Stereospecific Synthesis of β-D-Fructofuranosides Using Thioglycoside Donors and Internal Aglycon Delivery

Article abstract of DOI:10.1021/jo970983r

Stereospecific synthesis of β-D-fructofuranosides has been accomplished by the application of an internal acceptor delivery approach. The acceptor, ethanol or monosaccharides, is initially tethered to the fructofuranose 3-hydroxyl group, adjacent to the anomeric center and on the β-side of the furanose ring, as part of a mixed p-methoxybenzaldehyde acetal, which is formed by DDQ-oxidation of ethyl 1,4,6-tri-O-benzyl-3-O-(4-methoxybenzyl)-2-thio-D-fructofuranoside in the presence of the acceptor or of the p-methoxybenzylated acceptor in the presence of the corresponding 3-OH fructofuranoside. Then, activation of the thioglycoside with a thiophilic promoter allows the delivery of the acceptor from the acetal to the activated anomeric center to yield the β-linked fructofuranoside in high yields (76-85%). If promoters with nonnucleophilic anions (triflate, perchlorate) are used, the intermediate acetal decomposes to produce the β-fructofuranoside products as 3-OH derivatives. However, if NIS is used as promoter, the N-succinimide anion interacts with the benzylidene carbon to give the β-fructofuranoside products as mixed fructofuranoside-3-O-yl N-succinimide p-methoxybenzaldehyde acetals.

Full text of DOI:10.1021/jo970983r

1780
J . Org. Chem. 1998, 63, 1780-1784
Ster eosp ecific Syn th esis of â-D-F r u ctofu r a n osid es Usin g
Th ioglycosid e Don or s a n d In ter n a l Aglycon Deliver y†
Christian Krog-J ensen and Stefan Oscarson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
S-106 91 Stockholm, Sweden
Received J une 2, 1997
Stereospecific synthesis of â-D-fructofuranosides has been accomplished by the application of an
internal acceptor delivery approach. The acceptor, ethanol or monosaccharides, is initially tethered
to the fructofuranose 3-hydroxyl group, adjacent to the anomeric center and on the â-side of the
furanose ring, as part of a mixed p-methoxybenzaldehyde acetal, which is formed by DDQ-oxidation
of ethyl 1,4,6-tri-O-benzyl-3-O-(4-methoxybenzyl)-2-thio-D-fructofuranoside in the presence of the
acceptor or of the p-methoxybenzylated acceptor in the presence of the corresponding 3-OH
fructofuranoside. Then, activation of the thioglycoside with a thiophilic promoter allows the delivery
of the acceptor from the acetal to the activated anomeric center to yield the â-linked fructofuranoside
in high yields (76-85%). If promoters with nonnucleophilic anions (triflate, perchlorate) are used,
the intermediate acetal decomposes to produce the â-fructofuranoside products as 3-OH derivatives.
However, if NIS is used as promoter, the N-succinimide anion interacts with the benzylidene carbon
to give the â-fructofuranoside products as mixed fructofuranoside-3-O-yl N-succinimide p-
methoxybenzaldehyde acetals.
Sch em e 1a
In tr od u ction
Fructofuranosides are found in nature in both plants
and bacteria, in sucrose, in fructofuranans, 1f6-linked
inulins, and 1f2-linked levans, and as residues in
bacterial capsular polysaccharides.1 Apart from a few
exceptions, fructofuranosides in natural saccharides are
all â-linked. Hence, methods to stereoselectively con-
struct â-fructofuranosidic linkages is a prerequisite for
the synthesis of most fructose-containing structures from
nature. Recently, we reported the successful application
of the internal aglycon delivery approach2-6 in the
synthesis of â-fructofuranosides.7 In this paper, we now
give additional information of the scope of this reaction,
including the effects of various promoters, solvents,
acceptors, and donors.
a
Key: NaOMe, MeOH, -15 °C; (b) BnBr, NaH, DMF; (c)
TMSOTf, EtSH, CH2Cl2; (d) NaOMe, MeOH; (e) MBnBr, NaH,
DMF.
noside as an inseparable R/â-mixture. Treatment with
sodium methoxide in methanol gave the two 3-hydroxyl
compounds 3r and 3â, which now could be separated by
silica gel column chromatography. p-Methoxybenzylation
then gave derivatives 4r and 4â (Scheme 1).
Resu lts a n d Discu ssion
A benzylated fructofuranose thioglycoside donor with
a free 3-hydroxyl group was synthesized from the known
ortho ester derivative 18 by change of the benzoyl groups
into benzyl groups and then rearrangement of the ortho
ester 2 in the presence of an excess of ethanethiol to give
ethyl 3-O-benzoyl-1,4,6-tri-O-benzyl-2-thio-D-fructofura-
As discussed in our previous paper,7 acceptors can now
be linked to the â-side of the donor 4r as part of a mixed
p-methoxybenzaldehyde acetal by DDQ-oxidation of the
3-O-(p-methoxybenzyl) group in the presence of the
acceptor, as described by Ito and Ogawa.5,6 Activation
of the thioglycoside with a thiophilic promoter then allows
the delivery of the acceptor from the 3-O-acetal on the
â-side to the anomeric center to give exclusively the
â-linked fructofuranoside disaccharide as determined
from the 13C NMR chemical shift of the anomeric carbon
of fructose (δ ∼103-105 ppm â-linked, ∼107-109 ppm
R-linked).9,10 In this paper, the effects of different
solvents and different promoters in this reaction have
been investigated. The use of 4â as donor, instead of 4r,
† Dedicated to Professor Hans Paulsen on the occasion of his 75th
birthday.
