Are Deterministic Expert Systems for Computer-Assisted Structure Elucidation Obsolete?

Abstract

Expert systems for spectroscopic molecular structure elucidation have been developed since the mid-1960s. Algorithms associated with the structure generation process within these systems are deterministic; that is, they are based on graph theory and combinatorial analysis. A series of expert systems utilizing 2D NMR spectra have been described in the literature and are capable of determining the molecular structures of large organic molecules including complex natural products. Recently, an opinion was expressed in the literature that these systems would fail when elucidating structures containing more than 30 heavy atoms. A suggestion was put forward that stochastic algorithms for structure generation would be necessary to overcome this shortcoming. In this article, we describe a comprehensive investigation of the capabilities of the deterministic expert system Structure Elucidator. The results of performing the structure elucidation of 250 complex natural products with this program were studied and generalized. The conclusion is that 2D NMR deterministic expert systems are certainly capable of elucidating large structures (up to about 100 heavy atoms) and can deal with the complexities associated with both poor and contradictory spectral data.

A systematic approach for the generation and verification of structural hypotheses

“…Structure generation and subsequent ranking of the candidate structures in descending order of their probability consumes only a few minutes on a modern processor using today's expert systems. [18] Obviously the application of QM methods can play a decisive role in such cases when the analyzed structures contain 'exotic' fragments that were absent from the training set. Another situation whereby QM prediction could help to identify a preferable structure may occur when the differences between the experimental NMR chemical shifts and those calculated by empirical methods for several 'best structures' are too small to enable a certain choice.…”

The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry

“…[5,6,22] The difference between the deviations d A ( 13 C) found for the second and first ranked structures is not large (0.2 ppm), but this value is frequently observed in the structure elucidation process when the 'best structure' is selected. [22] It is worthy to note that in the stereoisomers 3, 4, 6 and 9, atoms H-17 and H-19 are situated on opposite sides of the macrocycle and are unlikely to be close enough in space to show a ROESY coupling. Since the authors [15] made the final choice between structures A and C on the basis of comparison of differences between experimental and calculated 13 C chemical shifts of all carbon atoms, we also compared these values (Fig.…”

“…We investigated what results would be obtained if the problem is solved using 1D and 2D NMR spectra and the empirical chemical shift prediction methods implemented into the expert system Structure Elucidator. [5,6,22] To perform this analysis structure 1 was input into the system and all carbon and hydrogen atoms were supplied with chemical shifts in accordance with the author's assignment. Then all 2 5 = 32 streoisomers were generated by the program and depicted using conventional designations for stereobonds.…”

“…Figure 2 shows that the correct stereoisomer was distinguished both by its 13 C and 1 H average deviations. Our experiences in the field of computer-aided structure elucidation have shown [22] that the d A ( 1 H) deviation is a less reliable criterion compared with d C and it is usually only used for additional confirmation of the most probable structural isomer. [5,6,22] The difference between the deviations d A ( 13 C) found for the second and first ranked structures is not large (0.2 ppm), but this value is frequently observed in the structure elucidation process when the 'best structure' is selected.…”

“…Our experiences in the field of computer-aided structure elucidation have shown [22] that the d A ( 1 H) deviation is a less reliable criterion compared with d C and it is usually only used for additional confirmation of the most probable structural isomer. [5,6,22] The difference between the deviations d A ( 13 C) found for the second and first ranked structures is not large (0.2 ppm), but this value is frequently observed in the structure elucidation process when the 'best structure' is selected. [22] It is worthy to note that in the stereoisomers 3, 4, 6 and 9, atoms H-17 and H-19 are situated on opposite sides of the macrocycle and are unlikely to be close enough in space to show a ROESY coupling.…”