Synthesis of raphanuside, an unusual oxathiane-fused thioglucoside isolated from the seeds of Raphanus sativus L.

Article abstract of DOI:10.1016/j.carres.2009.11.020

Raphanuside (1), an unusual oxathiane-fused thioglycoside isolated from the seeds of Raphanus sativus L., was synthesized via 10 steps and in 11% overall yield.{A figure is presented}.

Full text of DOI:10.1016/j.carres.2009.11.020

Carbohydrate Research 345 (2010) 309–314
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Synthesis of raphanuside, an unusual oxathiane-fused thioglucoside
isolated from the seeds of Raphanus sativus L.
*
Fei Yang, Gaoyan Lian, Biao Yu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2009
Received in revised form 5 November 2009
Accepted 13 November 2009
Available online 20 November 2009
Raphanuside (1), an unusual oxathiane-fused thioglycoside isolated from the seeds of Raphanus sativus L.,
was synthesized via 10 steps and in 11% overall yield.
OH
O
O
HO
HO
Ph
O
Keywords:
Thioglucoside
Synthesis
Oxathiane
Raphanuside
DDQ
S
O
OMe
OH
S
HO
O
OH
OMe
Raphanuside
OMe
MeO
OH
Ó 2009 Elsevier Ltd. All rights reserved.
Raphanuside (1) is an unusual oxathiane-fused thioglucoside
isolated from the seeds of Raphanus sativus L. (Cruciferaceae), a tra-
ditional Chinese herbal medicine used for expectorant, anti-cough,
and antiasthmatic purposes.1 The relevant oxathiane-fused glyco-
side structures have only been found in descurainoside (2), from
the seeds of Descurainia sophia L.,2 and in merosinigrin (3), a deriv-
ative from the potassium allylglucosinolate (sinigrin).3 In addition,
synthetic intermediates, such as 4,4 5,5 and 66 have been reported.
It is worth noting that the oxathiane-sulfonium compounds 5
(developed by Boons et al.) and 6 (developed by Turnbull et al.)
lysis with NaOH.7 Glycosylation of thiol 11 with 1,2,3,4,6-penta-O-
acetyl-b-
at 0 °C to rt provided the b-thioglucoside 12 in 99% yield (H-1:
4.47 ppm, d, J = 9.6 Hz). Thioglucoside 12 was then converted into
2,3-diol 13 (81%) via the removal of the acetyl groups and subse-
quent 4,6-O-benzylidene formation. Treatment of the (p-methoxy-
D
-glucopyranose underthe promotionof BF3ꢀEt2O in CH2Cl2
phenyl)ethyl b-D-thioglucoside 2,3-diol 13 with 1.2 equiv. DDQ
(2,3-dichloro-5,6-dicyano-benzoquinone) in CH2Cl2 at reflux fur-
nished the desired oxathiane 14 as the major product (43%). How-
ever, this reaction hardly proceeded at lower temperature (0 °C or
rt) or in the presence of a catalytic amount of the DDQ (up to
0.6 equiv). Increasing the amount of DDQ also decreased the yield
of the oxathiane 14; the use of 5 equiv of DDQ led to 14 in 36% yield.
Some highly polar by-products were formed that were not identi-
fied. Other oxidants such as CAN (ceric ammonium nitrate) and
PhI(OAc)2 were also tried but did not lead to the desired oxathiane
product. The structure of 14 was confirmed by 1H NMR analysis;
the signals of H-1 (4.46 ppm, d, J 8.4 Hz), H-7axial (3.12 ppm, dd, J
13.8, 10.8 Hz), H-7equitorial (2.73 ppm, dd, J 13.8, 1.5 Hz), and H-8
(4.69 ppm, dd, J 10.5, 1.5 Hz) in the nascent oxathiane ring are diag-
nostic of the structure. Removal of the 4,6-O-benzylidene in 14 with
p-TsOH afforded compound 7 cleanly.
are proposed to be intermediate donors for the a-selective glycos-
idation.5,6 Here we report a concise synthesis of raphanuside (1)
and its simple congener 7 (Fig. 1).
We envisioned the formation of the trans-fused oxathiane ring
in raphanuside (1) via oxidative cyclization of a p-hydroxyphenyl-
ethyl b-D-thioglucopyranoside precursor (i.e., 8) as shown in Figure
2. The feasibility of such a transformation was first examined in the
synthesis of a simple congener 7 (Scheme 1).
