Discovering catalytic strategies for transition metal-catalyzed reactions to construct topologically complex organic scaffolds

项目总结 构建富含Sp3(即高度三维)有机化合物的一般方法的发展 支架在有机合成中是一个长期存在的挑战。高SP3性状赋予有益的生物 活性和药代动力学特性转化为有机分子，但由于它们的复杂性，如 相对于富含sp2的化合物，化合物在药物发现的文库中的代表性较低。过渡金属 催化使富含sp2的有机支架的构建发生了革命性的变化，产生了一系列通用的 允许方便地合成用于开发的不同化合物类似物文库的转换 新的小分子疗法。建立类似的通用方法来合成富含SP3的有机化合物 从简单的起始材料开始，在催化方面进行创新是必要的。在此提出的研究 采用创新的配体和催化剂设计作为发现新的和通用的支架构建的手段 可以将简单的起始材料(即烯烃、双烯、芳烃)转化为功能和 结构复杂的产品。在一个领域，我们正在开发非传统的配体平台， 钯的配位空间稀缺区域对发展烯烃碳化反应的催化作用 反应。我们已经发现，来自尿素的配体占据了一小部分有机配体，这是 膦和N-杂环卡宾不能进入，有效地促进了杂环化反应 喜怒无常的人和双烯。此外，具有非常规空间构型的膦配体可以对配体进行控制。 二烯杂环反应的超中心选择性。今后这一领域的工作将集中在以下几个方面 开发一种统一的合成方法来制备各种脂肪族杂环，以及选择性地， 烯烃的多组分碳官能化反应。这些方法论的发展将成为可能 通过有理配基设计和计算机辅助配基发现。在另一个领域，我们正在建立 铜二胺络合物作为氧化自由基加成反应的通用催化剂。我们反应的中心 设计是将铜催化剂与底物配合，促进活性自由基的选择性生成 可以添加到烯烃和芳烃中的中间体。使用这种方法，我们发现了一种有氧氨基- 与不同芳基取代的烯烃接触并在温和条件下工作的内部烯烃的氧化作用 条件。设计增强铜的氧化电位并促进与底物配位的配体 将能够在氧化、自由基烯烃加成反应中发现新的催化反应性，并提供 开发高度对映选择性转化的框架。这些反应将使快速 具有良好的化学选择性催化剂控制的不同功能模体和环状支架的构建 和立体选择性。总而言之，拟议的研究计划将导致开发多功能催化剂 高效制备与发现化合物相关的功能分子的方法 治疗潜力，因此将对生物医学科学和人类健康产生重大影响。

PROJECT SUMMARY The development of general methods for the construction of sp3-rich (i.e. highly three-dimensional) organic scaffolds is a longstanding challenge in organic synthesis. High sp3 character imparts beneficial biological activities and pharmacokinetic properties into organic molecules, but because of their complexity, such compounds are underrepresented in libraries for drug discovery relative to sp2-rich compounds. Transition metal catalysis has revolutionized the construction of sp2-rich organic scaffolds, producing an array of general transformations that allow for the facile synthesis of diverse libraries of compound analogues for developing novel small molecule therapeutics. To establish similarly versatile methods for synthesizing sp3-rich organic scaffolds from simple starting materials, innovations in catalysis are needed. The research proposed herein employs innovative ligand and catalyst design as a means to discover novel and general scaffold-building methodologies that can transform simple starting materials (i.e. alkenes, dienes, arenes) into functionally and structurally complex products. In one area, we are developing unconventional ligand platforms that occupy underpopulated regions of ligand space for Pd catalysis for the development of olefin carbofunctionalization reactions. We have found that ligands derived from urea, which occupy a region of small organic ligands that is inaccessible to phosphines and N-heterocyclic carbenes, effectively promote heteroannulation reactions of ambiphiles and dienes. In addition, phosphine ligands with unconventional steric profiles can exert ligand control over site-selectivity for heteroannulations with dienes. Future work in this area will focus on expanding on these findings to develop a unified synthetic approach to preparing diverse aliphatic heterocycles, as well as selective, multicomponent carbofunctionalization reactions of olefins. These methodological developments will be enabled by both rational ligand design and computationally-aided ligand discovery. In another area, we are establishing Cu-diamine complexes as general catalysts for oxidative, radical addition reactions. Central to our reaction design is coordinating Cu catalysts to the substrate, which promotes selective generation of reactive radical intermediates that can add to olefins and arenes. Using this approach, we have discovered an aerobic amino- oxygenation of internal alkenes that engages diverse aryl-substituted alkenes and operates under mild conditions. Designing ligands that enhance the oxidative potential of Cu and facilitate coordination to substrates will enable the discovery of new catalytic reactivity in oxidative, radical olefin addition reactions, and provides a framework for the development of highly enantioselective transformations. These reactions will enable the rapid construction of diverse functional motifs and cyclic scaffolds with excellent catalyst control over chemoselectivity and stereoselectivity. In total, the proposed research program will result in the development of versatile catalytic methods for the efficient preparation of functional molecules that are relevant for discovering compounds with therapeutic potential, and thus will have a significant impact on biomedical sciences and human health.