Hypervalent Chalcogenonium Organocatalysis for the Direct Stereoselective Synthesis of Deoxyglycosides from Hemiacetals

Abstract

Lewis acids are frequently used as catalysts in glycosylation reactions, however these reagents often suffer from significant limitations such as sensitivity to moisture and poor stereocontrol. Chalcogenonium catalysts have recently emerged as a new class of catalysts with improved Lewis acidity and stability. Here we describe a proof of concept study of the use of 1,2-oxaselenonium salts as effective organocatalysts for the direct and stereoselective dehydrative glycosylation with 1-hydroxy carbohydrates to give deoxyglycosides. The reaction is high yielding, stereoselective and amenable to a wide range of nucleophiles, including primary, secondary and tertiary alcohols and thiols. Experimental and computational mechanistic investigations suggest that the reaction proceeds through a cooperative mechanism involving the hemiacetal donor, acceptor, and catalyst. In this process, the Lewis acidic selenonium catalyst activates the donor, while the incoming alcohol nucleophile engages in a stabilizing hydrogen-bond interaction with the chalcogenonium triflate counterion. DFT calculations suggest a loose S_N2-like transition state with a high degree of oxocarbenium ion character, reminiscent of the mechanism observed for glycosyl-modifying enzymes. The methodology is exemplified on the stereoselective synthesis of a tetrasaccharide in 52% yield.