Synthesis of vicenin-1 and 3, 6,8- and 8,6-di-C-β-d-(glucopyranosyl-xylopyranosyl)-4′,5,7-trihydroxyflavones using two direct C-glycosylations of naringenin and phloroacetophenone with unprotected d-glucose and d-xylose in aqueous solution as the key reactions

doi:10.1016/j.carres.2010.04.001

Carbohydrate Research

Volume 345, Issue 13, 3 September 2010, Pages 1825-1830

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Abstract

Vicenin-3 was synthesized from naringenin via a short five-step reaction, which included two regioselective direct C-glycosylations with d-glucose and d-xylose (yields: 22% and 30%, respectively) as the key reactions for a total yield of 4.4%. Vicenin-1 was also synthesized from phloroacetophenone via a 10-step reaction, including the same glycosylation described above, for a total yield of 2.7% with a vicenin-3 yield of 1.7%.

Graphical abstract

Introduction

Many flavonoids in plants include glycosides that are mostly present as water-soluble O-glycosides and, rarely, as C-glycosides. The C-glycosylflavonoids include a few bis-C-glycosides, mostly flavones. To date, 55 di-C-glycosylflavones have been isolated and their structures determined.¹ Many of them include apigenin (4′,5,7-trihydroxyflavone) as the aglycon. Some of these C-glycosylflavonoids show bioactivities different from the corresponding O-glycosylflavonoids and their aglycons, because of differences in their stability to hydrolysis.² Although there are a few reports on the efficient synthesis of mono-C-glycosylflavonoids,³ there are no reports on the synthesis of bis-C-glucosylflavonoids except for a recent report.⁴

We have achieved the synthesis of the naturally occurring di-C-β-d-glucosylflavone (vicenin-2, see Fig. 1), di-C-β-d-glucosyldihydrochalcone, and di-C-β-d-glucosylflavanone.⁴ In plants, however, it is rare to find a di-C-glycosylflavone consisting of two alternative sugars as a bis-C-glycoside, which consists of five kinds of d-sugars, such as glucose, galactose, xylose, arabinose, and rhamnose.¹ Three kinds of 6,8-di-C-glycosyl-4′,5,7-trihydroxyflavones have been isolated from plants: vicenin-1 and -3 [6-Xyl-8-Glc (1), 6-Glc-8-Xyl (2), see Fig. 1], violanthin and isoviolanthin (6-Glc-8-Rha, 6-Rha-8-Glc), and schaftoside and isoschaftoside (6-Glc-8-Ara, 6-Ara-8-Glc).¹ We have not yet attempted the synthesis of bis-C-glycosides that consist of different sugars.

We previously studied an environmentally friendly method for the direct C-glycosylation of acetylpolyphenol with a non-protected sugar in an aqueous solution in the presence of scandium trifluoromethanesulfonate [Sc(OTf)₃].⁵ The first synthesis of the three di-C-glycosylflavonoids listed above was achieved by application of our method.⁴ This article describes the total synthesis of 1 and 2 and the application of this direct C-glycosylation method to naringenin and phloroacetophenone.

Vicenin-1 and -3 (1, 2) were isolated from the leaves of Desmodium styracifolium MERR (Leguminosae), which has been used as a Chinese folk medicine for cholelithiasis, lithiasis, and inflammation of the liver, among other ailments.⁶ Vicenin-1 (1) has also been isolated from Vitex lucens (Verb.),⁷Arrhenatherum sp. (Gram.),⁸Cymophyllum fraseri (Cyp.),⁹Eminium spiculatum (Acer.),¹⁰Ephedra sp. (Ephed.),¹¹ and Rhynchosia jacobii (Leg.),¹² and 2 has been isolated from V. lucens (Verb.),⁷Camellia sinensis (Thea.),¹³Ephedra sp. (Ephed.),¹¹ and Premna integrifolia (Verb.).¹⁴ However, the bioactivity of these compounds has not yet been reported.

The synthesis of 1 and 2 was examined by two methods: (1) a readily available method of two regioselective direct C-glycosylations of naringenin, followed by oxidation, and (2) two direct C-glycosylations of phloroacetophenone, followed by aldol condensation, acid-cyclization, and then oxidation (Scheme 1).

