Abstract
(+)-Saxitoxin, a potent and reversible blocker of voltage-gated sodium channels, has attracted considerable interests as a scaffold for the development of novel analogs. Here, we report the design and synthesis of a tetracyclic analogue featuring an additional cis-fused five-membered ring (C5-C6), constructed via a novel photoinduced radical cycloaddition reaction. This transformation efficiently established the quaternary carbon center at C5, which is difficult to access by conventional methods. Although the IC(50) values of two analogues against hNa(V)1.4 showed a significant decrease in potency, this work introduces a new chemotype of saxitoxin, offering a foundation for future optimization efforts.