2-Allylphenyl glycosides as glycosyl donors for sugar coupling

Article abstract of DOI:10.1016/j.carres.2012.01.022

Glycosylations employing 2-allylphenyl glycoside, a new type of stable glycosyl donor, were optimized and explored with a variety of acceptors promoted by ICl/AgOTf. The utility of the protocol was further demonstrated with an efficient synthesis of the disaccharide fragment of bleomycins.

Full text of DOI:10.1016/j.carres.2012.01.022

Carbohydrate Research 352 (2012) 197–201
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
2-Allylphenyl glycosides as glycosyl donors for sugar coupling
b
b
b,c,
Shun-Yuan Luo a, , Ashish Tripathi , Medel Manuel L. Zulueta , Shang-Cheng Hung
⇑
⇑
a Department of Chemistry, National Tsing Hua University, 101, Sec. 2, Kuang-Fu Road, Hsinchu 300, Taiwan
b Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan
c Department of Applied Chemistry, National Chiao Tung University, No. 1001, Ta-Hsueh Road, Hsinchu 300, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Glycosylations employing 2-allylphenyl glycoside, a new type of stable glycosyl donor, were optimized
and explored with a variety of acceptors promoted by ICl/AgOTf. The utility of the protocol was further
demonstrated with an efficient synthesis of the disaccharide fragment of bleomycins.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 1 December 2011
Received in revised form 23 January 2012
Accepted 24 January 2012
Available online 7 February 2012
Keywords:
2-Allylphenyl glycoside
Bleomycin
Glycosylation
D-Mannose
Stereoselectivity
The ardent interests in glycobiology over the past few decades
fueled increasing demands for well-defined sugar motifs accessible
mainly through chemical synthesis.1 Carbohydrate scaffolds in bio-
logical systems exhibit diverse roles in crucial physiological events
such as fertilization,2 immune response,3 development,4 and bacte-
rial and viral infections.5,6 In addition, the inherent asymmetry of
sugar structures allowed them to serve as inexpensive chiral
sources.7,8 Oligosaccharide syntheses, however, have lagged far be-
hind their nucleic acid and protein counterparts because of the
highly functionalized and, in most cases, branched character of
the emulated naturally occurring sugars. An integral part in the
synthesis of an oligosaccharide is the formation of one or more gly-
cosidic bonds using saccharide building blocks.9 For over a century
since Koenigs and Knorr10 introduced the still widely used glycosyl
halides into the chemist’s armamentum, carbohydrate chemistry
has evolved amidst the abundance of glycosyl donors which can
be hand-picked to meet the constrains of the polymer assembly.11
Glycosyl donors can be further categorized as stable- or unstable-
type in relation to the lability of the leaving group on storage as
well as the reagents applied in various chemical transformations.
Consequently, several glycosylation promoters have been devel-
oped to match the distinct reactivities each donor manifests.12
Several leaving groups tolerate common protecting group
manipulations and can be activated independently for coupling
with an acceptor during sugar assembly. The most established do-
nors under this premise are the 4-n-pentenyl glycosides (NPG),
introduced by Fraser-Reid,13,14 and thioglycosides.15,16 Thioglyco-
sides, although quite common, are coupled with the use of awful
smelling thiols, which make their application driven by needs
rather than choice. NPGs (e.g., compound 1), on the other hand, riv-
al thioglycosides in versatility and are environmentally friendly.
Glycosylations involving NPGs are triggered by activation of the re-
mote double bond by halonium ions (e.g., Br+ or I+).17 It has been
understood that such a reaction operates with the formation of
the five-membered transition state 4 leading to the release of a
halomethylfuran and an oxocarbenium ion (5), the actual reactive
intermediate (Scheme 1). The intermediate 5, when supplemented
appropriately with a glycosyl acceptor, yields the desired saccha-
ride 6 in either of two possible outcomes, the a- and b-isomers.
Aiming to bring diversity toward NPG-type glycosides, we previ-
ously demonstrated the ability of 2-allyloxyphenyl donors for gly-
cosylation employing various acceptors in moderate to excellent
yields.18 Similarly, gem-dimethyl analogs of NPGs (i.e., compounds
2 and 3) were recently examined by Andrade and co-workers19 to
probe the ring closure acceleration affected by steric buttressing.
Continuing our efforts toward the exploration of NPG mimics for
glycosylation, we focused on the development of a stable and viable
glycosyl donor which can be accessed conveniently from cheap
materials and should, in particular, involve readily available mild
promoters for activation. In this regard, we wish to report the use
of 2-allylphenyl glycosides (7) as novel donors for carbohydrate
synthesis. We envisioned that the terminal double bond of 7 can,
in principle, be activated by an appropriate promoter to yield the
⇑
Corresponding authors present address: Department of Chemistry, National
Chung Hsing University, No. 250, Kuo-Kuang Road, Taichung 402, Taiwan (S.-Y.L.).
