Appl Biochem Biotechnol DOI 10.1007/s12010-014-0860-z
Biocatalytic Synthesis of Optically Active Hydroxyesters via Lipase-Catalyzed Decarboxylative Aldol Reaction and Kinetic Resolution Wei-Wei Zhang & Na Wang & Xing-Wen Feng & Yang Zhang & Xiao-Qi Yu
Received: 25 December 2013 / Accepted: 10 March 2014 # Springer Science+Business Media New York 2014
Abstract A two-step sequential biocatalytic process for the synthesis of chiral hydroxyesters that combines a lipase-catalyzed decarboxylative aldol reaction followed by kinetic resolution has been developed. The excellent combination of conventional and unconventional functions provides an attractive route for expanding the applications of biocatalysis. Keywords Biocatalysis . Lipase . Promiscuity . Decarboxylative aldol reaction . Kinetic resolution
Introduction Studies on the synthesis of optically active compounds have recently been conducted because of the increased demands for these compounds in fine chemicals. Although the large number of chemical synthesis methods have been constructed [1–3], biocatalysis as a green and efficient tool for organic synthesis has been increasingly recognized because of its high activity, excellent selectivity, and mild reaction conditions [4, 5]. Enzyme catalytic promiscuity has recently been well explored because it exhibits significant advantages and potential [6, 7], which can enrich the applicability of enzymes in organic synthesis. In particular, hydrolases [8] are widely used as green and efficient catalysts in organic synthesis because of their high stability, wide variety of sources, and broad range of substrates. Although hydrolases have mainly demonstrated a great versatility in conventional reactions, such as hydrolysis [9], transesterification [10], and aminolysis [11], several unconventional hydrolase-catalyzed reactions, including addition reactions [12], oxidation reactions [13], and racemization reactions [14] have also been described in the past decade.
Electronic supplementary material The online version of this article (doi:10.1007/s12010-014-0860-z) contains supplementary material, which is available to authorized users.
W.200 102 >200
a
Reaction conditions; 3aa 5 mg, the total volume of vinyl acetate and solvent was 1 mL, lipase 10 mg, and 30 °C. Conv=ee3aa/(ee3aa +ee4aa). The configuration of the product was assigned by the comparison with data in Reference [25]. c Determined by chiral HPLC analysis. d E=ln [1−c (1+ee4aa)]/ln [1−c (1−ee4aa)]. e 10 mg of CAL-B added b
The established optimized conditions for KR were applied on the resolution of the decarboxylative aldol adducts. Excellent enantioselectivities of over 90 % ee in most cases were obtained. The yields of some substrates were poor because of steric hindrance effects Table 3 Kinetic resolution of decarboxylative aldol adducts a
a b
Entry
3
4
Yieldb (%)
eeb (%)
1 2 3 4 5 6 7 8 9 10
3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ba 3ca
4aa 4ab 4ac 4ad 4ae 4af 4ag 4ah 4ca
46 32 25 12 8 13 10 20 30
98 97 93 90 91 93 95 95 84
Reaction conditions; 3 (5 mg), vinyl acetate 0.2 mL, toluene 0.8 mL, CRL 10 mg, 37 °C, and 48 h. Determined by chiral HPLC analysis
Appl Biochem Biotechnol
Scheme 4 Hydrolysis of an optically active hydroxyester
(Table 3, entries 5 and 7). No product was detected for 3ba because of strong ortho effects (Table 3, entry 9). To obtain a chiral hydroxy compound, we hydrolyzed an optically active hydroxyester in phosphate buffer solution (PBS) with acetonitrile to solubilize it. 3aa was obtained in the presence of CRL with high yield, and its enantioselectivity was maintained (Scheme 4).
Conclusion A facile biocatalytic process for the synthesis of chiral hydroxyesters has been developed. The process combined a lipase-catalyzed decarboxylative aldol reaction with KR. In most cases, a series of optically active hydroxyesters was obtained with over 90 % ee. The chiral hydroxyesters could be further transformed into other valuable building blocks to construct complex functional molecules and contribute to the future chiral molecular research. The method shown, herein, presents an excellent combination of natural and synthetic functions and may provide an attractive route for expanding the applications of biocatalysis. Based on the positive initial results of the combination of two functions of biocatalysts, we are currently working on the development of biocatalytic applications for other reactions, such as one-pot multistep reactions. Acknowledgments This work was financially supported by the National Program on Key Basic Research Project of China (973 Program, 2013CB328900) and the National Natural Science Foundation of China (Nos. 21321061, J1310008, and J1103315). We also thank the Sichuan University Analytical and Testing Center for the NMR analysis.
