Periphery-modified crown ethers. Synthesis of bis-5,8-dimethoxy-1,4- methanonaphthalene-fused crown ethers

Article abstract of DOI:10.1016/j.tet.2003.10.034

The easily accessible and multi-functionalized 5,8-dimethoxy-6,7-dihydroxy methyl-1,4-dihydro-1,4-methanonaphthalene (1) has been utilized as the basic building material to synthesize the symmetric bis-methanonaphthalene-fused crown ethers 14a-d (BMN-16-crown-4, BMN-22-crown-6, BMN-28-crown-8, and BMN-34-crown-10), that are constructed based on the connection between the α,β-bis-benzylic carbon atoms of diol 1 and oligoethylene glycols (9a-d) via two synthetic routes keyed upon the method of Williamson ether synthesis.

Full text of DOI:10.1016/j.tet.2003.10.034

Tetrahedron 59 (2003) 9939–9950
Periphery-modified crown ethers. Synthesis of bis-5,8-dimethoxy-
1,4-methanonaphthalene-fused crown ethers
*
Teh-Chang Chou, Shing-Yi Chen and Yie-Hsung Chen
Department of Chemistry and Biochemistry, National Chung Cheng University, 160 Sansying, Minsyong, Chiayi 621, Taiwan
Received 9 August 2003; revised 9 October 2003; accepted 10 October 2003
Abstract—The easily accessible and multi-functionalized 5,8-dimethoxy-6,7-dihydroxy methyl-1,4-dihydro-1,4-methanonaphthalene (1)
has been utilized as the basic building material to synthesize the symmetric bis-methanonaphthalene-fused crown ethers 14a–d (BMN-16-
crown-4, BMN-22-crown-6, BMN-28-crown-8, and BMN-34-crown-10), that are constructed based on the connection between the a,b-bis-
benzylic carbon atoms of diol 1 and oligoethylene glycols (9a–d) via two synthetic routes keyed upon the method of Williamson ether
synthesis.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
benzoquinone by oxidation and has a pair of masked
phenolic hydroxyl groups that could be made to connect
polyethylene glycolates to form additional crown-ether
loops or to attach photochromic moieties that make the
molecule to serve as a sensor. The strained double bond in
the norbornadiene ring would be amendable to incorporate
moieties with desirable functions or to undergo polymeriz-
ation via modes of vinylic14 or ROMP15 by transition metal
catalysts. With the intention to take advantage of these
intrinsic structural features in 1, we launched a program
aiming at the synthesis of macrocyclic polyethers and their
periphery-modified derivatives utilizing 1 as the basic
building material. The syntheses of mono-looped crown
ethers shown by the generic structures A (MN-[8þ3n]-
crown-[2þn]) and B (BMN-[16þ6n]-crown-[4þ2n]) based
on the a,b-bis-benzylic carbon atoms of diol 1 were first
undertaken (Scheme 1). The crown-ether rings were
Ever since Pedersen1 foresaw the potential applications of
macrocyclic polyethylene glycol ethers with the ability to
form complexes with metal ions, ‘crown ethers,’ as the
name he coined, have received a great deal of continuous
attention. During the last two decades extended develop-
ment in this research field by Cram’s and Lehn’s research
groups, that emerged the discipline on macrocyclic host–
guest chemistry,2,3 has motivated extensive synthetic
endeavor on the molecular designs and modification aiming
at exploration of basic knowledge and implementation of
the conceptual imagination of applications in various areas
of chemistry and material science.4 In general, design and
modification have focused on three elements of crown-ether
molecules: (1) the loop with regard to its size, interior donor
atoms (O, S, and N), and quantity (multiplicity), such as the
renowned cryptands;3,5 (2) the attachments at periphery,
such as lariat,6 carbocage,7 cyclophanes,8 porphyrin,9 and
fullerene10 that interfuse or link the crown-ether loop; and
(3) the guest that interplays with the crown-ether loop
(host), such as rotaxanes11 and catenanes.12
5,8-Dimethoxy-6,7-dihydroxymethyl-1,4-dihydro-1,4-
methanonaphthalene (1), readily made available from 2,3-
dicyano-1,4-benzoquinone,13 is multi-functionalized that
contains, besides the hydroxyl groups at a,b-bis-benzylic
carbon atoms, a 1,4-dimethoxybenzene ring and a double
bond in the norbornadiene moiety at the periphery. The 1,4-
dimethoxybenzene ring is a synthetic equivalent to 1,4-
Keywords: crown ethers; synthesis.
*
Corresponding author. Tel.: þ886-5-242-8116; fax: þ886-5-272-1040;
e-mail: chetcc@ccu.edu.tw
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.034

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T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
constructed by the methodology of Williamson ether
synthesis,16 in which an alkoxide (as a nucleophile)
undergoes a SN2 reaction with a halide or a tosylate.
Recently, we have accomplished the syntheses of four
methanonaphthaleno-crown ethers (A: n¼1, 2, 3, 4) and
four bismethanonaphthaleno-crown ethers (B: n¼0, 1, 2, 3).
The results of the synthesis of crown ethers As and their
complexes with metal ions will be reported separately
elsewhere, and herein in this paper we described in detail the
synthetic results of crown ethers Bs.
solution of 2 in refluxing acetone was treated with dimethyl
sulfate in the presence of K2CO3. Following the general
standard procedure, dicarbonitrile 4 was hydrolyzed with
KOH in hot methanol to afford, upon careful neutralization
of the reaction mixture with conc. HCl at 08C, directly the
carboxylic anhydride 5 in 65% yield. The above neutralized
reaction product could also be converted to the correspond-
ing diester 6 in 76% yield by the successive reaction with
thionyl chloride in refluxing methanol. Reduction of
anhydride 5 and diester 6 with lithium aluminum hydride
provided diol 1 in 70 and 91% yields, respectively.
2. Results and discussion
For the synthetic purpose and making the synthetic utility of
diol 1 more flexible, the corresponding a,b-bis-benzylic
dibromide 7, which could be used as an electrophilic
building unit in the Williamson ether synthesis, was
prepared by treatment of diol 1 with PBr3 (Scheme 3).
The bis(methoxymethyl)-substituted methanonaphthalene 8
was also prepared as a reference compound by the reaction
of diol 1 with dimethyl sulfate in THF in the presence of
NaH.
2.1. Preparation of methanonaphthalene diol 1
The preparation of diol 1, the nucleophilic building unit for
the synthesis of crown ethers of both types A and B, was
accomplished in overall yields of 30–40% following the
reaction sequence illustrated in Scheme 2. The synthesis
was composed of three major operations starting from 1,4-
methanonaphthalene-6,7-dicarbonitrile 2, which was made
available from the Diels–Alder reaction of 2,3-dicyano-1,4-
benzoquinone13 and freshly distilled cyclopentadiene under
thermodynamically controlled condition.17 When a solution
of 2 in dichloromethane was stirred with silica gel
overnight, the reaction generated the corresponding hydro-
quinone derivative 3 which, without further purification,
was subsequently subjected to bis-O-methylation in reflux-
ing acetone with dimethyl sulfate containing K2CO3 to
furnish the corresponding derivative 4 in an overall yield of
80%. Alternatively, dicarbonitrile 4 could also be obtained
in 87% yield from 2 by one-pot operation, in which a
Scheme 3.
The structure of bis(dihydroxymethyl)-substituted methano-
naphthalene 1, shown by elemental analysis to have
molecular formula C15H18O4, was secured by spectral
analysis. The observation of eight lines in the broadband-
decoupled 13C NMR spectrum for 15 carbon atoms is
consistent with the presence of a mirror-plane symmetry
element in diol 1. The existence of a,b-bis-hydroxymethyl
groups in 1 is indicated by (i) a strong absorption band at
3295 cm21 in the infrared spectrum, (ii) a signal at
56.8 ppm in the 13C NMR spectrum assignable to the
carbon bearing a hydroxyl group and two hydrogens, and
(iii) a broad signal at 2.86 ppm (–OH) and a four-proton
1
singlet at 4.72 ppm in the H NMR spectrum. Presumably,
the conformation of diol 1 was relatively unconstrained,
rendering the chemical-shift equivalence to the diastero-
topic hydrogens on the benzylic carbons, and thus resulting
1
in the observation of only seven signals in the H NMR
spectrum for eight groups of nonequivalent hydrogens.
2.2. Synthesis of bis-methanonaphthalene-fused crown
ethers of type B (14a–d)
Attempts to prepare bis-methanonaphthalene-fused macro-
cyclic ethers represented by generic structure B (14a–d) in
one-step by the NaH-promoted reactions using diol 1 and
bis-tosylates 11b or polyethylene glycols 9b–d and
dibromide 7 were not successful. The reactions usually
gave a complex mixture of products, including crown ethers
of type A, which rendered tedious and difficult separation.
Decision was thus made to employ stepwise methods,
namely protection–deprotection technique, for the con-
struction of macrocyclic ethers 14a–d (Schemes 4 and 5).
