Modification of Azepanobetulin at the Isopropenyl Group
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fication of Azepanobetulin at the Isopropenyl Group A. V. Petrovaa,*, T. V. Lopatinaa, A. G. Mustafina, and O. B. Kazakovaa a
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia *e-mail: [email protected] Received May 18, 2020; revised June 1, 2020; accepted June 13, 2020
Abstract—Modification of the isopropenyl group of biologically active azepanobetulin via oxidation with ozone and selenium dioxide, allylic bromination, azidation, amination, reduction, 1,3-dipolar cycloaddition, and Claisen–Schmidt condensation afforded a series of C30-derivatives with oxygen- and nitrogen-containing aliphatic and heterocyclic substituents. Keywords: triterpenoids, lupanes, azepanes, chalcones, 1,3-dipolar cycloaddition, 1,2,3-triazoles
DOI: 10.1134/S1070428020090134 Triterpenoids are widespread in nature, and they exhibit diverse biological activities [1]. The lupane triterpenoids betulin and betulinic acid are extensively involved in various modifications, including modifications at C19. For example, 20-amino derivative of platanic acid is a potent butyrylcholinesterase inhibitor [2]. Introduction of an aldehyde functionality to C30 of A-seco-lupanes gives rise to a pronounced cytotoxicity against several cancer cell lines [3]. Among the series of C30-1,2,3-triazolyl derivatives of 3-acetoxybetulinic acid, the conjugate containing a benzaldehyde moiety was most active against CCRF-CEM leukemia cell line [4]. Thus, modification of the isopropenyl group of lupanes can be regarded as promising for the design of new biologically active compounds. We have revealed a group of nitrogen-containing triterpenoid derivatives containing an azepane ring which showed a wide range of cytotoxicity against cancer cells [5–8], as well as antimicrobial [9–11] and antidiabetic activities [12]. We have developed a method for the synthesis of azepanobetulin from betulin and performed its O- and N-acylation and oxidation to azepanobetulinic acid [6, 13]. Azepanobetulin showed a high activity against melanoma cancer cells and antitubercular activity against MTB H37Rv and drug-resistant strains [6, 9]. In continuation of these studies, herein we report modifications of azepanobetulin (1) at the isopropenyl group. The transformations of azepanobetulin 1 included oxidations and introduction of nitrogen-containing fragments at C30. 29-Nor-20-oxoazepanobetulin 3 [9] obtained by ozonolysis of 1 reacted with pyridine-3-
carbaldehyde according to Claisen–Schmidt to give 84% of chalcone 4 (Scheme 1). The 1H NMR spectrum of 4 showed aromatic proton signals in the region δ 7.34–8.77 ppm, and signals of the double-bonded C30 and C31 carbon atoms were observed at δC 127 and 138 ppm, respectively, in the 13C NMR spectrum. The spin–spin coupling constant for protons at the double bond was 16.15 Hz, indicating their trans arrangement. Allylic oxidation of 1 with selenium dioxide according to [14] led to the formation of C30-aldehyde 5 in a good yield. The 1H NMR spectrum of 5 showed no C30H3 proton singlet at δ 2
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