Synthesis of a mannose hexasaccharide related to the cell wall mannan of candida dubliniensis and trychophyton mentagrophytes

Article abstract of DOI:10.1055/s-0029-1218719

2,6-Branched mannose hexasaccharide 1 related to the cell wall polysaccharide of Candida dubliniensis and Trychophyton mentagrophytes was concisely synthesized from 4-methoxyphenyl -d-mannopyranoside (6) in 11 steps in 26% total yield. The efficiency of the synthesis relies on the preparation of a trisaccharide acceptor 2 with three free hydroxy groups, which could be glycosylated with trichloroacetimidate 19 to provide the protected hexasaccharide 20 in one step. Compound 2 was obtained via sequential assembly from the building blocks, 2,6-di-O-allyloxycarbonyl-3,4-di-O-benzoyl -α-d-mannopyranose trichloroacetimidate (3), 4-methoxyphenyl 3,4-di-O-benzoyl -α-d-mannopyranoside (4), and 4-methoxyphenyl 4-O-acetyl-3-O-benzoyl -α-d-mannopyranoside (5). Structures of target compound and intermediates were characterized by ¹H and ¹C NMR, MS, HRMS, and elemental analysis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218719

1666
PAPER
Synthesis of a Mannose Hexasaccharide Related to the Cell Wall Mannan of
Candida dubliniensis and Trychophyton mentagrophytes
Guanghui Zong, Naili Yu, Yanjun Xu, Jianjun Zhang,* Daoquan Wang, Xiaomei Liang*
Key Laboratory of Pesticide Chemistry and Application Technology, Department of Applied Chemistry, China Agricultural University,
Beijing 100193, P. R. of China
Fax +86(10)62732219; E-mail: zhangjianjun@cau.edu.cn; E-mail: nmrlab@cau.edu.cn
Received 14 January 2010; revised 1 March 2010
the cell wall mannan of C. dubliniensis and T. mentagro-
Abstract: 2,6-Branched mannose hexasaccharide 1 related to the
phytes in the form of its 4-methoxyphenyl glycoside 1
(Figure 1). The choice of the 4-methoxyphenyl glycoside
1 will enable us to conjugate the synthetic oligosaccharide
cell wall polysaccharide of Candida dubliniensis and Trychophyton
mentagrophytes was concisely synthesized from 4-methoxyphenyl
a-D-mannopyranoside (6) in 11 steps in 26% total yield. The effi-
ciency of the synthesis relies on the preparation of a trisaccharide with suitable aglycon when necessary.
acceptor 2 with three free hydroxy groups, which could be glycosy-
lated with trichloroacetimidate 19 to provide the protected hexasac-
HO
HO
HO
OH
O
HO
HO
HO
O
charide 20 in one step. Compound 2 was obtained via sequential
assembly from the building blocks, 2,6-di-O-allyloxycarbonyl-3,4-
di-O-benzoyl-a-D-mannopyranose trichloroacetimidate (3), 4-
methoxyphenyl 3,4-di-O-benzoyl-a-D-mannopyranoside (4), and 4-
HO
HO
O
O
O
O
O
HO
O
O
O
O
HO
HO
HO
OPMP
methoxyphenyl
4-O-acetyl-3-O-benzoyl-a-D-mannopyranoside
HO
HO
HO
HO
HO
O
HO
(5). Structures of target compound and intermediates were charac-
1
terized by 1H and 13C NMR, MS, HRMS, and elemental analysis.
Key words: synthesis, oligosaccharide, mannose, Candida dublin-
iensis, Trychophyton mentagrophytes
HO
O
AcO
O
HO
O
OPMP
O
BzO
HO
BzO
AcO
BzO
Mannans with an a-(1→6)-linked backbone and branched
at O2 with varying numbers of linear oligomannosyl side
chains are characteristic structures of the cell wall
polysaccharides of many clinically important fungi, in-
cluding Trychophyton mentagrophytes, T. rubrum, Can-
dida dubliniensis and C. albicans.1 T. mentagrophytes and
T. rubrum are well known anthropophilic dermatophytes
which cause skin infections of the feet, body, and nails.2
While C. dubliniensis and C. albicans are important hu-
man opportunistic pathogens, they were originally identi-
fied in oral specimens from Irish HIV-infected and AIDS
patients with recurrent oral candidiasis and recently have
been recovered from oral samples of HIV-seropositive pe-
diatric patients.3 Cell wall polysaccharides are ubiquitous
structures on the cell surfaces of many bacterial species,
and they are involved not only in pathogenic processes,
but also in mediating resistance to host defense mecha-
nisms; the polysaccharides have been regarded as an im-
portant factor in the virulence of many animals and plant
pathogens.4 Synthetic studies on these polysaccharides
are of considerable importance in view of developing nov-
el vaccine candidates and studying structure–bioactivity
relationship of carbohydrates.5 In a collaborative project
for developing novel vaccines against C. dubliniensis and
T. mentagrophytes infection, we needed to prepare grams
of the 2,6-branched mannose hexasaccharide related to
BzO
BzO
2
AllocO
HO
AcO
BzO
OAlloc
O
OH
O
OH
O
HO
BzO
BzO
BzO
BzO
OCNHCCl3
OPMP
OPMP
4
5
3
Figure 1 Structure of the target hexasaccharide 1 and the building
blocks 2–5 used for its synthesis
Several papers have been devoted to 2,6-branched man-
nose oligosaccharides synthesis,6 however, the strategies
involved in these reports were not suitable for large-scale
preparation of the target hexasaccharide due to complex
protection-deprotection steps and low overall yields;
more efficient strategies are highly desired. In this com-
munication, we wish to present a novel approach for the
expeditious preparation of the hexasaccharide
1
(Figure 1), using trisaccharide triol acceptor 2 as the key
intermediate. We envisioned that mannosylation of the
three hydroxy groups in 2 will construct the hexasaccha-
ride 1 in its protected form in only one coupling reaction
and the synthetic procedure will thus be greatly simpli-
fied. The trisaccharide 2 could be produced from three
suitably protected monosaccharide building blocks 3, 4,
and 5, using the allyloxycarbonyl function as the orthogo-
nal protecting group.7
SYNTHESIS 2010, No. 10, pp 1666–1672
x
x.
x
x
.
2
0
1
0
Advanced online publication: 26.03.2010
DOI: 10.1055/s-0029-1218719; Art ID: F01110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Mannose Hexasaccharide
1667
monosaccharide donor 3 in satisfactory overall yield
(86%). According to our previously reported method,7b
deallyloxycarbonylation of 12 and 13 with palladium cat-
alyst [Pd(PPh3)4], sodium borohydride, and ammonium
acetate in tetrahydrofuran–methanol gave the monosac-
charide acceptors 4 and 5 in 94% and 92% yields, respec-
tively.
