Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Stereoselective Preparation and Stereochemical Behaviour of Organozinc and Organolithium Reagents Stephanie Seel aus Köln 2012 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Paul Knochel betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, am 05. November 2012 …..…………………………………… Stephanie Seel Dissertation eingereicht am: 06. November 2012 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Konstantin Karaghiosoff Mündliche Prüfung am: 01. Februar 2013 This work was carried out from November 2009 to November 2012 under the guidance of Prof. Dr. Paul Knochel at the Department Chemie und Pharmazie of the Ludwig- Maximilians-Universität, Munich. First, I would like to thank Prof. Dr. Paul Knochel for giving me the opportunity to do my Ph.D. in his group, for his generous support and guidance in the course of my scientific research. I am also very grateful to Prof. Dr. Konstantin Karaghiosoff for agreeing to be the second reviewer of this thesis as well as Prof. Dr. Hendrik Zipse, Prof. Dr. Heinz Langhals, Prof. Dr. Klaus Theodor Wanner and Prof. Dr. Manfred Heuschmann for their interest shown in this manuscript by accepting to be referees. I really would like to thank Tobias Thaler and Andreas Steib for the careful correction of this manuscript. I thank all past and present co-workers I have met in the Knochel group for their kindness and their help. Special thanks to my actual and former lab mates Dr. Tobias Thaler, Johannes Heppekausen, Andreas Steib, Dr. Hongjun Gao, Dr. Li-Na Guo, Dr. Coura Diene, Dr. Guillaume Dagousset and Dr. Elodie Sansiaume-Dagousset. I would like to thank Tobias Thaler for his support, the fun we had in the lab and for the fruitful collaborations. Additional thanks go to Rasmus Mose, Zhi-Liang Shen, Ning Yuan, Olesya Kuzmina, Dr. Ilaria Tirotta, Dr. John and Jen Markievicz, Lydia Klier, Klaus Groll, Kohei Moriya, Quan Chen, Dr. Christos Stathakis, Veronika Werner and Sophia Manolikakes for being fantastic colleagues. I explicitly thank Tobias Thaler, Guillaume Dagousset, Keishi Takatsu and Kohei Moriya who have contributed to the final success of this thesis. I also thank Cong Zhang and Prof. Dr. Hendrik Zipse for the performance of DFT calculations. Moreover, I am grateful to Prof. Dr. Konstantin Karaghiosoff for the performance and design of NMR studies and his outstanding support. I would also like to thank Renate Schröder, Simon Matthe, Dr. Vladimir Malakhov and Yulia Tsvik for their help in organizing everyday life in the lab and in the office, as well as the analytical team of the LMU for their invaluable help. Very special thanks to my parents and my brothers for their great support throughout my studies, my Ph.D and all the other years. Part of this Ph. D. thesis have been published: Seel, S. , Thaler, T., Takatsu, K., Zhang, C., Zipse, H., Straub, B. F., Mayer, P. & Knochel, P. Highly diastereoselective arylations of substituted piperidines. J. Am. Chem. Soc. 133 , 4774- 4777 (2011). Seel, S. , Dagousset, G., Thaler, T., Frischmuth, A., Karaghiosoff, K., Zipse, H. & Knochel, P. Preparation of stereodefined secondary alkyllithiums. Chem. Eur. J., accepted. TO MY PARENTS Table of Contents Abbreviations ........................................................................................................................... 1 A. Introduction ......................................................................................................................... 2 1. Overview ................................................................................................................................................. 2 2. Stereoselective Preparation of Organometallic Reagents ................................................................... 2 2.1. Preparation of Stereodefined Carbon-Lithium Bonds ..................................................................... 2 2.2. Preparation of Stereodefined Carbon-Magnesium Bonds ............................................................. 10 2.3. Preparation of Stereodefined Carbon-Zinc Bonds ........................................................................ 13 3. Objectives .............................................................................................................................................. 20 B. Results and Discussion ...................................................................................................... 22 1. Stereoselective Preparation, Configurational Stability and Reactivity of Substituted Cyclohexyllithium Derivatives ...................................................................................................................... 23 1.1. Introduction................................................................................................................................... 23 1.2. Results and Discussion ................................................................................................................. 23 2. Novel Insights into the Stereochemical Behaviour of Diastereomeric Cyclohexylzinc Reagents – Stereoconvergence through Distinct Stereochemical Pathways................................................................. 36 2.1. Introduction................................................................................................................................... 36 2.2. Results and Discussion ................................................................................................................. 39 3. Diastereo- and Enantioselective Cross-Coupling with Functionalized Cyclohexylzinc Reagents . 47 3.1. Synthesis of Chiral Protected Cyclohexyl Derivatives for the Enantio- and Diastereoselective Synthesis of 1-, 2-, 3-trisubstituted Cyclohexanes ....................................................................... 47 3.2. Investigations with [2-(1,3-Dioxolane-2-yl)cyclohexyl]- and [2-(5,5-Dimethyl-1,3-dioxane-2- yl)cyclohexyl]zinc Compounds .................................................................................................... 49 3.3. Development of an Enantioselective Version of the Diastereoselective Cross-Coupling ............. 54 3.4. Cross-Coupling with [8-(Ethoxymethoxy)decahydronaphthalen-1-yl](ethyl)zinc ....................... 56 4. Highly Diastereoselective Arylations of Substituted Piperidines ..................................................... 59 4.1. Introduction................................................................................................................................... 59 4.2. Results and Discussion ................................................................................................................. 60 5. Summary and Outlook ......................................................................................................................... 69 5.1. Stereoselective Preparation, Configurational Stability and Reactivity of Substituted Cyclohexyllithium Derivatives ..................................................................................................... 69 5.2. Novel Insights into the Stereochemical Behaviour of Diastereomeric Cyclohexylzinc Reagents – Stereoconvergence through Distinct Stereochemical Pathways ................................................... 70 5.3. Diastereo- and Enantioselective Cross-Coupling with Functionalized Cyclohexylzinc Reagents 71 5.4. Highly Diastereoselective Arylations of Substituted Piperidines ................................................. 72 C. Experimental Section ........................................................................................................ 74 1. General Considerations ....................................................................................................................... 75 1.1. Solvents ........................................................................................................................................ 75 1.2. Reagents ........................................................................................................................................ 75 1.3. Chromatography ........................................................................................................................... 77 1.4. Analytical Data ............................................................................................................................. 77 2. Stereoselective Preparation, Configurational Stability and Reactivity of Substituted Cyclohexyllithium Derivatives ...................................................................................................................... 79 2.1. Preparation of Starting Materials .................................................................................................. 79 2.1.1. Typical Procedure 1: Iodination of alcohols (TP1) ....................................................................... 79 2.2. I-Li Exchange and Subsequent Quenching with Electrophiles ..................................................... 84 2.2.1. Typical Procedure 2: I-Li exchange and subsequent quenching with electrophiles (TP2) ........... 84 3. Novel Insights into the Stereochemical Behaviour of Diastereomeric Cyclohexylzinc Reagents – Stereoconvergence through Distinct Stereochemical Pathways................................................................. 95 3.1. Deuterolysis