A concise synthesis of rhamnan oligosaccharides with alternating α-(1→2)/(1→3)-linkages and repeating α-(1→3)-linkages by iterative α-glycosylation using disaccharide building blocks

Article abstract of DOI:10.1016/j.carres.2017.11.005

A concise synthetic route to rhamnan oligosaccharides with alternating α-(1→2)/(1→3)-linkages and repeating α-(1→3)-linkages is reported. This synthesis was achieved by iterative α-glycosylation using disaccharide building blocks and through orthogonal co

Full text of DOI:10.1016/j.carres.2017.11.005

Accepted Manuscript
A concise synthesis of rhamnan oligosaccharides with alternating α-(1→2)/
(1→3)-linkages and repeating α-(1→3)-linkages by iterative α-glycosylation using
disaccharide building blocks
Hidenori Tanaka, Yu Hamaya, Nagatoshi Nishiwaki, Hideharu Ishida
PII:
S0008-6215(17)30749-8
10.1016/j.carres.2017.11.005
CAR 7483
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 10 October 2017
Revised Date: 9 November 2017
Accepted Date: 10 November 2017
Please cite this article as: H. Tanaka, Y. Hamaya, N. Nishiwaki, H. Ishida, A concise synthesis of
rhamnan oligosaccharides with alternating α-(1→2)/(1→3)-linkages and repeating α-(1→3)-linkages
by iterative α-glycosylation using disaccharide building blocks, Carbohydrate Research (2017), doi:
10.1016/j.carres.2017.11.005.
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Graphical abstract

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Title
A concise synthesis of rhamnan oligosaccharides with alternating α-(1→2)/(1→3)-linkages and
repeating α-(1→3)-linkages by iterative α-glycosylation using disaccharide building blocks
Hidenori Tanaka a, *, Yu Hamaya b, Nagatoshi Nishiwaki c, d, Hideharu Ishida b, e
a
Oceanography Section, Science Research Center, Kochi University, Monobe, Nankoku, Kochi
783-8502, Japan
b
Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu
University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan
c
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada,
Kami, Kochi 782-8502, Japan
d
Research Center for Material Science and Engineering, Kochi University of Technology,
Tosayamada, Kami, Kochi 782-8502, Japan
e
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University,
1-1 Yanagido, Gifu, Gifu 501-1193, Japan
Corresponding Author
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E-mail address: htanaka@kochi-u.ac.jp (H. Tanaka)
Abstract
A concise synthetic route to rhamnan oligosaccharides with alternating α-(1→2)/(1→3)-linkages and
repeating α-(1→3)-linkages is reported. This synthesis was achieved by iterative α-glycosylation
using disaccharide building blocks and through orthogonal coupling between thioglycosides of
L
-rhamnose. To investigate the detailed structure-activity relationship of rhamnan sulfate from
Monostroma nitidum against herpes simplex virus type 2, the synthesized oligosaccharides, bearing
different orthogonal protecting groups (i.e., benzoyl, benzyl, 2-naphthylmethyl, and/or
p-methoxybenzyl) are expected to be suitable for conversion into a range of rhamnan structures with
diverse sulfation patterns.
Keywords:
Rhamnan oligosaccharide, Iterative α-glycosylation, Orthogonal coupling, Rhamnan sulfate,
Monostroma nitidum, Herpes simplex virus type 2
1. Introduction
Sulfated polysaccharides from marine algae have been widely studied in recent years due to their
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unique chemical structures and interesting biological activities [1,2]. For example, fucoidan, which
has been isolated from brown seaweed, is a sulfated α-L-fucose-rich polysaccharide that exhibits
antitumor, anticoagulant, and anti-inflammatory activities [3,4]. Recently, Takahashi and Toshima et
al. demonstrated the structure-activity relationships of natural fucoidan and the corresponding
synthetic sulfated oligofucosides for the induction of apoptosis in MCF-7 human breast cancer cells
[5,6, 7]. In addition, sulfated rhaman polysaccharides (e.g., rhamnan sulfate, RS) from green
seaweed, which mainly composed of α-L-rhamnopyranosyl (Rha) residues, possess potent antiviral
effects against enveloped viruses [8,9]. Lee et al. elucidated the fine structure of RS extracted from
Monostroma nitidum, and found that it contained alternating (1→2)/(1→3)-linked and repeating
(1→3)-linked α-L-Rha moieties as its backbone (types I and II, respectively, Figure 1) [10]. They
also evaluated its antiviral activity against herpes simplex virus type 2 (HSV-2), and demonstrated its
potential for use as a novel anti-HSV-2 agent. However, it remains unclear which residues in this
structure are required to impart such anti-HSV-2 activity. Thus, with the future aim of investigating
the detailed structure-activity relationship of RS, we planned an efficient and convergent synthesis of
rhamnan oligosaccharides with diverse sulfation patterns. For this purpose, we herein describe a
concise synthetic route to type I and II rhamnan oligosaccharides via iterative α-glycosylation using
disaccharide building blocks.
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Figure 1. Chemical structure of rhamnan sulfate obtained from Monostroma nitidum.
2. Results and Discussion
Retrosynthetically, rhamnan oligosaccharides are efficiently assembled via iterative α-selective
glycosylation using building blocks 1 and 2, each possessing a 2-O-benzoyl (Bz) group that permits
neighboring group participation [11] (Scheme 1). Disaccharide 1, which can be constructed by
orthogonal coupling [12] between thioglycosides 3 and 4, is readily converted into 2 via two
synthetic steps, and the required thioglycosides are prepared from key intermediate 5 via a number
of protecting group manipulations.
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Scheme 1. Retrosynthetic analysis of rhamnan oligosaccharides with alternating
α-(1→2)/(1→3)-linkages and repeating α-(1→3)-linkages.
As shown in Scheme 2, our synthetic efforts began with the preparation of key intermediate 5.
