Preparation of macrocyclon analogues: calix[8]arenes with extended polyethylene glycol chains

Article abstract of DOI:10.1016/j.tet.2007.07.057

A one-pot methodology has been developed for the preparation of macrocyclon mimics, i.e., calix[8]arenes containing hydrophobic alkyl substituents on the upper rim and hydrophilic polyethylene glycol chains on the lower rim. Compounds containing PEG chains of up to 24 repeating ethylene oxide (EO) units can be prepared. With increasing molecular weight, these amphiphilic compounds can be classified as macromolecules, and can be difficult to characterise as single molecules. The limitations of conventional analytical techniques are discussed.

Full text of DOI:10.1016/j.tet.2007.07.057

Tetrahedron 63 (2007) 9947–9959
Preparation of macrocyclon analogues: calix[8]arenes with
extended polyethylene glycol chains
Franc¸ois A. Loiseau,a,y Alison M. Hillb and King Kuok (Mimi) Hiia,
*
aDepartment of Chemistry, Imperial College London, Exhibition Road, South Kensington SW7 2AZ, UK
bSchool of Biosciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 10 May 2007; revised 30 June 2007; accepted 19 July 2007
Available online 26 July 2007
Abstract—A one-pot methodology has been developed for the preparation of macrocyclon mimics, i.e., calix[8]arenes containing hydrophobic
alkyl substituents on the upper rim and hydrophilic polyethylene glycol chains on the lower rim. Compounds containing PEG chains of up to 24
repeating ethylene oxide (EO) units can be prepared. With increasing molecular weight, these amphiphilic compounds can be classified as
macromolecules, and can be difficult to characterise as single molecules. The limitations of conventional analytical techniques are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
derivative, which was non-toxic and exhibits greater anti-
tuberculosis activity than Streptomycin. Given the name of
macrocyclon, the compound was originally thought to be
conformational isomers of cyclic calix[4]arenes containing
glycol chains of between 10 and 12.5 ethylene oxide units.
Subsequently, work by Gutsche and co-workers5 established
that HOC and HBC are, in fact, calix[8]arene derivatives.
Thus, the structure of macrocyclon has been revised to con-
tain a p-octyl-calix[8]arene, flanked by highly substituted al-
kyl groups on the upper rim and variable polyethylene glycol
chains on the lower rim (Fig. 1).
Tuberculosis (TB) is one of the oldest diseases, yet it remains
among the top ten causes of death in the World. Declared in
2006 as a growing global pandemic by the World Health
Organization, the TB bacilli is estimated to be carried by
one-third of the global population, with a rate of one infec-
tion per second and causes 5000 deaths every day.1 Tragi-
cally, it is particularly prevalent amongst the impoverished
communities in developing and developed countries; largely
due to rapid global demographic changes and the HIV epi-
demic, which allow the disease to spread quickly. The prob-
lem is compounded by the inadequate implementation of TB
therapy, which led to the recurrence of the disease, as well as
the development of drug resistant (DR) and multi-drug resis-
tant (MDR) TB,2 fueling demands for more effective drug
therapies to combat the disease.3
In 1951, Cornforth and co-workers discovered a non-ionic
surface-active agent that suppresses experimental tuberculo-
sis in mice. This led to the examination of compounds with
analogous structures as anti-tuberculosis agents.4 The pre-
cursors were synthesised by the condensation of tert-alkyl
substituted phenols with formaldehyde, to afford crystalline
substances, from which high-melting compounds HOC and
HBC (High Octyl and Butyl Compounds, respectively) were
isolated.
O
O
O
O
O
O
O
O
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
10-12.5
t-Oct
=
8
The condensation of HOC with 45–50 molecules of ethylene
oxide under alkaline conditions produced a water-soluble
O
10-12.5
O
* Corresponding author. E-mail: mimi.hii@imperial.ac.uk
This work was F.A.L.’s postgraduate research, initiated at King’s College
London and completed at Imperial College London.
H
y
Figure 1. Proposed structure of macrocyclon.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.057

9948
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
More recently, biological studies showed that macrocyclon
exhibits a novel mechanism of action that is different from
drugs currently used against tuberculosis.6 This has re-
ignited substantial interest in the molecule as an exciting
therapeutic candidate for the treatment of MDR-TB.
furnish a partially functionalised macrocycle, followed by
NaH to deprotonate the remaining phenolic units in the sec-
ond step. Each PEGylation required 4 days, and column
chromatography was required for the purification of the par-
tially functionalised intermediate.
In the original work by Cornforth, the length of the polyeth-
ylene glycol chain was reported to have a profound effect on
the tuberculostatic properties.7 The objective of our project
is to synthesise a series of macrocyclon analogues, with sys-
tematic variations in the p-substituent (R), the terminal
group (R’) and the chain length (n), such that the biological
effect of each of these components can be delineated by SAR
studies.
In earlier work, we observed that longer polyethylene glycol
chains are unstable and are prone to elimination reactions in
the presence of strong bases such as t-BuOK and NaH.12
With this in mind, we investigated the use of Cs2CO3
as a milder base, which has been shown to deprotonate
calix[8]arenes slowly at multiple sites.13 Consequently,
calix[8]arenes 1a–d was treated twice with Cs2CO3
(2ꢁ16 equiv) over 24 h to allow full deprotonation to take
place. MeO–PEG3–X of 16 equiv (2a–e, where X¼Cl, Br,
I, OMs and OTs, respectively) was subsequently added
and the reaction mixture was refluxed for 3 days (Scheme 2,
Table 1).
2. Results and discussion
2.1. Synthesis of calix[8]arenes
R
R
Following published procedures, p-tert-butylcalix[8]arene
1a and p-tert-octylcalix[8]arene 1b were prepared on a large
scale by condensing the corresponding p-alkylphenol and
formaldehyde in a basic solution (Scheme 1).8 From 1a,
the unsubstituted p-H-calix[8]arene 1c can be prepared in
88% yield by a reverse Friedel–Craft reaction.9 On the other
hand, O-substituted calix[8]arenes allow the attachment of
PEG chains on both upper and lower rims. The correspond-
ing reaction between p-benzyloxyphenol and formaldehyde
required an elevated temperature (170 ꢀC), which led to an
unpredictable exothermic reaction. This can be avoided by
using an alternative procedure with a stronger base (t-
BuOK) and a different reaction stoichiometry, allowing the
reaction to proceed smoothly at 150 ꢀC to furnish 1d in
61% yield.10
1. Cs2CO3 (16 equiv),
THF-DMF (1:1)
80 °C, 18 h
8
2. Cs2CO3 (16 equiv)
8
OH
O
3.
Me
X
3
O
1a-d
X = Cl, Br, I, OMs, OTs, 2a-e
O
3
Me
3a-d
Scheme 2. PEGylation of calix[8]arenes.
The results show, unequivocally, that iodide derivatives af-
ford the best yield of the fully PEGylated calix[8]arene. A
slightly lower yield was achieved using the bromide precur-
sor under Finkelstein conditions (Table 1, entry 9). The
results also suggest that the p-substituent of the calix[8]arene
ring exerts little influence on these reactions (entries 3, 6, 10
and 15). Subsequent examination of reaction stoichiometry
revealed that the amount of electrophile can be reduced to
10 equiv (equating to 1.25 equiv of PEG for each phenolic
unit) without significant erosion in yield. Further increase
in reaction time and amount of base did not lead to any
R
R
for R = t-Bu, t-Oct
10N KOH
+ HCHO
xylene, Δ
8
OH
OH
R = CMe3 (1a)
R = CMe2CH2CMe3 (1b)
R = H (1c)
for R = OBn
AlCl3, PhOH
t-BuOK
Table 1. Effect of nucleofugesa
xylene, Δ
Yieldb (%)
m/zc
OBn
Entry
R
X
Product
1
2
3
4
5
6
7
8
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Oct (1b)
t-Oct (1b)
t-Oct (1b)
H (1c)
H (1c)
H (1c)
H (1c)
H (1c)
H (1c)
OTs
Br
I
OTs
Br
I
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
3c
3c
3d
3d
3d
44
46
61
37
44
56
19
54
68
74
38
53
35
48
69
2488.7 (F)
8
OH
2937.2 (E)
2040.2 (E)
1d
Scheme 1. Synthesis of various calix[8]arenes.
Cl
Br
Brd
I
OMs
OTs
OTs
Br
I
9
2.2. PEGylation of calix[8]arenes: reaction optimisation
10
11
12
13
14
15
The full functionalisation of calix[8]arenes at the lower rim
can be dependant on the nature of the p-substituent, as well
as the choice of base and electrophiles. The reaction out-
come is not always very predictable and, very often, only
partial functionalisation can be achieved. To date, the attach-
ment of eight [n]ethylene glycols has been reported only
once before,11 which was achieved in two steps, employing
different bases in each: K2CO3 was used in the first step to
OBn (1d)
OBn (1d)
OBn (1d)
2887.1 (F)
a
Calixarene (1 equiv), THF/DMF (1:1), Cs2CO3 (2ꢁ16 equiv), electro-
phile (16 equiv).
Isolated yields following purification by column chromatography.
Observed molecular ion: F¼FAB; E¼Electrospray.
KI of 16 equiv was added with the electrophile.
b
c
d

