Stereoselective synthesis of two type (E)-alkene dipeptide isosteres from a single substrate of β-aziridinyl- α,β-enoate

Abstract

Among various dipeptide isosteres, the potential of (E)-alkene isosteres as backbone replacement of amide bonds in peptides has been well documented in the past few years [1]. One of the most important factors in progress in such a pharmacodynamics of peptide-lead drugs would be strongly rested on the development of a new efficient synthetic route. The γ ,δ-epiminoα,β-unsaturated esters, which are intermediates for the synthesis of isosteres, can be easily prepared as a mixture of the cis-( E)-, cis(Z)-, trans(E)and trans(Z)-isomers (1–4) from the corresponding chiral amino aldehydes. Recently we reported that Pd(0)-catalyzed equilibrated reactions of various stereoisomers of γ ,δ -epimino-α,β−enoates (1–4) could afford predominantly the cis-( E)-isomer 1 [2]. In this study, the regioand stereo-selective ring-opening reactions of N-2,4,6-trimethylbenzenesulfonyl(Mts)-protected aziridines bearing an α,β-unsaturated ester by TFA and methanesulfonic acid (MSA) have been found. MSA treatment of the cis-(E)-enoate 1 gave the mesylate5, which could be converted into the L,D-type (E)-alkene isostere 6 via organocopper-mediated anti-SN 2' reaction [3]. In sharp contrast, treatment of the cis(E)-isomer 1 with the organocopper reagent exclusively gave the L,L -type (E)-alkene isostere 7 according to the reported method [4].