Efficient Synthesis of a High-Mannose-Type Pentasaccharide and Hexasaccharide Related to N-Glycans

Article abstract of DOI:10.1055/s-0035-1560323

Two high-mannose-type N-glycans, Man5 and Man6 oligosaccharides, were concisely synthesized from 4-methoxyphenyl α-d-mannopyranoside via 9 and 12 steps, and in 23% and 15% overall yields, respectively. The efficiency of the synthesis relies on the large-s

Full text of DOI:10.1055/s-0035-1560323

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 213–222
paper
213
R. Jiang et al.
Paper
Synthesis
Efficient Synthesis of a High-Mannose-Type Pentasaccharide and
Hexasaccharide Related to N-Glycans
Rui Jiang
HO
O
O
HO
HO
O
O
O
O
O
Xiao-mei Liang
Shu-hui Jin*
O
BzO
OCNHCCl3
HO
HO
OPMP
O
HO
O
BzO
HO
HO
BzO
O
HO
HO
BzO
O
HO
AcO
Hui-zhe Lu
BzO
BzO
OH
OH
OH
OH
OH
Yan-hong Dong
Dao-quan Wang
Jian-jun Zhang*
OH
HO
HO
HO
OBz
BzO
BzO
BzO
O
O
1. TMSOTf
OH
HO
O
D-mannose
HO O
O
2. NH3·CH3OH
O
HO
OCNHCCl3
BzO
O
HO
O
OPMP
HO
HO
O
HO
BzO
O
HO
O
OH
OH
OH
HO
Department of Applied Chemistry, China Agricultural
University, Beijing 100193, P. R. of China
shuhuij@cau.edu.cn
O
O
O
O
OPMP
HO
BzO
HO
BzO
OH
OH
HO
HO
OH
OH
OH
O
OH
zhangjianjun@cau.edu.cn
Received: 20.07.2015
Accepted after revision: 31.08.2015
Published online: 28.10.2015
the high mannose oligosaccharides in N-glycans are essen-
tial for human CD2 adhesion function2 and related to HIV
infection.3 As a highly contagious and deadly disease,
HIV/AIDS has become one of the most serious health issues
of modern times. The most effective way to prevent disease
global HIV epidemic depends on the development of an ef-
fective anti-HIV vaccine.4 Researchers believe that one of
the most promising targets for immunogen design is the
carbohydrate moieties on HIV-1 envelop protein gp120,5
which was confirmed by a potent neutralizing human
monoclonal antibody 2G12.6 In order for researchers to
study the recognition mechanism in detail, chemically syn-
thesized oligosaccharides are required because such homo-
geneous oligosaccharide samples can be obtained in only
very small amounts from natural sources.
Several papers have reported for the synthesis of high-
mannose-type oligosaccharides existing in N-glycans.7
However, the strategies involved in these reports are not
suitable for the large-scale preparation of the target penta-
saccharide and hexasaccharide due to complex protection–
deprotection steps and low overall yields. Therefore, more
efficient and practical methods are highly desired for the
synthesis of mannose oligosaccharides in N-glycans. In this
communication, we wish to present a novel approach for
the fast and efficient synthesis of the pentasaccharide 1 and
hexasaccharide 2 (Scheme 1), using disaccharide triol ac-
ceptor 3 and tetrasaccharide diol acceptor 4 as the key in-
termediates, respectively. We envisioned that mannosyla-
tion of the three hydroxyl groups in 3 and two hydroxyl
groups in 4 would provide the protected form of pentasac-
charide 1 and hexasaccharide 2, respectively, in a single
coupling reaction, and the synthetic procedure would thus
be greatly simplified. The disaccharide 3 could be produced
from two suitably protected monosaccharide building
blocks 7 and 8, using the allyloxycarbonyl function as an or-
thogonal protecting group.8,9 Similarly, the tetrasaccharide
DOI: 10.1055/s-0035-1560323; Art ID: ss-2015-f0446-op
Abstract Two high-mannose-type N-glycans, Man5 and Man6 oligo-
saccharides, were concisely synthesized from 4-methoxyphenyl α-D-
mannopyranoside via 9 and 12 steps, and in 23% and 15% overall yields,
respectively. The efficiency of the synthesis relies on the large-scale
preparation of a key disaccharide intermediate, 4-methoxyphenyl 3,6-
di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-D-mannopyranosyl-(1→6)-
2,4-di-O-benzoyl-α-D-mannopyranoside, with two hydroxyl groups par-
tially masked by allyloxycarbonyl protection. The disaccharide was ob-
tained in 84% yield by regioselective glycosylation of 4-methoxyphenyl
2,4-di-O-benzoyl-α-D-mannopyranoside with 3,6-di-O-allyloxycarbonyl-
2,4-di-O-benzoyl-α-D-mannopyranosyl trichloroacetimidate. The disac-
charide could be easily transformed to a tetrasaccharide diol acceptor
via condensation of 4-methoxyphenyl 3,6-di-O-allyloxycarbonyl-2,4-di-
O-benzoyl-α-D-mannopyranosyl-(1→6)-2,4-di-O-benzoyl-α-D-manno-
pyranoside with a disaccharide donor followed by removal of the two
allyloxycarbonyl groups in the resultant tetrasaccharide, or be convert-
ed into a triol acceptor by direct deallyloxycarbonylation. Glycosylation
of the triol or diol acceptor with 2,3,4,6-tetra-O-benzoyl-α-D-manno-
pyranosyl trichloroacetimidate provided the desired protected penta-
saccharide and hexasaccharide in one step in 64% and 67% yields, re-
spectively. Finally, the target compounds, pentasaccharide and
hexasaccharide, were obtained after deprotection. The structures of
target compounds and intermediates were characterized by 1H NMR,
13C NMR, and HRMS.
Key words synthesis, oligosaccharides, mannose, N-glycan
HIV-1 is reported to have two envelope glycoproteins,
the outer and inner envelope glycoproteins, that form tri-
meric complexes on the viral surface. The outer envelope
glycoprotein gp120 has 24 conserved N-glycosylation sites,
13 of which are complex-type N-glycans, and the rest are
high-mannose-type and/or hybrid-type N-glycans. N-Gly-
cans play a vital role in many basic biological processes
such as viral infection, cell differentiation, protein transpor-
tations, and tumor migration.1 Studies have revealed that
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 213–222

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R. Jiang et al.
Paper
Synthesis
HO
HO
O
O
O
HO
O
HO
O
HO
O
O
HO
O
O
O
HO
OPMP
O
HO
HO
HO
HO
OPMP
O
HO
HO
O
O
HO
HO
HO
OH
OH
OH
O
HO
HO
O
O
HO
O
O
OH
OH
OH
HO
OH
OH
OH
OH
HO
OH
OH
O
1
2
OH
OH
BzO O
BzO
O
BzO
O
O
BzO
HO
BzO
OPMP
O
BzO
HO
BzO
O
BzO
OAc
OPMP
OBz
OBz
O
O
HO
HO
HO
OBz
3
OBz
4
O
OBz
O
OBz
O
O
O
BzO
O
BzO
BzO O
OCNHCCl3
O
AllocO
BzO
OPMP
BzO
BzO
BzO
BzO
HO
BzO
BzO
AcO
AllocO
5
6
OBz
O
BzO
OH
O
AllocO
OBz
O
HO
BzO
HO
BzO
OBz
O
BzO
AcO
BzO
AllocO
BzO
BzO
OPMP
OPMP
OCNHCCl3
10
OCNHCCl3
8
7
9
OH
O
HO
HO
HO
OPMP
11
Scheme 1 Structure of the target pentasaccharide 1, hexasaccharide 2, and the building blocks 7–10 used for its synthesis
4 could be obtained from two suitably protected monosac-
charide building blocks 9 and 10 and one protected disac-
charide building block 5, which also use the allyloxycarbon-
yl group for orthogonal protection.8,9
carbonylation of the C6-OH of compound 15 with allyloxy-
carbonyl chloride in pyridine provided 16 (91%), which was
transformed to 17 after benzoylation. Significantly, com-
pound 17 could be obtained in a one-pot reaction by adding
allyloxycarbonyl chloride and benzoyl chloride to the reac-
tion mixture successively, thus greatly simplifying the
preparation. Finally, according to our previously reported
method,9 deallyloxycarbonylation of 17 with palladium cat-
alyst [Pd(PPh3)4, NaBH4, NH4OAc, THF–MeOH] gave the
monosaccharide acceptor 8 in 88% yields. On the other
hand, cleavage of the 4-methoxyphenyl group of 17 with
cerium(IV) ammonium nitrate, followed by trichloroacet-
imidation,12 provided the monosaccharide donor 7 in good
overall yield (87%). Compound 9 was obtained in 82% over-
all yield for three steps according to the reported method.13
Another key intermediate 10 was prepared through the
route shown in Scheme 3. 4-Methoxyphenyl α-D-mannopy-
ranoside (11)10 was first transformed into 2,3-O-isopro-
pylidene-α-D-mannopyranoside 19 with 2-methoxypro-
pene in N,N-dimethylformamide in the presence of catalyt-
ic amounts of 4-toluenesulfonic acid monohydrate
according to our previous reported method.14 Then benzoy-
lation of 19 with benzoyl chloride in pyridine followed by
removal of the isopropylidene protecting group in 70% ace-
For the synthesis of monosaccharide building blocks, 4-
methoxyphenyl α-D-mannopyranoside (11)10 was first
transformed into 4,6-O-isopropylidene-α-D-mannopyrano-
side 12 with 2-methoxypropene in N,N-dimethylform-
amide in the presence of catalytic amounts of 4-toluenesul-
fonic acid monohydrate.11 Regioselective allyloxycarbonyla-
tion of 12 in pyridine gave the 3-OH protected derivative 13
exclusively in 90% yield (Scheme 2). The presence of the O-
allyloxycarbonyl group at C3 was confirmed by the down-
1
field shift of the H3 signal in the H NMR spectrum of 13
(δ = 5.22) compared with the data for H3 signal of com-
pound 12 (δ = 4.12). It was found that keeping the reaction
temperature below –10 °C was necessary to ensure the de-
sired regioselectivity. Benzoylation of 13 with benzoyl chlo-
ride in pyridine provided 14, which was then transformed
to the key intermediate 15 after removal of the isopro-
pylidene protecting group in 70% acetic acid. It should be
noted that these three steps can be carried out successively
without chromatographic purification for the first two
steps, making the preparation of 15 on large scale possible
with high yield (88%). Subsequently, regioselective allyloxy-
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R. Jiang et al.
