A convenient synthesis of furanose-free D-fucose per-O-acetates and a precursor for anthrose

Article abstract of DOI:10.1002/ejoc.200701173

Methyl 3,4-O-isopropylidene-α- or β-D-galactopyranoside was iodinated with triiodoimidazole in the presence of triphenylphosphane and the corresponding 6-deoxy-6-iodo derivatives 5 or 6, respectively, were converted to furanose-free 1,2,3,4-tetra-O-acetyl-α,β-D-fucopyranose. A key intermediate for chemical synthesis of anthrose, a constituent of the tetrasaccharide of major glycoprotein of Bacillus anthracis exosporium, 1-O-acetyl-4-azido-2-O-benzoyl-3-O-benzyl-4,6-dideoxy-α, β-D-glucopyranose, was synthesized from 5 or 6 in 7 steps. The latter was readily converted into the corresponding 1-O-trichloroacetimidate. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701173

FULL PAPER
DOI: 10.1002/ejoc.200701173
A Convenient Synthesis of Furanose-Free
D
-Fucose Per-O-Acetates and a
Precursor for Anthrose
[a]
[a]
ˇ
Shujie Hou and Pavol Kovác*
Keywords: Latent anthrose donor / Acetolysis / Carbohydrates / Synthetic methods / Deoxygenation
Methyl 3,4-O-isopropylidene-α- or β-
D
-galactopyranoside
exosporium,
4,6-dideoxy-α,β-D
6 in 7 steps. The latter was readily converted into the corre-
sponding 1-O-trichloroacetimidate.
1-O-acetyl-4-azido-2-O-benzoyl-3-O-benzyl-
-glucopyranose, was synthesized from 5 or
was iodinated with triiodoimidazole in the presence of tri-
phenylphosphane and the corresponding 6-deoxy-6-iodo de-
rivatives 5 or 6, respectively, were converted to furanose-free
1,2,3,4-tetra-O-acetyl-α,β-D-fucopyranose. A key intermedi-
ate for chemical synthesis of anthrose, a constituent of the
tetrasaccharide of major glycoprotein of Bacillus anthracis
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Both - and -fucose occur in nature[1] but, commer-
cially, the -enantiomer is much more expensive than its -
counterpart. Several syntheses of -fucose have been de-
scribed, all based on deoxygenation at the 6-position of
various derivatives of -galactose. The most convenient
syntheses of -fucose are that of Schmidt[2] and its more
recent variation by Lerner,[3] which are based on further
conversion of the product of deoxygenation at C-6 in
1,2:3,4-di-O-isopropylidene-α--galactopyranose.
Figure 1. Structure of anthrose.
Results and Discussion
In their very carefully executed work, Leaback et al.[15]
showed convincingly that the product of acetylation of fu-
cose with the pyridine/Ac2O reagent contains furanoses,
even when the reaction is conducted at 0 °C. Their results
are in full agreement with our own findings.[4] Furannose
structures are also present among poducts of acetylation
of fucose with NaOAc/Ac2O reagent[4] or acetylation under
acidic conditions.[15] Clearly, recent claims in the literature
that acetylation of fucose with the Ac2O/pyridine reagent
afforded quantitative[7] or 98% yield of furanose-free mix-
tures of per-O-acetates,[8] or only the β-anomer (94%)[16]
are unrealistic. Similarly, the possibility of formation of fu-
ranosides during acid-catalyzed alcoholysis of 1,2:3,4-di-O-
isopropylidene-α--fucopyranose is often ignored, and the
proof of absence of furanosides in the product of such reac-
tion is not provided (for example ref.[17]). Crystalline
1,2,3,4-tetra-O-acetyl-α--fucopyranose has been iso-
lated[3,5] in up to 75% yield from products of acetolysis of
its most readily available synthetic intermediate, 6-deoxy-
1,2:3,4-di-O-isopropylidene-α--galactopyranose.[3,5,18]
Pure 1,2,3,4-tetra-O-acetyl-β--fucopyranose has not been
described previously. Essential to obtaining the title com-
pounds conveniently and in high yield is ready access to a
fucose derivative from which furanose structures can not be
formed under acetolysis conditions. Such intermediates are,
Per-O-acetates of - and -fucopyranose are essential
starting materials for making a variety of complex carbo-
hydrate derivatives. Unfortunately, acetylation of fucose,
either with NaOAc/Ac2O[4] or pyridine/Ac2O reagent[3,5] af-
fords a mixture of pyranose and furanose acetates. When
such mixtures are used as a starting material (e.g. ref.[6–8]
)
purification of products of further conversion may be diffi-
cult.
Anthrose [= 4,6-dideoxy-4-(3-hydroxy-3-methylbutyram-
ido)-2-methyl--glucopyranose, see Figure 1], is the up-
stream terminal moiety of the tetrasaccharide side chain of
the major glycoprotein of Bacillus anthracis exosporium.[9]
The original synthesis[10] of the rare sugar and a glycosyl
donor[11] for its precursor started with methyl α--mannop-
yranoside. Shorter syntheses of anthrose precursors have
been published.[7,12] More recently, Crich et al.[13] and
Doherty et al.[14] synthesized other anthrose precursors.
