Convenient one-pot synthesis of thiosugars and their efficient conversion to polyoxygenated cycloalkenes

Article abstract of DOI:10.1016/j.tet.2012.03.086

A convenient synthesis of polyoxygenated tetrahydrothiopyrans and thiepanes from various alditol derivatives with xylo, ribo, manno, gluco, galacto, and fuco configurations is described. The preparation started from the corresponding partially protected a

Full text of DOI:10.1016/j.tet.2012.03.086

Tetrahedron 68 (2012) 4242e4247
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Convenient one-pot synthesis of thiosugars and their efficient conversion to
polyoxygenated cycloalkenes
,
,
*
Jingjing Zhang a, Youhong Niu a b, Xiaoping Cao b, Xin-Shan Ye a
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, China
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of polyoxygenated tetrahydrothiopyrans and thiepanes from various alditol de-
rivatives with xylo, ribo, manno, gluco, galacto, and fuco configurations is described. The preparation
started from the corresponding partially protected alditols and proceeded in a ‘one-pot’ manner to afford
the final products in 80%e95% yield. Furthermore, thiosugar compounds 2b, 2d, and 2g were converted
to the optically pure polyoxygenated cycloalkenes through RambergeBacklund reaction in moderate to
good overall yield. The procedures can be used for the preparation of polyoxygenated thiosugars and
cycloalkenes on a relatively large scale.
Received 3 February 2012
Received in revised form 11 March 2012
Accepted 20 March 2012
Available online 24 March 2012
Keywords:
Tetrahydrothiopyrans
Thiepanes
Ó 2012 Elsevier Ltd. All rights reserved.
Thiosugars
Cycloalkenes
RambergeBacklund reaction
1. Introduction
cyclized with the sulfur functionality.9 The bielectrophilic sub-
strates include bis-epoxyhexitols,9c dibromoalditol derivatives,9b,9e
Thiosugars are carbohydrate analogs, in which one or more
oxygen atoms are substituted by a sulfur atom both in the pyran-
oside and furanoside structures.1 In the last two decades, these
compounds have attracted much attention from chemists and
biochemists due to their biological importance. For instance, thio-
sugars and their derivatives have shown potent inhibitory activities
toward glycosidases and some of these thiosugars have shown
good specificity.2b The inhibitory activities are attributed to the
stronger hydrophobic interaction between the sulfur-containing
carbohydrates and the enzymes.2 Thiosugars also can be de-
veloped as potential therapeutical agents, such as antineoplastic,3
antidiabetic,4 antiviral,5 and antithrombotic6 agents. Moreover,
they are important synthons for the preparation of inositol and
aminocyclitol derivatives.4 Given their diverse biological activities
and usefulness in organic synthesis, many strategies are now
available for the preparation of thiosugars, including chemical and
biochemical transformations.1,7
biscyclic sulfates,10 biscyclic thionocarbonates,11 and so on. All
these syntheses are based on a multi-step reaction sequence.
Therefore, more efficient approaches to prepare this type of com-
pounds in fewer steps are still needed. As part of our continuing
exploration of the syntheses and biological activities of carbohy-
drate mimetics,12 we describe here a convenient ‘one-pot’ pro-
cedure for the preparation of polyoxygenated tetrahydrothiopyrans
and thiepanes starting from alditols. Furthermore, these thiosugar
compounds can be converted to optically pure cycloalkenes, which
are also functioned as carbohydrate mimetics through Ram-
bergeBlacklund reaction in two steps.
2. Results and discussion
Our ‘one-pot’ synthesis started from different diols, which were
prepared from natural sugars or alditols according to literature
procedures.13 After the activation of two hydroxyl groups by mesy-
lation, the cyclization was subsequently achieved by the treatment
with Na2S$9H2O in DMF. The two reactions were performed in one
flask without the purification of the intermediates, and the final
products were obtained in high isolated yields. For example, when
2,3,4-tris(benzyloxy)pentane-1,5-diols 1a and 1b were mesylated
with methylsulfonyl chloride followed by the treatment with so-
dium sulfide, the corresponding tetrahydrothiopyrans 2a and 2b
werefurnished in 90% and 85% yields, respectively, (Table 1, entries 1
Tetrahydrothiopyrans and thiepanes are basic structures or key
intermediates of bioactive thiosugars.8 The syntheses of these
compounds, starting from partially protected alditols or semi-
protected aldoses, usually involve the activation of dihydroxyl
groups to form bielectrophilic substrates, which are subsequently
* Corresponding author. Fax: þ86 10 82802724; e-mail address: xinshan@
bjmu.edu.cn (X.-S. Ye).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.086

J. Zhang et al. / Tetrahedron 68 (2012) 4242e4247
4243
Table 1
Synthesis of tetrahydrothiopyrans and thiepanes from diols
Entry
1
Diol
Cyclic thioether
Yield (%)
OH OH
S
90%
85%
OBn
OBn
OBn
OBn
BnO
BnO
BnO
OBn
S
2a
2b
1a
1b
OH OH
2
3
OBn
OBn
BnO
OBn
S
OBn
OBn
OH OH
80%
95%
91%
OBn
OBn
OBn
OBn
BnO
BnO
OBn
S
1c
2c
OBn
OBn
OH OH
4
OBn
OBn
BnO
BnO
OBn
S
1d
2d
OBn
OBn
OH OH
5
OBn
OBn
OBn
OBn
BnO
BnO
OBn
S
1e
1f
2e
2f
OH OH
6
7
83%
90%
OBn
OBn
BnO
HO
BnO
BnO
OBn
S
OH
BnO
BnO
HO
BnO
OBn
OBn
OBn
BnO
OBn
2g
1g
OH
S
BnO
BnO
8
9
91%
89%
OBn
OBn
OBn
OBn
2h
2i
BnO
HO
1h
1i
OH
S
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
and 2). The same one-pot reaction was also applied to diols 1ce1f,
each of them possessed both a secondary and a primary hydroxyl
groups. As expected, the products 2ce2f were obtained smoothly in
80%e95% yields with the inversion of C5 chiral centers of diols 1ce1f
(Table 1, entries 3e6). Thus, polyoxygenated tetrahydrothiopyrans
were efficiently achieved in this way.
