Efficient synthesis of pyruvate ketals of carbohydrates

Article abstract of DOI:10.1016/j.tetlet.2006.09.159

An efficient method for the preparation of pyruvate ketals of carbohydrates has been developed using N-iodosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as activator and methyl 2,2-di(ethylthio)propionate. The method has been applied for the preparatio

Full text of DOI:10.1016/j.tetlet.2006.09.159

Tetrahedron Letters 47 (2006) 8493–8497
Efficient synthesis of pyruvate ketals of carbohydratesI
Geetanjali Agnihotri and Anup Kumar Misra*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001, UP, India
Received 24 July 2006; revised 21 September 2006; accepted 28 September 2006
Abstract—An efficient method for the preparation of pyruvate ketals of carbohydrates has been developed using N-iodosuccinimide
or 1,3-dibromo-5,5-dimethylhydantoin as activator and methyl 2,2-di(ethylthio)propionate. The method has been applied for the
preparation of a pyruvate ketal-containing trisaccharide present in the bacterial cell-wall of Mycobacterium smegmatis.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
carboxylate group by oxidation of a suitable precur-
sor.18–21 However, these procedures are not generally
applicable due to low yields or sensitivity of glycosides
under the reaction conditions. Earlier reports of the
preparation of pyruvic ketals by the reaction between
diols and methyl pyruvate dialkyl dithioacetal,22,23 acti-
vated by methyl triflate, dimethyl(methylthio)sulfonium
trifluoromethane sulfonate (DMTST), nitroso tetrafluo-
roborate (NOBF4) or SO2Cl2-trifluoromethanesulfonic
acid are limited because the yields or the stereochemical
outcome of these reactions was not satisfactory. There-
fore, the development of a convenient and efficient
methodology for the synthesis of pyruvate ketals of
carbohydrates is desirable and herein, we report an
expedient protocol for the synthesis of pyruvate ketal
derivatives and its application for the synthesis of a
pyruvate ketal-containing trisaccharide related to the
glycolipid found in Mycobacterium smegmatis. The
N-Iodosuccinimide (NIS) and trifluoromethanesulfonic
acid combination is a well known glycosyl promoter
used as a thioglycoside activator for the preparation of
several oligosaccharides.24 We envisioned that NIS
might efficiently activate pyruvate dithioketal in the
presence of a carbohydrate diol to furnish pyruvate
ketals.
Pyruvate ketals are present in many lipopolysaccharides
of bacterial origin, in capsular polysachharides,1 and
also in glycolipids isolated from fish nerve fibres.2 As a
result of the unique structural features including the
presence of a negative charge on the carboxyl functional
group and the chiral centre, pyruvate ketals influence
immunological specificity and patterns of immunologi-
cal cross reactivity and are therefore recognized as
immunodominant structural features of polysaccharides
which play an important role in cell–cell recognition
processes.3–8 It has also been proved that hexopyrano-
sides containing pyruvic acid ketals are very useful tools
for immunochemical studies of Klebsiella polysaccha-
rides.5,6 Therefore, efficient chemical syntheses of pyru-
vate ketal-containing oligosachharides are essential for
their use in immunochemical studies.
Most commonly, pyruvate ketals are present as 4,6-
ketals of hexose residues.9 However they also occur as
1,4-dioxolanes formed either from cis-axial-equato-
rial10,11 or trans-diequatorial hydroxyl groups.12 Pyru-
vate ketals can be synthesized by direct condensation
of a pyruvate ester with a diol in the presence of a Lewis
acid, but this is less preferred because of the electron-
withdrawing effect of the adjacent carboxylate
group.13–15 Therefore, several indirect methods for the
acetalization have been introduced including condensa-
tion with pyruvate derivatives16,17 or generation of the
In a set of initial experiments, methyl 2,3-di-O-acetyl-a-
D-glucopyranoside was treated with methyl 2,2-di(ethyl-
thio)propionate23 in the presence of NIS-TfOH in a
variety of solvents and reaction conditions. The use of
2.0 equiv of methyl 2,2-di(ethylthio)propionate and
3.8 equiv of NIS and 0.3 equiv of TfOH in anhydrous
acetonitrile furnished an excellent yield of the pyruvate
ketal (Scheme 1). Reduction of the proportion of
methyl 2,2-di(ethylthio)propionate and NIS produced
q C.D.R.I. Communication No. 7048.
