Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides

Abstract

The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN₃ relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.

Keywords: azides; desymmetrisation; meso-anhydride; γ-amino acids; γ-lactams.