USF Libraries
USF Digital Collections

Application of Pd catalyzed alkylation

MISSING IMAGE

Material Information

Title:
Application of Pd catalyzed alkylation synthesis of bicyclic furans, isoxazolines and new cyclopentane amino acid analogs
Physical Description:
Book
Language:
English
Creator:
Khan, Pasha Moeenuddin
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
Publication Date:

Subjects

Subjects / Keywords:
Palladium
Allylic acetate
Isoxazoline-2-oxides
Furans
Cylcopentane aminoacids
Dissertations, Academic -- Chemistry -- Doctoral -- USF   ( lcsh )
Genre:
non-fiction   ( marcgt )

Notes

Summary:
ABSTRACT: Palladium is probably the most useful metal in organic syntheses. It has shown great utility in various reactions such as C-C, C-N, C-O bond formation under mild conditions. The presence of abundant amount of palladium-chemistry related literature in the form of books, reviews emphasizes the growing importance of these reagents. Nowadays organopalladium chemistry is being used in various fields such as new methodology development, natural product synthesis, synthesis of polymers. Regio- and stereoselectivity is another facet of Pd catalyzed methodologies which has been extensively utilized in the last decade to obtain enantiopure compounds. The main emphasis of this work is to utilize Pd catalyzed allylic alkylation to synthesize new heterocycles including furans, isoxazolines and new cyclopentane amino-acid analogs in an enantioselective manner. The stereochemical outcome of these reactions is influenced by desymmetrization catalyzed by hydrolytic enzymes namely lipases.Chapter 1 reviews the recent advances in the field of palladium catalyzed synthesis of bicyclic furan analogs and provides a mechanistic explanation for these processes. Chapter 2 describes synthesis of new optically pure isoxazoline-2-oxide and furan analogs using Pd(0) catalyzed intramolecular cyclizations. Starting from a meso-diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the synthesis. The stereochemical outcome of the product (>99 % ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations. Chapter 3 describes Pd(0) catalyzed allylic alkylation of allylic esters using various 1⁰, 2⁰ nitroalkanes. This reaction resulted in the formation of nitro substituted aldehydes and ketones via an isomerization-alkylation step. The effect of various solvents, catalyst-ligand systems and bases was also studied.The presence of versatile nitro group in these compounds which can be easily converted to a ketone, reduced to amine or transformed into carboxyl group, imines, hydroxylamines, makes them an attractive starting material for various other synthetic compounds. Chapter 4 describes the chemoenzymatic synthesis of L-carbafuranomycin and related cyclopentane amino acids analogs. The synthesis utilizes the hydrolytic enzymes to induce enantioselectivity in the whole process. Out of all the peptidomimetics and related compounds, unnatural amino acids such as bicyclic and carbocyclic amino acids are of valuable interest as they have provided new building blocks for large number of potential drug candidates. The work presented here provides a more general and efficient route to these class of unnatural amino acids.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2008.
Bibliography:
Includes bibliographical references.
System Details:
Mode of access: World Wide Web.
System Details:
System requirements: World Wide Web browser and PDF reader.
Statement of Responsibility:
by Pasha Moeenuddin Khan.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 237 pages.
General Note:
Includes vita.

Record Information

Source Institution:
University of South Florida Library
Holding Location:
University of South Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 002007220
oclc - 401768065
usfldc doi - E14-SFE0002792
usfldc handle - e14.2792
System ID:
SFS0027109:00001


This item is only available as the following downloads:


Full Text

PAGE 1

Application of Pd Catalyzed Alkylation: Synt hesis of Bicyclic Furans, Isoxazolines and New Cyclopentane Amino acid Analogs by Pasha Moeenuddin Khan 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: Kirpal S Bisht Ph.D. Edward Turos, Ph.D. Mark L.McLaughlin, Ph.D. Abdul Malik, Ph.D. Date of Approval: November, 17th, 2008 Keywords: Palladium, Allylic acetate, isoxazo line-2-oxides, Furans, Cyclopentane amino acids, gamma-nitro carbonyl compounds Copyright 2008, Pasha Moeenuddin Khan

PAGE 2

DEDICATION This thesis is dedicated to my beloved parents who motivated me to pursue this degree and were always there to support me. I present this work as a token of appreciation and gratitude for a ll their efforts. I would also lik e to dedicate this thesis to my sister for her constant encouragement, inspiration and support at all times.

PAGE 3

ACKNOWLEDGMENTS I would like to express my sincere thanks to my major professor Dr Kirpal S Bisht for his support, valuable guidance and constant encour agement. I will always be grateful for his help and suggestions during my stay at his lab as a graduate student. I would also like to thank my committee members Dr Edward Turos, Dr Mark L McLaughlin Dr Abdul Malik for their helpful discussions and support of my research. I would also like to thank Bisht group members, Dr Talal-Al Azemi, Dr Jason A Carr, Dr Eric Dueno, Surbhi Bhatt, Ruizhi Wu, Sumedh Parulekar, Kiran Kirti Mupalla, Sridhar Reddy Kaulagari. I also thank all the undergraduate students who have worked with me. I also thank Dr Edwin Rivera and Dr Ted Gauthier for NMR and Mass spectral data I also want to thank my friends and roommates for their support and en couragement. Finally I would like to thank Department of Chemistry and University of South Florida for allowing me to carry out my research.

PAGE 4

i TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES LIST OF SCHEMES LIST OF SYMBOLS AND ABBREVIATIONS ABSTRACT CHAPTER 1: INTRODUC TION AND BACKGROUND 1.1 General Introduction 1.2 Cyclization of -Hydroxy Cyclic Alkenes 1.3 Carbonylation-Cyclization of Alkynes 1.4 Alkylation of Allylic meso -Diesters, Carbonates 1.5 Heck Reaction of 2,3-Unsaturated Glycosides 1.6 Pd(0) Catalyzed Intramolecular addition of Vinyl bromides 1.7 Pd Catalyzed Intramolecular 1,4 Addition to Conjugated Dienes 1.7.1 1,4-Oxyacetoxylation of Conjugated Dienes 1.7.2 1,4-Oxychlorination of Conjugated Dienes 1.7.3 1,4-Oxyalkoxylation of Conjugated Dienes 1.8 Oxidative Cyclization of Unactivated Olefins 1.9 Cyclization and Cross-Coupling Reaction of Acetylenic Alkoxides 1.10 Pd catalyzed Intramolecular Cyc lization of 7-Hydroxy1,3-diene with Aryl bromides 1.11 Oxidative Cyclization of 2-Carb omethoxycyclopentanol derivatives vi viii x xvi xviii 1 1 4 12 19 22 26 26 30 32 34 37 44 46 51

PAGE 5

ii 1.12 Conclusions 1.13 References CHAPTER 2: Pd(0) CATALYZE D INTRAMOLECULAR ALLYLIC ALKYLATION: STEREOSELECTIV E SYNTHESIS OF FURAN AND ISOXAZOLINE-2-OXIDE ANALOGS 2.1 General Introduction 2.2 Introduction to Furan a nd Isoxazoline ring systems 2.2.1 Furan Ring Systems in Natural Products 2.2.2 General Methods for Synthesis of Furan Ring Systems 2.2.3 Isoxazoline Ring Systems in Natural Products 2.2.4 Importance of Isoxazolines in Synthetic Chemistry 2.2.5 General Method for the Syntheses of Isoxazoline-2-oxide Analogs 2.3 Pd Catalyzed Syntheses of Furan and Isoxazoline-2-oxides 13a-h 2.3.1 Syntheses of Five membered Allylic Acetates 5, 9 and 10 2.3.2 Pd Catalyzed Allylic Alkylation of acetates 5, 9 and 10 using Soft Nucleophiles 2.3.3 Pd(0) Catalyzed Intramolecular Cyclization 2.4 Conclusion 2.5 Experimental 2.5.1 General 2.5.2 X-Ray Crystallography 53 54 61 61 63 63 65 66 68 69 70 71 74 77 84 85 85 85

PAGE 6

iii 2.5.2.1 Crystallographic X-ray data for compounds 8 2.5.2.2 X-ray crystallographic data for ( 13c ) 2.5.3 Experimental Procedure and Characterization Data for 5, 6 2.5.4 General Procedure for Preparation of Compounds 7, 8. 2.5.5 General Procedure for Preparation of Compounds 9 and 10. 2.5.6 General Procedure for Preparation of Compounds 11a-k 2.5.7 General Procedure for Preparation of Compounds 12a-k 2.5.8 General Procedure for Preparation of Compounds 13a-h ,k 2.6 References CHAPTER 3: A NEW ROUTE TO -CARBONYL COMPOUNDS VIA ONE POT Pd(0) CATALYZED ISOMERIZATION-ALKYLATION 3.1 General Introduction 3.2 Importance of Nitro Compounds 3.2.1 Nitro Group In Synthetic Organic Chemistry 3.2.2 Nitro Group In Natural Products 3.2.3 Palladium Catalyzed Reactions of Nitroalkanes 3.2.3.1 Previous Work-Pd Alkylation of Nitroalkanes 3.2.3.2 Synthesis of Bioactive Compounds Via Pd Catalyzed Alkylation of Nitroalkanes 3.2.3.3 Miscellaneous Reactions Involving Pd Catalyzed Alkylation of Nitroalkanes 86 88 91 92 92 93 98 101 104 110 110 112 112 113 116 117 125 127

PAGE 7

iv 3.3 Present Work-New Route to -nitro Carbonyl Compounds via Pd Catalyzed Alkylation-Isomerization 3.3.1 Pd Catalyzed Alkylation-Isom erization of Allylic Acetates Using Nitroalkanes 3.3.2 Optimization of reaction conditions for Pd catalyzed Alkylation-Isomerization of Ally lic Acetates Using Nitroalkanes3.3.3 Mechanistic Studies for Pd Catalyzed AlkylationIsomerization 3.4 Conclusion 3.5 Experimental 3.5.1 General Experimental Information 3.5.2 Preparation of Starting Materials ( 1-3 ) 3.5.3 General Procedure for Pd Alkylation of Nitroalkane 3.5.4 Procedure for the Time Study Using 1H-NMR Spectroscopy 3.6 References CHAPTER 4: CHEMOENZYMATIC SYNTHESIS OF LCARBAFURANOMYCIN AND RELA TED CYCLOPENTANE AMINO ACID ANALOGS 4.1 General Introduction 4.2 Biologically important Carbocyc lic Amino Acid and Its Analogs 4.3 General Methods for Synthe sis of Cyclic Amino Acids 4.4 Furanomycin and its Carba-analogs 4.5 Pd Catalyzed Synthesis of Carbafuranomycin Analogs 129 129 131 137 144 145 145 145 146 148 49 154 154 155 159 161 165

PAGE 8

v 4.6 Conclusions 4.7 Experimental 4.8 References APPENDICES Appendix A: Spectroscopic Data for Compounds of Chapter 2 Appendix B: Spectroscopic Data for Compounds of Chapter 3 Appendix C: Spectroscopic Data for Compounds of Chapter 4 ABOUT THE AUTHOR 173 173 177 184 185 218 231 End Page

PAGE 9

vi LIST OF TABLES Table 1-1 Cyclization of -Hydroxy Cyclic Alkenes Table 1-2 Synthesis of 2-Substituted 4,6a-Dihydro-3a H -cyclopenta[b]furan3-Carboxylates Table 1-3 Pd(0) Catalyzed Cyclization of Unsaturated Carbohydrates Table 1-4 Pd(0) Catalyzed Stereocontrolled cis 1,4-Oxyacetoxylation of Dienols Table 1-5 Pd(0) Catalyzed Stereocontrolled cis 1,4-Oxychlorination of Dienols Table1-6 Pd(0) Catalyzed Stereocontrolled cis 1,4-Oxyacetoxylation of Dienols Table 1-7 Optimization of Reaction Conditions for Pd(II) Catalyzed Oxidative Cyclization Table1-8 Pd(II) Catalyzed Oxidative Cyclization Using Various Substituted Pyridyl and Alkyl Amine Ligands Table 1-9 Pd(II) Catalyzed Oxidative Cycli zation of Primary Alcohols Table 1-10 Pd(II) Catalyzed Intram olecular Alkoxyarylation of 7-Hydroxy1,3-dienes Table 2-1 Diastereomeric Ratio & Yields for Pd(0) Catalyzed Allylic Alkylation of Acetates 5, 9 and 10 Table 2-2 Yields and Optical Rotation Data for Bicyclic Furan and Isoxazoline-2-oxide Analogs 13a-h 6 21 24 31 33 34 38 39 41 49 77 80

PAGE 10

vii Table 3-1 Optimizat ion of Reaction Conditions fo r Pd Catalyzed Alkylation of Nitroalkanes Table 3-2 Asymmetric Alkylation of Nitroalkanes via Pd Catalysis Table 3-3 Pd Catalyzed Alkylation of Allylic Acetates B earing an Allylic Carbonate Table 3-4 Pd Catalyzed Oxidation of Allylic Esters and Carbonates Table 3-5 Optimizaton of Reaction Conditions for Pd Catalyzed AlkylationIsomerization Table 3-6 Pd Catalyzed Alkylation-Isom erization in the Presence of Chiral Ligands Table 3-7 Pd Catalyzed Isom erization-Alkylation of Allylic Acetates 119 121 123 128 132 136 137

PAGE 11

viii LIST OF FIGURES Fig 1-1 Use of Palladium in Heterocyclic Chemistry Fig 1-2 Anti-helmintic Compounds With Bicyclic Furan System Fig 1-3 Structure of Azad irachtin Related Limonoids Fig 1-4 Tetrahydrofuran C ontaining Various Odorants Fig 1-5 Chiral bisoxazoline Ligands Used in Pd Catalyzed CarbonylationCyclization of Cyclic-2-methyl-2-propargyl-1,3-diols. Fig 1-6 Various Acyclic and Cyclic 4-yn-1-ones Subjected to Pd(II) Mediated Cyclization-Carbonylation Fig 1-7 Non-Reactive 7 and 8-hydroxy 1,3-dienes Under Pd Catalyzed Intramolecular Alkoxyarylation Fig. 2-1 Furan Ring System in Bioactive Natural Products Fig. 2-2 Isoxazolines in Natural Products and Other Bioactive Compounds Fig. 2-3 1H-NMR of Compound 13a in the Presence of (+)Eu(hfc)3 (a) Enantioenriched (b) Racemic Fig. E1 Ortep Plot for X-ray Structure of (1 S, 4R )-1-Phenylethynylcyclopent-2-ene-1,4-diol ( 8). Fig. E2 Ortep Plot for X-ray structure of Compound 13c Fig 3-1 Pd Catalyzed Allyli c Alkylation of Nitroalkanes Fig 3-2 Various Transformations of Nitro Group Fig 3-3 Peptides and Natu ral Products Containing NO2 Group Fig 3-4 Important Drugs Containing NO2 Group 1 3 3 4 16 18 50 64 67 83 86 89 111 113 114 115

PAGE 12

ix Fig 3-5 Structure of R -isomers of Baclofen and Preclamol HCl Fig 3-6 Chiral Ligand Used in Synthesis of R -isomers of Baclofen and Preclamol HCl Fig 3-7 1H-NMR Study of the Reaction of the Monoacetate 7 with PPh3 and Pd(PPh3)4 in THFd8 using 1H-NMR Fig 4-1 Biologically Important Carbocyclic Amino Acid Analogs Fig 4-2 Antifungal Activitie s of Cispentacin Analogs Fig 4-3 Biologically Important -amino Acids Containing a Carbocyclic System Fig 4-4 Structure of Vari ous Cycloalkane Amino Acids Fig 4-5 Taste Properties of L-As partyl-1-Amino-Cyclopropanecarboxylic Acid Fig 4-6 Combinatorial Synthesi s Based on Ugi Reaction Involving Cyclic Amino Acids Fig 4-7 Biosynthesis of Furanomyc in and Muscarine Involving Two Acetate and One Propionate Unit Fig 4-8 Furanomycin and Its Analogs Fig 4-9 Structures of Carbocyclic Nucleosides Containing Amino Acid Moiety Fig 4-10 Installation of Methyl Group on Monoacetate 11 126 126 141 154 156 157 157 158 159 162 163 164 171

PAGE 13

x LIST OF SCHEMES Scheme 1-1 Pd(II) Catalyzed Intramolecular Cyclization of Alkenols Scheme1-2 Catalytic Cycle for Pd(II) Ca talyzed Intramolecular Cyclization of -Hydroxy Alkenes Scheme 1-3 (a) Mechanistic Explanation for Higher Diastereoselectivity for Cyclic Substrates (b) Pd(0) Catalyzed Cyclization of -Hydroxy Acyclic Alkenes (c) Mechanistic Explanation for Lower Diastereoselectivity for Acyclic Substrates Scheme 1-4 Pd Catalyzed Car bonylation-Cyclization of Alkynes Scheme 1-5 Pd Catalyzed Carbonylation-Cyclization of Alkynes in Cyclic Substrates Scheme 1-6 Pd Catalyzed Carbonylati on-Cyclization of Cyclic 1,3-Diols. Scheme 1-7 Effect of Equatorial Substituents on ee of the Products Obtained by Pd Catalyzed Carbonylation-Cyclization of Cyclic-2-methyl-2propargyl-1,3-diols Scheme 1-8 Pd(II) Mediated Cycliz ation-Carbonylation of 4-yn-1-ones Scheme 1-9 Mechanism for Pd(II) Mediated Cyclization-Carbonylation Scheme 1-10 Pd Catalyzed Synthesis of Cyclopenta(b)furan analogs Scheme 1-11 Heck-Type Cycliza tion of 2,3-Unsaturated Glycosides Scheme 1-12 Mechanism for Pd Ca talyzed Heck-type Cyclization of 2,3Unsaturated Glycosides 5 9 11 13 14 14 17 17 19 20 23 25

PAGE 14

xi Scheme 1-13 Pd(0) Catalyzed Cyclization of Vinylic Bromides Scheme 1-14 Different Types of Intramolecular 1,4-Dialkoxylation Scheme 1-15 Pd(II) Catalyzed Synthesis of Amide-Containing Ethers via Cyclization-Carbonylation of 1,3-Dienes Scheme 1-16 Pd(II) Catalyzed Oxas pirocyclization of 1,3 Dienes Scheme 1-17 Effect of Addition of Li Cl on Pd (II) Catalyzed Intramolecular 1,4 Dialkoxylation Scheme 1.18 Mechanistic Explanation for the Effect of Clion on Pd Catalyzed 1,4-Diacetoxylation of 1,3-Dienes Scheme 1-19 Non-reactivity of Dienols 78, 79 Towards Pd catalyzed 1,4Oxychlorination Scheme 1-20 Mechanism for Pd Catalyzed Intramolecular 1,4 Addition to Conjugated Dienes Scheme 1-21 Oxidative Cyclization of Deuterium Labeled Primary Alcohols with Pyridine as a Ligand Scheme 1-22 Pathways for Pd(II) Catalyzed Oxidative Cyclization of Deuterium Labeled Primary Alcohols Scheme 1-23 Reaction Pathways for Pd(II) Oxidative Cyclization Scheme 1-24 Pd(II) Catalyzed Cycliza tion and Cross-Coupling Reaction of Acetylenic Alkoxides 26 27 27 28 29 30 34 36 41 43 44 44

PAGE 15

xii Scheme 1-25 Pd(II) Catalyzed Cycliz ation and Cross-Coupling Reaction of Acetylenic Alkoxides Scheme 1-26 Mechanism for Pd(II) Catalyzed Cyclization and Cross-Coupling Reaction of Acetylenic Alkoxides Scheme 1-27 Pd Catalyzed Intram olecular Alkoxyarylation of 7-Hydroxy-1,3Dienes Scheme 1-28 Mechanistic Pathways for Pd Catalyzed intramolecular Alkoxyarylation of 7-Hydroxy-1,3-Dienes Scheme 1-29 Pd(II) Catalyzed Oxidative Cylization of 2-[(E)-buten-2-yl-1]-2Carbomethoxycyclopentanol Scheme 1-30 Formation of Various Products via Pd(II) Catalyzed Oxidative Cylization of cis -2-[(E)-buten-2-yl-1]-2carbomethoxycyclopentanol Scheme 2-1 Pd(II) Catalyzed Three Co mponent Coupling of 2-(1-alkynyl)-2Alken-1-ones to Afford Te trasubstituted Furans Scheme 2-2 Pd(II) Catalyzed Intramolecular Cyclization of Cyclic Alkenols Scheme 2-3 Use of 2-isoxazolines as Ke y Intermediates in Organic Synthesis Scheme 2-4 General Methods for S ynthesis of isoxazoline-2-oxides Scheme2-5a Synthesis of isoxazoline -2-oxides from Fluoronitro compounds via Cycloaddition Scheme 2-5b Tandem Nitroaldol-Ring Cosure of Nitroacetic Esters to Synthesize Isoxazoline-2-oxides 45 46 47 48 51 52 65 66 68 69 70 70

PAGE 16

xiii Scheme 2-6 General Procedure for Syntheses of Isoxazoline-2-oxides and furan Analogs Via Pd Catalyzed Alkylation of Allylic Acetates 5, 9 and 10 Scheme 2-7 Synthesis of Allylic Monoacetate 5 via Enzymatic hydrolysis Scheme 2-8 Syntheses of Substituted Tertiary Allylic Monoacetates 9-10 by Addition of Alkyl lithiums Scheme 2-9 Pd Catalyzed A llylic Alkylation of Acetates 5, 9, 10 Using Various Active Methylene Compounds Scheme 2-10 General Catalytic Cycle for Pd (0) Catalyzed Allylic Alkylation Using Active Methylene Compounds Scheme 2-11 Synthesis of A cetates from Allylic Alcohols 11 a-k Scheme 2-12 Synthesis of Bicyclic Furan and Isoxazoline-2-oxides via Pd(0) Catalyzed Intramolecular Cyclization Scheme 2-13 Mechanism for Formation of bicyclic Furan and Isoxazoline-2oxides Via Pd(0) Catalyzed Intramolecular Cyclization Scheme 2-14 Proposed Mechanism for the Formation of 13k from 12k via Interconversion of the -allyl Ccomplexes I and II Scheme 3-1 Use of Nitroalkanes in Syntheses of Bioactive Compounds and Important Drug Molecules Scheme 3-2 Pd Catalyzed Alkylation of Nitroalkanes Using Allylic Substrates Scheme 3-3 Pd Catalyzed Alkylation of Nitroalkanes giving Isomerization Products 71 72 73 75 76 78 79 81 84 116 117 118

PAGE 17

xiv Scheme 3-4 Mechanism for Pd Ca talyzed Alkylation of Nitroalkanes Scheme 3-5 Asymmetric Alkylation of Nitroalkanes via Pd Catalysis Scheme 3-6 Pd Catalyzed Asymmetric Alkylation of Nitroethane Scheme 3-7 Pd Catalyzed Alkylation of Allylic Acetates Bearing an Allylic Carbonate Scheme 3-8 Proposed Mechanism for Pd Catalyzed Alkylation of Allylic Acetates Bearing an Allylic Carbonate Scheme 3-9 Isomerization of -allyl Complexes in a Pd Catalyzed Alkylation Scheme 3-10 Synthesis of Baclofen and Preclamol HCl via Pd Catalyzed Alkylation Scheme 3-11 Pd Catalyzed Oxidati on of Allylic Esters and Carbonates Scheme 3-12 Proposed Mechanism for Pd Catalyzed Oxidation of Allylic Esters and Carbonates Scheme 3-13 Pd-Catalyzed Alkylations of Nitroalkanes Scheme 3-14 Synthesis of Five and Six Membered Monoacetates Scheme 3-15 Synthesis of Substituted Acyclic Substrates 17, 18, 19 Scheme3-16 Reaction of Substituted Acyclic Substrates 18, 19 with 2nitropropane in the Pres ence of Pd(0) Catalyst Scheme 3-17 Mechanism Involving Formation of a Palladacyclobutane Intermediate Scheme 3-18 Plausible Mechanism I nvolving Formation of a Palladacycle Intermediate 120 120 121 122 124 125 127 127 129 130 133 136 137 138 139

PAGE 18

xv Scheme 3-19 Mechanism for Isomeriz ation of Allylic Acetate 7 to 3Cyclopentenone Scheme 3-20 Proposed Mechanism for Pd catalyzed Isomerization-Alkylation Scheme 3-21 Isomerization of -allyl Complex II to III Scheme 3-22 The Competi ng Alkylation: C-3 vs C-4 Scheme 4-1 Synthesis of Cyclohexane Amino acids Via Selective Reduction of Anthranilic Acid Analogs Scheme 4-2 Synthesis of Cyclohexane Amino Acids via Hofmann and Curtius Degradation Scheme 4-3 Synthesis of Cycloalkane Amino Acids from -Lactams Scheme 4-4 Retrosynthetic Analyses for L-Carbafuranomycin by Jager et al Scheme 4-5 Synthesis of Cyclopent ane Amino Acids via Pd(0) Catalysis Scheme 4-6 Retrosynthetic Analyses for Analogs of Carbafuranomycin Scheme 4-7 Synthesis of Analogs of Carbafuranomycin Scheme 4-8 Retrosynthetic Analyses for Carba-Analogs of Furanomycin Scheme 4-9 Synthesis of En antiopure Allylic Acetates 11 using Lipase Catalyzed Hydrolysis Scheme 4-10 Pd Catalyzed Alkylation of Acetate 19 Using Ethyl Nitroacetate Scheme 4-11 Easy Route to Carbocyc lic and Acyclic Amino Esters and Amino Acid Analogs 140 142 143 144 160 160 161 165 166 167 167 168 169 172 172

PAGE 19

xvi LIST OF SYMBOLS AND ABBREVIATIONS 1H 13C brsm BSA CDCl3 (CD3)CO COSY DBU DEPT-135 DMAP DMF DMSO ee ESI GC HMDS HRESIMS Chemical shift in parts per million Hapticity Isotope of hydrogen with mass of 1amu Isotope of carbon with mass of 12amu Based on remaining starting material N,O-Bis(trimethylsilyl)-acetamide Deuterated chloroform Deuterated acetone COrrelationSpectroscopY 1,8-diazabicyclo[5.4.0] undec-7-ene Distortionless Enhancement by Polarization Transfer at a flip angle of 45 degrees N,N-Dimethyl AminoPyridine N,N-Dimethyl formamide Dimethyl sulfoxide Enantiomeric excess ElectroSpray Ionization Gas Chromatography Hexamethyl disilazane High ResolutionElectrospray I onization Mass Spectrometry

PAGE 20

xvii NMR Novozym-45 ORTEP Pd PS-30 ppm R S THFd8 Nuclear Magnetic Resonance Lipase from Candida antarctica Oak Ridge Thermal Ellipsoid Plot Palladium Lipase from Psuedomonas cepacia parts per million R enantiomer S enantiomer Deuterated Tetrahydrofuran

PAGE 21

xviii APPLICATION OF Pd CATALYZED ALKYLATION: SYNTHESIS OF BICYCLIC FURANS, ISOXAZOLINES AND CYCLOPENTANE AMINO ACID ANALOGS Pasha M Khan ABSTRACT Palladium is probably the most useful metal in organic syntheses. It has shown great utility in various reactions such as C-C, C-N, C-O bond formation under mild conditions. The presence of abundant amount of palladium-che mistry related literatu re in the form of books, reviews emphasizes the growing importance of these reagents. Nowadays organopalladium chemistry is being used in various fields such as new methodology development, natural product synthesis, synthesis of polymers. Regioand stereoselectivity is another facet of Pd catalyzed methodologies which has been extensively utilized in the last decade to obtain enantiopure compounds. The main emphasis of this work is to utilize Pd cat alyzed allylic alkylati on to synthesize new heterocycles including furans isoxazolines and new cyclope ntane amino-acid analogs in an enantioselective manner. The stereochemical outcome of these reactions is influenced by desymmetrization catalyzed by hydrolytic enzymes namely lipases. Chapter 1 review s the recent advances in the fiel d of palladium catalyzed synthesis of bicyclic furan analogs and provides a mech anistic explanation for these processes.

PAGE 22

xix Chapter 2 describes synthesis of new op tically pure isoxazolin e-2-oxide and furan analogs using Pd(0) catalyzed intram olecular cyclizations. Starting from a meso -diol, optically pure compounds were prepared withou t utilizing chiral liga nds at any stage of the synthesis. The stereochemical outcome of the product (>99 % ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations. Chapter 3 describes Pd(0) catalyzed allylic alkylation of allylic esters using various 10, 20 nitroalkanes. This reaction resulted in the formation of nitro substituted aldehydes and ketones via an isomerizationalkylation step. The effect of various solvents, catalyst-ligand systems and bases wa s also studied. The presence of versatile nitro group in these compounds which can be easily converted to a ketone, reduced to amine or transformed into carboxyl group, imines, hydroxylamines, makes them an attractive starting material for va rious other synthetic compounds. Chapter 4 describes the chemoenzymatic synthesis of L-carbafuranomycin and related cyclopentane amino acids analogs. The synthesis utilizes the hydrolytic enzymes to induce enantioselectivity in the whole process. Out of all th e peptidomimetics and related compounds, unnatural amino acids such as bicyclic and carbocyclic amino acids are of valuable interest as they have provided new building blocks for large number of potential drug candidates. The work presented here provides a more general and efficient route to these class of unnatural amino acids.

PAGE 23

Chapter 1 INTRODUCTION AND BACKGROUND 1.1 General Introduction Palladium is probably the most useful metal in organic syntheses. It has shown great utility in various reactions such as C-C, C-N, C-O bond formation under mild conditions.1 The presence of abundant amount of pa lladium chemistry related literature in the form of books2 and reviews3 emphasizes the growing impor tance of these reagents. Nowadays organopalladium chemistry is bein g used across the spectrum of organic syntheses, from synthesis of complex natura l products to synthesis of polymers. Apart from carbon-carbon bond formation, palladium can also catalyze carbon-heteroatom bond formation resulting in various O, N, and S heterocycles under very mild conditions (Fig 1-1).1e,f,g Fig 1-1 Use of palladium in heterocyclic chemistry 1

PAGE 24

2 Regioand stereoselectivity is another facet of Pd catalyzed methodologies which has been extensively utilized in the last decade to obtain enan tiopure heterocycles. The last two decades have witnessed a huge growth in the use of Pd catalyst in synthetic organic chemistry including natural product syntheses2s and methodology developments. A large number of Pd catalyzed cross coupling reactions lik e Negishi coupling, Suzuki coupling, Stille coupling, Kumada coupling, Sonogashir a coupling, Heck reaction and Tsuji-Trost coupling have been extensively utilized in heterocyclic chemistry.1f Recently, we have reported chemoenzym atic synthesis of furan and isoxazoline derivatives via Pd catalyzed allylic alkyl ation and cyclizati ons starting from a meso -diol.3 This methodology provided a new route to bicyclic furan compounds using Pd(0) catalysis and the stereochemical outcome of the products was decided by enzymatic desymmetrization of meso starting materials. Furan deriva tives are widely distributed in large number of natural products,4 pharmaceuticals,5 agrochemicals6 and perfumes6. Fused bicyclic tetrahydrofuran compounds also provide important structural units to many bioactive natural products, lignans, macrodiolides, nucleosides and avermectins.44 A large number of anthelmintics belonging to the avermectin or milbemycin families also contain fused bicylic tetrahyd rofuran ring systems (fig 1-2).48 The remarkable activity and safety of the avermectins and milbemycins have made them key drugs in animal and human health and crop protection. The avermectins are structurally similar to the anti-bacterial macrolides.

PAGE 25

Fig 1-2 Anti-helmintic compounds contai ning bicyclic furan ring system Seeds of the Indian neem tree Azadirachta indica, used as insecticide preparations for ornamentals and food crops, are rich in bicyclic furanoids (fig 1-3).49 The advantages offered by neem-bicylic furanoids is specificity and slow activity as an insect antifeedant and growth regulator.50 Fig 1-3 Structure of azadirach tin related limonoids found in neem extract 3

PAGE 26

The bicylic furanoids are also found as an act ive component in large number of perfumes and odorants,51 e.g., Ambrox bearing an ambery smell is an active ingredient of Drakkar Noir fragrance (fig 1-4). Fig 1-4 Tetrahydrofuran containing various odorants The vast abundance of these novel ring syst ems has resulted in new methods for their synthesis. Pd catalyzed methodologies ha ve been leader in this field due to easy handling, functional group tolerance a nd high stereo and regioselectivities.2p,7 In this chapter we have focused on the advances made in the last fifteen years in Pd catalyzed synthesis of bicyclic furanoids and a mech anistic explanation of these new processes wherever applicable. The main purpose of this chapter is to summarize the new methods discovered for synthesis of bicycle furan ring systems and analogs. Also, the chapter introduces the reader to the mechanistic expl anation and experimental evaluation of these Pd catalyzed processes. Since Pd catalysis can be applied to a variety of substrates in order to obtain bicyclic hetero cycles, hence this chapter is broadly divided on the basis of the substrates involved in synthesi s of bicyclic O-heterocycles. 1.2 Cyclization of -hydroxy cyclic alkenes Pd catalyzed cyclization of -hydroxy alkenes was first reported by Semmelhack et al 8f where -hydroxy alkenes were treated with catalytic amount of PdCl2 and 3 equiv CuCl2 under CO atmosphere in methanol to yield tetrahydrofurans (Scheme 1-1, eq 1). Similar 4

PAGE 27

transformations were applied towards synthesis of several natural products as tetronomycin and goniothalesidol8g,h containing a tetrahydrofuran or tetrahydropyran core. Even though this methodology provided an easy access to bi cyclic furan ring systems but still suffered from some major draw backs. The diastereoselectivity of this Pd (II) catalyzed synthesis of Oheterocycles wa s low, specially for the substrates with no substitution at the allylic posit ion. Also this methodology is limited to installation of ester functionality at C-1(scheme 1-1) position. Recently Wolfe et al 8a-e tried to overcome the abovementioned shortcomings by carrying the cyclizations of various -hydroxy cyclic (eq 3, scheme 1-1) and acyclic (eq 2, scheme 1-1) alkenes with various aryl and alkenyl bromides in the presence of palladium catalyst generated in situ. Various -hydroxy acyclic and cyclic alkenes can be converted to furan 10 and bicyclic furan 11 analogs in good yields with moderate to high diastereoselectivity using Pd0/phosphane complex. Scheme 1-1 Pd(II) catalyzed intramolecular cy clization of cyclic alkenols 5

PAGE 28

The authors demonstrated that Pd catalyzed reaction of aryl or vinyl bromides and hydroxy alkenes can be used to synthesize various tetrahydrofur an analogs through formation of a C-C and C-O bond along with establishment of two new stereocenters.8 Table 1-1 shows the applicati on of this strategy on cyclic -hydroxy alkenes to yield bicyclic furan analogs in high yields and di astereoselectivity. As discussed in the latter section, an extensive mechanis tic studies conduc ted by Wolfe et al indicated an involvement of syn addition of the aryl gr oup and the oxygen atom across the olefin both in cyclic and acyclic internal alkene substrates. Table 1-1 Cyclization of -hydroxy cyclic alkenesa Entry Alcohol R-Br Product dr Yieldc 1a O6 H H OMe >20:1 69% (ref 8c) 2a >20:1 53% (ref 8c)

PAGE 29

3a,e >20:1 78% (ref 8c) 4 b >20:1 53% (ref 8b) 5 b 0% d (ref 8b) 6b 10:1 60% (ref 8b) 7b HO >20:1 70% (ref 8b) 8a >20:1 66% (ref 8b) a Conditions: 1.0 equiv of alcohol, 2. 0 equiv of ArBr, 2.0 equiv of NaOtBu, 2.5mol%of Pd2(dba)3, 10 mol% of P( o -tol)3, toluene(0.125M), 110oC. b Conditions: 1.0 equiv of alcohol, 2.0 equiv of ArBr, 2.0 equiv of NaOtBu, 1mol%of Pd2(dba)3, 2 mol% of dpephos, THF(0.13-0.25M), 65oC. c Yields represent average isol ated yields for two or more experiments. d oxidation of the alcohol substrate to 2-allylcyclopentanone was observed. e Xantphos (5 mol%) was used. The proposed catalytic cycle for cyclization of -hydroxy cyclic alkenes or carboetherification is shown in scheme 1.2 and begins with oxidative addition of aryl bromide to the Pd/phosphine complex followed by reaction with the alcohol 13 in the 7

PAGE 30

8 presence of a base to give complex 14.8d The complex 14 undergoes a syn -oxypalladation process which is rare in both catalytic a nd stoichiometric reactions of palladium alkoxides to yield new complex 15 which after a reductive elimination results in the desired product 16 and regeneration of Pd(0) catalyst.8b,d In case of -susbstituted cyclopentanol substrates (table 1.1 entry 4,5) the outcome of the reaction depended on stereochemistry of the starting material. Pd catalyzed reaction of cis alcohol (Table 1.1, entry 4) gave the desired product in 53% yield and >20:1 de but the reaction of analogous trans substrate (Table 1.1, entry 5) did not yiel d the desired bicyclic product but resulted in 2-allylcyclopentanone. Th e rate of the reaction also depends on the ring size as Pd catalyzed cylization of cyclohexene substrat es (table 1.1, entry 6,7) was faster than corresponding cyclopentene analogs. For exampl e the coupling of 4-bromo anisole with cyclopentene alcohol substrate (table 1.1, entr y 1) required two days to reach completion whereas the six member analog was consum ed within two hours (table 1.1, entry 8). Wolfe et al 8b also observed that the cyclic substrates (table 1.1) resulted in products with higher diastereoselectivity (> 20:1) as compar ed to their acyclic analogs (3-5:1) (scheme 1.3b). This observation was explained by conducting deuterium labeling experiments on the -hydroxy alkene substrates and comparing the intermediates involved in cyclic and acyclic substrates as shown in scheme 1.3.

