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

Autor:	Haas BC; Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States., Lim NK; Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, California 94080, United States., Jermaks J; Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, California 94080, United States., Gaster E; Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States., Guo MC; Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States., Malig TC; Department of Synthetic Molecule Analytical Chemistry, Genentech, Inc., South San Francisco, California 94080, United States., Werth J; Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States., Zhang H; Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, California 94080, United States., Toste FD; Department of Chemistry, University of California, Berkeley, California 94720, United States., Gosselin F; Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, California 94080, United States., Miller SJ; Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States., Sigman MS; Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2024 Mar 27; Vol. 146 (12), pp. 8536-8546. Date of Electronic Publication: 2024 Mar 13.
DOI:	10.1021/jacs.4c00374
Abstrakt:	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.
Databáze:	MEDLINE
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