Ligand and solvent control of selectivity in the C–H activation of a pyridylimine-substituted 1-naphthalene; a combined synthetic and computational study

The pyridylimine-substituted 1-naphthalenes, 2-(1-C10H7)-6-{CR[double bond, length as m-dash]N(2,6-i-Pr2C6H3)}C5H3N (R = Me HLMe, H HLH), react with Na2[PdCl4] in acetic acid at elevated temperature to afford either ortho-C–Hnaphthyl activated (LMe)PdCl (2ortho) or the unactivated adduct (HLH)PdCl2 (1b). Alternatively, 1b and its ketimine analogue (HLMe)PdCl2 (1a), can be prepared by treating (MeCN)2PdCl2 with either HLMe or HLH in chloroform at room temperature. Regio-selective ortho-C–H activation to form 2ortho can also be initiated by the thermolysis of 1a in acetic acid, while no reaction occurs under similar conditions with 1b. Interestingly, the C–H activation of HLMe to give 2ortho is found to be reversible with 100% deuteration of the peri-site occurring on reacting Na2[PdCl4] with HLMe in acetic acid-d4. By contrast, heating 1a in toluene gives a 55 : 45 mixture of 2ortho and its peri-activated isomer 2peri. Pure 2peri can, however, be obtained either from (LMe)PdOAc (3peri) by OAc/Cl exchange or by the sequential reactions of 1a with firstly silver acetate then with aqueous sodium chloride. Intriguingly, a peri to ortho interconversion occurs on heating 2peri in acetic acid to give 2ortho. DFT calculations have been used to investigate the C–H activation steps and it is found that in acetic acid ortho-C–H activation is kinetically and thermodynamically favoured but peri-CH activation is kinetically accessible (ΔΔG‡ = 2.4 kcal mol−1). By contrast in toluene, the reaction appears to be irreversible with the difference in barrier height for ortho- and peri-C–H activation being very small within the error of the method (ΔΔG‡ = 0.7 kcal mol−1), findings that are in agreement with the empirically observed product distribution for 2ortho and 2peri. Single crystal X-ray structures are reported for 1a, 1b, 2ortho and 2peri

Carprofen elicits pleiotropic mechanisms of bactericidal action with the potential to reverse antimicrobial drug resistance in tuberculosis

Background The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis. Objectives We aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria. Methods Integrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity. Results Carprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen’s anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice. Conclusions This immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations

Transformation catalytiques sélectives : Couplage carbone-carbone par catalyse au palladium, hydrogénation par catalyse au rhodium et au ruthénium, nouveaux ligands et aldolisation énantiosélective par organocatalyse

Thèse de Doctorat de l'Université de Rennes

C-H Functionalization: A New Strategy for the Synthesis of Biologically Active Natural Products

International audienc

Activation and functionalization of benzylic derivatives by palladium catalysts

International audienc

(S,S,S)-Perhydroindolic Acid: Efficient Catalyst for Direct Asymmetric Aldol Reaction of Aromatic Aldehydes.

International audienc

Diversity-oriented approach to CF3CHF-, CF3CFBr-, CF3CF2-, (CF3)2CH-, and CF3(SCF3)CH-substituted arenes from 1-(diazo-2,2,2-trifluoroethyl)arenes.

Arenes substituted with perfluoroalkyl groups are attractive targets for drug and agrochemical development. Exploiting the carbenic character of donor/acceptor diazo compounds, a diversity-oriented synthesis of perfluoroalkylated arenes, for late stage fluorofunctionalization, is described. The reaction of 1-(diazo-2,2,2-trifluoroethyl)arenes with HF, F/Br, F2, CF3H, and CF3SH sources give direct access to a variety of perfluoroalkyl-substituted arenes presenting with incremental fluorine content. The value of this approach is also demonstrated for radiochemistry and positron emission tomography with the [(18)F]-labeling of CF3CHF-, CF3CBrF-, and CF3CF2-arenes from [(18)F]fluoride