Triply bridged (1,3,5) cyclophanes from cystine and lanthionine linkers-a comparison

Article abstract of DOI:10.1016/j.tet.2010.03.091

The condensation of benzene 1,3,5-tricarbonylchloride with cystine-di-Me [H₂N-CH(COOMe)-CH₂-S-S-CH₂-CH(COOMe)-NH ₂] yielded triply bridged (1,3,5) cyclophane 1, which was shown by detailed spectral studies and molecular orbital calculations to have a D₃ symmetry with conformationally identical linkers and a spherical topology. In sharp contrast, the (1,3,5) cyclophane 2 from the rarely studied lanthionine di-Me [H₂N-CH(COOMe)-CH₂-S-CH₂-CH(COOMe)-NH ₂], showed only a equatorial twofold symmetry. This work highlights the special properties of the -S-S- bridge in cystine, which makes it an exceptional synthon in nature and organic synthesis.

Full text of DOI:10.1016/j.tet.2010.03.091

Tetrahedron 66 (2010) 3923–3929
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Triply bridged (1,3,5) cyclophanes from cystine and lanthionine
linkersda comparison
,
a
a
a
b
S. Ranganathan a , P. Venkateshwarlu , S.M. Babu , N.S. Reddy , S.J. Basha ,
*
A.V.S. Sarma b , D. Vijay , G.N. Sastry
,
c
c,
*
*
a D-212, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Centre for NMR, Indian Institute of Chemical Technology, Hyderabad 500 607, India
c Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The condensation of benzene 1,3,5-tricarbonylchloride with cystine-di-Me [H2N–CH(COOMe)–CH2–S–S–
CH2–CH(COOMe)–NH2] yielded triply bridged (1,3,5) cyclophane 1, which was shown by detailed spectral
studies and molecular orbital calculations to have a D3 symmetry with conformationally identical linkers
and a spherical topology. In sharp contrast, the (1,3,5) cyclophane 2 from the rarely studied lanthionine
di-Me [H2N–CH(COOMe)–CH2–S–CH2–CH(COOMe)–NH2], showed only a equatorial twofold symmetry.
This work highlights the special properties of the –S–S– bridge in cystine, which makes it an exceptional
synthon in nature and organic synthesis.
Received 26 January 2010
Received in revised form 23 March 2010
Accepted 24 March 2010
Available online 30 March 2010
Keywords:
Cystine(–S–S–) linker
Rigid
Ó 2010 Elsevier Ltd. All rights reserved.
Stable
Lanthionine (–S–) linker flexible
1. Introduction
The wealth of chemistry available relating to cystinedarising
from genetically coded cysteinedin organic and biological do-
Amongst the cyclophanes, triply bridged (1,3,5) cyclophanes (23
cyclophanes) have attracted more attention, possibly because they
represent optimum potential for further non-covalent assembly.
A number of strategies are available for the synthesis of 23 cyclo-
phanes.1 In the present work, the synthesis has been achieved by
linking of the core unit, benzene 1,3,5-tricarbonylchloride to either
cystine or lanthionine. Amongst the strategies for 23 cyclophanes
the linker method is sparingly used.2–5
mains, sharply contrasts to that of non-ribosomally synthesized
lanthionine, originally isolated from wool,11 where the –S–S–
bridge in the former is replaced by a single ‘–S–’. Whilst the bio-
chemistry of lanthionine is impressive, its organic chemistry is
sparsely studied. Lanthionine figures prominently in ‘lantibiotics’
the most important being ‘nisin’, the universal food preservative.
