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.

Synthesis of C-acyl furanosides via the cross-coupling of glycosyl esters with carboxylic acids

“…The dearth of furanosylation methods may be associated with the lack of furanosyl radical precursors that can be used for cross-coupling. Pyranosyl radicals have been generated from various unnatural glycosyl derivatives, including bromides, 18 xanthates, 19 glycals, 20 stannanes, 21 thiol ethers, 22 acyl tellurides, 23 and trifluoroborates. 24 Precursors to furanosyl radicals, however, are limited to unnatural tetrahydrofuran derivatives with a carboxylic acid at the C1 position, restricting the scope of carbohydrate substrates.…”

Light-Mediated Cross-Coupling of Anomeric Trifluoroborates

“…Anomeric selectivities for reactions shown in Scheme 5 can be rationalized by the kinetic anomeric effects of the putative radical 37. 30 In summary, we introduced here a new class of C1-trifluoroborates that are competent reagents for the formation of C-C and C-chalcogen bonds in 2-deoxy and fully substituted saccharides under the photoredox conditions. Although the overall transformation proceeds via singleelectron transfer mechanism, the observed selectivities result in the net stereoretention and complement other C-C cross-coupling technologies with anomeric nucleophiles.…”

Diastereoselective Synthesis of Aryl C‐Glycosides from Glycosyl Esters via C−O Bond Homolysis

“…These methods, however, have not been applied to glycosylation, possibly due to the instability of the corresponding glycosyl esters. [26] Dihydropyridine (DHP) has emerged as a versatile activating group to produce carbon radicals and carbamoyl radicals, from aldehydes and amines, respectively, via C À C bond homolysis (Schemes 2 B and C). [27] The former has been applied to synthesize unconventional glycosides via CÀC bond cleavage at the C4 or C5 position (Scheme 2 B).…”

“…All reactions favor formation of the a-anomer, since the concave b-face is sterically protected by C2, C3, and C4 substituents. The limitation with some electron-rich arenes (26) and heterocycles, such as furan and pyrrole (28 and 29), could be attributed to the incompatibility of these easily oxidizable substrates with the excited photocatalyst.…”