Model-Free Approach for the Configurational Analysis of Marine Natural Products

Abstract

The NMR-based configurational analysis of complex marine natural products is still not a routine task. Different NMR parameters are used for the assignment of the relative configuration: NOE/ROE, homo- and heteronuclear J couplings as well as anisotropic parameters. The combined distance geometry (DG) and distance bounds driven dynamics (DDD) method allows a model-free approach for the determination of the relative configuration that is invariant to the choice of an initial starting structure and does not rely on comparisons with (DFT) calculated structures. Here, we will discuss the configurational analysis of five complex marine natural products or synthetic derivatives thereof: the cis-palau’amine derivatives 1a and 1b, tetrabromostyloguanidine (1c), plakilactone H (2), and manzamine A (3). The certainty of configurational assignments is evaluated in view of the accuracy of the NOE/ROE data available. These case studies will show the prospective breadth of application of the DG/DDD method.

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

“…This is possible because “wrong” configurations can change during a molecular dynamics simulation in 4D space with a pseudo-force field restraining only observables from NMR data and distance ranges from the constitution. 54–59…”

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

“…17 In addition, molecular dynamics relies on physical force-fields, which may introduce a bias toward "low-energy" diastereomers; prominent examples in this context are the palau'amine congeners with high-energy trans-fused five-membered rings. 18 The interpretation of NOE and RDC data requires quality-of-fit measures that compare the experimental data with back-calculated values and are used to deduce the correct relative configuration of a given compound from the best-fit model. The χ 2 sum of squared violations (ΔX 2 ) of experimental and back-calculated parameters weighted by their squared standard deviations (σ X ) is an information criterion of this type (eq 1).…”

“…The negative Cartesian gradients −δE/δr set the forces under which the simulated models evolve as described in previous reports. 18,23,29 It is important to note that this procedure relies neither on any conventional (physical) force-field (FF) or any other parameters nor on any other precalculated structures. Here, molecular conf igurations and conformations can change dynamically, and in particular, configurational inversions become barrier-free, as in 4D space these are reduced to simple rotations only.…”

Programmable alignment media from self-assembled oligopeptide amphiphiles for the measurement of independent sets of residual dipolar couplings in organic solvents

“…19 Very recently the groups of Reggelin and Thiele proposed to make use of independent sets of RDCs as a means to resolve de novo the stereochemical conguration of organic compounds. [20][21][22][23] The increased amount of information provided by the use of independent data sets can, in principle, avoid the use of the generation of trial congurations. In principle, the independent data set should be obtained in alignment media as closely related as possible to minimize changes in the conformational space and this means the use of the same solvent.…”

“…A fundamental main prerequisite of these methods is the acquisition of multiple independent RDC datasets in the same organic solvent system. 20,[41][42][43] Furthermore, the effective measurements of RDC data in multiple alignment media have also been revealed to be essential for the extraction of dynamic properties of the molecules, 44,45 and paving the way for the determination of the relative conguration of small molecules using simulations of the alignment process. 46 To this end, the development of alignment media, with sufficiently divergent orientations, for the measurement of independent RDC datasets is urgently needed.…”