A concise, modular synthesis of chiral peraza-macrocycles using chiral aziridines

Article abstract of DOI:10.1021/ol025513k

(equation presented) Novel chiral peraza-macrocycles were synthesized from chiral aziridines as a common building block. Efficient syntheses of chiral [26]-N₆, [12]-N₄, [9]-N₃, and [14]-N₄ systems were accomplis

Full text of DOI:10.1021/ol025513k

ORGANIC
LETTERS
2002
Vol. 4, No. 6
949-952
A Concise, Modular Synthesis of Chiral
Peraza-Macrocycles Using Chiral
Aziridines
B. Moon Kim,* Soon Mog So, and Hye Jin Choi
Center for Molecular Catalysis, School of Chemistry and Molecular Engineering,
Seoul National UniVersity, Seoul 151-747, Korea
kimbm@snu.ac.kr
Received January 5, 2002
ABSTRACT
Novel chiral peraza-macrocycles were synthesized from chiral aziridines as a common building block. Efficient syntheses of chiral [26]-N ,
6
[12]-N , [9]-N , and [14]-N systems were accomplished.
4
3
4
Aza-crown macrocycles1 had been reported even before the
advent of crown ethers and continued to be the subject of
intense research.2 Peraza-crown macrocycles containing
transition metals have been utilized as artificial enzyme
models.3 In particular, the synthesis and application of cyclam
and cyclen derivatives have been the focus of much interest
due to their ability to bind transition and lanthanide metal
ions.4 Application of 1,4,7-triazacyclononane derivatives has
also been reported as redox metalloenzyme mimics for
oxidative organic transformations and artificial metallo-
hydrolases for the cleavage of DNA or RNA.3b,h,m,n,4b,c,i
Therefore, the development of efficient synthesis for peraza-
(1) (a) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Aza-Crown
Macrocycles; John Wiley & Sons: New York, 1993. (b) Parker, D. In
Macrocycle Synthesis; Parker, D. Ed.; Oxford University Press: Oxford,
1996.
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M. Crown Compounds: Their Characteristics and Applications; Elsevier:
New York, 1982.
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ReV. 1996, 96, 721. (b) Tolman, W. B. Acc. Chem. Res. 1997, 30, 227. (c)
Jang, B. B.; Lee, K. P.; Min, D. H.; Suh, J. H. J. Am. Chem. Soc. 1998,
120, 12008. (d) You, J. S.; Yu, X. Q.; Li, X. S.; Yan, Q. S.; Xie, R. G.
Tetrahedron: Asymmetry 1998, 9, 119. (e) Williams, N. H.; Takaskki, B.;
Wall, M.; Chin, J. Acc. Chem. Res. 1999, 32, 485. (f) Chen, K.; Que, L.,
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Kitamura, H.; Koike, T. Chem. Eur. J. 1999, 5, 3113. (h) de Vos, D. E.;
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Hearn, M. T. W.; Spiccia, L. Org. Lett. 2001, 3, 2855. (n) Sissi, C.; Rossi,
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Ed. Engl. 1996, 35, 2211 (c) Zondervan, C.; Hage, R.; Feringa, B. L. Chem.
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10.1021/ol025513k CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/26/2002

