Expeditious synthesis of new 3,4,6-trihydroxythiepanes from D-(-)-quinic acid

Article abstract of DOI:10.1080/00397910701490113

We report herein that the new seven-membered-ring thiosugars (thiepanes) have been synthesized from D-(-)-quinic acid. The key feature of the synthesis involves the thiocyclization of protected hexane-1,2,3,5,6-pentanol derivatives. The subsequent step of

Full text of DOI:10.1080/00397910701490113

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Expeditious Synthesis of New
3,4,6‐Trihydroxythiepanes from d‐(‐)‐Quinic
Acid
Tzenge‐Lien Shih a & Yi‐Chuan Fang a
a Department of Chemistry, Tamkang University, Taiwan, Republic of China
Published online: 05 Oct 2007.
To cite this article: Tzenge‐Lien Shih & Yi‐Chuan Fang (2007): Expeditious Synthesis of New
3,4,6‐Trihydroxythiepanes from d‐(‐)‐Quinic Acid, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:19, 3337-3349
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Synthetic Communicationsw, 37: 3337–3349, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701490113
Expeditious Synthesis of New
3,4,6-Trihydroxythiepanes
from D-(-)-Quinic Acid
Tzenge-Lien Shih and Yi-Chuan Fang
Department of Chemistry, Tamkang University, Taiwan,
Republic of China
Abstract: We report herein that the new seven-membered-ring thiosugars (thiepanes)
have been synthesized from D-(-)-quinic acid. The key feature of the synthesis involves
the thiocyclization of protected hexane-1,2,3,5,6-pentanol derivatives. The subsequent
step of acidic removal of protecting groups is critical in the reaction conditions to
obtain the required 3,4,6-trihydroxythiepanes. During the course of studies, the unex-
pected trihydroxythiopyrans are formed because of the ring contractions of their corre-
sponding trihydroxythiepanes under various conditions.
Keywords: quinic acid, thiepane, thiosugar
INTRODUCTION
The so-called thiosugars are, in terms of the oxygen atom in the ring of
carbohydrates, replaced with sulfur atom. However, naturally occurring or
synthetic thiosugars are scarce at present. There are only a few reports of
seven-membered-ring thiosugars (also called thiepanes), their syntheses,[1]
and their biological activity.[1b,1d,2] The existing thiosugars, including thio-
phenes, thiopyrans, and thiepanes, are relative lower in potency than their
corresponding azasugars against glycosidases.[1d] However, their syntheses
received little attention until the discovery of the potent a-glycosidase inhibi-
tors, salacinol[2–4] and kotalanol,[2,5] which possess unique zwitterionic
Received in Japan February 10, 2007
Address correspondence to Tzenge-Lien Shih, Department of Chemistry, Tamkang
University, Tamsui 25137, Taipei County, Taipei, Taiwan, Republic of China. E-mail:
tlshih@mail.tku.edu.tw
3337

3338
T.-L. Shih and Y.-C. Fang
Figure 1. Thiosugars with sulfonium-sulfate structures as potent glycosidase
inhibitors.
structures (Fig. 1). Recently we have synthesized a series of polyhydroxy-
lated azepanes for evaluation as potent glycosidase inhibitors.[6] Based on
a similar strategy, we report herein an expeditious synthesis of new
seven-membered-ring thiosugars, 3,4,6-trihydroxythiepanes 1a, 1b, and 1c,
from D-(-)-quinic acid. During the course of our studies, the formation of
unexpected six-membered-ring trihydroxythiopyrans 2a, 2b, and 2c was
most likely derived from the ring contraction of their corresponding precur-
sors 1a, 1b, and 1c, respectively, under the acidic conditions and prolonged
reaction time at 758C.
RESULTS AND DISCUSSION
The synthesis of our target 3,4,6-trihydroxythiepanes 1a, 1b, and 1c is
depicted in Scheme 1. Compound 6 was prepared from D-(-)-quinic acid.[7]
The double bond of 6 was dihydroxylated with RuCl3/NaIO4,[8] oxidatively
cleaved by NaIO4, and reduced by NaBH4 to give diol 7 in 89% yield over
three steps. The resulting diol 7 was mesylated to afford 8 in 78% yield.
[1a,1c,1d,1e,9]
(3 eq) in
.
The sulfur atom was then introduced by Na2S 9H2O
EtOH under refluxing condition to afford the protected seven-membered-
ring thiosugar derivative 9a. The following deprotection step was proved pro-
blematically. Initially, compound 9a was treated with BBr3[1d,1e] at 2788C to
simultaneously remove the benzyl and cyclohexyl moieties to afford 1a.
However, compound 9a was mainly decomposed and no desired product 1a
was received. Therefore, a two-step strategy was employed to pursue our
target. The benzyl group of 9a was first cleaved by 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) to afford 9b in 80% yield. The remaining
protecting group of 9b was then to be removed with 2 N HCl in 1,4-
dioxane at 758C for 3.5 h. After usual workup and column chromatography,
only one pure compound was obtain as a clear oil [54%, based on recovery
of 9b (34%), vide infra). The spectroscopic data of this oil is proved to be
pure thiepane 1a. To drive the deprotection of 9b into completion, the
reaction was then conducted under the same conditions but prolonged time
(72 h). In contrast to the previous results, the 1H NMR analysis of the

