The synthesis of new chiral dioxocyclens

Article abstract of DOI:10.1081/SCC-120020204

This article reports a short and efficient synthesis of chiral dioxocyclens starting from natural amino acids. Four new chiral dioxocyclens that contain different substituents at the chiral center were obtained. These dioxocyclens could not only be used f

Full text of DOI:10.1081/SCC-120020204

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The Synthesis of New Chiral Dioxocyclens
Quan Yuan a , Peng Xue a , Maohai Fang a , Enqin Fu a & Chengtai Wu a
a Department of Chemistry , Wuhan University , Wuhan, P.R. China
Published online: 17 Aug 2006.
To cite this article: Quan Yuan , Peng Xue , Maohai Fang , Enqin Fu & Chengtai Wu (2003) The Synthesis of New Chiral
Dioxocyclens, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:11, 1911-1916, DOI: 10.1081/SCC-120020204
To link to this article: http://dx.doi.org/10.1081/SCC-120020204
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 11, pp. 1911–1916, 2003
The Synthesis of New Chiral Dioxocyclens
Quan Yuan, Peng Xue, Maohai Fang,
*
Enqin Fu, andChengtai Wu
Department of Chemistry, Wuhan University,
Wuhan, P.R. China
ABSTRACT
This article reports
a
short and efficient synthesis of chiral
dioxocyclens starting fromnatural amino acids. Four new chiral
dioxocyclens that contain different substituents at the chiral center
were obtained. These dioxocyclens could not only be used for chiral
recognition, but provide a feasible way for the synthesis of chiral
cyclens.
Key Words: Chiral dioxocyclens; Synthesis; Amino acids.
One of the most interesting and challenging topics is chiral recogni-
tion in the field of molecular recognition because enantiomeric recog-
nition is a fundamental property of biological molecules. A better
*Correspondence: Enqin Fu, Department of Chemistry, Wuhan University,
Wuhan 430072, China; Fax: 0086-27-87686757; E-mail: fueq@chem.whu.edu.cn.
1911
DOI: 10.1081/SCC-120020204
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1912
Yuan et al.
understanding of the interactions occurring in chiral recognition may
help developing new methods for asymmetric synthesis and chromatog-
raphic resolution of enantiomers.[1]
Many kinds of host molecules, such as natural amino acids, cyclo-
dextrins and their derivatives, proteins, carbohydrates and synthetic
chiral macrocycles have been used for enantiomeric recognition and
separation. The synthetic chiral macrocyclic compounds have been recog-
nized as successful and promising chiral selectors mainly because of their
complexation ability and inherent reduced flexibility comparing to their
acyclic counterparts.[2] However, the preparation of these molecules is
often fraught with difficult procedures, low yields and laborious purifica-
tions. Only a few reports about the synthesis and application for chiral
perazamacrocycles appeared.[3]
We have previously reported the synthesis of chiral macrocyclic dioxo-
polyamine derived from L-proline.[4] NMR experiments were undertaken
to assess the chiral recognition property of these compounds.[5] The
results revealed that these chiral macrocyclic dioxopolyamines have dif-
ferent enantiomeric discrimination abilities to the mandelic acid and its
derivatives. It suggested that this type of dioxocyclens might be promis-
ing hosts for enantiomeric recognition, especially for neutral molecules
that contain carboxylic group.[6] Here, we report the synthesis of four
new dioxocyclens derived fromother amino acids. The synthetic route to
compound 1–3 is shown in Sch. 1.
The use of amino acids as building blocks not only allows a
convenient introduction of chiral unit into macrocyclic ring, which is
Scheme 1.

