Hydrogen-bonding-mediated dynamic covalent synthesis of macrocycles and capsules: New receptors for aliphatic ammonium ions and the formation of pseudo[3]rotaxanes

Article abstract of DOI:10.1002/chem.200900309

This paper describes a novel, highly efficient approach to the self-assembly of monomacrocycles and two-layered capsules by using dynamic covalent chemistry. Intramolecular hydrogen-bonding was used to preorganize aromatic amide-based monomers that contai

Full text of DOI:10.1002/chem.200900309

FULL PAPER
DOI: 10.1002/chem.200900309
Hydrogen-Bonding-Mediated Dynamic Covalent Synthesis of Macrocycles
and Capsules: New Receptors for Aliphatic Ammonium Ions and the
Formation of Pseudo[3]rotaxanes
Xiao-Na Xu, Lu Wang, Gui-Tao Wang, Jian-Bin Lin, Guang-Yu Li, Xi-Kui Jiang, and
Zhan-Ting Li*[a]
Abstract: This paper describes a novel,
highly efficient approach to the self-as-
sembly of monomacrocycles and two-
layered capsules by using dynamic co-
valent chemistry. Intramolecular hydro-
gen-bonding was used to preorganize
aromatic amide-based monomers that
contain aldehyde and tert-butoxycarbo-
nylamino units. As a result, in the pres-
ence of an excess of trifluoroacetic acid
(TFA), four monomers could self-
couple to produce macrocycles selec-
tively through the formation of three
imine or hydrazone bonds. Three dipo-
dal precursors were also prepared by
connecting two hydrogen-bonded seg-
ments with a flexible linker. In the
presence of TFA, these precursors
could also self-couple, leading to the
exclusive formation of two-layered cap-
sules. As a result of intramolecular hy-
drogen-bonding, all the macrocycles
and capsules were stable in solution
and could be purified by simple recrys-
tallization. The new capsules were able
to form complexes with linear propyle-
nediammonium derivatives to give
unique two-layered pseudo[3]rotax-
anes.
Keywords:
covalent chemistry · foldamers ·
hydrogen bonds macrocycles
molecular recognition
capsules
·
dynamic
·
·
Introduction
demonstrates the highly efficient covalent synthesis of a new
class of three-dimensional capsules by using dynamic cova-
lent chemistry (DCC).[5]
The formation of three-dimensional structures of natural
peptides and proteins heavily relies on the balance of the
domains of their secondary structures and flexible seg-
ments.[1] This enables them to adjust the active sites to real-
ize sophisticated functions such as ligand-binding, catalysis,
and ion transportation. To mimic natural secondary struc-
tures, chemists have constructed foldamers,[2,3] synthetic olig-
omers that adopt discrete compact conformation as a result
of noncovalent forces. More recently, hydrogen-bonding-
mediated folded segments have been utilized to promote
the formation of macrocycles of aryl amides.[4] This paper
In the past two decades, spherical architectures of defined
shape and size have received much attention due to their
applications as nanoreactors and molecular sensors and re-
ceptors. The studies of Cram[6] and Sherman[7] and their co-
workers focused on covalently linked rigid carcerands. Ad-
vances in self-assembly involving hydrogen-bonding, transi-
tion-metal coordination, and hydrophobic and electrostatic
interactions have allowed the construction of nanometer-
sized capsules with remarkably high efficiency.[8–11] Recently,
Warmuth and co-workers utilized DCC to construct several
single molecular capsules from preorganized calix[4]arene
monomers.[12] Herein we show how folded segments can be
used to modulate dynamic covalent synthesis.[13] By using
hydrogen-bonding to preorganize simple linear aryl amide
precursors we have been able to quantitatively construct
two-layered capsules. These capsules form complexes with
aliphatic diammonium ions, leading to the formation of
unique two-layered pseudo[3]rotaxanes.
[a] X.-N. Xu, L. Wang, G.-T. Wang, J.-B. Lin, Dr. G.-Y. Li,
Prof. Dr. X.-K. Jiang, Prof. Dr. Z.-T. Li
State Key Laboratory of Bio-Organic and
Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax : (+86)21-6416 6128
E-mail: ztli@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900309.
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Results and Discussion
afford 2a–c in yields of 52–60%. Then compound 3[15a] was
treated with N-bromosuccinimide to give the corresponding
dibromomethyl derivative, which was further treated with
hexamethyleneimine to give 4 in a yield of 30% (two steps).
The aldehyde was then hydrolyzed with sodium hydroxide
to acid 5 in a yield of 77%. Finally, 5 was condensed with
In recent years DCC has been successfully utilized to pre-
pare a number of imine-based macrocyclic systems.[14] We
previously demonstrated that hydrogen-bonded foldamers
of aryl amides are versatile frameworks for developing pre-
organized supramolecular synthons.[15] More recently we
found that they are particularly useful for the controlled for-
mation of planar bi- or trimacrocyclic architectures by
DCC.[16] We were therefore interested in assembling three-
dimensional structures from simple hydrogen-bonding-medi-
ated segments by using DCC. In the first step we prepared
compounds 6a–c to test their capacity for forming monoma-
crocycles (Scheme 1). The amino groups of 6a–c were pro-
1
2a–c to afford 6a–c in yields of 77–98%. The H NMR spec-
tra of 6a–c in CDCl3 exhibited signals corresponding to
their amide hydrogen atoms in the downfield region (9.96–
9.98 ppm), and these were concentration-independent. This
indicates that the amide hydrogen atoms are strongly hydro-
gen-bonded to the neighboring ether oxygen atoms.[2c–e] Sol-
utions of 6a–c in chloroform (50 mm) were stirred in the
presence of an excess of TFA, which led to the formation of
the corresponding macrocycles 7a–c in very high yields
(Scheme 1). All the macrocycles were stable and the purifi-
cations thus simple. After the reactions had reached equilib-
rium, the solutions were neutralized, dried, and concentrat-
ed, and the pure products could be obtained by recrystalliz-
ing the crude samples from methanol and ethyl acetate. The
reaction progress of 6c was also tracked in CDCl3 by
1H NMR spectroscopy (Figure 1). As expected, the reaction
Figure 1. Partial 1H NMR spectra of a) 6c, b) 6c+TFA (0.25 h), c) 6c+
TFA (1 h), d) 6c+TFA (4 h), e) 6c+TFA (10 h), f) 7c+TFA (10 h), and
g) 7c in CDCl3 ([6c]=5 mm, [7c]=1.7 mm, [TFA]=20 mm).
Scheme 1. Reagents and conditions: a) (Boc)2O, NEt3, THF, RT, 15 h;
b) i. NBS, (PhCO)2O, CCl4, reflux, 10 h; ii. (CH2)6N4, AcOH, 608C, 5 h,
30% (two steps); c) NaOH, MeOH/H2O, RT, 5 h, 77%; d) 2a–c,
ClCO2iBu, CHCl3, NEt3, RT, 24 h, 77–98%; e) TFA (20 equiv), CHCl3,
RT, 12 h.
first gave rise to discrete species, as indicated by the pres-
ence of complicated signals in the spectra. After approxi-
mately 10 h the spectrum had evolved into only one set of
signals (Figure 1b–f), which could be assigned to 7c by com-
parison of the spectrum of the pure sample recorded under
identical conditions. This result shows that initially the reac-
tion proceeded under dynamic control and then changed to
a thermodynamically controlled reaction owing to the rever-
sibility of the imine bond. Macrocycle 7c was more soluble
than 7a and 7b due to the presence of the longer octyl
tected with a tert-butoxycarbonyl (Boc) group to avoid the
formation of imine bonds prior to the ring-closing process. It
was envisioned that intramolecular three-centered hydro-
gen-bonding would induce the reaction sites,[2c–e] that is, the
aldehyde and amino units, to orientate at around 608, an
angle that is ideal for the formation of macrocyclic architec-
tures from three identical segments.[14g]
To prepare compounds 6a–c (Scheme 1), diamines 1a–c[4a]
were first treated with di(tert-butyl) dicarbonate in THF to
1
chains. The H NMR spectra of 7a–c in CDCl3 at room tem-
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Chem. Eur. J. 2009, 15, 5763 – 5774

Dynamic Covalent Synthesis of Macrocycles and Capsules
FULL PAPER
perature all exhibited a set of sharp signals, which indicates
that their imine units did not undergo configurational iso-
merization (Figure 1g). 2D NOESY 1H NMR experiments
showed that their imine carbon atoms were directed away
from the neighboring alkoxy group (cf. Scheme 2 below).
To extend the scope of the DCC approach, compound 14
was also prepared (Scheme 2) to construct a large macrocy-
troscopy, which revealed that the original complicated signal
patterns gradually evolved, after the reaction had reached
equilibrium within 8 h, into one set of signals for 15, as ob-
served for 7a–c. The solubility of the neutral sample of 15 in
chloroform was low, but good in a mixture of chloroform
and DMSO. Therefore, a 2D NOESY experiment was per-
formed for 15 in binary CDCl3 and [D6]DMSO (4:1), which
revealed a NOE contact between the Ha and Hb signals
(Scheme 2). This observation verifies that the imine hydro-
gen atoms are directed outwards and that all six carbonyl
groups are orientated inwards.
Encouraged by the above results, we then prepared dipo-
dal 19a to test if a three-dimensional structure could be con-
structed (Scheme 3). Three octyl units were introduced,
which were expected to render the target molecule soluble.
The two preorganized segments were linked with a flexible
chain, which we envisioned would enable the formation of
two macrocyclic units without weakening the intramolecular
three-center hydrogen-bonding. Compound 17 was first ob-
tained from the reaction of compounds 8 and 16 and then
Scheme 2. Reagents and conditions: a) nC8H17Br, K2CO3, KI, DMF, 14 h,
73%; b) LiOH, MeOH/H2O, RT, 4 h, 95%; c) NH2NHBoc, DCC,
DMAP, THF, RT, 12 h, 91%; d) H2, Pd/C, MeOH/THF, 8 h, 100%; e) 10,
ClCO2iBu, NEt3, CHCl3, 48 h, 63%; f) TFA, CHCl3, RT, 8 h, 95%.
cle through the formation of three hydrazone bonds. Several
peptides and U-shaped aryl amide derivatives bearing alde-
hyde and acyl hydrazide units have been reported to selec-
tively generate macrocycles or [2]catenanes.[16,17] To prepare
14, phenol 8[18] was first octylated to give intermediate 9,
which was hydrolyzed with lithium hydroxide to afford the
acid 10. With this acid available, compound 12 was prepared
in a yield of 91% from the coupling reaction of 11[19] and
NH2NHBoc in the presence of N,N-dicyclohexylcarbodi-
imide (DCC) and then hydrogenated to 13 quantitatively.
The aniline was then coupled with compound 10 to give 14
in a yield of 63%. In the presence of an excess of TFA, the
Boc group of 14 was removed quickly and the resulting in-
termediate self-coupled to give macrocycle 15 selectively.
Scheme 3. Reagents and conditions: a) 8, K2CO3, KI, DMF, 1058C, 18 h,
62%; b) NaOH, H2O/MeOH, reflux, 12 h, 88%; c) 2c, ClCO2iBu, NEt3,
CHCl3, RT, 24 h, 71%; d) TFA, CHCl3, RT, 14 h, 95%.
