The first synthesis of 7-(hydroxymethyl)thiepane-3,4,5-triols from d-(-)-quinic acid

Article abstract of DOI:10.1016/j.tet.2012.12.047

Seven thiepanes, the seven-membered-ring thiosugars, were first synthesized in 11-12 steps starting from d-(-)-quinic acid. Each thiepane is unique for its flexible conformation with a hydroxymethyl group at its C7 position. The key step was the deprotect

Full text of DOI:10.1016/j.tet.2012.12.047

Tetrahedron 69 (2013) 1897e1903
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The first synthesis of 7-(hydroxymethyl)thiepane-3,4,5-triols
from
D
-(ꢀ)-quinic acid
*
Tzenge-Lien Shih , Wei-Lin Gao
Department of Chemistry, Tamkang University, 25137 Tamsui Dist., New Taipei City, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2012
Received in revised form 10 December 2012
Accepted 18 December 2012
Available online 29 December 2012
Seven thiepanes, the seven-membered-ring thiosugars, were first synthesized in 11e12 steps starting
from
D-(ꢀ)-quinic acid. Each thiepane is unique for its flexible conformation with a hydroxymethyl group
at its C7 position. The key step was the deprotection of ether groups in compounds 7, 8, and 18e21 by
1.0 M BCl3 of CH2Cl2 solution at ꢀ78 ꢁC to lead to the corresponding thiepanes. These target molecules all
exhibited the twisted chair conformation that fully agreed with our previous report.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Glycosidase inhibitors
D
-(ꢀ)-Quinic acid
Thiepanes
Thiosugars
1. Introduction
as salacinol,12,13 kotalanol,13 and other analogues,14,15 have att-
racted interests to synthetic communities due to their intriguing
Glycosidases are important enzymes that are involved in the
hydrolysis of complex carbohydrates.1 Glycosidase inhibitors are
widely used in treatment of diseases, such as diabetes,2 anti-virus
infections,3 and cancers.4 Presently, many potent glycosidase in-
hibitors are either pyrrole- or piperidine-like azasugars. The most
notable agents are nojirimycin,5 1-deoxynojirimycin (DNJ),5 and
miglitol.6
structures and biological activities (Fig. 1).13e17 In addition to the
five-membered-ring thiosugar moiety, the thiopyrans and thie-
panes could also be incorporated with different sulfate side chains,
such as 1, 2 (Fig. 1).18 Thiepanes are seemingly as flexible as aze-
panes (seven-membered-ring azasugars).19,20 To the best of our
knowledge, only few synthetic thiepanes were reported and their
syntheses were mainly based on chiral-pool approaches.21e27
Fig. 1. Structures of salacinol, kotalanol, and analogues 1 and 2.
Beside the above-mentioned azasugars, the thiosugars were
also considered as potential glycosidase inhibitors as well as sugar
mimics of nucleoside analogues.7e11 Recently, five-membered ring
thiosugars with various forms of sulfate side chains, such
We have experienced in the synthesis of thiepanes starting from
D
-(ꢀ)-quinic acid.28 In that report, we obtained not only the re-
quired thiepanes but also thiopyrans during the reaction course.
Obviously, the intramolecular sulfur displacement of an adjacent
hydroxyl group of thiepanes led to the thiopyran formation. Such
ring contractions in the formation of thiophenes and thiopyrans
from the corresponding either seven- or eight-membered-ring
thiosugar derivatives were not unusual as have been
* Corresponding author. Tel.: þ886 286315024; fax: þ886 226209924; e-mail
address: tlshih@mail.tku.edu.tw (T.-L. Shih).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.047

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T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
reported.27,30 In order to synthesize thiepanes in higher yields as
well as minimize the possibility of ring contraction, we reported
herein a straightforward method to synthesize new and unique
experiments. The NOE signals were clearly observed between H5
and H7 in 19 and 21 but not in 18 and 20. These results allowed us
to conclude the stereochemistry at C6 of compounds 14e17
according to the SN2 mechanism.
Compound 7, 18, and 19 were deprotected by 1.0 M BCl3 in
CH2Cl2 at ꢀ78 ꢁC9 to give thiepanes 22 (50%), 25 (45%), and 26
(42%), respectively (Scheme 3). The same procedure was also ap-
plied on 8, however, it afforded a mixture that contained two in-
thiepanes 22, 23, and 25e29 from
D
-(ꢀ)-quinic acid.
2. Results and discussion
A common intermediate 329 was used for the syntheses of 7 and
8 (Scheme 1). Compound 3 was first subjected to dihydroxylation
by KMnO4/MgSO4 method31 to afford a diol derivative, which was
oxidatively cleaved by NaIO4 to give 4. The resulting syrup was
subsequently reduced by NaBH4 to receive the separable di-
astereomers 5 (32%, three steps) and 6 (13%, three steps) (vide in-
fra). While OsO4 and NMO were used as oxidants, the higher yields
of 5 (46%) and 6 (11%) were isolated. The absolute stereochemistry
at C6 of 5 and 6 was not easily to be confirmed at this stage. For-
tunately, their configurations were later determined after meth-
anesulfonation and thiocyclization of compounds 5 and 6 to
provide 7 (84%) and 8 (59%), respectively. Many reports have
demonstrated that these kinds of thiocyclizations underwent an
SN2 mechanism.9,12,23,32e34 Therefore, the newly generated ste-
reochemistry at C7 of 7 and 8 were determined by comparison with
their cross-coupling patterns between H5 and H7 of NOESY spectra.
Compound 7 exhibits space correlation between H5 and H7 but
compound 8 does not. Thus we could deduce the C6 configurations
of 5 and 6 as shown in Scheme 1.
separable compounds 23 and 24 in
a ratio of 70:30 that
determined by NMR spectroscopy in a 59% combined yield. Obvi-
ously, compound 24 was derived from the ring contraction of 23 to
give 23a as an intermediate and followed by the nucleophilic at-
tack by H2O to afford 24 as indicated (path a).27,30 Also compound
23 was recovered from 23a via path b. A very interesting phe-
nomenon was observed in deprotection of compounds 20 and 21.
The benzyl group at C3 of 20 resisted to be cleaved and give 27
(55%) after the other protecting groups were cleaved. Deprotection
of 21 also gave the C3 benzyl protected 28 (40%) as well as a fully
deprotected 29 (10%) as a minor product. Further attempts to
remove the benzyl groups of 27 and 28 by excess equivalents of
BCl3 (10 equiv, 1.0 M in CH2Cl2) from ꢀ78 ꢁC to ambient temper-
ature were not successful. Compounds 27 and 28 were fully re-
covered. We attempted to remove the benzyl groups in
compounds 7, 8, and 18e21 by 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ (5 equiv)/K2CO3) in CH2Cl2 under reflux con-
dition. However, only the C8 benzyl groups were removed and the
Scheme 1. Synthesis of thiocyclic compounds 7 and 8.
The same strategy was applied to synthesize 18e21 (Scheme 2).
