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The Total Synthesis of Cycloprodigiosin and Synthetic Efforts Toward the Pentacyclic Ambiguine Class of Natural Products

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The Total Synthesis of Cycloprodigiosin and Synthetic Efforts Toward the Pentacyclic Ambiguine Class of Natural Products The Total Synthesis of Cycloprodigiosin and Synthetic Efforts Toward the Pentacyclic Ambiguine Class of Natural Products by Rebecca Elizabeth Johnson 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 Assistant Professor Markita Landry Summer 2018 The Total Synthesis of Cycloprodigiosin and Synthetic Efforts Toward the Pentacyclic Ambiguine Class of Natural Products Copyright 2018 by Rebecca Elizabeth Johnson Abstract The Total Synthesis of Cycloprodigiosin and Synthetic Efforts Toward the Pentacyclic Ambiguine Class of Natural Products by Rebecca Elizabeth Johnson Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair The synthesis and absolute stereochemical determination of cycloprodigiosin has been com- pleted. Chapter 1 discusses the historical, synthetic, and biological background of prodiginine natural products, specifically of prodigiosin and cycloprodigiosin. Chapter 2 details our synthetic attempts for the synthesis of cycloprodigiosin and the strategy used to determine the absolute stereochemistry at the C4’ position of this prodiginine. The syntheses of both enantiomers of cycloprodigiosin were completed in an efficient five step sequence utilizing a Barton-Sch¨ollkopf- Zard pyrrole synthesis. Cycloprodigiosin was isolated from its parent bacterial source, Pseudoal- teromonas rubra, by Tristan de Rond in a collaboration with the Keasling group at UC Berkeley. The natural isolate was determined to exist as a scalemic mixture in a ratio of 83:17 (R):(S) at C4’. The enzyme responsible for the final oxidative cyclization event from prodigiosin to cycloprodi- giosin was identified as the alkylglycerol monooxygenase-like enzyme PRUB680. The second topic of this thesis details the first total synthesis of ambiguine P in 19 steps from (S)-carvone. The isolation, biosynthentic, and synthetic background of the ambiguine family of natural products is discussed in Chapter 3. The challenges associated with the synthesis of penta- cyclic ambiguines are described in Chapter 4 and focus on the formation of the pentacyclic core in addition to the installation of the C12 quaternary center. The1st generation synthetic approach to access the ambiguine pentacyclic core involves a key γ-enolate cross-coupling reaction to form the tetracyclic precursor. The intermediates in this approach were synthesized from indole and (S)- carvone using an intermolecular Nicholas alkylation. The 2nd generation synthetic route to access the key pentacyclic core involves an intramolecular Nicholas alkylation at C2 of indole, followed by Friedel-Crafts cyclization at C4 to successfully generate the pentacylic core. Chapter 5 describes the completion of ambiguine P; many strategies were explored to install the C12 quaternary center, and eventually a directed C–C bond construction utilizing formates was found that successfully formed the C–C bond on the desired α-face. The requisite vinyl group at C12 and the amide functionality at C11 were installed using an interrupted Peterson olefination strategy. Attempts are described to access ambiguine L from these late-stage intermediates using benzylic oxidation and hydration methodologies. 1 To my family for their unwavering love and support. i List of Abbreviations 9-BBN 9-borabicyclo[3.3.1]octane Ac acetyl AIBN azobis(iso-butyronitrile) b broad Boc tert-butyloxycarbonyl Bu butyl cat. catalytic CuTc copper(I)-thiophene-2-carboxylate d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DEAD diethylazodicarboxylate DEF diethylformamide DIBAL-H diisobutylaluminum hydride DMAP (4-dimethylamino)pyridine DMF dimethylformamide DMP Dess-Martinperiodinane DMSO dimethylsulfoxide DNPH 2,4-dinitrophenylhydrazine DTBP 2,6-di-tert-butylpyridine ii EI electronimpactionization equiv equivalent ESI electrospray ionization HPLC high-pressureliquidchromatography HRMS high-resolutionmassspectrometry IR infrared L-selectride lithium tri-(sec-butyl)borohydride LAH lithiumaluminumhydride LCMS liquidchromatographymassspectrometry LDA lithiumdiisopropylamide LHMDS Lithiumhexamethyldisilazane LHMDS lithiumhexamethydisilazide m multiplet Me methyl mp meltingpoint MTBD 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene n normal NaHMDS sodium hexamethyldisilazide NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance PDC pyridiniumdichromate Ph phenyl PIDA phenyliododiacetate PIFA [bis(trifluoroacetoxy)iodo]benzene prenyl 3,3-dimethylallyl PSMS zinc bis[(phenylsulfonyl)methanesulfinate] iii pyr. pyridine q quartet reverse prenyl 1,1-dimethylallyl rt room temperature s singlet sec secondary SEM 2-(trimethylsilyl)ethoxymethyl t triplet TBAF tetrabutylammoniumfluoride TBHP tert-butylhydroperoxide TBS tert-butyldimethylsilyl tert tertiary THF tetrahydrofuran TLC thin-layerchromatography TMS trimethylsilyl Ts para-toluenesulfonyl iv Contents Acknowledgments vii 1 Chapter 1 : Background to the Tripyrrole Natural Products Prodigiosin and Cy- cloprodigiosin 1 1.1 History of the Prodiginine Family of Natural Products . ............... 