Novel C1-symmetric chiral crown ethers bearing rosin acids groups: Synthesis and enantiomeric recognition for ammonium salts

Article abstract of DOI:10.1016/j.tet.2014.10.050

Four types of novel C₁-symmetric chiral crown ethers including 28-crown-8, 20-crown-6, 17-crown-5 and 14-crown-3 (9a-m) were synthesized and their enantiodiscriminating abilities with protonated primary amines (10-14) were examined by ¹H NMR spectroscopy. 20-crown-6 crown ethers exhibited good chiral recognition properties toward these guests and showed different complementarity to some chiral guests, indicating that 20-crown-6 crown ethers could be used as a chiral NMR solvating agent to determine the enantiopurity of these guests. In addition, the binding model and binding site between the hosts and guests were also studied by the computational modeling and experimental calculation.

Full text of DOI:10.1016/j.tet.2014.10.050

Tetrahedron 70 (2014) 9545e9553
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel C -symmetric chiral crown ethers bearing rosin acids groups:
1
synthesis and enantiomeric recognition for ammonium salts
Lu-zhi Liu a , Chun-huan He , Lin Yang , Yan Huang , Qiang Wu , Wen-gui Duan ,
,
b
c
a
c
a
b
a,
a,
*
*
Heng-shan Wang , Ying-ming Pan
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal
University, Guilin 541004, PR China
School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, PR China
Guangxi Institute of Traditional Medical and Pharmaceutical Science, Nanning 530022, Guangxi, China
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2014
Received in revised form 4 October 2014
Accepted 24 October 2014
Available online 29 October 2014
Four types of novel C -symmetric chiral crown ethers including 28-crown-8, 20-crown-6, 17-crown-5
and 14-crown-3 (9aem) were synthesized and their enantiodiscriminating abilities with protonated
1
primary amines (10e14) were examined by 1H NMR spectroscopy. 20-crown-6 crown ethers exhibited
good chiral recognition properties toward these guests and showed different complementarity to some
chiral guests, indicating that 20-crown-6 crown ethers could be used as a chiral NMR solvating agent to
determine the enantiopurity of these guests. In addition, the binding model and binding site between the
hosts and guests were also studied by the computational modeling and experimental calculation.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C -Symmetric chiral crown ethers
1
Levopimaric acid
Protonated primary amines
Enantiomeric recognition
Computational modeling
1
. Introduction
feasible and have received less attention. However, in contrast to C
, and D -symmetry chiral crown ethers, C -symmetry selectors
have some significant advantages. First, it is simple and convenient
to prepare the C -symmetry chiral macrocycles by introducing
numbers of chiral structures into crown, avoiding tedious multistep
synthesis and purification, particularly for the asymmetric reaction,
which would be difficult (or impossible) to obtain the compounds
with perfect optical purity. Second, they can easier be selectively
functionalized to synthesize various crown derivatives. Therefore, it
is very important to develop a new method for the synthesis of the
2
,
C
3
2
1
The development of chiral artificial receptors that are capable of
differentially binding enantiomeric amine or protonated amine
compounds is of great significance because these substrates are basic
building blocks of biological molecules and a number of them are
major components of proteins in natural living systems. Since the
pioneering research on the application of macrocyclic ligands in
chiral recognition was reported by Cram et al., a great number of
1
1
2
novel chiralcavitycompoundshave been designed andsynthesized.
As chiral selectors, chiral crown ethers have attracted increasing at-
tention owing to their superior selectivity in the enantiomers com-
plexation with racemic-amino acids and primary amines.
Chiral crown ethers possessing C , C , and D -symmetry usually
2 3 2
show high enantioselectivity because of their interaction in
1
C -symmetry chiral macrocycles with high selectivity in the en-
antiomer separation, which can expand the type of receptors and
find more different complex models in the hosteguest system.
Generally, the bulkiness of substituents, the rigidity and the
symmetry of the molecular frame, and the structural complemen-
3
a complementary way between substrates and chiral macro-
tarity are all expected to play an important role in enantioselective
cycles.1 In contrast, chiral macrocycles possessing C
a
-symmetry
recognition. For C
strates interact with the C
5
-symmetry chiral crown ethers, when the sub-
-symmetry selectors from one side, the
1
1
always show low or no enantioselectivity due to the ‘sidedness’
1
4
problems as described by Naemura, K. It has been believed that the
chiral barrier would protrude to the other sides, which minimize the
role of the chiral barrier, thus resulting in a low degree of the chiral
recognition. But if a suitable chiral structure (especial the large
natural chiral structure) is introduced into crown, it might lead to
1
chiral recognition in C -symmetry environments may not be
1
a
*
Corresponding authors. Tel.: þ86 773 5846279; fax: þ86 773 5803930; e-mail
addresses: whengshan@163.com (H.-shan Wang), panym2013@hotmail.com (Y.
ming Pan).
complementarity between the host and guest. Naturally occurring
enantiomeric levopimaric acid, including unique three-dimensional
-
http://dx.doi.org/10.1016/j.tet.2014.10.050
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
0

9546
L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
structure with more than one chiral centers, promises to be a better
structural complementarity with bio-supermolecular and an ex-
cellent material for chiral reagents. Recently, some derivatives of
reaction with pyridine and dimethyl sulfate afforded the com-
pounds 5 and 7, respectively. Subsequently, the reaction of these
6
intermediates with LiAlH
vided the compounds 6 and 8. Synthesis of the other alcohol 4
began with the treatment of compound 1 with PCl , then reduction
with LiAlH to afford triol 2 in an 83% yield. Compound 3 was
4 4
or NaBH in the presence of THF pro-
levopimaric acid have been applied in catalytic asymmetric re-
7
action. In our prior works, it has been reported to use levopimaric
3
acid derivatives in the separations of
D
/
L
-amino acids by capillary
4
electrophoresis.8 Apparently, attempt to design the C
-symmetry
produced by Williamson reaction of alcohol-protected 2 with
benzyl chloride. Subsequent deprotection of the benzyl group gave
alcohol 4 in an 80% yield.
1
chiral crown ethers with enantioselectivity and enantiomer sepa-
ration from natural products, levopimaric acid or its derivative, is
one of the best choice as the chiral substituents. As it turned out,
The ditosylates Z1eZ4 were prepared according to the synthetic
strategy shown in Scheme 3. Finally, four novels types of C1-
symmetric macrocycles 9aem such as 28-crown-8, 20-crown-6,
17-crown-5 and 14-crown-3(Scheme 4) were synthesized from
Z1eZ4 with compounds 2, 4, 6, and 8 via a regioselective ring
formation reaction in the presence of NaH in THF under high di-
lution conditions in 10.3%e9.3% yields, respectively. The products
1
a series of novel C -symmetry chiral 22-crown-6 ethers bearing
maleopimaric acid (the DielseAlder adduct of levopimaric acid with
maleic anhydride, Scheme 1) we synthesized, exhibited good chiral
recognition and showed different complementarity towards the
9
chiral guests in UVevis spectroscopy. However, this method is not
suitable for determining the enantiomeric purity of chiral guests.
1
13
Thus we synthesized another four types of novel C
1
-symmetric
were characterized by a combination of H NMR, C NMR, MS, IR
and elemental analysis.
chiral crown ethers including 28-crown-8, 20-crown-6,17-crown-5
and 14-crown-3 from maleopimaric acid, and studied their enan-
tiodiscriminating abilities towards protonated primary amines and
TsCl
Pyridine
O
O
OTs
O
O
OH
OH
1
amino acid methyl ester salts by H NMR spectroscopy.
(
0 o
(
C
OTs
)n
)n
60~70%
Z1: n=1
Z2: n=2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
O
O
Cl
TsCl
SOCl2
HO
OH
O
O
O
O
OTs
OTs
KOH
NaOH/THF
R
R
Cl
R=CH2OH, COOCH3
2 3
R=CH OH, COOCH
27.5%
Z3
1
Scheme 1. Structure of four novel C -symmetry chiral 22-crown-6 ethers.
O
O
O
O
OTs
OTs
2
2
. Results and discussion
.1. Synthesis
OH
TsCl
Cl
O
OH
OH K2CO3/DMF, 100 oC N(Et)3/CH2Cl2
0.3%
2
Z4
The different substituent maleopimaric acid (2, 4, 6, and 8),
Scheme 3. Synthesis of the diethylene glycol tosylate derivatives Z1eZ4.
possessing two hydroxyl groups served as linkage part of host
molecular in present crown ether synthesis, were prepared
according to the synthetic strategy shown in Scheme 2. Compound
1
was prepared according to the reported procedure,10 followed by
H
OH
OH
H
NaH,THF
H
OH
OH
R1
i, ii
iii, iv
v
H
R = CH CH OCH CH OCH CH
2
4
6
8
: R1=CH2OH
2
2
2
2
2
2
2
: R1=CH2OBn
: R1=CH2-(1-pyridyl)
: R1=COOMe
CH2OBn
9d: R1=CH2OH,
9e: R1=CH2OBn,
4
R2=
9
f: R1=CH2-(1-pyridyl),
g: R1=COOMe
9h: R =CH OH,
2
9
O
1
2
O
O
OH
OH
2
2 2 2 2
9i: R1=CH -(1-pyridyl), R = CH CH OCH CH
2
O
O
9j: R =COOMe,
1
i
SOCl /DMF
LiAlH /THF
O
R2= CH2CH2
R2=
CH2
CH2
ii
N
O
O
O
O
N
N
H
CO H
O
9m: R =CH OBn,
1
2
1
5
6
CH2OBn
1
Scheme 4. Synthesis of four types of novel C -symmetric chiral crown ethers 9aem.
