Synthetic routes toward the trisaccharide related to the lipopolysaccharide of Burkholderia sp. HKI-402 (B4)

Article abstract of DOI:10.1039/c4ra03954h

A stepwise and a three component one-pot sequential glycosylation reaction has been used for the synthesis of trisaccharide related to the LPS of Burkholderia sp. HKI-402 (B4) employing trichloroacetimidate and thio donors. This journal is

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DOI: 10.1039/C4RA03954H
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ARTICLE TYPE
Synthetic Routes Toward the Trisaccharide Related to the
Lipopolysaccharide of Burkholderia sp. HKI-402 (B4)
Nabamita Basu, Mana Mohan Mukherjee, Rina Ghosh*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Stepwise as well as a three component one-pot sequential
glycosylation reaction has been utilized for the synthesis of
trisaccharide related to the LPS of Burkholderia sp. HKI-402
(B4) employing trichloroacetimidate and thio donors.
HO
HO
O
O
NHAc
O
HO
HO
O
10 Introduction
A
O
The interactions between bacterial symbionts and their hosts
(higher organisms) can either be beneficial or detrimental to the
later.1 In many cases, living organisms harbour endosymbiotic
bacteria for providing improved defence mechanism, survival,
15 and even acquired virulence.2 The fungus Rhizopus microsporus
offers endosymbiotic bacteria asylum for the production of the
causal agent of rice seedling blight, rhizoxin. It has been proved
that rhizoxin is not biosynthesized by the fungus itself, but by
endosymbiotic bacteria of the genus Burkholderia sp. residing in
20 it.3 Rhizoxin, a lactone antibiotic, is a phytotoxin which exhibits
strong antimitotic activity in most eukaryotic cells, including
various human cancer cell lines. Owing to these, rhizoxin has
attracted considerable interest as a potential antitumor drug.4
Similarly there are innumerous antimitotic agents with different
25 potentialities, produced by several types of bacteria which could
unveil deadly effects such as chronic or acute toxic damage of
internal organs and many more.
HO
OH
Figure 1. Trisaccharide repeating unit present in the LPS of Burkholderia
sp. HKI-402 (B4).
50 Stepwise oligosaccharide syntheses6 are generally expensive and
tedious procedures since they demand extensive protecting group
manipulation and purification after each step. On the contrary,
one pot sequential oligosaccharide syntheses are more cost
viable, expeditious and more environment friendly. Owing to
55 these advantages many complex oligosaccharides have been
synthesized utilising one pot protocol, such as Globo-H
hexasaccharide, heparin pentasaccharide, Ley, α-Gal epitopes and
Gb3 saccharides.7 In continuation to our work on oligosaccharide
syntheses,8 we report herein the synthesis of the trisaccharide
60 related to the repeating unit present in the LPS of Burkholderia
sp. HKI-402 (B4) from the corresponding monosaccharide
building blocks as 3-(N-benzyloxycarbonyl) propyl glycoside by
stepwise and sequential one pot protocols.
Lipopolysaccharides (LPSs) are one of the major components
constructing the bacterial cell wall, and hence hugely responsible
30 for every kind of host-bacteria interaction. So, it is of immense
importance to identify and synthetically mimic the bacterial cell
wall LPSs in order to understand and manipulate their survival
ability and virulence property for vaccination purpose.
The synthesis of the trisaccharide related to the repeating unit
35 (Figure 1) present in the O-antigen LPS portion of Burkholderia
5
sp. HKI-402 (B4),
by stepwise and one-pot sequential
glycosylation reactions, will be discussed. To the best of our
knowledge, this is the first synthesis of this trisaccharide.
40 a Department of Chemistry, Jadavpur University, Kolkata 700 032, India..
Fax: +91-33-2414-6266
E-mail: ghoshrina@yahoo.com; jughoshrina@gmail.com
† Electronic Supplementary Information (ESI) available: General
experimental procedure, copies of !H-, 13C-, COSY- HSQC-NMR spectra
45 of compounds 1,
2
and HMBC-NMR spectra of 2. See
DOI: 10.1039/b000000x/
65
Figure 2. Retrosynthetic analysis of 1
.
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Results and Discussion
acetyl-
D
-glucosamine 1614 as anomeric mixture following
Retrosynthetic analysis of the fully protected trisaccharide 2 led
reported method. Thereafter, thiolation of 16 with thiophenol in
the presence of trimethylsilyltrifluoromethanesulfonate
(TMSOTf) or BF3.Et2O in CH2Cl2 furnished 3,4,6-tri-O-acetyl-2-
with donors 5a and 5b, and the glucosamine based acceptor 6 for 45 deoxy-2-phthalimido-1-thio-β- -glucopyranoside in
(17)12
to five monomeric sugar units, two orthogonal donors,
rhamnose based trichloroacetimidate 3 and thioglycoside 4 along
L-
5
D
exploiting stepwise as well as sequential one pot synthetic
approaches (Figure 2).
comparable yields (~85%). Glycosylation reaction was then
carried out on 17 and 3-(N-benzyloxycarbonyl) propanol as donor
Treatment of tetra acetylated
L
-rhamnose (7)9 with thiophenol
and acceptor, respectively using TCCA / TMSOTf15 activator
and BF3.Et2O in dry CH2Cl2 furnished phenyl 2,3,4-tri-O-acetyl-
system to provide 1815,16 in 86 % yield. It is to be noted that, this
10 1-thio-α-
D
-rhamanopyranoside (8)9 in 91% yield after purification 50 method15 furnished a better yield (86%) compared to the other
by column chromatography. Thioglycoside hydrolysis of 8 was
carried out using TCCA10 in aqueous (CH3)2CO to give 2,3,4-tri-
O-acetyl-
-rhamanopyranoside (9)9 in 88% yield. Treatment of 9
reported one16 (65%). Zemplén deacetylation of 18 generated 19
in quantitative yield. Benzylidenation of deacetylated product
was carried out using benzaldehyde dimethylacetal and catalytic
camphorsulphonic acid in dry CH3CN.
