Synthesis of tri- and tetrasaccharide glycosides of (4S)-4-hydroxy-d-proline relevant to the cell wall O-glycans of green alga Chlamydomonas reinhardtii

Article abstract of DOI:10.1016/j.tet.2016.04.038

The synthesis of tri- and tetrasaccharide glycosides of (4S)-4-hydroxy-d-proline 1 and 2 with unusual glycan motifs has been achieved efficiently. The assembly of the synthetically challenging 1,2-cis linked arabino- and galactofuranoside frameworks withi

Full text of DOI:10.1016/j.tet.2016.04.038

Tetrahedron 72 (2016) 3113e3123
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journal homepage: www.elsevier.com/locate/tet
Synthesis of tri- and tetrasaccharide glycosides of (4S)-4-hydroxy-
D-proline relevant to the cell wall O-glycans of green alga
Chlamydomonas reinhardtii
Kai Zhu, Jin-Song Yang *
Department of Chemistry of Medicinal Natural Products, and Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of tri- and tetrasaccharide glycosides of (4S)-4-hydroxy-D-proline 1 and 2 with unusual
Received 14 March 2016
Received in revised form 12 April 2016
Accepted 14 April 2016
glycan motifs has been achieved efficiently. The assembly of the synthetically challenging 1,2-cis linked
arabino- and galactofuranoside frameworks within the targets was realized by the use of a 2-
quinolinecarbonyl-assisted 1,2-cis furanosylation approach.
Available online 14 April 2016
Ó 2016 Published by Elsevier Ltd.
Keywords:
Chlamydomonas reinhardtii
Hydroxyproline
Furanose
Synthesis
Thioglycoside
1. Introduction
linked to the C2 position of the Araf residues; (2) there are two kinds
of 1,2-cis furanosidic linkages within 1 and 2, namely, 1,2-cis-
b-
Extensins, a type of hydroxyproline (Hyp)-rich glycoproteins,
are essential structural constituents of the plant cell wall. They
form crosslinked networks in the young cell wall and appear im-
arabinofuranoside and 1,2-cis- -galactofuranoside. It is known that
a
the 1,2-trans glycosides can be constructed in a straightforward
pattern by participation of an acyl-type groupon the C2 position. But
the stereocontrolled preparation of 1,2-cis glycoside counterparts,
such as the 1,2-cis furanosides mentioned above is still a great
1
portant for wall strength and disease resistance. It is known that
extensions generally consist of a repetitive serine (Ser)-Hyp
tapeptide motif. Besides, the Hyp residue is extensively O-glyco-
sylated with short and linear -arabinofuranose (Araf) chains while
4
pen-
4
challenge in carbohydrate chemistry. We chose 1 and 2 as synthetic
L
targets due to the architectural novelty and the synthetic challenge
posed by their sugar chains.
2
the Ser residue typically has a single galactose (Gal) attached.
In 2007, Waffenschmidt and co-workers reported the isolation of
linear Hyp-bound O-glycans fromoutercell wall glycoproteins of the
Several strategies have been developed and employed for the
preparation of the
b
-arabinofuranoside in the past. Among them,
3
0
5
unicellular green alga Chlamydomonas reinhardtii. Structural elu-
the 2 -carboxybenzyl (CB) glycoside and the p-cresol thioglyco-
6
cidation through chemical and spectroscopic methods revealed that
these glycans are composed of two novel Hyp-bound trisaccharide
side donors, reported by Kim and Lowary, respectively, have
shown special promise in stereocontrolled synthesis of b-D-Araf-
and tetrasaccharide, namely,
Araf-(1/4)-Hyp (1) and 3-O-methyl-
1/2)- -L-Araf-(1/2)- -L-Araf-(1/4)-Hyp (2) (see Fig. 1). The
unique structural features of the glycan motif of 1 and 2 include the
following: (1) compared to the Hyp-bound O-glycals isolated from
various land plants, the carbohydrate portions of these glycosyl
amino acids unusually contain a galactofuranosyl unit which is
a
-D-Galf-(1/2)-
b
-L-Araf-(1/2)-
b
-L-
containing oligosaccharides. Besides, the conformationally re-
7
b
-L-Araf-(1/5)-
a-D-Galf-
stricted activators such as 3,5-O-di-tert-butylsilylene (DTBS)-, 3,5-
8
9
(
b
b
O-tetraisopropyldisiloxanylidene (TIPDS)-, and 2,3-O-xylylene
protected thioglycoside donors were found to be effective as well
for the direct -arabinofuranosylations. In the synthesis of the Hyp-
linked -L-Araf structures of Art v 1, the major allergen of mugwort
pollen, Taylor and co-workers have applied the 3,5-O-DTBS pro-
tected glycosyl donors for the assembly of the key -L-arafur-
b
b
b
7
f
anosidic bonds within the targets. However, the chemical yields
and the glycosylation selectivity reported are low. Moreover, a 2-
*
Corresponding author. Tel./fax: þ86 28 85503723; e-mail address: yjs@scu.edu.
cn (J.-S. Yang).
http://dx.doi.org/10.1016/j.tet.2016.04.038
0
040-4020/Ó 2016 Published by Elsevier Ltd.

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K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
Fig. 1. Synthetic targets 1 and 2.
(
naphthyl)methyl (Nap) ether mediated intramolecular aglycon
required 1,2-cis anomeric selectivity of each glycosylation. Fur-
thermore, the Nap ether was chosen as the temporary C2 hydroxyl-
protecting group of donors 3aeb, thus facilitating the selective C2
delivery (IAD) strategy which was disclosed by Ito et al. has been
successfully utilized in the synthesis of a variety of oligosaccharides
containing 1,2-cis Araf units.
8
b,10
Recently, this means was
deprotection manipulation for further installment of additional b-
employed by Ito et al. for synthesizing the glycopeptides derived
(1/2)-linked Araf residues.
10c,d
from Hyp-rich glycoproteins.
On the other hand, for the stereoselective formation of
actofuranoside,11 the CB glycoside approach has also proved to be
a-gal-
2. Results and discussion
12
useful for direct
anhydro- -gulofuranosyl thioglycosides and sulfoxides, reported
by Lowary et al., have shown validity in stereoselective synthesis of
-D-Galf-containing carbohydrates, but the regioselective opening
a
-galactofuranosylation. Additionally, the 2,3-
The synthesis of the target molecules began with the prepara-
tion of the desired monosaccharide donors 3aeb (Scheme 1). To
this end, reaction of the known 1,2-O-isopropylidene-5-O-tribu-
D
17
a
tyldiphenylsilyl (TBDPS)-b-L-arabinofuranose 6 with benzyl bro-
1
3
of the 2,3-epoxide ring structure lowers the synthetic efficiency.
mide and methyl iodide furnished C3 benzyl ether 7a and methyl
ether 7b, respectively, in 87% and 90% yield. Subsequently, both 7a
and 7b were converted, respectively, into thioglycoside alcohols 8a
and 8b in 56% and 54% overall yield through a sequence of ace-
14
Recently, Demchenko and co-workers developed an efficient
hydrogen-bond-mediated aglycone delivery (HAD) methodology to
selectively prepare diverse 1,2-cis-pyranosides, including
a-gluco-,
b
-manno-, as well as -rhamnosides. In a typical HAD glycosylation
b
tolysis with Ac O/HOAc, condensation with ethanethiol catalyzed
2
protocol, the donor and acceptor are first mixed together in
a proper solvent prior to the addition of the promoter system. The
formed intermolecular hydrogen bonding between both glyco-
sylating substrates can direct the attack of the acceptor to one
specific face of the donor ring, thus achieving a high glycosylation
stereoselectivity.1 Based on such a concept, our group developed
a novel 2-quinolinecarbonyl (Quin)-assisted 1,2-cis-glycosylation
by boron trifluoride etherate (BF $Et O) in CH Cl , and deacetyla-
3
2
2
2
tion with NaOMe in methanol. Conversion of 8a/b to 9a/b involved
(i) etherification of the secondary C2-OH of 8a/b with 2-(bromo-
methyl)naphthalene (NapBr) or benzyl bromide in DMF and (ii)
desilylation of the obtained intermediates with TBAF in THF solu-
tion, affording the corresponding thioglycosides 9a/b in 81% and
86% yield, respectively. Esterification of the remaining C5-OHs in
9a/b with 2-quinoline carboxylic acid in the presence of 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 4-
4a
method for facile preparation of both b-arabinofuranosides and a-
galactofuranosides.15 The Quin group serving as a H-bond acceptor
exhibits a strong stereocontrolling ability in the coupling of ara-
bino- and galactofuranosyl thioglycoside donors with a wide range
of carbohydrate and non-carbohydrate acceptors. Then, using this
Quin-mediated 1,2-cis-furanosylation reaction as key steps, we
15a
dimethylaminopyridine (DMAP) in CH Cl
2
2
gave the desired 5-
O-Quin carrying
L-arabinofuranosyl thioglycoside donors 3a and 3b
in excellent yields.
As shown in Scheme 2, the preparation of monosaccharide do-
realized the construction of a
portion from mycobacterial cell wall polysaccharide and the total
b
-D-Araf-containing octasaccharide
nor 4 started with the known ethyl 1-thio-
b
-
D
-galactofuranoside
15a
15b
10
which was readily prepared from commercial -galactose.
D
0
15b
synthesis of complex marine glycosphingolipid vesparioside B.
Here, we planned to apply the Quin-mediated 1,2-cis-fur-
anosylation chemistry to the synthesis of both the -arabino- and
the -galactofuranosidic linkages possessed by the target com-
pounds 1 and 2. For this purpose, several monosaccharide building
5,6-O-Acetonide protection of compound 10 with 2,2 -dimethox-
ypropane in acetone gave saccharide 11 in 83% yield. The latter was
in turn transformed into 2,3-di-O-Bn protected thiogalactofurano-
side 12 by treatment with benzyl bromide and sodium hydride in
b
a
DMF followed by acetic acid in a THF/H O (1:1) co-solvent, giving
2
16
blocks 3aeb and 4, and Hyp aglycon synthon 5 were designed
see Fig. 2). The Quin directing functionality was installed on the
bottom side of these Araf and Galf thioglycosides to ensure the
rise to the thioglycoside 5,6-diol 12 in 78% over two steps. Then,
subjecting 12 to a regioselective monosilylation reaction with
1.5 equiv of tert-butyldimethylsilyl chloride (TBSCl) in acetonitrile
(
Fig. 2. Monosaccharide building blocks.

K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
3115
Scheme 1. Preparation of monosaccharide donors 3aeb.
led to the formation of 6-O-TBS ether 13 in a 91% yield. Finally, the
Quin functionality was introduced on the C5 position of 13 by re-
action with 2-quinoline carboxylic acid under conditions similar to
OMe acceptor 5 was glycosylated with
glycoside 3a (1.1 equiv) under the promotion of N-iodosuccinimide
L
-arabinofuranosyl thio-
(NIS) and catalytic trifluoromethanesulfonic acid (TfOH) in 1,2-
ꢀ
those above to provide the corresponding
a-galactofuranosyl thi-
dichloroethane (DCE) at ꢁ30/0 C for 1.5 h, resulting in the
b-L-
oglycoside donor 4 (94% yield).
arabinofuranosyl Hyp product 16 in a good 86% yield as exclusively
Scheme 2. Preparation of monosaccharide donor 4.
