University of Colorado, Boulder CU Scholar Chemistry & Biochemistry Graduate Theses & Chemistry & Biochemistry Dissertations Spring 1-1-2011 Cross-Metathesis of Electron-Deficient Polyenes and Studies Toward the Total Synthesis of Arenolide Carolynn Chin Arpin University of Colorado at Boulder, [email protected] Follow this and additional works at: http://scholar.colorado.edu/chem_gradetds Part of the Chemistry Commons Recommended Citation Arpin, Carolynn Chin, "Cross-Metathesis of Electron-Deficient Polyenes and Studies Toward the Total Synthesis of Arenolide" (2011). Chemistry & Biochemistry Graduate Theses & Dissertations. Paper 49. This Dissertation is brought to you for free and open access by Chemistry & Biochemistry at CU Scholar. It has been accepted for inclusion in Chemistry & Biochemistry Graduate Theses & Dissertations by an authorized administrator of CU Scholar. For more information, please contact [email protected]. Cross-Metathesis of Electron-Deficient Polyenes and Studies Toward the Total Synthesis of Arenolide by Carolynn C. Arpin B. S. Chemistry, Georgia Southern University, 2006 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Chemistry and Biochemistry 2011 This thesis entitled: Cross-Metathesis of Electron-Deficient Polyenes and Studies Toward the Total Synthesis of Arenolide written by Carolynn C. Arpin has been approved for the Department of Chemistry and Biochemistry _______________________________ Tarek Sammakia _______________________________ Xiang Wang Date ____________ The final copy of this thesis has been examined by the signatories, and we find that both the content and the form meet acceptable presentation standards of scholarly work in the above mentioned discipline. Arpin, Carolynn Chin (Ph.D., Chemistry) Cross-Metathesis of Electron-Deficient Polyenes and Studies Toward the Total Synthesis of Arenolide Thesis directed by Professor Tarek Sammakia The selectivity of the cross-metathesis reaction between electron-deficient polyenes and a general terminal alkene by use of different metathesis catalysts is presented. The reaction was found to be the most efficient when applied between a monoene or triene and the terminal alkene, providing the desired product in good to excellent yields. The selectivity is attributed to the reactivity of the terminal alkene of the triene which is furthest removed from the electron-withdrawing aldehyde or ester, rendering it the only alkene capable of reacting with the catalyst. Diene and tetraene substrates were not good partners in this reaction due to a lack of differentiation of the alkenes. Different approaches toward the total synthesis of arenolide, a 14-membered macrolide with unclear stereochemical assignment and bioactivity, are also discussed. The first approach utilizes a 1,5-anti aldol reaction that was found to lack diastereoselectivity when applied to the total synthesis. The second-generation approach focuses on alternative methods to produce the 1,5-anti relationship between the alcohols at C9 and C13 with the exo-methylene group at C11. All studies include the use of a key intramolecular vinylogous aldol macrocyclization developed in the Sammakia lab, which was shown to be effective on a model precursor very similar to that of arenolide. Efforts are underway to complete the total synthesis of arenolide. iii Acknowledgements First and foremost, thank you, Tarek. Thank you for believing in me from day one, and for your gracious and unwavering support. From tutoring sessions every other day in my first year to our valued collegial discussions in my final year, I am the chemist that I am all thanks to you. You are undoubtedly my most valued mentor and I cannot thank you enough for everything you’ve done for me. Matt and Joe, you guys are not only amazing mentors but also friends I cannot live without. Your guidance has shaped me in such a way I could not expect, and for that I am forever grateful. I admire you both immensely and I miss you every day. Xin, thank you for your aid and for always being open and approachable. Nolan, I cannot thank you enough for showing me that CU was the perfect fit for me. Morin, you are my absolute best friend, and every time I obtain something in the color purple, I think of you. I will never forget you. Jeff, I’m sorry you almost blew your face off my second year, but don’t worry – you’re still as handsome as ever. Thank you for your friendship and help with my “tricky” NMR spectra. Ryan, I will always remember our intense conversations, both drunken and sober. Will, I’m glad Tarek let you into the group despite my best efforts to keep you out. Mai, you are an amazing chemist and friend. Thank you for always being ready and willing to help, and for allowing me to teach you some English. Patty Feist, Andrew McKenzie, and Margaret Asirvatham, thank you for your support and encouragement throughout my teaching career at CU. You all aided my iv love for teaching to grow and flourish and I will always aspire to be the teachers you are. Rich, I looked forward to your boisterous personality every time I set foot in the NMR lab. There is no one else that can match your knowledge and passion for NMR spectroscopy, nor can anyone match the level to which you help any and everyone using your facilities. Doug Gin, your class was probably my favorite of my first year at CU, and I cannot thank you enough for being so engaging and insightful. You’ve always had your door open for me, and I can’t think of anyone else I absolutely had to have serve on my defense committee. Xiang, group meetings with your lab were some of the most beneficial and enjoyable in all of my time at CU, and I aspire to be the amazing and successful young professor that you are. Wei Zhang and Nick Kallan, I cannot thank you enough for agreeing to serve on my committee, especially with my defense date being so close to Christmas. Finally, and most importantly, I must thank the Lord, and my Mom and Dad. Your unconditional love and unending support has made me the person I am today. Thank you for everything you’ve brought to my life. And of course, Paul. My Ph. D. is secondary only to you, and I will forever remember my graduate career as that which led me to you. Thank you for listening to my unending complaints about chemistry, and for keeping me sane throughout it all. You are a remarkable and beautiful person whom I cannot live without. Thank you all! v Table of Contents Abstract ......................................................................................................................... i Acknowledgements .................................................................................................... iv Thesis Contents .......................................................................................................... vi List of Tables ............................................................................................................ viii List of Figures ............................................................................................................. ix List of Schemes .............................................................................................................x Chapter 1: Cross-Metathesis of Electron-Deficient Polyenes ..................................1 1.1 Olefin Metathesis Background .................................................................1 1.2 Selectivity in Olefin Cross-Metathesis .....................................................5 1.3 Polyene Metathesis in Natural Products Synthesis ...................................7 1.4 Previous Polyene Cross-Metathesis Studies ...........................................17 1.5 Cross-Metathesis of Electron-Deficient Polyenes ..................................24 1.5.1 Polyene Study ..........................................................................26 1.5.2 Synthesis of Polyene Substrates...............................................33 1.6 Conclusion and Future Direction ............................................................35 1.7 Experimental Information .......................................................................38 1.8 References ...............................................................................................51 vi Chapter 2: Studies Toward the Total Synthesis of Arenolide ...............................56 2.1 Arenolide Isolation, Characterization and Biological Activity ..............56 2.2 Retrosynthetic Analysis of Arenolide .....................................................58 2.3 Intramolecular Vinylogous Aldol Reaction ............................................60 2.4 A 1,5-Anti Aldol Approach to Arenolide ...............................................67 2.4.1 Model Study .............................................................................69 2.4.2 Arenolide Study .......................................................................75 2.5 Second-Generation Approach to Arenolide ............................................80 2.6 Conclusion and Future Direction ............................................................91 2.7 Experimental Information .......................................................................99 2.8 References .............................................................................................140 Bibliography .............................................................................................................146