Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Abstract

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C-C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4 N][Ph3 SnF2 ], which directly constructs the crucial C-C bond at the C11 position in SEA. The NaV Ch-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

Keywords: aldol reaction; heterocylces; natural products; saxitoxin; total synthesis.