Discovery and mechanistic analysis of new catalytic reactions

控制复杂分子反应的选择性是化学领域面临的一个严峻挑战。有效和快速地制备候选药物、研究生化过程的新材料和工具往往取决于选择性化学转化的发展。有机合成中的选择性是一个多方面的问题，包括立体选择性(控制原子在空间中的取向)、区域选择性(控制键形成的方向)、位置选择性(在具有相同反应基团的多个副本的分子中的位置选择性)和化学选择性(一组原子相对于另一组原子的反应活性)。在自然界中，这些类型的选择性是在酶催化剂的控制下进行的，酶催化剂加速了一条途径，使其能够超越其他可能性。催化剂控制选择性是自然界从一组简单的前体构建结构和功能不同的分子的主要方式之一。拟议研究的目标是开发合成(实验室)催化剂，以解决有机化合物制备中与区域选择性、立体选择性和位置选择性控制有关的重要问题。碳水化合物(糖)和核苷衍生物或类似物的合成或功能化的有效方法是一个特别关注的领域；这些类型的分子是低聚糖和多核苷酸这两类重要生物化合物的基础。它们的衍生物和类似物被广泛用于基础研究和未来的药物制剂，特别是作为抗病毒药物或抗生素。这些结构类提出了特别具有挑战性的选择性问题；迫切需要有效地在实验室合成它们的方法，以促进对人类健康和疾病的了解，并使开发新的候选药物成为可能。在我们之前的发现基金的支持下，我的团队开创了新的催化反应，这些反应已经被碳水化合物化学和糖生物学社区的最终用户广泛采用，以促进他们的研究工作，并激励了其他催化研究人员的进一步创新。在接下来的五年里，我的由不同的研究生和本科生组成的团队将进行实验室实验，以开发对碳水化合物、核苷和其他复杂化学目标的合成具有战略价值的新催化工艺。通过研究这些反应如何工作的细节，他们将建立对如何优化和推广它们的理解。这一结果将确定制备和研究生物化学、生物技术和药物化学领域迫切需要的化合物的新方法。在进行这项研究的同时，受训者将发展成为全面、有创造力和足智多谋的科学家，同时培养现代合成和光谱技术、实验设计、数据分析和解释方面的宝贵技能。

Controlling selectivity in reactions of complex molecules is a critical challenge for the chemistry field. The efficient and rapid preparation of drug candidates, new materials and tools for studying biochemical processes often hinges on the development of selective chemical transformations. Selectivity in organic synthesis is a multifaceted problem, encompassing stereoselectivity (control of the orientation of atoms in space), regioselectivity (control of the direction of bond formation), site-selectivity (positional selectivity in a molecule with several copies of the same reactive group) and chemoselectivity (reactivity of one group of atoms over another). In nature, these types of selectivity are under the control of enzyme catalysts, which accelerate one pathway so that it can outcompete other possibilities. Catalyst control of selectivity is one of the primary ways that nature constructs structurally and functionally diverse molecules from a set of simple precursors. The goal of the proposed research is to develop synthetic (laboratory) catalysts to address important problems related to the control of regioselectivity, stereoselectivity and site-selectivity in the preparation of organic compounds. Efficient methods for the synthesis or functionalization of carbohydrate (sugar) and nucleoside derivatives or analogs are a specific area of focus; these types of molecules are the building blocks for oligosaccharides and polynucleotides, two important classes of biological compounds. Their derivatives and analogs are used extensively in basic research and as prospective medicinal agents, particularly as antivirals or antibiotics. These structural classes pose particularly challenging selectivity issues; methods for their efficient laboratory synthesis are urgently needed to advance understanding of human health and disease and to enable the development of new drug candidates. Supported by our previous Discovery Grant, my group pioneered new catalytic reactions that have been widely adopted by end users in the carbohydrate chemistry and glycobiology communities to facilitate their research efforts, and have inspired further innovations by other catalysis researchers. Over the next five years, my team of diverse graduate and undergraduate students will conduct laboratory experiments to develop new catalytic processes of strategic value for the synthesis of carbohydrates, nucleosides and other complex chemical targets. By studying details of how these reactions work, they will build understanding of how to optimize and generalize them. The results will define new ways to prepare and study compounds that are urgently needed in the biochemistry, biotechnology and medicinal chemistry fields. While conducting this research, trainees will develop into well-rounded, creative and resourceful scientists while building valuable skills in modern synthetic and spectroscopic techniques, experimental design, data analysis and interpretation.