General one-step synthesis of free hexofuranosyl 1-phosphates using unprotected 1-thioimidoyl hexofuranosides

Article abstract of DOI:10.1021/jo0484934

(Chemical Equation Presented) A general one-step strategy is developed for the synthesis of hexofuranosyl 1-phosphates starting from new unprotected glycofuranosyl donors. It required first the preparation of new 1-thiohexofuranosides bearing a thioimidoyl heterocycle as a leaving group. The presence of sulfur and/or nitrogen atom(s) on the aglycon allowed remote activation of these thioglycofuranosides by anhydrous phosphoric acid and led to the target phosphates 9, 27, 29, and 30 in good to excellent selectivities and, more importantly, with very limited or no ring expansion. Moreover, this one-step phosphorylation reaction could be significantly improved by avoiding any tedious protecting group manipulations on negatively charged compounds and by focusing on a simple but general procedure of purification. This approach was applied to the diastereocontrolled synthesis of D-galactoand D-glucofuranosyl 1-phosphates and also to the preparation of rare epimer and/or deoxy counterparts, that is, D-manno- and D-fucofuranosyl derivatives.

Full text of DOI:10.1021/jo0484934

General One-Step Synthesis of Free Hexofuranosyl 1-Phosphates
Using Unprotected 1-Thioimidoyl Hexofuranosides
Ronan Euzen, Vincent Ferrie`res,* and Daniel Plusquellec
Ecole Nationale Supe´rieure de Chimie de Rennes, UMR CNRS 6052 Synthe`ses et Activations de
Biomole´cules, Institut de Chimie de Rennes, Avenue du Ge´ne´ral Leclerc, F-35700 Rennes, France
vincent.ferrieres@ensc-rennes.fr
Received August 27, 2004 (Revised Manuscript Received October 21, 2004)
A general one-step strategy is developed for the synthesis of hexofuranosyl 1-phosphates starting
from new unprotected glycofuranosyl donors. It required first the preparation of new 1-thiohexo-
furanosides bearing a thioimidoyl heterocycle as a leaving group. The presence of sulfur and/or
nitrogen atom(s) on the aglycon allowed remote activation of these thioglycofuranosides by
anhydrous phosphoric acid and led to the target phosphates 9, 27, 29, and 30 in good to excellent
selectivities and, more importantly, with very limited or no ring expansion. Moreover, this one-
step phosphorylation reaction could be significantly improved by avoiding any tedious protecting
group manipulations on negatively charged compounds and by focusing on a simple but general
procedure of purification. This approach was applied to the diastereocontrolled synthesis of D-galacto-
and D-glucofuranosyl 1-phosphates and also to the preparation of rare epimer and/or deoxy
counterparts, that is, D-manno- and D-fucofuranosyl derivatives.
Introduction
containing an arabinogalactan characterized by the pres-
ence of five-membered rings for both R-/â-L-arabinofura-
nose and â-D-galactofuranose (D-Galf).6 On the other
hand, Eubacterium saburreum, a Gram-positive bacteria
frequently isolated from human dental plaques, produces
a carbohydrate-based antigen with unique sugar compo-
sition since the linear chain of heptose is branched with
D-fucofuranosyl (D-Fucf) units characterized by R-ano-
meric configuration.7 It is also interesting to note that
D-glucose (D-Glc) and its 2-epimer D-mannose (D-Man)
were found as furanosyl residues in a rare nucleotide-
sugar Agrocine 848 and in a polymannan produced by the
oak lichen Evernia prunastri,9 respectively. Since all of
these hexofuranosides are exclusively found in lower
organism components, this offers novel opportunities for
designing new pharmacophores and molecular probes for
enzymatic studies.
An explosive number of discoveries in the field of
glycobiology over the past three decades have resulted
in a better understanding of the roles of carbohydrate-
based biomolecules.1 These findings were possible since
efficient purification procedures and analytical methods
have been developed. Among the majority of natural
glycoconjugates, it was shown that pentoses are equally
found in a furanose or in a pyranose configuration, while
hexoses generally exist in a pyranose form. However, the
striking presence of hexofuranosyl entities was estab-
lished in conjugates isolated from protozoae,2 fungi,3
bacteria,4 and archaebacteria.5 A well-known example is
connected with the cellular wall of the causative agent
of tuberculosis. Indeed, Mycobacterium tuberculosis is
able to biosynthesize a highly complex membrane notably
(1) (a) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99-110.
(b) Dwek, R. A. Chem. Rev. 1996, 96, 683-720.
(6) Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995, 64, 29-
63.
(2) de Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547-552.
(3) Ayer, W. A.; Kawahara, N. Tetrahedron Lett. 1995, 36, 7953-
7956.
(7) (a) Sato, N.; Nakzawa, F.; Ito, T.; Hishino, T.; Hoshino, E.
Carbohydr. Res. 2003, 338, 923-930. (b) Sato, N.; Nakazawa, F.; Sato,
M.; Hoshino, E.; Ito, T. Carbohydr. Res. 1993, 245, 105-111.
(8) (a) Moriguchi, T.; Wada, T.; Sekine, M. J. Org. Chem. 1996, 61,
9223-9228. (b) Thompson, R. J.; Hamilton, R. H.; Pootjes, C. F.
Antimicrob. Agents Chemother. 1979, 16, 293-296.
(9) Mic´ovic´, V. M.; Hranisavljevic´-Jakovljevic´, M.; Miljkovic´-Stojan-
ovic´, J. Carbohydr. Res. 1969, 10, 525-533.
(4) Nagaoka, M.; Hashimoto, S.; Shibata, H.; Kimura, I.; Sawada,
H. Yokohura, T. Carbohydr. Res. 1996, 281, 285-291.
(5) (a) Benvegnu, T.; Brard, M.; Plusquellec, D. Curr. Opin. Colloid
Interface Sci. 2004, 8, 469-479. (b) Koga, Y.; Nishihara, M.; Morii,
H.; Akagawa-Matsushita, M. Microbiol. Rev. 1993, 57, 164-182. (c)
Sprott, G. D. J. Bioenerg. Biomembr. 1992, 24, 555-566.
10.1021/jo0484934 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/06/2005
J. Org. Chem. 2005, 70, 847-855
847

Euzen et al.
The growing interest in glycoconjugates must also be
due to findings linked to pathways by which glycofura-
noconjugates and polyhexofuranosides are biosynthesized
and/or metabolized. Three families of enzymes have been
identified: some galactofuranosidases,10 a galactofura-
nosyltransferase,11 and the uridine diphosphogalactopy-
ranose (UDP-Galp) mutase.11,12 This mutase, which was
cloned and expressed from four bacteria strains, is the
only enzyme capable for catalyzing the galactose ring
contraction from UDP-Galp into a less-stable nucleotide-
galactofuranose (UDP-Galf). However, to the best of our
knowledge, no data dealing with the incorporation of
D-Glcf, D-Manf, and D-Fucf entities are published so far.
These observations explain why current efforts for a
better understanding of the UDP-Galp mutase are mainly
placed in the preparation of UDP-Galf. Since enzymatic
approaches could afford limited amounts of this target,12c,13
chemical synthesis has also been reported by a few
groups. All of them rely on a coupling between D-Galf
1-phosphate14 and an activated uridine monophosphate
(UMP) derivative.12b,15,16 Along with these contributions,
Thorson and co-workers17 proposed a quite general
method for the synthesis of UDP- and TDP-nucleotide-
sugars using an R-D-glucosyl phosphate thymidylyltrans-
ferase as a biocatalyst and hexosyl 1-phosphates as
substrates, but in a pyranose configuration. Nevertheless,
these studies open great opportunities for new applica-
tions of hexosyl 1-phosphates in chemoenzymatic syn-
thesis.
is often tedious on highly charged molecules, it may be
judicious to introduce the phosphate group directly on
unprotected substrates. However, such a strategy neces-
sarily involves a phosphorylation reaction preserving the
five-membered ring of the starting materials. Finally, one
must keep in mind that one of the drawbacks in carbo-
hydrate-containing derivatives still remains in the ste-
reocontrol of the coupling reactions, more particularly
within the furanose series in which competition between
anomeric effects and steric ones are generally observed.19
These main requirements were fulfilled by the follow-
ing: (i) remote activation of new unprotected thioimidoyl
hexofuranosides by dry phosphoric acid, and (ii) careful
and general isolation procedure. We present herein the
full details of synthesis of the thiofuranosidic precursors
and the desired D-Galf 1-phosphate as a model target.
The proposed methodology was further successfully
extended to the corresponding D-Glcf and D-Manf deriva-
tives, and also to D-Fucf 1-phosphate, described here for
the first time.
Results and Discussion
On the basis of the chemical structure of UDP-Galp,
and considering the key points previously disclosed, we
focused on developing a one-step chemical synthesis of
hexofuranosyl 1-phosphates characterized by a 1,2-cis
stereochemistry. Despite considerable progress in glyco-
chemistry, the preparation of 1,2-cis glycosides still
remains a challenge of particular interest.20 In this
context, Hanessian has proposed the attractive concept
of the remote activation process.21 While the best results
were obtained with the 3-methoxy-2-pyridyloxy (MOP)
group, orthogonal glycosylation was recently demon-
strated by Demchenko using 2-O-benzylated S-benzox-
azolyl22 or S-thiazolyl glycosides.23 In the present study,
we investigated the electrofugal character of protonated
aromatic aglycons belonging to the family of substituted
thioimidoyl derivatives containing a third heteroatom (S
or N) suitably placed to modulate the basicity of the hard
center. Then we first evaluated the feasibility of this
concept for the synthesis of the relevant Galf 1-phos-
phate. The desired S-galactosides 5-7 were readily and
exclusively obtained from known penta-O-acetyl galacto-
furanose (1)24 and 2-mercaptobenzimidazole, 2-mercap-
tobenzothiazole, or 2-mercaptopyrimidine, respectively,
upon activation by boron trifluoride etherate complex
(Scheme 1). While an anomeric mixture was obtained for
the benzothiazolyl derivative 3 (â/R, 6.7:1), complete
â-stereodirection was observed for benzimidazolyl and
pyrimidinyl furanosides 2 and 4. Subsequent deacylation
under basic Ze´mplen transesterification or in a hydro-
alcoholic solution of triethylamine afforded the desired
thiofuranosides 5-7.
