NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

手性药物的新型试剂和催化剂

• 批准号: 6271547
• 负责人: JOHN A SODERQUIST
• 金额: $ 10.9万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271547
• 关键词: biological products; boranes; chemical substitution; chemical synthesis; drug /agent; metals; method development; nuclear magnetic resonance spectroscopy; organic chemicals; organometallic compounds; organosilicon compound; silanes; stereochemistry

The project goals are to continue to develop new science at the cutting edge of modern synthetic chemistry. The student co-investigators are an integral part of the research process, not only through the execution of the experimental work and in the analytical spectroscopic evaluation and interpretation, but also, in the scientific development process through literature seminars, presentations and publications, procedures which assure the continued growth of knowledge, both now and in the future. The specific research proposed herein takes full advantage of research expertise developed in our laboratories over the past twenty years in the general area of Main Group organometallic reagents and reactions and their applications to the asymmetric synthesis of simple natural products and important pharmaceuticals. The project's focus will be directed toward the development of new chemistry as It relates to important pharmaceutical and potentially important natural and unnatural products. As specific studies: (1) We have prepared an entirely new type of chiral ouzaborolane which will be screened as a borane-based asymmetric reduction catalyst by analogy to Corey's CBS catalysts which have been employed for the asymmetric syntheses of Prozac, D1 antagonists, beta-agonists, prostaglandins thromboxane A2 and other pharmaceuticals. Numerous potential applications in the synthesis of antihypertensive drugs have been identified. (2) Following our recent successful new asymmetric syntheses of the chiral pheromones, frontalin and exo-brevicomin, the Suzuki protocol will be applied to the total synthesis of alpha- methoxylated fatty acid metabolites which have been isolated locally from the marine sponge, Spheciospongia cusudifera. (3) A new NMR protocol will be applied to the assay of organoborane mixtures. Also a new chiral silane which can effectively derivatize alcohols, amines and carboxylic acids is proposed as an effective new tool to assay the enantiomeric excess present in synthetic products and pharmaceuticals. (4) Our new stable isolable alkynylboranes will be examined particularly with respect to the asymmetric synthesis of propargylic alcohols through known CBS-type catalytic processes and with our new catalyst. Moreover, we plan to expand the Suzuki-Miyaura protocol developed in our laboratory to demonstrate that potential DNA-cleaving compounds of the enediyne type can be prepared through this new technology. (5) Our new simple method for carboxylate protection will be applied to the protection of amino acids for applications to peptide synthesis. (6) A number of remarkably stable silylamine derivatives have been prepared whose chemistry will be explored as new chiral lithium bases as a convenient entry to chiral enol ethers.

该项目的目标是继续开发前沿的新科学 现代合成化学的前沿。学生共同研究者是 研究过程的一个组成部分，不仅通过 实验工作和分析光谱的执行 评价和解释，也体现在科学发展中 通过文学研讨会、演讲和出版物进行过程， 确保知识持续增长的程序，无论是现在还是 将来。本文提出的具体研究充分 我们实验室开发的研究专业知识的优势 过去二十年在主族有机金属领域的发展 试剂和反应及其在不对称反应中的应用 简单天然产物和重要药物的合成。这 项目的重点将是开发新的 化学与重要的制药和潜在的相关 重要的天然和非天然产品。作为具体研究：（1）我们 制备了一种全新类型的手性 ouzaborolane，它将 类推筛选硼烷基不对称还原催化剂 Corey 的 CBS 催化剂已用于不对称反应 百忧解、D1 拮抗剂、β-激动剂、前列腺素的合成 血栓素A2等药物。众多潜力 在抗高血压药物合成中的应用 确定。 (2) 继我们最近成功的新型不对称 手性信息素、frontalin 和 exo-brevicomin 的合成 Suzuki方案将应用于α-的全合成 本地分离的甲氧基化脂肪酸代谢物 来自海洋海绵（Spheciospongia cusudifera）。 (3)新的核磁共振 该方案将应用于有机硼烷混合物的测定。还 一种新型手性硅烷，可有效衍生醇、胺 和羧酸被提议作为一种有效的新工具来测定 合成产品和药品中存在对映体过量。 (4) 我们将检验新型稳定的可分离炔基硼烷 特别是关于炔丙酸的不对称合成 醇通过已知的 CBS 型催化过程和我们的新 催化剂。此外，我们计划扩展铃木宫浦协议 我们实验室开发的，旨在证明潜在的 DNA 切割 烯二炔类型的化合物可以通过这种新方法制备 技术。 (5) 我们新的简单的羧酸盐保护方法将 应用于保护氨基酸，应用于肽 合成。 (6) 一批稳定性非常好的硅胺衍生物 已制备出其化学将作为新的手性进行探索 锂基作为手性烯醇醚的便捷入口。