Enantioselective chemoenzymatic synthesis of 2-arylpropionic acids and dihydropyrimidinones using lipases as biocatalysts [Elektronische Ressource] / María Alfaro Blasco

Enantioselective chemoenzymaticsynthesis of 2-arylpropionic acidsand dihydropyrimidinones usinglipases as biocatalystsEnantioselektive chemoenzymatische Synthese von2-Arylpropionsäuren und Dihydropyrimidinonen unterVerwendung von Lipasen als BiokatalysatorenDer Naturwissenschaftlichen Fakultätder Friedrich-Alexander-Universität Erlangen-NürnbergzurErlangung des Doktorgrades Dr. rer. nat.vorgelegt vonMaría Alfaro Blascoaus Valencia/SpanieniiAls Dissertation genehmigt von derNaturwissenschaftlichen Fakultät der Universität Erlangen-NürnbergTag der mündlichen Prüfung: 24. März 2011Vorsitzender derPromotionskommission: Prof.Dr. Rainer FinkErstberichterstatter: Prof.Dr. Harald GrögerZweitb Priv.-Doz. Dr. Norbert JuxGedruckt mit Unterstützung des Deutschen Akademischen AustauschdienstesContentsAbbreviations xiAcknowledgements xiii1 Introduction 12 Motivation and aim of the work 52.1 Enantioselective synthesis of -arylpropionic acid derivatives 1 . . . . . . . . . 62.2 of DHPM derivatives 2 . . . . . . . . . . . . . . . . 63 Enzymatic hydrolysis and racemization of 2-arylpropionic acid alkyl esters 93.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.2 State of the art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.2.1 Different enantioselective procedures to synthesize 2-arylpropionic acids(Profens, 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.2.1.
Publié le : samedi 1 janvier 2011
Lecture(s) : 24
Source : D-NB.INFO/1012199851/34
Nombre de pages : 200
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Enantioselective chemoenzymatic
synthesis of 2-arylpropionic acids
and dihydropyrimidinones using
lipases as biocatalysts
Enantioselektive chemoenzymatische Synthese von
2-Arylpropionsäuren und Dihydropyrimidinonen unter
Verwendung von Lipasen als Biokatalysatoren
Der Naturwissenschaftlichen Fakultät
der Friedrich-Alexander-Universität Erlangen-Nürnberg
zur
Erlangung des Doktorgrades Dr. rer. nat.
vorgelegt von
María Alfaro Blasco
aus Valencia/SpanieniiAls Dissertation genehmigt von der
Naturwissenschaftlichen Fakultät der Universität Erlangen-Nürnberg
Tag der mündlichen Prüfung: 24. März 2011
Vorsitzender der
Promotionskommission: Prof.Dr. Rainer Fink
Erstberichterstatter: Prof.Dr. Harald Gröger
Zweitb Priv.-Doz. Dr. Norbert JuxGedruckt mit Unterstützung des Deutschen Akademischen AustauschdienstesContents
Abbreviations xi
Acknowledgements xiii
1 Introduction 1
2 Motivation and aim of the work 5
2.1 Enantioselective synthesis of -arylpropionic acid derivatives 1 . . . . . . . . . 6
2.2 of DHPM derivatives 2 . . . . . . . . . . . . . . . . 6
3 Enzymatic hydrolysis and racemization of 2-arylpropionic acid alkyl esters 9
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.2 State of the art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.2.1 Different enantioselective procedures to synthesize 2-arylpropionic acids
(Profens, 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.2.1.1 Chemical processes and industrial applications . . . . . . . . . . . . 13
3.2.1.2 Enzymatic approaches and current limitations . . . . . . . . . . . . 26
3.2.2 Catalytic racemization methods . . . . . . . . . . . . . . . . . . . . . . 30
3.2.2.1 General methods . . . . . . . . . . . . . . . . . . . . 30
3.2.2.2 Racemization of -substituted propionic acids and ester derivatives . 34
3.3 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.4 Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.4.1 Synthesis of racemic alkyl 2-arylpropionates (rac-64) . . . . . . . . . . . 37