New 3,4,6-Trihydroxythiepanes
3339
Scheme 1. Reagents and conditions: (a) (i) RuCl3, NaIO4; (ii) NaIO4, MeOH; (iii)
.
NaBH4; (b) MsCl, pyr.; (c) Na2S 9H2O, EtOH; (d) DDQ; (e) 2 N HCl, 1,4-dioxane.
resulting oil showed a mixture of three stereoisomers, which were not
separable by column chromatography. Among them, thiepane 1a and six-
membered-ring thiosugar 2a were in a ratio of 4:17 in 67% combined yield.
In addition to compounds 1a and 2a, we believed that the remaining very
minor compound was most likely compound 4a, which was derived from
the rearrangement of 1a under the acidic conditions (Fig. 2, path a).
Although we could not rule out the possibility in formation of 4a, its yield
was relatively low by NMR analysis and its structure was barely determined.
In addition, we believed that the major compound 2a was derived from the

3340
T.-L. Shih and Y.-C. Fang
Figure 2. Formation of 2a and 4a from the ring contractions of 1a under acidic
conditions.
ring contraction of 1a under acidic and prolonged reaction conditions. The
preference of formation of thiopyran 2a might be due to the faster rate of
the intramolecular displacement of the least hindered hydroxyl group of 1a.
The rearrangement mechanism is depicted in path b (Fig. 2), and this result
is consistent with the similar cases of the reports.[1d,1e] The mixture from
deprotection of 9b (2 N HCl, 758C, 72 h) was peracetated to help in separ-
ation; however, column chromatography failed to separate any pure
compound. At this step, we observed that compound 3a formed predominantly
in the mixture, and no peracetated 1a was detected. It seemed that 1a was
mainly transformed into 2a followed by peracetylation to afford 3a.
We employed the same deprotection method on 18 and 19, which were
prepared from 10 and 11, respectively. In contrast to the results of deprotec-
tion of 9b, the short reaction time (2 N HCl, 758C, 3.5 h) applied to 18 and
19 gave a mixture containing most of 1b [83%, recovered 18 (27%)] and 1c
[81%, recovered 19 (17%)] along with two other minor stereoisomers, respect-
ively. Fortunately, compounds 1b and 1c could be isolated from its mixture by
fractional crystallization (acetone/MeOH) as white solids. Once most of 1b
1
and 1c were separated from mixtures, the H NMR analysis of the mother
liquid fractions indicated that thiosugars 2b and 2c were predominant over
the other unidentified and very minor stereoisomer, which were most likely
thiosugars 4b and 4c, respectively.
Again, the respectively hydrolytic cleavage of 18 and 19 was completed
under the longer reaction time (2 N HCl, 758C, 72 h). The 1H NMR analysis of
products from deprotection of 18, for example, indicated the resulting mixture
contained three stereoisomers in which compound 2b formed predominantly
over 1b. The remaining unidentified compound might be compound 4b.
While the mixture from deprotection of 18 was further peracetylated, pure
compounds 3b and 5b were isolated in a ratio of 9.3:1 in 65% combined
yield. No peracetated 1b was obtained at this stage. The higher yield of 3b
is definitely derived from the transformation of 1b into 2b followed by pera-
cetylation. This is indirect evidence of our previous assumption in the
formation of unidentified 5a in the peracetylation of the mixture from depro-
tection of 9b. The same phenomena also appeared in deprotection of 19.
However, mixture from deprotection of 19 and their peracetated derivatives
3c and 5c cannot be separated by column chromatography. Results from
these reaction conditions are summarized in Table 1.

Table 1. Formation of trihydroxythiopyrans and trihydroxythiepanes under different conditions
Compound
Condition A
Yield (SM)b
Condition B
Yield
Condition C
Yield
9b
18
19
1a:2a:4a ¼ 1:0:0
1c:2c:4c ¼ 10:1:(0)a
54% (34%)b
83% (27%)b
81% (17%)b
1a:2a:4a ¼ 4:17:(1)a
1b:2b:4b ¼ 1:5.8:(0)a
1c:2c:4c ¼ 6:13:(1)a
67%
51%
56%
3a:5a ¼ 20:(1)a
3b:5b ¼ 9.3:1
3c:5c ¼ 20:(1)a
89%
65%
79%
1b:2b:4b ¼ 9:1:(0)a
aStructure and ratio are not fully characterized. Ratio is based on integration of H NMR.
bRecovered yield of unhydrolyzed compound.
1
Notes. Condition A: 2 N HCl, 758C, 3.5 h; condition B: 2 N HCl, 758C, 72 h; condition c: (i) 2 N HCl, 758C, 72 h; (ii) Ac2O, pyr, 12 h.

