β-L-Arabinofuranosylation Conducted by 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl Trichloroacetimidate

Article abstract of DOI:10.1016/j.carres.2018.02.006

We describe a β-L-arabinofuranosylation method by employing the 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl trichloroacetimidate 10 as a donor. This approach allows a wide range of acceptor substrates, especially amino acid acceptors, to be used. Stereoselective synthesis of β-(1,4)-L-arabinofuranosyl-(2S, 4R)-4-hydroxy-L-proline (β-L-Araf-L-Hyp₄) and its dimer is achieved readily by this method. Both the stereoselectivities and yields of the reactions are excellent. To demonstrate the utility of this methodology, the preparation of a trisaccharide in a one-pot manner was carried out.

Full text of DOI:10.1016/j.carres.2018.02.006

Accepted Manuscript
β-L-Arabinofuranosylation conducted by 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl
trichloroacetimidate
Hong-Zhan Li, Jie Ding, Chun-Ru Cheng, Yue Chen, Xing-Yong Liang
PII:
S0008-6215(18)30019-3
10.1016/j.carres.2018.02.006
CAR 7522
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 13 January 2018
Revised Date: 6 February 2018
Accepted Date: 7 February 2018
Please cite this article as: H.-Z. Li, J. Ding, C.-R. Cheng, Y. Chen, X.-Y. Liang, β-L-
Arabinofuranosylation conducted by 5-O-(2-pyridinecarbonyl)-L-arabinofuranosyl trichloroacetimidate,
Carbohydrate Research (2018), doi: 10.1016/j.carres.2018.02.006.
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ACCEPTED MANUSCRIPT
β-
L-Arabinofuranosylation Conducted by 5-O-(2-Pyridinecarbonyl)-
L
-arabinofuranosyl Trichloroacetimidate
Hong-Zhan Li, Jie Ding, Chun-Ru Cheng, Yue Chen, Xing-Yong Liang
*
School of Chemistry Engineering, Sichuan University of Science & Engineering, Zigong 643000, China
ABSTRACT: We describe a β-
arabinofuranosyl trichloroacetimidate 10 as a donor. This approach allows a wide range of acceptor substrates, especially
amino acid acceptors, to be used. Stereoselective synthesis of -(1,4)- -arabinofuranosyl-(2S, 4R)-4-hydroxy- -proline (
Araf- -Hyp ) and its dimer is achieved readily by this method. Both the stereoselectivities and yields of the reactions are
L-arabinofuranosylation method by employing the 5-O-(2-pyridinecarbonyl)-L-
β
L
L
β-L-
L
4
excellent. To demonstrate the utility of this methodology, the preparation of a trisaccharide in a one-pot manner was carried
out.
Keywords: β-Arabinofuranosylation, β-L-Araf-L-Hyp , HAD Effect, One-pot Synthesis.
4
[4]
Araf-
Secondly, the hydroxyl group of (2S, 4R)-4-hydroxy-
proline is a poor nucleophile, in part because of its axial
orientation in the preferred C -exo conformation of the
pyrrolidine ring. Glycosylation with (2S, 4R)-4-hydroxy-
L-Hyp4 is not easy in carbohydrate chemistry.
1
. Introduction
The -arabinofuranosidic linkage is an essential struc-
L
-
β-L
ture in numerous natural products containing sugar chains
and glycosides of terpenes, steroids, polyphenols, and anti-
biotics. Most of them usually occur at the non-reducing
end of these polysaccharides and play a crucial role in nu-
γ
L
-
[1]
[5]
proline rarely proceeds in good yield.
To date, there have been several reports on the synthesis
-Araf- -Hyp and its derivatives. In 2010, Taylor and
[2]
merous biological events. Among them, β-L-Araf-L-Hyp
4
of
β
-L
L
was one of the most common fragments. In 2005, Altmann
and co-workers reported a heterogeneous glycoprotein
known as Art v 1 in Pollen from Artemisia vulgaris which
is a significant contributor to hay fever in Europe and
North America. Characterization of the glycoproteins by
NMR and mass spectrometry revealed that one fragment
was composed of clusters of contiguous β-L-Araf-L-Hyp .
4
The fragment was found to be a key recognition element
for antibodies generated in response to the natural protein.
4
co-workers applied the 3,5-di-O-DTBS protected arabino-
thioglycoside and sulfoxide for the assembly of -Araf-
The outcome of the two reactions was
β-L
[6]
L
-Hyp4.
unsatisfactory in both yield (<15%) and stereoselectivity.
When they used a per-O-benzylated thioglycoside as the
donor, they obtained the product in 60% yield as a 1:4 α:β
mixture, and the β-isomer could be separated easily. The
use of the corresponding sulfoxide donor gave the product
in a similar yield with better β-selectivity (25:1, β:α), but
separating the pure β-isomer from assorted by-products
was very difficult. In a subsequent report, Taylor and
[3]
It is well known that stereoselective formation of
Araf- -Hyp
reasons. Firstly, the stereo-controlled preparation of
β
-
L-
L
4
mentioned above is a challenge for two
β
-
L-

ACCEPTED MANUSCRIPT
coworkers used the per-O-benzylated thioglycoside to
synthesize the dimer, trimer and tetramer of -Araf-
In another report, a (naphthyl)methyl (Nap) ether
With the desired acceptor 2 in hand, the influence of the
β
-L
L-
5-O-directing group on reaction’s stereoselectivity was
studied. We first examined 2-Quinolinecarbonyl group
(Quin) and 2-pyridinecarbonyl group (Pico) which have
been shown to be good directing groups in glycosylations.
As shown in Table 1, Entry 1-2, the glycosylations of the
[7]
4
Hyp .
mediated intramolecular aglycon delivery (IAD) strategy
was used by Ito in the synthesis of Hyp-rich
[8]
glycoproteins. Both the yield and stereoselectivity were
good. Recently, Yang’s group has applied hydrogen-bond-
[
12]
5-O-Quin thioglycoside 8
and 5-O-Pico thioglycoside
[9]
[12]
mediated aglycone delivery (HAD) methodology to the
selective preparation of -Araf- -Hyp in 86% yield as
Notably, this method can be
9
with acceptor 2 afforded the corresponding products in
β
-
L
D
low yields (56% and 48%) with a similar β-selectivity (8:1,
β:α). Next, the effect of solvent was examined. We
4
[
10]
exclusively β-isomer.
conducted on grams scale.
[10]
replaced the solvent with 1,2-dichloroethane
which has been successfully used in the synthesis of
Araf- -Hyp4 in high yield and stereoselectivity. The
(DCE)
β
-L-
Due to the importance of the biologic effects and the
synthetic challenge of -Araf- -Hyp , we planned to
apply HAD strategy to the stereoselective synthesis of
Araf- -Hyp . The synthesis of the target molecules began
D
β
-
L
L
4
coupling reaction between 8 and 2 gave compound 11 in 69%
yield with excellent β-selectivity (20:1, β:α). However, the
β-L-
L
4
yield was about 20% lower than the yield of preparation of
with the preparation of (2S, 4R)-4-hydroxy-
L
-proline 2 and
[10]
β-L-Araf-D-Hyp reported by Yang’s group. That might
4
peptide 7 as illustrated in Scheme 1.
cause by the different activities between (2S, 4R)-4-
hydroxy- -proline and (2R, 4S)-4-hydroxy- -proline.