HO
OH
OH
OH
O
O
O
O
O
b, i
a
O
HO
HO
O
HO
BzO
7
OPMP
OPMP
6
OPMP
8
b
b, ii
OAlloc
O
HO
O
AllocO
OAlloc
O
OAlloc
O
O
c, i
HO
BzO
HO
BzO
b, iii
BzO
OPMP
OPMP
OPMP
c, ii
11
9
AllocO
14 R1 = H; R2 = PMP
AllocO
b
10
d
O
c
BzO
BzO
c
3
15 R1 = Ac; R2 = PMP
a
R1O
16 R1 = Ac; R2 = CNHCCl3
AllocO
O
OAlloc
O
+
AllocO
e
OAlloc
O
3
O
BzO
BzO
AcO
BzO
f
BzO
BzO
4
5
f
AllocO
4
OPMP
AllocO
BzO
OR2
13
O
12
OPMP
AcO
Scheme 1 Synthesis of building blocks 3–5. Reagents and condi-
tions: (a) 2-methoxypropene, DMF, TsOH·H2O, 2 h, 95%; (b) (i)
BzCl, py, –10 °C to r.t., 2 h, 90%; (ii) AllocCl, py, CH2Cl2, –10 °C to
r.t., 2 h, 95%; (iii) 70% AcOH, 75 °C, 1.5 h, 91% (86% overall in one-
pot from 7); (c) (i) AllocCl, py, CH2Cl2, –10 °C to r.t., 2 h, 93%; (ii)
BzCl, py, 0 °C to r.t., 3 h, 95% (88%, overall in one-pot from 10); (d)
(i) AllocCl, py, CH2Cl2, –10 °C to r.t., 2 h; (ii) Ac2O, py, r.t., 12 h,
91%; (e) CAN, MeCN–H2O (4:1), 30 °C, 20 min, then Cl3CCN,
DBU, CH2Cl2, r.t., 86% (2 steps); (f) NH4OAc, Pd(PPh3)4, NaBH4,
MeOH–THF, –10 °C, 4 min, 94% (4); 92% (5).
O
BzO
O
BzO
BzO
5
a
RO
O
+
O
AcO
BzO
16
17 R = H
b
OPMP
18 R = Ac
BzO
BzO
BzO
BzO
d
O
17
2
+
19
OCNHCCl3
a
For the synthesis of monosaccharide building blocks, 4-
methoxyphenyl a-D-mannopyranoside (6)8 was first
transformed into 4,6-O-isopropylidene-a-D-mannopyra-
noside 7 with 2-methoxypropene in N,N-dimethylform-
amide in the presence of catalytic amounts of 4-
toluenesulfonic acid;9 regioselective benzoylation of 7 in
pyridine gave exclusively 3-OH protected derivative 8 in
90% yield (Scheme 1). The presence of the O-benzoyl
group at C3 was confirmed by the downfield shift of the
OBz
O
BzO
BzO
BzO
BzO
BzO
BzO
OBz
O
e
1
O
O
AcO
O
O
O
O
BzO
O
O
BzO
BzO
O
BzO
BzO
OPMP
BzO
BzO
AcO
BzO
BzO
20
Scheme 2 Synthesis of target hexasaccharide 1. Reagents and con-
ditions: (a) TMSOTf, CH2Cl2, – 20 °C, 0.5 h, 87% (14), 85% (17),
91% (20); (b) Ac2O, py, r.t.,12 h, 95% (15), 92% (18); (c) CAN,
MeCN–H2O (4:1), 30 °C, 20 min, then Cl3CCN, DBU, CH2Cl2, r.t.,
77% (2 steps); (d) NH4OAc, Pd(PPh3)4, NaBH4, MeOH–THF (1:1),
–10 °C, 4 min, 94%; (e) MeOH–NH3, 120 h, then warm acetone, 83%.
1
H3 signal in the H NMR spectrum of 8 (d = 5.57) com-
pared with the data for nonbenzoylated 7 (d = 4.06); keep-
ing the reaction temperature below –10 °C is necessary to
assure the regioselectivity. Allyloxycarbonylation of 8
with allyloxycarbonyl chloride in pyridine provided 9
which was then transformed to the key intermediate 10 af-
ter removal of the isopropylidene protecting group in 70%
acetic acid. It is noteworthy that these three steps could be
carried out consecutively without chromatographic sepa-
ration for the first two steps, making the preparation of 10
on a large scale possible in high yield (86%). Subsequent-
ly, regioselective allyloxycarbonylation of the C6-OH of
compound 10 with allyloxycarbonyl chloride in pyridine
provided 11 (93%), which was transformed into 12 or 13
With the monosaccharide synthons 3, 4, and 5 in hand, the
hexasaccharide was prepared efficiently as outlined in
Scheme 2. Thus, coupling of compounds 3 and 4 in
dichloromethane at –20 °C promoted by trimethylsilyl
trifluoromethanesulfonate10 resulted in expected regio-
and stereoselective products, giving exclusively a-1→6-
linked mannose disaccharide 14 in 87% yield. The config-
uration of the glycosyl bond formed in the product was de-
duced from the corresponding coupling constants
(J1,2 = 1.5 Hz). The regioselectivity of the coupling was
1
after benzoylation or acetylation, respectively. The H
1
confirmed by acetylation of 14 to give 15, and the H
NMR spectrum of 12 or 13 showed characteristic triplets
for H4 of the mannose at d = 5.83 (J3,4 = J4,5 = 9.8 Hz) or
5.59 (J3,4 = J4,5 = 9.9 Hz), confirming the 6-selective allyl-
oxycarbonylation of 10 (→ 11, dH4 = 4.60). Importantly,
12 (or 13) could be obtained in a one-pot reaction by add-
ing allyloxycarbonyl chloride and benzoyl (or acetyl)
chloride to the reaction mixture successively, thus greatly
simplify the preparation. Finally, cleavage of the 4-meth-
oxyphenyl group of 12 with cerium(IV) ammonium ni-
trate, followed by trichloroacetimidation,10 provided the
NMR spectrum of 15 showed a newly emerged downfield
doublet of doublets at d = 5.67 with J1,2 = 1.7 Hz and
J2,3 = 3.1 Hz for H2, compared to that of 14. Removal of
the 4-methoxyphenyl group of 15 with cerium(IV) ammo-
nium nitrate and activation with trichloroacetonitrile in
the presence of DBU gave the disaccharide donor 16 in
good overall yield (77%). Condensation of 16 with the ac-
ceptor 5 selectively afforded the (1→6)-linked trisaccha-
ride 17 (85%). The regioselectivity of the reaction was
Synthesis 2010, No. 10, 1666–1672 © Thieme Stuttgart · New York

1668
G. Zong et al.
PAPER
5 H), 4.06 (dd, J2,3 = 3.2 Hz, J3,4 = 10.0 Hz, 1 H, H3), 3.77 (s, 3 H,
OMe), 2.94, 2.89 (br s, 2 H, OH), 1.55, 1.41 (2 s, 6 H, CMe2).
confirmed by acetylation of 17 to give 18 (92%) and the
1H NMR spectrum of 18 showed a newly emerged down-
field doublet of doublets at d = 5.41 with J1,2 = 1.8 Hz and MS (ESI): m/z [M + Na]+ calcd for C16H22O7Na: 349.1; found:
349.5.
J2,3 = 3.1 Hz for H2, compared to that of 17. Subsequent
removal of the two Alloc groups in compound 17 with
Pd(PPh3)4 provided the key triol acceptor 2 in high yield
(94%). Finally, the fully protected hexasaccharide 20 was
smoothly obtained by condensation of the triol 2 with
2,3,4,6-tetra-O-benzoyl-a-D-mannopyranosyl trichloro-
acetimidate (19) in 91% yield. For a complete transforma-
tion of the triol 2, excess monosaccharide donor 19 (4.5
Anal. Calcd for C16H22O7: C, 58.89; H, 6.79. Found: C, 58.60; H,
6.96.
