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：在这个更新提案中，主要研究人员指出 该项目的长期目标是高效 构建对映体纯的生物医学重要化合物， 其重点是利用手性催化剂来实现这一目标。 他报道了二铑(II)化合物与手性甲酰胺配体 （来自吡咯烷酮、恶唑烷酮和咪唑烷酮羧酸盐） 已被证明是非常有效的催化剂 选定的对映选择性（大于 90% ee）反应 导致分子内环丙烷化的重氮乙酸酯或 碳氢插入以及分子间环丙烯化 设计和开发的进一步进步将改善 现有转型的选择性，并且它们承诺 新应用取得重大突破。表明的是 分子内碳氢插入反应将用于 (-)-肠内酯的手性前列腺素前体的合成， 内源哺乳动物木酚素内酯家族的亲本，以及 独特的脱氧糖衍生物，包括2-脱氧木内酯、2- 脱氧核糖内酯及其甲基和杂原子衍生物。这 脱氧糖将转化为其腺嘌呤和/或胸苷 5'- 三磷酸衍生物，然后进行体外评价 HIV 逆转录酶和人类 DNA 聚合酶活性。这 主要研究者报告说，分子内环丙烷化 反应提供高度结构化的环丙烷衍生物，其 应用已经包括前置角鲨烯醇和肾素 抑制剂，其未来有望提供光学活性 γ-氨基丁酸（GABA）的环丙烷类似物等。 他指出，正在开发的催化方法提供了 控制非对映选择性、化学选择性和 区域选择性和对映选择性，从而实现 对映体纯的单一产物的合成。这是 表明重氮酯、重氮酰胺、重氮酮和 重氮膦酸盐是合适的反应物并且叶立德 生成/重排、N-H 和 O-H 插入、C-H 插入以及 环丙烷化是定向转化。对的影响 重氮丙酸酯中甲基相对于氢的选择性 重氮乙酸酯将被检查。值得注意的是，准确 通过评估可以预测绝对立体化学 由 C-H 插入、环丙烷化的过渡态组成 环丙烯化和计算模型是一致的。这 首席研究员表示，尽管有一系列例子 其中已实现对映体控制 94% 或更好的 ee， 据报道还有许多其他化合物的对映体控制程度较低至中等 来自第一代手性二铑(II)催化剂的使用 即将推出的第二代催化剂将使 对映体控制可能显着增强。他指出 此外，潜在应用的广度 在拟议的赠款期内进行评估的目的是确定 这种催化方法的总体综合优势/可行性。