L
with trichloroacetonitrile and DBU in dry CH2Cl2 provided the
15 trichloroacetimidate donor 39 in 89% yield. Zemplén
deacetylation11 of 8 resulted in quantitative formation of phenyl
1-thio-α-D
-rhamanopyranoside (10).9 2,3-O-Isopropylidenation of
10 with 2,2-dimethoxypropane and catalytic camphorsulphonic
acid in dry CH3CN followed by O-benzylation of the resulting
20 crude phenyl 2,3-O-isopropyl-1-thio-α-
D-rhamanopyranoside
(11)12 with benzyl bromide and sodium hydride in dry DMF
furnished
phenyl
4-O-benzyl-2,3-O-isopropyl-1-thio-α-D-
rhamanopyranoside (12).12 60% AcOH was used for 2,3-O-
isopropylidene removal in the next step. After column
25 chromatography,
71%
phenyl
4-O-benzyl-1-thio-α-D-
rhamanopyranoside (13)12 was obtained over 3 steps from 10.
Next, 2,3-O-stannylene acetal formation of 13 was carried out by
dibutyltinoxide in dry toluene. Then, benzyl bromide was added
in the same reaction vessel to furnish eventually phenyl 3,4-O-
30 benzyl-1-thio-α-D L-rhamnose
-rhamanopyranoside (4).13 Thus
55
based monosaccharide units 3 and 4 were gathered. Next the 2-
OH group of 4 was protected in various methods to furnish its O-
benzyl (5a),13a and O-napthylmethyl (5b)13b derivatives (Scheme
1).
Scheme 2. Synthesis of D-glucosamine based acceptor.
35
Scheme 1. Synthesis of L-rhamnopyranose based donor and acceptor.
The glucosamine based acceptor 6 was synthesized in six steps
from -glucosamine hydrochloride (Scheme 2). -glucosamine
40 hydrochloride (14) was converted to N-phth-protected tetra-O-
D
D
Scheme 3. Stepwise synthesis of the desired trisaccharide.
2
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With all the appropriately protected monomeric intermediates in
hand, the glycosylation protocol leading to the protected
trisaccharide (2) was first started from the non-reducing end of
end at δ 3.87 (s), 4.56 (brs) and 5.17 (d, J 8.5 Hz), respectively,
and the corresponding anomeric carbons at δ 98.7 (1JCH 173.8
Hz), 99.7 (1JCH 164.7 Hz) and 99.6 (1JCH 173.6 Hz), respectively.
the same. For this purpose, N-phthalimido based acceptor 6 was 45 The observed NMR spectral data indicate the presence of two α-
5
reacted with phenyl 2-O-benzyl / 2-O-napthylmethyl-3,4-O-
linked rhamnopyranose and one β-linked glucopyranose residues
in 2.
The trisaccharide derivative was deprotected in a stepwise
reaction scheme, starting with NPhth deprotection by ethylene
benzyl-1-thio-α-D-rhamanopyranosides, respectively in the
presence of NIS/TMSOTf.17 Both rhamnoside donors (5a and 5b)
led to fruitful respective glycosylations in 92 and 89% yields.
Unfortunately, deacylation following Zémplen’s method or based 50 diamine in butanol. Then acetylation using pyridine, acetic
10 on NEt3/MeOH/H2O failed to give the corresponding desired
anhydride, followed by selective de-O-acetylation under Zémplen
condition and finally global de-benzylation using hydrogen and
palladium-charcoal in a mixture of acetic acid, water and
product. Surprisingly both reactions proceeded with unusual
decomposition. For exploration of another route 21 was
denapthylmethylated with DDQ which progressed smoothly,
methanol ultimately produced the desired product (1) in overall
1
yielding the desired disaccharide acceptor (22) in 87% yield. But, 55 72 % yield (Scheme 4). Compound 1 was characterized by H-
15 when the thiorhamnoside donor 8 was allowed to react with 22 in
the presence of N-(p-methylphenylthio)-ε-caprolactam (NMPTC)
-TMSOTf18 or NIS/TMSOTf;17 both of these reactions failed to
produce the fully protected trisaccharide even after exploring
different temperature controls. Later, use of trichloroacetimidate
20 donor 3 instead of thiorhamnoside solved the problem yielding
the desired trisaccharide 2 in 73% yield (Scheme 3).
and 13C-NMR, DEPT, COSY, HSQC and HRMS techniques. The
three consecutive anomeric protons of 1 from the non-reducing
end appeared at δ 4.85 (s), 5.07 (s) and 4.58 (d, J = 8.5 Hz)
respectively.
60 Conclusion
In summary, our endeavor to reach the targeted trisaccharide via a
stepwise glycosylation approach with chain extension from the
non-reducing end as well as exploiting a sequential one-pot
glycosylation route has been successful. Our effort has been
65 rewarded particularly with the highly expeditious and high
yielding stereoselective one pot protocol of the desired
trisaccharide unit similar to repeating unit of the LPS of
Burkholderia sp. HKI-402 (B4). The NMR data recorded for the
synthetic target is in good agreement with the reported one, with
70 slight deviations due to the incorporation of the 3-(N-
benzyloxycarbonyl) propyl as the aglycon moiety.
After achieving the final protected trisaccharide via multistep
synthesis, we set out for a reverse synthetic route starting from
reducing end towards desired product now, by one pot sequential
25 glycosylation reaction. Compound 3 and 4 were coupled by
TMSOTf19 in dry CH2Cl2 at -30 °C (Scheme 4). After completion
of the initial reaction (indicated by TLC), acceptor 6 and NIS
were added to the reaction mixture in the same vessel. Reaction
temperature was then gradually increased to room temperature.
30 After completion, the crude product was purified by flash
chromatography to give 81% pure trisaccharide derivative (2). A
comparison of the one pot synthesis (Scheme 4) of the protected
trisaccharide (2) with the multistep one (Scheme 3) clearly
indicates the efficacy of the first one (overall 81%) over the
35 second one (overall 67.4%) in terms of reaction yield, atom
economy and environmental ground.
