NORTHWESTERN UNIVERSITY A Multi-Component Catalytic Assembly Reaction for the Synthesis of Nitrogen- Containing Heterocycles and Umpolung Transformations of Aldehydes and Acylsilanes. A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS For the degree DOCTOR OF PHILOSOPHY Field of Chemistry By Chris Galliford EVANSTON ILLINOIS June 2007 2 © Copyright by Chris Galliford 2007 All rights reserved 3 ABSTRACT A Multi-Component Catalytic Assembly Reaction for the Synthesis of Nitrogen- Containing Heterocycles and Umpolung Transformations of Aldehydes and Acylsilanes. Chris Galliford A catalytic, multi-component coupling reaction for the synthesis of nitrogen- containing heterocycles has been developed. The reaction of an imine, α-diazoester and unsaturated coupling partner in the presence of a copper(I) or rhodium(II) transition metal catalyst with excellent diastereoselectivities and high yields. The transition metal- catalyzed decomposition of a diazo compound in the presence of an imine generates a transient azomethine ylide that undergoes addition with various dipolarophiles in a convergent manner to substituted pyrrolidine and 3-pyrroline heterocycles. In addition to examining the general scope of the multi-component reaction, modification of the dipolarophile allowed access to more structurally complex 3,3’- pyrroldinyl spirooxindoles. Substitution of the α-diazoester with diazoacetonitrile allowed access to 1,2-diarylpyrroles. Umpolung reactions involving acylsilanes and aldehydes have also been developed. Acylsilanes treated sequentially with α-lithio diazoacetates followed by alkyl halides lead 4 to substituted β-ketoesters in a single-flask, multi-component operation. The treatment of aryl acylsilanes with tosylmethyl isocyanide (TosMIC) leads to the formation of 5- aryl-substituted oxazoles in excellent yield. Two catalytic Umpolung reactions of aldehydes were also developed. Using an azolium salt as a precursor to a N-heterocylic carbene (NHC) catalyst, a mechanistic investigation into the nucleophilic acylation of 2-chlorooxazoles was conducted. Finally, investigations into a reaction using a 2,3-epoxyalcohol as a starting material, a tandem oxidation mediated bis-acetoxyiodosobenzene (BAIB) with catalytic TEMPO followed by NHC-catalyzed esterification leading to acetate aldol-products is reported. ____________________________________ Thesis Advisor: Professor Karl A. Scheidt 5 ACKNOWLEDGEMENTS I’d like to thank my advisor Professor Karl A. Scheidt for the opportunity to study towards a Ph.D. in his research group. In addition to helpful discussions, advice and project guidance, he has played an important role in allowing me to develop scientific ideas and concepts into concrete experiments and results, and to mature as a scientist. In this regard I would also like to acknowledge my committee members Professors T. J. Marks and J. B. Lambert for illuminating conversations and feedback during my studies here at Northwestern. I would also like to thank my co-workers, who have provided me with a stimulating and entertaining environment, especially those who I have worked most closely alongside in the lab, including Bill Morris, Dan Custar, Brooks Maki and Anita Mattson and Audrey Chan. I am also grateful to Dr. Ashwin Bharadwaj, Dr. Margaret Biddle, Bob Lettan II, Dr. Alex Mathies, Dr. Juli Gibbs-Davis, Troy Reynolds, Eric Philips, Dr. Manabu Wadamoto for incisive and friendly advice. I’d also like to give a special mention to James Martenson, a talented undergraduate student who I had the opportunity to work closely with during my Ph.D. I have learned much from interacting with all of these people and I am grateful for their time and support. Recently joined Scheidt group members Dr. Tom Zabawa, Dustin Raup and Antoinette Nibbs have also been most personable, and I have enjoyed interacting with them. I would like to acknowledge Melissa Beenen for the synthesis of imines (Chapter 2) David Ballweg for solving crystal structure II-18, and Ms. Alisha Taylor for recording mass spectrometry samples. 6 I also benefited significantly from discussions with other group members, particularly Dr. Sven Schneider, (Marks laboratory) Dr. So-hye Cho (Nguyen group). Huihe Zhu (Lewis), Brooks Jones and Mike Salata (Marks). In addition to my colleagues friends and co-workers here at Northwestern, there are several other people I’d like to thank for helping me make the decision to pursue a Ph.D. in a foreign country. These are Professor Jonathan Clayden and Dr. Ian Watt, who were extremely supportive and kind in lending their time and advice. I also wish to thank Grace Yang, Dr. Suzy Kim, Dr. Ijen Chen, Dr. Claire Nunns, Geraint Jones, Dr. Justin Bower, Dr. Andy Potter, Dr. Andrew McRiner, and Alex Wormall for their roles in influencing my decision to come here. I would like to thank Dan Custar for proofreading this document, and lastly, I would like to thank my family and friends for their support and understanding during