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Biocatalysis

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Biocatalysis in continuous-flow mode: A case-study in the enzymatic kinetic resolution of secondary alcohols via acylation and deacylation reactions mediated by Novozym 435®

Juliana Christina Thomas / Martha Daniela Burich / Pamela Taisline Bandeira / Alfredo Ricardo Marques de Oliveira / Leandro Piovan
Published Online: 2017-02-24 | DOI: https://doi.org/10.1515/boca-2017-0003

Abstract

Enzymatic kinetic resolution reactions are a well-established way to achieve optically active compounds. When enzymatic reactions are combined to continuous-flow methodologies, other benefits are added, including reproducibility, optimized energy use, minimized waste generation, among others. In this context, we herein report a case study involving lipase-mediated transesterification by acylation and deacylation reactions of secondary alcohols/esters in batch and continuous-flow modes. Acylation reactions were performed with high values of enantiomeric excess (72 up to >99%) and enantioselectivity (E > 200) for both batch and continuous-flow modes. On the other hand, for deacylation reactions using n-butanol as nucleophile, enatiomeric excess ranged between 38 to >99% and E from 6 to >200 were observed for batch mode. For deacylation reactions in continuous-flow mode, results were disappointing, as in some cases, very low or no conversion was observed. Enantiomeric excess ranged from 16 to >99% and enantioselectivity from 5 to >200 were observed. In terms of productivity, continuous-flow mode reactions were superior in both strategies (acylation: r from 1.1 up to 18.1-fold higher, deacylation: 2.8 up to 7.4- fold higher in continuous-flow than in batch mode).

Keywords: enzymatic kinetic resolution; acylation/deacylation; continuous-flow chemistry; lipases; secondary alcohols

References

  • [1] Carvalho, A. C. L. M.; Fonseca, T. S.; Mattos, M. C.; Oliveira, M. C. F.; Lemos, T. L. G.; Molinari, F.; Romano, D.; Serra, I. Recent advances in lipase-mediated preparation of pharmaceuticals and their intermediates. Int. J. Mol. Sci., 2015, 16, 29682-29716.Web of ScienceCrossrefGoogle Scholar

  • [2] Loughlin, W. A. Biotransformations in organic synthesis. Bioresource Technol., 2000, 74, 49-62.CrossrefGoogle Scholar

  • [3] Junior, I. I.; Miranda, L. S. M.; Souza, R. O. M. A. Towards a continuous flow environment for lipase-catalyzed reactions. J. Mol. Catal. B: Enzym., 2013, 85-86, 1-9.Web of ScienceGoogle Scholar

  • [4] Schonstein, L.; Forro, E.; Fulop, F. Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers. Tetrahedron: Asymmetry, 2013, 24, 202-206.Web of ScienceCrossrefGoogle Scholar

  • [5] Wiles, C.; Watts, P. Continuous flow reactors: a perspective. Green Chem., 2012, 14, 38-54.CrossrefWeb of ScienceGoogle Scholar

  • [6] Machado, A. H. L.; Pandoli, O.; Miranda, L. S. M.; Souza, R. O. M. A. Micro reatores: novas oportunidades em sintese quimica. Rev. Virtual Quim., 2014, 6, 1076-1085.Google Scholar

  • [7] Souza, R. O. M. A.; Miranda, L. S. M. Reacoes sob fluxo continuo: da quimica verde a um processo verde. Rev. Virtual Quim., 2014, 6, 34-43.Google Scholar

  • [8] Kapoor, M.; Gupta, M. N. Lipase promiscuity and its biochemical applications. Process Biochem., 2012, 47, 555-569.CrossrefWeb of ScienceGoogle Scholar

  • [9] Clouthier, C. M.; Pelletier, J. N. Expanding the organic toolbox: a guide to integrating biocatalysis in synthesis. Chem. Soc. Rev., 2012, 41, 1585-1605.CrossrefWeb of ScienceGoogle Scholar