Experimental
NMR spectra were recorded on Bruker DPX 300 NMR
spectrometer operating at 300 MHz and 75 MHz for 1H- and 13C-
75 NMR, respectively, in CDCl3. HRMS data were recorded on a Q-
tof-Micro mass spectrometer by electron spray ionization method.
Specific rotations were measured on Jasco J-815 spectrometer.
2, 3, 4-Tri-O-acetyl-L
-rhamnopyranose (9)9
To a solution of compound 8 (2 g, 5.24 mmol) in aqueous
80 (CH3)2CO (4:1), TCCA (1.2 g, 5.24 mmol) was added at 0 °C
and kept on stirring for 40 min. Then the white precipitate was
filtered, and the bed was washed with CH2Cl2 (3×5 mL). The
combined filtrate and washings was evaporated, and the resulting
mass was again dissolved in CH2Cl2. This organic part was
85 washed subsequently with saturated NaHCO3 solution (200 mL)
and water (200 mL). The organic layer was dried over anhydrous
Na2SO4 and evaporated under vacuum to furnish compound 9.
Column filtration of the crude product furnished pure compound
1
as white solid (9, 1.34 g, 88 %). H NMR (500 MHz, CDCl3): δ
90 1.24 (d, J = 6.0 Hz, 3H), 1.99 (s, 3H, COCH3), 2.06 (s, 3H,
COCH3), 2.16 (s, 3H, COCH3), 3.19 (d, J = 3.0 Hz, 1H), 4.13 (m,
1H), 5.08 (t, J = 10.0 Hz, 1H), 5.17 (s, 1H), 5.28 (m, 1H), 5.36
(m, 1H).
Scheme 4. One-pot synthesis of the desired trisaccharide
1
The structure of 2 was confirmed by H- and 13C-NMR, COSY,
2,3,4-Tri-O-acetyl-L
-rhamnopyranosyl trichloroacetimidate (3)9
40 HMBC, HSQC and HRMS techniques. Compound 2 showed
95 To a solution of compound 9 (1 g, 3.45 mmol) and CCl3CN (0.52
three consecutive anomeric protons, listed from the non-reducing
mL, 5.18 mmol) in dry CH2Cl2 (15 mL) DBU (0.1 mL, 0.69
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mmol) was added at -5 °C, and the reaction was kept on stirring
(430.6 mg, 1.73 mmol) in dry toluene (10 mL) was refluxed in
at that temperature. After 5 h, excess solvent was removed, and 60 Dean-Stark apparatus for 5 h. Then, BnBr (0.26 mL, 2.16 mmol)
the resulting mass was purified through flash column
chromatography (PE/EtOAc, 3:1) to furnish pure compound 3 as
colorless syrup (1.33 g, 89 %). 1H (200 MHz, CDCl3): δ 1.26 (s, J
= 6.2 Hz, 3H, CH3), 2.00 (s, 3H, COCH3), 2.06 (s, 3H, COCH3),
and tetrabutylammonium bromide (232.1 mg, 0.72 mmol) were
added to the resulting clear solution. It was kept on stirring at 80
°C until completion of the reaction (indicated by TLC). Excess
toluene was removed under vacuum, and the resulting crude
5
2.18 (s, 3H, COCH3), 4.08 (m, 1H), 5.17 (t, J = 10.0 Hz, 1H), 65 product was directly used for column chromatography on silica
5.36 (dd, J = 3.4, 10.2 Hz, 1H), 5.45 (m, 1H), 6.19 (d, J = 1.5 Hz,
1H, C-1), 8.72 (s, 1H, NH).
gel. Column elution by PE/EtOAc, 3:1 furnished pure compound
25
4 as colorless syrup (0.57 g, 90%). [α]D -181.5 (c 1.5, CHCl3);
10 Phenyl -1-thio-α-
L
-rhamnopyranoside (10)9
lit13a [α]D25 -196.1 (c 1.2, CHCl3); 1H (300 MHz, CDCl3): δ 1.23
(s, 3H, J = 6.0 Hz, CH3), 2.61 (s, 1H), 3.45 (t, 1H, J = 9.3 Hz),
A suspension of compound 8 (2 g, 5.24 mmol) in 0.1 M NaOMe
in dry MeOH (10 mL) was stirred overnight at room temperature. 70 3.78 (dd, 1H, J = 3.3, 10.0 Hz), 4.12 (m, 1H), 4.16 (s, 1H), 4.57
After completion of the reaction (indicated by TLC), Dowex
50(H+) resin was poured into the clear solution, and it was
15 swirled occasionally. After 30 min the resin was filtered, and the
bed was washed with distilled MeOH (3×5 mL). The combined
(d, 1H, J = 11.1 Hz), 4.64 (s, 2H), 4.81 (d, 1H, J = 10.8 Hz), 5.44
(s, 1H), 7.14-7.37 (m, 15H, ArH).
Phenyl
rhamnopyranoside (5a)13a
2-O-benzoyl-3,4-di-O-benzyl-1-thio-α-L-
filtrate and washings was evaporated to dryness to furnish the 75 To a solution of compound 4 (524 mg, 1.2 mmol) and dry
title compound 10 in quantitative yield. It was dried thoroughly
and directly used without characterization for the next step.
