Synthesis of bis(C-glycosyl)flavonoid precursors

Article abstract of DOI:10.1016/S0008-6215(97)10084-2

Treatment of 3,5-dimethoxyphenol with one equivalent of O-glucosyl trichioroacetimidate I in the presence of TMSOTf as catalyst afforded, in a Fries-type reaction, C-glucosyl compound 4. Reaction of 4 with one equivalent of I or with one equivalent of O-g

Full text of DOI:10.1016/S0008-6215(97)10084-2

Carbohydrate Research 306 (1998) 463±467
Note
Synthesis of bis(C-glycosyl)¯avonoid
precursors
Emad El Telbani, Sayed El Desoky, Mahmoud A. Hammad,
A.H. Abdel Rahman, Richard R. Schmidt *
Fakultat Chemie, Universitat Konstanz, Fach M 725 D-78457 Konstanz, Germany
È È
Received 29 September 1997; accepted 12 November 1997
Abstract
Treatment of 3,5-dimethoxyphenol with one equivalent of O-glucosyl trichloroacetimidate 1 in
the presence of TMSOTf as catalyst a€orded, in a Fries-type reaction, C-glucosyl compound 4.
Reaction of 4 with one equivalent of 1 or with one equivalent of O-galactosyl trichloroacetimidate
8 gave, under similar reaction conditions, bis(C-glycosyl) compounds 5 and 9, respectively.
Hydrogenolytic O-debenzylation of 5 a€orded 3,5-dimethoxy-2,6-bis(ꢀ-d-glucopyranosyl)phenol
(6) in high yield. Due to hindered rotation around the C-glycosyl C-C bond, structural assignment
1
was carried out by recording H NMR spectra at elevated temperatures. # 1998 Elsevier Science
Ltd. All rights reserved
Keywords: C-Glycosyl compounds; ``C-Glycosides''; Bis(C-glycosyl)phenol derivatives; O-Glycosyltrichloro-
acetimidates; Fries rearrangement
Various types of bis(C-glycosyl)¯avonoids have
been found in nature [1]; some also exhibit inter-
esting biological properties [2]. Compounds having
two glycosyl residues attached to the 6- and 8-
position of the ¯avonoid skeleton which contain a
phloroglucinol moiety occur especially frequently.
Two typical examples are compounds A and B
(Scheme 1) exhibiting the potential presence of
identical and also of di€erent sugar residues.
Usually, C-glycosyl compounds are synthesized
by a Friedel-Crafts-type reaction of glycosyl
donors with electron-rich aromatic compounds as
glycosyl acceptors [3,4]. However, earlier attempts
to obtain bis(C-glycosyl)¯avonoids with glycosyl
bromides as glycosyl donors were met with little
success [1]. Recently, we have reported on a di€er-
ent strategy for the synthesis of phenolic C-glycosyl
derivatives via glycosylation of partially O-unpro-
tected phenol derivatives followed by Fries-type
rearrangement of the O-glycoside intermediate
[5,7]. Thus, with O-glycosyl trichloroacetimidates
as donors, only catalytic amounts of trimethylsilyl
tri¯ate as promoter are required for reaction with
phenol derivatives. A related method with rela-
tively reactive glycosyl ¯uorides as glycosyl donors
which are preferably activated by Lewis acids from
the Group IVa metallocenes (Cp2ZrCl2/AgClO4 or
Cp2HfCl2/AgClO4) in up to a ®vefold molar excess
has been also described [8].
E€orts to directly C-glycosylate via this approach
the ¯avanoid moiety or phloroglucinol precursors
having, for instance, electron withdrawing acyl
* Corresponding author.
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(97)10084-2

464
Emad El Telbani et al./Carbohydrate Research 306 (1998) 463±467
catalyst worked selectively, furnishing the O-
unprotected compound 6; O-acetylation as descri-
bed above led to the per-O-acetyl derivative 7
which could be also obtained from 5a via the same
reaction sequence. Again, 7 exhibited at room tem-
perature in its 1 H NMR spectrum (600 MHz,
chloroform-d) two data sets indicating the presence
of two conformers; at 100 ꢀC (250 MHz, dimethyl-
sulfoxide-d6) only one data set was present, yet for
the anomeric protons still a broad signal was
observed. Detailed conformational studies based
on these phenomena have been carried out [13,14].
