Revisiting the Structure of Cacospongionolide E: An Approach Based on Empirical Rules and NMR Calculations

In the field of natural product chemistry, the structures of several marine natural products have been erroneously determined. Here, we revisited the originally proposed structure of cacospongionolide E (1) using empirical rules in ¹³C NMR chemical shift analysis and density functional theory (DFT)-based NMR chemical shift calculations. Cacospongionolide E (1) is a marine natural product isolated from the Tyrrhenian sponge Fasciospongia cavernosa. Its originally proposed structure was established as sesterterpenoid of the trans-trans (TT) type, which adopts the trans-trans configuration of the 5-CH₃/10-H-8-CH₃/9-CH₃ fragment. However, the present analysis based on empirical rules revealed that the reported ¹³C NMR chemical shifts of cacospongionolide E were more consistent with those of cis-trans (CT) type 2, which adopts the cis-trans configuration of the 5-CH₃/10-H-8-CH₃/9-CH₃ fragment, than those of TT type 1. Furthermore, DFT-based ¹³C NMR chemical shift calculations, followed by the DP4 analysis, revealed that the reported ¹³C NMR chemical shifts of cacospongionolide E were more consistent with the calculated chemical shifts of CT type 2 than those of TT type 1. Thus, we propose the stereochemical revision of the structure of cacospongionolide E from the originally proposed structure 1 to our proposed structure 2. The study findings show that the proposed approach based on empirical rules and DFT-based NMR chemical shift calculations can identify the incorrect structures of marine natural products and provide the candidate for the correct structures.