Diversity-oriented synthesis of glycomimetics

Michael Meanwell,Weiwu Ren,Milan Bergeron-Brlek,Robert Britton,Christopher Adamson,Hayden Foy,Gaelen Fehr,Johannes Lehmann,Bharanishashank Adluri,Victoria Rose,Venugopal Rao Challa,Rozhin Rowshanpour,Travis Dudding,Louis-Charles Campeau,Steven M Silverman

doi:10.1038/s42004-021-00520-3

Abstract

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

Highlights

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments
The rational design of glycomimetic drugs often initiates with a structural analysis of the natural carbohydrate substrate bound to the protein target of interest, followed by iterative synthesis campaigns focused on stabilizing the bioactive conformation and Oseltamivir (1): neuraminidase inhibitor for influenza
We reported a complimentary proline-catalyzed α-fluorination/aldol reaction that supports the rapid synthesis of nucleoside analogs (e.g., 18)[28]

Summary

Introduction

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Loh reported a strategy for the diversification of carbohydrates using hydrogen- and halogen-bond-catalyzed strain release glycosylation to produce complex O,N-glycoside analogs 11 (Fig. 1)[19] This platform enabled the discovery of potential leads for treating acquired cancer resistance. While these limited examples highlight a clear role for DOS in the generation of glycomimetics, they underscore the need for new synthetic strategies that enable rapid sampling of more diverse regions of carbohydrateassociated chemical space[20]

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Conclusion