Exploiting π and Chalcogen Interactions for the β‐Selective Glycosylation of Indoles through Glycal Conformational Distortion

• Published in: Angewandte Chemie International Edition 2024-02, Vol.63 (7), p.e202316667-n/a
• Main Authors: Guo, Hao, Kirchhoff, Jan‐Lukas, Strohmann, Carsten, Grabe, Bastian, Loh, Charles C. J.
• Format: Article
• Language: English
• Subjects: Catalysis; Catalysts; Chalcogen Bonding; Conformation; Distortion; Glycosides; Glycosylation; Indoles; Magnetic resonance spectroscopy; NMR spectroscopy; Noncovalent Interactions; Organocatalysis; Reaction Mechanisms; Stereoselectivity
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202316667

Harnessing unconventional noncovalent interactions (NCIs) is emerging as a formidable synthetic approach in difficult‐to‐access glycosidic chemical space. C‐Glycosylation, in particular, has gained a flurry of recent attention. However, most reported methods are restricted to the relatively facile access to α‐C‐glycosides. Herein, we disclose a β‐stereoselective glycosylation of indoles by employing a phosphonoselenide catalyst. The robustness of this protocol is exemplified by its amenability for reaction at both the indolyl C‐ and N‐ reactivity sites. In contrast to previous reports, in which the chalcogens were solely involved in Lewis acidic activation, our mechanistic investigation unraveled that the often neglected flanking aromatic substituents of phosphonoselenides can substantially contribute to catalysis by engaging in π‐interactions. Computations and NMR spectroscopy indicated that the chalcogenic and aromatic components of the catalyst can be collectively exploited to foster conformational distortion of the glycal away from the usual half‐chair to the boat conformation, which liberates the convex β‐face for nucleophilic attack. Harnessing productive chalcogen bonding and π‐interactions, a phosphonoselenide catalyst was used for stereoselective C,N‐glycosylation. This unique activation manifold distorts the glycal conformation and enables both the C3 and N1 positions of indole to be appended directly to the anomeric position of glycals, thus providing access to an array of biologically important β‐indolyl glycosides.