H
O
H
H
O
H
H
OH
OH
O
(CH ) SO
O
NaBH
H
O
O
2.2. 1H NMR spectroscopy
CO H
CO CH
CO CH
1
7
8
In our previous report, we have known that rosin-based 22-
crown-6 ethers have excellent ability to form hosteguest com-
plexes and distinguish chiral primary amines. 20-crown-6 are the
Scheme 2. Synthesis of the glycol derivatives 4, 6, and 8: (i) PCl
3
, MeOH, reflux, 4 h; (ii)
LiAlH
4
, Et
2
O, reflux, 8 h; (iii) TsOH$H
2
O, PhCH(OMe)
2
, rt, 1 h; (iv) (n-Bt) NBr, BnCl, 5 h;
4
ꢀ
(
v) PPTS, Me
2
CO, 65 C, 5 h.

L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
9547
analogue as 22-crown-6, in which they possess a similar distribu-
tion of the oxygen atoms or coordination site of the cavity. Thus we
chose this type receptor to study their chiral recognition properties.
H
H
4
, H
5 8
and H of 10 were shifted to high field and the peaks except
8
were slip into two sets in 1:1 integration ratio, which nearly no
change even the crown/substrate ratio increased to 4:1. In combi-
nation with the sharpening of all the resonances, indicating that the
exchange rate of crownesubstrate complexes was fast on the NMR
time scale. The splitting of the resonances in the spectrum of 10 was
the result of enantiomeric discrimination under fast exchange
rather than separate bound forms of 10 with 9e, in agreement with
the literature reporting the chiral recognition properties of (18-
crown-6)-2,3,11,12-tetracarboxylic acid. These results clearly in-
dicated that chiral crown ether 9e could be used as a chiral NMR
solvating agent to determine the enantiopurity of 10 at ambient
temperature. The significant enantiomeric discrimination was ob-
served for the resonances of the methyl (0.082 ppm), methine
1
H NMR spectroscopy is a convenient and widely used method for
the study of chiral recognition. Discrimination occurs when the
addition of an optically pure chiral discriminating agent associates
with a pair of enantiomers to produce diastereomeric complexes
1
that exhibit different shifts in the NMR spectrum. H NMR spectra
3
i
of solutions of 9b, 9d, and 9e were recorded in the absence and
presence of various racemic ammonium salts (Scheme 5), such as
racemic
ylamine HCl (11),
methyl ester HCl (13) and
a
-(1-naphthyl)ethylamine HCl (10), racemic
-alanine methyl ester HCl (12),
-serine methyl ester HCl (14). Con-
a
-phenyleth-
D
,L
D,L-valine
D,L
sidering the solubility of all the guests and hosts in different sol-
vents and the chemical shift changes (DDd) of methyl protons (see
(0.013 ppm) and H
4
hydrogen (0.023 ppm) at a 4:1 crown/substrate
Supplementary data: Fig. S66 and Table S1), CDCl
v/v¼2:1) were chosen as the best solvent in which receptors had
good chiral recognition abilities.
3 3
/CD OD
ratio. In particular, the greatest enantiomeric discrimination DDd
for the resonances of H was up to 0.135 ppm (Table 1).
5
(
Table 1
Enantiomeric discrimination [DDd (ppm)] between enantiomers in the 1H NMR
spectra (500 MHz) of guests (5 mM) in the presence of chiral crown ethers (20 mM)
in CDCl /CD OD (2/1)
1
8
1
7
3
3
1
4
3
19
1
1'
2' 3' 4'
¦
Â
24
8'
6'
¦
Á
11
16
5'
7'
Guest
10
Proton
9b (DDd, ppm)
9d(DDd, ppm)
9e (DDd, ppm)
¦
Ã
12
O
O
O
O
O
O
9'
O
O
O
O
2
2
C
E
1
CH
CH
H4
3
0.025
0.027
0.164
0.031
0.009
0.014
Overlap
0.005
0.001
0.008
0.018
0.010
0.006
0.004
0.003
0.0726
0.0153
0.0233
0.0181
0.0259
0.0145
0
0.082
0.013
0.023
0.135
0
O
O
9"
2
3
20 10
9
15
5"
7"
8
6"
8"
2
3
1'' 2'' 3'' 4''
A
B
¦Á'
¦
Â' ¦ Ã'
7
4
5
6
H
H
5
2
1
R1
O
1
9d: R1=OH
9
e: R1=OBn
8
9
b: R1=OBn
1
1
2
CH
CH
CH
CH
OCH
3
NeCH
3
3
0.026
0.013
Overlap
0.008
0.004
Overlap
0.010
0.000
Overlap
0.003
D
1
Overlap
0.01495
0.0018
0.0030
Overlap
0.0027
Overlap
0.000
1
9
NH3+Cl-
NH3+Cl-
8
5
NH3 Cl
+
-
13
14
1
NH3+Cl-
1
+
-
7
6
2
3
NH3 Cl
CH3
6
5
2
3
CO2Me
OCH
NeCH
OCH
3
CO2Me
CO2Me
1
0
4
4
10
11
3
1
2
13
14
DDd (ppm)¼jDdR
ꢁ
DdSj, Dd¼(Chemical shift values of the protons specified in bold in
Scheme 5. Structures of 20-crown-6 macrocycles and primary ammonium salts
guests.
the presence of chiral crown ethers)ꢁ(chemical shift values in the absence of chiral
crown ethers).
Fig. 1 showed the 1H NMR spectra for racemic naph-
thylethylammonium chloride 10 (5 mM) in the absence and pres-
ence of the chiral crown ether 9e in different concentrations in
1
Furthermore, H NMR studies of the chiral crown ether 9e with
different molar ratios of (R)- or (S)-10 were examined (Fig. 2). The
methyl doublets of 10 separated into two doublet peaks with an
upfield shift. The methyl proton of (R)-10 appeared at lower field
3 3 3
a mixed solvent of CDCl /CD OD (2:1). The protons signals CH , CH,
Fig. 1. Partial 1H NMR spectrum of (þ/ꢁ)-10 (5 mM) with 9e at (a) 0 mM, (b) 0.5 mM, (c) 1 mM, (d) 2.5 mM, (e) 5 mM, (f) 10 mM, (g) 15 mM and (h) 20 mM in CDCl
3 3
/CD OD (2/1).

9548
L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
discrimination in the spectrum of 10 in the presence of 9e was large
for the proton H
resonances (DDd¼0.135 ppm), but the small
5
nonequivalence of this hydrogen resonances when the host was
instead by 9d. And its values DDd decreased sharply to 0.0181 ppm.
It was shown that the binding properties of 20-crown-6 ether were
significantly influenced by the different side chain. For 9d, there
were two binding sites (polyether ring and hydroxyl group) to-
wards 10 driven by hydrogen-bonding interactions. This competi-
tion would reduce the enantiomeric discrimination, and require
much higher concentrations of 9d to achieve any distinction.
In the light of these results, we can say the 20-crown-6 ethers
have good chiral recognition properties with primary ammonium
salts. To examine the influence of the different guests on the
binding interaction, we studied the complexation of these three 20-
Fig. 2. The methyl resonance in the 1H NMR of 10 (5 mM) with various enantiomeric
ratios in the presence of 9e (5 mM) in CDCl /CD OD (2/1) (a) 50% S-enantiomer, (b)
00% S-enantiomer, (c) 63.2% S-enantiomer, and (d) 93% S-enantiomer.
crown-6 ethers and the other primary ammonium salts 12, 13, and
3
3
1
1
4. Table 1 showed the H NMR up-field shift DDd of guests in host-
1
guest system. All guests exhibited some degree of enantiomeric
discrimination. It is noteworthy that these three chiral crown
ethers showed remarkable DDd towards protonated primary
amines, especially naphthylethylammonium chloride, but weak for
amino acid methyl ester salts. Their DDd increased in the order of
than that of (S)-10, which was confirmed by an increase of the
methyl proton signal of (S)-10 that was added into the complex of
racemic guests with 9e. This indicated that the interactions of host
9
e with the (R)- and (S)-forms of 10 were different, resulting in two
doublet resonances for the CH protons. The degree of signal sep-
aration of (R)- and (S)-10 depended greatly on the molar ratio of 9e/
0 (Fig. 1aeh). The value (DDd) of the signals of methyl proton
(12, 13, and 14)<11<10. In addition, the 1:1 stoichiometry of the
3
complexes between all receptors and guests were determined by
ESI-MS or APCI-MS (Supplementary data: Figs. S67e79).
