Preparation of phenolic chiral crown ethers and podands and their enantiomer recognition ability toward secondary amines

Article abstract of DOI:10.1016/S0957-4166(03)00031-4

Phenolic pseudo-24-crown-8 (S,S)-3, pseudo-27-crown-9 (S,S)-4, and podands (R,R)-5 and (R,R)-6 possessing phenyl groups as chiral barriers were prepared and their chiral recognition properties toward secondary neutral amines were examined. Pseudo-24-crown-8 (S,S)-3 and podand (R,R)-5 showed sufficient binding ability and moderate chiral recognition ability toward secondary amines.

Full text of DOI:10.1016/S0957-4166(03)00031-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 555–566
Preparation of phenolic chiral crown ethers and podands and
their enantiomer recognition ability toward secondary amines
Keiji Hirose,* Akihito Fujiwara, Kazuhisa Matsunaga, Nobuaki Aoki and Yoshito Tobe
Department of Chemistry, Faculty of Engineering Science, Osaka University, and CREST,
Japan Science and Technology Corporation (JST), Toyonaka, Osaka 560-8531, Japan
Received 7 November 2002; revised 19 December 2002; accepted 20 December 2002
This paper is dedicated to Emeritus Professor Soichi Misumi for his 77th birthday
Abstract—Phenolic pseudo-24-crown-8 (S,S)-3, pseudo-27-crown-9 (S,S)-4, and podands (R,R)-5 and (R,R)-6 possessing phenyl
groups as chiral barriers were prepared and their chiral recognition properties toward secondary neutral amines were examined.
Pseudo-24-crown-8 (S,S)-3 and podand (R,R)-5 showed sufficient binding ability and moderate chiral recognition ability toward
secondary amines. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiomeric recognition of amines and ammonium
salts compounds is a topic of considerable significance
since these compounds are basic building blocks of
biological molecules and a number of them are known
to possess potent biological activities which are differ-
ent from their antipodes.1 Among the numerous types
of host molecules studied, chiral 18-crown-6 derivatives
have been recognized as the most successful for chiral
discrimination of primary amine-containing com-
pounds. The mechanism of chiral discrimination and
molecular design of new chiral 18-crown-6 and their
analogs toward chiral primary amine compounds have
been well documented. In contrast, little has been
reported on chiral recognition of secondary amines
despite their synthetic and biological importance.
Indeed, there exist many biologically active chiral sec-
ondary amines,2 as exemplified by the well known
propranolol, ephedrine, and salbutamol and it has been
reported that their activity is frequently different from
the corresponding enantiomers.3 To the best of our
knowledge, there are only two reports regarding chiral
recognition of secondary amine derivatives, one with
chiral binaphthyl derivatives4a and the other with a
liquid chromatography stationary phase based on a
chiral 18-crown-6.4b Accordingly, it is important to
develop host molecules possessing high chiral recogni-
tion ability toward secondary amines.
Herein, we report on the design and synthesis of chiral
hosts capable of binding secondary amines and recog-
* Corresponding author. Tel.: +81-6-6850-6228; fax: +81-6-6850-6229;
e-mail: hirose@chem.es.osaka-u.ac.jp
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00031-4

556
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
nizing their chirality. Our design is based on pseudo-18-
crown-6 (S,S)-1 which exhibits not only excellent enan-
tioselectivity toward primary ethanolamine derivatives
but also shows a distinct difference in the color devel-
oped upon complexation with each guest enantiomer.5
The salient features of (S,S)-1 involve (i) a phenolic
hydroxy group which binds neutral amines to form a
salt complex; (ii) a strong electron-withdrawing group
attached to the para position of the hydroxy group
which facilitates binding with amines, and (iii) phenyl
groups in appropriate positions of the macrocyclic
framework as chiral barriers to effect maximum enan-
tiomeric discrimination. The macrocyclic framework of
pseudo-18-crown-6 (S,S)-1, is suitable for complexation
with primary amines but probably not with secondary
amines, since the cavity is too small to form stable
complexes with the latter. To achieve sufficient binding
with secondary amines, the macrocyclic framework
should be larger than that of 18-crown-6. Alternatively,
open chain type podands are also possible candidates.
Since Stoddart et al. reported that dibenzo-24-crown-8
formed stable complexes with dibenzylammonium and
other secondary ammonium ions,6 we first designed
(S,S)-3 having a pseudo-24-crown-8 framework. Since
the binding site of (S,S)-3 is supposed to be smaller
than that of dibenzo-24-crown-8, we also planned to
prepare pseudo-27-crown-9 (S,S)-4 possessing a larger
binding site. As open chain hosts, we designed (R,R)-5
and its methyl ether (R,R)-6. For comparison, pseudo-
18-crown-6 (S,S)-2 possessing the same ring size as that
of (S,S)-1 was also prepared.7
2. Results and discussion
All receptors designed here possess a nitro group
instead of a 2,4-dinitrophenylazo group at the para
position of the phenolic hydroxy group, as in (S,S)-1,
for the following reason. In a preliminary experiment,
we prepared podand type host 7 having a 2,4-dinitro-
phenylazo group, but found, however, that it existed as
both the azophenol 7 and its tautomeric hydrazone
forms 8 in a ratio of 5:1 in CDCl3 at 30°C (Scheme 1).
The nitro group was used in order to avoid this com-
plexity, since its electron-withdrawing properties are
almost identical to that of a 2,4-dinitrophenylazo
group.8
The synthesis of pseudo crown ethers (S,S)-2, (S,S)-3,
and (S,S)-4 is summarized in Scheme 2. The chiral
subunit (S)-9 was prepared from (S)-(+)-mandelic acid
as a mixture of two diastereomers according to the
reported procedure.8,9 Condensation of 2 equiv. of (S)-
9
with
5-bromo-1,3-bis(bromomethyl)-2-methoxy-
benzene8 in the presence of NaH followed by deprotec-
tion with pyridinium p-toluenesulfonate in ethanol gave
(S,S)-10 in 95% overall yield, which was used as a
common precursor for preparation of phenolic crown
ethers (S,S)-2, (S,S)-3, and (S,S)-4. Synthesis of (S,S)-
2 was initiated from ring closure of (S,S)-10 with
diethylene glycol di(p-toluenesulfonate) in the presence
of NaH in THF under high dilution conditions to give
(S,S)-11 in 44% yield. Reaction of (S,S)-11 with n-
BuLi in hexanes followed by quenching with water at
−78°C afforded (S,S)-12 in 62% yield. The intra-annu-
lar methyl ether of (S,S)-12 was selectively cleaved with
sodium ethanethiolate in DMF10 to furnish (S,S)-13 in
91% yield. By reaction with HNO3 and NaNO2,11 the
para position to the hydroxy group of (S,S)-13 was
selectively nitrated to give (S,S)-2 in 58% yield. Pseudo-
24-crown-8 (S,S)-3 and pseudo-27-crown-9 (S,S)-4
Scheme 1. Equilibrium between azophenol 7 and hydrazone 8
forms of podand 7.
Scheme 2. Reagents and conditions: (i) a. 5-Bromo-1,3-bis(bromomethyl)-2-methoxybenzene, NaH, b. pyridinium p-toluenesul-
fonate, ethanol, 95% (two steps); (ii) diethylene glycol ditosylate, NaH, 44% (n=1), tetraethylene glycol ditosylate, NaH, 36%
(n=3), pentaethylene glycol ditosylate, NaH, 25% (n=4); (iii) n-BuLi, then H2O, 62% (n=1), 62% (n=3), 68% (n=4); (iv) EtSNa,
91% (n=1), 86% (n=3), 30% (n=4); (v) HNO3, NaNO2, 58% (n=1), 34% (n=3), 42% (n=4).

K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
557
Scheme 3. Reagents and conditions: (i) (CH3O)2CH2, LiBr, TsOH, 50%; (ii) n-BuLi, then H2O, 71%; (iii) 6N HCl, 72%; (iv)
EtSNa, 76%; (v) HNO3, NaNO2, 25%; (vi) CH3I, NaH, 86%; (vii) n-BuLi, then H2O, 75%; (viii) EtSNa, 74%; (ix) HNO3, NaNO2,
58%.
were prepared by essentially the same procedure as that
used for the preparation of (S,S)-2. In the case of
(S,S)-3, ring closure of (S,S)-10 with tetraethylene gly-
col di(p-toluenesulfonate) gave (S,S)-14 in 36% yield,
which was transformed into (S,S)-3 in 18% yield (for
three steps) via (S,S)-15 and (S,S)-16. Pseudo-27-
crown-9 (S,S)-4 (through (S,S)-17, (S,S)-18, and (S,S)-
19) was prepared from (S,S)-10 and pentaethylene
glycol di(p-toluenesulfonate) in 2.1% overall yield.
marized in Tables 1 and 2. For complexation with
binding constants of this range (10–102 M−1), both the
1H NMR titration and the UV–visible titration meth-
ods can be used reliably.12b,13 In order to check if the
data obtained by the different methods are identical
within the experimental error, cross experiments were
carried out.14 In the case of (R,R)-5, however, only
UV–visible titration method was employed because of
its limited solubility in CDCl3.
For the synthesis of podands, the enantiomerically pure
chiral subunit (R)-9 was employed simply by chance
(Scheme 3). Thus, treatment of (R,R)-10, derived from
(R)-9, with LiBr, TsOH and formaldehyde dimethyl
acetal gave (R,R)-20 in 50% yield. Debromination of
(R,R)-20 afforded (R,R)-21 in 71% yield and subse-
quent deprotection with hydrochloric acid gave (R,R)-
22 in 72% yield. Demethylation of (R,R)-22 followed
by nitration at the para position of the hydroxy group
of the resulting (R,R)-23 furnished (R,R)-5 in 19% yield
for the two steps. For the preparation of (R,R)-6,
methylation of the hydroxy groups of (R,R)-10 was first
carried out to give (R,R)-24 in 86% yield. Subsequent
reduction, demethylation and nitration via (R,R)-25
and (R,R)-26 afforded (R,R)-6 in 32% yield for three
steps.
