Stereoselective glycosylations by nitrosyl tetrafluoroborate-catalyzed activation of glycosyl trichloroacetimidate derivatives

Article abstract of DOI:10.1055/S-0032-1317135

Efficient stereoselective glycosylation conditions have been developed by using nitrosyl tetrafluoroborate (NOBF₄) promoted activation of glycosyl trichloroacetimidate derivatives. A series of mono- and disaccharide derivatives were synthesized in excellent yield, and high stereoselectivity at the glycosylation center was observed in every case. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0032-1317135

LETTER
▌2341
lSettteer reoselective Glycosylations by Nitrosyl Tetrafluoroborate-Catalyzed
Activation of Glycosyl Trichloroacetimidate Derivatives
Glycosylation of Glycosyl Trichloroacetimidate Derivatives
Abhijit Sau, Abhishek Santra, Anup Kumar Misra*
Division of Molecular Medicine, Bose Institute, P-1/12, C. I. T. Scheme VII M, Kolkata 700054, India
Fax +91(33)23553886; E-mail: akmisra69@gmail.com
Received: 29.05.2012; Accepted after revision: 24.07.2012
Dedicated to Professor Richard R. Schmidt, Universität Konstanz, Germany on his 73rd birthday
transformation into other glycosyl donors such as thiogly-
cosides and 4-pentenyl glycosides; (d) their activation
under acidic reaction conditions for the preparation of ex-
clusively 1,2-trans or 1,2-cis glycosides depending on the
Abstract: Efficient stereoselective glycosylation conditions have
been developed by using nitrosyl tetrafluoroborate (NOBF4) pro-
moted activation of glycosyl trichloroacetimidate derivatives. A
series of mono- and disaccharide derivatives were synthesized in
excellent yield, and high stereoselectivity at the glycosylation cen- solvent used in the reaction. Glycosyl trichloroacetimi-
ter was observed in every case.
date derivatives have been introduced and exhaustively
used by Schmidt et al. as glycosyl donors in the synthesis
of a variety of complex oligosaccharides, which have be-
come one of the most attractive glycosylation protocols in
the synthesis of oligosaccharides.26,27 Conventional cata-
lysts for the activation of glycosyl trichloroacetimidate
derivatives are trimethylsilyl trifluoromethanesulfonate
(TMSOTf)26 and boron trifluoride diethyl etherate
(BF3·OEt2).27 However, a number of Lewis acids and me-
tallic salts have also been used to active glycosyl trichlo-
roacetimidate derivatives, including Yb(OTf)3,28
Sm(OTf)3,29 ZnBr2,30 acyl sulfonamide,31 and dibutyl-
boron triflate.32 Glycosylations using glycosyl trichloro-
acetimidate derivatives have also been reported in ionic
liquids33,34 and ‘on-column’ solvent-free conditions.35 De-
spite their usefulness, most of the activators mentioned
above suffer from a number of shortcomings such as
moisture-sensitivity, corrosiveness, expense, longer reac-
tion time, or poor stereoselectivity in product formation.
Therefore, the development of mild non-metallic reaction
conditions for the activation of glycosyl trichloroacet-
imidate derivatives would be pertinent. In an ongoing pro-
gram on the synthesis of complex oligosaccharides we
needed to synthesize a number of oligosaccharide frag-
ments using glycosyl trichloroacetimidate derivatives.
We sought to explore the catalytic potential of the com-
mercially available nitrosyl tetrafluoroborate (NOBF4) as
a non-metallic organocatalyst in the activation of glycosyl
trichloroacetimidate derivatives. Previously, NOBF4 had
been used to activate thioglycosides on a few occasions.36
In this communication, we would like to disclose our find-
ings on the activation of glycosyl trichloroacetimidate do-
nors by NOBF4 for stereoselective glycosylations
(Scheme 1).
Key words: glycosylation, glycosides, stereoselective synthesis,
oligosaccharides, carbohydrates
During the past few decades developments in glycobiolo-
gy research has amplified the demand for well-defined
oligosaccharide motifs for various biological studies.1–3
Oligosaccharides are involved in a variety of beneficial
biological events such as fertilization,4 cell growth and
differentiation5 (e.g., during embryogenesis) and immune
responses.6 They are also associated with damaging dis-
ease processes such as inflammation,7 viral8 and bacterial9
infections, and cancer metastasis.10 Glycosides and oligo-
saccharides are important structural components of the
cell wall of various microbial organisms, for example,
bacteria,11 viruses,12 and protozoa.13 They are also impor-
tant constituents of many natural products of medicinal
importance.14,15 The efficacy of several antibiotics is
closely associated with the carbohydrate structures pres-
ent in them.16–18 Stereoselective glycosylation reactions
are fundamental processes for the attachment of monosac-
charide units in the synthesis of complex oligosaccha-
rides.19,20
In
general,
glycosylation
involves
stereoselective condensation of glycosyl donors with gly-
cosyl acceptors either in the presence or absence of a pro-
moter. Because of their importance in oligosaccharide
synthesis, several stereoselective glycosylation tech-
niques have been developed to prepare 1,2-trans and 1,2-
cis glycosides using a variety of glycosyl donors, for ex-
ample, glycosyl halides, thioglycosides, glycosyl trichlo-
roacetimidates, 4-pentenyl glycosides, and many
others.21–25 Consequently, several glycosyl promoters
have also been developed for the stereoselective activa-
tion of glycosyl donors. Among several glycosyl donors,
glycosyl trichloroacetimidate derivatives have several no-
table features including (a) their preparation in basic me-
dium; (b) moderate chemical stability; (c) their
Initially, in a model experiment, 2,3,4,6-tetra-O-acetyl-α-
D-glucopyranosyl trichloroacetimidate (1) was treated
with methanol in the presence of a stoichiometric amount
of NOBF4 in CH2Cl2 at variable temperatures ranging
from 0 to –40 °C. After a series of studies that investigated
the effect of changing the reaction temperature and the
amount of alcohol and catalyst used, it was observed that
use of 2.0 equivalents of methanol and 0.3 equivalents of
SYNLETT 2012, 23, 2341–2348
Advanced online publication: 24.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317135; Art ID: ST-2012-D0459-L
© Georg Thieme Verlag Stuttgart · New York

