Scheme 2.3.

(224) (235) (236) (237)

Scheme 2.3

The pyrrolidine enamine of 2-methylcyclohexanone was shown to consist only of the tri-substituted isomer (238a) on the basis of NMR spectral data. The formation of the tetra-substituted isomer (238b) was excluded because of severe steric interactions

(Figure 2.2).91

An interesting and useful property of enamines of 2-substituted cyclohexanones is the fact that there is a substantial preference for the less substituted isomer to be formed.

This preference can be attributed to a steric effect, between the methylene group adjacent to the nitrogen atom and the 2-substituent. This steric interaction has been called A1'3 strain or allylic strain.92 In order to accommodate conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This results in steric repulsions when the enamine bears a (3-substituent

(Figure 2.2). Chapter Two 59

CH3 ' H3C

(238a) (238b)

(Figure 2.2)

Because of the same preference for coplanarity in the enamine system, an a-alkyl

substituent adopts a pseudo-axial conformation to minimize steric interactions with the

amino group (Figure 2.3j.93

H

R ^N-^V 1 H

Figure 2.3

2.3.2 Asymmetric Michael Addition Reactions Using Enamines

A useful application of enamines is their conjugate (Michael-type) addition to electrophilic alkenes. Many examples of the Michael-type addition of enamines to electron-deficient alkenes are found in the literature.94 The stereochemistry of the

Michael addition involving tertiary enamines was first investigated by Yamada95 who employed various proline esters (eg.(239)) as the Michael donor, and the best optical yields obtained were in the range of 40-60 %. More recently a better enantioselectivity

(86% ee) was observed by De Jeso et al.96 in the Michael addition of the organotin enamine (241) to methyl acrylate. Ito97 reported that the chiral enamine (243) reacted with methyl acrylate in the presence of magnesium chloride, to give the adduct ent-(242) with an excellent stereoselectivity (95 % ee) (Scheme 2.4). Chapter Two 60

C02Me 1. ^EWG

4 2. H30 EWG

(239) (240)

SnBuc 1. ^^COsMe

+ 2. H30 L J X02Me

(241) (242)

OTMS

^^C02Me ,\\H MgCl2

+ C02Me 2. H30

(243) e/i^-(242)

Scheme 2.4

In 1985, d'Angelo er a/.98 reported that addition of the enamine derived from the optically active imine (245) to methyl vinyl ketone gave the (#)-diketone (246) in 88% yield and in 91% ee. Methyl methacrylate polymerised in the presence of imine (245), however, a-(methylene)butyrolactone (247) gave the adduct (248) as a single diastereoisomer as shown in Scheme 2.5. The enantiomeric purity of (248) however, was not determined.98 Chapter Two 61

Me Ph PhA Me H-J.^ X

H NH2

(244) (245) (246)

Jb (245)

(247) (248)

Scheme 2.5

The reaction of the keto-enoate (249) with (#)-l-phenylethylamine (250) led to pyrrolidine (252), after reduction of the initial imine adduct with NaBH3CN to give the intermediate (251) and subsequent intramolecular /V-heterocyclisation. The cyclic product (252) was converted to the pyrrolidine (253) by a series of reduction steps.

Compound (252) was obtained as a 9:1 mixture ofthe trans and cis diastereoisomers respectively, however, both diastereoisomers of (253) were found to be racemic

(Scheme 2.6),94 Ph.A Me i. X (250) H NH O 2 NH C02Me {i NaBH3CN xNPh C02Me AM e (249) (251) I 1. LAH N ^Ph C02Me 2. H / Pd(OH) 2 2 A.Me (253) (252)

Scheme 2.6 Chapter Two 62

2.3.3 Asymmetric Synthesis of Amino Acids using (2S)- and (2R)-2-tert

Butyl-3-benzoyl-4-methylene-oxazoIidin-5-one and its Related

Imidazolidinone

In 1990 Beckwith et al."a described a method for the addition of alkyl radicals to

(5J-oxazolidinone (222) and imidazolidinone (254) with a high degree of diastereoselection (Scheme 2.7). For example, the addition of cyclohexyl radical to various AAprotected methylene oxazolidinones is outlined in Table 2.1. Additions to

AAbenzoyl and AAnaphthoyl oxazolidinones gave the cis diastereoisomer as the major product, (Table 2.1, entries 1 and 2) while all other N-protecting groups that were tried gave the trans diastereoisomer as the major product. These results showed that the diastereoselectivity was dependent upon the nature of the ring nitrogen protecting group of the oxazolidinone (222). The radical addition products were readily hydrolysed with

6N HC1 in sealed tubes at 220 °C for 4 hr to give a-amino acids with an ee between

75%-82%.99b y/ 0-Hgci

NaBH4' RT V Y Bu' H (255) (222) BuX 1= OH , Y= NCOPG (254) Y=NCH3, Y= NCOPG

Scheme 2.7 Chapter Two 63

Table 2.1. Addition of cyclohexyl radicals to various A7-protected methylene oxazolidinones (222)

Entry PG dr(%) yield

cis : trans 1 Phenyl 84: 16 89%

2 1-Naphthyl 84: 16 77%

3 CH2Ph 6:94 65%

4 Me 2:98 59%

5 OPh 2:98 49%

6 OMe 5:95 88%

7 OCH2Ph 2:98 60%

Crossley et a/.100 have reported a method for the synthesis of [3-substituted amino acids by demonstrating the conversion of (5 Aoxazolidinone (222) into the related leucine derivatives (257a) and (257b) with good diastereoselectivity (cis I trans = 84 :

16, 52% yield). The method involved the conjugate addition of nitropropane to chiral

(5j-oxazolidinone (222) followed by reductive removal of the nitro functionality as outlined in Scheme 2.8. The cis product (257a) was expected because protonation of the initially formed planar enolate intermediate was predicted to occur predominantly from the least hindered face of the oxazolidinonering, that is from the face anti to the bulky ter/-butyl group. Chapter Two 64

H ,0

02N- H O

PhOCN^ ^O — PhOCN^^O

Bu1 H Bu1 H \ H o

(222) (256) y-,H PhOCNN.0 Bu1 H

(257b) a) Nitropropane, TBAF, toluene; b) Bu3SnH, A.

Scheme 2.8

Chinchilla et a/.101 have reported the asymmetric synthesis ofthe two enantiomers of 2,3-methanovaline (259) by a cyclopropanation reaction of (5)-oxazolidinone (222).

They reported that the reaction of (222) with wo-propylidenetriphenylphosphorane at room temperature gave the corresponding cis and trans spirocyclopropane derivatives

(258) in a ratio of ca I : 1. These two diastereoisomers were separated and then treatment of the individual diastereoisomers with 2N HC1 at reflux gave enantiomerically pure (R) and (5J-2,3-methanovaline (259a,b) respectively as shown in Scheme 2.9. Chapter Two 65

c,d + PhOCN.^0 NH3 \ 1 Bu H C02" 0 (258a) (259a) a, b

H 3Q CH3 Bu1 H

(222) c,d H N^ ^y\ PhOCN.^0 - 3 "02C Bu1 H

(258b) (259b) a) Ph3P=CMe2, 30 min; b) H2O; c) 2N HC1, reflux, 90 min; d) Propylene oxide, EtOH, reflux, 30 min.

Scheme 2.9

In a very interesting study Seebach et al.102 have reported some diastereoselective transformations of (R)- or (5)-5-alkylidene-2-ferr-butyl-3-methyl-4-oxo-l- imidazolidinones (260) to unusual amino acids. They have used imidazolidinone (260) as a useful Michael acceptor in conjugate addition reactions with lithium dialkylcuprates for the preparation of the corresponding imidazolidinones (261). These reactions proceeded in greater than 95% diastereoisomeric excess (de) with addition to the alkylidene moiety having occurred with almost complete diastereoselectivity from the u- face of the alkene that is and to the tert-b\xiy\ group. Diastereoselective protonation of the intermediate enolate anion gave 2,5-cw-imidazolidinone products (261) (Scheme

2.10). R R2—J O / \ RACuLi .N. .N B°C' ^C 3 BF3OEt2in Et2° Bu1 H

(260) (261)

Scheme 2.10 Chapter Two 66

2.4 Michael Additions Reactions of Oxazolidinones (S) and (R)-(222) with Pyrrolidine Enamines.

One of the advantages of the Michael reaction of enamines is that they can be performed under mild conditions, in the absence of base or Lewis acid catalysts. Another advantage is that the starting materials are usually readily available, inexpensive or easy to synthesise. However all reactions of enamines should be conducted with rigorous exclusion of moisture because of their sensitivities to water.

2.4.1 Preparation of N-pyrrolidino-3-methyl-l-butene (223)

Because of the many advantages of pyrrolidine enamines we have used the readily available pyrrolidine enamine of cyclohexanone (224) and cyclopentanone (225) in our studies. We have also prepared the enamine (223), by a known method.103 Thus pyrrolidino-3-methyl-l-butene (223) was prepared by the condensation of 3-methyl-2- butanone (262) with pyrrolidine in diethyl ether in the presence of molecular sieves. *H

NMR studies of the product showed only the enamine (223), and none of its isomer

(263), had been formed. This can be attributed to an unfavourable steric interaction between the cw-methyl group and the a-methylene group of the pyrrolidinering in

(263). The *H NMR spectrum of (223) showed two one proton singlets at 3.37 and

3.50 ppm for the two methylene protons and two three proton doublets at 1.10 and 1.20 ppm for the two methyl groups of the isopropyl group. Chapter Two 67

molecular sieves ether, 24 hr, RT H (262) (223)

X

(263)

Scheme 2.11

2.4.2 Preparation of (2S)-and (2i?)-2-^rif-Butyl-3-benzoyI-4-methylene oxazolidin-5-one (222)

The (2S)- and (2/?>2-ferf-butyl-3-benzoyl-4-methylene-oxazolidin-5-one

(222)104 were synthesised according to the conditions described by Pyne et a/.105"107 as shown in Scheme 2.12. (25)-5-Methylcysteine (264) was treated with pivaldehyde and the resulting crude imino-acid was treated with benzoyl chloride to give a mixture of the cis and trans oxazolidin-5-ones (265a) and (265b). This mixture was then converted into a mixture of the corresponding sulfones (266a) and (266b) by oxidation with Oxone in acetonitrile in good yield. The sulfones (266a) and (266b) could be separated by column chromatography on silica gel. Treatment of diastereomerically pure

(266a) or (266b) with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) smoothly yielded

(5j-(222) or (R)-(222) respectively (Scheme 2.12). Chapter Two 68

SMe

i) Bu'CHO + OH «) PhCOCl PhCO PhCON^.0

1 Bu1 H H Bu (264) (2S, 4S)-(265a) (2R, 4S)-(265b)

Oxone

S02Me S02Me H .0 H O

PhCON^/0 PhCON^.0

Bu' H H Bu' (25, 4S)-(266a) (2R, 4S)-(266b)

DBU

H 2CA P HzQv P

PhCON^/0 PhCOR. ,0

Bu' H H Bu1

(S)-(222) (RH222)

Scheme 2.12

In this study the above synthesis was modified to improve the overall yields and to prevent epimerization at C-2 in the sulfones (266) during their separation by column chromatography. Thus the two sulfides (265a) and (265b) were first separated by crystallisation and then each individual sulfide was then oxidised to its corresponding sulfone (266). Treatment of the diastereomerically pure sulfones with DBU then gave the corresponding alkenes (R)- or (5)-(222) respectively in yields of 60% from their respective sulfides. Chapter Two 69

2.4.3. Michael Addition Reactions of Oxazolidinones (5)-(222) and (R)-

(222) with 2-Af-pyrrolidino-3-methyI-l-butene (223)

The oxazolidinone (S>(222) or (R)-(222) was treated with the enamine (223) at various reaction temperatures until TLC analysis indicated complete consumption of

(222). Mild hydrolysis of the reaction mixture with 10% aqueous acetic acid gave a mixture of the cis and trans 2,4-disubstituted oxazolidinone products (267) and (268)

(or their enantiomers from (R)-(222)). A 1.5 : 1 molar ratio of enamine to oxazolidinone was found necessary for optimum results.

PhCON^.0 CH2 Bu' H

(223) (S)-(222)

1.Solvent 2. 10%HOAc/H2O

(2S,4S)-(267)

Scheme 2.13

The diastereomeric ratios of the cis and trans adducts were determined by *H NMR (400

MHz) of the crude reaction mixtures and were found to be dependent upon the reaction temperature and solvent as shown in Table 2.2. Initial reaction temperatures of -78 °C followed by warming the reaction mixture to -20 °C or RT, to effect complete conversion of (222), gave mixtures in which the cis 2,4-substituted-oxazolidinone (267) was favoured over its trans counterpart (268) (Scheme 2.13). Chapter Two 70

The highest diastereoselectivity [(267) : (268) (83 : 17)] was achieved when the reaction mixture was initiated at - 78 °C in THF and was then held at -20 °C for 14 days

(Table 2.2, entry 1). When the reaction mixture was warmed to RT and dichloromethane was used as solvent the diastereoselectivity dropped to 75 : 25 (Table

2.2, entry 2). Reactions that were initiated at RT resulted in very poor diastereoselectivities (58 : 42) and slightly favoured the trans adduct (268).

Interestingly, at 70-80 °C the trans adduct (268) was favoured over its cis counterpart

(267). This latter reaction may be occurring under thermodynamically controlled conditions that would favoured the more stable trans adduct (268).

Table 2.2. Michael adducts from the reaction of oxazolidinone (222) and enamine (223).

Entry alkene (Temp.) Timea Solvent dr(%)b yieldc

(222) (°C) cis: trans 1 (S) -78 24 hr THF 83 : 17 78% -20 14 days

2 (S) -78 24 hr CH2C12 75 : 25 82% RT 1 day

ON CH C1 70 : 30 65% 3 (S) -10~> RT 2 2

4 (R) RT ON CH2C12 42 : 58 ND

5 (R) 70 3 hr CH2C12 30 : 70 ND

6 (R) 80 15 hr benzene 27 : 73 ND a ON = overnight (12-16 hr) b Determined on the crude reaction mixture by JH NMR. c After purification by column chromatography.

The two diastereomeric adducts (267) and (268) could be separated by column chromatography. A pure sample of the minor trans isomer (2R, 4S)-(268) could be obtained by recrystallization of a mixture of (2R, 4R)-(267) and (2R, 4S)-(268) Chapter Two 71 that was prepared from (R)-(222). The structure and stereochemistry of this compound was confirmed by a single crystal X-ray structure determination (Figure 2.5). The X- ray structure showed that the C-2 tert-butyl group and the C-4 hydrogen atom were on the same side of the oxazolidinone ring.

Figure 2.5: Molecular projection of the single crystal X-ray structure of the trans- adduct (2R, 4S )-(268), 20% thermal ellipsoids are shown for the non-hydrogen atoms; hydrogen atoms have arbitrary radii of 0.1 A. Chapter Two 72

The relative stereochemistry of (2R, 4S)-(268) was also evident from inspection of its

NOESY spectrum which showed a NOE cross peak between H-4 (4.51 ppm) and the

tert-butyl group (1.00 ppm) (Figure 2.6).

NOE (2R, 4S)-(26S)

I ppm)

- *rtr-- - te^B-^-^- *.*—_-* «—• 1ST.

yh.

n %r -: a

FI (ppm) Uu, Figure 2.6. 2D NOESY NMR spectrum (400 MHz, CDCI3) of the trans adduct (2R, 4S)-(268).

The NOESY spectrum of the cis compound (2R, 4R)-(267) also shows an expected NOE cross peak between H-2 (6.07 ppm) and H-4 (3.98 ppm) (Figure 2.7) confirming the cis stereochemical relationship between these two protons. Chapter Two 73

NOE (2R, 4R)-(267)

FJ i pp. i

H4<

«.5 ... -., -.. -,.-, .-,_,.._...,.. , 7.5 7.» G.5 (!-• S.S S.I FI (pp.1 H2

Figure 2.7. Expanded section of the NOESY NMR spectrum (400 MHz, CDCI3) of the cis adduct (2R, 4R)-(267).

From previous studies108 it has been shown that in related cis 2,4-disubstituted oxazolidinones, H-2 and H-4 resonate upfield of the corresponding protons in the related trans 2,4-disubstituted oxazolidinones. *H NMR analysis of the major cis adduct (267) Chapter Two 74 shows that both H-2 (6.07 ppm) and H-4 (3.98 ppm) resonate upfield of H-2 (6.23 ppm) and H-4 (4.51 ppm) in the related rrans-isomer (268).

Table 2.3. Comparison of *H NMR (400 MHz, CDCI3) data for the cis and frans-2,4-disubstituted oxazolidinones (267) and (268).

compound H-4 H-2 (ppm) (ppm)

cis (267) 3.98 6.07

trans (268) 4.51 6.23

Computer aided molecular modelling of the diastereoisomeric adducts (267) and (268) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods showed that the energy minimised structure for the cis diastereoisomer (268) is lower in energy than the trans diastereoisomer (267) by about 1.6 kcal / mole. Chapter Two 75

(2R, 4R)-(267), AHf = -139.8 kcal mor *

(2R, 4S)-(268), AHf =-138.2 kcal mol"!

Figure 2.8. Energy minimized structures for (2R, 4R)-(267) and (2R, 4S)-(268) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Chapter Two 76

2.4.4. Michael Addition Reactions of Oxazolidinone (R)-(222) with 1-N-

Pyrrolidino-cyclohexene (224)

The reaction of the oxazolidinone (R)-(222) with 1-AApyrrolidino-cyclohexane

(224) was studied using a variety of solvents (tetrahydrofuran, dichloromethane and benzene), reaction times and temperatures. Mild acid hydrolysis of the initial adducts using 10% aqueous HOAc resulted in a mixture of four diastereoisomeric products

[(269)-(272)] as shown in Scheme 2.14.

H2C .0

PhCONvD/O X t H Bu1 (224) (R)-(222)

ii. 10% HOAc/H20

H O

PhCONX/0 1 H Bu H Bu1

(l'S,2R,4S)-(269) (l'R,2R,4S)-(270) trans-adducts

0 H ¥ P ¥ P H PhCON^/O H Bu* ^ t H Bu1 PhCON. yO (l'S,2R,4R)-(27l) (l'R,2R,4R)-(272)

cis - adducts

Scheme 2.14 Chapter Two 11

Three of these adducts have been identified after separation by column chromatography

and crystallisation. The fourth diastereoisomer could not be isolated diastereomerically

pure.

Table 2.4. Michael adducts from the reaction of (R)-(222) and enamine (224)

Entry (Temp.) Time Solvent Ratiob'c Yieldd trans: cis (°C)

1 -82 4 hr THF 87 : 13 70% -78 48 hr (58/42):(53/47) -20 20 day

2 -78 24 hr THF 86 : 14 77% -20 19 days

3 -20 8 days THF 64 : 34 77%

4 -5 3 hr CH2C12 57 :43 84% RT ONa (76:24)/68:32)

5 0 2 hr CH2C12 52 :48 50% RT ON (89:11)/(82:18)

6 RT 48 hr CH2CI2 50 : 50 NDe (84:16/(84:16)

7 50 10 hr THF 39 : 61 NDe (34:66)7(78:22)

a ON = overnight (12-16 hr).D Determined on the crude reaction mixture by XH NMR (400 MHz). c The ratio of the two trans adducts to the two cis adducts is showed in brackets. d After purification by column chromatography. e ND = not determined.

The best diastereoselectivities were observed when the reactions were initiated at -82 or

-78 °C and then maintained at -20 °C for 19-20 days (Table 2.4, entries 1 and 2).

Under these conditions the ratio of trans [(269)+(270)] to cis [(271)+(272)] products Chapter Two 78

was 87-86 : 13-14 and the yield of four diastereoisomers after separation by column

chromatography was 70-77%. The major trans adducts were formed as a 42 : 58 mixture

of diastereoisomers [(269) : (270)] that differed in their stereochemistries at C-l', and

the minor cis products were formed as a 47: 53 [(271) : (272)] mixture of

diastereoisomers. Reactions at room temperature gave a 50 : 50 mixture of the cis and

trans adducts after 48 hr. Upon refluxing the reaction mixture in THF at 50 °C for 10 hr

then the cis isomers were favoured (Table 2.4).

The possibility of epimerization of the Michael adducts at C-T during the

hydrolysis step was investigated by treating of the trans compound (269) or the cis

compound (271) with 10% aqueous acetic acid in THF at RT for 2 hr. These

experiments resulted in 100% yield of the recovered starting compounds and thus epimerization during the hydrolysis step, after the initial Michael addition reaction of oxazolidinone (R)-(222) and 1-AApyrrolidino-cyclohexene (224), seemed unlikely.

The two trans diastereoisomers (269) and (270) and one cis isomer (271) were obtained diastereomerically pure after purification of the reaction mixtures by column chromatography. The stereochemistry of the cis isomer (271) was assigned on the basis of X-ray crystallography and NMR studies. *H NMR analysis of this compound and (272) showed that H-2 and H-4 for these compounds occurred upfield of H-2 and

H-4 in the rrans-isomers (269) and (270) (Table 2.5).

X Table 2.5. Comparison of the H NMR (400 MHz, CDC13) resonances for H-2 and H-4 in the compounds (269) - (272).

compound H-4 H-2 (ppm) (ppm) trans- (269) 4.68 6.21

trans -(270) 4.38 6.20

cis- (271) 4.00 6.07

cis-(272) 4.25 6.08 Chapter Two 19

The 2,5 cw-stereochemistry of (271) also was confirmed by a ID NOE difference experiment. Irradiation of the proton H-4 at 4.00 ppm resulted in a significant NOE enhancement of the signal at 6.07 ppm for H-2 as illustrated in Figure 2.9.

H-2

H-4

**" ae •• * a • - « ™ UP

;L. 1 '' i' 1111111111 M 1111111 n II |i 11111 mi 1111 • i • i M 11111 • A_ " I " " I i i i i | | i i i i i i i i i ), i i ,,,,, , , , 6-2 6.B S.B 5.6 5.41 5.2 s.e H.S 4.s H.A «.E t.e

—V/v" r 1 • 1 < • | •••• < I • 1 • • | ' ' t-i-| • • i • 111 • 11 • 1111 • 11 • 111 1111 i • i 111 1 • I ,-..,,.., | | ce s.s 5.6 5.4 S.2 5.8 4.8 H.6 4.-4 4.C 4,» ppn

Figure 2.9. ID NOE difference spectra of the cis compound (271). (a) Unperturbed spectra with irradiation off-resonance, (b) Irradiation of H-4 and (c) Irradiation of H-2. Chapter Two 80

The solid state structure of the cis diastereoisomer (271) (Figure 2.10) revealed its relative stereochemistry and showed that the cyclohexane ring adopted the more stable chair conformation with its C-2 substituent in the more stable equatorial position.

(l'S, 2R, 4R)-(27l)

Figure 2.10. Molecular projection of the single crystal X-ray structure of (l'S, 2R, 4R)-(271); 20% thermal ellipsoids are shown for the non- o hydrogen atoms; hydrogen atoms have an arbitrary radii of 0.1A.

Computer aided molecular modelling of this diastereoisomer, using SPARTAN and the AMI semi-empirical molecular orbital calculation methods showed that the Chapter Two 81 distance between the H-2 and H-4 of the oxazolidinone ring was about 3.60 A, almost identical to that estimated from the X-ray structure analysis of this compound, as shown in Figure 2.11. This proton-proton distance is within the limits of about 4.0 A in which an NOE is expected to be observed.

Figure 2.11. Energy minimized structure for compound (271) showing interatomic distance between H-2 and H-4 that was calculated using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. The double headed arrow indicates observed NOE enhancement in the difference ID NOE experiment.

The solid state structure of the trans diastereoisomer (1 fS, 2R, 4S)-(269) is shown in Figure 2.12 and again the cyclohexanone ring adopts the most stable chair conformation with the C-2 substituent occupying the equatorial position. Chapter Two 82

H ,0

(l'S,2R,4S)-(269)

H Bu4

Figure 2.12. Molecular projection of the single crystal X-ray structure of (1 'S, 2R, 4S)-(269). 20% thermal ellipsoids are shown for the non- o hydrogen atoms; hydrogen atoms have arbitrary radii of 0.1A. Chapter Two 83

Further evidence for the trans structure of (1 'S, 2R, 4S)-(269) came from an NOESY experiment on this compound which revealed a cross peak between H-4 (4.68 ppm) and the terf-butyl group (1.01 ppm) (Figure 2.13). H ^~%. o u r >—f (l'S,2R,4S)-(269) 1 H W

re

I' I l.e- "** t V?V i.s- j

2.e- o •>

E.5- / o 9 -* * • »©

a.s-

•

«.s- H4 f •—--9 5.9-

-i *»—, 1 1 1 • , . r -4- Bu(

Ftgwre 2.73. Expanded section of the NOESY spectrum (400 MHz, CDCI3) of the trans adduct (l'S, 2R, 4S)-(269). Chapter Two 84

2.4.4 Michael Addition Reactions of Oxazolidinone (S)- (222) with 1-N-

Pyrrolidino-cyclopentene (225)

The reaction of enamine (225) with (S)-(222) in THF at -20 °C for 7 days, followed by a mild acid hydrolysis with 10% aqueous acetic acid, gave a mixture of four diastereoisomeric adducts in 82% yield after column chromatography.

H2C 0

PhCON. ,0 X (225) Bu1(5>(222 H )

i. -20 °C, solvent ii. 10%HOAc/H2O 0 H .0 H .0

PhCON. /Ol PhCON.,0 3V2 1 Bu4 H Bu H (273) (274) cis-adducts

(275) (276) trans-adducts

Scheme 2.13 lH NMR analysis of the crude reaction mixture showed that the two cis isomers

[(273)+(274)] were favoured over the two trans isomers [(275)+(276)] by a ratio of 78 : 22. The major cis adducts were formed as a 89 : 11 mixture while the trans Chapter Two 85 diastereoisomers were obtained as a 75 : 25 diastereoisomeric mixture. When the enamine addition reaction was performed at higher temperature however, the cis to trans isomer ratio approached 50 : 50 and at room temperature the trans isomer was favoured

(61 : 39) (Table 2.6). The four diastereoisomeric products could not be separated by column chromatography, since in all solvent mixtures that were tried only one spot was evident by TLC analysis. One pure trans isomer (275) was obtained after six crystallisations of the mixture from ethyl acetate / hexane, while one pure cis isomer

(273) was obtained pure after five crystallisations of the mother liquors from methanol and then from ethyl acetate / hexane. Unfortunately the other trans (274) and cis (276) diastereomeric products could not be obtained diastereomerically pure.

Table 2.6. Michael adducts from the reaction of (S)-(222) and enamine (225)

Entry Temp Time Solvent dr(%)b>c yieldd (° C) cis.trans

1 -20 7 days THF 78 : 22 82% (89/ll):(75/25)

2 -10 2 hr CH2C12 57 :43 75% RT ONa (84/16):(73/37)

3 RT 48 hr THF 39 : 61 80% (74/26) :(65/35) a ON = overnight (12-16 hr).b Determined on the crude reaction mixture by !H NMR (400 MHz). c The ratio of the two cis adducts to the two trans adducts is shown in brackets. d After purification by column chromatography.

The ratio of (273) to (274) and of (275) to (276) varied slightly (10-20%) with each reaction and the ratios changed after purification on silica gel due to epimerization at C-l'. The absolute stereochemistry at C-l' of the individual adducts could not be ascertained.

The stereochemical assignments at C-2, C-4 and C-l' of these adducts were based on comparisons of their corresponding *H NMR signals for these protons with those for the Chapter Two 86

Michael adducts from the reaction of oxazolidinone (222) with 1-AApyrrolidino- cyclohexene (224) (see section 2.44), and the literature precedent that H-2 and H-4 in cw-2-ter£-butyl-4-substituted-oxazolidin-5-ones are observed upfield from their respective resonances for H-2 and H-4 in ?rans-2-ter?-butyl-4-substituted-oxazolidin-5-ones.15 The

AH NMR resonances for H-2 and H-4 for the four diastereoisomeric adducts were consistent with the cis and trans stereochemistry assigned to the adducts (273) - (276)

(Table2.7).

Table 2.7. Comparison of the *H NMR (400 MHz, CDC13) spectral data for cis and £ra/w-2,4-disubstituted oxazolidinones (273)-(276).

compound H-4 H-2 (ppm) (ppm) cis 4.00 6.07 (273) cis 4.35 6.09 (274) trans 4.46 6.23 (275) trans 4.85 6.20 (276)

Further evidence for the trans stereochemistry of (275) came from analysis of its

NOESY spectrum which showed a NOE cross peak between H-4 (4.46 ppm) and the tert-bvXy\ group (1.00 ppm) (Figure 2.14). Chapter Two 87

H4 < *

FI (ppm)

Figure 2.14. Expanded section of the NOESY spectrum (400 MHz, CDCI3) of the trans adduct (275).

