Synthesis of arabinofuranosides via low-temperature activation of thioglycosides

Article abstract of DOI:10.1016/S0040-4039(01)01133-9

The synthesis of oligosaccharides containing arabinofuranose residues is reported. Coupling of thioglycoside donors 4, 6, or 7 and with acceptors 8-17 using N-iodosuccinimide and silver triflate activation provided glycosides with varying degrees of stere

Full text of DOI:10.1016/S0040-4039(01)01133-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5829–5832
Synthesis of arabinofuranosides via low-temperature activation
of thioglycosides
Haifeng Yin and Todd L. Lowary*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA
Received 11 May 2001; accepted 18 June 2001
Abstract—The synthesis of oligosaccharides containing arabinofuranose residues is reported. Coupling of thioglycoside donors 4,
6, or 7 and with acceptors 8–17 using N-iodosuccinimide and silver triflate activation provided glycosides with varying degrees of
stereocontrol. © 2001 Elsevier Science Ltd. All rights reserved.
The cell wall complex of mycobacteria is composed
largely of two polysaccharides, an arabinogalactan
(AG) and a lipoarabinomannan (LAM).1 Mycobacte-
rial viability is critically dependent upon the ability to
synthesize these two polysaccharides. Consequently, the
emergence2 of drug resistant strains of Mycobacterium
tuberculosis has prompted efforts to identify new drugs
which act by inhibiting cell wall biosynthesis in this
organism.3 A distinguishing feature of AG and LAM is
that all of the arabinose and galactose residues exist in
the furanose ring form. Thus, there has recently been
increased interest in the synthesis of oligosaccharides
containing arabinofuranose4 and galactofuranose5
moieties.
In the course of our investigations, we recently reported
the synthesis of oligosaccharide 2.6,9,10 The key-step in
the synthesis was a stereoselective glycosylation reac-
tion that installed both b-arabinofuranosyl residues
simultaneously (Scheme 1). In the reaction of 3 with 4,
it was found that the stereoselectivity was highly depend-
ent upon the reaction temperature. At 0°C or room
temperature, all four possible stereoisomeric glycosides
were produced in roughly equal amounts. However,
when the reaction was initiated at −78°C and then
allowed to warm slowly to 0°C, 5 was produced in
excellent yield and stereoselectivity.
OH
β-arabinofuranosyl linkage
Over the past few years, we have synthesized a number
of arabinofuranosyl-containing oligosaccharide frag-
ments of mycobacterial AG and LAM.6 One of our
targets has been the hexasaccharide motif, 1, which is
an important constituent of both polysaccharides.
Oligosaccharide 1 presents a particular synthetic chal-
lenge in that it contains two b-arabinofuranosyl link-
ages. These glycosidic bonds are analogous to
b-mannopyranosyl and b-fructofuranosyl linkages that
are widespread in nature, and which are notoriously
difficult to synthesize in a stereocontrolled manner.
Although a number of routes have now been developed
for the stereoselective synthesis of b-mannopyrano-
sides,7 far fewer studies have explored methods for the
stereocontrolled formation of b-arabinofuranosides4a,6c
or b-fructofuranosides.8
O
HO
HO
O
HO
O
O
OH
HO
O
O
HO
OH
O
O
OR
O
HO
HO
O
HO
O
HO
β-arabinofuranosyl linkage
HO
1, R = H
2, R = CH3
Keywords: b-arabinofuranosides; mycobacteria; oligosaccharides;
thioglycosides.
