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Synlett 2022; 33(17): 1756-1762
DOI: 10.1055/a-1916-4858
letter

Immobilization of Functionalized epi-Cinchonine Organocatalysts on Controlled Porous Glass Beads: Applications in Batch and ­Continuous Flow

Ana C. Amorim
a   Chiratecnics, LDA, PO Box, 59, Rossio, Évora, 7006-802, Portugal Laboratory 007, Building A, Colégio Pedro de Fonseca, University of Évora, PITE Industrial and Technological Park, 7000 Évora, Portugal
,
Daniela P. Fonseca
b   Chemistry and Biochemistry Department, School of Science and Technology, University of Evora, 7000-671 Évora, Portugal
c   LAQV-REQUIMTE, Institute for Research and Advanced Studies, University de Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal
,
Elisabete P. Carreiro 
c   LAQV-REQUIMTE, Institute for Research and Advanced Studies, University de Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal
,
Gesine J. Hermann 
a   Chiratecnics, LDA, PO Box, 59, Rossio, Évora, 7006-802, Portugal Laboratory 007, Building A, Colégio Pedro de Fonseca, University of Évora, PITE Industrial and Technological Park, 7000 Évora, Portugal
,
Hans-Jürgen Federsel 
d   RISE, Research Institutes of Sweden, Box 5607, SE-114 86 Stockholm, Sweden
,
Anthony J. Burke  ∗
e   Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
f   Coimbra Chemistry Centre, Institute of Molecular Sciences, Chemistry Department, University of Coimbra, 3004-535 Coimbra, Portugal
› InstitutsangabenThis work received financial support from the Fundação para a Ciência e Tecnologia (FCT Portugal) through the project UIDB/50006/2020 | UIDP/50006/2020.
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Abstract

A well-known squaramide-cinchonine organocatalyst was immobilized in a controlled way onto three types of commercial porous glass beads EziG™ (EziG OPAL, EziG Amber, and EziG Coral) and applied in asymmetric Michael reactions. The performance of the immobilized catalysts was evaluated under batch and continuous-flow conditions, showing promising results in both approaches. In batch reactions, 0.8 and 1.6 mol% of the immobilized cinchonine-squaramide provided the products with excellent yields (up to 99%) and enantioselectivities (up to 99% ee). These excellent results were also verified in the case of continuous-flow reactions, where also 0.8 and 1.6 mol% of the catalyst immobilized onto the glass beads afforded the product with extraordinary yields (up to 99%) and very high enantioselectivities (up to 97% ee). The immobilized catalysts could be recycled (up to seven cycles) using both approaches.

Key words

cinchona alkaloids - EziGTM - immobilizations - batch reactions - continuous flow reactions - organocatalysis

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1916-4858.
  • Supporting Information


