Synthesis of D-fructofuranosides using thioglycosides as glycosyl donors

Article abstract of DOI:10.1021/jo951641t

Benzylated and benzoylated ethyl thioglycosides of D-fructofuranose have been synthesized and tested as glycosyl donors in couplings to various primary and secondary carbohydrate acceptors. Treatment of 2-O-acetyl-1,3,4,6-tetra-O-benzoyl-D-fructofuranose with ethyl mercaptan in a BF₃·-etherate-promoted reaction gave the benzoylated ethyl 2-thio-α,β-D-fructofuranosides, which after deacylation and benzylation afforded the benzylated derivatives. These thiofructofuranosides, using dimethyl(methylthio)sulfonium triflate (DMTST) or N-iodosuccinimide as promoter, were found to be excellent donors, which gave disaccharide coupling products in quantitative or almost quantitative yields with all tested acceptors, yields rarely found in oligosaccharide synthesis. The benzoylated donors gave only α-linked fructofuranosides, due to participation of the 3-O-benzoyl group, whereas the benzylated donors gave α/β-mixtures.

Full text of DOI:10.1021/jo951641t

1234
J . Org. Chem. 1996, 61, 1234-1238
Syn th esis of D-F r u ctofu r a n osid es Usin g Th ioglycosid es a s Glycosyl
Don or s
Christian Krog-J ensen and Stefan Oscarson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
S-106 91 Stockholm, Sweden
Received September 7, 1995X
Benzylated and benzoylated ethyl thioglycosides of D-fructofuranose have been synthesized and
tested as glycosyl donors in couplings to various primary and secondary carbohydrate acceptors.
Treatment of 2-O-acetyl-1,3,4,6-tetra-O-benzoyl-D-fructofuranose with ethyl mercaptan in a BF3‚-
etherate-promoted reaction gave the benzoylated ethyl 2-thio-R,â-D-fructofuranosides, which after
deacylation and benzylation afforded the benzylated derivatives. These thiofructofuranosides, using
dimethyl(methylthio)sulfonium triflate (DMTST) or N-iodosuccinimide as promoter, were found to
be excellent donors, which gave disaccharide coupling products in quantitative or almost quantitative
yields with all tested acceptors, yields rarely found in oligosaccharide synthesis. The benzoylated
donors gave only R-linked fructofuranosides, due to participation of the 3-O-benzoyl group, whereas
the benzylated donors gave R/â-mixtures.
In tr od u ction
a BF3‚etherate-promoted reaction. The yield was 95%
of an inseparable R/â-mixture (2). As observed by the
Russian workers, this mixture could be separated after
deacylation to give in quantitative yield 57% of the
R-anomer 3R and 43% of the â-anomer 3â, which were
benzylated to give the other donors 4R and 4â, in 80 and
76% yield, respectively (Scheme 1).
As acceptor compounds 5,8 6,9 and 7 were chosen, one
primary alcohol acceptor and two secondary, the latter
of interest for the synthesis of the â-fructofuranosidic-
containing repeating unit of the capsular polysaccharide
from Haemophilus influenzae type e.10
Dimethyl(methylthio)sulfonium triflate (DMTST)11 and
N-iodosuccinimide (NIS)12,13 were used as promoters.
N-Bromo and -chlorosuccinimide as well as methyl tri-
flate and a heterogenous catalyst, silver aluminum
silicate,14 were also tried together with the benzylated
donors 4R and â and aglycon 7 in attempts to optimize
the yield of â-fructofuranosidic product, but all the latter
promoters were markedly inferior to the other two used
(Table 3).
The results of the couplings are summarized in Schemes
2-4 and Tables 1-3. As criteria for the anomeric
configuration of the fructofuranosidic linkage in the
disaccharide products, the characteristic shifts of the C-2
signals in the 13C NMR spectra were used. C-2 signals
at higher fields around 103-4 ppm were assigned as
â-fructofuranosides, and C-2 signals at lower field around
107-8 ppm were assigned as R-linkages.15 These values
were originally assigned for unprotected fructofuranoses
Apart from in sucrose, D-fructofuranosides are also
found in nature in bacterial polysaccharides and in plant
polysaccharides.1 Generally, D-fructose occurs as â-fura-
nosyl residues; the only known exceptions are D-fructans
from Zymomonas mobilis and Yersinia intermedia, which
contain both R- and â-furanosidic residues.2,3 Our inter-
est in synthesizing structures from some of the bacterial
polysaccharides, which contain â-linked fructofurano-
sides, made us look for adequate glycosylation methods.
Syntheses of D-fructofuranosides using fructofuranosyl
donors are not very frequent; e.g., most syntheses of
sucrose have been performed with glucosyl donors and
fructosyl acceptors. Kotchetkov et al. have used fructo-
furanosyl thioorthoesters and thioglycosides as donors in
combination with tritylated acceptors,4,5 and recently,
Schmidt et al. investigated the use of anomeric phosphi-
tes as donors in the synthesis of fructofuranosides.6
Considering our earlier successful use of thioglycosides
as glycosyl donors, we decided to further evaluate the
use of these donors in the synthesis of fructofuranosides.