2342
A. Sau et al.
LETTER
R2OH
O
O
R1O
R1O
OR2
NOBF4, solvent, –15 °C
NH
O
R1O
O
HO
O
CCl3
OR3
O
NOBF4, solvent, –15 °C
O
OR3
Scheme 1 Activation of glycosyl trichloroacetimidate derivatives with NOBF4 for stereoselective glycosylations
NOBF4 could furnish methyl 2,3,4,6-tetra-O-acetyl-β-D- non-participating functionality at the C-2 position of the
glucopyranoside (30) in 82% yield at –15 °C in 20 min. donor furnished 1,2-cis products, with the exception of ni-
Reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl trile effect (Table 1, entry 10). The stereochemistry at the
trichloroacetimidate (2) instead of compound 1 with newly formed glycosyl bond was confirmed by the 1H and
methanol under similar reaction conditions also furnished 13C NMR spectra as well as 2D NMR spectra of the prod-
compound 30 in a similar yield. The reaction was carried ucts. In order to check the possibility of the formation of
out in a range of frequently used organic solvents such as a mixture of 1,2-cis and 1,2-trans products due to the pres-
CH2Cl2, toluene, MeCN, Et2O, and THF, and it was ob- ence of a non-participating group (e.g., benzyl, azido, and
served that use of CH2Cl2 gave the best result of glycosyl- 2,3-O-isopropylidene ketal) at the C-2 position of the gly-
1
ation in terms of yield and stereoselectivity at the cosyl donors, the H NMR spectra of the crude products
glycoside bond. To generalize the reaction conditions, a were recorded for compounds 37, 38, 41, and 44–47 (Ta-
series of aliphatic alcohols were treated with a diverse ble 1, entries 9, 10, 13, and 16–19). It was found that only
range of glycosyl trichloroacetimidate derivatives under compound 37 was formed together with its isomer
similar reaction conditions to furnish glycosylation prod- (α/β = 10:1; calculated from the integration values in the
ucts. Excellent yield of alkyl glycoside was obtained in 1H NMR spectrum); the rest of the products were formed
every case in 20–40 min. Furthermore, with the aim of as exclusively one isomer, perhaps due to the steric influ-
establishing the utility of the reaction conditions towards ence of the acceptor moieties and to solvent effects. The
the synthesis of disaccharide intermediates of oligosac- reaction conditions were also used in orthogonal glycosyl-
charide synthesis, a diverse range of glycosyl trichloro- ations using thioglycoside acceptors to prepare disaccha-
acetimidate derivatives were allowed to react with a ride thioglycoside derivatives (Table 1, entries 17, 18, and
variety of glycosyl acceptors (0.9 equiv) in the presence of 19). Scaled up preparations of monosaccharide derivative
NOBF4 (0.3 equiv). To our satisfaction, disaccharide de- 34 and disaccharide derivative 39 have also been carried
rivatives were formed in excellent yield with excellent out (10 mmol scale) using similar reaction conditions, and
stereoselectivity at the glycoside bond. The findings of the the yields obtained were quite similar to those of the
reaction of a wide range of donors with acceptors (alco- small-scale preparations (Table 1, entries 6 and 11). It is
hols and glycosyl acceptors) are presented in Table 1. To worth mentioning that the stereochemical outcome of the
achieve a better 1,2-cis stereo-outcome of the glycosyl- glycosylation is independent of the anomeric stereochem-
ation, a slight modification was made to the reaction con- istry of trichloroacetimidate derivatives, and excellent
ditions by replacing CH2Cl2 with a mixture of CH2Cl2– yields and stereoselectivity in product formation was ob-
Et2O (1:1) as the reaction solvent using glycosyl trichlo- served using relatively less reactive glycosyl acceptors
roacetimidate derivatives 7, 10 and 13–16, since it is well- (Table 1; entries 13, 14, 15, and 16). It is presumed that
documented that the use of ether as solvent improves the NOBF4 releases NO+, which activates the glycosyl tri-
formation of 1,2-cis glycoside using glycosyl donors with chloroacetimidate derivative to give a glycosyl oxocarbo-
a non-participating group at the C-2 position (Table 1; en- nium intermediate, which couples with the alcohol or
tries 9, 13 and 16–19). The reaction is equally effective glycosyl acceptor to furnish the expected glycoside deriv-
with α- and β-trichloroacetimidate derivatives. A wide ative.
