title: 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.
abstract: 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.
authors.affiliation: Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,6703 HB Wageningen, The Netherlands.
authors.forename: Arkadij
authors.initials: A
authors.lastname: Sobolev
authors.forename: Maurice C R
authors.initials: MC
authors.lastname: Franssen
authors.forename: Brigita
authors.initials: B
authors.lastname: Vigante
authors.forename: Brigita
authors.initials: B
authors.lastname: Cekavicus
authors.forename: Raivis
authors.initials: R
authors.lastname: Zhalubovskis
authors.forename: Huub
authors.initials: H
authors.lastname: Kooijman
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Spek
authors.forename: Gunars
authors.initials: G
authors.lastname: Duburs
authors.forename: Aede
authors.initials: A
authors.lastname: de Groot
mesh_terms: 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
chemical_list: 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