Corresponding author. Tel.: +91 522 2612411 18; fax: +91 522
*
2623938; e-mail: akmisra69@rediffmail.com
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.159

8494
G. Agnihotri, A. K. Misra / Tetrahedron Letters 47 (2006) 8493–8497
COOMe
as thiophilic activator for converting dithioacetals to
OH
O
the corresponding aldehydes as well as O,O-acetals.25
Earlier, DBDH had been used as a free radical bromi-
nating agent26 and as a source of active bromonium
ions.27 Therefore, it was reasoned that DBDH might
act as an economically convenient thiophillic activator.
O
Me
methyl 2,2-di(ethylthio)propionate
NIS, TfOH, CH3CN,0 oC, 20 min
HO
O
O
R1O
R1O
R1O
R1O
OR2
OR2
Scheme 1. Synthesis of pyruvate ketals using NIS-TfOH as the
thiophilic activator.
Treatment of methyl 2,3-di-O-acetyl-a-D-glucopyrano-
side with methyl 2,2-di(ethylthio)propionate in the pres-
ence of DBDH in a variety of solvents and reaction
conditions showed that the use of 2.0 equiv of methyl
2,2-di(ethylthio)propionate and 2.5 equiv of DBDH in
acetonitrile under anhydrous conditions furnished excel-
lent yields of the pyruvate ketals (Scheme 2 and Table 1).
a sluggish reaction which did not reach completion even
after 24 h. Under similar reaction conditions, a series of
pyruvate ketal derivatives of mono-, di- and tri-saccha-
rides were synthesized (Table 1). Most of the protecting
groups and the inter-glycosidic bond remained
unaffected.
NIS-TfOH activated formation of 4,6-O-pyruvate ketal
using methyl 2,2-di(ethylthio)propionate, is more stereo-
selective than DBDH activation, only a single isomer
(S-isomer) being formed (Table 1). The configurations
of the pyruvate ketals were confirmed by the 13C-chem-
In order to develop the pyruvate ketal formation using a
cheaper thiophilic activator, a series of parallel reactions
were carried out using 1,3-dibromo-5,5-dimethylhydan-
toin (DBDH). Recently, DBDH has been found to act
Table 1. Synthesis of pyruvate ketals using DBDH or NIS-TfOH
Entry
Substrate
Product
DBDH
Yield (%)
NIS
Yield (%)
S/R
S/R
COOMe
OH
O
O
O
Me
Me
HO
O
AcO
a
72
73
68
70
2:1
69
71
68
70
S
AcO
AcO
AcO
OMe
OMe
OMe
OMe
221
1
COOMe
OH
O
O
BnO
O
HO
BnO
O
b
c
1:1
2:1
2:3
2:1
BnO
BnO
415
3
COOMe
OH
Me
O
O
AcO
O
HO
AcO
O
S
OAll
OAll
NPhth
NPhth
5
6
Me
MeOOC
OH
HO
O
O
O
d
1:2
BnO
O
BnO
BnO
OMe
BnO
7
OMe
815
HO
HO
MeOOC
Me
O
O
O
O
O
O
e
58
—
55
—
H17C8
H17C8
10
O
O
O
O
9
COOMe
OH
O
HO
AcO
O
Me
O
O
O
AcO
NPhth
AcO
O
f
61
2:1
63
S
O
NPhth
AcO
O
AcO
AcO
AcO
AcO
OMe
11
OMe
12

G. Agnihotri, A. K. Misra / Tetrahedron Letters 47 (2006) 8493–8497
8495
ical shift of the ketal methyl carbon. The 4,6-O-pyruvate
1.1. Typical experimental protocol for the synthesis of
pyruvate ketals using NIS-TfOH
ketals of disaccharide 11 and trisaccharide 16 were
synthesized exclusively as single diastereomers applying
NIS-TfOH as promotor. However, in the case of benzyl-
ated derivatives, 2,3-di-O-benzyl-a-D-glucopyranoside 3
and 2,3-di-O-benzyl-a-D-galactopyranoside 7, diastereo-
meric mixtures of the pyruvate ketals were isolated. Fol-
lowing a similar reaction protocol, the 5,6-O-pyruvate
ketal of 3-O-octyl-a-D-glucofuranoside 10 was formed
in high yield. The configuration of the ketal carbon
was assigned using 13C NMR spectroscopy by compar-
ison with those previously reported.19,28,29 For 4,6-O-(1-
To a solution of methyl 2,3-di-O-acetyl-a-D-glucopyr-
anoside (1; 360 mg, 1.29 mmol) in dry acetonitrile
(10.0 mL) was added methyl 2,2-di(ethylthio)propionate
(404 mg, 1.92 mmol) and N-iodosuccinimide (1.1 g,
4.8 mmol) and the mixture was stirred at 0 °C for
10 min. To the reaction mixture, trifluoromethanesulf-
onic acid (35 lL, 0.4 mmol) was added and the reaction
mixture was stirred at 0 °C for a further 20 min. After
completion of the reaction (TLC), satd Na2S2O3 was
added, then the solvent was evaporated followed by
dilution with dichloromethane. The organic solution
was washed with satd NaHCO3 and water, dried
(Na2SO4) and concentrated under reduced pressure.
