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 [(η5-C5H5)­(η5-C5H4R)­TiCl2] (where R =
5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-α-d-xylofuranos-5-yl
(Xylf) (8a); R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-α-d-ribofuranos-5-yl (Ribf) (8b)) and [(η5-C5H4R)2TiCl2] (R = Xylf (9a); R = Ribf (9b)) were prepared by reaction of the corresponding lithium
cyclopentadienides 7a,b with an equimolar
amount of [(η5-C5H5)­TiCl3] or a 0.5 mol amount of [TiCl4(THF)2]. Titanocene difluorides of the general formula [(η5-C5H4R1)­(η5-C5H4R2)­TiF2] (R1 = H and R2 = Ribf (10); R1 =
R2 = Xylf (11a); R1 = R2 = Ribf (11b)) were obtained by fluorination of the
corresponding titanocene dichlorides 8b and 9 with the fluorinating agent {2-(CH2NMe2)­C6H4-κC,N}­(n-Bu)2SnF 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 [(η5-C5H4R)2Fe] (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 [(η5-C5H4R)2Fe] (R = 5-deoxy-1,2-di-O-isopropylidene-α-d-xylofuranos-5-yl (Xylf-OH)
(14a); R = 5-deoxy-1,2-di-O-isopropylidene-α-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 [(η5-C5H4R1)­(η5-C5H4R2)­Fe]
(R1 = Xylf and R2 = 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.