Lewis Acid-Promoted Site-Selective Transformation of Glycals for the Synthesis of 1,3-Annulated-2-deoxy Glycosides

Abstract

Deoxyglycosides represent an important class of bioactive molecules with broad medicinal significance. In this study, 1,3-annulated-2-deoxyglycosides were synthesized from glycals via a Lewis acid-mediated domino sequence. Unlike the classical Ferrier glycosylation, this work highlights the role of glycals in annulation reactions. Protected glycals such as acetylated d-galactal, d-arabinal, and l-fucal underwent highly regioselective glycosylation with external nucleophiles, affording 1,3-annulated-2-deoxyglycosides as the sole products. In contrast, glycals such as d-glucal, l-rhamnal, and d-xylal either failed to deliver the desired products under the same conditions or furnished them in lower yields. The substrate scope for 1,3-annulated-2-deoxyglycosides includes diverse protected glycals and acceptors, including 1-naphthols, 2-naphthols, phenols, and thionaphthalenes. Mechanistic investigations, supported by DFT calculations, revealed that the ortho positions of aromatic phenols preferentially attack the thermodynamically favorable C-3 position of the oxocarbenium ion rather than the anomeric center. These computational insights align with experimental observations, as a key reaction intermediate was isolated and characterized.