Compound 9 was reduced by diisobutylaluminium hydride and
then protected by benzyl groups to give an inseparable mixture of
10 and 11 (w1:1) in 68% combined yield (two steps).35,36 Fortu-
nately, the mixture was dihydroxylated to afford the separable
stereoisomers 12 (38%) and 13 (37%). The stereochemistry at C3 of
12 and 13 was easily determined according to the comparison of
NOESY spectra between H3 and H5 in 12 but not in 13. When the
double bond of compounds 12 was oxidatively cleaved and re-
duced, two diastereomers 14 (46%) and 15 (25%) were isolated.
While compound 13 was treated with the same procedure as above,
compounds 16 (54%) and 17 (26%) were obtained (vide infra). Again,
their respective stereochemistry could be indirectly deduced after
cyclizations of 14e17, which were conducted under the same
condition shown in Scheme 1 to afford compounds 18 (81%), 19
(50%), 20 (78%), and 21 (81%), respectively. The resulting stereo-
chemistry at C7 of 18e21 was again determined by NMR
C3 benzyl groups were remained intact in all cases. It is note-
worthy that thioadducts 7, 8, and 18e21 were decomposed when
boron tribromide (BBr3, 3 equiv) was used in CH2Cl2 at ꢀ78 ꢁC. We
found that compounds 7, 8, and 18e21 might be slightly labile
under deprotecting steps to give target molecules in relatively
lower yields along with various amounts of complex mixtures in
each reaction.
Structural optimizations of compounds 22, 23, and 25e29 all
exhibited the twisted chair conformers. These results were con-
sistent with azepane cases we reported earlier.37
3. Conclusion
In conclusion, we have first synthesized a series of 7-(hydrox-
ymethyl)thiepane-3,4,5-triols 22, 23, 25e29 in 11e12 steps starting
from
D
-(ꢀ)-quinic acid. These molecules are not only flexible in
structures but also unique with an external hydroxymethyl group

T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
1899
Scheme 2. Syntheses of thiocyclic compounds 18e21.
Scheme 3. Syntheses of thiepanes 22, 23, 25e29, and thiopyran 24.
at C7 of thiepane. The most suitable deprotecting agent is boron
4. Experimental section
4.1. General
trichloride that gave the corresponding thiepanes and minimized
the possibilities of ring contraction to thiopyrans, except 24. We
find that the fully deprotecting step occurs for compounds 7, 8, 18,
and 19 but 20 and 21. The biological activities of thiepanes will be
reported in due course.
All chemicals were purchased from commercial providers and
used without purification except otherwise mentioned. CH2Cl2 was

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T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
distilled from CaH2. 1H and 13C NMR spectra were recorded on
a Bruker Avance 600 spectrometer, respectively. Chemical shifts were
measured in parts per million (ppm) and referenced to the residual
C6D6 (7.16 ppm for 1H and 128.0 ppm for 13C) and D2O (4.63 ppm for
1H). OpticalrotationsweremeasuredbyHoribaSepa-300instrument.
HRMS (ESI/FAB) were carried out on model Finnigan MAT 95S.
addition of MeOH. This mixture was gradually warmed up to am-
bient temperature and the resulting mixture was concentrated. To
this syrup was added MeOH for coevaporation, and this step was
repeated for several times. Purification by flash chromatography
(230e400 mesh SiO2, MeOH/CH2Cl2¼1:10/1:8, 1% NH4OH) pro-
vided 22 (50%) as a clear to pale yellow syrup. The same procedure
was also applied in preparation of 23e29.
4.2. General procedures for dihydroxylation, oxidative cleavage,
and reduction
4.5. (2S,3R,4R,6R)-2,7-O-Bisbenzyl-3,4-O-cyclohexylidene-hep-
tane-1,2,3,4,6,7-pentanol (5)
(1) Compound 3 (0.11 g, 0.262 mmol) in 95% EtOH was treated
with an aqueous solution of KMnO4 (0.169 g, 1.07 mmol)/
MgSO4 (0.125 g, 1.04 mmol) (EtOH/H2O¼9:1, v/v, 0.1e0.3 M) at
0 ꢁC. The mixture was stirred at ambient temperature for 24 h.
At the end of reaction time, the mixture was passed through
a pad of Celite and washed with EtOH. The solution was con-
centrated, extracted with EtOAc, and dried (MgSO4). This
resulting pale yellow syrup in MeOH was treated with NaIO4
(0.96 g, 4.49 mmol) and stirred at ambient temperature for
24 h. At the end of time, the mixture was passed through a pad
of Celite and washed with MeOH. The solution was concen-
trated, diluted with H2O, extracted with EtOAc, and dried
(MgSO4). The resulting syrup 4 was dissolved in MeOH
and NaBH4 (4 equiv) was added at 0 ꢁC. Once the reaction was
complete, the reaction was quenched by addition of H2O,
concentrated, extracted with EtOAc, and dried over MgSO4.
Purification by flash column chromatography (230e400 mesh
SiO2, CH2Cl2/EtOAc¼20:1/15:1/10:1) provided compounds
5 (32%, three steps) and 6 (13%, three steps), respectively.
(2) Compound 3 (1.970 g, 4.684 mmol) was dissolved in t-BuOH/
pyridine/H2O (40.0:4.0:10.0 mL). To this mixture were added 4-
methylmorpholine N-oxide (1.646 g,14.051 mmol) and osmium
tetroxide (0.1 M solution in THF, 0.94 mL, 2 mol %) and heated at
100 ꢁC for 19 h. At the end of reaction time, to the mixture was
added Na2S2O3 (saturated) and stirred for 1 h. OsO4 was re-
moved by filtration through a pad of silica gel and washed with
EtOAc. The organic layer was washed with NaHCO3 (saturated),
dried with MgSO4, and purified by flash column chromatogra-
phy (230e400 mesh SiO2, Hex/EtOAc¼3:1/2:1) to provide
a white solid. The rest steps included oxidative cleavage and
reduction were the same as previous to afford 5 (46%, three
steps) and 6 (11%, three steps), respectively.
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/CH2Cl2¼1:20/1:15/1:10/1:5) afforded
a
clear
7.21
syrup. Yield¼46%. [
a]
26 þ18.8 (c 0.41, EtOAc). 1H NMR (C6D6)
d
D
(t, J¼7.6 Hz, 4H), 7.14e7.00 (m, 6H), 4.62 (ddd, J¼9.5, 5.6, 3.3 Hz,1H),
4.37 (d, J¼11.5 Hz, 1H), 4.30e4.22 (m, 2H), 4.20 (d, J¼11.5 Hz, 1H),
4.18e4.14 (s, 1H), 3.91e3.82 (m, 2H), 3.44 (dt, J¼8.2, 3.8 Hz, 1H),
3.33 (dd, J¼9.3, 4.3 Hz, 1H), 3.23 (dd, J¼9.3, 6.7 Hz, 1H), 2.49 (d,
J¼4.9 Hz, eOH), 2.00e1.95 (m, eOH), 1.88 (ddd, J¼13.1, 9.4, 3.2 Hz,
1H), 1.68 (ddd, J¼13.1, 10.1, 3.2 Hz, 1H), 1.65e1.46 (m, 8H), 1.27e1.16
(m, 2H). 13C NMR (C6D6)
d 139.2, 138.8, 130.0e125.0 (Are), 109.0,
78.1, 77.5, 75.5, 75.0, 73.7, 71.6, 68.6, 62.3, 38.8, 35.6, 34.1, 25.8, 24.9,
24.5. HRMS (ESI) calcd for C27H36O6 ([M]þ) 456.2512. Found:
456.2504.