The chemistry and biochemistry of lanthionine have been recently
reviewed.12
For quite some time, our group has highlighted the versatility of
the naturally occurring L-cystine, in the crafting of a variety of
The rigid –CH2–S–S–CH2– module present in cystine plays an
important role in maintaining the specific molecular conformations
of proteins. The universal adaptability of cystine is likely to arise
from this module having a dihedral angle close to 90ꢀ,13 that
imparts a screw sense making it chiral.14 The unit is rigid because of
structures. Cystine endowed with H2N–CH(COOH)– groups at the
terminals and having a mid, nearly orthogonally disposed disulfide
bridge, has proved itself an exceptionally versatile molecule in
structural chemistry.6
Other citations include the use of cystine in studies related to
protein de novo design,7 in the synthesis of collagen triple helix
models8 and in the synthesis of peptide dendrimers.9 In-
terestingly as a variant to the normal DNA synthesis the possi-
bility for the formation of the disulfide end groups has been
realised.10
considerable
lowest vacant
p
s
-type interaction of the filled 3p-orbital of S with the
orbital of the neighboring S, which, in turn, makes
*
the proximate methylenes more acidic. The unit is also part of
chromophore involved in d–d transition.14 None of these features
are present in lanthionine, which can be considered having a thio
ether profile that can be expected to show considerable flexibility.
The genesis of the present work is to design an appropriate system
that can explain in terms of variation of structural features arising
from replacement of cystine with lanthionine within the same
structural framework. To the best of our knowledge such a com-
parison has not been reported. Of various options, we selected the
* Corresponding authors. Tel.: þ91 40 2719 1648; fax: þ91 2716 0757; e-mail
address: ranga@iict.res.in (S. Ranganathan).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.091

3924
S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
23 cyclophanes, 1 and 2 prepared from the linking of benzene 1,3,5-
tricarbonylchloride with, respectively, cystine-dimethyl ester
dihydrochloride (3) and lanthionine dimethyl ester dihydro-
chloride (4).
2.1. Triply bridged (1,3,5) cyclophane from cystine (1)
The reaction of the cystine linker 3 with benzene 1,3,5-tri-
carbonylchloride in presence of NEt3 and excess methylene chlo-
ride led to the gradual precipitation of the desired 1, in quantitative
yields, as a white powder, mp 220–265 ꢀC. Surprisingly, the com-
pound was quite insoluble in most organic solvents except DMSO in
which it exhibited limited solubility. After several efforts at puri-
fication of the crude product, Soxhlet extraction proved satisfac-
tory. The crude product was charged on to a Soxhlet thimble and
extracted with a range of organic solvents (CCl4, CHCl3, MeOH). This
procedure enabled the removal of extraneous impurities to afford
87% of pure 1 as a white granular powder, mp 258–262 ꢀC (dec).
The compound gave acceptable elemental (C, H, N, S) analysis and
spectra (IR, 1H NMR, 13C NMR, MALDI-TOF MS, and HRMS) in
complete agreement with the assigned structure. Several attempts
to secure crystals of the compound were not successful.
The 500 MHz 1H NMR of 1 taken in DMSO-d6 showed very
clearly a threefold axial symmetry as well as a twofold equatorial
symmetry. Thus, all the three linkers were spatially equivalent from
vantage of NMR. The CbH2 protons appeared as two sets of doublet
of doublets (dd), the ester as a single peak, the CaH protons as
a clean quartet, the aromatic protons as a sharp singlet, and the
amide protons as a doublet. The TOCSY spectrum of 1 (Fig. 1)
enabled the assignment of peak positions and coupling constants
were obtained from 1H NMR (Table 1).
In principle, compounds 1 and 2 could exhibit a threefold
symmetry, which in the case of 1 would have a spherical profile and
harbor, in the equatorial plane, six sulfur centers.
2. Results and discussion
Cystine-di-Me$2HCl (3) was prepared in 68% yields by the
reaction of MeOH–HCl on
L-cystine (Scheme 1).
F2
(ppm)
1
2
3
4
5
6
7
8
9
Scheme 1.
The cystine linker 3 was transformed to the lanthionine linker
[(lanthionine di-Me$2HCl), (4)], in an overall yield of w50%,
involving as the key step, the facile removal of a single sulfur as
shown in Scheme 2.15
9
8
7
6
5
4
3
2
1
0
F1 (ppm)
Figure 1. TOCSY spectrum of 1.
Table 1
1H NMR of 1 (500 MHz, DMSO-d6):
d
Scheme 2.
