Transformation of linear oligoketosides into macrocyclic neoglycoconjugates

Article abstract of DOI:10.1016/j.tetlet.2009.03.056

The macrocyclization of linear d-galacto-2-heptulopyranose-containing oligoketosides has been carried out by intramolecular glycosidation and ring-closing metathesis. The aglycon fragment of the cyclic neglycoconjugates thus formed was an alkylidene or a

Full text of DOI:10.1016/j.tetlet.2009.03.056

Tetrahedron Letters 50 (2009) 3593–3596
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transformation of linear oligoketosides into macrocyclic neoglycoconjugates
*
*
Alessandro Dondoni , Alberto Marra
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The macrocyclization of linear D-galacto-2-heptulopyranose-containing oligoketosides has been carried
Received 1 March 2009
Revised 5 March 2009
Accepted 10 March 2009
Available online 14 March 2009
out by intramolecular glycosidation and ring-closing metathesis. The aglycon fragment of the cyclic
neglycoconjugates thus formed was an alkylidene or a polyether chain. One of the oligoketoside–crown
ethers showed a moderate asymmetric induction in the Cram model phenyl acetate–acrylate addition.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Crown ethers
O-Glycosylation
Macrocycles
Michael addition
Ring-closing metathesis
Both natural and synthetic macrocyclic glycoconjugates com-
bining structurally organized carbohydrate moieties and lipophilic
subunits have been the targets of numerous synthetic efforts be-
cause these compounds offer a great deal of opportunities as chiral
amphiphilic receptors in biological studies and in asymmetric syn-
thetic methodologies. Quite notable are the natural product macro-
cyclic resin glycosides (glycolipids) such as tricolorin A and G,
woodrosin, and sophorolipid lactone. The synthesis of these com-
pounds has been carried out in Fürstner laboratory via ring-closing
metathesis as the key macrocyclization step of dialkene or dialkyne
functionalized oligosaccharide fragments.1 Moreover, Heathcock
and co-workers reported2 the synthesis of tricolorin F via classical
macrolactonization of a heterotrisaccharide-hexadecanoic acid li-
pid.3 Biological activities have been described for these lipopoly-
saccharides including general cytotoxicity against several cancer
cell lines and plant toxicity.1,4 Another abundant class of macrocy-
clic glycoconjugates is constituted of synthetic carbohydrate–
crown ether hybrids.5 These compounds belong to the vast family
of chiral crown ether derivatives6 which rekindled great interest in
the last decades for their potential as catalysts in asymmetric reac-
tions and models of enzymatic systems. Macrocycles displaying
oligoketoside fragments are quite uncommon as the only known
compounds are cyclic oligomers of fructofuranose, the so-called
cyclofructins7 to emphasize their analogy to cyclodextrins. Cyclo-
fructins have been prepared by enzymatic degradation of the fruc-
tose polymer inulin. Hence, we would like to report here on the
first synthesis of macrocyclic glycoconjugates whose glycosidic
moiety is made up of D-galacto-2-heptulopyranose units while
the tether is constituted of a polymethylene or polyether chain
(Fig. 1).
A few years ago we reported8 on an iterative glycosylation pro-
tocol affording a set of linear a-(2,1)-D-galacto-2-heptulopyranose-
containing oligoketosides 1 up to the pentameric stage (Scheme 1).
These alcohols were suitably equipped with an anomeric O-pente-
nyl group with the aim to transform them into cyclic products via
intramolecular glycosylation. Indeed this reaction occurred to a
good extent with the linear disaccharide 1a (n = 0) and trisaccha-
ride 1b (n = 1) but failed with the higher oligomers 1c (n = 2) and
1d (n = 3) which instead decomposed under the glycosidation con-
ditions. We suspected that oligomers 1c and 1d adopted a spatial
arrangement that disfavored the intramolecular process. Hence
we thought that this drawback could be avoided by elongation of
the alcohol side chain. As shown in Scheme 1, a polyether chain
was introduced because the intramolecular glycosidation carried
OR
RO
OR
RO
RO
OR
O
O
RO
O
RO
OR
O
O
X
n
O
X = CH2, O
n = 0 - 3
RO
RO
X
* Corresponding authors. Tel.: +39 0532 455176; fax: +39 0532 455167 (A.D.),
tel.: +39 0532 455156; fax: +39 0532 455167 (A.M.).
RO
Figure 1. General structure of macrocyclic glycoconjugates prepared.
