STUDIES TOWARDS A TOTAL SYNTHESIS OF ALKALOIDS MANZAMINE A AND CYLINDROSPERMOPSIN AND DEVELOPMENT OF A COMPLEX EXAMPLE OF THE DOWD-BECKWITH REARRANGEMENT DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Fabien Havas ******* The Ohio State University 2004 Approved by Dissertation Committee Dr. David J. Hart, Advisor Dr. T.V. RajanBabu Dr. Jon R. Parquette Advisor Department of Chemistry ABSTRACT This dissertation describes efforts towards a total synthesis of manzamine A and cylindrospermopsin, and the development of a novel variant of the Dowd rearrangement. Manzamine A is a marine sponge alkaloid with a complex structure and potentially valuable biological activity. This thesis describes an approach to a manzamine A substructure involving an asymmetric Birch reductive alkylation of the amide derived from (L)-prolinol methyl ether and 2-methoxybenzoic acid as a key step. Another key step was projected to be a diastereoselective Keck allylation, however a novel Dowd- Beckwith rearrangement occurred instead, producing a substituted 2- oxabicyclo[3.3.0]octan-3,6-dione in good yield. A study of the scope and limitations of this process is described herein. This study illustrated that the rearrangement can be efficient and stereoselective, and culminated in a nontrivial synthesis of a bicyclo[3.3.0]octanone containing three contiguous quaternary stereocenters. Cylindrospermopsin is a highly toxic cyanobacterial guanidinium alkaloid. The work presented herein describes a synthesis of advanced intermediates in a projected synthesis of cylindrospermopsin. Key steps include a Roush crotylation reaction to establish several key stereogenic centers, an intramolecular conjugate addition to form a ii piperidine ring, a Curtius rearrangement with internal trapping to provide a hexahydroimidazo[1,5-a]pyridine-3-3one, and a Sonogashira coupling to attach the incipient D-ring pyrimidine. Whereas a synthesis was not accomplished, a 14-step synthesis of an intermediate that may serve as a cylindrospermopsin precursor is described. iii To my grandfather, Gyuri. iv ACKNOWLEDGMENTS “It is not yours to finish the task – neither are you free to desist from it” – Pirke Avot 2:16. I wish to thank Professor David J. Hart, my advisor, for his guidance and his instruction, both scientific and human, as well as for his kindness and inexhaustible patience. Dr. Hart is in my mind the best advisor any graduate student could want to work with. May he and his research group live long and prosper. I would also like to thank the members of the Hart group, past and present, and in particular Suzanne Patterson, the most unforgettable labmate a person could have. I thank my family for their love and support, which helped carry me throughout my life and especially through these past five and a half years. I have missed you. I will always keep a special place in my heart for my grandfather, who by showing his laboratory to a curious child, sparked, and later nurtured, my growing interest in chemistry. I would also like to thank the many exceptional people who befriended me in the United States, in particular Karl and Deborah Colón and Jennifer Clark, for their friendship, their unending support, and for making me feel welcome and at home here. You have been as older siblings to me, and if these have been wonderful years, that is in v great part thanks to you. I also owe a great deal to Rabbi Gary Huber, my spiritual mentor and teacher, for opening to me a world I did not know existed, and for welcoming me back amongst the children of Israel. I will always cherish your guidance. Furthermore, I would like to thank the technical support staff in the Chemistry Department: Mr. David Chang, Dr. Chris Hadad and Susan Hatcher for mass spectral analyses; Karl Vermillion for assistance with NMR work; and Judith Gallucci for X-ray crystallographic analysis. vi VITA January 04, 1976………………………………….. Born, Paris, France. 1993-1995………………………………………… Classes Préparatoires, Lycée Janson de Sailly, Paris, France. 1995-1997………………………………………… CPE Lyon School of chemistry and chemical engineering, Lyon, France. Organic Chemistry specialization. 1997-1998………………………………………… Organic synthesis internship Drug Discovery division, Merck-Lipha pharmaceuticals, Lyon, France. 1998-2004……………………………………… Graduate Teaching Assistant and research Associate, The Ohio State University, Columbus, Ohio, USA. vii PUBLICATION Hart, D. J.; Havas, F. “Complex examples of the Dowd-Beckwith rearrangement: a free radical route to 2-oxabicyclo[3.3.0]octan-3,6-diones” C. R. Acad. Sci. Paris, Chemistry 2001, 4, 591. FIELD OF STUDY Major field: Chemistry. Specialization in Organic Chemistry. viii TABLE OF CONTENTS Page Abstract………………………………………………………………………………... ii Dedication……………………………………………………………………………... iv Acknowledgements…………………………………………………………………… v Vita………………………………………………………………………………….. vii List of Schemes……………………………………………………………………… xii List of Figures………………...