The preparation of the Hyp building block 5 was carried out as
outlined in Scheme 3. The N-tert-butyloxycarbonyl (Boc)-protected
b
-isomer. The
anoside bond was unambiguously verified by the expected dou-
blet for anomeric signal of the Araf moiety (
¼4.9 ppm, d, JH1
¼4.8 Hz). After removal of the C2 Nap group of 16 with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) in wet CH Cl , the ob-
tained alcohol 17 was condensed efficiently and -stereo-
selectively with donor 3a (1.8 equiv) under the similar conditions
as above to cleanly generate the -arabinosyl disaccharide glyco-
side 18 (
H100¼5.3 ppm, d, JH100/H200¼4.2 Hz) in 74% yield. Again, no
isomer was observed in the glycosylation process. Then, by means
b-configuration of the newly formed arabinofur-
Hyp methyl ester 1416 was treated with 4-nitrobenzoic acid under
d
0
0
/
H1
ꢀ
19
standard Mistunobu reaction conditions (Ph
3
P, DEAD, THF, 0 C,
D
0
H2
18
overnight) to afford the trans-4-hydroxy-
-proline derivative
in 92% yield. Then, the 4-nitrobenzoyl group was selectively
cleaved under mild basic conditions (NaOMe, MeOH, 0 C, 30 min)
to give 5 in an excellent 90% yield.
2
2
16b
15
b
ꢀ
b
With the required building blocks in hand, we began to con-
struct the targets 1 and 2. As shown in Scheme 4, the chiral Hyp-
d
a-

3116
K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
Scheme 3. Preparation of aglycon alcohol 5.
of the same DDQ-oxidation protocol, compound 18 was trans-
formed into alcohol 19 (70% yield). Coupling of this -L-Araf Hyp
derivative 19 with the -thiogalactose donor 4 (2 equiv) using
a similar NIS/TfOH-activated protocol delivered the trisaccharide
glycoside 20 in 51% combined yield as a 20:1 mixture. The
anomeric configuration of the formed galactofuranosidic linkages
galactosylated trisaccharide glycoside 20 (
H2000¼4.2 Hz) was subjected to Zempl eꢀ n transesterification
d
H1000¼5.5 ppm, d, JH1000
/
b
2
D
(NaOMe, MeOH) and followed by regioselective installation of TBS
ethers on both C5 and C5 primary OH groups to afford tri-
saccharide alcohol 21 in 72% yield. At last, a similar NIS/TfOH ac-
tivated condensation between acceptor 21 with 3-O-Me
0
a
/
b
1
was deduced based on the H NMR spectroscopy in CDCl
3
. For the
substituted
produced the protected tetrasaccharide glycoside 22 in 96% yield
without formation of -anomeric product.
L
-arabinosyl thioglycoside 3b proceeded smoothly and
3
a
-galactofuranosyl anomer, the JH1/H2 value is 4.0e4.5 Hz, while,
for the
b
-anomer, the 3
J
H1/H2 is 0e2.0 Hz. Then, the pure
20
a
-
a
Scheme 4. Synthesis of protected 20 and 22.

K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
3117
The global deprotection of 20 was performed in the following
order (Scheme 5, eq 1): removal of the Quin functionality via
Zempl eꢀ n deacylation with NaOMe in MeOH, cleavage of the Boc and
furanosidic bonds including two or three
b
-Araf and one
a
-Galf
moieties within the target molecules were efficiently constructed
by using a Quin-assisted 1,2-cis furanosylation approach. Further
investigation into the biological function of the synthetic glycosyl
amino acids is currently underway.
TBS protecting group under acidic conditions, release of the car-
boxylic group via saponification with sodium hydroxide (NaOH) in
a dioxane/methanol (3:1) co-solvent, and finally cleavage of the Bn
ethers by catalytic hydrogenolysis. Purification of the deprotected
trisaccharide glycosyl amino acid was completed using gel filtration
chromatography on a Sephadex LH-20 column with MeOH as elu-
ent to give 1 as a colorless syrup in 40% yield over four steps.
Likewise, the target free tetrasaccharide glycosyl amino acid 2 was
successfully synthesized from the corresponding fully protected 22
4
4
. Experimental section
.1. General methods
All non-aqueous reactions were performed under a nitrogen
atmosphere and monitored by thin layer chromatography (TLC)
using Silica Gel GF254 plates with detection by charring with 10% (v/
(Scheme 5, eq 2) through a five-step deprotection procedure. It is
worth pointing out that the removal of the TBS ether should be
performed prior to the deprotection of the Boc group, otherwise
a complex mixture was obtained.
v) H
were distilled from appropriate drying agents prior to use. Silica gel
200e300 mesh) was used for column chromatography. Optical
2 4
SO in EtOH or by UV detection. Solvents used in the reactions
(
Scheme 5. Completion of synthesis of 1 and 2.
The structures of 1 and 2 were determined through the use of 1D
rotations were measured with a PE-314 automatic polarimeter at
(1
H, C, 400 MHz) and 2D NMR (gCOSY, gHMQC, and gHMBC) and
13
20ꢂ1 C for solutions in a 1.0 dm cell. HRESIMS spectra were ac-
ꢀ
1
1
13
ESIMS spectral analysis. Take compound 1 for example. In its
H
quired on Agilent 6210 TOF LC/MS instrument. H and C NMR
spectra were obtained on Bruker AC-E 200 or Varian INOVA-400/54
NMR spectrum, the three anomeric protons appeared as two sig-
nals at 5.23 and 5.15 ppm for the Araf residues and one signal at
5.05 ppm for the Galf residue. In addition, in the C NMR
spectrum, the chemical shifts of the anomeric carbons were at
00.2 and 99.9 ppm (for the Araf residues) and 101.8 ppm (for the
d
H
spectrometers in CDCl
reference. Chemical shifts (d
3
with tetramethylsilane (TMS) as internal
) are expressed in ppm downfield from
13
d
H
d
C
the internal TMS absorption. Standard splitting patterns are ab-
breviated: s (singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet). J values are given in Hz.
1
d
C
19
Galf residue). These data are characteristic of 1,2-cis-b-Araf and a-
Galf linkages.20 Moreover, the linkages of sugar residues were
confirmed by the gHMBC experiment. Further support for its
4.2. 3-O-Benzyl-5-O-tert-butyldiphenylsilyl-1,2-O-iso-
propylidene-b-L-arabinofuranose (7a)
structure came from the high-resolution MS data, which gave an
þ
(
MþNa) signal at m/z 580.1908 (calcd 580.1856).
To a solution of 6 (24.77 g, 57.80 mmol) in dry DMF (150 mL) was
ꢀ
3
. Conclusion
added benzyl bromide (13.7 mL, 115.4 mmol) at 0 C. The reaction
mixture was stirred at the same temperature for 15 min, and then
NaH (60% in mineral oil, 4.63 g, 115.8 mmol) was added and the
resulting mixture was warmed gradually to room temperature in
We have accomplished the synthesis of the structurally unusual
Hyp-linked tri- and tetrasaccharides 1 and 2 which are isolated
from green alga C. reinhardtii. All the difficult-to-obtain 1,2-cis
4
an hour. The reaction was quenched with saturated aqueous NH Cl,

3118
K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
diluted with EtOAc, and then the mixture was washed with water
and brine. The organic layer was separated and dried over anhy-
4.27e4.25 (m, 2H), 4.04 (s, 1H), 3.84 (dd, 1H, J¼11.2, 2.6 Hz), 3.63
(dd, 1H, J¼11.2, 2.0 Hz), 3.49 (d, 1H, J¼9.2 Hz), 2.78e2.64 (m, 2H),
13
drous Na
2
SO
4
, filtered, and concentrated. The obtained residue was
1.33 (t, 3H, J¼7.4 Hz), 1.02 (s, 9H); C NMR (100 MHz, CDCl
3
):
purified by silica gel column chromatography (30:1, petroleum
ethereEtOAc) to afford compound 7a (26.08 g, 87%) as a colorless
d 137.5, 135.54, 135.48, 132.3, 132.2, 129.9, 129.8, 128.4, 127.78,
127.76, 127.72, 91.3, 84.4, 83.5, 79.3, 72.0, 63.9, 26.6, 25.9, 19.0, 15.1;
2
0
þ
syrup. 7a: R
f
¼0.79 (5:1, petroleum ethereEtOAc); [
a
]
D
þ2.88 (c 0.8,
HRMS (ESI): m/z calcd for C30
found: 545.2188.
H
38
O
4
SSiNa [MþNa] : 545.2160,
1
CHCl
3
); H NMR (400 MHz, CDCl ):
3
d
7.69 (dd, 4H, J¼8.0, 1.6 Hz),
7
4
.45e7.25 (m, 11H), 5.92 (d, 1H, J¼4.0 Hz), 4.70 (d, 1H, J¼4.0 Hz),
.65 (d, 2H, J¼2.0 Hz), 4.26 (s, 2H), 3.83e3.82 (m, 2H), 1.38 (s, 3H),
4.5. Ethyl 3-O-methyl-5-O-tert-butyldiphenylsilyl-1-thio-a-L-
arabinofuranoside (8b)
1
3
1.33 (s, 3H), 1.08 (s, 9H); C NMR (100 MHz, CDCl
3
):
d
137.4, 135.5,
133.2, 133.0, 129.72, 129.67, 128.5, 127.8, 127.71, 127.67, 112.4, 105.7,
8
5.2, 85.1, 82.8, 71.6, 63.4, 26.9, 26.8, 26.1, 19.2; HRMS (ESI): m/z
Compound 8b was synthesized from 7b following the procedure
similar to that for 7a/8a. The crude product was purified by silica
gel column chromatograph (20:1, petroleum ethereEtOAc) to give
þ
calcd for C31
38
H O
5
SiNa [MþNa] : 541.2389, found: 541.2372.
4
.3. 3-O-Methyl-5-O-tert-butyldiphenylsilyl-1,2-O-iso-
compound 8b (54% for three steps) as a colorless syrup. 8b: R
f
¼0.5
); H NMR
d 7.72e7.67 (m, 4H), 7.51e7.35 (m, 6H), 5.31 (s,
2
0
1
propylidene- -arabinofuranose (7b)
b-L
(5:1, petroleum ethereEtOAc); [
400 MHz, CDCl ):
a
]
D
ꢁ111.9 (c 1.4, CHCl
3
(
3
Prepared from glycoside 6 (7.971 g, 18.62 mmol), iodomethane
2.32 mL, 37.26 mmol), and NaH (60% in mineral oil, 1.5 g,
7.5 mmol) in dry DMF (80 mL) following the procedure similar to
that for 6/7a. The crude product was purified by silica gel column
chromatograph (30:1, petroleum ethereEtOAc) to give compound
1H), 4.22e4.19 (m, 2H), 3.90 (dd, 1H, J¼11.2, 2.8 Hz), 3.83 (s, 1H),
(
3
3.75 (dd, 1H, J¼11.2, 2.0 Hz), 3.68 (d, 1H, J¼9.6 Hz), 3.42 (s, 3H),
13
2.76e2.65 (m, 2H), 1.32 (t, 3H, J¼7.4 Hz), 1.08 (s, 9H); C NMR
3
(100 MHz, CDCl ): d 135.6, 135.5, 132.4, 132.2, 130.0, 129.9, 127.82,
127.76, 91.3, 87.3, 83.6, 78.6, 64.2, 57.9, 26.7, 25.9, 19.1, 15.0; HRMS
þ
7
b (7.41 g, 90%) as a colorless syrup. 7b: R
f
¼0.53 (10:1, petroleum
(ESI): m/z calcd for C24
469.1843.
