Understanding ring-closing and racemization to prepare α-amino acid NCA and NTA monomers: a DFT study.

Polypeptides and polypeptoids are promising materials in biomedical applications bearing alpha-amino acid repeating units, which are prepared from ring-opening polymerizations of alpha-amino acidN-carboxyanhydride (NCA) orN-thiocarboxyanydride (NTA) monomers. Detailed studies on monomer synthetic routes are essential to explore new alpha-amino acid NCA and NTA monomers as well as the corresponding poly(alpha-amino acid) materials. In this contribution, density functional theory (DFT) is applied to investigate the mechanism of the Leuchs approach including two possible pathways, precursor structure and racemization in the ring-closing reaction. According to DFT calculations, pathway 2 is preferred with lower Delta Gthan pathway 1, and the rate-determining step is recognized as an S(N)2 substitution with releasing equivalent halogenated hydrocarbon, which explains our experimental observations. Racemization results from the reaction between the NTA monomer and a strong protonic acid, which can be suppressed by low temperature and short reaction time. Racemization is inhibited by steric hindrance in those NTAs of alpha-amino acids containing high bulkiness at the beta-carbon, such as leucine-NTA.