Chemoselective oxidation of oleanolic acid derivatives with ozone

Казакова, О. Б.; Medvedeva, N. I.; Куковинец, О. С.; Толстиков, Г. А.; Khusnutdinova, É. F.; Zaprutko, Lucjusz; Bednarczyk–Cwynar, Barbara; Paryzek, Z.

doi:10.1007/s10600-010-9627-0

Cited by 11 publications

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“…We recently showed that oxidation of oleanolic acid methyl ester with an excess of ozone produced 3,12-dioxoolean-28-oic acid [7]. Oxidation of 11-deoxoglycyrrhetic acid occurred analogously to form the 3,12-diketone [5].…”

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Oxidation of ursolic acid by ozone

et al. 2011

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Oxidation of methyl esters of ursolic and 3-acetoxyursolic acids by ozone formed products with a 12-oxo-11S,13R-oxetane moiety on ring C.Oleanolic (1) and ursolic (2) acids are classified as pentacyclic triterpenoids and have been detected in more than 100 plants of various species (e.g., apple and olive skins, ginseng root, calendula and silphium inflorescences, white mistletoe, etc.[1]). Their extracts exhibit several valuable medicinal properties.An effective method for functionalizing triterpenoids is oxidation by ozone [2][3][4][5]. For example, 3E,12D,13E-trihydroxy28o13-olide, the ozonolysis product of oleanolic acid, was discovered to inhibit D-glucosidase, the enzyme responsible for the blood glucose level [6].We recently showed that oxidation of oleanolic acid methyl ester with an excess of ozone produced 3,12-dioxoolean-28-oic acid [7]. Oxidation of 11-deoxoglycyrrhetic acid occurred analogously to form the 3,12-diketone [5]. Ozonolysis of ursolic acid derivatives has not been reported.We established that the product from reaction of acetylursolic acid methyl ester (3) with an excess of ozone was 12-oxo-11,13-epoxide (oxetane) 4 (Scheme 1). Moreover, the C-3 hydroxyl of ursolic acid methyl ester (5) was stable to the action of ozone, in contrast with oleanolic and 11-deoxoglycyrrhetic acids [5,7]. The reaction produced 3E-hydroxyoxetane 6.

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“…Moreover, the C-3 hydroxyl of ursolic acid methyl ester (5) was stable to the action of ozone, in contrast with oleanolic and 11-deoxoglycyrrhetic acids [5,7]. The reaction produced 3E-hydroxyoxetane 6.…”

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Oxidation of ursolic acid by ozone

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“…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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“…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].…”

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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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