Synthesis of a Series of Novel Chiral Aromatic Heterocyclic Macrocycles Containing L-Amino Acid and 2,5-Bisphenyl-1,3,4-triazole Subunits

Article abstract of DOI:10.1080/00397910902730879

An array of novel chiral aromatic heterocyclic macrocycles, which may show potential enantiomeric recognition to variable D- and L-amino acids, were synthesized in acceptable yield. The desired macrocycles 3a-c and 4a-c were obtained via the condensation

Full text of DOI:10.1080/00397910902730879

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Synthesis of a Series of Novel
Chiral Aromatic Heterocyclic
Macrocycles Containing
L-Amino Acid and 2,5-
Bisphenyl-1,3,4-triazole
Subunits
Hongwu Zhao a , Rugang Zhong a , Hong Yan a , Wei
Yang a , Jin Cui a & Wenting Hua b
a College of Life Science and Bio-engineering ,
Beijing University of Technology , Beijing, China
b Department of Chemistry , Peking University ,
Beijing, China
Published online: 03 Aug 2009.
To cite this article: Hongwu Zhao , Rugang Zhong , Hong Yan , Wei Yang , Jin Cui
& Wenting Hua (2009) Synthesis of a Series of Novel Chiral Aromatic Heterocyclic
Macrocycles Containing L-Amino Acid and 2,5-Bisphenyl-1,3,4-triazole Subunits,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:17, 3038-3044
To link to this article: http://dx.doi.org/10.1080/00397910902730879
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Synthetic Communications1, 39: 3038–3044, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730879
Synthesis of a Series of Novel Chiral Aromatic
Heterocyclic Macrocycles Containing L-Amino
Acid and 2,5-Bisphenyl-1,3,4-triazole Subunits
Hongwu Zhao,1 Rugang Zhong,1 Hong Yan,1 Wei Yang,1
Jin Cui,1 and Wenting Hua2
1College of Life Science and Bio-engineering,
Beijing University of Technology, Beijing, China
2Department of Chemistry, Peking University, Beijing, China
Abstract: An array of novel chiral aromatic heterocyclic macrocycles, which may
show potential enantiomeric recognition to variable D- and L-amino acids, were
synthesized in acceptable yield. The desired macrocycles 3a–c and 4a–c were
obtained via the condensation reaction of chiral diamine intermediates 2a–c with
2,5-bis(o-chloroformylphenyl)-1,3,4-triazole 5 in a presence of Et3N in a highly
diluted dichloromethane solution at room temperature.
Keywords: 2,5-Bisphenyl-1,3,4-triazole, chiral macrocycles, enantiomeric
recognition
Chiral recognition exists ubiquitously in many biological phenomena
such as ligand–receptor interaction, antigen–antibody interaction, and
enzyme-catalyzed biochemical transformation. Therefore, insight into
the mechanism of these processes will help develop some efficient biomi-
metic reactions, chiral catalysts, and chiral stationary phases. Since the
chiral crown ethers were first utilized by Cram and his coworkers to
recognize enantiomers of small chiral molecules in an efficient way,[1–3]
many novel macrocycles with diverse functionalities and parent
Received September 23, 2008.
Address correspondence to Hongwu Zhao, College of Life Science and
Bio-engineering, Beijing University of Technology, Beijing 100124, China.
E-mail: hwzhao@bjut.edu.cn
3038

Synthesis of Chiral Macrocycles
3039
skeletons have been extensively investigated with respect to asymmetric
catalysis,[4,5] enzymatic mimics,[6–8] chiral separation,[9–11] and the areas
related to chiral recognition. In general, the optical active macrocycles,
which exhibit perfect chiral recognition to enantiomers, always feature
the rigid conformation and strong nonbonding interaction with chiral
guest molecules. Furthermore, the incorporation of some heterocyclic
fragments, for example, pyridine, oxadiazole, triazole, and so on, are
most responsible for the enhanced chiral recognition of some structurally
diverse macrocycles.[12–16]
Herein, we report the design and synthesis of a series of novel
enantiopure macrocycles containing pyridine, 2,5-bisphenyl-1,3,4-
triazole, and L-amino acid residues as well (Schemes 1 and 2). It was
envisioned that the suitable installment of pyridine and 2,5-
bisphenyl-1,3,4-triazole subunit would confer a rigid conformation to
the synthesized macrocycles. The L-amino acid fragments would serve
as chiral source to induce chiral conformation, which will play a key role
in the chiral recognition. Along with pyridine and 2,5-bisphenyl-1,3,
4-triazole subunit within the frame structure of the synthesized
chiral macrocycles, the peripheral ester and amide functionalities may
function as potential hydrogen-bonding donors and acceptors. The key
Scheme 1. Synthesis of macrocycles 3a, 3b, 4a, and 4b.

