CATALYTIC, ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

催化、对映选择性羟醛加成反应

• 批准号: 2415329
• 负责人: ERICK M. CARREIRA
• 金额: $ 27.52万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2415329
• 关键词: X ray crystallography; aldehydes; catalyst; chemical addition; chemical bond; drug design /synthesis /production; enol; enolate; ethers; macrolide antibiotics; measurement; nuclear magnetic resonance spectroscopy; osmotic pressure; silicon compounds; stereochemistry; titanium

We have prepared two members of a class of Ti(IV) complexes which catalyze (0.5-2mol%) the addition of silyl enol eithers, alkyl enol ethers, and dienolates to aldehydes. The parent complex is readily prepared from Ti(OiPr)4 and a Schiff-base tridentate ligand derived from 2-amino-2'- hydroxy-1,1'-binapthyl. A ligand scaffolding motif based on this binaphthyl possesses several salient features for ligand design: (1) facile synthesis; (2) easy derivatization of the amine by condensation with aldehydes and sulfonyl chlorides, and, consequently, (3) amenability to incremental variation in the overall electronics and sterics of the metal- ligand complex. These feature will allow us to fully examine the scope of these catalysts for aldehyde addition reactions. On the basis of these preliminary observations, the broad aims of this proposals are: (1) To study the enantioselective aldol addition process with the intent of developing powerful catalytic, C-C bond-forming methodology for the addition of silyl and alkyl enolates and dienolates to aldehydes. (2) To expand our study of reaction parameters to include solvent effects, reaction concentration, and method of catalyst preparation with the intent of developing a practical large-scale protocol. (3) To develop a reagent based catalyst that is able to override the inherent stereochemical biases of chiral aldehyde chiral methyl ketone- enolate addition reactions. (4) To gain insight into the solution structure of the catalyst and catalyst-aldehyde complex by 1H NMR spectroscopy and X-ray crystallography. (5) To apply the catalytic process to the synthesis of macrolactin A, an antibiotic not readily available from natural sources but shown to protect T-lymphoblasts from HIV infection. The successful development of a catalytic, enantioselective methodology for the preparation of optically active beta-hydroxy esters and delta-hydroxy- alpha, beta-unsaturated esters provide access to compounds that are not otherwise directly available by modern, catalytic enantioselective methodology. moreover, these optically adducts are useful starting materials for the synthesis of stereochemically complex structures with potential applications in human medicine. We anticipate that the study of novel Ti(IV) complexes with tri-dentate ligands will lay a foundation for the development of other catalysts for related carbonyl addition reactions.

我们已经准备了两个催化的Ti（IV）络合物的两个成员 （0.5-2mol％）添加甲硅烷基烯醇，烷基烯醇醚和 二烯为醛。 父母综合体很容易从 ti（oipr）4和schiff-base Trentate Trentate配体来自2-amino-2'--- 羟基-1,1'-二邻苯二酚。 基于此的配体脚手架主题 Binaphyly具有配体设计的几个显着特征：（1） 便利合成； （2）通过与 醛和磺酰氯，因此，（3）对 金属的总体电子和集体的增量变化 配体配合物。 这些功能将使我们能够充分检查 这些用于醛添加反应的催化剂。 根据这些初步观察，这是广泛的目标 建议是： （1）研究意图 开发强大的催化，C-C键形成方法论 甲硅烷基和烷基烯醇和二烯为醛。 （2）扩大我们对反应参数的研究以包括溶剂效应， 反应浓度和催化剂制备方法 制定实用的大规模协议。 （3）开发基于试剂的催化剂，能够覆盖 手性醛手性甲基酮的固有立体化学偏见 - 掺杂添加反应。 （4）深入了解催化剂的溶液结构和 1H NMR光谱和X射线晶体学通过1H催化剂 - 醛配合物。 （5）将催化过程应用于大乳酸酯A的合成 抗生素不容易从天然来源获得，而是可保护的 来自艾滋病毒感染的T叶膜细胞。 成功开发了一种催化，对映选择性方法论 光学活性β-羟基酯和三角洲 - 羟基的制备 alpha，β-不饱和酯提供了对非化合物的访问 否则，现代催化对映选择性直接可用 方法论。 此外，这些光学上加合物很有用 与立体化学复杂结构合成的材料 人类医学的潜在应用。 我们预计研究的研究 带有三齿配体的新型Ti（IV）配合物将为 与羰基添加反应的其他催化剂的开发。