Cephalosporanic acids: a new look at reactions at the C-3' position

Nucleophilic displacement of the acetoxy group of cephalosporanic acids by thiols in aqueous solution at neutral pH provides 3-thiomethyl-substituted compounds with a broad spectrum of antibiotic activity. The aqueous displacement reaction is often destructive of much of the cephalosporanic acid, and products generally require extensive purification. Displacements at a lower pH are complicated by unwanted lactone formation. However, reactions conducted under acid conditions in a variety of anhydrous organic solvents give 3-thiomethyl-substituted compounds in very high yield and quality; no lactone formation is observed. The kinetics of the reaction support an SN1 mechanism. Protonation of the departing acetoxy group appears therefore critical; the more basic solvents, e.g. dimethylsulphoxide and N,N-dimethylformamide, significantly retard the rate of reaction.