Regio- and stereoselective synthesis of β-D-gluco-, α-L-ido-, and α- L-altropyranosiduronic acids from Δa4-uronates

Article abstract of DOI:10.1021/jo981477k

The stereoselective synthesis of β-D-glucopyranosiduronic, α-L- idopyranosiduronic, and α-L-altropyranosiduronic acids has been performed from different Δ⁴-uronate monosaccharides. Bromination of the C-4,5 double bond provided the trans-diaxial bromohydrin derivatives, which were converted to the corresponding epoxides in high yields. Direct reduction of the epoxides using boranetetrahydrofuran complex led to the corresponding glucuronic acids in low to good yields. Glucuronic acids were also obtained in satisfactory yields through a two-steps procedure involving bromination of the epoxide with titanium(IV) bromide followed by reduction using tributyltin hydride. Lewis acid-catalyzed rearrangement of these epoxides led to the corresponding α-L C-4 ketopyranosides adopting the ¹C₄ chair conformation. Hydride reduction afforded the α-L-idopyranosiduronic or the α-L- altropyranosiduronic acids, the stereoselectivity of the reduction being controlled by the appropriate substitution pattern.

Full text of DOI:10.1021/jo981477k

144
J . Org. Chem. 1999, 64, 144-152
Regio- a n d Ster eoselective Syn th esis of â-D-Glu co-, r-L-Id o-, a n d
r-L-Altr op yr a n osid u r on ic Acid s fr om ∆4-Ur on a tes
He´le`ne G. Bazin, Michael W. Wolff, and Robert J . Linhardt*,†
Division of Medicinal and Natural Products Chemistry and Department of Chemical and Biochemical
Engineering, The University of Iowa, PHAR-S328, Iowa City, Iowa 52242
Received J uly 27, 1998
The stereoselective synthesis of â-D-glucopyranosiduronic, R-L-idopyranosiduronic, and R-L-altro-
pyranosiduronic acids has been performed from different ∆4-uronate monosaccharides. Bromination
of the C-4,5 double bond provided the trans-diaxial bromohydrin derivatives, which were converted
to the corresponding epoxides in high yields. Direct reduction of the epoxides using borane-
tetrahydrofuran complex led to the corresponding glucuronic acids in low to good yields. Glucuronic
acids were also obtained in satisfactory yields through a two-steps procedure involving bromination
of the epoxide with titanium(IV) bromide followed by reduction using tributyltin hydride. Lewis
acid-catalyzed rearrangement of these epoxides led to the corresponding R-L C-4 ketopyranosides
1
adopting the C4 chair conformation. Hydride reduction afforded the R-L-idopyranosiduronic or the
R-L-altropyranosiduronic acids, the stereoselectivity of the reduction being controlled by the
appropriate substitution pattern.
Glycosaminoglycans are a family of linear, highly
ideally suited for gaining insight into the structure-
activity relationships glycosaminoglycan-protein inter-
actions.