4-Methoxyphenyl 3-O-Benzoyl-4,6-O-isopropylidene-a-D-man-
nopyranoside (8)
Compound 7 (3.26 g, 10.0 mmol) was dissolved in pyridine (20
mL), then BzCl (1.21 mL, 10.5 mmol) in pyridine (10 mL) was add-
ed dropwise to the soln at –10 °C over 30 min. The temperature was
slowly allowed to rise to r.t. and the mixture was stirred for 2 h; TLC
(PE–EtOAc, 2:1) indicated completion. The mixture was diluted
with CH2Cl2 (100 mL), washed with 1 M HCl and H2O, and dried
(Na2SO4). The soln was concentrated and purification of the residue
by column chromatography (PE–EtOAc, 4:1) gave 8 (3.86 g, 90%)
as a white solid; Rf = 0.49 (PE–EtOAc, 2:1).
1
equiv) was used in the coupling reaction. The H NMR
spectrum of 20 showed two acetyl signals (d = 2.09, 2.01),
4-methoxyphenyl signals (7.04–6.72) and six H1 signals
(d = 5.76, 5.37, 5.35, 5.22, 5.12, and 5.01), characteristic
of the structure of the hexasaccharide 20. Deprotection of
20 in ammonia-saturated methanol gave the title 4-meth-
oxyphenyl a-D-hexamannoside 1, which precipitated
from the solution phase as white solids when warm ace-
tone was added to the reaction mixture at the end of depro-
tection.
[a]D +92 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.09–7.43 (m, 5 H, HBz), 7.02–
6.98 (m, 2 H, HMp), 6.86–6.82 (m, 2 H, HMp), 5.57 (dd, J2,3 = 3.3 Hz,
J3,4 = 10.0 Hz, 1 H, H3), 5.46 (d, J1,2 = 1.6 Hz, 1 H, H1), 4.45 (m, 1
H, H2), 4.36 (dd, J3,4 = J4,5 = 10.0 Hz, 1 H, H4), 4.01–3.79 (m, 3 H),
In summary, we have successfully developed a highly ef- 3.77 (s, 3 H, OMe), 2.51 (d, J = 4.0 Hz, 1 H, OH), 1.53, 1.37 (2 s, 6
H, CMe2).
ficient strategy for the preparation of 2,6-branched man-
MS (ESI): m/z [M + Na]+ calcd for C23H26O8Na: 453.2; found:
453.5.
nose hexasaccharide 1 related to cell-wall mannans of
clinical important fungi C. dubliniensis and T. mentagro-
phytes. It is noteworthy that the overall yield of the entire
synthesis is ~26%, and the procedure is suitable for large-
scale preparation of the target hexasaccharide. Bioactivity
investigations of 1 are in progress and the results will be
reported in due course.
Anal. Calcd for C23H26O8: C, 64.18; H, 6.09. Found: C, 64.02; H,
6.33.
4-Methoxyphenyl 2-O-Allyloxycarbonyl-3-O-benzoyl-4,6-O-
isopropylidene-a-D-mannopyranoside (9)
Compound 8 (4.30 g, 10.0 mmol) was dissolved in anhyd CH2Cl2
(50 mL) containing pyridine (3.2 mL, 40.0 mmol), then under an N2
atmosphere, allyl chloroformate (1.58 mL, 15.0 mmol) in anhyd
CH2Cl2 (10 mL) was added dropwise to the soln at –10 °C over 30
min. The temperature was slowly allowed to rise to r.t. and the mix-
ture was stirred for 2 h; TLC (PE–EtOAc, 2:1) indicated comple-
tion. The mixture was diluted with CH2Cl2 (100 mL), washed with
1 M HCl and H2O, and dried (Na2SO4). The soln was concentrated
and purification of the residue by column chromatography (PE–
EtOAc, 5:1) gave 9 (4.90 g, 95%) as a foamy solid; Rf = 0.56 (PE–
EtOAc, 2:1).
Optical rotations were determined with a Perkin-Elmer model 241-
MC automatic polarimeter for soln in a 1-dm, jacketed cell. 1H and
13C NMR spectra were recorded with Bruker DPX300 and Bruker
Avance 600 spectrometers in CDCl3 or D2O solns. Internal refer-
1
ences: TMS (d = 0.000 for H), CDCl3 (d = 77.00 for 13C), HOD
1
1
(d = 4.700 for H). H NMR signals of some compounds were as-
signed with the aid of COSY. Elemental analysis was performed on
a Yanaco CHN Corder MF-3 automatic elemental analyzer. Matrix-
assisted laser-desorption ionization mass spectra (MALDI MS) and
Electrospray-ionization mass spectra (ESI-MS) were performed by
the Institute of Chemistry, Chinese Academy of Sciences. TLC was
performed on silica gel HF with detection by charring with 30%
H2SO4–MeOH or by UV detection. Column chromatography used
silica gel (200–300 mesh) with EtOAc–petroleum ether (PE) (bp
60–90 °C). Solns were concentrated at a temperature <60 °C under
reduced pressure.
[a]D +46 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.06–7.43 (m, 5 H, HBz), 7.03–
7.00 (m, 2 H, HMp), 6.85–6.82 (m, 2 H, HMp), 5.87 (m, 1 H,
CH2=CHCH2OCO), 5.70 (dd, J2,3 = 3.6 Hz, J3,4 = 10.2 Hz, 1 H,
H3), 5.49 (d, J1,2 = 1.6 Hz, 1 H, H1), 5.45 (dd, J1,2 = 1.6 Hz,
J2,3 = 3.6 Hz, 1 H, H2), 5.36–5.21 (m, 2 H, CH2=CHCH2OCO),
4.57–4.55 (m, 2 H, CH2=CHCH2OCO), 4.31 (dd, J3,4 = J4,5 = 10.2
Hz, 1 H, H4), 4.02 (m, 1 H, H5), 3.91–3.83 (m, 2 H, H6), 3.78 (s, 3
H, OMe), 1.57, 1.38 (2 s, 6 H, CMe2).
4-Methoxyphenyl 4,6-O-Isopropylidene-a-D-mannopyranoside
(7)
MS (ESI): m/z [M + Na]+ calcd for C27H30O10Na: 537.2; found:
537.1.
To a soln of 4-methoxyphenyl a-D-mannopyranoside (6, 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 an N2 at-
mosphere. The mixture was stirred at r.t. for 2 h; TLC (PE–EtOAc,
2:1) indicated completion. The mixture was poured onto crushed ice
and the product precipitate from the mixture to give 7 (6.20 g, 95%)
as white solid; Rf = 0.22 (PE–EtOAc, 2:1).
Anal. Calcd for C27H30O10: C, 63.03; H, 5.88. Found: C, 63.20; H,
5.91.
4-Methoxyphenyl 2-O-Allyloxycarbonyl-3-O-benzoyl-a-D-man-
nopyranoside (10)
Method 1: Compound 9 (5.15 g, 10.0 mmol) was dissolved in 70%
AcOH (200 mL) and stirred at 75 °C for 1.5 h; TLC (PE–EtOAc,
2:1) indicated completion. The mixture was concentrated under re-
duced pressure and then co-evaporated with toluene (2 × 40 mL).
[a]D +122 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 6.99–6.94 (m, 2 H, HMp), 6.85–
6.79 (m, 2 H, HMp), 5.45 (d, J1,2 = 1.4 Hz, 1 H, H1), 4.24–3.79 (m,
Synthesis 2010, No. 10, 1666–1672 © Thieme Stuttgart · New York

PAPER
Synthesis of a Mannose Hexasaccharide
1669
The residue was passed through a short silica gel column (PE–
EtOAc, 3:1) to give 10 (4.31 g, 91%) as a white solid.
was added dropwise to the soln at 0 °C over 30 min. The tempera-
ture was slowly allowed to rise 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 1 M HCl and H2O, and
dried (Na2SO4). The soln was concentrated, and purification of the
residue by column chromatography (PE–EtOAc, 4:1) gave 12 (6.12
g, 95%) as a foamy solid.
