Synthesis and structure of lower rim C-linked N-tosyl peptidocalix[4]arenes

Article abstract of DOI:10.1021/jo034275j

Chiral p-tert-butylcalix[4]arenes functionalized at the lower rim with amino acid residues have been prepared. The ¹H and ¹³C NMR spectra indicate that the macrocycles preferably adopt a cone conformation. Calix[4]arenes bearing amin

Full text of DOI:10.1021/jo034275j

Syn th esis a n d Str u ctu r e of Low er Rim C-Lin k ed N-Tosyl
P ep tid oca lix[4]a r en es
Sofiane Ben Sdira, Caroline P. Felix, Marie-Be´atrice A. Giudicelli, Pascal F. Seigle-Ferrand,
Monique Perrin, and Roger J . Lamartine*
LACE, CNRS UMR 5634, Universite´ Claude Bernard-Lyon 1, 43 bd du 11 Novembre 1918,
F-69622 Villeurbanne Cedex, France
r.lamartine@cdlyon.univ-lyon1.fr
Received March 3, 2003
Chiral p-tert-butylcalix[4]arenes functionalized at the lower rim with amino acid residues have
1
been prepared. The H and 13C NMR spectra indicate that the macrocycles preferably adopt a cone
conformation. Calix[4]arenes bearing amino acid moieties were prepared as a class of receptors
selective for anions that are bound through hydrogen bonding with the NH group. The association
constants are dependent on the nature of the substituents at the lower rim. Derivative 9 shows
the strongest complexation and the largest selectivity for N-tosyl-(L)-alaninate. Finally, a preliminary
X-ray crystal study of the difunctionalized receptor 6f shows the “flattened cone” conformation in
the solid state.
In tr od u ction
metric induction properties. Many approaches have been
developed with amino acids, especially the recent results
presented by Lazzarotto et al. which represent a novel
class of chiral receptors in that the amino acid units are
linked to the calix[4]arene platform through their carboxy
groups. The synthesis of calix[4]arenes bridged at the
upper rim with small peptides is described. They show
interesting in vitro antimicrobial activity5 toward Gram-
positive bacteria. Meanwhile M. Ziniæ and co-workers
gave clear evidence for the intra- and intermolecular
hydrogen-bonded organization of the calix[4]arene amino
acid derivatives.6 Very limited data are available in the
literature for the upper7 or lower rim8 C-linked pepti-
docalixarene 1,3-disubstituted (amino acid or dipeptide)
derivatives that describe the possibility of formation of
dimers through intermolecular hydrogen bonds. Amide
groups introduced into the upper9-14 or lower rim11of
calixarenes, which are able to form intramolecular hy-
drogen bonding, give strong conformational stability of
the calixarene substructure.15
Calixarenes and their derivatives have been exten-
sively used in the past few years as receptors to recognize
a wide variety of ions or inorganic and organic guest
molecules, forming host-guest or supramolecular com-
plexes.1
Many calixarene chemists focus their interest on the
syntheses of chiral analogues, which are expected to act
as synthetic enzymes. Their syntheses have so far been
carried out by simply attaching chiral residues to the
upper or lower rim of the calixarene skeleton and using
the inherent chirality of their structures.2
It would be interesting to incorporate amino acid or
peptide moieties into calixarenes to achieve the chirally
modified macrocyclic ligands.3,4 These chiral macrocyclic
derivatives may serve as good candidates in future
studies of chiral recognition, chiral catalysis, and asym-
(1) See, for example: (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713. (b) Gutsche, C. D. Calixarenes Revisited In Monographs
in Supramolecular Chemistry ; Stoddart, J . F., Ed.; The Royal Society
of Chemistry: Cambridge, UK, 1998. (c) Pochini, A.; Ungaro, R. In
Comprehensive Supramolecular Chemistry; Vo¨gtle, F., Ed.; Pergamon
Press: Oxford, UK, 1996; Vol. 2, p 103. (d) Calixarenes 2001; Asfari,
Z., Bo¨hmer, V., Harrowfield, J ., Vicens, J ., Eds.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 2001.
(2) (a) Arimura, T.; Kawabata, H.; Matsuda, T.; Muratmatsu, T.;
Satoh, H.; Fujio, K.; Manabe, O.; Shinkai, S. J . Org. Chem. 1991, 56,
301. (b) Ikada, A.; Nagasaki, T.; Shinkai, S. J . Phys. Org. Chem. 1992,
5, 699. Nagasaki, T.; Tajiri, Y.; Shinkai, S. Recl. Trav. Chim. Pays-
Bas 1993, 112, 407. Iwamoto, K.; Shimzu, H.; Araki, K.; Shinkai, S. J .
Am. Chem. Soc. 1993, 115, 3997.
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1994, 116, 2611. (b) Casnati, A.; Fabbi, M.; Pochini, A.; Sansone, F.;
Ungaro, R.; Di Modugno, E.; Tarzia, G. Bioorg. Med. Chem. Lett. 1996,
6, 2699. (c) Pen˜a, M. S.; Zhang, Y.; Warner, I. M. Anal. Chem. 1997,
69, 3239. (d) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, M.; Pochini,
A.; Ugozzoli, F.; Ungaro, R. Eur. J . Org. Chem. 1998, 897 and
references therein.
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36, 555. (b) Pen˜a, M. S.; Zhang, Y.; Thibodeaux, S.; McLaughlin, M.
L.; De la Pen˜a, A. M.; Warner, I. M. Tetrahedron Lett. 1996, 37, 5841.
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Ungaro, R.; Di Modugno, E.; Tarzia, G. Bioorg. Med. Chem. Lett. 1996,
6, 2699.
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J . 2000, 6, 442.
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Ungaro, R. Eur. J . Org. Chem. 2001, 595.
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J . Chem. 2001, 10, 1330.
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Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1090.
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Chem. 1994, 59, 3683. (b) Rudkevich, D. M.; Mercer-Chalmers, J . D.;
Verboom, W.; Ungaro, R.; J ong, F. d.; Reinhoudt, D. N. J . Am. Chem.
Soc. 1995, 117, 6124.
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Szemes, F.; Wear, T. J . Chem. Soc., Chem. Commun. 1994, 1269.
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G. D.; Ugozzoli, F. Tetrahedron 1986, 42, 2089.
