Synthesis of chiral 18-crown-6 ethers containing lipophilic chains and their enantiomeric recognition of chiral ammonium picrates

Article abstract of DOI:10.1016/j.tetasy.2005.06.039

Four new chiral 18-crown-6 ethers have been prepared to be used in enantiomeric recognition and extraction. The influence of the lipophilic character and bulkiness of the substituents on the complexation of different chiral ammonium picrates in CD₃CN has been evaluated. Racemic aqueous solutions of the ammonium salts have been enriched in one enantiomer after extraction experiments, and the enantiomeric excesses have been calculated.

Full text of DOI:10.1016/j.tetasy.2005.06.039

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2673–2679
Synthesis of chiral 18-crown-6 ethers containing lipophilic chains
and their enantiomeric recognition of chiral ammonium picrates
Manuel Colera,a Ana M. Costero,a,* Pablo Gavinab and Salvador Gila
˜
aDepartamento de Quı´mica Orga´nica, Universidad Valencia, C/ Doctor Moliner 50, 46100 Burjassot, Valencia, Spain
bInstituto de Ciencia Molecular, Quı´mica Orga´nica, Universidad Valencia, C/ Doctor Moliner 50, 46100 Burjassot, Valencia, Spain
Received 15 June 2005; accepted 29 June 2005
Abstract—Four new chiral 18-crown-6 ethers have been prepared to be used in enantiomeric recognition and extraction. The influ-
ence of the lipophilic character and bulkiness of the substituents on the complexation of different chiral ammonium picrates in
CD3CN has been evaluated. Racemic aqueous solutions of the ammonium salts have been enriched in one enantiomer after extrac-
tion experiments, and the enantiomeric excesses have been calculated.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
interesting to obtain this compound (or a related one)
enantiomerically pure. One way of addressing both
problems could be by attaching two chiral lipophilic
chains to the 18C6 ring.
The study of enantiomeric recognition of primary alkyl-
ammonium salts by chiral macrocyclic receptors is use-
ful in developing new methods of asymmetric synthesis
and chromatographic resolution of enantiomers.1
Among these macrocycles, optically active 18-crown-6
ethers (18C6) have been well investigated.2 These 18C6
derivatives are obtained by attachment of the appropri-
ate substituents to the aliphatic carbons of the polyether
ring. Interaction between the ring and the ammonium
group anchors the guest molecule, and the steric interac-
tions between the 18C6 side chains and the guest species
results in enantiomeric recognition.
As part of these ongoing studies, we herein report the
synthesis and characterization of new chiral 18C6 deriv-
atives containing lipophilic chains, 1–4 (Fig. 1), and
their binding constants and extraction properties with
two different chiral ammonium salts. For comparison
purposes, we also prepared and studied the macrocyclic
polyethers 5 and 6, whose enantiomers had been previ-
ously synthesized by others.4
For a long time, we have been interested in the develop-
ment of crown ether based allosteric systems, in which
cation complexing or extraction properties could be reg-
ulated by conformational changes. This led us to the
synthesis of a cyclohexane substituted 18C6 derivative,
whose conformation of the crown ether moiety is depen-
dent on the pH of the medium.3 One drawback of this
compound is its relatively high solubility in water, which
makes its use in extraction experiments difficult. On the
other hand, although the molecule is chiral, it is
obtained as a racemic mixture, which is not easy to
resolve by conventional methods (crystallization or
chromatographic resolution). It would thus be very
2. Results and discussion
2.1. Synthesis of the ligands
The procedure for the synthesis of related chiral crown
ethers with C2- and D2-symmetry is well established in
the literature4,5 and relies on the choice of appropriate
carbohydrate derivatives, with the terminal OH groups
usually protected as acetals or benzyl ethers. We selected
(ꢀ)-2,3-O-isopropylidene-D-threitol 7, which is commer-
cially available enantiomerically pure, as a convenient
source of chirality.
The syntheses of lipophilic ligands 1–4 as well as the
18C6 derivatives 5 and 6 are shown in Schemes 1 and
2. The key intermediates are the C2-symmetric triethyl-
ene glycol derivatives 11a,b, which upon condensation
*
Corresponding author. Tel.: +34 963544410; fax: +34 963543152;
e-mail: ana.costero@uv.es
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.039

2674
M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
O
O
O
R
R
R
R
O
O
R
R
O
O
O
O
O
O
O
O
O
O
O
O
O
(R,R)-1 R = OCH2Ph
(R,R)-2 R = OH
(R,R,R,R)-3 R = OCH2Ph
(R,R,R,R)-4 R = OH
O
O
O
O
O
R
pic
pic
H3N
Ph
H3N
R
O
AmII
AmI
(R,R)-5 R = OCH2Ph
(R,R)-6 R = OH
Figure 1.
