Synthesis and properties of chiral tetrahomodiazacalix[4]- and -[6]arenes -bridged by a cystine unit

Full text of DOI:10.1021/jo000738z

J . Org. Chem. 2000, 65, 8361-8366
8361
Notes
formation of chiral calixarene analogues bridged by a
cystine unit and their structural details based on NMR
and CD spectra.
Syn th esis a n d P r op er ties of Ch ir a l
Tetr a h om od ia za ca lix[4]- a n d -[6]a r en es
Br id ged by a Cystin e Un it
Resu lts a n d Discu ssion
Kazuaki Ito,* Yayoi Yamamori, Takanori Ohta, and
Yoshihiro Ohba
Bis(chloromethyl)phenol-formaldehyde oligomers (5
and 6) were prepared by a previously reported method.7
Cystine peptides (7d and 7e) were synthesized by a
solution-phase synthetic method according to the liter-
ature.6a,b We examined the cyclization reaction of the bis-
(chloromethyl)phenol-formaldehyde dimer (5a ) and cys-
tine peptide (7d ) under several reaction conditions as
shown in Table 1 (entries 7-14). The reaction 5a with
7d in chloroform in the presence of triethylamine did not
gave any macrocyclic compound (entry 7). In contrast,
the same reaction in DMF gave a macrocycle (3a ) in 21%
yield (entry 8). To evaluate the effect of the base in this
reaction, we carried out the reaction using Na2CO3,
K2CO3, and Cs2CO3 instead of triethylamine (entries 9,
10, and 11, respectively) and found that this cyclization
was best effected by employing Na2CO3 (entry 9). The
low and high reaction temperature (entries 12 and 13)
and the dilution condition (entry 14) tended to decrease
the yield. We also carried out analogous reactions of the
bis(chloromethyl)phenol-formaldehyde oligomer (5 or 6)
with a diamine derivative such as cystine dimethyl ester
(7a and 7c), cystaime (7b), or cystine peptide (7d and
7e) and obtained corresponding macrocycles (1-4) in
moderate yields (Table 1, Scheme 1).
Department of Materials Science and Engineering,
Faculty of Engineering, Yamagata University J ohnan,
Yonezawa 992-8510 J apan
tm382@dipfr.dip.yz.yamagata-u.ac.jp
Received May 15, 2000
In tr od u ction
Calixarenes are becoming an important class of mac-
rocyclic compounds in supramolecular chemistry for the
design of new host molecules due to their chemical
versatility and conformational properties.1 Although
many studies on the modification of calixarenes have so
far been made at the large and small rims of the
calixarene skeleton to introduce additional functionality,
modification of the methylene backbone has not been
exploited to any great extent.2,3,4 This situation inspired
us to make calixarene analogues, which were constructed
by changing the methylene moiety to another unit.
Therefore, we designed calixarene analogues bridged by
a cystine unit, which is known as an important structural
element of peptide and protein molecules, because the
disulfide unit in the proteins plays an important func-
tional role in redox processes and in restricting their
conformation.5 These properties are useful for the design
of artificial host molecules.6 Here, we present the facile
The structures of macrocycles (1-4) were established
on the basis of their elemental analyses, FAB-mass, and
NMR and IR spectra. The assignment of proton and
carbon atoms was done using 2D NMR experiments.
IR spectra of macrocycles (1-4) in CHCl3 show the
absorption for the hydroxyl stretching band at 3200-
* To whom correspondence should be addressed. Telephone: 011-
81-0238-26-3097; FAX: 011-81-0238-26-3413.
(1) (a) Gutsche, C. D. Calixarenes. In Monographs in Supramolecu-
lar Chemistry; Stoddart, J . F., Ed.; Royal Society of Chemistry:
London, 1989. (b) Gutsche, C. D. Calixarenes Revisited. In Monographs
in Supramolecular Chemistry; Stoddart, J . F., Ed.; Royal Society of
Chemistry: London, 1998.
1
3260 cm-1 (Table 2). In H NMR spectra in CDCl3 at 30
°C, the OH signals were observed in the range of 9.40-
15.27 ppm. These spectral data indicate the existence of
strong hydrogen bonds which are comparable to that of
calixarenes (νOH ) ca. 3200 cm-1, δOH ) ca. 10 ppm).8
The conformation of macrocycles (1-4) have been
studied using NMR spectroscopy. The ArCH2Ar methyl-
ene protons of 1-4 appear as pairs of doublets due to
the geminal coupling between Hexo and Hendo. It is known
that the chemical shift difference (∆δ) between the high-
and low-field magnetic resonances arising from the
ArCH2Ar methylene protons in calix[4]arenes is generally
0.9 ( 0.2 ppm for the cone conformation and zero for the
1,3-alternate conformation.9 Provided that the rule es-
tablished for calix[4]arene is also applicable to this
system, it follows that the adjacent aryl rings of the
oligomer moieties of macrocycles (∆δ ) 0.73-0.88 ppm)
(2) Ito, K.; Ohba, Y.; Sone, T. J . Chem. Soc., J pn. 1999, 217-229.