* Corresponding author. Tel.: 614-292-4926; fax: 614-292-1685;
e-mail: lowary.2@osu.edu
The degree of glycosylation stereoselectively under
these conditions is remarkable. Oligosaccharide 5 is the
only hexasaccharide isolated from the reaction. In addi-
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01133-9

5830
H. Yin, T. L. Lowary / Tetrahedron Letters 42 (2001) 5829–5832
tion, the product is produced in significantly better
yield than in another synthesis of this motif in which
the b-arabinofuranosyl linkages are formed via the
highly-stereoselective intramolecular aglycone delivery
(IAD) method.9a Furthermore, the ease with which the
reaction can be carried out is noteworthy, especially
when compared to the two-step IAD protocol, which
requires the manipulation of an unstable intermediate.
plants11) we wanted to explore the coupling of other
arabinofuranosyl thioglycosides with a range of glyco-
syl acceptors. Our interest was in determining the stereo-
chemical outcome of the reaction with substrates pos-
sessing protecting groups other than benzyl ethers and
with acceptors other than the 2-hydroxyl group of an
a-arabinofuranose ring. Accordingly, we report here the
reaction of thioglycosides 4,6a 6, and 7 with alcohols
8–17 (Scheme 2). Thioglycosides 6 and 7 were prepared,
without incident, as outlined in Scheme 3.12 Alcohols
8–17 are either commercially available or known.13
Using our method, we have since synthesized a range of
other oligosaccharide fragments of 1 containing b-ara-
binofuranose residues.10 In all cases, 4 was used to
glycosylate the 2-hydroxyl group of an a-arabinofura-
noside ring. Furthermore, the 3- and 5-hydroxyl groups
on the glycosylated ring were always protected as ben-
zyl ethers (e.g. 3).
With the appropriate substrates in hand, all glycosyla-
tions were carried out by cooling a solution of the
acceptor and donor in freshly distilled dichloromethane
to −78°C.14 N-iodosuccinimide and silver triflate were
then added and the reaction mixture was allowed to
warm to 0°C over 90–120 minutes. The initiation of the
reaction, as indicated by the appearance of the charac-
teristic reddish-orange color, took place at different
In the interest of extending this methodology to the
synthesis of other b-arabinofuranosides (e.g. b-
L-ara-
binofuranose containing oligosaccharides found in
BnO
OH
BnO
O
O
BnO
BnO
O
OBz
O
O
BnO
O
BnO
O
BnO
OBz
O
O
O
OBz
O
2
BnO
O
N-iodosuccinimide, AgOTf
CH2Cl2, -78 oC → 0 oC
OCH3
O
BnO
BzO
OBz
BnO
OH
O
O
3
OCH3
+
O
BzO
BnO
O
BnO
O
OBn
BnO
BnO
O
5
STol
81%
BnO
BnO
4
Scheme 1.
OBn
BzO
OBn
BzO
O
O
STol
STol
BzO
BnO
7
6
OH
O
OH
OH
O
BzO
BnO
BnO
BnO
O
OH
O
i-Pr2Si
CH3(CH2)7 OH
OH
O
OCH3
OCH3
i-Pr2Si
O
BzO
OCH3
8
9
10
HO
11
13
12
OBn
O
OBz
OBn
OBz
HO
BzO
HO
BnO
BnO
O
O
O
OCH3
OCH3
OCH3
BzO
BnO
HO
OCH3
14
15
16
17
Scheme 2.

H. Yin, T. L. Lowary / Tetrahedron Letters 42 (2001) 5829–5832
5831
as benzyl ethers. Such alcohols would be expected to be
the most reactive in that they are not sterically hindered
and their nucleophilicity is not attenuated by the pres-
ence of electron-withdrawing acyl groups at other posi-
tions on the ring.
OH
OH
O
OBn
HO
HO
O
O
b, c
O
a
i-Pr2Si
O
STol
STol
STol
i-Pr2Si
O
HO
HO
19
20
18
d
OH
Given the data presented in Table 1 and considering
that a-thioglycosides were used in these couplings, it is
plausible to speculate that reaction of 4 and the alco-
hols giving the highest b-selectivities (e.g. 15) may
proceed via an SN1-ion pair mechanism in which the
aglycone leaving group blocks attack from the bottom
face of the ring. This is consistent with earlier studies in
t-BuPh2SiO
O
f, g, h
e
7
6
STol
HO
21
Scheme 3. Synthesis of thioglycosides 6 and 7. (a) (Cl(i-
Pr)2Si)2O, pyridine 71%; (b) BnBr, NaH, DMF; (c) n-Bu4F,
THF, 64% from 19; (d) BzCl, pyridine, 83%; (e) t-BuPh2SiCl,
pyridine, 86%; (f) BnBr, NaH, DMF; (g) n-Bu4F, THF; (h)
BzCl, pyridine, 57% from 21.
