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Open Sacher - Phd Dissertation.Pdf The Pennsylvania State University The Graduate School Eberly College of Science PROGRESS TOWARD A TOTAL SYNTHESIS OF THE LYCOPODIUM ALKALOID LYCOPLADINE H A Dissertation in Chemistry by Joshua R. Sacher © 2012 Joshua R. Sacher Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2012 ii The dissertation of Joshua Sacher was reviewed and approved* by the following: Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee Raymond L. Funk Professor of Chemistry Gong Chen Assistant Professor of Chemistry Ryan J. Elias Frederik Sr. and Faith E. Rasmussen Career Development Professor of Food Science Barbara Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry *Signatures are on file in the Graduate School iii ABSTRACT In work directed toward a total synthesis of the Lycopodium alkaloid lycopladine H (21), several strategies have been explored based on key tandem oxidative dearomatization/Diels-Alder reactions of o-quinone ketals. Both intra- and intermolecular approaches were examined, with the greatest success coming from dearomatization of bromophenol 84b followed by cycloaddition of the resulting dienone with nitroethylene to provide the bicyclo[2.2.2]octane core 203 of the natural product. The C-5 center was established via a stereoselective Henry reaction with formaldehyde to form 228, and the C-12 center was set through addition of vinyl cerium to the C-12 ketone to give 272. A novel intramolecular hydroaminomethylation of vinyl amine 272 was used to construct the 8-membered azocane ring in intermediate 322, resulting in establishment of 3 of the 4 rings present in the natural product 21 in 9 steps from known readily available compounds. OH MeO OMe MeO OMe 1) PhI(OAc)2 OMe MeOH O OH Br Br 2) O2N NO2 5 Br 99% NO2 HO 84b 203 228 12 OH OH OTBDPS OTBDPS Br [Rh(cod)Cl]2, Xantphos Br H2N HN CO (10 bar), H2 (40 Bar) PhMe, HFIPA TBDPSO 135 °C, 18 h TBDPSO 322 272 75% OH O N O lycopladine H (21) iv TABLE OF CONTENTS LIST OF FIGURES .................................................................................................... v LIST OF TABLES ...................................................................................................... vi ACKNOWLEDGEMENTS ........................................................................................ vii CHAPTER 1 – INTRODUCTION AND BACKGROUND ......................................................... 1 1.1 – LYCOPODIUM ALKALOIDS ............................................................................. 1 1.2 – THE LYCOPLADINE ALKALOIDS .................................................................... 3 1.2.1 – LYCOPLADINES A–G .......................................................................... 3 1.2.2 – LYCOPLADINE H ................................................................................ 4 1.2.3 – SYNTHESIS OF LYCOPLADINE A AND RELATED COMPOUNDS ............... 8 CHAPTER 2 – SYNTHETIC EFFORTS TOWARD LYCOPLADINE H ....................................... 12 2.1 – INITIAL RETROSYNTHETIC ANALYSIS ............................................................ 12 2.2 – OXIDATIVE DEAROMATIZATION .................................................................... 13 2.2.1 – WESSELEY OXIDATION ...................................................................... 13 2.2.2 – NUCLEOPHILIC ADDITIONS TO O-QUINONE KETALS ............................ 14 2.2.3 – CYCLOADDITION REACTIONS OF O-QUINONE KETALS ......................... 17 2.2.4 – STEREOSPECIFIC OXIDATIVE DEAROMATIZATION OF PHENOLS ........... 24 2.2.5 – TANDEM OXIDATIVE DEAROMATIZATION/DIELS-ALDER REACTION IN NATURAL PRODUCTS SYNTHESIS ....................................................... 27 2.3 – DEHYDROAMINO ACIDS AS DIENOPHILES IN DIELS-ALDER REACTIONS ......... 31 2.4 – INTRAMOLECULAR DIELS-ALDER APPROACHES TO LYCOPLADINE H .............. 37 2.4.1 – NITRILE–BASED INTRAMOLECULAR APPROACHES TO THE LYCOPLADINE H CORE ........................................................................... 37 2.4.2 – ACID- AND ESTER-BASED APPROACHES TO THE LYCOPLADINE H CORE ..................................................................................................... 40 2.5 – INTERMOLECULAR DIELS-ALDER APPROACHES TO LYCOPLADINE H .............. 45 2.5.1 – REVISED RETROSYNTHETIC ANALYSIS ................................................ 45 2.5.2 – MODEL STUDY WITH CREOSOL .......................................................... 47 2.5.3 – REACTIONS OF 2-METHOXY-5-METHYLPHENOL AND RELATED SYSTEMS ................................................................................................ 49 2.5.4 – A MORE CONVERGENT STRATEGY VIA A HENRY REACTION OF AN ALKYL ALDEHYDES .................................................................................. 