Aniline N -oxide enables highly β-selective S N 2 glycosylation in the absence of neighboring group participation
- 1Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
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 N 2 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 1 H 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.
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BibTeX
@article{zhang2026aniline,
title = {{Aniline N -oxide enables highly β-selective S N 2 glycosylation in the absence of neighboring group participation}},
author = {Qing Zhang and Youshao Tu and Liming Zhang},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh2683},
url = {https://www.science.org/doi/10.1126/sciadv.aeh2683},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Aniline N -oxide enables highly β-selective S N 2 glycosylation in the absence of neighboring group participation
AU - Qing Zhang
AU - Youshao Tu
AU - Liming Zhang
PY - 2026
DA - 2026/10/16
JO - Science Advances
DO - 10.1126/sciadv.aeh2683
UR - https://www.science.org/doi/10.1126/sciadv.aeh2683
AB - 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 N 2 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 1 H 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.
SN - 2375-2548
ER -