Synthesis of intermediates for carbapenem antibiotics and synthetic analogues of dehydroepiandrosterone (DHEA)

Abstract

The work presented in this thesis is divided into two parts. Part one consists of the synthesis and chemical modification of β-lactams as potential intermediates for carbapenem antibiotics. Part two describes the synthesis of analogues of 3β-androst-5-ene-17-one (DHEA) and 3β-hydroxyandrost-5-ene-7,17-dione (7-oxo-DHEA) as potential therapeutic agents. The carbapenems are a group of non-classical β-lactam compounds containing a bicyclic carbapen-2-em-3-carboxylic acid nucleus. They possess potent antibacterial activity together with an unprecendented level of stability to a wide variety of β- lactamases. Thienamycin, the first known carbapenem was isolated from Streptomyces cattleya in 1976. The C-2 aminoethylthio substituent or a derivative thereof is accredited with the antipseudomonal activity demonstrated, while the hydroxyethyl or substituted alkyl C-6 substituent is thought to be responsible for the high degree of β-lactamase stability observed for these structures. Research to date involving the development of synthetic carbapenems has concentrated on the modification of the C-2 side chain. In this work the synthesis of monocyclic β- lactams containing a reactive C-3 vinyl side chain, which are suitably substituted to facilitate conversion to novel carbapenem compounds is presented.