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Synthesis
densation of triol 3 with 2,3,4,6-tetra-O-benzoyl-α-D-man-
nopyranosyl trichloroacetimidate (9).13 To ensure complete
conversion of the triol 3, excess monosaccharide donor 9
OH
HO
OH
OH
O
Me2C
Me2C
O
O
O
O
b, i
a
HO
O
O
HO
HO
AllocO
11
12
13
b, ii
OPMP
OPMP
OPMP
1
(4–4.5 equiv) was added in the coupling reaction. The H
b
NMR spectrum of 22 showed 4-methoxyphenyl signals (δ =
7.04–6.72) and five H1 signals (δ = 5.75, 5.41, 5.36, 5.17,
and 4.78), which are characteristic of the structure of the
pentasaccharide 22. Deprotection of 22 in ammonia-satu-
rated methanol gave the title 4-methoxyphenyl α-D-hex-
amannoside 1, which precipitated from the solution phase
as a white solid when dry acetone was added to the reac-
tion mixture at the end of the deprotection step.
OBz
O
OBz
O
OBz
O
Me2C
O
AllocO
HO
AllocO
HO
HO
b, iii
c, i
O
AllocO
AllocO
16
c, ii
15
14
OPMP
OPMP
OPMP
c
OH
O
OBz
O
d
e
HO
HO
HO
AllocO
BzO
AllocO
8
7
f
9
18
17
OPMP
Similarly, the target hexasaccharide was prepared effi-
ciently as outlined in Scheme 5. First of all, the coupling of
compounds 9 and 10 in dichloromethane at –20 °C promot-
ed by trimethylsilyl trifluoromethanesulfonate12 resulted in
α-1→2-linked mannose disaccharide 23 in 92% yield. Re-
moval of the 4-methoxyphenyl group of 23 with cerium(IV)
ammonium nitrate, and activation with trichloroacetoni-
trile in the presence of DBU gave the disaccharide donor 6
in good overall yield (87%). Condensation of 6 with the ac-
ceptor 5 afforded the (1→3)-linked tetrasaccharide 24
(84%). Subsequent removal of the two Alloc groups in com-
pound 24 with tetrakis(triphenylphosphine)palladium(0)
provided the key diol acceptor 4 in high yield (82%). Finally,
the fully protected hexasaccharide 25 was smoothly ob-
tained in 67% yield by the condensation of diol 4 with
2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl trichloroace-
timidate (9). Again, to ensure complete conversion of the
diol 4, excess 9 (4–4.5 equiv) was used in the coupling reac-
tion. The 1H NMR spectrum of 25 showed one acetyl signal
(δ = 1.91), 4-methoxyphenyl signals (δ = 7.04–6.72), and six
H1 signals (δ = 5.72, 5.46, 5.33, 5.16, 4.79, and 4.60), which
are characteristic of the structure of the hexasaccharide 25.
Deprotection of 25 in ammonia-saturated methanol gave
the title 4-methoxyphenyl α-D-hexamannoside 2, which
was precipitated from the reaction mixture as a white solid
by adding dry acetone at the end of the deprotection step.
In summary, we have successfully developed a highly ef-
ficient strategy for the preparation of high-mannose-type
pentasaccharide and hexasaccharide related to N-glycans. It
is noteworthy that the overall yield of the whole synthesis
is 23% and 15% for 1 and 2, respectively, from 4-methoxy-
phenyl α-D-mannopyranoside. The reported synthetic pro-
cedure is especially suitable for the large-scale preparation
of the target saccharides and we are currently working on
the application of this method to the synthesis of more
OH
Scheme 2 Synthesis of building blocks 7–9. Reagents and conditions:
(a) 2-methoxypropene, DMF, TsOH·H2O, r.t., 2 h, 95%; (b) (i) AllocCl,
pyridine, –10 °C to r.t., 2 h, 90%; (ii) BzCl, pyridine, CH2Cl2, –10 °C to r.t.,
3 h, 92%; (iii) 70% AcOH, 70 °C, 3 h, 94%; overall yield of the one-pot
preparation of 15 from 12: 88%; (c) (i) AllocCl, pyridine, CH2Cl2, –10 °C
to r.t., 2 h, 91%; (ii) BzCl, pyridine, –10 °C to r.t., 3 h, 96%; overall yield of
the one-pot preparation of 17 from 15: 86%; (d) NH4OAc, Pd(PPh3)4,
NaBH4, MeOH–THF, –5 °C, 5 min, 88%; (e) (i) CAN, MeCN–H2O (4:1), 30
°C, 20 min, (ii) Cl3CCN, DBU, CH2Cl2, r.t., 0.5 h, 87% for 2 steps; (f) (i)
BzCl, pyridine, –10 °C to 0 °C, 4 h, (ii) MeOH–NH3, MeOH–THF, 1 h, (iii)
Cl3CCN, DBU, CH2Cl2, 0 °C, 2 h, 82% for 3 steps.
tic acid provided the intermediate 20. Again, we were able
to perform these three steps successively without chro-
matographic purification for the first two steps, allowing 20
to be prepared on a large scale with high yield (84%). Subse-
quently, regioselective acetylation of the C3-OH of com-
pound 20 with acetyl chloride in pyridine provided 10 in
88% yield.
With the monosaccharide synthons 7, 8, 9, and 10 in
hand, the pentasaccharide target compound was prepared
efficiently as outlined in Scheme 4. The coupling of com-
pounds 7 and 8 in dichloromethane at –20 °C promoted by
trimethylsilyl trifluoromethanesulfonate12 resulted in ex-
pected regio- and stereoselective products, giving exclu-
sively α-1→6-linked mannose disaccharide 5 in 84% yield.
The configuration of the glycosyl bond in 5 was deduced
from the corresponding coupling constants. The regioselec-
tivity of the coupling reaction was confirmed by acetylation
of 5 to give 21 (92%), as the 1H NMR spectrum of 21 showed
a newly emerged downfield H3 signal. Subsequent removal
of the two Alloc groups in compound 5 with tetrakis(triph-
enylphosphine)palladium(0) provided the key triol acceptor
3 in high yield (84%). Finally, the fully protected pentasac-
charide 22 was smoothly obtained in 64% yield by the con-
OH
O
OH
O
O
OH
O
HO
HO
O
BzO
BzO
HO
BzO
BzO
AcO
HO
HO
HO
O
ref. 14
a, b
c
C
OPMP
OPMP
OPMP
OPMP
Me2
20
11
19
10
Scheme 3 Synthesis of building block 10. Reagents and conditions: (a) BzCl, pyridine, CH2Cl2, –10 °C to r.t., 2 h; (b) 70% AcOH, 70 °C, 3 h, 91% for 2
steps; (c) AcCl, pyridine, CH2Cl2, –10 °C to r.t., 2 h, 88%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 213–222

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Synthesis
BzO
O
OBz
O
AllocO
O
BzO
OBz
HO
BzO
HO
a
O
O
BzO
AllocO
BzO
BzO
AllocO
OPMP
+
RO
OPMP
OCNHCCl3
AllocO
7
8
5
R = H
b
21 R = Ac
BzO
O
O
O
BzO
BzO
O
O
BzO
O
BzO O
O
a
c
O
BzO
AllocO
BzO
OPMP
OPMP
BzO
BzO
3
BzO
BzO
BzO
O
9
HO
AllocO
O
BzO
BzO
O
5
BzO
OBz
OBz
OBz
OBz
OBz
22
d
22
1
Scheme 4 Synthesis of target pentasaccharide 1. Reagents and conditions: (a) TMSOTf, CH2Cl2, 4 Å MS, –20 °C to r.t., 0.5 h, 84% for 5, 64% for 22; (b) AcCl,
pyridine, –10 °C to r.t., 1 h, 92%; (c) NH4OAc, Pd(PPh3)4, NaBH4, MeOH–THF, –10 °C, 5 min, 84%; (d) (i) MeOH–NH3, r.t., 120 h, (ii) warm acetone, 82%.
