(Chlorosulfonyl)benzenesulfonyl Fluorides—Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library

Abstract

Multigram synthesis of (chlorosulfonyl)­benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)­aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…One more important modification includes reaction of sulfonyl halides and aliphatic N-silylamines in refluxing in MeCN. [152] Less reactive (hetero)aromatic amines react in the presence of pyridine in CHCl 3 at rt; [153,154] aniline is left intact by heating neat at 100 °C and can be sulfonylated only in an aqueous suspension. [130] Important methods with a broad applicability to aliphatic, aromatic, and heterocyclic amines rely on the use of Ca(NTf 2 ) 2 in tert-amyl alcohol, [155] DABCO in THF, [156] DMAP, [157,158] and N-hydroxybenzotriazole (HOBt) with organosilicon additives (e. g. 1,1,3,3-tetramethyldisiloxane).…”

Covalent Small Molecules as Enabling Platforms for Drug Discovery

“…This is already the case for serine and lysine, for which Grygorenko et al. have prepared a library of sulfonyl fluorides (Figure E). A 62‐member covalent fragment library was rapidly assembled using parallel synthesis from (chlorosulfonyl)benzenesulfonyl fluoride building blocks and was screened against trypsin.…”

“…D) Covalent fragment hit for HOIP, designed using the Statsyuk hypothesis . E) Selected examples of Lys and Ser‐reactive fragment warheads . In (A), (C), and (E) different reversible fragment recognition elements are represented by coloured circles.…”

A Broad‐Spectrum Catalytic Amidation of Sulfonyl Fluorides and Fluorosulfates**

“…NMR data were in agreement with the literature data. [40] 3-((2-Chloro-5-methylpyrimidin-4-yl)amino)benzenesulfonyl fluoride (11) (2.0 mL, 2.0 eq) in isopropyl alcohol (40 mL) was stirred at 70 C in an oil bath for 24 h. After the reaction was complete, the mixture was cooled to room temperature. The suspension was filtered, washed with cold isopropyl alcohol (14 mL), and dried at 35 C in a vacuum oven overnight to give an off-white product (13ʼ, the hydrochloride salt of 13).…”