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Progress Toward the Total Synthesis of Paclitaxel (Taxol®)

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Progress Toward the Total Synthesis of Paclitaxel (Taxol®) PROGRESS TOWARD THE TOTAL SYNTHESIS OF PACLITAXEL (TAXOL®) DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Matthew M. Kreilein, M.S. * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor Professor David J. Hart Professor T.V. RajanBabu _____________________________ Advisor Professor Pui-Kai Li Chemistry Graduate Program ABSTRACT Described herein is the continuation of efforts focused towards the synthesis of Taxol utilizing a route that is amenable to novel analog formation from advanced Taxol precursors. Elaboration of (1S)-(+)-10-camphorsulfonic acid to a highly functionalized taxane skeleton has been achieved in a total of twenty-two synthetic operations. Highlighting the brevity and efficiency of this series is the fact that only five operations thus far are protecting group manipulations, which tend to significantly increase the length and complexity of a synthetic route. Entry to a completed D-ring has been made by prevous researchers in a six-step sequence. After the revelation that formation of the densly functionalized A-ring in the presence of a completed D-ring was not possible, the focus became one of elaboration of the A-ring using the very useful diosphenol intermediate 3.1. Two areas of research have been explored and are described. First, the route to the bridge-migrated taxane 1.85 was reviewed and problems existing in the key alkenyl iodide coupling, dihydroxylation, C2 oxygenation, and bridge migration were investigated and resolved. ii With an efficient synthesis of 1.85 in hand, attention was focused on completion of the A-ring beginning with routes originating from 1.85. It was quickly realized that use of the diosphenol intermediate 3.1 would be advantageous, the optimization of its synthesis was explored and realized. A-Ring completion from 3.1 was attempted to no avail via early functionalization of the northern sector utilizing various methods. Attention was then focused on the southern sector in an attempt to bring about C14 deoxygenation at an early stage. Again, progress was halted and a new route had to be envisioned. Protection of C1 was employed to stave off undesired retro-aldol fragmentation of the A-ring; however, deoxygenation was again thwarted. The final approach explored has given rise to an oxygenation strategy that has allowed for the synthesis of the C12 ketone 3.49. With this ketone, arrival at the A-ring might be realized through four more transformations. At that point, the route would be at a point utilized in previous Taxol syntheses and arrival at 1.1 would be imminent providing a new method of entry into natural and unnatural taxanes. iii To Mom, Mike, Michael, and Dad iv ACKNOWLEDGMENTS I would first like to thank my advisor, Professor Leo Paquette. It has been a pleasure working with you on this project, sharing ideas, inspiration, and excitement. It has been a pleasure and an honor to be a member of this great research group that you have molded. Thank you for the opportunity. I would also like to thank Professors David Hart and T.V. RajanBabu for serving as dissertation committee members, instructors, and true colleagues throughout my time here at OSU. Thank you for all your time and hard work. Very special thanks to the members of Team Taxol that I have worked with in the past: Drs. Ruslan Arbit, Nancy Brennan, Xin Guo, John Hofferberth, and Ho Yin Lo. Your help on this project was invaluable. Thank you to Rebecca Martin and Donna Rothe. Without your efforts, this whole group would collapse. I must thank the entire Paquette research group for all your help and for being the best colleagues that I think I’ll ever have. Another special thank you to Ryan & Elizabeth Hartung and Dave & Tammy Hilmey for being great friends of mine here at OSU and for allowing me to have some surrogate pets, Ginger and Mr. Bojangles, the last few years I was here. In addition, Ryan and Dave v proofread this entire document. I know what a chore it was for you guys to read the entire Taxol saga over again. Thank you. I would like to thank my true lab mates: Dr. Dean Clyne, Dr. Jiyoung Chang, Xiaowen Peng, Brandon Shetuni, Dr. Feng Geng, Peter Selvaraj, Zhenjiao Tian (a.k.a. ZT and Mom-dude), Dr Adam Preston, and Dr. Marshall Stepanian for putting up with my moodiness, occasional anger, routine cursing, my music, and off-color humor over the years. You all have earned and extra medal for surviving in an enclosed space with me. I have the best family in the world. The extended family is to big to go into great detail about, but they all deserve a big thank you for all their support. Grandpa, you were a great man, who instilled the importance of education in your children and grandchildren, I thank you for that, and hope to embody you when the day comes with my family. Alex and Maxwell, stay in school. It is hard work, but you will never feel better about working hard than the day you get to write something like this. Finally, I have saved the best for last. There are four people who never faltered in their support of me at any point in my life, and I’m sure never will. This entire body of work is as much theirs as it is mine. Mom, Mike, Michael, and Dad, I cannot possibly begin to put into words what I owe you. All I can do is say that I appreciate the education you have given me, the many sacrifices you have made for me, and the support and love you have given me throughout my life. From the bottom of my heart, thank you. vi VITA May 21, 1977..................................................................... Born – Cincinnati, Ohio May 1999....................................................B.A. Chemistry, Saint Louis University November 2001...................................M.S. Chemistry, The Ohio State University September 1999 – September 2000............................................ University Fellow The Ohio State University October 2000 – October 2002 ..........................Dept. of Education GAANN Fellow The Ohio State University November 2002 – March 2004 ..............Graduate Teaching and Research Fellow The Ohio State University March 2004 – present......................................................Lubrizol Industrial Fellow The Ohio State University PUBLICATIONS Research Publications 1. “1,4-Dioxene” Electronic Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A. Ed.-in-Chief. John Wiley and Sons. FIELDS OF STUDY Major Field: Chemistry vii TABLE OF CONTENTS Abstract ................................................................................................................ ii Dedication ........................................................................................................... iv Acknowledgments ................................................................................................ v Vita ......................................................................................................................vii List of Tables .......................................................................................................xii List of Figures.....................................................................................................xiii List of Schemes.................................................................................................xvii List of Abbreviations ...........................................................................................xxi Chapters: 1. Background................................................................................................ 1 1.1 Introduction ..................................................................................... 1 1.2 History of the Yew Tree................................................................... 2 1.3 Isolation and Structural Determination of Taxol .............................. 3 1.4 Overview of the Biological Activity of Taxol..................................... 8 1.5 Review of Prior Total Syntheses of Taxol ..................................... 15 1.5.1 Syntheses Based on the Coupling of A-Ring and C/D-Ring Precursors ....................................... 17 1.5.2 Syntheses of Taxol Based on Initial B-Ring Formation...................................................... 21 viii 1.6 Taxane Synthesis in the Paquette Group: Motivation and Precedent ............................................................. 24 1.6.1 Examination of the Oxy-Cope Rearrangement: Proof of Concept ................................................................ 29 1.6.2 Synthesis and Utility of Early-oxygenated Substrates ........ 31 1.7 Development of a New Approach to Taxol.................................... 35 2. Synthesis and Functionalization of the B, C, and D-Rings....................... 38 2.1 Synthesis of Coupling Partners and Formation of the Pretaxane Core.................................................. 38 2.1.1 Synthesis of Coupling Partners 1.90 and 1.91 ................... 38 2.1.2 Alkenyl Iodide Coupling – Problems and Solution .............. 41 2.2 Further Functionalization of the B-Ring En Route to Bridge Migration ........................................................ 45 2.2.1 C-Ring Closure and Hydride Shift Reaction ....................... 45 2.3 Formation of a Bridge Migrated Taxane........................................ 50 2.3.1 Original Conditions for Bridge Migration Precursor Formation........................................................... 50 2.3.2 Second
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