Stereoretentive Reactions at the Anomeric Carbon

With the support of the Chemical Synthesis Program in the Division of Chemistry, Maciej Walczak of the University of Colorado at Boulder is studying methods to prepare carbohydrates and their derivatives to better understand their biological roles. The research features the development of techniques to produce unique and difficult-to-access chemical structures in a controlled manner and with high yields and it is envisioned that this work will translate into more efficient manufacturing processes for the production of value added materials. The broader impacts of the funded project will extend to the benefits accrued to society as Dr. Walczak and his team of coworkers engage in a range of educational and outreach activities. For example, the students conducting the research will receive training in sophisticated synthetic chemistry techniques preparing them to become the next generation of scientific leaders in the modern workforce. Additionally, the Walczak team will take part in public presentations at educational outreach events, such as CU Wizards, which are designed to attract a demographically diverse range of visitors and to promote the principles of science, technology, engineering, and mathematics (STEM) among a wide and general audience. The chemical synthesis of complex oligosaccharides and their isosteres has provided unprecedented insights into biological processes; however, current methods for the elaboration of carbohydrate derivatives are limited in their degree of efficiency and stereoselectivity. Accordingly, the funded project is directed toward the development and study of new and improved methods for the stereocontrolled synthesis of glycosides with a focus on challenging C-nucleoside and rare hexose systems. The approach of interest involves cross-coupling reactions employing stereodefined anomeric nucleophiles (i.e., C1 metalloid reagents) that have the capacity to install glycosidic bonds with high levels of stereoselectivity, and sometimes proceeding with complete stereospecificity, across a broad range of substrates. Practical methods to prepare the requisite anomeric nucleophiles using readily available reagents will be developed and the resultant synthons engaged in stereoretentive C-C bond forming cross-coupling reactions to generate saccharides that are difficult to access using established methods. The study aims to bridge an important knowledge gap in chemical synthesis by exploring two novel classes of reagents, C1 boronic acids and C1 silanes, which have hitherto received little attention in organic synthesis. Specific targets of interest include biologically active C-glycosides such as dapagliflozin and the antibiotic pseudouridimycin alongside rare, but also biomedically significant, L-hexoses and L-aminosugars. For the latter, a C1-homologation operation will be deployed to enable conversion of naturally abundant D-series carbohydrate residues into their less common L-series congeners. It is expected that the fundamental knowledge gained during the course of the funded project will advance the practice of catalytic methods for selective carbohydrate functionalization and our understanding of stereospecific cross-coupling reactions, in particular. From a broader perspective, the methods developed will facilitate the elaboration of complex carbohydrates and glycomimetic systems and ancillary benefits are therefore anticipated in allied disciplines such as glycobiology and medicinal chemistry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.