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.