Approaches for Directed Olefin Hydroamination

定向烯烃加氢胺化方法

• 批准号: 8596362
• 负责人: Juana Du
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2014-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596362
• 关键词: Affinity; Alkenes; Amines; Binding; Carbon; Complex; Development; Goals; Health; Human; Ligands; Link; Mediating; Metals; Methods; Nitrogen; Organic Synthesis; Palladium; Pharmacologic Substance; Phosphines; Process; Reaction; Relative (related person); Research; Research Proposals; Rhodium; Route; Ruthenium; Site; Solutions; Structure; System; Transition Elements; analog; base; catalyst; design; direct application; drug development; functional group; insight; interest; metal complex; method development; pi bond; public health relevance; research study; solid state; stem; tool

DESCRIPTION (provided by applicant): Nitrogen-containing motifs are ubiquitous in biologically active molecules. Thus, the development of new methods for the selective incorporation of nitrogen into organic structures is essential for the synthesis of medicinally important compounds. One efficient strategy for the formation of carbon-nitrogen bonds is hydroamination, the addition of an amine across a double bond. If this transformation could be directed to occur with high levels of regio- and stereoselectivity, the hydroamination of olefins would be an atom-economical method for synthesizing a wide range of nitrogen-containing molecules. The goal of this research proposal is to develop the first substrate-directed hydroamination of olefins into a synthetically useful transformation. This objective will be achieved through the use of cationic transition metal complexes that are able to exploit the coordinating ability of common polar functional groups to direct the addition of an amine across an unsaturated carbon-carbon bond. Several catalyst systems based upon late transition metals will be studied for their ability to mediate this transformation. The catalyst structures studied i this proposal will include ruthenium complexes containing a tethered ¿,¿-bidentate ligand framework, rhodium complexes of bidentate, bisphosphine ligands, and chelate-stabilized, ?2-olefin palladium complexes. Mechanistic studies to help identify the factors that govern the reactivity and selectivity of each catalyst system will also be conducted. These studies will include a complete characterization of the organometallic catalysts and their corresponding olefin complexes, both in solution and in the solid-state. Experiments to characterize how the amine, the olefin, and the directing group interact with the metal will be carried out. The relativ binding affinities of these components will also be determined. In addition, experiments to determine the stereochemical course of hydroamination will be conducted. Finally, these new catalysts will be employed to synthesize amine-analogues of medicinally important compounds. Because carbon-heteroatom bonds are ubiquitous in biologically relevant structures, substrate-directed hydroamination can be a powerful strategy for accessing a wide range of structurally diverse pharmaceutical derivatives with high atom economy. The selectivity and predictability of this approach will enable more efficient routes to biologically and pharmaceutically relevant structures in the drug development process.

描述（由申请人提供）：含氮基序在生物活性分子中普遍存在。因此，发展将氮选择性结合到有机结构中的新方法对于合成具有重要药用价值的化合物是必不可少的。形成碳氮键的一种有效策略是氢胺化，即在双键上加一个胺。如果这种转化能够以高水平的区域选择性和立体选择性发生，那么烯烃的氢胺化将是一种原子经济的方法，用于合成各种含氮分子。本研究计划的目标是开发第一个底物定向的烯烃氢胺化转化为合成有用的转化。这一目标将通过使用阳离子过渡金属配合物来实现，这种配合物能够利用共同极性官能团的配位能力来指导胺在不饱和碳-碳键上的加成。几种基于后期过渡金属的催化剂体系将被研究其介导这种转变的能力。本提案研究的催化剂结构将包括含有系留双齿配体框架的钌配合物，双齿配体的铑配合物，双膦配体，和螯合稳定的。2-烯烃钯配合物。还将进行机理研究，以帮助确定控制每种催化剂体系的反应性和选择性的因素。这些研究将包括有机金属催化剂及其相应的烯烃配合物的完整表征，包括溶液和固态。将进行表征胺、烯烃和导向基团如何与金属相互作用的实验。这些组件的相对结合亲和力也将被确定。此外，还将进行实验以确定氢胺化的立体化学过程。最后，这些新型催化剂将用于合成具有重要药用价值的化合物的胺类类似物。由于碳杂原子键在生物相关结构中普遍存在，因此底物导向的氢胺化可以作为一种强大的策略，用于获得具有高原子经济性的多种结构的药物衍生物。这种方法的选择性和可预测性将在药物开发过程中提供更有效的生物和药学相关结构途径。