Synthesis of raffinose family oligosaccharides by regioselective de-O-benzylation with Co2(CO)8/Et3SiH/CO system

Article abstract of DOI:10.1016/j.tet.2013.03.094

A convenient approach for synthesis of raffinose, stachyose, and verbascose using sucrose as the starting material is presented. The key step is the regioselective de-O-benzylation with Co₂(CO)₈/Et ₃SiH/CO system, followed by a high α-selective glycosylation. The newly developed de-O-benzylation system is efficient in removing the primary benzyl groups of sucrose and raffinose under mild condition and with high selectivity. Using thioglycoside as donor, NIS/AgOTf as promoter and DTBMP as additive, glycosylation of acid labile sucrose substrate is achieved in high yield.

Full text of DOI:10.1016/j.tet.2013.03.094

Tetrahedron 69 (2013) 5022e5028
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Tetrahedron
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Synthesis of raffinose family oligosaccharides by regioselective
de-O-benzylation with Co2(CO)8/Et3SiH/CO system
Yue-tao Zhao, Shan Niu, Lu-bai Huang, Ji-ming Wang, Zhao-jun Yin, Qing Li,
*
Zhong-jun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health
Science Center, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient approach for synthesis of raffinose, stachyose, and verbascose using sucrose as the starting
Received 29 January 2013
Received in revised form 18 March 2013
Accepted 25 March 2013
material is presented. The key step is the regioselective de-O-benzylation with Co2(CO)8/Et3SiH/CO
system, followed by a high a-selective glycosylation. The newly developed de-O-benzylation system is
efficient in removing the primary benzyl groups of sucrose and raffinose under mild condition and with
high selectivity. Using thioglycoside as donor, NIS/AgOTf as promoter and DTBMP as additive, glycosyl-
ation of acid labile sucrose substrate is achieved in high yield.
Available online 29 March 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Regioselective de-O-benzylation
Dicobalt octacarbonyl
Sucrose
Raffinose family oligosaccharides
Glycosylation
1. Introduction
Sucrose is a widely available disaccharide. Many approaches to
utilize sucrose as the raw material for the preparation of different
The benzyl ether protecting group is important in the chem-
istry of carbohydrates, because of its easy formation and stability
under various conditions.1 Despite many regioselective in-
troduction and removal methods of the benzyl protecting group
toward monosaccharides,2 there are still limited methods for the
selective de-O-benzylation of complex oligosaccharides.3 Benzyl
groups are primarily used as permanent protecting groups of
complex oligosaccharides that are not removed until the last step
of synthesis.
The organocobalt reagent Co2(CO)8 is an essential catalyst in
many important reactions, such as the Nicholas reaction,4 Pau-
soneKhand reaction,5 and carbonylation reactions.6 Murai et al.
found that the Co2(CO)8/Et3SiH/CO system was efficient in cata-
lyzing the silylformylation of olefins, alkynes, aldehydes, cyclic
ethers, esters, and acetals.7 Previous work in our laboratory showed
that this system can regioselectively remove the benzyl groups
protecting primary hydroxyls of carbohydrates (Fig. 1), including
complex disaccharides and trisaccharides. The actual catalyst is
thought to be Co(CO)4-SiEt3, which is generated from Co2(CO)8 and
Et3SiH in situ and sensitive to steric hindrance.8
organic compounds have been attempted.9 Because there are three
primary hydroxyl groups in sucrose, the main focus of sucrose
chemistry is to understand their relative reactivity and how to
control their transformation. However, due to the similarity of the
three hydroxyl groups, the terminal modification usually proceeds
with poor regioselectivity.10 Moreover, because of the instability of
the glycoside bond in the presence of acid,11 there are a limited
number of reagents suitable for the modification of sucrose.
Therefore, there is a need to develop selective and mild reagents for
sucrose manipulation.
Raffinose family oligosaccharides (raffinose, stachyose, verbas-
cose) are a group of carbohydrates with different numbers of ga-
lactose in the glucose residue of sucrose. They are called ‘good
Bifidus-Factors’ for the ability to promote the Bifidobacterium
growing in intestine and can act as anti-oxidation, anti-freeze, and
anti-cancer agents.12 Besides, stachyose is a healthcare product on
sale with effect on enhancing human immunity. Though raffinose is
easy to obtain from nature, it is still difficult to extract the longer
oligomers stachyose and verbascose with enough purity13aec and to
synthesize these oligosaccharides by chemical method.13d Consid-
ering the chemical character of the raffinose family oligosaccha-
rides and the good selectivity of Co2(CO)8/Et3SiH/CO systemin de-
O-benzylation of complex oligosaccharides, we herein report
a convenient synthesis of raffinose, stachyose, and verbascose using
sucrose as the starting material (Fig. 2).
* Corresponding author. Tel.: þ86 10 8280 1714; fax: þ86 10 8280 5496; e-mail
addresses: zjli@bjmu.edu.cn, zjli@mail.bjmu.edu.cn (Z.-jun Li).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.094

Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
5023
Fig. 1. Regioselective de-O-benzylation by Co2(CO)8/silane/CO system.
Fig. 2. Retro-synthetic strategy of raffinose family of oligosaccharides.
2. Results and discussion
donors and promoters. Considering the acid labile feature of su-
crose, we controlled the reaction condition to be as neutral as
possible (Table 1).
Regioselective modification of the three primary hydroxyl
groups of sucrose 1 is difficult to achieve, especially the selective
modification of the 60-OH and 6-OH groups. However, when su-
crose is fully protected by benzyl groups 2, the regioselective de-O-
benzylation could be implemented (Scheme 1).
Using 1-OH sugar 7a as donor, CBr4/PPh3 as promoter and
DMF as solvent, the monosaccharide can be glycosylated with
high yield and
with sucrose as the acceptor, no reaction occurred (entry 1). Using
a
-selectivity.16 But under the same condition
Scheme 1. Reagents and conditions: (a) BnBr/NaH, DMF, rt 75%; (b) Co2(CO)8 (1.5 equiv)/Et3SiH (10 equiv)/CO, PhH, 50 ꢀC, 85% with 3, 15% with 30; (c) TBAF/THF, then Ac2O/Py, 90%
in two steps; (d) Co2(CO)8 (6 equiv)/Et3SiH (20 equiv)/CO, PhH, 70 ꢀC, 70%; (e) TBAF/THF, 0.5 h, quantitative.
When treated with Co2(CO)8(1.5 equiv) and Et3SiH(10 equiv) at
50 ꢀC in benzene, the 60-OBn was removed first and transformed to
silyl ether (3, 85%), along with formation of a small percentage of
de-6,60-O-benzylation side-product (30, 15%). These results sug-
Table 1
Screening of different glycosylation conditions
gested that there was a certain difference of reactivity between the
60-OBn and 6-OBn, which could be caused by the steric hindrance
difference. Because of the concern about the stability of the silyl
ether in compound 3, we converted the silyl ether to acetate 4
before further manipulation, which is stable under Co2(CO)8/
Et3SiH/CO system reported by Murai et al.14
The condition required for the removal of 6-OBn in 4 was
harsher. We used more equivalents of Co2(CO)8 (6 equiv) and Et3SiH
(20 equiv) and higher reaction temperature (70 ꢀC), and the yield of
product 5 was moderate (70%). This result suggested that the steric
Entry
Donor
Promoter
Additives
Solvent/T
Yield/(a/b)
hindrance of 6-OBn was higher than that of 60-OBn. Rapid desilly-
lation of 5 by TBAF in 0.5 h produced compound 6, which was used
directly as a glycosylation acceptor.
