Preparation and temperature-dependent enantioselectivities of homochiral phenolic crown ethers having aryl chiral barriers: Thermodynamic parameters for enantioselective complexation with chiral amines

Article abstract of DOI:10.1016/S0957-4166(97)00638-1

Homochiral crown ether (S,S)-1 containing 1-naphthyl groups as chiral barriers together with the phenol moiety was prepared by using (S)-3 as a chiral subunit which was resolved in enantiomerically pure form by lipase- catalyzed enantioselective acylation of (±)-3. Homochiral phenolic crown ether (S,S)-2, containing phenyl groups as chiral barriers, was also prepared from (S)-5 which was derived from (S)-mandelic acid. The association constants for their complexes with chiral amines in CHCl₃ were determined at various temperatures by the UV-visible spectroscopic method demonstrating that the crown ethers (S,S)-1 and (S,S)-2 displayed the large Δ(R)-(S)ΔG values of 6.2 and 6.4 kJ mol^-1, respectively, towards the amine 21 at 15°C. Thermodynamic parameters for complex formation were also determined and a linear correlation between TΔ(R-S)ΔS and Δ(R-S)ΔH values was observed.

Full text of DOI:10.1016/S0957-4166(97)00638-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 563–574
Preparation and temperature-dependent enantioselectivities of
homochiral phenolic crown ethers having aryl chiral barriers:
thermodynamic parameters for enantioselective complexation
with chiral amines
Koichiro Naemura,∗ Kazuyuki Nishioka, Kazuko Ogasahara, Yasushi Nishikawa, Keiji Hirose
and Yoshito Tobe
Department of Chemistry, Faculty of Engineering Science, Osaka University, Toyonaka, Osaka 560 Japan
Received 6 November 1997; accepted 4 December 1997
Abstract
Homochiral crown ether (S,S)-1 containing 1-naphthyl groups as chiral barriers together with the phenol moiety
was prepared by using (S)-3 as a chiral subunit which was resolved in enantiomerically pure form by lipase-
catalyzed enantioselective acylation of (ꢀ)-3. Homochiral phenolic crown ether (S,S)-2, containing phenyl groups
as chiral barriers, was also prepared from (S)-5 which was derived from (S)-mandelic acid. The association
constants for their complexes with chiral amines in CHCl3 were determined at various temperatures by the
UV–visible spectroscopic method demonstrating that the crown ethers (S,S)-1 and (S,S)-2 displayed the large
∆
R−S∆G values of 6.2 and 6.4 kJ mol−1, respectively, towards the amine 21 at 15°C. Thermodynamic parameters
for complex formation were also determined and a linear correlation between T∆R−S∆S and ∆R−S∆H values was
observed. © 1998 Elsevier Science Ltd. All rights reserved.
A large number of homochiral crown ethers have been prepared by using various types of homochiral
compounds as chiral subunits.1 In regard to their chiral recognition on complexation, it is a generally
accepted view that an increase in the size of substituents at stereogenic centers usually increases the
degree of enantiomeric recognition. On the other hand, large repulsive interactions between host and
guest molecules may reduce the stability of the complex. Recently, in order to seek information on how
the size of the substituents at stereogenic centers might affect the enantioselectivity in complexation with
amines, we have prepared homochiral azophenolic crown ethers possessing the alkyl substituents as chiral
barriers and examined the temperature dependent enantioselectivity and thermodynamic parameters for
complexation.2 In this paper, we report the preparation of homochiral crown ethers (S,S)-1 and (S,S)-2
containing the 1-naphthyl substituents and the phenyl substituents, respectively, as chiral barriers together
with the p-(2,4-dinitrophenylazo)phenol moiety and the association constants of their complexes with
∗
Corresponding author. E-mail: hirose@chem.es.osaka-u.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00638-1

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neutral amines determined on the basis of the UV–visible spectrum of the complexes collected in CHCl3
at various temperatures. Further, thermodynamic parameters for complex formation were also determined
from the van’t Hoff plots of the Ka values.
1. Results and discussion
The enantioselective acylation of (ꢀ)-3 with isopropenyl acetate as an acylating agent was carried out
using lipase QL from Alcaligenes sp. In order to prepare directly homochiral 3 of high e.e., the reaction
was terminated at the esterification point of >50%. Silica gel chromatography of the products gave (+)-3
of 96% e.e. (by HPLC) in 33% yield together with the mixture of the monoacetates. Recrystallization of
(+)-3 of 96% e.e. from diethyl ether gave the partially resolved (+)-3 of 48% e.e. as a sparingly soluble

K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
565
solid and enantiomerically pure (+)-3, [α]D +75.8 (10−1 deg cm2 g−1) (CHCl3), was isolated in 31%
yield based on (ꢀ)-3 from the mother liquor. The absolute configuration of (+)-3 was determined by
chemical correlation with 8 of known absolute configuration.3 The primary hydroxy group of (+)-3 was
selectively tosylated to give (+)-7, [α]D +123 (CHCl3), in 60% yield. Treatment of (+)-7 with LiAlH4
gave (R)-(+)-8, [α]D +81.6 (MeOH), in 81% yield leading to the assignment of (S)-(+)-3.
