This project is directed toward the development of robust, practical, and general methods for glycosylating nucleophiles with predictable stereoselectivity and regioselectivity. Despite extraordinary efforts and advances over the past century, glycan synthesis remains a highly challenging endeavor largely reserved for specialists. Given the unquestioned importance of carbohydrates in virtually all facets of biological chemistry, methods that can be applied predictably and broadly for effecting glycosylations of molecules of interest are needed. Our laboratory has helped pioneer the use of small-molecule chiral H-bond donors as catalysts for enantioselective reactions. In an outgrowth of these studies, we have uncovered a new principle for effecting both stereoselective and site-selective glycosylation reactions. Precisely tailored bisthiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl chlorides and glycosyl phosphates via cooperative activation of both the nucleophile and the electrophile. Because the donors are quite stable and exist predominantly and often exclusively in the ?-configuration, and the catalysts are compatible with a wide range of functionalities, this mode of catalysis represents a widely applicable approach to the creation of ?- glycosidic linkages. We will seek to develop the scope and limitations of the catalytic principle in the context of model disaccharide couplings and the synthesis of glycosides of biologically important compounds. While broadly general protocols are sought, we will focus our efforts on especially challenging cis-1,2-glycosidic linkages in pyranosides and furanosides. We will also explore the ways by which the cooperative activation mechanism can be applied to site-selective activation and glycosylation of unprotected sugars and other polyfunctional nucelophiles. If developed fully and successfully, this methodology would greatly enable the synthesis of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates by non-specialists.

Public Health Relevance

We seek generally applicable and practical methods for achieving highly stereocontrolled synthesis of biologically relevant oligosaccharides. Our successful development of catalysts for ?-selective glycosylations of a wide variety of nucleophiles will enable the synthesis and production of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM132571-03
Application #
10106641
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Bond, Michelle Rueffer
Project Start
2019-04-01
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138