At the outset, effort was directed to the synthetic route
Scheme 2.

T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
9941
synthesis of crown ethers 14a, 14b, and 14c from dibromide
7 were 26, 48, and 46%, respectively.
Scheme 4.
shown in Scheme 4. Dibromide 7 was first subjected to the
reactions with the sodium salts of v-tetrahydropyranyl
polyethylene glycols 10a–c18 in THF under reflux to give
bis-v-tetrahydropyranyl polyethers 12a–c in yields of 55–
80%. Deprotection of ethers 12a–c under acidic condition
afforded diols 13a–c, which were converted to the sodium
salts in THF by NaH followed by treatment with dibromide
7 to provide bis-methanonaphthalene-fused crown ethers
14a–c in yields of 45–80%. The overall yields of three-step
All intermediates 12a–c and 13a–c were characterized by
their spectral analyses (1H and 13C NMR, IR, and MS). In
the 13C NMR spectra of ethers 12a–c, the appearance of a
distinct absorption line at ,99 ppm and three lines in the
region of 19–30 ppm, ascribed respectively to the acetal
and propylene carbons, manifested the presence of tetra-
hydropyranyl groups. Strictly speaking, bis-v-tetrahydro-
pyranyl polyethers 12a–c could be formed as a mixture of
diastereomers from the reactions of dibromide 7 with the
sodium salts derived from the racemic mixture of v-
tetrahydropyranyl polyethylene glycols 10a–c. However, in
the broadband-decoupled 13C NMR spectra, only (nþ1)/2
absorption lines were observed, where n is the number of
carbon atoms in the molecule, suggesting that in solution
polyethers 12a–c could behave as having preserved the
intrinsic mirror-plane symmetry element despite the fact
that additional chiral centers were introduced by the
tetrahydropyranyl groups.
Upon acid-catalyzed removal of the tetrahydropyranyl rings
from ethers 12a–c to form diols 13a–c, the corresponding
absorption signals disappeared and a well-defined AB-
quartet due to benzylic methylene hydrogens surfaced at
,4.6 ppm (4H) in their rather simple 1H spectra. Diols
13a–c exhibited 13C NMR spectra that were consistent with
having the molecular Cs-symmetry. The molecular consti-
tution of each diol 13a–c was suggested by the satisfactory
molecular weight that was analyzed by HRMS for the signal
of highest m/z value corresponding to the molecular ion
(Mþ) of diol 13a and 13b, and the Na-complexed ion
(MþNaþ) of 13c.
Although we adopted the reaction sequence shown in
Scheme 4 to successfully prepare crown ethers 14a–c, we
encountered a setback: availability of the monoprotected
Scheme 5.

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T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
glycol ethers 10a–c was limited by low yields and
reproducibility. We thus explored an alternative and
complementary approach that is illustrated in Scheme 5.
This synthetic route demanded only one task of making diol
1 monoprotected (i.e. 15) and utilized the bis-tosylates
11s,19 which could be prepared from polyethylene glycols
more easily and in higher yields than the monoprotected
glycol ethers 10s. Additionally, the synthetic route shown in
Scheme 5 would be more versatile, allowing one to
synthesize not only crown ethers 14a–d, but other multi-
methanonaphthalene-fused crown ethers of symmetrical
and unsymmetrical structures as well.
98.51 ppm, displayed a multiplet at 4.79–4.80 ppm in the
1H NMR spectrum and interestingly the through-space
interaction with only one of the methylene hydrogens at
benzylic carbon bearing tetrahydropyranyloxy group (4.61/
4.59 ppm). Since the tetrahydropyranyl group, and along
with it the stereogenic center was to be removed in later
synthesis, no effort was taken to separate these diaster-
eomers. The alcohol 15 was used as acquired.
En route for the bis-methanonaphthalene-fused crown
ethers 14a–d, the bilateral coupling of bis-tosylates 11a–
d with alcohol 15 was attempted by carrying out the reaction
in refluxing THF in the presence of sodium hydride.
Presumably owing to steric crowdedness, the reaction of
ethylene glycol bis-tosylate (11a, n¼0) with alcohol 15
encountered low-yield and reproducibility problems. How-
ever, the reactions of polyethylene glycol bis-tosylate
(11b–d, n¼1, 2, 3) with alcohol 15 went well without
difficulty to give a,v-dibenzyl polyethylene ethers 16b–d
in yields of ca. 70% (Scheme 5). The molecular constitution
of each polyethers 16b–d was suggested by the satisfactory
molecular weight provided by HRMS. There was no
hydroxyl group absorption band in the IR spectra of 16b–
d. The broadband-decoupled 13C NMR spectra of 16b–d
exhibited discernible lines less than the number of carbon
atoms in the molecule, but more than the number of
equivalent carbon atoms expected if taking mirror-plane
symmetry element into consideration. Since the stereogenic
centers in 15a and 15b were passed onto 16b–d, it was
likely that a mixture of diastereomeric products for each
a,v-dibenzyl polyethylene ethers 16b–d was obtained and
justified the observed 13C NMR spectra. It was also evident
Thus, bis-benzylic diol 1 was converted into (tetrahydro-
pyranyloxymethyl)-phenyl methanol 15 in 82% yield by
reaction with dihydropyran in dichloromethane using
pyridium p-toluenesulfonate (PPTS)20 as the catalyst
(Scheme 5). Alcohol 15 was obtained as colorless oil and
exhibited a strong IR absorption band at 3487 cm21
.
Protection of a hydroxyl group with dihydropyran would
create a stereogenic center and thus alcohol 15 was expected
to consist of diastereomers. The complex 1H and 13C NMR
spectra evidently suggested that the attained product was a
mixture of diastereomers 15a and 15b. The broadband-
decoupled 13C NMR spectrum of 15 exhibited discernible
lines more than (less than twice) the number of carbon
atoms in the molecule. Two singlets at 3.86 and 3.87 ppm
with total intensity equal to the three-hydrogen singlet at
3.79 ppm, designated to the hydrogens of two methyl ether
groups, were observed in the 1H NMR spectrum of 15
(Fig. 1). It is the methyl group near to the hydroxymethyl
group that shows chemical shift of larger difference for
diastereomers and at lower field than the other methyl
group, as revealed by COSY, HMQC, and NOESY spectral
analyses. The methylene hydrogens of the hydroxymethyl
group exhibited a multiplet at 4.67–4.69 ppm (2H), which
correlated with the broad signal at 3.17 ppm due to hydroxyl
hydrogen and the carbon resonance at 56.95 ppm. However,
the methylene hydrogens at benzylic carbon bearing
tetrahydropyranyloxy group displayed chemical shifts of
significant separation with one pair of doublets appearing at
4.92/4.90 ppm and the other pair at 4.61/4.59 ppm, each of
which had J¼10.7 Hz and integrated for one hydrogen
atom. Both hydrogen absorption signals correlated with
carbon resonance at 61.45/61.43 ppm and showed through-
space correlation (NOE) with the singlet at 3.79 ppm due to
the methyl ether group. The acetal methane hydrogen,
which correlated with carbon resonance at 98.56/
1
in the H NMR spectra of 16b–d, each of which was very
similar to that of 15 except in region between 3.60 and
3.70 ppm where additional signals appeared by the intensity
accountable for the number of ethylene hydrogen atoms
inherited from bis-tosylates 11b–d. Also, the a,v-dibenzyl
polyethylene ethers 16b–d were used as attained in the
reactions followed.
Acid-catalyzed removal of tetrahydropyranyl groups from
16b–d was easy and the diols 17b–d were obtained in
1
yields of more than 90%. Their IR, MS, H and 13C NMR
spectroscopic data were consistent with the structures. In
particular, the removal of the stereogenic center in the
tetrahydropyranyl rings re-established the molecular sym-
1
metry element and consequently much simpler H and 13C
NMR spectra were observed for diols 17b–d. All the
broadband-decoupled 13C NMR spectra consisted of n/2
lines, where n is the number of carbon atoms in the molecule
of 17b–d. In the 1H NMR spectra of 17b–d, the absorption
signals due to a,b-benzylic hydrogens were overlapped and
appeared at ,4.65 ppm as a multiplet (8H), which
correlated with carbon resonances at ,56.7 ppm (HO–
CH2–Ph) and ,65.8 ppm (RO–CH2–Ph).
With the acquisition of 17b–d, the final step to link the two
terminal hydroxy groups by a polyethylene glycolate was
called for. Thus, each of diols 17b–d in THF was treated
first with sodium hydride and then with the respective bis-
tosylates 11b–d. Symmetric bis-methanonaphthalene-fused
crown ethers 14b, 14c, and 14d were thereby obtained in
good yields (Scheme 5). The synthesis via this synthetic
Figure 1. Partial 1H NMR chemical shifts and the NOE experiment results
for 15.

T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
9943
route furnished crown ethers 14b, 14c, and 14d in 49, 53,
and 40% overall yields from 15, respectively.
angle of two aromatic rings being 638 for syn-14a and 668
for anti-14a.
