Transition metal-catalyzed syntheses of 'rod-like' thioglycoside dimers

Article abstract of DOI:10.1016/S0040-4039(99)02285-6

Using copper(I)-catalyzed Glaser reaction and palladium-catalyzed Sonogashira reaction, divalent 'rod-like' thiomanno-, gluco, galacto, and lactoside clusters were prepared in high yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02285-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1155–1158
Transition metal-catalyzed syntheses of ‘rod-like’ thioglycoside
dimers
Zhonghong Gan and René Roy ∗
Department of Chemistry, University of Ottawa, Ottawa, Ontario KIN 6N5, Canada
Received 20 October 1999; accepted 30 November 1999
Abstract
Using copper(I)-catalyzed Glaser reaction and palladium-catalyzed Sonogashira reaction, divalent ‘rod-like’
thiomanno-, gluco, galacto, and lactoside clusters were prepared in high yields. © 2000 Elsevier Science Ltd. All
rights reserved.
During the last 20 years, tremendous progress has been made in the area of transition metal-
mediated organic syntheses. Conjugated acetylenic compounds are very valuable materials for antitumor
antibiotics and multinanometer-sized molecular objects.1 In this respect, homo-coupling between sp and
sp carbon atoms and cross-coupling between sp2 and sp carbon atoms (such as Glaser2 and Sonogashira
reactions3) as methods to build such compounds have gained great interest. However, much less attention
has been paid to reactions with organic sulfur compounds4 which have long been known to act as poisons
for transition metal catalysts because of their strong coordinating properties. Additionally, these useful
reactions have rarely been used in carbohydrate chemistry. Some examples of these reactions have been
described by Vasella et al.5 in the synthesis of higher oligomers of acetylenosaccharides. Moreover,
no such reactions have been applied to thioglycosides, which are of special interest as enzyme inhibitors
because they offer the advantage of being resistant to enzymatic hydrolysis, thus being potential inhibitors
of glycosidases.6
Recently, molecular rods,7 which are considered as spacers and construction elements in giant
molecules and supramolecular assemblies, have drawn widespread attention. This encouraged us to look
for a facile way to build so called ‘rod-like’ carbohydrate dimers. Glaser and Sonogashira reactions make
it possible to prepare such kind of sugar rods, where the acetylenic bonds of two carbohydrate moieties
are connected to each other or onto an aromatic ring. Such dimers should have more rigid structures that
can diminish entropic loss that is usually associated with flexible carbohydrate ligands. Herein, we report
the syntheses of divalent ‘rod-like’ thioglycoside clusters by using Glaser and Sonogashira reactions.
The requisite starting material 2-propynyl thio-mannopyranoside 2 was synthesized by the alkylation
of the corresponding mannopyranosyl 2-thiopseudourea hydrobromide salt 18 with 2-propynyl bromide
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02285-6
tetl 16213

1156
and potassium carbonate in 80% yield. Other acetylenic carbohydrates (glucose 4, galactose 6, and
lactose 8) were also prepared from the analogous pseudothioureas 3, 5, and 78 by a procedure similar to
that used for 2 in good yields (Scheme 1).
Scheme 1.
Copper(I) halide-catalyzed oxidative coupling of acetylenes represents a convenient way to prepare
diynes.9 Pyridine or tetramethylethylenediamine (TMEDA) are normally used to solubilize the copper
salt and also to facilitate proton abstraction from the terminal alkyne. However, when pyridine was
used in homo-coupling of acetylenic thiosugar 2, the yield was rather low (30%) when compared to
the corresponding O-mannopyranoside.10 Addition of more CuCl, or diazabicycloundecene (DBU) had
no effect on the yield. The yield could be dramatically increased when TMEDA was used instead of
pyridine. In a typical experimental procedure, in a mixture of thiosugar 2 (1 mmol), CuCl (0.3 mmol),
and TMEDA (0.6 mmol) in N,N-dimethylformamide (10 mL) was bubbled O2 at 40°C for 2 h. After
usual work-up11 and purification by silica gel column chromatography, dimer 9 was obtained in 84%
yield. The structure of the product was fully confirmed by NMR and mass spectral analyses.11 This
procedure was successfully applied to other thiopropynyl glycosides (4, 6, and 8) to afford good yields
of the corresponding dimers. The results are summarized in Table 1.
Table 1
Cu(I)-catalyzed homo-coupling reactions of 2-propynyl glycosides