BzO O
BzO
O
O
BzO
AllocO
OPMP
9
O
BzO
a
a
b
O
O
BzO
BzO
OAc
6
OBz
OBz
O
OPMP
5
BzO
AllocO
BzO
BzO
BzO
10
OBz
OBz
OBz
O
AcO
24
O
23
O
OBz
BzO
O
O
BzO
O
O
BzO
O
BzO
OPMP
O
BzO
BzO
BzO
a
c
O
O
d
BzO
2
4
OAc
OBz
OBz
9
O
O
BzO
OBz
OBz
BzO
OBz
OBz
OBz
O
25
OBz
Scheme 5 Synthesis of target hexasaccharide 2. Reagents and conditions: (a) TMSOTf, CH2Cl2, 4 Å MS, –20 °C to r.t., 0.5 h, 92% for 23, 84% for 24, 67%
for 25; (b) (i) CAN, MeCN–H2O (4:1), 30 °C, 20 min, (ii) Cl3CCN, DBU, CH2Cl2, r.t., 0.5 h, 87% for 2 steps; (c) NH4OAc, Pd(PPh3)4, NaBH4, MeOH–THF,
–10 °C, 5 min, 82%; (d) (i) MeOH–NH3, r.t., 120 h, (ii) warm acetone, 78%.
complex Man7, Man8, and Man9 oligosaccharides. The bio-
activity of 1 and 2 is also being investigated and the results
will be reported in due course.
column of silica gel (200–300 mesh) with EtOAc–petroleum ether (PE,
bp 60–90 °C). Solutions were concentrated at <60 °C under reduced
pressure.
4-Methoxyphenyl 4,6-O-Isopropylidene-α-D-mannopyranoside
(12)
Optical rotations were determined with a Perkin-Elmer model 241-
MC automatic polarimeter for solutions in a 1-dm, jacketed cell. 1H
and 13C NMR spectra were recorded with Bruker DPX300 and Bruker
Avance600 spectrometers in CDCl3 or D2O solutions; internal refer-
ences: TMS (δ = 0.000 for 1H), CDCl3 (δ = 77.00 for 13C), HOD (δ = 4.700
for 1H). 1H NMR signals of some compounds were assigned with the
aid of COSY. The following designations are used: Hmp = H aryl of the
4-methoxyphenyl group, HBz = H aryl of the benzoyl group. HRMS was
performed by Peking University. TLC was performed on silica gel HF
with detection by charring with 30% (v/v) H2SO4 in MeOH or by UV
detection. Column chromatography was conducted by elution of a
To a solution of 4-methoxyphenyl α-D-mannopyranoside (11, 5.72 g,
20 mmol) in anhyd DMF (40 mL) was added TsOH·H2O (38 mg, 0.2
mmol) and 2-methoxypropene (2.2 mL, 22 mmol) under N2. The mix-
ture was stirred at r.t. for 2 h; TLC (PE–EtOAc, 2:1) indicated comple-
tion. The mixture was poured into crushed ice and the product pre-
cipitated from the mixture to give 12 as a white solid; yield: 6.20 g
(95%); [α]D +122 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 6.99–6.94 (m, 2 H, Hmp), 6.85–6.80 (m,
2 H, Hmp), 5.46 (d, J1,2 = 1.4 Hz, 1 H, H1), 4.22 (m, 1 H, H2), 4.12 (dd, J2,3
= 3.3 Hz, J3,4 = 9.4 Hz, 1 H, H3), 4.04–3.98 (m, 1 H), 3.82–3.78 (m, 3 H),
3.77 (s, 3 H, OMe), 2.87, 2.81 (br s, 2 H, OH), 1.53, 1.42 (2 s, 6 H, Me2C).
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R. Jiang et al.
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Synthesis
13C NMR (75 MHz, CDCl3): δ = 155.05, 149.84, 117.68, 114.63, 100.11,
4-Methoxyphenyl 3-O-Allyloxycarbonyl-2-O-benzoyl-α-D-manno-
99.12, 71.22, 70.99, 68.88, 64.61, 61.96, 55.58, 29.08, 19.22.
pyranoside (15) from 12
HRMS: m/z [M + H]+ calcd for C16H23O7: 327.14383; found: 327.14377.
Compound 12 (3.26 g, 10.0 mmol) was dissolved in pyridine (20 mL),
then allyl chloroformate (1.11 mL, 10.5 mmol) was added dropwise to
the solution over 30 min at –10 °C. The temperature was slowly
raised to r.t. and the mixture was stirred for 2 h; TLC (PE–EtOAc, 2:1)
indicated completion. The mixture was diluted with anhyd CH2Cl2 (50
mL), BzCl (1.7 mL, 15.0 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise over 30 min at –10 °C. The temperature was slowly raised to
r.t. and the mixture was stirred for 2 h; TLC (PE–EtOAc, 3:1) indicated
completion. Then the mixture was diluted with CH2Cl2 (100 mL),
washed with 1 M HCl, and the organic phase was concentrated to give
the crude product, which was dissolved in 70% AcOH (200 mL) and
stirred for 3 h at 70 °C. The mixture was concentrated under reduced
pressure and then co-evaporated with toluene (2 × 40 mL). The resi-
due was passed through a short silica gel column (PE–EtOAc, 3:1) to
give 15 as a white solid; yield: 4.2 g (88%); [α]D +148 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.06–8.00 (m, 2 H, HBz), 7.55–7.38 (m,
3 H, HBz), 7.01 (d, J = 9.0 Hz, 2 H, Hmp), 6.79 (d, J = 9.0 Hz, 2 H, Hmp),
5.95–5.82 (m, 1 H, CH2CHCH2O), 5.72 (m, 1 H, H2), 5.53 (d, J1,2 = 1.4
Hz, 1 H, H1), 5.38–5.20 (m, 3 H, H3, CH2CHCH2O), 4.64–4.58 (m, 2 H,
CH2CHCH2O), 4.35 (t, J3,4 = J4,5 = 9.7 Hz, 1 H, H4, 1 H), 3.98–3.82 (m, 3
H, H5, 2 H6), 3.74 (s, 3 H, OCH3), 3.7–2.2 (br s, 2 H, OH).
4-Methoxyphenyl 3-O-Allyloxycarbonyl-4,6-O-isopropylidene-α-
D-mannopyranoside (13)
Compound 12 (3.26 g, 10.0 mmol) was dissolved in pyridine (20 mL),
then allyl chloroformate (1.1 mL, 10.5 mmol) in pyridine (10 mL) was
added dropwise to the solution over 30 min at –10 °C. The tempera-
ture was slowly raised to r.t. and the mixture was stirred for 2 h; TLC
(PE–EtOAc, 3:1) indicated completion. The mixture was diluted with
CH2Cl2 (100 mL), washed with ice-water, 1 M HCl, and water, and
dried (Na2SO4). The solution was concentrated, and purification of the
residue by column chromatography (silica gel, PE–EtOAc, 4:1) gave 13
as a white solid; yield: 3.7 g (90%); [α]D +88 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): 6.99–6.95 (m, 2 H, Hmp), 6.83–6.80 (m, 2 H,
H
mp), 6.01–5.91 (m, 1 H, CH2CHCH2O), 5.45 (d, J1,2 = 1.6 Hz, 1 H, H1),
5.43–5.28 (m, 2 H, CH2CHCH2O), 5.22 (dd, J2,3 = 1.8 Hz, J3,4 = 10.0 Hz, 1
H, H3), 4.68 (dt, 2 H, CH2CHCH2O), 4.38 (m, 1 H, H2), 4.24 (t, J3,4 = J4,5
=
9.6 Hz, 1 H, H4), 3.91–3.78 (m, 3 H, H5, 2 H6), 3.76 (s, 3 H, OCH3), 2.56
(d, J = 3.3 Hz, 1 H, OH), 1.50, 1.39 (2 s, 6 H, CMe2).
13C NMR (75 MHz, CDCl3): δ = 154.99, 153.91, 149.60, 131.12, 119.00,
117.55, 114.54, 100.00, 99.05, 74.84, 69.21, 68.70, 68.35, 65.14, 61.88,
55.46, 28.91, 18.99.
13C NMR (75 MHz, CDCl3): δ = 165.42, 154.42, 149.76, 133.39, 131.14,
129.75, 128.39, 118.99, 117.86, 114.61, 96.82, 72.82, 69.90, 68.88,
68.44, 65.41, 61.58, 55.48.
HRMS: m/z [M + H]+ calcd for C20H27O9: 411.16496; found: 411.16425.
HRMS: m/z [M
475.15903.
