Oxidation of ursolic acid by ozone

Казакова, О. Б.; Khusnutdinova, É. F.; Лобов, А. Н.; Zvereva, T. I.; Suponitskii, K. Yu.

doi:10.1007/s10600-011-9777-8

Cited by 13 publications

(7 citation statements)

References 8 publications

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“…Thus, 13 C NMR spectra of 2-5 showed a resonance for the C-4 oxo group at G C 210.01-211.05 ppm. Oxetane 2 had characteristic resonances for the methine with H-11 at G C 94.2 ppm ( 13 C NMR) and G H 4.71 ppm (PMR) and quaternary C-12 at G C 189.9 and C-13 at G C 113.9 ppm, which agreed with resonances reported earlier for an ursolic acid derivative with an oxetane moiety [24]. Resonances of the methine with H-12 in 3 (11-oxo-12-ene derivative) were observed at G C 130.3 ppm ( 13 C NMR) and G H 5.15 ppm (PMR) in addition to resonances of quaternary C-11 (G C 130.3 ppm) and C-13 (G C 163.7 ppm).…”

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“…Proposed schemes for separating mixtures of ursolic and oleanolic acids, which occur together in natural sources, were based on the inertness of the C-12(13) unsaturated bond of the former to the action of m-CPBA and HCOOH/H 2 O 2 [21,22]. We found earlier that oleanolic acid methyl ester was oxidized by ozone to methyl 12-oxoolean-28-oate [23] whereas oxidation of the analogous ursolic acid derivative gave 12-oxo-11S,13R-oxetane on ring C [24]. Limitations of methods for synthesizing such chiral non-racemic oxetanes were noted [25].…”

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Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

et al. 2014

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oxetane. The last was formed by oxidation of intermediate 12-oxoursolate. Ozonolysis of the ursolic acid derivative with two unsaturated bonds in the C-4(23) and C-12(13) positions was non-selective, in contrast with that reported previously for an analogous oleanolic-acid derivative.The triterpenoids oleanolic and ursolic acids are widespread in the plant world and exhibit various biological activities including antidiabetic, anticancer, antiviral, etc. [1][2][3]. Oxygenation of ring C is an important technique for modifying their structures in order to prepare new biologically active compounds. Examples include the synthesis from oleanolic acid of bardoxolone methyl (2-cyano-3,12-dioxooleane-1(2),9(11)-dien-28-oic acid methyl ester), which passed phase I clinical trials for treating cancer and phase II for treating chronic kidney disease in type 2 diabetes patients [4]. 3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5]. 12E-Hydroxyurs-11-ene-13E,28-lactone was produced by oxidative transformation of ursolic acid by ruthenium porphyrins and was active against A431 human skin cancer cells [5,6].The structures of the starting substrates are known to affect considerably the oxidation of triterpenoids [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. For example, the reactivities of oleanolic and ursolic acid derivatives were found to differ during oxidation by dimethyldioxirane although these triterpenoids differ only by the location of the methyl in ring E [21]. Proposed schemes for separating mixtures of ursolic and oleanolic acids, which occur together in natural sources, were based on the inertness of the C-12(13) unsaturated bond of the former to the action of m-CPBA and HCOOH/H 2 O 2 [21,22]. We found earlier that oleanolic acid methyl ester was oxidized by ozone to methyl 12-oxoolean-28-oate [23] whereas oxidation of the analogous ursolic acid derivative gave 12-oxo-11S,13R-oxetane on ring C [24]. Limitations of methods for synthesizing such chiral non-racemic oxetanes were noted [25].Considering the aforementioned examples and continuing research on oxidative transformations of plant terpenoids [11,12,14,17,18,[26][27][28], we decided to determine the direction of the oxidation by ozone of 2-cyano-3,4-seco-4(23)-ene ursolic acid methyl ester (1) and to compare the results with those published for oxidation of the analogous oleanolic acid derivative [23].Oxidation of 1 with two unsaturated bonds in the C-4(23) (ring A) and C-12(13) (ring C) positions by ozone in CH 2 Cl 2 formed the three 2-cyano-3,4-seco-4-oxo derivatives 12-oxours-11S,13R-oxetane (2, 68%), 11-oxours-12-ene (3, 12%), and 12-hydroxy-4,11-dioxours-12-ene (4, 8%) (Scheme 1). Thus, oxidation of methyl 2-cyano-3,4-seco-4(23)-ene ursolate by ozone was non-selective, in contrast with the oxidation of the analogous oleanolic acid derivative, which enabled selective transformations of rings A and C to be carried out [23].

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Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

et al. 2014

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“…For example, the oxidation of methyl ursolate with ozone proceeds with generation of 12-oxo-11S,13R-oxetane fragment in the cycle С [21], whereas the oxidation of methyl oleanate leads to methyl 12-oxooleane [22]. Different courses of oxidation processes of triterpenoids belonging to the α-and β-amirine series with reagents like m-chloroperoxybenzoic acid and HCOOH-H 2 O 2 underlie their separation in the form of oxyderivatives, because in plants these metabolites often accompany each other [3,23,24].…”

