Development of Site-Selective Glycosylation of Unprotected Sugars

Yale University, New Haven CT

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Abstract

Project Summary/Abstract Carbohydrates are the most abundant organic molecules in living organisms and regulate many important biological processes. Synthetic carbohydrates are increasingly used as probes for biological research and as lead compounds for drug and vaccine discovery. However, such endeavors are complicated by a lack of efficient and general methods for the routine preparation of these important compounds. Conventional synthetic glycosylation methods to build complex carbohydrates depend on protecting group strategies to achieve selective synthesis. Unprotected sugars posses many hydroxyl groups that can participate in the reaction giving various undesired byproducts. Conversely, glycosylation of readily available sugars would constitute a simple, flexible, and powerful means to access these frameworks. The proposed research aims to develop a site-selective glycosylation of unprotected sugars for complex carbohydrate synthesis. It is envisioned that the ability of natural carbohydrate receptors could be mimicked in the form of ligands. The non-covalent coordination of the ligands to the glycosyl donors, glycosyl acceptors, and the catalyst would be crucial to achieve the site-selective glycosylation. This powerful new strategy will rely on the selective ability of the ligands to recognize and bind to specific sugar scaffolds. Ligand design that mimics the ability of carbohydrate receptors and reaction optimization will prove critical to this key transformation in order to avoid various undesired reaction pathways. Finally, the proposal aims to achieve derivatization of complex bioactive molecules via site-selective glycosylation. Specifically, glycosylation of glycopeptide antibiotics have experienced beneficial effects with respect to pharmacokinetic properties and biological activities.