Calixsugars: Preparation of upper rim O-ketopyranosyl calix[4]arenes

Full text of DOI:10.1021/jo960417g

J . Org. Chem. 1996, 61, 5155-5158
5155
Ca lixsu ga r s:† P r ep a r a tion of Up p er Rim
these ketoses the glycosylation of calixarenes. Various
synthetic elaborations of the resulting calixsugars were
foreseen via the facile transformation of the thiazole ring
into a readily manipulatable functionality such as the
formyl group.10 This synthetic equivalence plays a
pivotal role in this chemistry too. First of all the
aldehyde releasing from the thiazole ring is compatible
with the presence of the most common hydroxyl protec-
tive groups such as the benzyl, isopropylidene, and silyl.11
Second, the modest electron-withdrawing character of the
thiazole ring appears to affect much less dramatically
than others groups the glycosylation reaction via an
oxycarbenium ion intermediate.12
As a ketosyl donor we chose the readily available8
D-galacto derivative 1 whose reactions with trimethylsilyl
azide13 and sugar alcohols9 were already demonstrated.
Hence a model glycosylation reaction between 1 (1.5
equiv for each OH group) and the symmetrical bis-
(hydroxymethyl)-substituted calix[4]arene7,14 2 (Scheme
1) was generated under the same conditions, i.e., in CH2-
Cl2 at room temperature in the presence of trimethylsilyl
triflate (TMSOTf; 1.5 equiv for each OH group) and 4-Å
molecular sieves. The slow addition of the Lewis acid
by a syringe pump to the solution of 1 and 2 was
employed in order to avoid tethering in the latter by
intramolecular ether linkage formation (see Experimen-
tal Section). Under these conditions the R-linked di-O-
galactosyl calixarene 4 was isolated by flash chromatog-
raphy in 60% yield.15 While the fixed cone conformation
of the calixarene moiety in 4 was apparent from the
chemical shifts and multiplicity patterns16 of the proton
signals of the methylene bridges in its 1H NMR spectrum,
the stereochemistry at the anomeric center of the two
sugar moieties was established by 13C NMR analysis of
a product derived from it (see below). The high level and
sense of stereoselectivity observed in this reaction of the
galactoketose acetate 1 are very much in line with the
results of earlier glycosylation reactions of this substrate.9
O-Ketop yr a n osyl Ca lix[4]a r en es†
Alberto Marra, Alessandro Dondoni,* and
Francesco Sansone‡
Dipartimento di Chimica, Laboratorio di Chimica Organica,
Universita`, Ferrara, Italy
Received February 29, 1996
Calixarenes1 are quite popular macrocyclic oligomers
arising from the phenol-formaldehyde polymerization
and are currently of increasing interest. They provide
the basic architectural array for the construction of larger
molecular systems with defined structures and proper-
ties.2 Numerous potential applications of calixarene
derivatives as specific ligands for cations, anions, and
neutral molecules have been foreseen.3 The para-
substituted tetramer calix[4]arenes have attracted most
of the attention because their formation can be favored
by adopting suitable condensation conditions4 and their
conformational mobility can be controlled by placing
appropriate substituents in the phenyl rings.5 Among
the complex molecular fragments which have been in-
stalled at either rim of these macrocycles,6 those arising
from natural sugars may offer various opportunities for
molecular recognition in water of chiral highly polar
organic molecules. To this aim we and others have
recently described the preparation of calix[4]arenes
substituted at the lower and upper rims with O-glycosyl
groups derived from aldofuranoses and aldopyranoses.7
Given the ready preparation of various thiazolyl ketols8
and the role of their acetates to serve as efficient glycosyl
donors,9 it appeared quite interesting to us to extend to
† The trivial name calixsugars refers to calixarene derivatives
wherein one or more mono- or oligosaccharide moieties are bounded
at either the upper or lower rim by an O- or C-glycosidic bond. The
term has been created in analogy to that used for calixarene-crown
ether coupled systems (Alfieri, C.; Dradi, E.; Pochini, A.; Ungaro, R.;
Andreetti, G. D. J . Chem. Soc., Chem. Commun. 1983, 1075), which
were later referred to as calixcrowns (see: (a) Dijkstra, P. J .; Brunink,
J . A. J .; Bugge, K.-E.; Reinhoudt, D. N.; Harkema, S.; Ungaro, R.;
Ugozzoli, F.; Ghidini, E. J . Am. Chem. Soc. 1989, 111, 7567. (b)
Yamamoto, H.; Sakaki, T.; Shinkai, S. Chem. Lett. 1994, 469).
