O-Glycosylation Enabled by N-(Glycosyloxy)acetamides

Article abstract of DOI:10.1021/acs.joc.8b01003

A novel glycosylation protocol has been established by using N-(glycosyloxy)acetamides as glycosyl donors. The N-oxyacetamide leaving group in donors could be rapidly activated in the presence of Cu(OTf)₂ or SnCl₄ under microwave irr

Full text of DOI:10.1021/acs.joc.8b01003

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Article
O-Glycosylation Enabled by N-(Glycosyloxy)acetamides
Miao Liu, Bo-Han Li, De-Cai Xiong, and Xin-Shan Ye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01003 • Publication Date (Web): 25 Jun 2018
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The Journal of Organic Chemistry
OꢀGlycosylation Enabled by N-(Glycosyloxy)acetamides
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Miao Liu†‡, BoꢀHan Li‡, DeꢀCai Xiong*‡§, and XinꢀShan Ye*†‡
†National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China
‡State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
§State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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ABSTRACT: A novel glycosylation protocol has been established by using Nꢀ(glycosyloxy)acetamides as glycosyl donors. The Nꢀ
oxyacetamide leaving group in donors could be rapidly activated in the presence of Cu(OTf)2 or SnCl4 under microwave irradiation. This
glycosylation process afforded the coupled products in high yields, and the reaction enjoyed a broad substrate scope, even for disarmed
donors and hindered acceptors. The easy availability of the donors, the high stability of N-(glycosyloxy)acetamides, as well as the small
leaving group, make this method very practical.
■ INTRODUCTION
Oligosaccharides and glycoconjugates play significant roles in a large variety of biological processes.1 However, due to the limited
availability of homogeneous and structurallyꢀdefined oligosaccharides and glycoconjugates, the development in the area of glycobiology is
hindered. The isolation of oligosaccharides from natural sources is a formidable task because they often exist in highly microheterogeneous
forms.2 In many cases, chemical synthesis is the major route to obtain this type of compounds. The key reaction in the chemical synthesis
of oligosaccharides is the glycosylation reaction.3 Tremendous efforts have been made to develop effective glycosylation methods. Espeꢀ
cially, a large variety of glycosyl donors such as glycosyl halides,4 thioglycosides,5 glycosyl thioimidates,6 glycosyl trichloroacetimidates,7
glycals,8 hemiacetals,9 glycosyl phosphates,10 and alkynyl glycosides11 have been widely used for the assembly of oligosaccharides. Neverꢀ
theless, there is no general glycosylation method available and the synthesis of complex oligosaccharides is still difficult. Therefore, the
development of new glycosyl donors is highly desirable.
Among various glycosyl donors, there is a class of glycosyl donors which could be activated with the assistance of vicinal exoanomerꢀ
icꢀatom or remote functionalꢀsubstituent on leaving group. Elegant studies on glycosyl donors such as nꢀpentenyl glycosides,12 nꢀpentenyl
esters,13 glycosyl benzyl phthalates,14 alkynoates,15 glycosyl pentenoates,16 glycosyl orthoꢀalkynylbenzoates,11b 2ꢀ(2ꢀpropylsulfinyl)benzyl
glycosides,17 propargyl 1,2ꢀorthoesters,18 oꢀ(pꢀmethoxyphenylethynyl)phenyl glycosides,19 Sꢀbenzoxazolyl (SBox) glycosides,20 Sꢀ
thiazolinyl (STaz) glycosides,21 and glycosyl isoquinolineꢀ1ꢀcarboxylates,22 were reported. These donors possess auxiliary activation funcꢀ
tional groups such as alkenyl, alkynyl, SC=N and heterocyclic substituents, and they could be easily activated by either an electrophilic
reaction or a chelating reaction under mild conditions (Scheme 1a). Some of them are compatible with orthogonal or latentꢀactive oligoꢀ
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saccharide synthesis strategy. However, these donors still suffer from some drawbacks such as longer reaction time. Thus, we intend to
develop new type of glycosyl donors for glycosylation reactions.
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Hydroxamates usually have high affinity to Lewis acids or metal ions as bidentate ligands. Hydroxamate leaving groups have been
used in BF3•Et2Oꢀpromoted coupling reaction of mixed acetals with organotrifluoroborates by Bode’s group.23 Inspired by these studies,24
we envisaged that glycosylated hydroxamates might be good glycosyl donors for the construction of glycosidic bonds (Scheme 1b). Herein
we describe our investigation on the glycosylation reaction using Nꢀhydroxamate as the leaving group.
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Scheme 1. Glycosyl donors activated by either an electrophilic reaction or a chelating reaction
a) Previous work:
O
O
O
PGO
PGO
O
O
PGO
E+
O
O
O
PGO
O
O
O
O
E+
R
OR
E+
Kim's work (2004)
Fraser-Reid's work (1988 and 1991)
Kim's work (2006)
Imagawa and Nishizawa's work (2006)
Yu's work (2008)
OTf
O
O
O
O
PGO
S
PGO
S
X
PGO
X
Mn+
N
N
O
(X = O, S)
M
(X = O, S)
Tang's work n
Wan's work (2015 and 2016)
Demchenko's work (2006 and 2011)
+
(2017)
b) Our work:
O
O
ROH, microwave
PGO
O
O
PGO
MLn
OR
N
H
■ RESULTS AND DISCUSSION
To assess the feasibility of our idea, a systematic survey of substitution patterns on hydroxamate was carried out. For this purpose, gaꢀ
lactoside 3 with a phthalimidyl group,25 galactoside 4 with a succinimidyl group,18 galactoside 5 with a Nꢀmethylacetamidyl group,4a and
galactoside 7 with an acetamidyl group,26 were readily prepared from galactosyl bromide 1 (Scheme 2). With these glycosyl donors in
hand, we evaluated the glycosylation reactions of glycosyl acceptor 8 with these donors under different conditions (Table 1, Tables S1 and
S2 in the Supporting Information). The glycosyl donors 3 and 4 appeared inert to most of Lewis acids (Table 1, entries 1ꢀ4; Table S1),
probably due to the low reactivity of anomeric oxygen atom resulting from the introduction of two strong electronꢀwithdrawing carbonyl
groups. To our delight, the glycosyl donor 5 with an electronꢀdonating Nꢀmethyl group could smoothly react with the acceptor 8 in the
presence of 1.5 equiv. of SnCl4 at room temperature (Table 1, entry 5, 80% yield). Increasing the reaction temperature to 40 °C not only
shortened the reaction time to 40 min, but also improved the yield of coupled product 9 to 92% (Table 1, entry 6). Under the same reaction
conditions, the glycosyl donor 7 with an acetyl substituent also worked well (Table 1, entry 7, 96% yield). This reaction could be accelerꢀ
ated by microwave irradiation (Table 1, entry 19). Moreover, the comparable outcome for the glycosylation of acceptor 8 with donor 7
could also be obtained in the presence of 2.0 equiv. Cu(OTf)2 under microwave irradiation at 80 °C for one hour (Table 1, entry 15, 95%
yield). Thus, both NꢀoxyꢀNꢀmethylacetamide and Nꢀoxyacetamide could be used as leaving groups.