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9949
improvement. On the other hand, replacement of Cs2CO3 by
other bases (MgCO3, CaCO3, Na2CO3, K2CO3, KOH,
CsOH, t-BuOK, NaH and KH) led to much lower yields
(Supplementary data), suggesting that the presence of cae-
sium is crucial, probably by exerting a template effect
through complexation with phenolic and/or ether oxygen.14
of this discussion, the products are classified according to
length of the PEG chain (n) and its protecting group (R0).
Unsymmetrical THP(OCH2CH2)nI were initially used to fur-
nish calix[8]arenes up to 4500 Da, where n¼3 and 6 (Table
2, entries 1–8). Moderate to good yields of compounds 3e–l
can be obtained and their NMR spectra can be recorded with
good resolution, to enable accurate integration of the proton
signals that reflects the extent of functionalisation. The in-
tegrity of the terminal THP protecting group can be further
verified by 13C NMR spectroscopy, as the methylene signal
adjacent to the protecting group (CH2OTHP, 67 ppm) shifts
upfield to 62 ppm upon cleavage to CH2OH.
Compared to the previous procedure, the new synthetic
method has several advantages: it is conducted in one-pot us-
ing a single base, effectively halving the reaction time. Fur-
thermore, it offers a better yield, demonstrated by comparing
the isolated yields obtained for compounds 3a and 3b (Table
1, entries 3 and 6), which are 2–3 times greater than that pre-
viously achieved using the two-step procedure (yields of
30% and 19%, respectively). The products 3a–d can be pu-
rified by flash chromatography on silica gel. These com-
pounds were fully characterised by 1H and 13C NMR
spectroscopy, and MS analysis showed the molecular ions
as sodium adducts.
The THP ether can then be removed by treatment with
acid, to give compounds 4a–h (Table 2, entries 9–16).
Much better yields were obtained by employing non-
aqueous conditions, to minimise loss of the water-soluble
product during work-up. The structures of these unpro-
tected compounds were characterised by UV–vis, NMR
and mass spectrometry.
2.3. Macrocyclon analogues containing PEG3–6
To access the target molecules, iodo precursors
R0(OCH2CH2)nI (2f–p, where n¼3–24) were prepared by
the treatment of the corresponding monotosylates12 with po-
tassium iodide (Scheme 3). All of these reactions proceeded
smoothly in yields of >90%.
As was observed by other researchers, the purity of the prod-
ucts cannot be established by elemental analysis reliably, as
they are prone to absorb atmospheric H2O and CO2.15 In the
present case, the problem is exacerbated by the presence of
polyethylene glycol chains, which enhanced the hydrophi-
licity of the calix[8]arenes. Thus, to ensure homogeneity,
the compounds were subjected to repeated column chroma-
tography. Depending on the length of the PEG chain at-
tached to the calix[8]arene, up to four chromatographic
runs may be necessary to ensure the purity of the sample.
The first column was to remove starting materials, followed
by further chromatographic runs until a homogeneous sam-
ple can be obtained, as indicated by TLC analysis. The pres-
ence of any unreacted phenolic units was cross-checked by
performing UV–vis spectrometry: PEGylated calix[n]arenes
exhibit a pair of UV absorption bands around 270 and
280 nm. The addition of a base such as KOH deprotonates
any unreacted phenolic moieties, causing a distinctive batho-
chromic shift to 300 nm.7
KI, acetone
R'
I
R'
OTs
n
O
O
n
2
R' = THP, n = 3 (f), 6 (g)
R' = Bn, n = 6 (h), 9 (i), 12 (j), 18 (k), 24 (l)
R' = PMB, n = 6 (m), 9 (n), 12 (o), 18 (p)
Scheme 3. Preparation of iodide precursors 2f–p. PMB¼p-methoxybenzyl
(4-MeOC6H4CH2).
With the precursors in hand, a library of 30 PEGylated cal-
ix[8]arenes was initially assembled under optimised reaction
conditions. Some of these can be deprotected to release ter-
minal OH groups, giving a further 16 functionalised cal-
ix[8]arenes (Scheme 4, Table 2).
Interesting observations were made during the analysis of
these molecules by mass spectrometry: FAB ionisation
was mostly incompatible with these compounds, as it caused
many of the molecular mass ions to undergo extensive frag-
mentation. Thus, in most cases, ESI is a more suitable tech-
nique for establishing molecular identities. Even so, the loss
of the THP (entries 1, 2, 5, 6 and 8) or ethylene oxide (entries
13–15) units was inevitable in some cases. The interpreta-
tion of the ESI-MS spectra can be further complicated by
the occurrence of multiply charged ions and the formation
of Na adducts. Employment of the MALDI technique failed
to deliver a better alternative: In addition to interference of
adduct ions, the THP groups are generally unstable, giving
rise to fragmented ions in the spectra. For example, the spec-
trum of compound 3i (M+¼4097.5) showed the molecular
ion as a weak sodium adduct ion complexed with a-CHCA
(a-cyano-4-hydroxycinnamic acid, used to generate the ma-
trix), accompanied by fragmented ions in a recurring pattern
of 84 amu apart—corresponding to the successive loss of
C5H8O (dihydropyran) units (Fig. 2). In comparison, analy-
sis of this compound by ESI-MS revealed a doubly charged
R
1. Cs2CO3 (10+10 equiv)
THF-DMF (1:1)
1a-d
8
O
R'
I
(10 equiv)
2.
O
n
n
O
R'
R = t-Bu, t-Oc, H, OBn
R' = THP, PMB, Bn (3)
R' = H (4)
A, B or C
Scheme 4. PEGylation of calix[8]arenes and deprotection of the PEG chain.
Condition A (R¼THP): HCl, CH2Cl2/CH3OH (1:1), 4 h, rt; condition B
(R¼PMB): cerium ammonium nitrate (20 equiv), CH3CN/CH3OH (4:1),
6 h, rt; condition C: 20% Pd(OH)2/C, EtOH, 1,4-cyclohexadiene, 18 h,
reflux.
During the course of this work, the choice of the protecting
group was found to dictate the length of the ethylene glycol
chain that can be used in the reaction. Hence, for the purpose

9950
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
Table 2. Calix[8]arenes with PEG3–6 chainsa
Entry
R
R0
n
Yield (%)
m/z (observed)b
m/z (calculated)c
Assignment
1
2
3
4
5
6
7
8
t-Bu
t-Oct
H
OBn
t-Bu
t-Oct
H
OBn
t-Bu
t-Oct
H
OBn
t-Bu
t-Oct
H
THP
THP
THP
THP
THP
THP
THP
THP
H
H
H
H
H
3
3
3
3
6
6
6
6
3
3
3
3
6
6
6
6
55 (3e)
58 (3f)
63 (3g)
49 (3h)
43 (3i)
50 (3j)
48 (3k)
51 (3l)
82 (4a)
87 (4b)
80 (4c)
84 (4d)
86 (4e)
86 (4f)
81 (4g)
85 (4h)
2963.7 (ET)
1675.15 (E)
2578.6 (F)
3363.4 (F)
1979.0 (E)
2203.4 (E)
1825.5 (E)
2179.1 (E)
2376.8 (F)
1422.0 (E)
1927.6 (F)
2776.0 (F)
3389.2 (E)
1930.3 (E)
2940.6 (E)
1925.9 (E)
2962.8
1674.65
2578.4
3363.7
1979.2
2203.4
1825.5
2179.1
2376.4
1422.0
1927.9
2776.2
3389.1
1930.3
2940.6
1924.4
[MNaꢃC5H9O2]+
[MNa2ꢃC5H9OꢃC5H9O2]2+
[MH]+
[MNaꢃC5H9]+
[MNa2ꢃC5H8OꢃC5H9O2]2+
[MNa2ꢃC5H8OꢃC5H9O2]2+
[M+H2OꢃH]2+
[MNa2ꢃ2C5H9O]2+
[MKꢃCH2OH]+
[M+Na+4H]2+
9
10
11
12
13
14
15
16
[MNa]+
[MNa]+
[MNaꢃC2H3O2]+
[MNa2ꢃC2H3O2]2+
[MNaꢃC2H4O]+
[MNa2ꢃH]2+
H
H
H
OBn
a
Isolated yield of the purified compound. See Section 4 for general reaction conditions.
Observed molecular ion. Ionisation technique given in parenthesis: F¼FAB; E¼ESI; ET¼ES-TOF.
b
c
Calculated from average atomic mass.
mass ion at 1979.0356 (Table 2, entry 5), corresponding to
the di-sodium adduct with lost of C5H8O and OTHP groups.
error of 1–2 Da can be easily accommodated within the
resolution of the mass spectrum.
Due to the high molecular weight, the assignment of multi-
ply charged molecular ions obtained using ESI-MS can also
be difficult based on calculated value of M+. For example,
the compound 4h was detected as a doubly charged sodium
adduct. A good match between relative isotopic distribution
patterns of the observed and simulated ions indicates good
monodispersity and purity of the compound (Fig. 3). How-
ever, given the large number of oxygen atoms present, the
average mass calculated for the anticipated molecular spe-
cies [C208H281Na2O64]2+ (1924.4265) is lower than the sim-
ulated mass ion (1926.43), while the observed ion is found
between these two values (1925.9253). This margin of un-
certainty increases with molecular weight. As a result, an
2.4. Macrocyclon analogues containing PEG6–12
The fragility of the THP-protected compounds prompted us
to utilise PMB and Bn protecting groups for the preparation
of calix[8]arenes with longer [n]ethylene glycol chains
(where nꢂ6). Moderate yields of the fully functionalised
calix[8]arenes can be obtained (Table 3), and the resultant
compounds are more stable than their THP analogues for
MS analysis (Table 2, entry 12 vs Table 3, entries 1 and 8).
Nevertheless, with molecular masses in excess of 4500 Da,
structural characterisation of these compounds by NMR
spectroscopy became problematic—by increasing the PEG
chain length to ꢂ12, the spectra were dominated by intense
Figure 2. MALDI-TOF spectrum for 3i, showing successive loss of THP protecting groups (84 amu).

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9951
1926.4338
1926.9417
100
C208H281O64Na2
1925.9253
1926.4317
1925.9338
1925.4297
1927.4417
1926.9346
1927.4558
1925.4338
1924.9304
1927.9417
1922.7500
1928.4417
1928.9417
mass
0
1921
1923
1925
1927
1929
1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930
Figure 3. Observed (left) and simulated (right) isotopic distribution patterns for 4h (a doubly charged Na adduct).
resonance signals of the ethereal protons. As a result, the aro-
matic protons of the benzyl protecting group or the core of
the calix[8]arene were obscured, such that accurate integra-
tion was no longer possible. More problematically, slow mo-
lecular tumbling caused the appearance of resonance signals
to become broad and featureless (see 1H NMR spectrum of
compound 3y in Supplementary data). Attempts to improve
the appearance of the spectra either by VT NMR (up to
60 ꢀC) or by suppressing the ethereal protons’ resonance sig-
nal, proved futile. The problem was even more pronounced
in 13C NMR spectra, where resonance signals of tertiary and
quaternary carbons are practically invisible or unresolved.
For example, the bridging methylene carbon of compound
3v appeared as an extremely broad resonance signal at ca.
29 ppm (Supplementary data).
adducts between molecular ions and Na are common. How-
ever, in some cases, fragment ions resulting from the interac-
tion with a-CHCA were also observed16 (Table 3, entries 1
and 5). The loss of a methyl group from the highly
substituted upper rim was observed for some compounds
(Table 3, entries 2, 6 and 11). Not all compounds are amena-
ble to analysis by both ESI and MALDI-TOF techniques.
For example, most dodecathyelene glycol derivatives could
only be analysed by ESI, except 4m, which was only observ-
able using MALDI-TOF.
The PMB protecting groups can be removed using cerium
ammonium nitrate (CAN), substituting the water used in
the normal protocol by methanol, providing the hydroxy
compounds 4i–n. For compounds 3t–w, a transfer hydroge-
nation protocol using Pearlman’s catalyst, Pd(OH)2, was
applied for the removal of the benzyl group, whereas the
benzyloxy groups present on the upper rim of calixarenes de-
rived from 1d were also transformed into phenolic units, to
give compound 4o.
Hence, mass spectrometry remained as the chief character-
isation technique for these compounds, in particular ESI
and MALDI-TOF mass spectrometry, to provide the molec-
ular composition of these large, involatile and amphilic mol-
ecules. Using the ESI technique, the molecular ions were
mainly observed as multiply charged species, often as Na
adducts. Where the analysis was complicated or ambiguous,
MALDI-TOF was employed in a complementary manner,
to provide singly charged ions. As before, the formation of
Whilst the debenzylation works well for compounds con-
taining up to PEG9, the reaction of 3v–y failed to deliver
any products. For the p-benzyloxy substituted compound
3y, neither OBn groups can be removed despite our best
Table 3. Functionalised calix[8]arenes with PEG6–12 chains (Scheme 4)
Entry
R
R0
n
Yielda (%)
m/zb
m/z (calculated)c
Assignment
1
2
3
4
5
6
7
8
OBn
t-Bu
t-Oct
H
OBn
t-Bu
OBn
OBn
OBn
t-Bu
t-Oct
H
OBn
t-Bu
t-Oct
H
OBn
t-Bu
OBn
OH
PMB
PMB
PMB
PMB
PMB
PMB
PMB
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
6
9
9
9
9
12
12
6
52 (3m)
38 (3n)
42 (3o)
46 (3p)
37 (3q)
36 (3r)
34 (3s)
45 (3t)
43 (3u)
38 (3v)
33 (3w)
31 (3x)
29 (3y)
73 (4i)
78 (4j)
81 (4k)
75 (4l)
68 (4m)
65 (4n)
71 (4o)
4799.8 (MT)
2736.6 (E)
2958.7 (E)
2489.5 (E)
5916.8 (MT)
3265.0 (E)
3483.0 (E)
2288.1 (E)
5587.7 (MT)
3142.9 (E)
3369.2367 (E)
2920.6 (E)
3341.5 (E)
1554.1 (ET)
2478.7 (E)
4069.9 (MT)
4889.3 (MT)
5614.2 (MT)
2940.8 (E)
2096.9 (E)
4799.4
2736.6
2958.9
2490.3
5916.0
3264.9
3483.3
2288.1
5587.9
3142.9
3369.1042
2920.6
3341.8
1554.2
2478.6
4069.2
4889.5
5613.4
2940.6
2096.6
[M+COH*]+
[MNa2ꢃCH3]2+
[MNa+4H]2+
[MH2]2+
[M+C7H5*]+
[MNa2ꢃCH3]2+
[MNa2Kꢃ2H]2+
[MNa2]2+
9
9
[MH]+
10
11
12
13
14
15
16
17
18
19
20
12
12
12
12
9
9
9
9
[MNa+4H]2+
[MNa2ꢃCH3]2+
[MNa2]2+
[MHNa]2+
[McsNa2+2H]3+
[MNa2ꢃH2OꢃH]2+
[MNa+2H+CN*]+
[MNa]+
H
H
H
12
12
9
[MH+C6H3*]+
[MNa2ꢃC4H8O2]2+
[MNa2+H]2+
a
Isolated yield of the purified compound. See Section 4 for general reaction conditions.
Observed molecular ion. Ionisation technique given in parenthesis: F¼FAB; E¼ESI; ET¼ES-TOF.
Calculated from average atomic mass. *Fragment generated from a-CHCA.
b
c