E-mail addresses: adn@unife.it (A. Dondoni), mra@unife.it (A. Marra).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.056

3594
A. Dondoni, A. Marra / Tetrahedron Letters 50 (2009) 3593–3596
BnO
OBn
BnO
BnO
OBn
O
O
OH
BnO
O
OH
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
OBn
O
OBn
O
O
O
OH
Cl
Cl
HO
O
BnO
BnO
BnO
NaH, DMF, r.t.
(60-86%)
NaH, DMF, 60 °C
(45-50%)
n
n
BnO
BnO
OBn
OBn
O
O
O
O
BnO
1a-d
BnO
O
O
2a n = 0 (30%)
2b n = 1 (39%)
2c n = 2 (35%)
2d n = 3 (30%)
NIS, TMSOTf, CH2Cl2, 0 °C
n = 1
n = 2
n = 0
RO
RO
OR
RO
RO
OR
RO
RO
OR
O
O
O
O
O
O
O
RO
RO
OR
RO
O
O
O
O
O
O
O
O
RO
RO
RO
RO
O
O
O
O
O
OR
O
OR
O
OR
RO
RO
RO
RO
O
OR
O
OR
O
O
RO
RO
RO
OR
O
RO
OR
RO
OR
RO
RO
3a R = Bn (48%)
4a R = Me (46%)
3b R = Bn (43%)
4b R = Me (53%)
3c R = Bn (18%)
4c R = Me (50%)
1. Pd(OH)2, H2
2. CH3I, NaH
1. Pd(OH)2, H2
2. CH3I, NaH
1. Pd(OH)2, H2
2. CH3I, NaH
Scheme 1.
Table 1
out afterward will form a macrocyclic oligoketoside–crown ether
hybrid. This simple operation was carried out by treatment of
the linear oligoketosides 1a–d with bis(2-chloroethyl) ether and
then coupling the resulting alkyl chlorides with ethylene glycol.9
The new alcohols10 2a–d were then subjected11 to the standard
glycosylation conditions of O-pentenyl-armed carbohydrates, that
is, activation with N-iodosuccinimide-TMSOTf in CH2Cl2 at 0 °C.
The macrocyclization occurred readily with the alcohols 2a–c to
give the corresponding carbohydrate-based crown ethers10 3a–c
although in variable yields. The yields decreased substantially by
increasing the number of the heptuloside units in the oligoketoside
moiety. Therefore, no cyclic product was obtained from pentamer
2d while this oligomer decomposed under the glycosidation
conditions. Macrocycles 3a–c featuring perbenzylated carbohy-
drate fragments were readily transformed via debenzylation (H2,
Pd(OH)2) and alkylation (NaH, MeI) into the corresponding
O-methyl derivatives10 4a–c. This new element of diversity can
broaden the scope of these compounds as asymmetric molecular
receptors. Indeed macrocycles 3 and 4 were tested as chiral hosts
in the model Michael addition of methyl phenylacetate to methyl
acrylate in the presence of t-BuOM (M = Na+ and K+) according to
the classical Cram and Sogah procedure.12 The observed ee values
of the formed Michael adduct were in general low or moderate
using the tri- and tetraketoside-containing crown ethers 3b, 4b
and 3c, 4c, respectively, while higher ee’s (55% and 65%) were ob-
tained using the diketoside-based macrocycles 3a and 4a (Table 1).
Enantioselectivities of the same order of magnitude as those ob-
served here were registered in Michael additions and in other
asymmetric reactions using a variety of chiral crown ethers includ-
ing carbohydrate-based derivatives.13
Michael addition of methyl phenylacetate to methyl acrylate in the presence
of t-BuOM and crown ethers 3a–c and 4a–c
Host
Metal ion
Isolated yield (%)
ee (%) (R or S)
3a
3a
3b
3b
3c
3c
4a
4a
4b
4b
4c
4c
Na(+)
K(+)
60
70
65
86
85
90
86
94
60
85
72
78
55 (R)
5 (R)
40 (R)
<5 (S)
5 (S)
Na(+)
K(+)
Na(+)
K(+)
5 (R)
Na(+)
K(+)
15 (S)
65 (S)
30 (S)
45 (S)
30 (S)
40 (S)
Na(+)
K(+)
Na(+)
K(+)
We envisaged a second way to obtain macrocyclic glycoconju-
gates from oligoketosides 1 by the introduction of a second O-pen-
tenyl appendage at the non-reducing end and then performing a
ring-closing metathesis (RCM). Ring-closing alkene or alkyne
metathesis has been extensively exploited as a key process toward
macrocycle formation14 including the above-mentioned macrocy-
clic glycolipids1 and other carbohydrate containing macrocycles.15
Hence the linear O-alkenyl alcohols 1b–c were transformed into
the bis-O-pentenyl derivatives10 5b–d by coupling with pentenyl
bromide. These dialkenes were subjected16 to RCM using the sec-
ond-generation ruthenium carbene Grubbs catalyst as shown in
Scheme 2. The yields of the macrocycle alkenes 6b–d (E/Z mix-
tures) appeared to decrease substantially with the increasing of

A. Dondoni, A. Marra / Tetrahedron Letters 50 (2009) 3593–3596
3595
BnO
BnO
BnO
BnO
OBn
OBn
O
O
Mes N
Cl
N Mes
OH
O
BnO
BnO
Ru
PCy3
BnO
BnO
BnO
BnO
OBn
OBn
O
O
Ph
Cl
Br
O
O
, CCl4, 100 °C, 3 h (43-63%)
1.