Publikationsverlauf

Eingereicht: 18. Juni 2022

Angenommen nach Revision: 02. August 2022

Accepted Manuscript online:
02. August 2022

Artikel online veröffentlicht:
21. September 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 1 Eder U, Sauer G, Wiechert R. Angew. Chem., Int. Ed. Engl. 1971; 10: 496
    Crossref
  • 2 Hajos ZG, Parrish DR. J. Org. Chem. 1974; 39: 1615
    Crossref
  • 3 Burke AJ, Hermann GJ. In Organocatalysis: Stereoselective Reactions and Applications in Organic Synthesis . Benaglia M. Walter de Gruyter GmbH; Berlin/Boston: 2021: 85
    CrossrefGoogle Scholar
  • 4 List B, Lerner RA, Barbas CF. J. Am. Chem. Soc. 2000; 122: 2395
    CrossrefPubMed
  • 5 Ahrendt KA, Borths CJ, MacMillan DW. C. J. Am. Chem. Soc. 2000; 122: 4243
    CrossrefPubMed
  • 6 Melchiorre P. Angew. Chem. Int. Ed. 2010; 49: 3259
    Crossref
  • 7 Zhao W, Zhang Y, Qu C, Zhang L, Wang J, Cui Y. Catal. Lett. 2014; 144: 1681
    Crossref
  • 8 Kacprzak KM, Maier NM, Lindner W. Tetrahedron Lett. 2006; 47: 8721
    Crossref
  • 9 Porta R, Coccia F, Annunziata R, Puglisi A. ChemCatChem 2015; 7: 1490
    Crossref
  • 10 Cancogni D, Mandoli A, Jumde RP, Pini D. Eur. J. Org. Chem. 2012; 1336
    Crossref
  • 11 Rodríguez-Rodríguez M, Maestro A, Andrés JM, Pedrosa R. Adv. Synth. Catal. 2020; 362: 2744
    Crossref
  • 12 Porta R, Benaglia M, Coccia F, Cozzi F, Puglisi A. Adv. Synth. Catal. 2015; 357: 377
    CrossrefPubMed
  • 13 Fernandes S, Porta R, Barrulas P, Puglisi A, Burke A, Benaglia M. Molecules 2016; 21: 1182
    CrossrefPubMed
  • 14 Gleeson O, Davies G.-L, Peschiulli A, Tekoriute R, Gun’ko Y, Connon S. Org. Biomol. Chem. 2011; 9: 7929
    CrossrefPubMed
  • 15 Thompson MP, Derrington SR, Heath RS, Porter JL, Mangas-Sanchez J, Devine PN, Truppo MD, Turner NJ. Tetrahedron 2019; 75: 327
    Crossref
  • 16 Coloma J, Lugtenburg T, Afendi M, Lazzarotto M, Bracco P, Hagedoorn P.-L, Gardossi L, Hanefeld U. Catalysts 2020; 10: 899
    Crossref
  • 17 Cassimjee KE, Federsel H.-J. In Biocatalysis: An Industrial Perspective 2018; 345
  • 18 Engelmark Cassimjee K, Kadow M, Wikmark Y, Svedendahl Humble M, Rothstein ML, Rothstein DM, Bäckvall J.-E. Chem. Commun. 2014; 50: 9134
    CrossrefPubMed
  • 19 Böhmer W, Knaus T, Volkov A, Slot TK, Shiju NR, Engelmark Cassimjee K, Mutti FG. J. Biotechnol. 2019; 291: 52
    CrossrefPubMed
  • 20 Böhmer W, Volkov A, Engelmark Cassimjee K, Mutti FG. Adv. Synth. Catal. 2020; 362: 1858
    CrossrefPubMed
  • 21 di Paola M, Quarta A, Conversano F, Sbenaglia EA, Bettini S, Valli L, Gigli G, Casciaro S. Langmuir 2017; 33: 4490
    CrossrefPubMed
  • 22 Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416
    CrossrefPubMed
  • 23 Melchiorre P. Angew. Chem. Int. Ed. 2012; 51: 9748
    CrossrefPubMed
  • 24 Izquierdo J, Ayats C, Henseler AH, Pericàs MA. Org. Biomol. Chem. 2015; 13: 4204