Method 2: Compound 7 (3.27 g, 10.0 mmol) was dissolved in pyri-
dine (20 mL), then BzCl (1.21 mL, 10.5 mmol) was added dropwise
to the soln over 30 min at –10 °C. The temperature was slowly al-
lowed to rise to r.t. and the mixture was stirred for 2 h; TLC (PE–
EtOAc, 2:1) indicated completion. The mixture was diluted with an-
hyd CH2Cl2 (50 mL) and allyl chloroformate (1.58 mL, 15.0 mmol)
in anhyd CH2Cl2 (10 mL) was added dropwise at –10 °C over 30
min. The temperature was slowly allowed to rise to r.t. and the mix-
ture was stirred for 2 h; TLC (PE–EtOAc, 3:1) indicated comple-
tion. The mixture was diluted with CH2Cl2 (100 mL) and washed
with 1 M HCl and H2O and the organic phase was concentrated to
give a crude product, which was dissolved in 70% AcOH (200 mL)
and stirred at 75 °C for 1.5 h. 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 10 (4.10 g, 86%) as a white solid; Rf = 0.32
(PE–EtOAc, 1:1).
Method 2: Compound 10 (4.74 g, 10.0 mmol) was dissolved in an-
hyd CH2Cl2 (20 mL) containing pyridine (3.2 mL, 40.0 mmol), then
under an N2 atmosphere, allyl chloroformate (1.11 mL, 10.5 mmol)
in anhyd CH2Cl2 (10 mL) was added dropwise to the soln at –10 °C
over 30 min. The temperature was slowly allowed to rise to r.t. and
the mixture was stirred for 2 h. BzCl (1.7 mL, 14.6 mmol) in pyri-
dine (30 mL) was then added dropwise to the soln at 0 °C over 30
min. The temperature was slowly allowed to rise to r.t. and the mix-
ture was stirred for 12 h; TLC (PE–EtOAc, 3:1) indicated comple-
tion. The mixture was diluted with CH2Cl2 (100 mL), washed with
1 M HCl and H2O, and dried (Na2SO4). The soln was concentrated
and purification of the residue by column chromatography (PE–
EtOAc, 4:1) gave 12 (5.82 g, 88%) as a foamy solid; Rf = 0.38 (PE–
EtOAc, 3:1).
[a]D +78 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.06–7.42 (m, 5 H, HBz), 7.04–
7.01 (m, 2 H, HMp), 6.85–6.82 (m, 2 H, HMp), 5.89 (m, 1 H,
CH2=CHCH2OCO), 5.65 (dd, J2,3 = 3.4 Hz, J3,4 = 9.8 Hz, 1 H, H3),
5.53 (d, J1,2 = 1.8 Hz, 1 H, H1), 5.40 (dd, J1, 2 = 1.8 Hz, J2,3 = 3.4 Hz,
1 H, H2), 5.37–5.23 (m, 2 H, CH2=CHCH2OCO), 4.65–4.52 (m, 2
H, CH2=CHCH2OCO), 4.30 (dd, J3,4 = J4,5 = 9.8 Hz, 1 H, H4),
3.98–3.85 (m, 3 H, H5, H6), 3.77 (s, 3 H, OMe), 2.97, 2.21 (2 s, 2
H, 2 OH).
[a]D +14 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.97–7.34 (m, 10 H, HBz), 7.12–
7.09 (m, 2 H, HMp), 6.87–6.84 (m, 2 H, HMp), 5.95 (dd, J2,3 = 3.4 Hz,
J3,4 = 9.8 Hz, 1 H, H3), 5.92–5.80 (m, 2 H, 2 CH2=CHCH2OCO),
5.83 (dd, J3,4 = J4,5 = 9.8 Hz, 1 H, H4), 5.58 (d, J1,2 = 1.8 Hz, 1 H,
H1), 5.48 (dd, J1,2 = 1.8 Hz, J2,3 = 3.3 Hz, 1 H, H2), 5.37–5.20 (m,
4
H,
4
CH2=CHCH2OCO), 4.58–4.50 (m,
4
H,
4
CH2=CHCH2OCO), 4.45 (m, 1 H, H5), 4.38–4.29(m, 2 H, H6), 3.78
(s, 3 H, OMe).
MS (ESI): m/z [M + Na]+ calcd for C35H34O13Na: 685.2; found:
685.5.
MS (ESI): m/z [M + Na]+ calcd for C24H26O10Na: 497.1; found:
497.4.
Anal. Calcd for C24H26O10: C, 60.76; H, 5.52. Found: C, 60.70; H,
5.41.
Anal. Calcd for C35H34O13: C, 63.44; H, 5.17. Found: C, 63.31; H,
5.30.
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3-O-benzoyl-a-D-
mannopyranoside (11)
Compound 10 (4.74 g, 10.0 mmol) was dissolved in anhyd CH2Cl2
(20 mL) containing pyridine (3.2 mL, 40.0 mmol), then under an N2
atmosphere, allyl chloroformate (1.11 mL, 10.5 mmol) in anhyd
CH2Cl2 (10 mL) was added dropwise to the soln at –10 °C over 30
min. The temperature was slowly allowed to rise to r.t. and the mix-
ture was stirred for 2 h; TLC (PE–EtOAc, 3:1) indicated comple-
tion. The mixture was diluted with CH2Cl2 (100 mL), washed with
1 M HCl and H2O, and dried (Na2SO4). The soln was concentrated
and purification of the residue by column chromatography (PE–
EtOAc, 4:1) gave 11 (5.20 g, 93%) as a syrup; Rf = 0.26 (PE–
EtOAc, 3:1).
2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-a-D-mannopyra-
nosyl Trichloroacetimidate (3)
To a soln of 12 (5.7 g, 8.6 mmol) in MeCN (120 mL) was added suc-
cessively H2O (30 mL) and CAN (19.0 g, 34.4 mmol). The mixture
was stirred at 30 °C for 20 min; TLC (PE–EtOAc, 2:1) indicated
completion. The solvent was evaporated under reduced pressure at
50 °C to give a residue that was dissolved in CH2Cl2 and then
washed with H2O. The organic phase was dried (Na2SO4) and con-
centrated to give a residue that was purified by chromatography (sil-
ica gel, PE–EtOAc, 3:1) to afford 2,6-di-O-allyloxycarbonyl-3,4-
di-O-benzoyl-a-D-mannopyranoside as a slight yellow foamy solid.
A mixture of this compound (2.78 g, 5.0 mmol), Cl3CCN (2.0 mL,
20 mmol), and DBU (0.2 mL, 2 mmol) in anhyd CH2Cl2 (100 mL)
was stirred for 0.5 h and then concentrated. The residue was purified
by column chromatography (PE–EtOAc, 4:1) to give 3 (5.21 g,
86%, 2 steps); Rf = 0.64 (PE–EtOAc, 2:1).
