HBTU Mediated Synthesis of α,β‐Unsaturated γ‐Lactams from E‐α,β‐Unsaturated γ‐Amino Acids

Abstract

AbstractThe 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 α,β‐unsaturated γ‐lactams. Here, we are reporting the spontaneous transformation of E‐α,β‐unsaturated γ‐amino acids into α,β‐unsaturated γ‐lactam through in‐situ activation of free carboxylic acid using peptide coupling reagent HBTU and base DIPEA at room temperature. The transformation also involves the E→Z isomerization of α,β‐unsaturated γ‐amino acids. The reaction is also compatible with the peptides consisting of E‐α,β‐unsaturated amino acids at the C‐terminus. The α,β‐unsaturated γ‐lactams were isolated in very good yields. Even though the reaction required very mild conditions, the products were isolated in the form of a racemic mixture. However, the products can be separated under a chiral environment. No α,β‐unsaturated γ‐lactams were observed if the reaction was performed in the presence of free amines. In addition, no racemization was observed during the peptide synthesis. The analysis of the reactions of various substrates revealed that amide NH and γ‐CH are important for lactamization. No α,β‐unsaturated γ‐lactams or E→Z isomerization products were observed in the case of N‐Me‐(E)‐α,β‐unsaturated γ‐amino acids, whereas in the case of E‐α,β‐unsaturated γ,γ‐dimethyl amino acid α,β‐unsaturated γ‐lactam was isolated, however, with low yield.