Ab Initio Calculations on N-Methylmethanesulfonamide and Methyl Methanesulfonate for the Development of Force Field Torsional Parameters and Their Use in the Conformational Analysis of Some Novel Estrogens

We recently reported the isolation and structure determination of a novel estrogen (1), the phenyl ester of an ortho-substituted tritylsulfonic acid, isolated from commercial preparations of phenol red. The relative binding affinity of the sulfonate 1 and of three analogues (the corresponding sulfonamide 2, carboxylate 3, and carboxamide 4) for estrogen receptor suggests that the spatial disposition of the pendant phenyl ring is a critical factor in determining their affinity. Ab initio calculations on two model compounds, methyl methanesulfonate (5) and N-methylmethanesulfonamide (6a), reveal in the case of 5 a single-fold torsional barrier of 10.1 kcal/mol, an energy minimum at the torsion angle (C-S-O-C) = 180°, and 2.2-kcal/mol shoulders at the torsion angles ±120°. By contrast, the sulfonamide 6a shows a 2-fold torsional barrier (9.2 kcal/mol when both methyl groups are eclipsed and 7.5 kcal/mol when the N-H eclipses the S-CH₃ bond); the two energy minima are at the torsional angles (C-S-N-C) = -98.7° and +71.7°, respectively, the latter being 1.5 to 1.9 kcal/mol higher in energy. However, the two conformers may be interconverted by nitrogen inversion, with a hindrance of 2.2 kcal/mol. Torsional force-field parameters for the modeling program CHARMm were developed by a least-squares fit to a truncated Fourier series. For appropriate minimization of conformations of the sulfonamide, we adopted a strategy to allow for nitrogen inversion, by setting the improper torsional angles around nitrogen to zero. Conformational analysis of compounds 1-4 reveal that minimum energy conformers of the low affinity compounds 3 and 4 project the pendant phenyl ring into a tight half-torus, over and around the 1,2-disubstituted ring of the trityl system, while in the highest affinity compound (1, sulfonate) the pendant phenyl ring is disposed on the opposite side of the torus. The sulfonamide 2, which has intermediate binding affinity, has some higher energy conformations where the pendant phenyl group shares space with that of the sulfonate 1. The relative energies of the various conformational minima of the systems 1-2 are within the range of computational and experimental determinations.