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）的项目摘要：发现和开发新方法，用于有效合成含N 化学构建块是有机合成的重要目标，作为大量药物和其他生物活性分子在化学官能团的潜水员组中包含这些原子。更快此外类似药物脚手架的创新方法，包括发现新试剂和新催化剂/催化剂策略。该项目的当前目标属于三个主要重点领域。 1）我们将开发2个新颖的课程用于手性胺的无数催化对映选择性方法。将要开发的代表性反应包括6,3-，6,5-和5,6-Hydrodunctifactizations 与羰基和亚胺，水烷基化和氢化的还原耦合。 azadienes产生了在无数的下游，可以利用6,5-和5,6-甲状腺试剂的6,5-氢功能化。反应（包括其他催化过程复杂的手性胺通过顺序催化剂。 2）我们将扩展我们先前在对映选择性方面的工作 2-扎丁的转变，这是我们实验室中开发的一流的搪瓷umpolung试剂。例子包括与芳香族杂环的耦合减少，例如喹啉N-氧化物，催化用4,4-二氟-2-azadienes，级联反应反应，对映射性荧光功能化，并减少[3+2] -Cycloaditions。 3）我们将发展催化远程CC和C – B耦合反应导致从三氟甲基群中丧失了卤化物或从二氟甲基到的H原子抽象到在许多设置中传递Difluorocarbons。在一种情况下，我们将执行Borylation或对映选择性 3-三氟甲基吡啶支架的烷基化，以产生具有药物重要和高度功能化的3- （二氟甲基）吡啶。在另一个区域，我们将执行4--的自由基氢原子抽象二氟甲基-2-氮糖丁可提供difluoro-2- azapentadadideenyl自由基，然后可以参与其中催化交叉耦合以提供带有差异单元的手性的全能胺。这些事业将共同使新的化学空间可轻松获得药物发现的新化学空间简单试剂的巨大多样性。我们将更快地，与与已知方法相比，与已知方法相比，区域/立体控制的水平更高以及它们体现的新颖反应性。