Synthesis of chiral polyazamacrocycles of variable ring size

Article abstract of DOI:10.1039/c001228a

Synthesis and structure elucidation of optically active tri-, tetra-, and penta-azamacrocycles having 4-methoxyphenyl pendants are described. Regioselective ring opening of a nosylaziridine with secondary benzyl amines was repeatedly performed to afford the cyclization precursors. Intramolecular N-alkylation of N-(ω-haloalkyl) nosylamide provided tri-, tetra-, and penta-azamacrocycles. On the basis of our study of the tetra-azamacrocycle previously elucidated by X-ray single-crystal analysis and in solution by NMR analysis, we conclude that the tri-azamacrocycle does not mainly have a vase-type conformation because of the steric hindrance of the 4-methoxyphenyl groups but the penta-azamacrocycle has a vase-type conformation in CDCl ₃ and in CD₂Cl₂. The vase-type conformation of the penta-azamacrocycle is, however, not as much stable as that observed in the tetra-azamacrocycle because conformational flexibility of the penta-azamacrocycle was observed in deuterated benzene. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c001228a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of chiral polyazamacrocycles of variable ring size†
Seiji Kamioka,a Sakae Sugiyama,a Takashi Takahashia and Takayuki Doi*a,b
Received 20th January 2010, Accepted 12th March 2010
First published as an Advance Article on the web 1st April 2010
DOI: 10.1039/c001228a
Synthesis and structure elucidation of optically active tri-, tetra-, and penta-azamacrocycles having
4-methoxyphenyl pendants are described. Regioselective ring opening of a nosylaziridine with
secondary benzyl amines was repeatedly performed to afford the cyclization precursors. Intramolecular
N-alkylation of N-(w-haloalkyl) nosylamide provided tri-, tetra-, and penta-azamacrocycles. On the
basis of our study of the tetra-azamacrocycle previously elucidated by X-ray single-crystal analysis and
in solution by NMR analysis, we conclude that the tri-azamacrocycle does not mainly have a vase-type
conformation because of the steric hindrance of the 4-methoxyphenyl groups but the
penta-azamacrocycle has a vase-type conformation in CDCl3 and in CD2Cl2. The vase-type
conformation of the penta-azamacrocycle is, however, not as much stable as that observed in the
tetra-azamacrocycle because conformational flexibility of the penta-azamacrocycle was observed in
deuterated benzene.
four N-benzyl groups and four C-methoxybenzyl groups with (S)-
Introduction
stereochemistry are on a cyclic skeleton as pendant arms.6 In-
terestingly, all methoxybenzyl groups on the tetra-azamacrocycle
are oriented toward the same face by CH–p interactions of
the alkoxyphenyl rings to give a vase-type conformation, as
elucidated in the solid state by X-ray single-crystal analysis and
in solution by NMR analysis on the basis of computational
studies. For the synthesis of 1, we utilized regioselective ring
opening of N-nosylaziridine with secondary amines and efficient
macrocyclization of N-(w-iodoalkyl) nosylamide. In this article,
we report the details of the ring-opening reaction of C-substituted
aziridines with secondary amines and its application to the
synthesis of tri- and penta-azamacrocycles, 2 and 3, having 4-
methoxybenzyl pendants (Fig. 1).
Polyazamacrocycle–metal complexes have been studied as MRI
contrast agents in medicinal chemistry and as fluorescence probes
in chemical biology.1,2 We envisaged that chiral polyazamacro-
cyclic compounds with properly positioned substituents have a
vase-type conformation in which functional groups are oriented
toward the same face of the macrocyclic ring,3 and thus would be
useful as novel sensors with a molecular recognition site.
A C-nitrobenzyl cyclen derivative has been synthesized and the
nitro group used as a linker in the synthesis of a bifunctional
chelator.4 More complexed C-substituted polyazamacrocyclic
compounds have also been studied.5 We recently reported the
efficient synthesis of tetra-azamacrocyclic molecule 1, in which
aDepartment of Applied chemistry, Tokyo Institute of Technology, 2-12-1
Ookayama, Meguro, Tokyo, 152-8552, Japan
Results and discussion
bGraduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-
aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: doi_taka@
mail.pharm.tohoku.ac.jp; Fax: +81-22-795-6864; Tel: +81-22-795-6865
Ring opening of N-substituted aziridines with secondary
benzylamine
† Electronic supplementary information (ESI) available: Experimental
procedure and spectral data for 4 and 6, 1H and 13C NMR spectra of 1–3,
4a–4f, 6a–6f, and 8–18, COSY spectrum of10, COSY, HMQC, and HMBC
spectra of 1, and HMQC spectrum of 3. See DOI: 10.1039/c001228a
Aziridine derivatives 4 and secondary benzylamine 5 were readily
prepared from L-tyrosine in optically pure form.6 The ring-opening
reaction of 4 of various benzylamines can be adopted for preparing
Fig. 1 Polyazamacrocycles 1–3 having methoxybenzyl pendants.
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Table 1 Investigation of regioselective ring opening of N-substituted
aziridines 4 with secondary benzylamine 5a
4b produced 6b (81%). For N-2,2,2-trichloroethoxycarbonyl (N-
Troc) 4d, N-allyloxycarbonyl (N-Alloc) 4e, and N-Bz aziridine
4f, the desired products 6d–6f were produced in moderate to low
yields (8–48%) because of the decomposition of the aziridines
under the reaction conditions (entries 8–10). It should be noted
that in the previous reports, ring opening of N-tosyl- and N-nosyl-
C-substituted aziridines proceeded regioselectively with the less-
hindered amine under mild conditions.5b,5c,11
Finally, we investigated the effects of solvents (CH3CN,
CH3CN–HMPA, C2H5CN, DMF, DMSO and THF) and reaction
temperature (entries 11–15). Addition of HMPA in acetonitrile
promoted the reaction significantly (entry 11). Regioselective ring
opening of N-nosylaziridine 4b with secondary benzylamine 5
proceeded in acetonitrile–HMPA (9 : 1) at 100 ◦C in the presence
of 20 mol% Yb(OTf)3 to afford 6b in 98% isolated yield with
complete regioselectivity.
