Synthesis of Isopeptide Epoxide Peptidomimetics

Abstract

Two epoxide-containing peptidomimetics of the isopeptide, glutamyl-gamma-glutamate, have been synthesized via a route that should be generally applicable to the synthesis of isopeptide analogues in which an oxirane replaces the scissile peptide bond. Enzymes that catalyze the hydrolysis of peptides and isopeptides are often susceptible to inactivation by electrophilic substrate analogues. In this research, an epoxide was installed as an electrophilic replacement of the scissile isopeptide bond. The C-terminal glutamyl mimic was accessed by the stereospecific synthesis of suitably substituted cyclopentenes, 8 and 10, as surrogates for either the L- or D-enantiomer. The enantiomeric cyclopentenes were further elaborated to incorporate an appended sulfone that was reacted with a suitably protected glutamyl-gamma-semialdehyde in a Julia-Kocienski olefination reaction. This olefination afforded predominantly the desired E-olefin isosteres of L-glutamyl-gamma-D-glutamate and L-glutamyl-gamma-L-glutamate, following which peracid-mediated epoxidation and deprotection provided the epoxide-containing peptidomimetics, 4 and 5.