Environmental effects on molecular conformation: Bicalutamide analogs

Two bicalutamide analogs (N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfinyl-2-hydroxy-2-methyl-propane-amide 2 and its 4-cyano derivative 3) with an R-configured asymmetric carbon atom and a chiral sulfoxide group are described quantum chemically to determine their properties in dependence of their conformation and their (R,S)-configuration at the sulfoxide S atom. Compounds 2 and 3 are known to be novel androgen receptor antagonists with biological activities that depend significantly on the configuration of their stereogenic centers. For the purpose of a rapid differentiation between active and less active diastereomers of 2 and 3, relative energies, conformational preferences in different media, NMR chemical shift values, vibrational spectra, and vibrational circular dichroism (VCD) spectra are calculated for up to 12 different conformers. It is demonstrated that both 2 and 3 prefer strongly different conformations in dependence of the surrounding medium and as a consequence of the change from intra- to intermolecular H-bonding. The different diastereomers can be easily distinguished by specific NMR chemical shifts, infrared bands, or VCD rotational strengths.