Yield of Yield of
Entry
4
P
Lewis acid Solvent
6 b%
7 b%
1
2
3
4
5
6
7
8
4a Trt
4a Trt
4a Trt
4a Trt
4a Trt
4b Ns
4c Ts
Sc(OTf)3
CH3CN
31
27
33
25
43
81
51
48
41
8
13
14
12
6
Sm(OTf)3 CH3CN
Y(OTf)3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
5
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
Repeated ring-opening reactions using N-nosylaziridine for the
preparation of the polyamines
4d Troc
4e Alloc Yb(OTf)3
9
10
11d
12e
13e
14d
15
4f Bz
4b Ns
4b Ns
4b Ns
4b Ns
4b Ns
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
CH3CN–HMPAc 98
The coupling reaction was applicable to the synthesis of the
cyclization precursors (Scheme 1). Elongation of a 2-amino-1-(4-
methoxyphenylmethyl)ethylamino moiety involves the following
steps: 1) N-Benzylation of the resulting nosylamides with BnBr–
Cs2CO3; 2) Removal of the nosyl group with thiophenol–Cs2CO3;
3) Regioselective ring opening of the resulting secondary benzy-
lamine with N-nosylaziridine 4b. First, benzylation of the resulting
nosylamide 6b, followed by deprotection of the nosyl group,
afforded the secondary benzylamine in 93% yield in two steps.
Regioselective ring opening of 4b (1.2 equiv.) with the resulting
secondary benzylamine (1.0 equiv.) in acetonitrile–HMPA (9 : 1)
at 100 ◦C in the presence of 20 mol% Yb(OTf)3 afforded 8 in 91%
isolated yield as a single regioisomer.
Encouraged by this result, we investigated the scope and
generality of the sequential reaction. By the same process, repeated
elongation of the 2-amino-1-(4-methoxyphenylmethyl)ethylamino
moiety yielded tetra-, penta-, and hexa-azacompounds 9–11.
In fact, regioselective ring opening of the different-length of
secondary benzylamines with N-nosylaziridine 4b converted them
to the corresponding nosylamides in good yields (82–91%) with
complete regioselectivity, even though 3.0 equiv of 4b was
necessary in the synthesis of 10 and 11. Thus, our sequential
reaction process rapidly provides different-length nosylamides and
is practical because it was carried out in a 10 g scale.
C2H5CN
DMF
DMSO
THF
78
67
64
28
a Reaction of 4 (1.5 equiv.) and 5 (1.0 equiv.) was performed in the presence
of Lewis acid (0.2 equiv.) at 60 ◦C.◦b Isolated yield. c CH3CN:HMPA = 9 : 1.
d Reaction was performed at 100 C. e Reaction was performed at 80 ◦C.
cyclization precursors composed of different numbers of 2-
amino-1-(4-methoxyphenylmethyl)ethylamino moieties. Hansen
and Burg reported that cyclen was synthesized by a cyclic tetramer
of N-benzylaziridine.7 Tsuboyama et al. reported that optically
∑
active N-benzyl-C-ethylaziridine in the presence of BF3 OEt2
reacts to afford a cyclic tetramer in 30% yield.8 For the synthesis
of 1–3, it is necessary to perform regioselective ring opening of
C-substituted aziridine 4. We initially investigated the reaction
of sterically hindered N-trityl-(4-methoxybenzyl)aziridine 4a and
secondary benzylamine 5 (Table 1). We considered that the
trityl group would be effective for highly regioselective ring
opening and avoiding over-reaction with aziridine 4a. Although
the reaction proceeded in the presence of lanthanide triflates,
Sc(OTf)3, Sm(OTf)3, Y(OTf)3, and La(OTf)3, the desired product
6 was obtained in only moderate yield with low regioselectivity
(Table 1, entries 1–4). Interestingly, no significant steric effect
was observed in the reaction. The structures of 6 and 7 were
determined by analysis of COSY, HMQC, and HMBC spectra.
Use of Yb(OTf)3, however, resulted in the formation of 6 in 48%
yield with 90% regioselectivity (entry 5). As Yamamoto et al.
reported,9 Yb(OTf)3 is an effective Lewis acid for regioselective
ring opening of C-substituted aziridines with dibenzylamine. It
is noteworthy that metal species of lanthanide triflates affect
the regioselectivity of the ring-opening reaction of C-substituted
aziridines.
Synthesis of the poly-azamacrocycles
To investigate the application of macrocyclization using nosy-
lamides to the construction of tri-, tetra-, penta-, and hexa-
azamacrocycles, we removed the TBS groups in 8–11 by treatment
with TBAF to produce the corresponding alcohols 12–15 in 72–
95% yields (Scheme 2). We then investigated the synthesis of
tri-azamacrocycle 16 by halogenation of alcohol 12, followed
by intramolecular N-alkylation using the nosylamide.12,13 For
◦
Next, we investigated the effects of various N-substituents in
(4-methoxybenzyl)aziridines 4b–4f in place of N-trityl (N-Trt)
aziridine 4a (entries 6–10). All reactions proceeded regioselectively
to yield 6 without evidence of 7, as determined by HPLC
analysis. In particular, o-nitrobenzenesulfonyl (nosyl)10 aziridine
iodination of 12, we used I2–PPh3 in CH3CN at 0 C. Addition
of bases played a crucial role in this reaction; the use of 5.0
equiv. of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) in DIEA–
CH3CN was found to be optimal. The resulting iodo com-
pound was immediately subjected to macrocyclization to avoid
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Scheme 1 Repeated ring-opening reactions using N-nosylaziridine 4b.
decomposition during purification by silica gel column chro-
matography. Macrocyclization proceeded at 70 ◦C with Cs2CO3
underwent macrocyclization under the above conditions to pro-
duce the 15-membered 18 (69%). However, neither iodination nor
bromination of alcohol 15 proceeded sufficiently in spite of our
best efforts.
Tri-, tetra-, and penta-azamacrocycles 16–18 were converted to
the corresponding N-polybenzylpolyazamacrocycles. Removal of
the nosyl group in 16–18 with thiophenol–Cs2CO3 followed by N-
benzylation of the resulting secondary amine with BnBr–Cs2CO3
produced tri-azamacrocycle 2 (81%), tetra-azamacrocycle 1 (68%),
and penta-azamacrocycle 3 (67%), respectively.
˚
as a base in the presence of molecular sieves (4 A) in CH3CN–
HMPA (9 : 1) under high dilution conditions (1 mM)6 to provide
the desired 9-membered 16 (30%) accompanied by its cyclic dimer
(28%) in two steps.14 Although a template effect based on the size
of metal ions, i.e., K+ and Na+, was expected, macrocyclization
did not proceed smoothly with either K2CO3 or Na2CO3.