pyridine, BzCl (0.21 mL, 1.8 mmol) was added. It was kept on
stirring at ambient temperature until completion of the reaction
(indicated by TLC). Excess pyridine was removed under vacuum,
and was washed with brine solution. The organic layer was dried
20 Synthesis of phenyl 4-O-benzyl-1-thio-α-
(13)12 from 10
L-rhamnopyranoside
To a solution of compound 10 (1 g, 3.9 mmol) and 2,2- 80 over anhydrous Na2SO4 and concentrated to afford the
dimethoxypropane (0.72 mL, 5.85 mmol) in dry CH3CN, CSA
(271.8 mg, 1.17 mmol) was added at 0 °C. The reaction mixture
25 was kept on stirring for 5 h. After completion (indicated by TLC),
the reaction was quenched by addition of Et3N. Excess solvent
benzoylated product. Column elution by PE/EtOAc, 4:1 furnished
pure compound 5a as white foam (616 mg, 95%). H (500 MHz,
CDCl3): δ 1.41 (d, J = 6.0 Hz, 3H), 3.65 (t, J = 9.0 Hz, 1H), 4.05
(dd, J = 2.5, 9.0 Hz, 1H), 4.32 (m, 1H), 4.62 (d, J = 11.5 Hz, 1H),
1
was removed in vacuum, and the resulting mass was dissolved in 85 4.68 (d, J = 11.0 Hz, 1H), 4.81 (d, J = 11.5 Hz, 1H), 4.96 (d, J =
CH2Cl2. The organic solution was washed subsequently with
saturated NaHCO3 solution (100 mL) and water (100 mL). The
30 organic layer was dried over anhydrous Na2SO4 and evaporated
under vacuum to furnish crude product 11. This was used for the
11.0 Hz, 1H), 5.57 (s, 1H, PhCH), 5.86 (d, J = 1.5 Hz, 1H, H-1),
7.28-7.38 (m, 13H, ArH), 7.47-7.50 (m, 4H, ArH), 7.59-7.62 (m,
1H, ArH), 8.08-8.10 (d, J = 7.5 Hz, 2H, ArH). 13C (125 MHz,
CDCl3): δ 18.1, 69.2, 71.1, 71.7, 75.5, 78.5, 80.2, 86.2, 127.7,
next step without purification. To crude 11, 60 % oil suspension 90 127.8, 128.1, 128.2, 128.4, 128.5, 129.1, 129.9, 131.8, 133.3,
of NaH (234.0 mg, 5.85 mmol) and BnBr (0.7 mL, 5.85 mmol)
were added subsequently in dry DMF at 0 °C. After completion
35 (indicated by TLC), the reaction was quenched by MeOH, and
excess solvent was removed in vacuum. The resulting white paste
134.0, 137.7, 138.3, 165.7.
Phenyl
rhamnopyranoside (5b)13b
3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-1-thio-α-L-
To a solution of compound 4 (100 mg, 0.23 mmol) and dry DMF,
was dissolved in CH2Cl2 and washed with water (100 mL). The 95 60 % oil suspension of NaH (9 mg, 0.35 mmol) and NapBr
organic layer was dried over anhydrous Na2SO4 and evaporated
under vacuum to furnish crude product 12. Compound 12 was
40 treated with 80% AcOH (15 mL) at 60 °C for 6 h. Then excess
AcOH was co-evaporated with toluene, furnishing thick brown
(77.4 mg, 0.35 mmol) was added. It was kept on stirring at
ambient temperature until completion of the reaction (indicated
by TLC). Excess NaH was quenched with MeOH, DMF was
removed under vacuum, and was washed with brine solution. The
syrup. This was dissolved in CH2Cl2 and washed subsequently 100 organic layer was dried over anhydrous Na2SO4 and concentrated
with saturated NaHCO3 solution (100 mL) and water (100 mL).
The organic layer was dried over anhydrous Na2SO4 and
45 evaporated under vacuum to furnish crude product 13.
Purification of 13 by silica gel column chromatography
to afford the napthylmethylated product. Column elution by
PE/EtOAc, 5:1 furnished pure compound 5b as white solid (121.5
mg, 92%). 1H (300 MHz, CDCl3): δ 1.43 (d, J = 6.3 Hz, 3H), 3.79
(t, J = 9.4 Hz, 1H), 3.92 (dd, J = 9.4, 3.1 Hz, 1H), 4.09 (dd, J =
105 3.0, 1.7 Hz, 1H), 4.18 - 4.26 (m, 1H), 4.65 (d, J = 11.7 Hz, 1H),
4.69 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 10.8 Hz, 1H), 4.86 (d, J =
12.5 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.05 (d, J = 10.8 Hz,
1H), 5.56 (d, J = 1.5 Hz, 1H), 7.23 - 7.30 (m, 3H), 7.31 - 7.44 (m,
12H), 7.50 - 7.59 (m, 3H), 7.77 - 7.90 (m, 4H). 13C (75 MHz,
(PE/EtOAc, 2:1) yielded phenyl 4-O-benzyl-1-thio-α-L-
rhamnopyranoside as white solid (13, 0.96 g, 71% over 3 steps).
M.p. 110-112 °C. [α]25 -187.5 (c 1.5, CHCl3). Lit12 m.p. 111-
D
1
50 113 °C. [α]D -201 (c 0.9, CHCl3). H (500 MHz, CDCl3): δ 1.36
(d, J = 6.0Hz, 3H, CH3), 3.41 (t, J = 9.5 Hz, 1H), 3.94 (dd, J =
3.0, 9.0 Hz, 1H), 4.19 (m, 1H), 4.22 (m, 1H), 4.76 (s, 2H), 5.47 110 CDCl3) δ: 18.0, 69.5, 72.3, 72.4, 75.6, 76.6, 80.1, 80.6, 86.0,
(d, J = 1.0 Hz, 1H, C-1), 7.24-7.34 (m, 4H, ArH), 7.36-7.38 (m,
4H, ArH), 7.45-7.47 (m, 2H, ArH). 13C (125 MHz, CDCl3): δ
55 18.0, 68.7, 71.9, 72.6, 75.1, 81.8, 87.4, 127.4, 128.0, 128.1,
128.7, 129.1, 131.4, 134.2, 138.1.
126.05, 126.14, 126.2, 127.0, 127.3, 127.8, 127.9, 128.0, 128.1,
128.3, 128.5, 129.1, 133.1, 133.3, 134.7, 135.4, 138.3, 138.6.
