Conversion of β-D-C-glucopyranosyl phloroacetophenone to a spiroketal compound

Article abstract of DOI:10.1016/S0008-6215(98)00067-6

Treatment of β-D-C-glucopyranosyl phloroacetophenone in water in the presence of a catalytic amount of p-TsOH afforded a spiroketal product. This is the first demonstration of ring conversion in aryl C-glycoside. The structure of the product was determine

Full text of DOI:10.1016/S0008-6215(98)00067-6

Carbohydrate Research 308 (1998) 213±216
Note
Conversion of ꢀ-d-C-glucopyranosyl
phloroacetophenone to a spiroketal compound
a,
a
a
Toshihiro Kumazawa *, Nobutaka Asahi , Shigeru Matsuba ,
a
a
b
Shingo Sato , Kimio Furuhata , Jun-ichi Onodera
a
Department of Materials Science and Engineering, Faculty of Engineering, Yamagata University,
-3-16 Jonan, Yonezawa-shi, Yamagata 992, Japan
4
b
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirogane, Minato-ku,
Tokyo 108, Japan
Received 25 November 1997; accepted in revised form 7 March 1998
Abstract
Treatment of ꢀ-d-C-glucopyranosyl phloroacetophenone in water in the presence of a catalytic
amount of p-TsOH a€orded a spiroketal product. This is the ®rst demonstration of ring conver-
1
1
sion in aryl C-glycoside. The structure of the product was determined by H- H COSY, HMQC,
HMBC, NOESY, and single crystal X-ray analysis of the corresponding acetylated compound.
#
1998 Elsevier Science Ltd. All rights reserved
Keywords: ꢀ-d-C-Glucopyranosyl phloroacetophenone; Acidic treatment; Tetrahydrospiro{benzofuran-
0
2
(3H),2 -[2H]pyran}
In recent years, the synthesis of aryl C-glycosyl
compounds [1] and the evaluation of their biologi-
cal activity [2] has been a subject of considerable
interest. The C±C linkage between C-1 of the sugar
moiety and the carbon atom of aglycon in an aryl
C-glycosyl compound is resistant to hydrolysis. As
a result, these compounds would be potentially
useful as a source of therapeutic agents for clinical
use.
It would be of interest to better understand the
reactions and interactions which occur in the sugar
moiety of C-glycosyl compounds under conditions
of hydrolysis, even though the pseudoglycosidic
linkage is not cleaved during the reaction. In the
®eld of ¯avonoid chemistry, three types of reac-
tions occur at hydrolytic conditions: (i) the
Wessely±Moser rearrangement of the aglycon
moiety, but not the sugar; (ii) the expected pyr-
anose±furanose interconversion; and (iii) the acid-
catalyzed destruction of the C-glycoside [3].
Because of the complexity of these reactions, it is
possible that a number of reaction products have
not yet been isolated and characterized so far. In
addition, it is possible that the use of lower con-
centrations of acid might well allow the isolation of
important reaction products which have not yet
been identi®ed. We here report that ꢀ-d-C-gluco-
pyranosyl phloroacetophenone, on treatment with
water and a catalytic amount of p-toluenesulfonic
acid, gave a novel spiroketal compound in an
unexpectedly good yield.
*
Corresponding author.
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00067-6

214
T. Kumazawa et al./Carbohydrate Research 308 (1998) 213±216
Scheme 1.