H
34
O
4
SSiNa [MþNa] : 469.1847, found:
20
1
ethereEtOAc); [
a
]
D
ꢁ0.522 (c 1.1, CHCl
3
); H NMR (600 MHz,
CDCl
J¼3.6 Hz), 4.57 (d, 1H, J¼3.6 Hz), 4.14 (ddd, 1H, J¼7.8, 5.4, 2.4 Hz),
.98 (d, 1H, J¼2.4 Hz), 3.83e3.76 (m, 2H), 3.42 (s, 3H), 1.33 (s, 3H),
3
): d 7.68e7.66 (m, 4H), 7.44e7.36 (m, 6H), 5.85 (d, 1H,
4.6. Ethyl 2-O-(2-naphthylmethyl)-3-O-benzyl-1-thio-a-L-
arabinofuranoside (9a)
3
1
.29 (s, 3H), 1.06 (s, 9H); 1 C NMR (100 MHz, CDCl
3
3
): d 135.6, 135.5,
133.2, 133.1, 129.72, 129.68, 127.7, 112.3, 105.7, 84.9, 84.6, 63.3, 57.4,
To a solution of compound 8a (7.044 g, 13.47 mmol) and 2-
2
6.9, 26.8, 26.0, 19.2; HRMS (ESI): m/z calcd for C25
H
34
O
5
SiNa
(bromomethyl)naphthalene (4.47 g, 20.2 mmol) in dry DMF
(89 mL) was added NaH (60% in mineral oil,1.08 g, 27 mmol) at 0 C.
The reaction mixture was stirred for 30 min at the same temper-
þ
ꢀ
[MþNa] : 465.2076, found: 465.2072.
4
.4. Ethyl 3-O-benzyl-5-O-tert-butyldiphenylsilyl-1-thio-
a-
L-
ature, at the end of which time TLC indicated it was finished. The
arabinofuranoside (8a)
reaction was diluted with CH
washed with saturated aqueous NaHCO
layer was separated and dried over anhydrous Na
2
Cl
2
, and then the mixture was
and brine. The organic
SO , filtered, and
3
To a solution of compound 7a (38.16 g, 73.54 mmol) in acetic
2
4
acid (419 mL, 7.34 mol) were added acetic anhydride (50 mL,
concentrated. The obtained residue was purified by silica gel col-
umn chromatograph (100:1, petroleum ethereEtOAc) to afford
a colorless syrup. To a solution of the obtained syrup (8.04 g,
12.12 mmol) in dry THF (100 mL) was added slowly TBAF (13.5 mL,
1.0 M in THF, 13.5 mmol). The resulting mixture was stirred at room
temperature for 3 h, at the end of which time TLC indicated it was
finished. After the solvent was removed under reduced pressure,
5
0
21 mmol) and concentrated sulfuric acid (0.37 mL, 7.03 mmol) at
C. The resulting mixture was stirred for one hour at room tem-
ꢀ
perature, at the end of which time TLC indicated the reaction was
complete. The reaction was diluted with EtOAc, and then the
mixture washed with saturated aqueous NaHCO
organic layer was separated and dried over anhydrous Na
3
and brine. The
4
SO ,
2
filtered, and concentrated. The obtained residue was purified by
silica gel column chromatograph (20:1, petroleum ethereEtOAc) to
afford a colorless syrup. To a solution of the obtained syrup (32.75 g,
the obtained residue was dissolved with CH
lution was washed with saturated aqueous NH
organic layer was separated and dried over anhydrous Na
2
Cl
2
. The resulting so-
Cl and brine. The
SO
4
2
4
,
5
8.20 mmol) and ethanethiol (6.3 mL, 85.19 mmol) in CH
2
Cl
2
filtered, and concentrated. The obtained residue was purified by
silica gel column chromatograph (8:1, petroleum ethereEtOAc) to
(
415 mL) was added boron trifluoride diethyl etherate (44 mL,
3
0
48.3 mmol) dropwise, and the mixture was stirred for 30 min at
afford compound 9a as a colorless syrup (4.63 g, 81% for two steps).
ꢀ
20
C. The reaction was quenched with Et
3
N, diluted with CH
2
Cl
2
,
9a: R
f
¼0.25 (5:1, petroleum ethereEtOAc); [
a
]
D
ꢁ124 (c 0.6,
1
and then the mixture was washed with water and brine. The or-
ganic layer was separated and dried over anhydrous Na SO , fil-
tered, and concentrated. The obtained residue was purified quickly
by silica gel column chromatograph (30:1, petroleum ethereEtOAc)
to afford a syrup. To the solution of the obtained syrup (30 g,
CHCl ); H NMR (400 MHz, CDCl ): d 7.85e7.78 (m, 4H), 7.52e7.43
3
3
2
4
(m, 3H), 7.34e7.25 (m, 5H), 5.39 (d, 1H, J¼1.2 Hz), 4.76 (d, 1H,
J¼12.0 Hz), 4.65 (d, 1H, J¼12.0 Hz), 4.58 (d, 1H, J¼12.0 Hz), 4.53 (d,
1H, J¼12.0 Hz), 4.24 (s, 1H), 4.05 (m, 2H), 3.86 (dd, 1H, J¼12.0,
2.4 Hz), 3.70 (dd, 1H, J¼12.0, 3.2 Hz), 2.75e2.59 (m, 2H), 1.88 (s, 1H),
1
3
5
3.12 mmol) in CH
3
OH (350 mL) was added CH
3
ONa (2 g,
1.29 (t, 3H, J¼7.4 Hz); C NMR (100 MHz, CDCl
3
): d 137.6, 134.6,
37.04 mmol) at room temperature. The mixture was stirred for 2 h
133.2, 133.1, 128.4, 128.3, 127.9, 127.8, 127.75, 127.68, 126.9, 126.2,
at room temperature, at the end of which time TLC indicated it was
finished. The reaction was neutralized with Amberlite IR-120 H
126.1, 125.8, 88.6, 87.5, 82.8, 81.3, 72.4, 72.1, 61.8, 25.3, 14.8; HRMS
þ
þ
(ESI): m/z calcd for C25
H
28
O
4
SNa [MþNa] : 447.1608, found:
resin, diluted with CH
3
OH, filtered, and concentrated. The obtained
447.1566.
residue was purified by silica gel column chromatograph (20:1,
petroleum ethereEtOAc) to give compound 8a (21.54 g, 56% for
4.7. Ethyl 2-O-benzyl-3-O-methyl-1-thio-a-L-arabinofurano-
three steps) as a colorless syrup. 8a: R
f
¼0.27 (10:1, petroleum
side (9b)
20
1
ethereEtOAc); [
CDCl ):
7.67 (d, 2H, J¼6.4 Hz), 7.59 (d, 2H, J¼6.8 Hz), 7.47e7.26 (m,
1H), 5.31 (s, 1H), 4.72 (d, 1H, J¼12.0 Hz), 4.53 (d, 1H, J¼12.0 Hz),
a]
D
3
ꢁ126.7 (c 1.1, CHCl ); H NMR (400 MHz,
3
d
Compound 9b was synthesized from 8b following the procedure
similar to that for 8a/9a. The crude product was purified by silica
1

K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
3119
gel column chromatograph (8:1, petroleum ethereEtOAc) to give
compound 9b (86% for two steps) as a colorless syrup. 9b: R
room temperature. After one hour, the reaction was quenched with
Et N, and the solvent was evaporated under reduced pressure. The
obtained residue was purified by silica gel column chromatograph
(3:1, petroleum ethereEtOAc) to afford compound 11 (5.34 g, 83%)
f
¼0.21
3
2
0
1
(
(
5:1, petroleum ethereEtOAc); [
a
]
D
ꢁ138.2 (c 1.1, CHCl
3
); H NMR
400 MHz, CDCl ): 7.37e7.27 (m, 5H), 5.37 (s, 1H), 4.63 (d, 1H,
3
d
2
0
J¼12.0 Hz), 4.56 (d, 1H, J¼12.0 Hz), 4.19e4.15 (m, 1H), 3.92 (t, 1H,
J¼2.4 Hz), 3.88 (dd, 1H, J¼12.0, 2.8 Hz), 3.81 (dd, 1H, J¼6.4, 2.2 Hz),
as a colorless syrup.11: R
ꢁ103.1 (c 1.05, CHCl
f
¼0.41 (1:1, petroleum ethereEtOAc); [
a]
D
1
3 3
); H NMR (400 MHz, CDCl ): d 5.33 (s, 1H),
3
1
.74 (dd, 1H, J¼12.0, 4.0 Hz), 3.36 (s, 3H), 2.74e2.58 (m, 2H), 2.14 (s,
4.37 (td, 1H, J¼7.6, 1.6 Hz), 4.12 (d, 2H, J¼2.0 Hz), 4.09 (d, 1H,
J¼6.8 Hz), 4.04 (s, 1H), 4.01 (t, 1H, J¼8.0 Hz), 3.15 (br s, 1H),
13
H), 1.29 (t, 3H, J¼7.4 Hz); C NMR (100 MHz, CDCl
3
): d 137.1, 128.4,
1
3
127.93, 127.88, 88.0, 87.3, 85.1, 81.5, 71.8, 61.9, 58.1, 25.2, 14.7; HRMS
2.80e2.62 (m, 2H),1.44 (s, 3H),1.40 (s, 3H),1.31 (t, 3H, J¼7.2 Hz);
C
þ
(
ESI): m/z calcd for C15
H
22
O
4
SNa [MþNa] : 321.1139, found:
3
NMR (100 MHz, CDCl ): d 109.9, 89.6, 83.9, 81.2, 79.1, 75.7, 65.4,
3
21.1095.
29.6, 25.7, 25.5, 25.0, 14.8; HRMS (ESI): m/z calcd for C11
20
H O
5
SNa
þ
[MþNa] : 287.0931, found: 287.0933.
4
.8. Ethyl 2-O-(2-naphthylmethyl)-3-O-benzyl-5-O-(2-
-arabinofuranoside (3a)
quinolinecarbonyl)-1-thio-
a
-L
4.11. Ethyl 2,3-di-O-benzyl-1-thio-b-D-galactofuranoside (12)
To a solution of compound 9a (8.25 g, 19.43 mmol) in CH
196 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (9.3 g, 48.51 mmol), 4-dimethylaminopyridine (475 mg,
2
Cl
2
To a solution of compound 11 (4.57 g, 17.31 mmol) in dry DMF
ꢀ
(
(86 mL) was added benzyl bromide (8.2 mL, 69.05 mmol) at 0 C.
