Recently, the Hartwig group reported a tandem reaction in which a metalloenzyme and a metathesis catalyst worked cooperatively to yield products which cannot be generated in comparable yield by sequential reactions with the two catalysts. Although organometallic catalysts and enzymes have been shown to work cooperatively, metalloenzymes have rarely been combined with organometallic catalysts due to the radically different environments and mutual inactivation. The robustness of the second generation Grubbs-Hoveyda catalysts and their ability to work in the presence of water make them perfect candidates for cooperation with a metalloenzyme. The metathesis catalyst was used to produce a mixture of olefins by a cross metathesis reaction and the metalloenzyme (P450 BM3) converted selectively one of the olefins into an epoxide. The beauty of the cooperative process is that the combination of the two catalysts led to a dynamic equilibration of the olefins due to the selective oxidation of only one of the metathesis products with a particular chain length: 10-tridecenoic acid. The yields of the desired epoxide were considerably higher compared to sequential cross metathesis and oxidation.
It was shown that second generation Grubbs-Hoveyda catalysts and the metalloenzyme could work on their respective substrates in the presence of the other catalyst and their respective medium without a change in reactivity and selectivity. The metathesis catalyst was stable to the buffer components, NADPH regeneration system, oxygen and the P450 enzyme in a biphasic isooctanol/buffer mixture. In addition, the enzyme and the phosphite dehydrogenase regeneration system were stable in the presence of the metathesis catalyst for up to 12hrs. In the cooperative reaction, the C13 cross metathesis product was consumed by the oxidation and continued to be regenerated by the metathesis reaction to give excellent yields of the epoxide: 70% were reached with 1.5 eq of 3-hexene under optimized reaction conditions. That’s really remarkable considering that only 26% theoretical yield can be obtained if the two reactions were run sequentially. Even better yields were achieved by increasing the ratio of 3-hexene to 10-undecenoic acid to suppress the formation of the self-metathesis product: up to 90% of the epoxide were generated with 10 eq of 3-hexene.
This cooperative catalysis is not limited to fatty acids. The epoxide of an alkenyloxybenzoic acid, which is unnatural substrate for P450 BM3 was formed in excellent yield by the tandem process. These results show the power of combining the diversity of reactions catalyzed by organometallic complexes with the selectivity of enzymes. Such tandem processes have the potential to improve the efficiency of chemical transformations by reducing the number of purification steps and improving the stereochemical control and substrate scope. The cooperative effect between different catalysts can enhance reactivity and selectivity by driving equilibrium reactions to nearly full conversion siphoning one the components to the final product.