Stereodivergent Synthesis of C-Glycosides from Glycals by Ni-Catalyzed Cross-Hydrocarbonylation of Alkenes.

Abstract

C-Glycosides always significantly improve the physicochemical properties and pharmacokinetic characteristics of the native O- and N-glycosides and are one of the most powerful strategies for carbohydrate-based drug discovery. However, direct access to C-glycosides with control of stereochemistry from readily available, bench-stable, and cost-effective starting materials remains a formidable challenge. Herein, a Ni-catalyzed chemo- and regioselective iterative hydrocarbonylation of glycals with alkenes for the synthesis of stereodivergent C-acylated glycosides has been developed, representing the first example of synthesizing C-acylated glycosides from glycals. The reaction tolerates a wide range of glycals and unactivated alkenes, affording corresponding C-glycosides with diverse substitution patterns. Moreover, cross-carbonylation of primary-secondary and more sterically hindered secondary-secondary alkyl metallic intermediates was achieved, providing access to 2-deoxygenated C-glycosides from glycals without using any glycosyl electrophiles or alkyl electrophiles. Notably, both α- and β-anomers could be easily obtained with high diastereoselectivity, rendering this protocol useful for the synthesis of C-glycosides using alkenes as the sole coupling precursors.