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. 2022 Feb 2;13(1):632.
doi: 10.1038/s41467-022-28211-0.

Organocatalytic cycloaddition of alkynylindoles with azonaphthalenes for atroposelective construction of indole-based biaryls

Hui Yang #  1 , Huai-Ri Sun #  1 , Rui-Qing He  1 , Le Yu  1 , Wei Hu  1 , Jie Chen  1 , Sen Yang  1 , Gong-Gu Zhang  1 , Ling Zhou  2
Affiliations

Organocatalytic cycloaddition of alkynylindoles with azonaphthalenes for atroposelective construction of indole-based biaryls

Hui Yang et al. Nat Commun. .

Abstract

The axially chiral indole-aryl motifs are present in natural products and biologically active compounds as well as in chiral ligands. Atroposelective indole formation is an efficient method to construct indole-based biaryls. We report herein the result of a chiral phosphoric acid catalyzed asymmetric cycloaddition of 3-alkynylindoles with azonaphthalenes. A class of indole-based biaryls were prepared efficiently with excellent yields and enantioselectivities (up to 98% yield, 99% ee). Control experiment and DFT calculations illustrate a possible mechanism in which the reaction proceeds via a dearomatization of indole to generate an allene-iminium intermediate, followed by an intramolecular aza-Michael addition. This approach provides a convergent synthetic strategy for enantioselective construction of axially chiral heterobiaryl backbones.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Asymmetric construction of indole-based biaryls via cycloaddition strategies.
a Construction of indole derivatives via intramolecular cyclization. b CPA-catalyzed atroposelective intermolecular [3 + 2] cycloaddition.
Fig. 2
Fig. 2. Substrate scope.
aReactions were carried out with 7 (0.24 mmol), 8 (0.20 mmol), and 16c (0.004 mmol) in CHCl3 (2.0 mL) at −50 °C under N2. The yields shown are for isolated products and the ee values were determined by HPLC analysis. bThe reaction temperature is 40 °C.
Fig. 3
Fig. 3. Construction of diaxial compound 15ag.
The reaction was carried out with 7ag (0.05 mmol), 8a (0.125 mmol), and 16c (0.002 mmol) in CHCl3 (0.5 mL) at −50 °C under N2.
Fig. 4
Fig. 4. Gram-scale synthesis and transformations.
a Gram-scale synthesis of axially chiral compound 15a. b Transformation of compound 15a. c Synthesis of axially chiral organocatalyst.
Fig. 5
Fig. 5. Synthesis and application of chiral phosphine ligand.
a Synthesis of chiral phosphine ligand 25. b Asymmetric allylation using 25 as the ligand.
Fig. 6
Fig. 6. DFT calculations.
DFT-optimized chiral phosphoric acid-catalyzed transition states TS-1a–d, and their corresponding allene–iminium intermediates INT-2a–d.
See this image and copyright information in PMC

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