Synthesis of redox active large macrocyclic hosts and the recognition of secondary ammonium salts

Article abstract of DOI:10.1016/S0040-4020(02)01532-6

Interconvertible macrocyclic hosts containing thiol groups or a disulfide linkage in the binding cavity have been synthesized. The binding affinities of the reduced and oxidized forms toward benzylammoium derivatives are completely reverse. Formation of pseudorotaxane is suggested upon the host-guest complexation.

Full text of DOI:10.1016/S0040-4020(02)01532-6

Tetrahedron 59 (2003) 639–647
Synthesis of redox active large macrocyclic hosts
and the recognition of secondary ammonium salts
*
Tatsuya Nabeshima, Daisuke Nishida and Toshiyuki Saiki
Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
Received 5 November 2002; revised 26 November 2002; accepted 28 November 2002
Abstract—Interconvertible macrocyclic hosts containing thiol groups or a disulfide linkage in the binding cavity have been synthesized.
The binding affinities of the reduced and oxidized forms toward benzylammoium derivatives are completely reverse. Formation of
pseudorotaxane is suggested upon the host–guest complexation. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Scheme 1. Reaction of tosylates 2a and 2b with excess
catechol in the presence of K2CO3 gave 3a and 3b in 77 and
90% yield, respectively. 3a and 3b thus obtained were
treated with 4a and 4b in CH3CN to afford polyethers 5a and
5b. Removal of the benzyl group from 5a and 5b produced
the corresponding alcohols 6a and 6b. The compounds 6a
and 6b were also prepared from diols 7a and 7b by using
3,4-dihydro-2H-pyran. The protection of the hydroxy group
is necessary because the 1:1 cyclization product instead of
the desired 2:2 macrocycle was obtained from 7a and 8
(Scheme 2). Alcohols 6a and 6b reacted with 8 in dry THF
using NaH as a base to afford 9a and 9b in 88 and 89% yield.
Deprotection of 9a and 9b proceeded under acidic
conditions to give diols 10a and 10b. Reaction of 10a and
10b with 8 under high dilution conditions afforded cyclic
dibromides 11a and 11b in 50%. Lithiation of 11a and 11b
Recently, large macrocyclic compounds have been utilized
to synthesize topologically interesting molecules such as
catenanes and rotaxanes.1 Application of these compounds
to molecular machines and devices has also attracted much
attention.2 In general, a host bearing a large binding cavity
shows much lower affinity toward small guests such as a
metal ion than small hosts like 18-crown-6.3 If an external
stimulus conducts interconversion between a large host and
a small one, the host-binding ability would be regulated
coincidentally. Redox reactions between thiol and disulfide
are very useful to control molecular structures and functions
simultaneously.4 In the artificial recognition systems, all-or-
none regulation of Agþ binding is carried out by the redox
reactions.4e Formation of the disulfide bond closes the
binding site to diminish the binding affinity to metal ions,
whereas the thiol form as an open state provides a very
selective site for Agþ. This strategy can be extended to the
size regulation of a binding site of hosts, because
intramolecular disulfide formation would divide the large
cavity into the two corresponding half-sized cavities which
bind a small ion. Preliminary study on regulation of
paraquat recognition by these redox active hosts has been
reported.4g Herein we report the synthesis of the macro-
cyclic hosts 1 in detail and regulation of their unique
binding behaviour toward secondary ammonium salts by the
redox reactions.
followed by addition of S8 gave dithiol hosts 1ared and 1b
in 70 and 50% yield, respectively.
red
Interconversion between dithiol hosts (1a and 1b ) and
red
red
disulfide hosts (1aox and 1box) was successfully performed.
Oxidation of 1a and 1b with H2O2 produced 1aox and
red
red
1box in 96 and 91%, respectively. 1aox and 1box were
reverted to 1a (86%) and 1b (83%) by the reduction
with NaBH4 (Scheme 3).
red
red
The structures of 1a and 1b were identified by 1H NMR, 13
C
NMR, IR, MS spectroscopies and/or elemental analysis.
Furthermore, X-ray crystallographic analysis reveals that
1aox has two independent cavities separated by the disulfide
bond.5
2. Results and discussion
Ion recognition ability of 1 to secondary ammonium ion
1
12–14 (Fig. 1) was examined by H NMR spectroscopy.
The synthesis of crown ethers 1a and 1b is shown in
red red
Addition of 1box (1 equiv.) to 12 caused downfield shift
(Dd¼0.09 ppm) of the benzyl protons of 12 in CDCl3/
CD3CN (10:1, Fig. 2).6 However, the corresponding
Keywords: redox reactions; crown ethers; thiol; disufide.
*
Corresponding author. Tel.: þ81-298-53-4507; fax: þ81-298-53-6503;
e-mail: nabesima@chem.tsukuba.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01532-6

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T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
Scheme 1. Synthesis of 1ared and 1b
.
red
Scheme 2. Cyclization reaction of 8 and 7a.
Scheme 3. Interconversion between the reduced and oxidized forms of 1 by the redox reactions.

T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
641
Figure 1. Structure of guests 12–14.
