Synthetic cation transporters incorporating crown ethers and calixarenes as headgroups and central relays: A comparison of sodium and chloride selectivity

Article abstract of DOI:10.1039/b719235p

An earlier study showed that a calix[4]arene could function as a central relay unit to form an ion conductance pathway through a phospholipid bilayer membrane. The present study expands the range of compounds from calix[4]arene to calix[6]arene and incorporates them either as central units or as headgroups, substituting one or more diaza-18-crown-6 residues in functioning hydraphiles. Ion release was assayed by detecting either Na⁺ or Cl^- release from phospholipid vesicles. The ion transport activity for calix[4]arenes in either position is modest, but is almost non-existent when calix[6] residues were incorporated either as head groups or central relay units. The poor activity of the calix[6]arenes may result from an inability to penetrate to the midplane of the bilayer or pass entirely through it to form a conductance pathway. The transmembrane flip-flop may result from high polarity or steric bulk, or both. A hydraphile incorporating a single -NHCOC₆H₄OCH₂CONH- as a central relay proved to be an excellent Na⁺ conductor, but less selective for Cl ^-. The fact that this new hydraphile molecule shows selectivity for Na⁺ over Cl^- transport and possesses two secondary amide residues in the central relay suggests a means to control ion selectivity in synthetic ion transporters. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/b719235p

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Synthetic cation transporters incorporating crown ethers and calixarenes
as headgroups and central relays: a comparison of sodium and chloride
selectivityw
a
e
d
a
´
´
Jose Carlos Iglesias-Sanchez, Wei Wang, Riccardo Ferdani, Pilar Prados,
Javier de Mendozaab and George W. Gokel*cd
Received (in Durham, UK) 12th December 2007, Accepted 18th March 2008
First published as an Advance Article on the web 7th April 2008
DOI: 10.1039/b719235p
An earlier study showed that a calix[4]arene could function as a central relay unit to form an ion
conductance pathway through a phospholipid bilayer membrane. The present study expands the
range of compounds from calix[4]arene to calix[6]arene and incorporates them either as central
units or as headgroups, substituting one or more diaza-18-crown-6 residues in functioning
hydraphiles. Ion release was assayed by detecting either Na+ or Clꢀ release from phospholipid
vesicles. The ion transport activity for calix[4]arenes in either position is modest, but is almost
non-existent when calix[6] residues were incorporated either as head groups or central relay units.
The poor activity of the calix[6]arenes may result from an inability to penetrate to the midplane
of the bilayer or pass entirely through it to form a conductance pathway. The transmembrane
‘‘flip-flop’’ may result from high polarity or steric bulk, or both. A hydraphile incorporating a
single –NHCOC6H4OCH2CONH– as a central relay proved to be an excellent Na+ conductor,
but less selective for Clꢀ. The fact that this new hydraphile molecule shows selectivity for Na+
over Clꢀ transport and possesses two secondary amide residues in the central relay suggests a
means to control ion selectivity in synthetic ion transporters.
include the span of the channel, the polarity of the head-
Introduction
groups, the presence and type of selectivity filter, the presence
and type of central relay, and the general question of whether
the channel will be flexible or rigid. These issues have been
dealt with in a variety of ways by different investigators.9 Roks
and Nolte,10 for example, used stacked isocyanocrown ethers
as a rigid channel while Meillon and Voyer11 used crown
ethers oriented into a pore by an a-helical peptide backbone.
The span of synthetic unimolecular ion channels has varied,
but has typically been between 35 and 45 A. Where a distin-
guishable central relay was present, there was considerable
variation as well. Thus Lehn and co-workers used b-cyclodex-
trin12 while we13,14 and Fyles et al.15 used crown ethers. The
crown ethers often comprised both the selectivity filter and the
polar head groups. Of course, entirely different, unique, and
successful approaches have been reported.16–20
Less than a decade ago, no solid state structure had been
reported for any protein channel molecule. In the years
preceding the appearance of the Nobel prize winning1,2 struc-
tures,3,4 a number of synthetic ion channel mimics were
devised in the hope that they could model channel function
and reveal mechanistic details of transport. Several different
channel designs emerged, some of which were based on the
cation complexing and polar properties of crown ethers. The
crown compounds served in the earliest model systems as
headgroups5 and in others6,7 as what we have termed a
‘‘central relay.’’ The ‘‘central relay’’ that was designed into
synthetic channels is equivalent to the ‘‘water and ion filled
capsule’’ that was discovered in proteins8 when the first solid
state structures were reported.
In considering channel design, there are several structural,
steric, and polarity issues that must be considered. These
In addition to these important design variants, chemical
characterization and documented function are critical. De-
monstrating chemical purity is a routine matter for synthetic
laboratories, but assaying ion transport is less common.
Various methods have been used to detect ion transport.
Probably the most informative technique is the use of planar
bilayer voltage clamp methods.21 Although this method gives
comprehensive information about channel behavior, it re-
quires expensive instrumentation, considerable time, and op-
erator expertise. Alternative methods use NMR,22 various
fluorescent dyes,23 and ion selective electrodes (ISEs).24 Not
all methods give identical information, but it is critical for
claimed ion transport to be documented or a compound
designed to be a channel may not be a transporter at all.
a
´
Facultad de Ciencias, Departamento de Quımica Organica (C-I),
Universidad Autonoma de Madrid, 28049 Madrid, Spain
´
´
b Institute of Chemical Research of Catalonia (ICIQ), 43007
Tarragona, Spain
c Departments of Chemistry & Biochemistry and Biology, Center for
Nanoscience, University of Missouri – St. Louis, St. Louis, MO
63121, USA
d Department of Molecular Biology & Pharmacology, Washington
University, St. Louis, MO 63130, USA. E-mail: gokelg@umsl.edu;
Fax: 314/516-5342; Tel: 314/516-5321
e Department of Chemistry, Washington University, St. Louis, MO
63130, USA
w Dedicated to Professor Jerry Atwood on the occasion of his 65th
birthday.
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In a previous study, we used calixarenes as central units25 in
a crown ether headgroup channel. In these studies, we com-
pared synthetic systems in which the calixarenes were more or
less sterically encumbered. Transport in these systems was
assayed by using planar bilayer methods. In the work pre-
sented here, we have prepared ion transporters using calixar-
ene headgroups in concert with our well-studied diaza-18-
crown-6 central relay. The efficacy of these compounds as
transporters was determined by using ISE methods to detect
ion release from phospholipid vesicles.
possible to assess how the calixarenes compared to diazacrown
ethers either as head groups or as central relay elements.
Compounds studied
Eight compounds are compared in the present study. Com-
pounds 1 and 4 were prepared previously. Compound 1 is, as
noted above, the best studied13,14 member of the hydraphile
family. It is known to span the bilayer29 and to transport Na+
in a unimolecular fashion.30 Its transport efficacy constitutes
the benchmark for the present study.
Compounds 2 and 3 were prepared to serve as controls. The
4-acetyloxybenzoic acid central relay of 2 is a fragment of the
calixarene central units present in 5 and 6. Similarly, com-
pound 3 is a control for 7 and 8, which are terminated by
calix[4]arene or calix[6]arene head groups, respectively.
Results and discussion
To our knowledge, only limited use has been made of the
calixarene unit in ion transporters.26 In our previous report
on25 calix[4]arenes as central relay units the structures had the
form [PhCH2hN18Ni(CH2)12]2calix[(CH2)12hN18NiCH2Ph]2,
where hN18Ni represents 4,13-diaza-18-crown-6.27 Three de-
rivatives were prepared for the present study. One was a
control compound in which the calix[4]arene was in the cone
conformation. This means that all four of the
–(CH2)12hN18NiCH2Ph chains emanating from the calixarene
were oriented on the same side of that macrocycle. As such,
there was insufficient overall length to span the bilayer,
although all of the requisite structural elements were present.
Two 1,3-alternate calixarene derivatives were also prepared.
These were intended to probe channel formation per se and the
ability of a calix[4]arene to pass a cation through the center of
the calix. Each arene’s para position in the calix[4]arene was
either hydrogen (calix-H) or tert-butyl (calix-Bu). The planar
bilayer conductance evidence showed that the calix-H and
calix-Bu channels were similar in ion transport behavior. Since
the tert-butylated calixarene was too sterically hindered to
pass Na+ through its center, it was concluded that the
amphiphiles were forming pores that afforded Na+
conductance pathway.25
a
Design criteria
The calixarene-derived channels reported here incorporate
both calix[4]- and calix[6]arenes. The passage of Na+ through
the calixarene’s interior has been reported.28 To the extent this
occurs, passage of Na+ must be more favorable through a
calix[6]arene owing to its larger interior size. It is worth noting
that determining a precise size for the hole of calixarenes is
difficult owing to the conformational dynamics of these
macrocycles. Even so, calix[4]arene and calix[6]arene residues
were incorporated into putative channels as either head groups
or central relays in the expectation that they might be effective
but behave differently as transporters.
Compounds 5–8 are the major focus of this study. They
incorporate calix[4]arene or calix[6]arene residues either as a
central relay (5, 6) or as the amphiphile’s polar head groups
(7, 8). We anticipated that any free hydroxyl groups present on
the calix might make these structures too polar to insert into
the bilayer. A particular concern in this connection was that
the calixes of 5 and 6 needed to reside at the midplane of the
bilayer to serve as the central relay unit. The midplane is the
least polar portion of the bilayer and a component of the
channel having high polarity might simply disrupt the
membrane.
The compounds of the present study were designed based
on the successful benzyl-terminated hydraphiles that are
now well characterized. The best studied of these is
PhCH2hN18Ni(CH2)12hN18Ni(CH2)12hN18NiCH2Ph, 1. The
strategy was to replace either the two distal diaza-18-crown-6
macrocycles with calixarenes or to replace the central (medial)
macrocycle of 1 by a single calixarene. By doing so, it would be
An additional issue is that the formation of a conductance
pathway requires, in principle at least, compounds 5–8 to
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extend through both leaflets of the bilayer membrane. If the
calix is too large or too polar, it may be unable to penetrate the
hydrocarbon regime of the bilayer and anchor on the opposite
membrane surface. It is well known that the polar head groups
of phospholipids do not readily pass through (‘‘flip-flop’’) the
bilayer, even though they have high mobility within a single
membrane leaflet.
Synthetic access
Compounds 2 and 3 incorporated a 4-hydroxybenzoic acid
unit as a mimic of a calixarene, positioned either to function as
the central relay (2) or head groups (3). Calix[4]- and calix[6]-
arenes were incorporated as central units (5, 6) and as head-
groups (7, 8). Compound 2 was prepared in three steps from
ethyl 4-hydroxybenzoate. The ester was treated with methyl
bromoacetate and K2CO3 in acetone followed by KOH hy-
drolysis to give 4-(carboxymethyloxy)benzoic acid, 9, and
coupling with N-benzyl-N0-12-aminododecyl-4,13-diaza-18-
crown-6 (12BDA)13 (63% overall yield). The preparation of
3 was also accomplished from ethyl 4-hydroxybenzoate, by O-
benzylation, hydrolysis of the ethyl ester to give 4-benzyloxy-
benzoic acid, 10, and coupling with N,N0-bis(12-aminodecyl)-
4,13-diaza-18-crown-6 (12DA12)13 (64% overall).
As with the control structures 2 and 3, the preparation of 5–8
required extensive functionalization of the calixarene starting
materials (12, 15). Coupling of two 12BDA or one 12DA12
units on calixarenes 26–27 or 18–19, respectively gave 5–8 with
good yields. Details of this effort are presented in the Experi-
mental section. Therein, the conformational status of the
calixarene derivatives are addressed. The final coupling step
and the key calixarene derivatives are shown in Chart 1.