NaH, THF
with appropriate tosylated or mesylated triethylene gly-
cols under high dilution conditions, afford the desired
crown ethers.
(R,R)-1
(R,R)-5
11a-b
+
TsO
O
OTs
2
MsO
MsO
Alkylation of diol 7 by the p-toluenesulfonate derivative
8 was carried out with NaH in refluxing THF, to yield
acetal 9a (91%), which was hydrolyzed to diol 10a with
aq HCl in methanol at room temperature (Scheme 1).
Similarly, benzylation of 7 with benzyl bromide in the
presence of NaH in THF, followed by acidic hydrolysis
of the acetal moiety led to 1,4-di-O-benzyl-D-threitol 10b
in 90% overall yield.6 Chiral triethylene glycol deriva-
tives 11a,b were obtained by alkylation of diols 10a,b
with THP-protected 2-iodoethanol and subsequent
hydrolysis of the protective group with hydrochloric
acid in methanol.
O
11a, NaH, THF
OR
OR
MsCl, Et3N
CH2Cl2
11a
(R,R,R,R)-3
O
12 R = (CH2)6OBn
(R,R)-1
(R,R)-2
(R,R,R,R)-4
(R,R)-6
H2 , Pd/C
methanol
(R,R,R,R)-3
(R,R)-5
Scheme 2.
Reaction of 11a with triethylene glycol di-O-tosylate in
the presence of NaH in THF at reflux for 2 days led
to the C2-symmetric crown ether (R,R)-1 in 25% yield
after column chromatography (Scheme 2). On the other
hand, the cyclic polyether (R,R)-5 was obtained in 40%
yield by condensation of diol 11b with triethylene glycol
di-p-tosylate in a similar manner.4 For the preparation
of the D2-symmetric crown ether 3, diol 11a was first
mesylated with mesyl chloride and Et3N in dichloro-
methane (87%), and then allowed to react with 1 equiv
of 11a in the presence of NaH in THF under reflux.
(R,R,R,R)-3 was thus obtained in 20% yield after
O
O
O
NaH, THF
O(CH2)6OBn
O(CH2)6OBn
OH
OH
OTs
+
Ph
O
O
8
7
7
9a
1. NaH, THF
2. PhCH2Br
O
O
O
O
Ph
Ph
9b
HO
HO
1. NaH, THF
2. I(CH2)2OTHP
O
HO
HO
O
O
aq HCl, MeOH
OR
OR
OR
OR
OR
OR
3. aq HCl, MeOH
O
9a-b
10a-b
(R,R)-11a R = (CH2)6OBn
(R,R)-11b R = Bn
Scheme 1.

M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
2675
Table 1. Complexation constants (logK) and enantioselectivity in complexation determined in CD3CN by 1H NMR titration
Picrate
(R,R)-1
(R,R)-2
(R,R,R,R)-3
(R,R,R,R)-4
(R,R)-5
(R,R)-6
(R)-(ꢀ)-AmI
(S)-(+)-AmI
Log(KR/KS)
4.61
2.55
2.06
4.91
2.27
2.64
4.06
2.11
1.95
3.96
2.07
1.89
2.15
2.03
0.12
1.93
2.09
0.15
(R)-(+)-AmII
(S)-(ꢀ)-AmII
LogKR/KS
5.42
2.24
3.23
5.08
2.65
2.43
3.17
2.04
1.13
2.98
2.05
0.93
2.11
2.06
0.05
2.01
2.06
ꢀ0.05
chromatography as a pale yellow oil. Finally, the benzyl
groups in 1, 5 and 3 were removed by catalytic hydro-
genolysis over 10% palladium–carbon in methanol solu-
tion to give diols (R,R)-2, (R,R)-6 and (R,R,R,R)-4 in
almost quantitative yields.
higher complexation constant and enantiomeric recogni-
tion observed with this ligand.10
On the other hand, the results observed with ligands
(R,R,R,R)-3, (R,R,R,R)-4, (R,R)-5 and (R,R)-6 demon-
strate that the presence of the two hydrophobic chains
in ligands (R,R)-1 and (R,R)-2 give rise to the best envi-
ronment not only for complexation, but also for enan-
tiomeric recognition. Among the factors that should
be considered to understand these results, the lipophilic
effect of the chains seems to be very important because
complexation constants with ligands (R,R)-5 and
(R,R)-6 were clearly lower than with the other described
ligands. In addition, the effect was stronger in the com-
plexation of the (R)-enantiomer than in the (S)-enantio-
mer. Moreover, a smaller enantiomeric recognition was
observed for these two ligands (see Table 1). Another
effect to be considered in chiral complexation is the
bulkiness of the chiral substituents that also seems to
be important in this case.11 Thus, side chains in ligands
(R,R)-5 and (R,R)-6 are too short to have strong influ-
ence in complexation. By contrast, the four chains pres-
ent in (R,R,R,R)-3 and (R,R,R,R)-4 seem to prevent the
formation of complexes with the enantiomers and a low-
er chiral recognition was observed. This behaviour was
very clearly observed by comparing the complexation
of (R)-AmII with (R,R)-1 and (R,R,R,R)-3 where
logK = 5.42 for the former ligand and 3.17 for the later.
