Synthesis and structure of tetraols with convergent and divergent arrays of hydroxy groups

Article abstract of DOI:10.1039/a809834d

As hydrogen-bonding hosts with a partially flexible framework, two types of tetrahydroxy compounds with respectively convergent and divergent arrays of hydroxy groups were prepared. The structures of the tetraol with a diethyleneoxy bridge (1a), and that

Full text of DOI:10.1039/a809834d

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Synthesis and structure of tetraols with convergent and divergent
arrays of hydroxy groups
Hideki Takagi,a Takashi Hayashi,a Tadashi Mizutani,*a Hideki Masudab and
Hisanobu Ogoshia
a Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
b Department of Applied Chemistry, Nagoya Institute of Technology, Showa-ku,
Nagoya 466-8555, Japan
Received (in Cambridge) 17th December 1998, Accepted 10th May 1999
As hydrogen-bonding hosts with a partially flexible framework, two types of tetrahydroxy compounds with
respectively convergent and divergent arrays of hydroxy groups were prepared. The structures of the tetraol
with a diethyleneoxy bridge (1a), and that with a m-phenylenedioxy bridge (syn-13a and anti-13b) were determined
by X-ray crystallographic studies. syn-13a forms an inclusion crystal with 1,4-dioxane, one molecule of which is
bound in the cleft of syn-13a and the other in the intermolecular cavity.
During the recent development of host–guest chemistry, it was
recognized that the direction of recognition groups and their
fluctuation are important factors to determine the selectivity of
molecular recognition and the ability of self-assembly form-
ation. Attaching interaction groups to a scaffold in a con-
vergent fashion leads to a host that binds guest in solution,
while attaching them in a divergent fashion leads to a tecton1
that forms self-assembly either in solution or in the solid state.
For such chemistry both in the liquid phase and in the crystalline
phase, a number of host molecules with a rigid framework have
been synthesized, such as crown ethers, cryptands, carcerands,
cyclodextrins, cyclophanes, calixalenes, molecular cleft, and
porphyrins.2 In addition to the ability of a host to display
expected intermolecular interactions to bind a guest, conform-
ational changes triggered by intermolecular forces are another
important feature of functions of host molecules as exemplified
in induced-fit binding of substrates by enzymes.3 For the design
of these host molecules, partial flexibility should be given to the
host structure.4 However, controlling flexibility/rigidity of a
molecule requires extensive knowledge of potential energies of
all conformers, and we are still far away from our ultimate goal
of fine tuning of the flexibility of the host framework structure.
As part of our programme aimed at developing a new host
with controlled flexibility, we describe here the synthesis and
the structural characterization of novel host molecules, tetra-
hydroxylic compounds, where the arrangement and dynamics
of the hydroxy groups can be controlled by bridging groups
with varying flexibility.
HO
OH
O
O
HO
OH
1
ii
i
HO
O
O
EtOOC
O
O
O
O
O
2
3
iii
HO
OH
ii
HO
EtOOC
COOEt
EtOOC
O
5
4
iv
O
O
O
v
HO
O
EtOOC
OH
COOEt
6
7
vi
Results and discussion
OH
OH
Two types of tetraols were prepared, both of which have a
trans-cyclohexane-1,3-diol unit in common. Tetraol 1 has ethyl-
eneoxy bridging units while tetraol 13 has a m-phenylene unit in
addition to the ethyleneoxy unit to provide flexibility to the
dimeric structure. Scheme 1 shows the synthesis of the common
precursor 7.5
Nucleophilic addition of an enolate anion, generated from
ethyl acetate and lithium diisopropylamide, to the carbonyl
group of cyclohexane-1,3-dione gave the cyclohexane-1,3-
diol 5 in four steps. An attempt to perform the addition reaction
of two enolate anions to cyclohexane-1,3-dione in one step to
directly obtain diester 5 was unsuccessful. Thus, the reaction
between cyclohexane-1,3-dione and an excess of the ester enol-
HO
OH
8
Scheme 1 Reagents and conditions: i, ethylene glycol, TsOH(cat.), ben-
zene, reflux; ii, EtOAc, LDA, THF, Ϫ78 ЊC; then H3Oϩ; iii, Hϩ THF; iv,
(CH2O)n, EtOH, TsOH(cat.), benzene; then m-xylene; v, LiAlH4, THF;
vi, Hϩ MeOH.
ate anion afforded only the corresponding stable enolate from
the β-diketone, which was unreactive toward the nucleophile.
The addition reactions were, therefore, carried out stepwise via
J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892
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Fig. 1 1H NMR spectra of 8 in CDCl2CDCl2 in the temperature range of 23.5–135 ЊC.
1
cyclic ketal protection. The H NMR spectrum of 5 indicated
that this diester was a 1:1 mixture of cis and trans isomers: the
two sets of α-methylene proton signals at δ 2.43, 2.42 and δ 2.70,
2.60 were ascribed to the cis and trans isomers, respectively. The
Rf-values (TLC) of these isomers were so close that the separ-
ation of these isomers by silica gel column chromatography on
a large scale was, in practice difficult. In order to protect the two
hydroxy groups of diester 5, direct ketalization was examined
by using 2,2-dimethoxypropane, but failed possibly due to the
strained 1,3-dioxacyclane products. The mixture of cis/trans
isomers 5 was treated with paraformaldehyde under acidic con-
ditions to give a mixed acetal as an intermediate. Subsequent
thermal decomposition of the mixed acetal afforded cyclic
acetal 6 selectively from the cis isomer of 5, while the trans
isomer of 5 was converted to a lactone during pyrolysis. Cyclic
acetal 6 and the lactone were successfully separated by silica gel
column chromatography. A mixture of cis- and trans-5 was
recovered from the lactone by treating it with dilute sulfuric
acid. Reduction of acetal 6 with lithium aluminium hydride
gave diol 7, which adopts the chair-boat conformation as
confirmed by observation of 1H NMR nuclear Overhauser
enhancement (NOE) between the acetal methylene protons and
the cyclohexane ring protons. After hydrolysis of diol 7 with
aq. HCl, white crystalline solids were obtained; recrystallization
from CHCl3 gave 8 in 84% yield.