The preparation of calix channels 5–8 required the forma-
tion of the appropriate calixarene having one (7, 8) or two (5,
6) connection points on the same arene. Once the appropri-
ately functionalized precursors were in hand, a carboxylic acid
on the calixarene was coupled (using benzotriazol-1-yl-oxytri-
pyrrolidinophosphonium hexafluorophosphate PyBOPꢂPF6,
see Experimental section) with the appropriate azacrown
12DA12 and 12BDA, respectively. The key calixarene struc-
tures are shown as 12,31 15,32 18, 19, 26 and 27. Compounds 12
and 15 are the starting materials for the calix[4]arene and
calix[6]arene channels, respectively. Compounds 18 and 19 are
the head groups for channels 7 and 8. The central units of 5
and 6 were prepared from 26 and 27, respectively.
Ion transport behavior
As noted above, the calixarene transporters were designed to
incorporate the successful central relay system of the hydra-
philes14 but bring to the system greater size, polarity and
rigidity. The latter term may seem ambiguous considering
Chart 1 Final coupling steps to form calixarene derivatives 5, 6, 7 and 8.
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the conformational flexibility of the calixarenes. The much
larger surfaces of the arenes were expected to provide a better
defined entry portal or central relay than do the crowns. It was
known from previous studies that ion transport mediated by 4
did not permit passage of Na+ through the calixarene.25 It was
anticipated that this would be the case for calix[4]arene
compounds, whether the calix was incorporated as the central
relay (5) or as headgroups (7). The calix[6]arene derivatives
having larger central relay (6) or headgroup (8) elements were
expected to readily pass cations.
The planar bilayer voltage clamp method gives extensive
and detailed information concerning ion transport.21 Unfor-
tunately, this technique is both tedious and time-consuming.
Considering the number of compounds that were required to
be assayed, we decided to use ion selective electrode methods
to assess ion egress from liposomes.
The liposomes used in the studies reported here were pre-
pared by the method of Szoka and Papahadjoupolos33 from
1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). In the
Na+ release experiments, the internal buffer was 750 mM
NaCl–15 mM HEPES buffer at pH 7.0. The liposomes were
filtered through a 200 nm membrane and passed over a
Sephadex G25 column and then equilibrated in sodium-free
buffer (750 mM cholineCl–15 mM HEPES, pH 7.0). In the Clꢀ
release experiments, liposomes were prepared similarly, but
loaded with 600 mM KCl and 10 mM HEPES (pH = 7.0), then
equilibrated with an external buffer (400 mM K2SO4–10 mM
HEPES, pH = 7.0). The expected vesicle size (B200 nm) was
confirmed by light scattering measurements (particle analy-
zer). Ion efflux was measured by using either a pH/Na+
combination microelectrode24 or a chloride selective mem-
brane electrode relative to the final value determined after
vesicular lysis.
Fig. 1 Sodium (upper panel) and chloride (lower panel) release from
DOPC:DOPA liposomes mediated by synthetic ionophores.
The results of the Na+ release studies for compounds 1–3
and 5–8 are shown in the upper panel of Fig. 1. Hydraphile 1 is
equal or superior to all of the other compounds studied. It
released B95% of the available sodium during our customary
(arbitrary) 1500 s period of observation. We note that once a
conductance pore is formed, ion release occurs nearly in-
stantly. Thus, we presume that the curves shown in Fig. 1
reflect a combination of insertion dynamics and conforma-
tional adjustment required to establish an appropriate con-
ductance pathway.
go(oxyethylene) central units approached its transport effi-
cacy.14 Thus, the high release observed for 2 is particularly
interesting. The central unit of 2, i.e., –NHCOCH2OC6H4-
CONH–, contains two carbonyl groups that can serve as
H-bond acceptors from water and two NH residues that can
donate hydrogen bonds to water. The carbonyl groups and the
amide NH groups are both spaced about 9 A apart. The
carbonyl group spacing is too large for the carbonyl oxygens
to directly ligate with a transient cation—an interaction that
should dramatically slow transport. The activity of this com-
pound supports our general understanding of the central relay
unit, but is a very interesting alternative to crown ether relays.
The O–O or N–N spacing in diaza-18-crown-6 is typically
only about 6 A. In principle, any interaction with a transient
cation should be stronger with a crown owing to this shorter
distance. The carbonyl groups of 2 are farther apart but also
more polar. It is interesting to note that the selectivity filter of
the KcsA potassium selective channel uses carbonyl groups to
replace the solvation shell of a transient K+ cation.1 In any
event, sodium ion transport selectivity is apparent between
1 and 2.
Compound 2 is similar in overall structure to 1. It incorpo-
rates the –NHCOCH2OC6H4CONH– unit, a single element of
the calixarene central relay present in compounds 5 and 6. In
previous studies34 we noted that replacement of the diaza-
crown central relay of 1 by 4,40-bipiperidyl gave a hydraphile
that was 40% as active as 1. In this case, 2 is about 64% as
active as 1 in releasing Na+ from liposomes. Compound 3
contains the diazacrown central relay but lacks the crown
headgroups. Its distal residues were designed to mimic a single
calixarene element of 7 and 8. The transport activity of 3 is
measurable but too small to be of interest. Likewise, 5 and 7
show very low Na+ transport although it is above baseline.
Only 6 and 8 parallel the baseline for the entire 1500 s
observation period.
The Na+ transport ability of 2 stands in contrast to that of
3, which contains a diaza-18-crown-6 central relay. In this
case, the PhCH2OC6H4CONH– sidechains that replace the
distal diaza-18-crown-6 macrocycles of 1 apparently lack
sufficient polarity to function as headgroups or sufficient size
Benzyl channel 1 is an unusually effective Na+ transporter.
In previous studies, only hydraphiles having crown or oli-
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to serve as cation entry portals. The presence of this molecule
in the liposomal bilayer leads to Na+ release of barely 15%
during 1500 s.
Ion transport by calixarene-containing amphiphiles
Compounds 5–8 incorporate calix[4]arenes (5, 7) or calix[6]-
arenes (6, 8) as a central relay (5, 6) or as putative headgroups
(7, 8). Transport of Na+ by 5 or 7 is modest. The overall
transport behavior for 5 and 7 is indistinguishable from that
found for 3, i.e., B15% at 1500 s. Compounds 6 and 8 show
no evidence of Na+ transport during the 1500 s observation
period. Taken together, these observations reveal two facts.
First, and perhaps obviously, calix[6]arenes are bulkier and
more polar than their calix[4]arene counterparts. Second, for
the calix[4]arenes, it does not seem to matter whether a single
calix is present as a central relay unit or two are incorporated
as headgroups. Transport is poor suggesting that the forma-
tion of a stable conductance pathway is problematic.
Perhaps the most interesting observation is the inability of
compound 8, which incorporates two distal calix[6]arene
residues, to transport Na+ or Clꢀ, shown in the bottom panel
of Fig. 1. In the Clꢀ transport case, a more limited sample of
compounds was tested, but the results proved to be interesting.
As with Na+ transport, compounds 3 and 6 proved to be only
modest transporters, although both ultimately mediated the
release of about 25% of the available Clꢀ ion.
Fig. 2 Schematic representations of compounds (left to right) 5, 6, 7
and 8. Postulated non-conducting structure for calixarene derivative 8.
in part, for their efficacy as transporters, although transport
The low transport activity of calixarenes amphiphiles
mediated by 5 proved to be marginal.
In order to evaluate the behavior of compounds 5–8, it is
useful to consider the presumed active conformations. These
are shown in Fig. 2. Diaza-18-crown-6 is represented by the
ovals and the blocks represent the calixarenes.
Ion transport by compounds 1 and 2
The results obtained for 1 and 2 were especially interesting.
Although there is a minor difference in line shape, probably
reflecting small differences in insertion or conformational
dynamics, both compounds release about 90% of the available
Clꢀ ion by 1500 s. In previous studies of 1, we have focused on
Na+ transport and the competition with other cations, such as
K+ and Ag+. The fact that Clꢀ release is so effective is
surprising and will merit additional study, which is beyond
the scope of this work. Even so, it is interesting to compare 1,
which effectively releases both Na+ and Clꢀ, with 2.
In order for any of these molecules to form a conductance
pathway, the molecule must insert into the upper leaflet of the
bilayer and then unfold into the lower leaflet, ultimately
passing half of the structure through the midplane of the
bilayer to the opposite surface. Compounds 5–8 present a
challenge in this respect because the calixarenes are both large
and polar. The ability of the calixarene central units in either 5
or 6 to reside at the midplane of the bilayer is limited by their
polarity and their ability to penetrate the upper leaflet’s
hydrophobic regime. The problem is exacerbated in 7 because
one of the calix[4]arene units must pass all the way from the
outer leaflet surface to the inner leaflet surface, i.e., transverse
relaxation or ‘‘flip-flop’’, a process that occurs very slowly.
The problem is most severe for 8, in which the calix[6]arene is
both large and polar. The data of Fig. 1 show that 8 is
essentially inactive as a transporter either of cations or anions.
Compound 8 might prove active if it was present and incor-
porated into the bilayer during liposome formation, but this
experiment has not been attempted because insertion is critical
for these compounds to be of biological relevance. Fig. 2
shows schematically how 7 or 8 might insert in the upper
bilayer but fail to mediate ion transport.
The central relay in 2 is –NHCOCH2OC6H4CONH– rather
than 4,13-diaza-18-crown-6. Certainly either of these units can
serve to organize water, which would comprise the requisite
midplane polarity for transport. Both the amide carbonyl
groups of 2 and the ether oxygens of 1 would show an affinity
for alkali metal cations but only the amide NH groups of 2
should interact effectively with Clꢀ. Thus, it is not surprising
that 2 shows a modest 1.5 : 1 transport selectivity for Na+
over Clꢀ (cf. upper and lower panels). The transport efficacies
of the other compounds in this study are too low to determine
selectivity with any confidence.
The results presented here show that replacement of the
diazacrown central unit of 1 by a residue containing secondary
amides alters the Na+/Clꢀ transport selectivity. In previous
studies, we have prepared numerous amides,35 but in all cases
prior to this one, they have been tertiary. Presumably the
presence of a secondary amide alters the affinity of these
Presumably, the diaza-18-crown-6 residues of 1, 2, 4, 5 and 6
have sufficient polarity to serve as headgroups and entry (or
exit) portals, but they can still pass through the bilayer’s
hydrophobic regime to the opposite surface. This accounts,
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molecules for Clꢀ compared to Na+ but this remains to be
confirmed generally.
brated in sodium-free buffer (750 mM cholineCl–15 mM
HEPES, pH 7.0). Lipid concentration was measured as pre-
viously reported36 and vesicle size was confirmed by light
scattering (submicron particle analyzer) to be B200 nm.
Sodium efflux was measured by using a pH/Na+ combination
microelectrode (Thermo-Orion). Aliquots of the amphiphile
solution (15 mL, 5 mM in 2-PrOH, except 5, 5 mM in DMSO)
were added into the system after the base line is stable. Final
values were determined after vesicular lysis (n-octylglucose)
and curve calibration.