2.2. Complexation studies
The complexation capability of receptors 1–6 towards
two different chiral alkylammonium picrates, (+)-(S)-
and (ꢀ)-(R)-sec-butylammonium picrate AmI and (+)-
(R)- and (ꢀ)-(S)-a-methylbencylammonium picrate
1
AmII was evaluated by H NMR studies in CD3CN as
solvent. Table 1 contains the logK values for these chiral
ligands calculated using the method developed by Mer-
nyi.7 The data in Table 1 clearly show that ligands
(R,R)-1 and (R,R)-2 exhibit enantiomeric recognition
in CD3CN. Thus (R,R)-1 favoured (R)-AmI over (S)-
AmI and (R)-AmII over (S)-AmII by a DlogK of 2.06
and 3.23, respectively. Similar results were observed
with (R,R)-2 with DlogK = 2.64 and 2.43 for AmI and
AmII, respectively. These results indicated that the pres-
ence of the phenyl rings in ligand (R,R)-1 not only gives
rise to higher complexation constants with (R)-AmII
than with (R)-AmI (logK = 5.42 and 4.61, respectively)
but also increases the enantiomeric recognition
(DlogK = 2.06 for AmI and 3.23 for AmII). The
observed differences could be related to the presence
of a phenyl group in AmII that could interact with the
aromatic rings in the ligand. In addition, the observed
differences shown by (R,R)-2 in ammonium salts
complexation corroborate the influence of the phenyl
group in the recognition process. Structures estimated
by molecular mechanics by using PCModel (v. 8.0)8
for the complexes formed between ligand (R,R)-1 and
(R)- and (S)-AmII (Fig. 2) show different interactions
between the phenyl rings depending on the stereochem-
istry.9 The complex formed with (R)-AmII shows a p-
staking interaction that is not observed with (S)-AmII.
This type of interaction could be responsible for the
2.3. Extraction experiments
The influence that the enantiomeric recognition exhib-
ited by ligands 1–6 has in extraction experiments was
evaluated by using the method reported by Cram.12
Extraction experiments were carried out between chloro-
form and an aqueous phase. The calculated extraction
constants are shown in Table 2. Racemic picrates of
sec-butylammonium ( )-AmI and a-methylbenzylam-
monium ( )-AmII were used in the aqueous solution
with the corresponding ligands 1–6 dissolved in the
organic phase. Determination of the extraction constants
were carried out by using UV-spectroscopy. The
obtained results demonstrate that under these conditions
the extraction of a-methylbenzylammonium picrate
AmII was higher than the extraction of sec-butylammo-
nium picrate AmI with all the ligands prepared. This
behaviour could be related to the higher lipophilic char-
acter of AmII. On the other hand, even though ligands
(R,R)-5 and (R,R)-6 show higher extraction properties
than the other studied ligands, they do not give rise to
chiral discrimination, as shown by measuring the spe-
cific rotation of the resulting aqueous solutions after
the extraction experiments.
Figure 2. Structures estimated by molecular mechanics by using
PCModel (v. 8.0)8 for the complexes formed between ligand (R,R)-1
and (a) (S)-AmII, (b) (R)-AmII.

2676
M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
Table 2. Extraction constants (CHCl3/H2O) and ee in the aqueous phase after extraction experiments
Picrate
(R,R)-1
(R,R)-2
(R,R,R,R)-3
(R,R,R,R)-4
(R,R)-5
(R,R)-6
(
)-AmI
LogKe
2.64
+2.6
25
2.86
+2.8
27
2.16
+2.4
23
2.12
+2.45
23
2.27
0.00
0
1.84
0.00
0
20
½aꢁD
ee (%)
(
)-AmII
LogKe
3.64
ꢀ2.35
33
3.21
ꢀ2.4
33
3.89
ꢀ1.7
24
3.66
—
—
4.92
0.00
0
4.76
0.00
0
20
½aꢁD
ee (%)
Enantiomeric excess were determined by optical rotation measurements.
