Hedathiosulfonic acids A and B, novel thiosulfonic acids from the deep-sea urchin Echinocardium cordatum

Article abstract of DOI:10.1016/S0040-4020(02)00654-3

Hedathiosulfonic acids A and B were isolated from the deep-sea urchin Echinocardium cordatum and were determined to be novel 6-undecanethiosulfonic acids by 2D NMR, HRMS, and methylation reaction. The stereostructure of hedathiosulfonic acid A was determined by the analysis of its degradation product, a cyclic β-hydroxysulfone. Hedathiosulfonic acids exhibited acute toxicity. We carried out various model reactions of the olefinic compounds with thiosulfonic acids and proved that, as is the case with natural products, synthesized thiosulfonic acid possessing a carbon-carbon double bond was converted into β-hydroxysulfone in the presence of oxygen.

Full text of DOI:10.1016/S0040-4020(02)00654-3

Tetrahedron 58 (2002) 6405–6412
Hedathiosulfonic acids A and B, novel thiosulfonic acids from the
deep-sea urchin Echinocardium cordatum
a
Masaki Kita, Masami Watanabe, Noboru Takada, Kiyotake Suenaga, Kaoru Yamada
a
a
b
a
a,
*
and Daisuke Uemura
a
Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
b
Received 1 April 2002; revised 24 May 2002; accepted 25 May 2002
In honor of Professor Yoshito Kishi on the occasion of his award of the prestigious Tetrahedron Prize
Abstract—Hedathiosulfonic acids A and B were isolated from the deep-sea urchin Echinocardium cordatum and were determined to be
novel 6-undecanethiosulfonic acids by 2D NMR, HRMS, and methylation reaction. The stereostructure of hedathiosulfonic acid A was
determined by the analysis of its degradation product, a cyclic b-hydroxysulfone. Hedathiosulfonic acids exhibited acute toxicity. We carried
out various model reactions of the olefinic compounds with thiosulfonic acids and proved that, as is the case with natural products,
synthesized thiosulfonic acid possessing a carbon–carbon double bond was converted into b-hydroxysulfone in the presence of
oxygen. q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
isolated from echinoderms, there have been no previous
reports of a thiosulfonic acid like the hedathiosulfonic
3
In our continuing search for marine bioactive compounds,
we have directed our attention to the deep-sea invertebrates.
Because the deep-sea organisms survive in severe environ-
ments with features such as the absence of light, low levels
of oxygen, and high pressure, it is likely that they produce
different compounds from those that shallow water
organisms produce. With advances in deep ocean tech-
nology, the study of numerous bioactive compounds from
the bottom feeders has been possible. For example,
nortopsentins from the sponge Spongosorites ruetzleri,
g-indomycinone from a Streptomyces sp., and guaymasol
acids. Recently, the bacteria Thiothrix sp., which can
oxidize sulfide, have been reported as symbionts in
4
invertebrates from sulfur-rich habitats. A symbiotic
relationship has also been demonstrated between Thiothrix
5
sp. and E. cordatum. Therefore, the genus Thiothrix is
probably the actual source of hedathiosulfonic acids. We
report here the detailed isolation and structure determination
of 1 and 2, along with details of our studies of the model
reactions using the thiosulfonic acids.
1
from a Bacillus sp. have been reported. We have previously
reported the isolation and structural determination of
2. Results and discussion
hedathiosulfonic acids A (1) and B (2) from the deposit-
feeding deep-sea heart urchin Echinocardium cordatum
(Fig. 1). Although many substances that contain sulfur
atoms such as sulfonic acids, thiols, and sulfides have been
2.1. Isolation and structural determination
2
The aqueous 80% EtOH extract of the deep-sea urchin E.
cordatum, collected at a depth of 400 m off the Heda coast
of the Izu Peninsula, Japan, was partitioned between EtOAc
and H O. The EtOAc-soluble fraction was subjected to
2
fractionation guided by acute toxicity against mice using
column chromatography and reversed-phase HPLC to give
hedathiosulfonic acids A (1, 0.0037% yield based on wet
wt) and B (2, 0.0046% yield based on wet wt) as colorless
oils. Hedathiosulfonic acids A (1) and B (2) exhibited low
acute toxicity against mice, with LD s of 0.39 and
9
9
Figure 1. Structures of hedathiosulfonic acids A (1) and B (2).
0.36 g/kg, respectively.
Keywords: natural thiosulfonic acid; isolation; structure determination;
model reaction.
The fluorescent X-ray analysis of hedathiosulfonic acid A
(1) suggested the presence of two sulfur atoms. The
molecular formula of 1 was determined to be C H O S
2 24 2 2
*
Corresponding author. Tel./fax: þ81-52-789-3654;
e-mail: uemura@chem3.chem.nagoya-u.ac.jp
1
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00654-3

6
406
M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
OD
Table 1. NMR data for hedathiosulfonic acid A (1) and B (2) in CD
3
Atom
Hedathiosulfonic acid A (1)
Atom
Hedathiosulfonic acid B (2)
1
a
H
13
C
b
1
H
a
13 b
C
1
0.91 t (7.2), 3H
14.7 q
20.9 t
40.1 t
1a
4.98 br d (17.4)
5.01 br d (10.1)
5.83 ddt (10.1, 17.4, 7.2)
116.2 t
138.4 d
42.1 t
1
2
b
2
2
3
3
4
5
5
6
7
7
8
8
9
1
1
1
a
b
a
b
1.32 m
1.44 m
1.11 m
1.39 m
1.78 m
1.31 m
2.11 ddd (5.3, 7.3, 14.3)
2.86 dq (5.3, 5.1)
1.58 m
3a
3b
4
5a
5b
6
7a
7b
8a
8b
9
10
11
12
1.88 m
2.19 m
1.88 m
1.34 ddd (6.3, 6.6, 14.5)
2.13 ddd (5.8, 6.7, 14.5)
2.88 ddt (6.3, 5.8, 5.9)
1.57 m
2.19 m
2.23 ddt (7.2, 14.6, 7.6)
2.29 m
5.40 dddq (6.7, 7.2, 10.6, 1.7)
5.47 br dq (10.6, 6.7)
1.63 br d (6.7), 3H
0.93 d (6.2), 3H
31.8 d
39.9 t
32.1 d
39.5 t
a
b
70.8 d
32.7 t
70.7 d
32.7 t
a
b
a
b
2.18 m
2.23 ddt (7.7, 14.5, 7.2)
2.30 ddt (8.1, 14.5, 8.0)
5.40 br ddd (7.7, 8.1, 10.9)
5.47 br dq (10.9, 6.7)
1.63 d (6.7), 3H
0.92 d (6.6), 3H
25.9 t
25.8 t
131.3 d
125.3 d
13.0 q
20.6 q
131.2 d
125.3 d
13.1 q
20.2 q
0
1
2
a
Recorded at 800 MHz. Coupling constants (Hz) are in parentheses.