2
. Results and discussion
2S, 4R)-4-hydroxy- -proline (
converted into its derivative 2, upon treatment with Boc
in DMF and followed by allylation in Allyl-Cl and pyri-
L
D
Usage of DCE slightly increased the yield of the glycosy-
lation of 9 with 2, however, decreased β-selectivity a little
at the same time (entry 4, Table 1). For entries 1-4, the
yields of the glycosylations were unsatisfactory. According
to previous
(
L
L-Hyp , 1, Scheme 1) was
4
2
O
[11]
dine. Initially, we protected the 4-OH of 2 with Le-
vulinoyl group (Lev), however, Lev-group could not be
selectively removed in the end, so 2,2,2-trichloroethoxy-
carbonyl group (Troc) was employed instead. Esterification
of 2 with Troc-Cl in pyridine furnished compound 3 in 90%
yield. Then, selective cleavage of the Boc-group gave
amine 4. Deallylation with Pd(PPh ) in the presence of
Table 1. Glycosylations of Donors 8, 9 and 10 with Proline
2
3
4
morpholine afforded the acid 5. Both 4 and 5 were not puri-
fied, but instead were directly treated with HATU and i-
Pr NEt in dichloromethane. This sequence afforded 6 in 58%
2
yield from 3. Removing the Troc of 6 with Zinc powder in
acetic acid and THF afforded peptide 7 as a 3:1 mixture of
rotational isomers (Ratio of syn-rotamer and anti-rotamer
Time.
[12]
a
Product.
Yield , α/β )
of amide detected by NMR) in 81% yield.
Entry
Donor.
Solvent.
CH Cl
CH Cl2
(h)
b
c
(
1
2
3
4
8
9
2
2
3
3
2
3
3
1
11(56%, 1/8)
12(48%, 1/8)
2
8
ClCH
2
CH
2
Cl
11(69%, 1:20)
12(64%, 1/5)
9
ClCH CH Cl
2
2
d
5
10
10
ClCH
2
CH
2
Cl
12(62%, β-only)
12(77%, β-only)
e
6
CH Cl2
2
a
Glycosylations of donor (1.2 equiv.) and acceptor (1.0 equiv.) were
Scheme 1. Preparation of Protected (2S, 4R)-4-Hydroxy-L-
proline 2 and Its dimer 7. Reagents and conditions: (a) Troc-Cl,
o
b
run with NIS (1.5 equiv.) and TfOH (0.1 equiv.), at -30 C. Yields
c
are shown for isolated products. The ratios were detected by NMR.
pyridine, r.t., 12h, 90%; (b) TFA, CH
2
Cl
2
, 0 to 25 °C, 2h; (c)
d
o
Glycosylations were run with TMSOTf (0.1 equiv.), at -30 to 0 C.
Pd(PPh ) , morpholine, THF, r.t., 1h; (d) HATU, i-Pr NEt,
e
o
3
4
2
Glycosylations were run with TMSOTf (0.1 equiv.), at -80 to 0 C.
CH Cl , r.t., 12h, 58% over two steps from 3; (e) Zn, AcOH, THF,
r.t., 12h, 81%.
2
2
reports, the low yield was caused by the hydroxy group of
-Hyp , a poor nucleophile, which was not active in the
L
4
[5]
glycosylation. In order to improve the yield, we sought to
[12]
use a more active donor, trichloroacetimidate 10
.
2

ACCEPTED MANUSCRIPT
Fortunately, imidate 10 was stable enough to be preserved
for a long time at a low temperature. The glycosylation of
8
0%
imidate 10 with 2 under the promotion of TMSOTf (0.1
4
o
equiv) in DCE at -30 to 0 C gave 12 in 62% yield which
6 : 1
was no better than the yield of 9. Then, we changed the
solvent back to CH Cl and dropped the temperature to -80
2
2
o
C. Gratifyingly, the reaction provided disaccharide 12 in a
good yield (77.3%) as exclusive β-isomer (entry 6, Table
). Overall, the above optimization study indicated that the
OBz OMe
O
8
8%
1
5
HO
OBz
11 : 1
best results are obtained with imidate 10, using TMSOTf in
o
14d
CH Cl at -80 to 0 C.
2
2
1
The stereochemistry of the product was confirmed by H
1
3
[13]
3
NMR and C NMR in CDCl
3
.
For α-anomers, JH-1,H-2 is
8
7%
0
-3 Hz and signals of C-1 is 104-110 ppm, while for β-
3
6
7
anomers J
is 3-5 Hz and signals of C-1 is 97-104
H-1,H-2
1
13
β
-
only
ppm values. The H and C chemical shift of the anomeric
carbon of 12 was in the expected region for β-anomer
3
(
signals of H-1 is 5.01 and 4.97 ppm, JH-1,H-2 are 4.2 Hz,
signals of C-1 99.4, 98.8, 2:1 ratio of syn-rotamer and anti-
rotamer of amide).
9
0%
Table 2. Glycosylation of Imidate 10 with a Variety of Alcohols 7,
a
1
4a-j
5 : 1
OBn
O
OBn
O
OTCA
TMSOTf (0.1 eq), 4A M.S.,
PicoO
ROH
CH2Cl2, -80 to 0 oC, 1h PicoO
OR
OBn
1.2 eq)
OBn
3, 15a-j
(
(1.0 eq)
92%
1
10
7, 14a-j
8
9
2
0 : 1
yieldb
(β/α )
en-
try
accepors
products
c
9
0.2%
β
-only
5
9%
1
1
0 : 1
8
6%
1
0
2
0 : 1
8
3%
2
3
a
Reactions were carried out with donor 3 (1.2 equiv.), acceptor (1.0
β
-
only
o
equiv.), TMSOTf (0.1 equiv.), 4 A M.S. in CH
1
detected by NMR analysis of the corresponding anomeric mixtures.
2
Cl
2
at -80 to 0 C for
b
c
-2 h. yields shown are for isolated products. The α/β ratios were
With the optimal condition in hand, we then set out to
8
4%
explore the glycosylation of imidate 10 with peptide 7 and
a range of other alcohols (Table 2).
acceptors included amino acids (14a), phenols and simple
alcohols (14b-c) as well as carbohydrate acceptors (14d-j).
[14]
This panel of
β
-
only
We were pleased to find that all acceptors reacted very
well with 10, giving the corresponding glycoside products
1
5a-j in 59-92% yields with the β-anomers as the main
3

ACCEPTED MANUSCRIPT
products. To our delight, the selectivity of glycosylations of
0 with two amino acid acceptors 7 (10:1, β:α, entry 1,
Table 2) and 14a (β-only, entry 2, Table 2) was excellent.
The worst yield (59%, entry 1, Table 2) observed in the
reaction with peptide 7 was mainly caused by the low
the anomeric carbons were at δ 106.9(α), 106.2(α), and
C
1
13
1
100.8(β) ppm, respectively. Therefore, both H and
NMR data are consistent with the stereochemistry of 18.
C
3
. Conclusion
In summary, we have demonstrated that the 5-O-(2-
reactivity of the hydroxy group of L-Hyp . However, the
4
yield is acceptable for the synthesis of glycopeptides. On
the basis of the yields and β:α ratios shown in Tables 2, we
found a trend that the β-selectivity of the glycosylation
reactions decreases with increasing steric hindrance on the
acceptor alcohol. The β:α ratios were better than 11:1 in
most cases. The worst selectivity was observed in the
reactions of relatively hindered alcohols 14c (6:1,
β:α, entry 4, Table 2) and 14f (5:1, β:α, entry 7, Table 2)
with imidate 10. These results are consistent with the
pyridinecarbonyl)-L-arabinofuranosyl trichloroacetimidate
10 could be used in the highly stereoselective synthesis of
compounds that contain
especially in the synthesis of
glycopeptides. In addition, it could be used for the rapid
synthesis of oligosaccharides that contain a -Araf
moiety in a one-pot manner. Although syntheses of β-L-
β
-
L-arabinofuranosyl linkages,
β-L
-arabinofuranosyl
β-L
Araf residues have been previously reported, the
glycosylation conditions described here provide an
important alternative to the existing methods.
