Formal Synthesis of (+/-) Morphine via an Oxy-Cope/Claisen/Ene Reaction Cascade by Joel Marcotte Submitted to the Faculty of Graduate and Postdoctoral Studies In partial fulfillment of the requirements for the degree of Master of Science The University of Ottawa August, 2012 © Joel Marcotte, Ottawa, Canada, 2012 ABSTRACT For years now, opium alkaloids and morphinans have been attractive synthetic targets for numerous organic chemists due to their important biological activity and interesting molecular architecture. Morphine is one of the most potent analgesic drugs used to alleviate severe pain. Our research group maintains a longstanding interest in tandem pericyclic reactions such as the oxy-Cope/Claisen/ene reaction cascade and their application to the total synthesis of complex natural products. Herein we report the ventures towards the formal synthesis of (+/-)-morphine based on the novel tandem oxy- Cope/Claisen/ene reaction developed in our laboratory. These three highly stereoselective pericyclic reactions occurring in a domino fashion generate the morphinan core structure 2 via precursor 1 after only 7 steps. The formal synthesis culminated in the production of 3 after a total of 18 linear steps, with an overall yield of 1.0%, successfully intersecting two previous syntheses of the alkaloids, namely the ones of Taber (2002) and Magnus (2009). ii À ma famille, sans qui rien de cela n’aurait été possible iii ACKNOWLEDGEMENTS I would like to start by thanking my supervisor Dr. Louis Barriault, who has been my mentor in chemistry for the past three years. I am grateful for his guidance, patience and encouragements, especially when facing the many challenges that awaited me on this project. The freedom handed to me to create my own path and explore my own ideas coupled with Dr. Barriault’s endless source of advice and helpful discussions created an environment where one could easily learn and progress as a researcher, a problem-solver as well as a person. I also want to thank my parents (Colette and Daniel) who love me and supported me in the many ways that lessened the weight of the different burdens I faced in the last two years. I thank my brother (Raphael) for his endless source of entertainment and considerations. Finally I would like to extend a lot of gratitude and recognize the efforts made by my sweetheart of now 7 years (Cynthia) for tolerating me and my different mood swings, which depended on how chemistry treated me. This project and my accomplishments would not be the same without Kassandra Lepack who was my direct supervisor in the lab for my initial contact with chemistry in academic settings. I thank her for teaching me so much about chemistry as well as keeping my experiments clean and organized. I also want to thank Jason Poulin, for the many fruitful (and pointless but amusing) discussions about chemistry or life in general. As mentioned at some point in the document, he has had a significant impact on several experiments discussed therein. Thank you for being a co-worker but mostly, for being a good friend. On a similar note, I would like to thank Daniel and Genevieve for their uplifting attitude and unending source of entertainment, Boubacar for the numerous passionate discussions about technology, Travis, Frank, Pat, Gab, Guillaume for their frequent advices on many aspects of my project, Phil for his unique laugh and sense of humour and Steph for bearing with me during the last month of my degree. Finally my gratitude goes to the department of chemistry. I would like to specially thank several key staff members such as Dr. I Korobkov for achieving some difficult X-ray crystallography experiments as well as Dr. Beauchemin for the helpful discussions. I also want to thank Andrew Zlotorzynski for keeping us in a safe working environment and the numerous employees at the front desk and chemistry store for their help and professionalism. I would like to acknowledge and thank NSERC as well as the University of Ottawa for the funding received at the master’s level. iv TABLE OF CONTENTS Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................. iv Table of Contents ................................................................................................................ v Schemes .......................................................................................................................... viii Figures .............................................................................................................................. xi Tables ................................................................................................................................ xii Glossary of Abbreviations .................................................................................................. xiii CHAPTER 1: Introduction ............................................................................................... 1 1.1 Historical Aspect .................................................................................................... 1 1.1.1 Ancient History ............................................................................................... 1 1.1.2 Recent History ................................................................................................ 2 1.2 Biological ............................................................................................................... 3 1.2.1 Properties ....................................................................................................... 3 1.2.2 Biosynthesis ................................................................................................... 4 1.3 Chemical ............................................................................................................... 6 1.3.1 Properties ....................................................................................................... 6 1.3.1 First Synthesis ................................................................................................ 8 1.3.2 Potential Scalability .......................................................................................10 1.3.3 Palladium Catalyzed C12-C13 Formation ......................................................11 1.3.4 Unique Approaches .......................................................................................14 CHAPTER 2: Formal Synthesis of Morphine ............................................................... 18 2.1 Improvements on Previous Work ..........................................................................18 2.1.1 Original Synthesis .........................................................................................18 2.1.2 Friedel-Crafts ................................................................................................20 2.1.3 Access to α,β-Unsaturated Aldehyde 2.6 .......................................................21 2.1.4 Allylboration ...................................................................................................23 2.1.5 Pericyclic Reaction Cascade .........................................................................25 2.2 Lactol Opening .....................................................................................................32 2.2.1 Initial Post-Cascade Work By Kassandra ......................................................32 2.2.2 Devising Approaches to Opening of Lactol 2.10 ............................................33 2.2.3 Suarez Radical Opening ................................................................................39 2.2.4 Sidestepping Lactol 2.10 ...............................................................................42 2.3 Oxy-Cope/Claisen + Prins ....................................................................................44 v 2.3.1 Original Result ...............................................................................................44 2.3.2 Substrate Variation ........................................................................................47 2.4 Early Furan Synthesis and End Game ..................................................................52 2.4.1 Demethylation-Cyclization .............................................................................52 2.4.2 Leaving-Group Promoted Cyclization ............................................................58 2.4.3 Epoxidation ...................................................................................................64 2.4.4 End Game .....................................................................................................65 2.5 Conclusion ...........................................................................................................70 CHAPTER 3: Experimental and References ................................................................ 73 3.1 General Experimental ...........................................................................................73 2,5-Dibromo-7,8-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (2.13) ..........................73 7,8-Dimethoxy-3,4-dihydronaphthalene-1-carbaldehyde (2.6) .....................................74 1-(7,8-Dimethoxy-3,4-dihydronaphthalen-1-yl)-3-methylbut-3-en-1-ol (2.7) .................75 2-Hydroxy-11,12-dimethoxy-3a,4,6,6a,7,8-hexahydro-1H-phenanthro[4,4a-b]furan- 5(2H)-one (2.10) ..........................................................................................................76