Recorded at 201 MHz. Multiplicity was based on HMQC spectrum.
b
by HRFABMS (m/z 309.0951, calcd for C H Na O S ,
2 2 2
were converted into 3,5-dinitrobenzoate 6 and acetate 8,
respectively. The oxymethine protons in both 6 (dH-10 5.66)
and 8 (dH-9 4.80) were shifted to more than 1 ppm downfield
from those in 5 and 7, respectively.
1
2
23
3
09.0935). The NMR data for 1 are summarized in Table 1.
1
13
The H NMR, C NMR, and HMQC spectra of 1 showed
the presence of three methyl carbons, five methylene
carbons, two methine carbons, and two olefinic methine
carbons (d 125.3, 131.3). Based on the chemical shift, it
C
Since the stereochemistiy in hedathiosulfonic acid A (1)
could not be deduced by the spectroscopic analysis, that of
the sulfone 7 was determined as follows (Fig. 3). As the six-
membered sulfone ring part, the magnitude of
J8a,9¼10.0 Hz, J ¼3.9 Hz, and J ¼10.0 Hz suggested
was clarified that one methine carbon was attached to an
oxygenated sulfur atom (dH 2.86, dC 70.8). A detailed
analysis of the COSY spectrum enabled us to elucidate the
entire carbon framework. The geometry of the C-9 olefin
was determined to be 9Z based on the magnitude of
J9,10¼10.9 Hz. Furthermore, to determine the functional
group (S O H) at C-6, we methylated hedathiosulfonic acid
8b,9
9,10
that H-8a and H-9, H-9 and H-10 were located in anti
arrangement, respectively, and that H-8b and H-9 were
located in gauche arrangement. In the NOE experiments
(600 MHz) on 7, NOEs were observed for H-6/H-8a and
H-10, H-9/H-7a, and H-10/H-8a. These results suggested
that the protons H-6, H-7a, H-8a, H-9, and H-10 were
oriented in anti arrangements with respect to the six-
membered sulfone ring with the chair conformation. As the
alkyl side chain part, the magnitude of J5a,6¼7.2 Hz and
J5b,6¼5.4 Hz suggested that H-5a and H-6 were in anti
arrangement and that H-5b and H-6 were in gauche
arrangement. The stereochemistry of C-4 was not deter-
mined clearly because of the subtle difference of the
magnitude of J4,5a¼8.0 Hz and J4,5b¼7.3 Hz. In the NOE
2
2
A (1) with Me SO –Et N to give methyl thiosulfonate 3.
2
4
3
The chemical shifts of an additional methyl group (d 2.67,
H
dC 17.5) in 3 suggested that this methyl carbon was attached
to an non-oxygenated sulfur atom. As a result, we
determined the gross structure of hedathiosulfonic acid A
as 1, possessing a thiosulfonic acid functionality.
1
The H NMR spectrum of hedathiosulfonic acid B (2)
resembled that of hedathiosulfonic acid A (1), but the
presence of three additional vinyl protons (dH 4.98, 5.01,
5
HRFABMS (m/z 307.0761, calcd for C H Na O S ,
.83) and the molecular formula of 2 determined by
1
2
21
2 2 2
3
07.0778) suggested that 2 was a dehydro derivative of 1.
The NMR data for 2 are summarized in Table 1. We
determined that the geometry of the C-9 olefin is 9Z based
on the magnitude of J9,10¼10.6 Hz. As expected, the gross
structure of hedathiosulfonic acid B was determined to be 2
by similar analyses of COSY, HMQC, and HMBC spectra.
Hedathiosulfonic acid A (1) was unstable in air and
gradually decomposed into sulfonic acid 4, five-membered
cyclic sulfone 5, and six-membered cyclic sulfone 7 (Fig. 2).
The NMR data for these three compounds are summarized
in Table 2. The gross structures of 4, 5, and 7 were
determined using the 2D NMR and the mass spectra. To
confirm the position of the hydroxyl group, sulfones 5 and 7
Figure 2. The degraded compounds from hedathiosulfonic acid A (1) and
related compounds.

M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
6407
Table 2. NMR data for compounds 4, 5, and 7 in CD
3
OD
a
5
Atom
4
7
1
b
H
13
C
c
1
b
13
C
c
1
H
d
13 e
C
H
1
0.91 t (7.3), 3H
1.35 m
1.46 m
1.10 m
1.37 m
1.78 dq (12.9, 6.8)
1.30 m
1.91 m
2.73 dq (5.9, 5.9)
1.55 m
1.99 m
2.21 ddt (7.0, 15.0, 7.5)
2.28 ddt (7.0, 15.0, 7.5)
5.39 m
5.46 m
1.63 d (7.6), 3H
0.92 d (6.4), 3H
14.7 q
21.0 t
0.91 t (7.3), 3H
1.32 m
1.40 m
1.16 m
1.32 m
1.71 m
1.37 m
1.84 m
3.08 ddt (5.9, 14.5, 6.2)
1.60 dq (12.9, 5.9)
2.27 m
1.98 m
2.29 m
2.89 ddd (6.3, 7.7, 10.6)
4.07 dq (6.3, 6.3)
1.30 d (6.3), 3H
0.96 d (6.6), 3H
14.5 q
20.9 t
0.92 t (7.3), 3H
1.30 m
1.41 m
1.11 m
1.34 m
1.75 dq (7.3, 6.6)
1.22 dt (14.0, 7.1)
1.95 ddd (5.4, 7.3, 14.0)
3.03 m
1.56 m
14.6 q
20.7 t
2
2
3
3
4
5
5
6
7
7
8
8
9
1
1
1
a
b
a
b
40.2 t
40.4 t
39.6 t
31.6 d
39.4 t
31.3 d
36.2 t
31.0 d
34.3 t
a
b
58.7 d
32.1 t
61.5 d
28.7 t
59.0 d
27.6 t
a
b
a
b
2.02 ddt (2.7, 13.9, 7.0)
1.58 m
25.6 t
24.0 t
34.9 t
2.08 ddt (2.7, 12.8, 4.0)
3.51 dt (4.0, 10.5)
2.92 dq (10.5, 6.6)
1.41 d (6.6), 3H
0.96 d (6.6), 3H
131.2 d
125.3 d
18.1 q
20.4 q
68.6 d
66.3 d
22.0 q
19.9 q
72.2 d
64.1 d
6.9 q
0
1
2
20.3 q
a
b
c
d
e
Compound 5 was isolated as a mixture of two diastereomers (2:1 ratio), detected by the NMR analysis. The data for the major diastereomer were described.
Recorded at 600 MHz. Coupling constants (Hz) are in parentheses.
Recorded at 150 MHz. Multiplicity was based on DEPT analysis.
Recorded at 800 MHz. Coupling constants (Hz) are in parentheses.
Recorded at 201 MHz. Multiplicity was based on HMQC spectrum.
Figure 3. Relative stereochemistry of sulfone 7.
experiments on 7, NOEs were observed for H-5a/H-7a and
H-12/H-6. In particular, irradiation of the signal at H-4
strongly enhanced the signal for H-7b (6.0%). These results
suggested that the single bond rotation between C-4 and C-5
was restricted in part and that one of the stable confor-
mations of 7 was as shown in Fig. 3. Therefore, the relative
stereochemistry in the six-membered cyclic sulfone 7 was
p
p
p
p
suggested to be 4S , 6R , 9S , and 10R .
