Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues

A technology of C-3 and flavonoids is applied in the field of biflavonoids and C-3-coupled biflavonoid analogs, which can solve problems such as hindering the progress of drug development and the like

Inactive Publication Date: 2012-09-26
UNIVERSITY OF THE FREE STATE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, progress in drug development has been hampered because there is no stereoselective synthetic approach to obtain larger quantities of the pure compound and all studies are based on small numbers of isolated molecules from natural sources

Method used

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  • Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues
  • Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues
  • Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Example 1 Preparation of 3-arylflav-3-enes

[0211]

[0212] Dry (2R)-5,7,3',4'-tetra(methyloxy)flavan-3-one[1] (100 mg, 0.29 mmol) and 1,3,5-tri-O-methanol Phloroglucinol (120 mg, 0.710 mmol, 2.5 equiv) was dissolved in anhydrous dichloromethane (10 mL), and the mixture was cooled in an ice / NaCl bath. Tin(IV) chloride (1M solution in dichloromethane, 0.5 mL, 0.5 mmol, 1.7 equiv) was added dropwise to this solution and the reaction mixture was stirred under argon in a melted ice / NaCl bath 24 hours (TLC monitoring consumption of starting material). The reaction mixture was filtered on a pad of basic alumina and washed with ethyl acetate. Purification on a silica preparative TLC plate gave 3-(1,3,5-O-methylphloroglucinol)-5,7,3',4'-tetramethoxyflavin-3-ene[ 2] (R f 0.26, 70.2 mg, 49%).

[0213] 1 H NMR: δ(DMSO) 3.64-3.80(s, 21H, 7x OCH 3 ), 5.83 (br, 1H, 4-H), 6.03 (br s, 1H, 2-H), 6.26 (s, 2H, 3″ / 5″-H), 6.33 (d, J=2.0Hz, 1H , 6-H), 6.69 (dd, J=0.6, 2.0Hz, 1H...

Embodiment 2

[0216] Example 2 Preparation of 3-arylflavan-4-ones

[0217]

[0218] 3-(1,3,5-O-methoxyphloroglucinol)-5,7,3',4'-tetramethoxyflav-3-ene (2) (50mg, 0.10mmol) was dissolved in THF (5mL), and added OsO 4 (3.1 mg, 0.012 mmol) and N-methylmorpholine-N-oxide (56.2 mg, 0.48 mmol). The reaction mixture was stirred at room temperature under argon for 1-2 days (TLC monitored consumption of starting material). Sodium metabisulfite solution (10% in water) was added and the reaction mixture was stirred for 30 minutes. Then extracted 3 times with dichloromethane, with NaHCO 3 (saturated aqueous solution), NaCl (saturated aqueous solution) and washed with MgSO 4 dry. Evaporation left a crude material which was purified on a preparative TLC plate to give 3-(1,3,5-O-methoxyphloroglucinol)-5,7,3',4'- Tetramethoxyflavan-4-one (3) (15 mg, 0.29 mmol, 29%).

[0219] 1 H NMR: δ(CDCl 3 )3.35 (s, 3H, 4″-OMe), 3.63 (s, 6H, 2” / 6”-OMe), 3.77 (s, 3H, OMe), 3.80)s, 3H, OMe), 3.81 (s, 3H, OM...

Embodiment 3

[0222] Example 3 (2R)-3-[(2R,3S)-5,7,3',4'-tetra(methyloxy)-3-hydroxyflavan]-5,7,3',4' -Four Preparation of Methoxyflavin-3-ene (6)

[0223]

[0224] Dry (2R)-5,7,3',4'-tetra(methyloxy)flavan-3-one (1) (200 mg, 0.581 mmol) and (2R,3S)-5,7,3 ',4'-Tetra(methyloxy)flavan-3-ol (5) (400 mg, 1.162 mmol, 2 equiv) was dissolved in anhydrous dichloromethane (10 mL), and the mixture was dissolved in ice / NaCl Cool in a bath. Tin(IV) chloride (1M solution in dichloromethane, 1 mL, 1 mmol, 1.7 equiv) was then added dropwise to this solution, and the reaction mixture was stirred under argon in a melted ice / NaCl bath for 24 hours (TLC monitoring of consumption of starting material). The reaction mixture was then filtered on basic alumina and washed with ethyl acetate. Purification on silica preparative TLC plates (hexane-ethyl acetate 4:6) gave (2R)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy yl)-3-hydroxyflavan]-5,7,3',4'-tetramethoxyflavan-3-ene (6) (Rf0.20, 40.1mg, 0.060mmol, 10%)...

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Abstract

The invention relates to methods for the preparation of an optically inactive and optically active compounds which are selected from the group consisting of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues from a starting material or intermediate which are respectively selected from the group consisting of optically inactive or optically active flavan-3-ols and optically active flavan-3-ones, the method comprising the steps of (a) providing an optically inactive or active compound having a fIavan-3-ol structure or a compound which is a flavan-3-one, (b) if a compound having a flavan-3-ol structure with a hydroxy group on the C-3 carbon is selected as starting material, converting the hydroxy group on the C-3 carbon of the compound having the flavan-3-ol structure to an oxo group to form a flavan-3-one of that compound, (c); providing a compound having a nucleophilic aromatic moiety, which compound is selected from the group of compounds having a nucleophilic aromatic moiety and which have flavonoid base structures and compounds having a nucleophilic aromatic moiety and which do not have a flavonoid base structure, (d) contacting the flavan-3-one provided by step (a) or obtained by step (b) with the compound containing the nucleophilic aromatic moiety in the presence of a Lewis acid; (e) forming a first intermediate compound wherein the oxo group on the C-3 carbon is converted to a hydroxy group by virtue of nucleophilic addition when the compound containing the nucleophilic aromatic moiety is contacted to the C-3 carbon of the flavan-3-one, (f) subjecting the first intermediate compound to dehydration so as to introduce a double bond between the C-3 carbon and C-4 carbon of the intermediate compound with the concomitant removal of the hydroxy group from the C-3 carbon to form an optically active flavene compound which is substituted by the nucleophilic aromatic moiety on the C-3 carbon, (g).

Description

field of invention [0001] The present invention relates to a novel method for preparing C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues. Background of the invention [0002] Biflavonoids and triflavonoids are representatives of different families of dimers, trimers and oligomers of flavonoid monomers which are not linked via the C-4 heterocyclic carbon and thus are not Classified as proanthocyanidins. Unlike proanthocyanidins, they do not form colored anthocyanins when treated with acid. Flavonoids are characterized by having a carbonyl group or equivalent at the C-4 position (Figure 1). Together with proanthocyanidins, biflavonoids and triflavonoids constitute the two main types of "complex C 6 -C 3 -C 6 Secondary Metabolites” (Ferreira, D; Slade, D; Marais, J.P.J. Flavonoids Chemistry, Biochemistry and Applications), by Edited by M. Andersen Kenneth R. Markhams, CRC press 2006, 553-615, 1102-1135). [0003] [0004] Biflavonoids and triflavonoids ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/28
CPCC07D311/28C07D407/04
Inventor 扬·亨德里克·范德韦斯特赫伊曾苏珊娜·卢西亚·邦内特马修·阿基伦奴米罗斯拉夫·西沙
Owner UNIVERSITY OF THE FREE STATE
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