Tel.: +886 2 2787 1279; fax: +886 2 2789 8771.
E-mail addresses: syluo@dragon.nchu.edu.tw (S.-Y. Luo), schung@gate.sinica.
edu.tw (S.-C. Hung).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2012.01.022

198
S.-Y. Luo et al. / Carbohydrate Research 352 (2012) 197–201
Table 1
R1
R1
The results for coupling of the allyphenyl mannoside 12 with various alcohols
O
BnO
BnO
BnO
OBn
O
O
(PO)4
BnO
BnO
BnO
OBn
O
R
promoter
O
R
O
(PO)4
+
ROH
1: R = R1 = H
CH2Cl2, temp
O
2: R = Me, R1 = H
3: R = H, R1 = Me
OR
7
12
O
E+
BnO
E+
13: R =
14: R =
22
23
BnO
BnO
R1
OMe
E
E
BnO
BnO
+
+
R1
R
O
O
O
(PO)4
O
(PO)4
O
BnO
OMe
R
OBn
8
4
O
BnO
BnO
15: R =
24
OMe
+
ROH
BnO
BnO
BnO
O
OBn
O
O
(PO)4
(PO)4
OR
16: R =
17: R =
25
26
6
5
O
Scheme 1. An approach using NPG-type and 2-allylphenyl glycosides as glycosyl
BnO
donors.
BzO
O
18: R = CH3
19: R = PhCH2
27
28
29
oxocarbenium ion 5 through the release of the 4-allylphenyl moiety
as a benzofuran derivative via the transition state 8. The positive
charge in 8 is most likely stabilized through delocalization in the
neighboring benzene ring. This should also be responsible for the
facile generation of oxocarbenium ion 5 and the hereafter released
benzofuran moiety would be inert and unlikely to dictate the future
course of the glycosylation.
20: R =
n-C8H17
NHBoc
O-
t
-Bu
21: R =
30
O
Entry
ROH
Promoter
Temp
Product
Yield (%)
To test our hypothesis,
our study and the synthesis of the respective 2-allyphenyl 2,3,4,6-
D-mannose was selected as the model for
1
2
3
4
5
6
7
8
9
13
13
13
13
14
15
16
17
18
19
20
21
NIS/TESOTf
NIS/TMSOTf
NIS/TfOH
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
ICl/AgOTf
rt
rt
rt
22
22
22
22
23
24
25
26
27
28
29
30
47
43
63
74
61
65
63
63
67
89
74
53
tetra-O-benzyl-a-D-mannopyranoside (12), is outlined in Scheme
2. Treatment of the per-O-acetylated mannoside 920 with the cheap
compound 2-allyl phenol (10) in the presence of BF3ꢀEt2O delivered
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
the corresponding a
-glycoside 11 as a single isomer (3J1,2 = 1.8 Hz)
in an excellent 93% yield. The required glycosyl donor 12 was ac-
cessed via deacetylation under Zemplén condition (NaOMe, MeOH)
and subsequent per-O-benzylation of the ensuing tetraol with the
NaH/BnBr reagent combination. As anticipated, compound 12 was
found to be very stable toward air and moisture and can be conve-
niently stored for a few months with little precautions.
10
11
12
The feasibility of the allyphenyl mannoside 12 as donor for
chemical glycosylation was first evaluated by its coupling with
the glucopyranosyl alcohol 13 under the agency of some selected
promoters (Table 1). Triethylsilyl triflate (TESOTf) in combination
as a single isomer (3J1 ,2 = 2.2 Hz) in CH2Cl2 at room temperature
in a modest 47% yield (entry 1). No increase in yield was observed
when trimethylsilyl triflate (TMSOTf) was utilized as catalyst (en-
try 2). Fortunately, yield enhancement for compound 22 (63%)
was observed with triflic acid (TfOH) and NIS reagent tandem (en-
try 3). The reduced yield observed with TESOTf and TMSOTf was
probably the result of in situ silylation of the primary hydroxyl
group of the acceptor, which not only formed the undesired prod-
uct that was observed during the course of the reaction, but also
limited the catalyst needed to drive the reaction forward. We noted
that, under NIS/TfOH activation, the yield for the current donor is
lower than that of the corresponding allyoxyphenyl mannoside
the results of which were disclosed previously.18 The switch to
the ICl and silver triflate (AgOTf) combination proved favorable
as the yield increased further to 74% even at ice-cold condition (en-
try 4). With an amicable promoter for activation of 2-allylphenyl
glycosides, the scope of the reaction was extended to a range of
monosaccharide acceptors (14–17) and other aglycones (18–21).
