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A method for the synthesis of a series of monoterpene indole alkaloid skeletons and natural products based on free radical tandem reactions

A nitrobenzenesulfonyl, selected technology, applied in the field of photocatalytic free radical tandem reaction technology to synthesize a series of monoterpene indole alkaloid skeletons, can solve the problems of poor versatility, high cost, cumbersome routes, etc.

Active Publication Date: 2020-07-24
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although so far many research teams at home and abroad have carried out detailed research on the synthesis of monoterpene indole alkaloids (alkaloid chemistry, edited by Wang Fengpeng, Chemical Industry Press: Beijing, 2008; P293-340), known methods Usually only one or a few molecules in a certain type of skeleton can be synthesized, and there are problems such as cumbersome routes, low yield, high cost and poor versatility

Method used

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  • A method for the synthesis of a series of monoterpene indole alkaloid skeletons and natural products based on free radical tandem reactions
  • A method for the synthesis of a series of monoterpene indole alkaloid skeletons and natural products based on free radical tandem reactions
  • A method for the synthesis of a series of monoterpene indole alkaloid skeletons and natural products based on free radical tandem reactions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Preparation of compound IX

[0066]

[0067] Compound VII (10.0g, 0.056mol, 1.0equiv.), tert-butyl methyl maleate (12.3ml, 0.074mol, 1.3equiv.) and (2S)-2-(diphenyl[(trimethylsilyl) Ester)oxy]methyl]-pyrrolidine VIII (3.7g, 0.011mol, 0.2equiv.) was placed in a 250mL round bottom flask, and 100mL ethanol was added and stirred. After 16h reaction at room temperature, the solvent was drained. Column chromatography (petroleum ether: ethyl acetate, 5:1, v / v) obtained two diastereomers IX-a and IX-b (total 15.1g), the yield was 76%.

[0068] The detection data of compounds IX-a and IX-b are as follows: IX-a: TLC (petroleum ether: ethyl acetate, 5:1 v / v): R f = 0.30; 1 H NMR(400MHz, CDCl 3 ): δ9.68(s,1H), 7.81(d,J=8.8Hz,1H), 7.55(t,J=7.2Hz,1H), 7.46(d,J=7.6Hz,1H), 7.39(t ,J=8.4Hz,1H),4.56–4.50(m,1H),3.83(d,J=9.2Hz,1H),3.57(s,3H),3.12–2.97(m,2H),1.43(s, 9H); 13 C NMR(100MHz, CDCl 3 ):δ199.6,167.9,166.5,150.3,134.8,132.8,129.3,128.2,124.7,83.2,57.2,52.6,46.6,33.7,27.8,2...

Embodiment 2

[0069] Example 2: Preparation of Compound X

[0070]

[0071] After the mixtures IX-a and IX-b (40.2 g, 0.114 mol, 1.0 equiv.) were dissolved in dichloromethane (333 mL), trifluoroacetic acid (267 mL) was slowly added. After 3h reaction at room temperature, the solvent was drained. After the residue was dissolved in dichloromethane (200 mL), the solvent was drained. This operation was repeated three times to remove residual trifluoroacetic acid. After the crude product was dissolved in toluene (333 mL), triethylamine (23.7 mL, 0.170 mol, 1.5 equiv.) was added. The reaction was refluxed for 2h. After the solvent was drained, water (100mL) and saturated brine (200mL) were added. It was extracted three times with ethyl acetate (3×500mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was drained, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1, v / v) to obtain compound X ( 17.1g), the yield is 60%. HPLC (AD-H, isopro...

Embodiment 3

[0073] Example 3: Preparation of Compound I-a~I-j

[0074]

[0075] Take the preparation of I-a as an example:

[0076] Compound X (890mg, 3.55mmol, 1.0equiv.), 3-butene-1-amine (324μL, 3.91mmol, 1.1equiv.), glacial acetic acid (406μL, 7.10mmol, 2.0equiv.) and After the mixture of molecular sieves (powder, 890 mg) was dissolved in toluene (178 mL), it was heated to 80°C. After stirring for 8h at this temperature, the molecular sieve was filtered off, washed with dichloromethane, and the solvent was drained. The crude product was purified by column chromatography (petroleum ether: ethyl acetate, 5:1, v / v) to obtain XI-a (704 mg) with a yield of 73%. After compound XI-a (700mg, 2.57mmol, 1.0equiv.) was dissolved in methanol (35mL), activated zinc powder (1.8g, 0.028mol, 11.0equiv.) and ammonium formate (1.6g, 0.026mol, 10.0equiv.) .). The solid was filtered off, and the filtrate was drained. The residue was dissolved with dichloromethane and washed with saturated aqueous ammoniu...

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Abstract

The invention relates to the field of medicine and chemical industry, and discloses a series of monoterpene indole alkaloid skeletons and a synthesis method of natural products based on free radical series reactions. The three types of photocatalytic free radical tandem reactions provided by the present invention break through the traditional reaction mode of aniline and enamine, construct multiple C–N and C–C bonds with high selectivity, and rapidly form the complexity of molecular structure and functional group Diversity; Taking this method as a key step, an efficient and general strategy was developed to synthesize a series of monoterpene indole alkaloid skeletons and corresponding natural products. The synthesis method of the invention and the involved natural product synthesis steps are short and easy to operate, and the raw materials and reagents are cheap and easy to obtain, and can be widely popularized and applied.

Description

Technical field [0001] The present invention relates to the field of medicine and chemical industry, in particular to a method for synthesizing a series of monoterpene indole alkaloid skeletons and corresponding natural products by photocatalytic free radical tandem reaction technology. Background technique [0002] Natural products of monoterpene indole alkaloids have become the focus of attention in the fields of pharmacy, chemistry and biology due to their complex and diverse molecular structures and remarkable biological activities. There are many known natural products of monoterpene indole alkaloids and the types of skeletons, most of which show important pharmacological activities. Among them, the representative drug molecules used in clinical practice include reserpine, an antihypertensive drug. Arrhythmia drug ajmaline and anticancer drugs vinblastine and vincristine and so on. [0003] In biogenic synthesis (O'Connor, SE; Maresh, JJ Nat. Prod. Rep. 2006, 23, 532), monote...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/88C07D471/14C07D471/04C07B53/00C07D459/00
CPCC07B53/00C07B2200/07C07D211/88C07D459/00C07D471/04C07D471/14
Inventor 秦勇刘小宇宋颢张丹汪小蓓夏栋梁秦文芳周瑞捷周骁汉周启龙
Owner SICHUAN UNIV
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