References 1. Kumar, P., & Dwivedi, N. (2013). Proline catalyzed α-Aminoxylation reaction in the synthesis of biologically active compounds. Acc Chem Res, 46, 289–299. 2. Krasnov, V. P., Gruzdev, D. A., & Levit, G. L. (2012). Nonenzymatic acylative kinetic resolution of racemic amines and related compounds. Eur J Org Chem, 2012, 1471–1493. 3. Wallace, D. J., & Reamer, R. A. (2013). New synthesis of a selective estrogen receptor modulator using an enatioselective phosphine-mediated 2+3 cycloaddition. Tetrahedron Lett, 54, 4425–4428. 4. Huisman, G. W., & Collier, S. J. (2013). On the development of new biocatalytic processes for practical pharmaceutical synthesis. Curr Opin Chem Biol, 17, 284–292. 5. Li, S.-x., Lin, K., Pang, H.-Y., Wu, Y.-X., & Xu, J.–. H. (2013). Production, characterization, and application of an organic solvent-tolerant lipase present in active inclusion bodies. Appl Biochem Biotechnol, 169, 612–623.
Appl Biochem Biotechnol 6. Gatti-Lafranconi, P., & Hollfelder, F. (2013). Flexibility and reactivity in promiscuous enzymes. ChemBioChem, 14, 285–292. 7. Chen, Y.-L., Li, W., Liu, Y., Guan, Z., & He, Y.–. H. (2013). Trypsin-catalyzed direct asymmetric aldol reaction. J Mol Catal B Enzym, 87, 83–87. 8. Zhou, L.-H., Wang, N., Zhang, W., Xie, Z.-B., & Yu, X.-Q. (2013). Catalytical promiscuity of α-amylase: Synthesis of 3-substituted 2H-chromene derivatives via biocatalytic domino oxa-Michael/aldol condensations. J Mol Catal B Enzym, 91, 37–43. 9. Muñoz Solano, D., Hoyos, P., Hernáiz, M. J., Alcántara, A. R., & Sánchez-Montero, J. M. (2012). Industrial biotransformations in the synthesis of building blocks leading to enantiopure drugs. Bioresour Technol, 115, 196–207. 10. Kantak, J. B., & Prabhune, A. A. (2012). Characterization of smallest active monomeric lipase from novel Rhizopus strain: Application in transesterification. Appl Biochem Biotechnol, 166, 1769–1780. 11. Stavila, E., Alberda van Ekenstein, G. O. R., & Loos, K. (2013). Enzyme-catalyzed synthesis of aliphaticaromatic aligoamides. Biomacromolecules, 14, 1600–1606. 12. Xie, Z.-B., Wang, N., Jiang, G.-F., & Yu, X.-Q. (2013). Biocatalytic asymmetric aldol reaction in buffer solution. Tetrahedron Lett, 54, 945–948. 13. Chávez, G., Hatti-Kaul, R., Sheldon, R. A., & Mamo, G. (2013). Baeyer-Villiger oxidation with peracid generated in situ by CaLB-CLEA catalyzed perhydrolysis. J Mol Catal B Enzym, 89, 67–72. 14. Vongvilai, P., Linder, M., Sakulsombat, M., Humble, M. S., Berglund, P., Brinck, T., & Ramstrom, O. (2011). Racemase activity of B. cepacia Lipase leads to dual-function asymmetric dynamic kinetic resolution of α-aminonitriles. Angew Chem Int Ed, 50, 6592–6595. 15. Kourouli, T., Kefalas, P., Ragoussis, N., & Ragoussis, V. (2002). A new protocol for a regioselective aldol condensation as an alternative convenient synthesis of β-Ketols and α, β-unsaturated ketones. J Org Chem, 67, 4615–4618. 16. Feng, X.-W., Li, C., Wang, N., Li, K., Zhang, W.-W., Wang, Z., & Yu, X.-Q. (2009). Lipase-catalysed decarboxylative aldol reaction and decarboxylative Knoevenagel reaction. Green Chem, 11, 1933–1936. 17. Magdziak, D., Lalic, G., Lee, H. M., Fortner, K. C., Aloise, A. D., & Shair, M. D. (2005). Catalytic enantioselective thioester aldol reactions that are compatible with protic functional groups. J Am Chem Soc, 127, 7284–7285. 18. Evitt, A. S., & Bornscheuer, U. T. (2011). Lipase CAL-B does not catalyze a promiscuous decarboxylative aldol addition or Knoevenagel reaction. Green Chem, 13, 1141–1142. 19. Kapoor, M., Majumder, A. B., Mukherjee, J., & Gupta, M. N. (2012). Decarboxylative aldol reaction catalysed by lipases and a protease in organic co-solvent mixtures and nearly anhydrous organic solvent media. Biocatal Biotransform, 30, 399–408. 20. Chen, X.-Y., Chen, G.-J., Wang, J.-L., Wu, Q., & Lin, X.-F. (2013). Lipase/acetamide-catalyzed carboncarbon bond formations: a mechanistic view. Adv Synth Catal, 355, 864–868. 21. Strohmeier, G. A., Sovic´, T., Steinkellner, G., Hartner, F. S., Andryushkova, A., Purkarthofer, T., Glieder, A., Gruber, K., & Griengl, H. (2009). Investigation of lipase-catalyzed michael-type carbon–carbon bond formations. Tetrahedron, 65, 5663–5668. 22. Nair, M. S., & Joly, S. (2000). Lipase catalyzed kinetic resolution of aryl β-hydroxy ketones. Tetrahedron Asymmetry, 11, 2049–2052. 23. Edin, M., Backvall, J. E., & Armando, C.´r. (2004). Tandem enantioselective organo- and biocatalysis: a direct entry for the synthesis of enantiomerically pure aldols. Tetrahedron Lett, 45, 7697–7701. 24. Xu, F., Wang, J.-X., Liu, B.-K., Wu, Q., & Lin, X.-F. (2011). Enzymatic synthesis of optical pure bnitroalcohols by combining D-aminoacylase-catalyzed nitroaldol reaction and immobilized lipase PScatalyzed kinetic resolution. Green Chem, 13, 2359–2361. 25. Joly, S., & Nair, M. S. (2003). Studies on the enzymatic kinetic resolution of β-hydroxy ketones. J Mol Catal B Enzym, 22, 151.
Biocatalytic Synthesis of Optically Active Hydroxyesters via Lipase-Catalyzed Decarboxylative Aldol Reaction and Kinetic Resolution Wei-Wei Zhang & Na Wang & Xing-Wen Feng & Yang Zhang & Xiao-Qi Yu
Received: 25 December 2013 / Accepted: 10 March 2014 # Springer Science+Business Media New York 2014
Abstract A two-step sequential biocatalytic process for the synthesis of chiral hydroxyesters that combines a lipase-catalyzed decarboxylative aldol reaction followed by kinetic resolution has been developed. The excellent combination of conventional and unconventional functions provides an attractive route for expanding the applications of biocatalysis. Keywords Biocatalysis . Lipase . Promiscuity . Decarboxylative aldol reaction . Kinetic resolution
Introduction Studies on the synthesis of optically active compounds have recently been conducted because of the increased demands for these compounds in fine chemicals. Although the large number of chemical synthesis methods have been constructed [1–3], biocatalysis as a green and efficient tool for organic synthesis has been increasingly recognized because of its high activity, excellent selectivity, and mild reaction conditions [4, 5]. Enzyme catalytic promiscuity has recently been well explored because it exhibits significant advantages and potential [6, 7], which can enrich the applicability of enzymes in organic synthesis. In particular, hydrolases [8] are widely used as green and efficient catalysts in organic synthesis because of their high stability, wide variety of sources, and broad range of substrates. Although hydrolases have mainly demonstrated a great versatility in conventional reactions, such as hydrolysis [9], transesterification [10], and aminolysis [11], several unconventional hydrolase-catalyzed reactions, including addition reactions [12], oxidation reactions [13], and racemization reactions [14] have also been described in the past decade.
Electronic supplementary material The online version of this article (doi:10.1007/s12010-014-0860-z) contains supplementary material, which is available to authorized users.
