Stereoselective α-glycosylation with 3-O-acetylated D-gluco donors

Article abstract of DOI:10.1055/s-2006-939037

The effect of a 3-O-acetyl group on the stereoselectivity of α-glycosylation with 2-O-benzylated D-gluco glycosyl donors was studied. It was shown that 3-O-acetylated donors gave α-anomers predominantly or exclusively, whereas glycosylation with the corre

Full text of DOI:10.1055/s-2006-939037

LETTER
921
Stereoselective a-Glycosylation with 3-O-Acetylated D-Gluco Donors
Stereoselective
a
-G
a
lycosylatio
d
n
w
ith3-O
-
e
A
cetylated
z
D
-
G
luco Do
h
nors da Ustyuzhanina,a Bozhena Komarova,a Natalya Zlotina,b Vadim Krylov,b Alexey Gerbst,a Yury Tsvetkov,a
Nikolay Nifantiev*a
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow B-334, Russia
b
Higher Chemical College, Russian Academy of Sciences, Miusskaya sq., 125047 Moscow, Russia
Fax +7(95)1358784; E-mail: nen@ioc.ac.ru
Received 14 December 2005
To investigate the scope of this stereochemical effect, we
studied the influence of a 3-O-acetyl group on the stereo-
selectivity of glycosylation with D-gluco donors, such as
fully benzylated and 3-O-acetylated D-glucosyl N-phenyl
Abstract: The effect of a 3-O-acetyl group on the stereoselectivity
of a-glycosylation with 2-O-benzylated D-gluco glycosyl donors
was studied. It was shown that 3-O-acetylated donors gave a-ano-
mers predominantly or exclusively, whereas glycosylation with the
corresponding per-O-benzylated donors afforded mixtures of com- trifluoroacetimidates 118 and 2,18 D-glucuronyl bromides
314 and 4, and D-xylosyl trichloroacetimidates 5 and 6. All
parable amounts of a- and b-anomers. The higher a-stereoselectiv-
ity in the first case was accounted for by the remote anchimeric
these compounds have the same configuration at C-2, C-
assistance of the 3-O-acetyl group, which was confirmed by theo-
3, and C-4 (for this reason the xylosyl donors were includ-
retical calculations.
ed in the D-gluco series) but vary in the C-5 substituent
Key words: carbohydrates, glycosylations, remote participation,
stereoselectivity, a-glucosylation
and the leaving group at the anomeric center. Glycosyla-
tions of acceptors 7–9 with donors 1–6 were performed as
steps within the syntheses of several substances: glyco-
forms of the outer core of the Pseudomonas aeruginosa li-
popolysaccharide,18 heterosaccharide fragments of
fucoidans, and probes for the elucidation of xylosyltrans-
ferase activity. The synthesis of compounds 4, 5, and 6
will be reported elsewhere.
Although the glycosylation reaction has been known for
more than a century, the stereoselective formation of the
1,2-cis glycoside bond is still considered a challenging
problem in synthetic chemistry.1 The major principle of
the strategy is the use of a non-participating substituent on
C-2 to avoid formation of the acyloxonium intermediate.2
A number of factors should be taken into account, for
instance, the nature of leaving and protecting groups,
solvent, promoting system, the structure of the glycosyl
acceptor, and temperature.3,4 There are a few communica-
tions where the anchimeric assistance of remote substitu-
ents was used to improve the stereoselectivity of 1,2-cis
glycosylation. Noteworthy are the examples with 6-O-
acylated D-glucosyl and D-galactosyl donors,5,6 4-O-acyl-
ated D-galactosyl,7 L-fucosyl,8,9 D-mannosyl,10 and L-
rhamnosyl11 donors, and fully benzylated glucuronyl
donors bearing a participating COOAlk group at C-5.12,13
The anchimeric participation of a remote 3-O-acyl substit-
uent was also reported for the glycosylation with 2-deoxy-
ribo-hexopyranosyl donors.14–16 Recently we have shown
that glycosylation with 3-O-benzoyl-2,4-di-O-benzyl-fu-
cosyl bromide proceeded with high a-stereoselectivity.17
Moreover, the stereoselectivity of the glycosylation with
the latter donor was higher than that with the 4-O-benzo-
ylated isomer, indicating that the anchimeric assistance of
the 3-O-benzoyl group is more efficient than that of 4-O-
benzoyl. These results were in good correlation with
theoretical calculations on the ‘stabilization energy’ of the
glycosyl cations formed due to the participation of a
benzoyl group.
