Biocatalytic (De)Carboxylation of Phenolic Compounds: Fundamentals and Applications

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Biocatalytic (De)Carboxylation of Phenolic Compounds: Fundamentals and Applications Biocatalytic (De)carboxylation of Phenolic Compounds: Fundamentals and Applications Vom Promotionsausschuss der Technischen Universität Hamburg-Harburg Zur Erlangung des akademisches Grades Doktor der Naturwissenschaften (Dr. rer. nat.) genehmigte Dissertation von Lorenzo Pesci aus Rom 2017 Betreuer: Prof. Dr. Andreas Liese 1. Gutachter: Prof. Andreas Liese 2. Gutachter: Prof. Andrew Torda Datum der mündlichen Prüfung: 12.01.2017 Abstract Carbon dioxide is a pivotal compound in the biotic world of metabolism and in the abiotic world of chemical synthesis. These two worlds can merge, to some extent, when biological catalysts for (de)carboxylations are used to accelerate chemical conversions for industrial applications. A particular set of lyases which display this type of activity on phenolic starting materials belong to microbial degradation pathways. Such enzymes are hydroxybenzoic acid and phenolic acid (de)carboxylases, which catalyze reversible carboxylations and can be differentiated according to their regio-selectivity based on which the carboxylic group is added and removed: ortho and para , for phenolic compounds, and beta , for hydroxycinnamic acids. Because carbon dioxide and its hydrated form, bicarbonate, have considerably low standard Gibbs free energies, the equilibrium of the reactions often lie strongly on the decarboxylation side in physiological conditions. In this work, two ortho - (de)carboxylases and one beta -(de)carboxylase were studied in the reaction directions relevant for application. For ortho -selectivity, dihydroxybenzoic acid (de)carboxylases –from Rhizobium sp. and Aspergillus oryzae – were studied in the synthesis –“up-hill”– direction, which yields salicylic acids from phenols. This reaction resembles the abiotic Kolbe-Schmitt synthesis, which is conducted at elevated temperatures and pressures. Therefore, the establishment of an “enzymatic counterpart” for large scale production is highly desirable in order to achieve efficient CO 2 utilization for chemical synthesis. Fundamental studies on kinetics and thermodynamics revealed the reactions bottlenecks, allowed the proposition and verification of a catalytic mechanism and gave new insights on the biocatalysts’ substrate spectra. The development of an amine-coupled method to use carbon dioxide –instead of bicarbonate, the effective co-substrate usually accepted by these biocatalysts– reveled interesting properties of ammonium ions in determining approximately five-fold increases in reaction rates and approximately two-fold equilibrium conversions for the carboxylation of catechol. Moreover, the analyses of strategies to overcome the thermodynamic equilibrium are critically discussed and demonstrate how the system may have a realistic future only on the laboratory scale. Beta -(de)carboxylases catalyze the reversible (de)carboxylation on the C–C double bonds of abundant and naturally occurring para -hydroxycinnamic acids yielding para -hydroxystyrenes, which are normally obtained by using multistep synthesis, toxic reagents and high temperatures. Therefore, these enzymes represent a i promising tool for the deoxygenation of biomass-derived feedstocks. In the present work, a phenolic acid (de)carboxylase from Mycobacterium colombiense was studied as biocatalyst for the decarboxylation of ferulic acid, yielding 4-vinylguaiacol, an Food and Drug Administration-approved flavoring agent. Kinetic studies revealed the occurrence of strong product inhibition, which was then tackled by performing the biotransformation in two liquid-phase systems. The optimized reaction conditions using hexane as the organic phase were demonstrated also in gram scale, affording the target product in 75% isolated yield. A reactor concept including the integrated product separation is also presented and discussed. In order to further exploit this biocatalytic reaction for applications, a sequential Pd-catalyzed hydrogenation step was carried out in the organic layer, affording 4-ethylguaiacol, another industrially relevant flavoring agent. In gram scale, the whole reaction sequence afforded the final product in 70% isolated yield. Both biotransformation and chemo-enzymatic sequence were evaluated using the E-factor as a measurement of their environmental impact; a comparison with existing synthetic paths shows how the strategies developed in this work are promising “green” methods in view of large scale applications. ii Kurzfassung Kohlenstoffdioxid dient als Schlüsselkomponente im biotischen Stoffwechsel sowie in der abiotischen, chemischen Synthese. Mit einigen Ausnahmen können beide Bereiche zusammengeführt werden, indem im Hinblick auf industrielle Anwendungen Biokatalysatoren