10.1021/jo034275j CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/18/2003
6632
J . Org. Chem. 2003, 68, 6632-6638

Lower Rim C-Linked N-Tosyl Peptidocalix[4]arenes
TABLE 1. Syn th esis of N-Tosyl-2-a m in o Acid
Der iva tives 2
SCHEME 1. P r ep a r a tion of th e N-Tosyl-a m in o
Acid Ch lor id e Der iva tives 3
2
R
yield (%)
mp (°C)
a , D-alanine
Me
86
83
62
61
42
40
64
67
58
130-131
b, L-alanine
Me
c, D-valine
d , L-valine
e, D-phenylalanine
f, L-phenylalanine
g, D-leucine
h , L-leucine
i, L-isoleucine
i-Pr
i-Pr
CH2Ph
CH2Ph
i-Bu
i-Bu
144-146
156-157
122-124
134-136
CH(CH3)CH2CH3
SCHEME 2. Syn th esis of Ca lixa r en e Der iva tives 6,
7, a n d 9
Meanwhile, other groups have reported the synthesis
and properties of chiral calixarenes functionalized with
aminophosphonates,16 esteracetamides,17 cyclopeptides,18
ureas,19,20 sugars,21,22 amino acids,8,23-27 and peptides.28-33
In this paper, we describe the syntheses of various 1,3-
chiral cone p-tert-butyl calix[4]arenes functionalized with
D or L amino acid units. Their structures were determined
by NMR spectroscopy (1H, 13C), mass spectrometry, spec-
ific rotations, elemental analysis, IR, melting points, and
X-ray crystal structure for one of them. The amino acids
were D- and L-alanine, isoleucine, leucine, phenylalanine,
and valine and were introduced on the lower rim of p-tert-
butylcalix[4]arene. The host-guest complexation of vari-
ous anions was studied by H1 NMR spectroscopy.
Resu lts a n d Discu ssion
The amino acid chloride derivatives 3a -i were pre-
pared from the corresponding amino acid in two steps
(14) Scheerder, J .; Vreekamp, R. H.; Engbersen, J . F. J .; Verboom,
W.; Duynhoven, J . P. M. v.; Reinhoudt, D. N. J . Org. Chem. 1996, 61,
3476.
(15) Nomura, E.; Takagaki, M.; Nakaoka, C.; Uchida, M.; Taniguchi,
H. J . Org. Chem. 1999, 64, 3151.
(16) (a) Antipin, I. S.; Stoikov, I. I.; Pinkhassik, E. M.; Fitseva, N.
A.; Stibor, I.; Konovalov, A. I. Tetrahedron Lett. 1997, 38, 5865. (b)
Stoikov, I. I.; Repejkov, S. A.; Antipin, I. S.; Konovalov, A. I. Heteroatom
Chem. 2000, 11, 518.
(17) Ko¨nig, B.; Fricke, T.; Gloe, K.; Chartroux, C. Eur. J . Inorg.
Chem. 1999, 1557.
(18) Hu, X.; Chan, A. S. C.; Han, X.; He, J .; Cheng, J . P. Tetrahedron
Lett. 1999, 40, 7115.
(19) Castellano, R. K.; Nuckolls, C.; Rebek, J . J r. J . Am. Chem. Soc.
1999, 121, 11156.
(20) Rincu¨n, A. M.; Prados, P.; De Mendoza, J . J . Am. Chem. Soc.
2001, 123, 3493.
(21) Meunier, S. J .; Roy, R. Tetrahedron Lett. 1996, 37, 5469.
(22) Budka, J .; Tkadlecova´, M.; Lhota´k, P.; Stibor, I. Tetrahedron
2000, 56, 1883.
(23) Sansone, F.; Barnoso, S.; Casnati, A.; Fabbi, M.; Pochini, A.;
Ugozzoli, F.; Ungaro, R. Eur. J . Org. Chem. 1998, 897.
(24) Okada, Y.; Kasai, Y.; Nishimura, J . Tetrahedron Lett. 1995, 36,
555.
(25) Yuan, H. S.; Zhang, Y.; Hou, Y. J .; Zhang, X. Y.; Yang, X. Z.;
Huang, Z. T. Tetrahedron 2000, 56, 9611.
(26) Hu, X.; He, J .; Chan, A.S. C.; Han, X.; He, J .; Cheng, J . P.
Tetrahedron: Asymmetry 1999, 10, 2685.
(27) Rao, P. V.; Rao C. P.; Kolehmainen, E.; Wegelius, E. K.;
Rissanen, K. Chem. Lett. 2001, 1176.
(28) Hamuro, Y.; Crego Calama, M.; Soon Park, H.; Hamilton, A.
D. Angew. Chem., Int. Ed. Engl. 1997, 36, 2680.
(29) Sansone, F.; Barboso, S.; Casnati, A.; Sciotto, D.; Ungaro, R.
Tetrahedron Lett. 1999, 40, 4741.
(30) Hioki, H.; Yamada, T.; Fujiioka, C.; Kodama, M. Tetrahedron
Lett. 1999, 40, 6821.
(31) Beckham Shuker, S.; Esterbrook, J .; Gonzalez, J . Synlett 2001,
210.
as shown in Scheme 1. After protection of the amino
group with a tosyl group to give the N-tosyl-amino acid
derivatives 2a -i (Table 1),34 a chlorination reaction with
thionyl chloride gives the amino acid chlorides 3a -i.
The syntheses of all the amides 6, 7, and 9 were ac-
complished by using a condensation reaction of amino
acid chlorides 3a -i with the diamino (ethoxy or butoxy)
calix[4]arene derivatives 4 and 5 in dry CH2Cl2 with Et3N
as catalyst (Scheme 2). The calix[4]arene derivatives
substituted by chiral amino acid were obtained in high
1
yields. Their constitution was established by H NMR,
13C NMR, ESI data, and elemental analysis, and also-
confirmed by the amide group absorption in the FT-IR
spectra.
(32) Frish, L.; Sansone, F.; Casnati, A.; Ungaro, R. J . Org. Chem.
2000, 65, 5026.
(33) Soon Park, H.; Lin, Q.; Hamilton, A. D. J . Am. Chem. Soc. 1999,
121, 8.
(34) (a) Berry, M.B.; Craig, D. Synlett 1992, 41. (b) Beeckam, A. F.
J . Am. Chem. Soc. 1957, 79, 7.
J . Org. Chem, Vol. 68, No. 17, 2003 6633

Sdira et al.