Both benzoylated and benzylated ethyl R- and â-2-thio-
D-fructofuranosides were synthesized and tested as do-
nors in couplings with different carbohydrate acceptors
and promoters.
Resu lts a n d Discu ssion
In their publication, the Russian workers synthesized
benzoylated ethyl 2-thio-D-fructofuranosides through re-
arrangement of the corresponding thioorthoesters.5 We
found it more convenient and high-yielding to prepare
the thioglycoside directly from 2-O-acetyl-1,3,4,6-tetra-
O-benzoyl-D-fructofuranose7 (1) and ethyl mercaptan in
(7) Bouali, A.; Descotes, G.; Ewing, D. F.; Grouiller, A.; Lefkidou,
J .; Lespinasse, A.-D.; Mackenzie, G. J . Carbohydr. Chem. 1992, 11,
159.
(8) Bore´n, R. K.; Eklind, K.; Garegg, P. J .; Lindberg, B.; Pilotti, A° .
Acta Chem. Scand. 1972, 26, 4143.
(9) Gibbs, C. F.; Hough, L.; Richardson, A. C. Carbohydr. Res. 1965,
1, 290.
(10) Branefors-Helander, P.; Kenne, L.; Lindberg, B.; Petersson, K.;
Unger, P. Carbohydr. Res. 1981, 88, 77.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48, 279.
(2) Barrow, K. D.; Collins, J . G.; Rogers, P. L.; Smith, G. M. Eur. J .
Biochem. 1984, 145, 173.
(3) Gorshovska, R. P.; Kovalchuk, S. V.; Isakov, V. V.; Frolova, G.
M.; Ovodov, Yu. S. Bioorg. Khim. 1987, 13, 818.
(4) Backinowsky, L. V.; Balan, N. F.; Betaneli, V. I.; Kotchetkov, N.
K. Carbohydr. Res. 1982, 99, 189.
(5) Balan, N. F.; Backinowsky, L. V.; Betaneli, V. I.; Kotchetkov, N.
K. Bioorg. Khim. 1981, 7, 1566.
(11) Fu¨gedi, P.; Garegg, P. J . Carbohydr. Res. 1986, 149, C9.
(12) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J . H.
Tetrahedron Lett. 1990, 31, 1331.
(13) Konradsson, P.; Udodong, U. D.; Fraser-Reid, B. Tetrahedron
Lett. 1990, 31, 4313.
(14) van Boeckel, C. A. A.; Beetz, T. Recl. Trav. Chim. Pays-Bas
1987, 106, 596
(15) Angyal, S. J .; Bethell, G. S. Aust. J . Chem. 1976, 29, 1249.
(6) Mu¨ller, T.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1994,
27, 4763.
0022-3263/96/1961-1234$12.00/0 © 1996 American Chemical Society

Synthesis of D-Fructofuranosides
J . Org. Chem., Vol. 61, No. 4, 1996 1235
Sch em e 1. Syn th esis of Th iofr u ctofu r a n osid e Don or s
Ta ble 1. Resu lts a n d Con d ition s for Cou p lin gs betw een
Accep tor 5 a n d Differ en t Th iofr u ctofu r a n osid e Don or s
Ta ble 3. Resu lts a n d Con d ition s for Cou p lin gs betw een
Accep tor 7 a n d Differ en t Th iofr u ctofu r a n osid e Don or s
yield of
yield of
initial temp disaccharide
initial temp disaccharide
donor promoter solvent
(°C)
(%)
R:âa
donor promoter solvent
(°C)
(%)
R:âa
2
2
DMTST
DMTST
DMTST
DMTST
DMTST
DMTST
DMTST
DMTST
DMTST
NIS
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH3CN
-20
-35
-78
-78
-20
-20
rt
-35
-35
rt
95 (8)
100 (8)
100 (9)
100 (9)
99 (9)
99 (9)
100 (9)
91 (9)
89 (9)
87 (9)
97 (9)
97 (9)
R
2
DMTST
DMTST
DMTST
DMTST
DMTST
NIS
NIS
NIS
NIS
NIS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
-20
-78
-78
-20
-20
rt
-40
-40
-78
-35
-35
-35
rt
92 (12)
76 (13)
80 (13)
97 (13)
99 (13)
60 (13)
72 (13)
79 (13)
79 (13)
62 (13)
98 (13)
98 (13)
69 (13)
26 (13)
no reaction
no reaction
∼20 (TLC, 13)
R
R
4r
4â
4r
4â
4r
4r
4â
4r
4r
4r
4â
4r
4r
4r
4r
4â
4.2:1
4.2:1
3.4:1
3.5:1
2:1
4r
4â
4r
4â
4r
4r
4â
4r
4r
4r
3.6:1
3.2:1
2.3:1
2.2:1
1.6:1
2.5:1
2.1:1
1.7:1
1:1.6
2.1:1
1.4:1
1.4:1
1.3:1
2.2:1
1:1.3
1:1.3
1.4:1
1:1
NIS
NIS
-40
-35
NIS
NIS
NIS
NBS
a
The R/â ratio is determined from 1H NMR spectra by compar-
-40
-40
rt
ing the intensity of the OMe signals (see Experimental Section).