Vapour-pressure osmometry showed that the molecular weight
of 8 was 235 in a 0–0.023 M solution in CHCl3, suggesting that
8 is monomeric in CHCl3.
The synthetic route to 1a is illustrated in Scheme 2. For the
O
O
i
O
O
HO
TsO
OH
OTs
9
7
O
O
O
O
O
ii
+
7
9
O
10a
O
O
O
O
+
O
O
10b
OH
HO
OH
HO
Tetraol 8 was characterized by 1H and 13C NMR, mass spec-
troscopy, and elemental analysis. In the H NMR spectrum,
iii
O
O
1
the two methylene protons at the α-positions to the primary
hydroxy groups appear as magnetically inequivalent protons in
CDCl3, while they become equivalent in CD3OD. Similar
behaviour was observed for the β-methylene protons to the pri-
mary hydroxy groups. These observations indicate that intra-
molecular hydrogen bonding between the primary OH group
and the tertiary OH group is formed in CDCl3 and it breaks in
1a
Scheme 2 Reagents and conditions: i, p-TsCl, DMAP, Et3N, CH2Cl2;
ii, KOtBu, DME–DMSO; iii, Hϩ, MeOH.
dimer preparation, the two hydroxy groups of 7 were converted
to toluene-p-sulfonate, methanesulfonate, chloride, bromide, or
iodide as leaving groups, and the coupling reactions with 7 were
attempted. Various base–solvent combinations were tried to
obtain dimers 10a and 10b. The combination of ditosyl com-
pound 9 and potassium tert-butoxide in Me2SO gave dimers
10a and 10b in low yield. When other leaving groups (halogens)
were used, α,β-elimination took place in preference to the coup-
ling reaction. Treatment of a mixture of 10a and 10b with HCl
in methanol afforded the desired dimer 1a having cisoid
tetrahydroxy groups. syn Isomer 1a was isolated and purified by
medium-pressure liquid chromatography (MPLC), and charac-
1
CD3OD. The variable-temperature H NMR spectra of 8 in
CDCl2CDCl2 (Fig. 1) indicated that the methylene protons α to
the primary hydroxy group appear as multiplets centred at δ 3.9
at 23.5 ЊC and as a doublet of triplets at 135 ЊC. The intra-
molecular hydrogen bonding in an apolar solvent is thus
cleaved at high temperature. In contrast, the axial and
equatorial protons of the cyclohexane ring appeared separately,
and this spectral pattern did not change upon heating, showing
that the chair conformation with hydroxyethyl groups in the
equatorial position is rather rigid. Conformational analysis by
1H NMR of 1,3-disubstituted cyclohexanes has been reported.6
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Table 1 Crystal data for 13aؒ1.5C4H8O2
terized by NMR, MS and IR spectra, whereas the anti isomer
was not isolated because it formed only indistinct spots on
TLC.
Formula
Formula weight
C38H56O11
688.85
The syn geometry of 1a was confirmed by X-ray crystallo-
graphic analysis. The two cyclohexane rings assumed a chair
conformation and the hydrogen-bonding network among the
four hydroxy groups stabilized the rigid conformation with a
collapsed cleft between the two cyclohexane rings.7 The 1H
NMR spectrum of 1a in CDCl3 was similar to that in CD3OD,
indicating that 1a has a rigid framework as compared to 8. The
methylene protons β to the ether oxygen were shifted down-
field as the solvent changes from CDCl3 to CD3OD, indicating
Space group
a/Å
b/Å
c/Å
C2/c
21.458(2)
16.518(1)
21.437(2)
95.581(6)
7562.5(8)
8
β/Њ
Vol./Å3
Z
ρ (calc.)/g cmϪ3
Temp. T/ЊC
Crystal dimensions/mm
Radiation
1.21
23
0.25 × 0.25 × 0.25
graphite-monochromated Cu-Kα
1
some conformational changes. In the variable-temperature H
NMR spectra in CDCl2CDCl2 from 24 to 130 ЊC, almost no
changes in coupling constants were observed. The methylene
protons β to the ether oxygen were shifted downfield upon heat-
ing, which can be attributed to changes in conformation or
solvation.
For the synthesis of dimers 13a and 13b, dimesyl compound
11 was employed as a precursor (Scheme 3). The reaction of
radiation and a 12 kW rotating
anode generator
7.21
Linear absorption coeff./cmϪ1
Detector aperture
9.0 mm horizontal
13.0 mm vertical
ω–2θ
Scan type
Scan rate
2θ limits
Reflections measured
Reflections used
No. of variables
R
16.0Њ minϪ1 in ω
2.0Њ < 2θ < 120.1Њ
5477 total, 5321 unique
3894
O
O
494
0.062
O
O
i
HO
MsO
Rw
0.071
OH
OMs
7
11
CH2Cl2 to afford 12 in 65% yield. The combination of diol 12,
resorcinol and caesium carbonate in DMF gave dimers 13a and
13b in 6% yield. Each isomer was separated successfully by
MPLC, and characterized by NMR and MS spectra. The purity
of the dimers was higher than 95% as checked by 1H NMR and
13C NMR spectroscopy. The aromatic carbons of 13a and 13b
in the 13C NMR spectra in CDCl3 and CD3OD are diagnostic:
syn-13a displayed signals at δC 159.6 (C-1, -3) and at δC 107.5
(C-4, -6), while anti-13b displayed signals at δC 159.71 (C-1),
157.87 (C-3), 108.26 (C-4 or 6), 106.25 (C-6 or 4), whose
assignments were made by 1H–13C proton-detected single-
quantum coherence (HSQC) experiments. The number of mag-
netically inequivalent aromatic carbons observed in 13b was
consistent with its anti structure. From the 1H NMR spectra, it
was difficult to distinguish between the two isomers owing to
OH
OH
ii
MsO
OMs
12
HO
OH
iii
+
12
HO
OH
HO
OH
O
O
1
their similar coupling patterns. In the variable-temperature H
O
O
NMR spectra of 13a in CDCl2CDCl2, the aromatic 5-H (δ 7.11)
was shifted upfield by 0.04 ppm and the aromatic 4-H and 6-H
upfield by 0.02 ppm as the temperature was varied from 25 to
100 ЊC, suggesting that conformational changes of the bridge
occurred with increasing temperature.
