Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 626 _____________________________ _____________________________ Development and Application of New Chiral β-Amino Alcohols in Synthesis and Catalysis Use of 2-Azanorboryl-3-Methanols as Common Intermediates in Synthesis and Catalysis BY PEDRO PINHO ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy in Organic Chemistry presented at Uppsala University in 2001 ABSTRACT Pinho, P. 2001. Development and Application of New Chiral β-Amino Alcohols in Synthesis and Catalysis. Use of 2-Azanorbornyl-3-Methanols as Common Intermediates in Synthesis and Catalysis. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 626. 43 pp. Uppsala. ISBN 91-554-5091-9. The development and application of unnatural amino alcohols, prepared via hetero-Diels-Alder reactions, in synthesis and catalysis is described. The studies are concerned with the [i] scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents, [ii] application of amino alcohols in the ruthenium transfer hydrogenation of ketones, [iii] use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones, and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i] The use of chiral exo-2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl- amines is described. At the same time the scope of the hetero-Diels-Alder reaction, used in their preparation, is extended by manipulations of the dienophiles. [ii] Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones. This ligand (2 mol%) in combination with [RuCl2(p-cymene)]2 (0.25 mol%) gave rise to a very fast reaction (1.5 h) leading to the reduced products in excellent yields and enantioselectivities (up to 97% ee). [iii] Preparation of α-disubstituded 2-azanorbornyl-3-methanols, in situ generation of the corresponding oxazaborolidines, and use of the latter in reduction of aromatic ketones. Concentration, solvent, and temperature effects on the reaction outcome are described. [iv] Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N- (diphenylphosphinoyl) imines. Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results. Up to 98% ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N- (diphenylphosphinoyl) imines are described. Key words: Asymmetric synthesis, hetero-Diels-Alder reactions, chiral cyclopentyl-amines, chiral ligands and catalysts, amino alcohols, asymmetric reductions, ruthenium transfer hydrogenation, oxazaborolidines, asymmetric additions, dialkylzinc reagents. Pedro Pinho, Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden. [email protected] © Pedro Pinho 2001 ISSN 1104-232X ISBN 91-554-5019-9 Printed in Sweden by Uppsala Universitet Tryck & Medier, Uppsala 2001 Watching fate as it flows down the path we have chose -Trent Raznor 3 Papers included in the thesis This thesis is based on the following papers and appendix, referred to in the text by their Roman numerals I-VIII. I. Diels-Alder Reaction of Heterocyclic Imine Dienophiles. Pinho, P.; Hedberg, C.; Roth, P.; Andersson, P. G. J. Org. Chem. 2000, 65, 2810-2812. II. A novel synthesis of chiral cyclopentyl- and cyclohexyl-amines. Pinho, P.; Andersson, P. G. Chem. Commun. 1999, 597-598. III. (1S, 3R, 4R)-2-Azanorbornylmethanol, an Efficient Ligand for Ruthenium- Catalyzed Asymmetric Transfer Hydrogenation of Ketones. Pinho, P.; Alonso, D. A.; Guijarro, D.; Temme, O.; Andersson, P. G. J. Org. Chem. 1998, 63, 2749-2751. IV. (1S, 3R, 4R)-2-Azanorbornyl-3-methanol Oxazaborolidines in the Asymmetric Reduction of Ketones. Pinho, P.; Guijarro, D.; Andersson, P. G. Tetrahedron 1998, 54, 7897-7906. V. Enantioselective Addition of Dialkylzinc Reagents to N-(Diphenylphosphinoyl) Imines Promoted by 2-Azanorbornylmethanols. Pinho, P.; Guijarro, D.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530-2535. VI. A Theoretical and Experimental Study of the Asymmetric Addition of Dialkylzinc to N-(Diphenylphosphinoyl)benzalimine. Pinho, P.; Brandt, P.; Hedberg, C.; Lawonn, K.; Andersson, P. G. Chem. Eur. J. 1999, 5, 1692-1699. VII. Asymmetric Addition of Diethylzinc to N-(diphenylphosphinoyl) Imines. Pinho, P.; Andersson, P. G. Tetrahedron 2001, 57, 1615-1618. VIII. Appendix: Supplementary Material. Pinho, P. Reprints were made with permission from the publishers 4 Contents Papers included in the thesis List of abbreviations 1. Introduction 7 1.1 Towards enantiomerically pure or enriched compounds 8 1.2 Asymmetric synthesis – Ligands and metals 9 1.3 The use of simple β-amino alcohols as chiral ligands 11 2. Hetero-Diels-Alder reaction – Applications in synthesis and preparation of unnatural β-amino alcohols 13 2.1 Introduction 13 2.2 Studies on the scope of the aza-Diels-Alder reaction – Towards nicotinic acetylcholine receptors 14 2.3 Preparation of enantiomerically pure cyclopentyl- and cyclohexyl-amines 18 2.4 Access to unnatural β-amino alcohols 21 3. Ruthenium-catalysed asymmetric transfer hydrogenation of ketones 23 3.1 Introduction 23 3.2 The 2-azanorbornyl-3-methanol as a ligand for ruthenium 24 3.3.Reaction mechanism 26 4. Oxazaborolidines in the asymmetric reduction of ketones 29 4.1 Introduction 29 4.2 Reaction mechanism 29 4.3 Preparation of 2-azanorbornyl-3-methanol ligands and their application in the form of the corresponding oxazaborolidines 30 5. Enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines 34 5.1 Introduction 34 5.2 The 2-azanorbornyl-3-methanols as chiral auxiliaries for the addition reaction 35 5.2.1 The first generation ligands – Synthesis and results obtained 35 5.2.2 The second generation ligands – Synthesis and results obtained 36 5.3 Reaction mechanism 39 Acknowledgements 42 5 List of abbreviations Abs. Config. Absolute configuration Bn Benzyl n-Bu Butyl t-Bu tert-Butyl Cat. Catalytic CBS Corey, Bakshi, Shibata Config. Configuration CpH Cyclopentadiene DIBAL-H Diisobutylaluminium hydride ee Enantiomeric excess equiv. Equivalent Et Ethyl h Hour(s) HMB Hexamethylbenzene HPLC High Performance Liquid Chromatography LAH Lithium aluminium hydride M Metal Me Methyl min Minute(s) MS Molecular sieves 1-Napht 1-Naphtyl NMO N-methylmorpholine N-oxide NMR Nuclear Magnetic Ressonance Ph Phenyl i-Pr iso-Propyl n-Pr Propyl rt Room temperature Stoich. Stoichiometric TFA Triflouroacetic acid THF Tetrahydrofuran TIPSCl Triisopropylsilylchloride Ts p-Toluenesulphonyl TS Transition State X Halogen (Cl, Br, I) 6 “Life depends on chiral recognition, because living systems interact with enantiomers in decisively different manners.” Noyori, R.1 1. Introduction In 1849 Louis Pasteur resolved for the first time an enantiomeric pair by means of mechanical separation of their differently shaped crystals. Since then chirality has been recognised as of extreme importance, not only in chemistry and biology as academic subjects, but also in life itself. What then is chirality? A given molecule, or object in general is said to be chiral or disymmetric if it does not possess any improper rotation axis Sn of any order n, where S1 σ 2 corresponds to a symmetry plane ( ) and S2 to an inversion center (i). A consequence of this definition is that chiral objects are not superimposable on their mirror images and are able to rotate the plane of polarised light by the same angle, but in different directions, Figure 1.1. N COOH HOOC N H H (S)-Proline (R)-Proline Mirror plane Figure 1.1 The two enantiomers (“mirror images”) of the amino acid proline It is now widely accepted that Nature is chiral where amino acids, terpenes, carbohydrates, and alkaloids are all natural occurring substances that are often enantiopure or at least enantioenriched, i.e. one of the enantiomers predominates over the other. The presence of chirality in Nature implies that usually only one enantiomer of a certain compound is producing the correct response on a living organism. As a consequence normally only one enantiomer of a given drug has the desired activity, hence, medicinal 1 In Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994. 2 Klessinger, M.; Michl, J. Excited States and Photochemistry of Organic Molecules, Section 3.2; VCH Publishers, Inc.: New York, 1995. 7 chemistry has a very strong need for enantioselective processes in drug development. However, this is not the only field where processes of this kind are being developed. Tastes and smells may also be dependent on enantiomers, which raises the importance of chirality in the food flavouring and perfumery industries. Agrochemicals may be easier or harder to degrade depending on which enantiomer of the chemical substance is used. Due to the growing concern about environmental aspects in modern society this branch of industry has therefore an increasing need for enantioselective processes in the preparation of their products. These are only some of the reasons why synthetic organic chemistry has developed