Enantioselective Copper Catalyzed Alkyne–Azide Cycloaddition by Dynamic Kinetic Resolution

Abstract

The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle. Designing a chiral catalyst is further complicated by the complex mechanism of CuAAC. We report an enantio-selective CuAAC (E-CuAAC), enabled by dynamic kinetic resolution (DKR). The E-CuAAC is high yielding and affords up to 99:1 er. The E-CuAAC can directly generate α-chiral triazoles in a complex molecular environment.

Coinage Metal (Bisfluorosulfonyl)imide Complexes: Preparation, Characterization, and Catalytic Applications

“…Copper(II) salts bearing weakly coordinating counteranions, such as CuSO 4 and Cu(OTf) 2 , have been widely used as pre‐catalyst in transition metal catalysis . The commercially available Cu(II)(NTf 2 ) 2 , firstly reported by Sonoda et al in 1997, exhibited excellent catalytic activities in several copper catalyzed reactions .…”

Allylic azides: synthesis, reactivity, and the Winstein rearrangement

“…Recently, Topczewski and Liu reported an enantioselective CuAAC (E-CuAAC) with allylic azides that proceeds by dynamic kinetic resolution (Scheme 29f). 243 This reaction is noteworthy because the resulting triazole was isolated in high ee and high yield using the racemic azide as the limiting reagent. The authors provided several examples demonstrating that this reaction can proceed with good stereocontrol in a complex molecular environment.…”

Enantioselective synthesis of P-chiral tertiary phosphine oxides with an ethynyl group via Cu(i)-catalyzed azide–alkyne cycloaddition

“…[22][23][24] On the other hand, the application of CuAAC for the kinetic resolution of racemic alkynes or azides is in its infancy, 22,25 although Topczewski most recently made a notable advance with an elegant dynamic kinetic resolution of allylic azides. 26 We speculate that asymmetric CuAAC is a promising approach to access P-chiral synthons featuring an acetylene group, by desymmetrization or kinetic resolution (Scheme 1c). The advantages of this method include: (1) easy access to di-and monoethynyl-phosphine oxides 1 and 4 (onepot, 2-3 steps, see ESI †); and (2) the usefulness of the P-chiral phosphine oxides 3 and 4.…”