Methods and Strategies for Chemical Synthesis

化学合成的方法和策略

基本信息

批准号：
9900032
负责人：
Michael Kevin Brown
金额：
$ 52.02万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
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 2024-03-31
项目状态：
已结题

项目摘要

Project Summary/Abstract: The invention of new methods to access chiral organic molecules is a critical objective in modern organic chemistry as it is essential for the efficient synthesis of pharmaceutical agents. This is especially relevant as the pharmaceutical industry is making efforts to increase the 3D complexity of drug candidates. Despite substantial progress in the field of stereoselective chemical synthesis, many structures remain challenging to prepare in useful quantities. Therefore, development of new methods and strategies for the chemical synthesis of stereochemically and topologically complex molecules is of contemporary interest. The long-term goals of our research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult-to-access molecular frameworks found in important bioactive molecules. Towards this end, we are interested in the conversion of abundant and readily available alkenes to more complex structures through difunctionalization reactions. This approach is attractive because the rapid buildup of complexity can be achieved as two new bonds and two new stereocenters are generated in a single operation. The studies described in this application focus on two distinct programs. The first is the development of stereoselective cross-coupling reactions of Csp3-nucleophiles that are catalytically generated in situ from simple alkenes. Our rationale for development of these reactions is that widely available alkenes, diboron reagents, and organohalides are converted to synthetically versatile intermediates. Based on our earlier work, we are developing Pd/Cu-cooperative catalytic systems for the arylboration of activated alkenes and in particular demonstrating the functionalization of nitrogen containing heterocycles. In addition, we are developing a general strategy for unactivated alkene difunctionalization with Ni-catalysis. In the second program of research, we are developing methods for the enantioselective synthesis of cyclobutanes by [2+2] cycloaddition of alkenes and electron deficient allenes. Our rationale for the development of these reactions is that due to the concerted asynchronous nature of these processes, a broad range of alkenes can be utilized. This allows for the synthesis of a diverse range of stereochemically complex cyclobutanes. The rings generated by these transformations are directly found in bioactive molecules, can be subjected to a variety of reactions, and represent novel building blocks for drug discovery. Overall, these studies in reaction development will introduce new concepts and strategies as well as provide access to new building blocks for chemical synthesis by exploring new cross-coupling paradigms and cycloaddition reactions.

项目摘要/摘要：新方法获取手性有机分子的发明是现代有机物的关键目标化学对于有效合成药物是必不可少的。这特别重要制药行业正在努力提高候选药物的3D复杂性。尽管立体选择化学合成领域的实质进展，许多结构仍然具有挑战性准备有用数量。因此，开发新方法和化学策略立体和拓扑复杂的分子的合成具有当代利益。长期我们的研究计划的目标是为立体选择综合介绍一般有效的策略在重要的生物活性分子中发现的难以访问的分子框架。为此，我们是对通过大量且随时可用的烯烃转换为更复杂的结构的感兴趣双功能反应。这种方法很有吸引力，因为复杂性的迅速建立可能是作为两个新的键和两个新的立体中心的实现，在一次操作中生成。研究在此应用程序中描述的是两个不同的程序。首先是立体选择性的发展 CSP3-核粉的交叉偶联反应是由简单烯烃原位催化产生的。我们的这些反应开发的基本原理是广泛可用的烷烃，二迪伯龙试剂和有机盐转化为合成多功能中间体。根据我们早期的工作，我们是开发PD/CU合件催化系统，用于活化的烷烃芳基化，尤其是证明含有杂环的氮的功能化。此外，我们正在开发一个通过Ni-callysis进行未激活的烯烃进行双官能化的一般策略。在第二个程序中研究，我们正在开发通过[2+2] Cycloadition的对映选择性合成的对映选择性合成的方法烯烃和电子缺乏的艾伦。我们对这些反应的发展的理由是这些过程的一致性异步性，可以利用广泛的烯烃。这允许为了合成各种立体化学上复杂的循环机构。这些产生的环转化直接在生物活性分子中发现，可以经过多种反应，并且代表用于毒品发现的新颖基础。总体而言，这些反应发展的研究将介绍新的概念和策略，并为化学合成的新构建块提供访问通过探索新的交叉耦合范例和环加成反应。