New heterotopic, linked macrocyclic systems derived from selectively protected macrocycles

Article abstract of DOI:10.1016/j.tet.2006.02.012

The use of orthogonally protected cyclam and 1,9-dithia-5,13-diazacyclohexadecane macrocycles, in combination with aza-18-crown-6, has enabled the efficient synthesis of a new heterotritopic macrocyclic ligand incorporating N₄-, N₂S<

Full text of DOI:10.1016/j.tet.2006.02.012

Tetrahedron 62 (2006) 4173–4187
New heterotopic, linked macrocyclic systems derived from
selectively protected macrocycles
Jy D. Chartres,a Leonard F. Lindoyb and George V. Meehana,
*
aSchool of Pharmacy and Molecular Sciences, James Cook University, Townsville, Qld. 4811, Australia
bSchool of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
Received 13 October 2005; revised 13 January 2006; accepted 2 February 2006
Available online 7 March 2006
Abstract—The use of orthogonally protected cyclam and 1,9-dithia-5,13-diazacyclohexadecane macrocycles, in combination with aza-18-
crown-6, has enabled the efficient synthesis of a new heterotritopic macrocyclic ligand incorporating N4-, N2S2- and NO5-donor sites.
A similar strategy has allowed the incorporation of cyclam and 1,9-dithia-5,13-diazacyclohexadecane into a cofacial ligand. Further, the
synthesis of novel tetramacrocyclic ligands has been achieved in which the macrocycles are linked in a cyclic arrangement. The availability
of different binding sites in the respective products makes the latter suitable candidates for the synthesis of a range of mixed-metal
multinuclear complexes.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
interest, linked di- or polynuclear macrocyclic complexes
may also serve as models for the charge transfer, electron
transport and allosteric behaviour found in many metal-
containing biochemical systems.22,23
A major thrust in recent macrocyclic ligand research has
been the development of multi-component structures in
which individual macrocyclic units are linked.1–5 Examples
of such systems exist that display a range of molecular
architectures that include, linear, branched, stacked, and
dendritic arrangements of their macrocyclic components.
Such nanometre-scale structures have been employed in a
range of studies for binding two or more metal ions
simultaneously in defined positions with respect to each
other.
Previously, we have reported the facile synthesis of a number
of new linked, homo-17,24,25 and heteroditopic26 macrocycles
obtained via simple protecting group strategies. For example,
in one study, tris(N-Boc) cyclam and N-Boc protected S2N2-
donor macrocycles were linked via unsymmetrical linking
agents to yield intermediates such as 1.26
The majority of the investigations in the above area have
involved linked systems incorporating macrocycles of a
similar type.1–5 Examples include linked crown,6–8 aza-
crown,7,9–16 thiaazacrown17,18a–c and porphyrin-derived
systems19,20—in part, reflecting the ease of synthesis of
suitably functionalised derivatives involving these macro-
cyclic types.
Examples incorporating hetero-macrocyclic rings are much
less common even though such compounds have the
potential to produce new hetero-metal systems exhibiting
unusual properties, including unusual spectral, photoactive
and redox properties.21 Beside their considerable intrinsic
Based on the methodology developed in the above studies,
an aim of the investigation now reported was to undertake
the synthesis of structurally more elaborate linked species
such as the heterotritopic and cofacial derivatives exempli-
fied by 2 and 3. Motivation for the synthesis of such species
included the desire to obtain ligand systems capable of
promoting the binding of different metal ions in sterically
defined spatial and electronic environments.
Keywords: Linked macrocycle; Cofacial; Heterotopic; Orthogonal protec-
tion; Cyclam.
*
Corresponding author. Tel.: C61 7 4781 4543; fax: C61 7 4781 6078;
e-mail: george.meehan@jcu.edu.au
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.012

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sulfur-containing macrocycles due to poisoning of the
catalyst.
The 2,2,2-trichloroethoxycarbonyl (Troc) protecting group
was chosen for protection of one of the nitrogens of 7 since
this group can be readily removed under mild conditions in
the presence of the tert-butoxycarbonyl group.17 Thus,
addition of 0.8 equiv of Troc chloride to 1,8-di-Boc(cyclam)
7 gave the required triprotected cyclam 4 in 46% yield
(based on 7) (Scheme 2). This product was readily
1
characterised by H NMR, the t-butyl singlet at d 1.46 and
Troc methylene resonance at d 4.75 being diagnostic.
Attempts to increase the yield of 4 by using more Troc
chloride were unsuccessful and led instead to increased
isolation of the di-Troc derivative 8. The symmetry of 8
allows it to be easily distinguished from 4 by the presence of
a single resonance for the ring methylene groups b- to
nitrogen (d 1.83).
Alternatively, tetra-protected cyclam 8 was obtained in 85%
yield by reaction of 7 with excess Troc chloride. After
removal of the Boc groups from 8 to give 9 in 95% yield,
subsequent reaction with 0.8 equiv of Boc2O allowed the
isolation of the alternative triprotected cyclam 10, in 78%
yield (based on 9) (Scheme 3). This species, while not used
in the current synthesis, represents an alternative trihetero-
protected cyclam.30
2. Results and discussion
2.1. Protected macrocyclic precursors
The synthesis of 2 and 3 required the N-protection of cyclam
with two orthogonal protecting groups such that two (trans)
nitrogens could be separately functionalised. Protected
cyclams of this general type have been reported.27,28
However, these were not suitable for our purposes since
they require somewhat harsh conditions for deprotection
and, in any case, the isolation of the starting diprotected
macrocycle is not necessarily straightforward. Both of these
potential difficulties were satisfactorily circumnavigated by
synthesising the trihetero-protected cyclam 4.
The second macrocyclic component chosen for incorpor-
ation into the planned heterotopic systems was the
16-membered S2N2-donor macrocycle 11. Macrocycle 11
was a desirable component for the proposed systems as it
provides a very different coordination environment
compared to cyclam. The parent (unsubstituted) macrocycle
was originally reported by Kaden et al.31 However, the
synthetic approach employed in this previous study was not
suitable for our present purpose since it did not allow easy
chemical differentiation between the two ring nitrogen sites.
Access to trans-diprotected cyclams in large quantities and
high yields was made possible via the procedure reported by
Guilard et al. for the synthesis of 5.29 Subsequently, 5 was
reacted with 2 equiv of di-tert-butyl dicarbonate and the
benzyl groups removed by hydrogenation over palladium
catalyst to give 7 (Scheme 1). It appeared not to be possible
to use 5 directly for formation of the proposed linked hetero-
ring systems as our experience is that removal of benzyl
groups by hydrogenation is difficult in the presence of
Incorporation of 11 into linked homotopic systems,
including dendrimers, has been demonstrated previously
by our group,17,32 aided by the availability of syntheses for
Scheme 1.

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4175
Scheme 2.
Scheme 3.
several mono-protected derivatives that include 12 and 13.
The latter species appeared suitable for incorporation into
hetero-ring, ditopic systems of the type of interest in the
present study.
NMR spectrum of the product was in accord with the
expected product; in particular, the benzylic proton signal of
15 (d 4.59) was replaced by a singlet at d 3.51, characteristic
of a benzylamine derivative. The Troc-protected S2N2-
donor macrocycle 13 was alkylated with 15 under the same
conditions; the corresponding linked amide 17 was obtained
in 84% yield after chromatography (Scheme 4).
2.2. Synthesis of orthogonally protected linked
intermediates
Selective removal of the Troc group of 16 was achieved by
zinc reduction in glacial acetic acid to give 18 in 76% yield
(Scheme 4). As expected, deprotection was accompanied by
the disappearance of the Troc methylene resonance at d 4.75
Since different macrocyclic ring systems were to be linked,
a stepwise synthetic approach was employed as we have
previously demonstrated that such an approach is generally
applicable for obtaining linked hetero-ditopic macrocyclic
systems.26 4-(Chloromethyl)benzoyl chloride 14 was
employed as a difunctional linking reagent in our previous
studies,26 and was again used for the current synthesis.
Selectivity tends to be facilitated when using this linking
reagent due to the greater tendency for acylation, rather than
alkylation, to occur at the secondary amino groups present
in the (partially) protected macrocycles of interest.
1
in the H spectrum of 16. Removal of the Troc protecting
groups from 17 was again effected by treatment with zinc/
glacial acetic acid, with the desired product 19 being
isolated in 83% yield (Scheme 4).
2.3. Synthesis of a heterotritopic ligand
The selective Troc-deprotection of 16 enabled functionali-
sation of the resulting secondary amine ring of intermediate
18. Thus, acylation of 18 with 14 (triethylamine/dichloro-
methane) gave the chloroamide 20 in 93% yield (Scheme 5).
A solution of triprotected cyclam 4 in dichloromethane
containing triethylamine was reacted with 4-(chloro-
methyl)benzoyl chloride 14 to give chloroamide 15 in
95% yield (Scheme 4). As expected, the signals for the
methylene groups a- to the secondary nitrogen in 4 (d 2.16
and 2.78) are absent from the 1H spectrum of the amide 15.
Instead, these resonances are shifted downfield to ca. d 3.2
such that they overlap with the signals for the methylene
groups a- to carbamate nitrogens. The benzylic protons of
15 appear at d 4.59.
Based on the success of the above procedures, it was
decided to attempt the synthesis of a heterotritopic system in
which a third macrocycle was incorporated that had
different coordination characteristics to those of either the
(essentially) soft-donor character of the S2N2-donor
macrocycles or the intermediate character of the N4-donor
set of cyclam. The monoaza crown ether macrocycle 1-aza-
18-crown-6 21, with its five hard ether donors, appeared to
be an ideal precursor for the third ring. This system also had
the advantage that it contains a single secondary amine
linkage site without the need to protect other amino groups.
Accordingly, 21 was alkylated with 20 in acetonitrile in the
presence of sodium carbonate to give 22 in 50% yield after
chromatography on silica gel (Scheme 5). A second, lower
Rf component with a similar 1H NMR spectrum to that of 22
was also isolated from the chromatography. This lower Rf
For the synthesis of the heterotritopic ligand 2, it was
necessary that the protecting group on the S2N2-donor
macrocycle be orthogonal to the Troc group of the cyclam
moiety in order to facilitate further functionalisation of the
latter. Thus, the N-Boc-S2N2-derivative 12 was alkylated
with 15 to give the tris(Boc)-Troc-protected amide 16
(Scheme 4). The reaction was carried out in refluxing
acetonitrile in the presence of sodium carbonate over a
1
period of 24 h and 16 was isolated in 96% yield. The H

