New oligosaccharide analogues: Non-glycosidically linked thioether-bridged pseudodisaccharides

Article abstract of DOI:10.1055/s-2006-947338

The synthesis of six disaccharide analogues is reported. The pseudodisaccharides each consist of two monosaccharide residues linked non-glycosidically via a thioether functionality; both C₂-symmetric and unsymmetrically substituted examples are

Full text of DOI:10.1055/s-2006-947338

LETTER
1711
New Oligosaccharide Analogues: Non-Glycosidically Linked Thioether-
Bridged Pseudodisaccharides
New
Oli
a
gosaccharid
n
e
A
nalogues Cumpstey*
Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, 106 91 Stockholm, Sweden
Fax +46(8)154908; E-mail: cumpstey@organ.su.se
Received 24 March 2006
sugar mimics another by binding in a non-natural orienta-
tion. An axially substituted monosaccharide could mimic
an a-glycoside, whereas an equatorially substituted deriv-
ative could mimic a b-glycoside (Figure 1).
Abstract: The synthesis of six disaccharide analogues is reported.
The pseudodisaccharides each consist of two monosaccharide resi-
dues linked non-glycosidically via a thioether functionality; both
C2-symmetric and unsymmetrically substituted examples are de-
scribed. The synthesis was achieved by first introducing an acetate-
protected sulfur into partially protected carbohydrates by SN2 dis-
placement of sulfonate esters by thioacetate. Deacetylation of the
sulfur was followed by treatment with another carbohydrate sul-
fonate derivative, and a second SN2 displacement gave the pseudo-
disaccharide products.
OH
OH
HO
HO
a)
O
O
O
O
HO
OR
OH
O
OH
Key words: carbohydrates, sulfur, stereoselective synthesis, cou-
pling, pseudodisaccharides
OH
HO
OH
HO
HO
c)
O
OR
b)
OH
Oligosaccharides and polysaccharides are involved in
many processes in biological systems in which recogni-
tion of a specific carbohydrate motif is important, includ-
ing cell–cell interactions,1 bacterial adhesion,2 and
metastasis.3 Synthetic versions of these natural structures
may be used as biological tools or drug leads. The lability
of the glycosidic bond towards hydrolysis by glycosidases
or strong acid, as well as, to some extent, the difficulties
associated with the synthesis of oligosaccharides due to
the variable efficiency and stereoselectivity of the glyco-
sylation reaction, has led to the development of various
structurally diverse oligosaccharide analogues or mimet-
ics. Such molecules may have properties tailored towards
a particular aim, such as increased stability, or affinity for
a given carbohydrate binding protein. Examples of oli-
gosaccharide analogues include C-glycosides4 and thio-
oligosaccharides,5 as well as more outlandish structures,
such as decorated polypeptides.6
S
HO
R'O
OH
S
HO
O
O
O
HO
OR
OH
OH
HO
OH
HO
Figure 1 a) natural a- and b-glycosides; b) equatorial thioether to
mimic b-glycosidic linkage; c) axial thioether to mimic a-glycosidic
linkage
Reports of carbohydrate residues linked via thioether link-
ages are rather scarce. The formation of some C2-symmet-
ric thioethers has been reported, usually via opening of an
epoxide by a sulfur nucleophile,10–13 but there is one
example of the formation of a (6–6)-linked galactose de-
rivative from the primary tosylate, albeit in a rather poor
yield (15%).14 Only one example of a deprotected com-
pound in this class has been described,10 and thioethers
unsymmetrically substituted with two different carbo-
hydrate moieties are completely unknown. A few reports
of natural and synthetic ether-linked analogues exist.15
Monosaccharides are highly functionalised small mole-
cules. It has been shown that an individual monosaccha-
ride residue may bind to a protein in a way that mimics the
binding of a different monosaccharide, binding in a differ-
ent orientation, but maintaining a similar spatial topology
and similar key interactions with the protein. Examples
include thiodigalactoside as a lactose analogue7 and C2-
symmetric tetrasaccharides that mimic sialyl Lewis X;8
so-called looking-glass inhibitors may also work in this
way.9 Thus, I reasoned that sugar units linked together by
thioether functionalities could provide an interesting class
of hydrolytically stable mimetics, in which at least one
I conceived a strategy to synthesise C2-symmetric or un-
symmetrically substituted thioether disaccharides based
on reaction of a carbohydrate sulfonate ester with a carbo-
hydrate-derived thiol nucleophile, resulting in an SN2-
type displacement to form the thioether linkage. The
carbohydrate thiols could be accessed by hydrolysis of
thioacetates, themselves again introduced by displace-
ment of an appropriate sulfonate leaving-group from a
carbohydrate substrate. The preliminary results of this
study are described in this letter.
Thus the secondary triflates 116 and 217 and the primary
mesylate 3 were prepared from the respective alcohols 4,18
5 and 619 (Scheme 1). Subsequent treatment with potassi-
um thioacetate in hot DMF gave the thioacetate deriva-
tives 7–9 with inversion of configuration in the cases of 7
SYNLETT 2006, No. 11, pp 1711–1714
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947338; Art ID: D08806ST
© Georg Thieme Verlag Stuttgart · New York

