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Development of a Hetero-Diels-Alder Reaction to Synthesize 3-Hydroxypyridines and Its Application Toward the Total Synthesis of Nosiheptide

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Development of a Hetero-Diels-Alder Reaction to Synthesize 3-Hydroxypyridines and Its Application Toward the Total Synthesis of Nosiheptide Development of a Hetero-Diels-Alder reaction to synthesize 3-hydroxypyridines and its application toward the total synthesis of nosiheptide Zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) von der Fakultät für Chemie der Technischen Universität Dortmund angenommene DISSERTATION von M. Sc. Jin-Yong Lu aus Shandong, China Dekan: Prof. Dr. Heinz Rehage 1.Gutachter: Prof. Dr. Herbert Waldmann 2.Gutachter: Prof. Dr. Mathias Christmann Tag der mündlichen Prüfung: 1. Juli. 2009 Erklärung/Declaration Hiermit versichere ich an Eides statt, dass ich die vorliegende Arbeit selbständig und nur mit den angegebenen Hilfsmitteln angefertigt habe. I hereby declare that I performed the work presented independently and did not use any other but the indicated aids. Dortmund, June 2009 Jin-Yong Lu Die vorliegende Arbeit wurde unter Anleitung von Dr. Hans-Dieter Arndt am Fachbereich Chemie der Technischen Universität Dortmund und am Max-Planck-Institut für molekulare Physiologie, Dortmund in der Zeit von Mai 2004 bis Mai 2009 angefertigt. Dedicated to my family Where there is a will, there is a way. Acknowledgements This is by far the most important part of my thesis, a new beginning for my future. My greatest successes in the past several years have been the professional and personal relationships that encouraged me to this stage. I write the acknowledgements to show my appreciation to the people who helped me with tremendous gratitude. First and foremost, I would like to thank my Ph.D. advisor Dr. Hans-Dieter Arndt to offer me the opportunity to work on these challenging projects, also for his enthusiasm support and general concern for my development to become an organic chemist. I had a lot of fun as the first Ph.D student of Hans-Dieter. I am sad to be leaving, but I will enjoy watching the group development and looking forward to the future. I am deeply thankful to Prof. Dr. Herbert Waldmann for his continuous support in the past years and reviewing my thesis. I would like to thank Prof. Dr. Mathias Christmann for his kind effort for reviewing my thesis. I would like to thank Dr. Wei-Zheng Shen, Dr. Markus Schürmann for performing X-ray crystal structure analysis and Dr. Hans Preut for data refinement. I also would like to thank Dr. Petra Janning for helping to solve instrument problems, Evylene Merten for LC-MS analysis, Andreas Brockmeyer, Nina Meszaros, Sandra Hippler and Christiane Heitbrink for HR-MS analysis, Markus Hüffner for elemental analysis, and Bernhard Griewel for help with NMR. I would like to thank the whole AK Arndt group. My labmates Barhar Kilitoglu, Patrick Loos, Matthias Riedrich, Sebastian Schoof and Surendra Harkal, we worked together and had fun. My nosiheptide partner, Matthias Riedrich, we made great effort to the nosiheptide, we had very good collaboration. I would like to thank my cooperation partner, John A. Keith (Universität Ulm) for the calculations doing the investigations of the HDA reaction mechanism. I would like to thank Sebastian Schoof for spending his valuable time on correcting my thesis. I would like to thank Patrick Loos for translating the summary of my thesis to German. I would like to thank the International Max-Planck Research School in Chemical Biology (IMPRS-CB) for setting the opportunity of becoming a member. My sincere gratitude gave to Dr. Jutta Rötter, Brigitte Rose and Waltraud Hofmann-Goody for their kind support and help in official matters. I would like to thank all the department members for creating an excellent scientific working atmosphere. My office members Sebastian Schoof, Sebastian Koch, Kathrin Wittstein and Marion Müller, I would like to thank for the enjoyable office atmosphere. Last but not the least I would take the chance to acknowledge my parents for their unconditional love and moral support. The God gifts, my wife and my son, I thank for always supporting and encouraging me. Content 1. Introduction ..................................................................................................................... 1 1.1 Thiopeptides..................................................................................................................... 2 1.2 Thiopeptide Biosynthesis ................................................................................................. 4 1.3 Selected synthetic work on thiopeptide natural products................................................. 6 1.3.1 Total synthesis of thiostrepton by Nicolaou.............................................................. 6 1.3.2 Total synthesis of Siomycin A by Nakata............................................................... 11 1.3.3 Nosiheptide.............................................................................................................. 12 1.4 Aims of the thesis........................................................................................................... 19 2. Hetero-Diels-Alder (HAD) reactions for 3-hydroxypyridine formation........................23 2.1 Introduction .................................................................................................................... 24 2.2 Azadiene synthesis ......................................................................................................... 28 2.2.1 2-Azadiene synthesis............................................................................................... 28 2.2.2 1-Azadiene synthesis............................................................................................... 30 2.3 HDA reaction with alkynes............................................................................................ 33 2.3.1 Result and discussion .............................................................................................. 34 2.3.2. Pyrrole formation. .................................................................................................. 42 2.3.3 A plausible mechanism of the side product formation............................................ 42 2.4 HDA reaction with dicyano alkenes............................................................................... 44 2.4.1 Introduction. ............................................................................................................ 44 2.4.2 Result and discussion. ............................................................................................. 46 2.4.3 Additional investigations on HDA reactions. ......................................................... 57 2.5 HDA reaction with cycloalkynes ................................................................................... 57 2.6 Mechanistic considerations. ........................................................................................... 60 2.6.1 Mechanism study by DFT calculations................................................................... 60 2.6.2 Mechanism study by experimental proof................................................................ 64 2.7 Conclusion...................................................................................................................... 64 3. Toward a total synthesis of nosiheptide.......................................................................67 3.1 Introduction .................................................................................................................... 68 3.2 Retrosynthetic analysis and challenges.......................................................................... 68 3.3 Result and discussion. .................................................................................................... 70 3.3.1 HDA reaction with thiazolyl alkyne........................................................................ 70 3.3.2 Thiazole annulation................................................................................................. 74 3.3.3 Enantiomeric excess (ee) determination. ................................................................ 78 3.3.4 Regioselective hydrolysis........................................................................................ 80 3.3.5 Sc(OTf) 3 catalyzed reactions................................................................................... 87 3.3.6 Tristhiazolyl pyridine formation. ............................................................................ 89 3.3.7 Fragment union (generation 1)................................................................................ 91 3.3.8 Fragment union (generation 2)................................................................................ 93 3.3.9 Fragment union (generation 3)................................................................................ 96 3.3.10 Macrocycle formation (generation 1).................................................................. 103 3.3.11 Macrocycle formation (generation 2).................................................................. 105 3.3.12 Fragment union (generation 4)............................................................................ 109 3.3.13 Acid catalyzed protecting group exchange ......................................................... 110 3.3.14 Macrocycle formation (generation 3).................................................................. 111 3.3.15 Macrocycle formation (generation 4).................................................................. 112 3.3.16 Bis macrocycle formation (generation 1)............................................................ 114 3.3.17 Bis macrocycle formation (generation 2)...........................................................
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