Expeditious synthesis of bacterial, rare sugar building blocks to access the prokaryotic glycome

Article abstract of DOI:10.1039/c3ob40615f

Bacteria have unusual glycans which are not accessible by isolation. Herein, we describe a general and divergent strategy for the synthesis of the rare, bacterial deoxy amino hexopyranoside building blocks from d-mannose. The methodology is applied to the first total synthesis of the l-serine linked trisaccharide of Neisseria meningitidis. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40615f

Organic &
Biomolecular Chemistry
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Expeditious synthesis of bacterial, rare sugar building
blocks to access the prokaryotic glycome†
Cite this: Org. Biomol. Chem., 2013, 11,
3098
Madhu Emmadi and Suvarn S. Kulkarni*
Received 27th March 2013,
Accepted 28th March 2013
DOI: 10.1039/c3ob40615f
www.rsc.org/obc
Bacteria have unusual glycans which are not accessible by iso-
lation. Herein, we describe a general and divergent strategy for
the synthesis of the rare, bacterial deoxy amino hexopyranoside
building blocks from D-mannose. The methodology is applied
to the first total synthesis of the L-serine linked trisaccharide of
Neisseria meningitidis.
Introduction
Protein glycosylation, which was once believed to be restricted
to eukaryotes, is now shown to be common in prokaryotes.1 A
major difference between the two, however, lies in their glycan
structures. The bacterial glycoproteins and oligosaccharides
contain rare deoxy amino sugars which are not present on the
human cell surface. This important structural difference
which helps one to distinguish between the pathogen and the
host cell could be exploited for target specific drug discovery
and more importantly for carbohydrate based vaccine
development.2
In contrast to their eukaryotic counterparts, bacterial glyco-
proteins have atypical monosaccharides attached to L-serine or
L-threonine (Fig. 1). For example, O-linked glycans located on
the pilin of Neisseria gonorrhoeae and Neisseria meningitidis
consist of 2,4-diacetamido-2,4,6-trideoxyhexose (DATDH),3
whereas N-linked glycans of C. jejuni4 comprise a Bacillos-
amine (Bac) core. Likewise, N-acetyl fucosamine (FucNAc) is
found in O-linked glycans on flagellin of Pseudomonas aerugi-
nosa.5 The 2-acetamido-4-amino-2,4,6-trideoxyhexose (AAT)
forms a key component of the zwitterionic polysaccharides
(ZPSs) located on the surfaces of various bacteria.6–10 Vaccine
candidates against these bacteria are highly desired. For this
purpose, access to chemically pure and structurally well
Fig. 1 Structures of various bacterial glycans containing rare deoxy amino
sugars.
defined antigenic material is essential. However, the bacterial
carbohydrates could not be isolated from natural sources in
acceptable amounts and purity. Thus, chemical synthesis of
orthogonally protected building blocks of the rare deoxy
amino sugars is pivotal for synthesizing the bacterial glycans.
Given their biological importance, several routes are
reported for the synthesis of the rare sugars. While many of
these monosaccharide building blocks could be synthesized by
classical carbohydrate approaches,11–17 those strategies mostly
involve lengthy routes with extensive protecting group manipu-
lations and/or expensive starting materials. Very recently a
de novo strategy has been developed for AAT and other
related deoxy amino sugars from L-threonine18,19 and L-Garner
aldehyde,20 respectively. These elegant routes also involve a
number of steps and intermittent separation of diastereomers.