3342
T.-L. Shih and Y.-C. Fang
CONCLUSION
We have accomplished the synthesis of new 3,4,6-trihydroxythiepanes 1a, 1b,
and 1c from D-(-)-quinic acid. The preference of formation of either six- or
seven-membered-ring thiosugars is critical in reaction conditions. The short
reaction time (2 N HCl, 758C, 3.5 h) favors the formation of trihydroxythie-
panes, which can be easily separated from the mixture by either column
chromatography or fractional crystallization. On the other hand, the
prolonged reaction time initially formed trihydroxythiepanes 1a, 1b, and 1c;
then they were transformed into the more stable trihydroxythiopyrans 2a,
2b, and 2c as major compounds. However, it is relatively difficult to
separate six-and seven-membered-ring thiosugars from mixture by column
chromatography. The study of thiepanes containing sulfonium/sulfate ions
for potential glycosidase inhibitors is under investigation.
EXPERIMENTAL
NMR spectra were recorded on either Bruker AC-300 or Bruker 600 ultra-
shield instruments. Optical rotations were measured on a Horiba SEPA-300
polarimeter. Melting points were determined on Fargo MP-2D and are uncor-
rected. Mass spectra were obtained by FAB on a Jeol JMS-700 instrument.
General Procedure
Dihydroxylation
Compound
.
6 (3.10 g, 9.26 mmol), for example, was dissolved in
Na2HPO4 2H2O (satd., 15 mL) and EtOAc (45 mL) at 08C and followed
.
by addition of CH3CN (45 mL). To this mixture, RuCl3 3H2O (0.38 g,
0.55 mmol) and NaIO4 (2.97 g, 13.89 mmol) in H2O (15 mL) were added.
After stirring at that temperature for 10 min, the reaction was quenched by
Na2S2O3 (satd., 110 mL) and stirred for another 1 h. At the end of that time,
the mixture was diluted with EtOAc and washed with Na2S2O3 (satd.).
The organic layer was dried (MgSO4), concentrated, and purified by
flash-column chromatography.
Mesylation
Compound 7, for example, in pyridine was added to MsCl (4 eq) at 08C under
a nitrogen atmosphere. This mixture was stirred and gradually warmed up to
ambient temperature for 2 h. At the end of that time, the solvent was removed
under reduced pressure. The resulting mixture was diluted with CH2Cl2 and
washed by NaHCO3 (satd.). The organic layer was dried (MgSO4) and

New 3,4,6-Trihydroxythiepanes
3343
purified by flash column chromatography. This bismesylated compound 8 was
used immediately for the next step because of its instability.
Thiocyclization
.
Compound 8, for example, in 95% EtOH was added to Na2S 9H2O (3 eq) and
15-crown-5 (cat). This mixture was heated to reflux for 3 h. At the end of that
time, the solvent was removed under reduced pressure, and the resulting
mixture was diluted with CH2Cl2 and washed by NaHCO3 (satd.) and NaCl
(satd.). The organic layer was dried over MgSO4 and purified by flash
column chromatography.
Debenzylation
Compound 9a, for example, in CH2Cl2 was added to DDQ (3 eq) and NaHCO3
(3 eq). This mixture was stirred at ambient temperature for 48 h. At the end of
that time, this mixture was diluted with NaHCO3 (satd.) and extracted with
CH2Cl2. The organic layer was dried (MgSO4) and purified by flash-column
chromatography.
Data
(2R,3R,5S)-5-O-Benzyl-2,3-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]hexane-1,6-diol (7)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 1/1–1/2)
1
afforded a yellow syrup. [a]D24 þ127.6 (c 1.2, CHCl3). H NMR (300 MHz,
CDCl3):
d
7.34–7.26 (m, 5H), 4.62 (d, J ¼ 11.6 Hz, 1H), 4.52
(d, J ¼ 11.6 Hz, 1H), 3.79 (dd, J ¼ 9.0, 4.0 Hz, 1H), 3.75 (dd, J ¼ 9.0,
3.8 Hz, 2H), 3.70–3.50 (m, 4H), 3.25 (s, 3H), 3.23 (s, 3H), 1.84 (ddd,
J ¼ 14.6, 8.7, 3.9 Hz, 1H), 1.75 (ddd, J ¼ 14.6, 7.8, 3.1 Hz, 1H), 1.30
(s, 3H), 1.29 (s, 3H). 13C NMR (75 MHz, CDCl3): d 138.3, 128.4, 127.7,
127.4, 98.8, 76.3, 72.2, 71.8, 71.2, 65.2, 64.0, 62.1, 48.3, 47.9, 31.7, 17.5.
HRMS (FAB) calcd. for C19H30O7 ([M þ H]þ): 371.2017. Found: 371.2055.
(2R,3R,5S)-5-O-Benzyl-1,6-dimethanesulfonyloxy-2,3-O-[(2S,3S)-2,3-
dimethoxybutane-2,3-diyl]hexane (8)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–2/1)
1
afforded a yellow syrup. [a]D24 þ102.5 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3):
d
7.41–7.27 (m, 5H), 4.64 (d, J ¼ 11.4 Hz, 1H), 4.59
(d, J ¼ 11.4 Hz, 1H), 4.41 (dd, J ¼ 11.4, 3.3 Hz, 1H), 4.35 (dd, J ¼ 11.4,
5.4 Hz, 1H), 4.32 (dd, J ¼ 12.1, 2.4 Hz, 1H), 4.25 (dd, J ¼ 12.1, 4.2 Hz, 1H),
4.04–3.96 (m, 2H), 3.81 (ddd, J ¼ 9.9, 4.1, 2.4 Hz, 1H), 3.23 (s, 3H), 3.23

