A study to establish a general new method for the stereospecific preparation of bicyclic beta-lactams from monocyclic precursors will be undertaken. Phenylthionitromethane will be introduced as a highly versatile reagent for the conversion of derivatives of 3-[4-(2-oxoazetidinyl)]propanal and 4-[4-(2-oxoazetidinyl)] butanal (RCHO) into the corresponding antibiotics containing the penam and cephem nuclei. For example, 2-methyl-2-[4-(1-t-butyldimethylsilyl-2-oxoazetidinyl)] sulfonylpropanal will be condensed with phenylthionitromethane in the presence of potassium t-butoxide followed by dehydration using methanesulfonyl chloride and triethylanmine to produce the derived Z-nitroalkene [RCH=C(NO2)SPh]. In THF solution this will be reacted with tetrabutylamonium fluoride (to effect N-desilylation and cyclization) followed by ozone (to oxidatively cleave the (=NO2-) to produce the phenylthio ester of penicillanic acid sulfone. This simple and concise method will be extended to stereospecific total syntheses of 6-aminopenicillanic acid, analogs of penicillanic acid sulfone, the oxacephems, the phospha-dethia analog of penicillanic acid sulfone and several strained tricyclic beta-lactam including the cyclopropanocarbapenams. These studies should establish a general new synthetic methof for Beta-lactam synthesis, should introduce the protection of Beta-lactam carboxylic acids as phenylthioesters and should generate novel Beta-lactams for biological evaluation. Additionally the method will be applied to the total synthesis of the bulgecins, which are potent Beta-lactam synergists, and of simple analogs. All new synthetic Beta-lactams will be screened for both antibiotic activity and Beta-lactamase inhibition by the Lilly Research Laboratories. It is the intention that this work should lead both to the discovery of novel chemotherapeutic substances and useful nitroalkene chemistry.