CbH, 2.89, dd, 6H, J¼7.4, 13.6 Hz
CbH’, 3.23, dd, 6H, J¼7.4, 13.6 Hz
Ester, 3.62, s, 18H
A
1H NMR comparison of the linkers 3 and 4, the latter lacking
CaH, 4.90, q, 6H, J¼7.4 Hz
a single sulfur, shows that the b-methylene protons are up field
shifted from 3.38 to 3.14 ppm. Similarly the CaH protons are shifted
from 4.60 to 4.38 ppm.
Ar–H, 8.21, s, 6H
NH, 9.16, d, 6H, J¼7.4 Hz

S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
3925
The ROESY spectrum (Fig. 2) clearly brought out strong con-
nectivity between aromatic protons and amide protons and
a weaker one between the aromatic protons and the CaH as well
as CbH.
F2
(ppm)
1
2
3
4
5
6
7
8
F2
(ppm)
1
2
3
4
5
6
7
8
9
8
7
6
5
4
3
2
1
0
F1 (ppm)
Figure 3. TOCSY spectrum of 2.
Table 2
1H NMR for 2 (500 MHz, DMSO-d6):
d
Linker 1
Linker 2
Linker 3
CbH, 3.09, dd, 2H,
CbH, 3.12, dd, 2H,
CbH, 3.12, dd, 2H,
9
8
7
6
5
4
3
2
1
0
ab
ab
ab
J
¼4.8 Hza
J
¼5.4 Hza
J
CH–CH
¼5.4 Hza
CH–CH
CH–CH
CbH’, 3.20, dd, 2H,
CbH’, 3.25, dd, 2H,
CbH’, 3.23, dd, 2H,
F1 (ppm)
0
0
0
ab
ab
ab
J
¼8.2 Hza
J
¼7.8 Hza
J
¼7.9 Hza
CH–CH
CH–CH
CH–CH
Figure 2. ROESY spectrum of 1.
Ester, 3.70, s, 2ꢁ3H
CaH, 4.68,dt, 2H,
J¼8.2, 4.8 Hz
Ester, 3.72, s, 2ꢁ3H
CaH, 4.62, dt, 2H,
J¼7.8, 5.4 Hz
Ester, 3.72, s, 2ꢁ3H
CaH, 4.74, dt, 2H,
J¼7.9, 5.4 Hz
Ar–Ha, 8.25, t, 2H,
J¼1.6 Hz
Ar–Hb, 8.19, t, 2H,
J¼1.6 Hz
Ar–Hc, 8.28, t, 2H,
J¼1.6 Hz
2.2. Triply bridged (1,3,5) cyclophane from lanthionine (2)
NH, 8.67, d, 2H,
J¼8.2 Hz
NH, 8.50, d, 2H,
J¼7.8 Hz
NH, 8.48, d, 2H,
J¼7.9 Hz
The reaction of 3 equiv of the linker 4 with 2 equiv of benzene
1,3,5-tricarbonylchloride and slight excess of NEt3 in CH2Cl2
resulted in a clear solution in contrast to that with linker 3. Work up
followed by chromatography afforded 16% (TLC) of pure triply
bridged (1,3,5) cyclophane 2, mp 205–210 ꢀC. The structural
assignment for 2 is fully supported by 1H and 13C NMR and HRMS
data. Two different batches of 2 have been prepared recently and
they showed similar chromatographic behavior, TLC, and spectral
profile. Thus compound 2, like compound 1 is a single compound.
The TOCSY spectrum of 2 presented in Figure 3 exhibited normal
through bond correlations, which enabled the assignment of peak
positions and coupling constants. For many of the protons, these
were obtained from resolution enhanced 1H NMR spectrum
(Table 2). The result of the ROESY spectrum, presented in Figure 4
afforded spatial connectivity that exists between several protons.
The strong NOE connectivities between amide protons and ar-
omatic protons facilitated the identification of the three linkers. The
NOE correlation between CaH and aromatic protons further con-
firmed the above observation. Figure 5 illustrates the individual
NMR assignment and spatial connectivity found in compound 2, in
which the aromatic protons labeled a, b, and c and the three chains
are distinguished by labeling the amide protons as 1, 2, and 3. As
Table 2 shows, the peak positions of NH in all the three chains are
up field shifted compared to 1. This may be because the amide
a
Geminal coupling could not be measured due to the overlap with residual water
(DMSO-d6) and among themselves.