macrocycles has received much attention. However, there
are only a handful of chiral aza-macrocycles reported to date,
mostly in the form of oxaza-macrocycles, which have been
derived from naturally occurring oxygen-containing optically
active starting materials such as amino alcohols and carbo-
hydrates.5 For the synthesis of achiral peraza-macrocycles
such as cyclen and cyclam derivatives, a modular approach
has been successfully adopted.1 However, conventional
modular approaches cannot be applied to the synthesis of
chiral peraza-macrocycles, unless proper chiral building
blocks are available. Toward this goal, we have previously
reported an efficient, modular synthesis of chiral peraza-
macrocycles 1 and 2 as shown in Figure 1.6 Compounds 1
corresponding chiral amino alcohols and have been employed
as convenient starting materials for various chiral ligands.8
Indeed this new aziridine-based methodology could be
extended to the construction of a variety of chiral peraza-
macrocycles. Herein we report on the highly efficient
synthesis of chiral peraza-macrocycles equipped with various
R groups and having a variety of ring sizes such as [26]-N6,
[12]-N4, [9]-N3, and [14]-N4, Synthesis of chiral [26]-N6
system (1) could be achieved in five steps from the chiral
aziridine derivative as shown in Scheme 1. p-Nitroben-
Scheme 1a
a (a) NsCl, TEA, CH3CN; (b) PMBNH2, CH3CN; (c) (i) R,R′-
dibromo-p-xylene, CH3CN, K2CO3, (ii) n-propane thiol, CH3CN,
LiOH‚H2O.
Figure 1.
zenesulfonyl (nosyl)-protected chiral aziridine 6 was prepared
from (S)-valinol according to a known method.8a,c
and 2 (R ) CO2R′, Y ) CH2Ar) were prepared from a
common building block, cyclic sulfamidate 3.7
Opening of the chiral aziridine 6 with 0.5 equiv of
p-methoxybenzylamine provided the triamine unit 7 in a
remarkably good (83%) yield. For the construction of
compound type 1, a proper bridging unit, which would
facilitate a 2 + 2 Richman-Atkins-type coupling,9 would
be required for connecting the two chiral triamine units.
Synthesis of macrocycle 8 was accomplished from the
coupling reaction between triamine 7 and R,R′-dibromo-p-
xylene in a dilute solution in CH3CN followed by removal
of the nosyl protecting groups employing n-propanethiol10
in 53% overall yield. Construction of chiral, conformationally
constrained cyclen analogues is of much interest since the
In this case, the chiral sulfamidate 3 was an effective
“alanine â-cation synthon”. We envisioned that chiral
aziridine derivatives 5 could be used as yet another alanine
â-cation synthon in place of the cyclic sulfamidate 3 for the
preparation of various chiral peraza-macrocycles such as 1,
2, and 4. Chiral aziridines can be easily prepared from the
(5) (a) Moi, M. K.; Meares, C. F. J. Am. Chem. Soc. 1988, 110, 6266.
(b) Craig, A. S.; Helps, I. M.; Jankowski, K. J.; Parker, D.; Beeley, N. R.
A.; Boyce, B. A.; Eaton, M. A. W.; Millican, A.. T.; Millar, K.; Phipps,
A.; Rhind, S. K.; Harrison, A.; Walker, C. J. Chem. Soc., Chem. Commun.
1989, 794. (c) Cox, J. P. L.; Jankowski, K. J.; Kataky, R.; Parker, D.; Beeley,
N. R. A.; Boyce. B. A.; Eaton, M. A. W.; Millar, K.; Millican, A. T.;
Harrison, A.; Walker, C. J. Chem. Soc., Chem. Commun. 1989, 797. (d)
Wagler, T. R.; Burrows, C. J. Tetrahedron Lett. 1988, 29, 5091. (e) Cox,
J. P. L.; Craig, A. S.; Helps, I. M.; Jankowski, K. J.; Parker, D.; Eaton, M.
A.; Millican, A. T.; Millar, K.; Beeley, N. R. A.; Boyce, B. A. J. Chem.
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Madhusudanan, K. P.; Roy, R.; Nagaraj, R.; John, G. B. J. Am. Chem. Soc.
1997, 119, 11578. (g) Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron:
Asymmetry 1999, 10, 367. (h) Tripier, R.; Siri, O.; Rabiet, F.; Denat, F.;
Guilard, R. Tetrahedron Lett. 1999, 40, 79. (i) Achmatowicz, M.; Jurczak,
J. Tetrahedron: Asymmetry 2001, 12, 487. (j) Kon, N.; Takemura, H.;
Otsuka, K.; Tanoue, K.; Nakasima, S.; Yasutake, M.; Tani, K.; Kimoto, J.;
Shinmyozu, T.; Inaza, T. J. Org. Chem. 2000, 65, 3708. (k) Lee, C. W.;
Jung, E. J.; Ahn, K. H.; Kim, K. S. J. Org. Chem. 2000, 65, 7225. (l) Won,
D. H.; Lee, C. H. Tetrahedron Lett. 2001, 42, 1969. (m) Bhattacharyya,
T.; Nilsson, U. J. Tetrahedron Lett. 2001, 42, 2873.
(8) (a) Cernerud, M.; Skrinning, A.; Bergere, I.; Moberg, C. Tetrahedron:
Asymmetry 1997, 8, 3437. (b) Tanner, D.; Johansson, F.; Harden, A.;
Andersson, P. G. Tetrahedron 1998, 54, 15731. (c) Nelson, S. G.; Peelen,
T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121. 9742. (d) Holte, P. T.;
Wijgergangs, J. P.; Thijs, L.; Zwanenburg, B. Org. Lett. 1999, 1, 1095. (e)
Nelson, S. G.; Kim, B. K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122.
9318. (f) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed. 2000, 39,
1323. (g) Shi, M.; Jiang, J. K.; Feng, Y. S. Tetrahedron: Asymmetry 2000,
11, 4923. (h) Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2001, 66,
5801.
(9) (a) Richman, J. E.; Atkins, T. J. J. Am. Chem. Soc. 1974, 96, 2268.
(b) Atkins, T. J.; Richman, J. E.; Oettle, W. F. Org. Synth. 1976, 58, 86;
CV6, 652. (c) Hoye, R. C.; Richman, J. E.; Dantas, G. A.; Lightbourne, M.
F.; Shinneman, L. S. J. Org. Chem. 2001, 66, 2722.
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36, 6373. (b) Wuts, P. G. M.; Northuis, J. M. Tetrahedron Lett. 1999, 39,
3889.
(6) Kim, B. M.; So, S. M. Tetrahedron Lett. 1999, 40, 7687.
(7) Kim, B. M.; So, S. M. Tetrahedron Lett. 1998, 39, 5381.
950
Org. Lett., Vol. 4, No. 6, 2002