In this global context, our laboratory has initiated a
program dedicated to chemical synthesis of various
hexofuranosyl-containing derivatives,18 that is, oligosac-
charides, glycolipids, and anomeric phosphates. A chemi-
cal preparation of these hexofuranosyl 1-phosphates has
to take into account their thermal and chemical sensitiv-
ity. Consequently, because protecting group interchange
(10) (a) Marino, C.; Herczegh, P.; de Lederkremer, R. M. Carbohydr.
Res. 2001, 333, 123-128. (b) Chiocconi, A.; Marino, C.; de Lederkremer,
R. M. Carbohydr. Res. 2000, 323, 7-13. (c) Marino, C.; Marino, K.;
Miletti, L.; Manso Alves, M. J.; de Lederkremer, R. M. Glycobiology
1998, 8, 901-904.
(11) Houseknecht, J. B.; Lowary, T. L. Curr. Opin. Chem. Biol. 2001,
5, 677-682.
(12) (a) Zhang, Q.; Liu, H. W. J. Am. Chem. Soc. 2001, 123, 6756-
6766. (b) Zhang, Q.; Liu, H. W. J. Am. Chem. Soc. 2000, 122, 9065-
9070. (c) Barlow, J. N.; Blanchard, J. S. Carbohydr. Res. 2000, 328,
473-480. (d) Barlow, J. N.; Girvin, M. E.; Blanchard, J. S. J. Am.
Chem. Soc. 1999, 121, 6968-6969. (e) Lee, R. E.; Smith, M. D.; Nash,
R. J.; Griffiths, R. C.; McNeil, M.; Grewal, R. K.; Yan, W.; Besra, G.
S.; Brennan, P. J.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 6733-
6736. (f) Nassau, P. M.; Martin, S. L.; Brown, R. E.; Weston, A.;
Monsey, D.; McNeil, M. R.; Duncan, K. J. Bacteriol. 1996, 178, 1047-
1052.
(13) Lee, R.; Monsey, D.; Wetson, A.; Duncan, K.; Rithner, C.;
McNeil, M. Anal. Biochem. 1996, 242, 1-7.
(14) (a) de Lederkremer, R. M.; Nahmad, V. B.; Varela, O. J. Org.
Chem. 1994, 59, 690-692. (b) Chittenden, J. F. Carbohydr. Res. 1972,
25, 36-41.
(15) Tsvetkov, Y. E.; Nikolaev, A. V. J. Chem. Soc., Perkin Trans. 1
2000, 889-891.
(16) Marlow, A. L.; Kiessling, L. Org. Lett. 2001, 3, 2517-2519.
(17) (a) Jiang, J.; Biggins, J. B.; Thorson, J. S. Angew. Chem., Int.
Ed. 2001, 40, 1502-1505. (b) Jiang, J.; Biggins, J. B.; Thorson, J. S.
J. Am. Chem. Soc. 2000, 122, 6803-6804.
(19) Kirby, A. J. In The Anomeric Affect and Related Stereoelectronic
Effects at Oxygen; Springer-Verlag: Berlin, Heidelberg, New York,
1983.
(20) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35-79.
(21) Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443-4463.
(22) (a) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett.
2003, 5, 455-458. (b) Demchenko, A. V.; Kamat, M. N.; De Meo, C.
Synlett 2003, 1287-1290.
(23) Demchenko, A. V.; Pornsuiyasak, P.; De Meo C.; Malysheva,
N. N. Angew. Chem., Int. Ed. 2004, 43, 3069-3072.
(24) Ferrie`res, V.; Gelin, M.; Boulch, R.; Toupet, L.; Plusquellec, D.
Carbohydr. Res. 1998, 314, 79-83.
(18) (a) Gelin, M.; Ferrie`res, V.; Lefeuvre, M.; Plusquellec, D. Eur.
J. Org. Chem. 2003, 1285-1293. (b) Ferrie`res, V.; Roussel, M.; Gelin,
M.; Plusquellec, D. J. Carbohydr. Chem. 2001, 20, 855-865. (c) Gelin,
M.; Ferrie`res, V.; Plusquellec, D. Eur. J. Org. Chem. 2000, 1423-1431.
(d) Velty, R.; Benvegnu, T.; Gelin, M.; Privat, E.; Plusquellec, D.
Carbohydr. Res. 1997, 299, 7-14. (e) Ferrie`res, V.; Blanchard, S.;
Fischer, D.; Plusquellec, D. Bioorg. Med. Chem. Lett. 2002, 12, 3515-
3518.
848 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Free Hexofuranosyl 1-Phosphates
SCHEME 1. Synthesis of Galactofuranosyl Donors
5, 6, 7a
these unprotected donors correlate well with the observed
chemical shifts of H-1: the lower the chemical shift (5:
δH-1 5.75 ppm, 6â: δH-1 6.00 ppm, 7: δH-1 6.20 ppm), the
more reactive is the glycosyl donor.
To demonstrate the applicability of this methodology,
we further focused on a purification protocol that does
not alter the desired product, neither the ring size nor
the R/â ratio. Excess of phosphoric acid was first elimi-
nated as barium phosphate by adjusting the pH between
8 and 9 with a saturated solution of barium hydroxide
(Scheme 2). After centrifuging, the supernatant liquid
was carefully neutralized using a strong acidic resin so
that the phosphosugar remained as a barium salt.
Freeze-drying followed by selective removal of released
2-mercaptobenzimidazole gave the desired phosphate,
however, along with D-Gal. Removal of the reducing
carbohydrate required resin-assisted barium/ammonium
metathesis and an ionic exchange chromatography using
an anionic column (CO32--form). The crucial point of this
last step relied on a judicious choice of the eluting
solution since the target phosphate 9 is highly sensitive
in aqueous solution at pH below 7. In our hands, first
attempts of chromatographic purification using a molar
ammonium hydroxide aqueous solution unfortunately
resulted in detrimental degradation of 9 due to a too-
long retaining period. However, the ionic strength of the
eluant was advantageously increased by using an am-
monium carbonate aqueous solution, which was easily
freeze-dried after elution. As a consequence, galactofura-
nosyl 1-phosphate 9 was synthesized and isolated in a
58% yield as a 1.2:1 anomeric mixture of 9R and 9â,
characterized by NMR data similar to that of ammonium
and cyclohexylammonium derivatives.14a While this ste-
reoselectivity is slightly lower than that previously
described using a furanosyl bromide as a donor, our
methodology complements well that of de Lederkremer14a
since no protecting-group manipulation is required for
further use of the target phosphate. This approach is also
characterized by a shortened three-step synthetic scheme
and so resulted in a better overall yield. Indeed, phos-
phate 9 was obtained in 53% overall yield from the
pentacetyl galactofuranose (10).
a Reagentsandconditions: (a)2-mercaptobenzimidazole,BF3‚Et2O,
CH2Cl2 (91%); (b) 2-mercaptobenzothiazole, BF3‚OEt2O, CH2Cl2
[83% (R/â, 1:6.7)]; (c) 2-mercaptopyrimidine, BF3‚OEt2O, CH2Cl2
(99%); (d) MeONa, MeOH (5: 100%; 7: 98%); (e) MeOH, H2O, NEt3
[67% (R/â, 1:6.7)].
With these galactofuranosyl donors in hand, phospho-
1
rylation was first monitored by H NMR spectroscopy
using N,N-dimethylformamide-d7 as a solvent. Quite
surprisingly, the pyrimidinyl donor 7 was proved to be
highly stable under such conditions since neither phos-
phorylation, degradation, nor anomerization occurred.
Nevertheless, the thiogalactofuranoside 5, with a benz-
imidazolyl aglycon, was smoothly activated by phosphoric
acid (Figure 1). The resulting data indicated that 5 was
completely consumed after only 18 min at room temper-
ature and was indeed converted into the target phosphate
8 with less than 10% of released D-galatose, even after
1
prolonged reaction times. H NMR spectra unambigu-
ously showed characteristic data relevant for furanosyl
phosphates and notably suitable multiplicity for H-1
signals significantly different from that observed for their
pyranosyl counterparts.25,26 Indeed, compound 8R is
characterized by a doublet of a doublet with similar
JH-1,P and JH-1,H-2 values near 3.1 Hz at 5.54 ppm, while
the trans relationship between H-1 and H-2 in 8â was
deduced from a doublet with small JH-1,H-2 (<1 Hz) but
higher JH-1,P coupling constant (5.4 Hz) at 5.58 ppm. The
monitoring also revealed the faster formation of the
desired R-D-Galf 1-phosphate 8R. This result, therefore,
supports a mechanism involving protonation of the
â-leaving group followed by a nucleophilic attack by the
released oxyanion on the R-face. However, 8R slowly
anomerized into the less hindered 8â so that the R/â ratio
reached 0.6:1 at equilibrium.
The reaction was also carried out using benzothiazolyl
donor 6. A longer reaction time (13 h at 20 °C) resulted
in lower overall conversion yield and in poorer R-selectiv-
ity. Interpretation of phosphorylation results from fura-
nosides 5-7 could not rely only on the pKa values of the
leaving groups.21 Nevertheless, as previously described
in the pyranose series,21,27 the respective reactivities of
Encouraged by this successful result, this approach
was extended to the synthesis of furanosyl 1-phosphate
corresponding to D-Glcf, D-Manf, and D-Fucf. The benz-
imidazolyl gluco- and mannofuranosides 12 and 1528 were
obtained from 10 and 13,24 respectively, according to the
same procedure as in the galactose series (Scheme 3).
