A Total Synthesis of a New Type of Furo[3,2-h]isoquinoline Alkaloid, TMC-120B

Abstract

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid, TMC-120B (2) has been completed in sixteen steps.The key step is the synthesis of 7,8-disubstituted isoquinoline (17) based on the thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond.Three new furo[3,2-h]isoquinoline alkaloids, TMC-120A (1), B (2), and C (3) were isolated from a fermentation broth of Aspergillus ustus TC 1118 (Chart 1). 1 Their structures have been determined by extensive spectroscopic and chemical analyses.TMC-120C (3) is the racemic compound, and an absolute configuration of the chiral compound (1)has not yet been ascertained.In addition, the structure of TMC-120B (2) has been also elucidated by X-Ray analysis.TMC-120B (2) shows moderate inhibitory activity against the interleukin-5 mediated prolongation of eosinophil survival (IC 50 =2.0mM).We have been performing synthetic studies of biologically active condensed heteroaromatic compounds including natural products through the construction of functionalized frameworks based on the thermal electrocyclic reaction 2 of either a 6p-electron 3,4 or an aza 6p-electron 3,5 system incorporating the heteroaromatic or aromatic portion.In our research program, we planned a total synthesis of TMC-120A(1), B (2), and C (3). N