Isocyanates of N^α-[(9-Fluorenylmethyl)oxy]carbonyl Amino Acids: Synthesis, Isolation, Characterization, and Application to the Efficient Synthesis of Urea Peptidomimetics

Abstract

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.

Synthesis of Nα-protected formamides from amino acids using MgO nano catalyst: Study of molecular docking and antibacterial activity

“…The synthetic utilities of N -protected amino isocyanates in the preparation of peptidomimetics like peptidylureas have been described in the literature [44]. Herein, we present a useful application of amino acid derived isocyanates in the synthesis of the N-formylated gem-diamines by the reaction of N-protected amino isocyanates with formic acid in the presence of nano MgO (Scheme 1).…”

A Facile Synthesis of C-terminal Neoglycopeptides: Incorporation of Urea Moiety between Sugars and Peptides Employing Curtius Rearrangement

“…They were converted to corresponding acid azides via mixed anhydride. The Fmoc-peptidyl azides were subjected to Curtius rearrangement to furnish corresponding isocyanates (Patil et al, 2003;Sureshbabu et al, 2006) by exposing the solution of acid azide in toluene to microwave irradiation for 45 s (Scheme 2). All the peptidyl isocyanates were isolated as stable crystalline solids that can be stored under low temperature for long time.…”

A facile and one-pot synthesis of Nα-Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl ureas employing diphenylphosphoryl azide [DPPA]

“…17 Current strategies to synthesize N a -protected urealinked peptides are predominantly based on Curtius and Hoffmann rearrangements. Sureshbabu et al, reported an elegant procedure for the synthesis of Fmoc protected a-ureido peptides, 18 oligoureas, 19 and a variety of substituted phenyl-(9-fluorenylmethoxycarbonylamino)methyl carbamates 20 through the classical Curtius rearrangement employing a series of isocyanates derived from stable N aFmoc amino acid azides. 21 Guichard and co-workers, reported the stepwise synthesis of N,N 0 -urea-linked oligomers using O-succinimidyl (N a -urethane protected) methyl carbamates.…”