The asymmetric synthesis and conformational analysis of new C2-symmetric macrocycles derived from head-to-head linked α-amino acids and benzene or pyridine

Article abstract of DOI:10.1016/S0040-4020(00)01126-1

The synthesis of several novel 15-18-membered macrocycles containing 1,3-disubstituted benzene or 2,6-disubstituted pyridine in a chiral environment is described. The syntheses used a series of di(N^α-tosyl-L-alanylamido)alkanes, which could be prepared in good yield. The macrocyclisation reaction with 1,3-di(bromomethyl)benzene or 2,6-di(bromomethyl)pyridine was facilitated by the use of caesium carbonate as base, and NMR and molecular modelling were used to study the preferred conformations of the macrocycles.

Full text of DOI:10.1016/S0040-4020(00)01126-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1379±1386
The asymmetric synthesis and conformational analysis of new
C2-symmetric macrocycles derived from head-to-head linked
a-amino acids and benzene or pyridine
Patrick D. Bailey,a,p Simon R. L. Everitt,a Keith M. Morgana and Andrew G. Brewsterb
aDepartment of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
bAstraZeneca Pharmaceuticals, Mereside, Alderley Park, Maccles®eld, Cheshire SK10 4TG, UK
Received 14 July 2000; revised 9 November 2000; accepted 23 November 2000
AbstractÐThe synthesis of several novel 15±18-membered macrocycles containing 1,3-disubstituted benzene or 2,6-disubstituted pyridine
in a chiral environment is described. The syntheses used a series of di(Na -tosyl-l-alanylamido)alkanes, which could be prepared in good
yield. The macrocyclisation reaction with 1,3-di(bromomethyl)benzene or 2,6-di(bromomethyl)pyridine was facilitated by the use of
caesium carbonate as base, and NMR and molecular modelling were used to study the preferred conformations of the macrocycles.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
close spatial proximity to the pyridine ring at all times, as
shown schematically in Fig. 1, but that there should be
suf®cient space for chemical reactions to occur at the
pyridyl nitrogen.
Macrocyclic pyridine-based systems are important in:
² metal chelation and extraction;1
² host±guest systems2 and enzyme mimics;3
² antibiotics4 and natural products such as marine alkaloids.5
2. Results and discussion
2.1. Synthesis
Our own interest concerns the use of the pyridine moiety as a
key catalytic feature of enzyme mimics. This paper reports
our work on benzene and pyridine macrocycles, providing
results that relate to both the synthetic accessibility and the
preferred conformations of macrocyclic pyridine systems.
There are two apparently straightforward approaches to the
synthesis of the target molecule 1, as shown in Scheme 1.
Our initial work followed the more obvious Route A, which
in theory allows rapid access to a series of differently sized
macrocycles simply by changing the diamine cross-linker
(XL) used in the ®nal synthetic step. The early stages of this
synthesis proved relatively easy, but the macrocyclisation
step could not be achieved under a variety of conditions, and
as a result we turned our attentions to Route B. This required
a new series of head-to-head linked a-amino acids. Thus,
We identi®ed macrocyclic pyridine derivatives 1 as valu-
able targets, because the macrocyclic ring substituents
might be used to modify the chemistry at the pyridine nitro-
gen. One feature that we deemed as essential was chirality
close to the pyridine nitrogen, and we decided to use
a-amino acids as a readily available source of this chirality.
These macrocycles are C2-symmetric, which should ensure
that identical chiral environments are present on each face
of the macrocycle, regardless of the direction of approach
taken by an incoming species, e.g. the attack of a nucleo-
phile on a pyridinium±electrophile intermediate.6
It was felt that these macrocycles should also be of moderate
size and ¯exibility, such that the chiral centres are held in
Keywords: macrocycles; amino acids and derivatives; pyridines; molecular
modelling/mechanics.
p
Corresponding author. Tel.: 10131-451-3100; fax: 10131-451-3180;
e-mail: p.d.bailey@hw.ac.uk
Figure 1. The C2-symmetric target molecule 1; XLˆcross-linker, Pˆ
protecting group.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01126-1

1380
P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
Scheme 1. Retrosynthesis of the target macrocycles.
Scheme 2. Synthesis of the macrocycles 3a and 4a.
N-tosyl-protected l-alanine7 was coupled to several a,v-
diamines, using a variety of established amide-forming
techniques,8 to give a series of suitably protected diamides.
The synthesis of one such diamide, 1,2-di(Na-tosyl-l-alanyl-
amido)ethane 2a, is shown in Scheme 2.
Table 1. The yields of various diamides prepared using either DCC/HOBT
or EDC/HOBT coupling reagents. Both sets of reactions were carried out in
THF at room temperature
When dicyclohexylcarbodiimide (DCC) was employed in
the synthesis of the diamides, the removal of dicyclohexyl-
urea by-product necessitated lengthy chromatography
procedures. To avoid this, we opted to use the N-ethyl-N0-
(dimethylamino)propyl carbodiimide (EDC)9 as the
coupling agent. This afforded a water-soluble urea by-
product which was easily removed by aqueous washes. As
well as simplifying the work-up procedure, this modi®-
cation also signi®cantly increased the yields of the diamides
formed (see Table 1).
DCC/HOBT
yield (%)
EDC/HOBT
yield (%)
2a
2b
2c
2d
ZNH(CH2)2NHZ
ZNH(CH2)3NHZ
ZNH(CH2)4NHZ
ZNH(CH2)5NHZ
37
45
15
28
80
75
90
89
In order to investigate the [111] macrocyclisation reactions,
we decided to carry out model reactions using commercially
available 1,3-di(bromomethyl)benzene. We have shown
elsewhere10 in work concerning cyclic hexapeptides that
the tosyl (Ts) protecting group is capable of stabilising the
deprotonation of the N-terminus of an amino acid deriva-
tive. This feature of the protecting group allowed us to use
2e
2f
32
Ð
Ð
95
80
89
2g

P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
1381
Table 2. The percentage yields for the preparation of the benzene series of
15±18-membered macrocycles
Yield (%)
3a
3b
3c
3d
ZNH(CH2)2NHZ
ZNH(CH2)3NHZ
ZNH(CH2)4NHZ
ZNH(CH2)5NHZ
53
62
32
15
3e
3f
22
0
Figure 2. Possible conformations for the macrocycles; A planar, B saddle,
C twisted, D skewed.
caesium carbonate, a mild base with noted templating
effects,11 to carry out the cyclisation reaction. Thus, equi-
molar amounts of 1,3-di(bromomethyl)benzene and the
diamide 2a were stirred with 5 equivalents of Cs2CO3 in
DMF at room temperature for 48 h. After ®ltration to
remove the majority of the sparingly soluble base, and
puri®cation by column chromatography, the 15-membered
macrocycle 3a was obtained in good yield (Scheme 2).
nation to the caesium cation (if the latter is acting as a
template).
