September 29, 2022
by Mikhail Elyashberg, Leading Researcher, ACD/Labs
Gancao Cyclooctenone A
The herb Radix Glycyrrhizae has been used as a traditional Chinese medicine for more than a thousand years. Zhao et al  isolated a novel symmetrical cyclooctenone compound and elucidated its structure (1).
This compound attracted attention not only because of the proposed bis-bridgehead alkenes (correspondence to the Berdt’s rule), but also for the tertiary-butyl groups. Although bis-bridgehead alkenes are known, there is very little precedent of biosynthetic t-butyl groups. To verify this structure, data from the publication  as well as the proposed structure were entered into ACD/Structure Elucidator (ACD/SE) and 13C chemical shifts were assigned to carbon atoms according to the NMR data presented in . 13C chemical shift prediction was performed afterwards, using the three methods implemented into ACD/SE – Incremental, HOSE-code based and Neural Networks. The results are presented in Figure 1.
We see that the average chemical shift deviations are of acceptable values and correspond to those which are usually calculated for correct structures. The maximum deviation observed using the HOSE-codes based approach is 8.01 ppm, which is a bit higher than usual. To explore whether there could be a possible alternative to the structure 1, the 1H, 13C, HSQC and HMBC data available from the work  were entered into ACD/SE (Table 1).
Table 1. NMR spectroscopic data.
|C Label||δC||δCcalc (HOSE)||CHn||δH||M||H to C HMBC|
|C 3||148.000||143.860||CH||6.700||u||C 8, C 5, C 1|
|C 5||149.300||145.790||CH||6.580||u||C 3, C 1|
|C 7||29.900||18.120||CH2||3.220||u||C 6, C 5, C 1|
|C 9||29.800||29.350||CH3||1.250||s||C 2|
|C 10||28.200||29.290||CH3||1.370||s||C 4, C 3, C 5|
The program automatically created a Molecular Connectivity Diagram (MCD) which is shown in Figure 2.
No contractions were detected in the HMBC data, and therefore the strict structure generation was initiated. As a result, four structures were generated in one second. After prediction of 13C chemical shifts and structure ranking in increasing order of dA deviations, the following result was obtained:
We see that the proposed structure 1 is the second in the ranked file. Structures #3 and # 4 received huge deviations and consequently can be reliably rejected. The validity of structure #1 was confirmed by the calculation of DP4 probabilities for structures #1 and #2 (Figure 4).
According to our methodology , further confirmation of the revised structure #1 was obtained because of 13C chemical shift prediction using the DU8+ option of DFT approach. It turned out that RMSD = 0.85 ppm was found for structure #1, which is definite evidence of its validity. The revised structure of cyclooctenone A with assigned 13C chemical shifts is shown below
This example clearly shows that if the authors had used a CASE program for the elucidation of the structure of cyclooctenone A in work , the wrong structure 1 would had not been deduced.
- S. Zhao, Y. Zhao, Z. Xiang. (2021). A novel symmetrical cyclooctenone from Radix Glycyrrhizae. Nat. Prod. Res., 35, 88-91.
- M. Elyashberg, I. M. Novitskiy, R. W Bates, A. G. Kutateladze, C. M. Williams. (2022). Reassignment of Improbable Natural Products Identified through Chemical Principle Screening. European J. Org. Chem. e202200572, https://doi.org/10.1002/ejoc.202200572 (open access)
- A.V. Buevich, M. E. Elyashberg. (2008). Towards unbiased and more versatile NMR-based structure elucidation: A powerful combination of CASE algorithms and DFT calculations. Magn. Reson. Chem., 56, 493–504. DOI: 10.1002/mrc.4645