Beckmann rearrangement of 11-deoxo-glycyrrhetic acid 3-ketoxime

Abstract

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.