1712
I. Cumpstey
LETTER
Ph
O
Ph
O
SAc
O
O
O
(i)
(iii)
Ph
O
O
O
OMe
OMe
O
BnO
BnO
OMe
BnO
OH
OTf
4
1
7
O
O
O
O
O
O
(iii)
(i)
O
O
O
O
O
O
O
O
O
HO
TfO
AcS
8
5
2
HO
BnO
MsO
BnO
AcS
BnO
OBn
OBn
O
OBn
(ii)
(iii)
O
O
BnO
BnO
BnO
OMe
OMe
OMe
6
3
9
Scheme 1 Reagents and conditions: (i) Tf2O, pyridine, CH2Cl2, 0 °C; (ii) MsCl, pyridine, CH2Cl2, 0 °C; (iii) KSAc, DMF, 90 °C; 7, 84%; 8,
84%; 9, 88% (isolated yields over two steps).
O
In conclusion, this paper describes the synthesis of six
novel compounds that belong to a rather unexplored class
of oligosaccharide mimics: non-glycosidically linked
thioether-bridged pseudodisaccharides. This paper is the
first report of unsymmetrically substituted thioether-
linked pseudodisaccharides. Full details of the synthesis
of these and other thioether pseudodisaccharides in-
cluding their deprotection and structural analysis will be
reported elsewhere shortly.
R'O2SO
HS
OR
O
OR
1–3
S
O
O
OR''
OR''
10–14
7–9
Scheme 2 Reagents and conditions: (i) thioacetate 7–9, MeONa,
MeOH; (ii) sulfonate 1–3, NaH, DMF, 50 °C. For results see Table 1.
(gluco → manno) and 820 (allo → gluco). The acetate pro-
tection was removed from the sulfur using excess sodium
methoxide in methanol, and after an aqueous work-up, the
resulting crude thiols were treated with sulfonate esters 1–
3 as shown in Table 1 with sodium hydride in DMF. This
gave the thioether-linked pseudodisaccharides 10–15
Acknowledgment
Financial support from the Swedish Research Council (Vetenskaps-
rådet) is gratefully acknowledged.
(Scheme 2, Table 1)21 with inversion of configuration at References and Notes
the secondary centres of displacement (the isolated yields
(1) Varki, A. Glycobiology 1993, 3, 97.
given are over two steps from the thioacetates).22 Also
formed as by-products were the disulfides 16–18
(Figure 2) in 12–15% yield; the reaction mixtures were
degassed in order to suppress disulfide formation.
(2) Karlsson, K.-A. Curr. Opin. Struct. Biol. 1995, 5, 622.
(3) Kannagi, R.; Izawa, M.; Koike, T.; Miyazaki, K.; Kimura, N.
Cancer Sci. 2004, 95, 377.
(4) (a) Postema, M. H. D.; Piper, J. L.; Betts, R. L. Synlett 2005,
1345. (b) Postema, M. H. D. Tetrahedron 1992, 48, 8545.
(c) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides, 1st
ed. Vol. 13; Elsevier Science: Oxford, 1995. (d) Meo, P.;
Osborn, H. M. I. In Carbohydrates; Osborn, H. M. I., Ed.;
Academic Press: New York, 2003, 337.
(5) (a) Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106,
160. (b) Driguez, H. ChemBioChem 2001, 2, 311.
(c) Fairweather, J. K.; Driguez, H. Carbohydrates in
Chemistry and Biology, Vol. 1; Ernst, B.; Hart, G. W.; Sinay,
P., Eds.; Wiley-VCH: Weinheim, 2000, 531–564.
(6) Vázquez-Camposa, S.; St. Hilaire, P. M.; Damgaarda, D.;
Meldal, M. QSAR Comb. Sci. 2005, 24, 923.
Ph
O
O
O
O
O
O
O
O
O
MeO
BnO
O
S
S
S
S
O
O
O
OBn
OMe
O
O
O
16
Ph
17
BnO
(7) (a) Cumpstey, I.; Sundin, A.; Leffler, H.; Nilsson, U. J.
Angew. Chem. 2005, 44, 5110. (b) Leffler, H.; Barondes, S.
J. Biol. Chem. 1986, 261, 10119. (c) Bianchet, M. A.;
Ahmed, H.; Vasta, G. R.; Amzel, L. M. Proteins 2002, 40,
378.
O
BnO
S
S
OMe
BnO
BnO
O
BnO
OBn
MeO
18
(8) Geyer, A.; Reinhardt, S.; Bendas, G.; Rothe, U.; Schmidt, R.
R. J. Am. Chem. Soc. 1997, 119, 11707.
Figure 2 Disulfides formed as by-products
Synlett 2006, No. 11, 1711–1714 © Thieme Stuttgart · New York

