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.通式为[(η⁵-C₅H₅)(η⁵-C₅H₄R)TiCl₂]的二氯二茂钛类化合物（其中R=5-脱氧-1,2-二-O-异亚丙基-3-O-苄基-α-D-呋喃木糖基-5-基（Xylf，8a）；R=5-脱氧-1,2-二-O-异亚丙基-3-O-苄基-α-D-呋喃核糖基-5-基（Ribf，8b））以及[(η⁵-C₅H₄R)₂TiCl₂]（R=Xylf，9a；R=Ribf，9b），可通过相应的环戊二烯基锂7a、7b与等物质的量的[(η⁵-C₅H₅)TiCl₃]，或0.5倍物质的量的四氢呋喃（THF）合四氯化钛[TiCl₄(THF)₂]反应制得。通式为[(η⁵-C₅H₄R₁)(η⁵-C₅H₄R₂)TiF₂]的二氟二茂钛类化合物（R₁=H，R₂=Ribf，10；R₁=R₂=Xylf，11a；R₁=R₂=Ribf，11b），可通过相应的二氯二茂钛8b与9与氟化试剂{2-[(二甲基氨基)甲基]苯基-κC,N}二正丁基(n-Bu)氟化锡以高收率经氟化反应得到。此外，配合物11也可通过[TiF₄(THF)₂]与2倍物质的量的相应环戊二烯基锂7a、7b直接反应，以简便的一步法制备。二茂铁类配合物[(η⁵-C₅H₄R)₂Fe]（R=Xylf，12a；R=Ribf，12b），可通过2倍物质的量的环戊二烯基锂7a、7b与1倍物质的量的无水氯化亚铁(FeCl₂)发生复分解反应合成。对二茂铁类化合物12的苄基基团进行脱保护，可在Pd/C催化加氢条件下平稳且高效地进行，得到二茂铁二醇类产物[(η⁵-C₅H₄R)₂Fe]（R=5-脱氧-1,2-二-O-异亚丙基-α-D-呋喃木糖基-5-基（Xylf-OH，14a）；R=5-脱氧-1,2-二-O-异亚丙基-α-D-呋喃核糖基-5-基（Ribf-OH，14b））。若采用三乙基硅烷(Et₃SiH)作为氢源进行放大规模的苄基脱保护反应，则仅会脱去一个苄基基团，得到二茂铁单醇类配合物[(η⁵-C₅H₄R₁)(η⁵-C₅H₄R₂)Fe]（R₁=Xylf，R₂=Xylf-OH，13）。所制备的全部配合物均通过元素分析、熔点测定、核磁共振波谱(NMR)、红外光谱(IR)以及电喷雾电离质谱(ESI-MS)进行了表征，其中配合物9b的分子结构经X射线衍射分析得以确定。采用MTT细胞增殖-毒性检测法，评估了配合物8~14对A2780以及顺铂耐药型A2780cis癌细胞的细胞毒活性。二氟二茂钛类化合物10、11以及二茂铁二醇14a对A2780细胞展现出中低微摩尔浓度范围的细胞毒活性，而活性最优的配合物11b，相较于顺铂对照品，对A2780cis细胞的细胞毒活性提升了约40%。