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Accordingly, the acetylation of commercially available
L
-Rha 6 followed by coupling with
thiophenol in the presence of a boron trifluoride etherate catalyst gave per-O-acetylated
thioglycoside 7 [13] with good α-selectivity (α:β = 4:1) in 87% yield on the multigram scale (i.e., >
50 g). To facilitate analysis of the prepared compounds, α-isomer of 7 was employed for the
following synthetic sequence. Thus, a benzyl (Bn) group was introduced at the 4-position through
deacetylation of 7α and regioselective formation of the 2,3-O-acetonide. Following removal of this
acetonide group, the C3 hydroxyl moiety was alkylated using 2-napthylmethyl bromide (NAPBr) via
tin-acetal activation [14] to afford the key intermediate 5 in 53% yield from 7α. With compound 5 in
hand, alkylation at the 2-position with p-methoxybenzyl chloride (PMBCl) provided
monosaccharide donor 3 (92%), while treatment of 5 with benzoyl chloride (BzCl) in pyridine and
subsequent deprotection of the NAP group using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) [15]
yielded monosaccharide acceptor 4 (78%).
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Scheme 2. Preparation of monosaccharides 3, 4, and 5. Reagents and conditions: (a) Ac2O, pyridine,
23 °C, 17 h; (b) PhSH, BF3·Et2O/CH2Cl2, 23 °C, 5 h, 87% (α:β = 4:1) over two steps; (c) NaOMe,
MeOH, 23 °C, 1 h; (d) DMP, p-TsOH·H2O/MeCN, 23 °C, 1 h; (e) NaH/DMF, then BnBr, 4 °C to
23 °C, 1 h; (f) 90% aq. AcOH, 80 °C, 24 h; (g) Bu2SnO/toluene, 120 °C, 1 h; (h) NAPBr,
TBAI/toluene, 120 °C, 16 h, 53% over six steps from 7α; (i) NaH/DMF, then PMBCl, 4° C to 23 °C,
1 h, 92%; (j) BzCl, pyridine, 4°C to 23 °C, 1 h; (k) DDQ, MeOH/CH2Cl2, 23 °C, 12 h, 78% over two
steps. DMP = 2,2-Dimethoxypropane, TBAI = Tetrabutylammonium iodide
The synthesis of disaccharides 1 and 2 was then carried out as illustrated in Scheme 3. More
specifically, orthogonal coupling [12] of the armed thioglycoside 3 and the disarmed thioglycoside 4
was achieved in the presence of N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH)
[16] to yield the desired coupling product 1 in 50% yield. The observed vicinal JC1,H1 coupling
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constant and C1 chemical shift (i.e., 167 Hz and 100 ppm) of the non-reducing end L-Rha unit in 1
indicated that the α configuration was adopted at the anomeric center [17,18]. The conversion of 1
into 2 was achieved by removal of the PMB group [19] and subsequent benzoylation.
Scheme 3. Synthesis of disaccharide building blocks 1 and 2. Reagents and conditions: (a) NIS,
TfOH/CH2Cl2, −78 °C to −60 °C, 2 h, 50% (α only); (b) 90% aq. AcOH, 80 °C, 6 h, 68%; (c) BzCl,
pyridine, 4 °C to 23 °C, 30 min, 94%.
With disaccharides 1 and 2 in hand, the type I and II rhamnan oligosaccharides were prepared via
iterative α-glycosylation by neighboring group participation of the 2-O-Bz group. More specifically,
to prepare the oligosaccharide with alternating α-(1→2)/(1→3)-linkages (Scheme 4), the PMB
group was cleanly removed under mildly acidic conditions after capping the reducing end of 1 with
2-(trimethylsilyl)ethanol (SEOH) to ultimately furnish disaccharide acceptor 8 in 73% yield over
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two steps. The glycosylation of 8 with 1 using the NIS/TfOH system proceeded in an α-selective
manner to afford the desired coupling product 9 in 76% yield. Subsequent PMB deprotection of 9
gave 10, which was coupled with 1 to produce hexasaccharide 11 with complete α-selectivity but in
a rather poor yield (36%).
Double column
Scheme 4. Synthesis of oligosaccharides with alternating α-(1→2)/(1→3)-linkages using iterative
glycosylation from disaccharide building block 1. Reagents and conditions: (a) SEOH (1.5 equiv.),
NIS, TfOH/CH2Cl2, 4° C, 10 min, 70% (α only); (b) 90% aq. AcOH, 80 °C, 48 h, 73%; (c) 1 (1.2
equiv.), NIS, TfOH/CH2Cl2, 4 °C, 30 min, 76% (α only); (d) 90% aq. AcOH, 80 °C, 48 h, 73%; (e) 1
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(2.0 equiv.), NIS, TfOH/CH2Cl2, 4 °C, 30 min, 36% (α only).
We also elongated the oligosaccharide chain through repeating α-(1→3)-linkages (Scheme 5).
Initially, a two-step reaction sequence was followed consisting of end capping of compound 2 with
SEOH and removal of the NAP group to obtain acceptor 12. Finally, a synthetic cycle involving
α-glycosylation with 2 and NAP deprotection using DDQ was employed to systematically construct
tetrasaccharide 13 and hexasaccharide 15 (via acceptor 14) through high yielding coupling reactions
in 83% and 92%, respectively.
Scheme 5. Synthesis of oligosaccharides with repeating α-(1→3)-linkages using iterative
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glycosylation from disaccharide building block 2. Reagents and conditions: (a) SEOH (1.5 equiv.),
NIS, TfOH/CH2Cl2, 4 °C, 10 min, 67% (α only); (b) DDQ, MeOH/CH2Cl2, 23 °C, 12 h, 72%; (c) 2
(1.2 equiv.), NIS, TfOH/CH2Cl2, 4 °C, 30 min, 83% (α only); (d) DDQ, MeOH/CH2Cl2, 23 °C, 12 h,
70%; (e) 2 (2.0 equiv.), NIS, TfOH/CH2Cl2, 4 °C, 30 min, 92% (α only).
In summary, we successfully developed a concise synthetic route to rhamnan hexasaccharides with
alternating α-(1→2)/(1→3)-linkages and repeating α-(1→3)-linkages by iterative α-glycosylation
using disaccharide building blocks. It is particularly noteworthy that one of these disaccharides was
successfully constructed via orthogonal coupling between armed and disarmed thioglycosides
originating from L-rhamnose. The prepared oligosaccharides, bearing a range of different orthogonal
protecting groups (i.e., benzoyl, benzyl, 2-naphthylmethyl, and/or p-methoxybenzyl), are suitable for
conversion into several rhamnan structures with diverse sulfation patterns. Studies into the detail
structure-activity relationship of rhamnan sulfate against herpes simplex virus type 2 are currently
underway in our laboratory.