Indeed molecular modelling of these diastereoisomers, using SPARTAN and the

AMI semi-empirical molecular orbital calculation methods, shows that the heat of formation of the four compounds (273), (274), (275) and (276), were AHf =

-127.2 kcal mol"1* -127.8 kcal mol"1- -128.8 kcal mol'1 and -131.75 kcal mol"1 respectively. This calculation indicated that the trans products (275) and (276) should be thermodynamically favoured over the cis products (273) and (274). Chapter Two 88

H P

PhCONs^O PhCONs^O l Bu1 H Bu ^H

1 -l (273), AHf = -127.2 kcal mol' (274), AHf = -127.8 kcal mol

PhCO

Bu* H

1 1 (276), AHf = -131.7 kcal mol (275), AHf = -128.8 kcal mol

Figure 2.11. Energy minimized structures for (273), (274), (275) and (276), using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Chapter Two 89

2.5 Mechanistic Details of the Michael Addition Reaction of Enamines.

In 1963, the fundamental paper by Stork89 showed that the mechanism for the

reaction of enamines with Michael acceptors involved nucleophilic attack of the enamine to

the p-position of the unsaturated carbonyl derivative. The zwitterionic intermediate (277)

that was formed, could be in equilibrium with the Michael type adduct (278) which upon

hydrolysis was converted to the 1,5-diketone (279) (Scheme 2.16).

^\ R Uo o R O' +

(277)

H20

(279) (278)

Scheme 2.16

Several observations suggested that a cyclic transition state (and therefore a syn approach of the reactants) was involved in such addition reactions. Thus Pandit109 proposed, on the basis of the stereochemical results, that the addition of the ethylenic ester

(280) to the tertiary enamine (225) involves the syn approach of the reactants to give

(283), followed by an internal proton transfer to give (284) (Scheme 2.17).

Assuming the formation of the conventional dipolar intermediate (283), the ester (284) may arise either by an intramolecular proton transfer from the cyclopentane ring, as shown Chapter Two 90

in Scheme 2.17, or via intermolecular protonation-deprotonation of the iminium ion

(283). When the reaction was carried out in MeOD there was essentially no incorporation

of deuterium at the Cl-centre of the adduct (284). This result was consistent with an

intramolecular proton transfer mechanism.

(225)

C02Me MeOH, 20 °C

(280) (281)

H^ ^COzMe X,2 if ^-C02Me

(282) (283) (284)

Scheme 2.17

A similar mechanism can be used to understand the cis diastereoselectivity in addition of the enamines (223) and (225) to oxazolidinone (222).

A possible mechanism for the formation of cis product (267) from the reaction of pyrrolidine enamine (223) and the oxazolidinone (222) is presented in Scheme 2.18.

This mechanism involves an intermolecular proton transfer reaction from the least hindered side of the oxazolidinone ring via the six-membered ring transition state (A). Chapter Two 91

(A) six membered ring TS

intramolecular H-transfer

+ H30

cis product (267) (B) More substituted enamine

Scheme 2.18

The rate of the Michael reaction between (222) and enamine (223) was enhanced in the more polar solvent dichloromethane over benzene (compare entries 5 and 6 in Table

2.2). This observation is consistent with the formation of a zwitterion ion intermediate since a polar solvent would stabilize this intermediate more effectively and enhance the rate of reaction.

Risaliti et a/.110 have reported on the stereochemistry of the reaction of pyrrolidine enamine of cyclohexanone (224) with 1-nitropropene. They assumed (Scheme 2.19) a two step mechanism with formation of a dipolar intermediate (285) in which the C-2 Chapter Two 92 substituent of the cyclohexenering is axially oriented. The alternative chair conformer with this substituent equatorially orientated is indeed strongly destabilized by a large A1'3 strain between the equatorial substituent and the a-methylene group of the heterocyclic ring.

Furthermore, in (285) rotation around the axial C2-Cot bond is restricted and in the most stable rotomer the methyl group attached to the Ca atom is pointed outside the cyclohexanone ring.

H ,CH3 x -'-CH2N02 CH3-CH=CHN02 Jf

(224) (285) (286)

+ H30

H .CH3 x--CH N0 H 2 2 I X^V/C^CHs H I CH2N CH2N02 H 0

(288) (287)

Scheme 2.19

As a result, the carbon atom bearing the negative charge points inside the ring, near to the axial hydrogen at the C-6 position. Thus intramolecular transfer of this hydrogen to the negative carbon atom, through a six-membered ring transition state, forms the less substituted enamine (286), in the quasi-axial half-chair conformation to avoid A1-2 strain.

The above result and those previously reported on the reaction of this enamine with ethyl azodicarboxylate111 and phenyl vinyl sulfone112 suggested to us that this enamine may behave in a similar way with the oxazolidinone (222). Thus the preference for trans 2,4- Chapter Two 93 substituted oxazolidinone products (267) and (268) in the reaction of the pyrrolidine enamine of cyclohexanone (224) and oxazolidinone (222) may be due to a facile intramolecular proton transfer of the axial hydrogen (Hax) in the zwitterion intermediate

(289A) to the H-4 position on the oxazolidinone ring and formation of the less substituted enamine (290A) that, after hydrolysis with acid, is converted to the trans 2,4-substituted oxazolidinone products (269) and (270) (Scheme 2.20).113

H H Bu1, O PhCON X o H H H N

(289A) (290A)

(289B) (290B)

Scheme 2.20 Chapter Two 94

The alternative intermediate (289B), that would lead to the cis 2,4-disubstituted

oxazolidinone products, would seen less likely because of a steric interaction between the

axial C-4 hydrogen of the cyclohexane ring and the C-5 carbonyl group of the

oxazolidinone ring. A similar steric interaction between this hydrogen atom and the N-

benzamido group in (289A) would be expected to be less severe since the AAbenzamido

group can rotate away from the cyclohexane ring.

2-6 Asymmetric Synthesis of the Enantiomers of 5-Cis Iso- Propylproline (5CIPP)

2.6.1 Introduction

The asymmetric synthesis of the two enantiomers of cis wo-propylproline have not

been reported. However, Overberger et a/.50 reported the synthesis of racemic cis and

trans 5-rso-propylproline (see Chapter One for details) and the resolution of these

compounds.

2.6.2 Asymmetric Synthesis of (2S, 5i?)-C/5,-/5,o-propylproline

2.6.2.1 Hydrolytic Cyclization of Michael Adducts (267) and (268).

With successful results being obtained from the Michael addition of enamines to the

oxazolidinone (222) the remaining work involved a study of the hydrolytic cyclization of

the oxazolidinones (267) and (268) to yield the A^pyrrolines (292) and ent-(292) respectively, and their conversions to 5-wo-propylproline. There are several procedures for the hydrolysis of substituted oxazolidinones. One facile and efficient method involves heating a solution of the oxazolidinone in 6N HC1 at reflux. Thus the pure cis oxazolidinone (267) was heated in 6N HC1 at 110 °C for 2 hr. The aqueous phase was washed with dichloromethane and the pure product was obtained after evaporation of the aqueous layer in vacuo (Scheme 2.21). This product had *H NMR spectral data in Chapter Two 95

50 13 D6-DMSO similar to that reported by Overberger for the iminium salt (292). C NMR analysis of our product in D2O, however, showed resonances consistent with an

equilibrium mixture (ca 10 : 90) of (292) and the ketone (291) in which the ketone (291)

was the major component (13C NMR (D2O) 8 205.3, (CO), 172.0 (COOH)). Similarly,

the pure trans- oxazolidinone (268) was heated in 6N HC1 at 110 °C for 4 hr to give the

A^pyrroline ent-(292) with the (5R) configuration (Scheme 2.21).

COOH H + H3N cr COOH

(267) (291) (292)

H "'"•t—COOH A..„rtCOOH H3N+cr *H cr

(268) ent- (291) ent-(292)

Scheme 2.21

2.6.2.2 Reduction of (A^-pyrroline (292) and ent-(292)

To find optimal conditions for preparing the hydrochloride salt of 5-cis iso-

propylproline (293) and ent-(293) we tried different reducing agents (NaBH4,

NaCNBH3 and H2-Pd/C) to reduce the double bond of the iminium ion (292) and these

results are summarised in Table 2.8. The best diastereoselectivity was obtained by hydrogenation of an aqueous solution of the mixture of (291) and (292) over palladium on carbon. These conditions gave a 96 : 4 mixture of ci.y-5-/.s'0-propylproline hydrochloride (293) and its trans isomer (294). The hydrogenation of related iminium salts to give d.s-5-substituted prolines is well documented.114"116 Chapter Two 96

, &",xH reduction i c \..i»\H S)y«u COOH g+ COOH + JJ+^COOH Hd H Q" 2 H2Q (292) (293) (294) Scheme 2.22

Reduction of an aqueous solution of the mixture of ketone (291) and iminium salt

(292) with sodium borohydride (NaBH4) in presence of sodium bicarbonate at 0 °C and then RT for 24 hr gave a 54 : 46 mixture ofthe cis and trans isomers (293) and

(294) respectively. Reduction using sodium cyanoborohydride (NaCNBH3) at room temperature resulted in an almost identical diastereoselectivity (55:45).

Table 2.8. Reduction of (A^-pyrroline (292)

Reductant Cis Trans Yield (293) (294) NaBH4 54% 46% 65%

NaCNBH3 55% 45% 75%

H2-Pd/C 96% 4% 86%

Similarly, catalytic hydrogenation of an aqueous solution of the iminium salt ent-

(292) gave predominantly the m-S-iiSo-propylproline hydrochloride ent-(293) with the

(2R, 5S) absolute configuration (Scheme 2.23).

5 C00H »\.„»»COOH -COOH UX £< N+ \ H2-Pd/C H^\ /^H + H2Q H2 cr 48 hr ent-(293) ent- (294)

Scheme 2.23 Chapter Two 97

The ratio of the cis and trans diastereoisomers (293) and (294) was determined by

integration of their respective a-proton resonances in the *H NMR spectrum of their

corresponding methyl ester derivatives. This particular proton resonance is sensitive to the

location of the wo-propyl group relative to that of the carbomethoxy functionality on the

ring. Thus the crude reaction mixtures were methylated by treating them with thionyl

chloride in dry methanol Scheme 2.24.

1 H/»„.<+>£ n Pr //,,.. H Pri^ I >^ ^NT ^CO2H H^ ^N^C02H + H2cr H2cr (293) (294) SOCl2 MeOH 1

H//„. / \*4l^ Pr1'",.., n 1 C~\iV Pr ^ rf*co2CH3 ir N ^C02CH3 1 + i H H (295) (296) TosCl pyridine

H//„ 1 Pr N ""C02CH3 H2 S03-

Scheme 2.24

The chemical shift for the a-proton in the trans isomer of the methyl ester (296) (3.84 ppm, aCH) was further downfield of that in the cis isomer (295) (3.78 ppm, ccCH), consistent with the JH NMR data of these compounds that have been reported in the literature.50 For most resonances there were some slight differences between the multiplicity and chemical shifts of our compound (296) and that reported in the literature Chapter Two 98

for this compound. The differences could be attributed to differences in sample

concentration and temperature (Table 2.9). There was however, a significant difference

between the chemical shift for 8-CH for our compound and that reported in the literature.

We assume that the later value is in error.

Table 2.9. Comparison of the *H NMR (CDCI3) data of our methyl ester (296) with that in the literature.

Compound a-CH OCH3 8-CH CH(CH3)2 (296) multiplicity dd s dt d our data) (400 MHz) chemical 3.84 3.72 2.87 0.97 and 0.88 shift (ppm)

(296)a multiplicity t s q d (literature) (300 MHz) chemical 3.85 3.73 3.42 0.96 and 0.87 shift (ppm) a Fromreference 50.

The difference in reactivity of the cis and trans isomers to p-toluenesulfonyl chloride has been used to separate the two diastereoisomers of 3- or 5-alkylprolines.50 The cis isomer is known to form a sulfonamide quite readily while the trans isomer reacts very slowly resulting first in the hydrolysis of the sulfonyl chloride in the aqueous solution.

Thus a mixture of our cis and rran^-5-wo-propylproline methyl esters (295) and (296)

(55 : 45) was stirred with an equimolar amount of /?-toluenesulfonyl chloride in a pyridine- dichloromethane solution at room temperature for 4 hr. The *H NMR studies of the crude product showed only sulfonamide (297) had been extracted into dichloromethane during work up and that the tram diastereoisomer remained in the aqueous layer. Chapter Two 99

2.6.2.3 Preparation of the Free Amino Acids

Passing an aqueous solution of (293) or ent-(293) through a column of Dowex 50 [H+]

ion-exchange resin and elution with water and then aqueous ammonia gave the free amino

acid (151) or ent-(\S\) in 82% and 75% overall yield from (267) or (268)

respectively.

H//„. DOWEX 50 H/,„. /R 5)^H 1 v 1 Pr *' >r ^CO H Pr ^ ri ^C02H 2 pH = 6 H2cr H (293) (151)

1 1 Pr /,,,, H DOWEX 50 Pr /-,,..Q A^C02H H^ H Q

The !H NMR (400 MHz, D20) of (151) showed a doublet of doublets for H-8 at 3.20 ppm and one multiplet for H-a at 4.30 ppm. The signals for the two methyl groups of the

wo-propyl group appeared as two doublets at 0.99 (3H) and 1.12 (3H) ppm (Figure

13 13 2.17). The C NMR (400 MHz, D20) of (151) compared favourably to the C NMR data that has been reported in the literature for this compound.50 The comparison is shown in Table 2.10. The difference in chemical shifts which were observed may be attributed to differences in sample concentrations.

13 Table 2.10. Comparison of C NMR (D20) of (151) with that reported in the literature. Compound CO C« C5 Cp Cy CH(Me)2 (Me)2

(151)a 174.5 67.6 60.8 28.4 27.1 30.4 19.0, 18.3

(151)(Iit)b 177.2 70.5 63.3 30.9 29.5 32.8 21.3, 20.8 a At 100 MHz. b From reference 50 (70 MHz) Chapter Two 100

CHM£2

P

CHMe2 COOH

5-CIPP

—,—i—i—i—i—i—i—i—i—•—i—'—' > • i r_ Z I -• PI"

Figure 2.17. XH NMR (400 MHz, D2O) spectrum of (25, 5R)-(151) (* DHO signal) Chapter Two 101

The NOESY spectrum of (151) showed a cross peak between H-a (4.10 ppm) and H8

(3.30 ppm), which established their cis stereochemical relationship (Figure 2.18). The specific rotation of this compound ([CC]D23 -63.3, c .51, MeOH) was in close harmony

50 25 with that reported for (2S, 5R)-(151) (lit. [cc]D -65.3, c 0.9, MeOH) that had previously been prepared by resolution of the racemate.50

Fl (ppm)

Figure 2.18. Expanded section of the NOESY spectrum (400 MHz, CDC13) of (25, 5R)-(151).

The enantiomeric amino acid (2R, 5S)-ent-(151) had specific rotation [([aJo23

+56.3, (c 0.35, MeOH)] which was significantly lower than that reported50 for ent-(151) Chapter Two 102

([oc]D23 +64.7, (c 0.80, MeOH)]. The absolute (25, 5R) stereochemistry of (151) and

the (2R, 55) stereochemistry of ent-(\5V) was further confirmed by circular dichroism

studies.

2.6.2.4 Determination of the Absolute Configuration of cis and trans-5

/so-propylproline by Circular Dichroism (CD)

It is well known that circular dichroism (CD) can be used for the rapid assignment

of absolute configuration of optically active a-amino acids.117"121 All naturally occurring

and most synthetic L-a amino acids show a positive Cotton effect around 200 nm in water

(Table 2.11). This strong positive Cotton effect (CE) can be attributed to the presence of

the carboxyl chromophore attached to the chiral oc-carbon in amino acids.121

Table 2.11. Selected data3 from the CD spectra of substituted prolines.

H20 HC1 Substituted proline Ae X(nm) Ae l(nm) L-Proline 0.29 m 212 0.9 m 209 -0.69 m 193 cw-3-Methyl-D-proline -0.43 m 212 -1.08 m 220 0.25 m 195 *ra«£-3-Methyl-L-proline 0.47 m 207 0.90 m 207 cw-4-Methyl-D-proline -0.31 m 211 0.90 m 207 0.67 m 191

(+)-c/5-5-wo-propylproline 14.8 m 211 24.0 m 214b

(-)cw-5-wo-propylproline -14.8 m 211 -23.9 m 214b

(+>rrfln5-5-wo-propylproline -21.4 m 211 -46 m 214b

(-)-trans-5-iso-propy\pw\ine21.3 m 211 45.9 m 214b a Data from references 50 and 120. b CD data in EtOH.

Figure 2.20 shows the CD curves of proline, (25, 5R) cw-5-iso-propylproline (151) and its enantiomer (2R, 55)-cw-wo-propylproline ent-(l51). Chapter Two 103

Figure 2.20. CD spectra of proline (red), (25, 5R)-(151) (D.blue) and (2/?, 5S)-ent-(151) (green), in water. Chapter Two 104

It is evident that both L-proline and (25, 5R)-(+)-(151) display positive Cotton effects at

211-214 nm in water. Thus, it is clear that (25, 5R)-(+)-(151) belongs to the L-oc-amino acid series. On the other hand (2R, 5S)-(-)-ent-(151) shows a negative Cotton effect in this region and is therefore, assigned to be belong to the D-a-amino acid series.

2.6.2.5 Determination of Enantiomeric Purity (151) and ent-(151)

The enantiomeric purities of (151) and ent-(151) based on their optical rotations were expected to be (96%) and (87%). To quantify the enantiomeric purities of these compounds, (151) and ent-(15l) were converted to their methyl esters by treating them with thionyl chloride in dry methanol. The enantiomeric purities of (151) and ent-(151) were determined to be 92 and 58% respectively from XH NMR analysis of their diastereomeric carbamates (299) and (300) that were prepared by treatment of the individual esters (295) and ent-(295) with (R)-(+)- 1-phenylethylisocyanate (298) in deuterochloroform at RT for 1 hr (Scheme 2.26). Chapter Two 105

MeOH SOCl2 MeOH SOCl2

(i?)-Ph(CH3)CHNCO CDC13 (tf)-Ph(CH3)CHNCO CDC13 (298) RT, lhr (298) RT, lhr

o.J, A^COOMe

H >°° y .NH H3C

(300) (299) ee>58% ee>92%

Scheme 2.26

Integration of the resonances for the doublet signals for the methyl protons

(Ph(Me)CHNHCO) for the major and minor diastereoisomeric carbamates showed a ratio of 96 : 4 for the carbamates (299) : (300) respectively derived from (151)

(Figure 2.19). While a ratio of 79 : 21 for (300) and (299) was observed for the carbamates derived from ent-(\5\). Thus the enantiomeric purities of (151) and ent-(\51) were calculated to be 92 and 58% respectively. The reason for the low enantiomeric purity of ent-(151) was not clear. Chapter Two 106

1.495 1.490 !-«£ l-48t 1.47S 1-479 1.465 1-461

Figure 2.19. Expanded section of the *H NMR (400 MHz, CDCI3) spectrum of the major and minor diastereoisomers of carbamate derivatives (299) and (300) respectively, from ester (295).* major diastereoisomer ** minor diastereoisomer. Chapter Two 107

2.7. Synthesis of (2S, 3aS, 7aS) Perhydroindole-2-carboxylic acid (3)

As we described in Chapter One (Section 1.2.2.1), (2S, 3aS, 7aS)

-perhydroindole-2-carboxylic acid (3) is a precursor of the ACE inhibitor perindopril (1), a potent anti-hypertensive drug. Perhydroindole-2-carboxylic acid (3) contains three chiral centres and thus there is the possibility of eight stereoisomers for the general structure (3).

(2S, 3aS, 7a5)-Perhydroindole-2-carboxylic acid (3) give rise to the most active form of perindopril. Thus our goal was to synthesise (2S, 3aS, 7aS) perhydroindole-2-carboxylic acid (3) by using the hydrolytic cyclization of the Michael products (269) of (270) with known (5) stereochemistry at C-4.

^XT, COOH 7a N 1 H (3)

Me C02Et * Chiral centre perindopril (1)

2.7.1 Hydrolytic Cyclization of the Michael Adducts (269) and (270)

Hydrolysis of either of the trans adducts (269) or (270) using 10% hydrochloric acid at 110 °C for 4-5 hr gave a single diastereoisomeric iminium salt (302) from ^H

NMR (in D2O) analysis of the crude product. These spectra showed two multiplets for H-

2 and H-3a at 4.98 ppm and 3.23 ppm respectively. Chapter Two 108

HC16N

110°C H Bu1 HsN

(269) or (270) (301)

COOH COOH

(304) (303) (302)

Scheme 2.27

Molecular modelling (BIOSYM and the Insight II force field or PC MODEL and the MMX force field) of the two possible neutral imines (302a) and (304a) suggested that the former salt should be thermodynamically favoured over the latter and that both were favoured over the compound (303a) (Figure 2.23). Thus we assume that under the hydrolysis conditions epimerisation of H-3a in (302a) and (304a) occurs and thus the thermodynamically more stable isomer (302a) is favoured from either (269) or (270). Chapter Two 109

(302a) MMX energy= 11 kcal mol" Biosym " " = 19 kcal mol"

(304a)

MMX energy = 13 kcal mol" Biosym " " = 27 kcal mol-i

(303a)

MMX energy= 57 kcal moli-l" Biosym " " =98 kcal mol"1 Figure 2.23. Energy minimized structures for the neutral imines (302a), (303a) and (304a), using the INSIGHT II force field of BIOSYM or the MMX forcefield of PC MODEL

2.7.2 Reduction of the Iminium Salt (302)

Reduction ofthe iminium salt (302) using sodium cyanoborohydride (NaCNBH3) at room temperature overnight gave a 75: 25 mixture of the two diastereoisomeric amino acid hydrochloride salts, (2S, 3aS, 7a5j-perhydroindole-2-carboxylic acid (305) and (2S,

3aS, 7a/cJ-perhydroindole-2-carboxylicacid(306) (Scheme 2.28). In order to obtaine Chapter Two 110

a better diastereoselectivity for reduction of the iminium ion double bond of (302) we examined the hydrogenation of an aqueous solution of (302) over palladium on carbon.

Catalytic reduction of this compound however, showed only a slight improvement in the

diastereoselectivity and gave a 77 : 33 mixture of the amino acid hydrochloride salts of (2S,

3aS, 7a5jperhydroindole-2-carboxylic acid (305) and (2S, 3aS, 7oK,)perhydroindole-2- carboxylic acid (306) in 90% yield.

reduction (2S, 3aS, 7aS)- (305)

(302) s^."V H ./^COOs>C H H H2cr

(2S, 3aS, 7aR)-(306)

Scheme 2.28

The stereochemistry of (305) and (306) is discussed in the following Section

(2.7.3). Thus reduction of (302) has occurred mainly from the expected convex oc-face of the iminium ion (302) (Figure 2.24) however, the diastereoselectivity of this hydrogenation was much less than that observed in the mono-cyclic iminium ion (292). Chapter Two 111

(minor) H—H

MMX energy = 11 kcal mol"

H—H (major)

Figure 2.24. Hydrogenation of the neutral imine (302a) from the convex ct-face.

2.7.3 Preparation of Benzyl Esters of Perhydroindole-2-carboxyIic acid (3)

The mixture of the two diastereoisomeric hydrochloride salts of perhydroindole-2- carboxylic acid (305) and (306) was converted to a mixture ofthe benzyl esters (307a) and (307b) with thionyl chloride in benzyl alcohol at 0 °C as shown in Scheme 2.29.

Attempts to separate this mixture by preparative TLC were not successful due to the poor resolution of the two diastereoisomers. From lH NMR analysis of the crude product mixture of (307a) and (307b), the major diastereomeric product (307a) was identical to the benzyl ester of (25, 3aS, 7aS)-(3) that was prepared from an authentic sample of (25.

3aS, 7a5M3)57>59>122 that showed a doublet of doublets at 3.82 ppm for H-2, a quartet at

3.08 ppm for H-7a, and a singlet at 5.18 ppm for the benzylic protons. The minor product (307b) showed a triplet at 3.95 ppm for H-2, a quartet at 3.30 ppm for H-7a, and Chapter Two 112 one singlet at 5.16 ppm for benzylic protons. The 1H NMR spectral data for the minor isomer was identical to that reported for (307b).59 The deshielding of H-7a in (307a) is probably due to the 1,3-cis relationship between the carboxylic group and the H-7a proton.

*N + H H2cr

PhCH20H,S0Cl2 (307a) + + 0 °C to RT, ON

(307b)

Scheme 2.29

2.8 Conclusion

In conclusion, the Michael addition reactions of pyrrolidine enamines (223) and

(225) to the chiral oxazolidinones (S)-(222) or (R)-(222) favours cis 2,4-disubstituted oxazolidinone adducts while trans 2,4-disubstituted oxazolidinone adducts are favoured from the addition reactions of enamine (224). The diastereomeric adducts from the addition of (223) to (222) are readily separated and can be converted to (5R, 25) and

(55, 2/?)-cw-5-wo-propylproline, efficiently in good overall yield and in high enantiomeric purity. The extension of this protocol to the synthesis of perhydroindole carboxylic acid

(3) suffered from poor overall stereochemical control. The stereochemistry of the products has been elucidated by single crystal X-ray structure analysis, ID lU NOE difference spectroscopy, 2D JH NMR, (COSY and NOESY), ^C NMR spectroscopy, circular dichroism (CD) and computer molecular modelling. 113

CHAPTER THREE

SYNTHESIS OF POLYFUNCTIONALIZED PROLINES VIA ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION REACTIONS Chapter Three 114

3.1 Introduction

1,3-Dipolar cycloaddition reactions of electron deficient alkenes are one of the

most efficient methods available for the synthesis of heterocyclic compounds.64 In

particular, the 1,3-dipolar cycloaddition reactions of azomethine ylides with these alkenes

are very useful synthetic methods for the synthesis of functionalised proline derivatives.

It has been shown by Grigg66 and Kanamasa69 (see Introduction , Chapter One) that

stabilised metalloazomethine ylides occasionally provided cycloaddition adducts with a

high degree of regioselectivity and diastereoselectivity, even for adducts in which up to

four new stereocentres were created. In this Chapter, the synthesis of proline derivatives

via the asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides derived from

/Y-alkylidene or arylidene a-amino esters with the chiral oxazolidinone (222) will be

investigated. 3.2 Synthesis of Polyfunctionalized Prolines via Asymmetric 1,3-Dipolar Cycloaddition Reactions.

1,3-Dipolar cycloaddition reactions using either chiral nonracemic

dipolarophiles71a_f or dipoles72a~2 as stereocontrol elements or by utilizing a chiral metal

complex as catalyst73a"b have been employed in the asymmetric synthesis of

polyfunctionalized prolines (PFP).

Kanamasa et alP* discovered that when an 86 : 14 mixture of chiral oxazolidines

(308a) and (308b) was treated with the N-metallated azomethine ylide derived from

imine (201c) then only two diastereoisomeric cycloadducts, (309) and (310) were

formed. Separation of these products and then removal of the oxazolidine chiral controller from (309) and (310) provided the polyfunctional prolines (-)-(311) and

(+)-(311) respectively, in 80% and 87% yield respectively as outlined in Scheme

3.1. Chapter Three 115

O Ph OMe C02Me H Y

(308a) (201c) (308b)

LiBr, DBU THF -78°C, 3.5 h

C02Me N—1 f ^C02Me

MeOOC^^N^^Ph MeOOCv ~rf 'Ph I I H H (309) (310)

TsCl NEt3 TsCl NEt3

MeOH H2S04, Si02 MeOH H2S04, Si02

(MeO)2HC C02Me (MeO)2HC sNSC02Me

MeOOC'r "N" "Ph I H (-)-(311)

Scheme 3.1

Grigg et al.1^ reported that the reaction of the chiral dipolarophile (IR, 2S, 5R)-

(-)-menthyl acrylate (312) and methyl oc-(benzylideneamino)phenylacetate (201d) in the presence of base and using Ag(I), Ti(IV) or LiBr as catalysts gave the cycloadduct

(313). In all cases the polyfunctional proline (313) was obtained in > 95% de as shown in Scheme 3.2. They suggested a transition state (TS) for the formation of the product (313) from (IR, 2S, 5/?)-menthyl acrylate which is shown in Scheme Chapter Three 116

3.2. The ,y/-face of the dipole was shielded by the 2-i'jo-propyl group, thus cycloaddition takes place from the re-face of the dipole.

Ph^^ N^^C02Me AgOAc / NEt3 / MeCN Ph

(312) (201d)

4^< (re-face) Me yj^ N^^Vi^ ^OMe H Ph (TS)

Scheme 3.2

Yamamoto etal. 71f reported that methyl (3R, 7a5)-2-phenylperhydropyrrolo[l,2- c]imidazole-3(£)-propenate (314) acted as a chiral dipolarophile in its reaction with the azomethine ylide derived from £err-butyl(benzylidenearnino)acetate (315). Treatment of a mixture of (314) and (315) at -78 °C for 5 hr in THF, in the presence of lithium bromide and DBU, gave the cycloadduct (316) as a single diastereoisomer as shown in

Scheme 3.3. Removal of the heterocyclic chiral controller from (316) was readily achieved by first A^-tosylation of (316) and then hydrolysis of the aminal moiety. The suggested transition state for the cycloaddition reaction was TS-A, where the ylide added to the M-face of the dipolarophile via a .ryn-periplanar conformation. The Chapter Three 111 difference in steric hindrance between the ester group of the metallated azomethine ylide and H-7a of (314) in TS-A and that between and the ester group and the bridgehead nitrogen as shown in TS-B was thought to be a major factor in determining the stereochemical outcome of this reaction.

