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A new approach to kainoids

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Title:
A new approach to kainoids total syntheses of (-)-kainic acid and (+)-allokainic acid
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English
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Jung, Young Chun
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University of South Florida
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Tampa, Fla
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Subjects / Keywords:
C-H insertion
Y-lactam
Dephenylsulfonylation
Rhodium
Boron heck
Palladium
Dissertations, Academic -- Chemistry -- Doctoral -- USF
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bibliography   ( marcgt )
theses   ( marcgt )
non-fiction   ( marcgt )

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Abstract:
ABSTRACT: (-)-Kainic acid and its C-4 epimer, (+)-allokainic acid are parent members of a class of substituted pyrrolidines known as kainoids. They have been found to exhibit powerful biological properties, principally neuroexcitatory. Kainic acid has become especially important in the study of Alzheimer's disease, epilepsy, and other neurological disorders. The total syntheses of (-)-kainic acid and (+)-allokainic acid were achieved using (L)-glutamic acid as the starting material and the sole source ofstereochemical induction. The key steps for these successful syntheses involve formation of the gamma-lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the alpha-diazo-alpha-(phenylsulfonyl)acetamide intermediate and the stereoselective dephenylsufonylation.Pd(II)-catalyzed and oxygen promoted carbon-carbon bond formation methodologies using organoboronic reagents were developed. The first one is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen wasemployed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles.This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. The second one is the formation of symmetric biaryls and dienes via oxidative dimerization of aryl and alkenyl boronic acids. These conditions utilized Pd(II) catalysts under an oxygen atmosphere with water as the solvent. The use of phase transfer catalysts promotedefficient and mild syntheses of a wide range of materials.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2006.
Bibliography:
Includes bibliographical references.
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Mode of access: World Wide Web.
Statement of Responsibility:
by Young Chun Jung.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 233 pages.
General Note:
Includes vita.

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aleph - 001789656
oclc - 138377004
usfldc doi - E14-SFE0001464
usfldc handle - e14.1464
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ABSTRACT: (-)-Kainic acid and its C-4 epimer, (+)-allokainic acid are parent members of a class of substituted pyrrolidines known as kainoids. They have been found to exhibit powerful biological properties, principally neuroexcitatory. Kainic acid has become especially important in the study of Alzheimer's disease, epilepsy, and other neurological disorders. The total syntheses of (-)-kainic acid and (+)-allokainic acid were achieved using (L)-glutamic acid as the starting material and the sole source ofstereochemical induction. The key steps for these successful syntheses involve formation of the gamma-lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the alpha-diazo-alpha-(phenylsulfonyl)acetamide intermediate and the stereoselective dephenylsufonylation.Pd(II)-catalyzed and oxygen promoted carbon-carbon bond formation methodologies using organoboronic reagents were developed. The first one is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen wasemployed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles.This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. The second one is the formation of symmetric biaryls and dienes via oxidative dimerization of aryl and alkenyl boronic acids. These conditions utilized Pd(II) catalysts under an oxygen atmosphere with water as the solvent. The use of phase transfer catalysts promotedefficient and mild syntheses of a wide range of materials.
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A New Approach to Kainoids: Total Syntheses of (-)-Kainic Acid and (+)-Allokainic Acid by Young Chun Jung A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Edward Turos, Ph.D. Kyung Woon Jung, Ph.D. Bill J. Baker, Ph.D. Kirpal Bisht, Ph.D. Date of Approval: February 17, 2006 Keywords: C-H insertion, -lactam, dephenylsulfonylation, rhodium, boron heck, palladium Copyright 2006 Young Chun Jung

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Dedicated to Kyung Kim, Philip Jung, and Jane Jung My parents who are in heaven My parents-in-law

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Acknowledgments The Lord is my shepherd (Psalm 23:1). I would like to express my sincere gra titude to Dr. Kyung Woon Jung not only for his considerate guidance throughout my research but for his trust and support beyond academic matters. I would like to acknowledge Dr. Edward Tu ros, my official advisor, for his encouragement and guidance. I also thank Dr. Bill J. Baker and Kirpal Bisht for their support, guidance, and participation on my committee from my heart. I am especially thankful to my frie nd Dr. Yoon, for without his help my dissertation may not be what it is today. Many thanks are due to the now-andthen members of Jungs group for their friendship and the time shared in chemistry, which was both constructive and stimulating. Th anks Dr. Jay Parrish, Dr. Advait Nagle, Dr. David Flanigan, Dr. Hwang, Dr. Rajesh Kumar Mishra, Dr. Yoo, Woogie, Chiliu Chen, Iris Meng, Prassana, Kiana, Matt, Ki s oo, Gu, Thanks to my friend, Chris for his help with my English. Finally, my deepest appreciation and l ove to my wife Kyung for her selfless sacrifices, patience and support of my work and our family. To my children Philip and Jane, I love you..

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Table of Contents List of Tables v List of Figures vi List of Schemes vii List of Abbreviations x Abstract xvii Chapter One: Introduction of Kainoids 1 1.1 Isolation and Structural features 1 1.2 Biological Properties 3 1.3 Previous Syntheses of Kainic Acid 6 1.4 Previous Syntheses of Allokainic acid 23 1.5 References 31 Chapter Two: The Syntheses of (-)-Kainic acid and (+)-Allokainic acid 36 2.1 Theoretical Background 36 2.1.1 Chiral -Lactams from -Amino Acids via Rh-Catalyzed Intramolecular C-H Insertion 36 2.1.2 Intramolecular Michael Addition of Cyclic -Ketoester on Conjugated Acetylenic Ketone 38 2.1.3 Baeyer-Villiger Oxidation of Cyclohexeneone 42 2.2 Synthetic Strategy / the Core Intermediate 44 2.2.1 Retrosynthetic Analysis of (-)-Kainic Acid (First) 45 i

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2.2.2 Synthesis of the Bicyclic-Lactam Intermediate 47 2.2.3 Bicyclic-Lactam Intermediate 48 2.2.4 Synthesis of the Bicyclic-Lactam Intermediate 49 2.3 Total Synthesis of (+)-Allokainic Acid 51 2.3.1 Introduction of Isopropenyl Group 51 2.3.2 Synthesis of (+)-Allokainic Acid (1) ; Isopropenylation-Dephenylsulfonylation Route 53 2.3.3 Synthesis of (+)-Allokainic Acid (2) ; Dephenylsulfonylation-Isopropenylation route 56 2.3.4 Model Study and Other Endeavors 58 2.3.5 Conclusion 62 2.4 Total Synthesis of (-)-Kainic Acid 62 2.4.1 Retrosynthetic Analysis of (-)-Kainic Acid (Second) 62 2.4.2 Michael-type Cyclization 64 2.4.3 Synthesis of Bicyclic Cyclohexenone 65 2.4.4 Dephenylsulfonylation of Bicyclic Cyclohexenone System 67 2.4.5 Dephenylsulfonylation of the Silyl Enol Ether 67 2.4.6 NOE Study 69 2.4.7 Rationale for the Stereochemistry 74 2.4.8 Endgame for the Synthesis of (-)-Kainic Acid (1) 74 2.4.9 Endgame for the Synthesis of (-)-Kainic Acid (2) 77 2.4.10 Conclusion and Features 79 ii

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2.5 References 81 Chapter Three: Experimentals 86 Chapter Four: Oxygen-Promoted Pd(II) Catalysis for the C-C Bond Formation 122 4.1 Introduction 122 4.2 Oxygen-promoted Pd(II) Catalysis for the Coupling of Organoborons with Olefins 123 4.2.1 Heck Reaction in Water 123 4.2.2 Precedent Report 124 4.2.3 Oxygen Effect 125 4.2.4 Optimization of the Reaction Condition 126 4.2.5 Optimization of the Catalyst Amount 126 4.2.6 Effect of Electron Density on Olefins 127 4.2.7 The Versatility of the Arylboronic Acid 128 4.2.8 The Coupling with Allylbenzene 129 4.2.9 The Coupling with Highly Substituted Olefins 130 4.2.10 Phenol Formation 131 4.2.11 Competition Reaction and Reaction Cycle 132 4.2.12 Conclusion 134 4.3 Oxidative Dimerization: Pd(II) Catalysis in the Presence of Oxygen using Aqueous Media 135 4.3.1 Precedent Results of Homo Coupling with Organo Boron Reagent 135 4.3.2 Effect of Oxidant 136 4.3.3 Effect of PTC 137 iii

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4.3.4 Example of the Functionalized Phenylboronic Acid 137 4.3.5 Example of the Multiand Heterocyclic Arylboronic Acid 139 4.3.6 Synthesis of Diene 141 4.3.7 Conclusion 142 4.4 References 143 Chapter Five: Experimentals 148 Appendices 164 Appendix A: Selected 1 H NMR and 13 C NMR Spectra 164 About the Author End Page iv

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List of Tables Table 2-1 Model study of dephenylsulfonylation 58 Table 2-2 Summary of the syntheses of (-)-kainic acid and (+)-allokainic acid 80 Table 4-1 Effect of oxygen 125 Table 4-2 Dosage of catalyst 127 Table 4-3 Effect of electron density on olefins 128 Table 4-4 Various arylboronic acids coupled with tert-butyl acrylate 129 Table 4-5 Various aryl boron reagents coupled with allylbenzene 130 Table 4-6 Coupling with highly substituted olefins 131 Table 4-7 Phenol formation 132 Table 4-8 Effect of oxidant choice on oxidative dimerization of phenylboronic acid 136 Table 4-9 Formation of biaryls from boronic acids 138 Table 4-10 Formation of biaryls from boronic acids 140 Table 4-11 Formation of dienes from boronic acids 141 v

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List of Figures Figure 1-1 Structure of kainoids 1 Figure 2-1 Transition state of cyclization 37 Figure 2-2 Nucleophilic addition to ynone 39 Figure 2-3 Synthetic target 44 Figure 2-4 Retrosynthetic analysis of the total synthesis of (-)-kainic acid (first) 46 Figure 2-5 Synthetic strategy 47 Figure 2-6 Controlling factors 48 Figure 2-7 Retrosynthetic analysis of the total synthesis of (-)-kainic acid (second) 63 Figure 2-8 1 H NMR spectrum of C44 69 Figure 2-9 NOE H 1 spectrum 70 Figure 2-10 NOE H 2 spectrum 71 Figure 2-11 NOE H 4 spectrum 72 Figure 2-12 NOE H 5 spectrum 73 Figure 2-13 NOE experiment, overall 74 Figure 2-14 Silyl enol ether 74 Figure 4-1 Reaction cycle 134 vi

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List of Schemes Scheme 1-1 Oppolzers synthesis 8 Scheme 1-2 Knights synthesis 9 Scheme 1-3 Baldwins synthesis 10 Scheme 1-4 Takanos synthesis 11 Scheme 1-5 Yoos synthesis 12 Scheme 1-6 Monns synthesis 13 Scheme 1-7 Hanessians synthesis 14 Scheme 1-8 Naitos synthesis 15 Scheme 1-9 Ganems synthesis 16 Scheme 1-10 Claydens synthesis 17 Scheme 1-11 Andersons synthesis 18 Scheme 1-12 Trosts synthesis 20 Scheme 1-13 Lautens synthesis 21 Scheme 1-14 Fukuyamas synthesis 22 Scheme 1-15 Oppolzers synthesis 23 Scheme 1-16 Krauses synthesis 24 Scheme 1-17 DeShongs synthesis 25 Scheme 1-18 Mooiwers synthesis 26 Scheme 1-19 Murakamis synthesis 26 vii

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Scheme 1-20 Agamis synthesis 27 Scheme 1-21 Montgomerys synthesis 29 Scheme 1-22 Mas synthesis 29 Scheme 1-23 Cooks synthesis 30 Scheme 2-1 The preparation of -diazo--(phenylsulfonyl)acetamides 36 Scheme 2-2 C-H Insertion of -diazo compounds 37 Scheme 2-3 Intramolecular Michael addition 39 Scheme 2-4 Intramolecular Michael addition of phenylsulfone compound 41 Scheme 2-5 VBO of ,-unsaturated primary alkyl ketone 42 Scheme 2-6 VBO of -halo cyclohexnone 43 Scheme 2-7 Synthesis of acetylated compound C10 49 Scheme 2-8 C-H insertion reaction for -lactam intermediate 50 Scheme 2-9 Introduction of isopropenyl group 52 Scheme 2-10 Stereoselective dephenylsulfonylation 53 Scheme 2-11 Precursor for the ending game 54 Scheme 2-12 The synthesis of (+)-allokainic acid (1) 55 Scheme 2-13 The synthesis of (+)-allokainic acid (2) 57 Scheme 2-14 Bromination reaction 59 Scheme 2-15 Hydrogenation route (1) 60 Scheme 2-16 Hydrogenation route (2) 60 Scheme 2-17 -Diazo ester route 61 viii

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Scheme 2-18 Intramolecular Michael addition 63 Scheme 2-19 Preparation of ynone compound for Michael-type cyclization 64 Scheme 2-20 Dephenylsulfonylation of tricyclic system 66 Scheme 2-21 Preparation of bicyclic system 66 Scheme 2-22 Dephenylsulfonylation of bicyclic system 67 Scheme 2-23 Stereocontrol using dephenylsulfonylation of silyl enol ether 68 Scheme 2-24 Baeyer-Villiger oxidation 75 Scheme 2-25 Hydrogenation 76 Scheme 2-26 Claydens synthesis 76 Scheme 2-27 Hydrogenation route 77 Scheme 2-28 Ring opening and reduction 78 Scheme 2-29 Endgame for the total synthesis of (-)-kainic acid (2) 79 Scheme 4-1 Heck reaction in water 124 Scheme 4-2 Competition Reaction 133 ix

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List of Abbreviations 1,2-DCE 1,2-dichloroethane 13 C NMR C-13 nuclear magnetic resonance 1 H NMR proton nuclear magnetic resonance 2,2-DMP 2,2-dimethoxypropane 2,6-lut 2,6-lutidine Ac acetyl Ac 2 O acetic anhydride AcOH acetic acid AD-mix asymmetric dihydroxylation mix BF 3 OEt 2 boron trifluoride diethyl etherate Bn benzyl BnBr benzyl bromide BOC t-butoxy carbonyl BOMCl benzyloxymethyl chloride BrCH 2 COBr bromoacetyl bromide BuLi butyl lithium CBz benzyloxy carbonyl CDCl 3 chloroform-d CF 3 CH 2 OH trifluoroethanol CF 3 CO 2 H trifluoro acetic acid x

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(CH 2 O) n paraformaldehyde CH 2 (OMe) 2 dimethoxymethane CH 2 Cl 2 methylene chloride CH 2 N 2 diazomethane CH 3 COBr acetyl bromide Cl 3 CCN trichloroacetonitrile ClCH 2 COCl chloroacetyl chloride ClCO2C(CH3)=CH2 isopropenyl chloroformate cm -1 wavenumbers (COCl) 2 oxalyl chloride CsF cesium fluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N-dicyclohexylcarbodiimide de diastereomeric excess DIBAL-H diisobutylaluminum hydride DIC N,N-diisopropylcarbodiimide DIPEA diisopropylethylamine DMAP N,N-dimethylamino pyridine DMF N,N-dimethylformamide DMS dimethylsulfide ee enantiomeric excess Et ethyl xi

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Et 2 NH diethylamine EtOAc ethyl acetate EtOH ethanol Et 3 SiH triethyl silane H 2 hydrogen H 2 CO formaldehyde H 2 CrO 4 chromic acid H 2 O 2 hydrogen peroxide H 2 SO 4 sulfuric acid HCl hydrochloric acid HCO 2 H formic acid HCO 2 NH 4 ammonium formate Hex hexane HF hydrofluoric acid Imid imidazole IPA isopropyl alcohol i-Pr isopropyl i-PrCHO isobutyraldehyde i-PrMgBr isopropylmagnesium bromide i-PrOH isopropyl alcohol Jones Reagent H 2 CrO 4 solution K 2 CO 3 potassium carbonate xii

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KHMDS potassium bis(trimethylsilyl)amide KMnO 4 potassium permanganate LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium bis(trimethylsilyl)amide LiBH4 lithium borohydride LiBr lithium bromide LiOH lithium hydroxide M molarity m-CPBA 3-chloroperoxybenzoic acid Me methyl Me 2 AlCl dimethylaluminum chloride Me 2 CO acetone Me 3 OBF 4 trimethyloxonium tetrafluoroborate MeCN acetonitrile MeI iodomethane MeNH 2 methylamine MeOH methanol MHz megahertz MgI 2 magnesium iodide mL milliliter xiii

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MnO 2 manganese dioxide MOM methoxymethyl MOMCl methoxymethyl chloride N Normality N 2 nitrogen Na(Hg) sodium-mercury amalgam NaHCO 3 sodium bicarbonate Na 2 SO 4 sodium sulfate NaBH(OAc) 3 sodium triacetoxyborohydride NaBH 4 sodium borohydride NaClO 2 sodium chlorite NaH sodium hydride NaIO 4 sodium periodate NaN 3 sodium azide NaOH sodium hydroxide NaOMe sodium methoxide n-Bu normal butyl NEt 3 triethylamine NH 3 ammonia NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance O 3 ozone xiv

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OsO 4 osmium tetroxide P 2 O 5 phosphorous pentoxide p-ABSA 4-acetamidobenzenesulfonyl azide Pd(OH) 2 /C palladium hydroxide on carbon Pd(Ph 3 P) 4 tetrakis(triphenylphosphine)palladium(0) Pd/C palladium on carbon Ph phenyl PhCH 3 toluene PhSCH 2 CO 2 H (phenylthio)acetic acid PhSeBr phenylselenyl bromide PhSO 2 Na benzenesulfinic acid sodium salt PivCl pivaloyl chloride PMA phosphomolybdic acid PMB 4-methoxy benzyl PTC phase transfer catalyst pyr pyridine Rh 2 (cap) 4 rhodium (II) caprolactamate dimer Rh 2 (OAc) 4 rhodium (II) acetate dimer PNBA p-nitrobenzenesulfonyl azide r.t room temperature SnCl 4 tin (IV) chloride SOCl 2 thionyl chloride xv

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TBAF tetrabutylammonium fluoride TBSCl t-butyldimethylsilyl chloride TBSOTf t-butyldimethylsilyl trifluoromethanesulfonate t-Bu tert-butyl TEA triethylamine TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy TESCl triethylsilyl chloride TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid Tf 2 O trifluoromethanesulfonyl anhydride THF tetrahydrofuran TiCl 4 titanium (IV) chloride TMOF trimethyl orthoformate TMSCl trimethylsilyl chloride TMSCHN 2 trimethylsilyl diazomethane Tol toluene TPAP tetrapropylammonium perruthenate TsOH toluenesulfonic acid ZnMe 2 dimethyl zinc xvi

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A New Approach to Kainoids : Total Syntheses of (-)-Kainic Acid and (+)-Allokainic Acid Young Chun Jung ABSTRACT (-)--Kainic acid and its C-4 epimer, (+)--allokainic acid are parent members of a class of substituted pyrrolidines known as kainoids. They have been found to exhibit powerful biological properties, principally neuroexcitatory. Kainic acid has become especially important in the study of Alzheimers disease, epilepsy, and other neurological disorders. The total syntheses of (-)--kainic acid and (+)--allokainic acid were achieved using (L)-glutamic acid as the starting material and the sole source of stereochemical induction. The key steps for these successful syntheses involve formationof the -lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the -diazo--(phenylsulfonyl)acetamide intermediate and the stereoselective dephenylsufonylation. Pd(II)-catalyzed and oxygen promoted carbon-carbon bond formation methodologies using organoboronic reagents were developed. The first one is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles. This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded xvii

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competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. The second one is the formation of symmetric biaryls and dienes via oxidative dimerization of aryl and alkenyl boronic acids. These conditions utilized Pd(II) catalysts under an oxygen atmosphere with water as the solvent. The use of phase transfer catalysts promoted efficient and mild syntheses of a wide range of materials. xviii

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Chapter One Introduction of Kainoids 1.1 Isolation and Structural Features The kainoids 1 are an important class of natural non-proteinogenic amino acids which have a common characteristic structure consisting of a pyrrolidine nucleus with two carboxylic groups A1 (Figure 1-1). Common to all members of the kainoid family is the S-absolute stereochemistry at C-2 and a trans stereochemical relationship to the adjacent substituent at C-3. With the exception of allokainic acid A3, all of the kainoids isolated so far have possessed a cisrelative disposition of the C-3 and C-4 substituents. Some of the members of this family like (-)--kainic acid A2, domoic acid A4 or acromelic acids A A5 and B A6 show interesting biological properties as explained in Section 1-2. NH CO2H CO2H NH R CO2H CO2H 12345NH CO2H CO2H HO2C H NH CO2H CO2H NH CO2H CO2H NH O HO2C NH CO2H CO2H NH CO2H O A2 Kainic acidA4 Domoic acidA3 Allokainic acidA6 Acromelic acid BA5 Acromelic acid AA1 KainoidsFigure 1-1. Structure of kainoids 1

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The parent member, (-)--kainic acid A2 was first isolated in 1953 from the Japanese marine algae Digenea simplex 2 along with its C-4 epimer (+)-allokainic acid A3. Since then (-)--kainic acid A2 has been found in the related algae Centrocerus clavulatum 3 and the Corsican moss, Alsidium helminthocorton. 4 The structure was originally assigned as 3-carboxymethyl-4-isopropenylpyrrolidine2-carboxylic acid in a series of classical chemical degradations and syntheses of degradative products by several Japanese groups 5 in the mid 1950's. Among the early and important degradative reactions were a soda-lime distillation that led to the isolation of a pyrrole, and an ozonolysis which yielded formaldehyde. 5 Morimoto 6 was the first to deduce the relative stereochemistry of the pyrrolidine ring substituents by chemical studies, and this has been supported by X-ray evidence. 7 Since then a rigorous assignment of the absolute stereochemistry has been provided by Oppolzer and Thirring 8 in their concise synthesis of (-)--kainic acid A2. In a similar manner, the structure of the C-4 epimer, (+)--allokainic acid A3 has been established on the basis of chemical 9 and X-ray 7 evidence. (-)-Domoic acid A4 was originally isolated by Daigo et. al. 10 from another Japanese marine algae, the warm water algae Chondria armata. Since then it has been found in the Canadian phytoplankton Nitzschia pungens 11 and the algae Alsidium corallinum. 3,4 Levels in excess of 1% dry weight of the plankton have been observed. There is also a high probability that other phytoplankton such as Amphora coffaeformis 11 are primary producers of domoic acid A4. Domoic acid A4 has an octadienoic side chain at C-4, this was originally determined by a combination of classical degradations 2

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and spectral techniques. 12 This led to a proposed (trans-, trans-) diene geometry with undefined stereochemistry at C-5'. 12 This was later redefined as (cis-, trans-) and the absolute stereochemistry at C-5' was established (as R) by Ohfune and Tomita 13 in their total synthesis of (-)-domoic acid A4. A number of kainoids related to domoic acid A4 have also been isolated from the same algae. They include isodomoic acids A-F 14 the C-5' domoic acid diastereomer 15 and domoilactones A and B. 16 The acromelic acids A A5 and B A6, in which the C-4 substituent is a functionalized 2-pyridone, were first isolated in sub-milligram quantities in 1983, 17 and were found in quite a different organism to the previously described kainoids, namely the poisonous Japanese mushroom Clitocybe acromelalga. Due to the limited sample quantity only 1 H NMR and U.V. spectral data were available for structural assignment. From these data, the structure of the acromelatesA A5 and B A6 was deduced by comparison with those of related compounds including kainic acid A2 and domoic acid A4. Since then both acromelate structures have been confirmed by total synthesis. 18 Since the isolation of the acromelates, numerous other kainoid amino acids have been shown to be minor constituents of Clitocybe acromelalga, including the acromelic acids C, D and E. 18 1.2 Biological Properties The kainoid amino acids have attracted considerable interest largely because of their pronounced insecticidal, anthelmintic and principally neuroexcitatory properties. The ability of the kainoids to act as insecticides has long been utilized by inhabitants of 3

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Yakushima Island, Japan. They used an extract of red algae, from which kainic acid A2 and domoic acid A4 have since been isolated for its fly killing properties. Since then, domoic acid A4 and isodomoic acids A, C have shown to be potent insecticides when injected subcutaneously into the abdomens of the American cockroach (Periplaneta americana). 14 The insecticidal activity 19 is found to be strongly dependent on the nature of the side chain at the C-4 position of the pyrrolidine ring. Domoic acid A4 is 23 times more active on the American cockroach than isodomoic acid C. In comparison, the activity of domoic acid A4 was also compared with that of the well known pesticide 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), and it was found to be 14 times more active. 14 This illustrates the extremely strong insecticidal activity of domoic acid A4. Thealgae Digenea simplex, from which kainic acid A2 was first isolated, has been used for itsanthelmintic (anti intestinal worm) properties for more than a thousand years in Japan. Since then the active component, kainic acid A2, has been found to have an intense anthelmintic effect, about 10 times that of santonin without side effects. 7 The cis stereochemistry of the C-3 and C-4 substituents appears to be crucial to the anthelmintic function, as the C-4 epimer, allokainic acid A3, is said to have a very weak anthelmintic effect. Indeed, among the known stereoisomers of kainic acid A2, all show considerably reduced anthelmintic activity compared with that of kainic acid itself. 20 The anthelmintic behavior of domoic acid A4 has also been demonstrated. Thus Daigo 10 found that oral administration of domoic acid A4 was extremely effective in expelling ascaris and pinworm without observable side effects in Japanese children. 4

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The pronounced neuroexcitatory properties of the kainoids have been well investigated. 21 The kainoids have been shown to selectively block neuronal processes and as a consequence are valuable tools in the study of neurofunctioning. Their extremely potent activity, in both the vertebrate and invertebrate glutamergic system 22 leads to specific neuronal death in the brain. The pharmacological effects and patterns of neuronaldegeneration observed after injection of kainoids have been shown to mimic the symptoms observed in patients suffering from neuronal diseases such as Epilepsy 23 and Huntington's chorea. 24 In addition, there is a possibility that neuronal death caused by kainoids is a good experimental model for neuronal cell loss in senile dementia. 21 The potent neuroexcitatory activity of the kainoids is attributed to their action as conformationally restricted analogues of the neurotransmitter glutamic acid and numerousstructure activity investigations 25 26 of the kalnoids and analogue have been carried out. From these results it can be safely assumed that the C-4 stereoisomer, allokainic acid A3, is less of a neuroexcitant than A2 25b The nature of the C-4 substituent, a double bond is essential for excitatory activity 25c and its conformation, 25d play a critical role in binding and functional activation at the recognition site. This is further supported by the observation that domoic acid A4 is even more neuroexcitatory than kainic acid A2. 27 Domoic acid A4 has been identified as the toxin in paralytic shellfish poisons (PSPs) and was believed to be responsible for an outbreak of mussel Kainoid amino acid chemistry 4153 poisoning in Canada, which resulted in three deaths and 153 cases of intoxication. 28 The contamination of the mussel was thought to occur by ingestion of domoic acid A4 through its main food source, Nitzschia pungens, which is a primary producer of the toxin. 5

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More recently, domoic acid A4 intoxication of brown pelicans and cormorants in California have been reported. 29 The acromelic acids A A5 and B A6 were originally isolated from the mushroom Clitocybe acromelalga. Ingestion of the mushroom results in a sharp pain and a reddish oedemain the hands and feet after several days, which generally continue for up to a month. Since their isolation, the acromelates A5 and A6 have been tested for neuroexcita-tory activity. 22c,d Both were found to be even more potent than domoic acid A4, the acid B being slightly less potent than acid A. The acromelates also showed a different mode of action to kainic acid A2. 22e More recently, the lethal toxicity of acromelic acid C to mice was reported at a dose of 10mg/kg. 18 Similar lethal doses of 7 and 8mg/kg were observed for acromelic acid A and B respectively. Acromelic acid D has also been investigated and shown to be as potent a neuroexcitant as kainicacid A2. 30 The powerful neuroexcitatory properties of acromelate analogues 31 have stimulated considerable synthetic interest in this area. 1.3 Previous Syntheses of Kainic Acid 1.3.1 Synthetic Challenge The kainoid amino acids represent a considerable synthetic challenge. Especially, the natural product (-)--kainic acid, which is the parent kainoid, has attracted the most synthetic attention amongst the kainoids to-date. A kainoid synthesis needs to address the formation of a pyrrolidine-2-carboxylic acid with defined stereochemistry at the three 6

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contiguous stereocenters of the ring. The cis stereochemistry of the C-3 and C-4 positions, except for allokainic acid A3, needs special consideration. In recent years, electrophysiologic studies about the mammalian CNS show that the specific activity of these receptors is principally due to an unsaturated isopropylidene chain on C-4 of the pyrrolidine system. Analogues with an unsaturated chain in this position with invertedconfiguration at C-4 or without substituent at C-4 have very low agonist activity. Recently, a worldwide shortage 32 of kainic acid has stimulated the development of the total syntheses of kainic acid. 33 The biological activity of kainic acid is linked to the trans C-2/C-3 and cis C-3/C-4 stereochemistries, and thus, any synthesis should result in efficient control of this relative stereochemistry. In addition an ideal synthesis would allow the ability to introduce various side chains at the C-4 position in a convergent manner to afford all the known kainoids and various kainoid analogues. I will now give an account of various total syntheses of the kainic acid and allokainic acid. 1.3.2 Oppolzers Synthesis 33(o) The early syntheses of kainic acid A2 were relatively inefficient and non stereoselective. Since then, a number of stereoselective syntheses have been achieved, which in general have involved the construction of the C-3 / C-4 bond under the steric control of the C-2 substituent. The first enantioselective synthesis of kainic acid A2 was developed by Oppolzer and Thirring. The key step was a stereocontrolled intramolecular ene reaction (Scheme 1-1). The key diene A8 was prepared in good 7

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yield from (L)-glutamic acid and subjected to thermolysis in hot toluene. The ene cyclization reaction proceeded to furnish thedesired trisubstituted pyrrolidine A9 under the steric control of the chiral C-2 center. The relative stereochemistry of A9 was rigorously ascertained by conversion of this compound to kainic acid A2 in sixstraightforward steps. A related approach to ()-kainic acid A2 has since been reported. NHBoc CO2H EtO2C H NBoc EtO2C H OTBDMS NBoc CO2Et H OTBDMS TolueneReflux70%6 stepsNH CO2H CO2H A7A8A9A2Scheme 1-1. Oppolzer's Synthesis 1.3.3 Knights Synthesis 33(n) Knight and associates have developed an enantioselective synthesis of kainic acid A2 starting from the amino acid (L)-aspartic acid (Scheme 1-2). The key feature of their strategy is the use of a stereocontrolled enolate Claisen rearrangement to control the relative stereochemistry at the C-3, C-4 positions. The key 9-membered azalactone A10 was prepared from (L)-aspartic acid in modest overall yield. 8