3-(N-benzyloxycarbonyl) propyl 3,4,6-tri-O-acetyl-2-deoxy-2-
phthalimido-β-D
-glucopyranoside (18)15, 16
Phenyl 3,4-di-O-benzyl-1-thio-α-
L
-rhamnopyranoside (4)13
115 To a mixture of 17 (150.0 mg, 0.285 mmol) and 3-(N-
A suspension of compound 13 (0.5 g, 1.44 mmol) and Bu2SnO
benzyloxycarbonyl) propanol (50.0 mg, 0.238 mmol) in dry
4
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CH2Cl2 (5 mL), flame activated molecular sieves (4Å) were
mmol) in dry CH2Cl2 (12 mL) activated molecular sieves (4Å)
added. It was stirred at room temperature under argon 60 were added, and the reaction was kept on stirring under argon
atmosphere. After 40 min the mixture was cooled to -5ºC and
TCCA (55.3 mg, 0.238 mmol) was added to it. Then TMSOTf
(12.9 µL, 0.071 mmol) was added via a micro-syringe. After the
acceptor was consumed completely (checked by TLC) the
atmosphere for 45 min. After that NIS (67 mg, 0.30 mmol) and
TMSOTf (16 µL, 0.08 mmol) (via a micro syringe) were then
added to the reaction vessel keeping the temperature at -5 °C.
After the addition, reaction temperature was raised gradually to
5
reaction was quenched by Et3N (130.0 µL). The reaction mixture 65 room temperature. The reaction was completed after 15 min
was filtered off through Celite bed. The filtrate was diluted with
CH2Cl2 and washed subsequently with saturated NaHCO3
10 solution and water. The organic layer was dried over anhydrous
Na2SO4 and concentrated to afford the glycosylated product. The
(indicated by TLC). Reaction mass was then filtered through
Celite bed, and the bed was washed with CH2Cl2 (3×5 mL). The
combined filtrate was washed subsequently with saturated
aqueous NaHCO3 (1x100 mL), saturated aqueous Na2S2O3 (1x100
crude product was purified by column chromatography on silica 70 mL) and water (2x50 mL). The organic layer was dried over
gel (60-120 mesh) (PE:EtOAc 4:1) to afford 8 (128.7 mg) in 86%
as white foam. [α]25D + 10.9 (c 1.0, CHCl3); lit.15, 16 [α]D +18.1 (c
15 1.1, CHCl3). 1H (300 MHz, CDCl3): δ 1.68-1.70 (m, 2H), 1.85 (s,
3H, COCH3), 2.03 (s, 3H, COCH3), 2.07 (s, 3H, COCH3), 3.04-
anhydrous Na2SO4 and concentrated to furnish a syrupy
compound. The crude product was purified by column
chromatography (eluent: PE/EtOAc, 2:1) to afford the
1
disaccharide 20 as white foam (230 mg, 92 %). H NMR (500
3.16 (m, 2H), 3.55 (m, 1H), 3.82-3.89 (m, 2H), 4.19 (dd, J = 2.1, 75 MHz, CDCl3): δ 0.80 (d, J = 6.0 Hz, 3H), 1.67 (m, 2H), 3.08-3.12
12.2 Hz, 1H), 4.22-4.34 (m, 2H), 4.95 (m, 1H), 5.01 (s, 2H), 5.16
(t, J = 9.6 Hz, 1H), 5.38 (d, J = 8.5 Hz, 1H), 5.75 (dd, J = 9.1,
20 10.7 Hz, 1H), 7.30-7.35 (m, 5H, ArH), 7.70-7.73 (m, 2H, ArH),
7.81-7.83 (m, 2H, ArH). The spectral data were consistent with
those in the literature.15
(m,2H). 3.35 (t, J = 9.5 Hz, 1H), 3.53 (m, 2H), 3.65-3.68 (m, 2H),
3.81 (t, J = 10.0 Hz, 1H), 3.83-3.86 (m, 2H), 3.93 (m, 1H), 4.31
(dd, J = 8.5, 10.0 Hz, 1H), 4.38 (m, 1H), 4.44 (d, J = 11.5 Hz,
1H), 4.52 (d, J = 11.0 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.61-
80 4.65 (m, 2H), 4.81 (d, J = 11.0 Hz, 1H), 4.88 (brs,1H), 5.04-5.07
(m,3H), 5.25 (d, J = 8.5 Hz, 1H), 5.54 (s, 1H,PhCH), 7.22 (brs,
8H, ArH), 7.28-7.38 (m, 12H, ArH), 7.47-7.51 (m, 3H, ArH),
7.66-7.71 (m, 3H, ArH), 7.86 (bs, 2H, ArH). HRMS m/z for
(C59H58N2O14Na+) calcd: 1041.3786, found: 1041.3785.
3-(N-benzyloxycarbonyl)
propyl-2-deoxy-2-phthalimido-β-D-
glucopyranoside (19)
25 A suspension of compound 18 (1 g, 2.08 mmol) in 0.1 M NaOMe
in dry MeOH (10 mL) was stirred for 45 min at room
temperature. After completion of the reaction (indicated by TLC), 85 3-(N-benzyloxycarbonyl)
propyl
-rhamnopyranosyl-(1→3)-4,6-O-
benzylidene-2-deoxy-2-acetamido-β- -glucopyranoside (21)
3,4-di-O-benzyl-2-O-(2-
Dowex 50(H+) resin was poured into the clear solution, and it was
swirled occasionally. After 30 min the resin was filtered, and the
30 bed was washed with distilled MeOH (3×5 mL). The combined
filtrate was evaporated to dryness to furnish the title compound
naphthylmethyl)-α-
L
D
To a solution of 5b (88 mg, 0.15 mmol) and 6 (75 mg, 0.13mmol)
in dry CH2Cl2 (8 mL) activated molecular sieves (4Å) were
19 in quantitative yield. It was dried thoroughly and directly used 90 added, and the reaction was kept on stirring under argon
without characterization for the next step.