‡ On temporary leave from the University of Parma (Italy) for the
fulfilment of a Ph.D. Thesis in organic chemistry.
(1) (a) Gutsche, C. D. In Calixarenes, Monograph in Supramolecular
Chemistry, Vol. 1; Stoddart, J . F., Ed.; Royal Society of Chemistry:
Cambridge, 1989. (b) Calixarenes, a Versatile Class of Macrocyclic
Compounds; Vicens, J ., Bo¨hmer, V., Eds.; Kluwer Academic Publish-
ers: Dordrecht, 1991.
(10) Dondoni, A. In Modern Synthetic Methods; Scheffold, R., Ed.;
Verlag Helvetica Chimica Acta: Basel, 1992, pp 377-437. Dondoni,
A. In New Aspects of Organic Chemistry II; Yoshida, Z., Ohshiro, Y.,
Eds.; Kodansha: Tokyo, and VCH: Weinheim, 1992; pp 105-128.
(11) This feature favors the use of thiazole instead of furan since
the cleavage of the furan ring to carboxyl group requires strong
oxidative conditions which are not tolerated by the above protective
groups (Dondoni, A.; Marra, A.; Scherrmann, M.-C. Tetrahedron Lett.
1993, 34, 7323 and references cited therein). However, due to the
electron-donor character of the furan ring, the glycosylation reaction
should be favored by the presence of this heterocycle at the anomeric
position (see: (a) Danishefsky, S. J .; Pearson, W. H.; Segmuller, B. E.
J . Am. Chem. Soc. 1985, 107, 1280. (b) Danishefsky, S. J .; DeNinno,
M. P.; Chen, S. J . Am. Chem. Soc. 1988, 110, 3929).
(12) Although this matter has been already discussed in our previous
paper (see ref 9), it may be recalled here that O-glycosidations of sugar
bearing at C-1 an alkoxymethyl (i.e., ketoses) or an alkoxycarbonyl
group (i.e., ulosonic acids) can be efficiently carried out only if highly
reactive leaving groups are present at the anomeric position (e.g., -SR,
-SC(S)OEt, -OP(OR)2). For recent articles, see: (a) Lo¨nn, H.; Stenvall,
K. Tetrahedron Lett. 1992, 33, 115. (b) Mu¨ller, T.; Schneider, R.;
Schmidt, R. R. Tetrahedron Lett. 1994, 35, 4763. (c) Kondo, H.; Aoki,
S.; Ichikawa, Y.; Halcomb, R. L.; Ritzen, H.; Wong, C.-H. J . Org. Chem.
1994, 59, 864. (d) Heskamp, B. M.; Veeneman, G. H.; van der Marel,
G. A.; van Boeckel, C. A. A.; van Boom, J . H. Tetrahedron 1995, 51,
5657.
(2) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713.
(3) For recent reviews, see: (a) Takeshita, M.; Shinkai, S. Bull.
Chem. Soc. J pn. 1995, 68, 1088. (b) Gutsche, C. D. Aldrichimica Acta
1995, 28, 3. (c) Lhota´k, P.; Shinkai, S. J . Synth. Org. Chem., J pn.
1995, 53, 963.
(4) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234.
(5) Unmodified calix[4]arenes are conformationally mobile macro-
cycles which adopt a cone conformation because of strong hydrogen
bonds among the hydroxy groups. The n-propylation of these groups
inhibits the oxygen-through-the-annulus rotation and allows the
isolation of the blocked cone conformational isomer (see: (a) Araki,
K.; Iwamoto, K.; Shinkai, S.; Matsuda, T. Chem. Lett. 1989, 1747. (b)
Iwamoto, K.; Araki, K.; Shinkai, S. J . Org. Chem. 1991, 56, 4955).
(6) Besides the crown ether moieties, also porphyrin (Nagasaki, T.;
Fujishima, H.; Shinkai, S. Chem. Lett. 1994, 989) and â-cyclodextrin
(D’ Alessandro, F.; Gulino, F. G.; Impellizzeri, G.; Pappalardo, G.;
Rizzarelli, E.; Sciotto, D.; Vecchio, G. Tetrahedron Lett. 1994, 35, 629.
van Dienst, E.; Snellink, B. H. M.; von Piekartz, I.; Engbersen, J . F.
