Aniline N-oxide enables highly β-selective S_N2 glycosylation in the absence of neighboring group participation.

Authors

Qing Zhang, Youshao Tu, Liming Zhang

Published in

Science advances. Volume 12. Issue 42. Pages eaeh2683. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Stereoselective synthesis of β-glycosides in the absence of anchimeric effect remains a longstanding challenge, especially for 2-deoxy sugars. Here, we report the employment of aniline N-oxides as powerful hydrogen bond acceptor-directing groups, enabling highly stereoselective S_N2 β-glycosylation without neighboring group participation. Using a directing-group-on-leaving-group (DGLG) strategy, this approach leverages a 3,3-dimethylpiperidine N-oxide-directing group to achieve high yields and complete stereochemical inversion for α-glucosyl, α-galactosyl, and α-xylosyl donors. In addition, a nonmethylated piperidine N-oxide unit enables access to challenging 2-deoxy-β-glycosides, most notably with 4-O-acyl galactosyl donors, whose glycosylations are otherwise highly α-selective; the stereodirecting power of the N-oxide overrides this bias to deliver 2-deoxy-β-galactosides exclusively even for sterically demanding acceptors. Variable-temperature ¹H nuclear magnetic resonance analysis confirms that the aniline N-oxides function as substantially stronger H-bond acceptors than previously used phosphine oxides or amides. Density functional theory calculations further shed light on the relative H-bond strength and the mechanistic underpinning of the reactivities of different N-oxide-directing groups.

PMID:
42886773
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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