PAGE 31

LnPd0LnPd Ar Br R2 HO R1 O Pd Ar Ln H R2 R1 H O Pd Ar Ln H R2 R1 H O R1 H H R2 Ar Ar-Br 12 13 14 15 16 NaO t Bu Scheme 1-2 : Catalytic cycle for Pd(II) catalyz ed intramolecular cyclization of -hydroxy alkenes In general, it was also pointed out that the high diastereoselectivity in case of cyclic -hydroxy alkenes arises from the lack of -bond rotation and inability of reversible -H elimination in these substrates as explained below. Pd aryl alkoxide complex 17 obtained from the cyclic alkenol (table 1.1, entry13) can result in complex 18 by intramolecular insertion of the cycloalkene in Pd-O bond of complex 17.8 Complex 18 can directly break down (fast) to yield the desired product 19 or can undergo hydride elimination (slow), utilizing one -H atom syn to the palladium atom to yield complex 20. As shown in scheme 1-3 the Pd(Ar)(H) complex in 20 cannot be transferred to opposite face of alkene yielding 22 due to inability to form any -alkylpalladium complex and no C-C bond rotation in internal al kene. However, in principle, if complex 20 is formed it will readily collapse to give alkene 21 and Pd(Ar)(H) complex which will undergo a unimolecular C-H bond forming reductiv e elimination faster than regenerating the Pd complex 22 via a bimolecular alkene coordi nation and insertion into Pd-H bond. 9

PAGE 32

10 Hence in the case of cyclic substrates, the Pd catalyzed cyclizati on gave products with higher diatereoselectivity as the side reacti ons are minimized. Also, the same mechanism when applied to the acyclic substrate 23 can be used to explain the moderate diatereoselectivity. Treatment of the acyclic substrate (scheme 1-3c) with Pd(0) catalyst, aryl bromide and NaOtBu can result in the palladium aryl alkoxide complex 24, similar to the cyclic substrate (complex 17 ).9 Syn insertion of the alkene into Pd-O bond will result in intermediate 25 10 which can undergo reductive elimination to give the major diastereomer 26. Intermediate 25 can also undergo C-C bond rotation about C1-C2 bond followed by syn -hydride elimination to yield complex 27 which can be converted into complex 28 via reinsertion of alkene into the Pd-H bond with opposite regiochemistry.10,11 Palladium complex 28 has much more flexibility in terms of C-C bond rotation and can undergo rotation to 28. Complexes 28 and 28 can result in compounds 30 and 29 respectively via aseries of re-i nsertion and reductive elimination. Hence in aliphatic substrates the diasteromeric ratio is reduced due to more flexibility of the substrates in terms of C-C bond rotation.

PAGE 33

1-3a: Mechanistic explanation for higher dias tereoselectivity for cyclic substrates + Ar-Br Ar O HO cat.Pd2(dba)3cat.P(o-tol)3NaO t Bu,Toluene 110oC R1 R2 R1 R2 O O O Ph H H H FromE-alkene 73% 5:1 dr FromZ-alkene 71% 5:1 dr FromE-alkene 55% 5:1 dr Ph tBu 1-3b: Pd(0) catalyzed cyclization of -hydroxy acyclic alkenes 11

PAGE 34

OH D Me Pd Br Ar Ln23 O H Me Pd D Ar O H Me D Pd Ar 24 25 bond rotation O H Pd D Me Ar O Pd D Me Ar H 27 O Pd D Me Ar H 28 O Pd Me H Ar D bond rotation 28' O D H Ar Me 29 (minordiast.) O H Me H D H Ar 30 (regioisomer) O H Ar D Me 26 (majordiast.) A c y c l i c S u b s t r a t e : NaO t Bu 2 1' -Helimination reductiveelimination 1'21-3c: Mechanistic explanation for lower dias tereoselectivity for acyclic substrates Scheme 1-3: (a) Mechanistic explanation for higher diastereoselectivity for cyclic substrates (b) Pd(0) catalyzed cyclization of -hydroxy acyclic alkenes (c) Mechanistic explanation for lower diastereosel ectivity for acyclic substrates 1.3 Carbonylation-cyclization of alkynes Pd catalyzed carbonylation of alkynes has b een extensively used for synthesis of benzofurans and other compounds as acetylene carboxylates, and -lactones.13a-c For example Yamamoto et al13d utilized Pd(OAc)2 catalyzed reaction of carbon tethered acetylenic aldehydes with various aliphatic alcohols (MeOH, EtOH) to obtain five and 12

PAGE 35

six membered ketals (scheme 1-4, eq 1). Also recently Gabriele et al13e reported Pd catalyzed cyclization of 4-yn1-ols to yield a furan ring sy stem containing an acrylate group along with a mixture of ac etal in the presence of PdI2/KI at high temperature and pressure (scheme 1-4, eq 2). Scheme 1-4 : Pd catalyzed carbonylation-cyclization of alkynes. Kato et al 12 further optimized this Pd catalyzed carbonylation-cyclization of alkynes utilizing a Pd(0)/benzoquinone catalytic system to synthesize various furan ring systems (Scheme 1-4, eq 3). The formation of acetals as by-produc t of the reaction (scheme 1-4, eq 1,2 ) was circumvented by trapping the acid produced during the catalytic cycle (scheme 1-9) using p-benzoquinone. Benzoquinone also acts as an oxidizing agent to convert Pd(0) to Pd(II) in the catalytic cycle (scheme 1-9). This method is also applicable to acyclic substrates which gave rise to a furan nucleus (scheme 1-5). Five different catalysts were studied by the authors in th is oxidative cycliza tion and palladium(II) chloride and bis(acetonitrile)-dichloropalladium (II) gave superior results. Also preliminary studies showed that the presen ce of a free hydroxyl group in the substrate is indispensable for initiating the reaction. The substrates which had no free hydroxyl group 13

PAGE 36

(R3 H) did not react and the starting material was recovered in quantitative yield (scheme 1-5). Pd catalyzed carbonylat ion-cyclization approach was also applie d to acyclic substrates to obtain saturate d furan compounds containing an acrylate side chain (scheme 1-5). Scheme 1-5 Pd catalyzed carbonylati on-cyclization of alkynes in cyclic substrates. Kato et al also further extended Pd catalyzed carbonylation-cyclization approach to cyclic-2-methyl-2-propargyl-1,3-diols to ob tain bicyclic furan ring systems in an asymmetric fashion by using various ch iral bisoxazoline lig ands(fig 1-5).12 Scheme 1-6 Pd catalyzed carbonylation-cyclization of cyclic-2-methyl-2-propargyl-1,3diols. Conditions used: Pd(CH3CN)2Cl2 (5 mol%)/p -benzoquinone (1.1 eq), CO balloon MeOH. Seven different substrates including a six and a five membered cyclic-2-methyl-2propargyl-1,3-diols were examined for as ymmetric carbonylation-cyclization (scheme 1-14

PAGE 37

15 6). All the substrates (schem e 1-6) were treated with bis(acetonitrile)-dichloropalladium(II)/benzoquinone in methanol at 00C under CO atmosphere. In the case of meso -cyclopentane derivative 35e the authors reported no reaction and the starting material was recovered. In case of other meso diols 35b, c, f the formation of desired product is reported at low temperatures (-45OC). In case of diols 35d, g which have a 1,3 trans relationship only the hydroxy group cis to the propargyl gr oup reacted to yield the desired product. This also explains the non-reactivity of 35e due to absence of a hydroxy group cis to the propargyl group. The ee of the reaction depends on temperature, catalyst, solvent, ligands used and even on the structure of substrate. Kato et al used 35a as the model system to study the effect of ligands. The ee of the reaction decreased from 65% (98% yield) to 57% (90% yield) when the temperature was increased from -30OC to 0OC (ligand A, fig 1-5). The absence of a chir al ligand did produce the desired product as a racemic mixture in 85% yield. Although Pd(CF3CO2)2 was used as the catalyst for the most of the reac tions but other catalysts as Pd(CH3CN)4(BF4)2 was also employed giving a lower ee (ligand A, fig 1-5). Seven chiral li gands (figure 1-5) were utilized for this Pd catalyzed carbonylation-cyclization. Ligand E14 gave a moderate ee (56%) and other ligands B,16 C,15 F 15 G15 did yield the product but in low ees. The reactions conducted in presence of ligands D16and H16 proceeded in extremely poor yields and no ees. The authors also observed good yields and moderate enantioselectivity by addition of solvents like CH2Cl2, i PrOH. Changing the solvent system to THF:MeOH=10:1 resulted in slower rates and low yields and ees.

PAGE 38

Fig 1-5 Chiral bisoxazoline ligands used in Pd catalyzed carbonylat ion-cyclization of cyclic-2-methyl-2-propargyl-1,3-diols. The structure of the substrate also aff ected the yields and enantioselectivity (Scheme 1-7). It is also reported that when meso-diols 35a,b,f were subjected to asymmetric Pd catalyzed carbonylation-cyclizat ion, the enantioselectiv ities obtained were highly substrate de pendent. Substrate 35a yielded product 36a in relatively high ee (65%) as compared to the racemic product obtained in the 35 b, f This trend suggested that the presence of equatorial substituents (shown in bl ue in scheme 1-7) is an important factor which influences the ees of the products. 16

PAGE 39

Scheme 1-7 \Effect of equatorial substituents on ee of the products obtained by Pd catalyzed carbonylation-cyclization of cy clic-2-methyl-2-propargyl-1,3-diols The Pd(II) mediated cyclizatio n-carbonylation strategy was also extended to 4-yn-1-ones by Kato et al 12b as shown in scheme 1.8. Different open-chain and cyclic substrates (fig 1.6) were subjected to a (CH3CN)2PdCl2/p-benzoquinone system in methanol at room temperature under a carbon monoxide atmosphe re. Cyclic substrates resulted in the formation of the corresponding bicyclic furan analogs 38 along with methoxy acrylates 39. Scheme 1-8 Pd(II) mediated cyclization-carbonylation of 4-yn-1-ones 17

PAGE 40

MeO2C R O R=Me,H O MeO2C 3 X COOR R=Me,Et X=O,CH2Fig 1-6 Various acyclic and cyclic 4-yn-1-ones s ubjected to Pd(II) mediated cyclizationcarbonylation The authors also proposed a mechanis m explaining the forma tion of the products 38, 39. Pd(II) initially coordinates to the alkyne which is induced by attack of the carbonyl oxygen to alkyne from the side opposite to palladium to form intermediate A. A nucleophilic attack of MeOH on the carbon atom of the cationic ca rbonyl group from the side opposite the methyl ester group results in intermediate B. Intermediate B undergoes CO insertion (intermediate C) and subsequent reaction with MeOH, can yield the acetal products and generates Pd(0) (path I). Also Pd(0) gets reoxidized to Pd(II) using pbenzoquinone. On the other hand, the formati on of methoxyacrylate ca n be explained by the attack of MeOH (path II) on the olefinic carbon of the vinyl palladium intermediate A followed by CO insertion and subsequent reaction with MeOH. 18

PAGE 41

Scheme 1-9 Mechanism for Pd(II) mediated cyclization-carbonylation 1.4 Alkylation of allylic meso -diesters and dicarbonates using soft nucleophiles Pd catalyzed allylic alkylation has been extens ively used in natural product synthesis and bicyclic furan ring compounds are no exception.2s Bicyclic furan skeleton can also be constructed by Pd catalyzed allylic alkylation. Recently, our group has reported a chemoenzymatic synthesis of bicyclic furan ring systems.3 The synthesis involved lipase catalyzed desymmetrization as the key step for enantioinducti on without the use of chiral ligands. Also, Tanimori et al 17,18 have studied Pd catalyzed allylic alkylation to obtain various cyclopentafuran anal ogs (scheme 1.10) by carrying out sequential C-C and C-O bond formation utilizing 1mol% [Pd( 3-C3H5)Cl]2 and dppf (diphenylphosphinoferrocene) on diacetates and dicarbonates. The dicarbonates reacted 19

PAGE 42

in base-free conditions due to generation of base (alkoxide ) during the catalytic cycle whereas DBU was employed as a base in case of diacetates. Scheme 1-10 Pd catalyzed synthesis of cyclopenta(b)furan analogs. The authors also observed that a variety of -keto esters including aromatics and heteroaromatics, terminal alkenes, bulky a nd free hydroxyl substitute d were all suitable substrates for this methodology. Table 1.2 shows various 2-substituted 4,6a-Dihydro3a H -cyclopenta[b]furan-3-carboxy lates obtained by Tanimori et al. The non-reactivity of 41f is explained on the basis of steric hindrance due to bulky tert-butyl group. This method gives an easy access to 2-substituted bicyclic furan analogs. The process also shows tolerance to functionalities as alkene s, alkynes, hetroaromatics and even free hydroxyl group. 20

PAGE 43

Table 1-2 Synthesis of 2-substituted 4,6a-Dihydro-3aH -cyclopenta[b]furan-3carboxylates Entry R1 R2 Product %Yield 41a Me 52 41b Me 58 41c CH3(CH2)9 Me 59 41d PhCH(OH)CH2Me O C OOMe H H Ph H O 71a 41e S Et 43 41f t -Bu Me (expected) 0 a Obtained as an inseparable 1:1 mixture of diastereomers 21

PAGE 44

22 1-5 Heck reaction of 2,3-unsaturated glycosides Intramolecular Heck reaction on carbohydrate templates has been utilized to obtain bicylic furan analogs.19-21 Carbohydrates are easily availabl e and provide an easy route to optically active compounds with a variety of functional groups and stereochemical features. Sinou et al synthesized synthesized enantiopur e bicyclic O-hete rocycles using Pd catalyzed cyclizati on of appropriate glyc als and pseudoglycals. Sinou et al utilized palladium catalyzed Heck reaction on erythro or threo aryl 2,3unsaturated glycosides to obtain the corresponding bicyclic derivatives via alcoxyelimination by (scheme 1.11).19 Treatment of erythro carbohydrate derivatives 43 with Pd(OAc)2, PPh3, Et3N in the presence of tetrabut yl-ammonium sulfate gave the bicylic derivatives 44in moderate to good yields. Utilizing the same reaction conditions the threo derivatives 45 gave the corresponding tetr ahydrofuran derivatives 46 (Scheme 1.11). The yield of the reaction depended on the nature of the leaving group. A better leaving group as OEt resulted in a higher yield as compared to the substrates bearing an aryl ether substituent.

PAGE 45

O TBDMSO O OR Br cat Pd(OAc)2,/PPh3, Bu4NHSO4, Et3N MeCN/H2O 23-72% O O TBDMSO 43 44 O OTBDMS O R Br cat Pd(OAc)2,/PPh3, Bu4NHSO4, Et3N MeCN/H2O 30-51% O O OTBDMS 45 46 ( a ) R = H, ( b ) R = C 2 H 5 ( c ) R = p -t -Bu C 6 H 4 ( d ) R = p -NO 2 C 6 H 4 OH O TBDMSO 44' O R OH O OTBDMS 46' OR (a) R= C2H5, (b) R= p -t -BuC6H4, (c )R= p -NO2C6H4 Scheme 1-11: Heck-type cyclization of 2,3-unsaturated glycosides Table 1.3 shows the bicyclic tetrahydrofuran compound 44a-c obtained via a Heck cyclization of unsat urated carbohydrates 43, 45. The products were obtained in 23-72% yield depending on the nature of the anomer ic subsituent (entries 1,3,5, table 1.3). The authors also mentioned that for substrates 43b, c the reaction was conducted at lower temperatures since the substrat es underwent degradation at 80oC. Also changing the solvent from CH3CN-H2O to DMF resulted in formation of bicyclic product 44 along with tetrahydrofuran compound 44 in 50% and 20% yield respectively (entry 2, table 1.3). Compound 44 can be explained by cleavage of the C-O bond of the ring. However under same conditions substrate 43b resulted only in the bicyclic product 44 and can be explained on the basis of the fact that O-C6H4pBut ( 43b ) is a better leaving group than OEt ( 43a). 23

PAGE 46

24 Table 1.3 Pd(0) catalyzed cyclization of unsaturated carbohydrates 43 and 45 (ref 19)aEntry Starting material T 0C/Time (h) Solvent Products(yield) 1 43a 80/10 CH3CN-H2O(5:1) 44 (72%) 2 43a 80/24 DMF 44 (50%) + 44 (20%) 3 43b 50/30 CH3CN-H2O(5:1) 44 (32%) 4 43b 80/24 DMF 44 (70%) 5 43c 40/27 CH3CN-H2O(5:1) 44 (23%) 6 45a 50/17 ,, 46 (51%) 7 45b 80/10 ,, 46 (57%) 8 45c 50/53 ,, 46 (32%) 9 45d 40/29 ,, 46 (30%) aRatio of reactants 43 or 45 :Et3N:Bu4 NHSO4:Pd(OAc)2:PPh3=10:25:10:1:2 bIsolated yields after column chromatography on silica gel. Treatment of dihydropyran 45a with catalytic amount of Pd(OAc)2 in the presence of Bu4NHSO4 and Et3N resulted in the bicyclic tetrahydrofuran product 46a in 51% yield (entry 6, table 1.3) via a classical Heck-type cyclization. Also th e unsaturated threo derivative 45b resulted in the tetr ahydrofuran structure 46 (57% yield) due to cleavage of the cyclic C-O bond.20-21 On the other hand the substrates 45c,d resulted in the bicyclic product 46c,d due to fragmentation of the aglycon moiety in 32 and 30% yield (entries 8,9, table 1.3). Sinou et al have also utilized Pd catal yzed cylization of carbohydrate templates to obtain other enanti opure bi and tricyclic compounds.

PAGE 47

O TBDMSO O OR Br 43 O O TBDMSO Pd(0) O TBDMSO O OR Br[Pd] A O O TBDMSO OR [Pd]Br B 4 6 O O TBDMSO [Pd]Br OR-C dealkoxypalladation -Pd(0) -ROBr Scheme 1-12: Mechanism for Pd catalyzed Heck-type cy clization of 2,3-unsaturated glycosides Sinou et al also proposed the mechanism of th ese Pd catalyzed cyclizations of carbohydrate templates to involve a -vinyl palladium intermediate A (scheme 1.12) formed via an oxidative addition.20,21 Complex A undergoes associ ation-insertion process utilizing the unsaturation in the pyranose ring system to yield complex B. It was also proposed that the oxygen atom of the aglycon is coordinated to the metal center based on the reports of Jeffrey22 and Cacchi23 et al Intermediate B undergoes deoxypalladation to give ionic complex C which loses Pd(0) and ROBr to yield the final product 46. The authors also mentioned that only few examples of dehydroxypalladation are known in literature, including -bonded palladium(II) intermediate s of tetrahydrofurans and only few cases of -alkoxyelimination processes.24,25 Use of chelating diphosphines resulted in poor yields again by preventing the co mplexation of the aglycon oxygen atom to palladium. 25

PAGE 48

1.6 Pd(0) catalyzed intramolecular addition of vinyl bromides to vinyl sulfones O SO2Ph cat Pd(PPh3)4, Et3N CH3CN/THF, reflux R Br O SO2Ph R n n 0-73% 47 48a n=2; R=H (73%) 48b n=2; R=Me (No Reaction) 48c n=1; R=H (58%) Scheme 1-13: Pd(0) catalyzed cyclization of vinylic bromides Pd catalyzed cyclization of vinyl bromides 47(R=H) has also been utilized to obtain cis fused bicyclic ethers (Scheme 1.13).26 The reaction was dependent on the nature of substituents on the double bond. The presence of any substituents such as methyl resulted in no cyclization and starting material was recovered in 75 % yield. Also in order to promote the cyclization of vinyl bromide 48b 5 equivalents of AgNO3 was added to the reaction mixture, however no desired product was obtained.27 1-7 Pd catalyzed intramolecular 1 ,4 addition to conjugated dienes Palladium(II) catalyzed cyclization of 1,3-dienes has proven to be an important tool in organic synthesis.28-32 The first report of Pd(II) promot ed cyclization of 1,3-dienes was reported by Izumi and Kasahara in 1975.28 Later on Backvall and Andersson et al utilized this methodology to conduct 1,4-dialkoxylation of 1,3-dienes in an alcoholic solvent with catalytic amount of acid.29 In general there are three di fferent types of intramolecular 1,4-dialkoxylation depending on the position of alcohol side chain (Scheme 1.14). 26

PAGE 49

. Scheme 1-14: Different types of intr amolecular 1,4-dialkoxylation Recently Andersson et al30 utilized the type I intramolecular cyclzation of 1,3-dienes in the presence of CO and an amine to synt hesize amide containing ethers (Scheme 1.15). The reaction proceeds via an intramolecular nuc leophilic addition on the diene to give an intermediate -allyl palladium complex which is subs equently carbonylated to give either a overall 1,2or 1,4-addition over the diene. The ratio of the 1,4 addition product 50a and 1,2 addition product 50b can be altered by varying the CO pressure and choice of the solvent. OH Pd(OAc)2, Et2NH CO (1 atm), THF O H2N O O O NH2 49 50a 50b Scheme 1-15 Pd(II) catalyzed synthesis of amide-containing ethers via cyclizationcarbonylation of 1,3-dienes Bckvall et al31 have utilized type II and III Pd( II) catalyzed 1,4 dialkoxylation of 1,3 dienes to synthesize various spiro and bicyc lic oxygen heterocycles in a stereocontrolled manner (scheme 1.16). The diene alcohol 51 was cyclized to yield a cis product in the 27

PAGE 50

presence of 5 mol% Pd(OAc)2, 10 mol% MeSO3H, and 2 equivalents of p-benzoquinone in MeOH at room temperature.29h By changing the solvent to EtOH and BnOH the corresponding ethyl and benzyl ethers were obtained, repec tively. Authors also reported the synthesis of trans acetoxy product 53 by carrying the reaction in the presence of LiOAc in AcOH. Palladium catalyzed cyc lization of six memb ered diene alcohol 54 (n=1) with benzoquinone as oxidant was problem atic due to competing aromatization and Diels-Alder addition of diene. This problem was overcome by slow addition of the diene to the reaction mixture to obt ain the spiro-furan compounds 52,53. cat Pd(OAc)2,cat MeSO3H, Benzoquinone, ROH 51a OH O RO R= Me(>97% cis) R= Et (>97% cis) R= Bn (>97% cis) 52 51a,b OH cat Pd(OAc)2,Li2CO3, Benzoquinone, AcOH Acetone O AcO 9 examples with 40-86% yields n n n= 1, 2 n= 1, 2 53 Scheme 1-16 Pd(II) catalyzed oxaspirocyclization of 1,3 dienes Bckvall et al have also conducted an extensive study on palladium catalyzed oxidation of diene alcohols to yield tetrahydrofurans and tetrahydropyrans via an intramolecular 1,4-addition to the conjugated diene.29e The reactions are usually carried in acetone-acetic acid (4:1) mixture or an alcoholic solvent u tilizing palladium acetate as the catalyst and benzoquinone as the oxidant. Depending on the attacking species a 1,4-oxyacetylation (acetate) or 1,4-oxychlorination (chloride) or 1,4-oxyalkoxylation (alcohol) can be 28

PAGE 51

obtained. In general these reactions involve electrophilic addition of the alcohol and the palladium(II) catalyst to the diene to produce a -allyl intermediate which subsequently undergoes stereoselective substitution(scheme 1.18, 1.20). The stereochemistry of the products in the case of 1,4-oxyacetylation depe nds on the presence or absence of LiCl (Scheme 1.17).29e,i catPd(O A c)2,Li C l, A cOH p -Benzoquinone HO cat Pd(OAc)2, AcOH p -Benzoquinone O AcO O AcO n n=0,1,3,5 n n > 98% cis > 98% tra ns 55 56 54Scheme 1-17 Effect of addition of LiCl on Pd (II) catalyzed intramolecular 1,4 dialkoxylation The effect of LiCl (chloride ion) on these Pd (II) catalyzed reactions can be explained on the basis of the fact that in the presence of LiCl, after an initial trans acetoxypalladation of one of the double bonds an external trans attack by acetate on the intermediate palladium complex results in a final cis product. Whereas, in the absence of LiCl the acetate attached to palladium metal inserts in cis fashion resulting in an overall trans product (Scheme 1.18). 29

PAGE 52

Cl -Cl free Pd Cl O O Pd AcO O O trans attack by acetate cis insertion O A c OAc OAc OAc AcO AcO 57 59-cis 59-trans 58a 58bScheme 1-18 Mechanistic explanation for the effect of Clion on Pd catalyzed 1,4Diacetoxylation of 1,3-Dienes 1.7.1 1,4-oxyacetoxylation of conjugated dienes The dienol 60, 61 when subjected to the palladium catalyzed oxyacetoxylation in the presence of acetic acid. The authors condu cted the reaction under three different conditions: A (no LiCl), B (0.2 eq LiCl), C (2eq LiCl). As explained in scheme 1.23 the absence of LiCl (method A, table 1.4) resulted in trans oxyacetoxylation, 0.2 eq of LiCl (method B, table 1.4) gave an overall cis oxyacetoxylation product. The use of 2 equivalents of LiCl (method C) resulted in incorporation of chloride and an overall cis1,4 oxychlorination (table 1.5). 30

PAGE 53

Table 1-4 Pd(0) catalyzed stereocontrolled cis 1, 4-oxyacetoxylation of dienols (ref 29e)aEntry Dienol Method Product %yieldb Stereochemc 1 OH 60 A O AcO H H 66-t r an s 87 >98%trans 2 B O AcO H H 66c i s 82 cis:trans=91:9 3 HO 61 A O AcO H H 67-trans 87 >98%trans 4 B O AcO H H 67c i s 78 cis:trans=91:9 5 OH 62 A O AcO H H 68-t r an s 85 >98%trans 6 B O AcO H H 68c i s 86 cis:trans=91:9 7 OH 63 A O AcO H Me 69 65 >98%trans 8 A O H H AcO 70-trans 90 >98%trans 31

PAGE 54

9 OH 64 B O H H AcO 70-cis 81 >98%cis 10 HO 65 A O A cO H H 71-trans 86 cis:trans=25:75 11 B O A cO H H 71-cis 84 >98%cis a All reactions were performed in acetone-acetic acid (4:1) using 5 mol% Pd(OAc)2 and 2 eq benzoquinone, Method A: Absence of LiCl, Method B: 0.2 equiv LiCl. b Isolated yields. c Refers to the addition across the diene sytem. 1.7.2 1,4-oxychlorination of conjugated dienes Bckvall et al29e also conducted 1,4 oxychlorination of conjugated dienes and reported that the use of 2 equivalent s of LiCl resulted in an ove rall 1,4-oxychlorination (table 15). Also in few cases of oxychlorination and oxyacetoxylation the effect of substituents on the side chain of the dienol was also studi ed and it was concluded that the presence of substituents on the side chain do not effect the rate of the reaction. For example, dimethyl alcohol 75 (entries 5,6, table 1-4 and entry 3 table 1-5) gave the corresponding products in good yields. However, substitution at the 4-position of the diene decreases the rate of the reaction (ent ry 7, table 1.4 and entr y 4 table 1-5) but the stereoselectivity for these two reactions was still >98%. 32

PAGE 55

Table 1-5 Pd(0) catalyzed stereocontrolled cis 1,4-oxychlorination of dienolsaEntry Dienol Reaction timeb Product %yieldc Stereochemd 1 OH 60 12+0 O Cl H H 72 91 >98%cis 2 HO 61 12+12 O Cl H H 73 89 >98%cis 3 OH 62 12+24 O Cl H H 7 4 90 >98%cis 4 OH 63 12+24 O Cl H Me 75 72 >98%cis 5 OH 64 12+0 O H H Cl 76 88 >98%cis 6 HO 65 12+12 O Cl H H 77 81 >98%cis a All reactions were performed as in table 1.4 but in presence of 2 eq of LiCl b In all the substrates the addition time of th e diene was 12h. The second figure refers to the reaction time after completed addition. c Isolated yields. d Refers to the addition across the diene sytem. It was also pointed out that this Pd cata lyzed oxychlorination and oxyacetoxylation works well for six and seven membered dienes with two and three carbon chains. Hence this method can be applied to synt hesize fused [6,5], [6,6], [7 ,5],[7,6] tetrahydrofuran and tetrahydropyran systems But when this me thodology was extended to synthesize an annulated oxetane system from alcohol 78 or a seven membered oxygen containing ring 33

PAGE 56

system no cyclized product was obtained (scheme 1.19). In case of the alcohols 78, 7 9 a complex mixture of isomers was obtained when they were subjected to Pd catalyzed 1,4 oxychlorination. 78 OH HO 79 no cyclized product no cyclized productScheme 1-19 Non-reactivity of dienols 78, 79 towards Pd catalyzed 1,4oxychlorination 1.7.3 1,4-oxyalkoxylation of conjugated dienes Bckvall et al also converted diene alcohols 60-65 to the oxygen heterocycles via a Pd(II) catalyzed diacetoxylation (table 1.6).29eThe reaction was carried out in the presence of 5 mol% Pd(OAc)2, 10 mol% MeSO3H and 2 equivalent p-benzoquinone in various alcoholic solvents. The addition of catalytic amount of methanesulfonic acid increases the reactivity of the intermediate ( allyl) palladium complex. In all the cases the reaction was highly stereoselec tive. Three different alcoho ls MeOH, EtOH, BnOH were investigated during this study and the pr oducts were obtained in 55-87% yield. Table 1-6 Pd catalyzed intramolecular 1,4-Di alkoxylation of 1,3 cylohexadienesa Entry Dienol Solvent Product %yieldb Stereochemc 1 MeOH O MeO H H 80 75 cis:trans=91:9 34

PAGE 57

2 OH 60 EtOH O EtO H H 81 85 cis:trans=90:10 3 BnOH O BnO H H 82 75 cis:trans=90:10 4 HO 61 EtOH O EtO H H 83 86 >98%cis 5 OH 62 EtOH O EtO H H 8 4 83 cis:trans=91:9 6 OH 63 EtOH O EtO H Me 8 5 55 cis:trans=87:13 7 OH 64 MeOH O H H MeO 86 74 >98%cis 8 EtOH O H H EtO 87 87 >98%cis 9 BnOH O H H BnO 88 85 >98%cis 10 HO 65 EtOH O EtO H H 89 85 >98%cis a The reactions were performed in the approp riate alcohol (5mL/mmol) using 5mol% Pd(OAc)2, 10 mol% MeSO3H and 2 equiv of p -benzoquinone. b Isolated yields. c Refers to the addition across the diene sytem. 35

PAGE 58

The catalytic cycle for these intermolecular 1,4-oxidations is shown in scheme 1.20 and involves a ( allyl) palladium complex. An intermolecular attack by the alcohol on the initially formed ( diene) palladium complex results in the formation of the tetrahydrofuran or tetrahydropyran ring systems. These type of reactions of alcohols with dienes coordinated to palladium are well precendented in literature.31 The oxypalladation proceeds with trans stereochemistry. The role of benzoquinone is to coordinate 32 to the ( allyl) palladium complex and thereby indu cing the nucleophilic attack (B). During later steps in the catalytic process Pd(0)-benzoquinone co mplex(C) may be formed which would disproportionate to the hydr oquinone and palladium(II) upon reacting with the acid.33-34 Scheme 1-20 Mechanism for Pd catalyzed intramolecular 1,4 addition to conjugated dienes 36

PAGE 59

37 1.8 Oxidative cyclization of heteroatom nucleophile with unactivated olefins Pd can act both as a nucleophile in the form of Pd(0) and as an electrophile as in Pd(II) and this versatile property has been utilized in development of oxidative cyclization of alcohols to result in various O-heterocycles.35b-j Recently Stoltz et al 35a studied the oxidative cyclization of alcohols and phe nols using Pd(II) catalysts and molecular O2 as the oxidant. The importance of this process lies in the fact that it avoids the use of cocatalysts, organic oxidants (like benzoquinone ), donating solvents as DMSO which ahs been used in previous work on similar reactions.35b-j Stoltz work is based on a previous reacemic Pd(II) catalyzed oxida tion of alcohols by Uemura et al which involved Pd(II) catalyzed oxidation of alcohols .36 Stoltz et al 35a conducted oxidative cyclizati ons of various heteroatom nucleophiles with unactivated olefins using Pd (II) catalysts in pyridine using molecular oxygen as the only oxidant in a non-polar solvent as toluene. Five different type of nucleophiles: primary alcohols, phenols, carbox ylic acids, vinylogous acid, amines were utilized in this process. El ectron rich phenols proved to be excellent substrates for this oxidation resulting in oxidative cyclization products smoothly. Primary alcohols can resulted in both fused or spiro ring system s depending on the position of alcohol group with respect to th e tethered alcohol. The mechan istic studies conducted with stereospecifically deuterium labeled alc ohols indicated a syn oxypalladation mechanism rather than a trans oxypalladation in the cas e of both mono and bi-dentate ligands. In order to optimize the reaction conditions the authors conducted aerobic oxidation of 2(1,2-dimethyl-1-propenyl)phenol in the presence of various Pd(II) salts, O2, pyridine and MS 3 in toluene at 80o C (Table 1-7). These conditions were chosen on the basis of

PAGE 60

38 Uemuras alcohol oxidation conditions. 36 Some of the effective catalysts used in kinetic resolution chemistry such as Pd(nbd)Cl2 proved to be ineffective for this cyclization.37 After scanning a large number of Pd catalysts the authors concluded that electron deficient Pd(II) catalyst Pd(TFA)2 is the most effective catalyst for this cyclization. Out of all the exogenous bases used, sodium carbona te resulted in 95% yield in 30 minutes. Pd(0) catalysts were found to be poor catalyst for this oxidative cyclization resulting in product in trace amounts or no reaction. The aut hors also tried oxidative cyclization in the presence of elemental Hg which resulted in slower reaction ra te but did not prevent the reaction contraindicating the fact that Pd or Pd nanoparticle s are involved as the catalytic species. 38 Table 1-7 Optimization of reaction conditions for Pd(II) cataly zed oxidative cyclization Entry Pd source Additive Time Yielda 1 Pd(nbd)Cl2 none 24h 7% 2 PdCl2 none 24h 27% 3 Pd(OAc)2 none 24h 76% 4 Pd(TFA)2 none 60 min 87% 5 Pd(TFA)2 Na2CO3 20 min 95% 6 Pd2(dba)3 None 24h 25% 7 Pd black None 24h Nr 8 none None 24h Nr 9 Pd(TFA)2 None, no O2 24h 24% 10 b Pd(TFA)2 Na2CO3,Hg0 5 h 84% a Isolated yields. b With 5 mol% of (pyridine)2Pd(TFA)2, 10 mol% of pyridine, 2 equiv Na2CO3, 30 equiv Hg0.

PAGE 61

Various pyridine based ligands were also scanned during the optim ization conditions (table 1.8).39 Authors also found out that substitute d pyridyls which are less coordinating than pyridine resulted in precipitation of Pd black due to electroni c and steric reasons. Also bidentate ligands such as 2,2-dipyrid yl (table 1-8, entry 6), 4,7-dimethyl-1,10phenanthroline(table 1-8, en try 7), TMEDA(table 1.8, entr y 10), or TMPDA(table 1-8, entry 11) resulted in slower reaction rates. Weak alkylamine donors also resulted in precipitation of Pd black (table 1-8, en tries 8,9,11). On the other hand nicotinate derivatives (table 1-8, entries 4 and 5) resulted in some rate enhancement. Out of all the ligands used pyridine offered the best combin ation of reactivity, catalyst stability and availability. Table 1-8 Pd(II) catalyzed oxidative cyclization using various substituted pyridyl and alkyl amine ligands a Entryb Ligand No Additive 40% ligand 40% ligand+40% Na2CO3 1 39 N 98% 1h 99% 1h 99% 15min 2 85% 2.5h 96% 9h 99% 2h 3 50% 24hc 68% 24h 91% 5h 4 84% 8hc 99% 40min 96% 15min 5 70% 30minc 99% 30min 99% 5min 6 92% 18h 97% 5h 93% 5h

PAGE 62

40 N 7 N 94% 8h 96% 24h 99% 24h 8 N 82% 20hc 90% 5hc 92% 5hc 9 15% 24hc 15% 24hc 10% 24hc 10 73% 12h 97% 8h 99% 8h 11 34% 20 hc 54% 20hc 76% 11hc aReaction carried out with 5 mol% LnPd(TFA)2, 500mg/mmol of MS3, 1 atm O2, toluene (0.1M), 800C. b conversion determined by GC.c Pd black precipitate was observed in the reaction mixture. d For entries 6,7,10 and 11, 20 mol% of excess ligand was used. Authors also cyclized various aliphatic alcohol s using this oxidative cyclization protocol (table 1.9). In all the cases, the corresponding hetero cyclic compounds were obtained with little or no oxidation to aldehydes. The reaction pathway-cyclization versus oxidation to aldehydes depends not only on the nature of the al cohol but also the nature of palladium source.36 In order to conduct mechanistic studies, Stoltz et al36,37synthesized stereospecifically deuterium labeled subs trates (Scheme 1.21) and explained the formation of the specific products on the basis of one of the three basic mechanisms involving Pd(II) ca talyzed cyclizati ons (Scheme 1.22). As shown in scheme 1.21 treatment of trans98 with 10 mol% of (pyridine)2Pd-(TFA)2, 20 mol% pyridine, 2 equiv Na2CO3, 1 atm O2 and 500mg/mmol of MS3 in toluene at 800C for 3h provided 99d and 100d in a 4:1 ratio and 91% yield Similarly, the reaction of cis substrate yielded 99 and 101 in a ratio of 1:0.7 and almost quantitative yield.

PAGE 63

Table 1-9 Pd(II) catalyzed oxidative cy clization of primary alcohols a Entry Substrate Product Time yield 1b OH 90 O 94 3h 87% 2 OH 91 O 95 10h 93%c 3 OH 92 O 96 7.5h 69% d 4 OH 93 O 97 20h 60%e a With 5 mol% of Pd(TFA)2, 20 mol% pyridine, 2 equiv Na2CO3, 500mg/mmol of MS3, 1 atm O2, toluene (0.1M), 80oC. b mixture of E and Z olefins was used. c isolated with 7% of aldehyde. d isolated with 7% of olefin isomer. e Isolated as a 5:2.3:1 mixture of product:olefin isomer: aldehyde. OH O CO2Et D EtO2C CO2Et CO2Et D O CO2Et CO2Et D OH CO2Et D EtO2C O CO2Et CO2Et H O CO2Et CO2Et D 4.5h 91% yield 3h 99% yield trans -98 cis -98 99 d 100 99 101 4 : 1 1 : 0.7 N Pd(TFA)2 n (10 mol%) pyridine(30 mol%) Na2CO3 (2 equiv), MS3 toluene, O2, 800C Scheme 1-21 Oxidative cyclization of deuterium labe led primary alcohols with pyridine as a ligand. 41

PAGE 64

42 The mechanistic explanation for the products obtained from 98 is explained in scheme 1.22 using the cis substrate as the model. As stated earlier the authors compared all the three possible pathways for Pd (II) catalyzed oxidative cyclization. According to path A, Pd coordinated olefin is attacked by the pe ndant alcohol or alkoxide in an anti fashion. This is followed by -H elimination to give deuterium labeled product 99d which is not formed, hence ruling out this mechanism. According t path B oxypalladation occurs resulting in C-H(D) activation and subse quent reductive elimination upon formation of new C-O bond. Since for a Pd(II)-allyl electrophile, a primar y alcohol (alkoxide) comes under a soft nucleophile category, hence the reductive elimination will be anti. Also, unless selective C-D activation occurs (le ss probability), a mixture of labeled ( 99-d ) and non-labeled ( 99) compounds should be observed but a single product was obtained. Also, this pathway does not explain the formation of the minor product 101. The last pathway (C) involves syn oxypalladation invo lving Pd-alkoxide followed by syn -D elimination to yield the major product 99. The formation of the minor product 101 can be explained by re-insertion of Pd-D intermediate to the product double bond. Since the Pd(0) intermediate in path B does not account for the formation of olefin isomer 101, hence the authors favored syn oxypalladation path C.

