A practical synthesis of a gamma-secretase inhibitor.
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.
Scott
Jeremy P
JP
Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K. jeremy_scott@merck.com
Lieberman
David R
DR
Beureux
Olivier M
OM
Brands
Karel M J
KM
Davies
Antony J
AJ
Gibson
Andrew W
AW
Hammond
Deborah C
DC
McWilliams
Chris J
CJ
Stewart
Gavin W
GW
Wilson
Robert D
RD
Dolling
Ulf-H
UH
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
D053138:Cyclohexenes; D004791:Enzyme Inhibitors; C052568:cyclohexene; D053829:Amyloid Precursor Protein Secretases