[12]
previous work reported.
4
. Experiment procedures
4
.1 General
All non-aqueous reactions were performed under a nitro-
gen atmosphere and monitored by thin layer chromatog-
raphy (TLC) using Silica Gel GF254 plates with detection
by charring with 10% (v/v) H SO in EtOH or by UV de-
2
4
tection. Solvents used in the reactions were distilled from
appropriate drying agents prior to use. Silica gel (200-300
1
13
mesh) was used for column chromatography. H and
C
NMR spectra were recorded with Bruker Avance-600 or
1
13
4
1
00 spectrometers ( H NMR-600/400 MHz; C NMR-
50/100 MHz) for solutions in CDCl . High resolution
3
mass spectrometry (HRMS) was carried out on ESI-TOF
mass spectrometer.
Scheme 2. One-Pot Synthesis of Trisaccharide 18. Reagents
and conditions: (a) Reactions were carried out with donor 10
(
1.2 equiv), acceptor 16 (1.0 equiv), TMSOTf (0.1 equiv), 4 A
4
.2
(2S,
4R)-N-tert-Butyloxycarbonyl-4-O-
-proline Allyl ester (3)
o
MS in CH Cl at -80 to 0 C for 1 h.; (b) acceptor 14d (1.0
equiv), NIS (1.25 equiv), TfOH (0.1 equiv), CH Cl , -40 to -
2
2
trichloroethylformyl-
L
2
2
2
0 °C, 1h, 63% over two steps.
To a solution of 2 (1.2 g, 4.42 mmol) in pyridine (15
mL) was added 2,2,2-Trichloroethylchloroformate (0.92
mL, 6.64 mmol). The mixture was allowed to be stirred at
r.t. for 12h, then poured into cold water (30 mL) and
extracted with CH Cl (3 × 30mL). The organic layer was
To demonstrate the utility of the imidate 10, we finally
targeted the synthesis of a fragment -Araf-(1,5)-
Araf-(1,5)- -Araf in a one-pot manner as illustrated in
β
-
L
α-L-
[
15]
α-L
2
2
Scheme 2. First, the imidate 10 was coupled with the gly-
cosyl alcohol 16 by activation with catalytic TMSOTf in
CH Cl at -80 °C. Upon gradually warming to approxi-
mately 0 °C, a new spot, intermediate 17 was visible on
TLC. Then, the reaction was re-cooled to -40 °C and sub-
sequent addition of the alcohol 14d along with promoter
NIS-TfOH initiated the second glycosylation. Finally, the
reaction gave trisaccharide 18 after 1 h. After purification
by silica gel column chromatography, 18 was obtained in
washed with 1 M HCl, sat’d NaHCO
3
(50 mL) and brine
(
50 mL), dried over Na SO , filtered through celite and
2
4
2
2
concentrated. The residue was purified by column
chromatography (3:1, petroleum ether–EtOAc) to afford 3
f
as a light syrup (1.78 g, 90%). R 0.62 (2:1, petroleum
2
5
1
ether–EtOAc). [α]
MHz, CDCl ): 5.94−5.86 (m, 1H), 5.35 (dd, 1H, J =8.4
Hz, 17.4 Hz), 5.27-5.22 (m, 2H), 4.85-4.67 (m, 2H), 4.62-
D
3
-24.59 (c 0.4, CHCl ); H NMR (600
δ
3
4
2
.58 (m, 1H), 4.50-4.41 (m, 1H), 3.88-3.69 (m, 2H), 2.57-
6
3% yield, with just trace amount of α-isomer detected.
.50 (m, 1H), 2.28-2.23 (m, 1H), 1.63 (q, 1H, J = 6.6 Hz),
The structure of 18 was readily determined by NMR spec-
troscopy. In its H NMR spectrum, the characteristic reso-
nances due to the one H-1 signal of β-L-Araf appeared as
doublet ( J
H-1 signals of
1
1
3
1
1.45 (s, 9H); C NMR (150 MHz, CDCl ):
δ
172.1, 171.8,
53.9, 153.4, 153.3, 153.2, 131.7, 131.5, 119.1, 118.6,
94.2, 94.1, 80.8, 80.7, 77.6, 77.3, 77.0, 76.9, 76.8, 65.9,
5.9, 57.7, 57.4, 52.0, 51.9, 36.4, 35.4, 28.4, 28.2; HRMS
ESI) calcd for C H Cl NO [M+Na]+ 468.0360, found
3
1
3
are 4.2 Hz) at δ H 5.03 ppm and the two
H-1,H-2
6
(
3
α
-L-Araf appeared as doublet ( JH-1,H-2 are
16
22
3
7
.2 Hz) at δ H 5.60 ppm and singlets at δ H 5.49. Besides,
4
68.0374.
13
the C NMR spectrum revealed that the chemical shifts of
4

ACCEPTED MANUSCRIPT
4
.3 (2S, 4R)-4-O-trichloroethylformyl-
L
-proline Allyl ester
To a solution of 6 (400 mg, 0.54 mmol) in THF (8 mL)
(
4)
and AcOH (2 mL) was added Zinc powder (8.0 g). The
reaction mixture was stirred at r.t. for 2 h. The mixture was
filtered through celite and concentrated. The residue was
purified by column chromatography (15:1, CH Cl -MeOH)
To a solution of compound 3 (900 mg, 2.01mmol) in dry
CH Cl (15 mL) was added TFA (1.1 mL) and p-Thiocresol
2
2
2
2
(
251 mg, 2.01 mmol) at 0°C. The mixture was stirred at 0
C for 30 min, then warmed to r.t and stirred for another 3
h. The mixture was concentrated and filtered through a
flash column chromatography (10:1, CH Cl -MeOH) to
to afford 7 as a light syrup (172 mg, 82%). R 0.25 (15:1,
f
2
5
1
°
DCM-MeOH). [α]
MHz, CDCl ): 5.91−5.85 (m, 1H), 5.32 (dd, 1H, J = 1.8
Hz, 17.4 Hz), 5.24-5.21 (m, 1H), 4.73 (t, 1H, J = 9.0 Hz),
D
3
-67.04 (c 0.3, CHCl ); H NMR (600
3
δ
2
2
give crude product 4 as an orange coloured syrup (487 mg).
4
3
2
.65-4.55 (m, 4H), 4.45 (s, 1H), 4.18 (q, 1H, J = 10.2 Hz),
.64-3.61 (m, 2H), 2.41 (q, 1H, J = 13.2Hz), 2.26-2.15 (m,
4
.4
(2S,
4R)-N-tert-Butyloxycarbonyl-4-O-
-proline (5)
13
H), 1.96-1.90 (m, 4H), 1.41 (s, 9H), 1.40 (s, 2H);
C
Trichloroethylformyl-
L
NMR (150 MHz, CDCl ): δ 172.1, 171.7, 171.4, 155.0,
3
1
7
5
2
4
54.3, 131.7, 131.7, 118.7, 118.5, 80.7, 80.5, 77.3, 77.1,
6.8, 70.4, 70.1, 69.4, 65.9, 65.8,57.9, 57.6, 56.8, 56.2,
5.2, 55.1, 55.0, 54.4, 37.9, 37.8, 36.9, 31.4, 30.2, 29.7,
To a solution of compound 3 (770 mg, 1.73 mmol) and
Pd(PPh (200 mg, 0.173 mmol) in dry THF (30 mL) was
3 4
)
added morpholine (1.06 mL, 12.2 mmol). The reaction
mixture was stirred at r.t for 1 h . The solvent was
evaporated and the residue dissolved in CH Cl . The
8.5, 28.4. HRMS (ESI) calcd for C18
23.1534, found 423.1550.
28 2 7
H N O [M+K]+
2
2
organic layer was washed with 0.1M HCl, filtered through
celite and concentrated to give crude product 5 as a yellow
syrup which could be used without being purified.
