Synthesis and characterization of chiral, bridged resorcinarenes as templates for asymmetric catalysis

Article abstract of DOI:10.1016/j.tet.2005.10.029

A full study of the synthesis of chiral, bridged resorcinarenes (3a-3l, 13a, 13b) is presented using Mannich condensation of C_2v- tetraprotected resorcinarenes with chiral 1,n-diamines bearing homochiral α-methylbenzyl auxiliaries at each termi

Full text of DOI:10.1016/j.tet.2005.10.029

Tetrahedron 62 (2006) 977–991
Synthesis and characterization of chiral, bridged resorcinarenes
as templates for asymmetric catalysis
*
Gareth Arnott, Roger Hunter and Hong Su
Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
Received 22 June 2005; revised 29 September 2005; accepted 13 October 2005
Available online 7 November 2005
Abstract—A full study of the synthesis of chiral, bridged resorcinarenes (3a–3l, 13a, 13b) is presented using Mannich condensation of C2v-
tetraprotected resorcinarenes with chiral 1,n-diamines bearing homochiral a-methylbenzyl auxiliaries at each terminal nitrogen. The study
has revealed the methodology to be applicable to preparing a broad range of bridged structures with varying lengths of bridge, different
functionality in the bridge and various protecting groups on the upper rim. Reproducible and satisfactory yields in the reaction were only
obtained with the pendant R group as methyl. The bridged adducts have been fully characterized by a range of spectroscopic techniques, and
NMR has revealed varying trends in the way the various bridges protrude into the cavity. Low temperature NMR as well as X-ray structures
of tetramesylate 15 and tetratoluate 3g has revealed hydrogen bonding to the amine nitrogens in the bridge to be an important control element
for positioning the bridge relative to the cavity of the bowl. The derivatives provide chiral templates for asymmetric catalysis studies using
cooperative effects in the bowl.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
recognition phenomenon. We have recently reported the
first example of an asymmetric reaction taking place in the
bowl,6 which we have termed intracavity asymmetric
catalysis, using chiral, distally-bridged resorcinarenes of
the type shown in Figure 1. In this paper we discuss the
scope of the methodology used for the synthesis of chiral
bridged resorcinarenes, along with new examples for use in
the study of asymmetric reactions occurring in the bowl.
It has long been a desire for synthetic chemists to achieve in
the laboratory what is seemingly so effortlessly achieved in
biological systems. While it is well known that enzymes can
efficiently regio- and stereoselectively catalyse a vast array
of organic transformations under mild conditions, a
synthetic example has yet to be produced that can match
an enzyme in rate acceleration, turnover and specificity.1
Recently, attention has been directed at utilizing calixarenes
and resorcinarenes as platforms for asymmetric processes
with many examples now reported on the use of these
frameworks for chiral recognition and discrimination
studies.2 Regarding catalysis, while the literature contains
examples of calixarenes and resorcinarenes that are used as
catalysts,3 few of them describe asymmetric catalysis. In
this regard, Matt has shown that a lower-rim, inherently
chiral calixarene scaffold can be used in allylic alkylation
(palladium) and hydrogenation (rhodium), although low ees
were obtained.4 Others have shown that cooperative effects
may potentially be provided by supramolecular interactions
involving the concave bowl.5 However, a comprehensive
picture has yet to emerge regarding application of directing
effects in the bowl towards designing superior asymmetric
catalysts for carrying out reactions rather than purely for
OMe
MeO
N
N
HO
OH
TsO
TsO
OTs
OTs
OH
HO
CH3
CH3
CH3
CH3
Figure 1. Example of a chiral, distally-bridged resorcinarene.
2. Strategy
Our strategy (Scheme 1) involved using the Mannich
reaction to prepare chiral, bridged resorcinarenes6 as C2v-
symmetric templates for catalysis, in which a functional
group in the middle of the bridge would offer opportunities
for intracavity catalysis. Our choice of Mannich
Keywords: Resorcinarene; Catalytic template; Mannich reaction.
*
Corresponding author. Tel.: C27 21 650 2544; fax: C27 21 689 7499;
e-mail: roger@science.uct.ac.za
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.029

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G. Arnott et al. / Tetrahedron 62 (2006) 977–991
X
X
N
H
N
H
n
n
X
X
1
N
N
n
n
YO
OY
Mannich
HO
OY
OH
+
OH
HO
YO
OH
YO
HO
R
YO
OY
OY
OH
HO
R
R
R
R
3
R
R
R
2
Scheme 1. Retrosynthetic strategy for formation of bridged resorcinarenes.
methodology for bridge introduction was inspired by a
¨
practical simplicity, since the desired C2v–tetra-Cbz
derivative intermediate precipitates out of the reaction
medium as a complex with 2 equiv triethylammonium
hydrochloride, thus ensuring high purity and easy access
to the desired product. After functionalising the
remaining four hydroxyl groups with a suitable electro-
phile, the Cbz groups can be removed by facile
hydrogenolysis furnishing new C2v-tetraprotected
resorcinarenes.
7,8
precedent set by Bohmer and Shivanyuk, who demon-
strated that primary diamines undergo Mannich reactions
with C2v–tetraprotected resorcinarenes and formaldehyde to
afford bridged bis-benzoxazines. We sought to adapt this
precedent to using secondary 1,n-diamines bearing a chiral
a-methylbenzyl unit at each nitrogen as a chiral auxiliary
for generation of enantiomerically pure C2v-symmetric
bridged resorcinarenes as catalyst templates. This methodo-
logy would provide the opportunity to incorporate desirable
functionality in the bridge by using functionalized diamine
lines of type 1 (varying n and X). In addition, other
structural parameters for developing a structure–activity
profile of catalysis included the choice of upper-rim
protecting groups Y in the C2v–array of resorcinarene 2,
as well as the pendant benzylic R groups.
There were many possible protecting-group targets for our
study, but essentially the aim was to evaluate a selection of
both large and small ones that might affect the steric
environment in the bowl of the final catalyst. One restriction
in setting about these syntheses was that the methodology
was only really practical on the tetramethylresorcinarene (2;
RZCH3, YZH), since resorcinarenes with longer pendant
chains generally gave little or no product in the acylation
reactions.9 Further studies in this area, though, may result in
C2v-protected resorcinarenes with longer pendant chains
such as the tetraundecylresorcinarene tetratosylate (2c;
RZC11H23, YZTos) used to synthesize 3c.10
Our previous work6 described the synthesis of bridged
resorcinarenes with YZtosylate, nZ1 and varying length of
benzylic R with or without ketal X groups in the bridge as
described in Table 1. In the comprehensive study described
in this paper, emphasis was focused on two parameters,
namely the length and nature of the bridge (n and X) and the
size and nature of the upper-rim protecting groups (Y).
The large number of possibilities for protecting groups
resulted in the decision to evaluate other sulfonates of
varying sizes, in view of the success of the tetratosylates. A
methanesulfonyl group (Mes) was identified as a good
example of a smaller protecting group than tosylate, with
2,4,6-triisopropylbenzenesulfonate (Trips) as one with
greater steric bulk. It was also thought desirable to evaluate
groups other than the sulfonate functionality in order to
probe electronic effects. Thus the bridged resorcinarene
tetrabenzyloxycarbonate (Cbz) was identified, also in view
of its ready availability9 as already mentioned, as well as the
resorcinarene tetra(p-tolyl) (Tol) ester since it was also
available by direct acylation of the parent resorcinarene
with p-toluoyl chloride.9 It was thought that evaluating this
bridged analogue would provide an interesting comparison
to the resorcinarene tetratosylate 3a in view of similarity in
steric size but difference in donor character around the
respective oxygen atoms. Likewise, the resorcinarene
tetraacetate (Ac) was also considered as one for making
an informative comparison with the resorcinarene tetra-
mesylate on steric grounds while at the same time com-
plementing the ester series. A tetramethylated resorcinarene
was also targeted for this study.
Table 1. Previously synthesized chiral bridged resorcinarenes
Y
R
n
X, X
3a
3b
3c
3d
3e
Tos
Tos
Tos
Tos
Tos
CH3
C5H11
C11H23
CH3
1
1
1
1
1
H
H
H
OMe
OCH2C(CH3)2CH2O
CH3
In order to install different upper-rim protecting groups
on the bridged resorcinarenes, it was necessary to
synthesize a series of appropriately C2v-protected resor-
cinarenes, which could be used in the Mannich reaction
with suitable diamines (cf. Scheme 1). This could be
achieved by using and expounding methodology
¨
9
developed by Shivanyuk and Bohmer in 1998, involving
either direct functionalisation with 4 equiv of electrophile
or through formation of the tetra-Cbz derivative, which
may then be used to form other C2v-protected resor-
cinarenes via a protection, deprotection (CBz) protocol.
The latter methodology is powerful in view of its

