Configurational Analysis by Residual Dipolar Coupling Driven Floating Chirality Distance Geometry Calculations

Abstract

A new method implemented into a computer program (ConArch ) has been developed and applied to demonstrate the successful implementation of residual dipolar couplings (RDCs) in distance geometry (DG) calculations for the configurational assignment of chiral compounds. Unlike established protocols, the new approach combines floating chirality (fc) in 4D- and 3D-distance bounds driven dynamics (DDD) calculations with structural information from RDCs. Thus, relative configurations of chiral compounds were generated only by observables (e.g., NOEs, RDCs) rendering tedious evaluations of calculated structures against RDCs obsolete. We demonstrate the potential of this novel procedure by the simultaneous determination of the configuration and the conformation of three natural products, (-)-isopinocampheol (1), tubocurarine (2), and vincristine (3), as well as for diisopropylidene-β-d-fructopyranose (4).

2H and 13C NMR‐Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists

“…An interesting opportunity of this unexpected orientational property of PLA/PBLG mixtures may be the possibility to determine simultaneously two alignment tensors for a given solute in a single sample. Given the fact, that complex stereochemical and structural problems often require the analysis of multi‐alignment data sets, this beneficial behavior of the polymer mixture could be of great practical value ,,…”

Configurational analysis by residual dipolar couplings: A critical assessment of diastereomeric differentiabilities

“…A,B, A set of nine experimental residual dipolar couplings (RDCs) X = D exp and the back‐calculated values Y = D calc (as reported in Immel et al are compared with two diastereomers of IPC, 1a (model 1) and 1b (model 2). Based on the higher Pearson correlation coefficient r P and the lower Q ‐factor, model 1a (for which the data have been measured) seems to fit the data better than its C‐2 epimer 1b , yet a “quantitative reliability” is provided by neither the 95% confidence and prediction intervals (A,B) nor by comparing the distributions of the Pearson coefficients (C) or Q ‐factors (D) obtained from a 100,000 step Monte‐Carlo (MC) error analysis (all MC steps were carried out assuming errors in experimental RDCs of ±0.5Hz, and structure errors in bond lengths ±1% and angles ≈ ± 1.75 ° ).…”

“…Moreover, additional experimental data, eg, RDCs from multiple alignment media (MA), can be included in a straightforward way. The Z ‐test methodology simply requires an expansion of the correlation vectors XY 1⋯ k to include additional RDC data (first evaluations have already proven that the use of the MA approach significantly increases the diastereomeric differentiabilities of models), and in the A kaike analysis, the AIC scores only need to be added up for the multialignment data sets.…”

“…In particular, the latter quickly becomes prohibitively expensive when evaluating even moderately sized and flexible analytes. In this context, we have recently devised and implemented a new method that combines very fast restrained distance geometry (rDG) calculations with floating chirality RDC‐driven distance bounds–driven dynamics (DDD), which renders tedious verifications or falsifications of DFT‐derived structures against RDCs obsolete . Relying solely on experimental observables (no FFs) and without the necessity of having to initially generate 2 n‐1 diastereomeric structures, the RDCs exert forces that drive the DDD simulated annealing.…”

“…Thus, the structures automatically evolve from input structures of arbitrary configuration and conformation driven by experimental NMR parameters, rather than only being finally evaluated against them. Moreover, the floating chirality approach is enhanced by sampling in 4D and 3D space, because configurational inversions in 3D become simple rotations in 4D, and configurational and conformational space is sampled with high efficiency …”