Synthesis of (1-->4)-linked 2-deoxy-2-fluoroglucose oligomers. 1.

Article abstract of DOI:10.1021/ol006529i

[reaction: see text] Thioglycosides of natural monosaccharides are readily converted into their corresponding chlorides by diphenylchlorosulfonium chloride. This reagent can likewise effect the conversion of the more stable 4-chlorophenylthio 2-deoxy-2-fl

Full text of DOI:10.1021/ol006529i

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3489-3491
Synthesis of (1f4)-Linked
2-Deoxy-2-fluoroglucose Oligomers. 1
Shin Sugiyama, Wasim Haque,† and James Diakur*
Faculty of Pharmacy & Pharmaceutical Sciences, UniVersity of Alberta,
Edmonton, Alberta, Canada T6G 2N8
jdiakur@pharmacy.ualberta.ca
Received August 31, 2000
ABSTRACT
Thioglycosides of natural monosaccharides are readily converted into their corresponding chlorides by diphenylchlorosulfonium chloride.
This reagent can likewise effect the conversion of the more stable 4-chlorophenylthio 2-deoxy-2-fluoroglucose derivatives into chloride glycosyl
donors. On the basis of this activation strategy, it was possible to assemble unnatural oligosaccharides composed of 2-fluorodeoxy sugars.
Starch primarily consists of two glucan fractions, namely,
linear amylose which is composed of R-(1f4)-linked glucose
moieties and amylopectin which additionally contains
R-(1f6)-linked glucose branches.1 The amylose fraction
crystallizes in polymorphic forms known as the A and B
forms, both of which are right-handed double helices.2 A
third form, V-amylose, is found in the non-A and non-B
segments of amylose and is folded into a left-handed single-
helical motif. The helix of V-amylose contains six glucose
units per turn with a pitch height of approximately 8 Å.3
The properties of V-amylose closely resemble those of
the cyclodextrins and, in particular, R-cyclodextrin which
may be viewed as a mimetic of a single V-amylose turn.4
Glucose residues in both of these structures are in the syn
orientation, and the helical structure is stabilized by inter-
glucose hydrogen bonds between O(3)n-O(2)n+1. Additional
stability to the V-amylose helix is provided by O(6)n-O(2)n+6
hydrogen bond formation between the turns.5 This helical
arrangement provides a relatively hydrophobic interior cavity
which is suited for the inclusion of substances and may be
exploited for the purpose of drug delivery.6 As the fluorine
nucleus displays a wide chemical shift range in its NMR
spectra, it seemed reasonable to us that installation of this
reporter into the glucose residues7 of R-(1f4)-linked olig-
mers may prove useful in studying maltooligosaccharide
complexes. We report herein the preparation of (1f4)-linked
2-fluorodeoxyglucose (2-FDG) blocked donors/acceptors,
which are suitable for the preparation of larger 2-FDG-based
oligomers.
Surprisingly, there are few reports regarding the use of
2-fluorodeoxyhexosyl donors in oligosaccharide synthesis,8
and to date, we are not aware of any reports on the assembly
of simple 2,2′-difluoro-disaccharides nor of 2-deoxy-2-
† Medicure Inc., 24-64 Scurfield Blvd., Winnipeg, MB, Canada R3Y
1M5.
(1) Collins, P. M.; Ferrier, R. J. Monosaccharides, Their Chemistry and
Their Roles in Natural Products; John Wiley & Sons: Chichester, 1995;
Chapter 8.
(5) Gessler, K.; Uson, I.; Takaha, T.; Krauss, N.; Smith, S. M.; Okada,
S.; Sheldrick, G. M.; Saenger, W. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
4246-4251.
(6) Molteni, L. In Drug Carriers in Biology and Medicine; Gregoriadis,
G., Ed.; Academic Press: London, 1979; pp 107-125.
(7) For a comprehensive review on fluorosugars, see: Tsuchiya, T. AdV.
Carbohydr. Chem. Biochem. 1990, 48, 91-277.
(2) Imberty, A.; Chanzy, H.; Perez, S.; Buleon, A.; Tran, V. J. Mol.
Biol. 1988, 201, 365-378.
(3) Murphy, V. G.; Zaslow, B.; French, A. D. Biopolymers 1975, 14,
1487-1501.
(4) Hinrichs, W.; Buttner, G.; Steifa, M.; Betzel, C.; Zabel, V.;
Pfannemuller, B.; Saenger, W. Science 1987, 238, 205-208.
10.1021/ol006529i CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

finally 7b (95%). The latter compound was then acetylated
to provide fully protected fluorodeoxyglucose derivative 8b.
Both 8a and 8b were readily converted to their corresponding
chlorides 9a and 9b upon treatment with diphenylchloro-
sulfonium chloride.15 Reaction of 8a under these conditions
provided the chloride mixture 9b/9a (11:1), whereas 8b gave
9a as the sole product. Thus, conversion presumably proceeds
by inversion at the anomeric center. The result observed with
8b was totally unexpected as â-thioglycosides of natural
sugars typically provide a mixture of R:â chlorides.16 We
next studied the glycosyl donor protential of chlorides 9a
and 9b. Reaction of chloride 9a with acceptor 7b failed to
proceed under halide ion conditions17 or in the presence of
mercury bromide.18 Glycosylation of 7b (1 equiv) with 9a
(1 equiv) did proceed, however, using silver trifluoromethane-
sulfonate/2,6-di-tert-butylpyridine19 in chloroform-toluene
4:1 to provide a mixture of 10 and 12 (10:12 ) 40:60) in
65% yield (Figure 2). Reaction of this same acceptor with
chloride 9b provided 10 and 12 in a 45:55 ratio.20 Silver
promotion of the reaction between 7b and 9a in either
acetonitrile or tetrahydrofuran as solvent was remarkably
sluggish, and even donor 2 has been noted to be reasonably
stable to typical glycosylation conditions.8e Glycosidation was
therefore effected under forced conditions as follows: The
reaction mixture in acetonitrile-toluene 3:2 was concentrated
under reduced pressure (<40 °C) and coevaporated with
toluene several times. After workup and purification by silica
gel column chromatography, 10 and 12 were obtained in 83%
combined yield (10:12 ) 62:38). Silver-promoted glycosy-
lation of the 4-OH of a glucose acceptor with a 2-deoxy-2-
fluoromannosyl donor has previously been reported to
proceed with preferential R-stereoselectivity.8b The poor
stereoselectivity observed with the 2-deoxy-2-fluoroglucosyl
donors reported herein is potentially related to the nature
and reactivity of the fluoroglycosyl oxocarbonium intermedi-
ate. The product distribution obtained seems to be consistent
with an SN1-type reaction mechanism; however, further
studies are required in order to gain an understanding of the
precise mechanistic details.
Figure 1.
fluorohexose oligomers. Compound 1 (Figure 1) was the
starting point for the present synthetic work, and this material
was readily accessible from 1,3,4,6-tetra-O-acetyl-â-D-man-
nopyranose9 following published procedures.10 Thioglyco-
sylation of 1 with 4-chlorothiophenol in the presence of boron
trifluoride diethyl etherate (8 equiv) gave R-thioglycoside
3a (70%).11 De-O-acetylation of this thioglycoside with
sodium methoxide in methanol provided triol 4a, which was
reacted with benzaldehyde dimethyl acetal (catalytic amount
of p-toluenesulfonic acid) to give 5a (75%). Etherification
of the remaining hydroxyl moiety with sodium hydride and
benzyl bromide in tetrahydrofuran at 60 °C gave fully
protected 6a (72%), which was then subjected to reductive
ring opening conditions12 to provide di-O-benzyl thioglyco-
side 7a (80%). Acetylation of the free 4-OH group furnished
8a. Synthesis of the corresponding â-thioglycoside 8b
required the conversion of 1 to bromide 2,13 which was then
reacted under phase-transfer conditions14 with 4-chlorothiophe-
nol to give 3b (91%). The â-thioglycoside 3b was then
subjected to the same sequence of events as 3a to give
successively 4b (quantitative), 5b (76%), 6b (95%), and
The latter reaction conditions were selected for the
subsequent assembly of (1f4)-linked 2-deoxy-2-fluoroglu-
cose oligomers. Thus, disaccharide 10 was de-O-acetylated
to give glycosyl acceptor 11, and reaction of this compound
with chloride 9a under the aforementioned forced conditions
provided both the R- and â-trisaccharides 13 and 16 (85%
combined yield, 13:16 ) 54:46). Compound 13 was then
de-O-acetylated to give the trisaccharide glycosyl acceptor
15, while the trisaccharide glycosyl donor 14 was prepared
under the conditions used to generate chloride 9a. Again,
glycosylation of compound 15 with 14 was effected using
(8) (a) Vass, G.; Rolland, A.; Cleophax, J.; Mercier, D.; Quiclet, B,;
Gero, S. D. J. Antibiot. 1979, 32, 670-672. (b) Ogawa, T.; Takahashi, Y.
J. Carbohydr. Chem. 1983, 2, 461-467. (c) Shelling, J. G.; Dolphin, D.;
Wirz, P.; Cobbledick, R. E.; Einstein, F. W. B. Carbohydr. Res. 1984, 132,
241-259. (d) McCarter, J. D.; Adam, M. J.; Braun, C.; Namchuk, M.; Tull,
D.; Withers, S. G. Carbohydr. Res. 1993, 249, 77-90. (e) McCarter, J. D.;
Yeung, W.; Chow, J.; Dolphin, D.; Withers, S. G. J. Am. Chem. Soc. 1997,
119, 5792-5797.
(9) Pozgay, V.; Glaudemans, P. J.; Robbins, J. B.; Schneerson, R.
Tetrahedron 1992, 48, 10249-10264.
(10) Kovac, P. Carbohydr. Res. 1986, 153, 168-170.
(15) Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713-2715.
(16) Kovac, P.; Lerner, L. Carbohydr. Res. 1988, 184, 87-112.
(17) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056-4062.
(18) Helferich, B.; Wedemeyer, K. F. Liebigs Ann. Chem. 1949, 563,
139-145.
(19) Hanessian, S.; Banoub, J. Carbohydr. Res. 1977, 53, C13-C16.
(20) Reaction of 7a with 2 under the same conditions proceeds to give
the corresponding disaccharides in 74% yield (R:â ) 4.5/1).
(11) Thioglycoside formation is slow, however, long reaction times leads
to the formation of 3b (∼15% after 10 days).
(12) Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10-C11.
(13) Adamson, J.; Foster, A. B.; Westwood, J. H. Carbohydr. Res. 1971,
18, C10-C11.
(14) (a) Dess, D.; Kleine, H. P.; Weinberg, D. V.; Kaufman, R. J.; Sidhu,
R. S. Synthesis 1981, 883-885. (b) Rothermel, J.; Faillard, H. Biol. Chem.
Hoppe-Seyler 1989, 370, 1077-1084.
3490
Org. Lett., Vol. 2, No. 22, 2000

