An improved cyclization protocol for the synthesis of diazabicyclo[4.3.0]alkanes

We have recently described the synthesis of diazabicyclo[4.X.0]alkanes and their use as ligands for the prostate specific membrane antigene (PSMA). The key step of our synthetic route toward these diazabicycloalkanes is an oxidative cleavage of a bicyclic diol moiety followed by the attack of a nitrogen nucleophile to the resulting intermediate bisaldehyde. We herein describe the mechanism of this ring closure and its stereochemical consequences. In addition, we report a convenient method for trapping intermediate bisaldehydes by Wittig reagents. This trapping allows the synthesis of 3,5-disubstituted proline derivatives, which are shown to be versatile precursors for functionalized diazabicycloalkane dipeptide mimetics.