[a]D +12 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.07–7.43 (m, 5 H, HBz), 7.06–
7.03 (m, 2 H, HMp), 6.85–6.82 (m, 2 H, HMp), 5.99–5.83 (m, 2 H, 2
CH2=CHCH2OCO), 5.66 (dd, J2,3 = 3.5 Hz, J3,4 = 9.6 Hz, 1 H, H3),
5.54 (d, J1,2 = 1.8 Hz, 1 H, H1), 5.41–5.24 (m, 5 H, H2, 4
[a]D –14 (c 1, CHCl3).
CH2=CHCH2OCO), 4.66–4.41 (m,
6
H, H4, H5,
4
CH2=CHCH2OCO), 4.25–4.08 (m, 2 H, H6), 3.78 (s, 3 H, OMe),
2.79 (d, J = 4.8 Hz, 1 H).
MS (ESI): m/z [M + Na]+ calcd for C28H30O12Na: 581.2; found:
1H NMR (300 MHz, CDCl3): d = 8.86 (s, 1 H, CNHCCl3), 7.98–
7.33 (m, 10 H, HBz), 6.50 (d, J1,2 = 1.9 Hz, 1 H, H1), 5.95–5.79 (m,
4 H, H3, H4, 2 CH2=CHCH2OCO), 5.51 (d, J1,2 = 1.9 Hz, J2,3 = 3.2
Hz, 1 H, H2), 5.38–5.21 (m, 4 H, 4 CH2=CHCH2OCO), 4.59–4.56
(m, 4 H, 4 CH2=CHCH2OCO), 4.48 (m, 1 H, H5), 4.41–4.36 (m, 2
H, H6).
581.5.
Anal. Calcd for C28H30O12: C, 60.21; H, 5.41. Found: C, 60.09; H,
5.25.
MS (ESI): m/z [M + Na]+ calcd for C30H28Cl3NO12Na: 722.1; found:
722.4.
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-
a-D-mannopyranoside (12)
Method 1: Compound 11 (5.43 g, 9.72 mmol) was dissolved in py-
ridine (30 mL), then BzCl (1.7 mL, 14.6 mmol) in pyridine (10 mL)
Anal. Calcd for C30H28Cl3NO12: C, 51.41; H, 4.03; N, 2.00. Found:
C, 51.26; H, 4.29; N, 2.39.
Synthesis 2010, No. 10, 1666–1672 © Thieme Stuttgart · New York

1670
G. Zong et al.
PAPER
4-Methoxyphenyl 3,4-Di-O-benzoyl-a-D-mannopyranoside (4)
To a cooled (–10 °C) soln of 12 (3.5 g, 5.28 mmol) in MeOH–THF
(1:1, 60 mL) was added NH4OAc (4.1 g, 52.8 mmol). NaBH4 (0.12
g, 3.24 mmol), Pd(PPh3)4 (0.25 g, 0.21 mmol), and NaBH4 (0.48 g,
13.0 mmol) were added successively in 3 portions immediately one
after another; 4 min after the addition of the second portion of
NaBH4, TLC (PE–EtOAc, 1:1) indicated completion. The mixture
was concentrated under vacuum, the residue was dissolved in
CH2Cl2 (30 mL) and washed with brine (15 mL) and then the organ-
ic phase was dried (Na2SO4). Concentration of the organic phase
and purification of the residue by flash column chromatography
(PE–EtOAc, 3:1) afforded 4 as a white solid (2.44 g, 94%);
Rf = 0.21 (PE–EtOAc, 1:1).
by flash column chromatography (PE–EtOAc, 3:1) afforded 5 (0.80
g, 92%) as a white solid; Rf = 0.20 (PE–EtOAc, 1:1).
[a]D +80 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.11–7.41 (m, 5 H, HBz), 7.07–
7.02 (m, 2 H, HMp), 6.87–6.83 (m, 2 H, HMp), 5.74 (dd, J2,3 = 3.2 Hz,
J3,4 = 10.1 Hz, 1 H, H3), 5.67 (dd, J3,4 = J4,5 = 10.1 Hz, 1 H, H4),
5.55 (d, J1,2 = 1.8 Hz, 1 H, H1), 4.42 (dd, J1,2 = 1.8 Hz, J2,3 = 3.1 Hz,
1 H, H2), 3.95 (m, 1 H, H5), 3.78 (s, 3 H, OMe), 3.75–3.60 (m, 2 H,
H6), 3.22 (d, J = 5.5 Hz, 1 H, OH), 2.85 (d, J = 6.8 Hz, 1 H, OH),
1.99 (s, 3 H, CH3CO).
MS (ESI): m/z [M + Na]+ calcd for C22H24O9Na: 455.1; found:
455.5.
[a]D +36 (c 1, CHCl3).
Anal. Calcd for C22H24O9: C, 61.11; H, 5.59. Found: C, 60.96; H,
5.77.
1H NMR (300 MHz, CDCl3): d = 8.05–7.30 (m, 10 H, HBz), 7.12–
7.09 (m, 2 H, HMp), 6.87–6.84 (m, 2 H, HMp), 5.95 (dd, J2,3 = 3.1 Hz,
J3,4 = 10.0 Hz, 1 H, H3), 5.93 (dd, J3,4 = J4,5 = 10.0 Hz, 1 H, H4),
5.62 (d, J1,2 = 1.8 Hz, 1 H, H1), 4.49 (dd, J1,2 = 1.8 Hz, J2,3 = 3.1 Hz,
1 H, H2), 4.10 (m, 1 H, H5), 3.79 (s, 3 H, OMe), 3.78–3.67 (m, 2 H,
2 H6), 3.42 (br s, 1 H, OH), 3.18 (br s, 1 H, OH).
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-
a-D-mannopyranosyl-(1→6)-3,4-di-O-benzoyl-a-D-mannopyra-
noside (14)
Compound 4 (2.47 g, 5.00 mmol), 3 (3.85 g, 5.50 mmol) and 4 Å
molecular sieves (3 g) were dried together under high vacuum
(0.0067 mbar) for 2 h, then dissolved in anhyd, redistilled CH2Cl2
(50 mL). TMSOTf (36 mL, 0.2 mmol) was added dropwise at –20
°C under an N2 atmosphere. The mixture was stirred for 0.5 h, dur-
ing the course of which time the mixture was allowed to gradually
warm to r.t.; TLC (PE–EtOAc, 1:1) indicated completion. Then the
mixture was neutralized with Et3N and filtered and the filtrate was
concentrated. Purification of the residue by column chromatogra-
phy (PE–EtOAc, 4:1) gave 14 (4.50 g, 87%) as a foamy solid;
Rf = 0.39 (PE–EtOAc, 1:1).
MS (ESI): m/z [M + Na]+ calcd for C27H26O9Na: 517.1; found:
517.0.
Anal. Calcd for C27H26O9: C, 65.58; H, 5.30. Found: C, 65.55; H,
5.56.
4-Methoxyphenyl 4-O-Acetyl-2,6-di-O-allyloxycarbonyl-3-O-
benzoyl-a-D-mannopyranoside (13)
Compound 10 (4.74 g, 10.0 mmol) was dissolved in anhyd CH2Cl2
(20 mL) containing pyridine (3.2 mL, 40.0 mmol), then ,under an
N2 atmosphere, allyl chloroformate (1.11 mL, 10.5 mmol) in anhyd
CH2Cl2 (10 mL) was added dropwise to the soln at –10 °C over 30
min. The temperature was slowly raised to r.t. and the mixture was
stirred for 2 h. Ac2O (4.7 mL, 50 mmol) in pyridine (30 mL) was
added to the soln and the mixture was stirred at r.t. for 12 h; TLC
(PE–EtOAc, 3:1) indicated completion. The mixture was concen-
trated, and then the residue was purified by flash column chroma-
tography (PE–EtOAc, 3:1) to give 13 (5.46 g, 91%) as a foamy
solid; Rf = 0.35 (PE–EtOAc, 3:1).