Conclusions
Previous work showed that a calix[4]arene could function
effectively as a central unit to induce an ion conductance
pathway in a phospholipid bilayer. In this case, each arene
was substituted by a dodecylene chain terminated by a ben-
zyldiazacrown residue. Structural modification showed that
although a conductance path was formed, ions did not flow
through the calix[4]arene. The present study expanded the
calixarene size (4 and 6) and placed the calixarenes to function
as either headgroups or central units. Only modest ion trans-
port (cation or anion) was realized from compounds in which
the calix[4]arene was present in either position. When the
calixarene was placed to serve as a headgroup, low activity
was observed for the four-arene macrocycle and no transport
was apparent when the macrocycle was calix[6]arene. We
speculate that the lack of transport activity reflects the in-
ability of the large and polar calixarene to cross the bilayer
and establish a conductance pathway. Ultimately, the most
interesting and surprising observation relates to 1 and 2, which
were included as control compounds. Compound 1, which has
been extensively studied as a cation transporter, conducts Clꢀ
as well as it does Na+. The fact that 2 favors Na+ over Clꢀ
transport and possesses two secondary amide residues in the
central relay suggests a strategy to incorporate a selective
element in the design of more selective ion transporters.
Determination of chloride release by ISE methods
Liposomes were prepared as above, and loaded with 600 mM
KCl and 10 mM (HEPES, pH = 7.0), then equilibrated with
an external buffer (400 mM K2SO4, 10 mM HEPES, pH =
7.0). The pH of the buffers prepared was adjusted using 10%
NaOH. An Accumet Chloride Combination Electrode was
equilibrated (5 min) in external buffer (2.0 mL) and the vesicle
solution was added. After recording the baseline voltage,
aliquots of the amphiphile solution (5 mM in 2-PrOH, except
5, 5 mM in DMSO) were added. The amount of isopropyl
alcohol was limited to 15 mL to avoid alcohol-induced leakage.
Vesicles were lysed by addition of aqueous Triton X100
(100 mL, 2%). The lipid concentration used in the studies
presented here was 0.40 mM.
Data analysis
The data were acquired in mV units, which were converted to
concentration units by using the electrode calibration curve.
After conversion from mV to concentration units, the release
data were normalized to the total ion concentration, as
determined by lysing the vesicles. Data manipulation was
done using Origin Pro 7 software.
Experimental
General methods
Unless otherwise indicated, reactions were conducted under
dry and deoxygenated argon. Solvents were freshly distilled
and dried by standard methods before use. Melting points are
uncorrected and were measured in open capillaries on a
Gallenkamp melting point apparatus. The NMR experiments
(1H, 13C{1H}, COSY (H,H), HMQC and ROESY) were
carried out at 500 MHz (1H) or 125 MHz (13C) in CDCl3 at
ambient temperature, unless otherwise specified. Chemical
shifts (d, ppm) are externally referenced to solvent residual
signal. Mass spectra were performed on a REFLEX spectro-
meter (MALDI-TOF) using ditranol (1,8-dihydroxyanthrone)
as matrix and NaI as additive. Elemental analyses, performed
on a LECO CHN 932 microanalyser and reported as percen-
tage, indicated inclusion of solvent molecules for nearly all
calixarene products and were supported by separate 1H NMR
studies. TLC was performed on silica gel Alugram Sil
G/UV254 (Macherey–Nagel).
General procedure for azacrown-carboxylic acid coupling
To a solution of the carboxylic acid (1 mmol) was added
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluoro-
phosphate (PyBOPꢂPF6, 2.2 mmol), EtN3 (2.2 mmol), and
the corresponding azacrown (2.2 mmol) in THF (10 mL). The
mixture was stirred (under Ar) at rt for 24 h. The solvent was
removed in vacuo and the residue was partitioned between
CH2Cl2 and HCl (1 M). The organic soluble residue was
purified by flash column chromatography over silica gel
(solvent: 4% v/v MeOH in CH2Cl2).
N-Benzyldiaza-18-crown-6 (BDA, PhCH2hN18NiH) was
prepared as previously reported.13
N-Benzyl-N0-12-aminododecyl-4,13-diaza-18-crown-6
(12BDA, PhCH2hN18Ni(CH2)12NH2) was prepared as
previously reported.13
N,N0-Bis(12-aminodecyl)-4,13-diaza-18-crown-6 (12DA12,
H2N(CH2)12hN18Ni(CH2)12NH2) was prepared as previously
reported.13
Vesicle preparation and ion transport measurements
Liposomes were formed (20 s sonication) from 1,2-dioleoyl-sn-
glycero-3-phosphocholine (Avanti Polar Lipids, AL). The
buffer captured within the liposomes was 750 mM NaCl–
15 mM N-2-hydroxyethylpiperazine-N0-2-ethanesulfonic acid
(HEPES), pH 7.0. The liposomes were filtered (200 nm
membrane) and passed over a Sephadex G25 column equili-
N,N0-Bis[12-(N0 -benzyldiaza- 18- crown-6) dodecyl]diaza-18-
crown-6,
[C6H5CH2hN18Ni(CH2)12hN18Ni(CH2)12hN18NiCH2C6H5],
1, was prepared as previously reported.13
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C6H5CH2hN18Ni(CH2)12 NHCOCH2OC6H4CONH (CH2)12-
hN18NiCH2C6H5, 2. This was prepared by the coupling be-
tween 9 (44 mg, 0.22 mmol, general procedure), and 12BDA
(250 mg, 0.54 mmol). Yield: 201 mg, 73%. 1H NMR: 1.25 [m,
36H, (CH2)9], 1.59 (m, 4H, CH2), 2.18 (m, 16H, CH2–N–CH2),
2.82 (m, 4H, CH2NHCO + CH2N), 3.67 (m, 32H, CH2OCH2-
CH2OCH2), 3.76 (s, 4H, OCH2Ar), 6.11 (s, 2H, NH), 6.54 (s,
7.02 (d, 4H, J = 8.8 Hz, ArH), 7.38 (m, 4H, ArH), 7.46 (m, H,
NH), 6.96 (d, 2H, J = 8.7, Hz, ArH), 7.25 (m, 4H, ArH), 7.32
(m, 6H, ArH), 7.77 (d, 2H, J = 8.7 Hz, ArH); 13C NMR: 27.1,
27.5, 28.9, 29.2, 29.3, 29.4 [(CH2)10], 39.2, 40.2 (CH2NH), 46.1,
46.3 (CH2N), 53.9, 54.0 (CH2NCH2), 68.0 (OCH2CO), 69.8,
69.9 (CH2OCH2CH2OCH2), 70.4 (OCH2Ar), 114.5, 126.9,
128.2, 128.7, 128.9, 129.0 (ArH), 127.1, 139.5, 159.5 (ArC),
166.6, 167.4 (CO); MALDI-TOF MS m/z (Ditranol + NaI),
1231.9 [M + H]+. Anal. (%). Calc. for C71H118N6O11: C,
69.23; H, 9.66; N, 6.82. Found: C, 69.55; H, 9.82; N, 6.95.
2H, ArCH2Ar), 3.61 (s, 3H, OCH3), 3.68 (m, 8H, CH2OCH2-
CH2OCH2), 3.73 (s, 6H, OCH3), 4.40 (d, 2H, J = 9.8 Hz,
ArCH2Ar), 4.42 (d, 2H, J = 10.0 Hz, ArCH2Ar), 4.62 (s, 2H,
OCH2CO), 5.70 (br s, 1H, NH), 5.75 (br s, 1H, NH), 6.26 (s,
2H, ArH), 7.02 (s, 2H, ArH), 7.14 (s, 2H, ArH), 7.24 (s, 2H,
ArH); 13C NMR: 30.7, 31.4 [C(CH3)3], 30.9, 31.1 (ArCH2Ar),
33.8, 34.2 [C(CH3)3], 51.4, 51.9 (CO2CH3), 58.3, 60.5 (OCH3),
71.2 (OCH2CO), 169.0, 170.5 (CO); MALDI-TOF MS m/z
(Ditranol + NaI), 1722.5 [M]+, 1795.5 [M + Na]+. Anal.
(%): Calc. for C108H166N6O14: C, 73.18; H, 9.44; N, 4.74.
Found: C, 73.41; H, 9.57; N, 4.87.
Calix[6]arene channel, 6. This was prepared by general
procedure, from 27 (30 mg, 0.028 mmol) and (12BDA, 37
1
mg, 0.07 mmol). Yield: 36 mg, 60%. H NMR (C2D2Cl4, 388
K (115 1C): 0.95 [s, 9H, C(CH3)3], 1.00 [s, 18H, C(CH3)3], 1.22
[s, 18H, C(CH3)3], 1.32 [m, 36H, (CH2)9], 1.61 (m, 4H, CH2),
2.69 (m, 4H, CH2–N–CH2), 3.02 (br s, 4H, CH2NHCO), 3.16
(s, 2H, OCH2CO2), 3.26 (s, 6H, OCH3), 3.41 (s, 6H, OCH3),
3.46 (s, 3H, OCH3), 3.68 (m, 8H, CH2OCH2CH2OCH2), 3.92
(s, 8H, ArCH2Ar), 3.98 (s, 4H, ArCH2Ar), 5.02 (s, 4H,
OCH2Ar), 5.70 (br s, 1H, NH), 5.75 (1H, NH), 6.71 (s, 2H,
ArH), 6.73 (s, 2H, ArH), 6.85 (s, 2H, ArH), 7.04 (s, 4H, ArH),
7.22 (s, 2H, ArH), 729–735 (m, 10H, ArH); 13C NMR: 27.0,
29.3, 29.5, 29.7 [(CH2)10], 30.1, 30.2, 30.7 (ArCH2Ar), 30.8,
30.9, 31.3 [C(CH3)3], 33.4, 33.43, 33.5 [C(CH3)3], 40.1
(CH2NH), 50.4 (CH2NCH2), 59.5, 59.53, 59.9 (OCH3), 68.8
(OCH2CO2), 69.7, 69.9 (CH2OCH2CH2OCH2), 74.8
(OCH2Ar), 123.8, 124.2, 124.5, 126.5, 126.7, 132.0 (ArH)
123.9, 131.5, 132.3, 132.4, 132.7, 132.9, 134.5, 145.2, 145.6,
145.65, 153.0, 153.2 (ArC), 159.8, 167.1 (CO); MALDI-TOF
MS m/z (Ditranol + NaI), 2126.5 [M + H]+, 2148.0
[M + Na]+. Anal. (%): Calc. for C132H198N6O16: C, 74.71;
H, 9.39; N, 3.95. Found: C, 75.01; H, 9.57; N, 4.10.
