The asymmetric synthesis of L-699,392 (1) [3-[[(1S)-[3(E)-[2-(7-chloroquinolinyl)ethenyllphenyll-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 (-)-a-pinene. A very high asymmetric amplification is observed in which 95% ee product can be obtained from 70% optically pure a-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 7%.
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An Efficient Synthesis of LTD4 Antagonist L-699,392.-The synthesis of the title compound (IX) involves a palladium-catalyzed Heck reaction to form the main framework (IV), the asymmetric reduction of the ketone (IV), and the transformation of the benzoate (V) into the acetophenone (VII) using a novel magnesiate generated from methylmagnesium chloride (VI) and lithium hexamethyldisilazide. -(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.
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