Here we describe convenient preparation of furanose free
1,2,3,4-tetra-O-α,β--fucopyranose and a glycosyl donor
for an anthrose precursor from the commercially available
methyl α- or β--galactopyranoside.
[a] National Institutes of Health, LBC,
8 Center Drive, Bethesda, MD 20892
E-mail: houshu@niddk.nih.gov
kpn@helix.nih.gov
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1947

S. Hou, P. Kovácˇ
FULL PAPER
for example, methyl 2,3,4-tri-O-acetyl-α-[19,20] or β--fuco- virtually theoretical yield. All products in the sequence de-
pyranoside.[21,22] We can now generate these compounds scribed were fully characterized. Conversion of each of 7
very efficiently, which makes the title acetates readily avail- and 8 to the title acetates 9 and 10, namely hydrolysis of the
able.
O-isopropylidene group and acetylation/acetolysis, could be
Rather than making 1,2:3,4-di-O-isopropylidene-α--gal- performed as a one-pot transformation. The isopropylidene
actopyranose the starting point of our approach, we used group in 7 or 8 was first removed by AcOH-catalyzed hy-
the commercially available methyl α- (1) or β--galactopyr- drolysis, followed by H2SO4-catalyzed acetylation. The
anoside (2). (Scheme 1). Glycosides 1 and 2 were first con- amount of H2SO4 was kept low during the latter transfor-
verted[23] to the corresponding 3,4-O-isopropylidene deriva- mation, to avoid acetolysis of the glycoside before the acety-
tives 3 and 4, respectively. Subsequent deoxygenation at C- lation would be complete, lest acetolysis of HO-4-free com-
6 was effected by iodination, which was previously per- pound might lead to formation of furanose structures. The
formed by many investigators. Methyl 6-deoxy-6-iodo-3,4- acetolysis was then effected by increasing the concentration
O-isopropylidene-α--galactopyranoside (6) was first ob- of H2SO4. The TLC and NMR spectra of the mixture of 9
tained by Schmidt and Wernicke[24] who treated methyl and 10 did not reveal presence of furanoses. Thus, the crude
3,4-O-isopropylidene-6-O-tosyl-α--galactopyranoside with product of acetolysis performed in this way can be used for
NaI. According to the more recent reports,[25–27] direct io- further conversions when the absence of furanose structures
dination of diol 4 or its β-anomer 3 with iodine in the pres- is important but anomeric purity of the starting material is
ence of imidazole gave the corresponding 6-iodo derivatives not. The two anomeric acetates could, however, be sepa-
in yields up to 73%.[27] When we effected that conversion rated by chromatography, which allowed isolation and full
at optimized conditions we found it a one-product reaction, characterization of the hitherto unknown β-acetate 9. The
and obtained the desired 6-iodo derivatives 5 and 6 in 78 original mode of preparation and more negative value of
and 95% yield, respectively. The minimal losses encoun- [α]D found for 9, as compared to that reported,[5] indicates
tered during work-up and isolation were manipulative. Sub- that the material described previously contained some α an-
sequent hydrogenolysis gave fucose derivatives 7 and 8 in omer.
Scheme 1. Reagents and conditions: a. TPP, imidazole, I2, toluene, 110 °C; b. Pd/C, MeOH, H2; c. (1) 80% HOAc, 70 °C; (2) Ac2O,
Ac2O/HOAc/H2SO4; d. BzCl, pyridine; e. TFA, CH2Cl2; f. Bu2SnO, Bu4NI, BnBr, toluene; g. (1) MsCl, pyridine/CH2Cl2. (2). NaN3, 15-
crown-5 ether, DMF; h. Ac2O/HOAc/H2SO4; i. (1) hydrazine acetate, DMF. (2) DBU, CCl3CN, CH2Cl2.
1948
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1947–1952

-Fucose Per-O-Acetates and a Precursor for Anthrose
sumed. A solution of NaHCO3 (32 g) in H2O (100 mL) was added
slowly with stirring, followed by a small amount of iodine until
persistent color developed. 10% aqueous sodium thiosulfate was
added dropwise and, when the mixture became colorless, the mix-
ture was diluted with EtOAc, washed with brine, dried, concen-
trated and chromatography (hexane/EtOAc, 3:1) gave 5 (24.8 g,
78%). M.p. 117–118 °C (from EtOAc; ref.[25] 122 °C). [α]D = +22
[c = 0.9, CHCl3; ref.[25] [α]D = +31 (c = 1.1, CHCl3)]. 1H NMR
(600 MHz, CDCl3): δ = 4.31 (dd, J3,4 = 5.4, J4,5 = 2.2 Hz, 1 H, 4-
H), 2.56–2.45 (m, J1,2 = 8.3, J2,3 = 7.3, J3,4 = 5.4 Hz, 2 H, 1-H, 3-
The tetrasaccharide side chain of the major glycoprotein
of Bacillus anthracis exosporium is an important biomarker
for detection of Bacillus anthracis spores[28] and, possibly, a
key antigenic component of a future conjugate vaccine for
anthrax.[7,11,12] A prerequisite for making life science tools
involving the synthetic tetrasaccharide is ready access to
anthrose, whose synthesis often starts from fucose perace-
tate. With the intermediate 7 or 8 in hand, we used each of
them separately to prepare the same glycosyl donor for the
latent anthrose, the glycosyl imidate 20. Benzoylation at H), 3.92 (m, 1 H, 5-H), 3.58 (s, 3 H, OCH3), 3.54 (m, 1 H, 2-H),
3.45–3.40 (m, 2 H, 6-H), 2.47 (br. s, 1 H, 2-OH), 1.51 and 1.36 (2
s, each 3 H, 2 CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 110.2
(Cq), 103.1 (C-1), 78.6 (C-3), 73.8 (C-4), 73.7 (C-5), 73.4 (C-2),
57.0 (OCH3), 28.0 (CH3), 26.2 (CH3), 1.6 (C-6) ppm. C10H17IO5
(344.14): calcd. C 34.90, H 4.98; found C 35.09, H 5.02.
