CHIRAL CATALYSTS FOR ENANTIOSELECTIVE SYNTHESES

用于对映选择性合成的手性催化剂

• 批准号: 2770975
• 负责人: Michael PATRICK Doyle
• 金额: $ 12.09万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770975
• 关键词: carboxylate; catalyst; chemical models; chemical synthesis; cyclization; diazo compound; drug screening /evaluation; gamma aminobutyrate; imidazoledione; lactones; nitrogenous heterocyclic compound; organometallic compounds; oxazolidone; prostaglandin analogs; pyrrolidones; reverse transcriptase inhibitors; rhodium; stereochemistry; stereoisomer; ylide

DESCRIPTION: In this renewal proposal, the principal investigator states that the long-term objective of this project is the efficient construction of enantiomerically pure biomedically important compounds, and its focus is on the use of chiral catalysts to achieve this goal. He reports that dirhodium(II)compounds with chiral carboxamide ligands (from pyrrolidone, oxazolidinone-, and imidazolidinone-carboxylates) have proven to be remarkably effective catalysts for highly enantioselective (greater than 90 percent ee) reactions of selected diazoacetate esters that result in intramolecular cyclopropanation or carbon-hydrogen insertion as well as in intermolecular cyclopropenation and that further advances in design and development will improve selectivities with existing transformations, and that they promise significant breakthroughs in new applications. It is indicated that intramolecular carbon-hydrogen insertion reactions will be employed for the syntheses of chiral prostaglandin precursors, of (-)-enterolactone, the parent of a family of endogenous mammalian lignan lactones, and of unique deoxysugar derivatives, including 2-deoxyxylolactone, 2- deoxyribonolactone, and their methyl and heteroatom derivatives. The deoxysugars are to be converted to their adenine and/or thymidine 5'- triphosphate derivatives and then subjected to in vitro evaluation of HIV reverse transcriptase and human DNA polymerase activity. The principal investigator reports that intramolecular cyclopropanation reactions afford highly structured cyclopropane derivatives whose applications have already included presqualene alcohol and renin inhibitors, and whose future promises to deliver optically active cyclopropane analogs of gamma-aminobutyric acid (GABA), among others. He notes that the catalytic methodology being developed provides the opportunity to control diastereoselectivity, chemoselectivity, and regioselectvity, together with enantioselectivity, and thereby achieve the synthesis of single products that are enantiomerically pure. It is indicated that diazoesters, diazoamides, diazoketones, and diazophosphonates are suitable reactants and that ylide generation/rearrangement, N-H and O-H insertion, C-H insertion, and cyclopropanation are targeted transformations. The influence on selectivity of methyl in diazopropanoate esters relative to hydrogen in diazoacetate esters is to be examined. It is noted that accurate predictions of absolute stereochemistry are made possible by evaluations made of the transition state for C-H insertion, cyclopropanation, and cyclopropenation, and computational modeling is in agreement. The principal investigator indicates that although an array of examples exist in which enantiocontrol 94 percent or better ee has been achieved, there are many more for which low to modest enantiocontrol was reported from uses of first generation chiral dirhodium(II) catalysts and that the second generation catalysts that are becoming available will make possible significant enhancement in enantiocontrol. He states that furthermore, the breadth of potential applications that will be evaluated during the proposed grant period is intended to establish the overall synthetic advantages/feasibility of this catalytic methodology.

描述：在此续签建议中，首席研究员说 该项目的长期目标是有效的 构造对映体纯生物医学重要化合物的结构， 它的重点是使用手性催化剂来实现这一目标。 他报告说，Dirhodium（II）具有手性羧酰胺配体的化合物 （摘自吡咯酮，黄唑啉酮和咪唑啉酮羧酸盐） 被证明是高度有效的催化剂 选定的对映选择性（大于90％的EE）反应 重18酶乙酸酯，导致分子内环植物或 碳 - 氢插入以及分子间环丙烯 设计和开发的进一步进步将改善 具有现有转型的选择性，他们承诺 新应用程序的重大突破。表明 分子内碳 - 氢插入反应将用于 手性前列腺素前体的合成，（ - ） - 肠肠酮， 一个内源性哺乳动物木lan林的家族和 独特的脱氧衍生物，包括2-脱氧基甲酯，2- 脱氧核糖核酸酮及其甲基和杂原子衍生物。这 脱氧糖要转换为腺嘌呤和/或胸苷5'-- 三磷酸衍生物，然后进行体外评估 HIV逆转录酶和人DNA聚合酶活性。这 首席研究者报告说分子内环植物化 反应提供高度结构化的环丙烷衍生物 申请已经包括presqualene酒精和肾素 抑制剂，并且其未来有望提供光学活跃 γ-氨基丁酸（GABA）等的环丙烷类似物。 他指出，开发的催化方法提供了 控制非映射性，化学选择性和 区域选择性以及对映选择性，从而实现 在对照层上纯的单个产品的合成。这是 表明重氮植物，重18酶酰胺，重量扬酮和 直接膦酸盐是合适的反应物，ylide 发电/重排，N-H和O-H插入，C-H插入以及 环丙谁是针对性的转化。影响 甲基在不杂化酯中相对于氢的选择性 重氮乙酸酯将进行检查。注意到准确 通过评估使绝对立体化学的预测成为可能 由C-H插入，环丙者和 环丙烯和计算建模是一致的。这 主要研究人员指出，尽管一系列示例 存在实现对映体94％或更高的EE的存在， 还报道了更多低到适中的对映射控制 从第一代手性dirhodium（ii）催化剂的用途中 可用的第二代催化剂将使 对映体控制可能会显着增强。他说 此外，潜在应用的广度 在拟议的赠款期间进行的评估旨在建立 这种催化方法的总体合成优势/可行性。