Preparation of a new ruthenium(II) building block for the synthesis of mixed-metal complexes Isabelle Meistermann, Ganna V. Kalayda, Anna C. G. Hotze and Jan Reedijk * Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands Received 15 October 2003; revised 21 January 2004; accepted 30 January 2004 Abstract—A new tris(dimine)ruthenium(II) complex containing a free flexible tail on one ligand, available for the coordination of a second metal, has been synthesised. Ó 2004 Elsevier Ltd. All rights reserved. The field of bioinorganic chemistry has been rapidly developing and offers enormous potential for medicinal chemistry and real opportunities to the pharmaceutical industry. The worldwide success of the square-planar platinum(II) complex cis-diamminedichloroplatinum (cisplatin) as a leading anti-cancer drug, 1 has boosted research into the development of new metallo-drugs. Over recent years, the field has expanded further, and is now looking at the possibility of using transition-metal ions other than platinum. 2 Using different metals would give possibilities such as having additional co-ordination sites, different oxidation states and ligand affinities, as well as providing the opportunity for photodynamic therapy. 3 More recently, research groups have started looking at the possibility of coupling different metal complexes with different activities and modes of action with the purpose of synergising their effect and devel- oping more effective chemotherapeutic agents. 4;5 A new ruthenium(II) building block, with potential DNA photocleavage properties and a long flexible arm side chain available for binding another biologically active metal complex, has now been designed (Fig. 1). Based on the literature, 6 a ruthenium complex contain- ing different didentate ligands was prepared. The ligands, 1,4,5,8-tetra-azaphenanthrene (tap, 2) and a tetraazatriphenylene derivative (tatpd, 3), were chosen because they are commonly used for Ru(II) photoclea- vage agents. 7 Bridging ligand 3 synthesised from 1,10- phenanthroline-5,6-dione 4 (Fig. 2) possesses a long and flexible tail, which would enable the two metals to per- form their biological function independently. The suc- cessful synthesis of complex 1, is described in this paper. The synthesis of [Ru(tap) 2 (tatpd)] 2þ 1 required the preparation of 1,4,5,8-tetra-azaphenanthrene 2, 1,10- phenanthroline-5,6-dione 4 and the diamino-propionic acid derivative 8, which was necessary for the synthesis of the bridging ligand. 1,4,5,8-Tetra-azaphenanthrene was synthesised in four steps from the commercially available 4-nitro-1,2-phenylenediamine, as described by Nasielski-Hinkens et al. 8 1,10-Phenanthroline-5,6-dione 4 was prepared from the commercially available 1,10- phenanthroline according to a literature procedure by Nord en and co-workers. 9 The diamino-propionic acid derivative was prepared as shown in Scheme 1 and is described below. Scheme 1 summarises the three-step synthesis of 2,3- diamino-N-(7-tert-butoxycarbonylaminoheptyl)-propio- namide 8. N,N 0 -Di-trifluoroacetyl-2,3-diaminopropionic acid 6, prepared from 2,3-diaminopropionic acid Keywords: Ruthenium; Synthesis; Bridging ligand; Flexible arm. * Corresponding author. Tel.: +31-715274451; fax: +31-715274671; e-mail: reedijk@chem.leidenuniv.nl Figure 1. Spartan generated model of [Ru(tap) 2 (tatpd)] 2þ 1. 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.01.150 Tetrahedron Letters 45 (2004) 2593–2596 Tetrahedron Letters