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Paper | Regular issue | Vol 89, No. 1, 2014, pp.43-58
Published online, 27th November, 2013
DOI: 10.3987/COM-13-12839
Effective Method of Lipase-Catalyzed Enantioresolution of 6-Alkylsulfanyl-1,4-dihydropyridines

Zigmars Andzans,* Ilze Adlere, Aleksandrs Versilovskis, Laura Krasnova, Signe Grinberga, Gunars Duburs, and Aivars Krauze

*Dept. Organic Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia


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 (Novozym 435®, CAL-B) - and Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been investigated in water-saturated diisopropylether (IPE) at 25 and 45 oC. Further deacrylation and alkylation of enantioenriched 1,4-dihydropyridine-6-thiolates (-)4 and (+)4 gave rise to optically active 1,4-dihydropyridines (-)2, (+)2, (-)5 and (+)5 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.