(1) Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48, 279-
318.
(2) (a) Barresi, F.; Hindsgaul, O. J . Am. Chem. Soc. 1991, 113, 9376-
9377. (b) Barresi, F.; Hindsgaul, O. Synlett 1992, 759-761. (c) Barresi,
F.; Hindsgaul, O. Can. J . Chem. 1994, 72, 1447-1465.
(3) Stork, K.; Kim, G. J . Am. Chem. Soc. 1992, 114, 1087-1088.
(4) (a) Bols, M. J . Chem. Soc., Chem. Commun. 1992, 913-914. (b)
Bols, M. J . Chem. Soc., Chem. Commun. 1993, 791-792. (c) Bols, M.
Acta Chem. Scand. 1993, 47, 829-834.
(5) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765-
1767.
(6) Dan, A., Ito, Y.; Ogawa, T. J . Org. Chem. 1995, 60, 4680-4681.
(7) Krog-J ensen, C.; Oscarson, S. J . Org. Chem. 1996, 61, 4512-
4513.
(9) Angyal, S. J .; Bethell, G. S. Aust. J . Chem. 1976, 29, 1249.
(10) Krog-J ensen, C.; Oscarson, S. J . Org. Chem. 1996, 61, 1234-
1238.
(8) Helferich, B.; Bottenbruch, L. Chem. Ber. 1953, 86, 651-657.
S0022-3263(97)00983-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/20/1998

Synthesis of â-D-Fructofuranosides
J . Org. Chem., Vol. 63, No. 6, 1998 1781
Sch em e 2
(DMTST)12 was then tested as promoter, which did not
improve the yields. Slight alterations in the reaction
conditions for the acetal formation (the reagents were
added in a reversed order and triethylamine was added
to the reaction mixture prior to workup) gave a cleaner
reaction according to TLC, and now both acceptors gave
good yields with DMTST as promoter (entries 2 and 9,
Table 1). These new conditions were also tested with
MeOTf as promoter, but no increase in yield was noticed.
NIS was also tried as promoter, and a product was
isolated in good yield with both 5 or 6 as acceptor and
4r as donor (entries 6 and 11, Table 1), but both these
products had a different mobility on TLC compared to
the products obtained when using DMTST or methyl
triflate as promoter. NMR on these new products showed
them to be â-linked disaccharides but also showed the
presence of both a p-methoxyphenyl group (13C, δ ∼55,
113, and 159 ppm) and a succinimide moiety (13C, δ ∼29
and 176 ppm). This suggested that the nucleophilic
succinimide anion had reacted with the benzylidene
carbon, during or after the leaving of the acceptor moiety,
to form an N,O-acetal and give products 15 and 16, whose
structures were further confirmed by elemental analysis
and FAB-MS. A singlet at around 6.5 ppm in the 1H,
and an additional signal in the ring carbon region (∼60-
85 ppm) in the 13C NMR spectra, assigned as the acetal
proton and the acetal carbon, respectively, provided
additional proof to the suggested structures. According
to NMR, one of the two possible stereoisomers is formed
almost exclusively. Analogous N-succinimide isopropyli-
dene acetals were found by Baressi and Hindsgaul,
especially when using NBS as promoter in the activation.2c
However, in their case, the acetals were found only rarely
and as labile products, which could easily be hydrolyzed,
in contrast to ours, which were the sole product and quite
stable. Similar problems, with the nucleophilicity of the
N-succinimide anion, have been encountered in NIS-
promoted glycosylation with reactive donors and unre-
active acceptors. In these reactions the corresponding
anomeric succinimido N,O-acetal was formed.10,13,14 At-
tempts to hydrolyze the N,O-acetals in 15 and 16 with
Ta ble 1. Resu lts fr om th e Cou p lin gs
entry donor acceptor promoter/solvent product yield (%)
1
2
3
4
5
6
7
8
4r
4r
4r
4r
4r
4r
4r
4r
5
5
5
5
5
5
5
5
MeOTf/CH2Cl2
12
31
77
66
15
0
57
58
45
DMTST/CH2Cl2 12
DMTST/CH3CN 12
DMTST/toluene 12
DMTST/DMF
NIS/CH2Cl2
IDCT/CH2Cl2
IDCP/CH2Cl2
15
12
12
9
10
11
12
13
4r
4r
4r
4r
4r
6
6
6
6
6
DMTST/CH2Cl2 13
76
59
63
76
54
MeOTf/CH2Cl2
NIS/CH2Cl2
13
16
13
13
IDCT/CH2Cl2
IDCP/CH2Cl2
14
15
4â
4â
5
6
DMTST/CH2Cl2 12
DMTST/CH2Cl2 13
45
54
16
17
18
3r
3r
3r
8
8
9
DMTST/CH2Cl2 12
53
53
57
NIS/CH2Cl2
16
DMTST/CH2Cl2 13
19
20
21
22
4r
3r
3r
3r
7
10
10
10
DMTST/CH2Cl2
DMTST/CH2Cl2 14 + 18 25 + 60
NIS/CH2Cl2
0
17
14
85
76
IDCP/CH2Cl2
was also tried, as well as an “inverse” approach using
3r, with a free 3-hydroxyl group, as donor and p-meth-
oxybenzylated acceptors in the formation of the inter-
mediate acetal. Furthermore, the result with an ad-
ditional acceptor, ethanol, is included. With this accep-
tor, the intermediate acetal could be isolated and
characterized by NMR. The results obtained are sum-
marized in Scheme 2 and Table 1.
Methyl trifluoromethanesulfonate (MeOTf) was origi-
nally tried as promoter together with donor 4r, using the
conditions published by Ito and Ogawa.5 This gave
an acceptable yield of â-linked disaccharide with
acceptor 610 (f13, 59%, entry 10, Table 1) but a low yield
with acceptor 511 (f12, 31%, entry 1, Table 1). Di-
methyl(methylthio)sulfonium trifluoromethanesulfonate
(11) Bore´n, R. K.; Eklind, K.; Garegg, P. J .; Lindberg, B.; Pilotti, A° .
Acta Chem. Scand. 1972, 26, 4143.
(12) Fu¨gedi, P.; Garegg, P. J . Carbohydr. Res. 1986, 149, C9.
(13) O¨ berg, L. Licentiate Thesis, Stockholm University, 1996.

1782 J . Org. Chem., Vol. 63, No. 6, 1998
Krog-J ensen and Oscarson
acid were performed. However, these were surprisingly
stable, inter alia, due to the two stabilizing electron-
withdrawing carbonyl groups,15 so it was easier to cleave
the fructofuranosidic linkage than the N,O-acetal. This
undesired formation of the N,O-acetal should be pos-
sible to avoid if iodonium promoters with less nucleo-
philic anions were used. Iodonium collidine perchlorate
(IDCP)16,17 and iodonium collidine triflate (IDCT)18 were
therefore tried as promoters and were found to give
moderate to good yields of the 3′-OH disaccharides 12
and 13 (entries 7, 8, 12, and 13, Table 1).
The donor-acceptor pair 4r-5 and DMTST as pro-
moter were chosen to evaluate the effect of the solvent
in the reaction. CH2Cl2 was found to be the best solvent,
but MeCN could also be used. DMF and toluene,
however, were definitely inferior (entries 2-5, Table 1).
The effect of the anomeric configuration of the donor
was also investigated. The R-linked donor 4r was chosen
primarily, since there are indications that the displace-
ment of the activated thioglycoside with the internal
acceptor is a concerted reaction (e.g., we found, as did
Baressi and Hindsgaul,2 that addition of external accep-
tor in the activation of the tethered acetal does not
produce formation of any R-glycoside) and, thus, should
proceed more smoothly with the trans-R-anomer of the
donor. However, the â-linked donors were also found to
give only the â-linked disaccharides but in lower yields
(entries 14 and 15, Table 1).
In the formation of the intermediate acetal, so far only
p-methoxybenzylated donors and acceptors with a free
hydroxyl group had been used. However, it should be
possible to instead use an “inverse” approach, in which
the p-methoxybenzylated acceptor and a donor with a free
3-OH, e.g., 3, are used. This approach has been used
with silyl acetal tethering3,4 but, as far as we know, not
reported with isopropylidene or p-methoxybenzylidene
acetal tethering. The method, if successful, can have
definitive advantages, e.g., in the synthesis of the accep-
tor, in which then the p-methoxybenzyl group can be used
as a temporary protecting group at the position that is
going to be glycosylated. As can be seen from entries 16
and 18 in Table 1, this approach, with donor 3r and the
p-methoxybenzylated acceptors 8 or 9 activated by
DMTST, also gave the desired â-linked disaccharides 12
and 13, in these cases in slightly lower yields (compare
entries 2 and 9, Table 1). The use of NIS as promoter
gave the expected N,O-acetal product 16 (entry 17, Table
1).
A simpler acceptor alcohol was then tested, which
might allow the isolation and characterization of the
intermediate acetal, a task that had been proven difficult
with the acceptors used earlier. This expected simplifi-
cation, however, turned out to be a complication. With
donor 4r and ethanol (7), the acetal was not even formed
according to TLC (entry 19, Table 1). However, when
the reversed approach was tried, with 3r and ethyl
p-methoxybenzyl ether (10), the acetal 11 was smoothly
formed and could, if desired, be purified by silica gel
chromatography. Activation of the acetal 11 was then
attempted using the crude, not purified acetal. With
DMTST as promoter, the â-linked ethyl fructofuranoside
14 (13C NMR: δ 103.7 ppm, C-2 fructose) was produced,
but only in 25% yield (entry 20, Table 1). The major
product (∼60% yield) in this reaction was a derivative,
which was found to still contain a p-methoxybenzylidene
group but no ethanol. Further characterization of this
product proved it to be the 2,3-O-(p-methoxybenzylidene)
acetal 18. This product has also been found in reactions
with some other acceptors, e.g., 2,3,4,6-tetra-O-benzyl-
R-D-glucopyranose in an attempt to synthesize sucrose.19
Compound 18 is also formed if the reaction sequence, i.e.,
DDQ-oxidation and DMTST-activation, is performed in
the absence of an acceptor. Activation of acetal 11 with
NIS gave a high yield of ethyl â-fructofuranoside, but
once more as the N,O-acetal (17, entry 21, Table 1).