NCS
Ag-Al-Si CH2Cl2
MeOTf CH2Cl2
-40
Ta ble 2. Resu lts a n d Con d ition s for Cou p lin gs betw een
Accep tor 6 a n d Differ en t Th iofr u ctofu r a n osid e Don or s
a
The R/â ratio is determined from 1H NMR spectra by com-
parison of the intensity of the axial proton signals of the 4,6-
benzylidene group and also the CH2CH2Ph signals of the spacer
(see the Experimental Section).
yield of
initial temp disaccharide
donor promoter solvent
(°C)
(%)
R:âa
Ta ble 4. 13C NMR Va lu e for An om er ic F r u ctofu r a n osid e
Ca r bon s
2
DMTST
DMTST
DMTST
NIS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
-20
-20
-20
-40
-35
95 (10)
99 (11)
96 (11)
94 (11)
64 (11)
R
4r
4â
4r
4r
7:1
5:1
7:1
4:1
substance
C-2Fru
substance
C-2Fru
NIS
2r
2â
3r
3â
4r
4â
93.5
92.6
93.1
94.4
93.8
11r
107.1
104.2
108.9
108.9
104.8
99.8
11â
a
The R/â ratio is determined from 1H NMR spectra by compar-
ing the intensity of the OMe signals and also the axial proton
signals of the 4,6-benzylidene group (see the Experimental Sec-
tion).
12r
13r
13â
94.0
14
8r
9r
9â
107.0
107.9
104.4
107.3
15â,R
15R,R
15R,â
104.6
108.5
108.3
and furanosides but have also been used inter alia by
Kotchetkov et al.4,5 for protected derivatives. Our results
(Table 4) were also consistent with this assignment. All
couplings with participating protecting groups gave
products with typical anomeric R-values, whereas non-
participating protecting groups gave product mixtures
with both typical R- and â-values. It can also be seen
from Table 4 that the anomeric shift is hardly influenced
by the type of protecting groups on the fructofuranosidic
moiety and that the anomeric assignment of the thiogly-
cosides from their 13C spectra seems not to be possible.
One of the pure R-linked products, 8 (Scheme 2), obtained
from coupling with a benzoylated donor, was transformed
by debenzoylation and benzylation into 9R and was found
to have 13C NMR spectra identical with the R-assigned
part of the mixture obtained from the coupling with a
benzylated donor. The R/â-ratio in mixtures were deter-
mined by comparing integrals of separable signals in the
1H NMR spectra (see Tables 1-3 and the Experimental
Section). Generally, it was not possible to separate the
R/â-mixtures by chromatography.
10r
Sch em e 2. Syn th esis of F r u ctofu r a n osid es Usin g
5 a s Accep tor
sively the R-linked products 8, 10, and 12 was obtained
with all three aglycons. Thus, synthesis of R-linked
fructofuranosides seems to offer few problems. Kotch-
etkov et al. also obtained high yields (71-82%, only
R-product) using the perbenzoylated thioorthoester as
donor.4 With donor 2, using tritylium perchlorate as
When the benzoylated donor 2 and DMTST as pro-
moter were used, an almost quantitative yield of exclu-

1236 J . Org. Chem., Vol. 61, No. 4, 1996
Krog-J ensen and Oscarson
Sch em e 3. Syn th esis of F r u ctofu r a n osid es Usin g
6 a s Accep tor
the â-product but also lower yield (Table 2, Scheme 3).
For the other two aglycons 5 and 7, a more thorough
study on the dependence of the R/â-ratio of the products
on different conditions was made (Tables 1 and 3,
Schemes 2 and 4). The variation of the ratio was not
dramatic in any case; variations from 3.6/1 up to 1/1.6
were observed. These small variations also make it
difficult to discuss trends. When CH2Cl2 was used as
solvent, DMTST and NIS at room temperature gave
about the same ratio, but when the temperature was
lowered, DMTST gave more of the R-product whereas
NIS gave more of the â-product. The effect of acetonitrile
as solvent, often used as â-directing in D-hexopyranosyl
glycosylation without participating protecting groups,16
especially efficient with primary carbohydrate aglycons,
was diverse. With NIS as promoter and the primary
aglycon 5 the R/â-ratio actually increased compared to
CH2Cl2, whereas for the secondary acceptor 7 the ratio
decreased. The yields in these reactions also varied, but
when DMTST was used almost quantitative yields were
always obtained independent of solvent and with NIS the
yields were lowered with acetonitrile as solvent for
acceptor 6, improved for acceptor 7, and the same for
acceptor 5. Other solvents and promoters tried gave
inferior results (Table 3).
