Synthesis of (±)-Anatoxin-a and Analogues

A new and highly efficient synthesis of the potent nicotinic acetylcholine receptor agonist, anatoxin-a and its analogues is described, which uses a β-lactam ring opening–transannular cyclisation sequence to set up the bridged bicyclic framework of the natural product. The synthesis involves a cycloaddition of chlorosulfonyl isocyanate with cyclooctadiene followed by Boc protection of the resulting β-lactam. Reaction of the β-lactam with a variety of nucleophiles, followed by selenium-mediated cyclisation and oxidation gave the skeleton of anatoxin-a bearing various sidechains. The approach offers a flexible entry to useful quantities of anatoxin-a and its analogues.