An efficient synthesis of selectively functionalized D-rhamnose derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.01.064

D-Rhamnose is an important component of bacterial lipopolysaccharides. This paper describes a short and highly efficient synthesis of D-rhamnose from D-mannose. The synthesis of selectively C-4 modified d-rhamnosides and 6-deoxy-D-talosides as potential building blocks for complex oligosaccharide synthesis is also discussed.

Full text of DOI:10.1016/j.tetlet.2011.01.064

Tetrahedron Letters 52 (2011) 1296–1299
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of selectively functionalized D-rhamnose derivatives
⇑
Matthew Zunk, Milton J. Kiefel
Institute for Glycomics, Griffith University Gold Coast Campus, Queensland 4222, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
D
-Rhamnose is an important component of bacterial lipopolysaccharides. This paper describes a short and
Received 26 November 2010
Revised 20 December 2010
Accepted 14 January 2011
Available online 20 January 2011
highly efficient synthesis of -rhamnose from -mannose. The synthesis of selectively C-4 modified D-
D
D
rhamnosides and 6-deoxy-
is also discussed.
D-talosides as potential building blocks for complex oligosaccharide synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
D-Rhamnose
6-Deoxy- -talose
D
Building blocks
Pathogenic bacteria
Lipopolysaccharides
Bacterial cell surface carbohydrates are now widely recognized
as playing an essential role in disease progression and host defence
mechanisms. Lipopolysaccharides (LPS) are the major components
of Gram-negative outer cell membranes, and are known to be inti-
mately involved in pathogenesis in both animals and plants.1 Of
particular importance is the O-antigen component of the LPS,
which is displayed towards the external environment by the bacte-
rium and is known to be associated with host-pathogen cross-
talk.2
ogenic organisms.6 Given that
D-rhamnose is not present in hu-
mans, this rare sugar is an ideal template for drug discovery
strategies and vaccine development.
Although
hibitively expensive for large-scale synthetic chemistry. Several
chemical syntheses of
-rhamnosides have been reported,7–10
D-rhamnose is commercially available, its cost is pro-
D
however, in general these methods are not readily applicable to
the large scale approaches that are necessary for gaining access
to appropriate building blocks for oligosaccharide synthesis. A sig-
The role of bacterial LPS, and specifically O-antigens, in disease
has prompted a number of investigations into the chemical struc-
ture of these carbohydrate antigens, with a view to both under-
standing their role in pathogenesis and also using these antigenic
structures to develop vaccines.3 As our knowledge of the specific
monomers present in these carbohydrate antigens grows, so too
does the need for efficient chemical syntheses of the building
blocks required to construct appropriate oligosaccharides for vac-
cine development and pathogenicity studies. In this regard, 6-
nificant advancement in
the Roy group in 2007,11 wherein they synthesized the
side 1 in five steps from -mannose. Importantly, this work was
able to be carried out on a large scale, affording the -rhamnoside
1 in 87% overall yield from
-mannose.11 We report here our efforts
towards the synthesis of -rhamnose, and specifically functional-
ized -rhamnosides that may serve as useful building blocks for
D
-rhamnose chemistry was reported by
D
-rhamno-
D
D
D
D
D
oligosaccharide synthesis.
deoxy-
D
-hexoses are of interest, since these sugars are found in a
OH
OH
Me
OH
O
5 steps
number of important pathogens, including genera such as Burk-
holderia, Helicobacter, Pseudomonas, Xanthomonas, Citrobacter and
Bacillus.4,5
Despite the importance of 6-deoxy-
priate synthetic compounds as building blocks is limited by their
availability. 6-Deoxy- -mannosides or -rhamnosides are of partic-
ular interest. Whilst the precise role of this deoxy sugar remains
unclear, it does appear that -rhamnose is a key component of
HO
HO
O
HO
87% overall
HO
OH
O
pMP
D-mannose
1
D-hexoses, access to appro-
Our synthesis of D-rhamnose is shown in Scheme 1. Treatment
D
D
of
exclusively the
D
-mannose with benzyl alcohol under acidic conditions12 gives
a-benzyl-glycoside 2 in high yield (98%). Regiose-
D
lective iodination of the primary alcohol in 2 was achieved in high
yield (98%) using Mitsunobu conditions.9,11 Confirmation that the
iodide was attached to C-6 in 3 was obtained by noting the change
in the 13C NMR chemical shift of C-6 from d 60.7 in 2 to d 7.4 in 3,
consistent with the expected shielding effect of iodine. Reduction
the LPS of certain human pathogens as well as several phytopath-
⇑
Corresponding author. Tel.: +61 7 5552 7021; fax: +61 7 5552 8098.
