Synthesis of new polyoxapolycarboxylic ligands for lanthanide(III) ions complexation Silvio Aime, a Camilla Cavallotti, b Giancarlo Cravotto, c Giovanni B. Giovenzana b, * and Giovanni Palmisano d, * a Dipartimento di Chimica I.F.M., Via Giuria 7, 10125 Torino, Italy b Dipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, Via Bovio 6, 28100 Novara, Italy c Dipartimento di Scienza e Tecnologia del Farmaco, Via Giuria 9, 10125 Torino, Italy d Dipartimento di Scienze Chimiche e Ambientali, Via Valleggio 11, 22100 Como, Italy Received 21 April 2004; revised 21 May 2004; accepted 26 May 2004 Available online 19 June 2004 Abstract—The multidentate polyoxapolycarboxylic ligands 1 and 2 were obtained by a two-step synthesis from easily available chemicals. Preliminary data on their coordination properties are reported. Ó 2004 Elsevier Ltd. All rights reserved. In the last decade great efforts have been devoted to the development of new multidentate ligands for transition metal and lanthanide ions. The purpose was to obtain complexes whose stability, physical properties and bio- distribution would make them suitable as contrast agents for MRI (magnetic resonance imaging), 1 or as diagnostic–therapeutic radiopharmaceuticals 2 or as markers in fluorescence bioassays. 3 Most of these ligands were based on polyaminopolycarboxylic acids such as DTPA (diethylenetriaminopentaacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra- acetic acid) and many of their substituted or modified derivatives. 4 Recently interest has focused on polyoxa- polycarboxylic ligands, mainly in consideration of their easy synthetic accessibility. 5 Most of them derive from the carboxyalkylation of diols or triols, generating tetra- dentate or hexadentate ligands. 6 However, the com- plexation of lanthanide ions for medical applications requires a higher ligand denticity to achieve a sufficient thermodynamic stability. 4 In this paper we report the synthesis of two new poly- oxapolycarboxylic ligands (1 and 2, Fig. 1), containing 10 and 9 oxygen donor atoms, respectively. A pre- liminary assessment of the complexing ability of 1 towards lanthanide(III) ions is reported, in view of the potential diagnostic use of the corresponding paramag- netic complexes as contrast agents for magnetic reso- nance imaging (MRI). The synthesis of a high-denticity polyoxapolycarboxylic ligand was achieved by carboxylalkylation of the proper polyol substrate. The polyol chosen for this task was 2,2,6,6-tetrakis(hydroxymethyl)cyclohexanol 3, readily obtained in high yield by the base-catalyzed tandem cross-condensation–Cannizzaro dismutation of cyclo- hexanone with excess formaldehyde. 7 The choice of pentol 3 relied on the number of OH groups prone to functionalization (five, to yield a total of 10 donor groups after derivatization) and their conforma- tional arrangement, potentially favourable to metal chelation. O O O O O COOH COOH COOH COOH COOH OH O O O O COOH COOH COOH COOH 1 2 Figure 1. Keywords: Polyoxapolycarboxylic ligands; Lanthanide; MRI. * Corresponding authors. Tel.: +39-0321-37586; fax: +39-0321-375821 (G.B.G.); tel.: +39-031-2386440; fax: +31-031-2386449 (G.P.); e-mail addresses: giovenza@pharm.unipmn.it; giovanni.palmisano@ uninsubria.it 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.05.132 Tetrahedron Letters 45 (2004) 5901–5903 Tetrahedron Letters