Vitamin-B2 Photocatalysis for the alpha-C-H Functionalisation of Sulfides

Abstract

Riboflavin (Vitamin B2) and its derivatives have become increasingly popular candidates as photocatalysts for a plethora of photochemical reactions. The well-known ability of the flavin family to absorb blue light to furnish a highly oxidising excited state, together with its relatively low cost and impressive versatility, has provoked much interest from the scientific community in their potential application in innovative synthetic methods. Herein, novel flavin-mediated photocatalytic reactions are described for the synthesis of important molecular scaffolds and biologically relevant molecules. A novel photochemical strategy exploits the unique redox window of an excited state vitamin B2 photocatalyst in water to chemoselectively oxidise and deprotonate sulfides to generate key alpha-sulfur C-centred radicals. The latter can then engage in additions to a variety of electron-poor alkene traps to deliver complex alkylated sulfides in good to excellent yield. The methodology is further exploited for the synthesis of non-natural methionine analogues - by exploiting a new retrosynthetic disconnection - followed by the chemoselective modification of unsaturated residues in small peptides. The proposed reaction mechanism is supported by both experimental and computational studies. The flavin-mediated photochemical approach has also been extended to the multifaceted functionalisation of sulfides, enabling a crucial valorisation of unfunctionalised chemical feedstocks. This novel reactivity platform has been designed to engage a nucleophilic aplha-sulfur C-centred radical with electrophilic pi-systems bearing aryl sulfinate leaving groups, delivering functionalised products, and concomitantly allowing the turnover of the flavin catalytic cycle. The methodology has been successfully applied to the preparation of aplha-cyanated, alpha-alkynylated and alpha-alkenylated products in good yield and with excellent diastereoselectivity.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Procter (Supervisor), David Leys (Supervisor) & Sam Hay (Supervisor)