Harnessing Strained Intermediates to Access Complex Molecules

利用应变中间体访问复杂分子

• 批准号: 9523411
• 负责人: NEIL K GARG
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9523411
• 关键词: Alder plant; Alkaloids; Alkynes; Amines; Architecture; Area; Breathing; Chemical Structure; Chemistry; Complex; Coupling; Development; Face; Family; Generations; Lead; Medicine; Methodology; Methods; Molecular; Natural Products; Organic Synthesis; Periodicity; Pharmaceutical Preparations; Phase; Preparation; Reaction; Research; S Phase; c new; chemical synthesis; complex R; cycloaddition; drug discovery; member; novel therapeutics; operation; piperidine; propadiene; scaffold; small molecule; tool

Project Summary/Abstract The central objectives of this application are: (a) to develop new, reliable, and efficient, methodologies that enable the construction of stereochemically rich scaffolds and (b) to achieve the concise chemical syntheses of naturally occurring small molecules that possess intricate chemical structures. The synthesis of complex small molecules continues to be a vital area of research. In fact, most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past three decades. Additionally, it should be emphasized that natural products serve as valuable leads for the ultimate discovery of new medicines, in addition to inspiration for the development of new synthetic strategies and methods. However, one of the key challenges we now face is uncovering reliable means to construct ever more complex architectures, but with increased efficiency and predictability. This proposal is focused on the development of methodology that will allow chemists to harness transiently generated strained intermediates, such as arynes, heterocyclic alkynes, and heterocyclic allenes, in order to efficiently build complex molecular scaffolds. More specifically, we propose an enamine arylation/alkenylation reaction to establish quaternary stereocenters, in addition to three component couplings, which should allow for the formation of up to two new bonds and two sp3 centers. Next, the use of uncommon and highly reactive heterocyclic allenes to assemble complex architectures through the introduction of up to two new bonds and three sp3 centers is described. Preliminary results demonstrate the feasibility of the proposed methodologies. In the final section, we propose a concise and ambitious total synthesis of acantholactone, a member of the manzamine family of alkaloids that has yet to be synthesized. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.

项目总结/摘要 本申请的中心目标是：（a）开发新的、可靠的、 有效的方法，使立体化学丰富的支架的建设 和（B）实现天然存在的小分子的简明化学合成 具有复杂化学结构的分子。复杂小分子的合成 分子仍然是一个重要的研究领域。事实上，大多数药物在 市场上的大多数药物都是通过有机合成制备的，包括所有新药中的绝大多数。 在过去的三十年里已经变得可用。此外，它应该是 强调天然产品是最终发现的有价值的线索， 新药物，除了启发新的合成策略的发展， 和方法然而，我们现在面临的一个关键挑战是发现可靠的 意味着构建更复杂的架构，但效率更高， 可预测性 这项建议的重点是制定方法， 化学家利用瞬时产生的应变中间体，如芳炔， 杂环炔和杂环联烯，以有效地构建复合物 分子支架更具体地说，我们提出了烯胺芳基化/烯基化 除了三种组分外，还可以通过反应建立季立体中心 耦合，这应该允许形成多达两个新的键和两个sp3 中心.接下来，使用不常见的和高反应性的杂环联烯， 通过引入最多两个新键组装复杂的架构， 描述了三个sp3中心。初步结果表明， 提出的方法。在最后一节中，我们提出了一个简洁而雄心勃勃的总数， 五加内酯的合成，五加内酯是曼扎明生物碱家族的一员，具有 尚未合成。我们的研究结果应该会导致强有力的新战略 以及获取各种重要分子的工具，包括天然产品， 药