Ansa type compounds

Planar chirality occurring in cyclophanes and ansa-type compounds Presence of chiral side chain... 

Planar chirality occurs in cyclophanes and ansa type compounds. [2.2]Para-cyclophane is optically inactive. Its aromatic monosubstituted ring analogues can exist as optically active enantiomers despite the fact that there is no chiral carbon atom in these compounds [66] (Figure 2.22). 

A similar situation is encountered in ansa-type compounds (e.g., benzene derivatives in which para or meta positions are linked via heteroatoms containing bridge). In these compounds, as in cyclophanes, when a bridge is sufficiently short, the benzene ring rotation can be hindered, making feasible separation of individual optically active isomers. Figure 2.23 shows schematic representation of isomers of an ansa-type compound. 

FIGURE 2.23 Schematic representation of enantiomers of ansa-type compounds. 

The structure and absolute configuration of maytansine (72 R = H) has been established by V-ray crystallographic analysis of its 3-bromopropyl ether [72 R = (CH2)3Br]. °° Maytansine represents the first ansa macrolide-type compound that shows in vivo tumour inhibitory properties. ... 

A similar type of compounds, without the nitro group, was achieved by Wessjohann and coworkers (Scheme 15) [79]. Their approach also uses the Ugi reaction to build the linear peptoid intermediates, but a nucleophilic substitution is employed for the ring closure, which is a difficult task with a strained phenolate. A small library of macrocycles with general formula 15a was prepared, including also some 15-membered ansa-cycles (not shown). 

A p-anilyl-substituted an.va-titanocene 48 and titanocene 3 were tested on the growth of a wide variety of tumour cells in vitro on a panel 36 human tumour cell lines containing 14 different tumour types investigated in a cellular proliferations assay [34]. Titanocene 3 showed a significantly higher cytotoxic activity than the ansa-compound and reached, on average over the whole cell panel, the activity of cisplatin within a factor of 4. Nevertheless, there were three main targets for titanocene 3 identified, which are pleura mesothelioma, uterine and renal-cell... 

Compounds of the first type can be obtained starting Ifom butadiene zirconocene (with or without an ansa bridge). In the formation of (52), a pronounced property... 

The dialkyltitanium complexes shown in Scheme 76, supported by a macrocyclic ligand with a chelating imido side functionality, have been synthesized by treatment of the dichloro parent compounds with LiMe or LiCH2SiMe3 in benzene at room temperature. Comparisons between this macrocyclic ligand and ansa-bis-Cp and mono-Cp-amido-type ligands are established.151... 

Using the parent zirconocene-butadiene complex as a representative example, a typical bonding situation in these types of molecules is presented in Scheme 48. For 297, equilibration between the s-trans and the s-cis isomers occurs with a barrier of 23 kcal mol 1 at 283 K. The 72-olefin complex is believed to be a high-energy intermediate on the interconversion reaction surface. Significantly, structural data indicates that the s-cis complexes are best described as Zr(iv) compounds with a er2, ir ligand.158,175 The dynamic NMR measurements have also been extended to ansa-zirconocene and hafnocene butadiene complexes.176 Moreover, photoelectron spectroscopy has been used to determine the relative energetics of the two isomers for // -metallocenes.177... 

Lee and Chung reported a different approach that avoided using ethylene for the synthesis of the same type of aUcyl bridged ansa-zirconocenes 168. They reacted diyne 165 with norbornadiene giving a tricyclic compound which was functionalized with Me2CuIi to yield 166. When 166 was heated in a quartz tube at 420 °C, 167 was formed by means of a retro-Diels-Alder reaction followed by double bond isomerization (Scheme 49) [164]. 

The results obtained in the open series showed that the position of the ferrocenyl group and the nature of the substituents present on the molecule have a significant impact on the antiproliferative activity of the compounds. Another possible structural modification is to alter the nature of the ferrocenyl group. For example, the creation of a bond between the last carbon of the ethyl and the second cyclopentadiene ring immobilizes the ferrocenyl group in a fixed position relative to the rest of the molecule. This bond generates a new ferrocenyl derivative of the ansa-ferrocene or ferrocenophane type. The first derivative of ferrocenophane was synthesized by Plazuk et al. [128] in the form of a diphenol compound, 40 (Fig. 42.10). It was obtained by a McMurry coupling reaction between ferrocenophanone and dihydroxybenzophenone. 

Compound 40 shows an IC50 value of 0.09 0.01 p.M against MDA-MB-231 cells (Table 42.5), making it six times more active than ferrocidiphenol 15 (IC50 = 0.6 p.M). Another type of ansa compound is represented by 41. Its IC50 value is 0.96 0.03 p.M, showing that 41 is less active than hydroxyferrocifen 14 of the open series. 

---