  • [10] Lamble, H. J.; Royer, S. F.; Hough, D. W.; Danson, M. J.; Taylor, G. L.; Bull, S. D. A thermostable aldolase for the synthesis of 3-deoxy-2-ulosonic acids. Adv. Synth. Catal., 2007, 349, 817-821.Web of ScienceGoogle Scholar

  • [11] Preez, R.; Clarke, K. G.; Callanan, L. H.; Burton, S. G. Modelling of immobilised enzyme biocatalytic membrane reactor performance. J. Mol. Catal. B: Enzym., 2015, 119, 48-53.Web of ScienceGoogle Scholar

  • [12] Andrade, L. H.; Kroutil, W.; Jamison, T. F. Continuous flow synthesis of chiral amines in organic solvents: immobilization of E. coli cells containing both ω-transaminase and PLP. Org. Lett., 2014, 16, 6092-6095.CrossrefWeb of ScienceGoogle Scholar

  • [13] Zambelli, P.; Tamborini, L.; Cazzamalli, S.; Pinto, A.; Arioli, S.; Balzaretti, S.; Plou, F. J.; Arrojo, L. F.; Molinari, F.; Conti, P.; Romano, D. An efficient continuous flow process for the synthesis of a non-conventional mixture of fructooligosaccharides. Food Chem., 2016, 190, 607-613.Web of ScienceGoogle Scholar

  • [14] Tomaszewski, B.; Schmid, A.; Buehler, K. Biocatalytic production of catechols using a high pressure tube-in-tube segmented flow microreactor. Org. Process Res. Dev., 2014, 18, 1516-1526.CrossrefWeb of ScienceGoogle Scholar

  • [15] Ruiz, I. R.; Codina, E. M.; Ackermann, T. N.; Llobera, A. Photonic lab-on-chip (PhLOC) for enzyme-catalyzed reactions in continuous flow. Microfluid. Nanofluid., 2015, 18, 1277-1286.Web of ScienceCrossrefGoogle Scholar

  • [16] Madarasz, J.; Nemeth, D.; Bakos, J.; Gubicza, L.; Bakonyi, P. Solvent-free enzymatic process for biolubricant production in continuous microfluidic reactor. J. Clean. Prod., 2015, 93, 140-144.Web of ScienceGoogle Scholar

  • [17] Sutili, F. K.; Ruela, H. S.; Nogueira, D. O.; Leal, I. C. R.; Miranda, L. S. M.; Souza, R. O. M. A. Enhanced production of fructose ester by biocatalyzed continuous flow process. Sustain. Chem. Process., 2015, 3, 6.Google Scholar

  • [18] Sutili, F.; Nogueira, D. O.; Leite, S. G. F.; Miranda, L. S. M.; Souza, R. O. M. A. Lipase immobilized in microemulsion based organogels (MBGs) as an efficient catalyst for continuousflow esterification of protected fructose. RSC Adv., 2015, 5, 37287-37291.CrossrefGoogle Scholar

  • [19] Junior, I. I.; Flores, M. C.; Sutili, F. K.; Leite, S. G. F.; Miranda, L. S. M.; Leal, I. C. R.; Souza, R. O. M. A. Lipase-catalyzed monostearin synthesis under continuous flow conditions. Org. Process Res. Dev., 2012, 16, 1098-1101.CrossrefWeb of ScienceGoogle Scholar

  • [20] Wang, S. S.; Li, Z. J.; Sheng, S.; Wu, F. A.; Wang, J. Microfluidic biocatalysis enhances the esterification of caffeic acid and methanol under continuous-flow conditions. J. Chem. Technol. Biotechnol., 2015, 91, 555-562.Web of ScienceGoogle Scholar

  • [21] Woodcock, L. L.; Wiles, C.; Greenway, G. M.; Watts, P.; Wells, A.; Eyley, S. Enzymatic synthesis of a series of alkyl esters using Novozyme 435 in a packed-bed, miniaturized, continuous flow reactor. Biocatal. Biotransform., 2008, 26, 501-507.Web of ScienceGoogle Scholar

