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）：项目目标旨在 新型手性主族有机金属化合物的发明和开发 用于不对称合成的试剂和催化剂 药物和天然产物。研究重点是化学 硼和硅通常既环保又 表现出低毒性。这些结构健全的非金属系统提供 定义的立体化学特征，可以有效地利用 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axazaborolanes及相关化合物的合成与评价 硼烷基催化不对称还原前手性催化剂 酮类。由新型分子内氮利用构建 β-叠氮基烷基硼酸酯和硼烷，它们具有潜在的药用价值 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 还提出了衍生自二硼的硼氢化物。 (2) 补充 如上所述，基于以下提出了新的手性硼氢化钾试剂 10-三甲基甲硅烷基-9-硼双环[3.3.2]癸烷环系，其中含有一个 刚性系统中的 B-手性硼氢化物，一种潜在的多功能系统 许多酮类型的不对称还原。 (3) 初步数据也支持 生产多种氨基硼氢化钾的可行性 通过氨基硼烷与活化的氢化钾的简单反应， 似乎适合合成手性钾的过程 氨基硼氢化物，也将作为新型不对称系统进行检查 还原催化剂。 (4) 发现了一种新的 11B-NMR 方案，该方案将 进一步开发为有机硼烷的高效、直接分析 混合物。它在制药应用中的效用已经被 成功，提供了非对映异构体组成的清晰图像 用于药物合成的有机硼烷，这一发现可能 对于基于硼烷的不对称过程具有深远的意义。 (5) 这样的 利用技术制备了新型手性硅烷衍生剂， 它将被视为比 Mosher 酯更通用的方案 方法。 (6) 一种新的简单的基于硅烷的羧酸盐保护方法 应用于氨基酸，有可能应用于肽和不对称氨基酸 合成。