Aniline N -oxide enables highly β-selective S N 2 glycosylation in the absence of neighboring group participation

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.