Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis

Abstract

Controlling the enantioselectivity of hydrogen atom transfer (HAT) reactions has been a long-standing synthetic challenge. While recent advances on photoenzymatic catalysis have demonstrated the great potential of non-natural photoenzymes, all of the transformations are initiated by single-electron reduction of the substrate, with only one notable exception. Herein, we report an oxidation-initiated photoenzymatic enantioselective hydrosulfonylation of olefins using a novel mutant of gluconobacter ene-reductase (GluER-W100F-W342F). Compared to known photoenzymatic systems, our approach does not rely on the formation of an electron donor−acceptor complex between the substrates and enzyme cofactor and simplifies the reaction system by obviating the addition of a cofactor regeneration mixture. More importantly, the GluER variant exhibits high reactivity and enantioselectivity and a broad substrate scope. Mechanistic studies support the proposed oxidation-initiated mechanism and reveal that a tyrosine-mediated HAT process is involved.

Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN

“…It is intriguing that the significant reduction in reaction activity observed when styrenes with bulky substituents are utilized as substrates (( R )- 3k, 3l, and 3n ) may be attributed to the larger size of 4-methylbenzenesulfonohydrazide compared to 4-methylbenzenesulfinate. It should be noted that during this work submission, Ye and co-workers reported a similar hydrosulfonylation reaction using sulfinates as substrates . In comparison to Ye’s work, we demonstrate that using hydrazines as radical donors can expand the reactivity scope of photoenzymatic redox-neutral reactions.…”

From Ground-State to Excited-State Activation Modes: Flavin-Dependent “Ene”-Reductases Catalyzed Non-natural Radical Reactions

“…The principles and activation modes discovered during our studies are only the beginning of what is possible with radical biocatalysts. While the chemistry described relied on reductive radical formation, numerous opportunities exist to identify new chemistry using oxidative mechanisms with flavoproteins. − Our group and others have shown exogenous photocatalysts can aid in unlocking new reactivity with nicotinamide, flavin, − pyridoxal, and thiamin diphosphate-dependent enzymes . Beyond electron transfer, other groups have demonstrated the power of atom transfer mechanisms for radical initiation. − We hope this Account will serve as a resource for others interested in repurposing existing enzymes for radical chemistry.…”

Light-promoted photocatalyst-free and redox-neutral hydrosulfonylation of unactivated alkenes using sulfinic acid

“…Taking advantage of the green and efficient photochemical strategies, significant progress is being achieved in the synthesis of alkyl-substituted sulfones. Sulfonyl chlorides, 9–13 sulfinate salts, 14–17 sulfonamides, 18,19 tetrazole sulfones 20 and a mixture of DABCO·(SO 2 ) 2 and alkyl Hantzsch ester 21 have been employed as sulfonyl radical precursors in the anti-Markovnikov addition reaction to feedstock alkenes (Scheme 2). The Gouverneur group reported the elegant use of commercially available sulfonyl chlorides for photoredox-catalyzed hydrosulfonylation; however, external hydrogen atom donors such as tris(trimethylsilyl)silane are essential.…”