Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines

Abstract

Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.

Sulfur-Arylation of Sulfenamides via Chan–Lam Coupling with Boronic Acids: Access to High Oxidation State Sulfur Pharmacophores

“…Sulfilimines, the aza analogues of sulfoxides (Scheme B), serve as versatile common precursors to sulfoximines and sulfondiimines. Sulfilimines are traditionally prepared via imination of thioethers, though new disconnections are beginning to be explored. , For example, our group recently reported the synthesis of sulfilimines via unprecedented sulfur alkylation of readily accessible sulfenamides by rhodium-catalyzed coupling with a broad array of diazo compounds (Scheme B) . Based on this initial precedent, we hypothesized that S -arylation of sulfenamides could be achieved.…”

Redox-Neutral Synthesis of Sulfilimines through the S-Alkylation of Sulfenamides

“…[7][8][9][10] Therefore, chemists have been seeking better methods for constructing sulfilimines. Recent advances, such as the metal-free coupling method developed by Zhao and colleagues 11 and the S-alkylation of sulfenamides reported by Ellman and coworkers, 12 offer promising alternatives to traditional approaches. However, these methods still have limitations in terms of substrate scope and practicality, highlighting the continued need for further research in this area.…”

Synthesis of Sulfilimines Enabled by Copper-Catalyzed S-Arylation of Sulfenamides

“…Although a redox neutral process, the application of this approach is limited to substrates that can tolerate the reactive Grignard reagents employed. Very recently, Ellman and co-workers reported an elegant Rh-catalyzed enantioselective S -alkylation of sulfenamides with diazo compounds to deliver S -alkyl sulfilimines . Therefore, the development of mild and efficient synthetic methods to provide access to sulfilimines with broad functional group tolerance remains a challenge.…”

“…Very recently, Ellman and coworkers reported an elegant Rh-catalyzed enantioselective Salkylation of sulfenamides with diazo compounds to deliver Salkyl sulfilimines. 8 Therefore, the development of mild and efficient synthetic methods to provide access to sulfilimines with broad functional group tolerance remains a challenge.…”