SUMMARY
The mycobacterial biotin protein ligase (MtBPL) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases involved in lipid biosynthesis that catalyze the first step in fatty acid biosynthesis and pyruvate coenzyme A carboxylase, a gluconeogenic enzyme vital for lipid catabolism. Here we describe the design, development and evaluation of a rationally designed bisubstrate inhibitor of MtBPL. This inhibitor displays potent sub-nanomolar enzyme inhibition and antitubercular activity against multi- and extensively drug resistant Mtb strains. We show that the inhibitor decreases in vivo protein biotinylation of key enzymes involved in fatty acid biosynthesis and that the anti-bacterial activity is MtBPL-dependent. Additionally, the gene encoding BPL was found to be essential in M. smegmatis. Finally, the X-ray co-crystal structure of inhibitor bound MtBPL was solved providing detailed insight for further structure-activity analysis. Collectively, these data suggest that MtBPL is a promising target for further antitubercular therapeutic development.
The mechanism of the Pd-catalyzed diamination and carboamination of alkenes promoted by N-fluorobenzenesulfonimide (NFBS) was investigated. Stereochemical labeling experiments established that the diamination reaction proceeds via overall syn addition of the two nitrogen groups, whereas carboamination is the result of an anti addition of arene and nitrogen to the alkene. The intermediate Pd-alkyl complex arising from aminopalladation was observed, and an X-ray crystal structure of its 2,2'-bipyridine (bipy) complex was obtained, revealing strong chelation of the amide protecting group to palladium. Aminopalladation was shown to be an anti-selective process in both the presence and the absence of added ligands, proceeding via external attack of the nitrogen on a Pd-coordinated alkene. The intermediate Pd-alkyl complex was converted to diamination product upon exposure to NFBS with inversion of configuration via oxidative addition followed by dissociation of the benzenesulfonimide anion and S(N)2 displacement of the Pd-C bond. Conversely, arylation of the Pd-alkyl complex proceeds via retention of stereochemistry, consistent with C-H activation of the arene at the Pd(IV) center. A small intermolecular isotope effect (k(H)/k(D) = 1.1) and a large intramolecular isotope effect (k(H)/k(D) = 4) were measured for this process, indicating that C-H activation occurs via a poorly selective product-determining coordination of the arene followed by a highly selective C-H activation. Competition between arenes reveals an unusual reactivity order of toluene > benzene > bromobenzene > anisole.
This report describes a unique Pd-catalyzed oxidative carboamination of protected aminoalkenes in which inexpensive unactivated nucleophilic arenes are incorporated to give carboamination products in good yields. A variety of protected amide and carbamate groups are tolerated, and various five-, six-, and seven-membered rings are formed in good yields. Under these conditions, halobenzenes are activated at the C-H bond rather than the C-X bond, and very high regioselectivity for the para substitution product is observed in all cases. We propose that this carboamination takes place via electrophilic aromatic substitution of a Pd(IV) alkyl intermediate.
A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide (NFBS) as an aminating reagent is described. The reaction occurs in an intra/intermolecular fashion, incorporating one nitrogen donor from the substrate and the other from the NFBS, thereby generating cyclic diamine derivatives in a single step. The products are differentially protected at both nitrogens, allowing for maximal synthetic flexibility. The intermediacy of the Pd(IV) species is proposed to be responsible for the unusual reactivity of NFBS.
An enantioselective Pd-catalyzed vicinal diamination of unactivated alkenes using N-fluorobenzenesulfonimide as both an oxidant and a source of nitrogen is reported. The use of Ph-pybox and Ph-quinox ligands afforded differentially protected vicinal diamines in good yields with high enantioselectivities. Mechanistic experiments revealed that the high enantioselectivity arises from selective formation of only one of four possible diastereomeric aminopalladation products of the chiral Pd complex. The aminopalladation complex was characterized by X-ray crystallography.
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