0
0
with N-iodosuccinimide (NIS) furnished the desired
a-adduct 22
OH
AcO
AcO
AcO
OAc
O
AcO
AcO
OAc
O
, BF3•OEt2
Et3N, 93%
10
AcO
OAc
O
9
11
BnO
BnO
OBn
O
1. NaOMe, MeOH
2. NaH, BnBr
BnO
90% in 2 steps
O
Exclusive generation of
all the recruited alcohols in moderate to good yields. Notable here-
in is the generation of the 1?
10-dimannoside 25 generated in a
highly stereospecific fashion (entry 7). The protocol gains further
a-mannosides (23–30) were observed with
12
Scheme 2. Preparation of the 2-allylphenyl mannopyranoside 12.
a
a

S.-Y. Luo et al. / Carbohydrate Research 352 (2012) 197–201
199
importance with the formation of the a1?6-linked mannoside 24
1. Experimental
(entry 6), which is an essential constituent of glycosylphosphat-
idylinositol anchors associated with eukaryotes21 and phosphati-
1.1. General remarks
dylinositol
D-mannosides present in the Mycobacterium
tuberculosis cell wall.22 It should be mentioned that when we car-
ried out the activation of the disarmed mannoside 11 with ICl/
AgOTf in the presence of alcohol 13, the desired compound 22
was not isolated from the reaction mixture.
CH2Cl2 was purified and dried from a safe purification system
filled with anhydrous Al2O3. All other reagents, obtained from com-
mercial sources, were used without further purification. Flash col-
umn chromatography was carried out on Silica Gel 60 (230–
400 mesh, E. Merck). TLC was performed on pre-coated glass plates
of Silica Gel 60 F254 (0.25 mm, E. Merck); detection was executed by
spraying with a solution of Ce(NH4)2(NO3)6, (NH4)6Mo7O24, and
H2SO4 in water and subsequent heating on a hot plate. 1H and 13C
NMR spectra were recorded using 400 MHz, 500, and 600 MHz spec-
trometers. Chemical shifts are in ppm from Me4Si calibrated using
the resonance of the residual proton and carbon of the deuterated
solvent. Proton peak assignments were performed using 2D NMR
techniques (1H–1H COSY, HMQC, and NOESY); the hydrogen multi-
plicity of carbon peaks was determined using DEPT experiments.
Further in pursuit of demonstrating the utility of our 2-allyphe-
nyl donor toward the synthesis of biologically relevant scaffolds, we
chose to prepare the sugar unit present in bleomycin. Bleomycin re-
fers to a family of structurally related glycopeptides with antibiotic
properties usually associated with Streptomyces verticillus.23,24 They
hold immense therapeutic value and are used effectively for the
treatment of various types of cancers, mainly testicular cancer, lym-
phoma, and cancer of the head and neck. The carbohydrate moiety
of bleomycin, comprised of a
D-mannopyranose a1?2-linked to an
L-gulopyranose, was found to play a pivotal role in the therapeutic
ability of bleomycin by being involved in cell-surface recognition
and closely associated with the metal-binding domain.25 The effi-
cient synthesis of the bleomycin carbohydrate fragment is depicted
in Scheme 3. A highly regioselective triflation and acetylation of the
1.2. 2-Allylphenyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside
(11)
1,6-anhydro-
underwent nucleophilic substitution under the agency of NaNO2 in
hexamethylphosphoramide (HMPA) to afford the -gulopyranosyl
L
-idose 3126 in one pot generated the triflate 32, which
BF3ꢀEt2O (812
pentaacetate 9 (1.00 g, 2.56 mmol), 2-allylphenol (10, 371
2.82 mmol), and Et3N (179 L, 1.28 mmol) in CH2Cl2 (1 mL) at
lL, 6.40 mmol) was added to a mixture of the
l
L,
L
l
alcohol 33 in a 79% overall yield in three steps. With the required
acceptor 33 in hand, glycosylation was pursued employing our 2-
allylphenyl mannosyl donor 12 promoted by ICl/AgOTf in anhy-
0 °C under N2 atmosphere. The ice bath was removed and the mix-
ture was kept stirring at room temperature for 36 h. The reaction
mixture was neutralized with satd NaHCO3(aq) and then poured
into a biphasic solution of EtOAc (30 mL) and H2O (10 mL). The
crude target material was extracted with EtOAc (2 ꢁ 15 mL), and
the combined organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (EtOAc/hexanes = 1/2) to
drous CH2Cl2 at 0 °C. The a-linked disaccharide 34 was isolated in
a 63% yield as a single isomer; 18% of the acceptor 33 that remained
unreacted was recovered. Palladium-catalyzed debenzylation (10%
Pd/C, H2) of 34 followed by acetolysis with concomitant acetylation
(Ac2O, trifluoroacetic acid) supplied the peracetylated disaccharide
35 in an 85% yield (two steps). This disaccharide moiety was earlier
utilized by Umezawa and co-workers for the successful synthesis of
bleomycin A2.27
give compound 11 (1.11 g, 93%) as light yellow oil: ½a D24
ꢃ76.3 (c
ꢂ
0.1, CHCl3); IR (thin film):
m 3058, 2976, 2904, 1750, 1451, 1369,
1220, 1084, 1034 cmꢃ1 1H NMR (CDCl3, 400 MHz): d 7.18–7.09
;
In conclusion, we have presented a new type of stable glycosyl
donor, which is readily accessible from inexpensive commercial
sources and subsequently, glycosylations of various alcohols were
also demonstrated. The relative ease of preparation, storage, and
handling coupled with the inherent inertness of the 2-allylphenyl
moiety to common manipulations associated with carbohydrates
would enable them to be attractive donors in oligosaccharide
assembly.
