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.

项目概要/摘要 该应用程序的中心目标是：(a) 开发新的、可靠的、 能够构建富含立体化学的支架的高效方法 (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 市场上的药物都是通过有机合成制备的，包括绝大多数新药 这些都是在过去三十年中出现的。另外，应该是 强调天然产物是最终发现的宝贵线索 新药，以及开发新合成策略的灵感 和方法。然而，我们现在面临的关键挑战之一是发现可靠的 意味着构建更加复杂的架构，但效率更高， 可预测性。 该提案的重点是开发方法，使 化学家利用瞬时产生的应变中间体，例如芳炔， 杂环炔烃和杂环丙二烯，以有效构建复杂的 分子支架。更具体地说，我们提出了烯胺芳基化/烯基化 除三个组分外，还建立四元立构中心的反应 耦合，应允许形成最多两个新键和两个 sp3 中心。接下来，使用不常见且高反应性的杂环丙二烯 通过引入最多两个新键来组装复杂的架构 描述了三个sp3中心。初步结果证明了该方案的可行性 提出的方法。在最后一部分，我们提出了一个简洁而雄心勃勃的总体方案 棘内酯的合成，棘内酯是生物碱曼扎明家族的成员，具有 尚待合成。我们的研究结果应该会带来强有力的新策略 以及获取各种重要分子的工具，包括天然产物和 药物。