Moreover, this one-pot approach was perfectly extended to the
synthesis of the seven-membered polyoxygenated thiepanes as

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J. Zhang et al. / Tetrahedron 68 (2012) 4242e4247
well. Polyoxygenated thiepanes are potential inhibitors toward
glycosidases14 and HIV proteases.15 The existing methods for the
synthesis of thiepanes suffer from low yield and poor regiose-
lectivity due to the formation of rearranged products.9e Starting
from various 2,3,4,5-tetrakis-benzyloxy-hexane-1,6-diols, the pol-
yoxygenated thiepanes with different configurations were pre-
pared in a one-pot fashion. As shown in Table 1, the corresponding
thiepanes 2g, 2h, 2i were provided in 90%, 91%, and 89% yield, re-
spectively, and no rearrangement products were isolated (entries
7e9). In addition, all these reactions were able to be performed on
a relatively large scale (30e40 mmol) with practically no changes in
yields or the reaction time.
On the other hand, polyoxygenated cycloalkenes are the im-
portant structural units of many naturally occurring compounds,
such as prostaglandins,16 mannostatins,17 trehazolin,18 and pente-
nomycins.19 This type of compounds are also used as carbohydrate
mimetics. Currently, there are many methods for the synthesis of
polyoxygenated cycloalkenes including McMurry coupling,20 olefin
metathesis,21 free radical reaction, RambergeBacklund rearrange-
ment,22 and so on. It is known that thiosugars can be used as the
starting materials for the RambergeBacklund rearrangement.
Therefore the RambergeBacklund rearrangement reactions by us-
ing the synthetic tetrahydrothiopyrans and thiepanes to generate
polyoxygenated cycloalkenes were examined.
Tetrahydrothiopyran 2b was chosen for this purpose. After
treatment with N-chlorosuccinimide, compound 2b was converted
to the anomeric chloride, which was followed by in situ oxidization
to yield chlorosulfone 3b. Compound 3b was treated with t-BuOK in
THF at ꢀ15 ꢁC, affording optically pure polyoxygenated cyclo-
pentene 4b in 72% isolated yield. Likewise, using the same reaction
sequence, tetrahydrothiopyran 2d and thiepane 2g with four sub-
stituents were also transformed to the corresponding cyclopentene
4d and cyclohexene 4g in 40% and 51% overall yield, respectively,
(Scheme 1). The transformation from thiosugars to cycloalkenes on
a relatively large scale was also performed. Starting from 30 mmol
of 2d and 2g, the respective products 4d and 4g were obtained in
48% and 55% yield, which are even higher than the yields of small
scale reactions. Therefore, this is an efficient and practical strategy
for the preparation of polyoxygenated cycloalkenes from the thio-
sugar derivatives made by our one-pot procedure.
3. Conclusions
In summary, a convenient one-pot protocol was developed for
the synthesis of polyoxygenated tetrahydrothiopyrans and thie-
panes with xylo, ribo, gluco, manno, fuco, and galacto configurations
in good yields starting from various diols. And the conversion of
polyoxygenated tetrahydrothiopyrans and thiepanes to optically
pure polyoxygenated cycloalkenes also proceeded very well. The
procedures can be applied to the preparation of polyoxygenated
thiosugars and cycloalkenes on a relatively large scale. Due to these
merits, the disclosed strategy may find wide applications in the
synthesis of biologically important carbohydrate mimetics, such as
thiosugars and polyoxygenated cycloalkenes.
4. Experimental section
4.1. General
Reagents were purchased and used without further purification.
Tetrahydrofuran (THF) was distilled over sodium/benzophenone,
and dichloromethane (CH2Cl2) was dried over calcium hydride. All
reactions were carried out under argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions, unless oth-
erwise noted. Reactions were monitored with analytical TLC on
silica gel 60-F254 precoated aluminum plates and visualized under
UV (254 nm) and/or by staining with acidic ceric ammonium mo-
lybdate. Column chromatography was performed on silica gel
(35e75 m
m). 1H NMR spectra were recorded on a Varian VXR-300M
spectrometer at 20 ꢁC. 13C NMR spectra were obtained by using the
same Varian NMR spectrometers. Mass spectra were recorded us-
ing a PE SCLEX QSTAR spectrometer. Elemental analysis data were
recorded on PE-2400C elemental analyzer.
