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（根据应用程序改编）：项目目标是针对的 新颖，手性，主组有机金属的发明和发展 用于应用于不对称合成的试剂和催化剂 药品和天然产品。该研究重点是化学 硼和硅，它们通常都对环保，并且 表现出低毒性。这些结构上声音的金属系统提供 定义的立体化学特征，可以在 在化学中常用的合成和分析操作 卫生行业。该项目的具体目的包括：（1）设计， 合成和评估新型手性axazaborolanes及相关类型 基于硼烷的催化剂催化不对称减少 酮。由新颖的分子内氮就业建造 β-氮烷基硼酸酯和硼烷具有潜在的药物 应用（即百忧解，D1拮抗剂，β-激动剂，前列腺素， 血栓烷A2）类似于科里的CBS催化剂，包括 抗高血压药的合成。基于B型的替代催化剂 还提出了源自二木龙的硼氢化物。 （2）与 以上，提出了新的手性硼氢化钾试剂 10-三甲基甲硅烷基-9-borabicyclo [3.3.2]脱烷环系统，其中包含一个 刚性系统中的B型硼氢化物，这是一种潜在的通用系统 许多酮类型的不对称还原。 （3）初步数据也支持 产生多种氨基羟基氢钾的可行性 通过氨基烷烷与活化钾的简单反应，A 似乎适合合成手性钾的过程 氨基羟基氢化物，系统也将被检查为新型不对称 还原催化剂。 （4）已经发现了一种新的11B-NMR协议 进一步发展为有效的有效分析 混合物。它在药品应用中的实用性已经存在 成功，提供清晰的图画 药物合成中使用的有机菜烷，这一发现可能具有 基于硼烷的不对称过程的深远意义。 （5）这样 技术已被用来准备一种新的手性硅烷衍生剂， 它将被视为比Mosher Ester更通用的协议 方法。 （6）一种新的基于硅烷的基于羧酸盐保护的方法将是 应用于氨基酸，用于肽和不对称的潜在应用 合成。