O-2 followed by selective hydrolysis, to remove the 3,4-O-
isopropylidene group, afforded the 2-O-benzoyl--fuco-
pyranosides 13 or 14. Selective 3-O-benzylation via stan-
nylation (Ǟ15/16) was followed by mesylation (Ǟ17/18),
and treatment of the mesyl derivatives thus formed with
NaN3 furnished glycosides 17 or 18, which were acetolyzed
(Ǟ19). The ratio of anomeric acetates (α/β = 5–6:1) in 19
was independent of the configuration of the starting glyco-
side. Acetates 19 were converted into the anomerically pure
(TLC, NMR) α-trichloroacetimidate 20 by successive treat-
ment with hydrazine acetate and CCl3CN.
Methyl 6-Deoxy-6-iodo-3,4-isopropylidene-α-D-galactopyranoside
(6): Treatment of methyl 3,4-isopropylidene-α--galactopyranoside
(4)[23] as described for 3 gave 6 (95%). M.p. 87–88 °C (from EtOH;
ref.[27] 84–86 °C). [α]D = +113 [c = 1.0, CHCl3; ref.[27] [α]D = +118
1
(c = 1.0, CHCl3)]. H NMR (600 MHz, CDCl3): δ = 4.77 (d, J1,2
= 4.0 Hz, 1 H, 1-H), 4.32 (dd, J3.4 = 2.2, J4,5 = 6.3 Hz, 1 H, 4-H),
4.29 (t, J = 5.9 Hz, 1 H, 3-H), 4.13 (m, 1 H, 5-H), 3.86 (m, J1,2
=
4.1 Hz, 1 H, 2-H), 3.51 (s, 3 H, OCH3), 3.35–3.29 (m, 2 H, 6-H),
2.52 (d, J = 5.4 Hz, 1 H, 2-OH), 1.49 (s, 3 H, CH3), 1.35 (s, 3 H,
CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 109.7 (Cq), 98.2 (C-
1), 75.7 (C-3), 73.4 (C-4), 69.3 (C-5), 68.5 (C-2), 55.5 (OCH3), 27.3
(CH3), 25.6 (CH3), 2.76 (C-6) ppm. C10H17IO5 (344.14): calcd. C
34.90, H 4.98; found C 34.79, H 4.96.
Experimental Section
General Methods: Optical rotations were measured at ambient tem-
perature with a Perkin–Elmer automatic polarimer, Model 341. All
reactions were monitored by thin-layer chromatography (TLC) on
silica gel 60 or C18 RP silica-gel-coated glass slides. Column
chromatography was performed by elution from columns of silica
gel with CombiFlash Companion Chromatograph (Isco Inc.). Sol-
vent mixture less polar than those used for TLC were used at the
onset of separation. NMR spectra were measured at 300 MHz (1H)
and 75 MHz (13C) with a Varian Gemini or Varian Mercury spec-
trometers, or at 600 MHz (1H) and 150 MHz (13C) with a Bruker
Avance 600 spectrometer. Assignments of NMR signals were made
by homonuclear and heteronuclear 2-dimensional correlation spec-
troscopy, run with the software supplied with the spectrometers.
Liquid Chromatography-Electron Spray-Ionization Mass Spec-
trometry (ESI-MS) was performed with a Hewlett–Packard 1100
MSD spectrometer. Attempts have been made to obtain correct
combustion analysis data for all new compounds. However, some
compounds tenaciously retained traces of solvents, despite exhaus-
tive drying, and analytical %C values could not be obtained within
Ϯ0.4%. Structures of these compounds follow unequivocally from
the mode of synthesis and NMR and MS data. Solutions in organic
solvents were dried with anhydrous Na2SO4, and concentrated at
40 °C/2 kPa.
Methyl 3,4-Isopropylidene-β-D-fucopyranoside (7): Hydrogenolysis
of 5 (6.5 g, 18.8 mmol) over Pd/C (1.3 g), in the presence of Et3N
(4.0 g, 37.7 mmol) using methanol (55 mL) as solvent gave, after
chromatography, 7 (3.9 g, 95%). M.p. 67–69 °C (from EtOAc).