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N HO2C CO2Me N O O CO2Et O TIPS LDA, TBDMSClTHF, -100oCN O TBDMSO OTIPS CO2Et H 1. -100oC to r.t.2. K2CO3O TIPSScheme 1-2. Knight's SynthesisA10A11A12 Enolate formation in the presence of the silyl trapping agent, followed by rearrangement afforded (after silyl ester hydrolysis) the pyrrolidine A12, presumably via the boat-like transition state A11, in 55% yield. It is noted that the pseudo equatorial protected alcohol (CH 2 OTIPS) gives rise to the high diastereomeric purity obtained. Homologation of the acid A12 followed by oxidation furnished A2 in seven additional steps and good overall yield. 1.3.4 Baldwins Synthesis 34 Baldwin and co-workers have applied a cobaltmediated cyclization reaction to kainoid synthesis. Two approaches to (-)-kainic acid A2 have been reported, the first of which involved the cyclization of iodide A13 (Scheme 1-3). 9

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NI TBDMSOCO2Ph BnO Cobaloxime(I)N BnO CO2Ph TBDMSO N BnO CO2Ph TBDMSO +50%30%A13A14A15Scheme 1-3. Baldwin's Synthesis On treatment of A13 with cobaloxime(I), cyclization afforded a 5:3 mixture of the separable synand anti-pyrrolidines A14 and A15 in 80% yield. Significantly, in addition to pyrrolidine ring formation, the cobalt reaction introduces a double bond at the C-4 side chain via a dehydrocobaltation process. Compound A14 was elaborated to kainic acid A2 in six further steps, while the antiisomer A15 was transformed in a similar manner to allokainic acid A3. 1.3.5 Takanos Synthesis 35 The synthesis of kainic acid A2, and allokainic acid A3, from (L)-serine has beenreported by Takano and co-workers. In this approach, the vinyl iodide A16 was treated with the radical generating agent tributyltin hydride, in the presence of AIBN, to promote a diastereo selective radical cyclisation leading to A17 in an excellent 86% yield (Scheme 1-4). Pyrrolidine A17 was found to be a useful intermediate and was readily elaborated to A18 and A19. Two-step oxidation of the primary alcohol of A18 followed by reaction with 10 equiv. of BF 3 .Et 2 0 under dilute conditions in CH 2 C1 2 (1.7x10 -3 M) promoted a C-2 directed 10

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intramolecular protodesilylation and, after esterification, gave the kainic acid precursor A19 in 58% yield (together with 11% of the C-4 epimer). On treatment of A20 with 3 equiv. of BF 3 .Et 2 0 a C-3 directed intramolecular protodesilylation yielded the allokainic acid precursor A21 after reaction with diazomethane. N TBDPSOCO2Me MeO2C N CO2Ph TBDPSO I TMS TMS MeO2C N CO2Me TMS PivO HO N CO2Me MeO2C PivO N CO2Me TBDPSO TMS HO2C N CO2Me OH MeO2C Bu3SnH, AIBNBenzene, reflux1. (COCl)2, DMSO, Et3N2. NaClO2, NaHPO43. BF3OEt4. CH2N21. BF3OEt22. CH2N2A16A17A18A19A20A21Scheme 1-4. Takano's Synthesis 1.3.6 Yoos Synthesis 33(l) The Pauson-Khand reaction has also been utilized as the key step in the synthesis of (-)-kainic acid A2. On reaction of the glutamic acid derived ene-yne A22 with dicobalt octacarbonyl, followed by trimethylamine N-oxide 11

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(or 4-methylmorpholine N-oxide), the enone diastereomers A23 and A24 (1.7:1 ratio) were isolated as an inseparable mixture in 95% yield (Scheme 1-5). Enone A23, which possesses the desired trans C-2, C-3 stereochemistry, was then converted into kainic acid A2 in 41% yield. N O O H N O O O H 1. Co2(CO)82. Me3NOH N O O O H H H2, Pd/CH N OTMS OMOM H H Ts NH CO2H CO2H A22A23A24A25A2Scheme 1-5. Yoo's Synthesis 1.3.7 Monn Synthesis 33(m) Monn and Valli reported a concise stereocontrolled thiazolium ylide approach to kainic acid A2. This centers on a tandem cycloaddition-cyclization of the ylide derived from A26 with 2-cyclopentenone to afford the tetracycle as a 6.8: 1 mixture of diastereomers A27, A28 (Scheme 1-6). The diastereomers A27, A28, 12

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which could be prepared on a large scale (up to 1.5 mol), were isolated in 70-80% yield. Reductive cleavage of the thiazoline C-S bond with Bu 3 SnH followed by hydrolysis of the resulting hemiaminal and N-protection gave A29 in 64% yield. The bicyclic A29 was then converted to racemic A2 in 16% yield, via a concise six-step sequence. This approach represents an extremely short and efficient method. NS N S O HO EtO2C Br O TEA, CH3CNO H H CO2Et H Me H N S O O H H CO2Et H Me H 6.8:1 N O H H CO2Et CO2Bn 1. Bu3SnH, AIBN2. HCl, H2O3. BnOCOCl, NaOHN H H CO2Et CO2Bn A2+ A26A27A28A29A30Scheme 1-6. Monn's Synthesis 1.3.8 Hanessians Synthesis 33(k) A trimethylstannyl radical carbocyclization of a diene was utilized as a key step in the synthesis of (-)--kainic acid A2 and its C4 epimer (+)--allokainic acid A3. A diene compound A32 prepared from L-serine occurred, was treated with trimethyltin hydride generated under Storks conditions, 36 the resulting mixture of stannylated compounds 13

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were obtain-ed in only 50% yield, favoring the cis stereochemistry at the C-3, C-4 centers in a ratio of 2.8:1. However, a slow addition of sodium cyanoborohydride over aperiod of 1 h to a refluxing solution containing the substrate A32 and trimethyltin chloride afforded the cyclized products A33 and its C-4 isomer as an inseparable mixture in 88% yield without compromising the cis/trans ratio. The destannylation of the trisubstituted pyrrolidine nucleus was achieved via an oxidative cleavage of the N O O CO2tBu Me3SnClslow NaCNBH3tBuOH, AIBNrefluxN O O CO2tBu Me3Sn NH CO2H CO2H L-SerineN O O CO2tBu N O O CO2tBu Me3Sn NH CO2H CO2H Me3SnClslow NaCNBH3tBuOH, AIBNrefluxA31A32A33A34A35A2A3Scheme 1-7. Hanessian's Synthesis C-Sn bond with ceric ammonium nitrate. This provided a dimethyl acetal that was further transformed into the intended -kainic acid A2. When the same radical carbocyclization was attempted on a triene A34, the 2,3-trans/3,4-trans A35 and the 2,3-trans/3,4-cis adducts were obtained in a 2.5:1 ratio, respectively. This approach was used to synthesize (+)--allokainic acid A3. 14

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1.3.9 Naitos Synthesis 33(e) Sulfanyl radical addition/cyclization/elimination of diallylamines in the presence of thiophenol and AIBN gave the 2, 3, 4-trisubstituted pyrrolidine in high yield. This reaction was extended to a radical cyclization using a catalytic amount of thiophenol.A successful application was demonstrated by the asymmetric synthesis of ()-kainic acid. Sulfanyl radical addition/cyclization/elimination of A36 in the presence of thiophenol andAIBN proceeded smoothly to give a 1:1.5 mixture of the cyclized productsA37 and A38 in combined 94% yield. NR PhS OR PhSH,AIBNC6H6NR OR SPh NR OR SPh 1:1.5NH CO2H CO2H +A36A37A38A2Scheme 1-8. Naito's Synthesis Similarly, treatment of A36 with a catalytic amount of thiophenol gave A37 and A38 in an almost similar ratio. Next, A37 was converted to (-)--kainic acid in 8 steps. 1.3.10 Ganems Synthesis 37 Ganem and coworkers reported a metal-promoted enantioselective ene reaction that provides entry into the kainic acid ring system from very simple precursors. 15

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Moreover, the zirconium-mediated Strecker reaction demonstrates remarkable chemoselectivity and stereoselectivity. Diene A39 was prepared from N-prenylamine in 4 steps. The thermal and metal-catalyzed intramolecular ene reactions of dienes A39 formed cis-substituted and trans-substituted pyrrolidones A41 and A42 in 20/1 ratio (Scheme 1-8). Lactam A41 was transformed into (-)--kainic acid as depicted in Scheme 1-8. Reaction with Schwartzs reagent (Cp 2 ZrHCl, 1.5 equiv. in THF) generated an imine. It was subjected, without purification to cyanotrimethylsilane (TMSCN) in CH 2 Cl 2 to afford the all-cis nitrile A43 in 70% overall yield from A39. Although alkenes readily react with Schwartzs reagent, no hydrozirconation of the isopropenyl group in A39 was detected. Nitrile A43 was reacted with 4 N HCl-methanol and then directly basified with KOH to afford A2 in 97% yield. This procedure presumably involves alcoholysis of the nitrile in A3 to a diester, which undergo epimerization and saponification to A2. NR O EtO2C NR O EtO2C NR O EtO2C NR NC EtO2C NH HO2C HO2C Mg(ClO4)2, CH2Cl2, r.t.20:11. Cp2ZrHCl, THF2. TMSCN, CH2Cl2 N N O O Ph Ph +A39A40A41A42A43A2Scheme 1-9. Ganem's Synthesis 16

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1.3.11 Claydens Synthesis 33(b) Clayden and coworkers reported a dearomatizing cyclization method using chiral lithium amide bases, which are able to deprotonate N-benzyl-N-cumyl anisamides enatioselectively to yield enatiomerically enriched benzyl organo lithiums. Chiral lithium base A45 was used to promote the asymmetric cyclization of the precursor A44 to yield the partially saturated isoindolones A48. The hydrochloride salt A45HCl was dissolved in THF, and then 2 equiv. of BuLi were added to form a solution of chiral lithium amide A45 plus lithium chloride. Once the amide A44 had been added the mixture was allowed to warm, promoting asymmetric deprotonation to A46 and cyclization to the enolate A47. NBoc O CO2Me CO2Me N Ph OMe MeO O N Ph OMe MeO O NLi LiCl, THFLi N OLi OMe MeO Ph H N O OMe O Ph H H NH CO2H CO2H A44A45A46A47A48A2A49Scheme 1-10. Clayden's Synthesis 17

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An aqueous quench and acidic work-up returned the enone A48 in a good yield and enatiomeric excess. These isoindolone derivatives are converted in nine steps, among them a surprisingly resioselective Baeyer-Villiger reaction, to (-)-kainic acid A2. 1.3.12 Andersons Synthesis 38 A flexible route to the kainoid skeleton is exemplified by the synthesis of ()-kainic acid from 3-butyn-1-ol by Anderson. The route relies on the aza-[2,3]-Wittig sigmatropic rearrangement, to efficiently install the relative stereochemistry between C-2 and C-3. The C-4 stereocenter was derived from a diastereocontrolled iodolactonization. BocN OtBu SiPhMe2 CONMe2 HN CONMe2 SiPhMe2 OtBu Boc LDA HN CONMe2 OtBu Boc I2O NHBoc t-BuO I O NH HO Ot-Bu CO2H NCbz TsO OH CO2H NCbz OH CO2H [CH2=C(CH3)]2CuCNLi2NH CO2H CO2H TFA, KOH A50A51A52A53A54A55A56A2Scheme 1-11. Anderson's Synthesis 18

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The aza-[2,3]-Wittig rearrangement potentially allows structural diversity at C-3 and the displacement of the tosyloxy group with retention of stereochemistry allows structuraldiversity at C-4. The trans C-2 carboxylic acid functional group was found to be the most important for retention of the stereochemistry at C-4 upon treatment with a higher order cyano cuprate. The aza-[2,3]-Wittig rearrangement was induced by using LDA (1.4 equiv.) at -78 C with warming to 0 C for 2 h to give the pivotal unnatural amino acid derivative A51 in 78% yield. Protodesilylation was achieved by an optimum 1.5 equiv. of water in the first step of a two step process that furnished silanol and alkene A52 as a 1:2 mixture in the crude material. Direct treatment with excess TBAF gave A52 in 59% overall yield. Iodolactonization with I 2 in DME/H 2 Ogave a 7:1 mixture of A53 in 74% yields. Deprotection of the amine substituent followed by base-induced ring opening of the lactone gave the proline skeleton A54 after 5-exo-tet cyclization in 86% yield. They used a higher order diisopropenyl cyano cuprate, generated from CuCN and 2-lithiopropene. This reaction was very sensitive to reaction conditions and care had to be taken to rigorously dry the CuCN and perform the reaction under a positive pressure of argon. Optimum reaction conditions involved treatment of A55 with 5 equiv. of the higher order cuprate reagent at -78C followed by warming to room temperature for 2 h to give a 56% yield of the desired product. Retention of stereochemistry was verified by one dimensional nOe experiments. 19

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1.3.13 Trosts Synthesis 39 BnO HN OTBS TsN O BnO [CpRu(CH3CN)3]PF610%2% water/acetone96% ee, 80% yld TsN O HO SiMe2Ph 20%[Ir(cod)Py(PCy3)]PF6 2000psi, H2 TsN O HO SiMe2Ph HN HO2C CO2H Scheme 1-12. Trost's SynthesisA57A58A59A60A2 Trost group reported a novel route to kainic acid A2 using the key concept derived from a ruthenium-catalyzed cycloisomerization of a tethered alkyne propargyl alcohol A57 to form a cylic 2-vinyl-1-acyl compound A58. A single stereocenter introduced by an asymmetric reduction of a ketone sets the stage for all the other stereocenters. A novel 1,6-addition of silyl cuprate serves to install a hydroxyl group at the diene termines A60. The relative stereochemistry was then set by a directed hydrogenation of ,-unsaturated alkene A59. Removal of the benzyl group to reveal the more powerfully directing free hydroxyl group was then carried out with Crabtrees catalyst [Ir(cod)Py-(PCy 3 )]PF 6 with 1:1 formic acid/methanol to produce A60. 20

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1.3.14 Lautenss Synthesis 40 NPh2 O p-TolS N OMe O N O S O NPh2 OMe MgI2THF78%N O S O NPh2 OMe HO 9-BBN, THFthenNaOH/H2O291%N CO2Me CO2Me Ts NH CO2H CO2H reflux A61A62A63A64A65A2Scheme 1-13. Lautens's Synthesis Recently reported by Lautens was a concise and enantioselective synthesis of (-)-()-kainic acid A2 in 13 steps with an overall yield of 15%. The pyrrolidine kainoid precursor of A63with the required C-2/C-3 trans stereochemistry was prepared with excellent diastereoselectivity (>20:1) via a MgI 2 -mediated ring expansion of a tertiary methylene cyclopropyl amide A61. A selective hydroboration was then employed to set the remaining stereochemistry at the C-4 position enroute to (-)-()-kainic acid A2. 21

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1.3.15 Fukuyamas Synthesis 41 O OAc O Me3Si NBn OMe TFA(10 mole %)CH2Cl283%N H H CO2R" O OAc O N OMOM H H CO2R" MeN N H sec-BuLi, THF-73oCCO2(g)65%N OMOM H H CO2R" CO2H N OMOM H H CO2R" HO2C 19 : 81NH CO2H CO2H H H +A66A67A68A69A70A71A72A2Scheme 1-14. Fukuyama's Synthesis Very recently, Fukuyama reported a stereocontrolled total synthesis of (-)-kainic acid A2 using two key steps. cis-3,4-Disubstituted pyrrolidine ring A68 was constructed by [3 + 2] cycloaddition of azomethine ylide A67 with chiral butenolide A66. The crucial introduction of carboxyl group at the C-2 position was executed by regioand stereoselective lithiation of the pyrrolidine ring in the presence of a (+)-sparteine surrogate followed by trapping with carbon dioxide. The crucial 1,3-dipolar cycloaddition of the chiral butenolide A66 with the azomethine ylide A67 took place smoothly upon reatment of a mixture of A66 and A67 with 10 mol % of TFA. It afforded the desired ycloadduct A68 in 83% yield with high diastereoselectivity (20:1). OBrien and co-workers reported that the diamine could serve as a surrogate for (+)-sparteine A70 for nantioselective lithiation of N-Boc-pyrrolidine A69. 22

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OBriens group examined the lithiation-carboxylation protocol in the presence of the (+)-sparteine surrogate A70. The reaction in the presence of 2.5 equiv. of A70 only gave a mixture of the desired isomer A72 and its regioisomer A71 (81:19). Thus, they have successfully controlled the diastereoselectivity, albeit with similar regioselectivity. 1.4 Previous Syntheses of Allokainic acid (+)--Allokainic acid A3 is the C-4 epimer of the (-)--kainic acid. As described in Section 1.2 the cis stereochemistry of the C-3 and C-4 positions needs special consideration for the kainoid synthesis except (+)--allokainic acid. So, the non-stereoselective synthetic procedures used for kainic acid A2 have often also been utilized for allokainic acid A3. Other synthetic approaches to A3 which have not yet been mentioned are discussed below. 1.4.1 Oppolzers Synthesis 42 N Men O2C COCF3 EtO2C EtO2C Et2AlCl-35oC, 18h57%N EtO2C EtO2C Men O2C COCF3 A73A74Scheme 1-15. Oppolzer's Synthesis(-)Phen-(-)PhenA synthesis of (+)-allokainic acid A3 from (Z)--chloroacrylic acid was reported by Oppolzer and associates, there report stated the use of the high asymmetric induction 23

PAGE 45

obtained in a Lewis acid-promoted intramolecular ene-type reaction. The chiral precursor, (Z)-8-phenylmenthyl ester A73, was treated with a mild Lewis acid (e.g. 3 mole equiv. of Me 2 AlCl or Et 2 AlCl in dry CH 2 Cl 2 at -35 C) to afford the 3S,4R-pyrrolidine A74 in 57% yield (Scheme 1-15). It is noted that the use of the corresponding (E)-phenylmenthyl ester led to an opposite sense of induction and A74 was only formed in 9% yield (while the 3R, 4S diastereomer was found in 72% yield). Subsequent saponification and decarboxylation of A74 afforded enantiomerically pure allokainic acid A3, in which the configuration at C-2 was determined by the stereochemistry at the C-3 centre. 1.4.2 Krauss Synthesis 43 NS BnO O HO EtO2C Br N S O O BnO EtO2C NH O BnO EtO2C 1. TEA2. Silicagel1. Bu3SnH2. HCl, EtOH+A75A76A77A78Scheme 1-16. Krause's Synthesis Kraus and Nagy have made use of the 1,3-dipolar cycloaddition of an azomethine ylide to synthesis of ()-allokainic acid A3 (Scheme 1-16). They reacted the disubstituted olefin A75 with the ylide derived from A76 and the tricyclic compound 24

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A77 was isolated in 59% yield. Reaction of A77 with Bu 3 SnH followed by treatment with acidic ethanol afforded pyrrolidine A78 in good yield, which was then elaborated to allokainic acid A3 in eight steps (including epimerization of the C-2 position). 1.4.3 Deshongs Synthesis 44 DeShong has synthesized racemic allokainic acid A3 using a [3+2] dipolar cycloaddition of an azomethine ylide to establish the requisite pyrrolidine stereochemistry as shown in scheme 1-16. Upon heating aziridine A80 with enone A81 in a sealed tube at 175 C, the trisubstituted pyrrolidine A82 was obtained in 70% yield. This was elaborated to (+)-allokainic acid A3 in six steps including Wittig olefination (to introduce the C-4 isopropenyl moiety) and C-2 epimerization using aqueous sodium hydroxide. N MeO2C O TBDMSO N MeO2C N Bn MeO2C Bn TBDMSO O 175oC, 70%Bn A79A80A81A82Scheme 1-17. DeShong's Synthesis 25

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1.4.4 Moiweers Synthesis 45 NH AcO MeO2C CO2Me O N OMe OCO2Me TMS N HO EtO2C CO2Me CH2Cl2 then MeOH52%BF3OEt2A83A84A85Scheme 1-18. Mooiwer's Synthesis A racemic synthesis of A3 has been reported which centers on two allylsilane N-acyliminium ion reactions. An initial intermolecular N-acyliminium coupling reaction was employed in the synthesis of A83 which was subsequently elaborated to the key allylsilane intermediate A84 in four steps (scheme 1-18). On treatment of A84 with BF 3 .Et 2 O (4 equiv.) in CH 2 C1 2 followed by methanol, the trisubstituted pyrrolidine A85 was isolated in 52% yield via an intramolecular N-acyliminium cyclisation reaction. Pyrrolidine A85 was subsequently elaborated to A3 using standard methodology. 1.4.5 Murakamis Synthesis 46 N O TBDMSO EtO2C NC TBDMSO MeO2C OTMS COCH2OPh 1. Zn(OAc)22. (PhOCH2CO)2O52% N O TBDMSO EtO2C COCH2OPh H2, Pd-CaCO390%A86A87A88Scheme 1-19. Murakami's Synthesis One racemic synthesis of allokainic acid A3 was reported by Murakami, which 26

PAGE 48

employs a zinc acetate catalyzed cyclisation of an 7-isocyano silyl enol ether. The reaction of silyl enol ether A86 with Zn(OAc) 2 2H 2 O in DMSO containing ca. 2 equiv. ofmethanol, cyclisation proceeded smoothly to produce, after N-protection, predominantly the trans-2-pyrroline A87 in 52% yield (scheme 1-19). The corresponding cis isomer was isolated in 22% yield. Stereoselective hydrogenation of A87 was achieved in the presence of 5% Pd/CaCO 3 to afford the allokainic acid precursor A88. 1.4.6 Agamis Synthesis 47 HN HO t BuO OH Ph OHCCHO aq HCl:THFN t BuO OH O Ph HO N t BuO OH O Ph HO N O O t BuO HO Ph NH HO2C HO2C A89A90A91A92A3Scheme 1-20. Agami's Synthesis An enantioselective synthesis of the (-)-enantiomer of allokainic acid A3 has been reported using a tandem aza-Cope/Mannich reaction. The (E)-alkene A89, formed from (R)-phenylglycinol, was reacted with glyoxal in a slightly acidic 27

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(pH 4-5) aqueous medium to afford the desired bicyclic hemiacetal A92 (in 45% yield as 70:30 mixture of epimers) via the iminiumions A90 and A91 (Scheme 1-20). The three contiguous stereocenters are thus introduced in a one-pot reaction, using (R)-phenylglycinol as a chiral template. The axial attack of the double bond on iminium ion A90 establishes the stereochemistry at the C-2 position, while the (E)-stereochemistry of the double bond is responsible for the stereospecific formation of the C-3 center. The elaboration of A92 to (-)-A3 was accomplished in an additional ten steps. 1.4.7 Montgomerys Synthesis 48 A direct and highly stereoselective formal total synthesis of (+)--allokainic acid A3 was reported by Montgomery. The strategy involves the nickelcatalyzed cyclization of a D-serine derived alkynyl enone with trimethyl aluminum followed by a palladium-catalyzed allylic carbonate reductive transposition (Scheme 1-21). Cyclization of A93 with commercial trimethylaluminum and [Ni(cod) 2 ] (10 mol%) in THF afforded a 73% yield of A94 with a diastereomeric ratio (d.r.) of >97:3 in favor of the desired trans isomer, and commercial dimethylzinc under identical conditions afforded a 67% yield of A94, also with a >97:3 diastereomeric ratio. Treatment of A94 with [Pd 2 (dba) 3 ]/PBu 3 and HCO 2 H/Et 3 N cleanly produced A95 in74% yield with a 95:5 diastereomeric ratio in favor of the all-trans stereochemical relationship of the three substituents at the pyrrolidine ring, as seen in allokainic acid. 28

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N N O O O O O OTBS N O N O O O O OR N O N O O O O NH HO2C HO2C [Ni(cod)2]AlMe3Pd2dba3, PBu3HCO2H, Et3NTHF, refluxA93A94A95A3Scheme 1-21. Montgomery's Synthesis 1.4.8 Mas Synthesis 49 N O CO2Me CO2tBu COPh MgBr THF, -78 oCN OH CO2Me CO2tBu COPh N OCOMe CO2Me CO2tBu COPh Pd(PPh3)4, PPh3HCO2NH4N CO2Me CO2tBu COPh 4N, NaOHrefluxNH CO2H CO2H Ac2O, DMAPTEAA96A97A98A99A3Scheme 1-22. Ma's Synthesis 29

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Pd(PPh 3 ) 4 /PPh 3 -catalyzed hydrogenolysis of A98 derived from trans-4-hydroxy-L-proline A97 using ammonium formate as a hydride reagent, provides olefin A99 as a major product, which is hydrolyzed to give (+)--allokainic acid (Scheme 1-22). 1.4.9 Cooks Synthesis 50 The Pd-catalyzed carbocyclization of ketoamides A100 was investigated and found to be highly dependent on the phosphine ligand as well as the presence of coordinating counterions. Nitrogen heterocycles were formed without erosion of the stereochemical integrity. The utility of the lactam products was demonstrated by the formal synthesis of (+)--allokainic acid (Scheme 1-23). ON TBSO O O O Pd(0)EtOLi, EtOHCO2HN TBSO O O HN TBSO O O LnPd HN CO2H HO2C A100A101A102A3Scheme 1-23. Cook's Synthesis 30

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1.5 References 31 1 For reviews, see: (a) Parson, A. F. Tetrahedron, 1996, 52, 4149. (b) Moloney, M. G. Nat. Prod. Rep. 1998, 15, 205. (c) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485. 2 Murakami, S.; Takemoto, T.; Shimizu, Z., J. Pharm. Soc. Jpn., 1953, 73, 1026. 3 Impellizzeri, G; Mangiafico, S.; Oriente, G.; Piatelli, M.; Sciuto, S.; Fattorusso, E.; Magno, S.;Santacroce, S.; Sica, D., Phytochemistry, 1975, 14, 1549. 4 (a) Balansard, G.; Gayte-Sorbier, A.; Cavalli, C., Ann. Pharm. Fr., 1982, 40, 527. (b) Balansard, G.; Pellegrini, M.; Cavalli, C.; Timon-David, P., Ann. Pharm. Fr., 1983, 41, 77. 5 (a) Ueno, Y.; Nawa, H.; Ueyanagi, J.; Morimoto, H.; Nakamori, R.; Matsuoka, T., J. Pharm. Soc.Jpn., 1955, 75, 807, 811 and 814. (b) Honjo, M., J. Pharm. Soc. Jpn., 1955, 75, 853.(c) Murakami, S.; Takemoto, T.; Tei, Z.; Daigo, K., J. Pharm. Soc. Jpn., 1955, 75, 866 and 869. 6 Morimoto, H., J. Pharm. Soc. Jpn., 1955, 75, 901 and 943. 7 (a) Watase, H.; Tomiie, Y.; Nitta, I., Bull. Chem. Soc. Jpn., 1958, 31,714. (b) Watase, H., Tomiie, Y; Nitta, I., Nature (London), 1958, 181,761. 8 Oppolzer, W.; Thirring, K., J. Am. Chem. Soc., 1982, 104, 4978. 9 (a) Morimoto, H., J. Pharm. Soc. Jpn., 1955, 75, 766. (b) Murakami, S.; Daigo, K.; Takagi, N.; Takemoto, T; Tei, Z., J. Pharm. Soc. Jpn., 1955, 75, 1252. (c) Morimoto, H.; Nakamori, R., J. Pharm. Soc. Jpn., 1956, 76, 26. 10 (a) Takemoto, T. and Daigo, K., Chem. Pharm. Bull., 1958, 6, 578. (b) Daigo, K., J. Pharm. Soc. Jpn., 1959, 79, 350.

