Stereoretentive Reactions at the Anomeric Carbon

在化学系化学合成项目的支持下，位于博尔德的科罗拉多大学的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作用。该研究的特点是开发技术，以可控的方式和高产量生产独特和难以获得的化学结构，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参与一系列教育和外联活动，资助项目的更广泛影响将扩展到社会所获得的好处。例如，进行研究的学生将接受复杂的合成化学技术培训，使他们成为现代劳动力中的下一代科学领导者。此外，Walczak团队还将参加教育推广活动中的公开演讲，如CU Wizards，旨在吸引人口统计学上多样化的游客，并在广泛的普通观众中推广科学，技术，工程和数学（STEM）的原理。复杂寡糖及其电子等排体的化学合成为生物过程提供了前所未有的见解;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受到限制。因此，资助的项目是针对开发和研究新的和改进的立体控制合成糖苷的方法，重点是具有挑战性的C-核苷和稀有己糖系统。感兴趣的方法涉及使用立体定向的异头亲核试剂（即，C1类金属试剂），其具有在宽范围的底物上以高水平的立体选择性安装糖苷键的能力，并且有时以完全的立体特异性进行。将开发使用容易获得的试剂来制备所需的异头亲核试剂的实用方法，并且所得到的异头亲核试剂参与立体保留C-C键形成交叉偶联反应以产生难以使用已建立的方法获得的异头亲核试剂。这项研究的目的是通过探索两类新的试剂，C1硼酸和C1硅烷，迄今为止在有机合成中很少受到关注，以弥补化学合成中的一个重要知识空白。感兴趣的特定靶标包括生物活性C-糖苷，如达格列净和抗生素假尿嘧啶霉素，以及罕见但也具有生物医学意义的L-己糖和L-氨基糖。对于后者，C1同源化操作将被部署，以使自然丰富的D-系列碳水化合物残基转化为不太常见的L-系列同系物。预计在资助项目的过程中获得的基础知识将推进选择性碳水化合物官能化的催化方法的实践，特别是我们对立体特异性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模拟系统的阐述，因此预计在相关学科（如糖生物学和药物化学）中会产生辅助效益。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, 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.