The binding constants for the complexes were deter-
mined by 1H NMR titration in CDCl3 followed by
non-linear least-squares curve fitting or by UV–visible
titration in CHCl3 followed by Rose–Drago data treat-
ment.12 As representative examples, the titration curves
1
from the H NMR titration method for the complexa-
tion of (S,S)-3 with amine 32 and graphical expression
to appreciate the determined binding constants accord-
ing to the Rose–Drago method12b for the complexation
of (R,R)-5 with amine 35 are shown in Figs. 1 and 2,
respectively. The obtained binding constants are sum-
Figure 1. 1H NMR (270 MHz) titration curves for the com-
plexation of (S,S)-3 with (S)- and (R)-32 in CDCl3 at 15°C.

558
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
First, the binding ability of the prepared hosts toward
secondary amines was investigated using achiral amines
27–31. The binding constants of the hosts with amines
27–31 are summarized in Table 1. With N-methylben-
zylamine (27), crown ethers (S,S)-2, (S,S)-3, and (S,S)-
4 form complexes with binding constants of 14, 46, and
22 M−1, respectively at 15°C. Among them, pseudo-24-
crown-8 (S,S)-3 shows the largest binding constant,
suggesting that the cavity of (S,S)-2 is too small for 27,
while that of (S,S)-4 is too large. In addition, it should
be pointed out that the binding constant of podand
(R,R)-5 with 27 is larger than those of crown ethers
(S,S)-2, (S,S)-3, and (S,S)-4 despite the absence of the
cyclic structure.15 These results suggest that, as we
expected, receptors suitable for binding secondary
amines should possess macrocyclic rings which are
larger than 18-crown-6, or they can be an open chain
podand. Since we have reported that pseudo-18-crown-
6 like (S,S)-1 showed high binding ability and enan-
tiomer selectivity toward primary ethanolamine
derivatives,16 we examined the binding ability toward
Figure 2. Graph to appreciate the determined binding con-
stant (K) for the complexation of (R,R)-5 with (S)- and
(R)-35 according to the Rose–Drago method in CHCl3 at
15°C. mc: molar extinction coefficient of a complex. mh: molar
extinction coefficient of a host.
Table 1. Binding constants for the complexes of (S,S)-2, (S,S)-3, (S,S)-4, (R,R)-5, and (R,R)-6 with 27, 28, 29, 30, and 31
(S,S)-2
(S,S)-3
(S,S)-4
(R,R)-5
(R,R)-6
27
28
29
30
31
(1.490.2)×10a
(9.990.5)×103 d
(7.990.1)×10d
B1d
(4.690.1)×10a
(3.790.1)×102 d
(2.590.1)×102 d
B1d
(2.290.1)×10a
(1.090.1)×102 b
(3.590.3)×10d
(2.290.2)×102 d
B1d
–
–
6.290.8c
(9.590.1)×10d
(1.890.2)×10c
–
–
B1d
–
(2.190.1)×10d
(8.990.5)×10d
–
a Measured by 1H NMR spectroscopy (270 MHz) in CDCl3 at 15°C.
b Measured by UV–visible spectroscopy in CHCl3 at 15°C.
c Measured by 1H NMR spectroscopy (270 MHz) in CDCl3 at 30°C.
d Measured by UV–visible spectroscopy in CHCl3 at 30°C.
Table 2. Binding constants and enantiomer selectivities in complexation of (S,S)-2, (S,S)-3, (S,S)-4, and (R,R)-5 with 32, 33,
34, 35, and 36
(S,S)-2a
(S,S)-3
(S,S)-4a
(R,R)-5b
32c
33d
34c
35c
36c
KS
KR
KS/KR
KS
KR
KS/KR
KS
KR
KS/KR
KS
KR
B1
B1
–
–
–
–
–
–
–
–
–
–
–
–
–
(1.890.1)×10a
7.590.2
4.590.2
1.7
–
–
–
–
–
–
–
–
–
(1.090.1)×102
(7.290.2)10
1.4
8.890.3a
2.0
(1.690.1)×102 b
(9.890.7)×102
(8.990.7)×102
1.1
(1.390.1)×102 b
1.2
B1a
(5.390.2)×10
(4.790.5)×10
1.1
B1a
–
(1.690.1)×10a
(2.690.1)×10a
0.6
(3.190.2)×102
(1.890.1)×102
1.7
KS/KR
KS
KR
(5.390.1)×10a
(3.190.2)×10a
1.7
(1.890.1)×10
(1.590.1)×10
1.2
(2.390.1)×102
(3.790.1)×102
0.6
KS/KR
a Measured by 1H NMR spectroscopy (270 MHz) in CDCl3.
b Measured by UV–visible spectroscopy in CHCl3.
c Measured at 15°C.
d Measured at 30°C.

K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
559
ethanolamine 28, secondary ethanolamine 29, and ter-
tiary ethanolamine 30 at 30°C. As we expected, for the
primary amine 28, (S,S)-2 exhibits the best binding
properties. In the case of secondary amine 29, pseudo-
24-crown-8 (S,S)-3 has the best binding properties
among the hosts examined. However, none of the hosts
bind tertiary amine 30. Again, the binding constant of
podand (R,R)-5 toward 29 is similar to that of pseudo-
24-crown-8 (S,S)-3. On the other hand, the binding
constant of (R,R)-6 is very small. The binding con-
stants of the hosts with 29 at 30°C are greater than
those with 27 at 15°C, which does not have a hydroxy
group, probably due to the steric repulsion of the
phenyl group and hydrogen bonding between the phen-
oxide oxygen of the host and the hydroxy group of 29.
to that with 27, a moderate degree of enantiomer
selectivity was observed (KS/KR=2.0). Similarly,
pseudo-27-crown-9 (S,S)-4 exhibited a moderate degree
of enantiomer selectivity (KS/KR=1.7). In contrast with
crown ethers (S,S)-2, (S,S)-3, and (S,S)-4, the binding
constants of podand (R,R)-5 with 32 (KS=100 M−1,
KR=72 M−1) decreased only slightly compared to that
with achiral amine 27, resulting in relatively low enan-
tioselectivity (KS/KR=1.4). The binding constants for
pyrrolidinemethanol 33 with pseudo crown ether (S,S)-
3 and podand (R,R)-5 were next examined: in both
cases, although the binding constants are larger than
those with 32, the enantiomer selectivities are relatively
small. The binding constants toward 34 and 35 were
also measured using hosts (S,S)-3 and (R,R)-5 which
showed relatively high binding ability toward 32. How-
ever, (S,S)-3 did not bind both enantiomers of a-substi-
tuted 34 (K <1 M−1). On the contrary, (S,S)-3 formed
complexes with S and enantiomers of b-substituted 35
with binding constants 16 and 26 M−1, respectively, and
moderate degree of enantiomer selectivity (KS/KR=0.6)
was observed. This finding shows a dramatic difference
in the binding abilities with regard to the position of
the substituent. For podand (R,R)-5, although it binds
a-substituted 34, the enantiomer selectivity is marginal.
On the other hand, its binding constants with S and R
enantiomers of b-substituted 35 are considerably large,
and a moderate degree of enantiomer selectivity (KS/
KR=1.7) is observed. The relatively low binding abili-
ties of (S,S)-3 and (R,R)-5 toward 34 suggest a severe
steric repulsion between the a-phenyl group and the
host. Since (S,S)-3 and (R,R)-5 showed relatively high
binding constants and enantiomer selectivities toward
b-substituted ethanolamine 35, we employed propra-
nolol 36 as a guest, which is one of the well-known
bioactive amino alcohols possessing a hydroxy group
on a stereogenic center at the b-position of the amino
group. In this case, pseudo-27-crown-9 (S,S)-4 was also
examined in addition to (S,S)-3 and (R,R)-5. As we
expected, (S,S)-3 and (R,R)-5 showed relatively high
binding ability and a moderate degree of enantiomer
selectivity. In the case of (S,S)-4, however, both the
binding constant and the enantiomer selectivity are
smaller.
In order to investigate the effect of the hydroxy group
of guest amines, methoxyamine 31 was employed for
the complexation of (S,S)-3 and (R,R)-5, which showed
considerable binding ability toward hydroxyamine 29.
As a result, the binding constant of (S,S)-3 with 31 is
10 times smaller than that with 29 and that of (R,R)-5
with 31 is less than half of that with 29. We have
reported that the absorption maximum of the more
favorable complex of azophenolic pseudo-crown ether
such as (S,S)-1 with one enantiomer guest appeared at
shorter wavelength than that of the less stable complex
with the other enantiomer.17 Indeed, the absorption
maxima of the complexes of (S,S)-3 with 29 and 31 are
402 and 405 nm, respectively, and those of (R,R)-5 are
386 and 389 nm, respectively. These results are consis-
tent with the presence of hydrogen bonding between the
hydroxy group of 29 and the phenoxide oxygen of the
host.