Thus, the commercially available 2-(p-methoxyphenyl)ethanol
(9) was converted into thiol 11 in three steps (67%): bromination
with phosphorus tribromide, substitution with thiourea, and hydro-
A similar procedure was then applied to the synthesis of rapha-
nuside 1 (Scheme 2). Thus, (3,5-dimethoxy-4-hydroxyphenyl)eth-
* Corresponding author. Tel.: +21 64163300x1407; fax: +21 64166128.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.11.020

310
F. Yang et al. / Carbohydrate Research 345 (2010) 309–314
OH
O
6
3
OH
O
4
OH
O
5
HO
HO
HO
HO
1
S
S
HO
HO
2
S
7
O
O
8
O
O
OMe
OH
Me
OMe
CN
3
MeO
OH
OMe
2
Raphanuside (1)
OH
O
HO
HO
S
OTf
OH
OR
O
OR
O
S
O
O
OMe
OMe
HO
O
OTf
Ph
RO
RO
RO
RO
OH
OH
S
S
O
OMe
O
O
OH
Ph
Ph
OMe
7
HO
OMe
4
5
6
Figure 1. Oxathiane-fused thioglucosides.
OH
OR
OR
O
O
O
HO
HO
RO
RO
RO
S
S
S
RO
HO
OH
O
OMe
OH
OMe
OMe
OH
MeO
MeO
O
MeO
A
1
8
Figure 2. Retrosynthetic analysis of raphanuside (1).
SH
Br
CH2OH
a
b, c
d
MeO
S
MeO
MeO
AcO
11
9
10
OAc
O
O
Ph
O
O
g
e, f
S
AcO
HO
OAc
OH
OMe
OMe
13
12
HO
HO
HO
O
Ph
O
O
2O
O
O
1
S
S
h
HO
7
8
7
14
OMe
OMe
Scheme 1. Reagents and conditions: (a) Br3P, toluene, 90 °C, 80%; (b) thiourea, EtOH, reflux; (c) 3 N NaOH, reflux, 84% for two steps; (d) 1,2,3,4,6-penta-O-acetyl-b-D-
glucopyranose, BF3ꢀEt2O, CH2Cl2, 0 °C?rt, 99%; (e) MeONa, MeOH, rt; (f) PhCH(OMe)2, p-TsOHꢀH2O, DMF, 50 °C, 81% for two steps; (g) DDQ, 4 Å MS, CH2Cl2, reflux, 43%; (h) p-
TsOHꢀH2O, CH2Cl2–MeOH (1:1), rt, 100%.
anol 16 was prepared from (3,5-dimethoxy-4-hydroxyphenyl)ace-
tic acid 15 via reduction with BH3ꢀTHF (92%).7 However, the con-
version of 16 into the corresponding thiol was not successful
using the previous transformations (cf., 10?11). Instead the disul-
fide product was obtained during the substitution of the corre-
sponding bromide with thiourea. Alternatively, treatment of 16
with tosyl chloride in the presence of DABCO (1,4-diazabicy-
clo[2,2,2]octane) in CH2Cl2 gave bis-tosylate 17 (78%),8 which
was substituted with KSAc (DMF, 80 °C) to provide compound 18
in an excellent 94% yield. Removal of the resulting S-acetyl group
was carried out with LiAlH4 to afford the desired thiol 19 (84%).9
Glycosylation of thiol 19 with b-
D-glucose pentaacetate under the
promotion of BF3ꢀEt2O provided the expected b-
D
-thioglucoside
20 in 72% yield; a minor product in 27% yield was determined to
be the b-thioglucoside 21 in which the phenol tosylate was
cleaved. Treatment of both 20 and 21 with NaOMe in MeOH (at

F. Yang et al. / Carbohydrate Research 345 (2010) 309–314
311
MeO
HO
OH
MeO
HO
MeO
TsO
OTs
COOH
SAc
a
c
b
OMe
16
OMe
OMe
17
15
OAc
O
MeO
TsO
MeO
TsO
SH
AcO
AcO
d
e
OMe
OR
S
OAc
OMe
OMe
OMe
20 R = Ts
21 R = H
18
19
O
Ph
O
S
O
O
Ph
O
HO
O
OMe
OH
S
f, g
h
i
HO
O
1
OH
OMe
22
23
OMe
MeO
OH
Scheme 2. Reagents and conditions: (a) BH3ꢀTHF, THF, 0 °C?rt, 92%; (b) TsCl, DABCO, CH2Cl2, rt, 78%; (c) KSAc, DMF, 80 °C, 94%; (d) LiAlH4, CH2Cl2–Et2O, rt, 84%; (e) 1,2,3,4,6-
penta-O-acetyl-b-
-glucopyranose, BF3ꢀEt2O, CH2Cl2, 0 °C?rt, 72% (for 20), 27% (for 21); (f) MeONa, MeOH, rt (for 21) or reflux (for 20); (g) PhCH(OMe)2, p-TsOHꢀH2O, DMF,
50 °C, 75% (two steps from 20); 83% (two steps from 21); (h) DDQ, 4 Å MS, CH2Cl2, reflux, 24%; (i) p-TsOHꢀH2O, CH2Cl2–MeOH, rt, 100%.
D
rt and reflux, respectively) provided (3,5-dimethoxy-4-hydroxy-
phenyl)ethyl 1-thio-b- -glucopyranoside, which was subjected to
3 ꢁ 20 mL) and dried with Na2SO4 and then concentrated in vacuo.