Next, we attempted the synthesis of tetra-, penta-, and hexa-
azamacrocycles 17–19. In contrast to the low yield of 16,
iodination of 13, followed by macrocyclization under the above
mentioned optimal conditions proceeded effectively to provide
the desired 12-membered 17 in a remarkable 94% overall yield.6
In contrast, iodination of 14 and 15 failed to yield the 15-
membered 18 and 18-membered 19, probably because the alcohols
14 and 15 become too hindered as the number of the 2-amino-
1-(4-methoxyphenylmethyl)ethylamino moieties increases. After
optimization of reaction conditions, we found that phosphorus
reagents size and reaction temperature play a crucial role. Treat-
ment of alcohol 14 with CBr4–PMe3–DTBMP in DIEA–CH3CN
at 65 ◦C afforded the corresponding bromide, which immediately
Conformational analysis of the poly-azamacrocycles
Next, we investigated the three-dimensional structures of tri-
1
azamacrocycle 2 and penta-azamacrocycle 3. H and 13C NMR
spectra of 3 exhibited simple signals corresponding to the sin-
gle unit of 2-(benzylamino)-1-(4-methoxyphenyl)propyl, i.e., 13
carbon signals, as we previously reported for tetra-azamacrocycle
1.6 In contrast, the NMR spectrum of 2 exhibited unsymmetrical
conformation in the NMR time scale. The 4-methoxyphenyl
groups in 2 are probably too hindered to be oriented toward the
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Scheme 2 Synthesis of tri-, tetra-, and penta-azamacrocycles 2, 1, and 3.
Table 2 1H NMR analysis of 3 vs. 1
stacking with the benzene rings more strongly in benzene than in
CDCl3 and CD2Cl2.
CDCl3 a(Db) CD2Cl2 a(Db) Benzene-d6 a(Db)
Compound Proton (ppm)
(ppm)
(ppm)
Conclusion
3
1
Ha
Hb
Hc
Hd
6.82 (-0.33) 6.81 (-0.31)
6.79 (-0.08) 6.78 (-0.05)
6.57 (-0.58) 6.62 (-0.50)
6.80 (-0.07) 6.79 (-0.04)
7.07 (0.08)
6.99 (0.18)
6.53 (-0.46)
6.97 (0.16)
In summary, we have demonstrated the efficient synthesis and
elucidated the structures of tri-, tetra-, and penta-azamacrocycles
2, 1, and 3. Regioselective ring opening of a nosylaziridine with
secondary benzylamines was repeatedly performed to prepare
the cyclization precursors, which underwent intramolecular N-
alkylation using the nosylamides to produce 2, 1, and 3. On
the basis of the three-dimensional structure of 1 elucidated by
single-crystal X-ray analysis and NMR analysis in solution, we
conclude that 2 does not, but 3 does, dominantly have a vase-type
conformation in CDCl3 and CD2Cl2. The vase-type conformation
of 3 is, however, not as stable as that of 1 because of the
conformational flexibility of 3 observed in deuterated benzene.
Polyazamacrocycles 1–3 can contribute to the development of
novel sensors for use in the fields of materials and medicinal
chemistry, and further study is underway in our laboratory.
◦
a
1H NMR was measured at 25 C. b Differences in chemical shifts between
those of Ha and Hb in 3 and Hc and Hd in 1 and those of the corresponding
H–3 and H–2 in 4-methylanisole measured in the respective solvents (see
Fig. 1)
same face because 2 has a 9-membered ring, which is much smaller
than the 12- and 15-membered rings of 1 and 3.5d
For the penta-azamacrocycle 3, 1H NMR analysis using CDCl3
and CD2Cl2 exhibited high-field shifts for Ha (-0.33 ppm in
CDCl3, -0.31 ppm in CD2Cl2) and small high-field shifts for Hb
(-0.08 ppm in CDCl3, -0.05 ppm in CD2Cl2; Table 2 & Fig. 1). This
tendency toward a large high-field shift for Ha and a small high-
field shift for Hb is in good accordance with the results observed for
Hc and Hd in 1 as previously reported.6 Therefore, we conclude
that the vase-type conformation is dominant in 3 as well as in
1 in these solvents. In contrast, no noticeable high-field shifts
were observed in deuterated benzene for Ha (+0.08 ppm [low-
field shift]) and for Hb (+0.18 ppm [low-field shift]), suggesting
that the vase-type conformation of 3 is not as stable as that of
1 in solution. It is conceivable that benzene stabilizes the open-
type conformation of the 4-methoxybenzyl wings in solution by
Experimental section
General procedures
NMR spectra were recorded on a JEOL Model ECP-400
1
(400 MHz for H, 100 MHz for 13C) instrument in the indicated
solvent. Chemical shifts are reported in units parts per million
(ppm) relative to the signal for internal tetramethylsilane (0 ppm
for 1H) for solutions in CDCl3. 1H NMR spectral data are
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reported as follows: chloroform (d 7.26), methanol (d 3.30),
dichloromethane (d 5.30) and benzene (d 7.16). 13C NMR spectral
data are reported as follows: chloroform (d 77.1) and methanol (d
49.0). Multiplicities are reported by the following abbreviations: s;
singlet, d; doublet, t; triplet, q; quartet, m; multiplet, br.; broad,
J; coupling constants in Hertz. IR spectra were recorded on a
Perkin Elmer Spectrum One FT-IR spectrophotometer. Only the
strongest and/or structurally important absorption is reported as
the IR data given in cm-1. Optical rotations were measured with
a JASCO P-1020 polarimeter. All reactions were monitored by
thin-layer chromatography carried out on 0.2 mm E. Merck silica
gel plates (60F-254) with UV light, visualized by p-anisaldehyde
solution, ceric sulfate or 10% ethanolic phosphomolybdic acid.
Merck silica gel 60 (0.063–0.200 mm) was used for column
chromatography. ESI-TOF Mass spectra were measured with
Waters LCT PremierTM XE. HRMS (ESI-TOF) was calibrated
with leucine enkephalin (SIGMA) as an external standard.
