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

Version 1

      Publication Details (including relevant citation   information):

      Jarrod W. Johnson, Darryl P. Evanoff, Marc E. Savard, Gerald   Lange, Timothy R. Ramadhar, Abdeljalil Assoud, Nichloas J.   Taylor, Gary I. Dmitrienko. Journal of Organic   Chemistry, 2008, 73, 6970-6982.

      Abstract:

      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.

      Address (URL): http://dx.doi.org/10.1021/jo801274m