1
The reaction was also tracked in CDCl3 by H NMR spec-
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5765

Z.-T. Li et al.
hydrolyzed with sodium hydroxide to 18. The diacid was
then condensed with 2c to afford 19a. A solution of 19a in
chloroform was stirred in the presence of TFA (40 equiv) to
give the two-layered compound 20a exclusively. The time-
dependent 1H NMR spectra in CDCl3 indicated that this
conversion was also thermodynamically controlled and
nearly quantitative (Figure 2). The reaction reached equilib-
Figure 2. Partial 1H NMR spectra of a) 19a (5 mm), b) 19a (5 mm)
+
TFA (1 h), c) 19a (5 mm) + TFA (1.5 h), d) 19a (5 mm) + TFA (2 h),
e) 20a (1.7 mm) + TFA (2 h), and f) 20a (1.7 mm) in CDCl3 ([TFA]=
0.20m).
rium within 2 h, which was notably shorter than that needed
for 6a–c. Considering that the reaction involved the one-
step formation of six C=N bonds and that the water formed
was not removed from the solution, this result was impres-
sive and indicated that 20a is much more stable than any
other possible products. Capsule 20a was comprehensively
characterized by 1H and 13C NMR spectroscopy, (HR)MS
spectrometry, and elemental analysis. Its amide hydrogen
signals appeared at 9.91 ppm, which suggests that they main-
tained the intramolecular three-center hydrogen-bonding.
Scheme 4. Reagents and conditions: a) 8, K2CO3, KI, DMF, 1058C, 24 h,
84%; b) LiOH, THF/MeOH/H2O, RT, 20 h, 86 %; c) 2c, ClCO2iBu, NEt3,
CHCl3, RT, 24 h, 63%; d) TFA, CHCl3, RT, 12 h, 95%.
1
2D NOESY H NMR experiment in CDCl3 revealed NOE
10.01 ppm, which indicates that they are also involved in in-
tramolecular three-centered hydrogen-bonding.
contacts between Ha and Hb and Hd, but no NOE contact
between Ha and Hc (Scheme 3). This result verifies that its
imine hydrogen atoms are orientated inwards. Reducing the
concentration of 20a in CDCl3 to 0.5 mm did not lead to the
In principle, the two cyclophane moieties of the above
capsules might adopt two different orientations, that is, par-
allel or opposite arrangements. Their 1H NMR spectra
showed that only one isomer was formed, but did not differ-
entiate between them. To address this issue, we also pre-
pared dipodal 19c, which possesses a 3,3-dimethylpentylene
linker and four tri(ethylene glycol) chains. This new chain
was designed not only to render the corresponding capsule
soluble, but also to avoid any possible signal overlap with
signals of the methyl units on the linkers in the upfield area
1
appearance of new signals in the H NMR spectrum, which
indicates that the capsule is quite stable and does not
change to other species, even in dilute solution.
We then prepared dipodal 19b, which possesses a rigid p-
xylenene linker, to investigate its capacity for generating the
three-dimensional architecture. The synthesis is shown in
Scheme 4. Compound 22 was first prepared from the reac-
tion of 8 and 21 in a yield of 84% and then hydrolyzed with
lithium hydroxide to 23 in a yield of 86%. The diacid was
then coupled with 2c to give 19b in a yield of 63%. Treat-
ment of 19b with an excess of TFA in chloroform produced
capsule 20b also exclusively (>95% yield). Similar to that
1
1
of the H NMR spectrum. It was expected that the H NMR
spectrum of the parallel-arranged isomer would exhibit two
discrete singlets for the hydrogen atoms of the two methyl
units on the linker, whereas the corresponding atoms of the
opposite-arranged isomer would give rise to one singlet. The
synthetic route to 19c is shown in Scheme 5. Compound
24[20] was first treated with 2-[2-(2-methoxyethoxy)ethoxy]e-
1
of 20a, its H NMR spectrum in CDCl3 also displayed a set
of sharp signals. The amide hydrogen signals appeared at
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Dynamic Covalent Synthesis of Macrocycles and Capsules
FULL PAPER
thanol in DMF to give 25 in a yield of 85%. This intermedi-
ate was then hydrogenated to give 26 quantitatively and this
diamine was then treated with di(tert-butyl) dicarbonate to
afford 27 in a yield of 63%. With this intermediate avail-
able, 8 was treated with ditosylate 28[21] in DMF to produce
diester 29 in a yield of 74%. Diacid 30 was then prepared
by hydrolyzing 29 and then coupled with 27 to afford com-
pound 19c. The TFA-catalyzed reaction of 19c was then
performed in chloroform to afford an oily product that
formed only one spot on TLC plates. The 1H NMR spec-
trum of the product in CDCl3 showed that capsule 20c was
formed as the major product, but some minor byproducts
were also generated (see the Supporting Information),
which could not be removed by low-temperature recrystalli-
1
zation, as shown by H NMR spectroscopy.[22] However, the
signals of 20c in the upfield area could be assigned on the
1
1
basis of the 2D NOESY H NMR spectrum. The H NMR
spectrum exhibited only one strong singlet at 1.13 ppm for
the hydrogen atoms of the methyl units on the linker, which
shows that the two cyclophane moieties are arranged oppo-
sitely.
The C=O oxygen atoms of 7a–c and 20a–c are all direct-
ed inwards. Several hydrogen-bonding-mediated aryl amide
based foldamers and macrocycles have already been shown
to bind aliphatic ammonium or guanidinium cations through
[23,24]
À
intermolecular C=O···H N hydrogen-bonding.
There-
fore we investigated the binding ability of 7c, 20a, and 20b
towards 31a–e. Compounds 31c–e were prepared in high
yields from the reactions of aldehydes 32–35[25–27] with 33,
followed by reduction of the corresponding diimine inter-
mediates with sodium borohydride, and acidification of the
resulting diamines. Mixing 7c or 20a with 31a–c (1:1, 3 mm)
in CDCl3 caused a notable shift of their signals in the
1H NMR spectra.[28] For example, the signals of the ammoni-
um hydrogen atoms of 31a and 31b were shifted upfield by
0.02 and 0.03 ppm in the presence of 1 equiv of 7c. Upon
mixing 20b with 31c, the signals of the inward-directed Hb,
Hd, and Hg of 20b were shifted upfield by 0.03, 0.02, and
0.01 ppm, respectively, whereas those of Ha–Hd of 31c were
shifted by À0.14, À0.07, 0.12, and 0.04 ppm, respectively
(see the structures for numbering). In contrast, the outward-
directed hydrogen atoms of 20b did not exhibit any observa-
1
ble shifting of their signals. A H NMR DOSY experiment
was also performed for the solution of 20b and 31c (1:1,
[4d,29]
3 mm) in CDCl3
and revealed that the diffusion coeffi-
cients obtained from all the assignable signals of both mole-
cules were significantly lower (see the Supporting Informa-
tion for detailed results). All these results indicate that the
ammonium guests bind to the mono- and two-layered mac-
rocycles in the cavity.
Scheme 5. Reagents and conditions: a) MeACHTNURTGNEUNG(OCH2CH2)3OH, K2CO3,
DMF, RT, 11 h, 85%; b) H2 (50 atm), Pd/C, THF, RT, 7 h, 100%;
c) (Boc)2O, NEt3, THF, RT, 14 h, 63%; d) 8, K2CO3, DMF, 608C, 40 h,
74%; e) NaOH, THF/MeOH/H2O, reflux, 4 h, 76%; f) 27, ClCO2iBu,
NEt3, CHCl3, RT, 24 h, 71%; g) TFA, CHCl3, RT, 35 h, 82%.
The fluorescence of 7c, 20a, and 20b was notably en-
hanced in the presence of the ammonium guests. Therefore
quantitative fluorescent titrations were performed in chloro-
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Z.-T. Li et al.
form (see the Supporting Information) and the Benesi–Hil-
debrand[30] equation was applied to the resulting data. The
threaded through the two cyclophane units of the capsule,
as shown in Figure 3a. On the basis that the complex of 20a
and 31d is more stable, it would be reasonable to propose
that a similar structure is also formed for 20a·31d (Fig-
ure 3b). However, its decomposition should be much quick-
association constants (Kassoc) of the complexes 7c·31a,
7c·31b, 20a·31c, 20a·31d, 20b·31c, and 20b·31d were thus
determined to be 540, 240, 630, 590, 1500, and 970mÀ1, re-
spectively.
ESI mass spectrometry was also used to investigate the
binding patterns of the new complexes. Because 31b pos-
sesses a larger steric hindrance and less hydrogen atoms are
involved in the intermolecular hydrogen-bonding than 31a,
7c·31b is less stable than 7c·31a. However, the ESI mass
spectrum of a 1:1 mixture of 7c and 31b showed the ion
peak of complex 7c·31b to be the base peak ([MÀCl]+:
m/z=1894.1). In contrast, a 1:1 mixture of 7c and 31a only
exhibited a weak ion peak for complex 7c·31a ([MÀCl]+:
m/z= 1837.6; see the Supporting Information). These re-
sults suggest for 7c·31b that the two n-octyl chains of 31b
are not simply located on the same side of 7c. Instead the
molecule is threaded through the cavity of 7c to form a
pseudo[2]rotaxane, which would take longer to decompose.
ESI and MALDI-TOF experiments were also performed
on mixtures of 20a and 20b with 31a–d. These experiments
failed to produce the ion peaks of the corresponding com-
plexes. To gain an insight into the binding patterns of the
capsular molecules with the linear guests we prepared 31e
(Scheme 6), which bears two large 3,5-di(tert-butyl)phenyl
units. It was expected that if its linear propylenediammoni-
um segment was threaded through the two cyclophane units
of the capsules, the dethreading process would take even
longer. In fact this was the case. The MALDI-TOF mass
spectrum of a 1:1 mixture of 20a and 31e displayed a very
strong ion peak (base peak) for the complex 20a·31e
([MÀ2Cl]+: m/z=3660.2). In contrast, the MALDI-TOF
mass spectrum of a 2:1 mixture of 7c and 31e only exhibited
a very weak ion peak for the complex 7c·31e ([MÀCl]+:
m/z=2131.3; see the Supporting Information). These results
strongly suggest that the complex 20a·31e possesses the
structure of a pseudo[3]rotaxanes with the linear guest
Figure 3. The pseudo[3]rotaxane structures of the complexes formed be-
tween two-layered capsule 20a and a) 31e and b) 31d. The former com-
plex is less stable but takes longer to decompose.
er due to the lack of the large stoppers. Further evidence for
the threaded structure comes from 2D NOESY 1H NMR ex-
periments. The 1:1 solution of 20a and 31e (3 mm) in CDCl3
revealed intermolecular NOE contacts between Ha and Hb
of 20a and Ha of 31e (see the structure for labeling and also
the Supporting Information). Similar contacts were not ob-
served with the 1:1 solution of 7c and 31e. This can be ex-
plained by considering the above differences in the deth-
1
reading process. The resolution of the H NMR spectrum of
the above 1:1 solution of 20a and 31e was reduced signifi-
cantly relative to that of the solution of 20a or 31e alone at
the same concentration, but no signal splitting was observed
for either of them, even at a lower temperature (RT to
08C),[31] which implies that exchange between the threading
and dethreading states occurs on the 1H NMR timescale.
