Cycloadditions of Strained Cyclic Intermediates

项目摘要/摘要 含氮杂环广泛存在于生物活性天然产物和 药物，其中哌啶是#年发现的最常见的杂环 毒品脚手架。尽管在很大程度上没有得到研究，但紧张的氮杂环烯类化合物具有 有潜力作为构建密集功能化的 哌啶类药物。以受控方式操纵氮杂环烯将提供 制造具有重要应用价值的杂环阵列的新机会 医药工业和有机合成。这项提议的主要目标是 建立一个预测氮杂环的区域选择性和立体选择性的模型 二烯在Diels-Alder环加成反应中的应用 高官能化含氮杂环的合成。这项研究 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。 实验室在人工合成的界面上有着良好的合作记录 化学和机械。加格教授和胡克教授都是他们的 并在各自领域都有出色的指导记录 并确保他们的成功。因此，实习生将成为 在有机合成和计算化学领域都是专家。 该提案将通过两个具体目标来实现，其中包括 计算和实验相结合。在目标1中，一个预测模型用于 3‘和5’取代氮杂环烯的区域选择性Diels-Alder环加成反应 被开发出来。这项工作将涉及高精度的DFT计算和实验 对计算预测进行测试，以确认模型的可靠性。目标2将 涉及氮杂环的对映专一性Diels-Alder环加成反应的研究进展 阿伦斯。取代基在这些反应中的作用将通过计算进行研究，并 将开发一个简单的模型来预测立体专一性。计算性预测 将进行实验测试，并将建立预测模型的可靠性 氮杂环烯的种类。这项工作最终将证明 不对称合成中的张力环烯。

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.