Ozonolysis of 11-desoxoglycyrrhetic acid and its derivatives

Abstract

12-Oxo derivatives of 11-desoxolycyrrhetic acid and its derivatives were produced by oxidative transformation using ozone. acid was produced for the first time by exhaustive ozonolysis of 11-desoxoglycyrrhetic acid at -60°C.Oxidative transformations of bioactive plant triterpenoids is of great interest for preparing new oxygenated derivatives, seeking selective oxidizing reagents, and studying structure-activity relationships of derivatives of natural compounds. Introduction of additional oxygenated functional groups into triterpenoids can significantly affect their biological activity [1][2][3].Ozone is an effective and ecologically clean oxidant that has been used in various studies to prepare oxygenated derivatives of oleanolic acid and 18β-glycyrrhetic acid (GLA), the principal triterpenoid from licorice roots (Glycyrrhiza glabra L. and G. uralensis Fisher). It had been thought that the C12=C13 olefinic bond does not react with O 3 due to steric hindrance [4][5][6]. Prolonged (50 h) ozonation of GLA methyl ester acetate produced the methyl ester of 3-acetoxy-12,13-epoxy-18β-olean-11-on-30-oic acid in 40% yield [5].The goal of our work was to study transformations of 11-desoxo-GLA (1) and its derivatives 2 and 3 that were caused by ozone. 1: R = R 1 = H; 2: R = H, R 1 = Ac; 3: R = Me, R 1 = H Ozonolysis of 11-desoxo-GLA (1) in CH 2 Cl 2 at -60°C until ozone appeared at the outlet from the flask (until the solution turned blue) and subsequent reduction of the reaction products with Zn powder in CH 3 COOH for 1 h at 0°C produced a mixture of products that was separated by column chromatography (CC) over silica gel (SG). Compound 4 (36% yield), which was identified by its PMR and 13 C NMR spectra as olean-3,12-dion-30-oic acid (Scheme 1), and starting 1, the TLC and PMR spectrum of which agreed with a known sample, were isolated pure from the oxidation products.The PMR spectrum of 4 had seven singlets for methyls and a resonance for proton β-H13 at 2.8 ppm with spin-spin coupling constant 4 Hz. This was typical of derivatives of β-amyrin triterpenoids with oxygenated functional groups on C12 [4,7]. The 13 C NMR spectrum of 4 had resonances for 30 C atoms including typical resonances for C3=O and C12=O at 216.9 and 212.7 ppm, respectively. The chemical shifts for C12 and C13 (50.2 ppm) in 13β-H ketone 4 were similar to those of 13β-H-12-oxo-derivatives of oleanolic acid [8] and confirmed its configuration.

Chemoselective oxidation of oleanolic acid derivatives with ozone

“…Apparently the capability of C(3)-OH for facile oxidation depends on the type of triterpene framework. Analogous transformations were noted for glycyrrhetic acid derivatives and their mechanism was proposed [10]. Nevertheless, we have not observed oxidation by ozone of the alcohol groups of betulin derivatives.…”

Does One Keto Group Matter? Structure‐Activity Relationships of Glycyrrhetinic Acid Derivatives Modified at Position C‐11

“…Recrystallization from methanol yielded 3 (29.09 g, 91.1%) as a colourless crystalline solid; mp 254-2588C (lit. 254-2588C [12], 254-2568C [17], 248-2508C [18,19] Methyl 3b-hydroxy-oleana-9(11),12-dien-30-oate (4) To a solution of 3 (240 mg, 0.49 mmol) in dry THF (10 mL), borane (1 M in THF, 7 mL, 7 mmol) was slowly added. After 20 h of stirring at 258C, ethyl acetate (25 mL) was added and the organic layer was washed with a solution of citric acid (10%), a saturated solution of sodium hydrogen carbonate and water.…”

Oxidation of ursolic acid by ozone

“…Oxidation of 11-deoxoglycyrrhetic acid occurred analogously to form the 3,12-diketone [5]. Ozonolysis of ursolic acid derivatives has not been reported.…”

“…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].…”