Asymmetric synthesis of sulfoximines, sulfonimidoyl fluorides and sulfonimidamides enabled by an enantiopure bifunctional S(VI) reagent

• Published in: Nature chemistry 2024-02, Vol.16 (2), p.183-192
• Main Authors: Teng, Shun, Shultz, Zachary P., Shan, Chuan, Wojtas, Lukasz, Lopchuk, Justin M.
• Format: Article
• Language: English
• Subjects: 639/638/403/933; 639/638/549/933; 639/638/549/972; Analytical Chemistry; Asymmetric synthesis; Asymmetry; Biochemistry; Chemical properties; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Exchanging; Fluorides; Fluorine; Functional groups; Inorganic Chemistry; Intermediates; Organic Chemistry; Physical Chemistry; Reagents; Sulfur; Synthesis
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-023-01419-3

An increased interest to expand three-dimensional chemical space for the design of new materials and medicines has created a demand for isosteric replacement groups of commonly used molecular functionality. The structural and chemical properties of chiral S(VI) functional groups provide unique spatial and electronic features compared with their achiral sulfur- and carbon-based counterparts. Manipulation of the S(VI) centre to introduce structural variation with stereochemical control has remained a synthetic challenge. The stability of sulfonimidoyl fluorides and the efficiency of sulfur fluorine exchange chemistry has enabled the development of the enantiopure bifunctional S(VI) transfer reagent t -BuSF to overcome current synthetic limitations. Here, we disclose a reagent platform that serves as a chiral sulfur fluorine exchange template for the rapid asymmetric synthesis of over 70 sulfoximines, sulfonimidoyl fluorides and sulfonimidamides with excellent enantiomeric excess and good overall yields. Furthermore, the practical utility of the bifunctional S(VI) transfer reagent was demonstrated in the syntheses of enantiopure pharmaceutical intermediates and analogues. The stereochemical control and bifunctional manipulation of chiral sulfur functional groups is a long-standing challenge. Now, an enantiopure bench-stable S(VI) fluoride exchange reagent enables the asymmetric synthesis of sulfoximines, sulfonimidamides and sulfonimidoyl fluorides. The bifunctional nature of this reagent provides a practical method for the introduction of S(VI) functionality.