New nepenthone and thevinone derivatives Original Research Article

The diastereoselective reaction of thevinone (2a) and nepenthone (2c) and their dihydro derivatives (2b and d) with Grignard reagents afforded new N-substituted (20S)- and (20R)-phenyl-6,14-ethenomorphinan derivatives (6a–y). The Grignard reaction of the N-substituted-N-demethyl derivatives 4a–f and 4m–r with methylmagnesium iodide resulted in the (20R)-phenyl tertiary alcohols 5a–f and 5m–r, respectively, but the conversion of 4g–l and that of the N-substituted-dihydrothevinone derivatives with phenylmagnesium bromide afforded the (20S)-phenyl derivatives 5g–l and 5s–y, respectively. The N-cyclopropylmethyl-, N-β-phenylethyl-, and N-propyl derivatives were prepared by the 3-O-demethylation of compounds 5. For the synthesis of the N-allyl-, N-dimethylallyl-, and N-propargyl compounds 2a–d were reacted with the corresponding Grignard reagent, and treatment of the products with cyanogen bromide gave the cyanamides 8a–d. These latter compounds were transformed into 10a,b,d, whose alkylation led to the target derivatives 6d–f, j–l, p–r, and w–y. The biochemical investigation of these substances showed that the affinities to the δ-opioid receptors were high, but the selectivity was low. In two cases (6c and 11d) a μ-opioid receptor specificity was observed.