F2
(ppm)
1
2
3
4
5
6
7
8
protons are further shielded by the p-system as compared to 1. For
8
7
6
5
4
3
2
1
0
similar reason, the CaH protons in the three chains of 2 appear
within a small range are also up field shifted compared to 1. Weak
spatial interaction is also seen between CbH and amide protons of 2.
F1 (ppm)
Figure 4. ROESY spectrum of 2.

3926
S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
COOMe
3
S
C
H
4.74
8.28
NH
H
O
COOMe
3.23
3.12
8.48
c
4.62
C
2
N
H
H
3.25,3.12
O
8.50
a
b
8.19
H
S
H
8.25
1
HN
O
8.67
MeOOC
C
H
3.20, 3.10
4.68
S
Figure 5. Individual NMR assignment and spatial connectivity in 2(only one half of the
symmetrical pair is shown).
The 1H and 13C NMR of 1 and 2 suggest an axial threefold
symmetry and an equatorial twofold symmetry for 1and a equato-
rial twofold symmetry for 2. This is best exemplified by the 1H NMR
in DMSO-d6, where, for 1 the amide protons appear as a single
doublet and the aromatic protons as a sharp singlet and that for 2
the amide protons are seen as three clean doublets and the
aromatic protons as three clean triplets with a meta coupling of
1.6 Hz. In the 13C NMR in DMSO-d6 the aromatic carbons of 1 appear
as two clean peaks, and the multiple profile of 2 has been analyzed
by HMBC and HSQC.
3. Dynamic 1H NMR studies
A dynamic NMR experiment on 216 has been carried out in
DMSO-d6. For clarity, the three clear amide proton signals were
chosen for analysis. The outcome as shown below, clearly indicates
a propensity for the merger of the amide protons with increasing
temperature:
Figure 6. Cystine and lanthionine derived 1 and 2 from B3LYP/6-31G calculations.
*
T
ꢀC
D
(d
): 1ꢂ2
D(
d
): 2ꢂ3
30
40
50
60
70
0.185
0.179
0.16
0.149
0.117
0.09
0.066
0.051
0.029
0.027
C1 symmetry were considered. As the NMR data for 2 indicates the
presence of an equatorial twofold symmetry and lack of any
intramolecular hydrogen bonding the only conformation that
satisfies the NMR description was chosen and further optimized at
B3LYP/6-31G level leading to Figure 6, which exhibits a virtual
*
4. Molecular orbital calculations
equatorial twofold symmetry.
The space filling reorientations of 1 and 2 shown in Figure 7
clearly show the consequence of the replacement of the –S–S– in
cystine (1) with –S– of lanthionine (2). All calculations have been
carried out using Gaussian 03 program package.18
The foregoing analysis of the NMR data clearly reveals that
cystine derivative 1 possesses an axial threefold symmetry and an
equatorial twofold symmetry. We have undertaken an exhaustive
conformational search for the cystine derivative 1 at AM1 level. The
presence of the amide groups in the molecule can lead to intra-
molecular hydrogen bonding. Keeping the symmetry constraints
and the possibility of intramolecular hydrogen bonding in mind,
eight conformations were generated with D3 symmetry (wherein
both equatorial and axial symmetry are present), C3 symmetry
(with only axial symmetry), and C1 symmetry. The conformations
were initially optimized at the AM1 level,17 and as expected, the
hydrogen bonded systems have shown marginally higher stability.
However, as the NMR data indicate absence of any intramolecular
hydrogen bonding, only the D3 symmetric model was subjected to
5. Conclusion
The perfect threefold symmetry seen in the cystine compound 1
and the lack of it in the lanthionine analog 2 possibly arises from
the
equatorial plane providing a spherical profile. In the lanthionine
analog 2 this element offers considerable flexibility.
(dihedral angle w90ꢀ) segment present along the
A profile of the linkers present in 1 and 2 is presented in Figure 8.
