Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac-α-2,3-LacNPhth Trisaccharide

Article abstract of DOI:10.1002/asia.201801486

A concise approach to a Neu5Ac-α-2,3-LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2-NPhth group and the C6-OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated-α-galactopyranosyl trichloroacetimidate and p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2-phthalimido-β-d-glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac-α-2,3-LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d-glucosamine hydrochloride, the target Neu5Ac-α-2,3-LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.

Full text of DOI:10.1002/asia.201801486

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors
in Efficient Synthesis of Neu5Ac-α-2,3-LacNPhth Trisaccharide
Authors: Hai Dong, Ying Zhang, Fu-Long Zhao, Tao Luo, and Zhichao
Pei
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10.1002/asia.201801486
Chemistry - An Asian Journal
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Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors
in Efficient Synthesis of Neu5Ac-α-2,3-LacNPhth Trisaccharide
Ying Zhang,[a] Fu-Long Zhao,[a] Tao Luo,[a] Zhichao Pei*,[b] and Hai Dong*[a]
Abstract:
trisaccharide
A
concise approach to Neu5Ac-α-2,3-LacNPhth
derivative was developed. Firstly, the
against influenza. Several methods to synthesize the target
trisaccharide analogues (Neu5Ac-α-2,3-LacNAc derivatives)
have been developed, which have included enzymatic methods5
as well as chemical methods.6,7 Enzymatic methods have the
commonly known limitations in that enzymes are usually fragile
and expensive. The reported chemical methods usually have two
strategies. One strategy is to use a one-pot glycosylation of
sialylated disaccharide derivatives.6 The other strategy is to use
the direct sialylation of the lactosamine disaccharide derivatives
(Scheme 1a),7 where the preparation of lactosamine disaccharide
acceptors from glucosamine or lactose usually needs multi-steps
(11-13 steps) of protection, deprotection and modification, with
extremely low total yields (5.5-17.3%). Consequently, the
Neu5Ac-α-2,3-LacNPhth derivatives were only obtained in only 4-
8% total yields.
regio/stereoselective glycosylation between glycoside donors and
glucoNPhth diol acceptors was investigated. It was found that the
regioselectivity depends not only on the steric hindrance of the C2-
NPhth group and the C6-OH protecting group of the glucosamine
acceptors, but also on the leaving group and protecting group of the
glycoside donors. Under optimized conditions, LacNPhth derivatives
were synthesized up to a 92% yield through the regio/stereoselective
glycosylation
between
peracetylated-α-galactopyranosyl
trichloroacetimidate and p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-
2-deoxy-2-phthalimido-β-D-glucopyranoside, avoiding the formation
of glycosylated orthoesters and anomeric aglycon transfer. Secondly,
the LacNPhth derivative was deacylated and then protected on the
primary position by TBDPS to form a LacNPhth polyol acceptor.
Finally, the Neu5Ac-α-2,3-LacNPhth derivative was synthesized in a
48% yield through the regio/stereoselective glycosylation between the
LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from
D-glucosamine hydrochloride, the Neu5Ac-α-2,3-LacNPhth derivative
was synthesized in a total yield of 18.5% using only 10 steps.
Figure 1. Structure of the Neu5Ac-α-2,3 LacNAc (3'SLN)
Introduction
In the present study, we developed an efficient approach to
synthesize a Neu5Ac-α-2,3-LacNPhth derivative 3 resulting in a
total yield of 18.5% over only 10 steps starting from glucosamine
hydrochloride (Scheme 1b). The key to the synthesis of this
diasaccharide 3 is the highly efficient preparation of lactosamine
disaccharide. Hence, the effect of protecting group on
glucosamine acceptor, the effect of the leaving group and the
protecting group on the galactosyl donor has been studied.
Through the improvement on the regio/stereoselective
glycosylation between galactosyl donors and glucoNPhth diol
acceptors, the LacNPhth polyol acceptor 1 with four unprotected
hydroxyl groups was synthesized in total yield of 39% over 8 steps
starting from glucosamine hydrochloride. The further sialylation of
the LacNPhth polyol acceptor 1 with Neu5Ac donor 2 still showed
good selectivity even with four unprotected hydroxyl groups, thus
leading to a total 48% isolated yield of the target trisaccharide 3
over 2 steps.
The N-Acetylneuraminic acid (Neu5Ac) is widely distributed in the
terminals of oligosaccharide chains in a biological system.1 The
Neu5Ac has been demonstrated to be able to promote cell
adhesion, to regulate the information exchange between cells and
the environment, to control the life cycle of the body glycoprotein,
and to induce viral infection. It is thus related to many important
diseases, such as influenza and inflammation. In humans,
Neu5Ac always exists in the form of α-glycosidic linkage and
bonds to galactose and/or N-acetylgalactosamine through an α 2-
3-linked and/or
α 2-6-linked glycosidic linkage in various
glycoconjugates.2 Therefore, controlling the selectivity to obtain
the 2-α-glycosidic linkages during chemical synthesis is one of the
most challenging tasks in sialylation chemistry.3 The electron-
withdrawing C-1 carboxyl group and the lack of C-3 neighboring
participation groups have restricted the generation of single
stereoselective products. In addition, the anomeric elimination
can easily occur and lead to the formation of 2,3-dehydro
derivatives.
The
3'SLN
(Neu5Ac-α-2,3-LacNAc),
sialylated
Results and Discussion
oligolactosamine glycan structure being constituted through an α
2-3-linked glycosidic bond to the LacNAc disaccharide, is
ubiquitous in influenza infection (Figure 1).4 The access to this
compound is important for studying the potential resistance
Our initial studies on the synthesis of Neu5Ac-α-2,3-lactosamine
derivative focused on the highly efficient preparation of LacNPhth
acceptor. The Neu5Ac-α-2,3-lactosamine donor with
a 2-
phthalimido group instead of a 2-acetamido group favored the
glycosylation reaction with lipids or proteins.8 Several methods to
synthesize LacNPhth and LacNHAc derivatives have been
reported (Entries 1-10 in Table 1).7b,9 These methods can be
categorized into two types: one using acceptors where both the
C3-OH and C4-OH are unprotected (Entries 1-10 apart from 4 and
7 in Table 1) and the other using acceptors where only the C4-
OH is unprotected (Entries 4 and 7 in Table 1). However, all these
methods provided moderate yields of LacNPhth and LacNHAc
products.
[a] Ying Zhang, Fu-Long Zhao,Tao Luo, Prof. Hai Dong
Key laboratory of Material Chemistry for Energy Conversion and Storage,
Ministry of Education, School of Chemistry & Chemical Engineering,
Huazhong University of Science & Technology, Luoyu Road 1037, Wuhan,
430074, P. R. China.
E-mail:hdong@mail.hust.edu.cn
[b] Prof. Zhichao Pei
College of Chemistry and Pharmacy, Northwest A&F University, Yangling,
712100 Shaanxi, P. R. China.
E-mail: peizc@nwafu.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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Scheme 1. Comparison of this work with previous methods for the synthesis of Neu5Ac-α-2,3 lactosamine derivatives
In our initially attempt to obtain LacNPhth derivative through
glycosylation reaction, peracetylated-α-galactopyranosyl
nitrate (CAN).12 When 5l as the acceptor reacted with 4a, the
LacNPhth product 6e was isolated in an even more increased
yield of 92% (Entry 15 in Table 1).