Considering the low availability of D-fucose, preparation
of fucosyl donor 26 involved a multistep synthesis start-
ing from n-octyl galactofuranoside (16)29 (Scheme 4). The
primary hydroxyl was first selectively tritylated using
freshly prepared 4-N,N-(dimethylamino)-1-N-triphenyl-
methylpyridinium chloride.30 Subsequent benzylation,
(27) (a) Zhang, Z.; Ollman, I. R.; Ye, X. S.; Wischnat, R.; Baasov,
T.; Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734-753. (b) Douglas,
N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem. Soc., Perkin
Trans. 1 1998, 51-65.
(28) It is interesting to note that H-1 is characterized by a complex
and unusual signal assigned by 1H NMR. Indeed, because signals from
H-2 and H-3 are superimposed, second-order effects arose out of virtual
long-range coupling and so resulted in producing a more complex signal
(six peaks) than the expected doublet. See, for example: Kotowycz,
G.; Lemieux, R. U. Chem. Rev. 1973, 73, 669-698.
(25) Hanessian, S.; Lu, P. H. Ishida, H. J. Am. Chem. Soc. 1998,
120, 13296-13300.
(26) O’Connor, J. V.; Nunez, H. A.; Barker, R. Biochemistry 1979,
18, 500-507.
(29) Ferrie`res, V.; Bertho, J. N.; Plusquellec, D. Carbohydr. Res.
1998, 311, 25-35.
J. Org. Chem, Vol. 70, No. 3, 2005 849

Euzen et al.
FIGURE 1. Phosphorylation of donor 5: (a) Selected 1H NMR data (H-1 area); (b) distribution (O 5, × 8r, 4 8â, 0 Galp) vs
reaction time.
SCHEME 2. Synthesis of D-Galactofuranosyl
SCHEME 4. Preparation of Fucofuranoside 26a
1-Phosphate 9r,âa
a Reagents and conditions: (a) H3PO4, DMF, 18 min; (b)
Ba(OH)2; IR-120 (H+-form); EtOHabs, AcOEt (v/v 1:6); IR-120
(NH4+-form); Amberlyst A-26 (CO32--form) [58% overall yield
(R/â, 1.2:1)].
SCHEME 3. Synthesis of Thioglucoside 10 and
Mannofuranosyl Donor 12a
a Reagents and conditions: (a) 4-N,N-(dimethylamino)-1-N-
triphenylmethylpyridinium chloride, CH2Cl2 (80%); (b) BnBr, NaH,
DMF (99%); (c) AcOH, H2O, 100 °C (78%); (d) TsCl, DMAP, NEt3,
CH2Cl2 (96%); (e) LiAlH4, Et2O (90%); (f) H2, Pd(OAc)2, AcOH,
AcOEt (100%); (g) Ac2O, pyridine (96%); (h) Ac2O, H2SO4, CH2Cl2
[94% (R/â, 1:4)]; (i) 2-mercaptobenzimidazole, BF3‚OEt2, CH2Cl2
(90%); (j) MeOH, MeONa (93%).
num hydride to yield the fucofuranoside 21. Protecting
group interconversion followed by removal of the tem-
porary protecting alkoxy chain under carefully controlled
acetolysis further gave 2432 in 48% overall yield for eight
steps. The latter intermediate was converted into donor
26 through treatment with 2-mercaptobenzimidazole in
the presence of boron trifluoride etherate complex and
Ze´mplen deacetylation.
a Reagents and conditions: (a) 2-mercaptobenzimidazole,
BF3‚OEt2, CH2Cl2 (11: 67%; 14: 71%); (b) MeONa, MeOH (12:
100%; 15: 100%).
Subsequently, phosphorylation of these three donors
12, 15, and 26 was explored, and the reactions were
acidolysis,18d,31 and tosylation upon conventional proce-
dures afforded 20, which was reduced by lithium alumi-
(31) Pathak, A. K.; Pathak, V.; Seitz, L.; Maddry, J. A.; Gurcha, S.
S.; Besra, G. S.; Suling, W. J.; Reynolds, R. C. Bioorg. Med. Chem.
2001, 9, 3129-3143.
(32) Kinoshita, T.; Miwa, T.; Clardy, J. Carbohydr. Res. 1985, 143,
249-255.
(30) Hernadez, O.; Chaudhary, S. K.; Cox, R. H.; Poter, J. Tetrahe-
dron Lett. 1981, 22, 1491-1494.
850 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Free Hexofuranosyl 1-Phosphates
SCHEME 5. Synthesis of Furanosyl 1-Phosphates
27, 29, and 30a
for the trans-29R (δC-1 102.7 ppm) than that of 29â (δC-1
96.5 ppm).24,34 The NMR monitoring of the phosphory-
lation of 26 revealed that the 1,2-cis phosphate was
kinetically obtained in agreement with the proposed
mechanism, followed by fast anomerization into the much
more stable 1,2-trans counterpart. Moreover, it was
observed that this epimerization also occurred during
isolation of the desired ammonium salt. As a conse-
quence, 29 was obtained as a R,â mixture slightly en-
riched in R-anomer (29R/29â 1.6:1).
Conclusions
A highly general and concise synthesis of hexofuranosyl
1-phosphates was achieved using new unprotected hexo-
furanosyl donors. The strategy was based on the remote
activation of readily available thioimidoyl furanosides by
dry phosphoric acid. Our study on a set of galactofura-
nosides established that best results were obtained using
S-benzimidazolyl aglycon as a leaving group. It is par-
ticularly important to note that the furanoid ring of the
substrates was generally not altered under reaction
conditions nor during the purification steps so that
furanosyl 1-phosphates were prepared in good to excel-
lent yields and in interesting 1,2-cis stereoselectivities.
As a consequence, this approach not only allowed the
synthesis of known D-Galf 1-phosphate, D-Glcf, and
D-Manf epimers but also, to the best of our knowledge,
afforded for the first time the corresponding D-Fucf
derivative. This, therefore, opens a very interesting
opportunity for an easier access to rare nucleotide-
hexofuranoses that are crucial products for biological
studies of glycofuranoconjugates.
a Reagents and conditions: (a) H3PO4, DMF (27: 90 min; 29:
15 min; 30: 20 min); (b) purification procedure [27: 48% (R/â, 1.2:
1), 28: 3%; 29: 67% (R/â, 1.6:1); 30: 90% (R/â, 1.5:1)].
monitored by NMR to determine optimum reaction times.
As expected, formation of the corresponding phosphates
was found to be dependent on the hexose series. The
reactivity of glucofuranoside 12, which led to 27 (Scheme
5), seemed to be lower than that of its 4-epimer 5 since
3.5 h were required to have good R-stereoselectivity and
high conversion yield. Assignment of the anomeric proton
corresponding to 27â was characterized by a doublet at
5.39 ppm with a small coupling constant JH-1,H-2 (<1 Hz)
and a value of 7.1 Hz for JH-1,P, while 27R stood out from
the â-anomer by a double doublet at 5.65 ppm with a
JH-1,H-2 of 4.1 Hz and a distinct JH-1,P of 6.4 Hz. Moreover,
the NMR monitoring also showed the formation of a
byproduct that appeared after 90 min. Its chemical
structure was established on the basis of significant
chemical shifts and coupling constant values, that is, for
H-1, δ 6.00 ppm with a JH-1,H-2 of 4.1 Hz, and for P, δ
15.0 ppm with a JH-1,P of 16.8 Hz. These data are
indicative of a strained bicyclic compound33 with R-ano-
meric configuration and unambiguously correspond to the
1,2-cyclic phosphate 28. Formation of the latter can be
rationalized by an intramolecular dehydration of first-
formed 27R prior to anomerization of 27R into less
hindered 27â. Therefore, to minimize this cyclization, the
reaction was quenched after 90 min at room temperature.
The previously disclosed purification protocol gave the
target D-Glcf 1-phosphate 27 (R/â 1.2:1) isolated in 48%
yield, accompanied by cyclic phosphate 28 (3%).
Within the D-mannose and D-fucose series, remote
activation of 15 and 26 smoothly afforded 29 and 30,
respectively, after only 15-20 min reaction times. The
desired phosphates 29 and 30 were then isolated as
ammonium salts in 66 and 90% yield, respectively
(Scheme 5). Providing that ammonium carbonate was
used in the eluting solution during the last ionic exchange
chromatography, no byproduct was observed after puri-
fication. Anomeric configurations of 6-deoxy-galactofura-
nosyl derivatives 30R and 30â were determined from
significant NMR data close to that described for 9. For
D-Manf 1-phosphate 29, the relationship between H-1 and
H-2 was based on the assumption of a lower-field signal
Experimental Section
General Procedure A for the Synthesis of Acetylated
Thiofuranosides. To a solution of per-O-acetylated hexofura-
nose (5 mmol) in anhyd dichloromethane (80 mL) were
successively added the thione (15 mmol) and BF3‚OEt2 (45
mmol). The mixture was stirred for 24 h at the appropriate
temperature then diluted with dichloromethane (80 mL), and
washed successively with a saturated solution of aq NaHCO3
(3 × 50 mL) and water (3 × 100 mL). The aqueous layers thus
obtained were extracted with dichloromethane (3 × 50 mL),
and the combined organic layers were dried (MgSO4) and
finally concentrated. Purification of the residue by flash
chromatography on silica gel afforded the desired thioglyco-
furanoside.
