Synthesis of Peptides with C-terminal Z-γ-Lactam via E →Z isomerization

Abstract

The Z-α,β-unsaturated γ-lactams have been found in many biologically active peptide natural products. Due to their biological activities, extensive efforts have been made in the literature to synthesize the Z-γ-lactams. Generally, Z-γ-lactams have been found at the C-terminus of peptides, which restricts the solid-phase synthesis of these peptides. In addition, Z-γ-lactam synthesis involves very strong reagents, which are generally not suitable for use during or after peptide synthesis. Recently, we reported the spontaneous transformation of (E)-α,β-unsaturated γ-amino acids into Z-α,β-unsaturated γ-lactam through in-situ activation of the free carboxylic acid using the peptide coupling reagent HBTU and the base DIPEA at room temperature. The transformation also involves the (E)→(Z) isomerization of α,β-unsaturated γ-amino acids. We sought to examine the Z-γ-lactam synthesis on peptides consisting of (E)-α,β-unsaturated γ-amino acids at the C-terminus. In this work, we are reporting the synthesis of peptides with C-terminal Z-γ-lactam at room temperature using the peptide coupling agents HATU and the base DIPEA. These peptides were synthesized through solid-phase on CTC resin and cyclized after releasing from the solid support. This methodology can provide an opportunity to synthesize peptides with C-terminal γ-lactams without affecting other functional groups on the peptide backbone.