The binding constants and the enantioselectivity of the
hosts were determined for (S,S)-3, (S,S)-4, and (R,R)-5
with chiral amines 32, 33, 34, 35, and 36 (Table 2). The
measurements were carried out at 15°C because of the
relatively small binding constants at 30°C except in the
case of amine 33. Both enantiomers of 32, 33, and 36
are commercially available. Amines 34 and 35 were
prepared by N-isopropylation of the corresponding pri-
mary amines according to the reported procedure.18
N-Isopropylamines were selected because of the ease of
preparation of both enantiomers from commercially
available materials and because of the fact that many
biologically active secondary amines possess this
group.2 First, the binding ability and enantiomer selec-
tivity of (S,S)-2, (S,S)-3, (S,S)-4, and (R,R)-5 toward
N,a-dimethylbenzylamine 32 are compared. While
(S,S)-2 formed a complex with 27 with a binding
constants of 14 M−1, it did not bind S and R enan-
tiomers of 32 (K <1 M−1). Thus, the introduction of a
methyl group in the guest amine reduced the binding
ability of (S,S)-2 dramatically, suggesting severe steric
repulsion between the a-methyl group of 32 and the
host. Because of the poor binding ability of (S,S)-2
toward a chiral secondary amine, its binding constants
with other chiral secondary amine were not determined.
With pseudo-24-crown-8 (S,S)-3, although the binding
constants with S and R enantiomers of 32 were consid-
erably reduced (18 and 8.8 M−1, respectively) compared

560
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
Figure 3. Predicted geometries of complexes 37 and 38. The values in parenthesis are complexation induced shifts (CISs) of
(S,S)-3 with (S)- and (R)-32. CISs of H2a, H5, and H22a which are time-averaged with those of H22b, H19, and H2b,
respectively, are not shown.
Regarding the predictable R/S-selectivities of pseudo-
18-crown-6 ethers governed by enthalpy,5c we have
proposed an explanation in terms of steric repulsion
between the amine and the hosts on the basis of CPK
molecular model examination of the complexes. The
enantiomer selectivities of (S,S)-3 can be interpreted on
the same grounds regardless of the relatively poor
enantioselectivity (the maximum selectivity of KS/KR=
2.0 corresponds to ca. 0.4 kcal/mol), although the host
(S,S)-3 has a more flexible structure than that of
pseudo-18-crown-6. In Fig. 3, predicted geometries 37
and 38 are illustrated for the complexes (S,S)-3:(S)-32
and (S,S)-3:(R)-32, respectively, assuming the following
issues: (i) the phenoxide oxygen atom participates in the
binding with the amine; (ii) The phenyl substituents of
the host occupy pseudo-equatorial positions,16c making
the O-6 oxygen (shown by the arrow in Fig. 3) form
O···H–N+ hydrogen bond with the ammonium cation
nested in the cavity of crown ether; (iii) The protonated
amine 32H+ adopts a conformation in which the bulki-
est group is located in the anti position of the N-methyl
group. On the basis of these assumptions, two hydro-
gen atoms on the ammonium nitrogen of (S)-32H+
form hydrogen bonding with the phenoxide oxygen and
O-6 oxygen. The position of the methyl group on the
nitrogen atom is then on the 11 o’clock position. Con-
sequently, the phenyl group of (S)-32H+ is located at
the anti position of the N-methyl group, thereby adopt-
ing the 5 o’clock position. Thus, in complex 37, the
a-methyl group of (S)-32H+ is located at the less hin-
dered 9 o’clock position of (S,S)-3, and the smallest
group on the a-position (hydrogen atom) is located at
the most congested 2 o’clock position. On the other
hand, in the case with (R)-32H+, the complex must be
destabilized because either of the following two require-
ments cannot be satisfied: (i) the bulkiest phenyl group
is located at the anti position of the N-methyl group;
(ii) The smallest group (hydrogen) is located at the 2
o’clock position. The conformer shown as 38, having
the phenyl group at the 9 o’clock position, does not
fulfil the second requirement. In order to obtain spec-
troscopic support for this explanation, complexation
induced shifts (CISs) were calculated.19 Since the equi-
librium of the complexation between (S,S)-3 and 32 is
fast on the 1H NMR time scale even at −50°C, the
signals of the protons H5 and H19, H2b and H22a, and
H2a and H22b exchange rapidly to each other. The
CISs of these protons are shown in Fig. 3. While most
of the amine guests exhibited CISs of similar magnitude
for H2b and H22b, CIS for H19 is relatively small.20
Therefore, the proton H19 is suitable to probe the
anisotropic shielding effect of the phenyl ring of guest
32H+. The proton H19 shows a larger upfield shift with
(R)-32 than that with (S)-32 (DR–SCIS=−0.11), indicat-
ing that the proton H19 suffers anisotropic shielding
from phenyl ring of (R)-32 more effectively than that
from (S)-32. These results are in agreement with the
proposed conformations shown in Fig. 3.21
In conclusion, a general class of compounds (S,S)-1–
(R,R)-6, were prepared to develop hosts capable of
recognizing chirality of secondary amines. Moderate
enantiomer recognition of chiral secondary amines was
achieved with chiral pseudo-24-crown-8 (S,S)-3 and
podand type chiral host (R,R)-5. Further works to
improve the selectivity and to apply these compounds
to chiral chromatography are in progress in our
laboratories.
3. Experimental
3.1. General procedure
1H NMR spectra were recorded at 270, 300 or 400
MHz and 13C NMR spectra at 67.8 MHz on a JEOL
JNM-GSX-270, a Varian Mercury 300 or a JMN-AL-
400 in CDCl3 and with Me4Si or residual solvent as an
internal standard at 30°C. IR spectra were recorded as
a KBr disk or a neat film with a JASCO FTIR-410
spectrometer. UV spectra were recorded on a Hitachi
220A or a U-3310 spectrometer. Mass spectral analyses
were performed on a JEOL JMS-DX303HF spectrome-
ter or a JEOL JMS-700 spectrometer by EI and FAB
ionization. Elemental analyses were performed on a
Perkin–Elmer 2400II analyzer. Melting points were
measured with a hot-stage apparatus and are uncor-
rected. Optical rotations were measured using a JASCO

K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
561
DIP-40 polarimeter at ambient temperature and [h]D
values are given in units of 10−1 deg cm2 g−1. Column
chromatography and TLC were performed with Merck
silica gel 60 (70–230 mesh ASTM) and Merck silica gel
60 F254, respectively. Preparative HPLC separation was
undertaken with a JAI LC-908 chromatograph using
600 mm×20 mm JAIGEL-1H and 2H GPC columns
with CHCl3 as an eluent. All reagents were obtained
from commercial suppliers and used as received. Sol-
vents were dried (drying agent in parentheses) and
distilled prior to use: CDCl3 (P4O10), DMF (CaH2) and
THF (CaH2 followed by sodium benzophenone ketyl).
ethyl acetate, and the combined extract was washed
with water and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure and the
residue was chromatographed on silica gel (hex-
ane:ethyl acetate) to give (S,S)-11 as a colorless powder
(500 mg, 44% yield): mp 99–100°C; [h]2D8=+92.3 (c 1.24,
CHCl3); IR (KBr) 2864, 1470, 1430, 1359, 1227, 1096,
1
1003, 761, 703 cm−1; H NMR (CDCl3, 300 MHz) l
3.39–3.71 (m, 12H, CH2), 4.25 (s, 3H, OCH3), 4.52 (dd,
J=2.5, 8.3 Hz, 2H, OCH(Ph)CH2), 4.45, 4.69 (AB,
J=7.4 Hz, Dw=65.6 Hz, 4H, benzylic CH2), 7.28–7.37
(m, 10H, C6H5), 7.42 (s, 2H, MeOArH); MS (FAB)
m/z 558 (M+H)+. Anal. calcd for C29H33O6Br: C, 62.48;
H, 5.97. Found: C, 62.69; H, 6.12%.
3.2. 5-Bromo-1,3-bis[(4S)-4-hydroxy4-phenyl-2-
oxabutyl]-2-methoxybenzene, (S,S)-10
3.4. (5S,13S)-21-Methoxy-5,13-diphenyl-3,6,9,12,15-
pentaoxabicyclo[15.3.1]henicosa-1(20),17(21),18-triene,
(S,S)-12
A solution of (S)-(+)-2-phenyl-2-(tetrahydropyranyl-
oxy)ethanol (18.6 g, 83.7 mmol) in dry THF (150 mL)
which had been prepared from (S)-mandelic acid as the
mixture of two diastereomers8,9 was slowly added to a
suspension of sodium hydride (60% in mineral oil, 4.69
g, 0.117 mol) in dry THF (300 mL) at room tempera-
ture. After being refluxed for 1.5 h, a solution of
5 - bromo - 1,3 - bis(bromomethyl) - 2 - methoxybenzene8
(12.0 g, 32.2 mmol) in dry THF (150 mL) was added
slowly. After additional reflux for 6 h, water (35 mL)
was carefully added to the reaction mixture with ice-
cooling. Then the solvent was removed under reduced
pressure. The residue was extracted with a mixed sol-
vent containing hexane and ethyl acetate, the combined
extracts were washed with water and dried over anhy-
drous MgSO4, and then the solvent was removed under
reduced pressure. The residue was stirred with pyri-
dinium p-toluenesulfonate (0.966 g, 3.84 mmol) in etha-
nol (125 mL) for 12 h at 50°C. After the solvent was
removed under reduced pressure, the residue was dis-
solved in CHCl3, and washed with water, and dried
over anhydrous MgSO4. The solvent was removed
under reduced pressure and the residue was chro-
matographed on silica gel (hexane:ethyl acetate) to give
(S,S)-10 as a yellow oil (14.9 g, 95%): [h]2D5=+25.1 (c
1.03, CHCl3); IR (neat) 3431, 2871, 1454, 1211, 1105,
A 1.6 M solution of n-BuLi in hexanes (3.7 mL, 6.1
mmol) was added to a solution of (S,S)-11 (2.85 g, 5.11
mmol) in dry THF (40 mL) over a 15 min period at
−78°C under nitrogen. After stirring for 1.5 h at the
same temperature, water (3 mL) was added dropwise to
the reaction mixture at −78°C and the mixture was
stirred for an additional 1 h at the same temperature.
