Enzymatic resolution of 4-N-phenylacetylamino-derivatives obtained from multicomponent reactions using PenG amidase and in silico studies

The three component coupling reaction of aldehydes, phenylacetamide and dienophiles gave the corresponding N-phenylacetamidocyclohexene derivatives in good yields (55-70%) and high regioselectivity. For the first time, enzymatic kinetic resolution of this class of compounds has been achieved. The enantioselective hydrolysis of 4-N-phenylacetylamino-cis-3a,4,7,7a-hexahydroisoindole-1,3-dione derivatives using Penicillin G amidase (PGA) from Escherichia coli gave the remaining enantiomer with ee-values from 30 to 70% at 50% conversion. On the basis of molecular modeling predictions, 1-N-phenylacetylamino-2-cyano-5-cyclohexene derivatives were synthesized. The kinetic resolution resulted in ees up to 99%. The differences of the observed selectivities confirmed the in silico predictions based on the simulation of enzyme-substrate interactions. (C) 2003 Elsevier Ltd. All rights reserved.