13a
syn
+
By X-ray diffraction crystallographic study, the crystal struc-
tures of 1a, 13a, and 13b were determined. 13a crystallizes in
the monoclinic space group C2/c with eight molecules per unit
cell. 13b crystallizes in the monoclinic space group P21/c with
two molecules per unit cell. Crystal data are listed in Tables 1 and
2. As shown in Fig. 2, both 13a and 13b have a cavity consisting
of two benzene rings and two cyclohexane rings. The size of the
cavity is 5.9 Å (the H ؒ ؒ ؒ H distance between the closest hydro-
gens of the cyclohexane rings) × 6.3 Å (the H ؒ ؒ ؒ H distance
between the closest hydrogens of the benzene rings) for 13a and
5.8 × 6.4 Å for 13b, as clearly seen in the top views. As the side
views show, the benzene rings are almost parallel to the cyclo-
hexane rings for 13a, while they are nearly perpendicular to
them for 13b. It is noteworthy that the syn isomer, 13a, forms an
inclusion crystal with 1,4-dioxane, while other tetraols, 1a and
13b, do not. Two crystallographically different 1,4-dioxane
molecules are included in the crystal. One is bound with the
shallow cleft of 13a as shown in Fig. 3. The other is bound in an
intermolecular cavity (not shown). In the crystal, 13a assumes a
conformation where the cyclohexane ring is nearly coplanar to
the neighboring molecule, and the hydroxy groups form hydro-
gen bonds with those in the next molecule to form a linear array
of molecules. This arrangement of 13a makes intermolecular
OH
OH
O
O
O
O
HO
HO
13b
anti
Scheme 3 Reagents and conditions: i, MsCl, Et3N, CH2Cl2; ii, Ph3Cϩ-
BF4Ϫ, CH2Cl2; then aq. NaHCO3; iii, Cs2CO3, DMF.
cyclic acetal 11 with resorcinol in the presence of caesium
carbonate in the DME–DMF mixed solvent system also gave
corresponding cyclic acetal dimers in 10% yield, but various
attempts to deprotect the methylenedioxy group were un-
successful. This is presumably due to a side reaction in which
the generated formyl cation reacts with the resorcinol group
under acidic conditions. Therefore, the cyclic acetal had to be
removed prior to the coupling of the dimesyl unit with
resorcinol to prevent the foregoing reaction. The cyclic acetal
protecting group of 11 was removed by trityl tetrafluoroborate–
J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892
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Fig. 2 Structures of (a) 13a and (b) 13b obtained from X-ray crystallographic studies.
Table 2 Crystal data for 13b
Formula
Formula weight
C32H44O8
556.69
Space group
a/Å
b/Å
c/Å
P21/c
11.727(4)
10.915(4)
12.109(4)
112.25(2)
1434.6(8)
2
1.289
23
0.40 × 0.30 × 0.20
graphite-monochromated
Mo-Kα radiation and a 12 kW
rotating anode generator
0.91
β/Њ
Vol./Å3
Z
ρ (Calc.)/g cmϪ3
Temp. T/ЊC
Crystal dimensions/mm
Radiation
Fig. 3 Structures of a complex between 13a and 1,4-dioxane obtained
from X-ray crystallographic studies.
Linear absorption coeff./cmϪ1
performed at the Microanalysis Center of the Department of
Pharmaceutical Sciences, Kyoto University. Analytical TLC
was performed on plates coated with a 0.25 mm thickness of
silica gel 60-F254 (Merck). Column chromatography was per-
formed using Merck Kieselgel 60 (70–230 mesh) or Pharma
basic aluminium oxide activity grade I. Gas–liquid chrom-
atography was conducted on a Shimadzu GC-4B gas chrom-
atograph, equipped with a 3 m and a 1 m glass column packed
with 30% silicone DC550 on Celite 545 and silicone SE30.
MPLC was performed with a silica gel pre-packed column
[Lobar Größe A(240-10) LiChroprep Si 60 (40–63 µm, Merck)].
Single-crystal X-ray diffraction was performed on a Rigaku
AFC7R diffractometer.
Detector aperture
6.0 mm horizontal
6.0 mm vertical
ω–2θ
Scan type
Scan rate
2θ limits
Reflections measured
Reflections used
No. of variables
R
16.0Њ minϪ1 in ω
2.0Њ < 2θ < 60.0Њ
4584 total, 4395 unique
2939
270
0.036
0.052
Rw
cavities in the crystal, in which the second 1,4-dioxane is
included (Fig. 4).
Materials
Experimental
General remarks
Unless otherwise noted, materials were obtained from com-
mercial sources and used after distillation under nitrogen. THF,
diethyl ether, n-hexane, triethylamine, DME and diiso-
propylamine were distilled over sodium benzophenone ketyl
and stored under nitrogen. Ethyl acetate, DMSO, DMF and
1,2-dichloroethane were distilled from CaH2, and 1,4-dioxane
from LiAlH4.
1H NMR spectra were recorded on a JEOL A-500 (500 MHz), a
JEOL GX-400 (400 MHz), and a JEOL JNM FX 90Q (90
MHz) FT NMR spectrometer. Chemical shifts are reported in
parts per million and referenced to internal CHCl3 (1H δ 7.25)
or CDCl3 (13C δ 77.0). Coupling constants are reported in hertz
(Hz) and splitting patterns are designated as s (singlet), d (doub-
let), t (triplet), q (quartet), m (multiplet), AB q (AB quartet),
br (broad). IR spectra were recorded on a BIO-RAD FTS-7
FT-IR spectrometer. Mass spectra were obtained with a JEOL
JMS DX-300 mass spectrometer. Elemental analyses were
1,4-Dioxaspiro[4.5]decan-7-one 2
This compound was prepared according to the reported
method.8 A mixture of cyclohexane-1,3-dione (75.0 g, 0.669
1888
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Fig. 4 Perspective view of the crystal structure of 13aؒ1.5 1,4-dioxane.
mol), ethylene glycol (41.5 g, 0.669 mol) and toluene-p-sulfonic
Ethyl (1-hydroxy-3-oxocyclohexyl)acetate 4
acid monohydrate (TsOH) (1.27 g, 6.69 mmol) in 1.8 l of ben-
zene was efficiently stirred and refluxed for 4.5 h. Slightly more
than the theoretical amount of water was collected in a Dean–
Stark trap. The benzene solution was washed successively with
saturated aq. NaHCO3 (60 ml) and saturated aq. NaCl (50
ml × 2). After drying of the solution over anhydrous MgSO4
the solvent was distilled off and the product 2 was purified by
vacuum distillation at 62–75 ЊC/0.15 mmHg (71.5 g, 60%);
1H NMR (90 MHz, CDCl3) δ 1.75–2.46 (m, 6H), 2.58 (s, 2H),
3.95 (s, 4H, OCH2CH2O).