TABLE 2. Selected 1H NMR Da ta of 6a a n d 7g in Differ en t Solven tsa
solvent
NH-CO
NH-Ts
ArH
ArCH2Ar
ArCH2Ar
6a
7g
DMSO-d6
CDCl3
DMSO-d6
CDCl3
8.23
8.06
7.91
7.26
7.93
5.53
7.80
5.95
7.15
6.81, 7.03
7.10
4.1-4.3 (2 doublets)
4.16 and 4.24 (2 doublets)
4.17 (1 doublet)
3.4-3.5 (1 multiplet)
3.22 and 3.31 (2 doublets)
3.40 (1 doublet)
6.80, 7.10
4.25 and 4.26 (2 doublets)
3.3-3.4 (2 doublets)
a
Chemical shift are given in ppm
While the structures of derivatives 4 and 5 show the
typical splitting pattern for a disubstituted calixarene,
the 1H NMR spectra of compounds 6a -i and 7a -i
(CDCl3) are more complex, reflecting the chirality im-
1
posed by the amino acid moieties. The H NMR spectra
at ambient temperature were identical for each pair of
enantiomers. The signals of CH2O and CH2NH are broad
and poorly resolved, indicating a dynamic effect typical
for high molecular mass compounds with strong dipolar
interactions of nuclei and steric hindrance of rotation.35
The 1,3-N-tosyl peptidocalix[4]arenes 6a -i and 7a -i
show significant changes on going from nonpolar (CDCl3)
to polar solvent (acetone-d6 or DMSO-d6). In CDCl3, the
structure of alanine and leucine derivatives 6a and 7g
not only indicates that they possess the cone conforma-
tion, but also provides evidence for asymmetric structural
features. All of them have two pairs of doublets around
3.40 and 4.20 ppm (Table 2) that are due to the non-
equivalency of the protons of the methylene bridge (Ar-
CH2-Ar). As previously reported in the literature,7 this
can be explained by the presence of chiral substituents
and indicates a significant degree of structural rigidity.
In DMSO-d6, one singlet for the aromatic protons (7.15
and 7.10 ppm for 6a and 7g, respectively) is found
(Figures 1 and 2, Table 2), while in CDCl3 one singlet
and one doublet are observed for 6a (6.81 and 7.03 ppm,
respectively) and two singlets for 7g (6.80 and 7.10 ppm).
This is in accordance with C4 symmetry and suggests the
formation of a C2 flattened cone conformation.36
While the NH-CO signal appears at similar chemical
shifts in CDCl3 and in DMSO-d6 (Table 2), the signal of
NH-Ts is strongly shifted upfield in CDCl3 indicating
intramolecular hydrogen bond formation in apolar sol-
vent. A J CH-NH coupling constant of greater than 8 Hz
(8.46 and 8.28 Hz for 6a and 7g, respectively, in CDCl3)
was measured, indicating that the amino acid moieties
adopt an extended conformation.37 This allows us to point
out a possible dimerization of peptidocalix[4]arenes which
have been revealed by ESI mass studies.
F IGURE 1. Numbering scheme of compound 6f.
tween the amino acids units for 6-7 is observed, which
confirms that the calixarene derivatives adopt a flattened
cone conformation. In DMSO-d6, the intramolecular
hydrogen bonds are broken and the compounds adopt a
1,3-disubstituted cone conformation. The presence of
intramolecular hydrogen bonds in the solid state is
confirmed by the IR spectra in the solid state for all of
the calixarene derivatives 6 and 7. In the IR spectra of 6
and 7, the NH stretching bands at 3260-3360 cm-1
corresponding to hydrogen-bonded NH are much stronger
than those of free NH at 3420 cm-1 6
.
From X-ray analysis of 6f, it is shown that the
asymmetric unit contains two macrocycles and three
ethanol molecules. Figure 1 gives the numbering scheme
of 6f. Each macrocycle is noted A or B. The two macro-
cycles adopt the cone conformation. Due to the low quality
of the crystal, a well-refined high-resolution structure
could not be obtained. However, to describe the confor-
mation an isotropic refinement was made that permits
the description as follows.
The δ angles giving the orientations of the phenolic
units with respect to the reference plane of the methylene
groups38 have values of 117.3(4)°, 126.1(4)°, 115.9(5)°, and
129.0(5)° for A and 115.1(4)°, 129.6(4)°, 113.8(4)°, and
127.0(3)° for B. The representation of the molecular
conformation as described by Ugozzoli et al.39 is C1 - +,
- +, - +, - + for both molecules A and B. Concerning
the substituents at the OH groups, dihedral angles
between planes of the phenyl rings have been calculated.
For macrocycle A the I-II angle is 81.9(7)° and the III-
IV angle is 79.8(6)°. For macrocycle B the I-II angle is
79.7(6)° and the III-IV angle is 74.9(5)° (plane I: C34 f
C39, plane II: C43 f C48, plane III: C54 f C59, plane
ESI (positive-ion) mass spectra of 6g-i show the peak
of a dimer in addition to the peak of a monomer.
However, the peak intensities of the dimer are weaker
than that for the monomer ([dimer]+/[monomer]+) (8-
16%). For 7a -i, no peak corresponding to dimeric struc-
ture is visible.
Compound 6f gave crystals (from CH2Cl2/EtOH) suit-
able for a preliminary X-ray analysis. It confirmed that
these peptidocalix[4]arene derivatives 6a -i and 7a -i
adopt a flattened cone conformation. These results in the
solid state are in accordance with those in the liquid
state. In CDCl3, intramolecular hydrogen bonding be-
(38) Perrin, M.; Oehler, D. In Calixarenes. A versatile class of
Macrocyclic Compounds; Vicens, J ., Bo¨hmer, V., Eds.; Kluwer Aca-
demic Publishers: Dordrecht, The Netherlands, 1991; p 65.
(39) Ugozzoli, F.; Andreeti, G. J . Incl. Phenom. Mol. Rec. Chem.
1992, 13, 337.
(35) Iwanek, W. Tetrahedron: Asymmetry 9 1998, 67, 684.
(36) Mogck, O.; Bo¨hmer, V.; Vogt, W. Tetrahedron 1996, 52, 8489.
(37) Rinco´n, A. M.; Prados, P.; de Mendoza, J . Eur. J . Org. Chem.
2002, 640.
6634 J . Org. Chem., Vol. 68, No. 17, 2003

Lower Rim C-Linked N-Tosyl Peptidocalix[4]arenes
F IGURE 3. Titration curve of calix[4]arene 9 with Bu4NCl,
Bu4NBr, Bu4NHSO4, Bu4NH2PO4, and Bu4N-N-Ts-L-alaninate
in CDCl3. Concentration of the host is 10-2 M.
F IGURE 2. Packing view down “a” of compound 6f.
IV: C63 f C68). On the other hand we have calculated
the following angles: C28-C51-C54 is 93.7° for A and
94.9° for B and C26-C31-C34 is 95.0° for A and 94.1°
for B. These values near the perpendicularity show how
the substituants go outside the macrocycles. All the
values obtained show that the two independent macro-
cycles have the same conformation. Concerning hydrogen
bonds in the calixarene, we find only an intramolecular
bond between O25-O28 and O26-O27:
F IGURE 4. J ob plot of the titration of 0.01 M Bu4NCl with
10-2 M calix[4]arene 9 in CDCl3.