The crude product was purified over SiO2 using hex-
ane–EtOAc (5:1) to give pure pyruvate acetal 2
(322 mg, 69%).31
carboxymethyl)ethylidene-D-glucopyranoside
deriva-
tives 2, 4, 6, 12 and 17 (Table 1, Scheme 3) the methyl
group of the pyruvate ketal appeared at 24–26 ppm
for the S-isomers and at 17–19 ppm for the R-isomers
of the ketal carbon. In the case of D-galacto derivative
8, the methyl group showed peaks at 26 ppm, for the
major R-isomer and at 20.4 ppm for the minor S-isomer
of the ketal carbon.19,29 In the case of the five-membered
pyruvate ketal 10, there was no significant difference
between the chemical shifts of the two diastereomers,
as reported earlier.30 The significantly higher diastereo-
selectivity with NIS and TfOH can be explained by
assuming that under acidic conditions, the thermody-
namically less stable isomers rearranged to the thermo-
dynamically favoured ones which were finally isolated
as the sole or major products. In the case of 4,6-O-
ketals, the thermodynamically favoured isomers were
formed, with an axial methoxycarbonyl group (S-iso-
mers for D-Glcp and R-isomers for D-Galp
derivatives).15
1.2. Typical experimental protocol for the synthesis of
pyruvate ketals using DBDH
To a solution of methyl 2,3 di-O-acetyl-a-D-gluco-
pyranoside (1; 360 mg, 1.29 mmol) in anhydrous aceto-
nitrile (10.0 mL) was added methyl 2,2-di(ethylthio)-
propionate (540 mg, 2.58 mmol) and 1,3-dibromo-5,5-
dimethylhydantoin (DBDH, 925 mg, 3.23 mmol) and the
mixture was stirred at room temperature for 30 min.
After completion of the reaction (TLC), triethylamine
was added and the solvent was evaporated followed
by dilution with dichloromethane. The organic solution
was washed with satd Na2S2O3 and water, dried
(Na2SO4) and concentrated under reduced pressure.
The crude product was purified over SiO2 using
hexane–EtOAc (5:1) to give a diastereomeric mixture
of 2 (336 mg, 72%).
COOMe
OH
O
Me
O
methyl 2,2-di(ethylthio)propionate
DBDH, CH3CN, rt, 30 min
OR2
HO
R1O
O
O
R1O
R1O
R1O
OR2
Scheme 2. Synthesis of pyruvate ketals using DBDH as the thiophilic
activator.
This methodology was applied to the synthesis of a
pyruvate ketal-containing trisaccharide related to the
OH
O
Ph
O
O
O
Ph
AcO
AcO
O
O
O
O
O
a
SEt
BzO
+
BzO
BzO
AcO
AcO
AcO
AcO
O
BzO
O
OAc
OAc
OAc
O
OAc
13
15
14
OAc
OAc
O
AcO
b
AcO
COOMe
O
OH
O
O
BzO
Me
O
O
O
BzO
O
O
HO
BzO
AcO
AcO
BzO
c
AcO
O
OAc
OAc
AcO
AcO
OAc
O
AcO
O
OAc
OAc
OAc
O
17
16
AcO
d
COONa
O
O
AcO
O
Me
O
O
HO
HO
HO
HO
HO
O
OH
OH
OH
18
O
HO
˚
Scheme 3. Reagents and conditions: (a) N-iodosuccinimide, TfOH, CH2Cl2–toluene (1:1), 4 A MS, ꢀ30 °C, 30 min, 73%; (b) HClO4–SiO2, CH3CN,
rt, 30 min, 95%; (c) methyl 2,2-di(ethylthio)propionate, N-iodosuccinimide, TfOH, CH3CN, 0 °C, 20 min, 55%; (d) MeONa, MeOH, rt, 5 h, then five
drops of H2O, rt, 12 h, 86%.