To the crude product 3 (109.4 g) obtained above were added
THF (80 ml) and 10.5 M hydrochloric acid (80 ml) and the
mixture was stirred at ambient temperature for 9 h. To this
reaction mixture was added aq. NaHCO3 until the aqueous
layer was neutralized. The aqueous layer was extracted several
times with diethyl ether, and the combined extracts were washed
with saturated aq. NaCl and dried over Na2SO4. The solvent
was removed and the residue was distilled under reduced pres-
sure to yield a liquid (69.1 g, 68% based on monoketal 2), bp
100–136 ЊC/0.25–0.3 mmHg; 1H NMR (90 MHz, CDCl3) δ 1.27
(t, J = 7.3 Hz, 3H, CO2CH2CH3), 1.45–2.54 (m, 8H), 2.54 (s,
2H, CH2CO2Et), 4.21 (q, J = 7.3 Hz, 2H, CO2CH2CH3); IR
7-Ethoxycarbonylmethyl-7-hydroxy-1,4-dioxaspiro[4.5]decane 3
(liquid film, cmϪ1) 3488m, 2959w, 1714s (C᎐O).
᎐
To a solution of lithium diisopropylamide (LDA) (0.521 mol) in
dry THF (320 ml) was added dropwise ethyl acetate (45.9 g,
0.521 mol) at Ϫ78 ЊC under nitrogen with stirring. Stirring was
continued for an additional hour. A solution of ketal 2 (71.5 g,
0.401 mol) in dry THF (100 ml) was added dropwise to the
reaction mixture. After being stirred for 30 min, the reaction
mixture was hydrolyzed by adding 4 M hydrochloric acid (200
ml) in one portion. The organic layer was separated. The aque-
ous layer was neutralized and extracted several times with
diethyl ether. The combined organic extracts were washed with
saturated aq. NaCl and dried over anhydrous MgSO4. The sol-
vent was evaporated under reduced pressure to give 109.4 g of a
pale yellow oil, consisting mainly of the desired product as
determined by GLC. This material was used directly in the next
step without further purification. For analysis, a small portion
of 3 was purified by column chromatography (SiO2, hexane–
EtOAc = 2:1); TLC (silica gel) Rf 0.24 (hexane–EtOAc = 2:1);
1H NMR (90 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H,
CO2CH2CH3), 1.37–2.07 (m, 8H), 2.53 (s, 2H, CH2CO2Et), 3.97
(s, 4H, OCH2CH2O), 4.18 (q, J = 7.2 Hz, 2H, CO2CH2CH3); IR
Diethyl 1,3-dihydroxycyclohexane-1,3-diacetate 5
To a solution of LDA (0.346 mol) in dry THF (250 ml) was
added dropwise dry ethyl acetate (30.5 g, 0.346 mol) at Ϫ78 ЊC
under nitrogen with stirring. Stirring was continued for 1 h. A
solution of the hydroxycyclohexanone 4 (23.1 g, 0.115 mol) in
dry THF (150 ml) was added dropwise to the reaction mixture.
After being stirred for 1 h, the reaction mixture was hydrolyzed
by adding 4 M hydrochloric acid (170 ml) in one portion, and
the stirred solution was warmed to room temperature. The
organic layer was separated, the aqueous layer was neutralized,
and extracted several times with diethyl ether, and the com-
bined extracts were washed with saturated aq. NaCl and dried
over anhydrous Na2SO4. The solvent was removed and the resi-
due was distilled under reduced pressure to yield (31.3 g, 94%)
of a pale yellow liquid (mixture of cis and trans isomers); bp
1
138–151 ЊC/0.25 mmHg. The H NMR spectrum of the prod-
uct revealed that the ratio of the two isomers was ca. 1:1. For
analysis, the two isomers were separated by column chrom-
atography (SiO2, hexane–EtOAc = 3:1): cis isomer; TLC (silica
(liquid film, cmϪ1) 3512m, 2945w, 2882w, 1731s (C᎐O).
