Mild alkaline hydrolysis of some 7-O-flavone glycosides. Application to a novel access to rutinose heptaacetate

Article abstract of DOI:10.1016/j.tetlet.2005.04.085

Alkaline hydrolysis of some 7-O-flavone glycosides was performed through the 6,8-dibromo derivative. When the sugar linked to the aglycon has a 2-hydroxy group trans to the sugar-aglycon bond as in β-D-glucosides or rutinosides, hydrolysis occurred at room temperature under very mild conditions. Application to a novel preparation of rutinose heptaacetate by hydrolysis of a diosmin derivative is described.

Full text of DOI:10.1016/j.tetlet.2005.04.085

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4341–4343
Mild alkaline hydrolysis of some 7-O-flavone
glycosides. Application to a novel access to rutinose heptaacetate
*
´ ˆ
Jerome Quintin and Guy Lewin
´ ´
Laboratoire de Pharmacognosie (BIOCIS, UPRES-A 8076CNRS), Faculte de Pharmacie, av. J.B. Clement,
ˆ
92296Cha tenay-Malabry Cedex, France
Received 24 January 2005; revised 18 April 2005; accepted 22 April 2005
Available online 10 May 2005
Abstract—Alkaline hydrolysis of some 7-O-flavone glycosides was performed through the 6,8-dibromo derivative. When the sugar
linked to the aglycon has a 2-hydroxy group trans to the sugar–aglycon bond as in b-D-glucosides or rutinosides, hydrolysis occurred
at room temperature under very mild conditions. Application to a novel preparation of rutinose heptaacetate by hydrolysis of a
diosmin derivative is described.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Bromination–saponification of 5-hydroxyheptaacetyl-
diosmin 4
In a previous publication,1 we reported a regioselective
6-iodination of 5,7-dioxygenated flavones by benzyl-
trimethylammonium dichloroiodate (BTMAÆICl2). This
reagent allowed the 6-iodination of several natural
7-O-glycosylflavones such as diosmin 1 (7-O-rutino-
syldiosmetin), linarin 2 (7-O-rutinosylacacetin) and rhoi-
folin 3 (7-O-neohesperidosylapigenin).1,2 As iodination
by BTMAÆICl2 requires at least one free phenol and is
carried out in CH2Cl2–MeOH as solvent, reactions
were performed with 4, 8 and 9, the respective 5-hydroxy-
peracetylated derivatives of 1, 2 and 3,3 according to
the Kajigaeshi procedure.4 Replacing BTMAÆICl2 with
N-bromosuccinimide (NBS) did not display any 6-
regioselective bromination, but the subsequent saponifi-
cation stepled to the discovery of a new mild alkaline
cleavage of the sugar–aglycon bond in the flavonoid
field. This letter relates to the study of this bromi-
nation–saponification sequence applied to some 7-O-
glycosylflavones.
Reaction of 4 with 1 equiv of NBS (in CH2Cl2 or
CH2Cl2–MeOH 2:1, 3 h, rt) provided, according to
TLC, at least three compounds including the starting
flavone. A second equivalent of NBS simplified the mix-
ture, which led quantitatively to the 6,8-dibromoderiva-
tive 5. By saponification under very mild conditions
(THF–NaOH 0.5 N 1:1, 3.5 h, rt), 5 gave 6,8-dibromo-
diosmetin 6 (95%) instead of expected 6,8-dibromodiosmin
7, and rutinose [6-O-(a-L-rhamnopyranosyl)-D-gluco-
pyranose] as the main constituent of the recovered
sugar moiety. Rutinose was purified and identified as
rutinose heptaacetate (50% from 5).5 Under similar
saponification conditions, diosmin 1 was entirely recov-
ered from 4.
3. Bromination–saponification of other 5-hydroxy-
peracetylglycosyloxyflavones
Rutinose, neohesperidose [2-O-(a-L-rhamnopyranosyl)-
D-glucopyranose] and b-D-glucose are three of the most
frequent sugar moieties in the flavonoids. Therefore, the
bromination–saponification sequence was then studied
with 7-O-neohesperidosyl and 7-O-b-D-glucosyl flav-
ones. Bromination of 5-hydroxyheptaacetylrhoifolin 9
and 5-hydroxypentaacetyldiosmetin-7-O-b-D-glucoside
10 afforded, respectively, the 6,8-dibromo derivatives
Keywords: Flavone glycosides; Flavonoids; Diosmin; Rutinose; Bro-
mination; Alkaline hydrolysis; Glycosidic bond.
*
Corresponding author. Tel.: +33 146835593; fax: +33 146835399;
e-mail: guy.lewin@cep.u-psud.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.085