TABLE 3. Ka ss Va lu es (M-1) of 6a , 7a , a n d 9
-
compd
Cl-
Br- HSO4
H2PO4- N-tosyl-(L)-alaninate
7a
6a
9
988
5137 4212
4906 3885
1626
4836
6924
3856
2309
The title compound crystallizes with three ethanol
molecules. However, one of them is in a disordered posi-
tion with occupation 0.42 and 0.58. Due to the disorder
these two molecules were refined isotropically. There are
hydrogen bonds between two of them: O502- - -O602 )
2.857 Å. There are no hydrogen bonds between ethanol
and calixarene. Figure 2 shows the packing down “a”.
mined by the Benesi-Hildebrand method40and are sum-
marized in Table 3.
The data in Table 3 show that the association constant
for anion binding of the various calix[4]arene derivatives
is strongly dependent on the nature of the substituent
at the lower rim and confirm previously described
results.41 Thus, we observed that the complexation is
higher for derivative 7a than for 6a according to the
length of the spacer. In an attempt to further increase
the strength of the anion complexation, we prepared the
more lipophilic derivative 9. As shown in Table 3, this
compound gave the better binding constants. A good
selectivity for Cl- and Br- (compared to previously
described results42) is present and no complexation or
Com p lexa tion Stu d y
The introduction of hydrogen bonding donor and ac-
ceptor groups at the lower rim of calixarenes might have
affected their host-guest properties and gave rise to new
possibilities for anion complexation. We report a prelimi-
nary study of the complexation properties of various
anions such as tetrabutylammonium chloride, bromide,
dihydrogen phosphate, hydrogen sulfate, and N-tosyl-(L)-
alaninate. The recognition properties of compounds 6a ,
-
only weak complexation is observed for HSO4 and
H2PO4-. It is well-known that the size-fit relationship
between host and guest plays a crucial role in molecular
recognition. The size of the calix[6]arene seems to be
more suitable for these anions.43 According to the litera-
1
7a , and 9 were investigated by H NMR experiments in
CDCl3. A large downfield shift of the NH proton of the
amide function was observed upon addition of n-tetrabu-
1
tylammonium salts of anions to host derivatives. The H
NMR titration curve of complexation with Cl-, Br-,
HSO4-, H2PO4-, and N-tosyl-(L)-alaninate to host 9 is
depicted in Figure 3.
(40) Fielding, L. Tetrahedron 2000, 56, 6151.
(41) Lynam, C.; J ennings, K.; Nolan, K.; Kane, P.; McKervey, M.
A.; Diamond, D. Anal. Chem. 2002, 74, 59.
(42) Scheerder, J .; Fochi, M.; Engbersen, J . F.; Reinhoudt, D. N. J .
Org. Chem. 1994, 59, 7815.
(43) Scheerder, J .; Engbersen, J . F.; Casnati, A.; Ungaro, R.;
Reinhoudt, D. N. J . Org. Chem. 1995, 60, 6448.
In all cases the stoichiometry is 1:1 as was confirmed
by J ob plots (see for an example Figure 4). The associa-
tion constants of the three anion receptors were deter-
J . Org. Chem, Vol. 68, No. 17, 2003 6635

Sdira et al.
ture,44 a better selectivity of carboxylate over inorganic
anions was observed.
emental analyses were performed at the Service Central
d’Analyse, CNRS, Solaize, France.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e N-To-
syl-2-a m in o Acid 2. To a stirred suspension of amino acid 1
(22 mmol) in 50 mL of water at room temperature was added
2.64 g (66 mmol) of NaOH and 5 g (26.4 mmol) of p-toluene
sulfonyl chloride. The mixture was stirred at 60 °C for 6 h.
The combined basic layers were cooled to -5 °C and acidified
(pH 1) by the addition of concentrated HCl. The precipitate
was collected by filtration, washed with cold H2O and EtOH,
and air-dried to give the tosylamino acid 2 as a white solid.29
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o
Acid Ch lor id es 3. Thionyl chloride (0.1 mL, 1.46 mmol) was
added dropwise to a solution of the N-tosyl-2-amino acid 2
(0.977 mmol) in 20 mL of benzene and the mixture was stirred
at 60 °C for 3 h. The unreacted SOCl2 and solvent were
removed by distillation. Compounds 3 were used for the next
reaction without further purification.
The ligands 6a , 7a , and 9 strongly bind anions (the
Kas values vary from 1000 to 6900 M-1). These results
are better compared with previously described upper-rim
C-linked peptidocalixarenes.7 Our results are in ac-
cordance with those obtained with peptidocalixarenes in
which the conformational flexibility has been reduced at
the upper-rim.44 The authors show that these ligands
form strong complexes in acetone-d6 with carboxylate
anions such as N-acetyl-(L)-alaninate (Kas ) 4900 M-1).
Ungaro et al.45 reported that aromatic R-amino acids are
more strongly bounded than aliphatic ones. H-bonding
interactions between the carboxylate anions and the
amide NH groups, together with Π-Π stacking, are
mentioned to explain the selectivity of such anion recep-
tors. In our case, the N-tosyl protecting group may play
a cooperative role in the binding and could explain the
enhancement in the host-guest complexation of alani-
nate. The enantioselective recognition of chiral carboxy-
lates is an important goal. The anion receptors 6, 7, and
9 show promising ability for chiral discrimination.
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(a m in oet h oxy)-
26,28-d ih yd r oxyca lix[4]a r en e (4). Compound 4 was pre-
pared according to known procedures, reported previously in
the literature42,48,49 (for reduction we imposed the procedure
using BH3‚THF instead of LiAlH4).
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(a m in ob u t oxy)-
26,28-d ih yd r oxyca lix[4]a r en e (5). Compound 5 is obtained
by using the same procedure as for compound 4.42 The product
was purified by recrystallization (CH3OH/CHCl3) to give a
white powder (82%): mp 162-164 °C. 1H NMR δ 0.96 (s, 18H),
1.27 (s, 18H), 1.88-2.00 (br, 8H), 2.90-3.00 (br, 4H), 3.26 (d,
4H, J ) 12.2 Hz), 3.90-4.00 (br, 4H), 4.21 (d, 4H, J ) 12.2
Hz), 6.79 (s, 4H), 7.03 (s, 4H). 13C NMR δ 25.5, 27.6, 31.4, 32.0,
32.1, 34.2, 41.5, 76.6, 122.8, 125.5, 128.24, 129.3, 133.4, 142.7,
149.9, 153.4. IR 3352.68 (NH2). ES-MS (m/z) 813.6 [M + Na]+
(calcd 813.55), 791.5 [M + H]+ (calcd 791.56). Anal. Calcd for
Con clu sion
New chiral calix[4]arene-amino acid conjugates have
been prepared by using the reaction of the N-tosylated
acid chlorides of five (D or L) amino acids with calix[4]-
arene derivatives. We have verified that these hosts
adopt a rigid flattened cone conformation. The perpen-
dicular geometry of the phenyl rings participates in the
general chirality of the macro-ring. The introduction of
amino acid moieties into the lower rim of calix[4]arene
places the chiral groups distant from the internal aro-
matic cavity of calix[4]arene, which allows secondary
interactions of the amino acid functional groups with
homochiral guests. TREN-derived sulfonamides46 and
sulfonated47 and amino acid7 calix[4]arene derivatives
form complexes with anions. The N-tosylated calix[4]-
arene derivatives 6, 7, and 9 might be suitable for the
synthesis of hydrophobic neutral anion receptors which
are able to bind anions in a 1:1 stoichiometry through
hydrogen bonding. High binding constants are observed
and the better selectivity is obtained for N-tosyl-(L)-
alaninate as expected. This class of receptors opens new
horizons for chiral discrimination of carboxylate deriva-
tives.