PhCH2OC6 H4 CONH(CH2)12hN18Ni(CH2)12 NHCOC6H4O-
CH2Ph, 3. This was prepared by the general procedure from 10
(100 mg, 0.44 mmol) and 12DA12 (207 mg, 0.51 mmol). Yield:
1
376 mg, 82%, mp 217 1C. H NMR: 1.30 [m, 36H, (CH2)9],
1.64 (q, 4H, J = 7.1 Hz, CH2), 2.72 (m, 8H, CH2–N–CH2),
3.05 (br s, 4H, CH2NHCO), 3.45 (c, 4H, J = 7.1 Hz,
CH2NHCO), 3.65 (m, 16H, CH2OCH2CH2OCH2), 5.02 (s,
4H, OCH2Ar), 6.20 (s, 2H, NH), 7.02 (d, 4H, J = 8.8 Hz,
ArH), 7.38 (m, 4H, ArH), 7.46 (m, 6H, ArH), 7.77 (d, 4H, J =
8.8 Hz, ArH); 13C NMR: 27.0, 29.3, 29.5, 29.7 [(CH2)10], 40.1
(CH2NH), 50.4 (CH2NCH2), 69.7, 69.9 (CH2OCH2-
CH2OCH2), 70.1 (OCH2Ar), 114.6, 127.5, 128.2, 128.7
(ArH), 126.5, 136.5, 162.4 (ArC), 167.5 (CO); MALDI-TOF
MS m/z (Ditranol + NaI), 1049.4 [M + H]+, 1072.4 [M +
Na]+. Anal. (%): Calc. for C64H96N4O8: C, 73.25; H, 9.22; N,
5.34. Found: C, 73.30; H, 9.25; N, 5.41.
Calix[4]arene channel 4. This has been previously reported.25
Calix[4]arene channel 7. This was prepared by the general
procedure, from 18 (50 mg, 0.065 mmol) and 12DA12 (31 mg,
0.15 mmol). Yield: 107 mg, 77% (oil). Asymmetric partial
Calix[4]arene channel 5. This was prepared from 26 (50 mg,
0.068 mmol) by coupling (general procedure) with 12BDA (91
mg, 0.17 mmol). Yield: 82 mg, 69%. Asymmetric partial cone:
1H NMR: 0.84 [s, 9H, C(CH3)3], 1.12 [s, 9H, C(CH3)3], 1.25 [s,
9H, C(CH3)3], 1.32 [m, 36H, (CH2)9], 2.69 (m, 4H,
CH2–N–CH2), 2.75 (s, 3H, OCH3), 3.02 (br s, 4H,
CH2NHCO), 3.15–3.25 (m, 2H, ArCH2Ar), 3.62 (s, 3H,
OCH3), 3.68 (m, 8H, CH2OCH2CH2OCH2), 3.74 (s, 3H,
OCH3), 3.70–3.80 (m, 4H, ArCH2Ar), 4.17 (m, 1H, ArCH2-
Ar), 4.23 (m, 1H, ArCH2Ar), 4.35 (s, 2H, OCH2CO), 5.70 (1H,
NH), 5.75 (br s, 1H, NH), 6.34 (d, 1H, J = 2.0 Hz, ArH), 6.92
(d, 1H, J = 2.0 Hz, ArH), 7.13 (2H, ArH), 7.18 (s, 1H, J = 1.9
1
cone: H NMR: 0.99 [s, 9H, C(CH3)3], 1.22 [s, 9H, C(CH3)3],
1.30 [m, 36H, (CH2)9], 1.41 [s, 9H, C(CH3)3)], 1.64 (m, 4H,
CH2), 2.69 (m, 8H, CH2–N–CH2), 2.73 (s, 8H, OCH3
+
ArCH2Ar), 3.02 (s, 3H, OCH3), 3.13 (d, 1H, J = 13.5 Hz,
ArCH2Ar), 3.15 (d, 1H, J = 13.3 Hz, ArCH2Ar), 3.71–3.79
(m, 4H, ArCH2Ar), 3.72 (s, 3H, OCH3), 3.74 (s, 3H, OCH3),
4.08 (d, 1H, J = 13.5 Hz, ArCH2Ar), 4.17 (d, 1H, J = 13.3
Hz, ArCH2Ar), 4.78 (d, 1H, J = 8.0 Hz, OCH2Ar), 4.85 (d,
1H, J = 8.0 Hz, OCH2Ar), 5.81 (br s, 2H, NH), 6.33 (d, 1H,
J = 2.1 Hz, ArH), 6.92 (d, 1H, J = 2.1 Hz, ArH), 7.07 (d, 1H,
J = 2.2 Hz, ArH), 7.13 (d, 1H, J = 2.2 Hz, ArH), 7.15 (d, 1H,
J = 2.1 Hz, ArH), 7.27–7.28 (m, 2H, ArH), 7.30–7.38 (m, 3H,
ArH), 7.41–7.45 (m, 2H, ArH), 7.80 (d, 1H, J = 2.1 Hz, ArH);
13C NMR: 27.0, 29.3, 29.5, 29.7 [(CH2)10], 30.9, 31.2, 36.5,
36.9 (ArCH2Ar), 31.1, 31.5, 31.7 [C(CH3)3], 33.4, 33.8, 34.3
[C(CH3)3], 40.1 (CH2NH), 50.4 (CH2NCH2), 58.4, 59.8, 60.6
(OCH3), 69.7, 69.9 (CH2OCH2CH2OCH2), 76.7 (OCH2Ar),
124.9, 125.2, 126.2, 126.4, 127.3, 128.2, 128.3, 128.6, 128.61,
130.4, 131.8 (ArH), 132.0, 132.7, 132.8, 133.2, 134.6, 134.8,
135.8, 136.4, 137.3, 143.5, 144.2, 145.4, 151.6, 154.8, 155.3,
155.7 (Ar), 161.0 (CO). Cone: 1H NMR: 0.69 [s, 9H, C(CH3)3],
Hz, ArH), 7.34 (2H, ArH), 7.68 (d, 1H, J = 1.9 Hz, ArH); 13
C
NMR: 27.0, 29.3, 29.5, 29.7 [(CH2)10], 30.8, 31.6, 31.7
[C(CH3)3], 30.9, 31.2, 37.7, 38.4 (ArCH2Ar), 33.4, 33.8, 34.2
[C(CH3)3], 40.1 (CH2NH), 50.4 (CH2NCH2), 58.4, 59.8, 60.6
(OCH3), 69.7, 69.9 (CH2OCH2 CH2OCH2), 70.4 (OCH2CO),
124.9, 126.2, 126.4, 127.3, 128.2, 128.3, 128.6, 130.4, 131.8
(ArH), 132.0, 132.7, 132.8, 134.6, 134.8, 135.8, 136.4, 137.3,
143.5, 144.2, 145.4, 151.6, 154.8, 155.3, 155.7 (Ar), 169.0, 170.5
1
(CO). Cone: H NMR: 0.72 [s, 9H, C(CH3)3], 1.32 [m, 36H,
(CH2)9], 1.35 [s, 18H, C(CH3)3], 2.69 (m, 4H, CH2–N–CH2),
3.02 (br s, 4H, CH2NHCO), 3.27 (m, 2H, ArCH2Ar), 3.29 (m,
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1.30 [m, 36H, (CH2)9], 1.43 [s, 18H, C(CH3)3], 1.64 (m, 4H,
CH2), 2.69 (m, 8H, CH2–N–CH2), 3.18 (d, 2H, J = 13.1 Hz,
ArCH2Ar), 3.20 (d, 2H, J = 13.0 Hz, ArCH2Ar), 3.73 (s, 3H,
OCH3), 3.85 (s, 6H, OCH3), 4.38 (d, 2H, J = 13.1 Hz,
ArCH2Ar), 4.41 (d, 2H, J = 13.0 Hz, ArCH2Ar), 4.86 (s,
2H, OCH2Ar), 5.81 (2H, NH), 6.24 (s, 2H, ArH), 7.21 (br s,
6H, ArH), 7.27–7.28 (m, 2H, ArH), 7.41–7.45 (m, 3H, ArH);
13C NMR: 29.7, 30.0 (ArCH2Ar), 30.8, 31.3 [C(CH3)3], 34.2,
34.3 [C(CH3)3], 60.6, 62.4 (OCH3), 76.8 (OCH2Ar), 160.0
(CO); MALDI-TOF MS m/z (Ditranol + NaI), 2131.0
4-Benzyloxybenzoic acid (10).
A
suspension of ethyl
4-hydroxybenzoate (300 mg, 1.81 mmol) and NaH 60% (87
mg, 3.61 mmol) in DMF (20 mL) was stirred at rt for 1 h and
benzyl bromide (0.32 mL, 2.72 mmol) was added. The mixture
was stirred for 4 h, evaporated, and the residue was parti-
tioned between CH2Cl2 and HCl (1 M). The organic layer was
washed (H2O), dried (MgSO4), and evaporated. The residue
was dissolved in THF, KOH (50 mg) was added, and the
mixture was heated under reflux for 24 h. The solvent was
evaporated, the residue was partitioned between CH2Cl2 and
HCl (1 M), the organic layer was washed with H2O, dried
(MgSO4) and evaporated. The residue chromatographed
(flash, hexane–THF 9 : 1) to give 10, (320 mg, 78%) as a
[M]+, 2154.0 [M
138H192N4O14: C, 77.78; H, 9.08; N, 2.63. Found: C, 77.53;
H, 9.19; N, 2.83.
+
Na]+. Anal. (%): Calc. for
C
1
colorless solid, mp 89 1C. H NMR: 5.14 [s, 2H, OCH2Ar),
Calix[6]arene channel, 8. This was prepared by general the
procedure, from 19 (100 mg, 0.089 mmol) and 12DA12 (42 mg,
0.067 mmol). Yield: 189 mg, 75%, mp 254 1C; 1H NMR: 1.07
[s, 18H, C(CH3)3], 1.13 [s, 9H, C(CH3)3], 1.26 [s, 18H,
C(CH3)3], 1.30 [m, 36H, (CH2)9], 1.64 (m, 4H, CH2), 2.69
(m, 8H, CH2–N–CH2), 2.73 (s, 8H, OCH3 + ArCH2Ar), 3.04
(s, 3H, OCH3), 3.07 (4H, CH2NHCO), 3.29 (s, 6H, OCH3),
3.38 (m, 8H, CH2NHCO + ArCH2Ar), 3.64 (m, 16H,
CH2OCH2CH2OCH2), 3.83 (m, 4H, ArCH2Ar), 4.36 (m,
2H, ArCH2Ar), 4.91 (s, 2H, OCH2Ar), 5.81 (2H, NH), 6.81
(d, J = 2.4 Hz, 2H, ArH), 6.98 (d, J = 2.4 Hz, 2H, ArH), 7.02
(s, 2H, ArH), 7.18 (d, J = 2.4 Hz, 2H, ArH), 7.26 (d, J = 2.4
Hz, 2H, ArH), 7.31–7.40 (m, 3H, ArH), 7.47–7.49 (m, 2H,
ArH), 7.48 (s, 2H, ArH); 13C NMR: 27.0, 29.3, 29.5, 29.7
[(CH2)10], 29.7, 30.2, 31.2 (ArCH2Ar), 31.3, 31.5, 31.6
[C(CH3)3], 34.0, 34.1, 34.2 [C(CH3)3], 40.1 (CH2NH), 50.4
(CH2NCH2), 59.9, 58.0, 60.0 (OCH3), 69.7, 69.9 (CH2OCH2-
CH2OCH2), 74.8 (OCH2Ar), 124.8, 124.9, 126.8, 127.2, 127.7,
127.8, 128.0, 128.2, 128.5, 128.6, 129.7 (ArH), 132.2, 133.4,
133.5, 133.8, 135.9, 145.8, 146.2, 153.4, 154.3, 158.8 (ArC),
168.5 (CO); MALDI-TOF MS m/z (Ditranol + NaI), 2836.0
[M + H]+, 2859.0 [M + Na]+. Anal. (%): Calc. for
7.02 (d, 2H, J = 7.8 Hz, Ar), 7.36–7.44 (m, 5H, Ar), 8.06 (d,
2H, J = 7.8 Hz, Ar); 13C NMR: 70.8 (OCH2Ar), 114.2, 127.3,
127.5, 128.8, 131.9 (ArH), 121.9, 136.4, 162.3 (Ar), 169.3 (CO);
electrospray MS m/z, 229.2 [M]+. Anal. (%): Calc. for
C14H12O3: C, 73.67; H, 5.30. Found: C, 73.62; H, 5.27.
