TECHNISCHE UNIVERSITÄT MÜNCHEN FACHGEBIET FÜR ORGANISCHE CHEMIE Enantio-recognition of Oxoanions by Chiral Bicyclic Guanidinium Hosts Ashish Tiwari Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. M. Schuster Prüfer der Dissertation: 1. Univ.-Prof. Dr. F. P. Schmidtchen 2. Univ.-Prof. Dr. K. Köhler Die Dissertation wurde am 18.01.2012 bei der Technischen Universität München eingereicht und durch die Fakultät für Chemie am 22.02.2012 angenommen. To my parents Acknowledgements Work presented in this thesis was carried out from January 2009 to December 2011 in the Department of Organic Chemistry and Biochemistry at Technical University of Munich. I would like to thank Prof. Dr. F. P. Schmidtchen for his continuous encouragement and support. The work would not have been complete without his patience and understanding. His vast experience in the field of organic and supramolecular chemistry helped me to overcome every obstacle during the work. I would like to thank Mrs. Otte, Mr. Kaviani and Mr. Cordes for providing me mass spectra of the compounds prepared in this work. I would also like to thank Prof. Dr. Herbert Mayr for allowing me to use ITC facilities in his lab. I would take the opportunity to thank Dr. Wiebke Antonius and Dr. Laxman Malge for their continuous help throughout these years. I wish to thank Andrei Ursu for his help and fruitful discussions during the stay in laboratory. I thank all my friends for their support and encouragement throughout this period. I would be grateful to my parents and family members for their love and constant encouragement. Abbreviations Ac Acetyl Ala Alanine AMBER Assisted Model Building with Energy Refinement Arg Arginine Ar Aromatic Bn Benzyl t-Boc tert-Butoxycarbonyl bp boiling point CFF Consistent Force Field δ chemical shift d dublet DABCO 1,4-Diazabicyclo(2.2.2)-octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DCE 1,2-Dichloroethane DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DNA Deoxyribonucleic acid EDIPA Ethylenediisopropylamine ESI Electron Spray Ionization FT Fourier Tansform GROMOS GROningen MOlecular Simulation HPLC High Performance Liquid Chromatography IR Infrared ITC Isothermal Titration Calorimetry Kass Association Constant LDA Lithiumdiisopropylamide Lys Lysine MD Molecular Dynamics mp Melting point MPLC Medium pressure liquid chromatography MS Mass Spectroscopy MTBE Methyl tert butyl ether NAD+ Nicotinamide adenine dinucleotide NMR Nuclear magnetic resonance ppm Parts per million RCM Ring closing metathesis RMSD Root mean square deviation RP Reversed phase Rt Retention time RT Room temperature S singulet SPE Solid phase extraction t triplet TBDPS tert.–butyldiphenylsilyl t-Bu tert.-butyl TEA Triethylamine Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography Ts Tosyl UV Ultraviolet Val Valine VIS Visible ADP Adenosine 5’-diphosphate AMP Adenosine 5’-monophosphate ATP Adenosine 5’-triphosphate GMP Guanosine monophosphate Contents 1. Introduction ............................................................................ 1 1.1 Guanidinium based chiral receptors...................................................................................... 3 1.2 Enantiorecognition of carboxylates ...................................................................................... 8 1.2.1 Binaphthyl Based Receptors .......................................................................................... 8 1.2.2 Other Chiral Host Systems........................................................................................... 13 1.3 Equilibrium Ring Closing Metathesis (ERCM) .................................................................. 19 1.3.1 Reaction Time: ............................................................................................................. 20 1.3.2 Temperature: ................................................................................................................ 21 1.3.3 Concentration: .............................................................................................................. 22 1.3.4 Addition of a more reactive catalyst: ........................................................................... 23 1.3.5 Perturbing Equilibria:................................................................................................... 24 1.3.6 Microwave Assisted Ring Closing Metathesis: ........................................................... 27 2. Aim of the work ..................................................................... 29 3. Synthesis ............................................................................... 32 3.1 Synthesis of the macrocyclic bisphenol guanidinium host 116 .......................................... 32 3.2 Synthesis of the macrocyclic estradiol guanidinium host 124 ............................................ 41 4. Results and discussions of binding studies ........................... 48 4.1 ITC titration of host 115 with different chiral oxoanions ................................................... 54 4.2 ITC Titrations of the host 116 with different chiral oxoanions .......................................... 57 4.3 ITC titration of Host 117 with different chiral oxoanions .................................................. 61 4.4 ITC titration of host 120 with different chiral oxoanions ................................................... 64 4.5 ITC titration of host 122 with different chiral oxoanions ................................................... 67 4.6 ITC titration of host 124 with different chiral oxoanions ................................................... 70 4.6.1 ITC titrations in acetonitrile ......................................................................................... 70 4.6.2 ITC titrations in 1,2-dichloroethane ............................................................................. 72 4.7 Molecular Dynamics Simulations ....................................................................................... 74 4.7.1 MD simulations of host 116 with phosphate guests (81 and 82) ................................. 78 4.7.2 MD simulations of host 116 with phosphinate guests (85 and 86) .............................. 81 4.7.3 MD simulations of host 116 with mandelate guests (87 and 88) ................................. 84 4.7.4 MD simulations of host 115 with mandelate guest 87 ................................................. 86 4.7.5 MD simulations of estradiol host 120 with phosphate guests (81 and 82) .................. 87 5. Experimental Procedures ..................................................... 89 5.1 Reagents, Methods and Materials ....................................................................................... 89 5.2 Synthetic Procedures ........................................................................................................... 91 5.3 Experiments in-silico ........................................................................................................ 102 5.3.1 Topology file for guanidinium host 116 (MAC1) ..................................................... 103 5.3.2 Topology file for guanidinium host 120 (ESTO) ...................................................... 107 5.3.3 Topology file for binaphthyl phosphate guests 81 and 82 (RBNP and SBNP) ......... 112 5.3.4 Topology file for diphenyl phosphinate guests 85 and 86 (RDPP and SDPP) .......... 115 5.3.5 Topology file for mandelate guests 87 and 88 (MANR and MANS) ........................ 117 6. Summary ............................................................................. 119 7. References .......................................................................... 121 1. Introduction Whether or not a host-guest complex under study complies with the ultimate model of structural uniqueness, i.e., the lock-and-key picture, is of prime importance for addressing the various goals of molecular recognition1 The singularity of the binding mode plays a predominant role in all supramolecular applications targeting a peculiar geometrical identity as in assembly processes or in catalyses depending on a specific stereoelectronic disposition of the interaction partners. In contrast, supramolecular interactions aiming at maximum affinity for, e.g., two-phase extraction or rigorous blocking of a receptor site have less demand for structural uniqueness. The discrimination between two structures that exclusively differ in their geometry as it occurs in enantiorecognition clearly belongs to the former domain. Recognition of enantiomers of chiral anions holds an important place among various applications of supramolecular chemistry. Enantioselective anion sensing is included in a number of reviews covering much broader subjects, namely receptors of anions in general 1c, 2 and chromophoric sensors of anions3. There are also more specialized reviews dealing with receptors for anions based on amides4, guanidiniums5, crown ethers6, or lanthanoids7. The chemical and more importantly biological activity of any chiral substance depends on its stereochemistry, so recognition of these enantiomers depends exclusively on geometrical factors, but not at all on the differences in chemical nature or solvation of the competing partners. This is why design, synthesis and structure-activity relationships of enantioselective receptors are still very