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Dichocetide D Structure Elucidation

 

 

November 10, 2022

Dichocetide D

Shaker et al. [1] recently reported the isolation of Dichocetide D (1) from the marine fungus Dichotomomyces cejpii under oxygen stress conditions.

The structure of dichocetide D was revised by Elyashberg et al [2] on the basis of chemical considerations and utilization of ACD/Structure Elucidator (ACD/SE). The reported structure 1 is surprising as it is reported to contain two chlorohydrin groups (i.e. α-chloroalcohols). Such groups would be expected to decompose to hydrogen chloride and the corresponding aldehyde. Even the corresponding α-chloroethers are highly water sensitive. Thus, it seems unlikely that such a structure is possible, especially in a marine natural product.

To check the validity of compound 1, its structure and the 13C chemical shifts assigned in [1] was entered into ACD/SE together with the other published NMR spectroscopic data (HMBC) (Table 1).
Table 1.NMR spectroscopic data.

Label δC δC Calc (HOSE) XHn δH H to C HMBC
C 1 70 68.33 CH 4.2 C 2, C 3
C 2 46.1 46.18 CH2 3.74
C 3 68.5 70.25 CH2 4.07 C 1, C 4
C 4 156.2 156.74 C
C 5 114.1 115 CH 6.82 C 7
C 6 128 127.77 CH 7.14 C 4
C 7 144 143.65 C
C 10 41.9 42 C
C 11 31.1 31.42 CH3 1.64 C 10, C 6, C 7

Calculation of 13C chemical shifts was carried out using the empirical methods implemented into the program. Figure 1 shows the results.

Figure 1. Structure of dichocetide D (1) proposed by Shaker et al [1] for which 13C chemical shift prediction was carried out using HOSE code-based method, neural networks, and incremental approach. Average deviations of 13C chemical shifts determined by these methods are denoted as dA, dN and dI correspondingly. Each atom is colored to mark a difference between its experimental and calculated 13C chemical shifts. The green color represents a difference between 0 to 3 ppm, yellow was >3 to 15 ppm.

Figure 1 shows that the central part of the structure (green fragment) is in excellent agreement with the predicted 13C NMR data, while the maximum difference between experimental and calculated shifts for the chain carbons is 13 ppm. As a result, the average deviation values exceed those commonly found for correct molecules (1.5-2.5 ppm).

To solve the problem, a Molecular Connectivity Diagram (MCD) was created (Figure 2).

Figure 2. Molecular connectivity diagram (MCD) of dichocetide D. The hybridization of carbon atoms is marked by the corresponding colors: sp2 – violet, sp3 – blue, sp2 or sp3 (not sp) – light blue. Labels “ob” and “fb” are set by the program to carbon atoms for which neighboring with heteroatom is either obligatory (ob) or forbidden (fb). HMBC correlations are marked by green arrows.

Checking the MCD for the presence of nonstandard correlations (nJCH, n>3) was completed with the message: “Current Molecular Connectivity Diagram (MCD) passed all tests”. Therefore, strict structure generation was initiated, but no structure was generated. This is a hint to the fact that latent nonstandard correlations (NSCs) are present into the HMBC data. Missing these NSCs during the logical analysis of MCD may happen in 10% of cases because of the nature of the checking algorithm

Therefore, Fuzzy Structure Generation (FSG) was performed, with the generation options determined by the program automatically. Results: k = 19 → (structural filtering) → 5 → (duplicate removal) → 4, tg= 0.5 s.

13C chemical shift prediction was carried out for the structures generated and the output file was ranked in increasing order of dA(13C ) values (Figure 3).

Figure 3. The output structural file ranked in increasing order of dA deviations. Nonstandard correlations (NSCs) are marked by red arrows.

We see that predicted chemical shifts of the first ranked structure match remarkably with the experimental ones, which allows one to unambiguously determine the correct structure of dichocetide D. The structure with assigned carbon atoms is shown below

The solution obtained fully confirms the chemical considerations which led to the conclusion that structure 1 is unstable.

References

  1. S. Shaker, T.-T. Sun, L.-Y. Wang, W.-Z. Ma, D.-L. Wu, Y.-W. Guo, J. Dong, Y.-X. Chen, L.-P. Zhu, D.-P. Yang, H.-J. Li, W.-J. Lan. (2021). Reactive Oxygen Species Altering the Metabolite Profile of the Marine-Derived Fungus Dichotomomyces cejpii F31-1. Nat. Prod. Res., 35, 41–48.
  2. M.E. 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

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