Methyl 2-azido-2-deoxy-D-galactoside 718 was used as a
glycosyl acceptor in reactions with glucosyl donors 1 and
2. AgOTf-promoted glycosylation with fully benzylated
N-phenyltrifluoroacetimidate 1 (Table 1, entry 1) afford-
ed a 2:1 mixture of a- and b-isomers 10 and 11 in 95%
yield.19 The reaction of 3-O-acetylated donor 2 (Table 1,
entry 2) demonstrated a notably higher a-stereoselectivity
(12/13, a/b ratio, 4:1).20
A more pronounced stereochemical effect was observed
in the case of glucuronyl donors 3 and 4. The reaction of
per-O-benzylated bromide 3 with acetonide 821 in the
presence of AgOTf (Table 1, entry 3) led to a 2:1 mixture
of a- and b-anomers 14 and 15 (89%), whereas the use of
3-O-acetylated bromide 4 (Table 1, entry 4) strongly
enhanced the stereoselectivity of the reaction and gave the
a-isomer 16 exclusively (90%).22
Xylosyl donors 5 and 6 also provided evidence for the
stereocontrolling effect of the 3-O-acetyl group. Glyco-
sylation of allyl xyloside 923 with 2,3,4-tri-O-benzylated
trichloroacetimidate 5 (Table 1, entry 5) proceeded with
relatively low stereoselectivity (17:18, 2.5:1), while the
coupling of compounds 6 and 9 (Table 1, entry 6) afford-
ed only a-linked disaccharide 19 in 80% yield.24
We assumed that the higher stereoselectivity of reactions
with D-gluco donors 2, 4, and 6 is regulated by the remote
stereocontrolling effect of the 3-O-acetyl group resulting
in the formation of stabilized cation II (Scheme 1).
Nucleophilic attack on cation II is favored from the a-
side. To evaluate this possibility we calculated the energy
SYNLETT 2006, No. 6, pp 0921–0923
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939037; Art ID: G38605ST
© Georg Thieme Verlag Stuttgart · New York

922
N. Ustyuzhanina et al.
LETTER
R"
O
BnO
R'O
OR
OBn
ROH
β-product
β
R"
R"
10–19
O
O
BnO
R'O
BnO
R'O
+
X
ROH
OBn
glycosyl donor
1–6
OBn
R"
α
O
BnO
R'O
"non-stabilized" cation I
BnO
OR
α-product
R' = Ac
CH3
R"
ROH
O
O
+
O
α
BnO
OBn
"stabilized" cation II
Scheme 1
difference between the stabilized and non-stabilized corresponds to the a/b ratio of 4:1. ‘Stabilization energies’
forms I and II, which is referred to as the ‘stabilization –15.3 kcal/mol for xylosyl donor 6 and –21.6 kcal/mol in
energy’ (Table 1).
the case of glucuronyl donor 4 are in accordance with the
increase in a-stereoselectivity.
‘Stabilization energy’ calculations (Table 1) were per-
formed with an MM+Molecular mechanics force field In conclusion, a series of D-gluco donors was studied as
(HyperChem, Version 7.0). Electrostatic interactions a-glycosylating agents. It was found that the reactions
were considered in charge-charge approximation, the with donors bearing an acetyl group at O-3 provided
values of partial atomic charges were obtained from AM1 remarkably higher stereoselectivity than those with per-
single point calculations. Calculated energy data were in O-benzylated analogues. This finding can be applied to
good agreement with experimental results. Thus, the the efficient synthesis of a-glucosides.