57 2.5.5 – RETURN TO A FORMALDEHYDE-BASED APPROACH .............................. 66 2.6 – STUDIES ON THE FORMATION OF THE AZOCANE RING ................................... 73 2.6.1 – ATTEMPTED SAMARIUM DIIODIDE BARBIER ROUTE ............................ 73 2.6.2 – ATTEMPTED RING-CLOSING METATHESIS APPROACH TO AZOCANE ..... 81 v 2.6.3 – AZOCANE FORMATION VIA HYDROAMINOMETHYLATION ..................... 85 2.6.3.1 – HYDROAMINOMETHYLATION ................................................... 85 2.6.3.2 – INTRAMOLECULAR HYDROAMINOMETHYLATION AND RELATED REACTIONS ...................................................................... 90 2.6.3.3 – APPLICATION TO AZOCANE FORMATION ................................... 95 2.7 – EFFORTS TOWARD THE FORMATION OF THE LYCOPLADINE H 3-PIPERIDONE RING ............................................................................................................. 98 2.8 – CURRENT AND FUTURE WORK ..................................................................... 102 2.8.1 – CURRENT PROGRESS BY P. CHAUHAN ................................................. 102 2.8.2 – FUTURE STRATEGY FOR THE SYNTHESIS OF LYCOPLADINE H ............... 107 2.9 – CONCLUSION ............................................................................................... 109 CHAPTER 3 – EXPERIMENTAL PROCEDURES ................................................................. 111 3.1 – GENERAL METHODS .................................................................................... 111 3.2 – EXPERIMENTAL PROCEDURES AND ANALYTICAL DATA .................................. 112 REFERENCES ............................................................................................................... 180 APPENDIX: LIST OF ABBREVIATIONS ............................................................................. 191 vi LIST OF FIGURES Figure 1-1: The Classes of Lycopodium Alkaloids ....................................................... 1 Figure 1-2: Phlegmarine (4) from Coniine (5) ........................................................... 2 Figure 1-3: Lycopladines A–G .................................................................................... 4 Figure 1-4: Lycopladine H .......................................................................................... 5 Figure 1-5: COSY and Selected NOESY Correlations and 3D Stick Model of Lycopladine H ..................................................................................................... 6 Figure 2-1: Orbital Interactions in o-Quinone Ketal Dimerization ............................. 19 Figure 2-2: o-Quinone Ketal Substituents .................................................................. 20 Figure 2-3: Orbital Diagrams for the Diels Alder Reaction of Cyclopentadiene and Dehydroamino Acids .......................................................................................... 34 Figure 2-4: Endo/Exo Selectivity in the Desired Lycopladine H Synthesis ................. 36 Figure 2-5: ORTEP Structures of Diels-Alder Adduct 195 (a) and Henry Product 196 (b) ................................................................................................................ 49 Figure 2-6: ORTEP Structure of Henry Product 204 ................................................. 54 Figure 2-7: ORTEP Structure of Hydrogenation Product 205 ................................... 56 Figure 2-8: ORTEP Structure of Nitro Alcohol 225 ................................................... 65 Figure 2-9: Ball-and-Stick and Space Filling Models of Nitro Ketone 205 ................. 104 vii LIST OF TABLES Table 2-1: Diels-Alder of Dehydroamino Acid Derivatives with Cyclopentadiene ...... 33 Table 2-2: Attempted Henry Reactions with Nitro Ketone 203 .................................. 63 Table 2-3: Attempted Henry Reaction with Nitro Alcohols 225 and 226 ................... 66 Table 2-4: Attempted Reduction of Nitro Diol 228 .................................................... 70 Table 2-5: Attempted Reduction of Nitro Diesters 229a and 229b ............................ 72 Table 2-6: Ligand Effects in Rhodium-Catalyzed Hydroaminomethylation ............... 89 Table 2-7: Optimization of Hydroaminomethylation of Amine 272 ........................... 98 viii ACKNOWLEDGEMENTS I would like to thank Professor Steven M. Weinreb for his direction and advice; his insights have been valuable to both my projects and to my understanding of chemistry. I would also like to thank Dr. Raymond Funk, Dr. Gong Chen, and Dr. Ryan Elias for their service as members on my committee. The Weinreb group members, both past and present, deserve great recognition for their guidance, discussions, and support. They have
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