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Determination of Configuration and Conformation of a Reserpine Derivative with Seven Stereogenic Centers Using Molecular Dynamics with RDC‐Derived Tensorial Constraints **
Author(s) -
Sager Emine,
Tzvetkova Pavleta,
Gossert Alvar D.,
Piechon Philippe,
Luy Burkhard
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002642
Subject(s) - stereocenter , conformational isomerism , residual dipolar coupling , chemistry , tensor (intrinsic definition) , molecular dynamics , computational chemistry , singular value decomposition , conformational ensembles , configuration space , molecule , nuclear magnetic resonance spectroscopy , stereochemistry , computer science , physics , algorithm , mathematics , enantioselective synthesis , geometry , biochemistry , organic chemistry , quantum mechanics , catalysis
Abstract NMR‐based determination of the configuration of complex molecules containing many stereocenters is often not possible using traditional NOE data and coupling patterns. Making use of residual dipolar couplings (RDCs), we were able to determine the relative configuration of a natural product containing seven stereocenters, including a chiral amine lacking direct RDC data. To identify the correct relative configuration out of 32 possible ones, experimental RDCs were used in three different approaches for data interpretation: by fitting experimental data based singular value decomposition (SVD) using a single alignment tensor and either (i) a single conformer or (ii) multiple conformers, or alternatively (iii) using molecular dynamics simulations with tensorial orientational constraints (MDOC). Even though in all three approaches one and the same configuration could be selected and clear discrimination between possible configurations was achieved, the experimental data was not fully satisfied by the methods based on single tensor approaches. While these two approaches are faster, only MDOC is able to fully reproduce experimental results, as the obtained conformational ensemble adequately covers the conformational space necessary to describe the molecule with inherent flexibility.