Preparation, isolation, and characterization of Nα-Fmoc- peptide isocyanates: Solution synthesis of oligo-α-peptidyl ureas

(Chemical Equation Presented) The Nα-Fmoc-peptide isocyanates 3a-q, 4a-c, and 5a-c were prepared by the Curtius rearrangement of Nα-Fmoc-peptide acid azides in toluene under thermal, microwave, and ultrasonic conditions. All the Nα-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-α- peptidyl ureas 7a-f and 8a-c by the divergent coupling approach was demonstrated. The coupling of Nα-Fmoc-dipeptide isocyanates with amino acid ester or with N,O-bis(trimethylsilyl)amino acids resulted in Nα-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 α-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 Leu5enkephalin containing urea bonds at the 2, 3, 4 positions as well as at the 2, 4 and 2, 3, 4 positions. The analogue 21 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. © 2006 American Chemical Society