It can be seen from Figure 8, that while the cystine linker consists of
rigid modules that are stabilized in several ways excepting for the
chiral centers, the lanthionine module is highly flexible and devoid
of stabilizing factors with the exception of the terminal amide
further optimization at B3LYP/6-31G level (see Fig. 6). For lan-
*
thionine derivative 2 the initial conformational search was carried
out at AM1 level and eight different conformations with C3, C2, and

S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
3927
6. Experimental
6.1. General
Melting points were recorded on Fisher–Johns apparatus and
are uncorrected. Optical rotations were measured with an auto-
matic JASCO P1020 polarimeter (concentrations were in g/100 mL).
Infrared spectra were recorded on a Thermo Nicolet Nexus 670
spectrometer as KBr pellets and prominent peaks are expressed in
cmꢂ1. 1H and 13C NMR spectra were recorded on a Varian Gemini
200, Bruker Avance 300, Varion Inova 400, Inova 500, and Bruker
Avance 600 NMR spectrometer. The chemical shifts are expressed
in
d (parts per million) with TMS at 0.0000 as internal reference.
FABMS was measured using VG AUTOSPEC mass spectrometer,
ESI-MS was obtained on a micromass QUATTRO-LC instrument,
MALDI-TOF spectra on KRATOS ANALYTICAL instrument, and HRMS
obtained on a QSTAR XL instrument. Elemental data were obtained
using automatic analyzers. Reactions were monitored, wherever
possible by TLC. Silica gel G (Merck) was used for TLC and column
chromatography was done on silica gel (100–200 mesh). Columns
were generally made from slurry in chloroform and products were
eluted with a mixture of chloroform–methanol.
6.2. Synthesis
6.2.1. Cystine-di-Me dihydrochloride (3). To a suspension of L-cys-
tine (4.15 g, 17.30 mmol) in dry methanol (125 mL), a steady stream
of dry HCl was passed for 5 h, concentrated to 30 mL, refrigerated
overnight, filtered, and crystallized from methanol–ether to afford
4.00 g (68%) of 3 mp 165–171 ꢀC.
1H NMR (400 MHz, D2O):
d
3.30–3.45 (m, 4H, Cyst CbH2s), 3.88
(s, 6H, COOMe), 4.60 (m, 2H, Cyst CaHs).
FABMS (m/z) (%): 269 (MꢂHCl2)þ (100).
6.2.2. Preparation of
dihydrochloride (4).
6.2.2.1. N,N0-Bis(trifluoroacetyl)-
L
-(þ)-lanthionine dimethyl ester
-cystine-dimethyl ester (4a). A stir-
L
red suspension of 3 (4.5 g, 13.2 mmol) in trifluoroacetic acid (15 mL)
was cooled to ꢂ5 ꢀC and admixed with, in drops, trifluoroacetic
anhydride (10 mL). The resulting solution was stirred for 1 h at
ꢂ5 ꢀC and then 1 h at rt. The reaction mixture was poured over
200 mL of ice-H2O, stirred for 10 min, filtered, the crystalline 4a was
washed with water (w50 mL), and dried in vacuo to yield 6.0 g
(w100%) of 4a as white crystals, mp 151–153 ꢀC (lit.15 152–154 ꢀC).
Figure 7. Space filling representations of cystine and lanthionine derived 1 and 2 from
B3LYP/6-31G calculations.
*
groupings. The significant presence of cystine in nature and
synthesis, compared to lanthionine may arise from these factors.
1H NMR (200 MHz, CDCl3þDMSO-d6):
d 2.98–3.30 (m, 4H, Cyst
CbH2s), 3.77 (s, 6H, COOMe), 4.62–4.81 (m, 2H, Cyst CaHs), 9.60
(d, J¼8.3 Hz, 2H, amide NHs).
