Total synthesis of the marine alkaloid halichlorine: development and use of a general route to chiral piperidines.

The total synthesis of the marine alkaloid halichlorine is described, based on an approach that involves constructing the fully substituted asymmetric center at an early stage. The five-membered ring is formed by 5-exo-trig radical cyclization and the unsaturated six-membered ring by a process that formally represents a sequential combination of conjugate addition and S(N)2' displacement-a method that is general for making bicyclic compounds with nitrogen at a ring fusion position. A formal synthesis of (+)-halichlorine is also reported, based on the development of a general method for preparing optically pure piperidines. The key step of this method, which was used to make one of our intermediates, is the Claisen rearrangement of a 4-vinyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester. Such O-vinyl compounds are easily generated in situ from the corresponding alcohols, which are themselves readily assembled from serine and terminal acetylenes.