The molecular constitution of every crown ethers 14a–d as
being a 2:2 reaction product between diol 1 and bis-tosylates
11b–d (or dibromide 7 and oligoethylene glycols 9a–c)
was secured by the nature of synthetic courses (Schemes 4
and 5) and by the satisfactory molecular weight via FAB-
HRMS analysis for the signal of highest m/z value
corresponding to the molecular ion (Mþ or MþHþ). The
structures of crown ethers 14a–d were established via
1
analyses of their IR, MS, and H and 13C NMR spectro-
scopic data. All the broadband-decoupled 13C NMR spectra
of 14a–d displayed (nþ2)/4 lines, where n is the number of
carbon atoms in the molecule (Table 1). This observation
suggested that there are rotation-axis and mirror-plane
symmetry elements (C2 and sv or sh) present in the
molecule of each crown ethers 14a–d. In fact, the 13C NMR
spectra of 14a–c could only be distinguished by the
appearance of one, two, three, and four carbon absorption
lines in the region between 70 and 73 ppm, corresponding to
the number of the nonequivalent –OCH2– groups in 14a,
14b, 14c, and 14d, respectively. As the result of the
presence of C2 and sv (sh) symmetry elements, all crown
3. Conclusion
We have utilized the a,b-bis-benzylic carbon atoms of the
multi-functionalized 5,8-dimethoxy-6,7-dihydroxymethyl-
1,4-dihydro-1,4-methanonaphthalene (1) for the synthesis
of bis-methanonaphthalene-fused crown ethers 14a–d
represented by generic structure B (BMN-[16þ6n]-crown-
[4þ2n], n¼0, 1, 2, 3) via two synthetic routes based on the
protection–deprotection methodology (Schemes 4 and 5).
The presence of both syn- and anti-stereoisomeric crown
ethers 14a–d could not be established by spectral analysis,
but was expected as suggested by the X-ray crystal
structural analysis of 14a. The masked phenolic hydroxyl
groups in 1,4-dimethoxybenzene rings and the strained
double bonds in the norbornadiene rings would offer
opportunity for synthesizing multi-looped and polymerized
crown ethers. Works on investigation of the ability of crown
ethers 14a–d to form complexes with metal ions and
exploitation of synthetic utilization of 1 toward other crown
ethers of novel structures are under active pursuit.
1
ethers 14a–d showed similar H NMR spectra that could
only be differentiated by in the relative intensity of
absorption signals between 3.6 and 3.8 ppm, attributed to
the hydrogen atoms of –O–CH2CH2–O– and OCH3 units
(Table 1). The 12-hydrogen singlet for four –OCH3 groups
at aromatic rings appeared at 3.80 ppm.
One question remains to be addressed. Synthesis of the type-
B crown ethers 14a–d via either synthetic route shown in
Schemes 4 and 5 was expected to furnish two stereoisomers,
in which the two methano-bridges are either syn or anti to
each other (e.g. syn-14a and anti-14a). It was the final step
of synthesis (13a–c!14a–c) in Scheme 4 and the bilateral
coupling of bis-tosylates 11b–d with alcohol 15 (15!16b–
d) in Scheme 5 that would determine the formation of syn
and anti stereoisomeric crown ethers 14a–d. Experimen-
tally, however, each crude product of 14a–d obtained by
both synthetic routes was indicated to be homogeneous by
4. Experimental
1
the appearance of H and 13C NMR spectra. Attempts of
separation of diastereomers by column chromatography
were not successful. Crown ethers were oily material and
resisted recrystallization, except 14a that formed mono-
crystals suitable for X-ray crystallographic analysis. The
result revealed that both syn-14a and anti-14a coexist in a
unit cell (Fig. 2), and the molecule was twisted with dihedral
4.1. General remarks
Melting points were determined in capillaries on a
Thomas–Hoover apparatus and are uncorrected. Infrared
(IR) spectra were recorded as either a thin film pressed
between two sodium chloride plates or as a solid suspended
in a KBr disk. The 1H NMR spectra were obtained at
400 MHz (13C NMR at 100 MHz) using CDCl3 as solvent
(unless otherwise specified). All chemical shifts were
expressed in d (ppm) with reference to CHCl3 (d 7.26 for
1H and d 77.0 for 13C). Coupling constants are reported in
hertz. The number of attached hydrogen on the carbon atom
was determined by the DEPT analysis. Mass (MS) and
HRMS spectra were done in EI (70 eV) unless otherwise
indicated. All solvents used were either reagent grade or
were distilled prior to use. Analytical thin-layer chroma-
tography (TLC) was performed on E. Merck silica gel 60
F254 plate (0.20 mm). Flash chromatography was performed
on E. Merck silica gel (230–400 mesh). Microanalyses were
performed by the NSC Analytical Centers operated by the
Figure 2. Crystal structures of syn-14a and anti-14a in a unit cell.

Table 1. The 13C and 1H NMR chemical shifts (d) of crown ethers 14a–d, and ether 8a
n
C1,4
C2,3
142.6
142.5
142.6
142.6
142.5
C9
C5,8
C6,7
128.1
128.2
128.4
128.3
128.2
C4a,8a
C10,11
–OCH3
–OCH2–
8
47.8
47.7
47.7
47.7
47.7
68.6
68.6
68.6
68.6
68.5
150.0
149.9
150.0
150.0
150.0
143.8
143.8
143.8
143.8
143.7
65.8
64.8
64.7
64.4
64.4
62.3
62.3
62.4
62.4
62.3
58.4 (–OCH3)
71.9
71.1; 69.9
70.7; 70.6; 69.8
70.7; 70.6; 70.5; 69.8
0 (14a)
1 (14b)
2 (14c)
3 (14d)
b
c
d
H1,4
H2,3
H9
2.23 (dd)/2.16 (d)
H10,11
4.51 (d)/4.47 (d)
–OCH3
3.80 (s)
–OCH2–
3.42 (s, –OCH3)
8
4.16–4.17 (m)
4.15–4.16 (m)
4.14–4.15 (m)
4.14–4.15 (m)
4.14–4.15 (m)
6.78 (dd)
6.77 (dd)
6.77 (dd)
6.77 (dd)
6.77 (dd)
[2.19 (Ddppm¼0.062)]
[4.49 (Ddppm¼0.037)]
0 (14a)
1 (14b)
2 (14c)
3 (14d)
2.22 (dd)/2.16 (d)
[2.19 (Ddppm¼0.057)]
2.22 (dd)/2.15 (d)
4.66–4.75 (m, 8H)
3.80 (s)
,3.79 (s)
3.79 (s)
3.79 (s)
3.88 (s, 8H)
4.70 (d)/4.66 (d)
[4.68 (Ddppm¼0.040)]
3.75–3.80 (m, 8H);
3.68–3.70 (m, 8H)
3.67–3.75 (m, 16H);
3.66 (s, 8H)
3.62–3.78 (m, 24H);
3.66 (s, 8H)
[2.18 (Ddppm¼0.072)]
2.22 (dd)/2.15 (d)
[2.18 (Ddppm¼0.065)]
2.21 (dd)/2.14 (d)
4.66 (d)/4.62 (d)
[4.64 (Ddppm¼0.040)]
4.65 (d)/4.61 (d)
[2.18 (Ddppm¼0.070)]
[4.63 (Ddppm¼0.039)]
The spectra were recorded on a Bru¨ker DPX-400 spectrometer using CDCl3 as solvent. All chemical shifts were expressed in d (ppm) with reference to CHCl3 (13C: d 77.0; H: d 7.26).
a
1
b
c
d
J1¼J2¼1.8 Hz.
An AB-quartet, J¼7.2 Hz. Hydrogen atom at lower field is further coupled with J¼1.4 Hz.
An AB-quartet, J¼10 Hz.

T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
9945
Cheng Kung University, Tainan, or the Chung Hsing
University, Taichung, Taiwan.
4.2.2. 5,8-Dimethoxy-1,4-dihydro-1,4-methanonaphtha-
lene-6,7-dicarboxylic anhydride (5). A mixture of com-
pound 4 (340 mg, 1.35 mmol) in MeOH/H2O (40 mL/4 mL)
containing KOH (800 mg) was heated under reflux for 5 h.
The reaction mixture was cooled with an ice-water bath and
acidified by dropwise addition of concentrated HCl (ca.
8 mL), and then water (30 mL) was added. Most of
methanol was removed by evaporation under vacuum and
the aqueous residue was extracted with dichloromethane
three times. The organic layers were combined, washed with
brine and water, and dried (MgSO4). Filtered, and the filtrate
was concentrated to leave a yellow solid residue which was
rinsed with a small amount of methanol to give off-white
solids. Recrystallization from CH2Cl2/hexane (1:3 by vol.)
afforded pure anhydride 5 (240 mg, 65%) as white needles:
mp 143–1448C; IR 1834 (s), 1772 (s), 1569 (m), 1490 (s),
4.2. Materials
The adduct 217 was prepared from the Diels–Alder reaction
of freshly distilled cyclopentadiene and 2,3-dicyano-1,4-
benzoquinone, which was made according to the reported
method from commercially available 2,3-dicyano-1,4-
hydroquinone by oxidation with Pb(OAc)4 in ethyl
acetate.16 The v-tetrahydropyranyl-protected polyethylene
glycols 10a–c18 and v,v0-bis-tosylates 11a–d19 were
prepared from commercially available oligoethylene gly-
cols 9a–d according to the reported procedure and used
without further purification.
