Molecular structures of two tetrodotoxin analogs containing a monooxa-hydrocarbon cage: A computational study

• Two tetrodotoxin (TTX) analogs are investigated by DFT calculations.
• Each TTX analog possesses a monooxa-hydrocarbon cage.
• Structural changes are monitored by the chemical shifts computed with GIAOs.
• A QTAIM analysis reveals the different properties of the cage critical points.
• The carbon atom of the guanidinium moiety is positively charged.

Using quantum chemical calculations we investigate the molecular structures of two tetrodotoxin (TTX) analogs recently isolated from the Japanese toxic newt Cynops ensicauda popei. These novel analogs are characterized by a monooxa-hydrocarbon cage with a direct C5–C10 bond that replaces one of the ether bridges in the canonical dioxa-adamantane cage of TTX. The computed change in the 13C NMR chemical shifts is in good agreement with the change in the corresponding experimental values that results from the above chemical modification. This confirms the chemical structure assigned to the TTX analogs. A topological analysis of the theoretical electronic charge density indicates that the removal of the oxygen bridge in TTX increases the magnitude of the charge density at the cage critical point. A database search indicates that the monooxa-hydrocarbon cage is also present in other natural products such as cinnzeylanine and platensimycin whose molecular structures have been characterized by single-crystal X-ray diffraction analyses.

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