sulfated polysaccharides, consisting of repeating disac-
charide units composed of either â-D-glucopyranosidu-
ronic acid (â-D-GlcAp) or R-L-idopyranosiduronic acid (R-
L-IdoAp) and hexosamine residues to form linear chains
containing O-sulfo, N-sulfo, and N-acetyl groups. Com-
mercial glycosaminoglycans are a polydisperse mixture
of polysaccharide chains with an average molecular
weight of 104-106.1 Glycosaminoglycans bind to hundreds
of proteins,2 primarily through the interaction of their
sulfate and carboxylate groups with basic amino acid
residues present in shallow pockets or on the surface of
glycosaminoglycan-binding proteins.3 In the past decade,
glycosaminoglycans have been shown to play a role in
the regulation of a large number of important cellular
processes including cell growth and cell-cell interac-
tions.2,4 The exploitation of protein interactions with
specific glycosaminoglycan oligosaccharide sequences
might lead to important new therapeutic advances and
might be applied, for example, to wound healing/tissue
growth5 or to inhibition of angiogenesis in the eradication
of tumors.4 However, the variability in the substitution
pattern of glycosaminoglycans makes it difficult to elu-
cidate their specific protein binding site sequences. Thus,
synthetic oligosaccharide sequences of glycosaminogly-
cans corresponding to protein binding sites are the
targets of our synthetic program. These sequences are
Total chemical synthesis of glycosaminoglycans and
glycosaminoglycan oligosaccharides and their derivatives
using current, state of the art techniques has severe
limitations. The number of synthetic steps required to
construct an intricately substituted carbohydrate, while
displaying elegant chemistry,6-10 results in a product that
will simply cost too much. Enzyme-based synthesis has
made some impressive breakthroughs in the preparation
of small neutral or ulosonic acid-containing oligosaccha-
rides such as SLex.11 Unfortunately, the N-deacetylase,
N- and O-sulfotransferases, and C5 epimerase, required
for the intricate modification of glycosaminoglycans, have
not yet been fully purified and cloned.12 Cell culturing
and recombinant genetic technologies are not sufficiently
developed to prepare structurally defined glycosami-
noglycans.2,12
Polysaccharide lyases have been prepared from micro-
organisms including Flavobacterium heparinum13 and
Bacteroides stearcoris.14 These enzymes have been used
to produce ∆4-uronic acid disaccharides and higher oli-
gosaccharides from glycosaminoglycans.15 Our laboratory
is exploring the use of these enzymatically prepared
oligosaccharides as building blocks for the synthesis of
larger glycosaminoglycan oligosaccharides. This approach
requires the stereochemically controlled conversion of the
† FAX 319-335-6634, e-mail robert-linhardt@uiowa.edu.
(1) Comper W. D. In Heparin and related polysaccharides; Gordon
Breach: New York, 1981.
(2) Linhardt, R.; Toida, T. In Carbohydrates as Drugs; Witczak, Z.,
Nieforth K., Eds.; Dekker: New York, 1998; pp 277-341.
(3) Hileman, R. E.; Fromm, J . R.; Weiler, J . M.; Linhardt, R. J .
Bioassays 1998, 20, 156-167.
(4) Folkman, J .; Langer, R.; Linhardt, R. J .; Haudenschild, C.;
Taylor, S. Science 1983, 221, 719-725.
(5) Steed, D. L. Surgical Clinics of North America 1997, 77, 575-
586.
(8) Westman, J .; Nilsson, M.; Ornitz, D. M.; Svahn, C. Carbohydr.
Res. 1995, 14, 95-113.
(9) Goto, F.; Ogawa, T. Bioorg. Med. Chem. Lett. 1994, 4, 619-624.
(10) Sinay¨, P. Pure Appl. Chem. 1997, 69, 459-463.
(11) Ichikawa, Y.; Look, G. C.; Wong, C. H. Anal. Biochem. 1992,
202, 215-238.
(12) Conrad, H. E. In Heparin-binding; Academic Press: London,
1998.
(13) Lohse, D. L.; Linhardt, R. J . J . Biol. Chem. 1992, 267, 24347-
24355.
(6) Van Boeckel, C. A. A.; Petitou, M. Angew. Chem., Int. Ed. Engl.
1993, 32, 1671-1818.
(7) Ichikawa, Y.; Monden, R.; Kuzuhara H. Carbohydr. Res. 1988,
172, 37-64.
(14) Ahn, M. Y.; Shin, K. H.; Kim, D.-H.; J ung, E.-A.; Toida, T.;
Linhardt, R. J .; Kim, Y. S. Can. J . Microbiol. 1998, 44, 423-429.
(15) Pervin, A.; Gallo, C.; J andik, K. A.; Han, X.-J .; Linhardt, R. J .
Glycobiology 1995, 5, 83-95.