1
[α]D = +22.9 (c = 1.1, CHCl3). H NMR (600 MHz, CDCl3): δ =
4.05 (d, J1,2 = 8.2 Hz, 1 H, 1-H), 4.04 (dd, J2,3 = 7.3, J3,4 = 5.5 Hz,
1 H, 3-H), 4.00 (dd, J4,5 = 2.2, J3,4 = 5.5 Hz, 1 H, 4-H), 3.86 (m,
1 H, 5-H), 3.55–3.50 (m, 4 H, OCH3 and 2-H), 2.52 (d, J = 2.2 Hz,
1 H, 2-OH), 1.53 and 1.35 (2 s, each 3 H, 2 CH3), 1.42 (d, J5,6
=
6.6 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 109.8
(Cq), 103.1 (C-1), 78.7 (C-3), 76.2 (C-4), 73.6 (C-2), 69.1 (C-5),
56.8 (OCH3), 23.1 and 26.6 (2 CH3), 16.4 (C-6). C10H18O5 (231.6)
+0.75H2O: calcd. C 51.82, H 8.48; found C 51.67, H 8.48.
Methyl 3,4-Isopropylidene-α-D-fucopyranoside (8): Treatment of 6
1
as described for 5 gave amorphous 8 (94%). H NMR (600 MHz,
CDCl3): δ = 4.71 (d, J1,2 = 3.9 Hz, 1 H, 1-H), 4.19 (t, J = 6.7 Hz,
1 H, 3-H), 4.12–4.08 (m, 1 H, 5-H), 4.05 (dd, J3,4 = 2.4, J4,5
=
6.0 Hz, 1 H, 4-H), 3.78 (br. s, 1 H, 2-H), 3.43 (s, 3 H, OCH3), 2.63
(br. s, 1 H, 2-OH), 1.51 and 1.35 (2 s, each 3 H, 2 CH3), 1.32 (d,
J5,6 = 6.7 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ =
109.0 (Cq), 98.6 (C-1), 76.1 (C-3), 75.6 (C-4), 69.4 (C-2), 63.5 (C-
5), 55.3 (OCH3), 27.7 (CH3), 25.8 (CH3), 16.1 (C-6) ppm. ES-TOF-
MS (pos. ion.): m/z = 266.1 [M + Li+CH3CN]+. The compound
was fully characterized as the corresponding 2-O-benzoyl derivative
12, described below.
Methyl 3,4-Isopropylidene-β-D-galactopyranoside (3) and Methyl
3,4-Isopropylidene-α-D-galactopyranoside (4): These compounds
were prepared as described[23] 3: M.p. 137–138 °C (from EtOAc;
ref.[11] 134–135 °C). 4: M.p. 104–105 °C (from EtOAc; ref.[12] 103–
104 °C).
Methyl 6-Deoxy-6-iodo-3,4-isopropylidene-β-D-galactopyranoside
(5): The solvent (ca. 100 mL) was distilled off at atmospheric pres-
sure from a solution of methyl 3,4-isopropylidene-β--galactopyr-
anoside (3)[23] (21.8 g, 93.2 mmol) in toluene (300 mL). The solu-
tion was cooled to ca. 60–70 °C, then TPP (35.1 g, 134 mmol),
imidazole (20.7 g, 304 mmol), and iodine (31.2 g, 123 mmol) were
quickly added. The mixture was stirred at 110° for 1.5 h, when TLC
1,2,3,4-Tetra-O-acetyl-α-D-fucopyranoside (10) and 1,2,3,4-Tetra-O-
acetyl-β-D-fucopyranoside (9): A solution of 7 (700 mg, 3.2 mmol)
in 80% aqueous HOAc (5 mL) was stirred at 70 °C for 1.5 h, when
TLC (1:1 hexane/acetone) showed that the starting material was
consumed and that one slower moving product was formed. The
mixture was cooled to room temperature and the solvent was evap-
orated. The residue was dissolved in acetic anhydride (10 mL),
(1:1 hexane/EtOAc) showed that the starting material was con- Ac2O/HOAc/H2SO4 (10:4:0.1, 0.1 mL) was added, and the mixture
Eur. J. Org. Chem. 2008, 1947–1952
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1949

S. Hou, P. Kovácˇ
FULL PAPER
was stirred at ambient temperature for 1 h, when TLC (3:2 hexane/
(0.7 mL) at room temperature for 1 h. The mixture was concen-
acetone) indicated that the desired 2,3,4-tri-O-acetyl derivative was trated, and the residue was chromatographed (10:1 CH2Cl2/ace-
formed. The reaction was cooled to 0 °C, a mixture of Ac2O/
HOAc/H2SO4 (10:4:0.1, 1.0 mL) was added with stirring, the cool-
ing was removed, and the mixture was stirred for 45 min, when
TLC (RP, 1:1 acetone/water) showed that two slightly slower mov-
ing products were formed. NaOAc trihydrate (10 mg) was added,
to neutralize H2SO4, the mixture was concentrated, and the residue
was partitioned between EtOAc and a mixture of aqueous
NaHCO3 and brine. Concentration of organic phase gave a mixture
of title acetates. Chromatography (9:1 hexane/acetone) gave first 10
tone:) to give the title compound 13 (178 mg, 97%). M.p. 140–
142 °C (from EtOH). [α]D = –13.8 (c = 1.1, CHCl3). 1H NMR
(600 MHz, CDCl3): δ = 8.02–7.40 (m, 5 H, aromatic H), 5.17 (dd,
J1,2 = 8.0, J2,3 = 9.2 Hz, 1 H, 2-H), 4.16 (d, J1,2 = 7.9 Hz, 1 H, 1-
H), 3.80–3.77 (m, 2 H, 3-H and 4-H), 3.67 (dd, J5,6 = 6.6 Hz, 1 H,
H-5), 3.58 (d, J = 7.5 Hz, 1 H, OH), 3.48 (s, 3 H, OCH3), 3.12 (d,
J = 6.7 Hz, 1 H, OH), 1.37 (d, J5,6 = 6.6 Hz, 3 H, H-6) ppm. 13C
NMR (150 MHz, CDCl3): δ = 166.9 (CO), 133.1, 129.8, 129.7,
128.2, 101.7 (C-1), 73.7 (C-2), 73.0 (C-4), 71.8 (C-3), 70.5 (C-5),
56.6 (OCH3), 16.1 (C-6) ppm. C14H18O6 (282.29): calcd. C 59.57,
(850 mg, 80%). M.p. 93–94 °C (from EtOAc) (ref.[5] 93 °C), [α]D
=
+120 (c = 1.1, CHCl3); [ref.[5] [α]D = +122 (c = 1, CHCl3)]. 1H H 6.43; found C 59.38, H 6.58.