H N—Ph / 7a| N—Ph CC' 1 + Ph COOBu LiBr/THF _ \ N^/. DBU, -78 °C COOMe COOMe B^OOC

(314) (315) (316)

re-face

OMe « R0"C

TS-B

Scheme. 3.3

Recently Waldmann et al.124 reported that the metallated azomethine ylides of

(201), that were derived from the condensation of benzaldehyde and methyl a-amino

esters, underwent highly diastereoselective 1,3-cycloadditions with the chiral acrylamide

of proline benzyl ester (317) as illustrated in Scheme 3.4. In all cycloaddition

reaction studies only four of the eight possible diastereoisomers were detected, and one

diastereoisomer (318) was always favoured. In nearly all cases the cycloadducts were

formed with an endo/exo selectivity larger than 99 : 1 (Table 3.1). The best results

were obtained when triethylamine or DBU was used as base and when the reactions

were carried out at -40 °C to -78 °C in THF as solvent. The chiral auxiliary group could Chapter Three 118

be removed from the cycloadducts (318) by acidic hydrolysis with 9N HC1 at reflux to give the polyfunctionalized prolines (320).

O THF, -78 °C — -40 °C Ph \*^ OMe NEt or DBU, LiBr H R 3 (201)

Li O Li Ph\ ^ OCH Ph\ ^ + 3 OCH3 OCH3 R R

Bn02C (317)

Bn02C

(318)

Bn0>2\2Q o

H02Q,

I \ R2 9NHC1, 120°C,24hr I \ R2

vO, Rf R3 "^N^C02Me S^\;02H H H2 cr

(318) (320)

Scheme 3.4 Chapter Three 119

Table 3.1. Results of the asymmetric 1,3-dipolar cycloadditions of azomethine ylides derived from (201) and benzyl A7-acryIoyl-(5)-proline ester (317).

Entry Imine (201) T(°C) Time Endo/Exo(31$):(319) yield R (hr) ratio (%)

1 H -78 ->25 72 >99.T 93:7 43

2 CH3 -40 72 >99:1 91:9 48

3a pri -40->-25 72 >99:1 >99:1 30

4a Bui -40 72 >99:1 >99:1 30

5 Ph -78 ->25 48 >99:1 >99:1 67

a In entries 3 and 4, DBU was used as base; in all other cases triethylamine was employed.

In 1995 Pyne et a/.125 reported the ejco-diastereoselective 1,3-dipolar

cycloaddition reaction of azomethine ylides derived from a-amino esters to the (R)-

oxazolidinone (321). The cycloaddition products were conveniently converted to

polyfunctional substituted prolines in high enantiomeric purity as shown in Scheme

3.5. The azomethine ylides were generated in situ from (201e,f) in the presence of

(R)-(321) by treating a THF or MeCN solution of the imine (201e,f), (R)-(32l) and

a metal salt with base (DBU or Et3N) at -78 °C. In each case a mixture of endo-(323)

and exo-(324) products was formed and these could be conveniently separated by

column chromatography. The cycloadducts (324) were converted to the highly

functionalised proline derivatives (325a,b) by treatment with sodium carbonate in

methanol at RT. The enantiomeric purity of (325b) was determined to be 92%. Chapter Three 120

CH2 O Ph. PhCON V* jC OR2 THF/LiBr/DBU PhCON Ph" H -78°C

endo-(323) (201e); Ri = CH2Pr\ R2 = Me

(fl)-(321) (201f); Rx = CH2Ph, R2 = Et

+

H C02R2 C02Me I,n NHCOPh

Na2C03/MeOH PhCON RT

(325a); R = CHaPr1

(325b); R = CH2Ph

Scheme 3.5

Galley et al. 126 reported the 1,3-dipolar cycloaddition reactions of chiral enones

(326) with azomethine ylides derived from imine (201g) under various conditions

(Scheme 3.6). Whereas LiBr, even at low temperature, gave a diastereoisomeric mixture of cycloadducts (327) and (328), reactions with AgOAc proceeded with high regio- and diastereoselectivities and only the diastereoisomer (327) (according to ^H and

13C NMR spectroscopy) was obtained at room temperature in most cases. An investigation of the influence of the chiral controller R* in (326) on the product diastereoselectivity showed that the highest diastereoselectivity was achieved with the bulky dibenzylamino substituent in the y-position (326d and 326e). An examination of the NMR spectra of the major diastereoisomers (327a-e) showed that the relative orientation of the substituents at C2 / C3 and C3 / C4 was anti and that of C4 / C5 was syn. This stereochemistry could be obtained by the regiospecific endo-cycloaddition of the W-shaped dipole to the (^-configuration of the dipolarophile in the transition state. Chapter Three 121

COCH3

Et02C

0 R CH3 cat/DBU Ph\^N THF O OEt

vsxCOCH3 (326) (201g)

Et02C

Scheme 3.6

3.2.2 Chiral Auxiliary Attached to the Dipole

In contrast to the relatively common study of 1,3-dipolar cycloaddition reactions to chiral dipolarophiles there is little published literature on the asymmetric 1,3- cycloadditions of chiral azomethine ylides.

Pioneering studies in the area of asymmetric cycloadditions using chiral azomethine ylides as 1,3-dipoles were reported by Padwa's group.127 They found that when the optically active a-cyanoamino silane (329) was treated with benzaldehyde in the presence of silver fluoride then a 1 : 1 mixture of diastereoisomeric oxazolidines

(330) was obtained, as illustrated in Scheme 3.7. Chapter Three 122

NCH^ /CH2Si(CH3)3 N AgF I Ph'^i^C^ PhCHO H (329) (330)

Scheme 3.7

Rouden et a/.128 reported the preparation of the chiral azomethine ylides (333) and their cycloaddition reactions with the electron deficient alkenes shown in Scheme 3.8. The chiral ylides were prepared in situ by the reaction of compounds (331) with trimethylsilyltriflate (TMSOTf) and a tertiary amine at -78 °C in CH2CI2, via the intermediate iminium ions (332). Polyfunctionalized pyrrolidines (334) and (335) were realised in high yield and in nearly equal amounts.

P\

'f-\ a); EWG = CN EWG> b); EWG = CQ2Me (331)

a)TMSOTf, CH2C12 E E b) Pr^NEt, -78 °C \=/ Ph. Ph.

EWG\^N^ OTMS EWO^r^ QTMS

(332) (333)

EWG Q •>/EW G TMS TMSCL J Ph (334) (335)

Scheme 3.8 Chapter Three 123

Husson et alJ2a prepared chiral 1,3-dipoles by introducing a chiral group such as

menthol or 8-phenylmenthol into the ester moiety of azomethine ylides. They reported

an excellent diastereofacial selectivity and complete exo diastereoselectivity in the

cycloaddition reactions of their chiral azomethine ylide with dipolarophiles. For

example, the single cycloadduct (337), was obtained in 86% yield from the reaction of

imine (336) and AAphenylmaleimide with TMSOTf (Scheme 3.9). A possible

explanation is that in the transition state (TS, Scheme 3.9) one 7t-face of the ylide is

completely masked by the phenyl ring of the 8-phenylmenthyl moiety.

OTMS

R O—

TMSOTf, CH2C12, -78 °C, 4 hr R* = (-)-8-Ph menthyl

(336)

Scheme 3.9

3.2.3 Asymmetric 1,3-CycIoadditions using a Chiral Catalyst

In 1991 Grigg and Allway73a reported the first 1,3-dipolar cycloaddition reaction between the ylides of glycine methyl ester (338a) and methyl acrylate using Mn(II) and

Co(II) complexes of (IR, 25)-ephedrine derivatives (339) as chiral catalysts. The most effective catalyst was the Co(II) complex which gave the target molecule (340) in 84% Chapter Three 124

yield and in 96% e.e. In the pre-transition state complex model, the phenyl substituent of

the ephedrine ligand effectively shields one face of the coordinated imine. Deprotonation

of this complex then gave the corresponding metallo-dipole as shown in Scheme 3.10.

^\ C02Me C0 Me OMe Ph, Me 2 CoCl , 2 f \ HO N

(339) (338a); Ar = 2-naphthyl (340a); Ar = 2-naphthyl (338b); Ar = 4-Br-C6H4 (340b); Ar = 4-Br-C6H4 (338c); Ar = 4-MeOC6H4 (340c); Ar = 4-MeOC6H4

Scheme 3.10

Hansen et al.129 have recently reported the asymmetric synthesis of aziridines

(344) from the cycloaddition of the substituted imines (341a-c) and diazoacetate using the chiral ligand Cu(I) hexafluorophopsphate [Cu(PF6)(CH3CN)4] and chiral bis(dihydrooxazole) (342) as a catalyst. When an excessive amount of ethyl diazoacetate was used, the racemic proline derivative (343a-c) was also formed, but in low yield (Scheme 3.11). Thus treatment of (341b) with a single equivalent of ethyl diazoacetate in the presence of two equivalents of diethyl fumarate gave the polyfunctionalized proline (343b) in 10% yield and no aziridine product. Chapter Three 125

H Ph + N2CHC02Et Ar N"

(341a); Ar = /7-H3CC6H5 (341b); Ar = /»-ClC6H4 (341c); Ar = C6H5

cis-(344) trans-(3 44)

Scheme 3.11

The authors proposed that a transient bis(dihydrooxazole)copper carbene complex was generated that reacted either with the diazoester to form a mixture of diethyl maleate and fumarate or with the imine nitrogen lone pair to form a metal-complexed azomethine ylide. The complexed ylide, could then undergo intramolecular ring closure to form the aziridine (344). Alternatively it may reversibly dissociate from the metal-ligand complex to form a free azomethine ylide which could undergo 1,3-dipolar cycloaddition with dimethyl fumarate to generate the racemic polyfunctionalized proline (343).

3.2.4 Other Asymmetric 1,3-Dipolar Cycloaddition Reactions

Recently Murphy et a/.130 reported a new application of the above mentioned methods using solid-phase synthesis techniques to form functionalized prolines and proline analogues. Thus several commercially available polystyrene peptide synthesis Chapter Three 126

resins, that were preloaded with Fmoc-protected amino acids, were used as supports for

solid phase synthesis. Piperidine deprotection provided the a-amino esters, which

smoothly underwent condensation reactions with aromatic aldehydes in dry trimethyl

orthoformate as solvent. In the presence of triethyl amine in CH3CN the imines reacted

with methyl acrylate at room temperature to give the resin-bound proline derivatives in

good yields. An HPLC analysis of the preparative solid-phase synthesis of the

thioacetate proline analogues (345) showed that the crude product consisted

predominantly of a mixture of the two endo diastereoisomers (345a) and (345b) as

shown in Scheme 3.12.

O a, b,c NHFmoc Jy^ - .~o^ Ar R

Me02C

C02H

SAc SAc

(345a) (345b)

(a) 20% Piperidine in DMF, 20 min; (b) 1 M ArCHO in CH(OMe)3, 4 hr; (c)Ac20, NEt1Pr2, 15 min; (d) Methyl acrylate, 1M NEt3 in MeCN, 8 hr. * Fmoc: 9-Fluorenylmethoxycarbonyl

Scheme 3.12

3.3 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides (348) with Oxazolidinone (222)

The azomethine ylides (348) were prepared conveniently by deprotonation of the a-imino esters (201) with a base (DBU or NEt3) in a solution of THF or CH3CN in the presence of a metal salt (ML = LiBr or AgOAc in Scheme 3.13). The metal cation Chapter Three 111 serves as a Lewis acid, which by association with the carbonyl oxygen and / or the imine nitrogen, causes an enhancement of the acidity of the a-proton of the a-imino ester

(201) and also enables the formation of stable chelates as intermediates (eg. (347) and

(348). The imines (201b, d-g) were prepared in a straightforward manner by condensation of benzaldehyde with the hydrochlorides of a-amino esters (346) according to the literature (Scheme 3.13).133

O + H 0, Na C0 C1H3N 2 2 3 PhCHO,

ML, base THF or CH3CN

OR Ph^N 2 OR2

(348) (347)

b; Ri = Me, R2 = Me

d; Ri = Ph, R2 = Me i e; Ri = CH2Pr ,R2 = Me

f; Ri = CH2Ph, R2 = Et

g;Rl=H,R2 = Et

Scheme 3.13

In our investigations of the 1,3-dipolar cycloaddition reactions of azomethine ylides (348) with the oxazolidinone (S)-(222) we examined four different methods for generating the ylides. Method I involved treating the imines (201) with AgOAc and

DBU in THF as solvent In Method II we used lithium bromide as the metal salt instead of the silver acetate, and in Method III, we used the metal salt / base combination of,

LiBr / Et3N, in CH3CN as solvent. Method IV involved the use of LiBr and Et3N in

THF as solvent. Chapter Three 128

3.3.1 1,3 Dipolar Cycloaddition Reaction of Ethyl N-benzylidene glycinate (201g) with Oxazolidinone (S)-(222)

When a solution of ethyl TV-benzyhdene glycinate (201g) and oxazolidinone

(5)- (222) was treated according to Method I (AgOAc / DBU / THF) at -78 °C for

3 hr and then at RT overnight, an 81 : 19 mixture of the two diastereoisomers endo-

(349g) and exo-(350g), respectively was formed based on ^H NMR spectroscopic analysis (Scheme 3.14). The two diastereoisomers were separated by column chromatography using 20% ethyl acetate / hexane giving (349g) and

(350g) in a combined yield of 90% (Table 3.2). When this reaction was carried out at room temperature for 12 hr, the reaction proceeded with a poorer diastereoselectivity (62 : 38). When the reaction was performed using Method II

(LiBr / DBU in THF) at -78 °C for 3 hr or at RT for 10 min, or Method IH (LiBr /

Et3N in CH3CN) at -78 °C for 2 hr or at RT for 0.5 hr, then the Michael adducts

(351) were the main products. However, because of the complicated ^H NMR spectra of the crude reaction mixture, the ratio of diastereoisomeric cycloadducts could not be determined in these latter reactions. Attempts to separate the Michael adducts from the cycloadducts by column chromatography resulted in the isolation of the lactam (352) in the yields reported in Table 3.2. The lactam (352) was thought to arise from the Michael adduct (351) via hydrolysis of the imine group of

(351) on the silica gel and then cyclization of the resulting amino lactone to the lactam. Chapter Three 129

H2C O metal salt, solvent Ph PhCON^^O + OEt base Bu1 H H

(5j-(222) (201g) Li--

OEt OEt

H H N-4—c°2Et

Cycloadducts

endo-(349g)

+ Et0 C H Ph 2 H >N-V FL NNCOPh Michael adducts H \ hydrolysis on • O silica gel PhCON >° Buf H (352) (351) Scheme 3.14

The ratio of the cycloadducts to the Michael adducts was dependent on the reaction conditions as well as the metal atom. As can be seen in Table 3.2 , silver salts in the presence of DBU promote clean cycloaddition while the more exophilic lithium Chapter Three 130 salts, in the presence of DBU or Et3N in THF, gave mixtures of cycloadducts and

Michael adducts.

Table 3.2. Methods and conditions used for the reactions of azomethine ylide (348g) with oxazolidinone (5)-(222).

Method Conditions Yield (%) of lactam Yield (%) of (352) Cycloadducts (dr) (349g+350g) (dr) I AgOAc/DBU/THF (-78 oc, 12 hr) 0 90(81: 19)

I (RT, ON) 0 88 (62 : 38) II LiBr/DBU/THF (-78 °C, 2 hr) 57 (63 : 37) 13a

II (RT, 10 min) 63 (65 : 35) 12a

III LiBr/Et3N/CH3CN (-78 °C, 2 hr) 80 a 2a

III (RT, 0.5 hr) 65 (78 : 22) 10a

a Diastereoisomeric ratio not determined

Replacement of THF by CH3CN favoured the Michael adducts. This was thought to be due to the greater stabilization of the more polar Michael addition transition state by the polar solvent (CH3CN). Further details of structure of the Michael adducts and their resulting lactams (352) will be discussed in Chapter Four of this thesis.

The major diastereoisomeric cycloadduct (349g), was shown to have the 'endo ' stereochemistry by a single crystal X-ray structural determination. As shown in Figure

3.1, the X-ray structural analysis also indicated that the stereochemistry of (349g) was consistent with addition of the azomethine ylide (348g) to the 71-face of the

Figure 3.1. Molecular projection of the endo cycloadduct (349g) a) normal to the plane offive membere d ring; b) on the plane of C3NO. Chapter Three 132

The *H NMR spectrum of (349g) showed broad peaks for all protons, even at +55 °C.

This was thought to be due to restricted bond rotation about the benzamide N-C bond because of its sterically crowded environment.

The structure of the minor exo diastereoisomer (350g) was confirmed by comparison of its *H NMR spectrum (Table 3.4) with that of the compounds

(350e) and (350f) whose structures were established by single crystal X-ray structural analyses. In contrast to the lU NMR signals for (349g), those of

(350g) were relatively sharp, even at room temperature. The signals for the two upfield 'ortho'-aromatic and downfield 'meta'-aromatic protons of the C-5' phenyl group appeared as a doublet at 6.50 ppm and a triplet at 7.15 ppm respectively. The

H-5' proton appeared as a singlet at 4.71 ppm. Both H-3'a and H-3'(3 protons were observed as two doublet of doublets at 3.20 and 2.93 ppm (J = 13.5 Hz) respectively. From a previous study it has been shown that in related exo cycloadducts the signal for H-3'a appears downfield of that of H-3'P (Figure

3.2.).125 Chap,ter Three 133

,1

to

' S 3

o QTQ

LO

LO

8 to

iS td LO

Figwre 3.2. *H NMR (400 MHz, CDC13) spectrum of compound exo (350g) Chapter Three 134

The heats of formation for the endo cycloadduct (349g) and exo cycloadduct

(350g), using SPARTAN and the AMI semi-empirical molecular orbital calculation methods (Figure 3.3) , were AHf = -74.9 kcal mol1 and -109.4 kcal mok1

respectively. These values indicated that the exo product (350g) was thermodynamically more stable than the endo cycloadduct (349g). Consequently the

endo cycloadduct (349g) was expected to be the kinetically favoured product from the

reaction of the ylide (348g) and (5)-(222).

j^ \ ^C02Et

endo-(349g) exo-(350g)

cS 9 O0Qo 6&>

oo CP O P o o O 0 t)

1 -l AHf = -74.9 kcal mol AHf =109.4 kcal mol

Figure 3.3. Energy minimised structures for (349g) and (350g) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Chapter Three 135

3.3.2 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides (348 b, d-f) with Oxazolidinone (S)-(222)

1,3-Dipolar cycloaddition reactions of the azomethine ylides (348d,b-g) with oxazolidinone (S)-(222) were carried out via Methods I, II, III and IV for the reaction times and temperatures indicated in Table 3.3. Method II, involving LiBr /

DBU in THF, gave the best diastereoselectivities and resulted in only one diastereoisomer being formed from lH NMR (400 MHz) analysis of the crude reaction mixtures

(Scheme 3.15). When the Methods I, III, or IV were employed the reactions did not go to completion and unreacted oxazolidinone (S)- (222) remained even after one week at RT in the presence of an excess of the imine. The corresponding Michael adducts, that could arise from conjugate addition of (348) to (222), could not be detected.

H\ 7? PhCON^/O OR? H R! Bu* H (S)-(222) (201)

AgOAc, DBU THF, -78° C

Rl Ph-^^N OR;

b;Ri = Me,R2=Me

d; R! = Ph, R2 = Me Bu ! x4 * e; Ri = CH2Pr , R2= Me f;R1 = CH2Ph, R2=Et

y H Ri „« f-Ph H \kA+C02R2

R202C-V,0 PhCON^X PhCON f Bu<-llY° Bu1 \-0 0l H H' regioisomer-(353) e*o-(350)

Scheme 3.15 Chapter Three 136

When a solution of the oxazolidinone (S)-(222) was treated initially at -78 °C

with methyl /Y-benzylidine alaninate (201b) according to Method II, the reaction was

complete after 5 hr. However the cycloaddition reaction was complete within 1 hr when

the reaction was performed at RT. !H NMR of the crude reaction products showed only

a single diastereoisomeric cycloadduct had formed and no products from a competitive

Michael addition reaction could be detected. This single cycloadduct was readily purified

by column chromatography using 20% ethyl acetate / hexane. The reactions of the other

imines (348 d-f) with oxazolidinone (5)-(222) were performed using Method II for

the reaction times and temperatures given in Table 3.3. The crude products were

purified by column chromatography to give diastereomerically pure cycloadducts in the

yields indicated in Table 3.3.

Table 3.3. Asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides (348) with oxazolidinone (S)-(222)

Imine Ri R2 Temp Time Endo : Exo Yield (°C) of (350) (201b)a Me Me -78 5hr <2 : >98 84% RT lhr <2 : >98 4%

(201d)a Ph Me -78 6hr <2 : >98 77% RT 2hr <2 : >98 NDC

(201e)a CH2Pri Me -78 9hr <2 : >98 59% RT 3hr <2 : >98 68%

(201f)a CH2Ph Et -78 12 hr <2 : >98 72% RT 4hr NDC 65%

(201g)b H Et -78 3hr 81:19 90%d RT ON 62:38 88%d

a Using the conditions defined in Method H. b Using the conditions defined in Method I. c Not determined. d Combined yield of (349g) and (350g), in these reactions (349g) is the major diastereoisomeric product. Chapter Three 137

The exo stereochemistry of compounds (350e) and (350f) was established by single crystal X-ray structural analyses. The ORTEP plots of the crystal structures of

(350e) and (350f) are shown in Figure 3.4 and Figure 3.5 respectively. i H CH2Pr

ejco-(350e)

Figure 3.4. Molecular projection of the exo cycloadduct (350e) normal to the plane of five membered ring. Chapter Three 138

H CH2Ph V-4-*c°2Et

PhCO

exo-(350f)

Figure 3.5 Molecular projection of the exo cycloadduct (350f) normal to the plane of five membered ring.

The cycloadducts (350b) and (350d) were assigned the 'exo' stereochemistry from a comparison of their *H NMR spectra with that of compounds (350e) and Chapter Three 139

(350f). The chemical shifts for the two upfield 'ortho' and two downfield 'meta'

benzamide aromatic protons in the *H NMR spectra of these compounds were almost

identical and appeared as a doublet in the chemical shift range at 6.45-6.50 ppm and a

triplet in the chemical shift range at 7.11-7.16 ppm respectively (Table 3.4). In the

NOESY spectra of (350f) a strong cross peak was observed between the rerf-butyl

group at 0.61 ppm and the aromatic proton signals at 6.49 ppm, while a weak cross peak

was observed between theterf-butyl grou p and the aromatic proton at 7.16 ppm. These

experiments confirmed the assignment of these aromatic protons. Similar chemical shifts

for the 'ortho' aromatic protons was reported previously by Safaei 125 for the exo-

cycloadducts from the reaction of /V-benzylidene ylides and the oxazolidine (R)-(32\).

Likewise the chemical shifts for the H-2 in these compounds appeared in the narrow

range of 5.43-5.51 ppm. Some variations were notifed for the chemical shifts of H-3'a,

H-3'p and H-5' in these compounds due to the different nature of the C-2' substituent.

Table 3.4. Comparison of the *H NMR chemical shifts (CDCI3) of H-2, H-5', H-3a, H-3'p and o-aromatic and m -aromatic protons of the exo cycloadducts (350b,d-g).

cycloadduct H-2 H-5* H-3'a H-3'p 0 and in-ArH

(PP m) (ppm) (ppm) (PPin)

(350b) 5.48 4.94 3.68 3.42 6.48 7.16

(350d) 5.43 4.67 3.93 3.37 6.50 7.16

(350e) 5.45 4.80 3.30 2.62 6.46 7.14

(350f) 5.46 5.05 3.45 2.82 6.45 7.11

(350g) 5.51 4.71 3.20 2.93 6.50 7.14 Chapter Three 140

CO2CH3

Bu1

exo-(350e)

0-CH„ CHMeMe m-ArH

CH(Me)2

o-ArH H2 H5' NH H3'a H3'P

CHMeMe

LL. _J\__ JUL. Lxu UL

Frgwre 3.6. ^ NMR (400 MHz, CDCI3) spectrum of the exo cycloadduct (350e).

COSY experiments on the cycloadduct (350e) were used to assign the ^H NMR spectrum of this compound. The COSY spectrum of compound (350e) showed a strong cross peak between H-3'a (3.30 ppm) and H-3'p (2.62 ppm) and indicated that neither H-3'a nor H-3'p were coupled to other protons. In the !H NMR spectrum of this compound (Figure 3.7) the signals for these two protons appeared as two distinct doublets and there was no coupling between these protons and H-5' which confirmed that the 2',2',3',3',5'-pentasubstituted regioisomer (350) was obtained and not the Chapter Three 141 regioisomer (353) (Scheme 3.15). This structure was also established by X-ray structural analysis as showed in Figure 3.4.

CHACHBPr1 Pr1

CH CHp a CHACHBPr1

f^ IUU

F2 (ppml -e.«

0.5-

1.0-

1.5-

e.e-

S.5-

3.0-

3.5-

-i—|—i—i i i | i i—i—i—|—i i i—i | i i i i—| i i i i E.0 1.5 1.0 0.5 -0.0 FI (ppm)

Figure 3.7 COSY NMR spectrum (400 MHz, CDC13) of the exo cycloadduct (350e).

In the NOESY spectrum of (350f) a cross peak was observed between H-5'

(5.05 ppm) and the signal at 2.82 ppm (d, J= 14.4 Hz). This cross peak identified the Chapter Three 142 signal at 2.82 ppm as being associated with H3'P rather than the H3'a (3.45ppm, d, J =

14.4 Hz). A strong cross peak was observed between H-5' (5.05 ppm) and HA and HR of the CHA CHfiPh moiety as shown in Figure 3.8. This cross peak confirmed the cis stereochemical relationship of H-5' and the benzyl group and consequently the cis stereochemical relationship between the C-5' phenyl and C-2' COOEt groups. The strong cross peak between the terr-butyl group (0.61 ppm) and H-3'a (4.45 ppm) and H-

3'P (2.82 ppm) confirmed that the tert-bvXy\ group and C-3' were syn. This observation also confirmed that the 1,3-dipolar addition reaction took place from an exo type transition state, anti to rerf-butyl group of (5)-(222).

H3'cc

CHACHB^ H3'P ^ 3.S- CHACHg ^

Figure 3.8. NOESY NMR spectrum (400 MHz, CDC13) of the exo cycloadduct (350f). ChapterThree 143

These observed NOE cross peaks were consistent with the close proximity of H-

5' to H3'P and HA of CHACHRPII moiety, and also the tert-b\xty\ group and H3'-a and

H-3'-P in (350f) from the energy minimised structure of this compound as shown in

Figure 3.9.

Figure 3.9. Energy minimised structure for (350f) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Double headed arrows indicate interatomic distances and observed NOE cross peaks in the NOESY spectrum of this compound. Chapter Three 144

3.4 Mechanistic Details of the 1,3 Dipolar Cycloaddition

Reaction of Azomethine Ylides

As we explored in the Introduction of this Chapter (3.1), azomethine ylides show a high diastereoselectivity and high regioselectivity in their reactions with electron deficient alkenes. The regiochemistry of 1,3-dipolar cycloadditions is controlled by the magnitudes of the atomic coefficients in the participating frontier molecular orbitals

(FMO).64'131 It was found that the HOMO's of almost all the parent 1,3-dipoles have larger values of atomic coefficients for the 'anionic' terminus c than the 'neutral' terminus a (Figure 3.10). Control of regioselectivity by the dipole HOMO will lead to products with the substituent remote from the 'anionic' terminus for electron-deficient dipolarophiles and to products with the substituent near the 'anionic' terminus for electron rich dipolarophiles. From these generalizations and the magnitudes of atomic coefficients, Houk et alA32 have rationalized the regioselectivity of all 1,3-dipolar cycloadditions as shown in Figure 3.70.132 h ^x 4-substituted isomer HOMO of dipole a c a—b c + - z H

LUMO of dipole z * x a c 5-substituted isomer \-7

Figure 3.10. Regioisomer expected from HOMO or LUMO control by the dipole. Chapter Three 145

The dipolarophile (5)-(222) contains one electron withdrawing group (lactone carbonyl moiety) and one electron releasing / withdrawing (by induction) group (benzamido group) and would be expected to be moderately electron deficient (Figure 3.11).

Figure 3.11. The resonance structures for the carbonyl and benzamide groups which show the captodative effects in the oxazolidione (222).

It has been concluded that the azomethine ylides are electron rich species and react preferentially with alkenes to yield the cycloadducts via a transition state that favours 4- substituted adducts. These regioisomers arise from a favourable HOMOdipoie-

LUMOdipolarophile interaction.132 The FMO interaction can be used to explain the regiochemistry of the 1,3-dipolar cycloaddition reaction of the azomethine ylides (348) and oxazolidinone (5)-(222) to give only 2', 3', 3', 5', 5'-pentasubstituted cycloadducts and none of the regioisomer cycloadduct (353). The HOMO of azomethine ylides, shown in Figure 3.12, are similar to the HOMO of an allyl anion and have a node through the central N atom. Chapter Three 146

dipole dipolarophile 'exo' TS

Figure 3.12. FMO description of the interaction between the 1,3-dipole (348) and alkene (5)-(222) in the exo transition state.

