Synthesis of novel axially chiral cyclic benzopolysulfides

Article abstract of DOI:10.1016/j.tetlet.2007.05.117

Novel axially chiral benzopentathiepins were synthesized by sulfurization of dithiastannole. Naphthyl moiety was introduced near the pentathiepin ring by Suzuki-Miyaura cross-coupling reaction. Pentathiepins were found as diastereomeric mixture. Rotationa

Full text of DOI:10.1016/j.tetlet.2007.05.117

Tetrahedron Letters 48 (2007) 4991–4994
Synthesis of novel axially chiral cyclic benzopolysulfides
Ryu Sato,* Hidetoshi Ohta, Tatsuya Yamamoto, Shiduko Nakajo, Satoshi Ogawa
and Ashraful Alam
Department of Chemical Engineering, Faculty of Engineering, Iwate University, Morioka 020-8551, Japan
Received 9 May 2007; accepted 21 May 2007
Available online 24 May 2007
Abstract—Novel axially chiral benzopentathiepins were synthesized by sulfurization of dithiastannole. Naphthyl moiety was intro-
duced near the pentathiepin ring by Suzuki–Miyaura cross-coupling reaction. Pentathiepins were found as diastereomeric mixture.
Rotational energy barrier for C–C bond was estimated by theoretical calculation. Energy barrier for the inversion of pentathiepin
1
ring was experimentally determined by variable temperature H NMR.
ꢀ 2007 Published by Elsevier Ltd.
OMe
Axial chirality represents interesting stereochemical fea-
tures for modern synthetic chemistry. Axially chiral
molecules are widely found in nature and exhibit a
broad range of biological activities1 and therefore a
great deal of effort has been continuously devoted to
their synthesis.2
OMe
S
MeO
S
S
HO
S
S
S
S
S
S
S
NHR
NHR
1; R= H
3; R = H
O
O
There are many reports concerning the synthesis3 and
characterization4 of cyclic polysulfides fused to aromat-
ics, but only a few numbers of chiral benzopolysulfides
have appeared in the literature. Davidson et al. in
1991, discovered varacin (1) (Fig. 1), which showed
potential antifungal and cytotoxic activities.5 They also
2; R =
Si(CH3)3
4; R = COCF3
OMe
SMe
OMe
MeO
MeO
S
S
S
SMe
NH2
6
1
disclosed that the H NMR signals assigned to the side
chain methylene proton are unexpectedly complex,
attributing this to restricted rotation of the side chain
in 1 or 2.6 A high barrier to interconversion of the chair
conformation of the pentathiepin ring induces asymme-
try into the molecule, causing these protons to become
diasterotopic. At the same time, Searle et al. also ob-
served chirality for lissoclinotoxin A derivatives 3 and
4.7 They also quoted an interesting conclusion that
asymmetric pentathiepins are chiral at least on NMR
time scale as some compounds were racemized during
isolation. The origin of ‘the chirality for pentathiepin
and its derivatives are best explained by slow inversion
of the pentathiepin ring due to the exceptionally high
NH2
5
Figure 1.
barrier (24.0–29.0 kcal molÀ1) to ring inversion.8,9 An
interesting feature is that chirality is not yet observed
for its trithiole (5) and open ring derivatives (6). Since
then chiral benzopolysulfides have received considerable
attention in the light of structural diversity10 and biolog-
ical activities.11 Several chiral benzopentathiepins were
found to show biological activity,6,7 and we thus
appended our attention to develop benzopenathiepin
having a chiral auxiliary near the polysulfide ring.
Keywords: Axial chirality; Diastereomer; Naphthalene; Pentathiepin;
Ring inversion.
Axial chirality is often associated with the stereoisomers
resulting from the hindered rotation about the single
bond, where the barrier to rotation is high enough to
*
Corresponding author. Tel.: +81 19 621 6327; fax: +81 19 621
6326; e-mail: rsato@iwate-u.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.117

