Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant <i>S</i>-Methyl and <i>S</i>-Cyclopropyl Sulfoximines

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an <i>S</i>-methyl or an <i>S</i>-cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective <i>S</i>-alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for <i>tert</i>-butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with <i>S</i>-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, and -<i>tert</i>-butyl substituents and for sterically and electronically diverse <i>N</i>-acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an <i>N</i>-pivaloyl <i>S</i>-<i>tert</i>-butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the <i>S</i>-methyl <i>N</i>-pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the <i>N</i>-acyl group to give the <i>S</i>-methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provided the <i>S</i>-cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.