4.2.1. 5,8-Dimethoxy-1,4-dihydro-1,4-methanonaphtha-
lene-6,7-dicarbonitrile (4). Method A. A solution of adduct
2 (530 mg, 2.36 mmol) in CH2Cl2 (10 mL) was stirring with
silica gel (ca. 1 g) at room temperature overnight. The
reaction mixture was filtered and the residue was thoroughly
washed several times with EtOAc/n-Hex (1:1, 20 mL each).
The filtrate was concentrated in vacuo to furnish white
solids of 5,8-dihyroxyl-1,4-dihydro-1,4-methanonaphtha-
lene-6,7-dicarbonitrile (3): mp 2408C (acetone), decomp.,
IR 3273 (br), 2238 (m), 1589 (m), 1474 (s), 1302 (s), 1271
1305 (m), 1029 cm21 (s); 1H NMR
d 6.87 (dd,
J1¼J2¼1.8 Hz, 2H), 4.33–4.34 (m, 2H), 4.09 (s, 6H),
2.39 (d, J¼7.6 Hz, 1H), 2.31 (d, J¼7.6 Hz, 1H); 13C NMR d
160.7 (s), 155.5 (s), 148.6 (s), 142.7 (d), 119.8 (s), 70.0 (t),
62.2 (q), 48.2 (d); MS m/z (%) 272 (Mþ, 100), 257 (18), 227
(36), 225 (21), 213 (27), 197 (24), 185 (27), 169 (27), 138
(27), 127 (40), 113 (24). Anal. calcd for C15H12O5: C, 66.17;
H, 4.44. Found: C, 66.15; H, 4.48.
4.2.3. Dimethyl 5,8-dimethoxy-1,4-dihydro-1,4-methano-
naphthalene-6,7-dicarboxylate (6). A mixture of com-
pound 4 (6.20 g, 0.03 mol) and KOH (28.1 g, 0.05 mol) in
methanol (25 mL) was heated under reflux for 5 h, cooled
with an ice-water bath, and then acidified with conc. HCl.
The reaction mixture was filtered to remove inorganic salt
and the filtrate was concentrated. The residue was dissolved
in methanol (25 mL). Into the solution, cooled with an ice-
water bath, was added dropwise thionylchloride (5.87 mL,
0.05 mol) in a period of 0.5 h, and the reaction mixture was
then heated under reflux for 6 h. Most of methanol was
removed by evaporation under vacuum and the residue was
mixed with water (50 mL), extracted with EtOAc
(30 mL£3). The organic layers were combined, washed
subsequently with saturated NaHCO3 solution, brine and
water, dried (MgSO4) and filtered. The filtrate was
concentrated to leave a dark brown viscous oil which was
purified by column chromatography on silica gel using
EtOAc/n-Hex (1:1) as eluant (Rf¼0.8) followed by
recrystallization from ether to furnish pure diester 6
(5.94 g, 75%) as white crystalline: mp 74–758C (ether);
IR 1738 (s), 1444 (m), 1407 (m) 1310 (s), 1236 (s),
1
(s), 1218 (s) (m) cm21; H NMR (CD3OD) d 2.22 (AB
system, Dd¼0.074 ppm, J¼7.5 Hz, 2H), 4.26–4.27 (m,
2H), 4.90 (bs, 2H), 6.85 (dd, J1¼J2¼1.8 Hz, 2H); 13C NMR
(CD3OD) d 49.2 (d), 71.0 (t), 101.4 (s), 115.5 (s), 143.6 (d),
148.4 (s), 149.7 (s). This material was used for the
subsequent reaction without further purification.
A solution of 3 (7.50 g, 0.03 mol) in acetone (500 mL)
containing K2CO3 (41.0 g, 0.30 mmol) was stirred under
the nitrogen atmosphere for 30 min. Dimethyl sulfate
(6.40 g, 0.06 mol) was added, and the reaction mixture
was heated under reflux for 12 h. The reaction mixture
was then filtered, and the filtrate was concentrated to
leave a residue, which was taken into EtOAc (200 mL).
The solution was washed with water (100 mL£3), dried,
filtered, and concentrated to give dark brown oil. Flash
column chromatography of residual oil afforded white
solids of 4 (6.2 g, 85%).
Method B. A solution of adduct 2 (250 mg, 1.12 mmol) in
acetone (30 mL) containing K2CO3 (3.23 g, 23.4 mmol)
was stirred under the nitrogen atmosphere for 10 min.
Dimethyl sulfate (220 mg, 1.78 mmol) was added, and the
reaction mixture was heated under reflux in 4 h. The
reaction mixture was then filtered, and the filtrate was
concentrated to give a dark residue which was purified via
flash column chromatography and recrystallization from
EtOAc/n-Hex (1/3 by vol.) to afford pure 4 (800 mg, 87%)
as white flakes: mp 128–1298C; IR 2228 (m), 1576 (m),
1
1036 cm21 (s); H NMR d 6.81 (dd, J1¼J2¼1.8 Hz, 2H),
4.19–4.21 (m, 2H), 3.84 (s, 6H), 3.82 (s, 6H), 2.24 (AB
system, Dd¼0.056 ppm, J¼7.4 Hz, 2H); 13C NMR d 47.9
(d), 52.4 (q), 62.5 (q), 68.9 (t), 124.3 (s), 142.5 (d), 147.6 (s),
148.1 (s), 166.5 (s); MS m/z (%) 319 (11), 318 (Mþ, 100),
303 (15), 287 (56), 271 (37), 259 (30), 255 (38), 229 (21),
127 (34). Anal. calcd for C17H18O6: C, 64.14; H, 5.70.
Found: C, 63.95; H, 5.78.
1
1466 (s), 1407 (s), 1306 (s), 1277 (m), 1046 cm21 (s); H
NMR d 6.86 (dd, J1¼J2¼1.8 Hz, 2H), 4.31–4.32 (m, 2H),
4.00 (s, 6H), 2.35 (dd, J¼7.8, 1.4 Hz, 1H), 2.26 (d,
J¼7.8 Hz, 1H); 13C NMR d 152.3 (s), 150.6 (s), 142.6 (d),
113.6 (s), 106.8 (s), 69.3 (t), 62.1 (q), 48.5 (d); MS m/z (%)
252 (Mþ, 81), 237 (100), 221 (49), 84 (80), 77 (33), 51 (86).
Anal. calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.21; H, 4.86; N, 11.00.
4.2.4. 6,7-Dihydroxymethyl-5,8-dimethoxy-1,4-dihydro-
1,4-methanonaphthalene (1). Method A. Into a solution of
anhydride 5 (200 mg, 0.78 mmol) in THF (10 mL) cooled
with an ice-water bath was added portionwise LiAlH4
(89 mg, 2.34 mmol) under N2 atmosphere. After heating at
508C for 6 h, the reaction mixture was cooled with an ice-
water bath and water (10 mL) was added slowly to quench

9946
T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
the reaction. Most of THF was removed from the turbid
reaction mixture under vacuum, followed by addition of
10% aqueous HCl (20 mL). Extraction with CHCl3
(20 mL£3) and the combined organic layers were washed
with brine, dried (MgSO4), and filtered. The filtrate was
concentrated to leave viscous residue, which was purified
via flash column chromatography to give pure diol 1
(140 mg, 70%) as white crystallines.
Dimethyl sulfate (540 mg, 4.27 mmol) was added, and the
reaction mixture was heated under reflux in 48 h. The
reaction mixture was then cooled with an ice-water bath and
water (25 mL) was added to quench the reaction. Most of
the solvent was removed under reduced pressure and the
aqueous residue was extracted with CH2Cl2 (50 mL£3). The
combined organic layers were washed with brine, dried
(MgSO4), and filtered. The filtrate was concentrated to leave
a residue which was purified via flash column chromato-
graphy to afford pure 8 (450 mg, 72%) as a colorless oil: IR
(CHCl3) 1597 (w), 1452 (w), 1420 (w), 1220 (s), 1213 cm21
(s); 1H NMR d 6.78 (dd, J1¼J2¼1.8 Hz, 2H), 4.50 (d,
J¼10 Hz, 2H), 4.46 (d, J¼10 Hz, 2H), 4.16–4.17 (m, 2H),
3.8 (s, 6H), 3.42 (s, 6H), 2.22 (d, J¼7 Hz, 1H), 2.16 (d,
J¼7 Hz, 1H); 13C NMR d 150.0 (s), 143.8 (s), 142.6 (d),
128.1 (s), 68.6 (t), 65.8 (t), 62.4 (q), 58.4 (q), 47.8 (d); MS
(FAB) m/z (%) 291 (MþþH, 20), 290 (Mþ, 34), 289 (34),
258 (65), 243 (39), 229 (100). HRMS calcd for C17H22O4:
290.1518. Found: 290.1514.
Method B. Into a solution of diester 6 (2.50 g, 7.86 mmol) in
THF (80 mL) cooled with an ice-water bath and stirred
under N2 atmosphere was added in portions LiAlH4 (0.89 g,
23.6 mmol). After stirring at room temperature for 3 h, the
reaction mixture was cooled with an ice-water bath and was
slowly added 10% aqueous NaOH (20 mL) to quench the
reaction, followed by addition of 10% aqueous HCl
(20 mL). Organic layer was separated and aqueous layer
was extracted with EtOAc (50 mL£3). The organic layers
were combined, washed with saturated sodium bicarbonate
solution and brine, and dried (MgSO4), and filtered. The
filtrate was concentrated to leave an off-white solid.