The reaction mixture was warmed to room temperature
and extracted with a solvent containing hexane and
ethyl acetate. The combined extracts were washed with
water and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure and the residue
was chromatographed on silica gel (hexane:ethyl ace-
tate) to give (S,S)-12 as a colorless powder (1.52 g, 62%
yield): mp 129–130°C; [h]2D4=+147.1 (c 0.54, CHCl3);
IR (KBr) 2859, 1596, 1453, 1360, 1232, 1095, 995, 955,
790, 762, 703 cm−1; 1H NMR (CDCl3, 400 MHz) l
3.39–3.72 (m, 12H, CH2), 4.29 (3H, s, OCH3), 4.52 (dd,
J=2.4, 8.2 Hz, 2H, OCH(Ph)CH2), 4.51, 4.74 (AB,
J=7.1 Hz, Dw=61.6 Hz, 4H, benzylic CH2), 7.06 (t,
J=7.4 Hz, 1H, OMeArH), 7.25–7.35 (m, 12H,
OMeArH and C6H5); MS (FAB) m/z 479 (M+H)+.
1
757, 701 cm−1; H NMR (CDCl3, 300 MHz): l 2.78
3.5. (5S,13S)-21-Hydroxy-5,13-diphenyl-3,6,9,12,15-
pentaoxabicyclo[15.3.1]henicosa-1(20),17(21),18-triene,
(S,S)-13
(2H, br s, OH), 3.53–3.71 (m, 4H, CH2), 3.73 (3H, s,
OCH3), 4.60 (s, 4H, benzylic CH2), 4.94 (dd, J=2.9, 8.7
Hz, 2H, OCH(Ph)CH2), 7.27–7.41 (m, 10H, C6H5), 7.48
(s, 2H, MeOArH). MS (FAB) m/z 487 (M+H)+. Anal.
calcd for C25H27O5Br: C, 61.61; H, 5.58; Br, 16.39.
Found: C, 61.44; H, 5.51; Br, 16.12%.
To a suspension of sodium hydride (60% in mineral oil,
2.79 g, 69.8 mmol) in dry DMF (70 mL) was added
slowly ethanethiol (6.4 mL, 84 mmol) with ice-cooling.
After hydrogen evolution ceased, a solution of (S,S)-12
(1.66 g, 3.46 mmol) in dry DMF (150 mL) was added
to the resulting clear solution. The reaction mixture was
stirred for 2 h at 80°C, cooled to 5°C, neutralized with
hydrochloric acid and extracted with CHCl3. The com-
bined extract was washed with aqueous solution of
sodium hypochlorite, washed with water, and dried
over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was chro-
matographed on silica gel (hexane:ethyl acetate) fol-
lowed by recrystallization from hexane to give (S,S)-13
as colorless powder (1.47 g, 91% yield): mp 92–94°C;
[h]2D1=+117.1 (c 0.34, CHCl3); IR (KBr) 3366, 2867,
3.3. (5S,13S)-19-Bromo-21-methoxy-5,13-diphenyl-
3,6,9,12,15-pentaoxabicyclo[15.3.1]henicosa-
1(20),17(21),18-triene, (S,S)-11
A solution of (S,S)-10 (1.01 g, 2.06 mmol) and
diethylene glycol di(p-toluenesulfonate) (858 mg, 2.07
mmol) in dry THF (125 mL) was added dropwise to a
suspension of sodium hydride (60% in mineral oil, 349
mg, 8.73 mmol) in dry THF (85 mL) over a 9 h period
at 60°C. After being stirred for 18 h, 20 mL of water
was added carefully with ice-cooling and then the sol-
vent was removed under reduced pressure. The residue
was extracted with a solvent containing hexane and
1
1600, 1467, 1360, 1244, 1097, 754, 703 cm−1; H NMR

562
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
(CDCl3, 400 MHz) l 3.60–3.80 (m, 12H, CH2), 4.67 (dd,
J=2.8, 8.3 Hz, 2H, OCH(Ph)CH2), 4.76 (s, 4H, benzylic
CH2), 6.81 (t, J=7.4 Hz, 1H, phenol ring CH), 7.13 (d,
J=7.4 Hz, 2H, phenol ring CH), 7.27–7.35 (m, 10H,
C6H5), 8.14 (s, 1H, phenolic OH); MS (FAB) m/z 465
(M+H)+. Anal. calcd for C28H32O6: C, 72.39; H, 6.94.
Found: C, 72.15; H, 7.01%.
of (S,S)-12, treatment of (S,S)-14 (541 mg, 0.838 mmol)
with a 1.6 M solution of n-BuLi in hexanes (1.2 mL, 1.84
mmol) followed by water gave (S,S)-15 (294 mg, 0.519
mmol, 62% yield) as a colorless oil after chromatography
on silica gel (hexane:ethyl acetate): [h]3D0=+70.7 (c 0.43,
CHCl3); IR (neat) 2866, 1452, 1346, 1215, 1100, 1007, 760,
1
702 cm−1; H NMR (CDCl3, 270 MHz) l 3.45–3.79 (m,
20H, CH2), 3.97 (s, 3H, OCH3), 4.62 (dd, J=3.0, 8.2 Hz,
2H, OCH(Ph)CH2), 4.68, 4.72 (AB, J=11.4 Hz, Dw=10.7
Hz, 4H, benzylic CH2), 7.10 (t, J=7.5 Hz, 1H, MeOArH),
7.27–7.39 (m, 12H, MeOArH and C6H5); 13C NMR
(CDCl3, 67.8 MHz) l 63.32, 68.61, 68.93, 70.67, 70.75,
70.76, 75.28, 82.27, 123.82, 126.80, 127.75, 128.32, 130.13,
131.57, 139.19, 157.10; MS (FAB) m/z 567 (M+H)+, 589
(M+Na)+; HRMS (FAB) calcd for C33H42O8Na (M+Na)+
589.2778; found 589.2786.
3.6. (5S,13S)-21-Hydroxy-19-nitro-5,13-diphenyl-
3,6,9,12,15-pentaoxabicyclo[15.3.1]henicosa-
1(20),17(21),18-triene, (S,S)-2
A solution of sodium nitrite (0.590 g, 8.55 mmol) in water
(120 mL) and 0.3N nitric acid (34 mL) was added to a
solution of (S,S)-13 (1.00 g, 2.15 mmol) in CHCl3 (80 mL)
successively. The mixture was then stirred vigorously for
4 h at room temperature. The reaction mixture was
neutralized with saturated aqueous solution of sodium
hydrogencarbonate and the CHCl3 layer was separated.
The organic phase was washed with water and dried over
anhydrous MgSO4. After the solvent was removed under
reduced pressure, the residue was purified by chromatog-
raphy on alumina (hexane:ethyl acetate then ethanol) to
give (S,S)-2 as a yellow powder (636 mg, 58% yield): mp
52–54°C; [h]2D1=+97.2 (c 0.61, CHCl3); IR (KBr) 3319,
3.9. (5S,19S)-27-Hydroxy-5,19-diphenyl-3,6,9,12,15,18,
21-heptaoxabicyclo[21.3.1]heptacosa-1(26),23(27),24-
triene, (S,S)-16
In a manner similar to that described for the prepara-
tion of (S,S)-13, treatment of (S,S)-15 (1.00 g, 1.77
mmol) with sodium ethanethiolate in DMF gave
(S,S)-16 (838 mg, 86% yield) as a colorless oil after
chromatography on silica gel (hexane:ethyl acetate):
[h]2D6=+72.1 (c 0.84, CHCl3); IR (neat) 3361, 2866,
1598, 1453, 1347, 1225, 1100, 758, 703 cm−1; 1H
NMR (CDCl3, 270 MHz) l 3.51–3.78 (m, 20H,
OCH2), 4.69 (dd, J=3.7, 8.6 Hz, 2H, OCH(Ph)CH2),
4.74, 4.81 (AB, J=11.9 Hz, Dw=17.7 Hz, 4H, ben-
zylic CH2), 6.80 (t, J=7.7 Hz, 1H, phenol ring CH),
7.12 (d, J=7.7 Hz, 2H, phenol ring CH), 7.27–7.36
(m, 10H, C6H5), 8.05 (s, 1H, phenolic OH); 13C
NMR (CDCl3, 67.8 Hz) l 68.75, 70.52, 70.74, 70.76,
70.98, 75.21, 81.64, 119.25, 124.33, 126.89, 127.90,
128.23, 128.38, 138.76, 154.15; MS (FAB) m/z 553
(M+H)+, 575 (M+Na)+, HRMS (FAB) calcd for
C32H40O8Na (M+Na)+ 575.2621; found 575.2623.
1
2871, 1600, 1520, 1452, 1339, 1091, 749, 703 cm−1; H
NMR (CDCl3, 400 MHz) l 3.54–3.78 (m, 12H, CH2), 4.66
(dd, J=3.7, 7.2 Hz, 2H, OCH(Ph)CH2), 4.83 (s, 4H,
benzylic CH2), 7.30–7.38 (m, 10H, C6H5), 8.10 (s, 2H,
phenol ring CH), 9.20 (s, 1H, OH); 13C NMR (CDCl3,
67.8 Hz) l 69.0, 70.0, 70.6, 75.2, 76.5, 125.1, 125.2, 126.8,
128.1, 128.5, 138.0, 139.9, 161.2; MS (FAB) m/z 510
(M+H)+; HRMS (FAB) calcd for C28H32NO8 (M+H)+
510.2128; found 510.2102.