n
n
BnO
BnO
NaH, DMF, r.t.
2. TsNHNH2, AcONa, DME, 85 °C, 6 h (55-76%)
BnO
BnO
BnO
BnO
OBn
O
OBn
O
O
O
BnO
BnO
O
O
5b n = 1 (77%)
5c n = 2 (87%)
5d n = 3 (92%)
1b-d
n = 1
n = 2
n = 3
RO
RO
RO
RO
RO
OR
OR
OR
O
O
O
RO
OR
O
O
O
RO
RO
O
RO
OR
O
O
O
O
RO
RO
O
RO
RO
RO
O
RO
RO
OR
O
O
OR
O
OR
O
OR
O
OR
RO
O
O
O
OR
OR
OR
O
OR
O
O
RO
RO
RO
RO
O
OR
O
RO
RO
OR
OR
RO
OR
O
RO
OR
RO
RO
RO
OR
7b R = Bn (33%)
8b R = Ac (88%)
7c R = Bn (40%)
8c R = Ac (83%)
7d R = Bn (28%)
8d R = Ac (80%)
1. Pd(OH)2, H2
2. Ac2O, Py
1. Pd(OH)2, H2
2. Ac2O, Py
1. Pd(OH)2, H2
2. Ac2O, Py
Scheme 2.
Wessjohann, L. A.; Ruijter, E.; Garcia-Rivera, D.; Brandt, W. Mol. Diversity 2005,
9, 171–186.
the number of carbohydrate units in the linear ketoside. Neverthe-
less even the macrocycle 6d featuring a pentaketoside segment
was obtained in satisfactory yield (43%). The double bond of com-
pounds 6b–d was then reduced17 using diimide, generated in situ
from tosylhydrazide and sodium acetate,18 to give the correspond-
ing cyclic neoglycoconjugates10 7b–d. All these macrocycles fea-
tured a lipophilic moiety constituted of an eight carbon atom
alkyl chain. Then, the O-benzyl groups of compounds 7b–d were
removed by hydrogenolysis in the presence of Pd(OH)2 and the free
hydroxy groups esterified (Ac2O, Py) to give the corresponding
O-acetyl derivatives10 8b–d. Unlike the crown ether derivatives
3a–c and 4a–c, the macrocycles 7b–d and 8b–d did not serve as
chiral hosts in the model Michael addition because they failed to
recognize sodium and potassium cations as proved by 1H NMR
complexation experiments.8
5. Selected papers: (a) Miethchen, R.; Fehring, V. Synthesis 1998, 94–98; (b)
Dumont-Hornebeck, B.; Joly, J.-P.; Coulon, J.; Chapleur, Y. Carbohydr. Res. 1999,
320, 147–160; (c) Sharma, G. V. M.; Reddy, V. G.; Krishna, P. R. Tetrahedron:
Asymmetry 1999, 10, 3777–3784; (d) Faltin, F.; Fehring, V.; Kadyrov, R.; Arrieta,
A.; Schareina, T.; Selke, R.; Miethchen, R. Synthesis 2001, 638–646; (e) Faltin, F.;
Fehring, V.; Miethchen, R. Synthesis 2002, 1851–1856.
6. (a) Stoddard, J. F. Chem. Soc. Rev. 1979, 8, 85–142; (b) Jolley, S. T.; Bradshaw, J.
S.; Izatt, R. M. J. Heterocycl. Chem. 1982, 19, 3–19; (c) Stoddart, J. F. Top.
