Synthesis of new semi-synthetic dipodands and tripodands from naturally occurring polyether ionophores Adam Huczyn ´ ski a , Agata Doman ´ ska a , Izabela Paluch a , Joanna Stefan ´ ska b , Bogumil Brzezinski a, * , Franz Bartl c a Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland b Medical University of Warsaw, Department of Pharmaceutical Microbiology, Oczki 3, 02-007 Warsaw, Poland c Institute of Medical Physics and Biophysics Charité, Universitätsmedizin Berlin Campus Charité Mitte, Ziegelstr. 5/9, 10117 Berlin, Germany article info Article history: Received 22 April 2008 Revised 17 June 2008 Accepted 26 June 2008 Available online 1 July 2008 Keywords: Ionophores Monensin Lasalocid Synthesis Podands Antimicrobial activity abstract A new method to synthesize novel esters of Lasalocid acid 2–5 and of Monensin A, 7–9 (semi-synthetic di- and tripodands) is described. These new compounds are characterized by spectroscopic and microbi- ological methods. Ó 2008 Elsevier Ltd. All rights reserved. Typical podands have non-cyclic structures, in which several polyether chains are linked to the same binding centre, which can be N, P, Si or S atoms. Because of their specific properties, they are the so-called open-chain analogues of crown ethers and crypt- ands. Like these compounds, podands are able to form stable com- plexes with monovalent cations. 1 Due to this property, podands are used as promising anion activators in organic reactions and as suit- able ligands for solid–liquid phase transfer catalysis. 1–5 The two parameters that influence the ability of podand complex formation with cations 1 are the number of oxygen atoms and the varying length of the polyoxaalkyl chains. Typical podands show relatively low cation selectivity during complex formation as well as a lim- ited capacity to recognize selectively chiral compounds. 1,3–5 In the present study, we report the synthesis, spectroscopic and microbiological characterization of several new derivatives of Monensin A and Lasalocid acid, which can be defined as semi- synthetic dipodands and tripodands. In these new compounds the natural polyether ionophore moieties are connected by a hexamethyl- ene linker or bound to a benzene-1,3,5-trimethylene species. Lasalocid acid 1 and Monensin A 6 (Scheme 1) are carboxylic polyether ionophores isolated from Streptomyces lasaliensis and Streptomyces cinnamonensis, respectively. They are lipophilic che- lating agents of cations and are able to transport cations across lipid membranes of cells. 6 Monensin A exhibits significant preference to form complexes with monovalent cations, 7 such as Li + , Na + ,K + , Rb + , Ag + and Tl + , whereas Lasalocid acid is able to form complexes with mono- and bivalent metal cations, 8 such as Na + , Ag + , Ca 2+ and Ba 2+ . Both Monensin and Lasalocid derivatives also exhibit excellent enantiomer selectivity for chiral amines. 9 Both Monensin A and Lasalocid acid are very sensitive to acidic conditions and heating. For this reason we investigated mild reaction conditions for their esterification. We found a reliable strategy for the esterification of 1 and 6 based on direct alkylation of the carboxylate ions using alkyl bromides [1,3,5-tris(bromo- methyl)benzene or 1,6-dibromohexane] and 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU) as the catalyst. 10,11 The syntheses of compounds 2–5 and 7–9 are shown in Scheme 1. Using this ester- ification procedure, the thermally unstable carboxylic ionophores yielded stable esters without any indication of decomposition such as decarboxylation or other degradation processes. This esterifica- tion reaction shows, however, a remarkable solvent dependence. Among the solvents used (dichloromethane, chloroform, aceto- nitrile and toluene) the highest yield of the respective ester was obtained in toluene, probably because of the optimal solubility of the reactants and products in this solvent. All the products were purified easily by column chromato- graphy on silica gel. The structures of the esters were determined 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.06.116 * Corresponding author. E-mail address: bbrzez@amu.edu.pl (B. Brzezinski). Tetrahedron Letters 49 (2008) 5572–5575 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet