Impact of Secondary Interactions in Asymmetric Catalysis Anders Frölander Doctoral Thesis Stockholm 2007 Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 1:a juni kl 10.00 i sal D3, KTH, Lindstedtsvägen 5, Stockholm. Avhandlingen försvaras på engelska. Opponent är Professor Gerard van Koten, Utrecht University, Nederländerna. ISBN 978-91-7178-676-0 ISSN 1654-1081 TRITA-CHE-Report 2007: 29 © Anders Frölander Universitetsservice US AB, Stockholm Abstract This thesis deals with secondary interactions in asymmetric catalysis and their impact on the outcome of catalytic reactions. The first part revolves around the metal-catalyzed asymmetric allylic alkylation reaction and how interactions within the catalyst affect the stereochemistry. An OH–Pd hydrogen bond in Pd(0)–π-olefin complexes of hydroxy-containing oxazoline ligands was identified by density functional theory computations and helped to rationalize the contrasting results obtained employing hydroxy- and methoxy-containing ligands in the catalytic reaction. This type of hydrogen bond was further studied in phenanthroline metal complexes. As expected for a hydrogen bond, the strength of the bond was found to increase with increased electron density at the metal and with increased acidity of the hydroxy protons. The second part deals with the use of hydroxy- and methoxy-containing phosphinooxazoline ligands in the rhodium- and iridium-catalyzed asymmetric hydrosilylation reaction. The enantioselectivities obtained were profoundly enhanced upon the addition of silver salts. This phenomenon was explained by an oxygen–metal coordination in the catalytic complexes, which was confirmed by NMR studies of an iridium complex. Interestingly, the rhodium and iridium catalysts nearly serve as pseudo-enantiomers giving products with different absolute configurations. The final part deals with ditopic pyridinobisoxazoline ligands and the application of their metal complexes in asymmetric cyanation reactions. Upon complexation, these ligands provide catalysts with both Lewis acidic and Lewis basic sites, capable of activating both the substrate and the cyanation reagent. Lanthanide and aluminum complexes of these ligands were found to catalyze the addition of the fairly unreactive cyanation reagents ethyl cyanoformate and acetyl cyanide to benzaldehyde, whereas complexes of ligands lacking the Lewis basic coordination sites failed to do so. Keywords: asymmetric catalysis, secondary interaction, hydrogen bond, chiral ligand, allylic alkylation, hydrosilylation, cyanation, pymox, box, PHOX, pybox, palladium, iridium, rhodium, Lewis acid, Lewis base List of Publications This thesis is based on the following papers, referred to in the text by their Roman numerals I–V. I. OH–Pd(0) Interaction as a Stabilizing Factor in Palladium-Catalyzed Allylic Alkylations Kristina Hallman, Anders Frölander, Tebikie Wondimagegn, Mats Svensson, and Christina Moberg Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5400-5404. II. OH–Pd Hydrogen Bonding in Pd(0)–Olefin Complexes Containing Hydroxy-Substituted Ligands Anders Frölander, Ingeborg Csöregh, and Christina Moberg Preliminary manuscript. III. Conformational Preferences and Enantiodiscrimination of Phosphino-4- (1-hydroxyalkyl)oxazoline–Metal–Olefin Complexes Resulting from an OH–Metal Hydrogen Bond Anders Frölander, Serghey Lutsenko, Timofei Privalov, and Christina Moberg J. Org. Chem. 2005, 70, 9882-9891. IV. Ag+-Assisted Hydrosilylation: Complementary Behavior of Rh and Ir Catalysts (Reversal of Enantioselectivity) Anders Frölander and Christina Moberg Org. Lett. 2007, 9, 1371-1374. V. Bifunctional Pybox Ligands – Application in Cyanations of Benzaldehyde Anders Frölander, Mélanie Tilliet, Stina Lundgren, Vincent Levacher, and Christina Moberg Preliminary manuscript. Abbreviations and Acronyms Å angstrom abs conf absolute configuration acac acetylacetone box bisoxazoline BSA N,O-bis(trimethylsilyl)acetamide B3LYP 3-parameter hybrid Becke exchange/Lee–Yang–Parr correlation b/l branched/linear cat catalyst cod 1,5-cyclooctadiene conv conversion dba dibenzylideneacetone DFT density functional theory DMAP 4-(N,N-dimetylamino)pyridine DMF dimethylformamide DMM dimethyl malonate DMSO dimethyl sulfoxide EDC-HCl 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride ee enantiomeric excess ent enantiomer EXSY exchange spectroscopy GC gas chromatography HOBt 1-hydroxybenzotriazole HPLC high-performance liquid chromatography MS mass spectrometry NMM N-methylmorpholine NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Nu nucleophile PHOX phosphinooxazoline pybox pyridinobisoxazoline pymox pyridinooxazoline rt room temperature THF tetrahydrofuran