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded using JEOL ECA-500 and Bruker Ascend™-400
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spectrometers, respectively. High resolution mass spectrometry (HRMS) was carried out on a Bruker
Daltonics micrOTOF electrospray ionization time-of-flight (ESI-TOF) mass spectrometer. The
specific optical rotations of the products were determined using a Horiba SEPA-300 high sensitive
polarimeter. All reagents were purchased from Tokyo Chemical Industry (Tokyo, Japan), Wako Pure
Chemical Industries (Osaka, Japan), or Sigma-Aldrich (St. Louis, MO). All reaction solvents were
pre-dried using 4Å molecular sieves prior to use. Thin layer chromatography was performed using
glass-backed Merck silica gel 60 TLC plates coated with the F254 fluorescent indicator. The
developed TLC plates were observed using UV light (254 nm) and by staining with a p-anisaldehyde
solution. Purification was carried out using flash column chromatography (Kanto Chemical, Silica
Gel 60N, 40–50 µm) and gel filtration (Pharmacia, Sephadex LH-20). The NMR spectra of all new
compounds are available in the Supplementary Materials.
3.2. Phenyl 4-O-benzyl-3-O-(2-naphthylmethyl)-1-thio-α-L-rhamnopyranoside (5)
To a suspension of phenyl 2,3,4-tri-O-acetyl-1-thio-α-L-rhamnopyranoside 3 (46.0 g, 120 mmol) in
methanol (120 mL) was added sodium methoxide (28% wt. solution in methanol: 2.32 g, 12.0 mmol)
before stirring for 1 h at 23 °C under nitrogen atmosphere. The reaction mixture was acidified with
Muromac® (H+ form) and filtered off. The resulting solution was concentrated in vacuo and exposed
to high vacuum. For acetonide formation, the deacetylated crude product (120 mmol) was dissolved
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in a mixed solution of acetonitrile/2,2-dimethoxypropane (120 mL/29.5 mL, 240 mmol) before
treatment with p-toluenesulfonic acid monohydrate (2.28 g, 12.0 mmol). After stirring for 1 h at
23 °C under nitrogen atmosphere, the reaction mixture was quenched by triethylamine (33.5 mL,
240 mmol). The resulting solution was concentrated in vacuo and exposed to high vacuum. For
benzyl ether protection, the 2,3-O-acetonide crude product (120 mmol) was dissolved in
N,N’-dimethylformamide (120 mL) before cooling to 4 °C using ice bath under nitrogen atmosphere.
After addition of sodium hydride (60% wt. in oil: 7.18 g, 180 mmol) portionwise over 1 h, benzyl
bromide (17.1 mL, 144 mmol) was added and the reaction was stirred for additional 1 h at 23 °C.
The mixture was treated with triethylamine (16.7 mL, 120 mmol) for quenching unreacted benzyl
bromide and poured into satd. aq. NH4Cl (120 mL) to precipitate a pale brown solid. After filtration,
the solid was washed with water (600 mL) and 50% aq. methanol (600 mL). For acetonide
deprotection, the 2,3-O-acetonide-4-O-benzyl crude product (120 mmol) was dissolved in 80% aq.
acetic acid (240 mL) before heating to 60 °C using oil bath. After stirring for 24 h, the reaction
mixture was allowed to cool to 23 °C and concentrated in vacuo. The resulting syrup was dissolved
in hot ethyl acetate (200 mL) and cooled to 4 °C using ice bath to precipitate a white solid. After
filtration, the solid was washed with a mixed solution of ethyl acetate/hexane (200 mL/400 mL) to
give the corresponding 4-O-benzyl product S1 (34.8 g, 84%) as a white solid. For regioselective
2-napthylmethyl ether protection, S1 (3.46 g, 9.99 mmol) was dissolved in toluene (100 mL) before
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addition of dibutyltin oxide (2.48 g, 9.96 mmol). After stirring for 1 h at 120 °C using oil bath under
nitrogen atmosphere, the reaction mixture was cooled to 23 °C and evaporated until dry. The
resulting syrup was dissolved in toluene (100 mL) before addition of 2-napthylmethyl bromide (3.32
g, 15.0 mmol) and tetrabutylammonium iodide (369 mg, 1.00 mmol). After stirring for 16 h at 80 °C
using oil bath under nitrogen atmosphere, the reaction mixture was cooled to 23 °C and concentrated
in vacuo. The crude product was purified by flash column chromatography (silica gel, ethyl
acetate:hexane = 1:6 → 1:3) to give the title compound 5 (3.06 g, 63%) as a white foam.
[α]D −169.4° (c 3.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.84–7.21 (m, 17H, Ph), 5.52 (s, 1H,
H-1), 4.93–4.65 (m, 4H, -CHPh×4), 4.27 (brs, 1H, H-2), 4.20 (m, 1H, H-5), 3.92 (dd, 1H, J2,3 = 3.2
Hz, J3,4 = 9.3 Hz, H-3), 3.55 (t, 1H, J4,5 = 9.3 Hz, H-4), 2.76 (brs, 1H, OH), 1.31 (d, 3H, J5,6 = 6.2 Hz,
H-6); 13C NMR (100 MHz, CDCl3) δ 138.3, 135.0, 134.1, 133.2, 133.1, 131.4, 129.0, 128.4, 128.4,
127.9, 127.9, 127.7, 127.7, 127.3, 126.8, 126.2, 126.1, 125.8, 87.0, 80.1, 80.1, 75.4, 72.2, 70.1, 68.9,
17.8; HRMS (ESI-TOF) m/z: found [M+Na]+ 509.1751, C30H30O4S calcd for [M+Na]+ 509.1757.