26-Benzyloxy-11,17,23-tri-tert-butyl-25,27,28-trihydroxyca-
lix[4]arene, 11 (cone). A suspension of 25,27,28-tribenzoyloxy-
11,17,23-tri-tert-butyl-26-hydroxycalix[4]arene 12,31 (0.5 mg,
0.55 mmol) and NaH 60% (27 mg, 0.66 mmol) in DMF (200
mL) was stirred for 1 h at rt, benzyl bromide (0.79 mL, 0.66
mmol) was added, and the mixture was stirred for 4 h. After
evaporation of the solvent, the residue was partitioned be-
tween CH2Cl2 and HCl (1 M), the organic layer was washed
(H2O), dried (MgSO4) and evaporated. The residue was dis-
solved in THF, KOH (100 mg) was added, and the mixture
was heated (reflux) for 24 h. The solvent was evaporated, the
residue was partitioned between CH2Cl2 and HCl (1 M), the
organic layer was washed (H2O) dried (MgSO4), and evapo-
rated. Chromatography (flash, hexane–THF 9 : 1) gave 11
(cone), (350 mg, 93%) as a colorless solid, mp 221 1C. 1H
NMR: 1.23 [s, 9H, C(CH3)3)], 1.26 [s, 18H, C(CH3)3)], 3.43 (d,
2H, J = 13.7 Hz, ArCH2Ar), 3.45 (d, 2H, J = 13.1 Hz,
ArCH2Ar), 4.24 (d, 2H, J = 13.7 Hz, ArCH2Ar), 4.38 (d, 2H,
J = 13.1 Hz, ArCH2Ar), 5.23 (s, 2H, OCH2Ar), 6.95 (t, 1H, J
= 7.5 Hz, ArH), 7.02 (s, 2H, ArH), 7.04 (d, 2H, J = 2.4 Hz,
ArH), 7.07 (d, 2H, J = 2.4 Hz, ArH), 7.14 (s, 1H, ArH), 7.16
(s, 1H, ArH), 7.49–7.56 (m, 3H, ArH), 7.73–7.75 (m, 2H,
ArH), 9.28 (s, 2H, OH), 9.69 (s, 1H, OH). 13C NMR: 31.4,
31.5 [C(CH3)3], 32.1, 32.8 (ArCH2Ar), 33.9 [C(CH3)3], 79.3
(OCH2Ar), 125.2, 125.7, 125.9, 126.2, 128.95, 129.0, 129.1,
129.3 (ArH), 127.4, 127.9, 128.1, 134.7, 135.6, 143.1, 143.8,
147.0, 148.6, 151.5 (Ar); MALDI-TOF MS m/z (Ditranol +
NaI), 682.4 [M]+, 705.4 [M + Na]+. Anal. (%): Calc. for
C47H54O4: C, 82.66; H, 7.97. Found: C, 82.34; H, 7.98.
C
186H256N4O18: C, 78.77; H, 9.10; N, 1.98. Found: C, 78.95;
H, 9.29; N, 2.09.
4-Carboxymethyloxybenzoic acid, 9. A suspension of ethyl 4-
hydroxybenzoate (300 mg, 1.81 mmol) and K2CO3 (500 mg,
3.61 mmol) in Me2CO (25 mL) was stirred at rt (1 h) and
methyl bromoacetate (0.25 mL, 2.72 mmol) was added. After
stirring an additional 4 h, the solvent was removed in vacuo
and the residue was partitioned between CH2Cl2 and HCl (1
M). The organic layer was washed with H2O, dried (MgSO4)
and evaporated. The residue was dissolved in THF, then KOH
(50 mg) was added, and the mixture was heated under reflux
for 24 h. The solvent was evaporated, the residue was parti-
tioned between CH2Cl2 and HCl (1 M), and the organic layer
was washed (H2O), dried (MgSO4), and evaporated. The
residue was purified by flash column chromatography with
(hexane–THF 9 : 1) to give 9 (340 mg, 83%) as a colorless
solid, mp 97 1C. 1H NMR (DMSO-d6): 4.77 [s, 2H, OCH2CO),
25,27,28-Tribenzoyloxy-11,17,23-tri-tert-butyl-26-hydroxy-
calix[4]arene 12. This was prepared as previously reported.31
26-Benzyloxy-11, 17, 23-tri-tert-butyl-25, 27, 28-trimethoxy-
calix[4]arene, 13 (asymmetric partial cone : cone 3 : 1). A
suspension of 11 (200 mg, 2.9 mmol) and NaH 60% (70 mg,
1.74 mmol) in DMF (15 mL) was stirred for 20 min at rt, CH3I
(0.11 mL, 1.74 mmol) was added, and the mixture was stirred
for 2 h. The solvent was evaporated, the residue was parti-
tioned between CH2Cl2 and HCl (1 M), the organic layer was
7.02 (d, 2H, J = 7.5 Hz, Ar), 8.00 (d, 2H, J = 7.5 Hz, Ar); 13
C
NMR (DMSO-d6): 64.4 (OCH2CO), 113.9, 131.4 (ArH),
123.5, 161.9 (Ar), 168.2, 170.7 (CO); electrospray MS m/z,
196.0 [M]+. Anal. (%): Calc. for C9H8O5: C, 55.11; H, 4.11.
Found: C, 55.07; H, 4.08.
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washed (H2O), dried (MgSO4) and evaporated. Chromatogra-
phy (flash, hexane–THF 95 : 5) gave 13, (233 mg, 90%).
Asymmetric partial cone: 1H NMR: 1.07 [s, 9H, C(CH3)3)],
1.19 [s, 9H, C(CH3)3)], 1.38 [s, 9H, C(CH3)3)], 3.04 (s, 3H,
OCH3), 3.05 (d, 1H, J = 13.3 Hz, ArCH2Ar), 3.10 (d, 1H, J =
13.8 Hz, ArCH2Ar), 3.65–3.75 (m, 4H, ArCH2Ar), 3.65 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 4.06 (d, 1H, J = 13.8 Hz,
ArCH2Ar), 4.17 (d, 1H, J = 13.3 Hz, ArCH2Ar), 4.73 (d,
1H, J = 10.7 Hz, OCH2Ar), 4.82 (d, 1H, J = 10.7 Hz,
OCH2Ar), 6.23 (s, 2H, ArH), 6.34 (d, 1H, J = 7.2 Hz,
ArH), 6.44 (t, 1H, J = 7.2 Hz, ArH), 6.81 (d, 1H, J = 2.4
Hz, ArH), 6.88 (d, 1H, J = 7.2 Hz, ArH), 6.94 (d, 1H, J = 2.4
Hz, ArH), 7.01 (d, 1H, J = 2.4 Hz, ArH), 7.13 (d, 1H, J = 2.4
Hz, ArH), 7.36–7.44 (m, 3H, ArH), 7.51–7.53 (m, 2H, ArH).
13C NMR: 30.7, 31.1, 36.2, 36.6 (ArCH2Ar), 31.1, 31.2, 31.4
[C(CH3)3], 34.0, 34.2, 34.3 [C(CH3)3], 58.7, 59.7, 60.3 (OCH3),
76.0 (OCH2Ar), 122.0, 124.5, 124.9, 126.2, 126.3, 127.9, 128.4.
128.5, 130.7, 131.2 (ArH), 131.9, 132.5, 133.1, 134.7, 135.9,
136.2, 136.7, 137.6, 144.2, 144.5, 145.2, 154.9, 155.5 (Ar).
Cone: 1H NMR: 0.77 [s, 9H, C(CH3)3)], 1.41 [s, 18H,
C(CH3)3)], 3.18–3.19 (m, 4H, ArCH2Ar), 3.75 (s, 3H,
OCH3), 3.84 (s, 6H, OCH3), 4.36 (d, 2H, J = 14.0 Hz,
ArCH2Ar), 4.42 (d, 2H, J = 14.0 Hz, ArCH2Ar), 4.81 (s,
2H, OCH2Ar), 6.10 (s, 2H, ArH), 6.98 (m, 3H, ArH), 7.01 (s,
2H, ArH), 7.04 (s, 1H ArH), 7.08 (s, 1H ArH), 7.36–7,37 (m,
3H, ArH), 7.48–7.49 (m, 2H, ArH). 13C NMR: 31.4, 31.5
[C(CH3)3], 32.1, 32.7 (ArCH2Ar), 34.2, 34.3 [C(CH3)3], 60.5,
62.3 (OCH3), 79.8 (OCH2Ar), 125.3, 125.7, 125.8, 126.3, 128.8,
129.0, 129.1, 129.3 (ArH), 127.4, 127.8, 128.3, 134.9, 135.4,
143.2, 143.7, 146.8, 148.4, 151.5 (Ar); MALDI-TOF MS m/z
(Ditranol + NaI), 724.4 [M]+, 747.4 [M + Na]+. Anal. (%):
Calc. for C50H60O4: C, 82.83; H, 8.34. Found: C, 82.99; H,
8.20.
solution of 13 (500 mg, 0.67 mmol) in CHCl3 (50 mL) at 0 1C
and stirring was continued for 1 h. NaHSO3 (20 mL, 10% aq.)
was added to quench the reaction. The organic layer was
washed (H2O), dried (MgSO4), and evaporated. The residue
was precipitated from CHCl3–MeOH (3 : 1) to give 16 (498
mg, 90%). Asymmetric partial cone: 1H NMR: 1.07 [s, 9H,
C(CH3)3)], 1.10 [s, 9H, C(CH3)3)], 1.33 [s, 9H, [C(CH3)3)], 2.94
(s, 3H, OCH3), 3.05 (d, 1H, J = 13.4 Hz, ArCH2Ar), 3.09 (d,
1H, J = 13.4 Hz, ArCH2Ar), 3.62–3.64 (m, 4H, ArCH2Ar),
3.63 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 4.01 (d, 1H, J = 13.4
Hz, ArCH2Ar), 4.05 (d, 1H, J = 13.4 Hz, ArCH2Ar), 4.66 (d,
1H, J = 10.8 Hz, OCH2Ar), 4.73 (d, 1H, J = 10.8 Hz,
OCH2Ar), 6.38 (d, 1H, J = 2.4 Hz, ArH), 6.58 (d, 1H, J =
2.6 Hz, ArH), 6.93 (d, 1H, J = 2.4 Hz, ArH), 6.97 (d, 1H, J =
2.6 Hz, ArH), 7.03 (d, 1H, J = 2.4 Hz, ArH), 7.08 (d, 1H, J =
2.4 Hz, ArH), 7.13 (d, 1H, J = 2.4 Hz, ArH), 7.24 (d, 1H, J =
2.4 Hz, ArH), 7.36–7.44 (m, 3H, ArH), 7.51–7.53 (m, 2H,
ArH). 13C NMR: 30.9, 31.1, 36.3, 36.8 (ArCH2Ar), 31.2, 31.3,
31.5 [C(CH3)3], 34.1, 34.2, 34.4 [C(CH3)3], 58.6, 60.0, 60.8
(OCH3), 76.5 (OCH2Ar), 124.8, 125.2, 126.2, 126.5, 127.9,
128.4, 128.5, 130.2, 131.6 (ArH), 114.3, 131.9, 132.7, 133.1,
134.6, 134.9, 136.2, 136.3, 137.6, 143.2, 144.0, 145.2, 154.9,
1
155.3 (Ar). Cone: H NMR: 0.89 [s, 9H, C(CH3)3)], 1.31 [s,
18H, C(CH3)3)], 3.14 (d, 2H, J = 7.8 Hz, ArCH2Ar), 3.18 (d,
2H, J = 8.0 Hz, ArCH2Ar), 3.77 (s, 3H, OCH3), 3.80 (s, 6H,
OCH3), 4.29 (d, 2H, J = 8.0 Hz, ArCH2Ar), 4.31 (d, 2H, J =
8.00 Hz, ArCH2Ar), 4.75 (s, 2H, OCH2Ar), 6.50 (s, 2H, ArH),
6.69 (s, 2H, ArH), 7.08 (d, 2H, J = 2.4 Hz, ArH), 7.18 (d, 2H,
J = 2.4 Hz, ArH), 7.36–7.44 (m, 3H, ArH), 7.58–7.60 (m, 2H,
ArH). 13C NMR: 29.9, 30.1 (ArCH2Ar), 31.2, 31.5 [C(CH3)3],
34.2, 34.3 [C(CH3)3], 60.5, 62.7 (OCH3), 77.8 (OCH2Ar),
124.6, 124.7, 127.2, 127.7, 129.0, 131.5 (ArH), 115.0, 128.1,
130.7, 141.2, 143.3, 152.2, 153.1 (Ar); MALDI-TOF MS m/z
(Ditranol + NaI), 802.4 [M]+, 825.3 [M + Na]+. Anal. (%):
Calc. for C50H59O4; C, 74.70; H, 7.40. Found: C, 74.79;
H, 7.43.
