Methods and Strategies for Chemical Synthesis

化学合成的方法和策略

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9900032
• 关键词: 3-Dimensional; Alkenes; Catalysis; Complex; Coupling; Cyclobutanes; Development; Drug Industry; Electrons; Goals; In Situ; Methods; Modernization; Molecular; Nature; Nitrogen; Organic Chemistry; Outcome; Pharmacologic Substance; Process; Reaction; Reagent; Research; Structure; System; Work; base; chemical synthesis; cycloaddition; drug candidate; drug discovery; improved; interest; invention; novel; operation; programs; propadiene

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.

项目概要/摘要： 获得手性有机分子的新方法的发明是现代有机化学中的关键目标。 化学，因为它是必要的有效合成药剂。这一点尤其重要，因为 制药工业正在努力增加候选药物的3D复杂性。尽管 尽管在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， 准备好有用的数量。因此，开发新的化学方法和策略， 立体化学和拓扑学复杂分子的合成是当代的兴趣所在。长期 我们的研究计划的目标是介绍通用的和有效的策略，立体选择性合成 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 感兴趣的是通过以下方法将丰富且容易获得的烯烃转化为更复杂的结构： 双官能化反应。这种方法是有吸引力的，因为复杂性的快速积累可以 这是因为在一次操作中产生了两个新的键和两个新的立构中心。研究 在本申请中描述的集中于两个不同的程序。首先是立体选择性的发展 Csp 3-亲核试剂的交叉偶联反应，其由简单烯烃原位催化生成。我们 开发这些反应的基本原理是广泛可得的烯烃、二硼试剂和 有机卤化物被转化为合成通用中间体。根据我们以前的工作，我们 开发用于活化烯烃的芳基硼化的Pd/Cu协同催化体系， 证明了含氮杂环的官能化。此外，我们正在开发一个 镍催化未活化烯烃双官能化的一般策略。在第二个方案中， 在研究的基础上，我们正在开发通过[2+2]环加成反应对映选择性合成环丁烷的方法 烯烃和缺电子的联烯。我们发展这些反应的理由是，由于 由于这些方法的协同异步性质，可以使用宽范围的烯烃。这允许 用于合成多种立体化学复杂的环丁烷。这些产生的环 转化直接存在于生物活性分子中，可以进行各种反应， 代表了药物发现的新基石。总的来说，这些反应发展研究将 引入新概念和策略，并提供化学合成的新构件 通过探索新的交叉偶联范例和环加成反应。