Catalytic Enantioselective Azide–Alkyne Cycloaddition Chemistry Opens Up New Prospects for Chiral Triazole Syntheses

Abstract

Catalytic enantioselective azide−alkyne cycloaddition (E-AAC) is a highly efficient click technology for the construction of structurally diverse chiral triazoles, which have broad applications in fields of synthetic chemistry, medicinal chemistry, biological chemistry, and materials science. The past six years have seen impressive developments in copper-, nickel-, iridium-, and rhodium-catalyzed E-AAC reactions. This review provides a brief summary on this evolution according to the different strategies implemented.

A transition-metal-free azide–alkyne cycloaddition/hydroamination cascade reaction for the construction of triazole-fused piperazin-2-ones

“…Based on pioneering reports 2–4 and our experimental observations, a plausible reaction process was proposed as shown in Scheme 6. The tandem transformation may be initiated through an azide–alkyne[3 + 2] cycloaddition followed by an intramolecular hydroamination cascade reaction.…”

“…1 The most attractive strategy to construct 1,2,3-triazoles is the thermal 1,3-dipolar cycloaddition reaction of alkynes and azides developed by Huisgen in the 1960s. 2 The discovery of copper( i )-catalyzed regioselective cycloaddition of organic azides with terminal alkynes by Sharpless and Meldal independently in 2002 3,4 further provided a concise synthesis of 1,4-disubstituted 1,2,3-triazoles and stimulated the broad applications of such structures in medicinal chemistry, 5 materials chemistry, 6 physical chemistry 7 and other fields. Particularly, among diverse structures, 1,2,3-triazoles fused with other heterocyclic moieties have attracted great attention due to their broad bioactivities such as antiviral, anti-tumor, antibacterial, antiallergic, and herbicidal activities (Fig.…”

Copper-catalyzed atroposelective synthesis of C–O axially chiral compounds enabled by chiral 1,8-naphthyridine based ligands

“… 9 Nonetheless, the investigation of asymmetric CuAAC has remained rather limited. 10 The primary hurdle in developing highly efficient asymmetric CuAAC processes lies in the limited availability of suitable chiral ligands. The chiral ligand family commonly employed in asymmetric CuAAC is Pybox ligands, 11 and the use of other ligands, e.g.…”

Enantioselective copper-catalyzed azidation/click cascade reaction for access to chiral 1,2,3-triazoles

“…Since being simultaneously reported by the groups of Sharpless 9 , 10 and Meldal 11 , copper-catalyzed azide-alkyne cycloaddition, also known as click reaction 12 – 19 , has emerged as a highly efficient and biocompatible strategy for synthesizing 1,2,3-triazoles. Despite the well-explored racemic version, the synthesis of chiral triazoles remains challenging mainly due to no sp 3 stereogenic center in the triazole skeleton and the linear geometry of the azide and alkyne 20 , 21 . In this context, Zhou 22 – 26 , Fossey 27 – 29 , Topczewski 30 , 31 , and others 32 – 39 have employed strategies such as (dynamic) kinetic resolution or desymmetrization to achieve a series of enantioselective copper-catalyzed click reaction of azides and terminal alkynes, which generated enantioenriched 1,4-disubstituted triazoles regioselectively (Fig.…”