5-Bromo-11,17,23, 29, 35-penta-tert- butyl-38-hydroxy-37,39,-
40,41,42-pentamethoxycalix[6]arene, 14. Br2 (0.13 mL, 2.5
mmol) was added dropwise to
a 0 1C solution of
5, 11, 17, 23, 29-penta-tert- butyl-37-hydroxy-38, 39, 40, 41,42-
pentamethoxycalix[6]arene, 15, (500 mg, 0.50 mmol) in CHCl3
(50 mL). The solution was allowed to warm to ambient
temperature while stirring for 1 h, whereupon 10% aq. NaH-
SO3 (10 mL) was added to quench the reaction. The organic
layer was washed with water, dried (MgSO4), and evaporated.
The residue was triturated with MeOH to give 14, (490 mg,
38- Benzyloxy- 5- bromo-11, 17, 23, 29, 35- penta-tert- butyl-
37,39,40,41,42-pentamethoxycalix[6]arene, 17. A suspension of
14 (630 mg, 0.59 mmol) and NaH 60% (36 mg, 0.88 mmol) in
THF (40 mL) was heated at 80 1C for 1 h. Benzyl bromide
(0.11 mL, 0.88 mmol) was added and the mixture was refluxed
for 5 h. The solvent was evaporated and the residue was
partitioned between CH2Cl2 and HCl (1 M). The organic layer
was washed (H2O), dried (MgSO4) and evaporated. The
residue was precipitated from MeOH to give 17 (439 mg,
1
92%) as a colorless solid, mp 190 1C. H NMR: 0.95 [s, 9H,
C(CH3)3], 1.07 [s, 18H, C(CH3)3], 1.11 [s, 18H, C(CH3)3], 2.93
(s, 6H, OCH3), 3.14 (s, 6H, OCH3), 3.41 (s, 3H, OCH3), 3.69
(br s, 4H, ArCH2Ar), 3.85 (br s, 8H, ArCH2Ar), 6.83 (s, 2H,
ArH), 6.86 (d, J = 2.4 Hz, 2H, ArH), 6.91 (s, 2H, ArH), 6.94
(s, 4H, ArH), 6.99 (d, J = 2.4 Hz, 2H, ArH), 7.73 (s, 1H, OH).
MALDI-TOF MS m/z (Ditranol + NaI), 1064.6 [M + H]+,
1087.6 [M + Na]+.
1
65%), mp 205 1C. H NMR: 1.06 [s, 18H, C(CH3)3], 1.28 [s,
9H, C(CH3)3], 1.32 [s, 18H, C(CH3)3], 2.63 (s, 6H, OCH3), 2.77
(s, 3H, OCH3), 3.41 (s, 6H, OCH3), 3.53 (br s, 6H, ArCH2Ar),
3.86–4.00 (br s, 6H, ArCH2Ar), 4.97 (s, 2H, OCH2Ar), 6.77 (d,
J = 2.2 Hz, 2H, ArH), 6.87 (br s, 2H, ArH), 6.91 (d, J = 2.2
Hz, 2H, ArH), 7.15 (s, 2H, ArH), 7.17 (d, J = 2.2 Hz, 2H,
ArH), 7.20 (d, J = 2.2 Hz, 2H, ArH), 7.38–7.44 (m, 3H, ArH),
7.51–7.55 (m, 2H, ArH). 13C NMR: 30.9 (ArCH2Ar), 31.3,
31.5 [C(CH3)3], 34.1, 34.2 [C(CH3)3], 59.9, 60.0 (OCH3), 74.7
(OCH2Ar), 124.9, 126.6, 127.7, 127.9, 128.1, 128.6, 130.2
(ArH), 132.5, 133.4, 133.60, 133.64, 137.7, 145.8, 146.2,
153.4, 154.2 (ArC). MALDI-TOF MS m/z (Ditranol +
NaI), 1155.5 [M + H]+, 1177.4 [M + Na]+. Anal. (%): Calc.
5, 11, 17, 23, 29-Penta-tert-butyl-37-hydroxy-38,39,40,41,42-
pentamethoxycalix[6]arene, 15. This was prepared as pre-
viously reported.32
26-Benzyloxy-5-bromo-11, 17, 23-tri-tert-butyl-25, 27, 28-tri-
methoxycalix[4]arene, 16 (asymmetric partial cone : cone 5 : 1).
Br2 (0.13 mL, 2.5 mmol) was added dropwise to a cooled
ꢁc
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ꢂ
for C74H91BrO6 MeOH: C, 75.80; H, 8.06. Found: C, 75.92;
ArH), 7.07 (d, J = 2.4 Hz, 2H, ArH), 7.15 (d, J = 2.4 Hz, 2H,
ArH), 7.31–7.40 (m, 3H, ArH), 7.47–7.49 (m, 2H, ArH), 7.50
(s, 2H, ArH). 13C NMR: 29.7, 30.2, 31.2 (ArCH2Ar), 31.3,
31.5, 31.6 [C(CH3)3], 34.0, 34.1, 34.2 [C(CH3)3], 59.9, 59.96,
60.01 (OCH3), 74.8 (OCH2Ar), 124.8, 124.9, 126.8, 127.2,
127.7, 127.8, 128.0, 128.2, 128.5, 128.6, 129.7 (ArH), 132.4,
133.4, 133.5, 133.6, 135.7, 145.8, 146.2, 153.4, 154.3, 158.9
(ArC), 166.2 (CO). MALDI-TOF MS m/z (Ditranol + NaI),
1143.8 [M + Na]+. Anal. (%): Calc. for C75H92O8: C, 80.32;
H, 8.27. Found: C, 80.21; H, 8.49.
H, 8.14.
26-Benzyloxy-11,17,23-tri-tert-butyl-5-hydroxycarbonyl-25,27,-
28-trimethoxycalix[4]arene, 18,(asymmetric partial cone : cone 9 :
1). tert-Butyllithium (1.5 M solution in pentane) (0.96 mL, 1.3
mmol) was added dropwise to a ꢀ78 1C solution of 16 (0.5 mg,
0.63 mmol) in dry THF (10 mL). The resulting yellow solution
was stirred at ꢀ78 1C for 20 min. Cooling was continued at 0
1C and CO2 gas was bubbled in during 30 min. The solvent
was evaporated and the residue was partitioned between
CH2Cl2 and HCl (1 M). The organic layer was washed
(H2O), dried (MgSO4) and evaporated. The residue chroma-
tographed (flash, hexane–THF 8 : 1) to give 18 (395 mg, 82%).
Asymmetric partial cone: 1H NMR: 0.99 [s, 9H, C(CH3)3)],
1.22 [s, 9H, C(CH3)3)], 1.41 [s, 9H, C(CH3)3)], 3.02 (s, 3H,
OCH3), 3.13 (d, 1H, J = 13.5 Hz, ArCH2Ar), 3.15 (d, 1H, J =
13.3 Hz, ArCH2Ar), 3.71–3.79 (m, 4H, ArCH2Ar), 3.72 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 4.08 (d, 1H, J = 13.5 Hz,
ArCH2Ar), 4.17 (d, 1H, J = 13.3 Hz, ArCH2Ar), 4.78 (d,
1H, J = 8.0 Hz, OCH2Ar), 4.85 (d, 1H, J = 8.0 Hz,
OCH2Ar), 6.33 (d, 1H, J = 2.1 Hz, ArH), 6.92 (d, 1H, J =
2.1 Hz, ArH), 7.07 (d, 1H, J = 2.2 Hz, ArH), 7.13 (d, 1H, J =
2.2 Hz, ArH), 7.15 (d, 1H, J = 2.1 Hz, ArH), 7.27–7.28 (m,
2H, ArH), 7.30–7.38 (m, 3H, ArH), 7.41–7.45 (m, 2H, ArH),
7.80 (d, 1H, J = 2.1 Hz, ArH). 13C NMR: 30.9, 31.2, 36.5,
36.9 (ArCH2Ar), 31.1, 31.5, 31.7 [C(CH3)3], 33.4, 33.8, 34.3
[C(CH3)3], 58.4, 59.8, 60.6 (OCH3), 76.7 (OCH2Ar), 124.9,
125.2, 126.2, 126.4, 127.3, 128.2, 128.3, 128.6, 128.61, 130.4,
131.8 (ArH), 132.0, 132.7, 132.8, 133.2, 134.6, 134.8, 135.8,
136.4, 137.3, 143.5, 144.2, 145.4, 151.6, 154.8, 155.3, 155.7
(Ar), 161.0 (CO). Cone: 1H NMR: 0.69 [s, 9H, C(CH3)3)], 1.43
[s, 18H, C(CH3)3)], 3.18 (d, 2H, J = 13.1 Hz, ArCH2Ar), 3.20
(d, 2H, J = 13.0 Hz, ArCH2Ar), 3.73 (s, 3H, OCH3), 3.85 (s,
6H, OCH3), 4.38 (d, 2H, J = 13.1 Hz, ArCH2Ar), 4.41 (d, 2H,
J = 13.0 Hz, ArCH2Ar), 4.86 (s, 2H, OCH2Ar), 6.24 (s, 2H,
ArH), 7.21 (br s, 6H, ArH), 7.27–7.28 (m, 2H, ArH), 7.41–7.45
(m, 3H, ArH). 13C NMR: 29.7, 30.0 (ArCH2Ar), 30.8, 31.3
[C(CH3)3], 34.2, 34.3 [C(CH3)3], 60.6, 62.4 (OCH3), 76.8
(OCH2Ar), 160.0 (CO); MALDI-TOF MS m/z (Ditranol +
NaI), 768.4 [M]+, 791.4 [M + Na]+. Anal. (%): Calc. for
C51H60O6: C, 79.65; H, 7.86. Found: C, 79.05; H, 7.62.