4992
R. Sato et al. / Tetrahedron Letters 48 (2007) 4991–4994
allow for the isolation of the conformers. The conditions
for the existence of stereoisomerisms have been defined
as one where stereoisomers can be isolated and have a
half life of at least 1000 s.12 The most extensively studied
class of atropisomers is BINAP derivatives due to their
high barrier to rotation. Derivatizations of benzopenta-
thiepin with some chiral auxiliary would be expected to
provide diastereomeric products, which might be
separable as an optically pure isomer. Thus, the
naphthalene moiety was selectively attempted to incor-
porate at the neighbourhood of the polysulfide ring as
a Caryl–Cnaphthyl functionality to give a chiral axis.
the bulk of the reaction at neutral condition with di-
methyl tin(1V)dichloride, and expectedly 4-(1-naph-
thyl)-2,2-dimethyl-1,3,2-benzodithiastannole (12) was
isolated in 53% yield. Spectroscopic data anticipated
well for structural elucidation of 12.15
Initial attempts to get chiral benzotrithioles are pre-
sented in Scheme 2. Stannole 12 was treated with SOCl2
in dry THF to afford 4-(1-naphthyl)-1,2,3-benzotrithiole
2-oxide (13) quantitatively, according to Path A. In the
IR spectra, strong sulfinyl group stretching vibration
was observed at 1104 cmÀ1. The subsequent reduction
of 13 with TMSOTf/SmI2 in THF at À78 ꢁC yielded
4-(1-naphthyl)-1,2,3-benzotrithiole (14) in 26% yield as
a single isomer. According to Path B, treatment of 12
with 1.0 equiv of SCl2 gave 14 in 43% yield. Although
compound 14 was isolated as a single product, its 2-
oxide (13) was a diastereomeric mixture, as evident from
Herein, we report the novel synthesis of axially chiral
cyclic benzopolysulfides. The synthesis was achieved
by sulfurization followed by the Suzuki–Miyaura
cross-coupling reaction as an important step. The
barriers to rotation about the Caryl–Cnaphyl bond were
estimated by theoretical calculations.
1
the H NMR spectra. Spatial arrangements of sulfinyl
oxygen around the trithiole ring and its slow inversion
make the molecule into diastereomer.
The synthetic procedure is presented in Scheme 1. The
reaction of 1,2-benzenedithiol (7) with 2-iodopropane
afforded 1,2-bis(isopropylthio)benzene (8) in 79%
yield.13 Lithiation of 8 with n-BuLi/TMEDA in hexane
and successive iodination with I2/Et2O gave 1-iodo-2,3-
bis(isopropylthio)benzene (9) in 66% yield, a suitable
element for the Suzuki–Miyaura cross-coupling reaction
having C–S bonds with an aromatic ring. Asymmetric
C–C coupling reaction was performed between 9 and
1-napthaleneboronic acid in DMF/H2O in the presence
of Cs2CO3 as base and Pd(PPh3)4 as catalyst.14 1-[2,3-
Bis(isopropylthio)phenyl]naphthalene (10) was isolated
Asymmetric benzopentathiepin is a diastereomer for its
two conformational states of the polysulfide ring,9 while
the corresponding benzotrithiole exists as a single
isomer. The five-membered trithiole ring has one confor-
S
S
O
Path A
quant.
S
12
1
13
in excellent yields. In the H NMR spectra, compound
10 gave two AB-type doublets at d 1.44 and 1.46 ppm
for methyl protons of one isopropyl group, which is
located adjacent to the naphthalene moiety. Restricted
rotation of the methyl group in the isopropyl moiety
near naphthalene made the protons to be magnetically
nonequivalent. On the contrary, the outer isopropyl
group gave only a sharp doublet for all six methyl
protons due to their free rotation. Treatment of 10 with
Na/NH3 did not, however, remove isopropyl groups to
afford stable dithiols after subsequent acidification with
concd HCl. Therefore, thiol groups were protected in
Path B 43%
26%
S
S
S
14
Scheme 2. Reagents and conditions: Path A (i) SOCl2/THF, rt, 0.5 h,
(ii) TMSOTf/THF, SmI2, À78 ꢁC, 15 m; (Path B) (i) SCl2 (1.0 equiv),
THF, À78 ꢁC, 15 m.
SPri
SPri
SPri
SH
a
b
SPri
SH
I
7
8 (79%)
9 (66%)
B(OH)2
SPri
SPri
SH
SH
S
S
Me
Sn
Me
d
e
c
10 (95%)
11
12 (53%)
Scheme 1. Reagents and conditions: (a) 2-iodopropane, benzene/NaOH aq., TOMAC, rt, 12 h; (b) n-BuLi/TMEDA, hexane, I2/Et2O; (c) 2 mol%
Pd(PPh3)4, CsCO3 (1 equiv), DMF/H2O, 120 ꢁC, 6 h; (d) (i) Na (excess)/pyridine, reflux, 2 h, (ii) NaBH4/THF–EtOH, (iii) H3O+; (e) Me2SnCl2.