PAGE 65

E D E cis -98 99 101 OH OH E E D H {PdII} O E E D H {PdII} O E D E O E E D path A path B OH E E {PdII} H(D) -H(D)X O E H(D) E {Pd0} O E D E {PdII} H -allyl O E H(D) O E E (D)H E path C O E D H [Pd] E O E E D H {Pd} O E H E {Pd} D O E E {Pd} H D O E H E O E E D {Pd} H O E E H O E E H D 99-d not observed E= CO2EtScheme 1-22 Pathways for Pd(II) catalyzed oxidativ e cyclization of deuterium labeled primary alcohols Authors also used both monodentate and bi dentate ligand for this Pd(II) catalyzed oxidative cyclization.37 But these two type of ligands show considerable difference in reaction rates. This difference can be explained on the basis of degree of stabilization of the intermediates by the two ligands. As shown in scheme 1.23, a neutral monodentate ligand such as pyridine can dissociate to prov ide free coordination site while remaining in a neutral state. Whereas, in the case of a bidentate ligand like dipy ridyl, dissociation of a neutral ligand is difficult due to chelation, hence an an ionic ligand should dissociate resulting in a charged intermediate. These type of charged intermediates are high in energy resulting in lower reactivity. 43

PAGE 66

O Pd X L L -L O Pd L X syn oxypalladation +L O H Pd X L L -H elim.-L O Pd H X L O Pd L X L O Pd L L syn oxypalladation O H Pd L L X -H elim. O Pd H L L -X+X-X-102 103 104 105 106 107 108 109 Monodentate ligand Bidentate ligand Scheme 1-23 Reaction pathways for Pd(II) oxidativ e cyclization using A:monodentate, B: bidentate ligands. 1.9 Cyclization and cross-coupling reaction of acetylenic alkoxides Palladium catalyzed cyclization of acetyleni c alcohols has been used extensively to obtain mono and bicycle O-hetercycles.40b-e Luo et al synthesized stereodefined 2alkylidenetetrahydrofurans by treating al kyl/aryl acetyleni c alcohols with n-BuLi followed by addition of 10 mol% Pd(OAc)2 or PdCl2 and 1 equivalent of organic halide (Scheme 1-24).40a n 1.BuLi,THF 2. cat. Pd(II), PPh33.R'X n= 1,2 R= H, n-Bu, Ph R'=Ph, Me,Bn, 2-thienyl 110 111 O R R' OH R Scheme 1-24 Pd(II) catalyzed cyclization and cro ss-coupling reaction of acetylenic alkoxides According to this report40a both acetylenic aryl and alkyl alkoxides underwent cyclization and cross-coupling to yield five and six membered rings with high regioand 44

PAGE 67

stereoselectivities. Apart from Pd(OAc)2 and PdCl2 other Pd catalysts such as Pd(dba)2 and PdCl2(PPh3)2 gave lower yields. It wa s also discovered that surprisingly use of bases such as NaHCO3, MeONa resulted in no detectable amount of the desired products. OH OH OH OH O Ph O Ph O Ph no reaction Reaction conditions: (1) BuLi, THF, (2) Pd(II) cat., PPh 3 (3) PhI (60%) (47%) (54%) 110a 110b 111d 111c 111a 110d 110c Scheme 1-25 Pd(II) catalyzed cyclization and cro ss-coupling reaction of acetylenic alkoxides Scheme 1-25 shows various five and six membered acetylenic alcohols subjected to Pd catalyzed intramolecular cyclization and cross coupling to yield bicyclic furan analogs by Luo et al Compound 110b ( trans -2-(2-propynyl)cyclopentan ol) did not result in any cyclized product (scheme 1-25). 40 In order to explain the formation of the products the authors proposed an initial proton ab straction from the alcohol followed by complexation of the oxidative Pd(II) adduct with the triple bond to be involved in this one pot Pd catalyzed process. The comp lex undergoes trans-oxypalladation to give intermediate B which undergoes reductive elim ination to yield the pr oduct and regenerate Pd catalyst (Scheme 1-26). 45

PAGE 68

nOH R O Pd Pd(II) Pd(0) PPh3 R'I R'-Pd-I n-BuLinOLi R nOLi R R'-Pd-I R LiI R' O R' R n n A B Scheme 1-26 Mechanism for Pd(II) catalyzed cyclization and cross-coupling reaction of acetylenic alkoxides 1.10 Pd catalyzed intramolecular cycliz ation of 7-Hydroxy-1,3-diene with aryl bromides Recently, Yeh et al 41 studied palladium catalyzed intr amolecular reaction of 7-Hydroxy1,3-diene with various aryl bromides to obtain bicyclic furan analogs (Scheme 1.27). Various acyclic and cyclic substrates were subjected to this palladium catalyzed alkoxyarylation of 7-Hydroxy-1,3-dienes and de pending on the structure of the starting dienols, different types of products were obtained. In case of cycl ic 7-Hydroxy-1,3dienes, a 1,4-alkoxyarylation product was obtained via a 131 allylic rearrangement, whereas in the case of acyclic substrat es a 1,2 alkoxyarylation product was obtained.41 46

PAGE 69

R2 OH R1 ArBr Pd(PPh3)4(2mol%) dpe-phos (2 mol%) NaO t Bu (2.0 mol) THF, 2h O R1 R2 Ar 15 examples 36-84% yield 112-114 115-125Scheme 1-27 Pd catalyzed intramolecular alkoxy arylation of 7-Hydroxy-1,3-dienes The bicyclic tetrahydrofuran an alogs were obtained in high diastereoselectivity via this Pd catalyzed intramolecular alkoxyarylati on of 7-Hydroxy-1,3-dienes which can be explained on the basis of the proposed mechanism shown in scheme 1.28. The high diastereoselectivity indicates involvement of the Pd(Ar)-(OR)-olefin intermediate 126 which is derived from chelation/direction by the substrate as al so proposed by Wolfe et al .8a,b Intermediate 126 can result in insertion of olef in into the Pd-O bond to give 1 allylpalladium intermediate 129 which may undergo 131 allylic rearrangement to yield 1allylpalladium intermediate 130. Intermediate 130 can lead to reductive elimination to give 1,4 alkoxyarylation product 131 and 132 with simultaneous regeneration of Pd(0) catalyst or -hydride elimination to provide compound 133. Another possibility for intermediate 126 is insertion of the olef in into the Pd-C bond of the intermediate 126 resulting in the metallobicyclic intermediate 127 via path B (scheme 1.28). Later, intermediate 127 can led to 1,4-alkoxyarylation product 128 via reductive elimination. However compound 128 was not observed and he nce this reaction is proposed to not follow path B. This observation can also be explained on the basis of the fact that sterically congest ed bicyclic intermediate 127 may undergo Ph elimination to regenerate 126 which will result in 1, 4-alkoxyarylation product via path A (scheme 1.28). This Ph elimination can be considered as the reverse of the olefin insertion step in 47

PAGE 70

Heck reaction. Also it should be noted that ar ylpalladation reactions ar e not reversible in most cases except where the (aryl)(alkyl)p alladium intermediates do not have syn hydrogen atoms.42 Since intermediate 127 does not have any hydrogen atoms syn to palladium hence undergoing Ph elimination to give back intermediate 126 is favored. OH R R LnPd(Ar)Br O R R PdLn A r O PdLn Ar O LnPd Ar R R R R R = M e A r = e r ic hR = P h B n O Ar R R O R R O Ar R R path A path B O PdLn Ar R R -PdLn O R R Ar Not observed 112-114 126 127 128 129 130 131 133 132 NaO t Bu R= Me Ar= edeficientScheme 1-28 Possible mechanistic pathways for Pd catalyzed intramolecular alkoxyarylation of 7-Hydroxy-1,3-dienes It was also pointed out by the authors that the structure of the product and yields also depended on the nature of the aryl bromid es employed. In case of electron rich aryl bromides (table 1.10, entries 1-4) the produc ts obtained had the general structure with syn stereochemistry which also confirmed syn addition of the oxygen and the aryl group across the conjugated diene. 48

PAGE 71

Table 1-10 Pd(II) catalyzed intramolecular alkox yarylation of 7-Hydroxy-1,3-dienes Entry 1,3-diene alcohol aryl bromide Product yield 1 OH 112 O 115 55 2 O 11662 3 O MeO 11784 4 Br O 118 56 5 O Cl 11954 6 O Br Br 120 40 7 Br CF3 O F3C 121 36 8 Br O 122 65 9 N O 12348 49

PAGE 72

10 O Ph Ph 124 65 11 O Bn Bn 125 58 OH 50 Bn Bn 127 In case of electron-deficien t aryl bromides (table 1.10, entries 5-9) a double bond migration product 119-123 was obtained. Also, increasing th e bulk in the substrate also resulted in different products (table 1.10, entries 10-11). In case of alcohols with bulky dibenzyl and diphenyl groups at C-7, tetrahydrobenzofurans 124,125 were formed via a -hyride limination from the intermediate 130. OH 2 OH 2 OH 134 136 135Fig 1-7 Non-reactive 7 and 8-hydroxy 1,3-dienes under Pd catalyzed intramolecular alkoxyarylation Attempts to apply Pd cata lyzed intramolecular alkoxyaryla tion of 7-Hydroxy-1,3-dienes by Yeh et al to larger ring systems were unsu ccessful (fig 1-7). For example, intramolecular alkoxyarylation r eaction of 8-hydroxy-1,3-dienes 134 and 135 resulted in the recovery of starting dienols. Also, the Pd-catalyzed reaction of the primary alcohol 136 with bromobenzene did not result in tetrahydrofurans under the same reaction conditions albeit the corres ponding aldehyde was obtained re sulting from oxidation of the starting dienol.

PAGE 73

1-11 Oxidative cylization of 2-[(E)-but en-2-yl-1]-2-carbomethoxycyclopentanol Pecanha et al43 utilized a palladium acetate/cupric ace tate system to synthesize bicylic tetrahydrofuran ring systems in a diastereoselective manner (Scheme 1-29). Cyclopentanol 138 was synthesized from methyl -2-oxocyclopentanecarboxylate 137, in 95-97% yield which was then subjected to Pd catalyzed cyclization. The general reaction conditions used by the authors involved 10 mol% palladium acetate, 100 mol% cupric acetate in methanol:water system (100:8). O CO2Me 137 OH CO2Me Me Pd(OAc)2 (0.1 eq) Cu(OAc)2 (1 eq) MeOH/H2O (100:8), rt O CO2Me O CO2Me O CO2Me O CO2Me O CO2Me OMe OMe 138 139 140 141 142 143 product time 139 140 141 142 143 4ha 11% 31% 5% 0% 10% 8ha 10% 21% 10% 0% 8% 24ha 3% 0% 24% 13% 8% 24h b 10% 42% 0% 0% 7% a solvent sytem MeOH:water(100:8) b solvent sytem isopropanol with water content (20%) Scheme 1-29 Pd(II) catalyzed oxidative cylizat ion of 2-[(E)-buten-2-yl-1]-2carbomethoxycyclopentanol A time-study of the reaction was also conduc ted. After 4 hours at room temperature a mixture of 3 and 3 -vinyl bicyclic derivatives 140, 139 in 1:3 diatereomeric ratio. 51

PAGE 74

Apart from the desired bicyclic derivatives 139, 140 a cyclic ketal 141 was also obtained in 5% yield after 4 hours. Al so when the reaction time was doubled to 8 hours the amount of ketal being formed also increased (S cheme 1.30). Extending the reaction time to 24 hours resulted in bicyclic furan derivative in only 3% yield a nd the cyclic ketals 141 & 142 in 24% and 13% yield respectively. The au thors also tried to minimize the side reaction involving ketalization by changing the solvent system from methanol/water to an isopropanol/water system. Pd(OAc)2 O Me CO2Me Pd OH CO2Me Me 138 OAc H O Me CO2Me Pd OAc H D D' O Me CO2Me Hshift "Wacker type" oxidation A O CO2Me O CO2Me 139 140 Pd(OAc)2 O CO2Me PdOAc O CO2Me PdOAc E E' O CO2Me OMe 142 MeOH O CO2Me PdOAc B O CO2Me OMe 141 MeOH MeOH O CO2Me C O CO2Me 143 protonation MeOH Scheme 1-30 Formation of various products via Pd (II) catalyzed oxidative cylization of cis -2-[(E)-buten-2-yl-1]-2-carbomethoxycyclopentanol Authors explained the formation of vari ous products as shown in scheme 1.30. The formation of ketal 142 can result from the Wacker type intermediate A, followed 52

PAGE 75

53 by ketalization with the solvent. Ketal 141 can be formed by nucleophilic attack by the solvent (MeOH) on the allyl intermediate B. Formation of compound 143 can be explained by isomerization of enol ether intermediate C (scheme 1-30). 1-12 Conclusions In this chapter we have presented various useful Pd catalyzed methodologies to synthesize bicyclic furan ring systems. The la st two decades have witnessed a huge influx of new Pd catalyzed reactions in synthesis of various he terocycles. Palladium offers many advantages as it is usually required in catalytic amounts and is known to tolerate a large number of functional groups thereby minimizing the use of protecting groups. Furan is one of the most commonly studi ed heterocyclic compound and is widely distributed in large number of natural products, pharmaceuticals, agrochemicals and perfumes. Due to the importance of these he terocycles, new and more efficient methods are required to synthesize them in higher yields in a stereoselective manner and Pd catalysis has been a leader in this field. This chapter also gives a mechanistic perspective for all the Pd catalyzed processes included, which will help the reader to understand the formation of different products and the di astereoand enantiose lectivities of the processes involved.

PAGE 76

54 1-13 References 1. (a) Maitlis, P. M. The Organic Chemistry of Palladium ; Academic Press: New York, 1971; Vols. 1 and 2. (b) Tsuji, J. Organic Synthesis with Palladium Compounds ; Springer-Verlag: New York, 1980. (c) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic Press: New York, 1985. (d) Larock, R. C. In Ad vances in MetalOrganic Chemistry ; Liebeskind, L. S., Ed.; JAI Press: London, 1994; Vol. V, Chapter 3. (e) Tsuji, J. Palladium Reagents and Catalysts: Inno vations in Organic Synthesis ; Wiley and Sons: New York, 1995. (f) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: New York, 2000. (g) Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis ; Wiley and Sons: New York, 2002; Vols. 1 and 2. (h) Tsuji, J. Palladium Reagents and Ca talysts: New Perspecti ves for the 21st Century ; Wiley and Sons: New York, 2003. (i) Palladium in Organic Synthesis ; Tsuji, J., Ed.; Springer: Berlin, 2005.(j) Heumann, A.; Jens, K.-J.; Reglier, M. Progress in Inorganic Chemistry; Karlin, K. D., Ed.; W iley and Sons: New York, 1994; Vol. 42, pp 483-576. (k) Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley and Sons: New York, 1994; Chapter 5, pp 383-461 2. (a) Tsuji, J. J. Organomet. Chem 1986, 300, 281. (b) Kalinin, V. N. Russ. Chem. Re v. 1991, 60, 339. (c) Hegedus, L. S. Coord. Chem. Re V. 1996, 161, 129. (d) Hegedus, L. S. Coord. Chem. Re v. 1997 147, 443. (e) Larock, R. C. Pure Appl. Chem. 1999, 71, 1435. (f) Bckvall, J.-E. Pure Appl. Chem. 1999, 71, 1065. (g) Tsuji, J. Pure Appl. Chem. 1999, 71, 1539. (h) Beletskaya, I. P.; Cheprakov, A. V. Chem. Re v. 2000, 100, 3009. (i) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (j) Cacchi, S.; Fabrizi, G.;

PAGE 77

55 Goggiomani, A. Heterocycles 2000, 56, 613. (k) Zimmer, R.; Dinesh. C. U.; Nandanan, E.; Khan, F. A. Chem. Re v. 2000, 100, 3067. (l) Marshall, J. A. Chem. Re v. 2000, 100, 3163. (m) Special issue Years of the Cross-coupling Reaction. J. Organomet. Chem 2002, 653, 1. (n) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Re v. 2003, 103, 1875. (o) Negishi, E.; Anastasia, L. Chem. Re v. 2003, 103, 1979.(p) Zeni, G.; Larock, R. C. Chem. Re v. 2004, 104, 2285. (q) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005 7, 147. (r) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem 2003, 4101.(s) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. 3. Khan, P.M.; Wu, R.; Bisht, K.S. Tetrahedron 2007, 63, 1116. 4. (a) Rahmathullah, S. M.; Hall, J. E.; Bender, B. C.; McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W. J. Med.Chem. 1999, 42, 3994. (b) Di Florio, R.; Rizzacasa, M. A. J. Org. Chem. 1998, 63, 8595. (c) Hudlicky, T.; Ru lin, F.; Lovelace, T. C.; Reed, J. W. In Studies in Natural Products Chemistry, Stereoselective Synthesis part B, Vol. 3; Attaur-Rahman, Ed.; Elsevier Science: Amsterdam, 1989, 3. 5. (a) Lockhart, D. J.; Patel, H. K.; Mehta, S. A.; Milanov, Z. V.; Grotzfeld, R. M.; Lai, A. G. PCT Int. Appl. WO 2004110357 A2, 2004; Chem. Abstr. 2005, 142, 69180. (b) Castro-Hermida, J. A.; Gomez-Couso, H.; Ar es-Mazas, M. E.; Gonzalez-Bedia, M. M.; Castaneda-Cancio, N.; Otero-Espinar, F. J.; Blanco-Mendez, J. J. Pharm. Sci. 2004, 93, 197. (c) Anbazhagan, M.; Boykin, D. W. Heterocycl. Commun. 2003, 9, 117. 6. (a) Nizamuddin, G. M.; Srivastava, M. K. J. Sci. Ind. Res. 1999, 58, 1017. (b) Ito, H.; Takeshiba, H.; Ota, H.; Kato, S. Jpn. Kokai Tokkyo Koho JP 10114765, 1998; Chem. Abstr. 1998, 129, 24492. (c) Venters, K.; Trusuele, M.; Rozhkova, N.; Lukevics, E. Latv.

PAGE 78

56 PSR zinat. Akad. Vest. 1990, 10, 116. (d) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Frter, G. Angew. Chem. Int. Ed. 2000, 39, 2980. (e) Harris, E. C.; Fayter, R. C. Jr. US 4681703, 1987; Chem. Abstr. 1989 110, 23713. 7. For recent reviews, accounts, and highlights dealing with the synthesis of furans, see: (a) Muzart, J. Tetrahedron. 2006, 61 5955.(b) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (c) Bellur, E.; Feist, H.; Langer, P. Tetrahedron. 2007, 63, 10865. (d) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L. ; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955. (e) Keay, B. A. Chem. Soc. Re v. 1999, 28, 209. (f) Jeevanandam, A.; Ghule, A.; Ling, Y.-C. Curr. Org. Chem. 2002, 6, 841. (g) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850. (h) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. (i) D Souza, D. M.; Mller, T. J. J. Chem. Soc. Re v. 2007, 36, 1095. (j) Patil, N. T.; Yamamoto, Y. ARKIVOC 2007 121. (k) Balme, G.; B ouyssi, D.;Monteiro, N. Heterocycles 2007, 73, 87. 8. (a) J. P. Wolfe, M. A. Rossi, J. Am. Chem. Soc. 2004, 126, 1620. (b) M. B. Hay, A. R. Hardin, J. P. Wolfe. J. Org. Chem. 2005, 70, 3099.(c) M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005, 127, 16468. (d) M. B. Hay, J. P. Wolfe, Tetrahedron Lett. 2006 47, 2793. (e) Wolfe, J. Eur. J. Org. Chem 2007, 571.(f) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106 1496. (g) Semmelhack, M. F.; Epa, W. R.; Cheung, A. W-H.; Gu, Y.; Kim, C.; Zhang, N.; Lew, W. J. Am. Chem. Soc. 1994 116, 7455. (h) Babjak M.; Kapitan, P.; Gracza, T. Tetrahedron, 2005,61, 2471. 9. For sp2 C-O bond-forming reductive elimination from palladium(II) aryl alkoxide complexes, refer: (a) Widenhoefe r, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,

PAGE 79

57 6504. and references therein. (b) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109. 10. For syn -insertion of an alkene into a Pd-O or Pt-O bond refer: Pd:(a) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. Pt: (b) Bryndza, H. E. Organometallics 1985, 4, 406. (c) Bryndza, H. E.; Calabrese, J. C.; Wreford, S. S. Organometallics 1984 3, 1603. 11. Carbon-carbon bond-forming reductive elimination is believed to occur with retention of configuration. Refer: M ilstein, D.; Stille, J. K. J. Am. Chem.Soc. 1979, 101, 4981. 12. (a)Kato, K.; Nishimura, A.;Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2001, 42, 4203. (b) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43 4915. (c) Kato, K.; Tanaka, M.; Yamamoto, Y.; Akita, H. Tetrahedron. Lett. 2002, 43, 1511. 13. (a) Tsuji, J.; Takahash i, M.; Takahashi, T. Tetrahedron. Lett. 1980 21, 849. (b) Tamaru, Y.; Hojo, M.; Yoshida, Z.; J. Org. Chem. 1991, 56 1099. (c) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2,297. (d) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (e) Gabriele, B.; Salerno, G.; Pascali, F. D.; Costa, M.; Chiusoli, G. P. J.Organomet. Chem. 2000, 409, 593. 14. (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J Am Chem Soc 1981, 103, 2318; (b) Uozumi, Y.; Kato, K.; Hayashi, T. J Am Chem Soc 1997, 119, 5063; (c) Arai, M.-A.; Kuraishi, M.; Arai, T.; Sasai, H. J Am Chem Soc 2001, 123, 2907; (d) Elqisairi, A.; Hamed, O.; Henry, P.-M. J Org Chem 1998, 63, 2790. 15. Commercially available. 16. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J Am Chem Soc 1991, 113, 726.

PAGE 80

58 17. Tanimori, S.; Kato, Y.; Kirihata, M. Synthesis 2006, 5, 865. 18. Tanimori, S.; Kirihata, M. Synthesis, 2007, 1, 39. 19. Bedjeguelal, K.; Joseph, L.; Bolitt, V.; Sinou, D. Tetrahedron Lett. 1999, 40, 87. 20. Nguefack, J.-F.; Bolitt, V.; Sinou, D. J Org Chem 1997, 62, 1341. 21. Nguefack, J.-F.; Bolitt, V.; Sinou, D. J Org Chem 1997, 62, 6827. 22. Jeffery, T. Tetrahedron Lett. 1993 34, 1133. 23. Bernocchi, E.; Cacchi, S.; Ciatti ni, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 3073. 24. (a) Hacksell, U.; Daves, G. D., Jr. Organometallics 1983, 2, 772. (b) Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832. (c) Saito, S.; Hara, T.; Takahashi, N.; Hirai, M.; Moriwake, T. Synlett 1992, 237. (d) Hosokawa, T.; Sagafuji, T.; Yamanaka, T.; Murahashi, S. I. J. Organomet. Chem. 1994, 470, 253. (e) Ma, S.; Lu, X. J. Organomet. Chem. 1993, 447, 305. (f) Kimura, M.; Harayama, H.; Tanaka, S.; Tamaru, Y. J. Chem. Soc., Chem. Commun. 1994, 2531. 25. (a) Duanet, J. P.; Cheng, C. H. Tetrahedron Lett. 1993 34, 4019. (b) Moinet, C.; Fiaud, J.-C. Tetrahedron Lett. 1995, 36, 2051. 26. Fuchs, P. L.; Lee, S. W. Tetrahedron Lett. 1993, 34, 5209. 27.(a) Hallberg, A.; Karabela s, K.; Westerlund, C. J Org Chem 1985, 50, 3896. (b) Hallberg, A.; Karabelas, K. J Org Chem 1986, 51, 5286.(c) Hallberg, A.; Karabelas, K. J Org Chem 1989, 54, 1773. (d) Overman, L. E.; Abelman, M. M.; Oh, T.; J Org Chem 1987, 52, 4130.(e) Hallberg, A.; Nilsson, K. J Org Chem 1992, 57, 4015. 28. Izumi, T.; Kasahara, A. Bull. Chem. Soc. Jpn 1975, 48, 1673.

PAGE 81

59 29.(a) Bckvall, J. E.; Andersson, P. G. J. Am. Chem. Soc. 1990, 112, 3683. (b) Bckvall, J. E., Andersson, P. G. J. Org, Chem. 1991, 56, 2274. (c) Bckvall, J. E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J. Org. Chem. 1991, 56, 2988. (d) Andersson, P. G.; Bckvall, J. E. J. Org. Chem. 1991, 56, 5349. (e) Bckvall, J. E.; Andersson, P. G. J. Am. Chem. Soc. 1992, 114, 6374. (f) Andersson, P. G.; Bckvall, J. E. J. Am. Chem. Soc. 1992, 114, 8696. (g) Bckvall, J. E.; Granberg, K. L.; Andersson, P. G.; Gatti, R.; Gogoll, A. J. Org. Chem. 1993, 58, 5445. (h) Andersson, P. G.; Nilsson, Y. I. M.; Bckvall, J. E. Tetrahedron 1994, 50, 559. (i) Koroleva, E. B.; Bckvall, J. E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 5397. (j) Nilsson, Y. I. M.; Aranyos, A.; Andersson, P. G.; Bckvall, J. E.; Parrain, J. L.; Ploteau, C.; Quintard, J. P. J. Org. Chem. 1996, 61, 1825.(k) Bckvall, J.: J. E.; Vgberg, J. O. J. Org. Chem. 1988 53, 5695. 30. Andersson, P. G.; Aranyos, A. Tetrahedron Lett. 1994, 35 4441. 31. (a) Bckvall, J. E.; Nordbcrg, R. E.; Wilhelm, D. J. Am. Chem. Soc. 1985, 107, 6892. (b) Rowe, J. M.; White, D. A.; J. Chem. Soc. 1967, 1451. (c) Lukas, J.; Leeuven, P. W. N. M.; Volger, H. C.; Kouwenhoven, A.P. J. J. Organomet. Chem. 1973, 47, 153. 32. Bckvall, J. E .; Gogoll, A. Tetrahedron Lett 1988, 29, 2243. 33. Hiramatsu, M.; Shiozaki, K.; Fujinami, T.; Sakai, S. J. Organomet. Chem 1983, 246, 203. 34. Uhlig, E.; Fischer, R.; Krimse, R. J. Organomet. Chem. 1982, 239, 385. 35.(a)Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc 2005, 127, 17778. (b) Thorarensen, A.; Palmgren, A.; Itami, K.; Bckvall, J.-E. Tetrahedron Lett. 1997 38, 8541. (c) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem.Soc. 2005, 127, 6970. (d) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem.

PAGE 82

60 Soc. 1981, 103, 2318. (e) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997 119, 5063. (f) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907. (g) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450. (h) El-Qisairi, A.; Hamed, O.; Henry, P. M. J. Org. Chem.1998 63, 2790. (i) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (j) Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124, 12. 36. (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999 64, 6750. (b) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999 121, 2645. (c) Kakiuchi, N.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Org. Chem. 2001, 66, 6620. 37. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725. 38. (a) Anton, D. R.; Crabtree, R. H. Organometallics 1983, 2, 855. (b) Foley, P.; DiCosimo, R.; Whitesides, G. M. J. Am. Chem. Soc. 1980, 102, 6713. 39. For an example of a Pd-catalyzed phenol/ole fin cyclization using an N-heterocyclic carbene ligand, see: Mu iz, K. Adv. Synth. Catal. 2004, 346, 1425. 40. (a) Luo, F. T.; Schreuder, I.; Wang, R. T. J. Org. Chem., 1992, 57, 2213.(b) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (c) Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 5323. (d) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. Tetrahedron 1985, 41,3655 41. Yeh, M. C. P.; Tsao, W. C.; Tu, L. H. Organometallics 2005, 24, 5909. 42. (a) Campora, J.; Gutierrez-Puebla, E.; Lopez, J. A.; Monge, A.; Palma, P.; del Rio, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40 3641. (b) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994, 33, 2421. 43. Pecanha, E. P.; Fraga, C. A. M.; Barreiro, E. J. Heterocycles, 1998, 48 2621.

PAGE 83

61 Chapter 2 Pd(0) CATALYZED INTRAMOLECULAR ALLYLIC ALKYLATION: STEREOSELECTIVE SYNTHESIS OF FURAN AND ISOXAZOLINE-2-OXIDE ANALOGS 2.1 General introduction Palladium catalyzed nucleophilic s ubstitution of allylic compounds, also known as Tsuji-Trost reaction has been extensively used for C-C bond formation in organic syntheses.1 Allylic acetates are the most common substrates used in this reaction along with various active methylene compou nds as the nucleophile source. However other allylic substrates such as halides, ca rbonates, epoxides, sulf ones have also been utilized which gives Tsuji-Trost reaction a broader scope.2 Hence, synthesis of a large number of natural product synthesis have been accomplished via utilization of Pd catalyzed allylic alkylation. Pd catalysis has also been extensively uti lized in synthesis of analogs of bioactive compounds and the inherent skeleton in an ef ficient manner. Various aspects of this reaction including mechanism, substrates, cat alyst-ligand systems a nd nucleophiles have been studied and extensively reviewed.3 Over 100 different chir al ligands have been designed to induce excellent enantioselectiv ity by five different enantiodiscriminating events.3 The discovery of new chiral ligands ha s resulted in ability to conduct these Pd catalyzed alkylations in almost >99% ee, hence attracting more na tural product syntheses. These methods have already been utilized to synthesize numerous bi ological targets such as aflatoxin B,4a aristeromycin,4b,c carbovir,4b,c cyclophellitol,4d ethambutol,4e galanthamine,4f mannostatin,4g neplanocin.4b,c

PAGE 84

62 The work presented in this chapter ex tends the utilization of Pd catalysis towards synthesis of new bioactive furan a nd isoxazoline analogs which can further be modified into other biologically important compounds. One can find a large number of methods for synthesis of various furan5 and isoxazoline-2-oxide analogs6. The furan ring system can be obtained by various synthetic methodologies such as iodocyclization of 2alkenyl-1,3-dicarbonyl compounds, selenium-i nduced electrophilic cyclizations or oxidative addition of enoli zable carbonyl compounds to gi ve alkenes promoted by one electron oxidants.6a Similarly, the general strategy fo r synthesis of the isoxazoline-2oxides (five membered nitronate s) involves cyclization of -functionalized nitro compounds or [3+2] cycloaddition of nitrile oxides with olefins.6c Unfortunately most of these methods involve use of stoichiometr ic amount of reagents making the process economically non-viable. Furthermore, these reactions also involve multiple steps and harsh reaction conditions to obtai n the final products. In some methods such as synthesis of the isoxazoline-2-oxides (five memb ered nitronates) via cyclization of -functionalized nitro compounds the preparation of starting ma terials is itself tedious which makes the whole methodology less appealing to synthetic chemists. Also the nitrile oxides used in synthesis of isoxazoline-2-oxides have a tendency to undergo rapid dimerization to furoxan N-oxide, hence disfavoring this met hod for syntheses of the five membered Noxides.6d Furthermore, till date none of the syntheses for the tit le compounds have involved the usage of enzymes to induce enan tioselectivity hence making this work the first chemo-enzymatic syntheses of furan and isoxazoline-2-oxide analogs. This work also tries to minimize the use of any chiral ligands during the whole syntheses. Thirteen

PAGE 85

63 new furan and isoxazoline-2-oxide analogs we re obtained in high opt ical purity and high yields by utilizing lipases, a type of hydrolytic enzymes which are much milder and environment-friendly catalysts than all other organometallic catalysts used in previous synthesis to obtain high ees. The starting material fo r this methodology is a five membered meso -diacetate which can be easily obtai ned from commercially available dicylopentadiene. The meso -diacetate serves as a substrate for lipase catalyzed enzymatic desymmetrization which is the key step for the synthesis. The outcome of the reaction depends on the enantiopurity of the allylic aceta te being used and is also controlled by the selectivity of the enzyme use d. The enantiopure allylic acetat e can also be converted to its enantiomer by a couple of protection/deprotection steps hence providing an easy route to the other enantiomer of these fura n and isoxazoline analogs. The methodology presented here is highly versatile and pres ents a convenient and environment friendly route to obtain new furan and isoxazoline analogs in high yield and optical purity. The presence of functionalities as NO2, COOR, SO2Ph and alkenes gives a tool to modify these structure motifs to other biologically important systems. 2.2 Introduction to furan and isoxazoline ring systems 2.2.1 Furan ring systems in natural products and their bioactivity The furan moiety is found in many natural compounds (fig 2.1).7 Various polysubstituted furan compounds also serve as building bloc ks in synthetic organic chemistry. Furan derivatives are also widely distributed in biologically important compounds such as pharmaceuticals,8 agrochemicals,7 flavoring chemicals and perfumes.9 As shown in figure 2-1 furan moiety is found in large number of natural products as plagionicin A which belongs to a class of monotetrahydrof uran acetogenins and has exhibited a broad

PAGE 86

biological acivity including cytotoxicity in numerous tumor cell lines as well as antiparasitic, insecticidal, a nd immunosuppressive activities.10 Rubriflordilactone B is one of the two bisnortriterpenoids isolated from plants of genus Schisandra has shown cytotoxic activity against K562 cells and has anti HIV-activity.11 The tetrahydrofuran system is also found in some neurotoxic ami no acids as Dysiherbaine which was isolated from a Micronesian sponge Dysidea herbacea. Dysiherbaine represents a new class of amino acids containing unique cis-fused tetrasubstituted hexahydrofuro[3,2-b]pyran.12 This system is unusual and is only found in few compounds as halichondrins.12 (CH2)11 O OH OH OH OH O O Plagionicin ACytotoxic Monotetrahydrofuran AcetogeninsO O NH2 +CH3 OH -OOC NH3 + -OOC H H H Dysiherbaine -neurotoxic amino acid O O O O H H H H H O O H H Rubriflordilactone B -anti HIV activity O OH O O Heliespirones B-lead compound for new agrochemicals Halichondrin A Figure 2-1 Furan ring system in bi oactive natural products 64

PAGE 87

2.2.2 General methods for synthesis of furan ring systems The presence of polysubstiuted furan ring systems in a large number of natural products and their utility as building blocks in synthetic ch emistry has attracted chemists to devise new methods for their synthesis. The synthesis has been extensively reviewed in literature.5 Recently, a large number of metal catalyzed reactions focusing on synthesis of furan and its analogs have been developed such as cyclization of 2-(1-alkynyl)-2-alken-1ones,13 allenyl ketones,14 3-alkyn-1-ones,15 (Z)-2-en-4-yn-1-ols,16 and, cycloisomerization of cyclopropyl and propenyl ketones.17 Recently Zhang et al utilized Pd(II) catalyzed three component coupling to obtain functiona lized tetrasubstituted furans in moderate yields (Scheme 2-1).18 Me O Ph Ph NuH R R R X K2CO3 (4 equiv), CH3CN [PdCl2(CH3CN)2] (5 MOL%)O R R R Nu Ph Me Ph NuH = MeOH, BnOH, PhOH, i PrOH X = Cl R= H, Me, Ph, COOMe 42-89%Scheme 2-1 Pd(II) catalyzed three component coup ling of 2-(1-alkynyl)-2-alken-1-ones to afford tetrasubstituted furans Various cyclopentafuran compounds have been generated by Pd(II) catalyzed intramolecular cyclizatio n of cyclic alkenols.19 By using molecular oxygen as reoxidant in the presence of Pd(OAc)2 in DMSO/O2 various cyclic alkenols were converted to bicyclic cyclopentafuran 2 at room temperature(scheme 2-2). 65

PAGE 88

Scheme 2-2 Pd(II) catalyzed intramolecular cy clization of cyclic alkenols Wolfe et al 20 have synthesized that various tetra hydrofuran analogs can be synthesized from aryl or vinyl bromides and -hydroxy alkenes. These reactions led to formation of a C-C and C-O bond along with establishment of two new stereocenters in good to moderate stereoselectivity. Recently Tanimori et al 21 has utilized palladium catalyzed allylic alkylation to obtain furan analogs in low to moderate yields as a mixture of diastereomers. All these processes emphasize the importa nce of Pd catalysis in synthesis of these furan analogs. There is always a sc ope for modifying these methodologies to improve the yields and minimize the use of expensive and toxic chemicals to make the whole process more environment-friendly. Henc e keeping all these factors in mind, this work tries to incorporate the use of hydrol ytic enzymes (lipases) to influence the stereochemical outcome of the products. 2.2.3 Isoxazoline ring systems in natura l products and their bioactivity As shown in figure 2-2 isoxazolines and rela ted ring systems are found in a large number of natural products and bioactive compounds.6-7 For example Calafianin, a bromotyrosine derivative was extracted from the mexican marine Sponge Aplysina gerardogreeni.22 Bromotyrosine alkaloids (figur e 2-2) containing an amino-imidazole system coupled to another aromatic system act as potent inhi bitors of mycobacterial enzyme, mycothiol Sconjugate amidase (MCA) which is found in Mycobacterium tuberculosis the causative 66

PAGE 89

agent of tuberculosis. Also some bicyclic is oxazolines (figure 2-2) have been used as mechanism-based inhibitors of human leukocy te elastase (HLE) and cathepsin G (Cath G) which are responsible for chronic infl ammatory diseases such as pulmonary emphysema, cystic fibrosis, psoriasis and rheumatoid arthritis.23 Apart from being found in large number of natural products isoxazoli nes have also been utilized in material science as nanoscale connectors in molecular electronic devices.24 O N H N N H O O O O N O O O Br Br Calafianin O N NH H3CO O Br N HN HN Br HO NH2 OH HO O OH Br O H2N NOH N O N H NH NH2 H N O N R O O OSO2R1 R,R1=Me,Et, i Pr, i Bu,Bn HOMs.HN N O O H N SO2HN CO2H O N H2N Bromotyrosinealkaloid1 Bromotyrosinealkaloid2 DMP802GPIIb/IIIaReceptorAntagonistBicyclicisoxazolines (HumanLeukocyteElastaseinhibitor) (InhibitorsofMycothiolS-ConjugateAmidase)Bromotyrosinederivativefromthe MarineSponge AplysinagerardogreeniFigure 2-2 Isoxazolines in natural products and other bioactive compounds 67