The pyridine-derived macrocycles required the preparation
of 2,6-di(bromomethyl)pyridine. This was carried out
following Cram's method,12 although we succeeded in
raising the yield from 39% to 78%. The macrocyclisation
was carried out under identical reaction conditions to those
used for the benzene-derived macrocycles. The yields for
the different pyridine macrocycles (Table 3) are very similar
to those obtained for the related benzene analogues. Again,
the incidence of polymeric material was noted to increase
with increased cross-linker length, and little or no macro-
cyclic material could be isolated cleanly from reactions with
the aryl diamides 2e and 2f. An interesting result was
observed for macrocyclisation with the piperazine-derived
cross-linker. We had anticipated a low yield of macrocyclic
product 4g due to a preference for the cross-linker to adopt a
chair conformation. The high yield we obtained might be
explained by the boat conformation required for the macro-
cycle formation being stabilised by coordination to the Cs1
template.
This synthetic protocol was followed in the preparation of
the related benzene-derived macrocycles, using our series of
diamides (XL) (see Table 2).
The highest yield was obtained for the 16-membered macro-
cycle 3b, with yields steadily declining until none of the
19-membered macrocycle 3f could be isolated. The two
aryl diamides showed a related regio-dependence towards
the macrocyclisation process; when the two reactive ends of
the diamide cross-linker were para to one another, the
macrocycle could not form. The incidence of polymeric
material was noted to increase with increased cross-linker
³
length, probably due to an increase in DS for the larger
macrocycles, or possibly the reduced ef®ciency of coordi-
2.2. Preliminary conformational analysis and NMR
studies
Table 3. The percentage yields for the preparation of the pyridine series of
15±18-membered macrocycles
It is possible to identify four main structural types for these
macrocycles, as outlined in Fig. 2. Steric crowding around
the central cavity might be expected to preclude the planar
conformation A, thus leading to a saddle-shaped macrocycle
B. This saddle shape could effectively abolish the
C2-symmetry which was an important initial design con-
sideration (Fig. 1). Relief of steric crowding could also be
achieved by twisting the macrocycle as in C which would
maintain C2-symmetry, or by a skewed geometry as in D.
Yield (%)
4a
4b
4c
4d
ZNH(CH2)2NHZ
ZNH(CH2)3NHZ
ZNH(CH2)4NHZ
ZNH(CH2)5NHZ
58
51
35
15
Our initial NMR experiments were carried out on the ®rst
benzene-derived macrocycle 3a. The H NMR spectrum
revealed that the material was C2-symmetric on the NMR
timescale, with no line-broadening apparent at room
temperature. At ®rst sight this would appear to rule out
1
4g
48

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P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
Figure 3. Side and top views of the predicted lowest energy local minima for 4a (all within 2 kcal mol21); E global minimum, F plus 0.41 kcal mol21, G plus
1.05 kcal mol21, H plus 1.58 kcal mol21
.
the proposed conformations B and D. This benzene-derived
macrocycle also presented us with an opportunity to ªprobeº
the cavity using n.O.e. spectroscopy. Several interactions
between the aryl proton projecting into the cavity and the
alanyl methyl groups demonstrated the proximity of these
chiral groups to the 2-position of the benzene ring, and thus
further ruled out the conformation D. Thus the NMR results
appeared to suggest the presence of the C2-symmetric
conformations A or C.
C2-symmetric twisted. Crucially, all of these conformations
are so close in terms of calculated energy that we can predict
that they will all be populated to a signi®cant extent at room
temperature. We might also expect the interconversion
between these conformations to be relatively easy, and it
is possible to envisage ª¯ippingº of the saddle E via the
intermediacy of F/G and H. Thus the NMR should indicate
a C2-symmetric, time-averaged structure, as indeed was the
case.
A positive n.O.e. was also observed between the alanyl
methyl groups and the aromatic protons of the tosyl groups,
indicating that these groups spent at least some time in close
proximity. Because of conformational freedom, the NMR
spectra were not conclusive for these macrocycles, and we
decided to carry out extensive molecular modelling/confor-
mational analysis in parallel with the NMR studies.
In order to con®rm that inversion of the macrocycle through
a C2-symmetric intermediate was theoretically possible on
the NMR timescale, a long molecular dynamics run was
attempted. On short dynamics runs, of several thousand
steps, no inversion of the macrocycle was observed
(although the N-sulphonamide groups could undergo rela-
tively free rotation as expected). The dynamics routine
within XED98 uses torsional kinetic energy only, and so
cannot be directly related to time, but when using 10 million
steps (notionally equivalent to 10 ns), ª¯ippingº of the
saddle shape through C2-symmetric intermediates was
observed, even at room temperature. This further supports
the conformational search results in terms of the proposed
¯exibility and average C2-symmetry of these macrocycles.
2.3. Molecular modelling and conformational analysis
The smallest pyridine-containing macrocycle 4a was chosen
as a candidate for a careful conformational search using the
fast dynamics/Monte Carlo search routine within XED98.13
A large number of local minima were found to lie close to
the predicted global minimum in terms of potential energy.
Many of these conformations were the result of duplicates
arising when the macrocyclic ring bends to either side of the
pyridine ring, or were the result of relatively free rotation of
the N-sulphonamide groups. The four structures shown in
Fig. 3 represent four distinct conformations that the macro-
cyclic ring itself can adopt, all within 2 kcal mol21 of the
predicted global minimum (the N-sulphonamide groups
have been omitted for clarity). The predicted global mini-
mum E, and the related conformations F and G are all
saddle-shaped and therefore not C2-symmetric. The confor-
mations F and G are partially skewed off to one edge of the
pyridine ring, whilst another low-energy conformation H is
3. Conclusions
The benzene- and pyridine-derived macrocycles described
above are readily prepared in only two steps, via the for-
mation of head-to-head-linked a-amino acids followed by a
[111] macrocyclisation. The NMR spectra of these
materials suggest that they are C2-symmetric, but detailed
molecular modelling reveals that the macrocycles have
substantial conformational freedom and that the apparent
symmetry is due to ª¯ippingº of saddle-shaped structures
through a C2-symmetric intermediate.

