Total syntheses of (-)-lycoricidine, (+)-lycoricidine, and (+)-narciclasine via 6-exo cyclizations of substituted vinyl radicals with oxime ethers

The development of an approach to the total synthesis of the title alkaloids is described. The approach utilizes as the key strategic element a stereoselective 6-exo radical cyclization of a vinyl radical to an O-benzyloxime radical acceptor group. The vinyl radical was itself generated by regioselective addition of phenylthiyl radical to a disubstituted alkyne. The regiochemical issues of such additions, which result in different outcomes with tri-n-butylstannyl radicals and phenylthiyl radicals, are discussed. The first such synthesis described, that of (-)-lycoricidine, proceeded in 14 steps and 11% overall yield from 10 and served to develop the radical chemistry required. A second-generation synthesis, this time of the natural (+) enantiomer, was developed using insights gleaned from the first study and proved much more efficient, providing the target alkaloid in nine steps and 44% overall yield. This approach was then employed in the more demanding case of (+)-narciclasine. Several problems arising due to the more electron rich aromatic moiety present in this structure are described. The synthesis developed to deal with these aspects afforded (+)-narciclasine in 12 steps and 26% overall yield.