Enhancing computer‐assisted structure elucidation with DFT analysis of J‐couplings

Abstract

Computer-assisted structure elucidation (CASE) is the class of expert systems that derives molecular structures primarily from one-dimensional and twodimensional nuclear magnetic resonance data. Contemporary CASE systems, including Advanced Chemistry Development/Structure Elucidator (ACD/SE), consider cross-peaks in heteronuclear multiple bond coherence (HMBC) and correlation spectroscopy (COSY) spectra as two-or three-bond correlations by default. However, four and more bond correlations (nonstandard correlations [NSCs]) could be present in these spectra too. The indiscriminate addition of NSCs to the CASE computations is prohibitively expensive. To address this problem, the ACD/SE program performs a logical analysis of observed correlations and determines the minimum number of NSCs. Guided by this information, a more efficient fuzzy structure generation (FSG) algorithm is subsequently applied. Until now, the FSG algorithm was utilized without any verification of the reliability of found NSCs. Here, we report a verification method for NSCs based on the relationship between NSCs and J-couplings computed with high accuracy density functional theory (DFT) methods. We used the example of strychnine to show that 41 (32%) of 8-Hz HMBC crosspeaks were NSCs and were consistent with 4-6 J CH couplings greater than 0.3 Hz. This cutoff value was largely confirmed by the analysis of NSCs in 11 realworld natural products elucidated by ACD/SE. Additionally, utilizing the example of the CASE study of cleospinol A, we showed that the DFT-computed J-couplings of NSCs can distinctively differentiate the correct structure among six proposed isomers. The proposed approach of NSC verification should further improve the robustness of CASE analysis and can help reveal potential problems with reported experimental data.

ACD/Structure Elucidator: 20 Years in the History of Development

“…If several top ranked structures are characterized by close deviations, then the solution to the problem will be ambiguous. A method to resolve the ambiguity was suggested by Buevich and Elyashberg [56][57][58]. It has been reported [56,57] that the uncertainty in distinguishing the correct structure can be overcome by a DFT calculation of chemical shifts (and coupling constants if necessary) for the 4-6 top-ranked structures of the output file.…”

“…In a follow-up work [58] the application of DFT methods in CASE methodology was further expanded. The authors explored the possibility of applying DFT predictions of n J CH and n J HH couplings to confirm the correct structure selected by the ACD/SE program that utilizes the Fuzzy Structure Generation algorithm.…”

Computer Assisted Structure Elucidation (CASE): Current and future perspectives

“…CASE systems were traditionally based only on NMR chemical shifts. It was shown recently, [102] however, that the DFT-based calculation of n J HH and n J CH coupling constants corresponding to NSCs in the structures elucidated using ACD/SE in FSG mode can be used for verification of the solution reliability. Moreover, it was proved that long-range coupling constant calculation could serve as a tool for the selection of the most probable structure among a set of top-ranked structures generated in the FSG mode.…”

Application of INADEQUATE NMR techniques for directly tracing out the carbon skeleton of a natural product

“…88 Moreover, the NOAH super sequences can also incorporate NOESY (N) and/or a ROESY (R) "module" providing essential stereospecific information. 91 Since such super sequences provide all the essential information required for the structure elucidation of small molecules in a single measurement application of automated CASE systems [92][93][94][95] will allow routine deduction of even challenging proton deficient molecules and should be considered essential in all natural product elucidation campaigns. However, the versatility of the technique is such that it has been applied to challenging material such as fullerenes 22 but in this laboratory, it has been established as a routine technique to solve the unambiguous solution state structures of semisynthetic and synthetic analogues of natural products antimalarials (such as quinine derivatives, chloroquine, amodiaquine), antioxidants (Trolox C) and other compounds.…”