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

Abstract

NMR-based determination of the configuration of complex molecules containing many stereocentersi so ften 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 an atural product containings even stereocenters, including a chiral aminel acking direct RDC data. To identify the correct relative configurationo ut of 32 possible ones, experimental RDCs were used in three different approaches for data interpretation:b yf itting experimental data based singularv alue decomposition(SVD) using as ingle alignment tensor and either (i)asingle conformer or (ii)multiple conformers,o ra l-ternatively (iii)using molecular dynamics simulations with tensorialo rientationalc onstraints (MDOC). Even thoughi n all three approaches one and the same configurationc ould be selected and clear discrimination betweenp ossible configurations was achieved, the experimentald ata was not fully satisfied by the methods based on single tensor approaches. While these two approaches are faster,o nly MDOCis able to fully reproduce experimental results, as the obtained conformational ensemble adequately coverst he conformational spacen ecessary to describe the molecule with inherent flexibility.

Molecular enantiodiscrimination by NMR spectroscopy in chiral oriented systems: Concept, tools, and applications

“…Also, as already mentioned above, important developments remain to perform concerning the computational prediction of solute orientational orders (in polypeptide‐based system as PBLG) based on molecular dynamics approaches. Several papers have been reported on the subject, so far 75,180–186 . However, contrasted results were obtained depending on the model/parameter used, and authors remain more or less cautious about the relevance of predicted results.…”

“…[187][188][189] Although some achievements were obtained for predicting orientation behavior of analytes interacting with achiral, nematic orienting solvents, 190,191 or even polypeptide-based achiral systems (PBG), 75 the case of two enantiomers interacting with helicalpolymer-based CLCs remains still problematic despite some recent progresses. [181][182][183][184][185][186][187] We can, however, mention the attractive description of a mean torque potential sensitive to the M/P chirality of helical solutes aligned in helical-particles-based anisotropic media leading to the absolute enantiorecognition, when combined with simulation of order parameters using Monte-Carlo F I G U R E 3 8 Simplified principle of fitting of experimental 2 H-RQC dataset to a possible set of possible structures. Figure adapted from reference 177 with permission methods.…”

Study and quantification of the enantiodiscrimination power of four polymeric chiral LLCs using NAD 2D-NMR

“…All data highlighting the factors/parameters involved in the molecular orientation processes and/or the chiral discrimination mechanisms (noted in short CDMs) in polymer-based lyotropic liquid crystals (LLCs) are key for three reasons: (i) to understand the molecular shape recognition phenomena in helical systems (polypeptide or other types of polymers) and their contribution to the global phenomenon; [1][2][3][4][5][6][7][8] (ii) to optimize the computer simulation of the solute orientational behavior, and the prediction of their anisotropic observables (by molecular dynamics, for example) [9][10][11][12][13][14] with the final aim of determining the absolute configuration of chiral molecules; 15,16 and (iii) to structurally design novel helically chiral polymers as new efficient enantio-discriminating aligning media. [17][18][19][20][21][22] Collecting these data experimentally by all possible anisotropic 1D/2D-NMR methods, in order to assess/quantify their respective roles/effects on the enantiodiscrimination properties, therefore deserves special attention.…”

Bayesian Inference Applied to NMR-Based Configurational Assignments by Floating Chirality Distance Geometry Calculations

“…In general, experimental NMR data such as intramolecular distances (nuclear Overhauser effects, NOEs) and residual dipolar couplings (RDCs) are either used to find conformations of structures of known relative configurations (NOE) or evaluated against precomputed molecular models (RDCs). Alternatively, restrained molecular dynamics (rMD) using, for example, RDCs could serve a similar purpose, − but then averages have to be computed from MD simulations for all diastereomers individually . This can represent a major obstacle with the exponentially growing number of diastereomers as a function of stereogenic elements, and rMD does not apply to multialignment media-derived RDCs .…”