Conclusions
We have demonstrated that intramolecular hydrogen-bond-
ing can be used to preorganize rationally designed molecu-
lar monomers to direct the formation of two- and three-di-
mensional architectures by using dynamic covalent chemis-
try. The fact that stable molecular capsules have been as-
sembled in very high yields through the one-step formation
of six imine bonds illustrates the robust capacity of this new
DCC approach. One notable implication of this study is that
partially ordered segments can be used to efficiently assem-
ble three-dimensional systems. The formation of new unique
two-layered pseudo[3]rotaxanes from the capsule and ali-
phatic ammonium ions bodes well for the design of new
three-dimensional architectures for molecular encapsulation
or catalysis. Currently, we are trying to modify the preorgan-
Scheme 6. Reagents and conditions: a) i. toluene, reflux, 4 h; ii. NaBH4,
MeOH/THF, RT, 12 h; iii. CF3SO3H, MeOH, 86% (three steps); b) i. 33,
toluene, reflux, 5 h; ii. NaBH4, MeOH/THF, RT, 12 h; iii. HCl, MeOH,
94% (three steps); c) i. 33, toluene, reflux, 6 h; ii. NaBH4, MeOH/THF,
RT, 9 h, 94% (two steps); d) HCl, MeOH, 93%.
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Dynamic Covalent Synthesis of Macrocycles and Capsules
FULL PAPER
7.21 (d, J=8.7 Hz, 1H), 4.35 (t, J=6.5 Hz, 2H), 1.95–1.93 (m, 2H), 1.58–
1.55 (m, 2H), 1.03 ppm (t, J=7.2 Hz, 3H); MS (ESI): m/z: 221.0
[MÀH]À; elemental analysis calcd (%) for C12H14O4: C 64.85, H 6.35;
found: C 64.76, H 6.42.
ized segments and/or linkers to tune the width and length of
the capsules and also to introduce chiral units to assemble
chiral capsules.
Compound 6a: Isobutyl chloroformate (0.54 mL, 4.15 mmol) was slowly
added to a stirred solution of 5 (0.38 g, 1.69 mmol) and triethylamine
(0.58 mL, 4.19 mmol) in chloroform (15 mL). Stirring was continued for
30 min and then a solution of 2a (0.50 g, 1.69 mmol) in chloroform
(20 mL) was added. The solution was stirred for 24 h and then washed
with a saturated sodium bicarbonate solution (20 mL), water (20 mL),
and brine (20 mL), and dried over sodium sulfate. Upon removal of the
solvent, the crude product was recrystallized from methanol to give 6a as
a white solid. (0.65 g, 77%). 1H NMR (CDCl3): d=9.96 (s, 1H), 9.84 (s,
1H), 9.11 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.01 (dd, J1 =8.6 Hz, J2 =
2.2 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.78 (s, 1H), 6.51 (s, 1H), 4.32 (t,
J=6.9 Hz, 2H), 4.12–4.04 (m, 4H), 1.95–1.90 (m, 2H), 1.51–1.39 (m,
17H), 0.99–0.94 ppm (m, 3H); MS (ESI): m/z: 501.3 [M+H]+, 523.3
[M+Na]+; HRMS (ESI): calcd for C27H36N2O7Na [M+Na]+: 523.2391;
found: 523.2415.
Experimental Section
General methods: All reactions were carried out under a dry nitrogen at-
mosphere. All solvents were dried before use following standard proce-
dures. Unless otherwise indicated, all starting materials were obtained
from commercial suppliers and were used without further purification.
Analytical thin-layer chromatography (TLC) was performed on glass
plates precoated with 0.2 mm silica gel 60 and the F254 indicator. The 1H
and 13C NMR spectra were recorded on a Bruker Avance 300 or 400
DPX spectrometer in the indicated solvents. Chemical shifts are ex-
pressed in parts per million (d) and residual solvent protons were used as
internal standards (1H: chloroform: d=7.26 ppm; DMSO: d=2.49 ppm;
13C: CDCl3: d=77.2 ppm).
Compound 7a: TFA (0.68 mL, 8.88 mmol) was added to a stirred solu-
tion of 6a (0.22 g, 0.44 mmol) in chloroform (12 mL). The solution was
stirred at room temperature for 12 h and then a saturated sodium bicar-
bonate solution (10 mL) was added. After stirring for another 10 min,
chloroform (50 mL) was added. The organic phase was washed with a sa-
turated sodium bicarbonate solution (2ꢁ50 mL), water (50 mL), and
brine (50 mL), and dried over sodium sulfate. The solvent was then re-
moved with a rotavapor to give 7a as a yellow solid (0.17 g, 100%). The
product was recrystallized from methanol and ethyl acetate for analysis
(94%). 1H NMR (TFA/CDCl3, 1:10): d=10.22 (s, 3H), 9.05 (d, J=
9.3 Hz, 6H), 8.89 (s, 3H), 8.25 (s, 3H), 7.47 (d, J=8.7 Hz, 3H), 6.67 (s,
3H), 4.57–4.52 (t, J=6.9 Hz, 6H), 4.37–4.24 (m, 12H), 2.05–2.00 (m,
6H), 1.60–1.49 (m, 24H), 1.06–1.01 ppm (m, 9H); MS (MALDI-TOF):
m/z: 1147.3 [M+H]+; HRMS (MALDI-TOF): m/z: calcd for C66H80N6O12
[M+H]+: 1147.5732; found: 1147.5751; elemental analysis calcd (%) for
C66H78N6O12·H2O: C 68.02, H 6.92, N 7.21; found: C 68.14, H 7.02, N
7.09.
Compound 6b: White solid (82%). 1H NMR (CDCl3): d=9.97 (s, 1H),
9.73 (s, 1H), 9.00 (s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.02 (dd, J1 =8.6 Hz,
J2 =2.3 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 4.31
(t, J=6.9 Hz, 2H), 3.78–3.73 (m, 4H), 2.13–2.08 (m, 2H), 1.91–1.84 (m,
2H), 1.52 (s, 9H), 1.06–0.96 ppm (m, 17H); 13C NMR (CDCl3): d=190.7,
161.6, 161.1, 152.9, 144.8, 144.7, 137.2, 131.9, 130.1, 123.2, 121.4, 120.9,
114.2, 113.2, 98.3, 76.1, 75.6, 69.8, 30.8, 28.4, 28.3, 28.2, 19.3, 19.2, 19.0,
13.7 ppm; MS (ESI): m/z: 557.3 [M+H]+, 579.3 [M+Na]+; HRMS
(MALDI-TOF): m/z: calcd for C31H44N2O7Na [M+Na]+: 579.3029;
found: 579.3041.
Compound 7b: Yellow solid (96%). 1H NMR (CDCl3): d=9.99 (s, 3H),
8.80 (s, 3H), 8.77 (d, J=1.8 Hz, 3H), 8.69 (s, 3H), 8.36 (dd, J1 =8.0 Hz,
J2 =1.3 Hz, 3H), 7.14 (d, J=8.8 Hz, 3H), 6.60 (s, 3H), 4.34 (t, J=7.2 Hz,
6H), 3.88 (d, J=6.8 Hz, 12H), 2.22–2.18 (m, 6H), 1.97–1.92 (m, 6H),
1.54–1.46 (m, 6H), 1.01–0.97 ppm (m, 45H); 13C NMR (CDCl3): d=
190.7, 162.6, 158.4, 157.5, 150.1, 147.9, 137.0, 134.3, 130.5, 130.1, 122.7,
122.3, 113.5, 113.0, 101.0, 75.6, 69.9, 69.6, 30.9, 30.7, 28.7, 28.5, 28.4, 28.2,
19.4, 19.3, 19.1, 13.8, 13.7 ppm; MS (MALDI-TOF): m/z: 1315.8 [M+H]+,
1337.7 [M+Na]+; HRMS (MALDI-TOF): m/z: calcd for C78H103N6O12
[M+H]+: 1315.7646; found: 1315.7629; elemental analysis calcd (%) for
C78H102N6O12: C 71.21, H 7.81, N 6.39; found: C 70.89, H 8.15, N 6.27.
Compound 6c: Pale-yellow solid (98%). 1H NMR (CDCl3): d=9.98 (s,
1H), 9.80 (s, 1H), 9.07 (s, 1H), 8.82 (d, J=2.2 Hz, 1H), 8.03 (dd, J1 =
8.7 Hz, J2 =2.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.8 (s, 1H), 6.52 (s, 1H),
4.30 (t, J=6.9 Hz, 1H), 4.04–3.96 (m, 4H), 1.95–1.76 (m, 6H), 1.54 (s,
9H), 1.44–1.22 (m, 22H), 0.99–0.86 ppm (m, 9H); 13C NMR (CDCl3): d=
161.5, 161.1, 152.8, 144.5, 144.4, 137.1, 131.9, 130.2, 123.3, 121.6, 121.3,
113.9, 113.2, 98.5, 80.1, 69.9, 69.8, 69.4, 31.7, 31.6, 30.8, 29.3, 29.2, 29.1,
28.4, 26.0, 25.9, 22.6, 22.5, 19.0, 14.0, 13.9, 13.6 ppm; MS (ESI): m/z:
669.6 [M+H]+, 691.5 [M+Na]+; elemental analysis calcd (%) for
C39H60N2O7: C 70.03, H 9.04, N 4.19; found: C 69.63, H 9.36, N 3.98.
Compound 2a:
A solution of di(tert-butyl) dicarbonate (2.59 g,
11.9 mmol) in THF (10 mL) was added dropwise to a stirred solution of
1a (2.33 g, 11.9 mmol) and triethylamine (1.75 mL, 12.7 mmol) in THF.
The mixture was stirred at RT for 15 h and then concentrated with a ro-
tavapor. The resulting residue was dissolved in chloroform (30 mL) and
the solution washed with water (2ꢁ15 mL) and brine (15 mL) and dried
over sodium sulfate. After the solvent had been removed with a rotava-
por, the crude product was purified by column chromatography (petro-
leum ether/ethyl acetate, 15:1 to 10:1) to give 2a as a reddish solid
(2.10 g, 60%). 1H NMR (CDCl3): d=7.55 (s, 1H), 6.85 (s, 1H), 6.45 (s,
1H), 4.02–3.95 (m, 4H), 3.26 (s, 2H), 1.51 (s, 9H), 1.44–1.37 ppm (m,
6H); MS (ESI): m/z: 319.2 [M+Na]+; elemental analysis calcd (%) for
C15H24N2O4: C 60.79, H 8.16, N 9.45; found: C 60.76, H 7.97, N 9.36.
Compound 2b: Reddish oil (52%). 1H NMR (CDCl3): d=7.52 (s, 1H),
6.82 (s, 1H), 6.42 (d, J=2.1 Hz, 1H), 3.69–3.65 (m, 4H), 3.55 (s, 2H),
2.11–2.04 (m, 2H), 1.51 (s, 9H), 1.06–0.76 ppm (m, 12H); MS (ESI): m/z:
375.3 [M+Na]+; elemental analysis calcd (%) for C19H32N2O4: C 64.74, H
9.15, N 7.95; found: C 64.41, H 9.34, N 7.70.
Compound 2c: Reddish oil (59%). 1H NMR (CDCl3): d=7.53 (s, 1H),
6.84 (s, 1H), 6.44 (s, 1H), 3.92–3.88 (m, 4H), 3.25 (s, 2H), 1.79–1.72 (m,
4H),1.51–1.28 (m, 29H), 0.90–0.86 ppm (m, 6H); MS (ESI): m/z: 487.4
[M+Na]+; elemental analysis calcd (%) for C27H48N2O4: C 69.79, H
10.41, N 6.03; found: C 69.50, H 10.30, N 6.01.