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J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
Scheme 4.
component was much less soluble in chloroform. The only
discernable difference in the 1H NMR spectra of the
respective fractions was associated with proton signals
arising from the azacrown moiety.33 In view of this, it was
concluded that the lower Rf compound was likely the
sodium adduct of 22, with the sodium ion originating from
the sodium carbonate used in the synthesis. The chromato-
graphy of sodium adducts of azacrowns has been performed
previously by our group.34
the intermediate diamide 23 available for possible future
metal coordination studies. This latter product was obtained
by deprotection of 22 with methanolic hydrochloric acid.
Work-up involved basifying the reaction mixture with
aqueous ammonium hydroxide, instead of sodium or
potassium hydroxide, to avoid alkali metal adduct
contamination.
The final step in the synthesis of 2, the reduction of the
amide groups of 23 by borane–dimethylsulfide complex in
tetrahydrofuran, was achieved in 82% yield (Scheme 5) and
corresponded to the disappearance of the amide carbon
resonance (d 171.7) originally present in the 13C NMR
spectrum of 23. Likewise, a strong absorption at
1621.8 cmK1 in the infrared spectrum of 23, consistent
with an amide stretching frequency, was absent in the
corresponding spectrum of 2. HRMS data also supported the
proposed structure.†
The suspected sodium adduct was converted to the metal-
free product by partitioning it between chloroform and
water and continuously extracting the organic phase with
water (using a continuous extractor for liquid–liquid
extraction by upward displacement) over 3 days. The
material in the organic layer then ran at an identical Rf to the
1
initial crop of 22 and also displayed an identical H NMR
spectrum to it. Combining the two fractions gave an overall
yield of 22 of 82%. This combined product was dried by
azeotropic distillation of a toluene solution (rather than over
sodium sulfate).
The 1H NMR spectrum of 2 is noticeably sharper than that
of 23 reflecting the absence of amide rotamers in the
A two-step deprotection/reduction protocol (Scheme 5) was
used to obtain the target heterotritopic ligand 2 (even though
it has been reported that in a related synthesis both steps
could be accomplished simultaneously).35 In our case, the
two step procedure had the advantage that it made
† A preliminary metal-ion coordination study led to isolation of a dinuclear
copper(II) complex whose microanalysis corresponded to [Cu2-
L](ClO4)4$H2O (LZ2). This complex was then treated with sodium
perchlorate to give the sodium derivative, analysing as [Cu2-
NaL](ClO4)4$5H2O (LZ2)].

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4177
Scheme 5.
former;26 nevertheless, numerous chemical shift overlaps
were evident. The three types of protons for macrocyclic
ring methylene groups not adjacent to heteroatoms appear as
a complex multiplet between d 1.6 and 1.9. When the
spectrum was run at 333 K, three resonances were just
resolved in this region, with the other spectral resonances
remaining largely unchanged. A complex multiplet in the
region d 2.4–2.8 is assigned to a combination of the
macrocyclic ring methylene protons adjacent to the sulfur
and amino groups. The complex multiplet between d 3.5 and
3.8 corresponds to the methylene protons adjacent to
oxygen as well as to the benzylic protons. The aromatic
protons occur as a broad multipet in the region d 7.3–7.5.
In light of the initial low yield obtained for the cyclised
product, a further attempt was made to effect the cyclisation
via a bis-acylation reaction employing terephthaloyl
dichloride. Thus, addition of 19 and terephthaloyl dichloride
via the dual syringe pump to a solution of triethylamine in
dichloromethane under high dilution was carried out over
110 h (Scheme 6). After chromatography, the desired
tricyclic ligand 25 was this time isolated in 68% yield.
A small amount (11% yield) of a product was also isolated
during the above chromatographic procedure which had a
2.4. Synthesis of a hetero-ring cofacial ligand
Conversion of the linked bis(macrocycle) species 19 to its
cofacial analog required intramolecular linking of its two
secondary amino groups. The cyclisation involved the
simultaneous addition of 19 and a,a0-dibromo-p-xylylene
by means of a dual syringe pump to a suspension of sodium
carbonate in refluxing acetonitrile over 110 h under high
dilution conditions (Scheme 6). After chromatography, the
desired 1C1 cyclisation product 24 was obtained in 27%
yield, with HRMS supporting the target structure.
Scheme 6.

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J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
HRMS corresponding to a 2C2 cyclisation product.
Isomers are possible for such stoichiometry, the most likely
of which are given by 26 and 27. It is assumed that neither
one of these products would be favoured under the reaction
conditions employed. Nevertheless, only one component
was observed by TLC analysis using a variety of mobile
phases.36 As might be predicted, due to severe spectral
overlap the NMR spectra of the product were uninformative
with respect to possible isomeric composition. It is noted
that while a catenane consisting of two interlocked 1C1
cyclisation products would also yield the same mass, it
appears unlikely that such a product would form in
preference to products of type 26 and 27.
Scheme 7.
The ES-HRMS was in accord with this species being the
2C2 cyclisation product 33.
2.5. Synthesis of a cofacial ligand from a di-functiona-
lised cyclam
The use of 4-(chloromethyl)benzoyl chloride 14 as a
difunctional linking reagent was again used for bis-
acylation of 7 to produce 28 in 95% yield after
chromatography (Scheme 7).
The possibility of bis-N-alkylation of the parent 16-
membered S2N2-donor macrocycle 11 by the benzyl
chloride functionalities present in 28 was also explored.
The preparation of 11 was originally reported by Kaden
et al.31 However, in the present study a synthesis of 11 was
devised which employed intermediates already prepared in
the authors’ laboratory.17 Thus, cyclisation of N-Boc-
dichloride 29 and N-Boc-dithiol 30 afforded the di-N-Boc
macrocycle 31 in 60% yield (Scheme 8). Complete
deprotection of 31 with trifluoroacetic acid in dichloro-
methane subsequently gave the desired macrocycle 11 in
96% yield.
The identification of 32 by electrospray mass spectrometry
is complicated by the fact that this method may produce
dimers during the ionisation process. A singly protonated
dimer of 32 would give the same m/z parent ion as a singly
protonated molecular ion of 33, with an identical isotopic
distribution. However, it is suggested that this did not occur
as the mass spectra of 32 and 33 were dissimilar under the
same ionisation conditions. The spectrum of 32 is
unequivocal, with [MCH]C and [MCNa]C ions at m/z
895.5200 and 917.4958, respectively, with each peak
displaying the predicted isotopic distribution. Neither
[2MC2H]2C nor [2MCH]C ions were observed. For 33
[MCH]C and [MCNa]C ions at m/z 1789.9126 and
1811.8831 were observed; peaks at this m/z were not
observed for 32 under the same ionisation conditions. Also,
a peak occurs at m/z 895.5177 for 33, with an isotopic
distribution corresponding to that of a doubly protonated
ion, consistent with the presence of [MC2H]C. Other
parent molecular ions corresponding to [MCHCNa]2C and
Once again, using high-dilution conditions, macrocycle 11
and the bis(chloroamide) 28 were added simultaneously via
a dual syringe pump to a suspension of potassium carbonate
and sodium iodide in a large volume of refluxing acetonitrile
over 110 h (Scheme 7). After workup and chromatography,
the desired cofacial ligand 32 was isolated in 43% yield.
Interestingly, a second, lower Rf component was isolated in
11% yield from the chromatographic procedure employed.

