Synthesis of carbadisaccharide mimics of galactofuranosides

Article abstract of DOI:10.1016/j.tetlet.2009.06.115

A partially protected carbagalactofuranose was converted into a 1,2-anhydro derivative. This epoxide was opened with alcohol nucleophiles under Lewis acid catalysis to give β-carbagalactofuranose pseudodisaccharides with excellent regioselectivity.

Full text of DOI:10.1016/j.tetlet.2009.06.115

Tetrahedron Letters 50 (2009) 5142–5144
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Tetrahedron Letters
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Synthesis of carbadisaccharide mimics of galactofuranosides
*
Jens Frigell, Ian Cumpstey
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A partially protected carbagalactofuranose was converted into a 1,2-anhydro derivative. This epoxide was
opened with alcohol nucleophiles under Lewis acid catalysis to give b-carbagalactofuranose pseudodisac-
charides with excellent regioselectivity.
Received 20 May 2009
Revised 17 June 2009
Accepted 26 June 2009
Available online 1 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbasugars
Galactofuranose
Pseudodisaccharides
Ethers
Galactose is found in the unusual furanose configuration in bac-
teria and other lower organisms, some of which are pathogenic,
but not in mammals.1 The arabinogalactan from the cell wall of
Mycobacterium tuberculosis contains a polymeric region of galacto-
furanosides with alternating (b1?5)- and (b1?6)-linkages, an-
chored to the cell-wall peptidoglycan by a (b1?4)-linkage to
rhamnose.2 Hydrolytically stable mimics of fragments of this oligo-
saccharide may be of interest to investigate the substrate-binding
properties of the galactosyltransferases3–5 that assemble the cell
wall polysaccharide and could be interesting targets for inhibition.
Carbasugar6,7 pseudodisaccharides have been previously shown to
act as glycosyltransferase substrates.8
Diol 19 was converted into the epoxide 2 as follows: treatment
with tosyl chloride and pyridine gave the 1-tosylate as the major
product (42%) along with minor amounts of 2-tosylate (14%) and
1,2-ditosylate (5%). The orientation of substitution was determined
by NMR spectroscopy (coupling between the OH proton and either
H-1 or H-2). Treatment of the major regioisomer with sodium hy-
dride eliminated tosylate to give the required a-galacto epoxide 2
(87%). The same epoxide 2 was better obtained in one step as a sin-
gle diastereomer (87%) from the diol 1 under Mitsunobu conditions
(Scheme 1).
BnO
We recently reported the synthesis of a carbagalactofuranose
monomer 5.9 For the synthesis of carbasugar-containing pseudodi-
saccharides mimicking the Galf(b1?5)Galf and Galf(b1?6)Galf
linkages of arabinogalactan, the ether linkages should ideally be
constructed in a stereocontrolled manner, and we therefore con-
sidered SN2 type processes. A versatile approach would be to use
a carbagalactofuranose C-1 electrophile that could be attacked by
OH-6 or OH-5 carbasugar nucleophiles, or even other alcohols
should it be desirable to synthesise other carbagalactofuranosides.
1,2-Epoxides derived from carbapyranoses have been used as elec-
trophiles for the synthesis of pseudodisaccharides with alcohol
nucleophiles under Lewis acidic or basic conditions.10 In this Letter,
we report the extension of this concept to the five-membered ring
system, and describe the synthesis of some carbagalactofurano-
side-containing pseudodisaccharides.
BnO
O
BnO
BnO
a
b
BnO
OH
OH
2
HO
BnO
OBn
OBn
1
BnO
BnO
3
4
HO
HO
BnO
HO
OH
OH
OBn
OBn
c
HO
BnO
5
Scheme 1. Reagents and conditions: (a) DIAD, PPh3, THF, 0 °C, 86%; (b) (i) BnBr,
NaH, DMF, 92%; (ii) ZnCl2, Ac2O, AcOH, 76%; (iii) NaOMe, MeOH, rt, quant.; (c) (i)
acetone, CSA; (ii) BnBr, NaH, DMF; (iii) AcOH, H2O, 56% (three steps); (iv) Bu2SnO,
MeOH, 60 °C; (v) BnBr, CsF, DMF, 88% (two steps).
* Corresponding author. Tel.: +46 0 8 16 2481; fax: +46 0 8 15 4908.
E-mail address: cumpstey@organ.su.se (I. Cumpstey).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.115