26-Benzyloxy-11,17,23-tri-tert-butyl-25,27,28-trimethoxy-5-
methoxycarbonylcalix[4]arene, 20,(asymmetric partial cone :
cone 9 : 1). A suspension of 18 (250 mg, 0.33 mmol), Cs2CO3
(530 mg, 1.63 mmol) and CH3I (1 mL, 16.3 mmol) in THF (25
mL) was stirred for 12 hours at rt, the mixture was evaporated,
and the residue was partitioned between CH2Cl2 and HCl (1
M). The organic layer was washed (H2O), dried (MgSO4) and
evaporated. The residue was chromatographed (flash, hexa-
ne–THF 95 : 5) to give 20 (200 mg, 81%). Asymmetric partial
1
cone: H NMR: 0.86 [s, 9H, C(CH3)3], 1.10 [s, 9H, C(CH3)3],
1.28 [s, 9H, C(CH3)3], 2.91 (s, 3H, OCH3), 2.98–3.03 (m, 2H,
ArCH2Ar), 3.55–3.64 (m, 4H, ArCH2Ar), 3.58 (s, 3H, OCH3),
3.61 (s, 3H, OCH3), 3.66 (s, 3H, CO2CH3), 3.96 (d, 1H, J =
13.9 Hz, ArCH2Ar), 4.04 (d, 1H, J = 13.9 Hz, ArCH2Ar),
4.64 (d, 1H, J = 11.1 Hz, OCH2Ar), 4.72 (d, 1H, J = 11.0 Hz,
OCH2Ar), 6.22 (d, 1H, J = 2.0 Hz, ArH), 6.79 (d, 1H, J = 2.0
Hz, ArH), 6.96 (d, 1H, J = 2.2 Hz, ArH), 7.01 (d, 1H, J = 2.2
Hz, ArH), 7.02 (d, 1H, J = 2.1 Hz, ArH), 7.08 (s, 1H, ArH),
7.15 (s, 1H, ArH), 7.29–7.31 (m, 3H, ArH), 7.39–7.42 (m, 2H,
ArH), 7.60 (d, 1H, J = 2.1 Hz, ArH). 13C NMR: 30.9, 31.5,
31.7 [C(CH3)3], 30.9, 31.2, 36.6, 37.0 (ArCH2Ar), 33.4, 33.8,
34.2 [C(CH3)3], 51.4 (CO2CH3), 58.3, 59.8, 60.6 (OCH3), 76.6
(OCH2Ar), 124.9, 125.2, 126.2, 126.4, 127.3, 128.2, 128.3,
128.6, 128.61, 130.4, 131.8 (ArH), 132.0, 132.7, 132.8, 133.2,
134.6, 134.8, 135.8, 136.4, 137.3, 143.5, 144.2, 145.4, 151.6,
1
154.8, 155.3, 155.7 (Ar), 160.2 (CO). Cone: H NMR: 0.56 [s,
9H, C(CH3)3)], 1.31 [s, 18H, C(CH3)3)], 3.06–3.09 (m, 4H,
ArCH2Ar), 3.51 (s, 3H, CO2CH3), 3.64 (s, 3H, OCH3), 3.73 (s,
6H, OCH3), 4.24 (d, 2H, J = 9.8 Hz, ArCH2Ar), 4.29 (d, 2H, J
= 9.6 Hz, ArCH2Ar), 4.73 (s, 2H, OCH2Ar), 6.12 (s, 2H,
ArH), 7.01 (s, 2H, ArH), 7.08 (s, 4H, ArH), 7.26–7.31 (m, 3H,
ArH), 7.39–7.41 (m, 2H, ArH). 13C NMR: 30.7, 31.4
[C(CH3)3], 30.9, 31.0 (ArCH2Ar), 33.8, 34.2 [C(CH3)3], 51.3
(CO2CH3), 58.3, 60.5 (OCH3), 76.8 (OCH2Ar), 160.2 (CO);
MALDI-TOF MS m/z (Ditranol + NaI) 783.4 [M + H]+,
805.4 [M + Na]+. Anal. (%): Calc. for C52H62O6: C, 79.76; H,
7.98. Found: C, 79.55; H, 7.72.
38-Benzyloxy-11,17,23,29,35-penta-tert-butyl-5-hydroxycar-
bonyl-37,39,40,41,42-pentamethoxycalix[6]arene, 19. tert-Bu-
tyllithium (0.15 mL, 0.16 mmol) was added dropwise at
ꢀ78 1C to a solution of 17 (150 mg, 0.13 mmol) in dry THF
(10 mL). The resulting yellow solution was stirred at ꢀ78 1C
for 20 min, cooling was changed to an ice bath, and CO2 gas
was bubbled in during 30 min (0 1C). The solvent was
evaporated and the residue was partitioned between CH2Cl2
and HCl (1 M). The organic layer was washed (H2O), dried
(MgSO4) and evaporated. The residue was chromatographed
(flash, hexane–THF 8 : 1) to give 19 (110 mg, 76%) as a white
solid, mp 2201 C. 1H NMR (C2D2Cl4, 403 K (130 1C)): 0.99 [s,
18H, C(CH3)3], 1.20 [s, 9H, C(CH3)3], 1.25 [s, 18H, C(CH3)3],
2.69 (s, 6H, OCH3), 2.88 (s, 3H, OCH3), 3.29 (s, 6H, OCH3),
3.90 (s, 12H, ArCH2Ar), 4.97 (s, 2H, OCH2Ar), 6.72 (d, J =
2.4 Hz, 2H, ArH), 6.85 (d, J = 2.4 Hz, 2H, ArH), 7.04 (s, 2H,
38-Benzyloxy-11, 17, 23, 29, 35-penta-tert-butyl-37, 39,40,41,42-
pentamethoxy-5-methoxycarbonylcalix[6]arene, 21. A solution of
19 (230 mg, 0.21 mmol) and DCC (64 mg, 0.31 mmol) was
stirred at rt (5 h) in dry MeOH (5 mL), the solvent was
evaporated, and the residue was partitioned between CH2Cl2
and HCl (1 M). The organic layer was washed (H2O) dried
(MgSO4), evaporated, and chromatographed (flash, hexa-
ne–THF 9 : 1) to give 21 (175 mg, 75%) as a white solid,
mp 190 1C. 1H NMR: 0.98 [s, 18H, C(CH3)3], 1.27 [s, 9H,
C(CH3)3], 1.33 [s, 18H, C(CH3)3], 2.55 (s, 6H, OCH3),
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2.78 (s, 3H, OCH3), 3.42 (s, 6H, OCH3), 3.52 (s, J = 16.0 Hz,
2H, ArCH2Ar), 3.71 (s, 3H, CO2Me), 3.76 (s, J = 15.6 Hz,
2H, ArCH2Ar), 3.80 (s, J = 14.0 Hz, 2H, ArCH2Ar), 4.17 (s, J
= 14.0 Hz, 2H, ArCH2Ar), 4.20 (s, J = 15.6 Hz, 2H,
ArCH2Ar), 4.50 (s, J = 16.0 Hz, 2H, ArCH2Ar), 5.00 (s,
2H, OCH2Ar), 6.71 (d, J = 2.3 Hz, 2H, ArH), 6.87 (d, J = 2.3
Hz, 2H, ArH), 7.15 (s, 2H, ArH), 7.16 (d, J = 2.5 Hz, 2H,
ArH), 7.26 (d, J = 2.5 Hz, 2H, ArH), 7.35–7.44 (m, 5H, ArH),
7.54 (s, 2H, ArH). 13C NMR: 29.7, 30.5, 31.1 (ArCH2Ar),
30.2, 30.8, 31.5 [C(CH3)3], 34.0, 34.15, 34.2 [C(CH3)3], 51.7
(CO2Me) 59.9, 60.0 (OCH3), 74.8 (OCH2Ar), 124.7, 124.9,
126.8, 127.3, 128.0, 128.1 (ArH), 125.4, 128.6, 132.5, 133.4,
133.6, 135.4, 137.1, 145.7, 146.1, 153.4, 154.3 (ArC), 166.0
(CO). MALDI-TOF MS m/z (Ditranol + NaI), 1157.6 [M +
Na]+, 1233.6 [M + Na]+. Anal. (%): Calc. for C76H94O8: C,
80.38; H, 8.34. Found: C, 80.84; H, 8.12.
2H, ArH), 7.71 (s, 2H, ArH), 8.41 (s, 1H, OH). 13C NMR:
29.7, 30.9 (ArCH2Ar), 30.4, 31.3, 31.4 [C(CH3)3], 34.0, 34.1,
34.2 [C(CH3)3], 51.6 (CO2Me), 60.4, 60.42, 60.8 (OCH3),
125.4, 125.5, 125.9, 126.2, 126.5, 133.3 (ArH) 126.2, 130.3,
131.8, 132.9, 133.6, 133.7, 145.3, 145.7, 146.9, 152.8, 154.0,
154.4, 156.8 (ArC) 167.3 (CO). MALDI-TOF MS m/z
(Ditranol + NaI), 1067.6 [M + Na]+. Anal. (%): Calc. for
C69H88O8: C, 79.27; H, 8.48. Found: C, 79.57; H, 8.89.
11,17,23-Tri-tert-butyl-25, 27, 28-trimethoxy-5-methoxycar-
bonyl-26-methoxycarbonylmethyloxycalix[4]arene, 24 (asym-
metric partial cone : cone 9 : 1). A suspension of 22 (300 mg,
0.43 mmol) and K2CO3 (120 mg, 0.87 mmol) in CH3CN (50
mL) was heated at 80 1C for 1 h. Methyl bromoacetate (0.8
mL, 0.87 mmol) was added and heating continued for 3 h. The
solvent was evaporated, the residue was partitioned between
CH2Cl2 and HCl (1 M), the organic layer was washed (H2O),
dried (MgSO4), evaporated, and the residue was chromato-
graphed (flash, hexane–THF 8 : 2) to give 24 (190 mg, 69%).
Asymmetric partial cone: 1H NMR: 0.87 [s, 9H, C(CH3)3)],
1.08 [s, 9H, C(CH3)3)], 1.28 [s, 9H, C(CH3)3)], 2.71 (s, 3H,
OCH3), 3.12–3.15 (m, 1H, ArCH2Ar), 3.16–3.21 (m, 1H,
ArCH2Ar), 3.62 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.61 (s,
3H, CO2CH3), 3.70–3.80 (m, 4H, ArCH2Ar), 3.72 (s, 3H,
CO2CH3), 4.11 (d, 1H, J = 13.9 Hz, ArCH2Ar), 4.19 (d,
1H, J = 13.9 Hz, ArCH2Ar), 4.35 (d, 1H, J = 11.1 Hz,
OCH2CO), 4.57 (d, 1H, J = 11.0 Hz, OCH2CO), 6.34 (d, 1H,
J = 2.0 Hz, ArH), 6.92 (d, 1H, J = 2.0 Hz, ArH), 7.13 (br s,
2H, ArH), 7.18 (s, 1H, J = 1.9 Hz, ArH), 7.34 (br s, 2H, ArH),
7.68 (d, 1H, J = 1.9 Hz, ArH). 13C NMR: 30.8, 31.6, 31.7
[C(CH3)3], 30.9, 31.2, 36.3, 36.9 (ArCH2Ar), 33.4, 33.8, 34.2
[C(CH3)3], 51.5, 51.9 (CO2CH3), 58.4, 59.8, 60.6 (OCH3), 70.8
(OCH2CO), 124.9, 126.2, 126.4, 127.3, 128.2, 128.3, 128.6,
130.4, 131.8 (ArH), 132.0, 132.7, 132.8, 134.6, 134.8, 135.8,
136.4, 137.3, 143.5, 144.2, 145.4, 151.6, 154.8, 155.3, 155.7
(Ar), 159.8, 166.9 (CO). Cone: 1H NMR: 0.66 [s, 9H,
C(CH3)3)], 1.31 [s, 18H, C(CH3)3)], 3.20 (d, 2H, J = 10.0
Hz, ArCH2Ar), 3.23 (d, 2H, J = 9.8 Hz, ArCH2Ar), 3.19 (s,
3H, CO2CH3), 3.61 (s, 3H, OCH3), 3.73 (s, 6H, OCH3), 3.79
(s, 3H, CO2CH3), 4.40 (d, 2H, J = 9.8 Hz, ArCH2Ar), 4.42 (d,
2H, J = 10.0 Hz, ArCH2Ar), 4.49 (s, 2H, OCH2CO), 6.26 (s,
2H, ArH), 7.02 (s, 2H, ArH), 7.14 (s, 2H, ArH), 7.24 (s, 2H,
ArH). 13C NMR: 30.7, 31.4 [C(CH3)3], 30.9, 31.1 (ArCH2Ar),
33.8, 34.2 [C(CH3)3], 51.4, 51.9 (CO2CH3), 58.3, 60.5 (OCH3),
71.3 (OCH2CO), 159.8, 166.9 (CO); MALDI-TOF MS m/z
(Ditranol + NaI), 764.5 [M + H]+, 787.5 [M + Na]+. Anal.