Our previous results4 demonstrated that location of the phenyl substituents near the diethylene glycol
bridge resulted in a higher degree of enantiomeric recognition than is the case when the substituents
are located near the phenol moiety; in the phenolic crown ether having stereogenic centers at C-4 and
C-14 positions, the substituent at the stereogenic center and ‘ethyleneoxy barrier’2 recognize opposite
enantiomers of the amine resulting in a reduction of the degree of enantiomeric recognition in the
complexation of amines. In order to prepare the phenolic crown ether exhibiting a higher degree of
chiral recognition, the aryl substituents of the crown ethers (S,S)-1 and (S,S)-2 were located at the C-5
and C-13 positions.
Treatment of (S)-3 with triphenylmethyl chloride gave regioselectively (S)-4, [α]D +50.0 (CHCl3), in
72% yield. Condensation of two molar equivalents of (S)-4 with diethylene glycol bis(p-toluenesulfonate)
in the presence of NaH in THF gave (S,S)-9, [α]D +39.6 (CHCl3), which was deprotected with methanol
and p-toluenesulfonic acid to give (S,S)-10, [α]D +102 (CHCl3), in 57% overall yield for the two steps.
Ring closure of (S,S)-10 with 1,3-bis(bromomethyl)-2,5-dimethoxybenzene in the presence of NaH in
THF under high-dilution conditions gave (S,S)-13, [α]D +133 (CHCl3), in 78% yield. Treatment of (S,S)-
13 with sodium ethanethiolate in DMF cleaved selectively the inner methoxy group to give (S,S)-14,
[α]D +139 (CHCl3), in 94% yield. Oxidation of (S,S)-14 with cerium(IV) ammonium nitrate (CAN) in
acetonitrile gave (S,S)-17, which was immediately treated with 2,4-dinitrophenylhydrazine in a mixture
of ethanol, chloroform and conc. H2SO4 to give (S,S)-1 in 69% overall yield for the two steps.
Next, (S,S)-2 containing (S)-5 as a chiral subunit was prepared. Two molar equivalents of (S)-6,
which was derived from (S)-mandelic acid according to the reported procedure,5 were reacted with
1,3-bis(bromomethyl)-2,5-dimethoxybenzene in the presence of NaH to give (S,S)-11, deprotection of
which with pyridinium p-toluenesulfonate and ethanol gave (S,S)-12, [α]D +34.2 (CHCl3), in 80%
overall yield for the two steps. High-dilution condensation of (S,S)-12 with diethylene glycol bis(p-
toluenesulfonate) in the presence of NaH and KBF4 in THF gave (S,S)-15, [α]D +104 (CHCl3), in 42%
yield. Demethylation of (S,S)-15 gave (S,S)-16, [α]D +109 (CHCl3), in 77% yield, oxidation of which
followed by treatment with 2,4-dinitrophenylhydrazine afforded (S,S)-2 in 32% overall yield via (S,S)-18.
The association constants, Ka, of the complexes of the crown ethers (S,S)-1 and (S,S)-2 with chi-
ral amines; 2-aminopropan-1-ol 19, 2-amino-3-methylbutan-1-ol 20, 2-amino-2-phenylethanol 21, 1-
aminopropan-2-ol 22 and 1-phenylethylamine 23 were determined by the Rose–Drago method7 on the
basis of the UV–visible spectrum of the complexes in CHCl3 collected at various temperatures and the
observed Ka values are summarized in Table 1. The thermodynamic parameters, ∆H, ∆S and ∆G, for
complex formation were determined from the van’t Hoff plots of the Ka values and are listed in Table 2.
Table 2 shows that large repulsive interactions between host and guest molecules slightly reduced the
stability of the complex; all complexes of (S,S)-1 with the amines, except the (S,S)-1: (S)-21 complex,
showed a little less negative ∆G value at 298 K than did the corresponding complexes of (S,S)-2 with the
amines.