cyclen derivatives have been often employed in the design
of artificial hydrolytic enzymes.3 As shown in Scheme 2,
From coupling of triamine 11 with 2,6-pyridine dimethanol
bismethanesulfonate followed by deprotection of all nosyl
groups, we were able to obtain the unprotected compound
12 in 47% yield.
A chiral triamine unit could be used as yet another building
block for the synthesis of a chiral [9]-N3 peraza-macrocycle
from N-p-toluenesulfonylated (N-tosyl) chiral aziridine (13)12
as depicted in Scheme 3. Bistosylated chiral triamine 14 was
Scheme 2a
Scheme 3a
a (a) (i) LiN3, CH3CN, (ii) H2, Pd/C, MeOH, (iii) 13, CH3CN;
(b) CbzCl, TEA, CH2Cl2; (c) (i) 1,2-ethanediol bis(p-toluene-
sulfonate), DMF, Cs2CO3, (ii) H2, Pd/C, MeOH; (d) concentrated
H2SO4, heat.
a (a) (i) 2,6-Pyridine dimethanol (bismethanesulfonate), CH3CN,
K2CO3, (ii) n-propanethiol, CH3CN, LiOH‚H2O; (b) (i) LiN3,
CH3CN, (ii) PPh3, H2O, THF; (c) (i) 6, CH3CN, (ii) NsCl, TEA,
CH2Cl2; (d) (i) 2,6-pyridinedimethanol (bismethanesulfonate),
CH3CN, K2CO3, (ii) n-propane thiol, CH3CN, LiOH‚H2O.
obtained in the same way as shown in Scheme 2 in good
yield through opening with azide, reduction, and aziridine
opening in 74% overall yield. Protection of the free amine
of 14 with a carbobenzyloxy (Cbz) group was accomplished
to give 15 in 83% yield. Construction of chiral peraza-
macrocycle 16 using ethylene diol bistosylate according to
the Richman-Atkins protocol was accomplished in 59%
yield under high dilution conditions.
Deprotection of the tosyl groups from 16 yielded the chiral
cyclic triamine 17 in 70% yield. The structure of 17 was
confirmed through X-ray crystallographic analysis of its
nickel complex.13 An X-ray structure of a Ni cation and two
molecules of 17 ([Ni‚(17)2]Cl2‚H2O) was obtained as de-
[12]-N4 systems 9 and 12 containing a pyridine ring were
synthesized from the triamine intermediate 7 and 11,
respectively. For the construction of compound 9, a 1:1
cyclization process was utilized between 7 and 2,6-pyridine
dimethanol bismethanesulfonate to furnish the desired com-
pound in 49% yield after deprotection of the nosyl groups
(Method A). However, with possible foreseeable complica-
tion in the removal of the PMB group on the nitrogen in
mind, we decided to prepare unprotected compound 12
through a different route as depicted in Scheme 2 (Method
B).
The chiral aziridine 6 was treated with lithium azide to
provide a ring-opened product, which was reduced by PPh3
to give compound 10 in 75% overall yield.11 Using com-
pound 10 as a nucleophile for the opening of the aziridine
6, another triamine unit 11 was obtained in 85% yield. This
route opens up a possibility of preparing unsymmetrically
substituted chiral peraza-macrocycles of compound 12 type.
(11) Boger, D. L.; Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994,
116, 8544.
(12) The synthesis of chiral aziridines from N-tosyl-2-amino alcohols
was reported: (a) Barry, M. B.; Craig, D. Synlett 1992, 42. (b) Preparation
of (S)-N-tosyl-2-alkylaziridine (13, 18) from free amino alcohols: To a
solution of L-amino alcohol (8 mmol) and TEA (3.5 equiv) in dry CH3CN
(80 mL) was slowly added p-TsCl (2 equiv) and DMAP (0.1 equiv) at 0
°C with stirring for 30 min. The reaction mixture was stirred at room
temperature for 4-5 h. The solvent was removed under reduced pressure
and dissolved with EtOAc (100 mL). The organic layer was washed with
brine (40 mL × 2). The organic layer was dried over anhydrous MgSO4
and filtered, and the filtrate was concentrated under reduced pressure. The
crude product was purified on a silica gel column chromatography to give
white solid 13 (1.62 g, 82% yield) and 18 (1.21 g, 73% yield).
Figure 2. X-ray structure of [Ni‚(17)2]Cl2‚H2O
Org. Lett., Vol. 4, No. 6, 2002
951