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4179
Scheme 8.
[MC2Na]2C were also observed, at m/z values of 906.5088
and 917.5900, respectively.
present study was not able to be distinguished from that of
32. The small chemical shift differences that might be
expected between these two compounds are presumably
masked by the broadness of the spectra.
The 1H NMR of 32 suffers from extreme broadening, most
likely due to slow rotation of the amide rotamers.26 The Boc
singlet at d 1.46 is broader than the analogous resonance for
the linear bis(macrocycles) described above. Two broad
signals at d 1.74 and 1.89 are assigned to the macrocyclic
ring methylenes not adjacent to a heteroatom. Two broad
overlapping signals are found at d 2.41 and 2.59 which are
due to the ring methylenes adjacent to sulfur or a
benzylamino group. A number of overlapping broad signals
occur in the region d 3.2–3.8 for the ring methylenes
adjacent to amide nitrogens and the benzylic protons.
Finally, two broad signals at d 7.34 and 7.39 are due to the
aromatic protons. The 1H NMR spectrum of 33 in the
The serendipitous isolation of the novel tetramacrocycle
species 33 described above encouraged an attempt to
synthesise this compound by means of a more considered
(and hopefully higher yielding) strategy. To this end, the
bis-alkylating agent 28 was reacted with two equivalents
of the mono-Troc-protected macrocycle 13 to give the
hetero-protected species 34 in 86% yield (Scheme 9).
Removal of the Troc groups from 34 was performed with
zinc in glacial acetic acid in 75% yield to give the
tris(macrocyclic) species 35 containing two terminal NH
groups.
Scheme 9.

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J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
Scheme 10.
Subsequent reaction of 28 with 35 under high dilution
conditions was successful in affording the tetra-macrocyclic
species 33, but in the disappointingly low yield of 10%
(Scheme 9). This low yield (and presumably also that for the
product from the reaction of 28 with 11) is attributed to the
relatively large distance between the reacting termini of 35,
which lowers the prospect of ring closure but increases the
tendency for oligomerisation. Obviously, this procedure is
less than satisfactory for obtaining significant quantities of
33.
procedure. Conversely, 32 was synthesised in the lower
yield of 43%, but its precursor 28 is synthesised in three
fewer steps. Further, the high-dilution conditions required
for 25 (room temperature, dichloromethane) are perhaps
preferred over those for 32 (refluxing acetonitrile). On
balance, the synthesis of 3 is most efficiently achieved via
32; however, of course, this route can not be applied to
systems with unsymmetrical linkers.
3. Conclusions
2.6. Completion of target syntheses
The present paper describes the facile synthesis of new
heterotopic macrocyclic ligands, including a heterotritopic
tris(macrocyclic) ligand and a heteroditopic cofacial ligand.
This has been achieved via the development of new
orthogonal protecting group strategies enabling the selective
linking of different macrocyclic components—including the
linkage of four macrocycles incorporating two different
donor sets, in a cyclic arrangement. Based on the known
metal-ion chemistry of the constituent macrocycles, the
described ligands incorporate sites that will clearly exhibit
different affinities for particular metal ions. The new
derivatives thus lead the way for the synthesis of a range
of new hetero-metal complexes. Our efforts in this direction
will be reported in due course.
Deprotection of 33 was accomplished in hydrochloric acid/
methanol to give the tetraamide 36 in 96% yield (Scheme 9)
while the bis(Boc) cofacial ligand 25 was also readily
deprotected to give the cofacial amide 38 in 87% yield
(Scheme 10). Reduction of the respective amides was
performed with borane dimethyl sulfide complex in
tetrahydrofuran. Reduction of 36 gave 37 in 53% yield
(Scheme 9). To obtain the unsubstituted cofacial derivative
3, amide 38 was reduced with borane dimethyl sulfide
complex to yield 3 in 67% yield (Scheme 10).37
In contrast to the observations made for the linear tritopic
ligand 2, final reduction of the amide groups of 38 did not
lead to the expected sharpening of the 1H NMR spectrum of
the reduced product 3—possibly a result of the cyclic nature
of 3 restricting bond rotation to an intermediate rate on the
NMR time scale. Obtaining the spectrum at higher
temperatures did not result in a significant improvement.
Nevertheless, the spectrum could be reasonably assigned in
terms of the types of protons present. The macrocyclic ring
methylene protons not adjacent to a heteroatom give a broad
resonance at d 1.74 while the remaining ring methylene
resonances are found at d 2.4–2.8 (as broad overlapping
signals). Two distinct singlets at d 3.50 and d 3.68 are
assigned to the two types of non-equivalent benzylic
protons. The aromatic protons give rise to a multiplet
spanning d 7.1–7.3. Under the conditions employed, the 1H
NMR spectrum of 37 was essentially indistinguishable from
that of 3.
4. Experimental
4.1. General
Where available, all reagents were of analytical grade.
1,4,8,11-Tetraazacyclotetradecane (cyclam),38a,b N-tert-
butoxycarbonylbis(3-chloropropyl)amine 29,17 N-tert-
butoxycarbonylbis(3-mercaptopropyl)amine 30,17 1,8-
dibenzyl-1,4,8,11-tetraazacyclotetradecane 5,29 5-tert-
butoxycarbonyl-1,9-dithia-5,13-diazacyclohexadecane
12,17 5-(2,2,2-trichloroethoxycarbonyl)-1,9-dithia-5,13-dia-
zacyclohexadecane 1317 and 1-aza-18-crown-6 2139 were
synthesised as described previously. Tetrahydrofuran (THF)
was distilled from sodium benzophenone ketyl immediately
prior to use. Acetonitrile and dichloromethane were distilled
from calcium hydride. All reactions were carried out under
an inert atmosphere of dry nitrogen. NMR spectra were
recorded on a Bruker AM-300 spectrometer. Chemical
shifts are quoted in d units (ppm) relative to the residual
proton signal in CDCl3 (dH 7.26) or to CDCl3 (dC 77.0). The
majority of compounds prepared in this study were viscous
In gauging the success of the various strategies for
synthesising 3, two aspects deserve comment. These are
(i) the yield of the cyclisation step, and (ii) the ease of
synthesis of the precursors required for this cyclisation.
While 25 can be formed in a superior yield of 68%, the
synthesis of the precursor 19 represents an involved