4.6. (2S,3R,4R,6S)-2,7-O-Bisbenzyl-3,4-O-cyclohexylidene-hep-
tane-1,2,3,4,6,7-pentanol (6)
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/CH2Cl2¼1:20/1:15/1:10/1:5) afforded
a
clear
7.24
syrup. Yield¼11%. [
a]
26 þ46.4 (c 0.25, EtOAc). 1H NMR (C6D6)
d
D
(d, J¼7.5 Hz, 2H), 7.20 (d, J¼7.5 Hz, 2H), 7.15e7.05 (m, 6H),
4.37e4.28 (m, 4H), 4.18 (dd, J¼9.2, 5.8 Hz, 1H), 4.15e4.11 (m, 2H),
3.85e3.82 (m, 2H), 3.51 (dd, J¼9.4, 5.6 Hz, 1H), 3.40 (dd, J¼9.4,
5.2 Hz, 1H), 3.39e3.36 (m, 1H), 3.22 (s, eOH), 2.00 (dt, J¼14.0,
3.5 Hz, 1H), 1.84e1.78 (m, 2H), 1.60e1.57 (m, 2H), 1.53e1.41 (m, 6H),
1.20e1.15 (m, 2H). 13C NMR (C6D6)
d 139.4,138.8,130.0e128.0 (Are),
109.5, 78.1, 77.3, 77.2, 74.9, 73.8, 71.6, 70.7, 62.0, 38.5, 35.5, 34.3,
25.7, 24.8, 24.4. HRMS (ESI) calcd for C27H36O6 ([M]þ) 456.2512.
Found: 456.2519.
4.7. (3R,4R,5R,7S)-3,7-O-Bisbenzyl-4,5-O-cyclohexylidene-7-
(hydroxymethyl)thiepane-3,4,5-triol (7)
4.3. General procedure for thiocyclization
Purification by flash column chromatography (230e400 mesh
To compound 5 (0.0965 g, 0.199 mmol) in pyridine (3 mL) was
added methanesulfonyl chloride (0.062 mL, 0.794 mmol) at 0 ꢁC.
The reaction mixture was stirred at that temperature for 30 min
before this mixture was quenched by slow addition of saturated
NaHCO3 solution and EtOAc. The organic layer was separated,
washed by CuSO4 saturated solution, and dried (MgSO4) to provide
a yellow syrup. To this syrup were added 95% EtOH, Na2S (0.093 g,
1.194 mmol), 15-crown-6 (cat) and heated under reflux condition
(110e130 ꢁC, oil bath) for 2 h. At the end of reaction time, the
solvent was removed and the resulting mixture was washed with
saturated Na2S2O3 solution and extracted with EtOAc. The organic
layer was dried over MgSO4, concentrated, and purified by flash
column chromatography (230e400 mesh SiO2, Hex/EtOAc¼20:1)
to afford 7 (59%) in three steps. The same procedure was also ac-
cessible for synthesis of 8 (84%).
SiO2, EtOAc/Hex¼1:20/1:18/1:15) afforded a pale yellow syrup.
26
Yield¼59%. [
a]
ꢀ6.95 (c 1.81, CH2Cl2). 1H NMR (C6D6)
d 7.37 (d,
D
J¼7.4 Hz, 2H), 7.24 (d, J¼7.4 Hz, 2H), 7.20e7.10 (m, 4H), 7.08 (td,
J¼7.6, 0.8 Hz, 2H), 4.50 (s, 2H), 4.27 (dd, J¼7.1, 2.8 Hz, 1H), 4.24 (d,
J¼1.2 Hz, 1H), 4.23e4.18 (m, 1H), 3.85 (ddd, J¼5.3, 5.3, 2.7 Hz, 1H),
3.41 (dd, J¼9.1, 5.3 Hz, 1H), 3.33 (dd, J¼9.1, 7.1 Hz, 1H), 2.86 (dd,
J¼15.6, 5.4 Hz, 1H), 2.79 (dd, J¼13.2, 10.7 Hz,1H), 2.76e2.73 (m, 1H),
2.53 (ddd, J¼13.4, 3.8, 3.1 Hz, 1H), 2.35 (dd, J¼15.4, 5.2 Hz, 1H),
1.92e1.86 (m, 2H), 1.71e1.58 (m, 6H), 1.32e1.28 (m, 2H). 13C NMR
(C6D6) d 139.7, 139.3, 129.0e127.0 (Are), 108.8, 80.4, 78.3, 77.0, 74.4,
73.5, 73.0, 40.3, 37.4, 35.3, 34.7, 29.7, 26.1, 24.8, 24.6. HRMS (ESI)
calcd for C27H34NaO4S ([MþNa]þ) 477.2075. Found: 477.2062.
4.8. (3R,4R,5R,7R)-3,7-O-Bisbenzyl-4,5-O-cyclohexylidene-7-
(hydroxymethyl)thiepane-3,4,5-triol (8)
4.4. General procedure of debenzylation
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/Hex¼1:20/1:18/1:15) afforded a pale yellow syrup.
25
Compound 7 (0.0286 g, 0.0586 mmol) in CH2Cl2, for example,
was treated with BCl3 (1.0 M in CH2Cl2, 3 equiv) at ꢀ78 ꢁC. The
reaction mixture was stirred at that temperature for 4 h followed by
Yield¼84%. [
a
]
ꢀ36.5 (c 1.83, CH2Cl2). 1H NMR (C6D6)
d 7.29 (d,
D
J¼7.5 Hz, 4H), 7.18e7.15 (m, 4H), 7.10e7.06 (m, 2H), 4.45e4.41 (m,
1H), 4.42 (d, J¼12.1 Hz, 1H), 4.32 (d, J¼12.1 Hz, 1H), 4.27 (d,

T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
1901
J¼12.1 Hz, 1H), 4.26 (d, J¼12.1 Hz, 1H), 4.10 (ddd, J¼8.0, 5.8, 1.9 Hz,
1H), 3.71 (dt, J¼8.8, 1.1 Hz, 1H), 3.57e3.52 (m, 2H), 3.45 (dd, J¼9.5,
5.4 Hz, 1H), 3.39 (dd, J¼9.5, 7.0 Hz, 1H), 2.62e2.57 (m, 2H),
1.79e1.74 (m, 3H), 1.64e1.52 (m, 6H), 1.24e1.20 (m, 2H). 13C NMR
4.30e4.25 (m, 1H), 3.89e3.84 (m, 2H), 3.74 (ddd, J¼11.7, 8.0, 4.4 Hz,
1H), 3.51 (ddd, J¼9.4, 5.8, 2.0 Hz, 1H), 3.44e3.40 (m, 2H), 3.32 (d,
J¼1.7 Hz, eOH), 3.03 (s, 6H), 2.06 (t, J¼4.1 Hz, eOH), 1.96 (dt, J¼14.5,
3.2 Hz, 1H), 1.69 (dt, J¼14.5, 8.9 Hz, 1H), 1.22 (s, 3H), 1.18 (s, 3H). 13C
(C6D6)
d
139.4, 139.2, 130.0e128.0 (Are), 108.5, 83.1, 80.2, 73.9, 73.8,
NMR (C6D6) d 139.4, 139.2, 130.0e127.0 (Are), 99.7, 99.3, 77.8, 75.1,
73.2, 71.5, 40.0, 39.9, 36.7, 33.9, 28.8, 26.0, 24.7, 24.3. HRMS (ESI)
73.8, 73.3, 72.1, 70.2, 69.3, 62.0, 48.1, 48.0, 35.0, 18.2 (ꢂ2). HRMS
calcd for C27H34NaO4S ([MþNa]þ) 477.2075. Found: 477.2062.