Such a regioselectivity of cycloaddition reaction of these azomethine ylides to

alkene (321) was reported by Pyne and Safaei.125 It has also been reported that endo

cycloadducts are generally formed in 1,3-dipolar cycloaddition reactions of azomethines

and exo cycloadducts are not common in these reactions. To explain the preference for

the exo cycloadducts in the reaction of our alkene (5J-(222) and azomethines (348b,d-

f) and the preference for endo cycloadduct in the case of azomethine ylide (348g), we

suggested the transition states as shown in Scheme 3.16.

In the endo transition state for azomethine ylides (348b, d-e) where R2 * H, there is an

unfavourable steric interaction between the R2 group of the azomethine ylide and the benzamide group of the oxazolidinone that destabilises the endo transition state. In the case of azomethine ylide (348g, R2 = H) however, the steric interaction between hydrogen and the benzamide group is much less severe and the endo transition state is favoured because of a stabilizing secondary orbital interaction.133 In the exo transition state the metal cation can be chelated intramolecularly to the amide and ester carbonyl groups of the azomethine ylide and the A^-benzoyl carbonyl group of the chiral oxazolidinone ring. Chapter Three Ul

Li- — ,

steric interaction between R2 and benzamide group 'endo' TS 'exo' TS

Scheme 3.16

The stabilizing secondary orbital molecular interaction between the nitrogen of the

azomethine ylide and the benzamido nitrogen of the oxazolidinone (222) in the

HOMOdipoie-LUMOdipolarophile interaction is shown in Figure 3.13.133

HOMO

secondary orbital molecular interaction

LUMO

Figure 3.13. Secondary orbital molecular interaction between dipole (348) and dipolarophile (5)-(222) in the endo transition state.

Alternatively, the reaction leading to the cycloadduct might proceed via a stepwise mechanism similar to that proposed by Grigg134 (See Chapter Four, Section 4.6). Chapter Three 148

3.5 Synthesis of Polyfunctionalised Prolines

All attempts to convert cycloadducts (350) to polyfunctionalised prolines (353) by base catalysed methanolysis using sodium carbonate in methanol or sodium methoxide in methanol were not successful and only unreacted starting material was recovered. In the case of (350f,g) only ester exchange was observed. This kind of ring opening reaction was successful in previous work when the Ri or R2 group at C-2 in the oxazolidinone ring of the cycloadducts (229) was phenyl.133 It is possible that the sterically bulky rerr-butyl group at C-2 in the oxazolidinone moiety of the cycloadducts

(350f,g) is responsible for the lack of reactivity of thering carbonyl . Thus we prepared the polyfunctionalised proline (354) by hydrolysis of the endo-cycloadduct (349g) using 6N hydrochloric acid at 80 °C for 12 hr. The pure amino acid (354) was obtained in 93% yield by passing the crude hydrolysate through a DOWEX -50 [H] ion exchange column and eluting with 0.1 M aqueous ammonia. Surprisingly the benzamide group of

(349g) was resistant to hydrolysis. The lH NMR (300 MHz, D2O) spectrum of this compound showed a singlet at 5.60 ppm for H5, while the signals for H-2, which were coupled with H-3a and H-3p, appeared as a doublet of doublets at 6 4.45 ppm with coupling constants J = 11.2 and 7.5 Hz. The o-ArH of the phenyl moiety of the benzamide group appears as a doublet at 7.78 ppm. The !H NMR signals were readily assigned from a COSY NMR experiment on this compound. The 13C NMR (300 MHz,

D2O) spectrum of (354) showed the presence of three carbonyl groups. The signals at

174.9, 172.7 ppm were assigned to the carbonyl groups of the two carboxylic acid groups and one signal at 169.7 ppm was assigned to the carbonyl group of the benzamide group. The proline derivative (354) had a specific rotation of [a]D28-102° (c 0.015,

H20). Chapter Three 149

H C02Et C02Me ,u NHCOPh Na2C03/MeOH

or NaOMe in MeOH H

(325) (229); Ri = Ph, R2 = H

(350); Ri = H, R2= Bu* No reaction

H C02CH2CH3 C02H iH 3 __!!*• NHCOPh HC1 6N/ 80°C 5 i^H 12hr, Ion exchange H0 C PhCON 2 H

H Bu1 endo-(349g) (354)

Scheme 3.18

3.6 Conclusion

In this Chapter, the synthesis of polyfunctionalized proline derivatives via the asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides derived from N- arylidene imino esters (347) with the chiral oxazolidinone (5)-(222) as a dipolarophile have been presented. The cycloadducts were obtained with high regio- and diastereoselectivity resulting from addition to the exo-cyclic methylene of oxazolidinone

(5)-(222) from the less hindered side of the oxazolidinone ring. Good endo- diastereoselectivity and high yields were obtained from reaction of the dipolarophile (S)-

(222) and ethyl /Y-benzylidene glycinate (201g) using AgOAc as a metal salt. While the cycloaddition reactions of ylides derived from the a-substituted imines (201b,d-f) and (5)-(222) proceeded with high gjto-diastereoselectiviy using LiBr / DBU in THF as solvent. The stereochemistry of the products has been elucidated by single crystal X-ray structure analysis, 2D *H NMR, (COSY and NOESY), 13C NMR spectroscopy and computer molecular modelling. 150

CHAPTER FOUR

ASYMMETRIC MICHAEL ADDITION REACTIONS OF a-IMINO ESTERS TO CHIRAL OXAZOLIDINONES Chapter Four 151

4-1 Introduction

The asymmetric Michael addition reactions of a-imino esters, as a route to polyfunctional substituted proline derivatives, is an early development in asymmetric synthesis.134"13** This method involves the reaction of an electron deficient alkene with a sterically bulky AA-substituted a-imino ester. The latter are readily prepared from the condensation of a sterically bulky carbonyl compound, such as pivaldehyde, benzophenone or camphor, with an a-amino ester. One effective approach in obtaining a high degree of diastereoselectivity is via the double asymmetric induction method.

However, the reports of Michael additions that employ this approach using chiral imines and a chiral Michael acceptor are few.136

In this Chapter, the synthesis of polyfunctional substituted proline derivatives via the

Michael addition reactions of the chiral oxazolidinone (222) with imines of a-amino esters will be examined.

4-2 Asymmetric Michael Addition Reactions of a-Imino Esters

The Michael addition reaction of methyl [(2,2-dimethylpropyhdene)-amino]acetate

(212a) and methyl crotonate was reported by Kanemasa et al.77 They reported that the enolate (354), derived from imine (212a) under reversible protonation-deprotonation conditions using LiBr and DBU, reacted with methyl crotonate to give after 4 hr a 7 : 6 mixture of the two diastereoisomeric Michael adducts (355a) and (355b) (Scheme

4.1). The diastereoisomer ratio was dependent upon the reaction time and was found to be 1 : 1, after 24 hr at room temperature. When the reaction mixture was quenched after

10 minutes at room temperature, then the single anti adduct (355a) was the only isolated product in 77% yield. Kanemasa et al. also reported that a-substituted imines, for example, the alaninate imine (212b), and methyl crotonate gave the Michael adduct

(358) as a single diastereoisomer (Scheme 4.1). Epimerization of the Michael product by base is not possible in diis latter case. Chapter Four 152

Li Bu\ ^L ,C02Me LiBr/DBU Bu N THF OMe YH YH (212a) (354)

RT, 10 min 4hr, RT COMe Me/s / Me Me BuV .N C02Me t I DBU BuL^N^^^COzMe

H C02Me :02Me 7 : 6 mixture of (355a) and (355b) (355a)

HOAc MeOH

R

C02Me xY,H (356); R = H (357); R = Me

II HOAc

1 C02Me LiBr/DBU, THF Bu C02Me

H Me H Me C02Me ,C02Me Me' (358) (212b)

Scheme 4.1

The first Michael addition reaction of an a-substituted N- diphenylmethylideneglycinate (218a) with ethyl propiolate was reported by Rubio and

Ezquerra.139 Thus when the ketimine (218b), was reacted with ethyl propiolate, at Chapter Four 153

-78 °C in THF and in the presence of KOBu1 for 5 hr, a mixture of Michael adducts

(Z)-(359) and (£')-(359) was obtained in high yield. The (Z)-alkene was converted to

the 3,4-dehydropyroglutamate (360) during deprotection using 3N HC1, as outlined in Scheme 4.2.

Ph >=N N i. KOBu1 C02Et Ph \—C02Et R ii. RX (218a) (218b); R = CH3

.t1 ;: i. KOBu ii.HC=C02Et

Ph N. C02Et Ph r\^C02Et R + \ C02Et Et02C (Zj-(359) (E)-(359)

i. 3N HC1 ii. NaOH

C02Et

(360)

Scheme 4.2.

The lithium enolates derived from the camphor imines of a-amino esters were developed by Mcintosh's140"141 group for the asymmetric alkylation of a-amino acids.

They also reported that the Michael addition reactions of camphor imines to some a,P- unsaturated carbonyl compounds proceeded with low diastereoselectivities and low yields.

Wada et al.19 have developed this methodology further, using a-ketimines derived from camphor and glycine esters as chiral nucleophiles for the asymmetric Chapter Four 154

Michael addition reactions to a,P~unsaturated esters, as shown in Scheme 4.3.

Reaction of terr-butyl AAbornylideneaminoacetate (361) with n-butyllithium in THF

generated enolate (362) at -78 °C, that underwent a Michael addition reaction with tert-

butyl crotonate (363) in the presence of terr-butyl alcohol, to give a 95 : 5 mixture of

two diastereoisomeric adducts (364a,b). Formation of only two of four possible

diastereoisomers was due to the high anti selectivity displayed in the Michael addition.

On treatment of (364a,b) with hydroxylamine in acetic acid and ethanol, a single

diastereoisomer of terr-butyl ?rans-3-methyl-5-oxopyrrolidine-2-carboxylate (365) was

obtained. Reduction of the amide moiety of lactam (365) with borane-THF gave tert-

butyl rra«5-3-methyl-5-pyrrolidine-2-carboxylate (2R, 3i?)-(366). Ester (366) was

hydrolyzed with trifluoroacetic acid (TFA) to give (2/?,3/?)-3-methyl-2-pyrrolidine-2-

carboxylic acid (26a) in 57% yield. \y LDA-BulOH

-78°C OBu1 t C02Bu

(361)

Me ^^C02Bu' (363) CH3 l C02Bu 1 ^T^CO.Bu NH2OH/AcOH N EtOH H (365)

BH3.THF

.2V^C02R

(366);R = Bu4 TFA r (26a); R = H Scheme 4.3 Chapter Four 155

4-3 Double Asymmetric Induction in Michael Addition Reactions of Imines

Double asymmetric induction has been achieved in the Michael addition reaction of chiral imines to chiral a,P-unsaturated compounds. Tatsukawa et a/.138 reported a double asymmetric induction in the Michael addition reaction of the chiral acceptor, ethyl

(J5)-3-[(5)-2,2-dimethyl-l,3-dioxalan-4-yl]propen-2-ate (369), with ethyl N-[(1R, 4R)- bornylidene)glycinate (367). Thus lithium enolate (IR, 4R)-(368) was formed by treatment of (IR, 4R)-(367) with terr-BuOLi at -78 °C in THF. This enolate upon reaction with (369) at -78 °C for 2 hr, gave (370) as a single diastereoisomer in 73% yield after purification. The camphor auxiliary was removed from the Michael adduct by treatment of (370) with hydroxylamine acetate under reflux in ethanol to give lactam

(371) in good yield. The absolute configuration of (371) was determined to be

(2R, 3R) based on a single crystal X-ray analysis of its sulfonamide derivative (372)

In the proposed transition state (TS-(373)) for the formation of (370) the authors suggested that the adduct formed via the attack of the re-face of the enolate (368) to the si-face of (5)-(369) (Scheme 4.4). Chapter Four 156

9 \7/ 8 \/

LDA-BulOH Li O Ns 6-/ ^V ^\ THF,-78°C OEt 10 N^^C02Et H (367) (368)

2hr -78 °C

C02Et

NH2OH/AcOH EtOH / reflux

(371); R = H (370) (372); R = SOiQHiMe-/;

C02Et

TS-(373)

Scheme 4.4 Chapter Four 157

4.4 Asymmetric Michael Addition Reactions of Imines of oc-Amino Esters to Chiral Oxazolidinone (222)

The results of the Michael addition reactions of the aldimines142-143 (201g) and

(212a,b) and ketimines144 (218b-e) and (361)140 with oxazolidinones (S)-(222) and (R)-(222) are reported in this Chapter. In all cases, except the imine (201g) which gave a mixture of the Michael adducts and the 1,3-dipolar cycloaddition adducts, the

Michael adducts were the sole products and no cycloadducts were observed.

4.4.1 Asymmetric Michael Addition Reactions of Ethyl AA(benzylidene) glycinate (201g) to Oxazolidinone (S)-(222) and (R)-(222)

As was mentioned in Chapter Three (Section 3.3.1), the reaction of ethyl

AAbenzylidene glycinate (201g) with the oxazolidinone (222), in the presence of LiBr /

DBU in THF, gave a mixture of the Michael adducts (351a,b), as the major products, together with a mixture of the cycloadducts (349g) and (350g), as the minor products

(Table 4.1). The Michael adducts were too sensitive to be purified and hydrolytic decomposition occurred during their attempted purification on silica gel. The ratio of the diastereoisomeric Michael adducts was determined by converting them to their lactams

(352a) and (352b) (Scheme 4.6 and Scheme 4.7), by treatment of the crude reaction mixture with acetic acid in aqueous methanol and dioxane. Fortunately the pure major Michael adduct (351a) precipitated during the progress of the reaction and it could be obtained pure in 80% yield by filtration of the crude reaction mixture before aqueous work up. Treatment of the pure major Michael adduct (351a) with DBU and LiBr in

THF at RT for 16 hr gave a mixture (85 : 15) of the major and minor diastereoismers

(351a) and (351b), respectively. This experiment indicated that epimerisation at C-2' and / or C-4 was occurring during the Michael reaction of (201g) and (5)-(222). We suspect that epimerization is occurring by deprotonation of the more acidic proton H2' rather than at H4 on oxazolidinone ring. Based on these assumptions the stereochemistry of (351b) is assumed to be (2S, 4R, 2'R). Chapter Four 158

H2C

Ph N. ,C02Et + PhCON^ 0 LiBr / DBU H w Bo'" H ^S

(201g) (S)-(222)

(351a) + minor isomer (351b) + cycloadducts

Scheme 4.5

Table 4.1. Results of the asymmetric Michael addition reactions of oxazolidinone (222) with imine (201g) in the presence of LiBr / DBU in THF followed by hydrolysis of the crude Michael adducts to their corresponding lactams (352a) or ent-(352a).

Oxazolidinone Imine Michael Conditions Major lactam (222) (dr, yield) Temp Time (°C) (S) (201g) RT 15 min (352a)a (62 : 38, 57%) (R) (201g) -78 °C 2hr ent-(352a)a (65 : 35, 63%) (R) (201g) RTb 30 min enr-(352a)a (78 : 22, 65%) a Cycloadduct was also observed. b Et3N as base in CH3CN as solvent. Chapter Four 159

The structure of the Michael adduct (351a) was determined by ^-H NMR and 13C

NMR spectroscopy, IR spectroscopy, DEPT, COSY and NOESY experiments. The lB

NMR (400 MHz) spectrum of (351a) showed a singlet at 8.32 ppm which was assigned to the CH=N imine moiety of the Michael adduct (Figure 4.1). The carbon atom attached to this proton appeared at 165.6 ppm in the 13C NMR spectrum of (351a). A strong IR band was observed at 1636 cm"1 that was a characteristic absorption for the

HC=N moiety. Furthermore, two downfield doublet of doublets at 4.44 and 4.06 ppm were also consistent with the a-amino lactone and the a-imino ester methine groups in

(351a) respectively. Further evidence for this structure was obtained from 13C NMR and DEPT spectrum that showed that (351a) had two CH3 groups, two CH2 groups, ten CH groups, two quaternary carbons, one CH=N group and three C=0 groups as shown in Figure 4.2. Chapter Four 160

Crt ~) to 65

ac ac to o "1 lac o ac U>

L. ac

L. DC u> ac O

e cr r

Fi£wre 4.7. *H NMR (400 MHz, CDCI3) of the major Michael adduct (351a). * CHCL Chapter Four 161

n

in i—» 1 P

o

n O

o n

?J

13 Figwre 4.2. Decoupled C NMR (75 MHz, CDC13) spectrum of the major Michael adduct (351a). * CDCL Chapter Four 162

More substantial support for the structural assignment of (351a) was obtained from ID

NOE difference experiments of this compound which are shown in Figure 4.3. Upon

irradiation, the signal due to of H-4 (4.44 ppm) of the oxazolidinone, an enhancement in

the signal of the terr-butyl at 0.94 ppm was observed. Similarly, irradiation of the tert-

butyl group resulted in an enhancement of the H-4 signal at 4.44 ppm. These results

confirmed the cis relationship of the rerf-butyl group and H-4 and the (2S, 4R)

stereochemistry of the major Michael adduct.

c) %»»r»»h'»wii»i„i'iii»iin«iln'pi ltU>w»tw III'WI I*I li'ii^iMii'ili^iilfii ^,w w^^iiy^|i,i^i>)i)«.>.iW|l^|i|>i,),l^^i>|il^>,i,

b) nuii ' ln'ii't" Wi iJiM'lM'ii'i •lliil'iiiii^iilfiiiiiUriiMrt '<'n«,|>^7iir'*i^iiinirt||ii^' ii^i<||i>i'll''*|i''\ii i|i4 (,ii|juij iiq i|. , i )|,j J l 1 l U jr l i l i

Bu1

H-4

a) I OJ

c'b z-e 1-5 l.B , Figure 4.3 Difference *H NMR spectra from ID NOE experiment of the Michael adduct (351a). a) Unperturbed spectra with irradiation off- resonance, b) Irradiation of H-4. c) Irradiation of rerf-butyl group. Chapter Four 163

The (2S, 4R, 2'S) stereochemistry of (351a) was determined by comparing the lB. and

13C NMR spectra and optical rotation of its related lactam (352a) with that of the lactam ent-(352a). The lactam

/Y-(diphenylethylidene)glycinate (218b) and (R)-(222), whose structure was established by single X-ray structural analysis (Section 4.4.3).

When a solution of the pure major Michael adduct (351a), in aqueous acetic acid, methanol and dioxane, was heated to reflux overnight, ethyl frans-4-benzamido-5- oxopyrrolidine-2-carboxylate (352a) was obtained in 91% yield. This lactam was a single diastereoisomer and had a specific rotation of [a]D23 -15.1° (c 0.52, CHCI3)

(Scheme 4.6).

S J202Et

H NCOPh

HOAc / MeOH

H20 / dioxane 91%

(351a) (352a)

Scheme 4.6

Hydrolysis of a mixture of the crude Michael adducts enr-(351a,b) that was prepared from (R)-(222) at RT according to the Table 4.1, gave a 78 : 22 mixture of the lactams ent-(352a) and (352b). The lactam ent-(352a) could be obtained pure by column chromatography and had a specific rotation of [a]o27 +19.9° (c 0.30, CHCI3). Thus as expected (352a) and ent-(352a) had the same NMR spectra but specific rotations of opposite sign. The magnitudes of these specific rotations were not the same which suggested that they may have different optical purities. The minor lactam could not be obtained diastereisomerically pure by column chromatography. The ^H NMR of the minor diastereoisomeric lactam was very similar to that of the 2,4-cis lactam (386) (See

Scheme 4.20) and therefore it must have either the (2S,4S) or (2R,4R) Chapter Four 164

stereochemistry. A pure sample of this minor lactam however could not be obtained for

determination of its optical rotation and therefore the absolute stereochemistry could not

be unequivocally determined. The (2R, 4R) lactam, ercf-(352b), would arise from a

Michael adduct that had the (2R, 4R , 2'R) stereochemistry (ie from a cis- 2,4-

oxazolidinone), while the (2S, 4S) lactam, enf-(352b), would arise from a Michael

adduct that had the (2R, 4S, 2'S) stereochemistry (ie from the expected trans-2,4-

oxazolidinone ent-(352b)).

H PhCON; H

3 */a^ % W*«K\ HOAc/MeOH c /R\ ent-(35la) + ent-(35lb) ~ent-(352a) + jJ A--H (or (352a)) 2 // H20 / dioxane O^ J* ' C02Et H 65% ent-(352b) (78 : 22) Scheme 4.7

4.4.2 Asymmetric Michael Addition Reactions of Ethyl N-

(diphenylmethylene)glycinate (218a) and a-substituted N-

(diphenylmethylene)glycinates (218c-e) with (S) and (R)-

oxazolidinone(222)

4.4.2.1 Asymmetric Michael Addition Reactions of Ethyl N-

(diphenylmethylene) glycinate (218a) with (5) and (R) -

Oxazolidinone(222)

The asymmetric Michael addition reactions of ethyl N-

(diphenylmethylene)glycinate (218a) with oxazolidinone (R)-(222) were carried out

via Method I involving LiBr / DBU in THF. Thus when a solution of the oxazolidinone

(R)-(222) was treated with glycinate (218a), at -5 °C for 1 hr and then overnight at

RT, a 79 : 21 mixture of the two diastereomeric Michael adducts, ent-(374a) and ent-

(374b) were obtained. However, the ratio of adducts increased to 90 : 10 when this

reaction was performed at -5 °C for 1 hr and then at RT for 2 hr (Scheme 4.8a). Chapter Four 165

O H2C Q Ph LiBr/DBU ^"^-^OFt '"f __ v , PhCON T 0Et + PhCONVo — ^ \i-6 Ph >T THF

The highest diastereoselectivity (100 : 0) was obtained when the reaction was initiated at

-5 °C for 1 hr and was then warmed to 0 °C for 3 hr using either (S)- or (R) -(222) as the starting material. This reaction gave the Michael adduct (374a), or its enantiomer ent-(374a) as a single product in 75 and 80% yield respectively (Table 4.2). The major diastereoisomer (374a) (or ent-(374a)) could be obtained diastereoisomerically pure after purification of the crude reaction mixture by column chromatography using

20% ethyl acetate / hexane as the eluent. Unfortunately the pure minor diastereoisomer

(374b) could not be separated by column chromatography or crystallization. In contrast to (351a), treatment of the pure Michael adduct (374a) with DBU and LiBr in THF at

RT overnight gave only starting material (374a). This experiment indicated that no epimerisation at C-2' (or C-4) was occurring during the Michael reactions. This may be due to the more hindered environment about H-2*.

C02Et H2Q _0 LiBr/DBU 0Et YY + PhCO^c0 THF PhCO But 'H Vo Bu1 *H

(218a) (SM222) (374a)

Scheme 4.8b Chapter Four 166

Table 4.2. Results of the asymmetric Michael addition reactions of (R) and (5)-oxazolidinone (222) with ketimine (218a) in the presence of LiBr / DBU in THF.

Oxazolidinone Imine Temp Time Major Michael (222) (°C) adduct (dr, yield)

(R) (218b) -5°C lhr ent-(374a) RT 16 hr (79:21,ND) (R) (218b) -5°C 2hr ent-(374a) RT 3hr (90 : 10, 70%) (R) (218b) -5°C lhr ent-(374a) o°c 3hr (100 :0, 80%) (S) (218b) -5°C lhr (374a) 0°C 3hr (100 : 0, 75%)

lH NMR (400 MHz) analysis of (374a), or its enantiomer ent-(374a), showed a singlet at 5.88 ppm for H-2 of the oxazolidinone ring and two downfield doublet of doublets at 4.45 and 4.13 ppm for the a-amino lactone and a-imino ester methine groups respectively. A strong IR band at 1651 cm -1 was assigned to the (Ph)2C=N imine

moiety of the Michael adduct. The COSY spectrum of (374a) showed a large number of strong cross peaks allowing the coupling network and proton connectivities to be

established for this structure (Figure 4.4). Chapter Four 167

Et02C

PhCON v° H Bu1 (374a)

Figure 4.4. Expanded section of the COSY spectrum (400 MHz,

CDC13) of the Michael adduct (374a).

In the 13C NMR spectrum of (374a) the imine carbon atom that is attached to two phenyl groups appeared downfield of the three carbonyl groups and resonated at

173.4 ppm. The relative stereochemistry of the oxazolidinone ring in (374a) was evident from inspection of its NOESY spectrum that showed a NOE cross peak between

H-4 (4.45 ppm) and the terr-butyl group (0.96 ppm) (Figure 4.5). Chapter Four 168

Et02Q

PhCON NOE

H Bu1 (374a) TT

.0 1.0 0

0 0 0 2.0

Q o

3.0

•Rs- 4.0 ,X' "=& CD -^...... *«-- .xr> H4

5.0 ' • -""1 ' ' -—r 5.0 4.0 3.0 2.0 1.0 0.0 Fi(ppm) Bu1

Figure 4.5. Expanded section of the NOESY spectrum (400 MHz,

CDC13) of the Michael adduct (374a).

The stereochemistry of ent-(374a), was found to be (2R, 4S, 2'R), by a single crystal X-ray structural determination as shown in Figure 4.6. Chapter Four 169

Figure 4.6. Molecular projection of the single crystal X-ray structure of ent-(374a), 20% thermal ellipsoids are shown for the non-hydrogen o atoms; hydrogen atoms have arbitrary radii of 0.1 A. Chapter Four 170

The X-ray structural analysis indicated that the stereochemistry of ent-(374a)

arises from addition of the lithium enolate of (218a) to the rc-face of the exo-cyclic

methylene group of oxazolidinone (R)-(222), that is anti to the C-2 bulky tert-buty\

group, via an 'endo' like transition state (375). Protonation of the anionic intermediate

(376) syn to the tert-butyl group then gives ent-(374a) as shown in Scheme 4.9.

Ph \ ^ /0Et

(376)

C02Et

C02Et

ent-(374a)

Scheme 4.9

4.4.2.2 Hydrolytic Cyclization of the Michael Adducts

Acid hydrolysis of the Michael adducts (374a) or ent-(374a), with acetic acid in aqueous methanol and dioxane at reflux overnight, caused smooth hydrolysis of the imine moiety of (374a) or ent-(374a) and then cyclization by nucleophilic attack of nitrogen to the lactone carbonyl of the oxazolidinone ring, to give the lactam (352a) or

CHCI3) and [a]D20 +19.9° (c 0.15, CHCI3) respectively as shown at Scheme 4.10. Chapter Four 171

The sign of these rotations were consistent with those obtained from these lactams that

were prepared from (351a) and ent-(351a).

NHCOPh HOAc/MeOH ^3 R \2 (374a) oxH dioxane/H20 5 Ni co2a 90% H zl21 mno (352a) [a]D -19.9°(c0.20,CHCl3)

PhCOHN. H HOAc/MeOH ent-(37 4a) dioxane/H20 93% iU eiU-(352a) [a]D +19.9° (c 0.15, CHC13)

Ph li=N H2N Ph ! /s HOAc /MeOH (352a) dioxane/H20 PhCON PhCON r\ 0 (XY-0 Bu1 H Bu1 H

(374a) (377)

Scheme 4.10

The formation of these lactams was thought to occur via a geometrically favoured 5-exo-

trig cyclization process. To illustrate the stereoelectronic principles of the 5-exo-trig cyclization pathway, according to Baldwin's rules,75 the nucleophile can enter the required trajectory of 109° to the double bond (C=Y) in the 5-exo-trig pathway but this trajectory is not possible in a 5-endo-trig cyclization (Scheme 4.11). Chapter Four 172

5-exo-trig 5-endo-trig allowed disallowed

X 109 C=Y

C02Et s-exo. ^atfo^d

Scheme 4.11.

The structure of lactam ent-(352a) was evident from lW, 13C , COSY and

NOESY NMR spectra. This structure proved extremely useful for assignment of the

stereochemistry of the Michael adducts of oxazolidinone (222) with other imino esters

that are discussed later in this Chapter. In the lU NMR spectrum of ent-(352a) the NH

resonances of the benzamido group and the proline ring appeared at 6.87 ppm (d) and at

6.35 ppm (s, br), respectively. The signals at 4.28 (d, IH) and 4.54 ppm (ddd, IH)

were assigned to the protons H-2 and H-4 respectively, while the signals at 2.41 and

3.04 ppm were assigned to H-3a and H-3(3 respectively. COSY and NOESY

experiments were used to assign the *H NMR spectra of this lactam. The NOESY

spectrum (Figure 4.7) showed strong cross peaks between the o-ArH (7.88 ppm) and

the NH (6.87 ppm) of the benzamide moiety and between this latter proton and H-3a at

2.41 ppm. The strong cross peaks between the NH of the benzamide group and H-4

(4.54 ppm) and between the NH of the proline ring and H-2 (4.28 ppm) allowed their

unequivocal assignments to be made. Chapter Four 173

NOE

H ' PhCON^ H Ha Sel_/^H(3 3 5 / \^C02CH2CH3 0^ Ni H

NOE e«r-(352a)

fi lpf.1 r

1- — ----- f ^

e- * ° • 1 3- ft °

4- - . r« - - ^V

s- a

6-

NH _ __r

NHCOPh 7- • - T 1 Tl "T * i 8- T ' 1 * 1

i ! ! ' i ' • F•l tpp.) * o-ArH .—,—.—.—i—.—H< 4. ' i—i—.—•—•—i—I—i—•"-*•—'—l—•H2 CHa —

Figure 4.7. 2D NOESY NMR spectrum (400 MHz, CDCI3) of the lactam ent-(352a).