range of functional groups [e.g., p-methoxybenzyl
(PMB), p-methoxyphenyl (PMP), tert-butyldiphenylsilyl
(TBDPS), benzylidene, isopropylidene, allyl, benzyl, azi-
do, and N-phthalimido etc.] used in the protecting group
In summary, efficient reaction conditions have been de-
veloped for the stereoselective activation of glycosyl tri-
chloroacetimidate derivatives by nitrosyl tetra-
fluoroborate for the synthesis of alkyl glycosides and di-
manipulations of carbohydrate derivatives remained unaf-
saccharide derivatives.46 The reaction conditions are high-
fected under the reaction conditions. As an extension, us-
ly effective in the glycosylation of less reactive acceptors
ing similar reaction conditions, excellent yield of the
and orthogonal glycosylations. The reaction has several
notable features such as operational simplicity, high stere-
1,2-trans glycoside of 2-deoxy-2-azido-galactosamine
derivatives was also obtained by changing the solvent
oselectivity, high yields, and is reasonably rapid, suitable
from CH2Cl2 to MeCN, exploiting the nitrile effect in the
for orthogonal glycosylations, does not require any extra
glycosylation, which has been discussed in detail by
additives and does not generate metallic byproducts. The
Schmidt et al.37 (Table 1, entry 10). In general, the use of
reaction conditions may therefore be considered as a prac-
neighboring group participating groups at the C-2 position
tical alternative to existing protocols for the activation of
of the glycosyl trichloroacetimidate derivative led to the
glycosyl trichloroacetimidate derivatives in multistep oli-
formation of 1,2-trans glycosides, and the presence of a
gosaccharide synthesis.
Synlett 2012, 23, 2341–2348
© Georg Thieme Verlag Stuttgart · New York

LETTER
Glycosylation of Glycosyl Trichloroacetimidate Derivatives
2343
Table 1 Stereoselective Glycosylation of Glycosyl Trichloroacetimidate Donors Promoted by NOBF4 in CH2Cl2 at –15 °C
Entry Donor
Acceptor
Product
Time Yield Ref
(min) (%)a
OAc
O
OAc
O
AcO
AcO
AcO
NH
AcO
38
OMe
1
MeOH (18)
20
82
AcO
OAc
O
CCl3
30
30
1
OAc
O
18
NH
AcO
O
38
CCl3
AcO
2
20
25
25
20
80
78
75
82
OAc
2
OAc
O
AcO
AcO
O
O
39
3
4
5
1
1
HO(CH2)2N3 (19)
HO(CH2)2OPMP (20)
C8H17OH (21)
OAc
N3
31
OAc
O
AcO
AcO
40
OAc
OPMP
32
AcO
AcO
AcO
OAc
OAc
NH
O
O
41
OC8H17
O
AcO
AcO
CCl3
OAc
OAc
3
33
OAc
O
OAc
O
AcO
AcO
AcO
NH
AcO
AcO
20
80
6
7
8
20
–
25b
78b
OPMP
O
O
CCl3
34
4
5
OAc
OAc
NH
O
O
AcO
AcO
AcO
AcO
O
O
42
CCl3
H2C=CHCH2OH (22)
25
20
78
80
NPhth
NPhth
35
CCl3
NH
O
O
OPMP
O
O
AcO
AcO
20
–
–
–
AcO
AcO
OAc
OAc
36
6
OBn
OBn
O
AcO
AllO
O
AcO
84c
(α/β,
10:1)
NH
AllO
9
18
20
35
BnO
BnO
O
CCl3
OMe
37
7
AcO
OAc
AcO
OAc
O
O
AcO
OC6H12Br
NH
CCl3
AcO
10
HO(CH2)6Br (23)
70d
N3
N3
O
38
8
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2341–2348

2344
A. Sau et al.
LETTER
Table 1 Stereoselective Glycosylation of Glycosyl Trichloroacetimidate Donors Promoted by NOBF4 in CH2Cl2 at –15 °C (continued)
Entry Donor
Acceptor
Product
Time Yield Ref
(min) (%)a
O
OH
O
O
O
O
O
O
AcO
30
78
O
43
AcO
11
12
13
6
35b
75b
OAc
O
O
O
O
24
39
OBn
O
BnO
OBn
O
O
BnO
AcO
BnO
BnO
O
NH
44
O
24
30
77
AcO
O
O
CCl3
O
O
9
40
Ph
Ph
AcO
OBn
AcO
OBn
O
O
O
O
O
O
BnO
NH
BnO
72c
–
O
O
BnO
40
BnO
HO
O
OPMP
OPMP
O
CCl3
NPhth
NPhth
10
41
25
OTBDPS
O
HO
BzO
OBn
O
OTBDPS
O
NH
O
BzO
OBn
O
BzO
OBz
O
OPMP
BnO
CCl3
BzO
14
15
40
40
74
76
–
–
OBz
OBn
OPMP
BnO
OBn
11
26
42
Ph
Ph
O
O
Ph
O
BzO
NH
O
O
O
O
HO
O
OBz
O
O
BzO
O
O
O
BzO
CCl3
N3
N3
O
OPMP
OPMP
Ph
12
27
27
43
Ph
O
CCl3
NH
O
O
O
O
O
N3
BnO
O
OPMP
16
17
30
30
78c
–
–
O
BnO
O
O
O
13
44
Ph
OAc
O
O
CCl3
NH
Ph
O
O
O
OAc
O
O
O
O
HO
BnO
77c
SEt
O
BnO
BnO
SEt
OBn
BnO
OBn
28
14
45
Synlett 2012, 23, 2341–2348
© Georg Thieme Verlag Stuttgart · New York

LETTER
Glycosylation of Glycosyl Trichloroacetimidate Derivatives
2345
Table 1 Stereoselective Glycosylation of Glycosyl Trichloroacetimidate Donors Promoted by NOBF4 in CH2Cl2 at –15 °C (continued)
Entry Donor
Acceptor
Product
Time Yield Ref
(min) (%)a
–
OBn
O
OBn
O
BnO
BnO
BnO
SEt
NH
BnO
BnO
18
28
30
30
76c
O
BnO
O
O
CCl3
O
OAc
O
Ph
15
46
Ph
45
OAc
O
O
O
O
CCl3
O
NH
O
OBn
75c
SEt
O
19
28
OBn
OBn
BnO
OBn
BnO
16
47
OAc
O
PMBO
AcO
–
Ph
O
OH
O
OAc
O
PMBO
AcO
AcO
Ph
O
BnO
O
NH
AcO
O
20
40
78
O
O
BnO
O
O
CCl3
OPMP
OPMP
O
17
29
48
a Isolated yield.
b 10 mmol scale; PMP: p-methoxyphenyl; Phth: phthalimido; PMB: p-methoxybenzyl; All: allyl.
c Reaction carried out in CH2Cl2–Et2O (1:1).
d Reaction carried out in MeCN.
(9) Varki, A. Glycobiology 1993, 3, 97.
Acknowledgment
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A.S. and A.S. thank CSIR, New Delhi for providing Senior Re-
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LETTER
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2.08, 2.03, 1.98 (4 s, 12 H, 4 COCH3). 13C NMR (CDCl3,
125 MHz): δ = 171.1, 170.4, 170.2, 170.1 (4 COCH3),
154.5–115.1 (Ar-C), 98.1 (C-1), 69.9 (C-3), 69.4 (C-2), 68.9
(C-4), 67.8 (C-5), 67.3 (-CH2-), 66.5 (-CH2-), 62.8 (C-6),
56.1 (OCH3). MS (ESI): m/z = 521.1 [M + Na]+. Anal. Calcd
for C23H30O12 (498.17): C, 55.42; H, 6.07. Found: C, 55.25;
H, 6.30
2-(p-Methoxyphenoxy)ethyl 2,3,4-tri-O-acetyl-α-L-
rhamnopyranoside (36): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 6.86–6.82 (m, 4 H, Ar-H), 5.31–5.27 (m, 2 H,
H-2, H-3), 5.06 (t, J = 9.8 Hz each, 1 H, H-4), 4.83 (d,
J = 1.5 Hz, 1 H, H-1), 4.11–4.09 (m, 2 H, -OCH2-), 3.99–
3.93 (m, 1 H, -OCH2b-), 3.76 (s, 3 H, OCH3), 2.15, 2.04, 1.98
(3 s, 9 H, 3 COCH3), 1.21 (d, J = 6.3 Hz, 3 H, CCH3).
13C NMR (CDCl3, 125 MHz): δ = 170.5, 170.4, 170.3 (3
COCH3), 154.5–115.1 (Ar-C), 98.0 (C-1), 71.5 (C-3), 70.2
(C-2), 69.5 (C-4), 67.9 (C-5), 66.9 (CH2), 66.8 (CH2), 56.1
(OCH3), 21.3, 21.2, 21.1 (3 COCH3), 17.7 (CCH3). MS
(ESI): m/z = 463.1 [M + Na]+. Anal. Calcd for C21H28O10
(440.16): C, 57.27; H, 6.41. Found: C, 57.10; H, 6.60.
Methyl 4-O-Acetyl-3-O-allyl-2,6-di-O-benzyl-α-D-
glucopyranoside (37): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 7.32–7.23 (m, 10 H, Ar-H), 5.88–5.80 (m,
1 H, CH2=CH), 4.92 (t, J = 9.6 Hz each, 1 H, H-4), 4.77 (d,
J = 12.0 Hz, 1 H, PhCH2), 4.62 (d, J = 12.0 Hz, 1 H,
PhCH2), 4.56 (d, J = 3.5 Hz, 1 H, H-1), 4.48 (s, 3 H, OCH3),
4.33–4.29 (m, 1 H, H-6a), 4.11–4.07 (m, 1 H, H-6b), 3.78–
3.76 (m, 1 H, H-5), 3.75 (t, J = 9.5 Hz each, 1 H, H-3), 3.39–
3.42 (m, 3 H, H-2, OCH2-CH=CH2), 3.37 (s, 3 H, OCH3),
1.95 (s, 3 H, COCH3). 13C NMR (CDCl3, 125 MHz): δ =
169.7 (COCH3), 138.4–116.8 (Ar-C), 98.6 (C-1), 79.7 (C-5),
79.3 (C-3), 74.4 (PhCH2), 73.9 (PhCH2), 73.8 (C-5), 69.5
(OCH2-), 69.1 (C-6), 55.6 (OCH3), 21.2 (CHCH3). MS
(ESI): m/z = 479.2 [M + Na]+. Anal. Calcd for C26H32O7
(456.21): C, 68.40; H, 7.07. Found: C, 68.22; H, 7.28.
6-Bromohexyl 3,4,6-Tri-O-acetyl-2-azido-2-deoxy-β-D-
galactopyranoside (38): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 5.32 (d, J = 2.5 Hz, 1 H, H-4), 4.77 (dd,
J = 10.0, 3.0 Hz, 1 H, H-3), 4.36 (d, J = 8.0 Hz, 1 H, H-1),
4.19–4.09 (m, 2 H, H-6ab), 3.98–3.94 (m, 1 H, -OCH2-),
3.85–3.82 (m, 1 H, H-5), 3.37 (dd, J = 8.0 Hz each, 1 H, H-
2), 3.60–3.55 (m, 1 H, -OCH2-), 3.42–3.40 (m, 2 H, -CH2-),
2.15, 2.05, 2.04 (3 s, 9 H, COCH3), 1.89–1.85 (m, 2 H, CH2-),
(34) Pakulski, Z. Synthesis 2003, 2074.
