Asymmetric Synthesis of <i>S</i> -Trifluoromethyl Sulfoxide and Sulfoximine Pharmacophores

High Resolution Image Download MS PowerPoint Slide Chiral sulfoxides and sulfoximines are present in many approved drugs and clinical candidates, and as predicated by the extensive use of the trifluoromethyl group in medicinal chemistry, S -trifluoromethyl derivatives with potent biological activity have been reported. However, chiral S -trifluoromethyl sulfoxides and sulfoximines are underexplored, perhaps because the only published routes for their preparation proceed by racemic synthesis followed by chiral separation. Here we report the asymmetric syntheses of S -trifluoromethyl sulfoxides and sulfoximines utilizing highly enantioenriched S -trifluoromethyl sulfilimines as common intermediates, obtained by the enantioselective copper-catalyzed S -trifluoromethylation of a wide range of sulfenamides, including complex drug and natural product derivatives. Methods were developed for the efficient conversion of the S -trifluoromethyl sulfilimines to sulfoxides via hydrolysis with inversion and sulfoximines via oxidation with retention. Mechanistic studies of the conversion of S -trifluoromethyl sulfilimines to sulfoxides reveal that the sulfilimine N -acyl group is first cleaved to give the free-NH sulfilimine that then undergoes hydrolysis by backside displacement of the amine to give the sulfoxide with inversion of stereochemistry.