The relative stereochemistry in the five-membered cyclic
sulfone 5, isolated as a mixture of two diastereomers (2:1
ratio), was determined using 3,5-dinitrobenzoyl derivative 6
as follows (Fig. 4). As the major diastereomer of 6, the
NOESY correlations for H-6/H-7b and H-8a, H-7a/H-5a,
H-8b, and H-9, H-7b/H-8a, and H-8b/H-9 suggested that the
protons H-6 and H-9 were oriented in anti arrangements
with respect to the sulfone ring. As the minor diastereomer
of 6, the NOESY correlations for H-6/H-7a, H-8b, and H-9,
H-8b/H-7a and H-9 suggested that the protons H-6 and H-9
were oriented in syn arrangements with respect to the
sulfone ring. The stereochemistries of C-4 and C-10 in both
diastereomers of 6 were not determined, however, because
of the single bond rotations in the side chain part. Therefore,
Figure 4. Relative stereochemistry of sulfone 6.

6408
M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
Table 3. Reactions of thiosulfonic acid potassium salt 11 with cyclohexene
a
a
Entry
1
Amount of cyclohexene (equiv.)
Time (h)
Conditions
Products (%)
Recovered 11 (%)
1
3
15
17
18
67
77
83
175
128
24.5
22
23
15
Under air
Under air
Under air
11
–
–
6
–
7
9
–
16
–
–
6
–
2
–
52
76
–
71
–
b
2
3
c
94
66
4
5
Under O
Under O
2
2
c
36
a
Isolated yields.
Starting material 11 was treated with TFA before use.
equiv. of BHT were added.
b
c
5
the relative stereochemistry in the sulfone 5 was established
p
from the oxymethine protones in 14 (d 4.83) and in 16 (dH
H
4.74) into the carbonyl carbons in 14 (d 170.8) and in 16
C
p
p
p
to be 6R , 9R for the major diastereomer and 6R , 9S for
minor one.
(dC 170.6) confirmed that products 13 and 15 each
possessed a hydroxyl group, respectively. Treatment of 11
with trifluoroacetic acid before the reaction afforded mainly
The absolute stereochemistry in 7 was determined using the
6
10
modified Mosher’s method. Treatment of the sulfone 7
with (R)- or (S)-MTPAC1 gave (S)- or (R)-MTPA esters 9
18, and g-ketosulfone 17 was also formed (entry 2). Under
an oxygen atmosphere, degradation of 11 was more
accelerated (entry 4). Under any conditions, however, no
b-hydroxysulfones such as 12 were obtained. It should be
noted that thiosulfonic acid reacted with cyclohexene even
in the absence of moisture. In addition, a couple of radical
intermediates must be associated with those reactions
because thiosulfonic acid sodium salt 11 was recovered in
the presence of radical scavengers (entries 3 and 5).
1
and 10, respectively. The H NMR signals of the two MTPA
esters 9 and 10 were assigned on the basis of the 2D NMR
spectra, and the Dd values (d 2d , ppm) were then
S
R
calculated. The results indicated that the absolute stereo-
chemistry of C-9 was 9S, and that the absolute stereo-
chemistry in 7 was suggested to be 4S, 6R, 9S, and 10R.
Based on these results, the absolute stereochemistry in
hedathiosulfonic acid A (1) was established to be 4S and 6R.
We also examined intramolecular reactions (Scheme 1).
Several intramolecular additions of d-unsaturated thiyl and
2
.2. Model reactions with the synthesized thiosulfonic
acids
9
,11,12
sulfonyl radicals have also been reported.
of NaSH to 4-pentenesulfonyl chloride (20), which was
The addition
1
3
The compounds containing sulfonyl groups, such as
sulfonyl halides, sulfonyl cyanides, sulfonyl thiocyanides,
selenosulfonates, and thiosulfonates, are common precur-
sors of sulfonyl radicals, which are useful for their ability to
synthesized from 4-pentene-1-bromide (19) by King’s
method, gave thiosulfonic acid sodium salt 21 (85%).
Although 21 was stable under air for more than 2 weeks in
MeOH, the addition of aqueous hydrochloric acid led to
7
,
14,15
add to carbon–carbon multiple bonds in organic synthesis.
8
b-hydroxysulfone 22 (15%) and sulfonic acid 23 (43%).
Treatment of compound 21 with trifluoroacetic acid
followed by standing in the solvent-free condition under
In addition, the sulfur–sulfur bonds of thiosulfonates are
known to be cleaved in thermal conditions without the
9
addition of radical initiator or UV irradiation. Therefore,
we expected that thiosulfonic acids would also leave
sulfonyl radicals, and that cyclic sulfones 5 and 7 were
formed from hedathiosulfonic acid A (1) via the intra-
molecular addition of sulfonyl radicals into carbon–carbon
double bonds. To investigate the reaction mechanisms, we
examined intermolecular reactions using n-propylthio-
sulfonic acid potassium salt (11) (Table 3). Treatment of
1
1 with cyclohexene in CHCl –MeOH (1:1, v/v) in air gave
3
several unexpected adducts, b-hydroxysulfonate 13,
b-hydroxythiosulfonate 15, and sulfonic acid potassium
salt 18 (entry 1). Compounds 13 and 15 were converted into
acetates 14 and 16, respectively. The HMBC correlations
Scheme 1.

M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
6409
an oxygen atmosphere also gave compound 22 (23%). In
any case, however, five-membered hydroxysulfone was
not detected. From 4-pentenylthiyl radical both the five-
and six-membered sulfides have been synthesized in the
Mass spectra (FABMS) were recorded on a JEOL JMS-
LG2000 spectrometer. The matrix used in FABMS analysis
was m-nitrobenzyl alcohol.
1
1
ratio of 1:19. The predominance of the larger ring has
been explained by the reversibility of the addition of the
thiyl radical into carbon–carbon double bonds.
These results suggested that thiosulfonic acid sodium
salt 21 could also be cyclized under thermodynamic
4.2. Isolation and structure determination of
hedathiosulfonic acids A and B
The whole parts including shells (10.9 kg, wet wt) of the
urchin E. cordatum, collected at a depth of 400 m off the
Heda coast of the Izu Peninsula, Japan, were crushed in a
blender in aqueous 80% EtOH and extracted with the same
solvent (20 L) for 3 days. The alcoholic extract was
concentrated and partitioned between EtOAc (3£1 L) and
1
6
control.
The degradation reaction of 1 into the cyclic sulfones 5 and
was reproduced by synthetic analogs. In trying to
7
understand the mechanism of the novel degraded reaction
from hedathiosulfonic acid A (1) into sulfones 5 and 7, we
assumed that sulfonyl radicals were generated by the
cleavage of sulfur–sulfur bonds of thiosulfonic acids
followed by 5-exo or 6-endo cyclization and oxidation.
