Total Synthesis of Natural Products with Antimicrobial Activity

Abstract

Natural products are an essential source of many modern medicines. Examples of important natural products include the antibiotic penicillin and the antimalarial quinine. One significant class of bioactive natural products are non-ribosomal peptides (NRPs) and two prototypical members of this class are the extremely important antibiotics, penicillin and vancomycin. Currently, bacterial resistance to antibiotics is one of the most pressing global health issues. The need for new antibiotics with novel mechanisms of action is paramount. This thesis describes the total synthesis of the recently isolated antimicrobial NRPs teixobactin and skyllamycins A-C. Chapter two of this thesis describes the first total synthesis of teixobactin, a novel cyclic NRP antibiotic isolated in 2015. This was carried out via a solid-phase peptide synthesis (SPPS) strategy with a late stage cyclisation reaction. The synthetic natural product possessed potent activity against a number of clinically relevant Gram-positive bacterial pathogens. Chapters three and four describe investigations towards the total synthesis of skyllamycins A-C, a family of structurally complex cyclic NRPs. These natural products inhibit the growth of bacterial biofilms, a mechanism by which bacteria evade antibiotics. The most unusual feature of these natural products is the presence of an α-OH-glycine (Gly) moiety, which to date has only been found in one other linear peptide natural product. Chapter three details the synthesis of the non-proteinogenic amino acids present in the natural products and their incorporation into the synthesis of four skyllamycin analogues that omit the unusual α-OH-Gly residue. These analogues were analysed for their biofilm growth inhibition activity. Chapter four describes the completion of the first total synthesis of skyllamycins A-C. This was achieved through a SPPS strategy followed by a late stage cyclisation and concomitant formation of the unusual α-OH-Gly residue in one step