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

Abstract

C‐aryl glycosyl compounds offer better in vivo stability relative to O‐ and N‐glycoside analogues. C‐aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C‐aryl glycosides were derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional‐group compatibility, and practicality. Challenges remain in the synthesis of C‐aryl nucleosides and 2‐deoxysugars from easily accessible carbohydrate precursors. Herein, we report a cross‐coupling method to prepare C‐aryl and heteroaryl glycosides, including nucleosides and 2‐deoxysugars, from glycosyl esters and bromoarenes. Activation of the carbohydrate substrates leverages dihydropyridine (DHP) as an activating group followed by decarboxylation to generate a glycosyl radical via C−O bond homolysis. This strategy represents a new means to activate alcohols as a cross‐coupling partner. The convenient preparation of glycosyl esters and their stability exemplifies the potential of this method in medicinal chemistry.

StereoselectiveC‐Aryl Glycosylation by Catalytic Cross‐Coupling of Heteroaryl Glycosyl Sulfones

“…In contrast to a number of Ni‐catalyzed protocols [21, 43] that suffer from limitations in the scope of pyranoses accessible, our system involving 2‐benzothiazolyl sulfones is broadly applicable to both pyranoses ( 35 – 40 ) and furanoses ( 27 – 34 , 41 , 42 ). Across the board, high diastereoselectivity could be reliably achieved.…”

“…Particularly desirable is a set of broadly applicable protocols that harness the power of nonprecious base metal catalysis [3, 18, 19] to transform a readily available glycosyl precursor (donor), the saccharide component which bears a reactive functional group at the C1 position, into the C ‐aryl glycoside product by controlling the stereochemical outcome of C‐aryl bond formation [18] . In this regard, processes that convert glycosyl donors into glycosyl radical intermediates [16, 17, 20–23] en route to C ‐aryl glycosides are highly attractive (Scheme 1b), given that such glycosyl radical cross‐coupling reactions are less susceptible to undesired epimerization and elimination side reactions [16] . In contrast to stereospecific transformations, [24–26] the stereochemical purity of the donor is inconsequential, since both α and β isomers eventually converge to a single diastereomeric product, which means that anomeric mixtures of the substrate can be employed without rigorous purification.…”

Advances on the Synthesis of C-Aryl-glycosides Since 2019

“…28 Diao has developed a method involving the activation of hydroxy groups at non-anomeric positions of sugars through DHP esters to generate acyl radicals, followed by decarboxylation to produce sugar radicals, which combined with Ni catalysis, selectively generates a series of aryl carbon glycosides. 29…”

Boryl Radical-Promoted Deoxygenative Alkylation of Benzyl Acetates

“…8a 10 Recently, MacMillan reported a powerful strategy for C–O bond homolysis by using in situ formed N -heterocyclic carbene (NHC) adducts of alcohols. 11 Besides these alcohol derivatives, benzoates, 12 dihydropyridine (DHP) derived esters, 13 carbazates, 14 N -hydroxyphthalimides (NHPI), 15 and phosphites, 16 have been successfully used as carbon radical precursors (Scheme 1a ). Despite these advances, the application of readily accessible and more atom-economical acetates as the alcohol activation group remains less explored, mainly due to the poor leaving ability of the acetate group.…”