Sch em e 4. Syn th esis of F r u ctofu r a n osid es Usin g
7 a s Accep tor
When the reactions using 4 as donor and NIS as
promoter were followed by TLC, the formation of an
intermediate was observed prior to the formation of the
product. This intermediate was found to form also in the
absence of aglycon and was then stable. Isolation and
analysis of this intermediate proved it to be a N-
succinimide glycoside 14 (Scheme 5). Only one anomer
was isolated both from 4R and 4â, but the configuration
is not proven. The observation that only one anomer is
formed and that the optical rotation of this product is
+29° indicates that it is an R-anomer, but further proof
is needed. Attempted synthesis of the perbenzoylated
corresponding derivative failed. N-Succinimide pyrano-
sides have been previously synthesized by the reaction
between NIS and glycals17 or thioglycopyranosides.18 14
is probably not an actual intermediate in the glycosyla-
tion reaction, but only formed on the TLC-plate, since
addition of an acceptor to isolated 14 did not produce any
disaccharide. Furthermore, reversed addition of re-
agents, first mixing of donor and NIS and then addition
of aglycon, also resulted only in the formation of 14 and
no disaccharide product.
promotor, no product was obtained, but with donor 4 a
high yield (94%) of disaccharide product (R/â-mixture ≈
1:1) was obtained in a coupling with 1,2,3,4-tetra-O-
acetyl-6-O-trityl-â-D-glucopyranosyl as acceptor.5 Schmidt
et al. reported high yields of exclusively R-fructofurano-
sidic product with the perbenzoylated phosphite donor
with 6-OH or 1-OH in glucose as acceptor, but with
secondary hydroxyl groups as aglycons, â-products were
also obtained. Thus, coupling at 3′-OH in lactose and
4-OH in glucose was claimed to give exclusively the
â-fructofuranosidic product in 88 and 93% yields, respec-
1
tively.6 Unfortunately, only selected H-NMR data, no
13C NMR data, and no criteria for the determination of
the anomeric configuration are given in the paper. In
our hands, the benzoylated phospite donor with 7 as
acceptor using the conditions of Schmidt et al. gave only
the R-linked product as determined by the criteria
discussed above.
The synthesis of sucrose using a fructofuranosidic
donor was also attempted (Scheme 5). The crystalline
and commercially available derivative 2,3,4,6-tetra-O-
benzyl-R-D-glucopyranose was used as acceptor. The
temperature was kept low to avoid anomerization of the
glucopyranosyl moiety to the undesired â-form. DMTST
once more gave a quantitative yield of disaccharide
product but gave at this low temperature (-78 °C) mainly
the R-furanosidic linkage. NIS gave a lower yield (67%),
but also more of the desired â-furanosidic linkage.
According to 1H-NMR, 32% of the product mixture
consisted of sucrose, i.e., a total yield of about 20%, a yield
that compares well with syntheses performed with glu-
copyranosyl donors.19
Since most naturally occuring fructofuranosides are
â-linked, the synthesis of this linkage is perhaps more
interesting, but also much more complicated. Since our
ethyl thioglycosides with participating benzoate protect-
ing groups could not, as shown, be used, nonparticipating
benzyl groups were introduced. Couplings with the
benzylated donors 4R and 4â with the different aglycons
gave once more very high yields of disaccharide products
9, 11, and 13, this time as R/â-mixtures, most often with
the R-form dominating (Tables 1-3). The influence on
the R/â-ratio by different conditions such as temperature,
promoter, solvent, etc. was small and seemed to vary
between the different couplings. General rules were
difficult to find, and an optimization of â-linked product
has to be made for each separate combination of acceptor
and donor. One observation was consistent throughout
all experiments: the anomeric configuration of the donor
did not affect the yield or the stereochemical outcome of
the glycosylations to any greater extent. With acceptor
6, DMTST and NIS in CH2Cl2 gave the same R/â-ratio,
acetonitrile as solvent together with NIS gave more of
In conclusion, ethyl 2-thio-D-fructofuranosides are
excellent glycosyl donors, which in most cases give
(16) Braccini, I.; Derouet, C.; Esnault, J .; Herve´ du Penhoat, C.;
Mallet, J .-M.; Michon, V.; Sinay¨, P. Carbohydr. Res. 1993, 246, 23.
(17) Laupichler, L. Ph.D. Thesis, Hamburg University, 1992.
(18) Konradsson, P.; Oscarson, S.; O¨ berg, L. Unpublished results.
(19) Khan, R. Adv. Carbohydr. Chem. Biochem. 1976, 33, 235.

