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.

项目总结/摘要 手性β-氨基功能化的分子是常见的基序，经常出现在各种饱和杂环中 重要的药物分子。它们也是有机合成中普遍存在的手性结构单元， 例如，广泛用于不对称催化的手性恶唑啉基配体。功能 这些分子的重要性使得它们的合成一直处于高需求中。烯烃双官能化 代表了一个高度模块化的战略，对这些结构的基序作为基准，由可敬的 由Sharpless及其同事开发的锇催化方案。然而，仍然存在重大挑战 对于这类反应。该计划的主要目标是开发新型催化烯烃 双官能化，这将满足这些挑战的需求，并加快获得手性β-氨基 功能化的图案。具体而言，该提案将引入卤和高价碘催化， 平台，以解决这些反应中经常遇到的区域化学和对映选择性的挑战。 根据可靠的初步数据，拟议的研究将使我们能够：1）证明 用一系列双官能亲核试剂进行卤催化中区域化学控制的亲核控制; 2） 利用高价碘催化剂作为烯烃双官能化中区域控制的新元素;和3） 采用手性高价碘催化剂进行不对称诱导反应。我们的建议是 通过引入几种区域控制手段和基于单一 基本步骤。此外，这些方法使用简单且普遍存在的双官能试剂，例如酰胺， 脲、氨基甲酸酯等用于烯烃双官能化。最后，实现拟议战略将使 手性β-氨基官能化基序的直接合成。