PART A. Ni-CATALYZED ASYMMETRIC HYDROVINYLATION and RELATED REACTIONS
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PART A. Ni-CATALYZED ASYMMETRIC HYDROVINYLATION AND RELATED REACTIONS PART B. DEVELOPMENT OF EFFICIENT CYCLIZATION METHODS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Hwan Jung Lim, M.S. Graduate Program in Chemistry The Ohio State University 2009 Dissertation Committee: T. V. RajanBabu, Advisor Jon Parquette Craig Forsyth ABSTRACT In part A, Ni(II)-catalyzed asymmetric hydrovinylation (HV) and related reactions are described. Hydrovinylation has been successfully developed to generate all-carbon chiral quaternary centers. Using this efficient method, neuro-active (-)- desoxyeseroline and related natural products such as non-substituted (-)-physostigmine and key intermediates for the synthesis of its derivatives have been synthesized. The first generation synthesis was initiated by applying linear β-substituted styrenes with functional groups as hydrovinylation substrates. Substrates with a phthalimido functionality at the β-position underwent hydrovinylation reactions successfully, but the enantioselectivities were only modest. The desired hydrovinylation product was converted into the known key intermediate for the target compounds. In order to improve the enantioselectivity and efficiency, cyclic vinylarenes were tested instead of initial linear derivatives. These compounds gave excellent enantioselectivities in the HV reaction. Using a ring expansion/contraction strategy, the formal synthesis of (-)- desoxyeseroline has been completed in excellent overall selectivities. ii In a related objective in the development of the asymmetric HV reaction, the mechanism of Ni-phosphoramidite complex catalyzed reaction has been studied. The single crystals of (allyl)Ni(L1)Br (L1 = phosphoramidite) complex were obtained, whose three-dimensional structure confirmed the square planar geometry of the Ni-complex and the binding mode of the phosphoramidite ligand. Moreover, induced atropisomerism of the racemic biaryl by the appended chiral amine was confirmed by the X-ray structure. 31P NMR studies using three (allyl)Ni(L)Br and corresponding BARF complexes provided the first evidence of the hemilabile coordination of a pendant phenyl-group in phosphoramidite ligands. In addition, matched/mismatched ligand effects for hydrovinylation to generate all-carbon chiral quaternary centers were studied. Isomerization of terminal alkenes have been observed during hydrovinylation or cycloisomerization reactions of α,ω-dienes. Based on this observation, a new Pd(II)- and Ni(II)-catalyzed isomerization of terminal alkenes has been developed. Modified conditions for the generation of metal-hydride complexes were applied for selective isomerizations of terminal alkenes. These conditions gave the desired isomerized products in excellent yields and selectivities. Compared with two representative methods reported recently using Ir- and Ru-catalysts, these reactions appear to be cleaner and more selective. The Pd(II)-catalysts can isomerize even geminal disubstituted alkenes in good yields. Such a reaction is currently not known. In part B, new cyclization methods are described. Searching for a new method for the preparation of heterocyclic hydrovinylation substrates, seleniranium ion-triggered electrophilic cyclizations have been developed. Generated by AgSbF6 and PhSeBr, seleniranium ion-mediated cyclofunctionalizations give Friedel-Craft cyclization iii products in good to excellent yields even with substrates carrying non-activated aryl- groups. Detosylative and debenzylative cyclizations ensue when appropriate N- substituted derivatives are used. In pursuit of a biomimetic total synthesis of 7-bromoindolactam V, a key intermediate for all-carbon quaternary center-containing lynbyatoxin A, an unexpected Cu-mediated tandem cyclization has been discovered. This procedure which uses CuI/CsOAc is quite mild compared to the more harsh Buchwald-Hartwig amination conditions for macrolactamizations. In a dipeptide substrate an unexpected tetracyclic 2,5-diketopiperazine was formed in a tandem reaction in good yields. Structure of the new compound was confirmed by X-ray crystallography. Mechanism of the tandem reaction was studied in simplified model compounds. The simplified compounds - acyclic benzolactam-V8 - were made by Rh-catalyzed asymmetric hydrogenation. These substrates were successfully applied to the Cu-mediated tandem cyclization to get tricyclic DKPs, rigid synthetic congeners of benzolactam-V8. Schölkopf reagent, which can be used to prepare unnatural aminoacids, was used as a chiral building-block for the synthesis of DKP-containing heterocycles. iv Dedicated to my family, Soyeon and Taewook v ACKNOWLEDGEMENTS I would