Formal Synthesis of Vinigrol and Efforts towards the Total Synthesis of Digitoxigenin by Jason Poulin Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Philosophiae Doctor (Ph.D.) degree in chemistry Candidate Supervisor Jason Poulin Dr. Louis Barriault Ottawa-Carleton Chemistry Institute Faculty of Science University of Ottawa © Jason Poulin, Ottawa, Canada, 2013 Abstract Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid ii containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction. iii Acknowledgements Such an endeavour would not have been possible without the much appreciated help and support of the people surrounding me. First and foremost, I would like to thank Prof. Louis Barriault for allowing me to conduct cutting edge research as a part of his laboratory. His guidance and mentorship were an integral part of my studies and the independence which he grants his students fully promotes the development of autonomy and personal scientific thought. I would also like to thank my family and friends for their support and understanding during this process. I am very grateful to my parents, Dan and Charlene, for encouraging my curiosity throughout my life and always being there when I needed help. I also appreciated Sarah, Pat and Thierry’s advice and delicious food. Matt and Emma reminded me of the innocence of childhood and how simple life can be. Julie was also a big part of my life and was always there to cheer up an otherwise frustrating day. Without her, I would not be as happy in life. Finally, I would like to thank Shawn who has been like a brother to me for the past decade. I would like to thank the other members of the lab that I have had the privilege of working with over the years. Dr. Christiane Grisé-Bard was a true inspiration and the perfect example of having a well-balanced life, while excelling in chemistry. Kass and Joel were the best officemates and friends that someone could ask for. I’ll always remember the good times we had together and Joel’s foosball tournament losses. I’ll also never forget the good times had with Pat, Bouba and Gab, especially at conferences over some wings and beer. The trip to Mexico and scubadiving with Frank were also quite the adventures. Despite their interesting and sometimes frustrating choice in music, it was always fun chatting with Dan and Gen and I would also like to thank Max and Steve for introducing me to Worms and for the laughs shared over lunchtime. It was also great working with Eric, Marie-Christine, Anik and Guillaume. I would also like to wish lots of success to the lab’s newcomers: Phil, Steph and Matt. There are some members from other labs that also had an impact on me, such as Isabelle from the Beauchemin lab. She has always been a great friend, ever since undergrad iv and I’m sad to see that our paths have now diverged. I would also like to thank Dave and David from the Fagnou group for lending out chemicals and helpful discussions. I wish all of them lots of happiness throughout their lives. Finally, the entire professorial corps and staff at the University of Ottawa also contributed over the course of my studies providing interesting discussions and an enjoyable atmosphere. I would like to acknowledge Profs. André Beauchemin, Keith Fagnou, Rob Ben and Bill Ogilvie for their insights on various problems and for offering excellent courses over the semesters which were essential to my success. Julie Lamothe was a great TA supervisor for the undergraduate laboratories and a good friend. I want to give a special thank you to Glenn Facey (NMR), Cheryl McDowall (NMR), Clem Kazakoff (MS) and Ilia Korobkov (X-ray) for their help in obtaining spectroscopic data. v Table of Contents Abstract ............................................................................................................................................ ii Acknowledgements .................................................................................................................... iv Chapter 1 ........................................................................................................... 1 Total Synthesis ...................................................................................................................................... 1 The Diels-Alder Reaction ...................................................................................................................... 4 Molecular Orbital Analysis ............................................................................................................ 5 Regiochemical Outcome ................................................................................................................ 6 Lewis Acid Catalysis ..................................................................................................................... 7 Stereoselectivity ............................................................................................................................. 8 Recent Applications in Total Synthesis ......................................................................................... 9 Chapter 2 ......................................................................................................... 13 Introduction ......................................................................................................................................... 13 Isolation and Structure Elucidation ..................................................................................................... 14 Biological Effects ................................................................................................................................ 15 Biosynthesis ......................................................................................................................................... 16 Synthetic Efforts .................................................................................................................................. 18 Hanna’s Work .............................................................................................................................. 18 Paquette’s Approach .................................................................................................................... 22 Mehta’s Approach ....................................................................................................................... 23 Corey’s Work .............................................................................................................................. 23 Matsuda’s Approach .................................................................................................................... 26 Barriault’s Work .......................................................................................................................... 28 Fallis’ Approach .......................................................................................................................... 34 Njardarson’s Approach ................................................................................................................ 35 Baran’s Total Synthesis ............................................................................................................... 36 vi Chapter 3 ......................................................................................................... 38 Novel Retrosynthetic analysis ............................................................................................................. 38 Synthesis of Diels-Alder Precursor ..................................................................................................... 39 Attempts at functionalizing the A-ring ................................................................................................ 50 Hydrogenation ............................................................................................................................. 52 Thiol-ene reaction ........................................................................................................................ 53 Dihydroxylation route .................................................................................................................