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Scheme 2. Synthesis of Glycosyl Donors 3ꢀ7
OBz
OBz
O
OBz
OBz
O
OBz
OBz
OBz
O
OBz
O
O
O
O
N-hydroxy-N-methyl acetamide
N-hydroxyphthalimide
a. 85% N2H4•H2O, EtOH, rt
O
BzO
O
N
BzO
O
N
AgOTf, CH2Cl2, 0 °C to rt
OBz
BzO
Bu4NHSO4, 1 M Na2CO3, CH2Cl2
86%
b. Ac2O, DMAP, EtOH, rt
83% two steps
BzO
N
BzO
BzO
OBz
H
O
5 ( 4-Oax 59%)
6 ( 4-Oeq 70%)
Br
1 ( 4-Oax)
2 ( 4-Oeq)
7
3
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OBz
OBz
O
O
Bu4NHSO4, 1 M Na2CO3, CH2Cl2, rt
O
BzO
N
N-hydroxysuccinimide
BzO
81%
O
4
Table 1. Screening the Leaving Groupsa
entry
donor
promoter (equiv.)
T (oC)
t (h)
yield (%)b
1
2
3
3
4
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5
7
7
7
7
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7
BF3•Et2O (1.5)
TMSOTf (1.5)
BCl3 (1.5)
rt
rt
8
8
8
8
8
N.R.c
0
3
rt
0
4
SnCl4 (1.5)
rt
0
5
SnCl4 (1.5)
rt
80
92
96
81
0
6
SnCl4 (1.5)
40
40
40
40
40
40
rt
40 min
7
SnCl4 (1.5)
40 min
8
SnCl4 (0.8)
1
8
8
8
8
5
2
1
9
SnCl2 (1.5)
10
11
12
13
FeCl3 (1.5)
38
0
B(C6H5)3 (0.1)
Cu(OTf)2 (1.0)
Cu(OTf)2 (4.0)
15
94
65
95
rt
14d
15d, e
16d, f
17d, g
18d, h
19d
Cu(OTf)2 (2.0)
Cu(OTf)2 (2.0)
Cu(OTf)2 (2.0)
Cu(OTf)2 (2.0)
40
80
80
80
1
1
30
50
Cu(OTf)2 (2.0)
SnCl4 (1.5)
80
40
1
trace
96
0.5
aReaction conditions: donor (0.036 mmol), acceptor (0.026 mmol), CH2Cl2 (1.0 mL), under argon atmosphere. Isolated
yield. cN.R.: no reaction was detected. dMicrowave irradiation (100 W). eClCH2CH2Cl (1.0 mL). fEt2O (1.0 mL). gToluene
(1.0 mL). hCH3CN (1.0 mL).
b
Since the suitable leaving groups were identified, we then turned our attentions to check the glycosylation substrate scope of the Nꢀ
oxyꢀNꢀmethylacetamide leaving group (Table 2). Considering that the glycosylation reaction of the acceptor 8 with the disarmed donor 5
proceeded smoothly in high yield, the coupling reaction of disarmed donor 5 with hindered acceptor 10 was examined firstly. Yet the deꢀ
sired disaccharide 11 was obtained in 33% yield (Table 2, entry 1), accompanying the galactosyl chloride as the main byꢀproduct. The
reaction outcome of disarmed donors (5, 6) and secondary alcohol 12 with a free hydroxyl at the Cꢀ3 position was still unsatisfactory (Taꢀ
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ble 2, entries 2ꢀ 3), and the generated glycosyl chlorides did not continue to undergo the glycosylation at all. Besides, disaccharide 13 was
also obtained in poor yield with the use of microwave irradiation (20%, Table 2, entry 2). Gratifyingly, the glucosyl donor 6 coupled with
the acceptor 8 to afford the disaccharide 15 in 98% yield (Table 2, entry 4). Thus, the NꢀoxyꢀNꢀmethylacetamide leaving groupꢀcontaining
donors might be suitable for the glycosylation of acceptors with high nucleophilicity.
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Table 2. The Coupling Reaction of NꢀMethylacetamidyl Glycosidesa
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aReaction conditions: donor (0.036 mmol), acceptor (0.026 mmol), SnCl4 (0.039 mmol), CH2Cl2 (1.0 mL),
under argon atmosphere. bIsolated yield. cMicrowave (100 W, 40 °C)
Scheme 3. Synthesis of the donors of acetamidyl glycosides
O
NH
O
Br
O
N
O
a. 85%N2H4•H2O, EtOH, rt
N-hydroxyphthalimide
AgOTf, CH2Cl2, 0°C to rt
81%
O
O
BzO
BzO
O
O
b. Ac2O, DMAP, EtOH, rt
82%
BzO
BzO
18
BzO
20
OBz
OBz
BzO
OBz
19
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In view of the limited substrate scope, we next explored the glycosylation using glycosyl donors with Nꢀoxyacetamide leaving group
(Table 3). As shown in Scheme 3, various disarmed donors 17, 20, 23, 26 were able to be readily prepared from the corresponding glycoꢀ
syl bromides27 via phthalimidyl glycosides. Compounds 29ꢀ30 were obtained from compounds 27ꢀ28 by Mitsunobu reaction,28 which
were transformed to armed donors 31ꢀ32 smoothly. The compound 34 was prepared from thiogalactoside 33,29 which was further conꢀ
verted to donor 35. It is noteworthy that these donors were found to be very stable at room temperature for more than one year without
noticeable decomposition. With all the glycosyl donors in hand, the glycosylation reaction was carried out. Under the promotion of 2.0
equiv. Cu(OTf)2, the coupling reaction of the disarmed galactosyl donor 7 with acceptors 12, 36 and 38 afforded the corresponding disacꢀ
charides 13, 37 and 39 in 90%, 90% and 92% yields, respectively (Table 3, entries 2ꢀ4). Similarly, donor 7 could also react with acceptor
10 having a free hydroxyl group at the Cꢀ4 position, to produce disaccharide 11 in 75% yield (Table 3, entry 1). The coupling reaction of
7 with the hindered acceptors 40 and 42 also furnished the corresponding products 41 and 43 in 89% and 95% yields, respectively (Table
3, entries 5 and 6). Moreover, the glycosylation of the thioglycosyl acceptor 44 with the disarmed glycosyl donor 17 provided the desired
disaccharide 45 (Table 3, entry 7), implying that the N-(glycosyloxy)acetamides could be probably applied to the orthogonal glycosylaꢀ
tion strategy. The glycosyl coupling reaction of the benzoylated rhamnosyl, mannosyl, and ribosyl donors gave the desired disaccharides
in high yields as well (Table 3, entries 10ꢀ15).
To further expand the substrate scope, this glycosylation method was applied to the armed donors. To our disappointment, only 50%
yield of disaccharide 52 was obtained in the coupling reaction of donor 31 with 8 when using 1.5 equiv. of SnCl4 as a promoter. In conꢀ
trast, the use of Cu(OTf)2 (2.0 equiv.) as a promoter produced compound 52 in 89% yield. To our surprise, decreasing the amount of
SnCl4 to 0.5 equiv. led to the formation of product 52 in excellent yield (97%, Table 3, entry 16). However, further decrease in the quanꢀ
tity of SnCl4 gave the inferior result (Table S3 in Supporting Information). In the same conditions, the donor 31 reacted smoothly with
acceptors 10 and 12 to give the corresponding glycosylation products 53 and 54 in 85% and 90% yields, respectively (Table 3, entries 17
and 18). Notably, the glycosylation of the acidꢀsensitive acceptor 57 with donor 32 produced disaccharide 58 in 78% yield (Table 3, entry
21). The aminosugar donor 35 also worked in the glycosylation reaction (Table 3, entries 23 and 24). The glycosylation yields obtained
by using our donor are comparable/superior to the published data obtained by using trichloroacetimidate or thioglycoside donors, such as
88% vs 80% (using the trichloroacetimidate donor) yield of 56,30 and 85% vs 69% (using the thioglycoside donor 33) yield of 60.31
Table 3. The Substrate Scope of the Glycosylation Reactiona
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aReaction conditions: donor (0.036 mmol), acceptor (0.026 mmol), promoter, solvent (1.0 mL), under argon atmosphere. Isolated yield.