(35) Mukhopadhyay, B.; Maurer, S. V.; Rudolph, N.; van Well,
R. M.; Russell, D. A.; Field, R. A. J. Org. Chem. 2005, 70,
9059.
(36) Pozsgay, V.; Jennings, H. J. J. Org. Chem. 1987, 52, 4635.
(37) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694.
(38) Li, X.; Huang, L.; Hu, X.; Huang, X. Org. Biomol. Chem.
2009, 7, 117.
(39) Cheng, H.; Cao, X.; Xian, M.; Fang, L.; Cai, T. B.; Ji, J. J.;
Tunac, J. B.; Sun, D.; Wang, P. G. J. Med. Chem. 2005, 48,
645.
(40) Ghosh, S.; Misra, A. K. Tetrahedron: Asymmetry 2009, 20,
2688.
(41) Li, X.-B.; Ogawa, M.; Monden, T.; Maeda, T.; Yamashita,
E.; Naka, M.; Matsuda, M.; Hinou, H.; Nishimura, S.-I.
Angew. Chem. Int. Ed. 2006, 45, 5652.
(42) Fairweather, J. K.; Stick, R. V.; Tilbrook, D. M. G. Aust. J.
Chem. 1998, 51, 471.
(43) Mukherjee, C.; Misra, A. K. Synthesis 2007, 683.
(44) Kaji, E.; Hosokawa, Y.; Watanabe, Y.; Kobayashi, M.;
Yamakawa, M. Heterocycles 2003, 61, 459.
(45) Guchhait, G.; Misra, A. K. Glycoconjugate J. 2011, 28, 11.
(46) General Procedure: A solution of glycosyl
trichloroacetimidate derivative (1.0 mmol) and alcohol (2.0
mmol) or glycosyl acceptor (0.9 mmol) in anhydrous CH2Cl2
or CH2Cl2–Et2O (1:1) or MeCN (5 mL) was cooled to –15 °C
under argon. To the cooled reaction mixture was added
NOBF4 (35.0 mg, 0.3 mmol) and the reaction was stirred at
the same temperature for the appropriate time (Table 1). The
reaction mixture was diluted with CH2Cl2 and the organic
layer was successively washed with sat. NaHCO3 and water,
dried (Na2SO4), and concentrated. The crude product was
purified over SiO2 (hexane–EtOAc) to give pure glycoside
derivatives 30–48. All known compounds gave NMR
spectra that matched the data reported in the cited references.
Spectral data for those products that have not been
previously reported are as follows:
1.70–1.65 (m, 2 H, -CH2-), 1.49–1.40 (m, 4 H, -CH2). 13
NMR (CDCl3, 125 MHz): δ = 170.4, 170.1, 169.8 (3
C
COCH3), 102.4 (C-1), 70.9 (C-3), 70.6 (C-5), 70.5 (C-4),
66.3 (OCH2), 61.2 (C-6), 60.9 (C-2), 33.8 (CH2), 32.6 (CH2),
29.3 (CH2), 27.8 (CH2), 25.1 (CH2), 20.7, 20.6, 20.6 (3
COCH3). MS (ESI): m/z = 516.1 [M + Na]+. Anal. Calcd for
C18H28BrN3O8 (493.10): C, 43.73; H, 5.71. Found: C, 43.57;
H, 5.90.
p-Methoxyphenyl (4-O-Acetyl-2,3,6-tri-O-benzyl-α-D-
galactopyranosyl)-(1→3)-4,6-O-benzylidene-2-deoxy-2-
N-phthalimido-β-D-galactopyranoside (41): Colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 7.68–7.10 (m, 24 H, Ar-H),
6.78 (d, J = 9.0 Hz, 2 H, Ar-H), 6.62 (d, J = 9.0 Hz, 2 H, Ar-
H), 5.56 (d, J = 8.5 Hz, 1 H, H-1A), 5.32 (d, J = 2.4 Hz, H-
4B), 5.15 (s, 1 H, PhCH), 4.92 (d, J = 3.4 Hz, 1 H, H-1B),
4.85 (dd, J = 8.5, 8.5 Hz, 1 H, H-2A), 4.63 (d, J = 11.1 Hz,
1 H, PhCH2), 4.55 (dd, J = 10.5, 3.0 Hz, 1 H, H-3A), 4.50 (d,
J = 11.1 Hz, 1 H, PhCH2), 4.43 (d, J = 11.1 Hz, 1 H,
PhCH2), 4.28 (d, J = 11.1 Hz, 1 H, PhCH2), 4.19–4.17 (m,
3 H, H-6abA, PhCH2), 4.13 (d, J = 11.0 Hz, 1 H, PhCH2),
3.78–3.74 (m, 2 H, H-5A, H-5B), 3.71–3.68 (dd, J = 10.0,
3.1 Hz, 1 H, H-2B), 3.62 (s, 3 H, OCH3), 3.61–3.59 (dd,
J = 10.0, 3.0 Hz, 1 H, H-3B), 3.33 (br s, 1 H, H-4A), 2.95 (t,
J = 8.8 Hz each, 1 H, H-6aB), 2.72–2.69 (m, 1 H, H-6bB),
2-(p-Methoxyphenoxy)ethyl 2,3,4,6-Tetra-O-acetyl-α-D-
mannopyranoside (34): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 6.86–6.82 (m, 4 H, Ar-H), 5.35 (dd, J = 9.9,
3.4 Hz, 1 H, H-3), 5.30–5.26 (m, 2 H, H-2, H-4), 4.91 (d,
J = 1.5 Hz, 1 H, H-1), 4.28–4.25 (m, 1 H, H-5), 4.14–4.06
(m, 4 H, H-6ab, -OCH2ab-), 4.01–3.96 (m, 1 H, -OCH2a-),
3.88–3.84 (m, 1 H, -OCH2b-), 3.76 (s, 3 H, OCH3), 2.16,
Synlett 2012, 23, 2341–2348
© Georg Thieme Verlag Stuttgart · New York

LETTER
Glycosylation of Glycosyl Trichloroacetimidate Derivatives
2347
1.86 (s, 3 H, COCH3). 13C NMR (CDCl3, 125 MHz): δ =
(PhCH), 98.0 (C-1A), 97.6 (C-1B), 81.1 (C-3B), 80.2 (C-4A),
78.4 (C-2B), 75.9 (C-3A), 73.1 (C-4B), 72.9 (PhCH2), 68.7
(C-6A), 65.1 (C-5A), 64.2 (C-5B), 63.6 (C-2A), 55.7 (OCH3),
28.0 (CH3), 26.4 (CH3), 17.1 (CH3). MS (ESI): m/z = 698.2
[M + Na]+. Anal. Calcd for C36H41N3O10 (675.27): C, 63.99;
H, 6.12. Found: C, 63.82; H, 6.35.
