ASYMMETRIC-SYNTHESIS AND ENANTIOSELECTIVITY OF BINDING OF 1-ARYL-1,2,3,4-TETRAHYDROISOQUINOLINES AT THE PCP SITE OF THE NMDA RECEPTOR COMPLEX

A new method for the asymmetric synthesis of 1-substituted tetrahydroi soquinolines is presented. It is based on stereoselective addition rea ctions of organometallic compounds to the intermediate N-acyliminium i on 6, which is provided with an N-acyl group as a chiral auxiliary. In addition reactions with organomagnesium and organozinc reagents diast ereoselectivities from 70:30 to 95:5 (for 7/8) were observed with the zinc reagents in general leading to markedly improved stereoselectivit ies. By catalytic hydrogenation of 7 and 8 and after removal of the ch iral auxiliary the target compounds 11 and 12 were obtained. The enant iomerically pure 11c-g and 12c-g (ee > 99 %), 1-aryl-tetrahydroisoquin olines, were evaluated for their affinity to the PCP [1-(1-phenylcyclo hexyl)piperidine] binding site of the NMDA (N-methyl D-aspartate) rece ptor. In each case the enantiomers 11 exhibited a higher affinity than those of 12, with the potencies of the enantiomers differing by a fac tor of 4 (11/12g) to 27 (11/12c). The absolute configuration of the mo re potent enantiomers 11 is in accordance with the stereochemical requ irement found for FR 115427 (3) which is a close analogue.