3344
T.-L. Shih and Y.-C. Fang
(s, 3H), 3.08 (s, 3H), 3.00 (s, 3H), 1.85–1.81 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H).
13C NMR (75 MHz, CDCl3): d 137.6, 128.5, 127.9, 127.8, 99.2, 98.9, 73.6,
71.9, 70.7, 69.7, 69.4, 64.3, 48.4, 48.1, 37.8, 37.6, 31.5, 17.6, 17.4.
(3S,4R,6S)-6-O-Benzyl-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]thiepane (9a)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 10/1–7/1)
afforded a white solid. Mp 73.2–74.78C. [a]2D4 þ95.6 (c 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.35–7.25 (m, 5H), 4.57 (d, J ¼ 12.1 Hz, 1H), 4.51
(d, J ¼ 12.1 Hz, 1H), 3.83 (dd, J ¼ 9.4, 4.8 Hz, 1H), 3.76 (dd, J ¼ 9.4,
5.2 Hz, 1H), 3.49 (ddd, J ¼ 9.6, 9.3, 1.2 Hz, 1H), 3.25 (s, 3H), 3.23 (s, 3H),
2.94 (dd, J ¼ 15.3, 3.6 Hz, 1H), 2.79 (dd, J ¼ 14.5, 5.2 Hz, 1H), 2.70 (dd,
J ¼ 15.3, 4.5 Hz, 1H), 2.53 (dd, J ¼ 14.5, 9.3 Hz, 1H), 2.24 (dt, J ¼ 14.0,
9.9 Hz, 1H), 2.14 (dd, J ¼ 14.0, 5.9 Hz, 1H), 1.29 (s, 3H), 1.27 (s, 3H). 13C
NMR (75 MHz, CDCl3): d 138.3, 128.4, 127.6, 127.5, 98.9, 98.8, 74.7, 74.1,
70.3, 68.2, 48.0, 39.2, 35.9, 35.7, 17.6, 17.5. HRMS (FAB) calcd. for
C19H28O5S ([M]þ): 368.1657. Found: 368.2023.
(3S,4R,6S)-6-Hydroxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]thiepane (9b)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–3/1)
afforded a white solid. Mp 59–638C. [a]2D5 þ136.4 (c 1.3, CHCl3). 1H NMR
(300 MHz, CDCl3): d 4.13–4.09 (m, 1H), 3.73 (td, J ¼ 9.5, 5.3 Hz, 1H), 3.47
(dt, J ¼ 11.3, 5.3 Hz, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.86 (dd, J ¼ 15.4,
2.9 Hz, 2H), 2.77 (dd, J ¼ 14.5, 5.3 Hz, 1H), 2.71 (dd, J ¼ 15.4, 4.2 Hz,
1H), 2.52 (dd, J ¼ 14.5, 9.8 Hz, 1H), 2.12–2.00 (m, 2H), 1.78 (s, -OH, 1H),
1.27 (s, 3H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): d 98.8, 98.7, 77.4,
74.2, 67.8, 67.7, 48.0, 42.4, 39.1, 35.6, 17.5, 17.4. HRMS (FAB) calcd. for
C12H23O5S ([M þ H]þ): 279.1266. Found: 279.1466.
(3S,4R,6S)-Thiepane-3,4,6-triol ((3S,4R,6S)-trihydroxythiepane) (1a)
Flash-column chromatography (230–400 mesh SiO2, MeOH/CH2Cl2 ¼
1/14–1/7) afforded a clear syrup. [a]2D5 294.5 (c 0.3, H2O). 1H NMR
(600 MHz, D2O): d 4.12 (tt, J ¼ 12.7, 4.2 Hz, 1H). 3.85–3.80 (m, 2H), 3.01
(dd, J ¼ 15.5, 3.8 Hz, 1H), 2.90 (dd, J ¼ 14.2, 4.6 Hz, 1H), 2.77 (dd,
J ¼ 15.5, 4.0 Hz, 1H), 2.62 (dd, J ¼ 14.2, 8.3 Hz, 1H), 2.08–2.03 (m, 1H),
1.99 (dd, J ¼ 13.8, 4.2 Hz, 1H). 13C NMR (125 MHz, D2O): d 75.7, 72.0,
69.7, 40.9, 39.8, 37.1. HRMS (FAB) calcd. for C6H12O3S ([M]þ):
164.0507. Found: 164.0514

