Total Synthesis and Structure Elucidation of JBIR-39: A Linear Hexapeptide Possessing Piperazic Acid and γ-Hydroxypiperazic Acid Residues

The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)(3)-catalyzed acylation of a Piz(gamma-OTBS) derivative with piperazic acid chloride, providing the desired Piz-Piz(gamma-OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)-isoleucic acid at the N-terminus, amidation with the (R)-alpha-methylserine ester at the C-terminus, and deprotection afforded the desired (2R,8S)-hexapeptide, which is the assumed structure of JBIR-39. Although the spectral data of the (2R,8S)-hexapeptide was not identical to JBIR-39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR-39 to be (2S,6S,8S,11R,16S,21R,26S,27S).