Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation

Brittany C. Haas, Ngiap Kie Lim, Janis Jermaks, Eden Gaster, Melody C. Guo, Thomas C. Malig, Jacob Werth, Haiming Zhang, F. Dean Toste, Francis Gosselin, Scott J. Miller, Matthew S. Sigman

Research output: Contribution to journalArticlepeer-review

Abstract

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Original languageEnglish
Pages (from-to)8536-8546
Number of pages11
JournalJournal of the American Chemical Society
Volume146
Issue number12
DOIs
StatePublished - 27 Mar 2024
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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