title: Solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives employing support-bound tyrosine esters in the Pictet-Spengler reaction.
abstract: The solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxamides employing carboxyl-supported, o-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 (DIC) 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-1,2,3,4-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-1,2,3,4-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.
authors.affiliation: Discovery Partners International, ChemRx Division, 385 Oyster Point Boulevard, Suite 1, South San Francisco, California 94080, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Kane
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.forename: Daphne E
authors.initials: DE
authors.lastname: Kelly
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Dener