Since the protones H-9 and H-10 in 7 are oriented in anti
arrangement, the stereospecificity in C-9 should be lost
during the cyclization. It should be noted that sulfones 5 and
H O (2 L). The EtOAc extracts (29.8 g) showed an acute
2
toxicity against ddY mice (i.p. injection), which were
subjected to fractionation guided by the toxicity. One-
eleventh of the oily residue was chromatographed on ODS
(60 g, MeOH–H O, 60:40!85:15!95:5!100:0). A half
2
of the early fraction (343 mg) was separated by six rounds
of HPLC (Develosil ODS HG-5, 20£250 mm, 50%
aqueous MeOH, 5 mL/min, UV 205 nm) to give hedathio-
sulfonic acids A (1) (18.2 mg; LD99 0.39 mg/kg) and B (2)
(22.4 mg; LD99 0.36 mg/kg) as colorless oils.
7 could result in the cyclization of those radical inter-
mediates under thermodynamic control.
2
6
4
.2.1. Hedathiosulfonic acid A (1). [a] ¼þ2.18 (c 0.073,
D
) 3580–3260 (br), 1180, 1060 cm2 ; H
and C NMR data, see Table 1; MS (FAB) m/z 309
1 1
3. Conclusion
MeOH); IR (CHCl
3
1
3
þ
þ
Hedathiosulfonic acids A (1) and B (2) were isolated from
the deep-sea urchin E. cordatum, and were determined to be
novel 6-undecanethiosulfonic acids by 2D NMR, HRMS,
and methylation reaction. The stereostructure of 1 was
elucidated by the spectroscopic analysis of its degradation
product 7. Regarding model reactions of the decomposition
of hedathiosulfonic acid A (1), the synthetic analog,
thiosulfonic acid 21, was converted into b-hydroxysulfone
(M2Hþ2Na) ; HRMS (FAB) calcd for C12
H23Na O S
2 2 2
(M2Hþ2Na) 309.0935, found 309.0951.
2
6
4.2.2. Hedathiosulfonic acid B (2). [a]
MeOH); IR (CHCl ) 3520–3240 (br), 1640, 1180,
¼22.28 (c 0.28,
D
3
13
1060 cm2
1
;
1
H and C NMR data, see Table 1; MS
þ
(FAB) m/z 307 (M2Hþ2Na) ; HRMS (FAB) calcd for
þ
C
307.0761.
H
21Na
O
S
2
(M2Hþ2Na)
307.0778,
found
12
2
2
22 in acidic conditions. Further mechanistic studies on these
reactions are in progress.
4
.2.3. Procedure for methylation of hedathiosulfonic
acid A (1). To a solution of hedathiosulfonic acid A (1)
5.6 mg (21 mmol) in CH Cl (0.50 mL) was added triethyl-
4
. Experimental
2
2
amine 0.05 mL (0.36 mmol). The mixture was cooled to
08C, and dimethylsulfonic acid 0.10 mL (1.1 mmol) was
added. After the resulting mixture was stirred at room
temperature for 74 h, the mixture was diluted with EtOAc
(15 mL), washed with brine (5 mL), dried, and concen-
trated. The residual oil was purified by column chromato-
4
.1. General
Unless otherwise noted, materials were obtained from
commercial sources and used without further purification.
All solvents were purified by a standard procedure before
use. The starting materials were azeotropically dried with
benzene before use. All reactions were conducted under a
nitrogen atmosphere unless otherwise noted. Fuji silysia
silica gel BW-820 MH and Nacalai Tesque Cosmosil 75C -
OPN were used for column chromatography. Merck
precoated silica gel 60 F254 plates were used for thin-layer
chromatography (TLC). Fluorescent X-ray spectra was
recorded on a Horiba EMAX-5770W instrument. Optical
rotations were measured with a JASCO DIP-1000 polari-
meter. IR spectra were recorded on a JASCO FT/IR-230
spectrometer in chloroform. NMR spectra were recorded on
graphy
on
silica
gel
(0.5 g,
CHCl
–MeOH,
O,
3
10:0!9:1!4:1) and on ODS gel (0.2 g, MeOH–H
2
9:1), and HPLC was performed (YMC ODS-AQ,
4.6£150 mm, 80% aqueous MeOH, 1 mL/min, UV
215 nm) to give methyl thiosulfonate 3 (5.9 mg, quant.) as
1
8
2
8
a colorless oil: [a ]
1460, 1330, 1300, 1120 cm
CD
¼þ1.08 (c 0.28, MeOH); IR (CHCl
)
3
D
2
1
1
;
H NMR (800 MHz,
OD) d 5.55 (1H, dtq, J¼11.0, 1.4, 6.8 Hz), 5.38 (1H,
3
dtq, J¼11.0, 7.3, 1.8 Hz), 3.30 (1H, m), 2.66 (3H, s), 2.33
(1H, ddt, J¼15.0, 6.8, 6.8 Hz), 2.23 (1H, ddt, J¼15.0, 6.8,
6.8 Hz), 2.07 (1H, dddd, J¼5.1, 6.8, 8.8, 14.5 Hz), 1.96
(1H, ddd, J¼5.5, 7.0, 14.3 Hz), 1.75 (1H, m), 1.72 (1H, ddt,
J¼8.8, 14.5, 6.8 Hz), 1.64 (3H, d, J¼6.8 Hz), 1.46 (1H,
ddd, J¼5.1, 7.0, 14.3 Hz), 1.42 (1H, m), 1.35 (1H, m), 1.31
(1H, m), 1.15 (1H, m), 0.96 (3H, d, J¼6.6 Hz), 0.92 (3H, t,
1
13
a JEOL JNM-A400 (400 MHz for H and 100 MHz for C),
1
13
a JEOL JNM-A600 (600 MHz for H and 150 MHz for C),
1
or a JEOL JNM-ECP800 (800 MHz for H and 201 MHz for
1
3
C) instrument. The chemical shifts were referenced to the
solvent peaks: d 3.31 (residual CH D OD) and d 49.0 for
CD OD, d 7.26 (residual CHCl ) and d 77.0 for CDCl .
1
3
J¼7.3 Hz); C NMR (201 MHz, CD
OD) d 129.2 (d, C9),
3
H
2
C
126.0 (d, C10), 68.5 (d, C6), 39.0 (t, C3), 37.0 (t, C5), 30.1
3
H
3
C
3

6410
M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
(
1
2
d, C4), 30.0 (t, C7), 23.8 (t, C8), 19.9 (t, C2), 18.9 (q, C12),
chloride (102 mg, 0.44 mmol), and the mixture was stirred
at room temperature for 22.5 h. The reaction mixture was
diluted with toluene (5.0 mL) and concentrated in vacuo.
The residual oil was purified by column chromatography on
silica gel ((1) 3.0 g, hexane–EtOAc, 5:1!3:1!1:1; (2)
0.5 g, benzene–acetone, 1:0!30:1!0:1) to give 3,5-
dinitrobenzoate 6 (6.5 mg, 75%, 2:1 diastereomer mixture)
7.5 (q, C13), 13.3 (q, C1), 11.5 (q, C11); MS (FAB) m/z
þ
79 (MþH) ; HRMS (FAB) calcd for C H O S
1
3 27 2 2
þ
(
MþH) 279.1453, found 279.1458.
