Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides

Abstract

The rise of CuI‐catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in‐house preparation of a set of five Fmoc azido amino acids: β‐azido l‐alanine and d‐alanine, γ‐azido l‐homoalanine, δ‐azido l‐ornithine and ω‐azido l‐lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user‐friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2‐(1H‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses.Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Copper‐Free Solid‐Phase Synthesis of Triazolo[1,5‐a][1,4]diazepin‐6‐ones

“…The key building block in the suggested reaction sequence was Fmoc‐azidoalanine, which was prepared in two steps from Fmoc‐Asn‐OH according to a previously reported, slightly modified procedure [23] . The synthetic approach leading to target compounds is depicted in Scheme 1.…”

Tri‐Orthogonal Scaffolds for the Solid‐Phase Synthesis of Peptides

“…Overall, we have developed three variants of tripodal scaffolds, which enable an efficient stepwise synthesis of three different peptides on the same scaffold. Modification of scaffold I with pre‐prepared tripeptides containing azido‐amino acids was also attempted . This strategy was lengthy and rather unsuccessful because the CuAAC with azido‐peptides was inefficient, especially on the second and third arms.…”

“…Modification of scaffold I with pre-prepared tripeptides containing azido-amino acids was also attempted. [19] This strategy was lengthy and rather unsuccessful because the CuAAC with azido-peptides was inefficient, especially on the second and third arms. This underlines the advantage of the peptide synthesis directly on the scaffolds.…”

Functional stapled fragments of human preptin of minimised length

“…Unnatural amino acids Fmoc- l -Lys(N 3 )-OH, Fmoc- l -Pra-OH and an olefinic Fmoc-protected amino acid (Fmoc-S 5 -OH) were attached manually during the synthesis on the resin. 43 For the coupling of Fmoc- l -Lys(N 3 )-OH (2 eq.) and Fmoc- l -Pra-OH (2 eq.…”