(FAB) calcd for C27H38O8 [Mþ] 490.2567. Found: 490.2566.
4.9. (1S,2S,3R,4S,5S)-3,7-O-Bisbenzyl-1,2-[(2S,3S)-2,3-dimetho-
4.13. (2R,3S,4R,6R)-2,7-O-Bisbenzyl-3,4-[(2S,3S)-2,3-dimethoxy-
xybutan-2,3-dioxy]-cyclohexane-4,5-diol (12)
butan-2,3-dioxy]-heptane-1,2,3,4,6,7-hexaol (16)
Purification by flash column chromatography (230e400 mesh
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/CH2Cl2¼1:8/1:7/1:6/1:4/1:3) afforded a color-
SiO2, EtOAc/Hex¼1:4/1:3/1:2) afforded
a colorless syrup.
25
Yield¼44%. [
a]
þ94.2 (c 0.73, EtOAc). 1H NMR (C6D6)
d
7.35 (d,
less syrup. Yield¼54%. [
a
]
25 þ119.4 (c 0.58, EtOAc). 1H NMR (C6D6)
D
D
J¼7.2 Hz, 2H), 7.18 (d, J¼7.2 Hz, 2H), 7.16e7.06 (m, 6H), 5.09 (d,
J¼11.4 Hz, 1H), 4.69 (d, J¼12.0 Hz, 1H), 4.36 (ddd, J¼14.4, 9.6, 4.8 Hz,
1H), 4.19 (s, 2H), 3.84 (t, J¼9.6 Hz, 1H), 3.77 (t, J¼9.0 Hz, 1H), 3.73 (d,
J¼8.4 Hz, 1H), 3.34 (d, J¼9.0 Hz, 1H), 3.17 (m, 4H), 3.10 (s, 3H), 2.55
(s, eOH), 2.09 (dd, J¼13.2, 4.8 Hz, 1H), 1.86 (t, J¼12.6 Hz, 1H), 1.39 (s,
d
7.27 (d, J¼7.6 Hz, 2H), 7.19 (d, J¼7.1 Hz, 2H), 7.17e7.12 (m, 4H),
7.12e7.05 (m, 2H), 4.39 (s, 2H), 4.39e4.30 (m, 2H), 4.24 (s, 2H), 4.02
(dd, J¼10.1, 4.6 Hz,1H), 3.96 (dd, J¼11.4, 4.5 Hz,1H), 3.89 (dd, J¼11.4,
4.5 Hz, 1H), 3.49 (ddd, J¼9.5, 4.8, 1.4 Hz, 1H), 3.25 (dd, J¼9.2, 3.7 Hz,
1H), 3.21 (s, 3H), 3.17 (s, 3H), 3.15 (d, J¼9.2 Hz, 1H), 2.54 (d,
J¼11.5 Hz, eOH), 2.38 (s, eOH), 1.82 (t, J¼12.3 Hz, 1H), 1.52 (ddd,
J¼12.3, 10.2, 2.2 Hz, 1H), 1.31 (s, 3H), 1.30 (s, 3H). 13C NMR (C6D6)
3H), 1.37 (s, 3H). 13C NMR (C6D6)
d 140.2, 138.9, 128.9e128.0 (Are),
100.1, 99.8, 80.6, 75.5, 75.4, 74.5, 73.9, 73.4, 65.7, 47.9, 35.4, 18.5
(ꢂ2). HRMS (FAB) calcd for C27H37O8 [MþH]þ 489.2488. Found:
489.2489.
d
139.2, 139.1, 130.0e127.0 (Are), 99.2, 99.1, 80.0, 75.7, 73.7, 72.8,
72.2, 67.3, 67.0, 61.7, 48.3, 48.2, 35.4, 18.2, 18.1. HRMS (FAB) calcd for
C27H38O8 [Mþ] 490.2567. Found: 490.2570.
4.10. (1S,2S,3S,4R,5R)-3,7-O-Bisbenzyl-1,2-[(2S,3S)-2,3-dimeth-
oxybutan-2,3-dioxy]-cyclohexane-4,5-diol (13)
4.14. (2R,3S,4R,6S)-2,7-O-Bisbenzyl-3,4-[(2S,3S)-2,3-dimethoxy-
butan-2,3-dioxy]-heptane-1,2,3,4,6,7-hexaol (17)
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/Hex¼1:4/1:3/1:2) afforded
a
colorless syrup.
Purification by flash column chromatography (230e400 mesh
25
Yield¼27%. [
a
]
þ69.1 (c 0.57, EtOAc). 1H NMR (C6D6)
d
7.36 (d,
SiO2, EtOAc/CH2Cl2¼1:8/1:7/1:6/1:4/1:3) afforded a color-
D
25
J¼7.4 Hz, 2H), 7.18 (d, J¼7.4 Hz, 2H), 7.15e7.06 (m, 6H), 4.94 (d,
J¼11.6 Hz, 1H), 4.47 (d, J¼11.6 Hz, 1H), 4.36 (dd, J¼10.3, 2.9 Hz, 1H),
4.22e4.16 (m, 2H), 4.12 (t, J¼3.1 Hz, 1H), 4.08 (d, J¼11.9 Hz, 1H), 3.99
(d, J¼2.9 Hz, 1H), 3.72 (d, J¼9.4 Hz, 1H), 3.61 (d, J¼9.4 Hz, 1H), 3.11
(s, 3H), 3.10 (s, 3H), 2.92 (s, eOH), 2.77 (s, eOH), 2.18 (t, J¼12.5 Hz,
1H), 2.09 (dd, J¼12.5, 4.8 Hz, 1H), 1.38 (s, 3H), 1.37 (s, 3H). 13C NMR
less syrup. Yield¼26%. [
a
]
þ98.0 (c 0.54, EtOAc). 1H NMR (C6D6)
D
d
7.27 (dd, J¼7.0, 0.5 Hz, 2H), 7.23 (dd, J¼7.6, 1.1 Hz, 2H), 7.14e7.05
(m, 6H), 4.42 (d, J¼11.7 Hz, 1H), 4.38 (d, J¼11.7 Hz, 1H), 4.34 (d,
J¼12.1 Hz, 1H), 4.31 (d, J¼12.1 Hz, 1H), 4.28e4.23 (m, 1H), 4.12 (dd,
J¼9.2, 3.2 Hz, 1H), 4.09 (dd, J¼10.0, 2.9 Hz, 1H), 3.91 (dt, J¼11.5,
5.4 Hz, 1H), 3.84 (dt, J¼11.5, 5.2 Hz, 1H), 3.47 (dd, J¼9.2, 5.9 Hz, 2H),
3.36 (dd, J¼9.4, 5.2 Hz,1H), 3.24 (d, J¼1.6 Hz, eOH), 3.14 (s, 3H), 3.03
(s, 3H), 2.27 (t, J¼6.1 Hz, eOH), 1.98 (dt, J¼14.3, 3.2 Hz, 1H), 1.74 (dt,
(C6D6)
d 140.0, 138.9, 129e127.9 (Are), 100.4, 99.9, 79.1, 74.9, 74.7,
74.6, 73.8, 72.5, 71.7, 63.9, 48.0, 47.9, 35.3, 18.5 (ꢂ2). HRMS (FAB)
calcd for C27H37O8 [MþH]þ 489.2488. Found: 489.2489.