4.2. General procedure for the synthesis of polyoxygenated
tetrahydrothiopyrans and thiepanes
To a stirred solution of diol (1.0 mmol) in CH2Cl2 (30 mL) and
Et3N (3.0 mmol) cooled with an iceeacetone bath under argon,
MeSO2Cl (2.4 mmol) was added dropwise. The solution was stirred
for 2 h followed by the addition of saturated NaHCO3 (30 mL). The
S
O
O
S
Cl
t-BuOK
NCS, CCl4
BnO
OBn
BnO
OBn
m-CPBA,CH2Cl2
THF, 72%
BnO
OBn
OBn
OBn
73%
OBn
3b
2b
4b
OBn
OBn
BnO
O
O
S
S
Cl
NCS, CCl4
t-BuOK
m-CPBA,CH2Cl2
THF, 52%
BnO
OBn
OBn
BnO
OBn
BnO
OBn
76%
OBn
OBn
OBn
3d
4d
2d
O
O
S
Cl
S
NCS, CCl4
t-BuOK
BnO
BnO
BnO
OBn
BnO
OBn
OBn
THF, 65%
m-CPBA,CH2Cl2
BnO
OBn
78%
OBn
BnO
4g
3g
2g
Scheme 1. Synthesis of polyoxygenated cycloalkenes.

J. Zhang et al. / Tetrahedron 68 (2012) 4242e4247
4245
mixture was extracted with CH2Cl2 (3ꢂ30 mL), and the combined
organic phase was washed with brine (60 mL), dried over Na2SO4
and evaporated to give crude product. The crude product was dis-
solved in DMF (20 mL), to this solution excessive Na2S$9H2O
(1.5 mmol) was added, and the mixture was heated at 85 ꢁC until
the starting material disappeared. The solvent was removed under
reduced pressure, and the residue was purified by column chro-
matography on silica gel (petroleum ether:ethyl acetate¼
40:1e20:1) to afford the product.
CDCl3):
d
7.36e7.25 (m, 18H), 7.14 (dd, J¼7.2, 2.4 Hz, 2H), 4.72 (d,
J¼2.0 Hz, 1H), 4.57 (t, J¼12.3 Hz, 1H), 4.49e4.36 (m, 6H), 4.01e3.95
(ddd, J¼3.9, 6.0, 9.3 Hz, 1H), 3.87 (dd, J¼1.8, 4.8 Hz, 1H), 3.68e3.64
(m, 1H), 3.56 (td, J¼1.8, 8.4 Hz, 1H), 3.52e3.41 (m, 2H), 3.15 (t,
J¼12.6 Hz, 1H), 2.50 (dd, J¼3.6, 12.6 Hz, 1H). 13C NMR (75 MHz,
CDCl3):
d 138.60, 138.47, 138.06, 137.98, 128.36, 128.27, 128.20,
127.86, 127.73, 127.61, 127.52, 75.99, 75.73, 74.26, 73.22, 72.98,
72.85, 70.92, 68.76, 39.76, 25.44. HRMS calcd for C34H40NO4S
(MþNHþ4 ): 558.2673, found: 558.2666. Anal. calcd for C34H36O4S: C,
75.52; H, 6.71; found C, 75.29; H, 6.87.
4.2.1. (3S,4R,5R)-3,4,5-Tris(benzyloxy)etetrahydro-2H-thiopyran
(2a). This compound was prepared from 1a13a (60.0 mg,
0.14 mmol) according to the general procedure to give product 2a
4.2.6. (2R,3S,4R,5S)-3,4,5-Tris(benzyloxy)-2-methyletetrahydro-2H-
thiopyran (2f). This compound was prepared from 1f13d (35.0 mg,
0.08 mmol) according to the general procedure to afford product 2f
(54.2 mg, 90%) as an oil. 1H NMR (300 MHz, CDCl3):
d 7.41e7.25 (m,
15H), 4.87 (s, 2H), 4.60 (d, J¼12.0 Hz, 2H), 4.52 (d, J¼12.0 Hz, 2H),
(29.5 mg, 83%) as an oil. 1H NMR (300 MHz, CDCl3):
d 7.37e7.25 (m,
4.14 (s, 1H), 3.57 (d, J¼11.4 Hz, 2H), 3.04 (t, J¼11.4 Hz, 2H), 2.44 (m,
15H), 4.69 (d, J¼12.0 Hz, 1H), 4.55 (d, J¼12.0 Hz, 2H), 4.50 (d,
J¼6.0 Hz, 2H), 4.40 (d, J¼12.6 Hz, 1H), 3.85e3.82 (m, 1H), 3.71e3.68
(m, 2H), 3.37e3.32 (m, 1H), 3.13 (dd, J¼2.1, 14.1 Hz, 1H), 2.41 (dd,
J¼3.9, 14.1 Hz, 1H), 1.27 (d, J¼6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
2H). 13C NMR (75 MHz, CDCl3):
d 139.30, 138.32, 128.42, 128.09,
127.79, 127.63, 127.37, 80.22, 74.12, 70.73, 25.45. HRMS calcd for
C26H28NaO3S (MþNaþ): 443.1651, found: 443.1649. Anal. calcd for
C26H28O3S: C, 74.25; H, 6.71; found C, 74.37; H, 6.80.
