Micro-Flow N-Acylation Using Highly Electrophilic Acyl Ammonium Cations for Peptide and Urethane-Protected N -Carboxyanhydride Syntheses

Acyl ammonium cations can be readily prepared from inexpensive and commercially available nucleophilic tertiary amines and acid chlorides or chloroformates. The significantly electrophilic nature of these cations allows rapid acylations to occur. However, it also causes undesired reactions. The emergence of micro-flow technologies has enabled precise control of reaction time (< 1 s) and temperature that cannot be achieved by conventional batch technologies. In this account, we describe high-yielding, rapid, less wasteful, and low-cost syntheses of peptides and amino acid derivatives via highly electrophilic acyl ammonium cations in which undesired reactions were suppressed by micro -flow technologies. These technologies not only enabled the development of highly efficient synthetic processes, but also provided us deeper insights into the highly active acyl ammonium cation species involved. This is leading to novel discoveries regarding their value in syn-thesis.

Automated summary

Acyl ammonium cations can be prepared easily from inexpensive and commercially available nucleophilic tertiary amines and acid chlorides or chloroformates. The electrophilic nature of these cations allows rapid acylations, but also undesired reactions. The use of micro-flow technologies enables precise control over reaction time and temperature, suppressing undesired reactions and leading to more efficient and cost-effective syntheses of peptides and amino acid derivatives.