Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

✍ Scribed by Yao-Jun Shi; Kenneth M. Wells; Philip J. Pye; Woo-Baeg Choi; Hywyn R.O. Churchill; Joseph E. Lynch; Ashok Maliakal; Jess W. Sager; Kai Rossen; R.P. Volante; Paul J. Reider

• Book ID: 104209038
• Publisher: Elsevier Science
• Year: 1999
• Tongue: French
• Weight: 539 KB
• Volume: 55
• Category: Article
• ISSN: 0040-4020
• DOI: 10.1016/s0040-4020(98)01098-9

✦ Synopsis

A highly convergent, asymmetric synthesis of L-768,673, an Iks Class III antiarrythmic drug candidate, is described. Synthesis of the racemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(~-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolutionracemization of (_+)-amine provided the desired (+)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifiuoromethyl)benzene with n-BuLi in the presence of a catalytic amount of 2,2',6,6'-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefm. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifiuoromethyl)phenylacetic acid in 35% overall yield. A modified Sehotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.