3.4.2 Hydrolytic resolution of racemic 2-phenylpropionates rac-64 . . . . . . . 39
3.4.3 Optimization of the reaction conditions for the enzymatic hydrolysis of
2-phenylpropionates rac-64 . . . . . . . . . . . . . . . . . . . . . . . . 42
3.4.3.1 Influence of the solvent . . . . . . . . . . . . . . . . . . . . . . . . 42
3.4.3.2 Substrate spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.4.3.3 Effect of the temperature . . . . . . . . . . . . . . . . . . . . . . . 46
3.4.4 Organocatalytic racemization of ethyl (S)- and (R)-2-phenylpropionates
((S)-64a and (R)-64a) . . . . . . . . . . . . . . . . . . . . . . . . . . 48
vContents
3.4.4.1 Catalyst screening in a one-phase system . . . . . . . . . . . . . . 49
3.4.4.2 Solvent in a one-phase system . . . . . . . . . . . . . . . 52
3.4.4.3 Influence of temperature in a one-phase system . . . . . . . . . . . 53
3.4.4.4 Catalyst screening in a two-phase system . . . . . . . . . . . . . . 54
3.4.5 Organocatalytic racemization of ethyl (S)-2-(isobutylphenyl)propionate
((S)-65) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.4.5.1 Catalyst screening in a one-phase system . . . . . . . . . . . . . . 58
3.4.5.2 Influence of the catalyst concentration in a one-phase system . . . . 59
3.4.5.3 Catalyst screening in a two-phase system . . . . . . . . . . . . . . 60
3.4.6 Combination of the enzymatic hydrolysis and the racemization . . . . . . 61
3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4 Biocatalytic synthesis of (S)-monastrol 65
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.2 State of the art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.2.1 Importance of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs, 2) . . . . . . . 67
4.2.2 Multicomponent Biginelli reaction . . . . . . . . . . . . . . . . . . . . . 68
4.2.2.1 General aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.2.2.2 Synthesis of enantiomerically pure DHPMs (2) . . . . . . . . . . . 71
4.2.3 Control of remote stereogenic centers by using biocatalysts . . . . . . . . 75
4.3 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.4 Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.4.1 Substrate synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.4.1.1 Setup of the analytic methods . . . . . . . . . . . . . . . . . . . . 84
4.4.2 Initial concept: hydrolytic resolution of racemic DHPMs . . . . . . . . . 85
4.4.2.1 Enzyme screening for the hydrolysis of racemic dehydroxymonastrol
(rac-6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
4.4.2.2 Enzyme screening for the hydrolysis of racemic monastrol (7) . . . . 86
4.4.3 Hydrolytic resolution of O-acylated monastrol (rac-8) . . . . . . . . . . 87
4.4.3.1 Enzyme screening for the hydrolysis of racemic O-acylated monastrol
(rac-8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
4.4.3.2 Setup of the workup method after the enzymatic hydrolysis . . . . . 90
4.4.3.3 Optimization of the hydrolysis of O-acylated monastrol (8) . . . . . 92
4.4.3.4 Process development for the biocatalytic synthesis of (S)-monastrol
((S)-7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
viContents
5 Summary and outlook 99
6 Zusammenfassung und Ausblick 107
7 Experimental section 115
7.1 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
7.2 Synthesis and analytical data . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
7.2.1 Enzymatic hydrolysis and racemization of alkyl 2-arylpropionates (rac-64) 117
7.2.1.1 Standard Operation Procedure 1 (SOP1): Synthesis of alkyl rac-2-
phenylpropionates (rac-64) . . . . . . . . . . . . . . . . . . . . . . 117
7.2.1.1.1 Synthesis of ethyl rac-2-phenylpropionate (rac-64a) . . . . . 118
7.2.1.1.2 of n-propyl racropionate (rac-64b) . . . . 118