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cCu(OTf)2 (0.052 mmol), microwave (100 W, 80 °C), 1ꢀ2 h. SnCl4 (0.039 mmol), microwave (100 W, 40 °C), 30 min. SnCl4 (0.013
d
e
mmol), microwave (100 W, 40 °C), 30 min. fCu(OTf)2 (0.104 mmol), dry CH2Cl2, rt, 5ꢀ8 h. gCu(OTf)2 (0.104 mmol), 50 °C, 5ꢀ8 h.
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Interestingly, it was found that the leaving group could be detected in a very small amount after the simple filtration (see the Supportꢀ
ing Information), which would facilitate the separation. Finally, this protocol presents a great potential for the largeꢀscale preparation.
The reaction of the disarmed glycosyl donor 7 with glycosyl acceptor 40 was performed under the optimized conditions. A gramꢀscale
glycoside 41 was obtained in 85% isolated yield, which is almost consistent with the yield of the smallꢀscale reaction. This further proves
the practicality of the glycosylation protocol (Scheme 4).
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Scheme 4. GramꢀScale Synthesis of Compound 41
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■ CONCLUSION
In conclusion, we have systematically examined the feasibility that hydroxamates are used as the leaving groups of glycosylation reacꢀ
tions. A survey of substitution patterns on hydroxamate showed that the NꢀoxyꢀNꢀmethylacetamide and Nꢀoxyacetamide could be used as
the leaving groups. The NꢀoxyꢀNꢀmethylacetamidylꢀcontaining glycosides are suitable donors for the glycosylation of acceptors with high
nucleophilicity. The glycosylation using the Nꢀoxyacetamidylꢀcontaining glycosides as donors can rapidly afford the coupled products in
high yields in the presence of Cu(OTf)2 or SnCl4 under microwave irradiation. These new glycosyl donors are stable and can be convenꢀ
iently prepared from the corresponding phthalimidyl glycosides via hydrazinolysis and subsequent acetylation. The leaving group in glycoꢀ
syl donors could be precipitated from the reaction mixture, facilitating the subsequent separation. Moreover, this glycosylation process is
able to be used in the gramꢀscale synthesis. Thus, N-(glycosyloxy)acetamides are novel and practical glycosyl donors which provides an
alternative method for complex oligosaccharide synthesis.
■ EXPERIMENTAL SECTION
General Methods. All reagents and solvents were dried commonly before use according to standard methods. CH2Cl2 was disꢀ
tilled over CaH2, THF and toluene were distilled over sodium. Commercial reagents were used without further purification unless otherꢀ
wise noted. Reactions were monitored by analytical thinꢀlayer chromatography (TLC) on silica gelꢀcoated aluminium plates (60 F254).
Spots were detected under UV Light (254 nm) and charring with a solution of (NH4)6Mo7O24•4H2O (24.00 g, 19.4 mmol) and
Ce(NH4)2(NO3)6 (0.50 g, 0.90 mmol) in sulfuric acid (5%, 500 mL). Column chromatography was performed on silica gel (200ꢀ300 mesh).
The microwave reaction was carried out in a sealed microwave tube with Discover SP Microwave Synthesizer (CEM), and the reaction
temperature was measured by an external infrared sensor. 1H NMR spectra were recorded at room temperature in CDCl3 with TMS (δ = 0
ppm) as internal standard. 13C NMR spectra were obtained by using the same NMR spectrometer and were calibrated with CDCl3 (δ =
77.00 ppm). The following standard abbreviations are used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
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multiplet, dd = doublet of doublets, dt = doublet of triplets, and br = broad. High resolution mass spectra were performed on a mass specꢀ
trometer (QꢀTOF). Melting points were measured using a WRSꢀ2A microcomputer melting point apparatus.
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Preparation of Glycosyl Donors:
5
6
7
8
Phthalimidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (3). In an ovenꢀdried flask, compound 1 (1.22 mmol, 0.80 g), Nꢀ
hydroxyphthalimide (8.54 mmol, 1.39 g), CH2Cl2 (9.6 mL) and 1M Na2CO3 solution (9.6 mL) were added. Then Bu4NHSO4 (1.22 mmol,
0.41 g) was added with vigorous stirring. The reaction mixture was stirred at room temperature and the reaction was monitored by TLC.
After completion (~4 h), the mixture was extracted with CH2Cl2 for three times and the organic phases were combined, washed with water,
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (petroleum
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ether: ethyl acetate = 4: 1, v/v) to afford 3 as a white solid (0.77 g, 86%). The H NMR and 13C NMR data for 3 are in accordance with
those reported previously.18
Succinimidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (4). In an ovenꢀdried flask, compound 1 (1.22 mmol, 0.80 g), Nꢀ
hydroxysuccinimide (8.54 mmol, 0.98 g), CH2Cl2 (9.6 mL) and 1M Na2CO3 solution (9.6 mL) were added. Then Bu4NHSO4 (1.22 mmol,
0.41 g) was added with vigorous stirring. The reaction mixture was stirred at room temperature and the reaction was monitored by TLC.
After completion (~5 h), The mixture was extracted with CH2Cl2 for three times and the organic phases were combined, washed with waꢀ
ter, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (petroleum
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ether: ethyl acetate = 3: 1, v/v) to afford 4 as a white solid (0.68 g, 81%). The H NMR and 13C NMR data for 4 are in accordance with
those reported previously.18
NꢀMethylacetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (5). An ovenꢀdried flask fitted with a magnetic stirꢀbar
was charged with compound 1 (0.61 mmol, 0.40 g), NꢀhydroxyꢀNꢀmethylacetamide (1.22 mmol, 0.11 g), activated 4Å molecular sieves
(0.50 g), and CH2Cl2 (5 mL) under an argon atmosphere. After cooling to 0 °C, AgOTf (1.22 mmol, 0.32 g) dissolved in dry toluene (0.6
mL) was added. The reaction was warmed up, stirred at room temperature and monitored by TLC. After completion (~6 h), the reaction
was quenched with triethylamine (0.3 mL), then filtered through Celite and concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether: ethyl acetate = 3: 1, v/v) to afford 5 as a white solid (0.24 g, 59%). mp: 80.3 – 80.8 oC; 1H NMR
(400 MHz, CDCl3) δ 8.13 – 7.24 (m, 20H), 6.07 (d, J = 2.7 Hz, 1H), 5.92 (dd, J = 9.9, 8.8 Hz, 1H), 5.73 (dd, J = 10.3, 3.2 Hz, 1H), 5.27 (d,
J = 8.4 Hz, 1H), 4.71 (dd, J = 11.3, 7.1 Hz, 1H), 4.54 (dd, J = 11.4, 5.5 Hz, 1H), 4.46 (t, J = 6.1 Hz, 1H), 3.30 (s, 3H), 2.09 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 174.3, 166.0, 165.5, 165.4, 165.1, 133.8, 133.7, 133.5, 133.4, 130.0, 129.8, 129.7 (×2), 129.3, 128.9, 128.7
(×2), 128.6 (×2), 128.4, 105.4, 72.1, 71.6, 68.1, 68.0, 62.1, 36.7, 21.0; HRMS (ESI) calcd for C37H34NO11 [M+H]+ 668.2126, found
668.2128.
NꢀMethylacetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranoside (6). The same procedure for the synthesis of 5 was applied,
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yielding 6 (0.28 g, 70%) as a white solid. mp: 77.9 – 78.8 oC; H NMR (400 MHz, CDCl3) δ 8.06 – 7.78 (m, 8H), 7.60 – 7.23 (m, 12H),
5.96 (t, J = 9.7 Hz, 1H), 5.70 (t, J = 9.7 Hz, 1H), 5.62 (t, J = 9.1 Hz, 1H), 5.21 (d, J = 8.4 Hz, 1H), 4.72 (dd, J = 12.2, 2.8 Hz, 1H), 4.51 (dd,
J = 12.2, 5.7 Hz, 1H), 4.26 – 4.17 (m, 1H), 3.22 (s, 3H), 2.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.0, 165.7, 165.2, 164.9, 133.7,
133.6, 133.4, 133.3, 129.9, 129.8, 129.7 (×2), 129.4, 128.6 (×2), 128.5 (×3), 128.4, 104.8, 72.9, 72.6, 70.2, 69.2, 62.6, 36.6, 20.9; HRMS
(ESI) calcd for C37H34NO11 [M+H]+ 668.2126, found 668.2133.
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Acetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (7). To a solution of 3 (1.21 mmol, 0.90 g) in ethanol (35 mL) was
added slowly 85% hydrazine hydrate (1.44 mmol, 84 ꢁL), and the reaction mixture was stirred at room temperature and the reaction was
monitored by TLC. After completion (~4 h), DMAP (0.24 mmol, 0.03 g) and Ac2O (6.06 mmol, 0.57 mL) were added at 0 °C, and the
mixture was stirred for another 4 h. Then the reaction mixture was diluted with CH2Cl2, washed with sat. NaHCO3 solution and sat. NaCl
solution, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash column chromatography (petroleum
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ether: ethyl acetate = 1: 1, v/v) to afford 7 as a white solid (0.66 g, 83% yield over 2 steps). mp: 179.5 – 179.9 C; H NMR (400 MHz,
CDCl3) δ 8.08 – 7.22 (m, 20H), 6.03 (s, 1H), 5.87 (t, J = 9.2 Hz, 1H), 5.73 (d, J = 10.1 Hz, 1H), 5.19 (br s, 1H), 4.70 (br s, 1H), 4.43 (s,
2H), 1.99 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.0, 165.5, 165.4, 133.8, 133.6, 133.5, 133.4, 130.0, 129.9, 129.8, 129.3, 128.9, 128.8,
128.6, 128.5, 128.4, 103.9, 72.0, 71.4, 68.0, 67.9, 61.9, 20.0; HRMS (ESI) calcd for C36H32NO11 [M+H]+ 654.1970, found 654.1996.
Phthalimidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranoside (16). The same procedure for the synthesis of 3 was applied,
yielding 16 (0.64 g, 71%) as a white solid. The 1H NMR and 13C NMR data for 16 are in accordance with those reported previously.18
Acetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranoside (17). Glycosyl donor 17 were prepared according to the procedure
for the preparation of 7 (0.62 g, 79%) as a white solid. mp: 94.3 – 95.8 oC; 1H NMR (400 MHz, CDCl3) δ 8.72 (br s, 1H), 8.06– 7.28 (m,
20H), 6.00 (t, J = 9.5 Hz, 1H), 5.75 (t, J = 9.2 Hz, 1H), 5.64 (t, J = 8.7 Hz, 1H), 5.20 (br s, 1H), 4.72 (d, J = 11.9 Hz, 1H), 4.54 (dd, J =
12.2, 4.6 Hz, 1H), 4.30 – 4.21 (m, 1H), 1.98 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.1, 165.7, 165.1, 133.6, 133.4, 133.3, 130.0, 129.9,
129.8, 129.4, 128.6, 128.5 (×2), 128.4, 103.4, 72.9, 72.5, 70.1, 69.1, 62.7, 20.0; HRMS (ESI) calcd for C36H32NO11 [M+H]+ 654.1970,
found 654.1983.
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Phthalimidyl 2,3,4,ꢀtriꢀOꢀbenzoylꢀαꢀLꢀrhamnopyranoside (19). An ovenꢀdried flask fitted with a magnetic stirꢀbar was
charged with compound 18 (0.61 mmol, 0.33 g), Nꢀhydroxyphthalimide (1.22 mmol, 0.20 g), activated 4 Å molecular sieves (0.50 g), and
CH2Cl2 (5 mL) under an argon atmosphere, After cooling to 0 oC, AgOTf (1.22 mmol, 0.32 g) dissolved in dry toluene (0.6 mL) was addꢀ
ed. The reaction was warmed up, stirred at room temperature and monitored by TLC. After completion (~4 h), the reaction was quenched
with triethylamine (0.3 mL), then filtered through Celite and concentrated in vacuo. The crude product was purified by flash column chroꢀ
o
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matography (petroleum ether: ethyl acetate = 3: 1, v/v) to afford 19 as a white solid (0.31 g, 81%). mp: 102.3 – 103.8 C; H NMR (400
MHz, CDCl3) δ 8.14 – 7.23 (m, 19H), 6.17 (d, J = 1.6 Hz, 1H), 5.98 (dd, J = 10.0, 3.3 Hz, 1H), 5.80 (td, J = 10.0, 1.4 Hz, 1H), 5.67 (s,
1H), 5.22 – 5.08 (m, 1H), 1.43 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.8, 165.3, 165.1, 163.1, 134.7, 133.6, 133.4, 133.2,
130.0, 129.9, 129.8, 129.2, 129.1 (×2), 128.9, 128.6, 128.5, 128.3, 123.8, 102.7, 71.0, 69.6, 69.3, 68.6, 17.4; HRMS (ESI) calcd for
C35H31N2O10 [M+NH4]+ 639.1973, found 639.1984.
Acetamidyl 2,3,4,ꢀtriꢀOꢀbenzoylꢀαꢀLꢀrhamnopyranoside (20). Glycosyl donor 20 was prepared according to the procedure for
the preparation of 7 (0.53 g, 82% yield over 2 steps) as a white solid. mp: 83.4 – 84.1 oC; 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.06
– 7.24 (m, 15H), 5.87 – 5.75 (m, 2H), 5.70 (t, J = 9.8 Hz, 1H), 5.31 (s, 1H), 4.78 (br s, 1H), 2.04 (s, 3H), 1.39 (d, J = 6.0 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 165.8, 165.5 (×2), 133.6, 133.4, 133.2, 130.0, 129.8, 129.7, 129.2, 129.1, 129.0, 128.6, 128.5, 128.3, 102.1,
71.2, 69.8, 69.0, 68.6, 20.0, 17.6; HRMS (ESI) calcd for C29H31N2O9 [M+NH4]+ 551.2024, found 551.2031.
Phthalimidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀmannopyranoside (22). The same procedure for the synthesis of 19 was applied,
yielding 22 (0.36 g, 79% ) as a white solid. The 1H NMR and 13C NMR data for 22 are in accordance with those reported previously.18
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The Journal of Organic Chemistry
Acetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀmannopyranoside (23). Glycosyl donor 23 was prepared according to the procedure
for the preparation of 7 (0.63 g, 79% yield over 2 steps) as a white solid. mp: 183.6 – 184.5 oC; 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H),
8.17 – 7.27 (m, 20H), 6.23 (t, J = 9.9 Hz, 1H), 5.90 (d, J = 10.5 Hz, 2H), 5.43 (s, 1H), 5.31 (s, 1H), 4.81 (d, J = 12.2 Hz, 1H), 4.52 (d, J =
11.5 Hz, 1H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.3, 165.9, 165.4, 165.3, 133.5, 133.4, 133.1, 129.9, 129.8 (×2), 128.9 (×2),
128.8, 128.5 (×3), 128.4, 101.9, 77.3, 70.4, 68.5, 66.1, 62.5, 19.9; HRMS (ESI) calcd for C36H32NO11 [M+H]+ 654.1970, found 654.1974.
Phthalimidyl 2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranoside (25). The same procedure for the synthesis of 19 was applied, yielding
25 (0.30 g, 82%) as a white solid. The 1H NMR and 13C NMR data for 25 are in accordance with those reported previously.18
Acetamidyl 2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranoside (26). Glycosyl donor 26 was prepared according to the procedure for the
preparation of 7 (0.43 g, 83% yield over 2 steps) as a white solid. mp: 70.5 – 71.2 oC; 1H NMR (400 MHz, CDCl3) δ 9.66 (br s, 1H), 8.11 –
7.23 (m, 15H), 5.95 (br s, 1H), 5.75 (t, J = 5.6 Hz, 1H), 5.61 (s, 1H), 5.05 (br s, 1H), 4.75 – 4.60 (m, 2H), 1.99 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 167.4, 165.5, 164.9, 133.7, 133.6, 129.9 (×2), 129.8, 129.4, 128.9, 128.6 (×2), 128.4, 108.2, 81.8, 73.7, 72.2, 65.7, 20.0;
HRMS (ESI) calcd for C28H26NO9 [M+H]+ 520.1602, found 520.1615.
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Phthalimidyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranoside (29). In an ovenꢀdried flask, compound 27 (1.90 mmol, 1.03 g), Nꢀ
hydroxyphthalimide (2.30 mmol, 0.37 g) and PPh3 (2.30 mmol, 0.60 g) were added and dissolved in dry THF (10 mL) under an argon
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atmosphere. After the mixture was cooled to 0 C, diethyl azodicarboxylate (2.30 mmol, 0.5 mL) was added dropwise. Afterwards, the
reaction was warmed up and stirred at room temperature overnight. The reaction was quenched with sat. NaHCO3 solution. The mixture
was extracted with ethyl acetate, washed with sat. NaCl solution , dried over anhydrous Na2SO4 and concentrated. The crude product was
purified by flash column chromatography (petroleum ether: ethyl acetate = 4: 1, v/v) to afford 29 as a white solid (0.77 g, 59%, α/β = 3: 1).
1H NMR (400 MHz, CDCl3) δ 7.80 – 7.76 (m, 3H), 7.68 – 7.65 (m, 3H), 7.53 (t, J = 8.4 Hz, 3H), 7.43 – 7.15 (m, 30H), 5.67 (d, J = 3.8 Hz,
1H), 5.18 (d, J = 10.6 Hz, 0.38H), 5.06 (dd, J = 13.1, 9.6 Hz, 1.41H), 5.00 – 4.86 (m, 3.76H), 4.86 – 4.73 (m, 3.18H), 4.69 (d, J = 11.8 Hz,
0.55H), 4.61 (d, J = 11.3 Hz, 1.6H), 4.51 (dd, J = 27.5, 11.9 Hz, 2.32H), 4.43 – 4.36 (m, 1H), 4.29 (dd, J = 10.5, 3.9 Hz, 1H), 4.15ꢀ4.11
(m, 2.69H), 3.86 (d, J = 2.3 Hz, 0.4H), 3.69 – 3.51 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 163.5, 162.9, 138.8, 138.7 (×2), 138.6, 138.5,
138.4, 138.1, 134.5, 129.1, 129.0, 128.6, 128.5 (×2), 128.4 (×3), 128.3 (×2), 128.0, 127.8 (×2), 127.7 (×2), 127.6 (×2), 123.7, 123.6, 108.5,
102.7, 82.0, 78.3, 78.0, 75.5, 75.4, 75.1 (×2), 74.7 (×2), 73.6 (×2), 73.5 (×2), 73.3, 72.9, 71.1, 68.9, 68.3; HRMS (ESI) calcd for
C42H43N2O8 [M+NH4]+ 703.3014, found 703.3022.
Phthalimidyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀglucopyranoside (30). The same procedure for the synthesis of 29 was applied, yielding
30 (0.91 g, 70%, α/β = 2: 1) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.78 (m, 3H), 7.75 – 7.68 (m, 3H), 7.51 (dd, J = 18.6,
7.2 Hz, 3H), 7.41 – 7.13 (m, 28H), 5.62 (d, J = 3.8 Hz, 1H), 5.18 (d, J = 10.6 Hz, 0.5H), 5.11 (t, J = 9.1 Hz, 1.5H), 5.03 (d, J = 10.9 Hz,
1H), 4.94 (d, J = 11.0 Hz, 0.5H), 4.90 – 4.69 (m, 5.5H), 4.65 – 4.50 (m, 3.5H), 4.40 (d, J = 12.0 Hz, 1H), 4.13 (t, J = 9.5 Hz, 1H), 3.90 (dd,
J = 10.9, 2.2 Hz, 1H), 3.85 – 3.60 (m, 5.5H), 3.59 – 3.48 (m, 0.5H); 13C NMR (101 MHz, CDCl3) δ 163.4, 163.0, 138.8, 138.5 (×2), 138.4,
138.1, 138.0 (×2), 137.7, 134.6, 129.0 (×2), 128.7, 128.6, 128.5, 128.4 (×2), 128.3, 128.1 (×2), 128.0 (×2), 127.9, 127.7 (×2), 127.6, 127.5,
123.7, 123.6, 107.7, 102.4, 84.4, 81.5, 80.6, 78.7, 76.0, 75.9, 75.7, 75.2, 75.1, 75.0, 73.6, 73.5, 72.8, 72.4, 68.9, 68.1; HRMS (ESI) calcd
for C42H43N2O8 [M+NH4]+ 703.3014, found 703.3011.
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Acetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranoside (31). To a solution of 29 (0.24 mmol, 0.17 g) in methanol (10 mL)
was added slowly 85% hydrazine hydrate (0.72 mmol, 42 ꢁL). The reaction was stirred at room temperature and monitored by TLC. After
completion (~1 h), the mixture was concentrated. Then crude product was dissolved in CH2Cl2 (8 mL) and 1M K2CO3 solution (8 mL),
AcCl (3.70 mmol, 266 ꢁL) dissolved in dry CH2Cl2 (2 mL) was added slowly at 0 oC. The mixture was stirred at room temperature and the
reaction was monitored by TLC. After completion (~2 h), the mixture was extracted with CH2Cl2 for three times and the organic phases
were combined, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether: ethyl acetate = 2: 1, v/v) to afford 31 as yellow oil (119 mg, 83% yield over 2 steps, α/β = 2: 1).