2-Benzimidazolyl 2,3,5,6-Tetra-O-acetyl-1-thio-â-D-ga-
lactofuranoside (2). This compound was synthesized accord-
ing to the general procedure A from 1 (2 g, 5.12 mmol) at room
temperature. Chromatographic purification (light petroleum/
EtOAc, 1:1) gave 2 (2.25 g, 91%) as a colorless oil: Rf 0.3 (light
petroleum/EtOAc, 1:1); [R]20D -135.1 (c 1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 2.05, 2.09, 2.11, 2.13 (4s, 12H, CH3CO),
4.16 (dd, 1H, J ) 5.8, 11.7 Hz, H-6a), 4.49 (dd, 1H, J ) 3.8,
5.4 Hz, H-4), 4.55 (dd, 1H, J ) 5.8, 11.7 Hz, H-6b), 5.13 (dd,
1H, J ) 2.3, 5.4 Hz, H-3), 5.32 (t, 1H, J ) 2.3 Hz, H-2), 5.37
(td, 1H, J ) 3.8, 5.8 Hz, H-5), 5.94 (d, 1H, J ) 2.0 Hz, H-1),
7.23-7.27 (m, 2H, H-6′, H-7′), 7.47-7.71 (m, 2H, H-5′, H-8′),
10.41 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3) δ 20.7, 20.7,
20.9, 20.9 (CH3CO), 61.6 (C-6), 68.9 (C-5), 76.5 (C-3), 80.9, 80.9
(C-2, C-4), 89.2 (C-1), 110.7, 119.2 (C-5′, C-8′), 123.2 (C-6′, C-7′),
(34) For methyl D-mannofuranosides and protected derivatives, see
also: Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27-66.
(33) Fathi, R.; Jordan, F. J. Org. Chem. 1986, 51, 4143-4146.
J. Org. Chem, Vol. 70, No. 3, 2005 851

Euzen et al.
145.6 (C-2′, C-4′, C-9′), 169.2, 169.9, 170.1, 171.1 (CdO); HRMS
(ESI+) m/z calcd for C21H24N2NaO9S [M + Na]+ 503.1100, found
503.1100. Anal. calcd for C21H24N2O9S: C, 52.49; H, 5.03; N,
5.83; S, 6.67. Found: C, 52.37; H, 5.01; N, 5.69; S, 6.47.
4.18 (m 3H, H-2, H-3, H-4), 5.75 (d, 1H, J ) 3.9 Hz, H-1), 7.19-
7.23 (m, 2H, H-6′, H-7′), 7.48-7.52 (m, 2H, H-5′, H-8′); 13C
NMR (100 MHz, CD3OD) δ 64.1 (C-6), 72.1 (C-5), 78.0 (C-3),
83.4 (C-2), 84.5 (C-4), 92.1 (C-1), 115.3 (C-5′, C-8′), 123.6
(C-6′, C-7′), 140.5 (C-4′, C-9′), 149.6 (C-2′); HRMS (FAB+) m/z
calcd for C13H17N2O5S [M + H]+ 313.0858, found 313.0855.
2-Benzothiazolyl 2,3,5,6-Tetra-O-acetyl-1-thio-D-ga-
lactofuranoside (3). This compound was prepared as de-
scribed in general procedure A from 1 (50 mg, 0.13 mmol) at
room temperature. Chromatographic purification (CH2Cl2/
EtOAc, 95:5) gave an anomeric mixture (R/â, 1:6.7) of 3 (53
mg, 83%) as a yellow oil: Rf 0.5 (CH2Cl2/EtOAc, 9:1). 3R: 1H
NMR (400 MHz, CDCl3) δ 2.01, 2.09, 2.10, 2.11 (4s, 12H,
CH3CO), 4.14 (dd, 1H, J ) 6.8, 12.0 Hz, H-6a), 4.21-4.24 (m,
1H, H-4), 4.37 (dd, 1H, J ) 4.2, 12.0 Hz, H-6b), 5.32-5.38 (m,
2H, H-3, H-5), 5.63 (dd, 1H, J ) 4.3, 5.6 Hz, H-2), 6.55 (d, 1H,
J ) 5.6 Hz, H-1), 7.32 (td, 1H, J ) 1.0, 8.4 Hz, H-6′), 7.42 (td,
1H, J ) 1.3, 8.4 Hz, H-7′), 7.77 (dd, 1H, J ) 1.0, 8.4 Hz, H-8′),
7.90 (dd, 1H, J ) 1.3, 8.4 Hz, H-5′); 13C NMR (100 MHz, CDCl3)
δ 20.5, 20.6, 20.8, 21.0 (CH3CO), 62.4 (C-6), 69.3 (C-5), 75.5
(C-3), 76.3 (C-2), 81.2 (C-4), 86.9 (C-1), 121.1 (C-5′), 122.1
(C-8′), 124.8 (C-7′), 126.2 (C-6′), 135.7 (C-4′), 152.8 (C-9′), 162.2
(C-2′), 169.3, 169.6, 169.9, 170.4 (CdO). 3â: 1H NMR (400
MHz, CDCl3) δ 1.98, 2.10, 2.11, 2.13 (4s, 12H, CH3CO), 4.18
(dd, 1H, J ) 6.9, 11.8 Hz, H-6a), 4.32 (dd, 1H, J ) 4.3, 11.8
Hz, H-6b), 4.49 (dd, 1H, J ) 4.3, 5.3 Hz, H-4), 5.13 (dd, 1H, J
) 2.0, 5.3 Hz, H-3), 5.36 (t, 1H, J ) 2.0 Hz, H-2), 5.42 (dt, 1H,
J ) 4.3, 6.9 Hz, H-5), 6.27 (d, 1H, J ) 1.7 Hz, H-1), 7.31 (td,
1H, J ) 1.0, 7.9 Hz, H-6′), 7.41 (td, 1H, J ) 1.0, 8.1 Hz, H-7′),
7.76 (dd, 1H, J ) 1.0, 8.1 Hz, H-8′), 7.90 (dd, 1H, J ) 1.0, 7.9
Hz, H-5′); 13C NMR (100 MHz, CDCl3) δ 20.6, 20.6, 20.6, 20.8
(CH3CO), 62.4 (C-6), 69.0 (C-5), 76.4 (C-3), 80.9 (C-2), 81.5
(C-4), 89.3 (C-1), 121.0 (C-5′), 122.2 (C-8′), 124.9 (C-7′),
126.2 (C-6′), 135.7 (C-4′), 152.8 (C-9′), 162.2 (C-2′), 169.3,
169.7, 169.9, 170.4 (CdO); HRMS (ESI+) m/z calcd for
C21H23NNaO9S2 [M + Na]+ 520.0712, found 520.0719. Anal.
calcd for C21H23NO9S2: C, 50.69; H, 4.66; N, 2.82; S, 12.89.
Found: C, 50.49; H, 4.67; N, 2.85; S, 12.78.
2-Pyrimidinyl 2,3,5,6-Tetra-O-acetyl-1-thio-â-D-galacto-
furanoside (4). This intermediate was synthesized according
to the general procedure A from 1 (2 g, 5.12 mmol) at room
temperature. Chromatographic purification (light petroleum/
EtOAc, 1:1) gave 4 (2.24 g, 99%) as a yellow oil: Rf 0.3 (light
petroleum/EtOAc, 1:1); [R]20D -96.9 (c 1.03, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 2.00, 2.10, 2.11, 2.12 (4s, 12H, CH3CO),
4.16 (dd, 1H, J ) 7.1, 11.9 Hz, H-6a), 4.31 (dd, 1H, J ) 4.3,
11.9 Hz, H-6b), 4.39 (t, 1H, J ) 4.8 Hz, H-4), 5.11 (dd, 1H, J
) 1.0, 4.8 Hz, H-3), 5.36 (t, 1H, J ) 1.8 Hz, H-2), 5.40 (dt, 1H,
J ) 4.8, 7.1 Hz, H-5), 6.47 (br s, 1H, H-1), 7.03 (t, 1H, J ) 4.8
Hz, H-5′), 8.54 (d, 2H, J ) 4.8 Hz, H-4′, H-6′); 13C NMR (100
MHz, CDCl3) δ 20.7, 20.7, 20.8, 20.9 (CH3CO), 62.6 (C-6), 69.3
(C-5), 76.7 (C-3), 80.8 (C-2), 81.4 (C-4), 87.5 (C-1), 117.6
(C-5′), 157.6 (C-4′, C-6′), 169.5, 169.8, 170.1, 170.5 (CdO), 169.6
(C-2′); HRMS (ESI+) m/z calcd for C18H22N2NaO9S [M + Na]+
465.0944, found 465.0952. Anal. calcd for C18H22N2O9S: C,
48.86; H, 5.01; N, 6.33; S, 7.25. Found: C, 48.68; H, 4.94; N,
6.26; S, 7.09.