D
The residue was purified by silica gel column chromatography
(250:1 petroleum ether–EtOAc) to afford 10 (5.18 g, 80%) as a col-
orless liquid. 1H NMR (CDCl3, 300 MHz) d 7.13 d, J 8.1 Hz, 2H, ArH),
6.86 (d, J 8.7 Hz, 2H, ArH), 3.80 (s, 3H, OMe), 3.53 (t, J 7.5 Hz, 2H,
CH2), 3.10 (t, J 7.5 Hz, 2H, CH2).
4,6-O-benzylidene formation to give diol 22 in good yields. Treat-
ment of 22 with DDQ (1.2 equiv) in CH2Cl2 at reflux furnished
the desired oxathiane 23 in a low 24% yield. Finally, removal of
the 4,6-O-benzylidene group with TsOH afforded raphanuside 1
quantitatively. The analytical data of the synthetic 1 were virtually
identical to those reported for the natural product.1
1.3. 2-(4-Methoxyphenyl)ethanethiol (11)
In summary, raphanuside (1), an unusual oxathiane-fused thi-
oglucoside isolated from the seeds of R. sativus L., was synthesized
in a total of 10 steps and 11% overall yield from (3,5-dimethoxy-4-
Bromide 10 (540 mg, 2.5 mmol) and thiourea (380 mg,
5.0 mmol) were dissolved in anhydrous ethanol (10 mL). The mix-
ture was heated at reflux for 4 h, then 3 N NaOH (10 mL) was
added and the heating at reflux continued for another 2 h. After
the ethanol was evaporated, the water phase was extracted with
EtOAc (3 ꢁ 50 mL). The organic layer was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (100:1 petroleum ether–
EtOAc) to afford 11 (352 mg, 84%) as a colorless liquid. 1H NMR
(CDCl3, 300 MHz) d 7.12 (d, J 8.7 Hz, 2H, ArH), 6.85 (d, J 8.7 Hz,
2H, ArH), 3.80 (s, 3H, OMe), 2.87 (t, J 7.2 Hz, 2H, CH2), 2.71–2.79
(m, 2H, CH2), 1.37 (t, 7.8 Hz, 1H, SH); 13C NMR (CDCl3, 100 MHz)
d 158.3, 131.9, 129.6, 113.9, 55.3, 39.4, 26.4.
hydroxyphenyl)acetic acid and
D-glucose. In the route developed,
the oxathiane moiety was formed via an oxidative cyclization of
a 4-hydroxyphenylethyl 1-thio-b-D-glucopyranoside precursor.
1. Experimental
1.1. General methods
Commercial reagents were used without further purification
unless specified. The solvents were dried and redistilled prior to
use (dichloromethane was distilled from calcium hydride; tetrahy-
drofuran, ethyl ether, and toluene distilled from sodium wire; DMF
was dried with 4 Å molecular sieves). Thin layer chromatography
(TLC) was performed on precoated plates of Silica Gel HF254
(0.5 mm, Yantai, China). Flash column chromatography was per-
1.4. (40-Methoxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-1-thio-b-
D-
glucopyranoside (12)
To
a solution of 1,2,3,4,6-penta-O-acetyl-b-D-glucopyranose
formed on Silica Gel H (10–40 lm, Yantai, China). Optical rotations
(781 mg, 2.0 mmol) in dry CH2Cl2 (5 mL) was added thiol 11
(673 mg, 4.0 mmol) in CH2Cl2 (2 mL). The mixture was cooled in
ice-water bath and then BF3ꢀEt2O (0.3 mL, 2.2 mmol) was injected.
The temperature was raised up naturally. After the starting glucose
material was consumed, Et3N (1 mL) was added, and the resulting
mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography (4:1 petroleum ether–EtOAc)
were determined with a Perkin–Elmer Model 241 MC polarimeter.
1H and 13C NMR spectra were recorded on a Varian AM 300 or Bru-
ker AM 400 spectrometer with Me4Si as the internal standard.
Chemical shifts are recorded in d values and J values were given
in Hz. Mass spectra were obtained on a HP5989A or a VG Quatro
mass spectrometer.
to afford 12 (992 mg, 99%) as a colorless syrup. ½a D25
ꢃ30 (c 1.9,
ꢂ
1.2. 1-(2-Bromoethyl)-4-methoxybenzene (10)
CHCl3); 1H NMR (CDCl3, 300 MHz) d 7.12 (d, J 8.4 Hz, 2H, ArH),
6.84 (d, J 9.0 Hz, 2H, ArH), 5.21 (t, J 9.6 Hz, 1H, H-2), 5.06 (m, 2H,
H-3, H-4), 4.47 (d, J 9.6 Hz, 1H, H-1), 4.25 (dd, J 12.6, 4.8 Hz, 1H,
H-6a), 4.14 (dd, J 12.3, 2.1 Hz, 1H, H-6b), 3.79 (s, 3H, OMe), 3.65–
3.71 (m, 1H, H-5), 2.81–2.95 (m, 4H, CH2CH2), 2.06, 2.05, 2.03,
A mixture of 2-(methoxyphenyl)ethanol (4.74 g, 31.0 mmol)
and PBr3 (9.0 mL, 93.0 mmol) in toluene (40 mL) was heated at re-
flux for 1.5 h before it was allowed to cool to ambient temperature.
