DESIGN AND USE OF ASYMMETRIC HYDROGENATION CATALYSTS

不对称加氢催化剂的设计与应用

• 批准号: 2189803
• 负责人: MARK J BURK
• 金额: $ 10.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2189803
• 关键词: aminoacid; catalyst; chemical synthesis; hydrazines; ketones; protonation; saturated /unsaturated bonds; stereoisomer; synthetic peptide

DESCRIPTION: The main objectives of this revised application are to design and develop general and highly enantioselective hydrogenation methodologies that may be used for the preparation of various classes of biologically important compounds. The principal investigator notes that growing concern over the health risks associated with racemic drug development has greatly increased the demand for new effective strategies for enantioselective synthesis and that asymmetric catalytic methods are particularly appealing from the standpoint of efficiency, versatility, and economic feasibility. The principal investigator reports that his preliminary studies indicate that he may have discovered the most selective and broadly effective catalysts known for the hydrogenation of alpha-enamides to alpha-amino acid derivatives and that on the basis of these results, he proposes to employ his DuPHOS-Rh catalysts for the preparation of valuable beta- amino acids and alpha- aminophosphonic acids and that moreover, to expand the utility of his hydrogenation process for the production of nonproteinaceous alpha-amino acids, he proposes to fully develop a tandem catalysis procedure involving catalytic asymmetric hydrogenation of functional alpha-enamides, followed by palladium-catalyzed cross- coupling. He is to prepare a series of boronic acid- and tributyltin- substituted arylalanines, which are to provide simple access to a very diverse range of novel ring-substituted alpha-amino acids through cross- coupling with readily available organobromides and triflates. It is noted that incorporation of dihydroxyboryl-arylalanines into peptides could lead to a powerful method for the multiple, simultaneous synthesis of many analogous peptides from a single peptide intermediate. The principal investigator indicates that these studies will facilitate his long-term goals involving the design of novel bioactive peptides, such as chemoattractant receptor antagonists and peptides capable of sequence-specific binding to DNA. The second main objective is the development of general catalytic strategies for the production of enantiomerically pure hydrazines and amines. The principal investigator reports that he recently has achieved high enantioselectivity in hydrogenation of the C=N double bond of numerous N-benzoylhydrazones and that methods that should greatly improve the present process are proposed in an effort to develop a truly practical catalytic asymmetric reductive animation procedure for the conversion of prochiral ketones into chiral hydrazine and amine derivatives. He notes that he will exploit the unique suitability of this reaction for the preparation of specific alpha-hydrazino acids. It is further indicated that a second potentially general route to chiral amines also is proposed and involves enantioselective hydrogenation of the C=C double bond of enamides. The development of a broadly effective catalyst for the highly enantioselective hydrogenation of alpha-keto esters and simple, unfunctionalized ketones is said to remain an important goal. It is indicated that rhodium and ruthenium catalysts containing newly designed chiral bidentate and polydentate chiral ligands will be examined for activity and selectivity and that once optimized, these catalysts will be employed in an efficient asymmetric catalytic synthesis of the potent ACE inhibitor benazepril.

描述：此修订后的应用程序的主要目标是 设计和开发通用和高对映选择性氢化 可用于准备各种课程的方法 重要的生物化合物。 首席研究员指出， 人们越来越关注外消旋药物的健康风险， 发展大大增加了对新的有效的需求， 对映选择性合成策略及不对称催化 这些方法从效率的观点来看特别有吸引力， 多功能性和经济可行性。 首席研究员报告说他的初步研究表明 他可能发现了最有选择性和广泛有效的 已知用于α-烯酰胺氢化成α-氨基的催化剂 酸衍生物，并在这些结果的基础上，他建议， 使用他的DuPHOS-Rh催化剂制备有价值的β- 氨基酸和α-氨基膦酸，而且， 他的氢化方法用于生产 非蛋白质α-氨基酸，他建议充分开发一个串联 涉及催化不对称氢化的催化方法 功能性α-烯酰胺，然后是钯催化的交叉， 偶合器. 他要准备一系列硼酸-和三丁基锡- 取代的芳基丙氨酸，这是为了提供一个非常简单的途径， 各种各样的新的环取代的α-氨基酸，通过交叉， 与容易获得的有机溴化物和三氟甲磺酸酯偶联。 是 注意到将二羟基硼基-芳基丙氨酸掺入肽中 可能会导致一个强大的方法，多，同时合成 从一个单一的肽中间体的许多类似的肽。 的 首席研究员表示，这些研究将有助于他 长期目标涉及设计新的生物活性肽，如 作为化学引诱物受体拮抗剂和肽， 序列特异性结合DNA。 第二个主要目标是开发通用催化剂 生产对映体纯肼的策略， 胺。 首席研究员报告说，他最近 在C=N双键的氢化中实现了高的对映选择性 大量的N-苯甲酰腙， 改进目前的过程中提出了努力发展一个真正的 实用催化不对称还原胺化方法 将前手性酮转化为手性肼和胺 衍生物. 他指出，他将利用独特的适用性， 该反应用于制备特定的α-肼基酸。 还指出，第二种可能的通用路线是： 还提出了手性胺， 烯酰胺的C=C双键的氢化。 开发一种广泛有效的催化剂， α-酮酯的对映选择性氢化和简单， 据说未官能化的酮仍然是一个重要的目标。 是 表明，铑和钌催化剂含有新设计的 将检查手性二齿和多齿手性配体的 活性和选择性，并且一旦优化，这些催化剂将 可用于有效的不对称催化合成有效的 ACE抑制剂贝那普利。