3.7. (5S,19S)-25-Bromo-27-methoxy-5,19-diphenyl-
3,6,9,12,15,18,21-heptaoxabicyclo[21.3.1]heptacosa-
1(26),23(27),24-triene, (S,S)-14
In a manner similar to that described for the preparation
of (S,S)-11, treatment of (S,S)-10 (6.56 g, 13.5 mmol) with
tetraethylene glycol di(p-toluenesulfonate) (8.12 g, 16.1
mmol) and sodium hydride (60% in mineral oil, 4.93 g,
123 mmol) gave (S,S)-14 (3.14 g, 4.86 mmol, 36% yield)
as a colorless oil after chromatography on silica gel
(hexane:ethyl acetate) followed by alumina (CHCl3):
[h]2D9=+56.9 (c 1.00, CHCl3); IR (neat) 2867, 1453, 1346,
3.10. (5S,19S)-27-Hydroxy-25-nitro-5,19-diphenyl-3,6,9,
12,15,18,21-heptaoxabicyclo[21.3.1]heptacosa-
1(26),23(27),24-triene, (S,S)-3
In a manner similar to that described for the prepara-
tion of (S,S)-2, treatment of (S,S)-16 (660 mg, 1.19
mmol) with sodium nitrite and nitric acid gave (S,S)-
3 (240 mg, 34% yield) as a yellow oil after chro-
matography on silica gel (hexane:ethyl acetate)
followed by alumina (CHCl3): [h]2D5=+53.3 (c 1.06,
CHCl3); IR (neat) 3277, 2867, 1596, 1521, 1452, 1339,
1
1216, 1107, 1004, 757, 702 cm−1; H NMR (CDCl3, 270
MHz) l 3.46–3.77 (m, 20H, CH2), 3.93 (s, 3H, OCH3),
4.63 (dd, J=3.3, 8.0 Hz, 2H, OCH(Ph)CH2), 4.65, 4.70
(AB, J=11.6 Hz, Dw=13.2 Hz, 4H, benzylic CH2),
7.27–7.36 (m, 10H, C6H5), 7.51 (s, 2H, phenol ring CH);
13C NMR (CDCl3, 67.8 MHz) l 63.13, 67.95, 68.84, 70.60,
70.67, 70.70, 75.33, 82.31, 116.71, 126.75, 127.82, 128.35,
132.25, 133.91, 138.90, 155.66; MS (FAB) m/z 645
(M+H)+, 667 (M+Na)+; HRMS (FAB) calcd for
C33H42O8Br (M+H)+ 642.2043; found 642.2032.
1
1097, 751, 702 cm−1; H NMR (CDCl3, 270 MHz) l
3.45–3.87 (m, 20H, CH2), 4.70 (dd, J=5.8, 5.8 Hz,
2H, OCH(Ph)CH2), 4.81, 4.85 (AB, J=12.9 Hz, Dw=
17.9 Hz, 4H, benzylic CH2), 7.26–7.40 (m, 10H,
C6H5), 8.08 (s, 2H, phenol ring CH), 9.13 (1H, s,
OH); 13C NMR (CDCl3, 67.8 MHz) l 68.76, 69.86,
69.87, 70.73, 70.90, 75.50, 81.67, 123.63, 125.26,
126.82, 128.11, 128.49, 138.17, 140.22, 159.56; MS
(FAB) m/z 598 (M+H)+, 620 (M+Na)+; HRMS
(FAB) calcd for C32H40NO10 (M+H)+ 598.2652; found
598.2671.
3.8. (5S,19S)-27-Methoxy-5,19-diphenyl-3,6,9,12,15,18,
21-heptaoxabicyclo[21.3.1]heptacosa-1(26),23(27),24-
triene, (S,S)-15
In a manner similar to that described for the preparation

K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
563
3.11. (5S,22S)-8-Bromo-30-methoxy-5,22-diphenyl-3,6,9,
12,15,18,21,24-octaoxabicyclo[24.3.1]triaconta-
1(29),26(30),27-triene, (S,S)-17
(M+H)+, 619 (M+Na)+; HRMS (FAB) calcd for
C34H45O9 (M+H)+ 597.3064; found 597.3047.
3.14. (5S,22S)-30-Hydroxy-8-nitro-5,22-diphenyl-3,6,9,12,
15,18,21,24-octaoxabicyclo[24.3.1]triaconta-
1(29),26(30),27-triene, (S,S)-4
In a manner similar to that described for the preparation
of (S,S)-11, treatment of (S,S)-10 (9.30 g, 19.1 mmol)
with pentaethylene glycol di(p-toluenesulfonate) (10.4 g,
19.1 mmol) and sodium hydride (60% in mineral oil, 3.85
g, 96.3 mmol) gave (S,S)-17 (3.32 g, 25% yield) as a
colorless oil after chromatography on silica gel (hex-
ane:ethyl acetate) followed by alumina (CHCl3): [h]2D6=
+56.9 (c 1.10, CHCl3); IR (neat) 2867, 1453, 1347, 1246,
In a manner similar to that described for the preparation
of (S,S)-2, treatment of (S,S)-19 (330 mg, 0.553 mmol)
with sodium nitrite and nitric acid gave (S,S)-4 (149 mg,
42% yield) as a yellow oil after chromatography on silica
gel (hexane:ethyl acetate) followed by alumina (CHCl3
then ethanol): [h]2D7=+50.5 (c 0.84, CHCl3); IR (neat)
3282, 2868, 1595, 1520, 1453, 1338, 1100, 751, 703 cm−1;
1H NMR (CDCl3, 270 MHz) l 3.49–3.79 (m, 24H, CH2),
4.67 (dd, J=4.7, 6.7 Hz, 2H, OCH(Ph)CH2), 4.75, 4.82
(AB, J=12.7 Hz, Dw=19.3 Hz, 4H, benzylic CH2),
7.27–7.41 (m, 10H, C6H5), 8.08 (s, 2H, phenol ring CH),
9.24 (1H, s, OH); 13C NMR (CDCl3, 67.8 MHz) l 68.52,
69.60, 70.55, 70.61, 70.68, 75.36, 81.67, 123.91, 125.29,
126.83, 128.08, 128.46, 138.25, 140.18, 159.56; MS (FAB)
m/z 642 (M+H)+, 664 (M+Na)+; HRMS (FAB) calcd for
C34H44NO11 (M+H)+ 642.2914; found 642.2908.
1
1105, 1003, 857, 759, 703 cm−1; H NMR (CDCl3, 270
MHz) l 3.46–3.76 (m, 24H, CH2), 3.82 (s, 3H, OCH3),
4.61–4.71 (m, 6H, OCH(Ph)CH2 and benzylic CH2),
7.27–7.37 (m, 10H, C6H5), 7.51 (s, 2H, MeOArH); 13C
NMR (CDCl3, 67.8 MHz) l 62.71, 67.75, 68.79, 70.56,
70.58, 70.69, 70.71, 75.29, 82.14, 116.90, 126.83, 127.84,
128.36, 131.94, 133.87, 139.00, 155.26; MS (FAB) m/z
689 (M+H)+, 711 (M+Na)+; HRMS (FAB) calcd for
C35H45O9BrNa (M+Na)+ 711.2145; found 711.2158.
3.12. (5S,22S)-30-Methoxy-5,22-diphenyl-3,6,9,12,15,18,
21,24-octaoxabicyclo[24.3.1]triaconta-1(29),26(30),27-
triene, (S,S)-18
3.15.5-Bromo-1,3-bis[(4R)-4-hydroxy-4-phenyl-2-oxabut-
yl]-2-methoxybenzene, (R,R)-10
In a manner similar to that described for the preparation
of (S,S)-12, treatment of (S,S)-17 (2.40 g, 3.48 mmol)
with a 1.6 M solution of n-BuLi in hexanes (3.4 mL, 5.57
mmol) followed by water gave (S,S)-18 (1.44 g, 68%
yield) as a colorless oil after chromatography on silica gel
(hexane:ethyl acetate): [h]2D6=+60.0 (c 1.03, CHCl3); IR
(neat) 2866, 1594, 1453, 1347, 1249, 1105, 1006, 950, 788,
760, 703 cm−1; 1H NMR (CDCl3, 270 MHz) l 3.49–3.78
(m, 24H, CH2), 3.85 (s, 3H, OCH3), 4.63 (dd, J=3.2, 8.2
Hz, 2H, OCH(Ph)CH2), 4.68 (s, 4H, benzylic CH2), 7.10
(t, J=7.2 Hz, 1H, MeOArH), 7.28–7.41 (m, 12H, C6H5
and MeOArH); 13C NMR (CDCl3, 67.8 MHz) l 62.79,
68.31, 68.88, 70.62, 70.63, 70.74, 70.75, 75.22, 82.12,
123.98, 126.85, 127.75, 128.31, 129.65, 131.47, 139.23,
156.53; MS (FAB) m/z 611 (M+H)+, 633 (M+Na)+;
HRMS (FAB) calcd for C35H46O9Na (M+Na)+ 633.3040;
found 633.3021.
In a manner similar to that described for the preparation
of (S,S)-10, treatment of (R)-(−)-2-phenyl-2-(tetra-
hydropyranyloxy)ethanol7,8 (18.3 g, 91.5 mmol) with
5 - bromo - 1,3 - bis(bromomethyl) - 2 - methoxybenzene7
(14.0 g, 41.6 mmol) and sodium hydride (60% in mineral
oil, 4.87 g, 0.122 mol) followed by deprotection gave
(R,R)-10 (17.2 g, 94%) as a yellow oil after chromatog-
raphy on silica gel (hexane:ethyl acetate): [h]2D6=−26.3 (c
1.01, CHCl3); IR (neat) 3437, 2903, 1454, 1358, 1212,
1119, 1004, 760, 701 cm−1; 1H NMR (CDCl3, 270 MHz)
l 2.91 (bs, 2H, OH), 3.53–3.71 (m, 4H, CH2), 3.70 (3H,
s, OCH3), 4.58 (s, 4H, benzylic CH2), 4.92 (dd, J=3.2,
8.5 Hz, 2H, OCH(Ph)CH2), 7.24–7.38 (m, 10H, C6H5),
7.47 (s, 2H, OMeArH); MS (FAB) m/z 487 (M+H)+.
