Enantioselective Synthesis of Nitrogen-Containing Small Molecules

 描述（由申请人提供）：大部分新手性药物以单一对映体形式上市;然而，单一对映体有机合成方法的局限性阻碍了药物开发，特别是含氮小分子药物。中位氮丙啶去对称化是制备手性含氮小分子的有效方法。近年来，阳离子二膦钯（II）刘易斯酸在各种键结构中得到了快速发展。由二膦-钯（II）络合物催化的对映选择性氮丙啶去对称化反应是未知的。长期目标是发现用于生物活性小分子合成的新型催化方法。拟议研究的总体目标是实现长期目标的下一步，即开发对映选择性、钯（II）催化的重排和碳-碳键形成反应。这是由一个中心的假设，即阳离子钯配合物具有双重反应性，通过对映选择性氮丙啶去对称化生产不同的含氮小分子。所提出的研究的基本原理是完成该项目将定义新的反应性的二膦钯（II）催化剂在新的对映选择性小分子合成。在强有力的初步数据的指导下，研究计划包括客观地测试中心假设，从而通过追求以下两个具体目标来实现本申请的目的：1开发用于独特键结构的钯（II）催化的对映体选择性重排，以及2）通过碳-碳键形成获得单一对映体仲胺衍生物。每个目标将与一个工作假设，即二膦钯（II）配合物具有新的反应性，生物活性底物合成的对映选择性重排和氮丙啶开环与碳亲核试剂，使这种方法创新。我们的具体目标的预期成果如下：第一，开发新的钯（II）刘易斯酸催化的对映选择性反应;第二，合成对映富集的杂环化合物，供NIH分子库小分子库和NCI开发治疗计划测试;第三，制备结构多样的手性，神经活性小分子，提交给NIMH精神活性药物筛选计划。通过将N-酰基氮杂环丙烷确定为手性、生物活性小分子合成的关键中间体，这些结果将产生显着的积极影响。将开辟新的途径来生产以前未知的药物，以增进人类健康。

 DESCRIPTION (provided by applicant): A large majority of new chiral pharmaceuticals are marketed as single enantiomers; however, limitations in methods for single enantiomer organic synthesis hinder drug development, particularly for nitrogen-containing small molecules. Meso-aziridine desymmetrization is an efficient process for producing chiral, nitrogen-containing small molecules. Cationic diphosphine-palladium (II) Lewis acids have seen rapid development in recent years for various bond constructions. What is not known are enantioselective aziridine desymmetrization reactions catalyzed by diphosphine-palladium (II) complexes. The long-term goal is to discover novel catalytic methods for biologically-active small molecule synthesis. The overall objective of the proposed research, which is the next step toward attainment of the long-term goal, is to develop enantioselective, palladium (II)-catalyzed rearrangements and carbon-carbon bond forming reactions. This is driven by a central hypothesis that cationic palladium complexes possess dual reactivity for the production of diverse nitrogen-containing small molecules by enantioselective aziridine desymmetrization. The rationale that underlies the proposed research is completion of this project will define new reactivity for diphosphine-palladium (II) catalysts in novel enantioselective small molecule synthesis. Directed by strong preliminary data, the research plan includes objectively testing the central hypothesis and, thereby, attaining the objective of this application by pursuing the following two specific aims: 1 Develop palladium (II)-catalyzed, enantioselective rearrangements for unique bond constructions, and 2) Obtain access to single enantiomer secondary amine derivatives by carbon-carbon bond formation. Each aim will operate with a working hypothesis that diphosphine-palladium (II) complexes possess novel reactivity for biologically-active substrate synthesis by enantioselective rearrangements and aziridine ring opening with carbon nucleophiles, making this approach innovative. The expected outcomes of our specific aims are as follows: first, developing new enantioselective reactions catalyzed by palladium (II) Lewis acids; second, synthesis of enantioenriched heterocycles for testing by the NIH Molecular Libraries Small Molecule Repository and NCI Developmental Therapeutics Program; third, production of a structurally diverse collection of chiral, neurologically-active small molecules fo submission to the NIMH Psychoactive Drug Screening Program. These outcomes will have a significant positive impact by establishing N-acylaziridines as linchpin intermediates for chiral, bio-active small molecule synthesis. New pathways will be opened to produce previously unknown pharmaceuticals for the enhancement of human health.