[a]D +25 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.05–7.30 (m, 20 H, HBz), 7.19–
7.16 (m, 2 H, HMp), 6.94–6.91 (m, 2 H, HMp), 6.01 (dd,
J3¢,4¢ = J4¢,5¢ = 10.0 Hz, 1 H, H4¢), 5.94–5.80 (m, 3 H, H3¢, 2
CH2=CHCH2OCO), 5.79–5.71(m, 2 H, H3, H4), 5.58 (d, J1,2 = 1.6
Hz, 1 H, H1), 5.38 (dd, J1¢,2¢ = 1.5 Hz, J2¢,3¢ = 3.1 Hz, 1 H, H2¢),
5.34–5.19 (m, 4 H, 4 CH2=CHCH2OCO), 5.07 (d, J1¢,2¢ = 1.5 Hz, 1
H, H1¢), 4.61–4.52 (m, 5 H, H2, 4 CH2=CHCH2OCO), 4.43 (m, 1
H, H5¢), 4.34–4.21 (m, 2 H, H5, H6), 4.15 (d, J = 11.5 Hz, 1 H, H6),
4.02 (d, J = 11.2 Hz, 1 H, H6), 3.70 (m, 1 H, H6), 3.65 (s, 3 H,
OMe), 2.87 (d, J = 5.2 Hz, 1 H, OH).
[a]D +28 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.03–7.42 (m, 5 H, HBz), 7.08–
7.05 (m, 2 H, HMp), 6.85–6.82 (m, 2 H, HMp), 5.98–5.82 (m, 2 H, 2
CH2=CHCH2OCO), 5.77 (dd, J2,3 = 3.4 Hz, J3,4 = 9.9 Hz, 1 H, H3),
5.59 (dd, J3,4 = J4,5 = 9.9 Hz, 1 H, H4), 5.54 (d, J1,2 = 1.8 Hz, 1 H,
H1), 5.42 (dd, J1,2 = 1.8 Hz, J2,3 = 3.4 Hz, 1 H, H2), 5.38–5.20 (m,
MS (ESI): m/z [M + Na]+ calcd for C55H52O20Na: 1055.3;
found:1055.1.
Anal. Calcd for C55H52O20: C, 63.95; H, 5.07. Found: C, 63.83; H,
5.11.
4
H,
4
CH2=CHCH2OCO), 4.62–4.54 (m,
4
H,
4
CH2=CHCH2OCO), 4.38–4.25 (m, 3 H, H5, 2 H6), 3.78 (s, 3 H,
OMe), 1.99 (s, 3 H, CH3CO).
MS (ESI): m/z [M + Na]+ calcd for C30H32O13Na: 623.2; found:
623.5.
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-
a-D-mannopyranosyl-(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-
mannopyranoside (15)
To a soln of 14 (5.17 g, 5.0 mmol) in pyridine (20 mL) was added
Ac2O (4.7 mL, 50 mmol). The mixture was stirred at r.t. for 12 h;
TLC (PE–EtOAc, 2:1) indicated completion. The mixture was con-
centrated and then the residue was purified by flash column chro-
matography (PE–EtOAc, 3:1) to give 15 (5.11 g, 95%) as a foamy
solid; Rf = 0.35 (PE–EtOAc, 2:1).
Anal. Calcd for C30H32O13: C, 60.00; H, 5.37. Found: C, 59.75; H,
5.30.
4-Methoxyphenyl 4-O-Acetyl-3-O-benzoyl-a-D-mannopyrano-
side (5)
To a cooled (–10 °C) soln of 13 (1.22 g, 2.03 mmol) in MeOH–THF
(1:1, 40 mL) was added NH4OAc (1.56 g, 20.3 mmol). NaBH4 (0.05
g, 1.22 mmol), Pd(PPh3)4 (0.10 g, 0.08 mmol), and NaBH4 (0.18 g,
4.87 mmol) were successively added in 3 portions immediately one
after another with vigorous stirring; 4 min after the addition of the
second portion of NaBH4, TLC (PE–EtOAc, 1:1) indicated comple-
tion. The mixture was concentrated under vacuum, the residue was
dissolved in CH2Cl2 (20 mL) and washed with brine (10 mL), and
the organic phase was dried (Na2SO4). Evaporation and purification
[a]D +28 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.01–7.33 (m, 20 H, HBz), 7.18–
7.15 (m, 2 H, HMp), 6.94–6.91 (m, 2 H, HMp), 5.99–5.97 (m, 2 H, H3,
H3¢), 5.93–5.72 (m, 2 H, 2 CH2=CHCH2OCO), 5.81–5.71 (m, 2 H,
H4, H4¢), 5.67 (dd, J1,2 = 1.7 Hz, J2,3 = 3.1 Hz,1 H, H2), 5.53 (d,
J1,2 = 1.7 Hz, 1 H, H1), 5.38 (dd, J1¢,2¢ = 1.8 Hz, J2¢,3¢ = 2.8 Hz, 1 H,
H2¢), 5.34–5.18 (m, 4 H, 4 CH2=CHCH2OCO), 5.06 (d, J1¢,2¢ = 1.8
Hz, 1 H, H1¢), 4.54–4.50 (m, 4 H, 4 CH2=CHCH2OCO), 4.45 (m, 1
Synthesis 2010, No. 10, 1666–1672 © Thieme Stuttgart · New York

PAPER
Synthesis of a Mannose Hexasaccharide
1671
H, H5), 4.28–4.13 (m, 3 H, H5, H6), 4.01–3.70 (m, 2 H, H6), 3.66
(s, 3 H, OMe), 2.24 (s, 3 H, CH3CO).
(m, 4 H, 4 CH2=CHCH2OCO), 5.05 (d, J1,2 = 1.6 Hz, 1 H, H1), 5.00
(d, J1,2 = 1.3 Hz, H, H1), 4.58–4.50 (m, H, 4
1
4
CH2=CHCH2OCO), 4.47–4.39 (m, 3 H, 3 H5), 4.33–4.22 (m, 3 H,
H2, H6), 4.14–3.98 (m, 2 H, H6), 3.67–3.63 (m, 2 H, H6), 3.58 (s,
3 H, OMe), 3.45 (d, J = 8.1 Hz, 1 H, OH), 2.19, 1.97 (2 s, 6 H, 2
CH3CO).
13C NMR (75 MHz, CDCl3): d = 170.1, 169.8 (2 C, 2 CH3CO),
166.0, 165.7, 165.6, 165.4, 165.1 (5 C, 5 PhCO), 99.7, 97.2, 97.1 (3
C, 3 C1), 55.2 (1 C, OMe), 20.7, 20.6 (2 C, 2 CH3CO).
13C NMR (75 MHz, CDCl3): d = 170.2 (COCH3), 165.5, 165.4,
165.3, 165.1 (4 C, 4 COPh), 97.6, 97.1 (2 C, 2 C1), 55.4 (OMe),
20.7 (CH3CO).
MS (ESI): m/z [M + Na]+ calcd for C57H54O21Na: 1097.3; found:
1097.7.
Anal. Calcd for C57H54O21: C, 63.68; H, 5.06. Found: C, 63.82; H,
4.91.