trichloroacetimidate 4a was chosen as the donor and phenyl 3,6-
di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside
5i was chosen as the acceptor (Entry 11 in Table 1). The reactions
were carried out in dichloromethane in the presence of 4 Å
molecular sieves. Moderate yield of LacNPhth product 6a (71%)
was obtained due to the formation of orthoester 7 (15%) even
under the optimized condition (See in supporting information,
Table S1). Subsequently, the phenyl 6-O-benzoyl-2-deoxy-2-
phthalimido-1-thio-β-D-glucopyranoside 5j, synthesized via
regioselective benzoylation in 89% yield starting from phenyl 2-
deoxy-2-phthalimido-1-thio-β-D-glucopyranoside,10 was chosen
as the acceptor to react with the donor 4a. Under the optimized
By the comparison of the glycosylation results of entries 12, 13
and 14, it became clear that the protecting group at 6-position of
the phenyl 2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside
has a strong effect on the regioselectivity of 3- and 4-hydroxyl
groups in the glycosylation. The silyl groups showed the best
regioselectivities in the glycosylation. This finding was further
supported by experiments where 5m (6-OAc), 5n (6-OBz), 5o (6-
OPiv) and 5p (6-OBn) were separately used as the acceptors
(Entries 16-19 in Table 1). The obtained yields of LacNPhth
products 6f, 6g, 6h and 6i were 59%, 72%, 63% and 66%
respectively. Informed by literature, 5m,13 5n,10 5o,14 and 5p15
were synthesized starting from p-methoxyphenyl 2-deoxy-2-
phthalimido-β-D-glucopyranoside. However, with TBDPS group
protecting the 6-hydroxyl group, acceptors 5q (1-SEt), 5r (1-OAll),
5s (1-OMe) and 5t (1-OBn) all led to good isolation yields (80-
90%) of LacNPhth products (Entries 20-23 in Table 1), indicating
good regioselectivities in glycosylation respectively. Acceptor 5q
(1-SEt) led to a relative lower yield (80%) which is likely due to the
aglycon transfer. This aglycon transfer commonly occurs in
glycosylation of acceptors carrying a thio group at the anomeric
position.11
In the following experiments, we investigated the
regioselectivity of 3- and 4-hydroxyl groups of 5l in glycosylation
where donors other than 4a were used (Table 2). When the donor
4j (thiophenyl leaving group instead of trichloroacetimidate
leaving group for 4a) was allowed to react with 5l in the presence
of N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid
(TfOH), the LacNPhth product 6e was isolated in 76% yield (Entry
1 in Table 2). When the donor 4l (acetate leaving group instead
of trichloroacetimidate leaving group for 4a) was allowed to react
with 5l in the presence of TMSOTf, 36% and 67% of the LacNPhth
product 6e were obtained with 0.5 equiv. and 2 equiv. of TMSOTf
as the promoter, respectively (Entries 2 and 3 in Table 2). For
these reactions, the poor yields are due to poor glycosylation
conditions, not due to poor regioselectivity. Thus, in the following
investigation, we selected donors with a trichloroacetimidate
leaving group to react with 5l. It was found that the acyl protecting
o
condition (Entry 12 in Table 1: 0.1 equiv. of TMSOTf, -20 C),
LacNPhth product 6b was isolated in 69% yield (Optimization in
supporting information, Table S1). The major byproduct was β-
1,3-linked disaccharide as expected. The minor byproduct was
phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside likely
due to the occurrence of the aglycon transfer as reported by
C.Gildersleeve.11
Next, phenyl 6-O-tertbutyldimethylsilyl-2-deoxy-2-phthalimido-
1-thio-β-D-glucopyranoside 5e, the tert-butyldimethylsilyl (TBS)
group instead of the benzoyl group in 6-position, was chosen as
the acceptor to react with the donor 4a. Interestingly, although the
LacNPhth product 6c was isolated in 66% yield (Entry 13 in Table
1), the obtained byproduct 8 (18% yield) was found to be the one
that TBS group of 6c was lost due to the instability of TBS at acidic
conditions. The result actually indicated a good regioselectivity
(>84%). It is well-known that the TBDPS group was more stable
than the TBS group in resisting hydrolysis under acidic conditions.
Thus, phenyl 1-thio-β-D-glucopyranoside 5k, the TBDPS group
instead of TBS group, was chosen as the acceptor to react with
the donor 4a. To our delight, the LacNPhth product 6d was
isolated in an 83% yield (Entry 14 in Table 1). Furthermore, in
order to completely avoid the possible aglycon transfer of the
thiophenyl glycoside 5k, the thiophenyl group was replaced with
p-methoxyphenyl (MP) group to form 5l. The pseudo-orthogonal
MP group can be easily transferred to corresponding
trichloroacetimidate derivative by treatment with ceric ammonium
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Table 1. Optimization of glycosyl acceptors through glycosylation with donor 4a and comparison with literaturea
Product
By-product
(yield %)
Entry
Donor
Acceptor
Condition
(yield %)b
19a
29b
39c
47b
59d
69e
79f
4a
4a
4b
4c
4d
4e
4f
4g-j
4a
4k
4a
4a
5a
5b
5c
5g
5d
5f
5h
5aa
5aa, 5ab
5ac
5i
TMSOTf, -10 oC
TMSOTf, 0 oC
LacNPhth (76)
LacNPhth (70)
LacNPhth (77)
LacNPhth (79)
LacNPhth (73)
LacNPhth (64)
LacNPhth (70)
LacNHAc (78, 71, 82, 73)
LacNHAc (70, 68 )
LacNHAc (78 )
6a (71)
TMSOTf, 0 oC
TMSOTf, -78 oC
AgOTf-SnCl2, -15 oC
Cu(OTf)2, r.t.
β(1,3)-product
Orthoester (20)
AgOTf, -20 oC
89g
99g
109h
11
NIS/TfOH, -45oC
.
BF3 Et2O
NIS/TfOH, -50oC
TMSOTf (0.2), -20 oC
TMSOTf (0.2), -20 oC
Orthoester 7 (15)
12
5j
6b (69)
13
4a
5e
TMSOTf (0.1), -20 oC
6c (66)
14
15
16
17
18
19
20
21
22
23
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
5k
5l
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
TMSOTf (0.1), -20 oC
6d (83)
6e (92)
6f (59)
6g (72)
6h (63)
6i (66)
6j (80)
6k (90)
6l (88)
6m (86)
5m
5n
5o
5p
5q
5r
5s
5t
a Donor (1 equiv.), acceptor (1.1 equiv.), all the reactions were carried out in the presence of 4 Å MS under argon.
b Isolated yield, relative to donor
group of donors was very important for the regioselectivity of 3-
and 4-hydroxyl groups of 5l in glycosylation. For example, when
per-acetylated trichloroacetimidate 2-deoxy-2-phthalimido-D-
glucopyranoside donor 4m was allowed to react with 5l, the 1,4
glycosylation product 6n and the 1,3 glycosylation product 9a
were isolated in 51% and 42% yields separately (Entry 4 in Table
2), indicating an exceedingly poor regioselectivity. In comparison
with donor 4m, donor 4n (thiophenyl leaving group instead of
trichloroacetimidate leaving group), 4o (2-OAc instead of 2-
the importance of the acyl group at the 2-position for the
regioselectivity. Interestingly, the obtained 1,4 glycosylation
product 6s with 4q as the donor is a α/β (1:1.5) mixture, whereas
the 1,3 glycosylation product 9b is the absolute β-configuration.
The per-acetylated trichloroacetimidate mannoside 4r and the
per-acetylated trichloroacetimidate xyloside 4s as the donor gave
the 1,4 glycosylation products 6p and 6q in the yields of 85% and
71% separately (Entries 9, 10 in Table 2). As expected, the
glycosylation of 5l with armed donor gave poor regioselectivity. In
comparison of the good regioselectivity with donor 4a (92% yield
of 6e), the donor 4t (TBDPS group protecting 6-postion instead of
acetyl group for 4a) led to a significantly low yield of 1,4
glycosylation product 6t (68%) accompanied by a complex
mixture of by-products (Entry 11 in Table 2).
NPhth),
4p
(per-benzoylated
trichloroacetimidate-D-
glucopyranoside) and 4q (per-benzylated trichloroacetimidate-D-
glucopyranoside) were also tested in glycosylation (Entries 5-8 in
Table 2). Both 4n (6n/9a: 41/34) and 4q (6s/9b: 49/42) led to poor
regioselectivity (Entries 5 and 8 in Table 2), whereas 4o and 4p
led to good regioselectivity (Entries 6 and 7 in Table 2), indicating
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Table 2. Effects of different protecting groups and leaving group of glycosyl donors on the glyosylation with glycosyl acceptor 5la
Entry
1
2
3
4
5
6
7
8
Donor
4j
4l
Acceptor
Promoter
NIS (2.0)/TfOH (0.2)
TMSOTf (0.5)
TMSOTf (2)
TMSOTf (0.1)
NIS (2.0)/TfOH (0.2)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
Product(yield %)b
6e (76)
By-product(yield %)
5l
5l
5l
5l
5l
5l
5l
5l
5l
5l
5l
6e (36)c
6e (67)
4l
4m
4n
4o
4p
4q
4r
6n (51)
6n (41)
6o (87)
9a (42)
9a (34)
6r (81)
6s (49)d
6p (85)e
6q (71)
9b (42)
9
10
11
4s
4t
6t (68)
Complex mixture
a Donor (1 equiv.), acceptor (1.1 equiv.), -20oC, all the reactions were carried out in the presence of 4 Å MS under argon.
b Isolated yield, relative to donor
c Low conversion
d α/β = 1/1.5
eα(1,4)-product.
reactions. We have shown that the poor yield of LacPhth 6s or 6t
(Entries 8 and 11 in Table 2) was caused by the poor selectivity
in the glycosylation of 5l with the trichloroacetimidate donor (4t or
4q). The poor selectivity should be attributed to the relatively high
reactivity of 4t or 4q. Thus, the relatively low reactivity of the
disarmed trichloroacetimidate donor (4a or 4o) caused the best
regio/stereoselective glycosylation, which resulted in the best
yield of LacPhth. Obviously, the best yield of LacPhth/LacNAc
was obtained when using a disarmed trichloroacetimidate donor
than when using an armed thiophenyl donor.