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4181
oils and elemental composition (of chromatographically
homogeneous materials) is mainly supported by high-
resolution mass spectrometry (HRMS). High-resolution
electrospray ionisation mass spectra (ESI-MS) were
obtained on a Bruker BioApex 47e FTICR mass spec-
trometer. In some cases, the most abundant peak in the
spectra corresponded to the sodium adduct.
3.2–3.6 (12H, br m, CH2NBoc), 4.73 (2H, s, Cl3CCH2-
OCO); dC (CDCl3; 75 MHz) 28.5, 29.6, 30.8, w45–50
(broad overlapping signals), 75.1, 79.6, 95.7, 155.4, 156.2.
4.1.4. 1,8-Bis(tert-butoxycarbonyl)-4,11-bis(2,2,2-trichloro-
ethoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane 8.
1,8-Bis(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetrade-
cane 7 (1.00 g, 2.50 mmol) was dissolved in dry dichloro-
methane (50 cm3). Triethylamine (0.76 g, 7.5 mmol) and
then 2,2,2-trichloroethyl chloroformate (1.32 g, 6.25 mmol)
were added by syringe. The reaction mixture was stirred at
room temperature for 2 h. The organic layer was then washed
with water (2!30 cm3), dried (sodium sulfate) and
evaporated under reduced pressure. Purification of this
material was achieved by column chromatography on silica
gel (eluting with 1% MeOH–DCM). The title compound was
isolated as a yellow oil (1.59 g, 85%). [Found MCNaC,
771.1008 (ES). C26H42N4O8Cl6 requires MCHC,
4.1.1.
1,8-Dibenzyl-4,11-bis(tert-butoxycarbonyl)-
1,4,8,11-tetraazacyclotetradecane 6. To a solution of
1,8-dibenzyl-1,4,8,11-tetraazacyclotetradecane 5 (27.4 g,
0.072 mol) in dichloromethane was added di-tert-butyl
dicarbonate (39.3 g, 0.18 mol) in dichloromethane and the
mixture was stirred at room temperature for 4 h. The solvent
was removed under reduced pressure and the resulting oily
residue purified by column chromatography on silica gel
(eluting with 1% MeOH–DCM). The title compound was
isolated as a colourless oil (41.8 g, 100%). [Found (MC
H)C, 581.4067 (ES). C34H52N4O4 requires (MCH)C,
t
771.1026]; dH (CDCl3; 300 MHz) 1.45 (18H, br s, Bu),
t
581.4061]; dH (CDCl3; 300 MHz) 1.38 (18H, br s, Bu),
1.83 (4H, br m, CH2CH2CH2), 3.3–3.5 (16H, br m,
CH2NCO), 4.74 (4H, s, Cl3CCH2OCO); dC (CDCl3;
75 MHz) 28.3, w45–50 (broad overlapping signals), 75.0,
80.1, 95.3, 154.0, 155.8.
1.77 (4H, br m, CH2CH2CH2NH), 2.4–2.7 (8H, br m,
ArCH2NCH2), 3.2–3.6 (8H, br m, CH2NBoc), 3.55 (4H, s,
ArCH2), 7.30 (10H, br s, ArH).
4.1.2. 1,8-Bis(tert-butoxycarbonyl)-1,4,8,11-tetraazacy-
clotetradecane 7. 1,8-Dibenzyl-4,11-bis(tert-butoxycarbo-
4.1.5. 1,8-Bis(2,2,2-trichloroethoxycarbonyl)-1,4,8,11-
tetraazacyclotetradecane 9. Tetra-substituted cyclam 8
(3.50 g, 4.66 mmol) was dissolved in methanol (80 cm3)
and stirred with concentrated hydrochloric acid (4.7 cm3,
365 g/L, 47 mmol) at room temperature for 2 h. The
methanol was removed in vacuo and the residue partitioned
between 10% aqueous sodium hydroxide (50 cm3) and
dichloromethane (100 cm3). The layers were separated and
the aqueous layer re-extracted with dichloromethane (2!
100 cm3). The combined organic extracts were dried
(sodium sulfate) and evaporated under reduced pressure to
give the title compound as a yellow oil; this product was
used without further purification (2.20 g, 85%). [Found MC
HC, 549.0148 (ES). C16H26N4O4Cl6 requires MCHC,
549.0158]; dH (CDCl3; 300 MHz) 1.84 (4H, br m,
CH2CH2N), 2.73 (4H, br m, CH2CH2CH2NH), 2.88 (4H,
br m, TrocNCH2CH2NH), 3.4–3.6 (8H, br m, CH2NTroc),
4.75 (2H, s, Cl3CCH2OCO); dC (CDCl3; 75 MHz) 28.9,
w45–50 (broad overlapping signals), 74.7, 95.5, 154.5.
nyl)-1,4,8,11-tetraazacyclotetradecane
6
(20.9 g,
36.0 mmol) was dissolved in methanol (100 cm3) and
glacial acetic acid (2 cm3, 36.0 mmol) in a pressure
hydrogenation vessel under a stream of N2. Palladium on
charcoal (10%) (3.8 g, 3.6 mmol) was carefully added to the
solution and the mixture was then agitated under H2 (3 atm)
for 12 h. The catalyst was removed by filtration through
Celite and the solvent was evaporated under reduced
pressure. The residue was partitioned between 10% aqueous
sodium hydroxide (100 cm3) and dichloromethane
(300 cm3) then the aqueous layer was re-extracted with
dichloromethane (2!250 cm3). The combined organic
layers were dried (Na2SO4) and evaporated under reduced
pressure to give an oily residue, which was purified by
column chromatography on silica gel (eluting with 5%
MeOH–DCM). The title compound was isolated as colour-
less oil (14.4 g, 100%). The 1H NMR spectrum was as
previously reported.40
4.1.6. 4-tert-Butoxycarbonyl-1,8-bis(2,2,2-trichloro-
ethoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane 10.
Bis(Troc)-cyclam 9 (2.10 g, 3.81 mmol) was dissolved in
dry dichloromethane (40 cm3) to which was added di-tert-
butyl dicarbonate (0.67 g, 3.05 mmol) in dry dichloro-
methane (20 cm3) and the reaction mixture was stirred for
12 h. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography on
silica gel (eluting with 1% MeOH–DCM). The title
compound was isolated as a colourless oil [1.94 g, 78%
(based on 9)]. [Found MCNaC, 671.0493 (ES).
C21H34N4O6Cl6 requires MCNaC, 671.0502]; dH (CDCl3;
300 MHz) 1.46 (9H, br s, tBu), 1.77 (2H, br m, TrocNCH2-
CH2CH2NH), 2.05 (2H, br m, TrocNCH2CH2CH2NBoc),
2.65 (2H, br m, CH2CH2CH2NH), 2.87 (2H, br m,
TrocNCH2CH2NH), 3.2–3.6 (12H, br m, CH2NBoc), 4.76
(2H, s, Cl3CCH2OCO); dC (CDCl3; 75 MHz) 28.2, 29.4,
w45–50 (broad overlapping signals), 74.7, 79.4, 95.6,
154.0, 155.1.
4.1.3. 1,8-Bis(tert-butoxycarbonyl)-4-(2,2,2-trichloro-
ethoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane 4.
1,8-Bis(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetrade-
cane 7 (2.27 g, 5.67 mmol) was dissolved in dry dichloro-
methane (80 cm3). Triethylamine (0.69 g, 6.8 mmol) and
then 2,2,2-trichloroethyl chloroformate (0.96 g, 4.54 mmol)
in dichloromethane (30 cm3) were added. The reaction
mixture was stirred at room temperature for 12 h. The
organic layer was washed with water (2!50 cm3), dried
(Na2SO4) and evaporated under reduced pressure. Purifi-
cation of this material was achieved by column chroma-
tography on silica gel (eluting with 1% MeOH–DCM). The
title compound was isolated as a yellow oil (1.50 g, 72%).
[Found (MCNa)C, 597.2014 (ES). C23H41N4O6Cl3
requires (MCNa)C, 597.1984]; dH (CDCl3; 300 MHz)
t
1.46 (18H, br s, Bu), 1.71 (2H, br m, BocNCH2CH2CH2-
NH), 1.95 (2H, br m, BocNCH2CH2CH2NBoc), 2.61 (2H, br
m, CH2CH2CH2NH), 2.78 (2H, br m, BocNCH2CH2NH),

