Carbohydrates play an important role in many fundamental biological processes, as well as in the diagnosis and treatment of human disease. Efficient chemical methods for accessing oligosaccharides and glycoconjugates are crucial for continued progress in the field of glycobiology. Unlike amino acids and nucleotides, which form linear polymers, monosaccharides polymerize into a variety of different stereo- and regioisomeric structures. Control over the stereo- and regioselectivity of chemical glycosidation reactions is, therefore, paramount. However, the selective functionalization of one hydroxyl group in the presence of numerous others poses a significant chemical challenge, and most oligosaccharide syntheses must rely upon elaborate and lengthy protecting group strategies to promote reaction at only the desired site. The research described in this proposal focuses on the development of small-molecule catalysts capable of controlling both the stereochemistry and the regiochemistry of glycosidation reactions. The research approach involves the rational design of hydrogen-bond donor catalysts guided, in part, by protein-carbohydrate interactions found in nature. State-of-the-art synthetic, mechanistic and theoretical tools will facilitate the systematic evaluation and optimization of these catalysts towards the goal of controlling the relative reactivity of different carbohydrate hydroxyl groups. The successful development of this proposed research is anticipated to transform oligosaccharide synthesis, dramatically reducing the time and resources necessary to chemically synthesize complex carbohydrates. Further, fundamental mechanistic findings revealed en route to this goal are anticipated to contribute significantly to our understanding of carbohydrate molecular recognition and to lay the groundwork for catalytic approaches to more diverse site-selective functionalization reactions.

Public Health Relevance

Carbohydrates play an important role in biological systems, and are widely considered to be promising therapeutic targets for the treatment of cancer, viral infection, and inflammation. Advances in this area are hampered, however, by impractical and inefficient methods for the synthesis of complex carbohydrates. The research described in this proposal seeks to develop improved chemical methods for selective carbohydrate synthesis and, therefore, to these important biological and therapeutic tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM117787-03
Application #
9431228
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2016-03-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
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