E-mail address: m.kiefel@griffith.edu.au (M.J. Kiefel).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.064

M. Zunk, M. J. Kiefel / Tetrahedron Letters 52 (2011) 1296–1299
1297
N3
Me
OH
OH
O
I
OH
OH
O
Me
O
Me
OH
OH
O
OH
O
OBn
O
i
ii
RO
TfO
HO
i
iii
iv
O
HO
HO
HO
HO
HO
HO
O
HO
4
OH
OBn
OBn
OBn
OBn
11
D-mannose
9
2
3
iv
7 R = H
8 R = Tf
Me
ii
O
O
Me
Me
OH
O
OH
O
OR
iii
iv
HO
HO
HO
HO
OBn
10 R = H
12 R = Ac
OH
OBn
v
D-rhamnose
4
Scheme 1. Reagents and conditions: (i) BnOH, AcCl, 50 °C for 1.5 h, then rt for 12 h,
98%; (ii) PPh3, I2, imidazole, THF, reflux, 2 h, 98%; (iii) H2 (g), Pd(OH)2 on C, EtNiPr2,
MeOH, rt, 6 h, 100%; (iv) H+ resin, H2O, 80 °C, 12 h, 100%.
Scheme 2. Reagents and conditions: (i) 2,2-dimethoxypropane: acetone (1:1), p-
TsOH, 4 Å MS, 30 min, 100%; (ii) Tf2O, pyridine, À78 °C to 0 °C, 83%; (iii) dil HCl,
95%; (iv) NaN3, DMF, 60 °C, 4 h, 98%; (v) Ac2O, pyridine, 0 °C to rt, 15 h, 95%.
of the iodide in 3 using catalytic hydrogenation gave the expected
in 7 to d 4.57 in 8. Unfortunately, all attempts at nucleophilic dis-
placement of the triflate group in 8 with sodium azide failed, with
highly complex reaction mixtures being obtained in each instance.
An examination of the literature revealed that attempted nucleo-
philic displacement of the 4-O-sulfonate group in 6-deoxy-2,3-O-
isopropylidene pyranosides such as 8 resulted in an unusual rear-
rangement to give furanoside products with the nucleophile at-
tached to C-5.16–18 It has been suggested16,19 that the ring
contraction occurs through an initial SN2-like process whereby
the ring oxygen attacks C-4, due to the fact that the C-5 ring oxy-
gen bond is trans-antiparallel to the C-4 sulfonate group. The com-
plexity of our reaction mixture would be consistent with this type
of rearrangement.
D
-rhamnoside 4 in quantitative yield. The structure of 4 was con-
firmed by 1H NMR spectroscopy, most notably by the presence of
a 3-proton doublet at d 1.26. Significantly, the three-step conver-
sion of D-mannose to the rhamnoside 4 can be routinely carried
out on a 10 g scale.
To complete the synthesis of D-rhamnose itself, the a-benzyl-
glycoside in 4 can be removed in quantitative yield by exposure
of 4 to acidic resin in water at 80 °C for 12 h.
