Exploiting Unconventional Building Blocks in Chemical Synthesis

在化学合成中利用非常规构件

• 批准号: 10560628
• 负责人: NEIL K GARG
• 金额: $ 58.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560628
• 关键词: Alkynes; Amides; Area; Catalysis; Chemical Structure; Complex; Development; Intercept; Marketing; Medicine; Methodology; Methods; Molecular; Natural Products; Nickel; Organic Synthesis; Periodicity; Preparation; Research; Structure; Variant; chemical synthesis; functional group; novel therapeutics; propadiene; scaffold; small molecule; tool

Project Summary/Abstract The central objective of this application is to harness unconventional synthetic building blocks for the development of new, reliable, and efficient, methodologies. These methodologies are intended to enable the construction of stereochemically rich scaffolds, including those seen in naturally occurring small molecules and medicines. The development of new methods and the syntheses of complex small molecules continues to be vital areas of research. 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. The chemical structures of new drug entities are becoming increasingly complex, now often bearing sp3 centers rather than “flat” structures. This has led to an increased need for chemists to develop new methods that can reliably build intricate structures. The two unconventional building blocks we seek to harness in the proposed studies are amides and strained cyclic alkynes and allenes. Regarding amides, the C–N bond of amides has long been viewed as stable, such that synthetic methodologies that rely on C–N bond cleavage have remained limited. We seek to develop methods that utilize nickel catalysis to harness amide functional groups as synthons. We propose to assemble important linkages with defined stereocenters, including quaternary stereocenters, using catalysis and chemoenzymatic methods. These efforts provide new opportunities in the area of strong bond activation by nickel catalysis, along with new tools for the manipulation of amides via C–N bond cleavage. With regard to strained cyclic alkynes and allenes, we seek to intercept these transient, highly reactive species to efficiently build complex molecular scaffolds. Such methods should allow for the establishment of scaffolds bearing two new bonds and three sp3 centers. Enantiospecific and catalytic enantioselective variants will be targeted. Our methodologies will be evaluated in the context of several synthetic endeavors. 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 该应用的核心目的是利用非常规合成 开发新，可靠和高效的方法的基础。 这些方法旨在实现立体化学上丰富的构建 脚手架，包括在天然存在的小分子和药物中看到的脚手架。 新方法的发展和复杂小分子的合成 继续是研究的重要领域。市场上大多数医疗代理商是 由有机合成制备，包括所有具有的新药 在过去的三十年中可用。新药的化学结构 实体变得越来越复杂，现在通常带有SP3中心而不是 “平坦”结构。这导致化学家的需求增加了 可以可靠地构建复杂结构的方法。 我们寻求在拟议中利用的两个非常规的构件 研究是酰胺和紧张的环状炔烃和艾伦斯。关于酰胺，C – N 酰胺的键长期以来一直被视为稳定，因此合成方法 依靠C – N键裂解仍然有限。我们寻求开发方法 利用镍催化剂到利用酰胺官能团作为合成子。我们建议 与定义的立体中心组装重要的联系，包括第四纪 立体中心，使用催化和化学酶方法。这些努力提供了 通过镍催化激活牢固债券激活的新机遇，以及 通过C – N键裂解来操纵酰胺的新工具。关于 紧张的环状炔烃和艾伦斯，我们试图拦截这些短暂的，高反应的 物种有效地建立复杂的分子支架。这样的方法应允许 建立带有两个新债券和三个SP3中心的脚手架。 对照特异性和催化对映选择性变体的目标。我们的 方法将在几个合成努力的背景下进行评估。 我们的研究结果应导致强大的新策略和工具用于访问 各种重要的分子，包括天然产品和药物。