C
52H74N2O4: C, 78.94; H, 9.43; N, 3.54. Found: C, 78.71; H,
9.40; N, 3.49.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o
Acid Ca lixa r en e Der iva tives 6 a n d 7. The solution of amino
acid chloride 3 prepared above in dry CH2Cl2 (15 mL) was
added dropwise to a solution of p-tert-butylcalix[4]arene di-
amine 4 or 5 (0.4 mmol) and triethylamine (52 mg, 0.88 mmol)
in dry CH2Cl2 (35 mL) at 0 °C. The mixture was stirred at
room temperature for 12 h, washed with 1 N HCl (2 × 50 mL)
and water (50 mL), and dried over Na2SO4. The solvent was
removed in vacuo and the solid residue was purified by column
chromatography to give 6 and 7.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-a la n yl-
a m in oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6a ) a n d 5,-
11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-a la n yla m i-
n oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6b). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 6/4 to obtain 6a or 6b as a white powder
(6a : 141 mg, 61%; 6b: 132 mg, 56%): mp 241-243 °C. 6a : [R]20
D
+15.3 (c 0.15, CHCl3). 6b: [R]20 +5.8 (c 0.5, CHCl3). H NMR
1
D
δ 0.95 (s, 18H), 1.06 (d, 6H, J ) 6.9 Hz), 1.23 (s, 18H), 2.31 (s,
6H), 3.22 (AB, 2H), 3.31 (AB, 2H, J ) 13.4 Hz), 3.21-3.85 (m,
10H), 4.16 (AB, 2H, J ) 13.0 Hz), 4.24 (AB, 2H, J ) 13.4 Hz),
5.53 (d, 2H, J ) 8.46 Hz), 6.81 (s, 4H), 7.03 (d, 4H), 7.11 (d,
4H, J ) 8.1 Hz), 7.49 (d, 4H, J ) 8.28 Hz), 8.01 (s, 2H), 8.06
(br s, 2H). 13C NMR δ 19.7, 21.9, 31.4, 32.0, 32.3, 34.4, 40.0,
53.2, 75.8, 126.1, 127.5, 128.12, 130.1, 133.1, 137.5, 143.4,
148.3, 149.2, 171.9. IR 3289 (NH, OH), 1653 (CO). ES MS (m/
z) 1207.5 [M + Na]+ (calcd 1207.59), 1185.5 (calcd 1185.61).
Anal. Calcd for C68H88N4O10S2: C, 68.89; H, 7.48; N, 4.72.
Found: C, 68.69; H, 7.41; N, 4.77.
Exp er im en ta l Section
Gen er a l Meth od s. Solvents were purified and dried by
standard methods prior to use. All reactions were carried out
under nitrogen. Column chromatography was performed with
silica gel 60 (0.040-0.063 nm). Melting points are uncorrected.
1H NMR and 13C NMR spectra were obtained at 300.13 and
75 MHz (CDCl3, TMS as internal standard). Mass spectra were
obtained by electrospray technique (positive mode). The el-
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-D-va lyl-
a m in oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6c) a n d 5,-
11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-L-va lyla m i-
(44) Sansone, F.; Baldini, L.; Casnati, A.; Lazzarotto, M.; Ugozzoli,
F.; Ungaro R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4842.
(45) Casnati, A.; Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 36,
246.
(46) Wu¨thrich, K. In NMR of Proteins and Nucleic Acids; Wiley:
New York, 1986; p 17.
(47) Valiyaveettil, S.; Engbersen, J . F. J .; Verboom, W.; Reinhoudt,
D. N. Angew. Chem. 1993, 105, 942.
(48) Mozerin, Y.; Rudkevich, D. M.; Verboom, W.; Reinhoudt, D. N.
J . Org. Chem. 1993, 115, 7602.
(49) Smirnov, S.; Sidorov, V.; Pinkhassik, E.; Havlie`ek, J .; Stibor,
I. Supramol. Chem. 1997, 8, 187.
6636 J . Org. Chem., Vol. 68, No. 17, 2003

Lower Rim C-Linked N-Tosyl Peptidocalix[4]arenes
n oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6d ). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 5/5 to give 6c or 6d as white crystals (6c:
9.6 Hz), 8.04 (br s, 2H). 13C NMR δ 11.7, 15.8, 21.9, 24.4, 31.4,
32.4, 34.3, 38.5, 39.6, 62.0, 75.7, 126.0, 126.4, 126.8, 128.5,
128.6, 130.1, 133.0, 137.3, 143.4, 143.9, 148.2, 149.4, 149.7,
171.0. IR 3297 (OH, NH), 1668 (CO). ES-MS (m/z) 1291.6 [M
+ Na]+ (calcd 1292.68), 1269.6 [M + H]+ (calcd 1269.70),
2561.3 [2M + Na]+ (calcd 2561.38), 2539.4 [2M + H]+ (calcd
2539.40). Anal. Calcd for C74H100N4O10S2: C, 70.00; H, 7.94;
N, 4.41. Found: C, 69.34; H, 7.98; N, 4.40.
192.5 mg, 78%; 6d : 168 mg, 68%): mp 140-142 °C. 6c: [R]20
D
-15.7 (c 0.3, CHCl3). 6d : [R]20D +26.0 (c 0.3, CHCl3). 1H NMR:
δ 0.76-0.78 (dd, 12H, J ) 6.78 Hz, J ) 6.78 Hz), 1.06 (s, 18H),
1.31 (s, 18H), 2.08-2.14 (m, 2H), 2.37 (s, 6H), 3.36 (AB, 2H, J
) 13.2 Hz), 3.42 (dd, 4H, J ) 13.2 Hz), 3.61-3.66 (m, 6H),
3.96 (m, 4H), 4.26 (AB, 2H, J ) 13.2 Hz), 4.29 (AB, 2H, J )
13.0 Hz), 5.41 (d, 2H, J ) 8.67 Hz), 6.91 (s, 4H), 7.11 (s, 4H),
7.23 (d, 4H, J ) 8.1 Hz), 7.70 (d, 4H, J ) 8.28 Hz), 7.85 (s,
2H), 8.08 (br s, 2H). 13C NMR δ 17.4, 19.6, 21.9, 32,4, 31.5,
31.97, 32.4, 34.4, 39.6, 62.4, 75.7, 126.1, 126.4, 127.8, 128.4,
128.5, 130.0, 133.14, 137.3, 143.4, 148.3, 149.3, 149.7, 171.0.