PAGE 90

2.2.4 Importance of isoxazolines in synthetic chemistry An isoxazoline ring system provides an attrac tive intermediate for syntheses of more complex systems and its analogs can be synthesized under mild conditions.6 The isoxazoline ring represents a fairly responsive heterocyclic system, fo r its treatment with the appropriate sort of reagent and can yield access to (a) -amino alcohols, (b) hydroxy ketones (and thus -unsaturated ketones, allyli c alcohols, 1,3-diols, and 1,3dienes), (c) -hydroxy nitriles, acids, and esters, and (d) and -unsaturated oximes (Scheme 2-3). Scheme 2-3 Use of 2-isoxazolines as key inte rmediates in organic synthesis. 68

PAGE 91

2.2.5 General method for the syntheses of isoxazoline-2-oxide and analogs The conventional strategy for the preparation of cyclic fiveand sixmembered nitronates (isoxazoline-2-oxides) involve s intramolecular O-alkylation of properly functionalized aliphatic nitro compounds (Scheme 2-4, eq 1).6i, j Also, there is no general method for the synthesis of the these functionalized starting nitro compounds and each particular substrate requires special approach. Anothe r route for syntheses of these compounds involve a [4 + 2] cycloaddition between conjugate nitro alkenes and olefins (Scheme 2-4, eq 2)6g,h. Also these isoxazoline2-oxides 2 could be obtained by using nitrocarbenes as 1,3-dipoles in a 1,3-dipolar cycl oaddition (Scheme 2-4, eq 3).6a,b X NO2 n N O O n N OO N O ON OO N O O (1) (2) (3) (ref6i,j) (ref6g,h) (ref6a,b) Scheme 2-4 General methods for synthesis of isoxazoline-2-oxides Recently Kunetsky et al utilized 1,3 dipolar addition on halonitro compounds to obtain isoxazoline-2-oxides in moderate yiel ds after 2-7 days (scheme 2-5a).6a,b It was also found that the rate of cycloaddition increases in the order I < Cl ~ Br << F due to low activation energy6a in the case of F-analogs. This wa s also proved by the experimental conditions, for example the fluoro nitro compounds took 2 days at room temperature to yield the isoxazoline-2-oxides wherea s the bromo analogs took 3-7 days. 69

PAGE 92

Scheme 2-5a Synthesis of isoxazoline-2-oxides from fluoronitro compoundsvia cycloaddition R1 O R3 R2 Br NO2 EtOOC R1 O R3 R2 Br EtOOC NO2 Base N O EtOOC R1 R2 R3 O O Scheme 2-5b Tandem nitroaldol-ring closure of nitroacetic esters to synthesize isoxazoline-2-oxides Rosini et al have used a tandem nitroaldolring closure of ethyl nitroacetate with bromo enones to obtain isox azoline-2-oxides (scheme 2-5b).25 These reactions was tried under homogeneous as well as heterogeneous c onditions giving similar results. The rate and the yield of the reaction depended on the degree of substitution of the enone carbon. 2.3 Pd catalyzed Syntheses of Furan and Isoxazoline-2-oxides 13 a-h The syntheses of furan and isoxazoline-2-oxi de analogs (Scheme 2-6) were achieved by an intramolecular Pd(0) cat alyzed cyclization and also involves enzymatic desymmetrization of meso starting materials. The synthe tic approach described in this work brings the best of both (chemical and enzymatic) approaches in organic synthesis. 70

PAGE 93

Scheme 2-6 General procedure for syntheses of Isoxazoline-2-oxides and furan analogs via Pd catalyzed alkylation of allylic acetates 5, 9 and 10 2.3.1 Synthesis of five membered cycl ic allylic acetates 5, 9 and 10 The syntheses begins with a retro Diels-Alder re action where commercially available dicyclopentadiene was heated to 1700C to obtain the monomer cyclopentadiene (Scheme 2-7). The momoner thus obtained was oxidize d using peracetic acid to its monoepoxide (racemic).26 The monoepoxide was subsequently tr eated with acetic anhydride in the presence of Pd(PPh3)4 to obtain the meso -3,5-diacetoxycyclopentene ( 4). The desymmetrization of the meso diacetate ( 4) with lipase gave th e (+)-monoacetate ( 5) which was the pivotal chiral induction reacti on (Scheme 2-7). Unlike in resolution of a racemic substrate, in which the yield per enantiomer is limited to 50%, the desymmetrization of the meso diacetate allowed conversion of highe r than 97% to the enantiomerically pure single enantiomer.27 A simple protection/ deprotection strategy would enable access to the other enantiomer. 71

PAGE 94

DicyclopentadieneD=+68.9 []205 CH3CO3H NaOAc,CH2Cl200C O meso -4OAc AcO HO OAc 3lipasePS-30 pH=7phosp.bufferCyclopentadiene(>99%ee)Scheme 2-7 Synthesis of allylic monoacetate 5 via lipase catalyzed hydrolysis Enzymatic asymmetric induction is a powerful tool in developing elegant synthetic methodologies for natural products.28 A chemoenzymatic approach to enantioselective synthesis of both ( R and S) enantiomers of imperanene, a platelet aggregation inhibitor was recently reported from our laboratories.29 Desymmetrization of meso compounds is an extremely important reac tion and involves elimination of one or more symmetry elements in the substrat e. A large number of compounds including alcohols, esters, anhydrides, nitriles have been subjected to enzymatic desymmetrizations.28c Hydrolases are the enzymes wh ich have shown immense potential in carrying out these desymmetrizations. Out of all the hydrolases, lipases have been extensively used.28e For example, meso -2-Cycloalken-1,4-diols a nd diacetates have been subjected to enzymatic desymmetri zations utilizing lipase B from Candida antarctica (Novo SP-435) in organic and aqueous media.28e Of a number of different available lipases in our laboratories, the lipase from Pseudomonas cepacia (PS-30) was used to carry out hydrolytic desymme trization of the diacetate.28 PS-30 catalyzed reaction of 72

PAGE 95

meso -diacetate 4 produced monoacetate 5 in high enantiopurity (>97%) and 60% yield. The recovered diacetate was again subjected to hydrolysis with the recovered enzyme to obtain enantiopure monoacetate ( 5, [ ]D 20 (CHCl3) = +68.9; lit 27 [ ]D 20 (CHCl3) = +69.6) in total yield of 90%. The ab solute stereochemistry of th e monoacetate was established upon its comparison with the literature data27,28e as (+)-(1 S, 4R )4-acetoxycylcopent-2en-1-ol. The enantiopurity of monoacetate 5 was confirmed by GC analyses of the racemic and enzymatically prepared monoacetate on a cylcodexB (30m X 0.25mm, J&W scientific) chiral capillary column. HO OAc PCC CH2Cl2 O OAc excessR3Li Ether,-780C HO OH R3 Ac2O,DMAP THF HO OAc R3 5 6 7-8 9-107,9 :R3=Me 8,10 :R3= ; C C Ph Scheme 2-8 Syntheses of substituted ter tiary allylic monoacetates 9-10 by addition of alkyl lithiums. In order to study the ve rsatility of the pallad ium catalyzed methodology the monoacetate 5 was further modified by a series of transformations into other allylic monoacetated bearing a tertiary hydroxyl gr oup. As shown in scheme 2-8 enantiopure monoacetate 5 was oxidized to ketone 6 using PCC (pyridinium chlorochromate) in the presence of sodium acetate in CH2Cl2 .30 The unsaturated ketone 6 was treated with various alkyl lithiums to generate the cis -diols, 7 and 8 as the major product (>98%). Spectral data for compounds 7 was in complete agreement with 1H and 13C spectral data reported in the literature.31 Importantly, compound 8 produced colorless orthorhombic crystals and single crystal X -ray diffraction experiment co nfirmed that the two hydroxyl groups are on the same side of the cyclopentene ring thus confirming the cis relationship. 73

PAGE 96

74 The ORTEP plot and the diffr action data is included in section 2.5.2. The absolute stereochemistry of the molecule was also established as (1 S, 4R ). This preference for the formation of syn isomer 7 and 8 can be explained on the basis of the steric and electronic factors. The acetoxy group in compounds 7 and 8 is in the beta face hence it directs the incoming nucleophile (alkyl lithium) from alpha phase due to steric factors giving a syn diol. Furthermore, the acetoxy group in the st arting material when attacked by the alkyl lithium will form an alkoxide which will repel any nucleophile coming from the same (beta) face hence again favoring an alpha attack to give a syn product. The next step involved the synthesis of allylic acet ates which would set up the stage for the first palladium cataly zed allylic alkylati on. Hence, the diols 7 and 8 were treated with one mole of ace tic anhydride and catalytic am ount of DMAP to obtain the corresponding monoacetates 9 and 10 in quantitative yields (Scheme 2-8). 2.3.2 Pd catalyzed allylic alkylation of cyclic acetates 5, 9 and 10 using soft nucleophiles The monoacetates were then subjected to pa lladium catalyzed allylic alkylation using various active methylene compounds (soft nu cleophiles) as nitro and cyano esters, malonate diesters, sulphones (scheme 2-9). Pd catalyzed alkylation could result in formation of a 1,2or 1,4-adduct,32 but under the conditi ons studied the reaction proceeds with high regioand stereo-selectivity to give the 1,4 adducts, 11a-i The stereochemistry of the Pd-catalyzed alkylation has been studi ed extensively and is known to proceed with retention of configuration via double inversion.32

PAGE 97

O2N COOEt Pd(0),PPh3Base11a-c HO COOEt NO2 R3 HO OAc MeOC COOEt Pd(0),PPh3Base R3 11d-e HO COOEt COMe R3 5,9-10PhOC SO2Ph Pd(0),PPh3Base11f-h HO COPh SO2Ph R3 R3=H,Me, Ph NC COOEt Pd(0),PPh3Base11i HO COOEt CN HO OAc NC SO2Ph Pd(0),PPh3Base11j HO SO2Ph CN 5MeOOC COOMe Pd(0),PPh3Base11k HO COOMe COOMe Base:K2CO3,NaH,KOtBu Pd(0)=Pd(PPh3)4,Pd2dba3.CHCl3Scheme 2-9 Pd catalyzed allylic alkylation of acetates 5, 9, 10 using various active methylene compounds. As shown in scheme 2-9 allylic acetates 5, 9, 10 were coupled with various active methylene compounds using Pd (0) catalysis. Di fferent bases such as NaH, potassium 75

PAGE 98

tert-butoxide were used but potassium carbonate gave superior results and was used as the base for further investigations. Out of the various solvents used (CH2Cl2, diethyl ether) THF was chosen to carry out all the r eactions due to ease of handling and superior results. HO OAc 1 2 3 4 5 Pd(0) HO HO Pd(II) OAc L OAc coordination oxidativeaddition +L -OAc HO Pd(II) L L E' E HO E' E HO E' E ligand exchange substitutionthen reductiveelimination6 1 2 3 4 5Scheme 2-10 General catalytic cycle for Pd (0) catalyzed allylic alkylation using active methylene compounds. As evident from the mechanism for th ese alkylations (Scheme 2-10) compound 11a-j would be a mixture of a pair of diastereomers at the site of the carbon-carbon bond formation (C6). The diastereomeric ratio of 11a-j determined from integral value of the H-6, H-2, and H-3 resonances in their 1H spectra was calculated to be ~ 1:1 (Table 2-1). These pairs of diastereomers were inse parable on a chromatographic column and appeared as a single spot on a TLC plate. As the diastereotopic center (C-6) is prone to racemization (because of its proximity to the electron withdrawing groups) and is 76

PAGE 99

77 involved in generation of a carbanion in the following steps, no efforts were devoted to its resolution and the mixture was taken for further steps without separation. Table 2-1 Diastereomeric ratio & yields for Pd(0) catalyzed allylic al kylation of acetates 5, 9 and 10 Compound R1 R2 R3 Diastereomeric Ratioa Yield b 11a NO2 CO2Et H 1.07:1 62 11b NO2 CO2Et Me 1.12:1 70 11c NO2 CO2Et C C-Ph 1.13:1 60 11d COMe CO2Et H 1.04:1 68 11e COMe CO2Et Me 1.28:1 65 11f COPh SO2Ph H 1.07:1 68 11g COPh SO2Ph Me 1.15:1 71 11h COPh SO2Ph C C-Ph 1.06:1 61 11i CN COOEt H 1.05:1 60 11j CN PhSO2 H 1.23:1 68 11k CO2Me CO2Me H 73 a Diastereomeric ratio based on 1H-NMR analyses. b Isolated yields 2.3.3 Pd(0) catalyzed intramolecu lar cyclization to synthesize furan and isoxazoline2-oxide analogs The alcohols 11a-k offer another allylic system which can be further utilized to carry an intramolecular Pd(0) catalyzed cyclization to give furan or iosxazoline-2-oxide systems. Hence, the allylic alcohols 11a-k were acetylated using ace tic anhydride and catalytic amount of DMAP in THF (scheme 2-11).

PAGE 100

Ac2O,DMAPTHF1 2 a c11a-c HO COOEt NO2 R3 AcO COOEt NO2 R3 Ac2O,DMAPTHF1 2 d e11d-e HO COOEt COMe R3 AcO COOEt COMe R3 Ac2O,DMAPTHF1 2 f h11f-h HO COPh SO2Ph R3 AcO COPh SO2Ph R3 Ac2O,DMAPTHF1 2 i11i HO COOEt CN AcO COOEt CN Ac2O,DMAPTHF1 2 j11j HO SO2Ph CN AcO SO2Ph CN Ac2O,DMAPTHF1 2 k11k HO COOMe COOMe AcO COOMe COOMe R3=H,Me, Ph R3=H,Me, Ph R3=H,Me, Ph Scheme 2-11 Synthesis of acetates from allylic alcohols 11 a-k The secondary acetates 12 a, d, f, i-k were quite stable and were purified by column chromatography. Most tertiary a cetates with the exception of 12b were unstable and not amenable to purification on chromatographi c columns and hence, were subjected to palladium catalyzed alkylation w ithout any further purification. 78

PAGE 101

Scheme 2-12 Synthesis of bicyclic furan and isox azoline-2-oxides via Pd(0) catalyzed intramolecular cyclization Allylic acetates 12 were subjected to palladium catal yzed intramolecular cyclization in the presence of K2CO3 and Pd(PPh3)4 to yield bicyclic fura n and isoxazoline-2-oxides (scheme 2-12). Nitro esters 12a-c resulted in the formation of optically pure isoxazoline-79

PAGE 102

2-oxides. Keto-esters 12d-e and sulphones 12f-h resulted in the formation of cyclopentafuran compounds 13d-h ( table 2-2 ) Table 2-2 Yields and optical rotation data for bicyclic furan and isoxazoline-2-oxide analogs 13a-h Compound R1 R2 R3 Yielda D 20 (CH2Cl2) 13a NO2 CO2Et H 85 -95.2 13b NO2 CO2Et Me 64 -90.4 13c NO2 CO2Et C C-Ph 63 -182.3 13d Me CO2Et H 85 -77.8 13e Me CO2Et Me 57 -146.1 13f Ph SO2Ph H >98 -20.0 13g Ph SO2Ph Me 59 -16.7 13h Ph SO2Ph C C-Ph 65 -15.0 13i CN COOEt H b 13j CN SO2Ph H b aproduct isolated after column chromatography. bStarting material was recovered. It is noteworthy to mention that starting from a meso -diol, optically pure compounds were prepared without utilizing chiral lig ands at any stage of the reaction. The stereochemical outcome of the prod uct is solely influenced by the Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations. Literature reports on synthesis of the fu ran derivatives have been catalyzed by palladium(0) in presence of chiral lig ands leading to, at best, modest enantioenrichments.21,33 The cyclization reactions were also evaluated in presence of various bases, i.e., NaH, K2CO3, K t OBu (Scheme 2-12) in THF using catalytic amount of 80

PAGE 103

Pd(0) catalysts. The yield of the reaction wa s independent of the base used. For all reactions recorded in table 22 reaction was performed using K2CO3 as the base. Pd(PPh3)4 and Pd2(dba)3 were the two Pd(0) catalysts evaluated in this reaction and identical results were obtained. Pd(II) catalysts like PdCl2 did not catalyze the cyclization. The cyclizations were also attempted in abse nce of base or catalys t and such variations did not give the desired product indicating that both base and the catalyst are vital for this cyclization. Scheme 2-13 Mechanism for formation of bicyclic furan and isoxazoline-2-oxides via Pd(0) catalyzed intramolecular cyclization Mechanism for formation of compound 13a-h is shown in Scheme 2-13, where the base deprotonates the methine pr oton between the two electron-withdrawing groups. The carbanion thus generate d results in the formation of 13a-h via electron-flow through NO2 group (for isoxazoline-2-oxides) or e nolate oxygen (for furan) (Scheme 212). The stereochemical outcome of the reaction is the result of two sequential steps. First the formation of the Pd -allyl complex occurs on the oppo site side of the OAc leaving group because of steric control. In the second step, the attack of the nucleophile proceed 81

PAGE 104

82 in an anti fashion with respect to metal resulti ng in a highly stereoselective reaction.34 One of the isoxazoline-2-oxide, 13c produced colorless orthorhombic crystals. The single crystal X-ray diffraction experiment confirmed its structure (figure E2). Unfortunately, the X-ray data could not establish the absolute stereochemistry of 13c but it is deduced through the stereochemistry of the monoacetate 5 as (1 S,5S) -3-aza-4-(ethoxycarbonyl)-7phenylethynyl-2-oxabicyclo[3.3.0] oct-3,7-diene-3-oxide. Compounds 12i-j containing a cyano group, did not give the desired bicyclic system; starting material wa s always recovered and confirmed by 1H NMR. Even though compounds 12 i,j have an acidic proton which could be deprotonated by a base as shown in general mechanism (scheme 2-13) but the resultant bicyclic structure will have a highly strained aza-allene system, hence th ese two cyano esters did not cyclize when subjected to palladium catalysi s in the presence of a base. In order to obtain the ee compound 13a was treated with chiral shiftreagent, Europium tris[3-(hepta-fluoropr opylhydroxymethylene)-(+) -camphorate] and 1H NMR indicated enantiome ric excesses for compound 13a to be >97%. Figure 2-3 shows 1H NMR comparison of racemic and enantioenriched 13a in presence (+)-Eu(hfc)3. The H3 signals were used for calculation of % ee. The absence of doublet at 5.9 ppm in enantioenriched 13a indicated >97% ee.

PAGE 105

O N O COOEt 1 2 3 4 5 6 (b) (a) H-1 H-1 H-2 H-2 H-3 O N O COOEt 1 2 3 4 5 6(-) H-3 (-) (-) (+)() Figure 2-3 1H-NMR of compound 13a in the presence of (+)Eu(hfc)3 (a) Enantioenriched (b) Racemic Interestingly, compound 12k led to an unusual product 13k containing an exocyclic double bond. The formation of this unusual product can be explained by the interconversion between the two -allyl complexes I and II (Scheme 2-14).35 Recently Buono et al have studied Pd(0) catalyzed alkylation of a bicyclic allylic diacetate with stabilized nucleophiles such as malonate s and have proposed the interconversion of allyl complexes as the one shown in scheme 2-14.35 83

PAGE 106

AcO CO2CH3 CO2CH3 H Base Pd(PPh3)4,THF CO2CH3 CO2CH3 12k 13k H CO2CH3 CO2CH3 L2Pd H CO2CH3 CO2CH3 L2Pd H CO2CH3 CO2CH3 H B H B I II Scheme 2-14 Proposed mechanism for the formation of 13k from 12k via interconversion of the -allyl complexes I and II 2.4 Conclusion In summary, Pd catalyzed cyclization wa s utilized to obtain optically pure furan and isoxazoline-2-oxide analogs in a practical manner utiliz ing mild reaction conditions. The method involves tandem use of the enzy matic and chemical catalysis. It is noteworthy to mention that starting from a meso -diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the reacti on. The stereochemical outcome of the product is solely influenced by the Pseudomonas cepacia lipase and the stereoselective nature of the palladium catal yzed transformations. The key step is the desymmetrization of the meso diacetate ( 5) using commercially available Pseudomonas cepacia lipase (PS-30), in high ee. Hence, this methodology trie s to minimize the use of chiral ligands and again proves the importance and utility of enzymes in organic syntheses. The Pd(0) catalyzed cyclization is compatible with a wide spectrum of functional groups like NO2, COOR, COR, SO2R. This work provides a new pathway to 84

PAGE 107

85 obtain optically pure furan a nd isoxazoline-2-oxide analogs which are rather difficult to obtain via previous strategies. 2.5 Experimental 2.5.1. General Lipase PS-30 was generous gifts from Amano Enzymes. 1H-NMR and 13C-NMR spectra were recorded on a Brucker 250 MHz and Varian 400, 500 MHz spectrometer in CDCl3 and acetone-d6 with TMS as the standard. Chemical shifts are reported in ppm, multiplicities are indicated by s (singlet), d (doubl et), t (triplet), q (quartet), p (quintet), h (sextet), m (multiplet) and bs (broad singlet ). Optical rotations were measured with a Rudolph Research Analytical AutoPol IV Automatic polarimeter. Thin-Layer chromatography (TLC) was performed on glas s plates coated with 0.25 mm thickness of silica-gel. All solvents were dried and disti lled prior to use and organic solvent extracts were dried over Na2SO4. Mass measurements were carried out on an ESI LC MS system (Agilent Technologies). GC studies were carried out on Shimadzu gas chromatogram (Model 17A). A cyclodextrin column (30m X 0.25mm) from J&W Scientific was used for determining the ee of the monoacetate 5. 2.5.2 X-Ray Crystallography Single-crystal X-ray diffrac tion data for the compounds 8 and 13c was collected on a Bruker SMART-APEX CCD Diff ractometer with Kyroflex Low Temperature System using MoK radiation ( = 0.71073 ), operating in the and scan mode. Diffracted data were corrected for absorption using the SADABS program. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the

PAGE 108

Cambridge Crystallographic Da ta Centre as supplement ary publication numbers CCDC 622489 and 622490. For the crystal of (1 S, 4R )-1-Phenylethynyl-cyclopent-4-ene -1,4-diol, 4 molecules were found in each unit cell. The compound crys tallized in a orthorhombic space group P2 (1), with cell dimensions a=5.3082(10) b=8.4869(16) c=17.005(3) A total of 5642 unique reflection data were obtained to give a final R index [l>2 (I)] of R1 = 0.0337, wR2 = 0.0894 and R indices (all data) R1 = 0.0365, wR2 = 0.0918. 2.5.2.1 Crystallographic X-ray data for compounds 8 (1 S 4R )-1-Phenylethynylcyclopent-4-ene-1,4-diol Figure E1. Ortep plot for X-ray structure of (1 S, 4R )-1-Phenylethynyl-cyclopent-2-ene1,4-diol ( 8). 86

PAGE 109

87 Table E1. Crystal data and structure refinement for 8. Identification code kb0725 Empirical formula C13H12O2 Formula weight 200.23 Temperature 100(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 6.2734(9) = 90. b = 7.6864(11) = 90. c = 22.307(3) = 90. Volume 1075.6(3) 3 Z 4 Density (calculated) 1.236 Mg/m 3 Absorption coefficient 0.083 mm -1 F(000) 424 Crystal size 0.30 x 0.20 x 0.12 mm 3 Theta range for data collection 1.83 to 25.10. Index ranges -7<=h<=7, -9<=k<=7, -26<=l<=22 Reflections collected 5642 Independent reflections 1900 [R(int) = 0.0306] Completeness to theta = 25.10 99.7 %

PAGE 110

88 Absorption correction SADABS Max. and min. transmission 1.000 and 0.761 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 1900 / 0 / 141 Goodness-of-fit on F 2 0.872 Final R indices [I>2sigma(I)] R1 = 0.0337, wR2 = 0.0894 R indices (all data) R1 = 0.0365, wR2 = 0.0918 Absolute structure parameter -0.9(13) Largest diff. peak and hole 0.210 and -0.157 e. -3 2.5.2.2 X-ray crystallographic data for (13c). For the crystal of 13c 4 molecules were found in each unit cell. The compound crystallized in a orthorhombic space group P2(1)2(1)2(1), with cell dimensions a=6.630(4) b=10.067(6) c=21.631(11) A total of 3479 unique reflection data were obtained to give a final R index [l>2 (I)] of R1 = 0. 0626, wR2 = 0.1308 and R indices(all data) R1 = 0.0824, wR2 = 0.1444.

PAGE 111

Figure E2. Ortep plot for X-ray structure of compound 13c Table E2. Crystal data and structure refinement for 13c Identification code kb0825 Empirical formula C17H15NO4 Formula weight 297.30 Temperature 100(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 6.630(4) = 90. 89

PAGE 112

90 b = 10.067(6) = 90. c = 21.631(11) = 90. Volume 1443.7(15) 3 Z 4 Density (calculated) 1.368 Mg/m 3 Absorption coefficient 0.098 mm -1 F(000) 624 Crystal size 0.30 x 0.07 x 0.06 mm 3 Theta range for data collection 1.88 to 25.01. Index ranges -7<=h<=6, -11<=k<=8, -14<=l<=20 Reflections collected 3479 Independent reflections 2176 [R(int) = 0.0437] Completeness to theta = 25.01 87.8 % Absorption correction SADABS Max. and min. transmission 1.000 and 0.598 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2176 / 0 / 206 Goodness-of-fit on F 2 1.009 Final R indices [I>2sigma(I)] R1 = 0.0626, wR2 = 0.1308 R indices (all data) R1 = 0.0824, wR2 = 0.1444 Absolute structure parameter 0(3) Largest diff. peak and hole 0.251 and -0.201 e. -3

PAGE 113

91 2.5.3 Experimental procedure and characteri zation data for compounds 5 and 6. 2.5.3.1 (+)-(1 S 4R )4-acetoxylcylcopen t-2-en-1-ol (5).26-28 10g (0.054mol) of meso -diacetate 4,27, 28d was taken in a mixture of phosphate buffer (pH 7.0; 75ml) and acetone (5ml) in a round botto m flask. Lipase PS-30 (500mg) was added while maintaining the pH of the reaction mi xture at 7.0 using 1N NaOH solution. The reaction was stopped when no change in the pH of the reaction medium occurred. The conversion at this point was estimated to be ~60 % by tlc. The reaction mixture was extracted with ethyl acetate (3 x 200 mL ). The organic layer was dried over Na2SO4 and concentrated by rotoevaporation. The crude product was subjected to column chromatography over silica gel using ethyl acetate: hexane (1:3) to isolate the monoacetate 5 as a white solid, mp 40-42 C; D 20 (CHCl3) = +68.9; lit 27d D 20 (CHCl3) = +69.6); 1H NMR (CDCl3, 400 MHz): 1.60 (dt, 1H, J =14.8, 4.0 Hz), 2.01 (s, 3H), 2.76 (p, 1H, J =7.2 Hz), 4.6 (m, 1H), 5.4 (m, 1H), 5.94 (d, 1H, J =4.0 Hz), 6.06 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz): 20.5, 40.4, 74.6, 77.2, 132.3, 139.1, 171.3 ppm. 2.5.3.2 ( R )-4-Acetoxy-2-cyclopenten-1-one (6)30. viscous liquid; 1H NMR (CDCl3, 250 MHz): 2.03(s, 3H), 2.22 (dt, 1H, J =18.7, 2.2 Hz), 2.73 (dt, 1H, J =19.0, 6.75 Hz), 5.78 (m, 1H), 6.26 (d, 1H, J =5.7 Hz), 7.5 (m, 1H) ppm; 13C NMR (CDCl3, 62.5 MHz) : 20.8, 40.9, 71.9, 136.9, 158.9, 170.4, 204.8 ppm.

PAGE 114

92 2.5.4 General procedure for preparation of compounds 7 and 8. To a solution of ( R )-4-Acetoxy-2-cyclopenten-1-one 6 (200 mg, 1.428 mmol) in freshly distilled ether (15 ml) at -78 C was added 1.6 M solution of methyl lithium in ether (3.57 ml, 5.712 mmol) under a nitrogen atmosphere. The reaction was allowed to stir for 1h and was quenched using NH4Cl solution. The product was purified by column chromatography using ethyl acetate: hexane (2:1) to afford 7 (150 mg, yield =92%) as a viscous liquid. 2.5.4.1 (1 S 4R )-1-Methylcyclopent-2-ene-1,4-diol (7). viscous liquid; D 20(acetone) = +55.2 (c 0.02); 1H NMR (CDCl3, 250 MHz): 1.27(s, 3H, CH3), 1.71 (dd, 1H, J =14.5, 2.7 Hz), 2.29 (dd, 1H, J =14.5, 7.2 Hz), 3.9 (bs, 2H), 4.58 (d, 1H, J =6.2 Hz), 5.79 (m, 2H) ppm; 13C NMR (CDCl3, 62.5 MHz) : 27.5, 49.5, 75.2, 81.2, 134.0, 141.0 ppm. HRESIMS calcd for C6H11O2 ([M+H]+): 115.0759; found: 115.0758 2.5.4.2 (1 S 4R )-1-Phenylethynyl-cyclopent-4-ene-1,4-diol (8). White solid: mp=114116 C; D 20 (acetone) = +330.5 (c 0.11); 1H NMR (CDCl3, 250 MHz) : 1.97(s, 1H, OH), 2.00 (s, 1H, OH), 2.04 (dd, 1H, J =14.0, 3.2 Hz), 2.82 (dd, 1H, J =14.0, 6.7 Hz), 4.78 (dd, 1H, J =6.7, 3.2 Hz), 6.01 (s, 2H), 7.26-7.32 (m, 5H) ppm; 13C NMR ((CD3)2CO, 62.5 MHz) : 52.4, 75.0, 76.2, 83.3, 93.3, 123.9, 129.1, 129.3, 132.2, 136.9, 137.7 ppm. HRESIMS calcd for C13H13O2 ([M+H]+): 201.0916; found: 201.0921. 2.5.5 General procedure for preparation of compounds 9 and 10. To a solution of 7 (100 mg, 0.877 mmol) in dry THF (10 ml) at room temperature was added acetic anhydride (89 m g, 0.877 mmol), and catalyt ic amount of DMAP. The reaction was allowed to stir for 3h and then concentrated. The residue was taken in ethyl

PAGE 115

93 acetate (40 ml) and was treated twice with satu rated sodium bicarbonate solution (20 ml), followed by brine (10 ml). The organic layer was dried over sodi um sulfate and the resulting product 9 was purified by column chromatogr aphy using ethyl acetate: hexane (1:2) (80.25 mg, yield= 58.77%). 2.5.5.1 (1 R 4S )-4-Hydroxy-4-methyl-2-cyclo penten-1-yl Acetate (9): 1H NMR (CDCl3, 250 MHz) : 1.32 (s, 3H), 1.80 (dd, 1H, J =14.5, 3.5 Hz), 1.97 (s, 3H), 2.2 (bs, 1H), 2.36 (dd, 1H, J =14.5, 7.5 Hz), 5.46 (m, 1H), 5.76 (d, 1H, J =5.5 Hz), 5.92 (d, 1H, J =5.5 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz) : 21.2, 27.3, 46.7, 77.6, 80.9, 130.2, 143.2, 170.8 ppm. HRESIMS calcd for C8H13O3 ([M+H]+): 157.0865; found: 157.0871. 2.5.5.2 (1 R 4S )-4-Hydroxy-4-phenylethynyl-2-cyclopeneten-1-yl Acetate (10). viscous liquid; 1H NMR (CDCl3, 250 MHz) : 1.98 (s, 3H), 2.09 (dd, 1H, J =14.5, 3.7 Hz), 2.82 (s, 1H), 2.91 (dd, 1H, J =14.5, 7.2 Hz), 5.6 (m, 1H), 5.92 (dd, 1H, J =5.5, 2.2 Hz), 6.07 (d, 1H, J =5.5 Hz), 7.20-7.35 (m, 5H) ppm; 13C NMR (CDCl3, 62.5 MHz) : 21.2, 47.8, 76.0, 77.1, 84.5, 90.2,122.2, 128.3, 128.6, 131.6, 132.0, 139.7, 170.9 ppm. HRESIMS calcd for C15H15O3 ([M+H]+): 243.1021; found: 243.1018. 2.5.6 General procedure for preparatio n of compounds 11a-k (Scheme 2-9). To a solution of ethyl nitroacetate (100 m g, 0.752 mmol) in dry TH F (10 ml) at room temperature was added potassium carbona te (110 mg, 0.800 mmol) under a nitrogen atmosphere. The reaction was allowed to stir for 20 minutes and Pd(PPh3)4 (43.4 mg, 0.037 mmol), PPh3 (197 mg, 0.752 mmol), monoacetate 5 (106 mg, 0.752 mmol) dissolved in 5 ml THF was added to it. The reaction was allowed to stir at 40 0C for 12 h and then vacuum filtered through celite with s ubsequent concentration of the filtrate. The

PAGE 116

94 product was purified by column chromatogra phy using ethyl acetate : hexane (1:2) to afford 11a (120 mg, yield =62%) as a yellow viscous liquid. 2.5.6.1 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-2-cyclopenten-1-yl)-2-nitroacetate (11a). viscous yellow liquid; 1H-NMR (CDCl3, 400 MHz) : 1.25 (t, 3H, J =7.2 Hz), 1.57 (m, 1H), 1.92 (bs, 1H), 2.50 (m, 1H), 3.46 (t, 1H, J =2.4 Hz), 4.23 (q, 2H, J =6.8 Hz), 4.79 (bs, 1H), 5.06 (t, 1H, J =8.0 Hz), 5.74-5.83 (dd, 1H, J =6.0, 4.8 Hz), 5.95-5.97 (m, 1H). 13C-NMR (CDCl3, 100 MHz) : 14.0, 36.2, 36.8, 45.4, 45.1, 63.3, 76.0, 76.3, 91.0, 91.4, 131.6, 132.0, 137.7, 137.9, 163.8, 163.9 ppm. HRESIMS calcd for C9H14NO5 ([M+H]+): 216.0872; found: 216.0875. 2.5.6.2 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-4-methyl-2-cyclopenten-1-yl)-2nitroacetate (11b). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.21 (t, 3H, J =7.5 Hz), 1.34 (s, 3H), 1.79 (dt, 1H, J =14.2, 5.0 Hz), 1.95 (bs, 1H), 2.19 (dd, 1H, J =14.2, 8.2 Hz), 3.50 (m, 1H), 4.19 (q, 2H, J =7.5 Hz), 5.03 (t, 1H, J =8.2 Hz), 5.59 (2 dd, 1H, J =5.5, 2.0 Hz), 5.82 (dt, 1H, J =5.5, 2.0 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 13.9, 27.5,27.6, 42.2, 42.8, 45.1, 45.5, 63.1, 82.1, 82.4, 90.6, 91.0, 129.1, 129.6, 141.8, 142.1, 163.7 ppm. HRESIMS calcd for C10H16NO5 ([M+H]+): 230.1029; found: 230.1034. 2.5.6.3 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-4-phenylethynyl-2-cyclopenten-1-yl)2-nitroacetate (11c). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz ) : 1.24 (dt, 3H, J =6.7, 1.0 Hz), 2.1 (m, 1H), 2.53 (d, 1H, J =2.7 Hz, OH), 2.74 (m, 1H), 3.65 (m, 1H), 4.19 (q, 2H, J =6.7 Hz), 5.06 (dd, 1H, J =9.0, 1.0 Hz), 5.79, 5.87 (2 dd, 1H, J =5.5, 2.0 Hz) 6.00 (dt, 1H, J =5.5, 1.7 Hz), 7.22-7.36 (m, 5H) ppm; 13C-NMR (CDCl3, 62.5 MHz)

PAGE 117

95 :13.9, 43.7, 44.4, 44.9, 45.2, 63.21, 63.26, 76.5, 77.5, 85.2, 89.8, 90.6, 90.8, 122.1, 128.3, 128.7, 131.5, 131.6, 132.0, 138.8, 138.9, 163.5 ppm. HRESIMS calcd for C17H18NO5 ([M+H]+): 316.1185; found: 316.1180. 2.5.6.4 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-2-cyclopenten-1-yl)-3-oxobutanoate (11d). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.18 (t, 3H, J =7.2 Hz), 1.28 (t, 1H, J =7.0 Hz), 2.18 (s, 3H), 2.37 (p, 1H, J =7.2 Hz), 3.19 (m, 1H), 3.45 (m, 1H), 4.14 (q, 2H, J =7.2 Hz), 4.6 (m, 1H), 5.67-5.83 (m, 2H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.2, 29.7, 29.9, 37.2, 37.8, 43.1, 43.2, 61.0, 64.7, 65.1, 76.22, 76.28, 134.2, 134.6, 135.2, 135.5, 168.7, 169.0, 202.61, 202.66 ppm. HRESIMS calcd for C11H17O4 ([M+H]+): 213.1127; found: 213.1134. 2.5.6.5 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-4-methyl-2cyclopenten-1-yl)-3oxobutanoate (11e). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.20 (t, 3H, J =7.0 Hz), 1.29 (s, 3H), 1.50-1.71 (2 dd, 1H, J =14.0, 5.2 Hz), 2.16 (m, CH3+H-5), 2.55 (bs, 1H, OH), 3.24 (m, 1H), 3.47 (dd, 1H, J =8.7, 3.0 Hz), 4.13 (q, 2H, J =7.0 Hz), 5.525.62 (2 dd, 1H, J =5.2, 2.5 Hz), 5.7 (dd, 1H, J =5.5, 2.0 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.0, 27.5, 29.6, 30.0, 43.3, 43.5, 43.6, 44.2, 61.4, 64.1, 64.2, 82.2, 82.3, 131.8, 132.3, 139.7, 140.0, 168.8, 169.1, 202.3 ppm. HRESIMS calcd for C12H19O4 ([M+H]+): 227.1283; found: 227.1280. 2.5.6.6 2-Phenylsulfonyl (2 R / S 1 R 4 S )-2-(4-hydroxy-2-cyc lopenten-1-yl)-1phenyl-ethanone (11f). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.26-2.2 (dt, 1H, J =14.0, 4.5 Hz), 2.52 (m, 2H), 3.32 (m, 1H), 4.67-4.80 (m, 1H), 5.05 (dd, 1H, J =21.2, 9.5 Hz), 5.45-5.49 (ddd, 1H, J =5.7, 2.5, 1.0 Hz), 5.8-5.9 (dt, 1H, J = 5.7, 2.5 Hz),

PAGE 118

96 7.3-7.7 (m, 10H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 38.2, 38.4, 43.5, 44.0, 74.0, 74.3, 75.7, 128.7, 128.8, 128.9, 129.7, 129.8, 133.7, 13 4.0, 134.2, 134.6, 136.2, 137.1, 137.17, 192.9, 193.3 ppm. HRESIMS calcd for C19H19O4S ([M+H]+): 343.1094; found: 343.1097. 2.5.6.7 2-Phenylsulfonyl (2 R / S 1 R 4 S )-2-(4-hydroxy-4-methyl-2-cyclopenten-1yl)-1-phenyl-ethanone (11g). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.36 (s, 3H), 1.49 (dd, 1H, J =14.0, 5.0 Hz), 2.05 (m, 1H), 2.29 (s, 1H, OH), 3.16-3.39 (m, 1H), 5.14 (dd, 1H, J =9.7, 2.5 Hz), 5.53, 5.78 (from 2 di astereomers) (2 dd, 1H, J =5.5, 2.5 Hz), 6.14 (dd, 1H, J =5.2, 1.7 Hz), 7.29-7.86 (m, 10H). 13C-NMR (CDCl3, 62.5 MHz) : 27.5, 29.6, 43.3, 43.5, 43.6, 44.2, 64.1, 64.2, 82.2, 82.3, 127.9, 128.4, 128.5, 128.74, 128.76, 130.1, 130.4, 131.8, 132.3, 132.6, 133.8, 180.9, 190.4 ppm. HRESIMS calcd for C20H21O4S ([M+H]+): 357.1161; found: 357.1158. 2.5.6.8 2-Phenylsulfonyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-4-phenylethynyl-2cyclopenten-1-yl)-1-phenyl-ethanone (11h). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.72 (dd, .5H, J =14.2, 4.0 Hz), 2.47 (dd, .5H, J =14.2, 7.2 Hz), 2.73 (m, 2H), 3.47 (m, 1H), 5.15 (dd, .5H, J =15.0, 10.0 Hz), 5.49 (dd, .5H, J =5.2, 2.0 Hz), 5.84 (dd, 1H, J =5.2, 1.5 Hz), 5.99 (dd, .5H, J =5.2, 1.0 Hz), 6.47 (dd, .5H, J =5.2, 2.2 Hz), 7.157.86 (m, 15H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 43.5, 44.1, 45.4, 45.7, 73.5, 73.9, 76.5, 77.4, 84.9, 85.0, 90.2, 90.4, 122.2, 122.3, 128.3, 128.3, 128.5, 128.8, 128.92, 128.97, 129.7, 129.8, 131.6, 131.7, 133.9, 134.1, 134.2, 135.1, 136.9, 137.04, 137.08, 137.2, 137.6, 192.8, 193.2 ppm. HRESIMS calcd for C27H23O4S ([M+H]+): 443.1317; found: 443.1321.