(%): Calc. for C52H62O6: C, 75.36; H, 7.91. Found: C, 75.56;
H, 7.99.
11, 17, 23- Tri-tert- butyl-26-hydroxy-25,27,28-trimethoxy-5-
methoxycarbonylcalix[4]arene, 22 (cone : symmetric partial
cone 10 : 1). Hydrogen was bubbled into a suspension of 20
(0.5 g, 0.38 mmol), Pd/C (50 mg) in THF (50 mL) during 30
min. The mixture was filtered (celite), evaporated, and the
solid was triturated with EtOH, filtered, and dried to give 22
(262 mg, 100%). Cone: 1H NMR: 0.87 [s, 18H, C(CH3)3], 1.39
[s, 9H, C(CH3)3], 3.28 (d, 2H, J = 12.9 Hz, ArCH2Ar), 3.44
(d, 2H, J = 13.6 Hz, ArCH2Ar), 3.90 (s, 6H, OCH3), 3.96 (s,
3H, CO2Me), 4.01 (s, 3H, OCH3), 4.33 (d, 2H, J = 13.6 Hz,
ArCH2Ar), 4.35 (d, 2H, J = 12.9 Hz, ArCH2Ar), 6.56 (d, 2H,
J = 2.5 Hz, ArH), 6.63 (d, 2H, J = 2.5 Hz, ArH), 7.21 (s, 2H,
ArH), 7.30 (s, 1H, OH), 7.87 (s, 2H, ArH). 13C NMR: 31.1,
31.7 [C(CH3)3], 31.2, 31.3 (ArCH2Ar), 33.8, 34.2 [C(CH3)3],
51.7 (CO2CH3), 60.4, 63.0 (OCH3), 124.7, 125.4, 125.5, 130.3
(ArH), 120.2, 129.1, 130.8, 132.3, 135.7, 146.0, 152.9, 155.3,
158.3 (Ar), 167.7 (CO). Symmetric partial cone: 1H NMR: 1.14
[s, 18H, C(CH3)3)], 1.47 [s, 9H, C(CH3)3)], 2.59 (s, 3H, OCH3),
3.39 (d, 2H, J = 13.9 Hz, ArCH2Ar), 3.77 (s, 6H, OCH3), 3.89
(s, 4H, ArCH2Ar), 3.95 (s, 3H, CO2Me), 4.06 (d, 2H, J = 13.9
Hz, ArCH2Ar), 6.83 (d, 2H, J = 2.5 Hz, ArH), 7.08 (d, 2H, J
= 2.5 Hz, ArH), 7.33 (s, 2H, ArH), 7.82 (s, 1H, OH), 7.84 (s,
2H, ArH). 13C NMR: 31.1, 31.7 [C(CH3)3], 31.1, 38.4 (ArCH2-
Ar), 33.9, 34.2 [C(CH3)3], 50.9 (CO2CH3), 58.2, 60.8 (OCH3),
125.6, 127.0, 127.2, 130.3 (ArH), 120.2, 128.3, 131.7, 133.1,
133.5, 146.1, 146.3, 153.4 (Ar), 167.7 (CO); MALDI-TOF MS
m/z (Ditranol + NaI), 693.4 [M + H]+, 715.4 [M + Na]+.
Anal. (%): Calc. for C45H56O6: C, 78.00; H, 8.15. Found: C,
77.89; H, 8.03.
5, 11, 17, 23, 29-Penta-tert-butyl-38-hydroxy-37,39,40,41,42-
pentamethoxy-5-methoxycarbonylcalix[6]arene, 23. Hydrogen
was bubbled into a suspension of 21 (200 mg, 0.18 mmol),
Pd/C (20 mg) in THF (20 mL) during 30 min. The mixture was
filtered (celite), evaporated, and the solid was triturated with
EtOH. The mixture was filtered to give 23 (187 mg, 100%) as a
11,17,23,29,35-Penta-tert-butyl-37,39,40,41,42-pentamethoxy-
5- methoxycarbonyl- 38- methoxycarbonylmethyloxycalix[6]arene,
25. A suspension of 23 (150 mg, 0.14 mmol) and K2CO3 (29
mg, 0.21 mmol) in Me2CO (20 mL) was heated at 80 1C for 1
h. Methyl bromoacetate (19 mL, 0.21 mmol) was added and
heating continued for 5 h. The solvent was evaporated, the
residue was partitioned between CH2Cl2 and HCl (1 M), the
organic layer was washed (H2O), dried (MgSO4), evaporated,
and the residue was precipitated from MeOH to give 25 (135
mg, 87%) as a white solid mp 197 1C; 1H NMR: 1.03 [s, 18H,
1
white solid, mp 193–196 1C. H NMR: 1.06 [s, 9H, C(CH3)3],
1.17 [s, 18H, C(CH3)3], 1.19 [s, 18H, C(CH3)3], 3.02 (s, 6H,
OCH3), 3.32 (s, 6H, OCH3), 3.57 (s, 3H, OCH3), 3.83 (s, 3H,
CO2Me), 3.87 (s, 4H, ArCH2Ar), 3.98 (s, 8H, ArCH2Ar), 6.94
(s, 2H, ArH), 6.96 (d, J = 2.4 Hz, 2H, ArH), 7.02 (d, J = 2.5,
2H, ArH), 7.06 (d, J = 2.5 Hz, 2H, ArH), 7.11 (d, J = 2.4 Hz,
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C(CH3)3], 1.26 [s, 9H, C(CH3)3], 1.33 [s, 18H, C(CH3)3], 2.72
(s, 6H, OCH3), 2.84 (s, 3H, OCH3), 3.33 (s, 6H, OCH3), 3.74
(s, 3H, CO2Me), 3.79 (s, 3H, CO2Me), 3.98 (br s, 12H,
ArCH2Ar), 4.39 (s, 2H, OCH2CO2), 6.77 (s, 2H, ArH), 6.93
(s, 2H, ArH), 7.13 (s, 2H, ArH), 7.14 (s, 2H, ArH), 7.26 (s, 2H,
ArH), 7.58 (s, 2H, ArH). 13C NMR: 29.7, 30.1, 30.9 (ArCH2-
Ar), 29.5, 30.2, 31.4 [C(CH3)3], 34.0, 34.2, 34.2 [C(CH3)3],
51.8, 52.0 (CO2Me), 59.9, 60.0 (OCH3), 69.2 (OCH2CO2),
125.1, 126.6, 127.0, 127.5, 129.7 (ArH), 125.2, 125.8, 132.4,
133.3, 133.5, 133.6, 135.1, 145.6, 145.7, 146.3, 153.6, 154.2,
154.3, 157.7 (ArC), 166.3, 169.2 (CO); MALDI-TOF MS m/z
(Ditranol + NaI), 1139.7 [M + Na]+. Anal. (%): Calc. for
C72H92O10: C, 77.38; H, 8.30. Found: C, 77.05; H, 8.15.
3.46 (s, 3H, OCH3), 3.92 (s, 8H, ArCH2Ar), 3.98 (s, 4H,
ArCH2Ar), 6.71 (s, 2H, ArH), 6.73 (s, 2H, ArH), 6.85 (s,
2H, ArH), 7.04 (s, 4H, ArH), 7.84 (s, 2H, ArH). 13C NMR:
30.1, 30.2, 30.7 (ArCH2Ar), 30.8, 30.9, 31.3 [C(CH3)3], 33.4,
33.43, 33.5 [C(CH3)3], 59.5, 59.53, 59.9 (OCH3), 68.8 (OCH2-
CO2), 123.8, 124.2, 124.5, 126.5, 126.7, 132.0 (ArH), 123.9,
131.5, 132.3, 132.4, 132.7, 132.9, 134.5, 145.2, 145.6, 145.65,
153.0, 153.2 (ArC), 159.8, 167.1 (CO). MALDI-TOF MS m/z
(Ditranol + NaI), 1111.7 [M + Na]+. Anal. (%): Calc. for
C70H88O10: C, 77.17; H, 8.14. Found: C, 77.32; H, 8.41.
Acknowledgements
G. W. G. thanks the NIH for grants (GM 36262, GM 63190)
11,17,23-Tri-tert-butyl-5-hydroxycarbonyl-26-hydroxycarbo-
nylmethyloxy-25,27,28-trimethoxycalix[4]arene, 26 (asym-
metric partial cone : cone 9 : 1). A suspension of 24 (200 mg,
0.26 mmol) and KOH (50 mg) in THF (50 mL) was heated at
80 1C for 5 h. The solvent was evaporated, the residue was
partitioned between CH2Cl2 and HCl (1 M), the organic layer
was washed (H2O), dried (MgSO4), evaporated, and then
precipitated from MeOH to give 26 (175 mg, 92%).
Asymmetric partial cone: 1H NMR: 0.84 [s, 9H, C(CH3)3)],
1.12 [s, 9H, C(CH3)3)], 1.25 [s, 9H, C(CH3)3)], 2.75 (s, 3H,
OCH3), 3.15–3.25 (m, 2H, ArCH2Ar), 3.62 (s, 3H, OCH3),
3.74 (s, 3H, OCH3), 3.70–3.80 (m, 4H, ArCH2Ar), 4.17 (m,
1H, ArCH2Ar), 4.23 (m, 1H, ArCH2Ar), 4.35 (s, 2H, OCH2-
CO), 6.34 (d, 1H, J = 2.0 Hz, ArH), 6.92 (d, 1H, J = 2.0 Hz,
ArH), 7.13 (br s, 2H, ArH), 7.18 (s, 1H, J = 1.9 Hz, ArH),
7.34 (br s, 2H, ArH), 7.68 (d, 1H, J = 1.9 Hz, ArH). 13C
NMR: 30.8, 31.6, 31.7 [C(CH3)3], 30.9, 31.2, 37.7, 38.4
(ArCH2Ar), 33.4, 33.8, 34.2 [C(CH3)3], 58.4, 59.8, 60.6
(OCH3), 70.4 (OCH2CO), 124.9, 126.2, 126.4, 127.3, 128.2,
128.3, 128.6, 130.4, 131.8 (ArH), 132.0, 132.7, 132.8, 134.6,
134.8, 135.8, 136.4, 137.3, 143.5, 144.2, 145.4, 151.6, 154.8,
and P. P. and J. dM. thank the Ministero de Educacion y
´
Ciencia for grant (CTQ2005-08948) that supported this work.
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