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  • Asymmetric Metal-Catalyzed [3+2] Cycloadditions of Azomethine Ylides

    Inauguraldissertation

    zur

    Erlangung der Würde eines Doktors der Philosophie

    vorgelegt der

    Philosophisch-Naturwissenschaftlichen Fakultät

    der Universität Basel

    von

    Remo Stohler aus

    Basel und Ziefen/ Basel und Baselland

    Basel 2007

  • Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von:

    Prof. Dr. Andreas Pfaltz

    Prof. Dr. Wolf-Dietrich Woggon

    Basel, den 19.12.2006

    Prof. Dr. Hans-Peter Hauri

    Dekan

  • dedicated to my parents

  • Acknowledgments I would like to express my gratitude to my supervisor, Professor Dr. Andreas Pfaltz for giving

    me the opportunity of joining his group, for his constant support and his confidence as well as

    for the liberty I was given to work at my project.

    Special thanks to Professor Dr. Wolf-Dietrich Woggon for co-examing this thesis and the

    organization of a laboratory course I enjoyed at Kingston University.

    Furthermore I would like to thank Professor Dr. Marcel Mayor for chairing the examen.

    A big thanks goes to Florentine Wahl whose excellent work opened the door to intramolecular

    [3+2] cycloadditions. Dominik Frank is acknowledged for his synthetic work during his

    Wahlpraktikum.

    I am grateful to Markus Neuburger and Dr. Silvia Schaffner as well as to Eva Neumann and

    Stefan Kaiser for recording X-ray data and for refining X-ray structures. Dr. Klaus Kulicke,

    Axel Franzke and Aurélie Toussaint are acknowledged for their countless hours recording 2D

    NMR spectra and their help on the interpretation of the data. Dr. Heinz Nadig recorded the EI

    and FAB mass spectra and Antje Teichert is acknowledged for measuring the ESI mass

    spectra. Werner Kirsch determined all the elemental analyses. I would also like to thank all

    the members of the staff who run the department and make the work efficient and enjoyable.

    Special thanks to Aurélie Toussaint, Antje Teichert, Dr. Matthias Maywald, Dr. Stephen

    Roseblade, Dr. Geoffroy Guillemot and David Woodmansee for proof-reading the

    manuscript.

    A big thanks goes to the past and present members of the Pfaltz group for the good working

    atmosphere and the helpful discussions. I especially like to thank my colleagues from lab 208

    for an enjoyable time.

  • Contents

    1 Introduction 3

    1.1 Racemic Versus Enantiopure Drugs 3 1.2 Different Pharmacokinetic Properties of Enantiomers 3

    1.3 Different Pharmacodynamic Properties of Enantiomers 6

    2 Biological Activity of Pyrrolidines and Resulting Objectives 11

    2.1 Biological Active Pyrrolidines 11

    2.2 Objectives 13

    3 [3+2] Cycloadditions 17

    3.1 General Aspects 17 3.2 Reactivity and Regioselectivity of [3+2] Cycloadditions 19

    3.3 Mechanism of [3+2] Cycloadditions 25

    3.3.1 Concerted versus Stepwise Mechanism 25

    3.3.2 Mechanistic Aspects of [3+2] Cycloadditions of Metal-Stabilized Azomethine Ylides 26

    3.4 Diastereoselectivity of [3+2] Cycloadditions 29

    3.5 Enantioselectivity of [3+2] Cycloadditions 30

    4 Metals and Ligands Employed for [3+2] Cycloadditions of Azomethine Ylides 33

    4.1 Metals Used to Promote [3+2] Cycloaddition Reactions 33 4.2 Chiral Ligands Used for Cu(I)-Catalyzed [3+2] Cycloadditions 33 4.3 Chiral Ligands Used for Cu(II)-Catalyzed [3+2] Cycloadditions 35 4.4 Chiral Ligands Used for Zn(II)-Catalyzed [3+2] Cycloadditions 35

    4.5 Chiral Ligands Used for Ag(I)-Catalyzed [3+2] Cycloadditions 36

    5 Initial Metal and Ligand Screening for the [3+2] Cycloaddition of Azomethine Ylides 41

    5.1 Metal Screening 41

    5.2 Ligand Screening for the Ag(I)-Catalyzed [3+2] Cycloaddition 41

    5.2.1 Optimization of the Reaction Conditions 42

    5.2.2 Application of Different P,N-Ligands to the Ag(I)-Catalyzed [3+2] Cycloaddition 45

    5.2.3 Application of Different P,P-Ligands to the Ag(I)-Catalyzed [3+2] Cycloaddition 48

    5.2.4 Application of an N,N-Ligand to the Ag(I)-Catalyzed [3+2] Cycloaddition 49

    5.2.5 Application of Different Monodentate P-Ligands to the Ag(I)-Catalyzed [3+2] Cycloaddition 50

    5.2.6 Conclusion 51

    5.3 Ligand Screening for the Cu(I)-Catalyzed [3+2] Cycloaddition 52

    5.3.1 Application of Different P,N-Ligands to the Cu(I)-Catalyzed [3+2] Cycloaddition 52

    5.3.2 Application of Different P,P-Ligands to the Cu(I)-Catalyzed [3+2] Cycloaddition 54

    5.3.3 Application of an N,N-Ligand to the Cu(I)-Catalyzed [3+2] Cycloaddition 55

  • 5.3.4 Conclusion 55

    5.4 Au(I)-Catalyzed [3+2] Cycloaddition 56

    5.4.1 Application of Different PHOX-Ligands to the Au(I)-Catalyzed [3+2] Cycloaddition 57

    5.4.2 Conclusion 58

    5.5 Final Conclusion 59

    6 Phosphinooxazolines 63

    6.1 General Aspects 63 6.2 Synthesis of C5-Disubstituted Phosphinooxazoline Ligands 63 6.3 Synthesis of Phosphinooxazoline Ligands Bearing Two Chirality Centers at the Oxazoline Unit