Recrystallization from CH2Cl2 afforded pure diol 1
(87 mg, 91%) as white crystallines: mp 145–1468C; IR
3295 (s), 2939 (w), 1458 (s), 1308 (s), 1266 (s), 1067 cm21
(s); 1H NMR d 6.81 (dd, J1¼J2¼1.8 Hz, 2H), 4.72 (s, 4H),
4.18–4.19 (m, 2H), 3.81 (s, 6H), 2.86 (br, 2H), 2.25 (dd,
J¼7.2, 1.4 Hz, 1H), 2.18 (d, J¼7.2 Hz, 1H); 13C NMR d
149.2 (s), 143.4 (s), 142.6 (d), 130.6 (s), 68.6 (t), 62.4 (q),
56.8 (t), 47.8 (d); MS m/z (%) 262 (Mþ, 100), 244 (78), 229
(48), 215 (39), 185 (44), 128 (47), 127 (63), 115 (34), 114
(41). Anal. calcd for C15H18O4: C, 68.68; H, 6.92. Found: C,
68.92; H, 7.34.
4.3. General procedure for the preparation of
bis-v-tetrahydropyranyl ethers 12a–c
A solution of v-tetrahydropyranyl polyethylene glycols
10a–c (1.00 mmol) in dried THF (5 mL) was added NaH
(1.00 mmol) under N2 atmosphere and the reaction mixture
was heated under gentle reflux. Dibromide 7 (0.50 mmol) in
THF (5 mL) was added dropwise into the reaction mixture.
After refluxing for 3 h, another portion of NaH (1.00 mmol)
was added, and the reaction mixture was refluxed for
additional 18 h, and cooled down to room temperature.
Methanol (5 mL) was added to quench any unchanged NaH.
Solvent (THF) was removed prior to the addition of water
(30 mL) and the resulting solution was extracted with
EtOAc (30 mL£3). The combined organic layers were
washed with brine, dried (MgSO4), and filtered. Removal of
solvent left a pale yellow viscous liquid, which was then
subjected to column chromatography to afford pure 12a–c
as colorless oil.
4.2.5. 6,7-Dibromomethyl-5,8-dimethoxy-1,4-dihydro-
1,4-methanonaphthalene (7). Into a solution of diol 1
(0.5 g, 1.91 mmol) in toluene (20 mL) cooled with an ice-
water bath was slowly added PBr3 (0.12 mL, 1.27 mmol).
After addition was complete, the mixture was stirred at
room temperature for 2 h, and was added water. Organic
layer was separated and aqueous layer was extracted with
EtOAc (20 mL£3). The organic layers were combined,
washed with brine, and dried (MgSO4). After filtration, the
filtrate was concentrated to leave a pale yellow viscous
residue, which was purified via flash column chromato-
graphy to give dibromide 7 (0.68 g, 92%) as white solids:
mp 98–998C (pentane); Rf¼0.66 (EtOAc/n-Hex, 1:3); IR
1465 (m), 1412 (m), 1302 (m), 1271 (s), 1036 (s), 732 (w),
4.3.1. 6,7-Bis-(4-tetrahydropyran-20-yloxy-2-oxa-1-
butyl)-5,8-dimethoxy-1,4-dihydro-1,4-methanonaphtha-
lene (12a). Yield 57%. Rf¼0.68 (EtOAc/n-Hex, 1:1); IR
2939 (s), 2870 (m), 1461 (m), 1267 (m), 1124 (s), 1076 (s),
1
1034 (s) cm21; H NMR d 6.76 (dd, J1¼J2¼1.8 Hz, 2H),
4.60–4.62 (m, 6H), 4.13–4.14 (m, 2H), 3.82–3.87 (m, 4H),
3.78 (s, 6H), 3.68–3.71 (m, 4H), 3.59–3.61 (m, 2H), 3.44–
3.49 (m, 2H), 2.17 (AB quartet, Dd¼0.068 ppm, J¼7.1 Hz,
2H), 1.47–1.58 (m, 12H); 13C NMR d 150 (s), 143.7 (s),
142.5 (d), 128.2 (s), 98.7 (d), 69.7 (t), 68.5 (t), 66.5 (t), 64.3
(t), 62.3 (q), 62.0 (t), 47.6 (d), 30.5 (t), 25.4 (t), 19.3 (t); MS
m/z (%) 518 (Mþ, weak), 372 (16), 289 (37), 288 (40), 273
(100), 244 (39), 229 (58), 129 (29). HRMS calcd for
C29H42O8: 518.2880. Found: 518.2878.
1
583 cm21 (w); H NMR d 6.82 (dd, J1¼J2¼1.8 Hz, 2H),
4.71 (AB quartet, Dd¼0.054 ppm, J¼10 Hz, 4H), 4.20–
4.21 (m, 2H), 3.92 (s, 6H), 2.23 (AB quartet,
Dd¼0.065 ppm, J¼7.4 Hz, 2H); 13C NMR d 149.2 (s),
144.3 (s), 142.5 (d), 127.4 (s), 68.3 (t), 61.8 (q), 47.9 (d),
24.8 (t); MS m/z (%) 390 (Mþ4, 8), 388 (Mþ2, 19), 386
(Mþ, 8), 309 (100), 307 (91), 228 (72), 213 (40), 152 (36),
141 (35), 127 (30), 114 (29). Anal. calcd for C15H16Br2O2:
C, 46.42; H, 4.16; O, 8.25. Found: C, 46.35; H, 4.25; O,
8.24.
4.3.2. 6,7-Bis-(7-tetrahydropyran-20-yloxy-2,5-dioxa-1-
heptyl)-5,8-dimethoxy-1,4-dihydro-1,4-methano-
naphthalene (12b). Yield 67%. Rf¼0.70 (EtOAc); IR 2938
(s), 2870 (s), 1460 (m), 1350 (m), 1303 (m), 1267 (m), 1125
(s), 1077 (s), 1034 (s), 1021 cm21 (m); 1H NMR d 6.78 (dd,
J1¼J2¼1.7 Hz, 2H), 4.60 (m, 6H), 4.15 (m, 2H), 3.47–3.85
(m, 26H), 2.21 (AB quartet, Dd¼0.069 ppm, J¼7.1 Hz,
2H), 1.49–1.61 (m, 12H); 13C NMR d 149.9 (s), 143.6 (s),
4.2.6. 6,7-Dimethoxymethyl-5,8-dimethoxy-1,4-dihydro-
1,4-methanonaphthalene (8). Under N2 atmosphere,
sodium hydride (260 mg, 19.2 mmol) was added into a
stirring solution of diol 1 (560 mg, 2.14 mmol) in THF
(100 mL), and the mixture was heated under reflux for 0.5 h.

T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
9947
142.5 (d), 128.1 (s), 98.8 (d), 70.4 (t), 70.3 (t), 69.6 (t), 68.5
(t), 66.6 (t), 64.2 (t), 62.3 (q), 62.1 (t), 47.6 (d), 30.5 (t), 25.3
(t), 19.4 (t); MS (FAB, NBA) m/z (%) 606 (Mþ, 1), 605 (2),
416 (15), 311 (14), 309 (11), 229 (100), 215 (14), 149 (24),
85 (92), 57 (32). HRMS calcd for C33H50O10: 606.3404.
Found: 606.3406.
(100), 244 (16), 243 (26), 229 (44). HRMS calcd for
C23H34O8: 438.2254. Found: 438.2260.
4.4.3. 6,7-Bis-(10-hydroxy-2,5,8-trioxa-1-decyl)-5,8-
dimethoxy-1,4-dihydro-1,4-methanonaphthalene (13c).
