Enantioselective Synthesis of Phosphinate Derivatives

描述（由申请人提供）：在本研究计划中，我们计划研究脯氨酸衍生物催化的1-酮膦酸衍生物（或1-亚氨基膦酸衍生物）和酮/烯化醛的不对称醛醇（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，主要是作为酶抑制剂。对映体选择方法对于药物化学和制药工业来说是非常可取的，因为它可以节省高达50%的成本，并且避免了其他对映体的副作用。尽管如此，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物质开始，而不是从手性起始物质开始。虽然有几种方法可以获得这些化合物的光学活性形式，但在合成过程中没有一种是催化和对映选择性的。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选择性方法，该方法对环境无害，可耐受各种底物，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。本课题的具体目的包括：1)合理设计催化剂，实现1-酮膦酸衍生物与酮类和烯化醛的不对称醛醇反应；2) 1-亚氨基膦酸衍生物与酮类和烯化醛的不对称曼尼希反应；3)将该方法应用于重要生物产物的合成和初步抗菌研究。这项研究的基本原理是，这种对映选择性合成方法将使所需的膦酸衍生物的对映体容易获得，这反过来又将促进其生物活性的筛选，并最终加速其药用和制药应用。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。

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.