Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

Abstract

Innovation in drug discovery critically depends on the development of new bioisosteric groups.C hiral sulfoximines,w hich contain at etrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents,r epresent an emerging chiral bioisostere in medicinal chemistry.Chiral sulfoximines are conventionally prepared by as tereospecific nitrene transfer reaction to chiral sulfoxides; however,t he number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of ac lass of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains.Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions.T his stereospecific S-alkylation offers ag eneral and scalable approacht ot he asymmetric synthesis of chiral sulfoximines,w hichr epresent important substructures in bioactive molecules.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Practical Asymmetric Synthesis of Sulfoximines and Sulfimides from Sulfinamides

“…Our investigation commenced with a sulfur-selective alkylation of sulfinamides (Scheme 1 ). To prevent the preferential N -alkylation, the steric and electronic properties of the nitrogen atom of tert -butylsulfinamide 9a 13 were tuned by introducing a variety of N -substituents. Most N -protecting groups were ineffective, and only a trace amount of the desired sulfoximines was observed along with N -alkylation products (Scheme 1a ).…”

“…Under optimized conditions, various enantioenriched sulfoximines 2 could be obtained by the S -alkylation of optically pure sulfinamides ( S )- 1 without racemization (Scheme 2a ). 9a c 15 To our delight, N -pivaloyl-protected sulfinamides were also applicable to the Cu-catalyzed S -selective arylation with diaryliodonium salts as precursors of highly electrophilic aryl species (Scheme 2b ). 9b Readily accessible N -pivaloyl-protected ( R )- tert -butylsulfinamide 1b , obtained from commercially available ( R )- tert -butylsulfinamide, was converted into ( S )-alkyl or arylsulfinamides ( S )- 1 without racemization by S -alkylation or S -arylation and a subsequent de- tert -butylation with CF 3 CO 2 H (Scheme 2c ).…”

Strain-Enabled S-Arylation and S-Alkenylation of Sulfinamides

“…1C, strategy #2). 15,16 By taking advantage of the steric hindrance of a bulky N-pivaloyl group, the N-substitutions are suppressed.…”

“…Most importantly, functional groups including alkene(25,26), alkyne(27), alkyl bromide(28), amide(29, 30), and ketone (45, 46) were all well-tolerated. Some of these chemical handles could hardly survive in the previous S-arylation strategies where either harsh oxidation conditions12 (alkene and terminal alkyne incompatible) or strong bases15 (alkyl bromide incompatible) were applied. With our method, they could be left for diverse post-transformations.…”