1
2
3
4
5
7a
7b
7b
7c
7d
CBr4/PPh3
TMSOTf
TMSOTf
NIS/AgOTf
TMSOTf
d
DMF/rt
N.R.a
MS
CH2Cl2/0 ꢀ
CH2Cl2/0 ꢀ
C
C
0b
DTBMP/MS
DTBMP/MS
DTBMP/MS
75%/(1/1)
CH2Cl2/ꢁ78 ꢀC
90%/(
a only)
The glycosidic bond of sucrose is rather sensitive to acidic con-
ditions, and it can be hydrolyzed in 0.1% HCl in MeOH in 30 min.15
The chemical glycosylation of sucrose as substrate, either as donor
or as acceptor, has rarely been reported. We screened several
CH2Cl2/0 ꢀ
C
N.R.a
a
No reaction.
b
Acceptor was consumed but no product was found.

5024
Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
trichloroacetimidate 7b as donor, TMSOTf as promoter and 4A MS to
remove water, the sucrose acceptor was consumed but the product
was complex and no trisaccharide was obtained (entry 2). This re-
sult could be attributed to the generation of TfOH acid from TMSOTf,
which catalyzed hydrolysis of the glycosidic bond of sucrose. When
2,6-di-tert-butyl-4-methyl pyridine (DTBMP) was used as the ad-
ditive to neutralize the formed TfOH, the trisaccharide product was
obtained in 75% yield, but the stereoselectivity was poor (
entry 3).
a/b¼1/1,
Using thioglycoside 7c as the donor, NIS/AgOTf as promoter and
DTBMP/4A MS as additives, we got raffinose 8 with satisfactory
yield (90%) and selectivity (a only, entry 4). When using tri-
chloroacetyl ester 7d, which had been developed in our own group
as the donor,17 no reaction occurred (entry 5), likely because of the
lower reactivity of the trichloroacetyl ester compared to the tri-
chloroacetimidate and the thioglycosides.
Scheme 3. Reagents and conditions: (a) Co2(CO)8 (6 equiv)/Et3SiH (40 equiv)/CO/PhH,
50 ꢀC, 65% for 11 and 12 (not separated); (b) TBAF/THF (94%, 13/14¼1.2/1); (c) 7c/NIS/
AgOTf/MS/DTBMP, CH2Cl2, ꢁ78 ꢀC, 85%.
For the de-O-benzylation of 60-O-acetylated raffinose 8, the distal
primary benzyl was removed as expected, and the reaction went
more smoothly than that of 4. Fewer equivalent of Co2(CO)8 was
needed (3 equiv) and the yield was higher (72%). Removal of the silyl
group in 9 and glycosylation with 7c gave stachyose 10 (Scheme 2).
The regioselective de-O-benzylation of 10 was more compli-
cated. Up to 12 equiv Co2(CO)8 and 40 equiv Et3SiH could not
remove the primary benzyl group completely (65% removed), and
the de-10-O-benzylation by-product 12 was formed. Compound 12
and the desired de-6000-O-benzylation product 11 could not be
separated by column chromatography. However, the two products
were separated after removal of the silyl group (compound 13 and
14). The ratio of 13/14 was 1.2/1.
Scheme 4. Reagents and conditions: (a) i. Co2(CO)8 (3 equiv)/Et3SiH (10 equiv)/CO,
PhH, 50 ꢀC, 90%; ii. TBAF/THF, 97%; (b) 7b, TMSOTf, CH2Cl2, 0 ꢀC, 82%; (c) TBAF/THF,
96%; (d) NIS/AgOTf/MS/DTBMP, CH2Cl2, ꢁ40 ꢀC, 74%.
Using CH3ONa to remove the acetyl group, and the catalytic
hydrogenation to remove benzyl groups, the raffinose, stachyose,
and verbascose were finally prepared (Scheme 5).
Scheme 2. Reagents and conditions: (a) Co2(CO)8 (3 equiv)/Et3SiH (20 equiv)/CO, PhH,
70 ꢀC, 72%; (b) i. TBAF/THF, 96%; ii. 7c, NIS/AgOTf, DTBMP/MS, ꢁ78 ꢀC, 88%.
Scheme 5. Reagents and conditions: 1. Na/CH3OH, overnight; 2. H2 (0.4 MPa)/PdeC,
CH3OH, 2 days.
We tried lower temperatures and other silanes, such as
PhMe2SiH and EtMe2SiH, as well as other protecting groups to re-
place the acetyl group (such as Bz and TBDPS) to reduce the for-
mation of 12. However, 12 was always formed with similar ratio to
1.2/1. This result suggested that the steric hindrance of 10-OBn of 10
was similar to that of 6000-OBn. Glycosylation of 13 with 7c gave
pentasaccharides 15 successfully (Scheme 3).
Because of the low selectivity of de-O-benzylation of 10, the
synthesis of verbascose was not efficient enough, so we turned to the
[2þ3] glycosylation strategy to prepare verbascose. The disaccharide
donor 17 was synthesized from trichloroacetimidate 7b coupling
with 16, which was prepared by de-O-benzylation of 7c in two steps
with an overall yield of 87%.8 Glycosylation of 16 with 7b generated
3. Conclusion
In summary, we have developed a concise synthesis of the raf-
finose family oligosaccharides. The most important reaction is de-O-
benzylation with Co2(CO)8/Et3SiH/CO system. This system has high
efficiency and regioselectivity in removing the primary benzyl
group of sucrose and the raffinose family oligosaccharides under
mild and neutral condition. We could expect that this de-O-
benzylation procedure would be useful for the selective modifica-
tion of sucrose and other complex oligosaccharides, e.g., melezitose
and diglucomelezitose, and provide a short-cut for the rapid prep-
aration of saccharides with primary hydroxyl group glycosylated. In
addition, the glycosylation condition of the synthesis of raffinose
family of oligosaccharides was studied. The thioglycoside/NIS/AgOTf
17 (82%,
a
/
b
¼7/1, and the
a-product was separated by carefully
column chromatography). The trisaccharide acceptor 18 could be
readily prepared by the removal of the silyl group of 9. Coupling of 17
with 18 gave 15 with a yield of 74% (Scheme 4). This strategy to
verbascose was more efficient than that by coupling 13 with 7c.
system is mild and with high
DTBMP is necessary to protect the acid-sensitive glycoside bond.
a-selectivity, and the use of bulky base

Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
5025
4. Experimental
4.1. General
CH3OH/EtOAc (1/1). Pd/C (2 equiv) was added, and the mixture was
stirred under H2 atmosphere (0.4 MPa) for 2 days. The Pd/C was
filtered and the solvent was removed, the residue was solved in
water and freeze-dried to get final product.
All chemicals were purchased and used without further purifi-
cation, unless otherwise noted. Dichloromethane was distilled over
phosphorus pentoxide. Benzene was distilled over sodium. Ana-
lytical TLC was performed on precoated aluminum sheets, with
detection by fluorescence and/or by staining with 5% concentrated
sulfuric acid in EtOH. Column chromatography was performed by
employing silica gel (230e400 mesh, Merck). Optical rotations
were measured using an Optical Activity AA-10R type polarimeter.
1H NMR spectra were recorded on Advance DRX Bruker-400
spectrometers at 25 ꢀC. High-resolution mass spectrometry was
performed on a Bruker APEX IV mass spectrometer.
4.6. 1,3,4,6-Tetra-O-benzyl-
b-D-fructofuranosyl 2,3,4,6-tetra-
O-benzyl- -glucopyranoside (2)
a-D
To a solution of sucrose (3.42 g, 10 mmol) in DMF (200 ml), NaH
(11.52 g, 3 equiv/OH) was added and the mixture was stirred in ice
bath for 30 min. BnBr (25 ml, 2.5 equiv/OH) was added slowly and
the mixture was moved to room temperature for 24 hours’ stirring.