NMR (600 MHz, CDCl3): δ = 6.33 (d, J1,2 = 3.3 Hz, 1 H, 1-H),
Methyl 2-O-Benzoyl-α-D-fucopyranoside (14): Treatment of 12 as
5.36–5.30 (m, 3 H, 2-H, 3-H and 4-H), 4.29–4.28 (m, 1 H, 5-H),
2.18, 2.15, 2.02, 2.00 (4 s, each 3 H, 4 COCH3), 1.16 (d, J5,6
described for 11 gave 14 (95%). M.p. 168–170 °C (from EtOH).
[α]D = +156 (c = 1.1, CHCl3). 1H NMR (600 MHz, CDCl3): δ =
5.20 (dd, J1,2 = 3.9, J2,3 = 10.2 Hz, 1 H, 2-H), 4.98 (d, J1,2 = 3.9 Hz,
1 H, 1-H), 4.16 (dd, J2,3 = 10.2, J3,4 = 3.2 Hz, 1 H, 3-H), 4.06–4.04
(m, 1 H, 5-H), 3.87 (d, J = 2.7 Hz,1 H, 4-H), 3.39 (s, 3 H, OCH3),
1.34 (d, J5.6 = 6.6 Hz, 3H, 6-H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 167.0, 133.3, 129.9, 129.5, 128.3, 97.4 (C-1), 72.3 (2
=
6.5 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.3,
169.9, 169.7, 168.9, 89.7 (C-1), 70.3, 67.6, 67.0 (C-5), 66.3, 20.7,
20.4 (2 C), 20.3, 15.7 (C-6) ppm. C14H20O9 (332.30): calcd. C 50.60,
H 6.07; found C 50.93, H 6.37.
Eluted next was the amorphous compound 9 (143 mg, 13%). [α]2D5
= +32 [c = 2.1, CHCl3; ref.[5] +47 (c = 2.1, CHCl3)]. 1H NMR C, C-2, C-4), 68.8 (C-3). 65.2 (C-5), 55.4 (OCH3), 16.0 (C-6) ppm.
(600 MHz, CDCl3): δ = 5.68 (d, J1,2 = 8.4 Hz, 1 H, 1-H), 5.32 (t,
ES-TOF-MS (pos. ion.): m/z = 420.1 [M + Li + AcN]+, 379.1 [M
J = 9.8 Hz, 1 H, 2-H), 5.27 (d, J3,4 = 3.4 Hz, 1 H, 4-H), 5.08 (dd, + Li]+. C14H18O6 (282.29): calcd. C 59.57, H 6.43; found C 59.86,
J2,3 = 10.4, J3,4 = 3.5 Hz, 1 H, 4-H), 3.97 (q, J = 6.4, J = 12.9 Hz,
1 H, 5-H), 2.19, 2.12, 2.04, 2.00 (4 s, each 3 H, COCH3), 1.22 (d,
J5,6 = 6.4 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ =
170.5, 170.0, 169.4, 169.1, 92.0 (C-1), 71.8 (C-3), 70.1 (C-5), 69.8
(C-4), 67.8 (C-2), 20.8, 20.6 (2 C), 20.5, 15.8 (C-6) ppm. C14H20O9
(332.30): calcd. C 50.60, H 6.07; found C 50.76, H 6.24.
H 6.62.