W.200 102 >200
a
Reaction conditions; 3aa 5 mg, the total volume of vinyl acetate and solvent was 1 mL, lipase 10 mg, and 30 °C. Conv=ee3aa/(ee3aa +ee4aa). The configuration of the product was assigned by the comparison with data in Reference [25]. c Determined by chiral HPLC analysis. d E=ln [1−c (1+ee4aa)]/ln [1−c (1−ee4aa)]. e 10 mg of CAL-B added b
The established optimized conditions for KR were applied on the resolution of the decarboxylative aldol adducts. Excellent enantioselectivities of over 90 % ee in most cases were obtained. The yields of some substrates were poor because of steric hindrance effects Table 3 Kinetic resolution of decarboxylative aldol adducts a
a b
Entry
3
4
Yieldb (%)
eeb (%)
1 2 3 4 5 6 7 8 9 10
3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ba 3ca
4aa 4ab 4ac 4ad 4ae 4af 4ag 4ah 4ca
46 32 25 12 8 13 10 20 30
98 97 93 90 91 93 95 95 84
Reaction conditions; 3 (5 mg), vinyl acetate 0.2 mL, toluene 0.8 mL, CRL 10 mg, 37 °C, and 48 h. Determined by chiral HPLC analysis
Appl Biochem Biotechnol
Scheme 4 Hydrolysis of an optically active hydroxyester
(Table 3, entries 5 and 7). No product was detected for 3ba because of strong ortho effects (Table 3, entry 9). To obtain a chiral hydroxy compound, we hydrolyzed an optically active hydroxyester in phosphate buffer solution (PBS) with acetonitrile to solubilize it. 3aa was obtained in the presence of CRL with high yield, and its enantioselectivity was maintained (Scheme 4).
Conclusion A facile biocatalytic process for the synthesis of chiral hydroxyesters has been developed. The process combined a lipase-catalyzed decarboxylative aldol reaction with KR. In most cases, a series of optically active hydroxyesters was obtained with over 90 % ee. The chiral hydroxyesters could be further transformed into other valuable building blocks to construct complex functional molecules and contribute to the future chiral molecular research. The method shown, herein, presents an excellent combination of natural and synthetic functions and may provide an attractive route for expanding the applications of biocatalysis. Based on the positive initial results of the combination of two functions of biocatalysts, we are currently working on the development of biocatalytic applications for other reactions, such as one-pot multistep reactions. Acknowledgments This work was financially supported by the National Program on Key Basic Research Project of China (973 Program, 2013CB328900) and the National Natural Science Foundation of China (Nos. 21321061, J1310008, and J1103315). We also thank the Sichuan University Analytical and Testing Center for the NMR analysis.
References 1. Kumar, P., & Dwivedi, N. (2013). Proline catalyzed α-Aminoxylation reaction in the synthesis of biologically active compounds. Acc Chem Res, 46, 289–299. 2. Krasnov, V. P., Gruzdev, D. A., & Levit, G. L. (2012). Nonenzymatic acylative kinetic resolution of racemic amines and related compounds. Eur J Org Chem, 2012, 1471–1493. 3. Wallace, D. J., & Reamer, R. A. (2013). New synthesis of a selective estrogen receptor modulator using an enatioselective phosphine-mediated 2+3 cycloaddition. Tetrahedron Lett, 54, 4425–4428. 4. Huisman, G. W., & Collier, S. J. (2013). On the development of new biocatalytic processes for practical pharmaceutical synthesis. Curr Opin Chem Biol, 17, 284–292. 5. Li, S.-x., Lin, K., Pang, H.-Y., Wu, Y.-X., & Xu, J.–. H. (2013). Production, characterization, and application of an organic solvent-tolerant lipase present in active inclusion bodies. Appl Biochem Biotechnol, 169, 612–623.
