סמינר בכימיה אורגנית: Enantioselective Brønsted-Base Catalyzed Acylation of Underexplored S(VI) Functional Groups Using Privileged and Peptide-Based Catalysts

Abstract:

‘Privileged’ chiral catalysts, renowned for their high stereoselectivity across diverse substrates and mechanisms, have emerged as an essential platform for catalyst optimization. Despite their widespread success, these catalysts often encounter limitations in exploring their chemical space, particularly as the nature of the substrate or reaction increases in complexity. Meanwhile, peptide-based catalysts have demonstrated effectiveness across various chemical reactivities, benefiting from their modular nature, which allows for the exploration of a broad chemical space and high-complexity substrates.

Underexplored S(VI) functional groups, including sulfonimidamide (SIA) and sulfondiimine (SDI), have recently attracted considerable interest as chiral bioisosteres of carboxylic acids and sulfonamides in drug design. This study discloses the development of an enantioselective Brønsted-base-catalyzed acylation of SIA and SDI and provides a direct comparison between a ‘privileged’ Cinchona alkaloid catalyst and a Dmaa-based peptide scaffold, highlighting the distinct catalytic requirement for these two S(VI) substrate classes. Furthermore, we demonstrate the incorporation of these chiral functional groups into drug candidates. 

An earlier study examining the impact of 1,1,1,3,3,3-Haxefluoropropan-2-ol (HFIP), renowned for its strong hydrogen-bond-donating ability, on reaction selectivity and efficiency in the development of metal-catalyzed oxidative coupling of phenols and the autoxidation of methylarenes will also be discussed, highlighting the critical role of noncovalent interactions in governing reaction outcomes.

References:

1. Haas, B. C.; Lim, N.-K.; Jermaks, J.; Gaster, E.; Guo, M. C.; Malig, T. C.; Werth, J.; Zhang, H.; Toste, F. D.; Gosselin, F.; et al. Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation. Journal of the American Chemical Society 2024, 146 (12), 8536-8546. DOI: 10.1021/jacs.4c00374.

2. E. Gasterⴕ; H. S. Slocumbⴕ; Z. Jurić; T. E. Myers; N-K. Lim; T. C. Malig; F. D. Toste; F. Gosselin; M. S. Sigman; S. J. Miller. Assessment of Complementary Catalysts in an Uncharted Enantioselective Reaction of Sulfondiimines. Journal of the American Chemical Society 2026, 148 (18), 18791-18803. DOI: 10.1021/jacs.5c23