4182
J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4.1.7. 1,8-Bis(tert-butoxycarbonyl)-4-[4-(chloromethyl)-
benzoyl]-11-(2,2,2-trichloroethoxycarbonyl)-1,4,8,11-
tetraazacyclotetradecane 15. Bis(Boc)-Troc-cyclam 4
(1.96 g, 3.40 mmol) was dissolved in dry dichloromethane
(80 cm3). Triethylamine (0.45 g, 4.42 mmol) and then
4-(chloromethyl)benzoyl chloride 14 (0.775 g, 4.08 mmol)
were added by syringe. The reaction mixture was stirred at
room temperature for 12 h. The organic layer was washed
with water (2!50 cm3), dried (Na2SO4) and evaporated
under reduced pressure. Purification of this material was
achieved by column chromatography on silica gel (eluting
with 2% MeOH–DCM). The title compound was isolated as
a colourless glass (2.40 g, 95%). [Found (MCNa)C,
749.2037 (ES). C31H46N4O7Cl4 requires (MCNa)C,
(10 cm3). The aqueous layer was extracted with dichloro-
methane (3!50 cm3), the combined organic layers were
dried (sodium sulfate) and evaporated under reduced
pressure to give a brown oil that was purified by column
chromatography on silica gel (eluting with 2%
MeOH–DCM). The title compound was isolated as a
colourless glass (0.52 g, 84%). [Found (MCH)C,
1127.2973 (ES). C46H72N6S2O9Cl6 requires (MCH)C,
t
1127.3006]; dH (CDCl3; 300 MHz) 1.46 (18H, br s, Bu),
1.75 (4H, br m, CH2CH2NCH2Ar), 1.97 (8H, br m,
CH2CH2CH2NCO), 2.4–2.7 (12H, m, CH2S, CH2NCH2Ar),
3.1–3.8 (22H, br m, CH2NCO, ArCH2N), 4.76 (4H, s,
Cl3CCH2OCO), 7.2–7.4 (4H, br m, ArH); dC (CDCl3;
75 MHz) 27.7, 28.5, 29.2, 29.6, 29.7, 30.0, w45–50 (broad
overlapping signals), 47.5, 48.2, 52.8, 58.9, 75.0, 80.2, 94.4,
95.7, 126.3, 128.7, 135.0, 141.0, 154.3, 156.0, 171.7.
t
749.2013]; dH (CDCl3; 300 MHz) 1.47 (18H, br s, Bu),
1.6–2.0 (4H, br m, CH2CH2CH2N), 3.1–3.7 (16H, br m,
CH2NBoc), 4.58 (2H, s, ArCH2Cl), 4.75 (2H, s, Cl3CCH2-
OCO), 7.3–7.5 (4H, br m, ArH); dC (CDCl3; 75 MHz) 28.4,
45.3, w45–50 (broad overlapping signals), 75.1, 80.2, 95.3,
126.6, 128.6, 136.3, 138.5, 154.2, 155.8, 171.2.
4.1.10. 5-tert-Butoxycarbonyl-13-(4-{[4,11-bis(tert-
butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecan-1-
yl]carbonyl}benzyl)-1,9-dithia-5,13-diazacyclohexade-
cane 18. Tris(Boc)-Troc amide 16 (2.90 g, 2.75 mmol) was
dissolved in glacial acetic acid (30 cm3) and stirred with
activated zinc dust (9.0 g, 140 mmol) at room temperature
for 12 h. The reaction mixture was filtered through Celite
with excess glacial acetic acid; the acid was then removed in
vacuo. The residue was partitioned between 10% aqueous
sodium hydroxide (50 cm3) and dichloromethane (50 cm3)
at 0 8C. The layers were separated and the aqueous layer was
re-extracted with DCM (2!20 cm3). The combined
dichloromethane extract was dried (Na2SO4) and evapor-
ated under reduced pressure to give a brown oil. This
material was purified by column chromatography on silica
gel (eluting with 1% MeOH–DCM). The title compound
was isolated as a colourless glass (1.84 g, 76%). [Found
(MCH)C, 879.5458 (ES). C45H78N6S2O7 requires (MC
H)C, 879.5446]; dH (CDCl3; 300 MHz) 1.46 (27H, br s,
tBu), 1.73 (6H, br m, CH2CH2NCH2Ar, CH2CH2CH2NH),
1.90 (6H, br m, CH2CH2CH2NCO), 2.4–2.8 (16H, m, CH2S,
CH2NH, CH2NCH2Ar), 3.2–3.7 (16H, br m, CH2NCO),
3.51 (2H, s, ArCH2N), 7.2–7.4 (4H, br m, ArH); dC (CDCl3;
75 MHz) 27.7, 28.5, 29.7, 29.9, w43–50 (broad overlapping
signals), 47.4, 52.7, 58.8, 79.2, 79.4, 79.6, 126.4, 128.6,
135.4, 141.0, 154.5, 171.7.
4.1.8. 5-tert-Butoxycarbonyl-13-(4-{[4,11-bis(tert-butox-
ycarbonyl)-8-(2,2,2-trichloroethoxycarbonyl)-1,4,8,11-
tetraazacyclotetradecan-1-yl]carbonyl}benzyl)-1,9-
dithia-5,13-diazacyclohexadecane 16. 5-tert-Butoxycar-
bonyl-1,9-dithia-5,13-diazacyclohexadecane 12 (1.24 g,
3.43 mmol) was dissolved in dry acetonitrile (15 cm3) and
added to a refluxing mixture of chloroamide 15 (2.08 g,
2.86 mmol), sodium carbonate (0.455 g, 4.29 mmol) and
sodium iodide (0.086 g, 0.57 mmol) in dry acetonitrile
(5 cm3). The reaction was allowed to reflux for 24 h after
which the solvent was removed under reduced pressure and
the residue partitioned between dichloromethane (50 cm3)
and water (20 cm3). The aqueous layer was extracted with
dichloromethane (3!50 cm3), the combined organic layers
were dried (Na2SO4), then evaporated under reduced
pressure to give a brown oil that was purified by column
chromatography on silica gel (eluting with 2%
MeOH–DCM). The title compound was isolated as a
colourless glass (2.90 g, 96%). [Found (MCH)C,
1053.4485 (ES). C48H79N6S2O9Cl3 requires (MCH)C,
t
1053.4488]; dH (CDCl3; 300 MHz) 1.46 (27H, br s, Bu),
1.74 (4H, br m, CH2CH2NCH2Ar), 1.89 (8H, br m,
CH2CH2CH2NCO), 2.3–2.6 (12H, m, CH2S, CH2NCH2Ar),
3.1–3.7 (16H, br m, CH2NCO), 3.52 (2H, s, ArCH2N), 4.75
(2H, s, Cl3CCH2OCO), 7.3–7.4 (4H, br m, ArH); dC
(CDCl3; 75 MHz) 27.7, 28.5, w45–50 (broad overlapping
signals), 47.5, 52.8, 58.9, 75.2, 79.4, 80.1, 95.4, 126.3,
128.7, 135.0, 141.1, 154.3, 155.6, 171.7.
4.1.11. 5-(4-{[4,11-Bis(tert-butoxycarbonyl)-1,4,8,11-
tetraazacyclotetradecan-1-yl]carbonyl}benzyl)-1,9-
dithia-5,13-diazacyclohexadecane 19. Bis(Boc)-bis(Troc)
amide 17 (3.50 g, 3.10 mmol) was dissolved in glacial
acetic acid (20 cm3) and stirred with activated zinc dust
(6.5 g, 100 mmol) at room temperature for 2 h. The reaction
mixture was filtered through Celite with excess glacial
acetic acid; the acid was then removed in vacuo. The residue
was partitioned between 10% aqueous sodium hydroxide
(50 cm3) and dichloromethane (50 cm3) at 0 8C. The layers
were separated and the aqueous layer was re-extracted with
dichloromethane (2!50 cm3). The combined organic
extracts were dried (sodium sulfate) and evaporated under
reduced pressure to give a brown oil. This material was
purified by column chromatography on silica gel (eluting
with 5% MeOH–DCM). The title compound was isolated as
a colourless glass (2.0 g, 83%). [Found (MCH)C, 779.4888
(ES). C40H70N6S2O5 requires (MCH)C, 779.4921]; dH
(CDCl3; 300 MHz) 1.48 (18H, br s, tBu), 1.6–1.9 (8H, br m,
4.1.9. 5-(4-{[4,11-Bis(tert-butoxycarbonyl)-8-(2,2,2-tri-
chloroethoxycarbonyl)-1,4,8,11-tetraazacyclotetrade-
can-1-yl]carbonyl}benzyl)-13-(2,2,2-trichloroethoxy-
carbonyl)-1,9-dithia-5,13-diazacyclohexadecane 17. 5-
(2,2,2-Trichloroethoxycarbonyl)-1,9-dithia-5,13-diazacy-
clohexadecane 13 (0.29 g, 0.66 mmol) was dissolved in dry
acetonitrile (5 cm3) and this solution was added to a
refluxing mixture of chloroamide 15 (0.40 g, 0.55 mmol),
sodium carbonate (0.09 g, 0.83 mmol) and sodium iodide
(0.02 g, 0.11 mmol) in dry acetonitrile (5 cm3). The reaction
mixture was heated at reflux for 24 h after which the solvent
was removed under reduced pressure and the residue
partitioned between dichloromethane (30 cm3) and water