Further evidence for the structure of ew*-(352a) was obtained from 13C NMR and

DEPT experiments that showed the presence of one CH3 group, two CH2 groups, five

CH groups, one quaternary carbon and three carbonyl groups as shown in Figure 4.8. Chapter Four 174

n 11 o

as; in to 65

r J n o ac ac n U> ac o ac 8 ac UhJ ac

13 Figure 4.8. C NMR (75 MHz, CDC13) spectrum of lactam ent-(352a). Solvent Chapter Four 175

The observed NOE cross peaks were consistent with the close proximity of the benzamido NH and H-4, and the proline NH and H-2 in (352a) from its energy minimised structure using SPARTAN and the AMI semi-empirical molecular orbital calculation methods as shown in Figure 4.9.

Figure 4.9. Energy minimised structures for lactam (352a) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Double headed arrows indicate interatomic distances and observed NOE cross peaks in the NOESY spectrum of this compound. Chapter Four 176

4.4.2.3 Asymmetric Michael Addition Reactions of Ketimines

(218c-e) with Oxazolidinone (R)-(222)

All attempts at the Michael addition reactions of the a-substituted imines (218c- e) to oxazolidinone (R)-(222), using LiBr and DBU in THF, were not successful and only starting materials were recovered along with some impurities. The reactions of these imines with the oxazolidinone (R)-(222) under phase transfer conditions, using

K2CO3 and triethylbenzylammoniumchloride (TEBAC) were also was not successful

(Scheme 4.12). The enolate anions of (218c-e), that were formed by treatment of the imines (218c-e) with LDA in THF, failed to react with (R)-(222) to give the desired Michael adducts (378).

R Ph -t ^C02Me H2C, O \=NYL Ph / OMe W' \ LiBr/DBU/THF J* 0 UMe + PhC0N. R J) ~X*- N PhCON^ Rl /C orK2C03, TEBAC H W H' Bu' (218c-e) (R)-(222) (378)

c; Ri = Me d; Ri = Ph e; Ri = CH2Ph

Scheme 4.12

4.4.3. Asymmetric Michael Addition Reactions of Aldimines (212a-b) with

Oxazolidinone (5j-(222)

4.4.3.1 Asymmetric Michael Additions of Ethyl AT-(2,2- dimethylpropy!idene)glycinate (212a) with Oxazolidinone (5)-(222)

When ethyl /V-(2,2-dimethylpropylidene)glycinate (212a) was treated with the oxazolidinone (5)-(222), in the presence of LiBr / DBU in THF at RT for 30 min, a 69

: 31 mixture of two Michael adducts (379a) and (379b) was obtained. The ratio of the Chapter Four 111 two Michael adducts increased to 94 : 6 when the reaction was held initially at -78 °C for

2 hr and then at room temperature overnight. The highest diastereoselectivity (dr = 97 :

3) was obtained when this reaction was carried out at -78 °C for 2 hr and then at -20 °C for 12 hr (Table 4.3.).

H Bu' C0 Et J>=N-i 2 H C 0 2 o H Bu' N LiBr/DBU 0Et + PhCON.s 0 w THF PhCON H But 'H

(212a) (S>(222) + minor isomer (379b)

Scheme 4.13

Table 4.3. Results of the asymmetric Michael addition reactions of oxazolidinone (5)-(222) with imines (212a) in the presence of LiBr / DBU in THF followed by hydrolysis of the crude Michael adducts to their corresponding lactams.

Oxazolidinone Imine Michael Conditions Major lactam (222) (dr, yield)3 Temp (°C) Time

(S) (212a) RTb 30 min (352a)

(69 : 31, 71%)

(S) (212a) -78 2hr (352a)

RT 14 (94 : 6, ND)

(S) (212a) -78 4hr (352a)

-20 12 (97 : 3, 72%) Yield of lactams after hydrolysis of the crude reaction mixture ofthe Michael adducts.

Separation of the Michael adducts (379a) and (379b) by column chromatography on silica gel was not successful because of their readily hydrolytic decomposition. Thus in all of the above cases the crude Michael adducts (379a) and Chapter Four 178

(379b) were directly hydrolysed to their related lactams (352a) and (352b) (Scheme

4.14). The diastereoisomeric ratios and the purified yields of these lactams are shown in Table 4.3.

C02Et

aqueous HOAc + minor isomer PhCON _ vlvH (352b or ent-(352b)) MeOH / dioxane 1 C02Et Bu' H

(379a) (352a) + minor isomer (379b)

Scheme 4.14

4.4.3.2 Asymmetric Michael Addition Reactions of Methyl 2-[(2',2'- dimethylpropylidene)amino]propanoate (212b) with Oxazolidinone (S)-

(222)

When methyl 2-[(2',2'-dimethylpropylidene)amino]propanoate (212b) was treated with the oxazolidinone (S)-(222) in the presence of LiBr / DBU in THF at RT overnight then a 52 : 48 mixture of the two Michael adducts was (380a) and (380b) was obtained. The ratio of two Michael adducts increased to 61 : 39 when the reaction was held initially at -78 °C for 2 hr and then at -5 °C overnight These crude reaction mixtures was converted to a mixture of the lactams (380a) and (380b), in 56% and

60% yields respectively, upon hydrolysis with aqueous acetic acid in methanol and dioxane (Table 4.4). The two lactams could not be separated by column chromatography. The structure of these adducts was assigned on the basis of lU NMR,

13C NMR and COSY NMR experiments on a mixture of these two diastereoisomers. Chapter Four 179

But H2 = N V/° H Me OMe + ' \ H PhCONc 0 Bu' H (212b) (5)-(222)

LiBr / DBU THF

C02Me

+

PhCO^o

Bu' *H (380b)

aqueous HOAc MeOH / dioxane

H H 1 PhCOH I1 PhCON, J 74 * s\?.,rtC02Me „ ki?„rtCH3 + - O'" ^N"i CH O" " ^Ni C02Me 3 H (381a) (381b)

Scheme 4.15 Chapter Four 180

Table 4.4. Results of the asymmetric Michael addition reactions of oxazolidinone (S)-(222) with imines (212b) in the presence of LiBr / DBU in THF followed by hydrolysis of the crude Michael adducts to their corresponding lactams.

Oxazolidone Imine Michael Conditions Major lactam

(222) Temp (°C) Time (dr, yield)3

(S) (212b) -78 2 hr (381a)

RT ON (61 : 39, 56 %)

(S) (212b) RT ON (381a)

(52 : 48, 60 %) a Yield of lactams after hydrolysis of the crude reaction mixture of the Michael adducts.

In the NOESY spectrum of this mixture the major diastereoisomer (381a) showed an NOE cross peak between H4 at 4.85 ppm and the C-2 methyl group at 1.61 ppm that indicated the cis stereochemical relationship between these groups. No such

NOE cross peak was observed in the minor diastereoisomer (381b) (Figure 4.10).

The absolute stereochemistry assigned to (381a) and (381b) is tenuous, however, based on the previous Michael reactions the (K^configuration at the C-4 in these compounds was expected. The suggested mechanism for formation of the major Michael adduct is similar to the transition state suggested in Chapter 3 for the 1,3-cycloaddition reactions of a-substituted imino esters with (S)-(222). In the Michael reaction between the azomethine ylide of (212b) and (5)-(222) an 'exo' like transition state would be expected in order to avoid steric repulsion between the a-methyl group of the imine with the benzamido group of (5)-(222) (Scheme 4.15). Chapter Four 181

NOE H PhCON. V major isomer (381a)

N i C02Et

H4 in major

Figure 4.10. Expanded section of the NOESY spectrum (400 MHz,

CDC13) of lactams (381a) and (381b).

4.4.4 Asymmetric Michael Addition Reactions of tert-Buty\ N-[(1R, 4R)-

bornylidene]gIycinate (361) with Oxazolidinones (S)-(222) and (R)-(222)

When a mixture of (IR, 4R)-camphor imine (361) and (R)-(222) was treated

according to Method II ( LiBr / DBU in THF) at -78 °C for 8 hr and then at -20 °C

overnight a 81 : 9 : 7 : 3 mixture of four diastereoisomeric Michael adducts was obtained Chapter Four 182 in low yield (30%) (Scheme 4.16). The major Michael adduct (382) was separated

by column chromatography using 10% ethyl acetate / hexane as the eluent. \y \y LiBr, DBU THF, -78°C OBu' N^^CO^u'

(361)

H2C 0

PhCON R 0

H Bu' \y (R)-(222)

C02Bu'

3 other diastereoisomers PhCOVo Bu' H (382)

Scheme 4.16

However, repeating this reaction with 63% enantiomerically pure oxazolidinone (S)-

22 104 22 (222) ([a]D = -130°, c 1.00, CHCI3) (lit. [a]D = -206°, c 1.5, CHCI3) at -78

°C and then for 3 days at -20 °C gave a 81 : 19 mixture of (383) and (382) in 50%

yield (Scheme 4.17). The minor product (382) was the same as the major

diastereoisomer that was obtained from the reaction of (7?)-(222) with (361). Chapter Four 183 V \y LiBr, DBU THF, -78 °C OBu1 N^^CO^u'

(361)

H2C 0

PhCO 5/0 Bu' H (SM222)

22 [a]D = -130° \y ee = 63% R 7 H t H N^.X C02Bu' LN^^C02Bu' ^y * PhCON H^Bu'

(383) (382)

Scheme 4.17

Because of the unsatisfactory level of diastereoselectivities and the low yields that were observed in the above Michael addition reactions another method for the lithiation of imine (361) was needed, in order to obtain a high diastereoselectivity and yield. Thus when the lithium enolate (IR, 4R)-(362), that was formed by treating of imine (361) with ButOLi at -78 °C, was reacted with oxazolidinone (R)-(222) at -78 °C for 1-2 hr and then at -20 °C overnight the Michael adduct (382) was obtained as a single diastereoisomer in 65% yield (Table 4.5 and Scheme 4.18). Chapter Four 184

\y \y Bu'OLi THF, -78 °C l Ns t C02Bu "N^ "C02Bu

(361) (362)

(R)-(222)

PhCO^. H W (382)

Scheme 4.18

Table 4.5. Results of the asymmetric Michael addition reactions of (R) and (5)-oxazolidinone (222) with (361) in the presence of LiBr / DBU in THF.

Oxazolidinone Imine Temp Time Major Michael (222) (°C) adduct (dr, yield)

(R) (361) -78 °C lhr (382)

-20 °C ON (81 :9 :7:3,30%)

(S) (361) -78 °C 2-3 hr (383)

-20 °C ON (74 : 36 : 0 : 0), 50%)

(R) (361)* -78 °C 2hr (382)

-20 °C ON (100 : 0 : 0 : 0, 65%) Bu^Li was used as base.

The structures of the compounds (382) and (383) have been determined by !H

NMR and 13C NMR spectroscopy, DEPT, COSY and NOESY experiments. !H NMR Chapter Four 185

analysis of (382) showed a singlet at 6.04 ppm for H-2 of the oxazolidinone ring and

two doublet of doublets at 4.40 and 3.85 ppm for the a-amino lactone and a-imino ester

methine groups. In compound (383), the corresponding methine protons resonated as a

singlet at 6.07 ppm and as two pseudo-triplets at 4.63 and 4.12 ppm respectively. The

tert-bntyl groups of the oxazolidinonering and of the ester group appeal* as two singlets

at 1.28 and 1.02 ppm respectively for (382) and at 1.32 and 1.01 ppm for (383).

Three singlets at 0.95, 0.92 and 0.80 were consistent with the three methyl groups ofthe

camphor moiety of the Michael adduct (382) while the three singlets at 0.99, 0.92 and

0.76 ppm were assigned to these methyl groups in the Michael adduct (383). The

COSY spectrum of (382) showed a large number of strong cross peaks allowing the

coupling network and proton connectivities to be established for this structure. A strong

IR band at 1651 cm-1 was assigned to the C=N imine moiety of the Michael adduct

(382). In the 13C NMR spectra of (382) and (383) the imine carbon was deshielded

and appeared downfield (188.4 and 186.8 ppm respectively) from the signals for the

three carbonyl groups. Further evidence for these structures were obtained from 13C

NMR and DEPT experiments that showed that these two compounds individually had

five CH3 groups, four CH2 groups, seven CH groups and three quaternary carbons. ID

NOE difference experiments on the compound (382) showed that radiation of H-4 (4.40

ppm) of the oxazolidinone resulted in an enhancement in the signal of theter^-butyl at

1.02 ppm. Similarly irradiation of theterf-butyl grou p resulted in an enhancement ofthe

H-4 signal at 4.40 ppm which confirmed the cis stereochemical relationship between the

terr-butyl group and H-4 and the (2S, 4R) stereochemistry of the major Michael adduct (382).

The absolute stereochemistry of (382) was found to be (2R, 4S, 2 'R) by a single crystal X-ray structural determination as shown in Figure 4.12. The (2 7?) stereochemistry of this Michael adduct is consistent with the transition state showed in

Scheme 4.19 in which preferential attack occurred from the sterically less hindered side or re-face of the enolate to afford the (2 'R) product. Chapter Four 186

n II z

o 6

u» 00

n x n

o n a n n x n n re ^ }• n =

W c

13 FigKn? 4.11. C NMR spectrum (100 MHz, CDC13) of the Michael adduct (382). * CHCI3 Chapter Four 187 \y

(382)

Figure 4.12. Molecular projection of the single crystal X-ray structure of (382), 20% thermal ellipsoids are shown for the non-hydrogen o atoms; hydrogen atoms have arbitrary radii of 0.1A. Chapter Four 188

Further evidence for the relative (2R, 4S, 2'R) stereochemistry of this compound was confirmed by the fact that the (2R, 4S)-tert-butyl trans 4-benzamido-5- oxopyrrolidin-2-carboxylate (385) was the sole diastereoisomer produced upon hydrolytic removal of the camphor chiral auxiliary of (382)(see 4.4.3.2).

V

OBu' (382)

COPh

chelated-(e/wfo-TS-(384))

Scheme 4.19

4.4.3.2 Hydrolysis and Cyclization of the Michael Adducts (382) and

(383)

The camphor auxiliary was removed from the Michael adducts (382) or (383)

by treating them with hydroxylamine acetate under reflux in ethanol for 3-4 hr. This

gave the lactams (385) or (386), respectively, as single diastereoisomeric products in

87 and 90% yields, respectively (Scheme 4.20). Chapter Four 189 \y

H H NCOPh

NH2OH, AcOH 5/ „\^C0 Bu' PhCO 2 3Y2-R 0 1 EtOH, reflux 2 O-NTN f 87% H Bu1 (382) (385) 23 \y [«]D = +8.0° (c 0.10, CHC13)

C0 Bu' 2 H PhCON I1 A NH2OH, AcOH ' U 3 £\^C02Bu' EtOH, reflux PhCON _ Ni H 90% H Bu' H

(383) (386) [ato2 3 = -18.2° (c 0.04, CHCI3)

Scheme 4.20

(2R, 4S)-Tert-butyl trans 4-benzamido-5-oxopyrrolidin-2-carboxylate (385) showed a close correlation between its ^H NMR spectra with that of the (2R, 45)- lactam (352a) (Table 4.6). The signals for H-4, H3a and H3{3 in both these compounds had the same multiplicities and appeared at almost the same chemical shifts.

In contrast, the JH NMR spectrum of the 2,4-cw-lactam (386) was significantly different to that of (352a) and (385) and was similar to that of (352b) (Table 4.6). Chapter Four 190

Table 4.6. Comparison of *H NMR (300 MHz, CDC13) spectra of lactams (352a,b), (385) and (386).

lactam H4 H3a H3P 6 (ppm) 5 (ppm) 8 (ppm)

(352a) 4.54 (ddd) 3.04 (m) 2.41 (m)

(385) 4.56 (ddd) 2.83 (m) 2.38 (m)

(352b) 4.88 (dd) 3.17 (m) 2.05 (m)

(386) 4.95 (m) 3.13 (m) 2.10 (m)

In the lH NMR spectrum of (385) the NH resonances of the benzamido group and the proline ring appeared at 7.15 ppm (d) and at 6.67 ppm (s, br) respectively (Figure

4.13). A doublet of doublet of doublets at 4.56 ppm and a pseduotriplet at 4.19 ppm were assigned to the protons H-4 and H-2 respectively, while the H-4 and H-2 protons of theris-lactam (386) resonated downfield and appeared as two doublet of doublets at

4.88 ppm and 4.22 ppm respectively (Figure 4. 14) On the other hand the signals at

2.83 and 2.38 ppm were assigned to H-3a and H-3p in the lactam (385) while in (386) these two protons resonated at 3.17 ppm (m) and 2.05 ppm (m). COSY and NOESY experiments were used to assign the lH NMR spectrum of the lactam (385). The

NOESY spectrum showed a strong cross peak between the o-ArH of the benzamide moiety (7.15 ppm) and the NH of the benzamide moiety (6.67 ppm). The strong cross peak between the NH of the benzamide group (7.15 ppm) and H-4 at 4.56 ppm and also between the NH (6.67 ppm) of the proline ring and H-2 at 4.19 ppm confirmed the structure of (385). Further evidence for the structure of lactams (385) and (386) was obtained from 13C NMR and DEPT experiments. The13 C NMR spectrum of the former compound had 3 signals at 175.7, 170.9 and 167.7 ppm while the latter had three signals at 175.1, 171.1 and 167.5 ppm for the carbonyl groups. DEPT experiments showed that these compounds had one CH3 group, one CH2 group, 5 CH groups and one quaternary carbon individually as is shown in Figure 4. 15. for lactam (386). Chapter Four 191

2 ac n

u> oc cn

ac 4^ ac

ac U> R ac UJ "OB "^T

Figure 4.73. *H NMR (300 MHz, CDC13) spectrum of lactam (385) Solvent Chapter Four 192

6 3 ~\.. ac

Ui 00 ac ON 4^

v_ ac to

ac UJ R

ac UJ •OD ""N"

Figure 4.14. *H NMR (400 MHz, CDC13) spectrum of the lactam (386)

Solvent Chapter Four 193

n II o s-

Ui 00 3

n

o ac o ac

n UJ ac

Figwrc 4.75. 13C NMR (100 MHz, CDCI3) spectrum of the lactam (386).

Solvent

The structure of (386), was confirmed from ID NOE difference experiments.

Irradiation of H-4 (4.88 ppm) resulted in an enhancement in the signal of H-2 at 4.22 Chapter Four 194

Similarly, irradiation of H-2 resulted in an enhancement of the H-4 signal at 4.88 ppm which confirmed the cis relationship between these two protons and the (2R, 4R) stereochemistry of lactam (386). The NOESY spectrum of this compound also showed a cross peak between H-2 (4.22 ppm) and H-4 (4.88 ppm) as shown in Figure 4.16.

H PhCON I1 (386) ---74 3 A^C02Bu' V \i H- H

re ^ T "I [pp.:

H4

FI (pp.!

H2

Figure 4.16. Expanded section of the NOESY spectrum (400 MHz,

CDCI3) of the lactam (386) ChapterFour 195

Indeed these observed NOE cross peaks were consistent with the close proximity

of H-2 and H-4 in the cw-lactam (386) from the energy minimised structure of this

compound using SPARTAN and the AMI semi-empirical molecular orbital calculation

methods as shown in Figure 4.17.

Figure 4.17. Energy minimised structures for lactam (386) using SPARTAN and the AMI semi-empirical molecular orbital calculation methods. Double headed arrows indicate interatomic distance and observed NOE enhancement in ID NOE experiments of this compound.

4.5 Michael Addition Versus Cycloaddition in Reactions of Bulky Imines with Electron Deficient Alkenes.

Michael addition reactions between lithium enolates and a-p-unsaturated carbonyl

compounds usually occurred with awri-selectivity, for which several transition state Chapter Four 196

models have been proposed including the widely accepted Heathcock's chelation model. 144,145 jo explain the high a/trr-selectivity observed in the Michael additions of the lithium enolates of TV-alkylideneglycinates to enoates, Tatsukawa et al.135 have suggested the transition state structure (387) shown in Figure 4.18. In this transition state the lithium ion is intramolecularly coordinated with the imine nitrogen and further intermolecularly coordinated with the carbonyl oxygen of the acceptor molecule.

H 3 0R R2s. i / 3 Ri \ \ \ /O tfjyR5 8 F^l 7

R40"^~~~-~0 R4O

TS-(387) (388) Figure 4.18. Transition state structure proposed for the Michael addition reaction of lithium (Z)-enoIate of AAalkylideneglycinates to a- P-unsaturated esters.

By using semi-empirical molecular orbital calculation methods (MNDO and PM3) on the TS-(387), Tatsukawa has shown that a carbon-carbon bond was formed between C-3 and C-7 under the influence of some attractive molecular orbital interaction between the imine moiety at C-l and the unsaturated part of the acceptors at C-8 (Figure 4.19). The energy difference between the possible transition states for the reaction of the enolate and enoate, as shown in Figure 4.19, was found to be dependent upon the steric hindrance caused by the alkylidene moieties of the imines. When there was a high degree of steric hindrance around the alkylidene moiety (RiR2C=) then further cyclization of the dipole with the dipolarophile, to give a cycloaddition product, is inhibited and only the Michael adduct was observed. Chapter Four 197

R2v s-Y** R2v ~TZJ^ CH2=CHCHO R>^K ^O (389) Hi y^ (390a-d) (391a-d)

a);R1=H,R2 = H R3 = H,R4 = Me

b);Ph = H,R2 = H R3=Me, R4 = Me 1 c); Bu = H, R2 = H R3 = Me, R4 = Me

d); Rj , R2 = norbomyl, H R3 = Me, R4 = Me

OR 3 PR? R2SI Ls * fv ,/^N \ V

OR? R PR3 R2NI

Ri ^-/ 'X* R40>sf5S*0 FUO^ -~0 R40

(392a-d) (394a-d) (396a-d)

Figure 4.19. Reaction pathways of the associative chelate complexes of (391a-d) leading to 1,3-dipolar cycloadducts (396a-d) via Michael adducts (394a-d).

Tatsukawa135 suggested that the mechanism involved the two transition state structures

(393) and (395) : the first one, (393), directly connected the chelated complex (392) and the Michael adduct (394) and the second, (395), directly connected the Michael adduct (394) and the 1,3-cycloadduct (396) as shown in Figure 4.20. In the model system using methyleneaminoacetaldehyde (390a) and propenal (389), the transition Chapter Four 198 state (393a) for the Michael addition step leading to Michael adduct (394a) was calculated to be higher in energy than that for the cyclization step (ie 395a) leading to the

1,3-dipolar cycloadduct (396a) (by 5.8 and 3.8 kcal mol"1 in MNDO and PM3 calculation, respectively). These calculations indicated that the type of products depends upon the relative potential energies of (394a) and (396a).

Table 4.7 MNDO and PM3 calculation energies (in kcal mol-1) for transition states (393) and (395) and energy minimized for the reaction pathways leading to the Michael adduct (394) and the 1,3-dipolar cycloadduct (396).

Substrate Method E(393) E(394) E(395) E(396) AHa

(kcal mol"1)(kca l mol"1)(kca l moHXkcal mol" l)(kcal mol1;

(390a) MNDO 3.7 -16.5 -2.1 -24.6 14.4

(390a) PM3 2.1 -13.3 -1.7 -18.9 11.6

(390b) MNDO 19.5 2.3 14.6 -8.6 12.3

(390b) PM3 8.5 -1.3 7.9 -9.5 9.2

(390c) MNDO 16.4 -2.0 16.0 -2.5 18.0

(390c) PM3 8.1 -3.0 8.4 -6.3 11.4

(390d) MNDO 19.5 1.2 29.7 12.7 28.5

(390d) PM3 7.8 -4.4 12.9 -3.1 17.3 a Energy barrier for the cyclization step relative to the energy of the corresponding Michael adduct.

Since the 1,3-dipolar cycloadduct (396a) is much more stable than the Michael adduct

(394a), the reaction between (391a) and (389) goes to the cyclized product (396a).

Introduction of a phenyl substituent onto the imine carbon atom of the model donor

molecule (390a) reduces the energy barrier for the cyclization step. It was found that by

comparing the activation energies and barrier energies given in Table 4.7, the cyclized

product (396b) is thermodynamically more stable and the energy barrier for the

cyclization step is lower than that for the Michael-addition step. When the dipole Chapter Four 199 molecule contains a sterically hindered bulky group such as camphor imine (390d), the cyclization step becomes difficult and Michael addition products are preferred. The frontier molecular orbital energies of the Michael adducts (395a-d) were also calculated.

The energy differences between the HOMO and LUMO or between HOMO and SUMO at

C-8 and C-l are given in Table 4.8. Introduction of a phenyl substituent at Ri in the metallated imine (395) resulted in a reduction of the energy difference between the

HOMO and the LUMO and as a result the distance (d) between C-l and C-8 in (394b) is the shortest of all the Michael adducts (394a-d). This calculation indicated that the cyclization step from the Michael adduct (394) is easier than any other reaction. The bornylidene and 2,2-dimethylpropylidene substituents resulted in an increase in the energy gaps between the HOMO and the LUMO and as a result both reaction sites C-l and C-8 are too remote to form a new bond135 that would required to form cycloaddition products.

Table 4.7. PM3-calcuIations of the HOMO-LUMO energy differences and C1-C8 distances of the Michael adducts (394a-d) and the energy barriers for cyclization step (395) to (396).

Michael Ri R2 AEHOMO/LUMO d(A) AH adduct (eV) (kcal mol"1)

(394a) H H 7.41* 4.26 11.6

(394b) Ph H 6.4 3.18 9.2

(394c) Bu1 H 7.37a 3.21 11.4

(394d) bornylidene 10.10b 3.31 17.2 a Energy difference from second LUMO to HOMO." Energy difference from second LUMO to second HOMO.

4.6 Determination of the Optical Purity of the Michael

Adducts (382) and (383).

In order to determine the enantiomeric purity of the Michael adducts, the reduction of the lactams (352a) with sodium borohydride (NaBH4) in methanol was attempted Chapter Four 200 with the aim of preparing the alcohol (397) (Scheme 4.20). This reaction gave a water soluble product that showed *H NMR (in methanol-ck) signals at 4.79 (t, J = 9.6

Hz, IH), 3.58 (dd, J = 11.4, 4.5 Hz, IH), 3.56 (dd, J = 7.5, 4.5 Hz, IH), and 2.35

(m, 2H) ppm which were assigned to H-4, CHACHBOH, CHACHBOH and the methylene protons at C-3 of the alcohol (397) respectively. 13C NMR analysis and

DEPT NMR experiments showed that this compound had two CH2 groups and five CH groups while the electrospray MS of this product showed a molecular ion at m/z 235.3.

These spectral data were consistent with that expected for the alcohol (397). The microanalysis of this compound however, did not fit that expected for the alcohol (397) but was close to that expected for the borate complex (398). Attempts to hydrolyse

(398) back to (397) with hydrochloric acid resulted in recovery of unreacted starting material. Likewise, treatment of the expected borate complex (398) with Mosher's acid chloride resulted in recovered unreacted starting material.

H H NCOPh NCOPh

NaBH4 57 " /?\24xC02CH2CH3 MeOH NV*H H (352a)

H NCOPh MeO/^ Of MeCt NCF3 Ph x/ ClOC P^ Na^^ 6 2,vCH2-OOC 0 N^H pyridine NHCOPh H (399) (398)

Scheme 4.19 Chapter Four 201

Attempts to determine the optical purity of the lactams (352a), (385) and (386) using *H NMR and chiral shift reagents were inconclusive. *H NMR experiments on

(352a), (385) or (386) using the shift reagent tris(3-heptafluoropropyl- hydroxymethylene)-d-camphorate europium (III) (Eu(hfc)3) resulted in extensive broading of the *H NMR resonances of these compounds with no evidence of peak

splitting due to the present of two enantiomers. Time did not allowe these studies to be

pursued further.

4.7 Conclusion

In this Chapter, the synthesis of polyfunctionalized proline derivatives via the

asymmetric Michael addition reactions of lithium enolates derived from /V-alkylidene or

arylidene imino esters (348) to the chiral oxazolidinone (S) or (R) -(222) as a Michael

acceptor have been presented. High product diastereoselectivities and yields were

obtained from the reactions of the Michael acceptor (R)-(222) with the bulky imine

(218a) in the presence of LiBr / DBU / THF or with the camphor imine (361) using

ButOLi. The Michael adducts were readily converted to lactams upon exposure of the

Michael adducts (351), (379) and (380) to silica gel or by treating the Michael adducts

(374), (382) and (383) with aqueous acetic acid (or ammonium hydroxide, acetic acid)

in methanol or ethanol at reflux. The stereochemistry of the products has been

determined by single crystal X-ray structure analysis, ID NOE difference experiment, 2D

lH NMR, (COSY and NOESY), 13C NMR spectroscopy and computer molecular

modelling. CHAPTER FIVE

EXPERIMENTAL Chapter Five: Experimental 203

5.1 General Procedures

Melting points were determined on a Gallenkamp hot-stage apparatus and are uncorrected.

