Practical synthesis of valuable d-rhamnoside building blocks for oligosaccharide synthesis

Article abstract of DOI:10.1016/j.tetlet.2007.01.122

The efficient synthesis of d-rhamnoside and the corresponding methods for its regioselective protections and deprotections have been developed in order to provide key building blocks for complex oligosaccharide syntheses toward vaccines against bacterial infections.

Full text of DOI:10.1016/j.tetlet.2007.01.122

Tetrahedron Letters 48 (2007) 2385–2388
Practical synthesis of valuable D-rhamnoside building blocks
for oligosaccharide synthesis
*
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Regis Faure, Tze Chieh Shiao, Sonia Damerval and Rene Roy
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Department of Chemistry, Universite´ du Que´bec a Montreal, PO Box 8888, Succ. Centre-Ville, Montreal, Quebec, Canada H3C 3P8
Received 24 December 2006; revised 23 January 2007; accepted 23 January 2007
Available online 27 January 2007
Abstract—The efficient synthesis of D-rhamnoside and the corresponding methods for its regioselective protections and deprotec-
tions have been developed in order to provide key building blocks for complex oligosaccharide syntheses toward vaccines against
bacterial infections.
Ó 2007 Elsevier Ltd. All rights reserved.
It is now widely recognized that bacterial cell surface
carbohydrate antigens play essential roles in host de-
fense immunity against infections. Lipopolysaccharides
(LPSs) are ubiquitous components of the outer cell
membranes of Gram-negative bacteria and are thought
to be involved in host–pathogen cross-talk, notably
through their O-specific chains, which are exposed
toward the external environment.1–3 Exopolysaccharides
(EPSs) are also implicated in virulence and persistence
of bacterial infections.4 However, simple isolation and
characterization of these carbohydrate antigens are
insufficient to allow full elucidation of their contribution
to the molecular mechanism of phatogenesis.
Given the fact that D-rhamnose is only encountered in
microorganisms and not in humans, animals or plants,
this rare monosaccharide is a promising target for the
development of new anti-infective agents, including vac-
cines. Indeed, rhamnose-containing motifs should pro-
vide the basis for development of synthetic bacterial
O-polysaccharide conjugate vaccines.18
Very few syntheses of D-rhamnose oligosaccharides have
been hitherto reported,17,19–22 mainly because of the lack
of direct access to D-rhamnose in large quantities as pre-
cursor and as key building blocks. In addition, to our
knowledge, there is no commercial supply for D-rham-
nose and its known chemical synthesis only affords an
already partially protected derivative.22 A fast proce-
dure for the preparation of this rare sugar has been de-
scribed. This involves mild hydrolysis of bacterial LPS.23
Unfortunately, this method is not particularly adapted
for the production of therapeutic agents. The present
work focuses on an efficient synthesis of D-rhamnoside
3, and reports the well defined selection of regioselective
protection and deprotection pathways required to pro-
vide easy access to building blocks 4, 9–11, 14, 19, and
23 in high yields, for complex oligosaccharide synthesis.
Increasingly, 6-deoxy-D-hexoses are receiving attention,
notably concerning their significance toward infectious
diseases. This is because these relatively rare sugars are
frequently found on cell surface glycoconjugates of
pathogenic bacteria. In particular, D-rhamnose and its
4-formamido or 4-azido-4-deoxy derivatives are com-
mon components of LPSs and EPSs from human and
plant-pathogenic species, such as Burkholderia cepacia
complex,5,6 Pseudomonas aeruginosa,7,8 and other
pseudomonads,9–11 Helicobacter pylori,12 Citrobacter
freundii,13 Campylobacter fetus,14 Stenotrophomonas
maltophilia,15 Xanthomonas campestris,16 and Brucella.17
D-Rhamnoside 3 was synthesized from D-mannose in
87% overall yield (Scheme 1). Triflic acid-promoted
glycosydation of the per-O-acetylated mannose with
p-methoxyphenol, followed by de-O-acetylation using
Keywords: Pathogenic bacteria; Lipopolysaccharides; Exopolysaccha-
rides; Vaccines; D-Rhamnose; Protecting groups; Building-blocks;
Complex oligosaccharides.
