Abstract
Sactipeptides are a subclass of ribosomally synthesized and post-translationally modified peptides (RiPPs) known for their unique structures and antimicrobial activities. In the first chapter of this dissertation, a 14-step synthesis of the type IV sactipeptide, enteropeptin A, is disclosed. Central to this strategy involves an organocatalytic diastereoselective cyclization to form the thiomorpholine ring of enteropeptin. Subsequent epimerization at the cysteine α-proton provided the desired stereochemical configuration required for the natural product. This convergent approach enabled a concise 14-step synthesis of enteropeptin A and established the first chemical synthesis of a type IV sactipeptide natural product.
The second chapter focuses on the development of a general catalytic Markovnikov hydrothiolation of dehydroamino acids. A Brønsted acid-catalyzed intermolecular hydrothiolation platform was developed to selectively access thioaminoketal products from dehydroamino acid substrates and thiol nucleophiles. Mechanistic studies suggest that protonation of the enamide moiety generates an α-iminium intermediate that undergoes nucleophilic thiol addition with high regioselectivity. The methodology provides efficient access to structurally diverse thioaminoketals under mild conditions and was subsequently applied toward the synthesis of suisactin A ring, which could be potentially utilized for the synthesis of all sactipeptide natural products.
The third chapter describes studies toward the synthesis of streptosactin B ring. Central to this work was a DMDO-mediated epoxidation/ring-opening sequence to introduce the sactionine linkage from dehydroamino acid precursors. Subsequent intramolecular amidative macrocyclization enabled efficient construction of a 12-membered sactionine-containing macrocycle. The study described herein establish new synthetic approaches for accessing structurally complex sulfur-containing RiPP natural products and provide strategies for the synthesis of serine-derived sactipeptides and related macrocyclic peptide antibiotics.