Diversity-oriented synthesis of glycomimetics

• DOI: 10.1038/s42004-021-00520-3
• Publication Date: 2021-06-24T10:02:56Z
• Authors: Michael Meanwell; Gaelen Fehr; Weiwu Ren; Bharanishashank A...; Victoria Rose; Johannes Lehmann; Steven M. Silverman; Rozhin Rowshanpour; Christopher Adamson; Milan Bergeron-Brlek; Hayden Foy; Venugopal Rao Challa; Louis-Charles Cam...; Travis Dudding; Robert Britton
• Keywords: Aldol reaction; Kinetic resolution

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio azodicarboxylate functional groups. Using density theory calculations, demonstrate both steric electrostatic interactions play key diastereodiscriminating roles dynamic kinetic resolution. The utility this simple process for generating large diverse libraries demonstrated rapid production iminosugars, nucleoside analogues, carbasugars from common intermediates.