3.16. 5-Bromo-2-methoxy-1,3-bis[(4R)-4-methoxy-
methoxy-4-phenyl-2-oxabutyl]benzene, (R,R)-20
3.13. (5S,22S)-30-Hydroxy-5,22-diphenyl-3,6,9,12,15,18,
21,24-octaoxabicyclo[24.3.1]triaconta-1(29),26(30),27-
triene, (S,S)-19
LiBr·H2O (4.40 g, 24.6 mmol) and TsOH·H2O (3.10 g,
30.7 mmol) were added successively to a solution of
(R,R)-10 in formaldehyde dimethyl acetal (70 mL). After
stirring for 2 days at room temperature, the reaction
mixture was extracted with ethyl acetate, and combined
extracts were washed with water and dried over anhy-
drous MgSO4. After the solvent was removed under
reduced pressure, the residue was chromatographed on
silica gel (hexane:ethyl acetate) to give (R,R)-20 (3.39 g,
50% yield) as a yellow oil: [h]2D6=−95.1 (c 0.98, CHCl3);
IR (neat) 2890, 1455, 1359, 1212, 1152, 1104, 1035, 919,
In a manner similar to that described for the preparation
of (S,S)-13, treatment of (S,S)-18 (1.40 g, 2.29 mmol)
with sodium ethanethiolate in DMF gave (S,S)-19 as a
colorless oil (409 mg, 30% yield) after chromatography
on silica gel (hexane:ethyl acetate): [h]2D6=+55.8 (c 1.06,
CHCl3); IR (neat) 3361, 2866, 1598, 1453, 1348, 1223,
1
1104, 758, 703 cm−1; H NMR (CDCl3, 270 MHz) l
1
760, 702 cm−1; H NMR (CDCl3, 300 MHz) l 3.32 (dd,
3.50–3.77 (m, 24H, CH2), 4.65 (dd, J=4.0, 8.2 Hz, 2H,
OCH(Ph)CH2), 4.72, 4.76 (AB, J=12.1 Hz, Dw=12.4
Hz, 2H, benzylic CH2), 6.80 (t, J=7.7 Hz, 1H, phenol
ring CH), 7.10 (d, J=7.7 Hz, 2H, phenol ring CH),
J=7.7, 10.4 Hz, 2H, OCH(Ph)CH2), 3.37 (s, 6H,
OCH2OCH3), 3.61 (3H, s, OCH3), 3.76 (dd, J=4.0, 10.4
Hz, 2H, OCH(Ph)CH2), 4.55 (s, 4H, benzylic CH2), 4.60,
4.65 (AB, J=6.2 Hz, Dw=11.7 Hz, 4H, OCH2OCH3),
4.86 (dd, J=4.0, 7.7 Hz, 2H, OCH(Ph)CH2), 7.23–7.36
(m, 10H, C6H5), 7.44 (s, 2H, OMeArH); MS (FAB) m/z
575 (M+H)+.
7.28–7.35 (m, 10H, C6H5), 8.00 (s, 1H, phenolic OH); 13
C
NMR (CDCl3, 67.8 MHz) l 68.67, 70.39, 70.59, 70.66,
70.75, 70.81, 75.08, 81.57, 119.25, 124.23, 126.91, 127.88,
128.33, 128.36, 138.83, 154.17; MS (FAB) m/z 597

564
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
3.17. 2-Methoxy-1,3-bis[(4R)-4-methoxymethoxy-4-
phenyl-2-oxabutyl]benzene, (R,R)-21
3.20. 2-Hydroxy-1,3-bis[(4R)-4-hydroxy-4-phenyl-2-
oxabutyl]-5-nitrobenzene, (R,R)-5
In a manner similar to that described for the prepara-
tion of (S,S)-12, treatment of (R,R)-20 (248 mg, 0.43
mmol) with a 1.6 M solution of n-BuLi in hexanes (0.43
mL, 0.65 mmol) followed by water gave (R,R)-21 (153
mg, 71% yield) as a yellow oil after chromatography on
silica gel (hexane:ethyl acetate): [h]2D6=−103.2 (c 0.64,
CHCl3); IR (neat) 2888, 1594, 1455, 1366, 1213, 1152,
In a manner similar to that described for the prepara-
tion of (S,S)-2, treatment of (R,R)-23 (750 mg, 1.9
mmol) with sodium nitrite and nitric acid gave (R,R)-5
(212 mg, 25% yield) as a yellow powder after chro-
matography on silica gel (hexane:ethyl acetate) fol-
lowed by preparative recycling HPLC (CHCl3): mp
52–53°C; [h]2D6=−29.3 (c 1.01, CHCl3); IR (KBr) 3306,
2868, 1597, 1520, 1454, 1338, 1198, 1099, 909, 750, 701
1
1104, 1037, 919, 759, 701 cm−1; H NMR (CDCl3, 270
1
MHz) l 3.35 (s, 6H, OCH2OCH3), 3.62 (dd, J=7.8,
10.4 Hz, 2H, OCH(Ph)CH2), 3.65 (3H, s, OCH3), 3.77
(dd, J=4.0, 10.4 Hz, 2H, OCH(Ph)CH2), 4.59–4.68 (m,
8H, benzylic CH2 and OCH2OCH3), 4.86 (dd, J=4.0,
7.8 Hz, 2H, OCH(Ph)CH2), 7.06 (t, J=7.5 Hz, 1H,
OMeArH), 7.24–7.34 (m, 12H, OMeArH and C6H5);
MS (FAB) m/z 519 (M+Na)+.
cm−1; H NMR (CDCl3, 270 MHz) l 2.74 (s, 2H, OH),
3.65 (dd, J=8.6, 10.1 Hz, 2H, OCH(Ph)CH2), 3.78 (dd,
J=3.2, 10.1 Hz, 2H, OCH(Ph)CH2), 4.77 (s, 4H, ben-
zylic CH2), 5.00 (dd, J=3.2, 8.6 Hz, 2H,
OCH(Ph)CH2), 7.25–7.40 (m, 10H, C6H5), 8.09 (s, 2H,
phenol ring CH), 8.93 (s, 1H, phenolic OH); MS (FAB)
m/z 440 (M+H)+.
3.21. 5-Bromo-2-methoxy-1,3-bis[(4R)-4-methoxy-4-
phenyl-2-oxabutyl]benzene, (R,R)-24
3.18. 1,3-Bis[(4R)-4-hydroxy-4-phenyl-2-oxabutyl]-2-
methoxybenzene, (R,R)-22
A solution of (R,R)-10 (2.50 g, 5.10 mmol) in dry THF
(50 mL) was added dropwise to a suspension of sodium
hydride (60% in mineral oil, 620 mg, 15.5 mmol) in dry
THF (50 mL) over a 3 h period at 60°C. After the
mixture was cooled to room temperature, iodomethane
(2.50 ml, 41.0 mmol) was added dropwise to the reac-
tion mixture. After all the starting material (R,R)-10
had been vanished as indicated by TLC, the reaction
mixture was neutralized with water and 6N HCl with
ice cooling. After excess iodomethane and the solvent
were removed under reduced pressure, the residue was
extracted with ethyl acetate. The extract was dried over
anhydrous MgSO4 and the solvent was removed under
reduced pressure. Chromatography on silica gel (hex-
ane:ethyl acetate) of the residue gave (R,R)-24 as a
yellow oil (2.30 g, 86% yield): [h]2D6=−34.7 (c 0.94,
CHCl3); IR (neat) 2930, 1455, 1357, 1210, 1106, 1004,
A 0.1 mL of 6N HCl was added to a solution of
(R,R)-21 (898 mg, 1.80 mmol) in methanol with ice-
cooling. After being stirred for 2 days at room temper-
ature,
an
aqueous
solution
of
sodium
hydrogencarbonate was added to the reaction mixture.
After extraction with ethyl acetate, the extract was
washed with water and dried over anhydrous MgSO4.
The solvent was removed under reduced pressure and
the residue was chromatographed on silica gel (hex-
ane:ethyl acetate) to give (R,R)-22 (535 mg, 72% yield)
as a yellow oil: [h]2D6=−38.5 (c 1.08, CHCl3); IR (neat)
3443, 2863, 1595, 1455, 1359, 1212, 1102, 903, 761, 701
1
cm−1; H NMR (CDCl3, 300 MHz) l 2.93 (s, 2H, OH),
3.55 (dd, J=8.6, 9.8 Hz, 2H, OCH(Ph)CH2), 3.69 (dd,
J=3.2, 9.8 Hz, 2H, OCH(Ph)CH2), 3.77 (s, 3H, OCH3),
4.65 (s, 4H, benzylic CH2), 4.92 (dd, J=3.2, 8.6 Hz,
2H, OCH(Ph)CH2), 7.13 (t, J=7.4 Hz, 1H, OMeArH),
7.24–7.38 (m, 12H, OMeArH and C6H5); MS (FAB)
m/z 409 (M+H)+.