    69

    7 Optimization of the Ligand Structure for Ag(I)-Catalyzed [3+2] Cyclo-additions 73

    7.1 Introduction 73 7.2 Influence of Different Substituents at the Phosphorous Atom of the PHOX Ligand 74 7.3 Influence of Different Substituents at the Phenyl Backbone of the PHOX Ligand 76 7.4 Influence of Different Substituents at the C4 Position of the Oxazoline Ring 77 7.5 Influence of Different Substituents at the C5 Position of the Oxazoline Ring 78

    7.5.1 Influence of an Additional Chirality Center at the C5 Position of the PHOX Ligand 80 7.6 Conclusion 81

    8 Scope of the Asymmetric Ag(I)-Catalyzed Intermolecular [3+2] Cycloaddition 85

    8.1 Application of Differently Substituted Azomethine Ylides 85 8.2 Application of Differently Substituted Dipolarophiles 88 8.3 Conclusion 91

    9 Asymmetric Ag(I)-Catalyzed Intramolecular [3+2] Cycloadditions of Azomethine Ylides 95

    9.1 Introduction 95 9.2 Substrate Synthesis 98 9.3 Influence of Solvent and Reaction Temperature 99 9.4 Ligand Screening for the Ag(I)-Catalyzed Intramolecular [3+2] Cycloaddition 100 9.5 Absolute Configuration of a Tricyclic Product 101 9.6 Scope of the Ag(I)-Catalyzed Intramolecular [3+2] Cycloaddition 102 9.7 Aliphatic Substrates for the Intramolecular [3+2] Cycloaddition 106 9.8 Conclusion 107

    10 Structural Elucidation of a Ag(I)-PHOX Complex 111

    11 Ir(I)-Complexes of C5-Substituted PHOX Ligands as Catalysts for the Asym-metric Hydrogenation

    of Olefins and Imines 115

    11.1 Introduction 115

  • 11.2 Application of Ir(I)-Complexes Derived from C5-Substituted PHOX Ligands to Asymmetric Hydrogenation 118

    11.3 Conclusion 123

    12 Asymmetric Metal-Catalyzed [3+2] Cycloadditions of Azomethine Ylides 127

    13 Experimental Part 131

    13.1 Analytical Methods 131 13.2 Working Techniques 132 13.3 Synthesis of PHOX Ligands 133

    13.3.1 Synthesis of C5-Disubstituted PHOX Ligands 133 13.3.2 Synthesis of PHOX Ligands Bearing Two Chirality Centers at the Oxazoline Unit 164

    13.4 [3+2] Cycloadditions 173 13.4.1 Synthesis of Subatrates for [3+2] Cycloadditions 173 13.4.2 Asymmetric Ag(I)-Catalyzed [3+2] Cycloadditions 190

    13.5 Asymmetric Hydrogenation of Olefines and Imines 209 13.5.1 Preparation of Ir(I)-PHOX Complexes 209 13.5.2 Asymmetric Hydrogenations 225

    14 Appendix 231

    14.1 X-Ray Crystal Structures 231

    15 Bibliography 237

  • Introduction

    Abbreviations 3-NBA 3-nitro-benzyl alcohol (matric for

    FAB-MS) Å Ångström (10-10 m) Ar aryl B(ArF)4 tetrakis[3,5-

    bis(trifluoromethyl)phenyl]borate BINAP 2,2’-bis-(diphenylphosphino)-

    1,1’-bi-naphthalene BOX bisoxazoline br broad (NMR) c concentration cat. catalyst COD 1,5-cyclooctadien Conv. conversion COSY correlation spectroscopy (NMR) Cy cyclohexyl δ chemical shift DCM dichloromethane de diastereomeric excess DMF N,N-dimethylformamide DMSO dimethylsulfoxide ee enantiomeric excess EI electron impact ionization (MS) eq equivalent ESI electronspray ionization EtOAc ethyl acetate FAB fast atom bombardment FTIR fourier transform infrared GC gas chromatography HMBC heteronuclear multiple-bond

    correlation (NMR) HMQC heteronuclear multiple quantum

    coherence HPLC high performance liquid

    chromatography

    Hx hexane Hz Hertz J coupling constant M molar (mol/L) m.p. melting point MS mass spectroscopy 2-Naph 2-naphthalin n.d. not determined NMR nuclear magnetic resonance NOESY nuclear overhause effect

    spectroscopy Pe pentane Ph phenyl PHOX phoshinooxazoline ppm parts per million Py pyridine rac. racemic Rf retention factor rt room temperature tert tertiary THF tetrahydrofuran TLC thin-layer chromatography TOCSY total correlated spectroscopy Tol toluene tr retention time w weak υ~ wave number (IR) used to illustrate relative

    stereochemistry used to illustrate absolute

    stereochemistry

  • Chapter 1

    Introduction

  • Introduction

    3

    1 Introduction

    1.1 Racemic Versus Enantiopure Drugs

    For a long time the decision whether a drug should be developed as a racemate or

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