‘stabilization energy’ of –11.3 kcal/mol for the donor 2
Table 1 Glycosylation and the ‘Stabilization Energy’ of the Cationic Intermediates II
Glycosyl donor
X
Glycosyl acceptor
a-Product b-Product Yield
Ratio a/b Stabilization
energy
R¢
R¢¢
(kcal/mol)
OBn
HO
O
1
2
a/b-OC(=NPh)CF3 Bn
a/b-OC(=NPh)CF3 Ac
CH2OBn
CH2OBn
10
11
13
95%
90%
2:1
4:1
–
AcO
–11.3
N3
OMe
7
OAll
O
Me
OH
15
not
observed
3
4
a-Br
a-Br
Bn
Ac
COOMe
COOMe
14
16
89%
90%
2:1
–
–
O
–21.6
O
Me
Me
8
O
BnO
HO
18
not
observed
5
6
a/b-OC(=NH)CCl3 Bn
a/b-OC(=NH)CCl3 Ac
H
H
17
19
85%
80%
2.5:1
–
–
BnO
–15.3
OAll
9
Synlett 2006, No. 6, 921–923 © Thieme Stuttgart · New York

LETTER
Stereoselective a-Glycosylation with 3-O-Acetylated D-Gluco Donors
923
mixture was stirred at r.t. for 2 d and then filtered through
celite. The filtrate was washed with 1 M Na2S2O3, a sat. soln
of NaHCO3, and concentrated. After purification by column
chromatography (silica gel; toluene–EtOAc, 12:1) and gel-
permeation chromatography (BioBeads SX-3, toluene) a
mixture of a- and b-isomers 12 and 13 (71 mg, 90%, 4:1)
was obtained. The a/b ratio was determined by the inte-
gration of the H-3¢ signals (a, 5.58 ppm; b, 5.18 ppm) in the
1H NMR spectra. Selected signals for 12: 1H NMR (250
MHz, CDCl3): d = 4.83 (d, 1 H, J1,2 = 3.5 Hz, H-1), 4.87 (d,
1 H, J1¢,2¢ = 3.3 Hz, H-1¢), 5.18 (dd, 1 H, J2,3 = 11.3 Hz, H-3),
5.58 (t, 1 H, J2¢,3¢ = 9.8 Hz, H-3¢). Selected signals for 13: 1H
NMR (250 MHz, CDCl3): d = 4.90 (d, 1 H, J1,2 = 3.5 Hz, H-
1), 5.18 (t, 1 H, J2¢,3¢ = 10.0 Hz, H-3¢).
Acknowledgment
This work was supported by the Russian Foundation for Basic
Research (grants 03-03-32-556 and 05-03-08107) and the 1st
Program of the Division of Chemistry and Material Sciences. We
thank Mr. A. A. Grachev for recording NMR spectra.
References and Notes
(1) Demchenko, A. V. Lett. Org. Chem. 2005, 2, 580.
(2) Nukada, T.; Berces, A.; Zgierski, M.; Whitfield, D. M. J.
Am. Chem. Soc. 1998, 120, 13291.
(3) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
(4) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35.
(5) Ishikawa, T.; Fletcher, H. G. J. Org. Chem. 1969, 34, 563.
(6) Fletcher, J. M.; Schuerch, C. J. Am. Chem. Soc. 1972, 94,
604.
(7) Demchenko, A. V.; Rousson, E.; Boons, G.-J. Tetrahedron
Lett. 1999, 40, 6523.
(8) Dejter-Juszynski, M.; Flowers, H. M. Carbohydr. Res. 1972,
23, 41.
(9) Dejter-Juszynski, M.; Flowers, H. M. Carbohydr. Res. 1973,
28, 61.
(10) De Meo, C.; Kamat, M. N.; Demchenko, A. V. Eur. J. Org.
Chem. 2005, 706.
(11) Yamanoi, T.; Nakamura, K.; Takeyama, H.; Yanagihara, K.;
Inazu, T. Bull. Chem. Soc. Jpn. 1994, 67, 1359.
(12) Kováč, P.; Palovčík, R. Carbohydr. Res. 1977, 54, C11.
(13) Hirsch, J.; Koóš, M.; Kovač, P. Carbohydr. Res. 1998, 310,
145.