1
gradually raised with an increase in the concentration of 9e, sug-
gesting that increasing the concentration of chiral solvating agents
could promote the formation of the diastereomeric complexes and
enhance the extent of enantiomeric discrimination in the H NMR
spectrum.
Chiral recognition between 10 and 9b that contains softer cavity
compared with 9e, has also been investigated. More excellent en-
antiomeric discrimination was observed based on the larger
2
.3. Chiral recognition model
1
It is well-known that molecular structure plays an important
role in determining the chiral recognition properties of hosts. Pla-
nar molecule, large chiral barrier and rigid cavity usually show good
enantiomeric recognition for chiral macrocyclic receptors. In order
to investigate the spatial structure with the aim of forecasting the
chiral recognition model of title compound, we optimized the ge-
ometry of compound 9b and 9e with the HF method at the 6-31G/
level of GAUSSIAN 09. The optimized molecular structures are
shown in Fig. 3. Some selected geometric parameters are listed in
Table 2. The chiral barrier contains four crystallographically unique
rings: three cyclohexane rings A, B and C, and an aromatic ring D
chemical shift changes (DDd of CH, H
9
0
4
, H
b/10 ratio). These values were up to 0.027, 0.164, 0.031 and
.009 ppm, respectively. Importantly, the greatest enantiomeric
5 8
and H protons at a 4:1
11
discrimination observed for proton was at the 4-position or 5-
position on 10 in the 9be10 or 9ee10 systems, respectively. As
þ
far as we know,18-crown-6 unit can form 1:1 complex with NH
3
by
(labeled in Scheme 5).
the interaction of three hydrogen bonds. In general, the closer the
substrate’s stereogenic center is to the binding cavity, the larger
enantiomeric discrimination will be shown. According to the sig-
For 9b, Torsion angles show that ring A, B and C exhibit boat
nificant enantiomeric discrimination for the signals of H
8
on guest
10 in different hosts 9b and 9e. We could conclude that the cavity
size of 9b was more suitable to complex 10 and therefore showed
greater excellent chiral recognition. The possible reason was that
the soft cavity of 9b was easier to self-control its size to the slightly
larger guest molecular such as 10, but difficulty for 9e because of its
larger naphthalene group making the cavity greater rigidity.
However, when the guest structure was smaller, the rigidity cavity
would generate more effective enantiomeric discrimination. To
confirm this hypothesis, we studied the chiral recognition of 9b and
9
9
e with the model primary ammonium salt guest 11. As expected,
e gave a larger chemical shift change and discrimination of the
methyl signal of 11 than 9b. Its value of DDd was up to 0.026 ppm at
a 4:1 crown/substrate ratio, suggesting the better chiral recognition
property for 9e with 11.
Interestingly, compared to 9b, the 20-crown-6 ether 9e showed
greater enantiomeric discrimination of the methyl protons for both
of the guests 10 and 11. Considering the minimal interference from
other protons in the spectrum, 20-crown-6 ether 9d, bearing the
same cavity as 9e but different side chain on the maleopimaric acid
group, was studied for its chiral recognition ability toward the
guests 10 and 11. The results showed that its chiral recognition
abilities were not as efficient and sensitive as 9e based on the less
chemical shift change of guests. For example, the enantiomeric
Fig. 3. Equilibrium structures calculation of 9b (a and b) and 9e (c and d).
configurations. A and B form cis ring junction with two methyl
groups (C(17) and C(18)) in the axis positions. In addition, benzyl
and isopropyl was in the cis position between ring A, B and C. On
0
the basis of the torsion angles of (O
a
eOb
eO
geO
a
), the cavity of
crown is slightly twisted. As a result, the host can complex guest
through the up or down cavity of the crown (Fig. 4a).

L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
9549
Table 2
Selected bond lengths (A) and torsion angles ( )
ꢀ
ꢀ
9b
9e
ꢀ
Bond lengths (A)
C1eC4
C2eC5
C3eC10
C5eC8
C6eC9
C7eC10
C8eC12
C9eC16
3.090
2.830
2.880
2.850
3.000
2.890
2.570
2.870
3.010
8.310
6.540
6.465
5.542
4.520
5.440
3.000
2.950
3.010
2.870
Fig. 5. The complexes model of 9e-(R)-10 (a) and 9e-(S)-10 (b).
3.020
3.340
2.580
3.100
2.800
7.290
5.500
4.630
5.960
3.830
6.980
10 and isopropyl group was in the opposite direction between
cavity. Furthermore, the methyl and naphthalene group of (S)-10
are closer to naphthalene moiety or the cavity of crown 9e whose
shielding effect was stronger, indicating that these protons of (S)-10
appeared at upper field than that of (R)-10 in agreement with the
previous analysis by experiment. This result well explained the
excellent chiral recognition properties of 9e toward 10. The chiral
recognition model of 9e might be as Fig. 6.
C11eC15
0
0
0
O
O
O
O
O
O
a
a
b
b
g
g
eO
eO
eO
eO
eO
eO
a
b
b
g
b
0
0
0
g
ꢀ
Torsion angles ( )
C2eC1eC10eC5
C5eC4eC3eC2
C7eC6eC5eC10
C10eC9eC8eC7
C9eC11eC12eC16
36.86
24.28
36.36
34.99
51.67
59.78
53.39
ꢁ53.68
ꢁ34.86
ꢁ35.98
76.59
3
. Conclusions
C16eC15eC8eC9
66.68
122.92
1
Four types of novel C -symmetric chiral crown ethers including
8-crown-8, 20-crown-6, 17-crown-5, and 14-crown-3 (9aem)
0
O
a
eO
beO
geO
a
ꢁ15.73
2
were synthesized and their enantiodiscriminating abilities with
1
protonated primary amines (10e14) were examined by H NMR
spectroscopy. Complexation studies revealed that 20-crown-6
crown ethers exhibited good chiral recognition properties toward
these guests and showed different complementarity to some chiral
guests. It was observed that changes in the side chain on mal-
eopimaric acid unit as well as insertion of the naphthyl group into
the ring influence both binding model and enantiodiscrimination
ability of macrocyclic compounds against protonated primary
amines and amino acid methyl ester salts. The significant in-
formation gained in this study will help to further understand the
molecular recognition in the biological processes. More impor-
tantly, the chiral crown ether 9d possessing a hydroxyl group in the
side chain can easily be used as linkage group covalently bound to
silica gel in the preparing chiral stationary phases or membranes.
4
4
. Experimental
Fig. 4. The binding model of 9b (a) and 9e (b) with guest.
.1. General information
In contrast, compound 9e contains a naphthalene ring on the
other side of 20-crown-6. Its optimized structure show that ring B
and C exhibit boat configurations, while A and B form cis ring
junction with two methyl groups as 9b. The ring A exhibit chair
configuration. In addition, benzyl and isopropyl was in the trans
position between ring A, B, and C, which not like 9b. Furthermore,
Optical rotations were measured using polarimeter at ambient
temperature and
10 deg cm g . NMR spectra were measured in CDCl using TMS
[
a
]
D
-values were given in units of
ꢁ1
2
ꢁ1
3
as the internal standard. IR spectra were recorded on FTIR in-
strument. HR-ESI-MS were recorded in TOF. All the other chemicals
and organic solvents used in this work were of analytical grade
unless otherwise specified.
oxygen atoms in cavity
E
are coplanar. The torsion angle
0
(OaeObeOgeOa ) between rosin skeleton and naphthalene moiety
ꢀ
is 122.9 . It showed that the cavity of crown is greatly twisted at-
tributing to the steric hindrance of rosin skeleton and naphthalene
moiety. The whole structure of chiral macrocyclic receptor looks
like an arch bridge (Fig. 3c and d), which resulting that host-guest
complex can firm only on one side of the cavity (Fig. 4b).
1
4
.2. Enantiomeric separation in the H NMR spectra
The racemic ammonium salts (5 mM) and chiral crown ether
(
3 3
5 mM) were dissolved in 0.4 mL of CDCl /CD OD (2/1, v/v), and
In order to further understand the chiral recognition mecha-
nism, two model complexes 9e-(R)-10 and 9e-(S)-10 (in Fig. 5) are
calculated using the same theory level and basis set as the parent
uncomplexed crown 9e. By inspection of the data obtained, it is
believed that hydrogen bonding interactions between the oxygen
atoms of 9e and ammonium ion formed base on their NeO bond
length (see Supplementary data: Table S1) in these two complexes.
Symmetric cavity and planar molecular frame of model complexes
is much better compared to the parent free crown. The main dif-
ference between 9e-(R)-10 and 9e-(S)-10 is that the recognized (S)-
1
were assessed by H NMR at 500 MHz. Differences in the chemical
shifts between the enantiomers were then recorded. All chemical
shift values were referenced to the internal tetramethylsilane
standard.