P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
1383
In more general terms these results show that for antibiotics
and other bioactive pyridine-containing macrocyclic struc-
tures it may be necessary to consider both saddle and twisted
low-energy conformations when attempting to rationalise or
predict bioactivity.
THF was dried by distillation from sodium. Anhydrous
DMF was obtained from Aldrich, and was stored under
argon. HPLC grade CHCl3, CH2Cl2 and MeOH were
obtained from Aldrich for use in preparative work. Solvents
used for column chromatography were puri®ed by standard
procedures.
For the application of our pyridine-containing systems as
enzyme mimics, the conformational freedom of the macro-
cycle should allow the alanyl methyl groups to provide a
chiral environment at the pyridine nitrogen without neces-
sarily blocking reactions at that site, and we are currently
investigating the binding and catalysis capabilities of our
systems.
4.3. General procedure A for the preparation of alkyl
and aryl diamides using DCC/HOBT peptide coupling
agents
N-Tosyl-l-alanine was dissolved in dry THF with HOBT
(1.05 equivalents) and DCC (1.05 equivalents). This solu-
tion was stirred at room temperature under argon for 1 h,
during which time a white precipitate was formed (DCU).
The diamine (0.5 equivalents) was then added, and stirring
continued for 24 h. The THF was removed by evaporation,
and the residual white solid dissolved in EtOAc (100 ml).
The DCU was insoluble in EtOAc, and was removed by
®ltration, before the solvent was evaporated. The residue
was puri®ed by ¯ash chromatography on silica gel, eluted
with MeOH/CH2Cl2 (1:99) affording the diamide as a white
solid.
4. Experimental
4.1. Molecular modelling
This was performed on a Silicon Graphics O2 (R10k,
195 MHz) using XED98 and the default dielectric constant
of 4.
4.1.1. Conformational analysis of macrocycle 4a. Fifty
initial fast (high-temperature) torsional dynamics runs
generated 255 conformations which were within 10 kcal
mol21 of the lowest energy conformation found. Filtration
of these conformations based on overlay of the pyridine ring
left 77 conformations which were used as starting points in a
Monte Carlo-type conformational search. After ®ltration,
XED13a addition and careful minimisation (to an accuracy
of 0.001 kcal mol21), 134 conformations were recorded
within 10 kcal mol21 of the predicted global minimum.
Thirteen conformations were within 2 kcal mol21 of the
global minimum, although around half were duplicates
caused by the ¯exing of the macrocycle to either (equiva-
lent) side of the pyridine ring.
4.4. General procedure B for the preparation of alkyl
and aryl diamides using EDC/HOBT peptide coupling
agents
N-Tosyl-l-alanine was dissolved in dry THF with HOBT
(1.05 equivalents) and the required diamine (0.5 equiva-
lents). This mixture was stirred at room temperature under
an argon atmosphere for 15 min, before the addition of EDC
(1.05 equivalents) in a single portion. Further stirring over
6 h afforded a thick white precipitate (EDU). The THF was
evaporated, and the residual white solid was taken up into a
1:1 mixture of EtOAc and 1 M HCl (aq) (50 ml). After
shaking, the organic layer was washed with 1 M HCl (aq)
(1£25 ml), with 1 M NaOH (aq) (2£25 ml) and with sat.
brine (2£25 ml). The solvent was then dried over MgSO4,
®ltered, and evaporated to give the diamide.
4.1.2. Molecular dynamics of macrocycle 4a. This was
performed using the torsional dynamics available with
XED98. A dynamics run using 107 steps at 258C (notionally
equivalent to 10 ns), with a structure being recorded every
105 steps, took 10 days to complete.
4.4.1. Preparation of 1,2-di(Na -tosyl-l-alanylamido)-
ethane 2a. General procedure B was followed, using
N-tosyl-l-alanine (3.48 g, 14.3 mmol), EDC (2.92 g,
15.2 mmol), HOBT (2.94 g, 21.8 mmol), THF (50 ml) and
1,2-diaminoethane (0.49 ml, 7.16 mmol), affording 2.85 g
of 1,2-di(Na-tosyl-l-alanylamido)ethane 2a as a white
solid, m.p. 195±1968C (78% yield); Rf 0.09 in MeOH/
CHCl3 (5:95); 1H NMR (200 MHz) d: 1.01 (6H, d,
7.0 Hz, a-CH3), 2.36 (6H, s, Ar±CH3), 2.84 (4H, d,
6.7 Hz, NH±CH2±CH2±NH), 3.62 (2H, m, a-H), 7.35 and
7.67 (8H, AB system, 8.2 Hz, Ar±H), 7.72 (2H, s, NH±CO),
7.82 (2H, d, 8.0 Hz, NH±SO2); 13C NMR (50 MHz) d:
4.2. General synthetic experimental
Melting points were determined on a Riechert microscope
hot-stage apparatus, and are uncorrected. Elemental
analyses were performed at AstraZeneca Pharmaceuticals,
Alderley Park. NMR spectra were recorded on a Bruker
AC200 at 200 MHz and a Bruker DPX400 at 400 MHz.
Chemical shifts were measured in ppm scale down®eld
from tetramethylsilane as internal standard. The solvent
employed was CDCl3, unless otherwise stated. Infrared
spectra were recorded on a Perkin±Elmer 1600 series
FT-IR spectrophotometer. Optical rotations were recorded
on a Bendix-NPL 143D polarimeter at room temperature
(208C) using 2 ml of the solvent cited in the text. FAB
mass spectra were recorded on a VG MS9 double sector
spectrometer, with argon as the fast atom gas. Analytical
TLC was carried out on Merck aluminium sheet silica gel
60 F254 plates (thickness 0.2 mm) as the stationary phase.
18.77, 20.86, 37.94, 51.89, 126.53, 129.31, 138.06,
 Ã
20
D
142.52, 171.22;
a
ˆ249.3 (cˆ1.05, MeOH/CHCl3
(1:9)); IR nmax cm21: 3274, 1663, 1541, 1425, 1333, 1239,
1163, 1091, 970, 873, 813, 669, 562; FABMS m/e 533
(M1Na; 76%), 511 (M11; 100%), 286 (26%), 269
(12%), 198 (34%), 155 (34%), 139 (14%), 123 (8%).
Found: C 51.5%, H 6.10%, N 10.80%, S12.30%. Calcd: C
51.76%, H 5.88%, N 10.98%, S 12.55% for C22H30N4S2O6.