We previously described the reaction of 2,3,4,6-
tetra-O-benzyl-ꢁ-d-glucopyranosyl ¯uoride [4] with
,4-O-benzyl-protected phloroacetophenone in the
tion between the above-mentioned quarternary
0
0
0
0
carbon and H-3 , H-4 , H-6 a, H-6 b, H-3a, as well
as H-3b, and also showed a correlation between the
2
0
presence of boron tri¯uoride diethyl etherate lead-
ing to the C-glucoside 1 [5]. Hydrogenolytic
O-debenzylation of 1 with 10% palladium on acti-
vated carbon as a catalyst under a hydrogen
atmosphere gave the corresponding O-unprotected
compound 2 [6] in quantitative yield. Compound 2
dissolved in a large quantity of water and was
re¯uxed in the presence of a catalytic amount of
p-toluenesulfonic acid. Thin layer chromatography
of the reaction (25:35:5:1 Me CO±EtOAc±H O±
H-3 methylene protons and C-3 . These data
con®rm that the molecule contains a spiroketal
structure. The NOESY spectrum of 4 indicated a
0
0
correlation between H-3 and H-3a, between H-4
0
0
and H-6 b, but no correlation between H-3 and
H-3b. The NOESY spectrum also indicated a corre-
lation between H-4 and the methyl protons of a
C-acetyl group bonded to the aromatic ring and
0
0
between H-6 b and the above-mentioned methyl
protons, respectively (Fig. 1). The NOESY experi-
ment suggests that C-2 of the original glucopy-
ranosyl moiety of 2 is bonded to a hydroxyl group
2
2
AcOH) showed a main product, along with a large
amount of other by-products. After column chro-
matography, the fraction including the main product
was isolated and acetylated with acetic anhydride,
pyridine, and 4-dimethylaminopyridine (DMAP)
to give spiroketal 3 in 35% yield (Scheme 1).
which is ortho to the C-acetyl group and that the
1
pyranose ring of 4 was in the C conformation.
4
The absolute structure of this spiro compound was
con®rmed to be as shown in Fig. 1. The compound
has a 2H-benzofuran closing ring at the hydroxyl
group, which is ortho to the C-acetyl group. The
1
The H NMR spectra of 3 showed a signal
assignable to a chelated phenolic OH at 13.05 ppm
and a signal for a phenolic OH at 10.71 ppm, but
sugar portion, tri-O-acetyl-d-arabinopyranose,
0
0
1
H-3 and H-4 methine proton signals were over-
exists in the C conformation. In order to verify
4
0
0
lapped. In addition, C-3 and C-4 carbon signals
were also overlapped in the 13C NMR spectra. We
thus turned our attention to the corresponding
acetylated compound 4. The COSY spectrum of 4
showed the proton±proton coupling network from
the proposed molecular structure, 4 was character-
ized by a single crystal X-ray structure study1
(Fig. 2). In all probability, the fundamental skeletal
structure of 3 can be presumed to have the same
structure as 4.
0
0
H-3 methine to H-6 geminal methylene, but
showed no correlation for the H-3 geminal methy-
lene proton. The presence of a quarternary carbon
was observed at 112.3 ppm in the HMQC spectrum
of 4. The HMBC spectrum of 4 showed a correla-
1
Tables of atomic coordinates, bond lengths, and bond
angles have been deposited with the Cambridge Crystal-
lographic Data Centre. These tables may be obtained on
request from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK.

T. Kumazawa et al./Carbohydrate Research 308 (1998) 213±216
215
alcohol as the matrix. H NMR and 13C NMR
1
spectra were recorded on Varian INOVA 500
instruments using Me Si as the internal reference.
4
4
-Acetyl-2-b-d-glucopyranosyl-1,3,5-trihydroxy-
benzene (2).ÐA soln of 1 (2.414 g) and 10% palla-
dium-on-charcoal (120 mg) in EtOAc (15 mL) and
EtOH (40 mL) was stirred at room temperature for
6
h under an atmosphere of H . After ®ltering, the
2
®
ltrate was concentrated under reduced pressure to
Fig. 1. NOESY correlations of 4.
give 2 (0.915 g, quant.) as colourless crystals.
Recrystallization from EtOH a€orded 2 as colour-
ꢀ
22
D
EtOH); R 0.43 (25:35:5:1 Me CO±EtOAc±H O±
ꢀ
less crystals: mp 167±169 C; ‰ꢁŠ +55.2 (c 0.1,
f
2
2
AcOH); IR (KBr): 3361, 2929, 1626, 1510, 1450,
�
1
1
408, 1365, 1286, 1173, 1082, 1028, 822, 754 cm ;
1
H NMR (Me SO-d ): ꢂ 2.56 (s, 3 H, ArAc), 3.08±
2
6
0
0
0
3
(
.17 (m, 3 H, H-3 , 4 , 5 ), 3.40 (m, 1 H, H-6a), 3.65
0
d, 1 H, J 11.0 Hz, H-6 b), 3.88 (t, 1 H, J 9.5 Hz, H-
0
0
2
OH), 4.84 (br. s, 2 H, OH), 5.93 (s, 1 H, ArH),
), 4.50 (d, 1 H, J 9.8 Hz, H-1 ), 4.51 (br. s, 2 H,
Fig. 2. X-ray structure of 4.