Obviously, intermediate 4 is also useful for the
attachment of an other sugar residue. To this aim,
we selected the O-galactosyl trichloroacetimidate 8
[12,15]; reaction with 4 in the presence of catalytic
amounts of trimethylsilyl tri¯ate gave the desired
bis-C-glycosylated compound 9 in good yield. At
100 ꢀC the structural assignment could be based on
the 1H NMR data (250 MHz, dimethylsulfoxide-d6:
Scheme 1.
groups were less successful [9,10]. Therefore, we
undertook investigations in order to obtain a con-
secutive bis-C-glycosylation of partially O-pro-
tected phloroglucinol derivatives with O-glycosyl
trichloroacetimidates as glycosyl donors, thus
eventually leading to bis(C-glycosyl)¯avonoids
[11]. A recently reported related study using tetra-
O-benzylglucosyl ¯uoride as glycosyl donor and
3,5-di-benzyloxy-phenol as acceptor [10] prompts
us to report on our results with di-O-methylphlor-
oglucinol as acceptor (Scheme 2).
0
0
0
0
ꢂ: 4.93, d, J1 , 2 9.7 Hz; 5.10, d, J1 , 2 9.8 Hz). Thus,
based on the readily available bis(C-glyco-
syl)phloroglucinols, access to various types of
bis(C-glycosyl) ¯avonoids should be feasible.
1. Experimental
The previously described reaction of O-benzyl
protected O-glucosyl trichloroacetimidate 1 [12]
with 3,5-dimethoxyphenol (2) in the presence of
trimethylsilyl tri¯ate as catalyst led to C-glucoside
4 [6,11]. Contrary to the results with the corre-
sponding glucosyl ¯uoride as donor [10], neither
the ꢁ- nor the ꢀ-anomeric O-glucoside 3 was
obtained [6]. Ensuing reaction of 4 with a second
equivalent of 1 under similar reaction conditions
a€orded the desired bis(C-glycosyl) derivative 5 in
very high yield (93%). The structural assignment
by NMR spectroscopy was hampered by slow
rotation around the C±C bond between C-1 of the
sugar residues and the phenolic carbon atoms.
However, at 120 ꢀC in dimethylsulfoxide-d6 as sol-
vent, the C2-symmetry in the molecule became
obvious resulting in a doublet for H-1 of the two
glucopyranosyl residues (ꢂ: 4.94, d, J1,2 9.7 Hz),
thus indicating a ꢀ-con®guration and 3,5-attach-
ment of the sugar residues. O-Acetylation of 5 with
acetic anhydride in pyridine in the presence of
dimethylaminopyridine (DMAP) gave 5a which
exhibited even higher rotational hindrance than 5.
Hydrogenolytic O-debenzylation of 5 with Pd/C as
General methods.ÐSolvents were puri®ed and
dried by standard procedures before use; petro-
leum ether of boiling range 35±70 ꢀC was used.
1
Melting points are uncorrected. H NMR spectra:
Avance DRX600, Bruker AC 250, internal standard
tetramethylsilane (Me4Si): J-values in Hz. Ele-
mental analysis: Heraeus CHN-O-Rapid. Mass
spectra: Varian MAT 312/AMD 5000 FAB.
Flash chromatography: Silica Gel 60 (Baker
0.03±0.06 mm) at a pressure of 0.3 bar. Thin layer
chromatography (TLC): plastic foil plates, Kiesel
Gel 60 F254 (E. Merck; layer thickness 0.2 mm);
detection by treatment with a soln of 20 g of
ammonium molybdate and 0.4 g of cerium (IV)
sulfate in 400 mL of 10% H2SO4 and heating at
150 ꢀC. Optical rotations: Perkin±Elmer polari-
meter 241/MS, 1 dm cell.
