Chiral tetraazamacrocycles having four pendant-arms

Article abstract of DOI:10.1021/ol9005954

A chiral tetraazamacrocycle 9 having four pendant-arms was synthesized by repeating ring opening of an Ns-aziridine with secondary amines, followed by macrocyclization. The structure of 9 has been determined by single crystal X-ray diffraction analysis and NMR studies. Sugarhybrid molecules 12a-12f were synthesized based on the scaffold 9. NMR study showed that 12a-12f keep the similar conformation as 9 in solution.

Full text of DOI:10.1021/ol9005954

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2289-2292
Chiral Tetraazamacrocycles Having Four
Pendant-Arms
Seiji Kamioka,† Takashi Takahashi,† Susumu Kawauchi,‡ Hiroaki Adachi,§
Yusuke Mori,§ Kotaro Fujii,¶ Hidehiro Uekusa,¶ and Takayuki Doi*,†,§
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama,
Meguro, Tokyo 152-8552, Japan, Department of Organic and Polymeric Materials,
Tokyo Institute of Technology, Sosho, Inc., Department of Electrical, Electronic and
Information Engineering, Osaka UniVersity, CREST JST, 2-1 Yamadaoka, Suita,
Osaka, 565-0871, Japan, and Department of Chemistry and Materials Science, Tokyo
Institute of Technology, Graduate School of Pharmaceutical Sciences, Tohoku
UniVersity, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
doi_taka@mail.pharm.tohoku.ac.jp
Received March 21, 2009
ABSTRACT
A chiral tetraazamacrocycle 9 having four pendant-arms was synthesized by repeating ring opening of an Ns-aziridine with secondary amines,
followed by macrocyclization. The structure of 9 has been determined by single crystal X-ray diffraction analysis and NMR studies. Sugar-
hybrid molecules 12a-12f were synthesized based on the scaffold 9. NMR study showed that 12a-12f keep the similar conformation as 9 in
solution.
Cyclen, 1,4,7,10-tetraazacyclododecane, has been widely
studied in scientific fields as its metal complexes are utilized
for sensors, imaging and therapeutic agents.1,2 If a cyclen-
like derivative has four pendant-arms that orient to the same
face, it would have a vase-like three-dimensional structure
as a calix[4]arene scaffold.3,4 It could be applied to a novel
sensor and/or imaging agent having a molecular recognition
talent.
We designed tetraazamacrocycle 1 in which benzyl groups
† Department of Applied Chemistry, Tokyo Institute of Technology.
‡ Department of Organic and Polymeric Materials, Tokyo Institute of
Technology.
are on the nitrogen5 and alkoxybenzyl groups are on the
§ Sosho, Inc., Osaka University, Tohoku University.
¶ Department of Chemistry and Materials Science, Tokyo Institute of
Technology.
(3) (a) Hamuro, Y.; Calama, M. C.; Park, H. S.; Hamilton, A. D. Angew.
Chem., Int. Ed. 1997, 36, 2680–2683. (b) Park, H. S.; Lin, Q.; Hamilton,
A. D. J. Am. Chem. Soc. 1999, 121, 8–13. (c) Peczuh, M. W.; Hamilton,
A. D. Chem. ReV. 2000, 100, 2479–2494.
(1) Molecular and Cellular MR Imaging; Modo, M. M., Bulte, J. W. W.,
Eds.; CRC Press: Boca Raton, FL, 2007
.
(2) (a) Gunnlaugsson, T.; Leonard, J. P. Chem. Commun. 2005, 3114–
3131. (b) Bu¨nzli, J.-C. G.; Piguet, C. Chem. Soc. ReV. 2005, 34, 1048–
1077. (c) Parker, D.; Dickins, R. S.; Puschmann, H.; Crossland, C.; Howard,
(4) Far, A. R.; Shivanyuk, A.; Rebek, J. J. Am. Chem. Soc. 2002, 124,
2854–2855.
(5) (a) Hansen, G. R.; Burg, T. E. J. Heterocycl. Chem. 1968, 5, 305.
(b) Kalligeros, G. A.; Blinn, E. L. Inorg. Chem. 1972, 11, 1145–1148.
J. A. K. Chem. ReV. 2002, 102, 1977–2010
.
10.1021/ol9005954 CCC: $40.75
Published on Web 05/11/2009
 2009 American Chemical Society