PAGE 119

97 2.5.6.9 Ethyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-2-cyclopent en-1-yl)-2-cyanoacetate (11i). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.27 (t, 3H, J =7.7 Hz), 1.5 (tt, 1H, J =14.2, 4.0 Hz), 2.47 (s, 1H, OH), 2.56 (m, 1H), 3.23 (m, 1H), 3.53 (d, 1H, J =6.7 Hz), 4.2 (q, 2H, J =7.7 Hz), 4.76 (m, 1H), 5.73-5.83 (dt, 1H, J =5.5, 1.2 Hz), 5.99 (m, 1H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 13.9, 36.8, 43.0, 44.5, 44.8, 62.9, 76.0, 76.1, 116.1, 116.2, 132.0, 132.4, 137.6, 137.7, 165.3, 165.4 ppm. HRESIMS calcd for C10H14NO3 ([M+H]+): 196.0974; found: 196.0977. 2.5.6.10 Phenylsulfonyl (2 R / S 1 R 4 S )-2-(4-Hydroxy-2-cyclopenten-1-yl)-2acetonitrile (11j). viscous yellow liquid; 1H-NMR (CDCl3, 250 MHz) : 1.6 (dq, 1H, J =14.0, 4.5 Hz), 2.2 (bs, 1H, OH), 2.58 (m, 1H), 3.43 (m, 1H), 3.99 (dd, 1H, J = 27.2, 4.5 Hz), 4.76 (s, 1H), 5.76-6.02 (m, 2H), 7.55-7.71 (m, 5H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 37.1, 38.8, 41.6, 42.2, 61.9, 62.1, 75.8, 76.2, 113.5, 113.7, 129.4, 129.8, 131.71, 131.75, 135.43, 135.47, 136.2, 136.3, 138.32, 138.35 ppm. HRESIMS calcd for C13H14NO3S ([M+H]+): 264.0694; found: 264.0688. 2.5.6.11 2-(4-Hydroxy-cyclopent-2-enyl)-ma lonic acid dimethyl ester (11k). viscous liquid; 1H-NMR (CDCl3, 400 MHz) : 1.33 (m, 1H, J =14.0, 4.5 Hz), 2.35 (p, 1H, J =7.6 Hz), 3.05 (m, 2H), 3.30 (t, 1H, J =7.6 Hz), 3.58 (s, 6H), 4.63 (s, 1H), 5.67(d, 1H, J =5.2 Hz), 5.74 (s, 1H) ppm; 13C-NMR (CDCl3, 100 MHz) : 37.6, 43.8, 52.6, 56.4, 76.3, 134.1, 135.9, 169.0, 169.2 ppm. HRESIMS calcd for C10H15O5 ([M+H]+): 215.0919; found: 215.0922.

PAGE 120

98 2.5.7 General procedure for preparatio n of compounds 12a-k (Scheme 2-11). To a solution of 11a (100 mg, 0.465 mmol) in dry THF (10 ml) at room temperature was added acetic anhydride (51 mg, 0.5 mmol), and catalytic amount of DMAP. The reaction was allowed to stir for 3 hours and then concentrated. The residue was taken up in ethyl acetate (40 ml) and extracted twice with saturate d sodium bicarbonate solution (20 ml), followed by brine (10 ml). The orga nic layer was dried over sodium sulfate and the resulting product 12a (110 mg, yield= 92%) was obtained as light yellow liquid. 2.5.7.1 Ethyl (2 R / S 1 R 4 S )-2-(4-Acetoxy-2-cyclopenten-1-yl)-2-nitroacetate (12a). viscous liquid; 1H-NMR (CDCl3, 400 MHz) : 1.25 (t, 3H, J =7.2 Hz), 1.54-1.69 (m, 1H), 1.97 (s, 3H), 2.53-2.61 (m, 1H), 3.51 (bs, 1H), 4.25 (q, 2H, J =7.2 Hz), 4.96 (t, 1H, J =8.8 Hz), 5.58 (bs, 1H), 5.89-5.98 (m, 2H) ppm; 13C-NMR (CDCl3, 100 MHz) : 14.0, 21.3, 33.2, 33.7, 44.7, 44.8, 63.3, 78.1, 78.4, 91.1, 91.3, 133.8, 134.0, 134.3, 134.7, 163.5, 170.8 ppm. HRESIMS calcd for C11H16NO6 ([M+H]+): 258.0977; found: 258.0978. 2.5.7.2 Ethyl (2 R / S 1 R 4 S )-2-(4-Acetoxy-4-methyl-2cyclopenten-1-yl)-2nitroacetate (12b). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.21 (t, 3H, J =7.0 Hz), 1.5(s, 3H), 1.91(s, 3H), 2.02 (dt, 1H, J =14.2, 4.5 Hz), 2.21 (m, 1H), 3.52 (m, 1H), 4.2 (q, 2H, J =7.0 Hz), 4.99 (dd, 1H, J =9.2, 2.0 Hz), 5.71 (dd, .5H, J =5.5, 2.5 Hz), 5.76 (dd, .5H, J =5.7, 2.5 Hz), 6.13 (dt, 1H, J =5.5, 2.0 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 13.9, 22.0, 24.5, 24.6, 40.3, 41.0, 44.5, 45.0, 63.1, 90.1, 90.4, 90.8, 131.2, 131.6, 138.6, 138.8, 163.5, 170.4 ppm. HRESIMS calcd for C12H18NO6 ([M+H]+): 272.1134; found: 272.1131.

PAGE 121

99 2.5.7.3 Ethyl (2 R / S ,1 R ,4 S )-2-(4-Acetoxy-4-phenylethynyl -2-cyclopenten-1-yl)-2nitroacetate (12c). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.14 (dt, 3H, J =7.2, 2.0 Hz), 1.98(s, 3H), 2.24 (m, 1H), 2.83 (m, 1H), 3.68 (m, 1H), 4.18 (dq, 2H, J =7.0, 1.5 Hz), 4.97 (dd, 1H, J =9.2, 5.5 Hz), 5.9 (m, 1H), 6.27 (dt, 1H, J =5.5, 2.0 Hz), 7.19-7.35(m, 5H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 13.9, 21.6, 41.9, 42.4, 44.4, 44.8, 63.2, 63.3, 81.9, 82.1, 86.3, 86.7, 90.5, 122.0, 128.2, 128.7, 131.8, 133.2, 133.7, 135.9, 136.2, 163.3, 169.1 ppm. HRESIMS calcd for C19H20NO6 ([M+H]+): 358.1291; found: 358.1294. 2.7.7.4 Ethyl (2 R / S ,1 R ,4 S )-2-(4-Acetoxy-2-cyclopenten-1-yl)-3-oxobutanoate (12d). viscous liquid; 1H-NMR (CDCl3, 250 MHz ) : 1.12 (t, 3H, J=7.2 Hz), 1.4 (t, 1H), 1.96 (s, 3H), 2.18 (s, 3H), 2.9 (p, 1H, J=7.5 Hz ), 3.33 (m, 2H), 4.03 (q, 2H, J=7.2 Hz), 5.5 (m, 1H), 5.81-5.82 (m, 2H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.1, 21.2, 29.4, 29.7, 34.6, 34.7, 42.9, 43.0, 61.5, 61.6, 65.2, 65.3, 78.8, 78.9, 131.2, 131.3, 137.5, 137.6, 168.3, 170.7, 201.0, 201.9 ppm. HRESIMS calcd for C13H19O5 ([M+H]+): 255.1233; found: 255.1231. 2.5.7.5 2-Phenylsulfonyl (2 R / S ,1 R ,4 S )-2-(4-Acetoxy-2-cyclopenten-1-yl)-1phenyl-ethanone (12f). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.85-1.97 (s, 3H), 2.2-2.6 (m, 2H), 3.2-3.4 (m, 1H), 4.50 (dd, 1H, J =27.2, 10.2 Hz), 5.4-5.6 (m, 1H), 5.7-5.9 (dt, 1H, J =5.5, 2.2 Hz), 6.5 (m, 1H),7.34-7.78 (m, 10H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 21.1, 21.2, 34.8, 35.6, 43.1, 43.8, 60. 4, 65.1, 74.0, 74.2, 76.6, 128.8, 128.83, 128.89, 128.97, 129.92, 132.5, 134.1, 134.3, 134.4, 135.9, 136.6, 136.9, 137.1, 137.6, 170.4, 170.6, 192.5, 192.9 ppm. HRESIMS calcd for C21H21O5S ([M+H]+): 385.1100; found: 385.1103.

PAGE 122

100 2.5.7.6 Ethyl (2 R / S ,1 R ,4 S )-2-(4-Acetoxy-2-cyclopent en-1-yl)-2-cyanoacetate (12i). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.26 (t, 3H, J =7.0 Hz), 1.65 (m, 1H), 1.9 (s, 3H), 2.57 (p, 1H, J =6.5 Hz), 3.25 (m, 1H), 3.4-3.58 (2 doublets, (0.5 x 2H), J=6.5 Hz), 4.23 (q, 2H, J =7.0 Hz), 5.59 (m, 1H), 5.89-5.99 (m, 2H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.0, 21.1, 33.8, 34.5, 42.7, 44.3, 62.9, 78.2, 78.3, 115.1, 133.5, 134.73, 165.1, 170.7, 170.8 ppm. HRESIMS calcd for C12H16NO4 ([M+H]+): 238.1079; found: 238.1080. 2.5.7.7 Phenylsulfonyl (2 R / S ,1 R ,4 S )-2-( 4-Acetoxy-2-cyclopenten-1-yl)-2acetonitrile (12j). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.76-1.9 (m, 1H), 2.0 (s, 3H), 2.67 (m, 1H), 3.41 (m 1H), 3.87-4.05 (2 doublets, 1H, J =6.25, 5.0 Hz), 5.55 (m, 1H), 5.91-6.05 (m, 2H), 7.56-7.98 (m, 5H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 20.1, 32.8, 34.5, 40.5, 40.6, 60.5, 60.8, 76.9, 77.0, 111.8, 128.4, 128.5, 132.8, 133.0, 133.2, 133.5, 134.4, 134.9, 135.1, 169.7, 169.6 ppm. HRESIMS calcd for C15H16NO4S ([M+H]+): 306.0800; found: 306.0814. 2.5.7.8 2-(4-Acetoxy-cyclopent-2-enyl)-malon ic acid dimethyl ester (12k). viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.56 (dt, 1H, J =14.0, 4.5 Hz), 2.05 (s, 3H), 2.54 (dt, 1H, J =14.0, 8.0 Hz), 3.33 (m, 2H), 3.77 (s, 6H), 5.6 (m, 1H), 5.88 (dt, 1H, J =5.7, 2.0 Hz), 6.00 (dt, 1H, J = 5.7, 2.0 Hz) ppm; 13C-NMR (CDCl3,100 MHz) : 21.0, 34.5, 43.4, 52.3, 52.4, 56.7, 78.7, 131.3, 137.2, 168.4(splits into 2), 170.6 ppm. HRESIMS calcd for C12H17O6 ([M+H]+): 257.1025; found: 257.1029.

PAGE 123

101 2.5.8 General procedure for preparation of compounds 13a-h, 13k (Scheme 2-12) To a solution of 12a (70 mg, 0.272 mmol) in dry THF (10 ml) at room temperature was added potassium carbonate (37.6 mg, 0.272 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol). The reaction was allowed to stir for 12 h at 60 0C and then vacuum filtered over celite with subsequent concentration of the filtrat e. The product was purified by wet column chromatography using ethyl acetate: hexane (1:2) to afford 13a using column chromatography as a yellow viscous liquid (45 mg, yield =85%). 2.5.8.1 (1 S ,5S )-3-Aza-4-(ethoxycarbon yl)-2-oxabicyclo[3.3.0]oct-3,7-diene-3-oxide (13a) : viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.29 (t, 3H, J =5.8 Hz), 2.63-2.78 (m, 2H), 4.17-4.28 (m, 3H, CH2+H-4), 5.56-5.62 (m, 1H), 5.75-5.78 (m, 1H), 6.09-6.12 (m, 1H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.0, 38.2, 44.6, 61.4, 84.2, 111.3, 127.7, 137.0, 158.9 ppm; HRESIMS calcd for C9H12NO4 ([M+H]+): 198.0766; found: 198.0762. 2.5.8.2 (1 S ,5S )-3-Aza-4-(ethoxycarbonyl)-7-methyl-2 -oxabicyclo[3.3.0]oct-3,7-diene3-oxide (13b) : viscous liquid; 1H-NMR (CDCl3, 400 MHz) : 1.31 (t, 3H, J =6.8 Hz), 1.81 (s, 3H), 2.56 (d, 1H, J =17.6 Hz), 2.73 (dd, 1H, J =17.2, 8.0 Hz), 4.27 (m, 3H), 5.45 (s, 1H), 5.56 (d, 1H, J =8.8 Hz) ppm; 13C-NMR (CDCl3, 100 MHz) : 14.4, 16.6, 42.6, 45.6, 61.8, 85.1, 112.1, 122.6, 148.5, 160.0 ppm; HRESIMS calcd for C10H14NO4 ([M+H]+): 212.0923; found: 212.0918. 2.5.8.3 (1 S ,5S )-3-Aza-4-(ethoxycarbonyl)-7-pheny lethynyl-2-oxabicyclo[3.3.0]oct3,7-diene-3-oxide (13c) : white solid: mp=72-74 C; 1H-NMR (CDCl3, 250 MHz) : 1.26 (t, 3H, J=7.0 Hz), 2.81-3.04 (m, 2H), 4.27 (m,3H), 5.66 (d, 1H, J=9.0 Hz), 6.01 (d, 1H, J=2.0 Hz), 7.25-7.40 (m, 5H, Ph) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.2, 41.8,

PAGE 124

102 45.0, 61.8, 83.7, 83.9, 95.5, 110.9, 122.1, 128.4, 129.0, 131.0, 131.4, 131.7, 159.0 ppm; MS(ESI) m/z= 298.1[M+H]+. HRESIMS calcd for C17H16NO4 ([M+H]+): 298.1079; found: 298.1072. 2.5.8.4 (1 S ,5S )-4-(ethoxycarbonyl)-3-methyl-2-oxab icyclo[3.3.0]oct-3,7-diene(13d): viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.20 (t, 3H, J =7.2 Hz), 2.09 (s, 3H), 2.3 (m, 1H), 2.6 (m, 1H), 3.7 (t, 1H, J =8.4 Hz), 4.10 (q, 2H, J =6.8 Hz), 5.53 (d, 1H, J =9.2 Hz), 5.7 (bs, 1H), 5.9 (bs, 1H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.5, 14.6, 40.1, 43.9, 59.5, 91.9, 106.6, 128.5, 137.0, 166.4, 167.1 ppm; HRESIMS calcd for C11H15O3 ([M+H]+): 195.1021; found: 195.1018. 2.5.8.5 (1 S ,5S )-4-(ethoxycarbonyl)-3,7-dimethyl-2 -oxabicyclo[3.3.0]oct-3,7-diene (13e): viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.21 (t, 3H, J =7.0 Hz), 1.71 (m, 3H), 2.09 (d, 3H, J =1.2 Hz), 2.27-2.34 (m, 1H), 2.51-2.55 (m, 1H), 3.70 (dt, 1H, J =7.7, 1.0 Hz), 4.1 (m, 2H), 5.34 (m, 1H), 5.46 (d, 1H, J =8.8 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 14.42, 14.48, 16.5, 44.1, 44.6, 59.2, 92.3, 106.5, 123.0, 147.8, 166.3, 167.2 ppm; HRESIMS calcd for C12H17O3 ([M+H]+): 209.1178; found: 209.1181. 2.5.8.6 (1 S ,5S ) -3-phenyl-4-(phenylsulfonyl)-2-oxabicyclo[3.3.0]oct-3,7-diene (13f): viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 2.73 (dt, 1H, J =7.2, 2.2 Hz), 2.85 (p, 1H, J =2.2 Hz), 3.82 (dt, 1H, J =7.7, 5.2 Hz), 5.64 (doublet of p, 1H, J =7.2, 1.2 Hz), 5.74 (dq, 1H, J =5.7, 2.2 Hz), 6.06 (dt, 1H, J =5.7, 1.2 Hz), 7.18-7.6 (m, 10H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 40.1, 46.4, 91.9, 114.4, 127.0, 127. 4, 127.9, 128.7, 128.8, 129.4, 130.7, 132.6, 137.2, 142.2, 163.9, 192.3 ppm; HRESIMS calcd for C19H17O3S ([M+H]+): 325.0898; found: 325.0892.

PAGE 125

103 2.5.8.7 (1 S ,5S )-7-methyl-3-phenyl-4-(phenylsulfo nyl)-2-oxabicyclo[3.3.0]oct-3,7diene (13g): viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 1.76 (s 3H), 2.58-2.90 (m, 2H), 3.84 (dt, 1H, J =7.7, 2.2 Hz), 5.41 (t, 1H, J =2.0 Hz), 5.62 (d, 1H, J =9.0 Hz), 7.197.60 (m, 10H, PhSO2+COPh) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 15.5, 43.2, 46.2, 91.6, 113.3, 121.5, 125.9, 126.6, 127.7, 128.0, 128.4, 129.6, 131.5, 141.3, 147.3, 163.1 ppm; HRESIMS calcd for C20H19O3S ([M+H]+): 339.1055; found: 339.1050. 2.5.8.8 (1 S ,5S )-3-phenyl-7-phenylethynyl-4-(pheny lsulfonyl)-2-oxabicyclo[3.3.0]oct3,7-diene (13h): viscous liquid; 1H-NMR (CDCl3, 250 MHz ) : 2.89-3.17 (m, 2H), 3.94 (dt, 1H, J =8.2, 2.2 Hz), 5.70 (d, 1H, J =9.0 Hz), 6.00 (d, 1H, J =1.7 Hz), 7.26-7.61 (m, 15H); 13C-NMR (CDCl3, 62.5 MHz) : 43.7, 46.6, 84.5, 91.4, 94.8, 114.3, 122.5, 127.0, 127.7, 128.4, 128.6, 128.8, 129.4, 130.8, 131.0, 131.7, 131.9, 132.0, 132.7, 142.1, 164.2 ppm; HRESIMS calcd for C27H21O3S ([M+H]+): 425.1211; found: 425.1203. 2.5.8.9 2-Cyclopent-2-enylidene-maloni c acid dimethyl ester (13k): viscous liquid; 1H-NMR (CDCl3, 250 MHz) : 2.58 (m, 2H), 2.90 (m,2H), 3.70 (s, 3H), 3.73 (s, 3H), 6.76 (s, 2H) ppm; 13C-NMR (CDCl3, 62.5 MHz) : 31.0, 32.9, 51.8, 52.0, 115.3, 132.4, 152.4, 166.2, 166.6, 168.3 ppm; HRESIMS calcd for C10H13O4 ([M+H]+): 197.0814; found: 197.0812.

PAGE 126

104 2.6 References 1. (a) Metal-Catalyzed Cross-Coupling Reactions 2nd ed.; deMeijere, A.; Diederich, F.; Ed.; Wiley-VCH: Weinheim, 2004. (b) Hegedus, L. S.; Transition Metals in the Synthesis of Complex Organic Molecules 2nd ed., University Science Books: Sausalito, 1999. (c) Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.; Ed.; Wiley In terscience: New York, 2002. (d) Cross-Coupling Reactions: A Practical Guide; Miyaura, N.; Ed.; Springer: Berlin, 2002. (e) Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley a nd Sons: New York, 1994; Chapter 5, pp 383-461. 2. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. (b) Trost, B.M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292. (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103 2921. (d) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry. A Guide for the Synthetic Chemist; Pergamon: Amsterdam and New York, 2000; Vol. 20. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4442. (f) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. 3. Trost, B, M.; Chem. Pharm. Bull. 2002, 50, 1. Trost, B.M.; Crawley, M. L.; Chem. Rev. 2003, 103, 2921. 4. (a) Trost, B. M., Toste, F. D., J. Am. Chem. Soc. 1999, 121, 3543. (b) Trost, B. M., Madsen, R., Guile, S. D., Brown, B., J. Am. Chem. Soc. 2000, 122, 5947. (c) Trost, B. M., Li, L., Guile, S. D ., J. Am. Chem. Soc. 1992, 114, 8745. (d) Trost, B. M., Patterson, D. E., Hembre, E. J., Chem. Eur. J., 2001, 7, 3768. (e) Trost, B. M., Bunt, R. C., Lemoine, R., Calkins, T. L., J. Am. Chem. Soc., 2000, 122, 5968. (f) Trost, B.

PAGE 127

105 M., Toste, F. D., J. Am. Chem. Soc., 2000, 122, 11262. (g) Trost, B. M., Van Vranken, D. L., J. Am. Chem. Soc., 1993, 115, 444. 5. (a) Hou, X. L., Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y. T.; Wong, H. N. C.; Tetrahedron, 1998, 54, 1955. (b) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209. (c) Gilchrist, T. L. J. Chem. Soc. Perkin Trans. 1999, 1, 2849. (d) Sundberg, R. J. in Comprehensive Heterocyclic Chemisry, Vol. 5 (Eds.: A. R. Katrizky, C. W. Rees), Pergamon, New York, 1984, p. 313; (f) Heaney, H. in Natural Products Chemistry (Ed.: K. Nakanishi), Kodansha, Toyko, 1974, p.297 (g) Lipshutz, B. H., Chem. Rev. 1986, 86, 795. (h) Brown, T. H.; Armitage, M. A.; Blakemore, R. C.; Blurton, P. G.; Durant, J.; Ganellin, C. R.; Ife, R. G.; Parsons, M. E.; Rawlings, D. A.; Slingsby, B. P. Eur. J. Med. Chem. 1990 25, 217. (i) Shipman, M. Contemp. Org. Synth 1995, 2, 1. (j) Paquette, L. A. Org. Lett. 2000, 2, 4095. 6. a) Kunetsky, R. A.; Dilman, A. D.; Stru chkova, M. I.; Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis 2006, 13, 2265. (b) Kunetsky, R. A.; Dilman, A. D.; Ioffe, S. L.; Struchkova, M. I.; St relenko, Y. A.; Tartakovsky, V. A. Org. Lett. 2003, 5, 4907. (c) Torssell, K. B. G. In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis ; Feuer, H., Ed.; VCH Publishers: Weinheim, 1988; pp 55-74. (d) Whitney, R. A.; Nicholas, E. S. Tetrahedron Lett. 1981 35, 3371.(e) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (f) Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta. 1999, 82, 1829.(g) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (h) Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta 1999, 82,1829. (i) Galli, C.; Marotta, E.; Righi, P.; Rosini, G. J. Org.

PAGE 128

106 Chem. 1995, 60, 6624. (j) Gil, M. V.; Roman, E.; Serrano, J. A. Tetrahedron Lett 2000, 41, 3221. 7. (a) Rahmathullah, S. M.; Hall, J. E.; Bender, B. C.; McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W. J. Med.Chem. 1999 42, 3994. (b) Di Florio, R.; Rizzacasa, M. A. J. Org. Chem. 1998, 63, 8595. (c) Hudlicky, T.; Rulin, F.; Lovelace, T. C.; Reed, J. W. In Studies in Natural Products Chemis try, Stereoselective Synthesis part B, Vol. 3; Attaur-Rahman, Ed.; Elsevi er Science: Amsterdam, 1989, 3. 8. (a) Lockhart, D. J.; Patel, H. K.; Mehta, S. A.; Milanov, Z. V.; Gr otzfeld, R. M.; Lai, A. G. PCT Int. Appl. WO 2004110357 A2, 2004; Chem. Abstr. 2005, 142, 69180. (b) Castro-Hermida, J. A.; Gomez-Couso, H.; Ares-Mazas, M. E.; Gonzalez-Bedia, M. M.; Castaneda-Cancio, N.; Otero-Es pinar, F. J.; Blanco-Mendez, J. J. Pharm. Sci. 2004, 93, 197. (c) Anbazhagan, M.; Boykin, D. W. Heterocycl. Commun. 2003, 9, 117. 9. (a) Nizamuddin, G. M.; Srivastava, M. K. J. Sci. Ind. Res. 1999, 58, 1017. (b) Ito, H.; Takeshiba, H.; Ota, H.; Kato, S. Jpn. Kokai Tokkyo Koho JP 10114765, 1998; Chem. Abstr. 1998, 129 24492. (c) Venters, K.; Trusuele, M.; Rozhkova, N.; Lukevics, E. Latv. PSR zinat. Akad. Vest. 1990, 10, 116. (d) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Frter, G. Angew. Chem. Int. Ed. 2000, 39, 2980. (e) Harris, E. C.; Fayter, R. C. Jr. US 4681703, 1987; Chem. Abstr. 1989, 110, 23713. 10. Veronique, E.; Van Hung, N.; Odile, T.; Mari e-Therese, Martin.; Thierry, Sevenet.; Francoise, G. J. Nat. Prod. 2006, 69, 1289

PAGE 129

107 11. Xiao, W. L.; Yang, L. M.; G ong, N. Bo.; Wu, L.; Wang, R. R.; Pu, J. X.; Li, X. L.; Huang, S. X.; Zheng, Y. T.; Li, R. T.; L u, Yang.; Zheng, Q. T.; Sun, H. D. Org. Lett. 2006, 8, 991. 12. Sakai, R.; Koike, T.; Sasaki,M.; Shimamoto, K.; Oiwa, C.; Yano, A.; Suzuki, K.; Tachibana, K.; Kamiya, H. Org. Lett. 2001, 3, 1479. 13. a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164 (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005 70, 7679 (c) Liu, Y. H.; Zhou, S.; Org. Lett. 2005, 7, 4609. d) Patil, N. T.; Wu, H.; Yamamoto, Y.; J. Org. Chem. 2005, 70, 4531. 14. (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450 (b) Hashmi, A. S. K. Angew. Chem. 1995, 107, 1749. (c) Sromek, A.W.; Kelin,A. V.; Gevorgyan, V. Angew. Chem. 2004, 116, 23. (d) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925. (e) Dudnik, A.; Gevorgyan,V. Angew. Chem. 2007, 119, 5287. 15. a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org.Chem. 1991, 56, 5816 (b) Kellin, A.; Gevorgyan V. J. Org.Chem. 2002, 67, 95. 16. Liu,Y. H.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett 2005, 7, 5409. 17. (a) Ma, S., Zhang, J. Angew. Chem. 2003, 115 193; Angew. Chem.Int. Ed. 2003, 42, 183. (b) S. Ma, L. Lu, J. Zhang, J. Am. Chem.Soc. 2004, 126, 9645.(c) Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1991, 56, 6971. (d) Ma, S.; Zhang, J.; J. Am. Chem. Soc. 2003, 125, 12386. 18. Xiao,Y.; Zhang, J. Angew. Chem. Int. Ed. 2008, 47, 1903. 19. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 17725.

PAGE 130

108 20. (a) J. P. Wolfe, M. A. Rossi, J. Am. Chem. Soc. 2004, 126, 1620. (b) M. B. Hay, A. R. Hardin, J. P. Wolfe, J. Org. Chem.2005, 70, 3099.(c) M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005, 127, 16468. (d) M. B. Hay, J. P. Wolfe, Tetrahedron Lett. 2006, 47, 2793. (e) Wolfe, J. Eur. J. Org. Chem 2007, 571. 21. (a) Tanimori, S.; Kato, Y.; Kirihata, M. Synthesis 2006 5, 865. (b) Tanimori, S.; Kirihata, M. Synthesis, 2007, 1, 39. 22.Encarnacin, R. D.; Sandoval, E.; Malmstrm, J.; Christophersen, C J. Nat. Prod. 2000, 63, 874. 23. (a) Mousa, S. A.; Olson, R. E.; Bozarth, J. M.; Lorelli, W.; Forsythe, M. S.; Racanelli, A.; Gibbs, S.; Schlingman, K.; Bozarth, T.; Kapil, R.; Wityak, J.; Sielecki, T. M.; Wexler, R. R.; Thoolen, M. J.; Slee, A.; Reilly, T. M.; Anderson, P. S.; Friedman, P. J Cardiovasc Pharmacol 1998, 32, 169. (b) Groutas, W. C.; Venkataraman, R.; Chong, L. S.; Yoder, J. E.; Epp, J. B.; Stanga, M. A.; Kim, E-H. Bioorg. Med. Chem. 1995, 3, 125. 24. Lee, H. M.; Lee, C.; Cho, M.; Hwang, Y. G.; Lee, K. H. Bull. Korean Chem. Soc. 2004, 25, 1850. 25. (a) Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. J. Org. Chem. 1990, 55, 781. (b) Galli, C.; Marotta, E.; Righi, P.; Rosini, G. J. Org. Chem. 1995 60, 6624. 26. Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins, R. J.; Arrington, J. P. J. Org. Chem. 1968, 33, 423. 27. Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, 27, 1255.

PAGE 131

109 28. (a) Carr, J. A.; Al-Azemi, T. F.; Long, T. E. ; Shim, J. Y.; Coates, C.; Turos, E.; Bisht, K. S. Tetrahedron 2003 59, 9147. (b) Bisht, K. S.; Gross, R. A.; Kaplan, D. L. J. Org. Chem 1999, 64, 780. (c) Garcia-Urdiales, E. ; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313. (d) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides & Nucleotides. 1993, 12, 267. (e) Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33 7287. 29. Carr, J. A.; Bisht, K. S. O rg. Lett. 2004, 6, 3297. 30. Paquette, L. A.; Earle, M. J.; Smith, G. F. Organic Syntheses. 1996, 73, 36. 31. Roy, A.; Schneller, S. W. J. Org. Chem. 2003, 68, 9269. 32. Tsuji, J. In Palladium reagents and catalysts; Wiley: New York, 2004, pp 431-517. Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981 22, 2575. Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969. 33. (a) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett 1988, 29, 669. (b) Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016. 34. Fiaud, J. C.; Legros, J. Y. J. Org. Chem. 1987 52, 1907. Keinan, E.; Roth, Z. J. Org. Chem. 1983, 48, 1769. 35. Brunel, J. M.; Maffei, M.; Muchow, G.; Buono, G. Eur. J. Org. Chem. 2001, 1009.