MS (ESI): m/z [M + Na]+ calcd for C72H70O28Na: 1405.4; found:
1405.7.
2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-a-D-mannopyra-
nosyl-(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-mannopyranosyl
Trichloroacetimidate (16)
Anal. Calcd for C72H70O28: C, 62.51; H, 5.10. Found: C, 62.36; H,
5.25.
To a soln of 15 (10.75 g, 10.0 mmol) in MeCN (120 mL) and H2O
(60 mL) was added CAN (21.9 g, 40.0 mmol). The mixture was
stirred at 30 °C for 20 min; 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 washed with
H2O. The organic phase was dried (Na2SO4) and concentrated. Pu-
rification by column chromatography (PE–EtOAc, 3:1) afforded
2,6-di-O-allyloxycarbonyl-3,4-di-O-benzoyl-a-D-mannopyrano-
syl-(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-mannopyranoside as
a slight yellow foamy solid. The foamy solid was dried under high
vacuum (0.0067 mbar) for 2 h, then dissolved in anhyd CH2Cl2 (100
mL), and Cl3CCN (4.0 mL, 40 mmol) and DBU (0.05 mL, 0.4
mmol) were added successively under an N2 atmosphere. The mix-
ture was stirred for 0.5 h and then concentrated. The residue was pu-
rified by chromatography (PE–EtOAc, 4:1) to give 16 (8.61 g, 77%)
as a foamy solid; Rf = 0.38 (PE–EtOAc, 2:1).
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-
a-D-mannopyranosyl-(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-
mannopyranosyl-(1→6)-2,4-di-O-acetyl-3-O-benzoyl-a-D-man-
nopyranoside (18)
To a soln of 17 (120 mg, 0.087 mmol) in pyridine (1.0 mL) was add-
ed Ac2O (0.5 mL, 0.85 mmol). The mixture was stirred at r.t. for 12
h; TLC (PE–EtOAc, 2:1) indicated completion. The mixture was
co-evaporated with toluene and the residue was purified by flash
column chromatography (PE–EtOAc, 2:1) to give 18 (110 mg,
92%) as a white foamy solid; Rf = 0.39 (PE–EtOAc, 2:1).
[a]D +36 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.03–7.31 (m, 25 H, HBz), 7.17–
7.14 (m, 2 H, HMp), 6.92–6.88 (m, 2 H, HMp), 5.96 (dd,
J3,4 = J4,5 = 10.1 Hz, 1 H, H4), 5.92–5.70 (m, 7 H, 3 H3, 2 H4, 2
CH2=CHCH2OCO), 5.62 (dd, J1,2 = 1.9 Hz, J2,3 = 3.2 Hz, 1 H, H2),
5.56 (dd, J1,2 = 1.7 Hz, J2,3 = 3.3 Hz, 1 H, H2), 5.50 (d, J1,2 = 1.7 Hz,
1 H, H1), 5.41 (dd, J1,2 = 1.8 Hz, J2,3 = 3.1 Hz, 1 H, H2), 5.34–5.19
(m, 4 H, 4 CH2=CHCH2OCO), 5.09 (d, J1,2 = 1.9 Hz, 1 H, H1), 5.01
[a]D +6 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.91 (s, 1 H, CNHCCl3), 8.04–
7.34 (m, 20 H, HBz), 6.41 (d, J1,2 = 1.8 Hz, 1 H, H1), 6.02 (dd,
J3,4 = J4,5 = 10.2 Hz, 1 H, H4), 5.92–5.71 (m, 6 H, H2, H3, H3¢, H4¢,
2 CH2=CHCH2OCO), 5.35 (dd, J1¢,2¢ = 1.7 Hz, J2¢,3¢ = 3.0 Hz, 1 H,
H2¢), 5.33–5.19 (m, 4 H, 4 CH2=CHCH2OCO), 5.06 (d, J1¢,2¢ = 1.7
Hz, 1 H), 4.55–4.50 (m, 4 H, 4 CH2=CHCH2OCO), 4.45 (m, 1 H,
H5¢), 4.30 (m, 1 H, H5), 4.23–4.14 (m, 2 H, H6¢), 4.01–3.79 (m, 1
H, H6), 2.26 (s, 3 H, CH3CO).
(d, J1,2 = 1.8 Hz,
1
H, H1), 4.46–4.44 (m,
4
H,
4
CH2=CHCH2OCO), 4.35 (m, 1 H, H5), 4.30–4.25 (m, 2 H, H5),
4.22–4.11 (m, 2 H, H6), 4.05–3.97 (m, 2 H, H6), 3.74–3.68 (m, 2 H,
H6), 3.61 (s, 3 H, OMe), 2.22, 2.11, 2.04 (3 s, 9 H, 3 CH3CO).
MS (ESI): m/z [M + Na]+ calcd for C74H72O29Na: 1447.4; found:
1447.7.
MS (ESI): m/z [M + Na]+ calcd for C52H48Cl3NO20Na: 1136.2;
found: 1136.5.
Anal. Calcd for C74H72O29: C, 62.36; H, 5.09. Found: C, 62.30; H,
4.88.
Anal. Calcd for C52H48Cl3NO20: C, 56.10; H, 4.35, N, 1.26. Found:
C, 56.28; H, 4.44; N, 1.43.
4-Methoxyphenyl 3,4-Di-O-benzoyl-a-D-mannopyranosyl-
(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-mannopyranosyl-
(1→6)-4-O-acetyl-3-O-benzoyl-a-D-mannopyranoside (2)
To a cooled (–10 °C) soln of 17 (8.3 g, 6.0 mmol) in MeOH–THF
(1:1, 150 mL) was added NH4OAc (4.62 g, 60 mmol). NaBH4 (0.22
g, 6.0 mmol), Pd(PPh3)4 (0.35 g, 0.30 mmol), and NaBH4 (0.11 g,
3.0 mmol) were added successively in 3 portions one immediately
after another with vigorous stirring; 4 min after the addition of the
second portion of NaBH4, TLC (PE–EtOAc, 1:3) indicated comple-
tion. The mixture was concentrated under vacuum at 30 °C, the res-
idue 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, 1:2) af-
forded 2 (6.85 g, 94%) as a white foamy solid; Rf = 0.26 (PE–
EtOAc, 1:3).
4-Methoxyphenyl 2,6-Di-O-allyloxycarbonyl-3,4-di-O-benzoyl-
a-D-mannopyranosyl-(1→6)-2-O-acetyl-3,4-di-O-benzoyl-a-D-
mannopyranosyl-(1→6)-4-O-acetyl-3-O-benzoyl-a-D-manno-
pyranoside (17)
Compound 5 (3.24 g, 7.50 mmol), 16 (8.50 g, 7.65 mmol), and 4 Å
molecular sieves (3 g) were dried together under high vacuum
(0.0067 mbar) for 2 h, then dissolved in anhyd, redistilled CH2Cl2
(80 mL). TMSOTf (36 mL, 0.2 mmol) was added dropwise at –20
°C under an N2 atmosphere. The mixture was stirred for 0.5 h, dur-
ing which time the mixture was allowed to gradually warm to r.t;
TLC (PE–EtOAc, 2:1) indicated completion. The mixture was neu-
tralized with Et3N and filtered, and the filtrate was concentrated. Pu-
rification of the residue by column chromatography (PE–toluene–
EtOAc, 4:2:1) gave 17 (8.83 g, 85%) as a foamy solid; Rf = 0.53
(PE–EtOAc, 1:1).