J .; Reinhoudt, D. N. J . Chem. Soc., Chem. Commun. 1995, 1151) have
been covalently linked to calix[4]arenes.
(13) Dondoni, A.; Scherrmann, M.-C.; Marra, A.; Dele´pine, J .-L. J .
Org. Chem. 1994, 59, 7517.
(14) Casnati, A.; Fochi, M.; Minari, P.; Pochini, A.; Reggiani, M.;
Ungaro, R.; Reinhoudt, D. N. Gazz. Chim. Ital. 1996, 126, 99.
(15) Also isolated was unreacted thiazolyl ketol acetate 1 in 32%
yield.
(16) Calix[4]arenes having a cone conformation display the signals
for the equatorial and axial protons of the methylene bridges as well
resolved doublets at δ ∼3 and δ ∼4, respectively (see ref 1a, pp 108-
111).
(7) Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati, A.; Minari,
P.; Ungaro, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479.
(8) Dondoni, A.; Scherrmann, M.-C. J . Org. Chem. 1994, 59, 6404.
(9) Dondoni, A.; Marra, A.; Rojo, I.; Scherrmann, M.-C. Tetrahedron
1996, 52, 3057.
S0022-3263(96)00417-3 CCC: $12.00 © 1996 American Chemical Society

5156 J . Org. Chem., Vol. 61, No. 15, 1996
Notes
Sch em e 1
Accordingly, an identical explanation can be advanced,
i.e., the formation of a chairlike transition state17 derived
from an axial attack of the hydroxyl group of the acceptor
2 to the less hindered face of the oxycarbenium ion
intermediate (generated from 1 by the TMSOTf-promoted
removal of the acetoxy group) existing in a half-chair
conformation and bearing a nonparticipating group at
C-2.
precedents. Quite happily, successful unmasking took
place to give the dialdehyde 6 which, without purification,
was either reduced with sodium borohydride to the diol
7 (41% isolated yield) or oxidized19 with iodine in metha-
nolic KOH to the diester 8 (51% isolated yield). The
anomeric configuration of 8 was assigned on the basis of
the vicinal coupling constants between the carboxyl
carbon C-1 and the axial proton H-3 (ulosonic acid
numbering) following a rule established for sialic acid
derivatives.20 The 13C NMR spectrum, recorded with
selective decoupling of the methyl ester protons, showed
the C-1 signal as a singlet (3J C-1, H-3 < 1 Hz), as expected
for an R-D-ulosonate derivative in a 4C1 conformation
having nearly 60° dihedral angle C-1_C-2_C-3_H-3.21 The
stereochemistry assigned to diester 8 was assumed for
its precursors as well.
Quite unexpectedly, the removal of the benzyl protec-
tive groups from the diol 7 proved unsuccessful by
repeated attempts of hydrogenolysis in the presence of
various catalysts (Pd-C, Rh-C, Pd(OH)2). Instead,
substantial decomposition of this compound occurred to
give complex mixtures of products containing sugar
molecules arising from the cleavage of the anomeric
benzylic bond. On the other hand, satisfactory deben-
zylation of the diester 8 to compound 9 (48% isolated
yield) was carried out by reduction with hydrogen over
Pd-C at 4 bar. The saponification of 9 led to the totally
unprotected heptulosonic acid moieties shown in the
calixsugar 10. The same reaction sequence was unsuc-
cessful with the tetrathiazolyl derivative 5. The thiaz-
olyl-to-formyl unmasking protocol with this compound
The glycosylation reaction of the same ketosyl donor
1 (1.5 equiv for each OH group) with the tetrakis-
(hydroxymethyl) calix[4]arene7 3 under similar conditions
as above (CH2Cl2, rt, 1.5 equiv of TMSOTf for each OH
group) produced a complex mixture of di-, tri-, and
tetraadducts from which the tetrasubstituted calixsugar
5 (Scheme 1) was isolated by flash chromatography in
only 11% yield. Individual minor products were not
isolated. The poor yield of 5 is very likely due to the
restricted cone conformation of the macrocycle and the
increasing congestion of the system by the sequential
insertion of the bulky ketosyl fragments. Nevertheless,
calixsugar 5 appeared to be the product of stereoselective
glycosylation as well, since all the four sugar moieties
were installed through an R-glycosyl linkage. This
stereochemistry was assigned on the basis of strict
similarities between the 1H NMR spectrum of 5 and that
of the disubstituted calixsugar 4. To the best of our
knowledge, there are no precedents of polyol multigly-
cosylation with a ketose.
