Strategies for the Catalytic Synthesis of Nitrogen-Containing Molecules

含氮分子的催化合成策略

基本信息

批准号：
10698004
负责人：
Steven Joseph Malcolmson
金额：
$ 38.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-10 至 2027-06-30
项目状态：
未结题

项目摘要

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.

NIH R35 (MIRA) 项目摘要：含氮、含氟高效合成新方法的发现与发展化学构件是有机合成的一个重要目标，因为大量的药物和药物其他生物活性分子在不同的化学官能团中含有这些原子。和/或已知基序的选择性组装，以及新化学景观的制备，需要类药物支架的创新方法，包括发现新试剂和新催化剂/催化策略。该项目当前的目标分为三个主要重点领域：1）我们将开发2-氮杂三烯，一种新的类别。烯胺 umpolung 试剂，用于多种手性胺的催化对映选择性方法。将开发的代表性反应包括 6,3-、6,5- 和 5,6- 氢官能化，包括与羰基和亚胺进行还原偶联、加氢炔基化和氮杂二烯加氢芳基化。氮杂三烯试剂的 6,5- 和 5,6-氢官能化可用于无数下游反应，包括其他催化过程，从而提供了一种非对映发散途径，以实现高度通过顺序催化合成复杂的手性胺 2) 我们将扩展我们之前在对映选择性方面的工作。 2-氮杂二烯的转化，这是我们实验室开发的第一类烯胺umpolung试剂。例子包括与芳香杂环的还原偶联，例如喹啉 N-氧化物、催化 4,4-二氟-2-氮杂二烯的对映选择性氟官能化，级联去对称反应，和还原[3+2]-环加成 3) 我们将开发催化远程 C-C 和 C-B 偶联反应。导致三氟甲基失去卤化物或二氟甲基失去氢原子在一种情况下，我们将进行硼化或对映选择性。 3-三氟甲基吡啶支架的烷基化产生具有医学重要性且高度功能化的3- 在另一个领域，我们将进行 4- 自由基氢原子的抽象。二氟甲基-2-氮杂二烯提供二氟-2-氮杂戊二烯基，然后该基团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胺。总之，这些事业将使药物发现的新化学空间变得容易并具有我们将通过简单的试剂更快地获得更成熟的含氮基序。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的反应性。