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：发明获取手性有机分子的新方法是现代有机领域的一个关键目标化学对于药物的有效合成至关重要。这尤其重要，因为制药行业正在努力提高候选药物的 3D 复杂性。尽管立体选择性化学合成领域取得了实质性进展，但许多结构仍然具有挑战性准备有用的数量。因此，开发新的化学方法和策略立体化学和拓扑复杂分子的合成引起了当代的兴趣。长期来看我们研究计划的目标是引入立体选择性合成的通用且有效的策略在重要的生物活性分子中发现的难以接近的分子框架。为此，我们对通过将丰富且容易获得的烯烃转化为更复杂的结构感兴趣双官能化反应。这种方法很有吸引力，因为复杂性的快速增加可以通过在一次操作中生成两个新键和两个新立体中心来实现。研究本申请中描述的重点是两个不同的程序。首先是立体选择性的发展由简单烯烃原位催化生成的 Csp3-亲核试剂的交叉偶联反应。我们的开发这些反应的基本原理是广泛使用的烯烃、二硼试剂和有机卤化物被转化为合成用途广泛的中间体。根据我们之前的工作，我们开发用于活化烯烃特别是芳基硼化反应的 Pd/Cu 协同催化系统证明含氮杂环的官能化。此外，我们正在开发一个 Ni催化未活化烯烃双官能化的一般策略。在第二期节目中研究，我们正在开发通过[2+2]环加成对映选择性合成环丁烷的方法烯烃和缺电子丙二烯。我们发展这些反应的理由是，由于由于这些过程的协调异步性质，可以利用多种烯烃。这允许用于合成多种立体化学复杂的环丁烷。由这些产生的环转化直接存在于生物活性分子中，可以进行多种反应，并且代表了药物发现的新颖构建模块。总体而言，这些反应发展研究将引入新的概念和策略，并提供化学合成的新构建模块通过探索新的交叉偶联范例和环加成反应。