3.3. Phenyl
4-O-benzyl-2-O-(4-methoxybenzyl)-3-O-(2-naphthylmethyl)-1-thio-α-L-rhamnopyranoside (3)
To a solution of phenyl 4-O-benzyl-3-O-(2-naphthylmethyl)-1-thio-α-L-rhamnopyranoside 5 (2.44 g,
5.01 mmol) in N,N’-dimethylformamide (10.0 mL) was added sodium hydride (60% wt. in oil: 302
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mg, 7.55 mmol) portionwise over 20 min at 4 °C using ice bath under nitrogen atmosphere before
addition of p-methoxybenzyl chloride (0.82 mL, 6.05 mmol). After stirring for 1 h at 23 °C, the
reaction mixture was quenched with triethylamine (1.4 mL, 10.0 mmol) and satd. aq. NH4Cl (50 mL).
The resulting solution was extracted with ethyl acetate (50 mL×3) and washed with brine (50 mL).
The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by recrystallization with ethyl acetate/hexane to give the title compound 3 (2.79 g,
92%) as a white solid.
[α]D −32.2° (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.82–6.77 (m, 21H, Ph), 5.46 (s, 1H, H-1),
5.00–4.55 (m, 6H, -CHPh×6), 4.15 (m, 1H, H-5), 4.00 (brs, 1H, H-2), 3.90 (m, 1H, H-3), 3.70 (m,
4H, H-4 and OMe), 1.36 (d, 3H, J5,6 = 6.2 Hz, H-6); 13C NMR (100 MHz, CDCl3) δ 159.2, 138.5,
135.7, 134.6, 133.2, 132.9, 131.3, 129.8, 129.6, 128.9, 128.3, 128.0, 127.9, 127.8, 127.6, 127.5,
127.1, 126.4, 126.0, 125.8, 125.8, 113.7, 85.8, 80.5, 79.9, 76.0, 75.3, 72.0, 71.7, 69.3, 55.1, 17.9;
HRMS (ESI-TOF) m/z: found [M+Na]+ 629.2327, C38H38O5S calcd for [M+Na]+ 629.2332.
3.4. Phenyl 2-O-benzoyl-4-O-benzyl-1-thio-α-L-rhamnopyranoside (4)
To a solution of phenyl 4-O-benzyl-3-O-(2-naphthylmethyl)-1-thio-α-L-rhamnopyranoside 5 (1.90 g,
3.90 mmol) in pyridine (7.8 mL) was added benzoyl chloride (0.54 mL, 4.65 mmol) at 4 °C using ice
bath before stirring for 1 h at 23 °C under nitrogen atmosphere. After quenching with methanol (0.40
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mL, 0.99 mmol), the mixture was evaporated with toluene (10 mL×3) and purified by flash column
chromatography (silica gel, ethyl acetate:hexane = 1:8 → 1:6) to give the corresponding
2-O-benzylated compound S2 (2.20 g, 96%) as a yellow syrup.
S2 (1.01 g, 1.69 mmol) was dissolved in a mixed solution of dichloromethane/methanol (6.8 mL/1.7
mL) before addition of 2,3-dichloro-5,6-dicyanobenzoquinone (461 mg, 2.03 mmol). After stirring
for 12 h at 23 °C, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting
solution was washed with satd. aq. NaHCO3 (100 mL×2) and brine (100 mL). The aqueous layers
were extracted with ethyl acetate (100 mL×2). The combined organic layer was dried over Na2SO4
and concentrated in vacuo. The crude product was purified by flash column chromatography (silica
gel, ethyl acetate:hexane = 1:8 → 1:6) to give the title compound 4 (604 mg, 78%) as a white foam.
1
[α]D −118.2° (c 3.6, CHCl3); H NMR (400 MHz, CDCl3) δ8.04–7.22 (m, 10H, Ph), 5.61 (m, 1H,
H-2), 5.55 (s, 1H, H-1), 4.87 (d, 1H, J = 11.2 Hz, -CHPh), 4.77 (d, 1H, J = 11.2 Hz, -CHPh), 4.30 (m,
1H, H-5), 4.21 (dd, 1H, J2,3 = 3.2 Hz, J3,4 = 9.4 Hz, H-3), 3.56 (t, 1H, J3,4 = J4,5 = 9.4 Hz, H-4), 2.42
(brs, 1H, OH), 1.41 (d, 3H, J5,6 = 6.2 Hz, H-6); 13C NMR (100 MHz, CDCl3) δ 166.1, 138.0, 133.8,
133.2, 131.6, 129.7, 129.5, 128.9, 128.4, 128.3, 128.0, 127.8, 127.5, 85.8, 81.5, 75.0, 74.8, 70.9,
68.7, 17.9; HRMS (ESI-TOF) m/z: found [M+Na]+ 473.1399, C26H26O5S calcd for [M+Na]+
473.1393.
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3.5. Phenyl
4-O-benzyl-2-O-(4-methoxybenzyl)-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benz
oyl-4-O-benzyl-1-thio-α-L-rhamnopyranoside (1)
A mixture of donor 3 (757 mg, 1.25 mmol) and acceptor 4 (467 mg, 1.04 mmol) in dichloromethane
(2.1 mL) was premixed with molecular sieves 4Å (460 mg) for 30 min at 23 °C under nitrogen
atmosphere before cooling to −78 °C using dry ice/acetone. After addition of N-iodosuccinimide
(287 mg, 1.28 mmol) and trifluoromethanesulfonic acid (27 µL, 0.31 mmol), the reaction mixture
was stirred warming up to −60 °C over 2 h and quenched with trimethylamine (0.43 mL, 3.09 mmol)
at −60 °C before addition of a mixed solution of satd. aq. NaHCO3/satd. aq. Na2S2O3 (20 mL/20 mL)
at 4 °C using ice bath. After additional 10 min stirring, the resulting mixture was filtered through a
pad of Celite® with chloroform (40 mL). The organic layer was separated from the aqueous layer and
washed with brine (40 mL). The aqueous layers were extracted with chloroform (40 mL×2). The
combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was
purified by flash column chromatography (silica gel, ethyl acetate: hexane = 1:10 → 1:8) to give the
title compound 1 (482 mg, 50%) as a white foam.
