Development of New Stereoselective Metal-Catalyzed Organic Reactions

新型立体选择性金属催化有机反应的发展

• 批准号: 9266600
• 负责人: Simon John Meek
• 金额: $ 9.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266600
• 关键词: Address; Alcohols; Alkenes; Alkylation; Amines; Biological; Boron; Carbon; Characteristics; Chemical Structure; Chemicals; Complex; Coupling; Development; Electrons; Elements; Goals; Healthcare; Human; Lead; Metals; Methods; Molecular; Molecular Structure; Outcome; Pharmacologic Substance; Preparation; Process; Protocols documentation; Reaction; Reagent; Research; Route; Technology; Therapeutic Agents; Work; base; butyrolactone; carbene; catalyst; chemical reaction; chiral molecule; diene; functional group; improved; next generation; pi bond; programs; public health relevance; scaffold; small molecule

 DESCRIPTION (provided by applicant): Our ability to synthesize carbon-carbon bonds is integral to accessing the important biological activity of myriad organic molecules. Many valuable therapeutic agents exist in non-racemic form comprised of multiple stereogenic elements. Such characteristics highlight the critical need for new chemical reactions that allow chemists to efficiently prepare organic compounds with high levels of selectivity. The focus of this research program involves the development of new stereoselective metal-catalyzed processes for carbon-carbon bond formation via the addition of 1,1-bimetallic nucleophiles to a number of classes of electrophiles. These studies will lead to strategically alternative C-C bond disconnections that deliver important functional molecules in enantiomerically pure form. Many of the reactions described herein do not have existing catalytic protocols. (1) We will develop practical and robust Cu-catalyzed enantio-and diastereoselective alkylations of carbonyls and their derivatives with alkyl boron-containing reagents; these reactions will lead to the synthesis of a range of acyclic hydroxy- and amino-boronates that cannot be easily accessed by others methods. The value of these methods is increased by the installation of a highly versatile stereogenic C-B bond. (2) We will develop general enantioconvergent Cu-catalyzed processes for the addition of a range of alkyl-, alkenyl-, aryl-, allyl- substituted 1,1-heterobimetallic nucleophiles to electron-deficient alkenes. This reaction technology will lead to more efficient ways to synthesize homoallyl alcohols and amines common chemical structures found in bioactive molecules. (3) Reaction development will also demonstrate that 1,1-bimetallic reagents offer unique approaches to substrate-directed stereoselective catalytic reactions. The new catalysts and catalytic methods developed in this program offer unique and selective routes to the enantioselective synthesis of adaptable molecules. Through applications to concise synthesis of pharmacologically active agents, we will demonstrate the utility of our methods, in addition to identifying their limitations.

 描述（由申请人提供）：我们合成碳-碳键的能力对于获取无数有机分子的重要生物活性至关重要。许多有价值的治疗剂以由多种立体元件组成的非外消旋形式存在。这些特性凸显了对新化学反应的迫切需求，使化学家能够以高选择性有效制备有机化合物。该研究计划的重点涉及开发新的立体选择性金属催化工艺，通过将 1,1-双金属亲核试剂添加到多种亲电子试剂中来形成碳-碳键。这些研究将导致战略性地替代C-C键断裂，从而以对映体纯形式提供重要的功能分子。本文描述的许多反应没有现有的催化方案。 (1) 我们将开发实用且稳健的铜催化羰基及其衍生物与烷基含硼试剂的对映和非对映选择性烷基化反应；这些反应将导致一系列无环羟基硼酸酯和氨基硼酸酯的合成，而其他方法无法轻松获得这些硼酸酯。这些方法的价值通过安装高度通用的立体 C-B 键而增加。 (2) 我们将开发通用的对映体铜催化工艺，用于将一系列烷基、烯基、芳基、烯丙基取代的 1,1- 杂双金属亲核试剂加成到缺电子烯烃上。该反应技术将带来更有效的方法来合成生物活性分子中常见的化学结构高烯丙醇和胺。 (3) 反应开发还将证明 1,1-双金属试剂为底物导向的立体选择性催化反应提供了独特的方法。该项目开发的新催化剂和催化方法为适应性分子的对映选择性合成提供了独特的选择性途径。通过应用到药理活性剂的简明合成，我们将展示我们的方法的实用性，同时确定其局限性。