Figure 2. 1H NMR spectral changes of 12 by the addition of 1 or benzo-18-crown-6 (300 MHz, CDCl3/CD3CN¼10:1, [12]¼2.0£1023 M).
reduced form 1b resulted in much smaller effect on the
red
Table 1. Association constants of hosts 1 with ammonium salts 12–14
signal of the benzyl protons. In contrast, 1ared gave rise to an
upfield shift of the protons. Very small upfield shifts of Ha
were performed by 1aox. 18-Crown-6 shows practically no
affinity to 12. 1H NMR titration provided the binding
constants (K1) for the 1:1 complexation between 1 and the
guests (12–14) by using non-linear-least-squares regression
(Table 1). 1box shows the largest K1 values for 12 and 13
among the hosts 1. Interestingly, the 1:2 complexation
between 1box and 12 (or 13) is suggested, although K2
for the second binding step is significantly smaller than K1.
On the other hand, 1bred has a much lower affinity to 12 and
13 probably because the cavity is too large and flexible
Host
K1 (M21 a
)
12b
13c
14c
1a
red
1aox
1b
red
1box
250^30
d
140^10
d
260^30
d
–
170^30
–
130^10
–
160^20
d
850^250 (K2¼75^25)
675^125 (K2¼125^55)
–
a
K1¼[Host·Guest]/[Host][Guest], K2¼[Host·Guest2]/[Host·Guest][Guest],
determined by 1H NMR spectroscopy (CDCl3/CD3CN¼10:1).
[12]¼2.0£1023 M.
b
c
d
[Host]¼2.0£1023 M.
for effective host–guest interactions. 1a and 1aox exhibit
red
Not determined due to very small change in chemical shifts.

642
T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
1
Figure 3. H NMR spectral changes of ammonium salts 13, 14 by the addition of 1box.
lower or no affinity to the guests. From the CPK model
inspection and the X-ray analysis, the two cavities of 1aox
are too small to bind 12. Similarly to 1b , 1ared provides a
red
however, passes through the cavity because 13 consists of
benzyl and 3,5-di-t-Bu-phenylmethyl moieties. These
results strongly suggest that 1box binds 13 to give the
corresponding pseudorotaxane.
large binding cavity for the guests. ESI-MS confirms the 1:1
complexation between 1box and 12, although the peaks
1
assigned to the 1:2 complex were not observed. The H
NMR study points out that 1a , 1bred and 1box bind 13 with
Solid–liquid extraction experiment clearly indicated the
affinity of the hosts 1aox, 1box, 1bred to 12 (Fig. 5). 1H NMR
spectroscopy shows the guest 12 is sparingly soluble in
CDCl3. In the presence of the hosts, however, the amount of
12 extracted into the CDCl3 phase is remarkably enhanced.
As the binding constant suggested, the hosts solubilize 12
efficiently into the CDCl3 layer due to the formation of the
host–guest complex.
red
the K1 values similar to those for 12, but that only 1ared and
1bred bind 14 in a similar fashion. In contrast, 1aox and 1box
causes no chemical shift change of the benzyl protons in 14
(Fig. 3). The lack of affinity of 1aox and 1box to 14 suggests
that the complexation between 1box and 12 makes
pseudorotaxane. The CPK model examination indicates
that the bulky t-Bu groups of 14 prevents the penetration of
14 into the cavities of 1aox and 1box (Fig. 4). The cavities of
the reduced forms 1ared and 1bred are large enough to bind 14
without the steric hindrance. Thus, the K1 values for 14 are
nearly the same as those for 12 and 13. The guest 13,
3. Conclusion
In summary, recognition of the secondary ammonium

T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
643
Figure 4. Plausible complexation mode.
guests is finely controlled by using the redox active hosts 1.
1a binds the guests more strongly than 1aox, while 1box
exhibits much higher affinity to 12 and 13 than 1b . These
red
binding sites is very useful to control molecular recognition
ability. Thus, we believe that this strategy can be applied to
construction of molecular machines and devices such as a
molecular shuttle and a motor by an external stimulus.
red
results clearly indicate that regulation of the size of the
Figure 5. Solid-liquid extraction of 12 by (a) 1aox, (b) 1box, (c) 1bred (300 MHz, CDCl3, [Host]¼2.0 mM).

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T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
4. Experimental
4H), 4.64–4.61 (m, 1H), 4.58 (s, 2H), 4.20–4.15 (m, 4H),
3.90–3.83 (m, 6H), 3.78–3.72 (m, 4H), 3.66–3.59 (m, 3H),
3.51–3.47 (m, 1H), 1.85–1.48 (m, 6H). 13C NMR
(100 MHz, CDCl3): d (ppm) 149.0 (s), 138.2 (s), 128.3
(d), 127.7 (d), 127.5 (d), 121.6 (d), 114.9 (d), 98.9 (d), 73.2
(t), 70.8 (t), 70.7 (t), 69.8 (t), 69.7 (t), 69.4 (t), 68.9 (t), 66.7
(t), 62.1 (t), 30.5 (t), 25.4 (t), 19.4 (t). Anal. calcd for
C26H36O7·0.25H2O: C, 67.15; H, 7.91. Found: C, 67.14; H,
7.84.
