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
Ps. Hadfield et al., 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, Journal of the Chemical Society. Perkin transactions. I, (4), 1997, pp. 503-509
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.