Cooperative Bifurcated Chalcogen Bonding and Hydrogen Bonding as Stereocontrolling Elements for Selective Strain-Release Septanosylation

The exploitation of noncovalent interactions (NCIs) is emerging as a vital handle in tackling broad stereoselectivity challenges in synthesis. In particular, there has been significant recent interest in the harnessing of unconventional NCIs to surmount difficult selectivity challenges in glycosylations. Herein, we disclose the exploitation of an unconventional bifurcated chalcogen bonding and hydrogen bonding (HB) network, which paves the way for a robust catalytic strategy into biologically useful seven-membered ring sugars. Through 13C nuclear magnetic resonance (NMR) in situ monitoring, NMR titration experiments, and density functional theory (DFT) modeling, we propose a remarkable contemporaneous activation of multiple functional groups consisting of a bifurcated chalcogen bonding mechanism working hand-in-hand with HB activation. Significantly, the ester moiety installed on the glycosyl donor is critical in the establishment of the postulated ternary complex for stereocontrol. Through the C-13 kinetic isotopic effect and kinetic studies, our data corroborated that a dissociative S(N)i-type mechanism forms the stereocontrolling basis for the excellent alpha-selectivity.

Automated summary

The utilization of noncovalent interactions (NCIs) in synthesis to overcome broad stereoselectivity challenges is gaining importance, with particular interest in unconventional bifurcated chalcogen bonding and hydrogen bonding networks for glycosylation reactions. By combining experimental and theoretical approaches, this study demonstrates the simultaneous activation of bifurcated chalcogen bonding and hydrogen bonding, providing a robust catalytic strategy for the synthesis of biologically active seven-membered ring sugars.