Conversely, ligands (R,R)-1, (R,R)-2, (R,R,R,R)-3 and
(R,R,R,R)-4 show a moderate chiral discrimination in
extraction experiments being the (R)-enantiomer of both
picrates preferentially extracted. Data in Table 2 also
indicate that the number of chains on the crown ether
seems to have only small influence on extraction. Final-
ly, the results observed with both ammonium salts, ( )-
AmI and ( )-AmII, suggest that the structure of the
ammonium salts is not too important in these type of
experiments.
d = 137.2, 131.1, 127.2, 75.7, 69.8, 61.4, 29.6, 27.6,
26.6, 26.3, 20.9.
3.3. 1,4-Bis-O-(6-benzyloxyhexyl)-2,3-O-isopropylidene-
D-threitol 9a
2,3-O-Isopropylidene-D-threitol (7; 359 mg, 2.2 mmol) in
THF (10 mL) was added to a stirred suspension of NaH
(60% in mineral oil, 270 mg, 6.8 mmol) in THF (35 mL)
under an argon atmosphere. The mixture was stirred for
1 h at room temperature and then for 1 h at 80 °C. The
reaction mixture was cooled at 0 °C after which 8
(1.92 g, 5.3 mmol) in THF (15 mL) added. After stirring
under argon at 80 °C for 3 days, the reaction mixture was
cooled at 0 °C and a satd aq NH4Cl (30 mL) was added.
The organic solvent was removed and the aqueous phase
was extracted with ethyl acetate. The combined organic
phases were dried over Na2SO4 and evaporated. The res-
idue was subjected to column chromatography on silica
gel (hexane/CH2Cl2 9:1) to afford 9a as a pale yellow
3. Experimental
3.1. General
Column chromatography was performed with silica gel
60 (230–400 mesh, Merck). Silica gel 60 F254 (Merck)
plates were used for TLC. Optical rotations were taken
1
on a Perkin–Elmer 241 polarimeter. H and 13C NMR
1
spectra were recorded on either Bruker Avance 300 or
400 MHz spectrometers, with the deuterated solvent as
the lock and residual solvent as the internal reference.
Electronic impact high-resolution mass spectra (HRMS)
were recorded in the positive ion mode on a VG-AUTO-
SPEC. UV–vis spectra were recorded on a double beam
Shimadzu UV-2102 PC spectrophotometer using a 1 cm
pathlength quartz UV-cell. All measurements were
carried out at 293 K (thermostated). All commercially
available reagents were used without further purifica-
tion. THF was distilled from Na/benzophenone under
Ar prior to use.
oil (1.09 g, 91%). H NMR (300 MHz, CDCl3): d 7.36–
7.33 (m, 10H), 4.49 (s, 4H), 3.96 (t, J = 3.9 Hz, 2H);
3.55 (t, J = 3.9 Hz, 4H); 3.44 (t, J = 8.6 Hz, 8H); 1.64–
1.57 (m, 8H), 1.55–1.26 (m, 14H); 13C NMR (75 MHz,
CDCl3): d 138.6, 129.3, 127.6, 109.6, 72.8, 71.8, 71.5,
70.4, 60.4, 29.5, 27.0, 25.9, 21.0, 14.1.
3.4. 1,4-Di-O-benzyl-2,3-O-isopropylidene-D-threitol 9b
Reaction of diol 7 (1.04 g, 6.4 mmol), NaH (19.3 mmol)
and benzyl bromide (1.68 mL, 14.2 mmol) at 80 °C for
24 h, as described above for 9a, gave compound 9b6
(2.08 g, 95%) as a pale yellow oil after column chromato-
graphy (silica gel; hexane/ethyl acetate). 1H NMR
(300 MHz, CDCl3): d 7.26 (m, 10H), 4.56 (s, 4H),
4.23–3.50 (m, 6H); 1.41 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 138.4, 128.8, 128.1, 110.1, 73.9, 71.1, 27.4.
3.2. 6-(Benzyloxy)hexan-1-ol p-methylbenzenesulfonate 8
Pyridine (1.12 mL, 13.4 mmol) and p-toluenesulfonyl
chloride (2.18 g, 11.4 mmol) were added to a solution
of 6-(benzyloxy)hexan-1-ol13 (1.40 g, 6.7 mmol) in
CHCl3 (10 mL). The solution was stirred at 0 °C for
2 h and then at room temperature for 2 h. Diethyl ether
(25 mL) and water (10 mL) were added. The organic
phase was separated and washed with HCl (2 M), then
with NaHCO3 (5%) and finally with water, dried over
anhydrous Na2SO4 and concentrated. The resulting
oil was purified by column chromatography on silica
gel (hexane/ethyl acetate 1:1 as eluent) to yield 8 as a
colourless oil (2.38 g, 98%). 1H NMR (300 MHz,
CDCl3): d 7.77 (d, J = 10.0 Hz, 2H), 7.36–7.33 (m,
7H), 4.48 (s, 2H), 4.10 (t, J = 8.6 Hz, 2H), 3.42 (t,
J = 8.6 Hz, 2H), 2.44 (s, 3H), 1.64–1.56 (m, 4H),
1.34–1.26 (m, 4H); 13C NMR (75 MHz, CDCl3):
3.5. 1,4-Bis-O-(6-benzyloxyhexyl)-D-threitol 10a
To a solution of 9a (1.17 g, 2.2 mmol) in methanol
(25 mL) at 0 °C, 10% aqueous HCl (8 mL) was added
dropwise. The mixture was stirred for 4 h at rt, then it
was cooled again at 0 °C and neutralized with satd aq
NaHCO3. The solution was then extracted with ethyl
acetate. The combined organic phases were dried over
Na2SO4 and the solvent evaporated. The residue was
chromatographed on silica gel (hexane/ethyl acetate)
affording 10a (1.0 g, 90%) as
a colourless oil.