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
979
Scheme 2. Direct synthesis of C2v-protected resorcinarenes. Reagents and conditions: (i) YCl (4 equiv), Et3N (4 equiv), CH3CN, rt.
3. Results and discussion
It was also thought desirable to tetramethylate the
resorcinarene. Though resorcinarene tetratosylate 2a could
be tetramethylated using dimethyl sulphate, the tosyl groups
failed to be cleaved under basic conditions, a fact already
noted by Shivanyuk.9 Tetramethylation of the resorcinarene
tetracarbonate 2h or tetratoluate 2g unfortunately failed to
give the desired C2v-symmetrical product. Many conditions
were tried, using both dimethyl sulfate or methyl iodide as
methylating agent, and varying the type of base used
(sodium hydride, triethylamine, Hu¨nig’s Base). In one case
the reaction was attempted in neat methyl iodide, but in all
attempts the reactions gave mixtures of 3–5 unidentified
products, which were inseparable by chromatography. It
became clear, after stirring the tetracarbonate with sodium
hydride that the failure of these reactions was due to the
starting material undergoing some manner of transform-
ation. Tentatively it could be suggested that this was due to
the carbonate groups migrating around the resorcinarene
ring. Unfortunately, the phenolic hydroxyl oxygens are not
nucleophilic enough for direct alkylation and thus require
the use of a base to form the phenoxide, which resulted in
starting-material transformation. Direct methylation of
tetramethylresorcinarene (2; RZCH3 and YZH) did not
give the desired product; one isolated product revealed
tetramethylation by 1H NMR but did not show C2v-
symmetry.
3.1. Synthesis of alternative C2v-protected
resorcinarenes
Formation of the sterically demanding C2v-symmetrical
resorcinarene tetratripsylate 2f (2,4,6-triisopropyl-benzene-
sulfonate) was gratifyingly achieved in 34% yield† using the
methodology developed by Shivanyuk for tetratosylation
(Scheme 2).11 Similarly, both the C2v-resorcinarene tetra-
toluate 2g as well as the all-important C2v-resorcinarene
tetrabenzyloxycarbonate (CBz) 2h could be readily
obtained via the said literature procedure in 21 and 41%
yields, respectively.9
The resorcinarene tetraacetate 2k could be synthesized by
the method reported by Shivanyuk, involving acetylation of
the tetracarbonate 2h to give 2i in excellent yield followed
by quantitative cleavage of the protecting groups.9 For this
reaction, the authors used catalytic hydrogenolysis over
palladium supported on carbon in dioxane as a solvent. This
was probably due to the compound’s poor solubility in
ethanol. In the present work it was found that performing the
reaction in a solvent mixture of ethanol and THF (1:1 v:v) at
room temperature gave a better reaction profile than that
from using dioxane. Formation of the resorcinarene
tetramesylate 2l was also achieved in the same way as the
resorcinarene tetraacetate 2k (Scheme 3). To this end, mesyl
chloride was reacted with resorcinarene tetracarbonate 2h
in the presence of Hu¨nig’s base to give the required
tetramesylate derivative 2j in a good yield (75% after
recrystallization of the crude reaction product). The
mesylation was rapid being finished by tlc within 30 min
(from 0 8C to rt). Removal of the carbonate groups could
likewise be achieved as before using catalytic hydrog-
enolysis. Once again, a 1:1 mixture of ethanol and THF was
the preferred solvent, cleanly affording the desired
tetramesylate 2l after 6 h at room temperature.
3.2. Synthesis of bridged resorcinarenes
The synthesis of bridged resorcinarenes containing different
protecting groups, nZ1 and XZH, was achieved using the
methodology already described for synthesizing the bridged
resorcinarene tetratosylates.10 Thus each C2v-symmetrical
tetraprotected resorcinarene 2a–2l was heated in acetonitrile
with a slight excess of the diamine and paraformaldehyde in
large excess to yield distally-bridged products 3a–3l
(Scheme 4). Such conditions were found to be superior to
reaction with aqueous formaldehyde in ethanol, which
resulted in resorcinarene ethoxymethylation. Yields were
generally good except for the resorcinarene tetraacetate,
which was not optimized (Table 2).
† Yields for these types of reactions are typically less than 50% even
dropping to less than 10% owing to the formation of isomeric products.

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G. Arnott et al. / Tetrahedron 62 (2006) 977–991
2h
i
CbzO
OX
OH
XO
OCbz
XO
HO
OCbz
XO
OX
XO
OX
OX
CbzO
HO
OH
ii
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2i - 93% X = Ac
2j - 75% X = SO2CH3
2k - 100% X = Ac
2l - 100% X = SO2CH3
Scheme 3. Reagents on conditions: (i) XCl (5 equiv), i-Pr2NEt (6 equiv), DCM, rt; (ii) H2, Pd/C (10%), TH–FEtOH (1:1), rt.
Me
Me
H
H
N
N
OY
HO
OY
HO
YO
YO
HO
OH
OY
OH
YO
OY
YO
OH
HO
OH
i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2
3
Scheme 4. Reagents and conditions: (i) diamine 1 (1.2 equiv), (CH2O)n (10 equiv), 90 8C.
lithium aluminium hydride in refluxing THF to give diamine
6 in 95% yield for each step.
Table 2. Results for bridging reactions
Y
Yield (%)
3a
3f
3g
3h
3k
3l
Tos
Trips
Tol
Cbz
Ac
60
78
55
70
20
51
In a similar fashion, synthesis of the dimethoxy ketal-
functionalized diamine required 4-oxopimelic acid, which
could be derived from furfural in three steps. The first of the
steps converted furfural 7 into 3-(2-furyl)acrylic acid 8 via a
Knoevenagel reaction,12 by heating furfural with malonic
acid in pyridine at 100 8C for 2 1/2 h to give 8 in a good
overall yield (69% after recrystallization). Conversion of
acid 8 into the desired oxopimelic acid 9 was efficiently
carried out in two further steps by first refluxing the acid 8
in ethanol using a continuous passage of HCl gas.13
Distillation of the crude material obtained gave diethyl
pimelate as a clear oil which was readily saponified with
aqueous potassium hydroxide (3 M) at room temperature in
under 30 min, resulting in 4-oxopimelic acid 9 in 72%
overall yield. The coupling of a-methylbenzylamine was
again accomplished via a DCC coupling with the diacid to
give diamide 10 in good yield (83%). The penultimate step
required protection of the ketone carbonyl group as its
dimethoxy ketal, prior to reduction of the diamide. This was
Mes
3.3. Synthesis of longer diamines
The second parameter evaluated was the synthesis of
bridged resorcinarenes with longer bridges. Therefore it
became necessary to synthesize a longer diamine than type
1. This could be achieved using pimelic acid (heptanedioic
acid) 4 as starting material as shown in Scheme 5. Thus
pimelic acid was readily coupled to a-methylbenzylamine
under DCC conditions yielding the desired diamide 5 in
excellent yield. In this reaction the addition of hydroxy-
benzotriazole (HOBt) was found to be important for
preventing the formation of the N-acylated urea side-
product. Reduction of the diamide was achieved using
O
O
O
O
i
OH
Ph
HO
Ph
N
H
N
H
95%
4
5
95% ii
Ph
N
H
N
H
Ph
6
Scheme 5. Reagents and conditions: (i) a-methylbenzylamine, DCC, HOBt, CH2Cl2; (ii) LiAlH4, THF, reflux.

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
981
Scheme 6. Reagents and conditions: (i) malonic acid, pyridine, 100 8C; (ii) EtOH, HCl, reflux; (iii) KOH, H2O, rt; (iv) a-methylbenzylamine, DCC, HOBt,
CH2Cl2, rt; (v) CH(OCH3)3, MeOH, p-TsOH (cat), reflux; (vi) LiAlH4, THF, reflux.
achieved by refluxing 10 in excess trimethyl orthoformate
and catalytic p-toluenesulfonic acid overnight. This cleanly
afforded the desired ketal 11 in yields of up to 92%. Finally,
reduction of diamide 11 to diamine 12 was found to be
possible using lithium aluminium hydride in refluxing
diethyl ether, with the addition of triethylamine to attenuate
the slight Lewis acidity of the metal salts, Scheme 6.
1H and 13C NMR spectra to the bridged product 13a, the
only difference being that the signals in the 1H NMR were a
little less resolved. Its IR spectrum was no different to 13a,
but its optical rotation was opposite in sign and different in
magnitude (K7.08 vs C13.28 for 13a). MALDI-TOF mass
spectrometry revealed that this compound had a molecular
mass of 3047 amu corresponding to exactly twice the
molecular mass of bridged resorcinarene 13a. This
prompted us to conclude that the side-product isolated in
5% yield was dimer 14 (Fig. 2).
3.4. Synthesis of longer bridged resorcinarenes
The newly prepared longer chiral diamine line 6 was used to
bridge resorcinarene tetratosylate 2 (YZTos, RZCH3).
Using the standard reaction conditions, a maximum yield of
36% of the bridged product 13a was obtained (Scheme 7).
The low yield of bridged resorcinarene 13a was in contrast
to the better yields that were obtained for the bridged
resorcinarene using the shorter diamine line 3a.
This structure seems plausible as similar examples exist in
the literature, which have been well-documented and
reviewed.14 In 1998, Bohmer demonstrated this type of
¨
dimerisation with tetrapentylresorcinarene 2 (YZH, RZ
C5H11) and ethylenediamine under Mannich conditions,
giving an octabenzoxazine dimer linked by four bridges.15
¨
Bohmer reported that only ethylenediamine worked,
whereas 1,3-diaminopropane, and ethylenediamine deriva-
tives such as 1,2-diaminocyclohexane or N,N0-dimethyl-
ethylenediamine failed to give any defined reaction
product.15 This chiral resorcinarene dimer linked by two
bridges represents the first example of a dimer of this type.
This lower yield deserves mechanistic comment. It is
reasonable to assume that the bridging process is achieved
via two discrete steps, the first being the initial amino-
methylation, which is followed by a second, rate-determin-
ing aminomethylation step to close the bridge. The lower
yield for 13a from the longer line 6 may be accounted for by
assuming closure to be slower than for 3a on entropic
grounds (larger DS# Kve). The longer lifetime for the
mono-adduct from 6, would then increase the chances of an
intermolecular reaction. Careful scrutiny of the reaction tlc
revealed another product, which was slightly more polar
than the bridged product 13a. It had virtually identical
In a similar fashion, the functionalized, longer ketal-diamine
12 could be used to bridge resorcinarene 2 (YZTos,
RZCH3). This was performed in the usual manner at 90 8C
and gave 10% of the desired product 13b after one hour.
Increasing the number of equivalents of diamine from one to
three gave a vastly improved yield of 48%. With a slight
Scheme 7. Reagents and conditions: (i) diamine 6/12, (CH2O)n, CH3CN, 80 8C, 2 h.