´
Zemplen conditions (NaOMe, MeOH) led to p-meth-
oxyphenyl mannoside 1.24 Regioselective iodination of
the primary hydroxyl group of 1 was achieved in 93%
yield using triphenylphosphine, imidazole, and iodine
*
Corresponding author. Tel.: +1 514 987 3000x2546; fax: +1 514 987
4054; e-mail: roy.rene@uqam.ca
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.122

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R. Faure´ et al. / Tetrahedron Letters 48 (2007) 2385–2388
Scheme 1. Reagents and conditions: (i) (a) Ac2O/pyridine, cat. DMAP, rt, 12 h, quantitative (a only); (b) 2 equiv p-MPOH, 0.15 equiv TfOH,
CH2Cl2, 0 °C then rt, 7 h, 95%; (c) MeONa/MeOH, rt, 3 h, quantitative; (ii) 1.5 equiv I2, 1.5 equiv Ph3P, 2 equiv imidazole, THF, 65 °C, 2 h, 93%;
(iii) 1.5 equiv Bu3SnH, 0.1 equiv AIBN, toluene, 110 °C, 1 h, 98%.
in refluxing THF.22,25 The 13C NMR of 2 showed the
shielding of the C-6 signal from 61.3 to 6.2 ppm. Reduc-
tion of iodide 2 using tributyltin hydride in the presence
of AIBN gave the expected D-rhamnoside 326 in 98%
yield.27 The most indicative NMR data were the shield-
ing for the H-6 signal from 3.60–3.27 to 1.23 ppm and
the deshielding of the C-6 from 6.2 to 17.2 ppm. This
efficient procedure for preparing D-rhamnopyranoside
3, derived from D-mannose, was well suited to large
scale synthesis given the high yields and easy isolation
of intermediates at each steps.
ence of new signals corresponding to the methylene
groups at 2.84–2.70 (m, 4H) and to the methyl group
at 2.22 ppm of the levulinic ester confirmed the structure
of derivative 5. The BDA protecting group was then re-
moved by aqueous acid hydrolysis30 and then the result-
ing diol 6 was benzoylated or acetylated to provide
intermediates 7 and 8 in 82% and 84% yields over two
steps, respectively. Diol 6 might be selectively protected
as function of the difference of reactivity between both
hydroxyl groups (HO-3 > HO-4). The selective and mild
levulinyl group removal was achieved by treatment with
hydrazine hydrate in pyridine/acetic acid mixture for
10 min to afford 9 and 10 in very good yields.31 Upfield
displacements for the H-2 signals in the 1H NMR
spectra confirmed the levulynyl group cleavage.
The single step protection of the 3,4-trans-diol in the
presence of the 2,3-cis-diol using a-diketone, via tetra-
methoxyacetal formation, was particularly powerful
for the selective protection of our vicinal diequatorial
diol 3 (Scheme 2). Thus, reaction of butane-2,3-dione
with p-methoxyphenyl a-D-rhamnoside 3 in the presence
of Lewis acid catalysis (BF3ÆEt2O) and trimethyl ortho-
formate gave butane diacetal (BDA) 4 in near quantita-
tive yield.28,29 The 1H and 13C NMR data of 4 confirmed
the BDA structure with the typical signals at d 3.34, 3.26
(2s, 6H, OCH3), 1.34, 1.33 (2s, 6H, CH3), and 100.3,
99.9 (C-q), 48.1, 47.7 (OCH3), 17.8, 17.7 (CH3). The
fully protected rhamnoside 5 was obtained in quasi-
quantitative yield by the reaction of 4 with levulinic acid
in the presence of N,N0-diisopropylcarbodiimide (DIPC)
and 4-dimethylamino-pyridine (DMAP).19 The low-field
shifted signal of H-2 from 4.12 to 5.23 ppm and the pres-
Until now, the synthetic manipulations proposed by
Evans et al.32 constituted the most convenient route
toward an anomeric analog of the 2,3-O-isopropylidene
D-rhamnoside 11. However, in their procedure, this reac-
tion involved the competition between the formation of
1,3-dioxane and dioxolane rings using kinetic or ther-
modynamic controls. Therefore, graded acid hydrolysis
has to be employed to afford the acetonide mannoside
intermediate with a ‘moderate’ yield of 75%. In our case,
the key intermediate 3 reacted with 2,20-dimethoxypro-
pane and p-TsOH acid catalyst in acetone (Scheme 3).
Temporary protection at positions 2 and 3 was accom-
plished by the formation of acetonide 11 in excellent
Scheme 2. Reagents and conditions: (i) 1.1 equiv butan-2,3-dione, 0.5 equiv BF3ÆEt2O, 4 equiv CH(OMe)3, MeOH, rt, 20 h, 99%; (ii) 5.6 equiv
CH3C(O)CH2CH2CO2H, 6.6 equiv DIPC, cat. DMAP, CH2Cl2, rt, 12 h, 99%; (iii) TFA/H2O (9:1), rt, 3 min, 6: 62% or (a) TFA/H2O (9:1), rt, 3 min;
(b) 2.4 equiv RCl, pyridine, 0 °C then rt, 12 h, 7: R = Bz, 82% (over two steps), 8: R = Ac, 84% (over two steps); (iv) 1.2 equiv hydrazine hydrate,
pyridine/AcOH, 20 °C, 10 min, 9: R = Bz, 94%, 10: R = Ac, 90%.
