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Asymmetric Construction of Benzindoloquinolizidine: Application of An Organocatalytic Enantioselective Conjugate Addition-Cyclization Cascade Reaction

  • Kim, Cheolwoong (Department of Chemistry, College of Natural Science, Kyonggi University) ;
  • Seo, Seung Woo (Department of Chemistry, College of Natural Science, Kyonggi University) ;
  • Lee, Yona (Department of Chemistry, College of Natural Science, Kyonggi University) ;
  • Kim, Sung-Gon (Department of Chemistry, College of Natural Science, Kyonggi University)
  • Received : 2013.08.05
  • Accepted : 2013.11.09
  • Published : 2014.02.20
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Abstract

Keywords

Experimental

General Procedure. An amber 2-dram vial equipped with a magnetic stir bar, containing catalyst I (98 mg, 0.30 mmol), o-N-(3-indoleacetyl)aminocinnamaldehyde 1a (457 mg, 1.5 mmol) and 4-nitrobenzoic acid (50 mg, 0.30 mmol) was charged with DMF (8 mL) at 0 ℃. The solution was stirred for 5 min before the addition of dimethyl malonate 10a (257 L, 2.3 mmol). The resulting mixture was stirred at constant temperature until complete consumption of o-N-(3-indoleacetyl)aminocinnamaldehyde 1a was observed as determined by TLC. The resulting mixture was directly purified by silica gel chromatography (50% EtOAc/hexanes) to afford the desired compound 2a as a colorless gum (584 mg, 90% yield, 96% ee). To a solution of tetrahydroquinolin- 2-ol 2a (96 mg, 0.22 mmol) in CHCl3 (1.2 mL) at ˗78 ℃ was added HCl (0.44 mL, 1.8 mmol, 4 M solution in 1,4-dioxane). After 20 minutes, the mixture was allowed to warm up to room temperature and stirred for 2 h. The reaction was quenched with sat. NaHCO3 solution and extracted with CH2Cl2. The combined extract was washed with brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography (40% EtOAc/Hexane) to afford the benzindoloquinolizidine 3a as a colorless gum (52 mg, 56% yield). The enantioselectivity was determined by HPLC analysis of the tetrahydroquinolinone product, which was prepared by oxidation (PCC, CH2Cl2) of 2a, using a Chiralcel AD-H column and AD-H guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 220 nm); minor- isomer tr = 25.0 min and major- isomer tr = 37.6 min.

Dimethyl 2-((14R)-6,7,12,12b,13,14-Hexahydro-6-oxoindolo[2,3-a]quinolizine-14-yl)malonate (3a): ˗33.4 (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.41 (dd, J = 0.8, 8.4 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.01- 7.44 (m, 6H), 4.74 (dd, J = 2.8, 12.8 Hz, 1H), 3.75 (s, 3H), 3.60-3.72 (m, 2H), 3.57 (s, 3H), 3.43 (d, J = 19.6 Hz, 1H), 2.54 (d, J = 16.4 Hz, 1H), 1.51 (td, J = 4.4, 12.8 Hz, 1H), 1.17 (dt, J = 2.8,14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.1, 171.2, 168.0, 167.6, 155.2, 138.0, 136.2, 129.6, 129.3, 128.8, 127.0, 124.4, 123.7, 122.6, 122.1, 118.5, 57.7, 55.3, 52.9, 52.6, 38.6, 36.1, 25.6; HRMS (ESI): Calcd for C24H22N2O5Na (M+Na)+: 441.1426. Found: 441.1428.

Diethyl 2-((14R)-6,7,12,12b,13,14-Hexahydro-6-oxoindolo[2,3-a]quinolizine-14-yl)malonate (3b): ˗55.3 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.02-7.44 (m, 6H), 4.77 (dd, J = 2.8, 12.8 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.65-3.72 (m, 1H), 3.59 (d, J = 10.0 Hz, 1H), 3.43 (d, J = 16.4 Hz, 1H), 2.54 (d, J = 16.4 Hz, 1H), 1.50 (td, J = 4.4, 14.0 Hz, 1H), 1.22-1.30 (m, 4H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 171.2, 167.6, 167.3, 155.2, 138.0, 136.2, 129.8, 129.2, 128.7, 127.0, 124.5, 123.6, 122.6, 122.1, 118.4, 62.0, 61.7, 58.0, 55.4, 38.6, 36.0, 25.7, 14.1, 13.8; HRMS (ESI): Calcd for C26H26N2O5Na (M+Na)+: 469.1739. Found: 469.1738.