für (De)Carboxylierungs-Reaktionen zur Beschleunigung von chemischen Reaktionen eingesetzt werden. Einige Lyasen, die bezüglich phenolischer Ausgangsstoffe diese katalytische Aktivität aufweisen, sind an mikrobiellen Abbauprozessen beteiligt. Die Hydroxybenzoesäure- und Phenolsäure- (De)Carboxylasen katalysieren reversible Carboxylierungs-Reaktionen und werden anhand ihrer Regioselektivität bezüglich der Addition oder Abspaltung einer Carboxylgruppe differenziert: ortho und para für phenolische Komponenten und beta für Hydroxyzimtsäuren. Aufgrund der geringen freien Standard Gibbs-Energien von Kohlenstoffdioxid und seiner hydrierten Form als Hydrogencarbonat liegt das Gleichgewicht der Reaktionen unter physiologischen Bedingungen häufig deutlich auf der Seite der Decarboxylierung. In dieser Arbeit wurden zwei ortho - (De)Carboxylasen und eine beta -(De)Carboxylase untersucht, wobei für die Richtung der Reaktion die Relevanz für industrielle Anwendungen im Fokus stand. Bezüglich der ortho -spezifischen Selektivität wurden Dihydroxybenzoesäure-(De)Carboxylasen von Rhizobium sp. und Aspergillus oryzae in die sogenannte Syntheserichtung („up- hill“) untersucht, wodurch Salizylsäuren als Produkt ausgehend von Phenol gewonnen werden. Diese Reaktion ähnelt der abiotischen Kolbe-Schmitt Synthese, die unter erhöhten Temperaturen und Drücken durchgeführt wird. Daher ist es wünschenswert, ein alternatives Konzept unter Einsatz von Enzymen (“enzymatic counterpart“) im großen Maßstab zu etablieren, um eine effiziente CO 2-Nutzung zu ermöglichen. Durch detaillierte Studien der Kinetik und Thermodynamik wurden Einschränkungen der Reaktionen aufgezeigt, der katalytische Mechanismus beschrieben und verifiziert, sowie neue Einblicke in das Substratspektrum der Biokatalysatoren gewonnen. Die Entwicklung einer Amin gekoppelten Methode zur Nutzung von Kohlenstoffdioxid (anstatt von Bicarbonat, welches das effektive Cosubstrat der betrachteten Biokatalysatoren ist) zeigte einerseits erhöhte Reaktionsgeschwindigkeiten des Ammonium-Ions (ca. 5-fach) und andererseits höhere Gleichgewichts-Umsätze (ca. doppelt so hoch) für die Carboxylierung von Catechol. Darüber hinaus wurden Strategien zur Verschiebung des thermodynamischen Gleichgewichts diskutiert und ein Lösungsansatz für den zukünftigen Einsatz des iii Systems im Labormaßstab vorgestellt. Beta -(De)Carboxylasen katalysieren hingegen die reversible (De)Carboxylierung einer C–C-Doppelbindung natürlich vorkommender (und reichlich vorhandener) para -Hydroxyzimtsäuren. Als Produkt werden in diesen Reaktionen para -Hydroxystyrole erhalten, die in einem mehrstufigen chemischen Prozess unter Einsatz von toxischen Reagenzien bei hohen Temperaturen synthetisiert werden. Daher stellt die Anwendung der genannten Enzyme eine vielversprechende Möglichkeit zur Deoxygenierung aus Biomasse basierten Rohstoffen dar. In der vorliegenden Arbeit wurde zur Decarboxylierung von Ferulasäure eine Phenolsäure-(De)Carboxylase aus Mycobacterium colombiense untersucht, um den von der Food and Drug Administration genehmigten Aromastoff 4-Vinylguaiakol als Produkt zu gewinnen. In kinetischen Studien konnte eine starke Produktinhibierung beobachtet werden, welche durch die Überführung der Biotransformation in ein Zwei-Phasensystem umgangen werden konnte. Unter optimierten Reaktionsbedingungen mit Hexan als organischer Phase wurde das Zielprodukt mit einer isolierten Ausbeute von 75% im Gramm-Maßstab gewonnen. Zudem wurde ein Reaktorkonzept mit integrierte Produktabtrennung präsentiert und diskutiert. Um die biokatalytische Reaktion im Hinblick auf Anwendungen zu untersuchen, wurde eine sequentielle, Pd-katalysierte Hydrogenierung in der organischen Phase durchgeführt. Dadurch wurde 4-Ethylguaiakol als weiterer industriell relevanter Aromastoff mit einer isolierten Ausbeute von 70% im Gramm- Maßstab synthetisiert. Sowohl die Biotransformation, als auch die chemo- enzymatische Sequenz wurden auf Basis des E-Faktors als Maß für den Umwelteinfluss bewertet. Ein Vergleich mit bereits existierenden synthetischen Ansätzen zeigt die vielversprechende Entwicklung der vorgestellten Reaktionen als „grüne“ Methoden für Anwendungen im großen Maßstab. iv Contents 1 Introduction ........................................................................................................ 1 1.1 Biological, Industrial and Environmental Importance of Carbon Dioxide ................ 4 1.1.1 A Biochemical Perspective of (De)carboxylation Reactions.................................... 5 1.1.2 Carbon Dioxide in the Environment ...................................................................... 8 1.1.3 An Industrial Perspective of (De)carboxylation Reactions ..................................... 9 1.2 The Case of Aromatics ..........................................................................................
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