An Efficient Synthesis of LTD4 Antagonist L-699,392

A. O. King, E. G. Corley, R. K. Anderson, R. D. Larsen, T. R. Verhoeven, P. J. Reider, Y. B. Xiang, M. Belley, Y. Leblanc, M. Labelle, P. Prasit, R. J. Zamboni

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Abstract

The asymmetric synthesis of L-699,392 (1) [3-[[(1S)-[3(E)-[2-(7-chloroquinolinyl)ethenyl]phenyl]-3-(acetylphenyl)propyl]thio]-2(S)-methylpropanoic acid], a leukotriene antagonist, is accomplished in six steps starting from the monoaldehyde 2. The main framework of the molecule is formed via a Pd-catalyzed Heck reaction. The asymmetric center is introduced via the chiral reduction of the ketone 4 using optically active B-chlorodiisopinocampheylborane (10) derived directly from chloroborane and (−)-α-pinene. A very high asymmetric amplification is observed in which 95% ee product can be obtained from 70% optically pure α-pinene. Reagent 17, which is prepared in situ from methylmagnesium chloride and 2 equiv of lithium hexamethyldisilazide, is used to convert the methyl ester 5 to the methyl ketone 6 in one step with essentially no impurities formed under the reaction conditions. The thio side chain is finally incorporated by the displacement of the chiral mesylate 7 with complete inversion at the chiral center. The overall yield for the sequence is 42%.

Original languageEnglish (US)
Pages (from-to)3731-3735
Number of pages5
JournalJournal of Organic Chemistry
Volume58
Issue number14
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    King, A. O., Corley, E. G., Anderson, R. K., Larsen, R. D., Verhoeven, T. R., Reider, P. J., Xiang, Y. B., Belley, M., Leblanc, Y., Labelle, M., Prasit, P., & Zamboni, R. J. (1993). An Efficient Synthesis of LTD4 Antagonist L-699,392. Journal of Organic Chemistry, 58(14), 3731-3735. https://doi.org/10.1021/jo00066a027