AN UNEXPECTED MITSUNOBU REACTION - A DIRECT ROUTE TO THE 2,5-DIAZABICYCLO[2.2.1]HEPTAN-3-ONE SKELETON AS A GAMMA-LACTAM MIMIC OF BETA-LACTAM ANTIBIOTICS

Treatment of anilides of N-protected (2S,4R)-4-hydroxyproline, e.g. 1, with thioacetic acid under Mitsunobu conditions gives, unexpectedly, 2,5-diazabicyclo[2.2.1]heptan-3-ones, e.g. 2, the products of intramol ecular cyclisation. However, the less acidic N-benzylamides of these p roline derivatives, e.g. 7, are not sufficiently acidic and the hydraz ido anion generated in the Mitsunobu reaction displaces the activated hydroxy group in an intermolecular reaction to give 8. The bicyclic ga mma-lactams are potential analogues of the beta-lactam antibiotics and suitable derivatives 9, 10, 11 and 12 are found to be competitive inh ibitors of class A and C beta-lactamases, with K-i as low as 70 mu M.