Synthetic and Computational Studies on the ABC Trioxadispiroketal Subunit of the Marine Biotoxin Azaspiracid-1.

The trioxadispiroketal residue in the marine biotoxin azaspiracid-1, which exists in a configuration capable of exhibiting a double anomeric effect, is believed to be the thermodynamically most stable bis-spiroketal diastereomer. In order to get insight into how structural factors affect this equilibrium, a simplified ABC trioxadispiroketal analog of azaspiracid-1 was synthesized and subjected to equilbration and computational studies. Compound 7, which represents a double anomeric effect was obtained as the major isomer, together with diastereomers 14 and 15, in a respective ratio of 62:22:16. DFT calculations for 7, 14 and 15 qualitatively matched this observation. These results suggest that while a double anomeric effect may play a major role in the stability of the trioxadispiroketal configuration in the more complex natural product, the substitution pattern of the C ring is also a contributing factor.