PART 1: STUDY TOWARD THE TOTAL SYNTHESIS OF ACUTUMINE PART 2: ASYMMETRIC INTRAMOLECULAR HYDROAMINATION CATALYZED BY GROUP 3 METAL COMPLEXES by Khoi Quang Huynh A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry MONTANA STATE UNIVERSITY Bozeman, Montana October 2014 ©COPYRIGHT by Khoi Quang Huynh 2014 All Rights Reserved ii ACKNOWLEDGEMENTS I would like to express my gratitude and sincere appreciation to Professor Tom Livnghouse for his advice, assistance, and encouragement. His insight and creative thinking and enthusiasm to chemistry have inspired me. I would like to thank Professor Trevor Rainey for his generous advice and discussion. I am also grateful for the degree of independence, which he has allowed me to learn chemistry. To the members of my committee: Professor Paul Grieco, Mary Cloninger, Martin Teinzte, Stephanie Wettstein, I want to extend my appreciation for the time, effort, and valuable instructions I received in your courses. iii TABLE OF CONTENTS 1. ACUTUMINE INTRODUCTION ..................................................................................1 Background ......................................................................................................................1 Discovery .........................................................................................................................2 Biological Activity of Acutumine ....................................................................................3 Biosynthesis .....................................................................................................................4 Previous Total Synthesis ..................................................................................................7 Sorensen’s Strategy ..................................................................................................7 Castle’s Total Synthesis ...........................................................................................8 Herzon’s Total Synthesis .........................................................................................9 2. STUDY OF ETHYL ACETATE INDUCED PdII/IV CATALYZED SEMI-PINACOL REACTION FOR SPIROCYCLIC CORE OF ACUTUMINE ...................................................................12 Introduction ....................................................................................................................12 Background: Precedence of the Semi-Pinacol Reaction ................................................13 Semi Pinacol Rearrangement .................................................................................13 Rearrangement of Allylic Alcohol .............................................................14 Induced by Lewis Acid ..............................................................................15 Palladium II/IV Catalysis ...............................................................................................15 General Mechanistic Pd Catalytic Cycles of Cross Coupling Reactions ...............15 High-Valent Organometallic Palladium (PdII PdIV) Catalysis ..........................17 The Proposed Pd II/IV Semi-Pinacol Reaction .............................................................18 Synthesis of Dimethoxy-Indenyl Cyclobutanol .............................................................19 Synthesis of Indenyl Cyclobutanol ................................................................................21 Ethyl Acetate Induced Semi-Pinacol Reaction ..............................................................21 Recent Developed Semi-Pinacol Reactions Induced by Brønsted and Lewis Acids .............................................................................................25 3. PROGRESS TOWARD THE CONSTRUCTION OF THE TRICYCLIC CORE IN THE TOTAL SYNTHESIS OF ACUTUMINE ...........................................................................................................26 Retrosynthesis ................................................................................................................26 Key Steps and Precedence: Asymmetric Aldol Condensation ......................................27 Synthesis of Model Substrate Indene Dione ..................................................................28 Strategy for Tricyclic Ring Formation ...........................................................................28 Conclusion .....................................................................................................................30 iv TABLE OF CONTENTS – CONTINUED 4. HYDROAMINATION INTRODUCTION ...................................................................32 General Background ......................................................................................................32 Group III Metals: Lanthanide ................................................................................33 Mechanism of Intramolecular Hydroamination of Alkenes ..................................33 The First Group III Catalyzed Hydroamination .....................................................34 Asymmetric Hydroamination.........................................................................................37 First Lanthanide-Catalyzed Asymmetric Hydroamination ....................................37 Livinghouse Asymmetric Hydroamination from Bis-(thiolate) Complexes .........38 Hultzsch’s Asymmetric Hydroamination ..............................................................39 Development of New Hydroamination Catalyst System .......................................40 Substrate Scope Investigation ................................................................................42 Proposed Stereo-Chemical Model .........................................................................43 Synthesis of Aminoalkene Substrates ............................................................................44 5. SUBSTRATE STRUCTURAL EFFECT IN YTTRIUM(III)-CATALYZED HYDROAMINATION/ CYCLIZATION OF 1,2-DISUBSTITUTED AND 1,1,2-TRISUBSTITUTED AMINOALKENES TERMINATED BY 2-(2-HETEROARENYL) GROUPS ............................................46 Contribution of Authors and Co-Authors ......................................................................46 Manuscript Information Page ........................................................................................47 Abstract ..........................................................................................................................48 Introduction ....................................................................................................................48 Catalytic Hydroamination and Mechanistic Studies Involving Aminoalkenes Terminated by the 2-(phenyl)ethenyl Group .........................................49 Catalytic Hydroamination 1,2-Disubstituted and 1,1,2-Trisubstituted Aminoalkenes Terminated by 2-(2-Heteroarenyl) Groups ............................................53 6. N,N’-DIBENZOSUBERYL-1,1’-BINAPHTHYL-2,2’ -DIAMINE. A HIGHLY EFFECTIVE SUPPORTING LIGAND FOR THE ENANTIOSELECTIVE CYCLIZATION OF AMINOALKENES CATALYZED BY CHELATING DIAMIDE COMPLEXES OF LA(III) AND Y(III) ......................................................56 Contribution of Authors and Co-Authors ......................................................................56 Manuscript Information Page ........................................................................................57 Abstract ..........................................................................................................................58 Introduction ....................................................................................................................58 Catalyst Preparation .......................................................................................................59 v TABLE OF CONTENTS – CONTINUED Enantioselective Hydroamination/Cyclization Studies ...................................................60 Conclusion ......................................................................................................................65 7 HIGHLY ENANTIOSELECTIVE INTRAMOLEULAR HYDORAMINATION/CYCLIZATION OF AMINOALKENES CATALYZED BY TETRAAMIDE ANIONIC COMPLEXES OF LA(III) AND Y(III) ..................................................................................................66 Introduction ....................................................................................................................66 Catalyst Preparation .......................................................................................................66 Enantioselective Hydroamination/Cyclization Studies ..................................................68 8. CONCLUSIONS............................................................................................................75 9. EXPERIMENTAL SUPPORTING INFORMATION ..................................................77 REFERENCES ..................................................................................................................98 APPENDICES .................................................................................................................108 APPENDIX A: Substrate Structural Effect in Yttrium(III)-Catalyzed Hydroamination/Cyclization of 1,2-Disubstituted and 1, 1, 2 Trisubstituted Aminoalkenes Terminated by 2-(2- Heteroarenyl) Groups.................................................................109 APPENDIX B: N,N’-Dibenzosuberyl-1, 1’- Binaphthyl-2, 2’ – Diamine. A Highly Effective