Ciguatoxin (CTX1B) and its congeners, naturally occurring polycyclic ethers originating from marine unicellular alga, are the principal toxins associated with ciguatera fish poisoning. These compounds are extremely potent neurotoxins that bind to voltage-sensitive Na^+-channels (VSSC) and inhibit depolarization to allow Na^+ influx to continue. The structural complexity and exceptionally potent neurotoxicity, as well as their scarcity in natural sources, have attracted the interest of synthetic community. Practical synthetic access to ciguatoxins and their designed unnatural analogues are required for further studies aimed at fully defining the structural basis for their high-affinity binding to VSSC and/or its activation. We have recently developed a highly convergent synthetic route to the fused polycyclic ether structure based on B-alkyl Suzuki coupling reaction. Herein we describe our studies toward the total synthesis of 51-hydroxyCTX3C (1), a representative ciguatoxin congener with comparable toxicity to CTX1B. Our convergent synthetic plan for 1 involves the separate construction of two advanced intermediates representing the ABCD (2) and FGHIJKLM (3) ring fragments followed by their union via Horner-Wittig coupling and hydroxy thioketal cyclization. The ABCD ring fragment 2 was stereoselectively prepared via hydroboration-Suzuki coupling of the B and D rings (4 and 5, respectively) followed by closure of the C ring, and construction of the A ring by ring-closing metathesis reaction. The synthesis of the FGHIJKLM ring fragment 41, a potential precursor to 3, featured palladium-catalyzed carbonylation of lactone-derived enol phosphate to construct the nine-membered F ring and a two-stage B-alkyl Suzuki coupling of the FG (6), I (7) and KLM (8b) ring fragments. The present synthesis demonstrated the general applicability of our strategy based on B-alkyl Suzuki coupling to the convergent synthesis of polycyclic ether system. Progress toward the completion of the total synthesis of 1 through coupling of 2 and 3 is underway.