J. Frigell, I. Cumpstey / Tetrahedron Letters 50 (2009) 5142–5144
5143
BnO
BnO
BnO
BnO
BnO
BnO
a
OR
b
OR
O
BnO
BnO
OH
6a—h
BnO
OAc
7a—h
2
c R = tBu
2→6: 82%
6→7: 87%
b R = iPr
2→6: 61%
6→7: 48%
a R = Et
2→6: 75%
6→7: 98%
OBn
Ph
O
OBn
OBn
O
O
BnO
BnO
OMe
2→6: 65%
6→7: 89%
BnO
g
OMe
d
O
2→6: 69%
6→7: 84%
O
O
f
OBn
O
OBn
OBn
2→6: 52%
6→7: 86%
BnO
BnO
OMe
BnO
h
e
2→6: 77%
2→6: 55%
6→7: 99%
6→7: 99%
Scheme 2. Reagents and conditions: (a) ROH (equiv: a–c, 10; d, 3.9; e, 3.0; f, 3.2; g, h, 5.0), BF3ÁOEt2 (0.1 equiv), CH2Cl2, rt; (b) Ac2O, pyridine, DMAP, rt.
The required OH-6 and OH-5 alcohols (3 and 4) were prepared
as follows: perbenzylation of the carbasugar 1 was followed by
selective acetolysis of the O-6 benzyl ether and deacetylation to
give the primary alcohol 3. From the carbasugar 5,9 OH-5 and
OH-6 were protected as an isopropylidene acetal. The remaining
three hydroxy groups were benzylated, and the isopropylidene
protection was removed to give the 5,6-diol, which was selectively
protected at C-6 to give the secondary alcohol 4 (Scheme 1).
Next, we attempted the etherification reaction, first using mod-
el alcohols to open the epoxide 2 using BF3ÁOEt2 as promoter. Eth-
anol, isopropanol and tert-butanol (10 equiv) each gave a single
regioisomer 6a–c of the respective ethers in good yield. The regi-
oselectivity of the reaction was confirmed by acetylation of the
products to give acetates 7a–c; OH-2 was acetylated, as was evi-
dent from the downfield shift of H-2 in the 1H NMR spectra
(Scheme 2). Our assignment of the stereochemistry of the epoxide
2 (and thence the products of ring-opening 6) was confirmed by
ethylation of both the diol 1 and the alcohol 6a obtained from
opening of the epoxide 2 by ethanol. The two diethyl derivatives
8 obtained were identical with one another (Scheme 3).
give bis-carbadisaccharides 6d, e as the only pseudodisaccharide
products (Scheme 2).11 Primary and secondary pyranoid carbohy-
drate alcohols (Rha O-4,12 Man O-313 and Man O-614) also opened
the epoxide with complete regioselectivity to give pseudodisaccha-
ride products 6f–h resembling substructures of other bacterial
polysaccharides. That the sense of regioselectivity was the same
for the carbasugar and carbohydrate nucleophiles as for the simple
alcohols was confirmed by acetylation. By-products with mass
spectral data consistent with the pseudotrisaccharides arising from
attack of the product alcohols 6 on the epoxide 2 were also seen.
The explanation of the excellent regioselectivity in the epoxide
opening may be both steric and electronic in origin. C-1 is expected
to be less hindered than C-2 as the C-4a methylene group (flanking
C-1) is smaller than the corresponding benzyl-ether-substituted C-
3 (flanking C-2). Attack at C-1 leads to the all trans b-galacto con-
figuration, while attack at C-2 would give an
a-talo configuration
with a 2,3-cis relationship. Under Lewis acid catalysed epoxide
opening, attack will usually occur at the carbon most able to stabi-
lise a partial positive charge. The more electron-withdrawing nat-
ure of the oxygenated C-3 compared to the methylene C-4a is also
expected to favour attack at C-1 over C-2.
To conclude, we have synthesised carbafuranoside pseudodisac-
charides for the first time. The regioselective Lewis acid catalysed
epoxide opening gives the ether-linked pseudodisaccharides via at-
tack at C-1. Pseudodisaccharide mimics of all three galactofurano-
side linkages in mycobacterial arabinogalactan are accessible by
this method.
The primary and secondary carbasugar alcohols 3 and 4 both
opened the epoxide 2 under the same Lewis acid catalysed condi-
tions with essentially complete regioselectivity for attack at C-1 to
BnO
OH
BnO
BnO
OH
BnO
BnO
Acknowledgements
a
a
1
OEt
OEt
We gratefully acknowledge financial support from the Swedish
Research Council (Vetenskapsrådet) and an Ivar Bendixson grant.
BnO
BnO
BnO
OEt
OH
8
BnO
Supplementary data
6a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.115.
Scheme 3. Reagents and conditions: (a) NaH, EtBr (10 equiv), DMF, rt; 37% from 6a;
45% from 1.

5144
J. Frigell, I. Cumpstey / Tetrahedron Letters 50 (2009) 5142–5144
11. Representative procedure for epoxide-opening; synthesis of 6d: Epoxide 2
(31 mg, 0.072 mmol) and alcohol (150 mg, 0.28 mmol) were dissolved
in CH2Cl2 (0.75 mL) under N2 at rt. BF3ÁOEt2 (18
L, 0.14 mmol) was
dissolved in CH2Cl2 (2.5 mL), and 125 (7 mol) of this solution was
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