Total Synthesis of Luteoalbusin A and Formal Synthesis of T988 C

Lushun Wang; Xuelei Jia; Honghui Lei; Zhengshuang Xu; Tao Ye

doi:10.1055/s-0036-1591880

Synlett, Table of Contents

Synlett 2018; 29(05): 613-616
DOI: 10.1055/s-0036-1591880

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Total Synthesis of Luteoalbusin A and Formal Synthesis of T988 C

Lushun Wang

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, P. R. of China Email: yet@pkusz.edu.cn

,

Xuelei Jia

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, P. R. of China Email: yet@pkusz.edu.cn

,

Honghui Lei

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, P. R. of China Email: yet@pkusz.edu.cn

,

Zhengshuang Xu*

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, P. R. of China Email: yet@pkusz.edu.cn

,

Tao Ye *

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen, 518055, P. R. of China Email: yet@pkusz.edu.cn

› Author Affiliations

Abstract

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Abstract

An efficient total synthesis of luteoalbusin A was achieved in nine linear steps and in 17% overall yield from the known and easily accessible 3a-(3-indolyl)-hexahydropyrrolo[2,3-b]indole. A formal synthesis of (+)-T988 C through manipulation of the key intermediate is also reported.

Key words

total synthesis - natural products - alkaloids - indoles - stereoselective synthesis

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References

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26 Synthesis of luteoalbusin A (1): Hydrogen sulfide (ca. 2 mL) was condensed in a sealed tube (immersed in a Dewar at –78 °C) capped with a rubber septum. After a solution of 4 (9 mg, 14 μmol) in CH₂Cl₂ (2 mL) and BF₃·OEt₂ (18 μL, 0.14 mmol) were sequentially added by using syringes, the rubber septum was replaced with a sealed-tube stopper. The reaction vessel was slowly warmed to ambient temperature and stirred for 2 h. The reaction mixture was cooled to –78 °C again, and the sealed-tube stopper was changed to a rubber septum. The reaction vessel was connected by double-ended syringes to two tandem traps, which was filled with aqueous sodium hydroxide (100 mL, 20%). The cooling bath was removed, and the reaction solution was slowly warmed to room temperature. When gas evolution ceased, argon was used to purge for 0.5 h. Then the residue was dissolved in ethyl acetate (10 mL) and washed with a saturated aqueous solution of NH₄Cl (5 mL). The aqueous layer was back-extracted with ethyl acetate (2 × 5 mL). The combined organic layers were stirred at room temperature, a solution of I₂ (7 mg, 28 µmol) in ethyl acetate (1 mL) was added by using a syringe. The mixture was stirred for 2 min, and the reaction was quenched with sodium thiosulfate (5 mL, 10% aqueous solution). Layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: gradient, 25% ethyl acetate in hexane) to afford luteoalbusin A (1; 3.6 mg, 55%) as a white foam. TLC: R_f = 0.45 (50% ethyl acetate in hexane); [α]_D ²⁰ = 312.9 (c 0.5, acetone); ¹H NMR (500 MHz, acetone-d ₆): δ = 10.24 (br. s, 1 H), 7.57 (d, J = 8.2 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 1 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 8.0, 7.5 Hz, 1 H), 7.12 (dd, J = 7.9, 7.4 Hz, 1 H), 7.00 (dd, J = 8.0, 7.5 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.77 (dd, J = 8.0, 7.5 Hz, 1 H), 6.21 (br. s, 1 H), 5.99 (s, 1 H), 4.42 (d, J = 12.6 Hz, 1 H), 4.35 (d, J = 12.7 Hz, 1 H), 4.06 (d, J = 15.2 Hz, 1 H), 3.18 (s, 3 H), 3.10 (d, J = 15.3 Hz, 1 H). ¹³C NMR (125 MHz, acetone-d ₆): δ = 168.1, 164.4, 150.7, 139.6, 134.5, 130.6, 127.1, 125.9, 124.8, 123.7, 121.1, 121.1, 120.8, 118.4, 113.8, 111.6, 85.1, 79.1, 76.1, 61.8, 57.6, 45.7, 28.7. HRMS: m/z [M + Na]⁺ calcd. for C₂₃H₂₀N₄NaO₃S₂ ⁺: 487.0869; found: 487.0870.
27 Synthesis of 11: To a solution of compound 5 (16.0 mg, 0.026 mmol) and DTBMP (213 mg, 1.0 mmol) in acetonitrile (3 mL) at ambient temperature, trifluoroacetic anhydride (75 μL, 0.52 mmol) was added. After being stirred at room temperature for 14 h, the reaction mixture was diluted with ethyl acetate (50 mL). The organic solution was washed with an aqueous solution of NaHSO₄ (1 N, 2 × 10 mL), water (2 × 10 mL) and brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography (eluent: 15% ethyl acetate in hexanes) to afford 11 (13 mg, 86%) as a colorless oil. TLC: R_f = 0.81 (50% ethyl acetate in hexane); [α]_D ²⁰ = –6.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, acetone-d ₆): δ = 8.18 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.52 (s, 1 H), 7.41–7.31 (m, 3 H), 7.23 (d, J = 7.9 Hz, 1 H), 7.17–7.07 (m, 2 H), 6.91 (s, 1 H), 6.73 (s, 1 H), 5.72 (d, J = 1.1 Hz, 1 H), 5.06 (d, J = 1.2 Hz, 1 H), 3.24 (s, 3 H), 1.66 (s, 9 H), 1.55 (s, 9 H). ¹³C NMR (125 MHz, acetone-d ₆): δ = 155.4, 154.9, 152.7, 150.2, 143.0, 139.7, 137.2, 135.1, 134.6, 129.8, 129.0, 125.8, 125.4, 125.2, 125.0, 123.7, 121.1, 120.7, 120.2, 118.3, 116.5, 102.3, 85.1, 84.9, 82.8, 58.4, 29.8, 28.3, 28.3. HRMS: m/z [M + Na]⁺ calcd. for C₃₃H₃₄N₄O₆Na⁺: 605.2371; found: 605.2371.

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