(400 MHz, CDCl3) d 7.55 (d, 1H, J = 7.3 Hz, aromatic), 7.45 (d,
1H, J = 8.3 Hz, aromatic), 7.35 (d, 1H, J = 7.3 Hz, aromatic),
7.35–7.03 (m, 21H, aromatic), 6.87 (d, 2H, J = 8.8 Hz, aromatic),
6.71 (d, 2H, J = 8.8 Hz, aromatic), 6.69–6.61 (m, 12H, aromatic),
6.17 (d, 2H, J = 8.8 Hz, aromatic), 6.12 (d, 2H, J = 8.8 Hz,
aromatic), 5.06 (d, 1H, J = 5.4 Hz, NH), 3.94–3.56 (m, 6H), 3.92
(d, 1H, J = 14.2 Hz), 3.90 (d, 1H, J = 13.2 Hz), 3.76 (s, 3H,
OMe), 3.74 (s, 6H, OMe ¥ 2), 3.65 (s, 3H, OMe), 3.61 (s, 3H,
OMe), 3.61 (d, 1H, J = 13.2 Hz), 3.41 (d, 1H, J = 14.2 Hz), 3.12
(d, 1H, J = 11.2 Hz), 2.95–2.56 (m, 16H), 2.52 (dd, 1H, J = 2.4,
14.2 Hz), 2.41–2.29 (m, 4H), 2.23–2.14 (m, 2H), 1.00 (s, 9H, t-Bu),
0.14 (s, 3H, Me), 0.14 (s, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 157.7, 157.6 ¥ 2, 157.5 ¥ 2, 146.5, 140.9, 140.5, 140.3, 133.5,
133.3, 132.6, 132.5, 132.3, 130.4, 130.2 ¥ 2, 130.1 ¥ 2, 129.5, 129.1,
129.0, 128.9, 128.8, 128.6, 128.2, 128.1, 128.0, 126.8, 126.7, 126.5,
126.4, 125.4, 113.6, 113.3 ¥ 3, 113.0, 63.1, 62.7, 62.5, 62.0, 60.8,
57.2, 56.4, 55.7, 55.1 ¥ 2, 54.9, 50.5, 37.4, 36.3, 35.6, 34.4, 26.0,
18.2,–5.4,–5.5; HRMS (ESI–TOF) calcd for [C90H109N6O10SiS +
H]+ 1493.7690, found 1493.7722.
General procedure for ring opening of nosylaziridine 4b with
N-benzylamines
(2S,5S,8S,11S,14S,17S)-3,6,9,12,15-Pentabenzyl-1-[(1,1-dime-
thylethyl)dimethylsilyloxy]-2,5,8,11,14,17-hexakis(4-methoxyben-
zyl)-16-(2-nitrobenzenesulfonyl)-1,4,7,10,13,16-hexaazaoctade-
cane (11). Yield 82%; [a]2D6 +5.07 (c 1.48 in CHCl3); IR n
(neat, cm-1) 3061, 3028, 2934, 2835, 1612, 1513, 1247, 1176, 1110,
To a stirred solution of N-benzylamine (1.0 equiv.) in dry
acetonitrile (4.5 mL mmol-1) and HMPA (0.5 mL mmol-1) was
added N-(2-nitrobenzenesulfonyl)-2-(4-methoxybenzyl)aziridine
(4b) (1.05–3.00 equiv.) and ytterbium(III) trifluoromethanesul-
fonate (0.21–0.60 equiv.) at 0 ◦C. After being stirred at 100 ◦C,
the mixture was quenched with saturated aqueous sodium bi-
carbonate, and extracted with ethyl acetate. The extract was
washed with H2O and brine, dried over magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to afford nosylamide as a yellow oil.
1
1037, 837, 755, 738, 699; H NMR (400 MHz, CDCl3) d 7.53
(d, 1H, J = 8.3 Hz, aromatic), 7.43 (dd, 1H, J = 7.3, 7.8 Hz,
aromatic), 7.35–6.93 (m, 25H, aromatic), 6.84 (d, 2H, J = 8.3 Hz,
aromatic), 6.69 (d, 2H, J = 8.8 Hz, aromatic), 6.63–6.51 (m, 18H,
aromatic), 6.14 (d, 2H, J = 8.8 Hz, aromatic), 6.08 (d, 2H, J =
8.8 Hz, aromatic), 5.01 (d, 1H, J = 5.4 Hz, NH), 3.90–3.51 (m,
9H), 3.74 (s, 3H, OMe), 3.72 (s, 3H, OMe), 3.71 (s, 3H, OMe),
3.70 (s, 3H, OMe), 3.63 (s, 3H, OMe), 3.59 (s, 3H, OMe), 3.55
(d, 1H, J = 15.1 Hz), 3.53 (d, 1H, J = 14.2 Hz), 3.34 (d, 1H,
J = 14.2 Hz), 3.11 (d, 1H, J = 2.0, 12.7 Hz), 2.91–2.07 (m, 25H),
2.47 (dd, 1H, J = 2.4, 14.7 Hz), 1.50 (dd, 1H, J = 11.2, 14.2 Hz),
0.99 (s, 9H, t-Bu), 0.12 (s, 3H, Me), 0.10 (s, 3H, Me); 13C NMR
(100 MHz, CDCl3) d 157.7, 157.5 ¥ 2, 157.4 ¥ 3, 146.4, 140.9,
140.8, 140.5, 140.4, 133.8, 133.5, 133.4, 133.3, 132.5, 132.2, 130.4,
130.2 ¥ 3, 130.1 ¥ 2, 129.5, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6,
128.1 ¥ 2, 128.0, 126.8, 126.7, 126.6, 126.4, 125.4, 113.3 ¥ 3, 113.2,
112.9, 63.1, 62.7, 62.2 ¥ 2, 62.1, 60.7 ¥ 2, 57.1, 56.4, 55.6, 55.2,
55.1 ¥ 2, 54.9, 54.8, 54.6, 50.5, 43.2, 37.4, 36.3, 35.5, 34.3, 26.1,
18.2,–5.3,–5.4; HRMS (ESI–TOF) calcd for [C107H127N7O11SSi +
H]+ 1746.9162, found 1746.9142.
General procedure for N-benzylation of nosylamides
To a stirred solution of the nosylamide in DMF was added
caesium carbonate and benzyl bromide at 0 ◦C. After being
stirred at room temperature, the mixture was quenched with
saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate. The extract was washed with H2O and brine, dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was purified by column chromatography on silica gel to afford N-
benzylnosylamide as a yellow oil.
General procedure for removal of the nosyl group
To a stirred solution of N-benzylnosylamide in DMF was
added caesium carbonate and thiophenol at 0 ◦C. After being
stirred at room temperature, the mixture was quenched with
saturated aqueous sodium thiosulfate and saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The extract
was washed with H2O and brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified
by chromatography on silica gel to afford N-benzylamine as a
colorless oil.
