Isocyanates of N alpha-[(9-fluorenylmethyl)oxy]carbonyl amino acids: synthesis, isolation, characterization, and application to the efficient synthesis of urea peptidomimetics.
The Curtius rearrangement of Fmoc-amino acid azides 1 was carried out in toluene by refluxing the solution for 30 min. The resulting isocyanates 2 have been isolated as crystalline solids and are fully characterized by IR, (1)H NMR, (13)C NMR, and mass spectra. They are found to be stable for several months when stored at 4 degrees C. The acyl azides of Asp, Glu, Ser, Tyr, and Lys with side-chain protection having tert-butyl, benzyl, and Boc groups were also converted to the corresponding isocyanates 2h-m. The rearrangement of Fmoc-amino acid azides in toluene to isocyanates 2 under microwave irradiation was also accomplished. The direct exposure of solid azides to microwaves for 60 s led to the completion of the rearrangement. The resulting isocyanates, after recrystallization, were found to be analytically pure. The scale-up of the rearrangement, under microwave irradiation as tested up to 0.75 mol, posed no problems and led to the isolation of the isocyanates in 91-96% yield. The utility of isocyanates as building blocks in the synthesis of urea peptides 4 is demonstrated. Further, the coupling of isocyantes 2 directly with N,O-bis(trimethylsilyl) derivatives of amino acids 6 resulted in urea peptide acids 7 with good yield in high purity. Thus, the synthesis of urea peptide acids 7d-g containing Asp, Glu, Ser, and Tyr with a free side-chain functional group have been carried out.
Patil
Basanagoud S
BS
Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India.
Vasanthakumar
Ganga-Ramu
GR
Suresh Babu
Vommina V
VV
D000596:Amino Acids / Q000138:chemical synthesis* / Q000302:isolation & purification; D005449:Fluorenes / Q000138:chemical synthesis* / Q000302:isolation & purification; D017953:Isocyanates / Q000138:chemical synthesis* / Q000302:isolation & purification; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis*; D011480:Protease Inhibitors / Q000138:chemical synthesis; D014508:Urea / Q000737:chemistry
D000596:Amino Acids; D005449:Fluorenes; D017953:Isocyanates; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010455:Peptides; D011480:Protease Inhibitors; D014508:Urea