Compound 4: Benzoic anhydride (0.84 g, 3.50 mmol) was added to a so-
lution of 3 (14.0 g, 63.0 mmol) and NBS (12.3 g, 69.3 mmol) in CCl4
(100 mL). The mixture was heated under reflux for 10 h and then cooled
to RT The precipitate formed was filtered off and the solution concen-
trated. The resulting residue was dissolved in acetic acid (90 mL) and
then hexamethylenetetramine (10.6 g, 75.6 mmol) was added slowly. The
mixture was stirred at RT for 10 min and then water (90 mL) added. The
mixture was stirred at 608C for 5 h and concentrated again. The resulting
residue was triturated with AcOEt (400 mL). The solution was washed
with
a saturated sodium bicarbonate solution (2ꢁ400 mL), water
(400 mL), and brine (400 mL), and dried over sodium sulfate. Upon re-
moval of the solvent, the crude product was purified by column chroma-
tography (petroleum ether/AcOEt 5:1) to give 4 as a white solid (4.42 g,
30%). 1H NMR (CDCl3): d=9.84 (s, 1H), 8.25 (dd, J1 =7.9, J2 =2.3 Hz,
1H), 7.91 (d, J=2.3 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 4.07 (t, J=6.4 Hz,
2H), 3.85 (s, 3H), 1.79–1.76 (m, 2H), 1.49–1.44 (m, 2H), 0.93 ppm (t, J=
7.2 Hz, 3H); MS (ESI): m/z: 237.1 [M+H]+.
Compound 5: A solution of 4 (3.90 g, 16.5 mmol) and sodium hydroxide
(0.80 g, 19.8 mmol) in methanol (90 mL) and water (30 mL) was stirred
at RT for 5 h and then concentrated to about 30 mL. Water (50 mL) was
added and the solution was extracted with AcOEt (2ꢁ40 mL). Dilute hy-
drochloric acid (1m) was added to the aqueous phase to give pH 4. The
precipitate formed was filtered. After recrystallization from ethanol, 5
was obtained as a white solid (2.82 g, 77%). 1H NMR (CDCl3): d=9.98
(s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.13 (dd, J1 =8.7 Hz, J2 =2.2 Hz, 1H),
Chem. Eur. J. 2009, 15, 5763 – 5774
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5769

Z.-T. Li et al.
Compound 7c: Yellow solid (95%). 1H NMR (CDCl3): d=10.00 (s, 3H),
8.82 (s, 3H), 8.77 (d, J=1.8 Hz, 3H), 8.74 (s, 3H), 8.37 (dd, J1 =8.7 Hz,
J2 =1.7 Hz, 3H), 7.12 (d, J=8.8 Hz, 3H), 6.62 (s, 3H), 4.33 (t, J=7.1 Hz,
6H), 4.13 (t, J=6.8 Hz, 12H), 2.00–1.84 (m, 18H), 1.56–1.26 (m, 66H),
1.25–0.92 ppm (m, 27H); 13C NMR (CDCl3): d=162.5, 158.5, 157.4,
149.9, 147.7, 137.0, 137.5, 134.2, 130.5, 130.2, 122.9, 122.2, 113.2, 112.8,
101.1, 71.4, 69.6, 69.3, 31.8, 31.7, 31.0, 29.6, 29.5, 29.4, 29.3, 29.2, 29.2,
26.1, 25.9, 22.7, 22.6, 19.1, 14.1, 14.0, 13.8 ppm; MS (MALDI-TOF): m/z:
1652.1 [M+H]+; elemental analysis calcd (%) for C102H150N6O12: C 74.14,
H 9.15, N 5.09; found: C 74.29, H 9.23, N 5.17.
chloroform (5 mL) was stirred for 40 min and then a solution of 13
(0.97 g, 1.90 mmol) in chloroform (5 mL) was added dropwise. The solu-
tion was stirred for 48 h and then chloroform (100 mL) added. The solu-
tion was washed with water (2ꢁ50 mL) and brine (50 mL), and dried
over sodium sulfate. The solvent was then removed under reduced pres-
sure and the resulting residue purified by column chromatography (pe-
troleum ether/EtOAc, 3:1) to give compound 14 as a pale-yellow oil
1
(0.93 g, 63%). H NMR (300 MHz, CDCl3): d=9.96 (s, 1H), 9.67 (s, 1H),
9.53 (s, 1H), 9.06 (s, 1H), 8.75 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.12 (d,
J=8.7 Hz, 1H), 7.02 (s, 1H), 6.47 (s, 1H), 4.29 (t, J=8.6 Hz, 2H), 4.11–
4.07 (m, 4H), 1.96–1.80 (m, 6H), 1.48 (s, 9H), 1.45–1.22 (m, 30H), 0.90–
0.81 ppm (m, 9H); 13C NMR (125 MHz, CDCl3): d=190.5, 163.6, 161.7,
161.0, 155.0, 154.7, 152.7, 136.7, 132.2, 130.0, 125.6, 122.8, 121.5, 113.2,
111.8, 96.71, 81.18, 70.12, 69.90, 69.14, 31.72, 31.66, 29.31, 29.29, 29.24,
29.16, 29.10, 29.04, 28.83, 28.14, 26.10, 25.78, 25.70, 22.57, 22.53, 22.53,
14.12, 14.00, 13.96 ppm; MS (ESI): m/z: 790 [M+Na]+; HRMS (MALDI-
FT): m/z: calcd for C44H69N3O8Na [M+Na]+: 790.4977; found: 790.4963.
Compound 9: n-Octyl bromide (3.00 mL, 16.7 mmol) was added to a
stirred mixture of compound 8 (2.00 g, 11.1 mmol), potassium carbonate
(4.60 g, 33.3 mmol), and potassium iodide (0.20 g, 1.20 mmol) in DMF
(50 mL). The mixture was stirred at 808C for 14 h and then concentrated
with a rotavapor. The resulting slurry was triturated with ethyl acetate
(50 mL). The organic phase was then washed with water (2ꢁ25 mL) and
brine (25 mL), and dried over sodium sulfate. Upon removal of the sol-
vent under reduced pressure, the resulting residue was purified by
column chromatography (petroleum ether/EtOAc, 20:1) to give com-
Compound 15: A solution of compound 14 (0.12 g, 0.15 mmol) and TFA
(1.10 mL, 15.0 mmol) in chloroform (15 mL) was stirred at room temper-
ature for 8 h and then further chloroform (20 mL) was added. The solu-
tion was washed with a saturated sodium bicarbonate solution (2ꢁ
20 mL), water (2ꢁ20 mL), and brine (20 mL), and dried over sodium sul-
fate. Upon removal of the solvent with a rotavapor, the crude product
was recrystallized from methanol to give compound 15 as a yellow solid
(93 mg, 95%). 1H NMR (300 MHz, CDCl3/[D6]DMSO 4:1): d=11.11 (s,
3H), 9.95 (s, 3H), 9.27 (s, 3H), 8.92 (s, 3H), 8.25 (s, 3H), 7.64 (d, J=
8.4 Hz, 3H), 7.18 (d, J=8.4 Hz, 3H), 6.70 (s, 3H), 4.35 (t, J=6.9 Hz,
6H), 4.25–4.24 (m, 12H), 1.98–1.88 (m, 18H), 1.47–1.13 (m, 90H), 0.87–
0.86 ppm (m, 27H); 13C NMR (125 MHz, CDCl3/[D6]DMSO 4:1): d=
167.4, 167.2, 162.5, 159.1, 156.8, 137.1, 136.6, 133.0, 129.8, 127.6, 126.7,
118.6, 117.7, 102.1, 74.73, 74.14, 36.72, 36.66, 34.31, 34.28, 34.21, 34.16,
34.03, 33.92, 31.18, 30.73, 30.70, 27.52, 19.09, 5.996, 5.088 ppm; MS
(MALDI-TOF): m/z: 1971 [M+Na]+; HRMS (MALDI-FT): m/z: calcd
for C117H177N9O15Na [M+Na]+: 1971.3256; found: 1971.3265.
pound
9 as a
pale-yellow solid (2.40 g, 73%). 1H NMR (300 MHz,
CDCl3): d=9.89 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.98 (dd, J1 =2.1 Hz,
J2 =8.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.12 (t, J=6.3 Hz, 2H), 3.91 (s,
3H), 188–1.81 (m, 2H), 1.51–1.47 (m, 2H), 1.31–1.22 (m, 8H), 0.87 ppm
(t, J=6.9 Hz, 3H); MS (EI): m/z: 292 [M]+.
Compound 10: A solution of compound 9 (2.00 g, 6.80 mmol) and lithium
hydroxide monohydrate (1.10 g, 27.2 mmol) in a mixture of THF (30 m),
methanol (15 mL), and water (7.5 mL) was stirred at room temperature
for 4 h and then concentrated to 5 mL in a rotavapor. The resulting
slurry was diluted with hydrochloric acid (1n) to pH 1 and the mixture
extracted with ethyl acetate (40 mL). The organic phase was then washed
with water (2ꢁ20 mL) and brine (25 mL), and dried over sodium sulfate.
After removal of the solvent under reduced pressure, the crude product
was recrystallized from ethanol to give compound 10 as a white solid
(1.80 g, 95%). 1H NMR (300 MHz, CDCl3): d=9.97 (s, 1H), 8.68 (d, J=
2.1 Hz, 1H), 8.13 (dd, J1 =2.1 Hz, J2 =8.7 Hz, 1H), 7.19 (d, J=8.7 Hz,
1H), 4.35 (t, J=6.6 Hz, 2H), 2.01–1.91 (m, 2H), 1.51–1.43 (m, 2H), 1.36–
1.29 (m, 8H), 0.87 ppm (t, J=7.2 Hz, 3H); MS (EI): m/z: 278 [M]+.
Compound 17: Potassium carbonate (18.3 g, 133 mmol) and potassium
iodide (2.21 g, 13 mmol) were added to a solution of compounds 8
(4.76 g, 33.0 mmol) and 16 (12.0 g, 66.0 mmol) in DMF (100 mL). The
mixture was stirred at 1058C for 18 h and then concentrated. The result-
ing residue was triturated with AcOEt (200 mL). The organic phase was
then washed with a saturated sodium bicarbonate solution (100 mL),
water (100 mL), and brine (100 mL), and dried over sodium sulfate.
Upon removal of the solvent, the crude product was recrystallized from
methanol to give compound 17 as a yellow solid (8.84 g, 62%). 1H NMR
(CDCl3): d=9.90 (s, 2H), 8.32 (d, J=2.2 Hz, 2H), 7.99 (dd, J1 =8.7 Hz,
J2 =2.2 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 4.32 (t, J=4.7 Hz, 4H), 4.07 (t,
J=4.7 Hz, 4H), 3.88 ppm (s, 6H); 13C NMR (CDCl3): d=190.0, 165.2,
162.9, 134.4, 134.3, 129.2, 120.8, 113.4, 69.7, 69.2, 52.1 ppm; MS (MALDI-
TOF): m/z: 452.8 [M+Na]+; HRMS (MALDI-TOF): m/z: calcd for
C22H22O9Na [M+Na]+: 453.1158; found: 453.1156.