cyclic skeleton with (S)-stereochemistry as pendant-arms.6
It is expected that all the alkoxybenzyl groups could be
oriented to the same face by either π-π stacking or CH-π
interaction between the benzene rings (Figure 1). We report
Scheme 1. Synthesis of Tetraazamacrocycle 9
Figure 1. Designed tetraazamacrocyclic molecules 1.
the asymmetric synthesis of tetraazamacrocycle 1 and its
spectroscopic analysis as well as X-ray single crystal
structural analysis. We initially developed the regioselective
ring-opening of aziridine 3 with secondary benzylamine 2,
both of which are readily prepared from O-methyl-L-tyrosine
in optically pure form.7 Yb(OTf)3-catalyzed8 ring-opening
of aziridine 3 was successfully achieved when an aziridine
unit was protected with a nosyl (2-nitrobenzenesulfonyl, Ns)
group (Scheme 1).9,10 The desired 4 was provided in 98%
yield as a single regioisomer. After N-benzylation of Ns-
amide 4 (BnBr/Cs2CO3), the Ns group was removed (PhSH/
Cs2CO3). The resulting secondary benzylamine was used for
the next ring-opening reaction of Ns-aziridine 3. The reaction
was performed using 0.21 equiv of Yb(OTf)3 as previously
mentioned to afford the desired 1,4,7-triazanonane 5 in 91%
yield. This three-step process, N-benzylation, removal of the
Ns group, and the ring-opening of aziridine 3, was repeatedly
performed to provide 1,4,7,10-tetraazadodecane 6. It should
be noted that the ring-opening of Ns-aziridine 3 with various
secondary benzylamines proceeded in good yields with
complete regioselectivity. Removal of the TBS groups in 6
(TBAF/THF) provided the cyclization precursor 7. Alcohol
7 was converted to the corresponding iodide (I2/PPh3/ 2,6-
di-tert-butyl-4-methylpyridine (DTBMP)/(i-Pr)2EtN), which
was immediately subjected to macrocyclization using Cs2CO3
as base.11,12 The intramolecular alkylation smoothly pro-
ceeded at 70 °C in acetonitrile-HMPA (9:1) in the presence
of 4 Å molecular sieves leading to 12-membered tet-
raazamacrocycle 8 in 94% yield from 7. The reaction was
reproducible in a 10 g-scale. Removal of the Ns group in 8
and benzylation of the resulting secondary amine furnished
the desired tetraazamacrocycle 9 in 68% yield from 8.
The 13C NMR spectrum of 9 exhibited 13 carbon signals
corresponding to the simple unit of 2-(benzylamino)-1-
(6) Synthesis, conformational analysis, and metal complexes of chiral
tetra-C-ethylcyclens have been reported. (a) Tsuboyama, S.; Tsuboyama,
K.; Higashi, I.; Yanagita, M. Tetrahedron Lett. 1970, 45, 1367–1370. (b)
Tsuboyama, K.; Tsuboyama, S.; Uzawa, J.; Kobayashi, K.; Sakurai, T.
Tetrahedron Lett. 1977, 52, 4603–4606. (c) Kobayashi, K.; Takahashi, H.;
Nishio, M.; Umezawa, Y.; Tsuboyama, K.; Tsuboyama, S. Anal. Sci. 2000,
16, 1103–1104.
(7) Experimental details are described in Supporting Information.
(8) (a) Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994,
35, 7395–7398. (b) Meguro, M.; Yamamoto, Y. Heterocycles 1996, 43,
2473–2482.
(9) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373–6374. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831–5834
(10) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron
Lett. 1997, 38, 5253–5256
.
(12) (a) Kan, T.; Fujiawara, A.; Kobayashi, H.; Fukuyama, T. Tetra-
hedron 2002, 58, 6267–6276. (b) An, H.; Cummins, L. L.; Griffey, R. H.;
Bharadwaj, R.; Haly, B. D.; Fraser, A. S.; Wilson-Lingardo, L.; Risen, L. M.;
.
(11) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 1993,
125, 8112–8113
.
Wyatt, J. R.; Cook, P. D. J. Am. Chem. Soc. 1997, 119, 3696–3708
.
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Org. Lett., Vol. 11, No. 11, 2009

