New Methods for the Synthesis of Carbocycles and Heterocycles

碳环和杂环合成新方法

• 批准号: 9922950
• 负责人: JOHN P WOLFE
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922950
• 关键词: Air; Alkenes; Area; Biological; Carbon; Catalysis; Chemicals; Coupling; Development; Esters; Future; Generations; Goals; Health; Heterocyclic Compounds; Human; Knowledge; Lead; Metals; Methods; Natural Products; Nature; Nitrogen; Organic Synthesis; Palladium; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Procedures; Property; Public Health; Reaction; Reagent; Research; Solvents; Structure; Styrenes; analog; catalyst; drug development; enolate; experimental study; innovation; insight; interest; method development; programs; stereochemistry; user-friendly

Project Summary The stereoselective construction of saturated heterocycles and carbocycles remains an important challenge in organic synthesis, as many pharmaceutically relevant molecules and biologically active natural products contain these subunits. Although the development of methods for the construction of heterocycles and carbocycles has been of longstanding interest, a number of important targets are difficult to generate in a stereoselective manner using existing transformations. In addition, many methods are not readily amenable to the preparation of numerous analogs from a single precursor. The long-term goal of our research program is to develop new reactions for the construction of enantiomerically enriched, biologically active molecules. The objectives of the research outlined in this proposal, are to develop new alkene difunctionalization reactions for the construction of useful heterocycles and carbocycles, to develop new catalysts for alkene difunctionalization reactions, and to gain insight into factors that facilitate alkene heteropalladation and sp3C–N bond-forming reductive elimination. These objectives will be achieved by pursuing two specific aims: (1) to prepare functionalized carbocycles via alkene difunctionalization reactions between alkenes bearing pendant carbon-centered electrophiles and exogenous nucleophiles; and (2) to prepare substituted heterocycles via alkene difunctionalization reactions that employ nitrogen-centered electrophiles. The proposed studies are innovative because they will explore fundamentally new reactivity, such as the use of allylic electrophiles, nitrogen-centered electrophiles, or chiral enamine nucleophiles in Pd-catalyzed alkene difunctionalization reactions. Our experiments will result in new catalysts that facilitate challenging anti-heteropalladation reactions of hindered alkenes, which have been implicated as key steps in other synthetically useful transformations. These studies will also provide insight into factors that facilitate sp3C–N bond-forming reductive elimination from Pd(II), which is a rare step in catalysis, but has the potential to be broadly used as a key step in new reactions that lead to C–N bond formation. This knowledge will be of significant utility in the future development of other new palladium-catalyzed transformations. The proposed research is significant because the new transformations developed during these studies will provide access to important biologically active compounds that are difficult to generate with existing methods. This will broaden the range of carbocyclic and heterocyclic building blocks available for use in medicinal chemistry/drug development. In addition, these new transformations will also allow for facile generation of analogs of interesting molecules, that differ in either their stereochemistry or in the nature of their substituents, which can be used to optimize biological or pharmaceutical properties of lead compounds.

项目摘要 饱和杂环和碳环的立体选择性结构仍然是一个重要的 有机合成中的挑战，因为许多与药物相关的分子和生物活性天然 产品中含有这些亚单位。尽管杂环构筑方法的发展 和碳环一直是人们感兴趣的，许多重要的目标很难在 使用现有变换的立体选择性方式。此外，许多方法并不容易服从。 从一个单一的前体制备许多类似物。 我们研究计划的长期目标是为建设 富含对映体的生物活性分子。本研究概述的研究目标 建议开发新的烯烃双官能化反应，用于构建有用的杂环 和碳环，以开发用于烯烃双官能化反应的新催化剂，并深入了解 促进烯烃杂化和Sp3c-N成键还原消除的因素。这些 目标将通过追求两个具体目标来实现：(1)通过烯烃制备官能化碳环 含碳侧链的烯烃与外源亲电试剂的双官能化反应 以及(2)通过烯烃双官能化反应制备取代杂环，该反应使用 以氮为中心的亲电体。 拟议的研究具有创新性，因为它们将从根本上探索新的反应性，例如 烯丙基亲电剂、氮心亲电剂或手性烯胺亲核剂在钯催化中的应用 烯烃双官能化反应。我们的实验将产生新的催化剂，以促进挑战 受阻碍的烯烃的反杂多反应，这已被认为是其他 综合有用的变换。这些研究还将提供对促进Sp3c-N的因素的洞察 Pd(II)的成键还原消除，这是催化中罕见的一步，但有可能成为 广泛用作导致C-N键形成的新反应的关键步骤。这一知识将是 在其他新的钯催化转化的未来开发中具有重要的作用。 拟议的研究具有重要意义，因为在这些研究期间开发的新转型将 提供用现有方法难以产生的重要生物活性化合物的途径。 这将扩大可用于医药的碳环和杂环构建块的范围 化学/药物开发。此外，这些新的转换还将允许轻松生成 感兴趣的分子的类似物，它们在立体化学或性质上不同 取代基，可用于优化先导化合物的生物或药学性能。