EXPLORATORY STUDY OF IONOPHORIC SPIROETHERS AND SPIROKETALS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Peter Rajan Selvaraj ***** The Ohio State University 2006 Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor Professor Christopher M. Hadad _________________________________ Professor Jon Parquette Advisor Graduate Program in Chemistry ABSTRACT Abstract Bipolar disorder, also known as manic-depressive illness, is a brain disorder that can be treated, and people with this illness can be treated successfully with lithium salts. Lithium ionophores can be used to construct a Li+ ion selective electrode, which can in turn be used for effective monitoring of lithium levels in blood. Lithium ionophores synthesized previously in the group employing tetrahydrofuran units have been found to be good lithium ion specific ionophores. However, there have been problems with the solubility of these complexes. Consequently, two new molecules were designed by introducing oxygen atoms at strategic positions to enhance the solubility of the complexes formed with lithium. Methods to synthesize these compounds have been explored and described. The area of biphasic complexation has also been explored by synthesizing compounds with hydroxyethyl and alkoxyethyl side chains as ligating sites for metal ions. Desired compounds were synthesized starting from inositol in short and efficient routes. Complexation studies were performed in the solution phase and gas phase using picrate extraction studies and mass spec, respectively. En route to the synthesis of spiroether lithium ionophores some interesting properties were discovered. Cyclohexanones with spiroether units in the α and β position were found to equilibrate. Corresponding cyclopentanones were also found to exhibit this ii behavior. Influence of ring size of the equilibrium was investigated by synthesizing cyclopentanones containing a combination of five and six membered spiroether functionality. Oxonium ion-initiated pinacolic ring expansion reaction has been previously reported by our group. This discovery, which constitutes an extension of the long established Wagner-Meerwin and pinacol rearrangements, takes advantage of the fact that ketone adducts of metalated vinyl ethers are amenable to conversion to oxonium ions under acid-catalyzed conditions. This results in a diastereoselective ring expansion and spiroketone formation. Our next advance into spirocyclic chemistry involves application of pinacolic ring expansion methodology in the synthesis of 1,6-dioxaspiro[4.5]decane frameworks. Subsequent transformations result in the conversion of spiroketones formed to spiroketal frameworks. AL-2 and lissoketal are two naturally occurring spiroketals. Efforts were made to apply the pinacol ring expansion methodology in the synthesis of AL-2 and lissoketal. In order to arrive at 6.12, homologation was attempted to no avail via displacement of iodide 6.11 and ring opening of epoxides 6.6 and 6.7 utilizing various methods. Attention was then focused on initiating the synthesis with the desired chain length in place. Synthesis of lactone 6.8 was investigated and resolved. With an efficient synthesis of 6.19 in hand, attention was focused on alkylation at C3 position. However, alkylation was thwarted. The final approach has given rise to a strategy that involves construction of the unsaturated pyran ring from known spiroketal 6.26 and has allowed for the synthesis of Olefin 6.31. With Olefin 6.31 in hand, synthesis of lissoketal might be realized through more transformations. iii Dedication Dedicated to my parents iv ACKNOWLEDGMENTS Acknowledgments I wish to express my sincere gratitude and respect to my advisor, Dr. Leo A. Paquette, for his guidance and encouragement during my stay at The Ohio State University. Without his dedication, much of the research discussed in the dissertation would not have possible. I wish to thank Dr. Hadad and Dr. Parquette for serving on my dissertation committee. I also thank Rebecca Martin and Donna Rothe for their invaluable assistance to our research group. I would like to thank all the Paquette group members for their help and support. I would like to thank my lab mates Dr. Jiyoung Chang, Zhenjiao Tian, Dr. Adam Preston, and Dr. Marshall Stepanian for their companionship and help. In particular, I am thankful to Dr. Matthew Kreilein and Dr. Amy Hart for being excellent colleagues and helping proof read my thesis and proposal. I would like to thank Shaalon Joules for being my true friend and a part of my life for the last couple of years. Life would not have been so great without her support and understanding. I would also like to thank Mr. Leo Solomon, Mr. Kutralanathan, Mr. Karthik Venkatachalam, Dr. Mike Chang and Mr. Amresh Maadhava Raao for their friendship during my stay at The Ohio State University. This section would not be complete without thanking my parents and family. Whatever I am today is all because of your love and sacrifices. Thank you for giving me v this opportunity. Finally, I thank God for guiding and blessing me to accomplish this in the year of 2006. vi VITA Vita June 30, 1976 ..................................................... Born – Madras, India September 1999 ................................................. M.Sc. Indian Institute of Technology Madras, India September 2001 ................................................. M.S. Eastern Michigan University, Michigan 2001 – 2006........................................................ Graduate Teaching/Research Asst. The Ohio State University. PUBLICATIONS Research Publications 1. Paquette, L. A.; Hilmey, D. G.; Selvaraj, P. R., Direct access to heteropolycyclic spiroketones. 1,3-dichloroacetone as a cyclopropanone equivalent. Heterocycles 2005, 66, 57-60. 2. Paquette, L. A.; Selvaraj, P. R.; Keller, K. A.; Brodbelt, J. S., Is potential coordination of alkali metal ions to stereodefined polyoxygenated cyclohexanes an adequate driving force for fostering the adoption of axial conformers? Tetrahedron 2005, 61, (1), 231-240. 3. Hilmey, D.G.; Selvaraj, P.R.; Paquette, L.A. “Synthesis and Lewis Acid-Induced Isomerization of Mono-, Di-, and Trispiro α-Keto Tetrahydrofurans and –Pyrans” Can. J. Chem. Accepted for publication. 4. Chang, S.-K.; Selvaraj, P. “Copper(II) Hexafluoroantimonate” Electronic Encyclopedia of Reagents for Organic Synthesis, 2005, John Wiley and Sons. FIELDS OF STUDY Major Field: Chemistry vii TABLE OF CONTENTS Page Abstract...............................................................................................................................ii Dedication.......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita....................................................................................................................................vii List of Schemes.................................................................................................................. xi List of Tables ................................................................................................................... xiv List of Figures................................................................................................................... xv List of Abbreviations ......................................................................................................xvii Chapters: 1. Introduction .......................................................................................................... 1 1.1 Background ................................................................................................... 1 1.2 General structural features of ionophores ..................................................... 3 1.3 Naturally occurring polyether ionophores..................................................... 5 1.4 Applications of ionophores ........................................................................... 9 2. Efforts directed toward the multiple spiroketalization of cyclohexane.............. 16 2.1 Background ................................................................................................. 16 2.2 Efforts towards the synthesis of the 1,3,5-trispiro system 2.3 .................... 18 2.2.1 First generation synthesis ................................................................. 18 viii 2.2.2 Second generation synthesis............................................................. 21 2.2.3 Third generation synthesis................................................................ 25 2.3 Efforts towards the synthesis of the hexaspiro system 2.4.......................... 27 2.3.1 First generation synthesis ................................................................. 27 2.3.2 Second generation synthesis............................................................. 28 2.3.3 Third generation synthesis................................................................ 29 2.4 Conclusion................................................................................................... 33 3. Stereodefined polyoxygenated cyclohexanes as possible ionophores................ 34 3.1 Background ................................................................................................. 34 3.2 Synthesis of the polyoxygenated