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G. Arnott et al. / Tetrahedron 62 (2006) 977–991
resorcinarene. Thirdly, no hydroxyl signals were observed
suggesting a fast interconversion between hydrogen-bonded
modes to be occurring that creates very broad peaks on the
timescale of the NMR experiment. Fourthly, there was an
upfield shift of all the methylene protons on the bridge
relative to the starting diamine, with the central methylenes
experiencing the greatest shift; this feature is an important
indication that the bridge resides over the bowl, resulting in
anisotropic shielding by the aromatic rings comprising the
bowl.16 An increase in upfield shift from one resorcinarene
to another was interpreted as indication of the bridge
spending more time deeper within the cavity of the bowl.
Table 3 shows the variation in the chemical shift of the
central methylene group for the bridged resorcinarenes
synthesized. Going from 3a to 3b and then to 3c involving
lengthening of the pendant alkyl chain creates a confor-
mational change that encourages the bridge to spend more
time lower within the cavity. This may be due to increased
repulsion between the pendant R groups, resulting in the
upper-rim aromatic rings to fold inwards slightly forcing the
bridge to bury itself more into the cavity. In the case of 3a
versus 3h it would appear that the CBz protecting groups
have a similar effect, also resulting in the bridge to lie lower
in the cavity. Conversely, the sterically undemanding mesyl
groups with CH3 as the pendant R group (3l) releases the
line out of the cavity as indicated by a weaker shielding
effect compared to 3a. In the case of the longer bridge 13a,
the central methylene protons do not exhibit as great an
upfield chemical shift as 3a, indicating that the longer
bridge prefers to sit higher above the cavity than deeper in it,
presumably to maximize entropy.
Figure 2. Proposed structure of dimer 14.
decrease in reaction temperature, the yield could be further
optimized to 57%. Interestingly, in this case no dimer like 14
was observed, presumably because of the steric presence of
the ketal in the middle of the line.
4. Spectroscopic and conformational aspects
The NMR spectra of the bridged resorcinarenes were
remarkably straightforward to assign, owing to the high
degree of symmetry; a typical example of a 1H NMR
spectrum is shown in Figure 3 for resorcinarene 3h
(YZCBz). All of the NMR signals could be unambiguously
assigned using 2D-NMR techniques (HSQC and HMBC). A
Table 3. Comparison of chemical shifts for central methylene protons
1
n
Y
R
Central methylene Central methylene
(ppm)
few significant features of the H NMR spectra deserve
Dppm
comment. Firstly, the three singlets (marked with *) for the
resorcinarene aromatic methine protons of the bridged
products were used as markers to indicate that reaction had
successfully taken place at the positions ortho to both
hydroxyl groups of the tetraprotected resorcinarene.
1
1
1
1
1
1
1
1
1
1
2
2
—
—
1.27
0.90
0.72
0.70
0.99
0.93
0.77
0.84
1.05
1.32
1.10
—
3a
3b
3c
3f
3g
3h
3k
3l
Tos
Tos
Tos
Trips
Tol
Cbz
Ac
Ms
—
Tos
CH3
C5H11
C11H23
CH3
CH3
CH3
CH3
CH3
—
K0.37
K0.55
K0.57
K0.28
K0.34
K0.50
K0.43
K0.22
—
Secondly, a new signal between 3.71 and 3.78 ppm (singlet
in Figure 3, although in some cases appearing as a pair of
doublets owing to diastereotopicity; marked with Y) was
always observed for these structures corresponding to the
methylene protons on the carbon attaching the bridge to the
6
13a
CH3
K0.17
Figure 3. 1H NMR spectrum of resorcinarene 3h.

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
983
Me
Me
Me
Me
Me
H
N
Me
H
N
H
H
H
H
N
N
N
N
H
O
H
O
H
O
OTs
OTs
OTs
TsO
H
O
H
O
TsO
TsO
H
O
TsO
TsO
TsO
HO
OH
OH
OTs
OTs
OH
OTs
HO
OH
CH3
CH3
CH3
C2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C1
CH3
CH3
C2
Figure 4. Hydrogen bonded conformers of 3a.
Figure 5. High and low temperature 1H NMR spectra of 3a.
Finally, another important observation was the downfield
shift (O0.5 ppm) of the protons on the lower rim of the
protected resorcinol rings. Prior to bridging they were found
around 6.25 ppm, significantly upfield to what would be
expected. The reason for this has been attributed to the
resorcinarene existing in a boat conformation,17 since the
aromatic groups that are most horizontal have their protons
on the lower rim in the shielding zone of the vertical
aromatic rings. In the bridged compounds, the protons
appeared downfield at around 6.85 ppm (C/K0.20 ppm),
suggesting a change in shape towards the crown confor-
mation, though to what extent this change had occurred was
not pursued any further by NMR studies.
different hydrogen bonded modes slowed enough for the
individual diastereomers in Figure 4 to be observed. Figure 5
shows the aromatic region of the 1H NMR spectrum of 3a at
50 and K60 8C. At 50 8C there are 3 signals (marked with
Y) at 6.79, 6.83 and 7.11 ppm for the average of the
conformers. On cooling, the signals become increasingly
broadened and then resolved below K40 8C into separate
signals, becoming clear at K60 8C. By careful inspection
and integration it was possible to assign the signals for the
C1 conformer (5 signals marked with C), while 2 sets of 3
signals each could be seen for the C2 conformers (marked
with ) One extra signal could be attributed to a hydroxyl
proton.‡ Integration revealed that the different conformers
existed in an approximate ratio of 1:1:1 (C2:C2:C1). The
signal at dZ6.92 ppm integrates for 2H.
The possibility of hydrogen bonding between the tertiary
amine nitrogens on the bridge and the phenolic hydroxyl
groups on the resorcinarene was also considered as an
important structural feature. Such bonding would generate
three diastereomeric structures as shown in Figure 4; two
with C2 symmetry and one with C1 symmetry. The C1-
symmetric structure would be expected to show 5 singlets
It is possible that H-bonding could affect the conformation
of the bridged resorcinarene, and therefore the hydroxyl
substituents were suitably protected. The latter are however
not easy to functionalize,18 and it was thus decided to use
mesyl chloride as a small reactive electrophile. Mesylation
using excess mesyl chloride and Hu¨nig’s base in dichloro-
methane was successful in furnishing the desired tetra-
mesylated product 15 in a favourable 87% yield (Scheme 8).
1
for its aromatic methine protons in its H NMR spectrum,
while the C2-symmetric isomers would show three singlets
each. This distribution as expected was not seen at
temperatures above room temperature, owing to confor-
mational exchange. However, on cooling to 0 8C the
resorcinarene aromatic signals became very broad and
indistinct. Further cooling to K60 8C revealed a far more
complex picture, in which the rate of ‘flipping’ between the
‡ As mentioned, the hydroxyl protons are invisible at normal NMR
temperatures owing to the rapid hydrogen bonding exchange. On cooling,
the signals at 6.24 ppm and at 13.10 ppm (not shown) become visible.

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G. Arnott et al. / Tetrahedron 62 (2006) 977–991
Scheme 8. Reagents and conditions: (i) mesyl chloride (20 equiv), i-Pr2EtN (20 equiv), DCM, rt.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0
Figure 6. 1H NMR spectrum of resorcinarene 15.
1
from the H NMR, and also provided the answer to the
upfield shift of the pendant methyl groups. As can be seen in
Figure 7, the aromatic groups of the tosylate groups are
pointing downwards towards the lower rim in order to
The 1H NMR spectrum (Fig. 6) of 15 provided some
surprises, notably that the methylene protons in the centre of
the bridge were now found at K0.95 ppm, representing a
massive 2.22 ppm upfield shift from the diamine 1 (prior to
bridging). This could only be attributed to the bridge
spending a much higher percentage of its time deep within
the resorcinarene cavity. This might arise from the disruption
of the hydrogen bonding with the amines, allowing the bridge
to ‘collapse’ into the cavity, analogous to what happens if the
supports of a suspension bridge are removed.
Furthermore, another intriguing spectroscopic observation
was a 0.45 ppm upfield shift of the signals for the pendant
methyl groups on the resorcinarene (from 1.37 to 0.89 and
0.93 ppm). The reason for this was not made clear until a
single crystal X-ray structure determination was realised.
Great difficulty was experienced in trying to grow suitable
crystals for X-ray diffraction. Eventually a suitable crystal
was found in a solution of toluene, acetone and
dichloromethane. 15 crystallized in the space group
P21212 with ZZ4, with two dichloromethane molecules
of solvation which were located in five different positions
in the unit cell with partial occupancies. As a result, the
structure could not be refined satisfactorily because the
dichloromethane molecules were highly disordered with
large temperature factors. Therefore, the fractional atomic
coordinates of the structure are not reported. Only the unit
cell parameters are listed in the supplementary data. The
positions of the resorcinarene atoms alone were located
unambiguously and its molecular conformation can thus be
reported. This is given by the torsion angles listed in the
supplementary data.
The X-ray picture of 15 as an ORTEP diagram (ellipsoidal
model at 30% probability level) revealed the bridge to be
positioned inside the cavity in accordance with predictions
Figure 7. X-ray structure of 15.

