Departamento de Química Orgánica e Inorgánica Instituto Universitario de Biotecnología de Asturias Universidad de Oviedo Biocatalytic Preparation of Optically Active 4-( N , N - Dimethylamino)pyridine Analogues Using Lipases and Oxidoreductases Dr. Vicente Gotor Fernández Graz, 18th April 2006
Bioorganic Research Group University of Oviedo ♦ Enzymatic aminolysis and ammonolysis ♦ Natural Products ♦ Applied biocatalysis ♦ Microorganisms
Bioorganic Research Group University of Oviedo ♦ Enzymatic aminolysis and ammonolysis ♦ Natural Products ♦ Applied biocatalysis ♦ Microorganisms ♦ Synthesis of nucleophilic catalysts ♦ Preparation of pharmaceuticals ♦ Development of non-conventional processes
Bioorganic Research Group University of Oviedo ♦ Enzymatic aminolysis and ammonolysis ♦ Natural Products ♦ Applied biocatalysis ♦ Microorganisms ♦ Synthesis of nucleophilic catalysts (Chiral DMAP derivatives) NMe 2 ♦ Preparation of pharmaceuticals N ♦ Development of non-conventional processes
Biocatalytic Preparation of Optically Active 4-( N , N -Dimethylamino)pyridine Analogues Using Lipases and Oxidoreductases ♦ Introduction: NMe 2 • Importance of DMAP • Chiral DMAP derivatives N ♦ Objectives ♦ Results and Discussion: • Synthesis of 2- and 3-substituted DMAP derivatives using lipases • Synthesis of 2- and 3-substituted DMAP derivatives using oxidoreductases • Applicactions in asymmetric catalysis ♦ Conclusions and future aims
Introduction Chemical reactions: catalyst of different processes like NMe 2 acylation, Baylis-Hillman, carbonylation... Uses in industrial sector: pharmaceuticals, agrochemicals... N Application areas: alcohols, amino acids, stereoids... Some representative examples in “difficult” processes: OH OAc Ac 2 O, NEt 3 DMAP, CH 2 Cl 2 OH TBDMSCl, CH 2 Cl 2 OH OTBDMS + OH OTBDMS OTBDMS DMAP Ph Ph Ph O O O O ROH, DMAP + MeOH OMe OR Cyclohexane
Introduction NMe 2 Application in catalytic processes N NMe 2 Introduction of some type of chirality N Chiral DMAP derivatives for the development of asymmetric catalytic processes NMe 2 BIOCATALYSIS Me 2 N OH Transesterifications: lipases * R Bioreductions: oxidoreductases * N N OH
Objectives ♦ Preparation of enantiomerically pure DMAP derivatives: - Chemical synthesis and kinetic resolution of 2- and 3-substituted DMAP analogues using lipases Cl Acyl donor Cl Cl Lipase OH OAc OH + Solvent T, 250 rpm N N N - Chemoenzymatic synthesis of 2- and 3-substituted DMAP analogues using oxidoreductases Cl Cl O OH Oxidoreductase Solvent * T, 250 rpm N N ♦ Modification of DMAP derivatives and application in asymmetric catalysis Cl Me 2 N Alkoxycarbonylation reactions OH OR Rearrangements processes * * Use as chiral ligands N N
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases Chemical synthesis of racemic DMAP derivatives Cl Cl NMe 2 R R N N N + O _ OH OH R=Me, Et, Pr, Bu, Ph Kinetic resolution of racemic 2-(1-hydroxyalkyl)-4-(substituted)pyridines X Acyl donor X X Lipase + Solvent R R R T, 250 rpm N N N OH OAc OH R=Me, Et, Pr, Bu, Ph
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases Chemical synthesis of racemic 2-(1-hydroxyalkyl)-4-(substituted)pyridines 1) RMgX, Et 2 O Cl Cl NMe 2 Me 3 SiCN NH 4 Cl, HCl Cl Me 2 NH Me 2 NOCl 0 ºC to rt R R 2) NaBH 4 , MeOH 100 ºC CH 2 Cl 2 , rt N N N + quantitative N CN 0 ºC to rt (77%) O OH OH _ R=Me, Et, Pr, Bu, Ph 1 2 3a-e 4a-e Table 1. Transformation of 4-chloro- 2-cyanopyridine in alcohols 3a - e Reaction product R X Isolated Yield (%) 3a Me I 73 3b Et Br 76 3c Pr Br 76 3d Bu Cl 74 3e Ph Br 73 Next: enzymatic kinetic resolution, optimisation with compound 3a and 4a (R=Me)
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases X X X O Enzyme + + O Me Me Me THF N N N 30 ºC, 250 rpm OAc OH OH 5 (+)-6a, X=Cl (-)-3a, X=Cl (±)-3a, X=Cl (±)-4a, X=NMe 2 (+)-7a, X=NMe 2 (-)-4a, X=NMe 2 Table 2. Enzymatic acylation of 3a using 3 equivalents of 5 like acyl donor and THF as solvent ee S (%) a ee P (%) a c (%) b E c Entry Enzyme X t (h) 1 CAL-A Cl 38 -- -- -- -- 2 CAL-B (Novozyme) Cl 48 82 >99 42 >200 3 CAL-B (Chirazyme) Cl 70 70 >99 41 >200 4 PSL-C Cl 14.5 >99 (88) d >99 (85) d 50 >200 5 PSL-C NMe 2 38 52 >99 34 >200 a Calculated by HPLC, b c = ee s / (ee s + ee p ), c E = ln [(1 - c) × (1 - ee p )]/ ln [(1 - c) × (1 + ee p )], d Isolated yields in brackets