1
[α]D −73.7° (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 8.05–6.74 (m, 31H, Ph), 5.64 (brs, 1H,
H-2a), 5.56 (s, 1H, H-1a), 5.06 (s, 1H, H-1b), 4.88–4.45 (m, 8H, -CHPh×8), 4.25 (m, 1H, H-5a), 4.16
(dd, 1H, J2,3 = 3.0 Hz, J3,4 = 9.3 Hz, H-3a), 3.81–3.69 (m, 6H, H-2b, H-3b, H-5b and OMe), 3.60–3.53
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(m, 2H, H-4a and H-4b), 1.29 (d, 3H, J5,6 = 6.2 Hz, H-6a), 1.19 (d, 3H, J5,6 = 6.2 Hz, H-6b); 13C NMR
(100 MHz, CDCl3) δ 165.6, 159.1, 138.8, 138.0, 136.0, 133.8, 133.2, 133.2, 132.8, 131.8, 130.2,
129.9, 129.7, 129.3, 129.0, 128.4, 128.4, 128.1, 127.9, 127.8, 127.7, 127.6, 127.6, 127.4, 127.4,
127.3, 126.1, 126.0, 125.7, 125.7, 113.7, 100.1 (JC1,H1 = 167 Hz), 85.7, 80.3, 80.2, 79.4, 78.0, 75.3,
74.9, 74.5, 74.4, 72.2, 72.2, 69.1, 55.1, 17.9, 17.8; HRMS (ESI-TOF) m/z: found [M+Na]+ 969.3630,
C58H58O10S calcd for [M+Na]+ 969.3643.
3.6. Phenyl
2-O-benzoyl-4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-be
nzyl-1-thio-α-L-rhamnopyranoside (2)
Disaccharide 1 (200 mg, 211 µmol) was dissolved in 90% aq. acetic acid (4.2 mL) and the reaction
was allowed to warm to 80 °C using oil bath before stirring at the same temperature for 6 h. The
resulting mixture was evaporated with toluene (5 mL×2) and purified with flash column
chromatography (silica gel, ethyl acetate:hexane = 1:8 → 1:4) to give the corresponding de-PMB
product S3 (118 mg, 68%) as a white foam.
A solution of S3 (195 mg, 236 µmol) in pyridine (1.2 mL) was cooled to 4 °C using ice bath before
addition of benzoyl chloride (82 µL, 706 µmol). After stirring for 30 min at 23 °C under nitrogen
atmosphere, the reaction mixture was quenched with methanol (96 µL, 2.37 mmol) and evaporated
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with toluene (2 mL×2). The resulting syrup was dissolved in a mixed solution of ethyl acetate/water
(20 mL/20 mL). The organic layer was separated from the aqueous layer and washed with brine (20
mL). The aqueous layers were extracted with ethyl acetate (20 mL×2). The combined organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column
chromatography (silica gel, ethyl acetate:hexane = 1:8 → 1:6) to give the title compound 2 (207 mg,
94%) as a white foam.
1
[α]D −11.8° (c 3.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.08–7.16 (m, 32H, Ph), 5.69 (m, 1H,
H-2b), 5.67 (m, 1H, H-2a), 5.57 (s, 1H, H-1a), 5.24 (s, 1H, H-1b), 4.86–4.53 (m, 6H, -CHPh×6), 4.26
(m, 2H, H-3a and H-5a), 3.99 (dd, 1H, J2,3 = 3.1 Hz, J3,4 = 9.4 Hz, H-3b), 3.87 (m, 1H, H-5b), 3.66 (t,
1H, J3,4 = J4,5 = 9.4 Hz, H-4a), 3.53 (t, 1H, J4,5 = 9.4 Hz, H-4b), 1.34 (d, 3H, J5,6 = 6.2 Hz, H-6a), 1.23
(d, 3H, J5,6 = 6.2 Hz, H-6b); 13C NMR (100 MHz, CDCl3) δ 165.7, 165.6, 138.5, 137.7, 135.5, 133.8,
133.3, 133.2, 132.8, 129.9, 129.8, 129.7, 129.0, 128.5, 128.4, 128.2, 127.9, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 126.4, 125.8, 125.7, 99.6, 85.7, 80.4, 79.7, 78.0, 77.7, 75.5, 74.7, 74.3, 71.5,
69.7, 69.2, 68.9, 18.0, 17.9; HRMS (ESI-TOF) m/z: found [M+Na]+ 953.3334, C57H54O10S calcd for
[M+Na]+ 953.3330.
19

ACCEPTED MANUSCRIPT
3.7. 2-Trimethylsilylethyl
4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rha
mnopyranoside (8)
A mixture of disaccharide 1 (1.27 g, 1.34 mmol), 2-trimethylsilylethanol (0.29 mL, 2.02 mmol), and
N-iodosuccinimide (369 mg, 1.64 mmol) in dichloromethane (6.7 mL) was premixed with molecular
sieves 4Å (670 mg) for 30 min at 23 °C under nitrogen atmosphere before cooling to 4 °C using ice
bath. After addition of trifluoromethanesulfonic acid (36 µL, 199 mmol), the reaction mixture was
stirred for 10 min at the same temperature and quenched with a mixed solution of satd. aq.
NaHCO3/satd. aq. Na2S2O3 (20 mL/20 mL). After additional 10 min stirring, the resulting solution
was filtered through a pad of Celite® with chloroform (40 mL). The organic layer was separated
from the aqueous layer and washed with brine (40 mL). The aqueous layers were extracted with
chloroform (40 mL×2). The combined organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash column chromatography (silica gel, ethyl
acetate:hexane = 1:6 → 1:4) to give the desired glycoside S4 (897 mg, 70%) as a white foam.
S4 (218 mg, 228 µmol) was dissolved in 90% aq. acetic acid (4.6 mL) and the reaction was allowed
to warm to 80 °C using oil bath before stirring at the same temperature for 48 h. The resulting
mixture was evaporated with toluene (5 mL×2) and purified by flash column chromatography (silica
gel, ethyl acetate:hexane = 1:6 → 1:3) to give the title compound 8 (140 mg, 73%) as a white foam.