9952
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
efforts, including increasing the catalyst loading and pro-
longed reaction time (up to 3 days). We speculate that the
physical properties of the compounds are, somehow, prohib-
iting the interaction of the O-benzyl moieties and the hetero-
geneous catalyst under these reaction conditions.
a certain level, by using a one-pot procedure. This allows
the systematic modification of the macrocyclon structure,
containing different substitution at the upper rim and well-
defined PEGn chains (n¼3, 6, 9, 12, 18 and 24) on the lower
rim. Benzyloxy ether protecting groups are much more suit-
able than pyran ethers, as they are more stable during the re-
action and subsequent analysis. Beyond a certain molecular
weight and chain length (ca. n>12), the amphiphilic macro-
molecules are difficult to analyse due to their unique physi-
cal properties. Nevertheless, chemically distinct compounds
that mimic the component mixture of macrocyclon can be
produced.
Yet again, the unprotected PEG derivatives 4i–o were much
less stable towards MS analysis, as the spectra were compli-
cated by adduct formation and/or fragmentation of the
molecular ions (Table 3, entries 17 and 18).
2.5. Macrocyclon analogues containing PEG18–24
Finally, attempts were made to introduce even longer PEGn
chains (n¼18 and 24). At this point of the synthesis, the re-
actions were extremely sluggish and decomposition of the
elongated PEG chains became a competitive process. How-
ever, by employing the more stable benzyl-protected PEG
iodides, the corresponding macromolecules can be obtained
in low yields (Fig. 4, 9–24%).
Preliminary results of the anti-tuberculosis properties of
some of these compounds have been previously communi-
cated.6 New compounds prepared in this project will be
assessed, along with related compounds prepared by our
collaborators in a separate program of work, to be reported
in due course.
4. Experimental section
4.1. General
n = 18, R = t-Bu, R' = Bn (5a), 24%
R = t-Oc, R' = Bn (5b), 17%
R = H, R' = Bn (5c), 21%
R = OBn, R' = PMB (5d),16%
R = OBn, R' = Bn (5e), 23%
R = OBn, R' = H (5f), 51%
R
8
O
Reactions were performed using standard laboratory glass-
ware (dried overnight in a hot oven, T>100 ꢀC), or using
a Radley’s 12-place reaction carousel under an inert atmo-
sphere. Commercially available reagents were purchased
and used as received, unless otherwise indicated.
n = 24, R = t-Bu, R' = Bn (6a), 18%
R = t-Oc, R' = Bn (6b), 12%
R = H, R' = Bn (6c), 19%
R = OBn, R' = Bn (6d), 9%
n
O
R'
Figure 4. Calix[8]arenes containing PEG18 and PEG24 units.
Calix[8]arenes 1a,b,8 1c,9 1d,10 2a,18 2b,19 2d,20 2e21 and
unsymmetrical tosylated PEG’s12 were prepared according
to the literature procedures. NMR spectra were acquired
using a Bruker AM-360 spectrometer (operating frequen-
The compounds can be purified by multiple column chroma-
tography. Addition of KOH did not cause any shift in the UV
absorption band, thus supporting the absence of free pheno-
lic groups. With fully functionalised lower rims, molecular
weights of these compounds range between 7.2 and
11 kDa, whereupon ESI and MALDI-TOF MS remain the
only reliable characterisation techniques.17 However, nei-
ther of these could provide the required molecular mass
data. The propensity of these compounds to form multiple
adducts prevented determination of mass ions by ESI-MS.
On the other hand, very little or no molecular ion can be de-
tected with MALDI-TOF. For example, close scrutiny of the
spectrum recorded with compound 5b revealed a poorly re-
solved peak at 9093.33 amu. However, the signal was too
weak to allow resolution of the isotopic distribution pattern.
We conclude that these compounds possess certain combina-
tions of physical properties (amphiphilicity, ability to cap-
ture small molecules within its cavity, high molecular
weight), which allow it to interact strongly with the matrix,
and affected its detection by TOF.
1
cies of 360 and 90.5 MHz for H and 13C, respectively)
and CDCl3 as solvent. The peak positions are reported in
1
parts per million (d), H NMR spectra were referenced to
residual CHCl3 in the solvent (dH 7.27), and 13C to
CDCl3 (dC 77.00). Mass spectra were recorded using
a Bruker APEC-III spectrometer for electrospray (ES)
technique or a VG ZAB 2SE spectrometer for FAB (3-ni-
trobenzyl alcohol as the matrix). MALDI-TOF spectra
were recorded by Mr. E. Samuel at the London School of
Pharmacy, using an ABI-Voyager DE-STR mass spectro-
meter (using a-CHCA as the matrix). UV–vis spectra were
recorded on a DU7400 Beckman Spectrometer using a ther-
mostated (25 ꢀC) quartz cell of 1 cm path length. Samples
were prepared as solutions in methanol. Infrared spectra
were recorded on a Perkin–Elmer FTIR Spectrum One
spectrometer. Liquid samples were recorded as thin films
between NaCl plates.
Characterisation data for novel compounds 2f–p, 5a–f and
6a–d, tables summarising the result of reaction optimisation,
including the choice and stoichiometry of base and
The same physical properties may explain the failure of our
subsequent attempts to remove the benzyl groups by hydro-
genation. The only success was the synthesis of 5f by the
removal of the PMB group of 5d was achieved in a compar-
atively low 51% yield.
1
selected H (compounds 3a and 3g) and 13C (compounds
3c, 3g and 3v) NMR spectra are provided in the Supplemen-
tary data.
3. Conclusion
For brevity, the terminology of elongated polyethylene gly-
col chains suggested in our previous paper12 is adopted here,
i.e., the positions of oxygen atoms in the PEG chains are
This work demonstrates that calix[8]arenes can be fully de-
rivatised at the lower rim with [n]ethylene glycol units, to

