Selective Functionalization of Aliphatic Amines

首席调查员/项目主任(最后、第一、中间)：ROVIS，Tomislav 脂肪胺及其衍生物的选择性官能化 脂肪胺在药物化合物中普遍存在，推动了对 含氮分子的合成与官能化。传统策略使用官能团 合成胺的手柄。我们一直在进行一项使用常驻C-H键的研究计划 并将它们直接转换为感兴趣的功能。胺衍生物的主要挑战是， 因此，是一种位置选择性。在上一个供资期间提出了一些战略 取得了广泛的成功。 在下一个资助期，我们将扩大反应曲目、激活位置和 对现有方法的补充。我们将开发方法来芳基化脂肪胺中的C-H键，以 类似于烯烃去官能化，邻位C-H键去官能化，同样是完全位置去官能化 选择性和使用稀土丰富的金属盐来激活胺的远端C-H键。互补性 方法的目的是提供一种使叔胺上不可访问的C-H键官能化的方法， 许多FDA批准的药物的共同成分。这些将允许复杂的结构多样化 以及为生物活性分子提供同源支架的结构编辑方法。 最后，伯胺的存在范围之广令人惊讶，远远超过了卤代烃，甚至是羧酸。 酸，无疑是由于酰胺键结构的普遍存在和重要性。我们将开发一种 在交叉偶联化学中使用C-N键作为官能团处理的补充策略。 所有这些方法都旨在促进药物设计和发现，以追求更有效的药物 人类疾病的治疗方法。 本研究的具体目标如下： 1)脂肪胺的位置选择性远程官能化 2)叔烷基胺的选择性α官能化 3)伯胺的脱氨基功能化 PHS 398/2590(09/04版)页面续格式页面

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav Selective Functionalization of Aliphatic Amines and Derivatives Aliphatic amines are ubiquitous among pharmaceutical compounds, driving significant research into the synthesis and functionalization of molecules bearing nitrogen atoms. Traditional strategies use functional group handles to synthesize amines. We have been engaged in a research program that uses resident C-H bonds and transforms them directly into the functionality of interest. The central challenge to derivatizing amines, thus, was one of positional selectivity. A number of strategies were advanced in the previous funding period with broad success. In the next funding period, we will expand the repertoire of reactions, the positions of activation and the complementarity to existing methods. We will develop methods to arylate C-H bonds in aliphatic amines, to difunctionalize vicinal C-H bonds in analogy to olefin difunctionalization, again with complete positional selectivity and to use earth abundant metal salts to activate distal C-H bonds of amines. Complementary approaches will be aimed at providing a method to functionalize inaccessible C-H bonds on tertiary amines, common components of many FDA approved drugs. These will allow structural diversification of complex molecules as well as a structural editing approach to provide homologous scaffolds to bioactive molecules. Lastly, primary amines are surprisingly widely available, far more so than alkyl halides or even carboxylic acids, no doubt due to the ubiquity and importance of amide bond constructions. We will develop a complementary strategy that will use the C-N bond as a functional group handle in cross-coupling chemistry. All of these methods are designed to facilitate drug design and discovery in the pursuit of more efficacious treatments for human diseases. The specific goals of this research are as follows: 1) Site-Selective Remote Functionalization of Aliphatic Amines 2) Selective α-Functionalization of Tertiary Alkylamines 3) Deaminative Functionalization of Primary Amines PHS 398/2590 (Rev. 09/04) Page Continuation Format Page