Methods for Enantioselective Spirocycle Synthesis and Radical Hydroamination of Trisubstituted Alkenes

项目摘要/摘要 这项建议侧重于实验和计算在(1)理解基本原理方面的协同作用 在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 三取代烯烃的不对称螺环合成和自由基氢胺化方法。二 用芳基和烷基腈合成富对映体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化合物。含氮分子的药用性能 第四纪中心特别受到关注，因为第四纪中心与 临床成功的立体定向中心的数量。然而，这些结构主题的构建带有一个 高度的立体控制，特别是在合成Spiro中心方面，仍然是一个重大挑战 有机合成。拟议研究的目标是访问空间拥堵的螺环四元系 通过镍催化的内酯的酰化反应以立体选择性的方式中心(K99)。反应 首先将进行优化和底物范围研究，以确定与芳香腈的预期反应性。 在实验上验证了与芳基腈的预期反应性后，将进行计算以 了解反应机理并帮助指导底物范围扩展到烷基腈。 其次，芳香腈的化学性质将应用于含氮化合物的合成 杂环(R00)，它被认为是至关重要的，因为前20名最畅销的小 分子药物和近60%的小分子药物拥有它们。C-N键的传统研究方法 形成依赖于过渡金属催化的转变，如Chan-Lam偶合、Buchwald-Hartwig 胺化反应和乌尔曼反应。鉴于大多数这些金属催化的反应需要使用高密度的 温度和预官能化起始材料，过渡到基于自由基碳-氮键的形成，这 可以使用温和的条件和更简单的起始材料，是非常可取的。我的目标是建立一个独立的 研究计划侧重于研究以氮为中心的自由基的生成的硼基化学 和三取代烯烃的区域发散氢胺化反应(R00)。该项目将涉及1)初步计算 关于帮助确定允许氮杂环己烷和氮杂环己烷区域选择性形成的NHC硼烷的关键机械步骤 异喹啉支架和2)计算预测、反应优化和 底物范围研究。总之，对反应机理和立体声的起源进行了计算分析 上述转化中的区域选择性将为扩大镍催化的用途提供平台 螺环支架的对映选择性合成及C-N键的硼自由基化学应用 队形。

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.