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.