4
(
.3. Degraded compounds from hedathiosulfonic acid A
1) and related compounds
as a colorless oil: IR (CHCl ) 1735, 1630, 1550, 1460, 1340,
3
1 1
1280, 1160 cm2 ; H NMR (800 MHz, CDCl ) (noted only
4
.3.1. Isolation of the degraded compounds 4, 5, and 7.
3
The whole parts including shells (4.8 kg, wet wt) of E.
cordatum were crushed, extracted, and partitioned as
described in Section 2.1. The EtOAc extracts (14.8 g)
were chromatographed on silica gel (300 g, benzene–
acetone, 9:1!7:1!0:1, then MeOH). The eluates of
acetone (2.1 g) contained hedathiosulfonic acid (1) as a
major component. When stocked in air for 1 month,
compound 1 was decomposed to give 4, 5, and 7 as new
components, which were detected by the analyses of TLC
and NMR spectra. Two-thirds of the fractions were
chromatographed on silica gel (25 g, benzene–acetone,
the signal of the major diastereomer) d 9.25 (1H, br d,
J¼12.1 Hz), 9.14–9.11 (2H, m), 5.66 (1H, dq, J¼12.0,
6.2 Hz), 3.26 (1H, dt, J¼12.0, 7.4 Hz), 3.06 (1H, m), 2.40–
2.33 (2H, m), 2.04 (1H, m), 1.94 (1H, m), 1.74–1.65 (2H,
m), 1.62 (3H, d, J¼7.8 Hz), 1.41–1.31 (2H, m), 1.31–1.23
(2H, m), 1.12 (1H, m), 0.92 (3H, d, J¼6.6 Hz), 0.87 (3H, t,
þ
J¼7.1 Hz); MS (FAB) m/z 443 (MþH) ; HRMS (FAB)
þ
calcd for C H N O S (MþH)
443.1488, found
1
9 27 2 8
443.1464.
4.3.6. Acetate 8. To a solution of six-membered sulfone 7
0.5 mg (2.0 mmol) in pyridine (0.2 mL) cooled to 08C was
added Ac O (0.1 mL, 1.1 mmol), and the mixture was
1:0!3:2!0:1, then MeOH) to give four additional
fractions (fractions I–IV). Fraction II (0.44 g) was purified
2
by column chromatography on silica gel ((1) 9 g, n-hexane–
EtOAc, 7:3!1:1!3:7!1:9; (2) 9 g, CHCl –MeOH,
stirred at room temperature for 37.5 h. The reaction mixture
was diluted with toluene (5.0 mL) and concentrated in
vacuo. The residual oil was purified by column chromato-
graphy on silica gel (0.4 g, hexane–EtOAc, 1:1!MeOH)
to give acetate 8 (0.3 mg, 51%) as a colorless oil:
3
6
0:1!50:1!20:1) to give five-membered sulfone 5
(99.2 mg) as a colorless oil. Fraction III (0.36 g) was
separated by column chromatography on silica gel ((1) 10 g,
2
8
CHCl –MeOH, 15:1!9:1!16:3!7:2; (2) 2.5 g, CHCl –
[a ] ¼þ178 (c 0.023, MeOH); IR (CHCl ) 1750, 1310,
3
3
D
3
1140 cm2 ; H NMR (800 MHz, CD OD) d 4.80 (1H, dt,
1 1
MeOH, 15:1!7:2; (3) 1.5 g, acetone–MeOH, 1:1!0:1),
3
and by ODS gel (1.0 g, MeOH–H O, 1:9!3:7!
J¼4.0, 12.3 Hz), 3.29 (1H, dq, J¼12.3, 6.9 Hz), 3.15 (1H,
m), 2.35 (3H, s), 2.11 (1H, ddt, J¼15.2, 4.1 Hz), 2.08 (1H,
m), 1.96 (1H, ddd, J¼6.2, 7.7, 14.0 Hz), 1.76 (1H, m), 1.70
(1H, ddt, J¼3.6, 15.2, 14.3 Hz), 1.62 (1H, ddt, J¼2.8, 16.6,
14.3 Hz), 1.41 (1H, m), 1.34 (1H, m), 1.32 (3H, d,
J¼6.9 Hz), 1.30 (1H, m), 1.25 (1H, dt, J¼7.3, 14.0 Hz),
1.11 (1H, m), 0.97 (3H, d, J¼6.6 Hz), 0.92 (3H, t,
2
5
:5!7:3!0:1). The 30% aqueous MeOH fraction
(
15.0 mg) was purified by HPLC ((1) Develosil ODS MG-
5
2
, 20£250 mm, 60% aqueous MeOH, 5 mL/min, UV
05 nm; (2) Develosil ODS HG-5, 20£250 mm, 30%
aqueous MeOH, 5 mL/min, UV 205 nm) to give six-
membered sulfone 7 (4.5 mg) as a colorless oil. Fraction
IV (0.42 g) was purified by column chromatography on
þ
J¼7.2 Hz); MS (FAB) m/z 313 (MþNa) ; HRMS (FAB)
þ
ODS gel (10.0 g, MeOH–H O, 1:9!2:8!3:7!
calcd for C H NaO S (MþNa) 313.1450, found
2
14 26
4
5
1
:5!0:1) and on silica gel (4 g, CHCl –MeOH,
313.1450.
3
:0!7:1!14:5!0:1) to give sulfonic acid 4 (0.22 g) as
1
a colorless oil.
4.3.7. (S )-MTPA ester 9. A colorless oil; H NMR
(
600 MHz, CDCl ) d 7.48 (2H, d, J¼7.9 Hz), 7.44–7.40
3
2
8
4
.3.2. Sulfonic acid 4. [a ] ¼21.78 (c 0.70, MeOH); IR
(3H, m), 5.03 (1H, dt, J¼3.5, 11.0 Hz), 3.51 (3H, s), 3.06
(1H, dq, J¼11.0, 6.8 Hz), 2.82 (1H, m), 2.31 (1H, ddt,
J¼3.5, 13.2, 6.0 Hz), 2.06 (1H, m), 2.03 (1H, m), 1.76 (1H,
ddt, J¼3.5, 16.7, 13.6 Hz), 1.69 (1H, m), 1.52 (1H, m), 1.38
(1H, m), 1.38 (3H, d, J¼6.8 Hz), 1.32 (1H, ddd, J¼6.4, 8.2,
D
2
1 1
(
1
CHCl ) 3600–3100 (br), 1460, 1160, 1020 cm ; H and
3
3
þ
C NMR data, see Table 2; MS (FAB) m/z 271 (MþNa) ;
þ
HRMS (FAB) calcd for C H NaO S (MþNa) 271.1344,
1
2
24
3
found 271.1317.
1
4.5 Hz), 1.25 (1H, m), 1.24 (1H, m), 1.07 (1H, m), 0.95
4
.3.3. Five-membered sulfone 5. IR (CHCl ) 3600–3480
3
(3H, d, J¼6.6 Hz), 0.88 (3H, t, J¼7.2 Hz); MS (FAB) m/z
21
1
13
þ
(
br), 1160, 1460, 1300, 1280, 1110 cm ; H and C NMR
þ
465 (MþH) ; HRMS (FAB) calcd for C H F O S
2
2 32 3 5
þ
data, see Table 2; MS (FAB) m/z 271 (MþNa) ; HRMS
(MþH) 465.1923, found 465.1947.