d
138.52, 138.32, 138.15, 128.35, 128.27, 128.05, 127.66, 127.56, 81.57,
75.10, 74.65, 73.13, 72.38, 70.96. 34.59, 27.59, 16.97. HRMS calcd for
4.2.2. (3S,4S,5R)-3,4,5-Tris(benzyloxy)etetrahydro-2H-thiopyran
(2b). This compound was prepared from 1b13b (600.0 mg,
1.42 mmol) according to the general procedure to give product 2b
(507.0 mg, 85%) as a white solid. 1H NMR (300 MHz, CDCl3):
C27H34NO3S (MþNHþ4 ): 452.2254, found: 452.2252.
4.2.7. (3S,4S,5S,6S)-3,4,5,6-Tetrakis(benzyloxy) thiepane (2g). This
compound was prepared from 1g13e (70.0 mg, 0.13 mmol)
according to the general procedure to afford product 2g (51.3 mg,
d
7.34e7.25 (m, 15H), 4.86 (s, 2H), 4.72 (d, J¼11.7 Hz, 2H), 4.65 (d,
J¼11.4 Hz, 2H), 3.67 (dd, J¼4.5, 12.0 Hz, 1H), 3.64 (dd, J¼1.8, 6.6 Hz,
1H), 3.34 (t, J¼8.7 Hz, 1H), 2.75 (dd, J¼2.4, 13.2 Hz, 2H), 2.51 (t,
90%) as an oil. 1H NMR (300 MHz, CDCl3):
d 7.35e7.22 (m, 20H),
4.73 (d, J¼12.0 Hz, 2H), 4.59 (d, J¼11.4 Hz, 4H), 4.49 (d, J¼12.0 Hz,
2H), 4.03 (dd, J¼2.4, 9.6 Hz, 2H), 3.89 (s, 2H), 3.13 (dd, J¼9.6,
13.5 Hz, 2H), 2.66 (dd, J¼2.7, 13.5 Hz, 2H). 13C NMR (75 MHz,
J¼11.1 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d 138.81, 138.29, 128.42,
128.30, 128.07, 127.82, 127.73, 127.53, 86.71, 82.19, 76.35, 73.01,
31.45. HRMS calcd for C26H32NO3S (MþNHþ4 ): 438.2097, found:
438.2089. The spectroscopic data coincide with the previous
report.23
CDCl3):
d 138.58, 138.33, 128.30, 128.24, 127.62, 127.52, 78.87,
78.10, 73.42, 71.41, 26.98. HRMS calcd for C34H40NO4S (MþNHþ4 ):
558.2673, found: 558.2679. Anal. calcd for C34H36O4S: C, 75.52; H,
6.71; found C, 75.31; H, 6.68.
4.2.3. (2S,3S,4R,5R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)etet-
rahydro-2H-thiopyran (2c). This compound was prepared from
1c13c (80.0 mg, 0.15 mmol) according to the general procedure to
afford product 2c (64.4 mg, 80%) as an oil. 1H NMR (300 MHz,
4.2.8. (3S,4R,5S,6R)-3,4,5,6-Tetrakis(benzyloxy) thiepane (2h). This
compound was prepared from 1h13f (70.0 mg, 0.13 mmol) accord-
ing to the general procedure to afford product 2h (51.5 mg, 91%) as
CDCl3):
d
7.36e7.28 (m, 20H), 4.76e4.60 (m, 8H), 3.87e3.80 (m, 3H),
an oil. 1H NMR (300 MHz, CDCl3):
d
7.30e7.25 (m, 20H), 4.72e4.57
3.66 (m, 1H), 3.54 (t, J¼9.0 Hz, 1H), 3.08 (br s, 1H), 2.82 (t, J¼13.2 Hz,
(m, 8H), 4.30 (br s, 2H), 3.89 (br s, 2H), 2.97e2.83 (m, 4H). 13C NMR
1H), 2.61 (dd, J¼2.1, 13.2 Hz, 1H). 13C NMR (75 MHz, CDCl3):
(75 MHz, CDCl3):
d 138.66, 138.49, 128.27, 127.66, 127.55, 127.46,
d
138.76, 138.32, 138.19, 138.15, 128.38, 128.24, 128.05, 127.76,
81.80, 73.37, 71.46, 35.17. HRMS calcd for C34H40NO4S (MþNHþ4 ):
558.2673, found: 558.2675. Anal. calcd for C34H36O4S: C, 75.52; H,
6.71; found C, 75.31; H, 6.77.
