Cycloadditions of Strained Cyclic Intermediates

应变环状中间体的环加成

• 批准号: 9760790
• 负责人: Melissa Ramirez
• 金额: $ 3.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760790
• 关键词: Address; Alder plant; Area; Chemistry; Collaborations; Development; Drug Industry; Ensure; Environment; Goals; Laboratories; Lead; Mentors; Methods; Modeling; Natural Products; Nitrogen; Organic Synthesis; Outcome; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Reaction; Records; Research; Role; Synthesis Chemistry; Testing; Work; bioactive natural products; chemical synthesis; computational chemistry; computer studies; cycloaddition; experimental study; graduate student; novel therapeutics; phase 2 testing; piperidine; predictive modeling; professor; propadiene; scaffold; small molecule; success; tool

Project Summary/Abstract Nitrogen-containing heterocycles are prevalent in bioactive natural products and pharmaceuticals, with piperidine serving as the most prevalent heterocycle found in drug scaffolds. Although largely understudied, strained azacyclic allenes have the potential to serve as building blocks for the construction of densely functionalized piperidines. The manipulation of azacyclic allenes in a controlled manner would offer new opportunities for making arrays of heterocycles with valuable applications in the pharmaceutical industry and in organic synthesis. The primary goal of this proposal is to develop a model for predicting the regioselectivities and steroselectivities of azacyclic allenes in Diels–Alder cycloadditions, thereby accelerating their application in the synthesis of highly functionalized nitrogen-containing heterocycles. The research environment in the Garg and Houk laboratories at UCLA is ideal for achieving this goal. The laboratories have a track record of collaboration at the interface of synthetic chemistry and mechanism. Both Professor Garg and Professor Houk are leaders in their respective fields and are also known to have excellent track records of mentoring graduate students and ensuring their success. Thus, the trainee would become an expert in both the fields of organic synthesis and computational chemistry. The proposal will be accomplished through two specific aims involving a combination of computations and experiments. In Aim 1, a predictive model for regioselective Diels–Alder cycloadditions with 3’ and 5’ substituted azacyclic allenes will be developed. This effort will involve high accuracy DFT calculations and experimental testing of computational predictions to confirm the reliability of the model. Aim 2 will involve the development of enantiospecific Diels–Alder cycloadditions of azacyclic allenes. The role of substituents in these reactions will be studied computationally, and a simple model to predict stereospecificity will be developed. Computational predictions will be tested experimentally and will establish the reliability of the predictive model for a variety of azacyclic allenes. This work would ultimately demonstrate the utility of strained cyclic allenes in asymmetric synthesis.

项目总结/摘要 含氮杂环在生物活性天然产物中普遍存在， 在药物中，哌啶是最常见的杂环， 药物支架虽然在很大程度上研究不足，紧张的氮杂环丙二烯有 作为构建密集功能化的 哌啶。以受控的方式操纵氮杂环丙二烯将提供 制造杂环阵列的新机会， 制药工业和有机合成。该提案的主要目标是 建立了一个预测氮杂环化合物区域选择性和立体选择性的模型 Diels-Alder环加成反应中的联烯，从而加速了它们在 高度官能化的含氮杂环的合成。研究 加州大学洛杉矶分校Garg和Houk实验室的环境是实现这一目标的理想选择。 这些实验室在合成药物的接口方面有着合作的记录。 化学和机制。加尔格教授和霍克教授都是他们领域的领导者 在各自的领域，也被称为有良好的跟踪记录的指导 研究生，并确保他们的成功。因此，受训者将成为 有机合成和计算化学领域的专家。 该提案将通过两个具体目标来实现， 计算和实验的结合。在目标1中， 与3'和5'取代的氮杂环联烯的区域选择性Diels-Alder环加成将 发展。这项工作将涉及高精度DFT计算和实验 测试计算预测，以确认模型的可靠性。目标2将 涉及氮杂环的对映体特异性Diels-Alder环加成反应的发展 艾伦。将通过计算研究取代基在这些反应中的作用， 将开发预测立体特异性的简单模型。计算预测 将进行实验测试，并将建立预测模型的可靠性， 各种氮杂环联烯。这项工作最终将证明 不对称合成中的应变环联烯。