4.3. Synthesis
Compound 2 and Z1eZ2 were prepared according to the re-
12
ported procedure.

9550
L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
O
O
S
O
O
O
O
O
S
O
O
O
O
O
R
O
O
O
O
R
O
OBn
O
OBn
OBn
+
NH
3
Ph, Naphth etc
Fig. 6. A representative interaction of the macrocycle 9e with R- and S-protonated primary amines.
ꢀ
4
.3.1. Compound 2. Yield: 92.2%; mp 172.9e173.6 C (ref: mp
55.0, 61.1, 65.5, 73.2, 79.8, 125.0, 127.3, 128.2, 139.1, 147.9. m/z: 467
[MþH] .
ꢀ
13
25
D
1
þ
170 C ); ½
a
ꢂ
þ4.2 (c 1.50, CH
3
OH); H NMR (CD
3
OD, 500 MHz):
0
.59 (3H, s), 0.73 (3H, s), 0.783e0.86 (1H, m), 0.99, 1.00 (6H, dd,
J¼6.8 Hz), 1.07e1.17 (1H, m), 1.16e1.24 (2H, m), 1.31e1.34 (1H, m),
.37e1.52 (7H, m), 1.65 (1H, ddd, J¼13.1, 11.4, 2.6 Hz), 1.83 (1H, dt,
J¼9.9, 2.3 Hz), 2.02e2.03 (1H, m), 2.18e2.22 (2H, m), 2.35 (1H, br s),
.07 (1H, d, J¼10.9 Hz), 3.41 (1H, d, J¼10.6 Hz), 3.45 (1H, d,
J¼10.9 Hz), 3.51 (1H, dd, J¼11.4, 3.7 Hz) 3.58 (1H, t, J¼10.1 Hz), 3.76
1H, dd, J¼11.3, 1.9 Hz), 5.35 (1H, s).
4.3.4. Compound 5. To a solution of compound 1 (4.0 g,10 mmol) in
1
20 mL SOCl
2
was added 1 mL DMF. The reaction mixture was stirred
ꢀ
for 6 h at 79 C. After concentration under reduced pressure, 1,4-
diethylene dioxide (40 mL) was added to the residue under ice
bath. A mixture solution of 1-oxa-4-azacyclohexane (2.0 mL),
triethylamine (1.6 mL) and 1,4-diethylene dioxide (7.0 mL) was
added slowly. The solution was stirred for 8 h and then poured into
cold hydrochloric acid solution (6 mol/L). The precipitate was fil-
tered, dried and recrystallized from toluene to give 5 (4.4 g,
3
(
4.3.2. Compound 3. To the solution of triol 2 (5.6 g, 14.8 mmol) in
CH Cl (160 mL), dimethyl benzaldehyde (3.4 g, 22.4 mmol), and
2
2
ꢀ
p-toluenesulfonic acid (0.2 g, 1.17 mmol) were added. After
stirring at room temperature (1 h), the reaction mixture was
9.4 mmol) as white crystals. Yield 94.2%, mp 254.3e256.7 C, IR
ꢁ
1
(KBr,
n
, cm ): 2940 (CH
2
), 1836, 1770 (C]C), 1611 (C]C), 1085
þ
washed with NaHCO
3
solution (5%, 2ꢃ150 mL) and water
(CeO); MS (ESI) m/z: 468 (MþH ).
(
2ꢃ150 mL). The organic layer was separated, dried over Na
2
SO ,
4
and evaporated. The residue was crystallized from EtOAc to give
hydroxyl groups protected derivative 4.6 g as a white solid. To
4.3.5. Compound 6. To a solution of compound 5 (4.0 g, 8.6 mmol)
in 150 mL anhydrous tetrahydrofuran was added LiAlH (2.0 g,
4
the solution of this compound (4.6 g, 10 mmol) in CH
2
Cl
2
(5 mL),
52.6 mmol) under ice-bath. Then the reaction solution was stirred
for 16 h at refluxing temperature. After cooling to room tempera-
ture, 20 mL EtOAc and 40 mL hydrochloric acid solution (1 mol/L)
were added slowly to the solution, respectively, and then extracted
with EtOAc (50 mLꢃ3). The combined organic layer was dried over
5
0% aqueous NaOH (5 mL), tetrabutylammonium hydrosulfate
(
0.17 g, 0.5 mmol), and benzyl chloride (7 mL, 61 mmol) were
ꢀ
added. After stirring at 50 C (5 h), the reaction mixture was
washed with water to pH¼7. The organic layer was separated,
dried over Na
2
SO
4
, and evaporated. The residue was purified by
4
MgSO , filtered through Celite, and concentrated under reduced
column chromatography (petroleum ether: ethyl acetate, 4:1)
pressure. The crude product was recrystallized from EtOAc to give 6
(2.2 g, 5.0 mmol) as white crystals. Yield 58.1%, mp 177.5e178.0 C,
1
ꢀ
giving compound 3 as a colorless oil (4.2 g, 56%): H NMR (CDCl
00 MHz) 0.62 (3H, s), 0.78 (3H, s), 0.89 (1H, m), 1.07 (3H, d,
J¼6.8 Hz), 1.07 (3H, d, J¼6.8 Hz), 1.17 (1H, m), 1.33e1.42 (8H, m),
.56 (2H, m), 1.67 (1H, m), 1.94 (1H, m), 2.19 (1H, m), 2.25 (1H,
3
,
2
5
1
5
d
½
a
ꢂ
þ11.9 (c 1.003, CH
2 2 3
Cl ); H NMR (CDCl , 500 MHz) d 0.58 (3H,
D
s), 0.70 (3H, s), 0.83 (1H, m), 1.00 (3H, d, J¼6.6 Hz), 1.01 (3H, d,
J¼6.7 Hz), 1.06e1.55 (17H, m), 1.65 (1H, ddd, J¼9.8, 9.8, 2.5 Hz), 1.80
(1H, d, J¼14.0 Hz),1.84 (1H, m), 2.00 (1H, m), 2.16 (1H, d, J¼14.2 Hz),
2.20 (2H, m), 2.33 (1H, s), 2.42 (4H, s), 3.43 (1H, t, J¼10.5 Hz), 3.52
(1H, d, J¼11.0 Hz), 3.57 (1H, t, J¼10.3 Hz), 3.75 (1H, d, J¼10.8 Hz),
1
sept. d, J¼6.7, 1.2 Hz), 2.32 (1, m), 2.48 (1H, m), 2.94 (1H, d,
J¼8.8 Hz), 3.23 (1H, d, J¼8.8 Hz), 3.51 (2H, t, J¼12.3 Hz), 4.01 (1H,
dd, J¼12.5, 4 Hz), 4.28 (1, dd, J¼12.5, 4 Hz), 4.47 (1H, d,
J¼12.4 Hz), 4.57 (1H, d, J¼12.4 Hz), 5.25 (1H, s), 5.45 (1H, s),
13
3
3.99 (1H, s), 4.33 (1H, s), 5.35 (1H, s); C NMR (CDCl , 125 MHz)
7.28e7.42 (8H, m), 7.47 (2H, m).
d
16.1, 17.8, 19.2, 19.8, 20.5, 21.1, 24.2, 26.6, 30.5, 33.1, 36.5, 36.6, 38.0,
8.2, 38.4, 38.9, 40.1, 45.6, 48.7, 54.3, 55.1, 57.5, 61.0, 65.5, 69.8,
3
ꢁ1
4.3.3. Compound 4. To a solution of compound 3 (5.5 g, 10 mmol)
125.2,147.7; IR (KBr,
m/z: 444 (MþH ).
n
, cm ): 3325, 2925,1638,1110,1040; MS (ESI)
þ
in 150 mL propanone/water¼4:1 (v:v) was added pyridinum p-
toluenesulfonate (0.6 g, 2 mmol). The reaction mixture was stirred
ꢀ
for 5 h at 65 C. After concentration under reduced pressure, water
4.3.6. Compound 7. To a solution of compound 1 (30 g, 75 mmol)
and K CO (10 g, 72 mol) in 150 mL acetone was added dimethyl
(
30 mL) was added to the residue, and then extracted with
dichloromethane (30 mLꢃ3). The combined organic layer was
dried over Na SO and the dichloromethane was evaporated off.