[a]D +14 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.06–7.26 (m, 25 H, HBz), 7.23–
7.20 (m, 2 H, HMp), 7.00–6.97 (m, 2 H, HMp), 5.78 (dd,
J2,3 = J3,4 = 10.0 Hz, 1 H, H4), 5.72–5.67 (m, 4 H, 3 H3, H4), 5.62
(dd, J2,3 = J3,4 = 10.0 Hz, 1 H, H4), 5.50 (d, J1,2 = 1.3 Hz, 1 H, H1),
5.49 (m, 1 H, H2), 5.02 (d, J1,2 = 1.5 Hz, 1 H, H1), 4.96 (d, J1,2 = 1.4
Hz, 1 H, H1), 4.46 (m, 4 H, 2 H2, 2 H5), 4.15–3.60 (m, 7 H, H5, 6
[a]D +16 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.04–7.26 (m, 25 H, HBz), 7.24–
7.21 (m, 2 H, HMp), 6.99–6.86 (m, 2 H, HMp), 5.95–5.84 (m, 2 H, 2
CH2=CHCH2OCO), 5.82–5.67 (m, 6 H, 3 H3, 3 H4), 5.53 (dd,
J1,2 = 1.6 Hz, J2,3 = 3.2 Hz, 1 H, H2), 5.51 (dd, J1,2 = 1.6 Hz,
J2,3 = 3.1 Hz, 1 H, H2), 3.36 (d, J1,2 = 1.6 Hz, 1 H, H1), 5.32–5.17
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G. Zong et al.
PAPER
H6), 3.50 (s, 3 H, OMe), 2.73 (t, J = 6.5 Hz, OH), 2.17, 2.00 (2 s, 6
H, 2 CH3CO), 1.79 (s, 2 H, 2 OH).
13C NMR (75 MHz, CDCl3): d = 170.1, 169.8 (2 COCH3), 166.4,
166.1, 165.7, 165.6, 165.1 (5 COPh), 99.5, 99.1, 96.9 (3 C1), 55.1
(OMe), 20.8, 20.7 (2 COCH3).
MS (ESI): m/z [M + Na]+ calcd for C64H62O24Na: 1237.4; found:
1237.6.
1H NMR (300 MHz, D2O): d = 7.07–7.04 (m, 2 H, HMp), 6.94–6.92
(m, 2 H, HMp), 5.73 (d, J1,2 = 1.3 Hz, 1 H, H1), 5.05 (d, J1,2 = 1.2 Hz,
1 H, H1), 5.03 (d, J1,2 = 1.3 Hz, 1 H, H1), 4.97 (d, J1,2 = 1.4 Hz, 1 H,
H1), 4.87 (d, J1,2 = 1.5 Hz, 1 H, H1), 4.70 (d, J1,2 = 1.1 Hz, 1 H, H1),
3.76 (s, 3 H, OMe), 4.13–3.58 (m, 39 H, H2–6).
13C NMR (75 MHz, D2O): d = 102.3, 102.0, 99.1, 98.9, 97.8, 97.1
(6 C, 6 C1), 55.6 (1 C, OCH3).
MS (MALDI-TOF): m/z [M + Na]+ calcd for C43H68O32Na:
1119.36; found: 1119.42.
MS (ESI): m/z [M + Na]+ calcd for C43H68O32Na: 1119.3591; found:
Anal. Calcd for C64H62O24: C, 63.26; H, 5.14. Found: C, 63.01; H,
5.35.
4-Methoxyphenyl 2,3,4,6-Tetra-O-benzoyl-a-D-mannopyrano-
syl-(1→6)-[2,3,4,6-tetra-O-benzoyl-a-D-mannopyranosyl-
(1→2)]-3,4-di-O-benzoyl-a-D-mannopyranosyl-(1→6)-2-O-
acetyl-3,4-di-O-benzoyl-a-D-mannopyranosyl-(1→6)-[2,3,4,6-
tetra-O-benzoyl-a-D-mannopyranosyl-(1→2)]-4-O-acetyl-3-O-
benzoyl-a-D-mannopyranoside (20)
Compound 2 (6.08 g, 5.0 mmol), 2,3,4,6-tetra-O-benzoyl-a-D-man-
nopyranosyl trichloroacetimidate (19, 14.81 g, 20.00 mmol) and 4
Å molecular sieves (8 g) were dried together under high vacuum
(0.0067 mbar) for 2 h, then dissolved in anhyd CH2Cl2 (120 mL).
TMSOTf (54 mL, 0.3 mmol) was added dropwise at –20 °C under
an N2 atmosphere. The mixture was stirred for 0.5 h, during the
course of which time the mixture was gradually warmed to r.t.; TLC
(PE–EtOAc, 1:1) indicated completion. Then the mixture was neu-
tralized with Et3N and filtered, and the filtrate was concentrated. Pu-
rification of the residue by column chromatography (PE–toluene–
EtOAc, 4:2:1) gave 20 (13.43 g, 91%) as a foamy solid; Rf = 0.37
(PE–EtOAc, 1:1).
1119.3582.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (No. 20902108); the Chinese Universities Scientific
Fund (No. 2009-1-43).
References
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[a]D +56 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.15–7.15 (m, 85 H, HBz), 7.04–
6.72 (m, 4 H, HMp), 6.29–5.81 (m, 15 H), 5.76 (d, J1,2 = 1.8 Hz, 1 H,
H1), 5.67 (dd, J1,2 = 1.0 Hz, J2,3 = 3.3 Hz, 1 H, H2), 5.37 (d,
J1,2 = 1.0 Hz, 1 H, H1), 5.35 (d, J1,2 = 0.7 Hz, 1 H, H1), 5.22 (d,
J1,2 = 0.6 Hz, 1 H, H1), 5.12 (d, J1,2 = 0.9 Hz, 1 H, H1), 5.01 (d,
J1,2 = 1.1 Hz, 1 H, H1), 4.85–3.73 (m, 19 H), 3.66 (s, 3 H, OMe),
3.51 (m, 1 H), 2.09, 2.01 (2 s, 6 H, 2 CH3CO).
13C NMR (75 MHz, CDCl3): d = 170.1, 169.5 (2 COCH3), 166.1,
166.0, 166.0, 165.8, 165.8, 165.7, 165.7, 165.5, 165.4, 165.2, 165.1,
165.1, 164.8, 164.8, 164.8, 164.7, 164.7 (17 COPh), 100.1, 99.3,
98.9, 98.1, 97.9, 97.8 (6 C1), 55.5 (OMe), 20.7, 20.6 (2 COCH3).
Anal. Calcd for C166H140O51: C, 67.57; H, 4.78; found: C, 67.70; H,
4.59.
4-Methoxyphenyl a-D-Mannopyranosyl-(1→6)-[a-D-mannopy-
ranosyl-(1→2)]-a-D-mannopyranosyl-(1→6)-a-D-mannopyra-
nosyl-(1→6)-[a-D-mannopyranosyl-(1→2)]-a-D-mannopyra-
noside (1)
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MeOH (1500 mL). After 120 h at r.t., the mixture was concentrated
to a total volume of ~50 mL, then warm acetone (500 mL, 50 °C)
was added to the mixture under vigorous stirring, and a white solid
precipitate from the soln, after kept at 0 °C for 24 h, filtration gave
target compound 1 (4.1 g, 83%) as a white solid.
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[a]D +35 (c 1.0, H2O).
Synthesis 2010, No. 10, 1666–1672 © Thieme Stuttgart · New York