J¼15.0, 8.2 Hz, 1H), 1.24 (s, 3H), 1.20 (s, 3H). 13C NMR (C6D6)
d 139.4,
139.1, 130.0e128.0 (Are), 99.2, 99.1, 79.8, 75.2, 73.8, 72.3, 72.2, 70.3,
69.8, 61.8, 48.2, 35.7, 18.1, 18.0. HRMS (FAB) calcd for C27H38O8 [Mþ]
490.2567. Found: 490.2563.
4.11. (2S,3S,4R,6R)-2,7-O-Bisbenzyl-3,4-[(2S,3S)-2,3-dimethoxy-
butan-2,3-dioxy]-heptane-1,2,3,4,6,7-hexaol (14)
Purification by flash column chromatography (230e400 mesh
4.15. (3R,4S,5R,7S)-3-O-Benzyl-4,5-[(2S,3S)-2,3-dimethoxybutan-
SiO2, EtOAc/Hex¼1:4/1:3/1:2) afforded
a
colorless syrup.
2,3-dioxy]-7-benzyloxymethyl-thiepane-3,4,5-triol (18)
25
Yield¼46%. [
a
]
þ110.7 (c 0.38, EtOAc). 1H NMR (C6D6)
d 7.31 (d,
D
J¼7.6 Hz, 2H), 7.20 (d, J¼7.4 Hz, 2H), 7.16e7.12 (m, 4H), 7.11e7.05 (m,
2H), 4.59 (d, J¼11.9 Hz, 1H), 4.57 (ddd, J¼10.1, 10.1, 2.0 Hz, 1H), 4.46
(d, J¼11.9 Hz, 1H), 4.31 (ddd, J¼13.0, 6.8, 3.1 Hz, 1H), 4.26 (s, 2H),
3.94 (dt, J¼11.5, 5.3 Hz, 1H), 3.85 (dd, J¼10.0, 2.7 Hz, 1H), 3.84e3.80
(m, 1H), 3.47 (ddd, J¼5.0, 5.0, 2.7 Hz, 1H), 3.30 (dd, J¼9.2, 3.8 Hz,
1H), 3.22e3.18 (m, 1H), 3.20 (s, 3H), 3.05 (s, 3H), 2.50 (d, J¼3.8 Hz,
eOH), 2.12 (t, J¼6.4 Hz, eOH), 1.83 (ddd, J¼14.1, 10.0, 2.1 Hz, 1H),
1.47 (ddd, J¼14.0, 10.2, 2.4 Hz, 1H), 1.31 (s, 3H), 1.29 (s, 3H). 13C NMR
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/Hex¼1:15/1:10) afforded
a
colorless syrup.
25
Yield¼81%. [
a
]
þ87.2 (c 0.28, EtOAc). 1H NMR (C6D6)
d 7.33 (d,
D
J¼7.1 Hz, 2H), 7.23 (d, J¼7.1 Hz, 2H), 7.20e7.00 (m, 6H), 4.55 (d,
J¼11.8 Hz, 1H), 4.39 (d, J¼11.8 Hz, 1H), 4.28 (d, J¼12.2 Hz, 1H), 4.22
(d, J¼12.2 Hz, 1H), 4.17 (d, J¼12.2 Hz, 1H), 3.84 (dd, J¼9.6, 8.2 Hz,
1H), 3.60 (td, J¼8.4, 5.2 Hz, 1H), 3.46e3.41 (m, 1H), 3.35e3.30 (m,
2H), 3.27 (s, 3H), 3.30 (s, 3H), 2.48 (dt, J¼15.2, 5.2 Hz, 2H), 2.21 (d,
J¼15.3 Hz,1H), 1.89 (ddd, J¼15.3, 9.2, 6.3 Hz,1H),1.40 (s, 3H),1.36 (s,
(C6D6)
d 139.3, 139.2, 130.0e128.0 (Are), 99.7, 99.2, 78.4, 75.8, 73.7,
73.3, 72.3, 67.1, 65.7, 62.2, 48.1, 48.0, 34.8, 18.3, 18.2. HRMS (FAB)
3H). 13C NMR (C6D6)
d 140.0, 139.0, 130.0e128.0 (Are), 99.6, 98.9,
calcd for C27H38O8 [Mþ] 490.2567. Found: 490.2568.
83.6, 78.7, 73.6, 73.5, 72.9, 65.3, 48.1, 47.9, 39.2, 32.8, 28.4, 18.3, 18.1.
HRMS (FAB) calcd for C27H36O6S [Mþ] 488.2233. Found: 488.2234.
4.12. (2S,3S,4R,6S)-2,7-O-Bisbenzyl-3,4-[(2S,3S)-2,3-dimethoxy-
butan-2,3-dioxy]-heptane-1,2,3,4,6,7-hexaol (15)
4.16. (3R,4S,5R,7R)-3-O-Benzyl-4,5-[(2S,3S)-2,3-dimethoxybutan-
2,3-dioxy]-7-benzyloxymethyl-thiepane-3,4,5-triol (19)
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/Hex¼1:4/1:3/1:2) afforded
a
colorless syrup.
Purification by flash column chromatography (230e400 mesh
25
Yield¼46%. [
a
]
þ122.5 (c 0.31, EtOAc). 1H NMR (C6D6)
d
7.26 (dd,
SiO2, EtOAc/Hex¼1:18/1:15/1:10) afforded a colorless syrup.
