397 0009-3130/10/4603-0397 © 2010 Springer Science+Business Media, Inc. Chemistry of Natural Compounds, Vol. 46, No. 3, 2010 CHEMOSELECTIVE OXIDATION OF OLEANOLIC ACID DERIVATIVES WITH OZONE O. B. Kazakova, 1* N. I. Medvedeva, 1 O. S. Kukovinets, 1 UDC 547.824:542.91:548.737 G. A. Tolstikov, 1 E. F. Khusnutdinova, 1 L. Zaprutko, 2 B. Bednarczyk-Cwynar, 2 and Z. Paryzek 3 A method for preparing methyl esters of 12-oxoolean-28-oic and 3,12-dioxoolean-28-oic acids via ozonolysis of oleanolic acid methyl ester in CH 2 Cl 2 at –60°C was proposed. It was found that oxidation of 2-cyano- 3,4-seco-4(23)-oleanenoic acid was chemoselective depending on the amount of ozone used. Keywords: oleanolic acid, chemoselectivity, oxidation, ozonolysis. Oleanolic acid (1) belongs to a class of pentacyclic triterpenoids that is observed in >120 plants of various species (e.g., ginseng, apple and olive skin, calendulum and silphium flowerheads, white mistletoe, etc. [1]). It is responsible for several valuable medicinal properties of their extracts. Oleanolic acid and its derivatives exhibit a broad spectrum of pharmacological activity including hepatoprotective, anti-inflammatory, antimicrobial, antiviral, antitumor, etc. [2, 3]. Oleanolic acid is approved for use in China to treat liver diseases including hepatitis [4]. 2-Cyano-3,12-dioxoolea-1,9(11)-dien-28-oic acid (CDDO) inhibits proliferation of a large number of human tumor cells and is undergoing preclinical trials [5]. The nitrile of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid showed very strong inhibition of NO production in murine macrophages (IC 50 1 pM) [6]. The oleanolic acid ozonolysis product 3,12,13-trihydroxy-2813-olide was observed to inhibit -glucosidase, an enzyme controlling the glucose level in blood [7]. Thus, development of new synthetic approaches to transformations of oleanolic acid and its derivatives is a timely problem. Ozonolysis of polycyclic derivatives with a sterically hindered double bond occurs most often without destroying it [8, 9]. According to the literature [7], ozonolysis of oleanolic acid (1) occurs with formation of a C(12)-C(13) epoxide that reacts with the C(28)OOH carboxylic acid to form lactone 2. We showed that oleanolic acid methyl ester (3) reacts otherwise with ozone. Both the composition and structure of the products depend considerably on the amount of ozone passed through the solution. Passing two equivalents of ozone through a solution of 3 at –60°C forms 3-hydroxy-12-oxoolean-28-oic acid methyl ester (4) (Scheme 1). Increasing the amount of ozone to four molar equivalents per mole of 3 introduces a ketone at the site of the double bond and simultaneously oxidizes the C(3)-OH group to a ketone to form 3,12-dioxoolean-28-oic acid methyl ester (5) via oxidation by oxygen that is 1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, prosp. Oktyabrya, 71, Russia, e-mail: obf@anrb.ru; 2) Chair and Department of Organic Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences, Poland; 3) Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 336–338, May–June, 2010. Original article submitted December 3, 2009. HO COOH O 3 , CHCl 3 -MeOH 1 2 O HO O