Compound 12: DCC (1.10 g, 5.20 mmol) was slowly added to a stirred so-
lution of compound 11 (2.00 g, 4.70 mmol), NH2NHBoc (2.50 g,
18.8 mmol), and DMAP (0.20 g, 1.60 mmol) in THF (50 mL) cooled in an
ice bath. The mixture was stirred at room temperature for 12 h and then
filtered to remove the solid. The filtrate was concentrated with a rotava-
por and the resulting residue suspended in diethyl ether (10 mL). The
solid was filtered and the filtrate concentrated again. The resulting resi-
due was purified by column chromatography (CH2Cl2/EtOAc, 100:1) to
give compound 12 as a pale-yellow solid (2.30 g, 91%). M.p. 92–938C;
1H NMR (300 MHz, CDCl3): d=9.37 (s, 1H), 8.84 (s, 1H), 6.96 (s, H),
6.50 (s, 1H), 4.20 (t, J=6.6 Hz, 2H), 4.12 (t, J=6.6 Hz, 2H), 2.02–1.83
(m, 4H), 1.56–1.55 (m, 4H), 1.50 (s, 9H), 1.37–1.26 (m, 16H), 0.89 ppm
(t, J=6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=162.2, 161.4, 155.2,
133.4, 131.3, 111.9, 97.73, 81.93, 70.78, 70.38, 31.98, 31.96, 29.47, 29.43,
29.35, 29.37, 29.03, 28.38, 26.27, 26.01, 22.85, 19.37, 14.30 ppm; MS (EI):
m/z: 437 [MÀBoc+H]+; elemental analysis calcd (%) for C18H18O6: C
62.55, H 8.81, N 7.81; found: C 62.38, H 9.06, N 7.68.
Compound 18: A solution of compound 17 (3.22 g, 7.50 mmol) and
sodium hydroxide (0.72 g, 18.0 mmol) in THF (30 mL), water (10 mL),
and methanol (10 mL) was heated under reflux for 12 h and then concen-
trated to about 10 mL. The suspension was diluted with water (20 mL)
and the solution extracted with dichloromethane (2ꢁ10 mL). The aque-
ous phase was then acidified with dilute hydrochloric acid (2m) to pH 4
and then extracted with AcOEt (3ꢁ25 mL). The organic phase was then
washed with water (2ꢁ30 mL) and brine (30 mL), and dried over sodium
sulfate. Upon removal of the solvent with a rotavapor, the crude solid
was recrystallized from methanol to give 18 as a yellow solid (2.64 g,
88%). 1H NMR ([D6]acetone): d=9.98 (s, 2H), 8.38 (d, J=2.2 Hz, 2H),
8.07 (dd, J1 =8.7 Hz, J2 =2.2 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 4.48 (t, J=
4.6 Hz, 4H), 4.08 ppm (t, J=4.6 Hz, 4H); 13C NMR ([D6]DMSO): d=
191.0, 166.4, 161.8, 134.0, 132.5, 128.7, 122.0, 113.9, 68.9, 68.8 ppm; MS
(ESI): m/z: 401.1 [MÀH]+; HRMS (MALDI-TOF): m/z: calcd for
C20H18N9Na [M+Na]+: 425.0832; found: 425.0843.
Compound 13: A suspension of compound 12 (0.49 g, 0.90 mmol) and
Pd/C (10%, 50 mg) in methanol (20 mL) and THF (5 mL) was stirred
under 1 atm of hydrogen for 8 h. The solid was filtered off and the filtrate
concentrated with a rotavapor to give compound 13 as a brown oil
(0.46 g, 100%). 1H NMR (300 MHz, CDCl3): d=9.62 (s, 1H), 7.52 (s,
1H), 6.88 (s, 1H), 6.40 (s, 1H), 4.06 (t, J=6.3 Hz, 2H), 4.01 (t, J=6.3 Hz,
2H), 3.62 (br, 2H), 1.93–1.79 (m, 4H), 1.49 (s, 13H), 1.32–1.26 (m, 16H),
0.89 ppm (t, J=6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=164.9,
155.4, 151.4, 150.9, 130.5, 117.4, 111.6, 97.70, 81.33, 70.53, 68.74, 50.61,
31.98, 29.54, 29.50, 29.40, 29.36, 28.36, 26.33, 26.26, 22.83, 14.27 ppm; MS
(ESI): m/z: 508 [M+H]+; HRMS (MALDI-FT): m/z: calcd for
C28H49N3O5Na [M+Na]+: 530.3564; found: 530.3562.
Compound 19a: Isobutyl chloroformate (0.2 mL, 1.54 mmol) was added
to a stirred solution of compound 18 (0.11 g, 0.27 mmol) and triethyl-
amine (0.3 mL, 2.17 mmol) in chloroform (15 mL), cooled in an ice-bath.
Compound 14: A solution of compound 10 (0.64 g, 2.30 mmol), NEt3
(0.32 mL, 2.30 mL), and isobutyl chloroformate (0.30 mL, 2.30 mmol) in
5770
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5763 – 5774

Dynamic Covalent Synthesis of Macrocycles and Capsules
FULL PAPER
The solution was stirred for 30 min and then 2c (0.26 g, 0.55 mmol) was
added. After stirring for 24 h, the solution was concentrated. The result-
ing residue was recrystallized from methanol to give compound 19a as a
7.41 (s, 4H), 7.06 (d, J=8.7 Hz, 2H), 6.78 (s, 2H), 6.45 (s, 2H), 5.45 (s,
4H), 3.97 (t, J=6.5 Hz, 4H), 3.81 (t, J=6.7 Hz, 4H), 1.88–1.75 (m, 4H),
1.64 (s, 4H), 1.54 (s, 18H), 1.30–1.21 (m, 40H), 0.90–0.87 (m, 6H), 0.82–
0.79 ppm (m, 6H); 13C NMR (CDCl3): d=190.5, 161.2, 160.2, 152.8,
144.5, 144.2, 135.5, 131.7, 130.7, 127.4, 123.9, 121.5, 121.0, 114.0, 113.4,
97.9, 76.7, 70.9, 69.5, 69.3, 31.8, 31.7, 29.4, 29.3, 29.2, 29.1, 28.4, 26.1, 25.9,
22.7, 22.6, 14.1, 14.0 ppm; MS (MALDI-TOF): m/z: 1348.5 [M+Na]+;
HRMS (MALDI-TOF): m/z: calcd for C78H110N4O14Na [M+Na]+:
1349.7936; found: 1349.7911.
1
yellowish solid (0.24 g, 71%). H NMR (CDCl3): d=9.96 (s, 2H), 9.72 (s,
2H), 8.90 (s, 2H), 8.73 (d, J=2.2 Hz, 2H), 7.92 (dd, J1 =8.6, J2 =2.2 Hz,
2H), 6.95 (d, J=8.6 Hz, 2H), 6.76 (s, 2H), 6.41 (s, 2H), 4.27–4.23 (m,
4H), 3.93–3.88 (m, 12H), 1.81–1.64 (m, 8H), 1.55 (s, 18H), 1.45–0.83 ppm
(m, 52H); 13C NMR (CDCl3): d=190.4, 161.4, 160.5, 152.6, 144.8, 144.5,
136.4, 131.9, 130.5, 123.5, 121.6, 120.7, 113.9, 98.6, 70.1, 69.2, 69.1, 68.8,
31.7, 31.6, 29.3, 29.3, 29.2, 29.1, 28.3, 25.9, 25.7, 22.5, 22.4, 14.0, 14.9 ppm;
MS (MALDI-TOF): m/z: 1318.0 [M+Na]+; HRMS (MALDI-TOF): m/z:
calcd for C74H110N4O15Na [M+Na]+: 1317.7861; found: 1317.7860.
Compound 20b: TFA (0.70 mL, 9.10 mmol) was added slowly to a stirred
solution of compound 19b (0.30 g, 0.23 mmol) in chloroform (10 mL).
After stirring for 12 h, the solution was washed with a saturated sodium
bicarbonate solution (5 mL), water (5 mL), and brine (5 mL), and dried
over sodium sulfate. Upon removal of the solvent with a rotavapor, com-
pound 20b was obtained as a yellow solid (0.25 g, 100%). The product
was further recrystallized from ethyl acetate to give a sample for analysis
(0.24 g, 95%). 1H NMR (CDCl3): d=10.01 (s, 6H), 9.97 (s, 6H), 8.75 (d,
J=2.2 Hz, 6H), 8.10 (s, 6H), 7.92 (dd, J1 =8.8 Hz, J2 =2.2 Hz, 6H), 7.40
(s, 12H), 7.06 (d, J=8.8 Hz, 6H), 6.45 (s, 6H), 5.46 (s, 12H), 3.95 (t, J=
6.6 Hz, 12H), 3.80 (t, J=6.9 Hz, 12H), 1.83–1.80 (m, 12H), 1.51–1.13 (m,
132H), 0.89–0.81 ppm (m, 36H); 13C NMR (CDCl3): d=190.4, 161.2,
160.1, 143.0, 140.9, 136.4, 135.5, 132.0, 130.6, 130.0, 127.4, 124.1, 121.8,
114.0, 108.7, 99.4, 70.9, 69.9, 69.1, 31.8, 31.7, 29.5, 29.4, 29.3, 29.2, 29.1,
26.2, 25.9, 22.6, 22.5, 14.1, 14.0 ppm; MS (MALDI-TOF): m/z: 3275.1
[M+H]+, 3296.0 [M+Na]+; HRMS (MALDI-TOF): m/z: calcd for
Compound 20a: A solution of compound 19a (0.17 g, 0.13 mmol) and
TFA (0.2 mL, 2.61 mmol) in chloroform (10 mL) was stirred at RT for
14 h and then a saturated sodium bicarbonate solution (10 mL) was
added. After stirring for 10 min, the organic phase was separated and
washed with water (10 mL) and brine (10 mL), and dried over sodium
sulfate. Upon removal of the solvent, the resulting solid was recrystal-
lized from ethyl acetate and dichloromethane 10:1 to give compound 20a
as a yellow solid (0.12 g, 95%). 1H NMR (CDCl3): d=9.91 (s, 6H), 8.61
(d, J=1.8 Hz, 6H), 8.36 (s, 6H), 8.28 (dd, J1 =8.7 Hz, J2 =1.7 Hz, 6H),
7.13 (s, 6H), 6.54 (s, 6H), 6.38 (d, J=8.8 Hz, 6H), 4.22–4.04 (m, 12H),
4.01–3.88 (m, 36H), 1.89–1.75 (m, 24H), 1.47–1.22 (m, 120H), 0.87–
0.83 ppm (m, 36H); 13C NMR (CDCl3): d=162.2, 158.6, 150.5, 150.2,
148.9, 137.4, 135.5, 130.8, 129.9, 122.5, 121.2, 115.0, 112.8, 102.5, 71.6,
70.6, 67.9, 67.4, 31.8, 31.7, 29.7, 29.4, 29.3 (d), 29.2, 26.0, 25.8, 22.6, 22.6,
14.1, 14.0 ppm; MS (MALDI-TOF): m/z: 3178.7 [M+H]+, 3199.8
[M+Na]+; HRMS (MALDI-TOF): m/z: calcd for C192H270N12O27Na
[M+Na]+: 3199.0100; found: 3199.0016; elemental analysis calcd (%) for
C
204H271N12O24 [M+H]+: 3273.0429; found: 3273.0349.
Compound 25: A suspension of compound 24 (12.0 g, 59 mmol), Me-
AHCTUNGTRENN(GNU OCH2CH2)3OH (21.4 g, 0.13 mol), and potassium carbonate (20.7 g, 0.15
mol) in DMF (40 mL) was stirred at room temperature for 11 h and then
concentrated with a rotavapor. The resulting residue was extracted with
ethyl acetate (200 mL). The solution was washed with dilute hydrochloric
acid (1n, 50 mL), water (2ꢁ100 mL), and brine (100 mL), and dried over
sodium sulfate. Upon removal of the solvent under reduced pressure, the
resulting residue was purified by chromatography (petroleum ether/
AcOEt, 10:1) to give compound 25 as a yellow oil (24.7 g, 85%).
1H NMR (CDCl3): d=6.49 (s, 1H), 6.13 (s, 1H), 4.01 (t, 4H), 3.72–3.54
(m, 24H), 3.36 ppm (s, 6H); MS (ESI): m/z: 433.3 [M+H]+, 455.3
[M+Na]+.
