Studies Towards the Total Synthesis of Anti-infective Natural Products

Abstract

Natural products have served as important feedstocks for contemporary drug discovery. As a result of complex secondary metabolic pathways, natural products encompass an extremely wide range of chemical space and often have potent bioactive properties. In order to unlock the potential of ‘nature’s pharmacy’, total chemical synthesis is often employed to provide access to these compounds and allow further biological evaluation. The work within this thesis describes synthetic advances towards the total synthesis of three bioactive natural products. Chapter 2 describes a synthetic approach and structural reassignment of burkholdine 1097, a non-ribosomal cyclic lipopeptide with potent anti-fungal activity. This approach implements solid-phase peptide synthesis methodology and a late stage macrolactamisation reaction. The synthesis necessitated the preparation of several non-proteinogenic amino acids, including an unprecedented fatty acyl amino acid of polyketide origin. Chapter 3 describes studies towards an anti-trypanosomal natural product, janadolide. As a non-ribosomal peptide/polyketide hybrid, several strategies were trialled to arrive at a viable synthetic route to the polyketide moiety, with the successful strategy utilising a B-alkyl Suzuki reaction as the key step. Chapter 4 describes an approach to wickerol A and B - diterpenes that possess anti-influenza activity. These natural products have an unprecedented carbon skeleton with a high level of steric congestion making their synthesis a challenging undertaking. Several synthetic approaches were trialled towards a model system of these natural products with the successful route utilising a samarium(II) chloride-mediated ketyl radical cyclisation, Meyer-Schuster rearrangement and a Prins/carbonyl-ene reaction as key synthetic steps.