UNIVERSITY OF CALIFORNIA, SAN DIEGO SAN DIEGO STATE UNIVERSITY Part I: Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Addition of Alkenyl Groups From Alkenylzirconium and Alkenylzinc Reagents and Their Application Toward the Total Synthesis of Azaspirene Part II: Aqueous Wittig Chemistry Employing Stabilized Ylides and Aldehydes A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Amer Adnan El-Batta Committee in charge: University of California, San Diego Professor Joseph Adams Professor Simpson Joseph Professor Emmanuel A. Theodorakis San Diego State University Professor B. Mikael Bergdahl, Chair Professor Thomas Cole Professor Terrence Frey 2007 Copyright Amer Adnan El-Batta, 2007 All rights reserved. The dissertation of Amer Adnan El-Batta is approved, and is acceptable in quality and form for publication on microfilm: ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Chair University of California, San Diego San Diego State University 2007 iii TABLE OF CONTENTS Signature Page............................................................................................... iii Table of Contents........................................................................................... iv List of Figures................................................................................................ vii List of Schemes.............................................................................................. viii List of Tables................................................................................................. xi List of Abbreviations……………................................................................. xii Acknowledgements........................................................................................ xiv Vita……………………………………………………………………........xvi Abstract.........................................................................................................xvii Chapter 1: Introduction.................................................................................. 1 Part I: Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Addition of Alkenyl Groups From Alkenylzirconium and Alkenylzinc Reagents and Their Application Toward the Total Synthesis of Azaspirene……….... 6 Chapter 2: Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Addition of Alkenyl Groups From Alkenylzirconocene Reagents..........7 2.1 Introduction........................................................................................ 7 2.1.1 Background of Hydrozirconation………………………………….. 7 2.1.1.1 Preparation of Schwartz’s Reagent {Cp2Zr(H)Cl}…..…………….. 8 2.1.1.2 Applications of Hydrozirconation…………………………………. 10 2.1.2 Cu- and Ni-Promoted Conjugate Additions……………………….. 13 2.2 Results and Discussion…………………………………………….. 17 2.2.1 Additions to Enones and Enals…………………………………….. 17 2.2.2 Efficiency of the (CuI)4(SMe2)3 Complex…………………………. 20 2.3 Mechanistic Postulate…………………………………………….... 23 2.4 Conclusion…………………………………………………………. 24 iv Chapter 3: Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Addition of Alkenyl Groups From Alkenyl-Alkylzinc Reagents................................. 25 3.1 Introduction....................................................................................... 25 3.2 Results and Discussion…………………………………………….. 30 3.2.1 Additions to N-Enoyl Derived Oxazolidinones……………………. 30 3.2.2 Efficiency of the Zr→Zn Transmetalation Methodology in Cu(I)- Catalyzed 1,4-Additions of Alkenyl Groups to Enones and Enals.... 34 3.2.3 Efficiency of the (CuI)4(SMe2)3 Complex…………………………. 38 3.3 Mechanistic Postulate….…………………………………………... 39 3.4 Conclusion…………………………………………………………. 41 Chapter 4: Chemical Studies Toward the Total Synthesis of Azaspirene, a Novel Angiogenesis Inhibitor……………………...……….. 43 4.1 Introduction....................................................................................... 43 4.1.1 Biological Significance of Angiogenesis in Cancer……………….. 43 4.1.2 Mode of Action of Azaspirene…………………………………….. 45 4.2 Prior Total Syntheses of Azaspirene………………………………. 46 4.2.1 Hayashi’s Approach……………………………………………….. 47 4.2.2 Tadano’s Approach………………………………………………... 49 4.3 Retrosynthetic Strategy for Azaspirene……………………………. 51 4.4 Results and Discussion…………………………………………….. 53 4.4.1 Synthesis of the Amine Fragment………………………………….. 54 4.4.2 Synthesis of the Acid Fragment……………………………………. 55 4.4.3 Synthesis of Advanced Intermediate Toward Azaspirene…………. 58 4.5 Conclusion…………………………………………………………. 60 Part II: Aqueous Wittig Chemistry Employing Stabilized Ylides and Aldehydes……………………………………………… 61 Chapter 5: Aqueous Wittig Reactions………………………........................62 5.1 Introduction....................................................................................... 