1H NMR (400 MHz, CDCl3) δ 8.46 (br s, 1H), 7.54 – 7.16 (m, 20H), 5.23 (br s, 0.72H), 5.09 – 4.63 (m, 5.64H), 4.57 (d, J = 11.4 Hz, 1H),
4.50 (d, J = 11.6 Hz, 1H), 4.39 (d, J = 11.8 Hz, 1H), 4.24 (s, 1H), 4.14 (dd, J = 10.2, 3.8 Hz, 1H), 3.94 (s, 2.41H), 3.59 – 3.42 (m, 2H),
2.11 (s, 1H), 1.85 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 167.8, 138.4, 138.2, 138.0, 137.4 (×2), 128.2 (×2), 128.1, 127.7 (×2), 127.5,
127.3 (×2), 101.4, 78.1, 75.3, 74.8, 74.6, 73.3, 73.0, 72.8, 70.6, 69.1, 19.6; HRMS (ESI) calcd for C36H43N2O7 [M+NH4]+ 615.3065, found
615.3082.
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Acetamidyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀglucopyranoside (32). Glycosyl donor 32 was prepared according to the procedure for
the preparation of 31 (0.12 g, 84% yield over 2 steps, α/β = 2: 1) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.19 (br s, 1H), 7.42 – 7.23
(m, 17.45H), 7.14 – 7.12 (m, 1.88H), 5.21 (br s, 0.73H), 4.97 (d, J = 10.9 Hz, 1H), 4.92 – 4.74 (m, 3.61H), 4.56 (d, J = 12.1 Hz, 1H), 4.49
(dd, J = 11.5, 4.4 Hz, 1.83H), 4.06 (br s, 0.65H), 3.96 (t, J = 9.2 Hz, 1H), 3.70 – 3.50 (m, 3.84H), 1.91 (s, 2H), 1.70 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 168.1, 138.7, 138.2, 137.9, 137.7, 128.5 (×2), 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 101.0, 81.5, 78.9, 77.4, 75.7, 75.1,
73.6, 72.8, 71.9, 68.8, 19.9; HRMS (ESI) calcd for C36H43N2O7 [M+NH4]+ 615.3065, found 615.3070.
Phthalimidyl 2ꢀazidoꢀ2ꢀdeoxyꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀgalactopyranoside (34). An ovenꢀdried flask fitted with a magnetic stirꢀ
bar was charged with 33 (1.27 mmol, 0.74 g), Nꢀhydroxyphthalimide (6.13 mmol, 1.00 g), diphenyl sulfoxide (0.89 mmol, 0.18 g), activatꢀ
ed 4Å molecular sieves (0.80 g), and CH2Cl2 (8 mL) under an argon atmosphere. After cooling to ꢀ78 oC, Tf2O (0.76 mmol, 128 ꢁL) was
added dropwise. The reaction was warmed up slowly and monitored by TLC. After completion (~6 h), the reaction was quenched with
triethylamine (200 ꢁL), then filtered with Celite and concentrated in vacuo. The crude product was purified by flash column chromatogꢀ
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raphy (petroleum ether: ethyl acetate = 3: 1, v/v) to afford 34 as a pale yellow oil (0.59 g, 75%). For the αꢀisomer: H NMR (400 MHz,
CDCl3) δ 7.87 – 7.76 (m, 4H), 7.46 – 7.29 (m, 15H), 5.55 (d, J = 3.6 Hz, 1H), 4.94 – 4.90 (m, 2H), 4.83 – 4.74 (m, 2H), 4.60 (d, J = 11.6
Hz, 2H), 4.52 (d, J = 11.8 Hz, 1H), 4.25 – 4.19 (m, 2H), 4.15 (dd, J = 11.0, 2.4 Hz, 1H), 3.69 (t, J = 8.2 Hz, 1H), 3.58 (dd, J = 9.2, 5.6 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 163.2, 138.3, 138.2, 137.5, 134.6, 128.9, 128.6, 128.4 (×2), 128.2, 128.1, 127.9, 127.8 (×2), 127.7,
123.7, 103.5, 77.0, 75.1, 73.4, 73.2, 72.4, 71.3, 68.0, 59.0; HRMS (ESI) calcd for C35H33N4O7 [M+H]+ 621.2344, found 621.2345.
Acetamidyl 2ꢀazidoꢀ2ꢀdeoxyꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀgalactopyranoside (35). Glycosyl donor 35 was prepared according to the
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procedure for the preparation of 31 (0.10 g, 80% yield over 2 steps, α/β = 2: 1) as yellow oil. H NMR (400 MHz, CDCl3) δ 8.65 (br s,
1H), 7.40 – 7.23 (m, 15H), 5.13 (br s, 1H), 4.86 (d, J = 11.3 Hz, 1H), 4.76 – 4.65 (m, 2H), 4.52 (d, J = 11.5 Hz, 2H), 4.46 – 4.25 (m, 2H),
4.07 (dd, J = 10.7, 3.5 Hz, 1H), 4.01 (s, 1H), 3.94 (br s, 1H), 3.56 (dt, J = 16.0, 9.2 Hz, 2H), 2.16 (s, 1H), 1.88 (s, 2H); 13C NMR (101
MHz, CDCl3) δ 168.3, 138.1, 137.7, 137.4, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0 (×2), 127.9 (×2), 102.3, 77.3, 74.9, 73.6, 73.4, 72.3,
71.1, 68.9, 59.1, 19.8; HRMS (ESI) calcd for C29H33N4O6 [M+H]+ 533.2395, found 533.2399.
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The Journal of Organic Chemistry
General Glycosylation Procedures:
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General procedure A. An ovenꢀdried flask fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol), acꢀ
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ceptor (0.026 mmol), activated 4 Å molecular sieves (100 mg) and CH2Cl2 (1.0 mL) under an argon atmosphere. After cooling to 0 C,
SnCl4 (1.5 equiv., 0.039 mmol) was added, then the mixture was stirred at 40 °C for 40 min. After completion, the reaction was quenched
with triethylamine (5.0 ꢁL), then filtered through Celite and concentrated in vacuo. The crude product was purified by flash column chroꢀ
matography (eluting with petroleum ether/ethyl acetate) to give the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
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31
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35
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51
52
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55
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60
General procedure B. A dried microwave tube fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol),
acceptor (0.026 mmol), activated 4Å molecular sieves (100 mg), and ClCH2CH2Cl (1 mL) under an argon atmosphere. After stirring for 20
min, Cu(OTf)2 (2.0 equiv., 0.052 mmol) was added at 0 °C, then put into themicrowave reactor at 80 °C for 1ꢀ2 h. After completion, the
reaction mixture was quenched with triethylamine (0.1 mL) and the solids were filtered off through a pad of Celite. The filtrate was conꢀ
centrated and the residue was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to give the
desired product.
General procedure C. A dried microwave tube fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol),
acceptor (0.026 mmol), activated 4Å molecular sieves (100 mg), and ClCH2CH2Cl (1 mL) under an argon atmosphere. After stirring for 20
min, SnCl4 (1.5 equiv., 0.039 mmol) was added dropwise at 0 °C, then put into the microwave reactor at 40 °C for 30 min. After compleꢀ
tion, the reaction was quenched with triethylamine (0.1 mL) and the solids were filtered off through a pad of Celite. The filtrate was conꢀ
centrated and the residue was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to give the
desired product.
General procedure D. A dried microwave tube fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol),
acceptor (0.026 mmol), activated 4Å molecular sieves (100 mg), and ClCH2CH2Cl (1 mL) under an argon atmosphere. After stirring for 20
min, SnCl4 (0.5 equiv., 0.013 mmol) was added dropwise at 0 °C, then put into the microwave reactor at 40 °C for 30 min. After compleꢀ
tion, the reaction was quenched with triethylamine (0.1 mL) and the solids were filtered off through a pad of Celite. The filtrate was conꢀ
centrated and the residue was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to give the
desired product.