3-(N-benzyloxycarbonyl) propyl-4,6-O-benzylidene-2-deoxy-2-
atmosphere for 45 min. After that NIS (34 mg, 0.15 mmol) and
TMSOTf (8.3 µL, 0.05 mmol) (via a micro syringe) were then
added to the reaction vessel keeping the temperature at -5 °C.
After the addition, reaction temperature was raised gradually to
35 phthalimido-β-
D-glucopyranoside (6)
To a suspension of 19 (0.5 g, 1.41 mmol) and benzaldehyde
dimethylacetal (0.32 mL, 2.12 mmol) in dry CH3CN (25 ml), 95 room temperature. The reaction was completed after 15 min
anhydrous FeCl3 (68.6 mg, 0.42 mmol) was added, and it was
stirred at ambient temperature. After completion of the reaction
40 (indicated by TLC) solvent was evaporated under reduced
pressure. The solid mass was dissolved in CH2Cl2 and washed
(indicated by TLC). Reaction mass was then filtered through
Celite bed, and the bed was washed with CH2Cl2 (3×5 mL). The
combined filtrate was washed subsequently with saturated
aqueous NaHCO3 (1x50 mL), saturated aqueous Na2S2O3 (1x50
subsequently with saturated NaHCO3 solution (200 mL) and 100 mL) and water (2x50 mL). The organic layer was dried over
water (200 mL). The organic layer was dried over anhydrous
Na2SO4 and evaporated under vacuum to furnish the crude
45 product. It was purified by column chromatography on silica gel
(eluent: PE/EtOAc, 1:1) to give pure title compound 5 as white
anhydrous Na2SO4 and concentrated to furnish a syrupy
compound. The crude product was purified by column
chromatography (eluent: PE/EtOAc, 4:1) to afford the
1
disaccharide 21 as syrup (119.5 mg, 89%). H NMR (400 MHz,
foam (0.5 g mg, 81%). [α]25 -39.8 (c 1.48, CHCl3). 1H (300 105 CDCl3): δ 0.87 (d, J = 6.0 Hz, 3H), 1.69 (m, 1H), 3.10-3.14 (m,
D
MHz, CDCl3): δ 1.69 (m, 1H), 2.54 (m, 1H), 3.09-3.13 (m, 1H),
3.49-3.68 (m, 3H), 3.77-3.90 (m, 2H), 4.24 (dd, J = 8.4, 10.4 Hz,
50 1H), 4.38 (m, 1H), 4.62 (m, 1H), 4.90 (bs, 1H), 5.02 (s, 1H), 5.27
(d, 1H, J = 8.6 Hz), 5.30 (s, 1H), 5.55 (s, 1H, PhCH), 7.29-7.39
2H), 3.42-3.56 (m, 3H), 3.64-3.69 (m, 2H), 3.76-3.93 (m, 4H),
4.20 (s, 2H), 4.29 (t, J = 9.5 Hz, 1H), 4.40 (d, J = 11.0 Hz, 2H),
4.50 (d, J = 10.8 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.64 (t, J =
9.2 Hz, 1H), 4.75 (s, 1H), 4.83 (d, J = 10.8 Hz, 1H), 4.91 (bs,
(m, 8H, ArH), 7.48-7.51 (m, 2H, ArH), 7.69-7.72 (m, 2H), 7.81- 110 1H), 5.03 (s, 2H), 5.29 (d, J = 8.4 Hz, 1H), 5.54 (s, 1H, PhCH),
7.84 (m, 2H). 13C (75 MHz, CDCl3): δ 29.5, 29.8, 38.1, HRMS
m/z for (C64H70N2O20Na+) calcd: 1209.4420, found: 1209.4421.
55 3-(N-benzyloxycarbonyl) propyl 2-O-benzoyl-3,4-di-O-benzyl-α-
7.06 (d, J = 8.4 Hz, 1H, ArH), 7.24-7.36 (m, 18H, ArH), 7.43-
7.78 (m, 12H, ArH), 8.67 (bs, 1H, NH). 13C NMR (125 MHz,
CDCl3): δ 17.5, 29.6, 29.8, 38.1, 56.7, 66.6, 66.7, 67.6, 68.5,
68.8, 72.0, 72.6, 74.5, 75.1, 76.3, 77.4, 79.7, 80.4, 80.8, 98.6,
115 98.9, 102.0, 123.7, 125.4, 125.88, 125.92, 126.1, 126.5, 127.3,
127.49, 127.54, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3,
L-rhamnopyranosyl-(1→3)-4,6-O-benzylidene-2-deoxy-2-
acetamido-β- -glucopyranoside (20)
D
To a solution of 5a (160 mg, 0.30 mmol) and 6 (145 mg, 0.25
This journal is © The Royal Society of Chemistry [year]
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Page 6 of 8
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DOI: 10.1039/C4RA03954H
128.36, 128.38, 128.6, 129.2, 131.3, 133.0, 133.3, 134.6, 135.5,
0.09 mmol) and NIS (30.0 mg, 0.13 mmol) were then added to
136.8, 137.1, 138.7, 138.9, 156.4. HRMS m/z for 60 the same vessel. After the addition, reaction temperature was
(C63H62N2O13Na+) calcd: 1077.4150, found: 1077.4152.