New 3,4,6-Trihydroxythiepanes
3345
(3S,4R,6R)-3,4-Diacetoxy-6-acetoxymethylthiopyran (3a)
The assignment of the major isomer 3a is based on the substraction of the
minor signals from spectra. 1H NMR (600 MHz, CDCl3): d 4.87 (td,
J ¼ 10.4, 4.3 Hz, 1H), 4.77 (td, J ¼ 11.0, 6.9 Hz, 1H), 4.03 (dd, J ¼ 11.3,
6.2 Hz, 1H), 3.98 (dd, J ¼ 11.3, 6.7 Hz, 1H), 3.10 (ddd, J ¼ 12.5, 6.5,
2.3 Hz, 1H), 2.80 (dd, J ¼ 13.4, 4.3 Hz, 1H), 2.60 (dd, J ¼ 13.4, 10.6 Hz,
1H), 2.30 (ddd, J ¼ 12.9, 4.3, 2.5 Hz, 1H), 1.98 (s, 3H), 1.94 (s, 6H), 1.66
(dd, J ¼ 12.9, 11.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): d 170.5, 170.2
(ꢀ2), 72.6, 72.1, 65.6, 40.2, 36.8, 30.0, 21.0, 20.7.
(2S,3R,5S)-5-O-Benzyl-2,3-O-cyclohexylidene-hexane-1,6-diol (12)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 1/1–1/2)
1
afforded a clear syrup. [a]D24 þ10.4 (c 1.7, CHCl3). H NMR (300 MHz,
CDCl3):
d
7.36–7.26 (m, 5H), 4.60 (d, J ¼ 11.9 Hz, 1H), 4.56
(d, J ¼ 11.9 Hz, 1H), 4.31 (ddd, J ¼ 10.7, 6.1, 4.6 Hz, 1H), 4.19 (dd,
J ¼ 11.3, 6.3 Hz, 1H), 3.80–3.60 (m, 3H), 3.56 (d, J ¼ 2.7 Hz, 2H), 1.88–
1.79 (m, 2H), 1.70–1.50 (br m, 8H), 1.40–1.30 (br m, 2H). 13C NMR
(75 MHz, CDCl3): d 138.2, 128.4, 127.8, 108.9, 76.6, 72.5, 71.4, 63.2, 61.7,
38.0, 34.8, 30.1, 25.0, 24.1, 23.8. HRMS (FAB) calcd. for C19H28O5
([M þ H]þ): 337.2015. Found: 337.2020.
(2S,3S,5R)-5-O-Benzyl-2,3-O-cyclohexylidene-hexane-1,6-diol (13)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 1/1–1/2)
afforded a clear syrup. [a]D24 þ38.7 (c 2.6, CHCl3). H NMR (300 MHz,
1
CDCl3):
d
7.39–7.25 (m, 5H), 4.66 (d, J ¼ 11.5 Hz, 1H), 4.59
(d, J ¼ 11.5 Hz, 1H), 4.35 (ddd, J ¼ 9.8, 6.3, 3.2 Hz, 1H), 4.13 (dtd,
J ¼ 12.7, 6.3, 5.0 Hz, 1H), 3.78 (dd, J ¼ 11.3, 3.7 Hz, 1H), 3.72 (dd, J ¼ 8.4,
4.2 Hz, 1H), 3.62–3.50 (m, 3H), 1.69 (ddd, J ¼ 14.2, 10.0, 4.3 Hz, 1H),
1.62–1.45 (br m, 8H), 1.41–1.29 (m, 2H). 13C NMR (75 MHz, CDCl3): d
138.2, 128.4, 128.2, 127.8, 127.6, 108.6, 77.2, 73.1, 72.3, 64.3, 61.7, 37.9,
34.7, 31.4, 25.0, 24.0, 23.7. HRMS (FAB) calcd. for C19H28O3 ([M þ H]þ):
337.2015. Found: 337.2016.
(2S,3R,5S)-5-O-Benzyl-2,3-O-cyclohexylidene-1,6-O-
dimethanesulfonyloxy-hexane (14)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–2/1)
1
afforded a white solid. Mp 56–608C. [a]2D4 þ0.3 (c 4.3, CHCl3). H NMR
(300 MHz, CDCl3): d 7.35–7.30 (m, 5H), 4.63 (d, J ¼ 11.8 Hz, 1H), 4.55
(d, J ¼ 11.8 Hz, 1H), 4.39 (dd, J ¼ 11.1, 4.0 Hz, 1H), 4.33 (dd, J ¼ 11.1,
5.5 Hz, 3H), 4.22–4.10 (m, 3H), 3.02 (s, 3H), 2.99 (s, 3H), 1.85 (dd,
J ¼ 8.0, 5.5 Hz, 1H), 1.84 (dd, J ¼ 5.5, 1.6 Hz, 1H), 1.65–1.50 (br m, 8H),