In Figs 1 and 2, we plot ∆R−S∆G (=∆GR−∆GS) values for complexation of the crown ethers (S,S)-
1 and (S,S)-2, respectively, with the amines as a function of temperature. The plots indicate that the
enantioselectivities of the crown ethers (S,S)-1 and (S,S)-2 towards the amines; the (R)-selectivities of
both crown ethers towards the amines 19, 20, 21 and 22 and the (S)-selectivities of both crown ethers
towards 23 were substantially contributed to by ∆R−S∆H. In Fig. 3, using the data in Table 2, plotting

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Table 1
The association constants for the complexes of the crown ethers (S,S)-1 and (S,S)-2 with amines in
chloroform
T∆S at 298 K against ∆H affords two types of linear correlations; T∆S=0.739∆H +1.54, R=0.897 for
the complexations of (S,S)-1 and T∆S=0.757∆H +2.12, R=0.959 for those of (S,S)-2. Judging from the
slopes of the plot of α=0.739 and α=0.757, we infer that the processes of complexation of the crown
ethers (S,S)-1 and (S,S)-2 with the amines were accompanied with the same extent of conformational
changes.8
In Fig. 4, we plot T∆R−S∆S values at 298 K against ∆R−S∆H values giving a linear correlation;
T∆R−S∆S=0.742∆R−S∆H−0.459, R=0.915. The data demonstrate that the complexation showing the
larger ∆R−S∆H value is accompanied by the larger ∆R−S∆S value and the larger ∆R−S∆S value results
in the greater slope of the plot of ∆R−S∆G against temperature. Therefore, relative merits of the
enantioselectivity in the complexation may reverse at a certain temperature. For instance, on the basis
of the observed thermodynamic parameters, it is predictable that the ∆R−S∆G value for the (S,S)-1:21
complexation is larger below ca −40°C than that for the (S,S)-2:21 complexation. The enantioselectivity
observed at 15°C for the (S,S)-1:21 complexation (∆R−S∆G=−6.2 kJ mol−1) was lower than that for the
(S,S)-2:21 complexation (∆R−S∆G=−6.4 kJ mol−1). Thus (S,S)-1 having the larger substituents showed
a larger ∆R−S∆H value for the complexation with 21 than did (S,S)-2 but the large ∆R−S∆H value
was compensated for by the large ∆R−S∆S value sharply reducing its ∆R−S∆G value with increasing
temperature.
We have previously described that the more stable complex shows the λmax value at a shorter
wavelength than the less stable diastereomeric complex.9 Among the present data, the largest difference
in the λmax value between diastereomeric complexes was found for the (S,S)-1:21 complexes. The more
stable complex with (R)-21 showed λmax at a shorter wavelength; 553 nm (at 15°C) and 552 nm (at

K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
567
Table 2
Thermodynamic parameters for complexation of the crown ethers (S,S)-1 and (S,S)-2 with amines in
chloroform
6
Fig. 1. Temperature dependent enantioselectivity for the complexation of (S,S)-1 with amines; 19 (ꢀ), 20 (ꢁ), 21 (◦), 22 (♦)
and 23 (ꢂ)
42°C) in CHCl3 than did the less stable complex with (S)-21 showing λmax at 566 nm (at 15°C) and 563
nm (at 42°C). Similar correlations between ∆R−S∆G and ∆R−Sλmax values were observed for all other
diastereomeric complexes.
As mentioned above, the present results demonstrate that the combination of the crown ether and the
amine showing the larger ∆R−S∆H value does not always display the higher degree of enantiomeric
recognition at any temperature than the combination having the smaller ∆R−S∆H value because the large
∆R−S∆H value is usually accompanied by a large ∆R−S∆S value.

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K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
Fig. 2. Temperature dependent enantioselectivity for the complexation of (S,S)-2 with amines; 19 (ꢀ), 20 (ꢁ), 21 (◦), 22 (♦)
and 23 (ꢂ)
Fig. 3. Enthalpy–entropy compensation plot for complexation of (S,S)-1 (♦) and (S,S)-2 (ꢂ) with amines. The T∆S terms were
evaluated at T=298 K
Fig. 4. T∆R−S∆S−∆R−SH compensation plot for complexation of (S,S)-1 (♦) and (S,S)-2 (ꢂ) with amines. The T∆R−S∆S terms
were evaluated at T=298 K

K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
569
2. Experimental section
2.1. General
1H NMR spectra were recorded at 270 MHz on a JEOL JNM-MH-270 spectrometer for solutions in
CDCl3 with SiMe4 as an internal standard and J values are given in hertz. Mass spectra were recorded
with 3-nitrobenzyl alcohol as a matrix on a JEOL-DX-303-HF spectrometer. IR spectra were measured
on a JASCO FT-IR-410 spectrometer. UV and visible spectra were measured on a HITACHI 260-10
spectrometer. Optical rotations were measured using a JASCO DIP-40 polarimeter and [α]D values are
given in units of 10−1 deg cm2 g−1. HPLC analyses were carried out on a Shimadzu LC-6A using
a chiral column CHIRAL PAK AD (250×4.6 mm) (DAICEL). Elemental analysis data were collected
with a Perkin-Elmer 2400 II CHNS. All melting points are uncorrected. Lipase QL was supplied by Meito
Sangyo and used without further purification. The homochiral amines were purchased from the Aldrich
Chemical Company, Inc. The amine (S)-21 was used after recrystallization from benzene–hexane10 and
the other amines were used without further purification.
