Development of New Catalytic Reactions for Chemical Synthesis

 发明用于化学合成有机小分子的新的催化方法是现代有机化学的一个重要目标，因为它对于有效地制造药剂是必不可少的。一类反应 已被证明具有重大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。然而，尽管取得了进展，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。此外，这些过程的立体选择性变体甚至更加罕见，存在着更大的障碍。本申请中描述的研究试图通过引入交叉偶联反应来为这些问题提供创新的解决方案，该交叉偶联反应利用从简单烯烃原位催化生成的CSP3-亲核剂。我们开发这些反应的基本原理是，容易获得的原料(烯烃、二硼试剂和有机卤化物)将转化为合成多种用途的产品，这些产品可以很容易地操纵成各种具有生物意义的分子。我们实验室收集的初步数据为我们拟议的研究的成功提供了极其令人鼓舞的信息。在我们的计划的第一部分，我们将介绍钯催化的有机卤化物与亲核的Csp3-Cu-络合物的交叉偶联的方法，该偶联是通过CuBpin络合物在烯烃上的迁移插入而原位生成的。这些反应将为化合物提供独特的高效和模块化的方法，这些化合物很容易映射到各种已知的生物相关分子上。在我们第二阶段的研究中，将开发这些反应的立体选择性(包括非对映选择性和对映选择性)变体。这样的过程将允许在一次操作中产生多达三个新的立体中心。最后，这项反应发展的练习将通过探索新的交叉耦合范例来介绍化学合成中的新概念和新策略。

 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.