Finally, a good yield of ethyl â-D-fructofuranoside 14
could be obtained by the activation of acetal 11 with
IDCP as promoter (entry 22, Table 1).
In conclusion, stereospecific formation of â-linked
fructofuranosides can be performed in high yields by
internal delivery of the acceptor from a 3-O-(p-methoxy-
benzylidene) acetal of a thioglycoside donor after activa-
tion with a thiophilic promoter. The acetal can be formed
by oxidation with DDQ of either the 3-O-p-methoxyben-
zylated donor 4 and the acceptor or the 3-OH donor 3
and the p-methoxybenzylated acceptor. As promoters,
DMTST, IDCP, and IDCT were found to function well,
but both the formation of the tethered acetal and its
activation are sensitive reactions and an optimization
often has to be performed to find the best conditions and
promoter. The use of NIS as promoter gave good yields
of â-fructofuranosides, but as N-succinimidofructofura-
noside-3-O-yl p-methoxybenzylidene acetals.
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 ppm), unless otherwise stated. TLC was
performed on silica gel F254 (E. Merck) with detection by UV
light and/or charring with 8% sulfuric acid. Silica gel (0.040-
0.063 mm, Amicon) was used for column chromatography.
Reversed-phase TLC was performed on silanilized silica gel,
60 silanisiert (E. Merck). Silanilized silica gel (Kieselgel 60
silanisiert, 0.063-0.200 mm, E. Merck) was used for reversed-
phase flash chromatography. The reversed-phase columns
were eluted using a gradient of acetone-H2O 1:1 f 14:1.
HPLC was performed on a Gilson 305/306 using Dynamax-
60A (Si-111-c) column and detected by UV light (260 nm).
1,4,6-Tr i-O-ben zyl-2,3-O-[1-(ben zyloxy)ben zylid en e]-â-
D-fr u ctofu r a n ose (2). A solution of 1,4,6-tri-O-benzoyl-2,3-
O-[1-(benzyloxy)benzylidene]-â-D-fructofuranose8 (1, 17.2 g, 25
mmol) in MeOH/CHCl3 (200 mL, 1:1) was cooled to -15 °C,
whereafter NaOMe (6 mL, 1 M in MeOH) was added. The
mixture was left for 12 h at -15 °C and then concentrated
and dried in vacuo. The debenzoylated product (9.3 g, 25
mmol) and benzyl bromide (24 mL, 34.5 g, 202 mmol) dissolved
in DMF (50 mL) were added dropwise to a suspension of NaH
(80% in oil, 7.3 g, 302 mmol) in DMF (50 mL) at 0 °C. After
2 h, the reaction mixture was allowed to attain room temper-
ature and to react for another 10 h. The reaction was
(14) Oscarson, S.; Tedebark U.; Turek, D. Carbohydr. Res. 1997, 299,
159.
(15) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag:
Stuttgart, 1994, p 218.
(16) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J . H.
Tetrahedron Lett. 1990, 31, 1331.
(17) Konradsson, P.; Udodong, U. D.; Fraser-Reid, B. Tetrahedron
Lett. 1990, 31, 4313.
(18) van Boeckel, C. A. A.; Beetz, T. Recl. Trav. Chim. Pays-Bas
1987, 106, 596.
(19) Krog-J ensen, C. Doctoral Thesis, Stockholm University, 1997.

Synthesis of â-D-Fructofuranosides
J . Org. Chem., Vol. 63, No. 6, 1998 1783
quenched by the addition of MeOH (100 mL) at -5 °C, and
the mixture was then diluted with toluene, filtered through
Celite, washed with aq satd NaHCO3 and water, dried, and
concentrated. Crystallization of 2 was accomplished by the
addition of light petroleum (bp 40-60 °C). The crystals were
filtered off, and the mother liquor was concentrated and
purified on a silica gel column (toluene-EtOAc 20:1) to give
an additional amount of 2 (total yield: 10.3 g, 16 mmol, 64%):
mp 62.5-63.5 °C; [R]D +5.9°(c 1.04, CHCl3); 13C NMR δ 65.3,
70.1, 70.8, 71.5, 72.1, 73.1, 73.7, 83.0, 84.8, 85.2, 114.6, 122.9,
126.5-129.2, 137.3-138.3; 1H NMR δ 3.18 (m), 3.8-4.05 (dd),
3.9 (d), 4.16-4.4 (m), 4.45-4.6 (m), 4.96 (s), 7.05-7.7 (m). Anal.
