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.

项目概要/摘要 该提案重点关注实验和计算在（1）理解基础知识方面的协同作用 有机和有机金属转化中的反应性，以及（2）实现反应设计以发现 两种对映选择性螺环合成和三取代烯烃的自由基氢胺化方法。 使用芳基和烷基腈合成对映体富集的四元立体中心的不同方法 分别提出了含氮杂环和含氮杂环。 第四纪中心引起了特别关注，因为它们之间存在显着的正相关关系。 然而，这些结构基序的构建具有一定的临床成功性。 高度立体控制，特别是在螺中心的合成中，仍然是一个重大挑战 拟议研究的目标是获得空间拥挤的螺环四元化合物。 通过镍催化的内酯酰化反应（K99）以立体选择性方式形成中心。 首先将进行优化和底物范围研究，以确定与芳基腈的所需反应性。 通过实验验证与芳基腈的所需反应性后，将进行计算 了解反应机理并帮助指导底物范围扩展到烷基腈。 其次，芳基腈的化学性质将应用于含氮化合物的合成。 杂环化合物 (R00)，被认为至关重要，因为在最畅销的 20 种小分子化合物中，有一半以上 分子药物和近 60% 的小分子药物都具有 C-N 键的传统方法。 形成依赖于过渡金属催化转化，例如 Chan-Lam 偶联、Buchwald-Hartwig 鉴于大多数这些金属催化反应需要使用高浓度的胺化反应和乌尔曼反应。 温度和预功能化起始材料，过渡到基于自由基的 C-N 键形成，这 可以使用温和的条件和更简单的起始材料，是非常理想的，我的目标是建立一个独立的。 研究计划专注于研究硼基自由基化学以产生以氮为中心的自由基 和三取代烯烃的区域发散氢胺化 (R00) 该项目将涉及 1) 初始计算。 帮助识别 NHC 硼烷的关键机制步骤，这些硼烷可以区域选择性地形成氮杂卓和 异喹啉支架和 2) 计算预测、反应优化和的实验测试 总体而言，反应机理和立体或立体起源的计算分析。 上述转化中的区域选择性将为扩大镍催化的效用提供一个平台 用于螺环支架的对映选择性合成以及硼基自由基化学在 C-N 键上的应用 形成。