A Strategic Approach to α,β-Unsaturated γ-Lactam Synthesis via Trans-cis Isomerization of Carbon-Carbon Double Bonds in Vinylogous γ-Amino Acids

Abstract

The α,β-unsaturated γ-lactams represent important synthetic targets due to their presence in natural products, diverse biological activities, and their utility as building blocks for the synthesis of other compounds. These compounds have proven to be valuable scaffolds in many biologically active peptide natural products. Despite their wide range of applications, there are currently limited methods available for synthesizing α,β-unsaturated γ-lactams. We have been interested in understanding the conformation and chemical reactivity of α,β-unsaturated γ-amino acids. Previously, we studied the conformations of polypeptides composed of α,β-unsaturated γ-amino acids and also demonstrated base-mediated cyclization of α,β-unsaturated γ-amino acid amides into γ-lactams, involving multiple migrations of carbon-carbon double bonds. In this work, we have demonstrated the cyclization of α,β-unsaturated γ-amino acids under mild conditions. We have shown the spontaneous transformation of N-protected α,β-unsaturated γ-amino acid active esters into N-protected Z- α,β-unsaturated γ-lactams in the presence of a mild base. We studied the kinetics of the transformation. Further, we demonstrated the synthesis of Z-γ-lactams through in situ activation of E-α,β-unsaturated γ-amino acids using the peptide coupling reagent HBTU, DMF, and DIPEA at room temperature. Both methods gave excellent yields. Importantly, this transformation involves the remarkable E → Z isomerization of double bonds, a process uncommon in nature. This strategy also demonstrates the trans-cis isomerization of carbon-carbon double bonds without light or catalyst. By employing this strategy, we generated a library of α,β-unsaturated γ-lactams with diverse side chains in monomers and peptides with excellent yields. We also extended this strategy for the transformation of E-vinylogous amino acids into Z-vinylogous amino acids. We further applied this strategy for the synthesis of lactones. The analysis of the products and mechanistic analysis revealed the complete racemization of the products. To overcome the racemization of Z-γ-lactams, we redesigned the strategy and used (Z)-vinylogous amino acids as starting materials instead of E-vinylogous amino acids. The new strategy gave optically pure Z-γ-lactams. Overall, we have developed novel, mild, and effective strategies for the synthesis of Z-γ-lactams from both E- and Z-vinylogous amino acids and peptides through carboxylic acid activation. The lactamization involves the E → Z isomerization of carbon-carbon double bonds. This strategy can be applied for the synthesis of Z-vinylogous amino acids from E-vinylogous amino acids and also for the synthesis of lactones.