3040
H. Zhao et al.
Scheme 2. Synthesis of macrocycles 3c and 4c.
intermediate chiral diamines dihydrobromide 2a–c were prepared as
previously described starting from 2,6-pyridinedimethanol and carboxy-
benzyl (Cbz)-protected amino acids.[17] The cyclization reaction of the
intermediates 2a–c with 2,5-bis(o-chloroformyl phenyl)-1,3,4-triazole
5[18] produced [1 þ 1] cyclization products 3a–c and [2 þ 2] cyclization
products 4a–c simultaneously. It is obvious that the chemical yield of
the [1 þ 1] cyclization product is greater than that of the corresponding
[2 þ 2] cyclization product. It has been demonstrated by elemental analy-
sis that all the synthesized chiral macrocycles tend to form complexes
with methanol molecules in the variable molar ratio. The reaction condi-
tions significantly affect the chemical yield of the final macrocyclic pro-
duct. The highly diluted reaction solution and slow addition of the
2,5-bis(o-chloroformyl phenyl)-1,3,4-triazole 5 to a solution of 2a–c in
dichloromethane solvent at 0ꢀC are preferred to obtain the desired
macrocyclic products in acceptable yield.
In summary, we have first synthesized and characterized a series of
novel chiral macrocycles 3a–c and 4a–c in a concise way. The detailed
evaluation of chiral recognition of the titled macrocycles to a wide range
of chiral small molecules, among which include D- and L-amino acids,
will be reported in due course.

Synthesis of Chiral Macrocycles
EXPERIMENTAL
3041
Infrared (IR) spectra were obtained on a Bruker Vector 22
1
instrument. H NMR spectra were recorded on a Bruker ARX 400
spectrometer. Chemical shifts were indicated in d values (ppm)
downfield from internal tetramethylsilane (TMS). Multiplicities were
recorded as s (singlet), d (doublet), t (triplet), and m (multiplet). Fast
atom bombardment (FAB)–mass spectra (MS) were obtained on a
VG-ZAB-HS mass spectrometer. Elemental analysis was carried out
on Carlo-Erba-106 or Elementar Vario EL instruments. Melting
points were taken on a XT-4 melting-point apparatus and are uncor-
rected. Optical rotations were measured on a Perkin-Elmer 241 MC
polarimeter. Commercial-grade solvents were used without further
purification unless specified. CH2Cl2 was distilled from calcium
hydride. Starting materials were purchased from the Acros Chemical
Company unless otherwise noted.
Preparation of Chiral Macrocycles 3a and 4a
At 0ꢀC under N2, a solution of 2,5-bis(o-chloroformylphenyl)-1,3,4-
triazole 5 (320.4 mg, 0.9 mmol) in dried CH2Cl2 (10.0 mL) was added
to a well-stirred solution of 2a (400.0 mg, 0.9 mmol) and Et3N
(0.6 mL, 3.7 mmol) in anhydrous CH2Cl2 (120.0 mL) dropwise via
syringe. After addition, the resulting reaction mixture was stirred for
another 12 h. The precipitated white solid was removed by filtration,
and the filtrate was concentrated by evaporator under reduced pressure.
The crude product was purified by flash-column chromatography on
silica gel (eluent: CH2Cl2=EtOAc=petroleum=MeOH ¼ 2:1:0.1:0.25) to
afford white solid 3a (110.0 mg, 22% yield) and white solid 4a
(30.0 mg, 3% yield) respectively. Chiral macrocycle 3a: [a]25 ¼ þ20.9
D
1
(c ¼ 1.0, CH2Cl2); mp 124–126ꢀC; H NMR (400MHz, CDCl3): d 8.51
(br, 1 H), 7.94 (d, 2 H), 7.79 (t, 1 H), 7.61 (br, 6 H), 7.39 (d, 2 H), 5.22
(d, 2 H), 5.05 (t, 2 H), 4.57 (t, 2 H), 1.35 (d, 6 H); IR (KBr): 3482, 3415,
2362, 1749, 1735, 1651, 1638, 1558, 1540, 1455cmꢁ1; MS (FABþ):
M=Z ¼ 555 (M þ H)þ. Anal. calcd. for C29H26N6O6ꢂCH3OH (586): C,
61.43; H, 5.15; N, 14.33; O, 19.09. Found: C, 61.79; H, 4.90; N, 14.13; O,
19.18.
Chiral macrocycle 4a: [a]25 ¼ ꢁ12.0 (c ¼ 1.0, CH2Cl2); mp
D
1
238–240ꢀC; H NMR (400 MHz, CDCl3): d 13.96 (s, 2 H), 8.89 (s, 2
H), 8.61 (s, 2 H), 7.92 (d, 2 H), 7.80 (d, 2 H), 7.67 (t, 2 H), 7.57 (br, 6
H), 7.43 (m, 4 H), 7.28 (m, 6 H), 5.14 (d, 8 H), 4.60 (d, 4 H), 1.34 (s,
12 H); IR (KBr): 3419, 2381, 1748, 1739, 1651, 1540, 1455, 1168 cmꢁ1
;