8496
G. Agnihotri, A. K. Misra / Tetrahedron Letters 47 (2006) 8493–8497
4. Lew, J. Y.; Heidelberger, M. Carbohydr. Res. 1976, 52,
255–258.
5. Rao, A. S.; Liao, J.; Kabat, E. A.; Osserman, E. F.;
Haeboe, M.; Nimmich, W. J. Biol. Chem. 1984, 259, 1018–
1026.
6. Thayer, W. R.; Bazic, C. M.; Camphausen, R. T.; McNeil,
M. J. Clin. Microbiol. 1990, 28, 714–718.
7. Gray, J. X.; Rolfe, B. G. Mol. Microbiol. 1990, 4, 1425–
1432.
8. Hotter, G. S.; Scott, D. B. J. Bacteriol. 1991, 173, 851–
859.
9. Hirase, S. Bull. Chem. Soc. Jpn. 1957, 30, 68–79.
10. Choy, Y. M.; Dutton, G. G. S. Can. J. Chem. 1974, 52,
684–687.
11. Dutton, G. G. S.; Karunaratane, D. N. Carbohydr. Res.
1984, 134, 103–114.
12. Gorin, P. A. J.; Mazurek, M.; Duarte, H. S.; Duarte, J. H.
Carbohydr. Res. 1981, 92, C1–C4.
13. Liptak, A.; Szabo, L. J. Carbohydr. Chem. 1989, 8, 629–
644.
14. Valeshek, I. E.; Shakhova, M. K.; Mineav, V. A.;
Samokhvalov, G. I. Zh. Obshch. Khim. 1974, 44, 1161–
1164.
15. Hiruma, K.; Tamura, J.; Horito, S.; Yoshimura, J.;
Hashimoto, H. Tetrahedron 1994, 50, 12143–12158.
16. Zeigler, T.; Eckhardt, E.; Herold, G. Liebigs Ann. Chem.
1992, 441–451.
17. Zeigler, T.; Eckhardt, E.; Neumann, K.; Birault, V.
Synthesis 1992, 1013–1017.
18. Gorin, P. A. J.; Ishikawa, T. Can. J. Chem. 1967, 45, 521–
532.
19. Garegg, P. J.; Lindberg, B.; Kvarnstrom, I. Carbohydr.
Res. 1979, 77, 71–78.
20. Collins, P. M.; McKinnon, C.; Manro, A. Tetrahedron
Lett. 1989, 30, 1399–1400.
21. Aspinell, G. O.; Ibrahim, I. H.; Khare, N. K. Carbohydr.
Res. 1990, 200, 247–256.
cell-wall glycolipid of M. smegmatis. The trisaccharide,
b-D-Glcp-(1!6)-a-D-Glcp-(1!1)-D-a-Glcp is known to
have antigenicity.3–5,32,33 Furthermore, the pyruvate
ketal is supposed to provide the serological specificity
to the immunodominant oligosaccharide structure.
The synthesis of the pyruvylated trisaccharide is
presented in Scheme 3. Glycosylation of ethyl 2,3-di-
O-benzoyl-4,6-O-benzylidene-b-D-glucopyranoside 13,
prepared from D-glucose in five steps, with 2,3,4,6-
tetra-O-acetyl-a-D-glucopyranosyl)-(1!1)-2,3,4-tri-O-
acetyl-a-D-glucopyranose 14,34 prepared from a-D-
glucopyranosyl-(1!1)-a-D-glucopyranose (trehalose) in
three steps, using N-iodosuccinimide and trifluoro-
methanesulfonic acid gave 2,3-di-O-benzoyl-4,6-O-benz-
ylidene-b-D-glucopyranosyl)-(1!6)-2,3,4,6-tetra-O-acet-
yl-a-D-glucopyranosyl)-(1!1)-2,3,4-tri-O-acetyl-a-D-
glucopyranose 15 in 73% yield.35 Removal of the benzyl-
idene acetal from 15 using perchloric acid supported
on silica gel (HClO4–SiO2) furnished 2,3-di-O-benzoyl-
b-D-glucopyranosyl)-(1!6)-(2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl)-(1!1)-2,3,4-tri-O-acetyl-a-D-gluco-
pyranose 1636 which on pyruvylation using methyl
2,2-di(ethylthio)propionate and N-iodosuccinimide in
the presence of trifluoromethane sulfonic acid gave
2,3-di-O-benzoyl-4,6-[(S)-(1-carboxymethyl)ethylidene]-
b-D-glucopyranosyl)-(1!6)-(2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl)-(1!1)-2,3,4-tri-O-acetyl-a-D-glucopyr-
