New Alkene Difunctionalization Reactions for Organic Synthesis

用于有机合成的新型烯烃双官能化反应

• 批准号: 8324202
• 负责人: JOHN P WOLFE
• 金额: $ 27.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324202
• 关键词: Academia; Acetals; Alcohols; Alkaloids; Alkenes; Amines; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Biological Factors; Carbon; Chemicals; Complex; Development; Electronics; Esters; Exhibits; Funding; Future; Generations; Goals; Health; Human; Industry; Knowledge; Lead; Ligands; Local Anesthetics; Metals; Methods; One-Step dentin bonding system; Organic Synthesis; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphites; Phosphorus; Positioning Attribute; Preparation; Process; Property; Public Health; Pyrrolidines; Reaction; Relative (related person); Research; Route; Series; Stereoisomer; analog; catalyst; drug development; functional group; innovation; insight; interest; method development; phosphoramidite; pi bond; programs; pyrrolidine; scaffold; stereochemistry; tetrahydrofuran

DESCRIPTION (provided by applicant): The stereoselective construction of saturated heterocycles remains an important challenge in organic synthesis, as many biologically active natural molecules contain these subunits. Although the development of methods for the construction of heterocycles 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 heterocycles. The objectives of the research outlined in this proposal, which represent significant steps toward our long term goal, are to develop new alkene carboheterofunctionalization reactions for the synthesis of several specific classes of biologically relevant heterocycles, and to develop new catalysts for asymmetric carboheterofunctionalization reactions. These objectives will be achieved by pursuing three specific aims: (1) to develop new alkene carboheterofunctionalization reactions for the construction of complex bicyclic heterocycles; (2) to develop new asymmetric alkene carboheterofunctionalization reactions; and (3) to develop new alkene carboheterofunctionalization reactions for the enantioselective synthesis of molecules bearing acetal or aminal stereocenters. All three aims involve the invention of new types of Pd-catalyzed reactions of aryl/alkenyl halides with amines/alcohols bearing pendant alkenes. These reactions will form two bonds and two stereocenters in one step to generate the desired heterocycles in an efficient and stereoselective manner, and will be applied to the synthesis of biologically significant targets. The proposed studies are innovative because they will lead new strategy-level disconnections that can be applied to complex molecule synthesis by a variety of chemists in both industry and academia. In addition, these studies will extend the forefront of alkene carboheterofunctionalization processes, and will provide insight into factors that can be used to control asymmetric induction in this important class of transformations. The knowledge gained can be used for the future development of other new reactions. The proposed research is significant because the new transformations developed during these studies will provide facile access to important biologically active compounds that are difficult to generate with existing methods. This will broaden the range of 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, which can be used to optimize biological or pharmaceutical properties of lead compounds.

描述（由申请人提供）：饱和杂环的立体选择性构建仍然是有机合成中的一个重要挑战，因为许多生物活性天然分子含有这些亚基。尽管杂环构建方法的开发长期以来一直引起人们的兴趣，但许多重要的目标很难利用现有的转化以立体选择性的方式产生。此外，许多方法不容易从单一前体制备大量类似物。我们研究计划的长期目标是开发新的反应来构建对映体富集的、具有生物活性的杂环。该提案中概述的研究目标是开发新的烯烃碳杂官能化反应来合成几种特定类别的生物相关杂环，并开发用于不对称碳杂官能化反应的新催化剂，这代表了我们向长期目标迈出的重要一步。这些目标将通过追求三个具体目标来实现：（1）开发新的烯烃碳杂官能化反应以构建复杂的双环杂环； (2) 开发新型不对称烯烃碳杂官能化反应； (3)开发新的烯烃碳杂官能化反应，用于对映选择性合成带有缩醛或缩醛胺立构中心的分子。所有三个目标都涉及发明芳基/烯基卤化物与带有侧链烯烃的胺/醇的新型钯催化反应。这些反应将一步形成两个键和两个立体中心，以高效、立体选择性的方式生成所需的杂环，并将应用于具有生物学意义的靶标的合成。拟议的研究具有创新性，因为它们将导致新的策略层面的脱节，可以被工业界和学术界的各种化学家应用于复杂的分子合成。此外，这些研究将扩展烯烃碳杂官能化过程的前沿，并将深入了解可用于控制此类重要转化中不对称诱导的因素。获得的知识可用于其他新反应的未来开发。拟议的研究意义重大，因为在这些研究期间开发的新转化将提供容易获得用现有方法难以生成的重要生物活性化合物的途径。这将扩大可用于药物化学/药物开发的杂环结构单元的范围。此外，这些新的转化还将允许轻松生成感兴趣分子的类似物，这些类似物可用于优化先导化合物的生物或药物特性。