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Synlett 2007(20): 3137-3140  
DOI: 10.1055/s-2007-990911
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies on Haplophytine: Protective-Group-Controlled Rearrangement

Koji Matsumotoa, Hidetoshi Tokuyamaa,b, Tohru Fukuyama*a
a Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)58028694; e-Mail: fukuyama@mol.f.u-tokyo.ac.jp;
b Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
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Publication History

Received 8 October 2007
Publication Date:
21 November 2007 (online)

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Abstract

The characteristic tetracyclic structure of haplophytine containing a bridged ketone, aminal, and γ-lactam was constructed by oxidative rearrangement of a tetrahydro-β-carboline derivative.

Key words

haplophytine - aspidophytine - alkaloids - oxidations - rearrangements

    References and Notes

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16

Major product 17: mp 220-222 °C (dec.); IR (film): 3419, 3332, 2937, 1732, 1666, 1610, 1516, 1481, 1400, 912, 758 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.4 Hz, 1 H), 7.20 (t, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 6.98 (t, J = 8.4 Hz, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.38 (d, J = 8.0 Hz, 1 H), 3.59 (s, 3 H), 3.18-3.04 (m, 3 H), 2.84 (s, 6 H), 2.82-2.77 (m, 1 H), 2.69-2.60 (m, 2 H), 2.52-2.44 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 204.8, 169.1, 149.3, 143.0, 141.9, 139.9, 135.2, 127.9, 125.7, 124.4, 123.8, 121.3, 115.7, 104.7, 93.5, 64.0, 59.1, 58.4, 45.6, 42.1, 33.7, 31.3, 30.2. HRMS-FAB: m/z calcd for C23H25N3O4 [M + H]+: 408.1923; found: 408.1918.

17

Compound 25: IR (film): 2944, 1706, 1681, 1601, 1390, 1336, 1158, 912, 756 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 7.2 Hz, 1 H), 7.35-7.24 (m, 13 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.03 (t, J = 8.4 Hz, 1 H), 5.11 (br s, 4 H), 3.65-3.55 (m, 2 H), 3.62 (br s, 3 H), 3.59 (br s, 3 H), 3.44-3.35 (m, 1 H), 3.27-3.20 (m, 1 H), 3.20 (s, 3 H), 2.99 (dt, J = 7.2, 15.6 Hz, 1 H), 2.76 (dd, J = 3.6, 15.6 Hz, 1 H), 2.46 (dt, J = 5.2, 15.6 Hz, 1 H), 1.82 (dt, J = 7.2, 14.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 166.2, 155.9, 152.6, 150.2, 140.2, 137.1, 136.9, 136.4, 135.9, 133.2, 128.8, 128.7, 128.6, 128.5, 128.1, 124.6, 124.5, 123.2, 122.0, 115.9, 67.7, 67.4, 60.5, 60.1, 49.3, 41.9, 37.9, 33.4, 21.3, 14.5. HRMS-FAB: m/z calcd for C39H37N3O7: 659.2632; found: 659.2630.

18

Oxidative Rearrangement
To a solution of 25 (100 mg, 0.152 mmol) in CH2Cl2 (1.5 mL) was added NaHCO3 (38.2 mg, 0.455 mmol) and MCPBA (40.2 mg, 65% purity, 0.152 mmol) at 0 °C under an argon atmosphere. After stirring for 2 h at the same temperature, the reaction mixture was quenched with sat. Na2SO3 and stirred for 10 min. Then to the two-phase mixture was added CH2Cl2, and the organic layer was separated. The organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. Filtration and concentration on a rotary evaporator afforded a crude product. The crude product was purified by flash column chromatography on silica gel (neutral; 30-40% EtOAc in hexane, gradient elution) to give 26 (84.1 mg, 82%). IR (film): 2944, 1709, 1458, 1394, 1316, 1159, 912, 756 cm-1. 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ = 8.29 (d, J = 8.4 Hz, 0.5 H), 8.08 (d, J = 8.0 Hz, 0.5 H), 7.36-6.95 (m, 14 H), 6.80 (dd, J = 7.2, 11.2 Hz, 1 H), 5.15 (br s, 2 H), 5.12 (s, 2 H), 3.83-3.76 (m, 0.5 H), 3.68-3.52 (m, 1.5 H), 3.68 (br s, 1.5 H), 3.61 (br s, 1.5 H), 3.41-3.29 (m, 1 H), 3.25 (s, 3 H), 2.99 (br s, 1 H), 2.88-2.76 (m, 1 H), 2.80 (br s, 3 H), 2.66-2.43 (m, 1.5 H), 2.25-2.05 (m, 1 H), 1.95-1.86 (m, 0.5 H). 13C NMR (100 MHz, CDCl3, doubling due to rotamers): δ = 195.2, 171.9, 168.0, 155.4, 154.6, 149.4, 149.2, 140.2, 136.3, 136.2, 135.3, 135.1, 134.8, 132.8, 130.5, 128.4, 128.3, 128.0, 127.8, 127.2, 125.3, 123.9, 122.9, 122.2, 121.8, 120.8, 120.5, 120.2, 115.7, 81.4, 67.7, 67.6, 66.9, 59.9, 58.1, 56.4, 52.3, 46.1, 40.4, 39.3, 37.4, 36.1, 30.6, 30.3, 30.1, 21.0. HRMS-FAB: m/z calcd for C39H37N3O8: 675.2581; found: 675.2578.