Enantioselective Synthesis of Phosphinate Derivatives

次膦酸酯衍生物的对映选择性合成

• 批准号: 8208163
• 负责人: JOHN CONG-GUI ZHAO
• 金额: $ 25.03万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208163
• 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（由申请人提供）：在本研究计划中，我们计划研究1-酮基膦酸衍生物（或1-亚氨基膦酸衍生物）与酮/可烯醇化醛的脯氨酸衍生物催化的不对称羟醛（或Mannich）反应在对映选择性合成1-羟基（或氨基）次膦酸衍生物中的应用。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。对映体选择性方法对于药物化学和制药工业是高度期望的，因为它可以节省高达50%的成本并且避免另一对映体的不希望的副作用。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，因为这样的合成必须从外消旋起始材料而不是前手性起始材料开始。虽然有几种方法可以得到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，我们建议使用一个新的交叉羟醛/曼尼希反应在我们的实验室发现，以解决这个问题。本项目的长期目标是开发一种有机催化的高对映选择性方法，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。本论文的主要目标包括：1）催化剂的合理设计以及1-酮基膦酸衍生物与酮和可烯醇化醛的不对称羟醛缩合反应; 2）1-亚氨基膦酸衍生物与酮和可烯醇化醛的不对称Mannich反应; 3）该新方法在重要生物产物的合成和初步抗菌研究中的应用。研究的基本原理是，这种对映体选择性合成方法将使所需的次膦酸衍生物的对映体容易获得，这反过来又将有助于筛选其生物活性，并最终加速其医学和制药应用。这项研究得到了初步数据的有力支持，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。 膦酸酯衍生物的对映选择性合成在本项目中，将通过1-酮基或1-亚氨基膦酸酯衍生物的不对称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以高对映选择性合成所需产物，所述产物由于其酶抑制作用而为高度生物活性的化合物。这项研究将大大提高PI在获得非SCORE研究支持方面的竞争力。此外，这项研究还为培训有机催化前沿领域代表性不足群体的学生提供了绝佳的机会。

项目成果

Primary Amine-Catalyzed Biginelli Reaction for the Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones.

• DOI: 10.1002/ejoc.201000448
• 发表时间: 2010-07-01
• 期刊: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 2.8
• 作者: Ding, Derong;Zhao, Cong-Gui
• 通讯作者: Zhao, Cong-Gui

Organocatalyzed enantioselective aldol reaction of 1H-pyrrole-2,3-diones.

• DOI: 10.1016/j.tetlet.2011.11.056
• 发表时间: 2012-01-18
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Bhanushali, Mayur;Zhao, Cong-Gui
• 通讯作者: Zhao, Cong-Gui

Organocatalyzed synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles.

• DOI: 10.1016/j.tetlet.2009.12.139
• 发表时间: 2010-03-03
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Ding D;Zhao CG
• 通讯作者: Zhao CG

Hydrogen-bonding 2D metal-organic solids as highly robust and efficient heterogeneous green catalysts for Biginelli reaction.

• DOI: 10.1016/j.tetlet.2011.09.099
• 发表时间: 2011-11-23
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Li, Peng;Regati, Sridhar;Butcher, Raymond J.;Arman, Hadi D.;Chen, Zhenxia;Xiang, Shengchang;Chen, Banglin;Zhao, Cong-Gui
• 通讯作者: Zhao, Cong-Gui

Organocatalytic enantioselective tandem aldol-cyclization reaction of α-isothiocyanato imides and activated carbonyl compounds.

α-异硫氰酸酯和活化的羰基化合物的有机催化对映体串联链球化反应。

• DOI: 10.1016/j.tetasy.2011.06.028
• 发表时间: 2011-06-15
• 期刊: TETRAHEDRON-ASYMMETRY
• 作者: Guang, Jie;Zhao, Cong-Gui
• 通讯作者: Zhao, Cong-Gui