23
½aꢁD ¼ þ2.4 (c 1.72, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.37–7.26 (m, 10H), 4.49 (s, 4H), 3.96 (t,

M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
2677
J = 3.8 Hz, 2H), 3.55 (t, J = 3.8 Hz, 4H), 3.44 (t,
J = 8.6 Hz, 8H), 1.66–1.56 (m, 8H), 1.37–1.35 (m, 8H);
13C NMR (75 MHz, CDCl3): d 138.6, 129.3, 127.6,
127.5, 72.8, 71.8, 71.5, 70.4, 60.4, 29.5, 27.0, 25.9, 21.0.
pyranyl)ether derivative as a pale yellow oil (1.34 g,
38%) after column chromatography. 1H NMR
(300 MHz, CDCl3): d 7.46–7.22 (m, 10H), 4.61–4.60
(m, 2H), 4.52 (s, 4H), 3.87–3.48 (m, 18H), 1.79–1.50
(m, 12H); 13C NMR (75 MHz, CDCl3): d 138.6, 128.3,
127.6, 127.5, 98.8, 98.7, 79.2, 72.8, 71.4, 70.7, 70.4,
66.9, 62.1, 62.0, 30.6, 29.7, 26.0.
3.6. 1,4-Di-O-benzyl-D-threitol 10b
This compound was prepared from ketal 9b (2.28 g,
6.7 mmol) and hydrochloric acid in methanol as
described above for 10a. Crude 10b was obtained as a
white solid (1.90 g, 94%) and was used without further
Acidic hydrolysis of the above THP-protected diol
(650 mg, 1.2 mmol) followed by column chromatogra-
phy led to 11b [reference] as a colourless oil (466 mg,
23
24
24
purification. ½aꢁD ¼ þ6.2 (c 1.44, CHCl3) [lit.:6 ½aꢁD
¼
91%). [a]D = ꢀ2.5 (c 1.06, CHCl3) {lit.:4 ½aꢁD ¼ þ2.5 (c
1
þ6.16 (c 3.83, CHCl3)]; H NMR (300 MHz, CDCl3):
d 7.35–7.25 (m, 10H), 4.55 (s, 4H), 3.89–3.86 (m, 2H),
3.62–3.58 (m, 4H), 2.94 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 138.2, 128.8, 128.2, 74.0, 72.4, 71.0.
2.2, CHCl3)}; 1H NMR (300 MHz, CDCl3): d 7.45–
7.22 (m, 10H), 4.51 (s, 4H), 3.72–3.48 (m, 14H), 2.75
(s, 2H); 13C NMR (75 MHz, CDCl3): d 138.6, 128.3,
127.6, 79.8, 73.2, 72.9, 71.8, 70.3, 62.3.
3.7. 1,4-Bis-O-(6-benzyloxyhexyl)-2,3-bis-O-(2-hydroxy-
ethyl)-D-threitol 11a
3.9. Crown ether (R,R)-1
To a suspension of NaH (60% dispersion in mineral oil,
0.23 g, 5.8 mmol) in THF (5 mL) 11a (526 mg,
0.9 mmol) in THF (15 mL) was added dropwise under
argon. The resulting suspension was stirred at 80 °C
for 2 h. Triethylene glycol di-p-tosylate (476 mg,
1.0 mmol) in THF (30 mL) was slowly added dropwise
(ca. 75 min) at 60 °C. Once the addition was over, the
suspension was stirred at 80 °C for 2 days. The reaction
mixture was cooled to 0 °C and aq satd NH4Cl (20 mL)
added. The organic solvent was evaporated and the
resulting aqueous phase extracted with ethyl acetate.
