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 Hx hexane FAB-MS) Hz Hertz Å Ångström (10-10 m) J coupling constant Ar aryl M molar (mol/L) B(ArF)4 tetrakis[3,5- m.p. melting point bis(trifluoromethyl)phenyl]borate MS mass spectroscopy BINAP 2,2’-bis-(diphenylphosphino)- 2-Naph 2-naphthalin 1,1’-bi-naphthalene n.d. not determined BOX bisoxazoline NMR nuclear magnetic resonance br broad (NMR) NOESY nuclear overhause effect c concentration spectroscopy cat. catalyst Pe pentane COD 1,5-cyclooctadien Ph phenyl Conv. conversion PHOX phoshinooxazoline COSY correlation spectroscopy (NMR) ppm parts per million Cy cyclohexyl Py pyridine δ chemical shift rac. racemic DCM dichloromethane Rf retention factor de diastereomeric excess rt room temperature DMF N,N-dimethylformamide tert tertiary DMSO dimethylsulfoxide THF tetrahydrofuran ee enantiomeric excess TLC thin-layer chromatography EI electron impact ionization (MS) TOCSY total correlated spectroscopy eq equivalent Tol toluene ESI electronspray ionization tr retention time EtOAc ethyl acetate w weak FAB fast atom bombardment υ~ wave number (IR) FTIR fourier transform infrared used to illustrate relative GC gas chromatography stereochemistry HMBC heteronuclear multiple-bond used to illustrate absolute correlation (NMR) stereochemistry HMQC heteronuclear multiple quantum coherence HPLC high performance liquid chromatography Chapter 1 Introduction Introduction 1 Introduction 1.1 Racemic Versus Enantiopure Drugs For a long time the decision whether a drug should be developed as a racemate or as an enantiopure compound was left to the institution producing the drug. The situation changed when it was realized that there is often a significant difference between the enantiomers of chiral drugs regarding their pharmacodynamic and pharmacokinetic properties. In addition recent advances in stereoselective synthesis and analysis of chiral molecules helped to make the decision in favour of enantioselective synthesis of chemical entities. At present no regulatory institution has an absolute requirement for the development of enantiopure drugs but if a racemate is presented for marketing then its use must be justified. Arguments like the individual isomers are stereochemically unstable and readily racemize in vitro and/or in vivo or the use of a racemate produces a superior therapeutic effect than either individual enantiomer could for instance support the submission of a racemates. However, the trend towards the development of enantiopure drugs is clearly visible and therefore further development of stereoselective synthesis is highly desirable. This will be demonstrated by the following examples. 1.2 Different Pharmacokinetic Properties of Enantiomers Since drug absorbtion, distribution, metabolism and excretion involve an interaction between the enantiomers of a drug and a chiral biological macromolecule it is hardly surprising that enantioselectivity is observed during these processes.