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New Chiral Dioxocyclens
1913
expected to gain more steric rigidity at chiral carbon that may be helpful
in chiral recognition, but different substituents at the chiral center will
help to know more about chiral recognition mechanism. Furthermore,
amino acids could provide charged and polar functionalities, which
improves water-solubility and provides sites for hydrogen-bonding or
p–p interaction.
This synthetic approach has some advantages as that all products
were synthesized without N-protection. Mild conditions were chosen to
synthesize the intermediates 2 and only mono-substituted products were
obtained.
EXPERIMENTAL
General Methods
Infrared spectra were recorded on a Nicolet Avatar 360 FT-IR
spectrometer. 1H NMR spectra were recorded in CDCl3 on Varian
Mercury VX300 FT-NMR spectrometer (Varian, USA) operating at
298K. Chemical shifts were reported in parts per million (ppm) relative
to tetramethylsilane (TMS). 13C NMR spectra were recorded at 75 MHz
on the same instrument in CDCl3. Mass spectra were recorded on
ZAB 3F-HF spectrometer. Optical rotations were measured with a
Perkin–Elmer Model 341LC polarimeter using the sodium D line
at 589 nm.
L-Amino acids were purchased from Shanghai Chemical Reagents
Company, China National Medicines Group.
N-Methoxycarbonylmethyl-L-alanine Methyl Ester (2a)
L-Alanine (4.45 g, 0.050 mol) was converted to L-alanine methyl ester
hydrochloric salt (1a) as described in literature.[7] Then methyl chloro-
acetate (5.43 g, 0.050 mol) and the L-alanine methyl ester were added to a
suspension of anhydrous K2CO3 (10 g) in CH3CN (75 mL), stirred at
50ꢀC for 2 days in the atmosphere of nitrogen. The precipitate was
filtered off and the filtrate was concentrated under reduced pressure, a
colorless oil N-methoxyl carbonylmethyl-L-alanine methyl ester 2a was
obtained by distillation in vacuo, 5.10 g (yield 58%), 1H NMR (300 MHz,
CDCl3): ꢀ ¼ 4.17–4.30 (q, 1H, HNCHCO), 3.70 (s, 6H, 2OCH3),
3.36–3.52 (q, 2H, HNCH2CO), 2.69 (br, 1H, NH), 1.33–1.39 (d, 3H,
CH3). 2b–2d were prepared by the same method as that described for 2a.

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1914
Yuan et al.
N-Methoxycarbonylmethyl-L-phenylalanine methyl ester (2b): 2b was
1
given as a yellow oil, 9.51 g (yield 66%), H NMR (300 MHz, CDCl3):
ꢀ ¼ 7.17–7.31 (m, 5H, Ph), 3.66–3.67 (2s, 6H, 2OCH3), 3.57–3.60 (t, 1H,
HNCHCO), 3.30–3.46 (q, 2H, HNCH2CO), 2.96–3.03 (m, 2H, PhCH2).
N-Methoxycarbonylmethyl-L-valine methyl ester (2c): 2c was given as a
colorless oil, 8.50 g (yield 84%), 1H NMR (300 MHz, CDCl3): ꢀ ¼
3.74–3.75 (2s, 6H, 2OCH3), 3.38–3.68 (q, 2H, HNCH2CO), 3.08–3.10 (d,
1H, HNCHCO), 1.95–2.1 (m, 1H, CH(CH3)2 ), 0.96–0.98 (d, 6H, 2CH3).
N-Methoxycarbonylmethyl-L-ilenine methyl ester (2d): 2d was given as
a pale yellow oil, 5.72 g (yield 53%), 1H NMR (300 MHz, CDCl3);
ꢀ ¼ 3.72 (s, 6H, 2OCH3), 3.31–3.46 (q, 2H, HNCH2CO), 3.14–3.16
(d, 1H, HNCHCO), 1.91 (br, 1H, NH), 1.69–1.74 (m, 1H, CH2CHCH3),
1.17–1.59 (m, 2H, CHCH2CH3), 0.90–0.93 (d, 6H, 2CH3).
3-Methyl-(3S)-1,4,7,10-tetraazacyclododecane-2,6-dione (3a): 2a (8.75 g,
0.050 mol) was dissolved in absolute MeOH (100 mL) and then added to
a solution of diethylenetriamine (5.15 g, 0.05 mol) in 300 mL absolute
MeOH, stirred at 40ꢀC in nitrogen atmosphere for 5 days, then the solvent
was evaporated, and the white macrocycle 3a was afforded as white
powder by recrystallization fromCH 3CN. 1.04 g (yield 10%). M.p.
20
D
181–183ꢀC, ½ꢁŠ ¼ þ 23.71 (c ¼ 0.8, MeOH), 1H NMR (300 MHz,
CDCl3): ꢀ ¼ 7.55 (br, 1H, CONH), 7.38 (br, 1H, CONH), 3.17–3.24 (q,
3J ¼ 6.9 Hz, 1H, NHCHCO), 3.38–3.68 (m, 4H, 2CONHCHH,
NCH2CO), 2.58–3.11 (m, 6H, 2CONHCHH, 2NHCH2), 1.83 (br, 2H,
3
2NH), 1.34–1.36 (d, J ¼ 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
ꢀ ¼ 175.0, 172.0, 62.3, 53.9, 45.3, 45.1, 38.3, 37.6, 20.6; IR (KBr, cmꢁ1):
ꢂ ¼ 3424, 3312, 3288, 3088, 2930, 1652, 1559, 1437, 1379, 1150; MS (FAB):
215 [M þ 1]þ, Anal. calcd. for C9H18N4O2: C, 50.5; H, 8.5; N, 26.2; Found:
C, 50.6; H, 8.1; N, 25.4.
Compound 3b–3d were prepared by the same method as that
described for 3a.
3-Benzyl-(3S)-1,4,7,10-tetraazacyclododecane-2,6-dione (3b): The crude
product was recrystallization fromCH 3CN to give 3b as a white powder,
20
1.82 g (yield 16%). M.p. 192–194ꢀC, ½ꢁŠ ¼þ 40.34 (c ¼ 1.0, MeOH),
D
1H NMR (300 MHz, CDCl3): ꢀ ¼ 7.54 (br, 1H, CONH), 7.49 (br, 1H,
CONH), 7.26–7.42 (m, 5H, Ph), 3.27–3.64 (m, 5H, 2CONHCHH,
NHCH2CO, 1H, NHCHCO), 3.03–3.22 (m, 2H, 2CONHCHH),
2.64–3.01 (m, 6H, 2NHCH2, PhCH2), 1.94 (br, 2H, 2NH); 13C NMR
(75 MHz, CDCl3); ꢀ ¼ 173.7, 172.0, 137.3, 129.3(2C), 127.5, 67.5, 57.3,
45.3, 45.0, 39.9, 38.4, 37.6; IR (KBr, cmꢁ1): ꢂ ¼ 3449, 3321, 3287, 3082,
2918, 1651, 1559, 1379, 1372, 1298, 1150; MS (FAB): 291 [M þ 1]þ,
Anal. calcd. for C15H22N4O2: C, 62.1; H, 7.6; N, 19.3; Found: C, 61.6;
H, 7.3; N, 19.3.

