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.

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Conjugates of glycyrrhetic acid (GLA) with amino acids (L-isoleucine, -leucine, -valine, and -phenylalanine) were synthesized by the acid-chloride method using methyl or tert-butyl esters of the acids. Tests in MDCK cell culture showed that the GLA conjugate with phenylalanine exhibited high antiviral activity against influenza A/H1N1/pdm09 virus (ED 50 =4.4 Pg/mL, SI = 161).Chemical modification of plant triterpenoids has in the last decade produced a whole series of lead compounds that are medically promising as new antitumor, antiviral, and antidiabetic agents.The pentacyclic triterpenoid glycyrrhetic acid (GLA, 1) is the product from acid and enzymatic hydrolysis of glycyrrhizic acid, the principal constituent of Glycyrrhiza glabra L. and G. uralensis Fisher roots, and is a promising natural product for creating new drugs to treat and prevent oncological and inflammatory diseases, hepatoprotectors, antioxidants, antiulcer and antiviral agents, etc.[1]. The potential to produce new biologically active compounds through chemical modification of GLA has not been fully explored [2][3][4][5].In continuation of our research on the synthesis of new biologically active GLA derivatives, we synthesized aminoacid conjugates using GLA 3-O-acetate (2) as starting material. It was converted into acid chloride 3 via reaction with thionylchloride (SOCl 2 ) in benzene (Scheme 1). The amino acids were methyl or tert-butyl (t-Bu) esters of L-amino acid hydrochlorides and were acylated via reaction with 3 in CH 2 Cl 2 in the presence of Et 3 N or N-methylmorpholine (NMM) to afford conjugates 4-8 in 60-70% yields. The yields of the protected conjugates were higher if the amino-acid t-Bu esters were used as the amines.Analytically pure 4 and 5 were isolated by column chromatography (CC) over silica gel (SG). Conjugates 6-8 were reprecipitated from aqueous EtOH. The protecting groups were removed without further purification.Conjugates 4 and 5 in dioxane:MeOH were treated with aqueous NaOH (4 N) and acidified subsequently with HCl solution (5%) in order to remove the 3-O-acetyl and methyl ester. The t-Bu ester protecting group of 6-8 was removed by trifluoroacetic acid (TFA) in CH 2 Cl 2 at 20-22°C. Then, the 3-O-acetyl protection was removed in dioxane by alkaline hydrolysis using aqueous NaOH (4 N). The resulting compounds were chromatographed over SG to afford free GLA conjugates 9-12 containing free amino acids L-isoleucine (Ile), -leucine (Leu), -valine (Val), and -phenylalanine (Phe) in 53-57% yields.

Synthetic transformations of bioactive plant metabolites represent an active direction of modern organic and bioorganic chemistry that seeks to synthesize new biologically active compounds with new structures that are promising in medicine [1,2]. Beckmann rearrangement of triterpenoid ketoximes has been studied using as examples allobetulone [3], lupenone [4], β-amyrin [5], friedelin [6], 18α-and 18β-glycyrrhetic acids [7], and oleanolic acid [8]. As a rule, Beckmann rearrangement of triterpenoid 3-ketoximes forms lactams (aza derivatives) and 3,4-seco-nitriles. It was shown previously that aza derivatives of oleanolic acid are interesting as promoters of percutaneous transport of bioactive compounds [8]. This is very important for the development of external drug forms and cosmetics.In order to prepare new biologically active derivatives of 11-deoxo-glycyrrhetic acid (GLA) (1), one of the minor triterpenoids from roots of Glycyrrhiza glabra L. and G. uralensis Fisher, we performed synthetic transformations of the methyl ester of 11-deoxo-GLA (2) on ring A (Scheme 1). Oxidation of 2 by pyridinium dichromate (PDC) in CH 2 Cl 2 at room temperature produced the 3-ketone (3) in 70% yield, reaction of which with NH 2 OH⋅HCl in anhydrous Py by refluxing for 1 h formed the pure (TLC) 3-hydroxyimine (3-ketoxime) (4) in 84% yield. Its stereochemistry was not determined. The 13 C NMR spectrum of 4 contained a resonance at δ 166.5 ppm, which was shifted to strong field by 51 ppm compared with the spectrum of starting 3 as a result of forming the C=N-bond.Reaction of 4 with SOCl 2 in anhydrous dioxane at 10°C formed lactam 5, the methyl ester of A-homo-4-aza-3-oxo-11-deoxoolean-12-en-30-oic acid, as a result of a first-order Beckmann rearrangement. We demonstrated this previously using 3-hydroxyolean-9(11),12-dien-30-oic acid as an example [9]. The A-homo-4-aza derivative (5) was isolated in 76% yield after recrystallization from EtOH.

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