A micro-flow rapid dual activation approach for urethane-protected α-amino acid N-carboxyanhydride synthesis

This study demonstrated the rapid dual activation (10 s, 20 degrees C) of a combination of an alpha-amino acid N-carboxyanhydride and alkyl chloroformate in the synthesis of a urethane-protected alpha-amino acid N-carboxyanhydride in a micro-flow reactor. The key to success was the combined use of two amines that activated both substrates with proper timing. Three amines, i-Pr2NEt, Me2NBn, or N-ethylmorpholine, were used with pyridine in accordance with the steric bulkiness of a side chain in the alpha-amino acid N-carboxyanhydride. A variety of 16 urethane-protected alpha-amino acid N-carboxyanhydrides were synthesized in high yields. The role of amines was investigated based on the measurement of the time-dependent (0.5 to 10 s) decrease of alpha-amino acid N-carboxyanhydrides and alkyl chloroformates in the presence of amines via flash mixing technology using a micro-flow reactor. It was suggested that the in situ generated acylpyridinium cation was highly active and less prone to causing undesired decomposition compared with the acylammonium cation examined in this study. Thus, even at a very low concentration, the acylpyridinium cation facilitated the desired coupling reaction.

Automated summary

This study demonstrated the rapid dual activation of an alpha-amino acid N-carboxyanhydride and alkyl chloroformate in the synthesis of a urethane-protected alpha-amino acid N-carboxyanhydride using a micro-flow reactor. The use of two amines and proper timing activation was the key to success. Various urethane-protected alpha-amino acid N-carboxyanhydrides were synthesized in high yields.