Yield 91%. Rf¼0.92 (EtOAc); IR 3409 (br), 2936 (m),
2873 (s), 1460 (m), 1268 (m), 1081 (s), 1018 cm21 (m), 934
4.3.3. 6,7-Bis-(10-tetrahydropyran-20-yloxy-2,5,8-trioxa-
1-decyl)-5,8-dimethoxy-1,4-dihydro-1,4-methano-
naphthalene (12c). Yield 79%. Rf¼0.40 (EtOAc/n-
Hex,1:1); IR 2938 (s), 2875 (s), 1460 (m), 1267 (w), 1124
(s), 1072 (s), 1034 cm21 (s); 1H NMR d 6.76 (dd,
J1¼J2¼1.8 Hz, 2H), 4.57–4.62 (m, 6H), 4.13 (br, 2H),
3.82–3.85 (m, 6H), 3.78 (s, 6H), 3.58–3.68 (m, 20H),
3.45–3.51 (m, 2H), 2.17 (AB quartet, Dd¼0.071 ppm,
J¼7.1 Hz, 2H), 1.47–1.69 (m, 12H); 13C NMR d 150.0 (s),
143.7 (s), 142.5 (d), 128.1 (s), 98.9 (d), 72.5 (t), 70.5 (t),
70.4 (t), 69.6 (t), 68.5 (t), 66.6 (t), 66.5 (t), 64.2 (t), 62.3 (q),
62.1 (t), 47.6 (d), 30.5 (t), 25.4 (t), 19.4 (t); MS (FAB) m/z
(%) 694 (Mþ, weak), 460 (15), 377 (12), 311 (6), 229 (100),
228 (10), 85 (73), 45 (13). HRMS calcd for C37H58O12:
694.3928. Found: 694.3922.
(w); H NMR d 6.76 (dd, J1¼J2¼1.5 Hz, 2H), 4.59 (AB
1
quartet, Dd¼0.042 ppm, J¼10.1 Hz, 4H), 4.13 (br, 2H),
3.77 (s, 6H), 3.55–3.69 (m, 24H), 3.04 (br, 2H), 2.17 (AB
quartet, Dd¼0.072 ppm, J¼7 Hz, 2H); 13C NMR d 150.0
(s), 143.7 (s), 142.5 (d), 128.0 (s), 72.5 (t), 70.5 (t), 70.3 (t),
69.5 (t), 68.5 (t), 64.2 (t), 62.3 (q), 61.6 (t), 61.5 (t), 47.7 (d);
MS (FAB) m/z (%) 549 (MþþNa, 6), 515 (1), 376 (20), 375
(4), 229 (100), 199 (10), 133 (4), 89 (12). HRMS calcd for
C27H42O10·Naþ: 549.2676. Found: 549.2671.
4.4.4. Preparation of 6-Hydroxymethyl-7-(tetrahydro-
pyran-20-yloxymethyl)-5,8-dimethoxy-1,4-dihydro-1,4-
methanonaphthalene (15). Into a solution of diol 1 (0.50 g,
1.91 mmol) in CH2Cl2 (50 mL) containing a catalytic
amount of pyridinium p-toluenesulfonate (PPTS), cooled
with an ice-water bath, was slowly added a solution of DHP
(0.26 mL, 2.86 mmol) in a period of 30 min. After the
addition was complete, the reaction mixture was stirring at
room temperature and monitored by TLC every hour. Water
(20 mL) was added immediately when the formation of bis-
protected product was observed on TLC plate (4 h). Organic
layer was separated and washed with brine (20 mL£3),
dried (MgSO4), and filtered. Concentration of the filtrate to
give oily residue which was purified via flash column
chromatography to give 15 (0.49 g, 74%) as a colorless
viscous liquid: Rf¼0.48 (EtOAc/n-Hex, 1:1); IR 3487 (br),
2929 (s), 2853 (m), 1459 (m), 1266 (m), 1117 (m), 1073
4.4. General procedure for hydrolysis of
bis-v-tetrahydropyranyl ethers 12a–c. Formation
of v,v0-diols 13a–c
Ether 12a–c (0.20 mmol) was dissolved in methanol
(10 mL) with addition of two drops of conc. HCl and the
solution was stirred at room temperature for 2 h.
Methanol was removed from the reaction mixture after
it was neutralized with NaHCO3, and the residue thus
obtained was stirred with EtOAc (10 mL) for a few
minutes, and then filtered. The filtrate was concentrated
to leave a pale yellow viscous liquid, which was purified
via flash column chromatography to give v0-diol 13a–c
as a colorless oil.
1
(m), 1021 cm21 (s); H NMR d 6.82 (dd, J1¼J2¼1.7 Hz,
2H), 4.92/4.90 (2d, J¼10.7 Hz, 1H), 4.80–4.82 (m, 1H),
4.67–4.69 (m, 2H), 4.61/4.60 (2d, J¼10.7 Hz, 1H), 4.18–
4.20 (m, 2H), 3.91–3.97 (m, 1H), 3.87/3.86 (2s, 3H), 3.79
(s, 3H), 3.58–3.63 (m, 1H), 3.17 (br, 2H, –OH), 2.23/2.20
(unresolved AB quartet, 2H), 1.72–1.75 (m, 2H), 1.52–1.60
(m, 4H); 13C NMR d 149.53/149.48 (2s), 143.86 (s), 143.29/
143.26 (2s), 142.72/142.66 (2d), 142.61 (s), 132.09/132.07
(2s), 126.98/126.94 (2s), 98.56/98.51 (2d), 68.68 (t), 62.48
(q), 62.22 (t), 61.45/61.43 (2t), 56.95 (t), 47.78/47.75/47.72
(3d), 30.56/30.54 (2t), 25.25 (t), 19.25/19.23 (2t); MS (FAB,
NBA) m/z (%) 346 (Mþ, 66), 329 (20), 245 (100), 229 (93),
215 (34), 154 (62), 136 (44), 85 (90). HRMS calcd for
C20H26O5: 346.1780. Found: 346.1775.
4.4.1. 6,7-Bis-(4-hydroxy-2-oxa-1-butyl)-5,8-dimethoxy-
1,4-dihydro-1,4-methanonaphthalene (13a). Yield 99%.
Rf¼0.32 (EtOAc/n-Hex, 1:1); IR 3418 (br), 2935 (s), 2875
(m), 1612 (s), 1460 (s), 1268 (s), 1096 (s), 1068 (s),
1
1018 cm21 (s); H NMR d 6.82 (dd, J1¼J2¼1.8 Hz, 2H),
4.61 (AB quartet, Dd¼0.030 ppm, J¼10.5 Hz, 4H), 4.18–
4.19 (m, 2H), 3.81 (s, 6H), 3.66–3.70 (m, 8H), 2.66 (br,
C
2H), 2.23 (AB quartet, Dd¼0.052 ppm, J¼7.1 Hz, 2H); 13
NMR d 150.0 (s), 143.9 (s), 142.6 (d), 127.9 (s), 71.8 (t),
68.6 (t), 64.6 (t), 62.3 (q), 61.6 (t), 47.9 (d); MS (FAB) m/z
(%) 350 (Mþ, 4), 311 (9), 288 (44), 243 (18), 229 (100), 215
(15), 199 (12), 141 (8), 128 (9), 115 (9), 77 (6), 45 (9).
HRMS calcd for C19H26O6: 350.1729. Found: 350.1720.
4.5. General procedure for the preparation of bis-(1,4-
methanonaphthalen-6-yl)ethers 16b–d
4.4.2. 6,7-Bis-(7-hydroxy-2,5-dioxa-1-heptyl)-5,8-
dimethoxy-1,4-dihydro-1,4-methanonaphthalene (13b).
Yield 93%. Rf¼0.17 (EtOAc); IR 3416 (br), 2933 (s),
2875 (m), 1616 (w), 1459 (m), 1267 (m), 1127 (m), 1075 (s),
A solution of benzyl alcohol 15 (1.00 mmol) in dried THF
(20 mL) was added NaH (3.00 mmol) under N2 atmosphere
and the reaction mixture was heated under gentle reflux.
Bis-toluene-p-sulfonate 11b–d (0.50 mmol) in THF (5 mL)
was added dropwise into the reaction mixture. After
refluxing for 10 h, another portion of NaH (3.00 mmol)
was added, and the reaction mixture was refluxed for
additional 20 h, and cooled down to room temperature.
Methanol (10 mL) was added. Solvent (THF) was removed
prior to the addition of water (50 mL) and the resulting
solution was extracted with EtOAc (30 mL£3). The
1
1017 (m), 891 (w), 735 cm21 (w); H NMR d 6.78 (dd,
J1¼J2¼1.7 Hz, 2H), 4.69 (AB quartet, Dd¼0.042 ppm,
J¼10.3 Hz, 4H), 4.15–4.16 (m, 2H), 3.78 (s, 6H), 3.55–
3.71 (m, 16H), 2.19 (AB quartet, Dd¼0.066 ppm, J¼7.2 Hz,
2H); 13C NMR d 150.0 (s), 143.8 (s), 142.6 (d), 127.9 (s),
72.6 (t), 70.7 (t), 69.2 (t), 68.6 (t), 64.1 (t), 62.3 (q), 61.7 (t),
47.8 (d); MS (EI, 70 eV) m/z (%) 438 (Mþ, weak), 332

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T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
combined organic layers were washed with brine, dried
(MgSO4), and filtered. Removal of solvent left a pale yellow
viscous liquid, which was subjected to purification via
column chromatography to afford 16b–d as colorless oil.