2-Benzothiazolyl 1-Thio-D-galactofuranoside (6). Com-
pound 3 (840 mg, 1.69 mmol) was dissolved in a mixture of
MeOH/water/NEt3 (12 mL/2.5 mL/2.5 mL). After stirring at
room temperature for 1 h, the solvent was removed under
reduced pressure. The residue was then purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 9:1) to give an
anomeric mixture (R/â, 1:6.7) of 6 (370 mg, 67%) as a colorless
foam. 6R: Rf 0.2 (CH2Cl2/EtOAc, 9:1); 1H NMR (400 MHz,
CD3OD) δ 3.60-3.68 (m, 2H, H-6a, H-6b), 3.82-3.85 (m, 1H,
H-5), 4.03 (t, 1H, J ) 4.0 Hz, H-4), 4.29 (t, 1H, J ) 4.1 Hz,
H-3), 4.33 (t, 1H, J ) 4.4 Hz, H-2), 6.23 (d, 1H, J ) 4.4 Hz,
H-1), 7.36 (td, 1H, J ) 1.2, 8.4 Hz, H-6′), 7.45 (td, 1H, J ) 1.5,
8.4 Hz, H-7′), 7.84 (dd, 1H, J ) 1.2, 8.4 Hz, H-8′), 7.87 (dd,
1H, J ) 1.5, 8.4 Hz, H-5′); 13C NMR (100 MHz, CD3OD) δ 64.0
(C-6), 73.0 (C-5), 78.2 (C-3), 79.4 (C-2), 87.3 (C-4), 91.8 (C-1),
122.4 (C-5′), 122.5 (C-8′), 126.0 (C-7′), 127.5 (C-6′), 136.8
(C-4′), 154.0 (C-9′), 167.6 (C-2′). 6â: Rf 0.3 (CH2Cl2/EtOAc, 9:1);
1H NMR (400 MHz, CD3OD) δ 3.63-3.64 (m, 2H, H-6a, H-6b),
3.79 (td, 1H, J ) 3.0, 6.1 Hz, H-5), 4.15-4.17 (m, 1H, H-4),
4.19-4.21 (m, 2H, H-2, H-3), 6.00 (d, 1H, J ) 2.6 Hz, H-1),
7.36 (td, 1H, J ) 1.2, 8.4 Hz, H-6′), 7.45 (td, 1H, J ) 1.5, 8.4
Hz, H-7′), 7.84 (dd, 1H, J ) 1.2, 8.4 Hz, H-8′), 7.87 (td, 1H, J
) 1.5, 8.4 Hz, H-5′); 13C NMR (100 MHz, CD3OD) δ 64.2
(C-6), 72.0 (C-5), 78.1 (C-3), 83.5 (C-2), 85.4 (C-4), 92.9 (C-1),
122.4 (C-5′), 122.5 (C-8′), 126.0 (C-7′), 127.5 (C-6′), 136.8
(C-4′), 154.0 (C-9′), 167.5 (C-2′); HRMS (ESI+) m/z calcd for
C13H16NO5S2 [M + H]+ 330.0470, found 330.0478.
2-Pyrimidinyl 1-Thio-â-D-galactofuranoside (7). This
compound was synthesized as described in general procedure
B from 4 (2.23 g, 5.04 mmol) and isolated as a yellow foam
(1.35 g, 98%): Rf 0.4 (CH2Cl2/MeOH, 4:1); [R]20D -260.9 (c 1.01,
1
MeOH); H NMR (400 MHz, CD3OD) δ 3.59 (d, 2H, J ) 6.9
Hz, H-6a, H-6b), 3.75 (td, 1H, J ) 3.1, 6.9 Hz, H-5), 4.05 (dd,
1H, J ) 3.1, 6.0 Hz, H-4), 4.16 (dd, 1H, J ) 4.1, 6.0 Hz, H-3),
4.21 (dd, 1H, J ) 3.8, 4.1 Hz, H-2), 6.20 (d, 1H, J ) 3.8 Hz,
H-1), 7.18 (t, 1H, J ) 5.1 Hz, H-5′), 8.59 (d, 2H, J ) 5.1 Hz,
H-4′, H-6′); 13C NMR (100 MHz, CD3OD) δ 64.2 (C-6), 72.3
(C-5), 78.2 (C-3), 82.9 (C-2), 85.0 (C-4), 90.1 (C-1), 118.7
(C-5′), 158.9 (C-4′, C-6′), 172.2 (C-2′); HRMS (ESI+) m/z calcd
for C10H14KN2O5S [M + K]+ 313.0260, found 313.0252.
General Procedure C for the Preparation of Am-
monium Glycofuranosyl 1-Phosphates. To a solution of the
2-benzimidazolyl glycofuranoside (104 mg, 0.34 mmol) in dry
DMF (1 mL) was added a solution of orthophosphoric acid (238
mg, 2.43 mmol) in dry DMF (1.4 mL). This mixture was then
stirred at room temperature for an appropriate period, cooled
to 0 °C, and then diluted with water (15 mL). A saturated
solution of aq Ba(OH)2 was added dropwise until the pH value
reached 8-9. The precipitate of Ba3(PO4)2 could be removed
by centrifugation (15 000 rpm, 0 °C, 15 min) and the super-
natant liquid filtered. The resulting filtrate and washings (3
× 5 mL) were combined and carefully neutralized by addition
of Amberlite IR-120 (H+-form). After removal of the resin, the
solution was freeze-dried and the residue successively added
of absolute EtOH (2 mL) and EtOAc (12 mL). The precipitate
was collected by centrifugation (15 000 rpm, 0 °C, 15 min),
washed in the manner described above, and added to Et2O (14
mL). The solvent was removed after centrifugation (15 000
rpm, 0 °C, 15 min), and the crude barium salt was dried under
gentle vaccum. The solid thus obtained was then dissolved in
water (5 mL) and loaded on an Amberlite IR-120 (NH4+-form)
column (1 × 15 cm). After a slow elution with water (45 mL),
the pH value of the effluent was adjusted at 8.5-9 by adding
few drops of 1 M aq solution of NH4OH. This effluent was then
freeze-dried, and the residue was loaded on an Amberlyst A-26
(CO32--form) column (1 × 15 cm). Neutral compounds were
General Procedure B for the Preparation of Unpro-
tected Thiofuranosyl Donors. To a solution of the peracety-
lated thioglycofuranoside (4.2 mmol) in anhyd methanol (90
mL) was added a 0.1 M solution of sodium methylate in
methanol (4.2 mL, 0.42 mmol). The mixture was stirred at
room temperature until no starting product was detected by
TLC. Neutralization was then carefully performed by adding
Amberlite IR-120 (H+-form). The resin was filtered off and the
solvent removed under reduced pressure. The desired unpro-
tected glycofuranoside was isolated and then used without
further purification.
2-Benzimidazolyl 1-Thio-â-D-galactofuranoside (5). This
compound was synthesized according to the general procedure
B from 2 (2.22 g, 4.62 mmol) and isolated as a colorless foam
(1.44 g, 100%): Rf 0.1 (CH2Cl2/MeOH, 9:1); [R]20 -205.2 (c
D
1
1.02, MeOH); H NMR (400 MHz, CD3OD) δ 3.62 (d, 2H, J )
6.4 Hz, H-6a, H-6b), 3.77 (td, 1H, J ) 3.1, 6.4 Hz, H-5), 4.11-
852 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Free Hexofuranosyl 1-Phosphates
first removed by elution with water (50 mL), and the target
phosphate was recovered by elution with 0.21 M aq solution
of (NH4)2CO3 (50 mL). Finally, freeze-drying yielded the
desired ammonium glycofuranosyl 1-phosphate.
a quantitative yield: Rf 0.2 (CH2Cl2/MeOH, 9:1); [R]20D +234.7
(c 1.00, MeOH); 1H NMR (400 MHz, CD3OD) δ 3.61 (dd, 1H, J
) 5.3, 11.7 Hz, H-6a), 3.74 (dd, 1H, J ) 3.1, 11.7 Hz, H-6b),
3.97 (ddd, 1H, J ) 3.1, 5.3, 8.1 Hz, H-5), 4.07 (dd, 1H, J ) 2.0,
8.1 Hz, H-4), 4.22-4.26 (m, 2H, H-2, H-3), 5.62-5.65 (m, 1H,
H-1), 7.19-7.24 (m, 2H, H-6′, H-7′), 7.49-7.53 (m, 2H, H-5′,
H-8′); 13C NMR (100 MHz, CD3OD) δ 64.6 (C-6), 70.7 (C-5),
72.4 (C-3), 78.9 (C-2), 81.9 (C-4), 91.2 (C-1), 115.4 (C-5′, C-8′),
123.7 (C-6′, C-7′), 140.5 (C-4′, C-9′), 148.8 (C-2′); HRMS (ESI+)
m/z calcd for C13H16N2NaO5S [M + Na]+ 335.0678, found,
335.0673.
It is interesting to note that H-1 is characterized by a
complex and unusual signal assigned by 1H NMR. Indeed,
because signals from H-2 and H-3 are superimposed, second-
order effects arose out of virtual long-range coupling and so
resulted in producing a more complex signal (six peaks) than
the expected doublet. See for example: Kotowycz, G.; Lemieux,
R. U. Chem. Rev. 1973, 73, 669-698.
n-Octyl 6-O-Triphenylmethyl-â-D-galactofuranoside
(17). To a suspension of 16 (20 g, 68.41 mmol) in dry di-
chloromethane (200 mL) was added 4-N,N-(dimethylamino)-
1-N-triphenylmethylpyridinium chloride (32.91 g, 205.24 mmol).