PAGE 132

110 Chapter 3 A NEW ROUTE TO -CARBONYL COMPOUNDS VIA ONE POT Pd(0) CATALYZED ISOMERIZATION-ALKYLATION 3.1 General introduction The last few decades of 20th century have witnessed the emergence of transition metal catalysis as an indispensable t ool for carbon-carbon and carbon-heteroatom bond formation. Transition metal catalysts offer newer ways to form carboncarbon bonds between or within functionali zed and sensitive substrates which has not only helped in total synthesis of complex natural products but has also benefited fields such as process chemistry, as well as chemical biology and nanotechnology.1 Among all organometallic catalysts palladium based catalysis has been extensively studied and applied in organic syntheses.2 The nucleophiles used in Pd cataly zed alkylation includ es C-nucleophiles such as malonate esters, acetoacetates, Nnucleophiles such as primary and secondary amines, amides, azides and O-nucleophiles such as alcohols and phenols. Some of these nucleophiles such as nitro esters and alkanes exhibit ambident nature and can result in C as well as O alkylation. The ra tio of C versus O alkylation ca n be easily controlled by changing the reaction cond itions such as nature of ligand, solvent and alkyl groups on the substrate. Importantly, despite their utility in synthetic organic chemistry, nitroalkanes have received little attention in Pd catalyzed allylic alkylations as a nucleophile source. For example, nitro group can be easily converted to a ketone (Nef reaction), reduced to amine or transf ormed into carboxyl group, imines and hydroxylamines.3,4 Furthermore presence of some other functional groups such as

PAGE 133

carbonyl enhances the syntheti c utility of the nitro compounds. For example the -nitro ketones have been extensively us ed in synthesis of 2,3-dihydro-1 H cyclopenta[b]quinolin-9-ylamine relate d compounds which act as fructose-1,6bisphosphatase inhibitors and prazosin analogs which act as 1-adrenoreceptors.5 The scarce utilization of nitroalkane in Pd (0) cat alyzed allylic alkylations can presumably be attributed to their ambident nature (C vs O alkylation), low reactivity of bulky nitroalkanes and formation of side products.6 OCO2R RO2CO Pd(0), PR3 RO2CO NO2 R R OAc RO2CO CH3NO2 PdLn OAc O2N R2 R1 R3 OBoc R4 R5 NO2 R2 R1 R3 NO2 R5 R4 Pd(0) R2CHNO2ref 7b ref 7e ref 7fFig 3-1 Pd catalyzed allylic alkylation of nitroalkanes Pd catalyzed alkylation of nitroa lkanes has been reported on di fferent allylic substrates as carbonates, esters and allyli c alcohols resulting in a simple unsaturated nitro alkane (Fig 3-1). The survey of literature7 reveals that the new carbon-carbon is formed invariably at the allylic carbon of the electrophile, i.e., -unsaturated nitro compounds are formed (Fig 3-1). Recently, Shibasaki et al7f conducted allylic alkylation of various 20 nitroalkanes using Pd(0) catalysis giving -unsaturated nitro compounds. Trost et al7b has also Pd catalyzed asymmetric alkylation of nitroalkanes using cyclic esters. Deardorff et al7e has shown that in compounds containi ng both allylic acetate and carbonate, only 111

PAGE 134

112 the carbonate undergoes substitution giving allylic acetate as the product. Based on all these reports and the need of more allylic al kylations involving nitroalkane, Pd catalyzed alkylation of acetates using various 10, 20 30 nitroalkanes was conducted. Instead of the expected alkylated products contai ning nitroalkane moiety, saturated -nitro carbonyl compounds were obtained. This intriguing result prompted us to further investigate this reaction for not only mechanistic details but also for substrate generality. In this chapter the studies conducted on this new Pd catalyzed reaction of various nitroalkanes are presented. This Pd catalyzed alkylation of nitroalkanes is believed to involve an isomerization-alkylation and is th e first report of syntheses of -nitro carbonyl compounds using a Pd cata lyzed allylic alkylation. 3.2 Importance of nitro compounds 3.2.1 Nitro group in synthetic organic chemistry The nitro group is one of the most versatile functional group as it can be transformed into various other synthetically important functional groups, vi z.; amines, carboxylic acid, imines, oximes and aldehydes. Historical ly, aromatic nitro compounds have been important precursors to dyes and explosives.8

PAGE 135

Fig 3-2 Various transformations of nitro group Nitro compounds provide important intermediates for synt hesis of complex molecules and natural products. The importance of nitro compounds is further enhanced by their easy availability and ease of transf ormation to other func tional groups (Figure 32). Nitro group is also involved in a large number of named reactions such as Nef reaction which involves convers ion of nitro group to an aldehyde and ke tone. Henry reaction or nitro-aldol reaction is kknown fo r over 100 years is an extremely important carbon-carbon bond formation process and has been extensively used in natural product syntheses.3,4 3.2.2 Nitro group in natural products Nitro group is also found in a number of important bioactive peptides and natural products (fig 3-3).9 For example Psychrophilin A9a, a fungal metabolite isolated from the psychrotolerant fungus Penicillium ribeu and Nitropeptin, a dipept ide antibiotic isolated from the culture broth of Streptomyces xanthochromogenus 6257-MC1 both possess nitro 113

PAGE 136

group.9b Similarly, another nitro containing natural product, Kijanimicin is a spirotetronate antibiotic isolated from Actinomadura kijaniata a soil actinomycete. It has a broad spectrum of antimicrobial activity ag ainst gram-positive bacteria, anaerobes, and the malaria parasite Plasmodium falciparum and it has also show n antitumor activity.9c The structure of kijanimicin consists of a pe ntacyclic core, which is equipped with four L-digitoxose units and a rare nitrosuga r, 2,3,4,6-tetradeoxy-4 -(methylcarbamyl)-3C methyl-3-nitro-D-xylo -hexopyranose, commonly known as D-kijanose.9f More than 60 kijanimicin-related spirotetronate -type compounds have been reported.9e-g Psychrophilin A Kijanimicin N O NO2 N HN O O Tetrocarcin A Fig 3-3 Peptides and natural products containing NO2 group 114

PAGE 137

Nitroalkanes such as nitromethane, nitroeth ane, 1-nitropropane and 2-nitropropane act as versatile and inexpensive feedstocks. A larg e number of pharmaceutical products such as ranitidine, methyldopa and ethambutol ar e based on nitro-chemistry( fig 3-4).10 Fig 3-4 Important drugs containing NO2 group Apart from being an important part of common drugs (fig 3-4) nitro group also offer valuable synthons and intermediates for synthesis of various drugs and bioactive compounds. Scheme 3-1 shows how nitro chemistr y plays an important role in synthesis of various drugs and bioactive compounds us ing reactions such as Michael addition, Knoevenagel reaction and Henry reaction. 115

PAGE 138

Scheme 3-1 Use of nitroalkanes in syntheses of bioactive compounds and important drug molecules. 3.2.3 Palladium catalyzed react ions of nitroalkanes Pd catalyzed allylic alkylati on, also known as Tsuji-Trost reaction has been extensively used in organic syntheses.2 A large number of nucleophiles, including active methylene and methine compounds, and various heteroat om (N, O, S) nucleophiles have been employed in this reaction. In case of N nucleophiles, amines have been extensively utilized as the alkylation proceeds smoothly in the pr esence of various ligands. Interestingly, the other N-nucleophile, nitroalk anes have received litt le attention in Pd catalyzed allylic alkylations as a nucle ophile source even t hough nitro group can be easily converted to other functional groups.4 Wade et al studied the alkyl ation of various 116

PAGE 139

nitro compounds including primary and secondary nitroalkanes and observed the formation of both C as well as O alkylation products.7a The survey of literature 4 reveals that the new carbon-carbon bond is formed i nvariably at the al lylic carbon of the electrophile, i.e., unsaturate d nitro compounds are formed (Scheme 3-2). The scarce utilization of nitroalkane in Pd (0) cataly zed allylic alkylations can presumably be attributed to their ambident nature (C vs O alkylation), low reactivity of bulky nitroalkanes and formation of side products.5 3.2.3.1 Previous work on Pd cataly zed alkylation of nitroalkanes Aleksandrowicz et al 11 conducted a detailed study on Pd catalyzed alkylation of nitro alkanes. 2-nitropropane was used as the model compound to obtain the optimal alkylation conditions. The reaction was carried out using dichlorobis(triphenylphosphine)palladium PPh3 2-nitropropane in MeOH with MeONa as the base. Aleksandrowicz et al also obtained higher yields of the alkylated products in protic solvents as MeOH rather than in THF or DMSO due to low solubility of nitroalkane salts in aprotic solvents (scheme 3-2). Scheme 3-2 Pd catalyzed alkylation of nitroa lkanes using allylic substrates Wade et al7a also studied Pd catalyzed C-alkyla tion of cinnamyl acetate and 2-butenyl acetate using monoanions of primary nitroalkan es. Interestingly it was also pointed out that these reactions do not require extensive dr y conditions and in fact water is necessary 117

PAGE 140

in the reaction of nitroalkanes with allylic substrates.Also the authors reported the formation of allylic rearrangement products(s cheme 3-3) which can be explained on the basis of competitive attack on the two sites of allyl complex. Scheme 3-3 Pd catalyzed alkylation of nitroa lkanes giving isom erization products Recently, Shibasaki et al 7f reported the allylic alkylation of secondary nitroalkanes and observed that: 1. The nucleophiles were limited to nitromet hane, other primary nitroalkanes and 2nitropropane. However, bulkier nitroalk anes are not that reactive, i.e. 2nitrobutane and 2-nitro pentane are less re active than 2-nitr opropane. 2. A large amount of base was required to generate the carbanionand when catalytic or no external base was use d, a large amount of Pd catalys t or high temperature is required. 3. Nitroalkanes did suffer from competit ion between C versus O alkylation. 4. Enantioinduction at position of the NO2 group was also te dious and only few reports of this type of enantioinduction are known. 5. Shibasaki et al also optimized the reaction by ex amining various Pd ligands and catalysts.7f Also the Pd catalyzed allylic alkylation of nitroa lkanes was highly dependent on the nature of the solvent and base used For example, the reaction did not proceed in polar protic solvents as MeOH, tBuOH. Polar protic solvent solvents such as DMF and DM SO did favor the reaction. 118

PAGE 141

119 6. Several bases were also screened for Pd catalyzed allylic alkylation of nitroalkanes using DMSO as the solvent. As the basicity increased, the yield of the alkylation products also increased (table 3-1). Table 3-1 Optimization of reaction c onditions for Pd catalyzed al kylation of nitroalkanes Entry Base Solvent Yielda (%) 1 DABCO Toluene 6 2 DABCO CH2Cl2 4 3 DABCO THF 8 4 DABCO DMF 35 5 DABCO DMSO 50 6 DABCO t-BuOH 0 7 DABCO MeOH/CH2Cl2 0 8 None DMSO 8 9 La(O i -Pr)3 DMSO/THF(1:1) 14 10 i -Pr2NEt DMSO 15 11 TMG DMSO 75 12 TBD DMSO 71 13 DBU DMSO 86 a NMR analysis The proposed catalytic cycle by Shibasaki et al is shown in scheme 3-4. Initially formed Pd-complex II undergoes decarboxylation of the ally lic carbonate to generate complex III which reacts with the nitronate generated by deprotonation using an external base. The last step involves reductive elimin ation of palladium (0) from complex IV to generate the product V Also, the protonated form of th e base (DBU in the catalytic

PAGE 142

cycle) is neutralized by the tert -butoxide ion to regenerate the base and the corresponding alcohol. Scheme 3-4 Mechanism for Pd catalyzed alkylation of nitroalkanes. Diastereoand enantioselective allylation of substituted nitroalkanes has also been reported by Trost et al Allylic carbonate 2a was treated with nitroethane, chiral ligand 3, Pd(0) complex 4 and tetra-n-butylammonium chloride in CH2Cl2 resulted in monoalkylated product (83% yield, 98%brsm) in 22%ee after 48 hours. Scheme 3-5 Asymmetric alkylation of n itroalkanes via Pd catalysis The catalyst loading had a dramatic influence on the ee, i.e lowering catalyst loading from 0.5mol% to 0.25mol% resulted in an in crease in ee from 86 to 91% for compound 120

PAGE 143

5c Use of nitroethane as the nucleophile source resulted in more interesting results (table 3-2, scheme 3-6).When cesium carbonate wa s used as base in DMSO the product 6a was obtained as 1:1 mixture of diatereomers in 45% ee. Changing the base to O,Nbis(trimethylsilyl)-acetamide (BSA) in CH2Cl2 in the absence or presence of tetra-nbutylammonium chloride resulted in good diat ereoselectivity but m oderate ees (table 32, entry 2,3). As discussed earlier lowering the catalyst loading resulte d in an increase in both the diatereoselectivity and enantioselect ivity. Also changing the allylic carbonate to 2b gave the resultant product 6b in 55% yield (% brsm) in 5:1 diastereomeric ratio, wherein the major diasteremer was obtained in 96% ee. Scheme 3-6 Pd catalyzed asymmetric alkylation of nitroethane 121

PAGE 144

Table 3-2 Asymmetric alkylation of nitroalkanes via Pd catalysisEntrya mol% 3 mol% 4 Time(h) Isolated yield drf %eef,g 1d 6 2.0 16 84 1:1 45 2c 6 2.0 6 99 5:1 36 3 6 2.0 6 96 6:1 53 4 1.5 0.5 24 95 10:1 92 5 b 1.5 0.5 36 85(98)e 8:1 97 6 1.5 0.5 72 65(99)e 11:1 96 7 0.75 0.25 48 71(99)e 11:1 97 a All reaction were carried out in CH2Cl2 with 0.5M allyl substrate and 5-8 equivalents of nitromethane and (C4H9)4NCl as an additive and BSA as base b1.2 eq of nitromethane was used. c No additive was used. d Cs2CO3 was used as the base in DMSO. e Yields based on recovered starting material. f Base on chiral GC analyses. g enantiomeric excess was determined for the major diastereomer except for entry 1, where it represents the ee for both isomers. Deardorff et al 7e reported a two step conve rsion of allylic alcohols into homoallylic nitro compounds via a Pd(0) catalyzed alkylati on of ethyl carbonates (scheme 3-7). Scheme 3-7 Pd catalyzed alkylation of allylic acetates beari ng an allylic carbonate This reaction was effective for both prim ary and secondary ally lic substrates and tertiary substrates were not studied. This allylation provided the corresponding nitro compounds in high regioand stereoselectivities. In case of palladium catalyzed alkylation it is usually observe d that allylic carbonates react at a faster rate than allylic 122

PAGE 145

acetates. Hence when the allylic acetoxy carbonat e (table 3-3, entry 7) was subjected to allylic alkylation using nitr omethane, only the allylic ca rbonate reacted with the nucleophile. Table 3-3 Pd catalyzed alkylation of allylic a cetates bearing an allylic carbonate entry Alcohola T (oC) b Product % yieldc 1 rt 62 d 2 rt 74 3 rt 71 4 65 70e 5 65 71f 6 50 60 7 0 63 a Alcohols were converted to corresponding carbonates using pyridine and ethylchlorooformate at 00C.b fragmentation temperature. c isolated yields. d E/Z ratio 10:1. e ratio of regioisomers 3:1. f ratio of regioisomers 3.4:1 123

PAGE 146

The authors proposed palladium induced ioni zation-fragmentation sequence for Pd(0) catalyzed nitromethylation (scheme 3-8) via simultaneous generati on of transient Pd complex and alkoxide base in eq ual proportions. Evolution of CO2 after addition of the Pd(0) catalyst indicated toward s an initial decarboxylation st ep which also prevented any reversibility of the Pd complex back to th e allylic carbonate. This decarboxylation step also generated ethoxide ion deprotonates ni tromethane (pKa = 10.2), generating the stabilized nitronate ion. Scheme 3-8 Proposed mechanism for Pd catalyzed al kylation of allylic acetates bearing an allylic carbonate The stereochemistry of the major produ cts obtained was independent of the stereochemistry of the starting allylic carbona tes. All the allylic carbonates employed in this study resulted in the formation of E and Z products in a diastereomeric ratio of 10:1. Since, nucleophilic additions to the Pd-allyl systems results in Z-product in case of Zsubstrates and E-product in case of E-substrat es, the formation of the E isomer from both E and Z substrates suggests an isomeriza tion to be involved. The authors proposed a 124

PAGE 147

rearrangement between the s yn and anti complexes to occur at a faster rate than attack by the nitronate ion (scheme 3-9).7e Scheme 3-9 Isomerization of -allyl complexes in a Pd catalyzed alkylation Also the regiochemical outcome of the r eaction was also influenced by the steric parameters of the -allyl intermediate. In case of substrates 6 and 7 (table 3-3) the allylic polar heteratoms greatly influence the regi ochemistry of the product by directing the attack of the incoming nucleophi le towards less sterically hindered distal end of the allyl system. In case of subs trates lacking a directing heteratom (entry 2,3 table 3-3) a mixture of both regioisomers were obtained. 3.2.3.2 Synthesis of bioactive compounds via Pd catalyzed alkylation of nitroalkanes Palladium catalyzed asymmetric allylic alkylation has also been extended to synthesize new bioactive molecules. Hamada et al ut ilized Pd catalyzed allylic alkylation of nitromethane to synthesize ( R )preclamol and ( R )Baclofen (Fig 3-5).12-14 125

PAGE 148

Fig 3-5 Structure of R -isomers of Baclofen and Preclamol HCl 1,3-diphenyl ethyl propyl carbona tes (scheme 3-10) were chosen as the substrates for asymmetric allylic alkylation and were treat ed with nitromethane (3 equiv) in the presence of [( 3-C3H5PdCl)2](2.5mol%), ( S, Rp)-Ph-DIAPHOX (10 mol%), BSA (3 equiv) in CH2Cl2 at room temperature for 24 hours. The authors made some key observations while optimizing the reaction c onditions like even though the chemical yield was low when nitromethane was used as solv ent but it improved the enantioselectivity of the reaction. Also increasing the reaction time resulted in low yields and enantioselectivities. It has also been reported that silyl nitronates can be generated in the presence of BSA and an amine. Fig 3-6 Chiral ligand used in synthesis of R -isomers of Baclofen and Preclamol HCl 126

PAGE 149

O O OEt Cl Cl [( 3-C3H5PdCl)2](2.5mol%), ( S, RP)-Ph-DIAPHOX (10 mol%), BSA (3 equiv) in CH2Cl2N,N-DIPEA (50 mol%) CH3NO2 (0.1 M), rt NO2 Cl Cl 92% (isolated yield) (97% ee) ( R ) O O OEt OMe [( 3-C3H5PdCl)2](2.5mol%), ( S, RP)-Ph-DIAPHOX (10 mol%), BSA (3 equiv) in CH2Cl2N,N-DIPEA (50 mol%) CH3NO2 (0.1 M), rt NO2 OMe 91% (isolated yield) (98% ee) ( R ) MeO NH2.HCl Cl HO2C ( R )Baclofen hydrochloride N OH ( R ) Pre c lamol [ ( + ) -3-PPP ] OMe Scheme 3-10 Synthesis of Baclofen and Preclamol HCl via Pd catalyzed alkylation 3.2.3.3 Miscellaneous reactions involving Pd catalyzed alkylation of nitroalkanes Apart from utilization of Pd catalyzed alkylation of nitroa lkanes in synthesis of new bioactive and NO2 containing compounds, this method is also utilized fo r other reactions as oxidation of allylic esters. Recently Trost et al utilized nitrona tes as nucleophilic oxidants for allylic car bonates and esters to the corresponding enones (scheme 3-11, table 3-4).15 A bulky nitroalkane was chosen to overc ome the problem of C-alkylation in case of nitroalkane. Nitroalkane A was deprot onated using KHMDS which was generated in situ using KH and freshly distilled HMDS. Scheme 311: Pd catalyzed oxidation of a llylic esters and carbonates 127

PAGE 150

Table 3-4 Pd catalyzed oxidation of allylic esters and carbonates Entry Substrate Ti me Product Yield (brsm) 1 O O 128 NO2 NO2 SPh () <1 h O SPh 96% 2 O O NO2 NO2 N O () 1h O N O 92% 3 O O NO2 NO2 OH () 2 h O OH 82% 4 O O NO2 NO2 O O NO2 O2N () <1 h O O O NO2 O2N 88%

PAGE 151

5 O O NO2 NO2 OTBS () 2 h O OTBS 95% 6a OBz BzO 0.6h O BzO 61%(73%) b 7 O B z BzO 12 h O BzO 45%(95%)c 8a BzO O Bz 2 h BzO O 75% b a Absolute stereochemistry confirmed by compar ing the optical rotation of known compound. b 99%ee based on chiral GC or HPLC analyses c 98%ee The authors proposed that the reaction is believed to procee d via an initial O-alkylation followed by a fragmention sequence to result in the enone and the oxime (scheme 3-12). Scheme 3-12 Proposed mechanism for Pd catalyzed oxidation of a llylic esters and carbonates 3.3 Present Work-New route to -nitro carbonyl compounds via Pd catalyzed alkylation-isomerization 3.3.1 Pd catalyzed alkylation-isomerization of allylic acetates using nitroalkanes In our quest of synthesizing new amino acids and amino alcohols Pd catalyzed allylic alkylation was extended to nitroalkanes. As di scussed in the previous sections of this 129

PAGE 152

chapter palladium catalyzed ally lic alkylation of n itroalkanes has always resulted in the formation of a -unsaturated nitroalkane. Surprisingly, when the same Pd catalyzed strategy was applied to hydroxy allylic acetates 1-3 using 10 and 20 nitroalkanes nitro carbonyl compounds were obtained instead of th e usual unsaturated nitroalkanes (Scheme 3-13). Scheme 3-13: Pd-catalyzed alkylations of nitroalkanes Another interesting feature of this reaction was the change in the position of new C-C bond formation from expected C-4 to C-3 (Sch eme 3-13) suggesting an isomerization to be involved in the reaction pathway. This reaction adds a new tool to the arsenal of Pd mediated C-C bond forming methodologies. Interestingly, as detailed above, nitroalkanes have received little at tention in Pd catalyzed allylic al kylations as a nucleophile source even though nitro group can be easily converted to other functional groups.3 The scarce utilization of nitroalkane in Pd (0) cataly zed allylic alkylations can presumably be attributed to their ambident nature (C vs O alkylation), low reactivity of bulky nitroalkanes and formation of side products.6 Also, the survey of literature7 reveals that in Pd catalyzed alkylation of nitroalkanes th e new carbon-carbon bond is formed invariably 130

PAGE 153

131 at the allylic carbon of the electrophile, i. e., unsaturated nitro compounds are formed (Scheme 3-13). 3.3.2 Optimization of reaction conditions fo r Pd catalyzed alkylation-isomerization of allylic acetates using nitroalkanesTo understand the mode of the reaction various solvents, bases, catalyst-ligand systems were evaluated (Table 3-5). The reaction was highly dependent on the nature of the solvent. No reaction was observed in protic solvents ( t -butanol, t -BuOH+THF) or in nonpolar solvents (toluene, CHCl3), i.e., starting material was recovered. In polar aprotic solvents (DMF, DMSO, THF), howev er, the reaction resulted in the -nitro carbonyl compound 10c in 10-12 hours. Owing to its relative ease of handling, THF was selected as the solvent of choice for subsequent i nvestigations. The rate and outcome of the reaction also depended on the base used. Although K OtBu and DABCO led to the product formation, K2CO3 proved to be the most efficient base for this reaction. When bulkier and stronger bases such as Cs2CO3 were used in THF no product formation was observed and the starting material was obtaine d along with the corresponding diol. It was also found that Pd(OAc)2 and PdCl2 did not catalyze the reac tion, the reaction was only catalyzed by Pd(0). In order to study the substr ate generality and scope of the reaction, cyclic and acyclic allylic acetates and primary and sec ondary nitroalkanes were subjected to the alkylation (Table 3-7). The five and six membered allylic monoacetates were synthesized by enzymatic hydrol ysis of the corresponding di acetates (scheme 3-14). The diacetates were synthesized from the dienes via two different routes both involving Pd catalysis.

PAGE 154

Table 3-5 Optimizaton of reaction conditions for Pd catalyzed alkylation-isomerization Entry Base Solvent Yielda dr d 1 K2CO3 THF 60 1:1 2 K2CO3 DMF 54 1:1.1 3 K2CO3 DMSO 53 1:1 4 K2CO3 CHCl3 b 5 K2CO3 Toluene b 6 K2CO3 t -BuOH b 7 K2CO3 t -BuOH+THF(1:1) b 8 Cs2CO3 THF -c 9 KO t Bu THF 40c 1.7:1 10 DIPA THF b 11 DABCO THF 52 1.1:1 aIsolated yields. bStarting material was recovered. cmeso -cyclopent-2-en-1,4diol was also formed (20%). dDiastereomeric ratio (dr) based on GC analyses. 132

PAGE 155

Scheme 3-14 Synthesis of five and si x membered mono acetates Cyclic acetates 7 and 14 resulted in formation of corresponding -nitro ketones 10 and 11, respectively. The acyclic acetate 15 which was synthesized by monacetylation of butene1,4-diol led to -nitro aldehydes 12. 10 and 20 nitroalkanes reacted with equal ease under these reaction conditions; even bulky nitroalkanes such as nitrocyclohexane reacted with both acyclic and cyclic hydroxyl allylic substrates. The reaction required 5-8 mol % Pd(0) catalyst and was completed in 10-12 hours. The structures of the -nitro carbonyl compounds were established unambiguously from analysis of the 1Hand 13CNMR spectral data and its comparison with the literature data, when available.16 The reaction conversions were determined using GC chro matography and the products were isolated by column chromatography over silica gel. As shown in table 3-7 cyclic and acyclic substrates reacted with different nitroalkanes to yield the corresponding nitro-ketone or 133

PAGE 156

aldehyde. The products obtained were quite stable and could be purified by column chromatography. Apart from alkenes, alkynes like 4-acetoxy-2-butyn-1-ol were also subjected to this Pd catalyzed methodology but did not show any reactivity. Efforts to conduct the alkylation using Pd (II) catalysts as PdCl2, Pd(OAc)2 also proved to be futile. Table 3-6 Pd catalyzed alkylation-isomerizati on in the presence of chiral ligands Entry Ligand Pd catalyst Base de 1 R-BINAP Pd(PPh3)4 K2CO3 1:1.15 2 R-BINAP Pd[( -allyl)2Cl]2 K2CO3 1.08:1 3 S-ToL BINAP Pd2(dba)3 K2CO3 1:1.3 4 dppp Pd2(dba)3 K2CO3 1:1 5 S-ToL BINAP Pd[( -allyl)2Cl]2 NaH 1:1.2 The stereochemical analyses of the products identified these to be a mixture of diastereomers and enantiomers, e.g., starting from the optically pure (1 S, 4R )4acetoxylcylcopent-2-en-1-ol ( 7)7e a racemic mixture of the respective products 10a-e was obtained. Products 10b and 10c were separated into its corresponding diastereomers by column chromatography and were identified to be racemic mixture of enantiomers. The loss of optical purity was somewhat intrigui ng as the Pd (0) catalyzed reactions are known to proceed with stereochemical retention via a double inversion.2b,i,7 the use of different bases gave identical re sults with a diastereomeric ra tio of almost 1:1 except in case of KOtBu (table 3-5,entry 9) which resulted in a diastereomeric ratio of 1.7:1. Importantly, reactions performed in the presence of chiral ligands such as R -BINAP and S-TolBINAP did not lead to optically pure products; only marginal influence on diastereomeric ratio was observed. Also tryi ng different Pd(0) catalysts in the presence 134

PAGE 157

of both chiral as we ll as achiral (dppp, PPh3) ligands did not improve the diastereomeric ratio of the products ( 10 b,c ) (table 3-7) Compounds 10a, d, e, 14, 15 were obtained as a racemic mixture of the enantiomers. Base d on these results it is evident that the mechanistic pathway of the reaction involved loss of ster eochemistry possibly through racemization of the reaction intermediates. Table 3-7 Pd catalyzed isomerization-al kylation of allylic acetates Entry Acetate Nitroalkane Product Conv.a isolatedb 1 (> 99% ee) ( 7) CH3NO2 O NO2 10a88 (65) 2 C2H5NO2 O NO2 10b85 (59) 3 C3H7NO2 O NO2 10c83 (60) 4 O NO2 10d 88 (58) 5 O NO2 10e90 (62) 6 () ( 14) O NO2 11a 75 b 7 O NO2 11b85 b 8 ( 15) C3H7NO2 135 H NO2O 12a 82 (58) 9 H O NO2 12b 77 (53)

PAGE 158

10 H O NO2 12c 76 (60) a Based on GC analyses of the reaction mixture. bIsolated yield after column chromatography. The acyclic substrates were further modifi ed by replacing one of the allylic-H by a methyl group. The secondary acyclic acetates 19, 20 were synthesized starting from propargylic alcohol as shown in scheme 315. Propargylic alcohol was protected as a THP ether followed by treatment with 1 equivale nt of BuLi to generate the carbanion at the terminal alkyne carbon followed by a nucleophilic attack on acetaldehyde to obtain the substituted alkyne. The re duction of the al kyne to the alkene required careful monitoring of the reaction. Extended reac tion times resulted in a mixture of the corresponding alkene and alkanes. Ac2O, DMAP THF H OH OH OTHP OAc OTHP 1N HCl MeOH 1. DHP, p T S A 2.BuLi, CH3CHO (-780C) 3.Pd/ BaSO4, Quinoline OA c OH 16 17 18 19 Scheme 3-15 Synthesis of substituted acyclic substrates 17, 18, 19. Pd catalyzed reaction of allylic acetate 19 did not yield the desired nitro-aldehyde, albeit resulted in tranesterification and the two acetates were obtai ned in a ratio of 3:7 which was confirmed by NMR and GC analyses (scheme 3-16). In order to remove the possibility of transesterification the primary hydroxyl group in 19 was protected as THP ether and was subjected to Pd catalysis. The THP ether 18 did not yield the alkylation 136

PAGE 159

product but resulted in 2,4-diene system 21. These experiments show that in acyclic substrates the presence of substitution at allylic carbon slows the formation of -allyl complex, hence allowing transesterification to compete with the Pd catalyzed alkylation step. When THP protected acetate was subj ected to Pd catalyzed alkylation, the -allyl complex thus formed underwent -hydride elimination to give diene 21. Two important conclusions can be derived from these set of experiments. First, any substitution at the allylic center specially in acyclic substrates slows the formation of -allyl complex hence favoring any other competing reactions such as transesterification to proceed. Secondly, the presence of a free allylic-hydroxy group is pivotal for this novel isomerizationalkylation to work. Scheme 3-16 Reaction of substituted acyclic substrates 18, 19 with 2-nitropropane in the presence of Pd(0) catalyst 3.3.3 Mechanistic studies for Pd catalyzed alkylation-isomerization Since the products obtained during these Pd cat alyzed alkylation are different from the conventional products obtained, hence a surv ey of the Pd literature was done to 137

PAGE 160

understand this new Pd catalyzed C-C bond fo rming process. The first example of the nucleophilic attack at the center carbon of a -allyl system in a Pd catalyzed process was reported by Hegedus et al during cyclopropanation of es ter enolates(scheme 3-17).18 A mechanism involving palladacyclobutane form ed by a direct nucleophilic attack on the central carbon of the -allyl system was therefore considered (scheme 3-18). Scheme 3-17 Mechanism involving formation of a palladacyclobut ane intermediate The possibility of a direct nucleophilic attack on the C-3 carbon leading to a palladacyclobutane intermediate, followed by H elimination to produce the enol which tautomerizes to the give -nitro carbonyl compound as the final product is shown in scheme 3-18. The initial steps involve the oxidative addition of Pd to allylic acetate followed by the attack of th e nucleophile. This mechanism differs from a normal Pd catalyzed allylic alkylation becau se of the fact that the nu cleophile attacks the central carbon of the allyl system followed by a formation of 4-membered palladacycle B The palladacycle undergoes -elimination to give enol intermediate C which undergoes reductive elimination to give the final product E According to the mechanism shown in scheme 3-18 the product obtained should be optic ally pure but Pd catal yzed alkylation of 138

PAGE 161

nitroalkanes resulted in complete loss of optical purity and a racemic mixture was obtained. Scheme 3-18 Plausible mechanism involving forma tion of a palladacy cle intermediate Hegedus also reported that the palladacycle formation is only observed when HMPA and /or Et3N is used (instead of PPh3) which coordinates to the metal forming [ -allyl PdL3]+.18a Also, in the cyclopentane and cylcohexa ne monoacetate susbtrates, low kinetic stability of such a palladacyclobutane bearing a -OH substituent is certainly a cause for concern.19 Szab et al studied the effect of polar substituents on the stability of palladacyclobutane complexes and proposed that palladacyclobutan es bearing single bonded electronegative substituents such as OH have low kinetic stability of such species.19-20 Also, Backvall et al recently conducted an extensive study on central versus terminal attack in nucleophilic addition to ( -allyl) palladium complexes and concluded that -acceptor complexes such as PPh3, dppf direct the attack to the terminal carbon whereas -donor ligands such as TMEDA direct the attack to term inal carbon, based on 13C shifts. 19b In case of -acceptor ligands, the Pd-complex has more cationic character and the positive charge is located on the te rminal carbon of the allyl system. Based on 139

PAGE 162

above comments and observations the Pd catal yzed alkylation of nitroalkanes presented here is less likely to follow this pathway. Another plausible mechanism involving an initial isomerizati on of the allylic acetate to -unsaturated ketone followed by a Mich ael addition using nitroalkane as a nucleophile was also consid ered and investigate d. The formation of the -unsaturated ketone was not observed and c onsidering the fact that no C-3 alkylation was observed in alkylation with other nucleophi le (active methylene compounds), a different mechanism is suggested. Attempts at isolating the Pd complex were unsuccessful. Also in order to rule out the possibility of an initial isomerization of the allylic acetate to -unsaturated ketone, allylic monoacetaes were subjected however, 3-cyclopentenone23 was isolated as the only product upon treatment of the monoacetate 7 with PPh3 and Pd(PPh3)4 in absence of the nitroalkane (fig 3-7, scheme 3-19). The formation of 3-cyclopentenone can be easily explained from both -allyl complexes II, III via a -hydride elimination and tautomerization (scheme 3-19). HO OAc Pd(0) HO PdL2 HO L2Pd -hyd r ide elimination HO O 3-cyclopentenone 7 III HO L2Pd HO PdL2 IIIIIII Scheme 3-19 Mechanism for isomerization of al lylic acetate 7 to 3-cyclopentenone. 140

PAGE 163

141 HO OA c 1 2 3 4 5 C D O 6 7 6 7 6 7 B THF THF A 5 5 23 41 Fig 3-7 1H-NMR study of the reaction of the monoacetate 7 with PPh3 and Pd(PPh3)4 in THFd8 using 1H-NMR. A: Monoacetate B: Monoacetate + PPh3 C: Monoacetate+PPh3+Pd(PPh3)4 D: reaction mixture after 2.5 h at room temperature

PAGE 164

142 ore stabilized complex III somerization of -allyl palladium complexes has been put forward to explain loss of stereospecificity in some Pd catalyzed allylic alkylations.21 Based on the above mentioned facts and the following observati ons, i) carbonyl group instead of an allylic alcohol is formed, ii ) the new C-C bond formati on at C-3 instead of C-4 of the allylic system, a nd iii) the loss of stereochemistry, we herein propose a catalytic cycle for the isomerization-alkylati on reaction (Scheme 3-20). The catalytic cycle involves oxidative addition of Pd(0) to the allylic acetate resulting in formation of the Pd-allyl complex (I ) which upon ligand exchange generates the complex II. Complex II is a key intermediate as it can isomerize to a m I Scheme 3-20 Proposed Mechanism for Pd catalyzed isomerization-alkylation Complex III is attacked by the nitroalkane carban ion at the sterically favorable C-3 position to yield IV which undergoes reductive elimination to give the enol V and regenerates Pd(0). Enol V tautomerizes to give the nitro carbonyl compound. The isomerization of II to III is manifested in the formati on of the new C-C bond at the C-3

PAGE 165

143 rbonyl compounds. Importantly, the hydroxyl be ination will yield dienol complex B Complex B can be represented as 4 complex C which upon regioselective re-addition ( D ) and interconversion can yield complex III and not at the carbon bearing the leaving acetoxy group (C-4). The involvement of III also is supported by stereoch emical scrambling observed in 1, an optically pure substrate, resulting in optically inactive -nitro ca aring carbon in III is sp2 hybridized which makes the co mplex racemic and explains the loss of optical purity in the products. The isomerization of complex II can be explained as shown in scheme 3-21. Initially formed -allyl complex II can undergo interconversion to A which upon syn elim Scheme 3-21 Isomerization of -allyl complex II to III The formation of III via an isomerization of II is dependent on two very important factors, 1) The availabili ty of the free hydroxyl group to stabilize the resulting carbocation through nonbonding elec tron pair donation; 2) The slow generation of the carbanion from the nitroalkane. The large de gree of charge buildup on the carbon atom during deprotonation of the -hydrogen in nitroalkanes alo ng with inductive effects of the alkyl groups makes the w hole process extremely slow.22 This unusual property of the

PAGE 166

144 nitroalkane combined with the availability of the allylic hydroxyl gr oup results in this unusual isomerization-alkylation reaction resulting in -nitro carbonyl compounds. Scheme 3-22 The competing alkylation: C-3 vs C-4A schematic of the competing processes in an allylic alkylation of the nucleophiles generated from a diester and nitroalkane is depicted in Scheme 3-22.2b,i,7 The diethyl malonate (fast deprotonation) results in form ation of the allylic alcohols with the new Cthe C-4, while in nitroalk anes (slow deprotonation), the new C-C bond is f solvent. Careful optimization of reaction conditio ns proved potassium carbonate and THF C bond formed at ormed at the C-3 resulting in -nitro carbonyl compounds. 3.4 Conclusion In conclusion, isomerization-alkylation pro cess has been discovered which provides an easy route to synthetically important -nitro-ketones and alde hydes and a mechanistic explanation for the 'isomerization-alkylation' is also proposed. The reaction requires easily obtainable allylic monoacetates and work s with a variety of 1, 2 nitroalkanes. This new Pd(0)-catalyzed al kylation of nitroalkanes can be carried out under mild conditions and the outcome of the reaction is highly dependent on the nature of the

PAGE 167

145 thetically important analogs should be valuable a l product synthesis. logies). GC studies were carried out on Shimadzu gas chromatograph (Model 3.5.2 Preparation of starting materials (1-3): to be the best base and solvent, respectively. The resultant -nitro carbonyl compounds that can easily be converted to other syn as synthons in natur 3.5 Experimental 3.5.1. General experimental information: Lipase PS-30 was generous gifts from Amano Enzymes. 1H-NMR and 13C-NMR spectra were recorded on a Bruker 250 MHz spectro meter MHz and 62.5 MHz respectively in CDCl3 with TMS as the standard. Chemical shif ts are reported in ppm, multiplicities are indicated by s (singlet), d (doublet), t (tripl et), q (quartet), p ( quintet), h (sextet), m (multiplet) and bs (broad singlet). Optical rotations were measured with a Rudolph Research Analytical AutoPol IV Automatic polarimeter. Thin-Layer chromatography (TLC) was performed on glass plates coated with 0.25 mm thickness of silica-gel. All solvents were dried and distilled prior to use and organic solvent extracts dried over Na2SO4. Mass calculations were carried out on an ESI LC MS system (Agilent Techno 17A).

PAGE 168

146 mmetrization of 3.5.3 General Procedure for Pd catalyzed alkylation of nitroalkane: temperature was added Pd(PPh3)4 (40 mg, 0.035 mmol), PPh3 (184 mg, 0.704 mmol) 23atography using hed those found in the 1 13viscous liquid; H-NMR 3, 8H), 2.60-2.69 (m, 1H),4.23 viscous liquid; H-NMR 3=7.5Hz ), 1.42-2.50 (m, 8H), 2.63-2.68 (m, 1H),4.23 Optically pure 7 was prepared by lipase catalyzed enzymatic desy corresponding meso -diacetates.24 Compound 14 and 15 were prepared following the known literature procedures.25 To a solution of allylic acetate 7 (100 mg, 0.704 mmol) in dr y THF (10 mL) at room under a nitrogen atmosphere. The reaction was allowed to stir for 5 minutes and then nitropropane (63 mg, 0.704 mmol) and K CO (97 mg, 0.704 mmol) were added. The reaction was refluxed for 12 h and then vacuum filtered through celite with subsequent concentration of the filtrate. The product was purified by column chrom ethyl acetate: hexane (1:2) to afford 10c (72 mg, yield =60%) as a viscous liquid. 3.5.3.1 3-(Nitromethyl) cyclopentanone (10a)16 : NMR data matc literature and Hand Cspectra is presented in the later section. 3.5.3.2 3-(1-Nitroethyl) cyclopentanone (10b)16: NMR data matched those found in the literature and 1Hand 13Cspectra is presented in the later section. 3.5.3.3 3-(1-Nitropropyl) cyclopentanone (10c) (less polar): 1(CDCl 250 MHz) : 0.92 (t, 3H, J =7.5Hz ), 1.56-2.56 (m (dt, 1H, J =10.5, 3.25 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) :10.22, 25.99, 26.54, 37.97, 40.26, 41.35, 94.20, 215.50 ppm. HRESIMS calcd for C8H13NO3 Exact Mass: 172.0968 ([M+H]+); found: 172.0964 ([M+H]+). 3.5.3.4 3-(1-Nitropropyl) cyclopentanone (10c) (more polar): 1(CDCl 250 MHz) : 0.90 (t, 3H, J

PAGE 169

147 172.0968 + + matched those 1 13ose found 1 13 matched those 1 13 the la36H), 1.55-2.55 (m, 2H), 2.32-2.40 (m,1H), 2.492.66 (m, 1H), 4.26-4.34 (m, 2H), 9.67 32.23-2.28 (m, 1H) 2.37-2.39(m, 1H), 2.79 (m, (dt, 1H, J =9.75, 4.0 Hz) ppm; 13C-NMR (CDCl3, 62.5 MHz) :10.14, 25.91, 26.46, 37.91, 40.18, 41.27, 94.12, 215.42 ppm. HRESIMS calcd fo r C8H13NO3 Exact Mass: ([M+H] ); found: 172.0964 ([M+H] ). 3.5.3.5 3-(2-Nitropropane-2-yl) cyclopentanone (10d)16: NMR data found in the literature and Hand Cspectra is presented in the later section. 3.5.3.6 3-(1-Nitrocyclohexyl) cyclopentanone (10e)16 : NMR data matched th in the literature and Hand Cspectra is presented in the later section. 3.5.3.7 3-(2-Nitropropane-2-yl) cyclohexanone (11a)16: NMR data found in the literature and Hand Cspectra is presented inter section. 3.5.3.8 3-(1-Nitrocyclohexyl) cyclohexanone (11b)16: NMR data matched those found in the literature and 1Hand 13Cspectra is presented in the later section. 3.5.3.9 3-Methyl-4-nitrohexanal (12a): 1HNMR (CDCl 250 MHz) : 0.8-1.1 (m, (d, 0.5H, J =1.25Hz), 9.69 (s, 1H). 13CNMR (CDCl3, 62.5 MHz) : 10.35, 10.52, 15.48, 16.62, 24.0, 24.22, 31.0, 31.22, 46.45, 47.03, 93.37, 94.24, 199.93, 200.0. HRESIMS calcd for C7H17N2O3 ([M+NH4]+): 177.1233; found: 177.1231([M+NH4]+). 3.5.3.10 3,4-Dimethyl-4-nitropentanal (12b) : 1HNMR (CDCl 250 MHz) : 0.90 (d, 3H, J =7.0 Hz ), 1.47 (s, 3H), 1.49 (s, 3H), 1H), 9.66 (d, 1H, J =2.25 Hz) ppm; 13CNMR (CDCl3, 62.5 MHz) :15.36, 22.50, 23.84, 35.87, 46.14, 91.24, 199.91 ppm. HRESIMS calcd for C7H17N2O3 ([M+NH4]+): 177.1233; found: 177.1234 ([M+NH4]+).

