[Synthesis of enantiomerically pure 6,10-epoxybenzocycloocten-7-amines with CNS activity]

In an oxa-Pictet-Spengler reaction the methyl (S)-phenyllactate 6 and methyl levulinate (7a) are condensed to the 2-benzopyrans cis-8a and trans-8a, which react with CH3I to yield the dimethyl ethers cis-9a and trans-9a. Cis-9a and trans-9a can be separated by medium pressure liquid chromatography. In the subsequent Dieckmann-Cyclisation cis-9a is transformed to the laevorotatory beta-ketoester (-)-10a, while the dextrorotatory enantiomer (+)-10a is obtained from trans-9a after C-3-epimerisation. With Eu(hfc)3 the ketone (-)-11, prepared by saponification and decarboxylation of (-)-10a, proves to be enantiomerically pure. By reductive amination, ketone (-)-11 is transformed to the amines (-)-12a and (-)-12b. Symptoms typical for central damping are caused after i.p. application of (-)-12a and (-)-12b to mice. In the mouse writhing-test (-)-12a HCl affords an ED50-value of 7.0 mg/kg, comparable with the ED50-value of tramadol.