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）：项目目标是针对 新型手性主族有机金属化合物的发明和发展 不对称合成的试剂和催化剂 药品和天然产品。研究的重点是化学 硼和硅，它们通常既环保， 表现出低毒性。这些结构合理的类金属系统提供了 定义的立体化学特征，其可以有效地用于 化学中常用的合成和分析操作， 健康产业。本项目的具体目标包括：（1）设计， 新型手性氮杂硼杂环戊烷及其衍生物的合成与评价 用于硼烷基催化不对称还原前手性的催化剂 酮。由一种新型的分子内氮利用 β-叠氮烷基硼酸酯和硼烷，它们具有潜在的药物活性， 应用（即，百忧解、D1拮抗剂、β-激动剂、甘草素、 血栓烷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)互补于 以上，提出了新的手性硼氢化钾试剂，基于 10-三甲基甲硅烷基-9-硼双环[3.3.2]癸烷环系统，其含有 在刚性体系中的B-手性硼氢化物， 许多酮类的不对称还原。(3)初步数据也支持 生产多种氨基硼钾的可行性 通过氨基硼烷与活化的氢化钾的简单反应， 该方法似乎适合于手性钾的合成， 氨基硼氢化物，系统也将被检查为新的不对称 还原催化剂(4)一种新的11B-NMR协议已经发现， 可进一步发展为有机硼烷的高效直接分析 混合物。其在制药应用中的效用已经被 成功的，提供了一个清晰的图片的非对映体组成的 有机硼烷用于药物合成，这一发现可能会 对硼烷基不对称工艺具有深远意义。(5)等 利用技术制备了一种新的手性硅烷衍生剂， 这将被视为比Mosher酯更通用的方案 法(6)一种新的简单的基于硅烷的羧酸酯保护方法将在 适用于氨基酸的潜在应用肽和不对称 合成.