PAGE 170

148 H), 2.138 (m, 1H) 2.36-2.55 (m, 3H), 9.66 (d, J =1.75 Hz) ppm;13CNMR (CDCl3, 62.5 MHz) :15.05, 22.17, 22.26, 24.60, 31.21, 21N2O3 ([M+NH4]+): flon tape and was m temperature. The spectra D corresponds to the reaction mixture after 2.5h. two new peaks at 2.89 ppm and 6.1ppm start developing which ly of 3-cyclopentenone (fiq S1).23 3.5.3.11 3-(1-Nitrocyclohexyl)butyraldehyde (12c) : 1HNMR (CDCl3, 250 MHz) : 0.88 (d, 3H, J =6.75Hz ), 1.11-1.66 (m, 9 1H, 32.15, 36.16, 45.82, 94.17, 200.26 ppm. HRESIMS calcd for C10H 217.1586; found: 217.1582 ([M+NH4]+). 3.5.4 Procedure for the time study using 1H-NMR spectroscopy Allylic monoacetate 7 (10 mg, 0.07 mmoles) was dissolved in THFd8 (in a NMR-tube) and the spectral data was collected. Spectrum A corresponds to the 1H-NMR spectra of pure monoacetate 7. PPh3 (4 mg, 0.015 mmoles, 20 mol %) was added to the solution of monoacetate in THFd8 and the 1H-NMR data was again colle cted (Spectrum B). This was followed by addition of Pd(PPh3)4 (4 mg, 0.003 mmoles, 5 mol %) (Spectrum C). Also after the addition of the catalyst the NM R tube was sealed using te kept at roo As the reaction proceeds, correspond to H-6 and H-7 respective

PAGE 171

149 .; Ed.; Wiley In terscience: New York, 2002. (d) Cross-Coupling Reactions: 3.6 References: 1. (a) Metal-Catalyzed Cross-Coupling Reactions 2nd ed.; deMeijere, A.; Diederich, F.; Ed.; Wiley-VCH: Weinheim, 2004. (b) Hegedus, L. S.; Transition Metals in the Synthesis of Complex Organic Molecules 2nd ed., University Science Books: Sausalito, 1999. (c) Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E A Practical Guide; Miyaura, N.; Ed.; Springer: Berlin, 2002. (e) Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley a nd Sons: New York, 1994; Chapter 5, pp 383-461. 2. (a) Maitlis, P. M. The Organic Chemistry of Palladium ; Academic Press: New York, 1971; Vols. 1 and 2. (b) Tsuji, J. Organic Synthesis with Palladium Compounds ; Springer-Verlag: New York, 1980. (c) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic Press: New York, 1985. (d) Larock, R. C. In Ad vances in Metal-Organic Chemistry ; Liebeskind, L. S., Ed.; JAI Press: London, 1994; Vol. V, Chapter 3. (e) Tsuji, J. Palladium Reagents and Catalysts: Inno vations in Organic Synthesis; Wiley and Sons: New York, 1995. (f) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry ; Pergamon: New York, 2000. (g) Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis ; Wiley and Sons: New York, 2002; Vols. 1 and 2. (h) Tsuji, J. Palladium Reagents and Catalysts: New Perspecti ves for the 21st Century ; Wiley and Sons: New York, 2003. (i) Palladium in Organic Synthesis ; Tsuji, J., Ed.; Springer: Berlin, 2005 .(j) Heumann, A.; Jens, K.-J.; Reglier, M. Progress in Inorganic Chemistry ; Karlin, K. D., Ed.; Wiley and Sons: New York, 1994; Vol. 42, pp 483-576. (k) Tsuji, J. J. Organomet. Chem

PAGE 172

150 illaizeau, I.; York, 2001. on. esi, M. L.; 1986, 300, 281. (l) Kalinin, V. N. Russ. Chem. Re v. 1991, 60 339. (m) Hegedus, L. S. Coord. Chem. Re v. 1996, 161, 129. (n) Hegedus, L. S. Coord. Chem. Re v. 1997 147, 443. (o) Larock, R. C. Pure Appl. Chem. 1999, 71, 1435. (p) Bckvall, J.-E. Pure Appl. Chem. 1999, 71, 1065. (q) Tsuji, J. Pure Appl. Chem. 1999, 71, 1539. (r) Beletskaya, I. P.; Cheprakov, A. V. Chem. Re v. 2000, 100, 3009. (i) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33 314. (s) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2000, 56 613. (t) Zimmer, R.; Dinesh. C. U.; Nandanan, E.; Khan, F. A. Chem. Re v. 2000, 100, 3067. (u) Special issue Years of the Cross-coupling Reaction. J. Organomet. Chem 2002, 653, 1. (v) Agrofoglio, L. A.; G Saito, Y. Chem. Re v. 2003, 103, 1875. (w) Negishi, E.; Anastasia, L. Chem. Re v. 2003, 103, 1979.(x) Zeni, G.; Larock, R. C. Chem. Re v. 2004, 104, 2285. (y) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005 7, 147. 3. (a) Ono, N. The Nitro Group in Organic Synthesis ; Wiley-VCH: New (b) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen Compounds ; Oxford University: Oxford, 1994; pp 443. (c) The Chemistry of Amino, Nitro and Related Groups; Patai, S., Ed.; John Wiley & Sons: Chichester, 1996. 4. (a) Luzzio, F. A. Tetrahedron 2001, 57, 915. (b) Ballini, R.; Petrini, M. Tetrahedr 2004, 60, 1017. (c) Barrett, A. G. M.; Grabowski, G. G. Chem. Rev. 1986, 86, 751. (d) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem 2002 1877; (e) Seebach, D.; Colvin, E.W.; Lehr, F.; Weller, T. Helv. Chim. Acta. 1985, 68 1592. 5. (a) Rosini, M.; Mancini, F.; Tarozzi, A.; Co lizzi, F.; Andrisano, V. ; Bologn Hrelia, P.; Melchiorre, C. Bioorganic & Medicinal Chemistry 2006, 14, 7846. (b)

PAGE 173

151 Chem. 2003, 46, 4895. 1978, 19, 565. (d) Tsuji, J.; Shimizu, I.; .; Kanai, M.; t 1980, 33, 946. (e) Morimoto, M.; Fukui, M.; Ohkubo, S.; Tamaoki, T.; Tomita, F J. Antibiot. 1982, 35, Rosini, M.; Antonello, A.; Cavalli, A.; Bol ognesi, L. M.; Minarini, A.; Marucci, G.; Poggesi, E.; Leonardi, A.; Melchiorre, C. J. Med. 6. a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron 1982, 38, 1321. (b) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Monatsh. Chem. 1982, 113, 1221. (c) Genet, J. P.; Grisoni, S. Tetrahedron Lett. 1988, 29, 4543. (d) Rieck, H.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 1995, 34, 2687. 7. (a) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem 1982 47, 365. (b) Trost, B. M.; Surivet, J.-P. J. Am. Chem. Soc. 2000, 122, 6291. (c) Tsuji, J.; Yamakawa, T.; Mandai, T. Tetrahedron Lett. Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523. (e) Deardorff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.; Sheppeck, J. E.; Harger, D. C.; Aydin, N. J. Org. Chem 1996 61, 3616. (f) Maki, K Shibasaki, M. Tetrahedron, 2007, 63, 4250. 8.D. S. Moore, Rev. Sci. Instrum., 2 004, 75, 2499. 12 W. C. Trogler, in NATO ASI Workshop, Electronic Noses & Sensors for th e Detection of Explosives, ed. J. W. Gardner and J. Yinon, Kluwer Academic Publishers, Netherlands, 2004 9. (a) Dalsgaard, P. W.; Larsen,T. O.; Frydenvang, K.; Christophersen, C.; J. Nat. Prod. 2004, 67, 878. (b) Ohba, K.; Nakayama, H.; Furihata, K.; Shimazu, A.; Endo, T.; Seto, H.; Otake, N. J. Antibiot. 1987, 403, 709. (c) Tomita, F.; Tamaoki, T.; Shirahata, K.; Kasai, M.; Morimoto, M.; Ohkubo, S.; Mineura, K.; Ishii, S. J. Antibiot. 1980, 33, 668. (d) Tamaoki, T.; Kasai, M.; Shirahata, K.; Ohkubo, S.; Morimoto, M.; Mineura, K.; Ishii, S.; Tomita, F. J. Antibio

PAGE 174

152 Antibiot 1981, 34 1101. (g) Bradner, W. s, etrahedron 1982, 38, 1321. L. G. Life Sci. 1981, 28 1225. (b) ohansson, 84, 27, 1030. . 1033. (f) Waitz, J. A.; Horan, A. C.; Kalyan pur, M.; Lee, B. K.; Loebenberg, D.; Marquez, J. A.; Miller, G.; Patel, M. G. J. T.; Claridge, C. A.; Huftalen, J. B. J. Antibiot. 1983, 36, 1078. 10. (a) Danneberg, P.; Weber, K. H.; Br. J. Clin. Pharmacol. 1983 16, 231. (b) Rickel K.; Acta. Psychiatr. Scand. 2007, 74, 132. 11. Aleksandrowicz, P.; Piotrowska, H.; Sas, W. T 12. Nemoto,T.; Jin, L.; Nakamura, H.; Hamada, Y. Tetrahedron. Lett. 2006, 47, 6577. 13. Olpe, H. R.; Demiville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133 14. (a) Hjorth, S.; Carlsson, A.; Wikstrm, H.; Lindberg, P.; Sanchez, D.; Hacksell, U.; Arvidsson, L.-E.; Svensson, U.; Nilsson, J Wikstrm, H.; Sanshez, D.; Lindberg, P.; Hacksell, U.; Arvidsson, L.-E.; J A. M.; Thorberg, S.-O.; Nilsson, J. L. G.; Svensson, K.; Hjorth, S.; Clark, D.; Carlsson, A. J. Med. Chem. 19 15. Trost, B. M.; Richardson, J.; Yong, K. J. Am. Chem. Soc. 2006, 128, 2540. 16. Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (b) Hanessian, S.; Shao, Z.; Warrier J. S. Org. Lett. 2006, 8, 4787 17. (a) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, 27, 1255. (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides & Nucleotides. 1993, 12, 267. 18. (a) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980 45, 5193. (b) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 100

PAGE 175

153 K. J.; Bckvall, J. E. Angew. Chem., Int. Ed. 102, 4730. (b) K. L. (c) J. M. Brunel, M. R. J.; Arrington, J. P. J. 1255. (c) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides & Nucleotides. 1993 12, 267. 25. Baeckvall, J. E.; Nordberg, R. E. J. Am. Chem. Soc. 1981, 103, 4959. Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287. 19. (a) Castan, A. M.; Aranyos, A.; Szab, Engl. 1995, 34, 2551. (b) Aranyos, A.; Szab, K. J.; Castan, A. M.; Bckvall, J. E. Organometallics. 1997, 16, 1058. 20. Szab, K. J. Theochem 1998, 455, 205. 21. (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, Granberg, J. E. Bckvall, J. Am.Chem. Soc. 1992, 114, 6858. Maffei, G. Muchow, G. Buono, Eur. J. Org. Chem. 2000, 1799. (d) J. M. Brunel, M. Maffei, G. Muchow, G. Buono, Eur. J. Org. Chem. 2001, 1009. 22. Green, D.; Johnson, T. Innovations Pharm. Technol. 2000, 79. 23. Buckley, S. L. J.; Harwood, L. M.; M acias-Sanchez, A. J. ARKIVOC 2002, 8, 46. Tsuda, T.; Tokai, M.; Ishida, T.; Saegusa, T. J. Org. Chem 1986, 51, 5216. 24. (a) Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins, Org. Chem. 1968, 33, 423. (b) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, 27

PAGE 176

154 Chapter 4 research. Out of a ll the peptidomimetics and related compounds, unnatural amino acids such as bicyclic and carbocyclic amino acids are of valuable interest as they have provided new buildi ng blocks for large num ber of potential drug candidates (fig 4-1).3 CHEMOENZYMATIC SYNTHESIS OF L-CARBAFURANOMYCIN AND RELATED CYCLOPENTANE AMINO ACID ANALOGS 4.1 Introduction The last three chapters focused on Pd (0) cat alyzed alkylations i nvolving various soft nucleophiles such as nitroesters, diesters and nitroalkanes. A review on the importance of these Pd catalyzed reactions in synthesis of O,N heterocycles is presented in chapter 1. This chapter focuses on the application of the Pd catalyzed methodologies studied and discussed in the prior two chap ters. Pd catalyzed alkylation was utilized to synthesize new carbocyclic amino acid analogs which not only provide valuable synthons for a large number of bioactive compounds and drug candi dates but also show immense bioactivity on their own.The last few decades have seen the emergence of new therapeutics based on bioactive peptides and peptidomimetics.1-3 This class of compounds have not only attracted organic and medicinal chemists due to their novel stru cture but have also influenced biomedical Fig 4-1 Biologically important carbocyclic amino acid analogs

PAGE 177

155 receptor comple 4.2 Biological importance of carbocyc lic amino acid and its analogs Carbocyclic-amino acids offer diverse biological properties.4-6 For example, they can act as agonists and/or antagonists at both i onotropic and metabotropi c glutamate receptors7,8 and are involved in plant growth and fruit ripening9. They are also known to modify the biological properties of a protein or peptid e when incorporated as a building block.10 Compounds such as ACPD, MCCG (fig 4-1) have shown poten tial to act as N-methyl-Daspartate (NMDA) antagonists. Bicyclic amino acid LY 354740 was developed by Eli Lilly & Co as a highly potent and selective agonist of metabotropic glutamate (mGlu) receptor 2 and 3.11 Importantly, Ohfune et al showed that cyclic threonine analogues when incorporated as building blocks into peptides (e.g. Leu-enkepha lin) can alter their biological effects.12 Also, 1-aminocyclopropane, 1-aminocyclobutane (ACBC), and 1aminocyclopentanecarboxylic acid are reported as partial agonists of the NMDA x.13 Amino cyclopropane carboxylic acid anal ogs can also act concurrently as a glycine site partial agonist a nd as a glutamate site antago nist, thus protecting against neural cell death and has shown antipsychotic-like e ffects in animal models.13 A large number of amino acids also contain a carbocylic ring system. These amino acids form a new class of non-prot einogenic amino acids with cytotoxic, antibiotic and antifungal properties.14 The pharmacology and chemistry of these amino acids has been extensively reviewed.14 One of the first known amino acids include (1 R 2S)-2-aminocyclopenatnecarboxylic acid (cispentaci n) which is an antifungal metabolite isolated from Bacillus cereus and Streptomyces setonii .15 Cispentacin shows good therapeutic efficacy against a Candida infection in mice after either oral or parenteral administration. It also acts agai nst systematic infection with Cryptococcus neoformans

PAGE 178

156 gs showed that cyclohexane and norbornane analogs of cispentacin had no activity. An alogs of cispentacin like BAY 10-8888 with an exocyclic double bond showed better activity but introduct ion of double bond in the ring results in loss of activity(fig 4-2).15b-d and also lung and vaginal infection due to Candida albicans in mice.15b-d. Also a SAR study for cispentacin analo COOH NH2 COOH NH2 Cispentacin Bay 10-8888antifungal activity Aspergillus spp. : >500 Candida spp. :<0.25->32 Aspergillus spp. : not active Fig 4-2 Antifungal activities of cispentacin analogs Amipurimycin, a cyclopentane amino aci d containing compound, is strongly active against Pyricularia oryzae both in vitro and in vivo (fig 4-3).16 Additionally, synthetic compounds containing a carbocyclic -amino acid moiety have also shown potent bioactivity and applications. Tilidine ((In vitro Candida spp. : 8-50)-trans-2-(dimethyl-amino)-1-phenyl-3cyclohexene carboxylate hydrochloride) (fig 4-3) is used in therapy to control pain as an opioid analgesic.17 It is sold under various trade names as Findol, Grntin, Tilidalor, Tiligetic, Tilitrate, Valomerck, Valoron, Valtran.

PAGE 179

157 COOH NH2 2-ACPC Cispentacin O OH HO N N N N NH2 HN COOH O H2N HO H OH N Ph COOEt Amipurimycin TilidineFig 4.3 Biologically important -amino acids containing a carbocyclic system Specially, -Disusbtituted cycloalkane amino acids play an important role in the development of new peptides with enhanced properties(fig 4-4). 18-23 Incorporation of these cyclic structures in a peptide b ack-bone results in novel properties due to conformational restrictio ns present in these systems. Incorporating these unnatural amino acids in naturally occurring peptides can ha ve a pronounced effect on its bioactivity, the 18-23 resultant peptides offer high stability due to resistance to enzymatic degradation. OH HO2C NH2 OH HO2C NH2 OH HO2C NH2 OH HO2C NH2 (1 S 2 S) (1 R 2 R ) (1 S 2 R ) (1 R 2 S ) OH HO2C NH2 HO2C NH2 H2N HO2C CO2H OH NH2OH Fig 4-4 Structure of various five and six membered cycloalkane amino acids

PAGE 180

158 The novel properties of cycloalk ane amino acid analogs have attracted a large number of researchers. For example, several isomer s of L-aspartyl-1-aminocylopropanecarboxylic acid methyl ester shown in figure 4.5 differ sli ghtly in their struct ure but are found to have sweet to bitter taste properties when subjected to a taste test .24 H N CO2CH3 AsP H H N CO2CH3 AsP H H N COCH23 AsP H H N COCH 23AsP H sweet tasteless bitter bitte r Fig 4-5 Taste properties of L-aspartyl-1 -amino-cyclopropanecarboxylic acid Apart from offering various bioactive and pharmacological applications these novel amino acid and their analogs offer building blocks for other modified peptides and biologically active compounds such as -lactams and heterocycles These unnatural amino acids are also finding their way in the field of combinatorial chemistry. Figure 4.6 shows a schematic for combinatorial synt hesis of 1,5-benzodi azepine-2-ones, 2thioxopyrimidinones, cyclic -lactams.25

PAGE 181

COOH NH2 COOH NH2 COOH NH2 CN CN CN CHO CHO C HO Cl O2N N O O N H R3 R2 n n=0,1 COOH NH2 CHO R2 N R3 n N O O N H R3 R2 n n=0,1 Fig 4-6 Combinatorial synthesis based on Ugi reaction involving cyclic amino acids 4.3 General methods for synthe sis of cyclic amino acids A number of synthetic methods are availa ble for synthesis of cyclic amino acids. Depending on the type of reagent a racemic or an enantiopure poduct is obtained. Among the cyclic amino acids five and six membered analogs are most widely known due totheir easy availability from anthra nilic acid. The following section describes various methods to synthesize cyclic amino acids. 4.3.1 Selective reduction of anthranilic acid analogs26 2-Aminocyclohexanecarboxylic acids can be easily synthesized via selective reduction of anthranilic acid. This method is known for the last 100 years and is still used. Depending on the nature of the reducing agen t the cis:trans ratio can be altered. 159

PAGE 182

Anthranilic acid reduction using Rh-Al catalyst or Adams catalyst in acetic acid results in cis isomer exclusively. However, th e use of colloidal ruthenium in a H2 atmosphere gives in a cis-trans ratio of 6:1 (scheme 4-1). NH2 COOH NH2 COOH NH2 COOH NH2 COOH NH2 COOH 6: 1Adams catalyst acetic acid colloidal Ru H2 Scheme 4-1 Synthesis of cyclohexane anino acids via selective reduction of anthranilic acid analogs 4.3.2 Hofmann and Curtius degradation of 1,2-dicarboxylic anhydrides27 A large number of cyclohexane amino acids can be synthesized via Hofmann and Curtius degradation. 1,2 cyclohexane-dicarboxylic anhydride synthesized via a Diels-Alder reaction of maleic anhydrid e and butadiene is convert ed to the corresponding monoamides and monoesters (scheme 4-2) which are subjected to Hofmann and Curtius degradation respectively. O O O NH4OH COOR COOH COOH CONH2 1.ROH 2.OH-3.H+Hofmann degradation NaOH, Br2, DOWEX 50 Curtius degradation 1.SOCl22.NaN33.H C l COOH NH2 Scheme 4-2 Synthesis of cyclohexane anino acids via Hofmann and Curtius Degradation 160

PAGE 183

4.3.3 Hydrolysis of lactams28 Cyclic amino acids can also be accessed fr om lactams via an acid hydrolysis (Scheme 43). Cyclic beta lactams can be synthesized by 1,2 dipolar cycloaddition of chlorosulfonyl isocyanate (CSI) to different cycloalken es. These additions always occur in a Markovnikov fashion in high re gioand stereoselectivity. CSI, DCM N H O NH3COOH aq HCl room temp ClCSI, DCM NH O aq HCl room temp COOH NH3 Cl-+ CSI, DCM N H O aq HCl room temp COOH NH3 Cl-Cl S N C O O O CSI Scheme 4-3 Synthesis of cycloalkane amino acids from -lactams 4.4 Furanomycin and its carba-analogs Furanomycin, an -amino acid is a naturally occurring antibiotic isolated from metabolites of Streptomyces threomyceticus L-803 in 1967 by Katagiri et al .29 These metabolites inhibited the growth of Colipha ge T2. Further studies on these metabolites confirmed that they do also inhibit the growth of other organisms as Eschericihia coli, Bacillus subtilis and several Salmonella strains. Furanomycin, the active compound in these fungal metabolites is an unusual amino acid, which bears resemblance to agaric toxin muscarine whose bios ynthesis proceeds from pyruvate and glutamate. But labeling 161

PAGE 184

experiments proved that furanomycin is fo rmed via a polyketide pathway involving two acetate and one propionate unit (fig 4-7).30 The furan ring is formed by an intramolecular ring opening of epoxide.31 O O COOH O COOH NH2 O NMe3 -O GLUTAMATE AND PYRUVATE PATHWAY Furanomycin MuscarineFig 4-7 Biosynthesis of Furanomycin and Mu scarine involving two acetate and one propionate unit Incorporation of furanomycin in a bacterial protein instead of isoleucine results in its antibiotic activity.32 Also, the experiments conducted in E.coli indicated that furanomycin selectively inhibits the formation of isoleucylt -RNA without affecting aminoacylt RNA. The -methyl group in furanomycin plays a cr ucial role in substrate recognition and differentiation between Ile, Val and Leu. Since the mechanism of action for furanomycin is interesting from a pharmaceu tical point of view hence a number of derivatives and analogs have b een synthesized and studied fo r their bioactivity (figure 48).33 162

PAGE 185

O H2N COOH O H2N COOH O H2N COOH H2N COOH H2N COOH H2N COOH 2 1 4 3 6 5 Fig 4-8 Furanomycin and its analogs Norfuranomycin ( 2) has exhibited antib iotic activity against E. coli and several species of Pseudomonas strains.33a A growth-inhibitory activity st udy of various furanomycin derivatives has been conducted. This study s howed that modifying the structure of furanomycin and the position of methyl gr oup had a profound effect on the biological activity. For example removal of methyl group did not effect the activity against S.aureus but altered the activity against against E.coli to large extent. Cha nging the position of methyl group from C-5 to any other carbon in the ring resulted in poor activity indicating the importance of the C-5 position of methyl group.33b Furanomycin has been synthesized by various methodologies using carbohydrates,34 tartaric acid,35 serine,36 or furans,37 as starting materials. Recently, Krause et al synthesized furanomycin using a Au catalyzed cycloisomerization of -hydroxy allenes.38 There is a great deal of interest in the synthesis of the carbocyclic an alogs of furanomycin because of their structural similarity and perceived biological activity. A se ries of racemic furanomycin analogs, cyclopentylglycine, and cycl opentenylglycine have been synthesized utilizing ring-163

PAGE 186

closing metathesis, aldol additions, esterenolate Claisen rear rangements and aldol reactions.34,35,39 Importantly, carbocyclic nucleosides have also shown potent biological activity. An amino acid containing nucleoside, Sine fungin isolated from the cultures of Streptomyces griseolus and Streptomyces incarnatus has shown antiviral, antifungal, antiparasitical and amoebicidal activities in both in vivo and in vitro (fig 4.9).40 The primary amino group at C-6 center in si nefungin makes it similar to S-Adenosyl methionine and explains the antiviral, an tifungal, antiparasitical and amoebicidal activities in both in vivo and in vitro .41 N N N N NH2 X H2N H2N COOH HO OH N N N N NH2 O S Me H2N COOH HO OH X=O (Sinefungin) X=CH2(Carba-Sinefungin) S -Adenosyl methionine Fig 4-9 Structures of carboc yclic nucleosides containing amino acid moiety Recently, Jger et al synthesized carbafuranomycin in 16 steps (Scheme 4-4).34d The synthesis involved 1,3-dipolar cycloadd ition of a chiral nitrile oxide with cyclopentadiene and the introduc tion of methyl group by by an SN2 cuprate substitution. The cycloaddition was utilized to obtain a cyclopentaisoxazoline system which was further reduced to obtain amino alcohol. Installation of methyl group via organocuprate chemistry and later on series of oxidation a nd deprotections furnished carbafuranomycin. 164

PAGE 187

C OOH NH2 R' NHR OAc O N R' N R' OCarbafuranomycin 7 8Scheme 4-4 Retrosynthetic analyses for L-Carbafuranomycin by Jager et al 4.5 Pd catalyzed synthesis of Carbafuranomycin and analogs As pointed out earlier, the last two ch apters have involved development of new methodologies based on Pd(0) catalysis. This ch apter focuses on the application of Pd(0) catalysis towards synthesis of unnatural car bocyclic amino acids and their analogs. Pd catalyzed allylic alkylation using ethyl nitroe sters as a nucleophile source can result in installation of nitro ester moiety on a cycl opentane ring (scheme 4-5). The nitro ester moiety provides an easy route to amino acid esters and analogs. Also, as this reaction results in installation of a new stereocenter (C-6, scheme 4-5), the corresponding nitro esters were obtained as a 1:1 mixture of diastereomer s in 67% isolated yield. Attempts to separate the two diastereom ers were not successful and it was decided to answer the issue involving se paration of diastereomers in th e later stages of synthesis. The next step involved reduction of the n itro group to an amino group using Zn/HCl system in i -propanol to obtain the corresponding amino esters.42 The reduction required 20 equivalents of Zn dust and 10 equiv of HCl in i-propanol and furnished the corresponding amines in 85% yield as amixtu re of diatereomers. Fortunately, the two 165

PAGE 188

diastereomers 13a,b were easily separated using conven tional column chromatography (2 % MeOH-CH2Cl2)with silica gel pretreated with Et3N. HO OAc O2N COOEt K2CO3, Pd(PPh3)4PPh3, THF HO COOEt NO2 Zn/HCl i -propanol HO COOEt NH2 HO COOEt NH2 11 12 13a 13b 1 2 3 4 5 6 A cO OAc PS-30 pH=7 phosphate buffer acetone 13a:13b=1.07:1 >99%ee (based on GC analyses) (90%) 67% 85% meso -diacetate 10 Scheme 4-5 Synthesis of cyclopentane am ino acids via Pd(0) catalysis After successful synthesis and separation of the cyclopentane amino esters the strategy was further applied towards synthesis of car ba analogs of furanomycin (fig 4-8). As stated in the previous section Jger et al43 recently synthesized an unnatural amino acid carbafuranomycin in 16 steps (Scheme 4-6). Even though this synthe sis provided a route to carba analogs of furanomycin but had some shortcomings. The synthesis required 16 steps involving a large number of oxidation, reduction step s and protection-deprotection protocols to yield the title compound. Keeping all these facts in mind, two diffe rent Pd(0) catalyzed strategies involving less number of steps were designed toward s synthesis of carbafuranomycin analogs. These new strategies also try to incorporate lipase catayzed enzymatic hydrolysis to obtain the carbafuranomycin analogs in high enantiopurity without the use of expensive chiral catalysts. 166

PAGE 189

COOEt NH2 R C OOEt NH2 OAc O N C OOE t H H HO COOEt NO2 HO OAc >99% ee 14 15 18 11 12 Scheme 4-6 Retrosynthetic analyses for analogs of Carbafuranomycin As shown in scheme 4-6 alkyl group (R) in carbafuranomycin analogs can be installed via a SN2 cuprate addition to allylic acetate 15. The ring opening of isoxazoline 18 will furnish the required acetate 15 These isoxazolines are eas ily obtainable from the nitroesters 12 in high enatiopurity via Pd(0) cat alysis(chapter 2). Once again the stereochemical outcome of the whole process depends on the stereochemistry of the starting monoacetate 11 which can be easily modifi ed by a simple protectiondeprotection strategy or by use of a diffe rent enzyme for the hydrolysis of the meso diacetate precursor. HO COOEt NO2 HO OAc O2N COOEt Pd(0),PPh311 12 Ac2O, DMAP O N O COOEt H H SnCl2, CH3CN O N COOEt H H OH COOEt H H NH2 16 18 19 AcO COOEt NO2 Pd(0), K2CO3K2CO317 A cO OAc PS-30 pH=7 phosphate buffer acetone meso -diacetate 67% 95% (quantitative) 90% 90% >99%ee (based on GC analyses) 10 Scheme 4-7 Retrosynthetic analyses for analogs of Carbafuranomycin 167

PAGE 190

The synthesis of carbafuranomycin starts with enatiopure monoacetate 11 which is coupled with ethyl nitroacetate using Pd(0) catalysis to furnish compound 12 as a 1:1 diatereomeric mixture and 67% yiel d. The allylic alcohol in compound 12 is esterified using acetic anhydride and DMAP to yield the corresponding acetat e in 95% isolated yield. Allylic acetate 16 is a substrate for another intram olecular Pd catalyzed cyclization to an isoxazoline-2-oxide ring system 17. Isoxazoline-2-oxide 17 was easily deoxygenated using SnCl2 in acetonitrile in quantitative yields. The next step in the synthesis involved reduction of the isoxazoli ne ring system to furnish the corresponding amino alcohol 19. Various reducing agents such as L AH, Na/Hg were tried but they led to decomposition of the starting material (isox azoline 18). In the light of these difficulties the synthesis of carbafuranomycin analogs was further modified as shown in scheme 4-8. NH2 COOH R 21 20 11 22 NO2 C OOEt R NO2 COOEt R OAc HO OAc Pd(0) catalyzed alkylation RMgBr CuCNScheme 4-8 Retrosynthetic analyses for carba-analogs of Furanomycin This modified strategy involves initial inst allation of alkyl group via cuprate chemistry followed by Pd catalyzed alkylation. As show n in scheme 4-8 various carba analogs of furanomycin can be derived from reduction of the nitro ester 21 followed by the hydrolysis of the ester. Nitro esters 21 are the key compounds in the whole syntheses and can be easily obtained via a Pd(0) catalyzed allylic alkylation of acetates 22 using ethyl 168

PAGE 191

nitroacetate as the nucleophile source. Allylic acetates 22 can be obtained by an SN2substitution on en antiopure acetate 11 using organocuprate chemistry. The stereochemical outcome of th e products again depends on th e starting allylic monoacetate 11 which can be easily obtained in high yields and optical purity via alipase catalyzed desymmetrization of the corresponding meso -diacetate. A simple protection/deprotection strategy or changing the enzyme used for enzymatic hydrolysis would enable access to the other enantiomer of the acetate 11 HO OAc AcO OAc meso 10 lipase PS-30 pH=7 phosphate buffer 8 11 (>99% ee) O 9 ( )Ac2O, Pd(0) THF C H3 C O3H NaOAc, CH2Cl2 CyclopentadieneScheme 4-9 Synthesis of enantiopu re allylic acetates 11 using lipase catal yzed hydrolysis The synthesis begins with cyclopentadiene 8 which can be easily obtained from commercially available dicylopentadie ne via a retro-Diels alder reaction. Cyclopentadiene 8 is oxidized to the racemic epoxide 9 using peracetic acid. Monoepoxide 9 can be ring opened under Pd(0) catalys is using acetic anhydride as the nucleophile source to yiel d the meso-diacetate 10. The desymmetrization of the mesodiacetate 10 with lipase to give the (+)-monoacetate 11 is the pivotal stereodifferentiation reaction (Scheme 4-9). Unlike in resolution of a racemic substrate, in 169

PAGE 192

170 which the yield per enantiomer is limited to 50%, the desymmetrization of the meso diacetate allowed conversion of higher th an 97% to the enantiomerically pure single enantiomer.46 Enzymatic asymmetric induction is a powerful tool in developing elegant synthetic methodologies for natural products.44 Desymmetrization of meso compounds is an extremely important reaction and involve s elimination of one or more symmetry elements in the substrate. Hydrolases are the enzymes which have shown immense potential in carrying out thes e desymmetrizations. Out of a ll the hydrolases, lipases have been extensively used.44e meso -2-Cycloalken-1,4-diols a nd diacetates have been subjected to enzymatic desymmetri zations utilizing lipase B from Candida antarctica (Novo SP-435) in organic and aqueous media.44e Of a number of different available lipases, the lipase from Pseudomonas cepacia (PS-30) was used to carry out hydrolytic desymmetrization of the diacetate.44d PS-30 catalyzed reaction of meso -diacetate 10 produced monoacetate 11 in high enantiopurity (>99%) a nd 60% yield. So, the recovered diacetate was again subjected to hydrolysis with the recovered enzyme to obtain enantiopure monoacetate ( 11, D 20 (CHCl3) = +68.9; lit 44f D 20 (CHCl3) = +69.6) in total yield of 90%. The absolute stereochemistry of the monoacetate was established upon its comparison with the literature data 44f as (+)-(1 S, 4R )4-acetoxylcylcopent-2-en-1-ol. The enantiopurity of monoacetate 11 was confirmed by GC analyses upon injecting racemic and enzymatically prepared monoacetate through a cylcodexB (30m X 0.25mm, J&W scientific) chiral capillary column. Installation of methyl group onto monoacetate 11 was done using dialkyl cuprates generated in situ by a r eaction between CuCN and alkyl magnesium chloride.45 This reaction required few modifications from th e reported literature reference by Kobayashi

PAGE 193

et al.45 The dialkyl magnesium cuprate was gene rated by adding two equivalents of methyl magnesium chloride to 1 equivalent of CuCN in dry THF at -180C (using an ethylene glycol-dry ice bat h, instead of NaCl-water-ice bath as mentioned in the reference) (fig 4-10) Also af ter the addition of Grignard reag ent to a slurry of CuCN in THF, the reaction mixture has to be brought to room temperature to obtain a clear solution which indicates formation of the cuprat e (case A). Failure to heat up the reaction mixture to room temperature resulted in extr emely poor yields of th e final product with the major product being the corresponding diol 26 due to nucleophili c attack on the acetate group by the the grignard reagent (case B). CuCN(3eq) MeMgCl(6 eq) THF OH 11 23(-180C) MeMgCl (6 eq) (250C) (-180C) (-180C) CuCN (3eq) in THF (-180C to 250C) ( 250C to-180C) Me2(CuCN) (MgCl)2Me2(CuCN) (MgCl)2 HO OAc 4-5 hours HO ( 1eq) stir for 30 min Case A: MeMgCl (6 eq) (-180C) CuCN (3eq) in THF ( 00C to-180C) CuCN+ MeMgCl HO OAc 4-5 hours HO OH ( 1eq) (-180C) ( -180 C ) CuCN+ MeMgClstir for 30 min Case B: OAc OH 23 2675%Fig 4-10 Steps involved in installation of methyl group on monoacetate 23 171

PAGE 194

AcO Me EtOOC NO2 Me NO2 EtOOC Pd(0), PR3 Base HO Me 23 24 25Ac2O, DMAP THF 96% 56%Scheme 4-10 Pd catalyzed alkylation of acetate 19 using ethyl nitroacetate After installation of the methyl group on the allylic monoacetate 11, the next step involved Pd catalyzed alkylation using ethy l nitroacetate as the nucleophile source (scheme 4-10). This alkylation step also posed some initial difficulty as the standard conditions involving the use of K2CO3 as base and ligands such as dppp, PPh3 did not furnish the desired product an d the starting material was recovered back. It is also worthwile to mention that extended reac tion time (>12h) also resulted in partial hydrolysis (~20%)of the starting allylic a cetate to corresponding alcohol. Hence the reaction conditions were modified and use of NaH and PPh3 as the ligand did result in the desired product 25 (scheme 4-10). RO OR OH NO2 EtOOC n OH NH2 HOOC RO OR OH NO2 EtOOC OH NH2 HOOC *OR= ester, carbonate n=0,1,2,3Scheme 4-11 Convenient route to carbocyclic and acyclic amino esters and amino acid analogs 172

PAGE 195

173 This methodology can also be extended towa rds synthesis of othe r carba-furanomycin analogs by changing the alkyl cuprate used in the initial stages of synthesis. Also, diastereomeric mixtures of amino esters sy nthesized using this methodology were easily separated via column chromatography giving access to both the isomers, hence making the whole process more advantageous. The key feature of this methodology is reduction in the number of steps involved for synthesi s of carbocyclic amino esters and amino acid analogs and use of lipases to obtain enantiopure products starting from a meso substrate. This methodology can also be extended to other ring systems as well as open chain compounds as shown in scheme 4-11. 4.6 Conclusions As discussed in the first three sections of this chapter unnatu ral amino acids such as bicyclic and carbocyclic amino acids are of valuable interest as they have provided new building blocks for large number of pot ential drug candidates. There are various methodologies to synthesize these class of compounds. The work presented in this chapter is another effort to provide a gene ral synthesis for unnatural cyclopentane amino acid analogs. This methodology can also be ex tended to other ring systems as well as open chain compounds to obtain corresponding amino acid analogs. 4.7 Experimental 4.7.1 General experimental information Lipase PS-30 was generous gifts from Amano Enzymes. 1H-NMR and 13C-NMR spectra were recorded on a Bruker 250 MHz spectro meter MHz and 62.5 MHz respectively in CDCl3 with TMS as the standard. Chemical shif ts are reported in ppm, multiplicities are

PAGE 196

174 indicated by s (singlet), d (doublet), t (tripl et), q (quartet), p ( quintet), h (sextet), m (multiplet) and bs (broad singlet). Optical rotations were measured with a Rudolph Research Analytical AutoPol IV Automatic polarimeter. Thin-Layer chromatography (TLC) was performed on glass plates coated with 0.25 mm thickness of silica-gel. All solvents were dried and distilled prior to use and organic solvent extracts dried over Na2SO4. Mass calculations were carried out on an ESI LC MS system (Agilent Technologies). GC studies were carried out on Shimadzu gas chromatograph (Model 17A). 4.7.2 General Procedure for synthesis a nd spectral data for 11, 12, 16 and 17 Compounds 11, 12, 16 and 17 are compounds 5 11a, 12a, 13a discussed in chapter 2 and were synthesized using the same reaction conditions. 4.7.3 General procedure for deoxygenati on of isoxazoline-2-oxide (17) To a solution of isoxazoline-2-oxide 17 (100 mg, 0.507 mmol) in dry CH3CN (20 mL) at room temperature was added SnCl2. 2H2O (171 mg, 0.076 mmol). The reaction was refluxed for 12 h and then vacuum filtered th rough celite with subs equent concentration of the filtrate. The product was purified by column chromatography using ethyl acetate: hexane (1:2) to afford 18 (91 mg, yield =99%) as a viscous liquid.1H-NMR (250MHz, CDCl3) : 1.29 (t, 3H, J=5.8Hz), 2.63-2.78 (m, 2H), 4.17-4.28 (m, 2H,), 4.17-4.28 (m, 4H), 5.56-5.62 (m, 1H,), 5.75-5.78 (m, 1H,), 6.09-6.12 (m, 1H,). 13C-NMR (62.5MHz, CDCl3) : 14.0, 38.2, 44.6, 61.4, 84.2, 111.3, 127.7, 137.0, 158.96. 4.7.4 General procedure for preparation of compound 23 To a slurry of CuCN (1.88g, 21 mmol) in dr y THF was added 14 ml(42.0 mmol) of 3M solution of MeMgCl in THF at -180C. After complete addition of MeMgCl, the solution

PAGE 197

175 was warmed to room temperature. The solutio n was stirred at room temperature for 30 min which also resulted in complete diss olution of CuCN (confirming formation of cuprate species). The reaction mi xture was again cooled to -18oC and monoacetate 11 (1g, 7.0mmol) dissolved in THF, was added to the reaction mixture. The reaction was allowed to come to room temperature ov ernight and then quenched by addition of distilled water and 5 drops of 28% NH4OH solution. The product was purified by column chromatography using ethyl acetat e: hexane (1:2) to afford 23 (510 mg, yield =75%) as a volatile liquid. 1H NMR (CDCl3, 250 MHz): 0.94(d, 3H, CH3, J =7 Hz), 1.54-2.0 (m, 4H), 2.88 (m, 1H), 4.78 (m, 1H ), 5.70 (m, 1H), 5.80 (dd, 1H, J =5.5, 2 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz) : 20.9, 38.9, 42.4, 77.3, 131.9, 141.7 ppm. 4.7.5 General procedure for preparation of compound 24 To a solution of 23 (100 mg, 1.02 mmol) in dry THF ( 10 ml) at room temperature was added acetic anhydride (103 mg, 1.02 mmol), and cataly tic amount of DMAP. The reaction was allowed to stir for 3 hours and then concentrated. The residue was taken up in ethyl acetate (40 ml) and extracted twice with saturate d sodium bicarbonate solution (20 ml), followed by brine (10 ml). The orga nic layer was dried over sodium sulfate and the resulting product 24 (135 mg, yield= 96%) was obtained as colorless liquid. 1H NMR (CDCl3, 250 MHz): 0.96(d, 3H, CH3, J =7 Hz), 1.64-1.72 (m, 1H), 1.95 (s, 3H), 1.96 (m, 1H), 2.86(m, 1H), 5.6-5.7 (m, 2H), 5.92 (m, 1H) ppm; 13C NMR (CDCl3, 62.5 MHz) : 20.68, 21.30, 38.58, 38.89, 80.48, 128.05, 144.21, 171.06 ppm.