᎐
J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892
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gel) Rf 0.26 (hexane–EtOAc = 2:1); 1H NMR (400 MHz,
CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H, CO2CH2CH3), 1.32 (ddd,
stirred at ambient temperature for 3 days. The solvent was
evaporated under reduced pressure. The residue was chromato-
graphed on a silica gel column with EtOAc–ethanol (10:1) to
give 0.070 g (84%) of 8. An analytical sample was prepared by
recrystallization from EtOAc–ethanol to give white crystals; mp
101–104 ЊC; TLC (silica gel) Rf 0.32 (EtOAc–ethanol = 10:1);
3
2J = 13.7 Hz, J = 4.3, 13.7 Hz, 2H), 1.57 (d, J = 14.0 Hz, 1H),
2
1.52–1.60 (m, 1H), 1.85–1.79 (m, 2H), 1.95 (dt, J = 14.0 Hz,
4J = 2.6 Hz, 1H), 2.01 (dtt, 2J = 13.8 Hz, 3J = 3.7, 13.8 Hz, 1H),
2.42 (¹AB q, J = 15.0 Hz, 2H, CH2CO2Et), 2.43 (¹AB q,
¯
²
¯
²
1
J = 15.0 Hz, 2H, CH2CO2Et), 4.15 (q, J = 7.1 Hz, 4H, CO2-
CH2CH3); 13C NMR (100 MHz, CDCl3) δ 14.15, 16.67, 36.31,
44.32, 46.87, 60.58, 71.47, 171.80; IR (liquid film, cmϪ1) 3454
MS m/z 186 (Mϩ Ϫ H2O), 168 (Mϩ Ϫ 2H2O); H NMR (400
2
MHz, CDCl3) δ 1.20 (d, J = 13.8 Hz, 1H), 1.23 (ddd, J = 13.7
Hz, 3J = 4.4, 13.7 Hz, 2H), 1.52–1.59 (m, 1H), 1.63 (¹AB q dd,
¯
²
3
(br), 2981m, 2939m, 2875m, 1732s (C᎐O), 1196m: trans isomer;
2J = 14.8 Hz, J = 3.8, 6.3 Hz, 2H, CH2CH2OH), 1.73 (¹AB q
᎐
¯
²
1
TLC (silica gel) Rf 0.29 (hexane–EtOAc = 2:1); H NMR (400
dd, 2J = 14.8 Hz, 3J = 4.0, 8.1 Hz, 2H, CH2CH2OH), 1.89–1.83
(m, 2H), 1.99 (dtt, 2J = 13.8 Hz, 3J = 3.7, 13.8 Hz, 1H), 2.12 (dt,
2J = 13.9 Hz, 4J = 2.6 Hz, 1H), 3.09 (t, J = 3.8 Hz, 2H, primary
OH), 3.85–4.00 (m, 4H, CH2CH2OH), 4.781 (s, 2H, tertiary
OH); 13C NMR (22.5 MHz, CDCl3) δ 16.71, 37.64, 43.58, 44.58,
59.16, 74.08; IR (liquid film, cmϪ1) 3338br, 2939m, 1449w,
1422m, 1150m, 1029m, 852m (Calc. for C10H20O4: C, 58.80; H,
9.87. Found: C, 58.59; H, 9.82%).
MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 6H, CO2CH2CH3), 1.49–
1.68 (m, 6H), 2.60 (¹AB q, J = 16.0 Hz, 2H, CH2CO2Et), 2.70
¯
²
(¹AB q, J = 16.0 Hz, 2H, CH2CO2Et), 4.17 (q, J = 7.1 Hz, 4H,
¯
²
CO2CH2CH3); IR (liquid film, cmϪ1) 3501br, 2982m, 2940m,
2874m, 1727s, 1712s (C᎐O), 1192m.
᎐
Diethyl 2,4-dioxabicyclo[3.3.1]nonane-1,5-diacetate 6
The cyclohexane-1,3-diol 5 (5.03 g, 0.017 mol, a mixture of cis
and trans) was mixed with paraformaldehyde (3.14 g, 0.105
mol) in a mixture of ethanol (10.1 ml) and benzene (30 ml).
After addition of TsOH (0.066 g), the mixture was heated
at 50 ЊC (bath temp.) for 1 h and refluxed for 3 h with a Dean–
Stark trap. Evaporation of the solvent afforded the mixed
acetal. To this residue was added m-xylene (20 ml) and the reac-
tion mixture was heated at 150 ЊC for 2 h. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography (SiO2, hexane–EtOAc = 4:1) to
give 2.18 g (42%) of a colorless oil 6; TLC (silica gel) Rf 0.31
(hexane–EtOAc = 4:1); MS m/z 300 (Mϩ), 299 (Mϩ Ϫ H);
1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H,
Ditosyl unit 9
The procedure of Marshall9 was modified. To a stirred, cooled
(0 ЊC) solution of diol 7 (4.501 g, 0.021 mol), 4-(dimethyl-
amino)pyridine (DMAP) (130 mg), and triethylamine (8.7 ml,
0.062 mol) in CH2Cl2 (60 ml) was added toluene-p-sulfonyl
chloride (p-TsCl) (11.11 g, 0.058 mol). The reaction mixture
was stirred for 8.5 h at ambient temperature. The mixture was
treated with diethyl ether (50 ml) and filtered, and the filter cake
was washed with diethyl ether. The filtrate was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane–EtOAc = 2:1) to afford
9.997 g (92%) of ditosyl compound 9 as a viscous pale yellow
oil; 1H NMR (90 MHz, CDCl3) δ 1.79 (t, J = 7.4 Hz, 4H,
CH2CH2O), 0.97–2.20 (m, 8H), 2.44 (s, 6H, aryl CH3), 4.17 (t,
J = 6.8 Hz, 4H, CH2CH2O), 4.56 (¹AB q, J = 5.9 Hz, 1H,
2
3
CO2CH2CH3), 1.31 (ddd, J = 13.5 Hz, J = 4.9, 13.5 Hz, 2H),
1.50 (d, J = 14.3 Hz, 1H), 1.50–1.56 (m, 1H), 1.70–1.76 (m, 2H),
2
3
2.14 (dtt, J = 13.4 Hz, J = 4.8, 13.4 Hz, 1H), 2.44 (¹AB q,
¯
²
¯
²
J = 14.6 Hz, 2H, CH2CO2Et), 2.54 (¹AB q, J = 14.6 Hz, 2H,
OCH2O), 4.75 (¹AB q, J = 5.9 Hz, 1H, OCH2O), 7.39 (¹AB q,
¯
²
¯
¯
²
²
CH2CO2Et), 2.916 (dt, 2J = 14.4 Hz, 4J = 2.7 Hz, 1H), 4.12
(¹AB q, J = 7.2, 10.8 Hz, 2H, CH2CO2Et), 4.14 (¹AB q,
J = 8.7 Hz, 4H, ArH), 7.82 (¹AB q, J = 8.7 Hz, 4H, ArH); IR
¯
²
(liquid film, cmϪ1) 2950m, 2769w 1358s, 1190s, 1176s; MS m/z
524 (Mϩ), 481 (Mϩ Ϫ 43).
¯
²
¯
²
2J = 10.8 Hz, 3J = 7.2 Hz, 2H, CH2CO2Et), 4.70 (d, J = 5.7 Hz,
1H, OCH2O), 5.12 (d, J = 5.7 Hz, 1H, OCH2O).