2
3
sulfate (10.7 g, 85 mol). The reaction mixture was stirred for 6 h at
refluxing temperature. After cooling to room temperature, the so-
lution was filtered through Celite, and concentrated under reduced
pressure. The crude product was recrystallized from acetic acid to
give 7 (26.4 g, 63.7 mmol) as white crystals. Yield 85%, mp
2
4
The crude product was purified by column chromatography (pe-
troleum ether: ethyl acetate¼3:1) to give 4 (2.8 g, 6.1 mmol) as
2
5
1
a colorless oil. Yield 60.6%, ½
a
ꢂ
þ13.7 (c 1.65, CHCl
3
); H NMR
D
ꢀ
ꢀ
14
25
D
1
(
CDCl
J¼6.8 Hz), 1.01 (3H, d, J¼6.8 Hz), 1.07 (1H, m), 1.21e1.52 (10H, m),
.62 (1H, ddd, J¼12.6, 9.8, 2.8 Hz), 1.83 (1H, m), 1.94 (1H, dd, J¼9,
Hz), 2.19e2.22 (2H, m), 2.35 (1H, m), 2.95 (1, d, J¼8.9 Hz), 3.22
1H, d, J¼8.9 Hz), 3.45 (1H, t, J¼10.5 Hz), 3.52 (1H, dd, J¼11.0,
.5 Hz), 3.58 (1H, t, J¼10.5 Hz), 3.77 (1H, dd, J¼10.5, 2.2 Hz), 4.49
1H, d, J¼12.5 Hz), 4.54 (1H, d, J¼12.5 Hz), 5.35 (1H, s), 7.28e7.39
5H, m). 13C NMR (CDCl
, 125 MHz) 16.0, 17.4, 18.2, 19.6, 20.5, 21.1,
0.4, 33.2, 36.1, 36.3, 37.0, 38.0, 38.2, 38.8, 40.0, 45.8, 48.3, 54.1,
3
)
d
0.58 (3H, s), 0.76 (3H, s), 0.85 (1H, m), 0.99 (3H, d,
216e219 C (mp 211e213 C ), ½
a
ꢂ
ꢁ29.8 (c 1.5, CH
2 2
Cl ); H NMR
(CDCl , 500 MHz)
3
d
0.59 (3H, s), 0.94 (1H, m), 0.99 (3H, d, J¼6.7 Hz),
1
2
(
3
1.00 (3H, d, J¼6.8 Hz), 1.16 (3H, s), 1.20e1.28 (2H, m), 1.37e1.55 (7H,
m), 1.65e1.78 (3H, m), 2.26 (1H, sept. d, J¼6.6, 1.3 Hz), 2.51 (1H, dt,
J¼13.9, 3.2 Hz), 2.72 (1H, d, J¼8.7 Hz), 3.09 (1H, dd, J¼8.7, 3.0 Hz),
3.12 (1H, m), 3.68 (3H, s), 5.53 (1H, s).
(
(
3
d
4.3.7. Compound 8. To a solution of compound 7 (4.0 g, 10 mmol)
in 100 mL anhydrous tetrahydrofuran was added NaBH (1.51 g,
4
3

L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
9551
3
7.6 mmol) under ice-bath. Then the reaction solution was stirred
in paraffin oil) in dry THF (75 mL) was slowly added dropwisely
a mixture of 2 or 4 (6 mmol) and pentaethylene glycol ditosylate or
2,3-bis{2-[2-(p-tolylsulfonyl)ethoxy]ethoxy}naphthalene (6 mmol)
for 16 h at refluxing temperature. After cooling to room temper-
ature, 20 mL EtOAc and 40 mL hydrochloric acid solution (1 mol/L)
were added slowly to the solution, respectively, and then extrac-
ted with EtOAc (50 mLꢃ3). The combined organic layer was dried
ꢀ
in dry THF (75 mL) at 45 C. The suspension was stirred for 50 h at
refluxing temperature. After cooling to room temperature, a small
portion of water was add to the mixture in order to deactivate the
excess NaH and the mixture was filtered and concentrated in vacuo.
Water (20 mL) was added to the residue, and then extracted with
dichloromethane (50 mLꢃ3). The combined organic layer was dried
4
over MgSO , filtered through Celite, and concentrated under re-
duced pressure. The crude product was recrystallized from EtOAc/
petroleum ether to give 8 (2.1 g, 5.3 mmol) as white crystals. Yield
ꢀ
ꢀ
15
25
D
5
3.1%, mp 163e165 C (mp 163e164
C
), ½
a
ꢂ
þ33.1 (c 1.50,
1
EtOH); H NMR (CDCl
3
, 500 MHz)
d
0.59 (3H, s), 0.92 (1H, m), 0.99
4
over MgSO and the dichloromethane was removed. The residue
(
1
1
3
3H, d, J¼6.7 Hz), 1.00 (3H, d, J¼6.7 Hz), 1.07e1.15(5H, m),
was purified by chromatography over silica (petroleum ether/ethyl
acetate¼4:1) to give crown ether derivatives.
.35e1.55 (7H, m), 1.62e1.73 (3H, m), 1.84 (1H, dt, J¼9.8, 2.7 Hz),
.98 (1H, m), 2.20 (2H, m), 2.37 (1H, s), 3.43 (1H, t, J¼10.4 Hz),
13
25
.49e3.60 (2H, m), 3.67 (3H, s), 3.71e3.81 (2H, m), 5.33 (1H, s).
, 125 MHz) 15.8, 16.9, 17.2, 20.5, 21.2, 22.3, 30.1, 33.2,
6.1, 36.9, 37.7, 38.2, 38.2, 40.3, 45.8, 47.2, 49.4, 51.9, 54.1, 55.2, 61.1,
C
4.3.11. Compound 9a. Light yellow oil. Yield: 9.3%, ½
a
ꢂ
ꢁ4.4 (c 9.0,
D
1
NMR (CDCl
3
6
MS (APCI) m/z: 405(MþH ).
3
d
2 2 3
CH Cl ); H NMR (CDCl , 500 MHz) d 0.56 (3H, s), 0.70 (3H, s), 0.76
(1H, m), 0.98 (6H, t, J¼6.8 Hz), 1.08 (1H, m), 1.20e1.58 (11H, m), 1.75
(1H, dt, J¼9.3, 2.7 Hz), 1.93 (1H, m), 2.10 (1H, m), 2.18 (1H, sept. d,
J¼6.5, 1.2 Hz), 2.63 (1H, s), 2.93 (1H, t, J¼9.4 Hz), 2.97 (1H, t,
J¼9.6 Hz), 3.07 (1H, d, J¼10.8 Hz), 3.32 (1H, d, J¼10.8 Hz), 3.35e3.65
ꢁ1
5.5, 124.9, 148.1, 179.6; IR (KBr,
n
, cm ): 3224, 2928, 2867, 1719;
þ
13
4
.3.8. Compound Z3. Triglycol dichloride (10.8 g, 57.8 mmol) was
added to a stirred mixture of KOH (7.8 g, 139.3 mmol) in ethylene
glycol (60 mL) at room temperature under N . The reaction mixture
3
(22H, m), 5.31 (1H, s); C NMR (CDCl , 125 MHz) d 15.4, 16.7, 17.1,
18.8,19.6, 20.4, 28.8, 32.6, 34.8, 35.2, 35.5, 36.6, 37.4, 38.2, 39.2, 41.6,
47.6, 50.1, 55.2, 68.9, 69.5, 69.6, 69.9, 69.9, 70.0, 70.1, 70.1, 70.1, 70.2,
2
ꢁ
1
was stirred at refluxing temperature for 36 h. After cooling to room
temperature, the reaction mixture was filtered and concentrated
under reduced pressure to yield a viscous oil.
71.4, 71.2, 71.5, 124.4, 146.9; IR (KBr,
n
, cm ): 3466, 2925, 1643,
þ
1110; MS (APCI) m/z: 535.37 (MþH ). Anal. Calcd for C34
58 7
H O : C,
70.55; H, 10.10. Found: C, 70.70; H, 10.21.
To a stirred solution of the above viscous oil and NaOH (4.8 g,
ꢀ
25
1
20 mmol) in THF/H
2
O (v/v¼1/140 mL) cooled to 0 C under N
2
was
4.3.12. Compound 9b. Colorless oil. Yield: 10.3%, ½
a
ꢂ
ꢁ1.0 (c 0.933,
D
1
slowly added portions of p-toluenesulfonyl chloride (22 g,
15 mmol). After stirring for 3 h, water (100 mL) was added to the
reaction mixture. The product was extracted with CH Cl
20 mLꢃ3) and washed with brine (20 mLꢃ3). The combined or-
ganic layer was dried over MgSO and the CH Cl was evaporated
off. The crude product was purified by column chromatography
petroleum ether: ethyl acetate¼3:1) to give pure product (8.1 g) as
3 3
CHCl ); H NMR (500 MHz, CDCl ) d 0.58 (3H, s), 0.75 (3H, s), 0.83
1
(1H, m), 1.01 (3H, d, J¼6.5 Hz), 1.03 (3H, d, J¼6.5 Hz), 1.13 (1H, m),
1.27e1.43 (8H, m), 1.50e1.58 (3H, m), 1.80 (1H, d.t, J¼9.7, 2.7 Hz),
1.94 (1H, m), 2.15 (1H, m), 2.22 (1H, sept. d, J¼6.5, 1.2 Hz), 2.68 (1H,
s), 2.92 (1H, d, J¼8.9 Hz), 2.95 (1H, t, J¼9.5 Hz), 3.01 (1H, t,
J¼8.9 Hz), 3.19 (1H, d, J¼9.5 Hz), 3.41e3.80 (22H, m), 4.47 (1H, d,
2
2
(
4
2
2
(
J¼12.5 Hz), 4.52 (1H, d, J¼12.5 Hz), 5.35 (1H, s), 7.28e7.38 (5H, m);
1
13
yellow oil. Yield 27.5%, H NMR (CDCl
3
, 500 MHz)
4H, s), 3.59 (2H, s), 3.67 (2H, t, J¼4.8 Hz), 4.14 (2H, t, J¼4.8 Hz), 7.33
2H, d, J¼8.1 Hz), 7.78 (2H, d, J¼8.2 Hz).
