Microwave-assisted kinetic resolution of homochiral diols using - PowerPoint PPT Presentation

Microwave-assisted kinetic resolution of homochiral diols using lipase Hervé Rouillard, Emmanuel Deau, Lisianne Domon, Jean-René Chérouvrier, Marianne Graber, Valérie Thiéry Université de La Rochelle UMR CNRS 7266 Littoral, Environnement et Sociétés (LIENSs) 1

Aim of the project Better understanding of the influence of the microwave interaction with enzyme in various conditions : Aqueous or Non-aqueous medium Solvent free system High or Low Temperatures Under Pressure or Not To determine Microwave influence on the enzymatic properties : Activity Selectivity Stability Reusability Exploit the irradiation effects on the enzyme activation for the synthesis of interesting compounds

Stereoselective synthesis of methyl jasmonates O LGO H ( R ) OH OMs COOMe OH ( S ) OGP H Ent-epi- OH (1R,2R) (1R,2R) methyl jasmonate O COD LGO H ( S ) OH OGP COOMe OH ( R ) OMs H Epi - OH (1S,2S) (1S,2S) methyl jasmonate Efficient resolution of homochiral diols Used as precursor of methyl jasmonates

Enzymes and green chemistry Use of enzymes : •Chimioselectivity •Enantioselectivity •Reusability •Efficient catalyst for green chemistry •The activity/selectivity depend on the reaction conditions

Resolution of rac-diol and rac-diacetate OH OAc OH OH O vinylacetate * * + + + * Lipase * OH OH OH OH (1S,2S) (1R,2R) Resolution by acetylation Buffer phosphate OAc OAc OAc OAc + * * + + AcOH Lipase * * OAc OAc OH OAc (1R,2R) (1S,2S) Resolution by hydrolysis 5

Synthesis of rac-diacetate and rac-diols CH 3 CO 3 H O DCM 95% H 2 SO 4 , 2M aq. t.a., 65% OH OH + OH OH (1R,2R) (1S,2S) Ac 2 O 94% OAc OAc + OAc OAc (1R,2R) (1S,2S)

O OH OH OH OAc O O * + * + + * * 35°C OH OH OH OH classical heating Lipase (1R,2R) (1S,2S) Solvant (2.5mL) Diol Monoacetate Lipase c (%) ee (%) ee (%) Aspergillus carneus 3 2 50 (S,S) Rhizopus niveus 4 5 38 (S,S) Rhizopus arrhizus - - - Muccor miehei - - - Candida cylindracea - - - Candida antarctica 8 4 50 (R,R) Pseudomonas cepacia 17 12 60 (S,S) Candida antarctica immobilisée 16 9 55 (R,R) (acrylique) Pseudomonas cepacia immobilisée 26 12 57 (S,S) (diatomée) 7

Lipase-catalyzed desymmetrization of rac-diol O OH OH OAc OAc O O + + + OH OH OH OAc LBCA THF (2.5mL) (1R,2R) (1S,2S) (1R,2R) (1S,2S) Classical heating versus Microwave irradiation MW open vessel (10W), 14h OAc OAc OAc OAc OH OAc (1R,2R) (1S,2S) OH OAc (1R,2R) (1S,2S) Temperature Time ee ee Yield Yield ee ee Yield Yield (%) (%) ( ° C) (day) (%) (%) (%) (%) (%) (%) 35 22 28 42 6 >99,9 58 55 37 >99,9 50 7 30 50 20 >99,9 Optimisation of reaction 8

Lipase-catalyzed desymmetrization of rac-diol O OH OH OAc OAc O O + + + LBCA OH OH OH OAc THF (2.5mL) (1R,2R) (1S,2S) (1R,2R) (1S,2S) m.o. OAc OAc Influence of temperature OH OAc (1R,2R) (1S,2S) Thermal denaturation of Temperature Temps ee ee Yield Yield enzyme (%) (%) ( ° C) (h) (%) (%) 50 (10W) 14 58 55 37 99 80 (45W) 7 55 57 30 94 100 (syst. fermé, 40W) 7 - - - - 35 (300W) 7 42 67 2 99 Diol 51% ee: 50% 9

