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Synthetic methods for series of monoterpenoid indole alkaloid skeletons based on free radical tandem reactions and natural products

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 high cost, cumbersome routes, and poor versatility

Active Publication Date: 2017-12-01
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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  • Synthetic methods for series of monoterpenoid indole alkaloid skeletons based on free radical tandem reactions and natural products
  • Synthetic methods for series of monoterpenoid indole alkaloid skeletons based on free radical tandem reactions and natural products
  • Synthetic methods for series of monoterpenoid indole alkaloid skeletons based on free radical tandem reactions and natural products

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: the preparation of compound IX

[0066]

[0067] Compound VII (10.0g, 0.056mol, 1.0equiv.), tert-butylmethyl 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 of ethanol was added and stirred. After reacting at room temperature for 16 h, the solvent was drained. Column chromatography (petroleum ether: ethyl acetate, 5:1, v / v) gave two diastereoisomers IX-a and IX-b (total 15.1g), yield 76%.

[0068] The detection data of compound IX-a and IX-b are as follows: IX-a: TLC (petroleum ether: ethyl acetate, 5:1v / 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....

Embodiment 2

[0068] The detection data of compound IX-a and IX-b are as follows: IX-a: TLC (petroleum ether: ethyl acetate, 5:1v / 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, 27.8, 27.8; IR (neat): v max =1727,1355,845,749 cm -1 ;HRMS(m / z):[M+Na] + calcd.forC 17 h 21 NNaO 7 ,374.1210; found 374.1210; [α] D 25 = +63.4 (c 0.20, MeOR). IX-b: TLC (petroleum ether: ethyl acetate, 5:1v / v): R f =0.26; 1 H NMR (400 MHz, CDCl 3 ):δ9.68(s,1H),7.82(d,J=8.4Hz,1H),7.55(t,J=8Hz,1H),7.46 (d,J=7.6Hz,1H),7.38(t, J=7.6Hz, 1H), 4.53–4.47(m, 1H), 3.87(d, J= 9.6Hz, 1H), 3.73(s, 3H), 3.08–2.94(m, 2H), 1.20(s, 9H ); 13 C NMR (100MHz, CDCl 3 ): δ199.6, 168.4, 165.9, 150.2, 135.0, 132.9, 129.5, 128.2, 124.7, 82.8...

Embodiment 3

[0072] Embodiment 3: the preparation of compound I-a~I-j

[0073]

[0074] Take the preparation of I-a as an example to illustrate:

[0075] Compound X (890mg, 3.55mmol, 1.0equiv.), 3-buten-1-amine (324μL, 3.91mmol, 1.1equiv.), glacial acetic acid (406μL, 7.10mmol, 2.0equiv.) and The mixture of molecular sieves (powder, 890mg) was dissolved in toluene (178mL) and heated to 80°C. After maintaining the temperature and stirring for 8h, the molecular sieves were 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 (704mg), with a yield of 73%. Compound XI-a (700mg, 2.57mmol, 1.0equiv.) was dissolved in methanol (35mL), and activated zinc powder (1.8g, 0.028mol, 11.0equiv.) and ammonium formate (1.6g, 0.026mol, 10.0equiv.) were added .). The solid was filtered off and the filtrate was sucked dry. The residue was dissolved with dichloromethane,...

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Abstract

The invention relates to the field of pharmaceutical chemical engineering, and discloses synthetic methods for a series of monoterpenoid indole alkaloid skeletons based on free radical tandem reactions and natural products. Three kinds of photocatalytic free radical tandem reactions provided by the invention break conventional reaction modes of an aniline and an enamine, high selectively construct a plurality of C-N and C-C bonds, and rapidly form complexity of molecular structures and diversity of functional groups. The method is used as a key step to develop a high efficient and universal strategy for synthesizing a series of monoterpenoid indole alkaloid skeletons and the corresponding natural products. The synthetic methods provided by the invention and the related natural product synthetic steps are short and are simple in operation, and the raw materials and reagents are cheap and easily available, so that the methods and the natural product synthetic steps can be widely promoted and applied.

Description

technical field [0001] The 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 series reaction technology. Background technique [0002] Monoterpene indole alkaloid natural products have become the focus of research in the fields of pharmacy, chemistry and biology due to their complex and diverse molecular structures and significant biological activities. There are many known natural products of monoterpene indole alkaloids, and most of them exhibit important pharmacological activities. Among them, the representative drug molecules used in clinical practice include antihypertensive drug reserpine (reserpine), antihypertensive drug Arrhythmia drug Amarin (ajmaline) and anticancer drugs vinblastine (vinblastine) and vincristine (vincristine), etc. [0003] In terms of biogenesis (O'Connor, S.E.; Maresh, J....

Claims

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Application Information

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Patent Type & Authority Applications(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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