Computer‐Assisted 3D Structure Elucidation (CASE‐3D): The Structural Value of ²J_CH in Addition to ³J_CH Coupling Constants

Abstract

We present a method to use long‐range CH coupling constants to derive the correct diastereoisomer from the molecular constitution of small molecules. A set of 79 2JCH and 3JCH values collected from a single HSQMBC experiment on a sample of strychnine were used in the CASE‐3D (computer‐assisted 3D structure elucidation) protocol. In addition to the most commonly used 3JCH coupling constants, the subset of 32 2JCH values alone showed an excellent degree of configuration selection. The study is mainly based on comparison of DFT‐calculated 2,3JCH values with experimental ones, critical for the case of 2JCH. But the configuration selection also works well using 3JCH values predicted from a semi‐empirical Karplus‐based equation limited to H−C−C−C fragments. The robustness, shown using strychnine as a proof of concept, makes the J‐based CASE‐3D analysis a viable option for the application in fields such as peptide and carbohydrate research, organic synthesis, natural‐product identification and analysis, as well as medicinal chemistry.

Synergism of anisotropic and computational NMR methods reveals the likely configuration of phormidolide A

“…A recent report has demonstrated the utility of long-range Jcoupling constants for diastereomeric analysis. 30 Due to the computational demands of modelling such a highly flexible molecule, the models were truncated at C24 with only eight isomers considered. These isomers corresponded to isomeric permutations at the C7, C17 and C21/C23 stereocenters.…”