280584 Engineering Novel Tandem Catalytic Reactions Using Organometallic Catalysts and Metalloenzymes

Monday, October 29, 2012: 1:06 PM
Westmoreland Central (Westin )
Carl A. Denard1, Lars Martin Jarenmark2, Ramesh Giri3, Yichen Tan4, Levi Stanley5, John F. Hartwig3 and Huimin Zhao1,6,7,8, (1)Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, (2)Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, (3)Chemistry, University of California-Berkeley, Berkeley, CA, (4)University of California-Berkeley, Berkeley, CA, (5)Chemistry, Iowa State University, Arnes, IA, (6)Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, (7)Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, (8)Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL

Concurrent asymmetric tandem reactions, so called “multicast promoted tandem reactions,” still remain a synthetic challenge in terms of matching catalysts’ reaction rates, fine-tuning substrate and product selectivities, and reaction condition compatibility. Nonetheless, many wonderful examples of multicast promoted one-pot syntheses using chemical catalysts from various disciplines have found success. In contrast, multienzymatic systems in nature provide ample evidence of tandem catalysis in an aqueous environment. In addition, protein engineering towards industrial biocatalysis has emerged as a powerful tool for the biosynthesis of fine chemicals with high regio- and enantioselectivity.  The combination of catalysts from these two very different disciplines (chemical catalysts and enzymes) for the synthesis of high-value compounds is an attractive target and has recently seen increased interest. In the Zhao and Hartwig labs, we are focused on developing novel catalytic asymmetric tandem reactions using organometallic catalysts and metalloenzymes.

We have developed a tandem process to achieve successive olefin isomerization-enantioselective epoxidation, a reaction difficult to achieve occurring with a single catalytic system. This process can potentially provide a practical and efficient strategy for the enantioselective preparation of linear terminal epoxides in high ee from a mixture of simple substrates. By combining an isomerization catalyst with a purified P450 BM3 mutant in a biphasic reaction, we report for the first time that the two reactions work in tandem.  Using our tandem reaction, we have achieved the successive terminal to internal olefin isomerization followed by epoxidation to yield the internal epoxides, as well as the thermodynamically challenging internal to terminal olefin isomerization followed by the terminal olefin epoxidation. We have further expanded the substrate scope of the reaction system to straight and branched aliphatic olefins, unsaturated methyl esters, acids and ketones. Overall yields of 35% can be obtained, as well as interesting substrate-dependent reaction regioselectivities.

In parallel, using the robust and established chemistry of ruthenium carbene metathesis catalysts, we are investigating ways to couple them with metalloenzymes to develop novel tandem reaction systems. Several ruthenium metathesis catalysts were found to be active, stable in the presence of air and water, at room temperature and in several solvent: buffer systems to afford cross metatheses with moderate to high selectivities. We obtained preliminary data of a novel biphasic tandem cross metathesis-epoxidation/hydroxylation approach involving a Hoveyda-Grubbs 2nd generation complex and the versatile cytochrome P450 from Bacillus megaterium, for the selective hydroxylation and epoxidation of 5-dodecenoic acids in high yields. We are extending this platform to other challenging transformations, such as the epoxidation of 1-butenylbenzene generated by cross metathesis of cis-stilbene and trans-3-hexene as well as the enantioselective epoxidation of long chain alkenes generated by alkene chain elongation through cross- or self- metathesis of short chain alkenes.

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