Design and synthesis of novel amino acid-bearing macrocyclic calix[4]arenes

Article abstract of DOI:10.1081/SCC-200031049

A new family of macrocyclic calix[4]arenes (4a-d) potentially capable of chiral recognition were synthesized by incorporating the chirality inducing moieties, bis α-amino acylated polyethylene glycols, or tripeptide bis-Phe Cystine(OMe)₂ to the

Full text of DOI:10.1081/SCC-200031049

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3615–3621, 2004
Design and Synthesis of Novel Amino Acid-
Bearing Macrocyclic Calix[4]Arenes
GuoZhu Zhang,1 ZuCheng Li,1 Min Wang,1 JiaQi He,1
and JinPei Cheng1,2,
*
1Department of Chemistry, and 2State Key Laboratory of
Element-Organic Chemistry, Nankai University, Tianjin 300071, China
ABSTRACT
A new family of macrocyclic calix[4]arenes (4a–d) potentially capable of
chiral recognition were synthesized by incorporating the chirality indu-
cing moieties, bis a-amino acylated polyethylene glycols, or tripeptide
bis-Phe Cystine(OMe)2 to the lower rim.
Key Words: Calix[4]arenes; Chiral recognition; Macrocyclic
molecules.
Intensive research activities have been devoted to the design and synthesis
of macrocyclic molecules that bear good ability for chiral recognition.[1,2]
*
Correspondence: JinPei Cheng, Department of Chemistry, Nankai University, Tianjin
300071, China; E-mail: jpcheng@nankai.edu.cn or chengjp@mail.most.gov.cn.
3615
DOI: 10.1081/SCC-200031049
0039-7911 (Print); 1532-2432 (Online)
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Copyright # 2004 by Marcel Dekker, Inc.

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Zhang et al.
The main synthetic strategy for realizing this property is to immerse the active
sites in chiral surroundings derived from chiral moiety[3] In this respect, amino
acids and peptides should be good candidates for this purpose because of their
chiral inherence and biorelevance[4] On the other hand, calixarenes, the third
generation of the host cyclic molecules following crown ether and cyclodex-
trin, can serve as a versatile “platform” that can be modified by various selec-
tive receptors for ionic and small molecule recognition.[5–7] Several reports on
modifying calixarenes with chiral units have already appeared in the literature
and showed promising potential of this category of compounds in molecular
recognition, separation, and optical analysis.[8–12] Aiming at searching for
better chiral host molecules to mimic biological environment, we also con-
ducted a work on the synthesis and recognition study of certain chiral
residue modified calix[4]arenes.[6,9b,13a]
In the present communication, we wish to report the synthesis of a new
family of cyclic calix[4]arenes modified at the lower rim by L-amino acid
or peptides (4a–4d, Fig. 1). These chiral poly macrocycles may serve as
good candidates for chiral recognition and chiral catalysis.
EXPERIMENTAL
Melting points were taken on a Yanaco melting-point apparatus and were
uncorrected. 1H NMR spectra were registered on a Bruker AC-P300
Figure 1. Structures of hosts 4a–4d.

Novel Amino Acid-Bearing Macrocyclic Calix[4]Arenes
3617
spectrometer using TMS as the internal standard; chemical shifts are reported
in d values and the coupling constants (J) in hertz. Mass spectra were recorded
on a Finnigan Mat 90 and AEI MS-50/PS 30 instrument. Elemental analyses
were performed on a Perkin-Elmer 240 analytical instrument. Optical activi-
ties were measured on a WZZ-1 automatic polarimeter. Thin layer chromato-
graphy (TLC) was carried out on silica gel (60 GF254) and spots located with
ultraviolet (UV) light or iodine vapor. Dichloromethane was refluxed with
calcium hydride for 5 h and distilled. Triethylamine was dried over metal
sodium, refluxed, and then distilled.
The synthesis of 4a–4d was achieved through a one-step straightforward
procedure by reacting 2a–2d with 3. The synthesis of 2a–2d is shown in
Sch. 1. For preparation of 2a–2c, appropriate oligomers of ethylene glycols
were first reacted with NaZ-protected amino acid in the presence of equal
molar DCC and DMAP to give their bis NaZ-protected amino acid ester
derivatives. These intermediates were then N-deprotected by 5% Pd/C with
H2 in dry ethyl acetate to give 2a–2c in satisfactory overall yields. The
crude products were used in subsequent preparations without purification.
.
Tripeptide bis-Phe Cystine(OMe)2 2HCl, 2d, was prepared using a con-
vergent strategy and standard peptide coupling methods. The L-Cystine
dimethyl ester dihydrochloride was treated with two equimolar NaBoc-
protected phenylalanine in the presence of two equimolar DCC and triethyl
Scheme 1. The synthesis of 2a–2d.

