Comprehensive Summaries of Uppsala Dissertationsfrom 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 UPSALIENSISUPPSALA 2001

Dissertation for the Degree of Doctor of Philosophy in Organic Chemistry presented atUppsala University in 2001

ABSTRACT

Pinho, P. 2001. Development and Application of New Chiral β-Amino Alcohols in Synthesis andCatalysis. Use of 2-Azanorbornyl-3-Methanols as Common Intermediates in Synthesis and Catalysis.Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Facultyof Science and Technology 626. 43 pp. Uppsala. ISBN 91-554-5091-9.

The development and application of unnatural amino alcohols, prepared via hetero-Diels-Alderreactions, in synthesis and catalysis is described. The studies are concerned with the [i] scope of thehetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviralagents, [ii] application of amino alcohols in the ruthenium transfer hydrogenation of ketones, [iii] useof 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 theirpreparation, is extended by manipulations of the dienophiles.[ii] Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysedasymmetric 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 reducedproducts in excellent yields and enantioselectivities (up to 97% ee).[iii] Preparation of α-disubstituded 2-azanorbornyl-3-methanols, in situ generation of thecorresponding 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 therationalisation of the reaction mechanism and the development of a second generation of ligands thatimproved 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, chiralligands 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. pedro@kemi.uu.se

© Pedro Pinho 2001

ISSN 1104-232X

ISBN 91-554-5019-9

Printed in Sweden by Uppsala Universitet Tryck & Medier, Uppsala 2001

3

Watching fate as it flows down the path we have chose

-Trent Raznor

4

Papers included in the thesis

This thesis is based on the following papers and appendix, referred to in the text by theirRoman 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 AsymmetricReduction 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 ofDialkylzinc 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

5

Contents

Papers included in the thesis

List of abbreviations

1. Introduction 71.1 Towards enantiomerically pure or enriched compounds 81.2 Asymmetric synthesis – Ligands and metals 91.3 The use of simple β-amino alcohols as chiral ligands 11

2. Hetero-Diels-Alder reaction – Applications in synthesisand preparation of unnatural ββββ-amino alcohols 132.1 Introduction 132.2 Studies on the scope of the aza-Diels-Alder reaction – Towards nicotinic

acetylcholine receptors 142.3 Preparation of enantiomerically pure cyclopentyl- and cyclohexyl-amines 182.4 Access to unnatural β-amino alcohols 21

3. Ruthenium-catalysed asymmetric transfer hydrogenation of ketones 233.1 Introduction 233.2 The 2-azanorbornyl-3-methanol as a ligand for ruthenium 243.3.Reaction mechanism 26

4. Oxazaborolidines in the asymmetric reduction of ketones 294.1 Introduction 294.2 Reaction mechanism 294.3 Preparation of 2-azanorbornyl-3-methanol ligands and their application

in the form of the corresponding oxazaborolidines 30

5. Enantioselective addition of dialkylzinc reagentsto N-(diphenylphosphinoyl) imines 345.1 Introduction 345.2 The 2-azanorbornyl-3-methanols as chiral auxiliaries for the addition reaction 355.2.1 The first generation ligands – Synthesis and results obtained 355.2.2 The second generation ligands – Synthesis and results obtained 365.3 Reaction mechanism 39

Acknowledgements 42

6

List of abbreviations

Abs. Config. Absolute configurationBn Benzyln-Bu Butylt-Bu tert-ButylCat. CatalyticCBS Corey, Bakshi, ShibataConfig. ConfigurationCpH CyclopentadieneDIBAL-H Diisobutylaluminium hydrideee Enantiomeric excessequiv. EquivalentEt Ethylh Hour(s)HMB HexamethylbenzeneHPLC High Performance Liquid ChromatographyLAH Lithium aluminium hydrideM MetalMe Methylmin Minute(s)MS Molecular sieves1-Napht 1-NaphtylNMO N-methylmorpholine N-oxideNMR Nuclear Magnetic RessonancePh Phenyli-Pr iso-Propyln-Pr Propylrt Room temperatureStoich. StoichiometricTFA Triflouroacetic acidTHF TetrahydrofuranTIPSCl TriisopropylsilylchlorideTs p-ToluenesulphonylTS Transition StateX Halogen (Cl, Br, I)

7

“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

corresponds to a symmetry plane (σ) and S2 to an inversion center (i).2 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.

