Post-Ugi Transformations for the Access to Pyrrolobenzodiazepine Scaffolds with Different Degrees of Unsaturation

The synthesis of
three novel families of pyrrolo­[2,1-c]­[1,4]­benzodiazepine-5-ones
is described. The compounds were prepared
according to a three-step sequence, involving an Ugi reaction, building
of the pyrrolo nucleus, and reduction–cyclization to the corresponding
diazepine. Depending on the amine employed in the synthesis of the
Ugi adducts, different unsaturation degrees could be obtained in the
pyrrolo ring (saturated or with endo or exo unsaturations), a key
feature determining their biological activity, as it affects the affinity
of the pyrrolobenzodiazepines toward DNA and thus their cytotoxicity.
This synthetic methodology represents a significant improvement with
respect to those described in the literature so far, as it uses inexpensive
and commercially available starting materials without needing derivatization
or the use of protecting groups.