Slowly Exchanging cis‐PtA2B2 Atropisomers with A2 = Chiral Diamine Ligands and B = 5,6‐Dimethylbenzimidazole

Abstract

Abstractcis‐PtA2G2 complexes, in which A2 is a bidentate amine ligand and G is a unidentate guanine derivative bound to platinum through N7, are simple models of the G‐G cross‐link DNA lesion formed by the anticancer drug cisplatin. Rotation of the G bases about the Pt–N7 bonds is usually rapid except for bulky amine ligand(s). This paper concerns cis‐PtA2(Me2Bzm)2 adducts [A2 = 2,2'‐bipiperidine (Bip)and N,N,N',N'‐tetramethyl‐2,3‐diaminobutane (Me4DAB); Me2Bzm = 5,6‐dimethylbenzimidazole] for which the interconversion among possible rotamers (one HH and two HT) is slow on the NMR time scale. The amounts of the rarely observed HH conformer were 52 and 37 % at 5 °C for BipPt(Me2Bzm)2 and Me4DABPt(Me2Bzm)2, respectively, and increased to 60 and 44 % at 50 °C. This result represents the first reported clear evidence for the existence of the HH atropisomer in cis‐PtA2B2 adducts (B = G or Me2Bzm base) with fully substituted diamines, such as Me4DAB or Me4EN (Me4EN = N,N,N',N'‐tetramethyl‐1,2‐diaminoethane). The lack of an O‐substituent on the C4 atom of Me2Bzm (corresponding to C6 of G) undoubtedly allows for a relatively stable HH conformer. Thermodynamic parameters confirm the crucial role of the substituents in positions 4 and 6 of the base systems (for Me2Bzm and G derivatives, respectively) in determining the stability of different rotamers. The greater abundance of the HH rotamer for BipPt(Me2Bzm)2 than for Me4DABPt(Me2Bzm)2 indicates that an increase in the steric bulk of the carrier ligand favors the HT rotamers over the HH rotamer. For both BipPt(Me2Bzm)2 and Me4DABPt(Me2Bzm)2 adducts, the major HT rotamer has the six‐membered ring of each Me2Bzm ligand on the more crowded side of the cis amine with respect to the platinum coordination plane: the N–CH2– group in Bip and the N–Meeq (N–Meeq = quasi‐equatorial N–Me) in Me4DAB adducts. The latter result is in complete agreement with previous findings from our laboratories concerning BipPtG2 and Me4DABPtG2 compounds and gives further support to the view that the major HT rotamer is stabilized by the six‐membered ring of each base canted toward the cis base. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)