Asymmetric Synthesis of 1‐Substituted Tetrahydro‐3‐benzazepines as NMDA Receptor Antagonists

Abstract

Abstract A novel asymmetric synthesis of 1‐substituted tetrahydro‐3‐benzazepines ( R )‐ 15 and ( S )‐ 15 has been performed. Starting with o ‐phenylenediacetic acid ( 1 ) and ( R )‐phenylglycinol as chiral auxiliary the tricyclic oxazololactam (3 R )‐ 10 was synthesized as key intermediate. Deprotonation of (3 R )‐ 10 with LDA led to an enolate, which was trapped with different arylalkyl and alkyl halides to yield 6‐substituted oxazololactams (6 R )‐ 12 with high diastereoselectivity. The best diastereomeric ratio (about 95:5) was achieved with benzyl bromide and 2‐methylbenzyl bromide. The diastereomers were separated using preparative HPLC to obtain diastereomerically pure (6 R )‐ 12 . Two successive reduction procedures (LiAlH 4 /AlCl 3 , then NH 4 HCO 2 , Pd/C) led to enantiomerically pure 1‐substituted tetrahydro‐3‐benzazepines ( R )‐ 15 . Starting the synthesis with ( R )‐ and ( S )‐phenylglycinol provided both enantiomers ( R )‐ 15 and ( S )‐ 15 , which were investigated for their affinity to the PCP binding site of the NMDA receptor. The NMDA receptor affinities of the enantiomeric pairs are very similar. With a K i value of 1.66 μ M the 2‐methylbenzyl‐substituted derivative ( R )‐ 15c displays the highest NMDA receptor affinity in this series. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)