3346
T.-L. Shih and Y.-C. Fang
1.45–1.30 (br m, 2H). 13C NMR (75 MHz, CDCl3): d 137.5, 128.4, 127.9,
109.7, 74.3, 74.1, 72.1, 71.9, 70.4, 67.6, 37.8, 37.5, 34.6, 30.1, 24.9, 24.0, 23.7.
(2S,3R,5R)-5-O-Benzyl-2,3-O-cyclohexylidene-1,6-O-
dimethanesulfonyloxy-hexane (15)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–2/1)
afforded a white solid. Mp 68.1–69.58C. [a]2D3 þ15.3 (c 2.8, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.35–7.31 (m, 5H), 4.73 (d, J ¼ 11.3 Hz, 1H), 4.57
(d, J ¼ 11.3 Hz, 1H), 4.41 (dd, J ¼ 5.6, 3.8 Hz, 1H), 4.39 (t, J ¼ 3.8 Hz,
1H), 4.29 (dd, J ¼ 11.0, 6.0 Hz, 1H), 4.23–4.10 (m, 3H), 3.94 (dt, J ¼ 13.1,
4.1 Hz, 1H), 3.03 (s, 3H), 3.00 (s, 3H), 2.70 (dd, J ¼ 11.3, 6.2 Hz, 1H),
1.84–1.64 (m, 2H), 1.62–1.46 (br m, 8H), 1.44–1.24 (br m, 2H). 13C NMR
(75 MHz, CDCl3): d 137.5, 128.5, 128.0, 109.6, 74.3, 74.2, 72.9, 72.4, 70.6,
67.9, 37.7, 37.5, 34.6, 31.4, 24.9, 23.9, 23.7.
(3R,4R,6S)-6-O-Benzyl-3,4-O-cyclohexylidenethiepane (16)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼
1
12/1–10/1) afforded a yellow syrup. [a]2D6 þ44.5 (c 1.7, CHCl3). H NMR
(300 MHz, CDCl3): d 7.37–7.26 (m, 5H), 4.58 (d, J ¼ 11.9 Hz, 1H), 4.53
(d, J ¼ 11.9 Hz, 1H), 4.48–4.34 (m, 2H), 3.48 (tdd, J ¼ 10.5, 3.7, 1.8 Hz,
1H), 2.96–2.85 (m, 2H), 2.63 (dd, J ¼ 10.9, 3.2 Hz, 1H), 2.58 (dd,
J ¼ 10.9, 2.2 Hz, 1H), 2.25 (dd, J ¼ 13.9, 2.1 Hz, 1H), 2.02–1.85 (m, 1H),
1.70–1.50 (br m, 8H), 1.40–1.30 (br m, 2H). 13C NMR (75 MHz, CDCl3):
d 138.1, 128.4, 127.7, 127.5, 109.9, 78.2, 77.7, 75.8, 70.7, 38.2, 38.1, 37.7,
34.5, 31.9, 25.1, 24.0, 23.7. HRMS (FAB) calcd. for C19H26O3S ([M]þ)
334.1603. Found: 334.1591.
(3R,4R,6R)-6-O-Benzyl-3,4-O-cyclohexylidenethiepane (17)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 10/1–7/1)
afforded a yellow syrup. [a]D24 þ49.7 (c 1.8, CHCl3). H NMR (300 MHz,
1
CDCl3): d 7.37–7.25 (m, 5H), 4.73 (ddd, J ¼ 9.9, 6.6, 2.7 Hz, 1H), 4.57
(s, 2H), 4.49 (ddd, J ¼ 10.2, 6.6, 4.3 Hz, 1H), 4.00–3.85 (m, 1H), 2.86 (dd,
J ¼ 14.3, 4.5 Hz, 1H), 2.76–2.71 (m, 2H), 2.65 (dd, J ¼ 14.3, 10.1 Hz,
1H), 2.18 (ddd, J ¼ 14.7, 6.9, 2.6 Hz, 1H), 1.96 (ddd, J ¼ 14.7, 10.4,
1.2 Hz, 1H), 1.69–1.53 (br m, 8H), 1.39–1.30 (br m, 2H). 13C NMR
(75 MHz, CDCl3): d 138.2, 128.3, 128.1, 127.6, 127.5, 109.0, 78.1, 73.5,
73.3, 70.3, 37.7, 37.5, 34.5 (ꢀ2), 25.2, 24.0, 23.7. HRMS (FAB) calcd. for
C19H26O3S ([M]þ): 334.1603. Found: 334.1601.

