Engineering Novel Tandem Catalytic Reactions Using Organometallic Catalysts and Metalloenzymes

Organometallic chemistry and bioinorganic chemistry are two prominent disciplines of chemistry. Organometallic chemistry lies at the intersection of organic and inorganic chemistry, while bioinorganic chemistry lies at the intersection of biological and inorganic chemistry. Transition metal complexes lie at the core of both disciplines, but synthetic chemistry that exploits the complementary reactivity of the two systems in a cooperative fashion has rarely been developed. Often, the two classes of catalysts effect the same transformation with different rates and scope, but more often, they catalyze completely different types of reactions that are conducted in different vessels if they are used in the same synthetic sequence. Recently, synthetic catalysts and enzymes are beginning to be combined in new ways to work in tandem; however, there have been no reports in which organometallic catalysts and metalloenzymes have been combined and shown to work cooperatively. Such reactions are challenging to achieve, in part because the conditions in which these catalysts operate are typically different, and mutual inactivation of the catalysts typically occur when they are combined in the same medium. In our work, we use a biphasic reaction and show that 90% yield of a single epoxide can be obtained from a mixture of alkenes, a ruthenium metathesis catalyst and a P450 enzyme by a combination of a dynamic equilibration of alkenes and a selective epoxidation of the cross-metathesis products (Figure). We have expanded the scope of this tandem reaction to include unnatural P450 substrates, such as alkenyloxybenzoic acids, and P450 mutants with different regioselectivities. These results show the potential of combining the two classes of catalysts as synthetic catalysts become more tolerant of functional groups and enzymes become more tolerant of organic media. We are also exploring and evolving new metalloenzymes with different selectivities on internal alkenes for the selective epoxidation of dynamic cis-trans mixtures of alkenes established by transition metal catalysts. Lastly, we are creating hybrid transition-metal-metalloenzyme catalysts to create a P450 enzyme capable of performing both oxidation and metathesis reactions.