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Zhang et al.
amine, then it was N-deprotected with HCl/EtOAc to afford the desired
2d (70%).
The other condensation reagent, calix[4]arene diacid dichloride 3, was
prepared according to the literature procedure;[14] the yield was 70% As
shown in Sch. 2, reaction of 3 with 2a–2d in dichloromethane in the presence
of equal mole triethylamine in highly diluted solution at below 08C provided
the corresponding lower-rim-bridged calix[4]arenes 4a–4d in moderate
yields. A representative procedure for preparation of 4b is described as
follows: A solution of calix[4]arene diacid dichloride 3 (1.5 mmol) in dry
dichloromethane (35 mL) was added dropwise to a well-stirred and
Scheme 2. The synthesis of 4a–4d.

Novel Amino Acid-Bearing Macrocyclic Calix[4]Arenes
3619
ice-cooled solution of 2b (1.5 mmol) and triethylamine (3 mmol) in dry ethyl
acetate (100 mL) over 1 h. The mixture was stirred overnight at ambient temp-
erature, then concentrated under the reduced pressure, the residue was dis-
solved in 100 mL chloroform, loaded with 0.5 g silica gel, and purified by
chromatography using a solvent mixture of dichloromethane, ethyl acetate,
and methyl alcohol as eluent on silica gel (200–300 mesh).
1
The structures of 4a–4d were confirmed by H NMR, FAB-MS, and
elemental analysis. The mass spectra indicated that the bridged calix[4]arenes
were “1 þ 1” cyclization products. Compounds 4a–4d were found to be chiral
as resulted from the chiral sub-ring on the lower rim of calix[4]arenas; such
chiral subunits made the two methylenes connected to the same phenol ring
nonequivalent.[15] The NMR data showed that the bridged methylene
protons (ArCH2Ar) appeared in two sets of doublets covering a range of d
2.8–4.8 ppm. The NMR signals of the t-butyl at the upper rim of calix[4]arene
appeared as two equal singlets at around 1 ppm. These indicated that the com-
pounds all took the cone conformation, which is consistent with that found in
previous studies.[6,13,15]
It is reported that chiral crown ethers can serve as good catalysts for
stereoselective induction in some C-C bond formation reactions[16] and as
selective host molecules for recognizing enantiomers.[17] In this work, the
L-amino acids were introduced to the crown ether system as the chiral modi-
fier. The S-S unit of cystine residue in 4d may serve as an active site in rel-
evant enantioselective reactions according to the literature.[18] The rigid
calix[4]arene skeleton should provide not only strong topological constraint
but also additional binding sites. The straightforward synthesis of these
cyclic ligands is also one advantage for their application.
To summarize, we have designed and synthesized four new calix[4]arene
derivatives 4a–4d, which have two L-amino acid units as the chiral modifiers
at the lower rim of calix[4]arene moiety. The research of their chiral recog-
nition and catalysis properties is underway in our laboratory.
EXPERIMENTAL
Compound 4a: yield, 15%; Melting point (mp) 125–1278C; [a]2D0 ¼ þ21
(c 0.3, CH2Cl2); 1H NMR (CDCl3, 300 MHz) d 9.62 (d, J ¼ 8.4, 2 H, NH), 8.14
(s, 2 H, OH), 7.03 (d, J ¼ 8.4, 4 H, ArH), 6.96 (d, J ¼ 9, 4 H, ArH), 5.24
(d, J ¼ 15, 2 H, ArOCH2), 4.49 (d, J ¼ 15, 2 H, ArOCH2), 4.82 (m, 2 H,
OCHN), 4.71 (m, 2 H, OCH2CH2O), 4.12 (m, 2 H, OCH2CH2O), 3.85
(m, 4 H, OCH2CH2O), 3.73 (m, 4 H, OCH2CH2O), 4.20 (d, J ¼ 9, 8 H,
ArCH2Ar), 4.11 (d, J ¼ 9, 8 H, ArCH2Ar), 3.51 (d, J ¼ 9, 8 H, ArCH2Ar),
3.73 (d, J ¼ 9, 8 H, ArCH2Ar), 2.11 (m, 2 H, CHMe2), 1.25 (s, 18 H, But),