CH3OH was then added slowly to quench the excessive NaH and
BnBr and the solvent was removed at reduced pressure. The residue
was dissolved in EtOAc and the insoluble CH3ONa was filtered by
silica gel. The filtrate was concentrated and purified by flash
chromatography (PE/EA¼8/1) to give 2 as colorless oil (7.9 g, 75%).
4.2. General procedure A for de-O-benzylation
1H NMR (400 MHz, CDCl3)
d 7.18e7.30 (m, 40H), 7.13e7.15 (m, 2H),
Co2(CO)8 (1.5 equiv, 3 equiv or 6 equiv, purchased from Alfa
Aesar Chemicals Co. without further purification) was added to
a flask under CO atmosphere. Et3SiH (10 equiv, 20 equiv or 40 equiv,
purchased from Alfa Aesar Chemicals Co. without further purifi-
cation) was then added and the mixture was stirred for 20 min at
room temperature. A solution of perbenzylated carbohydrate in
anhydrous benzene (1 mmol/5 ml) was degassed and then added
using a syringe. The mixture was then heated in oil bath at set
temperature (50 ꢀC or 70 ꢀC) and the reaction was monitored by
TLC. After the disappearance of starting materials, the cobalt
complex was precipitated by the drop-wise addition of pyridine
and then bubbling oxygen through the solution for 20 min. The
content of the flask was filtered through 5 cm of silica gel and
eluted with ethyl acetate. The filtrate was evaporated and the res-
idue was subjected to flash chromatography.
5.72 (d, 1H, J¼3.5 Hz), 4.87 (d, 1H, J¼10.9 Hz), 4.80 (d, 1H,
J¼10.9 Hz), 4.70 (d, 1H, J¼10.9 Hz), 4.61e4.68 (m, 2H), 4.33e4.58
(m, 13H), 4.17e4.21 (t, 1H, J¼7.3 Hz), 4.06e4.14 (m, 2H), 4.91e4.96
(t, 1H, J¼9.3 Hz), 3.63e3.76 (m, 4H), 3.48e3.56 (m, 3H), 3.36e3.99
(dd, 1H, J¼10.5, 1.2 Hz). 13C NMR (100 MHz, CDCl3) 139.06, 138.78,
138.49, 138.36, 138.34, 138.32, 138.20, 138.07, 128.43, 128.41, 128.11,
128.06, 128.00, 127.86, 127.85, 127.78, 127.71, 127.67, 127.63, 104.73,
90.08, 84.04, 82.51, 82.07, 79.94, 75.62, 74.91, 73.53, 73.49, 73.34,
73.11, 72.63, 72.31, 71.51, 68.59.
4.7. 1,3,4-Tri-O-benzyl-6-O-triethyl-silyl-b-D-fructofuranosyl
2,3,4,6-tetra-O-benzyl- -glucopyranoside (3)
a-D
General procedure A using 2 (770 mg, 725 mmol) as substrate,
1.5 equiv of Co2(CO)8 and 10 equiv of Et3SiH were used and the
reaction was performed at 50 ꢀC in benzene, and 3 was isolated in
85% yield (684 mg, colorless oil). 1H NMR (400 MHz, CDCl3)
4.3. General procedure B for de-silylation and acylation
d
7.22e7.31 (m, 34H), 7.12e7.14 (m, 2H), 5.80 (d, 1H, J¼3.6 Hz), 4.92
TBFA$3H2O (1.2 equiv) was added to a solution of the substrate
in THF, and the mixture was stirred at room temperature for 30 min.
Then the solvent was removed at reduced pressure and the residue
was purified by flash chromatography. For acetylation, the depro-
tected product was dissolved in pyridine, then acetic anhydride
(4 equiv) was added slowly and the mixture was stirred over 3 h.
The reaction was stopped by the addition of CH3OH in ice bath, and
evaporation of the solvent afforded a residue, which was purified
by flash chromatography.
(d, 1H, J¼10.8 Hz), 4.81 (d, 1H, J¼10.9 Hz), 4.73 (d, 1H, J¼10.8 Hz),
4.65 (d, 1H, J¼11.5 Hz), 4.64 (d, 1H, J¼11.3 Hz), 4.35e4.59 (m, 10H),
4.22 (t, 1H, J¼6.9 Hz), 4.04 (d, 1H, J¼10.0 Hz), 3.98 (dd, 1H, J¼12.0,
5.7 Hz), 3.92 (t, 1H, J¼9.3 Hz), 3.84 (d, 2H, J¼5.6 Hz), 3.77 (d, 1H,
J¼11.0 Hz), 3.65 (t, 1H, J¼9.6 Hz), 3.50e3.58 (m, 3H), 3.41 (dd, 1H,
J¼10.6, 1.3 Hz), 0.93 (t, 9H, J¼7.9 Hz), 0.60 (q, 6H, J¼8.0 Hz). 13C NMR
(100 MHz, CDCl3)
d 139.0, 138.7, 138.5, 138.4, 138.2, 138.1, 138.0,
128.3, 128.2, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 104.5, 90.0, 84.3,
83.1, 82.0, 81.6, 79.9, 77.6, 75.5, 74.8, 73.4, 73.1, 72.4, 72.1, 70.9, 70.5,
68.5, 64.1, 6.8, 4.3. HRMS (ESI) calcd for C67H78O11Si [MþNa]þ
4.4. General procedure C for glycosylation
1109.5206. Found: 1109.5186. ½a D25
þ36.0 (c 1.0, CHCl3).
ꢂ
To a solution of acceptor in CH2Cl2 (0.1 mmol/ml), the sulfur
donor (1.5 equiv) was added and the mixture was stirred at room
temperature with molecular sieve for 30 min. Then DTBMP
(1.5 equiv), NIS (3 equiv), and AgOTf (0.5 equiv) was added suc-
cessively under dark condition, and the mixture was cooled to
ꢁ78 ꢀC or ꢁ40 ꢀC and stirred under argon. After TLC showed that
the reaction was completed, the MS was filtered and the filtrate was
eluted with Na2S2O3 and saturated NaCl solution and dried by an-
hydrous Na2SO4. Evaporation of the solvent gave a residue, which
was purified by flash chromatography.
4.8. 1,3,4-Tri-O-benzyl-6-O-triethyl-silyl-
b-D-fructofuranosyl
2,3,4-tri-O-benzyl-6-O-triethyl-silyl-
a-D
-glucopyranoside (30)
By-product of de-O-benzylation of 2 (123 mg, 15%, colorless oil),
and it could also be prepared by General procedure A using 3 equiv
of Co2(CO)8 and 10 equiv of Et3SiH and refluxing in toluene, which
was isolated in 90% yield. 1H NMR (400 MHz, CDCl3)
d 7.24e7.35 (m,
30H), 5.87 (d, 1H, J¼3.6 Hz), 4.91 (d, 1H, J¼10.7 Hz), 4.85 (d, 1H,
J¼11.0 Hz), 4.74 (d,1H, J¼10.7 Hz), 4.70 (d,1H, J¼11.3 Hz), 4.58e4.66
(m, 5H), 4.42e4.54 (m, 4H), 4.29 (t, 1H, J¼7.3 Hz), 3.81e4.00 (m,
5H), 3.74 (d, 1H, J¼11.0 Hz), 3.59e3.71 (m, 2H), 3.45e3.55 (m, 3H),
0.90e0.97 (m, 18H), 0.51e0.65 (m, 12H). 13C NMR (100 MHz, CDCl3)
4.5. General procedure D for de-protection of acetyl and
benzyl groups
d
139.0, 138.6, 138.5, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.9,
To a solution of the substrate in CH3OH, Na was added and the
mixture was stirred at room temperature overnight. Then Hþ cation
resin was added to neutralize the solvent. After filtering the resin,
CH3OH was evaporated and the substrate was dissolved in 5 ml
127.7, 127.6, 127.5, 127.4, 127.3, 104.3, 89.6, 84.3, 82.4, 82.1, 81.1, 80.3,
77.2, 75.7, 74.7, 73.5, 73.2, 72.6, 72.0, 71.5, 71.4, 63.5, 61.4, 6.9, 6.8,
4.5, 4.3. HRMS (ESI) calcd for C66H86O11Si2 [MþNa]þ 1133.5601.