which the glycosylation of 2,3,5-tri-O-benzyl-a-D-ara-
binofuranosyl chloride was studied.17 In reactions
providing glycosides with lower b-selectivity, loss of
stereocontrol can be rationalized by the conversion of
the donor to other intermediates. For example, the
formation of an oxonium ion intermediate or an a/b
mixture of glycosyl triflates18 would be expected to
lower the stereoselectivity of the glycosylation. Regard-
less of the mechanism, it can be concluded that for the
synthesis of a given b-arabinofuranoside via this
approach, best results will be obtained with a fully
alkylated donor species (e.g. 4 or 15).
temperatures depending upon the donor used. As
would be expected on the basis of the armed/disarmed
concept15 thioglycoside 4, which possesses no disarming
benzoyl groups, reacted at the lowest temperature.
Thioglycoside 6 showed intermediate reactivity and 7
was the least reactive.
A common problem in the synthesis of b-mannosides is
the sensitivity of the b:a ratio to seemingly small
changes in the structure of the donor and acceptor.7e,19
Upon completion of the reaction, the reaction mixture
was neutralized and the products isolated by chro-
matography. No attempt was made to separate the
isomeric glycosides. Instead, the column fractions con-
taining both isomers were pooled and concentrated.
The isolated yields and b:a ratio are given in Table 1.
The stereochemical outcome of the reaction was deter-
mined prior to product purification by standard one-
dimensional 1H NMR spectroscopy of the crude
reaction mixtures. Integration of the anomeric protons
of the newly formed glycosidic bond were used to
determine the ratios in Table 1. Distinguishing between
Table 1. Coupling of thioglycosides 4, 5, or 7 with alcohols
8−17.13
Entry
Donor
Acceptor
Yield (%)a
b:a Ratiob
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
6
6
7
7
7
7
7
7
7
7
7
8
9
82
73
71
72
62
74
83
85
78
91
88
81
83
78
76
71
81
88
82
86
78
77
82
68
70
88
66
69
1.4:1
3:1
3:1
1.1:1
1.2:1
3:1
10
11
12
13
14
15
16
17
8
3
the two anomers was done on the basis of JH1,H2
3
magnitudes. For the a-isomers JH1,H2 is small (0−2 Hz)
and larger (3−5 Hz) for the b-anomers. Furthermore, in
the 13C NMR spectra, C-1 of the b-isomers resonate
upfield relative to the a-isomers.16
2:1
4.5:1
4.5:1
2:1
3.9:1
1.6:1
2.4:1
1.1:1
1.2:1
2:1
2.7:1
2.5:1
1:1
1.5:1
1.1:1
1.1:1
1.1:1
1:2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
As is clear from the data presented in Table 1, all three
donors glycosylate the panel with alcohols in compara-
ble yields. In contrast, the observed stereoselectivities
are very much substrate dependent. In the best cases, a
4.5:1 b:a ratio is observed (entries 8 and 9); however,
there is often little stereoselectivity (e.g. entries 4 and 5).
9
10
11
12
13
14
15
17
8
Conclusions that can be drawn from this data are as
follows. First, there is a direct correlation between
b-stereoselectivity and donor reactivity. The most
armed donor, 4, provides an average b-selectivity of
2.6:1. Thioglycosides 6 and 7 provide average b-selec-
tivities of 2.1:1 and 1.4:1, respectively. Second, with the
carbohydrate acceptors, the selectivities are in general
higher with primary alcohols (entries 7–9, 17, 18, and
25–27) than with secondary alcohols. Third, the best
results are obtained when the most reactive donor, 4, is
coupled with primary carbohydrate alcohols in which
the other hydroxyl groups on the acceptor are protected
9
10
11
13
14
15
16
17
2.8:1
1.9:1
1.4:1
1.3:1
a Isolated yield.
b As determined by 1H NMR spectroscopy (see text).