3,5-Dimethoxy-2,6-bis(2,3,4,6-tetra-O-benzyl-b-
d-glucopyranosyl)phenol (5).ÐTo a soln of 4 [6]
(500 mg, 0.73 mmol) and 1 [12] (505 mg, 0.73 mmol)
in anhyd CH2Cl2 (5 mL) at 65 ꢀC was added tri-
methylsilyl tri¯ate (16 ꢃL, 0.1 equiv); the mixture
was stirred for 30 min. The temperature was raised
to room temperature within 3 h. The reaction was

Emad El Telbani et al./Carbohydrate Research 306 (1998) 463±467
465
Scheme 2.
quenched by addition of satd NaHCO3 soln (2 mL);
stirring was continued for 15 min and then water
(5 mL) was added. Extraction with CH2Cl2
(4Â5 mL), drying of the organic extracts over
anhyd MgSO4, and evaporation of the solvent
under reduced pressure gave a syrup. Flash silica
gel chromatography with light petroleum-EtOAc
(10:3) as eluent gave 5 (816 mg, 93%) as a colour-
less foam; mp 49±50 ꢀC; TLC (10:3 light petro-
pyridine (5 mL), a catalytic amount of DMAP
(5 mg) was added. The reaction mixture was stirred
at room temperature for 12 h. The solvent was
evaporated under reduced pressure. Flash chroma-
tography on silica gel of the residual brown syrup
with a mixture of light petroleum±EtOAc (5:2)
gave 5a (900 mg, 87%) as colourless crystals; mp
46±47 ꢀC, TLC (5:2 light petroleum±EtOAc): Rf
20
0.29; [ꢁ]D
+2.27 (c 1, CHCl3); 1H NMR
(250 MHz, Me2SO-d6, at 120 ꢀC); ꢂ 6.87±7.36 (m,
40 H, 8 C6H5), 6.63 (s, 1 H, Ar-H), 4.44±4.81 (m,
16 H, 7 CH2-benzylic, H-10,100), 4.50 (m, 2 H, CH2-
benzylic), 4.0±4.20 (m, 4 H, H-20,200,30,300), 3.80 (s, 6
H, 2 CH3O), 3.55±3.65 (m, 6 H, H-40,400,60a,
600a,60b,600b), 3.44±3.54 (m, 2 H, H-50,500), 2.16 (s, 3
20
leum±EtOAc): Rf 0.37; [ꢁ]D +5.42 (c 1, CHCl3);
1H NMR (250 MHz, Me2SO-d6 at 120 ꢀC): ꢂ 8.28
(s, 1 H, Ar-OH), 6.89±7.36 (m, 40 H, 8 C6H5), 6.25
(s, 1 H, Ar-H), 4.94 (d, 2 H, J1,2 9.7 Hz, H-10,100),
4.54±4.83 (m, 14 H, 7 CH2-benzylic), 4.26 (m, 2 H,
CH2-benzylic), 3.95±4.08 (m, 4 H, H-20,200,30,300),
3.61±3.78 (m, 14 H, H-5,500,60a,600a,60b,600b,40,400, 2
‡
H, OAc). FABMS: m/z 1264 ‰M ‡ NaŠ . Anal.
‡
CH3O). FABMS: m/z 1222 ‰M ‡ NaŠ . Anal.
Calcd for C78H80O14 (1241.48): C, 75.46; H, 6.49.
Found: C, 75.04; H, 6.32.
Calcd for C76H78O13 (1199.44): C, 76.10; H, 6.55.
Found: C, 75.80; H, 6.38.