(14) Wiesner, K.; Tsai, T. Y. R.; Ren, A.; Kumar, R.; Tsubuki, V.
Helv. Chim. Acta 1983, 66, 2632.
(15) Tsai, T. Y. R.; Jin, H.; Wiesner, K. Can. J. Chem. 1984, 62,
1403.
(16) Thiem, J.; Klaffke, W. Top. Curr. Chem. 1990, 154, 284.
(17) Gerbst, A. G.; Ustuzhanina, N. E.; Grachev, A. A.;
Khatuntseva, E. A.; Tsvetkov, D. E.; Whitfield, D. M.;
Berces, A.; Nifantiev, N. E. J. Carbohydr. Chem. 2001, 20,
821.
(18) Komarova, B.; Tsvetkov, Y.; Knirel, Y.; Zähringer, U.; Pier,
G.; Nifantiev, N. Tetrahedron Lett. 2006, in press.
(19) A mixture of donor 1 (53 mg, 0.069 mmol), acceptor 7 (17
mg, 0.048 mmol), and MS AW-300 (76 mg) in CH2Cl2 (0.8
mL) was treated with a soln of AgOTf (9 mg, 0.034 mmol)
in toluene (110 mL) overnight at r.t. under argon. The
reaction mixture was filtered through celite, the filtrate was
washed with 1 M Na2S2O3, a sat. soln of NaHCO3, and
concentrated. After purification by chromatography (silica
gel, toluene–EtOAc, 12:1) a mixture of a- and b-anomers 10
and 11 (40 mg, 0.045 mmol, 95%, 2:1) was obtained. The
ratio of 10/11 was determined by the integration of the H-3
signal intensities (a, 5.21 ppm; b, 5.32 ppm) in the 1H NMR
spectra. Selected signals for 10: 1H NMR (250 MHz,
CDCl3): d = 4.82 (d, 1 H, J1¢,2¢ = 4.0 Hz, H-1¢), 4.88 (d, 1 H,
J1,2 = 3.5 Hz, H-1), 5.21 (dd, 1 H, J2,3 = 11.2 Hz, J3,4 = 2.7
Hz, H-3). Selected signals for 11: 1H NMR (250 MHz,
CDCl3): d = 4.39 (d, 1 H, J1¢,2¢ = 9.4 Hz, H-1¢), 4.90 (d, 1 H,
(21) Takeo, K.; Aspinall, G. O.; Brennan, P.; Chatterjee, D.
Carbohydr. Res. 1986, 150, 133.
(22) Glycosylation with Glucuronyl Donors 3 and 4; General
Procedure. A mixture of glucuronyl bromide (0.052 mmol;
28 mg for 3, 26 mg for 4), acceptor 8 (12 mg, 0.05 mmol) and
MS 4 Å (200 mg) in anhyd CH2Cl2 (2 mL) was stirred at r.t.
for 30 min. Then AgOTf (15 mg, 0.057 mmol) was added at
–30 °C. The mixture was stirred for 15 min at –30 °C, then
quenched with Et3N (0.1 mL), and filtered through celite.
The filtrate was washed with 1 M Na2S2O3, H2O, dried over
Na2SO4, and concentrated. Column chromatography
(toluene–EtOAc, 15:1) of the residue afforded
disaccharides. The a/b ratios were determined by integration
of the signals corresponding to H-1¢ in the 1H NMR spectra.
Selected signals for 14: 1H NMR (250 MHz, CDCl3): d =
4.92 (d, 1 H, J1,2 = 3.1 Hz, H-1), 5.25 (d, 1 H, J1¢2¢ = 3.5 Hz,
H-1¢). Selected signals for 15: 1H NMR (250 MHz, CDCl3):
d = 4.98 (s, 1 H, H-1), 5.56 (d, 1 H, J1¢,2¢ = 8.5 Hz, H-1¢).
