Candida rugosa lipase-catalysed kinetic resolution of polycyclic analogues of 1,4-dihydropyridines

1,4-Dihydropyridines (1,4-DHPs) are an important class of calcium channel antagonists. Novel activities of 1,4-DHPs, such as neuroprotective, antineurodegenerative, cognition and memory enhancing, antidiabetic, anti-inflammatory and antiviral have been also described. Chirality plays an important role in the biological activity of 1,4-DHPs. The use of enantiopure and racemic drugs is regulated by specific rules in EC (ref.1). Classical Hantzsch synthesis of 1,4-DHPs is not enantioselective, so enantioselective synthetic methodologies have to be developed. Polycyclic analogues of 1,4-DHPs in enantiopure form are desired for extended pharmacological studies, since racemic 1,4-dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides 1 and 5-oxo-4,5-dihydro-1,4-indeno[1,2-b]pyridines 2 have exhibited coronary dilating and anticancer activities; they have been also found as active glutathione S-transferase inhibitors. The standard resolution technique of monocyclic 1,4-DHPs, such as incorporation of an enzymatically labile acyloxymethyl group2¿4 has been successfully applied for the kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy) phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate 3 (see Scheme). Careful screening yielded Candida rugosa lipase (CRL) as the preferred biocatalyst. A remarkably good E-value was obtained for the CRL-catalysed resolution of this bulky 1,4-DHP derivative. The enantioselectivity of C. rugosa lipase can be improved by changing the reaction medium and the temperature. The transition from water-saturated IPE to a solution of n-butanol in toluene that was water-saturated at 45 °C resulted in an increase of enantiomeric ratio from E = 12 to E = 28. More derivatives of the polycyclic 1,4-DHP will be studied