General procedure E. An ovenꢀdried flask fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol), acꢀ
ceptor (0.026 mmol), activated 4Å molecular sieves (100 mg), and CH2Cl2 (1 mL) under an argon atmosphere. After stirring for 20 min,
Cu(OTf)2 (4.0 equiv., 0.10 mmol) was added at 0 °C, then the mixture was stirred at room temperature for 5ꢀ8 h. After completion, the
reaction was quenched with triethylamine (0.1 mL) and the solids were filtered off through a pad of Celite. The filtrate was concentrated
and the residue was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to give the desired prodꢀ
uct.
General procedure F. An ovenꢀdried flask fitted with a magnetic stirꢀbar was charged with donor (1.4 equiv., 0.036 mmol), acꢀ
ceptor (0.026 mmol), activated 4Å molecular sieves (100 mg), and ClCH2CH2Cl2 (1 mL) under an argon atmosphere. After stirring for 20
min, Cu(OTf)2 (4.0 equiv., 0.10 mmol) was added at 0 °C, then the mixture was stirred at 50 °C for 8 h. After completion, the reaction was
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quenched with triethylamine (0.1 mL) and the solids were filtered off through a pad of Celite. The filtrate was concentrated and the residue
was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to give the desired product.
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (9). The reaction of
donor 5 (25.0 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure A, affording 9
(eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 24.8 mg, 92% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 8
(12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 9 (25.7 mg, 95% yield); The reaction of donor 7
(24.1 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 9 (25.9
mg, 96% yield). The 1H NMR data for 9 are in accordance with those reported previously.32
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (11). The reaction of
donor 5 (25.0 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure A, affording
11 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 8.9 mg, 33% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 10
(12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 11 (20.2 mg, 75% yield). The 1H NMR data for
11 are in accordance with those reported previously.33
Methyl 2,4,6ꢀtriꢀOꢀbenzylꢀ3ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (13). The reaction of
donor 5 (25.0 mg, 0.036 mmol) and acceptor 12 (12.1 mg, 0.026 mmol) was performed as described in the general procedure A, affording
13 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 7.8 mg, 29% yield); The reaction of donor 5 (25.0 mg, 0.036 mmol) and acceptor 12
(12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 13 (eluent: petroleum ether/ethyl acetate = 5: 1
(v/v); 5.4 mg, 20% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 12 (12.1 mg, 0.026 mmol) was performed as deꢀ
scribed in the general procedure B, affording 13 (24.3 mg, 90% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 12
(12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 13 (25.7 mg, 95% yield). The 1H NMR data for
13 are in accordance with those reported previously.34
Methyl 2,4,6ꢀtriꢀOꢀbenzylꢀ3ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)ꢀαꢀDꢀglucopyranoside (14). The reaction of
donor 6 (25.0 mg, 0.036 mmol) and acceptor 12 (12.1 mg, 0.026 mmol) was performed as described in the general procedure A, affording
14 (eluent: petroleum ether/ethyl acetate = 4: 1 (v/v); 8.7 mg, 32% yield); The reaction of donor 17 (24.1 mg, 0.036 mmol) and acceptor 12
(12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 14 (22.2 mg, 82% yield). The 1H NMR data for
14 are in accordance with those reported previously.35
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)ꢀαꢀDꢀglucopyranoside (15). The reaction of
donor 6 (25.0 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure A, affording
15 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 26.5 mg, 98% yield); The reaction of donor 17 (24.1 mg, 0.036 mmol) and acceptor 8
(12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 15 (24.4 mg, 90% yield); The reaction of donor
17 (24.1 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 15
(24.6 mg, 91% yield). The 1H NMR data for 15 are in accordance with those reported previously.36
Methyl 3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀO-(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (37). The reaction of
donor 7 (24.1 mg, 0.036 mmol) and acceptor 36 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording
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37 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 24.4 mg, 90% yield). The 1H NMR data for 37 are in accordance with those reported
previously.34
1
2
3
4
5
6
7
8
9
(1S,2R,5S)ꢀ(+)ꢀ1ꢀMentyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (39). The reaction of donor 7 (24.1 mg, 0.036 mmol)
and acceptor 38 (4 mg, 0.026 mmol) was performed as described in the general procedure B, affording 39 (eluent: petroleum ether/ethyl
acetate = 8: 1 (v/v); 17.6 mg, 92% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 38 (4 mg, 0.026 mmol) was perꢀ
formed as described in the general procedure C, affording 39 (17.2 mg, 90% yield). The 1H NMR data for 39 are in accordance with those
reported previously.22
10
11
12
13
14
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16
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19
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33
34
35
36
37
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48
49
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54
55
56
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58
59
60
Cholesteryl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (41). The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor
40 (10 mg, 0.026 mmol) was performed as described in the general procedure B, affording 41 (eluent: petroleum ether/ethyl acetate = 7: 1
(v/v); 22.3 mg, 89% yield); The reaction of donor 7 (1.21 g, 1.80 mmol) and acceptor 40 (500.0 mg, 1.30 mmol) was performed as deꢀ
scribed in the general procedure B, affording 41 (1.07 g, 85% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 40 (10
mg, 0.026 mmol) was performed as described in the general procedure C, affording 41 (22.3 mg, 89% yield); The 1H NMR data for 41 are
in accordance with those reported previously.37
Adamantyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (43). The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor
42 (4.0 mg, 0.026 mmol) was performed as described in the general procedure B, affording 43 (eluent: petroleum ether/ethyl acetate = 4: 1
(v/v); 18.0 mg, 95% yield); The reaction of donor 7 (24.1 mg, 0.036 mmol) and acceptor 42 (4.0 mg, 0.026 mmol) was performed as deꢀ
scribed in the general procedure C, affording 43 as a white solid (17.7 mg, 93% yield). mp: 240.6 – 241.9; 1H NMR (400 MHz, CDCl3). δ
8.15 – 7.19 (m, 20H), 5.96 (s, 1H), 5.77 (t, J = 9.1 Hz, 1H), 5.63 – 5.55 (m, 1H), 5.09 (d, J = 7.9 Hz, 1H), 4.66 – 4.55 (m, 1H), 4.46 (dd, J
= 11.3, 5.2 Hz, 1H), 4.32 (t, J = 6.4 Hz, 1H), 2.04 (s, 3H), 1.85 (d, J = 11.5 Hz, 3H), 1.69 (d, J = 11.6 Hz, 3H), 1.61 – 1.46 (m, 6H); 13C
NMR (101 MHz, CDCl3) δ 166.1, 165.8, 165.6, 165.1, 133.5, 133.2, 133.1, 130.2, 129.8, 129.7 (×2), 129.6 (×2), 129.1, 128.9, 128.6,
128.4 (×2), 128.3, 94.6, 75.8, 72.2, 71.2, 69.9, 68.3, 62.5, 42.4, 36.1, 30.6; HRMS (ESI) calcd for C44H46NO10 [M+H]+ 748.3116, found
748.3131.
4ꢀMethylphenyl 2,3,4ꢀtriꢀOꢀbenzoylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)ꢀβꢀDꢀ1ꢀthioꢀglucopyranoside (45).