  • [22] Varon, E. Y.; Joli, J. E.; Balcells, M.; Torres, M.; Garayoa, R. C. Synthesis of poly(ethyl acrylate-co-allyl acrylates) from acrylate mixtures prepared by a continuous solvent-free enzymatic process. RSC Adv., 2012, 2, 9230-9236.CrossrefWeb of ScienceGoogle Scholar

  • [23] Hernandez, A. L.; Otero, C.; Martin, E. H.; Garcia, H. S.; Hill, C. G. Interesterification of sesame oil and a fully hydrogenated fat using an immobilized lipase catalyst in both batch and continuous-flow processes. Eur. J. Lipid Sci. Technol., 2007, 109, 1147-1159.Google Scholar

  • [24] Tran, D. T.; Lin, Y. J.; Chen, C. L.; Chang, J. S. Modeling the methanolysis of triglyceride catalyzed by immobilized lipase in a continuous-flow packed-bed reactor. Appl. Energ., 2014, 126, 151-160.Web of ScienceGoogle Scholar

  • [25] Wang, J.; Gu, S. S.; Cui, H. S.; Wu, X. Y.; Wu, F. A. A novel continuous flow biosynthesis of caffeic acid phenethyl ester from alkyl caffeate and phenethanol in a packed bed microreactor. Bioresour. Technol., 2014, 158, 39-47.Web of ScienceGoogle Scholar

  • [26] Carnero, A.; Sanghvi, Y. S.; Gotor, V.; Fernandez, S.; Ferrero, M. Process development of biocatalytic regioselective 5′-O-levulinylation of 2′-deoxynucleosides. Org. Process Res. Dev., 2015, 19, 701-709.Web of ScienceGoogle Scholar

  • [27] Manoel, E. A.; Pais, K. C.; Flores, M. C.; Miranda, L. S. M.; Coelho, M. A. Z.; Simas, A. B. C.; Freire, D. M. G.; Souza, R. O. M. A. Kinetic resolution of a precursor for myo-inositol phosphates under continuous flow conditions. J. Mol. Catal. B: Enzym., 2013, 87, 139-143.Web of ScienceCrossrefGoogle Scholar

  • [28] Liu, Z.; Burgess, K. Continuous flow biocatalytic resolutions of methyl sulfinylacetates. Tetrahedron: Lett., 2011, 52, 6325-6327.Web of ScienceGoogle Scholar

  • [29] Reetz, M. T.; Wiesenhofer, W.; Francio, G.; Leitner, W. Biocatalysis in ionic liquids: batchwise and continuous flow processes using supercritical carbon dioxide as the mobile phase. Chem. Commun., 2002, 992-993.CrossrefGoogle Scholar

  • [30] Hellner, G.; Boros, Z.; Tomin, A.; Poppe, L. Novel sol-gel lipases by designed bioimprinting for continuous-flow kinetic resolutions. Adv. Synth. Catal., 2011, 353, 2481-2491.Web of ScienceGoogle Scholar

  • [31] Boros, Z.; Falus, P.; Markus, M.; Weiser, D.; Olah, M.; Hornyanszky, G.; Nagy, J.; Poppe, L. How the mode of Candida antarctica lipase B immobilization affects the continuous-flow kinetic resolution of racemic amines at various temperatures. J. Mol. Catal. B: Enzym., 2013, 85-86, 119-125.Web of ScienceGoogle Scholar

  • [32] Boros, Z.; Weiser, D.; Markus, M.; Abahaziova, E.; Magyar, A.; Tomin, A.; Koczka, B.; Kovacs, P.; Poppe, L. Hydrophobic adsorption and covalent immobilization of Candida antarctica lipase B on mixed-function-grafted silica gel supports for continuous-flow biotransformations. Process Biochem., 2013, 48, 1039-1047.Web of ScienceCrossrefGoogle Scholar

