Proceedings of the 2 nd International Seminar on Chemistry 2011 (pp. 156-159) Jatinangor, 24-25 November 2011 ISBN 978-602-19413-1-7 Aisyah & Didin Mujahidin 156 Synthesis of quinine-N-oxide Aisyah 1 , Didin Mujahidin 2, * 1 Chemistry Study Program, Faculty of Science and Technology, UIN Alauddin Makassar, Jl.Sultan Alauddin No. 36 Samata Gowa Makassar 2 Chemistry Study Program, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl. Ganesha No.10 Bandung *Corresponding author: didin@chem.itb.ac.id Abstract Quinine has long been used as an antimalarial drug, eventhough some strains of Plasmodium have recently shown resistancy toward quinine. Besides its important bioactivity, quinine also has been applied as the chiral ligands in several catalytic asymmetric reactions. The amine group at N-1 quinuclidine ring of quinine could be oxidized to quinine-N-oxide which could decrease basicity of the amine in the molecule. Quinine-N-oxide have been previously reported as a product from the biotranformation of quinine in Microsporum gypseum and as a unique metabolite isolated from endophytic fungi, Xylaria sp which hosted in Cinchona plant. However, due to its limited supply of quinine-N-oxide isolated from natural plants, its application is rarely investigated. Here we report the synthesis of quinine-N-oxide using a more simple methodology and a milder condition. By this procedure, quinine have been regioselectively oxidized to quinine 1-N-oxide without destroyed the quinine skeletone. Oxidation of quinine by a bubbling of ozone to the solution of quinine in acetone:water (95:5) with a low flow of ozone at temperature -12˚ to 0˚C produced quinine-N-Oxide in 72% yield. All spectroscopic data, including UV-Vis, FTIR, LC-MS, 1 H-NMR and 13 C-NMR and comparation data with literature indicates that the product is quinine-N-oxide. Keywords: asymmetric synthesis, chiral catalysis, ozone, quinine, quinine-N-oxide Introduction Cinchona alkaloids have been reported as metabolites of several species of cinchona plants. The two most popular are quinine and quinidine was formerly used as antimalarial and antiarrhythmic drugs. Recently, quinine mainly employed as a bitter additive in food and beverages industry (Song, 2009). Cinchona alkaloids not only function as bioactive compound, but also as catalyst in several asymmetric reactions. Sharples in 1987 introduced an asymmetric dihydroxylation (AD) of olefin by OsO 4 and N-methylmorpholine-N-oxide (NMO) using catalysis of quinine derivate. In 1992, AD was improved by using a chiral ligand as a co- catalyst which mimics the natural catalysis of protein binding pocket. This method utilized a class of phtalazine ligands named 1,4-bis(9-O- dihydroquinidine-phtalazine (DHQD 2 PHAL). In addition, many other asymmetric syntheses take the benefit of cinchona alkaloids as the catalyst, such as enone epoxidation (Corey & Zhang, 1999), asymmetric cycloadition (Kagan & Riant, 1992) and ketene-aldehyde cycloadition (Zhu et al., 2004). Quinine which is oxidized at the nitrogen of quinuclidin ring, is also a potential asymmetric catalyst. This metabolite is produced from the biotransformation of quinine in Cinchona pubescens by endophytic fungi, Xylaria sp (Shibuya et al., 2003). In addition, quinine-N-oxide has been isolated from Microsporum gipseum (Siebers-Wolf et. al., 1993). The problem in preparing this metabolite is the lack of raw material supply. HO N + H O N 1 6 5 4 2 3 10 11 7 8 9 1' 2' 3' 4' 5' 6' 7' 8' - O Figure 1 Quinine-N-Oxide Diaz-Arouzo & Cook (1990) synthesized this compound using a low concentration of hydrogen peroxide as the oxidant. Under this condition, the regioselectivity of the reaction is controlled so the oxidation is directed to the nitrogen of quinuclidine ring. However, it takes rather overnights reaction which will not be of efficient to be applied in industrial scale of production. Here, we introduce a simple methodology utilizing a flow of ozone to the quinine solution under a mild condition to oxidize at the desired site of reaction. Moreover, this condition aims to perform a group transformation only despite an olefin breakage.