LacNPhth 1 was easily obtained starting from 6e through two
steps (deacylation, then silylation). Therefore, we hypothesized
that the most concise route to synthesize 3'SLN derivative was
through straightforward sialylation of the LacNPhth 1 with the
Neu5Ac donor, assuming that a good regioselectivty for the 3-OH
of 1 could be obtained. The relative good regioselectivity for the
straightforward sialylation between galacto-type polyols and sialyl
N-phenyl trifluoroacetimidate donor has been previously
reported.16 Since sialyl phosphite donors are much more readily
prepared from inexpensive reagents than sialyl N-phenyl-
trifluoroacetimidate donors, we choose p-methoxyphenyl 6-O-
TBDPS-β-D-galactoside 10 as a model to test the sialylation with
the sialyl phosphite donor 2 (Table 3). Two major products formed
in the sialylation: one was the desired product 2,3 disaccharide
product 11 and the other was the elimination product 12 from the
Neu5Ac donor 2. Through varying the used amounts of the donor,
the temperature and the solvents, it was found that 11 was
obtained in a yield up to 63% when 1.5 equiv. of donor 2 was used
Figure 2. Comparison of the LacNAc yields by the glycosylation of thiophenyl
donors with the LacNPhth yields by the glycosylation of trichloroacetimidate
donors. Yield of LacNPhth/LacNAc: 4a (92), 4g (78), 4h (71), 4i (82), 4j (73), 4k
(78) in Table 1 and 4o (87), 4t (68), 4q (49) in Table 2.
An interesting result was found by comparing the literature9g,h with
this study. In this study, the obtained yield of LacNPhth with a
disarmed trichloroacetimidate donor (4a or 4o) is much higher
than that with a trichloroacetimidate donor (4t or 4q) whose 6-
position is protected by an armed protecting group. However, in
the literature (Entries 8 and 10 in Table 1),9g,h the obtained yield
of LacNAc with a disarmed thiophenyl donor (4h or 4j) is slightly
lower than that with a thiophenyl donor(4g, 4k or 4i) whose 6-
position is protected by an armed protecting group. The reason
may be due to that the best yield of LacNPhth/LacNAc depends
on the most appropriate reactivity of the donors (Figure 2). The
slightly poor yield of LacNAc (71 or 73) with the disarmed
thiophenyl donor (4h or 4j) may be caused by the relatively lower
reactivity of the donor. Thus, the relatively higher reactivity of the
thiophenyl donor (4g, 4k or 4i) led to the better yield of LacNAc
(78, 78 or 82). It is known that trichloroacetimidate donors usually
showed higher reactivity than thiophenyl donors in glycosylation
o
in acetonitrile at -40 C (Entry 3 in Table 3). Sialylation with this
sialyl phosphite donor 2 showed similar yield of 11 and even high
α-selectivity than the reported sialyl N-phenyltrifluoroacetimidates
donor.16 These results indicated that the straightforward
sialylation between the LacNPhth 1 and the Neu5Ac donor 2
should be feasible.
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Table 3. Straightforward sialylation with p-methoxyphenyl 6-O-TBDPS-β-D-galactoside 10.ᵅ
Entry
Donor (equiv.)
2 (0.9)
Promoter (equiv.)
TMSOTf(0.2)
TMSOTf(0.2)
TMSOTf(0.2)
TMSOTf(0.2)
TMSOTf(0.2)
TMSOTf(0.2)
Additive (equiv.)
Solvent
CH3CN
Time (h)
11 (yield %)b
39
1
2
----
----
----
----
----
----
40min→2h
51
63 (α:β = 8.1:1)
49
2 (1.2)
CH3CN
2h
2h
2h
2h
2h
3
2 (1.5)
CH3CN
4
2 (1.8)
CH3CN
N/D
5
2 (1.5)
CH2Cl2
6c
2 (1.5)
CH3CN-CH2Cl2 (1:1)
54 (α:β = 5.4:1)
ᵅ Reagents and conditions: donor 2 (100 mg, 1.5 equiv), acceptors 10 (47.5 mg, 1.0 equiv), and 4 Å molecular sieves in dry CH3CN(2 mL) was stirred
atroom temperature under argon for 30 min and then cooled to -40 °C for 15 min, TMSOTf (3.28 μL, 0.2 equiv) in CH3CN (0.3 mL) was added
with syringe and stirred at -40 °C for 2 h. b Isolated yields based on 10 and α/β-ratiodetermined by NMR. c Reaction at -70 oC.
In light of the results displayed in Table 3, LacNPhth 1 was
allowed to react with 1.5 equiv. of sialyl phosphite donor 2 in the
presence of 0.2 equiv. of TMSOTf in acetonitrile at -40 oC. A
similar regioselectivity to the use of 10 was observed. Thus, a
concise route to synthesize 3'SLN derivative 3 can be developed
starting from glucosamine hydrochloride (Scheme 2). The
glucosamine hydrochloride was equipped with Nphth group,
OTDPBS group and OMP group at C2, C6, and anomeric carbon
respectively to provide 5l in 47% yield over 5 steps of protections
and deprotections. Next, the following glycosylation of the
acceptor 5l with the donor 4a led to the disaccharide LacNPhth
derivative 6e in 92% yield. The LacNPhth disaccharide 6e was
then deacetylated in methanol with NaOH as a catalyst,17 followed
by the protection of TBDPS group at the primary position to form
the polyol disaccharide acceptor 1 in excellent yield (90% over
two steps). It should be noted that the phthalimide group is
unstable under strong basic conditions (pH > 10). With the
disaccharide acceptor 1 in hand, the linear synthesis of 3'SLN
derivative was naturally carried out (Scheme 2). Finally, the
selective sialylation of the polyol disaccharide acceptor 1 with the
Neu5Ac-2,3 LacNPhth trisaccharides by column chromatography.
Consequently, the pure per-acetylated Neu5Ac-a-2,3 LacNPhth
trisaccharide 3 was easily isolated by column chromatography in
48% yield over two steps.The trisaccharide 3 can be further
equipped with a suitable anomeric leaving group, whichcan be
used as a donor to prepare morecomplicated glycoconjugates6a,18
for biological activity studies (Scheme 3).
Conclusions
In the present study, we developed a concise approach to
synthesizing the 3'SLN analogue via regio/stereoselective
glycosylation and sialylation of diol and polyol acceptors, thereby
avoiding the need for numerous protection/deprotection steps.
Firstly, the method through regio/stereoselective glycosylation of
per-acylated trichloroacetimidate donors with 6-O-tert-
butyldiphenylsilyl-2-deoxy-2-phthalimido-β-D-glucoside
diol
acceptors was developed. The regio/stereoselectivity was found
to depend not only on the steric hindrance of the C2-NPhth group
and the C6-OH protecting group of the glucosamine acceptors,
sialyl phosphite donor
2 gave the Neu5Ac-2,3 LacNPhth
trisaccharidesS6 with high α-selectivity (α:β = 5.2:1). The reaction
mixture was further acetylated due to the difficult isolation of the
Scheme 2. Linear synthesis of the target Neu5Ac-α-2,3 LacNAc (3'SLN) derivative from glucosamine hydrochloride.ᵅ
ᵅReagents and conditions: a) (1) MeOH, Phthalic anhydride; (2) Py, Ac2O, DMAP, 65% yield over 2 steps; (3) MPOH or HSPh, BF3·Et2O, DCM; (4)
NaOH, MeOH; (5) TBDPSCl, Py, DMAP, 72% yield over 3 steps ; b) 4a, TMSOTf, DCM, -20oC, 92% yield; c) (1) NaOH, MeOH; (2) TBDPSCl, Py,
DMAP, 90% yield over 2 steps; d) 2, TMSOTf, CH3CN, -40oC, 4 Å MS; e) Ac2O, Py, DMAP, 48% yield over 2steps.
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Scheme 3. Reported biologically active compounds containing 3'SLN trisaccharide
respectively at 298 K in CDCl3, using the residual signals from D-
chloroform (1H, δ 7.25 ppm; 13C, δ 77.2 ppm), as internal standard.
Assignments were made by first-order analysis of the spectra, supported
by standard 1H-1H correlation spectroscopy (COSY).