(3) (a) Nagasaki, T.; Tajiri, Y.; Shinkai, S. Recl. Trav. Chim. Pays-
Bas 1993, 122, 407-411. (b) Casnati, A.; Fabbi, M.; Peizzi, N.; Pochini,
A.; Sansone, F.; Ungaro, R. Bioorg. Med. Chem. Lett. 1996, 22, 2699-
2704. (c) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, M.; Pochini, A.;
Ugozzoli, F.; Ungaro, R. Eur. J . Org. Chem. 1998, 897-905. (d)
Nomura, E.; Takagaki, M.; Nakaoka, C.; Uchida, M.; Taniguchi, H. J .
Org. Chem. 1999, 64, 3151-3156. (e) Castellano, R. K.; Nuckolls, C.;
Rebek, J ., J r. J . Am. Chem. Soc. 1999, 121, 11156-11163.
(4) (a) Khan, I. U.; Takemura, H.; Suenaga, M.; Shinmyozu, T.;
Inazu, T. J . Org. Chem. 1993, 58, 3158-3161. (b) Takemura, H.;
Shinmyozu, T.; Miura, H.; Khan, I. U.; Inazu, T. J . Incl. Phenom. 1994,
19, 193-206. (c) Hampton, P. D.; Tong, W.; Wu, S.; Duesler, E. N. J .
Chem. Soc., Perkin Trans. 2 1996, 1127-1130.
(5) (a) Branden, C.; Tooze, J . Introduction to Protein Structure;
Garland Publishing Inc.: New York, 1991. (b) Kishore, R.; Kumar, A.;
Balaram, P. J . Am. Chem. Soc. 1985, 107, 8019-8023. (c) Karle, I. L.;
Kishore, R.; Raghothama, S.; Balaram, J . Am. Chem. Soc. 1988, 110,
1958-1963. (d) Garcia-Echeverria, C.; Albericio, F.; Giralt, E.; Pons,
M. J . Am. Chem. Soc. 1993, 115, 11663-11670.
(7) (a) Ito, K.; Ohba, Y.; Sone, T. J . Heterocycl. Chem. 1998, 35,
1317-1323. (b) Ito, K.; Ohta, T.; Ohba, Y.; Sone, T. J . Heterocycl. Chem.
2000, 37, 79-85.
(8) Page 100 in ref 1a.
(9) Pages 110-111 in ref 1a.
(6) (a) Ranganathan, D.; Haridas, V.; Karle, I. L. J . Am. Chem. Soc.
1998, 120, 2695-2702. (b) Ranganathan, D.; Lakshmi, C.; Karle, I. L.
J . Am. Chem. Soc. 1999, 121, 6103-6107. (c) Hu, X.; Chan, A. S. C.;
Han, X.; He, J .; Cheng, J .-P. Tetrahedron Lett. 1999, 40, 7115-7118.
10.1021/jo000738z CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/28/2000

8362 J . Org. Chem., Vol. 65, No. 24, 2000
Notes
Ta ble 1. Rea ction Con d ition s a n d Yield of P r od u cts
form a chiral helicity and produce the chiral cyclophane
moiety.
temp, product
Figures 4 and 5 showed the circular dichroism (CD)
spectra of the macrocycles (1-4). The CD spectra were
clearly observed at ca. 290 nm due to the phenol chro-
mophore11 in chloroform at 20 °C, supporting the as-
sumption that phenol-formaldehyde oligomer moieties
are chiral.
To elucidate the temperature dependence of the ∆δ
values of the ArCH2Ar methylene protons and the
phenolic OH proton chemical shifts, we carried out a
variable temperature 1H NMR measurement in the range
of 55 to -60 °C in CDCl3, and these results are sum-
marized in Table 6. Lowering the temperature resulted
in a decrease in the ∆δ values of the ArCH2Ar methylene
protons and downfield shifts of the OH signals. These
results suggest that the contribution of the twisted form
is enhanced by cooling.
entry oligomer peptide solvent
base
°C
(yield %)
1
2
3
4
5
6
7
5a
5b
5b
5b
6b
6b
5a
7a
7a
7b
7c
7a
7b
7d
DMF
DMF
DMF
DMF
DMF
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
30
30
30
30
30
30
30
1a (20%)
1b (42%)
1c (24%)
1d (37%)
2b (48%)
2c (27%)
polymeric
materials
3a (21%)
3a (24%)
3a (6%)
3a (11%)
3a (19%)
3a (13%)
3a (18%)
3b (14%)
3c (14%)
polymeric
materials
4a (10%)
4b (18%)
CHCl3 NEt3
8
9
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
7d
7d
7d
7d
7d
7d
7d
7e
7d
7e
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NEt3
Na2CO3
K2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
30
30
30
30
0
50
30
30
30
30
10
11
12
13
14a
15
16
17
18
19
6a
6b
7d
7d
DMF
DMF
Na2CO3
Na2CO3
30
30
Con clu sion
In conclusion, we demonstrated the facile synthesis of
chiral bridged calixarene analogues, which were con-
structed from phenol-formaldehyde oligomers and the
cystine unit. The 1H NMR and CD spectra indicated that
the chirality of the phenol-formaldehyde oligomer moi-
eties were induced from the chirality of the cystine
bridge. The present system is a unique concept from the
viewpoint of the transmisson of the chirality from the
bridge to the cyclophane moiety.