The mixture was heated under reflux for 24 h, cooled to room
temperature, concentrated, and then diluted with ethyl acetate
(200 mL). The solution was washed successively with 5% aq
HCl (30 mL), a saturated solution of aq NaHCO3 (30 mL), and
brine (30 mL). The aqueous layers thus obtained were ex-
tracted with ethyl acetate (3 × 30 mL) and the combined
organic layers dried (MgSO4) and concentrated. Purification
by flash chromatography (light petroleum/EtOAc, 3:7) afforded
17 (27.42 g, 80%) as a colorless oil: 1H and 13C NMR data of
17 were identical to the reported data.31
n-Octyl 2,3,5-Tri-O-benzyl-6-O-tosyl-â-D-galactofura-
noside (20). Triethylamine (16.4 mL, 116.39 mmol), DMAP
(0.28 g, 2.33 mmol), and tosyl chloride (6.66 g, 34.92 mmol)
were successively added to a solution of 19 (13.10 g, 23.28
mmol) in dry dichloromethane (130 mL). The mixture was
heated under reflux for 8 h, then cooled to room temperature,
diluted with dichloromethane (70 mL), and washed succes-
sively with 5% aq HCl (50 mL), a saturated solution of aq
NaHCO3 (50 mL), and water (50 mL). The aqueous layers were
extracted twice with dichloromethane (2 × 50 mL) and the
combined organic layers dried (MgSO4) and concentrated. The
residue was finally purified by flash chromatography on silica
gel (light petroleum/EtOAc, 9:1) to give 20 (16.09 g, 96%) as a
colorless oil: Rf 0.3 (light petroleum/EtOAc, 4:1); [R]20D -46.1
(c 1.02, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J )
6.8 Hz, CH3), 1.22-1.35 [m, 10H, (CH2)5], 1.50-1.56 (m, 2H,
OCH2CH2), 2.41 (s, 3H, H3CC6H4SO2), 3.31 (dt, 1H, J ) 6.8,
9.7 Hz, OCH2CH2), 3.58 (dt, 1H, J ) 6.9, 9.7 Hz, OCH2CH2),
3.77-3.81 (m, 1H, H-5), 3.90 (dd, 1H, J ) 3.3, 7.1 Hz, H-3),
3.94 (dd, 1H, J ) 1.3, 3.3 Hz, H-2), 4.01 (dd, 1H, J ) 3.3, 7.1
Hz, H-4), 4.13 (dd, 1H, J ) 7.4, 10.4 Hz, H-6a), 4.20 (dd, 1H,
J ) 4.3, 10.4 Hz, H-6b), 4.25-4.60 (m, 6H, OCH2C6H5), 4.98
(br s, 1H, H-1), 7.18-7.37 (m, 17H, C6H4, C6H5), 7.73 (d, 2H,
J ) 8.4 Hz, C6H4); 13C NMR (100 MHz, CDCl3) δ 14.2 (CH3),
21.7 (H3CC6H4SO2), 22.8, 26.2, 29.4, 29.5, 29.5, 31.9 [(CH2)6],
67.9 (OCH2CH2), 70.3 (C-6), 72.0, 72.1, 73.8 (OCH2C6H5), 75.3
(C-5), 80.2 (C-4), 82.5 (C-3), 88.2 (C-2), 106.0 (C-1), 127.9, 127.9,
128.0, 128.0, 128.1, 128.4, 128.4, 128.5, 128.5, 129.9 (C6H5,
C6H4), 132.8 (Cp C6H4SO2), 137.6, 137.7, 137.7 (Cipso C6H5),
144.9 (Cipso C6H4SO2). Anal. calcd for C42H52O8S: C, 70.36; H,
7.31; S, 4.47. Found: C, 70.08; H, 7.33; S, 4.50.
Ammonium D-Galactofuranosyl 1-Phosphate (9). This
phosphate was obtained according to the general procedure C
from 5 (108 mg, 0.35 mmol) after stirring at room temperature
for 18 min. An anomeric mixture of 9 (R/â, 1.2:1) was then
isolated as an amorphous and colorless solid (56 mg, 58%):
9R: 1H NMR (500 MHz, D2O) δ 3.58 (dd, 1H, J ) 7.1, 11.7
Hz, H-6a), 3.65 (dd, 1H, J ) 4.6, 11.7 Hz, H-6b), 3.70 (ddd,
1H, J ) 4.6, 7.1, 9.4 Hz, H-5), 3.76 (dd, 1H, J ) 7.4, 9.4 Hz,
H-4), 4.05 (dd, 1H, J ) 4.6, 8.2 Hz, H-2), 4.19 (dd, 1H, J )
7.4, 8.2 Hz, H-3), 5.45 (dd, 1H, J ) 4.6, 4.8 Hz, H-1); 13C
NMR (125 MHz, D2O) δ 63.5 (C-6), 72.9 (C-5), 75.1 (C-3), 77.8
(d, J ) 7.2 Hz, C-2), 82.3 (C-4), 97.4 (d, J ) 5.6 Hz, C-1); 31P
NMR (162 MHz, D2O) δ 2.2; 9â: 1H, 13C, and 31P NMR
data were identical to the reported data;14a HRMS (ESI-) m/z
calcd for C6H12O9P [M - NH4 - NH3]- 259.0219, found,
259.0213.
2-Benzimidazolyl 2,3,5,6-Tetra-O-acetyl-1-thio-â-D-glu-
cofuranoside (11). Compound 11 was prepared as described
in general procedure A starting from 10 (0.56 g, 1.43 mmol)
under reflux. Chromatographic purification (light petroleum/
EtOAc, 3:2) gave 11 (0.46 g, 67%) as a colorless oil: Rf 0.3
(light petroleum/EtOAc, 1:1); [R]20 -147.0 (c 1.04, CH2Cl2);
D
1H NMR (400 MHz, CD3OD) δ 1.86, 1.95, 1.99, 2.10 (4s, 12H,
CH3CO), 4.09 (dd, 1H, J ) 5.1, 12.5 Hz, H-6a), 4.47 (dd, 1H,
J ) 3.8, 9.1 Hz, H-4), 4.56 (dd, 1H, J ) 2.5, 12.5 Hz, H-6b),
5.26-5.31 (m, 1H, H-5), 5.31 (br s, 1H, H-2), 5.42 (d, 1H, J )
3.8 Hz, H-3), 5.96 (s, 1H, H-1), 7.20-7.23 (m, 2H, H-6′, H-7′),
7.52-7.55 (m, 2H, H-5′, H-8′); 13C NMR (100 MHz, CD3OD) δ
20.5, 20.6, 20.6, 20.8 (CH3CO), 64.2 (C-6), 69.3 (C-5), 75.0
(C-3), 80.9 (C-4), 82.4 (C-2), 90.3 (C-1), 115.6 (C-5′, C-8′), 124.0
(C-6′, C-7′), 140.4 (C-4′, C-9′), 147.4 (C-2′), 170.4, 170.8, 171.3,
172.4 (CdO). Anal. calcd for C21H24N2O9S: C, 52.49; H, 5.03;
N, 5.83; S, 6.67. Found: C, 52.37; H, 5.00; N, 5.67; S, 6.70.
2-Benzimidazolyl 1-Thio-â-D-glucofuranoside (12). Com-
pound 12 was prepared according to the general procedure B
from 11 (410 mg, 0.85 mmol) and isolated as a colorless foam
(266 mg, 100%): Rf 0.1 (CH2Cl2/MeOH, 9:1); [R]20 -226.4 (c
D
1.04, MeOH); 1H NMR (400 MHz, CD3OD) δ 3.65 (dd, 1H, J )
5.6, 11.7 Hz, H-6a), 3.79 (dd, 1H, J ) 3.6, 11.7 Hz, H-6b), 4.06
(ddd, 1H, J ) 3.6, 5.6, 8.0 Hz, H-5), 4.17 (dd, 1H, J ) 3.6, 8.0
Hz, H-4), 4.25 (dd, 1H, J ) 1.1, 3.6 Hz, H-3), 4.37 (br s, 1H,
H-2), 5.75 (d, 1H, J ) 1.3 Hz, H-1), 7.16-7.21 (m, 2H, H-6′,
H-7′), 7.46-7.51 (m, 2H, H-5′, H-8′); 13C NMR (100 MHz,
CD3OD) δ 65.1 (C-6), 71.3 (C-5), 77.2 (C-3), 84.0 (C-2), 84.3
(C-4), 92.3 (C-1), 115.1 (C-5′, C-8′), 123.4 (C-6′, C-7′), 140.5
(C-4′, C-9′), 150.8 (C-2′); HRMS (ESI+) m/z calcd for
C13H16N2NaO5S [M + Na]+ 335.0678, found, 335.0681.
2-Benzimidazolyl 2,3,5,6-Tetra-O-acetyl-1-thio-r-D-man-
nofuranoside (14). Synthesis of 14 was performed according
to the general procedure A from 13 (0.7 g, 1.79 mmol) at room
temperature. Chromatographic purification (light petroleum/
EtOAc, 1:1) gave 14 (0.61 g, 71%) as a white solid: Rf 0.4 (light
petroleum/EtOAc, 1:1); mp 154 °C (CH2Cl2/cyclohexane); [R]20
D
+83.6 (c 1.01, CH2Cl2); 1H NMR (400 MHz, CD3OD) δ 1.95,
1.96, 2.02, 2.07 (4s, 12H, CH3CO), 4.07 (dd, 1H, J ) 5.8, 12.3
Hz, H-6a), 4.49 (dd, 1H, J ) 2.3, 12.3 Hz, H-6b), 4.54 (dd, 1H,
J ) 2.8, 9.2 Hz, H-4), 5.27 (ddd, 1H, J ) 2.3, 5.8, 9.2 Hz, H-5),
5.54-5.58 (m, 2H, H-2, H-3), 5.96 (d, 1H, J ) 6.1 Hz, H-1),
7.22-7.26 (m, 2H, H-6′, H-7′), 7.54 (br s, 2H, H-5′, H-8′); 13C
NMR (100 MHz, CD3OD) δ 20.2, 20.4, 20.5, 20.7 (CH3CO), 63.8
(C-6), 69.1 (C-5), 71.8 (C-3), 76.8 (C-2), 78.7 (C-4), 88.3 (C-1),
124.0 (C-6′, C-7′), 147.0 (C-2′), 171.2, 171.3, 171.8, 172.4
(CdO). Anal. calcd for C21H24N2O9S: C, 52.49; H, 5.03; N, 5.83;
S, 6.67. Found: C, 52.29; H, 4.96; N, 5.67; S, 6.54.
n-Octyl 2,3,5-Tri-O-benzyl-â-D-fucofuranoside (21). To
a solution of 20 (14.95 g, 20.85 mmol) in anhyd diethyl ether
(150 mL) was added portionwise LAH (2.37 g, 62.56 mmol).
After stirring under reflux for 3 h, the mixture was cooled to
0 °C and carefully added to ethyl acetate (50 mL). Ammonium
fluoride (20 g, 539.96 mmol) and then water (150 mL) were
added. The mixture was stirred at room temperature for 10
min, filtered, and the residue washed with diethyl ether (400
mL). After separation, the organic layer was successively
2-Benzimidazolyl 1-Thio-r-D-mannofuranoside (15).