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New Chiral Dioxocyclens
1915
3-Isopropyl-(3S)-1,4,7,10-tetraazacyclododecane-2,6-dione (3c). The
crude product was recrystallization fromCH CN to give 3c as a white
3
powder, 1.50 g (yield 12%). M.p. 201–203ꢀC, ½ꢁŠ ¼ þ 39.11 (c ¼ 1.0,
20
D
1
MeOH), H NMR (300 MHz, CDCl3): ꢀ ¼ 7.69 (br, 1H, CONH), 7.30
(br, 1H, CONH), 3.04–3.77 (m, 6H, NHCH2CO, 2CONHCH2),
2.67–2.99 (m, 5H, NHCHCO, 2NHCH2), 1.86 (br, 2H, 2NH), 1.61–2.12
(m, 1H, CH3CHCH3), 0.97–1.05 (m, 6H, 2CH3); 13C NMR (75 MHz,
CDCl3): ꢀ ¼ 173.9, 171.9, 72.5, 54.7, 45.7, 45.3, 38.1, 31.7, 19.7, 18.5;
IR (KBr, cmꢁ1): ꢂ ¼ 3441, 2926, 1654, 1562, 1384, MS (FAB): 243
[M þ 1]þ, Anal. calcd. for C11H22N4O2: C, 54.5; H, 9.2; N, 23.1; Found:
C, 53.8; H, 9.2; N, 23.3.
3-sec-Butyl-(3S)-1,4,7,10-tetraazacyclododecane-2,6-dione (3d). The
crude product was recrystallization fromCH CN to give 3d as a white
3
powder, 1.47 g (yield 11%). M.p. 213–215ꢀC, ½ꢁŠ ¼ þ 22.32 (c ¼ 1.0,
20
D
1
MeOH), H NMR (300 MHz, CDCl3): ꢀ ¼ 7.63 (br, 1H, CONH), 7.26
(br, 1H, CONH), 2.98–3.71 (m, 6H, NCH2CO, 2CONHCH2),
2.60–2.97 (m, 5H, 2NHCH2, NHCHCO), 1.72–1.78 (m, 3H, 2NH,
CH2CHCH3) 1.08–1.60 (m, 2H, CHCH2CH3), 0.89–0.97 (m, 6H, 2CH3);
13C NMR (75 MHz, CDCl3): ꢀ ¼ 174.1, 172.1, 71.4, 54.7, 45.5, 45.1, 38.4,
37.9, 37.9, 25.3, 15.9, 11.6; IR (KBr, cmꢁ1): ꢂ ¼ 3443, 3319, 3283, 2965,
1650, 1558, 1457, 1381, 1141; MS (FAB): 257 [M þ 1]þ, Anal. calcd. for
C12H24N4O2: C, 56.2; H, 9.4; N, 21.9; Found: C, 56.0; H, 9.1; N, 21.4.
ACKNOWLEDGMENT
This work was supported by Natural Science Foundation of Hubei
Province, China, and partly by a grant fromThe Education Ministry of
China for the visiting scholar to the Key Laboratory of Bioorganic
Chemistry and Molecular Engineering at Beijing University.
REFERENCES
1. Zhang, X.X.; Bradshaw, J.S.; Izatt, R.M. Enantionmeric recognition
of amine compounds by chiral macrocyclic receptors. Chem. Rev.
1997, 97, 3313–3361.
2. Bhattachatyya, T.; Nilsson, U.J. An efficient and convenient route
towards water-soluble, chiral and amphiphilic macrocycles.
Tetrahedron Lett. 2001, 42, 2873–2875.
3. (a) Kim, B.M.; So, S.M. A short synthesis of chiral perazmacrocycles
through opening of cyclic sulfamidates. Tetrahedron Lett. 1999, 40,

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1916
Yuan et al.
7687–7690 and references therein; (b) Achmatowicz, M.; Jurczak, J.
The synthesis of L-proline derived tetraazamacrocyclic ligands of C2
symmetry via intramolecular ester aminolysis. Tetrahedron:
Asymmetry 2001, 12, 111–119.
4. Fang, M.; Fu, E.; Yuan, Q.; Xue, P.; Wu, C.; Chen, J. A short
synthesis of chiral macrocyclic dioxopolyamines derived from
L-Proline. Syn. Commun (accepted ).
5. Fang, M. The synthesis of chiral macrocyclic dioxopolyamines and
application for chiral recognition. The Master Thesis of Organic
Chemistry, Whuhan University, 2001.
6. Yuan, Q.; Fu, E.; Wu, X.; Fang, M.; Xue, P.; Wu, C.; Chen, J.
A convenient synthesis of chiral dioxocyclens and application as
chiral solvating agent. Tetrahedron Lett. 2002, 43, 3935–3937.
7. Elliott, R.L.; Kopecka, H.; Lin, N.H.; He, Y.; Garvey, D.S. A short,
efficient synthesis of the novel cholinergic channel activator, ABT
418, from L-Proline. Synthesis 1995, 772–774.