Section snippets

Results and discussion

Direct C-glycosylation of naringenin, in which the phenolic hydroxyl groups are partially benzyl protected, has been attempted by our group^3c and by Oyama and Kondo,^3g whose attempts were unsuccessful. Kondo’s group achieved the C-glycosylation of naringenin after reduction of its carbonyl group to a methylene residue. We also tried the direct C-glycosylation of unprotected naringenin with d-glucose in an aqueous solution in the presence of catalytic amounts of Sc(OTf)₃ and found that this

Conclusions

We accomplished the first total synthesis of 6-C-β-d-glucosyl-8-C-β-d-xylosyl-4′,5,7-trihydroxyflavone, vicenin-3 (2) by a short, five-step reaction involving direct C-glycosylation with d-glucose and d-xylose performed twice, followed by oxidation of the acetate using iodine and pyridine, for a total yield of 4.4%. The first total synthesis of a regioisomer of 2, vicenin-1 (1), was achieved by two direct glycosylations of phloroacetophenone with d-glucose and d-xylose, followed by benzyl

General

Sc(OTf)_3. (Taiheiyo Kinzoku Co. Ltd) was purchased and used without any further purification. Reactions were monitored using TLC on 0.25-mm Silica Gel F254 plates (E. Merck), UV light, and a 7% ethanolic solution of phosphomolybdic acid, followed by heat, were used as detection methods. Column chromatography was performed on MCI gel CHP20P® (high porous polymer, 75–150 μm, Mitsubishi Chemical Corp.), and flash column chromatography was performed on silica-gel (40–50 μm, Kanto Reagents Co. Ltd,

References (17)

R.H. Johnson et al.
Biochem. Syst. Ecol.
(1988)
K.K. Purushothaman et al.
Indian Drugs
(1986)
W.E. Hillis et al.
Aust. J. Chem.
(1965)
H.-W. Voigtlaender et al.
Arch. Pharm.
(1983)
Y.-J. Lee et al.
J. Chin. Chem. Soc.
(2001)
J. Maurice
C-Glycosylflavonoids
L.B. Zavodnik
Radiat. Biol. Radiol.
(2003)
L.B. Zavodnik et al.
Biochemistry (Moscow)
(2000)
R.C. Lin et al.
Am. J. Clin. Nutr.
(1998)
K. Kawaguchi et al.
Planta Med.
(1998)
Y. Matsubara et al.
Jpn. Heart J.
(1980)
Y. Iizuka et al.
Agric. Biol. Chem.
(1986)
Y. Matsubara et al.
J. Synth. Org. Chem. Jpn.
(1994)
M. Kawasaki et al.
Phytochemistry
(1988)
T. Ohsugi et al.
Agric. Biol. Chem.
(1985)
W. Frick et al.
Liebigs Ann. Chem.
(1989)
J.-A. Mahling et al.
Liebigs Ann.
(1995)
T. Kumazawa et al.
Bull. Chem. Soc. Jpn.
(1995)
T. Kumazawa et al.
Carbohydr. Res.
(2000)
T. Kumazawa et al.
Carbohydr. Res.
(2001)
D.Y.W. Lee et al.
Tetrahedron Lett.
(2003)
K.-i. Oyama et al.
J. Org. Chem.
(2004)
S. Sato et al.
Carbohydr. Res.
(2006)
S. Sato et al.
Carbohydr. Res.
(2006)

There are more references available in the full text version of this article.

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Synthesis of vicenin-1 and 3, 6,8- and 8,6-di-C-β-d-(glucopyranosyl-xylopyranosyl)-4′,5,7-trihydroxyflavones using two direct C-glycosylations of naringenin and phloroacetophenone with unprotected d-glucose and d-xylose in aqueous solution as the key reactions

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Biochem. Syst. Ecol.

Indian Drugs

Aust. J. Chem.

Arch. Pharm.

J. Chin. Chem. Soc.

C-Glycosylflavonoids

Radiat. Biol. Radiol.

Biochemistry (Moscow)

Am. J. Clin. Nutr.

Planta Med.

Jpn. Heart J.

Agric. Biol. Chem.

J. Synth. Org. Chem. Jpn.

Phytochemistry

Agric. Biol. Chem.

Liebigs Ann. Chem.

Liebigs Ann.

Bull. Chem. Soc. Jpn.

Carbohydr. Res.

Carbohydr. Res.

Tetrahedron Lett.

J. Org. Chem.

Carbohydr. Res.

Carbohydr. Res.