CHIRAL CATALYSTS FOR ENANTIOSELECTIVE SYNTHESES

用于对映选择性合成的手性催化剂

• 批准号: 6179371
• 负责人: Michael PATRICK Doyle
• 金额: $ 13.78万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6179371
• 关键词: carbene; catalyst; chemical synthesis; copper; cyclization; cyclopropanes; lactones; lignans; organometallic compounds; rhodium; stereochemistry; stereoisomer; ylide

DESCRIPTION: (Applicant's Abstract) The long-term objective of this research is the effective and efficient synthesis of enantiomerically pure, biomedically important compounds by carbene methodologies that employ chiral dirhodium(II) or copper(I) catalysts. Carbene methodologies offer a spectrum of pathways for carbon-carbon bond formation extending from addition to insertion and ylide generation/rearrangement that have been used for the construction of lignans, 2-deoxyxylolactone, and a variety of lactones and lactams in high enantiomeric excess (94 percent or more ee) with exceptional diastereo-, regio-, and chemoselectivity. We have designed and synthesized four classes of dirhodium(II) carboxamidates whose reactivities and selectivities offer unique advantages to asymmetric syntheses that involve metal carbene intermediates, and a further expansion in catalyst capabilities is anticipated. Chiral copper catalysts, mainly based on chiral bis-oxazoline ligands, will also be evaluated. New methods are proposed for the highly selective synthesis of acetal-protected 2-deoxyxylolactone and 2-deoxyribonolactone, substituted derivatives, and their aza-sugar analogs via C-H insertion. This same transformation will be the core for the synthesis of imperanene, which shows aggregation inhibitory activity. Metal-assisted ylide generation and rearrangement will be directed to the asymmetric synthesis of multifunctional/multisubstituted amino acids as well as to lignans having a hydroxyl group at the alpha position, such as trachelogenin and wikstromol whose biological effects are reported to be intriguing. Ylide generation within peptides and proteins will be investigated to determine selectivity, local or remote. Macrocyclic cyclopropanation, a new and exceptionally facile methodology, offers convenient entry to casbene as well as to the diterpenoid lactones pinnatin A and pinnatin B which are cancer cell cytotoxins. Tandem reactions of bis-diazoesters either via cyclopropanation or insertion affords the opportunity to achieve complex syntheses with exacting selectivity that includes double diastereoselection (up to 99.4 percent ee). Finally, enantioselective cyclopropanation with diazo-methane, which has been elusive, will be examined in critical detail using chiral copper(I) and dirhodium(II) catalysts.

描述：（申请人的摘要）本研究的长期目标是 有效且高效地合成对映体纯的、生物医学的 采用手性二铑(II) 的卡宾方法得到的重要化合物 或铜(I)催化剂。卡宾方法学提供了一系列途径 碳-碳键的形成从加成延伸到插入和叶立德 用于构建木脂素的生成/重排， 2-脱氧木内酯，以及多种高对映体的内酯和内酰胺 过量（94% 或更多 ee），具有特殊的非对映异构体、区域异构体和 化学选择性。我们设计并合成了四类 二铑(II)甲酰胺酯，其反应活性和选择性提供了独特的 涉及金属卡宾中间体的不对称合成的优点， 预计催化剂能力将进一步扩大。手性铜 主要基于手性双恶唑啉配体的催化剂也将被 评价。提出了高选择性合成新方法 缩醛保护的 2-脱氧木内酯和 2-脱氧核糖内酯，被取代 衍生物及其通过 C-H 插入的氮杂糖类似物。这个同样的 转化将是合成imperanene的核心，这表明 聚集抑制活性。金属辅助叶立德生成和 重排将直接导致不对称合成 多官能/多取代氨基酸以及具有 α位羟基，例如trachelogenin和wikstromol 据报道，其生物效应很有趣。内叶立德生成 将研究肽和蛋白质以确定选择性、局部或 偏僻的。大环环丙烷化，一种新型且极其简便的方法 方法，提供了方便的进入 casbene 以及二萜类化合物的途径 内酯pinnatin A 和pinnatin B 是癌细胞的细胞毒素。串联 双重氮酯通过环丙烷化或插入反应可以得到 有机会以严格的选择性实现复杂的合成 包括双非对映选择（高达 99.4% ee）。最后， 重氮甲烷的对映选择性环丙烷化反应一直难以捉摸， 将使用手性铜 (I) 和二铑 (II) 进行关键细节检查 催化剂。