4.4.2. Preparation of 1,3-di(Na -tosyl-l-alanylamido)pro-

1384
P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
pane 2bGeneral procedure B was followed, using N-tosyl-
l-alanine (2.58 g, 10.6 mmol), EDC (2.16 g, 11.2 mmol),
HOBT (1.52 g, 11.2 mmol), THF (40 ml) and 1,3-diamino-
propane (0.44 ml, 5.3 mmol), affording 1.21 g of 1,3-di(Na-
tosyl-l-alanylamido)propane 2b as a white solid, m.p.
181.5±1828C (44% yield); Rf 0.17 in MeOH/CHCl3
3250, 1648, 1617, 1559, 1447, 1331, 1160, 1091, 816, 662,
618; FABMS m/e 553 (M11; 32%), 328 (14%), 306 (26%),
206 (28%), 194 (12%) 178 (12%), 149 (34%), 91 (50%), 55
(100%). Found: C 54.40%, H 6.70%, N 10.10%, S 11.70%.
Calcd: C 54.35%, H 6.52%, N 10.14%, S 11.59% for
C25H36N4S2O6.
1
(5:95); H NMR (400 MHz) in DMSO-d6 d: 1.02 (6H, d,
7.1 Hz, a-CH3), 1.29 (2H, q, 6.9 Hz, NH±CH2±CH2±CH2±
NH), 2.36 (6H, s, Ar±CH3), 2.84 (4H, dt, 5.3 Hz and 5.3 Hz,
NH±CH2±CH2±CH2±NH), 3.64 (2H, dt, 7.5 Hz and 7.5 Hz,
a-H), 7.34 and 7.65 (8H, AB system, 8.3 Hz, Ar±H), 7.75
(2H, br t, NH±CO), 7.82 (2H, d, 8.0 Hz, NH±SO2); 13C
NMR (50 MHz) in DMSO-d6 d: 18.89, 20.86, 28.73,
4.4.5. Preparation of 1,3-di(Na -tosyl-l-alanylamido-
methyl)benzene 2e. General procedure B was followed,
using N-tosyl-l-alanine (5.04 g, 20.7 mmol), EDC (4.18 g,
21.8 mmol), HOBT (2.93 g, 21.7 mmol), THF (50 ml) and
1,3-di(aminomethyl)benzene (1.36 ml, 13.6 mmol), afford-
ing 5.73 g of 1,3-di(Na -tosyl-l-alanylamidomethyl)benzene
2e as an amorphous white solid, m.p. 191±1928C (94%
yield); Rf 0.14 in MeOH/CHCl3 (5:95); 1H NMR
(200 MHz) in DMSO-d6 d: 1.06 (6H, d, 7.1 Hz, a-CH3),
2.37 (6H, s, Ts±CH3), 3.75 (2H, m, a-H), 4.12 (4H, m,
6.0 Hz, NH±CH2±Ar), 7.0 (3H, m, Ar±H), 7.22 (1H, t,
7.6 Hz, Ar±H), 7.35 and 7.68 (8H, AB system, 7.9 Hz,
Ar±H) 7.89 (2H, d, 4.9 Hz, Ts±NH), 8.28 (2H, t, 5.7 Hz,
Ar±CH2±NH±CO); 13C NMR (50 MHz) in DMSO-d6 d:
35.98, 51.87, 126.50, 129.32, 138.09, 142.50, 171.03;
a
 Ã
20
D
ˆ273.3 (cˆ1.01, MeOH/CHCl3 (1:9)); IR nmax cm21
(KBr disk) 3251, 1651, 1557, 1435, 1329, 1234, 1163, 1142,
1091, 978, 818, 697, 664, 567; FABMS m/e 547 (M1Na;
32%), 525 (M11; 100%), 300 (18%), 283 (20%), 249
(12%), 239 (10%), 198 (36%), 185 (8%), 176 (12%), 149
(14%). Found: C 52.7%, H 5.90%, N 10.40%. Calcd: C
52.67, H 6.11%, N 10.68% for C23H32N4S2O6.
18.91, 20.89, 41.92, 51.81, 126.33, 126.00, 126.49,
 Ã
20
4.4.3. Preparation of 1,4-di(Na -tosyl-l-alanylamido)-
butane 2c. General procedure B was followed, using
N-tosyl-l-alanine (5.01 g, 20.6 mmol), EDC (4.15 g,
21.6 mmol), HOBT (2.92 g, 21.6 mmol), THF (50 ml) and
1,4-diaminobutane (1.04 ml, 10.3 mmol), affording 4.99 g
of 1,4-di(Na-tosyl-l-alanylamido)butane 2c as a white
solid, m.p. 163±1648C (90% yield). Rf 0.13 in MeOH/
CHCl3 (5:95); 1H NMR (400 MHz) DMSO-d6 d: 1.01
(6H, d, 7.0 Hz, a-CH3), 1.17 (4H, br s, NH±CH2±CH2±
CH2±CH2±NH), 2.35 (6H, s, Ar±CH3), 2.84 (4H, br d,
NH±CH2±CH2±CH2±CH2±NH), 3.67 (2H, m, a-H), 7.34
and 7.65 (8H, AB system, 8.0 Hz, Ar±H), 7.71 (2H, t,
5.4 Hz, NH±CO), 7.79 (2H, d, 8.3 Hz, NH±SO2); 13C
NMR (50 MHz) in DMSO-d6 d: 19.05, 20.88, 26.12,
128.16, 129.34, 138.17, 138.95, 142.47, 171.14; a
ˆ
D
251.5 (cˆ1.03, MeOH/CHCl3 (1:9)); IR nmax cm21 (KBr
disk) 3411, 2961, 1734, 1654, 1617, 1534, 1448, 1382,
1337, 1164, 1092, 1018, 960, 876, 815, 662; FABMS m/e
587 (M11; 6%), 467 (4%), 388 (3%), 217 (20%), 131
(25%), 119 (52%), 100 (100%), 89 (15%). Found: C
57.30%, H 5.70%, N 9.40%. Calcd: C 57.33%, H 5.80%,
N 9.56% for C28H34N4S2O6.