Model synthetic elaborations were generated by the
cleavage of the two thiazole rings of the disubstituted
calixsugar 4 (Scheme 2) employing the usual one-pot
protocol constituted by three sequential and high-yield
reactions, i.e., N-methylation, reduction, and hydrolysis.18
The concomitant application of this procedure to two
thiazole rings belonging to the same substrate has no
(19) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett.
1992, 33, 4329.
(20) (a) Haverkamp, J .; Spoormaker, T.; Dorland, L.; Vliegenthart,
J . F. G.; Schauer, R. J . Am. Chem. Soc. 1979, 101, 4851. (b) Hori, H.;
Nakajima, T. Nishida, Y.; Ohrui, H.; Meguro, H. Tetrahedron Lett.
1988, 29, 6317. (c) Prytulla, S.; Lauterwein, J .; Klessinger, M.; Thiem,
J . Carbohydr. Res. 1991, 215, 345.
(17) Babirad, S. A.; Wang, Y.; Kishi, Y. J . Org. Chem. 1987, 52, 1370.
(18) Dondoni, A.; Marra, A.; Perrone, D. J . Org. Chem. 1993, 58,
275.
(21) The â-D-anomer having a nearly 180° dihedral angle should
display the C-1 signal as a doublet (3J C-1,H-3 ≈ 4.0 Hz).

Notes
J . Org. Chem., Vol. 61, No. 15, 1996 5157
using 3-nitrobenzyl alcohol as the matrix. Since the elemental
analyses of calixarenes are very often uncorrected24 (found
carbon values considerably lower than the calculated ones), the
identity and purity of the following new compounds were
established by MS and NMR analyses.
Sch em e 2
25,26,27,28-Tetr a p r op oxy-5,17-bis[[[2,3,4,6-tetr a -O-ben -
zyl-1-C-(2-th iazolyl)-r-D-galactopyr an osyl]oxy]m eth yl]calix-
[4]a r en e (4). A mixture of calix[4]arene 2 (130 mg, 0.2 mmol),
acetate 1 (400 mg, 0.6 mmol), activated 4-Å powdered molecular
sieves (0.60 g), and anhydrous CH2Cl2 (6 mL) was stirred at rt
for 15 min; then a solution of trimethylsilyl triflate (108 µL, 0.6
mmol) in anhydrous CH2Cl2 (1 mL) was added during 30 min
by means of a syringe pump apparatus equipped with a gas-
tight syringe. After an additional 15 min at rt, the mixture was
treated with an excess of Et3N, diluted with CH2Cl2, filtered
through Celite, and concentrated. The residue was eluted from
a column of silica gel with cyclohexane-AcOEt (5:1, then 2:1)
to afford first 4 (224 mg, 60%) as a syrup: [R]D ) +16.5 (c 1,
CHCl3). 1H NMR: δ 7.85 and 7.36 (2 d, 4 H, J ) 3.5 Hz, 2 Th),
7.35-7.18 (m, 40 H, 8 Ph), 7.09 and 6.93 (2 d, 4 H, J ) 1.5 Hz,
Ar), 6.25 (t, 2 H, J ) 7.5 Hz, Ar), 6.20 and 6.13 (2 dd, 4 H, J )
2.0, 7.5 Hz, Ar), 4.99 and 4.65 (2 d, 4 H, J ) 11.8 Hz, 2 PhCH2),
4.77 and 4.73 (2 d, 4 H, J ) 11.5 Hz, 2 PhCH2), 4.66 and 4.37 (2
d, 4 H, J ) 11.0 Hz, 2 PhCH2), 4.54 and 4.47 (2 d, 4 H, J ) 11.7
Hz, 2 PhCH2), 4.53 and 4.40 (2 d, 4 H, J ) 11.3 Hz, 2 ArCH2O),
4.41 (d, 2 H, J ) 13.0 Hz, 2 Hax of ArCH2Ar), 4.39 (d, 2 H, J )
13.0 Hz, 2 Hax of ArCH2Ar), 4.24 (dd, 2 H, J 2,3 ) 10.0, J 3,4 ) 2.2
Hz, 2 H-3), 4.16 (d, 2 H, 2 H-2), 4.09-4.04 (m, 4 H, 2 H-4, 2
H-5), 3.90-3.20 (m, 4 H, 2 CH3CH2CH2O), 3.82-3.73 (m, 4 H, 4
H-6), 3.71 (t, 4 H, 2 CH3CH2CH2O), 3.09 (d, 2 H, 2 Heq of ArCH2-
Ar), 3.08 (d, 2 H, 2 Heq of ArCH2Ar), 2.00-1.83 (m, 8 H,
4 CH3CH2CH2O), 1.09 (t, 6 H, J ) 7.0 Hz, 2 CH3CH2CH2O),
0.89 (t, 6 H, J ) 7.0 Hz, 2 CH3CH2CH2O). FAB-MS for
C
116H122N2O16S2: m/ z 1865.3 (M + H+). Eluted second was
unreacted 1 (128 mg, 32%).