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9953
denoted by the mathematical shorthand for arithmetic
progressions, e.g., 1-benzyloxy-35-iodo-3n333-undecaoxa-
pentatriacontane (2j) refers to 35-benzyloxy-35-iodo-
3,6,9,12,15,18,21,24,27,30,33-undecaoxapentatriacontane.
(8ꢁC(CH3)2), 57.4 (8ꢁCH2C(CH3)3), 59.1 (8ꢁOCH3),
70.0–71.3 (40ꢁCH2O), 72.8 (8ꢁCH2O), 126.4 (16ꢁCmeta),
132.7 (16ꢁCortho), 145.0 (8ꢁCpara), 153.3 (8ꢁCipso); m/z
(ES) 2937.2084 ([MNa+]), C176H288NaO32 requires
2937.0931.
4.2. General procedure for the preparation of iodo-
derivatives of polyethylene glycols (Scheme 2)
4.3.3. 5,11,17,23,29,35,41,47-Octakis-[8-methoxy-3n36-di-
oxaoctyloxy]-calix[8]arene (3c). Isolated as an orange oil,
from calix[8]arene 1c (0.50 g, 0.59 mmol) and I–PEG3–
OMe 2c (1.61 g, 5.89 mmol). Yield: 64% (0.76 g). Rf 0.63
(EtOAc/hexane, 4:1). Found: C, 66.65; H, 8.00.
C112H160O32 requires C, 66.65; H, 7.99%; lmax/nm 276
and 268; nmax (film)/cmꢃ1 1109 (CO) and 768 (CH); dH:
3.24 (24H, s, 8ꢁOCH3), 3.37–3.75 (80H, m, 32ꢁCH2O
and 8ꢁArCH2Ar), 3.80–3.82 (16H, m, 8ꢁCH2OCH3),
3.99 (16H, s, 8ꢁArOCH2), 6.62–6.83 (24H, m, 16ꢁHmeta
and 8ꢁHpara); dC: 28.3 (8ꢁArCH2Ar), 57.7 (8ꢁOCH3),
68.9–69.4 (32ꢁCH2O), 71.0 (8ꢁCH2O), 71.5 (8ꢁCH2O),
124.0 (8ꢁCpara), 128.8 (16ꢁCmeta), 134.2 (16ꢁCortho),
154.9 (8ꢁCipso); m/z (FAB) 2040.8 (MNa+, 46%), 2018.7
([MH]+, 13), 265.1 (6) and 103.0 (100); m/z (ES) 2040.23
([MNa]+, C112H160NaO32 requires 2040.08).
Sodium iodide (5 equiv) was added to a solution of the
mono-protected tosylated glycol R(OCH2CH2)nOTs12
(R¼THP, Bn or PMB, n¼3–24, 1 equiv) in acetone and
the solution was heated at reflux for 20–24 h. After this
time, the inorganic salts were removed by filtration and the
filtrate was concentrated under reduced pressure. The resi-
due was dissolved in a mixture of EtOAc/H2O (1:1, v/v)
and separated. The combined organic extracts were washed
with water and saturated aq sodium thiosulfate, dried over
MgSO4, filtered and evaporated under vacuum. The residue
was purified by column chromatography. Full characterisa-
tion data for these compounds are provided in Supplemen-
tary data.
4.3. General procedure for the PEGylation of
calix[8]arenes at the lower rim (Scheme 3)
4.3.4. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,51,
52,53,54,55,56-octakis-[8-methoxy-3n36-dioxaoctyloxy]-
calix[8]arene (3d). Isolated as an orange oil, from p-benzyl-
oxycalix[8]arene 1d (0.50 g, 0.29 mmol) and I–PEG3–OMe
2c (0.81 g, 2.94 mmol). Yield: 62% (0.52 g). Rf 0.49
(EtOAc/hexane, 4:1). lmax/nm 278 and 269; nmax (film)/
cmꢃ1 1121 (CO); dH: 3.22 (24H, s, 8ꢁOCH3), 3.31–3.72
(96H, m, 40ꢁCH2O and 8ꢁArCH2Ar), 3.89–3.90 (16H,
m, 8ꢁCH2OCH3), 4.52 (16H, s, 8ꢁCH2Ph), 6.42–6.53
Cs2CO3 (10 equiv) was added to a solution of the requisite
calix[8]arene (1 equiv) in a mixture of DMF/THF (1:1,
v/v) at 80 ꢀC. After stirring for 18 h, another portion of
Cs2CO3 (10 equiv) was added. After 6 h, a solution of the
polyethylene glycol iodide (10 equiv) in THF was added
dropwise via cannula. After 3 days, the reaction mixture
was quenched by the addition of 1 N HCl until a clear solu-
tion was obtained and this was extracted with EtOAc. The
organic extracts were combined and washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The remaining oil was purified by column chromatography.
(16H, m, 16ꢁHmeta), 7.00–7.31 (40H, m, 8ꢁHortho, Hmeta
,
Hpara); dC: 30.3 (8ꢁArCH2Ar), 58.4 (8ꢁOCH3), 69.9–71.1
(40ꢁCH2O), 72.3 (8ꢁCH2O), 73.3 (8ꢁCH2Ph), 115.3
(16ꢁCmeta), 127.9–128.8 (40ꢁCortho, Cmeta, Cpara), 132.5
(16ꢁCortho), 137.7 (8ꢁCipso), 149.2 (8ꢁCpara), 154.9
(8ꢁCipso); m/z (FAB) 2887.1 ([MNa]+), C168H208NaO40
requires 2888.4.
4.3.1. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,
53,54,55,56-octakis-[8-methoxy-3n36-dioxaoctyloxy]-calix-
[8]arene (3a).11 Isolated as an orange oil, from tert-butyl-
calix[8]arene 1a (0.50 g, 0.39 mmol) and I–PEG3–OMe 2c
(1.06 g, 3.85 mmol). Yield: 57% (0.54 g). Rf 0.61 (EtOAc/
hexane, 5:1). lmax/nm 277 and 269; nmax (film)/cmꢃ1 1114
(CO); dH: 0.89–0.98 (72H, m, 24ꢁCH3), 3.27 (24H,
s, 8ꢁOCH3), 3.39–3.87 (96H, m, 40ꢁCH2O and
8ꢁArCH2Ar), 3.93–3.96 (16H, m, 8ꢁCH2OCH3), 6.81–
6.83 (16H, m, 16ꢁHmeta); dC: 30.1 (8ꢁArCH2Ar), 31.4
(24ꢁCH3), 34.1 (8ꢁC(CH3)3), 58.7 (8ꢁOCH3), 69.8–71.3
(40ꢁCH2O), 72.7 (8ꢁCH2O), 125.4 (16ꢁCmeta), 133.8
(16ꢁCortho), 145.9 (8ꢁCpara), 154.9 (8ꢁCipso); m/z (FAB)
2488.7 ([MNa]+), C144H224NaO32 requires 2488.6.
4.3.5. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,
53,54,55,56-octakis-[8-(2H-tetrahydropyran-2-yloxy)-
3n36-dioxaoctyloxy]-calix[8]arene (3e). Isolated as an
orange oil, from tert-butylcalix[8]arene 1a (0.50 g,
0.39 mmol) and I–PEG3–OTHP 2f (1.32 g, 3.85 mmol).
Yield: 55% (0.64 g). Rf 0.43 (EtOAc/hexane, 6:1). lmax/nm
276 and 268; nmax (film)/cmꢃ1 1098 (CO); dH: 0.86–1.01
(72H, m, 24ꢁCH3), 1.43–1.75 (48H, m, 8ꢁH3, H4, H5),
3.52–3.82 (128H, m, 48ꢁCH2O, 8ꢁArCH2Ar and 8ꢁH6),
4.54–4.58 (8H, m, 8ꢁH2), 6.80–6.89 (16H, m, 16ꢁHmeta);
m/z (ES-TOF) 2963.7 ([MNaꢃC5H9O2]+), C172H266NaO38
requires 2962.8.
4.3.2. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,51,52,
53,54,55,56-octakis-[8-methoxy-3n36-dioxaoctyloxy]-
calix[8]arene (3b).11 Isolated as an orange oil, from tert-oc-
tylcalix[8]arene 1b (0.50 g, 0.29 mmol) and I–PEG3–OMe 2c
(0.78 g, 2.86 mmol). Yield: 54% (0.45 g). Rf 0.53 (EtOAc/
hexane, 5:1). lmax/nm 278 and 268; nmax (film)/cmꢃ1 1104
(CO); dH: 0.64–0.77 (72H, m, 8ꢁ(CH3)3), 1.04–1.26 (48H,
m, 8ꢁ(CH3)2), 1.41–1.59 (16H, m, 8ꢁCH2C(CH3)3), 3.28
(24H, s, 8ꢁOCH3), 3.41–3.98 (112H, m, 48ꢁCH2O and
8ꢁArCH2Ar), 6.53–6.70 (16H, m, 16ꢁHmeta); dC: 30.1
(8ꢁArCH2Ar), 32.3–32.9 (40ꢁCH3 and 8ꢁC(CH3)3), 38.0
4.3.6. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,51,52,
53,54,55,56-octakis-[8-(2H-tetrahydropyran-2-yloxy)-
3n36-dioxaoctyloxy]-calix[8]arene (3f). Isolated as an
orange oil, from tert-octylcalix[8]arene 1b (0.50 g,
0.29 mmol) and I–PEG3–OTHP 2f (0.98 g, 2.86 mmol).
Yield: 58% (0.58 g). Rf 0.48 (EtOAc/hexane, 5:1). lmax/nm
282 and 271; nmax (film)/cmꢃ1 1118 (CO); dH: 0.61–0.83
(72H, m, 8ꢁ(CH3)3), 1.00–1.24 (48H, m, 8ꢁ(CH3)2),
1.31–1.85 (64H, m, 8ꢁH3, H4, H5 and 8ꢁCH2C(CH3)3),
3.28 (24H, s, 8ꢁOCH3), 3.31–3.87 (128H, m, 48ꢁCH2O,

