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

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

Microwave-assisted kinetic resolution

• f homochiral diols using lipase

Aim of the project

To determine Microwave influence on the enzymatic properties : Activity Selectivity Stability Reusability 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 Exploit the irradiation effects on the enzyme activation for the synthesis of interesting compounds

Stereoselective synthesis of methyl jasmonates

H H LGO OH OMs OGP H H LGO OH OMs OGP OH OH OH OH O COOMe O COOMe

Ent-epi- methyl jasmonate

(R) (S) (S) (R)

Epi- methyl jasmonate (1R,2R) (1S,2S) COD (1R,2R) (1S,2S)

Efficient resolution of homochiral diols Used as precursor of methyl jasmonates

Use of enzymes :

• Chimioselectivity
• Enantioselectivity
• Reusability
• Efficient catalyst for green chemistry
• The activity/selectivity depend on the reaction conditions

Enzymes and green chemistry

OH OH OH OH OAc OH OH OH

O

(1R,2R) (1S,2S)

Resolution by acetylation + + vinylacetate Lipase * * * * + OAc OAc OAc OH OAc OAc OAc OAc Lipase Buffer phosphate + + AcOH

+

* * * * Resolution by hydrolysis

(1R,2R) (1S,2S) 5

Resolution of rac-diol and rac-diacetate

Synthesis of rac-diacetate and rac-diols

O DCM 95% CH3CO3H OH OH OH OH H2SO4 , 2M aq. t.a., 65%

+

(1R,2R) (1S,2S)

OAc OAc OAc OAc Ac2O 94%

+

(1R,2R) (1S,2S)

7

OH OH OH OH OAc OH OH OH

O O

O + 35°C classical heating Lipase Solvant (2.5mL) + +

(1R,2R) (1S,2S)

* * * *

Lipase c (%) Diol ee (%) Monoacetate 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 (acrylique) 16 9 55 (R,R) Pseudomonas cepacia immobilisée (diatomée) 26 12 57 (S,S)

8

Lipase-catalyzed desymmetrization of rac-diol

Temperature (°C) Time (day)

Yield

(%) ee (%)

Yield

(%) ee (%) 35 22 28 42 6 >99,9 50 7 30 50 20 >99,9

OH OH OH OH OAc OH OAc OAc

O O

O

+ LBCA THF (2.5mL) + +

(1R,2R) (1S,2S) (1R,2R) (1S,2S)

OAc OH

(1R,2R)

OAc OAc

(1S,2S)

Classical heating versus Microwave irradiation

Yield

(%) ee (%)

Yield

(%) ee (%) 58 55 37 >99,9

OAc OH

(1R,2R)

OAc OAc

(1S,2S)

MW open vessel (10W), 14h

Optimisation of reaction

9

Temperature (°C) Temps (h)

Yield

(%) ee (%)

Yield

(%) ee (%) 50 (10W) 14 58 55 37 99 80 (45W) 7 55 57 30 94 100 (syst. fermé, 40W) 35 (300W) 7 7

• 42
• 67
• 2
• 99

OH OH OH OH OAc OH OAc OAc

O O

O

+ LBCA THF (2.5mL) m.o. + +

(1R,2R) (1S,2S) (1R,2R) (1S,2S)

OAc OH

(1R,2R)

OAc OAc

(1S,2S)

Thermal denaturation of enzyme

Influence of temperature

Diol 51% ee: 50%

Lipase-catalyzed desymmetrization of rac-diol

10

Use of free PS

Temperature (°C) Time (j)

Yield

(%) ee (%)

Yield ee

(%) (%) 35°C 21 55 45 0 55°C 7 47 51 0

OH OH OH OH OAc OH OH OH

O O

O

+ PS-L THF (2.5mL) + +

(1R,2R) (1S,2S) (1S,2S) (1R,2R)

OAc OH

(1S,2S)

OH OH

(1R,2R)

Good conversion No selectivity at all !

11

Temperature (°C) Time (h)

Yield

(%) ee (%)

Yield

ee (%) (%) 50 (15W) 14 41 57 58 35 80 (35W) 7 12 35 66 5 100 (closed vessel) 7

• OH

OH OH OH OAc OH OH OH

O O

O

+ PS-D THF (2.5mL) M.W. + +

(1R,2R) (1S,2S) (1S,2S) (1R,2R)

OAc OH

(1S,2S)

OH OH

(1R,2R)

Modulation of selectivity High and fast thermal denaturation

Use of immobilized PS

12

Resolution by hydrolysis under MW irradiation

OAc OAc OAc OH OAc OAc OAc OAc PS-L ou D Buffer phosphate 0.1M pH 7.0

(1R,2R) (1S,2S)

+ + AcOH

+

(1R,2R) (1S,2S)

[α α α α]D = - 5.1°

(c=1.0 CHCl3)

[α α α α]D = - 21°

(c=1.0 CHCl3)

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 = - 52°

(c=1.0 CHCl3)

1rst Enantio-enrichment: 35% ee: 70%

13

OAc OAc OAc OH OAc OAc OAc OAc CALB Buffer phosphate 0.1M pH 7.0

(1R,2R) (1S,2S)

+ + AcOH

(1R,2R) (1S,2S)

20 % ee : 97% [α α α α]D = + 5,6°

(c=1.0 CHCl3)

80% ee : 34% [α α α α]D = +26°

(c=1.0 CHCl3)

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)

+

Control of the reaction selectivity by the choose of enzyme Enantio-enrichment 50°C (15W): 47% ee: 99%

Resolution by hydrolysis under MW irradiation

14

Enantiopure homochiral diols

OAc OAc OH OH OAc OH OH OH 8h 99% K2CO3, MeOH, 0°C

(1S,2S) (1S,2S)

8h 99% K2CO3, MeOH, 0°C

(1R,2R) (1R,2R)

[α]D = -21° (c = 1.0 CHCl3) [α]D = +20.8° (c = 1.0 CHCl3)

15

Conclusion

Optimisation d’une résolution enzymatique. Par choix judicieux des conditions :

OH OH OH OH OAc OH OAc OAc

O

OH OH

(1R,2R) (1S,2S)

+ + Vinylacetate CALB 14h MW + methanolyse

(1R,2R) (1S,2S)

Diol (1S,2S) Yield. 37 % under MW Diol (1R,2R) Yield 20% under MW.

OAc OAc OAc OH OAc OAc OAc OAc OH OH PS-D 14h MW Buffer phosphate + + AcOH

+

Resolution by hydrolysis

(1R,2R) (1S,2S) (1R,2R) (1S,2S)

Saponification

16

Thank you

ECSOC-17