It is urgent to develop novel anti-Pseudomonas agents that should also be active against multidrug resistant P. aeruginosa. Expanding the antibacterial spectrum of muraymycins toward P. aeruginosa was investigated by the systematic structure-activity relationship study. It was revealed that two functional groups, a lipophilic side chain and a guanidino group, at the accessory moiety of muraymycins were important for the anti-Pseudomonas activity, and analogue 29 exhibited antibacterial activity against a range of P. aeruginosa strains with the minimum inhibitory concentration values of 4-8 μg/mL.
The base-mediated intramolecular amination of bromoallenes having an axial chirality is described. The treatment of (4S,aR)-4-alkyl-4-[N-(arylsulfonyl)amino]-1-bromobuta-1,2-dienes with NaH in DMF affords 2,3-cis-2-ethynylaziridines in good to excellent selectivity (2,3-cis:trans = 92:8-99:1). The reaction of (4S,aS)-bromoallenes with NaH/DMF also gives 2,3-cis-2-ethynylaziridines selectively (79:21-91:9). These experimental results have been rationalized by B3LYP density functional calculations together with the 6-31+G(d) basis set and the Onsager solvation model. The transition structures for cis-aziridine formation of both (4S,aR)- and (4S,aS)-bromoallenes in DMF are favored over the corresponding trans transition structures by 4.35 and 1.41 kcal/mol, respectively. Furthermore, the calculations predicted that a less polar solvent gives higher cis selectivity for (4S,aS)-bromoallenes. In fact, improvement of the cis selectivity to 99:1 has been realized by using a less polar solvent such as THF. The cyclization of bromoallenes bearing a beta- or gamma-amino group also affords four- and five-membered azacycles in a highly cis-selective manner.
Palladium(0)-catalyzed tandem cyclization of allenenes is described. Treatment of allenenes with an aryl halide, potassium carbonate, and catalytic [Pd(PPh(3))(4)] in dioxane afforded tri- or tetracyclic heterocycles in moderate to good yields through insertion of arylpalladium(II) halide into the allenic moiety, intramolecular carbopalladation, and aromatic C--H bond activation. The substituent on the olefin terminus has proven to be essential for the success of the tandem cyclization. The reaction with heterocyclic aryl halides such as iodopyrazine or 4-bromo-1-methylindole afforded tri- or tetracyclic heteroaromatic products in good yields.
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