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4183
CH2CH2S), 2.13 (4H, br m, CH2CH2CH2NCO), 2.3–2.9
(20H, m, CH2S, CH2NH, CH2NCH2Ar), 3.2–3.8 (12H, br
m, CH2NCO), 3.51 (2H, s, ArCH2N), 7.2–7.4 (4H, br m,
ArH); dC (CDCl3; 75 MHz) 25.8, 27.5, 28.4, 28.5, 29.7,
30.0, w45–50 (broad overlapping signals), 45.6, 52.5, 58.7,
79.7, 126.6, 128.8, 135.1, 140.7, 155.8, 171.8.
4.1.14. 16-[4-({8-[4-(1,9-Dithia-5,13-diazacyclohexade-
can-5-ylmethyl)benzoyl]-1,4,8,11-tetraazacyclotetrade-
can-1-yl}carbonyl)benzyl]-1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecane 23. Tris(Boc) diamide 22 (0.90 g,
0.71 mmol) was dissolved in methanol (15 cm3) and stirred
with concentrated HCl (2.1 mL, 365 g/L, 21 mmol) at room
temperature for 2 h. The methanol was removed in vacuo
and the residue partitioned between saturated aqueous
ammonia solution (20 cm3) and dichloromethane (50 cm3).
The layers were separated and the aqueous layer re-
extracted with dichloromethane (2!50 cm3). The com-
bined dichloromethane extract was dried (Na2SO4) and
evaporated under reduced pressure to give the title
compound as a colourless oil that was used without further
purification (0.64 g, 94%). [Found (MCH)C, 958.5848
(ES). C50H83N7S2O7 requires (MCH)C, 958.5868]; dH
(CDCl3; 300 MHz) 1.4–2.0 (12H, br m, CH2CH2CH2), 2.4–
3.0 (30H, br m, CH2S, CH2NH, CH2NCH2Ar, NCH2CH2O),
3.2–3.8 (32H, br m, CH2NCO, ArCH2N, CH2O), 7.3–7.5
(8H, br m, ArH); dC (CDCl3; 75 MHz) 27.2, 28.9, 29.4,
29.6, w45–50 (broad overlapping signals), 47.0, 52.3, 53.5,
58.6, 59.3, 69.5, 69.9, 70.3, 70.5, 126.0, 128.2, 135.1, 140.7,
171.7.
4.1.12. 5-tert-Butoxycarbonyl-13-[4-({4,11-bis(tert-
butoxycarbonyl)-8-[4-(chloromethyl)benzoyl]-1,4,8,11-
tetraazacyclotetradecan-1-yl}carbonyl)benzyl]-1,9-
dithia-5,13-diazacyclohexadecane 20. Tris(Boc) amide 18
(1.82 g, 2.07 mmol) was dissolved in dry DCM (30 cm3).
Triethylamine (0.27 g, 2.7 mmol) and then 4-(chloro-
methyl)benzoyl chloride (0.470 g, 2.48 mmol) were added
by syringe. The reaction mixture was stirred at room
temperature for 12 h. The organic layer was then washed
with water (2!20 cm3), dried (Na2SO4) and evaporated
under reduced pressure. Purification of this material was
achieved by column chromatography on silica gel (eluting
with 1% MeOH–DCM). The title compound was isolated as
a colourless glass (1.99 g, 93%). [Found (MCH)C,
1031.5491 (ES). C31H46N4O7Cl4 requires (MCH)C,
t
1031.5475]; dH (CDCl3; 300 MHz) 1.46 (27H, br s, Bu),
1.74 (4H, br m, CH2CH2CH2NCH2Ar), 1.90 (8H, br m,
CH2CH2CH2NCO), 2.2–2.6 (12H, m, CH2S, CH2NCH2Ar),
3.0–3.8 (20H, br m, CH2NCO), 3.51 (2H, s, ArCH2N), 4.58
(2H, s, ArCH2Cl), 7.3–7.5 (8H, br m, ArH); dC (CDCl3;
75 MHz) 27.4, 28.2, 29.4, 29.6, w45–50 (broad overlapping
signals), 45.2, 47.2, 52.6, 58.6, 79.1, 79.7, 126.0, 126.4,
128.4, 134.7, 136.2, 138.3, 140.9, 154.2, 170.9, 171.5.
4.1.15. 16-[4-({8-[4-(1,9-Dithia-5,13-diazacyclohexade-
can-5-ylmethyl)benzyl]-1,4,8,11-tetraazacyclotetrade-
can-1-yl}methyl)benzyl]-1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecane 2. Diamide 23 (0.64 g, 0.67 mmol) was
dissolved in dry THF (5 cm3). A 2.0 mol dmK3 solution of
BH3$SMe2 (5 mL, 10 mmol) was added slowly and the
solution then heated to reflux for 24 h. The solution was
allowed to cool and the excess borane destroyed by careful
addition of methanol. The THF was removed under reduced
pressure and the residue hydrolysed in refluxing MeOH–H2-
O–concentrated HCl (20:10:10; 30 cm3) for 1 h. The
methanol was removed under reduced pressure and the
resulting solution partitioned between saturated aqueous
ammonia (20 cm3) and dichloromethane (50 cm3). The
aqueous layer was extracted with dichloromethane (2!
50 cm3) and the combined organic layers dried (Na2SO4)
and evaporated under reduced pressure. Purification of the
resulting material was achieved by column chromatography
on silica gel (eluting with 5% MeOH–DCM with 1%
saturated NH3 solution). The title compound was isolated as
a colourless oil (0.51 g, 82%). [Found (MCH)C, 930.6258
(ES). C50H87N7S2O5 requires (MCH)C, 929.6282]; dH
(CDCl3; 300 MHz) 1.6–1.9 (12H, br m, CH2CH2CH2), 2.4–
2.8 (36H, br m, CH2S, CH2NH, CH2NCH2Ar, NCH2CH2O),
3.5–3.8 (28H, br m, CH2NCO, ArCH2N, CH2O), 7.3–7.5
(8H, br m, ArH); dC (CDCl3; 75 MHz) 24.6, 27.5, 28.9,
29.6, 29.9, 47.2, 47.4, 48.1, 50.3, 51.1, 52.5, 53.6, 58.6,
58.8, 59.4, 69.7, 70.1, 70.5, 70.6, 128.5, 128.6, 129.2, 135.6,
135.7, 138.4, 138.6.
4.1.13. 16-(4-{[4,11-Bis(tert-butoxycarbonyl)-8-{4-[(13-
tert-butoxycarbonyl-1,9-dithia-5,13-diazacyclohexade-
can-5-yl)methyl]benzoyl}-1,4,8,11-tetraazacyclotetrade-
can-1-yl]carbonyl}benzyl)-1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecane 22. 1-Aza-18-crown-6 21 (0.38 g,
1.44 mmol) was dissolved in dry acetonitrile (20 cm3) and
added to a refluxing mixture of chloroamide 20 (1.24 g,
1.20 mmol), sodium carbonate (0.190 g, 1.80 mmol) and
sodium iodide (0.036 g, 0.24 mmol) in dry acetonitrile
(10 cm3). The reaction mixture was heated at reflux for 24 h
after which the solids were filtered off and washed with
dichloromethane (3!50 cm3). The filtrate and washings
were combined and the solvent removed under reduced
pressure. The resulting residue was partitioned between
chloroform (50 cm3) and water (20 cm3) and continuously
extracted with water (using a continuous liquid-liquid
extractor, by upward displacement) for 3 days. The organic
layer was separated, and evaporated to give a colourless oil
that was purified by column chromatography on silica gel
(eluting with 2% MeOH–DCM). The product was dried by
azeotropic distillation involving toluene. The title com-
pound was isolated as a colourless glass (1.20 g, 80%).
[Found (MCH)C, 1258.7474 (ES). C67H107N7S2O13
requires (MCH)C, 1258.7440]; dH (CDCl3; 300 MHz)
4.1.16. Bis(Boc)-tricyclic amide 24. Bis(Boc) amide 19
(0.413 g, 0.53 mmol) in dry acetonitrile (50 cm3) and a,a-
dibromo-p-xylene (0.14 g, 0.53 mmol) in dry acetonitrile
(50 cm3) were added simultaneously by syringe pump to a
suspension of potassium carbonate (0.73 g, 5.3 mmol) in
dry acetonitrile (2900 cm3) at reflux over a period of 110 h.
The reaction mixture was refluxed for a further 72 h and
then the solvent removed under reduced pressure. The
residue was dissolved in dichloromethane (80 cm3) and then
t
1.46 (27H, br s, Bu), 1.74 (4H, br m, CH2CH2NCH2Ar),
1.90 (8H, br m, CH2CH2CH2NCO), 2.4–2.6 (12H, m, CH2S,
CH2NCH2Ar), 2.84 (4H, br m, NCH2CH2O), 3.1–3.8 (44H,
br m, CH2NCO, ArCH2N, CH2O), 7.3–7.5 (8H, br m, ArH);
dC (CDCl3; 75 MHz) 27.6, 28.3, 28.4, 29.6, 29.8, w45–50
(broad overlapping signals), 47.4, 52.7, 54.1, 68.2, 99.9,
70.2, 70.3, 79.3, 80.1, 126.2, 126.3, 128.6, 129.4, 135.0,
141.0, 155.4, 171.6.