a
The reaction was carried out under
a 10 times dilution
condition.
take the preferable syn-orientation. The 13C NMR chemi-
cal shifts of the methylene carbon atoms of the ArCH2Ar
for calixarenes are now being used as a means for
assessing conformations. The methylene carbon reso-
nances for the calixarenes appear at ca. 30-33 ppm when
the adjacent aryl rings are syn and at ca. 36-38 ppm
when they are anti.10 Applying this information to this
system, all the syn-orientations of the adjacent aromatic
rings were confirmed (Table 2). The CPK model consid-
eration of 1-4 indicates that it adopts a cone conforma-
tion because it is difficult to construct a 1,2-alternate
model. The crystal structure of 1a , which was given in
Figure 1, also supports the fact that 1-4 adopt a cone
form.
Exp er im en ta l Section
Gen er a l P r oced u r e of th e P r ep a r a tion of Bis(ch lor om -
eth yl)p h en ol-F or m a ld eh yd e Oligom er s (5 a n d 6). To a
solution of bis(hydroxymethyl)phenol-formaldehyde oligomer7
(1.1 mol) in 10 mL of dry benzene was added a solution of thionyl
chloride (1.0 g, 8.0 mmol) in 10 mL of dry benzene over 0.5 h at
room temperature. After the addition was complete, the mixture
was allowed to stir at room temperature for 3 h. Removal of
benzene and excess thionyl chloride below 25 °C under a reduced
pressure gave bis(chloromethyl)phenol-formaldehyde oligomer
as a colorless powder, which was recrystallized from benzene to
give pure crystals, whose spectral chracteristics were identical
with those reported.7
Gen er a l P r oced u r e of th e P r ep a r a tion of Cystin e P ep -
tid es (7d a n d 7e). To a mixture of l-cystine dimethyl ester
dihydrochloride (1.71 g, 5.0 mmol), N-methylmorpholine (1.11
g, 11 mmol), and N-Boc protected amino acid (11 mmol) in 100
mL of chloroform was added a solution of DCC (2.27 g, 11 mmol)
in 12 mL of chloroform at 0 °C over 1 h. After the addition was
complete, the mixture was stirred at room temperature over-
night. The precipitated dicyclohexylurea was filtered off, and the
filtrate was condensed. The residue was subjected to column
chromatography on silica gel using hexane:ethyl acetate 1:1 as
an eluent to afford N-Boc protected cystine peptide in good
yield. The spectral chracteristics of N-Boc protected cystine
peptides were identical with those reported.6 Cystine pep-
tides (7d and 7e) were prepared by treatment of the pro-
tected peptide with excess HCl-ethyl acetate reagent at 0 °C
for 2 h. The residue was directly used for the next cyclization
reaction.
Considering that the ∆δ values of the NCH2Ar meth-
ylene protons are expected to be sensitive to the dihedral
angle between the methylene proton and the adjacent
aromatic ring,9 the difference between ∆δ HeHf and ∆δ
HqHr for 1-4 implies that phenol-formaldehyde oligomer
moieties are considered to adopt a twisted form (Figure
2). Since the smaller ∆δ values are ascribed to the
methylene protons HqHr (Table 3), it is reasonable to
assume that the methylene protons are located in an
equivalent magnetic field (conformation A in Figure 3).
This assumption was supported by the fact that the
hydroxyl proton signals (OH2 for 1 and 3, and OH3 for 2
and 4) were observed at the lowest field due to the
formation of the hydrogen bonding not only with the
hydroxyl group but also with the adjacent nitrogen atom.
In contrast, the larger ∆δ values (HeHf) indicate that the
adjacent aromatic ring is considered to adopt a somewhat
standup form (conformation B in Figure 3). On the basis
of these considerations, phenol-formaldehyde oligomer
moieties of 1 are considered to adopt a twisted structure
as shown in Figure 2. The chirality of the cystine bridge
causes the formation of the left-hand isomer in Figure
2.3d Therefore, phenol-formaldehyde oligomer moieties
Gen er a l P r oced u r e of th e P r ep a r a tion of th e Ca lix-
a r en e An a logu es (1, 2, 3, a n d 4) Br id ged by Cystin e Un it.
To a suspension of sodium carbonate (636 mg, 6.0 mmol) in 50
mL of dry DMF were added a solution of bis(chloromethyl)-
phenol-formaldehyde oligomer (2.0 mmol) in 50 mL of dry DMF
and a solution of cystine dimethyl ester, cystamine, or cystine
peptide (1.0 mmol) in 50 mL of dry DMF at 30 °C over 6 h under
(10) (a) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.; Sanchez,
C. J . Org. Chem. 1991, 56, 3372-3376. (b) Stewart, D. R.; Krawise,
M.; Kashyap, R. P.; Watson, W. H.; Gutsche, C. D. J . Am. Chem. Soc.
1995, 117, 586-601.
(11) Iwamoto, K.; Shimizu, H.; Araki, K.; Shinkai, S. J . Am. Chem.
Soc. 1993, 115, 3997-4006.

