The overall objective of this proposal renewal is to continue our development of an efficient and general strategy for the asymmetric synthesis of oligosaccharides (X = O) and to expand it to the synthesis of analogous oligo-cyclitols (X = CH2, Scheme 1). The method we propose has the potential to revolutionize the way oligosaccharides are synthesized. Our method revolves around the use of a highly stereoselective palladium catalyzed glycosylation (X = O: 2.1?/2.4? to 2.2 ?/2.5?) and cyclitolization (X = CH2;Scheme 1). There has been an astounding amount of research directed toward the synthesis of oligosaccharides; however, when it comes to unnatural oligosaccharides, the current state of the art is lacking. This deficiency is undoubtedly due to the limited number of carbohydrate starting materials (glucose, mannose, and galactose). A complementary approach would be to start with a significantly simplified structure and to sequentially increase its stereochemical and functional complexity to a range of structures (eg., 1.5/1.6 to 1.1-1.3;Scheme 1). The underlying hypothesis that guides our synthetic approach is the belief that there are many carbohydrate analogs, which remain undiscovered because of synthetic limitations. Thus, we believe a methodology that allows for the facile incorporation of simple sugars (i.e. under-functionalized) into oligosaccharide motifs will drastically enable the discovery of new structures with a wide range of functions.

Public Health Relevance

This project from the department of chemistry at West Virginia University proposes to develop a new technology (glycosylation/cyclitolization) for the preparation of natural and unnatural complex carbohydrates. These structures are based on naturally occurring structural motifs with potent biological properties. This approach will allow chemist to preform medicinal chemistry studies that current methodologies do not allow. Ultimately, we plan to uses these new compounds to development new pharmaceutical based therapies for the treatment of cancer, AIDS, tuberculosis and other microbial infections, etc.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM090259-05
Application #
8330298
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (CS))
Program Officer
Marino, Pamela
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$304,811
Indirect Cost
$108,791
Name
Northeastern University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Guo, Haibing; La Clair, James J; Masler, Edward P et al. (2016) De Novo Asymmetric Synthesis and Biological Analysis of the Daumone Pheromones inCaenorhabditis elegansand in the Soybean Cyst NematodeHeterodera glycines. Tetrahedron 72:2280-2286
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Wang, Yanping; O'Doherty, George A (2013) Cryptocaryols A and B: total syntheses, stereochemical revision, structure elucidation, and structure-activity relationship. J Am Chem Soc 135:9334-7
Wang, Hua-Yu Leo; Guo, Haibing; O'Doherty, George A (2013) De novo asymmetric synthesis of oligo-rhamno di- and tri-saccharides related to the anthrax tetrasaccharide. Tetrahedron 69:3432-3436

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