25,26,27,28-Tet r a p r op oxy-5,11,17,23-t et r a k is[[[2,3,4,6-
tetr a-O-ben zyl-1-C-(2-th iazolyl)-r-D-galactopyr an osyl]oxy]-
m eth yl]ca lix[4]a r en e (5). A mixture of calix[4]arene 3 (71 mg,
0.1 mmol), acetate 1 (400 mg, 0.6 mmol), activated 4-Å powdered
molecular sieves (0.60 g), and anhydrous CH2Cl2 (6 mL) was
stirred at rt for 15 min; then a solution of trimethylsilyl triflate
(108 µL, 0.6 mmol) in anhydrous CH2Cl2 (1 mL) was added
during 50 min by means of a syringe pump apparatus equipped
with a gas-tight syringe. At the end of the addition, the mixture
was treated with an excess of Et3N, diluted with CH2Cl2, filtered
through Celite, and concentrated. The residue was eluted from
a column of silica gel with 4:1 cyclohexane-AcOEt to give 5
together with uncharacterized byproducts. Column chromatog-
raphy (12:1 CH2Cl2-Et2O) of this mixture afforded pure 5 (35
mg, 11%) as a syrup: [R]D ) +12.3 (c 0.7, CHCl3). 1H NMR: δ
7.69 (d, 4 H, J 4,5 ) 3.2 Hz, H-4 of 4 Th), 7.31-7.20 (m, 84 H, 16
Ph, H-5 of 4 Th), 6.71-6.52 (2 d, 8 H, J ) 2.0 Hz, 4 Ar), 4.90
and 4.57 (2 d, 8 H, J ) 11.7 Hz, 4 PhCH2), 4.66 and 4.61 (2 d, 8
H, J ) 12.0 Hz, 4 PhCH2), 4.52 and 4.20 (2 d, 8 H, J ) 11.0 Hz,
4 PhCH2), 4.43 and 4.33 (2 d, 8 H, J ) 11.6 Hz, 4 PhCH2), 4.33
and 3.00 (2 d, 8 H, J ) 13.2 Hz, 4 ArCH2Ar), 4.16 and 3.93 (2 d,
8 H, J ) 11.7 Hz, 4 ArCH2O), 4.07-4.00 (m, 8 H, 4 H-2, 4 H-3),
3.98 (m, 4 H, 4 H-4), 3.82-3.68 (m, 16 H, 4 CH3CH2CH2O, 4
H-5, 4 H-6a), 3.54 (dd, 4 H, J 5,6a ) 4.4, J 6a,6b ) 8.1 Hz, 4 H-6b),
1.91-1.78 (m, 8 H, 4 CH3CH2CH2O), 0.92 (t, 12 H, J ) 7.4 Hz,
4 CH3CH2CH2O). Electrospray-MS for C192H196N4O28S4: m/ z
3135.83 ( 1.21 (M + H+).
followed by the reduction or oxidation of the crude
mixture as described above did not produce any isolable
product.
In conclusion, the preparation of calixsugars bearing
interesting functional groups in the sugar unit has been
shown here. This and previous work7 open the route for
the installation of various types of glycosidic fragments
at the lower and upper rims of calixarenes. The applica-
tion of these methodologies to designed structures and
the exploration of their physicochemical properties now
become of interest.
Exp er im en ta l Section
All moisture-sensitive reactions were performed under a
nitrogen atmosphere using oven-dried glassware. All solvents
were dried over standard drying agents22 and freshly distilled
prior to use. Commercially available powdered 4-Å molecular
sieves (50 µm average particle size) were used without further
activation. Flash column chromatography23 was performed on
silica gel 60 (230-400 mesh). Reactions were monitored by TLC
on silica gel 60 F254 with detection by charring with sulfuric acid.
