DETERMINATION OF CONFORMATION AND RELATIVE CONFIGURATION OF A SMALL, RAPIDLY TUMBLING MOLECULE IN SOLUTION BY COMBINED APPLICATION OF NOESY AND RESTRAINED MD CALCULATIONS

The conformation and relative configuration of seven stereogenic centers in a small, rapidly tumbling molecule have been determined simultaneously in CDCl3 by 2D NOE spectroscopy and restrained MD calculations. Two different methods of evaluating interproton distances from NOESY data were applied and their merits and drawbacks are discussed. The usefulness of the proton detected heteronuclear long range correlation experiment (HMBC) for the assignment of diastereotopic protons is demonstrated. A new approach for the determination of the relative configuration is introduced. By utilizing NOE restraints within molecular dynamic simulations that are larger than the energetic terms responsible for maintaining chirality, the chiral centers can switch and adopt the configuration consistent with the experimental measurements. This approach is illustrated here with the title compound 1 which is extremely well determined by the experimental constraints (58 distance restraints). It adopts a single conformation in CDCl3 solution with structural features similar to corresponding molecular fragments of X-ray structures from similar molecules.