title: A practical synthesis of a gamma-secretase inhibitor.
abstract: A practical and scaleable synthesis of the gamma-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.
authors.affiliation: Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K. jeremy_scott@merck.com
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Scott
authors.forename: David R
authors.initials: DR
authors.lastname: Lieberman
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Beureux
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Gibson
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Hammond
authors.forename: Chris J
authors.initials: CJ
authors.lastname: McWilliams
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Stewart
authors.forename: Robert D
authors.initials: RD
authors.lastname: Wilson
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053138:Cyclohexenes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D053138:Cyclohexenes; D004791:Enzyme Inhibitors; C052568:cyclohexene; D053829:Amyloid Precursor Protein Secretases