Syntheses of novel chiral calix[4]crown: Lariat calix[4]-1,3-aza-crowns with chiral amino acid groups as branched chains

Article abstract of DOI:10.1080/00397911.2010.518329

The first examples of lariat calix[4]-1,3-aza-crowns with chiral amino acid groups as branched chains (5a and 5b) were designed and synthesized via a 1+1 addition reaction of calix[4]-1,3-substituted benzaldehyde derivative (4) and amino acid hydrazide derivatives (3a and 3b) in yields of 70% and 75%, respectively. The preliminary extraction experiments suggested that hosts 5a and 5b possessed good complexation abilities for-amino acids.

Full text of DOI:10.1080/00397911.2010.518329

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Syntheses of Novel Chiral Calix[4]crown:
Lariat Calix[4]-1,3-aza-crowns with
Chiral Amino Acid Groups as Branched
Chains
Fafu Yang a b , Zhiqiang Liu a , Zhisheng Huang a , Hongyu Guo a &
Biqiong Hong a
a College of Chemistry and Materials Science, Fujian Normal
University , Fuzhou , China
b Fujian Key Laboratory of Polymer Materials , Fuzhou , China
Accepted author version posted online: 30 Jun 2011.Published
online: 01 Jun 2011.
To cite this article: Fafu Yang , Zhiqiang Liu , Zhisheng Huang , Hongyu Guo & Biqiong Hong (2011)
Syntheses of Novel Chiral Calix[4]crown: Lariat Calix[4]-1,3-aza-crowns with Chiral Amino Acid Groups
as Branched Chains, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:23, 3485-3490, DOI: 10.1080/00397911.2010.518329
To link to this article: http://dx.doi.org/10.1080/00397911.2010.518329
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Synthetic Communications1, 41: 3485–3490, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518329
SYNTHESES OF NOVEL CHIRAL CALIX[4]CROWN:
LARIAT CALIX[4]-1,3-AZA-CROWNS WITH CHIRAL
AMINO ACID GROUPS AS BRANCHED CHAINS
Fafu Yang,1,2 Zhiqiang Liu,1 Zhisheng Huang,1
Hongyu Guo,1 and Biqiong Hong1
1College of Chemistry and Materials Science, Fujian Normal University,
Fuzhou, China
2Fujian Key Laboratory of Polymer Materials, Fuzhou, China
GRAPHICAL ABSTRACT
Abstract The first examples of lariat calix[4]-1,3-aza-crowns with chiral amino acid groups
as branched chains (5a and 5b) were designed and synthesized via a 1 þ 1 addition reaction
of calix[4]-1,3-substituted benzaldehyde derivative (4) and amino acid hydrazide deriva-
tives (3a and 3b) in yields of 70% and 75%, respectively. The preliminary extraction
experiments suggested that hosts 5a and 5b possessed good complexation abilities for
a-amino acids.
Keywords Amino acid; aza; calix[4]crown; chiral; lariat
INTRODUCTION
Calixarenes are important supramolecular building blocks, which can be
modified by introducing suitable functional groups and=or structural groups to
create a specific interaction and target guest molecules.[1,2] In particular, the chiral
recognition of calixarene derivatives has attracted increasing research interest
because of potential applications in enantiomer discrimination processes.[3–5] To
obtain chiral calixarenes, the facile methods introduced chiral units on calix rims.
Therefore, a large number of chiral calixarenes have been synthesized using chiral
units as functional groups, such as amino acids,[6] amino alcohol,[7] peptides,[8]
alkaloids,[9] chiral amines,[10] pinene-like units,[11] glycidyl,[12] and guanidinium
Received December 18, 2009.
Address correspondence to Fafu Yang, College of Chemistry and Materials Science, Fujian
Normal University, Fuzhou, China. E-mail: yangfafu@fjnu.edu.cn
3485

