Preparation, Isolation, and Characterization ofN^α-Fmoc-peptide Isocyanates:  Solution Synthesis of Oligo-α-peptidyl Ureas

Abstract

The N(alpha)-Fmoc-peptide isocyanates 3a-q, 4a-c, and 5a-c were prepared by the Curtius rearrangement of N(alpha)-Fmoc-peptide acid azides in toluene under thermal, microwave, and ultrasonic conditions. All the N(alpha)-Fmoc-oligo-peptide isocyanates made were isolated as stable crystalline solids with 71 to 94% yield and were fully characterized by 1H NMR, 13C NMR, and mass spectroscopy. Their utility for the synthesis of oligo-alpha-peptidyl ureas 7a-f and 8a-c by the divergent coupling approach was demonstrated. The coupling of N(alpha)-Fmoc-dipeptide isocyanates with amino acid ester or with N,O-bis(trimethylsilyl)amino acids resulted in N(alpha)-Fmoc-tripeptidyl urea ester and acids containing one each of peptide bond and urea bond. The divergent approach is extended to the synthesis of tetrapeptidyl ureas by the 2 + 2 strategy using bis-TMS-peptide acid as an amino component. To incorporate urea bonds in adjacent positions, N(alpha)-Fmoc-peptidyl urea isocyanates 9a-d were prepared and employed in the synthesis of three tetrapeptidyl ureas 10a-b and 11 containing one peptide bond and two urea bonds in series from the N-terminal end. The protocol was then employed for the synthesis of five urea analogues 13-15, 18, and 21 of [Leu5]enkephalin containing urea bonds at the 2, 3, 4 positions as well as at the 2, 4 and 2, 3, 4 positions. The analogue 2l was made by the convergent synthesis by the N --> C terminal chain extension. Finally, two urea analogues 22 and 23 of repeat units of bioelasto polymers, namely Val-Pro-Gly-Val-Gly-OH and Pro-Gly-Val-Gly-Val-OH, were synthesized incorporating the urea bond by the concomitant isocyanate generation and urea bond formation under thermal conditions.

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.…”

Synthesis of N α -Protected Amino Acid–Derived Selenocarbamates Employing Isocyanates as Key Intermediates

“…[15] Our group has reported the preparation of isocyanates derived from Fmoc-a-amino acids (i.e., N a -Fmoc-amino alkyl isocyanates [16] ) obtained by the Curtius rearrangement of N a -Fmoc amino acid azides. [17] These key intermediates were employed in the synthesis of dipeptidyl ureas, oligo-a-peptidyl ureas, [18] retro-inverso peptides [19] employing Goldschmidt-Wick type reaction, N-formamides, [20] and isonitriles, [21] which are useful synthons in multicomponent reactions. With an aim to demonstrate newer applications of Fmoc-a-amino alkyl isocyanates, we envisaged the synthesis of selenocarbamates by the coupling of isocyanate with an appropriate selenating agent and alkyl=aryl halide.…”

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.…”