Synthesis of D-Fructofuranosides
Sch em e 5. Syn th esis of
J . Org. Chem., Vol. 61, No. 4, 1996 1237
dropwise to a mixture of 3R (2.22 g, 9.89 mmol) and NaH (1.6
g, 65.1 mmol) in DMF (20 mL). The mixture was stirred for
4 h at rt, quenched by adding 1 mL of methanol, diluted with
toluene (100 mL), and washed with saturated NaHCO3 solu-
tion (2 × 200 mL) and water (2 × 200 mL). Drying and
concentration followed by purification repeated twice on a silica
gel column (system A) yielded 4R (80%, 4.60 g, 7.87 mmol):
[R]D +38° (c 1.06, chloroform) (lit.5 [R]D +38.6°); 13C NMR δ
14.8, 22.3, 69.6, 70.4, 72.3, 73.0, 73.2, 73.5, 79.2, 84.0, 89.7,
93.8, 127.5-138.2.
N-D-F r u ctofu r a n osylsu ccin im id e a n d
D-F r u ctofu r a n osyl D-Glu cop yr a n osid es
Eth yl 1,3,4,6-Tetr a -O-ben zyl-2-th io-â-D-fr u ctofu r a n o-
sid e (4â). Compound 3â (1.67 g, 7.40 mmol) was benzylated
as described for 3R above to give 4â (76% , 3.33 g, 5.69 mmol):
[R]D -36° (c 0.73, chloroform) (lit.5 [R]D -37.3°); 13C NMR δ
14.8, 21.0, 71.4, 72.5, 72.8, 73.1, 73.3, 73.5, 80.5, 84.8, 85.0,
94.0, 127.6-138.1.
2-(p -Nit r op h en yl)et h yl 2-Azid o-4,6-O-b en zylid en e-2-
d eoxy-â-D-m a n n op yr a n osid e (7). Synthesis of this acceptor
will be presented elsewhere: mp 151 °C (from MeOH); [R]D
-82° (c 1.02, chloroform); 13C NMR δ 36.0, 64.6, 67.1, 68.3,
69.8, 69.9, 78.4, 100.6, 102.1, 123.6, 126.2, 128.3, 129.3, 129.9,
136.9, 146.3, 146.8. Anal. Calcd for C21H22O7N4 : C, 57.01;
H, 5.01. Found: C, 57.12 ; H, 5.03.
Glycosyla tion P r oced u r es. Meth od A (DMTST). The
donor (50-100 mg, 85-170 µmol) and the acceptor (40-80 mg,
1 equiv) were dissolved in 5-10 mL of distilled solvent together
with crushed molecular sieves (4 Å, 0.3-0.5 g). The mixture
was stirred under nitrogen and allowed to attain the desired
initial reaction temperature (-78 °C -25 °C). After 30 min,
DMTST (4 equiv) was added. The temperature program for
the cold (below -20 °C) reactions was 3-4 h at the initial
temperature, 12 h at -20 °C, and finally 30 min at rt. When
TLC (system C) indicated the reaction to be complete triethy-
lamine was added, whereafter the mixture was concentrated
and purified on a silica gel column (system B).
Meth od B (NIS, NBS, or NCS). The donor (50-65 mg,
85-110 µmol) and the acceptor (26-39 mg, 1 equiv) were
dissolved in 4-8 mL of distilled solvent together with crushed
molecular sieves (4 Å, 0.2-0.4 g). The mixture was stirred
under a nitrogen atmosphere and allowed to attain the desired
reaction temperature. After 30 min, NIS (1.5 equiv) was
added. Reaction temperature intervals were as for method
A. When TLC (system C) indicated the reaction to be
complete, the mixture was diluted with CH2Cl2 and filtered
through Celite into a separatory funnel, washed twice with
saturated Na2S2O3 solution and water, dried, concentrated,
and purified on a silica gel column (system B).
oligosaccharide products in quantitative or near-quanti-
tative yields using only a small excess of donor. Such
yields, in contrast to peptide and oligonucleotide synthe-
sis, are very rarely found in oligosaccharide couplings.
Benzoylated donors using DMTST as promoter give
almost quantitative yields of R-fructofuranosidic oligosac-
charides. Benzylated derivatives using DMTST as pro-
moter also give quantitative yields of fructofuranosides
but as an R/â-mixture. The use of NIS as promoter,
especially at lower temperatures, can improve the amount
of â-furanosidic product.
Exp er im en ta l Section
Gen er a l Rem a r k s. Melting points are corrected. Organic
solutions were dried over MgSO4 before concentration, which
was performed under reduced pressure at <40 °C (bath
temperature). NMR spectra were recorded at 25 °C at 270
MHz (1H) or 67.5 MHz (13C) in CDCl3 with Me4Si as internal
standard (δ ) 0), unless otherwise stated. The FAB mass
spectrum was recorded in the negative mode (matrix NBA).
