Development and Application of New Chiral Β-Amino Alcohols in Synthesis and Catalysis

Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 626

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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

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 cyclopentylamines 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]

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 enormously in the field of asymmetric synthesis during the last few decades.

1.1 Towards enantiomerically pure or enriched compounds There are three basic means to perform the synthesis of enantiomerically pure or enriched compounds. a) Resolution; the oldest of all processes is based on the synthesis of the racemic target molecule or intermediate in its synthetic sequence. The material is afterwards resolved with the help of an enantiomerically pure compound. Resolution is an important and still widely used process, but it suffers from a major drawback, i.e. the production of at least 50% of unwanted material. This drawback can sometimes be overcome by recovering/recycling of the unwanted enantiomer of the product, as for example in the dynamic kinetic resolution approach.3 An example of classic resolution (max. 50% yield) is outlined in Scheme 1.1, in this case the compound resolved is α-(1-naphthyl)ethylamine.4

H O O O 1) NH2 NH2 COOH H2O O O H (-)-DAG (S)-(-)-α-(1-naphthyl)ethylamine 2) 2M NaOH > 99% ee

Scheme 1.1 Resolution of α-(1-naphthy)ethylamine

3 For a review on dynamic kinetic resolution, see: Noyori, R.; Tokunaga, M.; Kitamura, N. Bull. Chem. Soc. Jpn. 1995, 68, 36.

8 b) “Chiral pool”; in this case the synthesis of the desired compound is based on a commercially available and enantiomerically pure starting material. The “chiral pool” approach strongly limits the possible synthetic strategies due to the still limited availability of the appropriate starting materials. Besides this fact, usually only one of the enantiomers of the starting material is naturally occurring further restricting the synthesis. Costs may also be a problem since unnatural enantiomers, which are man made, are usually much more expensive. An example of the “chiral pool” approach is depicted in Scheme 1.2 for the

5 synthesis of leukotriene A4.

O CO2Me O OH steps HO

HO OH from D-(-)-ribose (-)-Leukotriene A4

Scheme 1.2 Total synthesis of leukotriene A4 from D-(-)-ribose.

c) Asymmetric synthesis; involves the introduction of chirality by action of a chiral reagent, auxiliary or catalyst, which is not incorporated in the final product. This process is probably the choice, which provides the widest of possibilities. During the last few decades a variety of asymmetric transformations have been developed. Due to its importance, asymmetric synthesis and in particular asymmetric catalysis are treated in more detail in the following sections.

1.2 Asymmetric synthesis – Ligands and metals The chiral reagent and auxiliary methods6 require the use of at least one equivalent of enantiopure material, usually the most expensive component of a synthetic sequence. For this reason asymmetric synthesis is far more appreciated in the form of catalysis. Still, there are important processes that involve the use of stoichiometric amounts of

7 enantiopure materials, such as hydroboration using the chiral (Icp)2BH reagent, Scheme 1.3.

4 For the resolution of this chiral building block, see: Leimgruber, W.; Mohacsi, E. Org. Synth. 1976, 55, 80. 5 Marfat, A.; Corey, E. J. Advances in Prostaglandin, Thromboxane, and leukotriene Research; Pike, J. E. and Morton Jr., D. R. Eds.: Raven Press: New York 1985. 6 For a review on recent chiral auxiliary applications, see: Regan, A. J. Chem. Soc., Perkin Trans. 1 1999, 357. 7 (a) Brown. H. C.; Zweifel, G. Org. Synth. 1972, 52, 59; (b) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. Tetrahedron 1981, 37, 3547.

9 4 BF3 OEt2 + 3 NaBH4

2 B H + 3 NaBF + 4 Et O 2 6 4 2 HH BH B HO H2O2/NaOH 84 2 2

94% ee (Icp)2BH 95% ee 99.8% ee

Scheme 1.3 Hydroboration of olefins using (Icp)2BH

Catalysis is a process by which a small amount of a foreign material, the catalyst, increases the rate of a chemical transformation without itself being consumed. Metals are known to be extremely efficient catalysts for a wide variety of organic transformations, usually offering high selectivity under very mild reaction conditions. During the last few decades the importance of metals in organic synthesis has seen a tremendous growth and reactions catalysed by metals have become accepted as common transformations.8 One early example of a metal catalysed transformation is the osmium tetraoxide dihydroxylation of olefins,9 Scheme 1.4.

OH R Cat. OsO4 R R R Stoich. co-oxidant OH racemic Scheme 1.4 Catalytic dihydroxylation of olefins

If one then combines the chiral environment of an organic compound, able to co- ordinate a metal, with the catalytic power of a metal itself, a chiral catalyst may be obtained giving rise to a catalytic asymmetric process. Indeed, chiral metal complexes are among the most powerful methods to achieve discrimination between functional groups and enantiotopic faces of a pro-chiral substrate. Far are the days of the first reported example of a catalytic asymmetric transformation using this type of complexes, Scheme 1.5.10

8 (a) For examples of metal catalysed reactions, see: Tonks, L.; Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1 1998, 3637. 9 For a review on catalytic non-asymmetric dihydoxylation, see: Schröder, M. Chem. Rev. 1980, 80, 187. 10 Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1966, 5239.

10 Ph

N O Cu ON

Ph Ph CO2Et Ph Ph cis/trans : 1/2.3 %ee for trans isomer = 6% N2CHCOOEt CO2Et Scheme 1.5 The first reported example of a catalytic asymmetric process

It should be noted that the development of an asymmetric version of an existing process is usually a difficult goal to achieve. The development may require many years of research before the process becomes synthetically useful like the catalytic asymmetric dihydroxylation of olefins11 shown in Scheme 1.6.

N N N N O O Cat. O O

N N OH Cat. OsO4 R R R Stoich. NMO R OH up to 99% ee

Scheme 1.6 Catalytic asymmetric dihydroxylation of olefins

1.3 The use of simple β-amino alcohols as chiral ligands Due to their natural availability, it is not surprising that amino acids, or closely related compounds, such as the corresponding amino alcohols are among the most common ligands or ligand precursors for asymmetric catalysis.12 One successful example is the application of the CBS catalyst derived from the amino acid (S)-(-)-proline. This catalyst was introduced by

11 (a) For a review on this process, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483; (b) For a review regarding the application of this reaction in natural product synthesis, see: Cha, J. K.; Kim, N-S. Chem. Rev. 1995, 95, 1761. 12 For a review on the application of β-amino alcohols in asymmetric transformations, see: Ager, D. J.; Prahash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.

11 Corey and co-workers in the eighties and is used for the preparation of secondary alcohols from pro-chiral ketones, Scheme 1.7.13

Ph Ph O Cat. N B O OH BH3 99% yield, 97% ee, 13 Ph Ph in 1987 Stoich. BH3 Scheme 1.7 Reduction of acetophenone using the CBS catalyst

Despite the progress made and the discovery of alternative processes this is still one of the most efficient catalysts for this type of transformation. Many improved and simplified reaction procedures have been developed in order to optimise the performance of this powerful catalyst; acetophenone can nowadays be reduced to give the corresponding secondary alcohol in more than 99% ee.13

13 The CBS catalyst was introduced in 1987 by: Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. For further references and a more detailed discussion of the process, see Chapter 4 of this thesis.

12 2. Hetero-Diels-Alder reaction – Applications in synthesis and preparation of unnatural β-amino alcohols

2.1 Introduction The Diels-Alder reaction has, since its discovery in 1928 by Otto Diels and Karl Alder,14 been one of the cornerstones in synthetic organic chemistry. More recently, hetero- Diels-Alder reactions and particularly very efficient catalytic and enantioselective versions of this reaction have been developed.15 All the work presented in this thesis is based on chiral compounds containing the 2- azanorbornyl skeleton, i.e. a product from a hetero-Diels-Alder reaction, and it is therefore appropriate here to give special attention to this reaction.

Ph O N exo endo N Ph EtO2C CpH H O S CpH S H CO Et Si face 2 O 1b 1c

CF3COO 1) TFA S HN Ph H2NPh N Ph 2) BF OEt 3 2 O O δ O O BF3 δ

Re face

N PhCpH CpH Ph N H CO2Et exo R endo R H CO2Et 1a 1d Major product

Scheme 2.1 The aza-Diels-Alder reaction

14 Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98. 15 For a review on catalytic asymmetric hetero-Diels-Alder reactions, see: (a) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605; (b) Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558.

