Solid-Phase Synthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives Employing Support-Bound Tyrosine Esters in the Pictet-Spengler Reaction

摘要

The solid-phase synthesis of l,2,3,4-tetrahydroisoquinoline-3-carboxamides employing carboxyl-supported,<9-alkylated tyrosine esters in a Pictet-Spengler reaction is described.Esterification of [4-(hydroxyphenyl)-thiomethyl]polystyrene (Marshall resin) with ethers of N-BOC-L-tyrosine using diisopropylcarbodiimide (DIG) and 4-dimethylaminopyridine (4-DMAP) afforded the solid-supported ester derivatives.Removal of the BOC group with trifluoroacetic acid (TFA) afforded the carboxyl-supported tyrosine ester,which was then treated with paraformaldehyde and TFA to afford the desired solid-supported counterpart.Acylation of the secondary amine with arylsulfonyl chlorides followed by reaction with amines resulted in the formation of the desired 2-arylsulfonyl-7-alkoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxamides.Alternatively,the support-bound tetrahydroisoquinoline-3-carboxylate derivatives could be treated with an aldehyde and a reducing agent to give the corresponding support-bound tertiary amine.Exposure of these resin-bound products to amines afforded the corresponding 2-alkyl-7-alkoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxamides after cleavage from the resin.Alternative routes to the desired chemotypes,as well optimization of the conditions for the Pictet-Spengler reaction and the conditions for the acylation and reductive amination of the support-bound secondary amines,are also described.