170.2 (COCH3), 169.4, 167.6 (PhthCO), 155.9–114.7 (Ar-
C), 101.1 (PhCH), 99.1 (C-1A), 98.6 (C-1B), 76.4 (C-3B),
75.7 (C-2B), 75.4 (C-3A), 73.6 (PhCH2), 73.5 (PhCH2), 73.4
(2 C, C-4A, PhCH2), 72.2 (C-5B), 69.4 (C-4B), 68.8 (C-2A),
67.8 (C-6B), 67.3 (C-6A), 55.8 (OCH3), 52.7 (C-2A), 21.2
(COCH3). MS (ESI): m/z = 1000.3 [M +mNa]+. Anal. Calcd
for C57H55NO14 (977.36): C, 70.00; H, 5.67. Found: C,
69.83; H, 5.90.
Ethyl (2,3,4-Tri-O-benzyl-α-L-rhamnopyranosyl)-
(1→3)-2-O-acetyl-4,6-O-benzylidene-1-thio-α-D-
mannopyranoside (45): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 7.46–7.16 (m, 20 H, Ar-H), 5.56 (s, 1 H,
PhCH), 5.42 (d, J = 2.5 Hz, 1 H, H-2A), 5.24 (br s, 1 H,
H-1A), 4.93 (br s, 1 H, H-1B), 4.88 (d, J = 9.5 Hz, 1 H,
PhCH2), 4.73 (d, J = 10.0 Hz, 1 H, PhCH2), 4.67 (d,
J = 9.5 Hz, 1 H, PhCH2), 4.58 (d, J = 9.5 Hz, 1 H, PhCH2),
4.52 (d, J = 10.5 Hz, 1 H, PhCH2), 4.47 (d, J = 10.5 Hz, 1 H,
PhCH2), 4.29–4.22 (m, 2 H, H-5A, H-6aA), 4.19 (dd, J = 8.5,
3.0 Hz, 1 H, H-3A), 4.04–4.0 (m, 1 H, H-5B), 3.87 (t,
J = 8.0 Hz each, 1 H, H-4A), 3.85–3.81 (m, 1 H, H-6bA), 3.78
(dd, J = 8.5, 3.0 Hz, 1 H, H-3B), 3.61 (br s, 1 H, H-2B), 3.55
(t, J = 8.0 Hz each, 1 H, H-4B), 2.66–2.56 (m, 2 H,
p-Methoxyphenyl (2,3,4-Tri-O-benzoyl-6-O-tert-
butyldiphenylsilyl-β-D-glucopyranosyl)-(1→4)-2,3,6-tri-
O-benzyl-β-D-galactopyranoside (42): Colorless oil. 1H
NMR (CDCl3, 500 MHz): δ = 8.0–7.11 (m, 40 H, Ar-H),
6.94 (d, J = 9.0 Hz, 2 H, Ar-H), 6.71 (d, J = 9.0 Hz, 2 H, Ar-
H), 5.80 (t, J = 9.6 Hz each, 1 H, H-3B), 5.63 (t, J = 9.7 Hz
each, 1 H, H-4B), 5.52 (dd, J = 8.0, 8.0 Hz each, 1 H, H-2B),
5.23 (d, J = 8.0 Hz, 1 H, H-1B), 4.69 (d, J = 7.6 Hz, 1 H, H-
1A), 4.67 (d, J = 12.0 Hz, 1 H, PhCH2), 4.63 (d, J = 12.0 Hz,
1 H, PhCH2), 4.46 (d, J = 10.8 Hz, 2 H, PhCH2), 4.36 (d,
J = 11.5 Hz, 1 H, PhCH2), 4.05 (d, J = 2.3 Hz, 1 H, H-4A),
3.88–3.83 (m, 5 H, H-6abA,H-6abB, PhCH2), 3.76–3.74 (m,
1 H, H-5B), 3.73 (s, 3 H, OCH3), 3.64–3.61 (m, 1 H, H-5A),
3.55 (dd, J = 7.7, 7.7 Hz, 1 H, H-2A), 3.46 (dd, J = 10.0 Hz,
3.0 Hz, 1 H, H-3A), 1.03 (br s, 9 H, C(CH3)3). 13C NMR
(CDCl3, 125 MHz): δ = 166.2, 165.3, 165.2 (3 PhCO),
155.5–114.8 (Ar-C), 103.2 (C-1B), 101.6 (C-1A), 81.7 (C-
3A), 79.8 (C-2A), 75.5 (PhCH2), 75.3 (PhCH2), 74.9
SCH2CH3), 2.07 (s, 3 H, COCH3), 1.28 (t, J = 7.4 Hz each,
3 H, SCH2CH3), 1.14 (d, J = 6.0 Hz, 1 H, CCH3). 13C NMR
(CDCl3, 125 MHz): δ = 169.7 (COCH3), 139.0–125.9 (Ar-
C), 101.3 (PhCH), 94.8 (C-1B), 83.2 (C-1A), 80.4 (C-4B),
79.3 (C-3B), 76.8 (C-4A), 74.7 (PhCH2), 74.6 (C-2B), 72.3
(PhCH2), 71.6 (PhCH2), 70.3 (C-2A), 70.2 (C-3A), 68.4 (C-
6A), 67.8 (C-5B), 64.4 (C-5A), 25.3 (SCH2CH3), 20.8
(COCH3), 17.6 (CCH3), 14.7 (SCH2CH3). MS (ESI): m/z =
793.3 [M + Na]+. Anal. Calcd for C44H50O10S (770.31): C,
68.55; H, 6.54. Found: C, 68.40; H, 6.38.