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Zhang et al.
1.09 (s, 18 H, But), 0.92 (d, J ¼ 6.9, 6 H, CH3), 0.82 (d, J ¼ 6.9, 6 H, CH3);
FAB-Ms: 1077 (M þ 1)þ; Anal. Calcd for: C64H88O12N2: C, 71.35; H, 8.23;
N, 2.6; found: C, 71.37; H, 8.29; N, 2.56.
Compound 4b: yield, 12%; mp: 115–1178C; [a]2D0 ¼ þ25.0 (c 0.3,
CH2Cl2); 1H NMR (CDCl3, 300 MHz) d 9.64 (d, J ¼ 9, 2 H, NH),7.89
(s, 2 H, OH), 7.02 (s, 14 H, ArH), 6.88 (d, J ¼ 3, 4 H, ArH), 5.31 (m, 2 H,
CH), 5.12 (d, J ¼ 14, 2 H, ArOCH2), 2.93–4.65 (m, total 26 H; 12 H,
OCH2CH2O; 4 H, CH2C6H5; 2 H, ArOCH2; 8 H, ArCH2Ar), 1.28 (s, 18 H,
But), 1.04 (s, 18 H, But); FAB-Ms: 1173 (Mþ); Anal. calcd for:
C72H88O12N2: C, 73.69; H, 7.56; N, 2.39; found: C, 73.65; H, 7.54; N, 2.15.
Compound 4c: yield, 17%; mp: 110–1128C; [a]1D7 ¼ þ17.6 (c 0.34,
1
CH2Cl2); H NMR (CDCl3, 300 MHz) d 9.59 (d, J ¼ 8.1, 2 H, NH), 7.84
(s, 2 H, OH), 7.02 (s, 14 H, ArH), 6.86 (d, J ¼ 9.3, 4 H, ArH), 5.19 (m, 2 H,
CH), 5.06 (d, J ¼ 15, 2 H, ArOCH2), 3.08–4.45 (m, total 30 H; 16 H,
OCH2CH2O; 4 H, ArCH2; 2 H, ArOCH2; 8 H, CH2C6H5; 8 H, ArCH2Ar),
1.28 (s, 18 H, But), 1.03 (s, 18 H, But); FAB-Ms: 1217 (Mþ); Anal. calcd
for: C74H92O13N2: C, 73.00; H, 7.62; N 2.30; found: C, 72.95; H, 7.60; N, 2.30.
Compound 4d: yield, 25%; mp: 151–1538C; [a]2D0 ¼ 237.5 (c 0.4, CH2Cl2);
1H NMR (CDCl3, 300 MHz) d 9.34 (d, J ¼ 9, 2 H, NH-Phe),7.92 (s, 2 H, OH),
7.17 (m, 10 H, ArH), 7.03 (d, J ¼ 13.5, 4 H, ArH), 6.85 (s, 4 H, ArH),
6.24 (d, J ¼ 7.8, 2 H, NH-Cys), 5.18 (t, 2 H, CH-Benzyl), 5.02 (d, J ¼ 15, 2 H,
ArOCH2), 4.78 (t, 2 H, CHCO2Me), 4.15 (d, J ¼ 13, 2 H, ArOCH2), 4.06
(d, J ¼ 12.4, 2 H, ArCH2Ar), 3.71 (d, J ¼ 12.9, 2 H, ArCH2Ar), 3.27
(d, J ¼ 13.5, 2 H, ArCH2Ar), 2.95 (d, J ¼ 13.2, 2 H, ArCH2Ar), 3.71 (s, 6 H,
CH3), 3.21 (m, 4 H, CH2C6H5; 2H, SCH2), 3.02 (m, 2 H, SCH2), 1.28 (s, 18 H,
But), 1.02 (s, 18 H, But); FAB-Ms: 1292 (M þ 1)þ; Anal. calcd for:
C74H90O12N4S2: C, 68.81; H, 7.02; N, 4.34; found: C, 68.88; H, 7.05; N, 4.20.
ACKNOWLEDGMENTS
The financial support from the Major State Basic Research Development
Program of China (Grant No. G2000078100) and the Natural Science Foun-
dation of China (NSFC No. 20072020) is gratefully acknowledged.
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Received in the UK July 3, 2003