4184
J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
washed with water (2!20 cm3), dried (sodium sulfate) and
evaporated under reduced pressure. Purification of this
material was achieved by column chromatography on silica
gel (eluting with 3% MeOH–DCM). The product was
isolated as a colourless glass (0.128 g, 27%). [Found (MC
H)C, 881.5394 (ES). C48H76N6S2O5 requires (MCH)C,
881.5391] (difference between isotope peaks 1.0 amu); dH
overlapping signals), 80.4, 126.7, 128.6, 136.3, 138.7,
155.7, 171.4.
4.1.19. 1,9-Dithia-5,13-diazacyclohexadecane 11. (a) A
solution of dichloro compound 2917 (6.0 g, 23.0 mmol) and
dithiol 3017 (6.1 g, 23.0 mmol) in dry N,N-dimethylforma-
mide (500 cm3) was added over a period of 36 h to a stirred
suspension of caesium carbonate (16.9 g, 51.8 mmol) in dry
N,N-dimethylformamide (2.3 dm3) at 85 8C. The reaction
mixture was stirred at this temperature for a further 24 h.
The solvent was removed in vacuo, the residue taken up in
dichloromethane and the solids removed by filtration
through Celite. Evaporation of the solvent under reduced
pressure gave a brown oily crystalline solid that was purified
by column chromatography on silica gel (eluting with
EtOAc–petroleum ether, 1:9). 5,13-Bis(tert-butoxycarbo-
nyl)-1,9-dithia-5,13-diazacyclohexadecane 31 was obtained
as a low melting solid (6.4 g, 60%). dH (CDCl3, 300 MHz)
1.38 (18H, s, tBu), 1.79 (8H, quin, CH2CH2CH2), 2.48 (8H,
t, CH2S), 3.27 (8H, br s, CH2N). dC (CDCl3, 75 MHz) 28.3,
29.7, 47.2, 79.3. This material was used without further
characterisation as described below.
t
(CDCl3; 300 MHz) 1.2–1.5 (18H, br s, Bu), 1.5–2.0 (12H,
br m, CH2CH2CH2), 2.0–2.9 (20H, m, CH2S, CH2NCH2Ar),
3.0–3.8 (18H, br m, CH2NCO, ArCH2N), 7.2–7.6 (8H, br m,
ArH); dC (CDCl3; 75 MHz) 27.6, 28.6, 29.1, 29.6, 30.0,
w45–50 (broad overlapping signals), 52.7, 58.7, 75.2, 80.3,
95.5, 126.1, 128.6, 135.1, 141.2, 154.5, 171.7.
4.1.17. Bis(Boc)-tricyclic triamide 25. Bis(Boc) amide 19
(0.617 g, 0.79 mmol) in dry dichloromethane (50 cm3) and
terephthaloyl dichloride (0.161 g, 0.79 mmol) in dry
dichloromethane (50 cm3) were added simultaneously by
syringe pump to a solution of triethylamine (0.40 g,
3.96 mmol) in dry dichloromethane (2900 cm3) over a
period of 110 h at room temperature. The reaction mixture
was stirred for a further 36 h at room temperature and then
concentrated to a volume of approximately 50 cm3 under
reduced pressure. The organic layer was then washed with
water (2!20 cm3), dried (sodium sulfate) and evaporated
under reduced pressure. Purification of this material was
achieved by column chromatography on silica gel (eluting
with 3% MeOH–DCM). The title compound was isolated as
a colourless glass (0.49 g, 68%). [Found (MCNa)C,
931.4785 (ES). C48H72N6S2O7 requires (MCNa)C,
(b) Trifluoroacetic acid (0.91 g, 8.0 mmol) was added
slowly to di-N-Boc macrocycle 31 (0.463 g, 1.0 mmol) in
wet dichloromethane. The solution was stirred for 2 h after
which excess acid was neutralised with 10% aqueous
sodium hydroxide (25 cm3) and the aqueous layer extracted
with dichloromethane (3!50 cm3). The combined organic
layers were dried (sodium sulfate) and evaporated under
reduced pressure. Purification of the residue was achieved
by column chromatography on silica gel (eluting with 5%
MeOH–DCM) to give the title compound as a colourless oil
t
931.47796]; dH (CDCl3; 300 MHz) 1.44 (18H, br s, Bu),
1.5–2.1 (12H, br m, CH2CH2CH2), 2.2–2.7 (12H, m, CH2S,
CH2NCH2Ar), 3.1–3.8 (20H, br m, CH2NCO), 3.48 (2H, s,
ArCH2N), 7.2–7.6 (8H, br m, ArH); dC (CDCl3; 75 MHz)
27.7, 28.5, 29.2, 29.7, 30.0, w43–50 (broad overlapping
signals), 52.8, 58.9, 75.0, 80.2, 95.7, 126.3, 128.7, 135.0,
141.0, 154.3, 155.9, 171.7.
1
(0.25 g, 95%). The H NMR spectrum was as previously
reported.31
4.1.20. Bis(Boc)-tricyclic diamide 32. Bis(chloroamide)
28 (1.31 g, 1.86 mmol) in dry acetonitrile (50 cm3) and
1,9-dithia-5,13-diazacyclohexadecane 11 (0.487 g,
1.86 mmol) in dry dichloromethane (50 cm3) were added
simultaneously by syringe pump to a suspension of
potassium carbonate (2.6 g, 18.56 mmol) in dry refluxing
acetonitrile (2900 cm3) over a period of 110 h. The
reaction mixture was refluxed for a further 60 h and the
solvent removed under reduced pressure. The residue was
partitioned between dichloromethane (50 cm3) and water
(20 cm3) and the aqueous layer was extracted with
dichloromethane (3!20 cm3). The combined organic
layers were dried (sodium sulfate), and evaporated under
reduced pressure to give a brown oil that was purified by
column chromatography on silica gel (eluting with 2%
MeOH–DCM). The title compound was isolated as a
colourless glass (0.72 g, 43%). [Found (MCH)C,
895.5200; (MCNa)C, 917.4958 (ES). C48H74N6S2O6
requires (MCH)C, 895.5189; (MCNa)C, 917.5009]; dH
A small amount of lower Rf material isolated from this
chromatography was identified as 2C2 cyclisation products
(0.08 g, 11%). [Found (MC2H)2C, 909.5000 (ES).
C96H144N12S4O14 requires (MC2H)2C, 909.4977]. The
NMR spectra were indistinguishable from those of 25.
4.1.18. 1,8-Bis(tert-butoxycarbonyl)-4,11-bis[4-(chloro-
methyl)benzoyl]-1,4,8,11-tetraazacyclotetradecane 28.
To a solution of 1,8-bis(tert-butoxycarbonyl)-1,4,8,11-
tetraazacyclotetradecane 7 (1.91 g, 4.77 mmol) and triethyl-
amine (1.25 g, 12.4 mmol) in dry dichloromethane (50 cm3)
was added a solution of 4-(chloromethyl)benzoyl chloride
14 (2.16 g, 11.4 mmol) in dry DCM (20 cm3). The reaction
mixture was stirred at room temperature for 12 h after which
the reaction mixture was washed with water (2!50 cm3),
dried (sodium sulfate) and evaporated under reduced
pressure. Purification of this material was achieved by
column chromatography on silica gel (eluting with 2%
MeOH–DCM). The title compound was isolated as a
colourless glass (3.20 g, 95%). [Found (MCNa)C,
727.2997 (ES). C36H50N4O6Cl2 requires (MCNa)C,
t
(CDCl3; 300 MHz) 1.46 (18H, br s, Bu), 1.74 and 1.89
(12H, 2!br s, CH2CH2CH2), 2.41 and 2.59 (16H, 2!br
s, CH2S, ArCH2NCH2), 3.2–3.8 (20H, br m, CH2NCO,
ArCH2N), 7.34 and 7.39 (8H, 2!br s, ArH); dC (CDCl3;
75 MHz) 28.5, 30.0, 46.5, w45–50 (broad overlapping
signals), 52.6, 59.4, 80.3, 126.7, 128.6, 136.3, 138.7,
155.7, 171.4.
t
727.3000]; dH (CDCl3; 300 MHz) 1.46 (18H, br s, Bu),
1.7–2.1 (4H, br m, CH2CH2CH2), 3.2–3.8 (16H, br m,
CH2NCO), 4.58 (4H, s, ArCH2Cl), 7.3–7.5 (8H, br m, ArH);
dC (CDCl3; 75 MHz) 28.5, 30.1, 45.5, w45–50 (broad