Notes
J . Org. Chem., Vol. 65, No. 24, 2000 8363
Sch em e 1
Ta ble 2. P r oton Sign a ls in 1H NMR Sp ectr a a n d
Str etch in g Vibr a tion s of th e Hyd r oxyl Gr ou p , a n d th e
Ch em ica l Sh ifts of th e Meth ylen e Ca r bon Atom
(d, 2H, J ) 1.9 Hz), 6.62 (d, 2H, J ) 1.9 Hz), 4.42 (d, 2H, J )
11.9 Hz), 4.28 (d, 2H, J ) 13.5 Hz), 4.10 (d, 2H, J ) 14.3 Hz),
3.90 (d, 2H, J ) 15.4 Hz), 3.83 (d, 2H, J ) 12.4 Hz), 3.72 (s,
6H), 3.55 (dd, 2H, J ) 7.0, 8.0 Hz), 3.40 (d, 2H, J ) 13.8 Hz),
2.50 (dd, 2H, J ) 7.0, 14.3 Hz), 2.42 (dd, 2H, J ) 8.0, 14.3 Hz),
2.24 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 170.5, 151.5, 151.2,
131.5, 130.8, 130.0, 129.9, 129.1, 128.1, 127.7, 126.9, 123.6, 122.1,
60.7, 60.3, 58.9, 55.6, 51.4, 38.3, 30.7, 20.5, 20.4. FAB MS m/z:
773 [M + H]+. Anal. Found: C, 65.42; H, 6.41; N, 3.54. Calcd for
C42H48N2O8S2: C, 65.26; H, 6.26; N, 3.62.
13C NMR
νCdO amide I ArCH2Ar
δOH [ppm]
νOH [cm-1
]
[cm-1
]
[cm-1
]
[ppm]
1a
9.40, 11.15
1b 9.31, 10.85
1c 10.93
3260
3260
3260
1730
1730
-
1730
-
-
-
-
-
-
30.8
31.1
31.5
32.4, 32.5
32.8, 33.3
2b 9.06, 10.69, 13.13 3260
1b: colorless crystals mp 250-255 °C (decomp) (from ethyl
2c
9.51, 12.24, 15.27 3240
acetate-hexane). [R]20 +31° (c ) 0.1, CHCl3). 1H NMR (500
D
3a 10.50
3b 10.28
3c 10.60
3332, 3242 1747
3334, 3255 1747
3303, 3222 1747
1681 31.2
1674 31.1
1681 32.0
MHz, CDCl3) δ 10.85 (bs, 2H), 9.31 (bs, 2H), 7.31 (d, 2H, J )
2.4 Hz), 7.28 (d, 2H, J ) 2.4 Hz), 6.93 (d, 2H, J ) 2.4 Hz), 6.81
(d, 2H, J ) 2.4 Hz), 4.43 (d, 2H, J ) 12.0 Hz), 4.32 (d, 2H, J )
13.9 Hz), 4.16 (d, 2H, J ) 15.3 Hz), 3.91 (d, 2H, J ) 15.3 Hz),
3.88 (d, 2H, J ) 12.0 Hz), 3.74 (s, 6H), 3.61 (dd, 2H, J ) 5.9, 8.6
Hz), 3.46 (d, 2H, J ) 13.9 Hz), 2.41 (dd, 2H, 5.9, J ) 14.0 Hz),
2.26 (dd, 2H, J ) 8.6, 14.0 Hz), 1.29 (s, 18H), 1.28 (s, 18H). 13C
NMR (125 MHz, CDCl3) δ 170.3, 151.2, 151.1, 143.3, 142.4, 127.8,
127.6, 127.3, 127.1, 126.3, 123.2, 122.8, 121.6, 60.2, 59.2, 56.0,
51.4, 37.5, 33.9, 33.7, 31.5, 31.4, 31.1. FAB MS m/z: 941 [M +
H]+. Anal. Found: C, 68.93; H, 7.77; N, 2.99. Calcd for
4a
8.55, 9.05, 10.10 3363, 3291 1743
4b 8.45, 9.15, 10.60 3363, 3309 1743
1654 31.0, 31.7
1655 30.4, 31.9
a nitrogen atmosphere. After the addition was complete, the
mixture was allowed to stir at 30 °C for 12 h. Removal of DMF
under a reduced pressure gave pale yellow oily residue, which
was separated with column chromatography on silica gel to give
a calixarene analogue as a white powder.
C
54H72N2O8S2: C, 68.91; H, 7.71; N, 2.98.
