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Cationic Cyclizations of Iron Tricarbonyl Diene Complexes with Pendant Alkenes and Arenes……………………………………….....16

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Cationic Cyclizations of Iron Tricarbonyl Diene Complexes with Pendant Alkenes and Arenes……………………………………….....16 Cationic cyclizations of iron tricarbonyl diene complexes with pendant alkenes and arenes by Victor P. Ghidu 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. In memoriam Emilian Ghidu. TABLE OF CONTENTS List of Tables………………………………………………………………………..……vi List of Figures………………………………………………………………...………….vii Acknowledgments……………………………………………………………………....viii List of Abbreviations…………………………………………………………………......ix Abstract……………………………………………………………………………...……xi Chapter 1. Iron tricarbonyl diene complexes - general introduction……………...…1 1.1 Preparation of iron tricarbonyl diene complexes…………………………………...…3 1.2 Synthetic relevance of iron tricarbonyl diene complexes……………………………..5 1.3 Literature cited…………………………………………………...……………………9 Chapter 2. Cationic cyclizations of iron tricarbonyl diene complexes with pendant alkenes and arenes……………………………………….....16 2.1 Introduction. Stabilized acyclic iron tricarbonyl pentadienyl cations……………….17 2.2 Cyclization reactions of iron tricarbonyl pentadienyl cation with pendant nucleophiles……………………………………………………………….…….25 2.3 Studies on pendant alkenes with an increased substitution pattern………………….34 2.4 A new method for the cationic cyclizations of iron tricarbonyl stabilized pentadienyl carbocation with pendant alkenes and arenes…………………………...….37 2.5 Conclusions…………………………………………………………………………..49 2.6 Experimental section…………………………………………………………………50 2.7 Literature cited……………………………………………………………………….64 iv Chapter 3. Iron tricarbonyl pentadienyl cation as initiator for cascade polycyclization reactions……………………………………………………...70 3.1 Introduction to tandem bicyclizations. Biosynthetic relevance……………………...71 3.2 Polyene bicyclizations using iron tricarbonyl stabilized pentadienyl carbocation as initiator – a new method…………………………………………………76 3.2.1 Synthesis of polyene substrates…………………………………………....77 3.2.2 Cyclization studies……………………………………………………...….80 3.2.3 Stereochemistry assignment using 1D and 2D 1H-NMR…………………..87 3.3 Conclusions…………………………………………………………….…………….92 3.4 Experimental section…………………………………………………………………92 3.5 Literature cited………………………………………………………...……………103 Appendix. NMR Spectra of new compounds……………………………………..…111 Bibliography…………………………………………………………………………...150 v List of Tables Table 2.1 Substrates with a pendant olefinic nucleophile…………………….………41 Table 2.2 Substrates with a pendant aromatic / heteroaromatic nucleophile…………46 Table 3.1 Demetallation of double cyclization products...……………………………86 Table 3.2 Diagnostic hydrogen resonances for compound 3.50d………………….....91 vi List of Figures Figure 1.1 Zeise’s salt………………………………………………………………….….2 Figure 1.2 Enantiomerically pure iron tricarbonyl diene complexes obtained as such from enantiomerically pure diene precursors………………………………….….4 Figure 1.3 Iron tricarbonyl group restricts access to a neighboring group…………..……7 Figure 1.4 Iron atom can stabilize a neighboring cation……………………………….….8 Figure 2.1 Ψ-endo/exo diastereoisomers………………………………………………...21 Figure 2.2 Two key intermediates in the total synthesis of (+)-Ikarugamycin…………..25 Figure 2.3 A possible explanation for preferred 6- over 5-membered ring cyclization………………………………………………….…31 Figure 2.4 Poor economy due to low selectivity of the Grignard addition ……………...38 Figure 2.5 1H-NMR stereochemistry assignment for compound 2.103b………………...43 Figure 3.1 Diagnostic hydrogen resonances for the bicyclization product stereochemistry assignment………………………………………87 Figure 3.2 Overlapping resonances of interest in the metal complex …………………...88 Figure 3.3 Diagnostic cross peaks for H1-H5’ and H1’-H2’ interactions ….……………...89 Figure 3.4 Diagnostic cross peaks for H2’-H3’, H3’-H4’ and H4’-H5’ interactions …...…...89 Figure 3.5 Diagnostic cross peaks for H1-H4a, H1-H10a and H4a-H10a interactions…..