Resolution and absolute stereochemistry of 6,7-dimethoxy-4-phenyl- 1,2,3,4-tetrahydroisoquinoline. The crystal...

Stereospecific multistep synthesis and resolution of 6,7-dimethoxy-4- phenyl-1,2,3,4-tetrahydroisoquinoline (3) has been achieved from its racemic base. The absolute configurations of the optical antipodes converted into their hydrochloride salt forms have been determined by X-ray diffractometric analysis, thus permitting assignment of the antipodes as the (+)-(4R)-3 and (-)-(4S)-3 enantiomers. The crystal structures of the two enantiomers are related as mirror images and only the (4R)-3.HCl form has been fully determined by three-dimensional X-ray diffraction. In the solid state, the carbon atoms of the two methoxy groups deviate slightly from the benzene-ring plane and the chirally oriented phenyl substituent is almost perpendicularly tilted out of conjugation with the isoquinoline system. Examination of the enantiomers in several biochemical tests for 5-HT, NE and DA uptake inhibition-activity revealed an exclusive preference for the (4S)-enantiomer. These results are in accord with previous suggestions that the S-configurational state of the 4-phenyl substituent is important for biological activity.