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32 11 (a) Wright, J.L.C.; Boyd, R.K.; De Freitas, A.S.W.; Falk, M.; Foxall, R.A.; Jamieson, W.D.; Laycock, M.V.; McCulloch, A.W.; Mclnnes, A.G.; Odense, P., Pathak, V.P.; Quilliam, M.A.; Ragan, M.A.; Sim, P.G.; Thibault, P.; Walter, J.A.; Gilgan, M.; Richard, D.J.A.; Dewar, D., Can. J. Chem., 1989, 67, 481. (b) Villac, M.C.; Roelke, D.L.; Villareal, T.A.; Fryxell G.A., Hydrobiologia, 1993, 269-270, 213. 12 Takemoto, T.; Daigo, K.; Kondo, Y.; Kondo K., J. Pharm. Soc. Jpn., 1966, 86, 874. 13 Ohfune, Y.; Tomita, M., J. Am. Chem. Soc., 1982, 104, 3511. 14 (a) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.; Nomoto, K.; Fujita, T., Chem.Pharm. Bull,, 1986, 34, 4892. (b) Wright, J.L.C.; Falk, M.; Mclnnes, A.G.; Walter, J.A., Can. J. Chem., 1990, 68, 22. 15 Walter, J.A.; Falk, M.; Wright, J.L.C., Can. J. Chem., 1994, 72, 430. 16 Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.; Nomoto, K.; Fujita, T.,Tetrahedron Lett., 1987, 28, 633. 17 (a) Konno, K.; Shirahama, H.; Matsumoto, T., Tetrahedron Lett., 1983, 24, 939. (b) Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T., J. Am. Chem. Soc., 1988, 110, 4807. 18 (a) Fushiya, S.; Sato, S.; Kanazawa, T.; Kusano, G.; Nozoe, S., Tetrahedron Lett., 1990, 31, 3901. (b) Fushiya, S.; Sato, S; Kera, Y; Nozoe, S., Heterocycles, 1992, 34, 1277. 19 Maeda, M.; Kodama, T.; Tanaka, T.; Ohfune, Y.; Nomoto, K.; Nishimura, K.; Fujita, T., J. Pestic. Sci., 1984, 9, 27. 20 Husinec, S.; Porter, A.E.A.; Roberts, J.S.; Strachan, C.H., J. Chent Soc., Perkin

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33 Trans. 1, 1984, 2517. 21 (a) McGeer, E.G.; Olney, J.W.; McGeer, P.L., Eds., Kainic Acid as a Tool in Neurobiology, Raven Press, New York, 1978. (b) Simon, R.P., Ed., Excitatory Amino Acids, Thieme Medical Publishers, New York, 1992. (c) Wheal, H.V.; Thomson, A.M., Eds., Excitatory Amino Acids and Synaptic Transmission, Academic Press, London, 1991. (d) Watkins, J.C.; Krogsgaard-Larsen, P.; Honor6, T., Trends Pharmacol. Sci., 1990, 11, 25. 22 (a) Shinozaki, H.; Konishi, S., Brain Res., 1970, 24, 368. (b) Ishida, M.; Shinozaki, H., Brain Res., 1988, 474, 386. (c) Shinozaki, H.; Ishida, M.; Okamoto, T., Brain Res., 1986, 399, 395. (d) Maruyama, M.; Takeda, K., Brain Res., 1989, 504, 328. (e) Shinozaki, H.; Ishida, M.; Gotoh, Y.; Kwak, S., Brain Res., 1989, 503, 330. 23 Sperk, G., Prog. Neurobiol. (Oxford), 1994, 42,1. 24 (a) Coyle, J.T.; Schwarcz, R., Nature (London), 1976, 263, 244. (b) McGeer, E.G.; McGeer, P.L., Nature (London), 1976, 263, 517. 25 (a) Johnston, G.A.R.; Curtis, D.R.; Davies, J.; McCulloch, R.M., Nature (London), 1974, 248, 804. (b) Hansen, J.J.; Krogsgaard-Larsen, P., MecL Res. Rev., 1990, 10, 55. (c) Ishida, M.; Shinozaki, H., Br. J. Pharmacol., 1991, 104, 873. (d) Hashimoto, K.; Ohfune, Y.; Shirahama, H., Tetrahedron Lett., 1995, 36, 6235. 26 See for example: (a) Kozikowski, A.P.; Fauq, A.H., Tetrahedron Len., 1990, 31, 2967. (b) Slevin, J.T.; Collins, J.F.; Coyle, J.T., Brain Res., 1983, 265, 169. (c) Goldberg, O.; Luini, A.; Teichberg, V.I., Tetrahedron Lett., 1980, 21, 2355. 27 Biscoe, T.J.; Evans, R.H.; Headley, P.M.; Martin, M.R.; Watkins, J.C., Br. Z

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34 Pharmacol., 1976, 58, 373. 28 Todd, E.C.D., J. Food Prot., 1993, 56, 69. 29 (a) Work, T.M.; Beale, A.M.; Fritz, L.; Quilliam, M.A.; Silver, M.; Buck, K.; Wright, J.L.C., Dev. Mar. Biol., 1993, 3, 643. (b) Mestel, R., New Scientist, 1995, 147, 6. 30 Konno, K.; Hashimoto, K.; Shirahama, H., Heterocycles, 1992, 33, 303. 31 Shirahama, H., Organic Synthesis in Japan. Past, Present, and Future, Noyori, R. Ed., Soc. Synth. Org. Chem. Jpn., Tokyo Kagaku Dojin, 1992, 373. 32 (a) Tremblay, J.-F. Chem. Eng. News 2000, Jan 3, 14. (b) Tremblay, J.-F. Chem. Eng. News 2000, March 6, 131. 33 For recent reviews, see: (a) Parsons, A. F. Tetrahedron 1996, 52, 4149. Maloney, M. G. Nat. Prod. Rep. 2002, 19, 597. Selected examples: (b) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 4727. (c) Xia, Q.; Ganem, B. Org. Lett. 2002, 485. (d) Hirasawa, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 7587; Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 3181. (e) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 6199. (f) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 3194. (g) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 11139. (h) Rubio, A.; Ezquerra, J.; Escribano, A.; Remuinan, M. J.; Vanquero, J. J. Tetrahedron Lett. 1998, 2171. (i) Cossy, J.; Cases, M.; Pardo, D. G. Synlett 1998, 507. (j) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 18966. (k) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 8. (l) Yoo, S.; Lee, S. H. J. Org. Chem. 1994, 59, 8. (m) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 3. (n) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Chem.

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35 Commun. 1987, 1220. (o) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 8. 34 Baldwin, J.E.; Li, C-S., J. Chem. Soc., Chem. Commun., 1987, 166. 35 Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K., J. Am. Chem. Soc., 1988, 110, 6467. 36 Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303. 37 Qian and Ganem B.; Xia Q.ruce Org. Lett. 2001, 3, 485. 38 Anderson J. C.; Whiting M. J. Org. Chem. 2003, 68, 6160. 39 Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. 40 Lautens, M.; Scott, M. E. Org. Lett. 2005, 7, 3045. 41 Fukuyama, T.; Morita, Y.; Tokuyama, H. Org. Lett. 2005, 7, 4337. 42 (a) Oppolzer, W.; Robbiani. C., Helv. Chim. Acta., 1980, 63, 2010. (b) Oppolzer, W.; Robbiani, C.; Battig, K., Helv. Chim. Acta, 1980, 63, 2015. (c) Oppolzer, W.; Robbiani, C.; Btittig, K., Tetrahedron, 1984, 40, 1391. 43 Kraus, G.A.; Nagy, J.O., Tetrahedron, 1985, 41, 3537. 44 DeShong, P.; Kell, D.A., Tetrahedron Lett., 1986, 27, 3979. 45 Mooiweer, H.H.; Hiemstra, H.; Speckamp, W.N., Tetrahedron, 1991, 47, 3451. 46 Murakami, M.; Hasegawa, N.; Hayashi, M.; Ito, Y., J. Org. Chem., 1991, 56, 7356. 47 (a) Agami, C.; Cases, M.; Couty, F., J. Org. Chem., 1994, 59, 7937. (b) Agami, C.; Couty, F.; Lin, J.; Mikaeloff, A.; Poursoulis, M., Tetrahedron, 1993, 49, 7239. 48 Montgomery, J.; Chevliakov M. V. Angew. Chem. Int. Ed. 1998, 37, 3144. 49 Ma, D.; Wu, W.; Deng, P. Tetrahedron Lett., 2001, 42, 6929. 50 Cook, G. R.; Sun, L. Org. Lett., 2004, 6, 2481.

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Chapter Two The Syntheses of (-)--Kainic Acid and (+)--Allokainic Acid 2.1 Theoretical background 2.1.1 Chiral -Lactams from -Amino Acids via Rh-Catalyzed Intramolecular C-H Insertion Recently, Jungs group developed an intramolecular C-H insertion of -diazo-(phenylsulfonyl)acetamides to afford -lactams with high regio-and stereoselectivities. 1 The highly functionalized -lactams are key intermediates for the synthesis of natural products, 2 which are biologically active. -Diazo--(phenylsulfonyl)acetamides B3 was derived form from secondary amines B1 via the corresponding -(phenylsulfonyl) acetamides B2. Acylated compounds from secondary amines B1 and -haloacetyl halide in TEA and CH 2 Cl 2 at 0 C were treated with sodium benzenesulfinate in DMF at room temperature to afford -(phenylsulfonyl)acetamides B2. A diazo transfer reaction of B2 employing with p-acetamidobenzenesulfonyl azide (p-ABSA) and DBU yielded the corresponding -diazo--(phenylsulfonyl)acetamides B3 (Scheme 2-1). NR2R1 N2 PhO2S O NR2R1 PhO2S O HNR2R1 1. XCH2COX TEA, CH2Cl22. PhSO2Na DMF80-85%ABSADBUCH3CN85-90% Scheme 2-1. The preparation of -diazo--(phenylsulfonyl)acetamides.B1B2B3 Using -amino acids B4 as an amine source, the preparation of various bicyclc -lactams were explored via intramolecular C-H insertion of -diazo--(phenylsulfonyl) 36

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acetamides B6, which possess various functional groups. The cyclizations were highly regioand stereoselective and afforded chiral -lactam compounds B7 in high yields. 1(b) N O PhSO2 O N2 NO O H PhSO2 cat. Rh2(OAc)4R R CH2Cl2Scheme 2-2. C-H insertion of -diazo compounds.NH2 CO2H R N O PhSO2 O R B4B5B6B7 The high regioselectivity and stereoselectivity were rationalized using transition state of the reaction as shown in Figure 2-1. During the insertion reaction, the NOPhPhSO2ORh NOOPhSO2PhH NPhSO2ORh O Ph s-cis, B8s-trans, B8HN Ph H O Rh O HN H Ph O Rh O 1,3-diaxial interactionPhSO2PhSO2B9B10B11Figure 2-1. Transition state of cyclization conformationally restricted metallo carbenoid B8 adopts the scis conformer, 37

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due to the severe nonbonded interaction between the gem-dimethyl group and the carbonyl substituents present in the s-trans conformer B8. Only the s-cis conformer B8 is suitable for cyclization. Now, two possible transition states, B9 and B10, where the phenyl group can be located in either the pseudo axial or the pseudo equatorial positions, can be involved in the next C-H insertion reaction respectively. 3 The former case experiences a severe 1,3-diaxial nonbonded interaction, whereas the latter adopts a stable chairlike transition state with large groups occupying equatorial positions, which lead to relative stereochemistries at C-3, C-4, and C-5 of compound B11. The newly generated stereochemical configuration at C-3 and C-4 were induced by the chirality of the starting -amino acid during the insertion reaction. The stereochemical assignment for B11 was confirmed by X-ray crystallographic analysis. 1(b) 2.1.2 Intramolecular Michael Addition of Cyclic -Ketoester on Conjugated Acetylenic Ketone 4 Based on the known stereoelectronic principles, 5 the first intermediate generated in the nucleophilic addition on a conjugated acetylenic ketone (ynone) should be an allenic enolate, which on protonation produces the corresponding ,-unsaturated ketone (enone). Since allene cannot be accommodated without considerable strain in the rings smaller than cyclooctane, 6 the intramolecular Michael addition on ynone to produce small ring is not expected to take place. Contrary to this conclusion, the Michael type small ring formations from the intramolecular neuclephilic addition on ynones were 38

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reported by Deslongchamps. 4 They proposed a new stereoelectronically controlled pathway. The cyclization was carried out with cesium carbonate at room temperature. The results showed that the formation of five and six-membered rings takes place with ease and in good yield. Scheme 2-3. Intramolecular Michael addition CO2Me O R O n'n CO2Me O n'n R O O O R CO2Me nn' O O R CO2Me nn' B12B13B14B15Cs2CO3+ They also indicate that seven and eight-membered rings can be produced but in very low yield. The observation of an A/B cis junction was reported inall cases. Figure 2-2. Nucleophilic addition to ynoneCC H C O R +NuC Nu H O R C H Nu O R Nu H R O H Nu R O rearfronttopbottomB16B17B18B19B20 39

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According to the explanation, it is normally expected that the addition of a neucleophile onto an enone should take place on the bond of the triple bond which is conjugated with the carbonyl group. On that basis, the approach of neuclephile Nu on an ynone such as B16 can take place from the rear or from the front to produce the two enantiomeric allenic enolates B17 and B18 respectively. In another word, the formation of bicyclic B15 from cyclic -ketoester B12 should not take place because the intermediate bicyclic allenic enolate ion B17 would be too strained when n < 2. This led to the consideration of the possibility that the neucleophilic addition might occur on the non-conjugated bond of the triple bond of the ynone. Such an addition can take place from the top or the bottom of the face of ynone B16; producing the enone-anions B17 and B18 respectively. The non-bonded electron pair in these two anions is not conjugated with the carbonyl group. It is therefore expected that they are less stable than the allenic enolates B17 and B18. The enone-anions should therefore not be observed when it is possible to form the allenic enolates, however, when the latter cannot be produced, it might be possible to generate the formers. The intramolecular version of the process B16 + B20; the pathway B12 to B14 + B15 could indeed lead to the formation of bicyclic enone when n < 2. The anions B19 and B20 may be less basic than one could first anticipate because they are vinylic anions next to a carbonyl group. Indeed, the induc-tive effect of this group should reduce the basicity of the vinylic anions, which could have a basicintermediate between vinylic and an acetylenic anion. 40

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Theoretical calculation 7 were carried out for the allenic enolate (B17 or B18, Nu=H) and the two geometrically isomeric enone-anions (B19 and B20, Y=H). It showed that the allenic enolate is the most stable anion and the enone-anion B19 is 17 kcal/mole less stable. It was concluded that these calculations indicate that the allene enolate should be the only anion formed normally but when the formation of this anion is prohibited by other factors, the higher energy enone-anion B20 could well be generated and that would explain the results. Stereoelectronic principles predict that the anion must be produced in a conformation where the newly formed C-C bond must be parallel (i.e. pseudo-axial), to the system of the ketone group of ring A. Accepting this requirement, examination of molecular models shows that anion B14 is easily constructed when n = 0 or 1. There are howeversome steric constraints when n = 2, which become much more severe when n = 3. On that basis, formation of fiveand six-membered rings would occur via the formation of intermediate B19 and the formation, although in a low yield, of seven and eight membered rings would occur via intermediateB18 and B17 respectively. 8 NSO2Ph O O O Cs2CO3CH3CNNPhO2S O O O C46C45 Scheme 2-4. Intramolecular Michael addition of phenylsulphone compoundABC93% Based on these results, we applied the concept to our system, which is -phenyl sulphonyl--lactam compound B46. We received the desired cyclized product in 95% 41

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yield with a high regioand setereoselctivity. We are confident that the stereochemistry would be A/B cis junction and B/C cis junction based on the result for the intramolecular Michael addition of cyclic -ketoester on conjugated acetylenic ketone. 4 2.1.3 Baeyer-Villiger Oxidation of Cyclohexeneone The vinyl group of an ,-unsaturated primary alkyl ketone shows preferential migration in the Baeyer-Villiger oxidation (Scheme 2-5). 9 The most efficient method for oxidation of cyclohexenone B21 involved treatment of B21 with trifluoro peracetic acid generated from the reaction of trifluoroacetic anhydride and the urea hydrogen peroxide complex to give the desired enol lactone B22 in 92% yield. Hydrogenation of B22 provided the caprolactoneB23, and the usual hydrolytic removal of the chiral auxiliary gave the butyrolactone carboxylic acid B24. N O Et O OMe N O Et OMe O O N O Et OMe O O O O Et CO2H TFAAUHPNa2HPO4CH2Cl2 H2, Rh/C, THF TsOHPhH/H2OrefluxScheme 2-5. Baeyer-Villger oxidation of ,-unsaturated primary alkyl ketoneB21B22B23B24 Katzenellenbogen 10 reported the synthesis of halo enol lactones from -halo cycloenones, using Baeyer-Villiger oxidation, for the study of mechanism-based 42

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inactivators of serine proteases. During the course of this investigation they needed enol lactone compounds such as B26, B28. For these endocyclic lactones, Baeyer-Villiger oxidation was utilized(Scheme 2-6). The success of this strategy depended upon the preferential migration of the vinyl group over the primary alkyl group. Several examples of such vinyl migration are known. 11 However, the presence of the electron-withdrawing halogen on the vinyl group was expected to decrease its migratory aptitude to some extent. Another anticipated difficulty with these substrates was the potential for competing epoxidation of the olefin; this reaction could be avoided under relatively acidicoxidation conditions. Treatment of -bromocyclohexenone B27 with pertrifluoroacetic acid in a buffered system afforded the desired lactone in 68% yield afterchromatography on cyanopropyl functionalized silica gel. O O O Br Br CF3CO3HNa2HPO468% O O O Ph Br Br Ph CF3CO3HCH2Cl282%Scheme 2-6. Baeyer-Villger oxidation of -halo cyclohexenoneB25B26B27B28 1 H NMR analysis of the reaction products offered no evidence of competing alkyl migration. This method was also employed in the synthesis of the lactone B26, obtained in 82% yield from 2-phenyl-1,3-indandione B25. In this case, the vinylic-benzylic 43

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carbon migrated preferentially to the phenyl group, as anticipated. This method does provide an efficient route to these endocyclic lactones; however, the requirement for the vinylic migratory preference may limit potential substrate molecules to those with primary alkyl substituents at the position. 2.2 Synthetic Strategy / The Core Intermediate Early on in the development of our rhodium catalyzed intramolecular C-H insertion methodology, we discovered just how promising and effective this transforma-tion was. The applicability of our initial, acylic methodology was profoundly broadened by its adaptation to accommodate -amino acids as starting materials. 12 Figure 2-3. Synthetic targetNH CO2H CO2H NH HO2C HO2C NH CO2H CO2H A2 (-)-kainic acid NO O PhSO2 TBDMSO C31234512345S t e r e o s e l e c t i v e I n t r o d u c t i o n o f I s o p r o p e n y l g r o u p R e d u c t i o n o f C a r b n y l g r o u p o f t h e l a c t a m Using only the -amino acid as the source of stereogenic bias, -lactams were synthesized regioand stereoselectively yielding a single diastereomer. Two additional 44

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stereocenters were formed simultaneously as dictated by the original stereocenter of the starting material. Based on these precedent results 13 and theoretical background, we discussed in Section 2.1, we turned our full attention to the total synthesis of (-)-kainic acid A2. Compared with (-)--kanic acid A2, the key intermediate C3 has several important structural similarities. The key intermediate C3 can be prepared utilizing fore mentioned Rh-catalyzed C-H insertion reaction with high stereoselectity (Figure 2-3). The stereochemistries of C-2 and C-3 on the product A2 are same with C-4 and C-5 of the intermediate B3, which means that the stereochemistries would be installed via the C-H insertion reaction. The next challenging step for the synthesis of (-)--kanic acid A2 would be a stereoselective introduction of the isopropenyl group onto the C-3 position of the -lactam compound C3. The reduction of the amide carbonyl of the -lactam should be carried on in proper order and way to produce the pyrrolidine core of the (-)--kainic acid. With this basic strategy in mind, a retrosynthetic route was proposed as explained in Section 2.2.1. 2.2.1 Retrosynthetic Analysis of (-)-Kainic Acid (First) We had observed the application of C-H insertion reaction to (L)-glutamic acid yielded a highly functionalized -lactam that could be converted to the pyrrolidine core of (-)-kainic acid A2. Retrosynthetically we envisioned an expedient route to the target molecule featuring two key steps (Figure 2-4). 45

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(-)-Kainic acid A2 is readily available via Jones oxidation of the diol compound C1, which could be derived from the bicyclic -lactam C2 via the reduction of the carbonyl group and deprotection. The -lactam C2 is the product of the second key step of the synthesis, namely an introduction of isopropenyl group on the C-3 position having a syn relationship with the adjacent bulky alkyl group on C-4. The bicyclic -lactam C3 is a product of our Rh-catalyzed intramolecular C-H insertion methodology of a -diazo--(phenylsulfonyl)acetamides C4. This is the first key step in the synthetic route. The -diazo insertion precursor C4 can be efficiently derived from (L)-glutamic acid C5 (Figure 2-4). NO PhO2S O N2 NO O H PhO2S NH2CO2H (L)-glutamic acidHO2C OTBDMS TBDMSO NO O H TBDMSO NH OH HO Introduction ofIsopropenyl group NH CO2H CO2H C-HInsertionA2C1C2C3C4C5Figure 2-4. Retrosynthetic analysis of the total synthesis of (-)-kainic acid (first) 46

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2.2.2 Strategy for the Stereoselective Isopropenylation Figure 2-5. Synthetic StrategyNO O PhSO2 TBDMSO C312345NO O TBDMSO C212345 NO O PhSO2 TBDMSO NO O TBDMSO IsopropenylationDephenylsulfonylationIsopropenylationDephenylsulfonylation C15C24 The substitution of phenylsulfone group on the intermediate C3 to isopropenyl group would be an inavoidable process for the synthesis of (-)--kainic acid. Two plausible routes were proposed; one is the Isopropenylation-Dephenylsulfonylation route, the other one is the Dephenylsulfonylation-Isopropenylation route (Figure 2-5). As discussed in Section 1-3, an efficient control of the cis stereochemistry between C-3 and C-4 positions is the key issue for the successful synthesis. It was proved from the successful precedent reports that were depicted in Section 1-3. There are three main strategies, utilized for the control of the stereochemistry, in the successful precedent reports. One, the two bulky groups were introduced at the same time to derive the cis relationship via conserted reactions such as ene reaction, 14 Claisen rearrangement. 15 Two, the two bulky substituents were installed via a 47

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ring opening step, which usually were sterically rigid and formed at the early stage of the reaction. The typical ring formations such as Pauson-Khand reaction, 16 [3 + 2] cycloaddition 17 were employed for this purpose. Three, the syn relationship was obtained from the hydrogenation method of a double bond, which was between C-3 and C-4 position. 18 An exo vinyl group attached on C-4 position was another choice for the location in the hydrogenation route. Then, the reactions such as intramolecular protodesilylation, 19 hydroboration 20 were followed by for a stereocontrol. Which strategy can we choose for our synthesis? This was our main focus after getting the -lactam compound C3 in hand. The structural features and key factors in the key intermediate C3 were analyzed. 2.2.3 Bicyclic-Lactam Intermediate NO O PhSO2 TBDMSO C3 NO O SO2Ph OTBDMS 1,2-InductionConvex-Concave Figure 2-6. Controlling factors-position 31233 NO O OTBDMS Upon introducing a bulky isopropenyl group onto the C-3 position of the intermediate C3, there are three factors to be considered; (1) convex-concave interaction of the bicyclic system, (2) 1,2-induction derived from the adjacent bulky group, 48

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(3) an easy enolization character of the C-3 position due to adjacent carbonyl group and double bond. Unfortunately, the factors (1) and (2) were not surportive but competitive, and the factor (3) made worse the introduction of the isopropenyl group in syn fashion. Our long journey to the (-)-kainic acid got started with knowledge of these findings. 2.2.4 Synthesis of the Bicyclic-Lactam Intermediate Our endeavor into the synthesis of (-)-kanic acid began with the development of an efficient route for the synthesis of -lactam compound C3. Esterification reaction of L-glutamic acid C5 21 was conducted employing SOCl 2 in MeOH as an acid source. The HCl salt of the product of the ester was treated with NaHCO 3 to produce neutral L-glutamic acid dimethyl ester C6. Both ester groups were then reduced to diol by reacting with LAH to give amino alcohol C7 4 after Fisher work-up. NH2CO2HHO2C SOCl2, MeOHTBDMSOClO AcetoneMgSO4TBDMSO NaHTBDMSClOHN ON HO OHNH2 NH2CO2MeMeO2C LAH then NaHCO3HO OHN ClCH2COClC5C6C7C8C9C10Scheme 2-7. Synthesis of the acetylated compound C1099%70%91%85%88% 49

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The primary alcohol and the nitrogen of the amine were simultaneously protected as an acetonide by refluxing C7 in acetone in the presence of MgSO 4 In this reaction, 5-membered acetonide C8 was the main product, with a trace amount of side product including 7-membered acetonide. The remaining primary alcohol was protected with TBDMS group using NaH/TBDMSCl condition. 22 The general TBDMSCl protection such as TBDMSCl/imid, TEA/DMAP in CH 2 Cl 2 delivered poor yield of the desired product C9. N-Acylation using chloroacetyl chloride proceeded readily to give the chloride C10 in high yield. The choice of the chloroacetyl chloride instead of bromoacetyl bromide was a phenomenal decision in terms of the yield and the stability of the product. TBDMSOClO ON TBDMSOPhO2SO ON p-ABSADBU, CH3CNONTBDMSOPhO2SO N2 cat. Rh2(OAc)4CH2Cl2NO O PhSO2 H TBDMSO PhSO2NaC10C11C12C3Scheme 2-8. C-H insertion reaction for -lactam intermediate 91%89%92% The resulting chloride C10 was treated with PhSO 2 Na to displace the chlorine with a phenylsulfone group resulting in the formation of phenylsulfone compound C11 50

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in excellent yield. Diazo transfer to the -position of the acetamide C11 occurred readily using p-ABSA and DBU in acetonitrile providing the -diazo-(phenylsulfonyl)acetamide C12, which is a precursor for the C-H insertion reaction. The product was purified using a flash column chromatography. The standard reaction condition for our C-H insertion protocol was applied to the diazo compound C12. It provided us the bicyclic -lactam intermediate C13, which is a key intermediate, in high yield. The reaction was highly regioand stereoselective as expected providing only one diasereomer after a simple chromatography (Scheme 2-8). 2.3 Total Synthesis of (+)-Allokainic Acid 2.3.1 Introduction of Isopropenyl Group Upon obtaining the bicyclic -lactam C13 successfully, next challenging goal was the introduction of the isopropenyl group onto the -position of the -lactam C13. The stereoselectivity of the isopropenylation was the most important factor for the synthesis of (-)-kanic acid A2, which should have a cis relationship between C-3 and C-4 substituents. As discussed Section 1-3 and 1-4, the most of successful syntheses utilized their own strategy, which was to achieve the cis relationship. 23 The failure on the installation of the cis relationship between C-3 and C-4 substituents and obtaining a trans diastereomer usually resulted in the synthesis of (+)-allokainic acid A3, which is the C-4 epimer of (-)-kainic acid A2. 51

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Our initial endeavor into the stereocontrol began with the stereoselective dephenylsulfonylation route from the isopropenylated intermediate C15. The preparation of the isopropenylated compound C15 was accomplished as described in Scheme 2-9. NO O PhSO2 H TBDMSO NO O PhSO2 H TBDMSO O NO O PhSO2 H TBDMSO Ac2O, NaHTHFNO O PhSO2 H TBDMSO OTf Wittig, Tebbe, Takai Tf2O, KHMDS ZnMe2Pd(PPh3)4 C3C13C14C15Scheme 2-9. Introduction of isopropenyl group98%60%85% Acetylation onto the -position was utilized for the preparation of a synthon for the isopropenyl compound C15. A noble acetylation condition for this center was developed utilizing Ac 2 O and NaH in THF solution producing a high yield of the product C13 as a white solid. The reaction was regioand stereoselective giving only one diastereomer. We were confident with the stereochemistry of the compound C13 based on Meyers concept. It showed that alkylations of bicyclic systems typically occur on the -face (convex face in this case) of the molecule. Next, attention was focused to the vinylation of the carbonyl group in the acetyl compound C13. The typical olefination protocols, 52

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including Wittig, 24 Tebbe, 25 Lombardo, and Takai 26 were not effective in this system due to the easy deacetylation or dephenylsulfonylation. To circumvent the side reaction, we chose a by-pass of triflate C14 by treating the compound C13 with KHMDS and Tf 2 O. 27 The methylation reaction of the triflate C14 occurred readily using a Negishi type Pd(0) catalyzed alkylation protocol. 28 Dimethyl zinc was the choice of the reagent as a coupling partner for the reaction producing the isopropenyl compound C15. 29 2.3.2 Synthesis of (+)-Allokainic Acid (1) ; Isopropenylation-Dephenylsulfonylation Route With the isopropenylated compound C15 in hand, the stereoselective dephenylsulfonylation reaction 30 became the focus of the next leg of the synthesis. Surprisingly the reduction of phenylsulfone group using 10% Na(Hg) in MeOH occurred readily resulting in only one diastereomer C16 (Scheme 2-10). Na/HgNO O H TBDMSO NO O PhSO2 H TBDMSO C15C16Scheme 2-10. Stereoselective dephenylsulfonylization31288%MeOH The stereochemistry of the C-3 position on the lactam compound C16 was not known at the time of the first synthesis. The coupling constant (J) of the proton on C-3 position was 12.8 Hz implying a high possibility of trans-relationship with the proton on C-4 position. The result was surprising as we anticipated a degree of diastereoselection 53

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based on the single electron mechanism through, which this reaction proceeded. 11 The reaction was reproducible giving only one diasteromer. The stereochemistry of C-3 position became an issue because the final compounds, (-)-kainic acid A2 or (+)-allokainic acid A3, would be destined by the stereochemistry of C-3 position. There was no choice but to touch the final compound and verify its stereochemistry by comparing with the known data. So, we embarked on the later part of the synthesis with a hope for the syntheis of (-)-kainic acid A2. The acetonide in compound C16 was unmasked via Dowex 50W-8X condition in boiling MeOH resulted in the simultaneous TBDMS deprotection to give the diol C17. Both hydroxyl groups were protected with TBDMS group employing the regular TBDMS protection method delivering the amide C18. Subsequent BOC protection of the amide group resulted in the synthesis of the amide C19 (Scheme 2-11). NO O H TBDMSO Dowex 50W-8XNHOH O HO NHOTBDMS O TBDMSO NBocOTBDMS O TBDMSO TBDMSClBoc2OC16C17C18C19Scheme 2-11. Precursor for the ending game 99%85%92% 54

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Next, our attention turned to the reduction of the carbonyl group of the amide C19 to introduce a pyrrolidine core for kainoids synthesis. The Rubio method 31 was used for for this purpose to protect the sensitive functional groups including the alkene. The BOC protected amide C19 was treated with Superhydride at -78 C, resulting in high yield of the hemiaminal compound C20. Consecutive reaction with BF 3 OEt 2 in the presence of Et 3 SiH provided the reduced pyrollidine compound C21, along with TBDMS deprotected compounds. Jones OxA3 (+)-allokainic acidNBocOTBDMS O TBDMSO NBocOTBDMS OH TBDMSO NBocOTBDMS TBDMSO LiEt3BH TBAF NBocOH HO NBocCO2H CO2H NHCO2H CO2H CF3CO2HC19C20C21C22C23Scheme 2-12. The synthesis of (+)-allokainic acid (1) 85%BF3OEt2Et3SiH80%90%79%90% The undesired TBDMS deprotection was not an issue because the next step was the deprotection of both TBDMS protected hydroxyl groups. With the diol C22 in hand, the next step was an employment of the Jones reagent to oxidize the alcohol to the carboxylic acid C23. The deprotection of the BOC group using TFA in CH 2 Cl 2 55

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provided the final product. Much to our dislike, the final compound was proven to be (+)-allokainic acid from the NMR studies (Scheme 2-12). 32 With this knowledge, an intensive exploration for the correct stereochemistry in favor of (-)-kainic acid A2 was begun. 2.3.3 Synthesis of (+)-Allokainic Acid (2) ; Dephenylsulfonylation-Isopropenylation route The search for the method to get a correct stereochemistry on the C-4 position guided us to get another route of (+)-allokainic acid A3. It is the second strategy which was discussed in Section 2.2.2. The route was well described in Scheme 2-13. Reductive dephenylsulfonylation reaction of C3 occurred smoothly using Na(Hg) in MeOH. The reaction gave the bicyclic amide C24. With the bicyclic compound C24 elicited, we took advantage of the structural feature of the bicyclic compound. There are two factors that can affect the face selection for the aldol reaction (Section 2.2.3) ; one is the concave/convex interaction of the bicyclic system and the other one is the 1,2-induction induced from the bulky group on the C-4 position. Unfortunately the two factors contradicted each other, offering opposite stereoselectivities. The amide C24 was treated with LDA at -78C, the resulting enolate was reacted with acetone to yield the aldol products as a mixture of the two diastereomers. The mixture was separable and had a ratio of 5:1 = C25:C26 in favor of the synthesis of (+)-allokainic acid A3 and, not (-)-kainic acid A2. The 1,2-induction of the bulky group on the 56