4
.7
2,3-di-O-Benzyl-5-O-(2-pyridinecarbonyl)-L-
arabinofuranosyl trichloroacetimidate (10)
To a solution of 9 (1.50 g, 2.8 mmol) in acetone (55 mL)
4
.5
[(2’S,
4’R)-N-tert-Butyloxycarbonyl-4’-O-
-proline]-2-carbonyl-(2S, 4R)-4-O-
-proline Allyl ester (6)
and H O (0.25 mL, 14 mmol) was added NBS (1.5 g, 8.43
2
trichloroethylformyl-
trichloroethylformyl-
L
L
mmol). The reaction mixture was stirred at r.t. for 1 h. The
mixture was neutralized with satd NaHCO . The organic
3
2 4
layer was washed with water and brine, dried over Na SO ,
Amine 4 (522 mg, 1.28 mmol) and acid 5 (371 mg, 1.07
filtered, and concentrated. The residue was directly used
for the next step without further purification. To a stirred
solution of the obtained residue in dry dichloromethane (28
mL) was added trichloroacetonitrile (4.5 mL, 44.1 mmol)
and DBU (0.1 mL). The mixture was stirred at 0 °C for 10
min, warmed to r.t. over the next 2 h. At the end of which
mmol) were suspended in dry CH Cl (30 mL) at 0 °C for
2
2
1
2
5 min. Then, i-Pr NEt (0.53 mL, 415 mg, 3.21 mmol) and
HATU (488 mg, 1.28 mmol) were added in sequence. The
reaction mixture was allowed to stir overnight at r.t.. The
mixture was diluted with CH Cl , washed with 1M HCl,
2
2
,
sat d NaHCO and brine. The organic layer was dried over
3
time TLC (2:1, petroleumether-EtOAc, R = 0.20) indicated
f
Na SO , filtered and concentrated. The residue was purified
2
4
the reaction was complete. The mixture was concentrated
to remove dichloromethane. The residue was purified by
flash column chromatography, to give 10 as a light syrup
by column chromatography (3:2, petroleum ether-EtOAc)
to give 6 as an orange coloured syrup (511 mg, 65%). R
f
2
5
0
.35 (1:1, petroleum ether-EtOAc). [α]
-12.0 (c 0.5,
D
(
1.33 g, 81.4%).
1
CHCl ); H NMR (600 MHz, CDCl ): δ 5.92-5.85 (m, 2H),
3
3
5
4
.39-5.37 (m, 1H), 5.35-5.33 (m, 1H), 5.34-5.23 (m, 6H),
.86 (d, 1H, J = 12.0 Hz), 4.86 (d, 1H, J = 12.0 Hz), 4.82
General Procedure for the glycosylation:
(
d, 1H, J = 12.0 Hz), 4.81 (d, 1H, J = 12.0 Hz), 4.78 (d, 1H,
J = 12.0 Hz), 4.77 (d, 1H, J = 11.4 Hz), 4.76 (d, 1H, J =
2.0 Hz), 4.75 (d, 1H, J = 12.0 Hz), 4.74 (d, 1H, J = 12.0
Hz), 4.70-4.63 (m, 4H), 4.62-4.56 (m, 4H), 4.34 (d, 1H, J =
A mixture of donor 10 (1.20 equiv), acceptor (1.00
equiv), and freshly activated 4 Å molecular sieves in dry
CH Cl (0.1M) was cooled to -80 °C. The suspension was
1
2
2
stirred for 15 min, then TMSOTf (0.1 equiv) was added
The reaction mixture was stirred for 1-2 h at the same
temperature. Then, the resulting mixture was gradually
warmed to 0 °C. The reaction mixture was quenched with
Et N, diluted with CH Cl , filtered through celite and
1
3
1
2
1.4 Hz), 3.97-3.87 (m, 3H), 3.84 (d, 1H, J = 12.6 Hz),
.80 (t, 1H, J = 4.2 Hz), 3.78 (t, 1H, J = 3.6 Hz), 3.72 (d,
H, J = 12.6 Hz), 2.59-2.53 (m, 2H), 2.49-2.34 (m, 3H),
1
3
.28-2.23 (m, 3H), 1.42 (s, 8H), 1.41 (s, 8H); C NMR
3
2
2
(
150 MHz, CDCl3):
δ
172, 171.7, 171.4, 155.0, 154.3,
concentrated in vacuo. The crude material was quickly
purified by column chromatography to give the product.
The ratio of the isomers were detected by NMR in all
cases.
1
7
5
2
7
47.2, 131.7, 118.7, 118.5, 80.7, 80.4, 77.3, 77.0, 76.8,
0.4, 70.1, 69.9, 69.4, 65.9, 65.8, 57.9, 57.7, 56.8, 56.1,
5.2, 55.1, 55.0, 54.4, 37.9, 37.8, 36.9, 30.2, 29.7, 28.5,
8.4. HRMS (ESI) calcd for C24
54.9878, found 754.9870.
6 2
H30Cl N O11 [M+Na]+
4.8 (2S, 4R)-N-tert-Butyloxycarbonyl-4-O-[2,3-di-O-
Benzyl-5-O-(2-pyridinecarbony)-β-
proline Allyl Ester (12)
L-arabinofuranosyl]-L-
4
.6 [(2’S, 4’R)-N-tert-Butyloxycarbonyl-4’-hydroxy-L-
proline]-2-carbonyl-(2S, 4R)-4-hydroxy-L-proline Allyl
ester (7)
5

ACCEPTED MANUSCRIPT
The residue was purified by column chromatography
2:1, petroleum ether–EtOAc) to afford compound 12 as an
orange coloured syrup (yield of 77.3%, β-only). R 0.23
2:1, petroleum ether–EtOAc). [α]D +5.9 (c 2.00, CHCl3);
1H, J = 6.6 Hz), 4.10 (q, 1H, J = 7.2 Hz), 4.01 (qd, 2H, J =
3.6, 10.8 Hz), 1.40 (s, 9H); C NMR (100 MHz,
1
3
(
f
CDCl ): 170.1, 149.9, 147.5, 137.7, 137.4, 136.9, 131.5,
3
δ
25
(
128.4, 128.3, 127.9, 127.8, 127.6, 126.9, 125.3, 118.5,
101.3, 83.8, 81.9, 78.7, 77.3, 77.0, 76.6, 72.4, 72.2, 68.7,
1
H NMR (600 MHz, CDCl ):
=
6
δ
8.75 (s, 1H), 8.09 (d, 1H, J
7.8 Hz), 7.83 (td, 1H, J = 1.8, 7.8 Hz), 7.48 (q, 1H, J =
.6 Hz), 7.36-7.27 (m, 12H), 5.92-5.84 (m, 1H), 5.33-5.19
m, 2H), 5.01 (d, 1H, J = 4.2 Hz), 4.77-4.74 (m, 1H), 4.66-
3
6
6.5, 65.9, 54.0, 29.6, 28.2, 22.6, 14.0; HRMS (ESI) calcd
for C36H N O10 [M+Na]+ 685.2737, found 685.2737.