+ : 475.15987; found:
H]+ calcd for C24H27O10
4-Methoxyphenyl 3-O-Allyloxycarbonyl-2-O-benzoyl-4,6-O-iso-
propylidene-α-D-mannopyranoside (14)
Compound 13 (4.10 g, 10.0 mmol) was dissolved in anhyd CH2Cl2 (50
mL) containing pyridine (3.2 mL, 40.0 mmol), then under a N2 atmo-
sphere, BzCl (1.7 mL, 15.0 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise to the solution over 30 min at –10 °C. The temperature was
slowly raised to r.t. and the mixture was stirred for 3 h; TLC (PE–
EtOAc, 3:1) indicated completion. The mixture was diluted with
CH2Cl2 (100 mL), washed with water, 1 M HCl, and water, and dried
(Na2SO4). The solution was concentrated, and purification of the resi-
due by column chromatography (silica gel, PE–EtOAc, 5:1) gave 14 as
a foamy solid; yield: 4.73 g (92%); [α]D +102 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.09–8.03 (m, 2 H, HBz), 7.60–7.45 (m,
3 H, HBz), 7.02–6.99 (m, 2 H, Hmp), 6.84–6.81 (m, 2 H, Hmp), 5.96–5.85
(m, 1 H, CH2CHCH2O), 5.80 (q, 1 H, H2), 5.51 (d, J1,2 = 1.6 Hz, 1 H, H1),
5.41–5.29 (m, 2 H, H3, CH2CHCH2O), 5.25 (dq, 1 H, CH2CHCH2O), 4.67–
4.63 (m, 2 H, CH2CHCH2O), 4.31 (t, J3,4 = J4,5 = 9.8 Hz, 1 H, H4), 4.04–
3.98 (m, 1 H, H5), 3.93–3.85 (m, 2 H, 2 H6), 3.75 (s, 3 H, OCH3), 1.56,
1.42 (2 s, 6 H, CMe2).
4-Methoxyphenyl 3,6-Di-O-allyloxycarbonyl-2-O-benzoyl-α-D-
mannopyranoside (16)
Compound 15 (4.74 g, 10.0 mmol) was dissolved in anhyd CH2Cl2 (20
mL) containing pyridine (3.2 mL, 40.0 mmol), then under N2, allyl
chloroformate (1.12 mL, 10.5 mmol) in anhyd CH2Cl2 (10 mL) was
added dropwise to the solution over 30 min at –10 °C. The tempera-
ture was slowly raised to r.t. and the mixture stirred for 2 h; TLC (PE–
EtOAc, 3:1) indicated completion. The mixture was diluted with
CH2Cl2 (100 mL), washed with water and 1 M HCl, and dried (Na2SO4).
The solution was concentrated, and purification of the residue by col-
umn chromatography (silica gel, PE–EtOAc, 4:1) gave 16 as a syrup;
yield: 5.10 g (91%); [α]D +66 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.06–8.01 (m, 2 H, HBz), 7.57–7.39 (m,
3 H, HBz), 7.04 (d, J = 9.0 Hz, 2 H, Hmp), 6.79 (d, J = 9.0 Hz, 2 H, Hmp),
5.93–5.83 (m, 2 H, 2 CH2CHCH2O), 5.74 (m, 1 H, H2), 5.54 (s, 1 H, H1),
5.39–5.19 (m,
5 H, H3, 2 CH2CHCH2O), 4.61–4.43 (m, 6 H, 2
CH2CHCH2O, H4, H6), 4.28–4.20 (m, 1 H, H5), 4.10–4.06 (m, 1 H, H6),
3.72 (s, 3 H, OCH3), 3.36 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): δ = 165.27, 155.25, 155.13, 154.33, 149.80,
133.32, 131.31, 131.09, 129.81, 129.15, 128.34, 118.97, 118.69,
117.79, 114.56, 96.70, 75.45, 71.13, 69.64, 68.87, 68.52, 66.06, 65.26,
55.44.
13C NMR (75 MHz, CDCl3): δ = 165.44, 155.36, 15.94, 149.69, 133.47,
131.37, 129.86, 128.47, 118.77, 117.88, 114.65, 100.19, 97.59, 72.68,
70.31, 69.09, 68.76, 65.35, 62.04, 55.55, 29.00, 19.11.
HRMS: m/z [M
+ : 515.19117; found:
H]+ calcd for C27H31O10
515.19019.
HRMS: m/z [M
559.17433.
+ : 559.17468; found:
H]+ calcd for C28H31O12
4-Methoxyphenyl 3-O-Allyloxycarbonyl-2-O-benzoyl-α-D-manno-
pyranoside (15) from 14
Compound 14 (6.2 g, 12.0 mmol) was dissolved in 70% AcOH (200 mL)
and stirred for 3 h at 70 °C; TLC (PE–EtOAc, 2:1) indicated completion.
The mixture was concentrated under reduced pressure and then co-
evaporated with toluene (2 × 40 mL). The residue was passed through
a short silica gel column (PE–EtOAc, 3:1) to give 15 (5.4 g, 94%) as a
white solid.
4-Methoxyphenyl 3,6-Di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-
D-mannopyranoside (17) from 16
Compound 16 (4.82 g, 8.64 mmol) was dissolved in pyridine (30 mL),
then BzCl (1.5 mL, 14.6 mmol) in pyridine (10 mL) was added drop-
wise to the solution over 30 min at –10 °C. The temperature was
slowly raised to r.t. and the mixture was stirred for 3 h; TLC (PE–
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R. Jiang et al.
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Synthesis
EtOAc, 3:1) indicated completion. The mixture was diluted with CH2-
Cl2 (100 mL), washed with ice-water and 1 M HCl, and dried (Na2SO4).
The solution was concentrated, and purification of the residue by col-
umn chromatography (silica gel, PE–EtOAc, 4:1) gave 17 (5.48 g, 96%)
as a foamy solid.
13C NMR (75 MHz, CDCl3): δ = 165.27, 165.22, 159.67, 154.65, 153.99,
133.77, 133.69, 131.48, 130.98, 130.17, 130.02, 128.83, 128.80,
128.65, 128.54, 118.90, 118.85, 94.45, 90.56, 72.64, 71.37, 68.95,
68.68, 68.27, 66.41, 65.74.
4-Methoxyphenyl 2,4-Di-O-benzoyl-α-D-mannopyranoside (8)
4-Methoxyphenyl 3,6-Di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-
D-mannopyranoside (17) from 15
To a cooled (–5 °C) solution of 17 (4.1 g, 6.2 mmol) in MeOH–THF
(1:1, 60 mL) was added NH4OAc (4.76 g, 62 mmol). The mixture was
stirred vigorously and NaBH4 (0.15 g, 4 mmol), Pd(PPh3)4 (0.28 g, 0.25
mmol), and NaBH4 (0.55 g, 14.5 mmol) were added in 3 portions im-
mediately one after the other; 5 min after the addition of the second
portion of NaBH4, TLC (PE–EtOAc, 2:1) indicated that the reaction was
complete. The mixture was concentrated under vacuum, the residue
was dissolved in CH2Cl2 (30 mL) and washed with brine (15 mL), then
the organic phase was dried (Na2SO4). Concentration of the organic
phase and purification of the residue by flash column chromatogra-
phy (PE–EtOAc, 3:1) afforded 8 as a white solid; yield: 2.7 g (88%);
[α]D +74 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.13–8.06 (m, 4 H, HBz), 7.63–7.59 (m,
2 H, HBz), 7.51–7.44 (m, 4 H, HBz), 7.06–7.02 (m, 2 H, Hmp), 6.86–6.83
(m, 2 H, Hmp), 5.67 (d, J1,2 = 1.7 Hz, 1 H, H1), 5.64–5.57 (m, 2 H, H2,
H4), 4.66 (d, J = 9 Hz, 1 H, H3), 4.13–4.08 (m, 1 H, H5), 3.81–3.74 (m, 5
H, OCH3, 2 H6), 2.58, 2.38 (2 br, 2 H, 2 OH).
Compound 15 (5.7 g, 12.0 mmol) was dissolved in anhyd CH2Cl2 (40
mL) containing pyridine (3.9 mL, 48.0 mmol), then under N2, allyl
chloroformate (1.32 mL, 12.6 mmol) in anhyd CH2Cl2 (10 mL) was
added dropwise to the solution over 30 min at –10 °C. The tempera-
ture was slowly raised to r.t. and the mixture was stirred for 2 h; TLC
(PE–EtOAc, 3:1) indicated completion. Then BzCl (2.10 mL, 18 mmol)
in pyridine (30 mL) was added dropwise to the solution over 30 min
at 0 °C. The temperature was slowly raised to r.t. and the mixture was
stirred for 4 h; TLC (PE–EtOAc, 4:1) indicated completion. The mix-
ture was diluted with CH2Cl2 (100 mL), washed with ice-water, 1 M
HCl, and water, and dried (Na2SO4). The solution was concentrated,
and purification of the residue by column chromatography (silica gel,
PE–EtOAc, 4:1) gave 17 as a foamy solid; yield: 6.84 g (86%); [α]D +42
(c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.14–8.12 (m, 2 H, HBz), 8.05–8.02 (m,
2 H, HBz), 7.58–7.56 (m, 2 H, HBz), 7.48–7.40 (m, 4 H, HBz), 7.10 (d, J =
9.1 Hz, 2 H, Hmp), 6.85 (d, J = 9.1 Hz, 2 H, Hmp), 5.85–5.79 (m, 5 H, 2
CH2CHCH2O, H2, H3, H4), 5.62 (d, J = 1.7 Hz, 1 H, H1), 5.33–5.26 (m, 1
H, CH2CHCH2O), 5.23–5.18 (m, 1 H, CH2CHCH2O), 5.17–5.10 (m, 1 H,
CH2CHCH2O), 5.05–5.00 (m, 1 H, CH2CHCH2O), 4.56–4.53 (m, 2 H,
CH2CHCH2O), 4.50–4.47 (m, 2 H, CH2CHCH2O), 4.43–4.35 (m, 3 H, H5,
2 H6), 3.73 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 167.29, 166.00, 155.39, 149.94, 133.69,
133.61, 129.92, 129.15, 129.02, 128.60, 128.53, 117.81, 114.75, 96.75,
72.72, 71.23, 70.14, 68.52, 61.25, 55.62.