IR 3315 (NH, OH), 1669 (CO). ES-MS (m/z) 1263.6 [M + Na]+
(calcd 1263.65), 1241.6 [M + H]+ (calcd 1241.67). Anal. Calcd
for C72H96N4O10S2‚H2O: C, 68.64; H, 7.86; N, 4.45. Found: C,
68.98; H, 7.90; N, 4.49.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-a la n yl-
a m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7a ) a n d 5,-
11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-a la n yla m i-
n obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7b). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 6/4 to give 7a or 7b as a white powder
(7a : 147.5 mg, 58%; 7b: 152 mg, 60%): mp 135-137 °C. 7a :
[R]20 +30.5 (c 0.2, CHCl3). 7b: [R]20 -102.8 (c 0.5, CHCl3).
D
D
1H NMR δ 0.93 (s, 18H), 1.19 (d, 6H, J ) 6.96 Hz), 1.34 (s,
18H), 1.85-2.00 (br m, 8H), 2.41 (s, 6H), 3.35-3.57 (m, 10H),
3.92-4.10 (m, 6H), 4.22 (d, 2H, J ) 13.2 Hz), 4.28 (d, 2H, J )
13.0 Hz), 6.14 (d, 2H, J ) 8.64 Hz), 6.77 (s, 4H), 7.13 (s, 4H),
7.22 (s, 2H), 7.25 (d, 4H, J ) 8.10 Hz), 7.40 (br, 2H), 7.70 (d,
4H, J ) 8.28 Hz). 13C NMR δ 19.6, 21.9, 26.5, 27.50, 31.4, 32.0,
32.1, 34.3, 39.7, 53.0, 77.1, 125.6, 126.0, 127.5, 128.3, 128.49,
130.2, 132.5, 136.2, 137.7, 142.6, 143.9, 150.3, 172.7. IR 3298
(NH, OH), 1658 (CO). ES-MS (m/z) 1263.7 [M + Na]+ (calcd
1263.65), 1241.7 [M + H]+ (calcd 1241.67). Anal. Calcd for
C72H96N4O10S2‚H2O: C, 68.63; H, 7.86; N, 4.44. Found: C, 68.70;
H, 7.89; N, 4.59.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-p h en yl-
a la n yla m in oet h oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6e)
a n d 5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-p h en -
yla la n yla m in oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6f).
The product was purified by column chromatography on silica
gel eluting with EtOAc/hexane 5/5 to give 6e or 6f as a white
powder (6e:144 mg, 54%; 6f: 155 mg, 58%): mp 117-119 °C.
6e: [R]20D +113.5 (c 0.4, CHCl3). 6f: [R]20D -29.5 (c 0.4, CHCl3).
1H NMR δ 1.11 (s, 18H), 1.35 (s, 18H), 2.41 (s, 6H), 2.51 (d,
1H, J ) 13.5 Hz), 2.55 (d, 1H, J ) 13.6 Hz), 3.09 (d, 1H, J )
14.1 Hz), 3.13 (d, 1H, J ) 14 Hz), 3.33 (AB, 2H, J ) 13.2 Hz),
3.37 (AB, 2H, J ) 13.4 Hz), 3.92-4.25 (m, 10H), 4.36 (d, 2H,
J ) 12.6 Hz), 4.42 (d, 2H, J ) 13.4 Hz), 5.00 (d, 2H, J ) 6.27
Hz), 6.53 (d, 4H, J ) 7.17 Hz), 6.96-7.11 (m, 4H), 7.16 (s, 4H),
7.26 (d, 4H, J ) 8.1 Hz), 8.61 (s, 2H), 8.72 (br s, 2H). 13C NMR
δ 21.9, 31.5, 32.6, 32.6, 39.2, 40.0, 59.0, 76.3, 126.3, 126.6,
127.0, 128.1, 128.3, 126.2, 126.4, 129.9, 131.3, 133.3, 137.2,
136.3, 143.5, 143.5, 148.2, 149.3, 150.0, 171.0. IR 3316 (NH,
OH), 1671 (CO). ES-MS (m/z) 1359.6 [M + Na]+ (calcd
1359.65), 1337.4 [M + H]+ (calcd 1337.67). Anal. Calcd for
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-D-va lyl-
a m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7c) a n d 5,-
11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-L-va lyla m i-
n obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7d ). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 5/5 to give 7c or 7d as a white powder
(7c: 138 mg, 61%; 7d : 126 mg, 56%): mp 134-136 °C. 7c:
[R]20 +126.5 (c 0.2, CHCl3). 7d : [R]20 +11.0 (c 0.2, CHCl3).
D
D
1H NMR δ 0.72 (d, 6H, J ) 6.78 Hz), 0.83 (d, 6H, J ) 6.78
Hz), 0.96 (s, 18H), 1.32 (s, 18H), 1.85-2.00 (m, 8H), 2.40 (s,
6H), 3.31-3.40 (m, 8H), 3.67 (dd, 2H, J ) 5.10 Hz, J ) 5.07
Hz), 3.91-4.06 (m, 4H), 4.22 (d, 2H, J ) 13.2 Hz), 4.28 (d, 2H,
J ) 13.0 Hz), 5.79 (d, 2H, J ) 8.67 Hz), 6.80 (s, 4H), 7.07-
7.10 (m + d, 6H, J ) 2.64 Hz, ArH), 7.25 (d, 4H, J ) 8.49 Hz),
7.40 (s, 2H), 7.75 (d, 4H, J ) 8.28 Hz). 13C NMR δ 17.6, 19.6,
21.9, 26.4, 27.7, 30.1, 31.4, 32.1, 34.3, 39.8, 62.6, 76.7, 125.6,
126.0, 126.8, 128.2, 128.3, 130.0, 132.7, 137.4, 142.4, 143.8,
146.4, 150.2, 150.7, 171.6. IR 3296 (NH, OH), 1650 (CO). ES-
MS (m/z) 1319.8 [M + Na]+ (calcd 1319.71), 1297.6 [M + H]+
(calcd 1297.73). Anal. Calcd for C68H88N4O10S2: C, 68.89; H,
7.48; N, 4.72; O, 13.49. Found: C, 68.69; H, 7.41; N, 4.77.