General procedure for deprotection of the TBS group
To a stirred solution of the nosylamide in THF was added
tetrabutylammonium fluoride at 0 ◦C. After being stirred at 0 ◦C,
the mixture was quenched with saturated aqueous ammonium
chloride, extracted with ethyl acetate. The extract was washed
with H2O, saturated aqueous sodium bicarbonate and brine, dried
over magnesium sulfate, filtered and concentrated in vacuo. The
residue was purified by chromatography on silica gel to afford the
cyclization precursor as a yellow oil.
(2S,5S,8S,11S,14S)-3,6,9,12-Tetrabenzyl-1-[(1,1-dimethyl-
ethyl)dimethylsilyloxy]-2,5,8,11,14-pentakis(4-methoxybenzyl)-13-
(2-nitrobenzenesulfonyl)-1,4,7,10,13-pentaazapentadecane
(10).
(2S,5S,8S)-3,6-Dibenzyl-2,5,8-tris(4-methoxybenzyl)-9-(2-nit-
robenzenesulfonyl)-3,6,9-triaza-1-nonanol (12). Yield 87%; [a]D30
+65.7 (c 1.05 in CHCl3); IR n (neat, cm-1) 3027, 2936, 2837, 1612,
Yield 87%; [a]3D0 +12.4 (c 1.02 in CHCl3); IR n (neat, cm-1) 3361,
1
3027, 2835, 1612, 1540, 1512, 1247, 1037, 837, 756; H NMR
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1
1539, 1513, 1248, 1167, 1036, 756; H NMR (400 MHz, CDCl3)
Hz), 3.02–2.11 (m, 25H), 1.61–1.52 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 157.9 ¥ 2, 157.5 ¥ 2, 157.4, 146.4, 140.9, 140.7, 140.4,
140.3, 139.6, 133.8, 133.5, 133.3, 133.2, 132.5, 132.3, 131.0, 130.3,
130.2 ¥ 2, 130.0, 129.8, 129.5, 129.4, 129.1, 128.9, 128.7, 128.5 ¥ 2,
128.3, 128.2, 128.1, 128.0, 127.2, 126.7, 126.5, 126.3, 125.4, 113.8,
113.7, 113.4, 113.3, 113.2, 112.9, 63.7, 62.5, 62.4, 61.9, 60.9, 56.9,
56.3, 56.0, 55.1, 55.0, 54.8, 54.6, 51.2, 51.0, 50.8, 37.4, 37.1, 35.8,
35.5, 35.4, 31.1; HRMS (ESI–TOF) calcd for [C101H114N7O11S +
H]+ 1632.8297, found 1632.8297.
d 7.70 (d, 1H, J = 7.8 Hz, aromatic), 7.57 (d, 1H, J = 7.8 Hz,
aromatic), 7.50 (dd, 1H, J = 7.8 Hz, aromatic), 7.46 (dd, 1H, J =
7.8 Hz, aromatic), 7.28–7.09 (m, 10H, aromatic), 6.96 (d, 2H, J =
8.8 Hz, aromatic), 6.89 (d, 2H, J = 8.8 Hz, aromatic), 6.79 (d, 2H,
J = 8.8 Hz, aromatic), 6.76 (d, 2H, J = 8.8 Hz, aromatic), 6.61
(d, 2H, J = 8.8 Hz, aromatic), 6.36 (d, 2H, J = 8.8 Hz, aromatic),
3.77 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.65 (s, 3H, OMe), 3.61 (d,
1H, J = 13.7 Hz), 3.54 (d, 1H, J = 13.7 Hz), 3.51 (d, 1H, J =
13.7 Hz), 3.49–3.40 (m, 2H), 3.35 (d, 1H, J = 13.7 Hz), 3.08–3.00
(m, 3H), 2.96 (dd, 1H, J = 6.4, 13.2 Hz), 2.88 (dd, 1H, J = 5.8,
13.6 Hz), 2.78 (dd, 1H, J = 5.4, 13.7 Hz), 2.73 (dd, 1H, J = 4.9,
13.7 Hz), 2.63 (dd, 1H, J = 3.9, 14.2 Hz), 2.55 (dd, 1H, J = 7.8,
13.6 Hz), 2.47 (dd, 1H, J = 8.3, 13.7 Hz), 2.39 (dd, 1H, J = 4.4,
13.2 Hz), 2.36 (dd, 1H, J = 9.3, 13.7 Hz), 2.12 (dd, 1H, J = 9.8,
14.2 Hz); 13C NMR (100 MHz, CDCl3) d 157.9 ¥ 2, 157.7, 146.8,
139.5, 139.2, 134.4, 132.4 ¥ 2, 132.2, 131.2, 130.3, 130.1, 130.0,
129.9, 129.4, 129.3, 129.2, 128.4, 128.3, 127.1 ¥ 2, 125.1, 113.8 ¥ 2,
113.2, 62.2, 62.1, 60.7, 56.3, 56.1, 55.2, 55.1, 54.9, 54.8, 54.4, 49.7,
38.1, 33.8, 31.4; HRMS (ESI–TOF) calcd for [C50H57N4O8S + H]+
873.3892, found 873.3879.
(2S,5S,8S)-4,7-Dibenzyl-2,5,8-tris(4-methoxybenzyl)-1-(2-
nitrobenzenesulfonyl)-1,4,7-triaza-cyclononane (16). To a stirred
solution of (2S,5S,8S)-3,6-dibenzyl-2,5,8-tris-(4-methoxybenzyl)-
9-(2-nitrobenzenesulfonyl)-3,6,9-triaza-1-nonanol (12) (373 mg,
428 mmol) in acetonitrile (17 mL) was added DIEA (8.6 mL),
2,6-di-tert-butyl-4-methylpyridine (439 mg, 2.14 mmol), iodine
(1.09 g, 4.28 mmol) and PPh3 (561 mg, 2.14 mmol) at 0 ◦C.
After being stirred at 0 ◦C for 1 h, the mixture was quenched
with saturated aqueous sodium thiosulfate and saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The extract
was washed with H2O and brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was used for the
next reaction without further purification.
