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View Toward the Possibility of Ring Contraction A NEW SYNTHETIC PATHWAY FOR DIQUINANE AND ANGULAR TRIQUINANE SYSTEMS by Eun Hoo Kim Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Advisor: Prof. Anthony J. Pearson Department of Chemistry CASE WESTERN RESERVE UNIVERSITY May 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Eun Hoo Kim candidate for the Ph.D. degree*. (signed) Prof. Michael, Zagorski (Chair of the Committee, Department of Chemistry, CWRU) Prof. Anthony J. Pearson (Department of Chemistry, CWRU) Prof. Robert G. Salomon (Department of Chemistry, CWRU) Prof. Geneviève Sauvé (Department of Chemistry, CWRU) Prof. Bin Su (Department of Chemistry, Cleveland State University) Date: 26st Februray 2010 *We also certify that written approval has been obtained for any propriety material contained therein. To my family & my teachers Table of Contents List of Tables ……………………………………………………………………..……vi List of Figures ………………………………………………………………………….. vii List of Schemes …………………………………………………………………….…….ix Acknowledgements ……………………………………………………….…..…….…xii List of Abbreviations…………………………………………………….……………xiii Abstract …………………………..…………………………………………………..…xvi CHAPTER 1. Background: Iron Carbonyl Chemistry And Synthesis of Triquinane Natural Products ………………………………………………………………………......1 1.1 Background : Fe(0) chemistry .…………………………………………………..2 1.2 Synthesis of triquinane natural products………………………………..………14 1.2.1. Diquinanes …………………………………………………………………..…15 1.2.2. Triquinanes ………………………………………………………………….…16 1.2.3 Syntheses of pentalenene ………………………………………………….….18 1.3 References …………………………………………………………………….…27 CHAPTER 2. Synthesis of Azatriquinane System………………………………………30 2.1 Introduction …………………………………………………………………...…31 2.2 Synthesis of a model compound ……………………………………………..…36 2.2.1. Synthesis of iron complexed structure/demetallated structure ........……..36 iv 2.2.2. Oxidative cleavage of double bonds to give carbonyl compounds………47 2.3.4. Studies of aldol condensation conditions………………………………...54 2.3 Conclusions ……………………………………………………………………...57 2.4 Experimental section ……………………………………………………….……58 2.5 References ……….………………………………………………………………68 CHAPTER 3. Studies Directed Towards Synthesis of All-Carbon Triquinane Systems .71 3.1 Introduction ………………………………………………………………...........72 3.2 Single cyclization ………………………………………………………………..77 3.3 Double cyclization .……………………………………………………………...93 3.4 Conclusions ………………………………………………………………..….…97 3.5 Experimental section ………………………………………………………….....98 3.6 References ……………………………………………………………………...108 APPENDIX ..…………………………………………………………………………..110 BIBLIOGRAPHY ……………………………………………………………………...143 v List of Tables Table 1.1. Double cyclization of amide complexes 1.34 ……………………………...11 Table 2.1. Cyclization of amide complexes 2.32 ………………………….…………….43 Table 2.2. Dematallation of the iron complex 2.33 ……………………………………..45 Table 2.3. Ozonolysis of the compound 2.14 …………………………………………...48 Table 2.4. OsO4/NaIO4 oxidation of the compound 2.14 ………………………….……51 Table 2.5. RuO4 oxidation of the compound 2.14 ………………………………………52 Table 2.6. Intramolecular aldol cyclization to afford model compound 2.16 …………..55 vi List of Figures Figure 1.1. Z/E conformations of esters (thioesters) ………………………………….......4 Figure 1.2. Orbital interactions for amides, esters, and thioesters ………………………..4 Figure 1.3. Conformational preferences for amides ...........................................................4 Figure 1.4. Comparison of cis vs trans h3-metallacyle intermediate ……………………..6 Figure 1.5. NOE effects …………………………………………………………………12 Figure 1.6. Polyquinane carbocyclic skeletal …………………………………………...14 Figure 1.7. Diquinanes ……………………………………………………………….….15 Figure 1.8. Three major forms of triquinanes …………………………………………...17 Figure 1.9. Pentalenene pentalenic acid and pentalenolactone H system ……………….17 Figure 2.1. 1H NMR spectrum of iron complexed methyl ester 2.37 …………………...39 Figure 2.2. 1H NMR spectrum of iron complexed methyl ester 2.38 …………...………40 Figure 2.3. 1H NMR spectrum of iron complexed acid 2.39 ……………………………41 Figure 2.4. 1H NMR spectrum of iron complexed acid 2.32 ……………………………43 Figure 2.5. 1H NMR spectrum of cyclized product 2.33 ………………………………..45 Figure 2.6. 1H NMR spectrum of demetallated product 2.14 …………………………...46 Figure 2.7. 1H NMR spectrum of cleaved cyclized product 2.15 ……………………….53 Figure 2.8. 1H NMR spectrum of aldol reaction product 2.16 ………………….……….56 Figure 3.1. 1H NMR spectrum of cleavage product 3.37 ………………………………..79 Figure 3.2. 1H NMR spectrum of cleavage product 3.39 ………………………………..83 Figure 3.3. Four possible isomers from the Grignard reaction and cyclization …………87 Figure 3.4. 1H NMR spectrum of cleavage product 3.51 and 3.52 ………………….….89 Figure 3.5. 1H NMR spectrum of oxidation product 3.66 ………………………………91 vii Figure 3.6. 