TLC was performed on silica gel F254 (E. Merck) with detection
by UV light and/or by charring with 8% sulfuric acid. Silica
gel (0.040-0.063 mm, Amicon) was used for column chroma-
tography. Eluants used for column chromatography and
TLC: A, toluene-EtOAc 10:1; B, toluene-EtOAc 9:1; C,
toluene-EtOAc 6:1.
E t h yl 1,3,4,6-Tet r a -O-b en zoyl-2-t h io-D-fr u ct ofu r a n o-
sid e (2). BF3‚etherate (384 µL, 3.13 mmol) was added at 0
°C to a solution of ethyl mercaptan (348 µL, 4.70 mmol) and
2-O-acetyl-1,3,4,6-tetra-O-benzoyl-D-fructofuranoside7 (1, 2.0
g, 3.13 mmol) in dry chloroform (35 mL). The reaction mixture
was stirred at 0 °C for 2.5 h and then diluted with chloroform,
washed with saturated NaHCO3 solution and water, dried, and
concentrated. Purification of the residue on a silica gel column
(petroleum ether bp 60-70 °C-EtOAc 3:1) gave 2 (99%, 1.99
g, 3.10 mmol): 13C NMR δ 14.5, 14.8, 21.6 22.3, 62.7, 63.2,
64.6, 65.6, 77.6, 78.1, 78.9, 79.7, 79.8, 82.4, 92.6, 93.5, 128.3-
149.7, 164.9, 165.6, 165.68, 165.74, 166.0. Anal. Calcd for
C36H32O9S: C, 67.49; H, 5.03. Found: C, 67.40 ; H, 5.18.
E t h yl 2-Th io-r-D-fr u ct ofu r a n osid e (3r) a n d E t h yl
2-Th io-â-D-fr u ctofu r a n osid e (3â). Sodium methoxide in
methanol (1.5 mL, 1 M) was added to a suspension of 2 (11.1
g, 17.3 mmol) in methanol (200 mL). After 3 h, TLC (chloro-
form-methanol 5:1) showed two slower spots. Careful neu-
tralization with methanol-washed Dowex 50 (H+) ion exchange
resin, followed by filtration, concentration, and purification on
a silica gel column (chloroform-methanol 9:1), gave a quan-
titative yield of 3R (57%, 2.2 g, 9.89 mmol) [mp 93-94 °C; [R]D
+135° (c 1.1, H2O) (lit.5 mp 89-91 °C; [R]D +140°)] and 3â
(43%, 1.66 g, 7.40 mmol): [R]D -94° (c 1.3, H2O) (lit.5 [R]D
-93°);13C NMR (CD3OD-CDCl3 3:1, acetone as internal
standard δ ) 31.0): 3R, δ 15.1, 22.4, 60.0, 64.6, 80.7, 85.0,
85.1, 93.1; 3â, δ 15.0, 20.8, 63.4, 63.9, 76.5, 77.4, 83.0, 94.4.
Eth yl 1,3,4,6-Tetr a -O-ben zyl-2-th io-r-D-fr u ctofu r a n o-
sid e (4r). Benzyl bromide (5.8 mL, 48.6 mmol) was added
P r od u cts. Details on the conditions and yields for the
different couplings as well as the R/â-ratios of the products
are presented in Tables 1-3. The ratios were determined by
1
integration of peaks in H NMR, since none of the R/â-product
mixtures could be separated by chromatography. The peaks
used are given below for each R/â-mixture. The distinction
between the anomers is made from mixtures with a large
excess of R-compound as determined from the 13C NMR
spectrum. 13C NMR data is presented for the anomeric
fructofuranosidic carbons in Table 4.
Meth yl 2,3,4-Tr i-O-ben zyl-6-O-(1,3,4,6-tetr a -O-ben zoyl-
r-D-fr u ctofu r a n osyl)-R-D-m a n n op yr a n osid e (8). Coupling
of donor 2 and acceptor 5 according to method A: [R]D +29° (c
0.74, chloroform); 13C NMR δ 54.4, 59.6, 61.6, 63.4, 71.0, 72.1,
72.5, 74.3, 75.0, 79.3, 80.3, 81.0, 81.7, 98.6, 107.0, 126.1-138.8,
165.3, 165.4, 165.7, 166.8. Anal. Calcd for C62H58O15
71.39; H, 5.60. Found: C, 71.15 ; H, 5.59.
: C,
Meth yl 2,3,4-Tr i-O-ben zyl-6-O-(1,3,4,6-tetr a -O-ben zyl-
D-fr u ctofu r a n osyl)-r-D-m a n n op yr a n osid e (9). Coupling of
donor 4 and acceptor 5: 13C NMR δ 54.4, 61.2, 61.4, 67.3, 70.0,
71.2, 71.3, 71.4, 71.6, 72.0, 72.1, 72.2, 72.3, 72.4, 72.6, 72.6,
73.2, 73.5, 74.7, 74.7, 74.8, 74.9, 75.1, 75.4, 77.2, 79.0, 80.1,
80.2, 80.5, 84.0, 84.5, 84.7, 87.5, 98.6, 98.7, 104.4, 107.9, 127.2-
139.0; 1H NMR δ 3.13 (s, OMe, R-Fruf), 3.19 (s, OMe, â-Fruf).
