NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

手性药物的新型试剂和催化剂

• 批准号: 6240025
• 负责人: JOHN A SODERQUIST
• 金额: $ 10.83万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240025
• 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新的科学切割 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 实验工作的执行和分析光谱 评价和解释，而且，在科学发展 通过文献研讨会、演讲和出版物， 确保知识持续增长的程序，无论是现在还是 在未来本文提出的具体研究需要充分考虑 我们实验室开发的研究专业知识相对于 近二十年来在主族金属有机化合物的一般领域 试剂和反应及其在不对称 简单天然产物和重要药物的合成。的 项目的重点将是发展新的 化学，因为它涉及到重要的药物和潜在的 重要的天然和非天然产品。具体研究：（1）我们 已经制备了一种全新类型的手性乌扎硼杂环戊烷， 通过类比筛选为硼烷基不对称还原催化剂 Corey的CBS催化剂已经用于不对称 百忧解、D1拮抗剂、β-激动剂、野牡丹素的合成 血栓素A2和其他药物。许多潜在 在抗高血压药物合成中的应用已经被 鉴定(2)继我们最近成功的新的不对称 手性信息素，额脂素和外切短尾素的合成， Suzuki方案将被应用于α-氨基甲酸乙酯的全合成。 局部分离的甲氧基化脂肪酸代谢物 来自海绵Spheciospongia cusudifera (3)一种新的核磁共振 将该方案应用于有机硼烷混合物的测定。也 一种新的手性硅烷，可以有效地衍生醇，胺， 和羧酸是一种有效的新工具， 对映体过量存在于合成产品和药物中。 (4)我们的新的稳定的可分离的炔基硼烷将被检查 特别是关于炔丙基的不对称合成， 醇通过已知的CBS型催化工艺和我们的新的 催化此外，我们计划扩大铃木-宫浦协议， 在我们的实验室中开发的，以证明潜在的DNA切割， 烯二炔型化合物可以通过这种新的方法制备， 技术. (5)我们新的简单的羧酸保护方法将 用于保护氨基酸，用于肽的应用 合成. (6)许多非常稳定的硅胺衍生物 已制备，其化学性质将被探索为新的手性 锂碱作为手性烯醇醚的方便入口。