ꢀ
The reaction mixture was stirred at 0 C for 15 min, and then NaH
3
0
.89 mmol), and 2-quinoline carboxylic acid (6.73 g, 38.86 mmol) at
C. The mixture was stirred at room temperature for overnight.
(60% in mineral oil, 2.77 g, 69.25 mmol) was added and the
resulting mixture was warmed gradually to room temperature in
one hour. The reaction was quenched with saturated aqueous
ꢀ
Then the reaction mixture was diluted with CH
with brine. The organic layer was separated and dried over anhy-
drous Na SO , filtered, and concentrated. The obtained residue was
purified by silica gel column chromatograph (10:1, petroleum
ethereEtOAc) to afford compound 3a (10.68 g, 95%) as a colorless
2 2
Cl and washed
NH
water and brine. The organic layer was separated and dried over
anhydrous Na SO , filtered, and concentrated. The obtained residue
4
Cl, diluted with EtOAc, and then the mixture was washed with
2
4
2
4
was purified by silica gel column chromatograph (40:1, petroleum
ethereEtOAc) to afford a colorless syrup. Then, the obtained syrup
(6 g, 13.51 mmol) was dissolved in a mixture of acetic acid, water,
2
0
syrup. 3a: R
f
¼0.17 (5:1, petroleum ethereEtOAc); [
a
]
D
ꢁ59.1 (c
8.27 (d, 1H, J¼8.8 Hz),
.04 (d, 1H, J¼8.4 Hz), 8.00 (d, 1H, J¼8.8 Hz), 7.84e7.72 (m, 6H), 7.61
t, 1H, J¼7.2 Hz), 7.51e7.43 (m, 3H), 7.28e7.19 (m, 5H), 5.50 (d, 1H,
J¼1.8 Hz), 4.79 (d, 1H, J¼11.6 Hz), 4.71e4.63 (m, 3H), 4.61e4.56 (m,
1
3 3
1.05, CHCl ); H NMR (400 MHz, CDCl ): d
8
(
and tetrahydrofuran (3/1/1, v/v/v, 155 mL). The reaction was stirred
ꢀ
at 65 C for 2 h, then it was quenched with Et
3
N. The solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatograph (2:1, petroleum
ethereEtOAc) to afford 12 (5.42 g, 78% for two steps) as a colorless
13
3
H), 4.13e4.09 (m, 2H), 2.78e2.63 (m, 2H),1.31 (t, 3H, J¼7.4 Hz);
NMR (100 MHz, CDCl ): 164.7, 147.5, 147.4, 137.3, 137.0, 134.6,
33.1, 133.0, 130.7, 130.1, 129.1, 128.4, 128.3, 128.2, 127.82, 127.76,
27.6, 127.3, 126.8, 126.2, 126.0, 125.8, 121.0, 88.6, 87.4, 83.8, 78.9,
C
3
d
2
0
1
1
syrup. 12: R
f
¼0.28 (1:1, petroleum ethereEtOAc); [
a
]
D
ꢁ121.4 (c
1
0.95, CHCl ); H NMR (400 MHz, CDCl ): d 7.38e7.25 (m, 10H), 5.37
3
3
7
2.3, 72.1, 64.6, 25.3, 14.8; HRMS (ESI): m/z calcd for C35
H
33NO
5
SNa
(d, 1H, J¼2.0 Hz), 4.62 (d, 1H, J¼12.0 Hz), 4.59 (d, 1H, J¼12.0 Hz),
4.52 (d, 1H, J¼12.0 Hz), 4.50 (d, 1H, J¼12.0 Hz), 4.20 (dd, 1H, J¼6.8,
þ
[MþNa] : 602.1979, found: 602.1955.
3
.6 Hz), 4.09 (dd, 1H, J¼6.8, 2.8 Hz), 3.97 (t, 1H, J¼2.4 Hz), 3.79 (s,
4
1
.9. Ethyl 2-O-benzyl-3-O-methyl-5-O-(2-quinolinecarbonyl)-
-thio- -arabinofuranoside (3b)
1H), 3.71e3.67 (m, 2H), 2.73e2.57 (m, 2H), 2.55 (d, 1H, J¼6.4 Hz),
13
a-
L
2.24 (br s, 1H), 1.29 (t, 3H, J¼7.6 Hz). C NMR (100 MHz, CDCl
3
):
d
137.3, 137.0, 133.8, 128.50, 128.46, 128.1, 128.03, 128.00, 127.9, 88.0,
Prepared from glycoside 9b (420 mg, 1.41 mmol), 4-
dimethylaminopyridine (34 mg, 0.28 mmol), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (675 mg, 3.52 mmol), and 2-
87.8, 83.5, 81.7, 72.4, 72.0, 70.9, 64.6, 25.5, 14.9; HRMS (ESI): m/z
þ
calcd for C22
H
28
O
5
SNa [MþNa] : 427.1557, found: 427.1567.
quinoline carboxylic acid (488 mg, 2.82 mmol) in CH
2
Cl
2
(14 mL)
4.12. Ethyl 2,3-di-O-benzyl-6-O-tert-butyldimethylsilyl-1-
thio- -galactofuranoside (13)
following the procedure similar to that for 9a/3a. The crude
product was purified by silica gel column chromatograph (10:1,
petroleum ethereEtOAc) to give compound 3b (559 mg, 88%) as
b-D
To a stirred solution of compound 12 (5.135 g, 12.71 mmol) in
2
0
a colorless syrup. 3b: R
f
¼0.24 (5:1, petroleum ethereEtOAc); [
a
]
D
dry acetonitrile (64 mL) were added 1,4-diazabicyclo(2.2.2)octane
1
ꢀ
ꢁ
87.1 (c 0.9, CHCl
J¼8.4 Hz), 8.16 (s, 2H), 7.86 (d, 1H, J¼7.8 Hz), 7.78 (t, 1H, J¼7.8 Hz),
.65 (t, 1H, J¼7.2 Hz), 7.36e7.27 (m, 5H), 5.47 (d, 1H, J¼2.4 Hz), 4.74
dd, 1H, J¼12.0, 3.6 Hz), 4.69 (dd, 1H, J¼12.0, 3.6 Hz), 4.66 (d, 1H,
3
); H NMR (600 MHz, CDCl
3
):
d
8.30 (d, 1H,
(2.85 g, 25.45 mmol) and TBSCl (2.5 g, 16.59 mmol) at 0 C. The
reaction mixture was warmed to room temperature and stirred for
5 h, at the end of which time TLC indicated it was finished. The
reaction was diluted with acetonitrile, filtered, and concentrated.
The obtained residue was purified by silica gel column chroma-
tography (20:1, petroleum ethereEtOAc to afford compound 13
7
(
J¼12.0 Hz), 4.57 (d, 1H, J¼12.0 Hz), 4.50 (dd, 1H, J¼9.6, 5.4 Hz), 3.98
(t, 1H, J¼2.4 Hz), 3.87 (dd, 1H, J¼6.0, 2.4 Hz), 3.41 (s, 3H), 2.77e2.71
(
(
13
m, 1H), 2.70e2.64 (m, 1H), 1.31 (t, 3H, J¼7.5 Hz); C NMR
100 MHz, CDCl ): 164.8, 147.6, 147.5, 137.1, 130.7, 130.1, 129.2,
(5.823 g, 91%) as a colorless syrup. 13: R
f
¼0.68 (5:1, petroleum
2
0
1
3
d
ethereEtOAc); [
a
]
D
ꢁ103.3 (c 1.15, CHCl
3
); H NMR (600 MHz,
128.5, 128.4, 127.8, 127.4, 121.1, 88.1, 87.3, 86.3, 79.0, 72.0, 64.8, 58.1,
CDCl ):
3
d
7.37e7.25 (m, 10H), 5.39 (d, 1H, J¼1.4 Hz), 4.61 (d, 1H,
þ
2
4
5.2, 14.8; HRMS (ESI): m/z calcd for C25
76.1510, found: 476.1484.
H27NO
5
SNa [MþNa] :
J¼11.4 Hz), 4.59 (d, 1H, J¼12.6 Hz), 4.53 (d, 1H, J¼12.0 Hz), 4.49 (d,
1H, J¼12.0 Hz), 4.24 (dd, 1H, J¼6.6, 2.4 Hz), 4.13 (dd, 1H, J¼6.0,
2.4 Hz), 3.97 (t, 1H, J¼2.2 Hz), 3.78 (s, 1H), 3.67 (dd, 1H, J¼9.8,
4
.10. Ethyl 5,6-O-isopropylidene-1-thio-
b
-D-galactofurano-
7.2 Hz), 3.61 (dd, 1H, J¼9.9, 6.0 Hz), 2.73e2.67 (m, 1H), 2.65e2.60
(m, 1H), 2.44 (d, 1H, J¼5.4 Hz), 1.29 (t, 3H, J¼7.4 Hz), 0.89 (s, 9H),
side (11)
13
0
3
.06 (s, 6H); C NMR (100 MHz, CDCl ): d 137.6, 137.2, 128.41,
To a solution of compound 10 (5.46 g, 24.38 mmol) in dry ace-
128.36, 128.0, 127.9, 127.8, 88.1, 87.5, 83.4, 80.1, 72.3, 71.8, 71.0, 64.2,
tone (164 mL) were added 2,2-dimethoxypropane (6 mL,
25.8, 25.3, 18.2, 14.8, ꢁ5.4, ꢁ5.5; HRMS (ESI): m/z calcd for
þ
4
8.80 mmol) and p-toluenesulfonic acid (0.93 g, 4.89 mmol) at
C
28
H
42
O
5
SSiNa [MþNa] : 541.2422, found: 541.2467.