O
E
6.2.2.2. N,N0-Bis(trifluoroacetyl)-
L-lanthionine dimethyl ester
H
N
S
(4b). Under dry nitrogen, to a stirred suspension of 4a (8.0 g,
17.4 mmol) in dry benzene (87 mL) was added, in drops, neat
tris(diethylamino)phosphine (4.869 g, 19.7 mmol). The resulting
mixture was stirred under N2 for 10 min. The suspension of 4a
slowly dissolved and precipitated as a gel. The reaction mixture was
diluted with hexane (150 mL), the resulting suspension filtered,
and the white crystals of 4b were further washed well with hexane
(50 mL) to yield 7.057 g (95%) of 4b, mp 110–115 ꢀC (lit.15 117–
1
N
H
S
E
O
O
E
E
O
2
S
N
H
N
H
25
25
118 ꢀC). [
MeOH)).
a
]
ꢂ32.66ꢀ (c 0.4 MeOH); (lit.15
[a]
D
ꢂ32.4ꢀ (c 0.4
D
1H NMR (200 MHz, CDCl3þDMSO-d6):
d 2.92–3.30 (m, 4H, Lan
CbH2s), 3.77 (s, 6H, COOMe), 4.54–4.80 (m, 2H, Lan CaHs), 9.23–9.45
(m, 2H, amide NHs).
E = COOMe
Figure 8. A profile of linkers.
6.2.2.3.
L
-(þ)-Lanthionine (4c). A stirred solution of 4b (2.78 g,
In sum whilst incorporation of cystine could lead to rigid
systems that, with lanthionine may result in flexible ones.
6.5 mmol) in dioxane (30 mL) was cooled to 0 ꢀC and admixed with,
in drops, 1 N NaOH (54 mL, 54 mmol). After 0.5 h at 5 ꢀC, the

3928
S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
reaction mixture was acidified with 2 N HCl (24 mL, 48 mmol).
After adjusting the pH to 6.0 (2 N HCl), the solvent was removed in
vacuo. The residue was triturated with water (30 mL) and filtered to
afford 0.870 g (64%) of 4c, mp 280–285 ꢀC, which was used as such
in the following experiment.
stirred suspension of 4 (1.0 g, 3.24 mmol) in CH2Cl2 (100 mL) was
added in drops, NEt3 (1.36 g (1.88 mL), 13.57 mmol) followed by,
after 0.5 h, in drops, over a period of 0.75 h, a solution of benzene
1,3,5-tricarbonylchloride (0.572 g, 2.157 mmol) in CH2Cl2 (50 mL).
The reaction mixture was left stirred at rt overnight, washed with
2 N H2SO4 (20 mL), water (20 mL), satd NaHCO3 (20 mL), brine
(20 mL), dried (Na2SO4), and evaporated to yield 0.450 g (41%), mp
w225 ꢀC, of the crude product 2, which was chromatographed on
silica gel. Elution with CHCl3–MeOH, 95:5, gave 0.180 g (16%), mp
205–210 ꢀC.
6.2.2.4.
L
-(þ)-Lanthionine dimethyl ester dihydrochloride (4). An
ice-salt cooled and stirred suspension of 4c (0.870 g, 4.183 mmol) in
dry MeOH (20 mL) was admixed with acetyl chloride (1.313 g
(1.19 mL), 16.732 mmol). The reaction mixture was allowed to
attain rt, refluxed for 6 h, solvents evaporated in vacuo, and the
residue crystallized from methanol–ether to afford, 1.0 g, 77% of 4
as a white powder, mp 155–157 ꢀC.
IR (KBr): 3390, 3066, 2954, 2925, 1741, 1671, 1529, 1437, 1348,
1219, 1103, 1019 cmꢂ1. 1H NMR (500 MHz, DMSO-d6):
d 3.09, 3.12,
3.12 (dd, dd, dd, J¼4.8, 5.4, 5.4 Hzy, 6H, Lan CbH), 3.20, 3.25, 3.23 (dd,
dd, dd, J¼8.2, 7.8, 7.9 Hz,y 6H, Lan CbH), 3.70, 3.72, 3.72 (s, s, s, 18H,
COOMe), 4.68, 4.62, 4.74 (dt ,dt, dt, 6H, J¼8.2, 4.8; 7.8, 5.4; 7.9,
5.4 Hz Lan CaHs), 8.25, 8.19, 8.28 (t, t, t, J¼1.6 Hz, 6H, Ar H), 8.67,
8.50, 8.48 (ddd, J¼8.2, 7.8, 7.9 Hz, 6H, NH).
