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Asymmetric Synthesis of Potent and Selective σ 1 Receptor Ligands with Tetrahydro‐3‐benzazepine Scaffold
Author(s) -
Sarkar Soumya,
Schepmann Dirk,
Köhler Jens,
Fröhlich Roland,
Wünsch Bernhard
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200927
Subject(s) - chemistry , benzazepine , substituent , stereochemistry , moiety , amination , reductive amination , benzazepines , diastereomer , selectivity , enantioselective synthesis , enantiomer , bicyclic molecule , ring (chemistry) , catalysis , organic chemistry
A 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 ( R α ‐ R )‐ 6d and ( R α ‐ S )‐ 6e in a 80:20 ratio. Diastereoselective alkylation of ( R α ‐ R )‐ 6d , BH 3 ‐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 σ 1 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 σ 1 affinity, the configuration of the 3‐benzazepine ring system does not influence the σ 1 affinity considerably. Introduction of additional substituents in the 1‐position led to almost complete loss of σ 1 affinity. Potent σ 1 ligands show high selectivity against the σ 2 subtype and the NMDA receptor.