Development of Rhodium Catalysts for Alkene Hydroamination

描述（由申请人提供）：胺在生物活性分子，活性药物成分及其构建块中的存在是普遍存在的。烯烃氢胺化反应是指在不饱和碳-碳键上加成一个N-H键，代表了一种以简单烯烃为原料合成胺的高效、实用和原子经济的方法。在过去的几十年里，在发展这种反应方面取得了重大进展；然而，一种具有广泛官能团耐受性的非活化烯烃分子间氢胺化的通用和可靠的方法仍然是难以捉摸的。提出的研究概述了发展非活化烯烃氢胺化铑催化剂的策略。具体目的是：1)合成、分离和表征含一？6-芳烃与磷或氮供体相连。将合成一系列磷酸烷基烯和吡啶烷基烯配体并将其转化为相应的铑配合物，以便在后续的氢胺化研究中进行评价。2)测试作为Specific Aim 1的一部分制备的催化剂，用于当前系统不能催化的分子内和分子间氢胺反应。将研究的底物包括分子内氢胺化反应中烷基链上缺乏双取代的1,1-和1,2-二取代的氨基烯，以及分子间反应中未活化的烯烃，如1-戊烯。3)揭示ai1铑配合物催化氢胺化反应的机理。在Aim - 1配合物催化的反应中，限制周转的步骤是对配位烯烃的亲核攻击还是烷基铑中间体的质子分解，很难预测。为了解决这一问题，机理研究将集中在鉴定和分离由胺加成到配位烯烃的关键烷基铑中间体，并研究该中间体对质子酸的反应性。4)发展对映选择性氢胺化反应，这是一个长期的目标。手性铑配合物包含的结构核心的配合物的Aim 1将研究开发对映选择性氢胺化。公共卫生相关性：对于市场上的每一种药物，作为药物发现计划的一部分，数千种化合物被合成。随着新型高效的生物活性分子合成方法的发展，用于治疗疾病的新药将被更快地发现。

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.