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Oxidative lactonization of oleanane and ursane acids by treating with ozone

et al. 2015

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Features of process of oxidative lactonization of 3-oxooleanolic and 3-oxoursolic acids under treatment with ozone were established. The similarity of the processes consists in generation of 3-oxooleanolic or 3-oxoursolic 13β,28-lactones with 12-oxo or 12-hydroxy group. In the case of ursane derivative the generation exclusively of compounds with β-oriented 12-hydroxy group was observed, in the case of oleanane lactones prevailingly compounds with α-oriented 12-hydroxy group were obtained. The processes differ by the generation of the product of allylic oxidation, 3,11-dioxoursolic acid, or the isolation of the product of the lactone cycle opening with participation of the solvent, 3,12-dioxoolean-28-olic acid.Oleanolic and ursolic acids, belonging to triterpenoids of the series of β-and α-amirine, are widely spread in plants and exhibit various pharmacological properties [1, 2]. One of the directions of their modification is the oxyfunctionalization of cycles А, C, and E, leading to new bioactive compounds [3][4][5][6][7][8][9][10][11][12][13][14].One of the successful examples of oxidative functionalization of oleanolic acid that should be mentioned is the synthesis of 2-cyano-3,12-dioxo-olean-1 (2),9(11)-dien-28-olic acid (CDDO), possessing antiphlogistic, antitumor, antidiabetic, and antiangiogenic activity [15][16][17][18][19]. Methyl ester CDDO (methyl bardoxolone) passed the first phase of clinical trials as a drug for cancer treatment and second phase as a drug for treatment of chronical kidney diseases for patients suffering from sugar diabetes of the second type [5]. 12-Hydroxy-11-oxoolean-12-enes[3] exhibited a high cytotoxicity. 3β,12α-Dihydrooxyoleanolic 13β,28-olide is the key intermediate in the synthesis of endoteline of A receptors and a promising antidiabetic agent [8]. 2-Cyano-3-oxo-12α-fluorours-1-ene-13β,28-olide is effective against the cancer cells of pancreatic gland [20]. One of the products of oxidative transformation of ursolic acid in the presence of ruthenium porphyrins, 12β-hydroxyurs-11-ene-13β,28-olide, proved to be active against the cancer cells of human skin А431 [9, 10].Despite the fact that triterpenoids of the series of α-and β-amirine have very close structure and differ only by the position of a single methyl group in the E cycle, there is a significant difference in their oxidation processes. For example, the oxidation of methyl ursolate with ozone proceeds with generation of 12-oxo-11S,13R-oxetane fragment in the cycle С [21], whereas the oxidation of methyl oleanate leads to methyl 12-oxooleane [22]. Different courses of oxidation processes of triterpenoids belonging to the α-and β-amirine series with reagents like m-chloroperoxybenzoic acid and HCOOH-H 2 O 2 underlie their separation in the form of oxyderivatives, because in plants these metabolites often accompany each other [3,23,24].In continuation of our research on the oxidative transformations of vegetable terpenoids [25][26][27][28][29][30][31] we investigated in the present study the oxidation of С 12 =С 13 bond...

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“…The formation of two epoxide fragments changes conformations of the six-membered B and C rings. According to our previous data, the six-membered rings in triterpenoids containing an A-B-C tricyclic fragment had chair conformation as the most energetically favorable [1,[9][10][11][12][13], whereas the B ring in SYNTHESIS AND MOLECULAR STRUCTURE OF 1α,10α : 9β,1β : 19β,28-TRIEPOXY-...…”

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Synthesis and molecular structure of 1α,10α: 9β,1β: 19β,28-triepoxy-A-neo-5β-methyl-25-nor-18α-oleane

et al. 2012

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Ozonolysis of 19β,28-epoxy-A-neo-5β-methyl-25-nor-18α-olean-9-ene gave 23% of 1α,10α : 9β,11β : 19β,28-triepoxy-A-neo-5β-methyl-25-nor-18α-oleane whose structure was determined by X-ray analysis.Reactions of pentacyclic triterpenoids with ozone often lead to the formation of unexpected ozonolysis products [1][2][3][4][5]. Stereoselectivity of epoxidation of sterically hindered double bonds in triterpenoids can be determined, e.g., by X-ray analysis [2,6]. The present communication reports on the synthesis and molecular structure of one ozonolysis product of 19β,28-epoxy-A-neo-5β-methyl-25-nor-18α-olean-9-ene (I). The reaction of compound I with p-nitroperoxybenzoic acid gave 9,10-epoxy derivative [7]. We previously [8] observed allylic oxidation of triterpenoid I with ozone, which afforded 63% of 19β,28-epoxy-A-neo-5β-methyl-25-nor-18α-olean-9-en-1-one (II). While studying ozonolysis of oleanene derivative I, we isolated by chromatography diepoxide III in 23% yield (Scheme 1). Presumably, initial [2 + 1]-cycloaddition of ozone at the double C 9 -C 10 bond of compound I gives adduct A (Scheme 2); next follows 1,3-sigmatropic shift with formation of unstable allylic alcohol B, and dehydration of the latter yields 1(10),9(11)-diene C. Adduct A could also give rise to unstable allylic alcohol with C 1 -C 10 double bond, whose subsequent dehydration also leads to diene C. The oxidation of diene C with ozone is stereoselective, and the product is 1α,10α : 9β,11β-diepoxy derivative III.The structure of compound III was determined using NMR spectroscopy, and its molecular and crystalline structures were determined by X-ray analysis (see figure). The formation of two epoxide fragments changes conformations of the six-membered B and C rings. According to our previous data, the six-membered rings in triterpenoids containing an A-B-C tricyclic fragment had chair conformation as the most energetically favorable [1,[9][10][11][12][13], whereas the B ring in

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Oxidation of ursolic acid by ozone

Cited by 13 publications

References 8 publications

Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

Oxidative lactonization of oleanane and ursane acids by treating with ozone

Synthesis and molecular structure of 1α,10α: 9β,1β: 19β,28-triepoxy-A-neo-5β-methyl-25-nor-18α-oleane

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