Financial support from the National Natural Science Foundation of China (22071213), the Leading Talents of Special Support Program of Zhejiang Province High-level Talents (2020R52008), and Center of Chemistry for Frontier Technologies of Zhejiang University is gratefully acknowledged.
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.
1b
Ogawa H,
Yamashita H,
Kondo K,
Yamamura Y,
Miyamoto H,
Kan K,
Kitano K,
Tanaka M,
Nakaya K,
Nakamura S,
Mori T,
Tominaga M,
Yabuuchi Y.
J. Med. Chem. 1996; 39: 3547
82,6-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]D20 –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]: tR(major) = 8.680 min; tR(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-d6): 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-d6): 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.
9Methyl (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]D20 –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]: tR(major) = 14.899 min; tR(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
10Methyl (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)].