C
192H270N12O27·H2O: C 72.15, H 8.58, N 5.26; found: C 71.88, H 8.38, N
4.91.
Compound 22: A suspension of compounds 8 (4.00 g, 22.2 mmol) and 21
(2.85 g, 10.8 mmol), K2CO3 (6.09 g, 44.2 mmol), and KI (1.31 g,
7.88 mmol) in DMF (100 mL) was stirred at 1058C for 24 h and then con-
centrated. After work-up, the crude product was recrystallized from
methanol to give compound 22 as a white solid (4.17 g, 84%). 1H NMR
(CDCl3): d=9.92 (s, 2H), 8.37 (d, J=2.2 Hz, 2H), 7.99 (dd, J1 =8.7 Hz,
J2 =2.2 Hz, 2H), 7.54 (s, 4H), 7.14 (d, J=8.7 Hz, 2H), 5.30 (s, 4H),
3.94 ppm (s, 6H); 13C NMR (CDCl3): d=190.0, 165.4, 162.5, 135.7, 134.5,
134.3, 129.4, 127.2, 121.1, 113.7, 70.5, 52.3 ppm; MS (MALDI-TOF): m/z:
485.2 [M+Na]+; elemental analysis calcd (%) for C26H22O8·0.5H2O: C
66.24, H 4.92; found: C 66.58, H 4.80.
Compound 26: A suspension of 25 (0.83 g, 1.73 mmol) and Pd/C (10%,
0.10 g) in THF (40 mL) was stirred in an autoclave under hydrogen pres-
sure (50 atm) for 7 h. The solid was filtered off and the filtrate concen-
trated under reduced pressure to give 26 as a grey oil (0.80 g, 100%).
The diamine was unstable in air and was used for the next step without
further purification.
Compound 23: A solution of compound 22 (0.98 g, 2.11 mmol) and lithi-
um hydroxide monohydrate (0.39 g, 9.39 mmol) in THF (40 mL), water
(10 mL), and methanol (10 mL) was stirred at RT for 20 h and then con-
centrated. The resulting residue was added to water (50 mL) and the mix-
ture extracted with dichloromethane (2ꢁ20 mL). The aqueous phase was
acidified with hydrochloric acid (3m) to pH 4 and then refrigerated over-
night. The precipitate formed was filtered and purified by recrystalliza-
tion form ethanol to give compound 23 as a white solid (0.79 g, 86%).
1H NMR (CDCl3): d=13.05 (s, 2H), 9.92 (s, 2H), 8.20 (d, J=2.2 Hz,
2H), 8.04 (dd, J1 =8.7 Hz, J2 =2.2 Hz, 2H), 7.54 (s, 4H), 7.43 (d, J=
8.7 Hz, 2H), 5.35 ppm (s, 4H); 13C NMR (CDCl3): d=191.2, 166.6, 161.6,
136.0, 134.3, 132.6, 129.0, 127.4, 122.4, 114.2, 69.9 ppm; MS (MALDI-
TOF): m/z: 434.9 [M+H]+ ; HRMS (MALDI-TOF): m/z: calcd for
C24H18O8Na [M+Na]+: 457.0908; found: 457.0894.
Compound 27: Triethylamine (0.4 mL, 2.99 mmol) was added to a solu-
tion of the above product 26 in THF (15 mL). Then a solution of
(Boc)2O (0.38 g, 1.73 mmol) in THF (10 mL) was added dropwise whilst
stirring. Stirring was continued for 14 h and then the solvent was re-
moved. The resulting residue was dissolved in chloroform (20 mL) and
the solution was washed with water (3ꢁ10 mL) and brine (10 mL), and
dried over sodium sulfate. The solvent was then removed under reduced
pressure and the resulting crude product purified by column chromatog-
raphy (petroleum ether/AcOEt, 3:1 to 1:2) to give 27 as a brown oil
(0.57 g, 63%). 1H NMR (CDCl3): d=7.52 (s, 1H), 7.26 (s, 1H), 6.52 (s,
1H), 4.06–4.04 (m, 4H), 3.72–3.62 (m, 18H), 3.55–3.52 (m, 4H), 3.36 (s,
6H), 1.49 ppm (s, 9H); MS (ESI): m/z: 555.4 [M+Na]+; elemental analy-
sis calcd (%) for C25H44N2O10: C 56.38, H 8.33, N 5.26; found: C 55.66, H
8.69, N 4.75.
Compound 19b: A solution of compound 23 (0.46 g, 1.06 mmol) and tri-
ethylamine (0.90 mL, 6.51 mmol) in chloroform (15 mL) was cooled in an
ice-bath. Isobutyl chloroformate (0.70 mL, 2.13 mmol) was added slowly
to this stirred solution. Stirring was continued for 30 min and then a solu-
tion of 2c (0.99 g, 2.13 mmol) in chloroform (15 mL) was added drop-
wise. After stirring at RT for 24 h, the solution was washed with a satu-
rated sodium bicarbonate solution (15 mL), water (15 mL), and brine
(15 mL), and dried over sodium sulfate. Upon removal of the solvent
with a rotavapor, the resulting residue was purified by column chroma-
tography (CH2Cl2/MeOH, 100:1) to give compound 19b as a pale-yellow
Compound 29: A suspension of compounds 8 (1.80 g, 9.98 mmol) and 28
(2.17 g, 4.93 mmol), and potassium carbonate (2.78 g, 20.2 mmol) in DMF
(100 mL) was stirred at 608C for 40 h and then concentrated under re-
duced pressure. The resulting slurry was triturated with ethyl acetate
(50 mL) and the solution washed successively with dilute hydrochloric
acid (1n, 20 mL), water (30 mL), and brine (30 mL), and dried over
sodium sulfate. Upon removal of the solvent under reduced pressure, the
resulting residue was purified by column chromatography (petroleum
ether/AcOEt, 5:1 to 3:1) to give compound 29 as a colorless oil (1.66 g,
74%). 1H NMR (CDCl3): d=9.91 (s, 2H), 8.31 (d, J=2.2 Hz, 2H), 8.01
1
solid (0.88 g, 63%). H NMR (CDCl3): d=9.96 (s, 2H), 9.91 (s, 2H), 9.14
(s, 2H), 8.82 (d, J=2.2 Hz, 2H), 7.92 (dd, J1 =8.7 Hz, J2 =2.2 Hz, 2H),
Chem. Eur. J. 2009, 15, 5763 – 5774
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5771

Z.-T. Li et al.
(dd, J1 =8.7, Hz, J2 =2.2 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 4.25 (t, J=
6.9 Hz, 4H), 3.87 (s, 6H), 1.95 (t, J=6.9 Hz, 4H), 1.12 ppm (s, 6H);
13C NMR (CDCl3): d=190.0, 165.5, 163.0, 134.4, 134.3, 129.0, 120.8,
113.0, 66.4, 52.2, 40.3, 31.9, 21.7 ppm; MS (MALDI-TOF): m/z: 480.0
[M+Na]+; HRMS (MALDI-TOF): m/z: calcd for C25H28O8Na [M+Na]+:
479.1673; found: 479.1676.
(30 mL) and the solution successively washed with water (15 mL) and
brine (3ꢁ15 mL), and dried over sodium sulfate. Upon removal of the
solvent, the resulting solid was dissolved in dichloromethane (40 mL).
Trifluoromethanesulfonic acid (0.1 mL) was added to this solution, which
was then washed with water (20 mL) and brine (20 mL), and dried over
sodium sulfate. The solvent was then removed to give compound 31c as
a yellowish solid (0.48 g, 86% for three steps). 1H NMR (CDCl3): d=
7.74 (s, 4H), 7.29 (d, J=8.6 Hz, 4H), 6.84 (d, J=8.6 Hz, 4H), 4.03 (s,
4H), 3.86 (t, J=6.5 Hz, 4H), 3.01 (s, 4H), 2.77 (s, 4H), 2.32–2.16 (m,
2H), 1.81–1.64 (m, 4H), 1.41–1.26 (s, 32H), 0.87 ppm (t, J=6.6 Hz, 6H);
13C NMR (CDCl3): d=160.6, 131.7, 121.2, 115.4, 68.3, 52.0, 50.9, 44.3,
32.2, 29.9 (d), 29.8, 29.7, 29.6, 29.4, 26.2, 23.2, 22.9, 14.3 ppm; MS (ESI):
m/z: 623.6 [M+HÀ2Cl]+; elemental analysis calcd (%) for
C43H72F6N2O8S2·H2O: C 54.87, H 7.92, N 2.98; found: C 54.59, H 8.29, N
2.71.
Compound 30: A solution of compound 29 (0.21 g, 0.48 mmol) and
sodium hydroxide (88 mg, 2.20 mmol) in water (10 mL), THF (30 mL),
and MeOH (10 mL) was heated at reflux for 4 h and then concentrated
to approximately 10 mL under reduced pressure. The resulting suspen-
sion was acidified with dilute hydrochloric acid (1n) to pH 4 and then ex-
tracted with dichloromethane (3ꢁ10 mL). The organic phase was washed
with water (2ꢁ15 mL) and brine (15 mL), and dried over sodium sulfate.
After the solvent had been removed with a rotavapor, the resulting resi-
due was recrystallized from ethyl acetate to give compound 30 as a white
solid (0.16 g, 76%). 1H NMR (CDCl3): d=12.92 (s, 2H), 9.88 (s, 2H),
8.13 (d, J=2.1 Hz, 2H), 7.99 (dd, J1 =8.7, Hz, J2 =2.1 Hz, 2H), 7.37 (d,
J=8.7 Hz, 2H), 4.22 (t, J=6.7 Hz, 4H), 1.78 (t, J=6.70 Hz, 4H),
1.02 ppm (s, 6H); 13C NMR (CDCl3): d=191.0, 166.5, 161.9, 134.0, 132.3,
128.5, 122.1, 113.7, 66.2, 40.1, 31.4, 27.4 ppm; MS (MALDI-TOF): m/z:
451.9 [M+Na]+; HRMS (MALDI-TOF): m/z: calcd for C23H24O8Na
[M+Na]+: 451.1371; found: 451.1363.
Compound 31d: A solution of compounds 33 (0.23 g, 3.10 mmol) and 34
(1.68 g, 6.23 mmol) in toluene (60 mL) was heated at reflux azeotropical-
ly for 5 h and then concentrated under reduced pressure. The resulting
solid (diimine) was dissolved in dried methanol (35 mL) and THF
(8 mL). Sodium borohydride (3.80 g, 0.10 mol) was added to the solution
and the mixture stirred for 12 h. The solvent was removed with a rotava-
por and the resulting slurry triturated with dichloromethane (50 mL).
The solution was washed with water (25 mL) and brine (25 mL), and
dried over sodium sulfate. Upon removal of the solvent, the correspond-
ing diamine was obtained as a colorless oil (1.72 g, 95%). 1H NMR
(CDCl3): d=7.19 (d, J=8.6 Hz, 4H), 6.85 (d, J=8.6 Hz, 4H), 4.12 (t, J=
6.7 Hz, 4H), 3.87–3.82 (m, 4H), 3.74–3.55 (m, 20H), 3.37 (s, 6H), 2.69–
2.65 (m, 4H), 1.81 (s, 2H), 1.71 ppm (t, J=6.5 Hz, 2H); 13C NMR
(CDCl3): d=157.9, 130.8, 129.3, 114.7, 71.9, 70.8, 70.7, 70.6, 69.8, 67.5,
59.0, 53.3, 47.9, 29.7 ppm; MS (ESI): m/z: 601.3 [M+Na]+; HRMS
(MALDI-TOF): m/z: calcd for C31H51N2O8 [M+H]+: 579.3646; found:
579.3640.