HRMS: m/z [M + H]+ calcd for C27H27O9: 495.16490; found: 495.16496.
4-Methoxyphenyl 2,3-O-Isopropylidene-α-D-mannopyranoside
(19)
Compound 19 was prepared according to the literature procedure.14
White solid; yield: 8.6 g (84%); [α]D +69.7 (c 1.0 CHCl3).
1H NMR (300 MHz, CDCl3) δ = 7.00–6.82 (2 m, 4 H, Hmp), 5.67 (s, 1 H,
H1), 4.38 (d, J2,3 = 5.7 Hz, 1 H, H2), 4.32 (m, 1 H, H3), 3.84–3.78 (m, 7
H, H4, H5, H6, OCH3), 2.82 (d, J = 3.9 Hz, 1 H, 4–OH), 2.04 (m, 1 H, 6–
OH), 1.56, 1.41 (2 s, 6 H, Me2C).
13C NMR (75 MHz, CDCl3): δ = 165.54, 165.42, 155.64, 154.72, 154.18,
149.93, 133.66, 133.64, 131.56, 131.08, 130.12, 130.02, 129.13,
128.98, 128.65, 128.54, 128.47, 127.47, 126.92, 118.85, 118.67,
118.07, 114.81, 96.83, 72.86, 70.00, 69.34, 68.90, 68.61, 67.13, 65.99,
65.11, 55.61.
HRMS: m/z [M + NH4]+ calcd for C35H38O13N: 680.23377; found:
680.23206.
13C NMR (75 MHz, CDCl3): δ = 155.20, 149.81, 117.6, 114.73, 109.87,
96.53, 78.47, 75.63, 70.29, 69.36, 62.09, 55.62, 27.96, 26.21.
HRMS: m/z [M + NH4]+ calcd for C16H26NO7: 344.17038; found:
3,6-Di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-D-mannopyranosyl
Trichloroacetimidate (7)
344.17035.
To a solution of 17 (4.4 g, 6.6 mmol) in MeCN (120 mL) were added
water (30 mL) and CAN (14.6 g, 26.4 mmol) successively. The mixture
was stirred for 20 min at 30 °C; TLC (PE–EtOAc, 2:1) indicated com-
pletion. The solvent was evaporated under reduced pressure at 50 °C
to give a residue that was dissolved in CH2Cl2 and then washed with
water. The organic phase was dried (Na2SO4) and concentrated to give
a residue that was purified by chromatography (silica gel, PE–EtOAc,
3:1) to afforded 3,6-di-O-allyloxycarbonyl-2,4-di-O-benzoyl-D-manno-
pyranose as a slight yellow foamy solid. A mixture of this compound,
trichloroacetonitrile (2.0 mL), and DBU (0.2 mL) in anhyd CH2Cl2 (100
mL) was stirred at r.t. for 0.5 h and then concentrated. The residue was
purified by chromatography (PE–EtOAc, 4:1) to give 7 as a syrup;
yield: 4.04 g (87% for 2 steps); [α]D +54 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.88 (s, 1 H, NH), 8.14 (d, J = 7.3 Hz, 2
H, HBz), 8.02 (d, J = 7.3 Hz, 2 H, HBz), 7.63–7.56 (m, 2 H, HBz), 7.50–7.42
(m, 4 H, HBz), 6.51 (d, J1,2 = 1.8 Hz, 1 H, H1), 5.90–5.84 (m, 3 H, H2, H4,
CH2CHCH2O), 5.71–5.58 (m, 2 H, H3, CH2CHCH2O), 5.35–5.03 (m, 4 H,
2 CH2CHCH2O), 4.60, 4.51 (2 d, J = 5.6 Hz, 4 H, 2 CH2CHCH2O), 4.51–
4.34 (m, 3 H, H5, 2 H6).
4-Methoxyphenyl 4,6-Di-O-benzoyl-α-D-mannopyranoside (20)
Compound 19 (4.6 g, 14.1 mmol) was dissolved in anhyd CH2Cl2 (50
mL) containing pyridine (9.1 mL, 113 mmol), then under N2, BzCl (4.9
mL, 42.3 mmol) was added dropwise to the solution over 15 min at
–10 °C. The temperature was slowly raised to r.t. and the mixture was
stirred for 2 h; TLC (PE–EtOAc, 3:1) indicated completion. The mix-
ture was diluted with CH2Cl2 (100 mL), washed with ice-water, 1 M
HCl, and water, and dried (Na2SO4). The solution was concentrated,
and the residue was dissolved in 70% AcOH (200 mL) and stirred for 3
h at 70 °C; TLC (PE–EtOAc, 2:1) indicated completion. The mixture
was concentrated under reduced pressure and then co-evaporated
with toluene (2 × 40 mL). The residue was purified by chromatogra-
phy (PE–EtOAc, 4:1) to give 20 as a syrup; yield: 6.34 g (91% for 2
steps); [α]D +69 (c 1, CHCl3).
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R. Jiang et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 8.04–8.01 (m, 2 H, HBz), 7.88–7.85 (m,
2 H, HBz), 7.57–7.50 (m, 2 H, HBz), 7.48–7.32 (m, 2 H, HBz), 7.05–7.02
(m, 2 H, Hmp), 6.73–6.70 (m, 2 H, Hmp), 5.55 (d, J = 1.4 Hz, 1 H, H1), 5.46
(t, J3,4 = J4,5 = 9.6 Hz, 1 H, H4), 4.51–4.23 (m, 5 H, H2, H3, H5, 2 H6),
3.71 (s, 3 H, OCH3), 3.59 (br s, 2 H, 2 OH).
13C NMR (75 MHz, CDCl3): δ = 167.32, 166.22, 155.19, 149.91, 133.70,
133.01, 130.00, 129.76, 129.72, 129.05, 128.55, 127.96, 117.82,
114.65, 98.27, 71.25, 70.74, 70.45, 68.66, 63.62, 55.58.
4-Methoxyphenyl 3,6-Di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-
D-mannopyranosyl-(1→6)-3-O-acetyl-2,4-di-O-benzoyl-α-D-man-
nopyranoside (21)
To a cooled (–10 °C) solution of 5 (103 mg, 0.1 mmol) in anhyd pyri-
dine (3.2 mL, 40.0 mmol), then under N2, AcCl (0.14 mL, 2.1 mmol) in
anhyd pyridine (2 mL) was added dropwise to the solution over 30
min. The mixture was slowly raised to r.t. and stirred for 1 h, TLC (PE–
EtOAc, 2:1) indicated completion. The mixture was diluted with
CH2Cl2 (20 mL), washed with ice-water, 1 M HCl, and water, and dried
(Na2SO4). Concentration of the organic phase and purification of the
residue by flash column chromatography (PE–EtOAc, 4:1) afforded 21
as a white solid; yield: 99 mg (92%); [α]D +67 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.22–8.02 (m, 8 H, HBz), 7.61–7.37 (m,
12 H, HBz), 7.15 (d, J = 9.1 Hz, 2 H, Hmp), 6.90 (d, J = 9.1 Hz, 2 H, Hmp),
5.96–5.68 (m, 7 H), 5.65–5.1 (m, 2 H, H1, H3), 5.30–5.14 (m, 3 H),
5.09–5.05 (m, 2 H), 4.53–4.43 (m, 5 H), 4.16 (m, 3 H), 4.01 (m, 1 H),
3.72 (s, 3 H, OCH3), 3.67 (m, 1 H), 1.95 (s, 3 H, COCH3).
HRMS: m/z [M + H]+ calcd for C27H27O9: 495.16490; found: 495.16496.
4-Methoxyphenyl 3-O-Acetyl-4,6-di-O-benzoyl-α-D-mannopyra-
noside (10)
To a cooled (–10 °C) solution of 20 (4.94 g, 10.0 mmol) in anhyd
CH2Cl2 (60 mL) containing pyridine (3.2 mL, 40.0 mmol), then under
N2, AcCl (0.72 mL, 10.5 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise to the solution over 30 min. The temperature was slowly
raised to r.t. and the mixture was stirred for 2 h; TLC (PE–EtOAc, 3:1)
indicated that the reaction was complete. The mixture was diluted
with CH2Cl2 (100 mL), washed with ice-water, 1 M HCl, and water, and
dried (Na2SO4). Concentration of the organic phase and purification of
the residue by flash column chromatography (PE–EtOAc, 4:1) afford-
ed 10 as a white solid; yield: 4.72 g (88%); [α]D +102 (c 1, CHCl3).
HRMS: m/z [M
+ : 1075.31462; found:
H]+ calcd for C57H55O21
1075.31438.
4-Methoxyphenyl 2,4-Di-O-benzoyl-α-D-mannopyranosyl-(1→6)-
2,4-di-O-benzoyl-α-D-mannopyranoside (3)
1H NMR (300 MHz, CDCl3): δ = 8.01–7.99 (m, 2 H, HBz), 7.91–7.88 (m,
2 H, HBz), 7.59–7.33 (m, 6 H, HBz), 7.09–7.06 (m, 2 H, Hmp), 6.78–6.74
(m, 2 H, Hmp), 5.75 (m, 2 H, H3, H4), 5.55 (d, J1,2 = 1.8 Hz, 1 H, H1),
4.50–4.34 (m, 4 H, H2, H5, 2 H6), 3.73 (s, 3 H, OCH3), 2.46 (s, 1 H, OH),
2.02 (s, 3 H, CH3CO).
