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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：高效合成含氮、含氟化合物新方法的发现与发展化学构件是有机合成中的一个重要目标，因为大量的药物和其他生物活性分子在一系列不同的化学官能团中包含这些原子。更快和/或选择性地组装已知的基序，而且还需要准备新的化学景观药物类支架的创新方法，包括发现新的试剂和新的催化剂战略。该项目目前的目标分为三个主要重点领域。1)我们将开发2-氮三烯，这是一种新的类别烯胺试剂，用于手性胺的各种催化对映体选择性方法。将开发的代表性反应包括6，3-，6，5-和5，6-氢官能化，包括与羰基和亚胺的还原偶联、氢炔化反应和氢芳基化反应。生成氮二烯氮三烯试剂的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，从而提供了一条非对映发散途径，实现高度通过顺序催化合成复杂的手性胺。2)我们将在先前的对映选择性工作的基础上进行扩展本实验室开发的第一类烯胺类试剂2-氮二烯的转化。例子包括与芳香族杂环的还原偶联，如喹啉N-氧化物，催化与4，4-二氟-2-氮二烯的不对称对映体官能化，级联脱对称反应，和约化的[3+2]-环加成反应。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中损失卤化物或从二氟甲基中提取氢原子至在许多环境中提供二氟化碳。在一种情况下，我们将进行硼化或对映体选择性 3-三氟甲基吡啶支架的烷基化反应合成具有重要药用价值和高度功能化的3-三氟甲基吡啶 (二氟甲基)吡啶。在另一个领域，我们将执行4-的自由基氢原子抽象二氟甲基-2-氮杂二烯提供二氟-2-氮杂戊二烯基，然后可以参与催化交叉偶联以提供含有二氟烯烃单元的手性烯丙基胺。总之，这些承诺将使药物发现的新化学空间变得容易和与简单的试剂相比，差异很大。我们将更快地访问更多已建立的含N基序，并通过由于新试剂的发明，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奇的反应性。