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Total Synthesis of Salvinorin a Via an IMDA-Tsuji Allylation Strategy

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Total Synthesis of Salvinorin a Via an IMDA-Tsuji Allylation Strategy Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Nathan Jeffrey Line Graduate Program in Chemistry The Ohio State University 2016 Dissertation Committee: Professor Craig J. Forsyth, Advisor Professor Anita Mattson Professor David Nagib Copyright by Nathan Jeffrey Line 2016 ABSTRACT Salvia divinorum, a Mexican sage, was used for hundreds of years by the Mazatec Indians for both medicinal and religious purposes. These hallucinogenic properties have caused a recent interest in the recreational drug world and therefore, resulted in a multitude of laws/restrictions banning Salvia from the United States as well as many other countries around the world. In 1982, Ortega reported the first isolation of the neoclerodane diterpenoid, salvinorin A, from Salvia divinorum. Valdes later confirmed this finding independently two years later. It was determined that salvinorin A was the compound responsible for the hallucinogenic effects experienced through ingestion or inhalation of Salvia. Interestingly, salvinorin A was and has remained the only non- alkaloid hallucinogen as well as the first highly potent and selective κ-opioid receptor agonist. These properties have not only piqued the interest of synthetic chemists but also medicinal chemists towards its potential role as a therapeutic agent. Herein is a summary of my total synthesis of salvinorin A with the goals to innovate a flexible and reliable total synthesis of salvinorin A and analogs to pursue SAR studies. I have developed an efficient synthesis of the decalin core that overcame obstacles and scale-up issues in the routes established by previous members. Utilizing the linear dithiane Diels-Alder precursor, I was able to implement an intramolecular Diels-Alders (IMDA)/Tsuji allylation combination to stereoselectively install the decalin core with both quaternary centers. Bistriflate formation followed by a palladium- ii mediated methoxy carbonylation provided the functional group handles needed to construct the skeletal framework. The furan moiety was installed selectively using a BINOL-titanium catalyst with a furyltitanim nucleophile. Conjugate reduction of both the methyl ester and furyl-lactone functional groups using SmI2 followed by diol manipulation provided targeted natural product salvinorin A. iii This work is dedicated to my family for their everlasting support and love through all my endeavors. iv ACKNOWLEDGEMENTS First and foremost, I have to thank God for bestowing upon me the intellectual capabilities and determination necessary to pursue a career as challenging and rewarding as that of organic synthesis. It is only through Him that I am able to do anything and am unspeakable grateful for the opportunities of my past and of those yet to come. Secondly, I would like to thank my advisor, Professor Craig J. Forsyth, for the opportunity to work in this group. The knowledge that I have acquired during by time in this lab has provided me with the tools and techniques necessary in order to succeed in both chemistry and life. I will always be grateful for your advice, support, and confidence throughout my graduate career. My greatest experience and memories would be incomplete without the countless individuals that I have had the pleasure to meet. There is obviously not enough space to thank all of you for what you have done for me. I would like to start by thanking Dr. Matt Jackel for providing me with not only the first but also the most impactful graduate experiences I could have asked for. Your teachings of laboratory techniques along with your chemical wisdom have shaped me into the chemist that I am today. Not only that, you were and continue to be one of my greatest friends and I will always remember our times spent both inside and outside lab. v My time spent in 4028 Evans Lab/190 CBEC has provided me many fond memories and relationships. To Mr. Kedwin Rosa, words cannot express the value in our friendship. You have not only been a great source of intellectual discussion but our times together outside lab have been some of the best of my life. To Daniel Adu-Ampratwum, I thank you for all your chemical and technical advice. Your dedication and work ethic was impressive and impactful. To the rest of the Forsyth group members, Antony Okumu, Daniel Akwaboak, Nate Kenton, Li Xiao, and Charles Clay, you have all provided me with a great work environment and lasting friendships. I would not be were I am today without the love and support of my parents, Jeff and Mardee, and my brother, Ian. Growing up, you taught me a vast array of important life values including hard work, determination, sacrifice, and love, which have molded me into the man I am. I love you very much and hope I have made you proud. I would also like to thank Dick and Cyndy Fields for their continual support and encouragement. From the beginning, you cared for me like one of your own and for that I am ever grateful. I appreciate all you have done for Bethany and I and look forward to the future. Finally and most importantly, to my wife and the love of my life, Bethany, words cannot describe my gratitude. You sacrificed everything to be here with me. You have stood be my side this entire journey, through my highest high and lowest low. You are my biggest supporter, my best friend, and the rock with which I stand on. I hope that you are proud to call me your husband and I look forward to the rest of our lives together. I love you: FOREVER AND FOR ALWAYS! vi VITA August 1988 ...................................................Born, Crawfordsville, Indiana May 2007 .......................................................Southmont High School May 2011 .......................................................B.A. Chemistry, Wabash College June 2011-present .........................................Graduate Teaching and Research Associate Department of Chemistry and Biochemistry The Ohio State University PUBLICATIONS Line, N. J.; Burns, A. C.; Butler, S.; Casbohm, J.; Forsyth, C. J. Total Synthesis of Salvinorin A. J. Am. Chem. Soc. 2016, Submitted. FIELDS OF STUDY Major Field: Chemistry vii TABLE OF CONTENTS Page Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments ............................................................................................................... v Vita .................................................................................................................................... vii List of Figures .................................................................................................................. xiii List of Schemes ................................................................................................................ xiv List of Tables .................................................................................................................. xvii List of Abbreviations ..................................................................................................... xviii Chapters: 1. Isolation and Biological Significance of Salvinorin A ................................................... 1 1.1 Historical Background of Salvia divinorum ..................................................... 1 1.2 Isolation and Structure Elucidation of Salvinorin A ......................................... 2 1.3 Salvinorin Family.............................................................................................. 7 1.4 A Potent κ-Opioid Receptor Agonist ................................................................ 8 1.4.1 Opioid Receptors ..................................................................................... 8 1.4.2 κ-Opioid Receptor Binding ...................................................................... 8 viii 1.5 Biological Activity .......................................................................................... 13 1.5.1 Potential Medicinal and Therapeutic Role ............................................. 13 1.5.2 Structure-Activity Relationship Studies ................................................ 13 2. Previously Completed Total Synthesis/Additional Efforts Towards Salvinorin A ...... 15 2.1 Introduction to Prior Synthetic Efforts ........................................................... 15 2.2 Evans’ Total Synthesis .................................................................................... 16 2.2.1 Retrosynthetic Analysis ......................................................................... 16 2.2.2 Preparation of the Aldehyde Fragment 2.3 ............................................ 17 2.2.3 Synthesis of Vinyl Iodide 2.4................................................................. 19 2.2.4 Fragment Coupling and Transformation ................................................ 19 2.2.5 TBAF-Mediated Transannular Cyclization ........................................... 21 2.2.6 Completion of the Total Synthesis ......................................................... 22 2.3 Hagiwara 1st-Generation Total Synthesis ....................................................... 23 2.3.1 Retrosynthetic Analysis from (−)-Methyl Barbascoate ......................... 23 2.3.2 Synthesis of Diene
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