| Description |
The bis-guanidinium natural product saxitoxin (STX) and its natural congeners isolated from various marine sources have attracted many chemists due to their fascinating structure and relevance to voltage-gated sodium ion channel research. Utilizing a metal-catalyzed hydroamination approach developed previously in the Looper laboratory, we accessed the bis-guanidinium tricyclic core present in STX in a modular and robust fashion. This intermediate was amenable to the synthesis of natural and unnatural analogs of STX such as N7-PMBSTX and (−)-STX. In collaboration with the Du Bois laboratory, we studied these molecules in the context of probing voltage gated sodium ion channel (Nav). Among the >50 alkaloids structurally related to STX, zetekitoxin AB (ZTX) is the only natural product isolated from terrestrial environments. This bis-guanidinium toxin was first isolated in 1969 by Mosher and coworkers from the Panamanian golden frog Atelopus zeteki, a critically endangered species. However, thirty years passed until Yamashita and coworkers revealed the structure of this toxin in 2004. The key structural features of ZTX include the STX core, a 1,2-isoxazolidine ring fused in a macrocyclic lactam, and a pendant N7-hydroxymethyl carbamic acid linkage. In addition to this complex structure, ZTX acts a potent antagonist of Nav in comparison to STX. With previous methodology to access the STX core in hand, we initiated a synthetic strategy to access ZTX. While exploring these synthetic strategies, an intermolecular enolate C11-alkylation method made possible the synthesis of 11-saxitoxinethanoic acid, a natural iv analog of STX isolated from the xanthid crab Atergatis floridus belonging to Shikoku Island, Japan. As a convergent strategy to accomplish the arduous task of synthesizing ZTX, we performed a stereocontrolled synthesis of 1,2-isoxazolidine ring present in ZTX and attempted various inter- and intramolecular approaches to construct the macrocyclic ring. These studies have delivered key insights into the reactivity of the tricyclic bis-guanidinium core. |
