ChemicalBook CAS DataBase List TETRAHYDROALSTONINE

TETRAHYDROALSTONINE synthesis

7synthesis methods

Product Name:TETRAHYDROALSTONINE
CAS Number:6474-90-4
Molecular formula:C21H24N2O3
Molecular Weight:352.43

1H-Pyrano[3,4-c]pyridine-4-carboxylic acid, 4a,5,6,7,8,8a-hexahydro-7-[2-(1H-indol-3-yl)ethyl]-1-methyl-, methyl ester, (1S,4aS,8aS)-

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Yield: 41%

Reaction Conditions:

Stage #1:2,3-seco-2,3-dihydroakuammigine with mercury(II) diacetate;edetate disodium;acetic acid in water at 80; for 4.5 h;Inert atmosphere;
Stage #2: with sodium tetrahydroborate;sodium hydroxide in methanol;water; pH=9 at 0; for 0.333333 h;Inert atmosphere;

Steps:

18 Tetrahydroalstonine (5)
[00070] To a solution of 2,3-secoakuammigine (11 mg, 0.03 1 mmol) in 5% aq. AcOH (0.69 mL, 0.045 M) was added a solution of mercuric acetate (22 mg, 0.068 mmol, 2.20 equiv) and EDTA disodium salt (25 mg, 0.068 mmol, 2.20 equiv) in water (0.69 mL). The resulting solution was kept under inert atmosphere and heated to 80 °C for 4.5 h (reaction progress monitored by LCMS). The reaction was then cooled to 0 °C, CH3OH (0.69 mL) was added, and the pH was adjusted to 9 by the addition of 1 M aq. NaOH. To the cold reaction mixture was then added NaBH4 (16 mg, 0.434 mmol, 14.0 equiv), and the reaction stirred at 0 °C for 20 mm (reaction progress monitored by LCMS). The excess NaBH4 was then destroyed by drop-wise addition of AcOH. The reaction was then basified to pH 9 with 1 M aq. NaOH, and the mixture was extracted with CH2C12 (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by preparatory TLC (20:80 EtOAc/hexanes) provided tetrahydroalstonine (4.5 mg, 0.0 13 mmol, 41% yield) as a colorless amorphous solid.[00071] Analytical data for 5: [ci]D25: -86.0° (c 0.10, CHC13); IR (film) 3358, 2923,2852, 1703, 1629, 1454, 1438 cm’; ‘H NIVIR (500 MHz, CDC13) 7.79 (s, 1H), 7.56 (s, 1H),7.45 (d, J 7.7 Hz, 1H), 7.28 (d, J 8.0 Hz, 1H), 7.12 (ddd, J= 8.0, 7.1, 1.3 Hz, 1H), 7.07 (td, J= 7.5, 1.1 Hz, 1H), 4.50 (dq, J 10.3, 6.2 Hz, 1H), 3.75 (s, 3H), 3.36 (dd, J= 11.6, 2.4 Hz, 1H),3.11 (dd, J 12.3, 2.0 Hz, 1H), 2.99 -2.89 (m, 2H), 2.79 - 2.67 (m, 3H), 2.59 -2.53 (m, 1H),2.52-2.47 (m, 1H), 1.70 (d, J= 10.6 Hz, 1H), 1.54 (q, J 12.2 Hz, 1H), 1.41 (d, J 6.2 Hz,3H). ‘3CNIVIR(125 MHz, CDCl3) 168.1, 155.9, 136.1, 134.7, 127.4, 121.6, 119.6, 118.2, 110.9, 109.7, 108.3, 72.6, 60.0, 56.5, 53.7, 51.3, 38.6, 34.4, 31.5, 21.9, 18.7. HRIVIS (ESI): Mass calcd for C21H25N203 [M+H] = 353.1865; found 353.1867.

References:

NORTHWESTERN UNIVERSITY;SCHEIDT, Karl A.;YOUNAL, Ashkaan;ZENG, Bi-Shun;MELTZER, Herbert Y. WO2016/179184, 2016, A2 Location in patent:Paragraph 00070; 00071