Strategies for the Catalytic Synthesis of Nitrogen-Containing Molecules

NIH R35（MIRA）项目摘要： 含氮、含氟化合物高效合成新方法的发现与发展 化学结构单元是有机合成中的重要目标，因为大量的药物， 其它生物活性分子在一组不同的化学官能团中含有这些原子。更快速 和/或已知基序的选择性组装，以及新化学景观的制备，需要 药物样支架的创新方法，包括发现新试剂和新催化剂/催化剂 战略布局 该项目目前的目标属于三个主要重点领域。1)我们将开发2-氮杂三烯， 的烯胺聚合试剂，无数的催化对映体选择性的方法对手性胺。 将要开发的代表性反应包括6，3-、6，5-和5，6-氢官能化，包括 与羰基和亚胺的还原偶联、氢化炔基化和氢化芳基化。生成的氮杂二烯 从氮杂三烯试剂的6，5-和5，6-氢官能化可以用于无数下游反应中， 反应，包括其他催化过程，从而提供了实现高度非对映异构化的途径。 通过顺序催化来络合手性胺。2)我们将扩展我们以前的工作，在对映选择性 2-氮杂二烯的转化，这是我们实验室开发的第一类烯胺聚合试剂。 实例包括与芳族杂环如喹啉N-氧化物的还原偶联，催化偶联，以及与芳族杂环如喹啉N-氧化物的还原偶联。 用4，4-二氟-2-氮杂二烯的对映选择性氟官能化，级联去对称化反应， 和还原性[3+2]-环加成。3)我们将开发催化远程C-C和C-B偶联反应， 导致从三氟甲基失去卤素或从二氟甲基夺取H原子， 在许多环境中提供二氟碳化合物。在一种情况下，我们将进行硼化或对映选择性 3-三氟甲基吡啶骨架的烷基化，得到医学上重要的和高度官能化的3- （二氟甲基）吡啶。在另一个领域，我们将执行4-甲基-N 二氟甲基-2-氮杂二烯以提供二氟-2-氮杂戊二烯基，其然后可以参与 催化交叉偶联以提供带有二氟烯烃单元的手性烯丙基胺。 总之，这些承诺将使新的化学空间的药物发现容易获得， 从简单的试剂中获得巨大的多样性。我们将更快地访问更多已建立的含N基序， 由于新试剂的发明，与已知方法相比，区域/立体控制水平更高 以及它们所体现的新颖反应性。

Project Abstract for NIH R35 (MIRA): The discovery and development of new methods for the efficient synthesis of N-containing and F-containing chemical building blocks is an important goal in organic synthesis as a large number of pharmaceuticals and other bioactive molecules contain these atoms within a diverse set of chemical functional groups. More rapid and/or selective assembly of known motifs, and moreover the preparation of new chemical landscapes, requires innovative approaches to drug-like scaffolds, including the discovery of new reagents and new catalysts/catalytic strategies. The current goals of this project fall under three main focus areas. 1) We will develop 2-azatrienes, a novel class of enamine umpolung reagents, for myriad catalytic enantioselective approaches towards chiral amines. Representative reactions that will be developed include 6,3-, 6,5- and 5,6-hydrofunctionalizations including reductive couplings with carbonyls and imines, hydroalkynylations, and hydroarylations. Azadienes generated from 6,5- and 5,6-hydrofunctionalizations of the azatriene reagents may be utilized in myriad downstream reactions, including other catalytic processes, thereby providing a diastereodivergent avenue towards highly complex chiral amines through sequential catalysis. 2) We will expand upon our prior work in enantioselective transformations of 2-azadienes, the first class of enamine umpolung reagents developed in our laboratory. Examples include reductive couplings with aromatic heterocycles, such as quinoline N-oxides, catalytic enantioselective fluorofunctionalizations with 4,4-difluoro-2-azadienes, cascade desymmetrization reactions, and reductive [3+2]-cycloadditions. 3) We will develop catalytic remote C–C and C–B coupling reactions that result in the loss of a halide from a trifluoromethyl group or H-atom abstraction from a difluoromethyl group to deliver difluorocarbons in a number of settings. In one case, we will carry out borylation or enantioselective alkylation of a 3-trifluoromethylpyridine scaffold to yield medicinally important and highly functionalized 3- (difluoromethyl)pyridines. In another area, we will execute a radical hydrogen atom abstraction of 4- difluoromethyl-2-azadienes to furnish a difluoro-2-azapentadienyl radical, which then may be engaged in catalytic cross-couplings to furnish chiral allylic amines bearing a difluoroalkene unit. Together, these undertakings will enable new chemical space for drug discovery to be obtained readily and with great diversity from simple reagents. We will access more established N-containing motifs more quickly and with greater levels of regio/stereocontrol compared to known approaches because of the invention of new reagents and the novel reactivity that they embody.