ENANTIOSELECTIVE CROSS COUPLING REACTIONSA NEW ROUTE TO ENANTIOMERICALLY PURE-ARYLPROPIONIC ACIDSPromotor: Prof. Dr. R.M. Kellogg
ContentsChapter 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
SamenvattingInleiding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Dit proefschrift . . . . . . . . . . . . . . . . . . . . . . . . 110