PAGE 198

176 4.7.6 General procedure for preparation of compound 25 To a solution of ethyl nitroacetate (112 m g, 0.84 mmol) in dry THF (10 ml) at room temperature was added potassium carbona te (116 mg, 0.84 mmol) under a nitrogen atmosphere. The reaction was allowed to stir for 20 minutes and Pd(PPh3)4 (48 mg, 0.042 mmol), PPh3 (220 mg, 0.84mmol), monoacetate 24 (120 mg, 0.84 mmol) dissolved in 5 ml THF was added to it. The reaction was allowed to stir at 40 0C for 12 h and then vacuum filtered through celite with subsequent concentration of the filtrate. The product was purified by column chromatography using ethyl acetate: hexane (1:2) to afford 25 (100 mg, yield =56%) as a yellow viscous liquid.

PAGE 199

177 4.8 References (1) Cole, D. C. Tetrahedron 1994, 32, 9517. (b) Goto, T.; Toya, Y.; Ohgi, T.; Kondo, T. Tetrahedron Lett. 1982, 23, 1271. (c) Katayama, N.; Nozaki, Y.; Tsubotani, S.; Kondo, M.; Harada, S.; Ono, H. J. Antibiot. 1990, 43, 10. (d) Drey, C. N. C. In Chemistry and Biochemistry of the Amino acids ; Barret, G. C., Ed.; Chapman and Hall: New York, 1985; Chapter 3. (2) (a) Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas 1994, 113 1 (b). Sasaki, T.; Sakai, S. J. Synth. Org. Chem. Jpn. 1994, 52, 381. (c) 3. Bryson, J.W.; Betz, S. F.; Lu, H. S.; Suich, D. J.; Zhou, H. X.; ONeil, K. T.; DeGrado, W. F. Science 1995 270, 935. (d) Schneider, J. P.;Kelly, J.W. Chem. Rev. 1995, 95, 2169. (e) Tuchscherer, G.; Mutter, M. J. Biotech. 1995, 41, 197. (f) Tuchscherer, G.; Mutter, M. Pure Appl. Chem. 1996, 68, 2153. (g) Dolgikh, D. A; Kirpichnikov, M. P.; Ptitsyn, O. B.; Chemeris, V. V. Mol. Biol 1996, 30, 149. (h) Sun, S.; Brem, R.; Chan, H. S.; Dill, K. A. Protein Eng 1995, 8, 1205. (i) Cordes, M. H. J.; Davidson, A. R.; Sauer, R. T. Curr. Opin. Struct. Biol 1996, 6, 3. (j) Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers 1997, 43, 219 266.(k) Giannis, A.; Kolter, T Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (3) Drckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180. (4) Boge, T. C.; Georg, G. I.; Tamaiz, J. In Enantioselctive Synthesis of -amino acids ; Juaristi, E. Ed.; Wiley-VCH, Inc.: New York, 1997; pp 1 and 45. 5. Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.; Ober er, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913

PAGE 200

178 6. Appella, D.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071. 7. (a) Allan, R. D.; Hanrahan, J. R.; Hamb ley, T.W.; Johnston, G. A. R.;Mewett, K. N.;Mitrovic, A. D. J. Med. Chem 1990, 33, 2905; (b) Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C.-K.; Jane, D. E.;Watkins, J. C. J. Med. Chem 1994 37, 4288. 8. (a) Knpfel, T.; Kuhn, R.; Allgeier, H. J. Med Chem 1995 38, 1417; (b) Roberts, P. J.; Toms, N. J.; Salt, T. E.; Straton, P. C. Trends Pharmacol. Sci 1996, 1 7, 429; (c) Azerad, R.; Acher, F.; Tellier, F. J.; Brabet, I. N.; Fagni, L.; Pin, J.-P. J. Med. Chem 1997, 40, 3119. 9. (a) Pivrung, M.;McGeeham, G. J. J. Org. Chem 1986, 51, 2103; (b) Ichibara, A.; Shiraisi, A. Tetrahedron Lett 1997, 269. 10. (a) Lazarus, L. H.; Breveglieri, A.; Guerrini, R.; Salvadori, S.; Bianchi, C.; Bryant, S. D.; Attila, M. J. Med. Chem 1996, 39, 773; (b) Gershonov, E.; Granoth, R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J. Med. Chem 1996, 39, 4833; (c) Horikawa, M.; Shigeri, Y.; Yumoto, N.; Yoshikawa, S.; Nakajima, T.; Ohfune, Y. Bioorg. Med. Chem. Lett. 1998, 8 2027. 11. (a) Bond, A., Monn, J.A., Lodge, D., Neuroreport, 1997, 8, 1463. (b) Cappendijk, S.L., de Vries, R., Dzoljic, M.R., Eur. Neuropsychopharmacol. 1993,3, 111. 12. (a) Horikawa, M.; Kan, T.; Nakajima, T.; Nanba, K.; Ohfune, Y.; Takada, I. Chirality, 1997, 9, 459. (b) Horikawa, M.; Ohfune, Y. J. Synth. Org. Chem. 1997 55, 982. 13. (a) Marvizon, J-C. G.; Le win, A, H. Skolnick, P. J. Neurochem. 1989, 52, 992. (b) Gruca, R.; Papp, M.; Eur. Neuropsychopharmacol 1997, 7, S259.

PAGE 201

179 14. (a) Juaristi, E. Enantioselective Synthesis of -Amino Acids, Ed., Wiley-VHC: New York, 1997. (b) Cole, D. C. Tetrahedron 1994, 50, 9517.(c) Cardillo, G.; Tomassini, C. Chem. Soc. Rev. 1996, 23, 117.(d) Gademann, K.; Hinter mann, T.; Schreiber, J. V. Current Med.Chem 1999 6, 905. (e) Marastoni, M.; Guerrini, R.; Balboni, G.; Salvadori, S.; Fantin, G.; Fogagnolo, M.; Lazarus, L. H.; Tomatis, R. Arzneim.-Forsch./Drug. Res. 1999, 49, 6. (f) Ojima, I.; Lin, S.; Wang, T. Current Med. Chem 1999, 6, 927. (g) AbdelMagid, A. F.; Cohen, J. H.; Maryanoff, C. A. Current Med.Chem 1999, 6, 955. (h) Scarborough, R. M. Current Med. Chem 1999 6, 71. (i) Juaristi, E.; Lopez-Ruiz, H. Current Med. Chem 1999, 6, 983. 15. (a)Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.; Kawaguchi, H. J. Antibiotics 1989, 2, 1749. (b) Oki, T.; Hirano, M.; Tomatsu, K.; Numata, K.; Kamei, H. J.Antibiotics 1989, 42, 1756. (c) Iwamoto, T.; Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.; Okuhara, M.; Kohsaka, M.; Imanaka, H.; Kawabata, K.; Inamoto, .; Sakane, K. J. Antibiotics 1990, 43, 1.(d) Kawabata, K.; Inamoto, Y.; Sakane, K.; Iwamoto, T.; Hashimoto, S. J. Antibiotics 1990, 43 513. 16. (a) Goto, T.; Toya, Y.; Ohgi, T.; Kondo, T. Tetrahedron Lett. 1982, 23, 1271. (b)Knapp, S. Chem. Rev. 1995, 95, 1859. 17. (a) Martindale; The Complete Drug Reference, Parfitt, K. Ed., 32nd ed., Pharmaceutical Press: London, 1999; p 89.(b) Kleemann, A.; Engel, J. Pharmaceutical Substances 3rd ed.; Thieme: Stuttgart, 1999; pp 1878-1879. 18. (a) Varughese, K. I.; Srinivas an, A. R.; Stammer, C. H. Int. J. Pept. Protein Res 1985, 26, 242. (b) Mapelli, C.; Newton, M. G. ; Ringold, C. E.; Stammer, C. H. Int. J. Pept. Protein Res. 1987, 30, 498. (c) Barone, V.; Fraternali, F.; Cristinziano, P. L.; Lelj,

PAGE 202

180 F.; Rosa, A. Biopolymers 1988, 27, 1673. (d) Valle, G.; Crisma, M.; Toniolo, C.; Holt, E. M.; Tamura, M.; Bland, J.; Stammer, C. H. Int. J. Pept. Protein Res 1989, 34, 56. (e) Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone C.; Santini, A.; Crisma, M.; Valle, G.; Toniolo, C. Biopolymers 1989, 28 ,175. (f) Crisma, M.; Bonora, G. M.; Toniolo, C.; Barone, V.; Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini, A.; Fraternali, F.; Bavoso, A.; Lelj, F. Int. J. Biol. Macromol 1989, 11, 345. (g) Benedetti, E.; Di Blas io, B.; Pavone, V.; Pedone, C.; Santini, A.; Barone, V.; Fraternali, F.; Lelj, F.; Bavoso, A.; Crisma, M.; Toniolo, C. Int. J. Biol. Macromol 1989, 11, 353. (h) Zhu, Y.-F.; Yamazaki, T.; Tsang, J. W.; Lok, S.; Goodman, M. J. Org. Chem 1992 57, 1074. (i) McMath, A. R.; Guillaume, D.; Aitken, D. J.; Husson, H.-P. Bull. Soc. Chim. Fr 1997, 134, 105. 19. (a) Guichard, G.; Abele, S.; Seebach, D. Helv. Chim. Acta 1998, 81, 187. (b) Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew. Chem., Int. Ed. 1999, 38, 1595. (c) Seebach, D.; Overhand, M.; Khnle, F. N. M.; Martinoni, B.; Ober er, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913. (d) Abele, S.; Seebach, D. Eur. J. Org. Chem 2000, 1. 20. Andrews, M. J. I.; Tabor, A. B. Tetrahedron 1999, 55, 11711. 21. (a) Crowley, P. J.; Heaney, S. P.; Lawson, K. R.; Youle, D. PCT Int. Appl WO 95 07, 022, Chem. Abstr 1995, 123, 77144. (b) Crowley, P. J. Lawson, K. R.; Mound, W. R. GB 2,291, 872, Chem. Abstr 1996, 125, 10361. (c) Harada, S.; Shirasaki, M. Jpn. Kokai Tokkyo Koho JP 06, 321, 950, Chem. Abstr 1995, 123, 83099.

PAGE 203

181 22. (a) Brown, T. H.; Harling, J. D.; Orlek, B. S. PCT Int. Appl. WO 95 26, 327; Chem. Abstr. 1996, 124, 145497. (b) Lawson, K. R.; Warrington, R. P. Brit. UK Pat. Appl. GB 2, 290, 540, Chem. Abstr 1996, 124, 288995. 23. (a) LeBel, N. A.; Post, M. E.; Whang, J. J. J. Am. Chem. Soc 1964, 86, 3759. (b) Smissman, E. E.; Steinman, M. J. Med. Chem 1967, 10, 1054. 24. Zhu, Y-F.; Yamazaki, T.; Tsang, J. W.; Lok, S.; Goodman, M. J. Org. Chem. 1992, 57, 1074. 25.(a) Patek, M.; Drake, B.; Lebl, M. Tetrahedron Lett. 1994, 35, 9169. (b) Fulop, F.; 8th Blue Danube Symposium on Heterocyclic Chemistry Bled, Slovenia, September 24-27, 2000. Abstract PO26. 26. (a) Horvath-Dora, K.; Toth, G.; Tamas, J.; Clauder, O. Acta Chim. Acad. Sci. Hung. 1977, 94, 345. (b) LeBel, N. A.; Post, M. E.; Whang, J. J. J. Am. Chem. Soc.1964, 86, 3759. (c) Smissman, E. E.; Steinman, M. J. Med. Chem 1967, 10, 1054. 27. (a) Bernath, G.; Kovacs, K.; Lang, K. L. Acta Chim. Acad. Sci. Hung 1970, 64, 183. Satzinger, G. Liebigs Ann. Chem. 1972, 758, 43. (b) Satzinger, G. Liebigs Ann. Chem. 1972 758, (c) Armarego, W. L. F. J. Chem. Soc 1971, 1812. (d) Back, T. G.; Nakajima, K. Tetrahedron Lett. 1997, 38, 989. (e) Becker, D. P.; Husa, R. K.; Moormann, A. E.; Villamil, C. I.; Flynn, D. L. Tetrahedron 1999, 55, 11787. 28. (a) Moriconi, E. J.; Mazzocchi, P. H. J. Org. Chem 1966 31, 1372. (b) Moriconi, E. J.; Crawford, W. C. J. Org. Chem. 1968, 33, 370. (c) Kirmse, W.; Hartmann, M.; Siegfried, R.; Wroblowsky, H.-J.; Zang, B.; Zellmer, V. Chem. Ber. 1981 114, 1793. (d) Mazzocchi, P. H.; Halchak, T.; Tamburin, H. J. J. Org. Chem 1976, 41, 2808. (e) Malpass, J. R.; Tweddle, N. J. J. Chem. Soc., Perkin Trans. 1, 1977, 874.

PAGE 204

182 29. Katagiri, K.; Tori, K.; Kimura, Y.; Yoshida, T.; Nagasaki, T.; Minato, H. J. Med. Chem. 1967, 10, 1149. 30. Parry, R. J.; Bun, H. P J. Am. Chem. Soc. 1983, 105, 7446. 31. Parry, R. J.; Turakhia, R.; Bun, H. P J. Am. Chem. Soc. 1988, 110, 4035 32. Kohno, T.; Kohda, D.; Haruki, M.; Yokoyama, S. J. Bio. Chem 1990 12, 6931. 33. (a) Divanford, H. R.; Lysenko, Z.; Semple J. E.; Wang, P.-C.; Joulli, M. M. Heterocycles, 1981, 16, 1975. (b) Kazmaier, U; Pahler, S; Enderm ann, R; Habich, D; Kroll, H-P; Riedl, B. Bioorg. & Med. Chem. 2002, 10, 3905. 34.(a) Robins, M. J.; Parker, J. M. R. Can. J. Chem. 1983, 317. (b) Chen, S.-Y.; Joulli ,M. M. J. Org. Chem. 1984, 49, 1769. (c) Zhang, J.; Clive, D. L. J. J. Org. Chem. 1999, 64, 1754. (d) Zimmermann, P. J.; Bl anarikova, J.; Jger, V. Angew. Chem. 2000, 112, 936. Angew. Chem. Int. Ed. 2000, 39, 910. 35.Kang, S. H.; Lee, S. B. Chem. Comm. 1998, 761. 36.Van Brunt, M. P.; Standaert, R. F. Org. Lett. 2000, 5, 705. 37. (a) Masamune, T.; Ono, M. Chem. Lett. 1975, 625. (b) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joulli ,M. M. J. Am. Chem. Soc. 1980, 102, 7505. 38. Erdsack, J.; Krause, N. Synthesis, 2007, 23, 3741. 39.(a) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joulli, M. M. J. Am. Chem. Soc. 1980, 102, 7505. (b) Zhang, J. H.; Clive, D. L. J. J. Org. Chem. 1999, 64, 1754. (c) VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000 2, 705. 40. (a) Ghosh, A. K.; Liu, W. J. Org. Chem. 1996, 61, 6175. (b) Hamill, R. L.; Hoehn, M. M. J. Antibiot. 1973, 26 463; (c) Florent, J.; Lunel, J.; Mancy, D. US Patent 4, 1980, 189, 349. (c) Yin, X.; Zhao, G.; Schneller, S. W. Tetrahedron Lett. 2007, 48, 4809.

PAGE 205

183 41. (a) Pugh, C. S.; Borchardt, R. T. Biochemistry 1982, 21,1535; (b) Pugh, C. S. G.; Borchardt, R. T.; Stone, H. O. J. Biol. Chem 1978, 253, 4075.(c) Vedel, M.; Lawrence, F.; Robert-Gero, M.; Lederer, E. Biochem. Biophys. Res. Commun. 1978, 85, 371. (d) Hamill, R. L.; Nagarajan, R. US Patent 4,087,603, 1976. (e) Ferrante, A.; Ljungstrm, L.; Huldt, G.; Lederer, E. Trans. Roy. Soc. Trop. Med. Hyg. 1984, 78, 837. (f) Trager, W.; Tershacovec, M.; Chiang, P. K.; Cantoni, G. L. Exp. Parasitol. 1980, 50, 83. 42. Wurz, R.; P, Charette, A.; B. J. Org. Chem. 2004, 69, 1262. 43. Lee, J-Y; Schiffer, G; Jaeger, V. Org. Lett 2005, 7, 2317. 44. (a) Carr, J. A.; Al-Azemi, T. F.; Long, T. E.; Shim, J. Y.; Coates, C.; Turos, E.; Bisht, K. S. Tetrahedron 2003 59, 9147. (b) Bisht, K. S.; Gross, R. A.; Kaplan, D. L. J. Org. Chem 1999, 64, 780. (c) Garcia-Urdiales, E. ; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313. (d) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides & Nucleotides. 1993, 12, 267. (e) Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33 7287. (f) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, 27, 1255. 45. Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y. J. Org. Chem 2001 66, 5881.

PAGE 206

184 APPENDICES

PAGE 207

APPENDIX ASpectroscopic data for compounds of chapter 2Spectroscopic data for compounds of HO O A c 5 Figure A-1 1H and 13C-NMR of spectra of (+)-(1 S, 4R )4-acetoxylcylcopent-2-en-1-ol ( 5) 185

PAGE 208

186 O OAc6 O OA c 6Figure A-2 1H and 13C-NMR of spectra of ( R )-4-Acetoxy-2-cyclopenten-1-one (6)

PAGE 209

187 HO OH 7 HO OH 7 Figure A-3 1H and 13C-NMR spectra of (1 S, 4R )-1-Methylcyclopent-2-ene-1,4-diol (7)

PAGE 210

HO OH 8 Ph HO OH 8 Ph Figure A-4 1H and 13C-NMR spectra of (1 S, 4R )-1-Phenylethynyl-cyc lopent-4-ene-1,4diol (8) 188

PAGE 211

HO OAc 9 HO OAc 9 Figure A-5 1H and 13C-NMR spectra of (1 R 4S )-4-Hydroxy-4-methyl-2-cyclopenten-1yl Acetate (9) 189

PAGE 212

HO OAc Ph 10 HO OAc Ph 10 Figure A-6 1H and 13C-NMR spectra of (1 R ,4S)-4-Hydroxy-4-phenylethynyl-2cyclopeneten-1-yl Acetate (10). 190

PAGE 213

HO COOEt NO2 11a HO COOEt NO2 11a Figure A-7 1H and 13C-NMR of Ethyl (2 R / S, 1 R 4 S)-2-(4-Hydroxy-2-cyclopenten-1yl)-2-nitroacetate (11a) 191

PAGE 214

HO 11b COOEt NO2 HO 11b COOEt NO2 Figure A-8 1H and 13C-NMR of Ethyl (2R / S, 1 R 4 S )-2-(4-Hydroxy-4-methyl-2cyclopenten-1-yl)-2-nitroacetate ( 11b ). 192

PAGE 215

193 Figure A-9 1H and 13C-NMR of Ethyl (2 R / S, 1 R 4 S)-2-(4-Hydroxy-4-phenylethynyl2-cyclopenten-1-yl)-2-nitroacetate (11c). HO NO2 Ph COOEt 11c HO Ph COOEt NO2 11c

PAGE 216

HO COOEt COMe 11d HO COOEt COMe 11dFigure A-10 1H and 13C-NMR of Ethyl (2 R / S, 1 R 4 S )-2-(4-Hydroxy-2-cyclopenten1-yl)-3oxobutanoate (11d) 194

PAGE 217

195 COMe Figure A-11 1H and 13C-NMR of Ethyl (2 R / S, 1 R 4 S )-2-(4-Hydroxy-4-methyl-2cyclopenten-1-yl)-3-oxobutanoate (11e) HO 11e COOEt COMe HO 11e COOEt

PAGE 218

HO PhSO2 COPh 11f HO PhSO2 COPh 11fFigure A-12 1H and 13C-NMR of 2-Phenylsulfonyl (2 R / S, 1 R 4 S)-2-(4-hydroxy-2cyclopenten-1-yl)-1-phenyl-ethanone (11f). 196

PAGE 219

HO PhSO2 COPh 11g HO PhSO2 COPh 11g Figure A-13 1H and 13C-NMR of 2-Phenylsulfonyl (2 R / S, 1 R 4 S)-2-(4-hydroxy-2cyclopenten-1-yl)-1-phenyl-ethanone (11g). 197

PAGE 220

HO 11h Ph COPh SO2Ph HO 11h Ph COPh SO2Ph Figure A-14 1H and 13C-NMR of 2-Phenylsulfonyl (2 R / S, 1 R 4 S)-2-(4-Hydroxy-4phenylethynyl-2-cyclopente n-1-yl)-1-phenyl-ethanone (11h). 198

PAGE 221

199 11i HO CN COOEt 11i HO CN COO Et Figure A-15 1H and 13C-NMR of Ethyl (2 R / S, 1 R 4 S )-2-(4-Hydroxy-2-cyclopenten1-yl)-2-cyanoacetate (11i)

PAGE 222

HO PhSO2 CN 11j HO PhSO2 CN 11j Figure A-16 1H and 13C-NMR of Ethyl Phenylsulfonyl (2 R / S, 1 R 4 S)-2-(4-Hydroxy2-cyclopenten-1-y l)-2-acetonitrile (11j). 200

PAGE 223

COOMe 11k HO 201 Figure A-17 1H and 13C-NMR of Ethyl 2-(4-Hydroxycyclopent-2enyl)-malonic acid dimethyl ester (11k) 11k HO COOMe COOMe COOMe

PAGE 224

202 Figure A-18 1H and 13C-NMR of Ethyl (2 R / S,1 R 4 S)-2-(4-Acetoxy-2-cyclopenten- -yl)-2-nitroacetate (12a) 12a AcO COOEt NO2 NO2 1 12a AcO COOEt

PAGE 225

AcO COOEt NO2 12b AcO COOEt NO2 12b Figure A-19 1H and 13C-NMR of Ethyl (2R / S 1 R 4 S)-2-(4-Acetoxy-4-methyl-2ten-1-yl)-2-nitroacetate (12b). cyclopen203

PAGE 226

204 1H and 13C-NMR of Ethyl (2R / S,1 R ,4 S)-2-(4-Acetoxy-4-phenylethynyl- -cyclopenten-1-yl)-2-nitroacetate (12c). Figure A-20 2 AcO Ph COOEt NO2 12c NO2AcO Ph COOEt 12c

PAGE 227

205 AcO COOEt COMe 12d COMe AcO COOEt 12d

PAGE 228

206 igure A-21 1H and 13C-NMR of Ethyl (2 R / S,1 R ,4 S)-2-(4-Acetoxy-2-cyclopenten-1(12d). Fyl)-3-oxobutanoate AcO PhSO2 COPh 12f AcO PhSO2 COPh 12f Figure A-22 1H and 13C-NMR of 2-Phenylsulfonyl (2 R / S,1 R ,4 S)-2-(4-Acetoxy-2cyclopenten-1-yl)-1-phenyl-ethanone (12f).

PAGE 229

207 12i AcO CN CO OEt Figure A-23 1H and 13C-NMR of Ethyl (2 R / S,1 R ,4 S)-2-(4-Acetoxy-2-cyclopenten-1l)-2-cyanoacetate (12i). 12i AcO CN COOEt y

PAGE 230

208 PhSO2 Figure A-24 1H and 13C-NMR of Phenylsulfonyl (2 R / S,1 R ,4 S)-2-( 4-Acetoxy-2cyclopenten-1-yl)-2-acetonitrile (12j). AcO CN 12jPhSO2 AcO CN 12j

PAGE 231

209 Figure A-25 1H and 13C-NMR of (1S,5S )-3-Aza-4-(ethoxycarbonyl)-2oxabicyclo[3.3.0]oct-3,7-diene-3-oxide (13a). COOEt O N O13aCOOEt O N O13a

PAGE 232

210 1H and 13C-NMR of (1S,5 S)-3-Aza-4-(ethoxyca rbonyl)-7-methyl-2xabicyclo[3.3.0]oct-3,7-diene-3-oxide (13b) COOEtFigure A-25 o O N O13bCOOEt O N O13b

PAGE 233

COOEt O211 Figure A-2 6 1H and 13C-NMR of (1S,5S)-3-Aza-4-(ethoxycarbonyl )-7-phenylethynyl-2xabicyclo[3.3.0]oct-3,7-diene-3-oxide (13c) oN OPh 13c O N COOEt O13c Ph

PAGE 234

212 O CO OEt Me13d Figure A-27 1H and 13C-NMR of (1S,5S)-4-(ethoxycarb onyl)-3-methyl-2xabicyclo[3.3.0]oct-3,7-diene (13d) O COOEt Me 13do

PAGE 235

213 Figure A-28 1H and 13C-NMR of (1S,5S)-4-(ethoxycarbonyl)-3,7-dimethyl-2xabicyclo[3.3.0]oct-3,7-diene (13e) COOEt O Me 13e COOEto O Me 13e

PAGE 236

214 Figure A-29 1H and 13C-NMR of (1S,5S) -3-phenyl-4-(phenylsulfonyl)-2xabicyclo[3.3.0]oct-3,7-diene (13f) SO2Pho O SO2Ph Ph 13f O Ph 13f

PAGE 237

O SO2Ph Ph 13g O SO2Ph Ph13g Figure A-30 1H and 13C-NMR of (1S,5S)-7-methyl-3-phenyl-4-(phenylsulfonyl)-2oxabicyclo[3.3.0]oct-3,7-diene (13g) 215

PAGE 238

O SO2Ph Ph 13h Ph O SO2Ph Ph 13h Ph 216 Figure A-31 1H and 13C-NMR of (1 S,5S)-3-phenyl-7-phenylethynyl-4-(phenylsulfonyl)2-oxabicyclo[3.3.0]oct-3,7-diene (13h)

PAGE 239

MeOOC COOMe 13k MeOOC COOMe 13k217 2 1H and DEPT-135 of 2-Cyclopent-2-enylidene-malonic acid dimethyl ester 3k) Figure A-3 (1

PAGE 240

APPENDIX B Spectroscopic data for compounds of Chapter 3 O NO2 10a O NO2 10a 1H and 13C-NMR of spectra of 3-(Nitromethyl) cyclopentanone (10a) Figure B-1 218

PAGE 241

O NO2 10b (less polar) O NO2 10b (less polar) igure B-2 1H and 13C-NMR of spectra of 3-(1-Nitroethyl) cyclopentanone (10b-LP) F 219

PAGE 242

O NO2 10b(more polar) O NO2 10b(more polar) igure B-3 1H and 13C-NMR of spectra of 3-(1-Nitroethyl) cyclopentanone (10b-MP) F 220

PAGE 243

221 O NO2 10c (less polar) O NO2 10c (less polar) igure B-4 1H and 13C-NMR of spectra of 3-(1 -Nitropropyl) cyclopentanone (10c-LP) F

PAGE 244

O NO2 10c (more polar) O NO2 10c (more polar) igure B-5 1H and 13C-NMR of spectra of 3-(1 -Nitropropyl) cyclopentanone (10c-MP) F 222

PAGE 245

O NO2 10d O NO2 10d igure B-6 1H and 13C-NMR of spectra of 3-(1 -Nitropropyl) cyclopentanone (10d) F 223

PAGE 246

O NO2 10e O NO2 10e igure B-7 1H and 13C-NMR of spectra of 3-(1-Nitrocyclohexyl) cyclopentanone(10e) F 224

PAGE 247

O O2N 11a O O2N 11a igure B-8 1H and 13C-NMR of spectra of 3-(2-Nitropropane-2-yl) cyclohexanone (11a) F 225

PAGE 248

O 11b NO2 O 11b NO2 igure B-9 1H and 13C-NMR of spectra of 3-(1-Nitrocyclohexyl) cyclohexanone (11b) F 226

PAGE 249

H O NO2 12a H O NO2 12a igure B-10 1H and 13C-NMR of spectra 3-Me thyl-4-nitrohexanal (12a) F 227

PAGE 250

H O NO2 12b H O NO2 12b igure B-11 1H and 13C-NMR of spectra 3,4-D imethyl-4-nitropentanal (12b) F 228

PAGE 251

H O NO2 12c H O NO2 12c igure B-12 1H and 13C-NMR of spectra 3-(1-Nit rocyclohexyl)butyraldehyde (12c) F 229

PAGE 252

OTHP 21 OTHP 21 igure B-13 1H and 13C-NMR of spectra 2-Buta-1,3dienyloxy-tetrahydropyran(21) F 230

PAGE 253

231 APPENDIX C Spectroscopic data for compounds of Chapter 4 Figure C-1 1H and 13C-NMR of (+)ethyl-2amino-2-{(1 R 4 S)-4-hydroxycyclopent-2nyl)}acetate (13a) e NH2 COOEt HO 13a (+)isomer NH2COOEt HO 13a (+)isomer

PAGE 254

NH2 COOEt HO 13b (-)isomer232 NH2 CO OEt HO 13b (-)isomer Figure C-2 1H and 13C-NMR of (-)ethyl-2amino-2-{(1 R 4S)-4-hydroxycyclopent-2nyl)}acetate (13b) e

PAGE 255

233 igure C-3 1H and 13C-NMR of (1S,5S)-3-Aza-4-(ethoxycarbonyl)-2(18) O N COOE t 18 O N COOEt 18Foxabicyclo[3.3.0]oct-3,7-diene

PAGE 256

234 1H and 13C-NMR of (1 S ,4S)-4-methylcyclopent-2-enol (20) HO 20HO 20Figure C-4

PAGE 257

235 igure C-5 1H and 13C-NMR of (1 S ,4S)-1-acetoxy-4-methylcyclopent-2-ene (20) 1H and 13C-NMR of (1 S ,4S)-1-acetoxy-4-methylcyclopent-2-ene (20) A cO 21 A cO 21 F

PAGE 258

236 igure C-6 1H and 13C-NMR of Ethyl (2R / S, 1 S, 4 S )-2-(4-methyl-2-cyclopenten-1yl)-2-nitroacetate (24) C-NMR of Ethyl (2R / S, 1 S, 4 S )-2-(4-methyl-2-cyclopenten-1-nitroacetate (24) O2NFyl)-2 24EtOOC 24EtOOC ON2

PAGE 259

237 ABOUT THE AUTHOR studies in Chemistry from St Stephens Coll ege, Delhi University. Then he pursued a Masters degree in Chemistry from Delhi University. He joined the department of At USF he worked in Professor Kirpal S Bishts laboratories, exploring new methodologies involving palladium catalysts. As a graduate student, Pasha has won various departmental awards including Bu rsa Award, Castle Conference presentation awards. He has also presented his work at various ACS national meetings. His work at Pasha Moeenuddin Khan was born in New Delhi, India. He completed his undergraduate Chemistry at University of South Florida( USF) in Fall 2003 to pursue a doctoral degree. USF has also resulted in publications and patents.


xml version 1.0 encoding UTF-8 standalone no
record xmlns http:www.loc.govMARC21slim xmlns:xsi http:www.w3.org2001XMLSchema-instance xsi:schemaLocation http:www.loc.govstandardsmarcxmlschemaMARC21slim.xsd
leader nam 2200397Ka 4500
controlfield tag 001 002007220
005 20090617140634.0
007 cr mnu|||uuuuu
008 090617s2008 flu s 000 0 eng d
datafield ind1 8 ind2 024
subfield code a E14-SFE0002792
035
(OCoLC)401768065
040
FHM
c FHM
049
FHMM
090
QD31.2 (Online)
1 100
Khan, Pasha Moeenuddin.
0 245
Application of Pd catalyzed alkylation :
b synthesis of bicyclic furans, isoxazolines and new cyclopentane amino acid analogs
h [electronic resource] /
by Pasha Moeenuddin Khan.
260
[Tampa, Fla] :
University of South Florida,
2008.
500
Title from PDF of title page.
Document formatted into pages; contains 237 pages.
Includes vita.
502
Dissertation (Ph.D.)--University of South Florida, 2008.
504
Includes bibliographical references.
516
Text (Electronic dissertation) in PDF format.
520
ABSTRACT: Palladium is probably the most useful metal in organic syntheses. It has shown great utility in various reactions such as C-C, C-N, C-O bond formation under mild conditions. The presence of abundant amount of palladium-chemistry related literature in the form of books, reviews emphasizes the growing importance of these reagents. Nowadays organopalladium chemistry is being used in various fields such as new methodology development, natural product synthesis, synthesis of polymers. Regio- and stereoselectivity is another facet of Pd catalyzed methodologies which has been extensively utilized in the last decade to obtain enantiopure compounds. The main emphasis of this work is to utilize Pd catalyzed allylic alkylation to synthesize new heterocycles including furans, isoxazolines and new cyclopentane amino-acid analogs in an enantioselective manner. The stereochemical outcome of these reactions is influenced by desymmetrization catalyzed by hydrolytic enzymes namely lipases.Chapter 1 reviews the recent advances in the field of palladium catalyzed synthesis of bicyclic furan analogs and provides a mechanistic explanation for these processes. Chapter 2 describes synthesis of new optically pure isoxazoline-2-oxide and furan analogs using Pd(0) catalyzed intramolecular cyclizations. Starting from a meso-diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the synthesis. The stereochemical outcome of the product (>99 % ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations. Chapter 3 describes Pd(0) catalyzed allylic alkylation of allylic esters using various 1, 2 nitroalkanes. This reaction resulted in the formation of nitro substituted aldehydes and ketones via an isomerization-alkylation step. The effect of various solvents, catalyst-ligand systems and bases was also studied.The presence of versatile nitro group in these compounds which can be easily converted to a ketone, reduced to amine or transformed into carboxyl group, imines, hydroxylamines, makes them an attractive starting material for various other synthetic compounds. Chapter 4 describes the chemoenzymatic synthesis of L-carbafuranomycin and related cyclopentane amino acids analogs. The synthesis utilizes the hydrolytic enzymes to induce enantioselectivity in the whole process. Out of all the peptidomimetics and related compounds, unnatural amino acids such as bicyclic and carbocyclic amino acids are of valuable interest as they have provided new building blocks for large number of potential drug candidates. The work presented here provides a more general and efficient route to these class of unnatural amino acids.
538
Mode of access: World Wide Web.
System requirements: World Wide Web browser and PDF reader.
590
Advisor: Kirpal S. Bisht, Ph.D.
653
Palladium
Allylic acetate
Isoxazoline-2-oxides
Furans
Cylcopentane aminoacids
690
Dissertations, Academic
z USF
x Chemistry
Doctoral.
773
t USF Electronic Theses and Dissertations.
4 856
u http://digital.lib.usf.edu/?e14.2792