d
2.44 (3H, s), 3.57
3
C NMR (125 MHz, CDCl ) d 16.0, 17.4, 18.2, 19.5, 20.3, 21.0, 29.4,
(
(
33.3, 35.8, 36.1, 36.1, 37.0, 38.0, 38.7, 39.8, 42.2, 48.5, 50.7, 55.8, 69.7,
70.2, 70.3, 70.6, 70.7, 70.7, 70.7, 70.8, 70.8, 70.9, 71.1, 71.7, 73.1, 79.9,
25.0, 127.3, 127.3, 127.3, 128.2, 128.2, 139.2, 147.6; IR (KBr, n, cm ):
ꢁ
1
1
4
2
6
.3.9. Compound Z4. Solid 2,3-dihydroxynaphthalene (3.2 g,
0 mmol) was added to a stirred mixture of K CO (8.3 g,
. The
3082, 3062, 3028, 1496, 1455, 1641, 1112; MS (APCI) m/z: 669
þ
2
3
(MþH ). Anal. Calcd for C41
64 7
H O : C, 73.61; H, 9.64. Found: C, 73.77;
0.1 mmol) in dry DMF (20 mL) at room temperature under N
2
H, 10.13.
ꢀ
mixture was stirred at 90 C for 1 h before addition of 2-(2-
chloroethoxy) ethanol (4.3 mL, 43.8 mmol) and KI (6.8 g,
2
5
4.3.13. Compound 9c. Light yellow oil. Yield: 10.6%, ½
a
ꢂ
ꢁ10.2 (c
D
ꢀ
1
4
0.1 mmol). The reaction mixture was stirred at 100 C for 48 h.
3 3
1.65, CHCl ); H NMR (CDCl , 500 MHz) d 0.59 (s, 3H), 0.69 (3H, s),
After cooling to room temperature, the reaction mixture was dis-
solved in CH Cl (100 mL) and filtered to remove potassium salts.
The organics were dried over MgSO and concentrated under re-
0.81 (1H, m), 1.01 (3H, d, J¼6.6 Hz), 1.03 (3H, d, J¼6.5 Hz), 1.09e1.58
(18H, m), 1.75e1.81 (2H, m), 1.94 (1H, m), 2.09e2.16 (2H, m), 2.22
(1H, sept., J¼6.6 Hz), 2.41 (4H, br s), 2.69 (1H, s), 2.92 (1H, t,
J¼9.5 Hz), 2.98 (1H, t, J¼9.5 Hz), 3.37e3.72 (22H, m), 5.34 (1H, s);
2
2
4
duced pressure to yield a viscous red oil.
13
To a stirred solution of the above viscous red oil and Et
3
N (4 mL)
3
C NMR (CDCl , 125 MHz) d 16.2, 17.6, 19.2, 19.8, 20.3, 21.0, 24.2,
ꢀ
in dry CH
2
Cl
2
(20 mL) cooled to 0 C under N
2
was slowly added
26.6, 29.5, 33.3, 35.6, 36.3, 36.5, 38.0, 38.1, 38.4, 38.9, 39.9, 42.1,
48.8, 50.8, 55.8, 57.6, 69.8, 69.8, 69.9, 69.9, 70.0, 70.5, 70.6, 70.7,
portions of p-toluenesulfonyl chloride (5.5 g). After stirring at room
temperature for 24 h, water (20 mL) was added to the reaction
ꢁ
1
71.6, 125.3, 147.7; IR (KBr,
n
, cm ): 2928, 2867, 1642, 1110; MS (ESI)
N: C, 72.52; H, 10.45; N,
þ
mixture. The product was extracted with CH
washed with brine (20 mLꢃ3). The combined organic layer was
dried over MgSO and the CH Cl was evaporated off. The crude
2
Cl
2
(20 mLꢃ3) and
m/z: 646 (MþH ). Anal. Calcd for C39
67 6
H O
2.17. Found: C, 72.33; H, 10.58; N, 2.07.
4
2
2
2
5
product was purified by column chromatography (petroleum ether:
ethyl acetate¼2:1) to give pure product (2.6 g) as a white solid.
4.3.14. Compound 9d. White solid, Yield: 11%, ½
a
ꢂ
ꢁ14.7 (c 1.0,
D
1
2 2 3
CH Cl ); H NMR (CDCl , 500 MHz) d 0.57 (3H, s), 0.72 (3H, s), 0.76
ꢀ
1
Yield 20.3%, mp 93.2e93.6 C; H NMR (500 MHz, CDCl
3
)
d
2.37 (3H,
(1H, m), 0.97 (3H, d, J¼6.7 Hz), 0.98 (3H, d, J¼6.7 Hz), 1.07 (1H, m),
1.20e1.38 (8H, m),1.43e1.55 (3H, m),1.73 (1H, dt),1.94 (1H, m), 2.10
(1H, m), 2.19 (1H, sept. d, J¼6.5, 1.2 Hz), 2.63 (1H, s), 3.01 (1H, t,
J¼9.4 Hz), 3.06 (1H, t, J¼9.4 Hz), 3.09 (1H, d, J¼10.7 Hz), 3.35 (1H, d,
J¼10.7 Hz), 3.39e3.69 (5H, m), 3.70e3.81 (5H, m), 3.90e4.03 (4H,
m), 4.16e4.28 (4H, m), 5.31 (1H, s), 7.09 (1H, s), 7.12 (1H, s), 7.30
s), 3.82 (2H, t, J¼4.8 Hz), 3.87 (2H, t, J¼4.8 Hz), 4.18 (2H, t, J¼4.7 Hz),
4
.22 (2H, t, J¼4.7 Hz), 7.13 (1H, s), 7.26 (2H, d, J¼8.1 Hz), 7.36 (2H,
13
m), 7.68 (2H, m), 7.79 (2H, d, J¼8.2 Hz); C NMR (125 MHz, CDCl
3
)
d
21.5, 68.5, 69.0, 69.5, 69.7, 108.6, 108.6, 124.4, 124.4, 126.4, 126.4,
127.9, 127.9, 129.4, 129.8, 129.8, 133.1, 144.8, 148.9.
13
(
3
2H, m), 7.64 (2H, m); C NMR (CDCl , 125 MHz) d 16.0, 17.3, 17.7,
4
.3.10. General experimental procedure for the preparation of chiral
19.5, 20.2, 21.0, 29.5, 33.3, 35.3, 36.0, 36.1, 36.1, 37.2, 38.0, 38.7, 39.8,
42.4, 48.3, 50.8, 55.7, 68.9, 69.0, 69.7, 70.0, 70.4, 70.5, 70.6, 71.1, 71.7,
crown ethers (9aem). To a suspension of NaH (0.96 g, 24 mmol 60%

9552
L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
þ
7
2.3, 108.2, 109.1, 124.1, 124.2, 125.0, 126.3, 126.3, 129.4, 129.5, 147.5,
MS (APCI) m/z: 535.37 (MþH ). Anal. Calcd for C32
54 6
H O : C, 71.87;
ꢁ1
149.2, 149.4; IR (KBr,
n
, cm ): 3440, 2930, 1601, 1509, 1486, 1451,
H, 10.18. Found: C, 71.79; H, 10.25.
þ
1
628, 1111; MS (APCI) m/z: 677.44 (MþH ). HRMS (ESI) 699.4220
þ
25
[MþNa] , calcd for C42
60
H O
7
Na: 699.4232.
