Development of SN2-type Glycosylation for Automated Glycan Synthesis

在化学系化学合成项目的支持下，加州大学圣巴巴拉分校的张黎明教授正在研究一种在适合自动合成聚糖的条件下选择性地将不同糖分子连接在一起的方法。聚糖及其共轭形式（例如，糖蛋白、糖肽和糖脂等）是含有许多相互连接的糖单元的复杂分子，其涉及各种生物过程和病理事件，包括：信号转导、受精、癌症转移、细胞-细胞粘附和免疫应答。研究聚糖和聚糖缀合物的生物学功能对于管理各种疾病和促进医学治疗是必不可少的，但是这些努力受到难以制备用于研究的明确定义的聚糖的阻碍。正在开发的方法有可能帮助缓解聚糖研究的瓶颈，使广泛的，否则无法获得的聚糖结构的纯形式的自动化制备。预计这项工作将反过来加速聚糖疫苗和药剂的开发。资助项目的更广泛的影响延伸到社会的好处，因为张教授从事一系列的教育活动，包括严格的培训，他将提供给研究生同事进行研究。这些人将获得先进的有机化学知识，同时获得执行复杂合成操作所需的技能，在加入私营工业或学术界的劳动力队伍后，可能会为国家的科学事业做出宝贵的贡献。还将招募本科生，特别是那些属于物理科学代表性不足的群体的本科生，以帮助研究工作;学生在实验室环境中获得的包容性和支持性经验预计将鼓励他们考虑更高的教育目标和/或科学，技术，工程，该资助项目的重点是研究和进一步发展的指导小组对离开集团（DGLG）糖基化的策略，其中在C1位置配备有可活化的离核部分的糖基供体与糖基受体主要通过立体可逆亲核取代。SN 2样糖基化由异头离去基团内的氢键接受基团引导和促进/加速，所述氢键接受基团促进亲核试剂在亲电试剂中的弱化键上的反共线攻击轨迹。该研究的目的分为三个连续的阶段：（1）开发用于基于DGLG策略的糖基化反应的改进的反应条件和下一代离去基团，其适合于固相合成，但仍然适用于基本上任何类型的糖苷键的立体选择性形成（即，吡喃糖或呋喃糖系统中的1，2-顺式、1，2-反式、2-脱氧-α、2-脱氧-β型）;（2）在固相上验证和实施所开发的工艺;以及（3）在自动化聚糖合成的市售平台上证明工艺的可行性。预计该研究将导致复杂碳水化合物合成的理论和实践的根本性进展，并且由此发现的新兴技术将对糖生物学和药物化学等辅助学科产生影响。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.