The organic phase was dried over Na2SO4 and concen-
trated. The resulting oil was purified by column chroma-
tography on silica gel (hexane/ethyl acetate) to give
(R,R)-1 as a pale yellow oil (159 mg, 25%). [a]D = ꢀ4.7
Diol 10a (346 mg, 0.7 mmol) in dry THF (10 mL) was
added dropwise to a suspension of NaH (60% in
mineral oil, 116 mg, 2.9 mmol) in dry THF (15 mL).
The resulting suspension was stirred at 80 °C for 2 h
under argon. The reaction mixture was cooled to 0 °C
and O-(20-tetrahydropyranyl)-2-yodoethanol (653 mg,
2.6 mmol) in dry THF (10 mL) then added dropwise.
The resulting mixture was stirred under argon at
80 °C for 2 days. This was then cooled to 0 °C and a
satd aq NH4Cl (20 mL) added with stirring. The organic
solvent was removed and the aqueous phase extracted
with ethyl acetate. The combined organic phases
were dried over Na2SO4 and concentrated. The residue
was purified by column chromatography on silica gel
(hexane/ethyl acetate) to afford a pale yellow oil
1
(c 1.6, CHCl3) H NMR (400 MHz, CDCl3): d 7.48–
1
(184 mg, 36%). H NMR (300 MHz, CDCl3): d 7.48–
7.23 (m, 10H), 4.50 (s, 4H), 3.64–3.41 (m, 34H), 1.61–
1.35 (m, 16H); 13C NMR (75 MHz, CDCl3): d 138.7,
128.3, 127.6, 127.4, 72.8, 71.4, 71.3, 70.7, 70.6, 70.4,
70.0, 29.8, 29.7, 29.6, 26.0, 25.9; HRMS calcd for
C40H64O10: 704.450; found: 704.446.
7.23 (m, 10H), 4.63 (t, J = 3.9 Hz, 2H), 4.49 (s, 4H),
4.24–4.17 (m, 4H), 3.85–3.40 (m, 22H), 1.83–1.35
(m, 28H); 13C NMR (75 MHz, CDCl3): d 138.6,
128.3, 127.6, 127.5, 98.8, 98.7, 79.2, 72.8, 71.4, 70.7,
70.4, 66.9, 62.1, 62.0, 30.6, 29.7, 26.0, 25.4, 19.4,
19.3.
3.10. Crown ether (R,R)-5
To a solution of the previous bis(tetrahydropyranyl)
derivative (156 mg, 0.2 mmol) in ethanol (10 mL), concd
HCl (0.4 mL) was added, and the mixture refluxed for
3 h. The solution was cooled to 0 °C and neutralized
with solid Na2CO3. The suspension was filtered and
the solvent was evaporated. The resulting crude was
subjected to column chromatography on silica gel
(CH2Cl2/methanol) to yield 11a as a pale yellow oil
(102 mg, 91%). [a]D = ꢀ4.8 (c 1.0, CHCl3) 1H NMR
(300 MHz, CDCl3): d 7.47–7.23 (m, 10H), 4.49 (s, 4H),
3.85–3.40 (m, 22H), 1.83–1.35 (m, 16H); 13C NMR
(75 MHz, CDCl3): d 138.6, 128.3, 127.6, 127.5, 79.8,
73.2, 72.9, 71.8, 70.3, 62.3, 29.7, 29.4, 26.0, 25.9.
Condensation of 11b (313.4 mg, 0.8 mmol) with triethyl-
ene glycol di-p-tosylate (423.1 mg, 0.9 mmol), as
described above for compound (R,R)-1, yielded (R,R)-
5 (161 mg, 40%) as a pale yellow oil. [a]D = ꢀ4.8 (c
24
1.60, CHCl3) {lit.:4 ½aꢁD ¼ þ5.0 (c 2.1, CHCl3)};
1H NMR (300 MHz, CDCl3): d 7.43–7.25 (m, 10H),
4.51 (s, 4H), 3.85–3.46 (m, 26H); 13C NMR (75 MHz,
CDCl3): d 138.4, 128.3, 127.6, 127.4, 79.7, 73.2, 71.3,
71.0, 70.5, 70.2, 69.9; HRMS calcd for C28H40O8:
504.272; found: 504.267.
