EFFECTIVE METHOD OF LIPASE-CATALYZED ENANTIORESOLUTION OF 6-ALKYLSULFANYL-1,4-DIHYDROPYRIDINES

A series of 6-alkylsulfanyl-1,4-dihydropyridines (±)-2 bearing a methoxycarbonylethyl group as a mild easily removable protecting group at S atom have been prepared by alkylation of 6-thioxo-1,4-dihydropyridines 1 with methyl bromopropionate. Candida antarctica lipase B (Novozyme 435, CAL-B) and Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been investigated in water-saturated diisopropyl ether (IPE) at 25 and 45 C. After acrylic acid methyl ester as leaving group cleavage and alkylation of formed enantioenriched 1,4-dihydropyridine-6-thiolates (-)-4 and (+)-4, optically active 1,4-dihydropyridines (-)-2, (+)-2, (-)-5 and (+)-5 were obtained in 85-99% enantiomeric excess. The experiments present the 6-(methoxycarbonylethyl)sulfanyl group as an essentially new enzymatically labile (activating) group. The ester group being 6 bonds remote from the chiral center undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of racemic 1,4-DHPs. This developed method offers access to mild optically active nucleophilic tiolates, which could be easily derivatized with electrophilic reagents. INTRODUCTION 1,4-Dihydropyridine (DHP) scaffold represents a heterocyclic unit of remarkable pharmacological efficiency. DHP derivatives depending on their structure may bind to the L-, Tand N-types calcium, * Corresponding author. Tel.: +371 26309236; fax: +371 67550338; e-mail adress: zigmars.andzans@inbox.lv. HETEROCYCLES, Vol. 89, No. 1, 2014 43