1c: colorless crystals mp 238-241 °C (from dichloromethane-
1a : colorless crystals mp 250-253 °C (decomp) (from dichlo-
romethane-hexane). [R]20D +21° (c ) 0.1, CHCl3). 1H NMR (500
MHz, CDCl3) δ 11.15 (bs, 2H), 9.40 (bs, 2H), 7.10 (s, 4H), 6.71
hexane). 1H NMR (500 MHz, CDCl3) δ 10.93 (s, 4H), 7.27 (d,

8364 J . Org. Chem., Vol. 65, No. 24, 2000
Ta ble 3. Ch em ica l Sh ifts of Meth ylen e P r oton s in CDCl3 a t 500 MHz a t 20 °C
Notes
HeHf (J , Hz; ∆δa, ppm)
HiHj (J , Hz; ∆δa, ppm)
HmHn (J , Hz; ∆δa, ppm)
HqHr (J , Hz; ∆δa, ppm)
1a
1b
1c
2b
2c
3a
3b
3c
4a
4b
3.83, 4.42 (12.0, 0.59)
3.88, 4.43 (12.0, 0.55)
3.33, 4.36 (13.5, 1.03)
3.37, 4.33 (14.0, 0.96)
3.34, 4.30 (14.5, 0.96)
3.45, 4.51 (14.0, 1.06)
3.68, 4.92 (14.5, 1.24)
3.56, 4.61 (15.0, 1.05)
3.53, 4.42 (12.5, 0.89)
3.56, 4.45 (12.5, 0.86)
3.40, 4.28 (14.0, 0.88)
3.46, 4.32 (14.0, 0.86)
3.45, 4.33 (13.9, 0.88)
3.52, 4.35 (13.5, 0.83)
3.51, 4.40 (13.9, 0.84)
3.36, 4.25 (14.0, 0.89)
3.43, 4.36 (13.5, 0.93)
3.53, 4.39 (14.0, 0.86)
3.37, 4.55 (14.0, 1.18)
3.44, 4.60 (14.0, 1.16)
3.90, 4.10 (15.5, 0.20)
3.91, 4.16 (15.3, 0.25)
3.52, 4.25 (13.8, 0.73)
3.52, 4.25 (13.9, 0.73)
3.83b
3.84, 3.88 (14.9, 0.04)
3.11, 4.13 (12.5, 1.02)
3.34, 4.16 (12.5, 0.82)
3.36, 4.32 (13.0, 0.96)
2.99, 3.64 (14.0, 0.65)
3.13, 3.72 (14.0, 0.59)
3.40, 4.28 (13.5, 0.88)
3.49, 4.36 (14.0, 0.87)
a
b
∆δ HxHy ) δHx - δHy. Observed as a singlet.
F igu r e 3.
F igu r e 1. X-ray crystallograhic structure of the calixarene
analogue (1a ). The proton atoms are omitted.
F igu r e 2.
4H, J ) 2.2 Hz), 6.85 (d, 4H, J ) 2.2 Hz), 4.36 (d, 4H, J )
13.5 Hz), 4.33 (d, 2H, J ) 14.0 Hz), 3.45 (d, 2H, J ) 14.0
Hz), 3.33 (d, 4H, J ) 13.5 Hz), 2.55 (t, 4H, J ) 6.5 Hz), 2.11 (t,
4H, J ) 6.5 Hz), 1.29 (s, 36H). 13C NMR (125 MHz, CDCl3) δ
151.4, 142.6, 128.0, 126.8, 124.3, 122.5, 61.8, 53.4, 35.4, 33.9,
31.8, 31.5. FAB MS m/z: 825 [M + H]+. Anal. Found: C, 72.86;
H, 8.39; N, 3.18. Calcd for C50H68N2O4S2: C, 72.76; H, 8.31; N,
3.39.
1d : colorless crystals mp 258-260 °C (decomp) (from ethyl
acetate-hexane). [R]20D -35° (c ) 0.1, CHCl3). FAB MS m/z: 941
[M + H]+. Anal. Found: C, 69.10; H, 7.61; N, 3.10. Calcd for
C54H72N2O8S2: C, 68.91; H, 7.71; N, 2.98.
2b: pale yellow crystals. mp 203-207 °C (from ethyl acetate).
[R]20D +127° (c ) 0.1, CHCl3). 1H NMR (500 MHz, CDCl3) δ 13.13
(s, 2H), 10.69 (s, 2H), 9.06 (s, 2H), 7.27 (d, 2H, J ) 2.3 Hz), 7.24
(d, 2H, J ) 2.3 Hz), 7.18 (d, 2H, J ) 2.3 Hz), 7.17 (d, 2H, J )
2.3 Hz), 6.91 (d, 2H, J ) 2.3 Hz), 6.62 (d, 2H, J ) 2.3 Hz), 4.71
(dd, 2H, J ) 6.8, 7.3 Hz), 4.35 (d, 2H, J ) 14.0 Hz), 4.33 (d, 2H,
J ) 14.5 Hz), 4.25 (d, 2H, J ) 13.9 Hz), 3.87 (dd, 2H, J ) 6.8,
13.7 Hz), 3.83 (s, 4H), 3.79 (dd, 2H, J ) 7.3, 13.7 Hz), 3.64 (s,
6H), 3.52 (m, 4H), 3.37 (d, 2H, J ) 14.5 Hz), 1.27 (s, 18H), 1.26
(s, 18H), 1.21 (s, 18H). 13C NMR (125 MHz, CDCl3) δ 171.0,
F igu r e 4. CD spectra of 1 and 2 in CHCl3 at 20 °C.
152.0, 151.4, 147.5, 143.6, 143.4, 141.4, 128.5, 127.7, 127.5, 127.4,
126.9, 126.2, 125.7, 123.8, 119.8, 119.0, 64.5, 52.0, 50.9, 48.4,
44.8, 34.1, 34.0, 33.7, 32.5, 32.4, 31.7, 31.6, 31.5. FAB MS m/z:
1265 [M + H]+. Anal. Found: C, 72.06; H, 7.98; N, 2.21. Calcd
for C76H100N2O10S2: C, 72.12; H, 7.96; N, 2.21.
