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. 2020 Nov 27;3(1):177.
doi: 10.1038/s42004-020-00425-7.

N-Heterocyclic carbene-catalyzed enantioselective hetero-[10 + 2] annulation

Qiupeng Peng  1 , Shi-Jun Li  2 , Bei Zhang  1 , Donghui Guo  1 , Yu Lan  3   4 , Jian Wang  5
Affiliations

N-Heterocyclic carbene-catalyzed enantioselective hetero-[10 + 2] annulation

Qiupeng Peng et al. Commun Chem. .

Abstract

Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. NHC-catalyzed normal and higher-order cycloaddition.
a NHC-catalyzed normal order cycloaddition. b NHC-catalyzed high order cycloaddition. c NHC-catalyzed higher-order cycloaddition (this work).
Fig. 2
Fig. 2. Scope of ketones.
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), cat. F (15 mol%), additive H (5 mol%), PhCO2Na (0.20 mmol) and DQ (0.22 mmol), hexane (2.0 mL), room temperature, 4 Å MS (60 mg), Ar, 36–96 h.
Fig. 3
Fig. 3. Scope of indole-2-carbaldehydes 1.
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), cat. F (15 mol%), additive H (5 mol%), PhCO2Na (0.20 mmol) and DQ (0.22 mmol), hexane (2.0 mL), room temperature, 4 Å MS (60 mg), Ar, 36–96 h. bDCM-Hexane (1:5) was used.
Fig. 4
Fig. 4. Postulated mechanistic pathways.
Postulated catalytic mechanism of [10 + 2] annulation.
Fig. 5
Fig. 5. Plot of initial rates vs catalyst and substrates.
a Plot of initial rates vs. catalyst concentrations. b Plot of initial rates vs. 1a concentrations. c Plot of initial rates vs. 2a concentrations. d Plot of initial rates vs. DQ concentrations.
Fig. 6
Fig. 6. The DFT investigation on the enantioselectivity of the [10 + 2] annulation.
a The two transition states of TS(II–III)R and TS(II–III)S Gibbs free energy barriers and distortion energies comparing. b NCI analysis of the TS(II–III)R and TS(II–III)S. c The IRC of transition state TS(II)R.
Fig. 7
Fig. 7. Gram scale synthesis and transformation.
a Reaction conditions: 1e (4.0 mmol), 2a (4.8 mmol), F (0.60 mmol), DQ (4.4 mmol), additive H (0.20 mmol), PhCO2Na (4.0 mmol), Hexane (33.4 mL) and DCM (6.6 mL), room temperature, 4 Å M.S. (600 mg), Ar, 40 h. b Reaction conditions: 3d (0.05 mmol), 5 (0.10 mmol), K2CO3 (0.10 mmol) and Pd(PPh3)4 (0.005 mmol), toluene (0.5 mL), 80 °C, 18 h.
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