Development of New Catalytic Reactions for Chemical Synthesis

化学合成新催化反应的进展

基本信息

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
项目类别：
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

项目摘要

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）：用于化学合成小有机分子的新催化方法的发明是现代有机化学的一个关键目标，因为它对于药物制剂的有效制造至关重要。已被证明具有重要用途的是金属催化的交叉偶联，这些反应主要用于构建 Csp2-Csp2 键，但尽管取得了进展，但基于 Csp3 的二级和三级亲核试剂的交叉偶联仍然具有挑战性。这些过程的立体选择性变体更加罕见，并且存在更大的障碍，本申请中描述的研究试图通过引入利用交叉偶联反应来为这些问题提供创新的解决方案。由简单烯烃原位催化生成 Csp3-亲核体我们开发这些反应的基本原理是，将容易获得的起始材料（烯烃、二硼试剂和有机卤化物）转化为可轻松操作的各种具有生物学意义的合成多功能产品。我们实验室收集的初步数据对于我们拟议研究的成功非常令人鼓舞。在我们计划的第一部分中，我们将介绍 Pd 催化交叉偶联的方法。通过在烯烃上迁移插入 CuBpin 复合物而原位生成有机卤化物与亲核 Csp3-Cu 复合物，这些反应将为化合物提供独特的有效和模块化方法，这些化合物很容易映射到各种已知的生物学相关分子上。研究中，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反应中产生多达三个新的立体中心。最后，反应开发的这一练习将通过探索新的交叉偶联范式引入化学合成中的新概念和策略。