A general and simple route for accessing all the rare sugar
building blocks is still missing. We reasoned that a common
intermediate derived from an abundant and cheaply available
natural monosaccharide, such as D-mannose, could be efficien-
tly transformed into various rare sugar building blocks, if the
number of protection–deprotection steps could be decreased
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai,
400076, India. E-mail: suvarn@chem.iitb.ac.in; Fax: (+)(91-22) 2576 7152;
Tel: (+)(91-22) 2576 7166
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data for all new compounds, and copies of 1H, 13C and
2D NMR spectra. See DOI: 10.1039/c3ob40615f
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by carrying out regioselective and one-pot reactions. Here we
A sequential double serial C2, C4 inversion via displace-
present a short, efficient and general protocol for the synthesis ment of triflates was attempted next. Compound 2b was first
of various orthogonally protected, bacterial rare sugar building treated with Tf2O to obtain the corresponding 2,4-bis-triflate,
blocks. Our strategy involves a one-pot double serial and which upon treatment with a stoichiometric amount of tetra-
double parallel displacement of the D-mannose derived 2,4-bis- butylammonium azide (TBAN3) in CH3CN at −30 °C smoothly
trifluoromethanesulfonates (OTf, triflate) by azide, phthal- underwent a highly regioselective displacement of the C-2 tri-
imide and nitrite ions as nucleophiles. By changing the flyloxy group, exclusively. Evaporation of the solvent and
sequence of addition of nucleophiles, various orthogonally addition of potassium phthalimide (2 equiv.) in DMF in the
protected rare deoxy amino sugar building blocks could be same pot at RT displaced the remaining C4-OTf and afforded
rapidly synthesized. The inherent potential of the methodology the AAT building block 4 in 57% overall yield. The regioselec-
is exemplified by the first total synthesis of the L-serine linked tivity in this case is mainly governed by steric factors. Appar-
trisaccharide of Neisseria meningitidis.
ently, the C2-OTf of the β-isomers 2a/2b is more accessible as
compared to the C4-OTf. It is further tuned by employing an
exact stoichiometric amount of the reagent and conducting
the displacement at a low temperature.
Results and discussion
The high regioselectivity observed in the above reaction
prompted us to try a Lattrell–Dax reaction27–30 involving
nucleophilic displacement of triflate using nitrite anions.
Thus, compound 2b was subjected to triflation and concomi-
tant treatment with TBAN3 (1.0 equiv.) in CH3CN under
similar conditions at −30 °C. After the completion of the reac-
tion as indicated by TLC, tetrabutylammonium nitrite
(TBANO2) was added in the same pot, to displace the 4-OTf
and generate the D-fucosamine derivative 5, exclusively, in 60%
overall yield. In order to access the D-fucosamine derivative
with a 3-OH free, a different approach was used. Starting with
the C3-acetate 2a, the first two steps were repeated in an identi-
cal manner to obtain the corresponding 2-azido-4-OTf (quino-
vosamine) intermediate, as judged by TLC. Then, water was
added and the reaction mixture was heated to 65 °C to gener-
ate 3-hydroxy fucosamine 6 as a sole product in 62% overall
yield. Here, the 3-O-acetyl group migrated from C-3 to C-4
along the top face to displace the C4-triflyloxy group with
inversion at C-4. The Bac building block 7 was synthesized
from 5 by sequential triflation followed by azide displacement
with C4 inversion in an essentially one-pot manner (81%). In
this way, most of the bacterial rare sugar building blocks 3–7
could be procured in an expedient manner from a common
intermediate 2a or 2b via regioselective tandem reactions, after
a single chromatographic purification.‡ These valuable thiogly-
coside building blocks can be utilized as stable and flexible
glycosyl donors or acceptors to stereoselectively assemble the
bacterial glycoproteins and oligosaccharides.
Previous works in this field have shown that the presence of
the β-linkage in D-mannoside21,22 and the 3-O-acyl group22–24
are crucial for achieving success in nucleophilic displacements
using azide or nitrite anions, respectively. As shown in
Scheme 1, the primary hydroxyl group of 125 was regioselec-
tively tosylated and subsequently reduced with LAH to form
the corresponding C6-deoxy sugar (D-rhamnose), which upon a
highly regioselective tin mediated acylation26 with AcCl or
BzCl afforded 2,4-diols 2a and 2b, respectively, which served as
common intermediates to fashion various rare sugar building
blocks. Triflation of 2a and 2b, followed by the SN2 displace-
ment of the formed bis-triflates by a brief treatment with
excess NaN3, cleanly generated the 2,4-diazido derivatives
(DATDH) 3a (82%) and 3b (85%), respectively, with the inver-
sion of stereochemistry at C2 and C4, in an essentially one-pot
manner.
As an application of our methodology, we report herein the
first total synthesis of the α-L-serine linked trisaccharide of
N. meningitidis (Scheme 2). The O-linked trisaccharide was
identified in N. meningitidis pili, the filamentous glycoproteins
that are essential adhesins in capsular bacteria.3 Its structure
was proposed based on the linkage analysis by acid hydrolysis
and mass spectroscopic studies and has been shown to com-
prise the DATDH sugar attached to L-serine; the stereo-
chemistry at C4 of the DATDH sugar was not defined (Fig. 1a).
A major challenge in the synthesis was the stereoselective
installation of two consecutive α-linkages in 19. Achieving
α-stereoselectivity in coupling of the 6-deoxy monosaccharide
with the primary OH of the amino acid L-serine was very
Scheme 1 Synthesis of bacterial, rare deoxy amino monosaccharide building
blocks.
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It has been reported that the α-anomeric OMP glycosides
are reluctant to react with AcCl, ZnCl2 and cat. ZnI2 to form
glycosyl chlorides whereas the β-isomers react readily.31
However, we found that, by using a combination of AcCl,
BF3·OEt2 and cat. ZnI2, the α-anomeric OMP in 16 could be
easily replaced by chloride and the so formed α-glycosyl chlor-
ide 17 was coupled with the glycosyl amino acid acceptor 12
using AgOTf as a promoter to afford exclusively α-linked
product 18 (1H NMR δ 4.74, d, J1′,2′ = 3.6 Hz, H-1′)‡ in 80%
yield. The α-selectivity in this case is presumably arising
through the intermediacy of the β-triflate. Global deprotection
of 18 involving Staudinger reduction of azides, N-acetylation,
oxidative debenzylation,32 and de-O-acetylation afforded the
target molecule 19 in 51% overall yield.
Table 1 Stereoselective glycosylation of L-serine 10 with various donors
Entry Donor Promoter
Temp. (°C) Solvent α/β
Yield (%)
1
2
3
4
5
3b
8
8
8
Ph2SO/Tf2O −60
CH2Cl2 2.2/1 78
CH2Cl2 1.8/1 65
CH2Cl2 2.0/1 69
CH2Cl2 1.0/0 29
AgOTf
AgClO4
TBAI
−50
RT
RT
−78
Conclusions
9a/9b
TMSOTf
THF
1.0/0 92/93
In conclusion, we have developed a short and efficient protocol
to synthesize most of the bacterial rare deoxy amino hexoses
(FucNAc, Bac, AAT, and DATDH) as orthogonally protected,
stable thioglycoside building blocks. Thus, D-mannose can be
expediently transformed into various bacterial aminosugar
thioglycosides in a few steps. The methodology is applied
to the first synthesis of the L-serine linked trisaccharide of
N. meningitidis. The short and efficient protocol is expected to
speed up bacterial glycan assembly and give rapid access to
the prokaryotic glycome.
difficult. Advantageously, all our building blocks, being stable
thioglycosides, could be readily transformed into other types
of donors (Table 1). Of the various glycosyl donors tried, the
trichloroacetimidates worked the best (Table 1, entry 5). Coup-
ling of donor 9a/9b with L-serine acceptor 10 using TMSOTf as
a promoter at −78 °C in THF as a participating solvent cleanly
generated a single α-isomer 11aα/11bα individually, in 92%
and 93% yield, respectively. Selective removal of an acetate
group in 11aα using Et3N and methanol afforded acceptor 12
(80%). In parallel, the α-methoxyphenyl digalactoside 16
(Scheme 2) was prepared from a known OMP galactoside 13 in
5 steps via glycosylation of 4-OH acceptor 14 with imidate 15.‡
Experimental
All reactions were conducted under a dry nitrogen atmosphere.
