A computer-assisted structural elucidation (CASE-3D) strategy based on the use of isotropic and/or anisotropic NMR data is proposed to elucidate relative configuration and preferred conformation in complex natural products. The methodology involves the selection of conformational models through the use of the Akaike Information Criterion and scoring of the different configurations. As illustrative examples, the methodology furnished the correct configuration of the already known compounds artemisinin (1) and homodimericin A (2). Revised structures (5 and 6), including their absolute configuration, for the recently reported curcusones I (3) and J (4) are proposed.

Determination of relative configuration is frequently a rate-limiting step in the characterization of small organic molecules. Solution NMR-based nuclear Overhauser effect and scalar J-coupling constants can provide useful spatial information but often fail when stereocenters are separated by more than 4-5 Å. Residual dipolar couplings (RDCs) can provide a means of assigning relative configuration without limits of distance between stereocenters. However, sensitivity limits their application. Chemical shift is the most readily measured NMR parameter, and partial molecular alignment can reveal the anisotropic component of the chemical shift tensor, manifested as residual chemical shift anisotropy (RCSA). Hence, (13)C RCSAs provide information on the relative orientations of specific structural moieties including nonprotonated carbons and can be used for stereochemical assignment. Herein, we present two robust and sensitive methods to accurately measure and apply (13)C RCSAs for stereochemical assignment. The complementary techniques are demonstrated with five molecules representing differing structural classes.

We developed a new program, MSpin-RDC for the analysis of residual dipolar coupling data. This software, specially designed for small molecule analysis, can directly read many molecular-modeling and popular chemistry file formats and accept RDC values as a simple free-format table. Alignment tensor can then be computed by singular value decomposition, as well as predicted using inertia and gyration tensor-based methodologies. Trial structures are then ranked according to their Cornilescu's quality factor (Q) values. Analysis of multiconformational problems and fitting of RDC data to relative populations can be accomplished using the single-tensor approximation.

Together we are strong: A new, robust method allows the measurement of residual chemical shift anisotropies for the determination of conformation and configuration of molecules in organic solvents. The power of the method is shown by the example of estrone and 13‐epi‐estrone (see structures), where only the combined use of residual chemical shift anisotropies and residual dipolar couplings leads to the distinction of the two diastereomers.

Quantum chemical studies of cyclizations of enediynes and enyne-allenes have proven to be computationally tractable thanks to the success of the unrestricted broken spin symmetry (UBS) approach using GGA functionals for the description of open-shell biradicals; the results can further be improved through single-point energy coupled-cluster computations [CCSD(T), BD(T)]. This made comprehensive computational studies on substituent effects and heterosubstituted systems possible. For convenience and predicting new reactions, these transformations can be grouped within larger "families". Alternative cyclization modes are predicted and await experimental realization.

An enhanced computer-assisted procedure for the determination of the relative configuration of natural products, which starts from the molecular formula and uses a combination of conventional 1D and 2D NMR spectra, and residual dipolar couplings (RDCs), is reported. Having already the data acquired (1D/2D NMR and RDCs), the procedure begins with the determination of the molecular constitution using standard computer-assisted structure elucidation (CASE) and is followed by fully automated determination of relative configuration through RDC analysis. In the case of moderately flexible molecules the simplest data-explaining conformational model is selected by the use of the Akaike information criterion.

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The cyclization reactions of polyunsaturated systems such as enediynes, enyne-allenes, as well as many others, can be structurally related to the Cope reaction and grouped into two branches: 6pi (e.g., Cope, allenyl-Cope) and [2sigma + 4pi] systems (e.g., Bergman, Myers-Saito). After extensive computional (BCCD(T)/cc-pVDZ//UBLYP/6-31G) examination of a large set of Cope-related reactions, we derive the following simple rule: biradical intermediates are involved along the reaction path if they are stabilized by allylic resonance or aromaticity.