The click reaction as an efficient tool for the construction of macrocyclic structures

Abstract

The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC, known as the click reaction) is an established tool used for the construction of complex molecular architectures. Given its efficiency it has been widely applied for bioconjugation, polymer and dendrimer synthesis. More recently, this reaction has been utilized for the efficient formation of rigid or shape-persistent, preorganized macrocyclic species. This strategy also allows the installment of useful functionalities, in the form of polar and function-rich 1,2,3-triazole moieties, directly embedded in the macrocyclic structures. This review analyzes the state of the art in this context, and provides some elements of perspective for future applications.

Scheme 1

Prototypical conditions for the Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) reaction, a 1,3-dipolar cycloaddition, and the resulting product.

Scheme 2

Strategy for the modular synthesis of macrocyclic organo-peptide hybrids 5. The starting linear polypeptides comprise an N-terminal tail (orange), O-propargyl tyrosine, a target sequence (green), and a GyrA intein segment (light blue). Macrocyclization occurs upon coupling of this protein to a synthetic precursor (purple) by concomitant CuAAC and thioester-hydrazide coupling [31].

Figure 1

Cyclic peptides obtained by CuAAC or RuAAC click chemistries incorporating 1,4- or 1,5-disubtituted triazole linkages as trypsin inhibitors analogue of 6 [36].

Figure 2

Regioisomeric triazole-containing cyclic peptides composed of cis-β-furanoids and β-alanines [48].

Scheme 3

Synthesis of click macrocycles through the cyclization of oligosaccharide linear monomers of varying lengths [56].

Figure 3

Triazole and triazolium-containing macrocycles for the binding of anions. In Red: triazole or triazolium amide surrogates as the key functionalities responsible for binding [59,61,62].

Figure 4

Structures of macrocyle 17 and control compound 18, and (bottom) operating principles of the macrocyclic chiroptical sensor 17 in which the variation of the CD response of the Binol unit is the key sensing output [63].

Scheme 4

High yielding synthesis of “Sauvage-type” symmetrical catenane 20 [82].

Scheme 5

Synthesis of trefoil knot 23 by Leigh and co-workers [85].

Scheme 6

Terminal insertion of azide and “click” cyclization of polystyrene prepared via ATRP [96].