Progress in the Total Synthesis of Saxitoxin

Abstract

Saxitoxin (STX) is a typical guanidinium neurotoxin initially identified in shellfish poisoning incidents and primarily biosynthesized by organisms such as freshwater cyanobacteria and marine dinoflagellates. As one of the most representative members of the natural paralytic shellfish toxin (PST) family, over 50 structural analogues of STX and its derivatives have been discovered to date. This toxin exerts its neurotoxicity by selectively inhibiting voltage-gated sodium channels (NaV), making it a valuable molecular tool in neuropharmacology and ion channel research. The compact tricyclic fused skeleton and highly polar diguanidinium structure of the STX molecule present significant challenges for its chemical total synthesis. Concurrently, the potential application value of this class of toxins and their derivatives in drug development has attracted considerable attention from synthetic chemists for decades. This review systematically summarizes the progress in the total synthesis of STX, critically evaluates the design concepts and key steps of different synthetic strategies, and provides an outlook on future directions in this field.