General Procedure A for Glycosylation with Trifluoroacetimidate
Donors: A mixture of the trifluoroacetimidate donor (1.0 equiv), acceptors,
and 4 Å molecular sieves in dry CH2Cl2 was stirred at room temperature
under argon for 30 min and then cooled to -20 °C. TMSOTf (0.1 equiv)
dissolved in CH2Cl2 was added. After being stirred at -20 °C for 2 h, the
reaction was quenched with a few drops of triethylamine and warmed to
room temperature. The resulting mixture was filtered and concentrated
and chromatographed on a silica gel column to afford the desired coupling
products.
General Procedure B for Glycosylation with Thiophenyl Donors: A
mixture of the thiophenyl donor (1.0 equiv), acceptors, and 4 Å molecular
sieves in dry CH2Cl2 was stirred at room temperature under argon for 30
min and then cooled to -20 °C. NIS (2.0 equiv) and TfOH (0.2 equiv) was
added. After being stirred at -20 °C for 2 h, the reaction was quenched with
a few drops of triethylamine and warmed to room temperature. The
resulting mixture was filtered and concentrated and chromatographed on
a silica gel column to afford the desired coupling products.
but also on the leaving group and protecting group of the
glycoside donors. Different from the better yield of LacNAc
obtained with an armed thiophenyl donor in the literature,9g,h better
yield of LacNPhth is obtained when using
a disarmed
trichloroacetimidate donor in this study. The reason was also
discussed and proposed that the best yield of LacNPhth/LacNAc
depends on the most appropriate reactivity of the donors. The
better yield of LacNPhth/LacNAc can be obtained using the
disarmed trichloroacetimidate donor than using the armed
thiophenyl donor. Consequently, the highest synthesized yield of
92% of LacNPhth disaccharide product achieved via the
glycosylation
of
trichloroacetimidate
peracetylated-α-
galactopyranosyl donor with p-methoxyphenyl 6-O-tert-butyldi-
phenylsilyl-2-deoxy-2-phthalimido-β-D-glucopyranoside acceptor.
Secondly, the method through regio/stereoselective sialylation of
a sialyl phosphite donor with a LacNPhth polyol acceptor was
successfully developed, where
a
Neu5Ac-α-2,3-LacNPhth
trisaccharide derivative was synthesized in a 48% yield. By
making use of these two strategies, the Neu5Ac-α-2,3-LacNPhth
trisaccharide derivative was synthesized in a total yield of 18.5%
using only 10 steps starting from D-glucosamine hydrochloride.
Further investigation of the coupling of the Neu5Ac-α-2,3-
LacNPhth trisaccharide derivative with glycoside building blocks
or phosphatides to synthesize natural oligosaccharides and
glycoconjugates is currently underway.
Phenyl
galactopyranosyl)-2-deoxy-2-phthalimido-1-thio-β-gluco-pyranoside
6candPhenyl 4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-
6-O-tert-butyldimethylsilyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
deoxy-2-phthalimido-1-thio-β-gluco-pyranoside8
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5e (115.53 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6c as a colorless oil (113.8 mg, 66%) and 8 (26.8 mg, 18%). 6c:
1H NMR (400 MHz, CDCl3) δ 7.88-7.22 (m, 9H, Nphth, SPh), 5.60 (d, J =
10.8 Hz, 1H), 5.36 (d, J = 2.8 Hz, 1H), 5.23 (dd, J = 10 Hz, 8 Hz, 1H), 4.96
(dd, J = 10 Hz, 8 Hz, 1H), 4.60 (d, J = 8 Hz, 1H), 4.40 (t, J = 9.2 Hz, 1H),
4.17 (t, J = 10.4 Hz, 1H), 4.06 (t, J = 6.4 Hz, 3H), 3.97 (t, J = 6.8 Hz, 1H),
3.90 (d, J = 11.6 Hz, 1H), 3.76 (dd, J = 11.2 Hz, 3.2 Hz, 1H), 3.68 (t, J =
9.2 Hz, 1H), 3.53 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 2.12, 2.08, 1.98, 1.90 (4s,
Experimental section
General Information: All commercially available starting materials and
solvents were of reagent grade and dried prior to use. Chemical reactions
were monitored with thin-layer chromatography using precoated silica gel
60 (0.25 mm thickness) plates. High-resolution mass spectra (HRMS)
were obtained by electrospray ionization (ESI) and Q-TOF detection. Flash
column chromatography was performed on silica gel 60 (0.040-0.063 mm).
1H and 13C spectra were recorded with 400 and 100 MHz instruments
12H, 4OAc), 0.94 (s, 9H, C(CH3)3), 0.14 (d, J = 22.8 Hz, 6H, Si(CH3)2); 13
C
NMR (100 MHz, CDCl3) δ 170.4, 170.1, 170.0, 169.1, 168.1, 167.4, 134.1,
132.8, 132.2, 131.8, 131.7, 128.8, 127.9, 123.6, 123.3, 101.6, 83.4, 81.5,
78.8, 77.3, 71.2, 70.9, 70.8, 68.7, 66.8, 61.7, 61.4, 55.2, 25.9, 20.7, 20.6,
20.5, 20.3, 18.3, -4.9, -5.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C40H51NO15SsiNa868.2646; found 868.2645.8: 1H NMR (400 MHz, CDCl3)
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δ 7.93-7.23 (m, 9H, Nphth, SPh), 5.67 (d, J = 10.4 Hz, 1H), 5.36 (d, J = 3.2
Hz, 1H), 5.23 (dd, J = 10.4 Hz, 8.4 Hz, 1H), 5.04 (dd, J = 10.4 Hz, 3.2 Hz,
1H), 4.63 (d, J = 8 Hz, 1H), 4.45 (dd, J = 10.0 Hz, 8.4 Hz, 1H), 4.24 (d, J =
10.4 Hz, 1H), 4.06 (m, 3H), 3.89 (dd, J = 12.0 Hz, 2.0 Hz, 1H), 3.71 (t, J =
9.2 Hz, 1H) 3.65 (dd, J = 11.6 Hz, 3.2 Hz, 1H), 3.60 (dt, J = 10.0 Hz, 2.4
Hz, 1H), 2.13, 2.11, 1.98, 1.86 (4s, 12H, 4OAc); 13C NMR (100 MHz,
CDCl3) δ 170.4, 170.0, 169.9, 169.4, 168.1, 167.5, 134.2, 132.5, 131.8,
131.7, 131.6, 129.0, 128.1, 123.7, 123.3, 101.9, 83.5, 81.8, 78.1, 77.2,
71.3, 70.8, 70.7, 68.8, 66.8, 61.6, 61.0, 55.1, 20.7, 20.6, 20.5, 20.2; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C34H37NO15Sna 754.1782; found
754.1762.
p-Methoxyphenyl 6-O-pivaloyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl)-2-deoxy-2-phthalimido-β-D-glucopyranoside 6h
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5o (111.8 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6h as a colorless oil (106.5 mg, 63%).1H NMR (400 MHz, CDCl3)
δ 7.86-7.73 (m, 4H, Nphth), 6.88-6.70 (m, 4H, Ar-H in OMP), 5.76 (d, J =
8.4 Hz, 1H, H-1), 5.37 (d, J = 3.2 Hz, 1H), 5.29 (dd, J = 10 Hz, 8 Hz, 1H),
5.00 (dd, J = 10.4 Hz, 3.2 Hz, 1H), 4.60 (d, J = 8 Hz, 1H, H-1’), 4.43 (m,
4H), 4.05 (m, 4H), 3.89 (m, 1H), 3.72 (s, 3H, OCH3), 3.60 (t, J = 8.4 Hz,
1H), 2.15, 2.10, 1.96, 1.88 (4s, 12H, 4OAc), 1.23 (s, 9H, C(CH3)3); 13C
NMR (100 MHz, CDCl3) δ 178.1, 170.4, 170.0, 169.9, 169.5, 155.5, 150.7,
134.2, 131.7, 123.5, 118.7, 114.4, 102.1, 97.4, 83.8, 77.2, 72.2, 71.5, 70.9,
70.0, 68.6, 66.8, 63.0, 61.7, 55.7, 55.6, 38.8, 27.2, 20.6, 20.6, 20.5, 20.2;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C40H47NO18Na852.2691; found
852.2671.
p-Methoxyphenyl 6-O-benzyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-β-D-glucopyranoside 6i
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5p (113.1 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6i as a colorless oil (111.6 mg, 66%). 1H NMR (400 MHz, CDCl3)
δ 7.85-7.32 (m, 9H, Ar-H in OBn, Nphth), 6.89-6.71 (m, 4H, Ar-H in OMP),
5.74 (d, J = 8 Hz, 1H, H-1), 5.34 (d, J = 2.8 Hz, 1H), 5.20 (dd, J = 10.4 Hz,
8.4 Hz, 1H), 4.96 (dd, J = 10.4 Hz, 3.6 Hz, 1H), 4.72 (d, J = 12 Hz, 1H, H-
1’), 4.48 (m, 4H), 4.02 (m, 4H), 3.77 (m, 3H), 3.72 (s, 3H, OCH3), 2.13,
2.01, 1.98, 1.93 (4s, 12H, 4OAc).13C NMR (100 MHz, CDCl3) δ 170.5,
170.1, 169.9, 169.1, 155.5, 150.8, 138.0, 134.1, 131.7, 128.5, 127.9, 127.8,
118.8, 114.4, 101.5, 97.6, 81.9, 77.3, 74.3, 73.7, 71.2, 70.7, 69.7, 68.7,
67.8, 66.8, 61.5, 55.9, 55.6, 20.7, 20.6, 20.5, 20.3; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C42H45NO17Na 858.2585; found 858.2565.
