Enantioselective Synthesis of Phosphinate Derivatives

次膦酸酯衍生物的对映选择性合成

• 批准号: 7559214
• 负责人: JOHN CONG-GUI ZHAO
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559214
• 关键词: 3-hydroxybutanal; Acids; Adverse effects; Affect; Aldehydes; Amino Acids; Anti-Bacterial Agents; Applications Grants; Area; Benign; Biological; Carbon; Collaborations; Data; Development; Drug Industry; Electrons; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Goals; Grant; Imines; In Situ; Investigation; Ketones; Malignant Neoplasms; Methodology; Methods; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphinic Acids; Problem Solving; Productivity; Proline; Property; Reaction; Research; Research Project Grants; Research Proposals; Research Support; Screening procedure; Secure; Staging; Structure; Students; Testing; Training; United States National Institutes of Health; Withdrawal; Work; analog; base; carbonyl group; career; catalyst; cost; design; enantiomer; novel; research facility; success

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.

描述（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-酮次膦酸衍生物（或1-亚氨基次膦酸衍生物）与酮/烯醇化醛的不对称羟醛（或曼尼希）反应的应用用于1-羟基（或氨基）次膦酸衍生物的对映选择性合成。 1-羟基和1-氨基次膦酸衍生物是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。对映选择性方法对于药物化学和制药工业来说是非常理想的，因为它可以节省高达 50% 的成本，并避免其他对映体的不良副作用。尽管如此，磷酰基（P=O）在这些衍生物中通常是手性的，这使得这些化合物的对映选择性合成特别具有挑战性，因为这种合成必须从外消旋起始材料而不是前手性起始材料开始。尽管有几种方法可以获得这些光学活性形式的化合物，但它们在合成过程中都没有催化和对映选择性。在这个项目中，我们建议使用我们实验室发现的新型交叉羟醛/曼尼希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高度对映选择性方法，该方法对环境友好且耐受各种底物，用于合成光学活性1-羟基和1-氨基次膦衍生物，用于生物医学应用，例如抗菌、抗癌或抗病毒研究。该提案的具体目标包括：1）催化剂的合理设计以及1-酮次膦酸衍生物与酮和烯醇化醛的不对称羟醛反应； 2) 1-亚氨基次膦酸衍生物与酮和烯醇化醛的不对称曼尼希反应； 3）这种新方法在重要生物学产物的合成和初步抗菌研究中的应用。这项研究的基本原理是，这种对映选择性合成方法将使次膦酸衍生物的所需对映异构体易于获得，从而有助于筛选其生物活性，并最终加速其医学和制药应用。这项研究得到了验证所提出方法的初步数据的有力支持。此外，调查将在有利于其成功的优良研究环境和研究设施中进行。 次膦酸酯衍生物的对映选择性合成在本项目中，将通过1-酮或1-亚氨基次膦酸酯衍生物的不对称羟醛或曼尼希反应来研究一些1-羟基和1-氨基取代的次膦酸酯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），使得外消旋起始材料可以直接用于合成高对映选择性的所需产物，这些产物是高度生物活性的化合物，因为它们的酶抑制作用。该研究将大大增强PI在获得非SCORE研究支持方面的竞争力。此外，这项研究还为在有机催化前沿领域培训来自代表性不足群体的学生提供了绝佳的机会。