13C NMR (75 MHz, CDCl3): δ = 169.98, 166.07, 165.60, 155.19, 149.74,
133.49, 132.92, 129.82, 129.68, 129.64, 128.96, 128.49, 128.17,
117.74, 114.60, 98.23, 71.40, 69.46, 69.19, 67.27, 63.38, 55.51, 20.75.
To a cooled (–10 °C) solution of 5 (1.55 g, 1.5 mmol) in MeOH–THF
(1:1, 80 mL) was added NH4OAc (1.16 g, 15 mmol). The mixture was
stirred vigorously and NaBH4 (55 mg, 1.5 mmol), Pd(PPh3)4 (88 mg,
0.075 mmol), and NaBH4 (27.5 mg, 0.75 mmol) were added in 3 por-
tions immediately one after the other; 5 min after the addition of the
second portion of NaBH4; TLC (PE–EtOAc, 1:1) indicated completion.
The mixture was concentrated under vacuum at 30 °C, the residue
was dissolved in CH2Cl2 (10 mL) and washed with brine (10 mL), then
the organic phase was dried (Na2SO4). Evaporation and purification
by flash column chromatography (PE–EtOAc, 3:1) afforded 3 as a
foamy solid; yield: 1.09 g (84%); [α]D +84 (c 1, CHCl3).
HRMS: m/z [M
+ : 537.17552; found:
H]+ calcd for C29H29O10
537.17416.
1H NMR (300 MHz, CDCl3): δ = 8.15–8.03 (m, 8 H, HBz), 7.63– 7.35 (m,
12 H, HBz), 7.11 (d, J = 9.0 Hz, 2 H, Hmp), 6.87 (d, J = 9.0 Hz, 2 H, Hmp),
5.78–5.62 (m, 3 H, H4, 2 H2), 5.49–5.40 (m, 2 H, H4, H1), 5.04 (s, 1 H,
H1), 4.61 (dd, J2,3 = 3.2 Hz, J3,4 = 9.8 Hz, 1 H, H3), 4.46 (dd, J2,3 = 3.2 Hz,
J3,4 = 9.7 Hz, 1 H, H3), 4.34 (m, 1 H, H5), 3.97 (m, 1 H, H5), 3.79–3.64
(m, 5 H, OCH3, 2 H6), 3.45–3.42 (m, 2 H, 2 H6), 2.62 (br s, 3 H, 3 OH).
13C NMR (75 MHz, CDCl3): δ = 167.25, 166.79, 165.91, 165.84, 155.38,
149.88, 133.72, 133.67, 133.48, 129.94, 129.85, 129.80, 129.21,
129.17, 129.07, 129.00, 128.67, 128.55, 128.51, 117.87, 114.69, 97.47,
96.59, 72.68, 70.57, 70.09, 69.94, 69.67, 68.98, 68.52, 66.19, 60.95,
55.53.
4-Methoxyphenyl 3,6-Di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-
D-mannopyranosyl-(1→6)-2,4-di-O-benzoyl-α-D-mannopyrano-
side (5)
Compound 8 (2.47 g, 5.00 mmol), 7 (3.85 g, 5.50 mmol), and 4-Å mo-
lecular sieves (3 g) were dried together under high vacuum for 2 h,
then dissolved in anhyd, redistilled CH2Cl2 (50 mL). TMSOTf (36 μL,
0.2 mmol) was added dropwise at –20 °C under N2. The mixture was
stirred for 0.5 h, during the course of which time the mixture was al-
lowed to gradually warm to r.t.; TLC (PE–EtOAc, 3:1) indicated com-
pletion. Then the mixture was neutralized with Et3N and filtered, and
the filtrate was concentrated. Purification of the residue by column
chromatography (PE–EtOAc, 6:1) gave 5 as a foamy solid; yield: 4.34 g
(84%); [α]D +93 (c 1, CHCl3).
HRMS: m/z [M
+ : 865.27021; found:
H]+ calcd for C47H45O16
865.27048.
1H NMR (300 MHz, CDCl3): δ = 8.20–8.05 (m, 8 H, HBz), 7.60–7.31 (m,
12 H, HBz), 7.13 (d, J = 9.1 Hz, 2 H, Hmp), 6.88 (d, J = 9.1 Hz, 2 H, Hmp),
5.79–5.59 (m, 8 H), 5.30–5.18 (m, 3 H), 5.08–5.04 (m, 2 H), 4.52–4.48
(m, 7 H), 4.07–3.99 (m, 4 H), 3.71 (s, 3 H, OCH3), 2.58 (d, J = 8.7 Hz, 1
H, OH).
13C NMR (75 MHz, CDCl3): δ = 166.71, 166.03, 165.30, 155.48, 154.54,
153.81, 150.08, 13361, 133.49, 133.43, 131.49, 131.14, 130.00,
129.88, 129.18, 129.12, 129.03, 129.01, 128.73, 128.48, 128.44,
118.63, 118.06, 114.81, 97.37, 97.00, 72.88, 72.75, 69.91, 69.63, 69.52,
69.01, 68.64, 68.44, 66.76, 66.52, 65.63, 55.47.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-
(1→2)-3-O-acetyl-4,6-di-O-benzoyl-α-D-mannopyranoside (23)
Compound 10 (2.68 g, 5.00 mmol), 9 (4.06 g, 5.50 mmol), and 4-Å
molecular sieves (2 g) were dried together under high vacuum for 2 h,
then dissolved in anhyd, redistilled CH2Cl2 (50 mL). TMSOTf (36 μL,
0.2 mmol) was added dropwise at –20 °C under N2. The mixture was
stirred for 0.5 h, during the course of which time the mixture was al-
lowed to gradually warm to r.t.; TLC (PE–EtOAc, 2:1) indicated com-
pletion. Then the mixture was neutralized with Et3N and filtered, and
the filtrate was concentrated. Purification of the residue by column
chromatography (PE–EtOAc, 5:1) gave 23 as a foamy solid; yield: 5.12
g (92%); [α]D +47 (c 1, CHCl3).
HRMS: m/z [M + NH4]+ calcd for C55H56O20N: 1050.33902; found:
1050.33561.
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1H NMR (300 MHz, CDCl3): δ = 8.05–7.88 (m, 12 H, HBz), 7.74–7.29 (m,
18 H, HBz), 7.09–7.06 (m, 2 H, Hmp), 6.73–6.70 (m, 2 H, Hmp), 6.15 (t,
J3,4 = J4,5 = 9.8 Hz, 1 H, H4), 6.05 (dd, J2,3 = 3.2 Hz, J3,4 = 10.1 Hz, 1 H, H3),
5.85–5.83 (m, 3 H), 5.72 (d, J1,2 = 1.8 Hz, 1 H, H1), 5.36 (d, J1,2 = 1.7 Hz,
1 H, H1), 4.66–4.42 (m, 7 H), 3.72 (s, 3 H, OCH3), 2.11 (s, 3 H, CH3CO).
13C NMR (75 MHz, CDCl3): δ = 170.49, 166.09, 166.05, 165.54, 165.22,
165.19, 165.07, 155.23, 149.36, 133.50, 133.44, 133.13, 132.94,
132.90, 129.87, 129.77, 129.69, 129.62, 129.55, 129.47, 129.13,
129.04, 128.94, 128.72, 128.57, 128.46, 128.39, 128.27, 117.67,
114.60, 99.48, 97.22, 70.44, 7.09, 69.70, 69.46, 69.32, 67.53, 66.86,
63.47, 62.92, 55.48, 20.69.
13C NMR (75 MHz, CDCl3): δ = 169.53, 166.22, 166.05, 165.89, 165.49,
165.23, 165.20, 165.08, 164.94, 164.82, 164.74, 155.66, 154.48,
153.63, 149.92, 133.41, 133.31, 133.27, 133.09, 133.01, 132.94,
132.81, 132.73, 132.68, 131.39, 131.08, 130.11, 129.89, 129.79,
129.74, 129.68, 129.60, 129.41, 129.20, 129.06, 128.92, 128.74,
128.47, 128.42, 128.37, 128.34, 128.29, 128.23, 128.13, 128.07,
118.74, 118.50, 114.83, 114.71, 100.18, 99.51, 97.61, 97.35, 78.34,
75.18, 72.83, 71.78, 70.07, 69.70, 69.50, 69.42, 69.13, 68.69, 68.53,
68.32, 67.24, 66.72, 66.61, 66.13, 65.66, 63.57, 62.80, 55.33, 29.53,
20.49.
HRMS: m/z [M + H]+ calcd for C111H99O37: 2023.57824; found:
2023.57802.
