Engineering novel tandem reactions using organometallic catalysts and (metallo)enzymes

Denard, Carl

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Description

Title

Engineering novel tandem reactions using organometallic catalysts and (metallo)enzymes

Author(s)

Denard, Carl

Issue Date

2014-05-30T17:05:29Z

Director of Research (if dissertation) or Advisor (if thesis)

Zhao, Huimin

Doctoral Committee Chair(s)

• Hartwig, John F.
• Zhao, Huimin

Committee Member(s)

• Yang, Hong
• Schuler, Mary A.
• Kenis, Paul J.A.

Department of Study

Chemical & Biomolecular Engr

Discipline

Chemical Engineering

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• P450 BM3
• tandem catalysis
• enoate reductase
• asymmetric synthesis
• chemoenzymatic one-pot reaction
• heme porphyrin
• epoxidation
• reduction
• olefin metathesis

Abstract

Catalytic asymmetric synthesis is founded on three pillars: organometallic catalysis, organoca-talysis and biocatalysis. Over the years, catalysts of these three classes have enabled ground-breaking chemical transformations. The application of chemocatalysis to the manufacturing of chemicals is widespread, and biocatalysis is increasingly being used industrially. To streamline chemical syntheses, there has been and continuous to be a push to develop one-pot reactions, within which several catalysts from the same or disciplines are combined to catalyze numerous chemical steps and yield enantiopure products in high yield and selectivity. While this strategy is widespread in the respective fields of chemocatalysis and biocatalysis, examples in which chemocatalysts are combined with biocatalysts in one-pot are few and far between, apart from the seminal works of Backväll and Kim in which metal racemization complexes combined with lipases catalyze dynamic kinetic resolutions. The work presented in this thesis vows to bridge the gap between chemical catalysts and en-zymes by engineering one-pot tandem reactions between these two catalytic systems, with a par-ticular interest on combining cytochrome P450s and enoate reductases with organometallic cata-lysts. On the one hand, considerable efforts in transition-metal catalysis have culminated in prac-tical and efficient transformations such as isomerization, olefin metathesis, carbene-mediated insertions and others. On the other hand, metalloenzymes and reductases have been investigated and engineered to catalyze reactions with organic compounds that are synthetically and industri-ally important. First, we combined an isomerization of alkenes catalyzed by a ruthenium tri-phenylphosphine complex with cytochrome P450s variants that catalyze the epoxidation of these alkenes. While the isomerization catalyst and P450 BM3 variants could operate efficiently in a biphasic system, mass transfer limitations coupled with low enzyme TTNs greatly limited reaction yields. With a more active P450 BM3, namely the wild type P450, a biphasic reaction combining a cross metathesis reaction catalyzed by a ruthenium catalyst with a regioselective enzymatic epoxidation. A 90% yield of a single epoxide could be obtained selectively from the cross metathesis of two alkenes, a reaction that would yield a maximum 64% yield if ran sequentially. The scope of this tandem reaction was later extended to aromatic substrates, through a combina-tion of enzyme, substrate and reaction engineering. Lastly, we discovered that an electron defi-cient iron porphyrin catalyzed diazo coupling reactions in high yields in buffer and at room tem-perature. Its substrate scope included not diazoacetates, but also diazoketones to form dienones. When this catalyst was combined with an enoate reductase which catalyzes the reduction of α, β-unsaturated alkenes, in one pot, no mutual deactivation of the two catalytic species was ob-served. Complete reduction of the activated alkenes formed was observed. To form chiral diketones and diesters, we further combined the enzymatic reduction with a rhodium-catalyzed diazo coupling that forms prochiral alkenes.

Graduation Semester

2014-05

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Copyright 2014 Carl Denard

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