Catalytic Stereoselective 1,2-cis-Furanosylations Enabled by Enynal-Derived Copper Carbenes

Abstract

1,2-cis-Furanosides are present in various biomedically relevant glycosides, and their stereoselective synthesis remains a significant challenge. In this vein, we have developed a stereoselective approach to 1,2-cis-furanosylations using earth-abundant copper catalysis. This protocol proceeds under mild conditions at room temperature and employs readily accessible benchtop stable enynalderived furanose donors. This chemistry accommodates a variety of alcohols, including primary, secondary, and tertiary, as well as mannosyl alcohol acceptors, which have been incompatible with most known methods of furanosylation. The resulting 1,2-cisfuranoside products exhibit high yields and anomeric selectivity with both the ribose and arabinose series. Furthermore, the anomeric selectivity is independent of the C2 oxygen-protecting group and the anomeric configuration of the starting donor. Experimental evidence and computational studies support our hypothesis that copper chelation between the C2 oxygen of the furanose donor and an incoming alcohol nucleophile is responsible for the observed 1,2-cisstereoselectivity.

Catalytic Orthogonal Glycosylation Enabled by Enynal‐Derived Copper Carbenes

“…Furthermore, the same byproduct has been isolated in our corresponding copper catalyzed 1,2-cis-furanosylation studies. [34] Based on the above-described results, and literature precedence, [29d,35] we hypothesized a plausible mechanism to explain the 1,2-cis-selectivity with 4,6benzylidene donor (Scheme 5). First, the enynal moiety in the presence of copper(I) triflate forms the copper carbene intermediate 8 via a 5-exo-digcyclization.…”