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

Abstract

Diphenylphosphoryl azide (DPPA) mediated one-pot synthesis of N a -Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl ureas as well as phenyl/succinimidyl (N a -urethane protected) methyl carbamates starting from N a -protected amino acids is reported. The formation of an azide, its rearrangement and coupling with an amino component is accomplished in a sequence of one-pot operations. The protocol has incorporated urea linkages in a sterically hindered peptide.

Simple and Mild One-Pot Synthesis of Dipeptidyl Ureas via Carbamoyl Azides ofα-N-Protected Amino Acids

“…It is worth pointing out that when we attempted to synthesize Eoc-L-Phgw[NHCONH]-L-Ph-OMe (1cad) following the DPPA method proposed by Sureshbabu et al [18] the ESI-HPLC-MS analysis of the reaction mixture evidenced the presence of an equimolar mixture of the two epimers 1cad and Eoc-D-Phgw[NHCONH]-L-Ph-OMe (epi-1cad), demonstrating that a complete racemization had occurred. In addition, the same method employed in the reaction between N-Boc-L-phenylglycine (3cb) and 4d afforded a mixture of Boc-L-Phgw[NHCONH]-L-Ph-OMe (1cbd) and…”

“…More recently, the same authors have described the interesting and straightforward synthesis of a-NFmoc=Bsmoc=Boc=Z-protected ureido peptidomimetics starting from the a-Nprotected amino acid or peptide acid in the presence of diphenylphosphoryl azide (DPPA) followed by the one-pot addition of the amino acid ester. [18] On the other hand, the suitable isocyanate intermediates can also be prepared through the oxidative Hofmann or Lossen rearrangements of the C-terminal of a-N-protected Scheme 1. Overview of current approaches for the insertion of a ureido linkage w[NHCONH] between two neighboring a-amino acids.…”

Application of carbodiimide mediated Lossen rearrangement for the synthesis of α-ureidopeptides and peptidyl ureas employing N-urethane α-amino/peptidyl hydroxamic acids

“…25 The isocyanates obtained from N-protected a/b amino acid azides are also converted into methyl/ethyl carbamates 26 that are in turn used as activated monomers for urea synthesis. Synthesis of a-peptidyl ureas through diphenylphosphoryl azide (DPPA) mediated modified Curtius rearrangement has been recently reported 27 (Scheme 1). b-Peptidyl ureas are also synthesized in solution and solid phase by using the monomers obtained by coupling the amines resulting from reduction of the N-protected a-amino nitriles/amides or b-amino alkyl azides or by other methods.…”

1-Propanephosphonic Acid Cyclic Anhydride (T3P) as an Efficient Promoter for the Lossen Rearrangement: Application to the Synthesis of Urea and Carbamate Derivatives

“…4 Activated carboxylic acids in the form of acid chlorides or mixed anhydrides are subjected to azidolysis or the carboxylic acids are directly converted into acyl azides employing azide-transfer reagents and then the acyl azides are rearranged under thermal conditions. [5][6][7][8][9] Although decent yields are obtained, multistep sequences, the cost of some of the reagents and the potentially explosive nature of acid azides limit this method mainly to bench-scale preparations. Isocyanates can also be accessed via the Hofmann rearrangement, which involves oxidant-mediated conversion of an amide into isocyanate.…”