Found: 1133.5613. ½a D25
þ23.3 (c 1.2, CHCl3).
ꢂ

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Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
4.9. 1,3,4-Tri-O-benzyl-6-O-acetyl-
b-D
-fructofuranosyl 2,3,4,6-
138.8, 138.4, 138.2, 138.1, 138.0, 128.4, 128.3, 128.2, 128.1, 128.0,
tetra-O-benzyl-
a
-
D
-glucopyranoside (4)
127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 104.7, 98.3, 90.3, 83.8,
82.2, 81.9, 80.1, 78.3, 77.6, 77.4, 77.1, 76.8, 75.5, 75.2, 74.9, 74.8, 73.4,
72.9, 72.7, 72.1, 71.4, 71.0, 69.4, 68.9, 66.3, 65.3, 20.8. HRMS (ESI)
General procedure B using 3 (660 mg, 595
and 4 was isolated in 90% yield (555 mg, colorless oil) in two steps.
1H NMR (400 MHz, CDCl3)
7.23e7.32 (m, 34H), 7.11e7.14 (m, 2H),
mmol) as substrate,
calcd for C90H94O17 [MþNH4]þ 1464.6829. Found: 1464.6800. ½a 2D5
ꢂ
d
þ56.3 (c 2.4, CH3CN).
5.65 (d, 1H, J¼3.5 Hz), 4.92 (d, 1H, J¼10.9 Hz), 4.81 (d, 1H,
J¼10.9 Hz), 4.78 (d, 1H, J¼11.0 Hz), 4.25e4.65 (m, 14H), 4.07e4.14
(m, 3H), 3.96 (t, 1H, J¼9.3 Hz), 3.72 (d, 1H, J¼11.0 Hz), 3.64 (t, 1H,
J¼9.6 Hz), 3.58 (dd, 1H, J¼10.6, 3.3 Hz), 3.51e3.55 (m, 2H), 3.46 (dd,
4.13. 1,3,4-Tri-O-benzyl-6-O-acetyl-D-fructofuranosyl 2,3,4-
tri-O-benzyl-6-O-(2,3,4,-tri-O-benzyl-6-O-triethyl-silyl-
a-D-
galactopyranosyl)- -glucopyranoside (9)
a-D
1H, J¼10.5, 1.4 Hz), 1.99 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 170.6,
138.8, 138.4,138.2,138.0, 137.9,137.8,137.7,128.3,128.2, 127.9,127.8,
127.7, 127.6, 127.5, 127.4, 104.5, 90.0, 83.6, 82.0, 81.8, 79.6, 78.2, 77.6,
75.4, 74.8, 73.3, 72.8, 72.5, 72.4, 70.8, 70.6, 68.3, 65.2, 20.7. HRMS
(ESI) calcd for C63H66O12 [MþNa]þ 1037.4447. Found: 1037.4454.
General procedure A using 8 (220 mg, 150 mmol) as substrate,
3 equiv of Co2(CO)8 and 20 equiv of Et3SiH were used and the re-
action was performed at 70 ꢀC in benzene, and 9 was isolated in 72%
yield (161 mg, colorless oil). 1H NMR (400 MHz, CDCl3)
d 7.11e7.31
½
a 2D5
ꢂ
þ37.3 (c 1.5, CHCl3).
(m, 56H), 5.57 (s, 1H), 5.10 (s, 1H), 4.97e4.99 (d, 1H, J¼11.2 Hz),
4.90e4.93 (d,1H, J¼10.8 Hz), 4.78e4.86 (m, 3H), 4.68e4.72 (m, 3H),
4.61e4.64 (d, 4H, J¼10.9 Hz), 4.43e4.58 (m, 10H), 4.34e4.37 (d, 1H,
J¼11.9 Hz), 4.28 (s, 3H), 4.03e4.11 (m, 6H), 3.91e3.98 (m, 4H),
3.51e3.85 (m, 10H), 3.30e3.32 (d, 1H, J¼9.2 Hz), 1.92 (s, 3H),
0.90e0.94 (m, 9H), 0.53e0.58 (m, 6H). 13C NMR (100 MHz, CDCl3)
4.10. 1,3,4-Tri-O-benzyl-6-O-acetyl-
tri-O-benzyl-6-O-triethyl-silyl- -glucopyranoside (5)
b-D-fructofuranosyl 2,3,4-
a-D
General procedure A using 4 (600 mg, 578 mmol) as substrate,
6 equiv of Co2(CO)8 and 20 equiv of Et3SiH were used and the re-
d 170.6, 139.2, 139.1, 139.0, 138.8, 138.5, 138.2, 138.1, 137.9, 137.6,
action was performed at 70 ꢀC in benzene, and 5 was isolated in 70%
128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 127.6, 127.5, 127.4, 127.3, 104.8, 98.4, 90.3, 83.8, 83.7, 82.3,
81.9, 81.6, 80.5, 80.2, 78.4, 75.6, 75.1, 75.0, 74.9, 73.6, 73.5, 73.0, 72.9,
72.8, 72.7, 72.1, 72.0, 71.7, 71.6, 71.3, 71.0, 68.3, 66.2, 65.4, 64.9, 61.6,
20.9, 7.0, 4.5. HRMS (ESI) calcd for C89H106NO17Si [MþNH4]þ
yield (430 mg, colorless oil). 1H NMR (400 MHz, CDCl3)
d 7.23e7.33
(m, 39H), 5.66 (d, 1H, J¼3.5 Hz), 4.93 (d, 1H, J¼10.9 Hz), 4.86 (d, 1H,
J¼10.9 Hz), 4.80 (d, 1H, J¼10.8 Hz), 4.67 (d, 1H, J¼3.2 Hz), 4.57e4.65
(m, 6H), 4.54 (s, 1H), 4.51 (d, 2H, J¼4.6 Hz), 4.49 (d, 1H, J¼4.4 Hz),
4.45 (d, 1H, J¼7.2 Hz), 4.37 (d, 1H, J¼12.0 Hz), 4.30e4.31 (m, 2H),
4.10e4.17 (m, 2H), 3.91e4.00 (m, 3H), 3.65e3.72 (m, 3H), 3.47e3.60
(m, 4H),1.99 (s, 3H), 0.91e0.95 (m, 9H), 0.53e0.61 (m, 6H). 13C NMR
1488.7225. Found: 1488.7198. ½a D25
ꢂ
þ54.1 (c 3.7, CH3CN).
4.14. 1,3,4-Tri-O-benzyl-6-O-acetyl-
D
-fructofuranosyl 2,3,4-
(100 MHz, CDCl3)
d
170.7, 139.0, 138.9, 138.5, 138.1, 137.9, 128.5,
tri-O-benzyl-6-O-[2,3,4,-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-
benzyl- -galactopyranosyl)- -galactopyranosyl]- -glu-
copyranoside (10)
128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 104.6, 90.1, 83.8, 82.2,
82.0, 80.1, 78.2, 77.3, 75.7, 74.9, 73.5, 73.2, 73.1, 72.9, 72.6, 71.9, 71.2,
65.2, 61.5, 20.8, 6.9, 4.5. HRMS (ESI) calcd for C62H74O12 Si [MþNa]þ
a-
D
a
-D
a-D
1061.4842. Found: 1061.4858. ½a D25
ꢂ
þ34.7 (c 1.5, CHCl3).