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
985
5. Conclusions
This paper has extended the methodology developed
previously,6,9 to the synthesis of a range of new, chiral,
bridged resorcinarenes, which have been fully characterized
by NMR and X-ray techniques resulting in the observation
of some interesting aspects of bridge-positioning relative to
the cavity of the bowl. In the following paper, a
comprehensive study is presented on the use of these
derivatives as asymmetric templates for the catalyzed
enantioselective addition reaction of diethylzinc to benzal-
dehyde, which is considered to be one the first reported
examples of using the bowl of an asymmetrically
functionalized resorcinarene for promoting asymmetric
catalysis,6 as suggested recently by Iwanek.19 The results
are rationalized using a stereoselectivity model.
6. Experimental
6.1. General remarks
All reactions were carried out under nitrogen using dry
solvents. Nuclear Magnetic Resonance spectra were
recorded on a Varian Unity 400 (100 MHz for 13C) or
Varian Mercury 300 MHz (75 MHz for 13C) and were
carried out in chloroform-d. Optical rotations were obtained
using a Perkin Elmer 141 polarimeter at 20 8C. Melting
points were obtained using a Reichert Jung Thermovar hot-
stage microscope and are uncorrected. Elemental analyses
were performed using a Fisons EA 1108 CHN elemental
analyser. Infrared spectra were recorded on a Perkin–Elmer
Paragon 1000 FT-IR spectrometer in either dichloro-
methane or chloroform. Resorcinarenes 2a,g–i were
synthesized according to the literature procedures.9 Bridged
resorcinarenes 3a–e have been reported previously.6,10
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
273318 and 273319. Copies of the data can be obtained
free of charge from CCDC via www.ccdc.cam.ac.uk/
data_request/cif. Names and numbering of compounds
follows IUPAC ‘phane’ nomenclature rules;§ Figure 9
shows two examples of this.
Figure 8. X-ray structure of 3g.
minimize repulsion with the mesylate groups. As a result,
they are in a position to anisotropically shield the pendant
methyl groups.
It is clear from this X-ray structure that the hydrogen
bonding in the bridged resorcinarene is important in
maintaining a preferred shape by: (a) keeping the bridge
above the cavity, potentially allowing reactions to be
accommodated there; and (b) holding the protecting groups
up instead of down allowing for potential cooperative
effects in the bowl.
It was thus hoped that an X-ray structure of a hydrogen-
bonded bridged resorcinarene could be obtained. Suitable
crystals were not readily obtainable, but eventually slow
evaporation of a solution of tetratoluate 3g in diisopropyl
ether, pentane and dichloromethane resulted in the
formation of diffraction-quality crystals, although they
were very unstable outside their mother liquor. Bridged
resorcinarene 3g crystallized in the space group P1 with
ZZ2 as a dipentane solvate. There are thus two independent
resorcinarene host molecules and four pentane guest
molecules in the unit cell, all located at general positions.
We note that the comformation of the two independent
resorcinarene molecules are very similar, and Figure 8
shows one of these structures. The unit cell parameters and
other crystal data and refinement data are given in the
supplementary data.
6.1.1. 34,36,74,76-Tetrahydroxy-2,4,6,8-tetramethyl-
14,16,54,56-tetra(20,40,60-triisopropylbenzene-sulfonyl-
oxy)-1,3,5,7(1,3)tetrabenzenacyclooctaphane (2f). Tetra-
methyl-resorcinarene 2 (RZCH3, YZH) (3.27 g, 6 mmol)
was dissolved in acetonitrile (60 mL) and triethylamine
(3.35 mL, 24 mmol) added. The pink, heterogeneous
solution was stirred at room temperature for 15 min and
then 2,4,6-triisopropylbenzenesulfonyl chloride (5.16 g,
6 mmol) was added in one portion. The reaction was
allowed to stir at room temperature overnight, followed by
filtration of the solid precipitate formed. The precipitate was
washed with cold acetonitrile (2!20 mL) and then
dissolved in dichloromethane (75 mL). 1 M HCl (100 mL)
was added and the product extracted into dichloromethane
(3!50 mL). After drying (MgSO4) and evaporation, the
crude product was further purified by column
The X-ray structure of 3g reveals a boat-like conformation
and demonstrates the effect that hydrogen bonding has on
the positioning of the bridge, sustaining it over the cavity
and with the protecting toluate ester groups held up
towards the cavity (as apposed to hanging downwards
as in 15).
§ For a full description see http://www.chem.qmul.ac.uk/iupac/

986
G. Arnott et al. / Tetrahedron 62 (2006) 977–991
6.1.3. 34,36,74,76-Tetra(benzyloxycarbonyloxy)-14,16,
5
5
OY
YO
5
6
54,56-tetra(methylsulfonyloxy)-2,4,6,8-tetramethyl-1,3,
5,7 (1,3)tetrabenzenacyclooctaphane (2j). Diisopropyla-
mine (3.06 mL, 17.6 mmol) and resorcinarene tetra-Cbz 2h
(3.46 g, 3.2 mmol) were added to dry dichloromethane
(40 mL) and the solution cooled to 0 8C. Mesyl chloride
(1.24 mL, 16 mmol) was added slowly and the reaction
allowed to warm to room temperature. After 30 min the
reaction was checked for completion (tlc) and then poured
into 1 M HCl (100 mL). The product was then extracted into
dichloromethane (3!70 mL), dried with magnesium sul-
phate and the solvent evaporated in the usual way.
Recrystallization of the crude product from DMF/ethyl
acetate/petroleum ether gave the title compound 2j (3.34 g,
75%) as a white powder. Mp 246–248 8C (from DMF/ethyl
acetate/petroleum ether); nmax/cmK1 (CHCl3) 1763s (C]O,
ester), 1375sC1169s (–SO2–); dH (300 MHz, CDCl3) 1.50
(12H, d, JZ7.1 Hz, –CH3), 2.88 (12H, s, –SO2CH3), 4.65
6
5
HO
OH
YO
OY
1
4
4
3
6
1
4
7
HO
3
OH
5
4
6
1
1
3
1
3
3
2
2
2
2
4
8
6
2
CH3
CH3
CH3
CH3
Me
Me
H
5
H
α
α
7
N
N
10
5
5
OY
8
YO
2
6
3
4
4
4
3
YO
HO
OH
OY
3
3
6
16
4
2
1
6
HO
OH
13
11
4
5
2
1
5
1
1
1
2
2
6
6 17
12
15
14
CH3
CH3
CH3
CH3
(4H, q, JZ7.1 Hz, H-2,4,6,8), 5.25C5.30 (8H, 2!d, JAB
Z
Figure 9. Example of numbering format for resorcinarenes.
12 Hz, H-20), 6.19C7.26 (4H, s, H-12,52 and H-32,72),
7.21C7.23 (4H, s, H-15,55 and H-35,75), 7.34–7.47 (20H,
m, Ph); dC (75 MHz, CDCl3) 20.0 (–CH3), 31.9 (C-2,4,6,8),
38.1 (–SO2CH3), 70.7 (C-20), 116.1C116.4, 125.6, 126.6,
128.6, 128.7, 128.8 (PhCC-12,52 and C-32,72 and 35,75 and
C-15,55), 134.6 (Ph), 134.3C135.5 (C-11,13,31,33,51,53,
71,73), 145.5C146.6 (C-34,36,74,76 and C-14,16,54,56),
153.2 (C-10); MALDI-TOF m/z (rel. int.) 1431.51
[MCK]C(28), 1415.20 [MCNa]C(100). Found: C, 58.81;
H, 4.66; S, 9.05%; C68H64O24S4 requires C, 58.61; H, 4.63;
S, 9.20%.
chromatography (60 g silica gel, eluting with ethyl acetate/
petroleum ether 1:4). In this way, tetratripsylresorcinarene
2f (3.3 g, 34%) could be prepared as a white solid. Mp 190–
192 8C (from DMF/ethyl acetate/petroleum ether); nmax
/
cmK1 (CHCl3) 3476sC3387s (O–H, H-bonded), 3015s
(C–H, aromatic), 2964sC2931 (CH3), 1599mC1514s (aryl
stretch), 1346sC1180s (–SO2–); dH (300 MHz, CDCl3)
1.11C1.13 (48H, 2!d, JZ6.8 Hz, 70/90-i-Pr), 1.21 (24H, d,
JZ6.8 Hz, 80-i-Pr), 1.38 (12H, d, JZ6.8 Hz, –CH3), 2.88
(4H, spt, JZ6.8 Hz, H-80), 3.93 (8H, spt, JZ6.8 Hz, H-70/90),
4.39 (4H, q, JZ6.8 Hz, H-2,4,6,8), 6.02 (2H, s, H-15,55),
6.31 (2H, s, H-32,72), 6.57 (2H, s, H-35,75), 7.03 (2H, s,
H-12,52), 7.16 (4H, br, –OH), 7.18 (8H, s, H-30,50); dC
(75 MHz, CDCl3) 20.0 (CH3), 23.4 (80i-Pr), 24.4 (70/90i-Pr),
29.9 (C-70/90), 31.9 (C-2,4,6,8), 34.2 (C-80), 102.0 (C-15,55),
113.5 (C-35,75), 119.0 (C-11,13,51,53), 124.1 (C-30,50),
125.2 (C-12,52), 127.0 (C-32,72), 129.5 (C-10), 139.1
(C-31,33,71,73), 144.8 (C-34,36,74,76), 151.2 (C-20,60),
153.2 (C-14,16,54,56), 154.5 (C-40); MALDI TOF: m/z (rel.
int.) 1609.4 [MCKH] (81), 1342.91 [MCKSO2Ar] (69),
1076.09 [MCKSO2Ar!2] (70), 809.27 [MCKSO2Ar!3]
(53), 542.06 [MCKSO2Ar!4] (45). Found: C, 68.58;
H, 7.54; S, 7.71%; C92H120O16S4 requires C, 68.63; H, 7.51;
S, 7.97%.
6.1.4. 34,36,74,76-Tetrahydroxy-14,16,54,56-tetra(methyl-
sulfonyloxy)-2,4,6,8-tetramethyl-1,3,5,7(1,3)tetrabenzena-
cyclooctaphane (2l). Resorcinarene 2j (1.4 g, 1 mmol)
was dissolved in a 1:1 solvent mixture of THF and ethanol
(60 mL). 10% Palladium on carbon (100 mg, 0.1 mmol) was
added and the solution stirred at room temperature under a
positive pressure of hydrogen. After 6 h the reaction was
checked for completion (tlc) and the catalyst filtered off
through Celitew, washing with dichloromethane (100 mL).
Evaporation of the solvent afforded tetramesylate 2l
(850 mg, 99%) as an off-white solid. Mp O300 8C (dec.);
nmax/cmK1 (KBr) 3494sC3389s (O–H, H-bonded), 3032s
(C–H, aromatic), 2968sC2933s (CH3), 1619mC1520s
(aryl stretch), 1354sC1184s (–SO2–) dH (300 MHz,
DMSO-d6) 1.42 (12H, d, JZ6.9 Hz, –CH3), 2.93 (12H, s,
–SO2CH3), 4.63 (4H, q, JZ6.9 Hz, H-2,4,6,8), 6.12 (2H, s,
H-12,52), 6.42 (2H, s, 15,55), 7.18 (2H, s, 35,75), 7.48 (2H, s,
32,72), 9.16 (4H, s, –OH); dC (75 MHz, DMSO-d6) 20.3
(CH3), 29.7 (C-2,4,6,8), 37.0 (SO2CH3), 102.0 (C-15,55),
114.0 (C-35,75), 122.6 (C-11,13,51,53), 125.2 (C-12,52),
6.1.2. 34,36,74,76-Tetraacetoxy-14,16,54,56-tetrahydroxy-
2,4,6,8-tetramethyl-1,3,5,7(1,3)tetrabenzenacycloocta-
phane (2k)9. Resorcinarene 2i (1 g, 0.8 mmol) was
dissolved in a 1:1 solvent mixture of THF and ethanol
(50 mL). 10% Palladium on carbon (100 mg, 0.1 mmol) was
added and the solution stirred at room temperature under a
positive pressure of hydrogen. After 4 h the reaction was
checked for completion (tlc) and the catalyst filtered off
through Celitew, washing with dichloromethane (100 mL).
Evaporation of the solvent afforded tetraacetate 2k (570 mg,
100%) as a pale pink solid. The 1H NMR spectrum
corresponded to that published in the literature.9 dH
(300 MHz, DMSO-d6) 1.39 (12H, d, JZ7.1 Hz, CH3),
2.11 (12H, s, OAc), 4.39 (4H, q, JZ7.1 Hz), 6.30 (2H, s,
Ar-H), 6.41 (2H, s, Ar-H), 6.58 (2H, s, Ar-H), 7.33 (2H, s,
Ar-H), 8.82 (4H, br s, –OH).
126.8
(C-32,72),
136.3
(C-31,33,71,73),
144.4
(C-34,36,74,76), 152.4 (C-14,16,54,56); MALDI-TOF m/z
(rel. int.) 896.04 [MCCKC] (48), 879.94 [MCCNaC]
(100). Found: C, 50.28; H, 4.64; S, 14.85%; C36H40O16S4
requires C, 50.46; H, 4.70; S, 14.97%.
6.2. General procedure for the synthesis of bridged
resorcinarenes (3)
Tetraprotectedresorcinarene 2 (0.25–0.5 mmol, 1 equiv),
diamine 1, 6 or 12 (1.2 equiv) and paraformaldehyde
(10 equiv) were added to a high-pressure glass reaction