Stereochem. 1987, 17, 207–288.
7. (a) Immel, S.; Lichtenthaler, F. W. Liebigs Ann. 1996, 39–44; (b) Immel, S.;
Schmitt, G. E.; Lichtenthaler, F. W. Carbohydr. Res. 1998, 313, 91–105.
8. Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Bertolasi, V. Chem Eur. J. 2001, 7,
1371–1382.
9. To a stirred solution of alcohols 1a–d (0.10 mmol) in dry DMF (2 mL) was
added NaH (12 mg, 0.30 mmol, of a 60% suspension in mineral oil) and, after
15 min, bis(2-chloroethyl) ether (120 lL, 1.00 mmol). The mixture was stirred
at rt for an additional 3 h, then cooled to 0 °C, diluted with 1 M phosphate
buffer at pH 7 (10 mL), and extracted with Et2O (2 Â 50 mL). The combined
organic phases were dried (Na2SO4) and concentrated. The residue was eluted
In conclusion, the synthetic efforts invested in this program cul-
minated in the development of two synthetic routes leading to
new classes of macrocyclic neoglycoconjugates. The use of these
products as chiral receptors has been so far only scarcely investi-
gated. Hence addressing this issue now becomes of interest.
from
corresponding alkyl chlorides (60–86%). To
oligoketoside chlorides (0.05 mmol) and dry 1,2-ethanediol (140
a
column of silica gel with 5:1 cyclohexane–AcOEt to give the
stirred solution of the
L) in dry
a
l
DMF (1 mL) was added NaH (80 mg, 2.00 mmol, of a 60% suspension in mineral
oil). The mixture was stirred at rt for 15 min, then warmed to 60 °C, stirred for
14 h, cooled to to 0 °C, diluted with 1 M phosphate buffer at pH 7 (10 mL), and
extracted with Et2O (2 Â 30 mL). The combined organic phases were dried
(Na2SO4) and concentrated. The residue was eluted from a column of silica gel
with cyclohexane–AcOEt (from 3:1 to 1:1) to give 2a–d (45–50%).
References and notes
1. (a) Fürstner, A. Eur. J. Org. Chem. 2004, 943–958; (b) Fürstner, A.; Davies, P. W.
Chem. Commun. 2005, 2307–2320.
2. Brito-Arias, M.; Pereda-Miranda, R.; Heathcock, C. H. J. Org. Chem. 2004, 69,
4567–4570.
3. Tricolorins are part of the complex glycolipid mixture extracted from Mexican
plants belonging to the Morning Glory Species (Convolvulaceae). They differ for
the number and type of sugars in the carbohydrate fragment and the
appendages linked to the macrocyclic system.
4. (a) Pereda-Miranda, R.; Bah, M. Curr. Top. Med. Chem. 2003, 3, 111–131; (b)
Furukawa, J.; Sakairi, N. Trends Glycosci. Glycotechnol. 2001, 13, 1–10; (c)
10. Optical rotations were measured at 20 2 °C in CHCl3; values are given in
deg mL gÀ1 dmÀ1. MALDI-TOF mass spectra were acquired using
a
-cyano-4-
hydroxycinnamic acid as the matrix. The reported values refer to the sodium
and potassium adducts. Compound 2a: [ +37.3 (c 0.3); MS: 1346.3, 1362.3.
Compound 3a: [ D +32.2 (c 1.6); MS: 1258.4, 1274.8. Compound 4a: [
(c 1.0); MS: 650.6, 666.7. Compound 2b: [ D +30.4 (c 0.9); MS: 1898.4, 1914.6.
Compound 3b: [ +45.7 (c 2.0); MS: 1812.8, 1828.0. Compound 4b: [
+55.9 (c 1.1); MS: 900.6, 915.7. Compound 2c: [
2467.6. Compound 3c: [ +31.1 (c 0.9); MS: 2365.2, 2381.8. Compound
4c: [ +35.3 (c 1.0); MS: 1148.7, 1164.1. Compound 5b: [a] +36.0 (c 1.5);
D
a
]
D
a
]
a]D +39.1
a
]
a
]
D
a]
D
a
] +32.3 (c 1.2); MS: 2451.8,
D
a
]
D
a
]
D

3596
A. Dondoni, A. Marra / Tetrahedron Letters 50 (2009) 3593–3596
MS: 1836.1, 1852.3. Compound 7b: [
Compound 8b: [ D +57.1 (c 0.5); MS: 1233.0, 1248.4. Compound 5c: [
(c 1.1); MS: 2389.3, 2405.1. Compound 7c: [ +35.2 (c 0.7); MS: 2362.4,
2378.2. Compound 8c: [ +70.5 (c 0.4); MS: 1593.3, 1609.5. Compound 5d:
+33.6 (c 1.0); MS: 2941.1, 2957.4. Compound 7d: [a] +30.3 (c 1.0); MS:
D
a
]
+36.8 (c 0.5); MS: 1811.4, 1827.7.
