Approaches for Directed Olefin Hydroamination

描述(申请人提供)：含氮基序普遍存在于生物活性分子中。因此，开发选择性地将氮结合到有机结构中的新方法对于合成具有重要医学意义的化合物是至关重要的。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的区域和立体选择性进行，烯烃的氢胺化将是一种合成多种含氮分子的原子经济的方法。这项研究计划的目标是将第一个底物导向的烯烃氢胺化反应发展成一种综合有用的转化。这一目标将通过使用阳离子过渡金属络合物来实现，这些络合物能够利用常见极性官能团的配位能力来引导胺通过不饱和的碳-碳键进行加成。将研究几种基于后过渡金属的催化剂系统，以考察它们对这种转化的调节能力。在本方案中研究的催化剂结构将包括含有系链、双齿配体骨架的Ru络合物，双齿、双膦配体的Rh络合物，以及螯合物稳定的2-烯烃钯络合物。还将进行机理研究，以帮助确定控制每个催化剂系统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络合物的完整表征，无论是在溶液中还是在固体中。将进行实验，以表征胺、烯烃和导向基团如何与金属相互作用。还将确定这些组分的相对结合亲和力。此外，还将进行实验，以确定氢胺化的立体化学过程。最后，这些新型催化剂将被用于合成具有重要药用价值的化合物的胺类似物。由于碳-杂原子键普遍存在于生物相关结构中，底物定向氢胺化反应可以作为一种强有力的策略来获得结构多样、原子经济性高的药物衍生物。这种方法的选择性和可预测性将使药物开发过程中更有效地获得与生物和药物相关的结构。

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.