Synthesis of novel β-lactamase inhibitors from clavulanic acid. Preparation and chemical reactions of (5R)-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-en-7-one

Abstract

Three methods for the preparation of (5R)-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-en-7-one (2) have been developed; the most convenient method involves the reaction of clavulanic acid with NN-dimethylformamide dimethyl acetal. Hydrogenation of the diene (2) gave three products: (3S,5R)-3-ethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one and (E)- and (Z)-(5R)-3-ethylidene-4-oxa-1-azabicyclo[3.2.0]heptan-7-one. Reaction of the diene (2) with methanol gave 4-methoxy-1-(2-oxobut-3-enyl)azetidin-2-one and 2-hydroxy-3-methoxy-3-vinyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one and with both acetic acid and thiophenol, it gave products derived from reaction at the β-lactam moiety.

Thiophenol and oxygen reacted with the diene (2) to give a single 1,4-addition product, (Z)-(2S,5R)-3-(2-hydroxyethylidene)-2-phenylthio-4-oxa-1-azabicyclo[3.2.0]heptan-7-one and with thiophenol in the presence of a free-radical initiator, it gave three 1,4-addition products: (Z)-(5R)-3-(2-phenylthioethylidene)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one and (E)- and (Z)-(2S,5R)-3-ethylidene-2-phenylthio-4-oxa-1-azabicyclo[3.2.0]heptan-7-one.

Tetracyanoethylene, maleic anhydride, diethyl azodicarboxylate, singlet oxygen, acrylaldehyde, and nitroso-benzene all reacted with the diene (2) to give Diels–Alder adducts. With benzyl acrylate, (2) gives three adducts: benzyl (1S,5R,11S)-3-oxo-6-oxa-2-azatricyclo[5.4.0.0^2,5]undec-7-ene-11-carboxylate and benzyl(1S,5R,10R)- and (1S,5R,10S)-3-oxo-6-oxa-2-azatricyclo[5.4.0.0^2,5]undec-7-ene-10-carboxylate. Some of the above 1,4-addition products and Diels–Alder adducts were found to be β-lactamase inhibitors.