Dimesyl unit 11
2,4-Dioxabicyclo[3.3.1]nonane-1,5-diethanol 7
To a stirred, cooled (0 ЊC) solution of diol 7 (0.956 g, 4.42
mmol) and triethylamine (1.54 ml, 11.05 mmol) in CH2Cl2 (15
ml) was added methanesulfonyl chloride (MsCl) (1.114 g, 9.73
mmol). The reaction mixture was stirred for 4 h at ambient
temperature. A small amount of white solid was precipitated.
The mixture was filtered, and the mother liquor was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (CHCl3–EtOAc = 6:1) to afford
dimesyl compound 11, as a colorless oil, which slowly solidified
upon storage at room temperature in vacuo to give a white solid
To a suspension of lithium aluminium hydride (1.913 g, 0.050
mol) in dry THF (45 ml) was added dropwise a solution of
diester 6 in dry THF (15 ml) at 0 ЊC under nitrogen, and the
mixture was stirred at ambient temperature for 1 h. To the mix-
ture were added water (1.9 ml), 15% aq. sodium hydroxide (1.9
ml), and water (5.7 ml) in this order with vigorous stirring.
The precipitate was filtered off. After concentration of the fil-
trate, the residue was purified by column chromatography on
silica gel (EtOAc–ethanol = 10:1) to afford a white solid 7.
(4.19 g, 92%); TLC (silica gel) Rf 0.33 (hexane–EtOAc = 10:1);
MS m/z 216 (Mϩ), 215 (Mϩ Ϫ H); 1H NMR (400 MHz, CDCl3)
δ 1.16 (ddd, 2J = 13.5 Hz, 3J = 5.0, 13.5 Hz, 2H), 1.23 (d,
J = 14.4 Hz, 1H), 1.53–1.61 (m, 1H), 1.66 (¹AB q dd, 2J = 14.6
1
(1.390 g, 84%); H NMR (90 MHz, CDCl3) δ 1.02–2.28 (m,
7H), 1.94 (t, J = 6.6 Hz, 4H, CH2CH2O), 2.33–2.61 (m, 1H),
3.04 (s, 6H, CH3), 4.29–4.57 (m, 4H), 4.80 (¹AB q, J = 5.9 Hz,
¯
²
1H, OCH2O), 5.09 (¹AB q, J = 5.9 Hz, 1H, OCH2O).
¯
²
¯
²
Hz, 3J = 4.3, 6.0 Hz, 2H, CH2CH2OH), 1.81 (¹AB q dd,
¯
²
2J = 14.6 Hz, 3J = 4.9, 8.2 Hz, 2H, CH2CH2OH), 1.85–1.90 (m,
cis-1,3-Bis(2-mesylethyl)cyclohexane-1,3-diol 12
2
3
2H), 2.09 (dtt, J = 13.3 Hz, J = 4.8, 13.3 Hz, 1H), 2.43 (dt,
2J = 14.3 Hz, J = 2.7 Hz, 1H), 3.76 (¹AB q dd, J = 11.2 Hz,
3
2
Acetal 7 (5.358 g, 14.39 mmol) and trityl tetrafluoroborate
(5.894 g, 17.85 mmol) were stirred in dichloromethane (125 ml)
for 7 h at ambient temperature. To the reaction mixture was
added saturated aq. NaHCO3 (50 ml) and the two-phase mix-
ture was stirred for 15 min. The organic phase was washed with
water, dried over anhydrous Na2SO4, and evaporated in vacuo.
The residue was chromatographed over silica gel (CHCl3–
EtOAc = 1:1) to afford 3.394 g (65%) of 12 as an oil; 1H NMR
(90 MHz, CDCl3) δ 1.13–2.11 (m, 8H), 1.91 (t, J = 6.4 Hz, 4H,
CH2CH2O), 3.05 (s, 6H, CH3), 3.58 (br s, 2H, tertiary OH), 4.45
(t, J = 6.4 Hz, 4H, CH2CH2O); IR (liquid film, cmϪ1) 3485br,
2941m, 1350s, 1173s.
¯
²
3J = 4.9, 6.1 Hz, 2H, CH2CH2OH), 3.89 (¹AB q dd, J = 11.2
2
¯
²
Hz, 3J = 4.3, 8.2 Hz, 2H, CH2CH2OH), 4.73 (d, J = 5.7 Hz, 1H,
OCH2O), 5.11 (d, J = 5.7 Hz, 1H, OCH2O); 13C NMR (100
MHz, CDCl3) δ 17.75, 35.88, 37.64, 43.09, 58.64, 75.22, 84.14;
IR (liquid film, cmϪ1) 3385br, 2934m, 2772w, 1155m, 1087m,
1014m.
