In this project, funded by the Chemical Synthesis Program of the Chemistry Division, Professor David R. Mootoo, of the Department of Chemistry at Hunter College of The City University of New York, will develop a broad-based synthesis of glycomimetics. The methodology centers on the reaction of sugar-substituted crotyl-stannanes and boronates with chiral aldehydes. A key aspect of this study will be the examination of how substrate effects, the choice of Lewis acid catalyst, and the reaction conditions can be tuned to control stereoselectivity. A major focus will be on the synthesis of two classes of glycomimetics that have attracted much attention in glycobiology research, C- and carba-,glycoside analogues of O-glycosides in which the glycoside or ring oxygen, respectively, is replaced with a carbon substituent. The proposed crotylation method promises robust syntheses of these materials and may also be appropriate for unusual O-glycosides for which conventional O-glycoside synthesis is problematic. Specific synthetic goals are analogues of inositol hexosamines that activate protein phosphatases (PPs) and the immunostimulatory glycolipid alpha-galactosylceramide, and which provide a platform for the development of the scope of the crotylation methodology. Additional studies will include investigation of the conformational and PP activating behavior of the hexosamine inositol mimetics and determination of the cytokine profiles elicited by the glycolipid analogues.
Successful development of the proposed research will advance the use of carbohydrate reagents and auxiliaries in asymmetric synthesis, particularly in regard to applications in glycobiology, and provide insight on how carbohydrate ligands interact with and control the function of proteins, an important component of bioregulatory behavior. The interdisciplinary underpinnings of this research provide a framework for innovative strategies in the training of science students, from pre-undergraduate to graduate, including groups that are historically underrepresented in the sciences.