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

The first divergent synthesis of both gamma-amino acid and gamma-lactam derivatives frommeso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN(3)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 gamma-amino acids and theirN-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of gamma-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional gamma-N-carboxyanhydride (gamma-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.