4.3.19. Compound 9i. Light yellow oil. Yield: 36.8%, ½
a
ꢂ
ꢁ8.3 (c
D
1
1
3 3
.65, CHCl ); H NMR (CDCl , 500 MHz) d 0.60 (3H, s), 0.69 (3H, s),
2
5
4
.3.15. Compound 9e. Colorless oil. Yield: 9.3%, ½
a
ꢂ
ꢁ6.1 (c 1.45,
0.79 (1H, m), 1.02 (3H, d, J¼6.6 Hz), 1.04 (3H, d, J¼6.7 Hz), 1.10e1.58
(18H, m), 1.78e1.83 (2H, m), 1.96 (1H, m), 2.14 (2H, m), 2.23 (1H,
sept. d, J¼6.7, 1.3 Hz), 2.41 (4H, br s), 2.73 (1H, s), 2.89 (1H, t,
J¼10.0 Hz), 2.92 (1H, t, J¼10.0 Hz), 3.39e3.99 (18H, m), 5.35 (1H, s);
D
1
CHCl
3 3
); H NMR (500 MHz, CDCl ) d 0.56 (3H, s), 0.73 (3H, s), 0.79
(
1
1
1H, m), 0.97 (3H, d, J¼6.5 Hz), 0.98 (3H, d, J¼6.5 Hz), 1.07 (1H, m),
.21e1.43 (8H, m), 1.46e1.54 (3H, m), 1.75 (1H, dt, J¼9.7, 2.7 Hz),
13
.94 (1H, m), 2.10 (1H, m), 2.19 (1H, sept. d, J¼6.5, 1.2 Hz), 2.64 (1H,
3
C NMR (CDCl , 125 MHz) d 16.2, 17.8, 19.2, 19.8, 20.3, 21.0, 24.2,
s), 2.90 (1H, d, J¼8.9 Hz), 2.98 (1H, t, J¼9.5 Hz), 3.05 (1H, t,
J¼9.5 Hz), 3.14 (1H, d, J¼8.9 Hz), 3.41e3.70 (5H, m), 3.71e3.82 (5H,
m), 3.91e4.04 (4H, m), 4.20e4.29 (4H, m), 4.48 (1H, d, J¼12.5 Hz),
26.6, 29.5, 33.3, 35.4, 36.4, 36.5, 38.1, 38.4, 38.9, 39.8, 41.9, 48.7, 51.0,
55.8, 57.5, 69.7, 69.7, 69.9, 70.1, 70.4, 70.7, 70.8, 71.0, 71.5, 125.1,
ꢁ
1
147.8; IR (KBr,
n
, cm ): 2929, 2867, 1641, 1112; MS (APCI) m/z: 602
þ
4
7
.53 (1H, d, J¼12.5 Hz), 5.31 (1H, s), 7.09 (1H, s), 7.12(1H, s),
(MþH ). Anal. Calcd for C37
63 5
H O
N: C, 73.83; H, 10.55; N, 2.33.
13
.26e7.36 (7H, m), 7.65(2H, m); C NMR (125 MHz, CDCl
3
)
d
16.0,
Found: C, 73.63; H, 10.66; N, 2.20.
1
7.4, 18.2, 19.6, 20.3, 21.0, 29.5, 33.3, 35.9, 36.1, 37.0, 38.0, 38.7, 39.8,
2
5
4
7
1
2.3, 48.5, 50.8, 55.6, 68.9, 69.0, 69.7, 69.8, 70.1, 70.4, 70.5, 70.6, 71.2,
1.7, 73.2, 79.9, 108.0, 109.0, 124.1, 124.2, 125.1, 126.3, 126.4, 127.3,
27.4, 127.5, 128.1, 128.3, 129.3, 129.5, 139.2, 147.5, 149.2, 149.4; IR
4.3.20. Compound 9j. Light yellow oil. Yield: 10.8%, ½
a
ꢂ
ꢁ2.5 (c 0.8,
D
1
2 2 3
CH Cl ); H NMR (CDCl , 500 MHz) d 0.58 (3H, s), 0.90 (1H, m), 1.02
(6H, t, J¼6.3 Hz), 1.08e1.15 (4H, m), 1.31e1.56 (8H, m), 1.61e1.72
(3H, m), 1.82 (1H, dt, J¼9.8, 2.5 Hz), 1.92 (1H, m), 2.14 (1H, m), 2.22
(1H, sept. d, J¼6.7, 1.3 Hz), 2.74 (1H, s), 2.88 (1H, t, J¼9.4 Hz), 2.90
ꢁ1
(
KBr,
n
, cm ): 3081, 3062, 3028, 1602, 1509, 1487, 1453, 1628, 1115;
þ
MS (APCI) m/z: 767 (MþH ). Anal. Calcd for C49
66 7
H O : C, 76.73; H,
1
3
8
.67. Found: C, 76.91; H, 8.64.
(1H, t, J¼9.6 Hz), 3.37e4.06 (21H, m), 5.32 (1H, s); C NMR (CDCl
3
,
1
25 MHz) d 15.8, 16.8, 17.2, 20.2, 21.0, 22.3, 29.1, 33.3, 35.4, 36.0,
ꢀ
25
D
4
.3.16. Compound 9f. Yellow solid, Yield: 9.4%, mp 85e86 C, ½
a
ꢂ
36.8, 37.7, 38.2, 40.1, 42.1, 47.2, 49.4, 50.6, 55.9, 66.0, 69.6, 69.9, 70.1,
70.4, 70.7, 70.8, 71.0, 71.5, 124.66, 147.9, 178.9; IR (KBr,
1
ꢁ1
ꢁ
16.0 (c 1.00, CH
2
Cl
2
); H NMR (CDCl
3
, 500 MHz)
d
0.60 (3H, s),
n
, cm ):
þ
0
.72 (3H, s), 0.81 (1H, m), 1.00 (3H, d, J¼6.7 Hz), 1.01 (3H, d,
2930, 1638, 1116. MS (APCI) m/z: 507 (MþH ). Anal. Calcd for
J¼6.7 Hz), 1.08e1.57 (18H, m), 1.78 (1H, dt, J¼9.3, 2.3 Hz), 1.81 (1H,
m), 1.97 (1H, m), 2.11 (1H, m), 2.18 (1H, m), 2.23 (1H, sept.,
J¼6.7 Hz), 2.44 (4H, s), 2.67 (1H, s), 2.99 (1H, t, J¼9.5 Hz), 3.08 (1H,
t, J¼9.5 Hz), 3.48e3.72 (5H, m), 3.73e3.81 (5H, m), 3.95e4.03 (4H,
m), 4.25e4.28 (4H, m), 5.34 (1H, s), 7.15 (1H, s), 7.12 (1H, s), 7.34
31 54 5
C H O : C, 73.47; H, 10.74. Found: C, 73.31; H, 10.88.
2
5
D
4.3.21. Compound 9k. Colorless oil. Yield: 8.6%, ½
a
ꢂ
ꢁ2.72 (c 6.85,
1
3 3
CHCl ); H NMR (CDCl , 500 MHz) d 0.59 (3H, s), 0.76 (3H, s), 0.84
(1H, m), 1.03 (3H, d, J¼6.4 Hz), 1.06 (3H, d, J¼6.4 Hz), 1.14 (1H, m),
1.27e1.44 (8H, m), 1.48e1.58 (3H, m), 1.82 (1H, dt, J¼9.7, 2.7 Hz),
1.93 (1H, m), 2.11 (1H, m), 2.24 (1H, sept. d, J¼6.5, 1.3 Hz), 2.71 (1H,
s), 2.91e2.96 (3H, m), 3.18 (1H, d, J¼8.9 Hz), 3.37e3.80 (14H, m),
(
2H, m), 7.67 (2H, m); 13C NMR (CDCl
3
, 125 MHz)
d 16.2, 17.6, 19.2,
1
3
7
9.8, 20.3, 21.0, 24.3, 26.7, 29.7, 33.3, 35.9, 36.3, 36.5, 38.1, 38.4,
8.9, 39.9, 42.2, 48.8, 51.0, 55.7, 57.6, 68.9, 69.1, 69.7, 69.8, 69.8,
0.1, 70.4, 70.6, 71.2, 71.6, 108.1, 109.1, 124.1, 124.2, 125.2, 126.3,
4.49 (1H, d, J¼12.5 Hz), 4.52 (1H, d, J¼12.5 Hz), 5.35 (1H, s),
ꢁ
1
13
126.3, 129.3, 129.5, 147.5, 149.2, 149.4; IR (KBr,
n
, cm ): 3056,
7.29e7.38 (5H, m); C NMR (CDCl
3
, 125 MHz)
d
16.0, 17.4, 18.1, 19.6,
þ
1
600, 1511, 1489, 1456, 1627, 1110; MS (APCI) m/z: 744 (MþH ).
20.3, 21.0, 29.4, 33.4, 35.7, 36.1, 36.2, 37.0, 38.1, 38.7, 39.8, 42.4, 48.5,
51.1, 55.9, 69.1, 69.5, 69.6, 70.0, 70.2, 70.3, 71.3, 72.5, 73.2, 79.9,
, cm ): 3081, 3062, 3027,
496, 1454, 1638, 112; MS (FAB) m/z: 603 (MþNa ). Anal. Calcd for
69 6
Anal. Calcd for C47H O N: C, 75.87; H, 9.35; N, 1.88. Found: C,
ꢁ1
7
5.68; H, 9.43; N, 1.79.
124.9, 127.3, 128.2, 139.1, 147.9; IR (KBr,
n
þ
1
2
5
4.3.17. Compound 9g. White solid, Yield: 9.5%, ½
a
ꢂ
ꢁ17.5 (c 1.0,
C H
37 56
O
5
: C, 76.51; H, 9.72. Found: C,76.63; H, 9.83.
