Two-type 3-acyl-2, 4-pyrrolidine-diketone compound and synthesis method thereof

A compound, pyrrolidine technology, applied in the field of new organic compounds and biomimetic synthetic routes, can solve the problems of inefficient and large-scale synthesis, excessively long routes, long routes, etc., and achieve high yield, short routes and mild reaction conditions. Effect

Inactive Publication Date: 2014-01-22
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] 3) The total synthesis of (+)-fusarisetin A by Gao Shuanhu's group: In July 2012, Gao Shuanhu's group first reported the synthetic route of (+)-fusarisetin A, with a total of 12 steps and a total yield of 3.9%. A new synthetic strategy was adopted in the synthetic route to realize its biomimetic synthesis, but the route is still long and there are also stereoselective problems
[0012] 5) Total synthesis of (+)-fusarisetin A by Yang Zhen's group: In July 2013, Yang Zhen's group reported the third synthetic route of (+)-fusarisetin A, with a total of 16 steps and a total yield of 1.3%. In the synthesis, the Pauson-Khand reaction is used to construct the 6-6-5 tricyclic more efficiently, but a large number of steps are spent on functional group conversion, which makes the whole route too long
[0016] In summary, although (+)-fusarisetin A has good biological activity, its current existing synthetic route cannot be synthesized efficiently and in large quantities. The present invention transforms it based on the structure of (+)-fusarisetin A, Trying to find a new structural compound that not only keeps its biological characteristics but also facilitates synthesis, the present invention has synthesized the following new compounds

Method used

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  • Two-type 3-acyl-2, 4-pyrrolidine-diketone compound and synthesis method thereof
  • Two-type 3-acyl-2, 4-pyrrolidine-diketone compound and synthesis method thereof
  • Two-type 3-acyl-2, 4-pyrrolidine-diketone compound and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Synthesis of Compound 4:

[0040]

[0041] Weigh compound 2 (45mg, 0.12mmol) in a 25mL dry reaction flask, add 12mL (0.01M) of acetic acid, and add manganese acetate (6.3mg, 0.024mmol), and react at 25°C for 5h. After the reaction is complete, the acetic acid After pumping to dryness, add 10 mL of ethyl acetate, pass through diatomaceous earth, wash the organic phase with saturated sodium chloride (5 mL×2), dry over anhydrous sodium sulfate, and spin dry. Flash column chromatography (2% methanol / dichloromethane) gave a white solid that is compound 4 (43mg, yield 88%, dr=1.1:1.0 * ), R f =0.23 (30% ethyl acetate-petroleum ether). ESI[M+Na] + calcd for [C 23 h 33 NO 6 Na] + 442.22; found 442.17. 1 HNMR (400MHz, CDCl 3 )δ5.79(4,major,d,J=10.2Hz,1H),5.76 * (epi-4,minor,d,J=10.2Hz,1H),5.58(d,J=17.9,10.2Hz,1H),5.54 * (d,J=17.9,10.2Hz,1H)4.76(s,1H),4.62 * (s,1H),4.55–4.42(m,1H),4.41–4.32(m,1H),4.41–4.32 * (m,1H),4.34-4.31 * (m,1H),4.11* (s,1H),4.01(s,1H),3.06 ...

Embodiment 2

[0043] Synthesis of compound 5:

[0044]

