An efficient synthetic method for Z-fluoroalkene dipeptide isosteres:Application to the synthesis of the dipeptide isostere of Sta-Ala

摘要

Reaction of gamma,gamma-difluoro-alpha,beta-enoates having a 8-hydroxyl group with trialkylaluminum(R_3Al)was found to be promoted by CuI centre dot 2LiCl and to proceed in SN2' manner giving rise to the alpha-alkylated(Z)-gamma-fiuoro-beta,gamma-enoates,while reductive defluorination of gamma,gamma-difluoro-alpha,beta-enoates with Me_2CuLi followed by reaction with alkyl halides provided the corresponding(Z)-alpha-alkylated products in high yields.The latter reaction was applied to the preparation of the dipeptide(Z)-fluoroalkene isostere of Sta-Ala,which is the central dipeptide unit in Pepstatin,a natural inhibitor of aspartate proteases.