Conversion of diacetyl-C-(β-D-glucopyranosyl)phloroglucinol to spiroketal compounds

Article abstract of DOI:10.1016/j.carres.2003.09.035

Diacetyl-C-(β-D-glucopyranosyl)phloroglucinol was converted by refluxing in water to spiro(benzofuran-[2H]furan) a new compound, along with spiro(benzofuran-[2H]pyran). The stereochemistry of the quaternary carbon of both spiro compounds had an S-configuration.

Full text of DOI:10.1016/j.carres.2003.09.035

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 429–433
Note
Conversion of diacetyl-C-(b-
D
-glucopyranosyl)phloroglucinol
to spiroketal compounds
Shingo Sato,* Toshihiro Kumazawa, Ko-ichi Watanabe,
Shigeru Matsuba and Jun-ichi Onodera
Department of Chemistry and Chemical Engineering, Faculty of Engineering, Yamagata University, 3-5-6 Jonan, Yonezawa,
Yamagata 992-8510, Japan
Received 13 August 2003; accepted 30 September 2003
Abstract—Diacetyl-C-(b-D-glucopyranosyl)phloroglucinol was converted by refluxing in water to spiro(benzofuran-[2H]furan) a
new compound, along with spiro(benzofuran-[2H]pyran). The stereochemistry of the quaternary carbon of both spiro compounds
had an S-configuration.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Keywords: Diacetyl-C-(b-D
-glucopyranosyl)phloroglucinol; Spiro[benzofuran-2(3H),20-[2H]pyran]; Spiro[benzofuran-2(3H),20-[2H]furan]; Quater-
nary carbon; Stereochemistry; Pinnatifinoside
OH
We previously reported on the conversion of the
C-(b-
rivatives by refluxing in water in the presence of
p-toluenesulfonic acid (p-TsOH); C-(b- -glucopyr-
anosyl)phloroacetophenone and C-(b- -galactopyr-
D-glycopyranosyl)phloroacetophenone to spiro de-
O
HO
D
O
OH
D
COMe
HO
anosyl)phloroacetophenone to (2S,30S,40R,50R)-7-acetyl-
spiro[benzofuran-2(3H),20-[2H]pyran]-30,4,40,50,6-pentaol
(1)1 and (2R,30S,40S,50R)-7-acetyl-spiro[benzofuran-
2(3H),20-[2H]pyran]-30,4,40,50,6-pentaol (2),2 respec-
tively.
HO
2
At the time of our reports, these spiroketal com-
pounds were not known to be naturally occurring.3
However, in 2001, Zhang and Xu4 reported on the iso-
lation of four ketohexose furanosides from the leaves of
Crataegus pinnatifida Bge. var. major N.E.Br. (Rosa-
ceae), which is used as a medicinal plant to improve
digestion, inhibit the retention of food, promote blood
circulation, and resolve blood stasis both in traditional
and folk medicine.5 Pinnatifinosides A and B are flav-
ones (see structures), containing a spiro(benzofuran-
furan) ring in which the stereochemistry at C-30, C-40,
OH
HO
HO
O
HO
O
OH
COMe
1
and C-50 is analogous to that of
D-arabinose and the
stereochemistry of the spiro-quaternary carbon is R.
Pinnatifinosides C and D are also flavones that contain a
spiro(benzofuran-furan) ring, in which the stereochem-
istry at C-30, C-40, and C-50 is analogous to that of
* Corresponding author. Tel.: +81-238-26-3121; fax: +81-238-26-3413;
e-mail: shingo-s@yz.yamagata-u.ac.jp
0008-6215/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.09.035

430
S. Sato et al. / Carbohydrate Research 339 (2004) 429–433
D
-ribose, and the stereochemistry of the spiro-quater-
amined the conversion of diacetyl-C-(b-D-glucopyrano-
nary carbons is R and S, respectively. However, while
the naturally occurring spiroketal flavones all contain a
spiro(benzofuran-[2H]furan) ring, both of the spiroke-
tals synthesized by us also contain a spiro(benzofuran-
[2H]pyran) ring. The spiroketal skeletons of pinnatifi-
nosides A and B, and C and D could be constructed
syl)phloroglucinol (7) to the corresponding spiro com-
pound in a similar manner. Compound 7 could not be
obtained by the direct O fi C glycoside rearrangement
of diacetylphloroglucinol (3) (Scheme 1). However, an
O fi C glycoside rearrangement of the phloroacetophe-
none,6–8 followed by acetylation of the hydroxyl group,
and C-acetylation using BF3Æ2AcOH and O-deacetyl-
ation gave 7 in good yield (Scheme 2). Since the refluxing
of 7 in water in the presence of a catalytic amount of p-
TsOH caused deacetylation, resulting in the formation
from C-b-D-gluco- and -allopyranoside, respectively,
based on the reactions which we developed.
