Stereoselective Glycosylation of Amides with Glycal Catalyzed by a Solid-Liquid Phase-Transfer and Proton-Transfer Dual-Functional Pyridinium Catalyst.

Abstract

2-Deoxyglycosylamides have great potential for biochemical applications, but their streamlined synthesis remains underexplored. Herein, 2-pentafluorophenylpyridinium tetrafluoroborate was designed for highly stereoselective glycosylation of amides with glycals. Besides the challenging substrates like glucals, the method also works well with previously unexplored 6-deoxy-sugars, including rhamnals, xylals, and arabinals, and is additionally suitable for glycosylation of complex bioactive peptides. Experiments have revealed this new catalyst's unique phase-transfer and proton-transfer dual functionality by identifying reaction intermediates and products, as well as determining reaction kinetics and KIEs. The experimental evidence combined with DFT calculations led to the conclusion that glycals accept a proton from the catalyst to form oxocarbenium intermediates that are then nucleophilically attacked by amides from an equatorial direction, thereby explaining the high stereoselectivity that this method exhibits.

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