1
873, 759, 701 cm−1; H NMR (CDCl3, 400 MHz) l 3.30
(s, 6H, OCH3), 3.56 (dd, J=7.7, 10.4 Hz, 2H,
OCH(Ph)CH2), 3.63 (3H, s, ArOCH3), 3.70 (dd, J=3.8,
10.4 Hz, 2H, OCH(Ph)CH2), 4.41 (dd, J=3.8, 7.7 Hz,
2H,OCH(Ph)CH2), 4.51, 4.59 (AB, J=8.4 Hz, Dw=
20.6 Hz, 4H, benzylic CH2), 7.25–7.40 (m, 10H, C6H5),
7.43 (s, 2H, OMeArH); MS (FAB) m/z 515 (M+H)+.
3.19. 2-Hydroxy-1,3-bis[(4R)-4-hydroxy-4-phenyl-2-
oxabutyl]benzene, (R,R)-23
3.22. 2-Methoxy-1,3-bis[(4R)-4-methoxy-4-phenyl-2-
oxabutyl]benzene, (R,R)-25
In a manner similar to that described for the prepara-
tion of (S,S)-13, treatment of (R,R)-22 (465 mg, 1.10
mmol) with sodium ethanethiolate in DMF gave (R,R)-
23 (341 mg, 76% yield) as a colorless oil after chro-
matography on silica gel (hexane:ethyl acetate):
[h]2D6=−73.1 (c 1.01, CHCl3); IR (neat) 3376, 2864,
In a manner similar to that described for the prepara-
tion of (S,S)-12, treatment of (R,R)-24 (500 mg, 0.970
mmol) with a 1.6 M solution of n-BuLi in hexanes (0.90
mL, 1.44 mmol) followed by water gave (R,R)-25 (290
mg, 75% yield) as a yellow oil after chromatography on
silica gel (hexane:ethyl acetate): [h]2D6=−50.4 (c 0.52,
CHCl3); IR (neat) 2931, 1455, 1358, 1245, 1103, 1006,
1
1598, 1464, 1358, 1219, 1103, 901, 756, 701 cm−1; H
NMR (CDCl3, 300 MHz) l 3.50 (dd, J=8.8, 10.3 Hz,
2H, OCH(Ph)CH2), 3.56 (s, 2H, OH), 3.63 (dd, J=3.2,
10.3 Hz, 2H, OCH(Ph)CH2), 4.62, 4.63 (AB, J=12.4
Hz, Dw=2.3 Hz, 4H, benzylic CH2), 4.84 (dd, J=3.2,
8.8 Hz, 2H, OCH(Ph)CH2), 7.07 (d, J=7.7, Hz, 2H,
phenol ring CH), 7.40 (t, J=7.7 Hz, 1H, phenol ring
CH), 7.18–7.30 (m, 10H, C6H5), 7.94 (s, 1H, phenolic
OH); MS (FAB) m/z 395 (M+H)+.
1
760, 701 cm−1; H NMR (CDCl3, 400 MHz) l 3.29 (s,
6H, OCH3), 3.54 (dd, J=7.8, 10.3 Hz, 2H,
OCH(Ph)CH2), 3.67 (3H, s, ArOCH3), 3.70 (dd, J=3.9,
10.3 Hz, 2H, OCH(Ph)CH2), 4.41 (dd, J=3.9, 7.8 Hz,
2H,OCH(Ph)CH2), 4.57, 4.65 (AB, J=7.9 Hz, Dw=
20.6 Hz, 4H, benzylic CH2), 7.06 (t, J=7.6 Hz,

K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
565
OMeArH), 7.23–7.35 (m, 12H, OMeArH and C6H5);
MS (FAB) m/z 435 (M+−H).
CH(CH3)2) 3.46 (dd, J=8.7, 11 Hz, 1H, CH2OH), 3.67
(dd, J=4.7, 11 Hz, 1H, CH2OH), 3.86 (dd, J=4.7, 8.7
Hz, 1H, CHPh), 7.24–7.38 (m, 5H, C6H5); MS (EI) m/z
148 (M+−CH2ꢀOH). Anal. calcd for C11H17NO: C,
73.70; H, 9.56; N, 7.81. Found: C, 73.84; H, 9.65; N,
7.87%.
3.23. 2-Hydroxy-1,3-bis[(4R)-4-methoxy-4-phenyl-2-
oxabutyl]benzene, (R,R)-26
In a manner similar to that described for the prepara-
tion of (S,S)-13, treatment of (R,R)-25 (200 mg, 0.46
mmol) with sodium ethanethiolate in DMF gave (R,R)-
26 (144 mg, 74% yield) as a colorless oil after chro-
matography on silica gel (hexane:ethyl acetate):
[h]2D6=−53.5 (c 0.2, CHCl3); IR (neat) 3361, 2865, 2825,
1597, 1492, 1454, 1356, 1223, 1095, 869, 759, 701 cm−1;
1H NMR (CDCl3, 400 MHz) l 3.30 (s, 6H, OCH3),
3.61 (dd, J=7.9, 10.6 Hz, 2H, OCH(Ph)CH2), 3.70 (dd,
J=3.7, 10.6 Hz, 2H, OCH(Ph)CH2), 4.44 (dd, J=3.7,
7.9 Hz, 2H,OCH(Ph)CH2), 4.68, 4.72 (AB, J=12.4 Hz,
Dw=12.1 Hz, 4H, benzylic CH2), 6.80 (t, J=7.4 Hz,
phenol ring CH), 7.11 (d, J=7.7 Hz, 2H, phenol ring
CH), 7.25–7.38 (m, 10H, C6H5), 7.76 (s, 1H, phenolic
OH); MS (FAB) m/z 423 (M+H)+.
3.26. (S)-2-(Isopropylamino)-2-phenylethanol, (S)-34
In a manner similar to that described for the prepara-
tion of (R)-34, reaction of (S)-2-amino-2-phenylethanol
(1.00 g, 7.29 mmol) with acetone followed by sodium
borohydride gave (S)-34 (925 mg, 77% yield) as color-
less prisms after recrystallization: mp 76–78°C; [h]3D1=
+66.7 (c 0.91, EtOH); IR (KBr) 3270, 1472, 1169, 1134,
1
1064, 1041, 701 cm−1; H NMR (CDCl3, 270 MHz) l
1.02 (d, J=6.2 Hz, 3H, CHCH3), 1.04 (d, J=6.2 Hz,
3H, CHCH3), 2.67–2.81 (m, 1H, CH(CH3)2), 3.46 (dd,
J=8.7, 11 Hz, 1H, CH2OH), 3.67 (dd, J=4.7, 11 Hz,
1H, CH2OH), 3.86 (dd, J=4.7, 8.7 Hz, 1H, CHPh),
7.24–7.38 (m, 5H, C6H5); MS (EI) m/z 148 (M+−
CH2ꢀOH). Anal. calcd for C11H17NO: C, 73.70; H,
9.56; N, 7.81. Found: C, 73.66; H, 9.63; N, 7.91%.
3.24. 2-Hydroxy-1,3-bis[(4R)-4-methoxy-4-phenyl-2-
oxabutyl]-5-nitrobenzene, (R,R)-6
3.27. (R)-2-(Isopropylamino)-1-phenylethanol, (R)-35
In a manner similar to that described for the prepara-
tion of (S,S)-2, treatment of (R,R)-26 (173 mg, 0.409
mmol) with sodium nitrite and nitric acid gave (R,R)-6
(111 mg, 58% yield) as a yellow oil after chromatogra-
phy on silica gel (hexane:ethyl acetate) followed by
preparative recycling HPLC (CHCl3): [h]2D8=−71.0 (c
1.07, CHCl3); IR (neat) 3289, 2864, 1597, 1522, 1454,
In a manner similar to that described for the prepara-
tion of (R)-34, reaction of (R)-2-amino-1-phenylethanol
(975 mg, 7.12 mmol) with acetone followed by sodium
borohydride gave (R)-35 as colorless needles (904 mg,
71% yield): mp 83–85°C; [h]2D8=−26.7 (c 1.03, EtOH);
IR (KBr) 3293, 2968, 1604, 1450, 1345, 1088, 1062, 701
1
1
1338, 1274, 1201, 1090, 869, 816, 760, 701 cm−1; H
cm−1; H NMR (CDCl3, 270 MHz) l 1.07 (d, J=6.2
NMR (CDCl3, 270 MH) l 3.33 (s, 6H, OCH3), 3.69
(dd, J=7.9, 10.7 Hz, 2H, OCH(Ph)CH2), 3.73 (dd,
J=3.8, 10.7 Hz, 2H, OCH(Ph)CH2), 4.47 (dd, J=3.8,
7.9 Hz, 2H,OCH(Ph)CH2), 4.72 (s, 4H, benzylic CH2),
7.32–7.57 (m, 10H, C6H5), 8.10 (s, 2H, phenol ring
CH), 8.86 (s, 1H, phenolic OH); MS (FAB) m/z 468
(M+H)+. Anal. calcd for C26H29NO7: C, 66.80; H, 6.25;
N, 3.00. Found: C, 66.66; H, 6.31; N, 2.78%.
Hz, 6H, CHCH3), 2.76–2.87 (m, 1H, CH(CH3)2), 2.65
(dd, J=8.9, 12 Hz, 1H, CH2OH), 2.94 (dd, J=3.7, 12
Hz, 1H, CH2OH), 4.65 (dd, J=3.7, 8.9 Hz, 1H,
CHPh), 7.23–7.39 (m, 5H, C6H5); MS (EI) m/z 180
(M+−CH2ꢀOH). Anal. calcd for C11H17NO: C, 73.70;
H, 9.56; N, 7.81. Found: C, 73.74; H, 9.70; N, 7.81%.