7.2.1.1.3 Synthesis of iso-propyl rac-2-phenylp (rac-64c) . . . 119
7.2.1.1.4 of n-butyl racropionate (rac-64d) . . . . 119
7.2.1.1.5 Synthesis of n-pentyl rac-2-phenylp (rac-64e) . . . . 120
7.2.1.2 Standard Operation Procedure 2 (SOP2): Synthesis of ethyl
(S)-2-arylpropionates (S)-64a and (S)-65 . . . . . . . . . . . . . . 120
7.2.1.2.1 Synthesis of ethyl (S)-2-phenylpropionate ((S)-64a) . . . . . 121
7.2.1.2.2 of ethyl (S)-2-(4-iso-butylphenyl)propionate ((S)-65) 122
7.2.1.3 Standard Operation Procedure 3 (SOP3): Enzymatic hydrolysis of
alkyl rac-2-phenylpropionates rac-64 . . . . . . . . . . . . . . . . . 122
7.2.1.3.1 Enzymescreeningforthehydrolysisofethylrac-2-phenylpropion-
ate (rac-64a) in a two-phase system water/hexane (4:1, (v/v)) 123
7.2.1.3.2 Enzymescreeningforthehydrolysisofethylrac-2-phenylpropionate
(rac-64a) in a two-phase system water/MTBE (4:1, (v/v)) . 124
7.2.1.3.3 Influence of the ester alkyl chain on the hydrolysis of alkyl
rac-2-phenylpropionates (rac-64) . . . . . . . . . . . . . . . 125
7.2.1.3.4 Influence of the solvent mixture on the enzymatic hydrolysis of
ethyl rac-2-phenylpropionate (rac-64a) . . . . . . . . . . . . 126
7.2.1.3.5 Influence of the solvent mixture on the enzymatic hydrolysis of
n-propyl rac-2-phenylpropionate (rac-64b) . . . . . . . . . . 127
7.2.1.3.6 Influence of the solvent mixture on the enzymatic hydrolysis of
n-butyl rac-2-phenylpropionate (rac-64d) . . . . . . . . . . . 128
7.2.1.3.7 Influence of the temperature on the enzymatic hydrolysis of
ethyl rac-phenylpropionate (rac-64a) . . . . . . . . . . . . . 129
7.2.1.3.8 Influence of the temperature on the enzymatic hydrolysis of
n-propyl rac-phenylpropionate (rac-64b) . . . . . . . . . . . 129
viiContents
7.2.1.4 Standard Operation Procedure 4 (SOP4): Racemization of ethyl
(S)-2-phenylpropionate ((S)-64a) in a one-phase system . . . . . . 131
7.2.1.4.1 Screening of different organocatalysts in a one-phase system . 131
7.2.1.4.2 Effect of the solvent in a one-phase system . . . . . . . . . . 132
7.2.1.4.3 Effect of the base on the reaction rate in a one-phase system . 133
7.2.1.4.4 Effect of the temperature in a one-phase system . . . . . . . 134
7.2.1.5 Standard Operation Procedure 5 (SOP5): Racemization of ethyl
(S)-2-phenylpropionate ((S)-64a) in a two-phase system . . . . . . 135
7.2.1.5.1 Racemization at room temperature in a two phase-system wa-
ter/organic solvent (1:1, (v/v)) . . . . . . . . . . . . . . . . 136
7.2.1.5.2 Racemization at room temperature in a two phase-system wa-
ter/organic solvent (1:19, (v/v)) . . . . . . . . . . . . . . . . 136
7.2.1.5.3 Effect of the temperature on the racemization in a two-phase
system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7.2.1.6 Standard Operation Procedure 6 (SOP6): Racemization of ethyl
(S)-2-(4-isobutylphenyl)propionate ((S)-65) in a one-phase system . 138
7.2.1.6.1 Screening of different organocatalysts . . . . . . . . . . . . . 139
7.2.1.6.2 Effect of catalyst concentration . . . . . . . . . . . . . . . . 139
7.2.1.7 Standard Operation Procedure 7 (SOP7): Racemization of ethyl
(S)-2-(4-isobutylphenyl)propionate ((S)-65) in a two-phase system . 140
7.2.1.7.1 Racemization at 25°C in a two phase-system water/organic
solvent (1:4, (v/v)) . . . . . . . . . . . . . . . . . . . . . . . 141
7.2.1.7.2 Racemization at 25°C in a two phase-system water/organic
solvent (1:19, (v/v)) . . . . . . . . . . . . . . . . . . . . . . 141
7.2.1.8 Combinationofthehydrolysisandtheracemizationreactionof rac-64b142
7.2.1.8.1 Enzymatic of rac-64b . . . . . . . . . . . . . . . . 142
7.2.1.8.2 Catalyzed racemization of (S)-64b . . . . . . . . . . . . . . 143
7.2.1.8.3 Enzymatic hydrolysis and racemization of rac-64b coupled in