10.1021/jo981477k CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/15/1998

Synthesis of Pyranosiduronic Acids from ∆4-Uronates
J . Org. Chem., Vol. 64, No. 1, 1999 145
Sch em e 1a
a
(a) 30% HBr in AcOH, 0 °C, 2 h; (b) BnOH, Ag2CO3, MS 4 Å, CH2Cl2, rt, 24 h; (c) MeONa cat. MeOH, rt, 6 h; (d) DMP, p-TsOH ca.,
DMF, rt, 3 h; (e) NaH, 0 °C, 15 min; BnCl, rt, 15 h; (f) 60% AcOH, 80 °C, 15 min; (g) NaHCO3, KBr, TEMPO cat., NaOCl, THF, 0 °C, 20
min; (h) MeOH, IR-120 (H+), rt, 12 h; (i) BzCl or Ac2O, Pyr, rt, 10 h; (j) DBU, CH2Cl2, rt, 12 h; (k) Ac2O, Pyr, rt, 5 h; (l) Ac2O, H2SO4 cat.,
0 °C, 5 h; (m) TBDMSCl, Pyr, rt, 3 × 24 h; (n) n-Bu4NF, THF, rt, 2 h; (o) PMBTCA, p-TsOH cat., CH2Cl2, rt, 5 × 24 h.
Sch em e 2
terminal ∆4-uronic acid residues to either D-GlcAp or
L-IdoAp. We now report the regio- and stereoselective
synthesis of â-D-gluco-, R-L-ido-, and R-L-altropyranosi-
duronic acids from ∆4-uronate monosaccharides.
Resu lts a n d Discu ssion
The conversion of ∆4-uronate monosaccharides into
D-GlcAp or L-IdoAp was first investigated with the methyl
[benzyl 4-deoxy-2,3-O-(1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl)-R-L-threo-hex-4-enopyranosid]uronate (12a)16 and
the benzyl (benzyl 2,3-di-O-benzyl-4-deoxy-R-L-threo-hex-
4-enopyranosid)uronate.16,17 Both ∆4-uronates were suc-
cessfully converted into the corresponding D-GlcAp16,17
and 12a into L-IdoAp.16 To extend this strategy to other
protecting groups, the ∆4-uronates 12a -c (Schemes1 and
2) were synthesized. Because uronic acid residues in
glycosaminoglycans are often substituted with 2-O-sulfo
groups, it was necessary to introduce differential protec-
tion at the 2- and 3-hydroxyl groups. This was done by
synthesizing the ∆4-uronates 12d -e as model com-
pounds.
Syn th esis of ∆4-Ur on a te Mon osa cch a r id es. We
already described the synthesis of 12a 16 and 12b.18 The
synthesis of 12c was first attempted by direct benzylation
of the ∆4-uronate diol 9 (Scheme 1) using standard
conditions (sodium hydride, benzyl chloride).17 However,
very low yields of 12c were obtained, a result of partial
transesterification and probably low reactivity of this
unsaturated system. Benzylation under acidic condi-
tions19 using benzyl trichloroacetamidate19,20 failed. An-
other approach to 12c relied on the benzylation of methyl
(benzyl â-D-glucopyranosid)uronate, followed by subse-
quent â-elimination. However, the benzylation reaction
led to a complex mixture of saturated and unsaturated
methyl/benzyl esters.17 Finally, 12c was synthesized
(16) Bazin, H. G.; Kerns, R. J .; Linhardt, R. J . Tetrahedron Lett.
1997, 38, 923-926.
(17) Kerns, R. J . Ph.D. Thesis, University of Iowa, Iowa City, 1996.
starting from â-D-glucose pentaacetate, as described in
Scheme 1. Anomeric bromination of the â-D-glucose
pentaacetate using a 30% solution of hydrogen bromide
in acetic acid, followed by benzylation with benzyl
chloride and silver carbonate, and deacetylation, afforded
the benzyl â-D-glucopyranoside (1) in 67% yield. Isopro-
(18) Bazin, H. G.; Capila, I.; Linhardt, R. J . Carbohydr. Res. 1998,
309, 135-144.