Use of free PS O OH OH OAc OH O O + + + PS-L OH OH OH OH THF (2.5mL) (1R,2R) (1S,2S) (1S,2S) (1R,2R) OAc OH OH OH (1S,2S) (1R,2R) Temperature Time ee Yield ee Yield Good conversion (%) ( ° C) (j) (%) (%) (%) No selectivity at all ! 35 ° C 21 55 0 45 0 55 ° C 7 47 0 51 0 10

Use of immobilized PS O OH OH OAc OH O O + + + PS-D OH OH OH OH THF (2.5mL) (1R,2R) (1S,2S) (1S,2S) (1R,2R) M.W. OAc OH OH OH (1S,2S) (1R,2R) Modulation of selectivity Temperature Time ee ee Yield Yield High and fast thermal (%) ( ° C) (h) (%) (%) (%) denaturation 50 (15W) 14 41 57 58 35 80 (35W) 7 12 35 66 5 100 (closed vessel) 7 - - - 11

Resolution by hydrolysis under MW irradiation Buffer phosphate 0.1M OAc OAc OAc OAc pH 7.0 + AcOH + + OH OAc OAc OAc PS-L ou D (1R,2R) (1S,2S) (1R,2R) (1S,2S) PS-L 35°C 15j 34% ee : 99% ee 99% PS-L 35°C (MW) 14h - PS-D 35°C (MW) 14h - - PS-D 50°C (15W) 14h 10% ee 81% 90% ee: 28% [ α α α α ] D = - 5.1° [ α α α α ] D = - 21° (c=1.0 CHCl 3 ) (c=1.0 CHCl 3 ) 1rst Enantio-enrichment: 35% ee: 70% [ α α α α ] D = - 52° (c=1.0 CHCl 3 ) 12

Resolution by hydrolysis under MW irradiation Buffer phosphate 0.1M OAc OAc OAc OAc pH 7.0 + + + AcOH OH OAc OAc OAc CALB (1R,2R) (1S,2S) (1S,2S) (1R,2R) 35° 4j 17% ee : 67% diol: 3% 35° 14h - 50° (15W) 14h 20% ee : 97% 80% ee 34% 80° 7-14h - Open vessel (25W) closed vessel (35W) 80% 20 % ee : 34% ee : 97% [ α α ] D = +26° α α [ α α ] D = + 5,6° α α (c=1.0 CHCl 3 ) (c=1.0 CHCl 3 ) Enantio-enrichment 50°C (15W): 47% ee: 99% Control of the reaction selectivity by the choose of enzyme 13

Enantiopure homochiral diols OAc OH K 2 CO 3 , MeOH, 0°C 8h OH OH 99% (1R,2R) (1R,2R) [ α ] D = -21° (c = 1.0 CHCl 3 ) OAc OH K 2 CO 3 , MeOH, 0°C 8h OAc OH 99% (1S,2S) (1S,2S) [ α ] D = +20.8° (c = 1.0 CHCl 3 ) 14

Conclusion Optimisation d’une résolution enzymatique. Par choix judicieux des conditions : OH OAc OAc OH O Vinylacetate + + + CALB OH OH OH OAc 14h (1R,2R) (1S,2S) MW (1R,2R) (1S,2S) OH methanolyse OH Diol (1S,2S) Yield. 37 % under MW Buffer phosphate OAc OAc OAc OAc + + PS-D + AcOH OAc OAc 14h OH OAc MW (1R,2R) (1S,2S) (1R,2R) (1S,2S) OH Resolution by hydrolysis Saponification OH Diol (1R,2R) Yield 20% under MW. 15

Thank you ECSOC-17 16