3042
H. Zhao et al.
MS (FABþ): M=Z ¼ 1109 (M þ H)þ. Anal. calcd. for C58H52N12O12ꢂ1.5
CH3OH (1156): C, 61.76; H, 5.05; N, 14.52; O, 18.67. Found: C, 62.02;
H, 4.90; N, 14.25; O, 18.83.
Preparation of Chiral Macrocycles 3b and 4b
Macrocycles 3b and 4b were prepared by employing the same procedure
as that of 3a and 4a. Chiral macrocycle 3b: white solid. Yield: 20%;
1
[a]25 ¼ þ 23.3 (c ¼ 1.0, CH2Cl2); mp 148–150ꢀC; H NMR (400 MHz,
D
CDCl3): d 13.34 (br, 1 H), 7.99–8.99 (br, 2 H), 7.98 (br, 2 H), 7.79 (t,
1 H), 7.56 (br, 6 H), 7.38 (d, 2 H), 4.14–5.19 (br, 4 H), 4.38 (t, 2 H),
2.16 (br, 2 H), 0.94 (d, 12 H). IR (KBr): 3418, 2363, 1750, 1735, 1651,
1558, 1540, 1456, 1185 cmꢁ1; MS (FABþ): M=Z ¼ 611 (M þ H)þ. Anal.
calcd. for C33H34N6O6ꢂ0.5 CH3OH (626): C, 64.21; H, 5.79; N, 13.41;
O, 16.59. Found: C, 64.61; H, 5.78; N, 13.32; O, 16.29.
Chiral macrocycle 4b: white solid. Yield: 8%; [a]25 ¼ ꢁ13.2 (c¼ 1,
D
1
CH2Cl2); mp 138–140ꢀC; H NMR (CDCl3, ppm): d 13.71–14.05 (br, 2
H), 8.71 (br, 4 H), 7.81 (s, 4 H), 7.67 (t, 2 H), 7.48 (br, 12 H), 7.29 (d, 4 H),
5.13 (s, 8 H), 4.38 (t, 4 H), 2.12 (m, 4 H), 0.91 (m, 24 H). IR (KBr): 3418,
2390, 2362, 1749, 1651, 1558, 1456, 1186cmꢁ1; MS (FABþ): M=Z ¼ 1221
(Mþ H)þ. Anal. calcd. for C66H68N12O12ꢂCH3OH (1252): C, 64.21; H,
5.79; N, 13.41; O, 16.59. Found: C, 64.18; H, 5.67; N, 13.36; O 16.79.
Preparation of Chiral Macrocycles 3c and 4c
Chiral macrocycles 3c and 4c were prepared by following the same
procedure as that of compounds 3a and 4a. Chiral macrocycle 3c: white
solid. Yield: 8%; [a]25 ¼ þ22.6 (c ¼ 1, CH2Cl2); mp 180–182ꢀC; 1H
D
NMR (400 MHz, CDCl3) d 14.59 (br, 1 H), 7.98 (br, 2 H), 7.79 (br, 5 H),
7.36 (br, 4 H), 5.64 (br, 4 H), 4.92 (d, 2 H), 2.95 (br, 2 H), 2.84 (br, 2 H),
1.99 (br, 3 H), 1.47 (br, 5 H); IR (KBr): 3419, 2389, 1749, 1734, 1651,
1558, 1456, 1420 cmꢁ1; MS (FABþ): M=Z ¼ 607 (M þ H)þ. Anal. calcd.
for C33H30N6O6ꢂCH3OH (638): C, 63.94; H, 5.37; N, 13.16; O, 17.54. Found:
C, 64.03; H, 5.35; N, 12.81; O, 17.81.
Chiral macrocycle 4c: white solid. Yield: 2%; [a]25 ¼ ꢁ16.3 (c ¼
D
1
1, CH2Cl2); mp 198–200ꢀC; H NMR (400 MHz, CDCl3) d 13.95–14.26
(br, 2 H), 7.95 (br, 4H), 7.63–7.54 (br, 18 H), 5.09 (m, 8 H), 4.82 (t, 2 H),
4.02 (d, 2 H), 3.53 (br, 3 H), 3.13 (br, 2 H), 2.98 (br, 3 H), 2.19–1.65
(m, 16 H); IR (KBr): 3416, 2384, 1749, 1652, 1638, 1420, 1175cmꢁ1; MS
(FABþ): M=Z ¼ 1213 (M þ H)þ. Anal. calcd. for C66H60N12O12ꢂ1.5
CH3OH (1260): C, 64.28; H, 5.27; N, 13.33; O, 17.12. Found: C, 64.37;
H, 5.37; N, 12.98; O, 17.28.

Synthesis of Chiral Macrocycles
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