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Lipase Catalyzed Aminolysis As an Entry to Consecutive Multicomponent Reactions

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Lipase Catalyzed Aminolysis As an Entry to Consecutive Multicomponent Reactions Lipase Catalyzed Aminolysis as An Entry to Consecutive Multicomponent Reactions Inaugural-Dissertation for the attainment of the title of doctor in the Faculty of Mathematics and Natural Sciences at the Heinrich Heine University Düsseldorf presented by Sidra Hassan from Lahore, Pakistan Düsseldorf, September 2014 From the Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich-Heine University, Düsseldorf. Printed with the permission of the Faculty of Mathematics and Natural Sciences of the Heinrich Heine University, Düsseldorf. Research Supervisor: Prof. Dr. Thomas J. J. Müller Co-examiner: Prof. Dr. Jörg Pietruzska Date of Examination: I hereby declare that the work presented here is reflection of my own independent efforts and had been conducted without any unauthorized assistance. Wherever contributions and consultation of other sources are involved, every effort is made to indicate this clearly with due reference to the literature and acknowledgement of collaborative research and discussions, if any. Moreover the dissertation has never been submitted in any form to any other institution. Düsseldorf, 22.09.2014 (Sidra Hassan) The present work was conducted during the time period from April 2011 to January 2014, at the Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, under the supervision of Prof. Dr. Thomas J. J. Müller. Part of this work has already been published or submitted for publication or presented as posters at scientific meetings: Publication in Scientific Journal "Three-component Chemoenzymatic Synthesis of Amide Ligated 1,2,3-Triazoles" S. Hassan, R. Tschersich, T. J. J. Müller, Tetrahedron Lett. 2013, 54, 4641–4644. Poster Presentations "One-Pot Chemoenzymatic Synthesis of 1,2,3-Triazoles" Third Annual CLIB-GC Retreat 2012, 22-24.02.2012, Bergisch Gladbach, Germany. "One-Pot Chemoenzymatic Synthesis of 1,2,3-Triazoles" Biotrends: Sustainable Industrial Biocatalysis International Congress, 29-30.11.2012, Dortmund, Germany. "One-Pot Chemoenzymatic Synthesis of 1,2,3-Triazoles" Fourth Annual CLIB-GC Retreat, 13-15.02.2013, Lünen, Germany. "Three-component Chemoenzymatic Synthesis of 1,2,3-Triazoles" Heidelberg Forum of Molecular Catalysis: International Symposium, 28.06.2013, University of Heidelberg, Germany. Oral Presentations "Development of Chemoenzymatic Amidation-Coupling-Cycloisomerization (ACCI) Sequence in a One-pot Fashion for the Synthesis of Oxazoles" First Internal(Düsseldorf/Jülich) CLIB-GC Retreat Mülheim, Germany, 30-31.08.2011. "One-Pot Chemoenzymatic Synthesis of 1,2,3-Triazoles" Second Internal (Düsseldorf/Jülich) CLIB-GC Retreat Mülheim, Germany, 23-24.08.2012. "Application of Chemoenzymatic Catalysis in Multicomponent Reactions" Ecochem Congress: The Sustainable Chemistry and Engineering Event, Basel Switzerland, 19-21.11.2013. My Thanks to.... I would like to thank ALMIGHTY for blessing me with the wonderful opportunities in this life and conferring upon me the confidence and courage to pursue my dreams. My heartiest gratitude to my research supervisor Prof. Dr. Thomas J. J. Müller, right from the selection process till now, for his kindness, cooperation, guidance, and for giving me the opportunity to work in a highly competitive and productive environment on such an interesting research topic in his work group. I would like to thank my second supervisor Prof. Dr. Jörg Pietruszka for his approachability during the research project. I would like to thank Cluster of Industrial Biotechnology-Graduate Cluster (CLIB-GC) for providing the financial support for the research project. I feel deeply obliged to pay my thanks to CLIB-GC coordinator, Dr. Sonja Meyer zu Berstenhorst, for her continual help especially during my early days in Germany. I would like to thank Dr. Bernhard Mayer for his benevolence and for being consistently considerate. My deepest appreciation to all the past and the present members of the work group for welcoming me so warmly in the group and also for their unconditional support and help both on personal and professional levels. I would especially like to thank my lab fellows, Alissa Götzinger and Elena Dirksen, with whom I had a great time both on and off lab ventures together. My special thanks to all the members of the technical staff for their technical assistance throughout my research tenure. This also gives me an opportunity to thank my chemistry teacher and mentor Dr. Fehmida Tasneem Baqai, who I consider my "professional mother", for always instigating me to pursue my carrier actively. Last but not least, I must acknowledge my loving and caring family members back home, who not only supported me, prayed for my