The Advanced Floating Chirality Distance Geometry Approach―How Anisotropic NMR Parameters Can Support the Determination of the Relative Configuration of Natural Products

Abstract

The configurational analysis of complex natural products by NMR spectroscopy is still a challenging task. The assignment of the relative configuration is usually carried out by analysis of interproton distances from NOESY or ROESY spectra (qualitative or quantitative) and scalar (J) couplings. About 15 years ago, residual dipolar couplings (RDCs) were introduced as a tool for the configurational determination of small organic molecules. In contrast to NOEs/ROEs which are local parameters (distances up to 400 pm can be detected for small organic molecules), RDCs are global parameters which allow to obtain structural information also from long-range relationships. RDCs have the disadvantage that the sample needs a setup in an alignment medium in order to obtain the required anisotropic environment. Here, we will discuss the configurational analysis of five complex natural products: axinellamine A (1), tetrabromostyloguanidine (2), 3,7-epi-massadine chloride (3), tubocurarine (4), and vincristine (5). Compounds 1–3 are marine natural products whereas 4 and 5 are from terrestrial sources. The chosen examples will carefully work out the limitations of NOEs/ROEs in the configurational analysis of natural products and will also provide an outlook on the information obtained from RDCs.

Poly(arylisocyanides) as Versatile, Enantiodiscriminating Alignment Media for Small Molecules

“…The experimental RDCs ( 1 D exp ) together with DFT optimized structures (B3LYP/6‐311+G(d,p)) were used to calculate the alignment tensor by singular value decomposition [26] using our recently developed software package ConArch + [1a,b,8–9] . Following the standard procedure for the verification or falsification of structure models, the alignment tensor serves as a basis to back‐calculate theoretical RDCs [7] .…”

“…Recently, a conceptionally different approach (implemented into the new software ConArch + ) [8] has been introduced avoiding this verification or falsification of calculated structures. Herein, starting structures of an arbitrary configuration evolve under the influence of all types of isotropic and anisotropic NMR‐data into final structures of correct relative configuration [1b,8–9] …”

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

“…The lists of distance restraints for the DG calculations were constructed from the initial guess primary structures, using bond-lengths-derived upper and lower distance bounds (taken as ±1%), respectively; a detailed description of the DG methodology is given in Ref. [ 17 ]. The experimental interproton distances derived from NOESY or ROESY spectra were utilized with default error margins of ±10%, respectively.…”

“…Although recently, the application of anisotropic NMR data, such as residual dipolar couplings (RDCs) or residual chemical shift anisotropy (RCSA), has become more and more popular, the cross-relaxation (NOE or ROE) from which interproton distances can be obtained is still a major source of structural information. The use of NOE- or ROE-derived interproton distances for the configurational analysis is a mature technique [ 15 , 16 ] that can be amended by including RDCs in restrained distance geometry (rDG) simulations in a protocol that we have discussed in detail very recently [ 17 ]. Herein, we will concentrate on the NOE/ROE-restrained distance geometry [ 18 , 19 , 20 ] and distance bounds driven dynamics method (rDG/DDD) [ 21 , 22 ], which is, from our point of view, the method of choice for the configurational analysis of small organic molecules with several stereogenic centers [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…In all dynamics and optimization calculations, the partial derivatives ( for all atoms) of this pseudo energy term, with respect to 4D and 3D Cartesian atomic coordinates, are interpreted and used as forces governing the evolution of the system; a detailed description of this procedure is given in Refs. [ 17 , 21 , 22 ]. Finally, all emergent structures are ranked and sorted by their pseudo energies (total error; sum of total violations), and the lower this “energy” becomes, the more likely the corresponding molecular geometry represents the correct configuration (and conformation) of the compound under investigation ( Figure 1 ).…”