4.1. General methods
All chemical reagents were purchased and used without
further purification. THF was distilled from benzophenone
ketyl under nitrogen atmosphere prior to use. Tosylates 2a7
and 2b,8 phenol 3a,7 tosylates 4a9 and 4b,10 diols 7a11 and
7b,4b and tribromide 812 were prepared by previously
1
described methods. H NMR spectra were recorded on a
Bruker ARX400 at 400 MHz or a Bruker AC300 at
300 MHz. 13C NMR spectra were recorded on a Bruker
ARX400 at 100 MHz. Coupling constants (J) were
reported in Hz. NMR chemical shifts were reported in
ppm downfield from a tetramethylsilane peak. NMR
solvents were purchased and used without further purifi-
cation. IR spectra were recorded on a JASCO FT/IR-5000
spectrometer using KBr pellets or NaCl plates, and only
partial data are reported. Melting points were determined
on a Yanaco melting point apparatus, and not corrected.
ESI-MS spectra were recorded with a Perkin-Elmer
Sciex API-100 spectrometer. Elemental analyses were
performed at Chemical Analysis Center, University of
Tsukuba.
4.2.3. Synthesis of 5b. To a solution of 3b (18.65 g,
56.1 mmol) in CH3CN (300 ml) were added K2CO3
(9.405 g, 68.0 mmol) and a solution of 4b (21.75 g,
56.1 mmol) in CH3CN (50 ml), and the mixture was
refluxed for 14 h. After removal of the solvent, H2O
(150 ml) was added to the residue. The mixture was
extracted with CHCl3 (3£150 ml), and the organic phase
was dried over anhydrous MgSO4. The solvent was
removed under reduced pressure, and the crude product
was purified by column chromatography (SiO2, CH2Cl2/
EtOAc¼10:1) to afford 5b as a yellow oil (11.36 g,
1
34.2 mmol, 90%). H NMR (300 MHz, CDCl3): d (ppm)
7.34–7.27 (m, 5H), 6.94–6.90 (m, 4H), 4.64–4.61 (m, 1H),
4.56 (s, 2H), 4.16 (t, 4H, J¼5.1 Hz), 3.89–3.83 (m, 6H),
3.76–3.59 (m, 15H), 3.53–3.47 (m, 1H), 1.88–1.48
(m, 6H). 13C NMR (100 MHz, CDCl3): d (ppm) 149.0
(s), 138.2 (s), 128.3 (d), 127.7 (d), 127.6 (d), 121.6 (d),
114.9 (d), 98.9 (d), 73.2 (t), 70.8 (t), 70.71 (t), 70.66 (t), 70.6
(t), 69.8 (t), 69.4 (t), 68.8 (t), 66.6 (t), 62.2 (t), 30.6 (t), 25.4
(t), 19.5 (t). Anal. calcd for C30H44O9·0.25H2O: C, 65.14; H,
8.11. Found: C, 65.14; H, 8.07.
4.2. Preparation of crown ethers 1a and 1b
4.2.1. Synthesis of 3b. A solution of 2b (15.00 g,
38.0 mmol) in CH3CN (50 ml) was added dropwise to a
refluxing mixture of catechol (20.95 g, 0.190 mol) and
K2CO3 (6.85 g, 49.6 mmol) in CH3CN (300 ml) over
30 min. After the mixture was refluxed for 14 h, the solvent
was evaporated and then the residue was poured into H2O
(150 ml) and CHCl3 (150 ml). The mixture was acidified
(pH 3) with 3 M hydrochloric acid, and the aqueous phase
was extracted with CHCl3 (2£150 ml). The organic layers
were combined, dried over anhydrous MgSO4, and concen-
trated in vacuo. After removal of excess catechol by
sublimation at ca. 1308C in vacuo, the crude product was
purified by column chromatography (SiO2, CHCl3/EtOAc¼
10:1) to afford 3b as a yellow oil (11.36 g, 34.2 mmol,
90%). 1H NMR (300 MHz, CDCl3): d (ppm) 7.34–7.27 (m,
5H), 7.03 (brs, 1H), 6.92–6.85 (m, 3H), 6.81–6.77 (m, 1H),
4.57 (s, 2H), 4.15 (t, 2H, J¼4.4 Hz), 3.83 (t, 2H, J¼4.4 Hz),
3.74–3.63 (m, 8H). 13C NMR (100 MHz, CDCl3): d (ppm)
147.4 (s), 146.1 (s), 137.9 (s), 128.4 (d), 127.9 (d), 127.7 (d),
122.6 (d), 119.7 (d), 115.9 (d), 114.4 (d), 73.2 (t), 70.50 (t),
70.48 (t), 70.4 (t), 69.5 (t), 69.3 (t), 69.1 (t). Anal. calcd for
C19H24O5·0.33H2O: C, 67.44; H, 7.35. Found: C, 67.38; H,
7.49.