General procedure C using 9 (140 mg, 94
10 was isolated in 88% yield (157 mg, colorless oil). 1H NMR
(400 MHz, CDCl3)
mmol) as substrate, and
4.11. 1,3,4-Tri-O-benzyl-6-O-acetyl-
b-
D-fructofuranosyl 2,3,4-
d
7.13e7.33 (m, 83H), 5.53 (d, 1H, J¼4.0 Hz),
tri-O-benzyl- -glucopyranoside (6)
a
-D
5.06e5.07 (d, 1H, J¼4.0 Hz), 4.87e4.96 (m, 4H), 4.80e4.81 (d, 1H,
J¼3.2 Hz), 4.72e4.76 (m, 3H), 4.65e4.69 (m, 6H), 4.58e4.62 (m,
4H), 4.38e4.49 (m, 11H), 4.29e4.31 (dd, 1H, J¼7.6, 4.3 Hz),
4.23e4.27 (m, 2H), 4.00e4.08 (m, 5H), 3.89e3.97 (m, 7H),
3.75e3.86 (m, 3H), 3.45e3.67 (m, 10H), 3.26e3.30 (dd, 1H, J¼9.7,
General procedure B using 5 (430 mg, 405
and 6 was isolated quantitatively as colorless oil (380 mg). 1H NMR
(400 MHz, CDCl3)
mmol) as substrate,
d
7.24e7.34 (m, 33H), 5.60 (d, 1H, J¼3.6 Hz), 4.90
(d, 1H, J¼10.9 Hz), 4.84 (d, 1H, J¼10.9 Hz), 4.76 (d, 1H, J¼10.9 Hz),
4.65 (d, 1H, J¼11.4 Hz), 4.55e4.62 (m, 4H), 4.50e4.52 (t, 2H,
J¼4.4 Hz), 4.47 (d, 1H, J¼4.1 Hz), 4.42 (d, 1H, J¼7.0 Hz), 4.33e4.39
(m, 2H), 4.17e4.21 (dd, 1H, J¼12.0, 3.2 Hz), 4.08e4.14 (m, 2H),
3.95e4.05 (m, 3H), 3.65e3.69 (m, 2H), 3.40e3.59 (m, 5H). 13C NMR
3.5 Hz), 1.92 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 170.6, 139.1, 138.9,
138.8, 138.7, 138.6, 138.5, 138.2, 138.0, 137.9, 128.5, 128.4, 128.3,
128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 104.7, 98.5, 90.3,
83.7, 82.6, 82.1, 81.7, 80.1, 79.6, 78.4, 78.2, 77.8, 77.3, 75.5, 75.2, 75.1,
75.0, 74.7, 73.5, 73.4, 73.1, 73.0, 72.8, 72.7, 72.1, 71.4, 70.8, 69.4, 68.5,
68.4, 65.7, 28.6, 20.9. HRMS (ESI) calcd for C117H122O22 [MþNa]þ
(100 MHz, CDCl3)
d 170.9, 138.8, 138.3, 138.1, 137.9, 137.8, 137.7,
128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 104.7, 89.8, 83.5, 81.8,
81.5, 79.8, 78.0, 77.8, 77.2, 75.6, 75.0, 73.4, 72.9, 72.7, 72.6, 71.7, 71.2,
64.9, 62.1, 20.8. HRMS (ESI) calcd for C56H60O12 [MþNH4]þ
1901.8320. Found: 1901.8358. ½a D25
ꢂ
þ51.1 (c 2.4, CH3CN).
4.15. 1,3,4-Tri-O-benzyl-6-O-acetyl-D-fructofuranosyl 2,3,4-tri-
942.4423. Found: 942.4421. ½a D25
ꢂ
þ48.5 (c 3.3, H2O).
O-benzyl-6-O-[2,3,4,-tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-6-O-
triethyl-silyl- -galactopyranosyl)- -galactopyranosyl]-
-glucopyranoside & 1-O-triethyl-silyl-3,4-di-O-benzyl-6-O-
a-D
a
-D
a-
4.12. 1,3,4-Tri-O-benzyl-6-O-acetyl-
D-fructofuranosyl 2,3,4-
D
tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl- -galactopyr-
a
-
D
acetyl-
D
-fructofuranosyl 2,3,4-tri-O-benzyl-6-O-[2,3,4,-tri-O-
-galactopyranosyl)-
-glucopyranoside (11&12)
anosyl)- -glucopyranoside (8)
a
-D
benzyl-6-O-(2,3,4,6-tetra-O-benzyl-
galactopyranosyl]-
a
-D
a-D-
a-D
General procedure C using 6 (250 mg, 265
7c (383 mg, 1.5 equiv) as donor, and 8 was isolated in 90% yield
(348 mg, colorless oil). 1H NMR (400 MHz, CDCl3)
7.17e7.35 (m,
mmol) as acceptor and
General procedure A using 10 (150 mg, 79 mmol) as substrate,
d
6 equiv of Co2(CO)8 and 40 equiv of Et3SiH were used and the re-
action was performed at 70 ꢀC in benzene, and the mixture of 11
and 12 was isolated in 65% yield (98 mg, 11/12¼1.2/1, colorless oil).
62H), 5.56 (d, 1H, J¼3.5 Hz), 5.07 (d, 1H, J¼3.5 Hz), 4.88e4.94 (m,
2H), 4.83 (d, 1H, J¼11.0 Hz), 4.75e4.79 (m, 2H), 4.71 (s, 1H), 4.67 (d,
1H, J¼5.9 Hz), 4.64 (d, 1H, J¼4.1 Hz), 4.61 (s, 1H), 4.32e4.58 (m,
14H), 4.26e4.27 (m, 2H), 4.01e4.09 (m, 5H), 3.89e3.97 (m, 4H),
3.67e3.81 (m, 4H), 3.47e3.57 (m, 5H), 3.31e3.34 (dd, 1H, J¼9.6,
1H NMR (400 MHz, CDCl3)
d 7.19e7.36 (m, 72H), 5.56e5.58 (dd, 1H,
J¼5.1, 3.7 Hz), 5.10e5.12 (dd, 1H, J¼3.6, 3.5 Hz), 4.95e5.00 (m, 2H),
4.92e4.93 (d,1H, J¼1.8 Hz), 4.90 (s,1H), 4.84e4.85 (d,1H, J¼3.2 Hz),
4.72e4.81 (m, 5H), 4.68e4.70 (m, 3H), 4.65 (s, 2H), 4.61e4.64
3.6 Hz), 1.91 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 170.6, 139.1, 138.9,

Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
5027
(m, 2H), 4.42e4.55 (m, 9H), 4.33e4.40 (m, 2H), 4.25e4.30 (m, 2H),
1.95e1.96 (d, 3H, J¼2.4 Hz), 0.92e0.98 (m, 15H), 0.54e0.63 (m, 9H).
(m, 1H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
170.8, 139.1, 139.0,
138.9, 138.8, 138.7, 138.6, 138.5, 138.2, 138.0, 137.9, 128.3, 128.2,
128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 104.8, 98.9,
98.9, 98.7, 90.6, 85.1, 84.8, 84.6, 83.9, 82.6, 81.8, 80.2, 78.5, 78.3, 77.2,
76.2, 75.3, 74.9, 74.8, 74.7, 74.6, 73.5, 73.4, 73.3, 72.9, 72.7, 72.6, 72.1,
71.9, 71.6, 70.8, 69.6, 69.1, 66.6, 66.5, 65.6, 20.7. HRMS (ESI) calcd for
13C NMR (100 MHz, CDCl3)
d 169.8, 169.7, 138.3, 138.2, 138.1, 138.0,
137.9, 137.8, 137.7, 137.6, 137.4, 137.3, 137.2, 137.1, 137.0, 127.6, 127.5,
127.4,127.3,127.2,127.1,127.0,126.9,126.8,126.7,126.6,126.5,126.4,
104.0, 103.9, 103.1, 97.7, 97.6, 89.6, 89.5, 82.9, 81.7, 81.6, 81.3, 80.9,
79.2, 78.8, 78.6, 77.6, 77.5, 77.4, 76.9, 76.4, 75.5, 74.6, 74.4, 74.2, 74.1,
74.0, 73.9, 73.7, 72.9, 72.8, 72.7, 72.6, 72.5, 72.3, 72.1, 72.0, 71.8, 71.2,
71.1, 70.8, 70.6, 70.4, 69.9, 68.6, 68.5, 68.1, 67.7, 65.9, 65.4, 65.2,
64.9, 64.7, 60.6, 60.2, 28.9, 20.0, 6.0, 3.6. HRMS (ESI) calcd for
C116H130O22Si 1/2 [MþNH4]þ 969.4750. Found: 969.4780.