Infrared spectra were recorded on a BioRad Fourier Transform Infrared Spectrometer model FTS-7 as mulls in nujol.

Optical rotations were recorded with a JASCO, DIP-370, Digital Polarimeter in analytical reagent (AR) grade solvents. Specific rotations ([OC]D) are reported in degrees per decimeter, with the concentration (c) given in grams per 100 mL in the specified solvent.

*H NMR spectra were recorded on the following instruments: Varian Unity 400 F. T.

NMR Spectrometer operating at 400 MHz, and Varian Unity 300 F. T. NMR

Spectrometer operating at 300 MHz. Chemical shifts are reported as 8 values in parts per million (ppm). All spectra were recorded in deuterated chloroform unless otherwise noted. Tetramethylsilane (TMS) was used as the nominal standard for all spectra recorded in deuterated chloroform (0.00 ppm). Proton spectra recorded in dimethyl-dg- sulfoxide (DMSO) were referenced against the central solvent peak (2.49 ppm). Proton spectra recorded in CD3OD were referenced against the central residual methyl solvent peak (3.55 ppm). For proton spectra recorded in D2O, chemical shifts were referenced against the residual solvent peak (4.75 ppm). Data are recorded as follows: chemical shift

(8), integrated intensity, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, dd: doublet of doublets, etc. b: indicates some degrees of broadening in the signal), coupling constant(s) (Hz) and assignment (first order analyses of spectra were attempted where possible and, consequently, chemical shifts and coupling constants for multiplets may only be approximate). Chapter Five : Experimental 204

Two dimensional NMR experiments were carried out using the following instruments:

Varian Unity 400 F.T. and Varian Unity 300 F.T. The pulse sequences used were homonuclear O^W^H) correlation spectroscopy (COSY) and nuclear Overhauser effect spectroscopy (NOESY).

13C NMR were recorded on a Varian Unity 400 F.T. NMR Spectrometer (100 MHz) and a Varian Unity 300 F.T. NMR Spectrometer (75.6 MHz). The internal reference for 13C

NMR spectra was the central peak of CDCI3 (8 77.0 ppm), and the central peak of

CD3CN (1.3 ppm). For carbon spectra run in D2O a small quantity of methanol was used as an internal standard (49.0 ppm). Distortionless enhancement by polarisation transfer

(DEPT) was used in the assignment of carbon spectra.

Low resolution mass spectra were recorded on a VG Quattro triple quadrupole mass

Spectrometer. The protonated molecular ion (M+H+), if present, significantly high mass ions and the more intense low mass ions are reported. Data are presented in the following order: m/z value, fragmented ion and relative intensity as a percentage of the base peak.

Microanalyses were performed by the Microanalytical Service Unit, Australian National

University, Canberra or the Microanalytical Service Unit, Queensland University,

Queensland.

Analytical thin layer chromatography (TLC) was conducted on plastic sheets coated with

Merck Kieselgel 60 F254 at a 0.2 mm thickness. Preparative layer chromatography was conducted on glass plates coated with Merck Kieselgel 60 F254 at a 1.0 mm thickness.

The developed plates were visualised under shortwave ultraviolet light. Column chromatography was conducted on silica gel absorbent using Fluka Kieselgel 60 (0.063-

0.2 mm) as the absorbent and analytical reagent (AR) grade solvents as indicated. Chapter Five: Experimental 205

Solvents and reagents used in these reactions were purified according to well established procedures.146 Tetrahydrofuran (THF) and diethyl ether were dried over sodium metal and purified by distillation from a purple suspension of sodium/benzophenone ketyl under nitrogen. Dichloromethane (CH2CI2), chloroform, acetonitrile were distilled from calcium hydride and stored over molecular sieves (4A) under nitrogen. Methanol was purified by distillation from magnesium methoxide.

All reactions, particularly reactions involving n-BuLi were performed in glassware that had been oven-dried and cooled in a desiccator prior to use and under an anhydrous nitrogen atmosphere. All organic extracts were dried with anhydrous MgS04 and after filtration of these solutions, the bulk of the solvent was removed on a Buchi rotary evaporator. The last traces of solvent were removed under high vacuum.

Circular dichorism (CD) spectra were measured with a Jasco-500 spectropolarimeter, using a 0.2 cm cell (Macquarie University) or a Jobin Yvon Dichrograph 6 spectropolarimeter (University of Wollongong).

Molecular modelling was performed using PC MODEL (Serena Software, Box 3076,

Bloomington, Indiana) using the MMX force field parameters or Insight II, Version

2.3.0., Biosym Tecnologies, San Diego, C.A. or the Unix based program Spartan using the AMI semi-empirical molecular orbital calulation methods. Drawings presented here were drawn with Chem Draw and Chem Draw 3D software.

X-ray Structure Determinations.

The single crystal X-ray structural determinations were performed by Professor

Allan H. White at the University of Western Australia.

The room temperature (-295K) single crystal X-ray structure determinations are derivative of unique diffractometer data sets (2r/r scan mode; monochromatic Mo Ka radiation, X = 0.71093 A) yielding N independent reflections, N0 of these with / > 3a(7) being considered 'observed' and used in the full matrix least squares refinement without Chapter Five: Experimental 20( absorption correction after solution by direct methods. Anisotropic thermal parameters

were refined for C, N, O; (x, y, z, UiS0)H were also refined. Conventional residuals R, i?w on/P/are quoted at convergence, statistical weights derivative of o2(7) = o2(/diff) + 0.0004 cr4(7diff) being used; chiralities were adopted from the chemistry. Neutral atom

complex scattering factors were employed, computation using the XTAL 3.0 program system implemented by S. R. Hall.147 C. Details of the specimens and refinement are as follows:

4 (268) - O20H27NO4, M = 345.4. Orthorhombic, space group P2i2i2i (D2 , No. 19), a

3 3 = 19.154(7), b = 16.527(6), c = 6.054(5) A, V = 1916 A . DC(Z = 4) = 1.20 g. cm." ;

1 F(000) = 744. HMO = 0.8 cm." ; specimen: 0.12 x 0.15 x 0.62 mm. 2rmax = 55°; N =

2528, N0 =1120; R = 0.043, Rw = 0.040.

(269) - C21H27NO4, M = 357.5. Orthorhombic, space group P2\2\2\% a = 20.117(4),

3 3 b = 15.714(5), c = 6.064(3) A, V = 1917 A . DC(Z = 4) = 1.24 g. cm." ; F(000) =

1 768. IIMO = 0.9 cm." ; specimen: 0.79 x 0.48 x 0.08 mm. 2rmax = 50°; N = 1962, N0

=1246; R = 0.087, #w = 0.089. (271) - C21H27NO4, M = 357.5. Monoclinic, space group P2i (C22, No. 4), a =

3 3 9.267(3), b = 21.95(2), c = 10.321(3) A, V = 1982 A . DC(Z = 4) = 1.20 g. cm." ;

1 F(000) = 768. HMO = 0.8 cm." ; specimen: 0.38 x 0.57 x 0.43 mm. 2rmax = 50°; N =

3582, N0 =2839, R = 0.049, Rw = 0.055. (349g) - C26H3oN205,M = 450.5. trigonal, space group P3i (C32 No. 144), a =

3 3 12.258(60, c = 13.843(8) A, V = 1802 A . DC(Z = 4) = 1.25 g. cm." ;

4 (350e) - C29H36N2O5, M = 526.6. Orthorhombic, space group P2\2\2\, (D2 No. 19)a

3 3 = 29.20 (2), b = 10.397(9), c = 9.07(1) A, V = 2753 A . Dc = 1.19 g. cm." ; (350f) - C33H36N2O5, M = 540.7. Monoclinic, space group P2i (C22, No. 4), a =

3 9.377(4), b = 10.814(2), c = 14.337(6) A, p 102.39(4)V = 1420 A . Dc = 1.26 g. cm.--

4 (374) - C32H34N205,M = 526.6. Orthorhombic, space group P2\2\2\, (D2 No. 19)a

3 3 = 21.82 (2), b = 12.188(9), c = 11.104(4) A, V = 2953 A . Dc = 1.18 g. cm." ;

4 (382) - C31H44N2O5, M = 524.7. Orthorhombic, space group P2\2\2\, (D2 No. 19)a

3 3 = 23.246(7), b = 15.80(4), c = 8.392(3) A, V = 3083 A . Dc = 1.13 g. cm.- ; Chapter Five: Experimental 207

5.2 Experimental for Chapter Two

The oxazolidinones (S)-(222)™7, (R)-(222)™7 and enamine (223)103 were prepared

according to the literature. The other enamines were purchased from Aldrich Chemical

Company.

Preparation of N-pyrrolidino-3-methyl-l-butene (223).

To a solution of pyrrolidine (1.77 g, 25 mmol) in anhydrous diethyl ether (100

mL) was added 3-methyl-2-butanone (262) (0.43 g, 5 mmol) and 5A molecular seives

(4 g). The mixture was stirred at room temperature under a nitrogen atmosphere for 48 hr. The reaction mixture was then filtered and the residue was washed with diethyl ether

(100 mL). Evaporation of the solvent and then fractional distillation of the residue gave the desired enamine (223) as a colourless oil (0.90 g, 90%).

X Bp. 76-79 °C (35 mmHg); H NMR 8 3.50 (s, IH, =CH_AHB), 3.37 (s, IH,

=CHAHB), 3.09 (m, 4H), 2.46 (septet, J = 6.8 Hz, IH, CHMe2), 1.86 (m, 4H), 1.20

(d, J = 6.8 Hz, 3H, CHMeMe), 1.10 (d, J = 6.8 Hz, 3H, CHMeMe).

General Procedure for Michael addition Reactions of Enamine (223) with

Oxazolidinone (222).

To a stirred solution of the oxazolidinone (R)-(222) (0.057g, 0.22 mmol) in dry dichloromethane (5 mL) was added dropwise 2-Ar-pyrrolidino-3-methyl-l-butene (223)

(0.061 g, 0.4 mmol) at -78 °C The reaction mixture was kept at -78 °C for 24 hr and then in the freezer (-20 °C) for 14 days until no more of the starting material could be detected by TLC. Aqueous 10% acetic acid (5 mL) was then added and the mixture was stirred rapidly at room temperature for 2 hr. The solution was washed with a 5% aqueous solution of NaHC03, water, and then dried (MgS04). The solvent was removed in vacuo and the crude product was purified by column chromatography. Elution with 20% Chapter Five : Experimental 208 ethyl acetate / hexane gave a mixture of (267) and (268) (0.058 g, 78%). The two isomers (267) and (268) were separated by careful column chromatography on silica gel using 20% ethyl acetate / hexane as eluent.

(2/e,4/?)-3-BenzoyI-2-^^-butyl-4-[(3,-oxo-4,-methyI)-l'-pentyl] oxazolidin-5-one (267).

Q , H 0 2' ^"«»,- K

(267): Oil, [OC]D23+25.2° (C 0.88, CHCI3). iH NMR 8 7.39-7.50 (m, 5H, Ph), 6.07 (IH, H2), 3.98 (t, J = 7.2 , Hz, IH, H4),

2.75 (m, IH, HA2'), 2.73 (m, IH, HB2'), 2.50 (septet, J = 6.8 Hz, IH, CHMe2), 2.26

(m, IH, HA1'), 2.16 (m, 2H, HB1'), 1.03 (d, J = 6.8 Hz, 3H, CHMeMe), 1.03 (s, 9H, CMe3), 1.01 (d, J = 6.8 Hz, 3H, CHMeMe).

!3C NMR 8 212.4 (CO), 173.8 (CO), 172.0 (CO), 135.4 (C), 130.1 (CH), 128.7

(CH), 126.5 (CH), 95.6 (CH), 57.1 (CH), 40.7 (CH), 36.8 (CMe3), 36.3 (CH2), 28.4

(CH2), 25.1 (CMs3), I8.KCH3), 18.0 (CH3).

Mass spectrum (FAB, +ve) m/z 346 (12%, M+H+), 331 (15%), 260 (20%), 219

(11%), 196 (32%), 137 (26%), 106 (100%).

(2/?,45)-3-Benzoyl-2-^ri-butyl-4-[(3'-oxo-4'-methyl)-l'-pentyl] oxazolidin-5-one(268).

(2R, 4R)-(26S) -y ' phCQ3 ^ HY ^

23 (268): Mp 138°C, [a]D -79.2° (c 0.50, CHCI3). iH NMR 8 7.47-7.63 (m, 5H, Ph), 6.23 (s, IH, H2), 4.51 (dd, J=2.8, 6.4 Hz, IH,

H4), 2.48 (septet, J = 6.9 Hz, IH, CHMe2), 2.31 (t, J = 7.6 Hz, 2H, CH2), 1.94 (m, Chapter Five: Experimental 209

!H, HA1'), 1.53 (br, IH, HB1'), 1.04 (s, 9H, CMe^t). 1.02 (d, J = 7.2Hz, 3H, CHMeMe), 1.00 (d, J = 6.8Hz, 3H, CHMeMe).

13C NMR 8 211.4 (CO), 172.8 (CO), 170.8 (CO), 135.2 (C), 132.2 (CH), 129.0

(CH), 127.2 (CH), 94.6 (CH), 57.3 (CH), 40.6 (CH), 39.6 (CMe3), 33.2 (CH2), 25.4

(CH2), 24.5 (CMe3), 18.0 (CH3), 17.9 (CH3).

IR 1755, 1680, 1610, 1550, 1330, 1310, 1000, 920, 870, 715, 690, 650 cm"l.

Mass spectrum (FAB, +ve) m/z 346 (20%, M+H+), 260 (35%), 196 (98%), 136

(60%), 105 (100%).

Anal Cald for C20H27NO4: C, 69.54; H, 7.88.; N, 4.05. Found: C, 69.53; H, 8.00; N,

3.94%.

General Procedure for Michael Addition Reactions of Enamine (224) with

Oxazolidinone (222).

To a stirred solution of the oxazolidinone (R)-(222) (1.9g, 7.3 mmol) in dry

THF (30 mL), was added dropwise 1-N-pyrrolidino-cyclohexene (224) (3.70 g, 21 mmol) at -84 °C (liquid nitrogen / ethyl acetate slush bath). The reaction mixture was kept at -78 °C for 48 hr and then in the freezer (-20 °C) for 20 days. Aqueous 10% acetic acid (30 mL) was added and the mixture was stirred rapidly at room temperature for

2 hr. The solution was extracted with dichloromethane (2 x 40 mL) and the combined extracts were washed with a 5% aqueous solution of NaHC03, water and then dried

(MgS04). The solvent removed in vacuo. The product was purified by column chromatography using 20% ethyl acetate / hexane as eluent to give a mixture of four diastereoisomers (1.89 g, yield 70%). Separation of this mixture by careful column chromatography gave pure (269) and (270) and a mixture of two minor diastereoisomers (271) and (272). Pure (271) was obtained by crystallization of this mixture from ethyl acetate / hexane. Chapter Five: Experimental 210

(l'S, 2R , 4S)-3-Benzoyl-2-*er*-butyl-4-(2'-oxo-l cyclohexyl)methyloxazolidin-5-one (269).

H 0 (l'S, 2R, 4S)-(269) 3 2 X 1 H Bu1

(269): Mp 128-130 oc, [a]o23 +16.90 (c 1.51, CHCI3). iH NMR (400 MHz) 8 7.45-7.74 (m, 5H, Ph), 6.21 (s, IH, H2), 4.68 (dd, J = 4.4, 10 Hz, IH, H4), 2.81 (m, IH), 2.26 (m, 2H), 1.98 (m, IH), 1.81 (m, IH), 1.71 (m, IH), 1.65 (m, IH), 1.52 (m, IH), 1.50 (m, IH), 1.10 (m, IH), 1.05 (m, IH), 1.01 (s, 9H, CMe3). 13c NMR (400 MHz) 8 212.0 (CO), 172.9 (CO), 170.9 (CO), 135.5 (C), 132.1 (CH), 128.7 (CH), 127.8 (CH), 94.6 (CH), 55.9 (CH), 45.5 (CH), 41.7 (CH2), 40.0 (C-Me3), 34.9 (CH2), 33.2 (CH2), 27.8 (CH2), 24.8, 24.7 (CMe3). IR 1760, 1680, 1610, 1220, 1185, 1150, 1040, 1000, 720, 690, 650 cm"1. Mass spectrum (CI, +ve) m/z 358 (15%, M+H+), 272 (50%), 236 (30%), 208 (50%). Anal Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.70; H, 7.69;

N, 3.58%.

(l'R, 2R , 45 )-3-BenzoyI-2-*

H O (l'R, 2R, 4S)-(270) Vi'hCON o H Bu'

(270): Mp 155°C [OC]D 23 +62.6° (c 1.53, CHCI3). Chapter Five : Experimental 211

*H NMR (300 MHz) 8 7.43-7.63 (m, 5H, Ph), 6.20 (s, IH, H2), 4.38 (dd, J = 3, 9.3

Hz, IH, H4), 2.53 (m, IH), 2.11-2.40 (m, 3H), 2.00 (m, 2H), 1.25- 1.78 (m, 4H), 1.02 (s, 9 H, CMe3), 0.88 (m, IH). i3C NMR 8 210.3 (CO), 173.0 (CO), 170.6 (CO), 135.7 (C), 132.0 (CH), 129.0

(CH), 127.5 (CH), 94.8 (CH), 55.9 (CH), 45.5 (CH), 41.7 (CH2), 39.9 (CMe3), 33.0

(CH2), 31.5 (CH2), 27.5 (CH2), 24.8 (CH2), 24.7 (CMe.3).

(1*5, 2R , 4fl)-3-BenzoyI-2-*er*-butyl-4-(2'-oxo-1'- cyclohexyI)methyloxazoIidin-5-one (271).

O

(l'S, 2R, 4R)-(27l)

23 (271): Mp 169 °C, [a] D -5.6° (c .81, CHC13). iH NMR (400 MHz) 8 7.35-7.70 (m, 5H, Ph), 6.07 (s, IH, H2), 4.00 (dd, J = 3.6,

12 Hz, IH, H4), 2.60 (m, IH), 2.50 (m, IH), 2.40 (m, IH), 2.25 (m, IH), 2.00 (m, IH), 1.60 (m, 2H), 1.50 (m, 2H), 1.06 (s, 9H, CMeg). 0.60 (m, IH).

13c NMR 8 212.0 (CO), 174.2 (CO), 172.1 (CO), 135.7 (CH), 130.2 (CH), 128.0

(CH) 126.6 (CH), 95.5 (CH), 55.0 (CH), 46.0 (CH), 42.0 (CH2), 36.8 (CH2), 33.1

(CH2), 32.1 (CMe3), 27.7 (CH2), 25.1 (CMe3), 24.9 (CH2).

(272): iH NMR (400 MHz) (in part) 8 6.08 (s, IH , H2), 4.25 (dd, J = 4, 12.4Hz,

IH, H4), 1.03 (s, 9H, CMe?).

General Procedure for Michael addition Reactions of Enamine (225) with

Oxazolidinone (222).

To a stirred solution of the oxazolidinone (S)-(222) (1.9g, 7.3 mmol) in dry

THF (10 mL), was added dropwise 1-N-pyrrolidino-cyclopentene (225) (0.401 g, 3 Chapter Five: Experimental 212

mmol) at -78 °C. The reaction mixture was kept in the refrigerator (-20 °C) for 7 days.

Aqueous 10% acetic acid (5 mL) was then added and the mixture was stirred rapidly at

room temperature for 2 hr. The aqueous solution was extracted with dichloromethane

(2x10 ml) and washed with a 5% aqueous solution of sodium bicarbonate, water, and

then dried (MgS04). The solvent was removed in vacuo and the crude product was

purified by column chromatography using 30% ethyl acetate / hexane as eluent to give a

mixture of four diastereoisomers (0.28 g, yield 82%). These four diastereoisomers could

not be separated by column chromatography. One pure trans isomer (275) was obtained

after six crystallizations from ethyl acetate / hexane, while one pure cis isomer (273) was

obtained pure afterfive crystallizations of the mother liquors from methanol and then

from ethyl acetate / hexane. The other trans (274) and cis (276) diastereoisomeric

products could not be obtained diastereomerically pure.

(l'S, 25, 4S)-3-Benzoyl-2-*

methyloxazolidin-5-one (273). °H (l'S,2S,4S)-(273) /y£^~yL-J PhCON^

23 (273): Mp = 155 °C, [a]D -18.0° (c 0.50, CHC13).

JH NMR (400 MHz) 8 7.35-7.65 (m, 5H, Ph), 6.07 (s, IH, H2), 4.00 (dd, J = 3.2,

12 Hz, IH, H4), 2.60 (m, IH), 2.52 (m, IH), 2.30 (m, IH), 2.00 (m, IH), 1.90 (m,

2H), 1.71 (m, IH), 1.60 (m, IH), 1.05 (s, 9H, CMe^t ), 0.60 (m, IH).

IR 1755, 1700, 1615, 1330, 1300, 1113, 1010, 830, 800, 715, 695, 650 cm"1.

Mass spectrum ( ES, +ve) m/z 344 (M+H+, 100%), 288 (35% ), 252 (60%), 205

(28% ), 132 (65% ).

(274): XH NMR (400 MHz) (in part) 8 6.09 (s, IH, H2 ), 4.35 (dd, J = 4.4, 12.4 Hz,

IH, H4), 1.02 (s, 9H, CMe.3). Chapter Five: Experimental 213

(VR, 25, 4/0-3-Benzoyl-2-*er*-butyl-4-(2'-oxo-l'-cyclopentyl) methyloxazolidin-5-one (275).

(l'R, 2S, 4R)-(27S)

(275): Mp 215 °c, [a] D23 -88.O0 (c 0.25, CHCI3). iH NMR 8 7.55-7.6 (m, 5H, Ph), 6.23 (s, IH, H2), 4.46 (dd, J = 2.8, 10 Hz, IH,

H4), 2.18 (m, 2H), 1.92 (m, 3H), 1.70 (m, 2H), 1.49 (m, IH), 1.22 (m, IH), 1.00 (s, 9H, CM£3).

13C NMR 8 218.0 (CO), 172.8 (CO), 170.0 (CO), 135.3 (ArC), 132.3 (CH), 129.1

(CH), 127.5 (CH), 94.9 (CH), 56.7 (CH), 44.2 (CH), 40.0 (CMe3), 36.9 (CH2), 31.9 (CH2), 29.1 (CH2), 24.6 (C-Me3) 20.4 (CH2).

IR 1755, 1700, 1615, 1330, 1300, 1113, 1010, 830, 800, 715, 695, 650 cm"1.

Mass spectrum (ES, +ve) m/z 344 (M+H+, 100%), 288 (35% ), 252 (60%), 205

(28% ), 132 (65%). Anal Calcd for C20H25NO4: C, 69.95; H , 7.34; N , 4.08. Found: C, 70.13; H, 7.44;

N, 4.06%.

(276): iH NMR (400 MHz) (in part ) 8 6.20 (s, IH, H2 ), 4.85 (dd, J = 7.6, 3.6

Hz), 1.04 (s, 9H, CMe3).

(5S)-A'-2-/.S0-propyIpyrrolidine-5-carboxylic Acid hydrochloride (292).

2/ sYM (292) Y^NC"COOH Ha

A suspension of ketone (267) (1.00 g, 2.89 mmol) in 6N HC1 (10 mL) was heated at reflux (100-110°C) for 2 hr. The solution was cooled to room temperature and was then extracted with CH2CI2 (2 x 30 mL). The aqueous layer was evaporated to Chapter Five : Experimental 214 dryness under reduced pressure and the oily yellowish crude product (0.55g, 99%), was used in the following reduction step.

X H NMR (400 MHz, D20) 8 5.06 (t, IH, aCH), 3.21 (m, 2H), 3.09 (septet, J = 6.8

Hz, IH, CHMe2), 2.62 (m, IH), 2.33 (m, IH), 1.23 (d, J = 7.2 Hz, 6H, CHMe?).

XH NMR (400 MHz, d6-DMSO) 8 5.11 (t, IH, aCH), 3.20 (m, 3H, CH2, CHMe2),

2.50 (m, IH), 2.20 (m, IH), 1.24 (d, J = 6.8 Hz, 3H, Me), 1.22 (d, J = 6.8 Hz, 3H, Me).

13C NMR (75 MHz , D2O, MeOH as internal reference, 8 49.0) 8 205.3 (CO), 172.0

(CO), 66.8 (ccC), 34.9 (CH(Me)2), 34.9 ((3CH2), 23.9 (7CH2), 18.3 (MeMeCH), 18.2

(MeMeCH).

+ Mass spectrum (FAB, +ve) m/z 156 (CgHi4N02 , 100%), 110 (45%), 105 (20%).

(5/e)-A'-2-/s0-propyIpyrrolidine-5-carboxylic Acid hydrochloride ent-

(292). ^ i/T^^COOH ^-(292) ^>^N/\

The compound ent-(292) was obtained as a oil in 98% yield using the procedure described above for the synthesis of (292) except the mixture was refluxed for 4 hr.

Spectral data for ent-{292) were identical to that of (292).

(2S, 5/?)-cis-5-/so-propylproIine hydrochloride (293) and (2JR, 5S)-cis-5-

/50-propyIproIine hydrochloride ent-(293). a) Catalytic Reduction of Imine (292) or £#£-(292).

To a solution of the imine (292) (0.50 g, 2.61 mmol) in water (10 mL) was added 10% Pd/C (0.050 g) and the mixture was stirred under 1 atmosphere of hydrogen gas for 48 hr at RT. The mixture was then filtered and concentrated under reduced pressure to give the hydrochloride salt (293) as a white solid (0.45g, 89%). Chapter Five: Experimental 215 b) Sodium Borohydride Reduction of Imine (292).

A solution of imine (292) (200 mg, 10.4 mmol), sodium bicarbonate (150 mg) and sodium borohydride (9.2 mg, 24 mmol) in water (20 mL) was stirred at 0 °C for 1/2 hr and then at room temperature overnight. The crude reaction mixture was acidified with a solution of 5% aqueous hydrochloric acid and evaporated to give a (55: 45) mixture of cis- and rran^-5-wo-propylproline hydrochlorides (293) and (294) (150 mg, 75%).

(2S, 5/c)-cw-5-/,s0-propyIproline hydrochloride (293).

(2S,5RH293) >^Nt

iH NMR (300 MHz, D20) 8 4.25 (dd, J = 6, 9.3Hz, IH, aCH), 3.17 (m, IH, 8CH), 2.23 (m, IH, P1CH), 2.09 (m, 2H, 02CH> ylCH), 1.78 (m, IH, CHMe2), 1.58 (m,

IH, y2CH), 0.88 (d, J = 6.6 Hz, 3H, CHMeMe). 0.80 (d, J = 6.9 Hz, 3H, CHMeMe).

13c NMR (75 MHz, D2O) 8 180.4 (CO), 76.7 (aCH) 68.1 (SCH), 39.1 (CH(Me)2,

35.8 (7CH2), 35.7, ((3 CH2), 27.9 (Me), 27.3 (Me).

+ Mass spectrum FAB (+ve) m/z 158 (C8Hi6N02 , 100%), 112 (45%), 105 (20%).

(2R, 5S)-cw-5-/s0-propylproline hydrochloride ent-(293).

The compound ent-(293) was obtained as a white solid (0.40 g, 79%) using the procedure described above for the synthesis of (293). Spectral data were identical to that of (293). Chapter Five: Experimental 216

(25, 5/c)-(-)-cis-5-/so-propylproline (151).

(25,57?>(151) pri^^j,^,

The amino acid hydrochloride (293) or enf-(293) (400 mg, 2.65 mmol) was dissolved in water (15 mL) and poured on to a column of Dowex 50-X8 (H+). The column was eluted with water until the eluent had a pH of 6-7. The pure amino acid was obtained by eluting with 0.1 M aqueous ammonia. The basic eluent was evaporated under reduced pressure to dryness to give white crystals of (151) (305mg, 93%) which were crystallized from methanol and ether.

(151): Mp. 195°C (dec) (lit. 50 211-214 °C), [a]D23 -63.3° (c 0.51, MeOH)[ lit.50

[a]D-65.3° (c 0.90'MeOH]. iH NMR (300 MHz, D2O) 8 4.05 (dd, J = 4, 9.6 Hz, IH, aCH), 3.25 (m, IH, 8CH),

2.25 (m, IH, P1CH), 2.10 (m, 2H, p2CH, ylCH), 1.90 (m, IH, CHMe2), 1.58 (m, IH, 7CH2), 1.02 (d, J = 6.6Hz, 3H, MeMeCH), 0.93 (d, J = 6.9 Hz, 3H, MeMeCH).

13c NMR (75 MHz, D2O) 8 174.5 (CO), 67.6 (aCH), 60.8 (SCH), 30.4 (CHMe2),

28.4 (pCH2), 27.1 (7CH2), 19.0 (MeMeCH), 18.3 (MeMeCH).

Mass spectrum (FAB, +ve) m/z 158 (M+H+, 100%), 112 (40%).

IR 3420, 1580, 1270, 920 cm-1.

(2R, 5S)-(+)-cw-5-/s0-propyIproline ent-(151).

i Pr *»J/7^AC02H (2R, 5S)ent-(lSl) H^?vJ H

The compound enr-(151) was obtained as a white solid (300 mg, 91%) using the procedure described above for the synthesis of (151).

