DESIGN AND USE OF ASYMMETRIC HYDROGENATION CATALYSTS

描述：本修订申请的主要目标是 设计和开发通用型和高对映选择性加氢反应 可用于准备各种课程的方法 具有重要生物学意义的化合物。首席调查员注意到 人们对外消旋药物带来的健康风险的日益担忧 发展极大地增加了对新的有效的需求 对映体选择性合成及不对称催化策略 从效率的角度来看，方法特别吸引人， 通用性和经济可行性。 首席调查员报告说，他的初步研究表明 他可能已经发现了最有选择性和最广泛有效的 已知的用于α-烯胺加氢制α-氨基的催化剂 基于这些结果，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，扩大 HIS加氢工艺在甲苯加氢生产中的应用 非蛋白质的α-氨基酸，他建议完全开发一个串联 涉及催化不对称氢化的催化过程 功能性α-烯胺，然后是钯催化的交叉- 耦合。他将准备一系列的硼酸和三丁基锡- 取代芳基丙氨酸，这是提供一个非常简单的访问 不同种类的新的环取代的α-氨基酸通过交叉- 与现成的有机溴和三氟化物偶联。它是 注意到二羟基硼基芳基丙氨酸掺入到多肽中 可能导致一种强大的方法来进行多个同时合成 来自单一多肽中间体的许多类似的多肽。这个 首席调查员表示，这些研究将有助于他的 涉及设计新的生物活性多肽的长期目标，如 作为趋化受体拮抗剂和能够 与DNA的序列特异性结合。 第二个主要目标是开发通用催化剂 生产对映体纯肼和联氨的策略 胺。首席调查员报告说，他最近 在C=N双键加氢反应中获得高对映选择性 大量的N-苯甲酰肼类化合物，而这些方法应该大大 改进目前的工艺是为了努力开发一个真正的 实用的催化不对称还原动画程序 前手性酮转化为手性肼和胺 衍生品。他指出，他将利用这种独特的适宜性 该反应用于制备特定的α-肼基酸。 据进一步指出，第二条可能的一般路线是 手性胺也被提出并涉及对映体选择性。 烯胺类化合物中C=C双键的氢化。 一种广谱高效催化剂的开发 α-酮酯的对映选择性氢化和简单， 没有官能化的酮据说仍然是一个重要的目标。它是 表明含有新设计的Rh和Ru催化剂 手性双齿和多齿手性配体将被检查 活性和选择性，一旦优化，这些催化剂将 可用于高效的不对称催化合成 血管紧张素转换酶抑制剂苯那普利。

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.