127.65, 127.50, 82.65, 82.42, 81.95, 75.98, 73.15, 72.91, 72.82, 67.31,
41.89, 27.32. HRMS calcd for C34H40NO4S (MþNHþ4 ): 558.2673,
found: 558.2671. Anal. calcd for C34H36O4S: C, 75.52; H, 6.71; found
C, 75.33; H, 6.76. The spectroscopic data coincide with the previous
report.23
4.2.9. (3S,4S,5S,6R)-3,4,5,6-Tetrakis(benzyloxy) thiepane (2i). This
compound was prepared from 1i13g (93.0 mg, 0.26 mmol)
according to the general procedure to afford product 2i (83.0 mg,
4.2.4. (2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)etet-
rahydro-2H-thiopyran (2d). This compound was prepared from
1d13c (4.5 g, 8.4 mmol) according to the general procedure to afford
product 2d (4.3 g, 95%) as an oil. 1H NMR (300 MHz, CDCl3):
89%) as an oil. 1H NMR (300 MHz, CDCl3):
d 7.32e7.19 (m, 20H),
4.71 (d, J¼12.0 Hz, 1H), 4.65e4.45 (m, 7H), 4.58 (t, J¼6.9 Hz, 1H),
4.54e4.45 (m, 5H), 3.97 (br s, 1H), 3.89 (dd, J¼3.0, 10.5 Hz, 1H),
3.78e3.74 (m, 2H), 3.30 (dd, J¼10.8, 13.2 Hz, 1H), 3.20 (dd, J¼9.9,
14.4 Hz, 1H), 2.55e2.50 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
7.33e7.25 (m, 20H), 4.67 (d, J¼12.0 Hz, 1H), 4.59e4.49 (m, 6H),
4.43 (d, J¼12.0 Hz, 1H), 4.04 (dd, J¼2.4, 9.3 Hz, 1H), 3.86e3.84 (m,
1H), 3.74 (dd, J¼4.2, 9.6 Hz, 1H), 3.69e3.63 (m, 2H), 3.55e3.49 (m,
1H), 3.05 (dd, J¼2.1, 14.1 Hz, 1H), 2.51 (dd, J¼4.5, 13.8 Hz, 1H). 13C
d 138.31, 138.24, 138.23, 138.18, 128.35, 128.27, 127.82, 127.74,
127.66, 127.55, 127.46, 88.04, 82.05, 80.93, 79.89, 72.81, 71.78,
71.31, 29.60, 29.08. HRMS calcd for C34H40NO4S (MþNHþ4 ):
558.2673, found: 558.2674. Anal. calcd for C34H36O4S: C, 75.52; H,
6.71; found C, 75.51; H, 6.60.
NMR (75 MHz, CDCl3):
d 138.47, 138.25, 138.21, 138.09, 128.30,
128.02, 127.65, 77.21, 77.17, 75.49, 74.96, 73.09, 72.14, 71.10, 69.53,
40.82, 27.35. HRMS calcd for C34H40NO4S (MþNHþ4 ): 558.2673,
found: 558.2684. Anal. calcd for C34H36O4S: C, 75.52; H, 6.71; found
C, 75.33; H, 6.81.
4.3. Synthesis of a-chlorosulfones
4.3.1. (2R,3R,4S,5S)-2-Chloro-3,4,5-tris(O-benzyloxy)etetrahy-
drothiopyran 1,1-dioxide (3b). Tetrahydrothiopyran 2b (410.0 mg,
1.86 mmol) was dissolved in anhydrous CCl4 (20 mL), and the so-
lution were heated to 90 ꢁC. Then N-chlorosuccinimide (279.0 mg,
2.05 mmol) was added in one portion, and the reaction mixture was
4.2.5. (2S,3S,4R,5S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)etet-
rahydro-2H-thiopyran (2e). This compound was prepared from
1e13c (160.0 mg, 0.29 mmol) according to the general procedure to
afford product 2e (143.0 mg, 91%) as an oil. 1H NMR (300 MHz,

4246
J. Zhang et al. / Tetrahedron 68 (2012) 4242e4247
stirred at this temperature until TLC showed that the starting ma-
terial disappeared. After cooled to room temperature, the mixture
was filtered with exclusion of moisture. The filtrate was diluted
with CH2Cl2 (20 mL) and cooled at 0 ꢁC, then treated with m-
chloroperbenzoic acid (1.3 g, 5.58 mmol). After stirred for 18.5 h at
room temperature under argon, the thick slurry was partitioned
between dichloromethane (40 mLꢂ3) and saturated Na2S2O3
(20 mL). The combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (petroleum
ether:ethyl acetate¼8:1) to afford 3b as white solids (345.3 mg,
127.83, 127.65, 91.42, 86.28, 72.05, 71.03. HRMS calcd for C26H30NO3
(MþNHþ4 ): 404.2220, found: 404.2210.
