Selective Hydroxylation of Collagen Model Peptides by Metal Catalysis

Collagen is formed with a repeating structure of proline (Pro)-4-hydroxyproline-(4-Hyp)-glycine (Gly). In chemical synthesis, when synthesizing collagen sequences, it is necessary to protect the 4-Hyp side chain within them. Therefore, if (Pro-Pro-Gly)n could be synthesized followed by selective hydroxylation of proline residues using iron catalysts, improved synthetic efficiency could be expected. In this study, hydroxylation reactions were performed on Boc-Pro-OPac and Ac-Pro-OPac, where the N-termnus of proline is protected by Boc and Ac groups, respectively, and on Boc-Pro-Pro-OPac, a peptide containing multiple proline residues. Subsequent NMR structural analysis confirmed that hydroxyl groups were introduced at the 5-position of proline in Boc-Pro-OPac and at the 5-position of N-terminal proline in Boc-Pro-Pro-OPac. On the other hand, the reaction did not proceed for the proline at the C-terminal end of Ac-Pro-OPac and Boc-Pro-Pro-OPac. To investigate the reaction mechanism and whether the reaction proceeds, density functional theory (DFT) calculations were performed to clarify the optimal structure of the substrate and the charge distribution on each atom. The progress of this reaction is influenced by the electron density of the hydrogen atom at the 5-position of proline, but it has been clarified that steric hindrance near the 5-position of proline exerts a significant effect.