Methyl 2-O-Benzoyl-3-O-benzyl-β-D-fucopyranoside (15): The sol-
vent (40 mL) was removed from a mixture of 13 (3.1 g, 11 mmol)
and Bu2SnO (2.72 g, 11 mmol) in toluene (80 mL) which had been
heated under reflux for 1 h. After cooling to 60 °C, Bu4NI (811 mg,
2.19 mmol) and BnBr (1.7 mL, 14.3 mmol) was added, and the
mixture was stirred at 110 °C for 3.5 h. After concentration, the
residue was chromatographed (hexane/acetone, 9:1 ) to give the
amorphous compound 15 (3.1 g, 74%). [α]D = +48 (c = 1.0,
CHCl3). 1H NMR (600 MHz, CDCl3): δ = 8.03–7.14 (m, 10 H,
aromatic H), 5.43 (dd, J1,2 = 8.8, J2,3 = 9.8 Hz, 1 H, 2-H), 4.68–
4.51 (ABq, J = 12.3 Hz, 2 H, ArCH2), 4.39 (d, J1,2 = 8.0 Hz, 1 H,
Methyl 2-O-Benzoyl-3,4-isopropylidene-β-D-fucopyranoside (11):
Benzoyl chloride (0.3 mL, 2.19 mmol) was added to a solution of
7 (320 mg, 1.46 mmol) in pyridine (4 mL), and the reaction was
quenched after 1 h by addition of MeOH (2 mL). The mixture was
concentrated, the residue was partitioned between EtOAc and
brine, dried, and concentrated. Chromatography (5:1 hexane/
EtOAc) gave 11 (440 mg, 94%). M.p. 105–107 °C (from EtOH).
[α]D = +56 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
8.18–7.50 (m, 5 H, aromatic H), 5.22 (t, J = 8.0 Hz, 1 H, 2-H),
4.37 (d, J1,2 = 8.0 Hz, 1 H, 1-H), 4.31 (dd, J2,3 = 7.4, J3,4 = 5.5 Hz,
1 H, 3-H), 4.08 (dd, J3,4 = 5.5, J4,5 = 2.2 Hz, 1 H, 4-H), 3.94 (m,
1 H, 5-H), 3.46 (s, 3 H, OCH3), 1.62 and 1.35 (2 s, each 3 H, 2
CH3), 1.46 (d, J5,6 = 6.6 Hz, 3 H, H-6) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.67 (CO), 133.1, 130.2, 130.0, 128.4, 110.4 (Cq),
101.5 (C-1), 77.48 (C-3), 76.7 (C-4), 73.8 (C-2), 69.2 (C-5), 56.7
(OCH3), 28.0, 26.5 (2 CH3), 16.7 (C-6) ppm. C17H22O6 (322.35):
calcd. C 63.34, H 6.88; found C 63.37, H 6.88.
1-H), 3.88 (dd, J2,4 = 3.4, J4,5 = 1.1 Hz, 1 H, 4-H), 3.64 (dd, J2,3
=
9.7, J3.4 = 3.4 Hz, 1 H, 3-H), 3.62–3.61 (m, 1 H, 5-H), 3.45 (s, 3
H, OCH3), 1.42 (d, J5,6 = 2.5 Hz, 3 H, H-6) ppm. 13C NMR
(150 MHz, CDCl3): δ = 165.3 (CO), 137.0, 132.9, 129.9, 129.7,
128.2, 127.8, 127.7, 101.7 (C-1), 78.4 (C-3), 71.1 (ArCH2), 70.9 (C-
2), 70.2 (C-5), 68.6 (C-4), 56.3 (OCH3), 16.2 (C-6) ppm. ES-TOF-
MS (pos. ion.): m/z = 395.1471 ([M + Na]+; calcd. 395.1476).
C21H24O6 (372.41): calcd. C 67.73, H 6.50; found C 67.78, H 6.70.
Methyl 2-O-Benzoyl-3-O-benzyl-α-D-fucopyranoside (16): Treat-
ment of 14, as described for 13, gave amorphous 16 (83%). [α]D
=
+155 (c = 1.1, CHCl3). 1H NMR (600 MHz, CDCl3): δ = 5.38 (dd,
J1,2 = 3.8, J2,3 = 10.2 Hz, 1 H, 2-H), 5.01 (d, J1,2 = 3.8 Hz, 1 H, 1-
H), 4.69 (ABq, J = 12 Hz, 2 H, ArCH2), 4.03 (dd, J3,4 = 3.3, J2,3
= 10.1 Hz, 1 H, 3-H), 3.98–3.94 (m, 1 H, 5-H), 3.92 (dd, J3,4 = 3.3,
J4,5 = 1.2 Hz, 1 H, 4-H), 3.35 (s, 3 H, OCH3), 1.34 (d, J5,6 = 6.6 Hz,
Methyl 2-O-Benzoyl-3,4-isopropylidene-α-D-fucopyranoside (12):
Compound 12 was synthesized (97%) as described for the β an-
omer. M.p. 60–62 °C (from EtOH). [α]D = +184 (c = 1.1, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 5.13 (dd, J1,2 = 3.5, J2,3 = 8.2 Hz,
1 H, 2-H), 4.92 (d, J1,2 = 3.5 Hz, 1 H, 1-H), 4.48 (dd, J2,3 = 8.2, 3 H, H-6) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.0, 137.6,
J3,4 = 5.2 Hz, 1 H, 3-H), 4.17–4.13 (m, 2 H, 4-H and 5-H), 3.37 (s, 133.1, 129.9, 129.8, 128.4, 127.9, 127.7, 97.4 (C-1), 75.4 (C-3), 72.0
3H, OCH3), 1.56 (s, 3 H, CH3), 1.42 (d, J5,6 = 6.3 Hz, 3 H, 6-H),
1.36 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.0
(CO), 133.3, 130.1, 129.9, 128.5, 109.6 (Cq), 97.5 (C-1), 76.4 (C-4),
73.7 (C-3), 72.7 (C-2), 63.2 (C-5), 55.7 (OCH3), 28.2 (CH3), 26.6
(CH3), 16.1 (C-6) ppm. ES-TOF-MS (pos. ion.): m/z = 370.1 [M +
Li + AcN]+. C17H22O6 (322.35): calcd. C 63.34, H 6.88; found C
63.60, H 6.86.