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-acetyl-β-D-galactopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6e
The reaction for the donor 4a (100 mg, 0.204 mmol), acceptor 5l (146.3
mg, 0.224 mmol)was performed by following the general procedure A.
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6e as a colorless oil (184.5 mg, 92%).
The reaction forthe donor 4j (100 mg, 0.227 mmol), acceptor 5l (163.3 mg,
0.25 mmol)was performed by following the general procedure B. Purified
by flash column chromatography (Ethyl acetate/Petroleum ether, 1:2) gave
6e as a colorless oil (168.6 mg, 76%).
A mixture of the donor penta-O-acetyl-D-galactopyranosyl 4l(100 mg, 0.26
mmol), acceptors 5l (184.2 mg, 0.28 mmol), and 4 Å molecular sieves in
dry CH2Cl2 (3 mL) was stirred at room temperature under argon for 30 min
and then cooled to -20 °C. Subsequently, TMSOTf (2 equiv) dissolved in
CH2Cl2 was added. After being stirred at -20 °C for 2 h, the mixture was
quenched with a few drops of triethylamine and warmed to room
temperature. The resulting mixture was filtered and concentrated. The
residue was chromatographed (Ethyl acetate/Petroleum ether, 1:2) on a
silica gel column to afford 6e (171.2 mg, 67%).
6e: 1H NMR (400 MHz, CDCl3) δ 7.95-7.20 (m, 14H, Nphth, Si(Ph)2), 6.90-
6.70 (m, 4H, Ar-H in OMP), 5.78 (d, J = 8.4 Hz, 1H, H-1), 5.36 (d, J = 2.8
Hz, 1H), 5.22 (dd, J = 10.4 Hz, 8.8 Hz, 1H), 4.99 (dd, J = 10.4 Hz, 3.2 Hz,
1H), 4.72 (d, J = 8 Hz, 1H, H-1’), 4.53 (dd, J = 10.4 Hz, 8.0 Hz, 1H), 4.43
(dd, J = 10.8 Hz, 8.8 Hz, 1H), 4.11 (m, 2H), 3.94 (m, 5H), 3.73 (s, 3H,
OCH3), 3.68 (dd, J = 10.8 Hz, 2.8 Hz, 1H), 2.13, 1.99, 1.98, 1.65 (4s, 12H,
4OAc), 1.09 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.1,
169.9, 169.1, 155.4, 150.9, 135.9, 135.6, 134.1, 133.5, 132.4, 131.8, 129.9,
129.8, 127.9, 127.7, 118.8, 114.4, 101.3, 97.4, 80.9, 77.3, 74.8, 71.3, 70.8,
69.5, 68.7, 66.9, 61.7, 61.3, 56.2, 55.7, 26.9, 20.6, 20.5, 20.4, 20.2, 19.4;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C51H57NO17SiNa 1006.3293;
found 1006.3283.
p-Methoxyphenyl 6-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-β-D-glucopyranoside 6f
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5m (103.4 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6f as a colorless oil (94.7 mg, 59%). 1H NMR (400 MHz, CDCl3)
δ 7.85-7.73 (m, 4H, Nphth), 6.87-6.72 (m, 4H, Ar-H in OMP), 5.76 (d, J =
8.0 Hz, 1H, H-1), 5.37 (d, J = 2.8 Hz, 1H), 5.26 (dd, J = 10 Hz, 8.0 Hz, 1H),
5.02 (dd, J = 10.4 Hz, 3.2 Hz, 1H), 4.61(d, J = 8.0 Hz, 1H, H-1’), 4.42 (m,
4H), 4.10 (m, 4H), 3.85 (ddd, J = 7.2 Hz, 5.2 Hz, 2.0 Hz, 1H), 3.73 (s, 3H,
OCH3), 3.66 (t, J = 8 Hz, 1H), 2.15, 2.13, 2.10, 1.98, 1.87 (5s, 15H, 5OAc);
13C NMR (100 MHz, CDCl3) δ 170.6, 170.4, 170.0, 169.9, 169.5, 155.6,
150.7, 134.2, 131.7, 123.5, 118.7, 114.4, 102.0, 97.5, 83.3, 77.2, 72.0,
71.4, 70.8, 69.9, 68.7, 66.8, 62.6, 61.7, 55.6, 20.8, 20.6, 20.6, 20.5, 20.2;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C37H41NO18Na810.2221; found
810.2226.
p-Methoxyphenyl 6-O-benzoyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl)-2-deoxy-2-phthalimido-β-D-glucopyranoside 6g
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5n (114.7 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6g as a colorless oil (124.7 mg, 72%). 1H NMR (400 MHz, CDCl3)
δ 8.07-7.47 (m, 9H, Nphth, OBz), 6.89-6.66 (m, 4H, Ar-H in OMP), 5.81 (d,
J = 8.4 Hz, 1H, H-1), 5.37 (d, J = 3.2 Hz, 1H), 5.27 (dd, J = 10.4 Hz, 8.4
Hz, 1H), 4.98 (dd, J = 10.4 Hz, 2.8 Hz, 1H), 4.63 (m, 2H, H-1’), 4.47 (m,
4H), 4.03 (m, 4H), 3.73 (t, J = 6.4 Hz, 1H), 3.70 (s, 3H, OCH3), 2.15, 2.13,
1.97, 1.87 (4s, 12H, 4OAc); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.0,
169.9, 169.6, 166.1, 155.6, 150.6, 134.2, 133.4, 131.7, 129.7, 129.6, 128.5,
123.5, 118.8, 114.4, 102.1, 97.5, 83.7, 77.3, 72.2, 71.4, 70.9, 70.1, 68.7,
66.8, 63.2, 61.8, 55.7, 55.6, 20.7, 20.6, 20.5, 20.2; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C42H43NO18Na 872.2378; found 872.2359.
Ethyl
6-O-tert-butyldiphenylsilyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-1-thio-β-D-
glucopyranoside 6j
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5q (132.4 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6j as a colorless oil (150.3 mg, 80%). 1H NMR (400 MHz, CDCl3)
δ 7.91-7.33 (m, 14H, Nphth, Si(Ph)2), 5.35 (d, J = 10.4 Hz, 1H，H-1), 5.34
(d, J = 3.2 Hz, 1H), 5.21 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 4.96 (dd, J = 10.4
Hz, 3.2 Hz, 1H), 4.72 (d, J = 8 Hz, 1H, H-1’), 4.49 (dd, J = 10.4 Hz, 8.4 Hz,
1H), 4.27 (t, J = 10.4 Hz, 1H), 4.06 (m, 3H), 3.90 (m, 4H), 3.60 (d, J = 9.2
Hz, 1H), 2.70 (m, 2H, SCH2-), 2.13, 1.99, 1.99, 1.70 (4s, 12H, 4OAc), 1.21
(t, J = 7.2 Hz, 3H, -CH3), 1.12 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 170.4, 170.1, 169.9, 169.1, 168.1, 167.8, 136.0, 135.6, 134.1, 134.1,
133.5, 132.6, 131.9, 131.7, 129.9, 129.9, 127.9, 127.7, 123.7, 123.2, 101.2,
80.7, 80.4, 78.5, 77.3, 71.2, 70.8, 70.4, 68.7, 66.8, 61.9, 61.2, 55.4, 26.9,
23.3, 20.6, 20.5, 20.4, 20.3, 19.4, 14.8; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C46H55NO15SSiNa 944.2959; found 944.2963.
