A Novel Methodology for the Asymmetric Synthesis of beta-Lactams and beta-Amino Acids

Abstract

The first example of an intramolecular ester enolate-imine cyclisation reaction for the asymmetric synthesis of polycyclic B-lactams and cyclic B-amino acid derivatives has been developed.

In Chapter 1, the synthesis of monocyclic B-lactams using intermolecular ester enolate-imine cyclisation reactions is reviewed. The use of chiral auxiliaries contained within the ester or imino functionality to control the diastereoselectivity of the reaction is discussed, as well as enantioselective approaches. The utilization of this methodology for the synthesis of natural products such as Taxol is described, as well as the use of polymer support protocols to improve the efficiency of this reaction.

In Chapter 2, the synthesis of an appropriate cyclisation substrate containing an ester and imino functionality with a chiral auxiliary fragment is reported. Appropriate conditions were established that enabled an intramolecular enolate-imine cyclisation reaction to be used for the synthesis of the tricyclic B-lactam benzocispentacin in good yield and excellent de. The formation of B-amino ester side products was investigated and an explanation for the production of B-lactams as major products over their corresponding B-amino esters is proposed. This protocol was then applied to the asymmetric synthesis of six benzocispentacin derivatives all with good yields and excellent de, with the configuration of one of these derivatives being confirmed by X-ray crystallography. A deprotection methodology was then established to afford their corresponding tricyclic NH-B-lactams and cis and trans bicyclic B-amino esters.

In Chapter 3, the newly devised methodology was also applied to acyclic substrates for the synthesis of the antifungal cispentacin. The ability to access both cis- and transpentacin in both high yields and excellent de as monomers for foldamer synthesis is reported. A small series of bicyclic B-lactam analogues was prepared in a short and efficient methodology, with the intramolecular enolate-imine cyclisation reaction being the key step to all these syntheses.

Date of Award	30 Jun 2012
Original language	English
Awarding Institution	University of Bath
Supervisor	Steven Bull (Supervisor)