Calcd for C41H40O7: C, 76.38; H, 6.25. Found: C, 76.32; H,
6.30.
nopyranoside11 (5, 1 g, 2.2 mmol) was dissolved in DMF and
the solution cooled to 0 °C, whereafter NaH (207 mg, 8.6 mmol)
and, after 30 min, freshly distilled 4-methoxybenzyl bromide
(1.73 g, 8.6 mmol) were added. The reaction mixture was
allowed to attain room temperature and was, after 12 h,
quenched by the addition of MeOH (1 mL), filtered through
Celite, diluted with toluene (50 mL), and washed with aq satd
NaHCO3 and water, dried, concentrated, and purified by silica
gel chromatography (toluene-EtOAc 9:1) to give 8 (954 mg,
1.63 mmol, 74%): [R]D +29.5° (c 1.0, CHCl3); 13C NMR δ 54.7,
55.2, 68.8, 71.7, 72.1, 72.6, 73.0, 74.6, 74.9, 75.0, 80.2, 99.0,
113.7, 127.5-130.4, 138.4, 138.5, 159.1; 1H NMR δ 3.5 (s), 3.7-
4.0 (m), 3.73 (s), 4.4-4.9 (m), 6.8 (d), 7.1-7.4 (m). Anal. Calcd
for C36H40O7: C, 73.95; H, 6.90. Found: C, 73.73; H, 6.80.
E t h yl 1,4,6-Tr i-O-b en zyl-2-t h io-r-D-fr u ct ofu r a n osid e
(3r) a n d Eth yl 1,4,6-Tr i-O-ben zyl-2-th io-â-D-fr u ctofu r a -
n osid e (3â). Ethanethiol (116 mL, 1.58 mol) was added to a
solution of 2 (10.2 g, 15.9 mmol) in freshly distilled CH2Cl2
(500 mL) containing Drierite (25 g). The mixture was stirred
under an N2 atmosphere at room temperature for 30 min,
whereafter TMSOTf (287 µL, 1.58 mmol) was added. After 5
min, the reaction was quenched by the addition of triethyl-
amine (6 mL), and the mixture was filtered through Celite and
silica gel, concentrated, and purified by silica gel chromatog-
raphy (toluene-EtOAc 9:1) to give a quantitative yield of ethyl
3-O-ben zoyl-1,4,6-t r i-O-ben zyl-2-t h io-D -fr u ct ofu r a n o-
side: 13C NMR δ 14.6, 14.7, 21.7, 22.2, 69.0, 70.4, 72.2, 72.3,
73.0, 73.3, 73.6, 77.2, 79.2, 80.8, 80.9, 82.2, 82.5, 84.0, 93.8,
2-(4-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-(4-m eth oxyben zyl)-â-D-m a n n op yr a n osid e (9).
Barium oxide (38 mg, 249 µmol) and barium hydroxide
octahydrate (10.1 mg, 34 µmol) were added to a stirred solution
of 2-(4-nitrophenyl)ethyl 2-azido-4,6-O-benzylidene-2-deoxy-â-
D-mannopyranoside10 (6, 50 mg, 113 µmol) in DMF (1.5 mL)
containing molecular sieves (4 Å, 0.3 g). After 30 min,
4-methoxybenzyl bromide (135 mg, 670 µmol) was added.
After an additional 12 h at ambient temperature, the reaction
mixture was diluted with toluene and filtered through Celite.
The filtrate was further diluted with toluene and washed with
brine, dried, and concentrated. The residue was purified by
silica gel chromatography (light petroleum (bp 40-60 °C)-
EtOAc 3:1) to yield 9 (50 mg, 88.9 µmol, 79%); [R]D -43° (c
0.30, CHCl3); 13C NMR δ 36.0, 55.2, 63.6, 67.4, 68.3, 69.8, 72.6,
75.6, 77.1, 78.4, 100.4, 101.6, 113.9, 123.6, 126.0-129.9, 137.2,
1
93.9, 127.4-138.1, 164.9, 165.2; H NMR δ 1.07 (t), 1.23 (t),
2.63 (m), 3.6-3.8 (m), 4.1 (dd), 4.3-4.6 (m), 4.6-4.82 (dd), 5.6
(d), 6.05 (d), 7.1-8.0 (m). Anal. Calcd for C36H38O6S: C, 72.22;
H, 6.40. Found: C, 72.03; H, 6.32.
1
146.3, 146.3, 146.8, 149.0, 149.4, 149.8, 159.4; H NMR δ 3.0
(m), 3.3 (m), 3.59 (s), 3.65-3.9 (m), 3.98 (t), 4.2 (m), 4.52 (d),
4.63-4.71 (dd), 6.8-8.2 (m).
NaOMe (4.5 mL, 1M in MeOH) was added to this compound
dissolved in MeOH (100 mL). After 10 h at room temperature,
the mixture was neutralized with Dowex-50 H+ ion-exchange
resin, filtered, concentrated, and purified by silica gel chro-
matography (toluene-EtOAc 6:1) to give 3r (5.8 g, 11 mmol,
70%) and 3â (1.7 g, 3.2 mmol, 20%). 3r: [R]D +98° (c 1.0,
CHCl3); 13C NMR δ 15.1, 22.3, 69.2, 71.9, 72.1, 73.3, 73.9, 79.1,
84.7, 85.9, 93.5, 127.6-138.0; 1H NMR δ 1.2 (t), 2.58 (m), 3.55-
3.90 (m), 4.2 (m), 4.55 (m), 4.73 (m), 7.3 (m). Anal. Calcd for
Eth yl 4-Meth oxyben zyl Eth er (10). 4-Methoxybenzyl
bromide (1 mL, 1 g/mL toluene solution) was added to a
suspension of sodium hydride (750 mg, 25 mmol, 80% in oil)
in distilled DMF (5 mL). The mixture was stirred under N2
and cooled to 0 °C. Absolute ethanol (1.5 mL, 25 mmol) was
added dropwise during 20 min. After an additional hour, the
mixture was diluted with toluene, filtered through Celite and
silica gel, washed with aq satd NaHCO3 and brine, dried,
filtered, and evaporated with care. The remaining yellow oil
was further purified by silica gel chromatography (toluene-
EtOAc 12:1 + 0.5% pyridine) to give 10 (650 mg, 78%, 3.9
mmol): 13C NMR (CDCl3/pyridine-d6) δ 15.1, 55.1, 65.3, 72.3,
113.7, 128.1-130.6, 159.0; 1H NMR (CDCl3/pyridine-d6) δ 1.25
(t), 3.55 (q), 3.8 (s), 4.45 (s), 6.85-7.23 (m).
