Determination of the stereochemistry of natural products from nuclear magnetic resonance data by constrained molecular dynamics

We have developed a molecular modeling procedure to determine the relative configuration of a chiral molecule from nuclear magnetic resonance (NMR) data. Our procedure uses constrained molecular mechanics, and the constraints are interproton distances derived from the experimental nuclear Overhauser enhancement (NOE) data. The main feature is a period of high-temperature dynamics in which frequent inversions occur at most chiral sites. This allows the distance constraints to guide the molecule into configurations consistent with the NOE data. For molecules with complex ring systems, high-temperature dynamics alone may fail to invert certain chiral centers with sufficient frequency. We have countered this by allowing as an option additional inversions of selected chiral centers. The procedure tested successfully on organic molecules of known stereochemistry, with 5 to 17 chiral centers, provided that the number of available constraints was at least twice the number of chiral centers. The procedure is tolerant of large errors in the estimated interproton distances and is reasonably rapid. For a series of sugars, the time required increases less than quadratically with the number of atoms. © 1996 by John Wiley & Sons, Inc.