IRON CARBONYL MEDIATED CYCLIZATIONS AND THEIR POTENTIAL APPLICATION IN SYNTHESIS by Xiaolong Wang Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Dr. Anthony J. Pearson Department of Chemistry CASE WESTERN RESERVE UNIVERSITY January 2005 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Dedicated to my wife and son. ii TABLE OF CONTENTS Table of Contents………………………………………………………………...….……iii List of Equations………………………………………………………………………......v List of Schemes……………………………………………………………………….......vi List of Tables…………………………………………………………………..…………ix List of Figures…………………………………………………………………..………....x Acknowledgements……………………………………………………………………….xi List of Abbreviations………………………………..……..……………………………xiv Abstract……………………………………………………………………………………ii CHAPTER 1. Background: Introduction to Iron Carbonyls and Diene-Fe(CO)3 ......1 1.1 Iron Carbonyl Complexes. General Introduction, Mechanism Studies, and Preparation of Diene-Fe(CO)3 Complexes………………………………..………………..……....2 1.1.1 Isomerization of Double Bonds by Fe(CO)5..…………………...…..…………..2 1.1.2 Preparation of Some Representative Diene-Fe(CO)3 Complexes…………...….4 1.2 Cyclic Cationic Dienyl Iron Carbonyl Complexes and Their Applications….…….....6 1.3 Diene-Fe(CO)3/Olefin Ene-Cyclization……………………………………………...12 1.4 Literature Cited……………………………………………………………….….…..20 CHAPTER 2. Formation of Six-membered Sporolactams……….….…..…………..25 2.1 Preparation of 6-Membered Spirolactams……………………………………….…..26 2.2 Conclusions…………………………………………………………………………..31 2.3 Experimental Section……………………………………………………….…….….32 2.4 Literature Cited……………………………………………………………….….…..47 iii CHAPTER 3. Double Cyclization…………….……………….....…………………....49 3.1 Double Cyclization….……………………………………………………………….50 3.2 Conclusions…………………………………………………………………………..61 3.3 Experimental Section……………………………………………………….…….….62 3.4 Literature Cited……………………………………………………………….….…..75 CHAPTER 4. Bicyclization………..………….……………….....……….…………....77 4.1 Preparation of Bicyclic Molecules by Rearrangement-Cyclization Procedure…..….78 4.2 One-Pot Cyclization………………………………………………………………….83 4.3 Conclusions…………………………………………………………………………..90 4.4 Experimental Section……………………………………………………….…….….91 4.5 Literature Cited…………………………………………………...………….….….117 CHAPTER 5. Formation of All-carbon Spirocycles……...….....……….…………..119 5.1 Preparation of All-Carbon Spirocycles…………………………………..…………120 5.2 Conclusions…………………………………………………………………………131 5.3 Experimental Section……………………………………………………….………132 5.4 Literature Cited……………………………………………………...………..…….146 CHAPTER 6. Diastereoselective Spirocyclization: Studies toward Kinetic Dynamic Resolution during the Intramolecular Diene-Fe(CO)3/Olefin Coupling…….….....148 6.1 Diastereoselective Cyclization…………………………………….……..…………149 6.2 Conclusions…………………………………………………………………………159 6.3 Experimental Section……………………………………………………….………161 6.4 Literature Cited……………………………………………………...………..…….177 BIBLIOGRAPHY……………………………………..……………………………....178 iv LIST OF EQUATIONS Equation 1.1………………………………………………………………………………2 Equation 1.2………………………………………………………………………………2 Equation 1.3………………………………………………………………………………2 Equation 1.4………………………………………………………………………………2 Equation 1.5………………………………………………………………………………2 Equation 1.6………………………………………………………………………………2 Equation 1.7……………………………………………………………………………..12 Equation 3.1……………………………………………………………………………...51 Equation 3.2...…………………………………………………………………….….…..56 Equation 3.3……………………………………………………………………….……..61 Equation 4.1…...…………………………………………………………………………78 Equation 4.2...……………………………………………………………………………86 Equation 5.1...……………………………………………………………………….….122 v LIST OF SCHEMES Scheme 1.1 …………………………………………………….………………………2 Scheme 1.2 …………………………………………………….………………………3 Scheme 1.3 Preparation of Diene-Fe(CO)3 Complexes ………….……………………4 Scheme 1.4 ……………………………………………………….….………………...6 Scheme 1.5 ……………………………………………………….….……….…..……7 Scheme 1.6 Synthesis of Trichodermol Using Organoiron Chemistry ….…..…….…..9 Scheme 1.7 Unsuccessful Hydride Abstraction from p-Anisic Acid Derivatives ...….11 Scheme 1.8 Intramolecular Coupling of Olefin with Diene- Fe(CO)3 Moiety …..…..13 Scheme 1.9 Proposed Mechanism of the Spirocyclization ………….………...……...16 Scheme 1.10 ………………………………………………………….…….…………..17 Scheme 1.11 Racemization due to Precyclization Rearrangement ……………………18 Scheme 1.12 ……………………………………………………………………………18 Scheme 2.1 Proposed Mechanism for Double Cyclization …………………………..29 Scheme 2.2 ……………………………………………......…………………….…….30 Scheme 2.3 …………………………………………………………………...