Anal. Calcd for C62H66O11: C, 75.43; H, 6.74. Found: C, 74.70
; H, 6.80.
Meth yl 2,3,4-Tr i-O-ben zyl-6-O-(1,3,4,6-tetr a -O-ben zyl-
r-D-fr u ctofu r a n osyl)-r-D-m a n n op yr a n osid e (9r). Sodium
methoxide in methanol (0.1 mL, 1 M) was added to a solution

1238 J . Org. Chem., Vol. 61, No. 4, 1996
Krog-J ensen and Oscarson
of 8 (143 mg, 147 µmol) in methanol (20 mL). When TLC
showed the reaction to be complete, the mixture was neutral-
ized by methanol-washed Dowex 50(H+) ion exchange resin,
filtered, concentrated, and purified on a silica gel column
(chloroform-methanol 9:1) to yield methyl 2,3,4-tri-O-benzyl-
6-O-R-D-fructofuranosyl-R-D-mannopyranoside (86%, 79 mg,
126 µmol): 13C NMR δ 55.1, 59.3, 60.2, 61.9, 70.7, 72.2, 72.8,
74.1, 75.1, 75.2, 78.5, 79.8, 86.9, 99.2, 109.5, 127.6-138.4.
Benzylation of this intermediate (79 mg, 126 µmol) as de-
scribed for compound 3R above gave 9R (95%, 119 mg, 120
µmol): [R]D +39° (c 0.84, chloroform); 13C NMR δ 54.4, 61.2,
67.3, 70.0, 71.3, 72.0, 72.1, 72.4, 72.6, 73.2, 73.6, 74.8, 75.4,
80.2, 80.5, 84.6, 87.5, 98.6, 107.9, 127.4-138.8. Anal. Calcd
for C62H66O11: C, 75.43; H, 6.74. Found: C, 74.85 ; H, 6.86.
Met h yl 2-Ben za m id o-4,6-O-b en zylid en e-2-d eoxy-3-O-
(1,3,4,6-tetr a-O-ben zoyl-r-D-fr u ctofu r an osyl)-r-D-glu copy-
r a n osid e (10). Coupling of donor 2 and acceptor 6 using
method A: [R]D +30° (c 1.22, chloroform); 13C NMR δ 53.7,
55.5, 62.8, 63.1, 63.2, 69.0, 71.3, 76.9, 78.6, 80.6, 82.5, 99.2,
102.1, 107.3, 126.1-136.7, 164.8, 165.3, 165.4, 165.7. Anal.
Calcd for C55H49O15N: C, 68.53; H, 5.12. Found: C, 67.61; H,
5.10.
a nitrogen atmosphere was cooled to -78 °C and stirred for
30 min. Then NIS (30 mg, 132 µmol) was added, and the
temperature was allowed to rise. After 30 min (temperature
-20 °C), TLC indicated that all starting material was con-
sumed. The mixture was diluted with CH2Cl2, filtered through
Celite into a separatory funnel containing saturated Na2S2O3
solution, washed, dried, and concentrated. The residue was
purified on a silica gel column (system C) to yield 14 (91%, 63
mg, 101 µmol): [R]D +29° (c 1.0, chloroform); 13C NMR δ 28.4,
68.9, 69.9, 71.6, 72.6, 73.2, 73.4, 83.3, 83.5, 83.7, 99.8, 127.4-
138.3, 177.0; MS (FAB) m/e 620.2 (M+ - 1). Anal. Calcd for
C38H39O7N: C, 73.41; H, 6.32. Found: C, 73.16 ; H, 6.28.
Syn th esis of Su cr ose. Attempts to optimize the yield of
sucrose was made in four different couplings, using 4R as donor
and 2,3,4,6-tetra-O-benzyl-R-D-glucopyranose as acceptor.
1. Method A: CH2Cl2, -78 °C. Yield quantitative of mainly
the R,R-isomer.
2. Method B: CH2Cl2, -60 °C. See below.
3. Method B: CH3CN, -35 °C. Yielded no disaccharide
product.
4. Method B: CH2Cl2, -78 °C, 3 equiv of acceptor. Yield
as for 2.
