Gold-Catalyzed Synthesis of Heterocycles from Alkynyl Ethers. Synthesis of Leucascandrolide A. Mechanistic Analysis of Oxidative C–H Cleavages using Inter- and Intramolecular Kinetic Isotope Effects. by Hyung Hoon Jung B.S., Kyungwon University, 1998 M.S., Hanyang University, 2000 Submitted to the Graduate Faculty of The Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2012 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Hyung Hoon Jung It was defended on December 09, 2011 and approved by Dr. Paul E. Floreancig, Professor, Department of Chemistry Dr. Kay M. Brummond, Professor, Department of Chemistry Dr. Toby M. Chapman, Associate Professor, Department of Chemistry Dr. Billy W. Day, Professor, Department of Pharmaceutical Sciences Dissertation Director: Dr. Paul E. Floreancig, Professor, Department of Chemistry ii Copyright© by Hyung Hoon Jung 2012 iii ABSTRACT Gold-Catalyzed Synthesis of Heterocycles from Alkynyl Ethers. Synthesis of Leucascandrolide A. Mechanistic Analysis of Oxidative C–H Cleavages using Inter- and Intramolecular Kinetic Isotope Effects. Hyung Hoon Jung, PhD University of Pittsburgh, 2012 Gold complexes catalyze the cyclyzation of homopropargylic ethers to prepare saturated hetercyclic ketones through a sequence of alkyne hydration, alkoxy elimination, and intramolecular conjugate addition of pendant oxygen or nitrogen nucleophiles. This reaction was used in an efficient total synthesis of the natural product andrachcinidine. Regioselective hydration of internal alkynes on propargylic ethers rather than homopropargylic ethers expanded the scope of products. Leucascandrolide A was synthesized through an Electron Transfer- Initiated Cyclization (ETIC) reaction as a key step. The reaction sequence also had highlights as stereoselective BiBr3-mediated allylation, acetal formation as a fragment-coupling reaction, and a rhenium-mediated allylic alcohol transposition leading to stable macrolactol formation. Intra- and intermolecular kinetic isotope effects of oxidative carbon-hydrogen bond cleavage in DDQ- mediated cyclization reations were also explored. The carbon-hydrogen cleavage is rate determining and that a radical cation is most likely a key intermediate in the reaction mechanism. iv TABLE OF CONTENTS 1.0 Gold-Catalyzed Synthesis of Heterocycles from Alkynyl Ethers: Application to the Total Synthesis of Andrachcinidine ............................................................. 1 1.1 Introduction ...................................................................................................................... 1 1.1.1 General ...................................................................................................................... 1 1.1.2 Gold catalysis in activation of alkynes and alkenes .............................................. 2 1.1.3 Controversy between Brønsted acid and transition metal catalysts ................... 5 1.1.4 Summary ................................................................................................................... 8 1.1.5 Goals and objectives ................................................................................................ 8 1.2 Results and Discussion .................................................................................................... 9 1.2.1 Oxygen-containing heterocycle synthesis .............................................................. 9 1.2.2 Nitrogen-containing heterocycle synthesis ........................................................... 23 1.2.3 Total synthesis of (+)-andrachcinidine ................................................................. 30 1.2.4 Reaction with internal alkynes ............................................................................. 35 1.3 Conclusions ..................................................................................................................... 37 1.4 Experimental .................................................................................................................. 38 1.5 References ....................................................................................................................... 90 v 2.0 Synthesis of Leucascandrolide A ......................................................................................... 98 2.1 Introduction .................................................................................................................... 98 2.1.1 Isolation ................................................................................................................... 98 2.1.2 Biological Activity .................................................................................................. 99 2.1.3 Structure ............................................................................................................... 100 2.1.4 Previous Syntheses ............................................................................................... 101 2.1.5 Electron-Transfer-Initiated Cyclization (ETIC) ................................................110 2.1.6 Retrosynthesis ....................................................................................................... 111 2.2 Results and Discussion ................................................................................................. 113 2.3 Conclusion .................................................................................................................... 125 2.4 Experimental ................................................................................................................ 126 2.5 References ..................................................................................................................... 143 3.0 Mechanistic Analysis of Oxidative C–H Cleavages using Inter- and Intramolecular Kinetic Isotope Effects....................................................... 152 3.1 Introduction .................................................................................................................. 152 3.2 Results and Discussion ................................................................................................ 153 3.2.1 Background .......................................................................................................... 153 3.2.2 Substrate design and synthesis ........................................................................... 156 3.2.3 Isotope effect determination ................................................................................ 159 vi 3.2.4 Discussion ............................................................................................................. 160 3.3 Summary ...................................................................................................................... 164 3.4 Experimental ................................................................................................................ 166 3.5 References ..................................................................................................................... 188 APPENDIX A ............................................................................................................................ 192 Gold-Catalyzed Synthesis of Heterocycles from Alkynyl Ethers: Application to the Total Synthesis of Andrachcinidine (Supporting Information 1H and 13C NMR Spectra) APPENDIX B ............................................................................................................................ 274 Synthesis of Leucascandrolide A (Supporting Information 1H and 13C NMR Spectra) APPENDIX C ............................................................................................................................ 306 Mechanistic Analysis of Oxidative C–H Cleavages using Inter- and Intramolecular Kinetic Isotope Effects. (Supporting Information 1H and 13C NMR Spectra) vii LIST OF TABLES Table 1. Optimizing reaction condition with Au(I). ......................................................................11 Table 2. Optimizing reaction conditions with Au(III). ................................................................. 12 Table 3. Reaction scope of oxygen-containing heterocycle syntheses. ........................................ 18 Table 4. Further optimization of reaction condition. .................................................................... 27 Table 5. Reaction scope of nitrogen-containing heterocycle syntheses. ...................................... 28 Table 6. Gas chromatographic conditions. ................................................................................... 40 Table 7. Quantification of compound. .......................................................................................... 41 viii LIST OF FIGURES Figure 1. Proposed gold-mediated cyclization. ............................................................................ 21 Figure 2. Biphenyl phosphine ...................................................................................................... 27 Figure 3. Andrachcinidine. ........................................................................................................... 30 Figure 4. Calibration curve for compound. .................................................................................. 40 Figure 5. Structure of leucascandrolide A (1). ............................................................................. 98 Figure 6. Proposed ETIC