(m, 3H, Ar-H), 7.02–6.97 (m, 1H, Ar-H), 5.94 (ddt, 1H, J = 16.5,
10.0, 6.5 Hz, CH@CH2), 5.54 (dd, 1H, J = 10.0, 3.4 Hz, H-3), 5.50 (d,
1H, J = 1.8 Hz, H-1), 5.43 (dd, 1H, J = 3.4, 1.8 Hz, H-2), 5.36 (t, 1H,
J = 10.0 Hz, H-4), 5.12–5.02 (m, 2H, CH@CH2), 4.26 (dd, 1H,
J = 12.8, 6.0 Hz, H-6a), 4.08–4.03 (m, 2H, H-5, H-6b), 3.41 (d, 2H,
J = 6.5 Hz, CH2CH@CH2), 2.17 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.02
(s, 3H, OAc), 2.01 (s, 3H, OAc); 13C NMR (CDCl3, 100 MHz): d
170.6 (C), 170.1 (C), 170.0 (C), 169.9 (C), 153.7 (C), 136.7 (CH),
130.6 (CH), 129.4 (C), 127.6 (CH), 123.0 (CH), 116.0 (CH2), 114.3
(CH), 95.9 (CH), 69.6 (CH), 69.4 (CH), 69.1 (CH), 66.0 (CH), 62.7
(CH2), 34.9 (CH2), 21.0 (CH3 ꢁ 2), 20.8 (CH3 ꢁ 2); HRMS (FAB): m/
z Calcd for C23H29O10 ([M+H]+): 465.1761. Found: 465.1765; Anal.
Calcd for C23H28O10: C, 59.48; H, 6.08. Found: C, 59.85; H, 6.36.
Tf2O, pyridine;
O
O
HO
BnO
AcO
BnO
NaNO2
Ac2O
HMPA
79% from 31
HO
TfO
O
O
32
31
OBn
O
BnO
BnO
1.3. 2-Allylphenyl 2,3,4,6-tetra-O-benzyl-a-D-mannopyranoside
(12)
OH
BnO
O
12, ICl/AgOTf
AcO
BnO
O
CH2Cl2, 0 o
63%
C
NaOMe (24.3 mg, 0.45 mmol) was added to a solution of com-
pound 11 (1.05 g, 2.26 mmol) in MeOH (10 mL) at room tempera-
ture under N2 atmosphere. The mixture was stirred for 4 h and
then neutralized with an acidic resin. After filtration, the filtrate
was concentrated under reduced pressure. The vacuum-dried res-
idue was dissolved in DMF (6.50 mL), and BnBr (1.28 mL,
10.9 mmol) was added at room temperature followed by addition
of NaH (60% dispersion in mineral oil, 0.43 g, 10.9 mmol) at 0 °C.
The temperature was gradually elevated to ambient level, and
the mixture was kept stirring for 10 h. The reaction was quenched
by addition of H2O (20 mL) and the crude target material was ex-
tracted with EtOAc (3 ꢁ 20 mL). The combined organic layer was
O
O
AcO
BnO
33
O
34
AcO
OAc
AcO
1. 10% Pd/C, H2
2. Ac2O, trifluoroacetic acid
O
O
OAc
OAc
O
AcO
85% in 2 steps
OAc
AcO
35
Scheme 3. Synthesis of the disaccharide moiety of bleomycins.

