1,5‐Disubstituted 1,2,3‐Triazole‐Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics

Abstract

Peptidotriazolamers are hybrid foldamers combining features of peptides and triazolamers-repetitive peptidomimetic structures with triazoles replacing peptide bonds. We report on the synthesis of a new class of peptidomimetics, containing 1,5-disubstituted 1,2,3-triazoles in an alternating fashion with amide bonds and the analysis of their conformation in solid state and solution. Homo- or heterochiral peptidotriazolamers were obtained from enantiomerically pure propargylamines with stereogenic centers in the propargylic position and α-azido esters by ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave conditions in high yields. With such building blocks the peptidotriazolamers are readily available by solution phase synthesis. While the conformation of the homochiral peptidotriazolamer Boc-Ala[5Tz]Phe-Val[5Tz]Ala-Leu[5Tz]Val-OBzl resembles that of a β VIa1 turn, the heterochiral peptidotriazolamer Boc-d-Ala[5Tz]Phe-d-Val[5Tz]Ala-d-Leu[5Tz]Val-OBzl adopts a polyproline-like repetitive structure.

Chiral 1,5-disubstituted 1,2,3-triazoles – versatile tools for foldamers and peptidomimetic applications

“…16 Homo-and heterochiral peptidomimetics have been developed from enantiomerically pure propargylamines and α-azido acids using the RuAAC reaction. 17 NMR and MD simulations have shown the presence of a β-turn-like structure in homochiral peptido-triazolamers, while a heterochiral triazolamer shows a polyproline-like helix. Moreover, a well defined protocol for the synthesis of chiral propargylamines, with a side chain in the α-position, is feasible using Ellman's tertbutylsulfinamide as a chiral auxiliary.…”

“…During the preparation of this manuscript, a related report, concerning the synthesis of some 1,5-disubstituted peptidotriazolomers, was published by Sewald and co-workers. 17 While there are some touching points between the two studies, the present study describes the complete set of eight possible combinations for monoand disubstituted chiral derivatives. Thus, these studies are different both in terms of the triazoles prepared, as well as with respect to the computational studies performed.…”

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

“…d) Sonogashira cross-coupling, R = tert- butylsulfinyl, R’ = Me, CHMe 2 , CH 2 CHMe 2 , cyclohexyl [ 17 ]. e,f) Cu I or Ru II -catalyzed [3 + 2] cycloadditions (CuAAC, RuAAC) [ 18 – 21 ]. e) R = Boc, R’ = Bn [ 19 ].…”

“…e) R = Boc, R’ = Bn [ 19 ]. f) R = Boc, R’ = Me, CHMe 2 , CH 2 CHMe 2 , R’’ = Me, CHMe 2 , CH 2 Ph [ 21 ].…”

Convenient synthesis of 2-(4-amino-1H-1,2,3-triazol-1-yl) acetic acid

“…Більше того, триазольне кільце може бути сурогатом як транс-, так і цис-амідного зв'язку, залежно від того, який триазол застосовують -1,4-чи 1,5-дизамішений [2]. Потенціал триазолу як біоізостеру амідного зв'язку у дизайні пептидоміметиків продемонстровано у низці недавніх публікацій [3][4][5][6][7][8][9][10][11][12][13][14][15]. У більшості згаданих прикладів для синтезу 1,4-та 1,5-дизаміщених триазолів використовують Cu(I)-чи Ru(I)-каталізоване циклоприєднання азидів до алкінів [16], що є зручними і високопродуктивними підходами до формування 1,2,3-триазольного кільця.…”