  • [33] Thomas, J. C.; Aggio, B. B.; Oliveira, A. R. M.; Piovan, L. High-throughput preparation of optically active cyanohydrins mediated by lipases. Eur. J. Org. Chem., 2016, 36, 5964-5970.Web of ScienceCrossrefGoogle Scholar

  • [34] Csajagi, C.; Szatzker, G.; Toke, E. R.; Urge, L.; Darvas, F.; Poppe, L. Enantiomer selective acylation of racemic alcohols by lipases in continuous-flow bioreactors. Tetrahedron: Asymmetry, 2008, 19, 237-246.CrossrefWeb of ScienceGoogle Scholar

  • [35] Matsuda, T.; Watanabe, K.; Harada, T.; Nakamura, K.; Arita, Y.; Misumi, Y.; Ichikawa, S.; Ikariya T. High-efficiency and minimum-waste continuous kinetic resolution of racemic alcohols by using lipase in supercritical carbon dioxide. Chem. Commun., 2004, 2286-2287.CrossrefGoogle Scholar

  • [36] Lozano, P.; Verdugo, E. G.; Karbass, N.; Montague, K.; Diego, T.; Burguete, M. I.; Luis, S. V. Supported Ionic Liquid-Like Phases (SILLPs) for enzymatic processes: continuous KR and DKR in SILLP-scCO2 systems. Green Chem., 2010, 12, 1803-1810.Web of ScienceGoogle Scholar

  • [37] Reetz, M. T.; Wiesenhofer, W.; Francio, G.; Leitner, W. Continuous flow enzymatic kinetic resolution and enantiomer separation using ionic liquid/supercritical carbon dioxide media. Adv. Synth. Catal., 2003, 354, 1221-1228.Google Scholar

  • [38] Wang, B.; Jiang, L.; Wang, J.; Ma, J.; Liu, M.; Yu, H. A tandem and fully enzymatic procedure for the green resolution of chiral alcohols: acylation and deacylation in non-aqueous media. Tetrahedron: Asymmetry, 2011, 22, 980-985.CrossrefWeb of ScienceGoogle Scholar

  • [39] Debbeche, H.; Toffano, M.; Fiaud, J. C.; Zouioueche, L. A. Multi-substrate screening for lipase-catalyzed resolution of arylalkylethanols with succinic anhydride as acylating agent. J. Mol. Catal. B: Enzym., 2012, 66, 319-324.Web of ScienceGoogle Scholar

  • [40] Patel, R. N.; Banerjee, A.; Nanduri,, V.; Goswami, A.; Comezoglu, F. T. Enzymatic resolution of racemic secondary alcohols by lipase B from Candida antarctica. J. Am. Oil Chem. Soc., 2000, 77, 1015-1019.Google Scholar

  • [41] Shang, C. Y.; Li, W. X.; Zhang, R. F. Immobilized Candida antarctica lipase B on ZnO nanowires/macroporous silica composites for catalyzing chiral resolution of (R,S)-2-octanol. Enzyme Microb. Technol., 2014, 61-62, 28-34.Google Scholar

  • [42] Ren, L.; Xu, T.; He, R.; Jiang, Z.; Zhou, H.; Wei, P. A green resolution-separation process for aliphatic secondary alcohols. Tetrahedron: Asymmetry, 2013, 24, 249-253.Web of ScienceCrossrefGoogle Scholar

  • [43] Ferreira, H.; Rocha, L. C.; Severino, R. P.; Porto, A. L. M. Syntheses of enantiopure aliphatic secondary alcohols and acetates by bioresolution with lipase B from Candida antarctica. Molecules, 2012, 17, 8955-8967.Web of ScienceCrossrefGoogle Scholar

About the article

Received: 2016-12-04

Accepted: 2017-02-07

Published Online: 2017-02-24

Published in Print: 2017-01-01


Citation Information: Biocatalysis, Volume 3, Issue 1, Pages 27–36, ISSN (Online) 2353-1746, DOI: https://doi.org/10.1515/boca-2017-0003.

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© 2017. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0

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