(2S,5S,8S,11S,14S)-1,4,7,10-Tetrabenzyl-2,5,8,11,14-penta-
kis(4-methoxybenzyl)-13-(2-nitrobenzenesulfonyl)-1,4,7,10,13-
pentaazapentadecane (14). Yield 95%; [a]3D0 +25.0 (c 0.98 in
CHCl3); IR n (neat, cm-1) 3361, 2936, 2835, 1612, 1539, 1512,
1247, 1036, 754; 1H NMR (400 MHz, CDCl3) d 7.57 (d, 1H, J =
7.8 Hz, aromatic), 7.47 (dd, 1H, J = 7.8 Hz, aromatic), 7.45 (d,
1H, J = 7.8 Hz, aromatic), 7.36–7.06 (m, 21H, aromatic), 6.90 (d,
2H, J = 8.8 Hz, aromatic), 6.78 (d, 2H, J = 8.8 Hz, aromatic),
6.76 (d, 2H, J = 8.8 Hz, aromatic), 6.76–6.74 (m, 4H, aromatic),
6.68 (d, 2H, J = 8.8 Hz, aromatic), 6.66–6.59 (m, 4H, aromatic),
6.23–6.15 (m, 4H, aromatic), 5.14 (d, 1H, J = 4.9 Hz, NH), 3.84–
3.42 (m, 7H), 3.82 (d, 1H, J = 13.2 Hz), 3.78 (s, 3H, OMe), 3.77
(s, 3H, OMe), 3.75 (s, 3H, OMe), 3.66 (s, 3H, OMe), 3.62 (s, 3H,
OMe), 3.41 (d, 1H, J = 12.2 Hz), 3.38 (d, 1H, J = 13.2 Hz), 3.15
(dd, 1H, J = 6.4, 13.7 Hz), 3.06–2.19 (m, 21H), 2.61 (dd, 1H, J =
4.9, 13.7 Hz); 13C NMR (100 MHz, CDCl3) d 157.9 ¥ 2, 157.6,
157.5 ¥ 2, 146.5, 141.2, 140.5, 140.2, 139.5, 133.9, 133.5, 133.2,
132.6, 132.3 ¥ 2, 131.1, 130.4, 130.3, 130.1, 129.9, 129.6, 129.4,
129.2, 128.9, 128.8, 128.6, 128.5, 128.3, 128.2, 128.1, 127.4, 126.8,
126.7, 126.4, 125.4, 113.8 ¥ 2, 113.4, 113.3, 113.0, 63.7, 62.8, 62.4,
62.1, 61.0, 57.0, 56.4, 55.9, 55.5, 55.2, 55.1, 54.9, 54.6 ¥ 2, 51.2,
50.9, 50.8, 50.7, 37.5, 37.2, 36.0, 35.3, 31.1; HRMS (ESI–TOF)
calcd for [C84H95N6O10S + H]+ 1379.6825, found 1379.6881.
To a stirred suspension of caesium carbonate (1.39 g, 4.28
˚
mmol) and activated 4 A molecular sieves (1.0 g) in dry
acetonitrile (107 mL) and HMPA (13 mL) was slowly added
the residue in dry acetonitrile (21 mL) at 70 ◦C over 10 h.
After being stirred at the same temperature for 24 h, the
mixture was filtered and concentrated in vacuo. The residue was
diluted with H2O, and extracted with ethyl acetate. The extract
was washed with saturated aqueous sodium bicarbonate and
brine, dried over magnesium sulfate, filtered and concentrated
in vacuo. The residue was purified by column chromatography
on amine silica gel, eluting with 10% ethyl acetate in hexane to
afford (2S,5S,8S)-1,4-dibenzyl-2,5,8-tris(4-methoxybenzyl)-7-(2-
nitrobenzenesulfonyl)-1,4,7-triazacyclononane (16) (109 mg, 128
mmol, 2 steps 30%) as a yellow oil: [a]2D6 +100.2 (c 1.10 in CHCl3);
IR n (neat, cm-1) 3027, 2934, 2836, 1609, 1540, 1512, 1249, 756;
1H NMR (400 MHz, CDCl3) d 7.78 (d, 1H, J = 7.8 Hz, aromatic),
7.63 (d, 1H, J = 7.8 Hz, aromatic), 7.56 (dd, 1H, J = 7.8 Hz,
aromatic), 7.49 (dd, 1H, J = 7.8 Hz, aromatic), 7.30–7.21 (m,
10H, aromatic), 7.23 (d, 2H, J = 8.8 Hz, aromatic), 6.89 (d, 2H,
J = 8.8 Hz, aromatic), 6.87 (d, 2H, J = 8.8 Hz, aromatic), 6.84
(d, 2H, J = 8.8 Hz, aromatic), 6.65 (d, 2H, J = 8.8 Hz, aromatic),
6.48 (d, 2H, J = 8.8 Hz, aromatic), 6.15–6.08 (m, 1H), 3.80 (s,
3H, OMe), 3.70 (s, 6H, OMe ¥ 2), 3.88–3.56 (m, 6H), 3.35 (dd,
1H, J = 4.9, 14.6 Hz), 3.16 (dd, 1H, J = 5.9, 14.6 Hz), 3.11–3.07
(m, 1H), 2.83 (dd, 2H, J = 5.4, 13.2 Hz), 2.64 (dd, 1H, J = 6.3,
13.2 Hz), 2.55 (dd, 1H, J = 6.3, 14.2 Hz), 2.56–2.49 (m, 1H),
2.38 (dd, 1H, J = 5.8, 12.7 Hz), 2.40–2.35 (m, 2H), 2.14 (dd, 1H,
J = 6.4, 13.2 Hz); 13C NMR (100 MHz, CDCl3) d 159.0, 157.8,
157.7, 147.3, 139.1, 138.0, 135.1, 132.6, 132.4, 132.3, 132.1, 130.3,
129.9, 129.8, 129.7, 129.6, 128.3, 128.0, 127.4, 127.2, 126.9, 124.7,
124.0, 113.9, 113.6, 113.4, 58.4, 57.8, 56.1, 55.3, 55.1, 55.0, 54.7,
53.4, 52.1, 38.9, 33.4, 29.7, 23.4, 20.2; HRMS (ESI–TOF) calcd
for [C50H55N4O7S + H]+ 855.3786, found 855.3769.