Compound 19c: Isobutyl chloroformate (0.34 mL, 2.61 mmol) was added
to a stirred solution of compound 30 (0.21 g, 0.49 mmol) and triethyla-
mine (0.44 mL, 3.18 mmol) in chloroform (10 mL) cooled in an ice-bath.
The solution was stirred for 30 min and then a solution of compound 27
(0.54 g, 1.02 mmol) in chloroform (10 mL) was added dropwise. Stirring
was continued at RT for 24 h and then the solution was washed with
dilute hydrochloric acid (0.5n, 10 mL), water (10 mL), and brine
(10 mL), and dried over sodium sulfate. The resulting residue was puri-
fied by column chromatography (CH2Cl2/MeOH, 100:1 to 60:1) to give
19c as a brown oil (0.51 g, 71%). 1H NMR (CDCl3): d=9.96 (s, 2H),
9.75 (s, 2H), 9.16 (s, 2H), 8.74 (d, J=2.2 Hz, 2H), 7.97 (dd, J1 =8.8 Hz,
J2 =2.2 Hz, 2H), 7.09 (d, J=8.8 Hz, 4H), 6.61 (s, 2H), 4.37 (t, J=6.8 Hz,
4H), 4.15–4.10 (m, 8H), 3.88–3.78 (m, 4H), 3.76–3.64 (m, 16H), 3.59–
3.55 (m, 8H), 3.39–3.35 (m, 18H), 3.29 (s, 6H), 2.00 (t, J=6.8 Hz, 4H),
1.53 (s, 18H), 1.07 ppm (s, 6H); 13C NMR (CDCl3): d=190.5, 161.7,
160.8, 152.8, 143.9, 143.4, 136.5, 132.3, 130.2, 123.8, 123.7, 123.2, 113.3,
113.1, 102.0, 72.0, 71.8, 70.8, 70.7, 70.6, 70.5, 70.1, 69.9, 69.6, 69.4, 66.8,
59.0, 58.9, 40.2, 32.0, 28.5, 27.6 ppm; MS (MALDI-TOF): m/z: 1478.2
[M+Na]+; elemental analysis calcd (%) for C73H108N4O26: C 60.15, H
7.47, N 3.84; found: C 60.24, H 7.75, N 3.57.
Concentrated hydrochloric acid (0.5 mL) was slowly added to a solution
of the diamine (0.55 g, 0.95 mmol) in methanol (30 mL). The solvent was
then removed under reduced pressure to give 31d as a yellowish solid
(0.61 g, 100%). 1H NMR (CDCl3): d=10.20 (s, 4H), 7.44 (d, J=2.3 Hz,
4H), 6.88 (d, J=2.3 Hz, 4H), 4.08–3.54 (m, 28H), 3.36 (s, 6H), 2.62 ppm
(s, 6H); 13C NMR (CDCl3): d=159.7, 132.0, 121.6, 115.1, 71.9, 70.8, 70.6,
70.5, 69.6, 67.4, 59.0, 50.8, 43.3, 24.1 ppm. MS (ESI): m/z: 601.2
[M+NaÀ2Cl]+; elemental analysis calcd (%) for C31H52Cl2N2O8·H2O: C
55.60, H 8.13, N 4.18; found: C 56.09, H 8.67, N 3.91.
Compound 36: A solution of compounds 35 (1.37 g, 6.26 mmol) and 33
(0.23 g, 3.10 mmol) in toluene (60 mL) was heated at reflux azeotropical-
ly for 6 h and then concentrated under reduced pressure. The resulting
solid (diimine) was dissolved in dried MeOH (26 mL) and THF (8 mL).
Sodium borohydride (4.02 g, 106 mmol) was added to the solution and
the mixture stirred for 9 h and then concentrated. The resulting slurry
was triturated with CH2Cl2 (100 mL). The solution was washed with
water (50 mL) and brine (50 mL), and dried over sodium sulfate. The sol-
vent was then removed with a rotavapor to give 35 as a yellowish oil
(1.38 g, 94%). 1H NMR (CDCl3): d=7.32 (s, 2H), 7.15 (s, 4H), 3.80 (s,
4H), 2.78 (s, 4H), 2.03 (s, 2H), 1.80 (s, 2H), 1.31 ppm (s, 36H); 13C NMR
(CDCl3): d=151.8, 128.6, 124.8, 123.5, 52.1, 43.2, 34.9, 31.4, 31.3 ppm;
MS (ESI): m/z: 479.4 [M+H]+; HRMS (ESI): m/z: calcd for C33H55N2
[M+H]+: 479.4346; found: 479.4360.
Compound 20c: TFA (0.35 mL, 4.57 mmol) was added dropwise to a
stirred solution of compound 19c (0.18 g, 0.12 mmol) in chloroform
(18 mL). The solution was stirred at room temperature for 35 h and then
a saturated sodium bicarbonate solution (10 mL) was added. The mixture
was stirred for 10 min and then the organic phase was washed with water
(10 mL) and brine (10 mL), and dried over sodium sulfate. Upon removal
of the solvent under reduced pressure, the crude product was dissolved in
methanol and diethyl ether (5 mL, 1:1). The solution was cooled to 08C
to give an oily solid. Removal of the organic solvent afforded compound
20c as a brown oil (0.12 g, 82%). 1H NMR (CDCl3): d=9.66 (s, 6H),
8.59 (s, 6H), 8.54 (s, 6H), 8.25 (s, 6H), 7.68 (d, J=8.6 Hz, 6H), 6.68 (d,
J=8.6 Hz, 6H), 6.74 (s, 6H), 4.41–4.25 (m, 36H), 3.90–3.26 (m, 156H),
2.49–2.45 (m, 6H), 1.99–1.95 (m, 6H), 1.19 ppm (s, 18H); MS (MALDI-
TOF): m/z: 3664.6 [M+H]+, 3686.8 [M+Na]+. 13C NMR (CDCl3): d=
161.4, 157.9, 157.1, 156.4, 149.7, 145.8, 137.1, 135.1, 130.1, 129.3, 125.1,
121.3, 112.0, 105.7, 72.2, 71.9, 71.7, 71.6, 70.6, 70.4, 70.3, 70.2, 69.5, 69.1,
68.7, 65.7, 58.9, 58.8, 58.7, 37.8, 32.5, 29.5, 29.3, 29.1 ppm; HRMS
(MALDI-TOF): m/z: calcd for C189H264N12O60Na [M+Na]+: 3684.7900;
found: 3684.7868.
Compound 31e: Concentrated hydrochloric acid (0.2 mL) was added
slowly to a solution of compound 36 (0.62 g, 1.30 mmol) in methanol
(40 mL). The solvent was then removed under reduced pressure to give a
white solid, which was recrystallized from methanol to give compound
31e as a white solid (0.67 g, 93%). 1H NMR (CDCl3): d=10.27 (s, 4H),
7.43 (s, 2H), 7.32 (s, 4H), 4.09 (s, 4H), 2.68 (s, 6H), 1.32 ppm (s, 36H);
13C NMR (CDCl3): d=151.7, 128.5, 124.8, 123.5, 52.1, 43.2, 34.8, 31.3,
24.1 ppm; MS (ESI): m/z: 479.4 [MÀ2ClÀH]+; HRMS (ESI): m/z: calcd
for C33H55N2 [MÀ2Cl]+: 479.4346; found: 479.4360.
Compound 31c: A solution of compounds 32 (1.66 g, 5.71 mmol) and 33
(0.20 g, 2.72 mmol) in toluene (50 mL) was heated at reflux azeotropical-
ly for 4 h and then concentrated with a rotavapor. The resulting solid
(diimine) was dissolved in dried methanol (12 mL) and THF (12 mL).
Then sodium borohydride (3.02 g, 79.5 mmol) was added to the solution.
The mixture stirred at room temperature for 12 h and then was concen-
trated. The resulting residue was triturated with dichloromethane
5772
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5763 – 5774

Dynamic Covalent Synthesis of Macrocycles and Capsules
FULL PAPER
Raynond, Acc. Chem. Res. 2005, 38, 349–360; c) T. S. Koblenz, J.
Wassenaar, J. N. H. Reek, Chem. Soc. Rev. 2008, 37, 247–262.
[10] S. Liu, B. C. Gibb, Chem. Commun. 2008, 3709–3716.
[11] a) F. Corbellini, L. Di Costanzo, M. Crego-Calama, S. Geremia,
D. N. Reinhoudt, J. Am. Chem. Soc. 2003, 125, 9946–9947; b) F. Cor-
bellini, R. M. A. Knegtel, P. D. J. Grootenhuis, M. Crego-Calama,
D. N. Reinhoudt, Chem. Eur. J. 2005, 11, 298–307; c) G. V. Oshov-
sky, D. N. Reinhoudt, W. Verboom, J. Am. Chem. Soc. 2006, 128,
5270–5278.
Acknowledgements
We thank the National Science Foundation of China (Nos. 20621062,
20672137, 20732007, and 20872167), the National Basic Research Pro-
gram (2007CB808001) and the Chinese Academy of Sciences for finan-
cial support.
[12] Preorganized calix[4]arenes and cavitands have been used to pre-
pare capsules by DCC, see: a) X. Liu, Y. Liu, G. Li, R. Warmuth,
Angew. Chem. 2006, 118, 915–918; Angew. Chem. Int. Ed. 2006, 45,
901–904; b) Y. Liu, X. Liu, R. Warmuth, Chem. Eur. J. 2007, 13,
8953–8959; c) X. Liu, R. Warmuth, J. Am. Chem. Soc. 2006, 128,
14120–14127; d) X. Liu, R. Warmuth, Nat. Protoc. 2007, 2, 1288–
1296; e) D. Xu, R. Warmuth, J. Am. Chem. Soc. 2008, 130, 7520–
7521.
[13] The concept of “predisposition” has been used to prepare cinchoni-
dine-based macrocycles by ester exchange, see: S. J. Rowan, D. G.
Hamilton, P. A. Brady, J. K. M. Sanders, J. Am. Chem. Soc. 1997,
119, 2578–2579.
[1] C. I. Branden, Introduction to Protein Structure, Routledge, New
York, 1999, p. 410.
[2] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180; b) D. J. Hill,
M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001,
101, 3893–4011; c) B. Gong, Chem. Eur. J. 2001, 7, 4336–4342; d) I.
Huc, Eur. J. Org. Chem. 2004, 17–29; e) M. T. Stone, J. M. Heem-
stra, J. S. Moore, Acc. Chem. Res. 2006, 39, 11–20; f) C. M. Good-
man, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol. 2007, 3,
252–262; g) Z.-T. Li, J.-L. Hou, C. Li, H.-P. Yi, Chem. Asian J. 2006,
1, 766–778; h) Z.-T. Li, J.-L. Hou, C. Li, Acc. Chem. Res. 2008, 41,
1343–1353; i) B. Gong, Acc. Chem. Res. 2008, 41, 1376–1386;
j) W. S. Horne, S. H. Gellman, Acc. Chem. Res. 2008, 41, 1399.
[3] Foldamers: Structure, Properties and Applications (Eds.: S. Hecht, I.
Huc), Wiley-VCH, Weinheim, 2007, p. 428.
[4] a) L. Yuan, W. Feng, K. Yamato, A. R. Sanford, D. Xu, H. Guo, B.