The organic phase was washed with satd aq Na2S2O3–NaHCO3 (1:1,

312
F. Yang et al. / Carbohydrate Research 345 (2010) 309–314
2.01 (s each, 3H each, OAc); 13C NMR (CDCl3, 100 MHz) d 170.6,
170.0, 169.9, 169.7, 158.3, 132.0, 129.4, 113.9, 81.8, 77.4, 77.0,
76.7, 70.7, 70.5, 68.5, 67.5, 62.0, 55.3, 34.9, 31.7, 20.8, 20.70,
54.5, 35.0; HR-ESIMS (m/z) calcd for C
15H20O6S (M+Na+):
351.0873; found: 351.0875.
20.68, 20.6; HR-ESIMS (m/z) calcd for C23H30O10
S
(M+Na+):
1.8. 2-(4-Hydroxy-3,5-dimethoxyphenyl)ethanol (16)
521.1452; found: 521.1435.
To a solution of 2-(4-hydroxy-3,5-dimethoxyphenyl)acetic acid
15 (637 mg, 3.0 mmol) in dry THF (4 mL) in ice-water bath,
BH3ꢀTHF (9.0 mL, 1 M in THF) was slowly added. After 4 h, the
remaining borane was quenched by the addition of water. The
resulting mixture was extracted with EtOAc (3 ꢁ 50 mL), the or-
ganic layer was dried over anhydrous Na2SO4, and then concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (1:2 petroleum ether–EtOAc) to afford 16
(546 mg, 92%) as a white powder. 1H NMR (CDCl3, 300 MHz) d
6.46 (s, 2H, ArH), 5.46 (s, 1H, ArOH), 3.84–3.89 (m, 8H), 2.80 (t, J
6.3 Hz, 2H, CH2); 13C NMR (CDCl3, 100 MHz) d 147.0, 133.2,
129.3, 105.4, 63.7, 56.2, 39.2; HR-EIMS calcd for C10H14O4 (M+):
198.0892; found: 198.0890.
1.5. (40-Methoxyphenyl)ethyl 4,6-O-benzylidene-1-thio-b-
D-
glucopyranoside (13)
To a solution of thioglucoside 12 (1.7 g, 3.4 mmol) in MeOH
(8 mL), sodium methoxide (55 mg, 1.0 mmol) was added. After
stirring at rt for 2 h, H+ resin was added to neutralize the base
and the mixture was filtrated and concentrated in vacuo. The res-
idue was dried under vacuum. The crude product was dissolved in
dry DMF (4 mL), then benzaldehyde dimethyl acetal (0.8 mL,
5.1 mmol) and p-TsOHꢀH2O (195 mg) were added. The flask was
placed at 50 °C under low vacuum to remove the formed MeOH
for 4 h. Et3N (2 mL) was added and the solvent was then concen-
trated in vacuo. The residue was purified by silica gel column chro-
matography (1:1 petroleum ether–EtOAc) to afford 13 (1.2 g, 81%
1.9. 2,6-Dimethoxy-4-(2-(tosyloxy)ethyl)phenyl
toluenesulfonate (17)
for two steps) as a white solid. ½a D30
ꢂ
ꢃ34 (c 0.9, CHCl3); 1H NMR
(CDCl3, 300 MHz) d 7.47–7.51 (m, 2H, ArH), 7.36–7.39 (m, 3H,
ArH), 7.13 (d, J 8.1 Hz, 2H, ArH), 6.86 (d, J 8.7 Hz, 2H, ArH), 5.53
(s, 1H, PhCH), 4.42 (d, J 9.3 Hz, 1H, H-1), 4.35 (dd, J 11.2, 5.2 Hz,
1H, H-6a), 3.72–3.84 (m, 5H, Ome, H-4, H-6b), 3.43–3.59 (m, 3H,
H-2, H-3, H-5), 2.87–2.99 (m, 5H, CH2CH2, OH), 2.62 (d, J 2.1 Hz,
1H, OH); 13C NMR (CDCl3, 100 MHz) d 158.3, 136.9, 131.9, 129.5,
129.3, 128.4, 126.3, 114.0, 101.9, 86.6, 80.3, 74.5, 73.3, 70.5, 68.6,
55.3, 35.6, 32.1; HR-ESIMS (m/z) calcd for C22H26O6S (M+Na+):
441.1342; found: 441.1340.
