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UC San Diego UC San Diego Electronic Theses and Dissertations Title Progress towards the total synthesis of the hasubanan alkaloids and acutumine Permalink https://escholarship.org/uc/item/1n90s3wf Author Nguyen, Thong Xuan Publication Date 2009 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Progress Towards the Total Synthesis of the Hasubanan Alkaloids and Acutumine A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Thong Xuan Nguyen Committee in charge: Professor Yoshihisa Kobayashi, Chair Professor Daniel Donoghue Professor William Fenical Professor Kyriacos Nicolaou Professor Joseph O'Connor 2009 © Thong Xuan Nguyen, 2009 All rights reserved. The Dissertation of Thong Xuan Nguyen is approved, and it is acceptable in quality and form for publication on microfilm and electronically: chair University of California, San Diego 2009 iii To my family and friends iv TABLE OF CONTENTS Signature Page ...........................................................................................................iii Dedication ..................................................................................................................iv Table of Contents .......................................................................................................v List of Abbreviations .................................................................................................viii List of Figures ............................................................................................................xi List of Schemes ..........................................................................................................xiii List of Tables .............................................................................................................xviii Acknowledgments......................................................................................................xx Vita .............................................................................................................................xxi Abstract of the Dissertation .......................................................................................xxii CHAPTER ONE 1.1 Background to the Hasubanan Alkaloids ...............................................1 1.2 Biosynthesis of Morphine ......................................................................4 1.3 Biosynthesis of Hasubanonine ...............................................................5 1.4 Chemical Conversion of the Morphinan to Hasubanan Alkaloids ........7 1.5 Ibuka's Synthesis of Hasubanonine ........................................................8 1.6 Castle's Attempted Synthesis of Hasubanonine .....................................10 1.7 Background on Acutumine ....................................................................11 1.8 Biosynthesis of Acutumine ....................................................................14 1.9 Castle's Synthesis of Acutumine ............................................................19 1.10 Sorensen Synthesis of the Propellane Core Structure of Acutumine .....22 1.11 Conclusion .............................................................................................23 1.12 Notes and References .............................................................................24 CHAPTER TWO 2.1 Retrosynthetic Analysis .........................................................................28 2.2 Synthesis of Cyclic Imine ......................................................................33 v 2.3 Alternative Path to Reduce Cyano Group ..............................................35 2.4 Diastereoselective Construction of Cis-Fused Indolidine ......................36 2.5 Initial Attempts at Dieckmann Cyclization............................................38 2.6 Diastereoselective Construction of Cis-Fused Aminonitrile .................40 2.7 Dieckmann Cyclization with Formamide of Aminonitrile ....................41 2.8 The Hydrolysis of Sterically Hindered Carboxamide ............................44 2.9 The Completion of Propellane Synthesis ...............................................48 2.10 The Synthesis of a Series of 2-Tetralone Derivatives ............................51 2.11 Conclusion .............................................................................................52 2.12 Acknowledgements ................................................................................52 2.13 Experimental ..........................................................................................54 2.13.1 Materials and Methods ..........................................................54 2.13.2 Preparative Procedures..........................................................55 2.14 Notes and References .............................................................................73 2.15 APPENDIX ONE: Spectra Relevant to Chapter Two ..........................76 2.16 APPENDIX TWO: X-Ray Crystallography Reports Relevant to Chapter Two ......................................................................................111 CHAPTER THREE 3.1 Retrosynthetic Analysis .........................................................................124 3.2 Synthesis of the 2,3-Disubstituted Cyclopentenone Foundation ...........130 3.3 Initial Attempt to Access Aldehyde .......................................................132 3.4 Synthesis of the Photocycloaddition Precursor 144 ..............................136 3.5 Photocycloaddition Reaction of Dioxinone 144 ....................................140 3.6 Synthesis of Photocycloaddition Precursor 202 ....................................141 3.7 Photocycloaddition Reaction of Cyclopentenone 202 ...........................143 3.8 Synthesis of the Photocycloaddition Precursor 147 ..............................146 3.9 Photocycloaddition Reaction of Cyclopentenone 147 ...........................148 3.10 Conclusion .............................................................................................153 3.11 Acknowledgements ................................................................................153 vi 3.12 Experimental ..........................................................................................154 3.12.1 Materials and Methods ..........................................................154 3.12.2 Preparative Procedures..........................................................155 3.13 Notes and References .............................................................................178 3.14 APPENDIX ONE: Spectra Relevant to Chapter Three ........................181 3.15 APPENDIX TWO: X-Ray Crystallography Reports Relevant to Chapter Three .....................................................................237 vii LIST OF ABBREVIATIONS Ac acetyl, acetate AcOH acetic acid i-Am iso-Amyl aq. aqueous Ar aryl Bn benzyl BOC tert-butyloxycarbonyl bp boiling point br broad n-Bu normal-butyl t-Bu tertiary-butyl calcd calculated CAN ceric ammonium nitrate cat. catalytic amount CSA camphorsulfonic acid d doublet dr diastereomeric ratio DCM dichloromethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMP dess-martin periodinane DMS dimethylsulfide DMSO dimethylsulfoxide EI electron impact equiv. (eq.) equivalent Et ethyl h hour viii Hz hertz IBX 2-iodoxybenzoic acid IC inhibitor concentration IR infrared (spectrum) KHMDS potassium bis(trimethylsilyl)amide LDA lithium diisopropylamine LHMDS lithium bis(trimethylsilyl)amide m multiplet μm micromolar Me methyl min minutes mol mole MOM methoxymethyl mp melting point Ms methanesulfonyl (mesyl) nM nanomolar NMR nuclear magnetic resonance [O] oxidation Pd/C palladium on charcoal Ph phenyl PhH benzene Piv pivaloyl PMB para-methyoxybenzyl PMP para-methyoxyphenyl ppm parts per million PPTs pyridinium para-toluenesulfonate i-Pr iso-propyl Pro proline Py pyridine Quant. quantitative ix rt room temperature s singlet t triplet TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBDPS tertiary-butyldiphenylsilyl TBS tertiary-butyldimethylsilyl Tf trifluoromethanesulfonyl TFA trifloroacetic acid TFAA trifloroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography TMS trimethylsilyl (p-)TsOH para-toluenesulfonic acid UV-Vis Ultraviolet-Visible ∆ heat to reflux x LIST OF FIGURES Figure 1.1.1 Structure of the hasubanan family of alkaloids 1-7 and periglaucine A (8) ...................................................................1 Figure 1.1.2 Structure of the hasubanan and morphinan skeleton ..............2 Figure 1.7.1 Structure of (-)-acutumine (38) ...............................................12 Figure 1.7.2 Structure of scopolamine (39) ................................................13 Figure 2.1.1 Structure of the hasubanan alkaloids (1-7) and the common propellane 79 ............................................................28 Figure 2.4.1 ORTEP figure of cis-acetamide 103 .......................................38 Figure 2.7.1 ORTEP figure of enamine 110 ...............................................43 13 Figure 2.9.1 Difference in the C-NMR chemical shift (ppm, in CDCl3) of cephatonine (7) with those of propellane 84 prepared by us .........................................................................51 Figure 3.1.1 Structure of (-)-hasubanonine (1) and (-)-acutumine (38) ......124 Figure 3.7.1 Difference between calculated and