4.2.4. Synthesis of 6a. To a solution of 5a (16.02 g,
34.8 mmol) in THF (100 ml) was added 10% Pd-C
(1.648 g), and the mixture was stirred under H2 atmosphere
(1 atm) for 60 h. The catalyst was removed by filtration, and
the solvent was evaporated. The residue thus obtained was
purified by column chromatography (SiO2, EtOAc) to afford
6a as a pale yellow oil (10.67 g, 28.5 mmol, 83%). 1H NMR
(300 MHz, CDCl3): d (ppm) 6.90–6.87 (m, 4H), 4.62–4.60
(m, 1H), 4.16–4.12 (m, 4H), 3.89–3.44 (m, 14H), 1.9–1.4
(m, 6H). 13C NMR (100 MHz, CDCl3): d (ppm) 148.9 (s),
148.7 (s), 121.7 (d), 121.5 (d), 114.6 (d), 114.4 (d), 98.9 (d),
72.7 (t), 70.7 (t), 69.7 (t), 69.5 (t), 68.9 (t), 68.6 (t) 66.7 (t),
62.1 (t), 61.6 (t), 30.5 (t), 25.4 (t), 19.4 (t). Anal. calcd for
C19H30O7·0.4H2O: C, 60.43; H, 8.22. Found: C, 60.53; H,
8.32.
4.2.5. Synthesis of 6b. To a solution of 5b (22.48 g,
38.4 mmol) in THF (120 ml) was added 10% Pd-C
(1.011 g), and the mixture was stirred under H2 atmosphere
(1 atom) for 72 h. The catalyst was removed by filtration
and the solvent was evaporated to give 6b as a pale yellow
oil (17.73 g, 38.7 mmol, 100%), which was used in the
4.2.2. Synthesis of 5a. To a solution of 3a (9.930 g,
34.4 mmol) in CH3CN (150 ml) were added K2CO3 (5.22 g,
37.8 mmol) and a solution of 4a (12.05 g, 35.0 mmol) in
CH3CN (50 ml), and then the resulting mixture was refluxed
for 12 h. After removal of the solvent, H2O (150 ml) was
added to the residue. The mixture was extracted with
CHCl3 (3£150 ml), and the organic phase was dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure, and the crude product was purified by column
chromatography (SiO2, CH2Cl2/EtOAc¼10:1) to afford 5a
as a yellow oil (13.11 g, 28.5 mmol, 83%). 1H NMR
(300 MHz, CDCl3): d (ppm) 7.4–7.3 (m, 5H), 7.0–6.8 (m,
1
following reaction without further purification. H NMR
(400 MHz, CDCl3): d (ppm) 6.91 (s, 4H), 4.63 (t, 1H, J¼
3.6 Hz), 4.17 (t, 4H, J¼4.6 Hz), 3.89–3.85 (m, 6H), 3.77–
3.67 (m, 12H), 3.62–3.57 (m, 3H), 3.52–3.47 (m, 1H), 2.82
(brs, 1H), 1.86–1.49 (m, 6H). 13C NMR (100 MHz,
CDCl3): d (ppm) 148.84 (s), 148.75 (s), 121.64 (d),
121.57 (d), 114.5 (d), 98.9 (d), 72.7 (t), 70.83 (t), 70.78
(t), 70.6 (t), 70.5 (t), 70.3 (t), 69.8 (t), 69.7 (t), 68.7 (t), 66.6
(t), 62.2 (t), 61.7 (t), 30.5 (t), 25.4 (t), 19.5 (t). Anal. calcd

T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
645
for C23H38O9·0.5H2O: C, 59.08; H, 8.41. Found: C, 58.73;
H, 8.44.
69.7 (t), 69.4 (t), 68.6 (t), 68.3 (t), 61.6 (t). Anal. calcd for
C36H49BrO12: C, 57.37; H, 6.55. Found: C, 57.09; H, 6.73.
4.2.6. Synthesis of 9a. To a solution of 6a (12.48 g,
33.7 mmol) in dry THF (200 ml) were added NaH (60%
dispersion in oil, 1.498 g, 37.5 mmol) and 8 (5.722 g,
17.3 mmol), and then the mixture was refluxed for 51 h.
After removal of the solvent, H2O (200 ml) was added to the
residue. The mixture was extracted with CHCl3 (3£200 ml),
and the organic phase was dried over anhydrous MgSO4.
The solvent was evaporated, and the crude product was
purified by column chromatography (SiO2, CHCl3/EtOAc¼
1:1) to afford 9a as a yellow oil (13.69 g, 14.9 mmol, 88%).
1H NMR (400 MHz, CDCl3): d (ppm) 7.42 (d, 2H,
J¼7.8 Hz), 7.28 (t, 1H, J¼7.8 Hz), 6.95–6.88 (m, 8H),
4.647 (s, 4H), 4.64–4.60 (m, 2H), 4.19–4.16 (m, 8H),
3.91–3.85 (m, 12H), 3.81–3.79 (m, 4H), 3.76–3.73 (m,
8H), 3.64–3.59 (m, 2H), 3.50–3.47 (m, 2H), 1.83–1.48 (m,
12H). 13C NMR (100 MHz, CDCl3): d (ppm) 149.1 (s),
149.0 (s), 137.9 (s), 127.9 (d), 127.2 (d), 122.6 (s), 121.7 (d),
121.6 (d), 115.1 (d), 115.0 (d), 98.9 (d), 72.7 (t), 70.83 (t),
70.78 (t), 70.3 (t), 69.9 (t), 69.8 (t), 69.0 (t), 68.9 (t), 66.7 (t),
62.2 (t), 30.6 (t), 25.4 (t), 19.5 (t). Anal. calcd for
C46H65BrO14: C, 59.93; H, 7.11. Found: C, 59.81; H, 7.27.