C144H150O27 [MþNa]þ 2334.0257. Found: 2334.0356. ½a 2D5
ꢂ
þ63.3 (c
1.3, CHCl3).
4.19. p-Methylphenyl 2,3,4,6-tetra-O-benzyl-
anosyl-(1/6)-2,3,4-tri-O-benzyl-thio-b-D-galactopyrano-
side (17)
a
-
D
-galactopyr-
4.16. 1,3,4-Tri-O-benzyl-6-O-acetyl-
tri-O-benzyl-6-O-[2,3,4-tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-
-galactopyranosyl)- -galactopyranosyl]- -glucopyr-
anoside (13)
D-fructofuranosyl 2,3,4-
4A molecular sieve was added into a solution of 16 (60 mg,
108 mol) and 7b (1.5 equiv, 100 mg) was dissolved in 3 ml CH2Cl2
a
-D
a
-D
a
-D
m
and the mixture was stirred for 30 min, then TMSOTf (0.24 equiv)
was added in ice bath and the reaction was moved to room tem-
perature. After TLC showed the disappearance of 16, filtered the
molecular sieve, and the filtration was washed by saturated
NaHCO3 and NaCl solution and dried by Na2SO4. Column separation
(PE/acetone¼10/1) gave 17 as colorless oil in 82% yield (97 mg,
General procedure B using the mixture of 11 and 12 (98 mg,
mol) as substrate, and 13 was isolated in 55% yield (51 mg,
colorless oil).1H NMR (400 MHz, CDCl3)
7.17e7.36 (m, 76H), 5.51
51
m
d
(d, 1H, J¼3.1 Hz), 5.04 (d, 1H, J¼3.3 Hz), 4.86e4.93 (m, 4H),
4.79e4.83 (m, 3H), 4.60e4.76 (m, 13H), 4.39e4.57 (m, 10H),
4.30e4.33 (d, 1H, J¼12.0 Hz), 4.25 (d, 2H, J¼4.3 Hz), 4.05e4.11 (m,
2H), 3.96e4.03 (m, 4H), 3.89e3.94 (m, 4H), 3.83e3.86 (m, 4H),
3.72e3.79 (m, 2H), 3.58e3.70 (m, 7H), 3.47e3.50 (d, 1H, J¼11.1 Hz),
3.40e3.42 (d, 1H, J¼6.3 Hz), 3.28e3.31 (dd, 1H, J¼3.4, 9.6 Hz), 1.93
colorless oil). 1H NMR (400 MHz, CDCl3)
d 7.44e7.46 (d, 2H,
J¼8.0 Hz), 7.36e7.39 (m, 4H), 7.21e7.34 (m, 34H), 6.95e6.97 (d, 2H,
J¼7.8 Hz), 4.91e4.93 (d, 1H, J¼4.0 Hz), 4.89e4.90 (d, 1H, J¼5.4 Hz),
4.75e4.80 (m, 4H), 4.67e4.73 (m, 4H), 4.55e4.61 (m, 4H),
4.43e4.46 (d, 1H, J¼11.2 Hz), 4.35e4.38 (d, 1H, J¼11.6 Hz),
4.00e4.03 (dd, 1H, J¼10.1, 3.5 Hz), 3.92e3.96 (m, 2H), 3.82e3.89
(m, 4H), 3.62e3.65 (t, 1H, J¼6.3 Hz), 3.52e3.59 (m, 5H), 2.24 (s, 3H).
(s, 3H). 13C NMR (100 MHz, CDCl3)
d 170.0, 138.2, 138.1, 137.9, 137.8,
137.7, 137.5, 137.4, 137.3, 137.1, 137.0, 127.6, 127.5, 127.4, 127.3, 127.1,
127.0, 126.9, 126.8, 126.7, 126.6, 126.5, 103.9, 97.6, 89.6, 82.8, 81.7,
80.9, 79.2, 78.4, 77.5, 77.3, 75.5, 74.6, 74.3, 74.1, 74.0, 73.9, 73.6, 72.6,
72.5, 72.2, 71.9, 71.8, 71.3, 70.6, 70.1, 69.9, 68.3, 66.3, 65.6, 64.8, 61.4,
20.0. HRMS (ESI) calcd for C110H116O22 [MþNa]þ1811.7850. Found:
13C NMR (100 MHz, CDCl3)
d 139.0, 138.9, 138,7, 138.6, 138.5, 138.1,
137.2, 132.3, 130.3, 129.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.78,
127.7, 127.6, 127.5, 98.4, 87.9, 84.1, 79.3, 77.4, 77.0, 76.5, 75.7, 74.9,
74.4, 74.1, 73.7, 73.6, 73.0, 72.9, 69.4, 68.9, 67.3, 29.8, 21.2. HRMS
(ESI) calcd for C68H70O10S [MþNH4]þ 1096.5028. Found: 1096.5007.
1811.7831. ½a 2D5
ꢂ
þ54.3 (c 1.5, CHCl3).
½
a 2D5
ꢂ
þ15.4 (c 2.6, CHCl3).
4.17. 3,4-Di-O-benzyl-6-O-acetyl-
D
-fructofuranosyl 2,3,4-tri-
O-benzyl-6-O-[2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-
-galactopyranosyl)- -galactopyranosyl]- -glucopyr-
anoside (14)
4.20. 1,3,4-Tri-O-benzyl-6-O-acetyl-
tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-
D
-fructofuranosyl 2,3,4-
-galactopyranosyl)-a-
a
-D
a
-D
a
-D
a
-D
D-glucopyranoside (18)
General procedure B using mixture of 11 and 12 (98 mg,
mol) as substrate, and 14 was isolated in 45% yield (42 mg,
colorless oil). 1H NMR (400 MHz, CDCl3)
7.17e7.34 (m, 71H), 5.53
(d, 1H, J¼3.3 Hz), 5.05 (d, 1H, J¼3.4 Hz), 4.87e4.96 (m, 4H),
4.59e4.78 (m, 14H), 4.38e4.48 (m, 9H), 4.28e4.31 (m, 5H),
4.03e4.09 (m, 5H), 3.74e3.98 (m, 10H), 3.64e3.70 (m, 4H),
3.41e3.60 (m, 6H), 3.28e3.30 (m, 2H), 1.94 (s, 3H). 13C NMR
General procedure B using 9 (41 mg, 28
18 was isolated in 96% yield as colorless oil (36 mg). 1H NMR
(400 MHz, CDCl3)
mmol) as substrate, and
51
m
d
d
7.17e7.37 (m, 57H), 5.45 (d, 1H, J¼3.5 Hz), 5.13
(d, 1H, J¼3.5 Hz), 4.92 (d, 1H, J¼11.6 Hz), 4.86e4.90 (m, 2H),
4.75e4.8 (m, 3H), 4.66e4.70 (m, 3H), 4.57e4.63 (m, 4H), 4.41e4.46
(m, 5H), 4.22e4.28 (m, 3H), 4.12e4.15 (m, 1H), 4.00e4.07 (m, 3H),
3.94 (d, 1H, J¼9.4 Hz), 3.84e3.89 (m, 2H), 3.74e3.78 (m, 2H),
3.62e3.71 (m, 3H), 3.54e3.58 (m, 3H), 3.47e3.53 (m, 4H),
3.33e3.34 (dd, 1H, J¼9.7, 3.4 Hz), 2.0 (s, 3H). 13C NMR (100 MHz,
(100 MHz, CDCl3)
d 169.8, 138.2, 138.0, 137.9, 137.8, 137.7, 137.6,
137.5, 137.4, 137.2, 137.0, 127.7, 127.6, 127.5, 127.4, 127.3, 127.1, 127.0,
126.80, 126.7, 126.6, 126.5, 126.4, 103.9, 103.1, 97.6, 89.5, 82.9, 81.8,
81.4, 80.9, 79.2, 78.8, 77.6, 77.4, 77.0, 76.4, 76.0, 74.6, 74.2, 74.1, 73.8,
73.4, 72.5, 72.4, 72.1, 71.9, 71.8, 71.3, 70.6, 70.0, 68.5, 67.8, 65.9, 64.9,
61.2, 20.0. HRMS (ESI) calcd for C110H116O22 [MþNa]þ 1811.7851.