New 3,4,6-Trihydroxythiepanes
3347
(3R,4R,6S)-3,4-O-Cyclohexylidene-6-hydroxythiepane (18)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–3/1)
afforded a clear syrup. [a]D23 þ55.8 (c 1.2, CHCl3). H NMR (300 MHz,
1
CDCl3): d 4.49 (ddd, J ¼ 13.6, 6.7, 5.1 Hz, 1H), 4.43 (ddd, J ¼ 9.9, 6.7,
5.1 Hz, 1H), 4.00–3.84 (m, 1H), 2.86 (dd, J ¼ 14.7, 4.2 Hz, 1H), 2.77 (dd,
J ¼ 13.9, 3.6 Hz, 1H), 2.65 (dd, J ¼ 14.7, 9.6 Hz, 1H), 2.61 (dd, J ¼ 14.7,
9.0 Hz, 1H), 2.20–2.05 (dd, J ¼ 14.1, 9.7 Hz, 1H), 2.05–1.85 (m, 1H),
1.66–1.50 (br m, 8H), 1.42–1.35 (br m, 2H). 13C NMR (75 MHz, CDCl3): d
109.6, 78.2, 75.7, 71.3, 41.2, 39.7, 37.4, 34.3, 33.0, 25.1, 24.0, 23.7. HRMS
(FAB) calcd. for C12H20O3S ([M]þ): 244.1133. Found: 244.1132.
(3R,4R,6R)-3,4-O-Cyclohexylidene-6-hydroxythiepane (19)
Flash-column chromatography (230–400 mesh SiO2, hex/EtOAc ¼ 6/1–3/1)
afforded a white solid. Mp 83.5–85.08C. [a]2D6 þ55.5 (c 0.9, CHCl3). 1H NMR
(300 MHz, CDCl3): d 4.69 (ddd, J ¼ 10.3, 6.7, 3.3 Hz, 1H), 4.45 (ddd, J ¼ 10.9,
6.7, 4.4 Hz, 1H), 4.28 (tt, J ¼ 6.4, 1.0 Hz, 1H), 2.88 (ddd, J ¼ 14.4, 4.6, 0.8 Hz,
1H), 2.84 (dd, J ¼ 14.4, 2.4 Hz, 1H), 2.72 (dd, J ¼ 14.4, 5.2 Hz, 1H), 2.59
(dd, J ¼ 14.4, 10.5 Hz, 1H), 2.16 (ddddd, J ¼ 14.4, 10.4, 7.5, 3.0, 0.8 Hz,
1H), 2.10–1.95 (br m, 1H), 1.86 (dd, J ¼ 14.4, 10.9 Hz, 1H), 1.70–1.45
(br m, 8H), 1.42–1.30 (br m, 2H). 13C NMR (75 MHz, CDCl3): d 109.4, 78.4,
73.3, 66.3, 42.1, 37.5, 37.1, 34.3, 32.9, 25.1, 24.0, 23.6. HRMS (FAB) calcd.
for C12H20O3S ([M]þ): 244.1133. Found: 244.1144.
(3R,4R,6S)-Thiepane-3,4,6-triol ((3R,4R,6S)-trihydroxyhiepane) (1b)
Mp 114–117.98C. [a]2D6 þ50.0 (c 0.3, H2O). H NMR (600 MHz, D2O): d
1
4.07–4.03 (m, 2H), 3.74 (dd, J ¼ 10.0, 2.5 Hz, 1H), 2.76 (dd, J ¼ 15.1,
3.8 Hz, 1H), 2.70 (dd, J ¼ 15.2, 4.0 Hz, 1H), 2.62 (dd, J ¼ 15.2, 4.9 Hz,
1H), 2.53 (dd, J ¼ 15.1, 5.9 Hz, 1H), 2.27 (dt, J ¼ 14.0, 10.0 Hz, 1H), 1.64
(dd, J ¼ 10.0, 2.5 Hz, 1H). 13C NMR (125 MHz, D2O): d 72.0, 69.2, 68.2,
40.8, 37.0, 36.2.
(3R,4R,6R)-3,4-Dihydroxy-6-hydroxymethylthiopyran (2b)
A pale yellow syrup. 1H NMR (600 MHz, D2O): d 4.12 (dt, J ¼ 4.5, 2.2 Hz,
1H), 3.75 (dd, J ¼ 11.6, 5.0 Hz, 1H), 3.72 (ddd, J ¼ 11.4, 4.1, 2.8 Hz, 1H),
3.64 (dd, J ¼ 11.6, 7.6 Hz, 1H), 3.15–3.05 (m, 1H), 3.01 (dd, J ¼ 14.4,
1.8 Hz, 1H), 2.86 (dd, J ¼ 14.4, 4.7 Hz, 1H), 1.98 (ddd, J ¼ 12.9, 3.8,
2.9 Hz, 1H), 1.72 (td, J ¼ 12.9, 11.4 Hz, 1H). 13C NMR (125 MHz, D2O): d
70.4, 66.3, 64.6, 43.5, 32.7, 32.0. HRMS (FAB) calcd. for C6H13O3S
([M þ H]þ) 165.0585. Found: 165.0588.