Appl Biochem Biotechnol 6. Gatti-Lafranconi, P., & Hollfelder, F. (2013). Flexibility and reactivity in promiscuous enzymes. ChemBioChem, 14, 285–292. 7. Chen, Y.-L., Li, W., Liu, Y., Guan, Z., & He, Y.–. H. (2013). Trypsin-catalyzed direct asymmetric aldol reaction. J Mol Catal B Enzym, 87, 83–87. 8. Zhou, L.-H., Wang, N., Zhang, W., Xie, Z.-B., & Yu, X.-Q. (2013). Catalytical promiscuity of α-amylase: Synthesis of 3-substituted 2H-chromene derivatives via biocatalytic domino oxa-Michael/aldol condensations. J Mol Catal B Enzym, 91, 37–43. 9. Muñoz Solano, D., Hoyos, P., Hernáiz, M. J., Alcántara, A. R., & Sánchez-Montero, J. M. (2012). Industrial biotransformations in the synthesis of building blocks leading to enantiopure drugs. Bioresour Technol, 115, 196–207. 10. Kantak, J. B., & Prabhune, A. A. (2012). Characterization of smallest active monomeric lipase from novel Rhizopus strain: Application in transesterification. Appl Biochem Biotechnol, 166, 1769–1780. 11. Stavila, E., Alberda van Ekenstein, G. O. R., & Loos, K. (2013). Enzyme-catalyzed synthesis of aliphaticaromatic aligoamides. Biomacromolecules, 14, 1600–1606. 12. Xie, Z.-B., Wang, N., Jiang, G.-F., & Yu, X.-Q. (2013). Biocatalytic asymmetric aldol reaction in buffer solution. Tetrahedron Lett, 54, 945–948. 13. Chávez, G., Hatti-Kaul, R., Sheldon, R. A., & Mamo, G. (2013). Baeyer-Villiger oxidation with peracid generated in situ by CaLB-CLEA catalyzed perhydrolysis. J Mol Catal B Enzym, 89, 67–72. 14. Vongvilai, P., Linder, M., Sakulsombat, M., Humble, M. S., Berglund, P., Brinck, T., & Ramstrom, O. (2011). Racemase activity of B. cepacia Lipase leads to dual-function asymmetric dynamic kinetic resolution of α-aminonitriles. Angew Chem Int Ed, 50, 6592–6595. 15. Kourouli, T., Kefalas, P., Ragoussis, N., & Ragoussis, V. (2002). A new protocol for a regioselective aldol condensation as an alternative convenient synthesis of β-Ketols and α, β-unsaturated ketones. J Org Chem, 67, 4615–4618. 16. Feng, X.-W., Li, C., Wang, N., Li, K., Zhang, W.-W., Wang, Z., & Yu, X.-Q. (2009). Lipase-catalysed decarboxylative aldol reaction and decarboxylative Knoevenagel reaction. Green Chem, 11, 1933–1936. 17. Magdziak, D., Lalic, G., Lee, H. M., Fortner, K. C., Aloise, A. D., & Shair, M. D. (2005). Catalytic enantioselective thioester aldol reactions that are compatible with protic functional groups. J Am Chem Soc, 127, 7284–7285. 18. Evitt, A. S., & Bornscheuer, U. T. (2011). Lipase CAL-B does not catalyze a promiscuous decarboxylative aldol addition or Knoevenagel reaction. Green Chem, 13, 1141–1142. 19. Kapoor, M., Majumder, A. B., Mukherjee, J., & Gupta, M. N. (2012). Decarboxylative aldol reaction catalysed by lipases and a protease in organic co-solvent mixtures and nearly anhydrous organic solvent media. Biocatal Biotransform, 30, 399–408. 20. Chen, X.-Y., Chen, G.-J., Wang, J.-L., Wu, Q., & Lin, X.-F. (2013). Lipase/acetamide-catalyzed carboncarbon bond formations: a mechanistic view. Adv Synth Catal, 355, 864–868. 21. Strohmeier, G. A., Sovic´, T., Steinkellner, G., Hartner, F. S., Andryushkova, A., Purkarthofer, T., Glieder, A., Gruber, K., & Griengl, H. (2009). Investigation of lipase-catalyzed michael-type carbon–carbon bond formations. Tetrahedron, 65, 5663–5668. 22. Nair, M. S., & Joly, S. (2000). Lipase catalyzed kinetic resolution of aryl β-hydroxy ketones. Tetrahedron Asymmetry, 11, 2049–2052. 23. Edin, M., Backvall, J. E., & Armando, C.´r. (2004). Tandem enantioselective organo- and biocatalysis: a direct entry for the synthesis of enantiomerically pure aldols. Tetrahedron Lett, 45, 7697–7701. 24. Xu, F., Wang, J.-X., Liu, B.-K., Wu, Q., & Lin, X.-F. (2011). Enzymatic synthesis of optical pure bnitroalcohols by combining D-aminoacylase-catalyzed nitroaldol reaction and immobilized lipase PScatalyzed kinetic resolution. Green Chem, 13, 2359–2361. 25. Joly, S., & Nair, M. S. (2003). Studies on the enzymatic kinetic resolution of β-hydroxy ketones. J Mol Catal B Enzym, 22, 151.