1
1
0.10 (br. s, 1 H, ArOH), 10.99 (br. s, 1 H, ArOH),
3.83 (br. s, 1 H, ArOH); C NMR (Me SO-d ): ꢂ
13
2
6
0
0
0
In conclusion, acidic treatment of ꢀ-d-C-gluco-
pyranosyl phloroacetophenone in hot water in the
presence of a catalytic amount of p-toluenesulfonic
acid a€orded a novel, unique spiroketal product,
as an unusual example of a sugar ring conversion.
Studies of similar conversions of several other
C-glycosides are now under investigation.
32.4 (ArAc), 61.2 (C-6 ), 70.3 (C-4 ), 70.5 (C-2 ),
0
0
0
73.4 (C-1 ), 78.8 (C-3 ), 81.2 (C-5 ), 94.3 (C-6),
103.8 (C-2, 4), 161.8, 163.7, 164.6 (C-1, 3, 5), 202.5
+
+
(ArAc); FAB MS: m/z 331 [M+H] . Anal. Calcd
3
for C H O . / H O: C, 47.06; H, 5.92. Found:
18
14
9
2
2
C, 47.05; H, 5.75.
0
0
0
0
0
0
0
(2S,3 S,4 R,5 R)-7-Acetyl-3 ,4 ,5 ,6 -tetrahydro-
0
0
0
0
spiro[benzofuran-2(3H),2 -[2H]pyran]-3 ,4,4 ,5 ,6-
pentaol (3).ÐA soln of 2 (120 mg, 0.363 mmol) and
p-TsOH monohydrate (12 mg, 0.063 mmol, 0.17
1
. Experimental
equiv) in H O (50 mL) was re¯uxed for 3 d. After
2
General methods.ÐAll nonaqueous reactions
cooling, the H O was evaporated under reduced
2
were carried out under an atmosphere of dry argon
using freshly distilled solvents, unless otherwise
noted. All reactions were monitored by thin layer
chromatograpy (TLC carried out on 0.25 mm E.
Merck Silica Gel 60 F254 plates using either UV
light for visualization or an EtOH 5% soln of
pressure and the resulting syrup was column chro-
matographed on polyamide gel (1:1 MeOH±H O)
2
to give crude 3. Recrystallization from EtOH
a€orded 3 (40 mg, 35%) as colourless crystals: mp
ꢀ
22
ꢀ
278±280 C (dec.); ‰ꢁŠ � 139 (c 0.10, EtOH); R
D
0.58 (25:35:5:1 Me CO±EtOAc±H O±AcOH); IR
f
2
2
FeCl or an EtOH 5% soln of phosphomolybdic
3
(KBr): 3494, 3450, 3273, 3188, 2947, 2929, 1637,
1504, 1446, 1357, 1346, 1306, 1246, 1217, 1205,
1190, 1182, 1138, 1097, 1074, 1063, 1003, 960, 852,
acid with heat as developing agents. Wakogel
C-3001 (particle size 0.045±0.075 mm) or Wako
Polyamide C-2001 (particle size 0.075±0.15 mm)
was used for column chromatograpy. Melting
points are uncorrected. Optical rotations were
�
1
1
831, 798, 785, 750, 692, 635 cm ; H NMR
(Me SO-d ): ꢂ 2.55 (s, 3 H, ArAc), 2.73 (d, 1 H, J
2
6
15.6 Hz, H-3a), 3.23 (d, 1 H, J 15.6 Hz, H-3b), 3.62
0
recorded for solns in CHCl or EtOH on a JASCO
3
(dd, 1 H, J 1.7, 12.2 Hz, H-6 a), 3.67±3.71 (m, 1 H,
0 0 0
DIP-370 digital polarimeter. IR spectra were