9954
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
8ꢁArCH2Ar and 8ꢁH6), 4.39–4.44 (8H, m, 8ꢁH2), 6.58–
6.82 (16H, m, 16ꢁHmeta); m/z (ES) 1675.1561 ([MNa2ꢃ
C5H9OꢃC5H9O2]2+). C199H321Na2O37 requires 3349.3032.
3.24–3.85 (224H, m, 96ꢁCH2O, 8ꢁArCH2Ar and 8ꢁH6),
4.42–4.47 (8H, m, 8ꢁH2), 6.61–6.98 (24H, m, 16ꢁHmeta
and 8ꢁHpara); m/z (ES) 1825.4683 ([M+H2OꢃH]2+),
C192H305O65 requires 3651.0561.
4.3.7. 5,11,17,23,29,35,41,47-Octakis-[8-(2H-tetrahydro-
pyran-2-yloxy)-49,50,51,52,53,54,55,56-dioxaoctyloxy]-
calix[8]arene (3g). Isolated as an orange oil, from calix[8]-
arene 1c (0.50 g, 0.59 mmol) and I–PEG3–OTHP 2f (2.03 g,
5.89 mmol). Yield: 63% (0.96 g). Rf 0.34 (EtOAc/hexane,
8:1). lmax/nm 275 and 266; nmax (film)/cmꢃ1 1111 (CO)
and 773 (CH); dH: 1.29–1.63 (48H, m, 8ꢁH3, H4, H5),
3.31–3.79 (128H, m, 48ꢁCH2O, 8ꢁArCH2Ar and 8ꢁH6),
4.43–4.48 (8H, m, 8ꢁH2), 6.71–7.01 (24H, m, 16ꢁHmeta
and 8ꢁHpara); m/z (FAB) 2578.6 ([MH]+), C144H208O40
requires 2578.4.
4.3.12. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[17-(2H-tetrahydropyran-2-
yloxy)-3n315-pentaoxaheptadecyloxy]-calix[8]arene (3l).
Isolated as an orange oil, from p-benzyloxycalix[8]arene
1d (0.50 g, 0.29 mmol) and I–PEG6–OTHP 2g (1.40 g,
2.94 mmol). Yield: 51% (0.67 g). Rf 0.67 (EtOAc/acetone,
3:1). lmax/nm 279 and 269; nmax (film)/cmꢃ1 1109 (CO);
dH: 1.23–1.75 (48H, m, 8ꢁH3, H4, H5), 3.23–3.91 (224H,
m, 96ꢁCH2O, 8ꢁArCH2Ar and 8ꢁH6), 4.45–4.67 (24H,
m, 8ꢁCH2Ph and 8ꢁH2), 6.71–6.93 (16H, m, 16ꢁHmeta),
7.04–7.33 (40H, m, 8ꢁHortho, Hmeta, Hpara); m/z (ES)
2179.0839 ([MNa2ꢃ2C5H9O]2+), C238H334Na2O70 requires
4358.2371.
4.3.8. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[8-(2H-tetrahydropyran-2-
yloxy)-3n36-dioxaoctyloxy]-calix[8]arene (3h). Isolated as
an orange oil, from p-benzyloxycalix[8]arene 1d (0.50 g,
0.29 mmol) and I–PEG3–OTHP 2f (1.01 g, 2.94 mmol).
4.3.13. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[17-(p-methoxybenzyloxy)-
3n315-pentaoxaheptadecyloxy]-calix[8]arene (3m). Iso-
lated as an orange oil, from p-benzyloxycalix[8]arene 1d
(0.50 g, 0.29 mmol) and I–PEG6–OPMB 2m (1.51 g,
2.94 mmol). Yield: 52% (0.73 g). Rf 0.67 (EtOAc/acetone,
4:3). lmax/nm 278 and 270; nmax (film)/cmꢃ1 1115 (CO);
dH: 3.17–3.71 (208H, m, 96ꢁCH2O and 8ꢁArCH2Ar),
3.95 (24H, s, OCH3), 4.48–4.57 (32H, m, 8ꢁCH2Ph and
8ꢁCH2), 6.51–6.91 (32H, m, 16ꢁHmeta and 16ꢁHmeta),
7.03–7.32 (56H, m, 8ꢁHortho, Hmeta, Hpara and 16ꢁHortho);
dC: 30.1 (8ꢁArCH2Ar), 55.4 (8ꢁOCH3), 69.6–71.0
(88ꢁCH2O), 72.9 (8ꢁCH2O), 73.3 (8ꢁCH2Ph), 73.4
(8ꢁCH2), 114.3 (16ꢁCmeta), 116.1 (16ꢁCmeta), 127.9–
128.9 (40ꢁCortho, Cmeta, Cpara), 129.6 (16ꢁCortho), 130.6
(8ꢁCipso), 135.9 (16ꢁCortho), 138.0 (8ꢁCipso), 149.2
(8ꢁCpara), 155.1 (8ꢁCipso), 159.8 (8ꢁCpara); m/z
(MALDI-TOF) 4799.75 ([M+COH]+), C273H353O73 re-
quires 4799.39.
Yield: 49% (0.49 g). Rf 0.65 (EtOAc/hexane, 12:1). lmax
/
nm 279 and 268; nmax (film)/cmꢃ1 1106 (CO); dH: 1.37–
1.69 (48H, m, 8ꢁH3, H4, H5), 3.34–3.93 (128H, m,
48ꢁCH2O, 8ꢁArCH2Ar and 8ꢁH6), 4.51–4.60 (24H, s,
8ꢁCH2Ph and 8ꢁH2), 6.71–6.93 (16H, m, 16ꢁHmeta),
7.04–7.33 (40H, m, 8ꢁHortho, Hmeta, Hpara); m/z (FAB)
3363.4 ([MNaꢃC5H9]+), C195H247NaO47 requires 3363.7.
4.3.9. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[17-(2H-tetrahydropyran-2-
yloxy)-3n315-pentaoxaheptadecyloxy]-calix[8]arene (3i).11
Isolated as an orange oil, from tert-butylcalix[8]arene 1a
(0.50 g, 0.39 mmol) and I–PEG6–OTHP 2g (1.83 g,
3.85 mmol). Yield: 43% (0.68 g). Rf 0.76 (EtOAc/acetone,
3:1). lmax/nm 276 and 268; nmax (film)/cmꢃ1 1100 (CO);
dH: 0.93–1.07 (72H, m, 24ꢁCH3), 1.40–1.84 (48H,
m, 8ꢁH3, H4, H5), 3.41–3.79 (224H, m, 96ꢁ
CH2O, 8ꢁArCH2Ar and 8ꢁH6), 4.50–4.57 (8H, m, 8ꢁH2),
6.76–6.91 (16H, m, 16ꢁHmeta); m/z (ES) 1979.0356 ([MNa2ꢃ
C5H8OꢃC5H9O2]2+), C215H353Na2O61 requires 3957.4316.
4.3.14. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[26-(p-methoxybenzyloxy)-
3n324-octaoxahexacosyloxy]-calix[8]arene (3n). Isolated as
an orange oil, from tert-butylcalix[8]arene 1a (0.40 g,
0.31 mmol) and I–PEG9–OPMB 2n (1.98 g, 3.08 mmol).
4.3.10. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[17-(2H-tetrahydropyran-2-
yloxy)-3n315-pentaoxaheptadecyloxy]-calix[8]arene
(3j).11 Isolated as an orange oil, from tert-octylcalix[8]arene
1b (0.50 g, 0.29 mmol) and I–PEG6–OTHP 2g (1.36 g,
2.86 mmol). Yield: 50% (0.65 g). Rf 0.80 (EtOAc/acetone,
3:1). lmax/nm 275 and 267; nmax (film)/cmꢃ1 1109 (CO);
dH: 0.64–0.86 (72H, m, 8ꢁ(CH3)3), 0.97–1.21 (48H, m,
8ꢁ(CH3)2), 1.30–1.97 (64H, m, 8ꢁH3, H4, H5 and
8ꢁCH2C(CH3)3), 3.38–3.91 (224H, m, 96ꢁCH2O,
8ꢁArCH2Ar and 8ꢁH6), 4.40–4.47 (8H, m, 8ꢁH2), 6.47–
6.76 (16H, m, 16ꢁHmeta); m/z (ES) 2203.4539 ([MNa2ꢃ
C5H8OꢃC5H8O2]2+), C247H418Na2O61 requires 4406.9402.
Yield: 38% (0.75 g). Rf 0.43 (EtOAc/acetone, 1:2). lmax
/
nm 277 and 270; nmax (film)/cmꢃ1 1097 (CO); dH: 0.91–
1.20 (72H, m, 24ꢁCH3), 3.23–3.78 (304H, m, 144ꢁCH2O
and 8ꢁArCH2Ar), 3.87 (24H, s, 8ꢁOCH3), 4.51 (16H, s,
8ꢁCH2), 6.48–6.83 (32H, m, 16ꢁHmeta and 16ꢁHmeta),
7.08–7.25 (16H, m, 16ꢁHortho); dC: 29.9 (8ꢁArCH2Ar),
31.4 (24ꢁCH3), 34.0 (8ꢁC(CH3)3), 55.8 (8ꢁOCH3), 69.9–
72.0 (136ꢁCH2O), 72.4 (8ꢁCH2O), 73.3 (8ꢁCH2), 114.6
(16ꢁCmeta), 125.6 (16ꢁCmeta), 129.7 (16ꢁCortho), 130.9
(8ꢁCipso), 132.8 (16ꢁCortho), 145.0 (8ꢁCpara), 153.6
(8ꢁCipso), 159.9 (8ꢁCpara); m/z (ES) 2736.5727
([MNa2ꢃCH3]2+), C296H464Na2O88 requires 2736.5814.
4.3.11. 49,50,51,52,53,54,55,56-Octakis-[17-(2H-tetra-
hydropyran-2-yloxy)-3n315-pentaoxaheptadecyloxy]-
calix[8]arene (3k). Isolated as an orange oil, from
calix[8]arene 1c (0.50 g, 0.59 mmol) and I–PEG6–OTHP
2g (2.80 g, 5.89 mmol). Yield: 48% (1.03 g). Rf 0.51
(EtOAc/acetone, 5:2). lmax/nm 279 and 268; nmax (film)/
cmꢃ1 1109 (CO); dH: 1.15–1.57 (48H, m, 8ꢁH3, H4, H5),
4.3.15. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[26-(p-methoxybenzyloxy)-
3n324-octaoxahexacosyloxy]-calix[8]arene (3o). Isolated as
an orange oil, from tert-octylcalix[8]arene 1b (0.30 g,
0.17 mmol) and I–PEG9–OPMB 2n (1.11 g, 1.72 mmol).
Yield: 42% (0.42 g). Rf 0.46 (EtOAc/acetone, 1:2). lmax/nm

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9955
278 and 271; nmax (film)/cmꢃ1 1110 (CO); dH: 0.60–0.84
(72H, m, 8ꢁ(CH3)3), 0.92–1.15 (48H, m, 8ꢁ(CH3)2), 1.41–
1.63 (16H, m, 8ꢁCH2C(CH3)3), 3.27–3.84 (304H, m,
144ꢁCH2O and 8ꢁArCH2Ar), 3.95 (24H, s, 8ꢁOCH3),
4.46 (16H, s, 8ꢁCH2), 6.49–6.87 (32H, m, 16ꢁHmeta and
16ꢁHmeta), 7.17–7.30 (16H, m, 16ꢁHortho); dC: 29.8
(8ꢁArCH2Ar), 31.5–32.3 (40ꢁCH3 and 8ꢁC(CH3)3), 37.9
(8ꢁC(CH3)2), 55.6 (8ꢁOCH3), 57.3 (8ꢁCH2C(CH3)3),
69.9–71.9 (136ꢁCH2O), 72.7 (8ꢁCH2O), 73.4 (8ꢁCH2),
114.4 (16ꢁCmeta), 125.6 (16ꢁCmeta), 129.7 (16ꢁCortho),
130.8 (8ꢁCipso), 132.8 (16ꢁCortho), 145.0 (8ꢁCpara),
153.6 (8ꢁCipso), 160.0 (8ꢁCpara); m/z (ES) 2958.7341
([MNa+4H]2+), C329H535NaO88 requires 5917.7286.
72.7 (8ꢁCH2O), 73.2 (8ꢁCH2Ar), 114.7 (16ꢁCmeta),
125.6 (16ꢁCmeta), 129.9 (16ꢁCortho), 131.0 (8ꢁCipso),
132.8 (16ꢁCortho), 145.0 (8ꢁCpara), 153.7 (8ꢁCipso),
159.9 (8ꢁCpara); m/z (ES) 3265.0435 ([MNa2ꢃCH3]2+),
C344H560Na2O112 requires 6529.7920.
4.3.19. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[35-(p-methoxybenzyloxy)-
3n333-undecaoxapentatriacontyloxy]-calix[8]arene (3s).
Isolated as an orange oil, from p-benzyloxycalix[8]arene
1d (0.40 g, 0.24 mmol) and I–PEG12–OPMB 2o (1.83 g,
2.36 mmol). Yield: 34% (0.55 g). Rf 0.81 (EtOAc/acetone,
1:6). lmax/nm 280 and 268; nmax (film)/cmꢃ1 1108 (CO);
dH: 3.17–3.74 (400H, m, 192ꢁCH2O and 8ꢁArCH2Ar),
3.91 (24H, s, OCH3), 4.46–4.67 (32H, m, 8ꢁCH2Ph and
8ꢁCH2), 6.59–6.97 (32H, m, 16ꢁHmeta and 16ꢁHmeta),
7.03–7.35 (56H, m, 8ꢁHortho, Hmeta, Hpara and 16ꢁHortho);
dC: 30.0 (8ꢁArCH2Ar), 55.6 (8ꢁOCH3), 69.5–71.7
(184ꢁCH2O), 73.0 (8ꢁCH2O), 73.4 (8ꢁCH2Ph), 73.7
(8ꢁCH2Ar), 114.6 (16ꢁCmeta), 116.1 (16ꢁCmeta), 127.9–
129.0 (40ꢁCortho, Cmeta, Cpara), 129.8 (16ꢁCortho), 130.8
(8ꢁCipso), 136.0 (16ꢁCortho), 138.1 (8ꢁCipso), 149.3
(8ꢁCpara), 155.1 (8ꢁCipso), 159.8 (8ꢁCpara); m/z (ES)
3483.0287 ([(MNa2+Kꢃ2H]2+), C368H542KNa2O120 re-
quires 6966.5742.
4.3.16. 49,50,51,52,53,54,55,56-Octakis-[26-(p-methoxy-
benzyloxy)-3n324-octaoxahexacosyloxy]-calix[8]arene
(3p). Isolated as an orange oil, from calix[8]arene 1c (0.30 g,
0.35 mmol) and I–PEG9–OPMB 2n (2.28 g, 3.53 mmol).
Yield: 46% (0.81 g). Rf 0.39 (EtOAc/acetone, 2:3).
lmax/nm 275 and 268; nmax (film)/cmꢃ1 1107 (CO); dH:
3.27–3.80 (304H, m, 144ꢁCH2O and 8ꢁArCH2Ar),
3.65 (24H, s, 8ꢁOCH3), 4.47 (16H, s, 8ꢁCH2), 6.51–
6.78 (40H, m, 16ꢁHmeta
,
8ꢁHpara and 16ꢁHmeta),
7.02–7.21 (16H, m, 16ꢁHortho); dC: 30.1 (8ꢁArCH2Ar),
55.7 69.9–71.8 72.7
(8ꢁOCH3),
(136ꢁCH2O),
(8ꢁCH2O), 73.4 (8ꢁCH2), 114.6 (16ꢁCmeta), 124.0
(8ꢁCpara), 129.1 (16ꢁCmeta), 129.8 (16ꢁCortho), 131.0
(8ꢁCipso), 134.0 (16ꢁCortho), 154.8 (8ꢁCipso), 159.8
(8ꢁCpara); m/z (ES) 2489.4638 ([MH2]2+), C264H401O88
requires 4980.6981.
4.3.20. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[17-benzyloxy-3n315-pentaoxa-
heptadecyloxy]-calix[8]arene (3t). Isolated as an orange
oil, from p-benzyloxycalix[8]arene 1d (0.50 g, 0.29 mmol)
and I–PEG6–OBn 2h (1.42 g, 2.94 mmol). Yield: 45%
(0.60 g). Rf 0.67 (EtOAc/acetone, 4:3). lmax/nm 280 and
272; nmax (film)/cmꢃ1 1109 (CO); dH: 3.29–3.73 (208H, m,
96ꢁCH2O and 8ꢁArCH2Ar), 4.36–4.61 (32H, m,
16ꢁCH2Ph), 6.66–6.79 (16H, m, 16ꢁHmeta), 7.00–7.32
(80H, m, 16ꢁHortho, Hmeta, Hpara); dC: 30.0 (8ꢁArCH2Ar),
69.4–71.2 (88ꢁCH2O), 72.9 (8ꢁCH2O), 73.4 (8ꢁCH2Ph),
73.7 (8ꢁCH2Ph), 115.9 (16ꢁCmeta), 127.9–129.0
(80ꢁCortho, Cmeta, Cpara), 135.7 (16ꢁCortho), 137.9–138.1
(16ꢁCipso), 149.1 (8ꢁCpara), 155.1 (8ꢁCipso); m/z (ES)
4.3.17. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[26-(p-methoxybenzyloxy)-
3n324-octaoxahexacosyloxy]-calix[8]arene (3q). Isolated as
an orange oil, from p-benzyloxycalix[8]arene 1d (0.40 g,
0.24 mmol) and I–PEG9–OPMB 2n (1.52 g, 2.36 mmol).
Yield: 37% (0.51 g). Rf 0.51 (EtOAc/acetone, 1:2). lmax
/
nm 279 and 269; nmax (film)/cmꢃ1 1110 (CO); dH: 3.12–
3.68 (304H, m, 144ꢁCH2O and 8ꢁArCH2Ar), 3.87 (24H,
s, OCH3), 4.44–4.53 (32H, m, 8ꢁCH2Ph and 8ꢁCH2),
6.62–6.99 (32H, m, 16ꢁHmeta and 16ꢁHmeta), 7.07–7.31
(56H, m, 8ꢁHortho, Hmeta, Hpara and 16ꢁHortho); dC: 30.0
(8ꢁArCH2Ar), 55.7 (8ꢁOCH3), 69.9–71.5 (136ꢁCH2O),
73.1 (8ꢁCH2O), 73.3 (8ꢁCH2Ph), 73.5 (8ꢁCH2), 114.4
2288.1698
4576.2833.
([MNa2]2+),
C264H336Na2O64
requires
4.3.21. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,51,
52,53,54,55,56-octakis-[26-benzyloxy-3n324-octaoxahexa-
cosyloxy]-calix[8]arene (3u). Isolated as an orange oil,
from p-benzyloxycalix[8]arene 1d (0.30 g, 0.18 mmol) and
I–PEG9–OBn 2i (1.09 g, 1.77 mmol). Yield: 43% (0.43 g).
Rf 0.42 (EtOAc/acetone, 1:2). lmax/nm 281 and 273; nmax
(film)/cmꢃ1 1117 (CO); dH: 3.30–3.78 (304H, m,
144ꢁCH2O and 8ꢁArCH2Ar), 4.33–4.59 (32H, m,
16ꢁCH2Ph), 6.57–6.83 (16H, m, 16ꢁHmeta), 6.97–7.37
(80H, m, 16ꢁHortho, Hmeta, Hpara); dC: 30.1 (8ꢁArCH2Ar),
69.6–71.4 (136ꢁCH2O), 73.0 (8ꢁCH2O), 73.3 (8ꢁCH2Ph),
73.6 (8ꢁCH2Ph), 116.1 (16ꢁCmeta), 127.9–129.1
(80ꢁCortho, Cmeta, Cpara), 135.8 (16ꢁCortho), 137.9–138.1
(16ꢁCipso), 149.1 (8ꢁCpara), 155.0 (8ꢁCipso); m/z
(MALDI-TOF) 5587.73 (MH+), C312H433O88 requires
5587.94).
(16ꢁCmeta), 116.0 (16ꢁCmeta), 128.0–129.0 (40ꢁCortho
,
Cmeta, Cpara), 129.7 (16ꢁCortho), 130.8 (8ꢁCipso), 136.0
(16ꢁCortho), 138.1 (8ꢁCipso), 149.2 (8ꢁCpara), 155.1
(8ꢁCipso), 159.7 (8ꢁCpara); m/z (MALDI-TOF) 5916.81
([M+C7H5]+), C327H453O96 requires 5916.05.
4.3.18. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[35-(p-methoxybenzyloxy)-
3n333-undecaoxapentatriacontyloxy]-calix[8]arene (3r).
Isolated as an orange oil, from tert-butylcalix[8]arene 1a
(0.30 g, 0.23 mmol) and I–PEG12–OPMB 2o (1.79 g,
2.31 mmol). Yield: 36% (0.54 g). Rf 0.56 (EtOAc/acetone,
1:5). lmax/nm 276 and 267; nmax (film)/cmꢃ1 1102 (CO);
dH: 0.82–1.17 (72H, m, 24ꢁCH3), 3.17–3.82 (400H, m,
192ꢁCH2O and 8ꢁArCH2Ar), 3.78 (24H, s, 8ꢁOCH3),
4.46–4.51 (16H, m, 8ꢁCH2Ar), 6.50–6.84 (32H, m,
16ꢁHmeta and 16ꢁHmeta), 7.03–7.31 (16H, m, 16ꢁHortho);
dC: 29.8 (8ꢁArCH2Ar), 31.5 (24ꢁCH3), 33.9
(8ꢁC(CH3)3), 55.7 (8ꢁOCH3), 69.8–71.9 (184ꢁCH2O),
4.3.22. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[35-benzyloxy-3n333-undecaoxa-
pentatriacontyloxy]-calix[8]arene (3v). Isolated as an