42 2
(
4
.11
meta-t-Butyl-phenyl
2,3-di-O-Benzyl-5-O-(2-
4
3
1
.38 (m, 9H), 4.31-4.09 (m, 3H), 3.70-3.60 (m, 1H), 3.57-
.46 (m, 1H), 2.46-2.40 (m, 1H), 2.15-2.11 (m, 1H), 1.97-
pyridinecarbony)-β-
L
-arabinofuranoside (15b)
1
3
.89 (m, 1H), 1.43 (s, 3H), 1.36 (s, 6H); C NMR (100
172.5, 164.6, 153.7, 149.9, 147.5, 137.7,
37.2, 136.9, 131.8, 131.6, 128.5, 128.3, 128.1, 128.0,
The residue was purified by column chromatography
MHz, CDCl3):
δ
(
3:1, petroleum ether–EtOAc) to afford compound 15b as a
1
1
8
7
5
light syrup (yield of 84.3%, β-only). R 0.28 (2:1,
f
27.7, 127.6, 126.9, 125.2, 118.6, 118.2, 99.4, 98.7, 83.6,
2.1, 82.0, 80.2, 80.1, 78.7, 78.6, 77.3, 77.2, 77.0, 76.7,
4.9, 73.6, 72.5, 72.2, 66.7, 66.6, 65.5, 58.0, 57.7, 50.9,
0.4, 37.4, 36.4, 28.3, 28.1; HRMS (ESI) calcd for
25
1
petroleum ether–EtOAc). [α]D +78.4 (c 2.00, CHCl ); H
3
NMR (400 MHz, CDCl
.6 Hz), 7.70 (t, 1H, J = 7.2 Hz), 7.40-7.25 (m, 10H), 7.21
t, 1H, J = 8.0 Hz), 7.09-7.03 (m, 2H), 6.91 (d, 1H, J = 8.0
3
): δ 8.71 (s, 1H), 7.96 (d, 1H, J =
7
(
C H NO [M+Na]+ 710.2941, found 710.2944.
3
9
45
10
Hz), 5.55 (s, 1H), 4.87 (d, 1H, J = 11.6 Hz), 4.76-4.71 (m,
1H), 4.68 (d, 1H, J = 8.0 Hz), 4.63-4.57 (m, 2H), 4.52-4.45
4
.9 Diglyco-peptide (13)
(
1
m, 2H), 4.40 (d, 1H, J = 5.2 Hz), 4.29 (d, 1H, J = 2.8 Hz),
1
3
The residue was purified by column chromatography
1:3, petroleum ether–EtOAc) to afford compound 13 as an
.29 (s, 9H); C NMR (100 MHz, CDCl ): δ 164.4, 156.8,
3
(
152.7, 149.6, 147.4, 137.7, 137.1, 136.6, 128.7, 128.3,
128.2, 127.9, 127.8, 127.8, 127.6, 126.6, 125.1, 119.3,
114.5, 113.4, 99.2, 83.7, 82.0, 78.9, 77.2, 77.0, 76.7, 72.6,
orange coloured syrup (260 mg, 61%). R 0.30 (1:4,
f
20
1
petroleum ether–EtOAc). [α]
D
+27.7 (c 0.80); H NMR
(
400 MHz, CDCl ): δ 8.75 (s, 2H), 8.07 (d, 2H, J = 8.0 Hz),
72.5, 66.0, 34.5, 31.1; HRMS (ESI) calcd for C H NO6
3
35 37
7
.80-7.78 (d, 2H, J = 7.6 Hz), 7.54-7.45 (m, 3H), 7.33-7.25
[M+Na]+ 590.2519, found 590.2525.
(
(
(
(
(
m, 26H), 5.85-5.80 (m, 1H), 5.79-5.18 (m, 3H), 5.16-4.93
m, 1H), 4.78-4.70 (qd, 3H, J = 11.2, 18.4 Hz), 4.65-4.40
m, 22H), 4.29-4.22 (m, 4H), 4.17-4.11 (m, 4H), 3.97-3.90
m, 1H), 3.72-3.38 (m, 5H), 2.33-2.30 (m, 3H), 2.22-2.01
4.12 (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl 2,3-di-
O-Benzyl-5-O-(2-pyridinecarbony)-β-L-arabinofuranoside
(15c)
13
3
m, 5H), 1.41-1.27 (m, 30H). C NMR (100 MHz, CDCl ):
δ 171.3, 171.2, 171.0, 164.6, 154.0, 153.5, 149.9, 147.4,
The residue was purified by column chromatography
(4:1, petroleum ether–EtOAc) to afford compound 15c as a
1
1
1
1
8
7
5
3
2
37.7, 137.5, 137.4, 137.3, 137.2, 137.0, 132.8, 131.7,
31.6, 129.6, 129.4, 128.4, 128.3, 128.0, 127.7, 127.7,
27.6, 127.0, 125.2, 124.3, 123.8, 118.9, 118.4, 118.2,
00.9, 99.8, 99.0, 98.4, 83.8, 83.8, 83.6, 83.5, 82.4, 82.2,
1.8, 79.9, 79.6, 78.7, 78.5, 78.4, 77.2, 77.0, 76.7, 76.2,
5.7, 74.4, 73.8, 72.7, 72.4, 72.3, 66.7, 66.4, 65.7, 65.5,
7.8, 57.5, 56.6, 56.5, 51.5, 51.0, 50.9, 49.9, 45.6, 36.5,
6.0, 35.3, 34.9, 34.7, 31.8, 31.3, 30.2, 30.0, 29.6, 29.4,
9.2, 28.3, 28.2, 22.6, 14.0, 8.4, 0.8; HRMS (ESI) calcd for
light syrup (yield of 80.7%, Ratio of α/β is 1:6). R
0.50
f
25
(2:1, petroleum ether–EtOAc). [α] +9.6 (c 1.50, CHCl );
D
3
1
H NMR (400 MHz, CDCl ):
3
δ 8.78-8.74 (m, 1H), 8.12 (d,
1H, J = 7.6 Hz), 7.81 (t, 1H, J = 8.0 Hz), 7.48-7.41 (m,
1H), 7.35-7.26 (m, 4H), 7.24-7.23 (m, 6H), 5.17 (d, 1H, J =
4.4 Hz), 4.75-4.62 (m, 3H), 4.59-4.48 (m, 4H), 4.37-4.26
(m, 2H), 4.12-4.06 (m, 1H), 3.34 (td, 1H, J = 4.4, 10.8 Hz),
2.32-2.23 (m, 2H), 1.63-1.57 (m, 2H), 1.37-1.25 (m, 3H),
1
3
C
68
H
74
N
4
O17 [M+Na]+ 1241.4947, found 1241.4932.
0.83 (d, 3H, J = 9.6 Hz), 0.80-0.71 (m, 7H); C NMR (100
MHz, CDCl ): 164.6, 149.8, 147.6, 137.8, 137.5, 136.8,
36.7, 128.4, 128.2, 127.8, 127.6, 127.6, 127.6, 127.4,
3
δ
4
(
.10 N-tert-Butyloxycarbonyl-3-O-[2,3-di-O-Benzyl-5-O-
1
1
7
6
2
2-pyridinecarbony)-β- -arabinofuranosyl]- -Serine Allyl
L
L
26.8, 126.7, 125.2, 102.5, 88.6, 84.0, 83.8, 82.7, 81.8,
8.9, 78.2, 77.2, 77.0, 76.7, 74.4, 72.3, 72.1, 72.0, 67.3,
5.0, 48.2, 47.6, 43.3, 39.4, 34.4, 34.0, 31.5, 31.2, 25.0,
4.7, 22.8, 22.7, 22.2, 22.0, 20.9, 20.9, 15.7, 15.1; HRMS
ester (15a)
The residue was purified by column chromatography
2:1, petroleum ether–EtOAc) to afford compound 15a as a
(
(
ESI) calcd for C H NO [M+Na]+ 596.2988, found
35 43 6
light syrup (yield of 83.2%, β-only). R 0.35 (1:1,
f
5
96.2991.
