Directed SN2 Glycosylation Employing an Amide-Functionalized 1-Naphthoate Platform Featuring a Selectivity-Safeguarding Mechanism

This work implements a catalyticS(N)2 glycosylationbyemploying an amide-functionalized 1-naphthoate platform as a latentglycosyl leaving group. Upon gold-catalyzed activation, the amidegroup enables the S(N)2 process by directing the attack ofthe glycosyl acceptor via H-bonding interaction, which results instereoinversion at the anomeric center. Unique in this approach isthat the amide group also enables a novel safeguarding mechanism bytrapping oxocarbenium intermediates and, hence, minimizing stereorandomS(N)1 processes. The strategy is applicable to the synthesisof a broad range of glycosides with high to excellent levels of stereoinversionfrom anomerically pure/enriched glycosyl donors. These reactions aregenerally high-yielding, and their applications in the synthesis ofchallenging 1,2-cis-linkage-rich oligosaccharidesare demonstrated.

Automated summary

This work introduces a novel catalytic S(N)2 glycosylation method using an amide-functionalized 1-naphthoate platform as a latent glycosyl leaving group. The amide group facilitates the S(N)2 process by directing the attack of the glycosyl acceptor via H-bonding interaction, resulting in stereoinversion at the anomeric center. Additionally, the amide group enables a safeguarding mechanism by trapping oxocarbenium intermediates, minimizing stereorandom S(N)1 processes. This strategy allows for high-yielding synthesis of a wide range of glycosides with stereoinversion, including challenging 1,2-cis-linkage-rich oligosaccharides.