1,3-Dihydroxycyclohexane-1,3-diethanol 8
Acetal 7 (0.088 g, 0.407 mmol) was dissolved in methanol (2 ml)
and 2.0 M HCl–methanol (2 ml) was added. The mixture was
1890
J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892

View Article Online
Acetal dimers 10a and 10b
was stirred at room temperature under N2. A solution contain-
ing dimesyl compound 12 (0.676 g, 1.875 mmol) and resor-
cinol (0.206 g, 1.875 mmol) in DMF (10 ml) was added, and
the mixture was stirred vigorously at 50 ЊC for 2 days. The
solvent was removed in vacuo. The residue was taken up in
THF–ethanol (10:1), and applied to an alumina column,
which was eluted with THF–ethanol (10:1). After evapor-
ation of the solvent, the residual mixture was chromato-
graphed on a silica gel column with THF–CHCl3 (1:5). The
fractions containing products were combined and rechroma-
tographed at medium pressure (EtOAc–CHCl3 = 1:6) to give
dimers 13a and 13b as a white solid, total yield 30 mg (6%)
(anti isomer 16 mg, 3%; syn isomer 14 mg, 3%). 13a (syn
isomer): TLC (silica gel) Rf 0.60 (EtOAc–CHCl3 = 4:1); MS
m/z 556 (Mϩ), 538 (Mϩ Ϫ H2O), 520 (Mϩ Ϫ 2H2O), 502
(Mϩ Ϫ 3H2O), 484 (Mϩ Ϫ 4H2O); 1H NMR (500 MHz,
CDCl3 ϩ CD3OD) δ 1.34 (ddd, 2J = 13.6 Hz, 3J = 4.1, 13.6
Hz, 4H), 1.37 (d, J = 14.3 Hz, 2H), 1.47–1.53 (m, 2H), 1.59–
A mixture of diol 7 (0.433 g, 2.0 mmol) and potassium tert-
butoxide (0.494 g, 4.4 mmol) in dry DME (15 ml) was efficiently
stirred and heated at 80 ЊC (bath temp.) for 1 h. A solution
of ditosyl compound 9 (1.049 g, 2.0 mmol) in Me2SO (5 ml)
was added, and the reaction mixture was heated to reflux and
stirred for 13 h. The suspension was cooled to 25 ЊC, filtered,
and washed with diethyl ether. The solvent was removed under
reduced pressure. The residue was partitioned between 20 ml
of CH2Cl2 and 10 ml of water, the two layers were separated,
and the aqueous layer was extracted again with two 20 ml
portions of CH2Cl2. The combined organic phases were dried
over Na2SO4. The solvent was evaporated, leaving an oil, which
was chromatographed on silica gel (hexane–EtOAc = 4:1) to
give 16 mg (2.1%) of a mixture of syn and anti isomers as
a white solid. Analytical samples of each isomer were puri-
fied by MPLC (hexane–EtOAc = 10:1). First fraction: TLC
(silica gel) Rf 0.40 (hexane–EtOAc = 2:1); MS m/z 395 (Mϩ Ϫ
2
3
1.65 (m, 4H), 1.76 (¹AB q t, J = 14.6 Hz, J = 6.0 Hz, 4H,
H), 393 (Mϩ Ϫ 3H), 368 (Mϩ Ϫ C2H4), 320; H NMR (400
1
¯
²
CH2CH2O), 1.88 (m, 4H, CH2CH2O), 1.90–1.95 (m, 4H),
3.98 (¹AB q dd, J = 9.6 Hz, J = 5.5, 6.8 Hz, 4H, CH2CH2O),
4.07 (¹AB q dd, J = 9.6 Hz, J = 6.3, 6.3 Hz, 4H, CH2CH2O),
MHz, CDCl3) δ 1.32 (ddd, 2J = 13.3 Hz, 3J = 4.8, 13.3 Hz, 4H),
1.51 (d, J = 15.1 Hz, 2H), 1.40–1.53 (m, 6H), 1.65 (¹AB q dd,
2
3
¯
¯
²
²
2
3
¯
²
¯
²
2J = 15.0 Hz, 3J = 2.1, 7.2 Hz, 4H, CH2CH2O), 1.79 (¹AB q dd,
6.31 (t, J = 2.2 Hz, 2H, ArH), 6.37 (dd, J = 2.2, 8.3, 4H, ArH),
7.01 (t, J = 8.3 Hz, 2H, ArH); 13C NMR (125 MHz,
CDCl3 ϩ CD3OD) δ 16,63, 37.85, 41.88, 42.00, 63.87, 72.13,
100.11, 107.45, 129.78, 159.63; 13b (anti isomer): TLC (silica
gel) Rf 0.60 (EtOAc–CHCl3 = 4:1); MS m/z 556 (Mϩ), 538
(Mϩ Ϫ H2O), 520 (Mϩ Ϫ 2H2O), 502 (Mϩ Ϫ 3H2O), 484
2J = 15.0 Hz, 3J = 2.6, 8.5 Hz, 4H, CH2CH2O), 2.14 (dtt,
2J = 13.1 Hz, 3J = 4.8, 13.1 Hz, 2H), 2.65 (dt, 2J = 15.1 Hz,
4J = 2.5 Hz, 2H), 3.36 (ddd, J = 10.2 Hz, J = 2.1, 8.5 Hz, 4H,
CH2CH2O), 3.59 (ddd, 2J = 10.2 Hz, 3J = 2.6, 7.2 Hz, 4H,
CH2CH2O), 4.74 (d, J = 5.6 Hz, 2H, OCH2O), 5.16 (d, J = 5.6
Hz, 2H, OCH2O); 13C NMR (22.5 MHz, CDCl3) δ 18.10, 36.13,
36.60, 42.37, 67.59, 74.23, 85.22. Second fraction: TLC (silica
gel) Rf 0.40 (hexane–EtOAc = 2:1); MS m/z 395 (Mϩ Ϫ H), 393
(Mϩ Ϫ 3H), 368 (Mϩ Ϫ C2H4), 320; 1H NMR (400 MHz,
CDCl3) δ 1.29 (ddd, 2J = 13.4 Hz, 3J = 4.8, 13.4 Hz, 4H), 1.43 (d,
J = 15.1 Hz, 2H), 1.40–1.52 (m, 6H), 1.64 (¹AB q dd, 2J = 14.9
2
3
(Mϩ Ϫ 4H2O); H NMR (500 MHz, CDCl3 ϩ CD3OD) δ 1.34
1
(ddd, 2J = 13.5 Hz, 3J = 3.9, 13.5 Hz, 4H), 1.38 (d, J = 14.5 Hz,
2H), 1.49–1.55 (m, 2H), 1.70–1.76 (m, 4H), 1.84 (t, J = 7.0 Hz,
8H, CH2CH2O), 1.85–1.96 (m, 4H), 4.03–4.11 (m, 8H,
CH2CH2O), 6.32–6.40 (m, 6H), 7.00–7.04 (m, 2H); 13C
NMR (125 MHz, CDCl3 ϩ CD3OD) δ 16.85, 37.11, 41.93,
44.55, 63.91, 72.51, 101.98, 106.25, 108.26, 129.90, 157.87,
159.71.
¯
²
¯
²
Hz, 3J = 2.3, 7.9 Hz, 4H, CH2CH2O), 1.77 (¹AB q dd, 2J = 14.9
3
2
Hz, J = 2.4, 7.5 Hz, 4H, CH2CH2O), 2.14 (dtt, J = 13.2 Hz,
3J = 4.6, 13.2 Hz, 2H), 2.76 (dt, J = 15.1 Hz, J = 2.5 Hz, 2H),
2
4
2
3
3.38 (ddd, J = 10.2 Hz, J = 2.4, 7.5 Hz, 4H, CH2CH2O), 3.59
2
3
(ddd, J = 10.2 Hz, J = 2.3, 7.9 Hz, 4H, CH2CH2O), 4.77 (d,
J = 5.6 Hz, 2H, OCH2O), 5.18 (d, J = 5.6, 2H, OCH2O).