NH

NH

COOH HOOC

(S)-Proline (R)-Proline

Mirrorplane

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; VCHPublishers, Inc.: New York, 1995.

8

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

NH2 COOH

OH

O H

O

O

O

H2O

(-)-DAG

NH2

(S)-(-)-α-(1-naphthyl)ethylamine> 99% ee

1)

2) 2M NaOH

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.

9

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

synthesis of leukotriene A4.5

O OH

OHHO

HOsteps

from D-(-)-ribose

OCO2Me

(-)-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

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

10

3 NaBH44 BF3 OEt2

2 B2H6 3 NaBF4

8 4

BH

2

(Icp)2BH99.8% ee

94% ee

B

2

H HHO

95% ee

H2O2/NaOH

+

++ 4 Et2O

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.

RR

RR

OH

OH

Cat. OsO4

Stoich. co-oxidant

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. 11998, 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.

11

Ph

CuN

O N

O

Ph

Ph

N2CHCOOEtcis/trans : 1/2.3

%ee for trans isomer = 6%

Ph CO2Et Ph

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

ONN

N

O

O

N

O

RR

RR

OH

OH

up to 99% ee

Cat.

Cat. OsO4

Stoich. NMO

N

Scheme 1.6 Catalytic asymmetric dihydroxylation of olefins

1.3 The use of simple ββββ-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.

12

Corey and co-workers in the eighties and is used for the preparation of secondary alcohols

from pro-chiral ketones, Scheme 1.7.13

N BO

BH3

Ph

O

Ph

OHCat.

Stoich. BH3

99% yield, 97% ee,in 198713

PhPh

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.

13

2. Hetero-Diels-Alder reaction – Applications in synthesis and preparation

of unnatural ββββ-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.

S S

Re face

Major product

RR

exo endo

1a 1d

1c1b

δ

δ

Si face

N

H

CO2EtPh N

CO2Et

H

N

H

EtO2CN

CO2Et

HPh

O

O

O

O

O

NO

O

HN Ph

BF3

Ph1) TFA

CF3COO

exo endo

CpH

CpH CpH

CpH

H2N PhS

Ph

Ph

2) BF3 OEt2

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.

14

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.1 8 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.

15

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.

Me3NO

O

(-)-Epibatidine A(-)-NicotineAcetylcholine

HN

N Cl

N

H

N

N

N

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 Treatmentsof Central Nervous System Disorders. U. S. Patent 5,583,140, 1996.

16

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.

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

i ii

2 3

NAr

Ph

Ar N PhAr O

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.

17

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.

Aldehydea Reactionconditions YieldbEntry

CH3SO3H / TFA 87:131

2

4

5

7

8

CH3SO3H / TFA 80:20

90:10CH3SO3H

CH3SO3H 90:10

CH3SO3H

CH3SO3H

75:25

90:10

3CH3SO3H / TFA or

CH3SO3H e

6CH3SO3H / TFA or

CH3SO3H e

Diastereoselectivityd

> 99 %

> 99 %

> 99 %

> 99 %

> 99 %

> 99 %

---

---

80

60

---

80

79

---

60

80

exo/endoselectivityc

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.

2a

2b

2c

2d

2e

2f

2g

2h

Product

3a

3b

3d

3e

3g

3h

N

N

N

N

NH

N

NH

N

S

N

Ph

N

N

Ph

N

N

Ph

N

N

Ph

N

N

PhN

HN

N

PhN

S

O

NO

O

O

O

O

O

O

---

---

Table 2.1 Results of the cycloaddition reactions with heterocyclic imine dienophiles

18

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.

Reagents and conditions: (i) (S)-α-phenylethylamine, MS 4Å, CH2Cl2, rt; (ii) ZnCl2, isoprene, CH2Cl2/ether, rt.

i ii

2c 4

N NO N Ph N N

Ph

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. ResearchCommun. 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. Guaninederivatives: 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.

19

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).

O

NH

NH2

NHN

N

NN

NH2

HO

HO OH

(1R, 3S)-Amidomycin (-)-Aristeromycin Carbovir:NCS 614846

H2N

HN

N

NN

O

HO

H2N

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.

