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New Investigations in the Interrupted Nazarov Reaction by Owen Scadeng a Thesis Submitted in Partial Fulfillment of the Requirem New Investigations in the Interrupted Nazarov Reaction by Owen Scadeng A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry University of Alberta © Owen Scadeng, 2014 Abstract The five-membered carbocycle is a structural motif found in a plethora of natural products and bioactive compounds. The Nazarov reaction has emerged as an effective method to synthesize cyclopentenones and acts as a tool for adding structural complexity to molecular frameworks. This dissertation will discuss several projects involving the Nazarov cyclization and its use to build functionality to the cyclopentanoid framework. Chapter 1 provides a detailed recount of recent advances in Nazarov chemistry. Focus on methods to induce enantioselectivity, the use of alternative substrates as Nazarov reaction precursors, and the use of the Nazarov reaction in total synthesis is presented. Chapter 2 describes the formation of bridged bicyclic compounds via a [3+3]-cycloaddition between organoazides and the Nazarov intermediate. These cycloadducts were also found to thermally decompose to produce ring-enlarged dihydropyridones and 6-methylenepiperidinones. In Chapter 3, details the attempted development of a domino Nazarov cyclization/Baeyer-Villiger oxidation are provided. While the desired 3,4- dihydropyra-2-one was formed with the use of bis(trimethylsilyl)peroxide as the oxidant, optimization of the transformation failed to produce synthetically useful yields. Chapter 4 divulges the findings of Nazarov cyclizations of 2-hydroxyalkyl- 1,4-diene-3-ones. Originally proposed as substrates that could undergo domino Nazarov cyclization/semipinacol rearrangements, these compounds were found to readily produce alkylidene cyclopentenones under Lewis acid conditions. These ii substrates provided insight into the effect that 2-hydroxyalkyl substituents have on the charge density of the oxyallyl cation intermediate of the Nazarov reaction and subsequent alkene formation. iii Acknowledgements I would like to thank all the people who have helped me on the way to completing my degree. To my family, thank you for everything you have done for me. You have sacrificed so much time, encouraged and supported me through everything, and were always there when I needed you. To Fred, thank you for providing a place in your group for me to learn and grow as a chemist. I have learned a lot in my time in your group and am incredibly grateful for all the guidance you have provided me in research and career development. To former and current West group members, thank you for making coming to the lab fun. To Craig, Tina Grant, and Tina Bott, thank you for teaching me how to do the little things in chemistry that make a difference and for being patient with me along the way. To Lei, thanks for being my first lab partner and holding back judgment while I made countless rookie mistakes. To Verner, Tom, Yen-ku, and Yong, thanks for being great friends, great colleagues, and great people to share a large part of my day with. To Ryan, thanks for all the talks about things other than chemistry and for all the beers those talks were shared over. To Erin, I cannot thank you enough for everything you have done for me. You put up with me when I was angry, upset, burnt-out, tired, and miserable, but you kept pushing me and supporting me. You were the most understanding partner I could have asked for and your support kept me going. Thank you so very much. iv Table of Contents Chapter 1 1. The Nazarov Reaction......................................................................................................................... 1 1.1 The Nazarov Cyclization...................................................................................................... 1 1.1.1 Directed Nazarov Cyclization................................................................................... 3 1.1.2 Polarized Dienones. ..................................................................................................... 4 1.2 Asymmetric Nazarov Reactions. ...................................................................................... 8 1.2.1 Internal Asymmetric Induction............................................................................... 8 1.2.2 Diastereoselective Nazarov Reactions with Chiral Substrates............... 11 1.2.3 External Asymmetric Induction........................................................................... 11 1.2.4 Organocatalytic Asymmetric Induction............................................................ 14 1.2.5 Enantioselective Protonation................................................................................ 17 1.3 Alternative Substates for Nazarov Reactions.......................................................... 18 1.3.1 Electrophilic Activation of Vinyl Allenes.......................................................... 18 1.3.2 Vinyl Cyclopropane Opening................................................................................. 20 1.3.3 Vinylogous Nazarov Reactions............................................................................. 21 1.3.4 Domino Gold Catalyzed Rearrangement/Nazarov Cyclization .............. 22 1.3.5 Imino-Nazarov Cyclization..................................................................................... 24 1.4 Nazarov Cyclizations in Total Synthesis.................................................................... 28 1.4.1 Synthesis of (±)-Merrilactone A........................................................................... 28 1.4.2 Synthesis of (+)-Roseophilin................................................................................. 30 1.4.3 Synthesis of (±)-Rocaglamide ............................................................................... 32 1.4.4 Synthesis of (+)-Mandinoline A and B............................................................... 34 1.5 The Interrupted Nazarov Reaction .............................................................................. 38 1.6 Conclusions ............................................................................................................................ 38 1.7 References............................................................................................................................... 39 v Chapter 2 2. [3+3] Cycloadditions Between Organoazides and the Nazarov Intermediate and the Thermolysis of Their Cycloadducts................................................................................... 42 2.1 The Nazarov Reaction........................................................................................................ 42 2.1.1 The Interrupted Nazarov Reaction..................................................................... 43 2.1.2 Interrupted Nazarov Reactions with Nitrogen-Based Nucleophiles ... 48 2.2 [3+3] Cycloadditions Between Organoazides and the Nazarov Intermediate......................................................................................................................... 51 2.3 Reactivity of [3+3] Cycloadducts .................................................................................. 63 2.4 Conclusions ............................................................................................................................ 68 2.5 Future Directions................................................................................................................. 69 2.6 Experimental ......................................................................................................................... 71 2.6.1 General Information.................................................................................................. 71 2.6.2 Experimental Procedures and Characterization .......................................... 72 2.7 References............................................................................................................................... 91 Chapter 3 3. Domino Nazarov Cyclization/Baeyer-Villiger Oxidation.................................................. 93 3.1 3,4-Dihydropyran-2-ones ................................................................................................ 93 3.1.1 Synthesis of 3,4-Dihydropyan-2-ones............................................................... 93 3.1.2 Asymmetric Synthesisof 3,4-Dihydropyrna-2-ones.................................... 95 3.2 Domino Nazarov Cyclization/Baeyer-Villiger Oxidation ................................... 99 3.3 The Baeyer-Villiger Oxidation......................................................................................100 3.4 Domino Nazarov Cyclization/Baeyer-Villiger Oxidation .................................104 3.4.1 Bis(trimethylsilyl)peroxide .................................................................................106 3.4.2 Bis(trimethylsilyl)peroxide and the Nazarov Reaction...........................108 3.5 Conclusions ..........................................................................................................................113 3.6 Future Plans.........................................................................................................................113 3.7 Experimental .......................................................................................................................114 3.7.1 General Information................................................................................................114 vi 3.7.2 Experimental Procedures and Characterization ........................................115
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