A solution of 16 (200 mg, 1.0 mmol) and DABCO (453 mg,
4.0 mmol) in dry CH2Cl2 (2 mL) was cooled in ice-water bath, p-tol-
uenesulfonyl chloride (481 mg, 2.5 mmol) was added slowly in
portions. After stirring at rt for 3 h, the mixture was filtered and
washed with CH2Cl2. The filtrates were washed twice with an
aqueous HCl solution (20 mL), satd aq NaHCO3 solution, and brine
successively, and then dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (2.5:1 petroleum ether–EtOAc) to afford 17
(396 mg, 78%) as a white powder. 1H NMR (CDCl3, 300 MHz) d
7.86 (d, J 8.1 Hz, 2H, ArH), 7.64 (d, J 8.1 Hz, 2H, ArH), 7.34 (d, J
8.1 Hz, 2H, ArH), 7.29 (d, J 8.1 Hz, 2H, ArH), 6.27 (s, 2H, ArH),
4.21 (t, J 6.9 Hz, 2H, CH2), 3.58 (s, 6H, OMe ꢁ 2), 2.90 (t, J 6.9 Hz,
2H, CH2), 2.47 (s, 3H, ArMe), 2.43 (s, 3H, ArMe); 13C NMR (CDCl3,
100 MHz) d 153.1, 144.9, 144.5, 136.1, 134.8, 132.5, 129.7, 129.1,
128.3, 127.7, 126.9, 105.4, 70.1, 55.8, 35.7, 21.6, 21.5; HR-ESIMS
(m/z) calcd for C24H26O8S2 (M+Na+): 529.0961; found: 529.0960.
1.6. Oxathiane 14
A mixture of thioglucoside 13 (42 mg, 0.1 mmol) and 4 Å MS
(100 mg) was placed in a dry flask (25 mL) equipped with con-
denser under Ar, dry CH2Cl2 (2 mL) was added, followed by the
addition of DDQ (27 mg, 0.12 mmol). After heating at reflux for
2 h, the mixture was cooled and filtered, the filtrate was concen-
trated in vacuo. The residue was purified by silica gel column chro-
matography (3:1 petroleum ether–EtOAc) to afford 14 (18 mg,
43%) as a white foam. ½a D25
ꢂ
+56 (c 0.8, CHCl3); 1H NMR (CDCl3,
1.10. 2,6-Dimethoxy-4-(2-(acetylthio)ethyl)phenyl
toluenesulfonate (18)
300 MHz) d 7.49–7.52 (m, 2H, ArH), 7.35–7.39 (m, 3H, ArH), 7.28
(d, J 8.7 Hz, 2H, ArH), 6.90 (d, J 8.7 Hz, 2H, ArH), 5.58 (s, 1H, PhCH),
4.69 (dd, J 10.5, 1.5 Hz, 1H, H-8), 4.54 (d, J 9.0 Hz, 1H, H-1), 4.38
(dd, J 10.2, 4.5 Hz, 1H, H-6a), 3.92 (t, J 8.4 Hz, 1H, H-3), 3.64–3.84
(m, 7H), 3.12 (dd, J 13.8, 10.8 Hz, 1H, H-7a), 2.73 (dd, J 13.8,
1.5 Hz, 1H, H-7b); 13C NMR (CDCl3, 100 MHz) d 159.6, 136.8,
132.1, 129.3, 128.3, 127.3, 126.3, 114.0, 102.1, 84.5, 80.9, 80.4,
76.2, 72.1, 71.8, 68.4, 55.3, 35.6; HR-ESIMS (m/z) calcd for
C22H24O6S (M+Na+): 439.1186; found: 439.1180.
In a 25 mL flask equipped with a reflux condenser, sulfonate 17
(396 mg, 0.78 mmol) and potassium thioacetate (223 mg,
1.95 mmol) were stirred in DMF (5 mL) at 80 °C for 2 h. The reaction
mixture was diluted with brine (50 mL) and the aqueous layer was
extracted with Et2O (3 ꢁ 50 mL). The organic layers were combined
and washed with brine (100 mL), driedover sodiumsulfate, and con-
centrated under reduced pressure. The residue was purified by silica
gel column chromatography (4:1 petroleum ether–EtOAc) to afford
18 (300 mg, 94%) as a white powder. 1H NMR (CDCl3, 300 MHz) d
7.87 (d, J 8.4 Hz, 2H, ArH), 7.34 (d, J 8.7 Hz, 2H, ArH), 6.41 (s, 2H,
ArH), 3.68 (s, 6H, OMe ꢁ 2), 3.07–3.13 (m, 2H, CH2), 2.78–2.84 (m,
2H, CH2), 2.47 (s, 3H, ArMe), 2.36 (s, 3H, ArMe); 13C NMR (CDCl3,
100 MHz) d 195.7, 153.1, 144.3, 139.6, 134.9, 129.1, 128.3, 126.7,
105.0, 55.9, 36.4, 30.6, 30.1, 21.6; HR-ESIMS (m/z) calcd for
C19H22O6S2 (M+H+): 411.0931; found: 411.0930.