Allyl
6-O-tert-butyldiphenylsilyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-1-thio-β-D-
glucopyranoside 6k
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5r (131.3 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6k as a colorless oil (168.4 mg, 90%). 1H NMR (400 MHz, CDCl3)
δ 7.91-7.37 (m, 14H, Nphth, Si(Ph)2), 5.77 (m, 1H, -CH=), 5.35 (d, J = 3.2
Hz, 1H), 5.28 (d, J = 8.8 Hz, 1H，H-1), 5.21 (dd, J = 10.4 Hz, 8.4 Hz, 1H),
5.14 (m, 1H, CH2=), 5.08 (dd, J = 10.4 Hz, 1.2 Hz, 1H, CH2=), 4.98 (dd, J
= 10.4 Hz, 3.2 Hz, 1H), 4.74 (d, J = 8.0 Hz, 1H，H-1’), 4.46 (dd, J = 10.4
Hz, 8.4 Hz, 1H), 4.29 (m, 1H, OCH2-), 4.20 (dd, J = 10.8 Hz, 8.8 Hz, 1H),
4.14-3.73 (m, 8H, OCH2-), 3.57 (dd, J = 10.0 Hz, 2.2 Hz, 1H), 2.13, 1.98,
1.97, 1.69 (4s, 12H, 4OAc), 1.12 (s, 9H, C(CH3)3); 13C NMR (100 MHz,
CDCl3) δ 170.4, 170.1, 169.9, 169.1, 136.0, 135.6, 134.0, 133.8, 133.6,
132.6, 131.8, 129.9, 129.9, 127.9, 127.7, 117.2, 101.3, 96.8, 81.1, 77.3,
74.6, 71.2, 70.8, 69.5, 69.3, 68.8, 66.9, 61.9, 61.3, 56.2, 26.9, 20.6, 20.5,
20.4, 20.3, 19.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C47H55NO16SiNa 940.3188; found 940.3169.
Methyl
6-O-tert-butyldiphenylsilyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-1-thio-β-D-
glucopyranoside 6l
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5s (125.4 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6l as a colorless oil (159.9 mg, 88%). 1H NMR (400 MHz, CDCl3)
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Chemistry - An Asian Journal
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δ 7.91-7.36 (m, 14H, Nphth, Si(Ph)2), 5.36 (d, J = 3.2 Hz, 1H), 5.22 (dd, J
= 10.4 Hz, 8.4 Hz, 1H), 5.13 (d, J = 8.4 Hz, 1H，H-1), 4.99 (dd, J = 10.4
Hz, 1H, H-1’), 4.51 (dd, J = 10.8 Hz, 8.4 Hz, 1H), 4.43 (dd, J = 10.8 Hz, 8.4
Hz, 1H), 4.16 (m, 2H), 3.96 (m, 2H), 3.89 (dd, J = 11.2 Hz, 2.8 Hz, 1H),
3.76 (m, 1H),3.72 (s, 3H, OCH3), 3.66 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 2.03,
2.01, 2.01, 1.67 (4s, 12H, 4OAc), 1.10 (s, 9H, C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 170.5, 170.0, 169.3, 168.9, 155.4, 150.8, 135.9, 135.5,
134.1, 133.4, 132.2, 131.7, 129.9, 129.8, 127.9, 127.7, 118.8, 114.4, 100.9,
97.3, 80.9, 77.2, 74.7, 72.7, 72.1, 71.1, 69.4, 68.2, 61.6, 61.5, 56.2, 55.6,
26.8, 20.5, 20.5, 20.4, 20.1, 19.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C51H57NO17SiNa 1006.3293; found 1006.3279.
Hz, 3.2 Hz, 1H), 4.74 (d, J = 8.0 Hz, 1H，H-1’), 4.46 (dd, J = 10.4 Hz, 8.8
Hz, 1H), 4.19 (dd, J = 10.4 Hz, 8.8 Hz, 1H), 4.08 (m, 2H), 3.91 (m, 5H),
3.59 (dd, J = 10.4 Hz, 2.8 Hz, 1H), 3.44 (s, 3H, OMe), 2.13, 1.99, 1.97,
1.69 (4s, 12H, 4OAc), 1.11 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 170.4, 170.1, 169.9, 169.1, 136.0, 135.6, 134.0, 133.6, 132.6, 131.9,
129.9, 129.9, 127.9, 127.7, 101.3, 98.8, 81.1, 77.3, 74.6, 71.2, 70.9, 69.4,
68.8, 66.9, 61.8, 61.3, 56.4, 56.2, 26.9, 20.6, 20.5, 20.4, 20.3, 19.4; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C45H53NO16SiNa 914.3031; found
914.3041.
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-acetyl-β-D-mannopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6p
The reaction was performed by following the general procedure A using
Benzyl
6-O-tert-butyldiphenylsilyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2-deoxy-2-phthalimido-1-thio-β-D-
glucopyranoside 6m
the
donor
2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside
trichloro-
acetimidate 4r (100 mg, 0.204 mmol), acceptor 5l (146.3 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6p as a colorless oil (170.5 mg, 85%). 1H NMR (400 MHz, CDCl3)
δ 7.86-7.25 (m, 14H, Si(Ph)2, NPhth), 6.92-6.66 (m, 4H, Ar-H in OMP),
5.74 (d, J = 8.4 Hz, 1H), 5.35 (m, 2H), 5.24 (m, 2H), 4.60 (dd, J = 10.4 Hz,
8.4 Hz, 1H), 4.39 (dd, J = 10.4 Hz, 8.4 Hz, 1H), 3.98 (m, 3H), 3.80 (m, 3H),
3.70 (s, 3H, OCH3), 3.69 (m, 1H), 2.04, 2.03, 1.95, 1.88 (4s, 12H, 4OAc),
1.06 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 170.6, 170.2, 170.2,
169.5, 168.3, 155.3, 151.0, 150.9, 135.7, 135.6, 134.2, 133.2, 132.9, 131.6,
129.7, 127.8, 127.7, 123.5, 118.5, 114.4, 114.4, 98.7, 97.3, 78.6, 77.3,
75.5, 71.8, 69.7, 69.6, 69.0, 65.5, 63.2, 62.1, 56.8, 55.6, 26.8, 26.7, 20.8,
20.7, 20.7, 20.5, 19.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C51H57NO17SiNa 1006.3293; found 1006.3273.
The reaction was performed by following the general procedure A using
the donor 4a (100 mg, 0.204 mmol), acceptor 5t (142.5 mg, 0.224 mmol).
Purified by flash column chromatography (Ethyl acetate/Petroleum ether,
1:2) gave 6m as a colorless oil (169.6 mg, 86%). 1H NMR (400 MHz,
CDCl3) δ 7.90-7.33 (m, 14H), 7.18-7.05 (m, 5H), 5.35 (d, J = 2.8 Hz, 1H),
5.25 (d, J = 8.4 Hz, 1H, H-1), 5.21 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 4.98 (dd,
J = 10.4 Hz, 3.2 Hz, 1H), 4.85 (d, J = 12.4 Hz, 1H, PhCH2), 4.74 (d, J = 8.0
Hz, 1H, H-1’), 4.53 (d, J = 12.4 Hz, 1H, PhCH2), 4.46 (dd, J = 10.8 Hz, 8.4
Hz, 1H), 4.26 (dd, J = 10.8 Hz, 8.4 Hz, 1H), 4.09 (m, 2H), 3.99 (d, J = 10.8
Hz, 1H), 3.89 (m, 4H), 3.59 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 2.12, 1.98, 1.98,
1.72 (4s, 12H, 4OAc), 1.13 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 170.4, 170.1, 169.9, 169.1, 137.2, 136.0, 135.6, 133.9, 133.6, 132.6,
131.8, 129.9, 129.9, 128.2, 127.9, 127.7, 127.6, 127.5, 101.3, 96.8, 81.1,
77.3, 74.7, 71.3, 70.9, 70.2, 69.4, 68.8, 66.9, 61.9, 61.3, 56.9, 26.9, 20.6,
20.5, 20.4, 20.3, 19.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C51H57NO16SiNa 990.3344; found 990.3357.