200
S.-Y. Luo et al. / Carbohydrate Research 352 (2012) 197–201
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
(EtOAc/hexanes = 1/4) to give compound 12 (1.33 g, 90% in two
100 MHz): d 165.8 (C), 139.2 (C), 138.9 (C), 138.3 (C), 138.11 (C),
138.10 (C), 133.4 (CH), 130.0 (CH), 129.1 (CH), 128.5 (CH), 128.3
(CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 100.8 (CH),
99.3 (CH), 80.7 (CH), 79.6 (CH), 78.8 (CH), 76.7 (CH), 75.37 (CH2),
75.3 (CH), 75.1 (CH), 74.8 (CH2), 74.4 (CH), 73.6 (CH2), 72.9 (CH),
72.8 (CH2), 72.4 (CH2), 69.5 (CH2), 65.9 (CH2); HRMS (FAB): m/z
Calcd for C54H54O11 ([M]+): 901.3564. Found: 901.3578.
steps) as a light yellow oil: ½a D33
ꢂ
+60.2 (c 1.9, CHCl3); IR (thin film):
m
3030, 2904, 2867, 1600, 1492, 1451, 1229, 1094 cmꢃ1 1H NMR
;
(CDCl3, 400 MHz): d 7.39–7.23 (m, 18H, Ar-H), 7.19–7.10 (m, 5H,
Ar-H), 6.94 (td, 1H, J = 7.4, 1.1 Hz, Ar-H), 5.83 (ddt, 1H, J = 17.0,
10.3, 6.6 Hz, CH@CH2), 5.53 (d, 1H, J = 1.8 Hz, H-1), 4.98–4.91 (m,
2H, CH@CH2), 4.92 (d, 1H, J = 10.8 Hz, CH2Ph), 4.77 (s, 1H, CH2Ph),
4.76 (s, 1H, CH2Ph), 4.71 (d, 1H, J = 11.8 Hz, CH2Ph), 4.66 (d, 1H,
J = 11.8 Hz, CH2Ph), 4.65 (d, 1H, J = 11.8 Hz, CH2Ph), 4.54 (d, 1H,
J = 10.8 Hz, CH2Ph), 4.46 (d, 1H, J = 11.8 Hz, CH2Ph), 4.15 (t, 1H,
J = 9.5 Hz, H-4), 4.06 (dd, 1H, J = 9.5, 3.0 Hz, H-3), 3.87–3.82 (m,
2H, H-2, H-5), 3.79 (dd, 1H, J = 10.8, 4.5 Hz, H-6a), 3.68 (dd, 1H,
J = 10.8, 1.4 Hz, H-6b), 3.24 (dd, 1H, J = 15.4, 6.6 Hz, CH2CH@CH2),
3.18 (dd, 1H, J = 15.4, 6.6 Hz, CH2CH@CH2); 13C NMR (CDCl3,
100 MHz): d 154.3 (C), 138.5 (C), 138.3 (C ꢁ 2), 138.1 (C), 136.7
(CH), 129.9 (CH), 128.9 (C), 128.41 (CH), 128.35 (CH), 128.29
(CH), 128.2 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.74 (CH),
127.67 (CH), 127.5 (CH), 127.4 (CH), 122.2 (CH), 115.5 (CH2),
114.6 (CH), 96.6 (CH), 79.5 (CH), 75.1 (CH2), 74.9 (CH), 74.7 (CH),
73.3 (CH2), 72.7 (CH2), 72.6 (CH), 72.4 (CH2), 69.0 (CH2), 34.5
(CH2); HRMS (FAB): m/z Calcd for C43H44O6 ([M]+): 656.3138.
Found: 656.3130.
1.4.3. 3-O-(2,3,4,6-Tetra-O-benzyl-
butoxycarbonyl- -serine tert-butyl ester (30)
+21.9 (c 3.9, CHCl3); IR (thin film):
1717, 1681, 1496, 1455, 1390, 1365, 1153, 1100, 1055 cmꢃ1
a-D-mannopyranosyl)-N-tert-
L
½
a 2D8
ꢂ
m
3026, 2977, 2920,
1H
;
NMR (CDCl3, 400 MHz): d 7.37–7.25 (m, 18H, Ar-H), 7.18–7.15
(m, 2H, Ar-H), 5.32 (d, 1H, J = 8.8 Hz, NH), 4.87 (d, 1H, J = 10.8 Hz,
CH2Ph), 4.83 (d, 1H, J = 1.8 Hz, H-10), 4.74 (d, 1H, J = 12.4 Hz,
CH2Ph), 4.69 (d, 1H, J = 10.8 Hz, CH2Ph), 4.68 (d, 1H, J = 12.4 Hz,
CH2Ph), 4.64 (d, 1H, J = 11.8 Hz, CH2Ph), 4.60 (d, 1H, J = 11.8 Hz,
CH2Ph), 4.53 (d, 1H, J = 12.0 Hz, CH2Ph), 4.51 (d, 1H, J = 10.8 Hz,