3486
F. YANG ET AL.
groups.[13] On the other hand, some chiral calix[4]crowns were reported using chiral
spacers as bridging chains, such as binaphthyl amine,[11] diphenyl amine,[14]
dinaphthol ether,[5,15] and glucoside,[16] From these reports, it could be concluded
that the enantiomer recognition capabilities depended on the species, structures,
and conformations of chiral calix[4]arenene. In this article, we report the facile
synthesis of a novel chiral calix[4]crown: the lariat calix[4]-1,3-aza-crown with chiral
amino acid groups as branched chains.
The synthetic route is shown in Figure 1. L-leucine and L-Isoleucine were
converted to their ester derivatives 1a and 1b. Reacting compounds 1a and 1b with
p-toluene sulfonyl chloride afforded compounds 2a and 2b. Then, by ammonolysis
of compounds 2a and 2b with hydrazine hydrate, amino acid hydrazide derivatives
3a and 3b were prepared in ideal yields.[17] By reacting p-tert-butylcalix[4]arene with
p-tosyloxyethoxyl-benzaldehyde (mol. ratio ¼ 1:2) in a K2CO3=MeCN system for
48 h, calix[4]-1,3-substituted benzaldehyde derivative 4 was obtained.[18] By stirring
compound 4 with 3 in CHCl3-EtOH (V=V 1:1) at room temperature, novel chiral
calix[4]crown 5a and 5b were prepared via 1 þ 1 addition. They were purified con-
veniently by crystallization in CHCl3-MeOH in yields of 70% and 75%, respectively.
=
It was interesting that no Schiff base (containing C N bonds) condensation pro-
ducts were obtained in this reaction condition under any molar ratio of compounds
4 and 3. when these reactions were performed under refluxing conditions, the reac-
tion results became complicated and no purified compounds were separated success-
fully. To obtain Schiffbase condensation product, we also tried to react compound 1
with 4 directly, but no condensation reaction happened under any kind of reaction
conditions, which might be attributed to the low reaction activities of amino groups
in compound 1. To the best of our knowledge, compounds 5a and 5b were the first
examples of lariat calix[4]-1,3-aza-crowns with chiral amino acid groups as branched
chains.
Figure 1. The synthetic route of the title compounds.

NOVEL CHIRAL CALIX[4]CROWN
3487
Table 1. Extracting percentages (%E) of a-amino acids from water into CHCl3
Amino acids
Gly
Trp
His
Lys
Ile
Arg
Pro
Thr
5a
5b
15.3
13.1
48.3
56.8
17.6
23.4
24.8
18.6
26.4
23.3
10.9
14.2
18.2
13.7
23.3
24.6
The structures and conformations of novel chiral calix[4]arenes 5a and 5b were
characterized by electrospray ionization–mass spectrometry (ESI-MS) infrared (IR)
spectra, 1H NMR, and elemental analyses. The ESI-MS spectra of compound 5a and
5b showed clearly molecular base peaks at 1282.0 (MKþ) and 1243.3 (Mþ), respect-
ively, which indicated that these reactions were 1 þ 1 intermolecular addition
reactions, not Schiffbase condensation. This deduction was also supported by the
=
IR spectra of 5a and 5b, in which the C O absorption peak of compound 4 at
=
1694 cmꢀ1 disappeared, but no C N (Schiffbases) absorption peak appeared. In
1
1
the H NMR spectra of compounds 5a and 5b, all H NMR signals were assigned
to protons properly. Two singlets (1:1) for the tert-butyl groups, and one AB system
for the methylene bridges of the calix[4]arene skeleton indicated that the calix[4]arene
moiety adopted the cone conformation.[9–11,17]
To evaluate the complexation abilities of novel hosts 5a and 5b, the preliminary
extraction experiments for a-amino acids were studied. The results are summarized
in Table 1. It can be seen that compounds 5a and 5b exhibited reasonable extraction
abilities toward tested a-amino acids. Moreover, both 5a and 5b showed good
extraction selectivity for tryptophan. The extraction percentage of host 5b for tryp-
tophan was as high as 56.8%. The similar complexation abilities of 5a and 5b might
be attributed to their similar ‘‘pre-organized’’ bridging-crown structures. Further
complexation studies, such as enantiomer discrimination, are under investigation.
EXPERIMENTAL
Melting points are uncorrected. 1H NMR spectra were recorded in CDCl3 on a
Bruker-ARX 500 instrument at room temperature, using tetramethylsilane (TMS) as
an internal standard. ESI-MS spectra were obtained on a DECAX-30000 LCQ Deca
XP mass spectrometer. Elemental analyses were performed on a Vario EL III
Elemental Analyzer. IR spectra were recorded on a Perkin-Elmer 1605 Fourier
transform (FT)–IR spectrometer as KBr pellets. Calix[4]-1,3-substituted benzal-
dehyde derivative 4[18] and the hydrazide derivatives of L-leucine and L-iso-leucine
(3a and 3b),[19] were prepared according to the published procedures. All solvents
were purified by standard procedures.
Novel Chiral Calix[4]crowns 5a and 5b
Under an N2 atmosphere, the mixture of compound 4 (1 mmol, 0.94 g) and
amino acid derivative 3 (1.1 mmol, 0.33 g) was stirred in 40 mL CHCl3-EtOH (V=V
1:1) at room temperature for 24 h. Thin-layer chromatography (TLC) detection
showed the disappearance of materials. After distilling off the solvent under reduced
pressure at room temperature, the residue was treated with 15 mL MeOH. The yellow

