ISSN:
1434-193X
Keywords:
Asymmetric synthesis
;
Nitrogen heterocycles
;
N-Acyliminium ions
;
PCP site ligands
;
Pharmacological enantioselectivity
;
Chemistry
;
General Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
A new method for the asymmetric synthesis of 1-substituted tetrahydroisoquinolines is presented. It is based on stereoselective addition reactions of organometallic compounds to the intermediate N-acyliminium ion 6, which is provided with an N-acyl group as a chiral auxiliary. In addition reactions with organomagnesium and organozinc reagents diastereoselectivities from 70:30 to 95:5 (for 7/8) were observed with the zinc reagents in general leading to markedly improved stereoselectivities. By catalytic hydrogenation of 7 and 8 and after removal of the chiral auxiliary the target compounds 11 and 12 were obtained. The enantiomerically pure 11c-g and 12c-g (ee 〉 99 %), 1-aryl-tetrahydroisoquinolines, were evaluated for their affinity to the PCP [1-(1-phenylcyclohexyl)piperidine] binding site of the NMDA (N-methyl D-aspartate) receptor. In each case the enantiomers 11 exhibited a higher affinity than those of 12, with the potencies of the enantiomers differing by a factor of 4 (11/12g) to 27 (11/12c). The absolute configuration of the more potent enantiomers 11 is in accordance with the stereochemical requirement found for FR115427 (3) which is a close analogue.
Type of Medium:
Electronic Resource
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