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C-4 position was a more important factor for the stereoselectivity than concave/convex nature of the bicyclic system. NO O PhSO2 H TBDMSO NO O H TBDMSO Na/HgMeOHNO O H TBDMSO HO LDAacetoneNO O H TBDMSO HO 5 : 1+NO O H TBDMSO NO O H TBDMSO A3 (+)-allokainic acidA2 (-)-kainic acid PCl5PCl5C3C16C24C25C26C2Scheme 2-13. The synthesis of (+)-allokainic acid (2) 96%92%90%90% The two diatereomers were separated using a column chromatography. At this point, our attention turned to the dehydration of the tert-alcohol in the compounds C25 and C26 to introduce the isopropenyl group. PCl 5 33 was the choice for the reagent for elimination due to the high yield and short reaction time. The NMR of C16 was exactly the same as the product we got from the dephenylsulfonylation method as shown Scheme 2-10. The desired isopropenylated compound C2 for the synthesis of (-)-kainic acid A2, also successfully prepared using the same dehydration method. It was not meaningful to follow the later part of the synthesis for (-)-kainic acid A2 using the minor diastereomer. 57

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2.3.4 Model Study and Other Endaevors We embarked on the model study for the dephenylsulfonylation with a hope of getting the correct stereochemistry, in favor of (-)-kainic acid (Table 2-1). This reductive dephenylsulfonylation occurred readily, in high yield, to give the reduced products. Na/HgMeOH NO O PhSO2 H TBDMSO R NO O H TBDMSO R NO O H TBDMSO R +trans / cisentry123 R O MeO OHBr454/11/1N/A** Dehalogenation occured.Table 2-1. Model study of dephenylsulfonylationtrans only(C15)(C27)(C28)(C29)(C30)trans only Acetyl compound C27 delivered the trans compound exclusively (entry 2), as for the isopropenylated compound C15 (entry 1). Each of them is bulky and an activating group making the proton on the -position enolizable. The MOM group attached product, which is bulky but not activating, produced the mixture of the two diastereomers in a 4 to 1 ratio (entry 3). The -hydroxylated compound, which was prepared using the Davis oxazirididine, 34 delivered 1/1 mixtures of the diastereomers (entry 4). The 58

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bromide was not effective for this reaction due to the dehalogenation in the reaction condition (entry 5). NO O H TBDMSO C24NO O H TBDMSO Br C31NO O H TBDMSO Br C32+1/1Scheme 2-14. Bromination reactionLDANBS60% As an alternative route, the bromination reaction was studied to introduce a bromide group that could be substituted with the isopropenyl group via Sn2 type cuprate alkylation (Scheme 2-14). 35 The bromination reaction onto the -position of the bicyclic compound B14 utilizing LDA/NBS condition provided a 1/1 mixture of the diastereomers. Our endeavor to circumvent the stereochemistry issue was continued as described in Scheme 2-15, 16, and 17. A hydrogenation route featuring the use of -exo vinyl--lactam compound C35 as a key intermediate was tested. The concept is that hydrogen would approach from the -face due to the 1,2-induction from the adjacent substituent providing the desired cis compound C36. The aldol reaction of the dephenylsulfonylated compound C24 with -benzyloxy acetone occurred readily to provide the compound C33. The manipulation of function groups and dehydration reaction utilizing SOCl 2 condition derived the formation of the alkene compound C35. 59

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NBocOTBDMS TBDMSO O BnO NO O H TBDMSO HO LDAacetoneNO O H TBDMSO C2492% OBn O OBn NBocOTBDMS TBDMSO O OBn 3 stepsHO 40%SOCl2, Pyr H2, Pd/CMeOHNBocOTBDMS TBDMSO O HO 2 diastereomersNBocOTBDMS TBDMSO O 40% C33C34C35C36C19Scheme 2-15. Hydrogenation route (1) The reaction yield and regioselectivity for the exo vinyl compound C35 were not improved to our expected level. Next, hydrogenation was effective accompanying the debenzylation step to give the alcohol C36 in 40%. However the stereoselectivity in hydrogenationstep was not verified. The elimination step, which introduces the isopropenyl group, was not effective and made us to stop this route (Scheme 2-15). NO O H TBDMSO HO OBn NBocCO2Me CO2Me OBn HO C24C38Scheme 2-16. Hydrogenation route (2)NHOH H HO HO OBn C37NBocCO2Me CO2Me OBn C39 1. Dowex 50W-8X2. BH3, DME 70% 60

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The preparation of the alkene compound C39 was tried to get an intermediate for hydrogenation route. The compound C24 was unmasked and the resulting amide was reduced using boranein DME reflux condition. However, the elimination of the alcohol compound C38 to the alkene C39 was not effective (Scheme 2-16). As depicted in Scheme 2-17, the -diazo ester C41 was prepared from the ester C40 via LDA / PNBA condition. 36 The resulting complex was quenched with buffer solution (pH=7) to deliver yellowish diazo compound C41 successfully. ON MeO2C OTBDMS C40 ON MeO2C OTBDMS N2 C41 ON MeO2C TBSO ON MeO2C OTBDMS C43 Scheme 2-17. -Diazo ester route1. LDA2. PNBA3. Buffer pH765% Rh2(OAc)4C42 The nextchallenging step, C-H insertion reaction, using Rh(II) catalyst resulted in exclusive -hydride elimination reaction yielding the compound C43. The pyrollidine compound C42 was not isolated from the reaction. 61

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2.3.5 Conclusion The first generation of the retrosynthetic analysis (Figure 2-4) for the synthesis of (-)-kainic acid A2 did not work out. The two synthetic strategies depicted in Section 2.2.2 for the stereoselective isopropenylation were studied. Instead of (-)-kainic acid A2, (+)-allokainic acid A3 was synthesized from the two methods, which was developed during the study. The two route was efficient for the synthesis of (+)-allokainic acid A3 by producing the compound in 11% overall yields after 15 steps starting from (L)-glutamic acid C5. From the results and model study, it was inferred that the direct use of the phenyl-sulfone compound C3 for the stereoselective introduction of the isopropenyl group in a syn fashion neededanother concept to be considered. 2.4 Total Synthesis of (-)-Kainic Acid 2.4.1 Retrosynthetic Analysis of (-)-Kainic acid (Second) After a complete reevaluation of the proposed synthetic strategies, we inferred thatthe two substituents on C-3 and C-4 position should be handled together via ring formation until the late stage of the synthesis. Meanwhile, a new route was envisioned based on a precedented Michael type cyclization reaction, which is the formation of a bicyclic cyclohexenone from the cyclic -ketoester containing conjugated acetylenic ketone B12 (Scheme 2-18). 37 62

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CO2Me O O O O CO2Me B12B15 Cs2CO3CH3CN Scheme 2-18. Intramolecular Michael additionH H n, n' =1 The new and expedient route to the target molecule features three key steps; C-H insertion reaction, intramolecular Michael type cyclization, and stereoselective dephenylsulfonylation. Retrosynthetically, (-)-kainic acid A2 would be available from the cyclohexenone compound C44 via Baeyer-Villiger oxidation and ring opening. The bicyclic cyclohexenone compound C44 with an A/B cis junction could be derived utilizing stereoselective dephenylsulfonylation of the cyclized phenylsulfone compound C45. CyclizationN O CO2Me O Boc H H NPhO2S O O O NO O H PhO2S TBDMSO NH CO2H CO2H A2NH2CO2H (L)-glutamic acidHO2C C5C3C44C46Figure 2-7. Retrosynthetic analysis of the total synthesis of (-)-kainic acid (second)NSO2Ph O O O C45 63

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An intramolecular Michael type cyclization reaction would provide the tricyclic compound C46. The precursor for the cyclization reaction C46 could be prepared from the compound C3 via deprotection, oxidation, Grignard reaction, and oxidation. It was allowed us to take advantage of the C-H insertion as a first key reaction to prepare the -lactam compound C3 (Figure 2-7). 2.4.2 Michael type Cyclization NPhO2S O O TBDMSO TBAFNPhO2S CHO O O NPhO2S O O OH MgBr DMP NPhO2S O O HO DMPNPhO2S O O O C3C47C48C49C46Scheme 2-19. Preparation of ynone compound for Michael type cyclization123496%95%93%92% The goal of the next leg of the synthesis was to functionalize the C-4 substituent on the intermediate C3 and make a precursor C46 for the cyclization. The TBDMS group on the compound C3 was deprotected using TBAF. This was done to prepare the alcohol C47. The oxid-ation reaction of the alcohol to aldehyde C48 using Dess-martin periodinane 38 occurred readily in high yield. It was followed by a Grignard 64

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reaction using 1-propynylmagnesium bromide, which delivered the secondary alcohol C49. The secondary alcohol was oxidized to the ynone compound C46, which is a precursor for the Michael type cyclization (Scheme 2-19). NSO2Ph O O O Cs2CO3CH3CNNPhO2S O O O C46C45 Scheme 2-4. Intramolecular Michael addition of phenylsulphone compoundABC93% With the compound C46 in hand, we implemented the Michael type cyclization using Cs 2 CO 3 as a base. 1 The reaction occurred readily to provide the desired tricyclic compound C45 successfully. The low concentration (0.0025M) of the reaction solution was a key factor for the high yield. Prolonged reaction time and high concentration produced low yield of the product. The reaction is highly regio-and stereoselective to yield only one diastereomer. The other diastereomers were not detected at all. It was believed that the stereochemistry would be an A/B cis junction based on the Deslongchampss results (Scheme 2-4). 1 2.4.3 Synthesis of Bicyclic Cyclohexenone System At this point, it was expected that the dephenylsulfonylation would give the desired cis diastereomer exclusively, however, the two diastereomers C50, C51 was produced in a 1 to 1 ratio from the tricyclic compound C45 under the regular dephenylsulfonylationcondition (Scheme 2-20). 65

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NSO2Ph O O O N O O O H H N O O O H H Na/Hg+1 : 1C45C50C51Scheme 2-20. Dephenylsulphonylation of tricyclic system Next, a bicyclic system was prepared by unmasking the acetonide C45 and functionalizing the resulting alcohol to the ester compound C55, which was necessary for the kainic acid A2 (Scheme 2-21). NSO2Ph O O O DowexJonesOxNHSO2Ph O OH O NHSO2Ph O CO2H O NHSO2Ph O CO2Me O TMSCHN2Boc2OC45C52C53C54NSO2Ph O CO2Me O Boc C55 Scheme 2-21. Preparation of the bicyclic system50W-8X99%99%95%95% Treatment of the tricyclic compound C45 with Dowex 50W-8X in MeOH delivered the alcohol compound C52 quantitatively. It was followed by the Jones oxidation to make the acid C53, esterification using TMSCHN 2 39 for the ester compound C54. The BOC protection of an amide group on C54 produced the bicyclic precursor C55 for the challenging next step. 66

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2.4.4 Dephenylsulfonylation of Bicyclic Cyclohexenone System At this point, our focus was on the elucidation of the best intermediate for the clean and stereoselective dephenylsulfonylation. Some shortcomings on the amide C54 and BOC-protected bicyclic compound C55 were found. The amide C54 was a good intermediate to get cis junction product C56 but the reaction condition for a BOC protection ruined the stereochemistry, due to the unexpected side reaction leading to the diBOC compound C57. On the other hand, the BOC-protected bicyclic compound C55 was not stable under the Na(Hg) reduction condition and decomposed (Scheme 2-22). NHSO2Ph O CO2Me O NSO2Ph O CO2Me O Boc N O CO2Me O Boc H H NH O CO2Me O H H N OBoc CO2Me O Boc H Na/HgBoc2O Na/HgDecompositionMinor Scheme 2-22. Dephenylsulphonylation of bicyclic systemC54C56C57C55C4480%10%70% 2.4.5 Dephenylsulfonylation of the Silyl Enol Ether The idea, the formation and utilization of the the silyl enolether system derived from the cyclohexenone, 40 was tested. It was assumed that the diene system of the 6-membered ring would make the ring flat during the dephenylsulfonylation 67

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preventing epimerization. The silylation of the cyclohexenone C55 using TBSOTf in the presence of TEA occurred readily to give a mixture of two isomers C58 and C59. Both were subjected to the reduction condition using Na(Hg) at -20 C providing only one diastereomer in 98% yield. The stereochemistry was not known at the moment, but it was proved that the product C44 has a desired stereochemistry for (-)-kainic acid. TBS deprotection step after dephenylsulfonylation occurred simultaneously to yield the cyclohexenone compound C44. The mixture of THF/MeOH (90/10) was the choice of the solvent for the dephenylsulfonylation step to get high yield of the product C44 (Scheme 2-23). NSO2Ph O CO2Me O Boc TBSOTfTEAN O CO2Me O Boc H H Na/HgOne diastereomerN O CO2Me TBSO Boc H SO2Ph N O CO2Me TBSO Boc H SO2Ph +THF/MeOHC55C58C59C44Scheme 2-23. Stereocontrol using dephenylsulphonylation of silyl dienol ether 99%98% 68

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2.4.6 NOE study The stereochemical assignment of the compound C44 was made on the basis of NOE experiments and coupling constant analysis. We became confident with the stereochemistry after this point and verified the correct stereochemistry by making the final product, (-)-kainic acid A2. N O CO2Me O Boc H H H H H 12345123457.2Hz Figure 2-8. 1H NMR spectrum of C44 Firstly, each proton peak was assigned base on the 1 H-NMR, 13 C-NMR, COSY-NMR. The coupling constant of H 1 with H 2 was 7.2 Hz which was a typical coupling constant between syn hydrogens (Figure 2-8). 69

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N O CO2Me O Boc H H H H H 1234512345 Figure 2-9. NOE H1 spectrum 21 Secondly, significant NOE between H 1 and H 2 was observed when H 1 was irridiated; H 1 and H 2 are on the same face (Figure 2-9). 70

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1234521345 N O CO2Me O Boc H H H H H 12345 Figure 2-10. NOE H2 spectrum Thirdly, significant NOEs between H 2 and H 4 H 2 and H 1 were observed when H 2 was irridiated; H 2 and H 4 H 2 and H 1 are on the same face (Figure 2-10). 71

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1234521345 N O CO2Me O Boc H H H H H 12345 Figure 2-11. NOE H4 spectrum Fourthly, significant NOEs between H 4 and H 2 H 4 and H 5 were observed when H 4 was irridiated (Figure 2-11). 72

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1234521345 N O CO2Me O Boc H H H H H 12345 Figure 2-12. NOE H5 spectrum Fifthly, significant NOEs between H 5 and H 4 H 5 and H 3 were observed when H 5 was irridiated (Figure 2-12). 73

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2.4.7 Rationale for the Stereochemistry N O CO2Me O Boc H H H H H 1 2 3 4 5 Strong interaction betweenH1-H2, H2-H3, H4-H5 J 1, 2 = 7.2 HzFigure 2-13. NOE experiment, Overall The stereoselective dephenylsulfonylation from the silyl enol ether providing sole A/B cis junction could be explained from NOE study as summarized in Figure 2-13. The result could be rationalized using the model of the transition state in dephenylsulfonylation step. The sp 2 character on ring A made the ring system flat holding, when the enolate picks up the proton from a protic solvent in the reaction condition (Figure 2-14). N O Boc H CO2Me H TBSO sp2sp2sp2sp2Figure 2-14. Silyl enol ether HO CH3 face attackABRing A is flat 2.4.8 Endgame for the Synthesis of (-)-Kainic Acid (1) With the bicyclic -lactam in hand, ring opening of the cyclohexenone 74

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became the focus of the end game in the synthesis. Schultz reported a Baeyer Villiger oxidation of ,-unsaturated primary alkyl ketone to get 7-membered enol lactone (Scheme 2-5). 41 The cyclohexenone compound C44 in our system underwent a regioselective Baeyer-Villiger oxidation with pertrifluoroacetic acid prepared in situ, according to the procedure reported by Schultz, 5 whereby trifluoroacetic anhydride is reacted with urea-hydrogen peroxide in dichloromethane in the presence of sodium hydrogen phosphate. Under these reaction conditions the enol lactone C60 was stable but prolonged reaction time resulted in a low yield of the product. As an alternative peroxyacid, m-CPBA also gave an excellent regioselectivity and higher yield of the product C60 (Scheme 2-24). N O CO2Me O Boc H H N O CO2Me O Boc H H O C44C60Scheme 2-24. Baeyer-Villiger oxidation60%m-CPBACH2Cl2 The hydrogenation route was tested to introduce isopropenyl and ester group that were needed for the synthesis of (-)-kainic acid A2. Hydrogenation reaction 42 of the enol lactone C60 occurred readily with an excellent stereoselectivity to give 7-member lactone compound C61. The rationale for the assignment of the stereochemistry of C61 is based on the convex-concave concept, which leads to a favored approach of the hydrogen and catalyst to the less hindered -face of C60 (Scheme 2-25). 75

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N O CO2Me O Boc H H O H2, Pd/CEtOAcScheme 2-25. HydrogenationC61N O CO2Me O Boc H H O C60 4 After receiving the lactone C61, it was believed to be promising intermediate to get to the final compound, (-)-kainic acid A2, because the C-4 epimer of C61 was utilized as an intermediate for the synthesis of (-)-kainic acid A2 (Scheme 2-26). 43 N O CO2Me O Boc H H O C61(C-4 epi)N O CO2Me Boc H HO CO2Me C64(epi) (-)-kainic acidScheme 2-26. Clayden's synthesis Unexpectedly, the same condition with Claydens synthesis for the lactone ring opening gave a totally different product in our system (Scheme 2-27). Lactone compound C61 was reacted with NaOMe and the resulting alkoxide anion on C62 attacked the carbonyl of the BOC-protected amide group on C62. It resulted in the formation of -lactone compound C63. 76

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N O CO2Me O Boc H H O N O CO2Me Boc H HO CO2Me NaOMe, MeOH-78oCNHBoc O CO2Me CO2Me O H N O CO2Me Boc H H O MeO2C Scheme 2-27. Hydrogenation routeC61C62C63C64N O CO2Me Boc CO2Me Tetrahedron, 2002, 58, 4727(-)-kainic acid C65 2.4.9 Endgame for the Synthesis of (-)-Kainic Acid (2) Now, it was encouraging to go through the issue of the undesired competing reaction, the formation of -lactone compound C63, by developing a new reaction route. The ring opening at the enol lactone C60 stage using NaOMe at -78 C was tested. Fortunately, the aldehyde ester 44 compound C66, which is a noble compound, was obtained without epimerization on the -position of the -lactam ring. Next, one pot reduction of both the aldehyde and the amide carbonyl utilizing DIBAL at -78 C occurred readily to provide the hemiaminal alcohol compound C67 in high yield (Scheme 2-28). 77

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N OH CO2Me Boc MeO2C HO DIBALN O CO2Me OHC Boc MeO2C N O CO2Me O Boc H H O NaOMeMeOHC60C66C67Scheme 2-28. Ring opening and reduction 85%98% The mixture of four diastereomers was carried forward for the selective mesylation of the primary alcohol on C67. To be our delight, the reaction yielded the mesylated hemiaminal intermediate C68 selectively. Further reduction of the hemiaminal compound using Et 3 SiH and boron BF 3 OEt 2 protocol was followed to generate the pyrrolidine core for the kainoid synthesis. The mesylated pyrrolidine intermediate C68 was subjected to the elimination reaction of the mesyl group. This was done to introduce the isopropenyl group utilizing NaI/DBU condition, 45 in boiling DME, produced the isopropenyl pyrrolidine compound C70. The final deprotections took place on treatment with LiOH and trifluoroacetic acid. 46 After purification with ion-exchange resin, the final product, (-)-kainic acid A2, was obtained successfully. The total synthesis of A2 was accomplished in 25 steps with a 5% overall yield. The synthetic (-)-kainic acid A2 was identical spectroscopically to reported data. The other physical properties including specific rotation and melting point were coinciding with standard data of the natural product and the other synthetic product reported by other research groups. 47 78

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Et3SiHBF3OEtCH2Cl2-78oCN CO2Me Boc MeO2C MsO N OH CO2Me Boc MeO2C MsO MsCl, TEAN CO2Me Boc MeO2C NaI, DBUDMECH2Cl20oC1. LiOH2. TFAA2 (-)-kainic acidNH CO2H CO2H C68C69C70Scheme 2-29. Endgame for the total Synthesis of (-)-Kainic acidN OH CO2Me Boc MeO2C HO C67 75%75%85%85% 2.4.10 Conclusion and Features One, (-)--kainic acid A2 and (+)--allokainic acid A3 were synthesized stereosectively utilizing three key reactions; C-H insertion reaction, intramolecular Michael type cyclization, and stereoselective dephenylsulfonylation of silyl enol ether. Two, the trans relationship between C-2 and C-3 was installed by the C-H insertion reaction and the cis relationship between C-3 and C-4 was installed using the stereoselective dephenylsulfonylation of the silylenol ether. Three, all stereochemistries were introduced from (L)-glutamic acid without using any chiral auxiliary. Four, the total synthesis of (-)--kainic acid A2 was accomplished in 25 steps with a 5% overall yield. 79

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Total Synthesis of (-)--Kainic Acid Number of steps 25 steps Overall yield 5% Key reactions Rh(II) catalyzed intramolecular C-H insertion reaction Michael-type cyclization Stereoselective dephenylsulfonylatio Key points Regioand stereoselective No chiral auxiliary or expansive material ewre used All stereochemistries were introduced from (L)-glutamic acid Total Synthesis of (+)--Allokainic Acid Number of steps 19 steps Overall yield 9% Key reactions Rh(II) catalyzed intramolecular C-H insertion reaction Stereoselective dephenylsulfonylatio Key points Regioand stereoselective No chiral auxiliary or expansive material ewre used All stereochemistries were introduced from (L)-glutamic acid Table 2-2. Summary of the syntheses of (-)-kainic acid and (+)-allokainic acid 80

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2.5 References 81 1 (a) Yoon,C.H.; Zaworotko,M.J.; Moulton,B.; Jung,K.W. Org. Lett. 2001, 3, 3539. (b) Yoon,C.H.; Flanigan,D.L.; Chong,B.D.; Jung,K.W. J. Org. Chem. 2002, 67, 6582. (c) Yoon,C.H.; Nagle,A.; Chen,C.; Gandhi,D.; Jung,K.W. Org. Lett. 2003, 5, 2259 2 (a) Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352. (b) Paquette, L. A.; Macdonald, D.; Anderson, L. G.; Wright, J. J. Am. Chem. Soc. 1989, 111, 8037. (c) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36. (d) Hayasshi, Y.; Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org. Chem. 2002, 67, 9443 and references herein. (e) Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, J. P. J. Org. Chem. 1999, 64, 6005. (f) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434. (g) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621. (h) Roberson, C. W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 11342. (i) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485. (j) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, C.; Corey, E. J.; Schreiber S. L. Science, 1995, 268, 726 and references therein. (k) Corey, E. J.; Li, W. D. A. Chem. Pharm. Bull. 1999, 47, 1. (l) Masse, C. J.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513. (m) Yoon, C. H.; Flanigan, D. L.; Jung, Y. C.; Jung, K. W. submitted J. Am. Chem. Soc. (n) Yoon, C. H.; Flanigan, D. L.; Chong, B. D.; Jung, K. W. J. Org. Chem. 2002, 67, 6582. (o) Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W. In press Org. Lett. 2003. (p) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001; 123, 7534. (q) Snider, B. B.; Lin, H. Org. Lett. 2000, 2, 643. (r) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053.

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82 (s) Macdonald, S. J. F.; Clarke, G. D. E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166. (t) Andrews, D. M.; Carey, S. J.; Chaignot, H.; Coomber, B. A.; Gray, N. M.; Hind, S. L.; Jones, P. S.; Mills, G.; Robinson, J. E.; Slater, M. J. Org. Lett. 2002, 4, 4475. (u) Andrews, D. M.; Jones, P. S.; Mills, G.; Hind, S. L.; Slater, M. J.; Trivedi, N.; Wareing, K. J. Bioorg. Med. Chem. Lett. 2003, 13, 1657. 3 Taber, D. F.; You, K. K. Tetrahedron 1995, 117, 5757. 4 Deslongchamp, P.; Lavallee, J.; Berthiaume, G. Tetrahedron Lett. 1986, 27, 5455. 5 Deslongchamp, P. In Stereoelectronic effects in organic chemistry. Organic Chemistry Series. Vol. 1. Edited by J. E. Baldwin, Pergamon Press: Oxford, England, 1983. 6 (a) Dillon, P.W.; Underwood, G. R. J. Am. Chem. Soc. 1974, 96, 779. (b) Balci, M.; Jones, W. M. J. Am. Chem. Soc. 1980, 102, 7607. 7 Ditchfield, R.; Hehre, W. J. J. Chem. Phys. 1971, 54, 724. 8 Baldwin, J. E.; Thomas, R. C.; Silberman, L. J. Org. Chem. 1977, 42, 3846. 9 Schultz A.G.; Pettus, L. J. Org. Chem. 1997, 62, 6855. 10 Katzenellenbogen, J. A.; Krafft, G. A. J. Am. Chem. Soc. 1981, 103, 5459. 11 Bosecken, M.; Jacobs, R. Red. Trav. Chim. 1936, 55, 804. 12 Yoon, C. H.; Flanigan, D. L.; Chong, B. D.; Jung, K. W. J. Org. Chem. 2002, 67, 6582. 13 (a) Yoon,C.H.; Zaworotko,M.J.; Moulton,B.; Jung,K.W. Org. Lett. 2001, 3, 3539. (b) Yoon,C.H.; Flanigan,D.L.; Chong,B.D.; Jung,K.W. J. Org. Chem. 2002, 67, 6582. (c) Yoon,C.H.; Nagle,A.; Chen,C.; Gandhi,D.; Jung,K.W. Org. Lett. 2003, 5, 2259

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83 14 (a) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 8. (b) Qian and Ganem B.; Xia Q.ruce Org. Lett. 2001, 3, 485. 15 Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Chem. Commun. 1987, 1220. 16 Yoo, S.; Lee, S. H. J. Org. Chem. 1994, 59, 8. 17 (a) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 3. (b) Fukuyama, T.; Morita, Y.; Tokuyama, H. Org. Lett. 2005, 7, 4337. 18 Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. 19 Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K., J. Am. Chem. Soc., 1988, 110, 6467. 20 Lautens, M.; Scott, M. E. Org. Lett. 2005, 7, 3045. 21 Borchardt, R. T.; Houston, D. M; Dolence, E. K.; Keller, B. T. J. Med. Chem. 1985, 28, 467. 22 McDougal, P. G.; Rico, J. G.; Oh, Y.; Condon, B. D. J. Org. Chem. 1986, 51, 3388. 23 (a) Parsons, A. F. Tetrahedron 1996, 52, 4149. Maloney, M. G. Nat. Prod. Rep. 2002, 19, 597. Selected examples: (b) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 4727. (c) Xia, Q.; Ganem, B. Org. Lett. 2002, 485. (d) Hirasawa, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 7587; Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 3181. (e) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 6199. (f) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 3194. (g) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 11139. (h) Rubio, A.; Ezquerra, J.; Escribano, A.; Remuinan, M. J.; Vanquero, J. J.

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84 Tetrahedron Lett. 1998, 2171. (i) Cossy, J.; Cases, M.; Pardo, D. G. Synlett 1998, 507. (j) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 18966. (k) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 8. (l) Yoo, S.; Lee, S. H. J. Org. Chem. 1994, 59, 8. (m) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 3. (n) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Chem. Commun. 1987, 1220. (o) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 8. 24 Corey, E. J. ; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammerstrm, S. J. Am. Chem. Soc. 1980, 102, 1436. 25 (a) Tebbe, F. N. J. Am. Chem. Soc. 1978, 100, 3611. (b) Pines, S. H. Synthesis 1991, 165. 26 Takai, K. J. Am. Chem. Soc. 1986 108 7408 27 Crisp G. T.; Meyer, A. G. Tetrahedron 1995, 51, 5831. 28 N. Hadei, E. A. B.; Kantchev, C. J.; O'Brien, M. G. Org. Lett. 2005, 7, 3805. 29 Marshall, J. A.; Devender, E. A. J. Org. Chem. 2001, 66, 8037. 30 Yus, M.; Najera, C. Tetrahedron 1999, 55, 10547. 31 Collado, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1998, 63, 1995. 32 Cook, G. R.; Sun, L. Org. Lett., 2004, 6, 2481. 33 Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002, 67, 4261. 34 Davis, F. A.; Sheppard, A. C. J. Org. Chem. 1987, 52, 954. 35 Anderson J. C.; Whiting M. J. Org. Chem. 2003, 68, 6160. 36 Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc.1990, 112, 4011.

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85 37 Deslongchamp, P.; Lavallee, J.; Berthiaume, G. Tetrahedron Lett. 1986, 27, 5455. 38 Panek, J.S.; Hu, T.; Wuonola, M.; Gustafson, G. J. Org. Chem., 1998, 63, 2401-2406. 39 Clayden J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412. 40 Schaus, J.V.; Lam, K.; Palfreyman, M.G. Chem. Pharm. Bull. 1985, 33, 4102 41 Schultz A.G.; Pettus, L. J. Org. Chem. 1997, 62, 6855. 42 Chiara, J. L.; Bueno, J. M. Tetrahedron Lett. 2000, 41, 4379. 43 Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 4727. 44 Carnell, A. J.; Allen, G. Tetrahedron 2001, 57, 8193. 45 Murray A.; Grndahl, C. Bioorg. Med. Chem. Lett. 2002, 12, 715. 46 Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 8. 47 (a) Parsons, A. F. Tetrahedron 1996, 52, 4149. Maloney, M. G. Nat. Prod. Rep. 2002, 19, 597. Selected examples: (b) Clayden, J.; Menet, C. J. Tetrahedron 2002, 4727. (c) Xia, Q.; Ganem, B. Org. Lett. 2002, 485. (d) Hirasawa, H.; Ogasawara, K. Tetrahedron Lett. 2001, 7587; Nakagawa, H.; Sugahara, T. Org. Lett. 2000, 3181. (e) Miyata, O.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 6199. (f) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 3194. (g) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 11139. (h) Rubio, A.; Remuinan, M. J.; Vanquero, J. J. Tetrahedron Lett. 1998, 2171. (i) Cossy, J.; Pardo, D. G. Synlett 1998, 507. (j) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 18966. (k) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 8. (l) Yoo, S.; Lee, S.H. J. Org. Chem. 1994, 59, 8.

