Denard, C. A.; Bartlett, M. J.; Wang, Y.; Lu, L.; Hartwig, J. F.; and Zhao, H. “Development of a One-Pot Tandem Reaction Combining Ruthenium-Catalyzed Alkene Metathesis and Enantioselective Enzymatic Oxidation To Produce Aryl Epoxides” ACS Catal., 2015, 5, 3817.
Olefin metathesis is our favorite reaction here at All Things Metathesis because of its versatility in generating carbon-carbon bonds in a variety of contexts. This is in contrast to enzymatic reactions, which are very substrate specific and occur under very specific conditions. It’s worthy of note then, when new research marries these two disparate fields.
The Hartwig and Zhao groups have expanded on their work running tandem metathesis and enzymatic oxidation. Their previous work (which we covered here) coupled metathesis on a fatty acid, followed by enzymatic generation of an epoxide. Their recent report continues this work and expands the applicability beyond fatty acids. First, cross metathesis of (Z)-stilbene (1) with hexene or butene (2) generates vinylarene 3. Then in the same pot, vinylarene 3 is oxidized to epoxide 4 using a soluble (rather than membrane bound) bacterial cytochrome P450-BM3. The P450-BM3 imparts selectivity to this reaction by preferentially epoxidizing vinylarene 3 over other olefins present in the mixture, and to varying degree of ee. Grubbs Catalyst® 2nd Generation and Hoveyda-Grubbs catalysts were logical choices for this work because of their known tolerance to both the aqueous conditions and the presence of oxygen that are necessary for P450-BM3 function.
This reaction isn’t without its challenges though. (Z)-Stilbene has low aqueous solubility, and the mixture of Grubbs catalyst and (Z)-stilbene has to be carefully layered on top of the aqueous enzyme mix before sealing the reaction vessel. The yield is moderate, with up to 50% yield for reaction with (Z)-2-butene, and up to 22% yield for reaction with (E)-3-hexene. How then can this reaction be improved? Outside the realm of metathesis, one can try to improve the activity of P45-BM3 through generation of new mutant enzymes. The authors also suggest finding systems to form emulsions for the reaction mixture. This is under the assumption that the viscous P450-BM3 lysate interferes with access of (Z)-2-butene to the Grubbs catalyst, giving time for the unproductive formation of (E)-stilbene. Regardless of how this reaction is improved, it’s exciting to see progress in the area of tandem organometallic-enzymatic transformations. We’ll wait and see if Hartwig and Zhao can pull it off.