Sobolev Arkadij, Franssen Maurice C R, Vigante Brigita, Cekavicus Brigita, Zhalubovskis Raivis, Kooijman Huub, Spek Anthony L, Duburs Gunars, de Groot Aede
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,6703 HB Wageningen, The Netherlands.
J Org Chem. 2002 Jan 25;67(2):401-10. doi: 10.1021/jo0104025.
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.
由于2,6 - 二甲基 - 4 - 芳基 - 1,4 - 二氢吡啶3,5 - 二酯本身不会被市售水解酶水解，因此制备了带有可水解基团间隔基的衍生物。合成了5 - 甲基 - 和5 - (2 - 丙氧基乙基)4 - [2 - (二氟甲氧基)苯基]-2,6 - 二甲基 - 1,4 - 二氢 - 3,5 - 吡啶二甲酸的七种酰氧基甲酯，并在湿的二异丙醚中进行了皱褶假丝酵母脂肪酶(CRL)催化的水解反应。5位的甲酯和C3位的长或支链酰基链给出了最高的对映体比率(E值)。用3 - [(异丁酰氧基)甲基]5 - 甲基4 - (2 - 二氟甲氧基苯基)-2,6 - 二甲基 - 1,4 - 二氢吡啶 - 3,5 -二羧酸酯获得了最具立体选择性的反应(E = 21)，并且该化合物用于制备3 - 甲基5 - (2 - 丙氧基乙基)4 - [2 - (二氟甲氧基)苯基]-2,6 - 二甲基 - 1,4 - 二氢 - 3,5 - 吡啶二甲酸酯的两种对映体。通过对其1 - (R)-苯乙酰胺进行X射线晶体学分析，确定酶促产生的羧酸的绝对构型为4R。