like to thank Professor T. V. RajanBabu for his guidance and support. In his role as my advisor, he helped me head in the right direction throughout my entire PhD course. Especially, his deep knowledge and diverse interests challenged me to enter uncharted areas to find something meaningful and valuable. I would like to thank to Professors David Hart, Jon Parquette, and Craig Forsyth for all their help and showing me how to be an independent chemist. I will remember their classes for a long time. I really appreciate our past and present group members for their devotion and cooperation for developing our group’s research. I would like to thank Drs. Bin Wu, Ramakrishna Reddy Singidi, Wang Liu, and other group members for always being good friends and helpful colleagues eager to share their knowledge and resources. From the day when I decided to come to the US till today, I can not imagine succeeding in my PhD program without my wife’s unselfish support. I really appreciate Soyeon’s sacrifice and love for my family. I also appreciate my son for being a great kid, and I am proud of him. I also thank my parent for their love and taking good care of themselves. vi VITA August 21, 1973 . Born – Seoul, Korea 1997 . B.S. Chemistry, Inha University 1999 . M.S. Chemistry, Korea University 1999 – 2004 . Researcher, Drug Discovery Lab. Choongwae Pharma Co. 2005 – present . .. Graduate Teaching and Research Associate, The Ohio State University PUBLICATIONS Research Publication 1. Lim, H. J.; RajanBabu, T. V. “Seleniranium Ion-Triggered Reactions: New Aspects of Friedel-Crafts and N-Detosylative Cyclizations” Org. Lett. 2009, 11(13), 2924. 2. Lim, H. J.; Smith, C. R.; RajanBabu, T. V. “Facile Pd(II)- and Ni(II)-Catalyzed Isomerization of Terminal Alkenes into 2-Alkenes” J. Org. Chem. 2009, 74, 4565. (highlighted in Synfacts 2009, 9, 1001.) vii 3. Smith, C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. “Tunable Phosphoramidite Ligands for Asymmetric Hydrovinylation: Ligands par excellence for Generation of All- Carbon Quaternary Centers” Synthesis, 2009, 12, 2089 (invited special topic). FIELDS OF STUDY Major Field: Chemistry viii TABLE OF CONTENTS Page Abstract…………………………………………………………………………………ii Dedication………………………………………………………………………………v Acknowledgments………………………………………………………………………vi Vita……………………………………………………………………………………vii List of Schemes………………………………………………………………………xiv List of Tables…………………………………………………………………………xvii List of Figures…………………………………………………………………………xix List of Abbreviations…………………………………………………………………xxi Chapters: Part A. Ni-catalyzed Asymmetric Hydrovinylation and Related Reactions 1. Introduction 1.1. Hydrofunctionalizations……………………………………………………….1 1.2. Brief History of Hydrovinylation as a Heterodimerization…………………….5 1.3. Pd-catalyzed Hydrovinylation………………………………………………….5 1.4. Ru- and Co-catalyzed Hydrovinylation……………………………………….7 1.5. Ni-catalyzed Non-enantioselective Hydrovinylation……………………….8 ix 1.6. Ni(II)-catalyzed Heterodimerization Using Other Coupling Partners Other than Ethylene………………………………………………………….10 1.7. Ni-Catalyzed Asymmetric Hydrovinylation………………………………….12 1.8. Intramolecular Hydrovinylation Reactions………………………………….19 1.9. Summary…………………………………………………………………….21 1.10. References……………………………………………………………………22 2. Generation of All-carbon Chiral Quaternary Centers and Synthesis of (-)- Physostigmine 2.1. Introduction………………………………………………………………….26 2.1.1. Asymmetric Alkylations……………………………………………….27 2.1.2. Radical Reactions…………………………………………………….28 2.1.3. Diels-Alder Reactions………………………………………………….29 2.1.4. [2+3] Cycloadditions………………………………………………….30 2.1.5. Sigmatropic Rearrangements…………………………………………31 2.1.6. Intramolecular Heck Reactions for Syntheses of (-)-Physogmine and Related Compounds…………………………33 2.1.7. Miscellaneous………………………………………………………….35 2.1.8. Summary……………………………………………………………….36 2.2. Results and Discussion……………………………………………………….37 2.2.1. First Generation Synthesis of (-)-Physostigmine………………………38 2.2.2. Summary of the First Generation Synthesis………………………….45 2.2.3. Second Generation Synthesis of (-)-Physostigmine……………………46 2.2.4. Summary of the Second Generation Synthesis……………………….49 2.2.5. Third Generation Synthesis of (-)-Physostigmine……………………49 2.2.6. Summary of the Third Generation Synthesis……………………….56 2.2.7. Beckman Rearrangement of the Oxime 26a: A New Synthesis of Pyrrolo[1,2-a]indoline………………………….56 2.3. Summary………………………………………………………………………59 2.4. Experimental Procedures………………………………………………………61 2.4. References……………………………………………………………………94 x 3. Structural Studies of Ni(II)-phosphoramidite Complexes 3.1. Introduction…………………………………………………………………...97 3.1.1. General Mechanism of HV…………………………………………….98 3.1.2. Hemilabile Pendant Groups for HV…………………………………..100 3.1.3. Structures of Metal Complexes with Phosphoramidite Ligands…….106