H
CH2OR
O
of C-b-D-glucopyranosylphloroacetophenone, 7 was
HO
H
refluxed in water in the absence of any catalyst. The
conversion, as expected, proceeded slowly. After re-
fluxing for 1 day, the resulting product was acetylated by
treatment with acetic anhydride, pyridine, and a cata-
lytic amount of DMAP, giving two acetates, which were
separated and isolated by silica-gel column chromato-
graphy (n-hexane–EtOAc). A detailed spectroscopic
study of both acetates indicated that a new product,
spiro(benzofuran-[2H]furan) (9), was produced along
with spiro(benzofuran-[2H]pyran) (8) in 9.8% and 26.0%
yield, respectively. The 1H NMR spectrum of 8 was
analogous to that of 1 except for the presence of another
C-acetyl group. However, that of 9 was different from
any spiroketal synthesized thus far. The H-50 signal at
4.36 ppm (1H, ddd, J 4.0, 6.0, and 7.5 Hz) was shifted
upfield (Dd 1.11), and the H-60a at 4.21 ppm and the H-
60b at 4.43 ppm downfield (Dd 0.29 and 0.25) compared
to that of 8, respectively. The above findings suggest that
9 does not contain a pyran ring linked between the C-6
oxygen and a quaternary carbon (C-2) of the benzofu-
ran like 8, which contains a spiro[benzofuran-2(3H),20-
[2H]furan] ring linked between the C-5 oxygen and a
quaternary carbon (C-2). The following data point to
the presence of a spiro[benzofuran-3(2H),20-[2H]furan]
ring;4;9 the coupling constants for H-30, -40, and -50
(J3;4 ¼ 7:0, J4;5 ¼ 6:0 Hz) are not consistent with a pyran
ring like 8 (J3;4 ¼ 10:5, J4;5 ¼ 3:5 Hz). Further, the dif-
ference in chemical shifts between the methylene protons
on C-3 of the 2H-benzofuran (Dd 0.136) is apparently
larger than those for spiro(benzofuran-[2H]pyran) [1
(Dd 0.01), 2 (Dd 0.00), and 8 (Dd 0.04)]. To determine the
stereochemistry of 9 more precisely, nuclear Overhauser
and exchange spectroscopy (NOESY) and correlation
spectroscopy via long-range coupling spectrum (CO-
OH
H
O
O
O
HO
OH
R = H: Pinnatifinoside A
R = acetyl: Pinnatifinoside B
O
H
O
OH
H3CCOH2C
H
H
OH
OH
O
O
O
OH
Pinnatifinoside C
O
H
CH2OCCH3
O
HO
H
HO
OH
O
O
H
O
OH
Pinnatifinoside D
In an ongoing study of the conversion of C-glyco-
pyranosylphloroacetophenone to the spiroketal, we ex-
Scheme 1.

S. Sato et al. / Carbohydrate Research 339 (2004) 429–433
431
Scheme 2.
LOC) experiments were carried out (see Figs. 1 and 2).
