title: Practical asymmetric synthesis of a potent PDE4 inhibitor via stereoselective enolate alkylation of a chiral aryl-heteroaryl secondary tosylate.
abstract: A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor (L-869,298, 1) is described. Catalytic asymmetric hydrogenation of thiazole ketone 5a afforded the corresponding alcohol 3b in excellent enantioselectivity (up to 99.4% ee). Activation of alcohol 3b via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl 3-pyridylacetate N-oxide 4a generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters 2b to 1 was accomplished via a one-pot deprotection, saponification, and decarboxylation sequence in excellent overall yield.
authors.affiliation: Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec H9R 4P8, Canada. paul_oshea@merck.com
authors.forename: Paul D
authors.initials: PD
authors.lastname: O'Shea
authors.forename: Cheng-yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Weirong
authors.initials: W
authors.lastname: Chen
authors.forename: Philippe
authors.initials: P
authors.lastname: Dagneau
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Frey
authors.forename: Edward J J
authors.initials: EJ
authors.lastname: Grabowski
authors.forename: Karen M
authors.initials: KM
authors.lastname: Marcantonio
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Lushi
authors.initials: L
authors.lastname: Tan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Tillyer
authors.forename: Amélie
authors.initials: A
authors.lastname: Roy
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Dalian
authors.initials: D
authors.lastname: Zhao
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; C475430:L 869298; D011725:Pyridines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4