Clickable coupling of carboxylic acids and amines at room temperature mediated by SO₂F₂: a significant breakthrough for the construction of amides and peptide linkages

Abstract

A method of SO2F2 mediated direct clickable coupling of carboxylic acids with amines for the synthesis of a broad scope of amides and peptides was developed.

Installation of -SO2F groups onto primary amides

“…Sulfur(VI) fluoride exchange (SuFEx) is a new class of click chemistry developed by Sharpless and co-workers in 2014, for creating molecular connections based on the unique stability–reactivity pattern of the S(VI)–F bond with reliability and efficiency, which has been widely applied in organic synthesis, chemical biology and drug discovery [1–19]. Among all the developed S(VI)–F species, sulfonyl fluoride (RSO 2 F) was specifically recognized as unique scaffold for covalent protein inhibitors and biological probes with the affinity-driven activation for forming covalent linkages with the amino acid residues of protein binding sites (Fig.…”

Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride

“…5,6 An emerging area is the SO 2 F 2mediated activation of carboxylic acids (1, Scheme 1) for nucleophilic acyl substitutions (NAS). While valuable synthetic advances have been made, 7,8 these SO 2 F 2 -mediated NAS reactions have a limited nucleophile scope because the single addition conditions rely on minimizing the rate of the undesired reaction between the nucleophile (2) and SO 2 F 2 (k 2 ) compared to carboxylate activation (k 1 ). A more general SO 2 F 2 -mediated NAS strategy would involve using the same concept that was successfully employed in alcohol activation, in which an intermediate is rapidly formed, is stable under the reaction conditions, and is sufficiently reactive for a subsequent NAS.…”

“…These expedient and gentle reaction conditions, coupled with the formation of relatively unreactive sulfate byproducts, have resulted in a new wave of sulfuryl fluoride-mediated synthetic methods that couple multiple transformations in a single pot. , The majority of reports of one-pot reactions have focused on alcohols using alkyl and aryl fluorosulfate intermediates, as these can be readily formed, yet are typically sufficiently stable to allow for a second transformation. , An emerging area is the SO 2 F 2 -mediated activation of carboxylic acids ( 1 , Scheme ) for nucleophilic acyl substitutions (NAS). While valuable synthetic advances have been made, , these SO 2 F 2 -mediated NAS reactions have a limited nucleophile scope because the single addition conditions rely on minimizing the rate of the undesired reaction between the nucleophile ( 2 ) and SO 2 F 2 ( k 2 ) compared to carboxylate activation ( k 1 ). A more general SO 2 F 2 -mediated NAS strategy would involve using the same concept that was successfully employed in alcohol activation, in which an intermediate is rapidly formed, is stable under the reaction conditions, and is sufficiently reactive for a subsequent NAS.…”

Installation of sulfonyl fluorides onto primary amides

“…Sulfur(VI) fluoride exchange (SuFEx), is a new class of click chemistry developed by Professor K. B. Sharpless and coworkers in 2014, for creating molecular connections based on the unique stability-reactivity pattern of S VI -F bond with absolute reliability and unprecedented efficiency, which has been widely applied in organic synthesis, chemical biology and drug discovery [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Among all the developed S(VI)-F species, sulfonyl fluoride (RSO2F) was specifically recognized as unique scaffold for covalent protein inhibitors and biological probes with the affinity-driven activation for forming covalent linkages with the amino acid residues of protein binding sites (Figure 1) [20].…”