[0045] Weigh compound 4 (9mg, 0.024mmol) in a 10mL dry reaction tube, add 2.4mL (0.01M) of acetonitrile, and add trimethyl phosphite (85μL, 0.71mmol), react at 80°C for 2h, the reaction is complete The solvent is then spin-dried. Thin-layer chromatography (developing solvent 30% ethyl acetate / petroleum ether) gave a white solid that is compound 5 (4.1 mg, yield 48%), R f =0.11 (30% ethyl acetate-petroleum ether). ESI[M+H] + calcd for [C 23 h 33 NO 5 H] + 404.24; found 404.22. 1 HNMR (400MHz, CDCl 3 )δ5.72(ddd,J=10.0,4.6,2.7Hz,1H),5.53(d,J=10.0Hz,1H),4.52–4.17(m,3H),3.61(s,1H),3.55(d ,J=2.7Hz,1H),2.96(s,3H),2.95–2.91(m,1H),2.56(dd,J=11.1,4.6Hz,1H),1.84(t,J=14.1Hz,2H) ,1.73(d,J=12.4Hz,2H),1.65–1.51(m,2H),1.44(d,J=6.5Hz,3H),1.38(d,J=6.9Hz,3H),1.16–1.02( m,2H),0.99(d,J=6.9Hz,3H),0.91(t,J=10.6Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ 215.6, 168.2, 133.4, 125.8, 102.6, 76.0, 70.3, 63.7, 63.0, 52.7, 44.8, 43.5, 41.5, 38.1, 36.9, 35...

Embodiment 3

[0047] Synthesis of compound 6:

[0048]

[0049] Weigh compound 3 (31mg, 0.069mmol) in a 20mL dry reaction flask, add 7mL (0.01M) of acetonitrile, and simultaneously add methylene blue (4.4mg, 0.014mmol) and triethylamine (38μL, 0.28mmol), at 30°C After the reaction was complete, the acetonitrile was spin-dried, and 10 mL of ethyl acetate was added, passed through diatomaceous earth, and the organic phase was washed with saturated sodium chloride (5 mL×2), dried over anhydrous sodium sulfate, and spin-dried. Separation by thin layer chromatography (developer 30% ethyl acetate / petroleum ether) gave a light blue solid compound 6 (12 mg, yield 53%, dr=2.0:1.0 * ), R f =0.23 (40% ethyl acetate-petroleum ether). ESI[M-H] - calcdfor[C 28 h 34 NO 6 ] - 480.25; found 480.29. 1 H NMR (400MHz, CDCl 3 )δ7.11 (6, major; epi-6 * ,minor,d,J=8.3Hz,2H),6.76(d,J=8.3Hz,2H),5.84–5.70(m,1H),5.55(dd,J=18.2,10.2Hz,1H),4.44( tt,J=7.2,3.5Hz,1H),3.35(t,J=7.2Hz,1H),3.27–3.12(m,2H),2.83–2...

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Abstract

The invention discloses a two-type 3-acyl-2, 4-pyrrolidine-diketone compound and an efficient bionic synthesis route. The compound is provided with the structure shown in the formula, wherein R1 is hydrogen or alkyl; R2 is hydrogen or alkyl; and R3 is hydrogen, alkyl, aryl or a heteroatom group containing O and N. The compound has better biological activity and provides a foundation for the development of anti-cancer drugs. The synthesis raw materials are simple and easy to obtain, the synthesis process operation is simple, the stereo-selectivity is better, and the yield is higher.

Description

technical field [0001] The present invention relates to new compounds and their synthesis methods, especially these two types of novel organic compounds based on (+)-fusarisetin A structure and their biomimetic synthesis routes. Background technique [0002] [0003] In 2011, Korean and Japanese scientists Ahn, Kim, Osada and others jointly reported the isolation of (+)-fusarisetin A from the soil fungus (+)-fusariumsp.FN080326. This natural product belongs to the Tetramic acid class of natural products, and its novel and unique chemical structure has attracted widespread attention of synthetic chemists. In its biological tests, (+)-Fusarisetin A did not exhibit obvious side effects of inhibiting cell growth or inducing cell death. The results of these activity tests showed that this compound has the potential to selectively inhibit tumor cell metastasis, and is a very Drug lead compounds with promising drug development prospects. It currently has the following six synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048C07D491/056A61P35/00
CPCC07D491/107C07D491/113
Inventor 孔丽丽尹军高栓虎
Owner EAST CHINA NORMAL UNIV
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