þ
(
FAB) calcd for C H NaO S (MþNa) 271.1344, found
12
24
3
1
2
71.1353.
4.3.8. (R)-MTPA ester 10. A colorless oil; H NMR
(
600 MHz, CDCl ) d 7.50 (2H, d, J¼8.2 Hz), 7.44–7.39
3
2
8
4
MeOH); IR (CHCl ) 3640–3300 (br), 1600, 1460, 1300,
.3.4. Six-membered sulfone 7. [a] ¼þ4.18 (c 0.23,
(3H, m), 5.06 (1H, dt, J¼3.6, 11.2 Hz), 3.55 (3H, s), 3.05
(1H, dq, J¼11.2, 6.7 Hz), 2.84 (1H, m), 2.37 (1H, ddt,
J¼3.6, 12.6, 7.3 Hz), 2.06 (1H, m), 2.05 (1H, m), 1.78 (1H,
ddt, J¼3.6, 15.0, 12.6 Hz), 1.71 (1H, m), 1.65 (1H, m), 1.40
(1H, m), 1.33 (1H, m), 1.28 (1H, m), 1.25 (1H, m), 1.22 (3H,
d, J¼6.7 Hz), 1.08 (1H, m), 0.95 (3H, d, J¼6.6 Hz), 0.89
D
3
130 cm2 ; H and C NMR data, see Table 2; MS (FAB)
m/z 271 (MþNa) ; HRMS (FAB) calcd for C H NaO S
1
1
13
1
þ
1
2
24
3
þ
(
MþNa) 271.1344, found 271.1349.
þ
4
.3.5. 3,5-Dinitrobenzoate 6. To a solution of five-
membered sulfone 5 5.0 mg (20 mmol) in pyridine
1.0 mL) cooled to 08C was added 3,5-dinitrobenzoyl
(3H, t, J¼7.2 Hz); MS (FAB) m/z 465 (MþH) ; HRMS
þ
(FAB) calcd for C H F O S (MþH) 465.1923, found
2
2 32 3 5
(
465.1945.

M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
6411
4.4. Reactions of n-propylthiosulfonic acid potassium
salt (11) with cyclohexene
sulfonate 13 as described above (see Section 4.3.6) (71%) as
2
1
a colorless oil: IR (CHCl ) 1730, 1360, 1340, 1160 cm
3
;
1
H NMR (800 MHz, CDCl ) d 4.83 (1H, ddd, J¼4.8, 8.9,
3
4
7
.4.1. Under air (Table 3, entry 1). To a solution of 11
.8 mg (44 mmol) in CHCl –MeOH (1:1, v/v, 0.3 mL)
10.3 Hz), 4.58 (1H, ddd, J¼5.1, 8.9, 11.0 Hz), 3.06 (2H, dt,
J¼9.1, 6.6 Hz), 2.22 (1H, m), 2.08 (3H, s), 1.88 (2H, tq,
J¼6.6, 7.6 Hz), 1.77 (1H, m), 1.72 (1H, m), 1.62 (1H, m),
1.39 (1H, m), 1.36–1.31 (2H, m), 1.06 (3H, t, J¼7.6 Hz);
3
cyclohexene (0.3 mL, 3.0 mmol) was added under air, and
the mixture was stirred at room temperature for 24.5 h. The
reaction mixture was concentrated, and the residual oil was
separated by column chromatography on silica gel (0.5 g,
EtOAc!MeOH). The eluates of MeOH were purified by
column chromatography on silica gel (0.5 g, acetone!
MeOH) to give sulfonic acid potassium salt 18 (3.8 mg,
1
3
C NMR (201 MHz) d 170.8 (CH CO –); MS (FAB) m/z
3
2
þ
265 (MþH) ; HRMS (FAB) calcd for C H O S
1
1 21 5
þ
(MþH) 265.1110, found 265.1122.
4.4.6. Acetate 16. Compound 16 was synthesized from
thiosulfonate 15 as described above (see Section 4.3.6)
(56%) as a colorless oil: IR (CHCl ) 1730, 1360, 1340,
52%) as a colorless powder. The eluates of EtOAc were
purified by column chromatography on silica gel ((1) 2.0 g,
3
1160 cm2 ; H NMR (800 MHz, CDCl ) d 4.74 (1H, dt,
1 1
benzene–acetone, 50:1!30:1!20:1!10:1!0:1; (2)
3
0
.5 g, CHCl !acetone!MeOH) and by TLC on silica
J¼4.4, 9.8 Hz), 3.43 (1H, dt, J¼4.4, 9.8 Hz), 3.34 (2H,
ddd, J¼2.6, 5.8, 9.8 Hz), 2.33 (1H, m), 2.09 (3H, s), 1.96
(2H, m), 1.75 (1H, m), 1.73–1.68 (2H, m), 1.49 (1H, m),
3
gel (200£100£0.50 mm, n-hexane–EtOAc, 1:1) to give
sulfonate 13 (1.1 mg, 11%) and thiosulfonate 15 (0.7 mg,
6
1
3
.6%) as colorless oils.
1.45–1.35 (2H, m), 1.09 (3H, t, J¼7.4 Hz); C NMR
(
201 MHz) d 170.6 (CH CO –); MS (FAB) m/z 281
3
2
þ
281.0881, found 281.0877.
þ
4.4.2. Under an oxygen atmosphere (Table 3, entry 4). To
a solution of 11 5.0 mg (28 mmol) in CHCl –MeOH (1:1,
(MþH) ; HRMS (FAB) calcd for C H O S (MþH)
1
1 21 4 2
3
v/v, 0.3 mL) cyclohexene (0.50 mL, 4.9 mmol) was added
under a nitrogen atmosphere, and oxygen gas was bubbled
into the mixture for 5 min. The mixture was stirred at room
temperature for 15 h, and then the reaction mixture was
concentrated. The residual oil was separated by column
chromatography on silica gel ((1) 0.5 g, EtOAc!MeOH;
4.5. Intramolecular cyclization of thiosulfonic acid 21
into b-hydroxysulfone 22
4.5.1. Preparation of 4-pentenethiosulfonic acid sodium
salt (21). A mixture of 4-pentenesulfonyl chloride (20)
634 mg (3.76 mmol) and sodium hydrosulfide 1.06 g
(18.9 mmol) in MeOH (8 mL) was stirred at room
temperature for 8 h. The reaction mixture was filtered on
cotton, and the residue was washed with MeOH (5 mL). The
filtrate and washings were combined and concentrated. The
residual powder was purified by column chromatography on
silica gel ((1) 50 g, EtOAc!acetone!MeOH; (2) 30 g,
acetone!MeOH) to give 4-pentenethiosulfonic acid
sodium salt (21) (613 mg, 85%) as a colorless powder:
Mp 236–2398C; IR (KBr) 3470 (br), 1640, 1170,
(
2) 0.5 g, n-hexane–EtOAc, 4:1!3:1!2:1!3:2!0:1;
3) 0.5 g, n-hexane–EtOAc, 4:1!3:1!2:1!0:1; (4)
(
0
7
0
.5 g, CHCl ) and by TLC on silica gel ((1) 70£
3
0£0.25 mm, n-hexane–EtOAc, 1:1; (2) 100£200£
.25 mm, n-hexane–EtOAc, 3:2) to give sulfonate 13
(0.40 mg, 6.4%), thiosulfonate 15 (1.1 mg, 16%), g-keto-
sulfone 17 (0.1 mg, 1.8%), and sulfonic acid potassium salt
1
8 (2.9 mg, 71%) as colorless oils.
