Supplementary Informationle revista.iq.unesp.br | Vol. 47 | n. 2 | 2022 | 36 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Levetiracetam analogs: chemoenzymatic synthesis, absolute configuration assignment and evaluation of cholinesterase inhibitory activities Cintia Duarte de Freitas Milagre1+ , Bruno Sergio do Amaral1 , João Marcos Batista Junior2,3 , Adriana Ferreira Lopes Vilela4 , Carmen Lúcia Cardoso4 , Humberto Marcio Santos Milagre1 1. São Paulo State University, Institute of Chemistry, Araraquara, Brazil. 2. Federal University of São Carlos, Department of Chemistry, São Carlos, Brazil. 3. Federal University of São Paulo, Institute of Science and Technology, São José dos Campos, Brazil. 4. University of São Paulo, Faculty of Philosophy, Sciences and Letters, Ribeirão Preto, Brazil. +Corresponding author: Cintia Duarte de Freitas Milagre, Phone: +55 16 33019668, Email address: cintia.milagre@unesp.br ARTICLE INFO Article history: Received: July 19, 2021 Accepted: September 14, 2021 Published: April 01, 2022 Section Editor: Assis Vicente Benedetti Keywords 1. N-heterocycles 2. N-alkylation 3. biocatalysis 4. electronic circular dichroism (ECD) Spectra (1H NMR, 13C NMR, MS and IR) of all characterized compounds 2, 3, 4a–d, 5a–b, 5d, 7, 8a–d, 9a–b and 9d, spectra (1H, 13C, 19F NMR) of the synthesized ionic liquids and the ECD figures and the lower energy conformers. Figure S1. IR spectrum of compound 2. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 mailto:cintia.milagre@unesp.br https://orcid.org/0000-0001-5627-8616 https://orcid.org/0000-0001-6194-2390 https://orcid.org/0000-0002-0267-2631 https://orcid.org/0000-0001-9860-9866 https://orcid.org/0000-0001-6239-6651 https://orcid.org/0000-0001-9468-1166 Supplementary Information revista.iq.unesp.br 37 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S2. MS (EI, 70 eV) spectrum of compound 2. Figure S3. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 2. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 38 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S4. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 2. Figure S5. IR spectrum of compound 4a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 39 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S6. MS (EI, 70 eV) spectrum of compound 4a. Figure S7. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 4a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 40 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S8. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 4a. Figure S9. IR spectrum of compound 4b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 41 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S10. MS (EI, 70 eV) spectrum of compound 4b. Figure S11. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 4b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 42 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S12. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 4b. Figure S13. IR spectrum of compound 4c. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 43 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S14. MS (EI, 70 eV) spectrum of compound 4c. Figure S15. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 4c. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 44 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S16. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 4c. Figure S17. IR spectrum of compound 4d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 45 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S18. MS (EI, 70 eV) spectrum of compound 4d. Figure S19. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 4d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 46 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S20. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 4d. Figure S21. IR spectrum of compound 8a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 47 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S22. MS (EI, 70 eV) spectrum of compound 8a. Figure S23. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 8a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 48 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S24. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 8a. Figure S25. IR spectrum of compound 8b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 49 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S26. MS (EI, 70 eV) spectrum of compound 8b. Figure S27. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 8b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 50 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S28. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 8b. Figure S29. IR spectrum of compound 8c. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 51 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S30. MS (EI, 70 eV) spectrum of compound 8c. Figure S31. 1H NMR (300.19 MHz, DMSO-d6) spectrum of compound 8c. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 52 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S32. 13C NMR (75.48 MHz, DMSO-d6) spectrum and DEPT-135 experiment of compound 8c. Figure S33. IR spectrum of compound 8d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 53 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S34. MS (EI, 70 eV) spectrum of compound 8d. Figure S35. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 8d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 54 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S36. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 8d. Figure S37. IR spectrum of compound 5a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 55 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S38. MS (EI, 70 eV) spectrum of compound 5a. Figure S39. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 5a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 56 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S40. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 5a. Figure S41. IR spectrum of compound 5b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 57 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S42. MS (EI, 70 eV) spectrum of compound 5b. Figure S43. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 5b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 58 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S44. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 5b. Figure S45. IR spectrum of compound 5d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 59 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S46. MS (EI, 70 eV) spectrum of compound 5d. Figure S47. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 5d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 60 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S48. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 5d. Figure S49. IR spectrum of compound 9a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 61 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S50. MS (EI, 70 eV) spectrum of compound 9a. Figure S51. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 9a. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 62 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S52. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 9a. Figure S53. IR spectrum of compound 9b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 63 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S54. MS (EI, 70 eV) spectrum of compound 9b. Figure S55. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 9b. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 64 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S56. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 9b. Figure S57. IR spectrum of compound 9d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 65 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S58. MS (EI, 70 eV) spectrum of compound 9d. Figure S59. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 9d. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 66 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S60. 13C NMR (75.48 MHz, CDCl3) spectrum and DEPT-135 experiment of compound 9d. Figure S61. MS (EI, 70 eV) spectrum of compound 3. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 67 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S62. MS (EI, 70 eV) spectrum of compound 7. Figure S63. 1H NMR (300.19 MHz, CDCl3) spectrum of compound 7. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 68 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S64. 1H NMR (300.19 MHz, DMSO-d6) spectrum of compound BMIM.BF4. Figure S65. 13C NMR (75.48 MHz, DMSO-d6) spectrum and DEPT-135 experiment of compound BMIM.BF4. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 69 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S66. 19F NMR (376.48 MHz, DMSO-d6) spectrum of compound BMIM.BF4. Figure S67. 1H NMR (300.19 MHz, DMSO-d6) spectrum of compound BMIM.PF6. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 70 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S68. 13C NMR (75.48 MHz, DMSO-d6) spectrum and DEPT-135 experiment of compound BMIM.PF6. Figure S69. 19F NMR (376.48 MHz, DMSO-d6) spectrum of compound BMIM.PF6. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 71 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S70. 1H NMR (300.19 MHz, DMSO-d6) spectrum of compound BMIM.NTf2. Figure S71. 13C NMR (75.48 MHz, DMSO-d6) spectrum and DEPT-135 experiment of compound BMIM.NTf2. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 72 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S72. 19F NMR (376.48 MHz, DMSO-d6) spectrum of compound BMIM.NTf2. Figure S73. (a) Experimental (black) and calculated (CAM-B3LYP/TZVP, red) ECD spectra of (S)-5b. (b) Optimized structures, relative energies and Boltzmann populations of the lowest-energy conformers identified for (S)-5b at the B3LYP/6-31G(d)l level. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73 Supplementary Information revista.iq.unesp.br 73 Eclética Química Journal, vol. 47, n. 2, 2022, 36-73 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.2.2022.p36-73 Figure S74. (a) Experimental (black) and calculated (CAM-B3LYP/TZVP, red) ECD spectra of (S)-9a. (b) Optimized structures, relative energies and Boltzmann populations of the lowest-energy conformers identified for (S)-9a at the B3LYP/6-31G(d)l level. Figure S75. (a) Experimental (black) and calculated (CAM-B3LYP/TZVP, red) ECD spectra of (S)-9b. (b) Optimized structures, relative energies and Boltzmann populations of the lowest-energy conformers identified for (S)-9b at the B3LYP/6-31G(d)l level. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.2.2022.p36-73