The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery.

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Reaction of allene-substituted cyclohexa- and cyclohepta-1,3-dienes with [PdCl(2)(PhCN)(2)] gave eta(3)-(1,2,3)-cyclohexenyl- and eta(3)-(1,2,3)-cycloheptenylpalladium complexes, respectively, in which C-C bond formation between the allene and the 1,3-diene has occurred. Analysis of the (pi-allyl)palladium complexes by NMR spectroscopy, using reporter ligands, shows that the C-C bond formation has occurred by a trans carbopalladation involving nucleophilic attack by the middle carbon atom of the allene on a (pi-diene)palladium(II) complex. The stereochemistry of the (pi-allyl)palladium complexes was confirmed by benzoquinone-induced stereoselective transformations to allylic acetates.

In the palladium-catalyzed cyclization of allenic allylic esters using Pd(dba)2 as catalyst, it was shown that the allene acts as a carbon nucleophile. Intermediates were isolated and stereochemical studies established that the double bond of the allene has attacked the (pi-allyl)palladium intermediate on the face opposite to that of palladium.

The palladium-catalyzed carbocyclization of allene-diene derivatives leading to the stereospecific formation of various 4-substituted [4.3.0] and [5.3.0] bicyclic systems is presented. Different functionalities were introduced at the C-4 position of the bicyclic systems by using a range of external nucleophiles such as carboxylic acids, alcohols, phenols, and thiophenols. In the previous protocol acetic acid was used as solvent and also served as nucleophile. In this new methodology, reactions were run in nonnucleophlic solvents such as CH(2)Cl(2) or acetone in the presence of the appropriate nucleophile, making this new protocol a more versatile tool in organic synthesis. It is noteworthy that the Pd(II)-catalyzed cyclization of cycloheptadiene-derivative 1b gave exclusively the trans-annulated bicycle 4. Depending on the nature of the nucleophile, the regioselectivity of the reaction could be tuned to afford exclusively 4b or 4c' (Scheme 1). The mechanistic pathway is discussed.