Novel Large-Ring 1,3-Bridged 2-Azetidinones as Potential Inhibitors of Penicillin-Binding Proteins
(2009) European Journal of Organic Chemistry — n° 11, p. 1757-1770 (2009)
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- Novel bicyclic 2-azetidinones, in which the P-lactam moiety is embedded in a 1,3-bridging large ring, have been studied experimentally and theoretically. The compounds were prepared from (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-propyl-2-azetidinone (3) by sequential N1 and O5 functionalization with omega-alkenyl chains by acylation and/or alkylation reactions. Cyclization by ring-closing metathesis (RCM) gave a series of 12- and 13-membered-ring compounds 7, 12b,c, 17b,c and 24 featuring the internal HC=CH double bond with a preferential (E) configuration, and then the corresponding saturated 1,3-bridged bicycles 8, 13b,c, 18b,c and 25 after hydrogenation. Bridges of 9-11 atoms were inaccessible and bridges of 12 atoms appeared favoured over those with 13 atoms according to ab initio quantum chemistry calculations. This was confirmed experimentally because w-alkenyl double-bond migration occurred in competition with the RCM reaction in the case of 13-atom precursors, leading to a mixture of 12- and 13-membered rings. Modelling of the reactivity of our 1,3-bridged 2-azetidinones, towards hydrolysis and processing by serine enzymes, highlighted the important roles of geometrical and conformational factors and predicted a modest "acylating power" in comparison with classical penam compounds (antibiotics). Biochemical evaluation against the R39 bacterial enzyme (D,D-peptidase) revealed a weak inhibition effect of the 13-membered-ring 1,3-bridged O,N-bis(acylated) azetidinones 7 and 8. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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Urbach, A., Dive, G., & Marchand-Brynaert, J. (2009). Novel Large-Ring 1,3-Bridged 2-Azetidinones as Potential Inhibitors of Penicillin-Binding Proteins. European Journal of Organic Chemistry, 11, 1757-1770. https://doi.org/10.1002/ejoc.200801193 (Original work published 2009)