Rapid access to diverse and stereochemically enriched cyclic aza-sulfur(VI) compounds

Compounds with sulfur functional groups are ubiquitous in medicinal chemistry, agrochemistry and beyond. Many of these important molecules are sulfones and sulfonamides, of which the sulfur atom is in the most stable oxidation state VI. Sulfoximines and sulfonimidamides are attained by replacing S=O bonds on these functional groups with S=N bonds. These aza-sulfur(VI) analogues are highly attractive due to extra modularity in N-substituents and manifestation of a sulfur stereocentre, unlocking a rich chemical space for further exploration of new drugs, agrochemicals and chiral reagents. To accelerate the development of aza-sulfur(VI) with S=N bonds as next-generation pharmacophores, modern studies in synthetic chemistry have led to new methods to access aza-sulfur(VI) compounds of various type with high efficiency and stereoselectivity. Compared to acyclic aza-sulfur(VI) compounds, cyclic aza-sulfur(VI) compounds are heavily underexplored in all applications, yet potentially of much greater value due to a more well-defined and controllable stereochemical framework. However, there exists no common strategy to access them, especially in the context of stereocontrol. The very few existing reports of stereoselective construction of cyclic aza-sulfur(VI) compounds are restricted to a specific class of attainable scaffold each. The proposed research aims to directly address this shortcoming by developing an efficient, common strategy to a broad range of cyclic aza-sulfur(VI) scaffolds from three very simple chemical components: a carboxylic acid, primary amine, and a commercially available sulfinylamine reagent previously explored in the Willis group. The synthetic approach will not use any harsh reagents or conditions, and should be fully amenable to both diastereoselective and enantioselective construction of the sulfur stereocentre. This strategy will enable access to new stereoenriched cyclic scaffolds for design of superior drugs, agrochemicals and chiral reagents.