Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction.
A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schöllkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schöllkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-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 when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.
Ma
C
C
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
Liu
X
X
Li
X
X
Flippen-Anderson
J
J
Yu
S
S
Cook
J M
JM
D000478:Alkylation; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D010165:Palladium / Q000737:chemistry*; D010879:Piperazines; D014364:Tryptophan / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
C431472:6-methoxytryptophan; D026121:Indole Alkaloids; D007211:Indoles; D010879:Piperazines; C097858:tryprostatin A; D010165:Palladium; D014364:Tryptophan