(ArCH2), 70.6 (C-2), 69.8 (C-4), 65.1 (C-5), 55.3 (OCH3), 16.1 (C-
6). ES-TOF-MS (pos. ion.): m/z = 395.1[M + Na]+. C21H24O6
(372.41): calcd. C 67.73, H 6.50; found C 67.86, H 6.61.
Methyl
4-Azido-2-O-benzoyl-3-O-benzyl-4,6-dideoxy-β-D-gluco-
pyranoside (17): MsCl (4.2 mL, 50 mmol) was added at 0 °C to a
stirred solution of 15 (3.0 g, 8.0 mmol) in CH2Cl2 (15 mL) and pyr-
idine (5 mL). The cooling was removed, and the mixture was stirred
overnight. Aqueous NaHCO3 was added slowly, and when efferves-
cence ceased, the mixture was diluted with CH2Cl2, washed with
Methyl 2-O-Benzoyl-β-D-fucopyranoside (13): A solution of 11
(210 mg, 0.65 mmol) in CH2Cl2 (5 mL) was treated with TFA
1950
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Eur. J. Org. Chem. 2008, 1947–1952

-Fucose Per-O-Acetates and a Precursor for Anthrose
brine, the organic phase was dried, concentrated, and chromatog-
raphy (hexane/EtOAc, 4:1) gave methyl 2-O-benzoyl-3-O-benzyl-4-
O-mesyl-β--fucopyranoside (3.5 g, 97%). 1H NMR (600 MHz,
CDCl3): δ = 5.41 (dd, J1,2 = 7.9, J2,3 = 10.2 Hz, 1 H, 2-H), 5.05 (dd,
J3,4 = 3.1, J4,5 = 0.6 Hz, 1 H, 4-H), 4.74–4.50 (ABq, J = 11.7 Hz, 2
H, ArCH2), 3.78 (m, 1 H, 5-H), 3.74 (dd, J2,3 = 10.2, J3,4 = 3.1 Hz,
1 H, 4-H), 2.12 (s, 3 H, COCH3), 1.34 (d, J5,6 = 6.3 Hz, 3 H, 6-H)
ppm. 13C NMR (300 MHz, CDCl3): δ = 168.8, 137.1, 133.4, 130.0,
129.6, 129.1, 128.5, 128.3, 128.0,127.5, 89.5 (C-1), 78.0 (C-3), 75.4
(ArCH2), 72.3 (C-2), 68.2 (C-4), 67.4 (C-5), 59.8 (OCH3), 18.4
(C-6) ppm. ES-TOF-MS (pos. ion.): m/z = 473.2027 ([M + Li +
CAN]+ calcd. 473.2012). C22H23N3O6 (425.43): calcd. C 62.11, H
5.45; found C 61.95, H 5.47.
1 H, 3-H), 3.47 (s, 3 H, OCH3), 3.12 (s, 3 H, OMs), 1.45 (d, J5,6
=
6.6 Hz, 3 H, 6-H). ppm. 13C NMR (150 MHz, CDCl3): δ = 165.2
(CO), 136.4, 133.1, 129.7, 129.6, 128.3 (3 C), 128.0 (2 C), 101.7 (C-
1), 80.2 (C-4), 77.0 (C-3), 72.1 (ArCH2), 70.2 (C-2), 69.1 (C-5), 56.6
(OCH3), 39.1 (OMs), 16.6 (C-6) ppm.
4-Azido-2-O-benzoyl-3-O-benzyl-4,6-dideoxy-α-D-glucopyranose 1-
O-Trichloroacetimidate (20): Hydrazine acetate (44 mg, 0.48 mmol)
was added to a stirred solution of 19 (170 mg, 0.40 mmol) in DMF
(2 mL). After 2 h, the mixture was diluted with CH2Cl2 (35 mL)
and washed with brine. The organic phase was dried and concen-
trated. DBU (0.03 mL, 0.2 mmol) and CCl3CN (0.4 mL, 4 mmol)
was added at 0 °C to a solution of the above, crude product in
dried CH2Cl2 (2 mL), and the mixture was stirred for 2.5 h, when
TLC (4:1 hexane/EtOAc) showed that the conversion was complete.
