Tagging Peptides with a Redox Responsive Fluorescent Probe Enabled by Photoredox Difunctionalization of Phenylacetylenes with Sulfinates and Disulfides

Abstract

Herein, we describe a photoredox three-component atom-transfer radical addition (ATRA) reaction of aryl alkynes directly with dialkyl disulfides and alkylsulfinates, circumventing the utilization of chemically unstable and synthetically challenging S-alkyl alkylthiosulfonates as viable addition partners. A vast array of (E)-βalkylsulfonylvinyl alkylsulfides was prepared with great regio-and stereoselectivity. Moreover, this powerful tactic could be employed to tag cysteine residues of complex polypeptides in solution or on resin merging with solid phase peptide synthesis (SPPS) techniques. A sulfonyl-derived redox responsive fluorescent probe could be conveniently introduced on the peptide, which displays green fluorescence in cells while showing blue fluorescence in medium. The photophysical investigations reveal that the red shift of the emission fluorescence is attested to reduction of carbonyl group to the corresponding hydroxyl moiety. Interestingly, the fluorescence change of tagged peptide could be reverted in cells by treatment of H 2 O 2 , arising from the reoxidation of hydroxyl group back to ketone by the elevated level of reactive oxygen species (ROS).

Recent advances in the dichalcogenation reactions of unsaturated compounds via double functionalization

“…In 2022, a highly regio- and stereoselective synthesis of ( E )-β-alkylsulfonylvinyl alkylsulfides 77d was reported by Jia and coworkers via Ir-photoredox three-component thiosulfonylation of terminal aryl alkynes 77a with commercially available dialkyl disulfides 77b and sodium alkylsulfinates 77c using 15-crown-5 and ( t BuO) 2 (DTBP) as additives (Scheme 77). 105 The protocol obviated the preparation and application of chemically unstable and synthetically challenging S -alkyl alkylthiosulfonates, and was successfully used for the tagging of cysteine-derived polypeptides 77e in solution or on resin. Moreover, a sulfonyl-derived redox-responsive fluorophore probe was also introduced using this protocol, allowing imaging studies of peptides or proteins of interest in a biological context.…”

B(C6F5)3-catalyzed regio- and stereoselective thiosulfonylation of terminal alkynes with thiosulfonates

“…Nevertheless, despite considerable progress on the synthesis of functionalized vinyl sulfones, 3 the methods for the simultaneous incorporation of sulfones and sulfides in the alkene skeleton in one step remains scarce. 4–7 Compared with stepwise methods such as chlorosulfonylation of alkynes and sequential substitution with thiol nucleophiles, 3 f , g thiosulfonylation of alkynes with thiosulfonates is the most straightforward route to access thio-substituted vinylsulfones. 4–6,8 Recently, atom transfer radical addition (ATRA) as an elegant strategy has been successfully applied for such transformation.…”

“…4–7 Compared with stepwise methods such as chlorosulfonylation of alkynes and sequential substitution with thiol nucleophiles, 3 f , g thiosulfonylation of alkynes with thiosulfonates is the most straightforward route to access thio-substituted vinylsulfones. 4–6,8 Recently, atom transfer radical addition (ATRA) as an elegant strategy has been successfully applied for such transformation. For instance, Xu's group reported the synthesis of ( E )-β-(thio)vinyl sulfones via an ATRA of terminal alkynes with thiosulfonates enabled by gold and photoredox cooperative catalysis (Scheme 1a).…”

“…4 Later, Jia et al achieved regioselectivity inversion to access ( E )-β-arylsulfonylvinyl sulfides by using Eosin Y or an iridium complex as the photocatalyst (Scheme 1b). 5 Besides, a tert -butanol peroxide-mediated radical reaction of oxo-1,7-enynes with thiosulfonates was also disclosed for the synthesis of tetra-substituted β-(thio)vinyl sulfones with the ( E )-configuration. 6 Despite these significant advances, an approach for highly selective thiosulfonylation of alkynes is still very limited.…”

“…Given that the thiosulfonylation of alkynes reported previously almost underwent the radical mechanism, 4–6 to probe whether such transformation also proceeded via a radical process, we examined the reaction in the presence of radical scavengers. We found that the standard reaction still worked well in the presence of 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) to produce the desired products 3a in 58% yield, which suggested that no radical intermediate was involved in the catalytic cycle to some extent (Scheme 2).…”