4.4.2. 1-((((3S,4R,5S)-3,4,5-Tris(benzyloxy)cyclopent-1-enyl)me-
thoxy)methyl)benzene (4d). This compound was prepared from
compound 3d (112 mg, 0.18 mmol) following the same procedure
as described in the preparation of compound 4b, yielding 4d
(48.6 mg, 52%) as an oil. 1H NMR (300 MHz, CDCl3):
d 7.39e7.26 (m,
20H), 5.99 (d, J¼1.5 Hz, 1H), 4.80e4.78 (m, 1H), 4.74 (d, J¼11.7 Hz,
1H), 4.66e4.61 (m, 5H), 4.53 (d, J¼11.7 Hz, 2H), 4.48 (d, J¼12.0 Hz,
1H), 4.08 (s, 2H), 4.01 (dd, J¼5.1, 6.0 Hz, 1H). 13C NMR (75 MHz,
73%). 1H NMR (300 MHz, CDCl3):
d
7.34e7.25 (m, 15H), 4.93e4.82
CDCl3): d 142.22, 138.55, 138.32, 138.21, 138.01, 130.19, 128.38,
(m, 4H), 4.72 (d, J¼11.4 Hz, 1H), 4.67 (d, J¼10.8 Hz, 1H), 4.64 (d,
J¼12.0 Hz, 1H), 3.98 (ddd, J¼4.5, 9.0, 13.5 Hz, 1H), 3.82 (t, J¼9.9 Hz,
1H), 3.66 (t, J¼9.3 Hz, 1H), 3.54 (dd, J¼4.2, 14.4 Hz, 1H), 3.04 (dd,
128.27, 128.08, 127.90, 127.79, 127.69, 127.55, 86.33, 84.29, 78.76,
72.62, 72.21, 71.82, 71.40, 67.18. HRMS calcd for C34H38NO4
(MþNHþ4 ): 524.2838, found: 524.2827. The spectroscopic data co-
incide with the previous report.24
J¼11.4, 14.4 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d 137.67, 137.00,
136.80, 128.70, 128.49, 128.37, 128.21, 127.97, 127.74, 85.37, 80.70,
74.78, 73.81, 72.05, 51.57. HRMS calcd for C26H31ClNO5S (MþNHþ4 ):
504.1592, found: 504. 1595.
4.4.3. (3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)ecyclohex-1-ene
(4g). This compound was prepared from compound 3g (221 mg,
0.36 mmol) following the same procedure as described in the
preparation of compound 4b, yielding 4g (120 mg, 65%) as an oil. 1H
4.3.2. (2R,3R,4S,5R,6R)-2-Chloro-3,4,5-tris(O-benzyloxy)-6-
benzyloxymethyltetrahydrothiopyran 1,1-dioxide (3d). Compound
3d was prepared from tetrahydrothiopyran 2d (260 mg, 0.48 mmol)
following the same procedure as described in the preparation of
compound 3b, yielding 3d (221 mg, 76%) as white solids. 1H NMR
NMR (300 MHz, CDCl3):
d 7.34e7.25 (m, 20H), 5.83 (s, 2H), 4.70 (d,
J¼12.0 Hz, 2H), 4.64 (d, J¼12.3 Hz, 2H), 4.62 (d, J¼11.1 Hz, 2H), 4.58
(d, J¼12.3 Hz, 2H), 4.25 (s, 2H), 3.99 (s, 2H). 13C NMR (75 MHz,
CDCl3): d 138.64,128.30,128.12,128.07,127.87,127.68,127.55, 76.02,
(300 MHz, CDCl3):
d
7.40e7.13 (m, 20H), 4.99 (d, J¼3.3 Hz, 1H),
73.32, 73.28, 71.63. HRMS calcd for C34H38NO4 (MþNHþ4 ): 524.2838,
found: 524.2825. The spectroscopic data coincide with the previous
report.13d
4.71e4.58 (m, 4H), 4.49e4.21 (m, 5H), 4.19 (dd, J¼2.7, 11.1 Hz, 1H),
4.12 (dd, J¼5.7, 11.1 Hz, 1H), 3.87e3.84 (m, 2H), 3.67e3.69 (m, 1H).
13C NMR (75 MHz, CDCl3):
d 137.57, 137.16, 137.02, 136.90, 128.59,
128.37, 128.24, 128.19, 127.98, 127.79, 127.66, 74.67, 74.32, 73.96,
73.73, 73.53, 73.29, 69.32, 62.56, 61.98. HRMS calcd for C34H36ClO6S
(MþHþ): 624.2181, found: 624.2176. Anal. calcd for C34H35ClO6S: C,
67.26; H, 5.81; found C, 66.98; H, 5.89.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21072014) and ‘973’ grant from the
Ministry of Science and Technology of China (2012CB822100).