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
987
vessel with a screw top. Acetonitrile (40 mL) was added and
the vessel sealed and placed in an oil bath at 90 8C. After
40 min the reaction was checked by tlc for complete
consumption of 2. Silica gel (1–2 g) was then added and the
solvent removed under reduced pressure. The solid-
supported crude material was then finely ground and
subjected to column chromatography (30 g silica gel eluting
with ethyl acetate–petroleum ether 1:9–1:1) to furnish
bridged derivatives 3.
112,114), 165.8 (C]O); MALDI TOF: m/z (rel. int.)
1350.65 [MC] (79), 1247.25 (44). Found: C, 77.53; H,
6.54; N, 2.03%; C87H86N2O12 requires C, 77.31; H, 6.41; N,
2.07%.
6.2.3. (R,R)-134,136,164,166-Tetra(benzyloxycarbonyloxy)-
12,14,112,114-tetrahydroxy-12,14,15,17-tetramethyl-3,9-
bis(1-phenylethyl)-3,9-diaza-1,11(1,3,5),13,16(1,3)tetra-
benzenabicyclo[9.3.3]heptadecaphane (3h). Yield 70%. Mp
117–119 8C (from diethyl ether); [a]D C6.7 (c 1.00, CHCl3);
nmax/cmK1 (CHCl3) 3502s (O–H, H-bonded), 2971s (C–H,
aliphatic), 1757s (C]O, ester); dH (300 MHz, CDCl3) 0.77
(2H, qu, JZ7.1 Hz, H-6), 0.98 (4H, qu, JZ7.1 Hz, H-5,7),
1.40 (6H, d, JZ6.5 Hz, NCHCH3), 1.45 (12H, d, JZ6.5 Hz,
–CH3), 2.06 and 2.23 (4H, m, H-4,8), 3.71 (4H, s, H-2,10),
3.79 (2H, q, JZ6.5 Hz, H-a), 4.43 (4H, m, H-12,14,15,17),
5.32 and 5.34 (8H, 2!s, H-20), 6.85 (2H, s, H-132,162), 7.04
(2H, s, H-135,165), 7.19 (2H, s, H-16,116), 7.20–7.48 (30H, m,
Ph); dC (75 Hz, CDCl3) 18.0 (NCHCH3), 22.0 and 22.1
(–CH3), 24.8 (C-5,7), 25.5 (C-6), 30.5 (C-12,14,15,17), 49.5
(C-2,10), 51.6 (C-4,8), 62.1 (NCHCH3), 70.6 (20), 109.0
(C-13,113), 115.2 (C-135,165), 119.5 (C-11,15,111,115), 123.0
(C-16,116), 127.2 (C-132,162), 127.4C128.1C128.4C
128.5C128.7 (Ph), 135.0 (Ph), 137.7 (C-131,133,161,163),
141.5 (Ph), 146.3 (C-134,136,164,166), 152.9 (C-12,14,
112,114), 154.1 (C-10); MALDI-TOF m/z (rel. int.) 1416.36
[MCC2H] (100). Found: C, 73.88; H, 6.17; N, 2.02%;
C87H86N2O16 requires C, 73.82; H, 6.12; N, 1.98%.
6.2.1. (R,R)-12,14,112,114-Tetrahydroxy-12,14,15,17-
tetra-methyl-3,9-bis(1-phenylethyl)-134,136,164,166-
tetra(20,40,60-triisopropylbenzenesulfonyloxy)-3,9-diaza-
1,11(1,3,5),13,16(1,3)tetrabenzenabicyclo[9.3.3]heptade-
caphane (3f). Yield 78%. Mp 232–233 8C (from diethyl
ether–petroleum ether); [a]D C67.6 (c 1.40 in CHCl3);
nmax/cmK1 (CHCl3) 3516s (O–H, H-bonded), 2964sC
2872s (C–H), 1599mC1481m (aryl stretch), 1376sC
1180s (–SO2–O–); dH (300 MHz, CDCl3) 0.99 (2H, m, H-6),
1.11 (4H, m, H-5,7), 1.18 (204H, d, JZ6.6 Hz, 70/90 i-Pr),
1.31 (60H, br d, JZ6.6 Hz, 7 /80/90 i-PrC–CH3), 1.37 (6H,
d, JZ6.6 Hz, NCHCH3), 2.12 and 2.35 (4H, m, H-4,8), 2.96
(4H, m, H-80), 3.66 and 3.77 (4H, d, JABZ15.4 Hz, H-2,10),
3.74 (2H, m, NCHCH3), 4.13 (8H, m, H-70/90), 4.52 and
4.54 (4H, 2!q, JZ6.6 Hz, H-12,14,15,17), 6.74 (2H, s,
H-135,165), 6.80 (2H, s, H-132,162), 7.09 (2H, s, H-16,116),
7.18–7.31 (18H, m, PhCH-30,50); dC (75 MHz, CDCl3) 18.6
(NCHCH3), 21.6 and 22.3 (–CH3), 23.1 (C-6), 23.5 (80 i-Pr),
24.7 (70/90 i-Pr), 26.3 (C-5,7), 30.0 (C-70/90), 31.0 and 31.3
(C-12,14,15,17), 34.3 (C-80), 48.4 (C-2,10), 49.5 (C-4,8),
61.7 (NCHCH3), 108.4 (C-13,113), 115.6 (C-135,165), 118.1
and 119.1 (C-11,15,111,115), 123.7 (C-16,116), 124.0 and
124.1 (C-30,50), 127.3 (C-132,162), 128.0 and 128.5 (Ph),
130.3 and 130.6 (C-10), 139.6 and 140.2 (C-131,133,
161,163), 142.2 (Ph), 144.5 and 144.6 (C-134,136,164,166),
151.0 and 151.2 (C-20,60), 153.0 (C-12,14,112,114), 154.3
and 154.4 (C-40); MALDI TOF: m/z (rel. int.) 1942.89 [MC]
(53), 1838.6 [MCKPhCHCH3] (10). Found: C, 71.04; H,
7.72; N, 1.46; S, 6.38%; C115H150N2O16S4 requires C,
71.03; H, 7.77; N, 1.44; S, 6.60%
6.2.4. (R,R)-134,136,164,166-Tetraacetoxy-12,14,112,114-
tetra-hydroxy-12,14,15,17-tetramethyl-3,9-bis(1-phenyl-
ethyl)-3,9-diaza-1,11(1,3,5),13,16(1,3)tetra-benzenabicyclo-
[9.3.3]heptadecaphane (3k). Yield 20%. Mp 162–164 8C
(from diethyl ether - petroleum ether); [a]D C8.1 (c 1.62,
CHCl3); nmax/cmK1 (CHCl3) 3502s (O–H, H-bonded),
2972sC2874s (C–H, aliphatic), 1747s (C]O, ester); dH
(300 MHz, CDCl3) 0.84 (2H, m, H-6), 0.97 (4H, m, H-5,7),
1.40 (6H, d, JZ7.0 Hz, NCHCH3), 1.48 (12H, d, JZ7.1 Hz,
–CH3), 2.08 and 2.24 (4H, m, H-4,8), 2.39 (12H, s,
OC(O)CH3), 3.73 (4H, s, H-2,10), 3.81 (2H, q, JZ7.0 Hz,
H-a), 4.35 (4H, m, H-12,14,15,17), 6.85 (2H, s, H-135,165),
6.89 (2H, s, H-132,162), 7.28 (2H, s, H-16,116), 7.19–7.34
(10H, m, Ph); dC (75 MHz, CDCl3) 17.5 (NCHCH3), 21.0
(OC(O)CH3), 22.0 and 22.1 (–CH3), 25.0 and 25.7 (C-5,
6,7), 30.5 (C-12,14,15,17), 49.4 (C-2,10), 52.0 (C-4,8), 62.2
(NCHCH3), 109.2 (C-13,113), 115.9 (C-135,165), 119.9
(C-11,15,111,115), 122.7 (C-16,116), 127.1 (Ph), 127.3
(C-132,162), 128.0 and 128.4 (Ph), 137.1 and 137.2
(C-131,133,161,163), 141.5 (Ph), 145.8 and 145.9 (C-134,
136,164,166), 153.0 (C-12,14,112,114), 170.0 (C]O);
MALDI-TOF m/z (rel. int.) 1047.75 [MC] (100), 1003.60
[MCKCOCH3] (20), 943.60 [MCKCHCH3Ph] (75).
Found: C, 72.17; H, 6.59; N, 2.75%; C63H70N2O12 requires
C, 72.26; H, 6.74; N, 2.67%.
6.2.2. (R,R)-12,14,112,114-Tetrahydroxy-134,136,164,166-
tetra(4-methylbenzoyloxy)-12,14,15,17-tetramethyl-3,9-
bis(1-phenylethyl)-3,9-diaza-1,11(1,3,5),13,16(1,3)tetra-
benzenabicyclo[9.3.3]heptadecaphane (3g). Yield 55%.
Mp 193–195 8C (from diisopropyl ether–dichloromethane);
[a]D C7.8 (c 2.64 in CHCl3); nmax/cmK1 (CHCl3) 3480s
(O–H, H-bonded), 2972sC2873s (C–H, aliphatic), 1729s
(C]O, ester); dH (300 MHz, CDCl3) 0.93 (2H, m, H-6),
1.10 (4H, m, H-5,7), 1.40 (6H, d, JZ6.7 Hz, NCHCH3),
1.54 (12H, d, JZ6.7 Hz, –CH3), 2.19 and 2.33 (4H, m,
H-4,8), 2.46 (12H, s, H-70), 3.78 (6H, br, NCHCH3 and
H-2,10), 4.49 (4H, br m, H-12,14,15,17), 7.04 (2H, s, H-132,
162), 7.14 (2H, s, H-135,165), 7.22–7.30 (12H, br m,
H-16,116CPh) 7.34 (8H, m, H-30,50), 8.23 (8H, m, H-20,60);
dC (100 Hz, CDCl3) 17.7 (NCHCH3), 21.7 (C-70), 22.2
and 22.4 (–CH3), 24.8 (C-5,7), 25.9 (C-6), 30.6C30.7
(C-12,14,15,17), 49.8 (C-2,10), 52.0 (C-4,8), 62.3
(NCHCH3), 108.8 (C-13,113), 115.8 (C-135,165), 119.8
(C-11,15,111,115), 122.7 (C-16,116), 126.9 (C-10), 127.0
(Ph), 127.2 (C-132,162), 128.0C128.4 (Ph), 129.4 (C-30,50),
130.5 (C-20,60), 137.7 (C-131,133,161,163), 141.9 (Ph),
144.6 (C-40), 146.1 (C-134,136,164,166), 152.9 (C-12,14,
6.2.5. (R,R)-12,14,112,114-Tetrahydroxy-12,14,15,17-tetra-
methyl-134,136,164,166-tetra(methylsulfonyl-oxy)-3,
9-bis(1-phenylethyl)-3,9-diaza-1,11(1,3,5),13,16(1,3)-
tetra-benzenabicyclo[9.3.3]hepta-decaphane (3l). Yield
51%. Mp 201–203 8C (from dichloromethane–diethyl
ether); [a]D C8.1 (c 2.13, CHCl3); nmax/cmK1 (CHCl3)
3523s (O–H, H-bonded), 2975sC2875s (C–H), 1606mC
1481m (aryl stretch), 1370sC1183s (–SO2–O–); dH