D2O)
d 171.1, 139.0, 138.9, 138.8, 138.7, 138.3, 138.1, 137.9, 137.8,
128.5, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3,
104.7, 97.7, 90.4, 83.5, 82.7, 81.8, 80.0, 78.2, 78.1, 77.8, 77.2, 75.4,
74.9, 74.7, 74.5, 73.3, 73.1, 72.6, 72.2, 71.6, 71.0, 70.9, 70.8, 68.9,66.0,
62.7, 20.8. MS (ESI) calcd for C83H88O17 [MþNa]þ 1379.5919. Found:
Found: 1811.7805. ½a D25
ꢂ
þ55.2 (c 1.5, CHCl3).
1379.5837. ½a 2D5
þ68.1 (c 3.5, H2O).
ꢂ
4.18. 1,3,4-Tri-O-benzyl-6-O-acetyl-D-fructofuranosyl 2,3,4-tri-
O-benzyl-6-O-{2,3,4-tri-O-benzyl-6-O-[2,3,4-tri-O-benzyl-6-O-
(2,3,4,6-tetra-O-benzyl- -galactopyranosyl)- -galactopyr-
anosyl]- -galactopyranosyl}- -glucopyranoside (15)
4.21. O- -Galactopyranosyl-(1/6)-O-
(1/2)-b-D-fructofuranoside (raffinose) (19)
a
-
D
a-D-glucopyranosyl-
a
-D
a-D
a-D
a-D
General procedure D using 8 (90 mg, 61
19 was isolated in 83% yield as white solid (26 mg). 1H NMR
(400 MHz, D2O)
(d, 1H, J¼8.8 Hz), 3.96e4.02 (m, 3H), 3.93 (d, 1H, J¼2.9 Hz),
3.87e3.91 (t, 1H, J¼6.3 Hz), 3.82e3.86 (m, 2H), 3.76e3.80 (m, 2H),
3.68e3.75 (m, 4H), 3.60e3.63 (m, 3H), 3.46e3.52 (m, 2H). 13C NMR
mmol) as substrate, and
General procedure C using 13 (25 mg, 14 mmol) as accepter and
7c (3 equiv, 38 mg) as donor, and 15 was isolated in 85% yield
(28 mg, colorless oil). Or by general procedure C using 17 as donor
and 18 as acceptor and isolated in 74% yield. 1H NMR (400 MHz,
d
5.36 (d, 1H, J¼3.8 Hz), 4.93 (d, 1H, J¼3.7 Hz), 4.15
CDCl3)
d
7.18e7.31 (m, 91H), 5.53e5.56 (d, J¼1.2 Hz, 1H), 4.98e5.07
(m, 2H), 4.56e4.91 (m, 23H), 4.30e4.48 (m, 14H), 4.24e4.26 (d, 2H,
J¼5.7 Hz), 3.83e4.09 (m, 16H), 3.46e3.77 (m, 13H), 3.21e3.27
(100 MHz, D2O)
d 106.4, 101.1, 94.7, 83.9, 78.9, 76.6, 75.3, 74.0, 73.6,
72.0, 71.8, 71.1, 68.5, 65.0, 64.0, 63.7. HRMS (ESI) calcd for C18H32O16

5028
Y. Zhao et al. / Tetrahedron 69 (2013) 5022e5028
[MþNH4]þ 522.2029. Found: 522.2014. ½a 2D5
(lit.,18 þ83.4, c 0.8, H2O).
ꢂ
þ80.0 (c 3.0, H2O)
273e276; (b) Hori, H. i.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54,
1346e1353; (c) Martin, O. R.; Kurz, K. G.; Rao, S. P. J. Org. Chem. 1987, 52,
2922e2925; (d) Xie, J.; Menand, M.; Valery, J. M. Carbohydr. Res. 2005, 340,
481e487; (e) Falck, J. R.; Barma, D. K.; Venkataraman, S. K.; Baati, R.;
Mioskowski, C. Tetrahedron Lett. 2002, 43, 963e966; (f) Klemer, A.; Bieber, M.;
Wilbers, H. Liebigs Ann. Chem. 1983, 1416e1421; (g) Riley, G. J.; Grindley, T. B. J.
Carbohydr. Chem. 2001, 20, 159e169; (h) Antonello, P.; Silvia, V.; Matteo, A.;
Alfonso, I. Chem.dEur. J. 2011, 17, 5881e5889.
4.22. O-
(1/6)-O-
(stachyose) (20)
a
-D-Galactopyranosyl-(1/6)-O-
a
-D
-galactopyranosyl-
a
-D-glucopyranosyl-(1/2)-b-D-fructofuranoside
3. Lecourt, T.; Herault, A.; Pearce, A. J.; Sollogoub, M.; Sinay, P. Chem.dEur. J. 2004,
10, 2960e2971.
4. Selected works: (a) Heasley, V. L.; Shellhamer, D. F.; Gipe, R. K.; Wiese, H. C.;
Oakes, M. L.; Heasley, G. E. Tetrahedron 2002, 21, 4133e4170; (b) Green, J. R.
Curr. Org. Chem. 2001, 5, 809e826; (c) Diaz, D. D.; Betancort, J. M.; Martin, V. S.
Synlett 2007, 343e359.
5. For reviews: (a) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau,
A. Chem. Rev. 2011, 3, 1954e1993; (b) Lee, H.-W.; Yee, K.-F. Eur. J. Org. Chem.
2010, 5, 789e811; (c) Michelet, V.; Toullec, P. Y.; Pierre, G. J. Angew. Chem., Int.
Ed. 2008, 47, 4268e4315.
6. Selected works: (a) Ungvari, N.; Foerdos, E.; Kegl, T.; Ungvary, F. Inorg. Chim.
Aata. 2010, 363, 2016e2028; (b) Hess, W.; Treutwein, J.; Hilt, G. Synthesis-
Stuttgart 2008, 22, 3537e3562; (c) Ungvari, N.; Kegl, T.; Ungvary, F. J. Mol.
Catal. Chem. 2004, 219, 7e11; (d) Lee, J. T.; Thomas, P. J.; Alper, H. J. Org.
Chem. 2001, 66, 5424e5426; (e) Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J.
Org. Chem. 1999, 64, 518e521; (f) Happ, B.; Bartik, T.; Zucchi, C.; Rossi, M. C.;
Ghelfi, F.; Palyi, G.; Varadi, G.; Szalontai, G.; Horvath, I. T. Organometallics
1995, 14, 809e819.
