Jonathan S. Ward

Manganese(I)‐Catalyzed C−H Activation: The Key Role of a 7‐Membered Manganacycle in H‐Transfer and Reductive Elimination

Abstract Manganese‐catalyzed C−H bond activation chemistry is emerging as a powerful and complementary method for molecular functionalization. A highly reactive seven‐membered MnI intermediate is detected and characterized that is effective for H‐transfer or reductive elimination to deliver alkenylated or pyridinium products, respectively. The two pathways are determined at MnI by judicious choice of an electron‐deficient 2‐pyrone substrate containing a 2‐pyridyl directing group, which undergoes regioselective C−H bond activation, serving as a valuable system for probing the mechanistic features of Mn C−H bond activation chemistry.

A Flavoprotein Monooxygenase that Catalyses a Baeyer-Villiger Reaction and Thioether Oxidation Using Nadh as the Nicotinamide Cofactor.

A gene from the marine bacterium Stenotrophomonas maltophilia encodes a 38.6 kDa FAD‐containing flavoprotein (Uniprot B2FLR2) named S. maltophilia flavin‐containing monooxygenase (SMFMO), which catalyses the oxidation of thioethers and also the regioselective Baeyer–Villiger oxidation of the model substrate bicyclo[3.2.0]hept‐2‐en‐6‐one. The enzyme was unusual in its ability to employ either NADH or NADPH as nicotinamide cofactor. The KM and kcat values for NADH were 23.7±9.1 μM and 0.029 s−1 and 27.3±5.3 μM and 0.022 s−1 for NADPH. However, kcat/KM value for the ketone substrate in the presence of 100 μM cofactor was 17 times greater for NADH than for NADPH. SMFMO catalysed the quantitative conversion of 5 mM ketone in the presence of substoichiometric concentrations of NADH with the formate dehydrogenase cofactor recycling system, to give the 2‐oxa and 3‐oxa lactone products of Baeyer–Villiger reaction in a ratio of 5:1, albeit with poor enantioselectivity. The conversion with NADPH was 15 %. SMFMO also catalysed the NADH‐dependent transformation of prochiral aromatic thioethers, giving in the best case, 80 % ee for the transformation of p‐chlorophenyl methyl sulfide to its R enantiomer. The structure of SMFMO reveals that the relaxation in cofactor specificity appears to be accomplished by the substitution of an arginine residue, responsible for recognition of the 2′‐phosphate on the NADPH ribose in related NADPH‐dependent FMOs, with a glutamine residue in SMFMO. SMFMO is thus representative of a separate class of single‐component, flavoprotein monooxygenases that catalyse NADH‐dependent oxidations from which possible sequences and strategies for developing NADH‐dependent biocatalysts for asymmetric oxygenation reactions might be identified.

Visible-Light-Induced CO Release from a Therapeutically Viable Tryptophan-Derived Manganese(I) Carbonyl (TryptoCORM) Exhibiting Potent Inhibition against E. coli

The first visible-light-activated carbon-monoxide-releasing molecule (CO-RM) to exhibit a potent effect against Escherichia coli is described. The easily prepared tryptophan-derived manganese-containing complex (TryptoCORM) released 1.4 moles of CO at 465 nm, and 2 moles at 400 nm. A comprehensive synthetic, mechanistic and microbiological study into the behaviour of TryptoCORM is reported. The complex is thermally stable (i.e., does not release CO in solution in the absence of light), shows low toxicity against mammalian cells and releases tryptophan on photoinduced degradation, all of which point to TryptoCORM being therapeutically viable.

Redox-Tagged Carbon Monoxide-Releasing Molecules (CORMs): Ferrocene-Containing [Mn(C^N)(CO)4] Complexes as a Promising New CORM Class

This study describes the synthesis and characterization of a new class of ferrocene-containing carbon monoxide-releasing molecules (CORMs, 1-3). The ferrocenyl group is both a recognized therapeutically viable coligand and a handle for informative infrared spectroelectrochemistry. Deoxymyoglobin CO-release assays and in situ infrared spectroscopy confirm compounds 2 and 3 as photoCORMs and 1 as a thermal CORM, attributed to the increased sensitivity of the Mn-ferrocenyl bond to protonation in 1. Electrochemical and infrared spectroelectrochemical experiments confirm a single reversible redox couple associated with the ferrocenyl moiety with the Mn tetracarbonyl center showing no redox activity up to +590 mV vs Fc/Fc+, though no concomitant CO release was observed in association with the redox activity. The effects of linker length on communication between the Fe and Mn centers suggest that the incorporation of redox-active ligands into CORMs focuses on the first coordination sphere of the CORM. Redox-tagged CORMs could prove to be a useful mechanistic probe; our findings could be developed to use redox changes to trigger CO release.