Scheme 3. Reagents and conditions: (i) 2,20-dimethoxypropane/acetone (1:1), 0.2 equiv p-TsOHÆH2O, rt, 0.5 h, 98%; (ii) 3 equiv NaH, 3 equiv BnBr,
cat. Bu4NI, DMF, 0 °C then rt, 14 h, 99%; (iii) TFA/H2O/THF (1:1:4), 0 °C then rt, 1 h, 95%; (iv) 1.1 equiv Bu2SnO, toluene, reflux, 2 h then
1.1 equiv BnBr, 1.1 equiv Bu4NBr, 65 °C, 14 h, 81%.

R. Faure´ et al. / Tetrahedron Letters 48 (2007) 2385–2388
2387
98% yield. Building block 14 was synthesized from 11 by
benzylation and ketal cleavage in 94% yields over two
steps, followed by dibutyl-stannylidene mediated benzyl-
ation of the O-3. The high yield of 14 (81%) shows the
excellent regioselectivity of this method. Due to the sub-
tle differences of chemical shifts between ether-protected
and non-protected positions, the structures of com-
pounds 11–14,33 notably characterized through the
observation of signal muliplicities, were also confirmed
by COSY experiments.
Scheme 5. Reagents and conditions: (i) 1 equiv BzCl, pyridine, ꢀ50 °C
to rt, 12 h, 15: 24%, 16: 19%, 20: 59%, and 21: 2%.
The selective O-3 protection of key rhamnoside 3 was a
very useful procedure because it can substantially sim-
plify reaction pathways in complex oligosaccharide syn-
thesis (Scheme 4). The ‘stannylation method’, by which
unprotected 3 was activated with dibutyltin oxide, and
then alkylated in the presence of alkyl bromide and tet-
rabutylammonium halide, followed by benzoylation,
afforded 3-O-benzylated 16 and 3-O-allylated 17 in
77% and 64% yields, respectively, over three steps.34 An-
other strategy consisted of the direct high O-3 selective
treatment of 3 with triisopropylsilyl trifluoromethane-
sulfonate to give only silylated compound 18 in 70%
yields over two steps. Deprotection of compounds 16–
18, with no benzoyl migration, was accomplished in
99%, 74%, and 63% yields using the corresponding
smooth procedures, that is hydrogenolysis (palladium
on carbon and H2 at atmospheric pressure), palla-
dium-catalyzed de-O-allylation,19 and treatment with
tetrabutylammonium fluoride (TBAF), respectively.
Compounds 16–1935 gave NMR signals for H-3 upfield
and H-2 and H-4 downfield, clearly indicating the O-3
modifications compared to 2,4-di-O-benzoylation.
Scheme 6. Reagents and conditions: (i) Ac2O/pyridine, cat. DMAP, rt,
12 h, 99%; (ii) 10 equiv CAN, toluene/CH3CN/H2O (1:1.4:1), rt, 2.5 h,
76%.
intermediate 15, obtained during the synthesis of 3-O-
benzylated 16, by using 1 equiv of benzoyl chloride at
ꢀ50 °C mainly leads to the 2-O-benzoyl rhamnoside
20 (Scheme 5). Thus, the order of reactivity for the
hydroxyl groups of rhamnosides seemed to be in agree-
ment with the reported selective acylation of mannoside,
that is HO-3 > HO-2 > HO-4.36,37
The oxidative removal of the p-methoxyphenyl group of
per-O-acetylated rhamnoside 22 with ceric ammonium
nitrate (CAN) afforded hemiacetal 23 in 76% yield
(Scheme 6), which could be easily activated as trichloro-
acetimidate glycosyl donor (not shown). The formation
of 23 was observed in the NMR spectra and notably by
the disappearence of the AB system of the phenyl group
at d 7.02–6.98, 6.85–6.82 ppm and the singlet corre-
sponding to the methoxy group at 3.78 ppm.
An interesting observation was the isolation of p-meth-
oxyphenyl 2-O-benzoyl-3-O-triisopropylsilyl-a-D-rham-
noside in 21% yield during the preparation of 18 by
treatment with benzoyl chloride instead of benzoic
anhydride. In addition, the selective benzoylation of diol
In conclusion, an efficient large scale synthesis of D-
rhamnoside 3, a rare sugar, has been accomplished.
The orthogonal protection–deprotection pathways were
performed in very high yields, providing useful key
building blocks for the synthesis of D-rhamnose oligo-
saccharides that are common motifs of LPSs or EPSs
of pathogenic bacteria. Glycosylation reactions involv-
ing D-rhamnosides 4, 9, 10, 14, and 19 toward the prep-
arations of complex oligosaccharidic structures are
currently underway.
