Cyclobutanone Mimics of Penicillins: Effects of Substitution on Conformation and Hemiketal Stability

The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as β-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3β substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3α substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d₄.