First example of the solvent effect on absolute conformation of chiral 3,3-disubstituted 1,4-benzodiazepin-2-ones

Abstract

Chiral 3,3-disubstituted 1,4-benzodiazepin-2-ones (3S)- 7 and (3S)- 8 reveal solvent dependent conformational equilibria. The conformer with absolute P-conformation, with CH 2X (X = p-tosyl, Cl) group in a pseudoaxial (ψa) position and CH 2OAc group in a pseudoequatorial (ψe) position, prevails in nonpolar solvents, as shown by 1H-NMR and CD spectra. For (3S)- 7 only a small shift of the conformational equilibrium in a polar solvent (DMSO) is observed, whereas compound (3S)- 8 inverts to a prevailing M-conformer. The inversion barrier for M P equilibrium is estimated on the bases of TDNMR data. For compounds (3R)- 5 and (3S)- 7, 8 the relative stability of the M P conformers in the ground state is calculated by the MM2 method; comparison of these results with CD and 1H-NMR data reveal that nonpolar solvents invert the relative stability calculated for the two conformers.