picted in Figure 2. Complexes of a metal and achiral 1,4,7-
triazacyclononane have been well-studied, and numerous
metal complexes of this and related macrocyclic ligands have
been synthesized.14 In the X-ray structure, the constrained
ligand imposes a trigonal distortion since the ethylene bridge
is not large enough to allow the Ni(II)-linked nitrogen atoms
to span idealized 90° bond angles. For that reason, the
structure is observed to be an octahedral-like Ni(II) complex
of rigid tridentate chiral ligand 17.
In conclusion, we have developed a novel and concise
synthetic methodology for the construction of chiral peraza-
macrocycles through efficient opening of chiral aziridine
derivatives. By the judicious choice of dielectophiles, we
were able to obtain 1:1 or 2:2 cyclization products. We are
currently investigating the scope of this synthetic method
for the preparation of other classes of chiral peraza-
macrocycles and the utilization of the chiral peraza-macro-
cycles in the context of chiral artificial metalloenzymes and
molecular recognition.
Scheme 4a
Acknowledgment. We thank the Korea Science and
Engineering Foundation through Center for Molecular Ca-
talysis at Seoul National University for financial support.
S.M.S. and H.J.C. acknowledge Brain Korea 21 Fellowship
from the Ministry of Education, Korea.
Supporting Information Available: Experimental pro-
cedures, spectral characterization of all new compounds, and
crystallographic data for [Ni‚(17)2]Cl2‚H2O. This material
is available free of charge via the Internet at http://pubs.acs.org.
a (a) (i) 1,3-Diaminopropane, DMF, (ii) TsCl, TEA, CH2Cl2; (b)
1,3-propanediol bis(p-toluenesulfonate), DMF, Cs2CO3.
Utilization of 0.5 equiv of R,ω-diamines in the opening
of chiral aziridine 1812 followed by tosylation successfully
led to the preparation of chiral tetraamine 19 in 66% overall
yield. Construction of a chiral cyclam derivative 20 was
accomplished in 72% yield through reaction of 20 with 1,3-
dielectrophile under high dilution conditions.
OL025513K
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(13) See Supporting Information for the crystal data of [Ni‚(17)2]Cl2‚
H2O.
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Org. Lett., Vol. 4, No. 6, 2002