3348
T.-L. Shih and Y.-C. Fang
(3R,4R,6R)-3,4-Diacetoxy-6-acetoxymethylthiopyran (3b)
The assignment of the major isomer 3b is based on the substraction of the
minor signals from spectra. 1H NMR (600 MHz, CDCl3): d 5.14 (dt,
J ¼ 7.1, 2.8 Hz, 1H), 4.95 (dt, J ¼ 8.7, 3.1 Hz, 1H), 4.25–4.13 (m, 2H),
3.07 (ddd, J ¼ 14.8, 7.4, 3.7 Hz, 1H), 2.96 (dd, J ¼ 14.2, 7.1 Hz, 1H), 2.72
(dd, J ¼ 14.2, 2.5 Hz, 1H), 2.14–2.07 (m, 1H), 2.06 (s, 3H), 2.04 (s, 3H),
2.02 (s, 3H). 13C NMR (125 MHz, CDCl3): d 170.7, 170.3, 170.1, 70.2,
68.0, 66.0, 38.1, 31.5, 27.8, 21.1, 20.9.
(2R,3R,5S)-3,5-Diacetoxy-2-acetoxymethylthiopyran (5b)
[a]2D6 þ79.9 (c 0.72, CHCl3). 1H NMR (600 MHz, CDCl3): d 5.21 (dt,
J ¼ 12.0, 4.4 Hz, 1H), 4.95 (ddd, J ¼ 15.5, 9.7, 4.6 Hz, 1H), 4.45 (dd,
J ¼ 11.4, 8.8 Hz, 1H), 4.29 (dd, J ¼ 11.4, 4.7 Hz, 1H), 3.10 (dt, J ¼ 9.1,
4.7 Hz, 1H), 2.63 (d, J ¼ 13.2 Hz, 1H), 2.58 (dd, J ¼ 13.2, 5.0 Hz, 1H),
2.07 (s, 3H), 2.0 (s, 3H), 2.01 (s, 3H), 1.67 (dd, J ¼ 24.0, 12.2 Hz, 1H). 13C
NMR (125 MHz, CDCl3): d 171.0, 170.0, 169.8, 70.9, 70.4, 60.0, 39.4,
32.8, 27.1, 21.3, 21.2, 21.1. HRMS (FAB) calcd. C12H19O6S ([M þ H]þ):
291.0902. Found: 291.0917.
(3R,4R,6R)-Thiepane-3,4–6-triol ((3R,4R,6R)-trihydroxythiepane) (1c)
Mp 157.0–167.28C. [a]2D6 þ137.1 (c 0.5, H2O). H NMR (600 MHz, D2O):
1
d 4.27 (ddd, J ¼ 16.1, 10.6, 5.3 Hz, 1H), 4.22 (dd, J ¼ 9.9, 2.4 Hz, 1H),
4.15–4.12 (m, 1H), 3.04 (dd, J ¼ 15.1, 5.3 Hz, 1H), 2.92 (dd, J ¼ 14.8,
4.2 Hz, 1H), 2.70 (dd, J ¼ 14.8, 7.4 Hz, 1H), 2.63 (dd, J ¼ 15.1, 6.5 Hz,
1H), 2.58 (ddd, J ¼ 15.2, 10.3, 4.9 Hz, 1H), 1.73 (dd, J ¼ 15.2, 5.3 Hz,
1H). 13C NMR (125 MHz, D2O): d 73.4, 68.3, 67.1, 39.6, 36.2, 35.7.
HRMS (FAB) calcd. for C6H12O3S ([M]þ): 164.0507. Found: 164.0511.
ACKNOWLEDGEMENT
This work was financially supported by the National Science Council
(NSC94-2113-M-032-006) and Tamkang University.
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