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UC Berkeley UC Berkeley Electronic Theses and Dissertations UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids Permalink https://escholarship.org/uc/item/2ws9p3b7 Author Pflueger, Jason Jon Publication Date 2016 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids By Jason Jon Pflueger A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in Charge: Professor Richmond Sarpong, Chair Professor Thomas Maimone Professor Leonard Bjeldanes Fall 2016 Abstract Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids by Jason Jon Pflueger Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair Diterpenoid alkaloid natural products, isolated from plants in the Aconitum, Delphinium, Consolida, and Spiraea genera, possess complex, caged, highly oxygenated skeletons and display potent biological activities through interactions with voltage-gated ion channels. Several of these alkaloids are currently used clinically for the treatment of arrhythmia, while others act as incredibly potent neurotoxins. Until recently, there were very few successful total syntheses of any diterpenoid alkaloid natural products, a testament to the structural complexity of these molecules. We explored synthetic strategies targeting two major types of these natural products: the aconitine-type C19-diterpenoid alkaloids and the hetisine-type C20-diterpenoid alkaloids. Initial work explored Diels–Alder cycloadditions with maleic anhydride-derived dienophiles toward the eventual construction of aconitine-type diterpenoid alkaloids. We examined the selective ring-opening of these adducts with a variety of nucleophiles and utilized an ester-stabilized benzylic nucleophile to achieve C–C bond formation with complete positional selectivity. This product was rapidly elaborated to a vinyl lactone intermediate, which following amine addition and oxidation underwent a high-yielding, diastereoselective methylation reaction to install the challenging C18 carbon atom. Synthesis of the hetisine-type diterpenoid alkaloid cossonidine built off of previous work performed in the Sarpong lab. Reexamining the previously-developed route, we optimized several steps and implemented new reactions to increase the yield and reproducibility of the chemistry and reduce the overall step count. Subsequent functional group transformations involving deprotection and inversion of the C1 hydroxyl group and installation of the allylic alcohol moiety completed the first total synthesis of cossonidine. Recognizing the connections between the various diterpenoid alkaloid types, we explored ways to convert the vinyl lactone intermediate developed in our studies toward aconitine-type natural products into the hetisine-type skeleton of cossonidine. Following the introduction of an iodine atom on the aromatic ring, magnesium-halogen exchange leads to an intramolecular cyclization reaction to forge the central 6-7-6 tricycle with carbonyl groups at all three nitrogen- bearing carbon atoms following oxidation. Efforts to install the C18 methyl group and accomplish a triple reductive amination cascade to complete this second-generation total synthesis are ongoing. 1 TABLE OF CONTENTS Acknowledgements ...................................................................................................................... iii Chapter 1. Diterpenoid Alkaloid Natural Products: Classification, Biosynthesis, Biological Activities, and Selected Syntheses ................................................................................................1 1.1 Introduction ................................................................................................................................1 1.2 Structural Classification .............................................................................................................1 1.3 Biosynthesis ...............................................................................................................................3 1.4 Biological Studies ......................................................................................................................4 1.5 Previous Syntheses.....................................................................................................................4 1.5.1 Syntheses of C18- and C19-Diterpenoid Alkaloids .............................................................5 1.5.2 Syntheses of Denudatine-type C20-Diterpenoid Alkaloids ................................................7 1.5.3 Syntheses of the Hetidine-type C20-Diterpenoid Alkaloid Skeleton..................................8 1.5.4 Syntheses of the Hetisine-type C20-Diterpenoid Alkaloid Nominine ..............................10 1.6 Conclusion ...............................................................................................................................11 1.7 References ................................................................................................................................11 Chapter 2. Initial Efforts toward the Aconitine-type Skeleton: Diels–Alder Reactions with Maleic Anhydride-based Dienophiles and Subsequent Derivatization ...................................13 2.1 Introduction ..............................................................................................................................13 2.2 Retrosynthetic Analysis ...........................................................................................................13 2.3 Diels–Alder Cycloaddition Studies..........................................................................................14 2.4 Derivatization Studies of Bicyclic Anhydride 2.5 ...................................................................16 2.5 Synthesis and Elaboration of a Homologated Diels–Alder Adduct .........................................17 2.6 Conclusion ...............................................................................................................................20 2.7 Experimental Procedures and Characterization Data ..............................................................20 2.8 References ................................................................................................................................31 Appendix 1. NMR Spectra and Crystallography Data for Compounds Discussed in Chapter 2 ......................................................................................................................................33 Chapter 3. Total Synthesis of Cossonidine: A Benzyne-Insertion Route toward Hetisine- type C20-Diterpenoid Alkaloids ...................................................................................................73 3.1 Introduction ..............................................................................................................................73 3.2 Retrosynthesis and Previous Work toward the Heptacyclic Core of Cossonidine ..................74 3.3 Optimization of the Initial Route to the Heptacyclic Core ......................................................75 3.4 Completing the Total Synthesis of Cossonidine ......................................................................83 3.5 Conclusion ...............................................................................................................................87 3.6 Experimental Procedures and Characterization Data ..............................................................87 3.7 References ..............................................................................................................................101 Appendix 2. NMR Spectra for Compounds Discussed in Chapter 3 ....................................104 i Chapter 4. Exploring a Second-Generation Synthesis of Cossonidine: A Magnesiate- Insertion Route to the 6-7-6 Tricycle .......................................................................................129 4.1 Introduction ............................................................................................................................129 4.2 Initial Studies on C–C Bond Formation to Access the 6-7-6 Tricyclic Core ........................129 4.3 Late-Stage Iodination and Elaboration to Diketoaldehyde 4.18 ............................................133 4.4 Efforts to Elaborate Diketoaldehyde 4.18 to the Hetisine Core.............................................135 4.5 Conclusion .............................................................................................................................136 4.6 Experimental Procedures and Characterization Data ............................................................137 4.7 References ..............................................................................................................................140 Appendix 3. NMR Spectra and Crystallography Data for Compounds Discussed in Chapter 4 ....................................................................................................................................141 ii Acknowledgements First and foremost, I would like to thank my parents, Richard and Helen, for their constant support and inspiration. It is from you that I learned how to dream big, work hard, and give back more than
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