1.7. Oxathiane thioglucoside 7
To a solution of 14 (23 mg, 0.055 mmol) in CH2Cl2–MeOH (2 mL,
1:1), p-TsOHꢀH2O (50 mg, 0.26 mmol) was added. After stirring at
ambient temperature for 2 h, the mixture was neutralized by the
addition of Et3N. The mixture was then concentrated under re-
duced pressure, the residue was purified by silica gel column chro-
matography (20:1 CH2Cl2–MeOH) to afford 7 (19 mg, 100%) as a
colorless syrup. ½a D25
ꢂ
+123 (c 0.7, MeOH); 1H NMR (CD3OD,
1.11. 4-(2-Mercaptoethyl)-2,6-dimethoxyphenyl
toluenesulfonate (19)
300 MHz) d 7.33 (d, J 8.7 Hz, 2H, ArH), 6.89 (d, J 9.0 Hz, 2H, ArH),
4.62 (d, J 9.9 Hz, 1H, H-8), 4.46 (d, J 8.4 Hz, 1H, H-1), 3.88 (d, J
12.0 Hz, 1H, H-6a), 3.70 (s, 3H, OMe), 3.67 (dd, J 12.6, 4.5 Hz, 1H,
H-6b), 3.41–3.53 (m, 4H), 3.05 (dd, J 13.8, 11.1 Hz, 1H, H-7a),
2.74 (dd, 13.8, 1.5 Hz, 1H, H-7b); 13C NMR (CD3OD, 100 MHz) d
159.7, 133.2, 127.3, 113.5, 84.2, 82.0, 80.1, 75.7, 75.4, 70.6, 61.5,
To a suspension of lithium aluminum hydride (250 mg) in dry
Et2O (5 mL) was added a solution of compound 18 (540 mg,
1.3 mmol) in a mixed solvent of dry Et2O (5 mL) and CH2Cl2
(5 mL) slowly at ꢃ10 °C under nitrogen. After stirring for 3 h at

F. Yang et al. / Carbohydrate Research 345 (2010) 309–314
313
rt, the reaction was cooled to ꢃ10 °C, quenched by the addition of
saturated ammonium chloride solution (4 mL), and neutralized by
the addition of hydrochloric acid (3 N, 4 mL). The organic phase
was separated and the aqueous phase was extracted with Et2O
(2 ꢁ 30 mL). The combined organic phases were dried over sodium
sulfate and concentrated in vacuo. The residue was purified by gel
column chromatography (4:1 petroleum ether–EtOAc) to afford
thiol 19 (405 mg, 84%) as a white powder. 1H NMR (CDCl3,
300 MHz) d 7.87 (d, J 8.4 Hz, 2H, ArH), 7.34 (d, J 7.8 Hz, 2H, ArH),
6.38 (s, 2H, ArH), 3.70 (s, 6H, OMe ꢁ 2), 2.87 (t, J 6.9 Hz, 2H,
CH2), 2.79 (t, J 6.9 Hz, 2H, CH2), 2.46 (s, 3H, ArMe), 1.43 (t, J
7.8 Hz, 1H, SH); 13C NMR (CDCl3, 100 MHz) d 153.1, 144.4, 139.5,
134.8, 129.1, 128.3, 126.7, 105.1, 55.8, 40.7, 25.8, 21.6; HR-ESIMS
(m/z) calcd for C17H20O5S2 (M+Na+): 391.0644; found: 391.0648.
(s, 1H, ArOH), 4.45 (d, J 9.9 Hz, 1H, H-1), 4.36 (dd, J 10.5, 4.2 Hz,
H-6a), 3.73–3.86 (m, 8H), 3.47–3.61 (m, 3H), 2.95–3.01 (m, 2H,
CH2), 2.84–2.90 (m, 2H, CH2); 13C NMR (CDCl3, 100 MHz) d 147.0,
136.7, 133.3, 130.8, 129.3, 128.3, 126.2, 105.0, 101.9, 86.6, 80.3,
74.5, 73.2, 70.5, 68.5, 56.3, 36.5, 32.1; HR-ESIMS (m/z) calcd for
C23H28O8S (M+Na+): 487.1397; found: 487.1406. Compound 22
(75%) was also obtained from 20 in a similar manner as that for
21?22.