4.3.3. (2R,3S,4S,5R,6S)-2-Chloro-3,4,5,6-Tetrakis(O-benzyloxy)thie-
pane 1,1-dioxide (3g). This compound was prepared from com-
pound 2g (350 mg, 0.65 mmol) following the same procedure as
described in the preparation of compound 3b, yielding 3g
(306 mg, 78%) as white solids. 1H NMR (300 MHz, CDCl3):
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.086.
d
7.31e7.15 (m, 20H), 5.29 (d, J¼8.7H, 1H), 4.77 (d, J¼11.7 Hz, 1H),
4.65 (d, J¼12.6 Hz, 1H), 4.62 (d, J¼11.7 Hz, 1H), 4.60 (d, J¼12.9 Hz,
1H), 4.49 (d, J¼12.0 Hz, 1H), 4.46 (d, J¼12.3 Hz, 1H), 4.46e4.40
(m, 2H), 4.22 (d, J¼9.9 Hz, 1H), 4.02e3.90 (m, 3H), 3.80 (d,
J¼5.7 Hz, 1H), 3.36 (d, J¼15 Hz, 1H). 13C NMR (75 MHz, CDCl3):
References and notes
1. Yuasa, H.; Izukawa, Y.; Hashimoto, H. Curr. Top. Med. Chem. 2009, 9, 76e86.
2. (a) Yuasa, H.; Nakano, Y.; Hashimoto, H. Carbohydr. Lett. 1996, 2, 23e26; (b)
Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J. A., Jr.;
Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6187e6196.
3. (a) Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett. 1999, 40, 1937e1940; (b)
Miura, S.; Yoshimura, Y.; Endo, M.; Machida, H.; Matsuda, A.; Tanaka, M.; Sasaki,
T. Cancer Lett. 1998, 129, 103e110.
d
137.53, 137.09, 136.89, 136.69, 128.50, 128.17, 128.06, 127.95,
127.86, 78.21, 77.19, 75.34, 74.50, 74.13, 73.85, 73.60, 71.77, 71.54,
52.01. HRMS calcd for C34H39ClNO6S (MþNHþ4 ): 624.2181, found:
624.2171.
4. Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem. Soc. 1990, 112,
9439e9440.
5. (a) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.;
Jeong, L. S.; Beach, J. W.; Choi, W. B.; Yeola, S. Antimicrob. Agents Chemother.
1992, 36, 672e676; (b) Coates, J. A.; Cammack, N.; Jenkinson, H. J.; Jowett, A. J.;
Jowett, M. I.; Pearson, B. A.; Penn, C. R.; Rouse, P. L.; Viner, K. C.; Cameron, J. M.
Antimicrob. Agents Chemother. 1992, 36, 733e739; (c) Beach, J. W.; Jeong, L. S.;
Alves, A. J.; Pohl, D.; Kim, H. O.; Chang, C. N.; Doong, S. L.; Schinazi, R. F.; Cheng,
Y. C.; Chu, C. K. J. Org. Chem. 1992, 57, 2217e2219.
4.4. Synthesis of cycloalkenes from a-chlorosulfones
4.4.1. (3R,4R,5S)-3,4,5-Tris(benzyloxy)cyclopent-1-ene (4b). To a so-
lution of -chlorosulfone 3b (49.0 mg, 0.1 mmol) in dry THF (3 mL)
a
cooled at e15 ꢁC, t-BuOK (31.3 mg, 0.28 mmol) was added in one
portion. The reaction mixture was stirred at this temperature for
20 min, and the saturated NH4Cl aqueous solution (3 mL) was
added. Then THF was removed under reduced pressure, and the
residue was partitioned between CH2Cl2 (20 mLꢂ3) and water
(20 mL). The combined organic layer was rinsed with brine (20 mL),
dried over Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (petroleum ether:ethyl
acetate¼30:1e20:1) to afford product 4b as an oil (28.6 mg, 72%).
6. (a) Bozo, E.; Boros, S.; nos Kuszmann, J. Carbohydr. Res. 1998, 311, 191e202; (b)
ꢀ
Bozo, E.; Gati, T.; Demeter, A.; Kuszmann, J. Carbohydr. Res. 2002, 337, 1351e1365.
7. (a) Robina, I.; Vogel, P.; Witczak, Z. J. Curr. Org. Chem. 2001, 5, 1177e1214; (b)
Robina, I.; Vogel, P. Curr. Org. Chem. 2002, 6, 471e491.
8. (a) Merrer, Y. L.; Fuzier, M.; Dosbaa, I.; Foglietti, M. J.; Depezay, J. C. Tetrahedron
1997, 53, 16731e16746; (b) Cere, V.; Mantovani, G.; Peri, F.; Pollicino, S.; Ricci, A.
Tetrahedron 2000, 56, 1225e1231.
9. (a) Altenbach, H. J.; Merhof, G. F. Tetrahedron: Asymmetry 1996, 7, 3087e3090;
(b) Benazza, M.; Halila, S.; Viot, C.; Danquigny, A.; Pierru, C.; Demailly, G. Tet-
rahedron 2004, 60, 2889e2895; (c) Fuzier, M.; Merrer, Y. L.; Depezay, J. C. Tet-
rahedron Lett. 1995, 36, 6443e6446; (d) Passacantilli, P.; Centore, C.; Ciliberti,
E.; Piancatelli, G.; Leonelli, F. Eur. J. Org. Chem. 2006, 3097e3104; (e) Halila, S.;
Benazza, M.; Demailly, G. Tetrahedron Lett. 2001, 42, 3307e3310.