(4-methoxyphenyl)propyl. The structure of tetraazamacro-
cycle 9 was unambiguously determined by single crystal
X-ray diffraction analysis shown in Figure 2.13 It was found
by magnetic anisotropic effects derived from CH-π interac-
tion whereas no significant effect would be observed for Hb
(+0.02 ppm) (Table 1). 1H NMR analysis of 9 using various
Table 1. Calculation of the Chemical Shifts of Ha and Hb in 9
entry
9a (ppm)
4-methylanisolea (ppm)
∆ (ppm)
1
2
Ha
Hb
6.41
6.96
H-3
H-2
7.33
6.94
-0.92
0.02
a Chemical shift was predicted based on DFT calculation [B3LYP/
6-311G(2d,p)/B3LYP/6-31G(d,p)].
deuterated solvents exhibited large high-field shifts for Ha
(-0.58 ppm in CDCl3, -0.50 ppm in CD2Cl2 and -0.46
ppm in benzene-d6) and small shifts for Hb [-0.07 ppm in
CDCl3, -0.04 ppm in CD2Cl2 and +0.16 ppm in benzene-
d6] comparing with the chemical shifts of 4-methylanisole
in the corresponding solvents (Table 2). The tendency of
Figure 2. X-ray single crystal structure of 9.
that four methoxyphenyl groups are oriented to the top face
of the macrocyclic ring and four N-benzyl groups are oriented
to the bottom face of the macrocycle. Additionally, four
4-methoxyphenyl groups are in a direction perpendicular to
each other. The calculated distance of 3.402 Å between Ha
at the 2-position of the 4-methoxyphenyl groups shown in
Scheme 1 and the adjacent phenyl ring of the 4-methox-
yphenyl groups suggests CH-π interactions. On the basis
of the X-ray crystal structure of 9, the NMR chemical shifts
of Ha and Hb in 9 and H-3 and H-2 in 4-methylanisole were
calculated by the differences in the values from tetrameth-
ylsilane with a GIAO method at the B3LYP/6-311+G(2d,p)//
B3LYP/6-31G(d,p) level using Gaussian 03.14 It was sug-
gested that large high-field shift (-0.92 ppm) for Ha
compared with H-3 in 4-methylanisole would be expected
1
Table 2. H NMR analysis of 9
a
a
a
CDCl3 (∆b)
CD2Cl2 (∆b)
benzene-d6 (∆b)
entry
(ppm)
(ppm)
(ppm)
Ha
Hb
a
6.57 (-0.58)
6.80 (-0.07)
6.62 (-0.50)
6.79 (-0.04)
6.53 (-0.46)
6.97 (0.16)
1H NMR was measured at 25 °C. b Differences of the chemical shifts
of Ha and Hb in 9 compared with those of the corresponding H-3 and H-2
in 4-methylanisole measured in the respective solvents.
large high-field shift of Ha and small shift for Hb is in good
accordance with the results from the theoretical calculation
described above. Therefore, it is suggested that the confor-
mation of 9 shown in Figure 2 is also dominant in solution
as well as in the single crystal.
(13) The single crystal was obtained from a 1 mL solution of benzene
and hexane (65:35) containing 1 mg of 9. We investigated 44 combinations
of mixed solvents (CH2Cl2, CHCl3, CCl4, PhH) and (C5H12, C6H14, Et2O,
EtOAc, THF, 1,4-dioxane, toluene, MeOH, EtOH, i-PrOH, t-BuOH) for
crystallization. The single crystal X-ray diffraction data were collected on
a Rigaku R-AXIS RAPID imaging plate diffractometer with MoKR radiation
(λ ) 0.71075 Å). Crystal data for 9: C68 H76 N4 O4, C6 H6, Mr )1091.44,
Crystal System ) Triclinic, Space group ) P1 (no. 1), Lattice Parameters
a ) 10.4685(19) Å, b ) 14.642(3) Å, c ) 20.231(5) Å, R ) 79.047(9)°,
ꢀ ) 89.633(9)°, γ ) 81.328(7)°, V ) 3009.0(10) Å3, Z ) 2, T ) 93 K, R1
) 0.0444[ I > 2σ (I); 11424 refs.], wR ) 0.1160(all data; 13580 refs.), Gof
) 1.063. CCDC 706437 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/
data_request/cif.
(14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A.; Jr. Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision D.02; Gaussian, Inc.: Wallingford, CT, 2004.
Next, we investigated a method for the modification of
the RO groups in 1 using the new scaffold, tetraazamacro-
cycle 9. Since it is well-known that cluster glycosides exhibit
affinity enhancement,15 we planned the synthesis of the
sugar-hybrid molecules 12 having various glycosides utilizing
copper-catalyzed 1,3-dipolar cycloaddition (Scheme 2).16,17
Removal of all the methyl ethers with BBr3, followed by
O-alkylation of the resulting phenols with propargyl bromide
provided the alkyne-containing tetraazamacrocycle 10 in 51%
overall yield. The 1,3-dipolar cycloaddition of tetrayne 10
to azido-containing glycosides 11 proceeded at room tem-
perature in the presence of CuI in THF and (i-Pr)2EtN except
for a lactoside at 50 °C. The products were obtained as a
mixture of its Cu(II) complexes, which were treated with
cyclen in refluxing THF to remove the Cu(II) ion and all
acetyl groups in the glycosides. As depicted in Table 3,
(15) Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 321–327.
(16) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599
(17) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057–3064
.
.
Org. Lett., Vol. 11, No. 11, 2009
2291

