Enantioselective Synthesis of Phosphinate Derivatives

描述(申请人提供)：在本研究方案中，我们计划研究1-酮膦酸衍生物(或1-亚氨基膦酸衍生物)与酮/可烯醇化醛的不对称Aldol(或Mannich)反应在1-羟基(或氨基)膦酸衍生物的对映选择性合成中的应用。1-羟基和1-氨基膦酸衍生物是1-氨基酸的类似物。它们具有非常重要的生物活性，主要作为酶抑制剂。对映体选择性方法在药物化学和制药工业中是非常理想的，因为它可以节省高达50%的成本，并避免其他对映体的不必要的副作用。然而，在这些衍生物中，磷酰基(P=O)通常是手性的，这使得这些化合物的对映选择性合成特别具有挑战性，因为这样的合成必须从外消旋起始原料开始，而不是从前手性原料开始。虽然有几种方法以光学活性形式获得这些化合物，但在合成过程中没有一种方法是催化和对映体选择性的。在这个项目中，我们建议使用我们实验室发现的一种新的交叉Aldol/Mannich反应来解决这个问题。该项目的长期目标是开发一种有机催化的高度对映体选择性的方法，该方法对环境友好，可以容忍各种底物，用于合成光学活性的1-羟基和1-氨基膦衍生物，用于生物医学应用，如抗菌、抗癌或抗病毒研究。该方案的具体目标包括：1)催化剂的合理设计和1-酮膦酸衍生物与酮和烯醇化醛的不对称Aldol反应；2)1-亚氨基膦酸衍生物与酮和烯醇化醛的不对称Mannich反应；3)这一新方法在合成生物重要产品和初步抗菌研究中的应用。这项研究的基本原理是，这种对映体选择性的合成方法将使所需的膦酸衍生物的对映体容易获得，这反过来将有助于筛选它们的生物活性，并最终加速它们的医药和医药应用。这项研究得到了初步数据的有力支持，这些数据验证了所提出的方法。此外，调查将在有利于其成功的良好研究环境和研究设施中进行。 亚膦酸衍生物的不对称合成在本项目中，将通过1-酮或1-亚胺基膦酸衍生物的不对称Aldol或Mannich反应来研究一些1-羟基和1-氨基取代的亚膦酸衍生物的不对称合成。目前的方法克服了处理这些手性底物的困难(由于磷酰基的手性)，因此外消旋起始物质可以直接用于合成高对映体选择性的目标产物，因为它们具有酶抑制作用，是具有高度生物活性的化合物。这项研究将极大地提高PI在获得非分数研究支持方面的竞争力。此外，这项研究还提供了一个极好的机会来培训来自代表不足的群体的学生在有机催化的尖端领域。

DESCRIPTION (provided by applicant): In this research proposal, we plan to study the application of the proline derivative-catalyzed asymmetric aldol (or Mannich) reaction of 1-ketophosphinic acid derivatives (or 1-iminophosphinic acid derivatives) and ketones/enolizable aldehydes for the enantioselective synthesis of 1-hydroxy (or amino) phosphinic acid derivatives. 1-Hydroxy and 1-aminophosphinic acid derivatives are analogs of 1-amino acids. They have very important biological activities, mainly as enzyme inhibitors. An enantioselective method is highly desirable for the medicinal chemistry and pharmaceutical industry, as it may save the cost for up to 50% and avoid the unwanted the side-effects of the other enantiomer. Nonetheless, the phosphoryl group (P=O) is normally chiral in these derivatives, which makes the enantioselective synthesis of these compounds especially challenging, because such a synthesis would have to start with racemic starting materials instead of prochiral ones. Although there are a few methods to obtain these compounds in optically active forms, none of them are catalytic AND enantioselective during the syntheses. In this project we propose to use a novel cross aldol/Mannich reaction discovered in our lab to solve this problem. The long-term goal of this project is to develop an organocatalytic highly enantioselective method, which is environmentally benign and tolerates various substrates, for the synthesis of optically active 1-hydroxy and 1-aminophosphinic derivatives, for biomedical applications, such as anti-bacterial, anti-cancer or antivirus studies. The specific aims of this proposal include: 1) rational design of catalysts and asymmetric aldol reaction of 1-ketophosphinic acid derivatives with ketones and enolizable aldehydes; 2) asymmetric Mannich reaction of 1-iminophosphinic acid derivatives with ketones and enolizable aldehydes; and 3) applications of this novel method for the synthesis of biologically important products and preliminary antibacterial studies. The rationale that underlies the investigation is that such an enantioselective synthetic method will make the desired enantiomers of the phosphinic acid derivatives readily available, which, in turn, will facilitate the screening of their biological activities, and eventually accelerate their medicinal and pharmaceutical applications. This study is strongly supported by preliminary data that validate the proposed approach. Furthermore, the investigation will be performed in an excellent research environment and research facility that are conducive to its success. ENANTIOSELECTIVE SYNTHESIS OF PHOSPHINATE DERIVATIVES In this proposed project, the asymmetric synthesis of some 1-hydroxy and 1-amino-substituted phosphinate derivatives will be studied via the asymmetric aldol or Mannich reaction of 1-keto or 1-iminophosphinate derivatives. The current approach overcomes the difficulty in handling these chiral substrates (due to the chirality of the phosphoryl group), so that racemic starting materials may be directly used for the synthesis of the desired products in high enantioselectivities, which are highly biological active compounds because of their enzyme inhibitory effects. The research will greatly enhance the PI's competitiveness in securing non-SCORE research support. Additionally, this research also offers an excellent opportunity for training the students from the underrepresented groups in the cutting-edge area of organocatalysis.