this period of my life. 7 LIST OF ABBREVIATIONS Ac acetyl AcOH acetic acid AcOEt ethyl acetate AS azolium salt BAIB bis-acetoxyiodosobenzene Bn benzyl Bz benzoyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA diisopropylethylamine DMF dimethylformamide dr diasteroisomeric ratio EDA ethyl diazoacetate ee enantiomeric excess equiv equivalents GC gas chromatography HMPA hexamethyl phosphoramide HPLC high performance liquid chromatography IPA isopropanol IR infrared spectroscopy LDA lithium diisoproylamide LRMS low resolution mass spectormetry MALDI-TOF matrix-assisted laser desorption ionization time-of-flight 8 MCAR multi-component assembly reaction MOF metal-organic framework mp melting point NHC N-heterocyclic carbene NMR nuclear magnetic resonance SAR structure-activity relationship TEA triethylamine TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl radical THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl 9 Dedication For Dad, who will be remembered long after the content of this thesis is forgotten 10 TABLE OF CONTENTS Chapter 1. Pyrrolidinyl Spirooxindole Natural Products as Inspirations for 18 the Development of Potential Therapeutic Agents 1.1 The 3,3’-pyrrolidnyl Spiorooxindole Heterocycle in Natural Products 19 1.2 Danishefsky’s Synthetic Approach 22 1.3 MgI2-Promoted Ring Opening of Cyclopropyloxindoles 23 1.4 Asymmetric 1,3-Dipolar Cycloaddition Strategy 25 1.5 Schreiber’s Diversity-Oriented Synthesis Approach 27 1.6 Structure-Based Design of Potent MDM2 Inhibitors 34 1.7 Conclusion 41 Chapter 2. A Catalytic Multi-Component Assembly Reaction (MCAR) for 44 the Synthesis of Nitrogen-Containing Heterocycles 2.1 Introduction: Significance of the Pyrrolidine Heterocycle 45 2.1.1 Synthetic Approaches to the Heterocyclic Pyrrolidine Core 45 2.1.2 Synthesis of Pyrrolidines by 1,3-Dipolar Cycloaddition 46 2.2.1 Multi-Component React ions 46 2.2.2 MCAR for the Synthesis of 3-Pyrrolines and Pyrrolidines 47 2.3 3,3-[Pyrrolidinyl]spirooxindoles 47 2.3.1 Significance and occurrence of bioactive spirooxindoles 55 2.3.2 MCAR for the Synthesis of 3,3-[Pyrrolidinyl]spirooxindoles 55 11 2.3.3 Synergistic Activation of Forskolin in the Gene Transcription pathways 57 2.4 Pyrroles 61 2.4.1 Introduction: Significance of the Pyrrole Heterocycle 62 2.4.2 MCAR for the Synthesis of 3-Pyrroles 62 2.5 Experimental Section 63 2.5.1 General Information 68 2.6 MCAR for the Synthesis of Nitrogen-Containing Heterocycles 68 2.6.1 General Experimental Procedure A: MCAR for the Synthesis of 3- 69 Pyrrolines and Pyrrolidines 2.6.2 Characterization Data for 3-Pyrrolines and Pyrrolidines (II-12 to II-31) 69 2.7 MCAR for the Synthesis of 3,3-[Pyrrolidinyl]spirooxindoles 70 2.7.1 General Experimental Procedure A: MCAR for the Synthesis of 3,3- 78 [Pyrrolidinyl]spirooxindoles 2.7.2 Characterization Data for 3,3-Pyrrolinyl-spirooxindoles (II-33 to II-44) 78 2.8 MCAR for the Synthesis of Pyrroles 85 2.8.1 General Experimental Procedure A: MCAR for the Synthesis of 3- 85 Pyrrolines and Pyrrolidines 2.8.2 Characterization Data for Pyrroles (II-47 to II-54) 86 Chapter 3. Polarity-Reversal or Umpolung Chemistry of Acylsilanes 90 3.1 Introduction 91 3.2 Reaction of α-Lithio-Diazoacetates 94 12 3.3 Reaction of TosMIC with Acylsilanes Leading to 5-Aryl Oxazoles 98 3.4 Experimental Section 102 3.4.1 General Information 102 3.5 Synthesis of β-Ketoesters from Acylsilanes and Lithio-Diazoacetates 103 3.5.1 General Experimental Procedure A: Synthesis of β-Ketoesters 103 3.5.2 Characterization Data for β-Ketoesters 104 3.6 Synthesis of 5-Aryl Oxazoles from Acylsilanes and TosMIC 105 3.6.1 General Experimental Procedure A: Synthesis 5-Aryl Oxazoles 105 3.6.2 Characterization Data for 5-Aryl Oxazoles 105 Chapter 4. Polarity-Reversal or Umpolung Chemistry of Acylsilanes 107 4.1 Introduction to Umpolung or Polarity-Reversal 108 4.1.1 Catlaytic Umpolung Strategies 109 4.1.2 NHC-Catalyzed Nucleophilic Acylations of Aromatic Systems 110 4.2 NHC-Catalyzed Nucleophilic Acylations of 2-Chlorooxazoles 111 4.2.1 Mechanistic Investigation 112 4.2.2 Nucleophilic Acylation with Benzoyltrimethylsilane 115 4.2.3 2-Keotooxazoles as Bidentate Dyads for Metal-Organic Frameworks 116 4.4 Experimental Section 122 4.5 General Information 122 4.5.1 General Experimental Procedure A: Preparation of 2-Ketooxazoles 123 from Aldehydes and 2-Chloroxazoles 13 4.5.2 Characterization Data for 2-Ketooxazoles IV-10, IV-15, IV-18 and IV- 124 19 4.5.3 Characterization Data for Side Products IV-11 and IV-13 125 4.5.4 General Experimental Procedure B: Preparation of 2-Ketooxazoles 125 from Benzoyltrimethylsilane III-26 and 2-Chloroxazole IV-9 4.5.5 General Experimental Procedure C: Preparation of Deuterio-IV-11 126 4.5.6 General Experimental Procedure D: Sonogashira Coupling for MOF- 126 dyad Synthesis 4.5.7 Characterization Data for MOF-Dyad Synthesis 127 4.6 General Experimental Procedure E: BAIB-TEMPO, NHC-catalyzed 127 Oxidation-Esterification Reaction LIST OF FIGURES 1-1.