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 [1] isolated a novel symmetrical cyclooctenone compound and elucidated its structure (1).
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s1.png)
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 [1] 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 [1]. 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.
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s2.png)
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 [1] 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 1 | 186.700 | 186.170 | C | |||
C 2 | 144.700 | 143.820 | C | |||
C 3 | 148.000 | 143.860 | CH | 6.700 | u | C 8, C 5, C 1 |
C 4 | 67.800 | 69.060 | C | |||
C 5 | 149.300 | 145.790 | CH | 6.580 | u | C 3, C 1 |
C 6 | 136.700 | 137.490 | C | |||
C 7 | 29.900 | 18.120 | CH2 | 3.220 | u | C 6, C 5, C 1 |
C 8 | 35.300 | 35.060 | C | |||
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.
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s3.png)
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:
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s4.png)
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).
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s5.png)
According to our methodology [3], 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
![](https://www.acdlabs.com/wp-content/uploads/2022/09/2022_09_s6.png)
This example clearly shows that if the authors had used a CASE program for the elucidation of the structure of cyclooctenone A in work [1], the wrong structure 1 would had not been deduced.
References
- 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