jo070407n_si_002.cif (13.98 kB)
A Practical Synthesis of a γ-Secretase Inhibitor
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posted on 2007-05-25, 00:00 authored 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. DollingA 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.
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Secretasediastereoselectivemoietieconjugate reductionPractical Synthesisdifluorophenylconvergentchlorophenylsulfonylalternativeacrylonitriletrisubstituted cyclohexane coreDielproceedingregioselectivehydrogenationstrategysulfonedisubstituted cyclohexanoneracemic cyclohexenestereochemistryInhibitorAconfigurepropionic acidscaleable synthesissecretasedrcondensationcyclohexane coretrimethylsiloxybutadieneinhibitor
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