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-acetyl-β-D-xylopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6q
The reaction was performed by following the general procedure A using
the donor 2,3,4-tri-O-acetyl-α-D-xylopyranoside trichloro-acetimidate 4s
(100 mg, 0.238 mmol), acceptor 5l (171.3 mg, 0.262 mmol). Purified by
flash column chromatography (Ethyl acetate/Petroleum ether, 1:2) gave
6p as a colorless oil (153.9 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.86-
7.10 (m, 14H, Si(Ph)2, NPhth), 6.92-6.68 (m, 4H, Ar-H in OMP), 5.77 (d, J
= 7.6 Hz, 1H), 5.20 (t, J = 7.6 Hz, 1H), 4.99 (m, 2H), 4.79 (d, J = 8.0 Hz,
1H), 4.46 (m, 2H), 4.41 (dd, J = 11.6 Hz, 5.2 Hz, 1H), 4.05 (t, J = 8.8 Hz,
1H), 3.93 (m, 2H), 3.73 (s, 3H, OCH3), 3.63 (m, 2H), 3.31 (t, J = 11.2 Hz,
1H), 2.04, 2.04, 1.73 (3s, 9H, 3OAc), 1.09 (s, 9H, C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 170.0, 169.7, 169.1, 155.4, 150.9, 136.0, 135.5, 134.1,
133.4, 132.0, 131.8, 129.9, 129.8, 128.0, 127.7, 118.9, 114.4, 101.3, 97.4,
79.9, 77.3, 74.7, 72.3, 71.3, 69.4, 68.6, 62.9, 61.3, 56.3, 55.7, 26.8, 20.7,
20.3, 19.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C48H53NO15SiNa
934.3082; found 934.3062.
p-Methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(3,4,6-tri-
O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-2-deoxy-2-
phthalimido-β-D-glucopyranoside 6n and
p-Methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(3,4,6-tri-
O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-2-deoxy-2-
phthalimido-β-D-glucopyranoside 9a
The reaction was performed by following the general procedure A using
the
donor
3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-
galactopyranosidetrichloroacetimidate 4m (100 mg, 0.173 mmol),
acceptor 5l (124.3 mg, 0.19 mmol). Purified by flash column
chromatography (Ethyl acetate/Petroleum ether, 2:3) gave 6n and 9a as a
colorless oil (172.2 mg, 93%). 6n (94.4 mg, 51%): 1H NMR (400 MHz,
CDCl3) δ 7.86-7.21 (m, 18H, Nphth×2, Si(Ph)2), 6.77-6.54 (m, 4H, Ar-H in
OMP), 5.75 (dd, J = 10.4 Hz, 8.8 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H, H-1),
5.62 (d, J = 8.4 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.47 (dd, J = 10.8 Hz, 8.4
Hz, 1H, H-3), 4.37 (dd, J = 10.4 Hz, 8.4 Hz, 1H, H-2), 4.32 (dd, J = 10.0
Hz, 8.4 Hz, 1H), 4.17 (m, 2H), 3.97 (m, 2H), 3.87 (t, J = 8.8 Hz, 1H, H-4),
3.69 (m, 1H), 3.66 (s, 3H, OCH3), 3.60 (dd, J = 8.4 Hz, 3.6 Hz, 1H), 3.52
(dd, J = 11.2 Hz, 4.8 Hz, 1H), 2.02, 1.92, 1.81 (3s, 9H, 3OAc), 0.94 (s, 9H,
C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 170.4, 169.9, 169.4, 155.1, 150.8,
135.7, 135.6, 135.5, 134.2, 134.0, 133.5, 132.9, 130.7, 129.5, 129.4, 127.8,
127.5, 123.6, 118.5, 118.3, 114.4, 114.3, 98.1, 97.0, 80.4, 77.2, 74.9, 72.0,
70.4, 70.0, 68.9, 62.4, 62.1, 55.9, 55.5, 54.6, 26.8, 26.7, 20.5, 20.3, 20.2,
19.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C57H58N2O17SiNa
1093.3402; found 1093.3413. 9a (77.8 mg, 42%): 1H NMR (400 MHz,
CDCl3) δ 7.76-7.02 (m, 18H, 2×Nphth, Si(Ph)2), 6.78-6.56 (m, 4H, Ar-H in
OMP), 5.55 (t, J = 10.4 Hz, 1H), 5.42 (dd, J = 10.4 Hz, 8.4 Hz, 1H, H-1),
5.07 (t, J = 9.6 Hz, 1H), 4.66 (dd, J = 10.4 Hz, 7.6 Hz, 1H, H-3), 4.34 (m,
2H, H-2), 4.21 (m, 2H), 4.09 (m, 2H), 3.93 (m, 2H), 3.67 (m, 2H, H-4), 3.64
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-benzoyl-β-D-glucopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6r
The reaction was performed by following the general procedure A using
the donor 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate
4p (100 mg, 0.135 mmol), acceptor 5l (97.2 mg, 0.149 mmol). Purified by
flash column chromatography (Ethyl acetate/Petroleum ether, 1:2) gave 6r
as a colorless oil (134.6 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.16-7.12
(m, 34H, 4×OBz, Si(Ph)2, NPhth), 6.86-6.61 (m, 4H, Ar-H in OMP), 5.92 (t,
J = 9.6 Hz, 1H), 5.64 (m, 2H), 5.20 (d, J = 8.0 Hz, 1H), 4.82 (dd, J = 12.4
Hz, 2.4 Hz, 1H), 4.63 (dd, J = 10.8 Hz, 8.4 Hz, 1H), 4.45 (dd, J = 10.4 Hz,
8.4 Hz, 1H), 4.32 (dd, J = 12.0 Hz, 7.2 Hz, 1H), 4.15 (m, 2H), 3.79 (s, 2H),
3.69 (s, 3H, OCH3), 3.51 (m, 1H), 0.99 (s, 9H, C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 166.2, 165.6, 165.3, 164.8, 155.4, 150.9, 135.9, 135.4,
134.0, 133.8, 133.7, 133.4, 133.3, 132.2, 130.1, 130.0, 129.9, 129.7, 129.3,
128.7, 128.7, 128.5, 128.4, 128.3, 128.1, 127.7, 119.0, 114.4, 100.9, 97.4,
79.6, 77.3, 74.6, 73.2, 72.6, 71.6, 69.5, 69.3, 62.7, 61.4, 56.4, 55.6, 26.8,
19.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C71H65NO17SiNa
1254.3919; found 1254.3930.
(s, 3H, OCH3), 2.04, 1.99, 1.72 (3s, 9H, 3OAc), 1.05 (s, 9H, C(CH3)3);13
C
NMR (100MHz, CDCl3) δ170.5, 169.9, 169.3, 155.2, 150.9, 135.7, 135.6,
134.1, 133.5, 133.4, 130.8, 129.6, 129.5, 127.6, 123.3, 118.3, 114.3, 98.3,
97.4, 82.2, 77.3, 76.8, 71.9, 70.3, 69.9, 68.7, 63.5, 62.0, 55.5, 55.1, 54.5,
26.8, 20.6, 20.5, 20.2, 19.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C57H58N2O17SiNa 1093.3402; found 1093.3416.
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-benzyl-D-glucopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6s and
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2,3,4,6-
tetra-O-acetyl-β-D-glucopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 6o
p-Methoxyphenyl
6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(2,3,4,6-
tetra-O-benzyl-β-D-glucopyranosyl)-2-deoxy-2-phthalimido-β-D-
glucopyranoside 9b
The reaction was performed by following the general procedure A using
the donor 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside trichloroacetimidate
4o (100 mg, 0.204 mmol), acceptor 5l (146.3 mg, 0.224 mmol). Purified by
flash column chromatography (Ethyl acetate/Petroleum ether, 1:2) gave
6o as a colorless oil (174.5 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.98-
7.21 (m, 14H, Nphth, Si(Ph)2), 6.90-6.68 (m, 4H, Ar-H in OMP), 5.77 (d, J
= 8.4 Hz, 1H, H-1), 5.19 (t, J = 9.6 Hz, 1H), 5.04 (m, 2H), 4.81 (d, J = 8.4
The reaction was performed by following the general procedure A using
the donor 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosidetrichloroacetimidate
4q (100 mg, 0.146 mmol), acceptor 5l (105.2 mg, 0.161 mmol). Purified by
flash column chromatography (Ethyl acetate/Petroleum ether, 1:2) gave
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10.1002/asia.201801486
Chemistry - An Asian Journal
FULL PAPER
6s and 9b as colorless oil (156.1 mg, 91%).6s (84 mg, 49%, α/β = 1/1.5).