3,5-Dimethoxy-2,6-bis(b-d-glucopyranosyl)phenol
(6).ÐTo a soln of 5 (500 mg, 0.41mmol) in a mixture
of dioxane±EtOH±AcOH (1550.5 mL), 10%
palladium on charcoal (50 mg) was added, and the
1-Acetoxy-3,5-dimethoxy-2,6-bis(2,3,4,6-tetra-O-
benzyl-b-d-glucopyranosyl)benzene (5a).ÐTo a stirred
mixture of 5 (1 g, 0.83 mmol), Ac2O (10 mL), and

466
Emad El Telbani et al./Carbohydrate Research 306 (1998) 463±467
reaction mixture stirred at room temperature for 1 d
under H2 atmosphere. The catalyst was ®ltered o€
over Celite and the ®ltrate was concentrated; ¯ash
chromatography (2:1 CHCl3±MeOH) of the resi-
due yielded 6 (160 mg, 81%) as a colourless pow-
der; mp 185±186 ꢀC, TLC (1:1 CHCl3±MeOH): Rf
1H NMR (250 MHz, Me2SO-d6 at 100 ꢀC): ꢂ 6.09
(s, 1 H, Ar-H), 5.65 (m, 2 H, H-20,200), 5.25 (dd, 2
H, J2 ,3 =J2 ,3 =J3 ,4 =J3 ,4 9.4 Hz, H-30,300), 4.92
0
0
00 00
0
0
00 00
0
0
00 00
0
0
00 00
(dd, 2 H, J3 ,4 =J3 ,4 =J4 ,5 =J4 ,5 9.4 Hz, H-
40,400), 4.70 (m, 2 H, H-10,100), 3.87±4.15 (m, 6 H, H-
50,500,60a,600a,60b,600b), 3.85 (s, 6 H, 2 OMe), 2.3 (s, 3
H, OAc), 1.9±2.02 (sss, 18 H, 6 OAc), 1.7 (s, 6 H, 2
20
0.46; [ꢁ]D +30.67 (c 1, MeOH); 1H NMR
‡
(600 MHz, MeOH-d4, at 47 ꢀC): ꢂ 6.23 (s, 1 H,
Ar-H), 4.84 (d, 2 H, J1,2 9.9 Hz, H-10,100), 3.96 (m, 2
H, H-20,200), 3.78±3.83 (m, 8 H, H-600a,600b, 2
CH3O±), 3.71±3.74 (m, 2 H, H-60a,60b), 3.43±3.5
(m, 4 H, H-30,300,40,400), 3.36±3.38 (m, 2 H, H-50,500).
13C NMR (at 47 ꢀC): ꢂ 161.04 (Ar-), 157.826,
107.29, 90.17 (C-4), 82.27 (C-50,500), 79.88 (C-30,300),
76.15 (C-10,100), 72.97 (C-20,200), 71.64 (C-40,400),
62.58 (C-60,600), 56.53 (-OCH3), FABMS: m/z 479
-OAc). FABMS: m/z 879 ‰M ‡ NaŠ . Anal. Calcd
for C38H48O22 (856.78): C, 53.27; H, 5.64. Found:
C, 53.38; H, 5.18.
3,5-Dimethoxy-6-(2,3,4,6-tetra-O-acetyl-b-d-
galactopyranosyl)-2-(2,3,4,6-tetra-O-benzyl-b-d-
glucopyranosyl)phenol (9).ÐTo a soln of 4 [6]
(400 mg, 0.73 mmol) and
8
[12,15] (316 mg,
0.73 mmol), in anhyd CH2Cl2 (5 mL) at 70 ꢀC,
was added TMSOTF (16 ꢃL, 0.1 equiv); the reac-
tion mixture was stirred for 30 min. The tempera-
ture was raised to room temperature within 3 h.
The reaction was quenched by addition of satd
NaHCO3 soln (2 mL); stirring was continued for
15 min and then water (5 mL) was added. Extrac-
tion with CH2Cl2 (4Â5 mL), drying of the organic
extracts over anhyd MgSO4, and evaporation of
the solvent under reduced pressure gave a syrup
which was subjected to silica gel ¯ash chromatog-
raphy with light petroleum±EtOAc (5:3) as eluent
to give 9 (500 mg, 72%) as colourless crystals; mp
‡
‰M ‡ HŠ .
