Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

Novel bicyclic 2‐azetidinones, in which the β‐lactam moiety is embedded in a 1,3‐bridging large ring, have been studied experimentally and theoretically. The compounds were prepared from (3 S ,4 R )‐3‐[(1 R )‐1‐( tert ‐butyldimethylsilyloxy)ethyl]‐4‐propyl‐2‐azetidinone ( 3 ) by sequential N1 and O5 functionalization with ω‐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 ω‐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 .(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)