**3. Conclusions**

In this study, we have shown with the aid of five examples of natural products, that the ROEs or NOEs/RDCs driven floating chirality distance geometry (fc-rDG/DDD) approach represents a valuable method to assign the configuration (and conformation) of complex molecules in just one single calculation. Given the known constitution of a compound, the method produces all configurations that are in accordance with the experimental NMR data, without the necessity to carry out separate configurational and conformational analyses on 2*<sup>n</sup>*−<sup>1</sup> diastereomers for *n* stereogenic centers. In the case of the marine natural products **1**–**3**, the relative configuration of eight stereogenic centers is unequivocally derived in just one instead of individual 128 simulations. In addition, it was demonstrated for the terrestrial alkaloids **4** and **5**, that the DG method also clearly reveals remaining ambiguities if NOE data alone is insu fficient for configurational assignments–as e.g., for the long-range separated stereogenic centers of **4**–and indicates to the NMR spectroscopist that additional data such as RDCs has to be acquired. Successively adding RDC data obtained for di fferent alignment media as additional restraints to the DG calculations is straight forward, and can be easily repeated until the level of confidence of the assignment is raised beyond any reasonable doubt.

The method discussed here neither requires individual treatment of alternate diastereomers under consideration, nor does it rely on force-field based MM/MD or DFT derived pre-calculated structures. In particular the use of force-field parameters–which may not even be available for uncommon structural fragments of natural products–in the traditional MD approach introduces an implied bias towards low-energy structures (in a thermodynamic sense) that might be misleading as in the case of tetrabromostyloguanidine (**2**). Here, the correct configuration of two *trans*-anellated five-membered rings is about 24 kJ mol−<sup>1</sup> less favorable than the more stable wrong configuration with *cis*-fused rings (which represents the original palau'amine configuration from 1993 [64–68]; see Figure 11), and any MD approach would have to overcome this pronounced bias in order to identify the correct configuration of **2**.

Most importantly, the methodology outlined here does not depend on pre-calculated structures that are traditionally evaluated against experimental data, but DG represents the opposite approach, which produces structures that evolve from experimental restraints exclusively. The "FF- and DFT-free" types of simulations are unbiased, reliable, and fast (completed within minutes), and the NMR data itself governs the mode with which these structures emerge.

The full methodology outlined here for the interpretation of NOEs/ROEs and RDCs has been implemented in our ConArch+ (Configurational Architect) program, which also produces convenient pseudo energy and configuration sorted lists that were used for all plots presented here. The software can be obtained along with the source code (free of charge for academic institutions) from our web site (https://www.chemie.tu-darmstadt.de/reggelin).

**Figure 11.** Selected structure plots underpinning the importance of an unbiased rDG/DDD approach compared to the traditional force-field based rMD approach: the left plot of tetrabromostyloguanidine (**2**) features a wrong configuration of two C–11/C–12 *cis*-anellated five-membered ring systems, which is energetically significantly favored over the correct configuration with an *trans*-type anellation of both ring systems (energy difference given based on DFT B3LYP/6-311+G(2d,p) optimized structures including thermal corrections at *T* = 298.15 K, the lower dibromopyrrole ring and the side chain have been removed for clarity).