2.2. (ꢀ)-1-(1-Naphthyl)ethane-1,2-diol 3
A solution of 1-ethenylnaphthalene11 (5.02 g, 32.4 mmol) was added dropwise to a mixture of N-
methylmorpholine N-oxide (5.30 g, 45.3 mmol) and osmiumtetroxide (106 mg, 0.417 mmol) in 1,1-
dimethylethanol (80 cm3) and water (8 cm3) and the resulting mixture was then stirred for 4 h at
room temperature. After 0.2 M aq. sodium hydrogen sulfite (50 cm3) had been added to the reaction
mixture with ice-cooling, the solvent was removed under reduced pressure. The residue was extracted
with chloroform and the combined extracts were washed with water and dried over MgSO4. Evaporation
of the solvent under reduced pressure gave (ꢀ)-3 (4.98 g, 83% yield); mp 145–146°C (recrystallized
from hexane–ethyl acetate) (lit.12 mp 146–147°C); IR (KBr) 3230, 2942, 2856, 1653, 1595, 1109, 1067,
1030, 905, 865, 802 and 777 cm−1; δH (CDCl3), 3.45–3.54 (1H, m, CH2), 3.60–3.68 (1H, m, CH2), 4.79
(1H, t, J=5.2, primary OH), 5.28–5.35 (1H, m, CH), 5.37 (1H, d, J=2.0, secondary OH) and 7.43–8.16
(7H, m, ArH).
2.3. Resolution of (ꢀ)-3
A mixture of (ꢀ)-3 (10.0 g, 53.1 mmol), lipase QL (from Alcaligenes sp.) (5.3 g) and isopropenyl
acetate (15.7 g, 0.157 mol) in acetonitrile (1000 cm3) was stirred for 4 days at 30°C. The reaction was ter-
minated at the esterification point of 65% (by GLC) by filtration of the enzyme and volatile materials were
evaporated under reduced pressure. Silica gel chromatography of the residue (hexane:ethyl acetate=4:1
as eluent) gave a mixture of monoacetates (7.86 g, 64%) and 3 (3.27 g, 33%) (96% e.e. by HPLC,
hexane:ethyl acetate=4:1). Recrystallization of 3 from diethyl ether gave the partially resolved diol 3
(48% e.e. by HPLC) (0.156 g, 1.6%) as a sparingly soluble solid and removal of the solvent gave (+)-3
24
(>99% e.e. by HPLC) (3.10 g, 31%); mp 79–81°C (recrystallized from hexane–ethyl acetate); [α]D
+75.8 (c 0.225, CH3OH); spectral data were in accord with those of (ꢀ)-3. Anal. Calcd for C12H12O2:
C, 76.57%; H, 6.43%. Found: C, 76.45%; H, 6.55%.

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2.4. (S)-(+)-1-(1-Naphthyl)-2-(triphenylmethoxy)ethanol 4
To a solution of triethylamine (900 mg, 8.84 mmol) in dry DMF were added successively triphenyl-
methyl chloride (820 mg, 2.94 mmol), 4-(dimethylamino)pyridine (16 mg, 0.13 mmol) and (+)-3 (>99%
e.e.) (500 mg, 2.65 mmol) and the resulting mixture was then stirred for 15 h at room temperature.
After water had been added to the reaction mixture, the reaction mixture was extracted with chloroform.
Customary work-up, followed by silica gel chromatography of the products (hexane:ethyl acetate=4:1)
23
gave (+)-4 (820 mg, 72%); mp 187–189°C (recrystallized from hexane–ethyl acetate); [α]D +50.0 (c
0.095, CH3OH); IR (KBr) 3581, 3061, 2923, 2869, 1951, 1489, 1447, 1201, 1167, 1055, 981, 899, 775
and 699 cm−1; δH (CDCl3), 2.95 (1H, d, J=2.5, OH), 3.45 (1H, dd, J=8.7 and 10.3, CH2), 3.62 (1H, dd,
J=3.2 and 10.3, CH2), 5.57–5.64 (1H, m, CH) and 7.19–7.82 [22H, m, C10H7 and C(C6H5)3]; MS (FAB)
m/z (relative intensity) 430 (M+, 10) and 115 (100). Anal. Calcd for C31H26O2: C, 86.48%; H, 6.09%.
Found: C, 86.39%; H, 5.89%.
2.5. (S)-(+)-1-(1-Naphthyl)-2-(p-toluenesulfonyloxy)ethanol 7
To a solution of (+)-3 (>99% e.e.) (1.02 g, 5.31 mmol) in pyridine (7 cm3) was added p-toluenesulfonyl
chloride (810 mg, 4.25 mmol) and the mixture was then stirred for 5 h at 0–5°C. The reaction mixture was
poured onto ice–water, acidified (pH 2) with hydrochloric acid and extracted with chloroform. Customary
work-up, followed by silica gel chromatography of the products (hexane:ethyl acetate=4:1) gave (+)-7
27
(1.09 g, 60%); mp 84–85 (recrystallized from hexane–ethyl acetate); [α]D +123 (c 0.944, CHCl3); IR
(KBr) 3531, 3062, 2986, 2949, 2924, 1932, 1595, 1509, 1351, 1174, 967, 912, 877, 818 and 754 cm−1
;
δH (CDCl3), 2.43 (3H, s, CH3), 2.72 (1H, d, J=2.9, OH), 4.13 (1H, dd, J=8.8 and 10.7, CH2), 4.38 (1H,
dd, J=2.4 and 10.7, CH2), 5.79 (1H, ddd, J=2.4, 2.9 and 8.7, CH), 7.29 (2H, d, J=8.3, tosyl moiety ArH),
7.44–7.52 (3H, m, tosyl moiety ArH and C10H7), 7.69 (1H, d, J=7.3, C10H7) and 7.76–7.91 (5H, m,
C10H7). Anal. Calcd for C19H18O4S: C, 66.65%; H, 5.30%. Found: C, 66.62%; H, 5.19%.
