Engineering Metathesis-Oxidation Tandem Reactions by using a Grubbs-Hoveyda Catalyst and cytochrome P450 BM3

Olefin metathesis reactions catalyzed by organometallic catalysts with remarkable stability and activity are widely applied in the synthesis of pharmaceutical agents, natural products, and new materials. In the coupled oxidation reaction, of which the products are involved in various areas such as drug metabolism, P450 as well as its mutants can selectively oxidize long-chain olefins generated in the metathesis reaction. In our biphasic tandem metathesis-oxidation reaction, 5-hexenoic acid and trans-7-tetradecene react to form dodecen-5-oic acids (1:6 Z/E) with 65% yield and 70% selectivity. The P450 BM3 enzyme concurrently oxidizes the C₁₂ acid intermediates with nearly 100% selectivity to form a mixture of ω-1, ω-2, ω-3 and ω-4 hydroxylated products. Overall yields of 20% can be obtained for the tandem reaction, which is found to be nearly 15% more effective than performing the two reactions separately. One of the main reasons for the low overall yields could be the unmatched rates between the metathesis and the oxidation reaction due to the ineffective alcohol dehydrogenase NADPH regeneration system. Other regeneration enzymes, such as the NADP⁺-dependent phosphite dehydrogenase (PTDH) and glucose dehydronase (GDH) are being investigated. So far, the tandem reaction between 5-hexenoic acid and trans-7-tetradecene has been proven to function with great selectivity, though its total conversion is not high enough. We are expanding our tandem reaction to encompass not only fatty acids, but also aromatics and alkenes. This tandem reaction could be used as a platform for the synthesis of various attractive compounds requiring high regio- and enantio- selectivity.