The reaction of donor 17 (24.1 mg, 0.036 mmol) and acceptor 44 (15.5 mg, 0.026 mmol) was performed as described in the general proceꢀ
1
dure C, affording 45 (eluent: petroleum ether/ethyl acetate = 3: 1 (v/v); 24.6 mg, 65% yield). The H NMR data for 45 are in accordance
with those reported previously.38
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4ꢀtriꢀOꢀbenzoylꢀαꢀLꢀrhamnopyranosyl)ꢀαꢀDꢀglucopyranoside (46). The reaction of doꢀ
nor 20 (19.2 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 46
(eluent: petroleum ether/ethyl acetate = 4: 1 (v/v); 22.3 mg, 93% yield); The reaction of donor 20 (19.2 mg, 0.036 mmol) and acceptor 8
(12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 46 (22.3 mg, 93% yield). The 1H NMR data for
46 are in accordance with those reported previously.19
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4ꢀtriꢀOꢀbenzoylꢀαꢀLꢀrhamnopyranosyl)ꢀαꢀDꢀglucopyranoside (47). The reaction of doꢀ
nor 20 (19.2 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording
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47 (eluent: petroleum ether/ethyl acetate = 4: 1 (v/v); 20.4 mg, 85% yield). The 1H NMR data for 47 are in accordance with those reported
previously.33
1
2
3
4
5
6
7
8
9
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (48). The reaction of
donor 23 (24.1 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording
48 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 21.7 mg, 80% yield). The 1H NMR data for 48 are in accordance with those reported
previously.33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2,4,6ꢀtriꢀOꢀbenzylꢀ3ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (49). The reaction of
donor 23 (24.1 mg, 0.036 mmol) and acceptor 12 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording
49 (eluent: petroleum ether/ethyl acetate = 4: 1 (v/v); 24.4 mg, 90% yield). The 1H NMR data for 49 are in accordance with those reported
previously.39
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranosyl)ꢀαꢀDꢀglucopyranoside (50). The reaction of donor 26
(18.7 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 50 (eluꢀ
ent: petroleum ether/ethyl acetate = 5: 1 (v/v); 22.2 mg, 94% yield); The reaction of donor 26 (18.7 mg, 0.036 mmol) and acceptor 8 (12.1
mg, 0.026 mmol) was performed as described in the general procedure C, affording 50 (21.2 mg, 90% yield). The 1H NMR data for 50 are
in accordance with those reported previously.40
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranosyl)ꢀαꢀDꢀglucopyranoside (51). The reaction of donor 26
(18.7 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 51 (eluꢀ
ent: petroleum ether/ethyl acetate = 5: 1 (v/v); 15.3 mg, 65% yield). The 1H NMR data for 51 are in accordance with those reported previꢀ
ously.40
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (52). The reaction of doꢀ
nor 31 (21.5 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 52
(eluent: petroleum ether/ethyl acetate = 6: 1 (v/v); 22.8 mg, 89% yield, α/β = 2:1); The reaction of donor 31 (21.5 mg, 0.036 mmol) and
acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure D, affording 52 (24.9 mg, 97% yield, α/β = 2:1).
The 1H NMR data for 52 are in accordance with those reported previously.41
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (53). The reaction of donor 31
(21.5 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure D, affording 53 (eluꢀ
ent: petroleum ether/ethyl acetate = 5: 1 (v/v); 21.8 mg, 85% yield, α/β = 4:1); The reaction of donor 31 (21.5 mg, 0.036 mmol) and accepꢀ
tor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure E, affording 53 (21.3 mg, 83% yield, α/β = 4: 1). The
1H NMR data for 53 are in accordance with those reported previously.41
Methyl 2,4,6ꢀtriꢀOꢀbenzylꢀ3ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (54). The reaction of donor 31
(21.5 mg, 0.036 mmol) and acceptor 12 (12.1 mg, 0.026 mmol) was performed as described in the general procedure D, affording 54 (eluꢀ
ent: petroleum ether/ethyl acetate = 5: 1 (v/v); 23.0 mg, 90% yield, α/β = 4: 1 ); The reaction of donor 31 (21.5 mg, 0.036 mmol) and acꢀ
ceptor 12 (12.1 mg, 0.026 mmol) was performed as described in the general procedure E, affording 54 (21.8 mg, 85% yield, α/β = 4:1).
The 1H NMR data for 54 are in accordance with those reported previously.42
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(1S,2R,5S)ꢀ(+)ꢀ1ꢀMentyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀgalactopyranoside (55). The reaction of donor 31 (21.5 mg, 0.036 mmol) and acꢀ
ceptor 40 (4.0 mg, 0.026 mmol) was performed as described in the general procedure B, affording 55 (eluent: petroleum ether/ethyl acetate
= 5: 1 (v/v); 15.3 mg, 87% yield, α/β = 1:1). The 1H NMR data for 55 are in accordance with those reported previously.43
1
2
3
4
5
6
7
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀglucopyranosyl)ꢀαꢀDꢀglucopyranoside (56). The reaction of donor 32 (21.5
mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure B, affording 56 (eluent: peꢀ
8
9
1
troleum ether/ethyl acetate = 5: 1 (v/v); 22.6 mg, 88% yield, α/β = 2:1). The H NMR data for 56 are in accordance with those reported
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
previously.41
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀDꢀglucopyranosyl)ꢀ1,2:3,4ꢀdiꢀOꢀisopropylideneꢀαꢀDꢀgalactopyranose (58). The reaction of donor 32
(21.5 mg, 0.036 mmol) and acceptor 57 (7.0 mg, 0.026 mmol) was performed as described in the general procedure D, affording 58 (eluꢀ
1
ent: petroleum ether/ethyl acetate = 4: 1 (v/v); 15.9 mg, 78% yield, α/β = 2:1). The H NMR data for 58 are in accordance with those reꢀ
ported previously.44
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀDꢀglucopyranosyl)ꢀαꢀDꢀglucopyranoside (59). The reaction of donor 32 (21.5
mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure E, affording 59 (eluent:
petroleum ether/ethyl acetate = 5: 1 (v/v); 19.2 mg, 75% yield, α/β = 1:1). The 1H NMR data for 59 are in accordance with those reported
previously.44
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2ꢀazideꢀ2ꢀdeoxyꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (60). The reaction of
donor 35 (19.2 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure D, affording
60 (eluent: petroleum ether/ethyl acetate = 5: 1 (v/v); 19.2 mg, 80% yield, α/β = 1:1); The reaction of donor 35 (19.2 mg, 0.036 mmol) and
acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure F, affording 60 (24.4 mg, 85% yield, α/β = 1:1).
The 1H NMR data for 60 are in accordance with those reported previously.45
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2ꢀazideꢀ2ꢀdeoxyꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucopyranoside (61). The reaction of
donor 35 (19.2 mg, 0.036 mmol) and acceptor 10 (12.1 mg, 0.026 mmol) was performed as described in the general procedure F, affording
1
61 (eluent: petroleum ether/ethyl acetate = 4: 1 (v/v); 14.6 mg, 61% yield, α/β = 4:1). The H NMR data for 61 are in accordance with
those reported previously.45
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Screening of reaction conditions and NMR spectra for compounds (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: xinshan@bjmu.edu.cn.
*Eꢀmail: decai@bjmu.edu.cn.
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Notes
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The authors declare no competing financial interest.
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■ ACKNOWLEDGMENTS
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This work was financially supported by grants from the National Natural Science Foundation of China (Grant Nos. 21772006, 21572012)
and the State Key Laboratory of Drug Research (SIMM1803KFꢀ02). We thank Zeshi Li and Bang Wang at Peking University for their
initial efforts in this project.
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