4.2.9. Synthesis of 10b. To a solution of 9b (5.581 g,
5.08 mmol) in EtOH (20 ml) was added 3 M hydrochloric
acid (10 ml), and the mixture was stirred for 48 h at rt. After
addition of saturated aq. NaHCO3 (15 ml), the organic
solvent was evaporated. The mixture was poured into H2O
(30 ml), extracted with CHCl3 (3£40 ml), and the organic
phase was dried over anhydrous MgSO4. After removal of
the solvent, the crude product was purified by column
chromatography (SiO2, EtOAc to EtOAc/EtOH¼5:1) to
1
afford 10b as a yellow oil (4.440 g, 4.78 mmol, 94%). H
NMR (400 MHz, CDCl3): d (ppm) 7.42 (d, 2H, J¼8.0 Hz),
7.29 (t, 1H, J¼8.0 Hz), 6.91 (s, 8H), 4.63 (s, 4H), 4.17 (t,
4H, J¼5.0 Hz), 3.89–3.85 (m, 4H), 3.77–3.66 (m, 36H),
3.61–3.59 (m, 4H), 2.72 (brs, 2H). 13C NMR (100 MHz,
CDCl3): d (ppm) 148.7 (s), 148.6 (s), 137.9 (s), 127.9 (d),
127.2 (d), 122.6 (s), 121.6 (d), 121.5 (d), 114.4 (d), 114.3 (d),
72.71 (t), 72.66 (t), 70.8 (t), 70.7 (t), 70.5 (t), 70.2 (t), 70.1 (t),
69.70 (t), 69.66 (t), 68.6 (t), 68.5 (t), 61.6 (t). Anal. calcd for
C44H65BrO16·H2O: C, 55.75; H, 7.12. Found: C, 55.76; H,
7.17.
4.2.10. Synthesis of 11a. A solution of 8 (2.293 g,
6.69 mmol) and 10a (5.019 g, 6.67 mmol) in dry THF
(100 ml) was added dropwise to a refluxing suspension of
NaH (60% dispersion in oil, 0.587 g, 14.7 mmol) in dry
THF (250 ml) over 24 h, and then the mixture was refluxed
for 48 h. After removal of the solvent, H2O (50 ml) was
added and the mixture was extracted with CHCl3 (3£50 ml).
The organic phase was dried over anhydrous MgSO4, and
the solvent was removed under reduced pressure. The crude
product thus obtained was purified by column chroma-
tography (SiO2, CHCl3 to CHCl3/Et2O/EtOH¼10:10:1) and
recrystallization from EtOAc to afford 11a as a white
powder (3.117 g, 3.34 mmol, 50%). Mp 106.5–108.58C. 1H
NMR (300 MHz, CDCl3): d (ppm) 7.36 (d, 4H, J¼7.8 Hz),
7.24 (t, 2H, J¼7.8 Hz), 6.91 (s, 8H), 4.57 (s, 8H), 4.17 (t,
8H, J¼4.8 Hz), 3.88 (t, 8H, J¼4.8 Hz), 3.78 (t, 8H, J¼
4.6 Hz), 3.68 (t, 8H, J¼4.6 Hz). 13C NMR (100 MHz,
CDCl3): d (ppm) 149.0 (s), 137.9 (s), 127.9 (d), 127.2 (d),
122.6 (s), 121.6 (d), 114.7 (d), 72.7 (t), 70.8 (t), 70.2 (t), 69.9
(t), 69.1 (t). Anal. calcd for C44H54Br2O12: C, 56.54; H,
5.82. Found: C, 56.36; H, 5.92. ESI-MS m/z found:
[MþNa]þ, 955.2, C44H54Br2O12Naþ requires 955.2.
4.2.7. Synthesis of 9b. To a solution of 6b (6.002 g,
13.1 mmol) in dry THF (100 ml) were added NaH (60%
dispersion in oil, 0.680 g, 17.0 mmol) and 8 (2.249 g,
6.56 mmol), and then the mixture was refluxed for 51 h.
After removal of the solvent, H2O (100 ml) was added to the
residue. The mixture was extracted with CHCl3 (3£100 ml),
and the organic phase was dried over anhydrous MgSO4.
The solvent was evaporated, and the crude product was
purified by column chromatography (SiO2, CHCl3/EtOAc¼
1:1) to afford 9b as a yellow oil (6.354 g, 5.79 mmol, 89%).
