Synthetic Strategies Inspired by The Sactipeptide Natural Products
Creators: name: Milewska, Karen
Publisher: name: The Australian National University
Year: 2023

description: Sactipeptides are an important class of ribosomally synthesised post-transitionally modified peptides (RiPPs). The biosynthesis of sactipeptides involves the S-adenosyl methionine (SAM) super family of enzymes which play a crucial role in the post-translational formation of a thioether bridge between the sulfur of cysteine and the alpha-carbon of an opposing amino acid. This sactionine linkage is a distinctive feature of the members of this class of natural products with multiple new examples discovered in recent years. The intriguing structural features of this family result in constrained macrocyclic topologies which contribute to their antimicrobial activity as well as their structural integrity, making these natural products interesting targets for antibiotic development. This thesis will focus on synthetic strategies undertaken towards the synthesis of two sactipeptide targets, subtilosin A and sporulation killing factor (SKF). The key challenge posed by these fascinating peptide natural products is the unique thioether linkage. As chemical approaches for this cross-link are largely unexplored, strategies for the synthesis of this structural motif via building block approaches as well as late-stage modification strategies will be the main focus of this thesis. The thesis is comprised of the following chapters: Chapter 1 will serve as an introduction to peptide drugs, in particular focusing on post-translationally modified peptides. Members of the sactipeptide family of natural products will be introduced, delving deeper into their biosynthesis, structure and activity. This chapter will also provide an overview of existing synthetic strategies towards alpha-thioether amino acid linkages which are crucial for the synthesis of the sactionine linker. Chapter 2 will encompass the majority of the synthetic work undertaken and methodologies developed towards the synthesis of sactipeptide natural products subtilosin A and SKF as well as their analogues. It will explore multiple iterations of building block strategies towards the natural products, as well as late-stage strategies for the installation of the sactionine linkage. Chapter 3 will focus on an extension of the work presented in Chapter 2, specifically the development of a novel on-resin alkylation strategy for the synthesis of the key sactionine linkage within the sactipeptides as well as further exploration of the stability of this motif. Following a brief introduction, this chapter is presented as a published manuscript. Inspired by work presented in Chapter 2 on the synthesis of thiazolidine residues (cyclic alpha-thioether derivatives), Chapter 4 will highlight our investigative efforts into the incorporation of amino acid thiazolidines as well as selenozolidines (the corresponding selenium variant) into peptides. The structural features of peptides containing these underexplored residues will be investigated through NMR studies and their utility for late-stage peptide modification will also be examined. Chapter 5 will summarize the work undertaken towards the synthesis of sactipeptides as well as the broader exploration and investigation of the utility of alpha-thioether residues presented in this thesis. Future work and research directions will also be outlined in this chapter.