CH2Ph), 4.32 (d, 1H, J = 8.8 Hz, H-2), 4.03 (t, 1H, J = 9.6 Hz, H-40),
3.85–3.69 (m, 7H, H-3a, H-3b, H-20, H-30, H-50, H-60a, H-60b), 1.45
(s, 9H, CH3 ꢁ 3), 1.39 (s, 9H, CH3 ꢁ 3); 13C NMR (CDCl3,
150 MHz): d 169.3 (C), 155.4 (C), 138.4 (C), 138.3 (C), 138.2 (C),
128.4 (CH), 128.34 (CH), 128.29 (CH), 128.0 (CH), 127.8 (CH),
127.7 (CH), 127.63 (CH), 127.62 (CH), 127.5 (CH), 99.0 (CH), 82.0
(CH), 79.9 (CH), 75.1 (CH2), 74.7 (CH), 74.4 (CH), 73.4 (CH2), 72.6
(CH2), 72.3 (CH2), 72.2 (CH), 69.2 (CH2), 68.9 (CH2), 54.3 (CH),
29.7 (C), 28.3 (CH3), 28.0 (CH3); HRMS (FAB): m/z Calcd for
1.4. General procedure for glycosylation
ICl (1.2 equiv, 1 M solution in CH2Cl2) was added in a dropwise
fashion to a premixed solution of compound 12 (80–100 mg,
1.2 equiv), acceptor (1 equiv), and AgOTf (1.26 equiv) in CH2Cl2
(20 mL/g of 12) under N2 atmosphere at 0 °C. After the consump-
tion of the respective alcohol as evident from TLC analysis (2–
3 h), the mixture was diluted with 5% Na2S2O3(aq) (10 mL) and
extracted with EtOAc (3 ꢁ 20 mL). The combined organic layer
was washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by flash column chroma-
C
C
46H58O10N ([M+H]+): 784.4061. Found: 784.4066; Anal. Calcd for
46H57O10: C, 70.48; H, 7.33. Found: C, 71.01; H, 7.30.
1.4.4. 4-O-Acetyl-1,6-anhydro-3-O-benzyl-2-O-(2,3,4,6-tetra-O-
benzyl- -mannopyranosyl)-b- -gulopyranose (34)
ꢃ16.5 (c 0.9, CHCl3); IR (thin film): 2915, 2860, 1752,
1456, 1229, 1049 cmꢃ1 1H NMR (CDCl3, 500 MHz): d 7.36–7.20
a-
D
L
½
a 2D3
ꢂ
m
;
(m, 23H, Ar-H), 7.15–7.13 (m, 2H, Ar-H), 5.51 (d, 1H, J = 2.4 Hz, H-
10), 5.15 (dd, 1H, J = 9.6, 4.0 Hz, H-4), 5.04 (d, 1H, J = 1.8 Hz, H-1),
4.85 (d, 1H, J = 10.8 Hz, CH2Ph), 4.64 (d, 2H, J = 12.8 Hz, CH2Ph),
4.59 (d, 1H, J = 11.6 Hz, CH2Ph), 4.53–4.48 (m, 7H, CH2Ph ꢁ 6,
H-5), 3.99 (dd, 1H, J = 4.4, 2.4 Hz, H-20), 3.94–3.92 (m, 3H, H-30,
H-60a, H-60b), 3.87 (d, 1H, J = 7.8 Hz, H-6a), 3.83 (s, 1H, H-2), 3.76–
3.69 (m, 2H, H-40, H-50), 3.71 (t, 1H, J = 9.6 Hz, H-3), 3.59 (dd, 1H,
J = 7.7, 4.8 Hz, H-6b), 2.04 (s, 3H, OAc); 13C NMR (125 MHz, CDCl3):
d 169.9 (C), 138.5 (C), 138.3 (C ꢁ 2), 138.3 (C), 137.8 (C), 128.4 (CH),
128.3 (CH), 128.25 (CH), 128.16 (CH), 128.0 (CH), 127.9 (CH), 127.7
(CH), 127.55 (CH), 127.46 (CH), 127.41(CH), 100.8 (CH), 99.7 (CH),
79.8 (CH), 75.0 (CH2), 74.8 (CH), 74.7 (CH), 74.5 (CH), 73.3 (CH2),
72.5 (CH2), 72.35 (CH2), 72.26 (CH2), 72.1 (CH), 71.9 (CH), 71.4
(CH), 69.3 (CH2), 64.1 (CH2), 21.0 (CH3); HRMS (FAB): m/z Calcd
for C49H52O11Na ([M+H]+): 839.3407. Found: 839.3404.
tography to obtain the desired
a
-mannopyranosylated adducts.
