Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry

Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed CyClick chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073-19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in CyClick of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre-organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the CyClick of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses CyClick reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Automated summary

This study involves a computational investigation of CyClick chemistry, a reaction that selectively forms cyclic peptides from linear peptide aldehydes without the use of catalysts or directing groups. The research explores the role of intramolecular hydrogen bonds (IMHBs) in promoting the reaction mechanism and highlights the importance of IMHBs in stabilizing intermediate states and controlling product stereoselectivity. The study also examines the effect of ring strain energy on the reaction, finding that low ring strain energy promotes the formation of more stable cyclic peptides.