Optical rotations were measured at 20 ( 2 °C in the stated
solvent. 1H (300 MHz) and 13C (75 MHz) NMR were recorded
at rt for CDCl3 solutions, unless otherwise specified. Assigments
were aided by decoupling and/or homo- and heteronuclear two-
dimensional experiments. FAB mass spectra were acquired
25,26,27,28-Tetr a p r op oxy-5,17-bis[[(3,4,5,7-tetr a -O-ben -
zyl-r-D-ga la ct o-h e p t u lop yr a n osyl)oxy]m e t h yl]ca lix[4]-
a r en e (7). A mixture of thiazolyl ketoside 4 (186 mg, 0.1 mmol),
activated 4-Å powdered molecular sieves (0.2 g), anhydrous CH2-
Cl2 (0.5 mL), and anhydrous CH3CN (1 mL) was stirred at rt
for 10 min; then methyl triflate (28 µL, 0.26 mmol) was added.
The suspension was stirred at rt for 15 min and then concen-
trated to dryness. The crude bis(N-methylthiazolium) salt was
suspended in 1:1 MeOH-Et2O (2 mL) and treated with NaBH4
(15 mg, 0.4 mmol). The mixture was stirred at rt for an
(24) The issue regarding these discrepancies in elemental analyses
has been addressed by authoritative researchers in calixarene chem-
istry. See: (a) Bo¨hmer, V.; J ung, K.; Scho¨n, M.; Wolff, A. J . Org. Chem.
1992, 57, 790. (b) Gutsche, C. D.; See, K. A. J . Org. Chem. 1992, 57,
4527.
(22) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
(23) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

5158 J . Org. Chem., Vol. 61, No. 15, 1996
Notes
additional 5 min; diluted with acetone (1 mL), and concentrated.
The residue was suspended in CH2Cl2, filtered through Celite,
and concentrated. A solution of the crude thiazolidines in CH2-
Cl2 (0.5 mL) was diluted with CH3CN (1 mL) and H2O (0.1 mL),
and then treated with CuO (127 mg, 1.6 mmol) and CuCl2‚2H2O
(34 mg, 0.2 mmol). The mixture was sonicated at rt for 10 min
in an ultrasonic cleaning bath and then concentrated to dryness
(temperature not exceeding 40 °C). The brown solid was
triturated with Et2O (4 × 3 mL), and the liquid phase was
pipetted and filtered through Celite. The solution was concen-
trated to afford the dialdehyde 6 as a brown syrup which was
used in the next step without further purification. To a stirred
solution of crude 6 in Et2O (1 mL) and MeOH (0.5 mL) was added
NaBH4 (15 mg, 0.4 mmol). Stirring was continued at rt for 10
min; then acetone (1 mL) was added and the mixture was
concentrated. A solution of the crude diol in CH2Cl2 (30 mL)
was washed with H2O (5 mL), dried (Na2SO4), and concentrated.
Column chromatography (5:1 cyclohexane-AcOEt) of the residue
afforded 7 (72 mg, 41%) as a syrup: [R]D ) +21.9 (c 1, CHCl3).
1H NMR: δ 7.40-7.22 (m, 40 H, 8 Ph), 6.83 and 6.76 (2 d, 4 H,
J ) 2.0 Hz, Ar), 6.36-6.26 (m, 6 H, Ar), 4.99 and 4.78 (2 d, 4 H,
J ) 11.1 Hz, 2 PhCH2), 4.95 and 4.58 (2 d, 4 H, J ) 11.3 Hz, 2
PhCH2), 4.73 (s, 4 H, 2 PhCH2), 4.51 and 4.41 (2 d, 4 H, J )
11.8 Hz, 2 PhCH2), 4.49 and 4.42 (2 d, 4 H, J ) 12.0 Hz, 2
ArCH2O), 4.40 (d, 2 H, J ) 13.2 Hz, 2 Hax of ArCH2Ar), 4.39 (d,
2 H, J ) 13.2 Hz, 2 Hax of ArCH2Ar), 4.25 (d, 2 H, J 3,4 ) 10.0
Hz, 2 H-3), 4.11 (dd, 2 H, J 4,5 ) 2.6 Hz, 2 H-4), 4.01 (d, 1 H, J 5,6
) 1.0 Hz, 2 H-5), 3.94 (ddd, 2 H, J 6,7a ) J 6,7b ) 6.5 Hz, 2 H-6),
3.91-3.85 (m, 4 H, 2 CH3CH2CH2O), 3.75 (t, 4 H, J ) 7.0 Hz, 2
CH3CH2CH2O), 3.66 (dd, 2 H, J 1a,1b ) 11.8, J 1a,OH ) 9.2 Hz, 2
H-1a), 3.62-3.59 (m, 4 H, 4 H-7), 3.57 (dd, 2 H, J 1b,OH ) 3.5 Hz,
2 H-1b), 3.06 (d, 4 H, 4 Heq of ArCH2Ar), 2.38 (dd, 2 H, 2 OH),
1.98-1.83 (m, 8 H, 4 CH3CH2CH2O), 1.04 (t, 6 H, J ) 7.3 Hz, 2
CH3CH2CH2O), 0.92 (t, 6 H, J ) 7.3 Hz, 2 CH3CH2CH2O). FAB-
MS for C112H124O18: m/ z 1781.3 (M + Na+).
