Saccharides are one of the most prevalent classes of naturally occurring biomolecules, which decorate lipids, proteins, steroids, and many other molecules. Carbohydrates play an essential role in the regulation of numerous biological processes from cellular recognition to metabolism. These biomolecules have served as important lead structures for the development of therapeutics to treat a variety of conditions, such as type-II diabetes and cancer. One reason many carbohydrates have not translated into viable drugs is the poor pharmacokinetic properties of these molecules and the facile hydrolysis of the C?O glycosidic linkage. In order to eliminate any detrimental properties of native O-glycosides, chemists have systematically designed synthetic saccharides through a glycomimetic approach. Glycomimetic molecules contain all the crucial functionality to elicit the desired biological response, while eliminating potential liabilities. A frequently employed glycomimetic strategy for the synthesis of saccharide containing pharmaceuticals involves substituting the C?O glycosidic linkage for a more stable C?C linkage, and thus forming a C-glycoside. Although many synthetic approaches exist to access this biologically relevant C-glycoside motif, significant drawbacks arise from these routes, such as lengthy preactivation sequences, use of toxic reagents, and employing unstable precursors. Due to the relevance of C-glycosides in tackling issues related to human disease, a versatile approach to forge the key C?C bond and access a variety of C-glycosides is still desirable. The objective of the proposed research is to provide new synthetic approaches to synthesize C- glycosides from easily accessible and stable precursors, glycals and 1-deoxy-glycosides. Leveraging copper- redox catalysis, a simultaneous difunctionalization of the C1- and C2-positions of glycals with important pharmacophores will be viable. This catalyst system will be advanced to enable the site-selective C?H arylation at the C1-position of 1-deoxy-glycosides and cyclic ethers. The proposed research is expected to provide novel approaches to long-standing synthetic challenges, and permit entry to molecules with potent biological activities that would otherwise be challenging to synthesize. The Buchwald laboratory at Massachusetts Institute of Technology is the ideal environment to accomplish the proposed research and training goals in preparation for a career in academia. In the Buchwald research group, I will gain necessary training in diverse areas of synthetic chemistry, such as organometallic and physical organic chemistry. Furthermore, MIT will provide numerous opportunities to hone my skills as an educator through the MIT Teaching and Learning Laboratory. These factors have led me to choose MIT as the optimal institution to pursue my ambitious goals, and prepare me for a successful academic career.
C-glycosides are resistant to enzymatic liabilities that plague glycosides containing a C?O linkage, and thus carbohydrates containing this C?C glycosidic linkage play a vital role for the treatment of a variety of ailments, such as type-II diabetes and cancer. Previous approaches to these important molecules have necessitated on numerous synthetic operations, and often employed unstable starting materials. This proposal describes two approaches using copper-redox catalysis to forge the critical C?C linkage present in C-glycosides and an application of this methodology for enantioselective ?-arylation of ethers.