1.14. Oxathiane 23
A mixture of thioglucoside 22 (33 mg, 0.1 mmol) and 4 Å MS
(100 mg) was placed in a dry flask equipped with condenser under
Ar, dry CH2Cl2 (2 mL) was added, followed by the addition of DDQ
(24 mg, 0.11 mmol) with stirring. After heating at reflux for 2 h, the
mixture was cooled and filtered. The filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatogra-
phy (1.6:1 petroleum ether–EtOAc) to afford compound 23 (8 mg,
1.12. 2-(40-Toluenesulfonate-30,50-dimethoxyphenyl)ethyl
2,3,4,6-tetra-O-acetyl-1-thio-b-
hydroxy-30,50-dimethoxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-1-
thio-b- -glucopyranoside (21)
D
-glucopyranoside (20) and 2-(40-
D
24%) as a white foam. ½a D29
ꢂ
+47 (c 0.2, CHCl3); 1H NMR (CDCl3,
300 MHz) d 7.49–7.53 (m, 2H, ArH), 7.36–7.41 (m, 3H, ArH), 6.57
(s, 2H, ArH), 5.58 (s, 1H, PhCH), 5.53 (s, 1H, ArOH), 4.63–4.67 (m,
1H, H-8), 4.59 (d, J 9.0 Hz, 1H, H-1), 4.39 (dd, J 10.5, 4.5 Hz, 1H,
H-6a), 3.90–3.96 (m, 7H, OMe ꢁ 2, H-6b), 3.66–3.85 (m, 4H), 3.13
(dd, J 14.4, 10.8 Hz, 1H, H-7a), 2.72–2.77 (m, 2H, H-7b, OH); 13C
NMR (CDCl3, 100 MHz) d 147.1, 134.8, 129.3, 128.3, 126.3, 102.9,
102.0, 84.6, 81.1, 80.9, 76.2, 72.1, 71.8, 68.4, 56.4, 35.8; HR-ESIMS
(m/z) calcd for C23H26O8S (M+Na+): 485.1241; found: 485.1241.
To a mixture of dry 1,2,3,4,6-penta-O-acetyl-b-D-glucopyranose
(372 mg, 0.95 mmol) and thiol 19 (386 mg, 1.05 mmol) in dry
CH2Cl2 (5 mL) at 0 °C, BF3ꢀEt2O (0.1 mL, 1.1 mmol) was injected
and the temperature warmed to rt. After the starting material
was consumed as detected by TLC, Et3N (1 mL) was added. The
mixture was concentrated in vacuo and the residue was purified
by silica gel column chromatography (5:1?3:1 toluene–EtOAc)
to afford 20 (469 mg, 72%) and 21 (148 mg, 27%) as white foams.
Compound 20:
½
a 2D6
ꢂ
ꢃ29 (c 0.4, CHCl3); 1H NMR (CDCl3,
300 MHz) d 7.87 (d, J 8.4 Hz, 2H, ArH), 7.34 (d, J 8.1 Hz, 2H, ArH),
6.40 (s, 2H, ArH), 5.23 (t, J 9.6 Hz, 1H, H-2), 5.02–5.13 (m, 2H),
4.46 (d, J 9.9 Hz, 1H, H-1), 4.24 (dd, J 12.3, 4.8 Hz, 1H, H-6a), 4.14
(dd, J 12.9, 2.1 Hz, 1H, H-6b), 3.68–3.73 (m, 7H, OMe ꢁ 2, H-5),
2.90–2.97 (m, 2H, CH2), 2.81–2.87 (m, 2H, CH2), 2.47 (s, 3H, ArMe),
2.06, 2.05, 2.04, 2.02 (s each, 3H each, OAc); 13C NMR (CDCl3,
100 MHz) d 170.5, 170.1, 169.4, 153.2, 144.4, 139.7, 134.9, 129.1,
128.3, 105.1, 83.3, 75.9, 73.7, 69.6, 68.2, 62.0, 55.9, 36.5, 30.6,
21.6, 20.7, 20.6, 20.56, 20.53; HR-ESIMS (m/z) calcd for
C31H38O14S2 (M+Na+): 721.1601; found: 721.1640. Compound 21:
1.15. Raphanuside (1)
Compound 23 (4 mg, 0.0087 mmol) was dissolved in CH2Cl2–
MeOH (1 mL, 1:1), then treated with p-TsOHꢀH2O (8 mg,
0.043 mmol). After stirring at ambient temperature for 3 h, Et3N
was added. The mixture was then concentrated under reduced
pressure, the residue was purified by silica gel column chromatog-
raphy (20:1 CH2Cl2–MeOH) to afford 1 (3 mg, 100%) as a colorless
syrup. ½a 2D7
ꢂ
+85 (c 0.2, MeOH); lit.1
½
a 2D0 +64.5 (MeOH); 1H NMR
ꢂ
(CD3OD, 300 MHz) d 6.70 (s, 2H, ArH), 4.58–4.62 (m, 1H, H-8),
4.48 (d, J 8.7 Hz, 1H, H-1), 3.84–3.90 (m, 7H, OMe ꢁ 2, H-6a),
3.67 (dd, J 11.4, 4.8 Hz, 1H, H-6b), 3.39–3.55 (m, 4H, H-2, H-3, H-
4, H-5), 3.08 (dd, J 13.5, 10.5 Hz, 1H, H-7a), 2.77 (dd, J 13.8,
1.5 Hz, 1H, H-7b); 13C NMR (CD3OD, 100 MHz) d 149.2, 136.4,
133.1, 104.7, 85.5, 83.2, 81.9, 76.9, 76.6, 71.8, 62.8, 56.8, 36.3;
HR-ESIMS (m/z) calcd for C16H22O8S (M+Na+): 397.0928; found:
397.0934.