3488
F. YANG ET AL.
precipitation was then separated out. The precipitation was recrystallized by CHCl3-
MeOH, novel chiral calix[4]crowns 5a and 5b were then obtained in the yields of 70%
and 75%, respectively.
27
Compound 5a. Mp 243–245 ꢁC; ½aꢂD ¼ þ3:7 (c 0.20, CHCl3); 1H NMR
(500 MHz, CDCl3) d: 1.0 [s, 18 H, C(CH3)3], 1.03–1.09 [m, 6 H, C(CH3)2], 1.28 [s,
18 H, C(CH3)3], 2.20–2.45 (m, 4 H, ArCH3 and CHMe2), 1.38–1.46 (m, 2 H,
CCH2C), 3.30 (d, J ¼ 16.5 Hz, 4 H, ArCH2Ar), 3.33 (bs, 1 H, CHCO), 4.20 – 4.30
(m, 10 H, OCH2 and ArCH), 4.36 (d, J ¼ 16.5 Hz, 4 H, ArCH2Ar), 6.75 – 7.95 (m,
20 H, ArH), 8.38 (bs, 2 H, OH), 8.90 (bs, 2 H, OH), 9.78 (s, 1 H, NH), 9.83 (s, 1
H, NH); IR (KBr) n: 3429 (OH and NH), 1602 (CONH) cmꢀ1; MS m=z (%):
1282.0 (MKþ, 100). Anal. calcd. for C75H93O11N3S: C, 72.38; H, 7.53; N, 3.37.
Found: C,72.29; H, 7.62; N, 3.49.
27
Compound 5b. Mp 228–231 ꢁC; ½aꢂD ¼ þ3:1 (c 0.20, CHCl3); 1H NMR
(500 MHz, CDCl3) d: 1.01 [s, 18 H, C(CH3)3], 1.04–1.10 [m, 6 H, C(CH3)2], 1.29
[s, 18 H, C(CH3)3], 1.18–1.27 (m, 2 H, CH2Me), 2.18–2.43 (m, 4 H, ArCH3 and
CHMe), 3.31 (d, J ¼ 16.0 Hz, 4 H, ArCH2Ar), 3.30 (bs, 1 H, CHCO), 4.18–4.30
(m, 10 H, OCH2 and ArCH), 4.35 (d, J ¼ 16.0 Hz, 4 H, ArCH2Ar), 6.71 – 7.92 (m,
20 H, ArH), 8.37 (bs, 2 H, OH), 8.88 (bs, 2 H, OH), 9.72 (s, 1 H, NH), 9.94 (s, 1
H, NH); IR (KBr) n: 3430 (OH and NH), 1604 (CONH) cmꢀ1; MS m=z (%):
1243.3 (Mþ, 100). Anal. calcd. for C75H93O11N3S: C, 72.38; H, 7.53; N, 3.37. Found:
C, 72.27; H, 7.59; N, 3.47.
The Extraction Experiments of a-Amino Acids
According to the reported methods[20,21], 3 mL of chloroform solution contain-
ing calixarene derivative (1.0 ꢃ 10ꢀ4 M) and 3 mL of aqueous solution containing
amino acids (1.0 ꢃ 10ꢀ4 M) were placed in a flask. The mixture was shaken for
5 min and stored for 2 h at room temperature. The extraction ability was not affected
by further shaking, indicating that the equilibrium had been attained within 2 h. The
concentrations of amino acids after extraction were assessed by classical ninhydrin
tests.[22] The extracting percentage (E%) was determined by the decrease of the
amino acid concentration in the aqueous phase: E% ¼ f([Pic]blank ꢀ [Pic]water)=
[Pic]blankg ꢃ 100, where [Pic]blank denoted the amino acid concentrations in the aque-
ous phase after extraction with pure chloroform and [Pic]water denoted the amino
acid concentrations in the aqueous phase after extraction with chloroform solution
containing calixarene derivatives as extractants. An average of two independent
experiments was carried out. The measuring error for amino acid extraction test data
was less than 2%. Control experiments showed that the extraction percentages for
amino acids were less than 0.3% in the absence of the calixarene derivatives.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China
(No. 20402002) and Fujian Natural Science Foundation of China (No.
2009J01019) are greatly acknowledged.

NOVEL CHIRAL CALIX[4]CROWN
3489
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