A Test of the Single-Conformation Hypothesis in the Analysis of NMR Data for Small Polar Molecules: A Force Field Comparison

Abstract

A tricyclic ketone with seven stereogenic centers produced in >95:5 diastereomeric excess by an asymmetric Diels−Alder reaction has been subjected to a careful 2-D NMR(CDCl3)/MD analysis by Reggelin and co-workers and interpreted in terms of a single conformation in CDCl3 solution. The present work examines the validity of this interpretation. Specifically, the conformational profile of the endo isomer of the tricyclic ketone was examined by Monte Carlo searches with both the MM2* and MMFF force fields in MacroModel using the GB/SA CHCl3 solvent continuum model. The two sets of conformations were then combined and optimized with the MM3(96) force field. The structures of the resulting conformations and the NMR-derived geometric variables were together subjected to a NAMFIS analysis (NMR analysis of molecular flexibility in solution). Ideally, the procedure deconvolutes the thermally averaged NMR data into a small family of conformations that optimally represents the J-derived torsions and the NOE-derived ...