N N

HN

Ph

BrPh

Mg, THF+

B C D

PhNR

Mg Br

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.

20

9

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%.

5 7

NHCO2Et

NTsOH

8

NTsBr

NHTs

N PhCO2Et

1a

i ii

6

NTsCO2Et

iii

ivv

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.

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%.

NCO2Et

PhHO

HO NCO2Et

PhO

O

NTsO

OO O

NHTs

1a

NCO2Et

Ph i

10

ii

11

iii NHCO2Et

OO

12iv

OH

vi

14

NTsO

OBr

15

vii

16

NTsCO2Et

OO

v

13

Scheme 2.5 Multi-functionalisation of cyclopentadiene

21

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

17 18

i -vii

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%.

NCO2Et

PhO

O

NHTs

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 ββββ-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.

22

The use of the referred type of amino alcohol ligands, 2-azanorbornyl-3-methanols,

will be described in the following chapters of this thesis.

N NR

NH NH

CO2Et

CO2Et

1a

5OH

OHR''

R'Ph

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

23

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.

R R'

O

R R'

OHCat. "Ru", Cat. Chiral Ligand

Cat. Base, 2-Propanol

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.

NHTs

NH2

Ph

Ph

PhPNHHN

HO NHMe

Ph

OH

NH2

N

O

Ph2P

Fe

NHMe

NHMe

PhPh

19 20 21

242322

99% yield

98% ee 3195% yield91% ee 32a

96% yield20% ee 32d

70% yield91% ee32e

95% yield80% ee 32c

24% yield

94% ee 32b

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 (resultobtained 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.

24

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

Reagents and conditions: (i) LAH (2 equiv), THF, rt, 1h, 90%

5

NHCO2Et

25

NHOH

NH

OH

26, (S)-prolinol

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.

5 27 28 29

Reagents and conditions: (i) PhCH2Br, K2CO3, CH3CN, rt, 32h, 78%; (ii) MeMgBr, THF, rt, 2h, 84%; (iii) H2 (150psi), 5% Pd-C, EtOH, rt, 24h, 98%.

i ii iiiNHCO2Et

NCO2Et

Ph N

PhOH

NH

OH

Scheme 3.3 Synthesis of ligand 29

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

25

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.

S

S

Entry Ligand Yield% %eea Configb

25

29

261

2

3

16

92

85

Time/h

6.5

5

16c

8

95

rac. - -

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

2.5 mol% i-PrOK, i-PrOH

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.

Ph

O

Ph

OH

NH

OH

NHOH

NH

OH

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.

26

R R'

O

R R'

OH

Me HMB

Me HMB

Et HMB

n-Pr HMB

n-Bu HMB

n-Hexyl HMB

t-Bu HMB

Me p-cymene

Me p-cymene

Et p-cymene

n-Pr p-cymene

n-Bu p-cymene

n-Hexyl p-cymene

0.25 mol% [RuCl2(arene)]2

2.5 mol% i-PrOK

i-PrOH

Entry [RuCl2(arene)]2 Time/h Yield% %eeaR R'

1 5 92 95

2 3 100 94

3 5 81 83

4 5 81 90

5 5 70 89

6 5 17 83

7 5 b c

8 1.5 91 94

9 1.5 92 97

10 1.5 81 93

11 1.5 60 92

12 1.5 78 95

13 1.5 53 95

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.

Entry [RuCl2(arene)]2 Time/h Yield% %eeaR R'

NHOH

2 mol%

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.

27

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

M

O

H

O

H

M N

HH

M

O

a b 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.

RuO NH

RuO

NH2

HRuO

NH2

Cl

O

R R'

O

OH

R R'

OH

HRu N

HO

ClRu

ClRu

Cl Cl

OH NH2

ArTS c

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. Similarstudies 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.

28

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.

29

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. Synlett1996, 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.

30

N BO

H

BH3

PhPh

Me

NHOH

H PhPh

NB

O

H PhPh

Me

MeB(OH)2

O

NB

O MePh

Ph H2BO

H

NB

O MePh

Ph BH2

OH

NB

O

H PhPh

H2BO

H B

HH

HBH3

HH2BO

HCl

OH

31

30

ab

BH3

Toluene, ∆-H2O

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

31

(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.