988
G. Arnott et al. / Tetrahedron 62 (2006) 977–991
(300 MHz, CDCl3) 1.05 (2H, m, H-6), 1.19 (4H, m, H-5,7),
1.37 (6H, d, JZ6.8 Hz, NCHCH3), 1.50 (12H, d, JZ7.1 Hz,
–CH3), 2.18 and 2.37 (4H, m, H-4,8), 2.37 and 2.40 (12H,
2!s, –SO2Me), 3.78 (4H, s, H-2,10), 3.81 (2H, q, JZ
6.8 Hz, NCHCH3), 4.56 and 4.59 (4H, 2!q, JZ7.1 Hz, H-
12,14, 15,17), 6.80 (2H, s, H-132,162), 7.15 (2H, s, H-
16,116), 7.17–7.32 (10H, m, Ph), 7.47 (2H, s, H-135,165); dC
(75 MHz, CDCl3) 16.8 (NCHCH3), 21.8 and 22.0 (–CH3),
24.5 (C-5,7), 25.0 (C-6), 31.7 (C-12,14,15,17), 38.1
(SO2Me), 48.9 (C-2,10), 49.8 (C-4,8), 61.1 (NCHCH3),
108.5 (C-13,113), 116.4 (C-135,165), 118.2 (C-11,15,
111,115), 124.3 (C-16,116), 127.1 (C-132,162), 127.5 127.9
and 128.4 (Ph), 140.2 (C-131,133,161,163), 141.3 (Ph), 144.6
(C-134,136,164,166), 153.6 (C-12,14,112,114); MALDI-TOF
m/z (rel. int.) 1192.1 [MCC2H] (100). Found: C, 59.48; H,
5.98; N, 2.36; S, 10.52%; C59H70N2O16S4 requires C, 59.48;
H, 5.92; N, 2.35; S, 10.76%.
1.28 (4H, m!2, H-2,6), 1.35 (6H, d, JZ7.1 Hz, –CH3!2),
2.41 (6H, s, -Tos-CH3!2), 2.92 (4H, m, H-1,7), 5.15 (2H,
q, JZ7.1 Hz, H-a), 7.18–7.25 (10H, m, Ph), 7.28 (4H, d,
JZ8.0 Hz, –Tos), 7.71 (4H, d, JZ8.0 Hz, -Tos); dC
(75 MHz, CDCl3) 16.6 (–CH3), 21.4 (Tos-CH3), 26.6
(C-3,5), 28.2 (C-4), 30.4 (C-2,6), 44.1 (C-1,7), 55.2 (C-a),
127.1, 127.5, 128.2, 129.5, 138.4, 140.3 and 142.9 (Ph); m/z
(rel. int.) 669 [MCCNa] (100). Found C, 68.68; H, 7.16; N,
4.32; S, 9.92%; C37H46N2O4S2 requires C, 68.70; H, 7.17;
N, 4.33; S, 9.91%.
6.2.8. 4-Oxo-heptanedioic acid bis[(1-phenylethyl)-
amide] (10). Oxo-pimelic acid 9 (3.49 g, 20 mmol) and
hydroxybenzotriazole (1.35 g, 10 mmol) were dissolved in
dry dichloromethane (200 mL) and cooled to 0 8C.
Dicyclohexylcarbodiimide (10.3 g, 50 mmol) was added,
followed by slow addition of (R)-a-methylbenzylamine
(5.4 mL, 42 mmol). The reaction was allowed to warm to
room temperature slowly overnight. On completion, the
reaction was added to aqueous sodium carbonate (200 mL)
and extracted with dichloromethane (3!100 mL). The
organic layers were combined and dried with magnesium
sulphate and then reduced to yield a crude white product,
which was purified by column chromatography (100 g silica
gel, eluting with methanol–ethyl acetate 2:98). In this way,
diamide 10 (6.30 g, 83%) was obtained as a white powder.
Mp 160–161 8C (ethyl acetate–ethanol); [a]D C121.5
(c 2.20, EtOH); nmax/cmK1 (CHCl3) 3432m (N–H), 1716s
(C]O, ketone), 1672s (C]O, amide), 1508s (NH bend); dH
(400 MHz, CDCl3) 1.45 (6H, d, JZ6.9 Hz, 2!NCHCH3),
2.45 (4H, m, H-3,5), 2.76 (4H, m, H-2,6), 5.06 (2H, q, JZ
7.0 Hz, 2!H-a), 5.94 (2H, br d, JZ6.9 Hz, 2!N–H),
7.21–7.34 (10H, m, Ph); dC (100 MHz, CDCl3) 21.8 (–CH3),
30.2 (C-3,5), 37.6 (C-2,6), 48.9 (C-a), 126.1, 127.2, 128.6
and 143.3 (Ph), 170.7 (C-1,7), 208.8 (C-4); m/z (rel. int.)
381.2 [MCCH] (42), 260.1 [MCKPhCH(CH3)NH] (17),
156.0 (21), 120.0 [PhCH(CH3)NH] (25), 105.0 [PhCHCH3]
(100). Found C, 72.58; H, 7.26; N, 7.29%; C23H28N2O3
requires C, 72.61; H, 7.42; N, 7.36%.
6.2.6. Heptanedioic acid bis[(1-phenylethyl)amide] (5).
Pimelic acid 4 (641 mg, 4 mmol) and hydroxybenzotriazole
(270 mg, 2 mmol) were dissolved in dry dichloromethane
(50 mL) and cooled to 0 8C. Dicyclohexylcarbodiimide
(2.06 g, 10 mmol) was added, followed by slow addition of
(R)-a-methylbenzylamine (1.08 mL, 8.4 mmol). The
reaction was allowed to warm to room temperature slowly
overnight. On completion, the reaction was added to
aqueous sodium carbonate (100 mL) and extracted with
dichloromethane (3!70 mL). The organic layers were
combined and dried with magnesium sulphate and then
reduced to yield a crude white product, which was purified
by column chromatography (60 g silica gel, eluting with
methanol–ethyl acetate 2:98), to afford diamide 5 (1.40 g,
95%) as a colourless powder. Mp 157–158 8C (ethyl
acetate–ethanol); [a]D C108.5 (c 2.50, EtOH); nmax/cmK1
(CH2Cl2) 1670s (C]O stretch, amide I), 1506s (C]O,
amide II), 1262s; dH (300 MHz, CDCl3) 1.33 (2H, m, H-4),
1.46 (6H, d, JZ6.9 Hz, –CH3), 1.62 (4H, m, H-3,5), 2.14
(4H, m, H-2,6), 5.10 (2H, q, JZ6.9 Hz, H-a), 5.86 (2H, br d,
JZw7 Hz, NH), 7.21–7.35 (10H, m, Ph); dC (75 MHz,
CDCl3) 21.8 (–CH3), 25.1 (C-3,5), 28.5 (C-4), 36.3 (C-2,6),
48.6 (C-a), 126.1, 127.3, 128.6 and 143.4 (Ph), 171.9
(C]O); m/z (rel. int.) 367.2 [MCCH] (57), 263.2 (8), 246.2
(9), 142 (12), 120 [PhCH(NH)CH3] (18), 105 [PhCHCH3]
(100), 91 [PhCH2] (47). Found C, 75.49; H, 8.26; N, 7.60%;
C23H30N2O2 requires C, 75.38; H, 8.25; N, 7.64%.
6.2.9. 4,4-Dimethoxy-heptanedioic acid bis[(1-phenyl-
ethyl)-amide] (11). Diamide 10 (0.98 g, 2.5 mmol) was
dissolved in dry methanol (30 mL) with a catalytic amount
of p-toluenesulfonic acid (40 mg, 0.2 mmol). Trimethyl
orthoformate (2 mL, 18 mmol) was added and the reaction
heated to gentle reflux overnight. On completion of the
reaction, solid sodium carbonate was added and the
methanol reduced on a rotary evaporator. Ethyl acetate
(100 mL) was added to the crude material, which was then
washed with water (25 mL) and brine (25 mL). The organic
layer was then dried with magnesium sulphate and reduced
to give a crude oil which was purified via column
chromatography (50 g silica gel, eluting with methanol–
ethylacetate 2:98), to give dimethoxyketal diamide 11
(0.98 g, 92%) as fine white needles. Mp 129–131 8C (ethyl
acetate–ethanol); [a]D C86.9 (c 2.05, EtOH); nmax/cmK1
(CHCl3), 1663s (C]O, amide), 1505s (N–H bend); dH
(400 MHz, CDCl3) 1.45 (6H, d, JZ6.9 Hz, 2!NCHCH3),
1.89 (4H, m, H-3,5), 2.19 (4H, m, H-2,6), 3.13 (6H, s,
OCH3), 5.03 (2H, q, JZ7.0 Hz, 2!H-a), 6.13 (2H, br d,
JZ7.7 Hz, 2!N–H), 7.18–7.33 (10H, m, Ph); dC
(100 MHz, CDCl3) 21.8 (–CH3), 28.1 (C-3,5), 31.2
(C-2,6), 47.9 (–OCH3), 48.8 (C-a), 102.5 (C-4), 126.1,
6.2.7. N,N0-Bis(1-phenylethyl)heptane-1,5-diamine (6).
Di-amide 5 (4.30 g, 11.7 mmol) was dissolved in dry THF
(150 mL) and cooled to 0 8C. Lithium aluminium hydride
(1.78 g, 46.9 mmol) was added portion-wise to the reaction,
which was then heated to reflux for 18 h. After the reaction
was complete (tlc), it was cooled to 0 8C and quenched by
the slow addition of water (1.7 mL), 1 M sodium hydroxide
(3.4 mL) followed by water (3.4 mL). The reaction was
stirred at room temperature for 1 h, the salts removed via
filtration through Celitew, washing with dichloromethane
(100 mL), to afford diamine 6 (3.78 g, 95%) as a clear oil,
which was judged to be O95% pure for the next step. The
product was characterized as its ditosylate. Mp 137–138 8C
(ethanol–dichloromethane); [a]D C18.8 (c 2.6, CHCl3);
nmax/cmK1 (CHCl3) 3024s (C]C–H), 2940sC2856s (C–H,
aliphatic), 1599s (aryl), 1380sC1162s (SO2–O); dH
(400 MHz, CDCl3) 0.84 (6H, br m, H-3,4,5), 1.06 and

