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(Hive Addict) 08-14-04 00:43 No 525324 |
ENANTIOSELECTIVE CROSS COUPLING REACTIONS | |||||||
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 Just hold on to the thread...that keeps us going http://www.chiapaslink.ukgateway.net/ |
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