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ENANTIOSELECTIVE CROSS COUPLING REACTIONS
« on: August 14, 2004, 12:43:00 AM »
ENANTIOSELECTIVE CROSS COUPLING REACTIONS

A NEW ROUTE TO ENANTIOMERICALLY PURE-ARYLPROPIONIC ACIDS

Promotor: Prof. Dr. R.M. Kellogg




Contents

Chapter 1: Introduction

1.1 Profen Drugs . . . . . . . . . . . . . . . . . . . . . . . . 1
Introduction
Profens as anti-inflammatory agents
In vivo behaviour of different profen drug enantiomers
The importance of the S - enantiomer
The importance of the R- enantiomer
The use of single R- or S- profens as drugs: an evaluation
Conclusions

1.2 Synthetic strategies towards optical active profens . . . . . . . . 5
Asymmetric reaction
Methylation of 2-arylacetic acids
Hydrogenation of 2-arylpropenoic acids
Hydroformylation of styrenes
Hydrocarboxylation of olefins
Hydrovinylation
Katsuki-Sharpless epoxidation
Friedel-Crafts alkylation of aromatics
Grignard coupling reactions
Asymmetric cross coupling reactions
Enantioselective protonation
1,2-Aryl migration
Bimolecular nucleophilic substitution with allylic rearrangement
Resolution by diastereomeric salts, kinetic and enzymatic resolution

1.3 Relationship to IOP Katalyse . . . . . . . . . . . . . . . . 12

1.4 Incentives for this research . . . . . . . . . . . . . . . . 13

1.5 References . . . . . . . . . . . . . . . . . . . . . . . . . 14

Chapter 2: Asymmetric Cross Coupling Reactions

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 17

2.2 Cross coupling reactions . . . . . . . . . . . . . . . . . . 19
Catalytic pathway
Scope and limitations
Summary
Ligands and asymmetric induction

2.3 Extraneous influences upon enantioselection . . . . . . . . . 25
Introduction
I. Influence of the alkylating species RMX
II. Influence of the type of halide
III. Influence of solvent
IV. Influence of zinc halide
Evaluation

2.4 Incentives . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.5 Aims and survey . . . . . . . . . . . . . . . . . . . . . . . 30

2.6 References . . . . . . . . . . . . . . . . . . . . . . . . . 31

Chapter 3: Ligands for Asymmetric Catalysed

Cross Coupling Reactions

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 33

3.2 -Aminophosphines . . . . . . . . . . . . . . . . . . 35
Incentives and strategy
Synthesis of 3.9a and 3.9b

3.3 -Aminosulphides . . . . . . . . . . . . . . . . . . . . . . 37
Incentives and strategy
Synthesis of 3.10, 3.11, and 3.11a

3.4 Ligands with sulphur containing appendages . . . . . . . . . 38
Incentives and strategy
Synthesis and resolution of racemic amino acid amides
Aminophosphine and ~sulphide ligands bearing sulphur containing
appendages

3.5 Summary and conclusions . . . . . . . . . . . . . . . . . . . 41

3.6 Experimental section . . . . . . . . . . . . . . . . . . . . 42

3.7 References . . . . . . . . . . . . . . . . . . . . . . . . . 49

Chapter 4: Asymmetric Cross Coupling Reactions With

An Improved Grignard Reagent Solution

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 51

4.2 Grignard reagents - different mechanistic models . . . . . . 52
Introduction
The A model
The D model

4.3 Grignard reagents - in practical sense . . . . . . . . . . . . . . 55

4.4 Methods to prepare magnesium surfaces . . . . . . . . . 56

4.5 Grignard reagent solutions
in asymmetric cross coupling reactions . . . . . . . . . . 57
Varying halide X in [vinyl halide - Grignard reagent] combinations
Influence on ee by extraneous compounds in the reaction mixture

4.6 Improved Grignard reagent solution . . . . . . . . . . . . . 61
Enantiomeric excess determination of 4.4

4.7 Asymmetric cross couplings with improved Grignard solution . 64
New type of asymmetric ligands
Ligands with a -aminophospine structure
Ligands with a -aminosulphide structure
Ligands with -aminophosphine structure bearing a sulphur appendage

4.8 Summary, conclusions and perspectives . . . . . . . . . 69

4.9 Experimental section . . . . . . . . . . . . . . . . . . . . 69

4.10 References . . . . . . . . . . . . . . . . . . . . . . . . . 73

Chapter 5: Organozinc Reagents And
Asymmetric Cross Coupling Reactions

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 75
Influence of zinc halide on enantioselection in
asymmetric cross coupling reactions
Incentive to this research

5.2 Synthesis of organozinc compounds . . . . . . . . . . . . . . 78
Transmetallation and magnesium-salt removal with 1,4 dioxane
Activation of granular zinc by 'dry stirring'
Activation of metallic zinc with 1,2 dibromoethane

5.3 Organozinc solutions and asymmetric cross couplings . . . . . 82
Introduction
1-Phenylethylzinc solution [dioxan method] in cross couplings
1-Phenylethylzinc solution [dry stirring method] in cross couplings
1-Phenylethylzinc solution [EDB method] in cross couplings
Addition of MgBr - diethyl etherate 2
Addition of ZnBr2
Use of 1-phenylethyl bromide
Addition of alkoxide
Use of preformed catalysts

5.4 Summary, conclusions and perspectives . . . . . . . . . 85

5.5 Experimental section . . . . . . . . . . . . . . . . . . . . 85

5.6 References . . . . . . . . . . . . . . . . . . . . . . . . . 87

Chapter 6: Towards Enantioselective S 2' Reactions N

6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 89

6.2 An alternative route to compound 6.1: the S 2' reaction . . . 90 N

6.3 Strategy towards asymmetric catalysed S 2' reactions . . . . 92 N
Introduction
Recent developments
i) Reagents and regioselectivity
ii) Asymmetric ligands in S 2' reactions N

6.4 Substitution reactions in S 2' fashion . . . . . . . . . . . . . . 96 N
Organozinc reagents in S 2' reactions N
Asymmetric catalysts for S 2' reactions with methylzinc reagents N
Methylzinc reagents in S 2' reactions: conclusions N
Organotitanium reagents in S 2' reactions N
Synthesis of compound 6.11
Asymmetric catalysts for S 2' reactions with methyltitanate reagents N
Methyltitanate reagents in S 2' reactions: conclusions N

6.5 Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . 102

6.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . 103

6.7 Experimental section . . . . . . . . . . . . . . . . . . . . 103

6.8 References . . . . . . . . . . . . . . . . . . . . . . . . . 107

Samenvatting

Inleiding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Dit proefschrift . . . . . . . . . . . . . . . . . . . . . . . . 110