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Chapter Three Experimental Data All experiments were carried out under nitrogen atmosphere using oven dried glassware (or flame dried when necessary). All chemicals were purchased from Aldrich Chemical Co. and/or Acros Organics and used without further purification unless otherwise noted. CH 2 Cl 2 was distilled over calcium hydride. THF and diethylether were distilled over sodium metal. 1 H nuclear magnetic resonance (400 MHz) and 13 C (100 MHz) spectra were recorded at room temperature in CDCl 3 unless otherwise noted. All chemical shifts are reported as relative to CHCl 3 (H 7.26 ppm) and CDCl 3 (C 77.0 ppm) as internal standards, respectively, using a INOVA 400 spectrometer. Infrared spectra were recorded using a Nicolet Magna FTIR 550 spectrometer and are reported in reciprocal centimeters (cm -1 ). Mass analysis was preformed using Hewlett-Packard HRMS spectroscopy. Thin layer chromatography (TLC) was preformed on EMD precoated silica plates with silica gel 60 250 m thickness. Visualization of TLC was accomplished using a UV lamp (254 nm), iodine or charring solutions (ninhydrin and PMA). Flash column chromatography was performed on Whatman Purasil 60 (230-400mesh) silica gel. 3.1 Preparation of (L)-Glutamic acid Dimethyl ester C6 NH2CO2HHO2C SOCl2, MeOH NH2CO2MeMeO2C then NaHCO3C5C6 86

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Thionyl chloride (100 mL, 1.28 mol) was added dropwise to a solution of (L)glutamic acid (100 g, 0.64 mol) in methanol (700 mL) at 0 C, and the mixture was warmed to r.t. with stirring and kept stirring for 10 h. The resulting solution was concentrated under vacuum and dissolved in fresh MeOH (300ml). The solution was neutralized to pH=7.0 by adding solid NaHCO 3 with stirring. After filtration of the precipitate, the solvent was evaporated to give (L)-glutamic acid dimethylester as colorless oil. To the resulting oil 300 ml of CH 2 Cl 2 was added to precipitate the salts such as NaCl, NaHCO 3 The solution was filtered to afford the desired neutral (L)-glutamic acid dimethylester C6 as colorless oil (222 g, 99%). The crude product was used for the next step without further purification. For compound C6: 1 H NMR (400 MHz, CDCl 3 ) 7.68 (s, 1 H), 4.22 (t, 1 H, J = 5.6 Hz), 3.75 (s, 3 H), 3.61 (s, 3 H), 2.68-2.50(m, 2 H), 2.40-2.22(m, 2 H) ; 13 C NMR (100MHz, CDCl3) 173.0, 170.4, 53.4, 52.8, 52.0, 30.0, 25.9; IR (thin film, cm -1 ) 2954, 1736, 1439, 1225; HRMS (ESI + ) for MH + C 7 H 14 NO 4 : calcd 176.0913, found 176.0927 ;[] D 25 = + 92.8 (c = 1.93, MeOH) 3.2 Preparation of 2-amino-1, 5-pentanediol C7 HO OHNH2 NH2CO2MeMeO2C LAH C6C7 A solution of C6 (50g, 0.28 mol) in dried THF (100 ml) was added to the mixture of lithium aluminum hydride (27g, 0.70 mol) in dried THF (450 mL) at 0 C. The result-ing reaction mixture was stirred for 10 hours at room temperature and quenched by successive addition of water (27 mL) 20% NaOH (27 mL) water (54 mL). 87

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The precipitate was filtered and washed with THF. The filtrate was dried over Na 2 SO 4 and concentrated to give amino alcohol C7 as an oil (23 g, 70%), which was used for the next step without further purification. For compound C7: 1 H NMR (400 MHz, CD 3 OD) 3.60-3.42 (m, 3 H), 3.4-3.23 (m, 1 H), 2.80-2.70 (m, 1 H), 1.70-1.40 (m, 3 H), 1.39-1.25 (m, 1 H); 13 C NMR (100 MHz, CD 3 OD) 66.06, 61.76, 52.68, 29.63, 29.08; IR (thin film, cm -1 ) 3322, 2943, 1025 ; HRMS (ESI + ) for MH + C 5 H 14 NO 2 : calcd 120.1019, found 120.1017; [] D 25 = + 2.9 (c = 0.65, MeOH) 3.3 Preparation of acetonide C8 AcetoneMgSO4HO OHNH2 HO OHN C7C8 The mixture of the amino alcohol C7 (20 g, 0.17 mol) in acetone (400 mL) and CH 2 Cl 2 (400 mL) was warmed to 40 C with stirring. To the resulting solution anhydrous MgSO 4 (21 g, 0.17 mol) was added slowly. After refluxing the solution with stirring for 2h, the reaction mixture was filtered and concentrated to give the acetonide intermediate C8 (24 g, 91%). For compound C8: 1 H NMR (400 MHz, CDCl 3 ) 3.91 (t, 1 H, J= 7.2), 3 .62-3.43 (m, 2 H), 3.38-3.25 (m, 1 H), 3.17 (t, 1 H, J=8.0 Hz), 1.67-1.52 (m, 3 H), 1.521.41 (1, 1 H), 1.36 (s, 3 H), 1.24 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) 95.0, 70.9, 62.1, 58.3, 30.8, 30.5, 27.6, 26.6; IR (thin film, cm -1 ) 3388, 2936, 1364 ; HRMS (ESI + ) for MH + C 8 H 18 NO 2 : calcd 160.1332, found 160.1333 ; [] D 25 = + 11.6 (c = 0.79, MeOH) 88

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3.4 Preparation of TBDMS protected acetonide C9 TBDMSO NaHTBDMSClOHN HO OHN C8C9 Sodium hydride (3.1 g, 76 mmol) was suspended in THF (250 ml) after being washed with hexane. The solution of the alcohol C8 (10 g, 63 mmol) in THF (50 ml) was added to this mixture at 0C and the solution was warmed up to r.t and stirred for 45 min at which time a largeamount of an opaque white precipitate had formed. The solution of TBDMSCl (9.5 g, 63 mmol) and TEA (2ml) in dried THF (50 ml) was then added at 0C,and vigorous stirring was continuedfor 45 min at r.t. The mixture was poured into EtOAc (500 mL), washed with brine (100 mL), dried over Na 2 SO 4 and concentrated in vacuo to give the protected acetonide C9 (14 g, 85%).The resulting oil was used for the next step without further purification. For compound C9: 1 H NMR (400 MHz, CDCl 3 ) 3.92 (t, 1 H, J = 7.2 Hz), 3.59 (t, 2 H, J = 5.6 Hz), 3.40-3.32 (m, 1H), 3.20 (t, 1 H, J = 8.0 Hz), 1.60-1.42 (m, 4 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 0.85 (s, 9 H), 0.00 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) 95.0, 71.0, 62.7, 58.2, 30.2, 30.0, 27.7, 27.7, 26.4, 25.9, 25.8, 25.7, 18.2, -5.3, -5.5 ; IR (thin film, cm -1 ) 3388, 2936, 1364; HRMS (ESI + ) for MH + C 14 H 32 NO 2 Si: calcd 274.2197, found 274.2207; [] D 25 = +16.2 (c = 3.1, MeOH). 89

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3.5 Preparation of -chloro acetonide B10 TBDMSOClO TBDMSO OHN ON ClCH2COClC9C10 Chloroacetyl chloride (6.5 g, 4.6 mL, 58 mmol) was added to a mixture of acetonide compound C9 (14 g, 48 mmol) and TEA (9.7 g, 13 mL, 96 mmol) in CH 2 Cl 2 (240 mL) at 0 C. After stirring for 3 hours at 0 C, the reaction mixture was washed with brine, and the aqueous layer was extracted with CH 2 Cl 2 (100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (Hex/ EtOAc = 5/1) to give -chloroacetyl amide compound C10 (14 g, 88%) as colorless oil. For compound C10: 1 H NMR (400 MHz, CDCl 3 ) 4.06 (ABq, 1 H, J AB = 12.4 Hz), 3.94 (ABq, 1 H, J AB = 12.4 Hz), 3.93-3.87 (m, 2 H), 3.82-3.80 (m, 1 H), 3.66-3.55 (m, 2 H), 1.82-1.70 (m, 1 H), 1.60 (s, 3 H), 1.58-1.40 (m, 3 H), 1.46 (s, 3 H), 1.83 (s, 9 H), 0.00 (s, 6 H) ; 13 C NMR (100 MHz, CDCl 3 ) 168.3, 101.0, 72.4, 67.4, 62.8, 48.5, 36.5, 34.7, 31.9, 31.4, 31.3, 27.9, 23.7, 0.1, 0.00 ; IR (thin film, cm -1 ) 2976, 1736, 1655, 1410, 1247 ; HRMS (ESI + ) for MH + C 16 H 33 ClNO 3 Si : calcd 350.1913, found 350.1912 ; [] D 25 = + 16.6 (c = 3.43, CHCl 3 ). 90

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3.6 Preparation of Phenylsulfone C11 TBDMSOClO ON TBDMSOPhO2SO ON PhSO2NaC10C11 PhSO 2 Na (9.9 g, 60 mmol) was added to a solution of chloroacetyl amide compound C10 (14 g, 40 mmol) in DMF (200 mL) at r.t. After stirring for 6 hours, the reaction mixture was diluted with EtOAc, washed with water twice, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (Hex/EtOAc=2/1) to give -phenylsulfonyl acetamide C11 (16 g, 91%). For the compound C11: mp 118-119C ; 1 H NMR (400 MHz, CDCl 3 ) 7.91-7.52 (m, 5 H), 4.31 ( A Bq, 1 H, J AB = 13.6 Hz), 4.20-4.16 (m, 1 H), 3.98 ( A BX, 1 H, J AB = 9.2 Hz, J AX = 5.2 Hz), 3.97 (A B q, 1 H, J AB = 13.6 Hz), 3.83 (A B X, 1 H, J AB = 9.2 Hz, J AX = 0 Hz), 3.71-3.60 (m, 2 H), 1.82-1.70 (m, 1 H), 1.70-1.50 (m, 3 H), 1.56(s, 3 H), 1.47 (s, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (100 MHz, CDCl 3 ) 157.7, 138.7, 134.1, 129.0, 128.5, 95.4, 66.7, 62.1, 61.7, 58.0, 30.6, 29.2, 26.2, 25.8, 22.3, 18.2, -5.3, -5.5; IR (thin film, cm -1 ) 2950, 1646, 1428 ; HRMS (ESI + ) for MH + C 22 H 38 NO 5 SSi : calcd 456.2234, found 456.2233 ; [] D 25 = + 43.5 (c = 1.36, CHCl 3 ). 91

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3.7 Preparation of -Diazo--(phenylsulfonyl)acetamide C12 TBDMSOPhO2SO ON p-ABSADBU, CH3CNONTBDMSOPhO2SO N2 C11C12 To a solution of -phenylsulfonyl acetamide (9.5 g, 20 mmol) in acetonitrile (100 mL) was added p-N-acetylbenzosulfonylazide (p-ABSA, 5.8 g, 24 mmol) followed by DBU (7.5 mL. 50 mmol). The reaction mixture was stirred for 3 h at 0 C. After evaporation of acetonitrile the residue was diluted with EtOAc. The organic layers were washed with brine twice, dried over Na 2 SO 4 and then evaporated. The residue was purified by column chromatography to give -diazo--(phenylsulfonyl)acetamide C12 as yellow oil (8.5 g, 89%). For compound C12: 1 H NMR (400 MHz, CDCl 3 ) 7.98 (d, 2 H, J = 8.0 Hz), 7.62 (m, 1 H), 7.53 (m, 2 H), 3.99 ( A BX, 1 H, J AB = 8.8 Hz, J AX = 5.6 Hz), 3.94-3.87 (m, 1 H), 3.81 (A B X, 1 H, J AB = 8.8 Hz, J AX = 2.8 Hz), 3.64-3.57 (m, 2 H), 1.75-1.66 (m, 1 H), 1.59 (s, 1 H), 1.50-1.42 (m, 1 H), 1.39 (s, 3 H), 1.23 (s, 9 H), 0.04 (s, 6 H); 13 C NMR (100 MHz, CDCl 3 ) 207.9, 154.1, 142.3, 134.0, 129.3, 128.0, 96.8, 67.9, 62.6, 57.7, 44.7, 31.1, 29.4, 26.5, 26.2, 26.1, 23.9, 18.5, -5.0; IR (thin film, cm -1 ) 2956, 2089, 1744, 1646, 1375, 1239 ; HRMS (ESI + ) for [M+Na] + C 22 H 35 N 3 O 5 SSiNa : calcd 504.1959, found 504.1955 ; [] D 25 = + 94.8 (c = 1.86, CHCl 3 ). 92

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3.8 Preparation of -lactam C3 ONTBDMSOPhO2SO N2 cat. Rh2(OAc)4CH2Cl2NO O PhSO2 H TBDMSO C12C3 To a solution of the -diazo--(phenylsulfonyl)acetamide C12 (7.5 g, 15 mmol) in dry CH 2 Cl 2 (300 mL, C = 0.05 M) was added catalytic amount of Rh 2 (OAc) 4 (66 mg, 0.15 mmol) The mixture was refluxed with stirring for 12 hours under N 2 cooled to room temperature, and was then concentrated. The residue was purified by column chromatography (Hex/EtOAc = 2/1) to give -(phenylsulfonyl)--lactam C3 as a single isomer (6.2 g, 92%). For compound C3: mp 64-65C ; 1 H NMR (400 MHz, CDCl 3 ) 7.99 (d, 2 H, J = 7.2 Hz), 7.65 (m, 1 H), 7.54 (m, 2 H), 4.12 (d, 1 H, J = 10.0 Hz), 4.08 ( A BX, 1 H, J AB = 8.6 Hz, J AX = 5.4 Hz), 3.92-3.80 (m, 1 H), 3.78-3.50 (m, 2 H), 3.44 (A B X, J AB = 8.6 Hz, J BX = 9.0 Hz), 2.90-2.81 (m, 1 H), 2.38-2.29 (m, 1 H), 1.80-1.68 (m, 1 H), 1.46 (s, 3 H), 1.37 (s, 3 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) 161.7, 137.8, 134.3, 130.2, 129.0, 92.3, 75.1, 70.1, 63.8, 61.1, 37.4, 35.8, 26.6, 26.2, 26.1, 23.7, 18.5, -5.2; IR (thin film, cm -1 ) 2977, 2931, 1702, 1447, 1308, 833 ; HRMS (ESI + ) for MH + C 22 H 36 NO 5 SSi : calcd 454.2078, found 454.2090 ; [] D 25 = + 39.7 (c = 3.53, CHCl 3 ). 93

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3.9 Preparation of acetylated -lactam C13 NO O PhSO2 H TBDMSO NO O PhSO2 H TBDMSO O Ac2O, NaHTHFC3C13 To a solution of phenylsulfone C3 (1 g, 2.4 mmol) in dry THF (24 mL, 0.1M) was added NaH (190 mg, 4.8 mmol) in one portion at -10C. The resulting reaction mixture was stirred for 30 min at -10C and Ac 2 O (485 mg, 0.45 ml, 4.8 mmol) was added and stirred for 1 h. The reaction mixture was quenched by addition of saturated aqueous NH 4 Cl solution and extracted with 100 ml of EtOAc two times. The combined organic layer was washed with brine, dried over Na 2 SO 4 concentrated in vacuo. The product was separated using flash column chromatography (Hex/EtOAc = 2/1) to afford the acetylated compound C13 (1.1 g, 90%) as a white solid. For compound C13: 1 H NMR (400 MHz, CDCl 3 ) 8.02 (d, 2 H, J = 8.0 Hz), 7.60 (m, 1 H), 7.48 (m, 2 H), 4.00 (m, 1 H), 3.81 (m, 1 H), 3.65 (m, 1 H), 3.47 (m, 1 H), 3.24 (m, 1 H), 3.03 (m, 1 H), 2.42 (s, 3 H), 2.21 (m, 1 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 0.86 (s, 9 H), 0.03 (s, 3 H), 0.00 (s, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 208.6, 198.0, 161.6, 136.1, 134.2, 131.8, 128.4, 91.9, 90.7, 70.0, 63.2, 60.7, 42.5, 31.5, 31.2, 26.3, 26.0, 18.2, -5.5. 94

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3.10 Preparation of Vinyl triflate C14 NO O PhSO2 H TBDMSO O NO O PhSO2 H TBDMSO OTf KHMDS Tf2OC13C14 To a solution of ketone C13 (0.3 g, 0.61 mmol) in THF (6 mL, 0.1M) was added KHMDS (0.5M in toluene) (1.5 ml, 0.73 mmol) dropwise via syringe at -78C. The mixture was allowed to stir for 10 min upon which a solution of Tf 2 O (0.2 g, 0.123 ml, 0.73 mmol) in THF (1 ml) was added dropwise. The resulting reaction mixture was stirred for 1 h, quenched by addition of saturated NaHCO 3 allowed to warm to r.t. The reaction mixture was extracted with EtOAc (30ml 2) and the combined organic layers were dried over Na 2 SO 4 and then evaporated. The residue was purified by column chromatography (Hex/EtOAc = 5/1) to give the triflate C14 as colorless oil (272 mg, 71%). For compound C14: 1 H NMR (250 MHz, CDCl 3 ) 8.08 (d, 2 H, J = 11.9 Hz), 7.67 (m, 1 H), 7.54 (m, 2 H), 5.83 (d, J = 8.3 Hz, 1 H), 5.67 (d, J = 8.3 Hz, 1 H), 4.12 (m, 1 H), 3.88-3.77 (m, 2 H), 3.57 (m, 1 H), 3.45-3.31 (m, 2 H), 2.43-2.25 (m, 1 H), 1.72-1.60 (m, 1 H), 1.42 (s, 3 H), 1.37 (s, 3 H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H) 95

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3.11 Preparation of -isopropenyl--phenylsulfonyl--lactam C15 NO O PhSO2 H TBDMSO NO O PhSO2 H TBDMSO OTf ZnMe2Pd(PPh3)4C14C15 To a solution of triflate C14 (270 mg, 0.43 mmol) in THF (4.3 ml) was added Pd(PPh 3 ) 4 (24 mg, 5 mole%) at 0C. The mixture was allowed to stir for 15 min upon which a solution of ZnMe 2 (5.4 ml, 0.16M solution in THF, 0.86 mmol) was added dropwise. The resulting reaction mixture was allowed to warm to r.t and stirred for 24 h, quenched by addition of saturated NH 4 Cland extracted with EtOAc (30 ml 2). The combined organic layers were dried over Na 2 SO 4 andthen evaporated. The residue was purified by column chromatography (Hex/EtOAc = 5/1) to givethe triflate C15 as colorless oil (150 mg, 72%). For compound C15: 1 H NMR (250 MHz, CDCl 3 ) 8.09 (d, 2 H, J = 13Hz), 7.67-7.36 (m, 3 H), 5.46 (s, 1 H), 5.41 (s, 1 H), 4.11 (m, 1 H), 3.78-3.69 (m, 2 H), 3.52 (m, 1 H), 3.40 (m, 1 H), 3.20 (m, 1 H), 2.40-2.25 (m, 1 H), 1.94 (s, 3 H), 1.65-1.55 (m, 1 H), 1.42 (s, 3 H), 1.30 (s, 3 H), 0.94 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H) 3.12 Preparation of -isopropenyl--lactam C16 Na/HgMeOHNO O H TBDMSO NO O PhSO2 H TBDMSO C15C16 96

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10% Sodium amalgam (0.72 g, 3 mmol) was added to a solution of the -isopropenyl--phenylsulfone--lactam C15 (150 mg, 0.3 mmol) and anhydrous disodium hydrogen phosphate (0.17 g, 1.2 mmol) in dry methanol (6 mL) at -78 C. The mixture was allowed to be warmed to 0C and stirred for 3 h, quenched with NH 4 Cl, and filtered. The reaction solution was concentrated in vacuo, diluted with EtOAc (50ml). After phase separation, the water layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na 2 SO 4 filtered and concentrated. The product was separated using flash chromatography (Hex/EtOAc = 2/1) to give C16 as colorless oil (93 mg, 88%). For compound C16: 1 H NMR (250 MHz, CDCl 3 ) 5.00 (s, 1 H), 4.85 (s, 1 H), 4.15 (m, 1 H), 3.85 (m, 1 H), 3.65-3.55 (m, 3 H), 3.20 (d, J = 12.8, 1 H), 2.25 (m, 1 H), 1.76 (s, 3 H), 1.65 (s, 3 H), 1.70-1.50 (m, 2 H), 1.46 (s, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H). 3.13 Preparation of C18 NO O H TBDMSO 1. Dowex 50W-8X C16NHOTBDMS O TBDMSO 2. TBDMSClC18 To a solution of bicyclic acetonide C16 (0.75 g, 2.1 mmol) in MeOH (11ml, 0.2M) was added 2.5 g of Dowex-50W-8X in one pot. The resulting solution was heated under reflux condition for 3 h. The mixture was filtered and concentrated to provide the diol compound as pale yellowish oil. The product was used for the next step without further purification. The crude diol compound was dissolved in CH 2 Cl 2 97

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(11 ml, 0.2 M). To the resulting solution were added TEA (1.1 g, 1.5 mL, 10.5 mmol), DMAP (259 mg, 2.1 mmol), and TBDMSCl (0.8 g, 5.3 mmol) consecutively. After stirring the mixture for 12 h, the mixture was washed with brine, dried over Na 2 SO 4 filtered, and distillated to give the crude product. The product was separated using flash column chromatography (Hex/EtOAc = 1/1) to provide the amide C18 (0.63g, 70%). For compound C18: 1 H NMR (250 MHz, CDCl 3 ) 5.92 (s, 1 H), 5.00 (s, 1 H), 4.92 (s, 1 H), 3.80 (m, 1 H), 3.64 (t, J = 10.0 Hz, 2 H), 3.52-3.33 (m, 2 H), 2.92 (d, J = 9.7 Hz, 1 H), 2.25-2.05 (m, 1 H), 1.75 (s, 3 H), 1.77-1.65 (m, 2 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.06 (s, 6 H), 0.04 (s, 6 H). 3.14 Preparation of BOC-protected -lactam C19 NHOTBDMS O TBDMSO NBocOTBDMS O TBDMSO Boc2OC18C19 TEA (164 mg, 0.23 ml, 1.62 mmol), Boc-anhydride (0.64 g, 2.94 mmol) and DMAP (0.18 g, 1.47 mmol) were added to a solution of -lactam C18 (0.63 g, 1.47 mmol) in CH 2 Cl 2 (15 mL, 0.1M). The mixture was stirred for 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography (Hex/EtOAc = 2:1) to afford the title compound C19 as a colorless oil (0.56g, 80%). For compound C19: 1 H NMR (250 MHz, CDCl 3 ) 4.94 (s, 1 H), 4.87 (s, 1 H), 4.05 (m, 1 H), 3.75-3.55 (m, 5 H), 2.92 (d, J = 8.7 Hz, 1 H), 1.74 (s, 3 H), 1.77-1.65 (m, 2 H), 1.50 (s, 9 H), 0.85 (s, 9 H), 0.84 (s, 9 H), 0.00 (s, 12 H). 98

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3.15 Preparation of C20 NBocOTBDMS O TBDMSO NBocOTBDMS OH TBDMSO LiEt3BHC19C20 A 1.0M solution of LiEt 3 BH in THF (1.44 ml) was added to a solution of -lactam C19 (0.56 g, 1.2 mmol) in THF (12 ml) at -78 C under N 2 atmosphere. After 30 min the reaction mixture was quenched with saturated aqueous NaHCO 3 (2.5ml) and warmed to 0 C. 30% H 2 O 2 (5 drops) was added and the mixture was stirred at 0C. After 20 min, the organic solvent was removed in vacuo, and the aqueous layer was extracted with CH 2 Cl 2 (3 10ml). The combined organic layers were dried over Na 2 SO 4 filtered and concentrated. The crude product was used without purification (0.5 g, 90%). For compound C20: 1 H NMR (250 MHz, CDCl 3 ) 6.55 and 6.34 (s, 1 H), 4.80-4.78 (m, 2 H), 3.95-3.85 (m, 1 H), 3.70-3.55 (m, 4 H), 3.50-3.40 (m, 1 H), 3.10-2.90 (m, 1 H), 2.00-1.80 (m, 1 H), 1.83 (s, 3 H), 1.60-1.50 (m, 10 H), 0.86 and 0.84 (s, 18 H), 0.02 and 0.00 (s, 12 H). 3.16 Preparation of isopropenyl pyrrolidine C21 BF3OEt2Et3SiHNBocOTBDMS OH TBDMSO NBocOTBDMS TBDMSO C20C21 99

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A solution of hemiaminal compound C20 (0.5 g, 0.94 mmol) and Et 3 SiH (0.11 g, 0.15 ml, 0.94 mmol) in CH 2 Cl 2 (9 ml, 0.1M) was cooled at -78 C and BF 3 OEt 2 (0.15 g, 0.13 ml, 1.0 mmol) was then added dropwise under N 2 atmosphere. After 30 min Et 3 SiH (0.11 g, 0.15 ml, 0.94 mmol) and BF 3 OEt 2 (0.15 g, 0.13 ml, 1.0 mmol) were added. The resulting mixture was stirred 2 h at -78C. The reaction mixture was quenched saturated aqueous NaHCO 3 extracted with CH 2 Cl 2 and dried over Na 2 SO 4 Evaporation of the solvent and purification by flash column chromatography (Hex/EtOAc = 2/1) gave the product C21 as a colorless oil (300 mg, 75%). For compound C21: 1 H NMR (250 MHz, CDCl 3 ) 4.84 (s, 2 H), 3.80-3.61 (m, 6 H), 3.04 (m, 1 H), 2.45-2.30 (m, 1 H), 2.00-1.80 (m, 1 H), 1.70-1.60 (m, 1 H), 1.68 (s, 3 H), 1.44 (s, 9 H), 0.86 (s, 9 H), 0.01 (s, 6 H). 3.17 Preparation of diol C22 NBocOTBDMS TBDMSO TBAFNBocOH HO C21C22 To a solution of pyrrolidine C21 (200 mg, 0.39 mmol) in THF (3.9 ml) was added TBAF (1M in THF, 0.9 ml, 0.9 mmol) slowly. After stirring of the reaction mixture for 1 h at r.t, concentrated in vacuo and diluted with 10ml of EtOAc. The organic layer was washed with brine solution, dried over Na 2 SO 4 and concentrated in vacuo. The products were separated using flash column chromatography (EtOAc) to afford the diol B23 (88 mg, 80%) as a colorless oil. For compound C22: 1 H NMR 100

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(250 MHz, CDCl 3 ) 4.86 (s, 2 H), 3.75-3.55 (m, 6 H), 3.10 (m, 1 H), 2.40 (m, 1 H), 1.90-1.60 (m, 3 H), 1.70 (s, 3 H), 1.44 (s, 9 H). 3.18 Preparation of pyrrolidine-2-carboxylic acid C23 Jones Ox NBocOH HO NBocCO2H CO2H C22C23 Jones reagent (1.0 M, 1.4 mL, 1.4 mmol) was added to a solution of C22 (20 mg, 0.07 mmol) in acetone (1.4 ml) at r.t and the resulting mixture was stirred for 2 h at that temperature. The reaction was quenched with i-PrOH, concentrated in vacuo. The reaction solution was dissolved in 10 ml of CH 2 Cl 2 and 1ml of brine solution was added. After phase separation, the aqueous layer was extracted three times with CH 2 Cl 2 and the organic layers were combined, dried over Na 2 SO 4 and concentrated to give carboxylic acid compound C23 (15 mg, 70%) as a white solid, which was used for the next step without further purification. For compound C23: 1 H NMR (250 MHz, CDCl 3 ) 8.36 (broad s, 2 H), 4.92 and 4.87 (s, 2 H), 4.05 and 3.90 (d, J = 14.4 Hz, 1 H), 3.78-3.59 (m, 1 H), 3.40-3.20 (m, 1 H), 2.80-2.10 (m, 4 H), 1.70 (s, 3 H), 1.51 and 1.44 (s, 9 H). 101

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3.19 Preparation of (+)-allokainic acid A3 A3 (+)-allokainic acidNBocCO2H CO2H NHCO2H CO2H CF3CO2HC23 To a solution of diacid C23 (15 mg, 0.047 mmol) in CH 2 Cl 2 (1 ml) was added CF 3 CO 2 H (64 mg, 0.042 ml, 0.56 mmol) at r.t. After stirring the reaction mixture for 12 h, the solution was concentrated in vacuo to give the crude product. The crude product was added to a column containing Dowex-50 H+ (WX8-200, 8% cross-linking, 100200 wet mesh). Elution with NH4OH (1 N), evaporation afforded (+)-allokainic acid A3 (6 mg, 60%): [] D 25 = + 7.2 ( c= 0.2, H 2 O) [lit : [] D 25 = + 7.4 (c = 0.7, H 2 O)]; 1 H NMR (D 2 O) 4.85 (s, 2 H), 4.08 (d, J = 8.7 Hz), 3.50-3.30 (m, 1 H), 3.29-3.05 (m, 1 H), 2.85-2.70 (m, 1 H), 2.70-2.40 (m, 3 H), 1.56 (s, 3 H); 13 C NMR (62.5 MHz, D 2 O) 177.1, 175.3, 139.1, 115.9, 65.3, 51.1,47.6, 40.9, 34.3, 17.0. 3.20 Preparation of -lactam B25 NO O PhSO2 H TBDMSO Na/HgMeOHNO O H TBDMSO C3C24 10% Na(Hg) (5.4 g, 22.5 mmol) was added to a solution of the -phenylsulfone--lactam C3 (2.0 g, 4.5 mmol) and anhydrous disodium hydrogen phosphate (2.0 g, 13.5 mmol) in dry methanol (90mL) at 0C. The reaction mixture was warmed to r.t slowly 102