NB

O MePh

PhH2B

OPhH

NH

BO

Ph

Ph

OPh

Me

HH2B

Corey's proline based catalyststrictly α co-ordination

Itsuno's valine based catalystpossibility for both α and β co-ordination

H

NB

O MePh

PhH2B

OPhH

2-azanorbornyl-3-methanol basedoxazaborolidine - increased rigidity

OPh

HB

NB

O

Me

HH

Ph

Ph

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.

O

Me

32, R = 33, R =

34, R = 35, R =

36, R = 37, R =

38, R =

1a 5

32-3825, R = H29, R = CH3

i

ii iii 20-46%

N PhCO2Et

NHCO2Et

NHCR2OH

NHCR2OH

Cl

F3C

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.

32

N PhCO2Et

NH

17 39

i

Reagents and conditions: (i) Same as for the transformation of 1a to 25

OH

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.

0.1 equiv 32, 0.12 equiv B(OMe)3

Entry Initial amino alcohol concentration/Ma % eeb

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%.

1equiv BH3Ph

O

Ph

OH

Me2S

12

34

0.050.1

0.20.9

8384

8787

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 % eeTotal time / h

123456

THFCH2Cl2CH3CNToluene

THFTHF

rtrtrtrt

6 - 740

264282

87rac.23674979

Table 4.2 Solvents and temperatures

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

33

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.

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.

Entry Amino alcohol Ketone % ee Abs. Config.a

1 25 55 (S)

2 29 13b (S)

3 33 63 (S)

4 34 45 (S)

5 35 77 (S)

6 36 60 (S)

7 37 77 (S)

8 38 87 (S)

9 39 45 (S)

10 32 87 (S)

11 32 70c (S)

12 32 58 (S)

13 32 83b (S)

14 32 77b (S)

15 32 47 (S)

16 32 82 (R)

17 32 89 (R)

Entry Amino alcohol Ketone % ee Abs. Config.a

O O

O

O

O

O

O

OCl

OBr

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.

34

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.

HCO2H-Et3N

Et2Zn

99% yield95% ee45

90% yield91% ee46

1 equiv

nBuLi (2 equiv)

89% yield90% ee47

2.5 mol% [RuCl2(p-cymene)]2

5 mol%

1 equiv

N

O

O

Me

NH

O

OH Me

TsHN NH2

Ph Ph

Ph

N

O

Ph

HN

ONN

HH

HH

Ph NP

OPhPh Ph N

H

P

OPhPh

H

N OH

Me Ph

O

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 areview 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.

35

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

Et2Zn63% yield94% ee

1 equiv

Ph NP

OPhPh Ph N

H

P

OPhPh

HNBn

MeOH

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.

5

i

ii

iii

Reagents and conditions: (i) (R1)X, CH3CN, K2CO3; (ii) LAH, THF; (iii) (R2)MgBr, THF

27 (78%)40 (37%)

R1 = CH2PhR1 = Me

28 (84%)47 (20%)48 (47%)

R1 = CH2PhR1 = CH2PhR1 = CH2Ph

R2 = MeR2 = iPrR2 = Ph

NHCO2Et

NR1CO2Et

NR1OH

NR1C(R2)2OH

43 (74%)44 (76%)

R1 = CH2PhR1 = Me

45 (60%)46 (80%)

R1 = EtR1 = iPr

41 (80%)42 (82%)

R1 = EtR1 = iPr

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.

36

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%.

S

49a, Ar = Ph49b, Ar = 1-naphthyl

50a, Ar = Ph; R = Et50a', Ar = Ph; R = Me50b, Ar = 1-naphthyl; R = Et

Chiral Ligand

R2Zn, toluene

Entry Ligand (equiv) R Yield% %ee

123456

PhPhPhPhPhPh

504359634638

759285918568

EtEtEtEtEtEt

44 (1)45 (1)46 (1)43 (1)

43 (0.25)43 (0.10)

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

Ar

Ar NPO

PhPh Ar N

H

PO

PhPh

R H

Entry Ligand (equiv) R Yield% %ee

7891011

1-NaphtPhPhPhPh

6532655233

9283884316

EtMeEtEtEt

43 (1)28 (1)28 (1)47 (1)48 (1)

Ar

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.

