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.

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

“…Based on literature precedents and a previous radical trapping experiment, 29 we propose that the reaction follows the photoredox-nickel dual catalytic cycles shown in Scheme 3 . The key step involves the subsequent fragmentation of the DHP ester to afford the glycosyl radical upon release of Hantzsch pyridine and CO 2 .…”

“…Inspired by the success of alkyl dihydropyridine (DHP) as a radical precursor 28 and its utility in C5- and C6-functionalization of glycosides, 26 a , b we developed DHP-based redox auxiliary 1 by incorporating a carbonyl group between DHP and the glycoside, which can induce the homolysis of the strong anomeric C–O bond through CO 2 evolution. 29 The favorable condensation between 1 and furanoses and pyranoses readily furnishes glycosyl esters that are bench stable and compatible with all common native carbohydrates.…”

Stereoselective Preparation of C‐Aryl Glycosides via Visible‐Light‐Induced Nickel‐Catalyzed Reductive Cross‐Coupling of Glycosyl Chlorides and Aryl Bromides

“…Molander explored 1, 4‐dihydropyridines as glycosyl‐based radical precursors to realize the synthesis of reversed C ‐acyl glycosides through Ni/photoredox dual catalysis [10] . More recently, the Diao group reported decarboxylative coupling between glycosyl esters and aryl bromides [11] …”

Diastereoselective Decarboxylative Alkynylation of Anomeric Carboxylic Acids Using Cu/Photoredox Dual Catalysis

“…25 This approach was applied recently to carbohydrate substrates bearing the dihydropyridine (DHP) as an activating anomeric group to prepare C-aryl glycosides, including nucleosides and 2-deoxysugars. 26 Very recently, 2-deoxyglycosyl boronic acid derivatives were used as radical sources to synthesize a series α-C-glycosides mediated by a photoredox/nickel dual catalytic system. 27 Finally, Wang, Zhang and co-workers 28 demonstrated for the first time, that ribosyl acids are valuable partners in the photoredox/nickel dual-catalyzed cross-coupling with heteroaryl and vinyl bromides, furnishing various β-selective heteroaryl-C-nucleosides in good yields.…”