Diisopropyl 2-((14R)-6,7,12,12b,13,14-Hexahydro-6-oxo-indolo[2,3-a]quinolizine-14-yl)malonate (3c): ˗43.8 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.01-7.43 (m, 6H), 5.04 (septet, J = 6.4 Hz, 1H), 4.92 (septet, J = 6.4 Hz, 1H), 4.80 (dd, J = 2.8, 12.8 Hz, 1H), 3.64-3.71 (m, 1H), 3.53 (d, J = 10.0 Hz, 1H), 3.42 (d, J = 16.4 Hz, 1H), 2.52 (d, J = 16.4 Hz, 1H), 1.48 (td, J = 4.8, 14.0 Hz, 1H), 1.22-1.28 (m, 7H), 1.17 (d, J = 6.0 Hz, 3H), 1.03 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 171.4, 167.3, 167.0, 142.2, 138.2, 136.3, 130.1, 129.3, 128.7, 127.1, 124.8, 123.8, 122.7, 118.5, 69.9, 69.6, 61.0, 58.5, 55.6, 38.8, 35.8, 21.8, 21.7, 21.6, 21.5; HRMS (ESI): Calcd for C28H30N2O5Na (M+Na)+: 497.2052. Found: 497.2053.

Dibenzyl 2-((14R)-6,7,12,12b,13,14-Hexahydro-6-oxoindolo[2,3-a]quinolizine-14-yl)malonate (3d): ˗21.7 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 6.85-7.40 (m, 16H), 5.11 (s, 2H), 4.95 (dd, J = 12.4, 23.6 Hz, 2H), 4.57 (dd, J = 2.8, 12.8 Hz, 1H), 3.67-3.74 (m, 2H), 3.23 (d, J = 16.4 Hz, 1H), 2.43 (d, J = 16.4 Hz, 1H), 1.44 (td, J = 4.4, 14.4 Hz, 1H), 1.16 (ddd, J = 2.0, 3.2, 14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.6, 172.2, 171.4, 167.5, 148.6, 147.2, 138.2, 128.9, 128.8, 128.7, 128.6, 128.5, 124.3, 122.6, 121.7, 118.5, 116.4, 67.8, 67.7, 60.8, 58.0, 38.7, 36.1, 25.7; HRMS (ESI): Calcd for C36H30N2O5Na (M+Na)+: 593.2052. Found: 593.2055.

Dimethyl 2-((14R)-2-Chloro-6,7,12,12b,13,14-hexahydro-6-oxo-indolo[2,3-a]quinolizine-14-yl)malonate (3e): 13.1 (c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.17- 7.43 (m, 5H), 4.70 (dd, J = 2.8, 12.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.54-3.64 (m, 2H), 3.32 (d, J = 16.8 Hz, 1H), 2.53 (d, J = 16.8 Hz, 1H), 1.45 (td, J = 4.4, 13.6 Hz, 1H), 1.15 (dt, J = 2.4, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.9, 167.5, 154.7, 142.2, 142.1, 141.9, 141.6, 141.4, 140.0, 139.0, 134.8, 129.4, 128.9, 127.2, 126.2, 119.9, 57.6, 55.3, 52.9, 37.1, 29.8, 25.5; HRMS (ESI): Calcd for C24H21ClN2O5Na (M+Na)+: 475.1037. Found: 475.1038.

Dimethyl 2-((14R)-2-Bromo-6,7,12,12b,13,14-hexahydro-6-oxo-indolo[2,3-a]quinolizine-14-yl)malonate (3f): 44.3 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.20- 7.45 (m, 5H), 4.69 (dd, J = 2.8, 12.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.56-3.62 (m, 2H), 3.41 (d, J = 16.4 Hz, 1H), 2.52 (d, J = 16.8 Hz, 1H), 1.43 (td, J = 4.0, 14.0 Hz, 1H), 1.15 (dt, J = 2.4, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.4, 167.9, 167.45, 148.6, 135.8, 135.3, 132.4, 131.8, 129.5, 127.2, 126.6, 122.5, 122.4, 120.2, 116.5, 57.6, 55.3, 52.9, 38.6, 35.9, 25.5; HRMS (ESI): Calcd for C24H21BrN2O5Na (M+Na)+: 519.0532. Found: 519.0530.

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