Ts para-toluenesulfonyl Table of Contents 1. Introduction.....................................................................................................1 1.1 Secondary Interactions in Asymmetric Catalysis...................................1 1.2 Aim of This Thesis.....................................................................................3 2. OH–Metal Hydrogen Bond and its Consequences for Enantioselection ....5 2.1 Introduction...............................................................................................5 2.1.1 Transition Metal-Catalyzed Asymmetric Allylic Substitutions ...............5 2.2 Contrasting Behavior of Hydroxy-Containing Oxazoline Ligands in Asymmetric Allylic AlkylationsI ..................................................................11 2.2.1 Hydroxy- and Methoxy-Functionalized Bisoxazolines..........................13 2.3 The Hydroxy–Metal Hydrogen BondII ..................................................19 2.3.1 Experimental Studies .............................................................................19 2.3.2 Computational Studies ...........................................................................21 2.4 Application of Hydroxy- and Methoxy-Substituted Phosphinooxazoline Ligands in Asymmetric Allylic AlkylationsIII...........23 2.4.1 Ligand Synthesis....................................................................................23 2.4.2 Initial Computations...............................................................................25 2.4.3 Palladium-Catalyzed Allylations of Linear Substrates...........................27 2.4.4 Additional Computations .......................................................................29 2.4.5 Palladium-Catalyzed Allylations of Cyclic Substrates...........................31 2.4.6 Iridium Catalysis ....................................................................................32 2.5 Conclusions..............................................................................................34 3. Oxygen-Metal Coordination and its Consequences for Enantioselection 35 3.1 Introduction.............................................................................................35 3.1.1 Hydrosilylations.....................................................................................35 3.2 Hydroxy-Containing PHOX Ligands – Application in Rhodium- and Iridium-Catalyzed HydrosilylationsIV .........................................................37 3.2.1 Hydrosilylations of Prochiral Ketones ...................................................37 3.2.2 Study of the Oxygen–Metal Coordination .............................................40 3.3 Conclusions..............................................................................................41 4. Bifunctional Lewis Acid – Lewis Base Catalysis ........................................43 4.1 Introduction.............................................................................................43 4.1.1 Asymmetric Addition of Cyanide to Carbonyl Compounds ..................43 4.2 Ditopic Pybox Ligands – Application in Cyanations of AldehydesV...44 4.2.1 Synthesis of Amino-Functionalized Pybox Ligands ..............................44 4.2.2 Cyanations of Benzaldehyde..................................................................46 4.3 Conclusions..............................................................................................49 5. Concluding Remarks and Outlook ..............................................................51 6. Acknowledgements........................................................................................53 7. References......................................................................................................55 1 Introduction Asymmetric catalysis is one of the most important methodologies for producing chiral enantiomerically enriched substances. Its main advantage lies in the possibility of transferring the chirality of a small amount of reagent, the catalyst, to a large amount of product. Asymmetric catalysis may be divided into biocatalysis, organocatalysis, and metal catalysis. The 2001 Nobel Prize in Chemistry was entirely devoted to the latter. A metal catalyst normally consists of a chiral ligand bound to a metal. Several catalytic reactions, allowing highly enantioselective formation of C–H, C–O, C– C, C–N as well as many other bonds, have been developed. More and more insight is gained regarding the mechanisms of catalytic reactions, but none or few of these reactions are fully understood. A totally rational design of a catalyst is therefore at this point not possible. In addition to the steric and electronic properties