Enantioselective synthesis of chiral quinohelicenes through sequential organocatalyzed Povarov reaction and oxidative aromatization

Abstract

Heterohelicenes are of increasing importance in the fields of materials science, molecular recognition, and asymmetric catalysis. However, enantioselective construction of these molecules, especially by organocatalytic methods, is challenging, and few methods are available. In this study, we synthesize enantioenriched 1-(3-indol)-quino[n]helicenes through chiral phosphoric acid-catalyzed Povarov reaction followed by oxidative aromatization. The method has a broad substrate scope and offers rapid access to an array of chiral quinohelicenes with enantioselectivities up to 99%. Additionally, the photochemical and electrochemical properties of selected quinohelicenes are explored.

Fig. 1. Background introduction and overview of this work.

A The development of asymmetric synthesis of central-, axial- and helical- chirality. B Application examples of quino-containing helicenes. C Enantioselective synthesis of quinohelicenes. D Overview of this work.

Fig. 2. Energy barrier to racemization of 1-(3-indol)-quino[5]helicene.

The relative Gibbs free energy (kcal/mol) was calculated at the SMD(Toluene)/M06-2X-D3/def2-TZVPP//B3LYP D3(BJ)/def -2-SVP level of theory.

Fig. 3. Optimization of the reaction conditions.

Optimization of conditions for (A) the Povarov reaction and (B) the oxidative aromatization: ^aPovarov reaction conditions: 1a (0.05 mmol) and 2a (0.2 mmol) were heated in toluene (1.5 mL) at 110 °C for 12 h; then 3a (0.1 mmol) and CPA* (0.0025 mmol) were added at room temperature (rt), and the reaction was allowed to proceed for 12 h. The dr value for 4a was >20:1. ^bIsolated yields are reported. ^cThe ee values were determined by high-performance liquid chromatography with a chiral stationary phase. ^dOxidative aromatization conditions: 4a (0.05 mmol, 99% ee) and 1,2-dichloro-4,5-dicyanobenzoquinone (DDQ, 0.15 mmol) in solvent (2 mL) were allowed to react at rt for 3 h. ^eConversion percentage (cp) = ee_4a/ee_5a × 100%.

Fig. 4. Scope of the reaction.

Scope with respect to (A) aromatic aldehyde 2 and (B) indole 3. Reaction conditions: (1) 1a (0.1 mmol) and 2 (0.4 mmol) in toluene (2 mL) were heated at 110 °C for 12 h. After the mixture was cooled to room temperature, 3 (0.2 mmol) and (S)-A5 (0.005 mmol) were added, and the reaction was allowed to proceed for 12 h. Silica gel column chromatography gave 4. (2) Reaction of 4 and DDQ (0.3 mmol) in DCM (3 mL) at room temperature for 3 h afforded 5.

Fig. 5. Scope of the reaction.

Scope with respect to aromatic amines (A), (B), (C). Reaction conditions: (1) 1 (0.1 mmol) and 2a (0.4 mmol) in toluene (2 mL) were heated at 110 °C for 12 h. After the mixture was cooled to room temperature, 3a (0.2 mmol) and (S)-A5 (0.005 mmol) were added, and the reaction was allowed to proceed for 12 h. Silica gel column chromatography gave 4. (2) Reaction of 4 and DDQ (0.3 mmol) and DCM (3 mL) at room temperature for 3 h afforded 5.

Fig. 6. Synthetic application.

Experiments about (A) Large-scale reaction and synthetic transformation, and (B) One-pot reaction. ^aThe large-scale reaction was conducted under the optimized reaction conditions. ^bThe one-pot reaction was conducted with 1a (0.1 mmol), 2a (0.4 mmol), 3a, and (S)-A5 (0.005 mmol) in solvent (2 mL) at rt for 24 h; then DDQ (0.5 mmol) was added, and the reaction was allowed to continue for another 3 h.

Fig. 7. Racemization experiments.

Barriers to racemization of (A) helical chirality and (B) axial chirality. ^aExperimental relative Gibbs free energy (kcal/mol). ^bRelative Gibbs free energies were calculated at the SMD(Toluene)/M06-2X-D3/def2-TZVPP//B3LYP D3(BJ)/def −2-SVP level of theory.

Fig. 8. Photophysical properties of selected quinohelicenes.

A Summary of optical characterization data. B Solvent effect of 5a. C Acid effect of 5a. D Circular dichroic absorption (CD) of M/P-5a and M/P-5al. E Circular polarization luminescence (CPL) of M/P-5a and M/P-5al. ^aMeasured at a concentration of 1 × 10⁻⁵ M in DCM. ^bMaximum UV absorption. ^cMaximum fluorescence wavelength (λ_ex¹) and fluorescence lifetime (λ_ex²). ^dAbsolute fluorescence quantum efficiency for absorbance of < 0.1. ^eMeasured for compounds with 99% ee. g_abs = Absorption dissymmetry factors; g_lum = luminescence dissymmetry factors.