HRMS: m/z [M + Na]+ calcd for C63H54O19Na: 1137.31515; found:
1137.31225.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-
(1→2)-3-O-acetyl-4,6-di-O-benzoyl-α-D-mannopyranosyl-(1→3)-
[2,4-di-O-benzoyl-α-D-mannopyranosyl-(1→6)]-2,4-di-O-benzoyl-
α-D-mannopyranoside (4)
2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-(1→2)-3-O-acetyl-
4,6-di-O-benzoyl-α-D-mannopyranosyl Trichloroacetimidate (6)
To a solution of 23 (4.6 g, 4.1 mmol) in MeCN (120 mL) were added
water (30 mL) and CAN (9.05 g, 16.4 mmol) successively. The mixture
was stirred for 20 min at 30 °C; TLC (PE–EtOAc, 3:1) indicated com-
pletion. The solvent was evaporated under reduced pressure at 50 °C
to give a residue that was dissolved in CH2Cl2 and then washed with
water. The organic phase was dried (Na2SO4) and concentrated to give
a residue that was purified by chromatography (silica gel, PE–EtOAc,
3:1) to afford 2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→2)-3-
To a cooled (–10 °C) solution of 24 (1.41 g, 0.7 mmol) in MeOH–THF
(1:1, 60 mL) was added NH4OAc (1.08 g, 14 mmol). The mixture was
stirred vigorously and NaBH4 (20 mg, 0.53 mmol), Pd(PPh3)4 (32 mg,
0.028 mmol), and NaBH4 (20 mg, 0.53 mmol) were added in 3 por-
tions immediately one after the other; 5 min after the addition of the
second portion of NaBH4, TLC (PE–EtOAc, 1:1) indicated completion.
The mixture was concentrated under vacuum at 30 °C, the residue
was dissolved in CH2Cl2 (10 mL) and washed with brine (10 mL), then
the organic phase was dried (Na2SO4) Evaporation and purification by
flash column chromatography (PE–EtOAc, 3:1) afforded 4 as a foamy
solid; yield: 1.05 g (82%); [α]D +74 (c 1, CHCl3).
O-acetyl-4,6-di-O-benzoyl-D-mannopyranose as
a slight yellow
foamy solid. A mixture of this compound, trichloroacetonitrile (2.0
mL), and DBU (0.2 mL) in anhyd CH2Cl2 (40 mL) was stirred at r.t. for
0.5 h and then concentrated. The residue was purified by chromatog-
raphy (PE–EtOAc, 4:1) to give 6 as a yellow solid; yield: 4.13 g (87% for
2 steps).
1H NMR (300 MHz, CDCl3): δ = 8.12 (m, 2 H, HBz), 8.09–7.84 (m, 19 H,
H
Bz), 7.60–7.33 (m, 29 H, HBz), 7.06 (m, 2 H, Hmp), 6.83 (m, 2 H, Hmp),
5.96 (t, J3,4 = J4,5 = 10.2 Hz, 1 H, H4), 5.90–5.82 (m, 3 H, 2 H1, H4), 5.76–
5.69 (m, 2 H, H1, H4), 5.59 (m, 1 H, H2), 5.49–5.39 (m, 4 H, H1, H2, 2
H3), 5.02 (s, 1 H, H1), 4.76 (dd, J2,3 = 3.3 Hz, J3,4 = 9.5 Hz, 1 H, H3),
4.59–4.38 (m, 6 H), 4.36–4.25 (m, 3 H), 3.94–3.79 (m, 3 H), 3.70 (s, 3
H, OCH3), 3.62–3.52 (m, 3 H), 2.47 (d, J = 7.2 Hz, 1 H, OH), 2.29 (m, 1 H,
OH), 1.96 (s, 3 H, CH3CO).
13C NMR (75 MHz, CDCl3): δ = 169.71, 167.34, 166.32, 166.01, 165.99,
165.87, 165.57, 165.38, 165.02, 164.92, 164.87, 155.60, 149.74,
133.75, 133.63, 133.53, 133.49, 133.38, 133.23, 133.10, 133.06,
132.79, 130.10, 129.98, 129.91, 129.88, 129.79, 129.72, 129.69,
129.64, 129.29, 129.27, 129.22, 129.14, 129.11, 128.84, 128.64,
128.58, 128.54, 128.51, 128.39, 128.36, 128.25, 128.13, 118.44,
114.84, 114.66, 100.19, 99.61, 97.60, 97.10, 78.33, 75.28, 72.73, 71.76,
70.64, 70.17, 69.91, 69.61, 69.53, 69.27, 68.77, 68.42, 67.31, 66.62,
66.36, 63.66, 62.80, 61.11, 55.55, 20.64.
1H NMR (300 MHz, CDCl3): δ = 8.69 (s, 1 H, NH), 8.10–7.89 (m, 12 H,
H
Bz), 7.59–7.30 (m, 18 H, HBz), 6.58 (d, J1,2 = 1.7 Hz, 1 H, H1), 6.21 (t,
J3,4 = J4,5 = 10.0 Hz, 1 H, H4), 6.03–5.92 (m, 2 H, H3, H4), 5.85 (m, 1 H,
H2), 5.71 (dd, J2,3 = 3.2 Hz, J3,4 = 9.7 Hz, 1 H, H3), 5.38 (d, J1,2 = 1.2 Hz, 1
H, H1), 4.75–4.47 (m, 7 H, H2, 2 H5, 4 H6), 2.09 (s, 3 H, CH3CO).
HRMS: m/z [M + Na]+ calcd for C58H48Cl3NNaO18: 1174.1829; found:
1174.1831.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-
(1→2)-3-O-acetyl-4,6-di-O-benzoyl-α-D-mannopyranosyl-(1→3)-
[3,6-di-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-D-mannopyrano-
syl-(1→6)]-2,4-di-O-benzoyl-α-D-mannopyranoside (24)
Compound 5 (1.03 g, 1.00 mmol), 6 (1.26 g, 1.1 mmol), and 4-Å mo-
lecular sieves (1 g) were dried together under high vacuum for 2 h,
then dissolved in anhyd, redistilled CH2Cl2 (50 mL). TMSOTf (7.2 μL,
0.04 mmol) was added dropwise at –20 °C under N2. The mixture was
stirred for 0.5 h, during the course of which time the mixture was al-
lowed to gradually warm to r.t.; TLC (PE–EtOAc, 3:1) indicated com-
pletion. Then the mixture was neutralized with Et3N and filtered, and
the filtrate was concentrated. Purification of the residue by column
chromatography (PE–EtOAc, 6:1) gave 24 as a foamy solid; yield: 1.7 g
(84%); [α]D +106 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): 8.14–8.11 (m, 2 H, HBz), 8.05–7.82 (m, 22
H, HBz), 7.46–7.34 (m, 26 H, HBz), 7.08 (m, 2 H, Hmp), 6.92 (m, 2 H, Hmp),
5.96 (t, J3,4 = J4,5 = 9.2 Hz, 1 H, H4), 5.90–5.68 (m, 8 H), 5.64–5.55 (m, 4
H, 2 H1, H2, H3), 5.46 (m, 2 H, H1, H2), 5.28–5.15 (m, 3 H), 5.07–5.00
(m, 2 H), 4.76 (dd, J2,3 = 3.2 Hz, J3,4 = 9.5 Hz, 1 H, H3), 4.55–4.42 (m, 7
H), 4.40–4.28 (m, 4 H), 4.15–4.12 (m, 3 H), 3.93 (m, 2 H), 3.69 (s, 3 H,
OCH3), 3.62 (m, 1 H), 1.96 (s, 3 H, CH3CO).
HRMS: m/z [M + H]+ calcd for C103H91O33: 1854.53468; found:
1854.53427.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-
(1→6)-[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→3)]-2,4-
di-O-benzoyl-α-D-mannopyranosyl-(1→6)-[2,3,4,6-tetra-O-benzo-
yl-α-D-mannopyranosyl-(1→3)]-2,4-di-O-benzoyl-α-D-mannopy-
ranoside (22)
Compound 3 (4.32 g, 5 mmol), 9 (14.5 g, 20 mmol), and 4-Å molecular
sieves (4 g) were dried together under high vacuum for 2 h, then dis-
solved in anhyd, redistilled CH2Cl2 (80 mL). TMSOTf (72 μL, 0.4 mmol)
was added dropwise at –20 °C under N2. The mixture was stirred for
0.5 h, during the course of which time the mixture was allowed to
gradually warm to r.t.; TLC (PE–EtOAc–toluene, 3:1:1) indicated com-
pletion. Then the mixture was neutralized with Et3N and filtered, and
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R. Jiang et al.
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the filtrate was concentrated. Purification of the residue by column
chromatography (PE–EtOAc, 6:1) gave 22 as a foamy solid; yield: 8.3 g
(64%); [α]D +132 (c 1, CHCl3).
HRMS: m/z [M + H]+ calcd for C171H143O51: 3011.85218; found:
3011.85206.
