_____________________________ Asymmetric Catalysis: Ligand Design and Conformational Studies Kristina Hallman Stockholm 2001 Royal Institute of Technology Department of Chemistry Organic Chemistry ______________________________ Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av filosofie doktorsexamen i organisk kemi, fredagen den 14:e december, 2001, kl 13.00 i Kollegiesalen, Administrationsbyggnaden, KTH, Valhallavägen 79, Stockholm. Avhandlingen försvaras på engelska. ISBN: 91-7283-200-2 ISRN KTH/IOK/FR—01/67-SE ISSN 1100-7974 TRITA-IOK Forskningsrapport 2001:67 Kristina Hallman, Stockholm 2001 Tryck: Nykopia Global Print AB, Stockholm 2001 Hallman, Kristina; Asymmetric Catalysis: Ligand Design and Conformational Studies. Royal Institute of Technology, Stockholm, December 2001 Abstract This thesis deals with the design of ligands for efficient asymmetric catalysis and studies of the conformation of the ligands in the catalytically active complexes. All ligands developed contain chiral oxazoline heterocycles. The conformations of hydroxy- and methoxy-substituted pyridinooxazolines and bis(oxazolines) during Pd-catalysed allylic alkylations were investigated using crystallography, 2D-NMR techniques and DFT calculations. A stabilising OH-Pd interaction was discovered which might explain the difference in reactivity between the hydroxy- and methoxy-containing ligands. The conformational change in the ligands due to this interaction may explain the different selectivities observed in the catalytic reaction. Polymer-bound pyridinooxazolines and bis(oxazolines) were synthesised and employed in Pd-catalysed allylic alkylations with results similar to those of monomeric analogues; enantioselectivities up to 95% were obtained. One polymer-bound ligand could be re-used several times after removal of Pd(0). The polymer-bound bis(oxazoline) was also used in Zn-catalysed Diels-Alder reactions, but the heterogenised catalyst gave lower selectivities than a monomeric analogue. A series of chiral dendron-containing pyridinooxazolines and bis(oxazolines) were synthesised and evaluated in Pd-catalysed allylic alkylations. The dendrons did not seem to have any influence on the selectivity and little influence on the yield when introduced in the pyridinooxazoline ligands. In the bis(oxazoline) series lower generation dendrimers had a postive on the selectivity, but the selectivity and the activity decreased with increasing generation. Crown ether-containing ligands were investigated in palladium-catalysed alkylations. No evidence of a possible interaction between the metal in the crown ether and the nucleophile was discovered. A new type of catalyst, an oxazoline-containing palladacycle was found to be very active in oxidations of secondary alcohols to the corresponding aldehydes or ketones. The reactions were performed with air as the re-oxidant. Therefore, this is an enviromentally friendly oxidation method. Keywords: asymmetric catalysis, chiral ligand, oxazolines, conformational study, allylic substitution, polymer-bound ligands, dendritic ligands, crown ether, oxidations, palladacycle. Table of Contents Abstract List of Publications Abbrevations 1. Introduction 1 1.1 Asymmetric Catalysis 1 1.2 Allylic Alkylation 2 1.2.1 Background 2 1.2.2 Mechanism 3 1.3 Aim of the Study 7 2. Ligand Influence on the Asymmetric Induction 8 2.1 Background 8 2.2 Conformational Studies upon Steric Effects 12 2.2.1 Pyridyl Alcohol Ligands 12 2.2.2 Bis(oxazoline) Ligands 21 2.3 Electronic Effects 25 3. Polymer-Bound Ligands in Asymmetric Catalysis 27 3.1 Background 27 3.2 Polymer-Bound Pyridinooxazolines 29 3.2.1 Synthesis 29 3.2.2 Evaluation in the Allylic Alkylation 31 3.3 Polymer-Bound Bis(oxazoline) Ligands 32 3.3.1 Background 32 3.3.2 Synthesis 34 3.3.3 Evaluation in the Allylic Alkylation 34 3.3.4 Evaluation in the Diels-Alder Reaction 35 4. Dendrimers and Dendrons in Asymmetric Catalysis 38 4.1 Background 38 4.2 Synthesis and Evaluation in the Allylic Alkylation 43 5. Asymmetric Catalysis using Crown Ethers as Ligands 47 5.1 Background 47 5.2 Synthesis of Ligands and Evaluation of Rate Enhancement In the Allylic Alkylation 47 6. Palladium-Catalysed Oxidations using Air as Reoxidant 50 6.1 Background 50 6.2 Evaluation of the Catalyst 50 7. Concluding Remarks 53 Acknowledgments 54 List of Publications I. (Hydroxyalkyl)pyridinooxazolines in Palladium-Catalyzed Allylic Substitutions. Conformational Preferences of the Ligand Svensson, M.; Bremberg, U.; Hallman, K.; Csöregh, I.; Moberg, C. Organometallics, 1999, 18, 4900. II. OH-Pd(0) Interaction as a Stabilizing Factor in Palladium Catalyzed Allylic Alkylations Hallman, K.; Svensson, M.; Moberg, C. Manuscript. III. Enantioselective allylic alkylation using polymer-supported palladium catalysts Hallman, K.; Macedo, E.; Nordström, K.; Moberg, C. Tetrahedron: Asymmetry 1999, 10, 4037. IV. Polymer-bound bis(oxazoline) as a chiral catalyst Hallman, K.