Acyloxymethyl as a drug protecting group. Synthesis and reactivity of N-acyloxymethylsulfonamide prodrugs

Tertiary N-acyloxymethylsulfonamide prodrugs 3, encompassing penicillin and sulfonamide antibiotics, have been synthesised. The pH-independent hydrolysis of these compounds ocurrs via the rate-determining formation of an N-sulfonyl iminium ion. SCF-MO calculations using the PM3 method indicate that iminium ion formation is slightly favoured, when compared with the corresponding amides, by ca. 10 kJmol−1.