In the NOESY spectrum, a correlation was found be-
tween H-60a and H-40, and between H-60a and one of the
two acetyl groups on the benzene ring, as well as be-
tween H-30 and H-3a, respectively. These correlations
indicate that the stereochemistry of the quaternary car-
bon is an S-configuration and opposite to that of the
natural products, pinnatifinosides A and B. If the qua-
ternary carbon has an R-configuration, the above cor-
relation between H-60a and one of the two acetyl groups,
and between H-30 and H-3a would not exist. Thus, the
stereochemistry of the quaternary carbon is of the S-
configuration. The stereochemistry at C-3, C-4, and C-5
OAc
CH3
C
Ha
H
Hb
OAc
O
AcO
S
H
H
O
O
OAc
Ha
AcO
C
Hb
H3C
O
Figure 2. The COLOC correlation of 9.
is the same, as that of
D-glucose as was found for 8. In
the COLOC correlation of 9, H-3a and -3b showed a
correlation with the quaternary carbon (C-2:
117.4 ppm). Further, H-3b showed a correlation with
C-30 [77.7 p-4 (146.8 ppm), and C-7a (158.3 ppm)]. H-3a
also showed a correlation with the C-4 and C-7a. H-30
showed a correlation with C-40 (74.7 ppm), H-40 showed
a correlation with C-30 and C-50 (79.5 ppm), H-6a
showed a correlation with C-50. From the above struc-
tural data, we conclude that the hydrolysis of the di-
acetyl-C-(b-D-glucopyranosyl)phloroglucinol produced
mainly a spiro[benzofuran-2(3H),20-[2H]pyran] and a
new spiro[benzofuran-2(3H),20-[2H]furan]. Flavones
having a spiro[benzofuran(2H)furan] skeleton, pinn-
atifinosides A, B, C, and D might be also formed by the
hydrolysis of the corresponding C-(b-D-glycopyrano-
syl)flavones in nature. We are currently attempting the
synthesis of pinnatifinoside A using the above approach.
OAc
1. Experimental
1.1. General
CH3
Ha
H
4
Hb
OAc
C
3'
3a
O
3
AcO
4'
5
The anhydrous CH2Cl2 used in this reaction was pre-
pared in situ by distillation from CaH2. For separation
and purification, flash column chromatography was
performed on silica gel (230–400 mesh, Fuji-Silysia Co.,
Ltd., BW-300). HPLC was performed using an Inertsil
ODS-3 column (GL Science; 5 lm, 4.6 · 250 mm mobile
phase, MeOH–water). Melting points were determined
on a Yanagimoto micro-melting point apparatus and
are uncorrected. Mass spectral data were obtained by
2
2'
H
1
O
5'
6
1'
O
7a
H
OAc
7
6'
Ha
AcO
C
Hb
H3C
O
Figure 1. The NOESY correlation of 9.

432
S. Sato et al. / Carbohydrate Research 339 (2004) 429–433
fast-atom bombardment (FAB) using 3-nitrobenzyl al-
cohol (NBA) or glycerol as a matrix on a JEOL JMS-
AX505HA instrument. Optical rotations were recorded
on a JASCO DIP-370 polarimeter. Elemental analyses
were performed on a Perkin–Elmer PE 2400 II instru-
ment. NMR spectra were recorded on a Varian Inova
500 spectrometer using Me4Si as an internal standard.
5.33 (1H, t, J 9.4 Hz, H-30), 5.40 (1H, t, J 9.4 Hz, H-20),
9.25 (1H, s, OH), 16.17 (1H, s, chelated OH). FABMS
(NBA, m=z) 541 (M + H)þ. Calcd for C24H28O14: C,
53.33; H, 5.22. Found: C, 53.36; H, 5.04.
1.4. Diacetyl-C-(b-D-glucopyranosyl)phloroglucinol (7)
To a stirred solution of 6 (600 mg, 1.11 mmol) in MeOH
(5 mL), 0.5 mL of a 25% NaOMe solution was added,
followed by stirring at room temperature for 0.5 h.
Dowex 50W (Hþ) resin was added to the resulting
mixture until the reaction mixture reached neutrality.
After filtering, the filtrate was evaporated and recrys-
1.2. 1,3-Diacetyl-2,6-O-benzylphloroglucinol (3)
Compound 3 was synthesized via the diacetylation of
phloroglucinol, followed by mono-O-methoxymethyl-
ation, di-O-benzylation, and the O-demethoxymethyl-
ation of phloroglucinol in an overall yield of 40%, as
shown in Scheme 3.
tallized from EtOH to give 7 (397 mg, 95%) as colorless
25
D
prisms: mp 150–151 ꢁC. ½aꢁ +115 (c 0.52, MeOH). IR
Colorless needles (from n-hexane–EtOAc): mp 137 ꢁC.
