Enantioselective Synthesis of Nitrogen-Containing Small Molecules

 说明书(申请人提供)：绝大多数新手性药物是作为单一对映体上市的；然而，单一对映体有机合成方法的局限性阻碍了药物开发，特别是对于含氮小分子。Meso-aziridine去对称化是一种制备手性含氮小分子的有效方法。近年来，阳离子双膦-钯(II)路易斯酸在各种键结构方面得到了迅速发展。尚不清楚的是双膦-钯(II)络合物催化的氮杂环丙烷对映体选择性去对称化反应。长期的目标是发现新的催化方法来合成具有生物活性的小分子。这项拟议研究的总体目标是开发对映选择性的、钯(II)催化的重排反应和碳-碳键形成反应，这是实现长期目标的下一步。这是由一个中心假设驱动的，即阳离子钯配合物具有双重反应性，可通过对映体选择性氮杂环丙烷去对称化生成不同的含氮小分子。这项研究的基本原理是，该项目的完成将定义双膦-钯(II)催化剂在新的对映体选择性小分子合成中的新的反应性。在强大的初步数据的指导下，该研究计划包括客观地检验中心假设，从而通过追求以下两个具体目标来达到这一应用的目的：1发展钯(II)催化的独特的键结构的对映选择性重排，以及2)通过碳-碳键的形成获得单一的对映体仲胺衍生物。每个目标都基于一个工作假设，即双膦-钯(II)配合物通过对映体选择性重排和氮杂环与碳亲核试剂的开环，具有合成生物活性底物的新反应活性，使这一方法具有创新性。我们具体目标的预期结果如下：第一，开发由钯(II)路易斯酸催化的新的对映体选择性反应；第二，合成用于NIH分子库小分子储存库和NCI开发治疗计划测试的富含对映体的杂环；第三，生产结构多样化的手性、神经活性小分子集合，以提交给NIMH精神活性药物筛选计划。这些成果将为手性、生物活性的小分子合成建立关键中间体N-酰基氮杂环丙烷，从而产生重要的积极影响。将开辟新的途径，生产以前不为人知的药物，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.