C
29H34O5S: C, 70.42; H, 6.93. Found: C, 70.21; H, 6.94. 3â:
[R]D -14° (c 1.1, CHCl3); 13C NMR δ 14.7, 21.1, 71.2, 72.3, 73.1,
73.3, 73.7, 80.1, 80.9, 84.5, 94.9, 127.8-138.1; 1H NMR δ 1.08
(t), 2.77 (q), 2.81 (d), 3.65 (m), 4.15 (m), 4.45-4.77 (m), 7.3
(m). Anal. Calcd for C29H34O5S: C, 70.42; H, 6.93. Found:
C, 70.24; H, 6.84.
Eth yl 1,4,6-Tr i-O-ben zyl-3-O-(4-m eth oxyben zyl)-2-th io-
r-D-fr u ctofu r a n osid e (4r). A solution of 3r (1.0 g, 2.02
mmol) and 4-methoxybenzyl bromide (2.03 g, 10.1 mmol) in
DMF (5 mL) was added dropwise to a suspension of NaH (303
mg, 80% in oil, 10.1 mmol) in DMF (5 mL). The mixture was
allowed to react for 10 h at room temperature and then cooled,
and the reaction was quenched by careful addition of ice-
water. The mixture was diluted with toluene, filtered through
Celite, washed with aq satd NaHCO3 and water, dried, and
concentrated. Reversed-phase chromatography using a gradi-
ent of acetone-water 1:1-7:1, followed by silica gel chroma-
tography (toluene-EtOAc 10:1 + 0.5% pyridine), gave 4r (1.13
g, 1.84 mmol, 91%); [R]D +35° (c 1.0, CHCl3); 13C NMR δ 14.8,
22.3, 55.3, 69.7, 70.5, 72.3, 72.7, 73.2, 73.5, 79.2, 84.0, 89.3,
93.8, 113.8, 127.5-130.0, 138.0, 138.2, 159.2; 1H NMR δ 1.21
(t), 2.62 (m), 3.6-3.9 (m), 3.78 (s), 3.96 (dd), 4.03 (d), 4.2 (m),
4.4-4.7 (m), 6.8 (d), 7.3 (m). Anal. Calcd for C37H42O6S: C,
72.29; H, 6.89. Found: C, 72.06; H, 6.76.
Gen er al P r ocedu r e for th e For m ation of Mixed 4-Meth -
oxyben zylid en e Aceta ls. A solution of 4 (25 mg, 39 µmol)
and the acceptor (50.5 µmol) (or 3r and the 4-methoxybenzy-
lated acceptor) in distilled CH2Cl2 (2 mL) containing molecular
sieves (4 Å) was stirred at 0 °C for 30 min under an N2
atmosphere. DDQ (21 mg, 93 µmol) in CH2Cl2 (4 mL) was
added dropwise during 2 h. The reaction was allowed to
continue at ambient temperature until the reaction was
complete according to TLC (2-5 h) and then quenched by
addition of triethylamine (1 mL). The mixture was filtered
through a bilayer plug of Celite and silica gel, diluted with
CH2Cl2 (20 mL), washed with a water solution of NaOH (0.9%),
ascorbic acid (0.7%), citric acid (1.3%), and NaHCO3 (3.5%) (25
mL) and twice with aq satd NaHCO3 (25 + 50 mL), dried (Na2-
SO4), concentrated, filtered, and dried in vacuo for 1 h. The
residue was used without further purification in the following
step.
Eth yl 1,4,6-Tr i-O-ben zyl-3-O-(4-m eth oxyben zyl)-2-th io-
â-D-fr u ctofu r a n osid e (4â). 4â was prepared from 3â analo-
gously to 4r: yield 68%; [R]D -29° (c 1.0, CHCl3); 13C NMR δ
14.7, 21.0, 55.2, 71.4, 72.4, 72.5, 73.1, 73.3, 73.5, 80.5, 84.5,
r-Eth oxy r-(eth yl 1,4,6-tr i-O-ben zyl-2-th io-r-D-fr u cto-
fu r a n osid -3-O-yl)-4-m eth oxytolu en e (11) was prepared,
from 3r and 10, following the general procedure above. After
the workup procedure the crude product was purified on a
short silica gel column (toluene-EtOAc 9:1). This gave the
R/S-acetal 11, with only a trace of 3r left: 13C NMR (CDCl3/
pyridine-d6) δ 15.1, 15.1, 22.1, 22.2, 55.2, 60.2, 60.5, 69.6, 69.8,
70.2, 71.2, 72.1, 73.2, 79.6, 80.4, 84.2, 85.0, 86.4, 93.9, 94.0,
100.9, 102.4, 113.4, 113.5, 127.3-138.3, 159.6, 159.66; 1H NMR
(CDCl3/pyridine-d6) δ 1.15-1.25 (m), 2.6 (m), 3.33-3.9 (m),
1
84.8, 94.0, 113.7, 127.6-130.1, 138.0, 138.2, 138.2, 159.2; H
NMR δ 1.18 (t), 2.59 (m), 3.6-3.8 (m), 3.77 (s), 4.2 (q), 4.27
(t), 4.43-4.68 (m), 6.8 (d), 7.3 (m). Anal. Calcd for
C
37H42O6S: C, 72.29; H, 6.89. Found: C, 72.26; H, 6.88.