anose 17.37 Signals at d 1.49 (s, 3H) for the ketal methyl
1
(CCH3) in the H NMR and at d 99.6 (CCH3) and 25.5
(CCH3) in the 13C NMR spectra of compound 17 sug-
gested the S-configuration by comparison with literature
reports. Saponification of compound 17 using sodium
methoxide gave 4,6-[(S)-(1-sodium carboxylate)ethyl-
idene]-b-D-Glcp-(1!6)-a-D-Glcp-(1!1)-D-a-Glcp 18.38
22. Liptak, A.; Szabo, L. Carbohydr. Res. 1988, 184, C5–C8.
23. Liptak, A.; Bajza, I.; Kerekgyarto, J.; Hajko, J.; Szilagyi,
L. Carbohydr. Res. 1994, 253, 111–120.
24. (a) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B.
Tetrahedron Lett. 1990, 31, 4313–4316; (b) Veenemann, G.
H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 1331–1334.
25. Misra, A. K.; Madhusudan, S. K. Carbohydr. Res. 2005,
340, 497–502.
26. Eguchi, H.; Kawaguchi, H.; Yoshinaga, S.; Nishida, A.;
Nishiguchi, T.; Fujisaki, S. Bull. Chem. Soc. Jpn. 1994, 67,
1918–1921.
In conclusion, a high yielding reaction protocol with
good stereoselectivity for the synthesis of 4,6- as well as
5,6-O-pyruvate ketals has been developed. These conve-
nient and easy to perform reaction conditions have been
applied to the synthesis of a trisaccharide pyruvate ketal
related to the cell-wall glycolipid found in M. smegmatis.
27. Chassaing, C.; Handrechy, A.; Langlois, Y. Tetrahedron
Lett. 1997, 38, 4415–4416.
Acknowledgements
28. Zeigler, T.; Eckhardt, E.; Herold, G. Tetrahedron Lett.
1992, 33, 4413–4416.
29. Gorin, P. A. J.; Mazurek, M.; Duarte, H. S.; Iacomini, M.;
Duarte, J. H. Carbohydr. Res. 1982, 100, l–15.
30. Hiruma, K.; Tamura, J.; Hashimoto, H. Carbohydr. Res.
1996, 282, 299–306.
Instrumentation facilities from SAIF, CDRI are grate-
fully acknowledged. G.A. thanks CSIR, New Delhi,
for providing a senior research fellowship. This project
was partly funded by the Department of Science and
Technology (DST), New Delhi (SR/FTP/CSA-10/
2002), India.
31. Spectral data of novel pyruvate ketal-containing carbo-
hydrate derivatives:
Methyl 2,3-di-O-acetyl-4,6-O-[(S)-(1-methoxycarbonyl)-
25
ethylidene]-a-D-glucopyranoside 2: Yellow oil; ½aꢁD +97.1
(c 1.0, CHCl3); IR (neat): 2931, 2363, 1594, 1353, 1053,
References and notes
;
766 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.42 (t,
J = 9.6 Hz, 1H), 4.86 (d, J = 3.3 Hz, 1H), 4.83 (dd,
J = 9.9, 3.3 Hz, 1H), 4.03 (dd, J = 10.8, 4.8 Hz, 1H),
3.82 (s, 3H, COOCH3), 3.67–3.61 (m, 1H), 3.53–3.46 (m,
2H), 3.38 (s, 3H, OCH3), 2.07, 2.06 (2s, 6H, COCH3), 1.50
(s, 3H, CCH3); 13C NMR (75 MHz, CDCl3): d 170.6,
170.4, 169.9, 99.6, 97.9, 74.4, 71.7, 69.3, 65.7, 62.0, 55.7,
1. Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48,
279–318.
2. Araki, S.; Abe, S.; Yamada, S.; Satake, M.; Fujiwara, N.;
Kon, K.; Ando, S. J. Biochem. 1992, 112, 461–469.