4.4.6. Preparation of 1,4-di(Na -tosyl-l-alanylamido-
methyl)benzene 2f. General procedure B was followed,
using N-tosyl-l-alanine (1.90 g, 7.8 mmol), EDC (1.50 g,
7.8 mmol), HOBT (1.07 g, 7.9 mmol), THF (30 ml) and
1,4-di(aminomethyl)benzene (0.48 g, 3.5 mmol), affording
1.56 g of 1,4-di(Na -tosyl-l-alanylamidomethyl)benzene 2f
as an amorphous white solid, m.p. 216±217.58C; (80%
38.06, 51.80, 126.51, 129.31, 138.18, 142.44, 170.87;
a
 Ã
20
D
ˆ239.8 (cˆ1.03, MeOH/CHCl3 (1:9)); IR nmax cm21
1
(KBr disk) 3310, 3261, 1655, 1560, 1443, 1328, 1230, 1165,
1144, 1091, 990, 816, 662, 568, 547; FABMS m/e 561
(M1Na; 6%), 539 (M11; 10%), 176 (38%), 165 (10%),
149 (14%), 123 (34%). Found: C 53.50%, H 6.3%, N
10.30%, S 12.20%. Calcd: C 53.53%, H 6.31%, N
10.41%, S 11.90% for C24H34N4S2O6.
yield); Rf 0.43 in 1:9 MeOH/CHCl3; H NMR (200 MHz)
d: 1.12 (6H, d, 7.0 Hz, a-CH3), 2.35 (6H, s, Ar±CH3), 4.18
(2H, q, 6.9 Hz, a-H), 4.24 (4H, d, 9.0 Hz, Ar±CH2±N), 7.28
(4H, br s, Ar±H), 7.34 and 7.68 (8H, AB system, 7.9 Hz,
Ts±H), 7.84 (2H, br t, NH±CO); 13C NMR (50 MHz) d:
18.60, 22.98, 43.06, 52.43, 126.72, 129.33, 129.76, 136.51,
143.87, 146.17, 171.76; IR nmax cm21 3190, 1654, 1562,
1510, 1483, 1432, 1396, 1360, 1124, 823, 755; FABMS
m/e 587 (M11; 6%), 452 (8%), 219 (70%), 198 (30%),
150 (100%), 119 (28%), 91 (94%).
4.4.4. Preparation of 1,5-di(Na -tosyl-l-alanylamido)pen-
tane 2d. General procedure B was followed, using N-tosyl-
l-alanine (5.04 g, 20.7 mmol), EDC (4.17 g, 21.7 mmol),
HOBT (2.96 g, 21.8 mmol), THF (50 ml) and 1,5-diamino-
pentane (1.21 ml, 10.4 mmol), affording 5.12 g of 1,5-
di(Na -tosyl-l-alanylamido)pentane 2d as a white solid,
m.p. 176±1778C (89% yield); Rf 0.23 in MeOH/CHCl3
4.4.7. Preparation of 1,4-di(Na -tosyl-l-alanyl)piperazine
2g. General procedure B was followed, using N-tosyl-l-
alanine (2.64 g, 10.2 mmol), EDC (2.06 g, 10.7 mmol),
HOBT (1.47 g, 10.6 mmol), THF (40 ml) and piperazine
(0.44 g, 5.12 mmol), affording 2.44 g of 1,4-di(Na-tosyl-l-
alanyl)piperazine 2g as a white solid, m.p. 84.5±868C (89%
yield); Rf 0.20 in MeOH/CHCl3 (5:95); 1H NMR (200 MHz)
d: 1.25 (6H, d, 7.0 Hz, a-CH3), 2.42 (6H, s, Ar±CH3), 2.82
to 3.68 (8H, m, N(CH2CH2)2N), 4.22 (2H, m, a-H), 5.76
(2H, d, 8.1 Hz, NH±SO2), 7.30 and 7.74 (8H, AB system,
9.0 Hz, Ar±H); 13C NMR (50 MHz) d: 19.79, 21.43, 41.71
and 44.58, 48.37, 127.14, 129.54, 137.04, 143.67, 170.20;
IR nmax cm21 3231, 1734, 1641, 1425, 1337, 1288, 1224,
1164, 1092, 1048, 1013, 968, 816, 758, 666, 558; FABMS
1
(5:95); H NMR (400 MHz) in DMSO-d6 d: 1.02 (6H, d,
7.0 Hz, a-CH3), 1.08 (2H, br s, NH±CH2±CH2±CH2±CH2±
CH2±NH), 1.21 (4H, quintet, 7.0 Hz, NH±CH2±CH2±
CH2±CH2±CH2±NH), 2.35 (6H, s, Ar±CH3), 2.84 (4H, dt,
6.6 Hz and 6.5 Hz, NH±CH2±CH2±CH2±CH2±CH2±NH),
3.67 (2H, dq, 7.2 Hz and 7.2 Hz, a-H), 7.34 and 7.65 (8H,
AB system, 8.1 Hz, Ar±H), 7.69 (2H, t, 5.6 Hz, NH±CO),
7.79 (2H, d, 8.4 Hz, NH±SO2); 13C NMR (50 MHz) in
DMSO-d6 d: 19.01, 20.88, 23.48, 28.41, 38.30, 51.81,
 Ã
20
D
126.51, 129.29, 138.19, 142.42, 170.82; a ˆ251.7 (cˆ
1.05, MeOH/CHCl3 (1:9)); IR nmax cm21 (KBr disk) 3413,

P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
1385
m/e 539 (11%), 538 (21%), 537 (M11; 52%), 312
(39%), 290 (15%), 197 (49%), 165 (25%), 149 (20%), 124
(30%), 89 (90%), 77 (95%). Found: C 53.30%, H 5.90%, N
10.10%, Calcd: C 53.30%, H 6.01%, N 10.40% for
C24H32N4S2O6.
FABMS m/e 641 (M11; 25%), 485 (14%), 469 (6%), 391
(8%), 329 (4%), 289 (25%), 272 (6%), 165 (18%), 149
(36%), 105 (80%), 55 (100%).