D
25
J¼6.8, 4.8 Hz, 4H), 7.14e7.02 (m, 6H), 4.58 (d, J¼11.9 Hz, 1H), 4.40
(td, J¼9.9, 2.9 Hz, 1H), 4.37 (s, 2H), 4.36 (d, J¼10.5 Hz, 1H),
Yield¼50%. [
a]
þ63.8 (c 0.24, EtOAc). 1H NMR (C6D6)
d 7.31 (d,
D
J¼7.1 Hz, 2H), 7.23 (dd, J¼7.5, 0.5 Hz, 2H), 7.20e7.06 (m, 6H), 4.55 (d,

1902
T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
J¼11.9 Hz, 1H), 4.37 (d, J¼11.9 Hz, 1H), 4.26 (d, J¼12.2 Hz, 1H), 4.24
(d, J¼12.2 Hz, 1H), 4.13 (t, J¼9.7 Hz, 1H), 3.83 (t, J¼8.3 Hz, 1H), 3.63
(ddd, J¼11.3, 8.2, 3.2 Hz, 1H), 3.31 (dd, J¼9.2, 4.9 Hz, 1H), 3.27 (s,
3H), 3.17 (t, J¼8.8 Hz, 1H), 3.08 (s, 3H), 2.92 (ddd, J¼12.7, 7.1, 5.6 Hz,
1H), 2.59 (dd, J¼15.4, 11.3 Hz, 1H), 2.39 (dd, J¼15.4, 6.1 Hz, 1H), 2.36
(dt, J¼15.4, 3.2 Hz, 1H), 1.77 (ddd, J¼15.2, 12.3, 9.7 Hz, 1H), 1.42 (s,
1H), 1.95 (dt, J¼13.8, 6.4 Hz, 1H), 1.74 (ddd, J¼13.8, 10.6, 5.7 Hz, 1H).
13C NMR (D2O)
d 79.9, 74.2, 70.5, 65.3, 46.2, 34.6, 32.9. HRMS (ESI)
calcd for C7H14O4S [MþꢀH] 193.0535. Found: 193.0534.
4.21. (2R,3R,4R,6S)-Tetrahydro-2,6-bis(hydroxymethyl)-2H-thi-
opyran-3,4-diol (24)
3H), 1.37 (s, 3H). 13C NMR (C6D6)
d 140.0, 139.2, 130.0e128.0 (Are),
99.5, 99.0, 84.0, 79.0, 76.1, 73.6, 73.5, 68.5, 48.1, 48.0, 40.7, 34.4, 26.5,
18.2, 18.1. HRMS (FAB) calcd for C27H36O6S [Mþ] 488.2233. Found:
488.2232.
Minor isomer, structure determination was based on the sub-
traction of the signals from the mixture spectra with 23. 1H NMR
(D2O)
d
3.88 (t, J¼2.3 Hz, 1H), 3.68 (dd, J¼11.5, 6.0 Hz, 1H), 3.64 (dt,
J¼11.1, 3.4 Hz, 1H), 3.60 (d, J¼7.6 Hz, 2H), 3.53 (dd, J¼11.6, 5.3 Hz,
1H), 3.12 (td, J¼7.9, 2.1 Hz, 1H), 2.92 (ddd, J¼11.9, 7.7, 4.4 Hz, 1H),
4.17. (3S,4S,5R,7S)-3-O-Benzyl-4,5-[(2S,3S)-2,3-dimethoxybutan-
2,3-dioxy]-7-benzyloxymethyl-thiepane-3,4,5-triol (20)
1.95e1.91 (m, 1H),1.84 (dt, J¼13.7, 4.1 Hz,1H). 13C NMR (D2O)
d 69.0,
67.9, 63.1, 62.2, 45.1, 40.4, 30.4. HRMS (ESI) calcd for C7H14O4S
[MþꢀH] 193.0535. Found: 193.0534.
Purification by flash column chromatography (230e400 mesh
SiO2, EtOAc/Hex¼1:18/1:15/1:10) afforded a colorless syrup.
25
Yield¼81%. [
a
]
þ62.5 (c 0.29, EtOAc). 1H NMR (C6D6)
d 7.45 (dd,
D
4.22. (3R,4S,5R,7S)-7-(Hydroxymethyl)thiepane-3,4,5-triol (25)
J¼7.6, 0.5 Hz, 2H), 7.24e7.21 (m, 2H), 7.20 (d, J¼7.7 Hz, 2H),
7.15e7.10 (m, 3H), 7.07 (t, J¼7.3 Hz, 1H), 4.81 (d, J¼11.9 Hz, 1H), 4.62
(d, J¼11.9 Hz, 1H), 4.45 (dt, J¼9.5, 4.6 Hz, 1H), 4.24 (d, J¼1.0 Hz, 2H),
4.21 (dd, J¼9.8, 2.4 Hz, 1H), 3.79 (ddd, J¼7.7, 5.5, 2.4 Hz, 1H),
3.48e3.45 (m, 1H), 3.42 (d, J¼9.1, 7.4 Hz, 1H), 3.35 (dd, J¼9.1, 5.8 Hz,
1H), 3.10 (s, 3H), 3.06 (s, 3H), 2.73 (dd, J¼15.2, 7.5 Hz, 1H), 2.55 (dd,
J¼15.2, 5.5 Hz, 1H), 2.28 (ddd, J¼14.9, 9.7, 5.0 Hz, 1H), 2.14 (ddd,
J¼14.9, 4.3, 2.7 Hz, 1H), 1.39 (s, 3H), 1.35 (s, 3H). 13C NMR (C6D6)
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:8/1:6, 1% NH4OH) afforded a colorless
syrup. Yield¼45%. [
a
]
25 ꢀ15.0 (c 0.13, MeOH). 1H NMR (D2O)
d 3.71
D
(ddd, J¼10.1, 5.9, 4.6 Hz, 1H), 3.56 (dt, J¼11.9, 3.8 Hz, 1H), 3.53 (dd,
J¼11.3, 6.0 Hz, 1H), 3.43 (dd, J¼11.3, 7.1 Hz, 1H), 3.39 (t, J¼8.6 Hz,
1H), 3.13 (dt, J¼12.9, 6.1 Hz, 1H), 2.78 (dd, J¼15.5, 3.8 Hz, 1H), 2.57
(dd, J¼15.5, 7.7 Hz, 1H), 1.96e1.92 (m, 2H). 13C NMR (D2O)
d 78.9,
d
140.1, 139.3, 130.0e128.0 (Are), 99.6, 99.5, 78.2, 75.1, 74.9, 73.4,
74.3, 68.4, 64.8, 40.6, 33.7, 30.4. HRMS (FAB) calcd for C7H14O4S
73.3, 65.8, 47.9, 39.2, 34.2, 31.5, 18.4, 18.3. HRMS (FAB) calcd for
[Mþ] 194.0613. Found: 194.0616.
C27H36O6S [Mþ] 488.2233. Found: 488.2232.
4.23. (3R,4S,5R,7R)-7-(Hydroxymethyl)thiepane-3,4,5-triol (26)
4.18. (3S,4S,5R,7R)-3-O-Benzyl-3,4-[(2S,3S)-2,3-dimethoxybutan-
2,3-dioxy]-7-benzyloxymethyl-thiepane-3,4,5-triol (21)
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:8/1:6, 1% NH4OH) afforded a colorless
Purification by flash column chromatography (230e400 mesh
syrup. Yield¼42%. [
a
]
D
25 ꢀ78.0 (c 0.31, MeOH). 1H NMR (D2O)
d 3.63
SiO2, EtOAc/Hex¼1:18/1:15/1:10) afforded a colorless syrup.