3. Dudman, W. F.; Heidelberger, M. Science 1969, 164, 954–
955.

G. Agnihotri, A. K. Misra / Tetrahedron Letters 47 (2006) 8493–8497
8497
53.0, 25.6 (CCH3), 21.2, 21.0; ESI-MS: m/z 385.2 [M+Na];
Anal. Calcd for C15H22O10 (362): C, 49.72; H, 6.12.
Found: C, 49.48; H, 6.30.
aq Na2S2O3, satd NaHCO3, water, dried (Na2SO4) and
concentrated to a syrupy product. Column chromatogra-
phy of the crude product over SiO2 using hexane–EtOAc
25
Allyl 3-O-acetyl-2-deoxy-4,6-O-[(S)-(1-methoxycarbonyl)-
ethylidene]-2-phthalimido-b-D-glucopyranoside 6: yellow
(2:1) afforded pure 15 (1.25 g, 73%) as glassy solid; ½aꢁD
+105.4 (c 1.0, CHCl3); IR (KBr): 2961, 2363, 1753, 1597,
25
oil; ½aꢁD +17.7 (c 1.0, CHCl3); IR (neat): 3452, 2918,
1353, 1223, 1098, 766, 709 cmꢀ1 1H NMR (300 MHz,
;
2364, 1748, 1448, 1116, 1057, 748 cmꢀ1
;
1H NMR
CDCl3): d 7.95–7.92 (m, 3H, aromatic protons), 7.49–7.26
(m, 12H, aromatic protons), 5.77 (t, J = 9.6 Hz each, 1H),
5.54 (s, 1H, CHC6H5), 5.46–5.37 (m, 3H), 5.05–4.97 (m,
3H), 4.93 (d, J = 3.6 Hz, 1H), 4.89–4.80 (m, 2H), 4.78 (t,
J = 7.8 Hz, 1H), 4.43 (dd, J = 10.2, 4.8 Hz, 1H), 4.18 (t,
J = 6.0 Hz, 1H), 4.14–4.04 (m, 2H), 3.98–3.81 (m, 4H),
3.68 (t, J = 4.8 Hz, 1H), 3.55–3.49 (m, 1H), 2.07, 2.03,
2.00, 1.97 (4s, 21H, 7COCH3); 13C NMR (75 MHz,
CDCl3): d 170.4, 170.2, 170.0, 169.9, 169.8, 169.6 (2C),
166.2, 166.1, 133.3–126.5 (aromatic carbons), 102.3
(PhCH), 101.8, 92.3, 91.9, 79.0, 72.3, 72.1, 70.7 (2C),
70.3 (3C), 69.5 (2C), 68.9, 68.7, 68.4, 67.1, 62.2, 20.9 (2C),
20.8 (3C), 20.7 (2C); ESI-MS: m/z 1072 [M+Na]; Anal.
Calcd for C53H58O25 (1095): C, 58.13; H, 5.34. Found: C,
58.10; H, 5.49.
(300 MHz, CDCl3):
d 7.87–7.74 (m, 4H, aromatic
protons), 5.73–5.62 (m, 2H), 5.41 (d, J = 8.4 Hz, 1H),
5.10–5.04 (m, 1H), 4.27–4.21 (m, 2H), 4.14 (dd, J = 10.8,
3.9 Hz, 1H), 4.02 (dd, J = 12.9, 6.3 Hz, 1H), 3.86 (s, 3H,
COOCH3), 3.80–3.74 (m, 1H), 3.72–3.68 (m, 1H), 3.66–
3.61 (m, 2H), 1.96 (s, 3H, COCH3), 1.54 (s, 3H, CCH3);
13C NMR (75 MHz, CDCl3): d 170.4, 170.1, 134.4, 133.6,
131.9, 123.9, 118.1, 99.6, 97.9, 75.6, 70.5, 70.4, 70.2, 66.1,
65.4, 55.6, 52.9, 25.6 (CCH3), 20.9; ESI-MS: m/z 498
[M+Na]; Anal. Calcd for C23H25NO10 (475): C, 58.10; H,
5.30. Found: C, 57.82; H, 5.58.
1,2-O-Isopropylidene-5,6-O-(1-methoxycarbonyl)ethylidene]-
25
3-O-octyl-a-D-glucofuranose 10: yellow oil; ½aꢁD ꢀ18.2 (c
1.0, CHCl3); IR (neat): 2933, 2363, 1595, 1351, 1084,
670 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 5.86 (dd,
36. Agnihotri, G.; Misra, A. K. Tetrahedron Lett. 2006, 47,
3653–3658.
