A New Route to Papaverine Analogs via Photocyclization of Substituted N-Acyl-α-dehydrophenylalaninamides

Z)-N-Phenylacetyl-α-dehydro(3,4-dimethoxyphenyl)alaninamide derivatives [(Z)-1] were prepared in satisfactory yields, starting from 3,4dimethoxybenzaldehyde.On irradiation in methanol, regioselective photocyclization of these derivatives proceeded to give papaverine analogs in good yields.Substituents introduced into (Z)-1 were found to exert only a minor effect on the conversion of the starting isomers (1) as well as on the selectivity of the analogs which were formed along with 1-azetines.Photochemistry has continued to contribute to the development of efficient and selective transformations of organic materials into pharmaceutically important heterocyclic compounds. 1It is well-known that numerous biomolecules and natural products contain various types of heterocyclic compounds as their principal constituents.We have been interested in exploring the excited-state reactivities of αdehydroamino acid derivatives, one of the main constituents of some antibiotics, 2 as well as in demonstrating the synthetic utility of these photochemical reactions.Taking into account that α-dehydroamino acidderived products may possess high biological activities, we embarked on a systematic study regarding photochemical reactivities of aryl-substituted α-dehydroalanine derivatives and discovered novel photocyclization reactions forming pharmaceutically useful products. 3,4One of the important findings is that the photocyclization of substituted (Z)-N-acetyl-α-dehydrophenylalaninamides in methanol and acetonitrile constitutes a useful method for constructing the isoquinoline skeleton. 3 Very recently, we found that the introduction of a methoxy group at the meta position on the styryl benzene ring accomplishes regioselective photocyclization to give 6-methoxyisoquinoline derivative in a reasonable yield without forming any 8-methoxy derivative. 5 These findings stimulated us to photochemically synthesize analogs of papaverine, one of the isoquinoline alkaloids, as an extension of our study on the photocyclization of Nacyl-α-dehydroamino acid derivatives.To this end we designed and synthesized substituted (Z)-Nphenylacetyl-α-dehydrophenylalaninamides (1a-h), hoping to establish a new route to analogs of pharmaceutically important papaverine.The starting (Z)-isomers (1a-h) were prepared in high yields (>80%) by the ring opening reactions of (Z)-