Remote asymmetric induction in the organocatalytic azaDarzens synthesis of peptide aziridines: towards the assembly of new glycopeptide antibiotic analogues

The widespread development of bacterial resistance to antibiotics is an ongoing process which represents a growing problem for modern medicine. Vancomycin is used as a drug of last resort against methicillin-resistant Staphylococcus aureus (MRSA), but the increasing prevalence of vancomycin-resistant bacteria has intensified the search for new antibiotics. The introductory chapter of this thesis presents an overview of publications reporting the synthesis of glycopeptide analogues and derivatives in the last decade, highlighting the successful approaches which have brought new pharmaceutical drugs to the market. The results and discussion section of this work focusses first on the synthesis of a triaryl biether structure, which is a common feature of the glycopeptide antibiotic family and represents the beginning of a versatile synthetic approach towards natural products like orienticin C and vancomycin. The second discussion chapter describes the development of an asymmetric organocatalytic aza-Darzens aziridination protocol using diazopeptides and amino acid imines as substrates. A structurally diverse range of peptide aziridines are reported in yields and diastereoselectivity of up to 99%. It is anticipated that the remote asymmetric induction methodology described in this thesis will be applicable not only to the synthesis of novel glycopeptide antibiotics and other peptide-based pharmaceutical compounds, but also to the more general asymmetric synthesis of natural and unnatural amino acids.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2014

Author dc:creator

• Ashford, Polly-Anna

Language dc:language

en