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

Journal of Organic Chemistry

Volumn 73, Issue 18, 2008, Pages 6970-6982

  Johnson, Jarrod W ^a   Evanoff, Darryl P ^a   Savard, Marc E ^a   Lange, Gerald ^a   Ramadhar, Timothy R ^a   Assoud, Abdeljalil ^a   Taylor, Nicholas J ^a   Dmitrienko, Gary I ^a  

^a UNIVERSITY OF WATERLOO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AROMATIC HYDROCARBONS; CARBOXYLATION; CHEMICAL REACTIONS; CHLORINE; KETONES; METHANOL; SOLID SOLUTIONS; STEREOCHEMISTRY; SUBSTITUTION REACTIONS; SULFUR COMPOUNDS;

AB INITIO CALCULATIONS; ANOMERIC EFFECTS; AXIAL ORIENTATIONS; CARBOCYCLIC ANALOGUES; CHEMICAL EQUATIONS; CYCLOBUTANONE; DIASTEREOSELECTIVE; GAS-PHASE; LACTAMASE; SOLID STATES; STEREO-SELECTIVE; SULFURYL CHLORIDE; TETRAHYDROTHIOPHENE; X-RAY CRYSTAL STRUCTURES;

CRYSTAL ORIENTATION;

2 THIABICYCLO[3.2.0]HEPTAN 6 ONE 4 CARBOXYLIC ACID; ANTIBIOTIC AGENT; BETA LACTAMASE; BETA LACTAMASE INHIBITOR; CARBOXYLIC ACID DERIVATIVE; CYCLOBUTANONE DERIVATIVE; PENICILLIN DERIVATIVE; UNCLASSIFIED DRUG;

AB INITIO CALCULATION; ANTIBIOTIC THERAPY; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CHLORINATION; CRYSTAL STRUCTURE; DRUG CONFORMATION; ENZYME ACTIVITY; HYDROLYSIS; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; X RAY CRYSTALLOGRAPHY;

COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; CYCLOBUTANES; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PENICILLINS; QUANTUM THEORY; REFERENCE STANDARDS; STEREOISOMERISM;

EID: 52449105960     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo801274m     Document Type: Article

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132. 13C NMR data for cyclobutanones and cyclobutanone hemiketals, see Tables S5-S7 (Supporting Information).
133. Reaction rates were not determined quantitatively, but hemiketal formation was followed by NMR and plots of % hemiketal vs time have been supplied for each ketone in Supporting Information (Table S8).
134. 1H NMR at 500 MHz).
135. The approximate trend in relative rates of hemiketal formation is 23α-25α > 27 ≈ 26 ≈ 19 > 18 > 25β > 24β > 23β.
136. Hydrolysis of the ethyl ester functionality (in 23, for example) cannot be achieved cleanly in basic (NaOH) or acidic (HCl) conditions due to the sensitivity of the dichlorocyclobutanone ring and the S,O-acetal functionalities, respectively. Our group is currently pursuing the synthesis of the free acids via alternative esters that can be cleaved under mild conditions so that biochemical assays may be conducted.
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143. Incomplete conversion was observed when PhMe and TsOH were not predried.