…...90 vii Acknowledgments I thank Professor Anthony Pearson for giving me the chance to work under his patient guidance, for sharing with me and my colleagues his, apparently, infinite knowledge of chemistry, for his everyday example of professionalism and work ethic. I thank my best friend Titus for encouraging me to take this step and for so many other things, it would take another tome to tell the story. I thank Eugen for his generous help and encouragement during my first two years at Case. Many thanks to all the group members, past and present, for sharing with me their knowledge of chemistry and for making this period fun and interesting. Special thanks to Wenjing for tolerating me and my stupid music so well, Sheng (no, you are so smart!), Jin Bum (the loading dock was so empty after you left!!!), Brian for being my American friend. I thank the “Romanian community” for all their help and support. Thanks Simona and Attila for being my family away from my family and for keeping your door always open for me. I thank my little sister, Rodica, for supporting my decision and for filling in for me while I’m away. I thank my parents for their encouragement (you only cried a little when I left and that helped a lot), for overcoming so many difficulties and offering me and my sister the best childhood ever. I got here only because of you. viii List of Abbreviations Ac acetyl 9-BBN 9-borabicyclo[3.3.1]nonane borsm based on reacted starting material CAN cerium ammonium nitrate cat. catalytic COSY correlation spectroscopy DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess DIBAL-H diisobutylaluminum hydride DMF N,N-dimethylformamide eq. equation equiv. equivalent Et ethyl GC-MS gas chromatography- mass spectroscopy HRMS high resolution mass spectroscopy IR infrared Me methyl MHz megahertz mL milliliter m.p. melting point ix n normal NMR nuclear magnetic resonance NOE nuclear Overhauser effect Nu- nucleophile [ox] oxidation PCC pyridinium chlorochromate ppm parts per million psi pounds per square inch Py pyridine Rf retention factor rt room temperature s singlet s-cis single cis SN nucleophilic substitution s-trans single trans TBAF tetrabutylammonium fluoride THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilane pTs para toluenesulfonyl UV ultraviolet x Cationic cyclizations of iron tricarbonyl diene complexes with pendant alkenes and arenes. Abstract by Victor P. Ghidu A new method for cationic cyclization of iron tricarbonyl diene complexes with pendant alkenes and arenes is presented, improving an earlier method developed in the Pearson laboratory, both in terms of economy and reactivity. Previously reported dehydroxylation of diastereomeric alcohols is replaced by regiospecific protonation of a double bond adjacent to the iron tricarbonyl diene moiety (both processes occur with anchimeric assistance from the iron atom). (OC)3Fe (OC)3Fe (OC)3Fe OH H+ / Lewis acid Nu or Nu Nu (OC)3Fe (OC)3Fe H+ Nu Nu The method was tested in a simple synthetic application: bicyclization of polyene substrates toward octahydrophenanthrene derivatives. Complete diastereoselectivity and adherence to the Stork-Eschenmoser postulate was observed. R R (OC)3Fe (OC)3Fe R H+ [ox] xi Chapter 1. Iron tricarbonyl diene complexes - general introduction. - 1 - In 1825 Danish chemist William Christopher Zeise reported that on adding KCl to a concentrated solution of PtCl4 in ethanol, beautiful lemon-yellow crystals are obtained. Along with considerations on the physical and chemical properties of this substance, he noted that it has a “metallic, astringent and long lasting taste”! It would take about 35 years for this compound to be confirmed as an adduct of platinum and ethylene (Fig. 1.1), and another 100 years for the first X-ray structure. Despite disagreement by some major - Cl Cl Pt Cl K+ H2CCH2 Fig. 1.1 Zeise’s salt names of the day (Justus Liebig among others), Zeise suggested he had prepared a compound of PtCl2 and “olefiant gas”. He must be therefore credited with the first organometallic compound ever to be synthesized.1 Organometallic chemistry has come a long way since those days, in terms of compound variety, preparation methods, end uses and characterization methods. It is today mainstream chemistry, with numerous compounds used on industrial scale or in research, catalytically as well as stoichiometrically. The work described in this thesis belongs to the field of stoichiometric applications of organometallic complexes in organic synthesis,2,3 iron tricarbonyl diene complexes in particular.4 Hereafter we are going to present some basic concepts related to these complexes, in preparation for a detailed account of a new synthetic method to be presented in Chapters 2 and 3. - 2 - 1.1 Preparation of iron tricarbonyl diene complexes. Under various conditions, poly-carbonylated iron complexes, such as Fe(CO)5 and Fe2(CO)9 can react with an acyclic (1.1) or cyclic (1.3) diene, to afford iron tricarbonyl
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