Effect of acyl chain length and branching on the enantioselectivity of Candida rugosa lipase in the kinetic resolution of 4-(2-difluoromethoxyphenyl)-substituted 1,4-dihydropyridine 3,5-diesters.
Since 2,6-dimethyl-4-aryl-1,4-dihydropyridine 3,5-diesters themselves are not hydrolyzed by commercially available hydrolases, derivatives with spacers containing a hydrolyzable group were prepared. Seven acyloxymethyl esters of 5-methyl- and 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate were synthesized and subjected to Candida rugosa lipase (CRL) catalyzed hydrolysis in wet diisopropyl ether. A methyl ester at the 5-position and a long or branched acyl chain at C3 gave the highest enantiomeric ratio (E values). The most stereoselective reaction (E = 21) was obtained with 3-[(isobutyryloxy)methyl] 5-methyl 4-(2-difluoromethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and this compound was used to prepare both enantiomers of 3-methyl 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate. The absolute configuration of the enzymatically produced carboxylic acid was established to be 4R by X-ray crystallographic analysis of its 1-(R)-phenylethyl amide.
Sobolev
Arkadij
A
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,6703 HB Wageningen, The Netherlands.
Franssen
Maurice C R
MC
Vigante
Brigita
B
Cekavicus
Brigita
B
Zhalubovskis
Raivis
R
Kooijman
Huub
H
Spek
Anthony L
AL
Duburs
Gunars
G
de Groot
Aede
A
D001665:Binding Sites; D002175:Candida / Q000201:enzymology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D008049:Lipase / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D013379:Substrate Specificity
D002264:Carboxylic Acids; D004095:Dihydropyridines; D004952:Esters; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine; C038806:1,4-dihydropyridine; D006867:Hydrolases; D008049:Lipase