Asymmetric Synthesis of Potent and Selective σ1 Receptor Ligands with Tetrahydro‐3‐benzazepine Scaffold

Abstract

AbstractA new strategy for the synthesis of tetrahydro‐3‐benzazepinones 6 by reductive amination of keto acid 3 and subsequent carbonyl diimidazole (CDI) mediated cyclization was developed. Use of enantiomerically pure (R)‐1‐phenylethylamine led to the formation of diastereomeric lactams (Rα‐R)‐6d and (Rα‐S)‐6e in a 80:20 ratio. Diastereoselective alkylation of (Rα‐R)‐6d, BH3‐mediated reduction and exchange of the N‐phenylethyl substituent provided enantiomerically pure tetrahydro‐3‐benzazepines with various substituents in the 1‐, 3‐, and 4‐positions. High σ1 affinity was achieved with a benzyl, cyclohexylmethyl, or 1‐phenylethyl moiety at the N‐atom. Whereas (R)‐configuration of the N‐substituent is crucial for high σ1 affinity, the configuration of the 3‐benzazepine ring system does not influence the σ1 affinity considerably. Introduction of additional substituents in the 1‐position led to almost complete loss of σ1 affinity. Potent σ1 ligands show high selectivity against the σ2 subtype and the NMDA receptor.