(2S,5S,8S,11S,14S,17S)-3,6,9,12,15-Pentabenzyl-1-[(1,1-di-
methylethyl)dimethylsilyloxy]-2,5,8,11,14,17-hexakis(4-methoxy-
benzyl)-16-(2-nitrobenzenesulfonyl)-1,4,7,10,13,16-hexaazaocta-
decane (15). Yield 72%; [a]2D4 +21.2 (c 2.40 in CHCl3); IR n
(neat, cm-1) 2936, 2835, 1612, 1539, 1512, 1454, 1247, 1177, 1036,
738, 699; 1H NMR (400 MHz, CDCl3) d 7.53 (d, 1H, J = 7.8 Hz,
aromatic), 7.43 (d, 1H, J = 7.3 Hz, aromatic), 7.39 (d, 1H, J =
7.8 Hz, aromatic), 7.32–7.07 (m, 24H, aromatic), 6.96 (d, 2H, J =
6.8 Hz, aromatic), 6.85 (d, 2H, J = 8.3 Hz, aromatic), 6.86–6.72
(m, 6H, aromatic), 6.65–6.58 (m, 10H, aromatic), 6.53 (d, 2H,
J = 8.3 Hz, aromatic), 6.16 (d, 2H, J = 8.8 Hz, aromatic), 6.12
(d, 2H, J = 8.8 Hz, aromatic), 5.07 (d, 1H, J = 5.4 Hz, NH),
3.86–3.34 (m, 13H), 3.74 (s, 6H, OMe ¥ 2), 3.71 (s, 6H, OMe ¥ 2),
3.63 (s, 3H, OMe), 3.59 (s, 3H, OMe), 3.13 (dd, 1H, J = 6.4, 13.7
(2S,5S,8S,11S,14S)-1,4,7,10-Tetrabenzyl-2,5,8,11,14-penta-
kis(4-methoxybenzyl)-13-(2-nitrobenzenesulfonyl)-1,4,7,10,13-
pentaazacyclopentadecane (18). In a sealed tube, to a suspension
2534 | Org. Biomol. Chem., 2010, 8, 2529–2536
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of
(2S,5S,8S,11S,14S)-1,4,7,10-tetrabenzyl-2,5,8,11,14-penta-
was quenched with saturated aqueous sodium bicarbonate, and
extracted with ethyl acetate. The extract was washed with H2O
and brine, dried over magnesium sulfate, filtered and concentrated
in vacuo. The residue was purified by column chromatography
on amine silica gel, eluting with 30% ethyl acetate in hexane
to afford (2S,5S,8S)-1,4,7-tribenzyl-2,5,8-tris(4-methoxybenzyl)-
1,4,7-triazacyclononane (2) (88.5 mg, 116 mmol, 91%) as a yellow
oil: [a]2D8 -5.3 (c 0.99 in CHCl3); IR n (neat, cm-1) 3062, 2934,
2835, 1747, 1512, 1455, 1248, 1035, 743, 699; 1H NMR (400 MHz,
CDCl3) d 7.35–6.96 (m, 15H, aromatic), 7.29 (d, 2H, J = 8.8 Hz,
aromatic), 6.85 (d, 1H, J = 8.8 Hz, aromatic), 6.82 (d, 1H, J =
8.8 Hz, aromatic), 6.69 (d, 2H, J = 8.8 Hz, aromatic), 6.67 (d,
2H, J = 8.8 Hz, aromatic), 6.48 (d, 2H, J = 8.8 Hz), 6.41 (d, 1H,
J = 15.6 Hz, aromatic), 6.13–6.06 (m, 2H), 3.81 (s, 3H, OMe),
3.79 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.67 (d, 1H, J = 14.2 Hz),
3.58 (d, 1H, J = 14.2 Hz), 3.56 (d, 2H, J = 14.2 Hz), 3.39 (d,
2H, J = 14.2 Hz), 3.19 (dd, 1H, J = 5.9, 14.2 Hz), 3.13 (dd, 1H,
J = 7.3, 14.2 Hz), 3.00–2.87 (m, 2H), 2.85 (dd, 1H, J = 4.4, 14.2
Hz), 2.80 (dd, 1H, J = 4.9, 12.7 Hz), 2.61–2.54 (m, 2H), 2.49
(dd, 1H, J = 5.8, 14.2 Hz), 2.47 (dd, 1H, J = 7.8, 12.7 Hz), 2.33
(dd, 1H, J = 9.8, 12.2 Hz), 2.16 (dd, 1H, J = 10.2, 13.7 Hz);
13C NMR (100 MHz, CDCl3) d 159.1, 157.6, 140.8, 140.2, 139.6,
133.4, 133.3, 132.1, 130.6, 130.0 ¥ 2, 129.1, 128.9, 128.3, 128.2,
128.0, 127.4, 126.9, 126.5, 126.4, 125.2, 114.0, 113.6, 113.0, 61.1,
59.1, 58.2, 56.8, 55.3 ¥ 2, 55.1, 55.0, 53.8, 53.1 ¥ 2, 50.5, 36.9, 35.0,
29.7; HRMS (ESI–TOF) calcd for [C51H58N3O3 + H]+ 760.4473,
found 760.4484.
kis(4-methoxybenzyl)-13-(2-nitrobenzenesulfonyl)-1,4,7,10,13-
pentaazapentadecane (14) (315 mg, 228 mmol) in acetonitrile
(9.1 mL) was added DIEA (4.5 mL), 2,6-di-tert-butyl-4-
methylpyridine (234 mg, 1.14 mmol), tetrabromomethane (1.52 g,
4.57 mmol) and PMe3 (0.40 mL, 4.57 mmol) at 0 ◦C. After
being stirred at reflux for 6 h, the mixture was quenched with
saturated aqueous sodium thiosulfate and saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The extract
was washed with H2O and brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was used for the
next reaction without further purification.
