Development of Rhodium Catalysts for Alkene Hydroamination

描述(由申请人提供)：在生物活性分子、活性药物成分及其构件中存在的胺是普遍存在的。烯烃氢胺化反应，形式上是在不饱和碳-碳键上加成N-H键，是由简单的烯烃原料合成胺的一种有效、实用和原子经济的方法。在过去的几十年里，在发展这一反应方面已经取得了重大进展；然而，对于具有广泛官能团耐受性的未活化烯烃的分子间氢胺化反应，仍然缺乏一种通用而可靠的方法。这项拟议的研究概述了开发用于未活化烯烃氢胺化反应的催化剂的战略。其具体目标是：1)合成、分离和表征含有与磷或氮给体相连的？6-芳烃的铑催化剂。我们将合成一系列的膦-烷基-芳基和吡啶-烷基-芳基配体，并将其转化为相应的铑配合物，以便在随后的氢胺化研究中进行评价。2)测试作为特定目标1的一部分而制备的催化剂，用于当前系统不催化的分子内和分子间氢胺反应。将被研究的底物包括用于分子内氢胺化反应的烷基链上缺乏宝石二取代的1，1和1，2-二取代氨基烯，以及用于分子间反应的未活化的烯烃，如1-戊烯。3)揭示AIM 1的Rh络合物催化氢胺化反应的机理信息。很难预测Aim 1的络合物催化反应中的转化率限制步骤是对配位烯烃的亲核攻击还是烷基Rh中间体的质子化。为了解决这个问题，机理研究将集中在从胺到配位烯烃的加成反应中鉴定和分离关键的烷基铑中间体，并研究该中间体对质子酸的反应活性。4)发展对映体选择性氢胺，这是一个长期目标。含有AIM-1络合物结构核心的手性罗络合物将被用于开发对映体选择性氢胺。与公共健康相关：作为药物发现计划的一部分，市场上的每一种药物都合成了数千种化合物。随着新的、高效的生物活性分子合成方法的发展，人们将更快地发现治疗疾病的新药。

DESCRIPTION (provided by applicant): The presence of amines in biologically active molecules, active pharmaceutical ingredients, and their building blocks is widespread. The alkene hydroamination reaction, formally the addition of an N-H bond across an unsaturated carbon-carbon bond, represents an efficient, practical and atom-economical method for the synthesis of amines from simple alkene starting materials. Significant advances have been made over the past few decades in developing this reaction; however, a general and dependable method for the intermolecular hydroamination of unactivated alkenes with broad functional group tolerance remains elusive. The proposed study outlines a strategy toward the development of rhodium catalysts for the hydroamination of unactivated alkenes. The specific aims are: 1) To synthesize, isolate, and characterize rhodium catalysts containing an ?6-arene tethered to a phosphorus or nitrogen donor. A series of phosphinoalkylarene and pyridylalkylarene ligands will be synthesized and converted to the corresponding rhodium complexes for evaluation in subsequent hydroamination studies. 2) To test the catalysts prepared as part of Specific Aim 1 for intra- and intermolecular hydroaminations that current systems do not catalyze. Substrates that will be investigated include 1,1- and 1,2-disubstituted aminoalkenes that lack gem-disubstitution on the alkyl chain for intramolecular hydroaminations and unactivated olefins, such as 1- pentene, for intermolecular reactions. 3) To reveal mechanistic information about hydroaminations catalyzed by the rhodium complexes of Aim 1. It is difficult to predict whether the turnover-limiting step in reactions catalyzed by complexes of Aim 1 will be nucleophilic attack on the coordinated olefin or protonolysis of the alkylrhodium intermediate. To address this question, mechanistic studies will be focused on the identification and isolation of the key alkylrhodium intermediate from addition of amine to the coordinated olefin, and to study the reactivity of this intermediate toward protic acids. 4) To develop enantioselective hydroaminations, which represents a long-term objective. Chiral rhodium complexes containing the structural core of the complexes of Aim 1 will be investigated for the development of enantioselective hydroaminations. PUBLIC HEALTH RELEVANCE: For every drug on the market, thousands of compounds were synthesized as part of a drug discovery program. With the development of novel and efficient methods for the synthesis of biologically active molecules, new drugs will be discovered more rapidly for the treatment of disease.