1 1.2 Total Syntheses of Prodigiosin and Structural Confirmation.............. 3 1.3 Total Syntheses of Cycloprodigiosin and Structural Confirmation........... 7 1.4 Biosynthesis of Prodigiosin Natural Products and Their BiologicalActivity . 9 1.5ConclusionandOutlook. ..... 12 1.6References...................................... .. 13 2 Chapter 2 : Synthesis of Cycloprodigiosin Identifies the Natural Isolate as a Scalemic Mixture 15 2.1 Motivations for Pursuing the Synthesis of Cycloprodigiosin.............. 15 2.2 1st Generation Synthesis of Cycloprodigiosin Derived from Established Chemistry . 16 2.3 A Concise and Efficient 2nd Generation Approach for the Synthesis of Cycloprodigiosin 17 2.4 Biosynthetic Investigations Into the Late-Stage Oxidative Cyclization from Prodi- giosintoCycloprodigiosin . ... 22 2.5ConclusionandOutlook. ..... 23 2.6ExperimentalContributors . ....... 23 2.7MaterialsandMethods . .... 24 2.8ExperimentalMethodsandProcedures . ......... 25 2.9References...................................... .. 39 Appendix2.a: NMRSpectraRelevanttoChapter2 . ......... 41 Appendix 2.b : X-ray Crystallographic Data Relevant to Chapter2 ............ 68 3 The Isolation, Bioactivity, and Synthetic Background of the Pentacyclic Ambiguine Natural Products 74 3.1 The Isolation and Bioactivity of Ambiguine Natural Products............. 74 3.2 Biosynthetic Investigations of Hapalindole and AmbiguineNaturalProducts . 78 3.3 Previous Attempts to Synthesize Ambiguine Natural Products............. 84 3.4ConclusionandOutlook. ..... 93 3.5References...................................... .. 93 v 4 Chapter 4 : Synthetic Approaches to the Pentacyclic Class of Ambiguine Natural Products 95 4.1 Challenges Associated with the Synthesis of PentacyclicAmbiguines. 95 4.2 1st Generation Route Toward the Synthesis of the Pentacyclic Ambiguines . 99 4.3 2nd Generation Route Toward the Synthesis of the Pentacyclic Ambiguines . 103 4.4ExperimentalContributors . .......110 4.5MaterialsandMethods . .111 4.6ExperimentalMethodsandProcedures . .........111 4.7References...................................... 119 Appendix4.aNMRSpectraRelevanttoChapter4 . .........120 Appendix 4.b X-ray Crystallographic Data Relevant to Chapter4.............137 5 Chapter 5 : Late-Stage Strategies for the Synthesis of Pentacyclic Ambiguine Nat- ural Products 155 5.1InstallationoftheC12QuaternaryCenter . ...........155 5.2 Late-Stage Manipulations to Install the Vinyl Group and the Isonitrile Functionality . 163 5.3SynthesisofAmbiguineP. .167 5.4ConclusionandOutlook. .172 5.5ExperimentalContributors . .......175 5.6MaterialsandMethods . .175 5.7ExperimentalMethodsandProcedures . .........176 5.8References...................................... 190 Appendix5.aNMRSpectraRelevanttoChapter5 . .........192 Appendix 5.b X-ray Crystallographic Data Relevant to Chapter5.............235 vi Acknowledgments First I would like to thank my mentor, Professor Richmond Sarpong. Richmond gave me the opportunity to work in his lab which has been a truly meaningful experience from both a chemistry and personal development perspective. I have learned that excellence should always be the ultimate goal and that hard work is always worth the effort. He is a tremendous mentor in chemistry and I am lucky to have had the opportunity to learn from his expertise. I have to thank all of the Sarpong group members and specifically those who have helped edit this document, Magnus Pfaffenbach, Ian Bakanas, Shelby McCowen, Brian Wang, Melissa Hardy, and Nick O’Connor. I appreciate your thoughtful and constructive comments. I would also like to thank my lab mates who have worked in 832 these past few years. Kyle Owens, you may be shocked but I have actually learned a tremendous amount from you. You have an incredible way of performing chemistry and I am honored to have overlapped for 5 years with you. Also, this thesis would not have been written without your LaTex expertise. Shelby McCowen, you are a fantastic friend and I wish we had overlapped for a longer time but I am thankful to have had the opportunity to work next to you for 2 years. Hwisoo Ree, your patience and grace with chemistry and life has been inspirational to me and I am so thankful to have had the opportunity to work with you. I
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