Solvents (CH2Cl2 >99%, THF 99.5%, acetonitrile 99.8%, DMF
99.5%) were purchased in capped bottles and dried under
sodium or CaH2. All other solvents and reagents were used
without further purification. All glassware was oven-dried
before use. TLC was performed on precoated aluminum plates
of silica gel 60 F254 (0.25 mm, E. Merck). Developed TLC
plates were visualized under a short-wave UV lamp and by
heating plates that were dipped in ammonium molybdate/
cerium(IV) sulfate solution. Silica gel column chromatography
was performed using silica gel (100–200 mesh) and employed
a solvent polarity correlated with TLC mobility. NMR exper-
iments were conducted on a Bruker 400 MHz instrument
using CDCl3 (D, 99.8%) or (CD3)2CO (D, 99.9% or CD3OD
99.8%) as solvents. Chemical shifts are relative to the deuter-
1
ated solvent peaks and are in parts per million (ppm). H–1H
COSY and HSQC were used to confirm proton assignments.
Mass spectra were acquired in the ESI mode.
Phenyl 2-azido-3-O-benzoyl-2,4,6-trideoxy-4-phthalimido-
1-thio-β-D-galactopyranoside (4)
Trifluoromethanesulfonic anhydride (0.42 mL, 2.5 mmol) was
added dropwise at −10 °C to a stirred solution of 2b (0.15 g,
0.4 mmol), pyridine (0.43 mL, 5.4 mmol) in CH2Cl2 (7 mL)
Scheme 2 Synthesis of the α-L-serine linked trisaccharide of N. meningitidis.
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and the solution was gradually brought to 10 °C over 2 h. After 130.0, 129.2, 128.7, 128.6, 86.6, 76.8, 74.8, 69.4, 59.9, 16.8;
complete conversion of the starting material the reaction HR-ESI-MS (m/z): [M
Na]+ calcd for C19H19N3O4NaS,
+
mixture was diluted with CH2Cl2 and washed successively with 408.0994; found, 408.0974.
1 M HCl, aq. NaHCO3 and water. Combined organic layers
Phenyl 4-O-acetyl-2-azido-2,6-dideoxy-1-thio-β-D-
galactopyranoside (6)
were dried over Na2SO4, concentrated and the crude product
was used for the next step without any purification.
The crude product was dissolved in acetonitrile (11 mL),
and to this, TBAN3 (118 mg, 0.42 mmol) was added at −30 °C
and the reaction mixture was stirred at the same temperature
for 20 h. After 20 h the solvent was evaporated on a rotary evap-
orator under an N2 atmosphere and the residue was dissolved
in DMF (2 mL). To this clear solution, PhthNK (0.15 g,
0.83 mmol) was added. After 10 h the reaction mixture was
diluted with EtOAc and washed with water. The separated
aqueous layer was washed with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography on
silica gel (1 : 9 ethyl acetate–toluene) to obtain 4 as a viscous
liquid (0.12 g, 57%). 1H NMR (400 MHz, CDCl3) δ 7.89–7.83
(m, 3H, ArH), 7.79 (s, 3H, ArH), 7.72–7.66 (m, 2H, ArH),
7.64–7.61 (m, 1H, ArH), 7.49–7.27 (m, 5H, ArH), 5.39 (dd, J =
9.8, 7.0 Hz, 1H, H-3), 5.04 (dd, J = 7.0, 2.8 Hz, 1H, H-4), 4.91 (t,
J = 9.8 Hz, 1H, H-2), 4.72 (d, J = 9.8 Hz, 1H, H-1), 4.00 (qd, J =
6.4, 2.8 Hz, 1H, H-5), 1.20 (d, J = 6.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 168.5, 165.2, 134.5, 133.7, 133.5, 132.5,
129.8, 129.1, 128.8, 128.6, 128.1, 123.8, 88.9, 73.6, 73.2, 62.1,
Trifluoromethanesulfonic anhydride (0.83 mL, 4.9 mmol) and
pyridine (0.86 mL, 10.7 mmol) were added sequentially at
−10 °C to a stirred solution of 2a (0.24 g, 0.82 mmol) in
CH2Cl2 (12 mL). Then the reaction mixture was gradually
warmed to 10 °C over 2 h. After complete consumption of the
starting material, the reaction mixture was diluted with CH2Cl2
and washed successively with 1 M HCl, aq. NaHCO3 and brine.