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 1475. V. Dendritic Oxazoline Ligands in Enantioselective Palladium-Catalyzed Allylic Alkylations Hallman, K.; Malkoch, M.; Lutsenko, S.; Malmström, E.; Hult, A.; Moberg, C. Manuscript. VI. Chiral Ditopic Receptors Application to Palladium-Catalyzed Allylic Alkylation Bourguignon, J.; Bremberg, U.; Dupas, G.; Hallman, K.; Hortala, L.; Levacher, V.; Lutsenko, S.; Macedo, E.; Moberg, C.; Quéguiner, G.; Rahm, F. Manuscript. VII. Palldium(II)-Catalyzed Oxidation of Alcohols with Air as Reoxidant Hallman, K.; Moberg, C. Adv. Synth. Catal. 2001, 343, 260. The published papers were reprinted with kind permission from WILEY-VCH Verlag GmbH, Pappelallee, 3D-69469 Weinheim, Germany; The American Chemical Society, 1155 Sixteenth Street, N. W., Washington, DC 20036, USA and Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington, OX5 1GB, UK. Abbreviations BINAP 2,2-Bis(diphenylphosphanyl)-1,1'-binaphtyl BINOL 1,1'-Bi(2-naphthol) B3LYP A hybrid density functional method BSA N,O-Bis(trimethylsilyl)acetamide COSYgs Correlation spectroscopy, gradient spectroscopy; a 2D-NMR method that is used to detect heteronuclear couplings DCC N,N-Dicyclohexylcarbodiimide DDB 2,3-Dimethoxy-1,4-bis(dimethylamino)butane DEAD Diethyl azodicarboxylate DIOP 1,4-Bis(diphenylphosphino)-1,4-dideoxy-2,3-O-isopropylidene- threitol DiPAMP 1,2-Bis[(o-methoxy)phenylphosphino]ethane DFT Density Functional Theory DMAP 4-(Dimethylamino)pyridine DPCM A method used to calculate solvent effects dppf 1,1'-Bis(diphenylphosphino)ferrocene DPTS 4-(Dimethylamino)pyridinium-4-toluenesulfonate EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HMQCgs Heteronuclear multiple quantum coherence, gradient spectrsocopy; a 2D-NMR method that is used to detect homonuclear couplings lacvp* A basis set used in DFT calculations NOSEY Nuclear Overhauser effect spectroscopy PEG Poly(ethylene glycol) PS Polystyrene rac Racemate 1 Introduction 1.1 Asymmetric Catalysis The need for enantiopure compounds is increasing since the pharmaceutical industry today has limited use for racemates. The technique that still is the most popular for furnishing enantiopure material is resolution of racemates, despite the fact that the yield of the desired enantiomer is at best 50% using traditional methods. If the undesired enantiomer cannot be racemised and recycled it will also give rise to a waste problem. The use of chiral auxiliaries gives rise to the same problem; a lot of waste is generated if the auxiliary can not be reused. Since enantiopure starting materials from the chiral pool are not always available (particularly on a large scale), an attractive alternative method is enantioselective catalysis. There are basically two kinds of catalysts that can be used, biocatalysts and chiral synthetic catalysts. Why industry today, 30 years after the discovery of asymmetric catalysis, still uses “old-fashioned” methods may be due to several reasons. The price of the metal and the chiral catalyst along with the difficulties associated with the recycling and separation of the catalyst are maybe the most important factors. Nature is an expert in the synthesis of enantiopure compounds; the technique used is enzymatic enantioselective catalysis. Many scientists have, since the end of the sixties, tried to mimic the enantioselective processes mediated by enzymes and to achieve this, a plethora of chiral ligands have been developed. Some of these systems have levels of activity and selectivity approaching those of an enzyme. Several catalytic reactions have been developed allowing enantioselective formation of C-H, C-C, C-O, C-N, and other bonds, often with excellent results in terms of efficiency and selectivity. The two most important aspects of a new catalyst are its ability to increase reaction rate and improve enantioselectivity. This can be achieved via appropriate molecular architecture of the catalyst and optimised reaction conditions. In the design of a new, successful catalyst, the steric and electronic properties of the ligand as well as the nature of the metal are important. The metals used are usually transition metals. The ideal ligand should be easily accessible and the ligand- structure should be labile to systematic modification, allowing optimisation for participation in a specific application. 1 The aim of this introduction is to provide a background to the chemistry described in this thesis and not to give a review. There are several excellent reviews on this area. 1 1.2 Allylic Alkylation