The dehydration of various 6-(l-hydroxyethyl)penems to give E-and Z-6-ethylidenepenems is described. Both isomers have been shownto be potent broad spectrum inhibitors of bacterial /Mactamases capable of reducing the MICvalues of /Mactam antibiotics such as amoxycillin and cephaloridine against a widerange of resistant organisms.Since Woodward's1*first description of the penemnucleus the chemistry and biology of these interesting members of the /Mactam family have been the subject of numerous publications.2) Much of the effort has concentrated on the antibacterial properties of penems bearing a 1-hydroxyethyl function at the C-6 position. Wewish to report the dehydration of these compoundsto provide 6-ethylidenepenems,3) a novel class of penems with interesting biological properties. Antibacterial activity is much weaker than in the 6-(1 -hydroxyethyl) series, but the ethylidenepenems are potent inhibitors ofa wide range of/Mactamases. Subsequent to our undertaking this study, similar properties have been reported for one related compound, 6-acetylmethylene-2-methylpenem-3-carboxylate.4) j5-Lactamase inhibitory properties have also been described for the asparenomycins, a structurally related series of carbapenems.5) Chemistry Dehydration of the /ra«s-6-[(li?S)-hydroxyethyl]penem ester (la)3) under Mitsunobu conditions (triphenylphosphine/diethyl azodicarboxylate) gave the Z-ethylidenepenem ester (3a) as the major product. Similar treatment of the (VSR) isomer (2a)3) afforded the E-ethylidenepenem ester (4a). Both reactions exhibited good stereoselectivity the major/minor isomer ratios being approximately 10 : 1. Confirmation of the stereochemistry of the double bond was provided by the *H NMRdata. The olefinic proton of the Z-isomer (3a) showed the expected down field shift compared with that of the is-isomer (4a) due to the deshielding effect of the neighbouring /Mactam carbonyl group. The corresponding down field shift of the methyl group in the is-isomer comparedto the Z-isomer was also evident.Alternatively, dehydration could be achieved by a mesylation/elimination process (Scheme 1) albeit with a loss of stereoselectivity.Thus, treatment of the mesylate (5a)3) derived from the alcohol (la) with l, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave a 2 : 1 mixture of the Z-and £-penems (3a) and (4a). Similar treatment of the alcohols (lb and lc)3) gave mixtures of corresponding ethylidenepenems from which it was generally possible to isolate one or both isomers by chromatographic and/or fractional crystallisation techniques. Deprotection of the /?-nitrobenzyl (PNB) esters was accomplished by hydrogenolysis over palladium/carbon catalyst, providing the sodium salts (6 and 7) after treatment with sodium hydrogencarbonate. Chromatography on Biogel P2 provided materials which were homogeneous by NMR
The influence on the antibacterial activity of introducing a 6a-methoxy group into carbenicillin, and various 6a-substituents into sulbenicillin and piperacillin was examined. Further variations of the side chain aryl group were examined in the 6a-methoxy substituted series. This led to the identification of disodium 613-(D,L-2-carboxy-2-thien-3-ylacetamido)-6a-methoxypenicillanate (5b) as a 13-lactamase stable derivative with useful activity against Enterobacteriaceae, and disodium 6~-[D-2-(4-aminophenyl)-2-sulfoacetamido]-6a-methoxypenicillanate (6e) with slightly lower activity against the Enterobacteriaceae but more active against Pseudontonas aeruginosa.
Earlier reports from these laboratories outlined the preparationx) and biological properties2>3) of 6a-formamido penicillins. The catecholic acylureido derivative BRL 36650 (1) was the most potent, especially against Pseudomonas aeruginosa strains. We nowreport on analogues of 1 which either retain a catechol or dihydroxyphenyl unit or contain various catechol isosteres.
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