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 alkaloid s is described. The approach utilizes as the key strategic element a stereo selective 6-exo radical cyclization of a vinyl radical to an O-benzyloxime radical acceptor group. The vinyl radical was itself generated by regiosele ctive addition of phenylthiyl radical to a disubstituted alkyne. The regioc hemical issues of such additions, which result in different outcomes with t ri-n-butylstannyl radicals and phenylthiyl radicals, are discussed. The fir st such synthesis described, that of (-)-lycoricidine, proceeded in 14 step s and 11% overall yield from 10 and served to develop the radical chemistry required. A second-generation synthesis, this time of the natural (+) enan tiomer, was developed using insights gleaned from the first study and prove d much more efficient, providing the target alkaloid in nine steps and 44% overall yield. This approach was then employed in the more demanding case o f (+)-narciclasine. Several problems arising due to the more electron rich aromatic moiety present in this structure are described. The synthesis deve loped to deal with these aspects afforded (+)-narciclasine in 12 steps and 26% overall yield.