Cyclobutanone mimics of penicillins: effects of substitution on conformation and hemiketal stability

The Journal of Organic Chemistry
Jarrod W JohnsonGary I Dmitrienko

Abstract

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.

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Citations

Jul 19, 2013·Future Medicinal Chemistry·Dustin T King, Natalie C J Strynadka
Apr 17, 2016·The Journal of Chemical Physics·Lihong Liu, Wei-Hai Fang
Feb 6, 2017·Organic & Biomolecular Chemistry·Viktória HajzerRadovan Šebesta
Dec 20, 2016·Chembiochem : a European Journal of Chemical Biology·Prarthana Devi, Peter J Rutledge
Dec 19, 2017·Chemistry : a European Journal·Martine I AbboudGary I Dmitrienko
Jun 1, 2019·FEMS Microbiology Reviews·Mark LawsKhondaker Miraz Rahman
Sep 25, 2019·Angewandte Chemie·Jan Sietmann, Johannes M Wahl
Jan 10, 2020·Chemistry : a European Journal·Beeraiah BaireSanthi Jampani
Apr 25, 2015·Physical Review Letters·Dawei LuRaymond Laflamme

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