Patent Application: US-71213900-A

Abstract:
this invention is to develop novel transition metal catalysts for the practical synthesis of important chiral molecules . the invention emphasizes asymmetric catalysis based on chiral amine oxazolinyl ligands and related ligands . specially , a direct asymmetric hydrogenation system based on ru - ambox catalyst was discovered .

Description:
asymmetric catalytic transfer hydrogenation using 2 - propanol as a hydrogen source offers an attractive route of reducing unsymmetric ketones to chiral alcohols . 1 among the recently developed efficient transition - metal - based chiral catalysts , 2 the most notably is the ru ( ii - tsdpen ( n -( p - tolylsulfonyl )- 1 , 2 - diphenylethylene - diamine ) system reported by noyori . 3 they suggest that an nh moiety in the ligand may promote a cyclic transition state through hydrogen bonding to ketone substrate , hence greatly increases substrate affinity to the catalyst active site , inducing high activity and optical purity . earlier results from noyori and lemaire have also shown similar “ nh effect ”. 4 . 5 in a continuous effort of developing chiral tridentate ligands for asymmetric catalysis , 2a - c we have designed bis ( oxazolinylmethyl ) amine ( ambox ) ligand system . chiral tridentate ligands tend to form a deep chiral concave around the metal center once coordinated to a transition metal . the two r groups on oxazoline rings of pybox form a highly enantioselective “ chiral fence ”, which enables better differentiation of the re and si faces of incoming substrates . one property of the ligand ambox is a similar cyclic transition state as suggested by noyori , and effectively catalyzation of asymmetric transformations - for instance , hydride - transfer reduction of ketones ( fig1 ). we disclosed the synthesis of bis [ 4 -( r )- phenyloxazolin - 2 - yl - methyl ) amine ( 1 , ( r )- ph - ambox ) and its initial results from transfer hydrogenation of aromatic ketones before in y . jiang , q . jiang , x . zhang , j . am . chem . soc . 1998 , 120 , 3817 . in the current invention , a direct asymmetric catalytic hydrogenation procedure using h 2 is presented using the ru - ambox system . compared with the transfer asymmetric hydrogenation system , the direct hydrogenation system offers many advantages : 1 ) the reaction is irreversible and 100 % conversion can be achieved with high substrate concentration , 2 ) mild reaction condition such as about 5 atom h 2 pressure can be used and the reaction is clean ; 3 ) the reaction is highly practical and scalable because & gt ; 1000 turnovers can be conveniently achieved ; 4 ) a large number of ketones and in - dries can be reduced with the current system for the efficient synthesis of alcohols and amines . schemetic depiction of transition metal catalysts of chiral tridentate nitrogen ligands with an nh function . cycli ( transition state of transfer hydrogenation of prochiral ketones ( see fig9 ). under the optimal conditions , a variety of aromatic ketones have been reduced to their secondary alcohols with high ee and mostly satisfactory yield ( table 1 ). both ee and chemical yield are delicately affected by substrates &# 39 ; steric and electronic properties . the steric hindrance effect of the alkyl sides of ketone substrates is apparent . b % ee and % conversion were determined by gc analysis with supelco chiral capillary columns . absolute configurations were determined by comparing optical rotations with literature values . all major secondary alcohol products are of the s configuration . catalytic hydrogenation procedures : in a flame - dried 50 ml schlenk flask was added [ rucl 2 ,( pph 3 ) 3 ] ( 38 mg , 0 . 04 mmol ) and 20 ml 2 - propanol , followed by 0 . 44 ml ( r )- ph - ambox ligand solution ( 0 . 1 m in toluene ). the reaction was stirred under nitrogen on an oil bath ( 82 ° c .) for 5 hours , giving a clear dark green solution . after the removal of solvent on high vacuum , the greenish residue was washed with freshly distilled diethyl ether ( 3 × 5 ml ). it was then redissolved in 20 ml 2 - propanol and divided into ten equal parts . to each part ( 2 ml ) of the catalyst solution was introduced 0 . 4 mmol of a ketone substrate . the reaction mixture was stirred at rt for a brief period before 0 . 1 ml of naopr i solution ( 0 . 1 m in 2 - propanol ) was finally added in one portion . the ten reaction ampuls were placed in an autoclave and charged with hydrogen gas ( initial pressure 5 atm ). the reactions were allowed to stir at rt overnight . a small portion of each reaction mixture was passed through a silica gel plug , then eluted with diethyl ether . both reaction conversion and enantiomeric excess were then determined by gc analysis . 1 . reviews : ( a ) zassinovich , g . ; mestroni , g . ; gladiali , s . chem . rev . 1992 , 92 , 1051 . 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