62 5.2 Results and Discussion…………………………………………….. 65 5.2.1 Aqueous Wittig Reactions Employing Various Aromatic Aldehydes………………………………………………………….. 65 5.2.2 Aqueous Wittig Reactions Employing Various Heterocylic Aromatic Aldehydes……………………………………………….. 68 5.2.3 Aqueous Wittig Reactions Employing Various Aliphatic Aldehydes………………………………………………………….. 70 v 5.2.4 Role of Water in the Aqueous Wittig Reactions…………………... 72 5.3 Mechanistic Studies of the Aqueous Wittig Reaction……………... 76 5.4 Conclusion.………………………………………………………… 78 Chapter 6: Future Work................................................................................. 81 6.1 Asymmetric Conjugate Additions of Alkenyl Groups Using Copper Catalysis…………………………………………………… 81 6.1.1 Enantioselective Additions of Alkenylzirconium Reagents……….. 82 6.1.2 Enantioselective Conjugate Additions of Mixed Alkenyl- Alkylzinc Reagents………………………………………………… 83 6.2 Expansion of the Methodology of Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Addition of Alkenyl Groups...…... 84 6.2.1 Employing β–Oxy-Substituted α,β-Unsaturated Carbonyl Substrates…………………………………………………………... 84 6.2.2 Allylic Additions (SN2’)…………………………………………… 85 6.2.3 Electrophilic Trapping of Zinc Enolates in α–Alkylation Type Reactions…………………………………………………….. 86 6.3 Mechanistic Studies of the Copper(I) Iodide Dimethyl Sulfide Catalyzed 1,4-Additions of Alkenyl Groups………………………. 86 6.4 Completion of the Total Synthesis of Azaspirene…………………. 90 Chapter 7: Experimental Section................................................................... 94 7.1 Chemicals and Instrumentals............................................................. 94 7.2 Experimental Procedures................................................................... 95 7.3 Compounds Characterized…............................................................114 Appendix.......................................................................................................147 References.....................................................................................................265 vi LIST OF FIGURES Figure 2.1: Applications of alkenylzirconocenes in organic synthesis..................12 Figure 4.1: Role of angiogenesis in cancer development, growth and Metastasis………………………………………………………..…..44 Figure 4.2: Structures of azaspirene, psuerotin A and synerazol……...................47 Figure 5.1: TS models to account for the E/Z-selectivity..............................…... .77 vii LIST OF SCHEMES Scheme 1.1: Cu(I)-catalyzed 1,4-addition of alkenylzirconocene to enones and enals……………………………………………………………...1 Scheme 1.2: TMSOTf-promoted Cu(I)-catalyzed conjugate addition of mixed alkenyl-alkylzincate reagents to α,β-unsaturated imides……………..3 Scheme 1.3: Synthetic strategy toward azaspirene………………………………....4 Scheme 1.4: Wittig reaction of aldehydes and stabilized ylides in water………….4 Scheme 2.1: Hydrozirconation of alkenes and alkynes using Schwartz’s reagent...8 Scheme 2.2: First reports by Schwartz using zirconocene hydrochloride………....8 Scheme 2.3: Buchwald’s protocol for the preparation of Schwartz’s reagent….....9 Scheme 2.4: Change of regioselectivity by the addition of copper(I)……………..14 Scheme 2.5: Copper(I)-promoted formation of diene by Schwartz.………............14 Scheme 2.6: First Cu(I)-promoted alkenylzirconocene addition to an enone……..15 Scheme 2.7: Using Me2CuLi(LiCN) in the 1,4-addition of alkenylzirconium reagents to α,β-unsaturated ketones…………………….……………15 Scheme 2.8: First Cu(I)-catalyzed alkylzirconocene addition to an enone……......16 Scheme 2.9: Conjugate addition of alkyl- and alkenylzirconocene to enone…......18 Scheme 2.10: Formation of diene product in presence of Cu(I) catalyst………….. 22 Scheme 2.11: Proposed mechanism for the Cu(I)-catalyzed conjugate addition of alkenylzirconocenes……………………………………. 23 Scheme 3.1: AgClO4-catalyzed addition of alkenylzirconocenes to aldehydes…. 26 Scheme 3.2: Alkenylzirconocenes addition to epoxides catalyzed by AgClO4…. 26 Scheme 3.3: Transmetalation of an alkenylzirconium to an alkenylzinc reagent....27 viii Scheme 3.4: Wipf’s report on the vinylation of aldehydes using mixed alkenyl-alkylzincate reagents………………………………………..28 Scheme 3.5: Catalytic asymmetric Zr→Zn transmetalation/ketone addition……..29 Scheme 3.6: The first attempt of a Cu(I)-catalyzed conjugate addition of alkenylzirconocenes to α,β-unsaturated imides……………………...31 Scheme 3.7: TMSOTf-promoted Cu(I)-catalyzed conjugate addition of mixed alkenyl-alkylzincate reagents to α,β-unsaturated imides……..32 Scheme