(t, J¼9.1 Hz, 1H), 3.51 (td, J¼8.2, 3.1 Hz, 1H), 3.47 (dd, J¼11.4, 5.9 Hz,
1H), 3.41 (dd, J¼11.4, 6.5 Hz, 1H), 3.18 (t, J¼8.4 Hz, 1H), 2.92 (td,
J¼12.0, 5.9 Hz, 1H), 2.73 (dd, J¼15.4, 9.8 Hz, 1H), 2.39 (dd, J¼15.4,
3.1 Hz, 1H), 2.02 (dd, J¼14.9, 5.2 Hz, 1H), 1.66 (ddd, J¼14.9, 12.3,
25
Yield¼78%. [
a
]
ꢀ5.1 (c 0.36, EtOAc). 1H NMR (C6D6)
d 7.47 (d,
D
J¼7.1 Hz, 2H), 7.22 (d, J¼7.4 Hz, 2H), 7.19 (d, J¼7.7 Hz, 2H), 7.13e7.05
(m, 4H), 4.78 (d, J¼12.1 Hz, 1H), 4.68 (d, J¼12.1 Hz, 1H), 4.38 (ddd,
J¼10.6,10.6, 3.9 Hz,1H), 4.24 (s, 2H), 3.93 (td, J¼4.9, 1.3 Hz,1H), 3.89
(dd, J¼9.7, 1.3 Hz, 1H), 3.63e3.58 (m, 1H), 3.42 (dd, J¼9.3, 5.2 Hz,
1H), 3.30 (dd, J¼9.3, 7.9 Hz,1H), 3.05 (s, 6H), 2.86 (dd, J¼16.6, 4.9 Hz,
1H), 2.63 (ddd, J¼14.3, 3.7, 1.9 Hz, 1H), 2.50 (dd, J¼14.4, 3.7 Hz, 1H),
1.99 (dt, J¼14.3, 10.9 Hz, 1H), 1.38 (s, 3H), 1.36 (s, 3H). 13C NMR
10.3 Hz, 1H). 13C NMR (D2O)
d 81.1, 76.6, 70.6, 66.3, 43.1, 35.6, 28.7.
HRMS (FAB) calcd for C7H14O4S [Mþ] 194.0613. Found: 194.0611.
4.24. (2S,4R,5S,6S)-6-(Benzyloxy)-2-(hydroxymethyl)thiepane-
4,5-diol (27)
(C6D6)
d 139.8, 139.3, 130.0e128.0 (Are), 99.3, 99.0, 78.9, 76.7, 74.9,
73.5, 73.0, 68.2, 48.0, 47.9, 40.3, 39.1, 31.4,18.3. HRMS (FAB) calcd for
C27H36O6S [Mþ] 488.2233. Found: 488.2237.
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:30/1:20, 1% NH4OH) afforded a colorless
25
syrup. Yield¼55%. [
a
]
D
þ29.0 (c 0.2, MeOH). 1H NMR (D2O)
4.19. (3R,4R,5R,7R)-7-(Hydroxymethyl)thiepane-3,4,5-triol (22)
d
7.34e7.24 (m, 5H), 4.54 (d, J¼11.7 Hz, 1H), 4.49 (d, J¼11.7 Hz, 1H),
3.92 (td, J¼7.0, 2.8 Hz, 1H), 3.89e3.85 (m, 2H), 3.49 (dd, J¼11.3,
5.7 Hz, 1H), 3.41 (dd, J¼11.3, 6.8 Hz, 1H), 3.04 (ddd, J¼16.4, 6.2,
4.0 Hz, 1H), 2.86 (dd, J¼15.0, 7.8 Hz, 1H), 2.62 (dd, J¼15.0, 3.2 Hz,
1H), 1.98 (ddd, J¼15.5, 10.3, 2.8 Hz, 1H), 1.90 (ddd, J¼15.5, 6.4,
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:6/1:4, 1% NH4OH) afforded a pale yellow
syrup. Yield¼50%. [
a
]
25 ꢀ147.7 (c 0.11, MeOH). 1H NMR (D2O)
d 3.97
D
(d, J¼9.8 Hz, 1H), 3.94 (d, J¼1.5 Hz, 1H), 3.76 (dt, J¼10.6, 2.9 Hz, 1H),
3.45 (dd, J¼11.3, 6.1 Hz, 1H), 3.40 (dd, J¼11.3, 6.7 Hz, 1H), 2.95 (dd,
J¼12.1, 6.2 Hz, 1H), 2.92 (dd, J¼14.8, 10.8 Hz, 1H), 2.13 (dt, J¼16.0,
1.7 Hz, 1H), 2.09 (dd, J¼14.8, 9.8 Hz, 1H), 1.68 (dd, J¼14.8, 5.6 Hz,
3.9 Hz, 1H). 13C NMR (D2O)
d 137.5, 129.0e128.0 (Are), 79.2, 74.7,
71.6, 68.6, 65.6, 40.1, 32.8, 27.2. HRMS (FAB) calcd for C14H21O4S
[MþH]þ 285.1161. Found: 285.1161.
1H). 13C NMR (D2O)
d 75.9, 74.6, 70.7, 66.6, 42.9, 30.7, 26.4. HRMS
(ESI) calcd for C7H14O4S [Mþ] 194.0613. Found: 194.0617.
4.25. (2R,4R,5S,6S)-6-(Benzyloxy)-2-(hydroxymethyl)thiepane-
4,5-diol (28)
4.20. (3R,4R,5R,7S)-7-(Hydroxymethyl)thiepane-3,4,5-triol (23)
Purification by flash column chromatography (230e400 mesh
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:6/1:4, 1% NH4OH) afforded a pale yellow
SiO2, MeOH/CH2Cl2¼1:30/1:20, 1% NH4OH) afforded a colorless
25
syrup. Yield¼40%. [
a
]
ꢀ85.7 (c 0.22, MeOH). 1H NMR (D2O)
D
syrup. Major isomer: 1H NMR (D2O)
d
4.14 (dd, J¼9.5, 5.8 Hz, 1H),
d
7.35e7.22 (m, 5H), 4.56 (d, J¼11.5 Hz, 1H), 4.41 (d, J¼11.5 Hz, 1H),
3.97 (s, 1H), 3.81 (ddd, J¼11.2, 4.4, 2.5 Hz, 1H), 3.53 (dd, J¼11.6,
5.2 Hz, 1H), 3.38 (dd, J¼11.5, 7.0 Hz, 1H), 3.03 (ddd, J¼11.5, 6.6,
6.2 Hz, 1H), 2.70 (dd, J¼14.2, 11.3 Hz, 1H), 2.57 (dd, J¼14.2, 4.2 Hz,
3.94 (br s, 1H), 3.69 (t, J¼9.3 Hz, 1H), 3.47e3.35 (m, 3H), 3.05e2.97
(m, 1H), 2.80e2.70 (m, 2H), 2.03 (d, J¼14.9 Hz, 1H), 1.59 (dd, J¼14.9,
11.1 Hz, 1H). 13C NMR (D2O)
d 137.5, 128.7e128.3 (Are), 77.8, 76.6,

T.-L. Shih, W.-L. Gao / Tetrahedron 69 (2013) 1897e1903
1903
5. Afarinka, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239e1287.
6. Scott, L. J.; Spencer, C. M. Drugs 2000, 59, 521e549.
71.5, 70.6, 65.8, 42.0, 36.1, 26.3. HRMS (FAB) calcd for C14H21O4S
[MþH]þ 285.1161. Found: 285.1163.
