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Hydrogen-Bonding Institut für Organische Chemie der Justus-Liebig-Universität Gießen Hydrogen-Bonding (Thio)urea Organocatalysts in Organic Synthesis: State of the Art and Practical Methods for Acetalization, Tetrahydropyranylation, and Cooperative Epoxide Alcoholysiss Inaugural-Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften (doctor rerum naturalium – Dr. rer. nat.) der Naturwissenschaftlichen Fachbereiche der Justus-Liebig-Universität Gießen Vorgelegt von Mike K o t k e Diplom-Chemiker aus Hasselroth im Main-Kinzig-Kreis 2009 Hydrogen-Bonding (Thio)urea Organocatalysts in Organic Synthesis: State of the Art and Practical Methods for Acetalization, Tetrahydropyranylation, and Cooperative Epoxide Alcoholysis ……………………………………………………………………………… Wasserstoffbrücken-bildende (Thio)Harnstoff-Organokatalysatoren in der Organischen Synthese: Stand der Forschung und praktische Methoden zur Acetalisierung, Tetrahydropyranylierung und Kooperativen Epoxidalkoholyse Bewertung dieser Dissertation „Summa cum laude” (ausgezeichnet) Erstgutachter Univ.-Prof. Dr. Peter R. Schreiner, Ph.D. Zweitgutachter Univ.-Prof. Dr. Wolfgang Maison Einreichen der Dissertation beim 13. August 2009 Naturwissenschaftlichen Prüfungsamt Tag der Disputation 08. Oktober 2009 Prüfer der Disputation Univ.-Prof. Dr. Siegfried Schindler (AC) Univ.-Prof. Dr. Peter R. Schreiner, Ph.D. (OC) Univ.-Prof. Dr. Bruno K. Meyer (Physik) Die in dieser Dissertation dokumentierten Forschungsergebnisse entstanden in der Zeit von Juli 2002 bis Oktober 2008 am Institut für Organische Chemie der Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 58, D-35392 Gießen, unter der wissenschaftlichen Betreuung des Arbeitsgruppenleiters Herrn Prof. Dr. Peter R. Schreiner, Ph.D. The research results documented in this PhD thesis have been achieved in the research period between July 2002 and October 2008 at the Institute of Organic Chemistry, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany, under the scientific supervision of the group leader Prof. Dr. Peter R. Schreiner, Ph.D. Ich danke sehr meinem wissenschaftlichen Betreuer Herrn Prof. Dr. P. R. Schreiner, Ph.D für die Themenstellung aus einem aktuellen Forschungsgebiet der Organischen Chemie, die konstruktiven Diskussionen, sein stetes Interesse am Fortgang der Arbeit, die mehrjährige vertrauensvolle Zusammenarbeit sowie für die erwiesene Unterstützung und zugestandene forscherische Freiheit. Die Forschung der Arbeitsgruppe Schreiner auf dem Fachgebiet „Organokatalyse“ wurde von der Deutschen Forschungsgemeinschaft (DFG) im Rahmen des Schwerpunktprogrammes Organokatalyse (SPP 1179) unterstützt. Ich danke der DFG für die gewährte Unterstützung. Diese Dissertation ist in englischer Sprache verfasst, da sie nahezu vollständig als englischsprachige Fachliteratur publiziert ist oder publiziert werden wird (vgl. Publikationsliste/ ”List of Publications“). Dem englischen Hauptteil sind ein deutsches Vorwort und eine deutsche Zusammenfassung vorangestellt. Ich danke den Verlagen für die erteilte Erlaubnis, die Originalpublikationen in dieser Arbeit verwenden zu dürfen. Diese Publikationen sind urheberrechtlich geschützt und in der Originalformatierung nur von den Verlagen selbst zu beziehen. I thank the publishers for the reprint permission to present the original articles in this PhD thesis. These articles are protected by copyright and are only available from the respective publisher. Diese Dissertation ist meiner lieben Mutter Eva Kotke gewidmet, die mich nicht nur während der Jahre dieser Arbeit auf vielfältige Weise immer unterstützte. - in unbeschreiblicher Dankbarkeit, Hochachtung und Liebe - Meinem lieben Vater Eugen Kotke danke ich schon hier ganz herzlich für seine Unterstützung. In Erinnerung an meine lieben Omas Eva Semmel ∗ ( 22.12.1920 – †04.04.2005) Lydia Kotke ∗ ( 27.09.1911 – †23.01.1999) The present PhD thesis is a contribution to catalysis research. Die vorliegende Dissertationsarbeit ist ein Beitrag zur Katalyseforschung. “Chemistry without catalysis is like a sword without a hilt, a candle without light or a bell without sound.” „Chemie ohne Katalyse ist wie ein Schwert ohne Griff, eine Kerze ohne Licht oder eine Glocke ohne Klang.“ Alwin Mittasch (∗27.12.1869; †04.06.1953) German chemist, founder of BASF’s Catalysis Research Deutscher Chemiker, Begründer der BASF-Katalyseforschung PhD Thesis, Mike Kotke List of Publications List of Publications This PhD thesis represents a chronological and conceptual composition of the following publications that evidence own successful research activities and projects, respectively, predominantly towards hydrogen- bonding (thio)urea organocatalysts. The journal articles and the book chapter are published by the leading publishers in chemistry: ACS (American Chemical Society), Elsevier, Georg Thieme Verlag, and Wiley- VCH. Herein, the original articles are presented with reprint permission of the respective publisher and are available from there. The Journal Impact Factor JIF of each journal is given in parentheses. Journal Articles and Book Chapter 1. Mike Kotke, R. R. Schreiner, “(Thio)urea Organocatalysts”. Book chapter in "Hydrogen Bonding in Organic Synthesis”, 204 pages, Wiley-VCH Weinheim/Germany, Editor: P. M. Pihko, 2009. ISBN 978-3-527-31895-7, published. 