Gong, J. Am. Chem. Soc. 2004, 126, 11120–11121; b) H. Jiang, J.-M.
Lꢂger, P. Guionneau, I. Huc, Org. Lett. 2004, 6, 2985–2988; c) A.
Zhang, Y. Han, K. Yamato, X.-C. Zeng, B. Gong, Org. Lett. 2006, 8,
803–806; d) Y.-Y. Zhu, C. Li, G.-Y. Li, X.-K. Jiang, Z.-T. Li, J. Org.
Chem. 2008, 73, 1745–1751; e) B. Qin, X. Chen, X. Fang, Y. Shu,
Y. K. Yip, Y. Yan, S. Pan, W. Q. Ong, C. Ren, H. Su, H. Zeng, Org.
Lett. 2008, 10, 5127–5130.
[5] a) L. J. Prins, P. Timmerman, D. N. Reinhoudt, Pure Appl. Chem.
1998, 70, 1459–1468; b) J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455–
2463; c) S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders,
J. S. Stoddart, Angew. Chem. 2002, 114, 938–993; Angew. Chem. Int.
Ed. 2002, 41, 898–952; d) U. Lꢃning, J. Inclusion Phenom. Macrocy-
clic Chem. 2004, 49, 81–84; e) Z. R. Laughrey, B. C. Gibb, Top.
Curr. Chem. 2005, 249, 67–125; f) P. T. Corbett, J. Leclaire, L. Vial,
K. R. West, J.-L. Wietor, J. K. M. Sanders, S. Otto, Chem. Rev. 2006,
106, 3652–3711; g) B. de Bruin, P. Hauwert, J. N. H. Reek, Angew.
Chem. 2006, 118, 2726–2729; Angew. Chem. Int. Ed. 2006, 45, 2660–
2663; h) K. Severin, Chem. Commun. 2006, 3859–3867; i) J. R.
Nitschke, Acc. Chem. Res. 2007, 40, 103–112; j) C. D. Meyer, C. S.
Joiner, J. F. Stoddart, Chem. Soc. Rev. 2007, 36, 1705–1723; k) J.-M.
Lehn, Chem. Soc. Rev. 2007, 36, 151–160; l) S. Otto, K. Severin,
Top. Curr. Chem. 2007, 277, 267–288; m) R. F. Ludlow, S. Otto,
Chem. Soc. Rev. 2008, 37, 101–108.
[14] For representative examples, see: a) O. Storm, U. Lꢃning, Chem.
Eur. J. 2002, 8, 793–798; b) A. J. Gallant, M. J. MacLachlan, Angew.
Chem. 2003, 115, 5465–5468; Angew. Chem. Int. Ed. 2003, 42, 5307–
5310; c) C. T. L. Ma, M. J. MacLachlan, Angew. Chem. 2005, 117,
4250–4254; Angew. Chem. Int. Ed. 2005, 44, 4178–4182; d) K. S.
Chichak, S. J. Cantrill, A. R. Pease, S.-H. Chiu, G. W. V. Cave, J. L.
Atwood, J. F. Stoddart, Science 2004, 304, 1308–1312; e) A. R. Wil-
liams, B. H. Northrop, T. Chang, J. F. Stoddart, A. J. P. White, D. J.
Williams, Angew. Chem. 2006, 118, 6817–6821; Angew. Chem. Int.
Ed. 2006, 45, 6665–6669; f) C. S. Hartley, J. S. Moore, J. Am. Chem.
Soc. 2007, 129, 11682–11683; g) C. S. Hartley, E. L. Elliott, J. S.
Moore, J. Am. Chem. Soc. 2007, 129, 4512–4513; h) N. Christinat,
R. Scopelliti, K. Severin, Angew. Chem. 2008, 120, 1874–1878;
Angew. Chem. Int. Ed. 2008, 47, 1848–1852; i) M. Hutin, G. Bernar-
dinelli, J. R. Nitschke, Chem. Eur. J. 2008, 14, 4585–4593; j) J. Luo,
T. Lei, X. Xu, F.-M. Li, Y. Ma, K. Wu, J. Pei, Chem. Eur. J. 2008, 14,
3860–3865; k) K. R. West, R. F. Ludlow, P. T. Corbett, P. Besenius,
F. M. Mansfeld, P. A. G. Cormack, D. C. Sherrington, J. M. Good-
man, M. C. A. Stuart, S. Otto, J. Am. Chem. Soc. 2008, 130, 10834–
10835.
[15] a) Z.-Q. Wu, X.-B. Shao, C. Li, J.-L. Hou, K. Wang, X.-K. Jiang, Z.-
T. Li, J. Am. Chem. Soc. 2005, 127, 17460–17468; b) J.-L. Hou, H.-P.
Yi, X.-B. Shao, C. Li, Z.-Q. Wu, X.-K. Jiang, L.-Z. Wu, C.-H. Tung,
Z.-T. Li, Angew. Chem. 2006, 118, 810–814; Angew. Chem. Int. Ed.
2006, 45, 796–800; c) J. Zhu, J.-B. Lin, Y.-X. Xu, X.-B. Shao, X.-K.
Jiang, Z.-T. Li, J. Am. Chem. Soc. 2006, 128, 12307–12313; d) C. Li,
Y.-Y. Zhu, H.-P. Yi, C.-Z. Li, X.-K. Jiang, Z.-T. Li, Chem. Eur. J.
2007, 13, 9990–9998; e) W. Cai, G.-T. Wang, Y.-X. Xu, X.-K. Jiang,
Z.-T. Li, J. Am. Chem. Soc. 2008, 130, 6936- 6937; f) W. Cai, G.-T.
Wang, P. Du, R.-X. Wang, X.-K. Jiang, Z.-T. Li, J. Am. Chem. Soc.
2008, 130, 13450–13459.
[16] a) J.-B. Lin, X.-N. Xu, X.-K. Jiang, Z.-T. Li, J. Org. Chem. 2008, 73,
9403–9410; b) J.-B. Lin, J. Wu, X.-K. Jiang, Z.-T. Li, Chin. J. Chem.
2009, 27, 117–122.
[17] a) S. L. Roberts, R. L. E. Furlan, S. Otto, J. K. M. Sanders, Org.
Biomol. Chem. 2003, 1, 1625–1633; b) R. T. S. Lam, A. Belenguer,
S. L. Roberts, C. Naumann, T. Jarrosson, S. Otto, J. K. M. Sanders,
Science 2005, 308, 667–669; c) R. F. Ludlow, J. Liu, H. Li, S. L. Rob-
erts, J. K. M. Sanders, O. Sijbren, Angew. Chem. 2007, 119, 5864–
5866; Angew. Chem. Int. Ed. 2007, 46, 5762–5764.
[18] R. Lartia, C. Allain, G. Bordeau, F. Schmidt, C. Fiorini-Debuis-
schert, F. Charra, M.-P. Teulade-Fichou, J. Org. Chem. 2008, 73,
1732–1744.
[19] L. Yuan, A. R. Sanford, W. Feng, A. Zhang, J. Zhu, H. Zeng, K.
Yamato, M. Li, J. S. Ferguson, B. Gong, J. Org. Chem. 2005, 70,
10660–10669.
[6] Container Molecules and Their Guests (Eds.: D. J. Cram, J. M.
Cram), RSC, Cambridge, 1997, p. 223.
[7] a) J. C. Sherman, Tetrahedron 1995, 51, 3395–3422; b) A. Jasat, J. C.
Sherman, Chem. Rev. 1999, 99, 931–967.
[8] a) C. M. Morgan, J. Rebek, Jr., Chem. Rev. 1997, 97, 1647–1668;
b) J. Rebek, Jr., Angew. Chem. 2005, 117, 2104–2115; Angew.
Chem. Int. Ed. 2005, 44, 2068–2078; c) L. J. Prins D. N. Reinhoudt,
P. Timmerman, Angew. Chem. 2001, 113, 2446–2492; Angew. Chem.
Int. Ed. 2001, 40, 2382–2426; d) M. Crego-Calama, D. N. Reinhoudt,
M. G. J. ten Cate, Top. Curr. Chem. 2005, 249, 285–316; e) A.
Bogdan, Y. Rudzevich, M. O. Vysotsky, V. Bçhmer, Chem.
Commun. 2006, 2941–2952; f) L. R. MacGillivray, J. L. Atwood,
Angew. Chem. 1999, 111, 1080–1096; Angew. Chem. Int. Ed. 1999,
38, 1018–1033; g) A. Lꢃtzen, Angew. Chem. 2005, 117, 1022–1025;
Angew. Chem. Int. Ed. 2005, 44, 1000–1002; h) D. M. Vriezema,
M. C. Aragones, J. A. A. W. Elemans, J. J. L. M. Cornelissen, A. E.
Rowan, R. J. M. Nolte, Chem. Rev. 2005, 105, 1445–1489; i) C.
Schmuck, Angew. Chem. 2007, 119, 5932–5935; Angew. Chem. Int.
Ed. 2007, 46, 5830–5833; j) D. P. Weimann, C. A. Schalley, Supra-
mol. Chem. 2008, 20, 117–128.
[9] a) M. Fujita, M. Tominaga, A. Hori, B. Therrien, Acc. Chem. Res.
2005, 38, 369–380; b) D. Fiedler, D. H. Leung, R. G. Bergman, K. N.
[20] V. I. Siele, M. Warman, J. Org. Chem. 1962, 27, 1910–1911.
Chem. Eur. J. 2009, 15, 5763 – 5774
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5773

Z.-T. Li et al.
[21] C.-S. Chang, Y.-T. Lin, S.-R. Shih, C.-C. Lee, Y.-C. Lee, C.-L. Tai, S.-
N. Tseng, J.-H. Chern, J. Med. Chem. 2005, 48, 3522–3535.
[22] This result might reflect the fact that another minor isomer or other
byproducts existed that wunderwent exchange with the major prod-
uct in solution.
[23] a) C. Li, S.-F. Ren, J.-L. Hou, H.-P. Yi, S.-Z. Zhu, X.-K. Jiang, Z.-T.
Li, Angew. Chem. 2005, 117, 5871–5875; Angew. Chem. Int. Ed.
2005, 44, 5725–5729; b) H.-P. Yi, C. Li, J.-L. Hou, X.-K. Jiang, Z.-T.
Li, Tetrahedron 2005, 61, 7974–7980.
[26] C. Lottner, K.-C. Bart, G. Bernhardt, H. Brunner, J. Med. Chem.
2002, 45, 2079–2089.
[27] M. J. Plater, S. Aiken, G. Bourhill, Tetrahedron 2002, 58, 2405–2413.
[28] The hydrochloric acid salt of 31c has a low solubility in chloroform.
[29] J. Wu, J.-L. Hou, C. Li, Z.-Q. Wu, X.-K. Jiang, Z.-T. Li, Y.-H. Yu, J.
Org. Chem. 2007, 72, 2897–2905.
[30] H. Benesi, J. Hildebrand, J. Am. Chem. Soc. 1949, 71, 2703–2707.
[31] The sample precipitated at an even lower temperature.
[24] A. R. Sanford, L. Yuan, W. Feng, K. Yamato, R. A. Flowers, B.
Gong, Chem. Commun. 2005, 4720–4722.
[25] M. C. Lensen, J. A. A. Elemans, S. J. T. van Dingenen, J. W. Gerrit-
sen, S. Speller, A. E. Rowan, R. J. M. Nolte, Chem. Eur. J. 2007, 13,
7948–7956.
Received: February 5, 2009
Published online: May 6, 2009
5774
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5763 – 5774