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Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones

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Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones bearing a Quaternary Stereocenter and Reactions of Palladium Bisphosphine Complexes Relevant to Catalytic C-C Bond Formation by Ivory Derrick Hills B.S., Chemistry University of North Carolina - Chapel Hill, 1999 Submitted to the Department of Chemistry In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology August 2004 © 2004 Massachusetts Institute of Technology. All rights reserved. Signature of Author Department of Chemistry August 12, 2004 Certified by 4 J Gregory C. Fu Thesis Supervisor Accepted by Robert W. Field Chairman, Departmental Committee on Graduate Studies MASCUSTSN_!tT MASSACHUSETTS INSTITUTE OF TECHNOLOGY ,.--e- i SEP 15 2004 -Wvov tu - LIBRARIES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: ( Professor Stephen L. Buchwald Chairman Professor Gregory C. Fu t I ^ Thesis Supervisor Professor Rick L. Danheiser - 2 To Chrissy, my best friend 3 Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones bearing a Quaternary Stereocenter and Reactions of Palladium Bisphosphine Complexes Relevant to Catalytic C-C Bond Formation by Ivory D. Hills Submitted to the Department of Chemistry on August 12, 2004 In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Organic Chemistry ABSTRACT In Part I the development of a new method for the construction of oxindoles and benzofuranones bearing quaternary stereocenters is discussed. A planar-chiral PPY derivative catalyzes the O-to-C acyl group migration (Black rearrangement) in a highly efficient and enantioselective manner. The utility of this method is further demonstrated by the formal total synthesis of the natural product aplysin. " NI R 1 5% 1 S-N I R ~_OR catalyst (-)-1 .3 1 Ph Fe Ph i_ 't° CH2CI2, 35 °C . _. Jn PHn -r- -n 2 Ph R = CMe2 (CCI3 ) X = 0, NR 88-99% ee R1 = aryl, heteroaryl, alkyl 72 95% yield (-)-1.3 ,-~ Amp...... , H- = Me, enzyl 4 In Part II reactivity of bisphosphine palladium-complexes is discussed. It is shown that the oxidative addition of bisphosphine palladium-complexes bearing P(t-Bu2)Me occurs through an SN2-typemechanism. This discovery allows us rationalize the difference in catalytic activity between Pd(P(t-Bu2)Me)2 and Pd(P(t-Bu2)Et)2 for the cross-coupling of alkyl electrophiles. n-nonyl SN 2 I n-nonyl-Br L Pd -L L-Pd-L THF I 1 equiv L = P(t-Bu)2Me Br AGt = 20.8 kcal/mol (20 °C); AHt = 2.4 kcal/mol; ASt = -63 eu * added phosphine does not affect the rate Solvent Less Polar More Polar Leaving Group Fluoride << Chloride < Tosylate < Bromide << Iodide Substrate Branching a << fi < y < straightchain Slower Reaction Faster Reaction The reductive elimination of H-X from bisphosphine palladium-hydride complexes is also discussed. The discovery that (P(t-Bu)3)2PdHCl undergoes facile reductive elimination in the presence of Cy2NMe, while (PCy3)2PdHCl does not, is explained using X-ray crystal structures. These reactivity patterns may help to explain why Pd(P(t-Bu)3)2 is a much better catalyst than Pd(PCy3)2 for the Heck coupling of aryl chlorides. 5 This step can be kinetically slow and thermodynamically unfavorable! a reductive base-H x oxidative elimination LXPd(O) addition LnPd(O) Ar-X base - ,H Ar LnPds X LnPd" X I R Ar R LPd" H \ R Ar X ,-hydride elimination, olefin complexation, olefin decomplexatior 7 I ~ olefininsertion Finally, Part III describes preliminary work on a palladium-hydride catalyzed isomerization of allylic alcohols as well as initial attempts to study the mechanism of nickel-catalyzed cross-couplings of secondary alkyl-electrophiles. 6 Portions of this document have appeared in the following publications: Hills, I. D.; Fu, G. C. "Elucidating Reactivity Differences in Palladium- Catalyzed Processes: The Chemistry of Palladium Hydrides" J. Am. Chem. Soc. Accepted for publication. Hills, I. D.; Netherton, M. R.; Fu, G. C. "Toward in Improved Understanding of the Unusual Reactivity of Pd(0)/Trialkylphosphine Catalysts in Cross-Couplings of Alkyl Electrophiles: Quantifying the Factors That Determine the Rate of Oxidative Addition" Angew. Chem. Int. Ed. 2003, 42, 5749- 5752. Hills, I. D.; Fu, G. C. "Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones that Bear a Quaternary Stereocenter" Angew. Chem. Int. Ed. 2003, 42, 3921-3924. Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. "Boronic Acids: New Coupling Partners in Room-Temperature Suzuki Reactions of Alkyl Bromides. Crystallographic Characterization of an Oxidative-Addition Adduct Generated Under Remarkably Mild Conditions" J. Am. Chem. Soc. 2002, 124, 13662-13663. 