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: 8155084
• 负责人: JOHN P WOLFE
• 金额: $ 28.07万
• 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/8155084
• 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; Phosphorous; 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health, because these studies will lead to new methods for the synthesis of medicinally relevant compounds. These new synthetic methods will provide access to biologically active molecules that cannot be prepared using existing chemical transformations, which will be of great utility for the development of new pharmaceuticals that are beneficial to human health.

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，因为许多具有生物活性的天然分子含有这些亚基。尽管开发构建杂环的方法一直是人们长期关注的问题，但许多重要的靶标很难利用现有的转化以立体选择性的方式产生。此外，许多方法不容易适用于从单一前体制备许多类似物。我们的研究计划的长期目标是开发新的反应，以构建对映异构富集，生物活性的杂环。本研究的目标是开发新的烯烃碳杂化反应，用于合成几种特定类型的生物相关杂环，并为不对称碳杂化反应开发新的催化剂，这是我们实现长期目标的重要一步。这些目标将通过追求三个具体目标来实现：(1)开发新的烯烃碳杂化反应，以构建复杂的双环杂环；(2)开发新的不对称烯烃碳杂化反应；(3)开发新的烯烃碳杂化反应，用于对映选择性合成具有缩醛或动物立体中心的分子。这三个目标都涉及到发明新型pd催化的芳基/烯基卤化物与含垂坠烯烃的胺/醇的反应。这些反应将在一步中形成两个键和两个立体中心，以高效和立体选择性的方式生成所需的杂环，并将应用于合成具有生物学意义的靶标。提出的研究具有创新性，因为它们将引领新的战略层面的分离，可以应用于工业和学术界各种化学家的复杂分子合成。此外，这些研究将扩展烯烃碳杂化过程的前沿，并将提供对可用于控制这类重要转化中的不对称诱导的因素的见解。所获得的知识可用于未来开发其他新反应。拟议的研究意义重大，因为在这些研究中开发的新转化将为现有方法难以产生的重要生物活性化合物提供便利。这将扩大可用于药物化学/药物开发的杂环构建块的范围。此外，这些新的转化也将允许容易地产生感兴趣的分子的类似物，这可以用来优化先导化合物的生物或药物性质。