a two-reaction systems . . . . . . . . . . . . . . . . . . . . . 144
7.2.2 Biocatalytic synthesis of (S)-monastrol . . . . . . . . . . . . . . . . . . 145
7.2.2.1 Standard Operation Procedure 8 (SOP8): Synthesis of 3,4-dihydro-
pyrimidin-2(1H)-ones (DHPMs) . . . . . . . . . . . . . . . . . . . 145
7.2.2.1.1 Synthesisofracemic6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-
4H-pyrimidin-5-carboxylic acid ethyl ester (dehydroxymonas-
trol, 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
viiiContents
7.2.2.1.2 Synthesis of racemic 4-(3-hydroxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl
ester (monastrol, 7) . . . . . . . . . . . . . . . . . . . . . . 146
7.2.2.1.3 Synthesis of racemic 4-(4-hydroxyphenyl)-6-methyl-2-
thioH-pyrimidin-5-carboxylic acid ethyl
ester (117) . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
7.2.2.2 Standard Operation Procedure 9 (SOP9): Synthesis of racemic
O-acylated monastrol derivatives rac-8 . . . . . . . . . . . . . . . 147
7.2.2.2.1 Synthesis of racemic 4-(3-acetoxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl
ester (rac-8a) . . . . . . . . . . . . . . . . . . . . . . . . . 148
7.2.2.2.2 Synthesis of racemic 4-(3-(propionyloxy)phenyl)-6-methyl-2-
thioH-pyrimidin-5-carboxylic acid ethyl
ester (rac-8b) . . . . . . . . . . . . . . . . . . . . . . . . . 149
7.2.2.2.3 Synthesis of racemic 4-(3-(isobutyrylo
thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl
ester (rac-8c) . . . . . . . . . . . . . . . . . . . . . . . . . 150
7.2.2.2.4 Synthesis of racemic 4-(3-(butyryloxy)phenyl)-6-methyl-2-
thioH-pyrimidin-5-carboxylic acid ethyl
ester (rac-8d) . . . . . . . . . . . . . . . . . . . . . . . . . 151
7.2.2.2.5 Synthesis of racemic 4-(3-(hexanoylo
thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl
ester (rac-8e) . . . . . . . . . . . . . . . . . . . . . . . . . 152
7.2.2.3 Screening of lipases for the hydrolysis of 6-methyl-4-phenyl-2-thioxo-
1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl ester (dehy-
droxymonastrol, rac-6) . . . . . . . . . . . . . . . . . . . . . . . . 153
7.2.2.4 Standard Operation Procedure 10 (SOP10): Screening of lipases for
the hydrolysis of rac-monastrol (rac-7) . . . . . . . . . . . . . . . 154
7.2.2.4.1 Screeningofdifferentlipasesforthehydrolysisofrac-monastrol
(rac-7)inatwo-phasesystemwateranddichloromethane(4:1,
(v/v)) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
7.2.2.4.2 Screeningofdifferentlipasesforthehydrolysisofrac-monastrol
(rac-7) in a two-phase system water and hexane (4:1, (v/v)) . 155
7.2.2.4.3 Screeningofdifferentlipasesforthehydrolysisofrac-monastrol
(rac-7) in water and DMSO (4:1, (v/v)) . . . . . . . . . . . 156
7.2.2.5 Standard Operation Procedure 11 (SOP11): Enzymatic hydrolysis of
O-acylated monastrol derivatives rac-8 . . . . . . . . . . . . . . . 157
ix7.2.2.5.1 Enzymatic hydrolysis of 4-(3-acetoxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylic acid ethyl
ester (rac-8a) . . . . . . . . . . . . . . . . . . . . . . . . . 158
7.2.2.5.2 Enzymatic hydrolysis of 4-(3-(propionyloxy)phenyl)-6-methyl-
2-thioxo-1,2,3,4-tetrahydro-4H-pyrimidin-5-carboxylicacidethyl
ester (rac-8b) . . . . . . . . . . . . . . . . . . . . . . . . . 159
7.2.2.5.3 Influence of the acyl group on the hydrolysis of O-acylated
monastrol derivatives rac-8 . . . . . . . . . . . . . . . . . . 160
7.2.2.6 Standard Operation Procedure 12 (SOP12): Biocatalytic synthesis
of (S)-monastrol ((S)-7) . . . . . . . . . . . . . . . . . . . . . . . 161
7.2.2.6.1 First step: Biocatalytic resolution of rac-8d . . . . . . . . . . 161
7.2.2.6.2 Second step: Hydrolysis of the remaining substrate (S)-8d . . 162
Bibliography 165

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