Chem. Pharm. Bull. 53(9) 1152—1158 (2005)

synthesized from dipeptidyl chloromethyl ketones or methyl ketones. According to this novel procedure, various functional groups could be introduced into positions 3 and 6 of 1,2-dihydropyrazin-2-one by using appropriate amino acids (Chart 2). It had been assumed that the formation of the 1,2-dihydropyrazin-2-one ring from dipeptidyl chloromethyl ketones proceeded according to the mechanism shown in Chart 1. We previously reported that various opioid mimetics containing a series of 1,2-dihydropyrazin-2-one derivatives exhibited broad binding activity to mand d-opioid receptors whose affinities ranged from nanomolar to micromolar; although the binding activity and selectivity were lower than endomorphin-1 and -2, which are endogenous mammalian opioid ligands, but considerably greater than the endorphins or b-endorphin. To develop more potent, selective and longacting opioid ligands, a series of 1,2-dihydropyrazin-2-one derivatives (Fig. 1, 1—4), which possess two Z-protected aminoalkyl moieties as the side chains, were synthesized. Next, we attempted to convert these protected compounds (1—4) into compounds (5—8). With the exception of 4, compounds 1—3 were converted to 5—7, respectively, by catalytic hydrogenation over a Pd catalyst. However, catalytic hydrogenation of compound 4 produced an unexpected compound instead of 8. A preliminary report revealed that a special deamination from 6-Z-aminomethyl moiety on 1,2-dihydropyrazin-2-one occurred. This paper will describe the further details of the above side reaction and confirmation of the cyclization mechanism.