(PhCH2), 74.7 (C-3B), 71.1 (C-4B), 73.9 (C-2B), 73.8 (C-4A),
72.7 (C-5B), 71.0 (C-5A), 69.9 (C-6B), 63.3 (C-6A), 55.9
(OCH3), 27.1 (3 C, C(CH3)3), 19.5 (C(CH3)3). MS (ESI): m/z
= 1291.5 [M + Na]+. Anal. Calcd for C77H76O15Si (1268.49):
C, 72.85; H, 6.03. Found: C, 72.68; H, 6.25.
Ethyl (2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl)-
(1→3)-2-O-acetyl-4,6-O-benzylidene-1-thio-α-D-
p-Methoxyphenyl (2,3-Di-O-benzoyl-4,6-O-benzylidene-
β-D-glucopyranosyl)-(1→3)-2-azido-4,6-O-benzylidene-
2-deoxy-α-D-glucopyranoside (43): Colorless oil. 1H NMR
(CDCl3, 500 MHz): δ = 7.94–7.21 (m, 20 H, Ar-H), 6.84 (d,
J = 9.0 Hz, 2 H, Ar-H), 6.71 (d, J = 9.0 Hz, 2 H, Ar-H), 5.68
(t, J = 9.5 Hz each, 1 H, H-3B), 5.52 (s, 1 H, PhCH), 5.49
(dd, J = 7.5, 7.5 Hz, 1 H, H-2B), 5.34 (s, 1 H, PhCH), 5.28
(d, J = 3.5 Hz, 1 H, H-1A), 5.03 (d, J = 7.5 Hz, 1 H, H-1B),
4.31 (t, J = 9.5 Hz each, 1 H, H-4B), 4.17–4.12 (m, 2 H, H-
6abB), 3.98–3.95 (m, 1 H, H-5B), 3.87 (t, J = 9.5 Hz each,
1 H, H-3A), 3.71–3.69 (m, 1 H, H-6aA), 3.68 (s, 3 H, OCH3),
3.66–3.62 (m, 2 H, H-4A, H-6bA), 3.59–3.55 (m, 1 H, H-5A),
3.24 (dd, J = 10.0, 10.0 Hz, 1 H, H-2A). 13C NMR (CDCl3,
125 MHz): δ = 165.5, 165.3 (2 PhCO), 155.6–114.7 (Ar-C),
102.2 (C-1B), 101.5 (PhCH), 101.4 (PhCH), 98.2 (C-1A),
80.1 (C-3B), 78.5 (C-2B), 76.7 (C-3A), 72.8 (C-4A), 72.2 (C-
4B), 68.7 (C-5B), 68.6 (C-5A), 66.5 (C-6B), 63.5 (C-6A), 62.6
(C-2A), 55.6 (OCH3). MS (ESI): m/z = 880.2 [M + Na]+.
Anal. Calcd for C47H43N3O13 (857.27): C, 65.80; H, 5.05.
Found: C, 65.59; H, 5.25.
