Research Collection Doctoral Thesis Towards a Structural Revision of Mytilipin B Author(s): Jacobsen, Mathias Juul Publication Date: 2016 Permanent Link: https://doi.org/10.3929/ethz-a-010659305 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 23251 Towards a Structural Revision of Mytilipin B A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by MATHIAS JUUL JACOBSEN MSc, Aarhus University born on 20.05.1987 citizen of Denmark accepted on the recommendation of Prof. Dr. Erick M. Carreira, examiner Prof. Dr. Karl-Heinz Altmann, co-examiner 2016 i Acknowledgments First, I would like to thank my supervisor Prof. Erick M. Carreira for accepting me in his research group. I am grateful to have had the opportunity to work at ETH. I have definitely learned a lot during my time in his group. Prof. Karl-Heinz Altmann is greatly acknowledged for accepting to be my co-examiner without hesitation. His comments and corrections are highly valued. Credit is given to Dr. Matthew Webster, Philipp Sondermann, and Stefan Fischer for their support on this project. It has been a great help. This manuscript has evolved thanks to a team of proofreaders, consisting of Alberto Kravina, James Hamilton, Christian Ebner, Stefan Fischer, Hannes Zipfel, Matthias Westphal, and Simone Jacobsen. Their comments and corrections have led to substantial improvements. Working in the Carreira Group has been an exciting experience. I would like to thank past and present members of my lab, Dr. Nicolas Armanino, Dr. Stefan Diethelm, Dr. Lorenz Schneider, Matthias Westphal, Dr. Patrick Brady, Emma Robertson, and Philipp Sondermann. There was never a dull moment in H336 with Problem of the Day, Coopen Sie sessions, Fancy-Pants/Gangsta Fridays, and much, much more. It has been a great learning environment with countless interesting discussions. I would also like to thank the group as a whole for creating an inspiring atmosphere with friendly, helpful, and very knowledgeable individuals. Frau Anke Kleint is acknowledged for her professional and expedient handling of administrative matters. Outside of the lab, I have had the pleasure to spend time with awesome people. I would like to thank the skiing crew for some great recreational hours on the slopes (and the following Après-Ski). Thanks to Hannes Zipfel, Matthias Westphal, and Simon Krautwald for hotdogs and stupid-movie nights. Thanks to Dr. Simon Breitler for teaching me the art of the finest Swiss cuisine, Chäsfondue, and to Dr. Nikolas Huwyler for introducing me to the Swiss type of hiking, aka. Horse-Steak-Hike. I acknowledge Dr. Erik Funder for his help in spreading the Danish culture among the Carreira Group members. I greatly appreciate the time spent with Megan, Patrick, and Nolan Brady as well as the seemingly infinite cookie supply. ii Special thanks go to Hannes Zipfel and Matthias Westphal for being amazing friends and for providing endless support when needed, especially through the toughest times. Simone, I cannot express how lucky and thankful I feel to have you by my side. Thank you for your unconditional love, support, and patience as well as always believing in me. I cherish every moment with you and I am looking forward to our exciting future together, I love you! Thank you Albert for your laughs and hugs – and for keeping me awake at night during the writing process. Without you I would never have gotten this far. Til sidst vil jeg gerne takke min bror, Andreas, og mine forældre. Tak for, at I altid er der for mig og altid støtter mig. iii Publications and Presentations Publications: M. Pabst, I. Benešová, S. R. Fagerer, M. Jacobsen, K. Eyer, G. Schmidt, R. Steinhoff, J. Krismer, F. Wahl, J. Preisler, R. Zenobi, J. Proteome Res. [Online early access]. DOI: 10.1021/acs.jproteome.5b00899 “Differential Isotope Labeling of Glycopeptides for Accurate Determination of Differences in Site- Specific Glycosylation” M. J. Jacobsen, E. D. Funder, J. R. Cramer, K. V. Gothelf, Org. Lett. 2011, 13, 3418. “β-Olefination of 2-Alkynoates Leading to Trisubstituted 1,3-Dienes” Presentation: Oral Presentation at Janssen, Pharmaceutical Companies of Johnson&Johnson April 2015, Schaffhausen, Switzerland iv Table of Contents Acknowledgments ......................................................................................................................... i Publications and Presentations .................................................................................................. iii Table of Contents ........................................................................................................................ iv Abstract ....................................................................................................................................... vii Zusammenfassung ....................................................................................................................... ix Abbreviations, Acronyms, and Symbols ................................................................................... xi 1 Introduction ............................................................................................................................... 1 1.1 Halogenated Natural Products .............................................................................................. 1 1.1.1 Origins and Significance ............................................................................................... 1 1.1.2 Enzymatic Halogenations .............................................................................................. 4 1.1.3 Conclusions ................................................................................................................. 12 1.2 Chlorination Methods in Stereoselective Synthesis ........................................................... 13 1.2.1 Nucleophilic Substitutions .......................................................................................... 13 1.2.2 Dichlorination of Olefins ............................................................................................ 16 1.2.3 α-Chlorination of Carbonyl Compounds ..................................................................... 21 1.2.4 Indirect Stereoselective Chlorination Methods ........................................................... 24 1.2.5 Conclusions ................................................................................................................. 27 1.3 Chlorosulfolipids ................................................................................................................ 28 1.3.1 Discovery, Isolation, and Structural Elucidations ....................................................... 28 1.3.2 J-Based Configurational Analysis ............................................................................... 31 1.3.3 Biosynthetic Investigations ......................................................................................... 34 1.3.4 Tactics in Syntheses of Chlorosulfolipids ................................................................... 36 1.4 Summary ............................................................................................................................ 45 v 2 Revision of Mytilipin B ........................................................................................................... 46 2.1 Re-investigation of Isolation Data ...................................................................................... 47 2.1.1 Preliminary Considerations: The Planar Structure ...................................................... 47 2.1.2 Stereochemical Revisions ............................................................................................ 49 2.2 Structural Reflections ......................................................................................................... 59 3 Synthetic Strategy .................................................................................................................... 62 4 Towards Revised Mytilipin B ................................................................................................. 65 4.1 Synthesis of C1–C10 Sulfone Fragment .............................................................................. 65 4.2 Synthesis of C11–C24 Primary Alcohol Fragment ............................................................... 73 4.2.1 C19–C24 Phosphonium Iodide ...................................................................................... 73 4.2.2 The C11–C18 Primary Alcohol Fragment ..................................................................... 76 4.2.3 Coupling and Final Steps............................................................................................. 85 4.2.4 Structural Assignment ................................................................................................. 87 4.3 Completion of C1–C24 and Further Investigations.............................................................. 90 4.4 Future Studies ..................................................................................................................... 99 5 Conclusions and Outlook ...................................................................................................... 101 Experimental Section ..............................................................................................................