Meth yl 2,3,4-Tr i-O-ben zyl-6-O-(4-m eth oxyben zyl)-r-D-
m a n n op yr a n osid e (8). Methyl 2,3,4-tri-O-benzyl-R-D-man-

1784 J . Org. Chem., Vol. 63, No. 6, 1998
Krog-J ensen and Oscarson
3.77 (s), 3.80 (s), 3.96 (dd), 4.1 (dd), 4.2-4.65 (m), 5.58 (s), 5.64
(s), 6.8 (d), 7.2-7.4 (m).
n osid e]-4-m eth oxytolu en e (15) was further purified by
HPLC (hexane-EtOAc 7:3): [R]D -62° (c 1.0,CHCl3); 13C NMR
(CDCl3/pyridine-d6) δ 28.0, 54.5, 55.1, 60.8, 70.8, 71.3, 72.1,
72.3, 72.8, 73.3, 73.6, 74.8, 74.9, 75.2, 77.3, 79.4, 80.3, 81.6,
84.1, 84.5, 98.9, 103.3, 113.2, 122.3-129.1, 137.8, 138.4, 138.7,
138.9, 139.0, 159.3, 176.6; 1H NMR (CDCl3/pyridine-d6) δ 2.23
(m), 3.13 (s), 3.57 (s), 3.55-3.93 (m), 3.98-4.1 (m), 4.18 (t),
4.30 (d), 4.35-4.7 (m), 4.8 (d), 6.57 (s), 6.65 (d), 7.1-7.4 (m),
8.1 (2H, d). Anal. Calcd for C67H71O14N: C, 72.2; H, 6.42.
Found: C, 71.99; H, 6.31.
Gen er a l P r oced u r e for th e F or m a tion of Glycosid es
fr om th e Teth er ed Aceta ls: With DMTST or MeOTf a s
P r om oter . The promoter (4 equiv) was added under N2 and
at 0 °C to a stirred solution of the 4-methoxybenzaldehyde
acetal (1 equiv) in CH2Cl2 (2 mL) containing molecular sieves
(4 Å). The reaction mixture was allowed to attain room
temperature and react for 16 h, whereafter the reaction was
quenched by the addition of TEA (1 mL) and the mixture
filtered through Celite, concentrated, and purified by silica gel
chromatography (toluene-EtOAc 9:1).
r-N-Su ccin im id o-r-[2-(4-n itr op h en yl)eth yl 2-a zid o-4,6-
O-ben zylid en e-2-d eoxy-3-O-(1,4,6-tr i-O-ben zyl-â-D-fr u cto-
fu r a n osyl-3-O-yl)-â-D-m a n n op yr a n osid e]-4-m et h oxyt ol-
u en e (16): [R]D -51° (c 1.0, CHCl3); 13C NMR (CDCl3/pyridine-
d6) δ 27.9, 36.1, 55.2, 65.6, 67.4, 68.3, 69.56, 69.6, 71.6, 72.96,
73.0, 73.1, 73.6, 77.2, 79.7, 82.4, 83.1, 85.9, 100.0, 102.0, 102.9,
113.4, 123.6-129.9, 137.2, 137.3, 138.1, 138.2, 146.3, 146.8,
With NIS, IDCP , or IDCT a s P r om oter . The promoter
(NIS 3.4 equiv; IDCP or IDCT 1.5 equiv) was added under N2
and at 0 °C to a stirred solution of the 4-methoxybenzylidene
acetal (1 equiv) in CH2Cl2 (2 mL) containing molecular sieves
(4 Å). The reaction mixture was allowed to attain room
temperature and react for 16 h, whereafter the reaction was
quenched by the addition of TEA (1 mL) and the mixture
filtered through Celite, diluted with CH2Cl2, washed with aq
satd Na2S2O3, aq satd NaHCO3, and water, dried, concen-
trated, and purified by silica gel chromatography (toluene-
EtOAc 9:1).
1
159.5, 176.5; H NMR (CDCl3/pyridine-d6) δ 2.2 (m), 3.0 (m),
3.35 (dd), 3.45-3.8 (m), 3.75 (s), 3.95-4.15 (m), 4.2-4.5 (m),
5.5 (s), 6.55 (s), 6.7 (d), 7.1-7.5 (m), 8.1 (d); FAB-MS 1091.4
[M - H]+. Anal. Calcd for C60H61O15N5: C, 65.98; H, 5.63.