    CrossrefPubMed
  • 25 General Procedure for Batch ReactionsAcetylacetone or methyl 2-oxocyclopentane-1-carboxylate (1.1 equiv) and the EziG ™ immobilized cinchonine-squaramide (1.6 mol% of catalyst in the case of acetylacetone; 0.8 mol% of catalyst in the case of methyl 2-oxocyclopentane-1-carboxylate) were added to a solution of trans-β-nitrostyrene (1.0 equiv) in CH2Cl2 (3 mL). The reaction was carried out in an orbital shaker at room temperature at 300 rpm for 48 hours. The reaction mixture was then filtered to collect the catalyst, and the solvent was removed from the filtrate. The product was purified by flash column chromatography eluting with 5:1 (Hex:EtOAc). The filtered catalyst was used in the next cycle without further purification (see the Supporting Information for characterization data)
  • 26 General Procedure for Continuous-Flow ReactionsA solution of acetylacetone or methyl 2-oxocyclopentane-1-carboxylate (1.1 equiv) and trans-β-nitrostyrene (1.0 equiv) in CH2Cl2 was pumped through a packed-bed reactor in an Omnifit® assembly loaded with the EziG™ immobilized cinchonine-squaramide (1.6 mol% of catalyst in the case of acetylacetone; 0.8 mol% of catalyst in the case of methyl 2-oxocyclopentane-1-carboxylate), at a flow rate of 0.08 mL min–1, a residence time of 18.8 min, at room temperature, during 2 h. The reaction mixture was collected, concentrated, and purified by flash column chromatography eluting with 5:1 (Hex:EtOAc). The column was washed with 10 mL of CH2Cl2
  • 27 Compound 3: Yellow solid. 1H NMR (400 MHz, CDCl3): δ = 1.94 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 4.21–4.27 (m, 1 H, CH), 4.38 (d, J = 12 Hz, 1 H, CH), 4.62–4.64 (m, 2 H, CH2), 7.17–7.19 (m, 2 H, ArH), 7.29–7.35 (m, 3 H, ArH). 13C APT NMR (100 MHz, CDCl3): δ = 29.55 (CH), 30.45 (CH), 42.80 (CH3), 70.74 (CH3), 78.20 (CH2), 127.95 (2CH), 128.58 (CH), 129.36 (2CH), 135.99 (C), 201.03 (C=O), 201.80 (C=O)
  • 28 Compound 5: Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.81–2.08 (m, 4 H, 2CH2), 2.33–3.43 (m, 2 H, CH2), 3.77 (s, 3 H, CH3), 4.09 (dd, J = 4 Hz, 12 Hz, 1 H, CH), 5.00–5.06 (m, 1 H, CH2), 5.16–5.20 (m, 1 H, CH2), 7.24–7.34 (m, 5 H, ArH). 13C APT NMR (100 MHz, CDCl3): δ = 19.34 (CH2), 31.13 (CH2), 37.95 (CH2), 46.17 (CH3), 53.06 (CH), 62.46 (C), 76.42 (CH2), 128.35 (CH), 128.86 (2CH), 129.30 (2CH), 135.26 (C), 169.83 (COOCH3), 212.30 (C=O)
  • 29 Experimental procedures for the synthesis of catalysts CD2-5 are described in the Supporting Information.Catalyst CD2: dark-brown oil. 1H NMR (400 MHz, CDCl3): δ = 0.65–0.71 (m, 1 H, CH2), 1.35 (brt, J = 12 Hz, 1 H, CH2), 1.47–1.51 (m, 2 H, CH2), 1.54–1.55 (m, 1 H, CH), 2.23 (brs, 3 H, CH, NH2), 2.69–2.79 (m, 2 H, CH2), 2.96–3.08 (m, 1 H, CH), 3.13–3.24 (m, 2 H, CH2), 4.65 (d, J = 8 Hz, 1 H, CH), 4.89–4.96 (m, 2 H, CH2), 5.69–5.78 (m, 1 H, CH), 7.48 (d, J = 4 Hz, 1 H, ArH), 7.53 (t, J = 6 Hz, 1 H, ArH), 7.65 (t, J = 8 Hz, 1 H, ArH), 8.08 (d, J = 8 Hz, 1 H, ArH), 8.30 (brs, 1 H, ArH), 8.84 (d, J = 4 Hz, 1 H, ArH). 