Development of SN2-type Glycosylation for Automated Glycan Synthesis

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With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Liming Zhang of the University of California at Santa Barbara is studying a method that selectively links together different sugar molecules under conditions suitable for the automated synthesis of glycans. Glycans and their conjugated forms (e.g., glycoproteins, glycopeptides, and glycolipids etc.) are complex molecules containing many interlinked sugar units that are implicated in a variety of biological processes and pathological events, including: signal transduction, fertilization, cancer metastasis, cell-cell adhesion, and immune responses. Investigations of the biological functions of glycans and glycan conjugates are essential for managing various diseases and for the advancement of medical treatments, but these endeavors are hindered by the difficulty of preparing well-defined glycans for study. The method being developed has the potential to help alleviate bottlenecks in glycan research by enabling automated preparations of a broad range of otherwise inaccessible glycan structures in pure form. It is anticipated that this work will in turn accelerate the development of glycan-based vaccines and pharmaceutical agents. The broader impacts of the funded project extend to the benefits accrued to society as Professor Zhang engages in a range of educational activities including the rigorous training that he will provide to the graduate student coworkers conducting the research. These individuals, who will gain knowledge of advanced organic chemistry while acquiring the skills necessary to perform complex synthetic operations, are likely to make valuable future contributions to the Nation's scientific enterprise upon joining the workforce in private industry or academia. Undergraduate students, especially those belonging to groups underrepresented in the physical sciences, will also be recruited to help with the research effort; the inclusive and supportive experiences that the students gain in the laboratory environment are anticipated to encourage them to consider higher educational goals and/or careers in science, technology, engineering, and mathematics (STEM).The funded project focuses on the study and further development of the directing-group-on-leaving-group (DGLG) strategy for glycosylation in which glycosyl donors equipped with activatable nucleofugal moieties at the C1 position engage with glycosyl acceptors via largely stereoinvertive nucleophilic substitution. The SN2-like glycosylation is directed and facilitated/accelerated by a hydrogen bond-accepting group within the anomeric leaving group that promotes an anti-colinear attack trajectory of the nucleophile upon the weakened bond in the electrophile. The aims of the research are divided into three sequential phases: (1) development of improved reaction conditions and next-generation leaving groups for DGLG strategy-based glycosylation reactions that are appropriate for solid phase synthesis and yet are still applicable for the stereoselective formation of essentially any type of glycosidic bond (i.e., 1,2-cis, 1,2-trans, 2-deoxy-alpha, 2-deoxy-beta types in pyranose or furanose systems); (2) validation and implementation of the developed processes on the solid phase; and (3) demonstration of the feasibility of the processes in a commercially available platform for automated glycan synthesis. It is anticipated that the research will lead to fundamental advances in the theory and practice of complex carbohydrate synthesis and that the emergent technology arising from the discoveries will be impactful to ancillary 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.