9b (72.1 mg, 42%, only β): 1H NMR (400 MHz, CDCl3) δ 7.96-7.12 (m, 34H,
4×OBn, Si(Ph)2, NPhth), 6.86-6.61 (m, 4H, Ar-H in OMP), 5.75 (d, J = 8.4
Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.79 (m, 3H), 4.69 (m, 2H), 4.57 (m,
1H), 4.48 (m, 3H), 4.42 (m, 1H), 4.08 (dd, J = 11.2 Hz, 3.2 Hz, 1H), 4.03
(t, J = 9.2 Hz, 1H), 3.93 (m, 1H), 3.71 (s, 3H, OCH3), 3.62 (m, 2H), 3.46
(m, 2H), 1.02 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 155.3, 151.0,
138.4, 138.0, 137.9, 137.7, 135.8, 135.5, 134.0, 133.5, 132.7, 131.9, 129.5,
128.4, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.6,
127.6, 127.6, 127.5, 118.9, 114.4, 103.2, 97.5, 84.7, 81.8, 79.9, 77.5, 77.2,
75.8, 75.3, 75.2, 75.1, 74.7, 73.4, 73.3, 69.5, 68.4, 61.9, 56.6, 55.6, 31.9,
31.4, 30.2, 29.7, 29.3, 26.8, 22.7, 19.4, 14.1, 0.0; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C71H73NO13SiNa 1198.4749; found 1198.4729.
p-Methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(6-O-tert-
butyldiphen-ylsilyl-2,3,4-tri-O-acetyl-β-D-galactopyranosyl)-2-deoxy-
2-phthalimido-β-D-glucopyranoside 6t
Hz, 1H), 4.93 (dd, J = 11.6 Hz, 4.4 Hz, 1H), 4.85 (m, 1H), 4.80 (d, J = 7.6
Hz, 1H), 4.58 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 4.35 (m, 2H), 4.08 (m, 1H), 4.00
(d, J = 10.4 Hz, 1H), 3.91 (m, 4H), 3.85 (s, 3H, OCH3), 3.71 (m, 1H), 3.65
(s, 3H, OCH3), 3.55 (dd, J = 10.8 Hz, 1.6 Hz, 1H), 3.47 (m, 2H), 2.57 (dd,
J = 12.4 Hz, 4.4 Hz, 1H), 2.15, 2.08, 2.03, 2.01, 1.98, 1.85, 1.70 (7s, 21H,
6OAc and NHAc), 1.62 (m, 1H), 1.56 (s, 3H, OAc), 1.03, 0.98 (2s, 18H,
2×C(CH3)3);13C NMR (100 MHz, CDCl3) δ 170.9, 170.4, 170.4, 170.4,
169.8, 169.7, 169.3, 167.9, 167.8, 155.2, 150.8, 135.7, 135.7, 135.5, 135.5,
134.2, 133.9, 133.7, 133.1, 132.9, 132.6, 129.9, 129.9, 129.8, 129.7, 129.6,
129.5, 127.8, 127.7, 127.6, 123.7, 123.3, 118.3, 114.4, 100.8, 96.8, 96.7,
77.3, 76.7, 75.8, 72.9, 72.7, 72.0, 71.8, 70.7, 69.6, 67.6, 67.0, 66.8, 63.1,
62.5, 59.9, 55.6, 55.1, 53.1, 49.1, 37.4, 29.8, 29.7, 29.6, 29.6, 29.5, 29.4,
29.3, 29.3, 27.2, 26.8, 26.7, 25.6, 23.2, 22.7, 21.5, 20.8, 20.8, 20.8, 20.7,
20.5, 19.9, 19.4, 19.0; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C85H100N2O28Si2Na 1675.5899; found 1675.5879.
The reaction was performed by following the general procedure A using
the donor 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzoyl-α-D-galacto-
pyranosyl trichloroacetimidate 4t (100 mg, 0.145 mmol), acceptor 5l (104.5
mg, 0.160 mmol). Purified by flash column chromatography (Ethyl
acetate/Petroleum ether, 1:2) gave 6t as a colorless oil (116.3 mg, 68%).
1H NMR (400 MHz, CDCl3) δ 7.90-7.12 (m, 24H, 2×Si(Ph)2, NPhth), 6.90-
6.65 (m, 4H, Ar-H in OMP), 5.73(d, J = 8.4 Hz, 1H), 5.43 (d, J = 3.2 Hz,
1H), 5.17 (dd, J = 11.2 Hz, 8.8 Hz, 1H), 4.99(dd, J = 10.8 Hz, 3.2 Hz, 1H),
4.73 (d, J = 7.6 Hz, 1H), 4.57 (dd, J = 11.6 Hz, 9.2 Hz, 1H),4.43 (t, J = 9.2
Hz, 1H), 3.90 (m, 5H), 3.75 (m,1H), 3.71 (s, 3H, OCH3),3.67 (m,1H),3.51
(dd, J = 10.4 Hz, 6.8 Hz, 1H),1.97, 1.97, 1.61 (3s, 9H, 3OAc),1.09, 0.92
(2s, 18H, 2×C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 170.0, 169.9, 169.2,
155.4, 151.0, 135.9, 135.6, 135.5, 134.0, 133.5, 132.5, 132.3, 130.0, 129.9,
129.8, 127.9, 127.9, 127.7, 118.8, 114.4, 101.2, 97.4, 80.7, 77.3, 74.9,
73.9, 71.1, 69.6, 69.1, 66.9, 61.8, 61.2, 56.1, 55.6, 26.8, 26.6, 20.6, 20.5,
20.2, 19.4, 18.8; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C65H73NO16Si2Na 1202.4366; found 1202.4349.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This study was supported by the National Nature Science
Foundation of China (Nos. 21708010, 21772049). The
authors are also grateful to the staffs in the Analytical and
Test Center of School of Chemistry
Engineeringat HUST for support with the NMR instruments.
&
Chemical
p-Methoxyphenyl6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(6-O-tert-
butyldiphenylsilyl-β-D-galactopyranosyl)-2-deoxy-2-phthalimido-β-
D-glucopyranoside 1
Keywords: Neu5Ac-α-2,3-LacNPhth trisaccharide • TBDPS •
LacNPhth • D-glucosamine hydrochloride • sialyl phosphite
donor
To the solution of 6e (980 mg, 1.0 mmol) in 5 mL dry MeCN, was added
thiourea (114 mg, 1.50 mmol) and refluxed at 80 ℃ for 45 min. The EtI
(159 μL, 2 mmol) and Et3N (554 μL, 4 mmol) were added when the
temperature dropped to rt and stirred for 30 min. When the reaction was
complete (TLC), the reaction was diluted with ethyl acetate (10 mL),
washed with aqueous NaHCO3, and a brine solution. The organic layer
was then dried over Mg2SO4, filtered, and concentrated. Purified by flash
column chromatography (Ethyl acetate/Petroleum ether, 1:3) to afford 1 as
a white foam (948 mg, 90% over 2 steps). 1H NMR (400 MHz, CDCl3) δ
7.90-7.24 (m, 24H, 2×Si(Ph)2, NPhth), 6.87-6.68 (m, 4H, Ar-H in OMP),
5.71 (d, J = 8.4 Hz, 1H, H-1), 4.54 (dd, J = 10.8 Hz, 8.0 Hz, 1H, H-3), 4.42
(m, 2H, H-2,H-1’) , 4.00 (m, 2H, H-6), 3.85 (m, 2H, H-5, H-3’), 3.80 (d, J =
8.4 Hz, 1H, H-4), 3.72 (m, 1H, H-6’a), 3.71 (s, 3H, OCH3), 3.69 (m, 1H, H-
6’b), 3.59 (m, 2H, H-4’,H-2’), 3.45 (dd, J = 9.6 Hz, 2.8Hz, 1H, H-5’), 2.68
(brs, 3H), 1.07, 0.88 (2s, 18H, 2×C(CH3)3); 13C NMR (101 MHz, CDCl3) δ
155.3, 151.0, 135.9, 135.6, 135.6, 135.5, 133.9, 133.4, 132.8, 132.6, 132.5,
131.8, 129.9, 129.9, 129.8, 127.8, 127.8, 127.7, 118.7, 114.4, 103.9, 97.5,
82.2, 77.3, 75.2, 75.1, 73.5, 71.8, 69.8, 68.5, 63.2, 63.0, 56.0, 55.6, 26.9,
26.6, 19.3, 18.9; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C59H67NNaO13Si2Na 1076.4049; found 1076.4029.
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mg, 0.58 mmol) and activated powdered 4 Å molecular sieves in dry MeCN
(20 mL) was stirred at room temperature under an argon atmosphere for
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Ying Zhang,[a] Fu-Long Zhao,[a] Tao
Luo,[a] Zhichao Pei*,[b] and Hai Dong*[a]
Page No. – Page No.
Regio/Stereoselective Glycosylation
of Diol and Polyol Acceptors in
Efficient Synthesis of Neu5Ac-α-2,3-
LacNPhth Trisaccharide
An efficient approach to synthesize a Neu5Ac-α-2,3-LacNPhth derivative 3 was
developed, resulting in a total yield of 18.5% over only 10 steps starting from
glucosamine hydrochloride.
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