Figure 2.
the forced conditions to provide R- and â-hexasaccharides
17 and 18, respectively (54% combined yield, 17:18 ) 3:2).
In summary, we have extended the application of the
conversion of thioglycosides into their corresponding gly-
cosyl chlorides with diphenylchlorosulfonium chloride to
include the generation of 2-deoxy-2-fluoroglucose donors.
Control over stereoselectivity during glycosylation with
2-deoxy-2-fluoroglycosyl donors 9a and 9b proved to be
challenging, nevertheless, the assembly of novel (1f4)-
linked 2-deoxy-2-fluoroglucose oligomers using the resulting
glycosyl chlorides has been demonstrated. These reported
donors may be employed in the preparation of fluoromalto-
and fluorocellulo-oligosaccharides or, potentially, other
modified oligosaccharides. The deprotected 2-deoxy-2-
fluoromaltohexose may prove useful in subsequent 19F NMR
complexation studies, while the blocked hexasaccharide 17
may be useful in the preparation of a fluorinated R-cyclo-
dextin. Future efforts in our laboratory will be directed to
both of these ends.
Acknowledgment. This work was funded in part by a
TCP grant from the Alberta Heritage Foundation for Medical
Research.
Supporting Information Available: Spectral data for
compounds 3-18 and the experimental details for the
glycosylation reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006529I
Org. Lett., Vol. 2, No. 22, 2000
3491