Having established a highly efficient synthesis of the D-rhamno-
side 4, we next examined the usefulness of this compound as a
building block for possible oligosaccharide synthesis. In Nature,
D
-rhamnose is usually linked (1 ? 2) or (1 ? 3) with another D-
Rhap or linked (1 ? 6) or (1 ? 4) to other hexoses, notably Man
We reasoned that our inability to successfully displace the tri-
flate group in 8 was probably due to steric hindrance and ring
strain, since the 2,3-O-isopropylidene group adds rigidity into the
system and also sterically blocks the face that the incoming nucle-
ophile is attacking from. This observation is supported by the fact
that the analogous epimeric C-4 triflate to 8, with the triflate in an
axial orientation, can be readily displaced by sodium azide, to give
C-4 equatorial azido product.9 In an attempt to overcome these po-
tential steric problems, triflate 8 was deprotected to give the diol 9
(Scheme 2).
and Gal.4 Of particular interest in our work was selective function-
alisation at C-4 of D-rhamnose; C-4 modified D-rhamnose deriva-
tives could serve as useful building blocks in efforts to
incorporate specifically modified rhamnose derivatives into poly-
saccharide-based conjugate vaccines, such as the rhamnose-con-
taining analogue 513 of the Bacillus anthracis tetrasaccharide
6.10,14 In addition, functionalisation with epimerization at C-4
would produce 6-deoxy-talosides,15 which could also serve as use-
ful synthetic intermediates.
Interestingly, initial attempts at base-promoted displacement of
the triflate in 9 with sodium azide in DMF at elevated temperature
resulted in the rapid formation of the 3,4-anhydro derivative 10 as
the major product, rather than the anticipated talo-configured
product 11 (Scheme 2). Using trimethylsilyl azide as the nucleo-
phile also failed to furnish the desired product 11, returning unre-
acted starting material 9. Proof that the 3,4-anhydro derivative 10
had indeed been formed during the treatment of 9 with sodium
azide was obtained from careful analysis of the spectroscopic data
and comparison with related literature compounds.19,20 Most nota-
bly, a molecular mass of m/z 259 (M+Na) was consistent with the
loss of triflic acid from 9, whilst the change in the magnitude of
the coupling between H-4 and H-5 (from J = 9.6 Hz in 9 to 4.2 Hz
in 10) and H-3 and H-2 (from J = 3.6 Hz in 9 to 4.5 Hz in 10) was
consistent with the formation of the 3,4-anhydro system. Addition-
ally, acetylation of product 10 gave compound 12 which contained
a single acetyl group at C-2, confirming that the anhydro ring in 10
was formed between C-3 and C-4. Deliberate formation of the 3,4-
anhydro derivative 10 was achieved by treating triflate 9 with
K2CO3 in MeOH,19,21 resulting in quantitative formation of 10.
It is generally considered that direct nucleophilic displacement
reactions at C-4 of manno-configured pyranosides such as 9 is dif-
ficult, since the b-trans-axial group at C-2 can sterically hinder the
approaching nucleophile, and can also cause unfavourable polar
interactions.18,22,23 This apparent difficulty has prompted some to
avoid this transformation completely, and opt instead for an oxida-
tion—oximation—reduction strategy in order to introduce an axial
nitrogen-based functionality at C-4 when starting with a manno-
configured sugar.20 In a comprehensive study on the nucleophilic
O
Me
OH
O
H
NH
HO
OH
Me
HO
Me
O
O
O
HO
HO
O
HO
O
Me
O
Me
HO
O
O
NH
HO
H
O
OH
Me
O
Me
HO
O
O
O
O
HO
HO
O
Me
NH
HO
O
OH
HO
Me
O
OMe
O
H
NH
HO
6
OMe
5
Our initial strategy towards C-4 modified derivatives of 4 was
focused on introducing nitrogen-based functionality. Given that
the C-2 and C-3 hydroxys in 4 are cis with respect to each other,
they are ideally arranged to use a cyclic protecting group, thereby
leaving the C-4 hydroxy free for selective functionalisation. After
some refinement of reaction conditions, we found that treatment
of the benzyl rhamnoside 4 with 2,2-dimethoxypropane and ace-
tone in the presence of p-TsOH and 4 Å molecular sieves gave the
desired 2,3-O-isopropylidene derivative 7 in quantitative yield
(Scheme 2). In order to gain access to C-4 modified 6-deoxy-talo-
