Cycloadditions of Strained Cyclic Intermediates

应变环状中间体的环加成

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要含氮的杂环在生物活性天然产物中普遍存在药物，哌啶胺是在毒品脚手架。尽管在很大程度上是理解的，但紧张的Azacyclic Allenes有有可能充当构建不官能化的基础哌啶。以受控方式对Azacyclic Allenes的操纵将提供在制造有价值的应用程序中制造杂节阵列的新机会制药行业和有机合成。该提议的主要目标是开发一个模型来预测Azacyclic的区域选择性和立体选择性 Diels - Alder Cycloaditions中的Allenes，从而加速了其在高度功能化的含氮杂环的合成。研究加州大学洛杉矶分校的Garg和Houk实验室的环境非常适合实现这一目标。实验室在合成的界面上有协作的记录化学和机制。 Garg教授和Houk教授都是他们的领导者各自的领域，也众所周知具有出色的心理记录研究生并确保他们的成功。那，学员将成为一个有机合成和计算化学领域的专家。该提案将通过两个涉及的具体目标来完成计算和实验的组合。在AIM 1中，一个预测模型监管选择性的Diels - Alder Cycloaditions具有3'和5'取代的Azacyclic Allenes将会被开发。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。 AIM 2意志涉及开发Azacyclic的对照组的Diels- alder Cyclotitions 艾伦。这些反应在这些反应中的作用将在计算上进行研究，并且将开发一个简单的预测立体特异性的模型。计算预测将通过实验进行测试，并将建立预测模型的可靠性各种Azacyclic Allenes。这项工作最终将证明不对称合成中紧张的环肠。