Practical asymmetric synthesis of a potent PDE4 inhibitor via stereoselective enolate alkylation of a chiral aryl-heteroaryl secondary tosylate.
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.
O'Shea
Paul D
PD
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
Chen
Cheng-yi
CY
Chen
Weirong
W
Dagneau
Philippe
P
Frey
Lisa F
LF
Grabowski
Edward J J
EJ
Marcantonio
Karen M
KM
Reamer
Robert A
RA
Tan
Lushi
L
Tillyer
Richard D
RD
Roy
Amélie
A
Wang
Xin
X
Zhao
Dalian
D
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
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; C475430:L 869298; D011725:Pyridines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4