J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4185
A small amount of the [2C2] reaction product 33 was also
isolated (0.19 g, 11%). [Found (MC2H)2C, 895.5177 (ES).
C96H148N12S4O12 requires (MC2H)2C, 895.5189. Other
parent ions were observed at m/z 1789.9126 (MCH)C,
1811.8831 (MCNa)C, 906.5088 (MCHCNa)2C, and
917.5900 (MC2 Na)2C]; the 1H and 13C NMR spectra
were indistinguishable from those of 32.
1,4,8,11-tetraazacyclotetradecan-1-yl}carbonyl)benzyl]-
1,9-dithia-5,13-diazacyclohexadecane 35. Bis(Boc)-bis-
(Troc) diamide 34 (1.00 g, 0.66 mmol) was dissolved in
glacial acetic acid (30 cm3) and stirred with activated zinc
dust (0.87 g, 1.3 mmol) at room temperature for 12– h. The
reaction mixture was filtered through Celite with excess
glacial acetic acid, which was then removed in vacuo. The
residue was partitioned between 10% aqueous sodium
hydroxide (50 cm3) and dichloromethane (50 cm3) at 0 8C.
The layers were separated and the aqueous layer re-
extracted with dichloromethane (2!20 cm3). The com-
bined organic extracts were dried (sodium sulfate) and
evaporated under reduced pressure to give a brown oil. This
material was purified by column chromatography on silica
gel (eluting with 5% MeOH–DCM). The title compound
was isolated as a colourless glass (0.57 g, 75%). [Found
(MCH)C, 1167.28 (ES). C60H100N8S4O6 requires (MC
H)C, 1157.6721]; dH (CDCl3; 300 MHz) 1.46 (18H, br s,
tBu), 1.7–2.1 (20H, br m, CH2CH2CH2), 2.4–2.8 (32H, br
m, CH2S, ArCH2NCH2, CH2NH), 3.2–3.8 (20H, br m,
CH2NCO, ArCH2N), 7.3–7.5 (8H, br m, ArH); dC (CDCl3;
75 MHz) 27.5, 28.5, 29.1, 29.9, 46.8, w45–50 (broad
overlapping signals), 52.5, 59.2, 126.9, 128.3, 136.7, 138.5,
155.6, 171.3.
4.1.21. Tetrakis(Boc)-pentacyclic tetraamide 33. Bis(-
chloroamide) 28 (0.49 g, 0.69 mmol) in dry acetonitrile
(50 cm3) and bis(Boc) diamide 35 (see below) (0.80 g,
0.69 mmol) in dry dichloromethane (50 cm3) were added
simultaneously by syringe pump to a suspension of sodium
carbonate (0.37 g, 3.45 mmol) in dry refluxing acetonitrile
(2900 cm3) over a period of 110 h. The reaction mixture was
refluxed for a further 60 h and the solvent removed under
reduced pressure. The residue was partitioned between
dichloromethane (50 cm3) and water (20 cm3) and the
aqueous layer was extracted with dichloromethane (3!
20 cm3). The combined organic layers were dried (sodium
sulfate), and evaporated under reduced pressure to give a
brown oil that was purified by column chromatography on
silica gel (eluting with 2% MeOH–DCM). The title
compound was isolated as a colourless glass (0.12 g,
10%).
[Found
(MC2H)2C
,
895.5180
(ES).
C96H148N12S4O12 requires (MC2H)C, 895.5189]; dH
(CDCl3; 300 MHz) 1.46 (18H, br s, Bu), 1.6–2.1 (12H, br
4.1.24. Pentacyclic tetraamide 36. Tetrakis(Boc)-penta-
cyclic tetraamide 33 (0.10 g, 0.056 mmol) was dissolved in
methanol (30 cm3) and stirred with concentrated hydro-
chloric acid (5 cm3, 10 M, 50 mmol) at room temperature
for 4 h. The methanol was removed in vacuo and the residue
partitioned between 10% aqueous sodium hydroxide
(20 cm3) and dichloromethane (50 cm3). The layers were
separated and the aqueous layer re-extracted with dichloro-
methane (2!50 cm3). The combined organic extracts were
dried (sodium sulfate) and evaporated under reduced
pressure to give the title compounds as a colourless glass
that was used without further purification (0.075 g, 96%).
[Found (MCH)C, 1389.8200 (ES). C76H116N12S4O4
requires (MCH)C, 1389.8197]; dH (CDCl3; 300 MHz)
1.4–2.1 (24H, br m, CH2CH2CH2), 2.1–3.1 (42H, br m,
CH2S, CH2NH, CH2NCH2Ar), 3.1–3.8 (28H, br m,
CH2NCO, ArCH2N), 7.2–7.6 (16H, br m, ArH); dC
(CDCl3; 75 MHz) 27.6, 28.8, 29.0, 29.8, w43–50 (broad
overlapping signals), 52.7, 53.1, 58.7, 59.1, 126.1, 126.3,
128.4, 135.4, 137.3, 137.5, 137.7, 140.5, 141.0, 170.6,
171.0, 171.7.
t
m, CH2CH2CH2), 2.4–2.7 (16H, br m, CH2S, ArCH2NCH2),
3.2–3.8 (20H, br m, CH2NCO, ArCH2N), 7.3–7.5 (8H, br m,
ArH).
4.1.22. 5-(4-{[4,11-Bis(tert-butoxycarbonyl)-8-(4-{[13-
(2,2,2-trichloroethoxycarbonyl)-1,9-dithia-5,13-diaza-
cyclohexadecan-5-yl]methyl}benzoyl)-1,4,8,11-tetraaza-
cyclotetradecan-1-yl]carbonyl}benzyl)-13-(2,2,2-tri-
chloroethoxycarbonyl)-1,9-dithia-5,13-diazacyclohexa-
decane 34. 5-(2,2,2-Trichloroethoxycarbonyl)-1,9-dithia-
5,13-diazacyclohexadecane 13 (2.30 g, 5.25 mmol) was
dissolved in dry acetonitrile (25 cm3) and this solution
was added to a refluxing mixture of bis(chloroamide) 28
(1.77 g, 2.50 mmol) and sodium carbonate (0.61 g,
5.75 mmol) in dry acetonitrile (50 cm3). The reaction
solution was allowed to reflux for 24 h after which the
solvent was removed under reduced pressure and the residue
partitioned between dichloromethane (70 cm3) and water
(30 cm3). The aqueous layer was extracted with dichloro-
methane (3!50 cm3), the combined organic layers were
dried (sodium sulfate) and evaporated under reduced
pressure to give a brown oil that was purified by column
chromatography on silica gel (eluting with 1%
MeOH–DCM). The title compound was isolated as a
colourless glass (3.28 g, 87%). [Found (MCH)C,
1505.4798 (ES). C66H102N8S4O10Cl6 requires (MCH)C,
4.1.25. Tetramacrocyclic ligand 37. Pentacyclic tetra-
amide 36 (0.050 g, 0.036 mmol) was dissolved in dry
tetrahydrofuran (5 cm3). A 2.0 M solution of borane
dimethylsulfide complex (10 cm3, 20 mmol) was added
slowly and the solution then heated at reflux for 24 h. The
solution was allowed to cool and the excess borane was
destroyed by careful addition of methanol. The solvent was
removed under reduced pressure and the residue was
hydrolysed in refluxing methanol–water–concentrated
hydrochloric acid (20:10:10; 40 cm3) for 1 h. The methanol
was removed under reduced pressure and the resulting
solution was partitioned between 10% aqueous sodium
hydroxide (50 cm3) and dichloromethane (50 cm3). The
aqueous layer was extracted with dichloromethane (2!
25 cm3) and the combined organic layers were dried
(sodium sulfate) and evaporated under reduced pressure.
t
1505.4805]; dH (CDCl3; 300 MHz) 1.46 (18H, br s, Bu),
1.6–2.1 (20H, br m, CH2CH2CH2), 2.4–2.6 (24H, br m,
CH2S, ArCH2NCH2), 3.2–3.7 (28H, br m, CH2NCO,
ArCH2N), 4.76 (4H, s, Cl3CCH2OCO), 7.2–7.4 (8H, br m,
ArH); dC (CDCl3; 75 MHz) 27.7, 28.6, 29.3, 30.0, w45–50
(broad overlapping signals), 48.1, 52.7, 58.7, 75.2, 80.3,
95.4, 126.5, 128.5, 135.0, 141.3, 154.1, 155.9, 171.5.
4.1.23. 5-[4-({4,11-Bis(tert-butoxycarbonyl)-8-[4-(1,9-
dithia-5,13-diazacyclohexadecan-5-ylmethyl)benzoyl]-

4186
J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
Purification of the resulting material was achieved by
column chromatography on silica gel (eluting with 5%
MeOH–DCM containing 1% saturated NH3 solution). The
title compound was isolated as a colourless glass (0.025 g,
53%). [Found (MCH)C, 1333.9001 (ES). C76H124N12S4
requires (MCH)C, 1333.9027]; dH (CDCl3; 300 MHz) 1.6–
1.9 (24H, m, CH2CH2CH2N), 2.4–2.8 (66H, CH2N, CH2S),
3.50 (8H, s, ArCH2N), 3.68 (8H, s, ArCH2N), 7.1–7.3 (16H,
m, ArH); dC (CDCl3; 75 MHz) 25.8, 27.6, 30.0, 47.5, 49.9,
51.6, 52.5, 53.8, 59.1, 128.4, 128.5, 129.2, 129.3, 135.6,
135.9, 138.2, 138.3.
Acknowledgements
We thank the Australian Research Council for support of
this research and express our appreciation to Mr Rick Willis
of the Australian Institute of Marine Science for the
provision of high resolution mass spectral data.
References and notes
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Rev. 2001, 216, 249.
¨
4. Vogtle, F.; Weber, E. J. Incl. Phen. Mol. Recog. 1992, 12, 75.
5. Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Aza-Crown
Macrocycles; Wiley: New York, 1993.
4.1.26. Tricyclic triamide 38. Bis(Boc)-tricyclic triamide
26 (0.436 g, 0.49 mmol) was dissolved in methanol
(80 cm3) and stirred with concentrated hydrochloric acid
(15 cm3, 10 M, 150 mmol) at room temperature for 6 h. The
methanol was removed in vacuo and the residue partitioned
between 10% aqueous sodium hydroxide (30 cm3) and
dichloromethane (70 cm3). The layers were separated and
the aqueous layer re-extracted with dichloromethane (2!
50 cm3). The combined organic extracts were dried (sodium
sulfate) and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel
(eluting with 5% MeOH–DCM containing 1% saturated
NH3 solution). The title compound was isolated as a
colourless glass (0.30 g, 87%). [Found MCHC, 709.3919
(ES). C38H56N6S2O3 requires (MCH)C, 709.3928]; dH
(CDCl3; 300 MHz) 1.4–2.1 (12H, br m, CH2CH2CH2), 2.1–
3.0 (20H, br m, CH2S, CH2NH, CH2NCH2Ar), 3.1–3.8
(14H, br m, CH2NCO, ArCH2N), 7.2–7.6 (8H, br m, ArH);
dC (CDCl3; 75 MHz) 27.6, 28.8, 29.0, 29.8, w43–50 (broad
overlapping signals), 52.7, 53.1, 58.7, 59.1, 126.1, 126.3,
128.4, 135.4, 137.3, 137.5, 137.7, 140.5, 141.0, 170.6,
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4.1.27. Cofacial ligand 3. Tricyclic diamide 38 (0.190 g,
0.27 mmol) was dissolved in dry tetrahydrofuran (2 cm3). A
2.0 mol dmK3 solution of borane dimethylsulfide complex
(2.7 cm3, 5.36 mmol) was added slowly and the solution
was then heated at reflux for 24 h. The solution was allowed
to cool and the excess borane was destroyed by careful
addition of methanol. The solvent was removed under
reduced pressure and the residue was hydrolysed in
refluxing methanol–water–concentrated hydrochloric acid
(10:5:5; 20 cm3) for 1 h. The methanol was removed under
reduced pressure and the resulting solution was partitioned
between 10% aqueous sodium hydroxide (30 cm3) and
dichloromethane (70 cm3). The aqueous layer was extracted
with dichloromethane (2!25 cm3) and the combined
organic layers were dried (sodium sulfate) and evaporated
under reduced pressure. Purification of the resulting
material was achieved by column chromatography on silica
gel (eluting with 5% MeOH–DCM containing 1% saturated
NH3 solution). The title compound was isolated as a
colourless glass (0.12 g, 67%). [Found (MCH)C, 667.4529
(ES). C38H62N6S2 requires (MCH)C, 667.4550]; dH
(CDCl3; 300 MHz) 1.6–1.9 (12H, m, CH2CH2CH2N), 2.4–
2.8 (32H, m, CH2N, CH2S), 3.50 (4H, s, ArCH2N), 3.68
(4H, s, ArCH2N), 7.1–7.3 (8H, m, ArH); dC (CDCl3;
75 MHz) 25.8, 27.6, 28.4, 30.0, 47.5, 49.9, 53.8, 128.5,
129.2, 135.9, 138.2.
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J. D. Chartres et al. / Tetrahedron 62 (2006) 4173–4187
4187
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publication, it unequivocally shows the proposed connectivity
of the ligand.
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