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.

项目概要/摘要 含氮杂环广泛存在于具有生物活性的天然产物中 药物中，哌啶是最常见的杂环化合物 尽管尚未充分研究，但应变氮杂环丙二烯具有以下特点： 具有作为构建密集功能化建筑模块的潜力 以受控方式操纵氮杂环丙二烯将提供。 制造具有有价值应用的杂环阵列的新机会 该提案的主要目标是制药工业和有机合成。 开发预测氮杂环的区域选择性和立体选择性的模型 Diels-Alder 环加成反应中的丙二烯，从而加速了它们在 高功能化含氮杂环的合成研究 加州大学洛杉矶分校 Garg 和 Houk 实验室的环境非常适合实现这一目标。 实验室在合成材料界面方面拥有合作记录 Garg 教授和 Houk 教授都是化学和机理领域的领导者。 各自的领域，并以拥有出色的指导记录而闻名 研究生并确保他们的成功，因此，实习生将成为一名。 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，其中包括： 在目标 1 中，计算和实验相结合。 3'和5'取代的氮杂环丙二烯的区域选择性Diels-Alder环加成反应将 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。 涉及氮杂环对映特异性狄尔斯-阿尔德环加成反应的开发 取代基在这些反应中的作用将通过计算进行研究，并且 将开发一个预测立体特异性的简单模型。 将进行实验测试，并将建立预测模型的可靠性 这项工作最终将展示各种氮杂环丙二烯的实用性。 不对称合成中的应变环状丙二烯。