1H NMR (400 MHz, CDCl3): d (ppm) 7.42 (d, 2H, J¼
7.6 Hz), 7.28 (t, 1H, J¼7.6 Hz), 6.93–6.88 (m, 8H), 4.64–
4.61 (m, 6H), 4.18–4.15 (m, 8H), 3.88–3.84 (m, 12H),
3.77–3.67 (m, 28H), 3.63–3.58 (m, 4H), 1.89–1.45 (m,
12H). 13C NMR (100 MHz, CDCl3): d (ppm) 149.0 (s),
137.9 (s), 127.9 (d), 127.2 (d), 122.6 (s), 121.7 (d), 115.0
(d), 98.9 (d), 72.7 (t), 70.9 (t), 70.8 (t), 70.7 (t), 70.63 (t),
70.58 (t), 70.2 (t), 69.83 (t), 69.81 (t), 68.9 (t), 66.7 (t), 62.2
(t), 30.6 (t), 25.4 (t), 19.5 (t). Anal. calcd for C54H81BrO18·
H2O: C, 58.11; H, 7.50. Found: C, 58.34; H, 7.49.
4.2.8. Synthesis of 10a. To a solution of 9a (3.412 g,
3.70 mmol) in EtOH (20 ml) was added 3 M hydrochloric
acid (10 ml), and the mixture was stirred for 16 h at rt. After
addition of saturated aq. NaHCO3 (15 ml), the organic
solvent was evaporated. The mixture was poured into H2O
(10 ml), extracted with CHCl3 (3£20 ml), and the organic
phase was dried over anhydrous MgSO4. After removal of
the solvent, the crude product was purified by column
chromatography (SiO2, EtOAc to EtOAc/EtOH¼10:1) to
4.2.11. Synthesis of 11b. A solution of 8 (1.498 g,
4.37 mmol) and 10b (4.078 g, 4.39 mmol) in dry THF
(50 ml) was added dropwise to a refluxing suspension of
NaH (60% dispersion in oil, 0.472 g, 11.8 mmol) in THF
(300 ml) over 24 h, and then the mixture was refluxed for
48 h. After removal of the solvent, H2O (50 ml) was added
and the mixture was extracted with CHCl3 (3£50 ml). The
organic phase was dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The crude
product was purified by column chromatography (SiO2,
CHCl3 to CHCl3/Et2O/EtOH¼10:10:1) and recrystalliza-
tion from EtOAc to afford 11b as a white powder (2.427 g,
1
afford 10a as a yellow oil (2.311 g, 3.07 mmol, 83%). H
NMR (400 MHz, CDCl3): d (ppm) 7.42 (d, 2H, J¼7.6 Hz),
7.27 (t, 1H, J¼7.6 Hz), 6.92–6.90 (m, 8H), 4.64 (s, 4H),
4.19–4.14 (m, 8H), 3.92 (t, 4H, J¼5.0 Hz), 3.87–3.85 (m,
4H), 3.81–3.79 (m, 4H), 3.77–3.71 (m, 8H), 3.67–3.64 (m,
4H). 13C NMR (100 MHz, CDCl3): d (ppm) 148.7 (s), 148.5
(s), 137.8 (s), 128.0 (d), 127.2 (d), 122.8 (s), 121.6 (d), 121.4
(d), 114.0 (d), 113.9 (d), 72.9 (t), 72.7 (t), 70.7 (t), 70.1 (t),
1
2.19 mmol, 50%). Mp 84.0–85.58C. H NMR (400 MHz,
CDCl3): d (ppm) 8.39 (d, 4H, J¼7.8 Hz), 7.26 (t, 2H, J¼
7.8 Hz), 6.89 (s, 8H), 4.61 (s, 8H), 4.15 (t, 8H, J¼4.8 Hz),
3.86 (t, 8H, J¼5.0 Hz), 3.76–3.67 (m, 32H). 13C NMR

646
T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
(100 MHz, CDCl3): d (ppm) 149.0 (s), 137.9 (s), 127.9 (d),
127.2 (d), 122.6 (s), 121.6 (d), 114.8 (d), 72.7 (t), 70.9 (t),
70.8 (t), 70.6 (t), 70.2 (t), 69.8 (t), 69.0 (t). Anal. calcd for
C52H70Br2O16: C, 56.22; H, 6.35. Found: C, 56.30; H, 6.44.
ESI-MS m/z found: [MþNa]þ, 1131.5, C52H70Br2O16Naþ
requires 1131.3.
(300 MHz, CDCl3): d (ppm) 7.27–7.25 (m, 4H), 7.09 (t,
2H, J¼7.6 Hz), 6.90 (s, 8H), 4.60 (s, 8H), 4.58 (s, 2H), 4.15
(t, 8H, J¼5.0 Hz), 3.85 (t, 8H, J¼5.0 Hz), 3.80–3.60 (m,
32H). 13C NMR (100 MHz, CDCl3): d (ppm) 149.2 (s),
137.1 (s), 132.7 (s), 129.5 (d), 125.3 (d), 121.8 (d), 115.0
(d), 72.8 (t), 71.1 (t), 71.0 (t), 70.7 (t), 70.0 (t), 69.8 (t), 69.1
(t). IR: (NaCl) 2530 cm21 (–SH). Anal. calcd for
C52H72O16S2: C, 61.40; H, 7.13. Found: C, 61.33; H, 7.62.
ESI-MS m/z found: [MþNa]þ, 1039.4, C52H72O16S2Naþ
requires 1039.4.
