Selective Functionalization of Aliphatic Amines and Derivatives

项目摘要 现代药物发现要求对日益复杂的物质进行快速和模块化的组装。 与医学相关的分子绝大多数带有氮功能，1086个FDA中的910个小分子 分子药物至少含有一个N原子。在零售额排名前200位的药品(2012)中，73%是小型药品- 以分子为基础。在这些化合物中，67%含有脂肪胺，其定义是含有不属于杂环或 苯胺系。直接在C-H键上官能化单胺基前驱体是一个重要的问题。 这份提案描述了几种旨在解决这一问题的战略，这些战略相互补充 实现这一目标的战略。由此产生的产品将加快药物发现的步伐， 从抗生素、抗抑郁剂等多种生物活性物质中可见的常见基序 其他。本研究的具体目标如下： 1)制定了通过1，5氢原子转移对胺进行δ官能化的统一协议； 2)利用氮素上不同的导向基团实现互补的位置选择性； 3)通过钴和光氧化还原催化的合并来扩大自由基对。 这门科学的长期影响是使化学家能够快速组装具有高密度的复杂结构 效率。

Project Summary Modern drug discovery mandates the rapid and modular assembly of increasingly complex substances. Medicinally relevant molecules overwhelmingly bear nitrogen functionality with 910 of 1086 FDA small molecule drugs contain at least one N-atom. Of the Top 200 drugs by retail sales (2012), 73% are small- molecule based. Of these, 67% bear an aliphatic amine defined as having nitrogen not part of a heterocycle or aniline system. Functionalizing simple amine based precursors directly at C-H bonds is a significant problem. This proposal describes several strategies aimed at addressing this problem relying o complementary strategies to achieve the goal. The resultant products will facilitate the pace of drug discovery, with the common motifs visible in biologically active agents ranging from antibiotics, antidepressants among many others. The specific goals of this research are as follows: 1) Develop a unified protocol for δ functionalization of amines by 1,5 hydrogen atom transfer; 2) Exploit different directing groups on nitrogen to achieve complementary site selectivity; 3) Expand radical couples by merging cobalt and photoredox catalysis. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.