25
1
petroleum ether–EtOAc). [α]
NMR (600 MHz, CDCl ): 8.78 (d, 1H, J = 4.2 Hz), 8.11
d, 1H, J = 7.8 Hz), 7.83 (td, 1H, J = 1.2, 7.8 Hz), 7.48 (q,
D
3
+21.9 (c 1.70, CHCl ); H
δ
4.13 Methyl 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→5)-2,3-di-O-benzoyl-α-
arabinofuranoside (15d)
3
(
L
L-
1
5
1
4
H, J = 7.2 Hz), 7.38-7.23 (m, 12H), 5.87-5.81 (m, 1H),
.75 (d, 1H, J = 8.4 Hz), 5.18 (d, 1H, J = 10.2 Hz), 4.94 (d,
H, J = 4.2 Hz), 4.73 (d, 1H, J = 12.0 Hz), 4.63-4.52 (m,
H), 4.51-4.44 (m, 4H), 4.30 (q, 1H, J = 10.8 Hz), 4.25 (t,
The residue was purified by column chromatography
(5:3, petroleum ether–EtOAc) to afford compound 15d as a
6

ACCEPTED MANUSCRIPT
light syrup (yield of 88.4%, Ratio of α/β is 1:11). R 0.20
4H), 4.12-4.11 (m, 1H), 4.04 (t, 1H, J = 6.6Hz), 3.91-3.89
f
25
(
1
m, 1H), 3.68 (t, 1H, J = 9.0Hz), 1.51 (s, 2H), 1.40 (s, 2H),
(
2:1, petroleum ether–EtOAc). [α]D +27.9 (c 1.00,
13
1
.30 (d, 7H, J = 13.2 Hz); C NMR (150 MHz, CDCl ):
CHCl ); H NMR (600 MHz, CDCl ):
δ
8.72 (d, 1H, J =
.4Hz), 8.05 (t, 5H, J = 7.8 Hz), 7.75 (td, 1H, J = 1.8, 7.8
Hz), 7.59 (t, 1H, J =7.8 Hz), 7.50 (t, 1H, J =7.8 Hz), 7.46-
3
3
3
5
δ
164.6, 149.9, 147.8, 137.9, 137.7, 137.6, 137.5, 136.9,
136.8, 128.4, 128.1, 127.8, 127.7, 127.7, 126.8, 125.3,
09.3, 109.2, 108.5, 108.5, 106.6, 101.0, 99.9, 96.3, 87.6,
1
7
5
1
4
.39 (m, 3H), 7.37 (q, 4H, J = 15.6 Hz), 7.30-7.24 (m, 8H),
.52 (d, 1H, J = 6.6 Hz), 5.44 (d, 1H, J = 1.2 Hz), 5.17 (d,
H, J = 4.2 Hz), 5.15 (s, 1H), 4.75 (d, 1H, J = 12.0 Hz),
.66 (d, 1H, J = 12.0 Hz) 4.59-4.51 (m, 4H), 4.45 (td, 1H, J
83.9, 83.7, 82.8, 79.2, 78.8, 72.5, 72.1, 71.9, 71.9, 71.2,
70.8, 70.6, 70.6, 70.5, 70.5, 67.9, 67.3, 66.6, 66.2, 65.5,
64.9, 26.1, 26.1, 26.0, 25.9, 25.0, 24.9, 24.6, 24.3; HRMS
(
ESI) calcd for C H NO [M+Na]+ 700.2734, found
=
2.4, 6.0 Hz ), 4.33 (q, 1H, J = 12.6 Hz) 4.24-4.20 (m,
37 43 11
2
3
1
1
1
8
H), 4.14 (q, 1H, J = 7.2 Hz), 3.86 (q, 1H, J = 11.4 Hz),
.43 (s, 3H); C NMR (150 MHz, CDCl3): δ 165.8, 165.5,
64.6, 149.9, 147.8, 138.0, 137.6, 136.8, 133.4, 133.3,
29.9, 129.9, 129.2, 129.2, 128.4, 128.3, 128.3, 128.1,
27.8, 127.6, 127.6, 126.8, 125.2, 106.7, 101.2, 84.0, 82.9,
2.2, 82.1, 79.0, 77.5, 72.4, 72.2, 67.3, 67.1, 54.9; HRMS
700.2730.
1
3
4
.16 Methyl 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→3)-2,5-di-O-benzoyl-α-
arabinofuranoside (15g)
L
L-
The residue was purified by column chromatography
(
ESI) calcd for C45H43NO12 [M+Na]+ 812.2683, found
(
2:1, petroleum ether–EtOAc) to afford compound 15g as a
8
12.2692.
light syrup (yield of 91.8%, Ratio of α/β is 1:20). R 0.35
f
25
(
1:1, petroleum ether–EtOAc). [α]D +24.9 (c 1.00,
CHCl ); H NMR (400 MHz, CDCl ): δ 8.07 (d, 1H, J =
3 3
1
4
L
.14 Toluene 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→6)-3,4-di-O-isopropylidene-α-2-
deoxyl-1-thio- -galactofuranoside (15e)
7.6 Hz), 7.99-8.01 (m, 2H), 7.90–7.92 (m, 2H), 7.74 (td,
1H, J = 1.6, 7.6 Hz), 7.22–7.56 (m, 18H), 5.64 (s, 1H), 5.23
(d, 1H, J = 4.4 Hz), 5.04 (s, 1H), 4.76 (d, 1H, J = 11.6 Hz),
D
4
.68 (d, 1H, J = 11.6 Hz), 4.57–4.64 (m, 5H), 4.52 (dd, 1H,
The residue was purified by column chromatography
3:1, petroleum ether–EtOAc) to afford compound 15e as a
J = 4.4, 12.0 Hz), 4.45 (dd, 1H, J = 4.8, 8.4 Hz), 4.27–4.35
(m, 2H), 4.14–4.17 (m, 2H), 3.38 (s, 3H); C NMR (100
MHz, CDCl ): 166.2, 165.3, 164.5, 149.8, 147.7, 137.8,
137.4, 136.7, 133.2, 129.6, 129.6, 129.5, 129.2, 128.4,
128.3, 128.3, 128.2, 128.0, 127.6, 127.6, 126.6, 125.3,
107.0, 101.6, 84.1, 83.7, 82.5, 81.5, 80.5, 78.9, 77.3, 76.9,
76.6, 72.6, 67.0, 63.5, 54.7, 29.6; HRMS (ESI) calcd for
C H NO [M+Na]+ 812.2683, found 812.2682.
13
(
light syrup (yield of 87.1%, β-only ). R 0.46 (1:1,
δ
f
3
25
petroleum ether–EtOAc). [α]
+155.0 (c 1.00, CHCl3);
D
1
H NMR (400 MHz, CDCl3):
δ 8.77 (d, 1H, J = 4.0 Hz),
8
1
.17 (d, 1H, J = 7.6 Hz), 7.82 (t, 1H, J = 7.6 Hz), 7.47 (t,
H, J = 6.0 Hz), 7.40-7.31 (m, 4H), 7.28 (d, 7H, J = 10.4
Hz), 7.06 (d, 1H, J = 7.6 Hz), 5.78 (d, 1H, J = 5.2 Hz), 5.36
d, 1H, J = 4.0 Hz), 4.77 (dd, 2H, J = 4.0, 12.0 Hz), 4.65 (d,
4
5
43
12
(
1
4
H, J = 11.6 Hz), 4.59-4.50 (m, 1H),4.49-4.45 (m, 2H),
.38-4.27 (m, 4H), 4.19-4.17 (m, 1H), 4.11 (d, 1H, J = 12.4
4.17 Methyl 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→2)-3,5-di-O-benzoyl-α-
arabinofuranoside (15h)
L
L-
Hz), 3.95 (s, 1H), 3.85 (d, 1H, J = 12.4 Hz), 2.71 (td, 1H, J
5.6, 12.8 Hz), 2.25 (s, 3H), 2.08-2.00 (m,1H), 1.45 (s,
=
13
3
H), 1.41 (s, 3H), 1.28 (d, 2H, J = 11.2 Hz); C NMR (100
MHz, CDCl ): 164.6, 149.8, 147.6, 137.7, 137.4, 136.8,
36.5, 131.5, 130.3, 129.5, 128.3, 128.2, 128.1, 127.9,
The residue was purified by column chromatography
(
2:1, petroleum ether–EtOAc) to afford compound 15h as a
3
δ
1
1
7
2
light syrup (yield of 90.2%, β-only). R 0.35 (1:1,
f
25
1
27.6, 126.8, 125.4, 98.4, 95.9, 84.4, 83.6, 82.4, 79.0, 77.2,
7.0, 76.7, 72.4, 71.6, 68.2, 66.8, 63.4, 62.9, 31.6, 29.6,
petroleum ether–EtOAc). [α]
D
+9.7 (c 1.00, CHCl
3
); H
NMR (400 MHz, CDCl ):
δ 8.68 (d, 1H, J = 4.4 Hz), 8.03-
3
9.4, 20.9, 18.6; HRMS (ESI) calcd for C41
H45NO
9
S
8.07 (m, 2H),7.90–7.96 (m, 3H), 7.68 (td, 1H, J = 1.6, 7.6
Hz), 7.23–7.52 (m, 17H), 5.52 (dd, 1H, J = 2.4, 5.2 Hz),
[
M+Na]+ 750.2713, found 750.2718.