……….31 Scheme 3.1 …………………...……………………………………………………….50 Scheme 3.2 …………………………………….……………………………………...53 Scheme 3.3 ………………………………….………………………………………...57 Scheme 3.4 ………………………………….………………………………………...58 Scheme 3.5 ……………………………………………….…………………………...59 Scheme 3.6 ……………………………………………………………………………60 vi Scheme 4.1 …………………...……………………………………………………….78 Scheme 4.2 …………………………………….……………………………………...82 Scheme 4.3 ………………………………….………………………………………...83 Scheme 4.4 ………………………………….………………………………………...84 Scheme 4.5 ……………………………………………….…………………………...87 Scheme 4.6 Diastereoselective Complexation ………..………………………………88 Scheme 4.7 ……………………………………………………………………………89 Scheme 5.1 All-Carbon Cyclization via Ketone Intermediate ….…………………..120 Scheme 5.2 Proposed Rearrangement-Cyclization …...…………………………….121 Scheme 5.3 Rearrangement-Cyclization ……...…………………………………….123 Scheme 5.4 Regiocontrolled Rearrangement-Cyclization ………………………….124 Scheme 5.5 ……………………………………………….………………………….125 Scheme 5.6 …………………………………………………………………………..126 Scheme 5.7 Diastereoselective Rearrangement-Cyclization ………………………..128 Scheme 5.8 …………………………………………………………………………..129 Scheme 6.1 Proposed Diastereoselective Cyclization ..……………………………..149 Scheme 6.2 Preparation of Dienamines 6.8………………………………………….151 Scheme 6.3 Diastereoselective Cyclization ...……………………………………….152 Scheme 6.4 Stepwise Diastereoselective Double Cyclization ...…………………….153 Scheme 6.5 Retrosynthetic Analysis for 18-Deoxycytochalasin H ………………....154 Scheme 6.6 Preparation of Amine …………………………………………………..156 Scheme 6.7 Kinetic Dynamic Resolution .…………………………………………..157 Scheme 6.8 …………………………………………………………………………..159 vii Scheme 6.9 Proposed Synthesis of Synthon 6.25 toward 18-Deoxycytochalasin H...160 viii LIST OF TABLES Table 1.1 Examples of Nucleophilic Addition to Cyclohexadienyliron Complexes ……………………………………………………………..………………8 Table 2.1 Preparation of N-Butenyl Amide Complexes ……………..…………….27 Table 2.2 Cyclization of 2.2a-f………………………………………..……………28 Table 3.1 Cyclization of Amide Complexes 3.6……………………………………52 Table 3.2 Chemically Induced Cyclization of Amide Complexes 3.6a……………56 Table 4.1 Optimization of Cyclization Conditions for 4.7a………………..………79 Table 4.2 Preparation of Amide 4.7 and Its Cyclization….………………..………80 ix LIST OF FIGURES Figure 1.1 Potential Cation Precursors to Calonectrin and Verrucarol……….……..10 Figure 1.2 Z/E Conformations of Esters (Thioesters)………………………..….......14 Figure 1.3 Orbital Interactions for Esters, Thioesters and Amides……………....….14 Figure 1.4 Conformational Preferences for Amides…………….……………..…....14 Figure 1.5 Comparison of cis vs trans η3-Metallacycle Intermediate……………….16 Figure 2.1 ……………………….…………………………………….……………..26 Figure 3.1 ………………...………………………………………………………….59 Figure 6.1 Intermediates Comparison during Diastereoselective Cyclization……..150 Figure 6.2 Energy Calculation of Intermediates 6.43……………………………...158 x ACKNOWLEDGMENTS I am very grateful to all those who helped make my graduate work at Case an enjoyable experience. I am greatly indebted to Professor Anthony J. Pearson for his patient instruction, guidance, encouragement, and beyond, an example for many to follow. His philosophy, profound understanding about chemistry, and work ethic made these four years an invaluable experience for me. I am fortunate to have him as my advisor. The financial support provided by the National Science Foundation is greatly appreciated. Case Western Reserve University and the Chemistry Department are also acknowledged for giving me the opportunity to study in such a nice environment. I would like to express my thanks to my labmates, past and present, for a very congenial and supportive research group. I am especially grateful to Ismet B. Dorange for teaching me to do Birch reduction, to Sheng Cui for his help of some 2 D NMR experiments, to Avdhoot Velankar, my benchmate, for his helpful discussion about chemistry and life, and to Brian Servé for the discussion about America and the world. I also want to express my gratitude to my parents without whom nothing would have been possible. Above all, I would like to thank my wife for her everyday support. xi LIST OF ABBREVIATIONS Ac acetyl aq aqueous br broad COSY correlation spectroscopy Cp cyclopentadienyl d doublet DIBALH diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EDCI 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide equiv equivalent(s) Et ethyl FTIR Fourier transform infrared GC-MS gas chromatography-mass spectroscopy