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Total synthesis of natural product daldinin and its analogues

A technology of natural products and analogues, applied in organic chemistry, etc., can solve problems such as harsh conditions, difficult to realize, and difficulties, and achieve high ee value, simple and reliable synthesis conditions, and easy to obtain cheap raw materials and reagents

Active Publication Date: 2017-09-26
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is worth mentioning that the most direct and effective method to synthesize such chiral compounds is to obtain dihydrobenzofuran compounds with chiral substituents by asymmetric hydrogenation reduction of the benzofuran ring, and it has always been a Difficulties, especially to obtain two chiral groups with a specific configuration at one time, is extremely difficult
So far, only a few literatures have reported the synthesis of analogs, and the conditions are extremely harsh, and it is difficult to achieve under ordinary conditions

Method used

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  • Total synthesis of natural product daldinin and its analogues
  • Total synthesis of natural product daldinin and its analogues
  • Total synthesis of natural product daldinin and its analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: Preparation of Daldinin A

[0043] (1)

[0044]

[0045] Under the protection of argon at room temperature, take 6 mL of anhydrous THF and 180 mg (0.80 mmol) of compound 1 (see CN103159776A for its preparation) in a 50 mL single-necked bottle, and place it in a low-temperature reactor for cooling and stirring. Slowly add 0.8mL of lithium diisopropylamide solution into the reaction bottle at -78°C, continue to react for 30min after the dropwise addition, then add 0.2mL of acetone, continue to stir for 30min, turn off the refrigeration, and slowly rise to room temperature for 2h After stopping the reaction. Add 10 mL of saturated NH 4 Cl solution was extracted three times with ether (3×10 mL), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated by filtration and separated by silica gel column chromatography to obtain 174 mg of light yellow solid 2 with a yield of 79%; 20 mg of light ...

Embodiment 2

[0058] Embodiment 2: Preparation of Daldinin B

[0059]

[0060] Under argon protection, take 70mg (0.25mmol) Daldinin A and 2mL anhydrous CH 2 Cl 2 In a 50mL one-necked bottle, place it in an ice bath and stir for 10min, then slowly add 0.4mL trimethylsilane and 0.12mL boron trifluoride diethyl ether. After 1 h of reaction, TLC detected that the reaction was complete. Add 10 mL of saturated sodium bicarbonate solution to quench the reaction, CH 2 Cl 2 (3×10mL) was extracted three times, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 46mg Daldinin B (70%). , ee% value ≥ 98%.

[0061] Daldinin B 1 H NMR and 13 C-NMR data:

[0062] 1 H-NMR (400MHz, CDCl 3 )δppm:0.97(3H,t,J=7.2Hz),1.25(3H,s),1.34(3H,s),1.84-1.74(1H,m),2.18-2.09(1H,m),3.26(2H ,d,J=8.8Hz),3.36(2H,d,J=8.8Hz),4.87(1H,t,J=8.8Hz),5.50(1H,s),6.96(1H,d,J=7.2Hz ),7.53(1H,d,J=7.2Hz).

[0063] 13 C-NMR (100MHz, CDCl 3 )δppm: 9.1, 25.1, 25.4, 28.9, 30.5, 72.6, 84.5, 93...

Embodiment 3

[0064] Embodiment 3: Preparation of Daldinin C

[0065]

[0066] Under nitrogen atmosphere, add 85.0mg Daldinin B to a dry 25mL single-necked bottle, inject 5mL dry THF, place in ice water and stir for 30min, add 15mg (1.5equi) LiAlH 4 , Stir the reaction at 0°C for 30 min, add 5 ml of saturated NH 4 Cl solution quenched the reaction. CHCl 3 Extracted three times (3×8ml), dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated, and the product was separated by silica gel chromatography to obtain 78 mg of Daldinin C (90%).

[0067] Daldinin C 1 H NMR and 13 C-NMR data:

[0068] 1 H-NMR (400MHz, CDCl 3)δppm:0.94(3H,t,J=7.4Hz),1.20(3H,s),1.30(3H,s),1.77(2H,m),3.10(1H,dd,J=16.0,9.6Hz), 3.25(1H,dd,J=8.5,16.0Hz),4.58(1H,dd,J=8.5,9.4Hz),4.71(2H,s),4.88(1H,dd,J=6.3,7.2Hz),6.95 (1H,d,J=7.6Hz),7.09(1H,d,J=7.6Hz).

[0069] 13 C-NMR (100MHz, CDCl 3 )δppm: 11.0, 24.8, 25.7, 31.4, 32.4, 58.7, 72.6, 72.7, 90.2, 119.2, 120.0, 125.3, 127.0, 144.4, 15...

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Abstract

The invention relates to a universal, simple, and effective asymmetrical total synthesis method of natural products Daldinin A, B, and C and analogues thereof. The method comprises the following steps: synthesizing a chiral compound 6-ethylbenzo[1,2-b:5,6-c']difuran-3,8(2H,6H)-dione, introducing different groups to the alpha position of a benzofuran keto-carbonyl group through a nucleophilic reaction; and then carrying out a reduction reaction in the presence of a chiral reducing agent so as to construct a corresponding 2,3-dihydrobenzofuran chiral center to finish the asymmetrical total synthesis of the Daldinin. The synthesis can also be achieved through a route as follows: a compound A is subjected to a reductive elimination reaction so as to obtain optically-pure concentricolide and analogues thereof; and this route is not influenced by the racemization happening on the alkyl branch chains of phthalide lactone during the benzofuran ring establishment reactions. The synthesis method has the advantages of simple and reliable design, and mild reaction conditions, and is suitable for massive preparation. At the same time, the synthesis route has a very good universality. The synthesis method has a very important meaning for asymmetrical synthesis of compounds that take chiral functional groups namely dihydorbenzofuran and benzofuran keto-lactone as the matrix.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a method for the total synthesis of a class of natural products Daldinin A, B, C and analogues containing chiral substituted dihydrobenzofuran parent structures, especially suitable for the needs of benzofuran rings Total synthesis of compounds with two chiral groups constructed in one go. Background technique [0002] In 2005, Liu Jikai, Kunming Institute of Botany, Chinese Academy of Sciences, etc. discovered the compound Concentricolide for the first time from Carbonococcus collected in Lijiang, Yunnan, and found that it had significant and unique anti-HIV virus activity in preliminary research (X.D.Qing, Z.J.Dong, 2007 , the research group Shao Hongjun and others used the method of obtaining multiple secondary metabolites from one strain (One strain many compounds, namely OSMAC) and isolated a series of new compounds of carbonococcus from the fermentation broth of Carbonococc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04C07D307/80
CPCC07D307/80C07D493/04
Inventor 房立真路趁娟倪天军杨晓丽李欢欢吕庆华
Owner XINXIANG MEDICAL UNIV