(t), 62.36/62.29 (2q), 62.07/62.04 (2t), 61.05/61.01 (2t),
47.73/47.68 (2d), 30.69/30.67 (2t), 25.49 (t), 19.46/19.45
(2t); MS (FAB, NBA) m/z (%) 850 (Mþ, 4), 427 (44), 229
(100), 228 (92). HRMS (FAB) calcd for C48H66O13:
850.4503. Found: 850.4512.
4.5.1. 1,9-Bis[7-(tetrahydropyran-20-yloxymethyl)-5,8-
dimethoxy-1,4-dihydro-1,4-methanonaphthalen-6-yl]-
2,5,8-trioxanonane (16b). Yield 66%. Rf¼0.37 (EtOAc/n-
Hex, 1:1); IR 2936 (m), 2867 (m), 1459 (m), 1267 (m), 1134
4.6. Hydrolysis of ditetrahydropyranyl-substituted
ethers 16b–d. Formation of bis-benzylic diols 17b–d
1
(m), 1116 (m), 1076 (m), 1022 cm21 (s); H NMR d 6.77
The procedure for hydrolysis of bis-v-tetrahydropyranyl
ethers 12a–c to form v,v0-diols 13a-c was generally
followed.
(dd, J1¼J2¼1.8 Hz, 4H), 4.86/4.83 (2d, J¼10.3 Hz, 2H),
4.75 (m, 2H), 4.61/4.58 (2 AB quartets, Dd¼0.053/
0.054 ppm,
J¼10.0/9.9 Hz,
4H),
4.50/4.48
(2d,
J¼10.4 Hz, 2H), 4.14–4.16 (m, 4H), 3.94–3.99 (m, 2H),
3.78–3.80 (m, 12H), 3.62–3.66 (m, 10H), 2.19 (AB quartet,
Dd¼0.060 ppm, J¼7.1 Hz, 4H), 1.52–1.59 (m, 12H); 13C
NMR d 150.18/150.15 (2s), 150.02/150.00 (2s), 143.74/
143.72 (2s), 143.65/143.62 (2s), 142.58/142.54 (2d),
128.21/128.15/128.12 (3s), 98.64/98.59 (2d), 70.37 (t),
69.58 (t), 68.51 (t), 64.38 (t), 62.38/62.36 (2q), 62.31 (t),
62.07/62.03 (2t), 61.03/61.00 (2t), 47.72/47.66 (2d), 30.68/
30.66 (2t), 25.48 (t), 19.46/19.44 (2t); MS (FAB, NBA) m/z
(%) 762 (Mþ, weak), 426 (7), 334 (3), 229 (100), 228 (19),
141 (5), 185 (5). HRMS calcd for C44H58O11: 762.3979.
Found: 762.3991.
4.6.1. 1,9-Bis[7-hydroxymethyl-5,8-dimethoxy-1,4-dihy-
dro-1,4-methanonaphthalen-6-yl]-2,5,8-trioxanonane
(17b). Yield 96%. Rf¼0.50 (EtOAc/n-Hex, 1:1); IR 3491
(br), 2929 (s), 2857 (m), 1460 (m), 1380 (w), 1267 (s), 1121
(m), 1072 (m), 1023 cm21 (w); 1H NMR d 6.80 (dd,
J1¼J2¼1.7 Hz, 4H), 4.62–4.68 (m, 8H), 4.16–4.20 (m,
4H), 3.85 (s, 6H), 3.76 (s, 6H), 3.68–3.71 (m, 4H), 3.58–
3.60 (m, 4H), 2.21 (AB quartet, Dd¼0.063 ppm, J¼7.2 Hz,
4H); 13C NMR d 149.8 (s), 149.3 (s), 143.9 (s), 143.0 (s),
142.7 (d), 142.6 (d), 132.5 (s), 127.1 (s), 70.3 (t), 69.3 (t),
68.7 (t), 64.9 (t), 62.5 (q), 62.4 (q), 56.7 (t), 47.8 (d), 47.7
(d); MS (FAB) m/z (%) 595 (MþþH, weak), 441 (34), 245
(100), 229 (97). HRMS (FAB) calcd for C34H42O9·Hþ:
595.2912. Found: 595.2910.
4.5.2. 1,12-Bis[7-(tetrahydropyran-20-yloxymethyl)-5,8-
dimethoxy-1,4-dihydro-1,4-methanonaphthalen-6-yl]-
2,5,8,11-tetraoxadodecane (16c). Yield 69%. Rf¼0.24
(EtOAc/n-Hex, 1:1); IR 2938 (s), 2875 (m), 1460 (m),
1348 (m), 1304 (m), 1267 (s), 1116 (m), 1076 (m),
4.6.2. 1,12-Bis[7-hydroxymethyl-5,8-dimethoxy-1,4-
dihydro-1,4-methanonaphthalen-6-yl]-2,5,8,11-tetraoxa-
dodecane (17c). Yield 93%. Rf¼0.33 (EtOAc); IR 3485
(br), 2934 (m), 2869 (m), 1460 (m), 1304 (m), 1266 (s),
1
1022 cm21 (s); H NMR d 6.78 (dd, J1¼J2¼1.8 Hz, 4H),
1
4.86/4.83 (2d, J¼10.3 Hz, 2H), 4.75 (m, 2H), 4.60 (dt,
J1¼23.2 Hz, J2¼10 Hz, 4H), 4.50/4.47 (2d, J¼10.3 Hz,
2H), 4.15–4.16 (m, 4H), 3.93–3.99 (m, 2H), 3.79–3.81 (m,
12H), 3.60–3.67 (m, 14H), 2.20 (AB quartet,
Dd¼0.060 ppm, J¼7.1 Hz, 4H), 1.52–1.60 (m, 12H); 13C
NMR d 150.16/150.13 (2s), 149.99/149.96 (2s), 143.74/
143.72 (2s), 143.63/143.60 (2s), 142.57/142.56 (2d),
142.52/142.51 (2d), 128.19/128.11/128.08 (3s), 98.61/
98.57 (2d), 70.45 (t), 69.57 (t), 68.50 (t), 64.34 (t), 62.36/
62.29 (2q), 62.04/62.01 (2t), 61.02/60.98 (2t), 47.69/47.64
(2d), 30.66/30.64 (2t), 25.45 (t), 19.43/19.41 (2t); MS (FAB,
NBA) m/z (%) 806 (Mþ, 5), 705 (Mþ2–OTHP), 427 (35),
377 (17), 375 (16), 245 (57), 244 (89), 243 (99), 231 (24),
230 (88), 229 (100), 215 (40), 213 (42), 85 (98), 67 (33), 57
(57). HRMS (FAB) calcd for C46H62O12: 806.4241. Found:
806.4251.
1219 (m), 1085 (s), 1021 cm21 (s); H NMR d 6.81 (dd,
J1¼J2¼1.5 Hz, 4H), 4.61–4.65 (m, 8H), 4.16–4.19 (m,
4H), 3.85 (s, 6H), 3.77 (s, 6H), 3.58–3.66 (m, 12H), 2.21
(AB quartet, Dd¼0.065 ppm, J¼7.1 Hz, 4H); 13C NMR d
149.8 (s), 149.3 (s), 144.0 (s), 143.0 (s), 142.8 (d), 142.6 (d),
132.5 (s), 127.1 (s), 70.4 (t), 70.3 (t), 69.2 (t), 68.7 (t), 64.8
(t), 62.6 (q), 62.4 (q), 56.8 (t), 47.7 (d); MS (FAB, NBA) m/z
(%) 639 (Mþþ1), 620 (Mþ2H2O, 16), 429 (35), 427 (40),
377 (37), 246 (50), 245 (100), 244 (79), 243 (96), 230 (45),
229 (100), 215 (54), 213 (35), 163 (42), 154 (67), 136 (56),
128 (30), 115 (32), 89 (35), 77 (36). HRMS (FAB) calcd for
C36H46O10·Hþ: 639.3163. Found: 639.3166.