The separated organic layer was dried over Na2SO4 and
concentrated.
The crude product which was obtained after the removal of
solvents was dissolved in acetonitrile (17 mL), and to this,
TBAN3 (0.23 g, 0.82 mmol) was added at −30 °C and the reac-
tion mixture was stirred at the same temperature for 20 h.
Then the reaction mixture was concentrated to 5 mL, and to
this, water (0.33 mL, 18.0 mmol) was added and the reaction
mixture was kept for reflux at 65 °C for 1 h. It was diluted with
EtOAc and washed with water. The separated organic layer was
dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(1 : 9 ethyl acetate–pet ether) to obtain 6 as a pale yellowish
viscous liquid (0.16 g, 62%). 1H NMR (400 MHz, CDCl3)
δ 7.61–7.58 (m, 2H, ArH), 7.33–7.30 (m, 3H, ArH), 5.15 (d, J =
3.2 Hz, 1H, H-4), 4.45 (d, J = 10.0 Hz, 1H, H-1), 3.72–3.67 (m,
2H, H-3 and H-5), 3.49 (t, J = 10.0 Hz, 1H, H-2), 2.13 (s, 3H,
CH3) 1.38 (d, J = 6.4 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ 171.7, 133.1, 131.9, 129.0, 128.3, 86.5, 73.3, 73.1, 72.1,
62.4, 20.9, 16.9; HR-ESI-MS (m/z): [M + Na]+ calcd for
C14H17N3O4NaS, 346.0837; found, 346.0819.
51.7, 17.1; HR-ESI-MS (m/z): [M
+
Na]+ calcd for
C27H22N4O5NaS, 537.1209; found, 537.1134.
Phenyl 2-azido-3-O-benzoyl-2,6-dideoxy-1-thio-β-D-
galactopyranoside (5)
Trifluoromethanesulfonic anhydride (1.0 mL, 6.0 mmol) and
pyridine (1.0 mL, 13.0 mmol) were added sequentially at
−10 °C to a stirred solution of 2b (0.36 g, 1.0 mmol) in CH2Cl2
(15 mL). Then the reaction mixture was gradually warmed to
10 °C over 2 h. After complete consumption of the starting
material, the reaction mixture was diluted with CH2Cl2 and
washed successively with 1 M HCl, aq. NaHCO3 and brine. The
separated organic layer was dried over Na2SO4 and
concentrated.
Acknowledgements
This work was supported by DST (grant no. SR/S1/OC-40/2009)
and CSIR (grant no. 01(2376)/10/EMR-II). M.E. acknowledges
CSIR-New Delhi for a fellowship.
The crude product which was obtained after the removal of
solvents was dissolved in acetonitrile (20 mL), and to this,
TBAN3 (0.28 g, 1.0 mmol) was added at −30 °C and the reac-
tion mixture was stirred at the same temperature for 20 h.
TBANO2 (0.8 g, 3.0 mmol) was added and the reaction mixture
was stirred at RT for 1 h. It was diluted with EtOAc and washed
with water. The separated organic layer was dried over Na2SO4
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (1 : 9 ethyl acetate–pet
ether) to obtain 5 as a pale yellowish viscous liquid (0.23 g,
60%). 1H NMR (400 MHz, CDCl3) δ 8.07–8.04 (m, 2H, ArH),
7.64–7.57 (m, 3H, ArH), 7.47–7.37 (m, 2H, ArH), 7.36–7.34 (m,
3H, ArH), 4.99 (dd, J = 10.0, 2.9 Hz, 1H, H-3), 4.53 (d, J = 10.0
Hz, 1H, H-1), 4.01 (d, J = 2.9 Hz, 1H, H-4), 3.83 (t, J = 10.0 Hz,
1H, H-2), 3.77 (q, J = 6.4 Hz, 1H, H-5), 1.38 (d, J = 6.4 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 165.8, 133.8, 133.5, 131.6,
Notes and references
‡See ESI.
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