13C APT NMR (100 MHz, CDCl3): δ = 26.0 (CH2), 27.5 (2CH), 28.0 (CH2), 39.8 (2CH), 40.9 (CH2), 56.3 (CH2), 114.3 (CH2), 126.5 (CH), 127.8 (C), 128.9 (2CH), 130.4 (2CH), 141.8 (CH), 148.6 (C), 148.7 (C), 150.3 (CH).Catalyst CD3: white solid. 1H NMR (400 MHz, DMSO-d 6): δ = 0.63 (brs, 1 H, CH2), 1.33 (brs, 1 H, CH2), 1.53 (m, 3 H, CH, CH2), 2.24 (brs, 1 H, CH), 2.61–2.69 (m, 2 H, CH2), 3.12–3.18 (m, 1 H, CH), 3.35–3.43 (m, 2 H, CH2), 4.84–5.01 (m, 4 H, 2CH2), 5.83–5.92 (m, 1 H, CH), 6.04 (brs, 1 H, CH), 7.68–7.71 (m, 2 H, 2NH), 7.78 (t, J = 8 Hz, 1 H, ArH), 8.00–8.07 (m, 5 H, ArH), 8.28 (brs, 1 H, ArH), 8.49 (d, J = 8 Hz, 1 H ArH), 8.93 (d, J = 4 Hz, 1 H, ArH). 13C APT NMR (100 MHz, DMSO-d 6): δ = 25.9 (CH2), 27.2 (2CH), 27.3 (CH2), 39.3 (2CH), 40.1 (CH2), 45.8 (CH2), 55.5 (CH2), 114.3 (CH2), 121.2 (CH), 121.9 (C), 123.5 (CH), 124.6 (C), 126.4 (C), 127.1 (CH), 128.7 (CH), 128.7 (CH), 129.4 (CH), 129.9 (CH), 130.3 (C), 130.6 (C), 142.1 (2CH), 142.32 (2C), 145.5 (C), 148.1 (C), 150.4 (CH), 167.3 (C), 182.2 (C=O), 182.6 (C=O).Catalyst CD4: brown oil. 1H NMR (400 MHz, CDCl3): δ = 0.68–0.73 (m,1 H, CH2), 1.24–1.28 (m, 2 H, CH2), 1.64–1.65 (m, 2 H, CH2), 1.90 (brs, 1 H, CH2), 2.89–2.93 (m, 1 H, CH), 3.04 (brs, 3 H, CH, NH2), 3.31–3.33 (m, 1 H, CH), 3.43–3.53 (m, 2 H, CH2), 4.72 (brs, 1 H, CH), 5.45 (d, J = 8 Hz, 2 H, CH2), 7.20 (brs, 2 H, ArH), 7.26 (s, 1 H, TrzH), 7.34 (brs, 3 H, ArH), 7.47 (d, J = 4 Hz, 1 H, ArH), 7.58 (t, J = 8 Hz, 1 H, ArH), 7.70 (t, J = 8 Hz, 1 H, ArH), 8.12 (d, J = 8 Hz, 1 H, ArH), 8.32 (brs, 1 H, ArH), 8.83 (d, J = 4 Hz, 1 H, ArH). 13C APT NMR (100 MHz, CDCl3): δ = 25.9 (CH2), 27.5 (CH2), 27.6 (2CH), 33.0 (2CH), 41.0 (CH2), 54.1 (CH2), 55.6 (CH2), 120.5 (TrzCH), 126.7 (CH), 127.7 (C), 127.9 (2CH), 128.7 (2CH), 129.1 (3CH), 130.4 (2CH), 134.8 (C), 148.5 (C), 150.4 (CH), 151.0 (C), 151.1 (C). Catalyst CD5: brown oil. 1H NMR (400 MHz, CDCl3): δ = 0.81–0.87 (m, 1 H, CH2), 1.10–1.15 (m, 1 H, CH2), 1.52–1.73 (m, 4 H, 2CH2), 1.73 (brs, 1 H, CH), 1.85–1.93 (m, 2 H, CH2), 2.26–2.31 (m, 4 H, CH2, NH2), 2.93–3.07 (m, 4 H, 2CH2), 3.17–3.23 (m, 1 H, CH), 3.61 (s, 3 H, CH3), 3.78–3.83 (m, 1 H, CH), 4.26–4.35 (m, 2 H, CH2), 4.99 (d, J = 4 Hz, 1 H, CH), 7.22 (s, 1 H, TrzH), 7.49 (t, J = 8 Hz, 1 H, ArH), 7.58 (brs, 1 H, ArH), 7.63 (t, J = 8 Hz, 1 H, ArH), 8.04 (d, J = 8 Hz, 1 H, ArH), 8.39 (brs, 1 H, ArH), 8.83 (d, J = 4 Hz, 1 H, ArH). 13C APT NMR (100 MHz, CDCl3): δ = 21.6 (CH2), 24.8 (CH2), 26.5 (CH2), 28.9 (2CH), 29.7 (CH2), 33.1 (CH2), 33.3 (2CH), 46.4 (CH2), 49.6 (CH2), 49.9 (CH2), 51.7 (CH3), 120.7 (TrzCH), 126.2 (CH), 127.9 (C), 128.9 (2CH), 130.1 (2CH), 148.5 (C), 150.2 (C), 150.3 (CH), 173.4 (C=O)