IR (KBr) m 3444, 2945, 2884, 1699, 1612, 1585, 1367,
(KBr) m 3430, 2931, 1616, 1365, and 1292 cmꢀ1
.
1H
NMR (DMSO-d6) d 2.62 (6H, s, Ac · 2), 3.24–3.40 (5H,
m, H-30, -40, -50, -60a,b), 3.44 (1H, t, J 10.0 Hz, H-20),
4.74 (1H, d, J 10.0 Hz, H-10). FABMS (glycerol, m=z)
373 (M + H)þ. Calcd for C16H20O10Æ0.25H2O: C, 50.99;
H, 5.48. Found: C, 50.90; H, 5.44.
Compound 7 (550 mg, 1.46 mmol) was refluxed in
water (220 mL) for 1 day. After removing the water in
vaccuo, the residual syrup was acetylated by stirring
with a solution of acetic anhydride (20 mL), pyridine
(5 mL), and 4-dimethylaminopyridine (5 mg) at room
temperature for 1 day. After the usual workup, the res-
idue was column chromatographed on silica gel (1:1
n-hexane–EtOAc) to give 8 (218.6 mg, 26.4%) as color-
less prisms and 9 (85.2 mg, 9.8%) as a colorless oil.
1
1259, 1219, 1190, and 1099 cmꢀ1. H NMR (CDCl3) d
2.49 and 2.60 (each 3H, s, ArAc · 2), 4.93 and 5.13 (each
2H, s, benzylic CH2), 6.36 (1H, s, ArH), 7.34–7.42 (10H,
m, ArH), 13.47 (1H, ArOH). FABMS (NBA, m=z) 391
(M + H)þ. Calcd for C24H22O5: C, 73.83; H, 5.68.
Found: C, 73.78; H, 5.75.
1.3. b-C-(20,30,40,60-Tetra-O-acetyl-
D-glucopyranosyl)-
diacetylphloroglucinol (6)
Compound 5 (1.62 g, 2.60 mmol) was stirred at 50 ꢁC for
1 h in 10 mL of boron trifluoride–acetic acid complex
(BF3Æ2AcOH). The reaction mixture was poured into
water, and the solution was extracted with toluene twice.
The organic layer was washed with water and brine and
dried over anhydrous Na2SO4. After removing the sol-
vent, the residue was recrystallized from EtOH to give 6
1.5. (2S,30S,40R,50R)-30,4,40,50,6-Pentakis-acetoxy-5,7-
diacetyl-30,40,50,60-tetrahydrospiro[benzofuran-2(3H),
20-[2H]pyran] (8)
(881 mg, 62.8%) as colorless prisms: mp 206–206.5 ꢁC.
25
25
D
½aꢁ +18.8 (c 0.50, CHCl3). IR (KBr) m 3440, 3132, 2927,
Colorless prisms: mp 171–172 ꢁC. ½aꢁ )144 (c 1.025,
D
1755, 1633, 1365, 1236, and 1045 cmꢀ1
.
1H NMR
CHCl3). IR (KBr) m 1776, 1747, 1697, 1620, 1371, 1224,
and 1184 cmꢀ1. 1H NMR (CDCl3) d 2.05, 2.07, and 2.11
(each 3H, s, OAc · 3), 2.26 and 2.27 (each 3H, s,
ArOAc · 2), 2.42 and 2.62 (each 3H, s, ArAc · 2), 3.13
and 3.14 (each 1H, d, J 17.0 Hz, 3-CH2), 3.92 (1H, dd, J
2.0 and 13.0 Hz, H-6a), 5.47 (1H, dd, J 2.0, 3.5, and
(CDCl3) d 1.84, 2.02, 2.08, 2.14 (each 3H, s, OAc · 4),
2.71 (6H, s, ArAc · 2), 3.94 (1H, ddd, J 2.4, 3.5, and
10.2 Hz, H-50), 4.19 (1H, dd, J 2.4 and 12.6 Hz, H-60a),
5.24 (1H, dd, J 3.5 and 12.6 Hz, H-60b), 5.26 (1H, d, J
9.4 Hz, H-10), 5.28 (1H, dd, J 9.4 and 10.2 Hz, H-40),
Scheme 3.