9956
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
orange oil, from tert-butylcalix[8]arene 1a (0.40 g,
0.31 mmol) and I–PEG12–OBn 2j (2.30 g, 3.08 mmol).
127.9–129.2 (80ꢁCortho, Cmeta, Cpara), 135.8 (16ꢁCortho),
137.9 (8ꢁCipso), 138.5 (8ꢁCipso), 149.1 (8ꢁCpara), 155.1
Yield: 38% (0.73 g). Rf 0.44 (EtOAc/acetone, 1:5). lmax
/
(8ꢁCipso);
m/z
C361H533NaO112 requires 6683.5909.
(ES)
3341.4598
([(MHNa]2+),
nm 276 and 268; nmax (film)/cmꢃ1 1105 (CO); dH: 0.83–
1.22 (72H, m, 24ꢁCH3), 3.203–3.81 (400H, m,
192ꢁCH2O and 8ꢁArCH2Ar), 4.44–4.49 (16H, m,
8ꢁCH2Ph), 6.52–6.77 (16H, m, 16ꢁHmeta), 6.98–7.26
(40H, m, 8ꢁHortho, Hmeta, Hpara); dC: 28.7 (8ꢁArCH2Ar),
4.4. Removal of protecting groups
4.4.1. Removal of THP ethers. The THP-protected cal-
ix[8]arene was dissolved in a mixture of CH3OH and
CH2Cl2 (1:1). A few drops of concd HCl were added and
the solution was stirred at room temperature for 3 h.
NaHCO3 was added to neutralise the solution and the sol-
vents were removed under reduced pressure. EtOAc was
added to the residue and the resulting suspension was filtered
to remove the inorganic salt. Finally, the solvent was re-
moved and the product was subjected to column chromato-
graphy.
30.3
(24ꢁCH3),
33.0
(8ꢁC(CH3)3),
68.7–69.9
(184ꢁCH2O), 72.7 (8ꢁCH2O), 73.7 (8ꢁCH2Ph), 124.8
(16ꢁCmeta), 127.8–129.0 (40ꢁCortho, Cmeta, Cpara), 132.1
(16ꢁCortho), 138.3 (8ꢁCipso), 144.7 (8ꢁCpara), 152.1
(8ꢁCipso);
m/z
(ES)
3142.8937
([MNa+4H]2+),
C337H551NaO104 requires 6285.7725.
4.3.23. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[35-benzyloxy-3n333-undecaoxa-
pentatriacontyloxy]-calix[8]arene (3w). Isolated as an
orange oil, from tert-octylcalix[8]arene 1b (0.40 g,
0.23 mmol) and I–PEG12–OBn 2j (1.71 g, 2.29 mmol).
4.4.2. Removal of benzyl ethers. Pearlman’s catalyst (20%
Pd(OH)2, 0.27 g) was added to benzyl-protected calix[8]ar-
ene (1.90 mmol) in a mixture of ethanol and cyclohexa-1,4-
diene (25 mL, 3:2 v/v). After refluxing for 18 h, the cooled
reaction mixture was filtered through a small pad of Celite,
which was washed with EtOAc (100 mL). The combined fil-
trate was concentrated and the remaining oil was purified by
column chromatography.
Yield: 33% (0.51 g). Rf 0.64 (EtOAc/acetone, 1:5). lmax
/
nm 277 and 270; nmax (film)/cmꢃ1 1109 (CO); dH: 0.57–
0.88 (72H, m, 8ꢁ(CH3)3), 0.97–1.23 (48H, m, 8ꢁ(CH3)2),
1.37–1.62 (16H, m, 8ꢁCH2C(CH3)3), 3.27–3.97 (400H, m,
192ꢁCH2O and 8ꢁArCH2Ar), 4.40–4.51 (16H, m,
8ꢁCH2Ph), 6.49–6.87 (16H, m, 16ꢁHmeta), 6.97–7.37
(40H, m, 8ꢁHortho, Hmeta, Hpara); dC: 29.9 (8ꢁArCH2Ar),
31.3–32.4 (40ꢁCH3 and 8ꢁC(CH3)3), 38.0 (8ꢁC(CH3)2),
57.5 (8ꢁCH2C(CH3)3), 69.7–72.0 (184ꢁCH2O), 72.7
(8ꢁCH2O), 73.6 (8ꢁCH2Ph), 125.6 (16ꢁCmeta), 127.9–
129.0 (40ꢁCortho, Cmeta, Cpara), 132.8 (16ꢁCortho), 138.7
(8ꢁCipso), 145.0 (8ꢁCpara), 153.6 (8ꢁCipso); m/z (ES)
3369.2367 ([MNa2ꢃCH3]2+), C368H608Na2O104 requires
6738.2083.
4.4.3. Removal of PMB ethers. The PMB-protected calix-
[8]arene was dissolved in a mixture of CH3CN/CH3OH
(9:1, v/v) and cooled to 0 ꢀC. Cerium ammonium nitrate
(3 equiv) was added slowly portionwise over 1.5 h. The re-
action mixture was then allowed to warm to room tempera-
ture, where it was stirred for further 2.5 h. The mixture was
diluted with CH2Cl2 and filtered through a short pad of
Celite. The filtrate was evaporated, before purification by
column chromatography.
4.3.24. 49,50,51,52,53,54,55,56-Octakis-[35-benzyloxy-
3n333-undecaoxapentatriacontyloxy]-calix[8]arene (3x).
Isolated as an orange oil, from calix[8]arene 1c (0.30 g,
0.35 mmol) and I–PEG12–OBn 2j (2.64 g, 3.53 mmol).
4.4.3.1. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[8-hydroxy-3n36-dioxaoctyloxy]-
calix[8]arene (4a). Isolated as an orange oil, from 3e
(0.51 g, 0.17 mmol). Yield: 82% (0.33 g). Rf 0.47 (EtOAc).
lmax/nm 276 and 267; nmax (film)/cmꢃ1 3432 (OH) and
1105 (CO); dH: 0.91–1.09 (72H, m, 24ꢁCH3), 2.79 (8H, s,
8ꢁOH), 3.52–3.82 (112H, m, 48ꢁCH2O and 8ꢁArCH2Ar),
6.62–6.76 (16H, m, 16ꢁHmeta); dC: 29.9 (8ꢁArCH2Ar), 31.2
(24ꢁCH3), 33.9 (8ꢁC(CH3)3), 61.8 (8ꢁCH2OH), 70.0–71.6
(32ꢁCH2O), 72.8 (8ꢁCH2O), 125.3 (16ꢁCmeta), 133.8
(16ꢁCortho), 145.9 (8ꢁCpara), 155.0 (8ꢁCipso); m/z (FAB)
2376.8 ([MKꢃCH2OH]+), C136H208KO31 requires 2377.4.
Yield: 31% (0.63 g). Rf 0.78 (EtOAc/acetone, 1:5). lmax
/
nm 278 and 267; nmax (film)/cmꢃ1 1121 (CO); dH: 3.27–
3.80 (400H, m, 192ꢁCH2O and 8ꢁArCH2Ar), 4.47–4.56
(16H, m, 8ꢁCH2Ph), 6.51–6.78 (24H, m, 16ꢁHmeta and
8ꢁHpara), 7.01–7.28 (40H, m, 8ꢁHortho, Hmeta, Hpara); dC:
30.2 (8ꢁArCH2Ar), 69.8–71.8 (184ꢁCH2O), 72.6
(8ꢁCH2O), 73.4 (8ꢁCH2), 124.0 (8ꢁCpara), 129.2
(16ꢁCmeta), 127.9–129.2 (40ꢁCortho, Cmeta, Cpara), 134.0
(16ꢁCortho), 138.0 (8ꢁCipso), 154.8 (8ꢁCipso); m/z (ES)
2920.6518
5841.2067.
([MNa2]2+),
C304H480Na2O104
requires
4.4.3.2. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[8-hydroxy-3n36-dioxaoctyloxy]-
calix[8]arene (4b). Isolated as an orange oil from 3f (0.43 g,
0.12 mmol). Yield: 87% (0.30 g). Rf 0.56 (EtOAc). lmax/nm
275 and 264; nmax (film)/cmꢃ1 3456 (OH) and 1106 (CO);
dH: 0.64–0.87 (72H, m, 8ꢁ(CH3)3), 0.97–1.19 (48H, m,
8ꢁ(CH3)2), 1.41–1.63 (16H, m, 8ꢁCH2C(CH3)3), 2.89 (8H,
s, 8ꢁOH), 3.31–3.87 (112H, m, 48ꢁCH2O and
8ꢁArCH2Ar), 6.53–6.79 (16H, m, 16ꢁHmeta); dC: 30.0
(8ꢁArCH2Ar), 31.9–32.6 (40ꢁCH3 and 8ꢁC(CH3)3), 38.1
(8ꢁC(CH3)2), 57.6 (8ꢁCH2C(CH3)3), 62.0 (8ꢁCH2OH),
70.0–71.3 (32ꢁCH2O), 72.8 (8ꢁCH2O), 125.8 (16ꢁCmeta),
132.6 (16ꢁCortho), 144.9 (8ꢁCpara), 153.5 (8ꢁCipso); m/z
4.3.25. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,51,
52,53,54,55,56-octakis-[35-benzyloxy-3n333-undecaoxa-
pentatriacontyloxy]-calix[8]arene (3y). Isolated as an
orange oil, from benzyloxycalix[8]arene 1d (0.40 g,
0.24 mmol) and I–PEG12–OBn 2j (1.76 g, 2.36 mmol).
Yield: 29% (0.45 g). Rf 0.71 (EtOAc/acetone, 1:7). lmax
/
nm 280 and 273; nmax (film)/cmꢃ1 1115 (CO); dH: 3.53–
4.03 (400H, m, 192ꢁCH2O and 8ꢁArCH2Ar), 4.51–4.69
(32H, m, 16ꢁCH2Ph), 6.47–6.67 (16H, m, 16ꢁHmeta),
7.03–7.44 (80H, m, 16ꢁHortho, Hmeta, Hpara); dC: 30.0
(8ꢁArCH2Ar), 69.8–70.8 (184ꢁCH2O), 72.8 (8ꢁCH2O),
73.4 (8ꢁCH2Ph), 73.6 (8ꢁCH2Ph), 115.8 (16ꢁCmeta),

