Vinylogous Winstein Rearrangement: Unexpected Isomerization of an Azide-Substituted Cyclohexadiene-Fe(CO)3 Complex

In the course of our research into enzyme-triggered CO-releasing molecules (ET-CORMs), we were interested in using 2-acetoxy-5-azido-1,3-cyclohexadiene-Fe(CO)3 (rac-2) as a building block for further structural modification by means of Cu -catalyzed azide-alkyne cycloaddition (CuAAC click chemistry). Treatment of [2-acetoxy-cyclohexadienyl-Fe(CO)3]+[PF6]- with Zn(N3)2, TMS-N3, or NaN3 surprisingly afforded 2-acetoxy-1-azido-2,4-cyclohexadiene-Fe(CO)3 (rac-9) as the main product. We could show that rac-2 is primarily formed under kinetic control but undergoes a rapid isomerization to rac-9 (as the thermodynamic product) in a formal vinylogous Winstein rearrangement under concomitant migration of the Fe(CO)3 moiety. This unprecedented reaction displays a 1st order kinetics and appears to proceed via an ionic (rather than a concerted intramolecular) mechanism as supported by crossover experiments using deuterated compounds. The CuAAC reaction of rac-9 with propargylic alcohol afforded triazole rac-13, which was demonstrated (by headspace-gas chromatography (GC)) to act as an ET-CORM in the presence of porcine liver esterase

Head-to-Head Comparison of Selected Extra- and Intracellular CO-Releasing Molecules on Their CO-Releasing and Anti-Inflammatory Properties

Over the past decade, a variety of carbon monoxide releasing molecules (CORMs) have been developed and tested. Some CORMs spontaneously release CO once in solution, while others require a trigger mechanism to release the bound CO from its molecular complex. The modulation of biological systems by CORMs depends largely on the spatiotemporal release of CO, which likely differs among the different types of CORMs. In spontaneously releasing CORMs, CO is released extracellularly and crosses the cell membrane to interact with intracellular targets. Other CORMs can directly release CO intracellularly, which may be a more efficient method to modulate biological systems. In the present study, we compared the efficacy of extracellular and intracellular CO-releasing CORMs that either release CO spontaneously or require an enzymatic trigger. The efficacy of such CORMs to modulate HO-1 and VCAM-1 expression in TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC) was evaluated