To a stirred suspension of caesium carbonate (1.46 g, 4.56 mmol)
˚
and activated 4 A molecular sieves (3.0 g) in dry acetonitrile
(57 mL) and HMPA (5.7 mL) was slowly added the residue in
dry acetonitrile (11 mL) at 70 ◦C over 10 h. After being stirred
at the same temperature for 24 h, the mixture was filtered, and
concentrated in vacuo. The residue was diluted with H2O, and
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium bicarbonate and brine, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue was
purified by column chromatography on amine silica gel, eluting
with 15% ethyl acetate in hexane to afford (2S,5S,8S,11S,14S)-
1,4,7,10-tetrabenzyl-2,5,8,11,14-pentakis(4-methoxybenzyl)-13-
(2-nitrobenzenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane
(18) (214 mg, 157 mmol, 2 steps 69%) as a yellow oil: [a]2D8 +64.7
(c 0.99 in CHCl3); IR n (neat, cm-1) 2933, 2835, 1725, 1612, 1543,
1
1513, 1248, 1036, 755; H NMR (400 MHz, CDCl3) d 7.54–6.56
(m, 40H, aromatic), 6.18–6.13 (m, 4H, aromatic), 4.25–3.40 (m,
8H), 3.85 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.66 (s, 6H, OMe ¥ 2),
3.47 (s, 3H, OMe), 3.30–1.70 (m, 15H); 13C NMR (100 MHz,
CDCl3) d 158.2, 157.6 ¥ 2, 157.5, 157.2, 139.9, 133.3, 133.2,
132.9, 132.5, 132.3, 131.3, 130.9, 130.6, 130.4, 130.1, 130.0, 129.7,
129.6, 129.3, 129.0, 128.7, 128.4, 128.3, 128.2, 128.0, 127.8, 127.3,
126.8, 126.6, 126.4, 124.5, 114.0, 113.8, 113.6, 113.2, 113.0, 63.9,
60.2, 55.9, 55.4, 55.2, 55.1, 55.0, 52.4, 44.4, 35.9, 34.6, 34.2, 33.6,
29.7; HRMS (ESI–TOF) calcd for [C84H93N6O9S + H]+ 1361.6719,
found 1361.6752.
(2S,5S,8S,11S,14S)-1,4,7,10,13-Pentabenzyl-2,5,8,11,14-pen-
takis(4-methoxybenzyl)-1,4,7,10,13-pentaazacyclopentadecane
(3). To
tetrabenzyl-2,5,8,11,14-pentakis(4-methoxybenzyl)-13-(2-nitro-
benzenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane (18)
a stirred solution of (2S,5S,8S,11S,14S)-1,4,7,10-
(352 mg, 259 mmol) in DMF (13 mL) was added caesium
carbonate (843 mg, 2.59 mmol) and thiophenol (0.27 mL, 2.6
mmol) at 0 ◦C. After being stirred at room temperature for
12 h, the mixture was quenched with saturated aqueous sodium
thiosulfate and saturated aqueous sodium bicarbonate, and
extracted with ethyl acetate. The extract was washed with H2O
and brine, dried over magnesium sulfate, filtered and concentrated
in vacuo. The residue was purified by column chromatography on
amine silica gel, eluting with 50% ethyl acetate in hexane to afford
(2S,5S,8S,11S,14S)-1,4,7,10-tetrabenzyl-2,5,8,11,14-pentakis-(4-
methoxybenzyl)-1,4,7,10,13-pentaazacyclopentadecane (247 mg,
210 mmol, 81%) as a yellow oil.
(2S,5S,8S)-1,4,7-Tribenzyl-2,5,8-tris(4-methoxybenzyl)-1,4,7-
triazacyclononane (2). To a stirred solution of (2S,5S,8S)-1,4-
dibenzyl-2,5,8-tris(4-methoxybenzyl)-7-(2-nitrobenzenesulfonyl)-
1,4,7-triazacyclononane (16) (109 mg, 128 mmol) in DMF (6.4 mL)
was added caesium carbonate (417 mg, 1.28 mmol) and thiophenol
(66 mL, 640 mmol) at 0 ◦C. After being stirred at room temperature
for 12 h, the mixture was quenched with saturated aqueous
sodium thiosulfate and saturated aqueous sodium bicarbonate,
and extracted with ethyl acetate. The extract was washed with
H2O and brine, dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on amine silica gel, eluting with 50% ethyl
acetate in hexane to afford (2S,5S,8S)-1,4-dibenzyl-2,5,8-tris(4-
methoxybenzyl)-1,4,7-triazacyclononane (76.5 mg, 114 mmol,
89%) as a colorless oil.
To
a
stirred solution of (2S,5S,8S,11S,14S)-1,4,7,10-
tetrabenzyl-2,5,8,11,14-pentakis-(4-methoxybenzyl)-1,4,7,10,13-
pentaazacyclopentadecane (151 mg, 128 mmol) in DMF (6.4 mL)
was added caesium carbonate (417 mg, 1.28 mmol), benzyl
bromide (64 mL, 0.64 mmol) and catalytic amount of TBAI
at 0 ◦C. After being stirred at reflux for 12 h, the mix-
ture was quenched with saturated aqueous sodium bicarbon-
ate, and extracted with ethyl acetate. The extract was washed
with H2O and brine, dried over magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by col-
umn chromatography on amine silica gel, eluting with 30%
ethyl acetate in hexane to afford (2S,5S,8S,11S,14S)-1,4,7,10,13-
petrabenzyl-2,5,8,11,14-pentakis-(4-methoxybenzyl)-1,4,7,10,13-
pentaazacyclopentadecane (3) (134 mg, 106 mmol, 83%) as a yellow
To a stirred solution of (2S,5S,8S)-1,4-dibenzyl-2,5,8-tris(4-
methoxybenzyl)-1,4,7-triazacyclononane (85.7 mg, 128 mmol) in
DMF (6.4 mL) was added caesium carbonate (417 mg, 1.28 mmol),
benzyl bromide (64 mL, 640 mmol) and a catalytic amount of
◦
TBAI at 0 C. After being stirred at reflux for 12 h, the mixture
This journal is
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oil: [a]2D8 -42.7 (c 1.02 in CHCl3); IR n (neat, cm-1) 3412, 2953,
1612, 1513, 1456, 1251, 1180, 1034, 755; H NMR (400 MHz,
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1
CDCl3) d 7.37–7.06 (m, 25H, aromatic), 6.82 (d, 10H, J = 8.8 Hz,
aromatic), 6.78 (d, 10H, J = 8.8 Hz, aromatic), 3.68 (s, 15H,
OMe ¥ 5), 3.66 (d, 5H, J = 14.2 Hz, Bn), 3.06–3.00 (m, 10H), 2.97
(d, 5H, J = 14.2 Hz, Bn), 2.38–2.30 (m, 5H), 2.25–2.16 (m, 5H),
1.78–1.66 (m, 5H); 13C NMR (100 MHz, CDCl3) d 157.6, 140.1,
133.6, 130.5, 129.0, 127.9, 126.7, 113.3, 65.3, 58.0, 55.2, 52.1, 34.1;
HRMS (ESI–TOF) calcd for [C85H96N5O5 + H]+ 1266.7406, found
1266.7465.
Acknowledgements
This work was supported by a Grant-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology, Japan (No.
16350051).
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