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A Practical Synthesis of a γ-Secretase Inhibitor

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posted on 25.05.2007, 00:00 by Jeremy P. Scott, David R. Lieberman, Olivier M. Beureux, Karel M. J. Brands, Antony J. Davies, Andrew W. Gibson, Deborah C. Hammond, Chris J. McWilliams, Gavin W. Stewart, Robert D. Wilson, Ulf-H. Dolling
A practical and scaleable synthesis of the γ-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride configures the desired relative stereochemistry of the cyclohexane core with >99.9:0.1 dr. A second strategy, based on catalyst-controlled hydrogenation of racemic cyclohexene derivative 2, is more convergent but less diastereoselective (up to 75:25 dr). The common cyclohexanone intermediate 5 was constructed by a regioselective Diels−Alder condensation of a 1,1-disubstituted vinyl sulfone 6 with 2-trimethylsiloxybutadiene.