LETTER
New Oligosaccharide Analogues
1713
Table 1 Formation of Pseudodisaccharides
Entry
1
Thioacetate
Sulfonate
Product
Yield (%)
BnO
O
AcS
BnO
OBn
O
MsO
BnO
OBn
O
OMe
BnO
MeO
S
BnO
BnO
56
O
BnO
BnO
OBn
BnO
OMe
OMe
9
9
3
2
10
O
O
O
O
O
AcS
OBn
O
O
O
OBn
O
O
BnO
BnO
S
O
2
71
O
OMe
TfO
BnO
BnO
OMe
11
OMe
O
MsO
BnO
OBn
O
BnO
SAc
O
Ph
O
O
BnO
3
47
BnO
OBn
OBn
OMe
S
OMe
Ph
O
O
7
O
OMe
3
BnO
12
O
O
O
O
O
O
O
O
O
O
O
O
S
O
O
4
68
O
O
AcS
TfO
O
O
O
2
1
8
O
13
O
O
O
O
O
Ph
O
O
O
O
O
O
BnO
O
OMe
5
75
O
S
OTf
Ph
O
O
AcS
O
BnO
OMe
8
7
14
Ph
O
MeO
O
O
BnO
Ph
O
O
BnO
SAc
O
Ph
O
O
S
OMe
O
6
48
OMe
O
BnO
OTf
OBn
O
1
O
OMe
Ph
15
(9) (a) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu,
(10) Dahlgard, M. J. Org. Chem. 1965, 30, 4352.
L.; Okamoto, T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano,
N. J. Med. Chem. 2005, 48, 2036. (b) Blériot, Y.; Gretzke,
D.; Krülle, T. M.; Butters, T. D.; Dwek, R. A.; Nash, R. J.;
Asanod, N.; Fleet, G. W. J. Carbohydr. Res. 2005, 340,
2713. (c) Yu, C.-Y.; Asano, N.; Ikeda, K.; Wang, M.-X.;
Butters, T. D.; Wormald, M. R.; Dwek, R. A.; Winters, A.
L.; Nashe, R. J.; Fleet, G. W. J. Chem. Commun. 2004, 1936.
(11) Jesudason, M. V.; Owen, L. N. J. Chem. Soc., Perkin Trans.
1 1974, 2019.
(12) Kojima, M.; Wanatabe, M.; Taguchi, T. Tetrahedron Lett.
1968, 7, 839.
(13) Ihsiguro, S.; Tejima, S. Chem. Pharm. Bull. 1968, 1567.
(14) Trimnell, D.; Stout, E. I.; Doane, W. M.; Russell, C. R. J.
Org. Chem. 1975, 40, 1337.
Synlett 2006, No. 11, 1711–1714 © Thieme Stuttgart · New York

