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Asymmetric Construction of Benzindoloquinolizidine: Application of An Organocatalytic Enantioselective Conjugate Addition-Cyclization Cascade Reaction
Asymmetric Construction of Benzindoloquinolizidine: Application of An Organocatalytic Enantioselective Conjugate Addition-Cyclization Cascade Reaction
Bulletin of the Korean Chemical Society. 2014. Feb, 35(2): 625-628
Copyright © 2014, Korea Chemical Society
  • Received : August 05, 2013
  • Accepted : November 09, 2013
  • Published : February 20, 2014
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Cheolwoong Kim
Seung Woo Seo
Yona Lee
Sung-Gon Kim

Abstract
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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 CHCl 3 (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. NaHCO 3 solution and extracted with CH 2 Cl 2 . 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, CH 2 Cl 2 ) 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 t r = 25.0 min and major - isomer t r = 37.6 min.
Dimethyl 2-((14R)-6,7,12,12b,13,14-Hexahydro-6-oxoindolo[2,3-a]quinolizine-14-yl)malonate (3a):
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˗33.4 ( c 0.24, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 24 H 22 N 2 O 5 Na (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):
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˗55.3 ( c 0.26, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 26 H 26 N 2 O 5 Na (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):
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˗43.8 ( c 0.58, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 28 H 30 N 2 O 5 Na (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):
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˗21.7 ( c 0.26, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 36 H 30 N 2 O 5 Na (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):
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13.1 ( c 0.23, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 24 H 21 ClN 2 O 5 Na (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):
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44.3 ( c 0.60, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (100 MHz, CDCl 3 ) 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 C 24 H 21 BrN 2 O 5 Na (M+Na) + : 519.0532. Found: 519.0530.
Acknowledgements
This research was supported by Nano-Material Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2012M3A7B4049648).
References
Heo S. , Kim S. , Kim S.-G. 2013 Tetrahedron Lett 54 4978 -