37

1a 51 52 53

54, R = Ph (98%)55, R = Me (98%)56, R = iPr (78%)

57, R = Ph (96%)58, R = Me (93%)59, R = iPr (95%)

60, R = Ph (61%)61, R = Me (65%)62, R = iPr (64%)

i ii

iv

iii

vvi

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/CeCl3, THF, -78 °C, overnight; (v) H2 (300 psi), Pd(OH)2-C (20 wt%), EtOH, rt, 4days; (vi) PhCH2Br, K2CO3, CH3CN, rt, 32h.

N PhCO2Et

N PhCO2Et

N PhOH

N PhCHO

NR

PhOH

H

NHOH

H

RN

OHH

PhR

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.

i ii iii

iv

v

63, R = Ph64, R = Me

65, R = Ph (42%)66, R = Me (31%)

67, R = Ph (95%)68, R = Me (95%)

69, R = Ph (71%)70, R = Me (61%)

71, R = Ph (96%), R = Me (not isolated)

72, R = Ph (65%)

Reagents and conditions: (i) (S)-α-phenylethylamine, CH2Cl2, 0 °C; TFA, BF3.Et2O, 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.

R

O

ON Ph

CORN Ph

CORN Ph

H

ROH

NH

ROH

HN Ph

H

ROH

Scheme 5.5 The second generation ligands – Part II

51 Misunobu, O. Synthesis 1981, 1.

38

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.

1 equiv Chiral Ligand

Et2Zn, toluene

Entry Ligand Yield%a %eeb

1234

70685952

97937971

60616272

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

Ph NPO

Ph

Ph Ph NH

PO

Ph

Ph

H

50a49a

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.

12345678

toluenedichloromethane

diethylethertetrahydrofuran

benzeneethylbenzene

trifluorotolueneanisole

72------35385247

97------90909594

Entry Solvent Yield % ee %

9101112131415

p-methylanisolechlorobenzene

o-dichlorobenzenem-dichlorobenzene

o-chlorotoluenem-chlorotoluenep-chlorotoluene

43756059574669

92989694907795

Entry Solvent Yield % ee %

Table 5.3 The solvent effect

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

39

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.

Entry R Yield %

ee %

; Et2Zn (3 equiv)

toluene chlorobenzene

1 72 97 98

2 -- -- --

3 72 91 89

4 70 77 87

5 91 98 98

6 -- -- --

7 67 95 95

8 65 96 92

9 70 85 97

10 70 90 96

11 65 90 94

R NPO

Ph

Ph R NH

PO

Ph

Ph

H

Entry R Yield %

ee %

toluene chlorobenzene

O

N

O

O2N

Cl

Me

Br

NOH

H

PhPh

(1 equiv)

60

dry chlorobenzene or toluenert, 18h

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.

40

point for the evaluation of five types of transition states for the corresponding addition to

imines, Figure 5.1.

NZn1

Et

PO(Ph)2

Et

Et

PhR

NZn1

Et

PO(Ph)2

EtEt

PhR

N Zn1

EtP

EtEt

PhR

O

PhPh

A

B D

NZn1

Et

N

Et

Et

OZn2

PhRC

P

O

PhPh

N Zn1

Et

OP

EtEt

OZn2R

N

Ph

Ph

E Ph

H

N

O

Zn2

NO

Zn2

NO

Zn2

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.

Entry TS type Product enantiomer Config. at Zn1 eq / axa HF/3-21GB3PW91/b

//HF/3-21G

123456789

ADDDEEEEE

eqeqaxeqeq

38.412.721.218.00.02.27.71.12.5

22.412.216.515.20.02.79.51.82.6

RRSRRSRRS

SSSRSSRRR

B3PW91/b

//B3PW91/c

11.7

0.0

1.4

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

41

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.

1.981 2.191 2.374

1.370

2.1902.036

2.0272.212

1.984

Zn

P

O

N

C

1.985

2.033

2.018

2.1981.368

2.399

2.204

1.986

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%.

43604360

ChiralLigand

Productenantiomer

SSRR

B3PW91/a

//HF/3-21G

Out-of-plane angle

(Zn1-O-Zn2-(α-C))

Dihedral angle

∆(C-Zn2-N-C)

0.00.01.82.8

140°168°

-153°-155°

8°4°

-9°-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

42

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.

43

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.