Oxidative α,ω-diyne coupling as an approach towards novel peptidic macrocycles

Abstract

The Glaser-Hay diyne coupling proved to be an efficient cyclisation approach towards diyne containing peptidic macrocycles. A variety of tetrapeptide-based macrocyclic 1,3-diynes were obtained from O-propargylated serine or tyrosine residues using Cu(OAc)2·H2O and NiCl2 under an O2-atmosphere. The effect of the linear 1,3-diyne on peptide conformations was studied by NMR and compared with a macrocycle bearing a saturated linker.

Development of optimized conditions for Glaser-Hay bioconjugations

“…Several past experiments have successfully employed the Glaser-Hay reaction on biologically relevant molecules, though not necessarily under mild conditions. In 2015, oxidative coupling of terminal alkynes was reported with the formation of peptoid dimers at 90 °C in DMSO, and again with macrocyclization of tetrapeptides at 60 °C using Cu(OAc 2 ) and NiCl 2 catalysts [30,31]. …”

Synthesis of Heterocycle‐Bridged Peptidic Macrocycles through 1,3‐Diyne Transformations

“…[17,18] Also, 1,2-bisnucleophiles such as hydrazine and hydroxylamine have been used to prepare pyrazoles [21,22] and isoxazoles, [23] but such conversions have never been applied on peptidic substrates. [27,28] In continuation of our previous work regarding the synthesis of macrocyclic 1,3-diynes from tetrapeptides containing Opropargylated serine residues (Scheme 1), [1] we hereby report on the condensation of peptidic 1,4-dialkyl-1,3-diynes and 1-alkyl-4-aryldiynes with nucleophiles leading to a variety of heterocycle-bridged macrocycles. Treatment with NaHS or H 2 O as nucleophiles gave rise to 2,5-bridged thiophenes or furans, whereas the use of hydrazines and hydroxylamine gave rise to the corresponding pyrazole-and isoxazole-containing macrocycles.…”

“…[1][2][3][4] Cyclic peptides containing a 1,3diyne moiety can be prepared by either derivatization of peptide side chains with difunctionalized 1,3-diynes [5] or by Glaser-Hay-type oxidative alkyne-alkyne coupling reactions of α,ω-dialkynylated peptides. [1][2][3][4] Cyclic peptides containing a 1,3diyne moiety can be prepared by either derivatization of peptide side chains with difunctionalized 1,3-diynes [5] or by Glaser-Hay-type oxidative alkyne-alkyne coupling reactions of α,ω-dialkynylated peptides.…”

Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers

“…[27] Intramolecular macrocyclization of peptides was achieved by using a dual Cu(OAc) 2 and NiCl 2 catalytic system. [28] This approach suffers limitations, requiring N-terminal acetylation, protected residues, as well as the incorporation of a heterochiral D-Pro-L-Pro β -turn motif in the backbone to correctly preorganize the alkynes. The reaction has been applied to the highly stable β -barrel protein GFP, [29,30] facilitating AlexaFluor conjugation.…”