7 ACKNOWLEGMENTS I have many people to thank for helping me get to this point in my life. First I would like to thank all of the great teachers I had in high school. I would also like to express my gratitude for Professors Joseph Templeton, Maurice Brookhart, and Lee Pedersen, mentors who showed me that research could be lots of fun. I would also like to mention the support that I've received from the MIT Organic Faculty. Specifically, I learned a tremendous amount as a first-year student in Prof. Barbara Imperiali's tutorial class and in Prof. Tim Jamison's advanced organic class. These two great teachers helped prepare me for the latter parts of my graduate career. I would also like to thank Profs. Steve Buchwald and Tim Swager for many encouraging words and enlightening discussions concerning my future. I consider myself fortunate to be in the midst of a faculty that is committed to both educating students and performing excellent research. Of course it would have been difficult to conduct any research without the support of a group. I've had many co-workers over the years and would like to mention, by name, some the excellent scientists I've had the privilege of working with: Dr. Craig Ruble, Dr. Michael Lo, Dr. Brian Hodous, Dr. Beata Tao, Dr. Shih- Yuan Liu, Dr. Matthew Netherton, Dr. Wayne Tang, Mr. Jianrong (Steve) Zhou, Mr. Jon Wilson and of course Professor Ryo Shintani. I would also like to thank the group members who took time out of their busy schedules and help proofread this thesis: Jon, Wade, Steve, Kevin, Sheryl, Dave, and Christian. 8 I've been lucky enough to have a supportive family, which helped me through the tough times. This used to be exclusively the Hills family, which consisted of my parents and brother. Then I got married and somehow it was extended to the Adams, Kopp, Rosso, and Schultz families. All of these people have been tremendously caring over the years and they have my everlasting gratitude. I've made some great friends in graduate school, including Johann, Ryo, Martin and Liu. I'm grateful that we've been able to help each other through the tough times. We've also had the opportunity to share many happy moments, and I expect the future to hold more of the same. Finally, I should mention my advisor, Prof. Greg Fu, and my wife, Chrissy Kopp, the two most important people in helping me to get to this point in my life. Greg has helped me in immeasurable ways, simply by expecting me to do my best. He's the best role model I could have, and I'm eternally grateful for his guidance. Chrissy has also been supportive in more ways than I can describe here; however, I should mention she's been a great friend by encouraging me when my advisor was pushing me to do my best, which can be rather stressful to say the least. Thanks to both of you. 9 TABLE OF CONTENTS Abbreviations 12 Part I Enantioselective Synthesis Catalyzed by a Planar-Chiral Heterocycle Chapter 1 Synthesis of Oxindoles and Benzofuranones Bearing a Quaternary Stereocenter A. Introduction 16 B. Results and Discussion 22 C. Conclusions 31 D. Experimental 32 Part II Reactions of Palladium Bisphosphine Complexes Relevant to Catalytic C-C Bond Formation Chapter 2 Oxidative Addition of Alkyl Electrophiles to Palladium Bisphosphine Complexes A. Introduction 72 B. Results and Discussion 78 C. Conclusions 87 D. Experimental 88 Chapter 3 Reductive Elimination of H-X from Palladium Hydrides A. Introduction 121 B. Results and Discussion 125 10 C. Conclusions 131 D. Experimental 132 Part III Miscellaneous Chapter 4 Palladium-Hydride Catalyzed Isomerizations of Allylic Alcohols A. Introduction 155 B. Results and Discussion 158 C. Conclusion 163 D. Experimental 164 Chapter 5 Mechanistic Investigations of Nickel-Catalyzed Cross-Couplings of Secondary Alkyl Electrophiles A. Introduction 171 B. Results and Discussion 177 C. Conclusion 183 D. Experimental 184 CurriculumVitae 188 Appendix A X-ray Crystal Structure Data 189 Appendix B Selected H NMR Spectra 346 11 Abbreviations BP bathophenantroline bpy 2,2'-bipyridine cod cyclooctadiene DMA N,N-dimethylacetamide DMAP 4-(dimethylamine)pyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide eq equation equiv equivalent(s) GC gas chromatography HPLC high performance liquid chromatography HRMS high resolution mass spectrometry PPY 4-pyrrolidinopyridine r.t. room temperature THF tetrahydrofuran 12 13 Part I Enantioselective Synthesis Catalyzed by a Planar-Chiral Heterocycle 14 Chapter 1 Synthesis of Oxindoles and Benzofuranones Bearing a Quaternary Stereocenter 15 A. Introduction Heterocycles represent a vitally important class of molecules, which manifest themselves in both natural products and synthetic molecules with therapeutic properties.' In particular, molecules derived from aromatic-fused heterocycles such as oxindoles and benzofuranones have proven to be popular synthetic targets due to their interesting structure and biological activity.2 Several of these natural products bear quaternary stereocenters, such as diazonamide A,34 gelsemine,5 and aplysin6 (Figure 1.1). Recent advances have been made in the development of methods capable of constructing these 7 9 stereocenters.
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