20

ACCEPTED MANUSCRIPT
1
[α]D −14.1° (c 2.3, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04–7.15 (m, 22H, Ph), 5.31 (brs, 1H,
H-2a), 5.05 (s, 1H, H-1b), 4.83 (s, 1H, H-1a), 4.78–4.48 (m, 6H, -CHPh×6), 4.19 (dd, 1H, J2,3 = 3.3
Hz, J3,4 = 9.4 Hz, H-3a), 3.88 (brs, 1H, H-2b), 3.80–3.70 (m, 4H, H-3b, H-5a, H-5b and -CHCH2Si),
3.48 (m, 2H, H-4a and -CHCH2Si), 3.38 (t, 1H, J3,4 = J4,5 = 9.4 Hz, H-4b), 2.33 (brs, 1H, OH), 1.27
(d, 3H, J5,6 = 6.2 Hz, H-6a), 1.13 (d, 3H, J5,6 = 6.2 Hz, H-6b), 0.98–0.83 (m, 2H, -CH2CHSi×2), 0.00
(s, 3H, SiMe3); 13C NMR (100 MHz, CDCl3) δ 165.9, 138.6, 138.0, 135.4, 133.2, 133.1, 133.0,
130.1, 129.8, 128.5, 128.4, 128.2, 127.9, 127.8, 127.7, 127.6, 127.4, 126.5, 126.1, 126.0, 125.7,
101.2, 96.7, 80.6, 79.8, 79.6, 77.8, 77.2, 75.3, 74.6, 73.2, 72.2, 69.2, 68.2, 67.6, 65.3, 18.0, 17.9,
17.7, -1.3; HRMS (ESI-TOF) m/z: found [M+Na]+ 857.3682, C49H58O10Si calcd for [M+Na]+
857.3691.
3.8. 2-Trimethylsilylethyl
4-O-benzyl-2-O-(4-methoxybenzyl)-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benz
oyl-4-O-benzyl-α-L-rhamnopyranosyl-(1→2)-4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyran
osyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranoside (9)
A solution of donor 1 (184 mg, 194 µmol), acceptor 8 (133 mg, 159 µmol), and N-iodosuccinimide
(53.1 mg, 236 µmol) in dichloromethane (1.6 mL) was premixed with activated molecular sieves 4Å
(350 mg) for 30 min at 23 °C under nitrogen atmosphere before cooling to 4 °C using ice bath. After
21

ACCEPTED MANUSCRIPT
addition of trifluoromethanesulfonic acid (4.2 µL, 47 µmol), the reaction mixture was stirred at the
same temperature for 30 min and quenched with a mixed solution of satd. aq. NaHCO3/satd. aq.
Na2S2O3 (10 mL/10 mL). After additional 10 min stirring, the resulting mixture was filtered through
a pad of Celite® with chloroform (20 mL). The organic layer was separated from the aqueous layer
and washed with brine (20 mL). The aqueous layers were extracted with chloroform (20 mL×2). The
combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was
purified by gel filtration (sephadex LH-20, chloroform/methanol = 1/1) and flash column
chromatography (silica gel, ethyl acetate:hexane = 1:8 → 1:6) to give the title compound 9 (202 mg,
76%) as a white foam.
1
[α]D −25.3° (c 1.5, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04–6.68 (m, 48H, Ph), 5.55 (brs, 1H,
H-2c), 5.30 (brs, 1H, H-2a), 5.09 (s, 2H, H-1b and H-1c), 5.00 (s, 1H, H-1d), 4.86–4.33 (m, 15H, H-1a
and -CHPh×14), 4.24 (dd, 1H, J2,3 = 3.2 Hz, J3,4 = 9.4 Hz, H-3c), 4.13 (dd, 1H, J2,3 = 3.2 Hz, J3,4
=
9.3 Hz, H-3a), 3.86–3.39 (m, 17H, H-2b, H-2d, H-3b, H-3d, H-4a, H-4b, H-4c, H-4d, H-5a, H-5b H-5c,
H-5d, OMe and -CHCH2Si×2), 1.21 (d, 3H, J5,6 = 6.2 Hz, H-6a), 1.13 (m, 9H, H-6b, H-6c and H-6d),
0.99–0.84 (m, 2H, -CH2CHSi×2), 0.00 (s, 3H, SiMe3); 13C NMR (100 MHz, CDCl3) δ 165.9, 165.4,
159.1, 138.9, 138.8, 138.2, 138.0, 136.2, 135.9, 133.2, 133.2, 133.2, 133.0, 132.8, 132.8, 130.3,
130.2, 130.1, 129.8, 129.8, 128.4, 128.4, 128.1, 128.0, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6,
127.5, 127.3, 127.2, 126.2, 126.1, 125.9, 125.8, 125.7, 125.5, 113.6, 101.0, 99.8, 96.6, 80.4, 80.3,
22

ACCEPTED MANUSCRIPT
80.1, 79.8, 79.7, 79.0, 78.5, 76.0, 75.4, 75.1, 74.8, 74.6, 74.5, 73.1, 72.8, 72.3, 72.2, 72.1, 69.0, 68.3,
67.6, 65.3, 55.1, 18.0, 17.9, 17.8, 17.7, -1.3; HRMS (ESI-TOF) m/z: found [M+Na]+ 1693.7251,
C101H110O20Si calcd for [M+Na]+ 1693.7252.
3.9.
2-Trimethylsilylethyl
4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rha
mnopyranosyl-(1→2)-4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyranosyl-(1→3)-2-O-benzoy
l-4-O-benzyl-α-L-rhamnopyranoside (10)
Tetrasaccharide 9 (202 mg, 121 µmol) was dissolved in 90% aq. acetic acid (2.4 mL) and the
reaction was allowed to warm to 80 °C before stirring at the same temperature for 48 h. The
resulting mixture was evaporated with toluene (5 mL×2) and purified by flash column
chromatography (silica gel, ethyl acetate:hexane = 1:4 → 1:3) to give the title compound 10 (137 mg,
73%) as a white foam.
