Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines DOI

Zachary W. Boyer,

Na Yeon Kwon, Jonathan A. Ellman

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or S-cyclopropyl substituent. Here, we report on a general efficient sequence for the asymmetric synthesis of both these substitution patterns. The sulfilimine intermediates by first Ru-catalyzed enantioselective alkylation sulfenamides enables examples S-alkylation monosubstituted diazo compounds. reaction proceeds at ≤1 mol % Ru-catalyst loading, tert-butyl diazoacetate, high yields ≥98:2 er achieved exceedingly broad range sulfenamides, including S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, -tert-butyl substituents sterically electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug also alkylated 99:1 er. After oxidation N-pivaloyl S-tert-butyl acetate substituted to corresponding sulfoximine, treatment trifluoracetic acid aprotic solvent resulted decarboxylation while aqueous HCl cleavage group give NH sulfoximine. Alternatively, dibromoethane followed acid-mediated provided preclinical candidate LTGO-33 formal phase II ART0380 demonstrate utility disclosed approach.

Language: Английский

Sulfilimines from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery DOI
Nathaniel S. Greenwood,

Zachary W. Boyer,

Jonathan A. Ellman

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

While sulfoximines are nowadays a well established functional group for medicinal chemistry, the properties of sulfilimines significantly less studied, and no sulfilimine has progressed to clinic date. In this account, physicochemical in vitro reported compared those other more traditional groups. Furthermore, impact on real drug scaffolds is studied two series sulfilimine-containing analogs imatinib hNE inhibitors. We show that can be chemically configurationally stable under physiologically relevant conditions they basic highly polar thus often beneficial solubility metabolic stability, although at cost reduced permeability. conclude S-cyclopropyl,S-(hetero)aryl S,S-di(hetero)aryl so far neglected but potentially valuable S(IV) based pharmacophores deserve considered as part chemistry toolbox.

Language: Английский

Citations

3
Ligand-Enabled Copper-Catalyzed Ullmann-Type S–C Bond Formation to Access Sulfilimines DOI

Xianda Wu,

Jiayi Zheng, Fu‐Sheng He

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

A copper-catalyzed Ullmann-type cross-coupling reaction of sulfenamides with aryl iodides is developed. The key to success the use a 2-methylnaphthalen-1-amine-derived amide ligand, which enables formation an S-C bond access functionalized sulfilimines in good excellent yields at room temperature. This method has advantages mild conditions, broad substrate scope, functional group compatibility, and high chemoselectivity. utility this protocol highlighted through late-stage modification drug-relevant molecules sulfilimine product derivatization.

Language: Английский

Citations

5
Anionic Stereogenic-at-Cobalt(III) Complex-Enabled Asymmetric Oxidation of N,N-Dialkyl Sulfenamides DOI

Yue Shen,

Xiaobao Wu,

Hua‐Jie Jiang

et al.

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

An asymmetric oxidation of N,N-dialkyl sulfenamides is exhibited by using anionic stereogenic-at-cobalt(III) complexes as catalysts. This protocol provides an alternative approach to access a diverse set chiral tertiary sulfinamides with high enantioselectivities (24 examples, up 94:6 e.r.). Additionally, control experiments suggest that this could be accomplished through cationic S(IV) intermediate.

Language: Английский

Citations

0
Regioselective N-arylation of N-Acylsulfenamides Enabled by o-Quinone Diimides DOI
Xuebin Yan, Rui Zhao, Yu‐Hang Miao

et al.

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The functionalization of N-acylsulfenamides is a research focus in organosulfur chemistry, as the N-S array has unique properties and versatile applications. Although great progress been made S-functionalization, N-functionalization, especially N-arylation N-acylsulfenamides, rarely explored because lower nucleophilicity N-site. Herein, we report Brønsted acid-catalyzed regioselective reaction with o-quinone diimides. Under mild metal-free conditions, wide range N-arylated have prepared good yields excellent regioselectivity. ease gram-scale synthesis transformations into useful sulfonamides demonstrates their synthetic practicality.

Language: Английский

Citations

0
Cu-Catalyzed Enantioselective S-Arylation of Sulfenamides Enabled by Confined Ligands DOI
Xiaobao Wu,

Yue Shen,

Hua‐Jie Jiang

et al.

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Chiral sulfilimines, aza analogues of sulfoxides, are essential in natural products and pharmaceuticals, highlighting the importance their synthesis asymmetric catalysis. However, efficient approaches for synthesizing chiral diaryl sulfilimines still rare challenging, particularly those with two sterically similar aryl groups. Herein, we present a mild protocol generating diverse enantioenriched alkyl via copper-catalyzed enantioselective S-arylation N-acyl sulfenamides diaryliodonium salts. A bulky PyBox ligand is crucial stereocontrol, delivering various up to 95% ee (51 examples).

Language: Английский

Citations

0
Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines DOI

Zachary W. Boyer,

Na Yeon Kwon, Jonathan A. Ellman

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or S-cyclopropyl substituent. Here, we report on a general efficient sequence for the asymmetric synthesis of both these substitution patterns. The sulfilimine intermediates by first Ru-catalyzed enantioselective alkylation sulfenamides enables examples S-alkylation monosubstituted diazo compounds. reaction proceeds at ≤1 mol % Ru-catalyst loading, tert-butyl diazoacetate, high yields ≥98:2 er achieved exceedingly broad range sulfenamides, including S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, -tert-butyl substituents sterically electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug also alkylated 99:1 er. After oxidation N-pivaloyl S-tert-butyl acetate substituted to corresponding sulfoximine, treatment trifluoracetic acid aprotic solvent resulted decarboxylation while aqueous HCl cleavage group give NH sulfoximine. Alternatively, dibromoethane followed acid-mediated provided preclinical candidate LTGO-33 formal phase II ART0380 demonstrate utility disclosed approach.

Language: Английский

Citations

0