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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）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。