Methods and Strategies for Chemical Synthesis

化学合成的方法和策略

• 批准号: 10368143
• 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/10368143
• 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.

项目摘要/摘要： 手性有机分子新方法的发明是现代有机学的一个重要目标 化学，因为它是有效合成药剂的关键。这一点尤其相关，因为 制药行业正在努力增加候选药物的3D复杂性。尽管 立体选择性化学合成领域的实质性进展，许多结构仍然具有挑战性 准备大量有用的食物。因此，开发化学物质的新方法和新策略 立体化学和拓扑结构复杂分子的合成是当代的研究热点。长期的 我们的研究计划的目标是介绍立体选择性合成的一般和有效的策略 在重要的生物活性分子中发现的难以接近的分子骨架。为此，我们正在 对丰富的和容易获得的烯烃转化为更复杂的结构感兴趣 去官能化反应。这种方法很有吸引力，因为复杂性的快速积累可能会 因为在一次操作中产生了两个新的键和两个新的立体中心。这些研究 本申请中描述的重点是两个不同的程序。一是立体选材的发展 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 发展这些反应的基本原理是，广泛可用的烯烃、二硼试剂和 有机卤化物被转化为合成用途广泛的中间体。基于我们之前的工作，我们正在 活性烯烃芳基硼化钯/铜协同催化体系的研究进展 展示了含氮杂环的官能化。此外，我们正在开发一种 未活化烯烃镍催化双官能化的一般策略。在第二个节目中 研究，我们正在开发通过[2+2]环加成反应来不对称合成环丁烷的方法 由烯烃和缺电子的联烯组成。我们发展这些反应的理由是，由于 由于这些过程的协同异步性，可利用的烯烃种类繁多。这使得 用于合成各种立体化学复杂的环丁烷。由这些环生成的环 转化直接存在于生物活性分子中，可以进行各种反应，以及 代表着药物发现的新基石。总体而言，这些反应发展的研究将 引入新的概念和策略，并为化学合成提供新的基础材料 通过探索新的交叉偶联范例和环加成反应。