2.6. (R)-(+)-1-(1-Naphthyl)ethanol 8
To a suspension of LiAlH4 (110 mg, 2.92 mmol) in dry THF (10 cm3) was added a solution of (+)-7
(500 mg, 1.46 mmol) in dry THF (5 cm3) and the mixture was then stirred for 2 h at room temperature. To
the reaction mixture was carefully added aq. ammonium chloride with ice-cooling. The deposited solids
were removed by filtration and the solvent was evaporated under reduced pressure. The residue was
27
chromatographed on silica gel (hexane:ethyl acetate=9:1) to give (+)-8 (205 mg, 81%) as an oil; [α]D
+81.6 (c 0.303, CH3OH); IR (neat film) 3374, 3049, 2973, 1596, 1509, 1371, 1169, 1109, 1066, 1011,
800 and 778 cm−1; δH (CDCl3), 1.68 (3H, d, J=6.4, CH3), 1.89 (1H, d, J=2.9, OH), 5.68 (1H, dq, J=3.2
and 12.7, CH) and 7.46–8.16 (7H, m, C10H7). HPLC analysis of (+)-8 showed a single peak of Rt=42.4
min [CHIRAL PAK AD (250×4.6 mm) hexane:ethanol=98:2 (0.5 cm3 min−1)] for the (R)-enantiomer.13
A peak of Rt=39.0 min for the (S)-enantiomer13 was not found.
2.7. (2S,10S)-(+)-2,10-Di(1-naphthyl)-1,11-bis(triphenylmethoxy)-3,6,9-trioxaundecane 9
A solution of (S)-4 (1.02 g, 2.32 mmol) in dry THF (10 cm3) was added slowly to a suspension
of NaH (223 mg, 9.29 mmol) in dry THF (30 cm3) and the resulting mixture was then refluxed for
1.5 h. After the reaction mixture had been cooled to room temperature, a solution of diethylene glycol
bis(p-toluenesulfonate) (790 mg, 1.71 mmol) in dry THF (20 cm3) was added dropwise to the mixture

K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
571
and then the reaction mixture was gently refluxed for 6 days under a nitrogen atmosphere. After a small
amount of chilled water had been carefully added to the reaction mixture with ice-cooling, the solvent was
removed under reduced pressure. The residue was extracted with chloroform and the combined extracts
were washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue was
chromatographed on silica gel (hexane:ethyl acetate=19:1) to give (S,S)-9 (687 mg, 64%); mp 72–73°C
24
(recrystallized from hexane–ethyl acetate); [α]D +39.6 (c 0.716, CHCl3); IR (KBr) 3056, 2868, 1596,
1489, 1448, 1223, 1073, 776 and 705 cm−1; δH (CDCl3) 3.34 (2H, dd, J=4.8 and 9.7, CH2OPh3), 3.53
(2H, dd, J=7.1 and 9.7, CH2OPh3), 3.57–4.14 (8H, m, OCH2CH2O), 5.20 (2H, dd, J=4.8 and 7.1, CH),
6.99–7.91 [44H, m, C10H7 and C(C6H5)3]; MS (FAB) m/z (relative intensity) 929 [(M+−1), 3] and 73
(100). Anal. Calcd for C66H58O5: C, 85.13%; H, 6.28%. Found: C, 84.80%; H, 6.43%.
2.8. (2S,10S)-(+)-2,10-Di(1-naphthyl)-3,6,9-trioxaundecane-1,11-diol 10
A solution of (S,S)-9 (502 mg, 0.537 mmol) and p-toluenesulfonic acid (410 mg, 2.15 mmol) in
methanol (20 cm3) was stirred for 6 h at room temperature. After aq. sodium hydrogen carbonate had
been added to the reaction mixture, the volatile materials were removed under reduced pressure and the
residue was extracted with chloroform. Customary work-up, followed by silica gel chromatography of
28
the products (ethyl acetate) gave (S,S)-10 (217 mg, 94%) as an oil; [α]D +102 (c 0.853, CHCl3); IR
(neat film) 3434, 3049, 2869, 1644, 1595, 1112, 1000, 803 and 737 cm−1; δH (CDCl3), 3.67–3.93 (12H,
m, CH2), 4.54 (2H, dd, J=2.9 and 9.3, OH), 5.35 (2H, dd, J=3.3 and 8.2, CH) and 7.47–8.19 (14H, m,
C10H7). The high-resolution mass spectrum could not be recorded because of the very weak molecular
ion peak. MS (FAB) m/z (relative intensity) 469 [(M+Na+), 4], 447 [(M++1), 5] and 90 (100).