Selected signals for 16: 1H NMR (250 MHz, CDCl3): d =
1.35 (d, 3 H, 3 ꢀ H-6), 1.98 (s, 3 H, COCH3), 3.52 (dd, 1 H,
J1¢,2¢ = 3,6 Hz, J2¢,3¢ = 10.0 Hz, H-2¢), 3.73 (s, 3 H, CH3), 3.76
(m, 2 H, H-2, H-4¢), 4.04–4.22 (m, 5 H, H-3, H-4, H-5,
CH2CH=CH2), 4.42–4.80 (m, 5 H, H-5¢, 2 ꢀ CH2Ph), 4.88 (d,
1 H, J1,2 = 3.5 Hz, H-1), 5.20 and 5.35 (2 dd, 2 H,
CH2CH=CH2), 5.30 (d, 1 H, J1¢,2¢ = 3.6 Hz, H-1¢), 5.56 (t, 1
H, J2¢,3¢ = J3¢,4¢ = 9.6 Hz, H-3¢), 5.92 (m, 1 H, CH2CH=CH2),
7.24–7.35 (m, 10 H, 2 ꢀ Ph).
(23) Fukase, K.; Hase, S.; Ikenaka, T.; Kusumoto, S. Bull. Chem.
Soc. Jpn. 1992, 65, 436.
(24) Glycosylation with Xylosyl Donors 5 and 6; General
Procedure. A mixture of xylosyl trichloroacetimidate
(0.071 mmol; 40 mg for 5: 36 mg for 6), acceptor 9 (26 mg,
0.07 mmol) and MS 4 Å (200 mg) in anhyd CH2Cl2 (2 mL)
was stirred at r.t. for 30 min. Then a 0.1 M solution of
TMSOTf in anhyd CH2Cl2 (10 mL) was added at –30 °C. The
mixture was stirred for 15 min at –30 °C, then quenched with
Et3N (0.1 mL), and filtered through celite. The filtrate was
washed with H2O, dried over Na2SO4, and concentrated.
Column chromatography (toluene–EtOAc, 10:1) of the
residue afforded disaccharides. The a/b ratios were
determined by integration of the signals corresponding to H-
1¢ in the 1H NMR spectra. Selected signals for 17: 1H NMR
(250 MHz, CDCl3): d = 5.58 (d, 1 H, J1¢,2¢ = 3.5 Hz, H-1¢).
Selected signals for 18: 1H NMR (250 MHz, CDCl3): d =
4.93 (d, 1 H, J1¢,2¢ = 9.5 Hz, H-1¢). 1H NMR data for 19: 1H
NMR (250 MHz, CDCl3): d = 3.36 (dd, 1 H, J1¢,2 ¢ = 3.3 Hz,
J2¢,3¢ = 9.6 Hz, H-2¢), 3.43–3.74 (m, 7 H, H-2, H-4, H-4¢, 2 ꢀ
H-5, 2 ꢀ H-5¢), 3.91–4.20 (m, 3 H, H-3, CH2CH=CH2), 4.31–
4.79 (m, 9 H, 4 ꢀ CH2Ph, H-1), 5.20–5.35 (m, 2 H,
CH2CH=CH2), 5.54 (t, 1 H, J2¢,3¢ = J3¢,4¢ = 9.6 Hz, H-3¢), 6.67
(d, J1¢,2¢ = 3.3 Hz, H-1¢), 5.92 (m, 1 H, CH2CH=CH2), 7.08–
7.50 (m, 20 H, 4 ꢀ Ph).
J1,2 = 3.8 Hz, H-1), 5.32 (dd, 1 H, J2,3 = 11.0 Hz, J3,4 = 2.8
Hz, H-3).
(20) To a stirred mixture of acceptor 7 (33 mg, 0.095 mmol),
donor 2 (50 mg, 0.075 mmol), and MS AW-300 (140 mg) in
anhyd CH2Cl2 (2 mL) a soln of AgOTf (10 mg, 0.039 mmol)
in anhyd toluene (0.1 mL) was added. The reaction was
monitored by TLC, when donor 2 was consumed, a further
portion of the donor (29 mg, 0.044 mmol) in anhyd CH2Cl2
and AgOTf (6 mg, 0.023 mmol) were added. The reaction
Synlett 2006, No. 6, 921–923 © Thieme Stuttgart · New York