1714
I. Cumpstey
LETTER
(15) (a) Haines, A. H. Org. Biomol. Chem. 2004, 2, 2352.
(b) Takahashi, H.; Fukuda, T.; Mitsuzuka, H.; Namme, R.;
Miyamoto, H.; Ohkura, Y.; Ikegami, S. Angew. Chem. Int.
Ed. 2003, 42, 5069. (c) Pérez, G. S.; Pérez G, R. M.; Pérez
G, C.; Zavala S, M. A.; Vargas S, R. Pharm. Acta Helv.
1997, 72, 105. (d) Hodosi, G.; Kovac, P. Carbohydr. Res.
1998, 308, 63. (e) Farkas, J.; Sebesta, K.; Horska, K.;
Samek, Z.; Dolejs, L.; Sorm, F. Collect. Czech. Chem.
Commun. 1969, 34, 1118. (f) Whistler, R. L.; Frorein, A. J.
Org. Chem. 1961, 26, 3946. (g) Goueth, P. Y.; Ronco, G.;
Villa, P. J. Carbohydr. Chem. 1994, 13, 679. (h) Goueth, P.
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Carbohydr. Chem. 1994, 13, 697.
(1 H, d, H-1b), 4.60, 4.93 (2 H, ABq, JAB = 11.1 Hz, PhCH2),
4.60 (2 H, s, PhCH2), 4.69–4.80 (5 H, m, H-1a, 2 × PhCH2),
5.58 (1 H, s, PhCH), 7.21–7.48 (25 H, m, Ar-H). 13C NMR
(100 MHz, CDCl3): d = 36.1 (t, C-6a), 53.0 (d, C-2b), 55.0,
57.2 (2 × q, 2 × OCH3), 67.9 (d, C-5b), 68.8 (t, C-6b), 72.2,
72.4, 73.0, 75.2 (4 × t, 4 × PhCH2), 72.5, 75.0, 77.2, 78.1,
80.5 (5 × d, C-2a, C-3a, C-4a, C-5a, C-3b), 80.0 (d, C-4b), 99.0
(d, C-1a), 101.6 (d, PhCH), 103.2 (d, C-1b), 126.2, 127.7,
127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 129.0 (10 ×
d, Ar-CH), 137.7, 138.5, 138.5, 138.7, 138.5 (5 × s, 5 × Ar-
C). MS (MALDI): m/z = 874 [M + K+], 858 [M + Na+].
(22) Typical Procedure for the Formation of Thioether-
Bridged Pseudodisaccharides.
(16) Haradahira, T.; Maeda, M.; Omae, H.; Yano, Y.; Kojima, M.
Chem. Pharm. Bull. 1984, 32, 4758.
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1996, 281, 99.
Thioacetate 7–9 (0.1–0.4 mmol) was dissolved in MeOH
(3 mL) and the solution was degassed and put under argon.
MeONa (3 equiv) was added, and the mixture was stirred at
r.t. After complete conversion to the thiol, as shown by TLC
(approx 1 h), the mixture was poured into NH4Cl (30 mL of
a sat. aq solution) and extracted with CH2Cl2 (2 × 20 mL).
The combined organic extracts were dried (Na2SO4),
filtered, and concentrated in vacuo. Sulfonate 1–3 (1.5
equiv) was dissolved in DMF (4 mL) and added to the crude
thiol. NaH (60% in oil, 2 equiv) was added, and the mixture
stirred at 50 °C under argon. After TLC showed the complete
disappearance of thiol (approx. 30 min), the mixture was
poured into NH4Cl (25 mL of a sat. aq solution) and
extracted with Et2O (3 × 25 mL). The combined organic
extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by flash column
(21) Typical Data – (Methyl 3-O-Benzyl-4,6-O-benzylidene-2-
deoxy-b-D-mannopyranos-2-yl) (Methyl 2,3,4-Tri-O-
benzyl-6-deoxy-a-D-mannopyranos-6-yl) Sulfane (12).
A colourless oil; [a]D23 –2.0 (c 0.5 in CHCl3). 1H NMR (400
MHz, CDCl3): d = 2.98 (1 H, m, H-6a), 3.27–3.32 (2 H, m,
H-5b, H-6¢a), 3.34, 3.47 (6 H, 2 × s, 2 × OCH3), 3.55 (1 H, dd,
J1,2 = 1.5 Hz, J2,3 = 4.4 Hz, H-2b), 3.76–3.88 (6 H, m, H-2a,
H-3a, H-4a, H-5a, H-3b, H-6b), 4.07 (1 H, at, J = 9.4 Hz, H-
4b), 4.28 (1 H, dd, J5,6¢ = 4.8 Hz, J6,6¢ = 10.4 Hz, H-6¢b), 4.48
chromatography (pentane, EtOAc) to afford the thioether-
linked pseudodisaccharide 10–15 (see Table 1).
Synlett 2006, No. 11, 1711–1714 © Thieme Stuttgart · New York