Methods for Enantioselective Spirocycle Synthesis and Radical Hydroamination of Trisubstituted Alkenes

三取代烯烃的对映选择性螺环合成和自由基氢胺化方法

• 批准号: 10785901
• 负责人: Melissa Ramirez
• 金额: $ 12.08万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785901
• 关键词: Acids; Acylation; Alkenes; Amination; Area; Attention; Boranes; Carbon; Catalysis; Chemical Structure; Chemistry; Clinical; Complement; Computer Analysis; Coupling; Cyclization; Generations; Goals; High temperature of physical object; Hydrogen Peroxide; Hydrolysis; Isoquinolines; Lactones; Ligands; Mechanics; Medicine; Metals; Methods; Natural Products; Nickel; Nitriles; Nitrogen; Organic Synthesis; Periodicity; Pharmaceutical Preparations; Phase; Property; Reaction; Research; Solvents; Testing; Theoretical Studies; Training; Transition Elements; base; catalyst; chemical property; design; enolate; experimental study; method development; programs; quantum; scaffold; small molecule; success; synergism

Project Summary/Abstract This proposal focuses on the synergy of experiments and computations in (1) understanding fundamental reactivity in organic and organometallic transformations and (2) enabling reaction design for the discovery of methods for enantioselective spirocycle synthesis and radical hydroamination of tri-substituted alkenes. Two distinct approaches to using aryl and alkyl nitriles for the synthesis of enantioenriched quaternary stereocenters and nitrogen-containing heterocycles, respectively, are proposed. The medicinal properties of molecules bearing quaternary centers have drawn particular attention, as a significant positive correlation exists between the number of stereogenic centers with clinical success. However, the construction of these structural motifs with a high degree of stereocontrol, especially in the synthesis of spiro centers, remains a significant challenge in organic synthesis. The goal of the proposed research is to access sterically congested, spirocyclic quaternary centers in a stereoselective manner by means of nickel-catalyzed acylation reactions of lactones (K99). Reaction optimization and substrate scope studies will first be performed to establish the desired reactivity with aryl nitriles. Upon validating the desired reactivity with aryl nitriles experimentally, computations will be performed to understand the reaction mechanism and help guide substrate scope expansion to alkyl nitriles. Secondly, the chemical properties of aryl nitriles will be applied toward the synthesis of nitrogen-containing heterocycles (R00), which are considered critically important as more than half of the top 20 best-selling small molecule drugs and nearly 60% of all small molecule drugs possess them. Traditional approaches to C–N bond formation rely on transition-metal catalyzed transformations, such as Chan-Lam coupling, Buchwald–Hartwig amination, and Ullmann reaction. Given that most of these metal-catalyzed reactions require the use of high temperatures and pre-functionalized starting materials, the transition to radical-based C–N bond formation, which can use mild conditions and simpler starting materials, is highly desirable. My goal is to establish an independent research program focused on studying boryl radical chemistry for the generation of nitrogen-centered radicals and regiodivergent hydroamination of trisubstituted alkenes (R00). This project will involve 1) initial computations on key mechanistic steps to help identify NHC boranes that allow for regioselective formation of azepine and isoquinoline scaffolds and 2) experimental testing of computational predictions, reaction optimization, and substrate scope studies. Overall, computational analyses of reaction mechanism and the origins of stereo- or regioselectivity in the aforementioned transformations will provide a platform to expand the utility of Ni catalysis for enantioselective synthesis of spirocyclic scaffolds and the application of boryl radical chemistry for C–N bond formation.

项目总结/摘要 该建议侧重于实验和计算的协同作用，（1）理解基本原理 有机和有机金属转化中的反应性，以及（2）使反应设计能够发现 三取代烯烃的对映选择性螺环合成和自由基加氢胺化的方法。两 使用芳基和烷基腈合成对映体富集的季立体中心的不同方法 和含氮杂环化合物。携带分子的药物特性 四元中心引起了特别的关注，因为在它们之间存在显著的正相关性。 临床成功的立体基因中心数量。然而，这些结构图案的构建 高度的立体控制，特别是在螺环中心的合成中，仍然是一个重大的挑战， 有机合成该研究的目标是获得空间拥挤的螺环季铵盐， 中心的立体选择性的方式通过镍催化的酰化反应的内酯（K99）。反应 首先进行优化和底物范围研究以确定与芳基腈的所需反应性。 在实验上验证与芳基腈的期望反应性后，将进行计算以 了解反应机理，帮助指导底物范围扩展到烷基腈。 其次，将芳基腈的化学性质应用于含氮化合物的合成， 杂环（R 00），这被认为是至关重要的，因为超过一半的前20名最畅销的小 分子药物和近60%的小分子药物都拥有它们。C-N键的传统方法 形成依赖于过渡金属催化的转化，例如Chan-Lam偶联、Buchwald-Hartwig 胺化和Ullmann反应。考虑到大多数这些金属催化反应需要使用高浓度的有机溶剂， 温度和预官能化的起始材料，过渡到基于自由基的C-N键形成， 可以使用温和的条件和更简单的起始原料，是非常理想的。我的目标是建立一个独立的 一项研究计划，重点是研究硼基自由基化学，以产生氮中心自由基 和三取代烯烃的区域发散加氢胺化（R 00）。该项目将涉及1）初始计算 关键的机械步骤，以帮助确定NHC硼烷，允许区域选择性地形成氮杂卓， 异喹啉支架和2）计算预测的实验测试，反应优化，和 底物范围研究。总的来说，计算分析的反应机制和立体或起源 在上述转化中的区域选择性将提供一个平台，以扩大镍催化剂的效用 螺环骨架的对映选择性合成以及硼自由基化学在C-N键中的应用 阵