5
.10 (d, 1H, J = 4.4 Hz), 4.97 (s, 1H), 4.75 (d, 1H, J = 12.0
4
.15
2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-L-
Hz),4.42–4.70 (m, 9H), 4.25–4.33 (m, 2H), 4.16 (dd, 1H, J
13
arabinofuranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-α-
galactofuranose (15f)
D
-
= 4.4, 7.2 Hz), 3.41 (s, 3H); C NMR (100 MHz,
CDCl ): 166.1, 165.5, 164.4, 149.7, 147.5, 137.7, 137.3,
36.7, 133.1, 132.9, 129.7, 129.2, 128.4, 128.2, 128.0,
3
δ
1
1
7
The residue was purified by column chromatography
26.6, 125.2, 106.6, 100.2, 85.1, 83.9, 81.9, 80.0, 78.7,
8.4, 77.3, 77.0, 76.7, 72.6, 66.6, 64.3, 55.0, 29.5; HRMS
(
5:2, petroleum ether–EtOAc) to afford compound 15f as a
light syrup (yield of 90.3%, Ratio of α/β is 1:5). R
f
0.18
(ESI) calcd for C H NO [M+Na]+ 812.2683, found
812.2681.
45 43 12
2
5
(
2:1, petroleum ether–EtOAc). [α]D -1.9 (c 2.00, CHCl3);
1
H NMR (600 MHz, CDCl ):
δ
8.75 (s, 1H), 8.10 (d, 1H, J
7.2 Hz), 7.81 (t, 1H, J = 7.8Hz), 7.46-7.26 (m, 14H), 5.51
d, 1H, J = 3.0Hz), 5.08 (s, 1H), 4.75 (d, 1H, J = 11.4Hz),
.66 (d, 1H, J = 11.4Hz), 4.59-4.50 (m, 5H), 4.32-4.22 (m,
3
=
(
4
4.18 Methyl 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→4)-2,3-di-O-isopropylidene-α-
rhamnopyranoside (15i)
L
L-
7

ACCEPTED MANUSCRIPT
The residue was purified by column chromatography
1:1, petroleum ether–EtOAc) to afford compound 15i as a
light syrup (yield of 91.8%, Ratio of α/β is 1:20). R 0.25
129.9, 129.8, 129.2, 129.2, 129.1, 129.0, 128.5, 128.4,
128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.7, 127.7,
127.6, 126.8, 125.2, 106.9, 106.8, 106.1, 100.8, 83.9, 82.7,
(
f
25
8
7
3
2.0, 81.9, 81.8, 81.8, 81.6, 78.9, 77.9, 77.6, 77.2, 77.0,
6.8, 72.6, 72.4, 67.3, 67.1, 67.0, 60.4, 54.9, 31.9, 30.3,
0.1, 29.7, 29.6, 29.5, 29.3, 22.7, 21.0, 14.2, 14.1; HRMS
(
1:1, petroleum ether–EtOAc). [α]
+21.14 (c 1.00,
δ 8.76 (d, 1H, J =
D
1
CHCl ); H NMR (600 MHz, CDCl ):
3
3
3
.6 Hz), 8.09 (d, 1H, J = 7.8 Hz), 7.80 (td, 1H, J = 1.8, 7.8
Hz), 7.48-7.45 (m, 1H), 7.36 (d, 4H, J = 4.2 Hz), 7.33-7.23
m, 7H), 5.17 (d, 1H, J = 4.2 Hz), 4.80 (s, 1H), 4.76 (d, 1H,
J = 12.0 Hz), 4.69 (dd, 2H, J = 4.2, 12.0 Hz), 4.64-4.62 (m,
(
ESI) calcd for C64H59NO18 [M+Na]+ 1152.3630, found
1
152.3626.
(
1
6
3
=
H), 4.60-4.55 (m, 2H), 4.33-4.28 (m, 2H), 4.24 (t, 1H, J =
.6 Hz), 4.12 (q, 1H, J = 7.8 Hz), 4.05 (d, 1H, J = 6.0 Hz),
.61-3.57 (m, 1H), 3.31 (s, 3H), 1.47 (s, 2H), 1.29 (d, 3H, J
Acknowledgments
This work was supported by the NSFC (21402131) of Chi-
na, Scientific Research Foundation of Sichuan University
of Science & Engineering (2014RC06, LYJ4204)
13
6.0 Hz), 1.26 (d, 4H, J = 4.8 Hz); C NMR (100 MHz,
164.6, 149.9, 147.8, 137.8, 137.5, 136.7, 128.4,
28.3, 127.9, 127.8, 127.6, 126.8, 125.1, 109.0, 101.1,
CDCl ):
δ
3
1
9
6
7.9, 84.0, 82.3, 81.8, 78.4, 77.3, 77.0, 76.6, 75.6, 72.7,
7.1, 64.2, 54.7, 29.6, 27.9, 26.1, 17.7; HRMS (ESI) calcd
Author Information
for C H NO [M+Na]+ 658.2628, found 658.2638.
35
41
10
Corresponding Author:
4
L
.19 Methyl 2,3-di-O-Benzyl-5-O-(2-pyridinecarbony)-β-
-arabinofuranosyl-(1→5)-2,3-di-O-benzoyl-α-
E-mail address: levesonk@163.com.
L-
References
arabinofuranosyl-(1→5)-2,3-di-O-benzoyl-α-
arabinofuranoside (18)
L-
[
1] Lowary, T. L. In Glycoscience: Chemistry and Chemical
Biology; Fraser-Reid, B.; Tatsuta, K.; Thiem, J., Eds.;
Springer: Berlin, 2001; p 2005.
Imidate 10 (250 mg, 0.43 mmol, 1.20 equiv),
thioglycoside 16 (162 mg, 0.36 mmol, 1.0 equiv), and
freshly activated 4 Å molecular sieves (420 mg) in dry
CH Cl (8.0 mL) was stirred at room temperature for 15
2 2
min. Then the suspension was cooled to -80 °C, and a
solution of TMSOTf (8.3 µL, 0.043 mmol) in CH Cl (0.3
mL) was added dropwise. After being stirred for 1 h at the
same temperature, the reaction was gradually warmed to
0
[
2] (a) Fincher, G. B.; Stone, B. A.; Clarke, A. E. Annu. Rev.
Plant Physiol. 1983, 34, 47-70; (b) Ridley, B. L.; O’Neill, M.
A.; Mohnen, D. Phytochemistry. 2001, 57, 929-967.
