Chiral Phosphoric Acid Catalyzed Enantioselective [4+3]-Cyclization Reaction of Indol-4-ylmethanols and Quinone Esters

Abstract

An asymmetric [4+3]-cyclization reaction of racemic indol-4-ylmethanols and quinone esters catalyzed by chiral phosphoric acids has been developed. This method provides efficient access to biologically important [1]benzoxepino[5,4,3-cd]indoles featuring both axial and central chirality in good yields and up to 98% ee, as essentially single diastereomers, under mild reaction conditions.

Key words

chiral phosphoric acids - [4+3]-cycloaddition - asymmetric catalysis - indoles - quinones - benzoxepinoindoles

Publication History

Received: 22 April 2021

Accepted after revision: 03 June 2021

Accepted Manuscript online:
03 June 2021

Article published online:
25 June 2021

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• 8 2,6-Dihydro[1]benzoxepino[5,4,3-cd]indoles 3a–o: General Procedure To a mixture of the appropriate indol-4-ylmethanol 1 (0.05 mmol) and catalyst (S)-4a (0.0025 mmol, 5 mol%) in DCE (0.5 mL) was added the quinone ester 2 (0.06 mmol, 1.2 equiv), and the mixture was stirred at RT for 2 h. The resulting mixture was then purified by flash column chromatography [silica gel, EtOAc–PE (1:4)]. Methyl (6R)-10-Hydroxy-6-phenyl-2,6-dihydro[1]benzoxepino[5,4,3-cd]indole-11-carboxylate (3a) White solid; yield: 16.0 mg (86%; 98% ee); mp 260–261 °C; [α]_D ²⁰ –34.100 (c 1.00, CH₂Cl₂). HPLC [Daicel Chiralcel OD-H (250 × 4.6 mm), hexane/i-PrOH (70:30, 1.0 mL/min), λ = 254 nm]: t _R(major) = 8.680 min; t _R(minor) = 12.459 min. IR (film): 3391, 3297, 2952, 2925, 2853, 1705, 1536, 1443, 1319, 1212, 1125, 994, 864, 752 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.57 (d, J = 2.8 Hz, 1 H), 9.63 (s, 1 H), 7.64–7.13 (m, 7 H), 7.12–5.78 (m, 5 H), 3.80 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 169.94, 151.13, 140.19, 136.05, 135.94, 128.69, 128.43, 126.57, 126.51, 124.84, 123.29, 121.63, 121.32, 120.16, 117.39, 116.14, 113.32, 111.86, 111.36, 86.55, 52.73. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₃H₁₈NO₄: 372.1230; found: 372.1231.
• 9 Methyl (6R)-10-(Benzoyloxy)-6-phenyl-2,6-dihydro[1]benzoxepino[5,4,3-cd]indole-11-carboxylate (7) BzCl (0.1 mmol) was added to a mixture of 3a (0.1 mmol) and Et₃N (0.2 mmol) in CH₂Cl₂ (1 mL) cooled in an ice bath. The temperature was then increased to r.t and the mixture was stirred for 3 h then washed with H₂O. The organic phase was purified by flash column chromatography [silica gel, EtOAc–PE (1:4)] to give a white solid; yield: 41.3 mg (87%, 96% ee); mp 145–147 °C; [α]_D ²⁰ –25.8 (c 1.00, CH₂Cl₂). HPLC [Daicel Chiralpak AD-H column (250 × 4.6 mm), hexane–i-PrOH (70:30, 1.0 mL/min), λ = 254 nm]: t _R(major) = 14.899 min; t _R(minor) = 11.810 min. IR (film): = 3396, 3063, 3033, 2950, 2925, 1735, 1599, 1537, 1442, 1272, 1215, 1083, 1067, 1021, 731, 707, 669 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.71–8.63 (m, 1 H), 8.17 (dd, J = 8.0, 1.4 Hz, 2 H), 7.68–7.61 (m, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.47–7.34 (m, 6 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.16 (s, 1 H), 7.01 (t, J = 7.8 Hz, 2 H), 6.22 (d, J = 85.3 Hz, 2 H), 3.73 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.69, 164.89, 144.21, 139.20, 135.39, 133.78, 130.16, 128.98, 128.65, 128.42, 128.41, 128.31, 128.14, 127.09, 125.18, 124.51, 122.79, 122.08, 120.15, 118.16, 111.90, 111.11, 86.77, 77.20, 52.69. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₃₀H₂₁NNaO₅: 498.1312; found: 498.1313. CCDC 2081158 contains the supplementary crystallographic data for compound 7. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 10 Methyl (6R)-10-Hydroxy-6-phenyl-2,6-dihydro[1]benzoxepino[5,4,3-cd]indole-11-carboxylate (3a): 1 mmol Scale Reaction To a mixture of indol-4-ylmethanol 1a (1 mmol) and catalyst (S)-4a (0.05 mmol, 5 mol%) in DCE (5 mL) was added quinone ester 2a (1.2 mmol, 1.2 equiv), and the mixture was stirred at RT for 2 h. The mixture was then purified by flash column chromatography [silica gel, EtOAc–PE (1:4)] to give a white solid; yield: 289.5 mg [78%; 93% ee (99% ee after crystallization)].
• 11 Methyl 6-Phenyl-10-(tosylamino)-2,6-dihydro[1]benzoxepino[5,4,3-cd]indole-11-carboxylate (8) To a mixture of indol-4-ylmethanol 1 (0.05 mmol) and catalyst (R)-4h (0.005 mmol, 10 mol%) in DCE (0.5 mL) was added iminoquinone 8 (0.06 mmol, 1.2 equiv), and the mixture was stirred at RT for 6 h. The resulting mixture was then purified by flash column chromatography [silica gel, EtOAc–PE (1:4)] to give a white solid; yield: 21.4 mg (92%; 60% ee); mp 164–167 °C; [α]_D ²⁰ +14.023 (c 0.55, CH₂Cl₂). HPLC [Daicel Chiralpak IA column (250 × 4.6 mm), hexane/i-PrOH (70:30, 1.0 mL/min), λ = 254 nm]: t _R(major) = 15.998 min, t _R(minor) = 12.919 min. IR (film): 3400, 3268, 2955, 2925, 2854, 1609, 1545, 1479, 1385, 1305, 1159, 1091, 918, 813, 752, 665, 541 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.62 (d, J = 2.7 Hz, 1 H), 9.96 (s, 1 H), 7.68 (d, J = 2.7 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 2 H), 7.43 (d, J = 2.6 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.31 (m, 5 H), 7.21 (m, 2 H), 7.01 (dd, J = 7.7, 7.7 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.63 (dd, J = 8.6, 2.6 Hz, 1 H), 6.36 (d, J = 7.3 Hz, 1 H), 6.22 (s, 1 H), 2.33 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 152.65, 143.51, 139.92, 137.19, 136.72, 135.72, 133.91, 130.06, 129.66, 128.94, 128.54, 128.33, 127.25, 124.57, 124.33, 122.64, 121.58, 119.09, 118.50, 117.41, 113.39, 111.90, 85.42, 21.44. HRMS (ESI⁺): m/z [M + Na]⁺calcd for C₂₈H₂₂N₂NaO₃S: 489.1243; found: 489.1244.
• 12 Methyl 10-Hydroxy-2-methyl-6-phenyl-2,6-dihydro[1]benzoxepino[5,4,3-cd]indole-11-carboxylate (11) To a mixture of the indol-4-ylmethanol 10 (0.05 mmol) and catalyst (S)-4a (0.0025 mmol, 5 mol%) in DCE (0.5 mL) was added quinone ester 2a (0.06 mmol, 1.2 equiv) and the mixture was stirred at RT for 2 h. The mixture was then purified by flash column chromatography [silica gel, EtOAc–PE (1:4)] to give a yellow solid; yield: 16.2 mg (84%; 24% ee); mp 247–249 °C; [α]_D ²⁰ –6.830 (c 0.58, CH₂Cl₂). HPLC [Daicel Chiralcel OD-H column (250 × 4.6 mm), hexane–i-PrOH (70:30, 1.0 mL/min), λ = 254 nm]: t _R(major) = 12.721 min, t _R(minor) = 9.747 min. IR (film): 3439, 3377, 2925, 1728, 1537, 1466, 1322, 1266, 1207, 1122, 1066, 995, 750 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.67 (s, 1 H), 7.67–7.18 (m, 7 H), 7.11–5.87 (m, 5 H), 3.89 (s, 3 H), 3.85 (s, 3 H). ¹³C NMR (101 MHz, DMSO): δ = 169.79, 151.15, 140.11, 139.80, 136.69, 128.97, 128.70, 128.46, 127.26, 126.21, 126.07, 125.14, 124.79, 121.73, 120.10, 117.60, 113.41, 110.59, 110.18, 86.32, 52.87, 33.43. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₄H₂₀NO₄: 386.1387; found: 386.1386.