sides, we reasoned that a potential strategy could involve direct
displacement of a good leaving group at C-4 in 7. Accordingly,
exposure of 7 to triflic anhydride at low temperature proceeded
smoothly, with successful incorporation of the triflate group at C-
4 confirmed by examination of the 1H NMR spectrum of 8, which
showed the expected deshielding of the H-4 proton from d 3.42

1298
M. Zunk, M. J. Kiefel / Tetrahedron Letters 52 (2011) 1296–1299
Me
displacement of 4-sulfonyloxy groups in D-manno-configured sug-
Me
OR
O
O
O
N3
HO
i
ars (e.g. 13), Cicero et al. showed that the nature of the other sub-
stituents played an important role in the outcome of the
displacement reactions.22 For example, attempted thiocyanate dis-
placement of the C-4 sulfonate group in 14 resulted in attack at C-4
by the C-2 benzyloxy substituent, followed by benzoyl migration
to give a mixture of the three possible dibenzoate products.22
Interestingly, in the absence of protecting groups at C-2 and C-3,
attempted thiocyanate displacement of C-4 sulfonate in 15 gave
a mixture of both the talo- and manno-configured C-4 thiocyano
derivatives, presumably via a 3,4-anhydro transition state.22
OR
OBn
OBn
10 R = H
18 R = Bz
17 R = H
19 R = Bz
ii
Scheme 3. Reagents and conditions: (i) TMSN3, BF3ÁOEt2, rt, 1 h; (ii) BzCl, pyridine,
rt, 98%.
N3
Me
O
Me
OH
OAc
O
Me
O
O
TfO
HO
i, ii
OAc
AcO
Me
Me
Me
HO
OR
O
OR
O
O
O
OBn
OBn
R'O2SO
RO
R'O2SO
RO
OBn
9
20
12
OMe
13 R = H or Bz
OMe
OMe
Scheme 4. Reagents and conditions: (i) NaN3, DMF, 0 °C, 30 min; (ii) Ac2O, pyridine,
0 °C to rt, 15 h.
14 R = Bz, R' = p-NO2Ph
15 R = H, R' = p-NO2Ph
16
R' = p-MePh
or p-NO2Ph
the nucleophilic attack at C-4, resulting in the D-rhamnoside 19,
was obtained from examination of the 1H NMR data. In particular,
the magnitude of the coupling between H-4 and H-3 (J = 9.6 Hz) is
consistent with a trans-diaxial coupling, whilst H-3 also shows a
coupling to an exchangeable OH proton, clearly indicating that
the newly formed hydroxy group from epoxide opening is attached
to C-3.
The
a
-methyl glycoside analogue 16 of 10 has been used as a
key intermediate in the synthesis of 4-amino-4-deoxy-
D
-rham-
nose.21 In that work, the authors deliberately prepared the 3,4-
anhydro derivative 16 by treating the corresponding 4-O-mesy-
late-rhamnoside with sodium hydroxide. Treatment of 16 with
either sodium azide or ammonia in MeOH resulted in predominant
attack at C-3, whilst the use of aqueous dimethylamine gave a 12:1
mixture favouring attack at C-3 over C-4.21 Interestingly, introduc-
tion of a benzoyl protecting group on the C-2 hydroxy in 16 re-
sulted in a complete change in the regiochemical outcome of
azide opening, with the predominant product resulting from attack
at C-4.21 This finding was rationalized on the conformation of the
anhydro sugar, and the preference for a transition state that fa-
vours a trans-diaxial opening of the epoxide. It was reasoned that
the sterically demanding group at C-2 would result in destabiliza-
tion of the half-chair conformation that favours attack at C-3, thus
promoting attack at C-4.21 Several other examples of the nucleo-
philic opening of anhydro sugars have been reported, and in many
of these papers both the regio- and stereochemical outcome of the
opening can be controlled by varying either the type of nucleophile
being used or by alteration of hydroxy protecting groups.19,20,24–26
For our 3,4-anhydro derivative 10, nucleophilic attack at C-3
would result in an ido-configured sugar, whilst nucleophilic attack
at C-4 would return a manno-configured sugar. Unfortunately
however, in our hands the anhydro sugar 10, or the 2-acetyl ana-
logue 12, were surprisingly robust compounds. Exposure of 10 or
12 to NaN3 in DMF for extended reaction times and at elevated
temperature failed to produce any products, returning unreacted
starting material in all cases. Treatment of 12 with NaN3 in the
presence of either NH4Cl in aqueous MeOH20 or CeCl3 in aqueous
acetonitrile27 also resulted in recovered starting material. Non-
nitrogen based nucleophiles, including methoxide and sodium ace-
tate, also failed to react with 10.
