Stereoselective glycosylation via H-bond-mediated aglycone delivery

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The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Alexei Demchenko. Professor Demchenko is a faculty member in the Department of Chemistry and Biochemistry at the University of Missouri - St. Louis. Professor Demchenko's research group is developing new methods for accomplishing reactions that hook two sugar molecules together. These reactions, called glycosylations, are essentially for assembling the types of carbohydrate structures that are prevalent in a wide range of biological processes and applications of the glycolsylation reactions being developed range from therapeutic to diagnostic strategies. Key to the effort is work both better understand and further develop a unique reaction pathway that was discovered by the Demchenko group during the previous funding period. This discovery is enabling the construction on the bond connecting the two sugars in a highly selective manner. The project lies at the interface of organic, carbohydrate, and mechanistic chemistry, and it is well suited for the education of scientists at all levels. This study is investigating both mechanistic and practical aspects of the H-bond-mediated Aglycone Delivery (HAD) reaction pathway discovered by the PI's group. The goal of the work is to completely control the stereoselectivity of the glycosylation. With this in mind, two phenomena are being investigated. In the first, two previously developed methods, bromine-promoted glycosylation and HAD reaction are being combined in a manner that affords higher stereoselectivity for both alpha- and beta-glycosylation. In the second, conformational switches are being developed as handles for enhancing the utility of the HAD reaction. These endeavors are strategically advancing the field of glycosciences by offering new synthetic capabilities for obtaining challenging glycans and glycoconjugates with better stereocontrol and higher yields. The developed methods are serving to improve the synthesis of key targets from mammalian glycomes and microbial glycans with potential application as therapeutic agents or diagnostic platforms. Successful completion of the proposed research is not only advancing the field of glycosylation, but is also making contributions to the larger chemical, biological, and medical sciences. Integral to the success of this program is the active participation of undergraduate and graduate students who receive solid training in research methods and work to solve synthetic important synthetic challenges. The vigorous training and strong publication and presentation records that students are gaining in the PI's laboratory is preparing them for leading positions in academia and industry.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.