3-(N-benzyloxycarbonyl) propyl 3,4-di-O-benzyl-α-
rhamnopyranosyl-(1→3)-4,6-O-benzylidene-2-deoxy-2-
acetamido-β- -glucopyranoside (22)
raised gradually to room temperature. The second step of the
reaction was completed after 30 min (indicated by TLC). The
reaction mass was then filtered through Celite bed, and the bed
was washed with CH2Cl2 (3×5 mL). The combined filtrate was
L-
5
D
To a solution of 22 (64 mg, 0.06mmol) in CH2Cl2/H2O (5 mL, 65 washed subsequently with saturated aqueous NaHCO3 (2x50 mL)
19:1) DDQ (17 mg, 0.08 mmol) was added, and the reaction was
kept on stirring under ambient temperature for 2 hr. After that the
and water (2x50 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated to furnish syrupy
a
10 reaction mass was washed with water (2x100 mL) and the
organic layer was dried over anhydrous Na2SO4 and concentrated
compound. The crude product was purified by flash column
chromatography (eluent: PE/EtOAc, 1:1) to afford the desired
to furnish a syrupy compound. The crude product was purified by 70 fully protected trisaccharide 2 as white foam (86.0 mg, 81%).
column chromatography (eluent: PE/EtOAc, 2:1) to afford the
disaccharide acceptor 22 as syrup (48 mg, 87%). H NMR (500
15 MHz, CDCl3): δ 0.70 (d, J = 6.3 Hz, 3H), 1.59 (m, 1H), 2.94-3.05
(m, 2H), 3.15 (t, J = 9.0 Hz, 1H), 3.43 (m, 1H), 3.47-3.74 (m,
[α]25 -34.2 (c 1.30, CHCl3). 1H NMR (500 MHz, CDCl3): δ
0.72-0.76 (2d, J = 6.5 Hz, 6H, 2×CH3), 1.55 (m, 1H, CH2), 1.85
(s, 3H, COCH3), 1.91 (s, 3H, COCH3), 1.95 (s, 3H, COCH3),
2.98-3.03 (m, 2H, NCH2), 3.20-3.24 (apparent t, 1H, J = 9.5 Hz,
D
1
5H), 3.75-3.89 (m, 3H), 4.18 (dd, J = 8.7, 10.2 Hz, 1H), 4.31 (dd, 75 H-4'), 3.34 (br s, 1H, H-5'), 3.43 (m, 1H, CH2), 3.51-3.60 (m, 3H,
J = 5.6, 13.6 Hz, 1H), 4.39-4.46 (m, 3H), 4.49-4.55 (m, 3H),
4.58-4.67 (m, 2H), 4.76 (d, J = 8.0 Hz, 1H), 4.80 (bs, 1H), 4.95
20 (bs, 2H), 5.18 (d, J = 8.7 Hz, 1H), 5.44 (s, 1H, PhCH), 7.12-7.30
(m, 18H, ArH), 7.41-7.44 (m, 2H, ArH), 7.63-7.66 (m, 2H, ArH),
H-4, H-6a, PhCH2), 3.65-3.79 (m, 4H, H-5, H-2', H-3', CH2), 3.87
(s, 1H, H-1'), 4.15 (apparent t, J = 9.0, 10.0 Hz, 1H, H-2), 4.30
(dd, J = 4.5, 10.5 Hz, 1H, H-6), 4.35 (d, J = 12.0 Hz, 1H, PhCH2),
4.42-4.48 (m, 3H, H-3, H-5'', PhCH2), 4.56 (br s, 1H, H-1''), 4.69-
7.75-7.78 (m, 2H, ArH). 13C NMR (125 MHz, CDCl3): δ 17.4, 80 4.73 (m, 2H, H-4'', PhCH2), 4.77 (m, 1H, H-2''), 4.95 (br s, 2H,
29.8, 38.1, 56.8, 66.6, 67.6, 67.8, 68.7, 68.8, 72.0, 74.3, 75.2,
77.3, 79.8, 80.0, 80.9, 98.9, 99.6, 102.1, 123.9, 126.6, 127.7,
25 127.9, 128.0, 128.2, 128.3, 128.4, 128.60, 128.62, 129.2, 131.4,
134.7, 137.1, 138.0, 138.6, 156.4. HRMS m/z for
(C52H54N2O13Na+) calcd: 937.3524, found: 937.3523.
PhCH2), 5.02-5.03 (m, 2H, H-3', PhCH2), 5.17 (d, J = 8.5 Hz, 1H,
H-1), 5.44 (s, 1H, PhCH), 7.19-7.36 (m, 18H, ArH), 7.47-7.51
(m, 2H, ArH), 7.69-7.80 (m, 2H, ArH); 13C NMR (125 MHz,
CDCl3): δ 17.1 (CH3), 17.3 (CH3), 20.7 (COCH3), 20.79
85 (COCH3), 20.84 (COCH3), 29.5, 38.0, 56.6 (C-2), 66.4 (C-4),
66.6 (PhCH2, C-6a), 68.3 (OCH2), 68.7 (C-5), 68.8 (C-2', C-6,
PhCH2), 69.8 (C-3''), 71.0 (C-4''), 71.9 (2×PhCH2), 75.2
(2×PhCH2), 75.5 (C-2'', C-5'', C-3), 78.1 (C-5'), 79.0 (C-3'), 79.9
(C-4'), 80.7 (C-4), 98.7 (C-1), 99.6 (C-1'), 99.7 (C-1''), 102.0
Stepwise synthesis of 3-(N-benzyloxycarbonyl) propyl 2,3,4-tri-O-
acetyl-α-
30 rhamnopyranosyl-(1→3)-4,6-O-benzylidene-2-deoxy-2-
acetamido-β- -glucopyranoside (2)
L-rhamnopyranosyl-(1→2)-3,4-di-O-benzyl-α-L-
D
To a solution of 3 (22 mg, 0.05 mmol) and 22 (40 mg, 0.04mmol) 90 (PhCH), 126.4, 127.4, 127.47, 127.54, 128.0, 128.1, 128.2, 128.3,
in dry CH2Cl2 (5 mL) activated molecular sieves (4Å) were
added, and the reaction was kept on stirring under argon
35 atmosphere for 45 min. Then the reaction vessel was placed in a -
15 °C cold bath, and NIS (11.0 mg, 0.05mmol) and TMSOTf (4
128.4, 128.5, 129.1, 131.4. 134.2, 137.0, 138.5, 138.7, 156.3,
169.4, 169.8, 170.1; HRMS m/z for (C64H70N2O20Na+) calcd:
1209.4420, found: 1209.4421. NMR spectra of the compound 2
obtained by both protocol was identical.