Met h yl 2-Ben za m id o-4,6-O-b en zylid en e-2-d eoxy-3-O-
(1,3,4,6-tetr a -O-ben zyl-D-fr u ctofu r a n osyl)-r-D-glu cop yr a -
n osid e (11). Coupling of donor 4 and acceptor 6: NMR 13C δ
54.7, 54.9, 55.5, 63.1, 63.2, 69.1, 69.6, 70.7, 70.8, 71.5, 71.6,
72.2, 72.3, 72.8, 73.2, 73.5, 73.9, 78.8, 79.6, 80.7, 81.0, 81.5,
83.1, 85.4, 90.6, 98.9, 99.2, 101.6, 101.9, 104.2, 107.1, 126.1-
1,3,4,6-Tetr a -O-D-fr u ctofu r a n osyl 2,3,4,6-Tetr a -O-D-glu -
cop yr a n osid e (15). Using method B, 4R (65 mg, 111 µmol)
was reacted with 2,3,4,6-tetra-O-benzyl-R-D-glucopyranose (46
mg, 85 µmol) in CH2Cl2 at -60 °C. The total yield of
disaccharides was 67% (60.1 mg, 57 µmol): NMR 13C δ 68.2,
68.4, 69.1, 70.0, 70.5, 71.0, 71.2, 71.4, 71.5, 72.1, 72.2, 72.5,
72.6, 72.7, 73.0, 73.2, 73.4, 74.7, 74.8, 75.0, 75.5, 77.6, 79.6,
79.8, 80.4, 81.9, 82.4, 83.9, 84.3, 84.9, 87.8, 89.0, 89.9, 96.8,
104.6, 108.3, 108.5, 127.1-138.4; 1H δ 5.55 (d, J ) 3 Hz, H-1,
R-Glcp-R-Fruf), 5.72, (d, J ) 3 Hz, H-1, R-Glcp-â-Fruf). The
amount of 15â,R (octabenzyl sucrose) of the disaccharide
mixture was 32% as estimated from 1H NMR. The main side
product was the R,R-isomer (56%), and also the R,â-isomer
(isosucrose) (12%) could be detected. To be able to quantify
the amount of 15â,R, the NMR data was compared to octa-
benzyl sucrose synthesized from sucrose.20
1
138.3, 167.0, 167.4; H δ 4.97 (d, J 3.3 Hz, H-1, â-Fruf), 5.14
(d, J 3.3 Hz, H-1, R-Fruf), 5.53 (s, PhCH, â-Fruf), 5.55 (s,
PhCH, R-Fruf). Anal. Calcd for C55H57O11N: C, 72.75; H, 6.33.
Found: C, 72.37 ; H, 6.52.
2-(p -Nitr op h en yl)eth yl 2-Azid o-4,6-O-ben zylid en e-2-
d eoxy-3-O-(1,3,4,6-tetr a -O-ben zoyl-r-D-fr u ctofu r a n osyl)-
â-D-m a n n op yr a n osid e (12). Coupling of donor 2 and accep-
tor 7 by method A: [R]D -28° (c 1.1, chloroform); 13C NMR δ
36.0, 61.7, 63.4, 65.0, 67.8, 68.3, 69.8, 70.5, 76.3, 78.5, 82.1,
82.5, 100.6, 102.4, 108.9, 123.7-146.8, 164.6, 165.4, 165.9,
166.1. Anal. Calcd for C55H48O16N4: C, 64.70; H, 4.74.
Found: C, 64.57 ; H, 4.85.
2-(p -Nit r op h en yl)et h yl 2-Azid o-4,6-O-b en zylid en e-2-
d eoxy-3-O-(1,3,4,6-tetr a -O-ben zyl-D-fr u ctofu r a n osyl)-â-D-
m a n n op yr a n osid e (13). Coupling of donor 4 and acceptor
7: 13C NMR δ 35.9, 36.0, 65.7, 67.3, 67.8, 68.4, 69.2, 69.4, 69.6,
69.7, 70.0, 70.4, 71.3, 72.0, 72.5, 72.6, 72.8, 73.1, 73.2, 73.4,
73.6, 78.3, 81.8, 84.0, 88.5, 99.6, 100.3, 102.0, 102.2, 104.8,
108.9, 123.5-146.7; 1H NMR δ 2.96 (t, CH2CH2Ar, â-Fruf), 3.04
(t, CH2CH2Ar, R-Fruf), 5.51 (s, PhCH, â-Fruf), 5.53 (s, PhCH,
R-Fruf). Anal. Calcd for C55H56O12N4: C, 68.45; H, 5.85.
Found: C, 68.18 ; H, 5.84.
Ack n ow led gm en t. We thank Professor Per J . Gar-
egg for his interest in this work and the Swedish
Natural Science Research council for financial support.
1
Su p p or tin g In for m a tion Ava ila ble: 270 MHz H NMR
spectra for all fructose-containing derivatives and acceptor 7
(15 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O951641T
(1,3,4,6-Tetr a -O-ben zyl-D-fr u ctofu r a n osyl)-N-su ccin im -
id e (14). A solution of 4R or 4â (65 mg, 111 µmol) in CH2Cl2
(5 mL) containing 4 Å crushed molecular sieves (0.3 g) under
(20) Tate, M. E.; Bishop, C. T. Can. J . Chem. 1963, 41, 1801.