This compound was synthesized according to the general
procedure B starting from 14 (585 mg, 1.22 mmol). After
purification, 15 was obtained as a colorless foam (380 mg) in
J. Org. Chem, Vol. 70, No. 3, 2005 853

Euzen et al.
washed with 5% aq HCl (40 mL), a saturated solution of aq
NaHCO3 (40 mL), and brine (40 mL). The aqueous layers were
extracted with diethyl ether (2 × 40 mL) and the combined
organic layers dried (MgSO4) and concentrated. A flash chro-
matography (light petroleum/EtOAc, 19:1) purification afforded
21 (10.29 g, 90%) as a colorless oil: Rf 0.3 (light petroleum/
EtOAc, 19:1); [R]20D -52.7 (c 1.06, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 0.91 (t, 3H, J ) 7.1 Hz, CH3), 1.27 (d, 3H, J ) 6.4
Hz, H-6), 1.30-1.37 [m, 10H, (CH2)5], 1.59-1.66 (m, 2H,
OCH2CH2), 3.45 (dt, 1H, J ) 6.6, 9.6 Hz, OCH2CH2), 3.69-
3.76 (m, 2H, OCH2CH2, H-5), 3.99-4.05 (m, 3H, H-2, H-3, H-4),
4.40-4.68 (m, 6H, OCH2C6H5), 5.09 (s, 1H, H-1), 7.25-7.39
(m, 15H, C6H5); 13C NMR (100 MHz, CDCl3) δ 14.2 (CH3),
16.1 (C-6), 22.8, 26.3, 29.4, 29.5, 29.6, 31.9 [(CH2)6], 67.7
(OCH2CH2), 71.3, 71.9, 72.1 (OCH2C6H5), 73.3 (C-5), 83.3
(C-3), 83.7 (C-4), 88.7 (C-2), 105.8 (C-1), 127.6, 127.8, 127.9,
128.0, 128.3, 128.4, 128.5 (C6H5), 137.8, 138.0, 138.7 (Cipso
C6H5). Anal. calcd for C35H46O5: C, 76.89; H, 8.48. Found: C,
76.50; H, 8.44.
purified by flash chromatography (light petroleum/EtOAc, 3:2)
to give an anomeric mixture (R/â, 1:4.3) of 24 (0.55 g, 94%) as
a colorless oil: Rf 0.3 (light petroleum/EtOAc, 3:2). 24R: 1H
NMR (400 MHz, CDCl3) δ 1.21 (d, 3H, J ) 6.4 Hz, H-6), 2.07,
2.08, 2.09, 2.12 (4s, 12H, CH3CO), 3.97 (t, 1H, J ) 6.6 Hz,
H-4), 5.07-5.12 (m, 1H, H-5), 5.30 (dd, 1H, J ) 4.6, 6.6 Hz,
H-2), 5.50 (t, 1H, J ) 6.6 Hz, H-3), 6.30 (d, 1H, J ) 4.6 Hz,
H-1); 13C NMR (100 MHz, CDCl3) δ 15.8 (C-6), 20.6, 20.8, 20.8,
21.2 (CH3CO), 69.9 (C-5), 73.7 (C-3), 75.6 (C-2), 82.3 (C-4), 93.2
(C-1), 169.5, 170.0, 170.0, 170.2 (CdO). 24â: 1H NMR (400
MHz, CDCl3) δ 1.30 (d, 3H, J ) 6.3 Hz, H-6), 2.08, 2.11, 2.12,
2.12 (4s, 12H, CH3CO), 4.21 (dd, 1H, J ) 4.6, 5.1 Hz, H-4),
5.08 (dd, 1H, J ) 1.8, 5.1 Hz, H-3), 5.15 (qd, 1H, J ) 4,6, 6.3
Hz, H-5), 5.17 (dd, 1H, J ) 1.0, 1.8 Hz, H-2), 6.18 (br s, 1H,
H-1); 13C NMR (100 MHz, CDCl3) δ 16.0 (C-6), 20.8, 20.8, 21.1,
21.2 (CH3CO), 68.6 (C-5), 75.6 (C-3), 81.0 (C-2), 84.9 (C-4), 99.2
(C-1), 169.3, 169.5, 169.9, 170.2 (CdO). Anal. calcd for
C14H20O9: C, 50.60; H, 6.07. Found: C, 50.49; H, 6.01.
2-Benzimidazolyl 2,3,5,6-Tetra-O-acetyl-1-thio-â-D-fu-
cofuranoside (25). This compound was synthesized according
to the general procedure A from 24 (177 mg, 0.53 mmol) at
room temperature. Chromatographic purification (light petro-
leum/EtOAc, 1:1) gave the desired product 25 (202 mg, 90%)
n-Octyl â-D-Fucofuranoside (22). Acetic acid (5 mL) and
Pd(OAc)2 (100 mg) were added to a solution of 21 (1.03 g, 1.88
mmol) in ethyl acetate (5 mL). After stirring under hydrogen
(1 atm) at room temperature for 72 h, the mixture was
concentrated under reduced pressure, and traces of acetic acid
were coevaporated with methanol (5 × 20 mL). The crude
product was chromatographed on silica gel (CH2Cl2/MeOH, 9:1)
to afford target 22 (0.52 g, 100%) as a colorless oil: Rf 0.5
as a colorless foam: Rf 0.3 (light petroleum/EtOAc, 1:1); [R]20
D
-128.6 (c 1.02, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.34 (d,
3H, J ) 6.6 Hz, H-6), 2.10, 2.10, 2.14 (3s, 9H, CH3CO), 4.38
(t, 1H, J ) 5.1 Hz, H-4), 5.16 (dd, 1H, J ) 2.0, 5.2 Hz, H-3),
5.21-5.27 (m, 1H, H-5), 5.30 (t, 1H, J ) 2.0 Hz, H-2), 5.97 (d,
1H, J ) 2.3 Hz, H-1), 7.22-7.26 (m, 2H, H-6′, H-7′), 7.40-
7.70 (m, 2H, H-5′, H-8′), 9.94 (br s, 1H, NH); 13C NMR (100
MHz, CDCl3) δ 16.1 (C-6), 20.7, 20.7, 21.2 (CH3CO), 68.6
(C-5), 76.6 (C-3), 81.5 (C-2), 84.4 (C-4), 88.5 (C-1), 110.4,
119.1 (C-5′, C-8′), 123.0 (C-6′, C-7′), 146.1 (C-2′, C-4′, C-9′),
169.9, 169.9, 170.5 (CdO); HRMS (ESI+) m/z calcd for
C19H22N2NaO7S [M + Na]+ 445.1045, found, 445.1045. Anal.
calcd for C19H22N2O7S: C, 54.02; H, 5.25; N, 6.63; S, 7.59.
Found: C, 54.01; H, 5.26; N, 6.67; S, 7.77.
(CH2Cl2/MeOH, 9:1); [R]20 -89.3 (c 1.07, MeOH); 1H NMR
D
(400 MHz, CDCl3 + D2O) δ 0.87 (t, 3H, J ) 6.8 Hz, CH3),
1.24-1.30 [m, 10H, (CH2)5], 1.32 (d, 3H, J ) 6.6 Hz, H-6),
1.52-1.60 (m, 2H, OCH2CH2), 3.43 (dt, 1H, J ) 6.7, 9.6 Hz,
OCH2CH2), 3.72 (dt, 1H, J ) 6.9, 9.6 Hz, OCH2CH2), 3.90 (dd,
1H, J ) 2.0, 2.3 Hz, H-4), 3.92 (br s, 1H, H-3), 3.97 (br s, 1H,
H-2), 4.01 (qd, 1H, J ) 2.0, 6.6 Hz, H-5), 4.99 (s, 1H, H-1);
13C NMR (100 MHz, CDCl3 + D2O) δ 14.2 (CH3), 20.1 (C-6),
22.7, 26.2, 29.3, 29.4, 29.6, 31.9 [(CH2)6], 67.5 (C-5), 67.8
(OCH2CH2), 78.7 (C-3), 78.8 (C-2), 89.9 (C-4), 107.9 (C-1). Anal.
calcd for C14H28O5: C, 60.84; H, 10.21. Found: C, 60.48; H,
10.03.
2-Benzimidazolyl 1-Thio-â-D-fucofuranoside (26). Start-
ing from 25 (302 mg, 0.71 mmol), and according to the gen-
eral procedure B, the target thiofuranoside 26 was obtained
as a colorless foam (196 mg) in 93% yield: Rf 0.5 (CH2Cl2/
MeOH, 4:1); [R]20D -284.0 (c 1.08, MeOH); 1H NMR (400 MHz,
CD3OD) δ 1.24 (d, 3H, J ) 6.4 Hz, H-6), 3.84-3.89 (m, 2H,
H-4, H-5), 3.98 (dd, 1H, J ) 4.0, 6.1 Hz, H-3), 4.14 (t, 1H, J )
4.0 Hz, H-2), 5.77 (d, 1H, J ) 4.0 Hz, H-1), 7.20-7.24 (m, 2H,
H-6′, H-7′), 7.48-7.52 (m, 2H, H-5′, H-8′); 13C NMR (100 MHz,
CD3OD) δ 19.5 (C-6), 68.5 (C-5), 78.8 (C-3), 83.9 (C-2), 88.9
(C-4), 92.1 (C-1), 115.2 (C-5′, C-8′), 123.6 (C-6′, C-7′), 140.5
(C-4′, C-9′), 149.9 (C-2′); HRMS (ESI+) m/z calcd for
C13H16N2NaO4S [M + Na]+ 319.0729, found, 319.0729.