recorded on a Horiba FF-200 IR spectrometer as
KBr pellets. Mass spectra were recorded on a
JEOL JMS-AX-505-HA mass spectrometer under
FAB ionization conditions using 3-nitrobenzyl
H-3 , 4 ), 3.83 (m, 1 H, H-5 ), 3.91 (d, 1 H, J
0
0
12.2 Hz, H-6 b), 4.83 (d, 1 H, J 3.2 Hz, OH-5 ), 4.89
0
0
(d, 1 H, J 4.4 Hz, OH-3 or OH-4 ), 5.12 (d, 1 H, J
0
0
7.1 Hz, OH-4 or OH-3 ), 5.83 (s, 1 H, ArH), 10.71
(br. s, 1 H, ArOH), 13.05 (s, 1 H, ArOH); 13
C

2
16
T. Kumazawa et al./Carbohydrate Research 308 (1998) 213±216
C H O , FW=522.46, monoclinic, space group
NMR (Me SO-d ): ꢂ 31.6 (ArAc), 35.1 (C-3), 66.4
2
6
24 26 13
0
0
0
0
Ê Ê
Ê
(
(
(
C-6 ), 69.8 (C-5 ), 70.9 (C-3 , 4 ), 96.3 (C-5), 101.2
C-7), 103.4 (C-3a), 115.3 (C-2), 160.9 (C-4), 162.0
C-7a), 164.3 (C-6), 201.4 (ArAc); FAB MS: m/z
�
P21 (no. 4), a=9.326(2) A, b=8.846(3) A,
ꢀ
Ê
3
c=16.371(2) A, ꢀ=102.34(1) , V=1319.4(5) A ,
�
� 3
Z=2, Dcalc=1.315 g cm . Of the 2468 re¯ections
3
H, 5.16. Found: C, 53.82; H, 5.35.
11 [M� H] . Anal. Calcd for C H O : C, 53.85;
which were collected, intensity data of 2313 unique
re¯ections were collected in the range 0ꢁhꢁ10,
0ꢁkꢁ10, � 18ꢁlꢁ16. The structure was solved by
direct methods using PHASE [7], DIRDIF [8]
program system. The atomic coordinates and ani-
sotropic thermal parameters of the non-hydrogen
1
4
16
8
0 0 0 0 0 0
(
acetyl-3 ,4 ,5 ,6 -tetrahydrospiro[benzofuran-2(3H),
2
2S,3 S,4 R,5 R)-3 4,4 ,5 ,6-Pentakis-acetoxy-7-
0
0
0
0
0
-[2H]pyran]
(4).ÐCompound
3
(35 mg,
0
.11 mmol) was dissolved in Ac O (1 mL) and pyr-
2
idine (200 mL), and DMAP (10 mg) was then
added. The mixture was stirred at room tempera-
ture for 1 d. The reaction mixture was quenched
with 0.1 M HCl and extracted with EtOAc. The
extracts were washed with water and brine, dried
atoms were re®ned by full-matrix least-squares to
minimize
w ˆ 4Fo =ꢅ ꢂFo †, for 1440 observed re¯ections,
I>3.00ꢅ (I). The ®nal R and Rw values were 0.062
and 0.050, respectively.
2
the
functions
ÆwꢂjF j � jF j† ,
0
c
2
2
2
over anhydrous MgSO , and concentrated under
4
reduced pressure. The product was chromato-
graphed on a silica gel column (3:2 hexane±EtOAc)
to a€ord 4 (58 mg, quant.) as colourless crystals.
Recrystallization from 2-propanol a€orded col-
References
[
1] M.H.D. Postema, Tetrahedron, 48 (1992) 8545±
8599; C. Jaramillo and S. Knapp, Synthesis, (1994)
1±20; D.E. Levy and C. Tang, The Chemistry of C-
Glycosides, Elsevier, New York, 1995.