13 The dienophile for the aza-Diels-Alder reaction16 involved in the preparation of the 2- azanorbornyl-3-methanols presented throughout this text is generated in situ from freshly prepared methyl or ethyl glyoxylate and optically pure α-phenylethylamine,17 Scheme 2.1. Unlike the amino acid derived β-amino alcohols, this inexpensive source of chirality is available at the same price in both enantiomeric forms. This allows both enantiomers of the ligands to be prepared via the same synthetic sequence, as shown above for (S)-α- phenylethylamine. The selectivity in the cycloaddition between the formed imine and cyclopentadiene was reported16b to be 96:2:2 (1a:1b:1c+1d). The major isomer can then easily be obtained as a pure compound by means of flash chromatography. Moreover, it was observed that if the methyl ester is produced the product could be crystallised from n-pentane after the simple removal of polymeric material by filtration through silica.

2.2 Studies on the scope of the aza-Diels-Alder reaction – Towards nicotinic acetylcholine receptors Nitrogen containing bicyclic structures play an important role in the synthesis of many natural products and ligands for asymmetric catalysis. A very efficient method for the preparation of these structures is without any doubt the already mentioned aza-Diels-Alder reaction.18 It is therefore of no surprise that there is growing interest in producing new compounds by manipulations of the dienes and dienophiles used in the cycloaddition reaction. The observation that the scope of the reaction seemed to be limited to electron deficient imines, derived from similar types of aldehydes16 or from very small aldehydes,19 led to new ideas.

16 The aza-Diels-Alder reaction used to prepare 1a, Scheme 2.1, has been previously reported by: (a) Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant, B.; Declercq, J. P. Tetrahedron Lett. 1990, 18, 2603; (b) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707. For other similar aza-Diels-Alder reactions, see for example: (c) Waldmann, H.; Braun, M. Liebigs Ann. Chem. 1991, 1045; (d) Bailey, P. D.; Wilson, R. D.; Brown, G. R. J. Chem. Soc., Perkin Trans. 1 1991, 1337; (e) Bailey, P. D.; Brown, G. R.; Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991, 2, 1263; (f) Bailey, P. D.; Londesbrough, D. J.; Hancox, T. C.; Heffernan, J. D.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1994, 2543; (g) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633. 17 For reviews on other applications of α-phenylethylamine, see: (a) Juaristi, E.; Escalante, J.; Léon-Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715; (b) Juaristi, E.; Escalante, J.; Léon-Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1999, 10, 2441. 18 Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic Press: London, 1987, Chapter 2. 19 Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768.

14 Isolation of the alkaloid epibatine20 (Figure 2.1) from the poisonous frogs, epipedobates tricolor has led to a non-stop search for equally or even more powerful analgesic analogues that might present themselves as being less toxic. During this research a variety of compounds showing various properties have been prepared, especially compounds containing the nitrogen in different locations of the norbornane framework attracted attention.

NCl H O H N N Me N N 3 O N N

Acetylcholine (-)-Nicotine (-)-Epibatidine A Figure 2.1 Some biologically active compounds

Nicotine, epibatidine and some of their synthetic analogues are powerful acetylcholine (one of the human transmitter substances) receptor agonists, i.e. analgesics.21 The major problem with compounds such as nicotine and epibatidine is their toxicity, which makes dosage difficult and dangerous. More recently a patent report22 described the preparation of the racemic form, followed by chiral HPLC separation, of compound A, which has shown promising activity (Figure 2.1). It was therefore desirable to develop a general method for the preparation of compounds having similar structures, i.e. bicyclic nicotine analogues. It was considered that the presence of a second nitrogen, if placed in conjugation with the imine, might fulfil the role of an electron-withdrawing group under the usual acidic reaction conditions of the aza-Diels-Alder reaction. This would open-up a general route for isomers of epibatidine and/or nicotine and for new chiral ligands containing pyridine or a general heterocyclic moiety (Paper I).

20 (a) Isolation of epibatidine: Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475; (b) For a review on the discovery of alkaloids in amphibian skin, see: Daly, J. W. J. Nat. Prod. 1998, 61, 162. 21 For a review about drug research in this area, see: Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4169. 22 Bencherif, M.; Caldwell, W. S.; Dull, G. M.; Lippielo, P. M. Pharmaceutical Compositions for the Treatments of Central Nervous System Disorders. U. S. Patent 5,583,140, 1996.

15 Indeed, when pyridine-2-carboxaldehyde (2a) was subsequently treated with (S)-(-)- α-phenylethylamine and cyclopentadiene under acidic conditions a highly stereoselective cycloaddition took place giving compound 3a in good yield, Table 2.1. It was pleasing to confirm that the theory on the hetero-Diels-Alder reaction was correct and that the general synthetic sequence outlined in Scheme 2.2 could be used with heterocyclic imine dienophiles allowing the production, not only of potentially active compounds, but also that of new chiral ligand precursors.

i ii N Ar O Ar N Ph Ar Ph 23

α Reagents and conditions: (i) (S)- -phenylethylamine, MS 4Å, CH2Cl2, rt; (ii) Acid(s), CpH, -78 °C to rt. Ar = Heteroaromatic system

Scheme 2.2 Aza-Diels-Alder reaction of heterocyclic imine dienophiles

The choice of acid also proved to be essential for the outcome of the reaction. The use of Lewis acids only resulted in fast polymerisation of the aldehydes. A variety of protic acids were screened where methane sulphonic acid and/or triflouroacetic acid were found to be the most efficient. Furthermore, polymerisation could be reduced to a minimum by temperature control. Performing the reactions at –78 °C afforded a crude product eventually containing no polymers, but consisting in this case of simple diastereomeric mixtures that could be purified by means of chromatography. The need for conjugation of the second nitrogen with the imine system was also confirmed. As expected aldehydes 2c and 2f both failed to react, even if the corresponding imines were formed under the same conditions as for the remaining substrates. The results obtained with the different dienophiles are summarised in Table 2.1. As mentioned, these compounds could probably also find use in catalysis, since pyridine is a very good ligand for a large variety of metals. Unfortunately all attempts to deprotect compounds 3 failed, because no selectivity on these double bensylic-nitrogens could be observed.

16 The (S)-α-phenylethylamine was also exchanged for p-methoxy-(S)-α- phenylethylamine, but ammonium cerium (IV) nitrate cleavage did not afforded the desired product in practical yields. According to the crude proton NMR analysis, the desired product was one of the components in a complex crude mixture. Attempts to isolate this product, both via acidic aqueous extraction, flash chromatography or preparative reversed phase HPLC were unsuccessful.

Reaction exo/endo Entry Aldehydea b d conditions Yield selectivityc Diastereoselectivity Product

N N CH SO H / TFA 1 2a O 3 3 80 > 99 % 87:13 3a N Ph

N N N 2 2b CH SO H / TFA 60 > 99 % 80:20 3b O 3 3 Ph

CH SO H / TFA or 3 2c 3 3 ------e --- N O CH3SO3H

N CH SO H N 4 2d O 3 3 80 > 99 % 90:10 3d N Ph

N N 5 2e N CH3SO3H79 > 99 % 90:10 3e O Ph

O CH SO H / TFA or 6 2f 3 3 ------e --- N CH3SO3H H

N O NHN 7 2g CH3SO3H 60 > 99 % 75:25 3g N N H Ph

N N S 8 2h O CH3SO3H 80 > 99 % 90:10 3h S N Ph aAll aldehydes were used as received from commercial sources; bRefers to the isolated yield over the two isomers; cNo endo isomer could be observed; dDetermined by integration of the signals on the crude 1H-NMR; eThe imine of the corresponding aldehyde was formed but no Diels-Alder reaction occurred. Table 2.1 Results of the cycloaddition reactions with heterocyclic imine dienophiles

17 Isoprene could also be used in the cycloaddition reaction, but this was a peculiar case. Unlike cyclopentadiene the reaction was only effective using a Lewis acid (zinc etherate)23 and a non-conjugated imine, Scheme 2.3.

NNiiiNPh O NN

Ph 2c 4 α Reagents and conditions: (i) (S)- -phenylethylamine, MS 4Å, CH2Cl2, rt; (ii) ZnCl2, isoprene, CH2Cl2/ether, rt. Scheme 2.3 The isoprene case

2.3 Preparation of enantiomerically pure cyclopentyl- and cyclohexyl-amines A considerable variety of extremely important compounds in medicinal chemistry contain multi-functionalised chiral cyclopentylamines. This structural unit is present in many different antibiotics of the ribose mimic class. Amongst the more interesting are amidomycin,24 aristeromycin25 and carbovir,26 Figure 2.2. All of these compounds have been shown to have antiviral properties and carbovir is a promising antiviral agent used in the treatment of AIDS.27

23 Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4263. 24 (a) Sung, S-Y.; Frahm, A. W. Arch. Pharm. Pharm. Med. Chem., 1996, 329, 291; (b) Nakamura, S.; Karasawa, K.; Tanaka, N.; Yonehara, H.; Umezawa, H. J. Antibiot., Ser. A 1960, 392; (c) Nagata, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron: Asymmetry 1997, 8, 2679. 25 (a) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.; Mizuno, K. J. Antibiot. 1968, 255; (b) Arita, M.; Adachi, K.; Sawai, H.; Ohno, M. Nucleic Acids Research Symposium Series 1983, 12, 25. 26 (a) White, E. L.; Parker, W. B.; Macy, L. J.; Shaddix, S. C.; McCaleb, G.; Secrist III, J. A.; Vince, R.; Shannon, W. M. Biochem. and Biophys. Research Commun. 1989, 161, 393; (b) Vince, R.; Hua, M.; Brownell, J.; Daluge, S.; Lee, F.; Shannon, W. M.; Lavelle, G. C.; Qualls, J.; Weislow, O. S.; Kiser, R.; Canonico, P. G.; Schultz, R. H.; Narayanan, V. L.; Mayo, J. G.; Shoemaker, R. H.; Boyd, M. R. Biochem. and Biophys. Research Commun. 1988, 156, 1046. 27 Other related biologically active compounds: Neplanocin A: (a) Arita, M.; Adachi, K.; Sawai, H.; Ohno, M. Nucleic Acids Research Symposium Series 1983, 12, 25; (b) Lim, M-I.; Moyer, J. D.; Cysyk, R. L.; Marquez, V. E. J. Med. Chem. 1984, 27, 1536; Lim, M-I.; Marquez, V. E. Tetrahedron Lett. 1983, 24, 5559. Guanine derivatives: Reitz. A. B.; Goodman, M. G.; Pope, B. L.; Argentieri, D. C.; Bell, S. C.; Burr, L. E.; Chourmouzis, E.; Come, J.; Goodman, J. H.; Klaubert, D. H.; Maryanoff, B. E.; McDonnell, M. E.; Rampulla, M. S.; Schott, M. R.; Chen, R. J. Med. Chem. 1994, 37, 3561. Adenosin analogues: Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1966, 88, 3885. Tubercidin analogues: Montgomery, J. A.; Hewson, K. J. Med. Chem. 1967, 10, 665. Noraristeromycin: Siddiqi, S. M.; Oertel, F. P.; Chen, X.; Schneller, S. W. J. Chem. Soc., Chem. Commun. 1993, 708. Adenosine deaminase inhibitors: Schaeffer, H. J.; Godse, D. D.; Liu, G. J. Pharm. Sci. 1964, 53, 1510. γ-aminobutyric acid analogue: Milewska, M. J.; Polonski, T. Tetrahedron: Asymmetry 1994, 5, 359. Carboxylic sugars and nucleosides: (a) Ranganathan, S.; George, K. S. Tetrahedron 1997, 53, 3347; (b) Mulvihill, M. J.; Surman, M. D.; Miller, M. J. J. Org.Chem. 1998, 63, 4874.

18 Despite the importance of these structural units, methods for their preparation are too specific. A general method that would allow the modification of the substituents or functional groups would therefore be of great utility (Paper II, see also Appendix VIII).

N NH 2 H O NH H2N N O N N NH2 N N H N N HO N H2N HO HO OH

(1R, 3S)-Amidomycin (-)-Aristeromycin Carbovir: NCS 614846 Figure 2.2 Biologically active cyclopentylamines

During research to modify the 2-azanorbornyl structure an interesting reaction became apparent, that opens-up a new rapid route to substituted enantiomerically pure cyclopentylamines via ring-opening of the bicyclic structure. The attempted preparation of the Grignard reagent which would result from bromide B led instead to the very interesting reaction product, compound D in Figure 2.3.

H Mg, THF + N Ph N Ph NR N Ph Br Mg Br BCD

Figure 2.3 Ring-opening reaction of the bicyclic bromide B

Despite the low selectivity observed in the initial attempts (a 1:1 inseparable mixture of C and D) the importance of this structural unit (D) was encouraging to further proceed with this route of research. Success was met when the protecting group on the nitrogen was exchanged from phenylethyl to tosyl. The electron-withdrawing properties of this group facilitate the ring-opening mechanism outlined above allowing a complete control of the selectivity. Compound 9 was obtained as a sole reaction product in a high isolated yield. The synthetic route to the key intermediate 8 and reaction conditions are outlined in Scheme 2.4.

19 iii iii N Ph NH NTs NTs CO Et CO Et CO2Et 2 2 OH 1a 576

NHTs v NTs iv Br 9 8

Reagents and conditions: (i) H2 (150 psi), 5% Pd-C, EtOH, rt, 48h, 98%; (ii) TsCl, Et3N, CH2Cl2, rt, overnight, 92%; (iii) LiAlH4, THF, rt, 2h, 95%; (iv) CBr4, Ph3P, CH2Cl2, rt, 24h, 60%; (v) Mg, BrCH2CH2Br,THF, reflux, 24h, 90%. Scheme 2.4 Ring-opening of the bicyclic bromide 8

Manipulation of the original aza-Diels-Alder adduct (1a) allows the possibility of further functionalisation and as much as four functionalised chiral centers can be introduced into the five carbons of cyclopentadiene. Dihydroxylation of 1a, followed by ketal protection of the diol affords compound 11, which is converted into the analogue of 8 via the same synthetic sequence. Compound 15 is then ring-opened to the multi-functionalised cyclopentane 16 (Scheme 2.5). Completely selective functionalisation of cyclopentadiene is then achieved using this eight-step sequence.

HO O O Ph i Ph ii Ph iii N HO N O N O NH CO2Et CO2Et CO2Et CO2Et 1a 10 11 12 iv

NHTs vii O vi O v O NTs NTs NTs OO O O O Br OH CO2Et

16 15 14 13

Reagents and conditions: (i) OsO4, NMO/H2O, t-BuOH, 24h, 92%; (ii) (MeO)2C(CH3 )2, TsOH, warm MeOH, 15 min, 87%; (iii) ammonium formate, 10% Pd-C, EtOH, reflux, 1h, 99%; (iv) TsCl, Et3N, CH2Cl2 , rt, overnight, 90%; (v)LiAlH4, THF, rt, 2h, 92%; (vi) CBr4, Ph3P, CH2Cl2, rt, 24h, 59%; (vii) Mg, BrCH2CH2Br, THF, reflux, 32h, 89%. Scheme 2.5 Multi-functionalisation of cyclopentadiene

20 This new methodology could also be extended to larger bicyclic structures as in the case of the aza-bicyclo[2.2.2]octene (17), obtained using cyclohexa-1,3-diene in the hetero- Diels-Alder reaction. The ring-opening of this compound shows that the reaction is not only a consequence of the ring strain in the [2.2.1] system (Scheme 2.6).28

O i -vii N Ph CO2Et O NHTs 17 18

Reagents and conditions: (i) OsO4, NMO/H2O, t-BuOH, 24h, 92%; (ii) (MeO)2C(CH3)2, TsOH, warm MeOH, 15 min, 87%; (iii) ammonium formate, 10% Pd-C, EtOH, reflux, 1h, 99%; (iv) TsCl, Et3N, CH2Cl2, rt, overnight, 91%; (v) LiAlH4, THF,rt, 2h, 94%; (vi) CBr4, Ph3P, CH2Cl2, rt, 24h, 62%; (vii) Mg, BrCH2CH2Br, THF, reflux, 32h, 85%. Scheme 2.6 Ring-opening of the azabicyclo[2.2.2]octene 17

As mentioned before, this new methodology opens-up a practical route to multi- functionalised chiral cyclopentyl- and cyclohexylamines, thus, allowing modification of substituents or functional groups in a variety of antibiotics of the ribose mimic class.

2.4 Access to unnatural β-amino alcohols As mentioned in Chapter 1 (Section 1.3) β-amino alcohols derived from natural occurring amino acids are widely used as ligands or ligand precursors in asymmetric synthesis.12 Compounds 1a and 5 described above are direct intermediates in the synthesis of unnatural amino alcohols, Figure 2.4. Besides this fact other nitrogen containing ligands, such as amino-phosphines, amino-thiols or amino-oxazolines, which could also be prepared from precursors like 5, are widely used in the field of catalysis.29

28 For interesting compounds containing this structure unity see for example: (a) Keck, G. E.; Fleming, S. A. Tetrahedron Lett. 1978, 48, 4763; (b) Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991, 32, 6077; (c) Chretien, F.; Ahmed, S. I.; Masion, A.; Chapleur, Y. Tetrahedron 1993, 49, 7463; (d) Grabowski, S.; Armbruster, J.; Prinzbach, H. Tetrahedron Lett. 1997, 38, 5485; (e) Noguchi, H.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1997, 38, 2883. 29 For a recent review on nitrogen containing ligands, see: Fache, F.; Schultz, E.; Tommasino, M. L.; Lemair, M. Chem. Rev. 2000, 100, 2159.

21 The use of the referred type of amino alcohol ligands, 2-azanorbornyl-3-methanols, will be described in the following chapters of this thesis.

R' NNRPh CO2Et OH 1a R''

NH NH CO2Et OH 5 Figure 2.4 Preparation of unnatural β-amino alcohols from the aza-Diels-Alder adduct 1a

22 3. Ruthenium-catalysed asymmetric transfer hydrogenation of ketones

3.1 Introduction Ruthenium-catalysed transfer hydrogenation30 from 2-propanol to ketones (Scheme 3.1) is one of the most attractive processes to prepare enantioenriched secondary alcohols. Both from an industrial and economical point of view, 2-propanol is a very cheap hydrogen source and the catalyst loadings typical for these experiments are low. In addition, it avoids the use of explosive molecular hydrogen or reactive metal hydrides.

O Cat. "Ru", Cat. Chiral Ligand OH RR' Cat. Base, 2-Propanol RR' Scheme 3.1 Transfer hydrogenation reaction

Noyori and co-workers have reported one of the most successful examples in this field with the introduction of the diamine ligand 19,31 Figure 3.1. Chiral phosphorous and nitrogen ligands 20 to 2432 have also been used with variable levels of enantioselectivity being obtained in the reduction of acetophenone.

Ph NHTs O 99% yield Ph 95% yield 24% yield 31 32a 32b 98% ee 91% ee N 94% ee Ph NH2 HO NHMe Ph2P 19 20 21

NHMe N Ph 95% yield H 96% yield OH 70% yield Fe PhP Ph 80% ee 32c H 20% ee 32d 91% ee32e N NH2 NHMe 22 23 24 Figure 3.1 Some ligands used in transfer hydrogenation

30 For reviews on the subject, see: (a) Gladiali, S.; Mestroni, G. Transition Metals for Organic Synthesis, Vol. 2, Chapter 1.3; Wiley-VCH: Toronto 1998; (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97; (c) Palmer, M., J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. 31 Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521 (result obtained using formic acid-triethylamine mixture as hydrogen source). 32 (a) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyroi, R. Chem. Commun. 1996, 233; (b) Langer, T.; Helmchen, G. Tetrahedron Lett. 1996, 37, 1381; (c) Puntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett. 1996, 37, 8165; (d) Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38, 6565; (e) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62, 5226.

23 As mentioned before (Sections 1.3 and 2.4) the use of simple amino alcohols is especially attractive, but in the case of the ruthenium-catalysed transfer hydrogenation of ketones there are only a few successful applications of these kind of ligands, for example the compounds 20 and 24 in Figure 3.1.

3.2 The 2-azanorbornyl-3-methanol as a ligand for ruthenium Recently reported from this laboratory is the use of 2-azanorbornyl derivatives as ligands in asymmetric catalysis.33 The results obtained prompted the application of a few of these rigid proline analogues as ligands in the title transformation (Paper III). The simplest of all 2-azanorbornyl-3-methanols (25) was prepared from ethyl-2- azanorbornyl-3-carboxylate (5) in a single step as outlined in Scheme 3.2 (see Chapter 2 for the preparation of 5).

i OH NH NH N CO2Et OH H 5 25 26, (S)-prolinol Reagents and conditions: (i) LAH (2 equiv), THF, rt, 1h, 90%

Scheme 3.2 The simplest 2-azanorbornyl-3-methanol 25 and the (S)-prolinol analogue 26

Surprisingly, the use of (S)-prolinol (26) had never been reported in this reaction, so comparison of this widely used ligand structure with the rigid and sterically more demanding bicyclic analogue was a must. Moreover, it was also important to study the influence of α- substitution, hence the α-dimethyl ligand (29) was also prepared, Scheme 3.3.

N NH iiiN Ph iii NH CO2Et CO2Et OH OH Ph 5272829

Reagents and conditions: (i) PhCH2 Br, K2CO3, CH3CN, rt, 32h, 78%; (ii) MeMgBr, THF, rt, 2h, 84%; (iii) H2 (150psi), 5% Pd-C, EtOH, rt, 24h, 98%. Scheme 3.3 Synthesis of ligand 29

33 Södergren, M., J.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 7577.

24 The different ligands were screened using acetophenone, a common model substrate

for this type of study, and ruthenium dichloride hexamethylbenzene dimer, [RuCl2(HMB)]2, as the metal source.34 The results of this study are summarised in Table 3.1.

O OH 0.25 mol% [RuCl2(HMB)]2, 2 mol% Ligand

Ph 2.5 mol% i-PrOK, i-PrOH Ph

Entry Ligand Yield%Time/h %eea Configb

OH 1 N 26 16 6.5 8 S H

2 NH 25 92 5 95 S OH

3 NH 29 85 16c rac. - - OH

aDetermined by HPLC analysis (ChiralCel OD-H; 5% i-PrOH in hexane; 0.5 mL/min); bDetermined from the sign of rotation of the isolated product; cThe reaction was performed at 83 °C.

Table 3.1 The behaviour of the different ligands in the transfer hydrogenation of acetophenone

The use of (S)-prolinol (26) gave rise to an unselective reaction (Table 3.1, entry 1). However, it was pleasing to observe that the rigid analogue 25 led to an excellent result (Table 3.1, entry 2) after a reaction time of five hours. Unlike ligand 25, the sterically more hindered α-dimethyl analogue 29 did not performed so well. No conversion into product was observed at room temperature and only the racemic product was obtained at reflux temperature (Table 3.1, entry 3). As a natural consequence of these promising results it was decided to investigate a variety of substrates, as well as a different metal source, ruthenium dichloride p-cymene dimer, [RuCl2(p-cymene)]2. Indeed, this system turned out to be efficient for the reduction of other pro-chiral ketones to the corresponding secondary alcohols, Table 3.2. High enantiomeric excesses were obtained for most of the substrates, but in accordance with Noyori´s observations,30b ketones with a bulky substituent reacted very slowly under the applied reaction conditions (Table 3.2, entry 7).

34 For preparation of ruthenium complexes, see: (a) Bennet, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1974, 233; (b) Bennet, M. A.; Metheson, T. W.; Robertson, G. B.; Smith, A., K. Inorg. Chem. 1980, 19, 1014.

