Journal of the Chemical Society. Perkin transactions I p. 2699 - 2706 (1991)
Update date:2022-08-03
Topics:
Coulton, Steven
Francois, Irene
The key intermediate in the preparation of novel 6-(substituted methylene) carbapenem derivatives is p-methoxybenzyl (5R,6R)-6-bromo-7-oxo-1-azabicyclo<3.2.0>hept-2-ene-2-carboxylate 26, which was prepared in several steps from 6-aminopenicillanic acid 14 via (3R,4R)-4-allyl-3-bromoazetidin-2-one 21.Sequential treatment of the aforementioned ester 26 with either lithium diisopropylamide or lithium diphenylamide, 1-methyl-1H-1,2,3-triazole-4-carbaldehyde and acetic anhydride provided a diastereoisomeric mixture of acylated bromohydrins 28; reductive elimination then afforded the isomeric (E)- and (Z)-6-triazolylmethylene carbapenem esters 29 and 31, respectively.Lewis acid-mediated deprotection of the 6-bromo and 6-<(E)-triazolylmethylene> esters 26 and 29 gave the sodium salts of (5R,6R)-6-bromo-7-oxo-1-azabicyclo<3.2.0>hept-2-ene-2-carboxylic acid 27 and (5R)-6-<(E)-(1-methyl-1H-1,2,3-triazol-4-yl)methylene>-7-oxo-1-azabicyclo<3.2.0>hept-2-ene-2-carboxylic acid 30, respectively.In addition, condensation of the anion, generated by deprotonation of the 6-bromo ester, with acetaldehyde, followed by acylation and reductive elimination furnished the isomeric (E)- and (Z)-ethylidene carbapenem esters.Whilst the (E)-6-triazolylmethylene carbapenem displayed low levels of antibacterial activity, it possessed no β-lactamase-inhibitory activity whatsoever.The 6-bromocarbapenem was devoid of both antibacterial and β-lactamase-inhibitory activity.
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