25,26,27,28-Tetr a p r op oxy-5,17-bis[[(m eth yl 3,4,5,7-tetr a -
O-ben zyl-r-D-ga la cto-h ep tu lop yr a n osylon a te)oxy]m eth yl]-
ca lix[4]a r en e (8). The thiazolyl ketoside 4 (186 mg, 0.1 mmol)
was converted into the dialdehyde 6 as described for the
preparation of 7. To a vigorously stirred solution of crude 6 in
Et2O (1 mL) and MeOH (1 mL) were added, dropwise and
simultaneously, a 1 M solution of KOH in MeOH and a 0.5 M
solution of I2 in MeOH until the intermediate methyl hemiac-
etals formed in situ had disappeared (TLC analysis); then the
mixture was neutralized with AcOH and concentrated. The
crude diester was diluted with CH2Cl2 (30 mL), washed with
aqueous 10% Na2S2O3‚5H2O (2 × 5 mL), dried (Na2SO4), and
concentrated. The residue was eluted from a column of silica
gel with 6:1 cyclohexane-AcOEt to give 8 (92 mg, 51%) as a
syrup: [R]D ) -3.8 (c 0.9, CHCl3). 1H NMR: δ 7.38-7.21 (m,
40 H, 8 Ph), 7.07 and 6.95 (2 d, 4 H, J ) 1.8 Hz, Ar), 6.28-6.15
(m, 6 H, Ar), 4.97 and 4.66 (2 d, 4 H, J ) 11.8 Hz, 2 PhCH2),
4.87 and 4.70 (2 d, 4 H, J ) 11.5 Hz, 2 PhCH2), 4.85 and 4.47 (2
d, 4 H, J ) 11.4 Hz, 2 ArCH2O), 4.73 (s, 4 H, 2 PhCH2), 4.50
and 4.40 (2 d, 4 H, J ) 11.5 Hz, 2 PhCH2), 4.41 (d, 2 H, J ) 13.5
Hz, 2 Hax of ArCH2Ar), 4.39 (d, 2 H, J ) 13.5 Hz, 2 Hax of
ArCH2Ar), 4.37 (d, 2 H, J 3,4 ) 10.0 Hz, 2 H-3), 4.10 (dd, 2 H, J 4,5
) 2.7 Hz, 2 H-4), 3.99 (dd, 2 H, J 5,6 ) 1.0 Hz, 2 H-5), 3.96-3.91
(m, 4 H, 2 CH3CH2CH2O), 3.87 (ddd, 2 H, J 6,7a ) J 6,7b ) 6.5 Hz,
2 H-6), 3.70 (t, 4 H, J ) 7.0 Hz, 2 CH3CH2CH2O), 3.65-3.61 (m,
4 H, 4 H-7), 3.58 (s, 6 H, 2 COCH3), 3.07 (d, 4 H, 4 Heq of ArCH2-
Ar), 2.00-1.82 (m, 8 H, 4 CH3CH2CH2O), 1.08 (t, 6 H, J ) 7.5
Hz, 2 CH3CH2CH2O), 0.88 (t, 6 H, J ) 7.5 Hz, 2 CH3CH2CH2O).
13C NMR (selected data): δ 167.83 (2 CO2CH3), 100.44 (2 C-2),
52.42 (2 CO2CH3), 31.00 (4 ArCH2Ar), 23.45 and 23.01 (4
CH3CH2CH2O), 10.73 and 9.92 (4 CH3CH2CH2O). FAB-MS for
C
114H124O20: m/ z 1837.5 (M + Na+).
