NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

手性药物的新型试剂和催化剂

• 批准号: 6472787
• 负责人: JOHN A SODERQUIST
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6472787
• 关键词: biological products; biotherapeutic agent; boron; catalyst; chemical substitution; chemical synthesis; drug design /synthesis /production; method development; nuclear magnetic resonance spectroscopy; organic chemicals; organometallic compounds; organosilicon compound; reagent /indicator; silicon; stereochemistry; stereoisomer

Description (Adapted from Application): The project goals are directed toward the invention and development of novel, chiral, main-group organometallic reagents and catalysts for applications to the asymmetric synthesis of pharmaceuticals and natural products. The research focuses upon the chemistry of boron and silicon, which are generally both environmentally friendly and exhibit low toxicity. These structurally sound metalloidal systems provide defined stereochemical features, which can be utilized effectively in the synthetic and analytical operations commonly employed in the chemistry used in the health industry. Specific aims of the project include: (1) The design, synthesis, and evaluation of new types of chiral axazaborolanes and related catalysts for the borane-based catalytic asymmetric reduction of prochiral ketones. Constructed by a novel, intramolecular nitrogen-employing beta-azidoalkyl borinate esters and boranes, they have potential pharmaceutical applications (i.e., Prozac, D1 antagonists, beta-agonists, prostaglandins, thromboxane A2) by analogy to those of Corey's CBS catalysts, including the synthesis of anti-hypertensive drugs. Alternative catalysts based upon B-chiral borohydrides derived from diborons are also proposed. (2) Complementary to the above, new chiral potassium borohydride reagents are proposed, based upon the 10-trimethylsilyl-9-borabicyclo[3.3.2]decane ring system, which contain a B-chiral borohydride in a rigid system, a potentially versatile system for the asymmetric reduction of many ketone types. (3) Preliminary data also supports the feasibility of generating a wide variety of potassium aminoborohydrides through the simple reaction of aminoboranes with activated potassium hydride, a process which appears amenable to the synthesis of chiral potassium aminoborohydrides, systems which will also be examined as novel asymmetric reduction catalysts. (4) A new 11B-NMR protocol has been discovered which will be further developed as a highly effective, direct analysis of organoborane mixtures. Its utility in pharmaceutical applications has already been successful, providing a clear picture of the diastereomeric composition of the organoboranes employed in a drug synthesis, a finding that could have far-reaching significance for borane-based asymmetric processes. (5) Such technology has been utilized to prepare a new chiral silane derivatizing agent, which will be examined as a more versatile protocol than the Mosher ester method. (6) A new simple silane-based method for carboxylate protection will be applied to amino acids for potential applications to peptide and asymmetric synthesis.

描述(改编自应用程序)：项目目标针对的是 新型手性主族有机金属的发明与发展 试剂和催化剂在不对称合成中的应用 药品和天然产品。研究的重点是化学 硼和硅，它们通常对环境友好，而且 表现出低毒。这些结构良好的类金属系统提供了 已定义的立体化学特征，可有效地用于 化学中常用的合成和分析操作 健康产业。该项目的具体目标包括：(1)设计、 新型手性恶唑硼烷及其相关化合物的合成、表征 前手性硼烷催化不对称还原催化剂 酮类。由一种新型的分子内氮素使用法构建 β-叠氮烷基硼酸酯和硼烷，它们具有潜在的药物 应用(即百忧解、D1拮抗剂、β-激动剂、前列腺素、 血栓素A2)，类似于Corey的CBS催化剂，包括 抗高血压药物的合成。基于B-手性的替代催化剂 此外，还提出了由二硼化合物衍生的硼氢化物。(2)与 在此基础上，提出了新的手性硼氢化钾试剂 10-三甲基硅基-9-硼双环[3.3.2]正十二烷环体系，其中包含一个 B-手性硼氢化物在刚性体系中的应用，这是一种潜在的多功能体系 多种酮类的不对称还原。(3)初步数据也支持 生产多种氨基硼氢化钾的可行性 通过氨基硼烷与活性氢化钾的简单反应， 看似适合手性钾合成的过程 氨基硼氢化物，也将被视为新的不对称体系 还原催化剂。(4)已经发现了一种新的11B-核磁共振方案，它将 进一步发展成为一种高效、直接的有机硼烷分析方法 混合物。它在医药应用中的效用已经被 成功，提供了一幅清晰的图像，显示了 有机硼烷用于药物合成，这一发现可能 对基于硼烷的不对称工艺具有深远的意义。(5)该等 利用该技术制备了一种新型的手性硅烷衍生化试剂， 它将被视为比Mosher Ester更通用的协议 方法。(6)一种基于硅烷的新的简单的羧酸盐保护方法将是 氨基酸在多肽和不对称方面的潜在应用 综合。