5832
H. Yin, T. L. Lowary / Tetrahedron Letters 42 (2001) 5829–5832
It appears that glycosylations of these arabinofuranose
thioglycosides are similarly sensitive to such protecting
groups modifications. It also appears that the excellent
stereocontrol we obtained in the synthesis of 26a and its
fragments10 was an extraordinarily fortunate occur-
rence. Currently under investigation in our laboratories
is the use of other glycosylating agents for the stereo-
controlled synthesis of b-arabinofuranosides.20
11. Klis, F. M. New Compr. Biochem. 1995, 29a, 511–520.
12. Characterization of new compounds: [h]D+12.8
6
(CH2Cl2, c 0.2). Rf 0.49 (hexane:EtOAc 3:1). 1H NMR
(400 MHz, CDCl3, l): 5.47 (d, 1H, J=1.5 Hz, H-1),
4.37–4.54 (m, 5H, PhCH2, H-5, H-4), 4.06 (t, 1H, J=2.8
Hz), 3.95 (dd, 1H, J=3.0 Hz), 2.21 (s, 3H, Me). 13C NMR
(100 MHz, CDCl3, l): 91.18 (C-1), 88.79 (C-2), 84.18
(C-3), 79.50 (C-4), 72.89, 72.74 (Bn), 64.22 (C-5), 21.62
(Me). HRMS (ESI) calcd for (M+Na) C33H32O5S
563.186263, found 563.187152.
7 [h]D+20.6 (CH2Cl2, c 0.1). Rf 0.54 (hexane:EtOAc 2:1).
1H NMR (400 MHz, CDCl3, l): 5.72 (d, 1H, J=1.8 Hz,
H-1), 5.58 (dd, 1H, J=1.6 Hz, 4.3 Hz, H-3), 4.76 (dd, 1H,
J=4.6 Hz, 9.1 Hz, H-4), 4.72, 4.65 (d, 1H, J=12.1 Hz,
PhCH2), 4.67 (d, 2H, J=5.1 Hz, H-5), 4.35 (t, 1H, J=1.8
Hz, H-3), 2.25 (s, 3H, Me). 13C NMR (100 MHz, CDCl3,
l): 92.00 (C-1), 88.35 (C-2), 81.48 (C-4), 79.01 (C-3), 72.75
(Bn), 64.44 (C-5), 21.62 (Me). HRMS (ESI) calcd for
(M+Na) C33H30O6S 577.165528, found 577.16787.
20 [h]D+2.1 (CH2Cl2, c 0.1). Rf 0.21 (hexane:EtOAc 1:1).
1H NMR (400 MHz, CDCl3): 5.51 (d, 1H, J=3.3 Hz,
H-1), 4.67 (dd, 2H, J=11.7 Hz, PhCH2), 4.26 (dd, 1H,
J=4.0 Hz, 6.9 Hz, H-3), 4.15 (m, 1H, H-4), 4.05 (t, 1H,
J=3.6 Hz, H-2), 3.85 (dd, 1H, J=3.4 Hz, 12.2 Hz, H-5),
3.76 (dd, 1H, J=3.9 Hz, 12.2 Hz, H-5), 2.38 (s, 3H, Me).
13C NMR (100 MHz, CDCl3, l): 90.52 (C-1), 89.94 (C-2),
83.19 (C-4), 76.37 (C-3), 72.80 (PhC), 61.87 (C-5), 21.56
(Me). HRMS (ESI) calcd for (M+Na) C19H22O4S
369.113098, found 369.114885.
Acknowledgements
This work was supported by the National Institutes of
Health (AI44045-01) and the National Science Founda-
tion (CHE-9875163).
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