4
1
.4.3. Sulfonate 13. IR (CHCl ) 3640–3480 (br), 1450,
3
360, 1340, 1180 cm ; H NMR (800 MHz, CDCl ) d 4.43
3
2
1 1
21
1
1075 cm ; H NMR (800 MHz, CD OD) d 5.83 (1H,
3
(
1H, ddd, J¼4.9, 8.8, 12.0 Hz), 3.60 (1H, m), 3.15 (2H, m),
ddt, J¼16.9, 10.2, 7.7 Hz), 5.06 (1H, br dd, J¼16.9,
2.3 Hz), 4.99 (1H, br dd, J¼10.2, 2.3 Hz), 3.15 (2H, t,
J¼7.7 Hz), 2.19 (2H, br tt, J¼7.4, 7.0 Hz), 2.01 (1H, tt,
2
1
1
.17 (1H, m), 2.09 (1H, m), 1.93 (2H, dq, J¼15.0, 7.7 Hz),
.76 (1H, m), 1.72 (1H, m), 1.53 (1H, ddt, J¼4.0, 11.4,
2.8 Hz), 1.35 (1H, ddt, J¼3.7, 10.8, 12.0 Hz), 1.31 (1H,
1
3
J¼7.7, 7.4 Hz); C NMR (201 MHz, CD OD) d 139.0 (d),
3
dtt, J¼12.8, 3.3, 12.8 Hz), 1.26 (1H, dtt, J¼12.0, 3.3,
115.7 (t), 66.4 (t), 33.3 (t), 25.7 (t); MS (FAB) m/z 211
(MþNa) ; HRMS (FAB) calcd for C H NaO S
1
3
þ
1
CDCl ) d 85.9 (d), 72.7 (d), 53.0 (t), 33.2 (t), 31.6 (t), 24.2
2.0 Hz), 1.08 (3H, t, J¼7.7 Hz); C NMR (201 MHz,
5
10
2 2
þ
(MþNa) 210.9839, found 210.9847.
3
(
(
(
t), 23.6 (t), 17.6 (t), 13.0 (q); MS (FAB) m/z 245
þ
MþNa) ; HRMS (FAB) calcd for C H NaO S
4.5.2. Intramolecular cyclization of compound 21.
Method A. To a solution of thiosulfonic acid sodium salt
9
18
4
þ
MþNa) 245.0824, found 245.0854.
21 9.0 mg (48 mmol) in MeOH (1 mL) aqueous hydro-
4
1
.4.4. Thiosulfonate 15. IR (CHCl ) 3640–3480 (br), 1450,
3
chloric acid (1 M, 0.1 mL) was added under an oxygen
atmosphere. The reaction mixture was stirred at room
temperature for 4 days and then concentrated. The residual
powder was purified by column chromatography on silica
320, 1130 cm2 ; H NMR (800 MHz, CDCl ) d 3.49 (1H,
1
1
3
m), 3.47 (1H, m), 3.41 (1H, ddd, J¼6.5, 9.2, 13.6 Hz), 3.25
1H, ddd, J¼4.0, 9.9, 12.6 Hz), 2.27 (1H, m), 2.14 (1H, m),
.97 (2H, m), 1.79 (1H, m), 1.76 (1H, m), 1.54 (1H, ddt,
J¼3.6, 12.6, 12.6 Hz), 1.39 (1H, m), 1.36 (1H, m), 1.31
(
1
gel (0.5 g, CHCl –MeOH, 19:1!9:1!0:1) and by TLC on
3
silica gel (200£100£0.50 mm, CHCl –MeOH, 9:1) to give
3
1
3
(
1H, dtt, J¼12.8, 3.2, 12.8 Hz), 1.08 (3H, t, J¼7.5 Hz);
C
b-hydroxysulfone 22 (1.1 mg, 15%) and sulfonic acid
sodium salt 23 (3.5 mg, 43%) as colorless powders,
respectively.
NMR (201 MHz, CDCl ) d 73.7 (d), 64.6 (t), 58.6 (d), 35.4
3
(
t), 33.3 (t), 26.2 (t), 24.2 (t), 17.8 (t), 13.0 (q); MS (FAB)
þ
m/z 261 (MþNa) ; HRMS (FAB) calcd for C H NaO S
9
18
3 2
þ
(
MþNa) 261.0595, found 261.0578.
Method B. A mixture of 21 6.1 mg (32 mmol) and
trifluoroacetic acid (1 mL) was concentrated in vacuo. The
residue was stocked at room temperature under an oxygen
4
.4.5. Acetate 14. Compound 14 was synthesized from

6412
M. Kita et al. / Tetrahedron 58 (2002) 6405–6412
atmosphere for 7 days. The reaction mixture was purified as
described above to give 22 (1.1 mg, 23%) and 23 (2.1 mg,
Muralidharan, K. R. J. Org. Chem. 1990, 55, 4595. (g) Fang,
J.-M.; Chen, M.-Y.; Cheng, M.-C.; Lee, G.-H.; Wang, Y.;
Peng, S.-M. J. Chem. Res. Synop. 1989, 272. (h) de C. Alpoim,
M. C. M.; Morris, A. D.; Motherwell, W. B.; O’Shea, D. M.
Tetrahedron Lett. 1988, 29, 4173. (i) Wolf, G. C. J. Org.
Chem. 1974, 39, 3454. (j) Caddick, S.; Hamza, D.; Wadman,
S. N. Tetrahedron Lett. 1999, 40, 7285. (k) Narasaka, N.;
Mochizuki, T.; Hayakawa, S. Chem. Lett. 1994, 1705.
(l) Mochizuki, T.; Narasaka, N.; Hayakawa, S. Bull. Chem.
Soc. Jpn 1996, 69, 2317. (m) Kamigata, N.; Udodaira, K.;
Shimizu, T. J. Chem. Soc., Perkin Trans. 1 1997, 783.
(n) Chuang, C.-P.; Wang, S.-F. Synth. Commun. 1995, 25,
3549. (o) da Silva Corr eˆ a, C. M. M.; Fleming, M. D. C. M.;
Oliveira, M. A. B. C. S.; Garrido, E. M. J. J. Chem. Soc.,
Perkin Trans. 2 1994, 1993. (p) Chuang, C.-P. Synth.
Commun. 1993, 23, 2371. (q) Guennouni, N.; Rasset-Deloge,
C.; Carboni, B.; Vaultier, M. Synlett 1992, 581. (r) Barton,
D. H. R.; Jaszberenyl, J. Cs.; Theodorakis, E. A. Tetrahedron
3
8%).
Acknowledgments
This work was supported in part by Grants-in-Aid for
Scientific Research (No. 11558079) and Scientific Research
on Priority Areas (A) (No. 12045235) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
We are indebted to Wako Pure Chemical Industries, Ltd,
and Banyu Pharmaceutical Co., Ltd, for their financial
support. We thank Professors R. Noyori and M. Kitamura
(
COE, Nagoya University) for allowing us to use the NMR
instruments. We also thank Dr T. Matsumoto (Nagoya
University) for the measurement of the fluorescent X-ray
analysis.
1
992, 48, 2613. (s) Kameyama, M.; Kamigata, N.; Kobayashi,
M. J. Org. Chem. 1987, 52, 3312. (t) Asscher, M.; Vofsi, D.
J. Chem. Soc. 1964, 4962. (u) Barluenga, J.; Rodriguez, M. A.;
Campos, P. J.; Asensio, G. J. Chem. Soc., Chem. Commun.
References
1
987, 1491. (v) Liotta, D.; Monahan, III, R. Science
Washington, DC) 1986, 231, 356. (w) Liu, L. K.; Chi, Y.;
1
. (a) Sakemi, S.; Sun, H. H. J. Org. Chem. 1991, 56, 4304.
b) Schumacher, R. W.; Davidson, B. S.; Montenegro, D. A.;
(
(
Jen, K.-Y. J. Org. Chem. 1980, 45, 406. (x) Kang, Y.-H.; Kice,
J. L. J. Org. Chem. 1984, 49, 1507. (y) Back, T. G.; Collins, S.
Tetrahedron Lett. 1980, 21, 2215.
Berman, V. S. J. Nat. Prod. 1995, 58, 613. (c) Trischman, J. A.;
Jensen, P. R.; Fenical, W. Nat. Prod. Lett. 1998, 11, 279.
. Takada, N.; Watanabe, M.; Suenaga, K.; Yamada, K.; Kita,
M.; Uemura, D. Tetrahedron Lett. 2001, 42, 6557.
2
3
9. Serra, A. C.; da Silva Corre
ˆa, C. M. M. Tetrahedron Lett.
1991, 32, 6653.
. (a) Turner, E.; Klevit, R.; Hager, L. J.; Shapiro, B. M.
Biochemistry 1987, 26, 4028. (b) Findlay, J. A.; He, Z.-Q.;
Calhoun, L. A. J. Nat. Prod. 1990, 53, 1015. (c) Finamore, E.;
Minale, L.; Riccio, R.; Rinaldo, G.; Zollo, F. J. Org. Chem.
10. Compound 17 was identified with authentic data obtained in
spectroscopic analysis, see: Keim, W.; Herwig, J.; Pelzer, G.
J. Org. Chem. 1997, 62, 422.
1
991, 56, 1146. (d) Elliott, J. K.; Ross, D. M.; Pathirana, C.;
11. (a) Bastien, G.; Surzur, J.-M. Bull. Soc. Chim. Fr. II 1979, 601.
(b) Bastien, G.; Crozet, M. P.; Flesia, E.; Surzur, J.-M. Bull.
Soc. Chim. Fr. II 1979, 606. (c) Carbi, W.; Borghi, D.;
Arlandini, E.; Sbraletta, P.; Bedeschi, A. Tetrahedron 1993,
49, 6837. (d) Ikegami, S.; Ohichi, J.; Shimizu, Y. Heterocycles
1977, 6, 387. (e) Ikegami, S.; Ohichi, J.; Shimizu, Y.
Tetrahedron Lett. 1975, 3923. (f) Ren, X.-F.; Turos, E.;
Lake, C. H.; Churchill, M. R. J. Org. Chem. 1995, 60, 6468.
(g) Ren, X.-F.; Konaklieva, M. I.; Turos, E.; Krajkowski,
L. M.; Lake, C. H.; Janik, T. S.; Churchill, M. R. J. Org. Chem.
1995, 60, 6484. (h) Morita, H.; Oae, S. Heterocycles 1976, 5,
29.
Miao, S.; Andersen, R. J.; Singer, P. P.; Kokke, W. C. M. C.;
Ayer, W. A. Biol. Bull. 1989, 176, 73. (e) Burgoyne, D. L.;
Miao, S.; Pathirana, C.; Andersen, R. J.; Ayer, W. A.; Singer,
P. P.; Kokke, W. C. M. C.; Ross, D. M. Can. J. Chem. 1991,
6
9, 20. (f) De Riccardis, F.; Minale, L.; Riccio, R.; Iorizzi, M.;
Debitus, C.; Duhet, D.; Monniot, C. Tetrahedron Lett. 1993,
4, 4381.
3
4
5
6
7
. Temara, A.; De Ridder, C.; Kuenen, J. G.; Robertson, L. A.
Mar. Biol. 1993, 115, 179.
. Bringmon, R. L.; De Ridder, C. Appl. Environ. Microbiol.
1998, 64, 3491.
. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
12. (a) Johnson, M. D.; Derenne, S. J. Organomet. Chem. 1985,
286, C47. (b) Culshaw, P. N.; Walton, J. C. J. Chem. Soc.,
Perkin Trans. 2 1991, 1201. (c) Phillips, E. D.; Whitham, G. H.
Tetrahedron Lett. 1993, 34, 2537.
. Bertrand, M. P.; Ferreri, C. Radicals in Organic Synthesis,
Renaud, P., Sibi, M. P., Eds.; Wiley: Weinheim, 2001; Vol. 2,
pp 485–504.
13. King, J. F.; Harding, D. R. K. J. Am. Chem. Soc. 1976, 98,
3312.
8
. For intermolecular additions of RSO X to carbon–carbon
2
multiple bonds see: (a) Barton, D. H. R.; Csiba, M. A.;
Jaszberenyi, J. Cs. Tetrahedron Lett. 1994, 35, 2869. (b) Craig,
D. C.; Edwards, G. L.; Muldoon, C. A. Synlett 1997, 1318.
14. b-Hydroxysulfone 22 was identified with authentic data
obtained in spectroscopic analysis. See: Brunet, E.; Eliel,
E. L.; Kenan, Jr W. R. J. Org. Chem. 1986, 51, 677.
15. Sulfonic acid sodium salt 23 was identified with authentic data
obtained in spectroscopic analysis. See: Ref. 12.
(
c) Bull, J. R.; Desmond-Smith, N. S.; Heggie, S. J.; Hunter,
R.; Tien, F.-C. Synlett 1998, 900. (d) Yoshimatsu, M.;
Hayashi, M.; Tanabe, G.; Muraoka, O. Tetrahedron Lett.
16. Studies with thiosulfonic acids containing cis-disubstituted
alkenes are currently underway to get insight into the
stereoselectivities in the cyclization.
1996, 37, 4161. (e) Back, T. G.; Collins, S.; Kerr, R. G. J. Org.
Chem. 1983, 48, 3077. (f) Back, T. G.; Lai, E. K. Y.;