Mp. 195-198 °C (dec) (lit.50 216-214 °C), [CC]D23 +56.3° (c 0.35, MeOH) [lit.50 [

+64.7° (c 0.80], MeOH]. Chapter Five: Experimental 217

*H NMR spectrum was identical to that of (151) above.

Mass spectrum (FAB, +ve) m/z 158 (M+H+, 100%), 112 (40%).

(25, 5/?)-(-)-cis-5-/s0-propylproline methyl ester (295) and (2R, 5S)-(-)- cis- 5-Jso-propyIproline methyl ester ent-(295). a) From the free amino acid (151)

A solution ofthe free amino acid (151) (56 mg, .35 mmol) in methanol (10 mL) was treated dropwise with thionyl chloride (30 mg, 2.5 mmol) at 0 °C and the solution was allowed to stand at room temperature overnight. After evaporation of the methanol, the resultant methyl ester hydrochloride was dissolved in water. The aqueous mixture was carefully made basic with a 5% aqueous solution of sodium bicarbonate and then the solution was extracted with dichloromethane. The organic phase was dried (MgS04), filtered, and concentrated to give the methyl ester (40 mg, 66%) as a yellowish oil. b) From the hydrochloride salt of a mixture of (25, 5R)-cis-5-Iso- propylproline hydrochloride (293) and (2R, 5R)-trans-5-Iso-propylpro\\ne hydrochloride (294).

Using the same procedure to that described above, a mixture of the cis -and trans methyl esters (295) and (296) was obtained starting from a mixture of the hydrochloride salts of (25, 5#)-c/.y-5-/.y0propylproline (293) and (2R, 5R)-trans-5- wopropylproline (294).

(25, 5/?)-(-)-cw-5-/s0-propyIproline methyl ester (295):

Y P (2S, 5RH29S) H*^ \i*H i V / V Pr ^ N a C02CH3 H

(295): *H NMR (300MHz) 8 3.76 (dd, J = 6, 9 Hz, IH, aCH), 3.73 (s, 3H, OMe),

2.72 (m, IH, SCH), 2.07 (m, IH, pCH), 1.88 (m, 2H, CHMe2 and yCH), 1.60 (m, Chapter Five: Experimental 218

IH, P'CH), 1.32 (m, IH, yCH), 1.02 (d, J = 6.6 Hz, 3H, MeMeCH), 0.92 (d, J = 6.9

Hz, 3H, MeMeCH). Mass spectrum (FAB, +ve) m/z 172 (M+H+ 78%), 140 (M-OMe+T0%), 112 (M-

1 C02Me, 75%), 105 (47%). IR 3420, 1580, 1270, 920 cm- .

(2S, 5S)-(-)-*ra«s-5-Js0-propylproline methyl ester (296).

(296) P^4JsS ^C*H (296) H*^r,/>»Co2CH3

iH NMR (300 MHz, in part) 8 3.84 (dd, J = 6, 9 Hz, IH, aCH), 3.72 (s, 3H, OMe),

2.87 (m, IH, 8CH), 0.97 (d, J = 6.6 Hz, 3H, MeMeCH), 0.88 (d, J = 6.9 Hz, 3H,

MeMeCH).

(25, 5/c>/V-[4-methyl(benzenesulfonyI)]-5-W0-propylproline methyl ester

(297)

PH^^N^^COaCHg

S02 (297)

The crude mixture of (25, 5fl)-(-)-cw-5-w0-propylproline methyl ester (295) and

(25, 5S)-(-)-trarc-s-5-/j0-propylproline methyl ester (296) (60 mg, 0.35 mmol) and p-

toluensulfonyl chloride (96 mg, 0.45 mmol) were dissolved in CH2CI2 (3 mL). The

solution was cooled in an ice bath and then pyridine (0.05 mL) was added under an

atmosphere of nitrogen. The mixture was stirred at room temperature for 4 hr (TLC

showed no starting material). The solution was then washed with water, 5% aqueous

hydrochloric acid (5 mL), water (10 mL) and then dried (MgS04) and evaporated to dryness. The pure sulfonamide (297) (40 mg, 38%) was obtained after purification by

column chromatography using 10% ethyl acetate / hexane as eluent. Chapter Five: Experimental 219

*H NMR (400 MHz) 8 7.74 (d, J = 8.4 Hz, 2H, 0-C6H4); 7.32 (d, J = 8.4 Hz, 2H,

m-C6H4); 4.21 (dd, J = 8.4, 6.8 H, IH, Ha); 3.75 (s, 3H, OMe): 3.52 (s, IH, 8CH);

2.43 (s, 3H, Me-C6H4), 2.05 (m, 2H, CHMe2), 1.4-2.00 (m, 4H), 0.99 (d, J = 6.8 Hz, 3H, MeMeCH), 0.91 (d, J = 6.8 Hz, 3H, MeMeCH).

Enantiomeric purity of (25, 5#)-(-)-cw-5-/s0-pyopyIproline (151).

CR)-(+)-cc-Methylbenzylisocyanate (0.03 mL, 21 mmol) was added to a solution

of (25, 5/?)-ci5-5-i50-propylproline methyl ester (295) or (2R, 5S)-(-)-cis-5-iso-

propylproline methyl ester ent-(295) (15 mg, 0.15 mmol) in CDCI3 in an NMR tube.

After shaking the mixture for 30 min. the homogeneous solution was used directly for

*H NMR analysis of the optical purity of (295). The urea (299) was purified by

PTLC.

^r^N-^COOMe (299) / y^O H\NH 6 ee>92% (299): iH NMR (300 MHz) 8 7.20-7.36 (m, 5H, Ph ), 5.14 (d, J = 6.9 Hz, IH,

NH), 4.99 (dq, J = 6.6, 7.2 Hz IH, CH3CHN ), 4.37 (t, J = 7.2Hz, aCH ), 3.74 (m,

IH, 8CH), 3.70 (s, 3H, OMe), 2.06 (m, 3H, CHMe2, pCH2), 1.82 (m, 2H, 7CH2 ),

1.47 (d, J = 6.9Hz, MeNHCH), 0.95 (d, J = 6.9Hz, 3H, CHMeMe), 0.83 (d, J =

6.9Hz, 3H, CHMeMe). 13c NMR (75 MHz) 8 170.0 (CO), 158.0 (CO), 144.0 (ArC), 128.5 (CH), 126.9

(CH), 1215.8 (CH), 64.0 (aCH), 60 (yCH), 52.2 (OMe), 50.0 (CHPh), 30.7

(CH(Me)2), 27.9 (7CH2), 26.3 (PCH2), 23.0 (MeCHN), 19.9 (MeMeCH), 17.3

(MeMeCH).

Mass spectrum (ES +ve) m/z 319 (M++1, 100%), 172 (12%). Chapter Five: Experimental 220

Enantiomeric purity of (2R, 55>(-)-cw-5-/s0-pyopylproline ent-(151).

\^Y~YpOOMe (300) \m°

ee>58%

Using the procedure described above for the synthesis of (299).

(300) : *H NMR (300 MHz) in part 5.28 (d, J = 6.9 Hz, IH, NH), 4.97 (dq, J = 6.6, 7.2 Hz IH, CH3CHN ), 4.33 (t, J = 7.2Hz, aCH ), 3.77 (m, IH, 8CH), 3.75 (s, 3H,

OMe) 1.46 (d, J = 6.9Hz, MeNHCH), 0.90 (d, J = 6.9Hz, 3H, CHMeMe). 0.80 (d, J =

6.9Hz, 3H, CHMeMe).

(2S, 3aS)-3,3a,4,5,6,7-Hexahydro-(2H)-indole-2-carboxylic Acid hydrochloride (302).

A suspension of (269) (0.71g, 2 mmol) and 6 N hydrochloric acid (10 mL) was heated under reflux for 4-5 hr. After evaportion to dryness the yellow residue (0.40 g, yield 98%) was used in the following hydrogenation reaction without purification.

H r 3; (302) N+ COOH Her

XH NMR (400 MHz, D2O) 8 4.98 (m, IH, H2), 3.23 (m, IH), 2.94 (m, IH), 2.84

(m, IH), 2.65 (m, IH), 2.56 (m, IH), 1.45-2.30 (m, 7H).

+ + Mass spectrum (CI, +ve) m/z 168 (C9Hi4N02 , 20%), 124 (C9Hi4N02 -C02,

15%). Chapter Five: Experimental 221

Preparation of (25, 3aS, 7aS) and (2S, 3aR, 7aS)-Perhydroindole-2- carboxylic Acid Hydrochloride (305) and (306).

A mixture of imine (302) (0.40g, 2 mmol) and 10% Pd/C (0.09 g) in water

(5 mL) was hydrogenated for 16 hr under a balloon of hydrogen gas at room temperature.

The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give a mixture of the hydrochloride salts (305) and (306) (375 mg,

90%) in a ratio of 70: 30.

(2S,3aS, 7aS)- (305) T^r/COOH H HCl-

(305): iH NMR (400 MHz, D20, DHO internal reference at 8 4.75) 8 4.40 (t, IH,

H2), 3.73 (m, IH, H7a), 2.34 (m, 2H), 2.11 (m, IH), 1.80 (m, IH), 1.70-1.20 (m,

7H).

(306):iH NMR (400 MHz) (inpart) 8 4.49 (t, IH).

+ Mass spectrum (CI, +ve) m/z 170 (C9Hi6N02 , 100%), 124 (70%).

(25, 3aS, 7aS) and (2S, 3a/c, 7afl)-Perhydroindole-2-carboxylic Acid

Benzyl ester (307a) and (307b):

Thionyl chloride (59 mg, 5 mmol) was added dropwise to a solution of (305) and

(306) (205 mg, 1 mmol) and benzyl alcohol (5 mL) at -5 °C. After stirring overnight at room temperature water was added and the reaction mixture was extracted with diethyl ether. The aqueous layer was made basic with a saturated solution of aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was dried (MgS04), filtered and concentrated to give 215 mg (72%) of a mixture of benzyl esters (307a) and

(307b) that could not be separated by column chromatography. The 300 MHz lH NMR spectrum of this mixture was in agreement with the lU NMR of a sample of (307a) that was prepared from authentic (2S,3aS, 7aS)- (3).122 Chapter Five: Experimental 222

(307a) COOBn

(307a): 1H NMR (400 MHz) 8 7.35 (s, 5H, Ph ), 5.18 (s, 2H, CH2Ph), 3.82 (dd,

IH, H2), 3.08 (q, J = 4.8 Hz, IH), 2.19 (m, IH), 2.3-1.8 (m, 3H), 1.76-1.61 (m, 3H),

1.52-1.32 (m, 3H), 1.29-1.20 (m, 2H).

+ Mass spectrum (CI, +ve) m/z 260 (C9H23N02 , 100%), 170 (M-COOBn, 70%).

(307b):lH NMR (400 MHz) (in part) 8 7.38 (s, 5H, Ph ), 5.16 (s, 2H, CH?Ph).

3.95 (t, J = 8.4 Hz, IH, H2), 3.30 (q, J = 4.4 Hz, IH). Chapter Five: Experimental 223

5.2 Experimental for Chapter Three

General Procedure for the Synthesis of the Imines (201).

The amino acid ester hydrochloride (10 mmol) and sodium carbonate (10 mmol) were dissolved in water (20 mL). Benzaldehyde (1.16 g, 10 mmol) was added and the reaction mixture was stirred at 40 °C for 1-2 hr and then at room temperature for 16 hr.

The mixture was then extracted with chloroform (2 x 50 mL) and then combined organic layers were washed with water (2 x 50 mL) and then dried (MgS04). The solvent was evaporated under reduced pressure to give the crude imine which was used further without purification in the cycloaddition reactions.

Methyl A/-(benzylidene)alaninate (201b): Colourless liquid.

!H NMR (300 MHz) 8 8.30 (s, IH, CH=N), 7.35-7.88 (m, 5H, Ph), 4.15 (q, J = 6.6

Hz, IH, CHCO2CH3), 3.73 (s, 3H, CHCO2CH3), 1.52 (d, J = 6.6 Hz, 3H, CH3).

Methyl AMbenzylidenephenyl)gIycinate (201d): Colourless solid, Mp. 48 °C. iH NMR (300 MHz) 8 8.32 (s, IH, CH=N), 7.50-7.88 (m, 10H, Ph), 5.20 (s, IH,

CHCO2CH3), 3.71 (s, 3H, CHCO2CH3).

Methyl N-(benzylidene)leucinate (201e): Colourless liquid. iH NMR (300 MHz) 8 8.29 (s, IH, CH=N), 7.38-7.78 (m, 5H, Ph), 4.09 (dd, J = 6,

i 8.8 Hz, IH, CHCO2CH3), 3.73 (s, 3H, CO2CH3) , 1.85 (m, 2H, CH2(Pr )), 1.58(tm,

IH, CHMe2), 0.95 (d, J = 6.8 Hz, 3H, MeMe), 0.90 (d, J = 6.8 Hz, 3H, MeMe).

Ethyl 7V-(benzyIidene)phenylalaninate (201f): Colourless semi-solid. iH NMR (300 MHz) 8 7.92 (s, IH, CH=N), 7.15-7.68 (m, 10H, Ph), 4.17 (m, 3H,

CHCO2CH2CH3), 3.36 (dd, J = 5.6, 13.6 Hz, IH, CfiACHBPh), 3.14 (dd, J = 8.8,

13.6 Hz, IH, CHACHfiPh), 1.22 (t, J = 7.2 Hz, 3H, CH2CH3).

Ethyl A7-(benzylidene)glycinate (201g): Colourless liquid. iH NMR (300 MHz) 8 8.29 (s, IH, CH=N), 7.39-7.89 (m, 5H, Ph), 4.40 (s, 2H,

CH2C02Et), 4.23 (q, J = 7.2 Hz, 2H, CH2CH3), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3). Chapter Five: Experimental 224

General Procedure for Cycloaddition Reactions of Imines (201b,d-g) with

Oxazolidinone (S>(222).

Method I:

To a solution of imine (201g) (0.191 g, 1 mmol) and AgOAc (lmmol) in THF

(10 mL) was added, by the aid of a syringe at -78 °C under nitrogen, a solution of the oxazolidinone (5)-(222) (0.259 g, 1 mmol) in THF (5 mL). DBU (1.8 mL, 1.2 mmol) was then added dropwise and the mixture was stirred for the time period reported in

Table 3.3 (Chapter 3, p 136), until no starting material was detected by TLC. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride (15 mL) and was then extracted with dichloromethane (2 x 20 mL).

The combined extracts were dried (MgS04) and the solvent was evaporated under reduced pressure. The crude product was separated by column chromatography using

20% ethyl acetate / hexane to give the pure diastereoisomers (349g) and (350g) in a ratio 81 : 19 and in a combined of yield 90%.

Method II:

Lithium bromide (0.130 g, 1.5 mmol) was added to a solution of the imine

(201b, d-g) (1.2 mmol) in dry THF (5 mL) and the mixture was stirred at RT under nitrogen for a few minutes until all the lithium bromide had dissolved. The solution was cooled to -87 °C and a solution of the oxazolidinone (S)-(222) (0.25 g, 1 mmol) in dry

THF (5 mL) was added followed by the dropwise addition of DBU (0.152g, 1 mmol).

The resulting mixture was stirred at -78 °C then at RT for the period of time specified in

Table 3.3. A saturated aqueous solution of ammonium chloride (10 mL) was added and the mixture was extracted with dichloromethane or ether (3 x 20 mL). The combined organic extracts were dried (MgS04) and evaporated in vacuo. The residue was chromatographed on silica gel by using 20% ethyl acetate / hexane as eluent to give the cycloadducts (350b, d-f) in the yields indicated in Table 3.3. (Chapter 3). In the case of the imine (201g), a mixture of (349g), (350g) and the lactams (352a,b) Chapter Five : Experimental 225 were obtained. The spectral data for the compounds (352a,b) are given in the

Experimental Section for Chapter Four.

Method III :

The imine (201b, d-f) (1 mmol) and lithium bromide (0.095 g, 1.1 mmol) were dissolved in dry acetonitile (10 mL) under nitrogen. The solution was cooled to at -78 °C and a solution of the oxazolidinone (5)-(222) (0.259 g, 1 mmol) in THF (5 mL) and then Et3N (2 mL, 1.2 mmol) were added. The resulting mixture was stirred at -78 °C and then at RT for the period of time specified in Table 3.2. A saturated solution of aqueous ammonium chloride (10 mL) was added and the mixture was extracted with dichloromethane or ether (3 x 20 mL). The crude product was separated by column chromatography using 20% ethyl acetate / hexane to give the pure cycloadduct (350b, d-f) in the yields indicated in Table 3.2 (Chapter Three).

(2S, 2'S, 4R, 5'S)-3-Benzoyl-2-/erf-butyI-oxazolidin-5-one-4-spiro-4'-

(2,-ethoxycarbonyl-5'-phenyI)pyrrolidine (349g)

H r C02Et

(349g) H"^5'/^*0 PhCON / t^T01 H

Mp:80 oc, [oc]D28 -126.4° (c 0.50, CHCI3). iH NMR (300 MHz) 8 6.46-7.70 (m, 10H, Ph), 5.83 (s, br, IH, H2), 5.15 (s, br,

IH, H5'), 4.97 (s, br, IH, H2'), 4.27 (q, J = 6.9 Hz, 2H, OCH2CH3), 3.20 (br, IH,

H3'cc), 2.57 (dd, J = 12.9, 8.7 Hz, IH, H3'P), 1.32 (t, J = 6.9 Hz, 3H,OCH2CH3),

0.72 (s, 9H, Me3).

13C NMR (75 MHz) 8 173.5 (CO), 171.7 (CO), 169.0 (CO), 131.5(C), 128.8 (C),

128.5 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH), 126.8 (CH), 95.2 (CH), 72.1

(CH), 64.9 (CH), 61.2 (OCH2CH3), 58.4 (CH), 40.5 (CH2), 39.1 (C), 24.8 (Me3), 14.1 (OCH2CH3). Chapter Five : Experimental 226

IR 3275, 3058, 1785, 1729, 1643, 1577, 1195, 1111, 1043, 955, 872, 892 cm"1.

Mass spectrum (ES, +ve) m/z 452 (M+l, 100%) 301 (70%), 286 (28%), 105 (68%).

Anal Cald for C26H30N2O5 : C, 69.3; H , 6.72 ; N, 6.22%. Found: C, 69.5; H, 6.83; N, 6.12%.

(2S, 2'R, 4R, 57c)-3-Benzoyl-2-terf-butyl-oxazoIidin-5-one-4-spiro-4'-

(2AethoxycarbonyI-5Aphenyl)pyrrolidine (350g).

H r H H M-4>C02Et V y (350g) Ph^5'>^0 PhCON f t]WJi H

28 Mp:75 °C, [a]D -42.0° (c 0.33, CHCI3). iH NMR (300 MHz) 8 7.14-7.51 (m, 6H, Ph), 6.50 (d, J = 7.5 Hz, 2H, 0-ArH), 5.51

(s, IH, H2), 4.71 (s, IH, H5'), 4.35 (q, J = 7.2Hz, 2H, OCH2CH3), 4.20 (dd, J =

17.6, 8 Hz, IH, H2'), 3.20 (dd, J=13.5,10.9 Hz, IH, H3'a), 2.93 (dd, J=13.5,8.4

Hz, IH, H3'p), 1.37 (t, J = 7.2 Hz, 3H.OCH?CH^). 0.63 (s, 9H, Me3).

13C NMR (75 MHz) 8 176.0 (CO), 171.4 (CO), 171.1 (CO), 135.2 (C), 135.0 (C),

130.8 (CH), 128.6 (CH), 128.1 (CH), 127.8 (CH), 127.5 (CH), 127.0 (CH), 95.7

(CH), 76.0 (CH), 72.5 (CH), 62.0 (C), 61.4 (OCH2CH3), 44.2 (CH2), 39.1 (C), 25.1

(Me3), 14.2 (OCH2CH3).

IR 3300, 3060, 1701, 1713,1698, 1376, 897, 860 cm"1.

Mass spectrum (ES, +ve) m/z 452 (M+l, 100%) 417.5 (10%), 379 (8%).

Anal Cald for C26H30N2O5 : C, 69.3; H, 6.72; N, 6.22%. Found:C, 69.5; H, 6.72; N,

6.11%. Chapter Five: Experimental 227

(25, 27c, 4R, 57c)-3-Benzoyl-2-rer*-butyl-oxazolidin-5-one-4-spiro-4'-

(2,-methoxycarbonyl-2,-methyI-5'-phenyl)pyrrolidine (350b).

H r Me • j M__L*C02Me v y (350b) Phr^5'')

2 Mp:184 oc, [a]D 8 -31.8° (c 0.33, CHC13). iH NMR (400 MHz) 8 7.16-7.60 (m, 6H, Ph), 6.48 (d, J = 7.6 Hz, 2H, o-ArHJ, 5.48

(s, IH, H2), 4.94 (s, IH, H5'), 4.92 (s(br), IH, NH), 3.91 (s, 3H, OCH3), 3.68 (d,

J = 14 Hz, IH, H3'a), 3.42 (d, J = 14 Hz, IH, H3*p), 0.62 (s, 9H, Me3).

13C NMR (75 MHz) 8 176.0 (CO), 175.2 (CO), 171.1 (CO), 135.1.8 (C), 134.9 (C),

130.8 (CH), 128.6 (CH), 128.1 (CH), 127.8 (CH), 127.1 (CH), 126.9 (CH), 95.7 (C-

1 2), 74.6 (C-2 ), 74.1 (C-5'), 67.2 (C-4'), 52.7 (OCH3), 50.6 (CH2), 39.1 (C), 25.4

(CH3), 25.1 (Me3).

IR 2360, 1781, 1744, 1642, 1482, 11157, 1165, 1144, 899, 872, 669 cm"1.

Mass spectrum (ES, +ve) m/z 452 (M+l, 100%) 301 (70%), 286 (28%), 105 (68%).

Anal Cald for C26H30N2O5 : C, 69.3; H 6.72; N, 6.22%. Found: C, 69.5; H, 6.83; N,

6.12 %.

(2S, 2'S, 4R, 5'R)-3-Benzoyl-2-ferf-butyl-oxazolidin-5-one-4-spiro-4'-

(2'-methoxycarbonyl-2,,5'-diphenyl)pyrrolidine (350d).

H v Ph H K|__L*C02Me \J \2 (350d) Ph^5>)^^0 PhCON \ t>-201 Bu1^ 2 H 25 Mp 220 °C, [a]D -65.20 (c 0.35, CHCI3). iH NMR (400 MHz) 8 7.16-7.83 (m, 11H, Ph), 6.50 (d, J = 7.6 Hz, 2H, o-ArH),

5.43 (s, IH, H2), 4.67 (d, J = 14.8 Hz, IH, H5'), 4.56 (d, J = 14.8 Hz, IH, NH), Chapter Five: Experimental 228

3.93 (d, J = 14.4Hz, IH, H3'a), 3.81 (s, 3H, OCH3), 3.37 (d, J = 14.4Hz, IH,

H3'P), 0.65 s, 9H, Me3).

13C NMR (75 MHz) 8 176.2 (CO), 170.5 (CO), 170.8 (CO), 136.8 (C), 135.2 (C),

135.1 (C), 128.6 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 127.0 (CH), 126.5

1 1 (CH), 95.7 (C-2), 74.6 (C-2'), 74.2 (C-5 ), 61.3 (C-4 ), 50.1 (CH2), 51.9 (CH), 45.7

(CH), 43.3 (CH2), 39.1 (C), 25.1 (Me3), 14.1 (OCH3).

IR 2360, 1789, 1730, 1624, 1482, 1371, 1358, 1247, 1187,1050, 718, 698, 668 cm"1. Mass spectrum (ES, +ve) m/z 513 (M+H+, 25%) 164 (80%), 344 (25%), 122 (100%).

(2S, 2'R, 4R, 5'/c)-3-Benzoyl-2-^ri-butyl-oxazolidin-5-one-4-spiro-4'-

(2,-(2-methyl)propyI-2'-methoxycarbonyl-5'-phenyl)pyrroIidine (350e).

\\ v QH2PH u N—_L-»C02Me V y (350e) Ph^W/0 PhCON J Bu*^2 H Mp 178 °C, [a]D27 -19.2° (c 0.4, CHCI3). iH NMR (400 MHz) 8 7.14-7.60 (m, 6H, Ph), 6.46 (d, J = 7.6 Hz, 2H, o-ArH), 5.45

(s, IH, H2), 4.80 (d, J = 10.8 Hz, IH, H5'), 4.24 (br, IH, NH), 3.89 (s, 3H, OCH3),

3.30 (d, J = 14 Hz, IH, H3'a), 2.62 (d, J = 14 Hz, IH, H3'P), 2.23 (dd, J = 17.6, 8

Hz, IH, CIUHEPri), 1.88 (dd, J = 17.6, 8 Hz, IH, CHA^HfiPr1), 1.86 (m, IH, CH(Me)2), 0.97 (d, J = 6Hz, 3H, CHMeMe ), 0.87 (d, J = 6Hz, 3H, CHMeMe ), 0.61

(s, 9H, Me3).

13C NMR (75 MHz) 8 176.1 (CO), 175.3 (CO), 170.9 (CO), 135.2 (C), 130.6 (C),

128.5(CH), 127.7 (CH), 127.5 (CH), 127.4 (CH), 127.0 (CH), 95.6 (CH), 74.3 (CH),

70.3 (C), 52.3 (CMe3), 51.9 (CH), 45.7 (CH), 39.1 (CH), 25.0 (Me3), 24.7 (OMe),

24.3 (Me), 22.5 (Me).

IR 2359, 1786, 1740, 1648, 1482, 1368, 1049, 1015, 987, 860, 800, 722, 668 cm"1. Chapter Five: Experimental 229

Mass spectrum (ES, +ve) m/z 493.3 (M+H+, 100%) 389 (18%), 344 (25%),

343(100%), 244 (35%), 232 (28%), 170 (5%).

Anal Cald for C29H36N205: C, 70.7; H ,7.37; N, 5.69%. Found: C, 71.36; H, 7.51; N, 5.31%.

(2S, 2'R, 4R, 57c)-3-BenzoyI-2-tert-butyl-oxazolidinone-5-one-4-spiro-4A

[2,-benzyl-2'-ethoxycarbonyI-5'-phenyl]pyrrolidine (350f).

H r CH2Ph H N-4>C02Et \( y (3501) Ph^r'W/0 PhCON f B^^T2 H 25 Mp 205 °C, [a]D -8.9° (c 0.11, CHC13). iH NMR (400 MHz) 8 7.16-7.30 (m, 11H, Ph), 6.45 (d, J = 7.6 Hz, 2H, o-ArH),

5.46 (s, IH, H2), 5.05 (d, J = 14 Hz, IH, H5'), 4.23 (q, J = 7.2 Hz, 2H, OCH2CH3),

4.13 (d, J = 14Hz, IH, NH), 3.49 (d, J = MHz, IH, CHACHBPh), 3.43 (d, J =

14.4Hz, IH, H3'a), 3.19 (d, J = 14Hz, IH, CHaCHB-Ph), 2.82 (d, J = 14.4Hz, IH,

H3'p), 1.23 (t, J = 6.8Hz, 3H, OCH2CH3), 0.61 (s, 9H, Me3).

13C NMR (75 MHz) 8 176.2 (CO), 170.5 (CO), 170.8 (CO), 136.8 (C), 135.2 (C),

135.1 (C), 128.6 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 127.0 (CH), 126.5

(CH), 95.7 (CH), 74.6 (C), 74.2 (C), 72.1 (C), 61.3 (CH2), 50.1 (CH2), 43.3 (CH2),

39.1 (C), 25.1 (Me3), 14.1 (OCH3).

IR 2360, 1785, 1733, 1642, 1496, 1482, 1369, 1335 cm"1.

Mass spectrum (ES, +ve) m/z 493 (M+H+, 100%) 389 (18%), 344 (25%),

343(100%), 244 (35%), 232 (28%).

Anal Cald for C33H36N2O5 : C, 73.3; H , 6.72; N, 5.18.%. Found : C, 73.92; H,

6.77; N, 5.69%. Chapter Five: Experimental 230

(25, 45, 55)-4-Benzamido-5-phenylpyrrolidine-2,4-dicarboxylic Acid (354)

A suspension of the endo cycloadduct (350a) (50 mg, 1.45 mmol) in 6N HC1 (10 mL) was heated in tube sealed at 80 °C for 12 hr. The solution was allowed to cool to ambident temperature and then extracted with dichloromethane (2 x 30 mL). The aqueous layer was poured onto a column of Dowex 50-X8 (H+). The colmun was eluted with water until the eluent had a pH of 6-7. The pure amino acid was obtained by eluting with 0.1 M aqueous ammonia. The basic eluent was evaporated under reduced pressure to dryness to give (354) as a semi-solid (15 mg, 93%).