[α]D −18.3° (c 2.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05–7.12 (m, 44H, Ph), 5.54 (dd, 1H, J1,2
= 1.7 Hz, J2,3 = 3.2 Hz, H-2c), 5.29 (dd, 1H, J1,2 = 1.6 Hz, J2,3 = 3.2 Hz, H-2a), 5.09 (brs, 1H, H-1b),
5.06 (d, 1H, J1,2 = 1.7 Hz, H-1c), 5.00 (d, 1H, J1,2 = 1.5 Hz, H-1d), 4.84 (d, 1H, J1,2 = 1.6 Hz, H-1a),
4.82–4.26 (m, 12H, -CHPh×12), 4.24 (dd, 1H, J2,3 = 3.2 Hz, J3,4 = 9.4 Hz, H-3c), 4.13 (dd, 1H, J2,3
=
3.2 Hz, J3,4 = 9.4 Hz, H-3a), 3.90–3.63 (m, 9H, H-2b, H-2d, H-3b, H-3d, H-5a, H-5b H-5c, H-5d and
23

ACCEPTED MANUSCRIPT
-CHCH2Si), 3.51–3.37 (m, 5H, H-4a, H-4b, H-4c, H-4d and -CHCH2Si), 2.33 (brs, 1H, OH), 1.21 (d,
3H, J5,6 = 6.2 Hz, H-6a), 1.17 (d, 3H, J5,6 = 6.2 Hz, H-6d), 1.10 (m, 6H, H-6b and H-6c), 0.99–0.84 (m,
2H, -CH2CHSi×2), 0.00 (s, 3H, SiMe3); 13C NMR (100 MHz, CDCl3) δ 165.9, 165.4, 138.8, 138.6,
138.0, 138.0, 135.9, 135.4, 133.2, 133.2, 133.1, 133.1, 133.0, 132.8, 130.2, 130.1, 129.8, 129.8,
128.4, 128.4, 128.2, 128.1, 128.0, 128.0, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5, 127.4, 127.2,
126.5, 126.3, 126.1, 126.0, 125.9, 125.7, 125.7, 125.5, 101.0, 100.9, 98.9, 96.6, 80.5, 80.2, 79.9,
79.8, 79.7, 79.0, 78.4, 77.2, 77.1, 76.4, 75.1, 75.1, 74.7, 74.6, 73.2, 72.7, 72.3, 72.1, 69.1, 69.0, 68.4,
68.3, 67.6, 65.3, 18.0, 18.0, 17.9, 17.7, 17.7, -1.3; HRMS (ESI-TOF) m/z: found [M+Na]+
1573.6679, C93H102O19Si calcd for [M+Na]+ 1573.6677.
3.10.
2-Trimethylsilylethyl
4-O-benzyl-2-O-(4-methoxybenzyl)-3-O-(2-naphthylmethyl)-α-
L
-rhamnopyranosyl-(1→3)-2-O-benz
oyl-4-O-benzyl-α-L-rhamnopyranosyl-(1→2)-4-O-benzyl-3-O-(2-naphthylmethyl)-α-L-rhamnopyran
osyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranosyl-(1→2)-4-O-benzyl-3-O-(2-naphthylmeth
yl)-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranoside (11)
A mixture of donor 1 (170 mg, 179 µmol), acceptor 10 (137 mg, 88.3 µmol), and N-iodosuccinimide
(60.4 mg, 268 µmol) and in dichloromethane (2.7 mL) was premixed with activated molecular sieves
4Å (270 mg) for 30 min at 23 °C under nitrogen atmosphere before cooling to 4 °C using ice bath.
24

ACCEPTED MANUSCRIPT
After addition of trifluoromethanesulfonic acid (4.7 µL, 53.1 µmol), the reaction mixture was stirred
at the same temperature for 30 min and quenched with a mixed solution of satd. aq. NaHCO3/satd.
aq. Na2S2O3 (10 mL/10 mL). After additional 10 min stirring, the resulting mixture was filtered
through a pad of Celite® with chloroform (20 mL). The organic layer was separated from the
aqueous layer and washed with brine (20 mL). The aqueous layers were extracted with chloroform
(20 mL×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by gel filtration (sephadex LH-20, chloroform/methanol = 1/1) and flash
column chromatography (silica gel, ethyl acetate:hexane = 1:4 → 1:3) to give the title compound 11
(76.7 mg, 36%) as a colorless syrup.
1
[α]D −6.2° (c 3.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.05–6.67 (m, 70H, Ph), 5.57 (brs, 1H,
H-2e), 5.53 (brs, 1H, H-2c), 5.29 (brs, 1H, H-2a), 5.08 (m, 3H, H-1b, H-1c H-1d and H-1e), 4.99 (s, 1H,
H-1f), 5.00 (d, 1H, J1,2 = 1.5 Hz, H-1d), 4.84 (d, 1H, J1,2 = 1.6 Hz, H-1a), 4.86–4.32 (m, 21H, H-1a
and -CHPh×20), 4.25 (dd, 1H, J2,3 = 3.0 Hz, J3,4 = 9.4 Hz, H-3e), 4.20 (dd, 1H, J2,3 = 2.6 Hz, J3,4
=
9.4 Hz, H-3c), 4.13 (dd, 1H, J2,3 = 2.9 Hz, J3,4 = 9.6 Hz, H-3a), 3.87–3.39 (m, 23H, H-2b, H-2d, H-2f,
H-3b, H-3d, H-3f, H-4a, H-4b, H-4c, H-4d, H-4e, H-4f, H-5a, H-5b, H-5c, H-5d, H-5e, H-5f, OMe and
-CHCH2Si×2), 3.51–3.37 (m, 5H, H-4a, H-4b H-4c, H-4d and -CHCH2Si), 2.33 (brs, 1H, OH), 1.21 (d,
3H, J5,6 = 6.2 Hz, H-6a), 1.13 (m, 15H, H-6b, H-6c, H-6d, H-6e and H-6f), 0.99–0.84 (m, 2H,
-CH2CHSi×2), 0.00 (s, 3H, SiMe3); 13C NMR (100 MHz, CDCl3) δ 165.9, 165.4, 159.0, 138.9, 138.8,
25

ACCEPTED MANUSCRIPT
138.1, 137.9, 136.2, 135.9, 135.9, 133.2, 133.1, 133.1, 133.0, 132.8, 130.3, 130.2, 130.1, 130.1,
129.8, 129.7, 129.2, 128.4, 128.3, 128.3, 128.3, 128.1, 128.1, 128.0, 127.8, 127.8, 127.7, 127.7,
127.6, 127.6, 127.6, 127.5, 127.5, 127.3, 127.2, 126.2, 126.2, 126.0, 125.9, 125.9, 125.8, 125.7,
125.5, 113.6, 101.0, 100.6, 99.7, 98.9, 98.7, 96.6, 80.3, 80.2, 80.1, 80.1, 79.9, 79.8, 79.7, 79.1, 79.0,
78.5, 77.2, 76.9, 76.3, 75.9, 75.4, 75.1, 75.0, 74.7, 74.6, 74.6, 74.5, 73.1, 72.8, 72.7, 72.3, 72.2, 72.1,
72.0, 69.0, 68.9, 68.9, 68.3, 68.3, 67.5, 65.3, 55.1, 18.0, 18.0, 18.0, 17.8, 17.8, 17.8, 17.7, -1.3;
HRMS (ESI-TOF) m/z: found [M+Na]+ 2410.0227, C145H154O29Si calcd for [M+Na]+ 2410.0237.