3120
K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
4
.13. Ethyl 2,3-di-O-benzyl-5-O-(2-quinolinecarbonyl)-6-O-
4.16. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2-O-(2-
naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-
arabinofuranosyl]- -proline methyl ester (16)
tert-butyldimethylsilyl-1-thio- -galactofuranoside (4)
b-
D
b-L-
D
Prepared from glycoside 13 (5.823 g, 11.24 mmol), 4-
dimethylaminopyridine (137 mg, 1.12 mmol), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (4.3 g, 22.43 mmol), and 2-
A mixture of a glycosyl donor 3a (1.468 mg, 2.53 mmol),
glycosyl acceptor 5 (0.618 g, 2.52 mmol), and freshly activated
ꢁ
quinoline carboxylic acid (3.893 g, 22.48 mmol) in CH
112 mL) following the procedure similar to that for 9a/3a. The
crude product was purified by silica gel column chromatograph
2
Cl
2
4 A molecular sieves (4.17 g) in dry ClCH
2
CH
2
Cl (361 mL) was
(
stirred under nitrogen for 1 h. The mixture was cooled to
ꢀ
ꢁ30 C, then NIS (1.14 g, 5.07 mmol) and TfOH (45
mL,
(
8:1, petroleum ethereEtOAc) to give compound 4 (7.11 g, 94%) as
0.51 mmol) were added and the resulting mixture was gradually
warmed to 0 C. The reaction mixture was stirred for 1.5 h at
the same temperature, at the end of which time TLC indicated it
2
0
ꢀ
a colorless syrup. 4: R
ꢁ
f
¼0.22 (10:1, petroleum ethereEtOAc); [
a
]
D
1
3 3
72.6 (c 0.95, CHCl ); H NMR (400 MHz, CDCl ): d 8.30 (d, 1H,
J¼8.4 Hz), 8.06 (q, 2H, J¼8.4 Hz), 7.82 (d, 1H, J¼8.0 Hz), 7.77 (t, 1H,
J¼7.6 Hz), 7.63 (t, 1H, J¼7.6 Hz), 7.32e7.16 (m, 10H), 5.53 (dt, 1H,
J¼6.4, 2.8 Hz), 5.49 (d, 1H, J¼2.0 Hz), 4.60e4.54 (m, 4H), 4.41 (d, 1H,
J¼11.6 Hz), 4.07 (dd, 1H, J¼6.4, 2.4 Hz), 4.00 (t, 1H, J¼2.8 Hz), 3.97
was finished. Then the reaction was quenched with Et
3
N, diluted
with CH Cl , filtered, and concentrated in vacuo. The obtained
2
2
residue was purified by silica gel column chromatography (3:1,
petroleum ethereEtOAc) to afford 16 (1.65 g, 86%) as a colorless
2
0
(
2
dd, 1H, J¼10.0, 6.4 Hz), 3.91 (dd, 1H, J¼10.0, 6.4 Hz), 2.78e2.60 (m,
syrup. 16: R
f
¼0.32 (1:1, petroleum ethereEtOAc); [
a
]
D
þ53.2 (c
13
1
H), 1.32 (t, 3H, J¼7.4 Hz), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H);
): 164.4, 147.66, 147.63, 137.4, 137.2, 137.0,
30.8, 130.1, 129.2, 128.4, 128.31, 128.27, 127.9, 127.8, 127.7, 127.4,
C
1.0, CHCl ); H NMR (600 MHz, CDCl ): d 8.27e8.25 (m, 2H),
3
3
NMR (100 MHz, CDCl
1
3
d
8.16 (8.13) (d, 1H, J¼7.8 Hz), 7.88e7.74 (m, 6H), 7.64 (q, 1H,
J¼7.2 Hz), 7.51e7.48 (m, 3H), 7.31e7.20 (m, 5H), 4.95 (4.93)* (d,
0
1
21.2, 88.7, 87.3, 83.4, 79.0, 74.0, 72.5, 71.9, 61.2, 25.7, 25.3, 14.9,
1H, J¼4.8 Hz, H1 -Araf), 4.81e4.72 (m, 4H), 4.63e4.48 (m, 2H),
þ
ꢁ
5.4, ꢁ5.5; HRMS (ESI): m/z calcd for C38
H47NO
6
SSiNa [MþNa] :
4.40e4.29 (m, 4H), 4.17 (dd, 1H, J¼6.6, 4.8 Hz), 3.77e3.50 (m,
2H), 3.73 (3.71) (s, 3H), 2.31e2.27 (2.20e2.15) (m, 1H),
6
96.2793, found: 696.2769.
13
2
.06e1.98 (m, 1H), 1.38 (1.37) (s, 9H); C NMR (100 MHz,
CDCl ): 173.4 (173.1)*, 164.8 (164.7), 154.2 (153.4), 147.6
147.4), 137.7, 137.24 (137.20), 134.9 (134.7), 133.10 (133.08),
33.0, 130.7, 130.3 (130.2), 129.3, 128.7 (128.5), 128.4, 128.3,
27.9, 127.7, 127.4, 127.1 (126.9), 126.28 (126.25), 126.2 (126.1),
26.0 (125.9), 121.2 (121.0), 99.5 (99.4), 84.0 (83.8), 82.6 (82.4),
3
d
4
.14. N-tert-Butoxycarbonyl-trans-4-(4-nitrobenzoyloxy)-D-
(
1
1
1
8
5
proline methyl ester (15)
To a solution of compound 14 (6.83 g, 27.84 mmol) in anhydrous
THF (137 mL) were added Ph
3
P (11 g, 41.94 mmol), 4-nitrobenzoic
0.2 (80.1), 78.8 (78.6), 74.7 (74.9), 72.8 (72.9), 72.7, 67.0 (66.9),
ꢀ
acid (5.6 g, 33.51 mmol), and DEAD (6.6 mL, 41.92 mmol) at 0 C.
The reaction mixture was stirred overnight at room temperature, at
the end of which time TLC indicated it was finished. The white
precipitate was filtered and the solvent was removed in vacuo. The
obtained residue was purified by silica gel column chromatography
7.7 (57.3), 52.2 (52.0), 35.9 (34.7), 29.6, 28.1 (28.2); HRMS (ESI):
þ
m/z calcd for
C
44
H
46
N
2
O
10Na [MþNa] : 785.3052, found:
7
85.3057. *Values in parentheses signify a second signal due to
a minor rotamer.
(
8:1, petroleum ethereEtOAc) to afford compound 15 (9.74 g, 92%)
4
.17. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[3-O-ben-
1
as a colorless oil. 15: R
NMR (400 MHz, CDCl ):
f
¼0.65 (2:1, petroleum ethereEtOAc);
H
zyl-5-O-(2-quinolinecarbonyl)-b-L-arabinofuranosyl]-D-pro-
line methyl ester (17)
3
d
8.31 (d, 2H, J¼8.8 Hz), 8.20 (d, 2H,
J¼8.4 Hz), 5.58 (d, 1H, J¼2.4 Hz), 4.46 (4.53)* (t, 1H, J¼8.0 Hz),
3
1
.95e3.70 (m, 2H), 3.79 (s, 3H), 2.65e2.52 (m, 1H), 2.42e2.23 (m,
H), 1.44 (1.47) (s, 9H); 13C NMR (100 MHz, CDCl
): 172.8 (172.6)*,
To a stirred solution of compound 16 (2.732 g, 3.58 mmol)
in CH Cl (45 mL) containing a small amount of H O (2 mL)
was added 2,3-dichloro-5,6-dicyanoquinone (DDQ, 2.43 g,
0.7 mmol) at room temperature. The reaction mixture was
vigorously stirred for 3 h. Then the reaction mixture was di-
luted with CH Cl and washed with 10% aqueous Na SO , sat-
urated aqueous NaHCO and brine. The organic layer was
separated and dried over anhydrous Na SO , filtered, and con-
3
d
2
2
2
1
(
*
64.0 (163.9), 153.5 (150.6), 134.9, 130.7, 123.5, 80.72 (80.68), 73.6
74.2), 57.8 (57.4), 52.4 (52.2), 52.1 (51.9), 36.5 (35.5), 28.2 (28.1).
Values in parentheses signify a second signal due to a minor
rotamer.
1
2
2
2
3
3
4
.15. N-tert-Butoxycarbonyl-trans-4-hydroxy-
D
-proline
2
4
methyl ester (5)
centrated. The obtained residue was purified by silica gel col-
umn chromatography (2:1, petroleum ethereEtOAc) to afford
To a solution of compound 15 (4.45 g, 11.7 mmol) in anhydrous
compound 17 (1.937 g, 86%) as a colorless syrup. 17: R
f
¼0.235
ꢀ
20
1
MeOH (59 mL) was added CH
3
ONa (0.5 g, 9.26 mmol) at 0 C. The
(1:1, petroleum ethereEtOAc); [
a
]
D
þ36.7 (c 1.0, CHCl
3
);
H
reaction mixture was stirred for 30 min at the same temperature, at
NMR (400 MHz, CDCl ): 8.34e8.27 (m, 2H), 8.17 (t, 1H,
3
d
the end of which time TLC indicated it was finished. The reaction
was neutralized with Amberlite IR-120 H resin. After filtration, the
J¼7.6 Hz), 7.90 (d, 1H, J¼8.0 Hz), 7.80 (s, 1H), 7.67 (t, 1H,
þ
0
J¼6.0 Hz), 7.36e7.23 (m, 5H), 5.20 (t, 1H, J¼4.8 Hz, H1 -Araf),
filtrate was concentrated in vacuo. The obtained residue was pu-
rified by silica gel column chromatography (1.5:1, petroleum
ethereEtOAc) to give compound 5 (2.58 g, 90%) as a colorless syrup.
4.81 (dd, 1H, J¼11.2, 8.0 Hz), 4.67 (d, 1H, J¼11.6 Hz), 4.60e4.56
(m, 1H), 4.52e4.46 (m, 2H), 4.39 (d, 2H, J¼4.0 Hz), 4.15e4.05
(m, 2H), 3.74e3.39 (m, 2H), 3.67 (3.65)* (s, 2H), 2.25e2.20
2
2
13
5
: R
f
¼0.21 (1:1, petroleum ethereEtOAc); [
a
]
D
þ108 (c 1.0, EtOH);
(2.18e2.10) (m, 1H), 2.04e1.97 (m, 1H), 1.36 (1.37) (s, 9H);
NMR (100 MHz, CDCl ):
C
1
H NMR (600 MHz, CDCl ): 4.47 (s, 1H), 4.39 (4.44)* (t, 1H,
3
d
3
d
173.2 (173.0), 164.6 (154.0), 147.4
J¼7.8 Hz), 3.74 (3.73) (s, 3H), 3.64e3.59 (m, 1H), 3.54 (3.45) (d, 1H,
(147.2), 137.5, 130.5 (130.4), 129.4, 128.84 (128.76), 128.4, 127.8,
127.7, 127.5, 121.0 (120.9), 101.1 (101.4)*, 85.7 (85.5), 80.3, 80.0
(79.9), 78.0 (77.9), 75.9, 75.2, 71.9, 66.7 (66.6), 57.5 (57.1), 54.7,
J¼10.8 Hz), 3.0 (2.9) (s 1H), 2.33e2.22 (m, 1H), 2.10e2.02 (m, 1H),
1
1
.46 (1.41) (s, 9H); The specific rotation and H NMR data corre-
16a 13
sponded to the literature values.
C NMR (100 MHz, CDCl
3
):
52.3 (52.2), 52.0, 35.9 (35.0), 29.7, 28.1 (28.2); HRMS (ESI): m/z
þ
d
173.7 (173.5)*, 154.0 (154.5), 80.3 (80.2), 69.0 (69.8), 57.9 (57.4),
4.5 (54.6), 52.0 (52.2), 38.9 (38.3), 28.1 (28.2). *Values in paren-
calcd for C33
H
38
N
2
O
10Na [MþNa] : 645.2426, found: 645.2432.
5
*Values in parentheses signify a second signal due to a minor
rotamer.
theses signify a second signal due to a minor rotamer.