D
1
CH
3H, d, J¼6.5 Hz), 0.98 (3H, d, J¼6.5 Hz), 1.09 (1H, m), 1.13 (3H, s),
.21e1.43 (8H, m), 1.46e1.54 (3H, m), 1.75 (1H, dt, J¼9.6, 2.9 Hz),
.92 (1H, m), 2.10 (1H, m), 2.19 (1H, sept. d, J¼6.5, 1.2 Hz), 2.65 (1H,
s), 3.00 (1H, t, J¼9.5 Hz), 3.05 (1H, t, J¼9.3 Hz), 3.39e3.70 (8H, m),
.71e3.82 (5H, m), 3.91e4.04 (4H, m), 4.20e4.29 (4H, m), 5.30 (1H,
2 2 3
Cl ); H NMR (CDCl , 500 MHz) d 0.56 (3H, s), 0.87 (1H, m), 0.97
2
5
(
1
1
4.3.22. Compound 9l. Light yellow oil. Yield: 15.3%, ½
a
ꢂ
ꢁ13.1 (c
D
1
3 3
1.65, CHCl ); H NMR (CDCl , 500 MHz) d 0.60 (3H, s), 0.70 (3H, s),
0.82 (1H, m), 1.04 (3H, d, J¼6.5 Hz), 1.05 (3H, d, J¼6.4 Hz), 1.09e1.59
(18H, m), 1.81 (1H, dt, J¼9.7, 2.7 Hz), 1.95 (1H, m), 2.05e2.12 (2H,
m), 2.17 (1H, d, J¼14.1 Hz), 2.24 (1H, sept. d, J¼6.5, 1.3 Hz3), 2.43
(4H, br s), 2.71 (1H, s), 2.88e2.94 (2H, m), 3.36e4.33 (14H, m), 5.35
(1H, s); C NMR (CDCl , 125 MHz) d 16.1, 17.3, 18.9, 19.9, 20.3, 21.0,
3
24.5, 26.4, 29.7, 33.4, 35.7, 36.2, 36.3, 38.1, 38.3, 38.4, 39.8, 42.3,
49.4, 51.1, 55.8, 57.1, 69.1, 69.5, 69.6, 70.0, 70.2, 70.3, 71.3, 72.5, 125.1,
3
13
s), 7.09 (1H, s), 7.13 (1H, s), 7.32 (2H, m), 7.65 (2H, m); C NMR
CDCl , 125 MHz) 15.8, 16.8, 17.2, 20.2, 21.0, 22.3, 29.2, 33.3, 35.9,
6.0, 36.9, 37.7, 38.2, 40.1, 42.5, 47.3, 49.5, 50.7, 51.9, 55.9, 69.0, 69.1,
9.7, 69.8, 70.1, 70.5, 70.5, 70.6, 71.2, 71.7, 108.2, 109.1, 124.2, 124.3,
24.9, 126.3, 126.4, 129.4, 129.6, 147.6, 149.2, 149.4, 179.6; IR (KBr,
13
(
3
6
3
d
ꢁ
1
1
n
,
147.8; IR (KBr,
n
, cm ): 2928, 2866, 1641, 1122; MS (ESI) m/z: 658
ꢁ
1
þ
cm ): 2926, 1602, 1508, 1486, 1451, 1723, 1629, 1116; MS (APCI) m/
(MþH ). Anal. Calcd for C35
59 4
H O
N: C, 75.36; H, 10.66; N, 2.51.
þ
z: 705.33 (MþH ). Anal. Calcd for C43
60
H O
8
: C, 73.26; H, 8.58.
Found: C, 75.23; H, 10.79; N, 2.37.
Found: C, 73.19; H, 8.66.
2
D
5
4
.3.23. Compound 9m. Colorless oil. Yield: 10.7%, ½
a
ꢂ
ꢁ6.78 (c
2
5
1
4.3.18. Compound 9h. Light yellow oil. Yield: 11.2%, ½
3
0
a
ꢂ
ꢁ3.0 (c
9.73, CHCl ); H NMR (CDCl , 500 MHz) d 0.60 (3H, s), 0.77 (3H, s),
3 3
D
1
.98, CH
2
Cl
2
); H NMR (CDCl
3
, 500 MHz)
d
0.60 (3H, s), 0.74 (3H, s),
0.85 (1H, m), 1.03 (3H, d, J¼6.8 Hz), 1.06 (3H, d, J¼6.8 Hz), 1.13 (1H,
m),1.28e1.45 (8H, m), 1.50e1.60 (3H, m),1.79 (1H, dt, J¼9.7, 2.8 Hz),
1.95 (1H, m), 2.14 (1H, m), 2.24 (1H, sept. d, J¼6.7, 1.3 Hz), 2.68 (1H,
s), 2.95 (1H, d, J¼8.9 Hz), 2.99 (1H, t, J¼9.5 Hz), 3.04 (1H, t,
J¼9.5 Hz), 3.20 (1H, d, J¼8.9 Hz), 3.38e3.79 (14H, m), 4.49 (1H, d,
J¼12.5 Hz), 4.53 (1H, d, J¼12.5 Hz), 5.35 (1H, s), 7.29e7.38 (5H, m);
.80 (1H, m), 1.01 (3H, d, J¼6.5 Hz), 1.03 (3H, d, J¼6.5 Hz), 1.10 (1H,
m),1.23e1.40 (8H, m),1.48e1.58 (3H, m),1.81 (1H, dt, J¼9.8, 2.4 Hz),
.96 (1H, m), 2.13 (1H, m), 2.23 (1H, sept. d, J¼6.7, 1.3 Hz), 2.71 (s,
H), 2.92 (2H, t, J¼9.7 Hz), 3.09 (1H, d, J¼10.8 Hz), 3.35 (1H, d,
1
1
13
J¼10.8 Hz), 3.37e3.73 (18H, m), 5.34 (1H, s); C NMR (CDCl
3
,
13
1
3
7
25 MHz)
d
15.3, 16.7, 17.1, 18.8, 19.6, 20.4, 28.8, 32.6, 34.7, 34.8, 35.5,
3
C NMR (CDCl , 125 MHz) d 16.0, 17.4, 18.2, 19.6, 20.3, 21.0, 29.5,
6.5, 37.3, 38.1, 39.1, 41.4, 47.5, 50., 55.2, 68.9, 69.1, 69.4, 69.7, 69.9,
33.3, 35.9, 36.1, 36.2, 37.1, 38.1, 38.7, 39.9, 42.4, 48.6, 50.7, 55.8, 69.7,
70.1, 70.2, 70.6, 70.7, 70.8, 71.8, 73.2, 80.0, 125.1, 127.3, 128.2, 139.2,
ꢁ1
0.0, 70.4, 70.7, 71.2, 124.2; IR (KBr, n, cm ): 3443, 2925,1636,1113;

L.-zhi Liu et al. / Tetrahedron 70 (2014) 9545e9553
9553
ꢁ
1
(
9
47.4; IR (KBr,
n
, cm 1): 3082, 3063, 3027,1496,1454,1641,1108; MS
Hosgoren, H. J. Incl. Phenom. Macro. 2006, 54, 29e33; (c) Tan, G. H.; Xue, J. Y.;
Hyun, M. H. J. Sep. Sci. 2006, 29, 1407e1411; (d) Xia, Y. X.; Zhou, H. H.; Shi, J.; Li,
S. Z.; Zhang, M.; Luo, J.; Xiang, G. Y. J. Incl. Phenom. Macro. 2012, 74, 277e284;
þ
FAB) m/z: 1183 (MþNa ). Anal. Calcd for C80
112
H O10: C, 77.88; H,
.15. Found: C, 77.67; H, 9.28.
(
e) Nagata, H.; Nishi, H.; Kamigauchi, M.; Ishida, T. Chem. Pharm. Bull. 2006, 54,
52e457; (f) Tang, M. L.; Zhang, J.; Zhuang, S. L.; Liu, W. P. TrAC, Trends Anal.
Chem. 2012, 39, 180e194; (g) Lovely, A. E.; Wenzel, T. J. Chirality 2008, 20,
70e378; (h) Lovely, A. E.; Wenzel, T. J. Org. Lett. 2006, 8, 2823e2826; (i) Lovely,
4
Acknowledgements
3
A. E.; Wenzel, T. J. J. Organomet. Chem. 2006, 71, 9178e9182.
This study was supported by the National Natural Science
Foundation of China (No. 81260472, 21362002, 21431001), Guangxi
Natural Science Foundation of China (No. 2013GXNSFBA019033,
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2
011GXNSFD018010, 2014GXNSFDA118007), Bagui Scholar project
114, 1511e1512.
and the Foundation of Ministry of Education Innovation Team (No.
IRT1225). We thank Prof. Jian-yi Wang from School of Chemistry
and Chemical Engineering, Guangxi University, for his kind help on
the calculation of optimized molecular structures and the com-
plexes model.
6
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Supplementary data
A. G. Chirality 2004, 16, S40eS50.
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2
006, 27, 3428e3433; (b) Wang, H. S.; Zhao, S. L.; He, M.; Zhao, Z. C.; Pan, Y. M.;
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Supplementary data available: copies of H NMR and 13C NMR
spectra. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.10.050.
1
2
1
0. Ye, F.; Wang, H. S.; Huang, B.; Zhao, S. L. Electrophoresis 2010, 31, 1488e1492.
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