R. Sato et al. / Tetrahedron Letters 48 (2007) 4991–4994
4993
Table 1. Calculated biaryl rotational energy barriers for 1-phenyl-
naphthalene, 14 and 15 (energy difference between the most stable
conformer and the transition state of the aryl–aryl rotation)
S
S
S
S
S
S
S
S
S
S
Compound
Relative energy/kcal molÀ1
a
12
B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d)
1-Phenylnaphthalene 11.75
15a(rac)
15b(rac)
14
15
18.97
25.49
15 (53%)
Diastereomeric ratio = 55 : 45
Scheme 3. Reagents and conditions: (a) S2Cl2 (1.5 equiv)/BF3ÆOEt2,
CH2Cl2, rt, 1 h.
the separated fraction (Fig. 2a) was back to the original
mixture (Fig. 2b) again. In solution, diastereomer (15a
or 15b) cannot exist in the pure state for a slow revers-
ible inversion of the pentathiepin ring. In order to verify
the inversion energy of the pentathiepin ring of 15, its
mational state.16 The appearance of complex multiplets
of 13 in the 1H NMR spectra also implied that it existed
as a diastereomeric mixture at least on the NMR time
scale. Pentathiepin having axial chirality was our main
goal. Therefore, compound 12 was treated with
1.5 equiv of S2Cl2 in CH2Cl2 in the presence of BF3ÆOEt2
to give 15 in an overall 53% yield (Scheme 3).
1
isomerization was monitored by H NMR spectroscopy
at 303 K, 308 K, 313 K and 318 K. The value of 298DG#
was about 24.28 kcal/mol, suggesting that the inversion
of the pentathiepin ring proceeds at room temperature.
Therefore, the chromatographic separation period is
not sufficient for isolation of the individual diastereomer.
Diastereomeric peaks were clearly observed for com-
pound 15 by 1H NMR. One doublet at d 7.15 ppm
and another double doublet at d 7.23 ppm appeared in
a 45:55 isomeric ratio by indicating two distinct prod-
ucts. Partial recrystallization had failed to separate the
isomers. Thus, the mixture was attempted to be ana-
lyzed by gel permeation liquid chromatography (GPLC)
for further resolution of diastereomers. Two isomers
were almost separated after 24 h and the separated frac-
Restricted rotation of the chiral axis and conformation
of pentathiepin rings made each optically pure diaste-
reomer (15a or 15b) into an enantiomer. Compound
13 was also a diastereomer while compound 14 was race-
1
mic. H and 13C NMR spectra were, however, not per-
fectly assigned for these compounds because of their
incomplete resolution. Optically pure benzopentathiepin
is yet to be resolved by any author and all previous
assignments were also on the basis of NMR signals after
partial separation.6,7
1
tion was studied using H NMR spectrum (Fig. 2). The
sharp doublet at d 7.23 ppm (marked by a circle) had
almost disappeared after a long recycling of the mixture
in the column while the remaining doublet had more
clearly appeared.
Two reasons are notable concerning generation of
diastereomerism for 15: (a) The energy barrier for the
inversion of the pentathiepin ring from their low energy
chair conformation to boat conformation and the NMR
time scale is adequate to recognize them.9,12 (b) A
sufficiently high rotational energy barrier of the
Caryl–Cnaphthyl bond enables one to resolve them into
diastereomers. Calculated rotation energy barriers are
provided in Table 1. For compound 15, the value was
found to be ca. 25.49 kcal molÀ1 and it was high enough
to generate corresponding diastereomers. The naphthyl
moiety acted like an asymmetric chiral center for
benzopentathiepin.
The separated individual fraction from each chromato-
gram was collected but the product was a mixture rather
than a pure diastereomer. Partial recrystallization of the
isolated fraction at <À20 ꢁC also did not afford a single
product. Furthermore, in due course, the minor dia-
stereomer was seen more in the solution. After two days
In conclusion, we were successful in synthesis, character-
ization and partial separation of novel axially chiral
benzopentathiepins. Diastereomers were detected by
1
the analysis of H NMR spectra, and polysulfides ring
sizes were assigned by mass fragments, GPLC retention
time and elemental analysis. Syntheses of axially chiral
benzopentathiepins having a higher rotational energy
barrier are underway.
Supplementary data
Figure 2. Partial 1H NMR (400 MHz) spectra of (a) single diastereo-
mer of 15 and (b) diastereomeric mixture of 15. Both spectra were
recorded in CDCl3 at 25 ꢁC.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.05.117.

4994
R. Sato et al. / Tetrahedron Letters 48 (2007) 4991–4994
(b) Golik, J.; Dubey, G.; Groenewold, G.; Kawaguchi, H.;
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(d, 6H, J = 6.7 Hz, CH3), 1.44 (d, 3H, J = 4.6 Hz, CH3),
1.46 (d, 3H, J = 4.6 Hz, CH3), 3.05 (sept, 1H, J = 6.7 Hz,
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7.84–7.88 (m, 2H, ArH); 13C NMR (101 MHz, CDCl3) d
22.7, 22.8, 23.0, 35.9, 38.9, 124.8, 125.5,125.5, 125.8, 126.2,
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352 (M+). Anal. Calcd for C22H24S2: C, 74.95; H, 6.86.
Found: C, 74.94; H, 6.9.
4-(1-Naphthyl)-2,2-dimethyl-1,3,2-benzodithiastannole (12):
colourless solid; mp 219–221 ꢁC (decomp.); 1H NMR
(400 MHz, CDCl3) d 0.87 (s, 6H, CH3), 6.89–6.91 (m, 1H,
ArH), 6.99–7.03 (m, 1H, ArH), 7.36–7.42 (m, 2H, ArH),
7.44–7.48 (m, 1H, ArH), 7.50–7.58 (m, 3H, ArH), 7.86–
7.89 (m, 2H, ArH); 13C NMR (101 MHz, CDCl3) d 2.04,
123.9, 125.4, 125.7, 125.9, 126.3, 126.7, 127.0, 127.9, 128.2,
129.3, 131.6, 133.7, 139.0, 139.1, 141.1, 141.7; IR (KBr)
3048, 1383, 779 cmÀ1; MS (70 eV) m/z 416 (M+). Anal.
Calcd for C18H16S2Sn: C, 52.07; H, 3.88. Found: C, 52.38;
H, 4.00.
4-(1-Naphthyl)-1,2,3-benzotrithiole (14): orange needles;
mp 107–109 ꢁC (decomp.); 1H NMR (400 MHz, CDCl3) d
7.10–7.12 (m, 1H, ArH), 7.16–7.20 (m, 1H, ArH), 7.35–
7.37 (m, 1H, ArH), 7.45–7.54 (m, 4H, ArH), 7.60–7.63 (m,
1H, ArH), 7.90–7.93 (m, 2H, ArH); 13C NMR (101 MHz,
CDCl3) d 122.7, 125.2, 125.6, 126.2, 126.5, 126.6, 128.4,
128.9, 129.3, 129.3, 130.6, 133.6, 137.3, 138.8, 141.0, 142.7;
IR (KBr) 3043, 1387, 777 cmÀ1; UV (n-C6H14) kmax 222 (e
5.7 · 104), 284 (e 1.1 · 104) nm; MS (70 eV) m/z 298 (M+);
Anal. Calcd for C16H10S3: C, 64.39; H, 3.38. Found: C,
64.41; H, 3.65.
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