4512
J . Org. Chem. 1996, 61, 4512-4513
Sch em e 1a
Ster eosp ecific Syn th esis of
â-D-F r u ctofu r a n osid es Usin g th e In ter n a l
Aglycon Deliver y Ap p r oa ch
Christian Krog-J ensen and Stefan Oscarson*
Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University, S-106 91 Stockholm, Sweden
Received April 29, 1996
a
Key: (a) NaOMe, MeOH, -15 °C; (b) BnBr, NaH, DMF; (c)
TMSOTf, EtSH, CH2Cl2; (d) NaOMe, MeOH; (e) MBnBr, NaH,
DMF.
Syntheses of fructofuranosides using fructofuranosyl
donors are not very frequent. Only a small number of
papers have been published on this subject.1-4 Although
the methods used generally give high yields of fructo-
furanosides, a definitive drawback is that exclusively the
R-fructofuranoside (when a participating group at the
3-position is used) or a mixture of R- and â-anomers (if a
nonparticipating group is used) are obtained. A further
complication is that these anomeric mixtures often are
impossible or difficult to separate by chromatography.
Since most fructofuranosides found in nature are â-linked,5
the need for a stereospecific â-glycosylation method for
fructofuranosides is obvious.
In a program directed toward synthesis of capsular
polysaccharides (CPS:s) from Haemophilus influenzae, we
became interested in the synthesis of â-fructofuranosides,
since this is a motif in the type e CPS.6 Our earlier
successful experience with thioglycosides as glycoside
donors led us to synthesize and try this type of donors in
the fructofuranosidic field as a continuation of the work
of Kochetkov and co-workers.1,2 Although exceptionally
high yields of fructofuranosides were obtained, the best
ratio of â- to R-linked product obtained was 1.6/1 in
inseparable mixtures.4
Since 1,2-cis-pyranosides, especially the difficult â-D-
manno-configuration and also the R-D-gluco-configura-
tion, have successfully been synthesized using the inter-
nal aglycon delivery approach,7-11 we decided to try this
method with furanosides. Of the existing variation of
silicon and carbon acetals used earlier, the p-methoxy-
benzaldehyde acetal, introduced by Ito and Ogawa,10
seems to be the most promising, especially in oligosac-
charide synthesis.11 Thus, the key thioglycoside ethyl
1,4,6-tri-O-benzyl-3-O-(4-methoxybenzyl)-2-thio-R-D-fructo-
furanoside (4R) was synthesized together with its â-ano-
mer (Scheme 1). The known,12 crystalline orthoester 1
was deacylated using sodium methoxide and then ben-
zylated to give 2 in an overall yield of 64%. Rearrange-
ment of the anomeric orthoester using trimethylsilyl
trifluoromethylsulfonate in the presence of a large excess
of ethyl mercaptan (∼100 equiv) gave ethyl 1,4,6-tri-O-
benzyl-3-O-benzoyl-2-thio-D-fructofuranoside as an in-
separable R/â-mixture. Debenzoylation of this mixture
afforded the 3-OH compounds, which could easily be
separated by silica gel chromatography to give pure 3R
and 3â in overall yields of 74 and 22%, respectively, from
2. Then p-methoxybenzylation gave the key intermedi-
ates 4R (91%) and 4â (68%), ready for acetal tethering
with different aglycons.
Two different acceptors, both used in the earlier
work,4 were chosen as model compounds, one primary
alcohol, methyl 2,3,4-tri-O-benzyl-R-D-mannopyranoside
(5), and one secondary, 2-(4-nitrophenyl)ethyl 2-azido-
4,6-O-benzylidene-2-deoxy-â-D-mannopyranoside (8), the
latter of interest for the synthesis of the Haemophilus
influenzae type e CPS. When a slight modification of the
published procedure was used,11 the two intermediate
acetals 6 and 9 were formed in high yields, according
to TLC, when 4R was reacted with DDQ in the pres-
ence of 5 or 8, respectively (Schemes 2 and 3). No
characterization of the tethered acceptor-donor ace-
tals 6 and 9 were performed, but immediately after
workup they were activated by a promoter. The addition
of dimethyl(methylthio)sulfonium trifluoromethanesulfo-
nate13 (DMTST) to a solution of either of the two acetals
in CH2Cl2 gave a main product, which was found to
be the pure â-fructofuranosyl disaccharide, no R-product
was isolated. 6 gave 7 in 77% yield and 9 gave 10 in
76% overall yield from 4R (Schemes 2 and 3). Methyl
trifluoromethanesulfonate11 gave lower yields, especially
with the primary acceptor 5 (31% yield of 7, 59% yield
of 10).
(1) Balan, N. F.; Backinowsky, L. V.; Betaneli, V. I.; Kochetkov, N.
K. Bioorg. Khim. 1981, 7, 1566-1577.
(2) Backinowsky, L. V.; Balan, N. F.; Betaneli, V. I.; Kochetkov, N.
K. Carbohydr. Res. 1982, 99, 189-193.
The â-furanosyl configuration in disaccharide products
7 and 10 was assigned using the 13C chemical shift of
the anomeric carbon. O-â-linked fructofuranosides give
resonance at a higher field (∼103-105 ppm) than the
corresponding R-anomer (∼107-109 ppm).14 The C-2′
shift in derivative 7 was 104.0 ppm, whereas that in
disaccharide 10 was found to be 105.0 ppm. These values
can also be compared to the values of the corresponding
3′-O-benzyl derivatives, obtained earlier as R/â-mix-
tures, which were 107.9/104.2 ppm and 108.9/104.8
(3) Mu¨ller, T.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1994,
27, 4763-4766.
(4) Krog-J ensen, C.; Oscarson, S. J . Org. Chem. 1996, 61, 1234-
1238.
(5) Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48, 279-
318.
(6) Branefors-Helander, P.; Kenne, L.; Lindberg, B.; Petersson, K.;
Unger, P. Carbohydr. Res. 1981, 88, 77-84.
(7) (a) Barresi, F.; Hindsgaul, O. J . Am. Chem. Soc.1991, 113, 9376-
9377; (b) Synlett 1992, 759-761; (c) Can. J . Chem. 1994, 72, 1447-
1465.
(8) Stork, K.; Kim, G. J . Am. Chem. Soc. 1992, 114, 1087-1088.
(9) (a) Bols, M. J . Chem. Soc., Chem. Commun.1992, 913-914; (b)
J . Chem. Soc., Chem. Commun. 1993, 791-792; (c) Acta Chem. Scand.
1993, 47, 829-834.
(10) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765-
1767.
(12) Helferich, B.; Bottenbruch, L. Chem. Ber. 1953, 86, 651-
657.
(13) Fu¨gedi, P.; Garegg, P. J . Carbohydr. Res. 1986, 149,
C9-C12.
(11) Dan, A.; Ito, Y.; Ogawa, T. J . Org. Chem. 1995, 60, 4680-
4681.
(14) Angyal, S. J .; Bethell, G. S. Aust. J . Chem. 1976, 29, 1249-
1265.
S0022-3263(96)00776-1 CCC: $12.00 © 1996 American Chemical Society
Krog-Jensen, Christian