10. Glacon, V.; Benazza, M.; Beaupere, D.; Demailly, G. Tetrahedron Lett. 2000, 41,
5053e5056.
1H NMR (300 MHz, CDCl3):
d 7.35e7.25 (m, 15H), 5.91 (s, 2H), 4.68
(s, 2H), 4.60 (s, 4H), 4.48 (d, J¼3.9 Hz, 2H), 4.22 (t, J¼3.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3):
d 138.29, 138.13, 132.15, 128.37, 127.91,

J. Zhang et al. / Tetrahedron 68 (2012) 4242e4247
4247
11. Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett. 2002, 43, 815e818.
12. See, for example: (a) Wang, G.-N.; Xiong, Y.; Ye, J.; Zhang, L.-H.; Ye, X.-S. ACS
Med. Chem. Lett. 2011, 2, 682e686; (b) Zhang, G.-L.; Zhang, L.-H.; Ye, X.-S. Org.
Biomol. Chem. 2010, 8, 5062e5068; (c) Pang, L.-J.; Wang, D.; Zhou, J.; Zhang, L.-
H.; Ye, X.-S. Org. Biomol. Chem. 2009, 7, 4252e4266; (d) Wang, G.-N.; Re-
inkensmeier, G.; Zhang, S.; Zhou, J.; Zhang, L.; Zhang, L.-H.; Butters, T. D.; Ye, X.-
S. J. Med. Chem. 2009, 52, 3146e3149; (e) Zhou, J.; Zhang, Y. M.; Zhou, X.; Zhou,
J.; Zhang, L.-H.; Ye, X.-S.; Zhang, X.-L. Bioorg. Med. Chem. 2008, 16, 1605e1612;
(f) Zhang, L.; Sun, F.; Li, Y.; Sun, X.; Liu, X.; Huang, Y.; Zhang, L.-H.; Ye, X.-S.;
Xiao, J. ChemMedChem 2007, 2, 1594e1597; (g) Ye, X.-S.; Sun, F.; Liu, M.; Li, Q.;
Wang, Y. H.; Zhang, G. S.; Zhang, L.-H.; Zhang, X.-L. J. Med. Chem. 2005, 48,
3688e3691.
15. Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada, Y.; Swaminathan,
S.; Bischofberger, N.; Chen, M. S.; Cherrington, J. M.; Xiong, S. F.; Griffin, L.;
Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W. J. Med. Chem. 1996, 39,
3431e3434.
16. Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 4718e4726.
17. (a) Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morishima, H.; Nagai, M.; Hamada, M.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1989, 42, 883e889; (b) King, S. B.; Ganem,
B. J. Am. Chem. Soc. 1991, 113, 5089e5090; (c) Li, C.; Fuchs, P. L. Tetrahedron Lett.
1994, 35, 5121e5124; (d) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1991,
113, 6317e6318; (e) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115,
444e458; (f) Trost, B. M. Pure Appl. Chem. 1992, 64, 315e322.
18. de Gracia, S. I.; Dietrich, H.; Bobo, S.; Chiara, J. L. J. Org. Chem. 1998, 63,
5883e5889.
13. (a) Violante de Paz Banez, M.; Moreno, J. A. A.; Galbis, J. A. J. Carbohydr. Chem.
2008, 27, 120e140; (b) Gallos, J. K.; Koftis, T. V.; Karamitrou, V. I.; Koumbis, A. E.
J. Chem. Soc., Perkin Trans. 1 1997, 2461e2462; (c) Jiang, Y. H.; Fang, Z. J.; Zheng,
Q. G.; Jia, H. L.; Cheng, J.; Zheng, B. H. Synthesis 2009, 16, 2756e2760; (d) Tsuda,
Y.; Nunozawa, T.; Yoshimoto, K. Chem. Pharm. Bull. 1980, 28, 3223e3231; (e)
Mabiala-Bassiloua, C. G.; Zwolinska, M.; Therisod, H.; Sygusch, J.; Therisod, M.
Bioorg. Med. Chem. Lett. 2008, 18, 1735e1737; (f) Ackermann, L.; Tom, D. E.;
Furstner, A. Tetrahedron 2000, 56, 2195e2202; (g) Matos, M.-C.; Murphy, P. V. J.
Org. Chem. 2007, 72, 1803e1806.
19. Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41, 4291e4293.
20. (a) McMurry, J. E. Chem. Rev. 1989, 89, 1513e1524; (b) Ephritikhine, M. Chem.
Commun. 1998, 2549e2554.
21. Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.; Diver, S. T. Org.
Lett. 2007, 9, 1203e1206.
22. Ramberg, L.; Backlund, B. Ark. Kemi. Mineral. Geol. 1940, 27, 1e50.
23. Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto, B. M. J. Am. Chem.
Soc. 2004, 126, 12458e12469.
ꢁ
14. Arcelli, A.; Cere, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron: Asymmetry 2002,
24. Agrofoglio, L. A.; Amblard, F.; Nolan, S. P.; Charamon, S.; Gillaizeau, I.; Zevaco, T.
13, 191e196.
A.; Guenot, P. Tetrahedron 2004, 60, 8397e8404.