Synthesis of a Neuropeptide Y Antagonist

Significance

Compound G is under clinical trials for the treatment of obesity owing to its antagonism of neuropeptide Y (NPY), an important regulator of feeding behavior. A major challenge in the synthesis of G was the control of the relative ste­reochemistry between the spirocyclic center and the carboxyl appendage in intermediate C. The problems here were (a) that the addition to the ketone B was not particularly stereoselective and (b) that the equilibration was useless because the thermodynamic product was the wrong cis isomer.