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.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Cyclic N-Oxides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Cyclic N-Oxides/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Pyridines/pharmacology , StereoisomerismABSTRACT
[reaction: see text] The palladium-catalyzed cyanation reaction is known to be sensitive to dissolved cyanide. Investigation into some causes of high levels of dissolved cyanide is presented here, along with a robust solution to this problem.