1st edition available Oct. 2009. 2. E. Lamy, C. Crößmann, A. Saeed, P. R. Schreiner, Mike Kotke, V. Mersch-Sundermann, “Three Structurally Homologous Isothiocyanates Exert ‘‘Janus’’ Characteristics in Human HepG2 Cells”. Environ. Mol. Mutagen. 2009, 50, 164–170. (JIF 2.361, year 2007) 3. T. Weil, Mike Kotke, C. M. Kleiner, P. R. Schreiner, “Cooperative Brønsted Acid-Type Organocatalysis: Alcoholysis of Styrene Oxides”. Org. Lett. 2008, 10, 1513–1516. Highlights in Current Synthetic Organic Chemistry: “Cooperative Brønsted Acid Catalysis”. Synfacts 2008, 6, 644. (Org. Lett.: JIF 5.128, year 2008) 4. Mike Kotke, P. R. Schreiner, “Generally Applicable Organocatalytic Tetrahydropyranylation of Hydroxy Functionalities with Very Low Catalyst Loading”. Feature article, Synthesis 2007, 5, 779–790. (JIF 2.257, year 2007) 5. Mike Kotke, P. R. Schreiner, “Acid-free, Organocatalytic Acetalization”. Tetrahedron 2006, 62, 434–439. (JIF 2.897, year 2009) 6. P. R. Schreiner, A. A. Fokin, Mike Kotke, T. Weil, “Non-covalent Organocatalysis”. Ann. Polish Chem. Soc. 2004, 3, 21–24. 7. C. M. Kleiner, Mike Kotke, T. Weil, P. R. Schreiner, “Organocatalytic 1,3-Dioxolane Formation from Styrene Oxides”. 2009, manuscript in preparation. Poster Presentations 1. Mike Kotke, P. R. Schreiner, “Non-covalent Organocatalysis: Novel Application of the Thiourea Motif”. ORCHEM, Vortragstagung der Liebig-Vereinigung für Organische Chemie, Bad Nauheim, Germany, 2006. 2. Mike Kotke, P. R. Schreiner, “Acid-free, Organocatalytic Acetalization”. GDCh Jahrestagung, Düsseldorf, Germany, 2005. 3. Mike Kotke, P. R. Schreiner, “Metal-Free, Non-covalent Enantioselective Organocatalysis by Hydrogen-Bonding Chiral Thiourea Derivatives”. BASF Transfer-Workshop, Ludwigshafen, Germany, 2003. 4. Mike Kotke, P. R. Schreiner, “Metal-Free Non-covalent Enantioselective Organocatalysis of Diels-Alder Reactions by Hydrogen-Bonding Chiral Thiourea Derivatives”. WISOR XII (Postgraduate Winter School on Organic Reactivity), Bressanone, Italy, 2003. PhD Thesis, Mike Kotke Table of Contents Table of Contents I. Preface and Motivation ………………………………………………………. I II. Summary …………………………………………………………………......... III III. Vorwort und Motivation (Preface and Motivation) ……….……………………… X IV. Zusammenfassung (Summary) …………………………………………………. XII Chapter 1: Hydrogen Bonding in Organic Synthesis – (Thio)urea Organocatalysts ... 1 published: Mike Kotke, R. R. Schreiner, "(Thio)urea Organocatalysts", 204 pages, book chapter in "Hydrogen Bonding in Organic Synthesis”, Wiley-VCH Weinheim/Germany, Editor: P. M. Pihko, 2009. ISBN 978-3-527-31895-7. Preface…………………………………………………………………………... 1 1.1 Introduction and Background ……………………………………..……………. 2 1.2 Synthetic Applications of Hydrogen-bonding (Thio)urea Organocatalysts ..…... 8 1.2.1 Non-stereoselective (Thio)urea Organocatalysts …..………………………... 8 1.2.1.1 Privileged Hydrogen-bonding N,N′-bis[3,5-(trifluoromethyl)phenyl]thiourea .... 8 1.2.1.2 Miscellaneous Non-stereoselective (Thio)urea Organocatalysts ...….......……... 26 1.2.2 Stereoselective (Thio)urea Organocatalysts ………...……………………….. 34 1.2.2.1 (Thio)ureas Derived from trans-1,2-Diaminocyclohexane ..…………………… 34 and Related Chiral Primary Diamines 1.2.2.2 (Thio)ureas Derived from Cinchona Alkaloids ...………………………………. 81 1.2.2.3 (Thio)ureas Derived from Chiral Amino Alcohols ..…………………………… 107 1.2.2.4 Binaphthyl-based (Thio)urea Derivatives ..…………………………………….. 113 1.2.2.5 Guanidine-based (Thio)urea Derivatives ..……………………………………... 121 1.2.2.6 Saccharide-based (Thio)urea Derivatives ..…………………………………….. 128 1.2.2.7 Miscellaneous Stereoselective (Thio)urea Derivatives .……………………….. 134 1.3 Summary and Outlook ...….……………………………………………………... 139 1.4 Acknowledgement …….…..……………………………………………………. 139 1.5 References and Notes ………………..…………………………………………. 140 Chapter 2: Journal Publications on Organocatalysis …………………………….… 146 Preface ………………………………………………………………………….. 146 2.1 Acid-free, Organocatalytic Acetalization …………………………………… 147 published: Mike Kotke, P. R. Schreiner, Tetrahedron 2006, 62, 434–439. 2.2 Generally Applicable Organocatalytic Tetrahydropyranylation …………... 153 of Hydroxy Functionalities with Very Low Catalyst Loading published: Mike Kotke, P. R. Schreiner, feature article, Synthesis
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