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

项目概要 开发富含sp3（即高度三维）有机结构的通用方法 支架是有机合成中长期存在的挑战。高 sp3 特性赋予有益的生物特性 有机分子的活性和药代动力学特性，但由于其复杂性，例如 与富含 sp2 的化合物相比，这些化合物在药物发现库中的代表性不足。过渡金属 催化彻底改变了富含 sp2 的有机支架的构建，产生了一系列通用的 允许轻松合成各种化合物类似物库的转化，用于开发 新型小分子疗法。建立类似的通用方法来合成富含 sp3 的有机物 从简单的起始材料开始支架，需要催化方面的创新。本文提出的研究 采用创新的配体和催化剂设计作为发现新颖和通用支架构建的手段 可以将简单的起始材料（即烯烃、二烯、芳烃）转化为功能性和功能性的方法 结构复杂的产品。在一个领域，我们正在开发非常规配体平台，该平台占据了 Pd 催化的配体空间稀疏区域用于烯烃碳功能化的发展 反应。我们发现源自尿素的配体占据了一个小的有机配体区域，即 与膦和N-杂环卡宾无法接触，有效促进杂环化反应 两亲物和二烯。此外，具有非常规空间分布的膦配体可以发挥配体控制作用 与二烯的杂环化的过度位点选择性。该领域未来的工作将集中于扩展这些 研究结果开发了一种统一的合成方法来制备多种脂肪族杂环，以及选择性、 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 通过合理的配体设计和计算辅助配体发现。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。我们反应的核心 设计是将铜催化剂与基材配位，促进反应自由基的选择性生成 可加成烯烃和芳烃的中间体。通过这种方法，我们发现了一种需氧氨基酸 内部烯烃的氧化，与多种芳基取代的烯烃相结合，并在温和的条件下进行 条件。设计增强铜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 构建多种功能基序和环状支架，对化学选择性具有出色的催化剂控制 和立体选择性。总的来说，拟议的研究计划将导致多功能催化的开发 有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.