2c: colorless crystals. mp 233-236 °C (from dichloromethane-
hexane). 1H NMR (500 MHz, CDCl3) δ 15.27 (s, 2H), 12.24 (s,
2H), 9.51 (s, 2H), 7.29 (d, 2H, J ) 2.2 Hz), 7.28 (d, 2H, J ) 2.2
Hz), 7.17 (s, 4H), 6.89 (d, 2H, J ) 2.2 Hz), 6.68 (d, 2H, J ) 2.2
Hz), 4.40 (d, 2H, J ) 13.5 Hz), 4.30 (d, 2H, J ) 14.0 Hz), 4.25
(d, 2H, J ) 13.8 Hz), 4.09 (m, 2H), 3.88 (d, 2H, J ) 14.9 Hz),
3.84 (d, 2H, J ) 14.9 Hz), 3.63 (m, 4H), 3.52 (d, 2H, J ) 13.8
Hz), 3.51 (d, 2H, J ) 13.5 Hz), 3.34 (d, 2H, J ) 14.0 Hz), 2.79
(m, 4H), 1.27 (s, 36H), 1.23 (s, 18H). 13C NMR (125 MHz, CDCl3)
δ 153.9, 152.3, 148.3, 143.2, 142.0, 141.6, 129.1, 128.2, 128.1,
127.7, 127.5, 127.3, 127.0, 126.2, 125.6, 123.2, 118.8, 117.4, 55.2,
52.7, 47.7, 41.8, 34.1, 34.0, 33.8, 31.7, 31.5. FAB MS m/z: 1149

Notes
J . Org. Chem., Vol. 65, No. 24, 2000 8365
Ta ble 6. Obser ved P r oton Ch em ica l Sh ifts a n d th e
Differ en ce (∆δ) of th e Ch em ica l Sh ifts Betw een Hexo a n d
Hen d o of th e Ar CH2Ar P r oton s a t Va r iou s Tem p er a tu r es
in CDCl3 a t 500 MHz
∆δ
∆δ
∆δ
∆δ
°C
HeHf HiHj
H
mHn HrHq δOH1 δOH2 δOH3
55 0.54 0.88
30 0.55 0.86
-
0.31
0.27
0.18
0.13
0.10
0.0
0.0
0.0
0.0
0.0
9.40
9.30
9.38
9.50
9.58
9.03
9.06
9.07
9.07
9.04
9.40
10.85
11.35
11.80
12.11
10.65 13.03
10.69 13.13
10.73 13.24
10.74 13.34
10.72 13.41
-
-
-
-
-
-
-
-
-
1b
2b
0
0.60 0.85
-30 0.65 0.83
-60 0.68 0.81
55 0.96 0.85
30 0.94 0.83
0.74
0.73
0.71
0.70
0.68
0
0.92 0.79
-30 0.90 0.77
-60 0.90 0.73
14.5 Hz), 2.67 (d, 2H, J ) 11.0 Hz), 2.20 (s, 6H), 2.15 (s, 6H).
13C NMR (125 MHz, CDCl3) δ 171.1, 170.5, 150.5, 150.4, 138.2,
131.6, 131.0, 129.7, 129.6, 129.5, 129.4, 128.6, 128.1, 127.7, 126.8,
126.1, 122.7, 120.5, 62.8, 55.9, 54.4, 52.5, 52.4, 40.9, 31.2, 27.5,
20.4, 20.3. FAB MS m/z: 1067 [M + H]+. Anal. Found C, 67.62;
H, 6.55; N, 5.50. Anal. Calcd for C60H66N4O10S2 : C, 67.52; H,
6.23; N, 5.25.
F igu r e 5. CD spectra of 3 and 4 in CHCl3 at 20 °C.
3b: mp 211-214 °C (from dichloromethane-hexane). [R]20
D
1
Ta ble 4. Su m m a r y of Cr ysta l Da ta a n d Da ta Collection
1a
-256° (c ) 0.1, CHCl3). H NMR (500 MHz, CDCl3) δ 10.28 (br
s, 4H), 7.13 (d, 2H, J ) 1.5 Hz), 7.04 (d, 2H, J ) 1.5 Hz), 7.02
(d, 2H, J ) 3.5 Hz), 6.70 (d, 2H, J ) 1.5 Hz), 6.67 (d, 2H, J )
1.5 Hz), 4.92 (d, 2H, J ) 14.5 Hz), 4.72 (ddd, 2H, J ) 4.0, 11.0,
14.0 Hz), 4.36 (d, 2H, J ) 13.5 Hz), 4.16 (d, 2H, J ) 12.5 Hz),
3.76 (s, 6H), 3.68 (d, 2H, J ) 14.5 Hz), 3.43 (d, 2H, J ) 13.5
Hz), 3.34 (d, 2H, J ) 12.5 Hz), 3.32 (dd, 2H, J ) 4.0, 14.0 Hz),
2.87 (d, 2H, J ) 10.5 Hz), 2.85 (dd, 2H, J ) 11.0, 14.0 Hz), 2.49
(m, 2H), 2.23 (s, 6H), 2.22 (s, 6H), 1.06 (d, 6H, J ) 7.0 Hz), 0.75
(d, 6H, J ) 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ 172.8, 171.5,
150.7, 150.6, 131.8, 131.3, 129.6, 129.4, 129.3, 128.6, 127.7, 126.9,
123.2, 121.1, 64.3, 57.3, 53.6, 52.6, 52.0, 36.9, 31.1, 27.2, 21.0,
20.7, 20.5, 20.4. FAB MS m/z: 943 [M + H]+. Found C, 65.98;
H, 7.18; N, 3.01. Anal. Calcd for C52H66N2O10S2: C, 66.22; H, 7.05;
N, 2.97.
