A rapid access to aliphatic sulfonyl fluorides

Tianxiao Xu,Tianpeng Cao,Mingcheng Yang,Ruting Xu,Saihu Liao

doi:10.1038/s41467-019-11805-6

Abstract

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

Highlights

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit
To the recent significant progress in synthetic methodology development and polymer preparation[6,7,8,9,10,11], another intriguing application of Sulfur(VI) Fluoride Exchange (SuFEx) chemistry could be the use of sulfonyl fluorides in chemical biology and molecular pharmacology as a privileged type of warheads[12,13,14,15,16,17,18,19,20,21]
We conceived that the combination of carboxylic acid as a radical source with an appropriate SO2F-containing radical acceptor would forge a general approach to various sulfonyl fluorides (Fig. 1c)

Summary

Introduction

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Aliphatic sulfonyl fluorides are prepared via fluoride-chloride exchange with the corresponding sulfonyl chlorides, which can be prepared from thiols, halides, or sultones (Fig. 1b) These methods have very limited sources of starting compounds[2]. We conceived that the combination of carboxylic acid as a radical source with an appropriate SO2F-containing radical acceptor would forge a general approach to various sulfonyl fluorides (Fig. 1c). With this aim in mind, we found carboxylic acids are known to readily undergo decarboxylation to release a Selected examples of aliphatic RSO2F inhibitors.

Methods

Results

Conclusion