Continuous Flow Silyl Ether Exchange Methodologies to Achieve Site-Specific Functionalization of Polydroxylic Natural Products

有了这个奖项，美国国家科学基金会化学部的化学合成项目资助了杰奎琳·格维-黑格教授的研究，她正在开发高效的连续流动方法，使多羟基天然产物（如糖）发生位点特异性变化。连续流化学是一种将反应物混合到管中，使化学反应在精确控制的条件下发生的过程，其中许多反应条件可以调节。这种方法在化学工业中越来越重要，它被用于多步骤过程，从而有效地生产药品和其他增值化学品。在该技术提供的精心实验控制下，反应条件（如温度、压力和反应时间）产生了传统“一锅”化学合成中无法观察到的化学结构和反应性之间的新关系。参与这项研究的学生正在研究复杂的化学反应，这为他们提供了表达自己制作天然产品的创造性设计的机会。使用核磁共振（NMR）光谱作为预测化学反应性的主要工具，可以进一步了解化学键的性质及其固有的反应性。本研究为博士和硕士研究生在先进制造业的学术、企业和工业环境中开展科学事业，造福社会提供了一个肥沃的学习平台。该研究的智力价值集中在将成功的批化学转移到连续流动反应上，以提高选择性、化学多样性和生产率，同时提高安全指标。重要的是，微尺度分段流技术提供了产品形成的快速评估，并使连续流优化成为未来自动化的基础。区分看似相等的羟基以实现特定功能化的能力是化学合成发展的主要挑战。通常，需要几个保护和去保护步骤，这增加了生产时间，降低了步骤经济性。此外，许多程序需要合成专业知识，这限制了化学合成领域以外的科学家的可及性。包括多肽和核酸合成在内的自动化合成平台已被非专业人士广泛采用，并改变了化学生物学的研究。在美国国家科学院最近发表的一篇关于糖科学未来的出版物中，增加生物医学研究人员获得天然产物类似物的途径被宣布为头等大事。本研究开发了硅醚到酯、醚和醇等替代功能的位点特异性转化的连续流动方法。该奖项反映了美国国家科学基金会的法定使命，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 this award, the Chemical Synthesis Program of the NSF Division of Chemistry is funding the research of Professor Jacquelyn Gervay-Hague who is developing efficient continuous flow methods to make site-specific changes of polyhydroxylic natural products, such as sugars. Continuous flow chemistry is a process in which reactants are mixed together into tubes allowing a chemical reaction to occur under precisely controlled conditions where numerous reaction conditions can be adjusted. This method is of increasing importance in the chemical industry where it is used in multi-step processes leading to the efficient production of pharmaceuticals and other value-added chemicals. With the careful experimental control offered by this technology, the reaction conditions such as temperature, pressure, and reaction time result in new relationships between chemical structure and reactivity that are not observable in traditional "one-pot" chemistry synthesis. Students involved in this research are investigating complex chemical reactions providing them the opportunity to express their own creative design of making natural products. The use of Nuclear Magnetic Resonance (NMR) spectroscopy as a major tool for predicting chemical reactivity gives further insight into the nature of chemical bonds and their inherent reactivity. This research provides a fertile learning platform for both doctoral and masters graduate students to launch scientific careers that benefit society through gainful employment in academic, entrepreneurial, and industrial settings in advanced manufacturing.The intellectual merit of the research focuses on transferring successful batch chemistries to continuous flow reactions to increase selectivity, chemical diversity, and productivity with improved safety metrics. Importantly, microscale segmented flow techniques provide rapid assessment of product formation and enable continuous flow optimization as a basis for future automation. The ability to differentiate between seemingly equivalent hydroxyl groups in order to achieve specific functionalization is a major challenge for chemical synthesis development. Typically, several protection and deprotection steps are required, which increases production time and decreases step economy. In addition, many of the procedures require synthetic expertise, which limits accessibility to scientists outside the chemical synthesis arena. Automated synthesis platforms including peptide and nucleic acid synthesizers have been widely adopted by non-experts and have transformed chemical biology research. Increasing access of natural product analogs to biomedical researchers was proclaimed a top priority in a recent National Academy of Sciences publication on the future of glycosciences. This research developes continuous flow methodologies for site-specific conversion of silyl ethers to alternative functionalities such as esters, ethers, and alcohols.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.