G. Arnott et al. / Tetrahedron 62 (2006) 977–991
989
127.3, 128.6 and 143.2 (Ph), 171.7 (C-1,7); m/z (rel. int.)
449.2 [MCCNa] (5), 395.2 [MCKOCH3] (56), 259.1 (19),
142.0 (15), 105.0 [PhCHCH3] (100). Found C, 70.71; H,
8.01; N, 6.74%; C25H34N2O4 requires C, 70.40; H, 8.03; N,
6.57%.
57.1 (C-a), 108.8 (C-13,133), 114.8 (C-155,185), 118.5 and
118.9 (C-11,15,131,135), 123.6 (C-16,136), 127.0 (Ph),127.4
(C-152,182), 128.0 (Ph), 128.4, 128.5 and 128.6 (C-20,60C
Ph), 130.1 (C-30,50), 132.9 (C-10), 139.8 and 140.0 (C-151,
153,181,183), 140.2 (Ph), 144.8 and 145.0 (C-154,156,
184,186), 145.6 (C-40), 153.1 and 153.8 (C-12,14,132,134);
MS: m/z (rel. int.) 1523.4 [MC] (55), 1417.3 [MCK
H–PhCHCH3] (13), 1370.3 (7), 1185.1 (7), 1028.3 (3),
875.1 (3), 547.1 (7), 339.3 (57), 105.1 [PhCHCH3] (100).
Found C, 66.98; H, 5.98; N, 1.84; S, 8.05%; C85H90N2O16S4
requires C, 66.99; H, 5.95; N, 1.84; S, 8.42%.
6.2.10. 4,4-Dimethoxy-N,N0-bis-(1-phenylethyl)heptane-
1,7-diamine (12). Diamide 11 (1.11 g, 2.6 mmol) and
triethylamine (1.8 mL, 13 mmol) were added to dry diethyl
ether (100 mL) and cooled to 0 8C. Lithium aluminium
hydride (395 mg, 10.4 mmol) was added to the solution in
small portions. Thereafter, the reaction was heated to reflux
for 4–6 h until reduction was complete (tlc control). The
reaction was then cooled to 0 8C and quenched by the
addition of H2O (0.4 mL), 1 M NaOH (0.8 mL) and H2O
(0.8 mL) in that order. The heterogeneous solution was
allowed to stir at room temperature for approximately one
hour until all the salts had turned white. These were then
filtered off through Celitew and washed with dichloro-
methane (200 mL). The filtrate was then reduced to afford
diamine 12 (880 mg, 85%) as an oil. [a]D C37.5 (c 2.92,
CHCl3); nmax/cmK1 (CHCl3) 3013s (aromatic C–H),
2954sC2831s (aliphatic C–H), 1602w (aryl ring), 1188m
(C–N), 1113s (C–O–C); dH (400 MHz, CDCl3) 1.39 (3H, d,
JZ6.6 Hz, –CH3), 1.32–1.61 (10H, m, H-2,3,5,6CNH!2),
2.42C2.50 (4H, 2!dt, JZ11.4, 7.1 Hz, H-1,7), 3.08 (6H, s,
OCH3), 3.78 (2H, q, JZ6.6 Hz, NCHCH3), 7.20–7.35 (10H,
m, Ph); dC (100 MHz, CDCl3) 23.9 (CH3), 24.1 (C-2,6),
30.2 (C-3,5), 47.6 (C-1,7COMe), 58.4 (NCHCH3), 103.1
(C-3), 126.6, 127.0, 128.4 and 144.8 (Ph).
6.2.12. (R,R,R,R)-12,14,132,134,172,174,292,294-Octa-
hydroxy-14,16,30,32,33,35,36,38-octamethyl-3,11,19,27-
tetra(1-phenylethyl)-154,156,314,316,344,346,374,376-octa-
(p-toluenesulfonyloxy)-3,11,19,27-tetraaza-1,13,17,29
(1,3,5),15,31,34,37(1,3)tricyclo[27.3.3.313,17]octatriacon-
ta-phane (14). From synthesis of bridged resorcinarene
13a. Mp 161–165 8C (diisopropyl ether–dichloromethane);
[a]D K7.0 (c 1.33 in CHCl3); nmax/cmK1 (CHCl3): 3527s
(O–H, H-bonded), 3022s (C–H, aromatic), 2930m (C–H,
aliphatic), 1598s (aryl stretch), 1371sC1177s (–SO2–);dH
(300 MHz, CDCl3) 1.03 (4H, m, H-7,23), 1.21 (12H, d, JZ
6.8 Hz, NCHCH3), 1.27 (8H, m, C-5,6,8,9,21,22,24,25),
1.36 and 1.39 (24H, d, JZ6.7 Hz, KCH3), 2.02 and 2.40
(8H, br m, H-4,10,20,26), 2.45 (24H, s, H-70), 3.34 (8H, s,
H-2,12,18,28), 3.65 (4H, q, JZ6.8 Hz, NCHCH3), 4.43 and
4.48 (8H, 2!q, JZ7.0 Hz, H-14,16,30,32,33,35,36,38),
6.44 (4H, s, H-152,312,342,372), 6.72 (4H, s, H-155,315,
345,375), 7.00 (4H, s, H-16,136,176,296), 7.02–7.17 (20H, m,
Ph), 7.35 (16H, d, JZw8.1 Hz, H-30,50), 7.88 (16H, d, JZ
w8.1 Hz, H-20,60); dC (75 MHz, CDCl3) 16.0 (NCHCH3),
20.4C20.6 (–CH3), 21.7 (C-70), 26.7, 27.4 and 30.0
(C-5,6,8,9,21,22,24,25), 31.7 and 31.9 (C-14,16,30,32,33,
35, 36,38), 46.9 (C-2,12,18,28), 49.3 (C-4,10,20,26), 58.1
(C–NCHCH3), 109.0 (C-13,133,173,293), 114.5 (C-155,315,
345, 375), 118.9 (C-11,15,131,135,171,175,291,295), 123.3
(C-16,136,176,296), 127.2 (Ph), 127.4 (C-1520,312,342,372),
128.1 (Ph), 128.4, 128.4 and 128.5 (C-20,6 CPh), 130.0
(C-30,50), 133.2 and 133.4 (C-10), 139.7 and 140.1
(C-151,153, 311,313,341,343, 371,373), 140.4 (Ph), 144.9
and 145.1 (C-154,156,314,316,344,346,374,376), 145.5 and
145.6 (C-40), 153.5 and 153.8 (C-12,14,132,134,172,
174,292,294); MALDI TOF: m/z (rel. int.) 3047.3 [MC]
(15), 1524.7 [MC/2CH] (72). Found C, 66.52; H, 5.96; N,
1.86; S, 8.16%; C170H180N4O32S8$H2O requires C, 66.60;
H, 5.98; N, 1.83; S, 8.37%.
6.2.11. (R,R)-12,14,132,134-Tetrahydroxy-14,16,17,19-
tetra-methyl-3,11-bis(1-phenylethyl)-154,156,184,186-tetra-
(p-toluenesulfonyloxy)-3,11-diaza-1,13(1,3,5),15,18(1,3)
tetrabenzenabicyclo[11.3.3]nona-decaphane(13a).
Tetratosylresorcinarene 2a (465 mg, 0.5 mmol), diamine 6
(203 mg, 0.6 mmol) and paraformaldehyde (300 mg,
10 mmol) were added to a high-pressure glass reaction
vessel with a screw top. Acetonitrile (40 mL) was added and
the vessel sealed and placed in an oil bath at 80 8C. After
two hours the reaction was checked by tlc for complete
consumption of 2a. Silica gel (2–3 g) was then added and
the solvent removed under reduced pressure. The solid-
supported crude material was then finely ground and
subjected to column chromatography (40 g silica gel eluting
with ethyl acetate–petroleum ether 3:7). In this manner,
bridged resorcinarene 13a (220 mg, 36%) eluted first,
followed by dimer 14 (80 mg, 5%). Mp 133–137 8C
(diisopropyl ether–dichloromethane); [a]D C13.2 (c 2.40,
CHCl3); nmax/cmK1 (CHCl3): 3528s (O–H, H-bonded),
2974mC2932m (C–H, aliphatic), 1598s (aryl-H), 1371sC
1176s (–SO2–O–); dH (300 MHz, CDCl3) 1.07–1.44 (10H,
m, H-5,6,7,8,9), 1.30 (6H, d, JZ6.9 Hz, NCHCH3), 1.41
(12H, d, JZ7.0 Hz, –CH3), 1.99 and 2.40 (4H, m, H-4,10),
2.47 and 2.49 (12H, 2!s, H-70), 3.60 and 3.69 (4H, AB d,
JABZ14.6 Hz, H-2,12), 3.79 (2H, q, JZ6.9 Hz, H-a), 4.52
and 4.55 (4H, 2!q, JZ7.0 Hz, H-14,16,17,19), 6.45 (2H, s,
H-152,182), 6.78 (2H, s, H-155,185), 7.07 (2H, s, H-16,136),
7.17–7.33 (10H,0 m, Ph), 7.39 and 7.41 (8H, 2!d,0 JZ
w8.0 Hz, H-30,5 ), 7.94 (8H, 2!d, JZw8.0 Hz, H-2 ,60);
dC (75 MHz, CDCl3) 14.1 (NCHCH3), 20.6 and 20.7
(–CH3), 21.7 (C-70), 25.0, 25.8 and 26.4 (C-5,6,7,8,9),
31.8 and 31.9 (C-14,16,17,19), 46.4 (C-2,12), 48.4 (C-4,10),
6.2.13. (R,R)-12,14,132,134-Tetrahydroxy-14,16,17,19-
tetra-methyl-7,7-dimethoxy-3,11-bis(1-phenyl-ethyl)-
154,156, 184,186-tetra(p-toluenesulfonyloxy)-3,11-diaza-
1,13(1,3,5),15,18(1,3)tetrabenzenabicyclo[11.3.3]nona-
decaphane (13b). Tetratosylresorcinarene 2a (580 mg,
0.5 mmol), diamine 12 (590 mg, 1.48 mmol) and para-
formaldehyde (300 mg, 10 mmol) were added to a high-
pressure glass reaction vessel with a screw top. Acetonitrile
(40 mL) was added and the vessel sealed and placed in an
oil bath at 80 8C. After 1 1/2 h the reaction was checked by
tlc for complete consumption of 2a. Silica gel (2–3 g) was
then added and the solvent removed under reduced pressure.
The solid-supported crude material was then finely ground
and subjected to column chromatography (50 g silica gel
eluting with ethyl acetate–petroleum ether 3:7), to afford