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for 3 h, quenched with aqueous NH 4 Cl. After filtration, the reaction solution was concentrated in vacuo, diluted with 100 ml of EtOAc, wished with brine. The organic layer was dried over Na 2 SO 4 filtered and concentrated to give C24 as colorless oil (1.4 g, 96%). For compound C24: 1 H NMR (400 MHz, CDCl 3 ) 4.04 (m, 1 H), 3.86 (m, 1 H), 3.54 (m 1 H), 3.45 (m, 1 H), 2.57 ( A BX, 1 H, J AB = 16.1 Hz, J AX = 5.6 Hz), 2.46 (A B X, 1 H, J AB = 16.1 Hz, J AX = 12.0 Hz), 2.3-2.2 (m, 1 H), 1.75-1.62 (m, 1 H), 1.59 (s, 3 H), 1.39 (s, 3 H) 0.83 (s, 9 H), -0.01 (s, 6 H) ; 13 C NMR (100 MHz, CDCl 3 ) 176.3, 96.6, 75.0, 72.4, 66.7, 49.4, 43.0, 41.4, 32.1, 31.4, 31.3, 29.2, 23.7, 0.16, 0.00. 3.21 Preparation of alcohol C25 LDAacetoneNO O H TBDMSO C24 NO O H TBDMSO HO C25NO O H TBDMSO HO C26+ To a solution of LDA (17.22 ml, 8.61 mmol, 0.5M solution in THF) was added the solution of -lactam C24 (1.8 g, 5.74 mmol) in dry THF (15 mL) at -78 C, and the mixture was stirred at -78 C for 1 h. Dry acetone (0.5g, 8.61 mmol, 1.5 equiv) was then added, and the mixture was stirred at -78 C for an additional 1 h. The reaction mixture was quenched with saturated NH 4 Cl solution and allowed to warm to r.t. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 30 ml). The organic extracts were combined, dried over anhydrous Na 2 SO 4 and then filtered. The solvent was removed, and the residual pale yellow oil consisted of a 5:1 mixture of C25 and C26. The products were separated using flash chromatography 103

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(Hex/EtOAc = 1/1) to give the alcohols (1.96 g, 92%) : For compound C25: 1 H NMR (400 MHz, CDCl 3 ) 5.19 (s, 1 H), 4.06 (dd, J = 8.0 Hz, 5.6 Hz, 1 H), 3.80 (m, 1 H), 3.63 (m, 1 H), 3.49 (m, 1 H), 3.41 (m, 1 H), 2.63 (d, J = 10 Hz, 1 H), 2.10-0.91 (m, 2 H), 1.61 (s, 3 H), 1.42 (s, 3 H), 1.21 (s, 3 H), 1.17 (s, 3 H), 0.84 (s, 9 H), 0.00 (s, 6 H): For compound C26: 1 H NMR (400 MHz, CDCl 3 ) 4.05 (dd, J = 8.0 Hz, 5.2 Hz, 1 H), 3.92 (m, 1 H), 3.88 (s, 1 H), 3.63 (m, 1 H), 3.46 (m, 1 H), 3.40 (m, 1 H), 2.74 (d, J = 9.2 Hz, 1 H), 2.46 (m, 1 H), 2.01 (m, 1 H), 1.61 (s, 3 H), 1.41 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 0.88 (s, 9 H), 0.00 (s, 6 H). 3.22 Preparation of -isopropenyl--lactam B17 NO O H TBDMSO NO O H TBDMSO HO PCl5C16C25 To a solution of C25 (100 mg, 0.27 mmol) in dry CH 2 Cl 2 (3 mL) at -78 C was added PCl 5 (56mg, 1.0 equiv, 0.27 mmol), and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with saturated NaHCO 3 solution and then extracted with CH 2 Cl 2 (3 mL). The combined organic extracts were dried over Na 2 SO 4 and the solvent was removed to give a yellow oil. Purification by column chromatography (Hex/ EtOAc = 2/1) gave C16 as a colorless oil (83 mg, 90%): For compound C16: 1 H NMR (250 MHz, CDCl 3 ) 5.00 (s, 1 H), 4.85 (s, 1 H), 4.15 (m, 1 H), 3.85 (m, 1 H), 3.65-3.55 (m, 3 H), 3.20 (d, J = 12.8, 1 H), 2.25 (m, 1 H), 1.76 (s, 3 H), 1.65 (s, 3 H), 1.70-1.50 (m, 2 H), 1.46 (s, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H). 104

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3.23 Preparation of the alcohol C47 NPhO2S O O TBDMSO TBAF NPhO2S O O HO C3C47 To a solution of -lactam C3 (5 g, 11.4 mmol) in THF (57 mL) was added TBAF (17mL, 1M in THF) slowly. After stirring of the reaction mixture for 2 h at r.t, concentrated in vacuo and diluted with 100ml of EtOAc. The organic layer was washed with brine solution, dried over Na 2 SO 4 and concentrated in vacuo. The products were separated using flash column chromatography (EtOAc) to afford the alcohol C47 (3.7g, 96%) as a colorless oil. For compound C47: 1 H NMR (400 MHz, CDCl 3 ) 7.96 (d, 2 H, J = 7.2 Hz), 7.62 (m, 1 H), 7.53 (m, 2 H), 4.16 (d, J = 9.2 Hz, 1 H), 4.10 ( A BX, 1 H, J AB = 8.6 Hz, J AX = 5.6 Hz), 3.88-3.82 (m, 1 H), 3.77-3.65 (m, 2 H), 3.46 (A B X, 1 H, J AB = 8.6 Hz, J AX = 8.8 Hz), 2.92-2.83 (m, 1 H), 2.22 (broad s, 1 H), 2.23-2.15 (m, 1 H), 1.89-1.79 (m, 1 H), 1.46 (s, 3 H), 1.35 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) 161.8, 137.7, 134.5, 130.1, 129.1, 92.5, 75.2, 69.7, 64.4, 60.5, 36.4, 36.2, 26.7, 23.6; IR (thin film, cm -1 ) 3507, 2987, 1701, 1263, 1147, 774 ; HRMS (ESI + ) for MH + C 16 H 22 NO 5 S : calcd 340.1213, found 340.1216; [] D 25 = + 46.8 (c = 3.53, CHCl 3 ). 105

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3.24 Preparation of aldehyde C48 NPhO2S CHO O O NPhO2S O O HO DMPC47C48 To a stirred solution of 4g (11.8 mmol) of alcohol C47 in CH 2 Cl 2 (118 ml) at r.t was added NaHCO 3 (3 g, 3equiv.) and Dess-Martin periodinane solution (35ml, 1.4 equiv., 15 wt% in CH 2 Cl 2 ). The reaction mixture was stirred for 20 min and quenched by addition of the 1:1 mixture of NaHCO 3 and Na 2 S 2 O 3 aqueous solution (118 ml). The resulting solution was stirred for 1 h and the layers were separated and the aqueous layer was extracted with EtOAc (50ml 3). The combined organic layers were dried over Na 2 SO 4 filtered, and evaporated. The product was separated using flash column chromatography (Hex/EtOAc = 1/2) to afford the aldehyde C48 (3.8 g, 95%) as colorless oil. For compound C48: 1 H NMR (400 MHz, CDCl 3 ) 9.75 (s, 1 H), 7.97 (d, 2 H, J = 7.2 Hz), 7.66 (m, 1 H), 7.54 (m, 2 H), 4.17 ( A BX, 1 H, J AB = 8.9 Hz, J AX = 5.5 Hz), 3.71-3.64 (m, 1 H), 3.58 (A B X, 1 H, J AB = 8.9 Hz, J AX = 9.3 Hz), 3.43 ( A BX, 1 H, J AB = 19.3 Hz, J AX = 2.7 Hz), 3.10-3.00 (m, 1 H), 2.85 (A B X, 1 H, J AB = 19.3 Hz, J AX = 10.5 Hz) 1.42 (s, 3 H), 1.38 (s, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 199.6, 161.1, 137.3, 134.6, 130.2, 129.1, 92.4, 73.9, 70.3, 64.2, 47.3, 33.7, 26.6, 23.6 ; IR (thin film, cm -1 ) 2985, 1735, 1706, 1240, 1044 ; HRMS (ESI + ) for MH + C 16 H 20 NO 5 S : calcd 338.1057, found 338.1058 ; [] D 25 = 0.4 (c = 0.54, CHCl 3 ). 106

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3.25 Preparation of alcohol B45 NPhO2S CHO O O NPhO2S O O OH MgBr C48C49 To a solution of aldehyde C48 (3.5 g, 10.3 mmol) of in dry THF (50 mL) under N 2 atmosphere at -78 C was added 1-propynylmagnesium bromide (45.4 mL, 22.7 mmol, 0.5M solution in THF) dropwise and the mixture was warmed to 0C. After stirring the mixture for 1 h, 25 ml of saturated aqueous NH 4 Cl solution was added at 0C. The mixture was warmed to r.t and stirred for 15 min. The aqueous layer was extracted with EtOAc (3ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The product was separated using flash column chromatography (Hex/EtOAc = 1/2) to produce the propagyl alcohol C49 (3.6 g, 92%) as a colorless oil. For compound C49 (1:1 mixture of two diastereomers): 1 H NMR (400 MHz, CDCl 3 ) 8.01 (m, 2 H), 7.65 (m, 1 H), 7.55 (m, 2 H), 4.55-4.40 (m, 1 H), 4.20-4.05 (m, 2 H), 3.97-3.83 (m, 1 H), 3.47 (m, 1 H), 3.10-2.82 (m, 1 H), 2.50-2.40 (m, 1 H), 2.09-1.90 (m, 1 H), 1.89-1.80 (m, 3 H), 1.50-1.39 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ) 161.5, 137.7, 137.6, 134.5, 134.4, 130.3, 130.1, 129.0, 128.9, 92.5, 92.4, 82.9, 82.4, 75.2, 74.9, 70.1, 70.0, 64.7, 64.3, 61.2, 61.0, 41.8, 40.4, 36.3, 35.9, 26.7, 23.7, 3.8 ; IR (thin film, cm -1 ) 3448, 2983, 1734, 1703, 1146 ; HRMS (ESI + ) for MH + C 19 H 24 NO 5 S : calcd 378.1370, found 378.1367 ; [] D 25 = + 15.4 (c = 1.4, CHCl 3 ). 107

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3.26 Preparation of alkynyl ketone C46 NPhO2S O O OH DMPNPhO2S O O O C49C46 To a stirred solution of alcohol C49 (3.5 g, 9.3 mmol) in CH 2 Cl 2 (93 ml) at r.t was added NaHCO 3 (2.3 g, 2.9 equiv.) and of Dess-Martin periodinane solution (28 ml, 1.4 equiv., 15wt% in CH 2 Cl 2 ). The reaction mixture was stirred for 1 h and quenched by addition of 1:1 mixture of NaHCO 3 and Na 2 S 2 O 3 aqueous solution (93 ml). The resulting solution was stirred for1 h and the layer was separated and the aqueous layer was extracted with EtOAc (40ml 3). The combined organic layers were dried overNa 2 SO 4 filtered, and evaporated. The product was separated using flash column chromatography (Hex/EtOAc = 1/2) to afford the ketone C46 (3.3 g, 93%) as a colorless oil. For compound C46: 1 H NMR (400 MHz, CDCl 3 ) 7.98 (d, 2 H, J = 7.2 Hz), 7.66 (m, 1 H), 7.55 (m, 2 H), 4.16 ( A BX, 1 H, J AB = 8.9 Hz, J AX = 5.5 Hz), 4. 10 (d, 1 H, J = 10.4 Hz), 3.72-3.65 (m, 1 H), 3.55 (A B X, 1 H, J AB = 8.9 Hz, J AX = 9.3 Hz), 3.50 ( A BX, 1 H, J AB = 19.3 Hz, J AX = 2.7 Hz), 3.10-3.00 (m, 1 H), 2.88 (A B X, 1 H, J AB = 19.3 Hz, J AX = 10.5 Hz), 2.03 (s, 3 H), 1.42 (s, 3 H), 1.34 (s, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 185.0, 161.0, 137.3, 134.6, 130.2, 129.1, 92.5, 92.3, 79.9, 73.7, 70.4, 64.2, 48.6, 34.7, 26.6, 23.6, 4.4 ; IR (thin film, cm -1 ) 2985, 2222, 1734, 1706, 1671, 1242, 1147 ; HRMS (ESI + ) for MH + C 19 H 22 NO 5 S : calcd 376.1213, found 376.1219 ; [] D 25 = 19.4 (c = 1.2, CHCl 3 ). 108

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3.27 Preparation of tricyclic enone compound B47 NSO2Ph O O O Cs2CO3CH3CNNPhO2S O O O C46C45 To a solution of ketone C46 (3.2 g, 8.5 mmol) in CH 3 CN (1700 ml, 0.005M) at r.t was added Cs 2 CO 3 (3.3g, 10.2 mmol). After stirring the mixture for 2 h, 50ml of saturated aqueous NH 4 Cl solution was added and stirred for 15 min. The reaction solution was concentrated and diluted with 200ml of EtOAc. The organic layer was washed with brine, dried over Na 2 SO4 and concentrated in vacuo. The product was separated using flash column chromatography (Hex/EtOAc = 1/1) to produce the tricyclic enone C45 (3.0 g, 93%) as colorless oil. For compound C45: 1 H NMR (400 MHz, CDCl 3 ) 8.03 (d, 2 H, J = 8.8 Hz), 7.69 (m, 1 H), 7.56 (m, 2 H), 6.27 (s, 1 H), 4.11 ( A BX, 1 H, J AB = 8.6 Hz, J AX = 5.8 Hz), 3.74-3.66 (m, 1 H), 3.40 (A B X, 1 H, J AB = 8.6 Hz, J AX = 8.6 Hz), 3.19-3.15 (m, 1 H), 2.91 ( A BX, 1 H, J AB = 18.2 Hz, J AX = 6.4 Hz), 2.26 (A B X, 1 H, J AB = 18.2 Hz, J AX = 0.0 Hz), 1.96 (s, 3 H), 1.44 (s, 3 H), 1.37 (s, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 193.9, 162.4, 146.5, 136.2, 135.2, 133.6, 131.4, 129.2, 93.4, 80.0, 68.7, 61.3, 41.7, 35.0, 26.2, 23.5, 21.7; IR (thin film, cm -1 ) 2985, 2928, 1705, 1673, 1146 ; HRMS (ESI + ) for MH + C 19 H 22 NO 5 S : calcd 376.1213, found 376.1211 ; [] D 25 = + 7.7 (c = 0.73, CHCl 3 ). 109

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3.28 Preparation of alcohol C52 NSO2Ph O O O Dowex 50W-8XNHSO2Ph O OH O C45C52 To a solution of tricyclic acetonide C45 (3 g, 8 mmol) in MeOH (40 mL, 0.2M) was added Dowex-50W-8X (9 g) in one portion. The resulting solution was heated under reflux condition for 10 h. The mixture was filtered and concentrated to provide the alcohol C52 (2.6g, 95%) as pale yellowish oil. The product was used for the next step without further purification. For compound C52: 1 H NMR (400 MHz, CD 3 OD) 7.98 (d, 2 H, J = 8.0 Hz), 7.76 (m, 1 H), 7.62 (m, 2 H), 6.28 (s, 1 H), 3.80-3.20 (m, 4 H), 2.35 (d, J = 2.8, 2 H), 2.16 (s, 3 H) ; 13 C NMR (100 MHz, CD 3 OD) 195.3, 167.7, 147.9, 136.1, 135.0, 133.3, 130.7, 129.3, 74.9, 60.4, 57.2, 38.6, 33.0, 21.1; IR (thin film, cm -1 ) 3340, 2945, 2834, 2071, 1716, 1671, 1448 ; HRMS (ESI + ) for MH + C 16 H 18 NO 5 S : calcd 336.0900, found 336.0900 ; [] D 25 = + 4.3 (c = 1.59, MeOH). 3.29 Preparation of carboxylic acid B49 JonesOxNHSO2Ph O OH O NHSO2Ph O CO2H O C52C53 Jones reagent (1.0 M, 103 mL, 103 mmol) was added to a solution of C52 (2.5 g, 7.5 mmol) in acetone (75 mL, 0.1M) at room temperature and the resulting mixture was stirred for 2 h at that temperature. The reaction was quenched with i-PrOH, 110

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concentrated in vacuo. The reaction solution was dissolved in 50 ml of CH 2 Cl 2 and 2ml of brine solution was added. After phase separation, the aqueous layer was extracted three times with CH 2 Cl 2 and the organic layers were combined, dried over Na 2 SO 4 and concentrated to give carboxylic acid compound C53 (2.6 g, 99%) as a white solid, which was used for the next step without further purification. For compound C53: mp 216-218 C ; 1 H NMR (400 MHz, CD 3 OD) 8.00 (d, 2 H, J = 7.6 Hz), 7.78 (m, 1 H), 7.64 (m, 2 H), 6.32 (s, 1 H), 3.83 (d, J = 9.6 Hz), 3.31 (m, 1 H), 2.68 ( A BX, 1 H, J AB = 18.6 Hz, J AX = 0.1 Hz), 2.46 (A B X, 1 H, J AB = 18.6 Hz, J AX = 7.3 Hz), 2.12 (s, 3 H) ; 13 C NMR (100 MHz, CD 3 OD) 194.67, 170.89, 167.2, 147.2, 135.9, 135.2, 133.6, 130.7, 129.3, 74.3, 56.5, 41.2, 33.5, 20.9 ; IR (thin film, cm -1 ) 3352, 2985, 2071, 1718, 1673, 1025 ; HRMS (ESI ) for M-H C 16 H 14 NO 6 S : calcd 348.0543, found 348.0543 ; [] D 25 = 3.4 (c = 0.29, MeOH). 3.30 Preparation of ester B50 NHSO2Ph O CO2H O NHSO2Ph O CO2Me O TMSCHN2C53C54 The acid C53 (2.6 g, 7.4 mmol) was dissolved in a mixture of methanol (74 mL) and toluene (185 mL) and to it was added TMSCHN 2 (5.5 mL, 11.1 mmol, 2 M solution in ether) dropwise. After 5 min the reaction was quenched with acetic acid (2 drop) and the solvent removed under reduced pressure. The resulting solution was diluted with EtOAc (100 mL) and washed with brine, dried over Na 2 SO 4 concentrated in vacuo 111

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to give the crude product. Purification by flash chromatography (EtOAc) afforded the product C54 as colorless oil (2.3 g, 91%). For compound C54: 1 H NMR (400 MHz, CDCl 3 ) 7.94 (d, 2 H, J = 8.0 Hz), 7.68 (m, 1 H), 7.54 (m, 2 H), 6.25 (s, 1 H), 3.80 (d, J = 9.6 Hz), 3.73 (s, 3 H), 3.42 (m, 1 H), 2.69 ( A BX, 1 H, J AB = 18.4 Hz, J AX = 0.4 Hz), 2.60 (A B X, 1 H, J AB = 18.4 Hz, J AX = 6.8 Hz), 1.98 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) 193.6, 169.5, 167.1, 146.3, 136.0, 135.4, 134.1, 131.0, 129.5, 74.4, 56.5, 53.4, 41.1, 34.2, 21.8 ; IR (thin film, cm -1 ) 2985, 1724, 1675, 1149; HRMS (ESI + ) for MH + C 17 H 18 NO 6 S : calcd 364.0849, found 364.0844 ; [] D 25 = + 27.1 (c = 1.33, CHCl 3 ). 3.31 Preparation of Boc protected amide C55 NSO2Ph O CO2Me O Boc NHSO2Ph O CO2Me O Boc2OC54C55 Et 3 N (0.77g, 1.1 ml, 7.6 mmol), Boc-anhydride (2.7g, 12.6 mmol) and DMAP (0.77g, 6.3 mmol) were added to a solution of -lactam C54 (2.3g, 6.3 mmol) in CH 2 Cl 2 (63 mL). The mixture was stirred for 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography (1:1 Hex/EtOAc) to afford the tile compound C55 as colorless oil (2.8 g, 95%). For compound C55: 1 H NMR (400 MHz, CDCl 3 ) 8.02 (d, 2 H, J = 8.0 Hz), 7.73 (m, 1 H), 7.60 (m, 2 H), 6.31 (s, 1 H), 4.00 (d, J = 10.0 Hz), 3.76 (s, 3 H), 3.38 (m, 1 H), 2.90 ( A BX, 1 H, J AB = 18.2 Hz, J AX = 6.8 Hz), 2.55 (A B X, 1 H, J AB = 18.2 Hz, J AX = 0.0 Hz), 112

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1.87 (s, 3 H), 1.43 (s, 9 H) ; 13 C NMR (100 MHz, CDCl 3 ) 192.8, 169.2, 163.8, 147.9, 145.3, 135.8, 135.5, 134.5, 131.4, 129.5, 85.8, 75.0, 60.5, 53.2, 37.5, 33.5, 27.9, 21.7; IR (thin film, cm -1 ) 2985, 1795, 1754, 1678, 1144 ; HRMS (ESI + ) for [M+Na] + C 22 H 25 NO 8 SNa : calcd 486.1193, found 486.1188 ; [] D 25 = 28.8 (c = 0.32, CHCl 3 ). 3.32 Preparation of silylenol ether C58 + C59 NSO2Ph O CO2Me O Boc TBSOTfTEAN O CO2Me TBSO Boc H SO2Ph N O CO2Me TBSO Boc H SO2Ph +C55C58C59 To a stirred solution of ester C55 (2.8 g, 6.0 mmol) in CH 2 Cl 2 (240 mL, 0.025M) at 0 C was added freshly distilled (KOH) Et 3 N (3.0 g, 4.2 ml, 30 mmol) and TBSOTf (4.8 g, 4.1 ml, 18 mmol) in CH 2 Cl 2 (5 mL). After 1 h at 20C (TLC checked) the mixture was poured into aqueous saturated NaHCO 3 and extracted with CH 2 Cl 2 The combined organic phases were dried over Na 2 SO 4 and evaporated to give a residue (3.5 g, 100%) that was chromatographed through a silica gel column with elution by Hex/EtOAc:Et 3 N (5:1:1%) to give mixture of C58, C59 (3.5 g, 100%). For compound C58, C59: 1 H NMR (400 MHz, CDCl 3 ) 7.94-7.40 (m, 5 H), 5.54 (s, 1 H), 4.87 (s, 1 H), 4.53 (s, 1 H), 4.03 (d, J = 10.4 Hz, 1 H), 3.77 and 3.70 (s, 3 H), 3.50-3.40 (m, 1 H), 2.80 ( A BX, 1 H, 113

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J AB = 18.0 Hz, J AX = 5.8 Hz), 2.23 (A B X, 1 H, J AB = 18.0 Hz, J AX = 0.2 Hz), 1.42 and 1.39 (s, 9 H), 0.90 and 0.84 (s, 9H), 0.25 and 0.18 and 0.00 (s, 6 H) ; 13 C NMR (100 MHz, CD 3 OD) 172.2, 171.4, 171.2, 167.8, 166.7, 152.6, 149.7, 149.6, 137.6, 136.1, 136.0, 135.9, 135.2, 133.0, 132.3, 132.2, 131.7, 130.0, 129.9, 129.5, 127.8, 118.4, 109.2, 107.5, 97.3, 86.3, 86.2, 84.8, 75.9, 73.3, 68.1, 64.9, 63.9, 63.3, 61.8, 58.9, 56.3, 53.6, 53.4, 53.2, 41.2, 37.7, 37.5, 31.9, 30.2, 28.5, 28.1, 28.0, 27.9, 26.7, 26.4, 26.2, 26.0, 25.9, 22.7, 20.0, 18.9, 18.7, -4.1, -4.2, -4.7 ; IR (thin film, cm -1 ) 2960, 2214, 2070, 1742, 1242, 1122 ; HRMS (ESI + ) for MH + C 28 H 40 NO 8 SSi : calcd 578.2238, found 578.2233 ; [] D 25 = + 24.1 (c = 0.78, CHCl 3 ). 3.33 Preparation of bicyclic enone C44 N O CO2Me O Boc H H Na/HgN O CO2Me TBSO Boc H SO2Ph N O CO2Me TBSO Boc H SO2Ph +THF/MeOHC58C59C44 10% Sodium amalgam (6.9 g, 30 mmol) was added to a solution of the silyl enol ether compound C58 + C59 (3.5 g, 6.0 mmol) and anhydrous disodium hydrogen phosphate (2.6 g, 18 mmol) in dry methanol (12 mL) and THF (108 mL) at -78 C. The reaction mixture was warmed to -20 C and stirred for 3 h. The reaction solution was quenched with aqueous NH 4 Cl and warmed to r.t. After filtration, 114

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the reaction solution was concentrated in vacuo and diluted with EtOAc (100 mL). The organic solution was wished with brine, dried over Na 2 SO 4 filtered and concentrated. The crude product was chromatographed through a silica gel column with elution by Hex/EtOAc (1/1) to give mixture the product C44 (1.85 g, 95%) as a colorless oil. For compound C44: 1 H NMR (400 MHz, CDCl 3 ) 5.94 (s, 1H), 4.25 (s, I H), 3.77 (s, 3 H), 3.39 (d, J = 7.2 Hz, 1 H), 2.99-2.92 (m, 1 H), 2.61 ( A BX, 1 H, J AB = 16.1 Hz, J AX = 5.6 Hz), 2.38 (A B X, 1 H, J AB = 16.1 Hz, J AX = 12.0 Hz), 2.18 (s, 3 H), 1.46 (s, 9 H): 13 C NMR (100 MHz, CDCl 3 ) 195.1, 170.5, 168.9, 154.5, 149.5, 128.0, 84.7, 62.4, 53.1, 47.1, 38.5, 35.5, 28.1, 23.7; IR (thin film, cm -1 ) 2980, 1790, 1750, 1670, 1304, 1148 ; HRMS (ESI + ) for [M+Na] + C 16 H 21 NO 6 Na : calcd 346.1261, found 346.1257; [] D 25 = 41.6 (c = 1.53, CHCl 3 ). 3.34 Preparation of enol lactone C60 N O CO2Me O Boc H H N O CO2Me O Boc H H O mCPBA C44C60CH2Cl2 To a solution of the enone compound C44 (1.8g, 5.5 mmol) in CH 2 Cl 2 (55 mL, 0.1M) was added m-CPBA (1.9g, 11 mmol) in one portion at r.t. After stirring at room temperature for 48 h, the reaction was quenched with saturated sodium sulfite. The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 The combined organic layers were dried and evaporated. A flash chromatography (Hex/EtOAc = 1/2) gave C60 as colorless oil (1.1 g, 60%). For compound C60: 115

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1 H NMR (400 MHz, CDCl 3 ) 6.37 (d, J = 1.2, 1 H), 4.58 (s, 1 H), 3.76 (s, 3 H), 3.25 (d, J = 8.8 Hz, 1 H), 3.08-3.02 (m, 2 H), 2.60-2.53 (m, 1 H), 1.85 (d, J = 1.6 Hz, 3 H), 1.45 (s, 9 H); 13 C NMR (100 MHz, CDCl 3 ) 170.6, 170.3, 168.4, 148.9, 137.3, 122.4, 84.6, 62.5, 53.1, 47.6, 39.4, 36.8, 28.0, 20.1 ; IR (thin film, cm -1 ) 2980, 2200, 1793, 1756, 1265, 907 ; HRMS (ESI + ) for [M+Na] + C 16 H 21 NO 7 Na : calcd 362.1210, found 362.1208 ; [] D 25 = + 15.7 (c = 1.11, CHCl 3 ). 3.35 Preparation of aldehyde C66 N O CO2Me OHC Boc MeO2C N O CO2Me O Boc H H O NaOMeMeOHC60C66 Sodium methoxide (4.77 mmol, 1 M in MeOH) was added dropwise over 0.5 h to a solution of the enol lactone C60 (1.1 g, 3.2 mmol) in methanol (64 ml, 0.05M) at -78 o C. The reaction mixture was stirred for 20 min and quenched with saturated NH 4 Cl solution and warmed to r.t. The reaction mixture was concentrated in vacuo and diluted with 50 ml of EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to afford the crude product. Purification by flash chromatography (Hex/EtOAc = 1:1) gave the ester aldehyde compound C66 (1.0 g, 87%, two diastereomeric mixture) as a colorless oil. For compound C66: 1 H NMR (400 MHz, CDCl 3 ) 9.79 and 9.58 (s, 1 H), 4.45 and 4.39 (s, 1 H), 3.79 and 3.71 and 3.67 (s, 6 H), 3.2-2.2 (m, 6 H), 1.46 (s, 9 H), 1.37 and 1.10 (d, J = 7.2, 3 H); 13 C NMR 116

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(100 MHz, CDCl 3 ) 201.9, 201.7, 172.2, 171.4, 171.3, 170.8, 170.6, 149.6, 84.5, 84.3, 62.5, 61.9, 60.6, 53.1, 53.0, 52.5, 52.4, 47.2, 45.5, 44.0, 43.0, 34.9, 34.6, 34.0, 33.3, 28.1, 12.2 ; IR (thin film, cm -1 ) 2980, 1790, 1735, 1309, 1150 ; HRMS (ESI + ) for [M+Na] + C 17 H 25 NO 8 Na : calcd 394.1472, found 394.1469 ; [] D 25 = 1.4 (c = 0.59, CHCl 3 ). 3.36 Preparation of diol C67 N OH CO2Me Boc MeO2C HO DIBALN O CO2Me OHC Boc MeO2C C66C67 A solution of DIBAL (21.6 mL, 8 equiv., 1.0M in THF) was added dropwise to a stirred solution of the aldehyde C66 (1.0g, 2.7 mmol) in THF (27 ml) at -78 o C under nitrogen. After 1 h, the reaction was quenched by adding methanol and the mixture was warmed to r.t. To the resulting solution were added saturated potassium tartrate solution and EtOAc. The mixture was stirred for 15 min. The layers were separated and aqueous layer was extracted with ethyl acetate. The combined organic layer were washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to afford the diol compound C67 (1.0g, 97%). The crude product was used for the next step without further purification. For compound C67: 1 H NMR (400 MHz, CDCl 3 ) 5.52-5.35 (m, 1 H), 4.24 and 4.17 (s, 1 H), 3.87 (d, J = 2.8 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.60-3.50 (m, 1 H), 3.42-3.35 (m, 2 H), 2.73-2.60 (m, 2 H), 2.12-1.82 (m, 2 H), 1.36 (s, 9 H), 1.04 (d, J = 6.4, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 173.6, 172.7, 154.6, 82.2, 81.4, 117

