Enzymatic deracemization of halogenated dihydroindenols and dihydroindenediols substituted in benzene ring

TitleEnzymatic deracemization of halogenated dihydroindenols and dihydroindenediols substituted in benzene ring
Publication TypeJournal Article
Year of Publication2020
AuthorsPrysiazhnuk, DV, Kolodiazhna, ОО, Kolodiazhnyi, OI
Abbreviated Key TitleDopov. Nac. akad. nauk Ukr.
Date Published3/2020

The optically active halodihydroindenols and dihydroindenediols are components of many biologically active na tural compounds, being important pharmacophore groups. In the present work, to obtain the above compounds with a high degree of optical purity, the resolution of racemates into enantiomers using enzymes is proposed. Dihydroindenones, which were reduced with sodium borohydride to dihydroindenols, were used as starting compounds. Burkholderia cepacia lipase (BCL) was used to separate racemic indenols. Racemic indenols were kinetically trans-esterificated with vinyl acetate in organic media in the presence of a BCL biocatalyst. As a result, acylated indenols of (R)-ab solute configuration and unreacted indenol of (S)-configuration, which were separated into individual compounds by column chromatography, were obtained. The enzymatic resolution of halodihydrinindene acetates by hydrolysis in the presence of Candida antarctica B lipase immobilized on diatomite was also investigated. Enantiomerically enriched halodihydroindenols and halodihydrinindene acetates were obtained when racemic halodihydrinindene acetates were treated with Novozym 435® in MTBE for 20—30 hours at 30—40 ºC. The enantiomeric purity of the compounds was determined by the derivatization with Mosher acid. The absolute configuration of the compounds was established by the Kazlauskas method.

Keywords1, 2-aminocycloalkanols, 2-diaminocycloalkanes, Burkholderia cepacia lipase, Candida antarctica lipase B, enzymes, kinetic resolution

1. Shankar, S. S., Dubé, M. P., Gorski, J. C., Klaunig, J. E. & Steinberg, H. O. (2005). Indinavir impairs endothelial function in healthy HIV-negative men. Am. Heart J., 150, pp. 933. Doi: https://doi.org/10.1016/j.ahj.2005.06.005
2. Liu, F., Boross, P. I., Wang, Y. F., Tozser, J., Louis, J. M., Harrison, R. W. & Weber, I. T. (2005). Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S. J. Mol. Biol., 354, pp. 789-800. Doi: https://doi.org/10.1016/j.jmb.2005.09.095
3. Eira, M., Araujo, M. & Seguro, A. C. (2006). Urinary NO3 excretion and renal failure in indinavir-treated patients. Braz. J. Med. Biol. Res., 39, pp. 1065-1070. Doi: https://doi.org/10.1590/S0100-879X2006000800009
4. Igarashi, Y., Otsutomo, S., Harada, M. & Nakano, S. (1997). Enzymatic resolution of indene bromohydrin acetate using immobilized lipase. Tetrahedron: Asymmetry, 8, No. 16, pp. 2833-2837. Doi: https://doi.org/10.1016/S0957-4166(97)00351-0
5. Luo, Z., Qin, F., Yan, S. & Li, X. (2012). An efficient and promising method to prepare Ladostigil (TV3326) via 25 asymmetric transfer hydrogenation catalyzed by Ru-Cs-DPEN in an HCOONa-H20-surfactant system. Tetrahedron: Asymmetry, 23, pp. 333-338. Doi: https://doi.org/10.1016/j.tetasy.2012.02.022
6. Weinreb, O., Mandel, S. & Bar-Am, O. (2009). Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer’s disease drugs. Neurotherapeutics, 6, No. 1, pp. 163-174. Doi: https://doi.org/10.1016/j.nurt.2008.10.030
7. Weinstock, M., Luques, L., Bejar, C. & Shoham, S. (2006). Ladostigil, a novel multifunctional drug for the treatment of dementia co-morbid with depression. J. Neural Transm. Suppl., 70, pp. 443-446. Doi: https://doi.org/10.1007/978-3-211-45295-0_67
8. Yoshimatsu, S., Yamada, A. & Nakata, K. (2018). Silylative kinetic resolution of racemic 1-Indanol derivatives catalyzed by chiral guanidine. J. Org. Chem., 83, pp. 452-458. Doi: https://doi.org/10.1021/acs.joc.7b02493
9. Murase, K., Nligata, K., Mase, T. & Murakami, M. (1972). Synthesis of new indent derivatives with ß-adrenergic blocking properties. Yakugaku Zasshi, 92, Iss. 11, pp. 1358-1363. Doi: https://doi.org/10.1248/yakushi1947.92.11_1358
10. Pat. 2006/0199974 А1 US, IPC C07C 271/40, Process for the synthesis of enantiomeric indanylamine derivatives. Boulton, L.T., Lennon, I.C. & Bahar, E., Publ. 07.09.2006.
11. Kišić, A., Stephan, M. & Mohar, B. (2015). ansa-Ruthenium(II) complexes of R2NSO2DPEN-(CH2)n (n6-aryl) conjugate ligands for asymmetric transfer hydrogenation of aryl ketones. Adv. Synth. Catal., 357, pp. 2540-2546. Doi: https://doi.org/10.1002/adsc.201500288
12. Pat. 6,645,961 Bl US, IPC A61K 31/535, A61K 31/495, A61K 31/47, Dry granulation formulation for an HIV protease inhibitor. Lui, C.Y., Ostovic, D., Katdare, A.V. & Stelmach, C., Publ. 11.11.2003.
13. Pat. WO 2012/101011, IPC C07C 237/24, C07D 257/00, C07D 311/00, C07D 333/00, C07D 271/00, C07D 305/00, A61P 13/12, A61K 31/165, A61K 31/4245, A61K 31/41, New aryl-benzocycloalkyl amide derivatives, Aebi, J., Binggeli, A., Hertel, C, Konkar, A.A., Kuehne, H., Kuhn, B., Maerki, H.P. & Wang, H., Publ.02.08.2012.
14 Pat. 120692 UA, IPC C07C 27/08, C07C 27/22, Method of producing stereoisomers of dihydro-1-indoles of formula 1 using kinetic separation of racemates in the presence of Burkholderia cepacia lipase or Candida antarctica lipase B enzymes, Kolodiazhnyi, О.І., Kolodiazhna, А.О. & Kolodiazhna, О.О., Publ. 10.11.2017 (in Ukrainian).