The use of residual dipolar coupling for conformational analysis of structurally related natural products

Abstract

Determining the conformational preferences of molecules in solution remains a considerable challenge. Recently, the use of residual dipolar coupling (RDC) analysis has emerged as a key method to address this. Whilst to date the majority of the applications have focused on biomolecules including proteins and DNA, the use of RDCs for studying small molecules is gaining popularity. Having said that, the method continues to develop and here we describe an early case study of the quantification of conformer populations in small molecules using RDC analysis. Having been inspired to study conformational preferences by unexpected differences in the NMR spectra and the reactivity of related natural products, we showed that the use of more established techniques was unsatisfactory in explaining the experimental observations. The use of RDCs provided an improved understanding which, following use of methods to quantify conformer populations using RDCs, culminated in a rationalisation of the contrasting diastereoselectivities observed in a ketone reduction reaction.

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

“…RDCs encode for the relative orientation of internuclear vectors (e.g., CH bonds) with respect to the alignment tensor regardless of the distance between them. Hence, RDCs can be employed for determination of the relative configuration even in the presence of some degree of molecular flexibility . In an analogous way, the orientation between the principal axis system of chemical shielding tensors relative to the alignment tensor can be determined by measurement of residual chemical shift anisotropies (RCSAs).…”

“…Hence, RDCs can be employed for determination of the relative configuration even in the presence of some degree of molecular flexibility. [4][5][6][7][8] In an analogous way, the orientation between the principal axis system of chemical shielding tensors relative to the alignment tensor can be determined by measurement of residual chemical shift anisotropies (RCSAs). However, chemical shielding tensors, differently from the dipolar coupling ones, have an isotropic part, and therefore, measurement of RCSAs necessitates two different alignment conditions.…”

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

“…Indeed, the presence of structural conformers is very common in extraction procedures of natural products. [130][131][132] Therefore, to interpret data characterizations, such as data obtained by spectroscopy, and/or diffraction techniques, the optimized geometries of the target compounds can be useful. In this sense, RM1 semiempirical method was employed to evaluate various conformer possibilities of organic compounds that are formed during chemical reactions.…”

Computer‐Assisted 3D Structure Elucidation of Natural Products using Residual Dipolar Couplings

“…Scoring quantities, which penalize the number of employed independent variables, can be used to select the minimum ensemble (model) that explains the observed data within a given level of uncertainly. One of this model selectors is the Akaike information criterion (AIC), a selector based in information theory, which has been recently employed in RDC analysis of small molecules . In this context, the AIC is expressed as Equation : …”