The total synthesis of azaspiracid-3 has been completed. The azaspiracids are a unique class of structurally complex, highly oxygenated natural products that originate from the dinoflagellate Azadinium spinosum. These toxins endanger human food supplies via oceanic food chains, where they bioaccumulate in edible shellfish, effecting a broad range of cyto-, neuro-, and gastrotoxic symptoms in mammals, even at extremely low concentrations (1 x 10-6 % w/w or less). Due to their natural paucity, isolation efforts have largely been supplanted by organic synthesis, although preparation of these compounds remains challenging. Azaspiracid total syntheses have been reported by the Nicolaou group (azaspiracids -1, -2, and -3) and the Evans group (ent-azaspiracid-1); however, neither of these campaigns produced sufficient quantities of the natural product to fully profile its biological interactions. The azaspiracids were pursued in these laboratories due to three principle motivations: the desire to further probe their biological mechanism of action, the need for larger quantities of azaspiracids for environmental monitoring efforts, and the opportunity to expand existing synthetic methodology for compounds of its class and related polyether-type natural products. To date, 2 mg of azaspiracid-3 has been prepared and authenticated via 1H-NMR spectroscopy, 13C NMR spectroscopy, optical rotation, and high-resolution mass spectrometry. This novel approach forms the central C21-C22 bond at a late stage from two advanced precursors: a C21 aldehyde containing the intact ABCD ring system (C1-C21), and a C22 alkynyl iodide containing the FGHI ring system (C22-C40); these compounds were successfully coupled in equal stoichiometry using modified Nozaki-Hiyama-Kishi (NHK) conditions—subsequent C21 oxidation, conjugate copper hydride-mediated reduction of the resulting Δ22-23 ynone, and global deprotection yielded the fully elaborated ABCDEFGHI ring system, which required only C1 oxidation to complete the natural product.

Total synthesis of (–)-azaspiracid-3

255th National Meeting (2018)

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