1157
In order to further increase the interglycosidic distance, while maintaining the rigidity within the linker,
palladium-catalyzed Sonogashira cross-coupling between alkynes and aryl iodides was next considered.
The Sonogashira coupling reaction between 2-propynyl thio-mannopyranoside 2 and 1,4-
diiodobenzene was investigated by using Pd2(dba)3, CuI, and PPh3 in DMF and Et3N solution
(1:1, v/v) under nitrogen at room temperature for 1 h. The sulfur-containing compound 2 showed not
to poison the palladium catalyst. The cross-coupling dimer 13 was formed in 82% yield. However, the
oxidative homo-coupling of acetylenic mannopyranoside 2 to symmetrical diyne 9 (10% yield) was also
catalyzed under such conditions. The separation of the diyne from the desired product was very difficult
because of their close polarity.
To reduce the side reaction, some methods such as strict exclusion of oxygen12 or slow addition of
alkyne13 could be used. Copper(I) iodide was a particularly effective cocatalyst to facilitate the coupling
and to allow the reaction to occur at room temperature. A likely assumption was that a copper alkynylide
was formed. We thought this intermediate could cause the side reaction. So the modified Sonogashira
reaction without addition of copper salt was carried out. In a typical reaction, treatment of 2-propynyl
thio-mannopyranoside 2 (1 mmol) and 1,4-diiodobenzene (0.45 mmol) in a degassed solution of DMF
and Et3N (1:1, v/v) in the presence of Pd2(dba)3 (0.05 mmol) and PPh3 (0.1 mmol) at 60°C under
nitrogen atmosphere for 2 h afforded the desired dimer 13 in 95% yield. No diyne was found under these
conditions. To demonstrate the scope of this new application, we also examined Sonogashira coupling of
diiodobenzene with other carbohydrates (4, 6, and 8). All of them provided good yields of dimer 13–16
in yields ranging from 89% to 93%. The results are summarized in Table 2.
Table 2
Palladium-catalyzed Sonogashira coupling of 2-propynyl glycosides
In conclusion, copper(I)-catalyzed Glaser reaction and palladium-catalyzed Sonogashira reaction have
been applied toward the synthesis of divalent ‘rod-like’ thioglycoside clusters. The reactions are general,
high yielding, and compatible with the usual acetate protecting groups.
Acknowledgements
We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial
support.

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References
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11. Work-up procedure: the reaction mixture was poured into water (10 mL). The mixture was extracted with dichloromethane
(2×10 mL). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated
under vacuum. All new compounds showed satisfactory NMR (Bruker AMX 500 MHz) and mass spectral data. Selected
data for compound 9: FAB: calcd for C34H42O18S2 802.2. Found 803.2 (M+1); 1H NMR (CDCl3) δ 5.37 (d, 2H, J1,2 1.4 Hz,
H-1), 5.29 (dd, 2H, J2,3 3.4 Hz, H-2), 5.25 (dd, 2H, J4,5 9.7 Hz, H-4), 5.13 (dd, 2H, J3,4 10.0 Hz, H-3), 4.27–4.22 (m, 4H,
H-6a, H-5), 4.02 (m, 2H, H-6b), 3.42 (ABq, 2H, J 16.7 Hz, -SCHAC^), 3.27 (ABq, 2 H, -SCHBC^), 2.10, 2.02, 1.98, 1.91
(s, 24H, OAc0s); 13C NMR (CDCl3) δ 170.4, 169.6, 169.5, 169.4 (C=O0s), 81.5 (C-1), 73.6 (-C≡C), 70.1 (C-2), 69.5 (C-3),
69.3 (C-5), 67.8 (-C^C), 66.0 (C-4), 62.1 (C-6), 20.7, 20.7, 20.6, 20.5 (OAc0s), 18.9 (-CH2C^).
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