Regio- and Enantioselective Alkene Difunctionalizations for the Synthesis of Bioactive Molecules.

用于合成生物活性分子的区域选择性和对映选择性烯烃双官能化。

• 批准号: 10046958
• 负责人: Wei Li
• 金额: $ 45.15万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046958
• 关键词: Adopted; Alkenes; Amides; Amino Alcohols; Benchmarking; Carbamates; Catalysis; Chemicals; Collection; Coupling; Cross-Linking Reagents; Data; Development; Elements; Goals; Iodine; Ligands; Methods; Nitriles; Nitrogen; Organic Synthesis; Osmium; Pharmaceutical Preparations; Pharmacologic Substance; Protocols documentation; Reaction; Solid; Structure; Urea; base; catalyst; chemical reaction; cycloaddition; design; drug candidate; drug discovery; drug production; innovation; invention; novel; programs; public health relevance

Project Summary/Abstract Chiral β-amino functionalized molecules are common motifs often found in a variety of saturated heterocycles of important drug molecules. They are also ubiquitous chiral building blocks in organic synthesis to access, for example, chiral oxazoline-based ligands that are broadly useful in asymmetric catalysis. The functional importance of these molecules renders their syntheses continuously in high demand. Alkene difunctionalization represents a highly modular strategy towards these structural motifs as benchmarked by the venerable osmium-catalyzed protocols developed by Sharpless and coworkers. However, significant challenges remain for this class of reactions. The main objective of this program is to develop new classes of catalytic alkene difunctionalizations that will meet the demands of these challenges and expedite access to chiral β-amino functionalized motifs. Specifically, this proposal will introduce halonium and hypervalent iodine catalysis as platforms to resolve the regiochemical and enantioselective challenges often encountered in these reactions. Based on solid preliminary data, the proposed studies will enable us to: 1) demonstrate the feasibility of nucleophile-control for regiochemical control in halonium catalysis with a range of bifunctional nucleophiles; 2) utilize hypervalent iodine catalysts as a new element for regiocontrol in alkene difunctionalizations; and 3) adopt chiral hypervalent iodine catalyst for asymmetric induction of the reactions proposed. Our proposal is innovative by introducing several means of regiocontrol and asymmetric induction based on a single elementary step. Additionally, these methods use simple and ubiquitous bifunctional reagents such as amide, urea, carbamate, etc. for alkene difunctionalizations. Finally, realization of the proposed strategy will enable straightforward synthesis of chiral β-amino functionalized motifs.

项目摘要/摘要 手性β-氨基功能化分子是常见的基序，通常在多种饱和杂环中发现 重要的药物分子。它们也是有机合成中无处不在的手性构建块，用于 例如，在非对称催化中广泛有用的手性黄唑啉基配体。功能 这些分子的重要性使它们的合成在高需求中不断。烯烃进行的烯烃 代表了针对这些结构基序的高度模块化策略，如尊贵的基准 Sharpless及其同事制定的Osmium催化协议。但是，仍然存在重大挑战 对于这类反应。该计划的主要目的是开发新的催化烯烃类 可以满足这些挑战需求并加快手性β-Amino的要求的功能化化 官能化基线。特别是，该提案将引入卤素和高价值碘催化作用 解决这些反应经常遇到的水平化学和对映选择性挑战的平台。 基于稳定的初步数据，拟议的研究将使我们能够：1）证明 核对手控制，用于与一系列双功能核亲核试剂的葡萄膜催化中的水平对照； 2） 利用高价值的碘催化剂作为烯烃可进行的重新控制的新元素； 3） 采用手性高价值碘催化剂，以不对称诱导提出的反应。我们的建议是 通过引入几种基于单一的giocontrol和不对称感应方式来创新 基本步骤。此外，这些方法使用简单且普遍存在的双功能试剂，例如酰胺， 尿素，氨基甲酸酯等，用于烯烃连接性化。最后，实现拟议策略将使 手性β-氨基功能化基序的直接合成。