Titanocene Dihalides and Ferrocenes Bearing a Pendant α-D-Xylofuranos-5-yl or α-D-Ribofuranos-5-yl Moiety. Synthesis, Characterization, and Cytotoxic Activity

Titanocene dichlorides of general formula [(eta(5)-C5H5)(eta(5)-C5H4R)TiCl2] (where R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-alpha-D-xylofuranos-5-yl (Xylf) (8a); R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-alpha-D-ribofuranos-5-yl (Ribf) (8b)) and [(eta(5)-C5H4R)(2)TiCl2] (R = Xylf (9a); R = Ribf (9b)) were prepared by reaction of the corresponding lithium cyclopentadienides 7a,b with an equimolar amount of [(eta(5)-C5H5)TiCl3] or a 0.5 mol amount of [TiCl4(THF)(2)]. Titanocene difluorides of the general formula [(eta(5)-C5H4R1)(eta(5)-C5H4R2)TiF2] (R-1 = H and R-2 = Ribf (10); R-1 = R-2 = Xylf (11a); R-1 = R-2 = Ribf (11b)) were obtained by fluorination of the corresponding titanocene dichlorides 8b and 9 with the fluorinating agent {2-(CH2NMe2)C6H4-kappa C,N}(n-Bu)(2)SnF in high yields. Alternatively, complexes 11 were prepared in a straightforward way by direct reaction of [TiF4(THF)(2)] with 2 equiv of the corresponding lithium cyclopentadienide 7a,b. Ferrocene complexes [(eta(5)-C5H4R)(2)Fe] (R = Xylf (12a); R = Ribf (12b)) were synthesized by metathesis of 2 equiv of lithium cyclopentadienide 7a,b and 1 equiv of anhydrous FeCl2. Deprotection of the benzyl group in ferrocenes 12 proceeded cleanly by a catalytic hydrogenation on Pd/C and afforded the ferrocene diols [(eta(5)-C3H4R)(2)Fe] (R = 5-deoxy-1,2-di-O-isopropylidene-alpha-D-xylofuranos-5-yl (Xylf-OH) (14a); R = 5-deoxy-1,2-di-O-isopropylidene-alpha-D-ribofuranos-5-yl (Ribf-OH) (14b)). A scaled up benzyl deprotection with Et3SiH as a hydrogen source led to the replacement of only one benzyl group, which gave the ferrocene alcohol [(eta(5)-C5H4R1)(eta(5)-C5H4R2)Fe] (R-1 = Xylf and R-2 = Xylf-OH (13)). The prepared complexes were characterized by elemental analysis, melting point determination, NMR, IR, and ESI-MS, and the molecular structure of 9b was determined by X-ray diffraction analysis. The cytotoxic activity of complexes 8-14 against A2780 and A2780cis cancer cells was evaluated by MTT tests. Titanocene difluorides 10 and 11 and ferrocene diol 14a showed cytotoxicity against A2780 cells in the medium to low micromolar range, while the most active species, 11b, displayed about 40% higher cytotoxicity against A2780cis in comparison to a cisplatin standard.