4.4.11. Preparation of pentyl cross-linked benzene cyclo-
phane 3d. General procedure was followed, using
1,3-di(bromomethyl)benzene (29.0 mg, 114 mmol), [Ts±
Ala±NH(CH2)2]2CH2 2d (63.0 mg, 1.17 mmol), Cs2CO3
(0.186 g, 573 mmol) and DMF (15 ml), affording 12.0 mg
of cyclophane 3d as a colourless foam (15% yield); Rf 0.25
4.4.8. Preparation of ethyl cross-linked benzene cyclo-
phane 3a. General procedure was followed, using 1,3-
di(bromomethyl)benzene (14.6 mg, 57.0 mmol), [Ts±Ala±
NHCH2]2 2a (29.3 mg, 58.0 mmol), Cs2CO3 (0.093 g,
0.29 mmol) and DMF (10 ml), affording 19.0 mg of cyclo-
phane 3a as a colourless foam (53% yield); Rf 0.44 in
1
in MeOH/CHCl3 (5:95); H NMR (200 MHz) d: 0.85 (2H,
m, NH±CH2±CH2±CH2), 1.14 (6H, d, 7.0 Hz, a-CH3), 1.32
(4H, quintet, 6.8 Hz, NH±CH2±CH2±CH2), 2.36 (6H, s,
Ts±CH3), 2.58 and 3.20 (4H, 2£m, NH±CH2±CH2±CH2),
4.06 and 4.56 (4H, AB system, 15.2 Hz, Ar±CH2±N), 4.42
(2H, q, 7.0 Hz, a-H), 6.36 (2H, br s, NH±CO), 7.34 and
7.76 (8H, AB system, 8.4 Hz, Ts±H), 7.40 (3H, m, ArH),
7.72 (1H, br s, ArH); FABMS m/e 677 (M1Na; 8%), 655
(11%), 391 (6%), 259 (6%), 193 (8%), 165 (18%), 123
(40%), 109 (62%).
1
MeOH/CHCl3 (5:95); H NMR (200 MHz) d: 1.12 (6H, d,
7.2 Hz, a-CH3), 2.44 (6H, s, Ts±CH3), 2.66±2.96 (2H, m,
NH±CH2±CH2±NH), 3.81 and 4.81 (4H, AB system,
14.0 Hz, Ar±CH2±N), 4.46 (2H, q, 7.3 Hz, a-H), 6.75
(2H, br s, NH±SO2), 7.29 (3H, m, ArH), 7.33 and 7.73
(8H, AB system, 8.0 Hz, Ts±H), 7.69 (1H, br s, ArH); 13C
NMR (50 MHz) d: 11.52, 21.49, 40.62, 46.58, 54.11,
126.98, 128.78, 129.14, 129.99, 130.79, 136.72, 136.87,
 Ã
20
D
143.87, 170.84; a ˆ128.0 (cˆ1.00, CHCl3); IR nmax
cm21 (KBr disk) 3412, 2941, 1674, 1521, 1340, 1157,
1090, 996, 872, 816, 786, 726, 659; FABMS m/e 613
(M11; 14%), 571 (8%), 459 (10%), 302 (8%), 191(14%),
107 (30%), 77 (19%).
4.4.12. Preparation of m-xylyl cross-linked benzene
cyclophane 3e. General procedure was followed, using
1,3-di(bromomethyl)benzene (32.0 mg, 1.24 mmol), 1,3-
di[Ts±Ala±NHCH2]2-benzene 2e (73.2 mg, 125 mmol).
Cs2CO3 (0.73 g, 625 mmol) and DMF (20 ml), affording
18.7 mg of cyclophane 3e as a colourless foam (22%
yield); Rf 0.22 in MeOH/CHCl3 (5:95); 1H NMR
(200 MHz) d: 1.18 (6H, d, 7.24 Hz, a-CH3), 2.42 (6H, s,
Ts±CH3), 3.89 and 4.52 (4H, AB system, 14.1 Hz, Ar±
CH2±NH), 3.95 and 4.44 (4H, 2£d, Ar±CH2±N), 4.38
(2H, q, 7.1 Hz, a-H), 6.55±7.24 (10H, m, Ar±H1NH±
CO), 7.31 and 7.67 (8H, AB system, 8.4 Hz, Ts±H); 13C
NMR (50 MHz) d: 13.15, 21.51, 43.90, 47.98, 56.61,
127.30, 127.69, 127.72, 127.85, 127.98, 128.35, 128.74,
144.22, 170.08; FABMS m/e 689 (M11; 12%), 533 (6%),
464 (5%), 290 (10%), 274 (8%), 206 (10%), 167 (30%), 149
(50%).
4.4.9. Preparation of propyl cross-linked benzene cyclo-
phane 3b. General procedure was followed, using 1,3-
di(bromomethyl)benzene (14.5 mg, 57.0 mmol), [Ts±Ala±
NHCH2]2CH2 2b (29.0 mg, 56.0 mmol), Cs2CO3 (92 mg,
0.28 mmol) and DMF (10 ml), affording 22.0 mg of cyclo-
phane 3b as a colourless foam (62% yield); Rf 0.39 in
1
MeOH/CHCl3 (5:95); H NMR (200 MHz) d: 1.14 (6H, d,
7.0 Hz, a-CH3), 1.21 (2H, m, CH2±CH2±CH2), 2.42 (6H, s,
Ts±CH3), 2.52 and 2.94 (4H, 2£m, NH±CH2±CH2±CH2±
NH), 3.88 and 4.74 (4H, AB system, 15.0 Hz, Ar±CH2±N),
4.43 (2H, q, 7.0 Hz, a-H), 6.56 (2H, br t, NH±SO2), 7.22
(3H, m, ArH), 7.33 and 7.76 (8H, AB system, 7.9 Hz, Ts±
H), 7.81 (1H, br s, ArH); 13C NMR (50 MHz) d: 11.91,
21.48, 28.93, 34.31, 46.58, 54.47, 126.98, 128.51, 129.34,
4.4.13. Preparation of ethyl cross-linked pyridine cyclo-
phane 4a. General procedure was followed, using 2,6-
di(bromomethyl)pyridine (28.0 mg, 109 mmol), [Ts±Ala±
NHCH2]2 2a (56.0 mg, 107 mmol), Cs2CO3 (0.178 g,
548 mmol) and DMF (20 ml), affording 39.0 mg of cyclo-
phane 4a as a colourless foam (58% yield); Rf 0.35 in
129.95, 131.98, 136.75, 136.97, 143.75, 169.83;
a
 Ã
20
D
ˆ113.8 (cˆ1.02, CHCl3); IR nmax cm21 (KBr disk)
3385, 2941, 1668, 1534, 1339, 1165, 1098, 729, 659;
FABMS m/e 626 (M11; 26%), 549 (8%), 471 (12%), 378
(14%), 249 (10%), 149 (28%), 91 (35%).
1
MeOH/CHCl3 (5:95); H NMR (200 MHz) in DMSO-d6
4.4.10. Preparation of butyl cross-linked benzene cyclo-
phane 3c. General procedure was followed, using 1,3-
d: 1.14 (6H, d, 7.1 Hz, a-CH3), 2.39 (6H, s, Ar±CH3),
3.08 (4H, br s, NH±CH2±CH2±NH), 4.18 (2H, q, 7.1 Hz,
a-H), 4.27 (4H, AB system, 13.0 Hz, Ar±CH2), 7.37 and
7.73 (8H, AB system, 7.8 Hz, Ts±H), 7.40 (2H, d, 6.5 Hz,
py±H), 7.81 (1H, t, 7.0 Hz, py±H), 8.02 (2H, br s, CO±NH±
CH2); 13C NMR (60 MHz) in DMSO-d6 d: 15.07, 20.90,
di(bromomethyl)benzene (33.7 mg, 132 mmol), [Ts±Ala±
NH CH2
Á
] 2c (71.0 mg, 129 mmol), Cs2CO3 (21.4 mg,
2
2
660 mmol) and DMF (15 ml), affording 27.0 mg of cyclo-
phane 3c as a colourless foam (32% yield); Rf 0.37 in
MeOH/CHCl3 (5:95); H NMR (200 MHz) d: 0.75 (4H,
1
50.57, 54.84, 57.56, 122.38, 127.29, 129.52, 136.72,
 Ã
20
D
m, NH±CH2±CH2), 1.12 (6H, d, 6.9 Hz, a-CH3), 2.45
(6H, s, Ts±CH3), 2.67 and 3.22 (4H, 2£m, NH±CH2±
CH2), 3.94 and 4.73 (4H, AB system, 15.9 Hz, Ar±CH2±
N), 4.38 (2H, q, 7.07 Hz, a-H), 6.19 (2H, m, NH±CO),
7.29±7.45 (3H, m, ArH), 7.36 and 7.73 (8H, AB system,
8.3 Hz, Ts±H), 7.59 (1H, br s, ArH); 13C NMR (50 MHz) d:
12.09, 20.71, 25.27, 38.79, 47.03, 55.52, 127.19, 128.45,
137.58, 143.23, 156.21, 169.61;
a
ˆ240.6 (cˆ0.64,
CH2Cl2); IR nmax cm21 (KBr disk) 3426, 2924, 1670,
1596, 1522, 1338, 1156, 1090, 879, 789, 659; FABMS m/
e 636 (M1Na; 72%), 614 (M11; 100%), 480 (10%), 458
(26%), 307 (8%), 289 (8%), 176 (16%), 163 (12%).
Elemental composition by FABMS m/e 614.2114 for
C29H36N5O6S2: Calcd 614.2107.
128.89, 129.80, 130.05, 135.93, 137.14, 144.19, 169.85;
ˆ153.1 (cˆ0.96, CHCl3); IR nmax cm21 (KBr disk)
 Ã
20
a
3420, 2925, 1677, 1526, 1337, 1157, 1090, 727, 660;
4.4.14. Preparation of propyl cross-linked pyridine
cyclophane 4b. General procedure C was followed,
D

1386
P. D. Bailey et al. / Tetrahedron 57 (2001) 1379±1386
using 2,6-di(bromomethyl)pyridine (20.8 mg, 81.3 mmol),
[Ts±Ala±NHCH2]2CH2 2b (42.0 mg, 82 mmol), Cs2CO3
(0.132 g, 407 mmol) and DMF (20 ml), affording 26.0 mg
of cyclophane 4b as a white solid, m.p. 96.5±97.58C (51%
yield); Rf 0.37 in MeOH/CHCl3 (5:95); 1H NMR (200 MHz)
d: 1.06 (6H, d, 7.0 Hz, a-CH3), 1.70 (2H, br quintet, NH±
CH2±CH2±CH2±NH), 2.24 (6H, s, Ar±CH3), 3.10 (4H, br s,
NH±CH2±CH2±CH2±NH), 4.02 and 4.18 (4H, AB system,
16.0 Hz, Ar±CH2), 4.20 (2H, q, 7.0 Hz, a-H), 7.13 and 7.56
(8H, AB system, 9.0 Hz, Ts±H), 7.22 (2H, d, 8.5 Hz, py±
H), 7.55 (1H, t, 8.5 Hz, py±H), 8.10 (2H, br t, CO±NH±
CH2); 13C NMR (60 MHz) d: 14.23, 21.12, 25.30, 35.161,
50.77, 57.56, 123.44, 127.18, 129.62, 135.78, 138.04,
143.92, 156.21, 170.91; IR nmax cm21 (KBr disk) 3402,
2937, 1668, 1596, 1526, 1455, 1337, 1157, 1090, 790,
659; FABMS m/e 628 (M11; 68%), 472 (26%), 392
(8%), 318 (8%), 190 (15%), 149 (34%), 133 (25%).
3.46, 4.08 and 4.32 (8H, 4£m, piperazine±H), 3.72 and 4.18
(4H, AB system, 16.2 Hz, Ar±CH2±N), 4.88 (2H, q, 7.0 Hz,
a-H), 7.12 and 7.28 (8H, AB system, 8.1 Hz, Ts±H), 7.16
(2H, br d, py±H3,5), 7.56 (1H, t, 6.0 Hz, py±H4); 13C NMR
(60 MHz) d: 14.57, 21.83, 39.14, 45.39, 50.04, 55.44,
123.74, 128.03, 129.64, 136.59, 137.07, 144.24, 156.87,
 Ã
20
D
169.57: a ˆ1158.8 (cˆ1.00, MeOH/CHCl3 (1:9)); IR
nmax cm21 (KBr disk) 3449, 2925, 1648, 1595, 1458,
1338, 1226, 1158, 1089, 1011, 886, 813, 747, 688;
FABMS m/e 640 (M11; 16%), 484 (12%), 344 (26%),
303 (12%), 190 (32%), 145 (80%), 91 (100%); Elemental
composition by FABMS m/e 640.2259 for C31H38N5O6S2:
Calcd 640.2263.
Acknowledgements
This work was jointly supported in a LINK initiative by
EPSRC, DTI, and AstraZeneca Pharmaceuticals Ltd.
Thanks are also extended to Dr A. S. F. Boyd for NMR
spectra, Dr R. Fergusson and Mr I. Scullion for mass
spectrometry, Mrs C. Graham for optical rotations, Mr
D. G. Temesi for elemental analysis, and Dr J. G. Vinter
for providing the XED98 software.
4.4.15. Preparation of butyl cross-linked pyridine cyclo-
phane 4c. General procedure was followed, using 2,6-
di(bromomethyl)pyridine (37.8 mg, 147 mmol), [Ts±Ala±
NH CH2
Á
] 2c (79.0 mg, 150 mmol), Cs2CO3 (0.239 g,
2
2
735 mmol) and DMF (25 ml), affording 33.0 mg of cyclo-
phane 4c as a colourless foam (35% yield); Rf 0.38 in
MeOH/CHCl3 (5:95); H NMR (200 MHz) d: 1.00 (4H,
1
m, NH±CH2±CH2±CH2±CH2±NH), 1.13 (6H, d, 7.1 Hz,
a-CH3), 2.39 (6H, s, Ar±CH3), 2.89 (4H, m, NH±CH2±
CH2±CH2±CH2±NH), 4.22 and 4.44 (4H, AB system,
16.9 Hz, Ar±CH2), 4.36 (2H, q, 7.1 Hz, a-H), 7.35 (2H,
d, 7.8 Hz, 2-H), 7.41 and 7.76 (8H, AB system, 8.1 Hz,
Ts±H), 7.53 (1H, br t, py±H); FABMS m/e 664 (M1Na;
42%), 642 (M11; 100%), 486 (36%), 344 (14%), 190
(12%).
References
1. (a) Elwahy, A. H. M.; Abbas, A. A. Tetrahedron 2000, 56,
885. Recent examples include: (b) Valencia, L.; Adams, H.;
Ru®na, B.; de Blas, A.; Fenton, D. E.; Macias, A.; Rodriguez,
A.; Rodriguez-Blas, T. Inorg. Chim. 2000, 300±302, 234.
(c) Marchand, A. P.; Chong, H.; Alihodzic, S. Tetrahedron
1999, 55, 9867.
4.4.16. Preparation of pentyl cross-linked pyridine cyclo-
phane 4d. General procedure was followed, using 2,6-
di(bromomethyl)pyridine (47.0 mg, 181 mmol), [Ts±Ala±
NH(CH2)2]2CH2 2d (0.101 g, 184 mmol), Cs2CO3 (0.297 g,
9.16 mmol) and DMF (25 ml), affording 18.0 mg of cyclo-
phane 4d as a colourless foam (15% yield) (oil). Rf 0.41 in
MeOH/CHCl3 (5:95); 1H NMR (400 MHz) in DMSO-d6 d:
1.04 (2H, m, NH±CH2±CH2±CH2±CH2±CH2±NH), 1.16
(6H, d, 7.04 Hz, a-CH3), 1.28 (4H, quintet (tt.), 6.5 Hz,
NH±CH2±CH2±CH2±CH2±CH2±NH), 2.38 (6H, s, Ar±
CH3), 2.91 and 3.16 (4H, AB system, NH±CH2±CH2±
CH2±CH2±CH2±NH), 4.22 and 4.48 (4H, AB system,
16.7 Hz, Ar±CH2), 4.35 (2H, q, 7.1 Hz, a-H), 7.35 (2H,
m, 2-H), 7.35 and 7.75 (8H, AB system, 8.3 Hz, Ts±H),
7.81 (1H, t, 7.8 Hz, py±H), 7.98 (2H, t, 9.2 Hz, CO±NH±
CH2); 13C NMR (60 MHz) in DMSO-d6 d: 15.71, 20.93,
23.46, 27.91, 50.44, 54.75, 57.25, 121.40, 127.28, 129.64,
136.52, 137.60, 143.54, 156.65, 169.65, 169.07; FABMS
m/e 678 (M1Na; 20%), 656 (M11; 32%), 500 (8%), 289
(14%), 193 (12%), 165 (16%).
2. Jullian, V.; Sheperd, E.; Gelbrich, T.; Hursthouse, M. B.;
Kilburn, J. D. Tetrahedron Lett. 2000, 41, 3963.
3. Talma, A. G.; Jouin, P.; De Vries, J. G.; Troostwijk, C. B.;
Werumeus Buning, G. H.; Waninge, J. K.; Visscher, J.;
Kellogg, R. M. J. Am. Chem. Soc. 1985, 107, 3981.
4. An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. D.
Tetrahedron 1998, 54, 3999.
5. Morimoto, Y.; Yokoe, C.; Kurihara, H.; Kinoshita, T.
Tetrahedron 1998, 54, 12197.
6. Fersht, A. R.; Jencks, W. P. J. Am. Chem. Soc. 1970, 92, 5432.
7. Kataoka, T.; Yoshimatsu, M.; Noda, Y.; Sato, T.; Shimizu, H.;
Hori, M. J. Chem. Soc., Perkin Trans 1 1993, 121.
8. Bailey, P. D.; Collier, I. D.; Morgan, K. M. In Comprehensive
Organic Functional Group Transformations; Katritzky, A. R.;
Meth-Cohn, O.; Rees, C. W., Eds.; Pergamon: Oxford, 1995;
Volume 5, pp 257±307, Section 5.06.
9. (a) Sheehan, J. C.; Cruickshank, P.-A.; Boshart, G. I. J. Org.
Chem. 1961, 26, 2525. (b) Bodanszky, M. In Principles of
Peptide Synthesis; Springer: New York, 1984; pp 9±58.
10. Bailey, P. D.; Carter, S. R.; Clarke, D. G. W.; Crofts, G. A.;
Tyszka, J. H. M.; Smith, P. W.; Ward, P. Tetrahedron Lett.
1992, 33, 3211.
4.4.17. Preparation of piperazine cross-linked pyridine
cyclophane 4g. General procedure was followed, using 2,6-
di(bromomethyl)pyridine (29.0 mg, 112 mmol), 1,4-di(Na-
tosyl-l-alanyl)piperazine 2g (61.1 mg, 114 mmol), Cs2CO3
(0.185 g, 571 mmol) and DMF (20 ml), affording 35 mg of
cyclophane 4g as a colourless foam (48% yield); Rf 0.37 in
MeOH/CHCl3 (5:95); 1H NMR (400 MHz) in DMSO-d6 d:
1.26 (6H, d, 7.0 Hz, a-CH3), 2.36 (6H, s, Ts±H), 3.28 (td.),
È
11. Ostrowicki, A.; Koepp, E.; Vogtle, F. Top. Curr. Chem. 1991,
161, 37.
12. Newcomb, M.; Timko, J. M.; Walba, D. M.; Cram, D. J. J. Am.
Chem. Soc. 1977, 99, 6392.
13. (a) Vinter, J. G. J. Comput. Aided Mol. Res. 1996, 10, 417.
(b) Morley, S. D.; Jackson, D. E.; Sanders, M. R.; Vinter, J. G.
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