Chemoselective Synthesis of N-Terminal Cysteinyl Thioesters via β,γ-C,S Thiol-Michael Addition

Abstract

Dehydroalanine (ΔAla) is a highly electrophilic residue that can react efficiently with sulfur nucleophiles to furnish cysteinyl analogues. Herein, we report an efficient synthesis of N-terminal cysteinyl thioesters, suitable for S,Nacyl transfer, based on β,γ-C,S thiol-Michael addition. Both ionic and radical-based methodologies were found to be efficient for this process.

Applications of Thiol-Ene Chemistry for Peptide Science

“…Recently, the Scanlan group applied radical TEC coupling to dehydroalanine (Dha) for synthesis of N-terminal cysteinyl thioesters suitable for S, N-acyl transfer (Petracca et al, 2019). Radical TEC between N-protected Dha and either thioacetic acid or a glycine thioacid was effected using DPAP and MAP in aqueous buffer at pH 6.…”

Thiyl Radicals: Versatile Reactive Intermediates for Cyclization of Unsaturated Substrates

“…A publication [117] by Mallick et al reported comparable results, employing the same reactions conditions previously developed in the Sahoo group (Section 2.4, Dutta et al). Mallick and co-worker's approach employed a N-hydroxyphthalimide-mediated radical cyclization of yne-dienones, yielding 3-thioaryl- [6,6]-dihydrochromenone derivatives. Altering the substituents of the aryl thiol, or the functional groups presented by the yne-dienone were again well tolerated in the cascade.…”

“…Since the turn of the millennium, organosulfur compounds have garnered substantial interest in the fields of medicinal chemistry, chemical biology and material science [1][2][3][4][5][6][7]. Of the diverse biochemical processes involving free radicals, many are thiyl radical mediated, highlighting the chemoselectivity, efficiency and biocompatibility of these reactive intermediates [8].…”

“…Thiyl radicals are well known to react efficiently at sites of unsaturation, through the thiol-ene and thiol-yne reactions. A full analysis of the utility of these reactions is beyond the scope of this review, and readers are directed to the reviews already present in the literature [6,[24][25][26][27][28][29]. This account will It may be expected that the trans isomer would dominate in this process, whether for steric reasons or otherwise, but in fact a general preference for the cis isomer is observed.…”

“…Thiyl radicals are well known to react efficiently at sites of unsaturation, through the thiol-ene and thiol-yne reactions. A full analysis of the utility of these reactions is beyond the scope of this review, and readers are directed to the reviews already present in the literature [ 6 , 24 , 25 , 26 , 27 , 28 , 29 ]. This account will focus exclusively on the intramolecular trapping of the nascent carbon radical formed via thiyl radical addition, and how these radicals form rings and products in cascade reactions.…”