3.28. (S)-2-(Isopropylamino)-1-phenylethanol, (S)-35
3.25. (R)-2-(Isopropylamino)-2-phenylethanol, (R)-34
In a manner similar to that described for the prepara-
tion of (R)-34, reaction of (S)-2-amino-1-phenylethanol
(979 mg, 7.14 mmol) with acetone followed by sodium
borohydride gave (S)-35 as colorless needles after
recrystallization (973 mg, 76%): mp 82–83°C; [h]2D8=
+28.3 (c 1.10, EtOH); IR (KBr) 3293, 2968, 1604, 1450,
1345, 1088, 1062, 701 cm−1; 1H NMR (CDCl3, 270
MHz) l 1.07 (d, J=6.2 Hz, 6H, CH(CH3)2), 2.77–2.89
(m, 1H, CH(CH3)2), 2.66 (dd, J=8.9, 12 Hz, 1H,
CH2OH), 2.95 (dd, J=3.7, 12 Hz, 1H, CH2OH), 4.66
(dd, J=3.7, 8.9 Hz, 1H, CHPh), 7.22–7.39 (m, 5H,
C6H5); MS (EI) m/z 180 (M+−CH2ꢀOH). Anal. calcd
for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C,
73.52; H, 9.53; N, 7.82%.
To a solution of (R)-2-amino-2-phenylethanol (900 mg,
6.56 mmol) in ethanol (10 mL), acetone (1.2 mL, 10.9
mmol) was added and the reaction mixture was stirred
for 30 min at room temperature. After all the starting
amine had been consumed as indicated by gas chro-
matography, sodium borohydride (370 mg, 9.78 mmol)
was added with ice-cooling. After being stirred for 30
min, 1N HCl was added dropwise to adjust the solution
to pH 1, and the solvent was removed under reduced
pressure. 5 M aqueous KOH solution was added to
adjust the solution to pH 11, and the mixture was
extracted with CH2Cl2. The solution was dried over
anhydrous MgSO4 and the solvent was removed under
reduced pressure. The crude product was recrystallized
from hexane to give (R)-34 as colorless prisms (0.98 g,
83%): mp 76–78°C; [h]3D1=−68.7 (c 1.05, EtOH); IR
3.29. General procedures for determination of binding
constants
(KBr) 3270, 1472, 1169, 1134, 1064, 1041, 701 cm−1; H
The titration experiment for complexation of host
1
NMR (CDCl3, 270 MHz) l 1.02 (d, J=6.2 Hz, 3H,
CH3), 1.04 (d, J=6.2 Hz, 3H, CH3), 2.68–2.82 (m, 1H,
(S,S)-3 with chiral amine (S)-32 is described here as an
1
example for determination of binding constants by H

566
K. Hirose et al. / Tetrahedron: Asymmetry 14 (2003) 555–566
NMR spectroscopy. A solution of (S,S)-3 (22.3 mM) and
a solution of (S)-32 (81.1 mM) each in CDCl3 were
prepared. An initial 1H NMR spectrum of 600 mL of this
host (S,S)-3 solution was recorded. Samples were made
by adding the guest solutions to the host solution.
Namely, a 600 mL portion of the host solution and 0.0,
10, 20, 30, 40, 50, 60, 80, 100, 130, 160, and 200 mL
portions of the guest (S)-32 solution were mixed. Then,
spectra of these samples were recorded. The association
constant for the complex of (S,S)-3 with (S)-32 was
calculated by the non-linear least-squares method follow-
ing the chemical shift of one of the benzylic protons (Hb
shown in Fig. 3) of (S,S)-3. The titration curve is shown
in Fig. 1.
5. (a) Naemura, K.; Fuji, J.; Ogasahara, K.; Hirose, K.; Tobe,
Y. Chem. Commun. 1996, 2749–2750; (b) Naemura, K.;
Nishioka, K.; Ogasahara, K.; Nishikawa, Y.; Hirose, K.;
Tobe, Y. Tetrahedron: Asymmetry 1998, 9, 563–574; (c)
Hirose, K.; Ogasahara, K.; Nishioka, K.; Tobe, Y.; Nae-
mura, K. J. Chem. Soc., Perkin Trans. 2 2000, 1984–1993.
6. (a) Glink, P. T.; Schiavo, C.; Stoddart, J. F.; Williams, D.
J. Chem. Commun. 1996, 1483–1490; (b) Ashton, P. R.;
Bartsch, R. A.; Cantrill, S. J.; Hanes, R. E., Jr.; Hicking-
bottom, S. K.; Lowe, J. N.; Preece, J. A.; Stoddart, J. F.;
Talanov, V. S.; Wang, Z. H. Tetrahedron Lett. 1999, 40,
3661–3664.
7. Part of this work has been reported in a preliminary form:
Hirose, K.; Fujiwara, A.; Matsunaga, K.; Aoki, N.; Tobe,
Y. Tetrahedron Lett. 2002, 43, 8539–8542.
8. Naemura, K.; Nishikawa, Y.; Fuji, J.; Hirose, K.; Tobe,
The titration experiment for complexation of host (R,R)-
5 with chiral amine (R)-35 is described here as an example
for determination of binding constants by UV–visible
spectroscopy. A solution of (R,R)-5 in CHCl3 was
prepared and an initial UV spectrum of this solution was
recorded. The concentration was calculated to be 0.036
mM based on its molar extinction coefficient. Separately,
a solution of (R)-35 in CHCl3 was prepared. Samples
were made by adding the guest solution to the host
solution and diluted with CHCl3 to make the total
volume up to 4.0 mL, so that the concentrations of the
guest in each samples were 0.0, 2.0, 5.0, 8.0, 14, 20 mM,
respectively. The concentration of the host was kept
constant at 0.036 mM in each sample. Then, the spectra
of these five different solutions were recorded. The
binding constants were calculated from absorption inten-
sity of the complex at the absorption maximum (388 nm)
based on the Rose–Drago method using the spreadsheet
in Ref. 12b. A graphical expression to appreciate the
binding constant is shown in Fig. 2.
Y. Tetrahedron: Asymmetry 1997, 8, 873–882.
9. Huszthy, P.; Bradshaw, J. S.; Zhu, C. Y.; Izatt, R. M. J.
Org. Chem. 1991, 3330–3336.
10. Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970,
16, 1327–1328.
11. Browne, C. M.; Ferguson, G.; McKervey, M. A.; Mulhol-
land, D. L.; O’Connor, T.; Parvez, M. J. Am. Chem. Soc.
1985, 107, 2703–2712.
12. (a) Rose, N. J.; Drago, R. S. J. Am. Chem. Soc. 1959, 81,
6138–6141; (b) Hirose, K. J. Incl. Phenom. Macrocyclic
Chem. 2001, 39, 193–209.
13. Wilcox, C. J. In Frontiers in Supramolecular Organic
Chemistry and Photochemistry; Schneider, H. J.; Durr, H.;
Lehn, J. M., Eds.; VCH: Weinheim, New York, 1991; pp.
123–144.
14. We measured binding constants of (S,S)-3 with S- and
R-enantiomers of N,a-dimethylbenzylamine (32) by the 1H
NMR titration and UV–vis titration methods. The binding
constants of (S,S)-3 with (S)- and (R)-32 obtained by the
1H NMR titration method were (1.8 0.1)×10 M−1 and
8.8 0.3 M−1, respectively (KS/KR=2.0), and those deter-
mined by the UV–vis titration were (2.1 0.3) and (1.0
0.1)×10 M−1, respectively (KS/KR=2.1).
The binding constants thus determined are summarized
in Tables 1 and 2.
15. The reason for this rather unexpected observation is not
fully understood.
Acknowledgements
16. (a) Naemura, K.; Ogasahara, K.; Hirose, K.; Tobe, Y.
Tetrahedron: Asymmetry 1997, 8, 19–22; (b) Naemura, K.;
Matsunaga, K.; Fuji, J.; Ogasahara, K.; Nishikawa, Y.;
Hirose, K.; Tobe, Y. Anal. Sci. 1998, 14, 175–182; (c)
Ogasahara, K.; Hirose, K.; Tobe, Y.; Naemura, K. J.
Chem. Soc., Perkin Trans. 1 1997, 3227–3236.
This work was partially supported by SUNBOR founda-
tion from Suntory Institute for Bioorganic Research and
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports and Culture of Japan.
17. (a) Naemura, K.; Ueno, K.; Takeuchi, S.; Hirose, K.;
Tobe, Y.; Kaneda, T.; Sakata, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 383–388; (b) Naemura, K.; Ueno, K.;
Takauchi, S.; Tobe, Y.; Kaneda, T.; Sakata, Y. J. Am.
Chem. Soc. 1993, 115, 8475–8476.
18. Saavendra, J. E. J. Org. Chem. 1985, 50, 2271–2273.
19. Attempts to measure NOE between the hosts and the
guests were unsuccessful.
References
1. For a comprehensive review, see: Zhang, X. X.; Bradshaw,
J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 3313–3361.
2. Main, B. G.; Tucker, H. In Medicinal Chemistry; 2nd ed.;
Genellin, C. R.; Roberts, S. M., Eds.; London: Academic
Press, 1993; pp. 187–208.
20. For example, CISs of H2b, H22b, and H19 with isopropyl-
methylamine are −0.45, −0.24, and −0.08 ppm, respec-
tively. The large negative CISs of H2b and H22b is ascribed
to the conformational change of the host (S,S)-3 upon
complexation.
21. Although the enantiomer selectivities for other host–guest
combinations may be similarly explained, we were unable
to obtain spectroscopic (NOE and CIS) support for them.
3. (a) Millership, J. S.; Fitzpatrick, A. Chirality 1993, 5,
573–576; (b) Patil, P. N.; LaPidius, J. B.; Tye, A. J. Pharm.
Sci. 1970, 59, 1205–1234; (c) Brittain, R. T.; Farmer, J. B.;
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