3.11. 1,4-Bis-O-(6-benzyloxyhexyl)-2,3-bis-O-(2-
hydroxyethyl)-D-threitol dimethanesulfonate 12
3.8. 2,3-Bis-O-(2-hydroxyethyl)-1,4-di-O-benzyl-D-
threitol 11b
Mesyl chloride (0.50 mL, 3.75 mmol) in CH2Cl2 (6 mL)
was added dropwise to a 0 °C solution of 11a (456 mg,
0.8 mmol) and triethylamine (0.8 mL, 4.56 mmol) in
CH2Cl2 (25 mL) and the solution stirred under argon
at 0 °C for 3 h. The mixture was washed with cooled
water, dried over anhydrous Na2SO4 and concentrated
In a similar way, the reaction of diol 10b (1.91 g,
6.3 mmol), NaH (21.8 mmol) and THP-protected yodo-
ethanol (4.97 g, 19.4 mmol) yielded the bis(tetrahydro-

2678
M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
to yield an oil, which was purified by column chroma-
tography on silica gel (CH2Cl2/hexane). Compound 12
(520 mg, 87%) was isolated as a pale yellow oil. 1H
NMR (300 MHz, CDCl3): d 7.45–7.23 (m, 10H), 4.50
(s, 4H), 4.33–4.31 (m, 4H), 3.95–3.40 (m, 18H), 3.04
(s, 6H), 1.77–1.34 (m, 16H); 13C NMR (75 MHz,
CDCl3): d 138.6, 128.8, 128.0, 127.9, 73.3, 70.7, 70.4,
69.8, 69.6, 38.0, 30.0, 29.5, 26.5.
(75 MHz, CDCl3): d 79.6, 73.0, 71.9, 70.6, 70.5, 70.2,
69.7; HRMS calcd for C14H28O8: 324.1784; found:
324.1780.
3.16. General procedure for the synthesis of ammonium
picrates
Equimolar proportions of the chiral amine and picric
acid were dissolved in ethanol, and the mixture was stir-
red at rt for 2 h. The solvent was removed and the result-
ing yellow solid was recrystallized from a toluene/
ethanol to afford crystalline ammonium picrates as yel-
low needles.
3.12. Crown ether (R,R,R,R)-3
NaH (60% dispersion in mineral oil, 339 mg, 8.5 mmol)
was added to a solution of 11a (470.2 mg, 0.84 mmol) in
THF (22 mL). The resulting suspension was stirred
under argon at 80 °C for 2 h. Compound 12 (672 mg,
0.9 mmol) in THF (35 mL) was slowly added dropwise
at 60 °C during 75 min and the mixture was stirred at
80 °C for 3 days. The reaction mixture was cooled to
0 °C and satd aq NH4Cl (20 mL) added. The organic
solvent was removed and the aqueous phase extracted
with ethyl acetate. The resulting organic phase was
dried over Na2SO4, filtered and evaporated. The result-
ing oil was subjected to column chromatography on sil-
ica gel (hexane/ethyl acetate) to yield (R,R,R,R)-3 as a
pale yellow oil (192 mg, 20%). [a]D = ꢀ2.6 (c 11.0,
sec-Butylammonium picrate, AmI: 1H NMR (300 MHz,
CD3CN): d 8.67 (s, 2H), 3.22–3.26 (m, 1H), 1.56–1.68
(m, 3H), 1.27 (d, J = 7.0 Hz, 2H), 0.97 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CD3CN): d 148.7, 126.5,
51.6, 30.8, 21.6, 10.3; (R)-AmI, [a]D = ꢀ10.5 (c 1.01,
H2O); (S)-AmI, [a]D = +10.6 (c 1.02, H2O).
a-Methylbenzylammonium picrate, AmII: 1H NMR
(300 MHz, CD3CN): d 8.68 (s, 2H), 7.34–7.47 (m, 8H),
4.47 (q, J = 7.0 Hz, 2H), 1.62 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CD3CN): d 148.7, 126.5, 131.1, 128.9,
46.7, 27.6; (R)-AmII, [a]D = +8.0 (c 0.98, H2O); (S)-
AmII, [a]D = ꢀ7.9 (c 1.01, H2O).
1
CHCl3) H NMR (400 MHz, CDCl3): d 7.42–7.24 (m,
20H), 4.50 (s, 8H), 3.80–3.43 (m, 44H), 1.61–1.36 (m,
32H); 13C NMR (75 MHz, CDCl3): d 139.1, 128.7,
127.9, 72.8, 71.4, 71.3, 70.7, 70.6, 70.4, 70.0, 30.1,
26.5; HRMS calcd for C68H104O14: 1144.743;
found = 1144.712.
3.17. Complexation experiences
Binding constants of chiral crown ethers 1–6 towards
1
chiral ammonium picrates were evaluated by H NMR
3.13. Crown ether (R,R)-2
studies. A 0.01 M solution of the ligand in CD3CN
(0.7 mL) was titrated by adding 3 lL aliquots of the
appropriate ammonium picrate (0.1 equiv each aliquot)
dissolved in a mixture of CD3CN/CD3OD 95:5 and reg-
istering the 1H NMR spectrum after each addition.