1.4.1. (2,3,4,6-Tetra-O-benzyl-a-D-mannopyranosyl)-2,3,4,6-
tetra-O-benzyl-
+30.8 (c 3.5, CHCl3); IR (thin film):
1631, 1451, 1210, 1104 cmꢃ1 1H NMR (CDCl3, 400 MHz): d 7.37–
a-D-mannopyranoside (25)
½
a 2D8
ꢂ
m 3017, 2919, 2862,
;
7.20 (m, 20H, Ar-H), 5.21 (d, 1H, J = 1.8 Hz, H-1), 4.90 (d, 1H,
J = 10.6 Hz, CH2Ph), 4.67–4.64 (m, 3H, CH2Ph), 4.56 (d, 1H,
J = 11.0 Hz, CH2Ph), 4.55 (s, 2H, CH2Ph), 4.53 (d, 1H, J = 11.0 Hz,
CH2Ph), 3.99 (t, 1H, J = 9.6 Hz, H-4), 3.75–3.58 (m, 5H, H-2, H-3,
H-4, H-5, H-6a, H-6b); 13C NMR (CDCl3, 100 MHz): d 138.48 (C),
138.47 (C), 138.4 (C), 138.1 (C), 128.6 (CH), 128.5 (CH), 128.46
(CH), 128.2 (CH), 128.1 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH),
93.5 (CH), 79.6 (CH), 75.4 (CH2), 74.8 (CH), 74.2 (CH), 73.6 (CH2),
72.8 (CH), 72.6 (CH2), 72.2 (CH2), 69.2 (CH2); HRMS (FAB): m/z
Calcd for C68H71O11 ([M+H]+): 1063.4996. Found: 1063.4991.
1.5. 4-O-Acetyl-1,6-anhydro-3-O-benzyl-b-L-gulopyranose (33)
Triflic anhydride (Tf2O, 0.18 mL, 1.07 mmol) was added to a
solution of diol 31 (0.20 g, 0.79 mmol) in CH2Cl2 (2 mL) and pyri-
dine (1.4 mL) at 0 °C. After 11 h, Ac2O (0.22 mL, 2.38 mmol) was
added to the reaction flask at room temperature, and the solution
was stirred further for 2 h. The reaction was quenched with satd
NH4Cl(aq) (20 mL), and the crude target material was extracted
with EtOAc (3 ꢁ 20 mL). The combined organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure to
get the crude triflate derivative 32. HMPA (2 mL) and NaNO2
(0.55 g, 7.97 mmol) were added to the residue followed by stirring
at room temperature for 12 h. The mixture was diluted with EtOAc
(50 mL) and washed with H2O (2 ꢁ 10 mL). The organic solution
was dried over MgSO4, concentrated, and purified by flash column
chromatography (EtOAc/hexanes = 1/5) to furnish 33 (184 mg, 79%
1.4.2. 1,6-Anhydro-2-O-benzoyl-3-O-benzyl-4-O-(2,3,4,6-tetra-O
-benzyl-
+77.1 (c 0.8, CHCl3); IR (thin film):
1651, 1637, 1451, 1360, 1270, 1102 cmꢃ1
a
-
D
-mannopyranosyl)-b-
L
-idopyranose (26)
3031, 2913, 2867, 1719,
1H NMR (CDCl3,
½
a 2D8
ꢂ
m
;
400 MHz): d 8.01 (dd, 2H, J = 7.9, 0.7 Hz, Bz-H), 7.59 (t, 1H,
J = 7.4 Hz, Ar-H), 7.45 (t, 2H, J = 7.4 Hz, Ar-H), 7.36–7.25 (m, 18H,
Ar-H), 7.21–7.45 (m, 5H, Ar-H), 7.45–7.10 (m, 2H, Ar-H), 5.50 (d,
1H, J = 1.8 Hz, H-10), 5.13 (d, 1H, J = 1.9 Hz, H-1), 5.03 (dd, 1H,
J = 8.2, 1.8 Hz, H-20), 4.86 (d, 1H, J = 10.8 Hz, CH2Ph), 4.83 (t, 1H,
J = 4.3 Hz, H-3), 4.67–4.54 (m, 8H, CH2Ph), 4.50 (d, 1H, J = 10.8 Hz,
CH2Ph), 4.04 (d, 1H, J = 8.0 Hz, H-5), 3.94 (dd, 1H, J = 8.0, 4.3 Hz,
H-4), 3.91–3.84 (m, 2H, H-30, H-60a), 3.81 (dd, 1H, J = 9.0, 3.0 Hz, H-
60b), 3.74–3.64 (m, 5H, H-6a, H-6b, H-2, H-40, H-50); 13C NMR (CDCl3,

S.-Y. Luo et al. / Carbohydrate Research 352 (2012) 197–201
201
from 31) as a light yellow oil. ½a D23
ꢂ
+33.5 (c 1.1, CHCl3); IR (thin
m ;
Acknowledgements
film):
3413, 2922, 2881, 1742, 1409, 1212, 1130 cmꢃ1 1H NMR
(CDCl3, 600 MHz): d 7.36–7.31 (m, 2H, Ar-H), 7.31–7.26 (m, 3H,
Ar-H), 5.47 (d, 1H, J = 2.42 Hz, H-1), 5.13 (ddd, 1H, J = 9.16, 4.44,
0.80 Hz, H-4), 4.65 (d, 1H, J = 11.94 Hz, CH2Ph), 4.54 (d, 1H,
J = 11.94 Hz, CH2Ph), 4.51 (t, 1H, J = 4.44 Hz, H-5), 3.94 (dd, 1H,
J = 4.73, 2.42 Hz, H-2), 3.88 (d, 1H, J = 7.77 Hz, H-6a), 3.67 (dd, 1H,
J = 4.73, 9.16 Hz, H-3), 3.62 (ddd, 1H, J = 7.77, 4.44, 0.80 Hz, H-6b),
2.59 (br s, 1H, 2-OH), 2.01 (s, 1H, CH3); 13C NMR (CDCl3,
125 MHz): d 169.4 (C), 137.1 (C), 128.5 (CH ꢁ 2), 128.1 (CH),
127.8 (CH ꢁ 2), 98.8 (CH), 86.8 (CH), 76.7 (CH), 75.4 (CH2), 72.7
(CH), 72.6 (CH), 65.9 (CH2), 20.6 (CH3); HRMS (FAB): m/z Calcd
for C15H18O6 ([M]+): 294.1103. Found: 294.1107.