X-Ray crystal structure determinations
Diffraction data were collected at 295 K with a Rigaku AFC-7R
four-circle diffractometer having a rotating anode and using
graphite-monochromated Cu-Kα (λ = 1.541 78 Å) and Mo-Kα
(λ = 0.710 69 Å) radiations for 13aؒ1.5C4H8O2 and 13b, respect-
ively. The crystal data and details of the parameters associated
with data collection for the two crystals are given in Tables 1
and 2. The unit-cell parameters were derived from least-squares
refinement of 25 well centred reflections. The reflection inten-
sities were monitored by three standard reflections for every 150
reflections, and the decay of intensities was within 2% for the
two crystals. Reflection data were corrected for Lorentz and
polarization effects. An empirical absorption correction, based
on ψ scans, was applied.10
The structures for the compounds were solved by the direct
method11 and successive Fourier techniques12 and refined
anisotropically for non-hydrogen atoms by full-matrix least-
squares calculations. Refinements were continued until all shifts
were smaller than one-third of the standard deviations of the
parameters involved. Atomic scattering factors and anomalous
dispersion terms were taken from the literature.13 All the hydro-
gen atoms were located from the difference Fourier maps, and
their parameters were isotropically refined. The R- and Rw-
values were 0.062 and 0.071 for 13aؒ1.5C4H8O2 and 0.036 and
0.052 for 13b, respectively. The weighting scheme wϪ1 = σ2(Fo)
was employed for both crystals. The final difference Fourier
maps did not show any significant features in both cases. The
calculations were performed on an IRIS Indigo XS-24
computer by using the program system teXsan.14
Tetraol dimer I 1a
Acetal 10 (mixture of syn and anti isomers) (38.8 mg, 0.098
mmol) was dissolved in 2.0 M HCl in methanol (2 ml), and the
mixture was stirred at room temperature for 20 h. After evapor-
ation of the solvent under reduced pressure, the residue was
chromatographed on a silica gel column with EtOAc–CHCl3
(4:1). The fractions containing product were combined and
rechromatographed at medium pressure (EtOAc–CHCl3 = 1:6)
to give 8.4 mg (46%) of 1a (syn isomer) as a white solid. An
analytical sample was prepared by recrystallization from ethyl
acetate to give white crystals, mp 210–215 ЊC; TLC (silica gel)
Rf 0.41 (EtOAc–CHCl3 = 4:1); MS m/z 372 (Mϩ), 354
(Mϩ Ϫ H2O), 336 (Mϩ Ϫ 2H2O), 329, 318 (Mϩ Ϫ 3H2O); H
NMR (400 MHz, CDCl3) δ 1.13 (ddd, J = 13.5 Hz, J = 4.3,
1
2
3
2
13.5 Hz, 4H), 1.20 (d, J = 13.2 Hz, 2H), 1.34 (dt, J = 14.8 Hz,
3J = 2.2 Hz, 4H, CH2CH2O), 1.36–1.44 (m, 2H), 1.69–1.76 (m,
2
3
4H), 1.97 (dtt, J = 13.8 Hz, J = 3.7, 13.8 Hz, 2H), 2.07 (ddd,
2J = 14.8 Hz, 3J = 4.6, 12.9 Hz, 4H, CH2CH2O), 2.17 (dt,
4
2J = 13.2 Hz, J = 2.4 Hz, 2H, CH2CH2O), 3.55 (¹AB q dd,
¯
¯
²
²
3
2J = 9.3 Hz, J = 2.3, 4.5 Hz, 4H, CH2CH2O), 3.71 (¹AB q dd,
2J = 9.3 Hz, 3J = 2.3, 12.8 Hz, 4H, CH2CH2O), 5.35 (s, 4H, ter-
tiary OH); 13C NMR (22.5 MHz, CDCl3) δ 16.67, 39.64, 39.88,
41.55, 67.31, 71.75; IR (KBr, cmϪ1) 3397s, 2935m, 2866m,
1175w, 1128w (Calc. for C20H36O6ؒ1/4H2O: C, 63.72; H, 9.76.
Found: C, 63.72; H, 9.92%).
CCDC reference number for 13aؒ1.5C4H8O2 and 13b 207/
329. See http://www.rsc.org/suppdata/p1/1999/1885 for crys-
tallographic files in .cif format.
Dimer II 13a and 13b
A suspension of Cs2CO3 (0.733 g, 2.250 mmol) in DMF (70 ml)
J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892
1891

View Article Online
6695; (e) M. Inouye, M. Ueno and T. Kitao, J. Org. Chem., 1992, 57,
1639; ( f ) T. Hayashi, T. Asai, H. Hokazono and H. Ogoshi, J. Am.
Chem. Soc., 1993, 115, 12210; (g) T. Mizutani, S. Yagi, A. Honmaru
and H. Ogoshi, J. Am. Chem. Soc., 1996, 118, 5318.
5 For a review of design of flexible molecules, see R. W. Hoffmann,
Angew. Chem., Int. Ed. Engl., 1992, 31, 1124.
6 N. Morelle, J. Gharbi-Benarous, F. Acher, G. Valle, M. Crisma,
C. Toniolo, R. Azerad and J.-P. Girault, J. Chem. Soc., Perkin Trans.
2, 1993, 525.
7 For preliminary accounts of preparation and X-ray crystal struc-
ture of 1a, see T. Hayashi, H. Takagi, H. Masuda and H. Ogoshi,
J. Chem. Soc., Chem. Commun., 1993, 364.
8 M. P. Mertes, J. Org. Chem., 1961, 26, 5236.
9 J. A. Marshall, B. S. DeHoff and D. G. Cleary, J. Org. Chem., 1986,
51, 1735.
Acknowledgements
We thank T. Kobatake and H. Fujita for their kind help in the
mass and NMR spectroscopy measurements. This work was
supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture, Japan.
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Paper 8/09834D
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J. Chem. Soc., Perkin Trans. 1, 1999, 1885–1892