The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral ...fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F(•) transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
A simple hydrido‐cobalt complex efficiently catalyses the highly regio‐ and stereoselective dimerisation of various terminal arylacetylenes under mild conditions. The corresponding (E)‐1,4‐enynes are ...obtained as sole isomers with good to excellent yields. DFT calculations revealed that the reaction proceeds via a CH activation/hydrocobaltation pathway.
Go cyclic! The use of Co(H)(PMe3)4 as a cobalt catalyst allows the previously unattainable catalytic version of the cobalt‐mediated cycloaddition of enediynes without the requirement of thermal or ...light activation (see scheme). The importance of a chelating group on the substrate that can selectively direct the reaction pathway toward the classical polycyclic 1,3‐cyclohexadienes or a new family of bicyclic trienes is also demonstrated.
Ynamides were used as precursors for the in situ generation of highly reactive ketenimines that could be trapped with imines in a 2+2 cycloaddition. This imino‐Staudinger synthesis led to a variety ...of imino‐analogs of β‐lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.
Base Jump: Under strongly basic conditions ynamides gave highly reactive ketenimines that could be trapped with imines in a 2+2 cycloaddition. This imino‐Staudinger synthesis led to a variety of imino analogues of β‐lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.
The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient ...β-lactamases which render most β-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of β-lactams (namely azetidinimines) as efficient non-covalent inhibitors of β-lactamases. Despite the structural and mechanistic differences between serine-β-lactamases KPC-2 and OXA-48 and metallo-β-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki’s below 0.3 μM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 μM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of β-lactamases.
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•Forty azetidinimines synthesized and evaluated for their activity against carbapenemases.•Several compounds are submicromolar inhibitors of both MBLs (NDM-1) and SBLs of class A (KPC-2) and D (OXA-48).•One compound is also active against 4 other MBLs (NDM-4, NDM-7, NDM-9 and VIM-1), CTX-M-15 (class A) and CMY-2 (class C).•The same compound can repotentiate imipenem against a NDM-1-producing clinical isolate of E. coli.
Ynamides were used as precursors for the in situ generation of highly reactive ketenimines which were trapped with imines in a 2+2 cycloaddition under microwave irradiation. Twenty novel ...azetidinimines have been prepared in this straightforward and operationally simple manner. Furthermore, the products arising from this imino‐Staudinger synthesis were functionalized using a wide range of protocols that leave the four‐membered amidine ring intact. (Illustration by E. Menneteau, CNRS‐PRC 2017). More information can be found in the Communication by R. H. Dodd, K. Cariou et al. on page 12991.
According to Waddington's epigenetic landscape concept, the differentiation process can be illustrated by a cell akin to a ball rolling down from the top of a hill (proliferation state) and crossing ...furrows before stopping in basins or "attractor states" to reach its stable differentiated state. However, it is now clear that some committed cells can retain a certain degree of plasticity and reacquire phenotypical characteristics of a more pluripotent cell state. In line with this dynamic model, we have previously shown that differentiating cells (chicken erythrocytic progenitors (T2EC)) retain for 24 h the ability to self-renew when transferred back in self-renewal conditions. Despite those intriguing and promising results, the underlying molecular state of those "reverting" cells remains unexplored. The aim of the present study was therefore to molecularly characterize the T2EC reversion process by combining advanced statistical tools to make the most of single-cell transcriptomic data. For this purpose, T2EC, initially maintained in a self-renewal medium (0H), were induced to differentiate for 24H (24H differentiating cells); then, a part of these cells was transferred back to the self-renewal medium (48H reverting cells) and the other part was maintained in the differentiation medium for another 24H (48H differentiating cells). For each time point, cell transcriptomes were generated using scRT-qPCR and scRNAseq. Our results showed a strong overlap between 0H and 48H reverting cells when applying dimensional reduction. Moreover, the statistical comparison of cell distributions and differential expression analysis indicated no significant differences between these two cell groups. Interestingly, gene pattern distributions highlighted that, while 48H reverting cells have gene expression pattern more similar to 0H cells, they are not completely identical, which suggest that for some genes a longer delay may be required for the cells to fully recover. Finally, sparse PLS (sparse partial least square) analysis showed that only the expression of 3 genes discriminates 48H reverting and 0H cells. Altogether, we show that reverting cells return to an earlier molecular state almost identical to undifferentiated cells and demonstrate a previously undocumented physiological and molecular plasticity during the differentiation process, which most likely results from the dynamic behavior of the underlying molecular network.
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