……………………………………………………... xvi List of abbreviations………………………………………………………………… xvii Chapters: 1. Studies towards a total synthesis of manzamine A………………………………. 1 1.1 Introduction…………………………………………………………….….. 1 1.2 The biosynthesis of manzamine A………………………………………….. 3 1.3 Previous synthetic studies towards manzamine A – a brief survey………… 5 1.3.1 Winkler’s total synthesis of manzamine A…………………………. 6 1.3.2 Martin’s enantioselective total synthesis of manzamine A………… 9 1.4 Synthetic studies on manzamine A in the Hart group……………………. 12 1.5 Latest synthetic efforts towards manzamine A…………………………… 18 1.5.1 Introduction of the problem………………………………………. 18 1.5.2 Model studies for the first steps………………………………….. 20 1.5.3 Modified synthetic strategy………………………………………. 31 1.5.4 Free ketone strategy………………………………………………. 36 1.5.5 Study of internal acetal formation………………………………... 41 1.5.6 Successful iodolactone synthesis – unexpected allylation results... 43 2. Development of a complex example of the Dowd-Beckwith rearrangement….. 48 ix 2.1 The Dowd rearrangement – a brief introduction…………………………. 48 2.2 Initial observations………………………………………………………..51 2.3 Radical reduction experiments with iodolactone 136…………………….. 52 2.4 Varying substitution patterns……………………………………………... 54 2.4.1 Synthesis of starting materials……………………………………. 54 2.4.2 Rearrangement studies – radical allylation reactions…………….. 59 2.4.3 Rearrangement studies – radical reduction reactions…………….. 60 2.5 Conclusions………………………………………………………………. 62 3. Studies towards a total synthesis of cylindrospermopsin………………………. 63 3.1 Introduction………………………………………………………………. 63 3.1.1 Isolation and characterization of cylindrospermopsin……………. 63 3.1.2 Toxicity of cylindrospermopsin………………………………….. 65 3.1.3 Cylindrospermopsin biosynthesis…………………………………66 3.2 Synthetic studies towards cylindrospermopsin…………………………… 67 3.2.1 Snider’s synthesis of cylindrospermopsin………………………... 67 3.2.2 Weinreb’s synthesis of cylindrospermopsin……………………… 71 3.2.3 White group synthesis of 7-epicylindrospermopsin……………… 77 3.3 Hart group approach to cylindrospermopsin……………………………... 80 3.3.1 Initial approach……………………………………………………80 3.3.2 Ridenour – revised synthetic strategy towards CYN…………….. 86 3.4 Current results……………………………………………………………. 91 3.4.1 Research plan……………………………………………………...91 3.4.2 Asymmetric synthesis of carboxylic acids of type 234…………... 92 3.4.3 Early steps…………………………………………………………93 3.4.4 Installation of C12-C14…………………………………………….. 96 3.4.5 Synthesis of an AC ring intermediate towards CYN…………..… 98 3.4.6 Attempted improvement of the 284 → 295 conversion………….... 102 3.4.7 D ring installation………………………….………………………. 107 3.4.8 Guanidine formation………………….……………………………. 110 3.4.9 Conclusions and future directions……………………………….... 121 x 4. Experimental………………………………………………………………….…. 123 List of references………………………………………………………………….… 253 Appendix A – 1H and 13C NMR spectra for selected compounds…………………... 263 xi LIST OF SCHEMES Scheme Page 1.1 The Baldwin – Whitehead Hypothesis………………………………………… 4 1.2 Winkler’s synthesis of a Manzamine ABCD core unit.……………………….. 7 1.3 Completion of Winkler’s synthesis of Manzamine A…………………………. 8 1.4 Early steps in Martin’s synthesis of Manzamine A…………………………. 10 1.5 Martin’s completion of Manzamine A………………………………………. 11 1.6 Campbell’s Retrosynthetic analysis of Manzamine A………………………. 13 1.7 Synthesis of synthetic intermediate 47……………………………………… 14 1.8 Campbell’s synthesis of an ABD unit of Manzamine………………………. 15 1.9 Campbell’s synthesis of ABCD units of Manzamine A…………………….. 16 1.10 Filippini’s most advanced intermediates……………………………………. 17 1.11 Ellman-Davis sulfinimine addition chemistry………………………………. 19 1.12 A potential solution to stereocontrol at C21…………………………………. 20 1.13 Schultz’s asymmetric reductive alkylation chemistry………………………. 21 1.14 Planned model studies for the first steps…………………………………….. 22 1.15 Snieckus ortho-metallation pathway to 69…………………………………... 23 1.16 The Comins ortho-Metallation……………………………………………… 24 1.17 Synthesis of 69 through transmetallation chemistry………………………… 25 1.18 Synthesis of alkylating agent 87…………………………………………….. 26 1.19 Reductive alkylation of model compound 69……………………………….. 26 1.20 Dehydrobromination as a possible side reaction……………………………. 27 1.21 Halolactonization attempts on model compound 88………………………… 27 1.22 Attempted dihydroxylation of 88……………………………………………. 29 1.23 Attempted epoxidation of 88………………………………………………... 30 xii 1.24 Modified strategy for the early steps towards Manzamine A……………….. 31 1.25 Revised strategy