Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction

A novel and concise synthesis of optically active tryptophan derivatives wa s developed via a palladium-catalyzed heteroannulation reaction of substitu ted o-iodoanilines with an internal alkyne. The required internal alkyne 14 a or 25 was prepared in greater than 96% de via alkylation of the Schollkop f chiral auxiliary 19 employing diphenyl phosphate as the leaving group. Th e Schollkopf chiral auxiliary was chosen here for the preparation of L-tryp tophans would be available from D-valine while the D-isomers required for n atural product total synthesis would originate from the inexpensive L-valin e (300-g scale). Applications of the palladium-catalyzed heteroannulation r eaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-metho xy-D-tryptophan 62 was prepared by this protocol on a large scale (> 300 g) . This should permit entry into many ring-A oxygenated indole alkaloids whe n coupled with the asymmetric Pictet-Spengler reaction. In addition, an imp roved total synthesis of tryprostatin A (9a) was accomplished in 43% overal l yield employing this palladium-mediated process.