p-Methoxyphenyl (4-O-Benzyl-2,3-O-isopropylidene-α-
L-rhamnopyranosyl)-(1→3)-2-azido-4,6-O-benzylidene-
2-deoxy-α-D-glucopyranoside (44): Colorless oil. 1H NMR
(CDCl3, 500 MHz): δ = 7.37–7.17 (m, 10 H, Ar-H), 6.94 (d,
J = 9.0 Hz, 2 H, Ar-H), 6.77 (d, J = 9.0 Hz, 2 H, Ar-H), 5.42
(s, 1 H, PhCH), 5.40 (d, J = 3.5 Hz, 1 H, H-1A), 5.23 (br s,
1 H, H-1B), 4.76 (d, J = 11.5 Hz, 1 H, PhCH2), 4.48 (d,
J = 11.5 Hz, 1 H, PhCH2), 4.32 (t, J = 9.5 Hz each, 1 H, H-
3A), 4.18–4.14 (m, 3 H, H-2B, H-6abA), 4.03–3.98 (m, 1 H, H-
5A), 3.85–3.80 (m, 1 H, H-5B), 3.70 (s, 3 H, OCH3), 3.64 (t,
J = 10.0 Hz each, 1 H, H-4B), 3.51 (t, J = 9.5 Hz each, 1 H,
H-4A), 3.37 (dd, J = 10.0, 3.5 Hz, 1 H, H-2A), 3.04 (dd,
J = 10.0, 6.0 Hz, 1 H, H-3B), 1.42, 1.33 (2 s, 6 H, 2 CH3),
0.68 (d, J = 6.0 Hz, 3 H, CCH3). 13C NMR (CDCl3, 125
MHz): δ = 155.6–114.8 (Ar-C), 109.2 (C(CH3)2), 102.3
mannopyranoside (46): Colorless oil. 1H NMR (CDCl3,
500 MHz): δ = 7.40–6.92 (m, 25 H, Ar-H), 5.48 (s, 1 H,
PhCH), 5.31 (d, J = 3.5 Hz, 1 H, H-1B), 5.30 (br s, 1 H, H-
2A), 5.24 (br s, 1 H, H-1A), 4.91–4.42 (7 d, J = 11.0 each,
7 H, PhCH2), 4.32–4.26 (m, 3 H, H-2B, PhCH2), 4.22–4.16
(m, 2 H, H-5A, H-6aB), 3.83 (t, J = 10.0 Hz each, 1 H, H-4A),
3.80 (t, J = 9.5 Hz each, 1 H, H-3B), 3.78–3.74 (m, 1 H, H-
6bB), 3.70–3.62 (m, 2 H, H-6abA), 3.55 (t, J = 9.5 each, 1 H,
H-4B), 3.44 (dd, J = 10.0, 3.5 Hz, 1 H, H-3A), 2.70–2.58 (m,
2 H, SCH2CH3), 2.18 (s, 3 H, COCH3), 1.29 (t, J = 7.4 Hz
each, 3 H, SCH2CH3). 13C NMR (CDCl3, 125 MHz): δ =
170.0 (COCH3), 138.9–126.4 (Ar-C), 102.4 (PhCH), 97.5
(C-1B), 83.5 (C-1A), 81.1 (C-3B), 79.3 (C-5A), 78.7 (C-3A),
77.4 (C-4B), 75.4 (PhCH2), 74.7 (PhCH2), 73.7 (PhCH2),
73.4 (C-2B), 71.6 (PhCH2), 71.6 (2 C, C-2A, C-4A), 68.6
(C-6A), 68.4 (C-6B), 64.5 (C-5B), 25.5 (SCH2CH3), 21.1
(COCH3), 14.9 (SCH2CH3). MS (ESI): m/z = 899.3 [M +
Na]+. Anal. Calcd for C51H56O11S (876.35): C, 69.84; H,
6.44. Found: C, 69.68; H, 6.68.
2-(p-Methoxyphenoxy)ethyl [2,3,4-Tri-O-acetyl-6-O-(p-
methoxybenzyl)-α-D-mannopyranosyl]-(1→2)-3-O-
benzyl-4,6-O-benzylidene-α-D-mannopyranoside (48):
Colorless oil. 1H NMR (CDCl3, 500 MHz): δ = 7.50–6.81
(m, 18 H, Ar-H), 5.67 (s, 1 H, PhCH), 5.44–5.43 (m, 1 H, H-
2B), 5.37 (dd, J = 9.9, 3.5 Hz, 1 H, H-3B), 5.24 (t,
J = 10.0 Hz each, 1 H, H-4B), 5.07 (br s, 1 H, H-1B), 4.95 (br
s, 1 H, H-1A), 4.82 (d, J = 12.1 Hz, 1 H, PhCH2), 4.60 (d,
J = 12.1 Hz, 1 H, PhCH2), 4.49, 4.39 (2 d, J = 12.0 Hz each,
2 H, PhCH2), 4.24–4.20 (m, 1 H, H-5A), 4.12 (t, J = 9.9 Hz
each, 1 H, H-4A), 4.07 (br s, 1 H, H-2A), 4.06–4.02 (m, 1 H,
OCH2), 4.0–3.93 (m, 3 H, H-5B, H-6abA), 3.89–3.86 (m, 2 H,
H-6abB), 3.85–3.77 (m, 1 H, OCH2), 3.75, 3.74 (2 s, 6 H, 2
OCH3), 3.56–3.52 (m, 2 H, OCH2), 3.48 (dd, J = 10.0,
3.0 Hz, 1 H, H-3A), 2.09, 1.99, 1.94 (3 s, 9 H, 3 COCH3). 13
NMR (CDCl3, 125 MHz): δ = 170.4, 170.2, 170.1 (3
C
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2341–2348

2348
A. Sau et al.
LETTER
COCH3), 151.6–114.1 (Ar-C), 101.9 (PhCH), 100.1 (2 C,
C-1A, C-1B), 79.4 (C-4A), 77.4 (C-4A), 76.1 (C-4B), 73.6
(PhCH2), 73.5 (MPhCH2), 70.6 (C-3B), 69.8 (OCH2), 69.7
(OCH2), 69.1 (2 C, C-5A, C-2B), 68.0 (C-5B), 67.3 (C-2A),
66.5 (C-6B), 64.4 (C-6A), 56.1 (OCH3), 55.6 (OCH3), 21.3 (2
C), 21.1 (3 COCH3). MS (ESI): m/z = 939.3 [M + Na]+. Anal.
Calcd for C49H56O17 (916.35): C, 64.18; H, 6.16. Found: C,
64.0; H, 6.38.
Synlett 2012, 23, 2341–2348
© Georg Thieme Verlag Stuttgart · New York