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

Shi Yao-Jun, 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

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

A highly convergent, asymmetric synthesis of L-768,673, an I(ks) Class III antiarrhythmic 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 resolution-racemization of (±)-amine provided the desired (+)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)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 olefin. Ru- catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.

Original languageEnglish (US)
Pages (from-to)909-918
Number of pages10
JournalTetrahedron
Volume55
Issue number4
DOIs
StatePublished - Jan 22 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Asymmetric synthesis
  • Benzodiazepines
  • Oximes
  • Resolution-racemization

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    Yao-Jun, S., Wells, K. M., Pye, P. J., Choi, W. B., Churchill, H. R. O., Lynch, J. E., Maliakal, A., Sager, J. W., Rossen, K., Volante, R. P., & Reider, P. J. (1999). Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673. Tetrahedron, 55(4), 909-918. https://doi.org/10.1016/S0040-4020(98)01098-9