Development of New Catalytic Reactions for Chemical Synthesis

化学合成新催化反应的进展

• 批准号: 8861869
• 负责人: Michael Kevin Brown
• 金额: $ 28.02万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8861869
• 关键词: Affect; Alkenes; Catalysis; Complex; Coupling; Data; Development; Drug Industry; Evaluation; Exercise; Generations; Goals; Health; Human; In Situ; Investigation; Lead; Literature; Maps; Metals; Methods; Molecular Structure; Organic Chemistry; Outcome; Pharmacologic Substance; Phase; Preparation; Process; Reaction; Reagent; Research; Scheme; Solutions; Styrenes; Transition Elements; Variant; base; catalyst; chemical synthesis; diene; improved; innovation; method development; novel; operation; programs; public health relevance; small molecule; stereochemistry; success

 DESCRIPTION (provided by applicant): The invention of new catalytic methods for chemical synthesis of small organic molecules is a critical objective in modern organic chemistry because it is essential for the efficient manufacture of pharmaceutical agents. One class of reactions that has proven to be of significant utility is metal-catalyzed cross-couplings. These reactions are primarily used for the construction of Csp2-Csp2 bonds. Despite progress, however, cross-coupling of secondary and tertiary Csp3-based nucleophiles is still challenging. Furthermore, stereoselective variants of these processes are even more rare and present even greater obstacles. The studies described in this application seek to provide innovative solutions to these problems through the introduction of cross-coupling reactions that utilize Csp3-nucleophiles catalytically generated in situ from simple alkenes. Our rationale for development of these reactions is that readily available starting materials (alkenes, diboron reagents and organohalides) will be converted to synthetically versatile products that can be easily manipulated to a variety of biologically significant molecules. Preliminary data gathered in our lab are extremely encouraging for success in our proposed studies. In the first part of our program we will introduce methods for Pd-catalyzed cross-coupling of organohalides with nucleophilic Csp3-Cu-complexes generated in situ by migratory insertion of CuBpin complexes across alkenes. These reactions will provide uniquely efficient and modular approaches to compounds that readily map onto a variety of known biologically relevant molecules. In the second phase of our studies, stereoselective (both diastereoselective and enantioselective) variants of these reactions will be developed. Such processes will allow for up to three new stereogenic centers to be generated in a single operation. Finally, this exercise in reaction development will introduce new concepts and strategies in chemical synthesis by exploring new cross-coupling paradigms.

 描述（由申请人提供）：发明用于化学合成小有机分子的新催化方法是现代有机化学中的关键目标，因为它对于有效制造药剂是必不可少的。一类反应， 已被证明具有重要实用性的是金属催化的交叉偶联。这些反应主要用于构建Csp 2-Csp 2键。然而，尽管取得了进展，基于Csp 3的二级和三级亲核试剂的交叉偶联仍然具有挑战性。此外，这些过程的立体选择性变体甚至更罕见，并且存在甚至更大的障碍。本申请中描述的研究试图通过引入交叉偶联反应来提供这些问题的创新解决方案，所述交叉偶联反应利用由简单烯烃原位催化产生的Csp 3-亲核试剂。我们开发这些反应的基本原理是，容易获得的起始材料（烯烃，二硼试剂和有机卤化物）将被转化为合成通用的产品，可以很容易地操纵到各种生物学上重要的分子。在我们实验室收集的初步数据是非常令人鼓舞的成功，在我们提出的研究。在我们的计划的第一部分中，我们将介绍Pd催化的交叉偶联的有机卤化物与亲核Csp 3-Cu-络合物原位生成的迁移插入的CuBpin络合物跨越烯烃的方法。这些反应将为化合物提供独特有效和模块化的方法，这些方法容易映射到各种已知的生物学相关分子上。在我们研究的第二阶段，将开发这些反应的立体选择性（非对映选择性和对映选择性）变体。这样的过程将允许在单个操作中产生多达三个新的立体中心。最后，这个反应发展的练习将通过探索新的交叉偶联范例来引入化学合成中的新概念和策略。