C
80H96N4O10S2: C, 71.83; H, 7.23; N, 4.19. Found: C, 71.68; H,
7.19; N, 4.00.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-leu cyl-
a m in oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6g) a n d 5,-
11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-leu cyla m i-
n oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6h ). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 3/7 to give 6g or 6h as white crystals (6g:
170 mg, 67%; 6h : 157 mg, 62%): mp 144-146 °C. 6g: [R]20
D
+5.2 (c 0.5, CHCl3). 6h : [R]20 -33.4 (c 0.5, CHCl3). H NMR
1
D
δ 0.48 (d, 6H, J ) 5.67 Hz), 0.65 (d, 6H, J ) 5.82 Hz), 1.20 (s,
18H), 1.29 (s,18H), 1.42-1.46 (m, 4H), 1.83 (br, 2H), 2.39 (s,
6H), 3.41 (dd, 4H, J ) 12.8 Hz, J ) 13.2 Hz), 3.74-3.87 (m,
6H), 3.99-4.05 (m, 4H), 4.30 (d, 2H, J ) 13.0 Hz), 4.34 (d,
2H, J ) 13.2 Hz), 5.32 (d, 2H, J ) 9.03 Hz), 6.91 (s, 4H), 7.11
(s, 4H), 7.22 (d, 4H, J ) 8.07 Hz), 7.68 (d, 4H, J ) 8.31 Hz),
8.17 (s, 2H), 8.34 (br s, 2H). 13C NMR δ 21.0, 21.0, 21.9, 23.4,
31.5, 32.0, 32.5, 34.3, 39.7, 42.9, 55.9, 76.0, 126.2, 126.5, 127.8,
128.2, 128.3, 128.6, 130.0, 133.1, 137.3, 143.6, 148.4, 149.2,
149.9, 172.1. IR 3319 (NH, OH), 1659 (CO). ES-MS (m/z)
1291.6 [M + Na]+ (calcd 1291.68), 1269.6 [M + H]+ (calcd
1269.70) 2561.30 [2M + Na]+ (calcd 2561.38), 2539.30 [2M +
H]+ (calcd 2539.40). Anal. Calcd for C74H100N4O10S2: C, 70.00;
H, 6.94; N, 4.41. Found: C, 69.71; H, 7.95; N, 4.33.
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-L-isole-
u cyla m in oeth oxy)-26,28-d ih yd r oxyca lix[4]a r en e (6i). The
product was purified by column chromatography on silica gel
eluting with EtOAc/hexane 3/7 to give 6i as a white powder
(186 mg, 74%): mp 143-145 °C. 6i: [R]20D -6.0 (c 0.15, CHCl3).
1H NMR δ 0.68-0.77 (m, 12H), 0.6-1.04 (s + m, 20H), 1.32-
1.40 (s + m, 20H), 1.72-1.74 (m, 2H), 2.37 (s, 6H), 3.35 (dd,
4H, J ) 13.2 Hz), 3.64-4.05 (m, 10H), 4.30 (dd, 4H, J ) 13.2
Hz, J ) 13.2 Hz), 5.43 (d, 2H, J ) 9.03 Hz), 6.90 (s, 4H), 7.12
(s, 4H), 7.24 (d, 4H, J ) 8.28 Hz), 7.72-7.75 (s + d, 6H, J )
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-p h en yl-
a la n yla m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7e)
a n d 5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-p h en -
yla la n yla m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7f).
The product was purified by column chromatography on silica
gel eluting with EtOAc/hexane 6/4 to give 7e or 7f as a white
powder (7e: 195 mg, 74%; 7f: 174 mg, 64%): mp 111-113 °C.
7e: [R]20 +5 (c 0.5, CHCl3). 7f: [R]20 -23.3 (c 0.15, CHCl3).
D
D
1H NMR δ 0.97 (s, 18H), 1.34 (s, 18H), 1.91-2.10 (br m, 8H),
2.38 (s, 6H), 3.31 (dd, 2H, J ) 8.50 Hz), 3.02 (d, 2H, J ) 13.0
Hz), 3.06 (d, 1H, J ) 5.60 Hz), 3.33-3.46 (br m), 3.98-4.06
(br m, 6H), 4.29 (t, 4H, J ) 12.6 Hz, J ) 12.0 Hz), 5.78 (d, 2H,
J ) 7.92 Hz), 6.81 (s, 4H), 6.90-6.93 (m, 4H), 6.93-7.26 (m,
16H), 7.48 (s, 2H), 7.49 (d, 4H, J ) 8.28 Hz). 13C NMR δ 21.9,
26.3, 27.5, 31.4, 32.1, 32.6, 39.3, 39.9, 58.8, 76.9, 125.6, 126.0,
127.1, 127.5, 128.3, 128.9, 129.7, 130.0, 132.7, 136.3, 136.8,
142.4, 143.6, 147.4, 150.3, 150.7, 171.5. IR 3305 (OH, NH),
1656 (CO). ES-MS (m/z) 1415.5 [M + Na]+ (calcd 1415.71),
1394.6 [M + H]+ (calcd 1393.73). Anal. Calcd for C84H104N4O10S2‚
H2O: C, 71.14; H, 7.58; N, 3.96. Found: C, 71.52; H, 7.56; N,
3.99.
J . Org. Chem, Vol. 68, No. 17, 2003 6637

Sdira et al.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-D-leu cyl-
a m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7g) a n d 5,-
11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-leu cyla m i-
n obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7h ). The product
was purified by column chromatography on silica gel eluting
with EtOAc/hexane 3/7 to give 7g or 7h as a white powder
(7g: 161 mg, 64%; 7h : 151 mg, 60%): mp 179-181 °C. 7g:
[R]20 +179.0 (c 0.1, CHCl3). 7h : [R]20 -20.8 (c 0.5, CHCl3).
Hz, 4H), 7.81 (d, J ) 8.31 Hz, 4H). 13C NMR δ 11.20, 19,53,
21.97, 23.97, 26.44, 28.23, 31.50, 31.62, 32.09, 34.02, 34.43,
40.79, 53.19, 74.83, 77.64, 124.91, 125.82, 127.56, 130.25,
132.57, 135.57, 137.29, 144.22, 144.42, 145.12, 153.09, 154.85,
172.12. IR 1656.52 (CONH), 3284.26 (NH). ES-MS (m/z) [M +
Na]+ 1347.8 (calcd 1347.74), [M + H]+ 1325.8 (calcd 1325.76),
[M + K]+ 1363.8 (calcd 1363.71). Anal. Calcd for C78H108N4O10S2:
C, 70.66; H, 8.21; N, 4.23. Found: C, 70.22; H, 8.07; N, 3.98.
Sin gle-Cr ysta l X-r a y Diffr a ction . Single crystals were
obtained from CH2Cl2/EtOH and mounted on a glass fiber.
X-ray data were collected at 173 K on a Kappa CCD diffrac-
tometer at the Centre de Diffractometrie Henri Longchambon
(UCB LYON 1). All calculations were performed with DEN-
ZO,50 SHELXS97,51 SHELXL97,51 and PLUTON.52 Non-H
atoms were refined anisotropically; H atoms were included at
calculated positions and refined riding on C, N, or O.