2.9. (+)-1,3-Bis[(4S)-4-hydroxy-4-phenyl-2-oxabutyl]-2,5-dimethoxybenzene 12
A solution of (S)-66 (10.0 g, 45.0 mmol) in dry THF (150 cm3) was added to a suspension of NaH
(2.16 g, 90.0 mmol) in dry THF (150 cm3) and the resulting mixture was then stirred for 1.5 h at 60°C.
The reaction mixture was cooled to room temperature and to the mixture was slowly added a solution
of 1,3-bis(bromomethyl)-2,5-dimethoxybenzene (7.30 g, 22.5 mmol) in dry THF (250 cm3). After the
reaction mixture had been refluxed for 15 h, a similar work-up to that described for the preparation of 9
gave 11 as an oil, which was stirred with pyridinium p-toluenesulfonate (1.13 g, 4.50 mmol) in ethanol
(350 cm3) for 12 h at 60°C. Customary work-up, followed by silica gel chromatography of the products
(chloroform) gave (S,S)-12 (7.90 mg, 80%) as an oil; [α]D25 +34.2 (c 1.98, CHCl3); IR (neat film) 3443,
2904, 1650, 1482, 1359, 1321, 1213, 1174, 1151, 1108, 1005, 903, 760 and 701 cm−1; δH (CDCl3),
3.78 (2H, s, OH), 3.71 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.56 (2H, br s, benzylic CH2), 4.65 (2H,
br s, benzylic CH2), 4.74 (4H, dd, J=3.2 and 9.9, CH2), 4.94 (2H, dd, J=3.2 and 8.7, CH), 6.89 [2H, s,
(MeO)2ArH] and 7.28–7.40 (10H, m, C6H5); MS (FAB) m/z (relative intensity) 438 (M+, 18) and 136
(100).
2.10. (5S,13S)-(+)-19,21-Dimethoxy-5,13-di(1-naphthyl)-3,6,9,12,15-pentaoxabicyclo[15.3.1]-
henicosane-1(21),17,19-triene 13
A solution of (S,S)-10 (2.36 g, 5.29 mmol) and 1,3-bis(bromomethyl)-2,5-dimethoxybenzene (1.72 g,
5.30 mmol) in dry THF (500 cm3) was slowly added to a suspension of NaH (127 mg, 5.28 mmol) in dry
THF (300 cm3) over a 26 h period under reflux and the mixture was refluxed for a further 18 h under a
nitrogen atmosphere. After a small amount of chilled water had been added to the reaction mixture with

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K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
ice-cooling, the solvent was removed under reduced pressure. The residue was extracted with chloroform
and the combined extracts were washed with water, dried over MgSO4 and evaporated under reduced
pressure. Silica gel chromatography of the products (hexane:ethyl acetate=4:1) gave (S,S)-13 (1.96 g,
78%); mp 155–156°C (recrystallized from hexane–ethyl acetate); [α]D29 +133 (c 1.04, CHCl3); IR (KBr)
3047, 2863, 1595, 1510, 1483, 1352, 1245, 1227, 1097, 1003, 955, 866, 801 and 745 cm−1; δH (CDCl3)
3.45–3.59 (8H, m, CH2), 3.71–3.88 (4H, m, CH2), 3.75 (3H, s, C-19 OCH3), 4.36 (3H, s, C-21 OCH3),
4.53 (2H, d, J=10.9, benzylic CH2), 4.78 (2H, d, J=10.9, benzylic CH2), 5.37 (2H, dd, J=2.2 and 8.7,
CH), 6.85 [2H, s, (MeO)2ArH] and 7.43–8.13 (14H, m, C10H7); MS (FAB) m/z (relative intensity) 647
[(M+K+), 3], 631 [(M+Na+), 8], 447 (M+, 29) and 107 (100).
2.11. (5S,13S)-(+)-21-Hydroxy-19-methoxy-5,13-di(1-naphthyl)-3,6,9,12,15-pentaoxabicyclo[15.3.1]-
henicosane-1(21),17,19-triene 14
To a suspension of NaH (150 mg, 6.25 mmol) in dry DMF (4 cm3) was slowly added ethanethiol (480
mg, 7.80 mmol) and then a solution of (S,S)-13 (190 mg, 312 mmol) in dry DMF (7 cm3) was added to
the resulting clear solution. The reaction mixture was stirred for 4 h at 90°C and cooled to 0–5°C. After a
small amount of hydrochloric acid had been added to the chilled reaction mixture, the volatile materials
were evaporated under reduced pressure and the residue was extracted with chloroform. The combined
extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure. Silica gel
chromatography of the products (hexane:ethyl acetate=1:1) gave (S,S)-14 (174 mg, 94%); mp 70–71°C
29
(recrystallized from hexane–ethyl acetate); [α]D +139 (c 1.04, CHCl3); IR (KBr) 3388, 3049, 2865,
1486, 1354, 1249, 1098, 870, 802 and 780 cm−1; δH (CDCl3), 3.67–3.89 (13H, m, CH2 and OH), 3.75
(3H, s, OCH3), 4.79 (2H, d, J=10.9, benzylic CH2), 4.91 (2H, d, J=10.9, benzylic CH2), 5.47 (2H, dd,
J=4.2 and 7.1, CH), 6.77 [2H, s, (HO)ArH] and 7.41–8.12 (14H, m, C10H7); MS (FAB) m/z (relative
intensity) 647 [(M+K+), 3], 631 [(M+Na+), 10], 447 (M+, 21) and 91 (100).
