Asymmetric Synthesis of Potent and Selective sigma(1) Receptor Ligands with Tetrahydro-3-benzazepine Scaffold

作者：Sarkar Soumya; Schepmann Dirk; Koehler Jens; Froehlich Roland; Wuensch Bernhard

来源：European Journal of Organic Chemistry, 2012, 2012(30): 5980-5990.

DOI：10.1002/ejoc.201200927

• Drug discovery
• Reduction
• Amination
• Asymmetric synthesis
• Dia-stereoselectivity
• Receptors

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 (Ra-R)-6d and (Ra-S)-6e in a 80:20 ratio. Diastereoselective alkylation of (Ra-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 s1 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 s1 affinity, the configuration of the 3-benzazepine ring system does not influence the s1 affinity considerably. Introduction of additional substituents in the 1-position led to almost complete loss of s1 affinity. Potent s1 ligands show high selectivity against the s2 subtype and the NMDA receptor.

• 出版日期2012-10