Degree Name

Doctor of Philosophy


Department of Chemistry


This thesis describes three new approaches to the asymmetric synthesis of chiral proline derivatives from (R) and (S)-tert-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-tert-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 (5S,2R)-cis-5-iso-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 N-arylidene 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 presence of AgOAc and DBU in CH3CN . While the cycloaddition reactions of (222) and the α-substituted imines (201b-g) proceeded with high exo-diastereoselectiviy 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 (R)-(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.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.