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%.
All Science Journal Classification (ASJC) codes
- Organic Chemistry