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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.
Journal article

Determination of Configuration and Conformation of a Reserpine Derivative with Seven Stereogenic Centers Using Molecular Dynamics with RDC-Derived Tensorial Constraints.

  • Sager E Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
  • Tzvetkova P Institut für Biologische Grenzflächen 4-Magnetische Resonanz, Karlsruher Institut für Technologie (KIT), Postfach 3640, 76021, Karlsruhe, Germany.
  • Gossert AD Novartis Pharma AG, Novartis Institutes for Biomedical Research, 4002, Basel, Switzerland.
  • Piechon P Novartis Pharma AG, Novartis Institutes for Biomedical Research, 4002, Basel, Switzerland.
  • Luy B Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
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  • 2020-08-04
Published in:
  • Chemistry (Weinheim an der Bergstrasse, Germany). - 2020
molecular dynamics
natural products
quinolizidine
reserpine
residual dipolar couplings
structure elucidation
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/213355
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