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases X X X O Enzyme + + O Me Me Me THF N N N 30 ºC, 250 rpm OAc OH OH 5 (+)-6a, X=Cl (-)-3a, X=Cl (±)-3a, X=Cl (±)-4a, X=NMe 2 (+)-7a, X=NMe 2 (-)-4a, X=NMe 2 Table 2. Enzymatic acylation of 3a using 3 equivalents of 5 like acyl donor and THF as solvent ee S (%) a ee P (%) a c (%) b E c Entry Enzyme X t (h) 1 CAL-A Cl 38 -- -- -- -- 2 CAL-B (Novozyme) Cl 48 82 >99 42 >200 3 CAL-B (Chirazyme) Cl 70 70 >99 41 >200 4 PSL-C Cl 14.5 >99 (88) d >99 (85) d 50 >200 5 PSL-C NMe 2 38 52 >99 34 >200 a Calculated by HPLC, b c = ee s / (ee s + ee p ), c E = ln [(1 - c) × (1 - ee p )]/ ln [(1 - c) × (1 + ee p )], d Isolated yields in brackets
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases Enzymatic resolution of racemic 4-chloro-2-(1-hydroxyalkyl)pyridine derivatives Cl Cl Cl O PSL-C + + O R R R THF N N N 30 ºC, 250 rpm OAc OH 5 OH (+)-6a-e (-)-3a-e (±)-3a-e Table 3. Enzymatic acylation of 3a - e using 3 equivalents of 5 like acyl donor, THF as solvent and PSL-C as biocatalyst ee S (%) a ee P (%) a c (%) b E c Entry R t (h) 1 Me 14.5 >99 (88) d >99 (85) d 50 >200 2 Et 14.5 >99 (88) d >99 (77) d 50 >200 3 Pr 14.5 88 >99 47 >200 4 Pr 38 >99 (89) d 99 (97) d 50 >200 5 Bu 14.5 49 >99 33 >200 6 Bu 60 >99 (89) d >99 (88) d 50 >200 7 Ph 96 -- -- -- -- a Calculated by HPLC, b c = ee s / (ee s + ee p ), c E = ln [(1 - c) × (1 - ee p )]/ ln [(1 - c) × (1 + ee p )], d Isolated yields in brackets
Results and Discussion Chemical synthesis and kinetic resolution of 2-substituted DMAP analogues using lipases Enzymatic resolution of racemic 4-chloro-2-(1-hydroxyalkyl)pyridine derivatives Cl Cl Cl O PSL-C + + O R R R THF N N N 30 ºC, 250 rpm OAc OH 5 OH (+)-6a-e (-)-3a-e (±)-3a-e Table 3. Enzymatic acylation of 3a - e using 3 equivalents of 5 like acyl donor, THF as solvent and PSL-C as biocatalyst ee S (%) a ee P (%) a c (%) b E c Entry R t (h) 1 Me 14.5 >99 (88) d >99 (85) d 50 >200 2 Et 14.5 >99 (88) d >99 (77) d 50 >200 3 Pr 14.5 88 >99 47 >200 4 Pr 38 >99 (89) d 99 (97) d 50 >200 5 Bu 14.5 49 >99 33 >200 6 Bu 60 >99 (89) d >99 (88) d 50 >200 7 Ph 96 -- -- -- -- a Calculated by HPLC, b c = ee s / (ee s + ee p ), c E = ln [(1 - c) × (1 - ee p )]/ ln [(1 - c) × (1 + ee p )], d Isolated yields in brackets
Results and Discussion Chemical synthesis and kinetic resolution of 3-substituted DMAP analogues using lipases Chemical synthesis of racemic DMAP derivatives Cl Cl OH Me 2 N OH R R + _ N N N Cl N Kinetic resolution of racemic 3-(1-hydroxyalkyl)-4-(substituted)pyridines Cl OH Acyl donor Cl OAc Cl OH Lipase R R + R Solvent T, 250 rpm N N N R=Me, Et, Pr, Bu, Ph
Results and Discussion Chemical synthesis and kinetic resolution of 3-substituted DMAP analogues using lipases Chemical synthesis of 4-chloro-3-(1-hydroxyalkyl)pyridine derivatives Cl Cl Cl OH 1) LDA, Et 2 O NaOH R + 2) R-CHO _ N N N Cl N 7 (±)-9a-e 8 Table 4. Synthesis of 4-chloro-3-(1-hydroxyalkyl)pyridines and 4-chloro-3-(1-hydroxybenzyl)pyridine Entry R LDA (eq) Isolated Yield (%) 1 Me 2 68 2 Et 2 61 3 Pr 2 63 4 Bu 2 65 5 Ph 1 82
Results and Discussion Chemical synthesis and kinetic resolution of 3-substituted DMAP analogues using lipases Cl OAc Cl OH Cl OH O Enzyme + + O Solvent N N N T, 250 rpm (5, VA) (+)-10a (±)-9a ( - )-9a Table 5. Enzymatic kinetic resolution of 4-chloro-3-(1-hydroxyethyl)pyridine through transesterification Entry Solvent 5 (eq) T (ºC) Enzyme t (h) ee S (%) a ee P (%) a c (%) b E c 1 THF 3 30 PSL-C 62 20 >99 17 >200 2 THF 3 30 CAL-B 38 45 >99 31 >200 3 THF 3 45 PSL-C 62 31 >99 23 >200 4 THF 3 45 CAL-B 38 58 >99 37 >200 5 THF 10 60 PSL-C 62 40 >99 29 >200 6 THF 10 60 CAL-B 91 96 >99 49 >200 7 VA - 60 CAL-B 14 >99 >99 50 >200 a Calculated by HPLC, b c = ee s / (ee s + ee p ), c E = ln [(1 - c) × (1 - ee p )]/ ln [(1 - c) × (1 + ee p )]
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