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.

项目摘要/摘要 本应用程序的主要目标是：（a）开发新的，可靠的，并且 有效的方法论，可以构建立体化学上丰富的脚手架 （b）实现天然发生的小型化学合成 具有复杂化学结构的分子。复杂小的合成 分子仍然是研究的重要领域。实际上，大多数药物 市场是由有机合成制备的，包括所有新药中的绝大多数 在过去的三十年中，这些产品已被销售。另外，应该是 强调天然产品是最终发现的宝贵线索 除了开发新合成策略的灵感外，新药物 和方法。但是，我们现在面临的主要挑战之一是揭露可靠的 构建越来越复杂的架构的手段，但效率提高和 可预测性。 该提案的重点是方法，该方法将允许 化学家暂时生成的扭曲中间体，例如Arynes， 为了有效地建造复合物 分子支架。更具体地说，我们提出了一个谜芳基化/烷基化 除了三个成分之外，要建立第四纪立体中心的反应 耦合，应允许形成多达两个新键和两个SP3 中心。接下来，使用不常见和高反应性杂环艾伦 通过引入多达两个新债券来组装复杂的体系结构， 描述了三个SP3中心。初步结果证明了 建议的方法。在最后一节中，我们提出了一个简洁而雄心勃勃的总体 acantholactone的合成，这是有生物碱家族的成员 尚未合成。我们的研究结果应导致强大的新策略 以及用于访问各种重要分子的工具，包括天然产品和 药物。