2.12. (5S,13S)-(+)-19,21-Dimethoxy-5,13-diphenyl-3,6,9,12,15-pentaoxabicyclo[15.3.1]henicosane-
1(21),17,19-triene 15
A solution of (S,S)-12 (3.95 g, 9.01 mmol) and diethylene glycol bis(p-toluenesulfonate) (3.73 g, 9.01
mmol) in dry THF (500 cm3) was slowly added to a mixture of NaH (864 mg, 36.0 mmol) and KBF4
(1.13 mg, 9.01 mmol) in dry THF (200 cm3) over a 9 h period under reflux and the mixture was refluxed
for further 20 h under a nitrogen atmosphere. After a similar work-up to that described above, silica gel
25
chromatography of the products (chloroform) gave (S,S)-15 (1.90 g, 42%); mp 83–85°C; [α]D +104
(c 0.615, CHCl3); IR (KBr) 3030, 2893, 2857, 1611, 1487, 1357, 1243, 1230, 1170, 1099, 1053, 1023,
957, 923, 849, 763, 704, 666 and 579 cm−1; δH (CDCl3), 3.40–3.74 (12H, m, CH2), 3.79 (3H, s, C-19
OCH3), 4.19 (3H, s, C-21 OCH3), 4.52 (2H, dd, J=2.6 and 8.5, CH), 4.48 (2H, d, J=10.8, benzylic CH2),
4.71 (2H, d, J=10.8, benzylic CH2), 6.84 [2H, s, (MeO)2ArH] and 7.27–7.37 (10H, m, C6H5); MS (FAB)
m/z (relative intensity) 531 [(M+Na+), 4], 508 (M+, 35) and 165 (100). Anal. Calcd for C30H36O7: C,
70.84%; H, 7.14%. Found: C, 70.64%; H, 7.06%.
2.13. (5S,13S)-(+)-21-Hydroxy-19-methoxy-5,13-diphenyl-3,6,9,12,15-pentaoxabicyclo[15.3.1]-
henicosane-1(21),17,19-triene 16
In a similar manner to that described above, demethylation of (S,S)-15 (1.00 g, 1.97 mmol) was carried
out using NaH (943 mg, 0.393 mmol) and ethanethiol (2.90 g, 0.472 mmol). Silica gel chromatography

K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
573
of the products (hexane:ethyl acetate=1:1) gave (S,S)-16 (751 mg, 77%) as an oil; [α]D25 +109 (c 0.850,
CHCl3); IR (neat film) 3372, 2850, 1600, 1492, 1358, 1320, 1248, 1200, 1100, 1028, 950, 860, 762, 735
and 700 cm−1; δH (CDCl3), 3.58–3.81 (12H, m, CH2), 3.75 (3H, s, OCH3), 4.68 (2H, dd, J=2.9 and 8.6,
CH), 4.73 (2H, d, J=11.1, benzylic CH2), 4.76 (2H, d, J=11.1, benzylic CH2), 6.73 [2H, s, (HO)ArH],
7.28–7.36 (10H, m, C6H5) and 7.66 (1H, s OH); MS (FAB) m/z (relative intensity) 517 [(M+Na+), 4],
494 (M+, 49) and 121 (100).
2.14. (5S,13S)-5,13-Di(1-naphthyl)-3,6,9,12,15-pentaoxabicyclo[15.3.1]-henicosane-17,20-diene-19,
21-dione 17
A solution of (S,S)-14 (101 mg, 0.168 mmol) in acetonitrile (7 cm3) was added to a solution of
CAN (180 mg, 0.328 mmol) in acetonitrile (10 cm3) and then the resulting mixture was stirred for 1
h at room temperature. After the reaction mixture had been cooled to 0–5°C, water was added to the
reaction mixture and the solvent was evaporated under reduced pressure. The residue was extracted with
chloroform and customary work-up followed by silica gel chromatography of the products (hexane:ethyl
acetate=4:1) gave (S,S)-17 (94 mg, 96%) as a yellow solid; δH (CDCl3), 3.54–3.87 (12H, m, CH2), 4.68
(2H, d, J=14.8, benzylic CH2), 4.81 (2H, d, J=14.8, benzylic CH2), 5.39 (2H, dd, J=3.2 and 7.4, CH),
6.85 (2H, s, quinone moiety CH) and 7.44–8.16 (14H, m, C10H7). This was used for the next reaction
without further purification.