General procedure D using 10 (48 mg, 25
20 was isolated in 81% yield as white solid (14 mg). 1H NMR
(400 MHz, D2O) 4.98 (s, 2H), 4.09e4.22 (m, 2H), 3.98e4.02 (m,
mmol) as substrate, and
d
5H), 3.86e3.88 (m, 3H), 3.79e3.84 (m, 4H), 3.77 (s, 1H), 3.70e3.74
(m, 4H), 3.66e3.68 (m, 3H), 3.49e3.56 (m, 3H). 13C NMR (100 MHz,
D2O)
d 106.6, 101.1, 100.9, 95.0, 84.1, 79.1, 76.8, 75.5, 74.1, 73.8, 73.7,
72.3, 72.2,72.1, 72.0, 71.6, 71.2, 71.1, 69.2, 68.6, 65.3, 64.2, 63.9.
HRMS (ESI) calcd for C24H42O21 [MþNa]þ 689.2111. Found:
689.2096. ½a 2D5
ꢂ
þ133.3 (c 2.7, H2O) (lit.,19 þ131.3, c 4.5, H2O).
4.23. O- -Galactopyranosyl-(1/6)-O-
(1/6)-O- -galactopyranosyl-(1/6)-O-
(1/2)-b-D-fructofuranoside (verbascose) (21)
a
-D
a
-D
-galactopyranosyl-
a
-D
a-D-glucopyranosyl-
7. For reviews, see: (a) Murai, S.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1979, 18,
837e846; (b) Chatani, N.; Murai, S. Synlett 1996, 414e424.
General procedure D using 15 (40 mg, 17
21 was isolated in 79% yield as white solid (11 mg). 1H NMR
(400 MHz, D2O)
5.42 (d, 1H, J¼3.8 Hz), 4.98 (t, 3H), 4.16e4.23 (m,
3H), 3.97e4.10 (m, 7H), 3.80e3.92 (m, 8H), 3.78 (s, 1H), 3.62e3.75
(m, 9H), 3.47e3.58 (m, 2H). 13C NMR (100 MHz, D2O)
106.6, 101.1,
mmol) as substrate, and
8. (a) Yin, Z.-J.; Wang, B.; Li, Y.-B.; Meng, X.-B.; Li, Z.-J. Org. Lett. 2010, 12, 536e539;
(b) Wang, B.; Yin, Z.-j.; Li, Y.-B.; Yang, T.-X.; Meng, X.-B.; Li, Z.-J. J. Org. Chem.
2011, 76, 9531e9535.
d
9. For recent reviews, see: (a) Peters, S.; Rose, T.; Moser, M. Top. Curr. Chem. 2010,
294, 1e23; (b) Queneau, Y.; Jarosz, S.; Lewandowski, B.; Fitremann, J. Adv.
Carbohydr. Chem. Biochem. 2008, 61, 218e292; (c) Goodby, J. W.; Saez, I. M.;
Cowling, S. J.; Gortz, V.; Draper, M.; Hall, A. W.; Sia, S.; Cozquer, G.; Lee, S. E.;
Raynes, E. P. Angew. Chem., Int. Ed. 2008, 47, 2754e2787; (d) Goodby, J. W.;
Goertz, V.; Cowling, S. J.; Mackenzie, G.; Martin, P.; Plusquellec, D.; Benvegnu,
T.; Boullanger, P.; Lafont, D.; Queneau, Y.; Chambert, S.; Fitremann, J. Chem. Soc.
Rev. 2007, 36, 1971e2032.
10. Selected works: (a) Barros, M. T.; Petrova, K. T.; Correia-da-Silva, P.; Potewar, T.
M. Green Chem. 2011, 13, 1897e1906; (b) Karl, H.; Lee, C.-K.; Khan, R. Carbohydr.
Res. 1982, 101, 31e38; (c) Mach, M.; Jarosz, S.; Listkowski, A. J. Carbohydr. Chem.
2001, 20, 485e493; (d) Gagnaire, J.; Toraman, G.; Descotes, G.; Bouchu, A.;
Queneau, Y. Tetrahedron Lett. 1999, 40, 2757e2760; (e) Molinier, V.; Fitremann,
J.; Bouchu, A.; Queneau, Y. Tetrahedron: Asymmetry 2004, 15, 1753e1762; (f)
Giry, P. N.; Descotes, G.; Bouchu, A.; Queneau, Y. Eur. J. Org. Chem. 1999,
3393e3398; (g) Scherrmann, M. C.; Boutboul, A.; Estramareix, B.; Hoffmann, A.
S.; Lubineau, A. Carbohydr. Res. 2001, 334, 295e307.
d
100.8, 100.5, 94.9, 84.1, 79.1, 76.8, 75.5, 74.2, 74.1, 73.8, 73.7, 72.3,
72.2, 72.1, 72.0, 71.9, 71.6, 71.4, 71.2, 71.1, 69.2, 68.7, 65.2, 64.1, 63.9.
HRMS (ESI) calcd for C30H52O26 [MþNa]þ 851.2639. Found:
851.2668. ½a 2D5
ꢂ
þ152.4 (c 2.1, H2O) (lit.,20 þ146, c 2.1, H2O).
Acknowledgements
The National Basic Research Program of China (973 program, No.
2012CB822100), the National Natural Science Foundation of China
(Nos. 20972012, 21072016) and the National Science & Technology
Mega Project for Primary Drug Innovation from Ministry of Science
and Technology of China (No. 2012ZX09502001-001) are gratefully
acknowledged for financial support of this research.
11. (a) Manley, H. M.; Richards, G. N. Carbohydr. Res. 1993, 240, 183e196; (b)
Moreau, C.; Durand, R.; Alies, F.; Cotillon, M.; Frutz, T.; Theoleyre, M. A. Ind.
Crops Prod. 2000, 11, 237e242.
12. (a) Dinoto, A.; Marques, T. M.; Sakamoto, K.; Fukiya, S.; Watanabe, J.; Ito, S.;
Yokota, A. Appl. Environ. Microbiol. 2006, 72, 7739e7747; (b) Martinez, V. C.;
Frias, J.; Vidal, V. C.; Gomez, R. J. Food Prot. 2005, 6, 1246e1252; (c) Mikkelsen,
L. L.; Bendixen, C.; Jakobsen, M.; Jensen, B. B. Appl. Environ. Microb. 2003, 69,
654e658; (d) Hartemink, R.; Kok, B. J.; Weenk, G. H.; Rombouts, F. M. Microbiol.
Methods 1996, 1, 33e44; (e) Faraji, F.; Lindsay, R. C. J. Agric. Food Chem. 2004, 52,
7164e7171; (f) Tuncer, P. B.; Bucak, M. N.; Sariozkan, S.; Sakin, F. ,; Yeni, D.;
Cigerci, I. H.; Atessahin, A.; Avdatek, F.; Gundogan, M.; Buyukleblebici, O.
Cryobiology 2010, 61, 89e93; (g) Goun, E.; Cunningham, G.; Solodnikov, S.;
Krasnykch, O.; Miles, H. Fitoterapia 2002, 73, 692e694.
Supplementary data
Copies of 1H, 13C NMR spectra of relative compounds. These data
include MOL files and InChiKeys of the most important compounds
described in this article. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.03.094.
13. (a) Gama, F. M.; Mota, M. Carbohydr. Polym. 1998, 37, 279e281; (b) Peterbauer,
T.; Richter, A. Plant Physiol. 1998, 117, 165e172; (c) Peterbauer, T.; Mucha, J.;
Mach, L.; Richter, A. J. Biol. Chem. 2002, 277, 194e200; (d) Suami, T.; Otake, T.;
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References and notes
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