990
G. Arnott et al. / Tetrahedron 62 (2006) 977–991
bridged resorcinarene 13b (450 mg, 57%). Mp 146–148 8C
(diisopropyl ether–dichloromethane); [a]D C1.0 (c 2.40,
CHCl3); nmax/cmK1 (CHCl3): 3526s (O–H, H-bonded),
2971m (C–H, aliphatic), 1599s (aryl stretch), 1371sC1177s
(–SO2–), 1092s (C–O–C, ether); dH (300 MHz, CDCl3) 1.29
(6H, d, JZ6.9 Hz, NCHCH3), 1.26–1.37 (8H, m, H-5,6,
8,9), 1.42 (12H, d, JZ7.1 Hz, –CH3), 2.02 and 2.45 (4H, m,
H-4,10), 2.48 and 2.49 (12H, 2!s, H-70), 3.02 (6H, s,
–OCH3), 3.60 and 3.66 (4H, AB d, JABZ14.8 Hz, H-2,12),
3.80 (2H, q, JZ6.9 Hz, H-a), 4.52 and 4.57 (4H, 2!q, JZ
7.1 Hz, H-14,16,17,19), 6.44 (2H, s, H-152,182), 6.73 (2H, s,
H-155,185), 7.07 (2H, s, H-16,136), 7.17–7.30 (10H, m, Ph),
7.40 (8H, 2!d, JZ8.4 Hz, H-30,50), 7.94 (8H, 2!d, JZ
8.3 Hz, H-20,60); dC (75 MHz, CDCl3) 14.0 (NCHCH3), 20.3
and 20.5 (–CH3), 21.6 (C-5,9), 21.7 (C-70), 30.8 (C-6,8),
31.9 and 32.1 (C-14,16,17,19), 46.3 (C-2,12), 47.6
(–OCH3), 48.7 (C-4,10), 57.1 (C-a), 103.0 (C-7), 108.7
(C-13,133), 115.1 (C-155,185), 118.6 and 119.1 (C-11,15,
131,135), 123.6 (C-16,136), 127.1 (Ph),127.5 (C-152,182),
128.0 (Ph), 128.4, 128.5 and 128.6 (C-20,60CPh), 130.1
(C-30,50), 133.3 (C-10), 139.9 and 140.1 (C-151,153,181,
183), 140.2 (Ph), 145.0 and 145.1 (C-154,156,184,186), 145.6
(C-40), 153.1 and 154.0 (C-12,14,132,134); MS: m/z (rel.
int.)Z1584.1 [MCCH] (4), 1520.9 (3), 1413.8 (3), 1185.5
(5), 1031.5 [-Tos] (3), 875.4 [–Tos] (3), 719.4 [–Tos] (3),
335.4 (70), 175.1 (67), 105.1 [PhCHCH3] (100). Found C,
65.98; H, 5.96; N, 1.76; S, 7.76%; C87H94N2O18S4 requires
C, 65.97; H, 5.98; N, 1.77; S, 8.10%.
30.0 (C-12,14,15,17), 38.0 and 38.6 (–SO2Me), 48.4
(C-4,8), 51.8 (C-2,10), 62.9 (NCHCH3), 116.5 (C-135,
165), 123.7 (C-16,116), 126.5 (C-132,162), 127.0 (Ph), 1270.7
(Ph), 129.2 (C-20,60), 130.0 (C-30,50), 132.6 and 132.8 (C-1 ),
134.8 (C-13,113), 136.6 and 137.2 (C-11,15,111,115,131,
133,161,163), 143.0 (Ph), 143.4, 144.3, 144.8 and 144.7 (C-
12,14,112,114,134,136,164,166), 145.9 (C-40); m/z (rel.
int.)Z1807.9 [MCH]C(57), 1728.9 (21), 1653.0 (12),
510.4 (12), 105.1 [PhCHCH3] (100). Found C, 57.18; H,
5.31; N, 1.72; S, 14.05%; C87H94N2O24S8$H2O requires C,
57.22; H, 5.30; N, 1.53; S, 14.05%.
References and notes
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6.2.14. (R,R)-12,14,112,114-Tetramethanesulfonyloxy-12,
14,15,17-tetramethyl-3,9-bis(1-phenylethyl)-134,136,164,
166-tetra(p-toluenesulfonyloxy)-3,9-diaza-1,11(1,3,5),
13,16 (1,3)tetrabenzenabicyclo[9.3.3]heptadecaphane
(15). Bridged resorcinarene 3a (450 mg, 0.3 mmol) and
diisopropylethylamine (1.05 mL, 6 mmol) were dissolved in
dry dichloromethane (15 mL). The solution was cooled to
0 8C in an ice-water bath and methanesulfonyl chloride
(0.46 mL, 6 mmol) was added dropwise. The solution was
then allowed to warm to room temperature. After the
reaction was complete (tlc), it was poured into sat. NaHCO3
(25 mL) and extracted with dichloromethane (3!25 mL) in
the usual manner. After drying the organic layers with
magnesium sulphate, and evaporation of the dichloro-
methane, the crude product was purified via column
chromatography (40 g silica gel eluting with ethyl acet-
ate–petroleum ether 1:1). The resulting material was then
recrystallized (dichloromethane/ethyl acetate/petroleum
ether) to give 15 (470 mg, 87%). Mp 194–195 8C
(dichloromethane/ethyl acetate/petroleum ether); [a]D
K20.0 (c 2.9, CHCl3); nmax/cmK1 (CHCl3): 3021m (aryl
stretch), 2940s (C–H aliphatic), 1598m (aryl stretch), 1452s
(CH3), 1377sC1178s (–SO2–O–); dH (400 MHz, CDCl3)
K0.95 (2H, m, H-6), K0.62 and K0.54 (4H, m, H-5,7),
0.89 and 0.93 (12H, 2!d, JZ7.1 Hz, –CH3), 1.20 (6H, d,
JZ6.8 Hz, NCHCH3), 1.35 and 1.52 (4H, m, H-4,8), 2.46
and 2.47 (12H, 2!s, H-70), 3.24 (12H, s, –SO2CH3), 3.44
and 4.00 (4H, d, JABZ14.7 Hz, H-2,10), 3.88 (2H, q, JZ
6.8 Hz, NCHCH3), 4.96 and 5.08 (4H, 2!q, JZ7.1 Hz,
H-12,14,15,17), 6.84 (2H, s, H-132,162), 7.01–7.12 (10H, m,
Ph), 7.36 and 7.39 (8H, 2!d, JZ8.5 Hz, H-30,50), 7.44 (2H,
s, H-16,116), 7.70 0(2H, s, H-135,165), 7.91 and 7.97 (8H, d,
JZ8.5 Hz, H-20,6 ); dC (75 MHz, CDCl3) 13.7 (NCHCH3),
21.2 (C-6), 21.4 (C-70), 21.7 and 22.2 (–CH3), 25.1 (C-5,7),
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