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Synthesis of Benzomorphan Scaffolds by Intramolecular Buchwald–Hartwig Arylation and Approach Towards the Total Synthesis of the Macrolide Queenslandon

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Synthesis of Benzomorphan Scaffolds by Intramolecular Buchwald–Hartwig Arylation and Approach Towards the Total Synthesis of the Macrolide Queenslandon Synthesis of Benzomorphan Scaffolds by Intramolecular Buchwald–Hartwig Arylation and Approach Towards the Total Synthesis of the Macrolide Queenslandon Synthese von Benzomorphan Scaffolds durch Intramolekulare Buchwald–Hartwig Arylierung und ein Zugang zur Totalsynthese des Macrolids Queenslandon DISSERTATION der Fakultät für Chemie und Pharmazie der Eberhard-Karls-Universität Tübingen zur Erlangung des Grades eines Doktors der Naturwissenschaften 2007 vorgelegt von ANTON S. KHARTULYARI Tag der mündlichen Prüfung: 14.06.2007 Dekan: Prof. Dr. L. Wesemann 1. Berichterstatter: Prof. Dr. M. E. Maier 2. Berichterstatter: Prof. Dr. Th. Ziegler 3. Berichterstatter: Prof. Dr. S. Laschat This doctoral thesis was carried out from August 2003 to October 2006 at the Institut für Organische Chemie, Fakultät für Chemie und Pharmazie, Eberhard-Karls-Universität Tübingen, Germany, under the guidance of Professor Dr. Martin E. Maier. Foremost, I am indebted to Prof. Dr. Martin E. Maier, my supervisor, for his support and excellent guidance during this research work. I thank him not only for providing me with the lab facilities but also for his confidence and unlimited trust in me and for the multitude of little advices he has given me during the course of this work. I would like to thank Prof. Dr. Thomas Ziegler for his helpful reviewing the doctoral thesis and for giving precious comments and suggestions. I personally thank Mr. Graeme Nicholson and Mr. Paul Schuler for their skilful technical assistance in numerous measurements, Mrs. Maria Munari for well organized supply of chemicals and her great help in the laboratory. I thank all my working group members for valuable discussions and their friendly nature. I would like to specially thank Viktor Vintonyak, Vaidotos Navickas, Markus Ugele, and Dr. Manmohan Kapur for their assistance in the synthesis of many important substances. I thank all my friends and specially Georgy Varseev, Evgeny Prusov, Pavel and Anna Levkin and Dr. Srinivasa Marimganti for their help during my stay in Tübingen. Special thanks to V. V. Menshikov for introducing me into the fantastic world of chemistry. Thank you for planting the virus of loving chemistry in me. Finally, I am thankful to the love of my parents, without whom I would not be what I am today. And of course I thank my bride, Stefanie Reit, who has standed me all times, for her infinite love and support that gave me the courage and perseverance to achieve this milestone in my life. my Mother Publications: A. S. Khartulyari, M. E. Maier, Synthesis of Benzomorphan Analogues by Intramolecular Buchwald-Hartwig Cyclization. Eur. J. Org. Chem. 2007, 317–324. A. S. Khartulyari, M. Kapur, M. E. Maier, A Concise Strategy to the Core Structure of the Macrolide Queenslandon. Org. Lett. 2006, 8, 5833–5836. M. Kapur, A. Khartulyari, M. E. Maier, Stereoselective Synthesis of Protected 1,2-Diols and 1,2,3-Triols by a Tandem Hydroboration-Coupling Sequence. Org. Lett. 2006, 8, 1629–1632. A. Y. Lebedev, A. S. Khartulyari, A. Z. Voskoboynikov, Synthesis of 1-Aryl-1H-indazoles via Palladium-Catalyzed Intramolecular Amination of Aryl Halides. J. Org. Chem. 2005, 70, 596– 602. A. L. Krasovsky, A. S. Hartulyari, V. G. Nenajdenko, E. S. Balenkova, Efficient Syntheses of new CF3-containing diazolopyrimidines. Synthesis, 2002, 1, 133–137. A. Z. Voskoboynikov, V. V. Izmer, A. F. Asachenko, I. P. Beletskaya, P. I. Dem'yanov, D. N. Kazyul'kin, A. Yu. Lebedev, M. V. Nikulin, V. S. Petrosyan, A. N. Ryabov, A. S. Khartulyari, K. Yu. Chernichenko, Chemistry of Metallocene Catalysts for Olefin Polymerization: Technological Aspects. Ross. Khim. Zhurnal 2001, 45, 118–125 (journal written in russian). Poster presentations: A. Khartulyari, M. E. Maier, Approach to the Macrolide Queenslandon. International Symposium on Chemistry, Biology and Medicine (C.B.M. 06), Cyprus, Paphos 2006. A. Khartulyari, M. Kapur, M. E. Maier, Total Synthesis of the Macrolide Queenslandon. 9th SFB-Symposium (SFB 380 "Asymmetric Syntheses with Chemisty and Biology Methods"), Germany, Aachen 2005. M. Kapur, A. Khartulyari, M. E. Maier, Synthesis of anti-Diols by a Hydroboration-Suzuki Sequence: A Stereoselective Approach to the Core Structure of the Macrolide Queenslandon. 