4.2.12. Synthesis of 1ared. To a solution of 11a (0.600 g,
6.42£1024 mol) in dry THF (100 ml) was added n-BuLi
(1.54 M) in hexane (1.50 ml, 2.31 mmol) dropwise at
2758C. After stirring for 5 min, elemental sulfur (0.150 g,
4.69 mmol as S) was added by using an additional flask and
then the reaction mixture was stirred at 2758C for 8 h. The
mixture was poured into 3 M hydrochloric acid and the
organic solvent was evaporated. The mixture was extracted
with CHCl3 (3£30 ml), and the organic phase was dried
over anhydrous MgSO4. After removal of the solvent, the
crude product was purified by column chromatography
(SiO2, CHCl3 to CHCl3/Et2O/EtOH¼10:10:1) and recrys-
4.2.15. Synthesis of 1box. 5% aq. H2O2 (5 ml, 7.35 mmol)
and K2CO3 (78.4 mg, 5.67£1024 mol) were added to a
solution of 1b
(0.148 g, 1.45£1024 mol) in CH2Cl2
red
(20 ml), and the mixture was stirred for 20 min at rt. The
organic layer was dried over anhydrous MgSO4. After
removal of the solvent, 1box was obtained as a yellow oil
(0.135 g, 1.33£1024 mol, 91%), which was used in the next
step without further purification. 1H NMR (300 MHz,
CDCl3): d (ppm) 7.43–7.35 (m, 6H), 6.90 (s, 8H), 4.46
(brs, 8H), 4.17 (t, 8H, J¼4.7 Hz), 3.91 (t, 8H, J¼4.8 Hz),
3.81–3.78 (m, 8H), 3.70–3.65 (m, 16H), 3.52 (brs, 8H). 13C
NMR (100 MHz, CDCl3): d (ppm) 149.0 (s), 143.1 (s),
131.5 (s), 130.2 (d), 127.2 (d), 121.6 (d), 114.7 (d), 71.0 (t),
70.79 (t), 70.75 (t), 70.5 (t), 70.0 (t), 69.9 (t), 69.2 (t). Anal.
calcd for C52H70O16S2: C, 61.52; H, 6.95. Found: C, 61.36;
H, 7.11. ESI-MS m/z found: [MþNa]þ, 1037.5,
C52H70O16S2Naþ requires 1037.4.
tallization from EtOAc to afford 1a as a white powder
red
(0.457 g, 4.49£1024 mol, 70%). Mp 91.5–93.08C. 1H NMR
(400 MHz, CDCl3): d (ppm) 7.25 (d, 4H, J¼7.2 Hz), 7.09 (t,
2H, J¼7.2 Hz), 6.90 (s, 8H), 4.58 (s, 8H), 4.52 (s, 2H),
4.15 (t, 8H, J¼4.8 Hz), 3.84 (t, 8H, J¼4.8 Hz), 3.74–3.72
(m, 8H), 3.64–3.61 (m, 8H). 13C NMR (100 MHz, CDCl3):
d (ppm) 149.1 (s), 136.9 (s), 132.4 (s), 129.2 (d), 125.1 (d),
121.6 (d), 114.9 (d), 72.5 (t), 70.7 (t), 69.8 (t), 69.5 (t), 69.1
(t). IR: (NaCl) 2537 cm21 (–SH). Anal. calcd for
C44H56O12S2·0.5H2O: C, 62.17; H, 6.76. Found: C, 61.90;
H, 6.64. ESI-MS m/z found: [MþNa]þ, 863.5,
C44H56O12S2Naþ requires 863.3.
4.2.16. Synthesis of 1ared (reduction of 1aox). To a solution
of 1aox (78.2 mg, 9.32£1025 mol) in 20% EtOH/THF
(10 ml) was added NaBH4 (52.1 mg, 1.38 mmol) and the
mixture was stirred for 1 h at rt. The mixture was poured
into 3 M hydrochloric acid and the organic solvent was
removed under reduced pressure. H2O (10 ml) was added to
the residue and the mixture was extracted with CHCl3
(3£10 ml). The organic phase was dried over anhydrous
4.2.13. Synthesis of 1aox. 5% aq. H2O2 (5 ml, 7.35 mmol)
and K2CO3 (88.5 mg, 6.40£1024 mol) were added to a
solution of 1a
(0.179 g, 2.13£1024 mol) in CH2Cl2
red
(20 ml), and the mixture was stirred for 30 min at rt. The
organic layer was dried over anhydrous MgSO4. After
removal of the solvent, 1aox was obtained as a white powder
(0.172 g, 2.05£1024 mol, 96%), which was used in the next
step without further purification. 1H NMR (400 MHz,
CDCl3): d (ppm) 7.42 (brs, 4H), 7.32 (t, 2H, J¼7.6 Hz),
6.90 (s, 8H), 4.44 (brs, 8H), 4.17 (t, 8H, J¼4.6 Hz), 3.91 (t,
8H, J¼4.2 Hz), 3.78 (brs, 8H), 3.59 (brs, 8H). 13C NMR
(100 MHz, CDCl3): d (ppm) 148.9 (s), 143.1 (s), 131.8 (s),
130.2 (d), 127.6 (d), 121.5 (d), 114.2 (d), 70.9 (t), 70.6 (t), 70.2
(t), 69.7(t), 69.2(t). Anal. calcd for C44H54O12S2· 0.25H2O: C,
62.65; H, 6.51. Found: C, 62.64; H, 6.56. ESI-MS m/z found:
[MþNa]þ, 861.4, C44H54O12S2Naþ requires 861.3.
