NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

手性药物的新型试剂和催化剂

• 批准号: 6107134
• 负责人: JOHN A SODERQUIST
• 金额: $ 0.94万
• 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/6107134
• 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在切割方面发展新的科学 现代合成化学的前沿。学生联合调查员是 研究过程中不可或缺的一部分，不仅通过 执行实验工作和在分析光谱中 评价和解读，也是在科学发展中 通过文学研讨会、演示文稿和出版物， 确保知识持续增长的程序，无论是现在还是 在未来。在此提出的具体研究充分说明了 我们实验室开发的研究专业知识相对于 近二十年来主族金属有机材料的发展 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。这个 该项目的重点将指向开发新的 化学，因为它与重要的药物和潜在的 重要的天然和非天然产品。作为具体研究：(1)我们 已经制备了一种全新类型的手性哇扎博洛烷，它将 类比筛选出一种硼烷基不对称还原催化剂 到科里的CBS催化剂，这些催化剂已经用于不对称 百忧解、D_1拮抗剂、β-激动剂、前列腺素类药物的合成 血栓素A2和其他药物。无数的潜力 在抗高血压药物合成中的应用 确认身份。(2)继我们最近成功的新不对称 手性信息素、前列环素和外野胡萝卜素的合成 铃木方案将应用于α-半乳糖的全合成 已在当地分离到的甲氧基化脂肪酸代谢物 取自海洋海绵Spheciospongia cuudifera。(3)一种新的核磁共振 该方法将应用于有机硼烷混合物的分析。也是 一种能有效衍生化醇、胺的新型手性硅烷 而羧酸被认为是一种有效的新的分析工具。 合成产品和药品中存在的对映体过量。 (4)我们的新的稳定的可分离的炔基硼烷将被检验。 特别是关于丙叉酸的不对称合成 通过已知的CBS类型的催化过程和我们的新技术 催化剂。此外，我们计划扩大铃木-宫村议定书 我们实验室开发的用来证明潜在的DNA裂解 通过这种新的方法可以制备烯二炔类化合物。 技术(5)我们的新的简单的羧酸盐保护方法将 应用于多肽的氨基酸保护 综合。(6)一些非常稳定的硅胺衍生物 已经制备了其化学将作为新的手性进行探索 锂碱作为手性烯醇醚的方便入口。