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Ann Arbor, M I 48106 STUDIES TOWARD THE SYNTHESIS OF PTILOMYCALIN A ANALOGS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Anne-Laure Grillot The Ohio State University 1 9 9 3 Dissertation Committee: Approved by Dr. David J. Hart Dr. Leo A. Paquette Dr. Viresh H. Rawal Adviser Department of Chemistry To My Parents ACKNOWLEDGEMENTS I wish to thank my adviser, Dr. David J. Hart, for his support, encouragement and guidance throughout my graduate work at the Ohio State University. His enthusiasm for chemistry and his sharing of knowledge were highly motivating, and his nice attitude about life helped to make my stay enjoyable. I would also like to thank Dr. Jean Huet from the Lyon School of Chemistry (France) for providing me with the opportunity to study in the United States. Past and present group members are greatly acknowledged. Special thanks go to Brian Filippini for being such a good labmate, for proofreading this thesis and for providing me with "hints" about America and American people. I also thank Vincent Leroy for encouraging me when the work got tough, and for helpful discussions. Next, I wish to thank Carl Engelman, Dr. Dirk Friedrich and Dr. Charles Cottrell for recording 13C NMR spectra and running other NMR experiments, as well as Dr. David Chang for recording mass spectra. Finally, I wish to acknowledge my friends in Columbus for their help and support. I also wish to express my sincere gratitude to my parents for their emotional and financial support during my undergraduate and graduate studies. VITA September, 13, 1967 .................................................................Bom, LaTronche, France. 1984-1986 ...................................................................................Mathematiques Superieures and Mathematiques Spedales, Lycee Champollion, Grenoble, France. 1986-1988 ....................................................................................Engineer Degree, ESCIL, Lyon, France. 1988-1991 ...................................................................................Teaching Assistant, The Ohio State University, Columbus. 1992-1993 ...................................................................................Research Assistant, The Ohio State University, Columbus. PUBLICATIONS Grillot, A.-L.*; Hart, D. J. "Studies Toward the Synthesis of Ptilomycalin A Analogs", 25th Central Regional Meeting of the American Chemical Society, Pittsburgh, Pa, October 4-6,1993. FIELD OF STUDY Major Reid: Chemistry Studies in Organic Chemistry IV TABLE OF CONTENTS DEDICATION................................................................................................................................... ii ACKNOWLEDGEMENTS...............................................................................................................iii VITA.................................................................................................................................................iv LIST OF FIGURES.........................................................................................................................viii LIST OF SCHEMES........................................................................................................................ ix CHAPTER PAGE I ISOLATION, STRUCTURE DETERMINATION AND BIOLOGICAL ACTIVITY OF PTILOMYCALIN A AND RELATED COMPOUNDS........................................... 1 A. Introduction ..............................................................................................1 B. A New Class ot Biologically Active Marine Alkaloids: Isolation, Biological Activity and Structure Elucidation .........................................1 C. Objectives ................................................................................................7 II A SURVEY OF LITERATURE METHODOLOGIES FOR THE SYNTHESIS OF GUANIDINES..............................................................................................................9 A. General Methods ...................................................................................10 B. Synthesis of Chiral, C 2 Symmetric Bicyclic Guanidines ...................... 21 C. Synthesis of Guanidine-Containing Natural Products .........................26 III SYNTHESIS OF THE AMIDO-ALCOHOL PORTION OF PTILOMYCALIN ...........A 35 A. Retrosynthetic Analysis .35 B. Synthesis of the Amido-Alcohol Portion of Ptilomycalin A ................. 35 C. Synthesis of Acetate 7 ........................................................................40 IV SYNTHESIS OF A SIMPLE STRUCTURAL ANALOG OF PTILOMYCALIN .........A 42 A. Introduction ...........................................................................................42 B. Attempted Synthesis of Guanidine 177 via an Intermediate Monocyclic Guanidine ........................................................................... 42 C. Attempted Synthesis of Guanidine 177 via an Intermediate Monocyclic Urea .................................................................................... 46 D. Attempted Synthesis of Guanidine 177 via an Intermediate Acyclic Triamine ..................................................................................... 56 E. Synthesis of Guanidine 177 via an Intermediate Acyclic Triamine 59 F. Synthesis of Ptilomycalin A Analog 14 ............................................... 64 V STUDIES TOWARD THE SYNTHESIS OF A TRICYCLIC STRUCTURAL ANALOG OF PTILOMYCALIN A............................................................................ 70 A. Retrosynthetic Analysis ...................................................................... 70 B. Synthesis of a Thiolactam of Type 281 .............................................. 72 C. Sulfide Contraction .............................................................................. 74 D. One-Carbon Homologation ................................................................. 78 E. Attempted Double Bond Reduction .................................................. 79 VI STUDIES TOWARD THE SYNTHESIS OF A PENTACYCLIC STRUCTURAL ANALOG OF PTILOMYCALIN A............................................................................ 83 A. Retrosynthetic Analysis ...................................................................... 83 B. Synthesis of a Vinylogous Amide of Type 320 .................................. 84 C. Double Bond Reduction and Stereochemistry Determination ...........93 D. Studies Toward the Synthesis of a Compound of Type 318 ............. 98 VII RECENTLY PUBLISHED APPROACHES TO THE TOTAL SYNTHESIS OF PTILOMYCALIN A AND GENERAL CONCLUSION.............................................102 vi A. Introduction ..........................................................................................102 B. A Biomimetic Synthesis of the Internal Tricyclic Core of Ptilomycalin A .......................................................................................102 C. Synthesis of an Advanced Intermediate en Route to the Total Synthesis of Ptilomycalin A .................................................................105 D. Conclusion ...........................................................................................107 VIII EXPERIMENTAL............................................................................................... 108 LIST OF REFERENCES............................................................................................................. 202 APPENDIX...................................................................................................................................209 1H NMR and 13C NMR Spectra of Selected Compounds vii LIST OF FIGURES FIGURE PAGE 1. The Structure of Ptilomycalin A and Derivatives .................................................... 2 2. Spermidine Derivatives .............................................................................................3