7. Dande, P.; Prakash, T. P.; Sioufi, N.; Gaus, H.; Jarres, R.; Berdeja, A.; Swayze, E. E.;
Griffey, R. H.; Bhat, B. J. Med. Chem. 2006, 49, 1624e1634.
8. Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett. 1999, 40, 1937e1940.
9. Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata, S.; Sasaki,
T.; Matsuda, A. J. Org. Chem. 1996, 61, 822e823.
4.26. (3S,4S,5R,7R)-7-(Hydroxymethyl)thiepane-3,4,5-triol (29)
Purification by flash column chromatography (230e400 mesh
SiO2, MeOH/CH2Cl2¼1:8/1:6, 1% NH4OH) afforded a colorless
10. Selwood, D. L.; Carter, K.; Young, R. J.; Jandu, K. S. Bioorg. Med. Chem. Lett. 1996,
6, 991e994.
syrup. Yield¼10%. [
a
]
22 ꢀ223.8 (c 0.16, MeOH). 1H NMR (D2O)
d 4.07
11. Tber, B.; Fahmi, N.-E.; Ronco, G.; Villa, P.; Ewing, D. F.; Mackenzie, G. Carbohydr.
Res. 1995, 267, 203e215.
12. Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551e1580.
13. Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka, O. Bioorg. Med.
Chem. 2002, 10, 1547e1554.
D
(ddd, J¼7.4, 3.7, 1.6 Hz, 1H), 3.71 (td, J¼9.4, 1.4 Hz, 1H), 3.46 (dd,
J¼11.4, 5.9 Hz, 1H), 3.42 (dd, J¼11.4, 6.5 Hz, 1H), 3.36 (dd, J¼9.4,
3.4 Hz, 1H), 2.95e2.88 (m, 1H), 2.89 (dd, J¼15.6, 1.7 Hz, 1H), 2.58
(dd, J¼15.6, 7.4 Hz, 1H), 2.06 (ddd, J¼14.9, 4.6, 1.5 Hz, 1H), 1.59 (ddd,
14. Eskandari, R.; Jones, K.; Rose, D. R.; Pinto, B. M. Bioorg. Med. Chem. Lett. 2010, 20,
5686e5689.
J¼14.9, 11.8, 9.5 Hz, 1H). 13C NMR (D2O)
d 78.5, 69.8, 69.0, 66.5, 42.4,
15. Eskandari, R.; Kuntz, D. A.; Rose, D. A.; Pinto, B. M. Org. Lett. 2010, 12,
1632e1635.
16. Muraoka, O.; Xie, W.; Osaki, S.; Kagawa, A.; Tanabe, G.; Amer, M. F. A.;
Minematsu, T.; Morikawa, T.; Yoshikawa, M. Tetrahedron 2010, 66,
3717e3722.
36.4, 29.4. HRMS (FAB) calcd for C7H14O4S [Mþ] 194.0613. Found:
194.0615.
17. Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara, J.; Tanabe,
G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367e8370.
18. Gallienne, E.; Benazza, M.; Demailly, G.; Bolte, J.; Lemaire, M. Tetrahedron 2005,
61, 4557e4568.
19. Johnson, H. A.; Thomas, N. R. Bioorg. Med. Chem. Lett. 2002, 12, 237e241.
20. Tilekar, J. N.; Patil, N. T.; Jadhav, H. S.; Dhavale, D. D. Tetrahedron 2003, 59,
1873e1876.
Acknowledgements
The National Science Council (NSC-101-2113-M-032-002) and
Tamkang University are gratefully acknowledged for the financial
support of this research. Authors thank Prof. Hsiu-Fu Hsu for
valuable discussion, the National Center for High-Performing
Computing and Instrumentation Center, National Taiwan Univer-
sity for MS experiments.
21. Benazza, M.; Halila, S.; Viot, C.; Danquigny, A.; Pierru, C.; Demailly, G. Tetrahe-
dron 2004, 60, 2889e2895.
22. Halila, S.; Benazza, M.; Demailly, G. Carbohydr. Res. 2003, 338, 177e182.
23. Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett. 2002, 43, 815e818.
ꢁ
24. Arcelli, A.; Cere, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron: Asymmetry 2002,
13, 191e196.
Supplementary data
25. Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett. 2001, 42, 3307e3310.
26. Arcelli, A.; Cere, V.; Peri, F.; Pollicino, S.; Sabatino, P. Tetrahedron: Asymmetry
ꢁ
Copies of 1H, 13C NMR spectra and Tables 1e6 for all new
products. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.12.047.
2000, 11, 1389e1395.
27. Fuzier, M.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1995, 36, 6443e6446.
28. Shih, T.-L.; Fang, Y.-C. Synth. Commun. 2007, 37, 3337e3349.
29. Shih, T.-L.; Yang, R.-Y.; Li, S.-T.; Chiang, C.-F.; Lin, C.-H. J. Org. Chem. 2007, 72,
4258e4261.
ꢁ
30. Cere, V.; Peri, F.; Pollicino, S. J. Org. Chem. 1997, 62, 8572e8574.
31. Shih, T.-L.; Li, H.-Y.; Ke, M.-S.; Kuo, W.-S. Synth. Commun. 2008, 38, 4139e4149
and references cited therein.
References and notes
32. Muraoka, O.; Yoshikai, K.; Takahashi, H.; Minematsu, T.; Lu, G.; Tanabe, G.;
Wang, T.; Matsuda, H.; Yoshikawa, M. Bioorg. Med. Chem. 2006, 14, 500e509.
33. Gunasundari, T.; Chandrasekaran, S. J. Org. Chem. 2010, 75, 6685e6688.
34. Zhang, J.; Niu, Y.; Lao, X.; Ye, X.-S. Tetrahedron 2012, 68, 4242e4247.
35. Alves, C.; Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron 1999, 55,
8443e8456.
1. Davies, G. J.; Gloster, T. M.; Henrissant, B. Curr. Opin. Struct. Biol. 2005, 15,
637e645.
2. Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr. Pharm. Des. 2003, 9,
ꢀ
1177e1189.
€
3. Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3,
513e523.
36. Shing, T. K. M.; Cui, Y.-X.; Tang, Y. Tetrahedron 1992, 48, 2349e2356.
37. Yeh, P.-L.; Tai, C.-K.; Shih, T.-L.; Hsiao, H.-L.; Wang, B.-C. J. Mol. Struct. 2012, 1018,
64e71.
4. Nishimura, Y. In Iminosugars from Synthesis to Therapeutic Applications;
Compain, P., Martin, O. R., Eds.; Wiley-VCH: Weinheim, 2007; pp 269e294.