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66.4, 64.6, 52.5, 52.0, 46.8, 40.7, 34.7, 31.4, 28.4, 15.9 ; IR (thin film, cm -1 ) 3440, 2977, 1739, 1685, 1368 ; HRMS (ESI + ) for [M+Na] + C 17 H 29 NO 8 Na : calcd 398.1785, found 398.1785 ; [] D 25 = 22.6 (c = 1.11, CHCl 3 ). 3.37 Preparation of alcohol C68 N OH CO2Me Boc MeO2C HO N OH CO2Me Boc MeO2C MsO MsCl, TEACH2Cl20oCC67C68 p-Methanesulfonyl chloride (189.0 mg, 1.7 mmol) was added at 0C to a stirred solution of alcohol C67 (400 mg 1.1 mmol) and TEA (278 mg, 0.38 ml, 2.75 mmol) in CH 2 Cl 2 (11 mL). After having been stirred for 15 min at 0 C, the reaction mixture was quenched by addition of aqueous NaHCO 3 solution, diluted with EtOAc (30 ml), and washed with brine solution. The organic layer was dried over Na 2 SO 4 filtered, and concentrated to afford the crude product. Purification by flash chromatography (Hex/EtOAc = 1:1) gave the mesylated compound C68 (300mg, 65%) as a colorless oil. For compound C68 : 1 H NMR (400 MHz, CDCl 3 ) 5.50-5.38 (m, 1 H), 4.25 and 4.18 (s, 1 H), 4.10-3.92 (m, 2 H), 3.81 (d, J = 2.8 Hz, 1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 2.96 (s, 3 H), 2.78-2.57 (m, 3 H), 2.20-2.02 (m, 2 H), 1.35 (s, 9 H), 1.10 (d, J = 6.0, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 173.1, 172.4, 154.4, 81.9, 81.5, 72.5, 64.6,52.6, 52.1, 46.4, 40.5, 37.6, 34.5, 29.4, 28.4, 15.8 ; IR (thin film, cm -1 ) 3436, 2977, 1736, 1697, 1355, 1173 ; HRMS (ESI + ) for [M+Na] + C 18 H 31 NO 10 SNa : calcd 476.1561, found 476.1555 ; [] D 25 = 18.2 (c = 1.01, CHCl 3 ). 118

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3.38 Preparation of pyrrolidine diester C69 Et3SiHBF3OEtCH2Cl2-78oCN CO2Me Boc MeO2C MsO N OH CO2Me Boc MeO2C MsO C68C69 A solution of hemiaminal compound C68 (200mg, 0.44 mmol) and Et 3 SiH (52 mg, 0.072 ml, 0.44 mmol) in CH 2 Cl 2 (4.4 ml) was cooled at -78C and BF 3 OEt 2 (67 mg, 0.061 ml, 0.48 mmol) was then added dropwise under N 2 atmosphere. After 30 min Et 3 SiH (52 mg, 0.072 ml, 0.44 mmol) and BF 3 OEt 2 (67 mg, 0.061 ml, 0.48 mmol) were added. The resulting mixture was stirred for 2 h at -78 C. The reaction mixture was quenched saturated aqueous NaHCO 3 extracted with CH 2 Cl 2 and dried over Na 2 SO 4 Evaporation of the solvent and purification by flash column chromatography (Hex/EtOAc = 1/1) gave the product C69 (138 mg, 72%) as a colorless oil. For compound C69 : 1 H NMR (400 MHz, CDCl 3 ) 4.21-3.90 (m, 2 H), 3.80-3.60 (m, 6 H), 3.40 (m, 1 H), 3.10-2.90 (m, 4 H), 2.80-2.60 (m, 2 H), 2.30-2.10 (m, 2 H), 1.90 (m, 1 H), 1.50-1.35 (m, 9 H), 1.10-0.93(m, 3 H) ; 13 C NMR (100 MHz, CDCl 3 ) 172.6, 172.4, 172.3, 154.1, 82.0, 80.6, 72.4, 64.9, 64.6, 52.7, 52.3, 52.2, 48.5, 48.3, 46.4, 42.5, 41.7, 41.3, 40.5, 40.3, 37.7, 32.8, 32.4, 29.4, 28.6, 28.4, 15.9; IR (thin film, cm -1 ) 2989, 2974, 1738, 1697, 1355, 1172 ; HRMS (ESI + ) for [M+Na] + C 18 H 31 NO 9 SNa : calcd 460.1612, found 460.1608 ; [] D 25 = 10.0 (c = 0.28, CHCl 3 ). 119

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3.39 Preparation of isopropenyl pyrrolidine C70 N CO2Me Boc MeO2C MsO N CO2Me Boc CO2Me NaI, DBUDMEC69C70 To a solution of the mesylate C69 (100 mg, 0.22 mmol) in DME (2.2 ml) was added NaI (66 mg, 0.44 mmol) in one portion. After stirring the reaction mixture for 5 h at 60C, DBU (100 mg, 0.66 mmol) was added and the reaction mixture was heated at reflux with stirring for 3 h. After the reaction mixture had cooled to r.t, EtOAc (30 mL) and H 2 O (20 mL) were added and the layers were separated. The combined organic layers were washed with saturated NaHCO 3 solution and brine, dried over Na 2 SO 4 Evaporation of the solvent and purification by flash column chromatography (Hex/EtOAc = 2/1) gave the product C70 (60 mg, 79%) as a colorless oil. For compound C70 (two rotamers) : 1 H NMR (400 MHz, CDCl 3 ) 4.89 (s, 1 H), 4.67 (s, 1 H), 4.13 and 4.04 (d, J = 3.2 Hz, 4.0 Hz, 1 H), 3.74 and 3.73 (s, 3 H), 3.68 and 3.66 (s, 3 H), 3.70-3.58 (m, 1 H), 3.48-3.36 (m, 1 H), 3.02-2.95 (m, 1 H), 2.85-2.78 (m, 1 H), 2.36-2.20 (m, 2 H), 1.67 (s, 3 H), 1.44 and 1.38 (s, 9 H) ; 13 C NMR (100 MHz, CDCl 3 ) 172.6, 172.4, 172.3, 172.2, 154.3, 153.7, 141.4, 141.2, 113.4, 113.1, 80.2, 80.1, 64.0, 63.6, 52.3, 52.2, 51.8, 47.8, 47.6, 46.0, 45.2, 41.9, 40.9, 32.9, 28.4, 28.2, 22.3, 22.2 ; IR (thin film, cm -1 ) 2989, 2975, 1740, 1701, 1397, 1170 ; HRMS (ESI + ) for [M+Na] + C 17 H 27 NO 6 Na : calcd 364.1731, found 364.1729 ; [] D 25 = 18.9 (c = 1.03, CHCl3), [lit: [] D 25 = 19.1 (c = 0.62, CHCl 3 )]. 120

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3.40 Preparation of -(-)-kainic acid A2 N CO2Me Boc CO2Me 1. LiOH2. CF3CO2HA2 (-)-kainic acidNH CO2H CO2H C70 3. Resin The diester compound C70 (30 mg, 0.088 mmol) was dissolved in a mixture of THF (1 mL) and a 2.5% solution of KOH (1mL). The reaction mixture was stirred for 12 h at r.t, and a solution of HCl (2M) was added until pH 3. The mixture was extracted with EtOAc and the organic layers were combined and dried over Na 2 SO 4 and concentrated under reduced pressure. To the resulting residue, CH 2 Cl 2 (2 mL) and TFA (12 equiv.) were added, and the reaction mixture was refluxed for 2 h. After removal of the solvent, the crude product was added to a column containing Dowex-50 H+ (WX8-200, 8% cross-linking, 100200 wet mesh). Elution with NH 4 OH (1 N), evaporation afforded (-)kainic acid 2A (15 mg, 80%): mp 242-244 C [lit : mp 243-244]; HRMS (ESI ) for [M-H] C 10 H 14 NO 4 : calcd 212.0928, found 212.0932 ; [] D 25 = -13.9 ( c= 0.33, H 2 O). [lit : [] D 25 = 14.2 (c = 0.18, H 2 O)]; 1 H NMR (D 2 O) 5.03 (s, 1 H), 4.74 (s, 1 H), 4.06 (d, 1 H, J = 3.1 Hz) 3.62 (dd, 1H, J = 11.6, 7.3 Hz), 3.44 (dd, 1H, J = 11.7, 10.7 Hz), 3.08-2.95 (m, 2 H), 2.29 (dd, 1 H, J = 15.7, 6.4 Hz), 2.16 (dd, 1H, J = 15.7, 8.1 Hz), 1.78 (s, 3H); 13 C NMR (100 MHz, D 2 O) 178.6, 174.3, 140.9, 114.1, 66.6, 47.2, 46.6, 42.1, 35.4, 23.0. 121

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Chapter Four Oxygen-Promoted Pd(II) Catalyzed Carbon-Carbon Bond Formation 4.1 Introduction Palladium catalysis has achieved the status of an indispensable tool for organic synthesis. Among basic types of palladium catalyzed transformations, the Heck reaction and related chemistry is one of the most widely used standard tools for carbon-carbon bond-forming reactions in organic synthesis. 1 In addition to the conventional Heck reaction of unsaturated compounds with organic halides and triflates as an electrophile, the use of nucleophilic organo-metallic reagents such as organosilanes, 2 organoantimony, 3 and organotins 4 have attracted much attention. However, these organometallic reagents and their byproducts are highly toxic 5 and difficult to remove. 6 Comparatively, organoboron reagents are less toxic, 7 stable in air, and easilyaccessible, it is worthwhile to explore their synthetic utility for the various organic reactions. Two oxygen-promoted Pd(II) catalyzed carbon-carbon bond formation reactions are developed and described. One is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the Na2CO3, DMFCO2tBu PhB(OH)2+50oCCO2tBuPh Pd(OAc)2, O2(1) resultant Pd(0) species back to Pd(II) during catalytic cycles. This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings (eq. 1). 122

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Another reaction, which uses similar reaction condition and concept, is a method for the formation of symmetric biaryls and dienes via oxidative dimerization of aryl and alkenyl boronic acids. These conditions also utilized Pd(II) catalysts under an oxygen atmosphere with water as the solvent. The use of phase transfer catalysts promoted efficient and mild syntheses of a wide range of materials (eq. 2). ArB(OH)2 ArAr Pd(OAc)2,O2, NaOAc PTC, H2O, 23 oC (2) 4.2 Oxygen-promoted Pd(II) Catalysis for the coupling of organoborons with olefins Our group has reported an improved method for the aryl-alkenyl coupling by utilizing arylstannanes via Pd(II) catalysis in the presence of oxygen or Cu(II) oxidants. 8 Due to the shortcomings of organometallic reagents including toxicity and difficulty of removing, it was strongly encouraged to develop alternative methods, which are more efficient and environmentally friendly. By utilizing a similar protocol with aryl-aryl coupling reaction of organoboron compounds (Section 4-3), 9 we embarked on the development of a mild and versatile condition of the Heck-type coupling reaction using organo boron reagents. 4.2.1 Heck reaction in water Upon receiving successful results using water for the homo coupling reaction, water was firstly tested for the solvent in the Heck type reaction in the presence of phase transfer catalyst (Scheme 4-1). The reaction condition, which use water as a solvent and air as an oxidant, should be a green and environmentally friendly. Excitement grew from 123

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the promising preliminary results; the desired products D3, D6 were isolated in moderate yields. The formation of homo coupling product D4, D7, which was a main side reaction, was blamed for the low yield. A long reaction time was needed for the starting materials to be consumed completely under the reaction condition. To circumvent the problem, the reaction condition was optimized as described in Section 4.2.4 resulting in the high yield of the product and short reaction time. Pd(OAc)2, O2Water, NaOAc50 oC MeO B(OH)2 Ph +Ph MeO OMe OMe +50%30%24 hPd(OAc)2, O2Water, NaOAc50 oC B(OH)2 Ph +Ph +30%50%24 hPTCAc Ac Ac Ac Scheme 4-1. Heck reaction in waterD1D2D3D4D5D6D7D2 4.2.2 Precedent report Uemura reported a Pd(0)-catalyzed cross coupling of boronic acids and alkenes via oxidative addition of Pd(0) to a carbon-boron bond. 10 In this case, the reactions required long reaction times (20-38 h) and acetic acid as a solvent. Mori reported a Pd(II)-catalyzed pathway for the reaction between organoboron reagents and alkenes in the presence of Cu(OAc) 2 as an oxidant, which involved transmetalation 124

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As the initial step in the catalytic cycle. 11 However, the reaction conditions remained harsh (100 C, DMF) and excess Cu(II) reagent was utilized as an oxidant, generating a poisonous waste. 12 The use of molecular oxygen as a sole reoxidant has been reported in palladium-catalyzed methodologies, encompassing oxidation of alcohols to carbonyl compounds, 13 cyclization of olefinic compounds, 14 and synthesis of hydrogen peroxide. 15 Recently, arylzinc compounds, 16 triarylbismuths, 17 and arylboronic acids 18 were reported to be dimerized in the presence of oxygen. 4.2.3 Oxygen effect As mentioned earlier, the use of oxygen for the oxidative homocouplings of aryl and akenylboronic acids has been reported. 9 The mechanistic aspect of aerobic oxida-tion of palladium catalysts via peroxopalladium(II) species has been well rationalized by Stahl. 19 Na2CO3, DMFCO2tBu PhB(OH)2+50oC, 3 hCO2tBuPh Pd catalystb O2O2Pd(OAc)2Pd(OAc)2Pd(OAc)285%oxidant87%entry123yield0%a N2 condition. b10 mole%."cat. Pd"Pd2(dba)344%12%NoneaAirPd2(dba)345NoneaD8D10D9Table 4-1. Effect of Oxygen Described herein is the use of molecular oxygen as the catalyst oxidant in Pd(II)-catalyzed couplings of organoboron compounds and olefins. The presence of oxygen was critical for catalyst reoxidation as reported earlier. 8, 9 As shown in Table 4-1, 125

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a low yield of the product was obtained when the reaction was run under a nitrogen condition (entry 1). Under air and oxygen, the product was obtained in 44 and 87% yields, respectively (entries 2 and 3). Interestingly, Pd(0) catalyst was also effective in delivering the desired product in 85% yield in the presence of oxygen (entry 4), whereas no product was observed under nitrogen conditions (entry 5). From these results, it was inferred that molecular oxygen played a pivotal role in Pd(II)-catalyzed reaction through the reoxidation of Pd(0) species to Pd(II). 4.2.4 Optimization of the Reaction Condition In a further study, it was found that Pd(OAc) 2 was the choice of the catalyst and Na 2 CO 3 proved to be the best. Several bases such as NaOAc, Cs 2 CO 3 and K 2 CO 3 were effective as well under these aerobic conditions. DMF was the choice of the solvent, whereas protic solvents, including water and EtOH, delivered biaryls via homocoupling reaction exclusively. 18 Regarding temperature, optimal results were obtained at 50 C, while longer reaction times (12-24 h) were required to complete the reactions at 23 C; increased amounts of homocoupling products were produced at higher temperatures such as 100 C. 4.2.5 Optimization of the Catalyst Amount To verify the efficiency of this this protocol, a study for the optimum catalyst dosage wasconducted (Table 4-2). Comparable results were obtained when 5 mol% Pd(OAc) 2 was used and the decreased yield was observed when 1 mole% Pd(OAc) 2 126

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was used. CO2tBu CO2tBuPh PhB(OH)2+Pd(OAc)281%79%42%yieldtime10 mole%5 mole%2.5 mole%1 mole%66%3 h5 h24 h24 h 1 mmole1 mmole Table 4-2. Dosage of catalyst*Reaction conditions: O2, Pd(OAc)2, Na2CO3, DMF, 50 oC, 3 h D8D9D10 4.2.6 Effect of Electron Density on Olefins To examine substrate versatility, we first probed the effect of electron density on olefins as shown in Table 4-3. tert-Butyl acrylate, which is an electron-poor alkene, was converted smoothly to tert-butyl trans-cinnamate D10 in 87% yield. An electron-rich alkene, n-butyl vinyl ether delivered 73% of -butoxystyrene D11 with an isomeric ratio of 2/1 at 23 C after 10 h. Styrene, an aromatic nonallylic alkene, reacted with phenylboronic acid to give 90% of trans-stilbene D12. Allylbenzene was converted to (E)-1,3-diphenylpropene D13 smoothly in 86% yield. This newly developed protocol was effective regardless of the electron density on olefins and was regioselective to provide an (E)-isomer exclusively except with an electron-rich alkene. 127

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10 mole% Pd(OAc)2, O2 Na2CO3, DMF, 50 oC, 3 hRPh R 73% a87%Table 4-3. Effect of Electron Density on Olefines90%86%E/Z =2/1(D10)(D11) a 2.0 eq of n-butylvinylether, 23oC, 10 h. Yields were calculated based on boronic acid. PhB(OH)2 CO2tBuPh PhPh CH2PhPh OBuPh (D12)(D13) 4.2.7 The Versatility of the Arylboronic Acid After screening olefins, we investigated the scope and limitation of organoboron compounds as summarized in Table 4-4. 4-Methoxyphenylboronic acid D1, which has an electron-donating group, and 3-acetylphenylboronic acid D2, which has an electron-withdrawing group, showed similar reactivities, furnishing the desired arylated products in 79 and 78% yields, respectively. Indole derivatization on the C-3 position was also possible by coupling 1-(phenylsulfonyl)3-indoleboronic acid D14 with alkene D8 in good yield. 2,2-Dimethyl-1,3-propanediol benzeneboronate D15 was prepared from the corresponding arylboronic acids 20 and subjected to the Pd(II) catalysis, giving rise to the exclusive synthesis of tert-butyl trans-cinnamate. Likewise, 3,5-dimethyl-4-methoxybenzene catechol boronate D16 furnished the corresponding arylated product in 79% yield. No biphenyl product was observed at all. 128

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Fused aromatic and heterocyclic boronic acids were also effective inthis protocol. The arylboronates of 1-naphthaleneboronic acid D17 and 4-dibenzofuranboronic acid D18 afforded 85 and 77% yields of the desired arylated products, respectively. OBOO NB(OH)2SO2Ph MeOB(OH)2 B(OH)2Ac CO2tBu ArB(OR)2, 10 mole% Pd(OAc)2, O2 Na2CO3, DMF, 50oC, 3 hCO2tBuAr BOO BMeOOO BOO BOOS ArB(OR)2ArB(OR)2 Table 4-4. Various Aryl Boronic acids Coupled with tert-Butyl acrylateD5D1D14D15D17D16D18D19D8yield79%75%79%77%78%92%85%52%yield Next, the coupling with 2,2-dimethyl-1,3-propanediol boronate of thianaphthene-2-boronic acid D19 was smooth with moderate yield. 4.2.8 The Coupling with Allylbenzene Table 4-5 shows the reactions of allylbenzene D20 with various boron compounds. Various arylboron compounds were coupled with allylbenzene smoothly to 129

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deliver the mixture ofthe double-bond-migrated isomers. Electron density in arylboronic acids did not have a significant influence on the results, still giving the desired products in high yields (entries 1, 2). ArB(OR)2ArB(OR)2, 10 mole% Pd(OAc)2, O2 Na2CO3, DMF, 50oC, 3 hPhAr Ph Table 4-5. Various Aryl Boron Reagents Coupled with Allylbenzeneyieldentry34152D5D180% (1/1.0)a86% (1/1.6)a83% (1/1.3)85% (1/5.4)82% (1/3.0)aD17D16D18a Reaction solvent = CH3CN.D20 Arylboronates containing bulky fused aromatic or heterocyclic groups were equally effective in this protocol to provide the regioisomeric mixtures (entries 3-5). 4.2.9 The Coupling with Highly Substituted Olefins Having obtained satisfactory results with monosubstituted alkenes, the research was expanded to the arylation of a highly substituted system as depicted in Table 4-6. Ethyl trans-crotonate reacted with phenylboronic acid to give 70% yield of ethyl -methylcinnamate D21 with exclusive (E)-configuration. trans--Methylstyrene reacted smoothly with both phenylboronic acid and 3-acetylphenylboronic acid to furnish the corresponding trans--methylstilbenes D22, D23 in high yields. Conversely, -methylstyrene delivered an inseparable mixture of trans--methylstilbene and -benzylstyrene D24 in 69% yield in a ratio of 1/1.5. Cyclohexene, a cyclic disubstituted olefin, was also effective in our protocol 130

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to furnish a 1/2 mixture of 3-phenylcyclohexene and 4-phenylcyclohexene D25 in 48% yield. These data implied that this oxygen protocol could be applicable to most highly substituted olefin systems, resulting in outstanding (E)-selectivity. 10 mole% Pd(OAc)2, O2 Na2CO3, DMF, 50 oC, 3 hPhCO2Et PhPh PhPh +PhPh Ph PhAc 70%82%69%(1/1.5)48%(1/2)Product86%a a 3-Acetylphenylboronic acid was used as a coupling partner.Olefin(D21)(D22)(D23)(D24)(D25)D9, Table 4-6. Coupling with Highly Substituted Olefins 4.2.10 Phenol Formation During the research, it was found that phenols were sometimes observed as minor side products along with the aforementioned biaryls. 18c When arylboronic acids were utilized as couplingpartners the phenols were isolated in 5% yield, whereas arylboronates functioned as benign coupling partners for this methodology, decreasing theformation of side products such as biaryls and phenols (Table 4-7). From these data, some mechanistic insight was inferred and a catalytic passway were suggested for the homo coupling reactions after conducting further experiment later on. 131

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CO2tBu CO2tBuPh PhB(OR)2+ PhPh PhOH ++D8D10D33D60PhB(OR)2 (1.0 eq)D10D33D60D9D1581%7%5%90%4%traceTable 4-7. Phenol formation*Reaction conditions: O2, Pd(OAc)2, Na2CO3, DMF, 50 oC, 3 h 4.2.11 Competition Reaction and Reaction Cycle To elucidate the catalytic pathway of this oxygen protocol, we conducted the competition reactions using tert-butyl acrylate (D8, 3 mmol), 21 2,2-dimethyl-1,3-propanediol boronate of 3-acetylphenylboronic acid (D26, 1 mmol), and 2-iodoanisole (D27, 1 mmol). As shown in Scheme 4-1, 71% of Pd(II) catalysis product D28 and 26% of Heck coupling product D29 were isolated using oxygen conditions, while only 18% of D30 was isolated together with Heck product as the major product using oxygen free conditions (argon atmosphere). The Suzuki coupling product 22 D30 was detected in low yield under both conditions. The side products, 17,21 D31 and D32, were detected with oxygen conditions in 5 and 6% yields, respectively. From these results, it was inferred that molecular oxygen promoted the desired Pd(II) catalysis and suppressed the competing Pd(0) catalytic pathways (Scheme 4-2). 132

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CO2tBu Ar1BOO +Ar2I Ar1CO2tBu Ar2CO2tBu Ar1Ar2 O2dArAr1Ar1 Ar1OH + Scheme 4-2. Competition Reaction71%26%0.5%18%74%1%a Ar1 = 3-acetylphenyl. b Ar2 = 2-methoxyphenyl.(D8, 3 mmole)(D26, 1 mmole)a(D27, 1 mmole)bHeck Suzukic5%0%D316%0%D32 d Oxygen was delivered by bubbling into the reaction solution slowly.Pd(II) catalysisD28D29D30 c 20 mole% Pd(OAc)2, Na2CO3, DMF, 50 ?C, 6 h. Although the details are not yet known, a mechanistic catalytic cycle was proposed as shown in Figure 4-1. Presumably, the Pd(II) works as the active species throughout the reaction as suggested by Mori. 11 As delineated in cycle I, transmetalation of arylboronic acid gives Ar-Pd-L, and migratory insertion of the olefin is followed by -hydride elimination to produce the desired product and Pd(0) species. Molecular oxygen then oxidizes the Pd(0) to Pd(II) species, possibly via a peroxopalladium(II) complex. 19 The high efficiency of the Pd(0) complex, Pd 2 (dba) 3 can be explained by this scheme involving the oxidation step of Pd(0) species by oxygen. The preference of our oxygen-promoted Pd(II) catalysis to the conventional Heck or Suzuki catalysis under an oxygen atmosphere can also be explained by this reaction scheme involving rapid oxidation of Pd(0) species. Therefore, Pd(0)-catalyzed oxidative addition of 2-iodoanisole can be suppressed to follow Heck or Suzuki pathways (cycle II). 133

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Figure 4-1. Reaction Cycle Pd(0) Pd(II) R R Ar Ar'-X C y c l e I C y c l e I I O2 Heck CatalysisSuzuki CouplingOxygen promotedPd(II) CatalysisAr'-Pd-XAr-B(OR)2Ar-Pd-L"Oxidative addition""Fast" R Ar' Ar-Ar' or"Slow""Transmetalation" R Ar Pd-L 4.2.12 Conclusion In conclusion, a mild and efficient Pd(II) catalysis, an organometallic variation of Heck reaction was elaborated. The newly developed protocol uses an environmentally friendly and inexpensive oxidant, molecular oxygen, and provides various aryl-alkenyl coupling products from a broad spectrum of olefins and arylboron compounds in good to excellent yields. This oxygen protocol demonstrates a new mechanistic concept that oxygen would promote the Pd(II) catalytic pathway and in turn suppress the competing Pd(0) catalysis encompassing Heck or Suzuki couplings. 134

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4.3 Oxidative Dimerization: Pd(II) Catalysis in the Presence of Oxygen using Aqueous Media The synthesis of biaryls has been widely studied beginning with the classic Ullmann coupling. 23 Many reactions including Stille and Suzuki couplings allow for the syntheses of both symmetric and unsymmetrical biaryls in high yields. 24 Recent interest in oxidative dimerizations for the synthesis of symmetric biaryls has resulted in a number of studies, mostly employing organostannanes. 25 Our group has reported improved conditions for the rapid synthesis of biaryls from stannanes using Cu(II) salts as Pd(II) catalyst reoxidants. 26 However, organotin compounds and their by-products are difficult to remove and highly toxic. 27 To alleviate the problems associated with organostannanes, alternatives employing less-toxic analogs such as boronic acids are desirable. Additionally, aryl and vinyl boronic acids are becoming more readily available from commercial sources. 28 4.3.1 Precedent Results of Homo Coupling with Organo Boron Reagent There have been several reports utilizing boronic acids in oxidative dimerizations 29 and others using oxygen conditions. 30 Jackson et al. reported Pd(II) catalyzed couplingsof arylboronic acids using oxygen conditions. 31 However, the reaction conditions gave side products resulting in low yields of desired products and provided limited examples. To minimize side reactions, useof phase transfer catalysts (PTC) was reported for the couplings of arylboronic acids with olefins in aqueous 135

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media. 32 Report herein is the palladium-catalyzed carbon-carbon bond formation via the oxidative dimerization of boronic acids. By using oxygen as the catalyst reoxidant, rapid formation of dimerized products can be obtained in aqueous media under PTC conditions. 33 As a distinguishing feature, the procedure allows for the synthesis of dienes in good yields with limited side products. 4.3.2 Effect of Oxidant The role of the catalyst reoxidant in the dimerization of phenylboronic acid D9 was critical. The reaction was run under nitrogen, air, and oxygen as oxidants, which were delivered either by bubbling or via balloon (Table 1). Very low yields (<10%) of biphenyl D33 were obtained when the reaction was run under nitrogen conditions, indicating the need for an oxygen source (entry 1). oxidantO2timeyield3 h95%air24 h21%48 h>10%N2entry123 PhPh Pd(OAc)2, oxidant NaOAc, H2O, 23 oC D9D33Table 4-8. Effect of oxidant choice on oxidative dimerization of phenylboronic acidPhB(OH)2 With the use of air, only 21% yield of the desired product was obtained (entry 2). With oxygen, a 95% yield of D33 was achieved in a shorter reaction time (entry 3). Surprisingly, no other side products were detected in the reaction mixture. From these results, it was inferred that oxygen was the source of reoxidation and best applied in the pure oxygen form. Then the optimum reaction conditions were established using NaOAc 136

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as the base in aqueous media. In most cases, water was a highly effective solvent either with or without PTC. 4.3.3 Effect of PTC The PTC employed depended on the substrates being screened, but it was found that PTCs with long chain alkyl groups were generally effective for this protocol with fewexceptions (Tables 4-9, 10, and 11). The exact mechanism of PTC in this reaction was not investigated. However, it was found that it increased the compatibility of arylboronic acids with water and palladium catalysts dramatically and minimized the side reactions using catalytic amounts. 4.3.4 Example of the Functionalized Phenylboronic Acid A screening test of a variety of substituted phenylboronic acids was conducted as shown in Table 4-9. Electron rich 4-methoxyphenylboronic acid gave 4,4-dimethoxy biphenyl D34 in 95% yield after 3 h without the use of a PTC. Likewise, similar substrate 4,4-diphenoxybiphenyl D35 was prepared in 95% yield after 10 h. As stated previously, the need for PTC to facilitate dimerization is dependent on the boronic acid employed. Assuch, the dimerization of 3,4-(methylenedioxy)phenyl boronic acid required cetyltrimethylammonium hydrogensulfate (10 mol%, 0.1 M solution) as a PTC. The reaction was completed after 10 h to give the product D36 in 84% yield. No deacetalization products were detected in the reaction mixture. The dimerization of 4-(dimethylamino)phenyl boronic acid was smooth to provide the biphenyl D37 in 93% 137

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yield after 10 h. No side products resulting from direct oxidation of the nitrogen were detected. Electron withdrawing groups did not appear to have an effect on the course of the reaction as has been seen in other cases. 34 3-Cyanophenylboronic acid gave 3,3-dicyanobiphenyl D38 in 98% yield after 10 h in the presence of PTC. Pd(OAc)2, O2, NaOAcPTC, H2O, 23 oC 95%95% MeO 84%93%98%99%61%Phase transfer catalyst (PTC) employed, 10 mol%, 0.1 M H2O solution: A = CH3(CH2)15N(CH3)3HSO4; B = CH3(CH2)13N(CH3)3Br; C = CH3(CH2)11OSO3NaArB(OH)2 ArAr F NC OO PhO N 58%BABC 94%Ac Table 4-9. Formation of biphenyls from boronic acids OMe OPh N CN F Ac OO D34D35D36D37D38D39D40D41D42 4,4-Difluorobiphenyl D39 was prepared in nearly quantitative yield after only 3 h without the need for PTC. The 4-bromo and 4-iodo congeners were also screened, but produced low yields of desired products (<30%) despite our best efforts. 138