LogKc was calculated using the method reported by
Mernyi et al.7
A mixture of (R,R)-1 (150 mg, 0.21 mmol) and a cata-
lytic amount of 10% Pd(C) in methanol (40 mL) was
stirred for 24 h in the presence of an H2 atmosphere
(53 psi). The mixture was then filtered through Celite
and the solvent evaporated to afford diol (R,R)-2 as a
yellow oil (105 mg, 95%). [a]D = ꢀ4.7 (c 2.0, CHCl3);
1H NMR (400 MHz, CDCl3): d 3.64–3.41 (m, 34H),
2.13 (s, 2H), 1.61–1.35 (m, 16H); 13C NMR (75 MHz,
CDCl3): d 72.8, 71.4, 71.3, 70.7, 70.6, 70.4, 70.0, 29.8,
29.7, 29.6, 26.0, 25.9; HRMS calcd for C26H52O10:
524.356; found: 524.350.
3.18. Extraction experiments
Into a 20 mL centrifuge tube was introduced 1 mL of a
0.015 M aqueous solution of ammonium picrate and
1 mL of a 0.045 M solution of the corresponding crown
ether in ethanol-free chloroform. The tube was stop-
pered and shaken at 20 °C for 2 h in a Heidolph REAX
2 shaker. It was then left unshaken for another hour to
allow the separation of the aqueous and the organic
phase. A 100 lL aliquot of the organic layer was diluted
to 2 mL with acetonitrile and transferred into a UV cell.
The UV absorption at k = 295 nm was measured against
a blank experiment. Three repetitions were run for each
ligand-salt pair, and concentrations were calculated
using the Beer–LambertÕs law relationship. Extinction
coefficients (e) in CH3CN (HPLC-quality grade) on the
dynamic range of 10ꢀ4 to 10ꢀ5 were determined using
a set of standard solutions of different concentrations
of each salt. LogKe were calculated using the model
reported by Cram.12 Enantiomeric excesses of the ammo-
nium picrates after the extractions were evaluated by
measuring the optical rotations of the resulting aqueous
phases.
3.14. Crown ether (R,R,R,R)-4
Hydrogenolysis of (R,R,R,R)-3 (183.3 mg, 0.2 mmol)
with 10% Pd(C) in methanol as described above for
compound (R,R)-2 (40 mL) yielded (R,R,R,R)-4
(134 mg, 92%) as a yellow oil. [a]D = ꢀ2.6 (c 11.0,
1
CHCl3); H NMR (400 MHz, CDCl3): d 3.77–3.20 (m,
48H), 1.58–1.36 (m, 32H);13C NMR (75 MHz, CDCl3):
d 75.5, 72.7, 70.9, 70.1, 68.7, 63.8, 33.2, 30.0, 26.1, 25.7;
HRMS calcd for C40H80O14: 784.554; found: 784.523.
3.15. Crown ether (R,R)-6
(R,R)-5 (143 mg, 0.28 mmol) was hydrogenolyzed with
10% Pd(C) affording (R,R)-6 (84 mg, 92%) as a yellow
1
oil. [a]D = ꢀ4.2 (c 2.10, CHCl3); H NMR (400 MHz,
CDCl3): d 3.80–3.46 (m, 26H), 1.81 (s, 2H); 13C NMR

M. Colera et al. / Tetrahedron: Asymmetry 16 (2005) 2673–2679
2679
4. For the synthesis of the enantiomers (S,S)-5 and (S,S)-6 as
well as (S,S)-10b and (S,S)-11b: Ando, N.; Yamamoto, Y.;
Oda, J.; Inouye, Y. Synthesis 1978, 688–690.
5. (a) Girodeau, J.-M.; Lehn, J.-M.; Sauvage, J.-P. Angew.
Chem., Int. Ed. Engl. 1975, 14, 764; (b) Curtis, W. D.;
Laidler, D. A.; Stoddart, J. F.; Jones, G. H. J. Chem. Soc.,
Acknowledgements
The present research has been financed by Spanish
DGCYT (PPQ2002-00986) and Generalitat Valenciana
(Grupos 03/206). P.G. acknowledges Spanish MCYT
´
for a Ramon y Cajal contract. M.C. also acknowledges
´
Chem. Commun. 1975, 833–835; (c) Bako, P.; Bajor, Z.;
the Spanish Government for a Ph.D. grant. Finally,
SCSIE (Universidad de Valencia) is gratefully acknowl-
edged for all the equipment employed.
Toke, L. J. Chem. Soc., Perkin Trans. 1 1999, 3651–3655.
6. Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S.
B. Org. Synth., Coll. Vol. 8, 1993, 155 (Org. Synth. 1989,
68, 92–101).
7. Kholin, Y. V.; Konyaev, D. S.; Mernyi, S. A. Kharkov
University Bulletin No. 437 (Chemistry Series, Issue 3)
1999, 17–35.
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