Effects of Six-Membered-Ring Conformation on the Rotamer Distribution and Rate of Atropisomerization in Platinum(II)−Guanine Compounds:  2,4-Bis(methylamino)pentane Complexes

NMR and CD spectroscopy and molecular mechanics and dynamics (MMD) calculations were used to characterize (Me 2 DAP)Pt(G) 2 complexes (G = N9-substituted guanine derivative; Me 2 DAP = 2,4-bis(methylamino)pentane with N, C, C, and N stereochemistries of S,R,S,R, S,R,R,R, and R,R,R,R ). NMR and MMD results indicated that the favored Me 2 DAP chelate ring conformations were chair. There are two possible head-to-tail rotamers (ΔHT and ΛHT) and, depending on the Me 2 DAP stereochemistry, one or two head-to-head (HH) rotamers. Rotation of the G bases around the Pt−N7 bond was found to be rapid on the NMR time scale for all compounds in D 2 O at room temperature; in contrast, slow rotation was reported for (Me 2 DAB)Pt(G) 2 (Me 2 DAB = 2,3-bis(methylamino)butane by Xu et al.) Because of the additional flexibility of the six-membered chelate ring in the Me 2 DAP systems versus the five-membered ring in Me 2 DAB, the N -methyl groups of Me 2 DAP can occupy more pronounced axial positions, allowing a low-energy path to rotation as suggested by MMD calculations. The fast rotation necessitated that the rotamer preference be assessed by CD spectroscopy. For the S,R,S,R complexes, the G N9 substituent strongly influenced which HT rotamer was preferred. The ΛHT rotamer was favored for the R,R,R,R complexes at pH 3 regardless of the G used. MMD calculations on the [( R,R,R,R )-(Me 2 DAP)Pt(9-EtG) 2 ] 2+ complex suggested amine-O6 hydrogen bonding in the ΛHT rotamer and indicated an unfavorable nonbonded interaction between the G O6 and an axial cis C -methyl group in the ΔHT rotamer. This nonbonded interaction was also observed in calculated structures of the [( S,R,R,R )-(Me 2 DAP)Pt(9-EtG) 2 ] 2+ complex, for which experimental data showed a preference for the ΛHT rotamer as well. Thus, the orientations of the N - and C -methyl groups appear to be important in determining both the rate of rotation and the rotamer preference of the (Me 2 DAP)Pt(G) 2 systems.