9th SFB-Symposium (SFB 380 "Asymmetric Syntheses with Chemisty and Biology Methods"), Germany, Aachen 2005. A. Khartulyari, M. E. Maier, Synthesis of Benzomorphan Analogs: Palladium-Catalyzed Intramolecular Arylation of Piperidone Derivatives. International Symposium on Advances in Synthetic, Combinatorial, and Medicinal Chemistry (A.S.C.M.C. 04), Russia, Moscow 2004. V. Nenajdenko, A. Gavryushin, E. Zakurdaev, A. Karpov, N. Shevchenko, D. Gribkov, A. Hartulyari, M. Lebedev, N. Khajrutdinov, E. Balenkova, A library of tryptamines as building blocks for synthesis of pharmacologically active compounds. XIXth European colloquium on heterocyclic chemistry, Aveiro, Portugal 2000. Table of Contents Table of Contents Chapter I Synthesis of Benzomorphan Scaffolds by Intramolecular Buchwald- Hartwig Arylation 1 Introduction .........................................................................................................................1 2 Literature Review................................................................................................................6 2.1 Benzomorphans – a Structural Feature of Analgesic Drugs ........................................6 2.2 Clinically Used Benzomorphan Derivatives ..............................................................10 2.3 Overview of Known Methods for the Preparation of Various Benzomorphans ........15 2.3.1 The Tetralone Route .......................................................................................15 2.3.2 Grewe-type Cyclization..................................................................................31 2.3.3 Other Routes to the Benzomophan Ring Skeleton .........................................34 3 Goal of Research................................................................................................................41 4 Results and Discussion ......................................................................................................45 4.1 Synthesis of Benzomorphans by Intramolecular Buchwald-Hartwig Arylation of Substituted N-Benzyl-Piperidone Derivatives ...........................................................45 4.2 Synthesis of Benzomorphans by Intramolecular Buchwald-Hartwig Arylation of Substituted N-Methyl-Piperidone Derivatives ...........................................................53 4.3 Preparation of Benzomorphan Scaffold and Its Derivatization..................................56 5 Conclusion I .......................................................................................................................60 Chapter II Approach towards the Total Synthesis of the Macrolide Queenslandon 6 Introduction .......................................................................................................................63 7 Literature review ...............................................................................................................66 7.1 The Family of 14-Membered Resorcylic Acid Lactones ...........................................66 7.2 Chemical Syntheses of 14-Membered RALs .............................................................73 8 Results and Discussion ......................................................................................................99 8.1 Retrosynthetic Analysis..............................................................................................99 8.2 Syntheses of the Key Precursors ..............................................................................103 8.2.1 Substitued β-iodostyrenes.............................................................................103 8.2.2 Protected (R)-δ-hydroxyhexanal (8-6)..........................................................105 8.2.3 Chiral glycolate auxiliary (8-7)....................................................................108 Table of Contents 8.3 Model Studies on the Tandem Hydroboration/Suzuki Coupling Sequence.............111 8.3.1 Preparation of the Required Substrates ........................................................116 8.3.2 Studies on the Tandem Hydroboration/Suzuki Coupling Sequence ............ 120 8.4 Synthesis of the Core Structure of the Macrolide Queenslandon ............................128 9 Conclusion II....................................................................................................................134 10 Experimental Section ......................................................................................................136 10.1 General Remarcs ......................................................................................................136 10.1.1 Chemicals and working techniques..............................................................136 10.1.2 NMR-spectroscopy.......................................................................................136 10.1.3 Mass Spectrometry.......................................................................................137 10.1.4 Infrared Spectroscopy...................................................................................137 10.1.5 Polarimetry ...................................................................................................137 10.1.6 Melting Points ..............................................................................................138 10.1.7 Chromatographic Methods...........................................................................138
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