This work was supported by the National Science Council (NSC
97-2113-M-001-033-MY3, NSC 98-2119-M-001-008-MY2) and
Academia Sinica (summit project and investigator award project).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2012.01.022.
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1.6. 3,4,6-Tri-O-acetyl-2-O-(2,3,4,6-tetra-O-acetyl-
a-D-manno-
pyranosyl)- -gulopyranosyl acetate (35)
L
A solution of 34 (30 mg, 37 lmol) in a mixed solvent [EtOAc/
MeOH (1/3), 4 mL] was hydrogenated under 50 psi pressure in
the presence of 10% Pd/C (31 mg) at room temperature for 18 h.
The mixture was filtered through Celite, and the filtrate was con-
centrated in vacuo to give the crude debenzylated pentaol. To this
crude compound was added Ac2O (1 mL) and trifluoroacetic acid
(0.1 mL), and the mixture was stirred at room temperature for
4 h. The reaction was quenched by MeOH (1 mL), and the resulting
solution was kept stirring for 30 min. The mixture was concen-
trated in vacuo, and the residue was purified by flash column chro-
matography (EtOAc/hexanes = 1/1) to afford the expected product
35 (21 mg, 85%,
a/b = 1/4). The NMR spectrum of compound 35
corroborated with the literature report.28 1H NMR (CDCl3,
600 MHz): d 6.26 (d, 0.25H, J = 4.14 Hz), 5.86 (d, 1H, J = 8.40 Hz),
5.40 (t, 1.02H, J = 3.57 Hz), 5.29 (t, 0.30H, J = 3.66 Hz), 5.27–5.20
(m, 1.32H), 5.12 (dd, 1.05H, J = 10.02, 3.42 Hz), 5.08–5.03 (m,
1.87H), 4.99–4.91 (m, 2.43H), 4.50 (td, 0.26H, J = 6.84, 0.78 Hz),
4.33 (td, 1.03H, J = 12.99, 1.29 Hz), 4.29–4.21 (m, 0.69H), 4.21–
4.15 (m, 1.88H), 4.15–4.09 (m, 1.78H), 4.09–4.02 (m, 2.50H), 3.99
(ddd, 0.31H, J = 10.07, 4.97, 2.33 Hz), 3.96 (dd, 1.03H, J = 8.43,
3.33 Hz), 2.16 (s, 0.86H), 2.15 (s, 3.00H), 2.14 (s, 0.96H), 2.12 (s,
3.08H), 2.11–2.10 (m, 6.47H), 2.094 (s, 1.01H), 2.087 (s, 2.85H),
2.08 (s, 1.08H), 2.03 (s, 0.82H), 2.035 (s, 0.88H), 2.029 (s, 0.84H),
2.02 (s, 3.01H), 2.00 (s, 3.07H), 1.94–1.92 (m, 3.70H); 13C NMR
(CDCl3, 150 MHz): d 170.5 (C), 170.4 (C), 169.9 (C), 169.8 (C),
169.7 (C), 169.52 (C), 169.50 (C), 169.47 (C), 169.42 (C), 169.24
(C), 169.21 (C), 168.6 (C), 95.8 (CH), 94.9 (CH), 90.6 (CH), 89.3
(CH), 71.3 (CH), 69.8 (CH), 69.6 (CH), 69.2 (CH), 68.7 (CH), 68.6
(CH), 68.5 (CH), 67.61 (CH), 67.58 (CH), 67.3 (CH), 65.8 (CH), 65.7
(CH), 65.51 (CH), 65.45 (CH), 65.3 (CH), 63.8 (CH), 62.2 (CH2),
62.0 (CH2), 61.6 (CH2), 61.3 (CH2), 20.80 (CH3), 20.77 (CH3), 20.70
(CH3), 20.64 (CH3), 20.60 (CH3), 20.53 (CH3).