Catalytic and Photochemical Strategies to Stabilized Radicals Based on Anomeric Nucleophiles

Abstract

Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp³)-S cross-coupling reactions. Mechanistic studies and DFT calculations revealed that the C-S bond-forming step occurs via the transfer of the anomeric radical directly to a sulfur electrophile bound to Cu(II) species. This pathway complements a radical chain observed for photochemical metal-free conditions where a disulfide initiator can be activated by a Lewis base additive. Both strategies utilize anomeric nucleophiles as efficient radical donors and achieve a switch from an ionic to a radical pathway. Taken together, the stability of glycosyl nucleophiles, a broad substrate scope, and high anomeric selectivities observed for the thermal and photochemical protocols make this novel C-S cross coupling a practical tool for late-stage glycodiversification of bioactive natural products and drug candidates.

Scheme 1

Scheme 2.. Reaction Development with C1–Stannanes

^aReaction conditions: 17d (1.5 equiv), 22 (0.100 mmol, 1.0 equiv), CuCl (20 mol %), ligand (25 mol %), and 1,4-dioxane (2.0 mL) under N₂, 130 °C, 24 h. Unless otherwise specified, only the α anomer was detected. Anomeric selectivities determined by ¹H NMR analysis of unpurified reaction mixtures. ^bMulliken charge on C5/C5′ calculated at the B3LYP/6-31G(d) level of theory. ^cNinety-six hour reaction time. Entry 9: 5 W blue LED lamp was used.

Scheme 3.. Scope of Cu(I)-Catalyzed Thio(seleno)glycosylation^c

^aCuCl (20 mol %), 26 (1.5 equiv), L1 (25 mol %), KF (3 equiv), 1,4-dioxane (2 mL), 130 °C, 96 h. ^bCuCl (20 mol %), 26 (1.5 equiv), L1 (25 mol %), KF (3 equiv), m-xylene:1,4-dioxane (1:1, 2.00 mL), 130 °C, 96 h. ^cGeneral reaction conditions: diaryl disulfides or diaryl diselenides (0.100 mmol, 1 equiv), CuCl (20–40 mol %), 26 (1.5 equiv), L11 (25–45 mol %), KF (3 equiv), blue LED (5 W), 1,4-dioxane (2 mL), 120 °C, 96 h; isolated yields. Anomeric selectivities determined by ¹H NMR analysis of unpurified reaction mixtures.

Scheme 4.

(A) Proposed Mechanism of Cu(I)-Catalyzed Thioetherification; (B) Deuterium Kinetic Isotope Effect Studies of Stereoretentive C(sp³)–S Cross Coupling; (C) Deuterium Kinetic Isotope Effect Studies for Stereoconvergent C(sp³)–S Cross Coupling; (D) ¹³C Kinetic Isotope Effect Studies of Stereoconvergent C(sp³)–S Cross Coupling

Scheme 5.. DFT-Computed Gibbs Free Energy Diagrams of Proposed Reaction Pathways for Generation of α- and β-Glycosides

^aTrivial hydrogens are omitted for clarity for optimized structures of key transition states.

Scheme 6.. Photochemical Thioglycosylation with Anomeric Stannanes^d

^aα:β 10:1. ^bα-Stannanes were used. ^c18 (0.150 mmol, 1 equiv), 49 (1.5 equiv), L11 (45 mol %), KF (3 equiv), blue LED (5 W), 1,4-dioxane (3 mL), 120 °C, 48 h, then 2,3,4-tri-O-benzyl-α-d-glucopyranoside 50 (0.100 mmol), NIS (2.0 equiv), AgOTf (10 mol %), CH₂Cl₂ (5 mL), 23 °C, 10 h. ^dGeneral reaction conditions: disulfide (0.100 mmol, 1 equiv), anomeric stannanes (1.5 equiv), L11 (45 mol %), KF (3 equiv), blue LED (5 W), 1,4-dioxane (2 mL), 120 °C, 48 h. Unless otherwise specified, only the α anomer was detected. Anomeric selectivities determined by ¹H NMR analysis of unpurified reaction mixtures.