Found: C, 65.78; H, 5.52.
r-N-Su ccin im id o-r-(eth yl 1,4,6-tr i-O-ben zyl-â-D-fr u cto-
fu r a n osid -3-O-yl)-4-m eth oxytolu en e (17): [R]D -47° (c 1.0,
CHCl3); 13C NMR δ 15.4, 28.0, 55.2, 57.4, 71.3, 71.5, 72.6, 73.4,
73.43, 78.7, 81.6, 83.4, 84.0, 103.4, 113.4, 127.4-128.8, 138.0,
P r od u cts. For yields see Table 1.
Met h yl 2,3,4-t r i-O-b en zyl-6-O-(1,4,6-t r i-O-b en zyl-â-D-
fr u ctofu r a n osyl)-r-D-m a n n op yr a n osid e (12) was further
purified by HPLC (hexane-EtOAc 3:1): [R]D +23° (c 0.72,
CHCl3); 13C NMR δ 54.5, 60.9, 69.4, 71.2, 71.8, 72.1, 72.7, 73.1,
73.6, 74.6, 74.7, 75.0, 79.1, 80.0, 84.2, 98.8, 103.9, 127.5-138.6;
1H NMR δ 3.13 (s), 3.5-4.0 (m), 4.08-4.15 (m), 4.4 (d), 4.45
(d), 4.48-4.72 (m), 4.77 (d), 4.87 (d), 7.25-7.45 (m). Anal.
Calcd for C55H60O11: C, 73.64; H, 6.74. Found: C, 73.24; H,
6.39.
2-(4-Nit r op h en yl)et h yl 2-a zid o-4,6-O-b en zylid en e-2-
d eoxy-3-O-(1,4,6-t r i-O-b en zyl-â-D-fr u ct ofu r a n osyl)-â-D-
m a n n op yr a n osid e (13) was further purified by HPLC (hex-
ane-EtOAc 3:1): [R]D -16° (c 0.80, CHCl3); 13C NMR (CDCl3/
pyridine-d6) δ 36.0, 66.2, 66.6, 68.2, 69.4, 71.6, 72.1, 73.7, 73.8,
76.8, 78.5, 78.7, 79.1, 99.4, 102.0, 105.0, 123.6-129.9, 136.5-
138.1, 146.3; 1H NMR (CDCl3/pyridine-d6) δ 2.5 (m), 2.95 (m),
3.3-3.95 (m), 4.03 (dd), 4.14 (t), 4.37-4.67 (m), 5.52 (s), 7.0-
7.5 (m), 8.15 (d). Anal. Calcd for C48H50O12N4: C, 65.89; H,
5.76. Found: C, 65.93; H, 5.65.
1
138.5, 159.4, 176.2, 176.5; H NMR δ 1.0 (t), 2.3 (s), 3.5-3.7
(m), 3.75 (s), 4.07 (m), 4.2 (t), 4.37 (d), 4.47-4.63 (m), 6.5 (s),
6.8 (d), 7.1-7.2 (m). Anal. Calcd for C41H43O9N: C, 70.97; H,
6.24. Found: C, 69.53; H, 6.38.
1,4,6-Tr i-O-b en zyl-2,3-O-(4-m et h oxyben zylid en e)-â-D-
fr u ctofu r a n ose (18): mp 110-111.5 °C; [R]D +28° (c 1.05,
CHCl3); FAB-MS 591.4 [M + Na]+; 13C NMR (CDCl3/pyridine-
d6) δ 55.3, 69.6, 70.7, 72.0, 73.55, 73.63, 81.8, 82.6, 86.8, 103.9,
112.1, 113.7, 127.5-128.6, 137.4, 138.0, 138.1, 160.8; 1H NMR
(CDCl3/pyridine-d6) δ 3.6-3.9 (m), 3.8 (s), 4.2 (m), 4.5-4.8 (m),
4.9 (d), 6.0 (s), 6.8 (d), 7.2-7.4 (m). Anal. Calcd for C35H36O7:
C, 73.92; H, 6.38. Found: C, 74.00; H, 6.53.
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.
Eth yl 1,4,6-tr i-O-ben zyl-â-D-fr u ctofu r a n osid e (14) was
further purified by HPLC (hexane-EtOAc 3:1): [R]D -11° (c
0.50, CHCl3); 13C NMR (CDCl3/pyridine-d6) δ 15.4, 57.1, 69.0,
71.6, 71.9, 73.3, 73.6, 79.5, 80.2, 85.0, 103.7, 127.6-138.2; 1H
NMR (CDCl3/pyridine-d6) δ 1.1 (t), 3.5-3.7 (m), 3.93 (t), 4.13
(1H, m), 4.35 (d), 4.5-4.65 (m), 4.8 (d), 7.3 (m). Anal. Calcd
for C29H34O6: C, 72.78; H, 7.16. Found: C, 72.52; H, 7.10.
r-N-Su ccin im ido-r-[m eth yl 2,3,4-tr i-O-ben zyl-6-O-(1,4,6-
tr i-O-ben zyl-â-D-fr u ctofu r a n osyl-3-O-yl)-r-D-m a n n op yr a -
Su p p or t in g In for m a t ion Ava ila b le: 270 MHz 1H and
67.5 MHz 13C NMR spectra of compounds 11 and 14-18 (12
pages). This material is contained in libraries on microfiche,
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 O970983R