1H NMR (300 MHz, D2O):
d
3.01–3.27 (m, 4H, Lan CbH2s), 3.80
(s, 6H, COOMe), 4.35–4.41 (m, 2H, Lan CaHs).
6.2.3. Reaction of benzene 1,3,5-tricarbonylchloride with 3: synthesis
of triply bridged (1,3,5) cyclophane: hexamethyl 4,13,19,28,31,40-
hexaoxo-8,9,23,24,35,36-hexathia-5,12,20,27,32,39-hexaazate-
tracyclo[14.14.10.13,29.114,18]dotetraconta-1,3(41),14,16,18(42),29-hex-
aene-6,11,21,26,33,38-hexacarboxylate 1. To an ice-cooled and
stirred solution of 3 (1.023 g, 3 mmol) in CH2Cl2 (35 mL), was added
triethylamine (0.65 g (0.89 mL), 6.4 mmol) followed by, after 0.5 h,
a further lot of triethylamine (1.33 g (1.83 mL), 13.18 mmol) and
admixed with, in drops, a solution of benzene 1,3,5-tricarbonyl-
chloride (0.53 g, 2 mmol) in CH2Cl2 (16 mL). The reaction mixture
was left stirred at 0 ꢀC for 3 h, left stirred at rt for 30 h, and the
product filtered; yield 1.2 g (w100%), mp 220–265 ꢀC (dec).
The above product was, in two batches, charged on to a Soxhlet
thimble and each batch extracted with, CCl4 (120 mL, 5 h), 2ꢁCHCl3
(120 mL, 5 h), EtOAc (150 mL, 6 h), CHCl3–MeOH (1:1) (150 mL, 7 h)
and finally with MeOH (150 mL, 7 h). The insoluble residues,
collected from the thimbles were combined to afford 0.970 g (87%)
of white granular powder, mp 258–262 ꢀC (dec).
13C NMR (150 MHz, DMSO-d6):
d
32.97, 32.82, 32.82 (Lan Cb),
53.18, 52.93, 52.95 (Lan Ca), 52.08, 52.13, 52.16 (OCH3), 133.15,
132.33, 132.27, 130.21, 129.12, 127.15 (Ar C), 164.46, 164.18, 164.11
(CONH2), 171.01, 170.93, 170.83 (COOMe).The assignments were
made with the help of HMBC and HSQC experiments. ESI-MS (m/z)
(%):1021(MþH)þ (28), 1043 (MþNa)þ (100). HRMS (ESI): m/z calcd
for C42H48N6O18NaS3 (MþNa)þ 1043.2084, found 1043.2075.
Temperature dependent NMR (500 MHz, DMSO-d6) in the range
of 30–70 ꢀC afforded for the three amide NHs d
d/dT values,
respectively, 9.02, 7.6, 5.75 ppb/ꢀC suggesting absence of intra-
molecular hydrogen bonding.
Acknowledgements
P.V. and S.R. are grateful to the Council of Scientific and
Industrial Research, New Delhi, for the award of a Fellowship and
financial assistance.
IR (KBr): 3384, 3221, 3059, 2951, 1743, 1637, 1541, 1436, 1405,
1339, 1212, 1103, 1015 cmꢂ1. 1H NMR (500 MHz, DMSO-d6):
d 2.89
References and notes
(dd, J¼7.4, 13.6 Hz, 6H, Cyst CbHs), 3.23 (dd, J¼7.4, 13.6 Hz, 6H, Cyst
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(s, 6H, Ar Hs), 9.16 (d, J¼7.4 Hz, 6H, amide NHs). 13C NMR
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MALDI-TOF MS (m/z) (%): 1116 (M)þ (100). Anal. Calcd for
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d
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y
Geminal coupling could not be measured due to the overlap, with residual
water (DMSO-d6) and among themselves.

S. Ranganathan et al. / Tetrahedron 66 (2010) 3923–3929
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