Scheme 2
.
Synthesis of Sugar-Hybrid Molecules 12
Table 3. Copper-Catalyzed 1,3-Dipolar Cycloaddition of 10 and
11 and the H NMR Chemical Shifts of the Hc and Hd in 12
1
a Differences of the chemical shifts of Hc and Hd in 12 compared with
those of the 4-methylanisole-containing sugar unit. b 1H NMR spectra were
measured at 80 °C in DMSO-d6. c 1H NMR spectra were measured at 100
°C in DMSO-d6. d Reaction was performed at 50 °C.
sugar-hybrid molecules 12 were exclusively obtained in high
yields (79-88% in 2 steps). The conformation of sugar-
hybrid molecules 12 was elucidated by the 1H NMR analysis.
If sugar-hybrid molecules 12 have kept the same conforma-
tion as 9 like four 4-alkoxyphenyl groups are at right angles
to each other, high-field shift for Hc will be observed by
magnetic anisotropic effects derived from CH-π interaction
and chemical shift for Hd will not be affected comparing to
the 4-methoxyphenol-containing sugar unit. Indeed, 1H NMR
analysis using deuterated DMSO exhibited high-field shifts
(-0.25 to -0.35 ppm) for Hc and no significant shift (up to
+0.02 ppm) for Hd (Table 3). These results suggested that
all sugar-hybrid molecules 12 have the similar conformation
that four methoxyphenyl groups face on one side of the
macrocyclic ring without relying on the species of sugars,
the stereochemistry of anomeric positions and the number
of sugars.
In summary, we have demonstrated the efficient synthesis
of tetraazamacrocycle 9 utilizing ring-opening of an Ns-
aziridine with secondary benzylamines and intramolecular
alkylation with the Ns-amides as key steps. The structure of
tetraazamacrocycle 9 was unambiguously determined by
single crystal X-ray diffraction analysis. Comparing the high-
field shift of Ha in 1H NMR spectrum of 9 with the expected
shift by theoretical calculation of magnetic anisotropic effects
based on the X-ray structure, it is suggested that the solid-
state conformation is dominant in solution. Hybridization of
9 with various glycosides was performed using regioselective
1
copper-catalyzed 1,3-dipolar cycloaddition. The H NMR
study suggests that the sugar-hybrid tetraazamacrocycles 12
have kept the similar conformation as 9 in solution.
Therefore, it is expected that various molecular recognition
sites could be introduced to 1 utilizing this method. Further
study for metal chelation and introduction of cyclic peptides
to 1 is in progress.
Acknowledgment. We thank Prof. Shigeki Kuwata
(Tokyotech) and Prof. Hajime Iwamoto (Niigata Univ.) for
helpful discussion for structure elucidation. This work was
supported by a Grant-in-Aid from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (No.
16350051).
Supporting Information Available: Experimental details
and NMR spectra of 2-10 and 12a-12f. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9005954
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Org. Lett., Vol. 11, No. 11, 2009