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9957
(ES) 1422.0047 ([MNa+4H]2+), C169H278NaO32 requires
2844.0102.
(0.56 g). Rf 0.45 (EtOAc/acetone, 5:2). lmax/nm 275 and
263; nmax (film)/cmꢃ1 3389 (OH) and 1120 (CO); dH: 2.93
(8H, s, 8ꢁOH), 3.35–3.81 (208H, m, 96ꢁCH2O and
8ꢁArCH2Ar), 6.57–6.91 (24H, m, 16ꢁHmeta and 8ꢁHpara);
dC: 29.9 (8ꢁArCH2Ar), 62.1 (8ꢁCH2OH), 70.0–71.5
(80ꢁCH2O), 73.0 (8ꢁCH2O), 124.0 (8ꢁCpara), 129.0
(16ꢁCmeta), 134.0 (16ꢁCortho), 154.7 (8ꢁCipso); m/z (ES)
2940.6127 ([MNaꢃC2H4O]+), C150H236NaO55 requires
2940.5668.
4.4.3.3. 49,50,51,52,53,54,55,56-Octa-[8-hydroxy-3n36-
dioxaoctyloxy]-calix[8]arene (4c). Isolated as a brown
oil, from 3g (0.78 g, 0.30 mmol). Yield: 80% (0.46 g). Rf
0.63 (EtOAc/hexane, 4:1). lmax/nm 275 and 263; nmax
(film)/cmꢃ1 3389 (OH) and 1120 (CO); dH: 2.61 (8H, s,
8ꢁOH), 3.45–3.73 (112H, m, 48ꢁCH2O and 8ꢁArCH2Ar),
6.62–6.83 (24H, m, 16ꢁHmeta and 8ꢁHpara); dC: 29.8
(8ꢁArCH2Ar), 62.3 (8ꢁCH2OH), 70.2–71.4 (40ꢁCH2O),
72.8 (8ꢁCH2O), 123.9 (8ꢁCpara), 128.9 (16ꢁCmeta), 134.0
(16ꢁCortho), 154.6 (8ꢁCipso); m/z (FAB) 1927.6 ([MNa]+),
C104H144NaO32 requires 1927.9.
4.4.3.8. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[17-hydroxy-3n315-pentaoxahep-
tadecyloxy]-calix[8]arene (4h). Isolated as a brown oil,
from 3l (0.50 g, 0.11 mmol). Yield: 85% (0.36 g). Rf 0.48
(EtOAc/acetone, 3:1). lmax/nm 279 and 270; nmax (film)/
cmꢃ1 3409 (OH) and 1104 (CO); dH: 3.01 (8H, s, 8ꢁOH),
3.29–3.73 (208H, m, 96ꢁCH2O and 8ꢁArCH2Ar), 4.50–
4.61 (16H, m, 8ꢁCH2Ph), 6.57–6.68 (16H, m, 16ꢁHmeta),
7.07–7.32 (40H, m, 8ꢁHortho, Hmeta, Hpara); dC: 30.2
(8ꢁArCH2Ar), 62.0 (8ꢁCH2OH), 69.8–71.3 (80ꢁCH2O),
72.9 (8ꢁCH2O), 73.4 (8ꢁCH2Ph), 115.9 (16ꢁCmeta),
127.9–128.8 (40ꢁCortho, Cmeta, Cpara), 135.7 (16ꢁCortho),
137.9 (8ꢁCipso), 149.1 (8ꢁCpara), 155.1 (8ꢁCipso); m/z
(ES) 1925.9253 ([MNa2ꢃH]2+), [C208H281Na2O64]2+ is
3848.853.
4.4.3.4. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,50,
51,52,53,54,55,56-octakis-[8-hydroxy-3n36-dioxaoctyloxy]-
calix[8]arene (4d). Isolated as a brown oil, from 3h (0.38 g,
0.11 mmol). Yield: 84% (0.26 g). Rf 0.54 (EtOAc). lmax/nm
281 and 271; nmax (film)/cmꢃ1 3412 (OH) and 1118 (CO);
dH: 2.67 (8H, s, 8ꢁOH), 3.26–3.69 (112H, m, 48ꢁCH2O
and 8ꢁArCH2Ar), 4.58 (16H, s, 8ꢁCH2Ph), 6.50–6.61
(16H, m, 16ꢁHmeta), 7.04–7.29 (40H, m, 8ꢁHortho, Hmeta
,
Hpara); dC: 30.2 (8ꢁArCH2Ar), 61.9 (8ꢁCH2OH), 70.0–
71.4 (32ꢁCH2O), 72.6 (8ꢁCH2O), 73.2 (8ꢁCH2Ph),
115.6 (16ꢁCmeta), 128.0–128.9 (40ꢁCortho, Cmeta, Cpara),
135.7 (16ꢁCortho), 137.8 (8ꢁCipso), 149.1 (8ꢁCpara),
155.0 (8ꢁCipso); m/z (FAB) 2776.0 ([MNa]+),
C160H192NaO40 requires 2776.3.
4.4.3.9. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[26-hydroxy-3n324-octaoxahexa-
cosyloxy]-calix[8]arene (4i). Isolated as a brown oil, from
3n (0.53 g, 0.10 mmol). Yield: 73% (0.44 g). Rf 0.73
(EtOAc/acetone, 1:3). lmax/nm 277 and 266; nmax (film)/
cmꢃ1 3431 (OH) and 1106 (CO); dH: 0.87–1.10 (72H, m,
24ꢁCH3), 3.00 (8H, s, 8ꢁOH), 3.35–3.91 (304H, m,
144ꢁCH2O and 8ꢁArCH2Ar), 6.62–6.94 (16H, m,
16ꢁHmeta); dC: 29.9 (8ꢁArCH2Ar), 31.4 (24ꢁCH3), 33.9
(8ꢁC(CH3)3), 62.0 (8ꢁCH2OH), 69.9–71.9 (128ꢁCH2O),
73.1 (8ꢁCH2O), 125.5 (16ꢁCmeta), 133.8 (16ꢁCortho),
146.0 (8ꢁCpara), 155.0 (8ꢁCipso); m/z (ES) 1554.1
([MCsNa2+2H]3+), C233H405CsNa2O80 requires 4662.64.
4.4.3.5. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[17-hydroxy-3n315-pentaoxahep-
tadecyloxy]-calix[8]arene (4e).11 Isolated as a brown oil,
from 3i (0.51 g, 0.12 mmol). Yield: 86% (0.37 g). Rf 0.41
(EtOAc/acetone, 3:1). lmax/nm 280 and 270; nmax (film)/
cmꢃ1 3428 (OH) and 1110 (CO); dH: 0.93–1.12 (72H, m,
24ꢁCH3), 2.98 (8H, s, 8ꢁOH), 3.43–3.85 (208H, m, 96ꢁ
CH2O and 8ꢁArCH2Ar), 6.57–6.81 (16H, m, 16ꢁHmeta);
dC: 29.8 (8ꢁArCH2Ar), 31.3 (24ꢁCH3), 34.0 (8ꢁC(CH3)3),
61.9 (8ꢁCH2OH), 70.1–71.8 (80ꢁCH2O), 73.0 (8ꢁCH2O),
125.4 (16ꢁCmeta), 133.8 (16ꢁCortho), 146.0 (8ꢁCpara),
155.1 (8ꢁCipso); m/z (ES) 3389.1941 ([MNaꢃC2H3O2]+),
C183H303NaO54 requires 3389.0940.
4.4.3.10. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[26-hydroxy-3n324-octaoxahexa-
cosyloxy]-calix[8]arene (4j). Isolated as a brown oil, from
3o (0.31 g, 0.05 mmol). Yield: 78% (0.20 g). Rf 0.81
(EtOAc/acetone, 1:3). lmax/nm 277 and 269; nmax (film)/
cmꢃ1 3424 (OH) and 1107 (CO); dH: 0.61–0.87 (72H, m,
8ꢁ(CH3)3), 0.96–1.16 (48H, m, 8ꢁ(CH3)2), 1.33–1.61
(16H, m, 8ꢁCH2C(CH3)3), 2.87 (8H, s, 8ꢁOH), 3.23–3.79
(304H, m, 144ꢁCH2O and 8ꢁArCH2Ar), 6.51–6.72 (16H,
m, 16ꢁHmeta); dC: 30.0 (8ꢁArCH2Ar), 31.6–32.4
(40ꢁCH3 and 8ꢁC(CH3)3), 37.9 (8ꢁC(CH3)2), 57.6
4.4.3.6. 5,11,17,23,29,35,41,47-Octa-tert-octyl-49,50,
51,52,53,54,55,56-octakis-[17-hydroxy-3n315-pentaoxahep-
tadecyloxy]-calix[8]arene (4f).11 Isolated as a brown oil,
from 3j (0.47 g, 0.10 mmol). Yield: 86% (0.34 g). Rf 0.37
(EtOAc/acetone, 3:1). lmax/nm 276 and 268; nmax (film)/
cmꢃ1 3441 (OH) and 1112 (CO); dH: 0.58–0.83 (72H, m,
8ꢁ(CH3)3), 0.95–1.12 (48H, m, 8ꢁ(CH3)2), 1.38–1.59
(16H, m, 8ꢁCH2C(CH3)3), 3.02 (8H, s, 8ꢁOH), 3.31–3.87
(208H, m, 96ꢁCH2O and 8ꢁArCH2Ar), 6.49–6.68 (16H,
m, 16ꢁHmeta); dC: 29.9 (8ꢁArCH2Ar), 31.7–32.5 (40ꢁ
CH3 and 8ꢁC(CH3)3), 38.0 (8ꢁC(CH3)2), 57.4 (8ꢁ
CH2C(CH3)3), 61.8 (8ꢁCH2OH), 69.8–71.5 (80ꢁCH2O),
72.6 (8ꢁCH2O), 125.6 (16ꢁCmeta), 132.5 (16ꢁCortho),
144.8 (8ꢁCpara), 153.5 (8ꢁCipso); m/z (ES) 1930.3768
([MNa2ꢃC2H3O2]2+), C215H368Na2O54 requires 1930.2923.
(8ꢁCH2C(CH3)3),
62.1
(8ꢁCH2OH),
69.7–71.6
(128ꢁCH2O), 72.9 (8ꢁCH2O), 125.7 (16ꢁCmeta), 132.5
(16ꢁCortho), 144.9 (8ꢁCpara), 153.5 (8ꢁCipso); m/z (ES)
2478.7321 ([MNa2ꢃH2OꢃH]2+), C265H464Na2O79 requires
2478.6043.
4.4.3.11. 49,50,51,52,53,54,55,56-Octakis-[26-hydroxy-
3n324-octaoxahexacosyloxy]-calix[8]arene (4k). Isolated as
a brown oil, from 3p (0.58 g, 0.12 mmol). Yield: 81%
(0.38 g). Rf 0.66 (EtOAc/acetone, 1:4). lmax/nm 277 and
265; nmax (film)/cmꢃ1 3394 (OH) and 1114 (CO); dH: 3.01
(8H, s, 8ꢁOH), 3.31–3.78 (304H, m, 144ꢁCH2O and
4.4.3.7. 49,50,51,52,53,54,55,56-Octakis-[17-hydroxy-
3n315-pentaoxaheptadecyloxy]-calix[8]arene (4g). Isolated
as a brown oil, from 3k (0.85 g, 0.23 mmol). Yield: 81%