formula
molar mass
color
crystal size, mm
crystal system
space group
a, Å
C42H48O10N2S2
804.97
colorless
0.30 × 0.25 × 0.25
monoclinic C
C2
17.054(2)
13.840(3)
16.541(3)
92.39(1)
3900(1)
4
b, Å
c, Å
â, deg
V, Å3
Z
scan mode
2θmax, deg
ω-2θ
3c: mp 210-217 °C (from dichloromethane-hexane). [R]20
D
48.5
1
-120° (c ) 0.1, CHCl3). H NMR (500 MHz, CDCl3) δ 10.60 (br
d
calcd, g cm-3
1.371
s, 4H), 7.38 (d, 2H, J ) 2.0 Hz), 7.30-7.35 (m, 10H), 7.28 (d,
2H, J ) 2.0 Hz), 7.19 (d, 2H, J ) 6.0 Hz), 7.06 (d, 2H, J ) 2.0
Hz), 6.91 (s, 2H), 4.67 (m, 2H), 4.61 (d, 2H, J ) 15.0 Hz), 4.39
(d, 2H, J ) 14.0 Hz), 4.31 (d, 2H, J ) 15.0 Hz), 3.61 (s, 6H),
3.56 (d, 2H, J ) 15.0 Hz), 3.53 (d, 2H, J ) 14.0 Hz), 3.44 (d, 2H,
J ) 9.5 Hz), 3.36 (d, 2H, J ) 13.0 Hz), 3.25 (dd, 2H, J ) 9.5,
11.5 Hz), 3.24 (dd, 2H, J ) 4.5, 14.5 Hz), 3.07 (dd, 2H, J ) 7.5,
14.5 Hz), 2.73 (d, 2H, J ) 11.5 Hz), 1.33 (s, 18H), 1.28 (s, 18H).
13C NMR (125 MHz, CDCl3) δ 170.9, 170.5, 150.5, 143.0, 142.9,
138.2, 129.5, 128.7, 128.3, 128.1, 126.8, 126.0, 123.9, 122.4, 120.0,
63.1, 56.6, 54.8, 52.5, 52.4, 41.1, 34.0, 32.0, 31.5, 27.2. FAB MS
m/z: 1236 [M + H]+. Anal. Found C, 69.74; H, 7.12; N, 4.82.
Anal. Calcd for C72H90N4O10S2: C, 69.99; H, 7.34; N, 4.53.
λ (Mo KR)
µ(Mo KR), cm-1
T, K
0.71069
1.99
293
1704.00
3471
F(000)
no. of refls obsd
no. of refls used
(I0 > 3σI0)
R
1277
0.057
0.047
Rw
Ta ble 5. CD Sp ectr a l Absor p tion in CHCl3 a t 20 °C
λext [nm]
(θ[deg cm2 dmol-1])
4a : mp 202-206 °C (from dichloromethane-hexane). [R]20
macrocycle
D
1
-140° (c ) 0.1, CHCl3). H NMR (500 MHz, CDCl3) δ 10.10 (br
1a
1b
1d
2b
3a
3b
3c
4a
4b
288 (-16600)
299 (7500)
298 (4300)
297 (-5000)
293 (9500)
s, 2H), 9.05 (br s, 2H), 8.55 (br s, 2H), 8.33 (d, 2H, J ) 6.0 Hz),
7.22-7.32 (m, 10H), 7.04 (d, 2H, J ) 1.5 Hz), 7.00 (d, 2H, J )
1.0 Hz), 6.86 (d, 2H, J ) 2.0 Hz), 6.84 (d, 2H, J ) 2.0 Hz), 6.77
(d, 2H, J ) 1.5 Hz), 6.10 (s, 2H), 4.55 (d, 2H, J ) 14.0 Hz), 4.42
(d, 2H, J ) 12.5 Hz), 4.34 (m, 2H), 4.28 (d, 2H, J ) 13.5 Hz),
3.77 (dd, 2H, J ) 6.5, 6.5 Hz), 3.75 (s, 6H), 3.64 (d, 2H, J ) 13.5
Hz), 3.53 (d, 2H, J ) 12.5 Hz), 3.47 (dd, 2H, J ) 3.0, 14.5 Hz),
3.41 (dd, 2H, J ) 7.0, 14.0 Hz), 3.40 (d, 2H, J ) 13.5 Hz), 3.37
(d, 2H, J ) 14.0 Hz), 3.28 (dd, 2H, J ) 8.5, 14.5 Hz), 3.10 (dd,
2H, J ) 7.0, 14.0 Hz), 2.99 (d, 2H, J ) 14.0 Hz), 2.24 (s, 6H),
2.16 (s, 6H), 2.14 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 171.4,
170.4, 150.5, 150.1, 146.5, 140.1, 131.9, 131.8, 131.5, 130.1, 129.6,
129.5, 129.4, 129.3, 129.0, 128.5, 128.4, 128.0, 126.3, 122.4, 120.9,
63.8, 54.0, 52.6 × 2, 52.4, 40.4, 31.7, 31.0, 30.6, 20.5, 20.4, 20.2.
