Exploiting Unconventional Building Blocks in Chemical Synthesis

在化学合成中利用非常规构件

• 批准号: 10330994
• 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/10330994
• 关键词: Alkynes; Amides; Area; Catalysis; Chemical Structure; Complex; Development; Intercept; Lead; 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.

项目概要/摘要 该应用的中心目标是利用非常规合成材料 开发新的、可靠的、高效的方法的构建模块。 这些方法旨在能够构建富含立体化学的 支架，包括天然存在的小分子和药物中的支架。 新方法的开发和复杂小分子的合成 仍然是重要的研究领域。市场上销售的大部分药物都是 通过有机合成制备，包括绝大多数新药 在过去的三十年里变得可用。新药化学结构 实体变得越来越复杂，现在通常具有 sp3 中心而不是 “扁平”结构。这导致化学家越来越需要开发新的 可以可靠地构建复杂结构的方法。 我们寻求在提议中利用的两个非常规构建模块 研究领域包括酰胺和紧张的环状炔烃和丙二烯。对于酰胺，C-N 酰胺键长期以来被认为是稳定的，因此合成方法 依赖 C-N 键断裂的方法仍然有限。我们寻求开发方法 利用镍催化作用来利用酰胺官能团作为合成子。我们建议 用定义的立体中心组装重要的连接，包括四元 立体中心，使用催化和化学酶方法。这些努力提供 镍催化强键活化领域的新机遇，以及 通过 C-N 键断裂操作酰胺的新工具。关于 紧张的环状炔烃和丙二烯，我们试图拦截这些瞬态的、高反应性的 物种有效地构建复杂的分子支架。此类方法应允许 建立具有两个新键和三个sp3中心的支架。 对映特异性和催化对映选择性变体将成为目标。我们的 将在多项综合努力的背景下对方法进行评估。这 我们的研究结果应该会带来强大的新策略和工具来获取 各种重要的分子，包括天然产物和药物。