K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
3121
þ
4
.18. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2-O-(2-
HRMS (ESI): m/z calcd for C55
H
57
N
3
O
15Na [MþNa] : 1022.3690,
naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-
arabinofuranosyl-(1/2)-3-O-benzyl-5-O-(2-
b-
L
-
found: 1022.3696. *Values in parentheses signify a second signal
due to a minor rotamer.
quinolinecarbonyl)-b-L-arabinofuranosyl]-D-proline methyl
ester (18)
4.20. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2,3-di-O-
benzyl-5-O-(2-quinolinecarbonyl)-6-O-tert-butyldime-
A mixture of a glycosyl donor 3a (3 g, 5.18 mmol), glycosyl ac-
ceptor 17 (1.776 g, 2.85 mmol), and freshly activated 4 A molecular
thylsilyl-
quinolinecarbonyl)-b-L
a
-
D
-galactofuranosyl-(1/2)-3-O-benzyl-5-O-(2-
-arabinofuranosyl-(1/2)-3-O-benzyl-
ꢁ
sieves (7.8 g) in dry ClCH
2
CH
2
Cl (530 mL) was stirred under ni-
5-O-(2-quinolinecarbonyl)-b-L-arabinofuranosyl]-D-proline
methyl ester (20)
ꢀ
trogen for 1 h. The mixture was cooled to ꢁ30 C, then NIS (2.33 g,
10.36 mmol) and TfOH (92
m
L, 1.04
m
mol) were added and the
ꢀ
resulting mixture was gradually warmed to 0 C. The reaction
mixture was stirred for 1 h at the same temperature. Then it was
A mixture of a glycosyl donor 4 (519 mg, 0.77 mmol), glycosyl
ꢁ
acceptor 19 (386 mg, 0.386 mmol), and freshly activated 4 A mo-
quenched with Et
trated in vacuo. The obtained residue was purified by silica gel
column chromatography (2:1, petroleum ethereEtOAc) to afford 18
3
N, diluted with CH
2
Cl
2
, filtered, and concen-
lecular sieves (2 g) in dry ClCH
2
CH
2
Cl (70 mL) was stirred under
ꢀ
nitrogen for 1 h. The mixture was cooled to ꢁ30 C, then NIS
(347 mg, 1.54 mmol) and TfOH (13.6 mL, 0.154 mmol) were added
(
2.401 g, 74%) as a colorless syrup. 18: R
f
¼0.23 (1:1, petroleum
and the resulting mixture was gradually warmed to room tem-
perature. The reaction mixture was stirred for 2 h at the same
temperature. Then it was quenched with Et N, diluted with CH Cl ,
3 2 2
filtered, and concentrated in vacuo. The obtained residue was pu-
rified by silica gel column chromatography (3:2, petroleum ether-
20
1
ethereEtOAc); [
a
]
D
þ32.5 (c 1.15, CHCl
3
); H NMR (600 MHz,
CDCl
H, J¼8.4 Hz), 8.09 (d, 1H, J¼8.4 Hz), 8.06 (8.04) (d, 1H, J¼8.4 Hz),
.83e7.78 (m, 6H), 7.76e7.73 (m, 2H), 7.64e7.60 (m, 2H), 7.54 (t, 1H,
J¼8.4 Hz), 7.47e7.44 (m, 2H), 7.32e7.28 (m, 2H), 7.24e7.21 (m, 5H),
3
):
d
8.23 (d, 2H, J¼8.4 Hz), 8.19 (d, 1H, J¼8.4 Hz), 8.14 (8.12) (d,
1
7
eEtOAc) to afford the major
a colorless syrup. 20: R
¼0.47 (1:1.5, petroleum ethereEtOAc); [
); H NMR (600 MHz, CDCl ): 8.30e8.25 (m, 2H),
a-isomer 20 (317 mg, 51%) as
00
20
7
.12e7.06 (m, 3H), 5.30 (t, 1H, J¼4.2 Hz, H1 -Araf), 5.24 (5.23)* (d,
f
a]
D
0
1
1
1
5
H, J¼4.2 Hz, H1 -Araf), 4.94 (dd, 1H, J¼10.8, 8.4 Hz), 4.79 (4.78) (d,
þ31.3 (c 1.1, CHCl
3
3
d
H, J¼3.9 Hz), 4.77e4.72 (m, 2H), 4.69e4.63 (m, 4H), 4.57e4.43 (m,
H), 4.37e4.24 (m, 5H), 3.72 (d, 1H, J¼4.2 Hz), 3.70 (3.47) (dd, 1H,
8.24e8.16 (m, 5H), 8.09e8.02 (m, 2H), 7.85 (t, 1H, J¼8.4 Hz), 7.79 (d,
1H, J¼8.4 Hz), 7.78e7.72 (m, 3H), 7.64 (q, 2H, J¼7.2 Hz), 7.59 (t, 1H,
J¼7.2 Hz), 7.40 (d, 2H, J¼7.8 Hz), 7.33 (d, 2H, J¼7.2 Hz), 7.29e7.13 (m,
J¼11.4, 4.2 Hz), 3.69 (3.67) (s, 3H), 2.37e2.32 (2.26e2.20) (m, 1H),
13
000 000
7H), 7.13e7.03 (m, 8H), 5.55e5.50 (m, 2H, H1 -Galf, H5 -Galf), 5.18
2
d
.12e2.02 (m, 1H), 1.29 (1.23) (s, 9H); C NMR (100 MHz, CDCl
3
):
0
0
0
173.2 (172.9)*, 164.8, 164.63 (164.61), 154.1 (153.3), 147.55
147.48), 137.7 (137.5), 137.2, 135.1 (135.0), 133.2 (133.0), 130.70
130.68), 130.2, 130.1, 129.2, 128.6, 128.5, 128.32, 128.27, 127.9, 127.8,
27.7, 127.6, 127.4, 126.80 (126.75), 126.1, 126.0, 125.9, 121.1, 121.0,
20.9, 99.4, 99.3, 83.9, 82.8, 81.9 (81.6), 80.2, 79.4, 79.3 (79.1), 74.9
74.7), 72.6 (72.5), 72.0, 66.5 (67.3), 57.7 (57.3), 52.2 (52.0), 35.7
34.6), 28.1; HRMS (ESI): m/z calcd for C66
162.4316, found: 1162.4323. *Values in parentheses signify a sec-
(d, 1H, J¼3.8 Hz, H1 -Araf), 5.14 (t, 1H, J¼4.2 Hz, H1 -Araf), 4.93 (d,
1H, J¼10.8 Hz), 4.84 (d, 1H, J¼11.4 Hz), 4.74 (dd, 1H, J¼10.8, 7.2 Hz),
4.70 (d, 1H, J¼11.4 Hz), 4.64 (d, 2H, J¼13.2 Hz), 4.60e4.54 (m, 1H),
4.53e4.42 (m, 6H), 4.42e4.33 (m, 4H), 4.32e4.25 (m, 4H),
4.24e4.17 (m, 1H), 4.02e3.88 (m, 3H), 3.84 (3.81) (dd, 1H, J¼11.4,
5.4 Hz), 3.49 (3.71) (dd, 1H, J¼12.0, 2.4 Hz), 3.68 (3.66) (s, 3H),
2.23e2.22 (2.20e2.13)* (m, 1H), 2.11e2.04 (m, 1H), 1.40 (1.36) (s,
(
(
1
1
(
(
þ
H
65
N
3
O
15Na [MþNa] :
1
3
1
9H), 0.79 (0.78) (s, 9H), ꢁ0.04 to 0.00 (m, 6H); C NMR (100 MHz,
CDCl ): 173.3 (172.9)*, 164.8, 164.6, 164.5, 154.1 (153.4), 148.0,
47.7, 147.63 (147.59), 147.5 (147.3), 138.1 (138.0), 137.9 (137.8),
ond signal due to a minor rotamer.
3
d
1
4
.19. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[3-O-ben-
zyl-5-O-(2-quinolinecarbonyl)- -arabinofuranosyl-(1/2)-
-O-benzyl-5-O-(2-quinolinecarbonyl)- -arabinofuranosyl]-
-proline methyl ester (19)
137.6, 137.5 (137.4), 137.2, 137.1, 137.0, 130.8, 130.7, 130.3, 130.2,
130.0, 129.3, 129.2, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0,
127.7, 127.6, 127.5, 121.3, 121.1, 121.0, 99.1 (C1-Araf ), 99.0 (98.9) (C1-
b-L
0
3
D
b
-L
Araf), 97.9 (97.8) (C1-Galf), 84.1 (83.7), 83.0 (82.8), 81.3 (81.2), 80.7
(80.5), 80.4, 79.4, 79.04 (78.96), 78.9, 78.7 (78.6), 77.3 (77.1), 75.1
Prepared from glycoside 18 (1.787 g, 1.57 mmol), 2,3-dichloro-
,6-dicyanoquinone (DDQ, 1.066 g, 4.70 mmol) in CH Cl (20 mL)
O (1 mL) following the procedure
similar to that for 16/17. The crude product was purified by silica
gel column chromatograph (2:1, petroleum ethereEtOAc) to give
(74.6), 72.9, 72.3, 71.8, 71.6 (71.5), 67.4, 66.8, 61.7 (61.5), 57.6 (57.1),
5
2
2
52.4, 52.2 (52.1), 36.1 (34.8), 28.2 (28.3), 18.1, ꢁ5.4; HRMS (ESI): m/z
þ
containing a small amount of H
2
calcd for C91
98
H N
4
O
21SiNa [MþNa] : 1633.6393, found: 1633.6421.
*Values in parentheses signify a second signal due to a minor
rotamer.
compound 19 (1.1 g, 70%) as a colorless syrup. 19: R
f
¼0.47 (1:2,
2
0
1
petroleum ethereEtOAc); [
a
]
D
þ41.4 (c 1.3, CHCl
3
); H NMR
4.21. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2,3-di-O-
(
(
(
(
600 MHz, CDCl
3
):
d
8.28e8.24 (m, 3H), 8.17 (q, 1H, J¼4.2 Hz), 8.12
benzyl-6-O-tert-butyldimethylsilyl-
(1/2)-3-O-benzyl-5-O-tert-butyldimethylsilyl-
furanosyl-(1/2)-3-O-benzyl-5-O-tert-butyldimethylsilyl-
arabinofuranosyl]- -proline methyl ester (21)
a
-
D
-galactofuranosyl-
q, 1H, J¼8.4 Hz), 8.02 (d, 1H, J¼8.0 Hz), 7.87 (d, 1H, J¼7.8 Hz), 7.81
d, 1H, J¼8.4 Hz), 7.79e7.74 (m, 2H), 7.67e7.60 (m, 2H), 7.35e7.07
m,10H), 5.15 (d,1H, J¼4.2 Hz), 5.12 (5.14)* (d,1H, J¼4.2 Hz), 4.85 (d,
b-L-arabino-
b-L-
D
1
H, J¼11.4 Hz), 4.75 (t, 1H, J¼11.4 Hz), 4.70 (d, 1H, J¼12.0 Hz), 4.62
(
dd, 1H, J¼12.0, 4.5 Hz), 4.59e4.55 (m, 2H), 4.53 (dd, 1H, J¼11.4,
To a solution of compound 20 (500 mg, 0.31 mmol) in anhydrous
MeOH (10 mL) was added CH ONa (50 mg, 0.93 mmol). The re-
7.2 Hz), 4.50e4.48 (m, 2H), 4.46e4.41 (m, 2H), 4.40e4.34 (m, 3H),
3
4
.22 (4.26) (t, 1H, J¼6.0 Hz), 4.07 (t, 1H, J¼5.7 Hz), 3.76e3.49 (m,
action mixture was stirred for 5 h at room temperature. Then the
reaction was neutralized with Amberlite IR-120 H resin, filtered,
þ
2
H), 3.71 (3.72) (s, 3H), 2.38e2.33 (2.27e2.23) (m, 1H), 2.16e2.06
1
3
(
(
1
1
m, 1H), 1.41 (1.40) (s, 9H); C NMR (100 MHz, CDCl
173.0)*, 164.74, 163,69, 154.1 (153.5), 147.6 (147.4), 147.3, 137.6,
37.3, 137.2 (137.1), 130.7 (130.6), 130.3 (130.2), 129.3 (129.2),
28.65, 128.59, 128.3, 128.2, 127.72 (127.70), 127.6, 127.5 (127.4),
21.1 (121.0), 120.9, 103.1 (103.0), 99.5 (99.1), 84.4, 82.5 (82.4), 82.2,
3
):
d
173.3
and concentrated in vacuo. The obtained residue was purified by
silica gel column chromatography (1:1.5, petroleum ethereEtOAc)
to afford a colorless syrup. To a solution of the obtained syrup
(242 mg, 0.211 mmol) in dry acetonitrile (4.2 mL) were added 1,4-
diazabicyclo(2.2.2)octane (236 mg, 2.11 mmol) and TBSCl (254 mg,
1
ꢀ
8
6
0.3 (80.2), 79.7, 79.2 (79.1), 77.7 (77.6), 75.3 (74.7), 72.5 (72.0), 67.1,
6.4 (66.3), 57.6 (57.1), 53.4, 52.2 (52.1), 35.5 (34.6), 28.23 (28.17);
1.69 mmol) at 0 C. The reaction mixture was warmed to room
temperature and stirred overnight. Then the reaction was filtered,

3122
K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
þ
and the filtrates were concentrated to give a residue, which was
purified by silica gel column chromatography (10:1, petroleum
ethereEtOAc) to afford compound 21 (210 mg, 72% for two steps) as
[MþNa] : 1787.8429, found: 1787.8411. *Values in parentheses
signify a second signal due to a minor rotamer.
