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 beta-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 3beta substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3alpha 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.
Johnson
Jarrod W
JW
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1.
Evanoff
Darryl P
DP
Savard
Marc E
ME
Lange
Gerald
G
Ramadhar
Timothy R
TR
Assoud
Abdeljalil
A
Taylor
Nicholas J
NJ
Dmitrienko
Gary I
GI
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003503:Cyclobutanes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010406:Penicillins / Q000138:chemical synthesis / Q000737:chemistry*; D011789:Quantum Theory; D012015:Reference Standards; D013237:Stereoisomerism
D003503:Cyclobutanes; D010406:Penicillins