Expanding the Scope of Successive Ring Expansion

Abstract – Expanding the Scope of Successive Ring Expansion

This Thesis describes the development of new methodologies to perform ring expansion reactions to generate novel cyclic molecules. Chapter 1 provides an introduction into methods for the synthesis of cyclic peptides and macrocycles, particularly those utilizing ring expansion reactions, and also outlines the research objectives. In Chapter 2, a study to expand the scope of amino acids compatible with Successive Ring Expansion (SuRE) reactions is reported. A variety of N-Fmoc N-alkylated amino acids were synthesized and implemented in ring expansions to access functionalized medium sized rings with a peptoid-like structure.

Chapter 3 describes the development of a new SuRE variant utilizing protected thiols to synthesize macrocyclic thiolactones via ring expansion, with three complementary protecting group strategies explored. Alongside the synthesis, ring expansions were studied using computational tools, which can be used predictively to assess the viability of the reactions.

Chapter 4 describes efforts to develop a cascade ring expansion methodology to allow many ring expanded products to be formed from a common imide starting materials. The development of a conjugate addition-ring expansion cascade reaction (CARE) allowed the synthesis of functionalized medium sized rings from primary amines in two steps. Using acryloyl imides and a primary amine, an aza-Michael addition occurs followed by concomitant ring expansion. This cascade reaction is protecting-group free, high yielding, and very broad in scope, particularly with respect to the primary amine component, allowing the rapid synthesis of libraries of cyclic peptide mimetics. CARE reactions regenerate a secondary amide, which allows the reaction to be performed iteratively, enabling β-peptoid cyclic peptide mimetics to be ‘grown’ in sequential reactions with a defined sequence of nitrogen substituent at each stage. CARE reactions using carbon nucleophiles were developed with ring expansion via C−C bond formation at the carbonyl. Finally, a dihydroxylation/ring expansion cascade was demonstrated to furnish lactone products.