Ammonium D-Glucofuranosyl 1-Phosphate (27). This
compound was prepared as described in general procedure C
starting from donor 12 (59 mg, 0.19 mmol). After stirring for
90 min and workup, an amorphous colorless solid (27 mg)
containing an anomeric mixture of 27 (R/â, 1.9:1; 48%), 28 (3%),
and glucose (1%) was then isolated. 27R: 1H NMR (500 MHz,
D2O) δ 3.66 (dd, 1H, J ) 5.6, 12.0 Hz, H-6a), 3.74 (dd, 1H, J
) 2.8, 12.0 Hz, H-6b), 3.80-3.85 (ddd, 1H, J ) 2.8, 5.6, 8.4
Hz, H-5), 4.10 (dd, 1H, J ) 2.6, 4.1 Hz, H-2), 4.14 (dd, 1H, J
) 4.3, 8.4 Hz, H-4), 4.26 (dd, 1H, J ) 2.6, 4.3 Hz, H-3), 5.65
(dd, 1H, J ) 4.1, 6.4 Hz, H-1); 13C NMR (125 MHz, D2O) δ
62.7 (C-6), 69.5 (C-5), 75.5 (C-3), 77.3 (d, J ) 4.8 Hz, C-2), 78.3
(C-4), 98.0 (d, J ) 3.2 Hz, C-1); 31P NMR (162 MHz, D2O) δ
3.3. 27â: 1H NMR (500 MHz, D2O) δ 3.66 (dd, 1H, J ) 5.6,
12.5 Hz, H-6a), 3.79 (dd, 1H, J ) 2.8, 12.5 Hz, H-6b), 4.02 (ddd,
1H, J ) 2.8, 5.6, 8.4 Hz, H-5), 4.08 (dd, 1H, J ) 4.3, 8.4 Hz,
H-4), 4.17 (d, 1H, J ) 4.3 Hz, H-3), 4.19 (br s, 1H, H-2), 5.39
(d, 1H, J ) 7.1 Hz, H-1); 13C NMR (125 MHz, D2O) δ 63.3
(C-6), 70.0 (C-5), 75.3 (C-3), 80.8 (d, J ) 6.5 Hz, C-2), 81.5
(C-4), 103.3 (d, J ) 4.0 Hz, C-1); 31P NMR (162 MHz, D2O) δ
2.6; HRMS (ESI-) m/z calcd for C6H12O9P [M - NH4 - NH3]-
259.0219, found 259.0215.
n-Octyl 2,3,5-Tri-O-acetyl-â-D-fucofuranoside (23). To
a solution of 22 (0.52 g, 1.88 mmol) in dry pyridine (4.57 mL,
55.45 mmol) was added Ac2O (5.3 mL, 55.45 mmol). After
stirring at room temperature for 21 h, the mixture was
evaporated to dryness under reduced pressure, and the result-
ing oil was then partitioned between ethyl acetate (100 mL)
and 5% aq HCl (20 mL). The organic layer was washed with
a saturated solution of aq NaHCO3 (3 × 20 mL) and water
(20 mL). The aqueous layers were extracted with ethyl acetate
(2 × 20 mL) and the combined organic layers dried (MgSO4)
and concentrated. Purification of the residue by flash chro-
matography on silica gel (light petroleum/EtOAc, 4:1) gave 23
(0.73 g, 96%) as a colorless oil: Rf 0.6 (light petroleum/EtOAc,
3:2); [R]20D -62.4 (c 1.01, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 0.88 (t, 3H, J ) 7.1 Hz, CH3), 1.27-1.29 [m, 10H, (CH2)5],
1.31 (d, 3H, J ) 6.6 Hz, H-6), 1.55-1.63 (m, 2H, OCH2CH2),
2.08, 2.10, 2.10 (3s, 9H, CH3CO), 3.45 (dt, 1H, J ) 6.3, 9.7 Hz,
OCH2CH2), 3.66 (dt, 1H, J ) 6.9, 9.7 Hz, OCH2CH2), 4.07 (dd,
1H, J ) 4.1, 5.9 Hz, H-4), 4.99 (dd, 1H, J ) 1.8, 5.9 Hz, H-3),
5.00 (br s, 1H, H-1), 5.03 (d, 1H, J ) 1.8 Hz, H-2), 5.15 (qd,
1H, J ) 4.1, 6.6 Hz, H-5); 13C NMR (100 MHz, CDCl3) δ 14.2
(CH3), 16.3 (C-6), 20.8, 20.9, 21.2 (CH3CO), 22.7, 26.1, 29.3,
29.4, 29.5, 31.9 [(CH2)6], 67.8 (OCH2CH2), 68.8 (C-5), 77.3
(C-3), 81.9 (C-2), 82.7 (C-4), 105.4 (C-1), 169.9, 170.2, 170.4
(CdO). Anal. calcd for C20H34O8: C, 59.68; H, 8.51. Found: C,
59.64; H, 8.39.
1,2,3,5-Tetra-O-acetyl-D-fucofuranose (24). Tri-O-acety-
lated D-fucofuranoside 23 (0.71 g, 1.76 mmol) was dissolved
in dry dichloromethane (7 mL). Acetic anhydride (670 µL, 7.13
mmol) and concd sulfuric acid (20 µL, 0.38 mmol) were
successively added. After stirring for 24 h at room tempera-
ture, the reaction was quenched by adding few drops of
triethylamine and then concentrated. The residue was finally
854 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Free Hexofuranosyl 1-Phosphates
Ammonium D-Mannofuranosyl 1-Phosphate (29). This
compound was synthesized according to the general procedure
C from 15 (54 mg, 0.17 mmol) after stirring for 15 min. An
anomeric mixture of 29 (R/â, 1.6:1) was then isolated as an
amorphous colorless solid (32 mg, 67%). 29R: 1H NMR (500
MHz, D2O) δ 3.59 (dd, 1H, J ) 5.2, 12.2 Hz, H-6a), 3.66 (dd,
1H, J ) 2.9, 12.2 Hz, H-6b), 3.81 (ddd, 1H, J ) 2.9, 5.2, 8.7
Hz, H-5), 4.03-4.06 (m, 1H, H-4), 4.09 (t, 1H, J ) 4.1 Hz, H-2),
4.29 (t, 1H, J ) 4.1 Hz, H-3), 5.36 (dd, 1H, J ) 3.8, 6.1 Hz,
H-1); 13C NMR (125 MHz, D2O) δ 63.1 (C-6), 69.4 (C-5), 71.2
(C-3), 78.1 (d, J ) 7.2 Hz, C-2), 79.7 (C-4), 102.7 (d, J ) 4.8
Hz, C-1); 31P NMR (162 MHz, D2O) δ 3.0. 29â: 1H NMR (500
MHz, D2O) δ 3.60 (dd, 1H, J ) 5.8, 11.9 Hz, H-6a), 3.74 (dd,
1H, J ) 3.0, 11.9 Hz, H-6b), 3.85 (dd, 1H, J ) 4.1, 8.3 Hz,
H-4), 3.95 (ddd, 1H, J ) 3.0, 5.8, 8.3 Hz, H-5), 4.03-4.06 (m,
1H, H-2), 4.14 (t, 1H, J ) 4.7 Hz, H-3), 5.41 (dd, 1H, J ) 4.8,
6.4 Hz, H-1); 13C NMR (125 MHz, D2O) δ 63.1 (C-6), 70.4
(C-5), 70.5 (C-3), 72.5 (d, J ) 6.4 Hz, C-2), 79.7 (C-4), 96.5 (d,
J ) 4.8 Hz, C-1); 31P NMR (162 MHz, D2O) δ 3.0; HRMS (ESI-)
m/z calcd for C6H12O9P [M - NH4 - NH3]- 259.0219, found
259.0207.
(C-6), 69.2 (C-5), 75.4 (C-3), 77.7 (d, J ) 7.2 Hz, C-2), 85.9 (C-
4), 96.4 (d, J ) 5.6 Hz, C-1); 31P NMR (162 MHz, D2O) δ 3.1.
30â: 1H NMR (500 MHz, D2O) δ 1.16 (d, 3H, J ) 5.8 Hz, H-6),
3.76-3.84 (m, 3H, H-3, H-4, H-5), 4.06 (br s, 1H, H-2), 5.36
(d, 3H, J ) 6.4 Hz, H-1); 13C NMR (125 MHz, D2O) δ 18.3 (C-
6), 68.2 (C-5), 77.6 (C-3), 82.2 (d, J ) 7.2 Hz, C-2), 88.1 (C-4),
102.6 (d, J ) 4.0 Hz, C-1); 31P NMR (162 MHz, D2O) δ 2.5;
HRMS (ESI-) m/z calcd for C6H12O8P [M - NH4 - NH3]-
243.0270, found 243.0274.
Acknowledgment. We are grateful to the French
Ministry of Education, Research, and Technology for a
grant to R.E. We also thank Martine Lefeuvre and Jean-
Paul Gue´gan (ENSCR) and Sourisak Sinbandhit (Cen-
tre Re´gional de Mesures Physiques de l’Ouest, Univer-
sity of Rennes 1, France) for recording NMR spectra and
Serge Pilard (University of Amiens, France) for record-
ing mass spectra. We are finally grateful to Franc¸oise
Chre´tien and Yves Chapleur (University of Nancy) for
helpful discussions.
Ammonium D-Fucofuranosyl 1-Phosphate (30). This
compound was prepared according to the general procedure
C from 26 (50 mg, 0.16 mmol) after stirring for 20 min. An
anomeric mixture of 30 (R/â, 1.5:1) was isolated as an amor-
phous colorless solid (42 mg, 90%). 30R: 1H NMR (500 MHz,
D2O) δ 1.11 (d, 3H, J ) 6.4 Hz, H-6), 3.45-3.49 (m, 1H, H-4),
3.76-3.84 (m, 1H, H-5), 3.95-4.01 (m, 2H, H-2, H-3), 5.39 (dd,
1H, J ) 3.8, 5.1 Hz, H-1); 13C NMR (125 MHz, D2O) δ 17.8
Supporting Information Available: One-dimensional
1
and two-dimensional correlational NMR spectra, H-1H and
1H-13C for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0484934
J. Org. Chem, Vol. 70, No. 3, 2005 855