1H NMR (300 MHz, CDCl3): δ = 8.23–7.30 (m, 80 H, HBz), 7.08 (d, J = 9.1
Hz, 2 H, Hmp), 6.78 (d, J = 9.1 Hz, 2 H, Hmp), 6.16 (t, J3,4 = J4,5 = 10.0 Hz, 1
H, H4), 6.11–6.04 (m, 2 H), 6.02–5.95 (m, 2 H), 5.93–5.88 (m, 2 H),
5.79–5.68 (m, 4 H, H2, H1, 2 H3), 5.58 (m, 1 H, H2), 5.48 (m, 1 H, H2),
5.41 (d, J1,2 = 1.4 Hz, 1 H, H1), 5.36 (m, 2 H, H1, H2), 5.17 (s, 1 H, H1),
4.87 (dd, J2,3 = 3.3 Hz, J3,4 = 9.7 Hz, 1 H, H3), 4.78 (d, J1,2 = 1.2 Hz, 1 H,
H1), 4.67–4.61 (m, 2 H), 4.57–4.52 (m, 3 H), 4.50–4.32 (m, 4 H), 4.29–
4.21 (m, 4 H), 4.01 (m, 1 H), 3.81 (m, 1 H), 3.47 (s, 3 H, OCH3), 3.44 (m,
1 H).
4-Methoxyphenyl α-D-Mannopyranosyl-(1→6)-[α-D-mannopyra-
nosyl-(1→3)]-α-D-mannopyranosyl-(1→6)-[α-D-mannopyranosyl-
(1→3)]-α-D-mannopyranoside (1)
Compound 22 (13 g, 5 mmol) was dissolved in sat. NH3–MeOH (1000
mL). After 120 h at r.t., the mixture was concentrated to a total vol-
ume of ca. 50 mL, then warm acetone (500 mL, 50 °C) was added to
the mixture under vigorous stirring, and a white solid precipitated
from the solution, which was then kept at 0 °C for 24 h; filtration gave
1 as a white solid; yield: 3.8 g (82%); [α]D +46 (c 1, H2O).
13C NMR (75 MHz, CDCl3): δ = 166.14, 166.11, 166.09, 166.01, 165.90,
165.69, 165.54, 165.47, 165.15, 165.13, 165.06, 164.98, 164.64,
164.63, 164.57, 16.52 (16 COPh), 155.52, 149.84, 133.17, 130.18,
130.03, 129.98, 129.86, 129.84, 129.75, 129.72, 129.70, 129.68, 129.1,
129.59, 129.57, 129.44, 129.19, 129.07, 128.99, 128.94, 128.64,
128.55, 128.47, 128.41, 128.35, 128.33, 128.21, 128.08, 118.39,
114.65, 99.92, 99.67, 97.52, 97.33, 97.09 (5 C1), 72.03, 71.95, 70.17,
70.09, 69.7, 69.63, 69.54, 69.34, 69.21, 68.78, 68.14, 66.55, 66.43,
66.39, 62.65, 62.55, 62.50, 55.31.
1H NMR (300 MHz, MeOD–D2O): δ = 7.08 (d, J = 9.1 Hz, 2 H, Hmp), 6.92
(d, J = 9.1 Hz, 2 H, Hmp), 5.32 (d, J = 1.6 Hz, 1 H, H1), 5.17 (d, J = 1.6 Hz,
1 H, H1), 5.08 (d, J = 1.3 Hz, 1 H, H1), 4.89 (d, J = 1.3 Hz, 1 H, H1), 4.76
(d, J = 1.5 Hz, 1 H, H1), 4.27 (m, 1 H), 4.06–4.02 (m, 4 H), 3.91–3.66 (m,
28 H).
13C NMR (75 MHz, MeOD–D2O): δ = 155.06, 150.40, 117.77, 114.27,
102.40, 102.27, 99.70, 99.55, 99.44, 79.37, 78.79, 73.43, 73.23, 72.79,
72.31, 71.18, 70.93, 70.89, 70.56, 70.52, 70.45, 69.88, 69.70, 67.23,
67.04, 66.03, 65.93, 65.80, 65.64, 61.21, 61.13, 54.78.
HRMS: m/z [M + H]+ calcd for C149H123O43: 2599.73658; found:
2599.73635.
HRMS: m/z [M
+ : 935.32382; found:
H]+ calcd for C37H59O27
935.32395.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl-
(1→6)-[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→3)]-2,4-
di-O-benzoyl-α-D-mannopyranosyl-(1→6)-[2,3,4,6-tetra-O-benzo-
yl-α-D-mannopyranosyl-(1→2)-3-O-acetyl-4,6-di-O-benzoyl-α-D-
mannopyranosyl-(1→3)]-2,4-di-O-benzoyl-α-D-mannopyranoside
(25)
4-Methoxyphenyl α-D-Mannopyranosyl-(1→6)-[α-D-mannopyra-
nosyl-(1→3)]-α-D-mannopyranosyl-(1→6)-[α-D-mannopyranosyl-
(1→2)-α-D-mannopyranosyl-(1→3)]-α-D-mannopyranoside (2)
Compound 25 (11.2 g, 3.7 mmol) was dissolved in sat. NH3–MeOH
(1200 mL). After 120 h at r.t., the mixture was concentrated to a total
volume of ca. 50 mL, then warm acetone (500 mL, 50 °C) was added to
the mixture under vigorous stirring, and a white solid precipitated
from the solution, which was kept at 0 °C for 24 h and filtered to give
2 as a white solid; yield: 3.2 g (78%); [α]D +38 (c 1, H2O).
1H NMR (300 MHz, D2O): δ = 7.01 (d, J = 7.0 Hz, 2 H, Hmp), 6.87 (d, J =
7.0 Hz, 2 H, Hmp), 5.39 (d, J = 1.6 Hz, 1 H, H1), 5.33 (d, J = 1.5 Hz, 1 H,
H1), 4.97 (m, 2 H, 2 H1), 4.78 (d, J = 1.5 Hz, 1 H, H1), 4.63 (d, J = 1.4 Hz,
1 H, H1), 4.20 (m, 1 H), 4.0–3.55 (m, 38 H).
13C NMR (75 MHz, D2O): δ = 15.51, 149.29, 118.33, 115.07, 102.24,
102.19, 100.76, 99.6, 98.96, 98.62, 7847, 78.43, 73.35, 73.21, 73.19,
72.63, 71.45, 70.70, 70.54, 70.37, 70.31, 70.06, 69.93, 69.43, 66.92,
66.71, 66.68, 65.88, 65.68, 65.37, 65.22, 60.98, 60.92, 55.77, 48.85.
Compound 4 (1.86 g, 1 mmol), 9 (2.22 g, 3 mmol), and 4-Å molecular
sieves (2 g) were dried together under high vacuum for 2 h, then dis-
solved in anhyd, redistilled CH2Cl2 (30 mL). TMSOTf (14.4 μL, 0.08
mmol) was added dropwise at –20 °C under N2. The mixture was
stirred for 0.5 h, during the course of which time the mixture was al-
lowed to gradually warm to r.t.; TLC (PE–EtOAc–toluene, 3:1:2) indi-
cated completion. Then the mixture was neutralized with Et3N and
filtered, and the filtrate was concentrated. Purification of the residue
by column chromatography (PE–EtOAc, 6:1) gave 25 as a foamy solid;
yield: 2 g (67%); [α]D +124 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.07–7.22 (m, 90 H, HBz), 7.08 (d, J = 9.1
Hz, 2 H, Hmp), 6.83 (d, J = 9.1 Hz, 2 H, Hmp), 6.11–5.89 (m, 7 H), 5.85–
5.70 (m, 5 H, H1, 2 H2, 2 H3), 5.60–5.58 (m, 2 H, 2 H2), 5.47–5.43 (m,
3 H, H1, H2, H3), 5.34 (d, J1,2 = 1.4 Hz, 1 H, H1), 5.16 (d, J1,2 = 1.6 Hz, 1
H, H1), 4.86 (dd, J2,3 = 3.4 Hz, J3,4 = 9.7 Hz, 1 H, H3), 4.80 (d, J1,2 = 1.4 Hz,
1 H, H1), 4.63–4.43 (m, 9 H), 4.37–4.28 (m, 3 H), 4.24–4.15 (m, 5 H),
3.97–3.93 (m, 2 H), 3.77 (m, 1 H), 3.47 (s, 3 H, OCH3), 3.39 (m, 1 H),
1.91 (s, 3 H, COCH3).
HRMS: m/z [M
+ : 1097.37664; found:
H]+ calcd for C43H69O32
1097.37691.
Acknowledgment
13C NMR (75 MHz, CDCl3): δ = 166.34, 166.12, 66.08, 165.98, 165.88,
16587, 165.62, 165.53, 165.46, 165.36, 165.12, 165.07, 164.98,
164.94, 164.82, 164.67, 164.54, 133.62, 133.47, 133.37, 133.31, 33.25,
133.20, 133.09, 133.03, 133.00, 132.91, 132.75, 130.14, 129.96,
129.88, 129.84, 129.81, 129.74, 129.67, 129.65, 129.55, 129.45,
129.40, 129.33, 129.3, 2927, 129.23, 129.15, 129.10, 129.06, 129.01,
129.00, 128.91, 128.79, 128.64, 128.57, 128.53, 128.52, 128.49,
128.42, 128.38, 128.34, 128.29, 128.18, 128.06, 118.78, 114.62,
100.12, 99.78, 99.51, 97.56, 97.46, 97.36, 75.22, 71.89, 71.83, 70.1,
70.09, 69.80, 69.69, 69.56, 69.28, 69.14, 68.73, 68.58, 68.02, 67.30,
66.55, 66.40, 66.32, 65.92, 63.65, 62.69, 62.39, 55.27, 20.55.
This work was partially supported by Chinese Universities Scientific
Fund (2015QC069), the NSFC (21172257) and the National S&T Pillar
Program (2011AA10A206, 2015BAK45B01) of China.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560323.
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