Towards stereochemical and conformational assignment in flexible molecules using NOEs and molecular modelling

Abstract

The title methods are used firstly to assign the relative stereochemistry of the four diastereomers of a 2,3-dihydrobenzofuran derivative, and secondly to define the preferred conformation of one diastereomer. The experimental constraints are obtained from steady-state NOE measurements and coupling constants, and are compared to calculated values using low-energy conformations calculated using the molecular mechanics program PCMODEL. The significance of the results is assessed by using a statistical analysis, based on an estimation of the magnitude of experimental errors, which produced the correct relative stereochemistries, showed that the experimental data are not fitted by any single conformation, and generated a preferred conformation which is very similar to that found in an X-ray structure. The method can give information on the relative stereochemistry of chiral centres several bonds apart.