9958
F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
8ꢁArCH2Ar), 6.61–6.97 (24H, m, 16ꢁHmeta and 8ꢁHpara);
dC: 29.9 (8ꢁArCH2Ar), 62.0 (8ꢁCH2OH), 70.0–71.8
(128ꢁCH2O), 72.9 (8ꢁCH2O), 123.9 (8ꢁCpara), 129.1
(16ꢁCmeta), 133.9 (16ꢁCortho), 154.8 (8ꢁCipso); m/z
(8ꢁCH2O), 116.9 (16ꢁCmeta), 132.1 (16ꢁCortho), 136.8
(8ꢁCipso), 154.9 (8ꢁCpara); m/z (ES) 2096.8627
([MNa2+H]2+), C200H337Na2O88 requires 4193.17.
(MALDI-TOF) 4069.98 ([MNa+2H+CN]+), C201H338
NNaO80 requires 4069.23.
-
Acknowledgements
4.4.3.12. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,
50,51,52,53,54,55,56-octakis-[26-hydroxy-3n324-octaoxa-
hexacosyloxy]-calix[8]arene (4l). Isolated as a brown
oil, from 3q (0.35 g, 0.06 mmol). Yield: 75% (0.22 g). Rf
0.69 (EtOAc/acetone, 1:3). lmax/nm 277 and 268; nmax
(film)/cmꢃ1 3454 (OH) and 1099 (CO); dH: 3.04 (8H, s,
8ꢁOH), 3.31–3.78 (304H, m, 144ꢁCH2O and
8ꢁArCH2Ar), 4.53–4.62 (16H, m, 8ꢁCH2Ph), 6.53–6.71
Studentship support from KCL is acknowledged. We are
grateful to Johnson Matthey plc for a loan agreement, which
provided Pd catalysts used in this project. We thank Mr. John
Barton (Imperial College London) for help with the MS in-
terpretations and the production of the simulated isotopic
distribution pattern in Figure 3.
(16H, m, 16ꢁHmeta), 7.05–7.29 (40H, m, 8ꢁHortho, Hmeta
,
Supplementary data
Hpara); dC: 30.3 (8ꢁArCH2Ar), 62.2 (8ꢁCH2OH), 70.0–
72.1 (128ꢁCH2O), 73.1 (8ꢁCH2O), 73.5 (8ꢁCH2Ph),
116.0 (16ꢁCmeta), 128.0–128.9 (40ꢁCortho, Cmeta, Cpara),
135.9 (16ꢁCortho), 138.0 (8ꢁCipso), 149.1 (8ꢁCpara),
155.2 (8ꢁCipso); m/z (MALDI-TOF) 4889.31 ([MNa]+),
C256H384NaO88 requires 4889.54.
(1) Characterisation data for compounds 2f–p, 5a–f and 6a–
d; (2) tables summarising the result of reaction optimisation,
including the choice and stoichiometry of base and (3) se-
1
lected H (compounds 3a and 3g) and 13C (compounds 3c,
3g and 3v) NMR spectra were provided. Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2007.07.057.
4.4.3.13. 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,
51,52,53,54,55,56-octakis-[35-hydroxy-3n333-undecaoxa-
pentatriacontyloxy]-calix[8]arene (4m). Isolated as
a brown oil, from 3r (0.38 g, 0.06 mmol). Yield: 68%
(0.22 g). Rf 0.39 (EtOAc/acetone, 1:6). lmax/nm 275 and
266; nmax (thin film)/cmꢃ1 3452 (OH) and 1121 (CO); dH:
0.83–1.07 (72H, m, 24ꢁCH3), 3.04 (8H, s, 8ꢁOH), 3.36–
3.97 (400H, m, 192ꢁCH2O and 8ꢁArCH2Ar), 6.57–6.90
(16H, m, 16ꢁHmeta); dC: 29.7 (8ꢁArCH2Ar), 31.6
(24ꢁCH3), 34.1 (8ꢁC(CH3)3), 62.4 (8ꢁCH2OH), 69.5–
71.7 (176ꢁCH2O), 73.0 (8ꢁCH2O), 125.6 (16ꢁCmeta),
133.8 (16ꢁCortho), 146.1 (8ꢁCpara), 155.0 (8ꢁCipso); m/z
(MALDI-TOF) 5614.18 ([MH+C6H3]+), C287H503O104 re-
quires 5614.40.
References and notes
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2006; (b) Becker, K.; Hu, Y.; Biller-Andorno, N. Int. J. Med.
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2. (a) Anti-Tuberculosis Drug Resistance in the World: Third
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4.4.3.14. 5,11,17,23,29,35,41,47-Octa-benzyloxy-49,
50,51,52,53,54,55,56-octakis-[35-hydroxy-3n333-undecaoxa-
pentatriacontyloxy]-calix[8]arene (4n). Isolated as a
brown oil, from 3s (0.34 g, 0.05 mmol). Yield: 65% (0.19 g).
Rf 0.72 (EtOAc/acetone, 1:6). lmax/nm 276 and 269; nmax
(film)/cmꢃ1 3444 (OH) and 1103 (CO); dH: 3.08 (8H, s,
8ꢁOH), 3.30–3.82 (400H, m, 192ꢁCH2O and 8ꢁ
ArCH2Ar), 4.55–4.63 (16H, m, 8ꢁCH2Ph), 6.49–6.77 (16H,
m, 16ꢁHmeta), 7.03–7.31 (40H, m, 8ꢁHortho, Hmeta, Hpara);
dC: 30.1 (8ꢁArCH2Ar), 62.0 (8ꢁCH2OH), 70.0–72.7
(176ꢁCH2O), 73.0 (8ꢁCH2O), 73.6 (8ꢁCH2Ph), 116.1
(16ꢁCmeta), 127.9–129.1 (40ꢁCortho, Cmeta, Cpara), 135.9
(16ꢁCortho), 138.0 (8ꢁCipso), 149.0 (8ꢁCpara), 155.0
(8ꢁCipso); m/z (ES) 2940.8313 ([MNa2ꢃ2C2H4O]2+),
C300H472Na2O110 requires 2940.5568.
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ꢀ
ꢀ
4.4.3.15. 5,11,17,23,29,35,41,47-Octa-hydroxy-49,50,
51,52,53,54,55,56-octakis-[26-hydroxy-3n324-octaoxahexa-
cosyloxy]-calix[8]arene (4o). Isolated as a brown oil, from
3u (0.35 g, 0.06 mmol). Yield: 71% (0.18 g). Rf 0.63
(EtOAc/acetone, 1:3). nmax (film)/cmꢃ1 3257 (OH) and
1103 (CO); dH: 2.75 (8H, s, 8ꢁOH), 3.28–3.87 (304H, m,
144ꢁCH2O and 8ꢁArCH2Ar), 6.50–6.91 (16H, m,
16ꢁHmeta), 9.46 (8H, s, 8ꢁOH); dC: 30.0 (8ꢁArCH2Ar),
61.9 (8ꢁCH2OH), 69.9–71.8 (128ꢁCH2O), 73.1
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Neri, P. Org. Lett. 2001, 3, 1605–1608 and references therein.

F. A. Loiseau et al. / Tetrahedron 63 (2007) 9947–9959
9959
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