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Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione

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Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione by Vanessa M. Marx Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia May 2011 © Copyright by Vanessa M. Marx, 2011 DALHOUSIE UNIVERSITY DEPARTMENT OF CHEMISTRY The undersigned hereby certify that they have read and recommend to the Faculty of Graduate Studies for acceptance a thesis entitled “Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione” by Vanessa M. Marx in partial fulfilment of the requirements for the degree of Doctor of Philosophy. Dated: May 19, 2011 Supervisor: _________________________________ Readers: _________________________________ _________________________________ _________________________________ Departmental Representative: _________________________________ ii DALHOUSIE UNIVERSITY DATE: May 19, 2011 AUTHOR: Vanessa M. Marx TITLE: Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione DEPARTMENT OR SCHOOL: Department of Chemistry DEGREE: PhD CONVOCATION: October YEAR: 2011 Permission is herewith granted to Dalhousie University to circulate and to have copied for non-commercial purposes, at its discretion, the above title upon the request of individuals or institutions. I understand that my thesis will be electronically available to the public. The author reserves other publication rights, and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author’s written permission. The author attests that permission has been obtained for the use of any copyrighted material appearing in the thesis (other than the brief excerpts requiring only proper acknowledgement in scholarly writing), and that all such use is clearly acknowledged. _______________________________ Signature of Author iii There is no such thing as failure - only success and learning experiences. iv Table of Contents List of Figures .................................................................................................................. viii List of Schemes ................................................................................................................... ix List of Tables ................................................................................................................... xiii Abstract ............................................................................................................................. xiv List of Abbreviations and Symbols Used .......................................................................... xv Acknowledgements ........................................................................................................... xix CHAPTER 1. Introduction................................................................................................... 1 1.1 New Reaction Discovery ...................................................................................... 1 1.2 Pericyclic Reactions ............................................................................................. 2 1.3 The Nazarov Reaction ......................................................................................... 3 1.3.1 Stereoselectivity in the Nazarov Reaction .......................................................... 4 1.3.2 Regioselectivity in the Nazarov Reaction ........................................................... 6 1.3.3 Steric Influence of Į-Substitutents in the Nazarov Reaction .............................. 7 1.4 The Polarized Nazarov Reaction ........................................................................ 8 1.5 The Interrupted Nazarov Reaction .................................................................. 10 1.6 The Nazarov Reaction of Allenyl Vinyl Ketones ............................................. 11 1.7 Synthetic Applications of the Nazarov Reaction ............................................. 14 1.7.1 Use of the "Normal" Nazarov Reaction in Synthesis ....................................... 14 1.7.2 Use of the Polarized Nazarov Reaction in Synthesis ........................................ 15 1.7.3 Use of the Nazarov Cyclization of Allenyl Ethers in Synthesis ....................... 16 1.8 Proposed Exploitation of Allenyl Vinyl Ketones in Interrupted Nazarov Reactions ....................................................................................................................... 17 CHAPTER 2. Synthesis of Allenyl Vinyl Ketones ........................................................... 19 2.1 Introduction ........................................................................................................ 19 2.2 Allenyl Vinyl Ketone Synthesis ......................................................................... 21 2.3 Summary ............................................................................................................. 26 2.4 Experimental Section ......................................................................................... 27 2.4.1 General Considerations ..................................................................................... 27 2.4.2 Preparation and Characterization Data ............................................................. 28 v CHAPTER 3. The Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones with Heteroatom Nucleophiles ................................................................................................... 44 3.1 Introduction ........................................................................................................ 44 3.2 Initial Screening Conditions for Interrupted Nazarov Cyclizations ............. 44 3.3 Scope of TFA-Mediated Interrupted Nazarov Cyclizations .......................... 47 3.4 Reactivity of AVKs of Type 2 and Type 3 in the Absence of Nucleophilic Species ................................................................................................................. 49 3.5 Mechanistic Rationale for Reactivity Differences of AVKs of Type 1, Type 2, and Type 3 ....................................................................................................... 51 3.6 Screening of Other Lewis Acids for the Interrupted Nazarov Cyclization .. 53 3.7 Scope of Indium-Mediated Interrupted Nazarov Cyclizations ..................... 54 3.8 Scope of Titanium-Mediated Interrupted Nazarov Cyclizations .................. 57 3.9 Synthesis of Doubly-Functionalized Cyclopent-2-enones via the Initial Addition of Bromine or Iodine .......................................................................... 58 3.10 Summary ............................................................................................................. 62 3.11 Experimental Section ......................................................................................... 63 3.11.1 General Considerations ................................................................................... 63 3.11.2 Preparation and Charaterization Data ............................................................. 65 CHAPTER 4. The Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones with Carbon-Carbon Bond Formation ....................................................................................... 95 4.1 Introduction ........................................................................................................ 95 4.2 Synthesis of Bicyclic Ketones by Reaction with Substituted Butadiene Derivatives .......................................................................................................... 97 4.3 Synthesis of Bicyclic Ketones and/or Cyclopent-2-enones by Reaction with Activated Alkenes .................................................................................... 102 4.4 Synthesis of Functionalized Cyclo-pent-2-enones by Reaction with Cyclic Dienes ..................................................................................................... 108 4.5 Mechanistic Rationale for the Observed Regio- and Stereoselectivity in Interrupted Nazarov Reactions of Allenyl Vinyl Ketones ............................ 115 4.5.1 Implications of Regioselectivity of Interrupted Nazarov Reactions of AVKs with Cyclic Dienes ........................................................................................ 116 4.5.2 Computational Investigation of the Oxyallyl Cationic Intermediate .............. 117 4.5.3 Implications of Regioselectivity of Interrupted Nazarov Reactions of AVKs with Butadiene Derivatives ........................................................................... 119 vi 4.5.4 Implications of Stereoselectivity of Interrupted Nazarov Reactions of AVKs with Butadiene Derivatives .......................................................................... 119 4.5.5 Implications of Stereoselectivity of Interrupted Nazarov Reactions of AVKs with 1,3-Cyclohexadiene and (Z)-Ethylpropenylether ................................. 122 4.6 Summary ........................................................................................................... 123 4.7 Experimental Section ....................................................................................... 124 4.7.1 General Considerations ..................................................................................
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