D
D
1H NMR δ 0.57 (d, 4H, J ) 5.67 Hz), 0.81 (d, 4H, J ) 5.46
Hz), 0.96 (s, 18H), 1.33 (s, 18H), 1.51-1.53 (br m, 6H), 1.79-
1.98 (br m, 8H), 2.40 (s, 6H), 3.33-3.39 (m, 8H), 3.86-4.01
(m, 6H), 4.25 (d, 2H, J ) 13.2 Hz), 4.26 (d, 2H, J ) 13.0 Hz),
5.25 (d, 2H, J ) 8.28 Hz), 6.80 (s, 4H), 7.10 (s, 4H), 7.26 (br,
2H), 7.26 (d, 4H, J ) 7.92 Hz), 7.42 (s, 2H), 7.76 (d, 4H, J )
8.28 Hz). 13C NMR δ 21.3, 21.9, 23.4, 24.7, 26.4, 27.5, 31.4,
32.1, 32.2, 39.8, 42.8, 56.1, 77.0, 125.6, 126.0, 127.8, 128.3,
130.0, 132.7, 137.4, 142.4, 143.9, 147.4, 150.3, 151.4, 172.9.
IR 3361 (NH), 3113 (OH), 1665 (CO). ES-MS (m/z) 1347.7 [M
+ Na]+ (calcd 1347.74), 1325.7 [M + H]+ (calcd 1325.76). Anal.
Calcd for C78H108N4O10S2: C, 70.66; H, 8.21; N, 4.23. Found:
C, 70.64; H, 8.61; N, 3.93.
Cr ysta l d a ta for C74H100N4O10S2 (6f): a ) 16.440(3) Å, b
) 19.767(4) Å, c ) 25.584(5) Å, â ) 98.27(3)°, V ) 8228(3) Å,
monoclinic, space group P21, Z ) 4, Dx ) 1.151 g‚cm-3, µ )
1.25 cm-1. Full-matrix least-squares isotropic refinement was
based on 9768 reflections for 843 parameters; R ) 0.108 [I >
2σ(I)], Rw ) 0.340, GOF ) 1.249, largest difference peak )
5,11,17,23-Tet r a -4-ter t-b u t yl-25,27-d i(N-t osyl-L-isole-
u cyla m in obu toxy)-26,28-d ih yd r oxyca lix[4]a r en e (7i). The
product was purified by column chromatography on silica gel
1.16 e Å-3
.
1HNMR Titr a tion s. A 10 mM solution of the host in CDCl3
was prepared. To 0.5 mL of this solution was added 0-5 equiv
of tetrabutylammonium salts in the 1H NMR tube and the
spectra were recorded. The chemical shifts of the NH proton
were followed and plotted against the equivalents of guest
added.
eluting with EtOAc/hexane 3/7 to give 7i as white crystals (130
1
mg, 55%): mp 162-164 °C. 7i: [R]20 -25.7 (c 0.3, CHCl3). H
D
NMR δ 0.71 (d, 6H, J ) 6.78 Hz), 0.70-0.85 (m, 6H), 0.97 (s,
18H), 0.95-1.10 (m, 2H), 1.32 (s, 18H), 1.40-1.50 (m, 2H),
1.69-1.95 (m, 10H), 2.40 (s, 6H), 3.32-3.38 (m, 8H), 3.70-
3.74 (dd, 2H, J ) 5.50 Hz), 3.97-4.03 (m, 4H), 4.26 (dd, 4H, J
) 13.0 Hz), 5.75 (d, 2H, J ) 8.67 Hz), 6.80 (s, 4H), 7.08-7.09
(br m, 6H), 7.25 (d, 4H, J ) 6.78 Hz), 7.40 (s, 2H), 7.75 (d, 4H,
J ) 8.28 Hz). 13C NMR δ 11.7, 15.9, 21.9, 24.6, 26.4, 27.7, 31.4,
32.1, 32.2, 34.3, 38.5, 39.8, 62.1, 76.7, 11.9, 125.6, 126.0, 127.8,
128.3, 130.0, 132.8, 137.4, 142.3, 143.9, 147.4, 150.2, 150.7,
171.5. IR 3358 (OH, NH), 1665 (CO). ES-MS (m/z) 1347.8 [M
+ Na]+ (calcd 1347.74), 1325.4 [M + H]+ (calcd 1325.76). Anal.
Calcd for C78H108N4O10S2‚2H2O: C, 68.77; H, 8.31; N, 4.11.
Found: C, 68.40; H, 8.38; N, 3.84.
J ob P lot. Stick solutions for the host (10 mM) and for the
tetrabutylammonium salts (10 mM) in CDCl3 were prepared.
The 1H NMR tubes were filled with 500-µL solutions of the
host and guest in the following volume ratios: 50:450, 100:
400, 150:350, 200:300, 250:250, 300:200, 400:100, and 450:50.
Ack n ow led gm en t. The authors thank the CMCU
and EZUS-LYON I, ANVAR for their financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR (300 MHz)
spectra of 6a and 7g in DMSO-d6 and in CDCl3. This material
is available free of charge via the Internet at http://pubs.acs.org.
5,11,17,23-Tetr a -4-ter t-bu tyl-25,27-d i(N-tosyl-L-a la n yl-
am in obu toxy)-26,28-dipr opoxycalix[4]ar en e (9). The prod-
uct was purified by column chromatography on silica gel
eluting with EtOAc/hexane 5/5 to give 9 as a white powder
(80 mg, 45%): mp 126-128 °C. 9: [R]20D -22.8 (c 0.75, CHCl3).
1H NMR δ 0.89 (s, 18H), 1.06 (t, J ) 7.35 Hz, 6H), 1.26-1.31
(s + d, 24 H), 1.50-1.57 (m, 4H), 1.91-1.96 (q, J ) 7.35 Hz),
2.12-2.18 (m, 4H), 2.45 (s, 6H), 3.14 (AB, J AB ) 12.42 Hz),
3.70 (t, J ) 7.35 Hz), 3.89 (q, J ) 7.35 Hz, 2H), 4.01 (t, J )
8.10 Hz), 4.38 (AB, J AB ) 12.42 Hz), 6.03 (d, J ) 7.89 Hz),
6.52 (s, 4H), 6.93 (s t large, 2H), 7.06 (s, 4H), 7.32 (d, J ) 8.10
J O034275J
(50) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307.
(51) Sheldrick, G. M. Shelxs97, Program for Crystal Structure
Solution; Shelxl97, Program for Crystal Structure Refinement; Uni-
versity of Gottingen: Gottingen, Germany, 1997.
(52) Spek, A. L. Platon, A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, The Netherlands.
6638 J . Org. Chem., Vol. 68, No. 17, 2003