2
0
a colorless syrup. 21: R
f
¼0.34 (5:1, petroleum ethereEtOAc); [
a
]
D
4.23. trans-4-Hydroxy-4-O-[
arabinofuranosyl-(1/2)- -arabinofuranosyl]-D
a
-D
-galactofuranosyl-(1/2)-
b-L-
1
þ88.8 (c 1.2, CHCl
3
); H NMR (600 MHz, CDCl ): 7.41e7.38 (m, 4H),
.32e7.22 (m, 14H), 7.17e7.13 (m, 2H), 5.29 (5.33)* (d, 1H, J¼4.2 Hz),
3
d
b-L
-proline (1)
7
5.12e5.07 (m, 2H), 4.88 (t, 1H, J¼9.9 Hz), 4.80 (d, 1H, J¼11.4 Hz),
4.72 (d,1H, J¼12.0 Hz), 4.68 (dd, J¼11.4, 4.8 Hz,1H), 4.62 (dd, J¼11.4,
3.6 Hz, 1H), 4.53e4.42 (m, 4H), 4.40e4.29 (m, 3H), 4.27e4.19 (m,
2H), 4.15e4.13 (m, 2H), 4.08e4.03 (m, 1H), 3.94e3.76 (m, 3H), 3.74
To a solution of compound 20 (280 mg, 0.17 mmol) in MeOH
(7 mL) was added CH ONa (35 mg, 0.65 mmol). The reaction mix-
ture was stirred for 5 h at room temperature, at the end of which
time TLC indicated it was finished. Then the reaction was neutral-
ized with Amberlite IR-120 H resin, filtered, and concentrated in
3
þ
(
s, 3H), 3.70e3.64 (m, 2H), 3.62e3.50 (m, 5H), 3.45e3.41 (m, 1H),
2
0
CDCl
.77 (t, 1H, J¼4.8 Hz), 2.28e2.10 (m, 2H), 1.47 (1.42) (s, 9H),
vacuo. The obtained residue was purified by silica gel column
chromatography (1:1.5, petroleum ethereEtOAc) to afford a color-
13
.89e0.83 (m, 27H), 0.08e0.04 (m, 18H); C NMR (100 MHz,
): 173.3 (172.9)*, 153.1 (154.5), 138.2, 138.1, 137.8, 128.4,
28.3, 128.2, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 98.9
3
d
less syrup. To a solution of this obtained syrup (192 mg,
ꢀ
1
0.167 mmol) in CH
2
Cl
2
(7 mL) was added TFA (3.5 mL) at 0 C. The
(
(
7
(
(
C
97.99), 97.96 (97.9), 97.2 (97.6), 84.2 (83.9), 83.4 (83.1), 82.9, 82.8
82.7), 82.3 (82.2), 81.1, 80.8 (80.7), 79.6 (79.5), 79.1 (78.9), 74.8,
3.5, 72.6, 72.24 (72.2), 71.93 (71.86), 71.4, 65.6, 65.5 (65.2), 63.7
reaction mixture was stirred for 1 h at the same temperature. Then
the reaction was diluted with CHCl and washed with saturated
aqueous NaHCO . The organic layer was separated and dried over
anhydrous Na SO , filtered, and concentrated. The obtained residue
was purified by silica gel column chromatography (50:1, DCM-
MeOH) to afford a colorless syrup. The obtained syrup was dis-
solved in a mixture of 1 M aqueous NaOH, dioxane and methanol
3
3
63.6), 57.7 (57.1), 52.4 (52.3), 52.1 (52.0), 35.8 (35.0), 29.7, 28.4
2
4
28.2), 25.9, 22.7, 14.1, 18.3 (18.2), ꢁ5.4; HRMS (ESI): m/z calcd for
þ
73
H111NO18Si
3
Na [MþNa] : 1396.7009, found: 1396.7015. *Values
in parentheses signify a second signal due to a minor rotamer.
(1/3/1, v/v/v, 4.0 mL). The reaction mixture was stirred for 1 h at the
room temperature. Then the resulting mixture was neutralized
þ
4
.22. N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2-O-ben-
zyl-3-O-methyl-5-O-(2-quinolinecarbonyl)- -arabinofur-
anosyl-(1/5)-2,3-di-O-benzyl-6-O-tert-butyldimethylsilyl-
-galactofuranosyl-(1/2)-3-O-benzyl-5-O-tert-butyldime-
thylsilyl- -arabinofuranosyl-(1/2)-3-O-benzyl-5-O-tert-
with Amberlite IR-120 H resin, filtered. The filtrates were con-
b-L
centrated to give a residue, which was directly used for the next
step without further purification. To a solution of the obtained
a
-
D
residue in MeOHeH
Pd/C (150 mg). The reaction mixture was stirred under an atmo-
sphere of H for 48 h. The catalyst was then filtered-off, washed
with MeOH and H O, and the filtrate was concentrated under re-
duced pressure. The obtained residue was purified by column
chromatography on Sephadex LH-20 (CH OH) to afford compound
1 (38 mg, 40% for four steps) as a colorless oil; 1: [
2
OeHOAc (5 mL/1 mL/0.1 mL) was added 10%
b-L
butyldimethylsilyl-
ester (22)
b-L
-arabinofuranosyl]-D-proline methyl
2
2
A mixture of glycosyl donor 3b (206 mg, 0.454 mmol), glycosyl
3
ꢁ
20
acceptor 21 (256 mg, 0.186 mmol), and freshly activated 4 A mo-
lecular sieves (1 g) in dry ClCH
a]
D
þ129.4 (c 0.5,
1
0
2
CH
2
Cl (57 mL) was stirred under
CH
3
OH); H NMR (600 MHz, D
2
O):
d
5.23 (d,1H, J¼4.2 Hz, H1 -Araf),
ꢀ
00
000
nitrogen for 1 h. The mixture was cooled to ꢁ30 C, then NIS
5.15 (d, 1H, J¼4.2 Hz, H1 -Araf), 5.05 (d, 1H, J¼4.8 Hz, H1 -Galf),
4.57 (t, 1H, J¼3.6 Hz), 4.25 (t, 1H, J¼4.5 Hz), 4.24 (t, 1H, J¼4.2 Hz),
4.22e4.17 (m, 2H), 4.16 (d, 1H, J¼7.2 Hz), 4.14 (t, 1H, J¼7.8 Hz), 4.09
(dd, 1H, J¼8.4, 4.2 Hz), 3.91e3.88 (m, 1H), 3.85e3.81 (m, 1H), 3.77
(dd, 1H, J¼7.2, 4.8 Hz), 3.76e3.72 (m, 2H), 3.72e3.70 (m, 1H), 3.65
(dd, 1H, J¼12.0, 6.4 Hz), 3.63 (dd, 1H, J¼12.0, 4.2 Hz), 3.60 (dd, 1H,
J¼12.6, 5.4 Hz), 3.56e3.51 (m, 2H), 3.43 (dd, 1H, J¼12.6, 4.2 Hz),
(
204 mg, 0.907 mmol) and TfOH (8
mL, 0.09
m
mol) were added and
ꢀ
the resulting mixture was gradually warmed to 0 C. The reaction
was stirred for 1.5 h at the same temperature. Then it was quenched
with Et N, diluted with CH Cl , filtered, and concentrated in vacuo.
3 2 2
The obtained residue was purified by silica gel column chroma-
tography (3:1, petroleum ethereEtOAc) to afford 22 (316 mg, 96%)
13
as a colorless syrup. 22: R
f
¼0.34 (2:1, petroleum ethereEtOAc);
); H NMR (600 MHz, CDCl ): 8.30 (d, 1H,
J¼8.4 Hz), 8.25 (t, 1H, J¼7.8 Hz), 8.17 (8.16) (d, 1H, J¼8.4 Hz), 7.86 (d,
H, J¼8.4 Hz), 7.78 (ddd, 1H, J¼8.4, 6.6, 1.2 Hz), 7.66 (t, 1H, J¼7.2 Hz),
.40 (t, 4H, J¼7.8 Hz), 7.35 (d, 2H, J¼7.2 Hz), 7.33e7.20 (m, 18H),
2.49e2.44 (m, 1H), 2.11e2.05 (m, 1H); C NMR (150 MHz, D
2
O):
175.8, 101.8 (C1 -Galf), 100.2 (C1 -Araf), 99.9 (C1 -Araf), 83.6,
83.2, 82.90, 82.86, 81.5, 78.2, 78.1, 75.7, 74.3, 73.7, 73.4, 64.5, 64.3,
2
0
1
000
00
0
[
a
]
D
þ78 (c 1.2, CHCl
3
3
d
d
1
7
63.7, 61.8, 53.3, 36.8; HRMS (ESI): m/z calcd for C21
[MþNa] : 580.1856, found: 580.1908.