1-Acetoxy-3,5-dimethoxy-2,6-bis(2,3,4,6-tetra-O-
acetyl-b-d-glucopyranosyl)benzene (7).Ð(a) From
5a: To a soln of 5a (400 mg, 0.32 mmol) in a mixture
of dioxane±EtOH±AcOH (15:50.5 mL), 10% pal-
ladium±charcoal (40 mg) was added, and the reac-
tion mixture stirred at room temperature for 1 day
under H2 atmosphere. The catalyst was ®ltered
over Celite, and the ®ltrate evaporated under
reduced pressure. The residue subsequently was
dissolved in Ac2O (10 mL) and pyridine (5 mL) in
the presence of DMAP (5 mg). The mixture was
stirred at room temperature for 1 day. The solvent
was evaporated under reduced pressure, ¯ash
chromatography (2:1 EtOAc±light petroleum) of
the residue yielded 7 (200 mg, 81%) as colourless
79±80 ꢀC; TLC (5:3 light petroleum±EtOAc): Rf
20
0.22; [ꢁ]D
+12.7 (c 1, CHCl3); 1H NMR
(250 MHz, Me2SO-d6, at 120 ꢀC): ꢂ 8.06 (br, 1 H,
Ar-OH), 6.96±7.33 (m, 20 H, 4 C6H5), 6.22 (s, 1 H,
00
00 00
00 00
Ar-H), 5.87 (dd, 1 H, J1 ,2 =J2 ,3 9.8 Hz, H-200
solid; mp 116±117 ꢀC; TLC (2:1 EtOAc±light pet-
Gal), 5.41 (dd, 1 H, J3 ,4 3.4, J4 ,5 <1 Hz, H-4
00 00
00 00
00 00
roleum): Rf 0.43, [ꢁ]D
28.97 (c 1, CHCl3). (b)
Gal), 5.20 (dd, 1 H, J3 ,4 3.4, J2 ,3 9.8 Hz, H-300
20
00 00
Gal), 5.10 (d, 1 H, J1 ,2 9.8 Hz, H-100 Gal), 4.93 (d,
00 00
From 6: 6 (100 mg, 0.20 mmol) was dissolved in
Ac2O(5 mL) and pyridine (2 mL) in the presence of
a catalytic amount of DMAP (5 mg) following the
same procedure as described above yielding 7
(60 mg, 70%); 1H NMR (600 MHz, CDC13),
shows the presence of two conformers in slow
1 H, J1 ,2 9.7 Hz, H-10 glc), 4.30±4.88 (m, 8 H, 4
CH2-benzylic), 4.19 (m, 1 H, H-500 Gal), 3.91±4.11
(m, 3 H, H-20 Glc,60b,600b Gal), 3.84 (s, 3 H, CH3O),
3.63±3.75 (m, 8 H, H-30 Glc,40 Glc, 50 Glc,60a,600a
Glc, CH3O), 2.10 (s, 3 H, OAc), 1.92±1.94 (ss, 6 H,
2-OAc), 1.66 (s, 3 H, OAc). FABMS: m/z 1029
0
0
0
0
exchange. ꢂ 6.30 (s, 1 H, Ar-H), 5.94 (dd, 1 H, J1 ,2
‡
0
0
0
00 00
9.1, J2 ,3 9.3 Hz, H-2 ), 5.53 (dd, 1 H, J1 ,2 9.7,
00 00
[M ‡ NaŠ . Anal. Calcd for C56H62O17 (1007.09):
J2 ,3 8.5 Hz, H-200), 5.22±5.23 (m, 2 H, H-30,300),
5.12 (m, 2 H, H-40,400), 4.96 (d, 1 H, J1 ,2 9.7 Hz,
C, 66.78; H, 6. 22. Found: C, 66.53; H, 6.42.
00 00
H-100), 4.23 (br, 1 H, H-10), 3.92, 4.38 (m, 2 H,
H-60b,600b), 4.07±4.16 (m, 2 H, H-60a,600a), 3.87 (s,
3 H, CH3O), 3.79 (s, 3 H, CH3O), 3.70 (m, 1 H,
H-500), 3.59 (m, 1 H, H-50), 2.36 (s, 3 H, -OAc),
1.66±2.02 (m, 24 H, 8 OAc). 13C NMR: ꢂ 76.44 (C-
500), 76.28 (C-50), 74.69 (C-300), 74.99 (C-30), 71.98
(C-100), 73.37 (C-10), 70.30 (C-200), 69.09 (C-20),
68.68 (C-400), 68.68 (C-40), 62.5 (C-60), 62.09 (C-600).
Acknowledgements
This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. We are grateful to Dr
Armin Geyer for his help in the structural assign-
ments. E.E. is grateful for a stipend within the

Emad El Telbani et al./Carbohydrate Research 306 (1998) 463±467
467
framework of the internal mission system from the
Egyptian Government.
325±328; J.-A. Mahling, K.-H. Jung, and R.R.
Schmidt, Liebigs Ann., (1995) 461±466.
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[8] T. Matsumoto, M. Katsuki, and K. Suzuki, Tetra-
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