J = 9.9, 3.3 Hz, 1H), 4.54–4.52 (m, 1H), 4.44–429 (m,
1H), 4.28–4.22 (m, 2H), 4.14 (t, J = 5.4 Hz, 1H), 3.88 (dd,
J = 12.0, 3.3 Hz, 1H), 3.79 (s, 3H, OCH3), 3.63–3.58 (m,
1H), 3.58–3.54 (m, 1H), 1.59, 1.56 (2s, 6H, C(CH3)2), 1.50
(s, 3H, CCH3), 1.31–128 (m, 12H), 0.90 (t, J = 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 170.1, 111.8, 105.3,
100.1, 82.5, 82.1, 80.6, 73.6, 70.7, 69.1, 31.8, 29.7, 29.2,
26.8, 26.3, 26.0, 22.6 (CCH3), 14.0; ESI-MS: m/z 439
[M+Na]; Anal. Calcd for C21H36O8 (416): C, 60.56; H,
8.71. Found: C, 60.31; H, 8.83.
37. (2,3-Di-O-benzoyl-4,6-O-[(S)-(1-methoxycarbonyl)ethyl-
idene]-b-D-glucopyranosyl)-(1!6)-(2,3,4,6-tetra-O-acet-
yl-a-D-glucopyranosyl)-(1!1)-2,3,4-tri-O-acetyl-a-D-gluco-
pyranose 17: Prepared following the NIS-TfOH promoted
25
general reaction protocol. Yield 55%; yellow oil; ½aꢁD
+98.9 (c 1.0, CHCl3); IR (neat): 1749, 1225, 1038,
713 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.96–7.34 (m,
1
10H, aromatic protons), 5.58 (t, J = 9.6 Hz each, 1H),
5.40–5.25 (m, 3H), 4.99–4.89 (m, 3H), 4.83–4.75 (m, 2H),
4.70 (d, J = 4.8 Hz, 1H), 4.17–4.11 (m, 2H), 4.02–3.96 (m,
2H), 3.92–3.87 (m, 2H), 3.83 (s, 3H, COOCH3), 3.76–3.68
(m, 3H), 3.58–3.44 (m, 2H), 2.08, 2.06, 2.02, 2.00, 1.98,
1.96 (6s, 21H, 7COCH3), 1.49 (s, 3H, CCH3); 13C NMR
(50 MHz, CDCl3): d 170.4 (2C), 170.0, 169.8 (2C), 169.6
(2C), 165.7, 165.1, 133.7–128.7 (aromatic carbons), 102.1,
99.6 (CCH3), 92.3, 91.8, 75.0, 72.2 (2C), 70.8, 70.3 (2C),
69.5 (2C), 68.8 (2C), 66.8, 66.7, 66.6, 65.2, 62.2, 52.9
(COOCH3), 25.5 (CCH3), 20.9 (3C), 20.8 (4C); ESI-MS:
m/z 1113.3 [M+Na]; Anal. Calcd for C50H58O27 (1090): C,
55.05; H, 5.36. Found: C, 54.87; H, 5.50.
Methyl (3-O-acetyl-2-deoxy-4,6-O-[(S)-(1-methoxycarbon-
yl)ethylidene]-2-phthalimido-b-D-glucopyranosyl)-(1!6)-
25
2,3,4-tri-O-acetyl-a-D-glucopyranoside 12: yellow oil; ½aꢁD
+45.2 (c 1.0, CHCl3); IR (neat): 3406, 2363, 1746, 1228,
1038, 770 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 8.28–8.12
(m, 4H, aromatic protons), 6.04 (t, J = 9.0 Hz each, 1H),
5.78 (d, J = 8.4 Hz, 1H), 5.64 (t, J = 9.9 Hz each, 1H),
5.12 (t, J = 9.6 Hz each, 1H), 5.02 (dd, J = 10.2, 3.6 Hz,
1H), 4.88 (d, J = 3.3 Hz, 1H), 4.58–4.50 (m, 2H), 4.18 (s,
3H), 4.17–4.08 (m, 3H), 4.05–4.00 (m 2H), 3.87–3.75 (m,
1H), 3.45 (s, 3H), 2.39, 2.32, 2.29, 2.22 (4s, 12H, 4
COCH3), 1.90 (s, 3H, CCH3); 13C NMR (50 MHz,
CDCl3): d 170.2, 169.6 (2C), 169.3, 167.9 (2C), 134.3–
123.7 (aromatic carbons), 99.5 (CCH3), 99.3, 96.6, 79.4,
75.4, 74.2, 73.3, 70.6, 70.1, 69.2, 68.0, 55.7, 55.4, 55.1, 52.9,
55.3, 54.9, 25.5 (CCH3), 20.9 (2C), 20.7 (2C); ESI-MS: m/z
760 [M+Na]; Anal. Calcd for C33H39NO18 (737): C, 53.73;
H, 5.33. Found: C, 53.60; H, 5.58.
