Solid-phase organic synthesis of chiral, non-racemic 1,2,4-trisubstituted 1,4-diazepanes with high σ1 receptor affinity.

The aim of this work was to transfer the established chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes in solution on the solid phase. For this purpose, (S)-configured amino acids, (S)-alanine, and (S)-leucine, with a small methyl and a larger isobutyl moiety were attached to the solid support 9 by reductive amination. After five reaction steps on the solid support, the 1,4-diazepanes (S)-19a,b were cleaved off and reductively alkylated to afford the 1,2,4-trisubstituted 1,4-diazepanes (S)-20a and (S)-21b, respectively. Both compounds show high σ1 affinity and selectivity over the σ2 subtype.