Comparison of the mechanisms of reactions of β-lactams and β-sultams, including their reactions with some serine enzymes

Abstract

The strain energy of the four-membered ring of β-lactams is not released in the transition state to lower the activation energy of reactions involving ring-opening. The alkaline hydrolysis of N-aroyl β-lactams occurs with competitive exo- and endocyclic CN ring fission, the ratio of which varies with the aryl substituent. β-Sultams are four-membered cyclic sulfonamides and are about 10³ fold more reactive than analogous β-lactams. Nucleophiles usually attack N-acylsulfonamides at the carbonyl centre resulting in CN bond fission, but the hydrolysis of N-acyl β-sultams occurs with SN fission and opening of the four-membered ring. The 3-oxo-β-sultams are a unique combination of both β-lactams and β-sultams and therefore are susceptible to nucleophilic attack at either the acyl or the sulfonyl centre, but they hydrolyse with exclusive SN bond fission. β-Sultams are novel inhibitors of the serine enzymes elastase, transpeptidase and β-lactamase due to sulfonylation of the active-site serine residue. Structure–activity relationships are used to identify differences in transition-state structures between β-sultams as inhibitors and β-lactams as substrates. Copyright © 2006 John Wiley & Sons, Ltd.