S. Sato et al. / Carbohydrate Research 339 (2004) 429–433
433
1.5 Hz, H-50), 4.18 (1H, dd, J 1.5 and 13.0 Hz, H-6b),
5.30 (1H, dd, J 3.5 and 10.5 Hz, H-40), 5.63 (1H, d, J
10.5 Hz, H-30). 13C NMR (CDCl3) d 20.6 (OAc · 2),
20.6, 20.9, 20.9 (OAc · 3), 31.4, 31.9 (ArAc · 2), 36.3 (C-
3), 63.9 (C-60), 68.40, 68.46, 68.56 (C-30, C-40, C-50),
112.9 (C-2), 114.4 (C-5*), 117.9 (C-7*), 123.1 (C-3a*),
145.7 (C-4**), 146.8 (C-6**), 158.7, 167.0, 169.0, 169.9,
170.1, 170.4 (OAc · 5), 195.2, 197.2 (ArAc · 2). *, **:
interchangeable. FABMS (glycerol, m=z) 565 (M + H)þ,
523, 481. Calcd for C26H28O14: C, 55.32; H, 5.00. Found:
C, 55.44; H, 4.97.
31.9 (ArAc · 2), 34.8 (C-3), 64.4 (C-60), 74.7 (C-40), 77.7
(C-30), 79.5 (C-50), 114.2 (C-2), 116.4 (C-3a), 117.38 (C-
7), 117.39 (C-5), 145.5 (C-6), 146.8 (C-4), 158.3 (C-7a),
195.5 and 197.4 (ArAc · 2). FABMS (glycerol m=z) 565
(M + H)þ. Calcd for C26H28O14: C, 55.32; H, 5.00.
Found: C, 55.06; H, 5.12.
References
1. Kumazawa, T.; Asahi, N.; Matsuba, S.; Sato, S.; Furuhata,
K.; Onodera, J. Carbohydr. Res. 1998, 308, 213–316.
2. Kumazawa, T.; Chiba, M.; Matsuba, S.; Sato, S.; Onodera,
J. Carbohydr. Res. 2000, 328, 599–603.
3. Jay, M. In The Flavonoids: Advances in Research Since
1986; Harborne, J. B., Ed.; Chapman and Hall: London,
1994; pp 57–93, and references cited therein.
4. Zhang, P.-C.; Xu, S.-X. Phytochemistry 2001, 57, 1249–
1253.
5. Ammon, H.; Handel, M. Planta Med. 1981, 43, 209–239.
6. Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988,
1005–1007.
7. Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett.
1988, 29, 6935–6938.
1.6. (2S,30S,40R,50R)-30,4,40,6,60-Pentakis-acetoxy-5,7-
diacetyl-50-acetoxymethylspiro[benzofuran-2(3H),
20-[2H]furan] (9)
25
D
Colorless amorphous powder. ½aꢁ )15.3 (c 1.035,
CHCl3). IR (KBr) m 2925, 1778, 1749, 1697, 1624, 1371,
and 1180 cmꢀ1. 1H NMR (CDCl3) d 2.05, 2.06, and 2.07
(each 3H, s, OAc · 3), 2.26 and 2.27 (each 3H, s,
ArOAc · 2), 2.42 and 2.61 (each 3H, s, ArAc · 2), 3.25
and 3.38 (each 1H, 3-CH2), 4.21 (1H, dd, J 7.5 and
12.0 Hz, H-6a), 4.36 (1H, ddd, J 4.0, 6.0, and 7.5 Hz, H-
50), 4.43 (1H, dd, J 4.0 and 12.0 Hz, H-6b), 5.44 (1H, dd,
8. Kumazawa, T.; Ohki, K.; Ishida, M.; Sato, S.; Onodera, J.;
Matsuba, S. Bull. Chem. Soc. Jpn. 1995, 68, 1379–1384.
9. Bheemasankara Rao, C. H.; Ramana, K. V.; Venkata Rao,
D. J. Nat. Prod. 1988, 51, 954–958.
J 6.0 and 7.0 Hz, H-40), 5.59 (1H, d, J 7.0 Hz, H-30). 13
NMR (CDCl3) d 20.7 and 21.0 (ArOAc · 2), 31.3 and
C