25 0.25 mol% [RuCl2(arene)]2

O 2 mol% NH OH OH RR' 2.5 mol% i-PrOK RR' i-PrOH

a a EntryRR' [RuCl2(arene)]2 Time/h Yield% %ee EntryRR' [RuCl2(arene)]2 Time/h Yield% %ee

1Me HMB 5 92 95 8Me p-cymene 1.5 91 94

2Me HMB 3 100 94 9Me p-cymene 1.5 92 97

3Et HMB 5 81 83 10Et p-cymene 1.5 81 93

4n-Pr HMB 5 81 90 11n-Pr p-cymene 1.5 60 92

5n-Bu HMB 5 70 89 12n-Bu p-cymene 1.5 78 95

6n-Hexyl HMB 5 17 83 13n-Hexyl p-cymene 1.5 53 95

75bt-B u HMB c

aDetermined by HPLC analysis (ChiralCel OD-H; 5% i-PrOH in hexane; 0.5mL/min). The predominant product was, in all cases the S isomer. bLess than 5% conversion after 5h. cNot determined. Table 3.2 Transfer hydrogenation of different substrates using ligand 25

It was also observed that the use of [RuCl2(p-cymene)]2 instead of [RuCl2(HMB)]2 resulted in higher reaction rates and improved selectivity for the substrates studied. This study therefore demonstrates the efficiency of catalysts based on structure 25 and

[RuCl2(p-cymene)]2 in the enantioselective transfer hydrogenation of aromatic ketones.

3.3 Reaction mechanism The mechanism for the reaction has previously been proposed in the literature30 to involve a direct hydride transfer from ruthenium to the ketone via a six-member ring transition state. The outcome of the reaction is in this case determined by the steric and electronic differentiation between the two non-bonding electron pairs of the carbonyl oxygen.

26 A combined theoretical/experimental study was recently performed in this laboratory35 aiming to distinguish between the three most probable mechanistic alternatives. Metal catalysed transfer hydrogenation may be divided into three different types, (a) direct transfer of α-hydrogen from the alcohol to the ketone, (b) migratory insertion of the coordinated ketone into the metal hydride or (c) concerted transfer of proton and hydride, Figure 3.2.

O H O M H M H H O O MN

ab c Figure 3.2 The three different transition states

These combined theoretical/experimental studies35a strongly support the literature proposal, suggesting that the reaction indeed takes place via the mechanism outlined in Scheme 3.4, i.e. via a transition state of type c.

Cl Cl Ru Ru Cl Cl OH O

OH NH2

O H H Ru Ru Ru Cl Ru N O H O ONH NH NH2 Ar 2 TS c

OH O

RR' RR' Scheme 3.4 Mechanism for the ruthenium-catalysed transfer hydrogenation

35 (a) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580. Similar studies leading to the same conclusions have been published afterwards: (b) Petra, D. G. I.; Reek, J. N. H.; Handgraaf, J-W.; Meijer, E. J.; Dierkes, P.; Kamer, P. C. J.; Brussee, J.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. Chem. Eur. J. 2000, 6, 2818. (c) Yamakawa, M.; Ito, M; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466.

27 The mechanism is an example of metal-ligand bi-functional catalysis, i.e. the ligand is not only providing the chiral environment for the metal, but also stabilising the transition state through a hydrogen bond between the nitrogen and the carbonyl oxygen of the substrate. As mentioned before the outcome of the reaction is determined by steric and electronic differentiation between the two non-bonding electron pairs of the carbonyl oxygen. Although, this is not the only reason for the high enantioselectivities obtained with ligand 25. The rigidity of this ligand structure makes the face selectivity at the amine nitrogen complete when the ligand co-ordinates to the metal. Hence, the generation of an enantiopure ruthenium complex is achieved by the use of a rigid ligand (25) that strongly disfavours one specific configuration of the co-ordinated amine.35a It is important to notice that, as consequence of microscopic reversibility, the same transition state is involved in the reverse process. This, if the oxidation/reduction potentials will allow, can lead to racemisation of the secondary alcohol. However, this phenomena has not been observed with our catalytic system, the enantiomeric excess remains constant at different conversion levels and the reaction can reach completion without compromising the enantiopurity of the product.

28 4. Oxazaborolidines in the asymmetric reduction of ketones

4.1 Introduction An alternative route to the ruthenium-catalysed transfer hydrogenation in the preparation of enantioenriched secondary alcohols (Chapter 3) is the use of chiral borane complexes. This methodology already mentioned in Section 1.3, was first introduced by Itsuno et al. in the early eighties.36 However, it was not until 1987 that the process became attractive with the publication of Corey´s promising results on a catalytic version of this reaction. The reaction as since undergone some major improvements37 and is now an established process38 that finds application in the synthesis of many natural products.39

4.2 Reaction mechanism In 1992 Corey and co-workers isolated and X-rayed crystals of the very air and moisture sensitive (S)-2-(diphenylhydroxymethyl)-pyrrolidine40 borane complex.41 The isolation of this oxazaborolidine borane complex (Scheme 4.1, 31) opened-up research towards the understanding of the reaction mechanism leading to the proposal described in Scheme 4.1. The mechanism proposed by Corey and co-workers38b allows an explanation for the absolute configuration of the product, the high enantiomeric excess, the rate enhancement of the reaction, and the turnover of the catalyst. According to this proposal (S)-diphenyl prolinol reacts first in an acid/base fashion (Brønsted sense) with the added borane forming species 30. Subsequent addition of a borane complex (Lewis acid) then leads to the formation of the catalytic active species 31 via co-ordination to the lone pair of the nitrogen (Lewis base) of the pyrrolidine moiety on the α face of 30.

36 (a) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem. Soc., Chem. Commun. 1981, 315; (b) Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. J. Chem. Soc., Perkin Trans. 1 1983, 1673. 37 (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925; (b) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowsky, E. J. J. J. Org. Chem. 1991, 56, 751; (c) Masui, M.; Shiori, T. Synlett 1996, 49; (d) Masui, M.; Shiori, T. Synlett 1997, 273. 38 For reviews on the process, see: (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 12, 1475; (b) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986. 39 Corey, E. J.; Cheng, X-M. The Logic of Chemical Synthesis; John Wiley & Sons: New York, 1995. 40 For the preparation of diphenyl prolinol, see: Xavier, L. C.; Mohan, J. J.; Mathre, D. J. Thompson, A. S.; Carroll, J. D.; Corley, E. G.; Desmond, R. Org. Synth. 1996, 74, 50. 41 Corey, E. J.; Azimioara, M.; Sarshar, S. Tetrahedron Lett. 1992, 33, 3429.

29 Ph Ph H H Ph Ph MeB(OH)2 Ph BH3 H Ph OH Toluene, ∆ O NH -H O N O 2 B N B 30 Me BH3 Me

H2BO H 31 Ph H Ph b a O O N B H2B O H H B BH 3 H HCl H

Ph Ph O Me O Me B B OH N O N O Ph B H Ph H2B H2 H

Scheme 4.1 Borane reduction mechanism

Complex 31 possesses an activated hydride donor (BH3 co-ordinated to nitrogen) as well as a strong Lewis acid on the endocyclic boron atom. This last property allows the rapid but selective co-ordination of the ketone, only via the less sterically hindered lone pair a, see Scheme 4.1. The hydride transfer can then occur through a six-member transition state to form the non-dissociated reduction product, which is released to regenerate the catalyst by either of two possible pathways. Reaction of the alkoxide ligand attached to the endocyclic boron atom with the adjacent boron atom regenerating 30 and the borinated product, or addition of borane to form the depicted six-member borane bridged species that decomposes into 31 and the borinated product. The borinated product is then hydrolysed to the secondary alcohol upon quenching with hydrochloric acid.

4.3 Preparation of 2-azanorbornyl-3-methanols ligands and their application in the form of the corresponding oxazaborolidines As previously described in Chapter 3 of this thesis 2-azanorbornyl derivatives are very efficient ligands in ruthenium-catalysed transfer hydrogenation. At the same time it had been suggested38a that a rigid analogue of the CBS catalyst could further improve the selectivity of this catalytic system. This can be explained in the same way as why Corey’s catalyst (proline based) shows improved selectivity when compared to Itsuno’s catalyst

30 (valine based), Figure 4.1. Although a trans relation between the i-Pr group and the added borane is preferred in Itsuno’s system, the cis relative conformation can not be completely excluded. Due to the rigidity of Corey’s system, only the trans relationship is available. For this reason higher enantioselectivities are obtained with the latter system.

H2B H Ph Ph H Ph O O Me O B B N N Me Ph O PhH H2B H Ph Itsuno's valine based catalyst possibility for both α and β co-ordination

N Me Ph B Ph O Me O O B N Ph Ph Ph O B H H2B H Ph H H Corey's proline based catalyst 2-azanorbornyl-3-methanol based strictly α co-ordination oxazaborolidine - increased rigidity

Figure 4.1 Comparison of different oxazaborolidine catalysts

With the objective of investigating different oxazaborolidines (Paper IV), a variety of ligands based on the 2-azanorbornyl framework, i.e. increased rigidity in comparison to diphenyl prolinol, were prepared, Scheme 4.2.

NPh i NH 32, R = 33, R = Cl CO2Et CO2Et 1a 5 34, R = O 35, R =

ii iii 20-46%

36, R = Me 37, R = F3C NH NH CR2OH CR2OH 38, R = 25, R = H 32-38 29, R = CH3 Reagents and conditions: (i) See Chapter 2; (ii) See Chapter 3; (iii) RMgBr, THF, rt, 1h

Scheme 4.2 Aza-norbornyl oxazaborolidine precursors

Using cyclohexa-1,3-diene in the aza-Diels-Alder reaction, an azabicyclo [2.2.2]octene (17) was obtained (see Chapter 2) and converted to a less rigid analogue of 25, ligand 39 in Scheme 4.3.

31 i NPh NH CO2Et OH 17 39 Reagents and conditions: (i) Same as for the transformation of 1a to 25

Scheme 4.3 Preparation of ligand 39

All reductions were performed using a procedure37c,d where the catalytically active oxazaborolidine is generated in situ using trimethyl borate, borane dimethyl sulphide complex and the corresponding amino alcohol. The influence of different reaction parameters on the enantiomeric excess was studied using acetophenone as the model substrate and amino alcohol 32 as the oxazaborolidine precursor. During these studies it appeared that the concentration of the solution had an influence on the outcome of the reaction and this was therefore studied further. The results of this study are summarised in Table 4.1 and a clear effect can be observed.

Entry Initial amino alcohol concentration/Ma % eeb 1 0.05 83 O OH 0.1 equiv 32, 0.12 equiv B(OMe)3 2 0.1 84 Ph 1equiv BH3 Me2S Ph 3 0.2 87 4 0.9 87

aInitial concentration means the concentration of 32 in THF before any other addition; bIsolated yields of the corresponding secondary alcohol were in all cases >95%. Table 4.1 Ligand concentration effects

Since the reaction is known to be extremely solvent and temperature dependent, it was decided to study these effects using a fixed ligand concentration at 0.2M. The results were in complete agreement with those previously reported; i.e. the best conditions were found to be tetrahydrofuran at room temperature42 (Table 4.2).

Entry Solvent Temperature / °C Total time / h % ee

1 THF rt 2 87 2 CH2Cl2 rt 6 rac. 3 CH3CN rt 4 23 4 Toluene rt 2 67 5 THF 6 - 7 8 49 6 THF 40 2 79

Table 4.2 Solvents and temperatures

42 Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465.

32 Finally, under the optimised reaction conditions the different amino alcohol ligands were tested on the reduction of acetophenone. The best results were obtained when using ligands 32 or 38. The other prepared ligands turned out to be unsuitable for the reaction, leading to low enantioselectivities of the product independently of their electronic effects. Steric effects could also be observed and the less demanding ligands 25, 29 and 39 led to very poor results, Table 4.3.

Entry Amino alcohol Ketone % ee Abs. Config.a Entry Amino alcohol Ketone % ee Abs. Config.a

O O 1 25 55 (S) 10 32 87 (S)

O 2 29 13b (S) 11 32 70c (S)

O 3 33 63 (S) 12 32 58 (S)

O 4 34 45 (S) 13 32 83b (S)

O 5 35 77 (S) 14 32 77b (S)

O 6 36 60 (S) 15 32 47 (S)

O 7 37 77 (S) 16 32 Cl 82 (R)

O Br 8 38 87 (S) 17 32 89 (R)

9 39 45 (S) aDetermined by comparison of the optical rotation sign with the ones available for commercial products or reported in the literature; bResult obtained using a initial concentration of 0.1 M; cReduction with amino alcohol 38 gave the corresponding secondary alcohol in 81% ee. Table 4.3 Different ligands and substrates

Using compound 32 the work was also extended to other pro-chiral ketones and as can be seen from Table 4.3 a decrease in the steric differentiation between the two faces of the substrate leads to a reduced value of the enantiomeric excess, as expected from the mechanistic model. Entry 15 represents an exception, since the large steric difference between the two faces of the ketone should lead to higher enantiomeric excess than that actually observed.

33 5. Enantioselective addition of dialkylzinc reagents to N-(diphenyl phosphinoyl) imines

5.1 Introduction Chapters 3 and 4 of this thesis dealt with the asymmetric reduction of the carbonyl functionality in ketones. Unlike these reactions43 the corresponding asymmetric reduction or addition of organometallic reagents to imines, as a method for the preparation of enantioenriched amines has not yet been subject of the same attention and only a few successful examples can be found in the literature,44 Scheme 5.1.

Ph Ph O 5 mol% O TsHN NH 2 99% yield N NH 45 O 2.5 mol% [RuCl2(p-cymene)]2 O 95% ee HCO H- Et N Me 2 3 H Me H H N 1 equiv O N O H 90% yield H 91% ee46 N HN nBuLi (2 equiv) Ph Ph

Me Ph

1 equiv NOH O O O Ph H Ph 89% yield P P 47 Ph N PhEt2Zn Ph N Ph 90% ee H Scheme 5.1 Some successful examples of asymmetric transformations of imines

This laboratory has previously reported on the use of simple aziridino alcohols as chiral ligands for the enantioselective addition of diethylzinc to N-(diphenylphosphinoyl)

43 For an extensive review on the addition of organozinc reagents to carbonyl compounds, see: Pu, L.; Yu, H-B. Chem. Rev. 2001, 101, 757. 44 For an excellent review, see: Kobayashi, S.; Ishitani, H. Chem. Rev. 1999,99, 1069. 45 Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. For a review of Noyori´s work on the field see reference 30b. 46 (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J-C. J. Am. Chem. Soc. 1994, 116, 8797; (b) For a review, see: Denmark, S. E.; Nicaise, O. J-C. Chem. Commun. 1992, 999. 47 Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992, 1097 and references cited therein.

34 imines,48 Scheme 5.2. At the same time, enantioselective addition of diethylzinc to aldehydes had been successfully promoted using N-substituted 2-azanorbornyl-3-methanol and thiol as ligands.49

Me OH 1 equiv O N O Ph Bn H Ph P P 63% yield Ph N PhEt2Zn Ph N Ph 94% ee H Scheme 5.2 Enantioselective addition promoted by simple aziridino alcohols

It was therefore decided to investigate the performance of these types of ligands in the addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines (Papers V, VI and VII).

5.2 The 2-azanorbornyl-3-methanols as chiral auxiliaries for the addition reaction

5.2.1 The first generation ligands – Synthesis and results obtained The first generation ligands were prepared from the ethyl-2-azanorbornyl-3- carboxylate 5, using the synthetic sequence depicted in Scheme 5.3.

ii NR1 OH

43 (74%) R1 = CH2Ph i 44 (76%) R1 = Me NH NR1 CO2Et CO2Et 45 (60%) R1 = Et 46 (80%) R1 = iPr 5 27 (78%) R1 = CH2Ph NR 40 (37%) R = Me 1 1 iii C(R2)2OH 41 (80%) R1 = Et 42 (82%) R1 = iPr 28 (84%) R1 = CH2Ph R2 = Me 47 (20%) R1 = CH2Ph R2 = iPr 48 (47%) R1 = CH2Ph R2 = Ph Reagents and conditions: (i) (R1)X, CH3CN, K2CO3; (ii) LAH, THF; (iii) (R2)MgBr, THF Scheme 5.3 The first generation ligands

Compounds 28 and 43 to 48 were then used as chiral auxiliaries in the title transformation and the results obtained are given in Table 5.1. As it can be seen from this

48 (a) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727; (b) Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364. 49 (a) Nakano, H.; Kumagai, N.; Kabuto, C.; Matsuzaki, H.; Hongo, H. Tetrahedron: Asymmetry 1995, 6, 1233; (b) Nakano, H.; Kumagai, N.; Kabuto, C. Matsuzaki, H.; Hongo, H. Tetrahedron: Asymmetry 1997, 8, 1391; (c) Nakano, H.; Iwasa, K.; Hongo, H. Heterocycles 1991, 44, 435.

35 table structures 43 and 45 proved to be superior (entries 2 and 4) to all others and the obtained enantioselectivities were in both cases above 90%.

O Chiral Ligand O Ph RH Ph P P Ar N PhR2Zn, toluene ArS N Ph H 49a, Ar = Ph 50a, Ar = Ph; R = Et 49b, Ar = 1-naphthyl 50a', Ar = Ph; R = Me 50b, Ar = 1-naphthyl; R = Et

Entry Ar Ligand (equiv) R Yield% %ee EntryAr Ligand (equiv) R Yield% %ee

1 Ph 44 (1) Et 50 75 7 1-Napht 43 (1) Et 65 92 2 Ph 45 (1) Et 43 92 8 Ph 28 (1) Me 32 83 3 Ph 46 (1) Et 59 85 9 Ph 28 (1) Et 65 88 4 Ph 43 (1) Et 63 91 10 Ph 47 (1) Et 52 43 5 Ph 43 (0.25) Et 46 85 11 Ph 48 (1) Et 33 16 6 Ph 43 (0.10) Et 38 68

a Isolated after flash chromatography (silica gel, pentane/acetone); bDetermined by HPLC analysis using a chiral column (ChiralCel OD-H)

Table 5.1 Results obtained with the first generation ligands

These promising results also prompted the use of substoichiometric amounts of the chiral auxiliary. Unfortunately the selectivity in the reaction dropped as the amount of ligand was decreased (entries 4, 5 and 6). Noteworthy is the fact that up to 90% of the auxiliary could be recovered during purification and re-used without loss of asymmetric induction.

5.2.2 The second generation ligands – Synthesis and results obtained The second generation ligands are compounds that contain a secondary alcohol functionality. These were prepared via the 2-azanorbornyl-3-carboxaldehyde 53 (Scheme 5.4). The ligands from this generation were developed as a consequence of the theoretical study of the reaction mechanism (Section 5.3), which suggested that secondary alcohols with the correct absolute configuration would further improve the selectivity. Preparation of the key intermediate (aldehyde 53) was straightforward, but a simple Grignard addition did not led to the desired product in satisfactory yield and selectivity. This problem, however, was overcome by the use of the corresponding organocerium reagent, prepared in situ by reaction of anhydrous cerium (III) chloride and the organomagnesium species.50

50 (a) For a review on organocerium reagents in organic synthesis, see: Liu, H-J.; Shia, K-S.; Shang, X.; Zhu, B- Y.; Tetrahedron 1999, 55, 3803; For experimental procedure, see: (b) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392; (c) Imamoto, T.; Takeda, N. Org. Synth. 1998, 76, 228.

36 iiiiii NPh NPh NPh NPh CO2Et CO2Et OH CHO 1a 51 52 53

iv R R Ph vi R v N NH N Ph OH OH OH H H H 60, R = Ph (61%) 57, R = Ph (96%) 54, R = Ph (98%) 61, R = Me (65%) 58, R = Me (93%) 55, R = Me (98%) 62, R = iPr (64%) 59, R = iPr (95%) 56, R = iPr (78%)

Reagents and conditions: (i) H2 (1atm), Pd-C (10 wt%), EtOH, rt, 4h, 92%; (ii) LAH, THF, rt, 2h, 95%; (iii) Swern Oxidation, 92%; (iv) RMgX/CeCl 3, THF, -78 °C, overnight; (v) H2 (300 psi), Pd(OH)2-C (20 wt%), EtOH, rt, 4days; (vi) PhCH2Br, K2CO3, CH3CN, rt, 32h. Scheme 5.4 The second generation ligands – Part I

Having isolated compounds 54, 55 and 56, it was intended to use the Mitsunobu reaction51 to invert the absolute configuration at the secondary alcohol, since this would allow verification of the computational results. However, the reaction did not take place, probably due to steric hindrance of the substrate. Instead, another route to the desired diastereomers had to be developed. If one diastereomer could be obtained via Grignard addition to the aldehyde 53, the other one should be possible to prepare through hydride reduction of the analogue ketone. This approach called for the development of a new aza-Diels-Alder reaction involving imine dienophiles derived from keto-aldehydes instead of ester-aldehydes. This approach proved to be effective and the synthetic route to these new ligands is described in Scheme 5.5.

O H ii i iii N Ph R NPh NPh COR OH O COR R 63, R = Ph 65, R = Ph (42%) 67, R = Ph (95%) 69, R = Ph (71%) 64, R = Me 66, R = Me (31%) 68, R = Me (95%) 70, R = Me (61%)

iv H v H N Ph NH OH OH R R 72, R = Ph (65%) 71, R = Ph (96%), R = Me (not isolated) α . Reagents and conditions: (i) (S)- -phenylethylamine, CH2 Cl2, 0 °C; TFA, BF3 Et2 O, CpH, CH2Cl2, -78 °C, overnight; (ii) H2 (1 atm), Pd-C (10 wt%), MeOH, K2CO3, rt, 4h; (iii) LAH, THF, -78 °C, overnight; (iv) H2 (300 psi), Pd(OH)2 -C (20 wt%), EtOH, rt, 4 days; (v) PhCH2Br,

K2CO3, CH3CN, rt, 32 h. Scheme 5.5 The second generation ligands – Part II

51 Misunobu, O. Synthesis 1981, 1.

37 The use of sodium boron hydride in the reduction of compounds 67 and 68 led to very low conversion to products 69 and 70 (20% conversion after two days). If DIBAL-H was used a faster reaction was observed, although the selectivity remained lower than what was desired (70:30). Finally, the use lithium aluminium hydride gave the right diastereomer in good yield, > 60% over the pure major diastereomer, and selectivity, 80:20. Compounds 60, 61, 62 and 72 were then tested in the addition reaction and indeed the presence of an additional stereocenter turned out to be important. The right choice of the absolute configuration at this new chiral center improved the enantioselectivity in the reaction from 91% to 97% (Table 5.2), thus, turning this method into an attractive tool in the synthesis of chiral amines from the corresponding N-(diphenylphosphinoyl) imines.

a b O 1 equiv Chiral Ligand O Entry Ligand Yield% %ee Ph H Ph P P 1 60 70 97 Ph N PhEt2Zn, toluene Ph N Ph 2 61 68 93 H 3 62 59 79 49a 50a 4 72 52 71 aIsolated after flash chromatography (silica gel, pentane/acetone); bDetermined by HPLC analysis using a chiral column (ChiralCel OD-H)

Table 5.2 Results obtained with the second generation ligands

Due to the rather low number of publications dedicated to this transformation, solvent studies are rare and only one example was found in the literature.52 It was therefore decided to test this new and efficient chiral auxiliary performance in solvents other than toluene, using the imine 49a as the model substrate. As it can be seen from the results of this study summarised in Table 5.3, the non-aromatic solvents proved to be completely inadequate for this transformation (entries 2 to 4), while different aromatic solvents led to product formation in variable yields and selectivity.

Entry Solvent Yield % ee % Entry Solvent Yield % ee %

1 toluene 72 97 9 p-methylanisole 43 92 2 dichloromethane -- -- 10 chlorobenzene 75 98 3 diethylether -- -- 11 o-dichlorobenzene 60 96 4 tetrahydrofuran -- -- 12 m-dichlorobenzene 59 94 5 benzene 35 90 13 o-chlorotoluene 57 90 6 ethylbenzene 38 90 14 m-chlorotoluene 46 77 7 trifluorotoluene 52 95 15 p-chlorotoluene 69 95 8 anisole 47 94

Table 5.3 The solvent effect

52 Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem. Commun. 1994, 317.

38 Although the difference in the results obtained using toluene or chlorobenzene as solvents cannot be consider significant it was decided to try both solvents with the remaining substrates.

Ph N Ph (1 equiv) ; Et Zn (3 equiv) OH 2 O H O Ph 60 H Ph P P RNPhdry chlorobenzene or toluene R N Ph rt, 18h H ee % ee %

Entry R Yield % toluene chlorobenzene Entry R Yield % toluene chlorobenzene

1729798 76795 95 Cl

2 ------865 96 92

O 37291 89 9708597 Me

4707787 10 70 90 96 N

59198 98 11 65 90 94 O Br

6 ------O2N

Table 5.4 The addition of diethylzinc to different imines

From the results depicted in Table 5.4 it can be observed that some of the products were obtained in considerably better enantiomeric excess when the reactions were performed in chlorobenzene rather than toluene.

5.3 Reaction mechanism The mechanism of the reaction was investigated in order to further improve the ligand system, which in fact was achieved. As suggested by the theoretical calculations, ligand 60, which gave the addition product in 97% ee, allowed an improvement on the previous result obtained with ligand 43, 91% ee. This shows that secondary alcohols with the appropriate stereochemistry are a way of improving the selectivity in the title transformation. The addition of dialkylzinc reagents to aldehydes had recently been investigated by quantum chemical methods53 and the transition state for this reaction was used as a starting

53 Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327.

39 point for the evaluation of five types of transition states for the corresponding addition to imines, Figure 5.1.

Et Et Ph Ph PO(Ph) P Zn1 2 Zn1 N N N N O O O 2 2 Ph R Zn Et R Zn Et Et Ph Ph Ph C P A Zn1 Et Et N O O N H R 2 Et Et Ph Zn Et Ph E 1 PO(Ph)2 P Et Ph Zn N Zn1 N N N O O O R Zn2 R Ph Et Ph Zn2 B D Et Et Et Figure 5.1 The different transition states

According to the calculation results, transition state A can be excluded, since it is too high in energy. Structures B and C optimised to structures A and D respectively. We had previously invoked transition state D as a possible path for the reaction, but a fifth possibility proved to be even more reliable. It is now believed that structure E is the actual transition state for the reaction. The relative energies of the different transition states are listed in Table 5.5.

B3PW91/b B3PW91/b Entry TS type Product enantiomer Config. at Zn1 eq / axa HF/3-21G //HF/3-21G //B3PW91/c

1 A S R 38.4 22.4 2 D S R 12.7 12.2 11.7 3 D S S 21.2 16.5 4 D R R 18.0 15.2 5 E S R eq 0.0 0.0 0.0 6 E S S eq 2.2 2.7 7 E R R ax 7.7 9.5 8 E R R eq 1.1 1.8 1.4 9 E R S eq 2.5 2.6 aThis refers to the orientation of the aryl substituent of the imine in the TS of type E; bThe basis set used was 6-311+G* for Zn and 6-31G* for P, C, N, O and H; c The basis set used was 6-311+G for Zn and 6-31G for P, C, N, O and H Table 5.5 Transition states relative energies (in kcal/mol)

To rationalise the enantioselectivity for the addition reaction, sixteen different transition states of type E were initially considered. Co-ordination of the nitrogen to Zn1 requires an R configuration at this position; this is due to the steric requirements of the ligand in the (S)-Zn1 transition state, Figure 5.1. This places the –OH group and the co-ordinated

40 zinc center in a syn arrangement, thus, lowering the number of energetically viable transition states to eight. The number of transition states was then further reduced by the equatorial/axial selectivity concerning the orientation of the aryl substituent of the imine. The equatorial configurations proved to be energetically favoured and the number of transition states was now reduced to four. The lower transition states for the addition reaction are depicted in Figure 5.2, these structures are the ones corresponding to entries 5 and 8 in Table 5.5.

Zn 1.985 1.981 2.191 2.374

2.212 2.027 2.033 P 1.370 2.036 2.018 1.986 2.190 O 1.984 2.198 2.204 1.368 N 2.399

Figure 5.2 The two lowest transition states

The face selectivity of the imine then determines the enantioselectivity of the reaction, and both calculations and experimental results pointed towards a preferential formation of the S product. The difference between the lowest S and lowest R transition states arises from the orientation of the four-member ring, Zn2-C-C-N, where an exo orientation is favoured, Figure 5.2. This last parameter was evaluated for ligands 43 and 60, showing that the latter should lead to an improved enantioselectivity for the reaction, as seen by the energy differences in Table 5.6. These theoretical results were confirmed experimentally and as mentioned in Section 5.2 the level of enantioselectivity could be raised by up to 98%.

Chiral Product B3PW91/a Out-of-plane angle Dihedral angle Ligand enantiomer //HF/3-21G (Zn1-O-Zn2-(α-C)) ∆(C-Zn2-N-C) 43 S 0.0 140° 8° 60 S 0.0 168° 4° 43 R 1.8 -153° -9° 60 R 2.8 -155° -12° The comparison refers to the lowest S and the lowest R TS in table 5.5; aThe basis set used was 6-311G* for Zn and 6-31G* for P, C, N, O and H Table 5.6 Ligand substituent effects on the energies and selected geometrical parameters

41 Acknowledgements

I wish to express my gratitude to all the people of the department of Organic Chemistry at Kemicum, especially Prof. Pher G. Andersson for accepting me as a PhD student in his group, Assoc. Prof. Adolf Gogoll for all help with the different NMR experiments, and the technical staff Lief, Tomas, Gunnar, Wik, and Eva for all the help in solving the simple problems.

Thanks to all those with whom I had the pleasure to work with and learn from: Dr. David Guijarro, Dr. Diego A. Alonso, Dr. Oliver Temme for all the nights out in Uppsala and Münster, Dr. Peter Brandt, Dr. Klaus Lawonn, Mr. Christian Hedberg for the enthusiastic discussions and some football games, and Ph. Lic. Peter Roth. Also acknowledged are all the remaining past and present members of the PGA group with whom I did not had the pleasure to work with or had less productive co-operation.

A very special thanks to all my other chemistry friends: Mr. Magnus Engqvist, ”That which does not kill you makes you stronger”, Ms. Jenny Ekegren for the good fights in the lab, Ph. Lic. Magnus Besev for your interest in chemistry, music and everything else, ”Ein Stuhl in der Hoelle”, and Mr. Stefan Modin for all the jokes and help with artificial intelligence?!

Thanks to all the ones that read the first raw versions of this thesis and made constructive or destructive critics: Dr. Angelika Magnus, Mr. Christian Hedberg, Dr. Henrik Ottosson, and Mr. Stefan Modin. Also acknowledge is Mr. Niclas Sandström for reading the final version, for the good times in the office during my last months, and for helping me playing with some calculations.

Thanks to my parents, sister, and family for all support in the past and care at present.

42 True and deep thanks to all my friends for making life worth living: In Portugal, Victor Belo for visiting me in Sweden and for the good times with the rest of the Freaks – keep going your own way!, Fred for the unforgettable good times in Porto’s night life – take care and keep riding H.D., Carlos for all late night philosophic discussions, Rui another one of the Freaks for all music, Júlio which was never a Freak for all good times and music, Nando for the late film evenings, and all the ones I might have forgotten, but which will always be remembered; In Sweden, Magnus Engqvist for the beers, parties, coffees, …, but above everything for being who you are, Anna “space flower” Håkansson for all the good times we spent and all dancing, Janne and Jordi, António Castillejo and Marta Castellote (the spanish party friends), Arnaud Gayet, and Zina for sharing the same music taste. Without you all life would have been impossible to enjoy! Sorry to the ones that I have not mentioned, you are by no means less important to me.

Last, but most definitely not least a very special thanks to the person without whom I would have never been able to do what I did, thank you Ida.