1H NMR spectrum of oxidation product 3.67 ……………………..………..91 viii List of Schemes Scheme 1.1. Intramolecular coupling of olefin with diene-Fe(CO)3 moiety …………….2 Scheme 1.2. Proposed mechanism of the spirocyclization ……………………………....5 Scheme 1.3. The stereochemistry of intermediates ………………………………………7 Scheme 1.4. Racemization due to precyclization rearrangement ………………………..8 Scheme 1.5. The use of methoxy group at 3-positon …………………………………….9 Scheme 1.6. Steroselective tandem double cyclization ………………………………….9 Scheme 1.7. Consideration of the mechanism …………………………………………..10 Scheme 1.8. Proposed mechanism for double cyclization under thermal conditions …...12 Scheme 1.9. Formation of the trans-fused diquinane system …………………………...16 Scheme 1.10. The first synthesis of epi-pentalenene ……………………………………19 Scheme 1.11. [3+2]-Annulation strategy to pentalenolactone-E methyl ester ………….20 Scheme 1.12. Stereospecific pathway to pentalenolactone ……………………………..21 Scheme 1.13. Stereospecific pathway to pentalenic acid ……………………………….22 Scheme 1.14. New rapid assembly method using cascade pathway ……………………23 Scheme 1.15. Stereospecific pathway to pentalenolactone ……………………………..24 Scheme 1.16. The formation of pentalenene from farnesyl diphosphate ……………….24 Scheme 1.17. Two pathways to pentalenene and intermediates ………………………...25 Scheme 2.1. Iron promoted [6+2] ene type of spirocyclization …………………………31 Scheme 2.2. Cyclization of dienyl amide complex with 3-position substitution ………..32 Scheme 2.3. A new pathway to triquinane systems ……………………………………..33 Scheme 2.4. 6- to 5-membered ring contraction pathway ………………………………34 Scheme 2.5. Aldol reaction in total synthesis of silphinene …………………………….35 ix Scheme 2.6. Proposed synthesis of model compound 2.21 ……………………………..36 Scheme 2.7. Synthesis of iron-complexed acid 2.39 ……………………………………37 Scheme 2.8. Direct iron complexation of 1,4-diene compound 2.35 …………………...38 Scheme 2.9. Preparation of amine 2.41 …………………………………………………39 Scheme 2.10. Ozonolysis to cleave double bonds of complex molecules ………………47 Scheme 2.11. OsO4 oxidative cleavage reactions ……………………………………….49 Scheme 2.12. OsO4 oxidation used in preparing natural product stephaoxocane 2.56 …49 Scheme 2.13. OsO4/NaIO4 cleavage and aldol reactions applied to aphidicolin and phytuberin intermediates ………………………………………………………………...50 Scheme 2.14. Mild conditions of intramolecular aldol reaction for tricyclic structure …54 Scheme 3.1. Single cyclizations of esters from iron-complexed acid ………………….62 Scheme 3.2. Single cyclizations of amides and thioesters from iron-complexed acid ….63 Scheme 3.3. Proposed mechanism of the cyclization …………………………………...63 Scheme 3.4. Optimization of single cyclization ………………………………………...74 Scheme 3.5. Proposed mechanistic rationale for the cyclization ………….…………….75 Scheme 3.6. Proposed synthesis of an all-carbon angular triquinane ..………………….76 Scheme 3.7. Intramolecular iron-mediated diene/olefin cyclocoupling ………………...77 Scheme 3.8. Preparation of pendant ene compound …………………………………….78 Scheme 3.9. Undesired nucleophilic addition product ………………………………….78 Scheme 3.10. Formation of mesylate and anhydride ……………………………………80 Scheme 3.11. Generation of alkoxide in Grignard reaction ……………………………..81 Scheme 3.12. Alternative Grignard reaction using aldehyde 3.41 …………...…………84 Scheme 3.13. Preparation of the iron-complexed aldehyde 3.41 ……………………....85 x Scheme 3.14. Overall comparison of the synthetic methods of aldehyde 3.41 …………86 Scheme 3.15. The result of single cyclization reaction ……………………………..….90 Scheme 3.16. Proposed scheme to construct a triquinane system ………………..…….94 Scheme 3.17. Preparation of bromide 3.73 for Grignard reaction ………………………95 xi Acknowledgements I would like to express my sincere appreciation and thanks to Prof. Anthony J. Pearson for his support and understanding throughout my thesis. With his patience and knowledge, I was encouraged to finish this long journey. His mentorship and understanding has helped me tremendously in achieving my goal. Without him this thesis would not have been completed. I would like to thank the Department of Chemistry, Case Western Reserve University and National Science Foundation for financial contributions. I would like to thank my committee members, Dr. Michael Zagorski, Dr. Robert Salomon, Dr. Geneviève Sauvé, and Dr. Bin Su for their help and advice. I would also like to thank Dr. Kee-Jung Lee for introduction to organic chemistry at Hanyang University in South Korea. I would like to thank my friends and colleagues from the Pearson group, especially to Huikai Sun who gave a lot of advice and worked with me in the laboratory. All the lab members made my stay worth remembering. Finally, I would like to thank my parents and family
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