Having shown that we could successfully generate 4-azido
manno-configured
D-rhamnosides from 3,4-anhydro compounds
such as 10 and 18, we returned to our original strategy involving
a direct displacement of the C-4 triflate group in 9, with a view
to generating C-4 modified sugars with a talo-configuration (i.e.
an axial C-4 substituent). Our original experiments had shown that
3,4-anhydro derivative 10 formed quite readily from the 4-triflate
9, being present (by TLC analysis) in the reaction mixture even
after a few minutes. We therefore reasoned that lowering the reac-
tion temperature may limit the formation of 10. Accordingly, treat-
ment of 9 with NaN3 in DMF at 0 °C for 30 min resulted in a
mixture of two products with similar mobility on silica gel. To as-
sist with the separation of these two components, the crude reac-
tion mixture was acetylated prior to chromatographic purification.
In that way the desired 4-azido talo-configured derivative 20 was
isolated in a respectable 62% yield (based on 9) together with the
3,4-anhydro derivative 12 (35%) (Scheme 4).
At this stage we have not been able to prevent completely the
formation of 3,4-anhydro derivative 10, but our experiments have
shown that milder conditions reduce substantially the proportion
of 3,4-anhydro sugar being formed. Further studies in this regard
will be reported in due course.
In conclusion, our four-step synthesis of
D-rhamnose from
D-
mannose represents the most efficient route for preparing
D
-rham-
nose reported to date. Importantly, the type of chemistry employed
means that the four steps can be routinely carried out on a large
scale, making this an attractive route for those requiring multi-
gram quantities of this valuable 6-deoxy sugar. Additionally, our
syntheses of 4-azido rhamnoside 19 and 4-azido taloside 20 are
important, since these compounds have obvious application as
building blocks in studies aimed at generating novel compounds
for developing conjugate vaccines or as probes for carbohydrate-
binding proteins associated with various bacterial virulence
factors.
The use of Lewis acids in conjunction with TMSN3 appears to be
a mild and highly regioselective method for opening epoxy alco-
hols.24,25,28 A postulated benefit of using the Lewis acid is that
the epoxide oxygen coordinates to the metal of the Lewis acid.
Accordingly, exposure of 10 to TMSN3 and BF3ÁOEt2 provided the
4-azido-D-rhamnoside 17 in a modest 26% yield (Scheme 3), to-
gether with several other minor products. In an attempt to improve
this outcome, we decided to protect the hydroxy group in 10 prior
to epoxide opening. Treatment of 10 with either acetic anhydride
or benzoyl chloride, under standard conditions, gave the corre-
sponding C-2 esters 12 and 18, respectively, in high yields. Inter-
estingly, whilst exposure of 12 to TMSN3/BF3ÁOEt2 gave
complex mixture of products (similar to the outcome with 10),
reaction of 18 under the same conditions gave 4-azido- -rhamno-
side 19 in a 59% yield. Proof that epoxide opening had occurred via
Acknowledgements
We thank Griffith University for a Ph.D. scholarship (to M.Z.)
and the Institute for Glycomics for financial support. Prof David
O’Hagan (University of St. Andrews, UK) and Dr. Robin Thomson
(Institute for Glycomics, Griffith University) are thanked for helpful
discussions.
a
D

M. Zunk, M. J. Kiefel / Tetrahedron Letters 52 (2011) 1296–1299
1299
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T.; Choma, A.; Russa, R. Carbohydr. Res. 2009, 344, 2519–2527.
Supplementary data
Supplementary data associated (full experimental details and
spectroscopic characterization of all compounds is provided, along
with copies of 1H NMR data of several key compounds) with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.01.064.
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