success, but also exhibited great patience and goodwill throughout the fairly long period of my studies here. Whatever little I have achieved in my life or strive for achieving, I owe this to my ever supporting mother and brother for their encouragement and providing me with a constant sense of reliance. To my mother for making me certain that it's absolutely normal not to be a normality ...."your longing for Me is My message to you all your attempts to reach Me are in reality My attempts to reach you".... (An excerpt from Chanting the Name by Rumi) "So it was that I began to study not for praise or good opinion of others, but for the independence I thought it could give me. My studies were soon my life. They gave me refuge as well as occupation, for when I was sunk in my books I felt myself not alone, but in company: a company of enlightened souls whose passion was the enlightenment of others. I felt privileged to eavesdrop on the discourse of these great minds, and sometimes resented the intrusion of daily life. I can admit this to you because I know you will understand the temptation of a scholarly existence. Sometimes I think if I had not taken that road, a tumult of emotions might have overwhelmed me. Anger, sorrow and loneliness lay in wait on every side. I had only to stray a step or two from the path and I would be lost to them, and to despair. For what use are the tears of a few gentle souls against the cruelty of so many?" (An excerpt from The Einstein Girl by Philip Sington) Contents Contents List of Abbreviations ............................................................................................... 1 1. Summary .............................................................................................................. 5 2. Introduction .......................................................................................................... 9 2.1. Enzyme Catalysis in Organic Solvents ....................................................... 9 2.2. Enhancement of Enzyme Activity via Excipients ........................................ 10 2.3. Stabilization of Enzyme via Immobilization ................................................. 11 2.4. Enzyme Selectivity ..................................................................................... 11 2.5. Chemoenzymatic Multicomponent Reactions (MCRs) ................................ 12 2.5.1. MCRs Utilizing Enzymatic Resolution of Racemic Mixtures ................ 13 2.5.1.1. Ugi Four-Component Reaction .................................................... 13 2.5.1.2. Passerini Multicomponent Reaction ............................................ 16 2.5.1.3. Biginelli Multicomponent Reactions ............................................. 18 2.5.1.4. Synthesis of Cyclic Systems ....................................................... 18 2.5.1.5. Strecker Reaction........................................................................ 20 2.5.2. Enzyme Catalyzed Multicomponent Reactions ................................... 20 3. Aim of the Project ................................................................................................ 25 4. Literature Review ................................................................................................. 27 4.1. Mechanistic Aspects of Lipase Catalyzed Aminolysis ................................. 27 4.2. Development of Lipase Catalyzed Aminolysis ............................................ 28 4.3. Development of Synergy of Biocatalysis with Click Multicomponent Syntheses of Triazoles ...................................................................................... 37 4.4. Synergy of Biocatalysis with Palladium Catalyzed Coupling Reactions ...... 41 4.5. Heterocyclization of Propargylamides ........................................................ 44 4.5.1. Oxazole Syntheses .......................................................................... 44 4.5.2. Intramolecular Cycloisomerization of Terminal Propargylamides ...... 46 4.5.3. Intramolecular Cycloisomerization of Non-terminal Propargylamides ....................................................................................... 48 Contents 4.5.4. Coupling and Cycloaddition Reactions of Propargylamides .............. 48 5. Results and Discussion ....................................................................................... 51 5.1. Optimization of Enzyme Catalyzed Aminolysis ..................................... 51 5.1.1. Solvent Selection ............................................................................. 51 5.1.2. Screening of Enzymes ..................................................................... 52 5.1.3. Substrate (Acyl Donor) Selection ...................................................... 54 5.1.3.1. Substrates with Heteroatom Side Chain Linkers ................... 55 5.1.3.2. N-Protected
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