25,26,27,28-Tetr a p r op oxy-5,17-bis[[(m eth yl r-D-ga la cto-
h ep tu lop yr a n osylon a te)oxy]m eth yl]ca lix[4]a r en e (9).
A
vigorously stirred mixture of 8 (91 mg, 0.05 mmol) and 10%
palladium on activated carbon (45 mg) in 2:1 MeOH-AcOEt (10
mL) was degassed under vacuum and saturated with hydrogen
three times. The suspension was stirred for an additional 4 h
at rt under 4 bar of H2 and then filtered through a plug of cotton
and concentrated. The residue was eluted from a Sephadex LH-
20 column (2 × 80 cm) with 5:1 CH2Cl2-MeOH to give 9 (26 mg,
48%) as an amorphous solid: [R]D ) +42.8 (c 0.5, MeOH). 1H
NMR (CD3OD): δ 6.90 and 6.82 (2 d, 4 H, J ) 2.0 Hz, Ar), 6.52-
6.40 (m, 6 H, Ar), 4.46 (d, 4 H, J ) 13.3 Hz, 4 Hax of ArCH2Ar),
4.46 and 4.32 (2 d, 4 H, J ) 11.0 Hz, 2 ArCH2O), 3.94-3.74 (m,
16 H, 2 H-5, 2 H-6, 4 H-7, 4 CH3CH2CH2O), 3.91 (d, 2 H, J 3,4
)
9.8 Hz, 2 H-3), 3.80 (s, 6 H, 2 COCH3), 3.73 (dd, 2 H, J 4,5 ) 3.5
Hz, 2 H-4), 3.15 (d, 4 H, 4 Heq of ArCH2Ar), 2.02-1.86 (m, 8 H,
4 CH3CH2CH2O), 1.06 (t, 6 H, J ) 7.5 Hz, 2 CH3CH2CH2O), 0.99
(t, 6 H, J ) 7.5 Hz, 2 CH3CH2CH2O).
25,26,27,28-Tet r a p r op oxy-5,17-b is[[(r-D-ga la cto-h ep t u -
lop yr a n osylon ic a cid )oxy]m eth yl]ca lix[4]a r en e (10).
A
solution of 9 (33 mg, 0.03 mmol) in 9:1 MeOH-H2O (3 mL) was
treated with freshly prepared 6 M NaOH (0.3 mL) for 3 h at rt
and then applied to a short column (0.5 × 10 cm) of Amberlite
IR 120 (16-45 mesh, H+ form) and eluted with 9:1 MeOH-H2O
to give 10 (32 mg, 100%) as a solid: mp 118 °C dec; [R]D ) +40.4
(c 0.5, MeOH). 1H NMR (CD3OD): δ 7.23 and 6.99 (2 d, 4 H, J
) 2.0 Hz, Ar), 6.37-6.28 (m, 6 H, Ar), 4.55 and 4.45 (2 d, 4 H,
J ) 10.7 Hz, 2 ArCH2O), 4.45 (d, 4 H, J ) 13.3 Hz, 4 Hax of
ArCH2Ar), 3.99-3.71 (m, 16 H, 2 H-5, 2 H-6, 4 H-7, 4 CH3-
CH2CH2O), 3.90 (d, 2 H, J 3,4 ) 9.7 Hz, 2 H-3), 3.78 (dd, 2 H, J 4,5
) 3.2 Hz, 2 H-4), 3.15 (d, 4 H, 4 Heq of ArCH2Ar), 2.04-1.86
(m, 8 H, 4 CH3CH2CH2O), 1.09 (t, 6 H, J ) 7.5 Hz, 2 CH3CH2-
CH2O), 0.96 (t, 6 H, J ) 7.5 Hz, 2 CH3CH2CH2O). FAB-MS for
C
56H72O20: m/ z 1088.2 (M + Na+).
Ack n ow led gm en t. Financial support has been pro-
vided by the Ministero dell' Universita` e della Ricerca
Scientifica e Tecnologica (Italy). We thank Mr. P.
Formaglio (University of Ferrara, Italy) for NMR mea-
surements and Dr. M. Hamdan (Glaxo Wellcome Re-
search Center, Verona, Italy) for MS determinations.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4, 5, 7, 8, 9, and 10 as evidence of the degree of
purity (6 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O960417G