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3-Acetylphenylboronic acid gave the biphenyl product D40 in 94% yield in 3 hours. Next focus was determining the steric effects in the reaction. o-Tolylboronic acid was screened and gave only 61% yield of the biphenyl product D41. Likewise, 2,6-dimethylphenylboronic acid gave a 58% yield of the corresponding biphenyl D42 in 10 h using sodium dodecyl sulfate. Interestingly, this reaction was not effected using cetyltri-methylammonium hydrogensulfate. From these results, we inferred that steric effects hindered product formation of these two substrates as compared with the result of phenylboronic acid. Additionally, it was attributed that the lower yields of these substrates to thelow solubility of the boronic acids in water, even under PTC conditions. If steric effects were a main factor, the addition of the extra methyl in D42 would have decreasedthe yieldproportionally.As gleaned from the experimental results, the yields for the products D41, D42 arevirtually the same, implying that steric effect is not a sole governor on the reaction. 4.3.5 Example of the Multiand Heterocyclic Arylboronic Acid Having obtained satisfactoryresults in the dimerization of phenylboronic acids, thetest ofversitility of aryl boronic acids was expanded to the multiand heterocyclic arylboronic acids as shown in Table 4-10. Thus, 2-naphthaleneboronic acid was dimerized in 10 h and in 95% yield to provide D43. Likewise, 1-naphthaleneboronic acid reacted to give an 87% yield of corresponding biaryl compound D44, albeit without the need of PTC. 139

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Pd(OAc)2, O2, NaOAcPTC, H2O, 23 oC RB(OH)2 RR 87%95% 98%79%62%Phase transfer catalyst (PTC) employed, 10 mol%, 0.1 M H2O solution: A = CH3(CH2)15N(CH3)3HSO4; B = CH3(CH2)13N(CH3)3BrB O S S OHC ABATable 4-10. Formation of biaryls from boronic acids O S S CHO D43D44D45D46D47 Next, 4-dibenzofuranboronic acid reacted under PTC conditions in very high yield of the product D45. Without the use of PTC conditions, we found numerous side products occurred. Phenol formation was the major side product, resulting from the addition of water to the palladium complex. Additionally, proton exchange also occurred with the boron moiety to generate the unfunctionalized aromatic. 35 Next, the dimerization of heterocyclic boronic acids was studied. The dimerization of thianaphthene2-boronic acid was efficient, but gave only 79% yield of the product D46 after 10 h. Furthermore, 5-formyl2-thiopheneboronic acid reacted to give the biaryl D47 in only 62% yield. In both cases, the starting material was completely consumed and only phenol and 140

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unfunctionalized aromatic products were isolated. The dimerizations of other furan and thiophenebased boronic acids were attempted, but withlimited success. 4.3.6 Synthesis of Diene The synthesis of dienes through the oxidative dimerization of vinylboronic acids was efficient as shown in Table 4-11. trans-2-Phenylvinylboronic acid gave good yield of the (E,E)-diene product D48 under PTC conditions. Only one isomer was isolated with no side products detected, and the remainder of the reaction mixture was unreacted starting material. The 4-fluoro congener reacted to give the (E,E)-diene D49 exclusively in 73% yield after 10 h. Pd(OAc)2, O2, NaOAcPTC, H2O, 23 oC 85%73%75% 79%65%R B(OH)2 R R Phase transfer catalyst (PTC) employed, 10 mol%, 0.1 M H2O solution: A = CH3(CH2)13N(CH3)3Br; B = CH3(CH2)15N(CH3)3HSO4; C = Bu4NOHABBCCTable 4-11. Formation of dienes from boronic acids F Cl F Cl D48D49D50D51D52 Additionally, the 4-chloro compound gave 85% yield of the desired diene D50 under similar conditions. The synthesis of long chain dienes was also effective using our protocol. For example, the dimerization of trans-1-hexen-1-ylboronic acid gave (5E,7E)141

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5,7dodecadiene D51 exclusively in 79% yield after 10 h. Additionally, trans-1-octen-1-ylboronic acid gave (7E,9E)-7,9-hexadecadiene D52 in 65% yield. The remainder of the reaction mixture in D51 and D52 was unreacted starting material. With the long chain alkenyl boronic acids, we screened the standard PTCs that had been used with previous examples in Tables 4-9, 10, and 11. However, these catalysts were ineffective and gave mostly unidentified side productsinstead of the desired dimerized materials. Fortunately, the use of tetrabutylammon-ium hydroxide facilitated the dimerization of long chain alkenyl boronic acids. 4.3.7 Conclusion In conclusion, we have developed a method for the formation of symmetric biarylsand dienes via the oxidative dimerization of boronic acids. These conditions utilize Pd(II)catalysts under an oxygen environment with water as the solvent. The use of PTCs allowsfor the efficient and mild synthesis of a wide range of products in a rapid fashion. Our reaction allows for a more environmentally benign and cost-effective alternative to standard oxidative dimerization conditions with organostannanes. Additionally, our protocol enhances previous examples of boronic acid dimerization by increasing utility of the reaction. We have achieved this by broadening the range of substrates employed to include substituted phenyls, biaryls, heterocycles, and dienes. 142

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4.4 References 1 For reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (b) Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles 1999, 51, 1957. (c) Shibasaki, M.; Boden, C. O. J.; Kojima, A. Tetrahedron 1997, 53, 7371. (d) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth.1996, 3, 447. (e) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. ReV. 1996, 96, 365. (f) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (g) Heck, R. F. Org. React. 1982, 27, 345. (h) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. 2 (a) Hirabayashi, K.; Nishihara, Y.; Mori, A.; Hiyama, T. Tetrahedron Lett. 1998, 39, 7893. (b) Hirabayashi, K.; Kondo, T.; Toriyama, F.; Nishihara, Y.; Mori, A. Bull. Chem. Soc. Jpn. 2000, 73, 749. (c) Hirabayashi, K.; Ando, J.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 1409. 3 Motoba, K.; Motofusa, S.; Cho, C. S.; Uemura, S. J. Organomet. Chem. 1999, 574, 3. 4 (a) Oda, H.; Morishita, M.; Fugami, K.; Sano, H.; Kosugi, M. Chem. Lett. 1996, 811. (b) Fugami,K.; Hagiwara, S.; Oda, H.; Kosugi, M. Synlett 1998, 477. (c) Hirabayashi, K.; Ando, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Synlett 1999, 99. (d) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. (e) Heck, R. F. J. Am. Chem. Soc. 1969, 91, 6707. 5 For toxicology studies, see: (a) Smith, P. J. Toxicological Data on Organotin Compounds; Publication 538; International Tin Research Institute: London, 1978. (b) Chau, Y. K.; Wong, P. T. S. Some EnVironmental Aspects of Organo-arsenic, Lead and Tin; NBS Special Publication (United States), 1981, 618, 65-80. (c) Sandhu, G. K. J. Chem. Sci. 1983, 9, 36. (d) Barnes, J. M.; Magos, L. Organomet. Chem. ReV. 1968, 3 (2), 143

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137. 6 Pyrene, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworth: Boston, 1987; pp 36-37. 7 Ullmanns Encyclopedia of Industrial Chemistry, 6th ed., June 2001 Electronic Release; Wiley-VCH: Weinheim, Germany, 2001. 8 Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W. J. Org. Chem. 2002, 67, 7127. 9 Parrish, J. P.; Jung, Y. C.; Floyd, R. J.; Jung, K. W. Tetrahedron Lett. 2002, 43, 7899. 10 Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465, 85. 11 Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001, 21, 3313. 12 For toxicology studies, see; (a) Beritic, T.; Dimov, D. ArhiV Za Higijenu Rada I Toksikologiju 1970, 21 (3), 285. (b) Grebennikov, E. P. SoVetskaia Meditsina 1969, 32 (4), 94. 13 (a) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002, 124, 766. (b) Brink, G. T.; Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636. (c) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185. 14 (a) Rohn, M.; Backvall, J.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749. (b) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584. 15 (a) Bianchi, D.; Bortolo, R.; DAloisio, R.; Ricci, M. Angew. Chem., Int. Ed. 1999, 38, 706. (b) Thiel, W. R. Angew. Chem., Int. Ed. 1999, 38, 3157. 16 Hossain, K. M.; Kameyama, T.; Shibata, T.; Tagaki, K. Bull. Chem. Soc. Jpn. 2001, 74, 2415. 144

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17 Ohe, T.; Tanaka, T.; Kuroda, M.; Cho, C. S.; Ohe, K.; Uemura, S. Bull. Chem. Soc. Jpn. 1999, 72, 1851. 18 (a) Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio, S.; Naeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131. (b) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087. (c) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai. A. Tetrahedron Lett. 2003, 44, 1541. 19 (a) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.Chem. Soc. 2001, 123, 7188. (b) Stahl, S. S.; Thorman, J. L.; de Silva, N.; Guzei, I. A.; Clark, R. W. J. Am. Chem. Soc. 2003, 125, 12. 20 Shi, B.; Boyle, R. W. J. Chem. Soc., Perkin Trans. 1 2002, 11, 1397. 21 Suzuki coupling product was detected in low yield from boron reagent and halide; thus, excess alkene was used to maximize the efficiency of the other reactions. 22 In a separate Suzuki coupling reaction between 24 and 25, the desired product 28 was isolated in 31% yield under oxygen and 71% yield under argon conditions (20 mol % Pd(OAc)2, Na2CO3, DMF, 50 C, 6 h). 23 For the reviews of the Ullmann coupling, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433; (b) Kozhevnikov, I. V.; Matveev, K. I. Russ. Chem. Rev. 1978, 47, 649; (c) Fanta, P. E. Synthesis 1974, 9. 24 For the Stille reaction, see: (a) Mitchell, T. N. In Metal-Catalyzed Cross Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley: New York, 1998, pp. 167; (b) Mitchell, T. N. Synthesis, 1992, 803; (c) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. For the 145

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Suzuki reaction, see: (d) Suzuki, A. In Metal-Catalyzed Cross Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley: New York, 1998, pp. 49; (e) Miyaura, N. Chem. Rev. 1995, 95, 2457; (f) Suzuki, A. Pure Appl. Chem. 1994, 66, 213. 25 For selected examples of oxidative dimerization reactions, see: (a) Kang, S.-K.; Baik, T.-G.; Jiao, X. H.; Lee, Y.-T. Tetrahedron Lett. 1999, 40, 2383; (b) Kang, S.-K.; Namkoong, E.-Y.; Yamaguchi, T. Synth. Commun. 1997, 27, 641; (c) Wright, M. E.; Porsch, M. J.; Buckley, C.; Cochran, B. B. J. Am. Chem. Soc. 1997, 119, 8393; (d) Tamao, K.; Ohno, S.; Yamaguchi, S. J. Chem. Soc., Chem. Commun. 1996, 1873; (e) Boons, G.-J.; Entwistle, D. A.; Ley, S. V.; Woods, M. Tetrahedron Lett. 1993, 34, 5649; (f) Liebeskind, L. S.; Riesinger, S. W. Tetrahedron Lett. 1991, 32, 5681; (g) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Velder, Y. L.; Spirikhin, L. V. Synthesis 1989, 633. 26 For our studies, see: Parrish, J. P.; Flanders, V. L.; Floyd, R. J.; Jung, K. W. Tetrahedron Lett. 2001, 42, 7729. 27 For toxicology studies, see: (a) Smith, P. J. Toxicological Data on Organotin Compounds, Publication 538. International Tin Research Institute: London, 1978. For examples of purification techniques, see: (b) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: Boston, 1987, pp. 36. 28 Aldrich Chemical Catalog 2000, Aldrich Chemical Co., Milwaukee. 29 For oxidative dimerizations with boronic acids, see: (a) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087; (b) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346; (c) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 146

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1995, 60, 176. 30 For oxygen-promoted carboncarbon bond formations, see: (a) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337; (b) Matoba, K.; Motofusa, S.-I.; Cho, C. S.; Ohe, K.; Uemura, S. J. Organomet. Chem. 1999, 574, 3; (c) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211. 31 Smith, K. A.; Campi, E. A.; Jackson, W. R.; Marcuccio, S.; Naeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131. 32 For the use of PTCs, see: (a) Lautens, M.; Roy, A.; Fukuoka, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358; (b) Grasa, G. A.; Nolan, S. P. Org. Lett. 2000, 3, 119. 33 Jones, R. A. Quaternary Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions; Academic Press: New York, 2001. 34 For the effects of substituents on transition-metal coupling reactions, see: (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379; (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (d) Sonogashira, K. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley: New York, 1998, pp. 203. 35 For mechanistic considerations of the oxidative dimerization of boronic acids and formation of side products, see: Ref. 7b. 147

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Chapter Five Experimental Data All experiments were carried out under nitrogen atmosphere using oven dried glassware (or flame dried when necessary). All chemicals were purchased from Aldrich Chemical Co. and/orAcros Organics and used without further purification unless otherwise noted. CH 2 Cl 2 was distilled over calcium hydride. THF and diethyl ether were distilled over sodium metal. Proton nuclear magnetic resonance (250 MHz) and 13C (62.5 MHz) spectra were recorded at r.t in CDCl 3 unless otherwise noted. All chemical shifts are reported as relative to CHCl 3 (H 7.26 ppm) and CDCl 3 (C 77.0 ppm) as internal standards, respectively, using a Buruker DPX 250 spectrometer. Infrared spectra were recorded using a Nicolet Magna FTIR 550 spectrometer and are reported in reciprocal centimeters (cm -1 ). Mass analysis was preformed using Hewlett-Packered HRMS spectroscopy. Thin layer chromatography (TLC) was preformed on EMD precoated silica plates with silica gel 60 250 m thickness. Visualization of TLC was accomplished using a UV lamp (254 nm), iodine or charring solutions (ninhydrin and PMA). Flashcolumn chromatography was performed on Whatman Purasil 60 (230-400mesh) silica gel. 148

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5.1 Oxygen-promoted Pd(II) Catalysis for the coupling of organoborons with olefins 5.1.1 Representative Experimental Procedure : Preparation of (E)tert-butyl cinnamate,D10 CO2tBuPh D10 tert-Butyl acrylate (64 mg, 0.5 mmol, 1 equiv.) was dissolved in DMF (2.5 mL, 0.2 M solution), and stirred at room temperature. To the clear solution, was added phenylboronic acid (74 mg, 0.6 mmol, 1.2 equiv.) followed by a single addition of Na2CO3 (106 mg, 1.0 mmol, 2 equiv.) and Pd(OAc)2 (11 mg, 0.05 mmol, 0.1 equiv.). The reaction flask was fitted with an oxygen balloon, heated to 50 C, and stirred for 3 h. The mixture was then diluted with EtOAc (20 mL), and washed with aqueous brine solution (3 10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and subjected to flash chromatography (30 g of SiO 2 ). Elution withHex (100 mL), then 10:1 Hex/EtOAc afforded tert-butyl trans-cinnamate (89 mg, 87%) as a colorless oil. Rf=0.6 (9:1 hexanes/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.59(d, J=16.0 Hz, 1 H), 7.50(m, 2 H), 7.38(m, 3 H), 6.37(d, 1 H, J=16.0Hz), 1.54 (s, 9 H); 13 C NMR (62.5 MHz, CDCl 3 ) 166.3, 143.5, 134.6, 129.9, 128.8, 127.9, 120.1, 80.5, 28.2. 149

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5.1.2 Preparation of (E)-stilbene, D12 PhPh D12 Rf=0.4 (Hex); 1 H NMR (250 MHz, CDCl 3 ) 7.55 (m, 4 H), 7.40 (m, 4 H), 7.30 (m, 2 H), 7.15 (s, 2 H); 13 C NMR (62.5 MHz, CDCl 3 ) 137.3, 128.7, 128.6, 127.6, 126.5. 5.1.3 Preparation of (E)-(2-butoxyvinyl)benzene, D11 OBuPh D11 Rf=0.5 (Hex); 1 H NMR (250 MHz, CDCl 3 ) 7.60-7.11 (m, 5 H), 7.07 (d, 1 H, J = 23.5 Hz), 5.83 (d, 1 H, J = 23.5 Hz), 3.84 (t, 2 H, J = 6.5 Hz), 1.76-1.44 (m, 4 H), 1.00 (t, 3 H, J = 7.3 Hz). 5.1.4 Preparation of (E)-prop-1-ene-1,3-diyldibenzene, D13 Ph D13Ph Rf=0.8 (10:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.43-7.20 (m, 10 H), 6.55-6.34 (m, 2 H), 3.59 (d, 2 H, J = 6.1 Hz); 13 C NMR (62.5 MHz, CDCl 3 ) 140.2, 137.5, 131.1, 129.2,128.7, 128.5, 127.1, 126.1, 39.4. 150

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5.1.5 Preparation of (E)-ethyl 3-(4-methoxyphenyl)acrylate CO2tBu MeO Rf=0.4 (1:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.54 (d, 1 H, J = 15.9 Hz), 7.45 (d, 2 H, J = 8.7 Hz), 6.89 (d, 2 H, J = 8.7 Hz), 6.23 (d, 1 H, J= 15.9 Hz), 3.83 (s, 3 H), 1.53 (s, 9 H); 13 C NMR (62.5 MHz, CDCl 3 ) 166.7, 161.1, 143.2, 129.5, 127.3, 117.6, 114.2, 114.1, 80.2, 55.3, 28.2. 5.1.6 Preparation of (E)-ethyl 3-(3-acetylphenyl)acrylate CO2tBu Ac Rf=0.4 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.07 (s, 1 H), 7.92 (m, 1 H), 7.67 (m, 1 H), 7.60 (d, 1 H, J = 16 Hz), 7.47 (m, 1 H), 6.43 (d, 1 H, J = 16 Hz), 2.62 (s, 3 H), 1.53 (s, 9 H) ; 13 C NMR (62.5 MHz, CDCl 3 ) 197.5, 165.9, 142.3, 137.6, 135.1,132.1, 129.5, 129.1, 127.5, 121.6, 80.8, 28.1, 26.6. 5.1.7 Preparation of (E)-ethyl 3-(1-(phenylsulfonyl)-1H-indol-3-yl)acrylate CO2tBu NSO2Ph 151

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Rf=0.7 (2:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.01 (d, J = 7.8 Hz), 7.90 (m, 2 H), 7.79 (m, 2 H), 7.68 (d, 1 H, J = 16.1 Hz), 7.56-7.31 (m, 5 H), 6.45 (d, 1 H, J = 16.1 Hz), 1.54 (s, 9 H) ; 13 C NMR (62.5 MHz, CDCl 3 ) 166.3, 137.7, 135.6, 134.3, 129.4, 129.2, 128.2, 127.8, 126.8, 125.5, 124.1, 120.7, 118.5, 113.6, 80.6, 57.6, 28.2. 5.1.8 Preparation of (E)-ethyl 3-(4-methoxy-3,5-dimethylphenyl)acrylate CO2tBu MeO Rf=0.5 (10:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.48 (d, 1 H, J=15.9 Hz), 7.17 (s, 2H), 6.25 (d, 1 H, J =15.9 Hz), 3.73 (s, 3 H), 2.28 (s, 6 H), 1.52 (s, 9 H) ; 13 C NMR (62.5 MHz, CDCl 3 ) 166.5, 158.6, 143.3, 131.3, 130.1, 128.6, 118.8, 80.2, 59.7, 28.2, 16.1. 5.1.9 Preparation of (E)-ethyl 3-(naphthalen-1-yl)acrylate CO2tBu Rf=0.7 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.43 (m, 1 H), 8.20 (m, 1 H), 7.88(m, 2 H), 7.74 (m, 1 H), 7.58-7.44 (m, 3 H), 6.47 (d, 1 H, J = 15.7 Hz), 1.59 (s, 9 H); 13 C NMR (62.5 MHz, CDCl 3 ) 166.2, 140.5, 133.6, 132.0, 131.4, 130.2, 128.6, 126.7, 126.1, 125.4, 124.9, 123.4, 122.8, 80.6, 28.2. 152

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5.1.10 Preparation of (E)-(4-benzofuranyl) tert-butyl acrylate CO2tBu O Rf=0.6 (2:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.95 (m, 2 H), 7.89 (d, 1 H, J=16.1 Hz), 7.68-7.31 (m, 5 H), 7.00 (d, 1 H, J=16.1 Hz), 1.60 (s, 9 H); 13 C NMR (62.5 MHz, CDCl 3 ) 166.6, 156.1, 154.3, 138.2, 128.1, 127.5, 124.9, 123.6, 123.4, 123.1, 122.9, 121.9, 120.7, 119.9, 111.9, 80.6, 28.2. 5.1.11 Preparation of (E)-ethyl 3-(benzo[b]thiophen-2-yl)acrylate CO2tBu S Rf=0.7 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.77 (d, 1 H, J = 15.6 Hz), 7.76 (m, 2 H), 7.43 (s, 1 H), 7.37 (m, 2 H), 6.23 (d, 1 H, J = 15.6 Hz), 1.54 (s, 9 H); 13 C NMR (250 MHz, CDCl3) 165.8, 140.0, 139.7, 139.6, 136.6, 128.2, 126.0, 124.8, 124.3, 122.4, 121.5, 80.8, 28.1. 5.1.12 Preparation of D20 + D1 MeO Ph Rf=0.8 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.38-7.15 (m, 7 H), 6.86 (m, 2 H), 6.45-6.18 (m, 2 H), 3.81 (s, 3 H), 3.56-3.49 (d, 2 H). 153

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5.1.13 Preparation of D20 + D5 Ac Ph Rf=0.5 (2:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.93-7.77 (m, 2 H), 7.54-7.20 (m, 9 H), 6.52-6.35 (m, 2 H), 3.60 (d, 2 H), 2.60 (s, 3 H). 5.1.14 Preparation of D20 + D16 MeO Ph Rf=0.6 (10:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.34-7.15 (m, 5 H), 6.98 (s, 1 H), 6.84 (s, 1 H), 6.38-6.05 (m, 2 H), 3.66 (s, 3 H), 3.47 (d, J = 6.3 Hz, 1 H), 3.39 (d, J = 6.4 Hz, 1 H), 2.22 (s, 6 H). 5.1.15 Preparation of D20 + D17 Ph Rf=0.6 (9:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.10-7.19 (m, 12 H), 6.60-6.30 (m, 2 H), 4.02, 3.70 (d, J = 4.7, 7.6 Hz, 2 H) 154

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5.1.16 Preparation of D20 + D18 O Ph Rf=0.6 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.10-7.25 (m, 12 H), 6.54 (m, 2 H), 3.93, 3.70 (d, J = 5.1, 5.7 Hz, 2 H) 5.1.17 Preparation of (E)-ethyl 3-phenylbut-2-enoate, D21 PhCO2Et D21 Rf=0.7 (10:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.48 (m, 2 H), 7.38 (m, 3 H), 6.14(d, J = 1.2 Hz, 1 H), 4.22 (q, J =7.1 Hz, 2 H), 2.58 (d, J = 1.2 Hz, 3 H), 1.32 (t, J = 7.1 Hz); 13 C NMR (62.5 MHz, CDCl 3 ) 166.8, 155.5, 142.2, 128.9, 128.4, 126.3, 117.1, 59.8, 17.9, 14.3. 5.1.18 Preparation of (E)-methyl stilbene, D22 PhPh D22 Rf=0.8 (10:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.56 (m, 2 H), 7.43-7.27 (m, 8 H), 6.87 (s, 1 H), 2.31 (s, 3 H); 13 C NMR (62.5 MHz, CDCl 3 ) 143.9, 138.3, 137.4, 129.1, 128.3, 128.1, 127.6, 127.1, 126.4, 126.0, 17.5. 155

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5.1.19 Preparation of D23 PhAc D23 Rf=0.7 (2:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.12 (s, 1 H), 7.88 (d, J =7.7 Hz, 1 H), 7.73(d, J =7.7 Hz, 1 H ), 7.50-7.26 (m, 6 H), 6.89 (s, 1 H), 2.65 (s, 3 H), 2.31(s, 3 H); 13 C NMR (62.5 MHz, CDCl 3 ) 198.3, 144.4, 137.9, 137.2, 136.5, 130.6, 129.1, 128.7, 128.6, 128.2, 127.1, 126.7, 125.7, 26.8, 17.5. 5.1.20 reparation of cyclohex-2-enylbenzene, cyclohex-3-enylbenzene D25 Ph D25 Rf=0.9 (Hex); 1 H NMR (250 MHz, CDCl 3 ) 7.34-7.15 (m, 5 H), 5.92-5.69 (m, 2 H), 3.40 and 2.81 (m, 1 H), 2.20-1.52 (m, 6 H). 156

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5.2 Oxidative dimerization: Pd(II) catalysis in the presence of oxygen using aqueous media 5.2.1 Representative Experimental Procedure : Preparation of Biphenyl, D33 D33 Phenylboronic acid (122 mg, 1.0 mmol, 1 equiv.) was mixed with water in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc)2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 was placed over the neck of the flask and the solution was stirredat room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (73 mg, 95%). Rf=0.9 (Hex); 1 H NMR (250 MHz, CDCl 3 ) 1.57(s, 9 H), 6.37(d, 1 H, J =16.0 Hz), 7.38(m, 3 H),7.50(m, 2 H), 7.59(d, 1 H, J =16.0 Hz); 13 C NMR (250 MHz, CDCl3) 28.2, 80.5, 120.1, 127.9, 128.8, 129.9, 134.6, 143.5, 166.3. 157

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5.2.2 Preparation of 4,4'-dimethoxybiphenyl, D34 MeO OMe D34 Rf=0.4 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.49 (d, 4 H, J =8.4 Hz), 6.97(d, 4 H, J =8.4 Hz), 3.85 (s, 6 H); 13 C NMR (62.5 MHz, CDCl 3 ) 158.6, 133.4, 127.7, 114.1, 55.3. 5.2.3 Preparation of N4,N4,N4',N4'-tetramethylbiphenyl-4,4'-diamine, D37 N N D37 Rf=0.4 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.56 (d, J = 8.8 Hz, 4 H), 7.88 (d, J = 8.8 Hz, 4 H), 3.05 (s, 12 H). 5.2.4 Preparation of 1,1'-binaphthyl, D44 D44 Rf=0.8 (1:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.96 (m, 4 H), 7.61 (m, 2 H), 7.52-7.39 (m, 6 H), 7.30 (m, 2 H). 158

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5.2.5 Preparation of 5,5'-bibenzo[d][1,3]dioxole, D36 OO OO D36 3,4-(Methylenedioxy)Phenylboronic acid (126 mg, 1.0 mmol, 1 equiv.) was mixed with a 0.1 M stock aqueous solution of cetyltrimethylammonium hydrogensulfate in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc) 2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 was placed over the neck of the flask and the solution was stirredat room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (100 mg, 84%). Rf=0.7 (1:1 Hex/EtOAc); 1 H NMR (250MHz, CDCl 3 ) 6.99-6.95 (m, 4 H), 6.87-6.83 (m, 2 H), 5.99 (s, 4 H). 159

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5.2.6 Preparation of 2,2'-binaphthyl, D43 D43 Rf=0.7 (1:1 hexanes/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 8.18 (s, 2 H), 7.99-7.87 (m, 8 H), 7.57-7.48 (m, 4 H). 5.2.7 Preparation of 2,2'-dimethylbiphenyl, D41 D41 o-Toluylboronic acid (136 mg, 1.0 mmol, 1 equiv.) was mixed with a 0.1 M stock aqueous solution of tetradecyltrimethylammonium bromide in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc) 2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 wasplaced over the neck of the flask and the solution was stirred at room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (60 mg, 61%). Rf=0.8 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.31-7.13 (m, 8 H), 2.10 (s, 6 H). 160

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5.2.8 Preparation of biphenyl-3,3'-dicarbonitrile, D38 NC CN D38 Rf=0.6 (1:1 Hex/EtOAc); 1 H NMR(250MHz, CDCl 3 ) 7.90-7.75 (m, 4 H), 7.70 (m, 2 H), 7.62 (m, 2 H). 5.2.9 Preparation of (1E,3E)-1,4-diphenylbuta-1,3-diene, D48 D48 trans-2-Phenylvinylboronic acid (148 mg, 1.0 mmol, 1 equiv.) was mixed with a 0.1 M stock aqueous solution of cetyltrimethylammonium hydrogensulfate in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc) 2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 wasplaced over the neck of the flask and the solution was stirred at room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (80 mg, 75%). Rf=0.7 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.55-7.20 (m, 10 H), 7.05-6.85 (m, 2 H), 6.75-6.60 (m, 2 H). 161

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5.2.10 Preparation of (1E,3E)-1,4-bis(4-fluorophenyl)buta-1,3-diene, D49 F F D49 trans-2-(4-fluorophenyl)vinylboronic acid (166 mg, 1.0 mmol, 1 equiv.) was mixed with a 0.1 M stock aqueous solution of tetradecyltrimethylammonium bromide in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc) 2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 wasplaced over the neck of the flask and the solutionwas stirred at room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (60 mg, 61%). Rf=0.8 (1:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 7.40 (m, 4 H), 7.02 (m, 4 H), 6.88-6.81 (m, 2 H), 6.65-6.58 (m, 2 H). 162

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5.2.11 Preparation of (1E,3E)-1,4-bis(4-fluorophenyl)buta-1,3-diene, D51 D51 trans-1-hexene-1-ylboronic acid (128 mg, 1.0 mmol, 1 equiv.) was mixed with a 0.1 M stock aqueous solution of tetrabutylammonium hydroxide in the reaction flask (10.0 mL, 0.1 M solution) and rapid stirring was begun. Into the solution was added NaOAc (272 mg, 2.0 mmol, 2 equiv.) and Pd(OAc) 2 (11 mg, 0.05 mmol, 0.05 equiv.). A balloon of O 2 wasplaced over the neck of the flask and the solution was stirred at room temperature for 3 h. The mixture was then diluted with 1:1 HexEtOAc (10 mL), extracted with 1:1 HexEtOAc (3 mL), then washed with brine (10 mL). The organic layer was concentrated in vacuo, and subjected to flash chromatography (30 g SiO 2 eluted with 10:1 HexEtOAc) to afford biphenyl (65 mg, 79%). Rf=0.9 (5:1 Hex/EtOAc); 1 H NMR (250 MHz, CDCl 3 ) 6.02-5.97 (m, 2 H), 5.61-5.53 (m, 2 H), 2.06-1.97 (m, 4 H), 1.50-1.25 (m, 8 H), 1.00-0.88 (m, 6 H). 163

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About the Author Young Chun Jung was born in Jeonju, Korea in 1965. He received a Bachelor of Science drgree in chemistry (1989) and a M.S. drgree in organic chemistry (1991) from Seoul National University, Seoul, Korea. He then joined SK Corporation, Seoul, Korea in 1991 and spent 10 years in the R&D fields of pharmaceutical and finechemical department until 2001. He had a plan to pur suit Ph.D. degree and began his doctoral studies at the University of South Florid a in 2001 working under the supervision of Dr. Kyung Woon Jung in the area of natural product synthesis and related methodology development. He has co-authored numerous publications and presented at one national American Chemical Society meeting a nd two local symposiums. He plans to be a great professor in organic chemistry.