Method for asymmetric synthesis of Aspidosperma alkaloids

An alkaloid and asymmetric technology, applied in asymmetric synthesis, organic chemistry methods, chemical instruments and methods, etc., can solve chiral synthesis with low abundance and inability to achieve structural diversity, single achiral natural products, etc. question

Active Publication Date: 2017-11-03
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they are low in abundance in nature and difficult to extract, which increases the difficulty of research on their physiological and pharmacological activities and hinders further research and application of this type of compound
Most of the routes in the past can only synthesize a single achiral natural product, and cannot achieve chiral synthesis of structural diversity

Method used

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  • Method for asymmetric synthesis of Aspidosperma alkaloids
  • Method for asymmetric synthesis of Aspidosperma alkaloids
  • Method for asymmetric synthesis of Aspidosperma alkaloids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Synthesis of formula (2a) compound

[0119]

[0120] The compound of formula (1) (4.09g, 2.61mmol, 1.0equiv.) was dissolved in toluene (100mL), and diisobutylaluminum hydride (10mL, 3.91mmol, 1.5equiv., 1.5Mintoluene) The reaction was raised to -40°C and stirred for 3 hours. The reaction was quenched with saturated sodium potassium tartrate solution (20 mL), and stirred at room temperature until the reaction solution was clear. The toluene was removed under reduced pressure, and the aqueous phase was extracted with ethyl acetate (3x50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a colorless oily liquid (no need for separation and purification by column chromatography).

[0121] Dissolve this oily liquid in toluene (100mL), add Ph 3 P=CHCO 2 Me (5.05g, 3.41mmol, 1.5equiv.), the reaction was raised to reflux at 110°C for 4 hours. After removing toluene under reduced pressure, direct column chromato...

Embodiment 2

[0124] Synthesis of formula (3a) compound

[0125]

[0126] The compound of formula (2a) (3.55g, 7.65mmol, 1.0equiv.) was dissolved in dichloromethane (76mL), and Dess-Martin oxidant (3.89g, 9.17mmol, 1.2equiv.) was added at 0°C to react Warm to room temperature and stir for 1 hour. After completion of the reaction, add saturated sodium thiosulfate solution (25mL) and saturated sodium bicarbonate solution (25mL) successively, extract the system with dichloromethane (3x50mL) and dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and perform column chromatography Isolation (petroleum ether: ethyl acetate = 10:1) gave white foam formula (3a) compound (3.23g, 92%).

[0127] The detection data of formula (3a) compound is as follows: 1 HNMR (500MHz, CDCl 3 )δ7.38–7.35(m,5H),7.15(s,1H),6.99(d,J=16.2Hz,1H),5.73(d,J=16.2Hz,1H),5.19(s,1H), 5.14–5.10(m,1H),4.70(d,J=7.8Hz,1H),3.73(s,3H),3.61–3.53(m,1H),3.47–3.39(m,1H),3.09(dt, J=12.8,8.3Hz,1H),2.35...

Embodiment 3

[0129] Synthesis of formula (4a) compound

[0130]

[0131] Formula (3a) (3.23g, 7.01mmol, 1.0equiv), 4A, MS (1.26g), sodium carbonate (2.45g, 14.02mmol, 2.0equiv.) and 3-methoxyphenylhydrazine (1.48g, 14.02 mmol, 2.0 equiv.) was dissolved in toluene (140 mL), and the reaction was raised to 110° C. and refluxed for 12 hours. Sodium carbonate (2.45 g, 14.02 mmol, 2.0 equiv.) and 3-methoxyphenylhydrazine (1.48 g, 14.02 mmol, 2.0 equiv.) were added. After the reaction was completed, it was cooled to room temperature, and the benzene was removed under reduced pressure to obtain a brown solid directly (without separation and purification by column chromatography). The brown solid was dissolved in 1,2-dichloroethane (140 mL), and the reaction was raised to 80° C. and trifluoroacetic acid (15.96 g, 140.2 mmol, 20.0 equiv) was added to reflux for 1 hour. After the reaction was completed, cool to room temperature, adjust the pH to 8-9 with saturated sodium bicarbonate solution, ex...

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Abstract

The invention discloses a method for asymmetric synthesis of Aspidosperma alkaloids. According to the method, a bridged ring compound as shown in a formula (1) is subjected to reduction, the Wittig reaction, oxidation, Fischer indole rearrangement and the like so as to obtain a key intermediate, i.e., a compound as shown in a formula (4); the compound as shown in the formula (4) undergoes a variety of conversion so as to obtain a series of Aspidosperma alkaloids; and reaction routes are as shown in a route (1). The method provided by the invention starts with the compound as shown in the formula (1) and can provide good technical support for subsequent mass production of Aspidosperma alkaloids and research on structure-activity relationship.

Description

technical field [0001] The invention belongs to the technical field of synthetic process application of organic compounds, and in particular relates to a method for asymmetrically synthesizing Quaia alkaloids. Background technique [0002] Indole alkaloids are a class of compounds that widely exist in nature. Vinblastine and Vincristine are widely used anti-cancer drugs developed by Eli Lilly, and vintafolide is a compound developed by Endocyte for the treatment of non-small cell carcinoma, which is currently in clinical phase II. They belong to the class of bisindole vinca alkaloids. Another class of monoterpene indole alkaloids—Quainia alkaloids (Aspidosperma alkaloids) also has good biological activity. For example, the inhibitory effect of Tabersonine on human cancer cell line SK-BR-3 is better than that of cisplatin ( Cisplatin), Jerantinine-E has stronger cytotoxicity to human KB cells and so on. However, their abundance in nature is low and extraction is difficult,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/20C07D487/10C07D209/08C07B53/00
CPCC07B53/00C07B2200/07C07D209/08C07D471/20C07D487/10
Inventor 姜雪峰王能中白磊阳
Owner EAST CHINA NORMAL UNIV
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