38. 4,6-O-[(S)-(1-Sodium carboxylate)ethylidene]-b-D-gluco-
pyranosyl-(1!6)-a-D-glucopyranosyl-(1!1)-D-a-Glcp 18:
A solution of compound 17 (400 mg, 0.36 mmol) in
0.05 M sodium methoxide in methanol (5.0 mL) was
stirred at room temperature for 5 h. Then five drops of
distilled water were added to the reaction mixture which
was allowed to stir at room temperature for 12 h. The
reaction mixture was neutralized with Dowex 50W-X8
(H+), filtered and the filtrate was evaporated to dryness to
give a glassy solid, which was again dissolved in distilled
water and treated with Dowex 50W-X8 (Na+) and
concentrated. The crude product was purified through
Sephadex LH-20 using 80% aqueous EtOH as eluant to
give pure trisaccharide 18 as its sodium salt (185 mg, 86%);
32. Ohta, M.; Pan, Y. T.; Laine, R. A.; Elbein, A. D. Eur. J.
Biochem. 2002, 269, 3142–3149.
33. Saadat, S.; Ballou, C. E. J. Biol. Chem. 1983, 258, 1813–
1818.
´
´
´
´
34. Szurmai, Z.; Kerekgyarto, J.; Harangi, J.; Liptak, A.
Carbohydr. Res. 1987, 164, 313–325.
35. 2,3-Di-O-benzoyl-4,6-O-benzylidene-b-D-glucopyranosyl)-
(1!6)-(2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl)-(1!1)-
2,3,4-tri-O-acetyl-a-D-glucopyranose 15: To a solution of
compound 13 (1.28 g, 2.46 mmol) and compound 14
(1.0 g, 1.57 mmol) in anhydrous CH2Cl2: toluene (1:1;
25
glassy solid; ½aꢁD +14 (c 1.0, H2O); IR (KBr): 3760, 2375,
1595, 1352 cmꢀ1 1H NMR (300 MHz, D2O): d 5.12 (d,
;
J = 3.3 Hz, 1H, H-1), 5.10 (d, J = 3.3 Hz, 1H, H-10), 4.51
(d, J = 8.1 Hz, 1H, H-100), 4.04–4.02 (m, 1H), 3.97 (d,
J = 4.8 Hz, 1H), 3.84–3.77 (m, 5H), 3.72–3.71 (m, 2H),
3.68 (d, J = 4.5 Hz, 1H), 3.61–3.56 (m, 4H), 3.47 (t,
J = 9.6 Hz, 1H), 3.42–3.36 (m, 3H), 1.41 (s, 3H); 13C
NMR (75 MHz, D2O): d 170.0, 102.1 (C-100), 100.2 (ketal-
C), 92.0 (2C), 74.6, 72.7, 71.5, 71.2 (2C), 70.9, 69.7 (2C),
68.4, 68.1, 67.4, 64.6, 62.9, 59.3 (2C), 23.4; ESI-MS: m/z
619.1 [M+Na]; Anal. Calcd for C21H33NaO18 (596): C,
42.29; H, 5.58. Found: C, 42.05; H, 5.80.
˚
20 mL) was added powdered 4 A MS (3.0 g) and the
mixture was stirred under argon for 1 h. N-Iodosuccini-
mide (580 mg, 2.58 mmol) was added to the reaction
mixture at room temperature which was then cooled to
ꢀ40 °C. Trifluoromethanesulfonic acid (22 lL, 0.25 mmol)
was added to the reaction mixture and it was allowed to
stir for 30 min at ꢀ40 °C. The reaction mixture was
filtered through Celite and the filtrate was washed with 5%