Total Synthesis of Saxitoxins

This review deals with our synthetic efforts for guanidine alkaloid of saxitoxin (STX), a paralytic shellfish toxin. STX shows potent inhibitory activity against voltage-gated sodium channels (NaVs), which are membrane proteins that involve in the generation and propagation of action potentials in neurons. More than 50 analogs of STX have been isolated from nature, and these analogs commonly possess characteristic tricyclic core skeleton including two kinds of 5-memberd and 6-memberd cyclic guanidine. For the synthesis of the core structure, we have developed a neighboring acyl group assisted cyclization strategy to give tricycle with a fully protected form of saxitoxinol under quite mild conditions. This key intermediate allows us total synthesis of (＋)-decarbamoyl saxitoxin (dcSTX), (＋)-gonyautoxin 3 (GTX3) including and STX. Besides, we have achieved the synthesis of 11-saxitoxinethanoic acid (SEA), which is an unusual STX derivative bearing carbon-carbon bond at the C11 position by applying Mukaiyama aldol condensation reaction with silyl enolether derived from the key intermediate of fully protected saxitoxinol. NaV inhibitory activities of some synthetic derivatives with C11-substituents in STX were also described.