[3] (a) Himly, M.; Jahn-Schmid, B.; Altmann, F.; Van Ree, R.;
Briza, P.; Richter, K.; Ebner, C.; Ferreira, F. FASEB J. 2003,
2
2
1
7, 106-108.; (b) Leonard, R.; Petersen, B. O.; Himly, M.;
Kaar, W.; Wopfner, N.; Kolarich, D.; Van Ree, R.; Ebner, C.;
Duus, J. O.; Ferreira, F.; Altmann, F. J. Biol. Chem. 2005,
°C, at the end of which time TLC indicated the complete
2
80, 7932-7940.
consumption of the starting materials. The resulting slurry
was re-cooled to -40°C, a solution of acceptor 14d (133
mg, 0.36 mmol, 1.0 equiv) in CH Cl (0.5 mL) was added.
Then NIS (102 mg, 0.45 mmol) and TfOH (2 µL) were
added. The reaction mixture was stirred for 1 h at -
[4] (a) Lowary, T. L. Curr. Opin. Chem. Biol. 2003, 7, 749-756;
(b) Nigudkar, S. S.; Demchenko, A. V. Chem. Sci. 2015, 6,
2
687-2704.
2
2
[
[
5] (a) Taylor, C. M.; Weir, C. A.; Jorgensen, C. G. Aust. J. Chem.
2
2
002, 55, 135-140; (b) Shaffer, K. J.; Taylor, C. M. Org. Lett.
006, 8, 3959-3962.
2
0°C.The reaction was quenched with triethylamine,
6] Xie, N.; Taylor, C. M. Org. Lett. 2010, 12, 4968-4971.
diluted with CH Cl2 and filtered. The filtrate was
2
[7] Xie, N.; Taylor, C. M. J. Org. Chem. 2014, 79, 7459-7467.
[8] (a) Kaeothip, S.; Ishiwata, A.; Ito, Y. Org. Biomol. Chem.
2013, 11, 5892-5907; (b) Ishiwata, A.; Kaeothip, S.; Takeda,
Y.; Ito, Y. Angew. Chem., Int. Ed. 2014, 53, 9812-9816.
concentrated to give a residue, which was purified by
column chromatography (1.5:1, petroleum ether–EtOAc) to
afford 18 as a light syrup (256.0 mg, 63%, the ratio of α/β
[
9] (a) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc.
012, 134, 20097-20102; (b) Yasomanee, J. P.; Demchenko,
f
of first formed glycosidicbond is 1:12). R 0.25 (3:2,
2
25
1
petroleum ether–EtOAc). [α]
D
+14.2 (c 1.00); H NMR
8.68 (d, 1H, J = 4.2Hz), 8.04-7.95
m, 9H), 7.71 (td, 1H, J = 1.8, 7.8 Hz), 7.56 (t, 1H, J = 7.2
A. V. Angew. Chem., Int. Ed. 2014, 53, 10453-10456; (c)
Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Org.
Lett. 2014, 16, 716-719; (d) Ruei, J.-H.; Venukumar, P.;
Ingle, A. B.; Mong, K.-K. T. Chem. Commun. 2015, 51,
(
(
600 MHz, CDCl3): δ
Hz), 7.52-7.47 (m, 3H), 7.43-7.31 (m, 12H), 7.28-7.24 (m,
H), 7.20 (t, 1H, J = 7.2Hz), 5.60 (d, 1H, J = 1.2 Hz), 5.50
dd, 1H, J = 1.2, 5.4 Hz), 5.47 (d, 1H, J = 1.2 Hz), 5.43 (s,
5
394-5397; (e) Yasomanee, J. P.; Demchenko, A. V. Chem. -
9
(
Eur. J. 2015, 21, 6572-6581; (f) Kayastha, A. K.; Jia, X.-G.;
Yasomanee, J. P.; Demchenko, A. V. Org. Lett. 2015, 17,
1
1
7
1
H), 5.43 (dd, 1H, J = 1.8, 6.6 Hz), 5.14 (s, 1H), 5.02 (d,
H, J = 4.2 Hz), 4.69 (t, 2H, J = 11.4 Hz), 4.62-4.48 (m,
H), 4.33-4.30 (m, 1H), 4.28 (t, 1H, J = 6.6 Hz), 4.24 (dd,
H, J = 3.6, 11.4 Hz), 4.12 (dd, 1H, J = 4.2, 6.6 Hz), 4.09
4
448-4451.
[
10] Zhu, K.; Yang, J.-S. Tetrahedron. 2016, 72, 3113-3123.
[11] Stefano, C.; Peter, W.; Bruno, L. J. Org. Chem. 2004, 69,
5897-5905.
[
[
12] Liu, Q.-W.; Bin, H.-C.; Yang, J.-S. Org. Lett. 2013, 15,
3974-3977;
13] (a) Mizutani. K.; Kasai. R.; Nakamura. M.; Tanaka. O.
Carbohydrate Res. 1989, 185, 27-38. (b) Gadikota, R. R.;
(
9, 1H, J = 5.4 Hz), 3.98 (q, 1H, J = 5.4 Hz), 3.85 (dd, 1H,
13
J = 3.6, 11.4 Hz), 3.46 (s, 3H); C NMR (150 MHz,
CDCl ): 165.8, 165.6, 165.5, 165.2, 164.6, 149.8, 147.7,
37.9, 137.6, 136.9, 133.4, 133.3, 133.3, 133.2, 129.9,
3
δ
1
8

ACCEPTED MANUSCRIPT
Callam, C. S.; Wagner, T.; Fraino, B. D.; Lowary, T. L. J.
Am. Chem. Soc. 2003, 125, 4155-4165.
[
[
14] Alcohols 14b and 14c are commercially available. All others
were prepared by reported methods. 14a: Arnaud, O.;
Koubeissi, A.; Ettouati, L.; Falson, P. J. Med. Chem. 2010,
5
3, 6720-6729. 14d, g, h: ref 12. 14e: Attolino, E.; Catelani,
G. Eur. J. Org. Chem. 2006, 23, 5279-5292. 14f: Wouters,
Ana D. Synthesis, 2013, 45, 2222-2233. 14i: Capozzi, G. J.
Org. Chem. 2001, 66, 8787-8792.
15] For one-pot syntheses oligosaccharides, see: (a) H. Yamada,
T. Harada and T. Takahashi, J. Am. Chem. Soc. 1994, 116,
7
919-7920; (b) T. Takahashi, M. Adachi, A. Matsuda and T.
Doi, Tetrahedron Lett. 2000, 41, 2599-2603; (c) B. Yu, Z.-Y.
Yang and H.-Z. Cao, Curr. Org. Chem. 2005, 9, 179-194; (d)
Y.-H. Wang, X.-S. Ye and L.-H. Zhang, Org. Biomol. Chem.
2
007, 5, 2189-2200. (e) H. Tanaka, M. Adachi and T.
Takahashi, Chem. Eur. J. 2005, 11, 849-862; (f) A.
Miermont, Y.-L. Zeng, Y.-Q. Jing, X.-S. Ye and X.-F.
Huang, J. Org. Chem. 2007, 72, 8958-8961. (g) L.-M. Deng,
X. Liu, X.-Y. Liang and J.-S. Yang, J. Org. Chem. 2012, 77,
3
025-3037.
9

ACCEPTED MANUSCRIPT
Highlights
•
•
•
We reported a β-arabinofuranosylation method by employing the
-O-(2-pyridinecarbonyl)- -arabinofuranosyl trichloroacetimidate as a donor
5
L
.
β-L-Araf-Hyp and its dimer were synthesized in high yields and stereoselectivities
by this method
.
A trisaccharide which contains β-L-Araf moiety was efficiently synthesizing in a
one-pot manner.