Regio- and Site-Selective Processes Using Transition Metal and Biological Catalysts

 描述(由申请人提供)：快速和可靠地获取合成衍生的化学结构在生物医学研究的许多方面起着至关重要的作用。这项提议的基本目标是为高选择性键的形成提供根本上的新战略，使人们能够更快、更有效地获得具有潜在治疗价值的生物活性化合物。整个提案的一个共同主题是开发当结构中存在两个或更多类似活性部分时实现高选择性键形成的方法。使用小分子过渡金属催化剂，将解决简单结构亚基的区域选择性衍生化反应，如烯烃和炔烃。通过仔细的机制分析，将提供新的见解，以指导在广泛的背景下实现这一目标的一般战略。利用工程生物催化剂，将开发一种新的底物工程方法，将细胞色素P450介导的氧化引导到复杂分子框架中所需的C-H键，从而实现复杂底物中C-H键的区域选择性氧化。还将讨论碳水化合物安装的新方法的开发。一类新的碳水化合物衍生的硅烷试剂将在糖苷键的安装过程中实现相当大的通用性和立体化学控制。这一研究计划的目标，包括精确地生成分子骨架，选择性地氧化C-H键，以及安装固定定义的碳水化合物，都是影响和增强复杂结构的生物学特性的高效策略。总而言之，这些战略提供了一个工具箱，用于使合成生物活性化合物的新方法成为可能。在协作工作中，这些研究将与生物合成酶的独特能力相结合，提供合成和生物催化的协同组合，以解决制备生物活性结构的关键障碍。该方法代表了很少结合的化学和生物学领域的合并：过渡金属催化、C-H氧化方法、碳水化合物化学和生物催化。这种独特的多学科视角使我们能够审查传统方法无法解决的战略。这项研究使进入生物医学重要结构成为可能，这将使人们能够更有效地研究它们的生物学功能和治疗潜力。

 DESCRIPTION (provided by applicant): Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of this proposal is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. A common theme throughout the proposal is the development of methods that accomplish highly selective bond formations when two or more similarly reactive parts of a structure are present. Using small molecule transition metal catalysts, the regioselective derivatization of simple structural subunits such as alkenes and alkynes will be addressed. Through careful mechanistic analysis, new insights will be provided to guide general strategies toward this objective in a broad range of contexts. Using engineered biological catalysts, strategies will be developed to enable regioselective oxidations of C-H bonds in complex substrates, using a novel substrate engineering approach that directs cytochrome P450-mediated oxidations towards a desired C-H bond embedded within a complex molecular framework. The development of new methods for the installation of carbohydrates will also be addressed. A new class of carbohydrate-derived silane reagents will enable considerable generality and control of stereochemistry during the installation of glycosidic bonds. The goals of this research program, including the precise generation of molecular frameworks, the selective oxidation of C-H bonds, and the installation of stereodefined carbohydrates, are all highly effective strategies for impacting and enhancing the biological properties of complex structures. Put together, the strategies present a toolbox of methods for enabling novel approaches for the synthesis of bioactive compounds. In collaborative work, these studies will be combined with the unique capabilities of biosynthetic enzymes to provide a synergistic combination of synthesis and biocatalysis to address key hurdles in the preparation of biologically active structures. The approach represents a merger of rarely combined fields of chemistry and biology: transition metal catalysis, C-H oxidation methodology, carbohydrate chemistry, and biocatalysis. This unique multidisciplinary perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.