14. (a) Leeuwenburgh, M. A.; van der Marel, G. A.; Overkleeft, H. S. Curr. Opin. Chim.
D
a
]
a
]D +34.7
Biol. 2003, 7, 757–765; (b) Gradillas, A.; Pérez-Castells, J. Angew. Chem., Int. Ed.
2006, 45, 6086–6091.
15. (a) Walter, A.; Westermann, B. Synlett 2000, 1682–1684; (b) Chen, G.;
Kirschning, A. Chem. Eur. J. 2002, 8, 2717–2729; (c) Velasco-Torrijos, T.;
Murphy, P. V. Org. Lett. 2004, 6, 3961–3964; (d) Dörner, S.; Westermann, B.
Chem. Commun. 2005, 2852–2854.
a
]
D
a
]
D
[
a
]
D
2915.2, 2930.9. Compound 8d: [a] +74.3 (c 0.3); MS: 1954.1, 1970.3.
D
11. To a cooled (0 °C), stirred mixture of alcohols 2a–c (0.05 mmol), activated 4 Å
molecular sieves (0.50 g), finely powdered N-iodosuccinimide (22 mg,
0.10 mmol), and dry CH2Cl2 (5 mL) was added a 0.5 M solution of TMSOTf in
16.
A
solution of oligoketoside 5b–d (0.03 mmol) and commercially available
Grubbs catalyst (6.8 mg, 8.0 mol) in dry CCl4 (1.5 mL) was stirred in a screw-
capped vial at 100 °C (oil-bath temperature) for 3 h, then cooled to rt and
concentrated. The residue was eluted from column of silica gel with
l
dry CH2Cl2 prepared immediately before the use (100 lL, 0.05 mmol) in four
portions during 1 h. The reaction mixture was stirred at 0 °C for an additional
15 min, then diluted with Et3N (0.1 mL), warmed to rt, filtered through a pad of
Celite, and concentrated. A solution of the residue in CH2Cl2 (50 mL) was
washed with 10% aqueous Na2S2O3 (2 Â 5 mL), dried (Na2SO4), and
a
cyclohexane–AcOEt (from 9:1 to 6:1) to give the corresponding macrocycles
6b–d as E/Z mixtures (43–83%).
17. To a warmed (85 °C), stirred solution of alkenes 6b–d (0.02 mmol) and freshly
recrystallized p-toluenesulfonyl hydrazide (22 mg, 0.12 mmol) in
dimethoxyethane (1 mL) was added 1 M aqueous sodium acetate (120 L) in
concentrated. The residue was eluted from
a column of silica gel with
cyclohexane–AcOEt (from 2:1 to 1:1) to give 3a–c (18–48%).
l
12. Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625–628.
13. (a) Bunet, E.; Poveda, A. M.; Rabasco, D.; Oreja, E.; Font, L. M.; Batra, M.;
Rodríguez-Ubis, J. C. Tetrahedron: Asymmetry 1994, 5, 935–948; (b) Bakó, P.;
Czinege, E.; Bakó, T.; Czugler, M.; Toke, L. Tetrahedron: Asymmetry 1999, 10,
4539–4551; (c) Bakó, T.; Bakó, P.; Keglevich, G.; Bombicz, P.; Kubinyi, M.; Pál,
K.; Bodor, S.; Makó, A.; Toke, L. Tetrahedron: Asymmetry 2004, 15, 1585–1589;
(d) Bakó, P.; Makó, A.; Keglevich, G.; Kubinyi, M.; Pál, K. Tetrahedron:
Asymmetry 2005, 16, 1861–1871.
six portions during 3 h. After an additional 3 h at 85 °C the mixture was diluted
with H2O (5 mL) and extracted with CH2Cl2 (2 Â 30 mL). The organic phase was
dried (Na2SO4) and concentrated. The residue was eluted from a column of
silica gel with cyclohexane–AcOEt (from 9:1 to 6:1) to give 7b–d
(55–76%).
18. (a) Dewey, R. S.; van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83, 3729; (b) Hart, D.
J.; Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665–4673.