4.6.3. 1,15-Bis[7-hydroxymethyl-5,8-dimethoxy-1,4-
dihydro-1,4-methanonaphthalen-6-yl]-2,5,8,11,14-pen-
taoxadodecane (17d). Yield 99%. Rf¼0.18 (EtOAc); IR
3486 (br), 2935 (m), 2869 (m), 1459 (m), 1304 (m), 1267
(s), 1218 (m), 1089 (s), 1021 (s), 732 cm21 (m); 1H NMR d
6.81 (dd, J1¼J2¼1.2 Hz, 4H), 4.62–4.66 (m, 8H), 4.16–
4.19 (m, 4H), 3.85 (s, 6H), 3.77 (s, 6H), 3.58–3.67 (m,
16H), 2.21 (AB quartet, Dd¼0.065 ppm, J¼7.2 Hz, 4H);
13C NMR d 149.8 (s), 149.3 (s), 144.0 (s), 142.9 (s), 142.7
(d), 142.6 (d), 132.5 (s), 127.0 (s), 70.5 (t), 70.4 (t), 70.3 (t),
69.2 (t), 68.7 (t), 64.8 (t), 62.5 (q), 62.4 (q), 56.8 (t), 47.7 (d);
MS (FAB, NBA) m/z (%) 705 (MþþNa, 40), 429 (26), 229
(100), 215 (84). HRMS (FAB) calcd for C38H50O11·Naþ:
705.3251 Found: 705.3259.
4.5.3. 1,15-Bis[7-(tetrahydropyran-20-yloxymethyl)-5,8-
dimethoxy-1,4-dihydro-1,4-methanonaphthalen-6-yl]-
2,5,8,11,14-pentaoxadodecane (16d). Yield 61%. Rf¼0.66
(EtOAc); IR 2938 (s), 2869 (m), 1612 (w), 1459 (m), 1348
(m), 1304 (m), 1267 (s), 1116 (s), 1078 (s), 1022 (s), 905
1
(m), 731 cm21 (m); H NMR d 6.78 (dd, J1¼J2¼1.6 Hz,
4H), 4.86/4.83 (2d, J¼10.3 Hz, 2H), 4.75 (m, 2H), 4.60 (dt,
J1¼22.9 Hz, J2¼10 Hz, 4H), 4.50/4.48 (2d, J¼10.3 Hz,
2H), 4.15 (m, 4H), 3.94–3.99 (m, 2H), 3.80–3.82 (m, 12H),
3.56–3.69 (m, 18H), 2.20 (AB quartet, Dd¼0.059 ppm,
J¼7.1 Hz, 4H), 1.48–1.60 (m, 12H); 13C NMR d 150.20/
150.17 (2s), 150.02/150.00 (2s), 143.74/143.72 (2s), 143.63/
143.60 (2s), 142.58/142.55 (2d), 128.24/128.16/128.13 (3s),
98.64/98.60 (2d), 70.55/70.47 (2t), 69.61 (t), 68.52 (t), 64.38
4.7. Synthesis of crown ethers 14b–d
Method A. From dibromide 7 and v,v0-diols 13a–c. Under

T.-C. Chou et al. / Tetrahedron 59 (2003) 9939–9950
9949
N2 atmosphere, a solution of v,v0-diols 14a–c (0.14 mmol)
in dried THF (20 mL) was added NaH (0.84 mmol) and the
reaction mixture was heated under gentle reflux. Dibromide
7 (0.14 mmol) in THF (10 mL) was added dropwise into the
reaction mixture. After refluxing for 2 h, the reaction
mixture was cooled down to room temperature and
methanol (10 mL) was added. Solvent (THF) was removed
prior to the addition of water (20 mL) and the resulting
solution was extracted with ethyl acetate (20 mL£4). The
combined organic layers were washed with brine, dried
(MgSO4), and filtered. Removal of solvent left a pale yellow
viscous liquid, which was subjected to purification via
column chromatography to afford pure 14a as a white solid
in 47% yield, and 14b and 14c as colorless oil in 78 and 64%
yields, respectively.
4.7.4. 18,25,43,50-Tetramethoxy-3,6,9,12,15,28,31,
34,37,40-decaoxaheptacyclo[40.8.0.120,23.145,48.017,26
19,24.044,49]dopentaconta-1(42),17,19(24),25,43,46,49-
octene (14d). Rf¼0.29 (EtOAc); IR 2930 (s), 2871 (s), 1462
NMR (see Table 1); MS (FAB) m/z (%) 840 (Mþ, 8), 647
(34), 243 (90), 229 (100). HRMS calcd for C46H64O14:
840.4296. Found: 840.4305.
.
0
(m), 1267 (m), 1098 (s), 1018 cm21 (m); 1H NMR and 13
C
4.8. X-Ray crystallography
Single crystals of crown ether 14a suitable for X-ray
crystallographic analysis were obtained from a mixture of
ether–dichloromethane. It crystallized in a monoclinic
form, space group Cc (No. 9). The X-ray crystallographic
data were recorded with a Bruker Smart APEX CCD
diffractometer. Graphite monochromatized Mo Ka radi-
Method B. From diols 17b–d and bis-toluene-p-sulfonate
11b–d. A solution of bis-benzyl alcohol 17b–d
(0.10 mmol) in dried THF (10 mL) was added NaH
(0.50 mmol) under N2 atmosphere and the reaction mixture
was heated under gentle reflux. Bis-toluene-p-sulfonate
11b–d (0.10 mmol) in THF (5 mL) was added dropwise
into the reaction mixture. After refluxing for 10 h, another
portion of NaH (0.5 mmol) was added, and the reaction
mixture was refluxed for additional 20 h, and cooled down
to room temperature. Methanol (10 mL) was added. Solvent
(THF) was removed prior to the addition of water (30 mL)
and the resulting solution was extracted with EtOAc
(20 mL£3). The combined organic layers were washed
with brine, dried (MgSO4), and filtered. Removal of solvent
left a pale yellow viscous liquid, which was subjected to
purification via column chromatography to afford 14b, 14c,
and14dascolorlessoilin78, 83, and65%yields, respectively.
˚
ation [l¼0.71073 A] and temperature of 273(2) K were
used. The CCD data were processed with SAINT and the
structures were solved by direct method (SHELXS-9721)
and refined on F 2 by full-matrix least-squares techniques
(SHELXL-9722). The hydrogen atoms were located from
the difference Fourier and refined isotropically. Crystal-
lographic data (excluding structure factors) for 14a has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 216665.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk].
Compound 14a. C34H40O8, monoclinic, space group Cc,
˚
˚
˚
a¼9.0852(12) A,
b¼25.122(3) A,
c¼26.700(4) A;
3
˚
a¼91.585(4)8, V¼6091.5(15) A , Z¼8 (two independent
4.7.1. 9,16,25,32-Tetramethoxy-3,6,19,22-tetraoxahepta-
cyclo[22.8.0.111,14.127,30.08,17.010,15.027,30]tetratriaconta-
1(24),8,10(15),12,16,25,28,31-octene (14a). Mp 176–
1778C (CH2Cl2/acetone); Rf¼0.31 (EtOAc/n-Hex, 1:1); IR
2936 (m), 2870 (m), 1460 (s), 1267 (s), 1097 (s), 1019 (s),
975 (m), 735 cm21 (w); 1H NMR and 13C NMR (see Table
1); MS m/z (%) 576 (Mþ, 3), 501 (8), 300 (9), 288 (53), 287
(34), 229 (85), 228 (100), 213 (40), 199 (40), 141 (32), 128
(38). HRMS calcd for C34H40O8: 576.2723. Found:
576.2729.
molecules),
0.3£0.2£0.1 mm3.
Dcalcd¼1.258 Mg/m3,
crystal size
total of 34983 reflections
A
(235#h#34, 212#k#11, 232#l#32) were collected at
T¼300(2) K in the range from 1.53 to 28.38, of which 14360
were unique (Rint¼0.0508); All nonhydrogen atoms were
refined anisotropically. Hydrogen atoms were placed in
calculated idealized positions. The residual peak and hole of
electron densities were 1.169 and 20.204 e A23. The final R
indices [(I.2s(I))]: R(F)¼0.0638, wR(F 2)¼0.1745;
˚
GOF¼0.855 (for 345 parameters).
4.7.2. 12,19,31,38-Tetramethoxy-3,6,9,22,25,28-hexaoxa-
heptacyclo[28.8.0.114,17.133,36.011,20.013,18.032,37]tetra-
conta-1(30),11,13(18),15,19,31,34,37-octene (14b).Rf¼0.71
(EtOAc); IR 2930 (s), 2869 (s), 1461 (m), 1355 (m), 1303
(m), 1267 (m), 1136 (m), 1093 (m), 732 cm21 (s); 1H NMR
and 13C NMR (see Table 1); MS (FAB) m/z (%) 664 (Mþ,
6), 452 (6), 332 (45), 243 (53), 228 (100), 213 (18), 199
(15), 127 (17). HRMS calcd for C38H48O10: 664.3247.
Found: 664.3254.
Acknowledgements
We thank the financial support from National Science
Council of Taiwan.
References
4.7.3. 15,22,37,44-Tetramethoxy-3,6,9,12,25,28,31,34-
octaoxaheptacyclo[34.8.0.117,20.139,42.014,23.016,21.038,43]-
hexatetraconta-1(36),14,16(21),18,22,37,40,43-octene
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(see Table 1); MS m/z (%) 752 (Mþ, 1), 452 (4), 377 (17),
376 (20), 375 (12), 243 (46), 229 (100), 199 (22), 133 (20).
HRMS calcd for C42H56O12: 752.3772. Found: 752.3776.
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