µL, 0.02 mmol) (via a micro syringe) were then added to it. After 95 3-(N-benzyloxycarbonyl) propyl α-
L
-rhamnopyranosyl-(1→2)-α-
-rhamnopyranosyl-(1→3)-2-deoxy-2-acetamido-β-
glucopyranoside (1)
10 min complete consumption of both the starting materials was
observed. The reaction mass was then filtered through Celite bed,
40 and the bed was washed with CH2Cl2 (3×5 mL). The combined
filtrate was washed subsequently with saturated aqueous
L
D-
Protected trisaccharide 2 (60 mg, 0.034 mmol) was refluxed in
butanol (6 mL) and ethelene diamine (1.5 mL) for 8 h and then
NaHCO3 (1x50 mL), saturated aqueous Na2S2O3 (1x50 mL) and 100 excess solvent was removed under reduced pressure. Residual
water (2x50 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated to furnish a syrupy compound. The
45 crude product was purified by flash column chromatography
(eluent: PE/EtOAc, 1:1) to afford the desired fully protected
trisaccharide 2 as white foam (40.5 mg, 78%).
water was co-evaporated with toluene (2 x 5 mL) and the
resulting compound was treated with dry pyridine (5 mL) and
Ac2O (2 mL) for 12 h at room temperature. After complete
conversion excess solvent was removed under vacuum. The crude
105 mass was column filtered (PE/EtOAc, 3:2) and the pure product
was dissolved in MeOH (7 mL) and NaOMe (1 M in MeOH, 0.5
mL) was added. The mixture was stirred for 10 h and then
reaction was quenched with Dowex-50W cation exchange resin
(H+). The resin was filtered off and then washed with MeOH (4 x
One-pot sequential synthesis of 3-(N-benzyloxycarbonyl) propyl
2,3,4-tri-O-acetyl-α-
-rhamnopyranosyl-(1→3)-4,6-O-benzylidene-2-deoxy-2-
acetamido-β- -glucopyranoside (2)
L-rhamnopyranosyl-(1→2)-3,4-di-O-benzyl-
50 α-
L
D
To a solution of 3 (50.0 mg, 0.11 mmol) and 4 (43.6 mg, 0.10 110 5 mL). The combined filtrate and washings was evaporated under
mmol) in dry CH2Cl2 (8 mL) activated molecular sieves (4Å)
were added, and the reaction was kept on stirring under argon
55 atmosphere for 45 min. Then the reaction vessel was placed in a -
30 °C cold bath, and TMSOTf (5.4 µL, 0.03 mmol) was added to
reduced pressure. The resulting mass and 10% Pd-C (70 mg) was
taken in AcOH (1 mL), MeOH (3 mL), H2O (1 mL) and kept on
stirring under H2 atmosphere for 24 h. The catalyst was filtered
through Celite bed, and the bed was washed with MeOH (3 x 5
it via a micro syringe. After 10 min complete consumption of 115 mL). The combined filtrate and washings was concentrated under
both the starting materials was observed. Acceptor 6 (53.0 mg,
reduced pressure. It was passed through a 0.45µm Millipore
6
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4RA03954H
[14] (a) J. M. Hernández-Torres, S.-T. Liew, J. Achkar and A. Wei.,
Synthesis, 2002, 487. (b) R. K. Jain and K. L. Matta, Carbohydr.
Res., 1992, 226, 91. (c) H. Paulsen and M. Paal, Carbohydr. Res.,
1984, 135, 53.
[15] N. Basu, S.K. Maity and R. Ghosh, RSC Adv., 2012, 2, 12661.
[16] S. Hanessian, O. M. Saavedra, V. Mascitti, W. Marterer, R. Oehrlein
and C-P. Mak, Tetrahedron, 2001, 57, 3267.
70 [17] P. Konradsson, U. E. Udodong and B. Fraser-Reid, Tetrahedron
Lett., 1990, 31, 4313.
[18] S.K. Maity, N. Basu and R. Ghosh, Carbohydrate Res., 2012, 354,
membrane, and lyophilized to afford 1 as white foam (30.0 mg,
90 %); H NMR (500 MHz, D2O): δ 1.25-1.30 (2d, 6H, J = 6.0
1
65
Hz, 2×CH3), 1.87-1.90 (m, 2H), 2.10 (s, 3H, COCH3), 2.93-2.99
(m, 2H), 3.43-3.54 (m, 4H), 3.59 (apparent t, J = 8.0, 9.5 Hz, 1H),
3.71-3.86 (m, 7H), 3.94-4.05 (m, 4H), 4.58 (d, J = 8.5 Hz, 1H),
4.85 (s, 1H), 5.07 (s, 1H). 13C (75 MHz, D2O): δ 16.5, 16.9, 22.5,
23.1, 26.8, 37.5, 55.6, 60.7, 67.7, 68.6, 68.9, 69.1, 69.8, 70.1,
72.1, 75.9, 80.4, 81.4, 99.7, 100.5, 102.7, 174.6.. HRMS (ESI-
TOF) Calcd for C23H42N2O14Na [M + Na]+ 593.2534, found
5
40.
[19] R. R. Schmidt, Angew. Chem, Int. Ed. 1986, 25, 212.
10 593.2531.
75
Acknowledgments
Financial supports from DST-SERB, India (Scheme No.
SR/S1/OC-61/2012) to RG and from CAS-UGC and FIST-DST,
India to the Department of Chemistry, Jadavpur University are
15 acknowledged. NB (SRF) and MMM (SRF) thank CSIR and
UGC, India respectively, for their fellowships.
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Journal Name, [year], [vol], 00–00 | 7

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DOI: 10.1039/C4RA03954H
Synthetic Routes Toward the Trisaccharide Related to the
Lipopolysaccharide of Burkholderia sp. HKI-402 (B4)
Nabamita Basu, Mana Mohan Mukherjee, Rina Ghosh*
Stepwise and one-pot sequential synthesis of the trisaccharide using trichloroacetimidate and
thioglycosyl donors along with 3-(N-benzyloxycarbonyl) propyl glycoside acceptor.