Stereoretentive Reactions at the Anomeric Carbon

在化学系化学合成计划的支持下，科罗拉多大学博尔德分校的Maciej Walczak正在研究制备碳水化合物及其衍生物的方法，以更好地了解它们的生物学作用。这项研究的特点是开发了以受控方式和高产量生产独特和难以获得的化学结构的技术，预计这项工作将转化为生产增值材料的更有效的制造工艺。随着Walczak博士和他的同事团队开展一系列教育和外联活动，资助项目的更广泛影响将延伸到为社会带来的好处。例如，进行研究的学生将接受复杂的合成化学技术培训，为他们成为现代劳动力中的下一代科学领导者做准备。此外，Walczak团队将参加教育推广活动的公开演讲，如CU Wizards，旨在吸引不同人口统计范围的参观者，并在广泛和一般的受众中宣传科学、技术、工程和数学(STEM)原理。复杂低聚糖及其异构体的化学合成提供了对生物过程的前所未有的洞察；然而，目前制备碳水化合物衍生物的方法在效率和立体选择性方面存在局限性。因此，该资助项目旨在开发和研究新的和改进的糖苷立体控制合成方法，重点是挑战C-核苷和稀有己糖系统。感兴趣的方法包括交叉偶联反应，使用立体定义的异构体亲核试剂(即，C1类金属试剂)，这些亲核试剂能够在广泛的底物上安装具有高立体选择性的糖苷键，有时还具有完全的立体专一性。将开发使用现成的试剂制备所需的异构体亲核试剂的实用方法，所得到的合成子参与立体保留的C-C键，形成交叉偶联反应，以生成使用现有方法难以获得的糖类。这项研究旨在通过探索两类在有机合成中迄今鲜有人关注的新型试剂--c1硼酸和c1硅烷，来弥合化学合成中的一个重要知识鸿沟。感兴趣的具体靶点包括生物活性C-糖苷，如达格列夫津和抗生素伪红霉素，以及罕见但具有生物医学意义的L-己糖和L-氨基糖。对于后者，将部署C1同源操作，使天然丰富的D系列碳水化合物残基能够转化为不太常见的L系列同系物。预计在资助项目过程中获得的基本知识将促进选择性碳水化合物官能化催化方法的实践，特别是促进我们对立体定向交叉偶联反应的理解。从更广泛的角度来看，开发的方法将促进复杂碳水化合物和糖代谢系统的精加工，因此在相关学科如糖生物学和药物化学中预计会产生辅助效益。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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, 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.