ꢀ
22
ourless prismatic crystals: mp 182±182.5 ; ‰ꢁŠ
D
156 (c 0.10, CHCl ); R 0.41 (1:1 hexane±
ꢀ
�
3
f
EtOAc); IR (KBr): 3072, 2983, 2942, 2897, 2848,
1
751, 1691, 1618, 1417, 1371, 1308, 1259, 1244,
�
[2] B.K. Catarte, S. Carr, C. DeBrosse, M.E. Hemling,
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1
1
1
221, 1144, 1072, 1055, 1018, 970, 906, 795 cm ;
H NMR (CDCl ): ꢂ 2.01, 2.02, 2.19, 2.27, 2.29 (s,
3
each 3 H, ±OAc), 2.61 (s, 3 H, ArAc), 3.11 (d, 1 H,
J 16.8 Hz, H-3a), 3.15 (d, 1 H, J 16.8 Hz, H-3b),
3
27.
3] E. Besson and J. Chopin, Phytochemistry, 22
1983) 2051±2056; M.K. Park, J.H. Park, Y.G.
[
0
3
J 1.3, 13.3 Hz, H-6 b), 5.37 (dd, 1 H, J 3.4, 10.7 Hz,
.90 (dd, 1 H, J 1.8, 13.3 Hz, H-6 a), 4.19 (dd, 1 H,
0
(
Shin, W.Y. Kim, J.H. Lee, and K.H. Kim, Planta
Med., 62 (1996) 363±365; B.C.B. Bezuidenhoudt,
E.V. Brandt, and D. Ferreira, Phytochemistry, 26
(1987) 531±535.
0
0
H-4 ), 5.47 (ddd, 1 H, J 1.3, 1.8, 3.4 Hz, H-5 ), 5.62
0
13
(
d, 1 H, J 10.7 Hz, H-3 ), 6.51 (s, 1 H, ArH);
C
NMR (CDCl ): ꢂ 20.6, 20.8, 21.0 (±OAcÂ5), 32.0
3
0
0
(
(
(
(
ArAc), 36.3 (C-3), 63.6 (C-6 ), 68.46 (C-3 ), 68.52
[4] M. Hayashi, S. Hashimoto, and R. Noyori, Chem
Lett., (1984) 1747±1750.
[5] T. Kumazawa, K. Ohki, M. Ishida, S. Sato, J.
Onodera, and S. Matsuba, Bull. Chem. Soc. Jpn.,
68 (1995) 1379±1384.
0
0
C-5 ), 68.7 (C-4 ), 110.6 (C-5), 112.3 (C-2), 114.2
C-7), 116.5 (C-3a), 148.7 (C-4), 149.6 (C-6), 158.6
C-7a), 167.2, 169.6, 169.9, 170.2, 170.5 (±OAc),
+
+
1
Calcd for C H O : C, 55.17; H, 5.02. Found: C,
95.3 (ArAc); FAB MS: m/z 523 [M+H] . Anal.
[
[
[
6] J. Onodera, M. Takano, Y. Kishi, N. Yokoyama,
and R. Ishida, Chem. Lett., (1983) 1487±1488.
7] J.C. Calbress, PhD thesis, University of Wisconsin-
Madison, 1972.
8] P.T. Beurskens, DIRDIF, Direct methods for dif-
ference structuresÐan automatic procedure for
phase extension and re®nement of di€erence struc-
ture factors, Technical Report 1984/1, Crystal-
lography Laboratory, Toernooiveld, Nijmegen,
The Netherlands.
2
4
26 13
5
5.03; H, 5.00.
Crystal structure analysis.ÐA colourless crystal
with dimensions 0.1Â0.20Â0.30 mm was mounted
on a glass ®bre. Intensity data for 4 were collected
with graphite-monochromated Cu-K radiation
ꢁ
�
1
Ê
(
ꢃ=7.97 cm , ꢄ=1.54178 A) on
a
Rigaku
AFC5S di€ractorneter at 23 C corrected for
ꢀ
Lorentz polarization e€ect. Crystal data for 4: