Synthesis, optical resolution and absolute configuration of inherently chiral calixarene carboxylic acids M.A. Kliachyna a , O.A. Yesypenko a , V.V. Pirozhenko a , S.V. Shishkina b , O.V. Shishkin b , V._. Boyko a , V.I. Kalchenko a, * a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02660 Kyiv-94, Murmanska Str., 5, Kyiv, Ukraine b STC ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, Lenin Ave., 60, Kharkiv 61001, Ukraine article info Article history: Received 6 March 2009 Received in revised form 19 May 2009 Accepted 11 June 2009 Available online 17 June 2009 Keywords: Inherently chiral calixarenes Diastereomers Enantiomers Optical resolution abstract Both enantiomers of inherently chiral calixarene carboxylic acids with ABCD substitution patterns have been prepared by the benzoylation of 25-propoxy-27-(R)-N-(a-phenylethyl)amidomethyloxycalix[4]arene followed by resolution of the diastereomers formed, monobromination of them and removal of the benzoyl and a-phenylethylamide auxiliary groups. The absolute configuration of the calixarenes obtained has been established by X-ray analysis. Preliminary study of the chiral recognition properties of calixarene carboxylic acid was performed. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Calixarenes due to their unique vase-shaped structure are widely used as effective and selective receptors of ions and mole- cules. 1 Chiral calixarene-based receptors able to bind and recognize optical antipodes of chiral ‘guests’ attract considerable attention. 2 The compounds can be used as ligands for metallocomplexing catalysts 3 or organocatalysts 4 for asymmetrical synthesis, enan- tioselective sensors, 2a,5 chiral stationary phases for column chro- matography, 6 chiral shift reagents for NMR 7 etc. Of particular interest are ‘inherently’ chiral calixarenes the chirality of which derives from the asymmetric substitution of macrocyclic platform. 8 Despite a great number of ‘inherently’ chiral calixarenes being described, most of them have been obtained as racemates or di- astereomeric mixtures. 9 Only a few of them have been resolved into individual isomers 9b–12 and characterized by X-ray structural ana- lysis. 5b,9b,10,12a Therefore, the development of effective methods for the synthesis of optically pure inherently chiral calixarenes and determination of their absolute configuration is of great importance. In this work, we report on the simple and effective synthesis of optically pure inherently chiral calix[4]arenes with ABCD substitution pattern, determination of their structure in solution and crystalline state, and preliminary chiral recognition result. 2. Results and discussion Chiral calix[4]arenes 3a and 3b showing an ABCD substitution of the macrocycle have been obtained from 25-propoxy-calix[4]arene 1 13 in two stages (Scheme 1). The reaction of calixarene 1 with 1 equiv of chiral (R)-N- (a-phenylethyl)bromoacetamide in the presence of K 2 CO 3 in refluxing acetonitrile gave 25-propoxy-27-(R)-N-(a-phenylethyl)amido- methyloxycalix[4]arene 2 in 98% yield. The structure of compound 2 was proved by 1 H and 13 C NMR analysis. Characteristic signals of ArCH 2 Ar methylene protons appearing as four pairs of overlapping AB doublets with an average coupling constant 2 J HH ¼13.3 Hz and the difference between resonances of the axial and equatorial protons (Dd is near 0.8 ppm) confirmed the cone conformation of calixarene 2. 14 In the 13 C NMR spectrum of calixarene 2, the carbon atoms of the methylene bridges occured as four signals between 31.38 and 31.61 ppm, which is typical for the cone conformation. 15 Due to the asymmetrical carbon atom on the narrow rim, some protons and carbon atoms of calixarene 2 show diastereotopicity: the ArCH 2 Ar protons (four pair of overlapping doublets); hydroxyl groups (two singlets at 7.51 and 7.56ppm); OCH 2 protons of propyl group (multiplet at 3.84–3.90 ppm); and methylene protons of OCH 2- C(O)NHCH(Me)Ph residue (a pair of doublets at 4.48 and 4.57 ppm). * Corresponding author. Tel.: þ38 044 559 06 67; fax: þ38 044 573 26 43. E-mail address: vik@ioch.kiev.ua (V.I. Kalchenko). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.06.039 Tetrahedron 65 (2009) 7085–7091 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet