Total Synthesis and Structural Elucidation of Azaspiracid-1. Final Assignment and Total Synthesis of the Correct Structure of Azaspiracid-1

The molecular structure of azaspiracid-1, a neurotoxin isolated from mussels, has been elucidated by total synthesis which also enriched its supplies. The degradatively derived fragments of this marine biotoxin, compounds 5 (EFGHI), 6 (FGHI), and 40 (ABCD), were matched with synthetic materials, thus confirming their structural identities. Based on this detective work, a new structure of azaspiracid-1 (i.e., 1) was proposed and constructed by total synthesis. The final strategy for the total synthesis of azaspiracid-1 featured a dithiane anion (C21−C27 fragment) reacting with a pentafluorophenol ester (C1−C20 fragment) followed by a Stille-type union of an advanced allylic acetate substrate (C1−C27 fragment) with a vinyl stannane as the main coupling processes to assemble the carbon skeleton of the molecule. In addition to the total synthesis of azaspiracid-1 (1), the syntheses of its C1−C20 epimer (2) and of several truncated analogues for biological investigations are described.