FAB MS m/z: 1306 [M + H]+. Anal. Found C, 70.02; H, 6.22; N,
4.10. Anal. Calcd for C76H80N4O12S2: C, 69.92; H, 6.18; N, 4.29.
285 (-15200)
285 (19200)
284 (-10100)
297 (-53900)
297 (-62400)
294 (-41200)
284 (41100)
281 (32800)
297 (-3400)
294 (-6400)
[M + H]+. Anal. Found: C, 75.37; H, 8.42; N, 2.44. Calcd for
C72H96N2O6S2: C, 75.22; H, 8.42; N, 2.44.
3a : mp 202-205 °C (from dichloromethane-hexane). [R]20
D
1
-123° (c ) 0.1, CHCl3). H NMR (500 MHz, CDCl3) δ 10.50 (br
s, 4H), 7.02-7.12 (m, 19H), 6.98 (s, 2H), 6.81 (m, 2H), 6.65 (s,
2H), 6.63 (s, 2H), 4.62 (m, 2H), 4.51 (d, 2H, J ) 14.0 Hz), 4.25
(d, 2H, J ) 14.0 Hz), 4.13 (d, 2H, J ) 12.5 Hz), 3.54 (s, 6H),
3.45 (d, 2H, J ) 14.0 Hz), 3.36 (d, 2H, J ) 14.0 Hz), 3.32 (d, 2H,
J ) 9.0 Hz), 3.19 (dd, 2H, J ) 3.5, 14.5 Hz), 3.11 (d, 2H, J )
12.5 Hz), 3.09 (dd, 2H, J ) 9.0, 11.0 Hz), 2.99 (dd, 2H, J ) 8.0,
4b: mp 130-134 °C (from dichloromethane-hexane). [R]20
D
-93° (c ) 0.1, CHCl3). 1H NMR (500 MHz, CDCl3) δ 10.60 (br s,
2H), 9.15 (br s, 2H), 8.45 (br s, 2H), 8.48 (d, 2H, J ) 6.5 Hz),

8366 J . Org. Chem., Vol. 65, No. 24, 2000
Notes
7.21-7.30 (m, 10H), 7.27 (d, 2H, J ) 2.0 Hz), 7.23 (d, 3H, J )
2.0 Hz), 7.09 (s, 4H), 6.93 (d, 2H, J ) 2.0 Hz), 6.50 (d, 2H, J )
2.0 Hz), 4.60 (d, 2H, J ) 14.0 Hz), 4.45 (d, 2H, J ) 12.5 Hz),
4.40 (m, 2H), 4.36 (d, 2H, J ) 14.0 Hz), 3.80 (dd, 2H, J ) 6.5,
6.5 Hz), 3.76 (s, 6H), 3.72 (d, 2H, J ) 14.0 Hz), 3.56 (d, 2H, J )
12.5 Hz), 3.49 (d, 2H, J ) 14.0 Hz), 3.45 (dd, 2H, J ) 3.5, 14.5
Hz), 3.44 (d, 2H, J ) 14.0 Hz), 3.38 (dd, 2H, J ) 6.5, 14.5 Hz),
3.28 (dd, 2H, J ) 8.0, 14.5 Hz), 3.13 (d, 2H, J ) 14.0 Hz), 3.12
(dd, 2H, J ) 6.5, 14.5 Hz), 1.28 (s, 18H), 1.23 (s, 18H), 1.17 (s,
18H). 13C NMR (125 MHz, CDCl3) δ 171.4, 170.4, 150.3, 150.0,
146.5, 144.5, 143.2, 140.1, 129.3 × 2, 129.2, 128.5 × 2, 128.4,
128.3, 127.8, 127.6, 126.3, 126.2, 126.1, 125.0, 124.9, 121.9, 120.4,
63.8, 53.8, 53.0, 52.7, 52.6, 40.3, 34.0, 33.9, 33.8, 31.9, 31.6, 31.5,
31.4, 31.3, 30.4. FAB MS m/z: 1560 [M + H]+. Anal. Found C,
72.55; H, 7.69; N, 3.84. Anal. Calcd for C94H118N4O12S2: C, 72.37;
H, 7.62; N, 3.59.
Ack n ow led gm en t. The authors are indebted to
emeritus Professor T. Sone (Yamagata University) for
his useful suggestions. The authors thank Professors
K. Saito and H. Masuda and Dr. M. Mizutani (Nagoya
Institute of Technology) for the X-ray single crystal
analysis. This work was partially supported by a Grant-
in-Aid from the Ministry of Education, Science, Sports,
and Culture of J apan (Research No. 10750617).
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for 1a . This material is available free of charge
via Internet at http://pubs.acs.org.
J O000738Z