2.15. (5S,13S)-5,13-Diphenyl-3,6,9,12,15-pentaoxabicyclo[15.3.1]-henicosane-17,20-diene-19,21-
dione 18
In a similar manner to that described above, (S,S)-16 (500 mg, 1.01 mmol) was oxidized with CAN
(1.10 g, 2.00 mmol). Silica gel chromatography of the products (chloroform) gave (S,S)-18 (474 mg,
98%) as a yellow solid; δH (CDCl3), 3.42–3.79 (12H, m, CH2), 4.60 (2H, d, J=14.8, benzylic CH2), 4.61
(2H, dd, J=2.8 and 7.5, CH), 4.69 (2H, d, J=14.8, benzylic CH2), 6.78 (2H, s, quinone moiety CH) and
7.28–7.38 (10H, m, C6H5). This was used for the next reaction without further purification.
2.16. (5S,13S)-21-Hydroxy-19-(20 ,40-dinitrophenylazo)-5,13-di(1-naphthyl)-3,6,9,12,15-
pentaoxabicyclo[15.3.1]-henicosane-1(21),17,19-triene 1
A solution of 2,4-dinitrophenylhydrazine (1.90 g, 9.60 mmol) in ethanol (100 cm3) containing conc.
H2SO4 (8.4 cm3) was added to a solution of (S,S)-17 (1.10 g, 1.90 mmol) in a mixture of chloroform (50
cm3) and ethanol (50 cm3) and the resulting mixture was stirred for 1 h at room temperature. The reaction
mixture was diluted with water and extracted with chloroform. Customary work-up, followed by silica
gel chromatography of the products (hexane:ethyl acetate=1:1) gave (S,S)-1 (1.09 g, 76%) as a red glass;
λmax (CHCl3) 403 nm (ε 2.34×104); IR (KBr) 3291, 3059, 2866, 1597, 1532, 1466, 1430, 1344, 1292,
1113, 906, 832, 802, 780 and 745 cm−1; δH (CDCl3), 3.68–3.96 (12H, m, CH2), 4.92 (2H, d, J=11.1,
benzylic CH2), 4.98 (2H, d, J=11.1, benzylic CH2), 5.39 (2H, dd, J=4.3 and 6.6, CH), 7.46–7.55 (6H,
m, C10H7), 7.67 (2H, d, J=7.1, C10H7), 7.80–7.82 [3H, m, C10H7 and (NO2)2ArH], 7.88–7.90 [4H, m,
C10H7 and (HO)ArH], 8.14 (2H, d, J=7.9, C10H7), 8.48 [1H, dd, J=2.3 and 8.9, (NO2)2ArH], 8.75 [1H,
d, J=2.2, (NO2)2ArH] and 9.28 (1H, s, OH). The high-resolution mass spectrum could not be recorded
because of the very weak molecular ion peak. MS (FAB) m/z (relative intensity) 797 [(M+K+), 3], 781
[(M+Na+), 7], 766 [(M+Li+), 3], 756 [(M++1), 4] and 245 (100).

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K. Naemura et al. / Tetrahedron: Asymmetry 9 (1998) 563–574
2.17. (5S,13S)-21-Hydroxy-19-(20 ,40-dinitrophenylazo)-5,13-diphenyl-3,6,9,12,15-pentaoxabicyclo-
[15.3.1]-henicosane-1(21),17,19-triene 2
In a similar manner to that described above, (S,S)-18 (484 mg, 1.01 mmol) was treated with 2,4-
dinitrophenylhydrazine (1.00 g, 5.05 mmol) and the product was purified by silica gel chromatography
(chloroform) followed by preparative recycling HPLC (JAIGEL 1H and 2H column, chloroform) to give
(S,S)-2 (210 mg, 32%) as a red solid; mp 73–75°C; λmax (CHCl3) 402 nm (ε 2.29×104); IR (KBr)
3292, 2867, 1600, 1534, 1466, 1430, 1345, 1290, 758 and 701 cm−1; δH (CDCl3), 3.58–3.81 (12H,
m, CH2), 4.70 (2H, br s, CH), 4.85 (4H, br s, benzylic CH2), 7.28–7.40 (10H, m, C6H5), 7.84 [2H, s,
(HO)ArH], 7.85 [1H, d, J=8.8, (NO2)2ArH], 8.47 [1H, dd, J=2.5 and 8.8, (NO2)2ArH], 8.74 [1H, d,
J=2.5, (NO2)2ArH] and 9.16 (1H, s, OH). The high-resolution mass spectrum could not be recorded
because of the very weak molecular ion peak. MS (FAB) m/z (relative intensity) 697 [(M+K+), 2], 681
[(M+Na+), 15], 659 [(M++1), 20] and 135 (100).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science and Culture of Japan.
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