3.11. 2-Trimethylsilylethyl
2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranosi
de (12)
A mixture of disaccharide 2 (107 mg, 115 µmol), 2-trimethylsilylethanol (25 µL, 174 µmol), and
N-iodosuccinimide (32.0 mg, 138 µmol) in dichloromethane (0.58 mL) was premixed with
molecular sieves 4Å (120 mg) for 30 min at 23 °C under nitrogen atmosphere before cooling to 4 °C
using ice bath. After addition of trifluoromethanesulfonic acid (3.1 µL, 35.0 µmol), the reaction
mixture was stirred for 10 min at the same temperature and quenched with a mixed solution of satd.
aq. NaHCO3/satd. aq. Na2S2O3 (10 mL/10 mL). After additional 10 min stirring, the resulting
solution was filtered through a pad of Celite® with chloroform (20 mL). The organic layer was
26

ACCEPTED MANUSCRIPT
separated from the aqueous layer and washed with brine (20 mL). The aqueous layers were extracted
with chloroform (20 mL×2). The combined organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash column chromatography (silica gel, ethyl
acetate:hexane = 1:12 → 1:8) to give the desired glycoside S5 (72.3 mg, 67%) as a colorless syrup.
S5 (647 mg, 689 µmol) was dissolved in a mixed solution of dichloromethane/methanol (2.8 mL/0.7
mL) before addition of 2,3-dichloro-5,6-dicyanobenzoquinone (154 mg, 678 µmol) After stirring for
12 h at 23 °C, the reaction mixture was evaporated until dry and dissolved in ethyl acetate (40 mL).
The resulting solution was washed with satd. aq. NaHCO3 (40 mL×2), and brine (40 mL). The
aqueous layers were extracted with ethyl acetate (40 mL×2). The combined organic layer was dried
over Na2SO4 and concentrated in vacuo. The resulting syrup was purified by flash column
chromatography (silica gel, ethyl acetate:hexane = 1:8 → 1:4) to give the title compound 12 (396 mg,
72%) as a white foam.
[α]D +30.5° (c 3.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.07–7.18 (m, 20H, Ph), 5.38 (brs, 1H,
H-2b), 5.32 (brs, 1H, H-2a), 5.17 (s, 1H, H-1b), 4.91–4.60 (m, 5H, H-1a and -CHPh×4), 4.26 (dd, 1H,
J2,3 = 3.2 Hz, J3,4 = 9.4 Hz, H-3a), 4.07 (m, 1H, H-3b), 3.89–3.73 (m, 3H, H-5a, H-5b and -CHCH2Si),
3.60 (t, 1H, J3,4 = J4,5 = 9.4 Hz, H-4a), 3.48 (m, 1H, -CHCH2Si), 3.40 (t, 1H, J4,5 = 9.5 Hz, H-4b),
2.08 (brs, 1H, OH), 1.31 (d, 3H, J5,6 = 6.2 Hz, H-6a), 1.25 (d, 3H, J5,6 = 6.2 Hz, H-6b), 0.98–0.83 (m,
2H, -CH2CHSi×2), 0.00 (s, 3H, SiMe3); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.9, 138.2, 137.9,
27

ACCEPTED MANUSCRIPT
133.2, 133.2, 129.9, 129.8, 129.8, 129.7, 128.5, 128.4, 128.3, 128.3, 128.2, 127.8, 127.7, 127.7, 99.4,
96.7, 81.2, 80.8, 77.2, 75.5, 73.9, 73.2, 73.1, 69.8, 68.2, 67.7, 65.2, 18.1, 17.9, 17.8, -1.3; HRMS
(ESI-TOF) m/z: found [M+Na]+ 821.3325, C45H54O11Si calcd for [M+Na]+ 821.3328.
3.12.
2-Trimethylsilylethyl
2-O-benzoyl-4-O-benzyl-3-O-(2-naphthylmethyl)-α-
L
-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-be
nzyl-α-L-rhamnopyranosyl-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranosyl-(1→3)-2-O-benzo
yl-4-O-benzyl-α-L-rhamnopyranoside (13)
A mixture of donor 2 (141 mg, 151 µmol), acceptor 12 (103 mg, 129 µmol), and N-iodosuccinimide
(43.1 mg, 192 µmol) in dichloromethane (1.3 mL) was premixed with activated molecular sieves 4Å
(560 mg) for 30 min at 23 °C under nitrogen atmosphere before cooling to 4 °C using ice bath. After
addition of trifluoromethanesulfonic acid (3.4 µL, 38 µmol), the reaction mixture was stirred at the
same temperature for 30 min and quenched with a mixed solution of satd. aq. NaHCO3 /satd. aq.
Na2S2O3 (10 mL/10 mL). After additional 10 min stirring, the resulting mixture was filtered through
a pad of Celite® with chloroform (20 mL). The organic layer was separated from the aqueous layer
and washed with brine (20 mL). The aqueous layers were extracted with chloroform (20 mL×2). The
combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was
purified by flash column chromatography (silica gel, ethyl acetate:hexane = 1:6 → 1:4) to give the
28