This project has as its aim the development of robust, practical, and general methods for glycosylating nucleophiles with predictable stereoselectivity. Our laboratory has helped pioneer the use of small-molecule chiral H-bond donors as catalysts for enantioselective reactions. As an extension of these studies, we have uncovered a new principle for effecting selective glycosylation reactions. Precisely designed macrocyclic bis-thiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl chlorides. Because glycosyl chlorides are quite stable and exist predominantly and often exclusively in the a-configuration, this mode of catalysis represents a widely applicable solution to the creation of -glycosidic linkages. We will seek to explore the scope and limitations of the macrocylic catalysts devised thus far in the context of model disaccharide couplings and the synthesis representative biologically important oligosaccharides. The rate of glycosylation is correlated to the Lewis basicity of the carbonyl group on the catalyst, and our current mechanistic hypothesis invokes a functional role for this moiety as a general base to activate the acceptor nucleophile in a manner that mimics invertive glycosyltransferases. We will carry out a systematic mechanistic study of the catalytic reaction in order to ascertain whether a biomimetic general-base mechanism is indeed operative, and to identify the optimal nature and position of the Lewis base component for maximum reactivity and scope. We will also explore whether this cooperative activation mechanism might be extended to the design of catalysts that promote a-selective glycosylations via doubly invertive substitutions. If developed fully and successfully, this methodology would enable the synthesis of complex oligosaccharides in a programmable manner that could be applied by non-specialists, and also allow the production of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates on a practical scale.

Public Health Relevance

We seek a generally applicable and practical strategy for achieving highly stereocontrolled synthesis of biologically relevant oligosaccharides. Our successful development of catalysts for a- and -selective glycosylations of stable activated sugars enable the synthesis and production of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1)
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Marino, Pamela
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Harvard University
Schools of Arts and Sciences
United States
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Park, Yongho; Harper, Kaid C; Kuhl, Nadine et al. (2017) Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. Science 355:162-166
Kwan, Eugene E; Park, Yongho; Besser, Harrison A et al. (2017) Sensitive and Accurate 13C Kinetic Isotope Effect Measurements Enabled by Polarization Transfer. J Am Chem Soc 139:43-46