Concentration and chromatography (8:1 hexane/EtOAc with 1%
Et3N) afforded amorphous 16 (156 mg, 74%). 1H NMR (600 MHz,
CDCl3): δ = 8.5–7.0 (m, 10 H, aromatic H), 6.52 (d, J1,2 = 3.3 Hz,
1 H, 1-H), 5.34 (dd, J1,2 = 3.3, J2,3 = 9.7 Hz, 1 H, 2-H), 4.80 (ABq,
J = 10.9 Hz, 2 H, C6H5CH2), 4.14 (t, J = 9.7 Hz, 1 H, 3-H), 3.86
A solution of the above product (2.9 g, 6.4 mmol) in DMF(15 mL)
was treated at 120 °C with NaN3 (1.5 g, 23 mmol) and 15-crown-5
ether (500 mg, 2.2 mmol) for 4 h. After concentration, the residue
was chromatographed (hexane/EtOAc, 5:1) to give compound 17
(2.32 g, 91%). M.p. 76–77 °C (from EtOH). [α]D = +166 (c = 1.1,
CHCl3). 1H NMR (600 MHz, CDCl3): δ = 5.25 (dd, J1,2 = 8.0, J2,3
= 9.5 Hz, 1 H, 2-H), 4.74–4.63 (ABq, J = 10.8 Hz, 2 H, ArCH2),
4.39 (d, J1,2 = 8.8 Hz, 1 H, 1-H), 3.69 (t, J = 9.3 Hz, 1 H, 3-H),
3.44 (s, 3 H, OCH3), 3.36–3.28 (m, 2 H, 4-H and 5-H), 1.41 (d, J5,6
= 6.6 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 165.0
(CO), 137.0, 133.2, 129.8, 129.7, 128.2 (2 C), 127.8, 101.7 (C-1),
81.2(C-3), 74.9 (ArCH2), 73.7 (C-2), 70.8 (C-5), 67.6 (C-4), 56.7
(OCH3), 18.3 (C-6) ppm. C21H23N3O5 (397.42): calcd. C 63.46, H
5.83; found C 63.36, H 5.77.
(m, 1 H, 5-H), 3.37 (t, J = 10.0 Hz, 1 H, 4-H), 1.39 (d, J5,6
=
6.1 Hz, 3 H, 6-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 165.3,
160.4, 137.0, 133.5, 129.7, 129.0, 128.4, 128.3, 128.2, 127.9, 93.6
(C-1), 77.5 (C-3), 75.4 (ArCH2), 72.6 (C-2), 69.2 (C-5), 67.2 (C-4),
18.4 (C-6) ppm. ES-TOF-MS (pos. ion.): m/z = 67 [M + K]+, 549
[M + Na]+, 549.0453 ([M + Na]+ calcd. 549.0475).
Methyl 4-Azido-2-O-benzoyl-3-O-benzyl-4,6-dideoxy-α-D-glucopy-
ranoside (18): Compound 16 (2.2 g, 5.9 mmol) was treated as de-
scribed for 15, to give after chromatography, syrupy methyl 2-O-
benzoyl-3-O-benzyl-4-O-mesyl-α--glucopyranoside (2.54 g, 96%).
Acknowledgments
1H NMR (600 MHz, CDCl3): δ = 5.35 (dd, J1,2 = 3.8, J2,3
=
10.8 Hz, 1 H, 2-H), 5.08 (dd, J3,4 = 3.2, J4,5 = 1.3 Hz, 1 H, 4-H),
5.03 (d, J1,2 = 3.8 Hz, 1 H, 1-H), 4.77–4.62 (ABq, 2 H, J = 11 Hz,
ArCH2), 4.15 (dd, J2,3 = 10.6, J3,4 = 3.2 Hz, 1 H, 3-H), 4.11–4.08
(m, 1 H, 5-H), 3.37 (s, 3 H, OCH3), 3.06 (s, 3 H, OMs), 1.37 (d,
J5,6 = 6.6 Hz, 3 H, H-6) ppm. 13C NMR (150 MHz, CDCl3): δ =
165.9, 136.9, 133.3, 129.6, 128.0, 97.4 (C-1), 80.8 (C-4), 73.8 (C-3),
72.9 (ArCH2), 70.3 (C-2), 64.6 (C-5), 55.5 (OCH3), 39.1 (OMs),
16.5 (C-6) ppm. ES-TOF-MS (pos. ion.): m/z = 473.1237 ([M +
Na]+ calcd. 473.1246). The above product (2 g, 4.4 mmol) was
This research was supported by the National Institutes of Health
(NIH) (Intramural Research Program) and the National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK).
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128.5, 128.3, 97.3 (C-1), 78.3 (C-3), 75.6 (ArCH2), 74.4 (C-2), 68.2
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pyranoside (19): A solution of 17 (1.0 g, 2.5 mmol) in Ac2O/HOAc/
H2SO4 (14 mL, 14:4:0.1) was stirred at room temperature for 2 h.
NaOAc trihydrate (300 mg) was added, and the mixture was pro-
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β products 19 (984 mg, 92%, α/β ≈ 5:1–6:1). A similar mixture in
comparable yield was obtained by treatment of 18 in the same way.
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Eur. J. Org. Chem. 2008, 1947–1952
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1951

S. Hou, P. Kovácˇ
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1952
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Eur. J. Org. Chem. 2008, 1947–1952