C02H 3 _4^NHCOPh (354) H*J Y5 2, Ho2c^ r Ph H

28 [oc]D -102.0° (c 0.015, H20). iH NMR (300 MHz) 8 7.30-7.78 (m, 5H, Ph), 5.6 (s, IH, H2), 4.45 (dd, J = 11.2,

7.5 Hz, H-5), 3.30 (dd J = 13.2, 11.4 Hz, IH, H3A), 2.60 (dd, J = 13.2, 7.5 Hz, IH,

H3'B). 13c NMR (75 MHz) 8 174.9 (CO), 172.7 (CO), 169.7 (CO), 133.5 (C), 132.9 (C),

130.1 (CH), 129.7 (CH), 129.1(CH), 127.9 (CH), 127.9 (CH), 127.0 (CH), 61.7

(CH), 58.5 (CH), 50.1 (CH2), 34.8 (CH2). Chapter Five: Experimental 231

5.4 Experimental for Chapter Four

General Procedure for Synthesis of Ketimines (218a, c-d)

A solution of benzophenone imine (1.14 g, 6.33 mmol) and an equimolar amount offinely groun d amino acid ester hydrochloride (6.33 mmol) in dichloromethane (30 mL) was stirred at room temperature for 24 hr with the exclusion of moisture (CaCl2 tube).

The reaction mixture was filtered to remove NH4CI and evaporated to dryness on a rotatory evaporator. The residue was dissolved in ether (30 mL), filtered, washed with water (30 mL) and then dried (MgS04). Evaporation of the solution to dryness on a rotatory evaporator gave the crude ketimine (218) that was sufficiently pure to use in the

Michael reaction reactions.

Ethyl A7-(diphenyImethylene)glycinate (218a): Mp 50-52 °C (lit.143 50-51 °C)

iH NMR (400 MHz) 8 6.90-7.50 (m, 10H, Ph), 4.08 (s, 2H, NCH2CO), 4.00 (q,

2H, OCH2CH3), 1.2 (s, 3H, OCH2CH3).

Methyl A7-(diphenylmethylene)-L-alaninate (218c): oil. XH NMR (300 MHz)

8 7.10-7.80 (m, 10H, Ph), 4.18 (q, J = 6.9 Hz, IH, CHCH3), 3.71 (s, 3H, OCH3),

1.42 (d, J = 6.9 Hz, 3H, CH3).

Methyl AA(diphenylmethylene)phenylglycinate (218d): oil. XH NMR (300

MHz) 8 7.03-7.80 (m, 15H, Ph), 5.17 (s, IH, NCHPh), 3.69 (s, 3H, OCH3).

Ethyl AKdiphenylmethylene)-L-phenylaIaninate (218e): oil. *H NMR (300

MHz) 8 6.60-7.80 (m, 15H, Ph), 4.2 (m, 3H, OCH2CH3) CHCH2Ph) 3.10-3.30 (s,

3H, OCH2CH3), 1.20 (t, J = 7.2 Hz, 3H, CH2CH3).

General Procedure for Synthesis of Aldimines (212)

Method I: Glycine ethyl ester hydrochloride (2.00 g, 10.2 mmol) was suspended in

dichloromethane (20 mL). Pivaldehyde (1.2 mL, 11 mmol) and MgS04 (2 g) were added

and the reaction mixture was colded to 0 °C. Triethylamine (1.7 mL, 10.2 mmol) was

added dropwise and the mixture was stirred at room temperature overnight. The reaction Chapter Five: Experimental 232 mixture was diluted with ether (50 mL), filtered and evaporated to give aldimine (212) as a colourless oil that was sufficiently pure to use in the Michael reaction reactions.

Method II: To a suspension of glycine ethyl ester hydrochloride (0.279g, 2 mmol) in dichloromethane (20 mL) was added triethylamine (0.202g, 2 mmol) at room temperature. The mixture was stirred at room temperature for 10 min, then MgS04

(0.36lg, 3 mmol) and pivaldehyde (0.172g, 2 mmol) were added and the mixture was further stirred for 30 min. After evaporation of the solvent in vacuo, the residue was washed with ether (2 x 30 mL). Evaporation of the combined etheral extracts gave the desired aldimines (212a,b) as colourless oils.

Ethyl 7Y-(2,2-dimethylpropyIidene)glycinate (212a): 1H NMR (300 MHz) 8

7.55 (s, IH, N=CH), 4.2 (q, J = 7.2 Hz, 3H, OCH2CH3), 4.15 (s, 2H, CH2), 1.28 (t,

J = 7.2 Hz, 3H, OCH2CH3), 1.11 (s, 9H, Mer).

MethyI-/Y-(2,2-dimethylpropylidene)alaninate (212b): XH NMR (300 MHz)

8 7.60 (s, IH, N=CH), 3.98 (q, J = 6.6 Hz, IH, CHCH3), 3.79 (s, 3H, OCH3), 1.40

(d, J = 6.6 Hz, 3H, CH3), 1.09 (s, 9H, MeO. tert-Butyl glycinate:

Anhydrous ammonia was bubbled through a soultion of tert-butyl glycinate hydrochloride (2 g, 1.18 mmol) in chloroform (10 mL) for 2 hr. The resulting white residue was filtered and solvent evaporated to give rerr-butyl glycinate (0.77g, 97% yield). tert-Butyl N-[(1R, 4/c>bornylidene]gIycinatate (361):

A solution of ferf-butyl glycinate (1.14 g, 8.8 mmol) and (IR, 4/?)-thiocamphor

(purchased from the Aldrich Chemical Company) (1.4g, 8.3 mmol) in toluene (20 mL) were refluxed for 36 hr. The solution was cooled and concentrated under vacuum. The crude product was chromatographed using 30% ethyl acetate / hexane to give the imine

(361) as a colourless oil (1.6 g, 72%). Chapter Five: Experimental 233

*H NMR (300 MHz) 8 4.00 (ABq, JAB = 16.2 Hz, 2H, CHACHE), 2.15-2.45 (m,

IH), 1.35-2.00(m, 6H), 1.46(s, 9H, Me3), 1.01 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.79 (s, 3H, CH3).

General Procedure for the Michael Addition Reactions of Lithiated Imines

(201g), (212a,b) or (361) with Oxazolidinone (222).

To a mixture of LiBr (1.5 mmol, 0.130g), imine (201g) or (218a) or (212a)

(218b) or (361) (1.2 mmol) and oxazolidinone (222) (0.259g, 1 mmol) in dry THF

(10 mL) was added DBU (0.18 mL, 1.2 mmol) under nitrogen at -78 °C. The reaction was stirred at -78 °C and then at -20 °C or at RT for the times specified in Tables 4.1,

4.2, 4.3, and 4.2 respectively. A saturated aqueous solution of ammonium chloride

(10 mL) was added, and the mixture was extracted with dichloromethane or ether (3 x 20 mL). The combined organic layers were dried (MgS04) and evaporated in vacuo. The residue was chromatographed on silica gel by using 20% ethyl acetate / hexane as eluent

(Table 4.2 and Table 4.4) or converted to their corresponding lactams (Table 4.1 and Table 4.3).

Nb: The Michael adducts (379a), (379b), (380a) and (380b) could not be purified since they were readily converted to the lactams (352a), (352b), (381a) and (381b), respectively, upon exposure to silica gel. In the case of Michael adduct (351a) this compound precipitated during the course of the reaction and could be isolated by gravity filtration.

Michael Reaction of Camphor Imine (361) with Oxazolidinone (222) in the Presence of w-Butyl lithium /tert-BuOH.

To a solution of the imine (361) (.398 g, 1.5 mmol) in dry THF (5 mL) was added, at -78 °C under nitrogen, n-butyl lithium (1.12 M in hexane, 1.33 mL, 1.48 mmol) followed by a solution of tert-BuOH (0.133g, 1.8 mmol) in THF (2.5 mL). The oxazolidinone (222) (0.383, 1.5mmol), in dry THF (5 mL) was then added. The Chapter Five: Experimental 234

solution was stirred at -78 °C for 1 hr and maintained at -20 °C overnight. The mixture

was then treated with a saturated aqueous solution of ammonium chloride and then

extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried

(MgS04) and evaporated in vacuo. The crude residue was chromatographed on silica

gel using 20% ethyl acetate / hexane to give the pure Michael product (382) (0.50 g,

65%) as a white solid.

Nomenclature:

Michael adducts of similar structure to (351a) have been named as substituted 4'-

(oxazolidin-5'-one)-propanoates with the numbering shown in structure (351a). This

numbering system is slightly different to that used in Chapter Four of this thesis where

emphasis has been placed on the stereochemistry of the oxazolidinone ring.

Ethyl (4,/?)-(3'-Benzoyl-(2'S)-^rt-butyl-oxazolidin-5,-one)-(25)-A7-

(benzylidene)propanoate (351a).

EtOgQ1 pj.

(351a) > ^ PhCON * 3\*-0 r Bu1 H

(351a): Mp:175 °C; [cc]D22 -244 ° (c 0.51, CHCI3).

iH NMR (400 MHz) 8 8.32 (s, IH, CH=N), 7.42-7.77 (m, 10H, Ph), 5.89 (s, br,

IH, H-2'), 4.44 (dd, IH, J = 12.8, 1.2 Hz, H-4'), 4.06 (m, 3H, H-2 and OCH2CH3),

2.60 (t, J = 12.8, Hz, IH, H-3A), 1.95 (s, br, IH, H-3B), 1.15 (t, J = 7.2 Hz, 3H,

OCH2CH3), 0.94 (s, 9H, Me3).

13C NMR (75 MHz) 8 172.2 (CO), 170.4 (CO), 169.7 (CO), 165.6 (C=N), 135.3

(C), 135.2 (C), 132.2 (CH), 131.4 (CH), 129.0 (CH), 128.8 (CH), 128.7 (CH), 128.4

(CH), 127.6 (CH), 94.4 (CH), 66.3 (CH), 61.2 (OCH2CH3), 55.6 (CH), 39.7 (C),

33.75 (CH2), 24.6 (Me3), 13.9 (OCH2CH3). Chapter Five: Experimental 235

IR 2968, 2932, 1790 (CO), 1733 (CO), 1636 (C=N), 1578 1463, 1377, 1195 ,1046, 769, 721cm-1.

Mass spectrum (ES, +ve) m/z 450.1 (M+l, 100%) 301 (70%), 286 (28%), 105 (68%).

Anal Cald for C26H30N2O5 : C, 69.31; H , 6.71 ; N, 6.22%. Found: C, 68.9; H, 6.8; N, 6.1%.

Ethyl (4'R)-(3'-Benzoyl-(2'S)-tert-buty\-oxazo\idin-5'-one)-(2S)-N-

(benzylidene)propanoate (351b)

(351b): iH NMR (400 MHz, in part) 8 5.97 (s, IH, H-2'), 1.14 (t, J = 7.2 Hz,

3H,OCH2CH3), 1.05 (s, 9H, Me3).

Ethyl (4'5)-(3,-Benzoyl-(2'i?)-^rt-butyl-oxazolidin-5,-one-(2/?)-A7-

(diphenylmethyene)propanoate ent-(374a)

Ph PK e/tf-(374a)

3'VS-Or H Bu1

2 (374a): Mp: 198-200 °C; [cc]D 6+130.8 ° (c 0.32, CHCI3). iH NMR (400 MHz) 8 7.19-7.63 (m, 15H, Ph), 5.88 (s, br, IH, H-2'), 4.45 (dd, IH,

J = 7.8, 1.8 Hz, H-4'), 4.13 (dd, IH, J = 11.1, 3.31 Hz, H-2) 3.89 (q, J = 6.9 Hz, 2H,

OCH2CH3), 2.58 (t, J = 1.8 Hz, IH, H-3A), 1.92 (s, br, IH, H-3B), 104 (t, J = 6.9

Hz, 3H, OCH2CH3), 0.96 (s, 9H, Me3).

13C NMR (75 MHz) 8 173.4 (C=N), 172.4 (CO), 170.66 (CO), 170.2 (CO), 138.8

(C) 135.6 (C), 135.4 (C), 129.1 (CH), 128.9 (CH), 128.8 (CH), 128.7 (CH), 128.4

(CH), 128.3 (CH), 128.2 (CH), 128.0 (CH), 127.9 (CH), 127.5 (CH), 94.4 (CH),

60.9 (OCH2CH3), 59.9 (CH), 55.8 (CH), 39.9 (C), 34.8 (CH2), 24.7 (Me3), 13.9,

(OCH2CH3). Chapter Five : Experimental 236

IR 2970, 2957, 1789 (CO), 1736 (CO), 1651 (C=N), 1614, 1480, 1180, 1115, 1055, 938,884,827,771cm-1. Mass spectrum (ES, +ve) m/z 527.4 (M+l, 100%) 126 (70%), 211.3 (28%), 81 (68%).

Anal Cald for C32H34N2O5 : C, 72.98; H , 6.71 ; N, 5.32%. Found: C, 72.97; H, 6.54; N, 5.12%.

, , 7 Ethyl (4'/?>)-3 -Benzoyl-(2'5>)-rerr-butyl-oxazolidin-5 -one-(25)-A - (diphenylmethyene)propanoate (374a)

(374a) Ph

PhCON c 1 Bu*»/V2 H' The compound (374a) was obtained as a white solid in 75% yield. The spectral data of (374a) were identical to that of ent-(374a), mp: 200 °C; [cc]D28 -130.6° (c 0.91, CHCI3).

Ethyl (4'S)-(3'-Benzoyl-(2'/?)-^rf-butyl-oxazolidin-5'-one)-(2/?)-A7- (diphenylmethyene)propanoate (374b)

Minor diastereoisomer (374b): iH NMR (400 MHz, in part) 8 6.06 (s, IH, H-2), 1.14 (t, J = 7.2 Hz, 3H,OCH2CH3), 0.94 (s, 9H, Me3). tert-Butyl (4'S)-(3'-benzoyl-(2'R)-tert-butyl-oxazolidin-5'-one)-(2R)-N- [(l"R, 4'7c)-bornylidene)]propanoate (382):

4" H N^ C02Bu* (382)

PhCON r Chapter Five : Experimental 237

22 (382): Mp:151 °C; [cc]D +137 ° (c 0.52, CHCI3). iH NMR (400 MHz) 8 7.45-7.60 (m, 5H, Ph), 6.04 (s, br, IH, H-2'), 4.40 (dd, IH,

J = 7.5, 1.8 Hz, H-4'), 3.85 (dd, IH, J = 11.6, 2.4 Hz, H-2), 2.50 (m, IH, H-3A),

2.34 (s (br), IH, H-3B), 1.40-2.85 (m, 7H, camphor), 1.28 (s, 9H,C02Me_3), 1.02 (s,

9H, Me3), 0.95 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.80 (s, 3H, CH3).

13C NMR (75 MHz) 8 188.4 (C=N), 172.2 (CO), 170.8 (CO), 168.8 (CO), 135.5

(C), 132.UCH. 128.9 (C), 127.5 (CH), 94.1 (CH), 81.2 (CMe3), 59.5 (CH), 56.0

(CH), 54.6 (C), 47.6 (C), 43.77 (CH), 39.8 (C), 36.1 (CH2), 33.5 (CH2), 31.1

(CH2), 29.5 (CH2), 27.7 (OCMe3), 24.6 (Me3), 19.5 (CH3), 18.8 (CH3), 11.2

(CH3).

IR 2962, 2359, 180 (CO), 1736 (CO), 1651(C=N), 1577, 1195, 1111, 1043, 955,

872, 892, 724 cm"1.

Mass spectrum (ES, +ve) m/z 525.7 (M+l, 100%) 301 (70%), 286 (28%), 105

(68%).

Anal Cald for C31H44N2O5 : C, 70.96; H , 8.46 ; N, 5.34%. Found: C, 70.99; H,

8.64; N, 5.34%. terf-Butyl (4'/?)-(3'-benzoyl-(2'5)-^r/-butyl-oxazolidin-5'-one)-(2/?)-/Y-

[(1"R, 4"/?)-(bornylidene)]propanoate (383):

7^H%SC02BU< 4R H > P O (383) 4^C PhCON * 3 V^O i' tA* 25 Bu* H (383): oil. [a]D -130 0 (c 0.52, CHCI3). iH NMR (300 MHz) 8 7.45-7.67 (m, 5H, Ph), 6.07 (s, br, IH, H-2'), 4.63 (t, J = 6.4

Hz, IH, H-4'), 4.12 (dd, IH, J = 13.1, 7.9 Hz, H-2) 2.50 (m, IH, H-3A), 2.34 (s Chapter Five : Experimental 238

(br), IH, H-3B), 1.40-2.85 (m, 7H, camphor), 1.32 (s, 9H.CO?Me^). 1.01 (s, 9H,

Me3), 0.99 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.76 (s, 3H, CH3). i3C NMR (75 MHz) 8 186.8 (C=N), 172.6 (CO), 170.4 (CO), 169.7 (CO), 136.4

(C), 131.5(CH), 128.9 (CH), 127.7 (CH), 94.9 (CH), 81.3 (OCMe3), 61.1 (CH), 56.7

(CH), 54.3 (C), 47.7 (C), 43.6 (CH), 39.9 (C), 36.3 (CH2), 33.6 (CH2), 31.6 (CH2),

29.6 (CH2), 27.8 (OCMe3), 24.8 (Me3), 19.6 (CH3), 19.0 (CH3), 11.3 (CH3).

IR 3275, 3058, 1785, 1729, 1643, 1577, 1195, 1111, 1043, 955, 872, 892, 724 cm-1.

Mass spectrum (ES, +ve) m/z 525 (M+l, 100%) 301 (70%), 286 (28%), 105 (68%).

General Method for the Hydrolytic Cyclization of the Michael Adducts to

Lactams (352a,b) and ent-(325a)

A solution of the Michael adduct (351a) (0.45 g, 1 mmol) in aqueous methanol

(5 mL, 1 mL H2O) containing acetic acid (0.5 mL) and dioxane (5 mL) was heated to reflux for 24 hr at 80 °C. After removal of the solvent with a rotatory evaporator, the residue was made basic with a 5% aqueous solution of sodium hydrogen carbonate (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the combined organic layers were dried (MgS04) and evaporated under reduced pressure. The residue was separated by preparative plate chromatography to give lactam (352a) as a white solid (0.24 g, 93%).

(2S, 4R)- Ethyl trans 4-benzamido-5-oxo-pyrrolidine-2-carboxylate

(352a)

H NHCOPh

23 (352a): Mp:144 OQ [a]D -15.1° (c 0.52, CHCI3). iH NMR (400 MHz) 8 7.88 (dd, J = 6.9 Hz, 2H, o-ArH), 7.20-7.50 (m, 3H, Ph),

6.87 (d, J = 4.8Hz, IH, NHCOPh), 6.35 (s, IH, NH)), 4.54 (ddd, J = 10.7, 9.0, 5.1 Chapter Five : Experimental 239

Hz, IH, H-4), 4.28 (t,J = 1.5 Hz , IH, H-2), 4.25 (q, J = 9.6 Hz, 2H, OCH2CH3),

3.04 (m, IH, H-3p), 2.41 (m, IH, H-3a), 1.32 (t, J = 7.2 Hz, 3H,OCH2CH_3) 13C NMR (100 MHz) 8 175.3 (CO), 171.6 (CO), 167.8 (CO), 133.2 (C), 132.0 (CH),

128.5 (CH), 127.0 (CH-Ar), 62.1 (OCH2CH3), 53.1 (CH), 49.8 (CH), 33.1 (CH2), 14.1 (OCH2CH3).

IR 3302, 2961, 1730, 1729, 1654, 1579, 1260, 1210, 1074, 862, 801, 724 cm"1.

Mass spectrum (ES, +ve) m/z 277.3 (M+H+, 100%) 259 (2%), 244 (2%), 228 (4%), 104.7 (6%).

Anal Cald for Ci4Hi6N204 : C, 60.86; H , 5.84 ; N, 10.14%. Found: C, 60.78; H, 5.89; N, 9.82%.

Starting with (374), and using the procedure described above for the synthesis of

(352a) from (351a), the lactam (352a) was obtained as a white solid in 90% yield, mp : 145 °C; [OC]D21 -19.9° (c 0.20, CHCI3). Spectral data for this compound were identical to that of (352a) described above.

(2R, 45)- Ethyl trans 4-benzamido-5-oxo-pyrrolidine-2-carboxylate ent-

(352a) PhCOHNH

/ ^V«*\C02Et O N H H ew*-(352a)

Starting with ent-(351a) and using the procedure described above for the synthesis of

(352a), the compound ent-(352a) was obtained as a white solid in 91% yield, mp :

27 145 °C; [oc]D +19.9° (c 0.30, CHCI3). The spectral data for ent-(352a) were identical to that of (352a). Chapter Five: Experimental 240

(2R, 4R)- Ethyl *rans-4-benzamido-5-oxpyrroIidine-2-carboxyIate (352b)

H u PhCON H (352b) F 5/ ^ttC02CH2CH3 H

(352b) : iH NMR (400 MHz, in part) 8 4.95 (m, IH, H-4), 4.28 (m, IH, H-2), 3.13

(m, IH, H-3'a), 2.10 (m, IH, H-3P), 1.26 (t, J = 9.6 Hz, 3H, OCH2CH3).

Hydrolytic Cyclization of the Michael Adducts (380a,b) to Lactams

(381a,b)

A solution of a mixture of the Michael adducts (380a) and (380b) (0.43g, 1 mmol) in aqueous methanol (5 mL, 1 mL H2O), containing acetic acid (0.5 mL) and dioxane (5 mL) was heated to reflux for 24 hr at 80 °C. After removal of the solvent with a rotatory evaporator, the residue was made basic with a 5% aqueous solution of sodium hydrogen carbonate (10 mL) and extracted with dichloromethane (3 x 10 mL).

The combined organic layers were dried (MgS04) and evaporated under reduced pressure. The residue was purified by column chromatography to give a mixture of the lactams (381a) and (381b) as a white solid (0.150 g, 55%).

(2R, 4R)-Methyl 4-benzamido-5-oxo-pyrrolidine-2-carboxylate (381a)

H u PhCON H \l± 3 (381a) J* A3.«Me O^ NiXOgMe

Major diastereoisomer (381a):XH NMR (400 MHz) 8 7.20-7.50 (m, 5H, Ph), 6.95 (s,

IH, NHCOPh), 4.85 (m, IH, H-4), 3.79 (s, 3H, OCH3), 2.81 (dd, J = 13.2, 8.8 Hz,

IH, H-3A), 2.33 (dd, J = 13.2, 9.6 Hz, IH, H-3B), 1.61 (s, 3H, CH3).

13C NMR (100 MHz) 8 174.5 (CO), 173.9 (CO), 167.1 (CO), 133.9 (C), 131.4 (CH),

128.2 (CH), 126.9 (CH), 59.6 (OCH3), 52.8 (CH), 49.8 (C), 39.6 (CH2), 25.2

(OCH3). Chapter Five: Experimental 241

IR 3310, 2961, 2924,1736, 1711, 1693, 1543, 1262, 1196, 711 cm"1.

Mass spectrum (ES, +ve) m/z 277.7 (M+H+, 100%) , 259.6 (15%), 206 (5%).

Anal Cald for Ci4Hi6N204 : C, 60.86; H , 5.84 ; N, 10.14%. Found: C, 59.86; H, 5.92; N, 9.20%.

(2R, 4S)-Methyl-4-benzamido-5-oxo-pyrrolidine-2-carboxyIate (381b).

H H NCOPh

(38lb) I Y>C02Me

Minor diastereoisomer (381b): 1H NMR (400 MHz) 8 7.20-7.50 (m, 5H, Ph), 6.58

(s, IH, NHCOPh), 4.63 (m, IH, H-4), 3.79 (s, 3H, OCH3), 3.28 (dd, J = 13.2, 8.8

Hz, IH, H-3A), 1.99 (dd, J = 13.2, 10.8 Hz, IH, H-3B), 1.60 (s, 3H, CH3).

13C NMR (100 MHz) 8 175.1 (CO), 174.4 (CO), 167.4 (CO), 133.2 (C), 131.6 (CH),

128.3 (CH), 127.0 (CH), 59.7 (OCH3), 52.9 (CH), 51.0 (C), 40.4 (CH2), 25.7

(OCH3).

Removal of Camphor Moiety from the Michael Adducts (382) or

(383) to give the Lactams (385) or (386).

To a solution of (382) and (383) (0.070g, 0.13 mmol) in ethanol (5 mL) was

added hydroxylamine hydrochloride (0.017g, 0.26 mmol) and sodium acetate trihydrate

(0.034 g, 0.26 mmol). The mixture was heated under reflux for 12 hr. After

evaporation of the solvent, the residue was purified by PTLC (80% ethyl acetate /

hexane) to give lactam (385) or (386) in 87% and 90% yields, respectively.

(2R, 4S)- terf-Butyl frans-4-benzamido-5-oxo-pyrrolidine-2-carboxylate

(385)

H H NCOPh (385) iok^Bu* 0AN,H H Chapter Five: Experimental 242

2 (385): Mp:80 °C; [a]D 3 = +8.0 o (c 0.10, CHC13). iH NMR (400 MHz) 8 7.35-7.78 (m, 5H, Ph), 7.15 (d, J = 5.7 Hz, IH. NHCOPh),

6.67 (s, IH, NH)), 4.56 (ddd, J = 9.3, 5.4,3.9 Hz, IH, H-4), 4.19 (t, J = 4.8 Hz, IH,

H-2), 2.83 (m, IH, H-3A), 2.38 (m, IH, H-3B), 1.49 (s, 9H, COOMe3)

13C NMR (100 MHz) 8 175.7 (CO), 170.9 (CO), 167.7 (CO), 133.3 (C), 131.7 (CH),

128.4 (CH), 127.1 (CH), 82.8 (C), 53.9 (CH), 49.9 (CH), 33.0 (CH2), 27.9 (Me3).

IR 3275, 3058, 1785, 1729, 1643, 1577, 1195, 1111, 1043, 955, 872, 892, 724 cm"1.

Mass spectrum (ES, +ve) m/z 305.1 (M+l, 100%), 284.5 (90%), 256.8 (80%),

248.8 (45%), 172.6 (10%), 78.9 (72%).

Anal Cald for C16H20N2O4 : C, 63.14; H , 6.62 ; N, 9.2%. Found: C, 63.14; H, 6.88;

N, 8.69%.

(2R, 4R)-tert-Butyl cis,-4-benzamido-5-oxo-pyrrolidine-2-carboxylate

(386)

H H PhOCN, H \IA 3 - , (386) 5r ^2uttC02Bu ^s*v *yz*. O^NT^H H 23 (386): Mp: 180-182 °C; [oc]D = -18.2 ° (c 0.04, CHCI3). iH NMR (400 MHz) 8 7.20-7.80 (m, 5H, Ph), 7.11 (s (br), IH, NH), 4.88 (dd, J =

16.4, 8.8 Hz, IH, H-4), 4.22 (dd, J = 8.8, 7.2 Hz, IH, H-2), 3.17 (m, IH, H-3A),

2.05 (m, IH, H-3B), 1.48 (s, 9H,COOMe3)

13C NMR (100 MHz) 8 175.1 (CO), 171.1 (CO), 167.5 (CO), 133.1 (C), 131.7 (CH),

128.4 (CH), 127.0 (CH), 83.2 (C), 53.2 (CH), 50.6 (CH), 34.2 (CH2), 28.0 (Me3).

Mass spectrum (ES, +ve) m/z 631.1 (2M+Na+, 100%), 327 (M+Na+, 80%), 305.1

(M+H+, 100%), 288.3 (90%), 270.0 (80%).

IR 3278, 3058, 2968, 1795, 1729, 1649, 1655, 1158, 1111, 1044 cm"1. Chapter Five: Experimental 243

(35, 5/c)-3-Benzamido-5-hydroxmethyl-2-oxo-pyrrolidine (397) or its Borate complex (398).

A solution of lactam (352a) (0.50 g, 0.18 mmol) in dry methanol (10 mL) was treated with NaBH4 (20 mg). After stirring 2 hr at room temperature the solution was then treated with acetone (3 mL) at 0 °C for 15 min. The solvent was evaporated to give the compound (397) as a white solid (0.42 g, 95%).

H NCOPh H NCOPh J\H (397) ^H^HA (398) °T1 oW" Na+ rv> H*\^WNHCOPh H 23 Mp: 198-200 °C, [oc]D = +59.5° (c 0.63, CHC13)

iH NMR (400 MHz, Methanol-d4) 8 7.42-7.86 (m, 5H, Ph), 4.79 (t, 9.6 Hz, IH, H-

4), 3.78 (m, IH, H-2), 3.58 (dd, J = 11.4, 4.5 Hz, IH, CHAHBOH), 3.56 (dd, J =

7.5, 4.5 Hz, IH, CHAHBOH), 2.35 (m, 2H, CH2). 13C NMR (75 MHz, DMSO) 8 174.7 (CO), 167.7 (CO), 134.3 (C), 131.3 (CH),

128.5 (CH), 127.5 (CH), 64.4 (CH2), 52.2 (CH2), 49.5 (CH), 30.5 (CH). Mass spectrum (ES, +ve) m/z 492.1 (2M+Na+, 2%), 257.7 (M+Na+, 80%), 235.3 (M+H+, 100%), 217 (M-OH, 21%). IR 2902, 2860, 1686, 1630, 1540, 1281, 1104, 875, 738 cm"1.

Anal Cald for borate complex (398) C24H26N407BNa . H20: C, 55.83; H, 5.08 ; N, 10.85%. Found: C, 55.74; H, 5.64; N, 10.61%. REFERENCES References 245

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