Acknowledgement
Scheme 4. Reagents and conditions: (i) (a) 1.05 equiv Bu2SnO,
toluene/MeOH (10:1), reflux, Dean–Stark, 2 h; (b) 1.05 equiv BnBr,
1.05 equiv Bu4NI, toluene, 65 °C, 20 h, 78% (over two steps); (c)
2.4 equiv BzCl, pyridine, 0 °C then rt, 12 h, 99%; (ii) (a) 1.05 equiv
Bu2SnO, toluene/THF (10:1), reflux, Dean–Stark, 2 h; (b) 1.05 equiv
AllBr, 1.05 equiv Bu4NBr, toluene, 65 °C, 12 h, 65%; (over two steps);
(c) 2.4 equiv BzCl, pyridine, 0 °C then rt, 12 h, 99%; (iii) (a) 1.05 equiv
TIPSOTf, 1.6 equiv 2,6-lutidine, CH2Cl2/DMF (9:1), 0 °C, 3 h; (b)
3 equiv Bz2O, pyridine, cat. DMAP, reflux, 8 h, 70% (over two steps);
(iv) H2, cat. Pd–C, EtOH/CH2Cl2 (10:1), cat. HCl, rt, 12 h, 99%; (v)
0.3 equiv PdCl2, MeOH/CH2Cl2 (3:2), rt, 5 h, 74%; (vi) 5 equiv TBAF,
5.5 equiv AcOH, THF, 0 °C then rt, 8 h, 63%.
This work received support from the Natural Science
and Engineering Research Council of Canada (NSERC)
for
a Canadian Research Chair in Therapeutic
Chemistry.
References and notes
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(OCH3) 17.2 (C-6); ES-MS: m/z = 293.1 [M+Na]+; ES-
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25
rhamnopyranoside (14): Rf 0.20 (hexane/EtOAc, 3:1); ½aꢁD
+84 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz):
d = 7.44–7.31 (m, 10H, PhCH2), 7.02–6.96, 6.87–6.81 (m,
3
4H, C6H4OCH3), 5.46 (d, 1H, J1,2 = 1.7 Hz, H-1), 4.93,
4.68 (2d, 2H, 2JH,H = 10.9 Hz, PhCH2), 4.24–4.22 (m, 1H,
3
3
H-2), 4.06 (dd, 1H, J2,3 = 3.4 and J3,4 = 9.1 Hz, H-3),
3.94–3.84 (m, 1H, H-5), 3.79 (s, 3H, OCH3), 3.55 (t, 1H,
3
3J4,5 = 9.4 Hz, H-4), 2.68 (d, 1H, J2,OH = 1.8 Hz, OH-2),
3
1.30 (d, 3H, J5,6 = 6.2 Hz, H-6); 13C NMR (CDCl3,
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75 MHz): d = 154.8, 150.1 (C-q of C6H4OCH3), 138.3,
137.8 (C-q of PhCH2), 128-6-127.7 (others PhCH2), 117.5,
114.6 (others C6H4OCH3), 97.8 (C-1), 79.9, 79.8, 75.4,
72.2, 68.5, 67.9 (C-2, C-3, C-4, C-5 and PhCH2), 55.6
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D-rhamnopyranoside (19): Rf 0.44 (hexane/EtOAc, 2:1);
25
½aꢁD +21 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz):
d = 8.17–8.09, 7.66–7.46 (m, 10H, COPh), 7.10–7.04,
6.89–6.85 (m, 4H, C6H4OCH3), 5.60–5.58 (m, 2H, H-1,
3
and H-2), 5.36 (t, 1H, J3,4 = J4,5 = 9.9 Hz, H-4),
4.57–4.50 (m, 1H, H-3), 4.29–4.20 (m, 1H, H-5), 3.80 (s,
3
3H, OCH3), 2.61 (d, 1H, J2,OH = 7.4 Hz, OH-3), 1.33
(d, 3H, 3J5,6 = 6.3 Hz, H-6); 13C NMR (CDCl3, 75 MHz):
d = 167.0, 166.0 (COPh), 155.2, 150.1 (C-q of
C6H4OCH3), 133.6–128.5 (COPh), 117.7, 114.6 (others
C6H4OCH3), 96.5 (C-1), 75.4, 73.0, 68.8, 66.9 (C-2, C-3,
C-4, and C-5), 55.6 (OCH3) 17.6 (C-6); ES-MS: m/z =
501.2 [M+Na]+.
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sen, M. R.; Madsen, R. Synthesis 2002, 12, 1721–1727.
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side (3): Rf 0.67 (CH3CN/H2O, 9:1); mp 101–103 °C
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1369–1378.
25
(AcOEt/petroleum ether); ½aꢁD +96 (c 1.0, CH3OH); 1H
NMR (D2O, 300 MHz): d = 7.13–7.07, 7.00–6.96 (m, 4H,
3
C6H4OCH3), 5.42 (d, 1H, J1,2 = 1.9 Hz, H-1), 4.16 (dd,