Urethane-protected alpha-amino acid N-carboxyanhydrides and peptide synthesis

The preparation, physical properties and analytical data are reported for seventy urethane-protected (Boc, Cbz, FMOC) amino acid N-carboxyanhydrides (UNCAs). Most of the UNCAs are crystalline and the X-ray diffraction patterns for several of these are described. UNCAs are stable to routine laboratory manipulations and can be stored for extended periods of time (1-2 years at below 0 degrees C). Most are completely stable to the conditions commonly employed for peptide synthesis. The correct choice of base is key for the successful introduction of urethane protecting groups into NCAs. N-Methylmorpholine is used for the introduction of FMOC, Cbz or Boc from the chloroformates, and pyridine is used for the introduction of the Boc group from Boc anhydride. UNCAs represent a unique class of preactivated, isolable and stable amino acid derivatives that generate no side products or co-products, other than CO2, during condensation reactions. The application of UNCAs in peptide synthesis in both solid phase and in solution is reviewed in detail.