4342
J. Quintin, G. Lewin / Tetrahedron Letters 46(2005) 4341–4343
11 and 12 in a quantitative yield. Saponification of 12
allowed recovery of 6 from 5, while the sugar–aglycon
bond of 11 proved to be completely resistant (no trace
of 6,8-dibromoapigenin even after 48 h).
the aglycon.7–10 Comparative behaviour of dibromo
derivatives 5, 11 and 12 agrees with this mechanism: 5
and 12 with a potential trans 2-hydroxy groupon the
glucosyl moiety underwent the hydrolysis unlike 11 hav-
ing the glucosyl C-2 involved in the interglycosidic link.
Despite a rutinosyl structure, resistance to hydrolysis of
15 can be explained by its conversion in the alkaline
medium to the open chalcone phenolate with a
decreased electron-withdrawing character.
4. Bromination–saponification of 5-hydroxyheptaacetyl-
hesperidin 14
Compound 14 was prepared from hesperidin 13, the fla-
vanone precursor of diosmin, then was converted to its
6,8-dibromo derivative 15 ( 96%), which revealed a resis-
tance of the sugar–aglycon bond to alkaline hydrolysis
(only traces of rutinose after 48 h according to TLC).
To the best of our knowledge, the cleavage of the sugar–
aglycon bond in 5 and 12 is the first example of an alka-
line hydrolysis of 7-O-flavone glycosides with recovery
of the aglycon [in 1969, Litvinenko and Makarov
OR1
R4
8
B
R3
R4
O
O
R2
2
3
A
6
OH
R1
R2
R3
R4
1
2
3
4
8
9
Me
Me
H
OH
H
rutinosyl
H
H
H
H
H
H
rutinosyl
H
neohesperidosyl
hexaacetylrutinosyl
hexaacetylrutinosyl
hexaacetylneohesperidosyl
Me
Me
Ac
OAc
H
H
10
13
14
Me
OAc
tetraacetyl-β-D-glucosyl
H
2,3-dihydroderivative of 1
2,3-dihydroderivative of 4
5
Me
Me
Me
Ac
OAc
hexaacetylrutinosyl
OH
Br
Br
Br
Br
Br
6
OH
7
OH
rutinosyl
11
12
15
H
hexaacetylneohesperidosyl
tetraacetyl-β-D-glucosyl
Me
OAc
2,3-dihydroderivative of 5
HO
O
O
6
OH
O
O
HO
O
O
2
OH
HO
Me
O
O
HO
2
HO
OH
HO
OH
Me
HO
OH
rutinosyl
neohesperidosyl
5. Mechanism of the hydrolysis of the sugar–aglycon bond
described the cleavage of 7-O-apigenin and luteolin ruti-
nosides (0.5% aq KOH 100°, 30 min),11 but in our hands
no reaction occurred with diosmin 1 under these condi-
tions]. Moreover, as bromine atoms can be easily
removed by hydrogenolysis, this bromination–
saponification sequence constitutes a new mild hydroly-
sis of some flavone glycosides besides the classic acid
and enzyme methods. In other respects, in the special
Alkaline degradation of phenol glycosides is known to
proceed well mainly by nucleophilic displacement of
the aglycon. This displacement requires a sugar moiety
with a neighbouring trans 2-hydroxy groupto give a
1,2-anhydro sugar as the first intermediate,6 and is facili-
tated by the presence of electron-withdrawing groups on

J. Quintin, G. Lewin / Tetrahedron Letters 46(2005) 4341–4343
4343
1
case of the diosmin derivative 4, our method is a novel
chemical access to rutinose. As aforementioned,6 the
recovery of the intact sugar by alkaline hydrolysis was
not expected. However, addition of THF as cosolvent
in our procedure makes flavone 5 soluble at room tem-
perature ; so the very mild conditions of saponification
allow the recovery of rutinose in fair yield. Until now,
almost all the chemical synthesis of rutinose from a fla-
vonoid started from rutoside 16 (9–59% yields).12–17
saponification sequence; H and 13C NMR data of 4–
6, 9, 11, 12 and 15.
References and notes
1. Quintin, J.; Lewin, G. Tetrahedron Lett. 2004, 45, 3635–
3638.
2. Quintin, J.; Lewin, G. J. Nat. Prod. 2004, 67, 1624–1627.
3. Prepared from 1, 2 and 3 by a two-steps sequence (a)
Ac2O-pyridine, rt, 48 h; (b) TFA, rt, 6 h.
4. Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.;
Kondo, M.; Okamoto, T. Chem. Lett. 1987, 2109–2112.
5. By comparison with an authentic sample from Extra-
OH
B
HO
O
OH
A
`
synthese.
rutinosyl
6. Reactivity of this intermediate depends on the structure of
the sugar and experimental conditions: sugars with a free
CH2OH at C-6 give as final compound a 1,6-anhydro
sugar by nucleophilic attack of the 1,2-epoxy system; in
the absence of this free CH2OH, the reaction leads to
methyl glycoside in MeONa–MeOH by nucleophilic
attack at C-1, and to tars in hot aqueous alkaline medium
by degradation of the sugar. In any case, the intact sugar is
not recovered at the end of the reaction.
7. Ballou, C. E. Adv. Carbohydr. Chem. 1954, 9, 59–95.
8. Nath, R. L.; Rydon, H. N. Biochem. J. 1954, 57, 1–10.
9. Wagner, G.; Nunh, P. Pharmazie 1966, 21, 205–214.
10. Koehler, L. H.; Hudson, C. S. J. Am. Chem. Soc. 1950, 72,
981–983.
O
OH
16
The best result was obtained by cleavage of the rutino-
syl–aglycon bond with dihalomethyl methyl ethers, but
this procedure was not at all selective with diosmin,
which gave mainly a rhamnose derivative.14 So, our
method uses the readily available diosmin as a raw
material for production of rutinose.
11. Litvinenko, V. I.; Makarov, V. A. Khim. Prir. Soedin.
1969, 5, 366–369.
Acknowledgement
´
12. Zemplen, G.; Gerecs, A. Ber. 1938, 71B, 2520.
The authors are grateful to J.-C. Jullian for NMR
measurements.
13. Bognar, R.; Farkas Szabo, I.; Farkas, I.; Gross, H.
Carbohydr. Res. 1967, 5, 241–243.
14. Koeppen, B. H. Carbohydr. Res. 1969, 10, 105–112.
15. Looker, J. H.; Sozmen, M.; Kagal, S. A.; Meyerson, S.
Carbohydr. Res. 1970, 13, 179–183.
Supplementary data
16. Japanese Patent JP 50059313 1975; Chem. Abstr. 83,
131900.
17. Kim, Y. C.; Higuchi, R.; Komori, T. Liebigs Ann. Chem.
1992, 575–579.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.04.085. General procedure of the bromination–