H35NO16Na
þ
0000
7
1
4
.10e7.05 (m, 2H), 5.52 (5.50)* (d, 1H, J¼4.2 Hz, H1 -Araf), 5.40 (d,
0
00
0
00
H, J¼4.2 Hz, H1 -Galf), 5.06e5.03 (m, 2H, H1 -Araf and H1 -Araf),
.93 (d, 1H, J¼10.8 Hz), 4.87 (4.86) (d, 1H, J¼11.4 Hz), 4.81 (t, 1H,
4.24. trans-4-Hydroxy-4-O-[3-O-methyl-
b-
L
-arabinofur-
-arabinofur-
D-proline (2)
anosyl-(1/5)-
anosyl-(1/2)-
a
-
-
D
-galactofuranosyl-(1/2)-
-arabinofuranosyl]-
b-L
J¼11.4 Hz), 4.77 (d, 1H, J¼12.0 Hz), 4.72 (d, 1H, J¼12.0 Hz), 4.64 (d,
b
L
2
(
4
H, J¼5.4 Hz), 4.62e4.54 (m, 3H), 4.53 (t, 1H, J¼7.2 Hz), 4.43e4.39
m, 2H), 4.38e4.32 (m, 1H), 4.31e4.26 (m, 1H), 4.25e4.13 (m, 5H),
.11e4.03 (m, 3H), 4.00e3.95 (m, 2H), 3.95e3.73 (m, 5H), 3.67
To a solution of compound 22 (300 mg, 0.17 mmol) in MeOH
(6 mL) was added CH ONa (30 mg, 0.56 mmol). The reaction mixture
3
(
(
3.66) (s, 3H), 3.63e3.49 (m, 4H), 3.46 (s, 3H), 3.45e3.41
3.39e3.36) (m, 1H), 2.14e1.98 (m, 2H), 1.46 (1.40) (s, 9H),
was stirred for 1 h at room temperature. Then the reaction was
neutralized with Amberlite IR-120 H resin, filtered, and concen-
þ
13
0
CDCl
1
1
1
(
(
.85e0.79 (m, 27H), ꢁ0.12 to 0.02 (m, 18H); C NMR (100 MHz,
): 173.1 (172.8)*, 164.8, 154.2 (153.4), 147.7, 138.3 (138.1),
38.0, 137.9, 137.1, 130.8, 130.2, 129.2, 128.5, 128.4, 128.3, 128.2,
28.15, 128.10, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 127.3, 127.1,
21.1, 102.0, 98.8 (98.2), 98.2 (98.1), 97.8 (97.6), 84.6 (84.5), 84.3
trated in vacuo. The obtained resulting residue was purified by silica
gel column chromatography (3:1, petroleum ethereEtOAc) to afford
a colorless syrup. To a solution of the obtained syrup in dry THF
(2 mL) was added TBAF (0.4 mL, 1.0 M in THF, 0.4 mmol) at room
temperature. The resulting mixture was stirred for overnight at room
temperature. Then it was evaporated under reduced pressure, and
the obtained resulting was purified by silica gel column chromatog-
3
d
84.0), 83.4 (83.3), 83.2, 82.9, 82.8 (82.7), 82.4, 82.0 (81.9), 81.5
81.3), 81.2, 80.6 (80.3), 79.6, 78.6 (78.5), 78.2, 77.2, 74.8 (73.6), 72.6,
7
5
ꢁ
1.9, 71.8, 71.7, 71.4, 67.6, 65.6, 65.4 (65.1), 63.2, 58.4, 57.6 (57.1),
2.2, 52.1 (51.9), 35.9 (34.9), 28.4 (28.2), 25.9 (25.8), 18.3 (18.2),
5.4 (ꢁ5.5); HRMS (ESI): m/z calcd for Na
raphy (EtOAc) to afford a crude syrup. To a solution of the obtained
ꢀ
syrup in CH Cl
2 2
(4 mL) was added TFA (2 mL) at 0 C. The reaction
C
96
H
132
N
2
O
23Si
3
mixture was stirred for 1 h at the same temperature. Then the

K. Zhu, J.-S. Yang / Tetrahedron 72 (2016) 3113e3123
3123
resulting mixture was diluted with CHCl
aqueous NaHCO . The organic layer was separated and dried over
anhydrous Na SO , filtered, and concentrated. The obtained residue
was purified by silica gel column chromatography (30:1,
CH Cl eMeOH) to afford a colorless syrup. The obtained syrup was
dissolved in a mixture of 1 M aqueous NaOH, dioxane and methanol
1/3/1, v/v/v, 4.0 mL). The reaction mixture was stirred for 30 min at
3
and washed with saturated
References and notes
3
1. Lamport, D. T. A.; Northcote, D. H. Nature 1960, 188, 665.
2
4
2
. (a) Lamport, D. T. A. Nature 1967, 216, 1322; (b) Lamport, D. T. A. Structure,
Biosynthesis and Significance of Cell Wall Glycoproteins In Recent Advances in
Phytochemistry; Nozzolillo, C., Lea, P. J., Loewus, F. A., Eds.; Plenum Publishing
Corporation: New York, NY, 1977; p 79.
2
2
3
. Bollig, K.; Lamsh o€ ft, M.; Schweimer, K.; Marner, F.-J.; Budzikiewiczc, H.; Waf-
(
fenschmidt, S. Carbohydr. Res. 2007, 342, 2557.
4. For reviews on stereoselective synthesis of 1,2-cis glycosides, see: (a) Nigudkar,
S. S.; Demchenko, A. V. Chem. Sci. 2015, 6, 2687; (b) Demchenko, A. V. Synlett
the room temperature, then it was neutralized with Amberlite IR-120
þ
H
resin, filtered, and concentrated in vacuo. To a solution of the
OeHOAc (5 mL/1 mL/0.1 mL) was
added 10% Pd/C (150 mg). The reaction mixture was stirred under an
atmosphere of H for 48 h. The catalyst was filtered-off, and washed
with MeOH and H O, concentrated in vacuo. The obtained residue
was purified by column chromatography on Sephadex LH-20
2003, 1225.
obtained residue in MeOHeH
2
5. Lee, Y. J.; Lee, K.; Jung, E. H.; Jeon, H. B.; Kim, K. S. Org. Lett. 2005, 7, 3263.
6. (a) D’Souza, F. W.; Lowary, T. L. Org. Lett. 2000, 2, 1493; (b) Yin, H.-F.; D’Souza, F.
W.; Lowary, T. L. J. Org. Chem. 2002, 67, 892.
2
7. (a) Zhu, X.-M.; Kawatkar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem. Soc. 2006, 128,
2
11948; (b) Rao, Y.; Boons, G.-J. Angew. Chem., Int. Ed. 2007, 46, 6148; (c) Crich, D.;
Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org. Chem. 2007, 72, 1553; (d) Joe,
M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am. Chem. Soc. 2007, 129, 9885; (e)
Wang, Y.-X.; Maguire-Boyle, S.; Dere, R. T.; Zhu, X.-M. Carbohydr. Res. 2008, 343,
(
CH
3
OH) to afford compound 2 (43 mg, 36% for five steps) as a col-
20
1
orless oil; 2: [
d
a]
D
þ109.4 (c 0.65, CH
3
OH); H NMR (600 MHz, D
2
O):
3100; (f) Xie, N.; Taylor, C. M. Org. Lett. 2010, 12, 4968.
0
0000
5.22 (d, 1H, J¼4.2 Hz, H1 -Araf), 5.19 (d, 1H, J¼4.8 Hz, H1 -Araf),
8
9
. (a) Ishiwata, A.; Akao, H.; Ito, Y. Org. Lett. 2006, 8, 5525; (b) Ishiwata, A.; Ito, Y. J.
Am. Chem. Soc. 2011, 133, 2275.
. Imamura, A.; Lowary, T. L. Org. Lett. 2010, 12, 3686.
00
000
5
.18 (d, 1H, J¼4.2 Hz, H1 -Araf), 5.05 (d, 1H, J¼4.8 Hz, H1 -Galf), 4.57
(
(
4
3
3
2
t, 1H, J¼4.2 Hz), 4.25 (dd, 1H, J¼8.4, 4.2 Hz), 4.24e4.17 (m, 4H), 4.15
dd, 1H, J¼7.8, 4.8 Hz), 4.14 (dd, 1H, J¼7.8, 4.8 Hz), 4.09 (dd, 1H, J¼8.4,
10. (a) For a review, see: Ishiwata, A.; Leea, Y. J.; Ito, Y. Org. Biomol. Chem. 2010, 8,
3596; (b) Ishiwata, A.; Munemura, Y.; Ito, Y. Eur. J. Org. Chem. 2008, 4250; (c)
.8 Hz), 3.92e3.85 (m, 4H), 3.84e3.81 (m, 1H), 3.81e3.78 (m, 1H),
.78e3.70 (m, 4H), 3.69e3.62 (m, 3H), 3.60 (dd, 1H, J¼12.0, 5.7 Hz),
.58e3.55 (m,1H), 3.44e3.40 (m,1H), 3.42 (s, 3H), 2.47e2.42 (m,1H),
Kaeothip, S.; Ishiwata, A.; Ito, Y. Org. Biomol. Chem. 2013, 11, 5892; (d) Ishiwata,
A.; Kaeothip, S.; Takeda, Y.; Ito, Y. Angew. Chem., Int. Ed. 2014, 53, 9812.
11. For reviews on stereoselective synthesis of 1,2-cis a-galactofuranoside, see: (a)
Richards, M. R.; Lowary, T. L. ChemBioChem 2009, 10, 1920; (b) Liang, X.-Y.; Deng,
L.-M.; Yang, J.-S. Chin. J. Org. Chem. 2013, 33, 245.
12. (a) Lee, Y. J.; Lee, B.-Y.; Jeon, H. B.; Kim, K. S. Org. Lett. 2006, 8, 3971; (b) Baek, J.
13
0000
.12e2.06 (m, 1H); C NMR (150 MHz, D
2
O):
d
175.7, 104.1 (C1 -
0
00
00
0
Araf), 101.2 (C1 -Galf), 100.1 (2C, C1 -Araf, C1 -Araf), 84.9, 83.5, 83.2,
Y.; Joo, Y. J.; Kim, K. S. Tetrahedron Lett. 2008, 49, 4734.
83.1, 82.6, 81.9, 81.8, 78.2, 78.1, 77.8, 75.8, 74.1, 73.6, 64.3, 64.2, 63.6,
13. (a) Bai, Y.; Lowary, T. L. J. Org. Chem. 2006, 71, 9658; (b) Bai, Y.; Lowary, T. L. J.
6
2.7, 61.6, 59.8, 53.3, 36.8; HRMS (ESI): m/z calcd for C27
H45NO20Na
Org. Chem. 2006, 71, 9672.
þ
[MþNa] : 726.2435, found: 726.2394.
14. (a) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012, 134, 20097; (b)
Yasomanee, J. P.; Demchenko, A. V. Angew. Chem., Int. Ed. 2014, 53, 10453; (c)
Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Org. Lett. 2014, 16, 716; (d)
Yasomanee, J. P.; Demchenko, A. V. Chem.dEur. J. 2015, 21, 6572; (e) Kayastha,
A. K.; Jia, X.-G.; Yasomanee, J. P.; Demchenko, A. V. Org. Lett. 2015, 17, 4448.
Acknowledgements
1
5. (a) Liu, Q.-W.; Bin, H.-C.; Yang, J.-S. Org. Lett. 2013, 15, 3974; (b) Gao, P.-C.; Zhu,
S.-Y.; Cao, H.; Yang, J.-S. J. Am. Chem. Soc. 2016, 138, 1684.
We appreciate NSFC (21572145, 21372166, 21321061) of China
for financial support.
16. (a) Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787; (b) Pandey, A. K.;
Naduthambi, D.; Thomas, K. M.; Zondlo, N. J. J. Am. Chem. Soc. 2013, 135, 4333.
1
7. Airoldi, C.; Merlo, S.; Nicotra, F. J. Carbohydr. Chem. 2010, 29, 30.
Supplementary data
1
8. K u€ rti, L.; Czak oꢀ , B. Strategic Applications of Named Reactions in Organic Synthesis;
Elsevier: San Diego, CA, 2005; p 294.
Supplementary data (Copies of the H and 13C NMR spectra of all
new compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tet.2016.04.038.
1
19. Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.; Matsuura, H. Carbohydr. Res.
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