½
a 2D6
ꢂ
ꢃ18 (c 1.2, CHCl3); 1H NMR (CDCl3, 300 MHz) d 6.43 (s, 2H,
ArH), 5.46 (s, 1H, ArOH), 5.20–5.31 (m, 1H, H-2), 5.03–5.13 (m,
2H), 4.49 (d, J 10.2 Hz, 1H, H-1), 4.26 (dd, J 12.3, 4.8 Hz, 1H, H-
6a), 4.14 (dd, J 12.6, 2.1 Hz, 1H, H-6b), 3.89 (s, 6H, OMe ꢁ 2),
3.69–3.75 (m, 1H, H-5), 2.90–2.96 (m, 2H, CH2), 2.80–2.85 (m,
2H, CH2), 2.06, 2.05, 2.04, 2.02 (s each, 3H each, OAc); 13C NMR
(CDCl3, 100 MHz) d 170.6, 170.1, 169.4, 169.3, 146.9, 133.2,
131.0, 105.0, 83.4, 75.9, 73.7, 69.6, 68.2, 62.1, 56.2, 36.2, 31.3,
20.7, 20.6, 20.55, 20.53; HR-ESIMS (m/z) calcd for C24H32O12
S
Acknowledgments
(M+Na+): 567.1507; found: 567.1513.
This work was financially supported by the Ministry of Science
and Technology of China (2009ZX09311-001) and the Natural
Science Foundation of China (20621062).
1.13. 2-(4-Hydroxy-3,5-dimethoxyphenyl)ethyl 4,6-O-
benzylidene-1-thio-b-D-glucopyranoside (22)
To a solution of thioglucoside 21 (124 mg, 0.23 mmol) in MeOH
(1 mL) at rt was added NaOMe (4 mg, 0.068 mmol). After stirring
for 3 h, H+ resin was added to neutralize the base. The mixture
was filtered and the filtrate was concentrated in vacuo. The residue
was dissolved in dry DMF (0.2 mL), followed by the addition of
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.11.020.
benzaldehyde dimethyl acetal (70
l
L, 0.46 mmol) and p-TsOHꢀH2O
References
(13 mg). The flask was placed at 50 °C under low vacuum to re-
move the formed MeOH for 1 h. Et3N (0.2 mL) was added and the
solvent was then concentrated in vacuo. The residue was purified
by silica gel column chromatography (1:2 petroleum ether–EtOAc)
1. (a) Duan, L.; Feng, B.; Wang, W.; Chen, F.; Cai, G.; Pei, Y.; Wang, Y. Helv. Chim.
Acta 2006, 89, 2953–2957; (b) Feng, B.; Duan, L.; Tang, L.; Pei, Y.; Wang, Y.
Heterocycles 2008, 75, 173–176.
2. Sun, K.; Li, X.; Liu, J.-M.; Wang, J.-H.; Li, W.; Sha, Y. J. Asian Nat. Prod. Res. 2005, 7,
853–856.
to afford 22 (88 mg, 83% for two steps) as a white foam. ½a D26
ꢃ34 (c
ꢂ
0.5, CHCl3); 1H NMR (CDCl3, 300 MHz) d 7.47–7.51 (m, 2H, ArH),
3. (a) Benn, M. Can. J. Chem. 1980, 58, 1892–1893; (b) Richardson, J. F.; Benn, M. H.
Can. J. Chem. 1984, 62, 1236–1237.
7.36–7.39 (m, 3H, ArH), 6.43 (s, 2H, ArH), 5.54 (s, 1H, PhCH), 5.46

314
F. Yang et al. / Carbohydrate Research 345 (2010) 309–314
4. Fernandez, J. M. G.; Mellet, C. O.; Defaye, J. J. Org. Chem. 1998, 63, 3572–3580.
5. Kim, J.-H.; Yang, H.; Park, J.; Boons, G.-J. J. Am. Chem. Soc. 2005, 127, 12090–
12097.
6. Fascione, M. A.; Adshead, S. J.; Stalford, S. A.; Kilner, C. A.; Leach, A. G.; Turnbull,
W. B. Chem. Commun. 2009, 5841–5843.
7. Hori, M.; Ozeki, H.; Iwamura, T.; Shimizu, H.; Kataoka, T.; Iwata, N. Heterocycles
1990, 31, 23–26.
8. Hartung, J.; Hünig, S.; Kneuer, R.; Schwarz, M.; Wenner, H. Synthesis 1997, 1433–
1438.
9. Simian, H.; Robert, F.; Blank, I. J. Agric. Food. Chem. 2004, 52, 306–310.