MgSO4 and the solvent was evaporated to give 1a as a
red
white powder (67.2 mg, 7.99£1025 mol, 86%).
4.2.17. Synthesis of 1bred (reduction of 1box). To a
solution of 1box (70.0 mg, 6.89£1025 mol) in 20% EtOH/
THF (5 ml) was added NaBH4 (0.110 g, 2.91 mmol) and the
mixture was stirred for 1 h at rt. The mixture was poured
into 3 M hydrochloric acid and the organic solvent was
removed under reduced pressure. H2O (20 ml) was added to
the residue and the mixture was extracted with CHCl3
(2£20 ml). The organic phase was dried over anhydrous
MgSO4 and the solvent was evaporated to give 1b as a
red
4.2.14. Synthesis of 1bred. To a solution of 11b (1.088 g,
9.79£1024 mol) in dry THF (90 ml) was added n-BuLi
(2.47 M) in hexane (2.00 ml, 4.94 mmol) dropwise at
2758C. After stirring for 10 min, elemental sulfur
(0.197 g, 6.16 mmol as S) was added by using an additional
flask, and the mixture was stirred for 8 h at 2758C. The
mixture was poured into 3 M hydrochloric acid, and the
organic solvent was evaporated. The mixture was extracted
with CHCl3 (3£30 ml), and the organic phase was dried
over anhydrous MgSO4. After removal of the solvent, the
crude product was purified by column chromatography
(SiO2, CHCl3 to CHCl3/Et2O/EtOH¼10:10:1) and recrys-
white powder (58.0 mg, 5.70£1025 mol, 83%).
4.2.18. Synthesis of 6a (from 7a). To a mixture of 7a
(18.011 g, 62.9 mmol) and p-toluenesulfonic acid mono-
hydrate (1.148 g, 6.04 mmol) in CH2Cl2 (100 ml) was
added a solution of 3,4-dihydro-2H-pyran (5.332 g, 63.4
mmol) in CH2Cl2 (10 ml) dropwise over 10 min at 48C, and
the solution was stirred at 48C for 5 h. Excess K2CO3 was
added, and then the mixture was stirred for further 3 h. The
solution was washed with 5% aq. NaHCO3 (100 ml), and the
organic layer was dried over anhydrous MgSO4. After
removal of the solvent, the crude product was purified by
column chromatography (SiO2, EtOAc) to afford 6a as a
pale yellow oil (9.576 g, 25.9 mmol, 41%).
tallization from EtOAc to afford 1b as a white powder
red
(0.502 g, 4.93£1024 mol, 50%). Mp 67.0–68.08C. 1H NMR

T. Nabeshima et al. / Tetrahedron 59 (2003) 639–647
647
3950–3955. (c) Nabeshima, T.; Sakiyama, A.; Yagyu, A.;
Furukawa, N. Tetrahedron Lett. 1989, 30, 5287–5288.
(d) Nabeshima, T.; Furusawa, H.; Yano, Y. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1750–1751. (e) Nabeshima, T.;
Furusawa, H.; Tsukuda, N.; Shinnai, T.; Haruyama, T.; Yano,
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4.2.19. Synthesis of 6b (from 7b). To a mixture of 7b
(27.421 g, 73.2 mmol) and p-toluenesulfonic acid mono-
hydrate (1.486 g, 7.81 mmol) in CH2Cl2 (100 ml) was
added a solution of 3,4-dihydro-2H-pyran (6.164 g, 73.7
mmol) in CH2Cl2 (30 ml) dropwise over 15 min at 48C, and
then the solution was stirred at 48C for 12 h. Excess K2CO3
was added, and the mixture was stirred for further 3 h. The
solution was washed with 5% aq. NaHCO3 (100 ml), and the
organic layer was dried over anhydrous MgSO4. After
removal of the solvent, the crude product was purified by
column chromatography (SiO2, EtOAc) to afford 6b as a
pale yellow oil (16.113 g, 35.1 mmol, 48%).
5. Nabeshima, T.; Nishida, D.; Horn, E. Z. Kristallogr. NCS
2001, 216, 80–82.
6. Similar downfield shifts of the benzyl protons of benzyl-
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dibenzocrown and benzocrown ethers with the ammonium
guests. (a) Ashton, P. R.; Campbell, P. J.; Chrystal, E. J. T.;
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Tasker, P. A.; Williams, D. J. Angew. Chem., Int. Ed. Engl.
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Glink, P. T.; Menzer, S.; Schiavo, C.; Spencer, N.; Stoddart,
J. F.; Tasker, P. A.; White, A. J. P.; Williams, D. J. Chem. Eur.
J. 1996, 2, 709–728. (c) Dykes, G. M.; Smith, D. K.; Seeley,
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8. Jullien, L.; Canceill, J.; Lacombe, L.; Lehn, J.-M. J. Chem.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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