Synthesis of Phosphonomethyl Tetrahydrofurans via the Mori-Tamaru Reaction of Phosphonodienes.

Nickel-catalyzed reductive addition of phosphonodienes to aldehydes (the Mori-Tamaru reaction) gives hydroxy vinyl phosphonates in good yields with excellent control of the relative stereochemistry. Base-induced cyclization of the vinyl phosphonates yields phosphonomethyl-substituted tetrahydrofurans. Inversion of the hydroxyl stereochemistry by Mitsunobu reaction and then cyclization yields a different set of phosphonomethyl-substituted tetrahydrofuran diastereoisomers.

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus.

Twelve new Cyclophostin and Cyclipostins analogues (CyC19-30) were synthesized, thus extending our series to 38 CyCs. Their antibacterial activities were evaluated against four pathogenic mycobacteria (Mycobacterium abscessus, Mycobacterium marinum, Mycobacterium bovis BCG, and Mycobacterium tuberculosis) and two Gram negative bacteria. The CyCs displayed very low toxicity toward host cells and were only active against mycobacteria. Importantly, several CyCs were active against extracellular M. abscessus (CyC17/CyC18ß/CyC25/CyC26) or intramacrophage residing mycobacteria (CyC7(α,ß)/CyC8(α,ß)) with minimal inhibitory concentrations (MIC50) values comparable to or better than those of amikacin or imipenem, respectively. An activity-based protein profiling combined with mass spectrometry allowed identification of the potential target enzymes of CyC17/CyC26, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the CyCs against mycobacteria, including the most drug-resistant M. abscessus, through the cumulative inhibition of a large number of Ser- and Cys-enzymes participating in key physiological processes.

Relay cross metathesis reactions of vinylphosphonates.

Dimethyl (ß-substituted) vinylphosphonates do not readily undergo cross metathesis reactions with Grubbs catalyst and terminal alkenes. However, the corresponding mono- or diallyl vinylphosphonate esters undergo facile cross metathesis reactions. The improved reactivity is attributed to a relay step in the cross metathesis reaction mechanism.