Quantitative comparison of chiral catalysts selectivity and performance: A generic concept illustrated with cyclododecanone monooxygenase as baeyer-villiger biocatalyst

Contribución equivalente como primer autor: Fink, Michael J. y Rial, Daniela V. Within this work a generic tool for chiral catalyst evaluation is established based on the application-oriented properties activity and selectivity; the concept aims at quantitatively comparing catalyst performance in general on a multitude of substrates. It is designed and intended to serve as decision guidance for challenges in catalysis and comprehensible information extraction from already recorded but unrefined data sets. The underlying algorithm assigns function points to catalytic entities via a statistically solid model possessing high flexibility and generates a relative ranking. This is coupled to an automated iterative refinement process towards maximum information content of results employing Shannon entropy optimization. Consequently, the developed workflow facilitates high distinguishability between catalysts even in low-scattering data sets. The numerical ranking is complemented by a clearly arranged graphic representation permitting facile and reliable visual interpretation of generality or niche capabilities of catalysts. Usefulness of the title concept is demonstrated by the performance evaluation of cyclododecanone monooxygenase, a highly versatile Baeyer-Villiger enzyme. To retain broad applicability, an open-source MATLAB® script is provided in electronic form.Fil: Fink, Michael J.. Vienna University of Technology; AustriaFil: Rial, Daniela Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas Centro Científico Tecnológico - CONICET -Rosario. Instituto de Biologia Molecular y Celular de Rosario; ArgentinaFil: Kapitanova, Petra. Vienna University of Technology; AustriaFil: Lengar, Alenka. Institute Of Applied Synthetic Chemistry; AustriaFil: Rehdorf, Jessica. ERNST MORITZ ARNDT UNIVERSITÄT GREIFSWALD (UG);Fil: Cheng, Qiong. No especifíca;Fil: Rudroff, Florian. Vienna University of Technology; AustriaFil: Mihovilovic, Marko D.. Vienna University of Technology; Austri

Synthesis and biooxidation of polycyclic and linear ketones

Zsfassung in dt. SpracheChirale Laktone und Ester sind wichtige Intermediate bei der Synthese von biologisch aktiven Verbindungen. In der Forschungsgruppe von Prof. Marko Mihovilovic wurden in den vergangenen Jahren bereits viele Studien über die Anwendung von Baeyer-Villiger Monooxigenasen (BVMO) in der synthetischen organischen Chemie durchgeführt. Die bestehende Substratbibliothek enthält monozyklische- bizyklische- und überbrückte bizyklische- Ketone, welche sich als gute Substrate für einige bekannte BVMO- Überexpressionssysteme erwiesen, deren Anwendungen in der synthetischen Chemie bis zum gewissen Grad etabliert sind.Die Aufgabe dieser Dissertation was es, den Anwendungsbereich und Grenzen dez Substratakzeptanz dieser Enzyme zu untersuchen und dafür die Substratbibliothek zu erweitern, indem man neue trizyklische überbrückte Ketone und funktionalisierte lineare Ketone herstellte und deren Substratakzeptanz mit den verfügbaren BVMOs prüfte.Die gewünschten polyzyklischen Substrate wurden mittels [4+3]-Zykloaddition hergestellt. Die gewünschten bizyklischen Substrate wurden mittel Olefin Metathese aus den polyzyklischen Substraten dargestellt. Die gewünschten linearen [beta]-Hydroxyketone wurden mittels Aldolkondenation aus Aceton und den entsprechenden Aldehyden hergestellt. Die gewünschten funktionalisierten linearen Ketone wurden einerseits aus den linearen [beta]-Hydroxyketonen durch Derivatisierung und andererseits aus den entsprechenden [beta]-ungesättigeten Ketonen mittels Michael-Addition hergestellt.Die so erhaltenen Substrate wurden mittels Biokatalyse zu Laktonen und Estern oxidiert. Dabei wurden Desymmetrisation und kinetische Resolution der prochiralen und chiralen Substrate ausgeführt um optisch reine Produkte zu erhaltenChiral lactones and esters are important intermediates in the synthesis of biologically active compounds.In the research group of Prof. Marko Mihovilovic, many studies about application of Baeyer-Villiger monooxigenases (BVMO) in the synthetic organic chemistry and preparation of chiral lactones were conducted within the past years. The existing substrate library contains monocyclic-, bicyclic- and bridged bicyclic ketones, which turned out to be quite good substrates for some of the known BVMO overexpression systems and whose applications in synthetic chemistry are to some extend established.The task of this thesis was to explore the scope and limitations of the substrate acceptance of the BVMOs and therefore extend the substrate library in synthesizing tricyclic bridged ketones and acyclic functionalized ketones and examine the acceptance with the available BVMOs.The desired polycyclic substrates for biooxidation were synthesized via [4+3] cycloaddition and subsequent olefin metathesis.Linear [beta]-hydroxyketones were synthesized via Aldol Addition reaction. Functionalized linear ketones were synthesized by derivatisation of [beta]-hydroxyketones or via Michael-Addition from the corresponding 3-en-2-ones.Beside conversion to the desired products also desymmetrisation and kinetic resolution of linear ketone substrates in particular was executed to obtain optically pure products.22