(19) Wessel, H. P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 37, 2247-2252.
(20) Patil, V. J . Tetrahedron Lett. 1996, 37, 1481-1484.

146 J . Org. Chem., Vol. 64, No. 1, 1999
Bazin et al.
Ta ble 1. Yield s (%) for Com p ou n d s 13-17, 19, a n d 20
pylidenation of 1 using 2,2-dimethoxypropane-p-toluene-
sulfonic acid, followed by benzylation with sodium hy-
dride-benzyl chloride, and deacetalation in 60% aqueous
acetic acid afforded the benzyl 2,3-di-O-benzyl-â-D-glu-
copyranoside (2) in 54% yield. Regioselective oxidation
of the primary 6-hydroxyl group with sodium hypochlo-
rite in the presence of a catalytic amount of TEMPO
(2,2,6,6-tetramethyl-1-pyperidinyloxy) afforded the cor-
responding carboxylate, which was esterified in acidic
methanol giving the methyl ester 3 in 75% yield. Acety-
lation of 3, using pyridine-acetic anhydride, followed by
â-elimination with DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene), gave the corresponding ∆4-uronate 12c in 82% yield.
The 2-O-benzyl-3-O-benzoyl ∆4-uronate 12d was synthe-
sized from methyl R-D-glucopyranoside using a similar
strategy (Scheme 1). After acetylation of the methyl 2,3-
di-O-benzyl-R-D-glucopyranoside (4), the anomeric methyl
was acetolyzed by acetic anhydride, in the presence of a
catalytic amount of concentrated sulfuric acid at 0 °C
until all the starting material had disappeared. The
acetolysis took place, as expected, at the anomeric center
and also unexpectedly at the 3-position. The substitution
of the 3-O-benzyl group by an acetate was clearly
demonstrated by 1H NMR spectroscopy through the
presence of one benzyl and four acetates and the large
deshielding of H-3, from 3.79 ppm (4) to 5.40 ppm (5) or
5.23 ppm (6). The two anomeric acetates 5 (R) and 6 (â)
were obtained in 73% yield from 4 and in a ratio R (5):â
(6) 3.2:1.0, as determined by 1H NMR spectroscopy.
During anomeric bromination of the anomeric mixture
5-6, partial hydrolysis of the 2-O-benzyl group was
observed, leading to the peracetylated R-bromide side
product in less than 10% yield if the reaction was
conducted for 2 h and in 75% yield for a 10 h reaction.
Anomeric benzylation, followed by deacetylation, oxida-
tion, methyl esterification, benzoylation and â-elimina-
tion, afforded the corresponding ∆4-uronate 12d in good
yield. The ∆4-uronate diol 9 was used to prepare 12e in
four steps as described in Scheme 1. Regioselective
silylation of 9 using the bulky tert-butyldimethylsilyl
(TBDMS) group, followed by benzoylation, afforded 10
in 88% yield. Desilylation of 10 using tetrabutylammo-
nium fluoride gave 11 in 62% yield. Acid-catalyzed
benzylation of 11 using p-methoxybenzyl trichloroaceta-
midate19,20 afforded 12e that was isolated, after purifica-
tion by chromatography on silica gel, together with a
contaminant, not removable at this stage. The structure
compounds
a
b
c
d
e
bromohydrins
13
14
15
16
17
19
20
87
9
92
41
54
60
56
21
81
26
26
67
22
92
64
14
85
54
78
70a
10a
90
epoxides
C-5 bromides
glucuronic acids
iduronic acids
altruronic acids
60
82
45
49
a
Estimated by TLC.
hydroxyl group, such as hydroboration or direct epoxi-
dation using m-chloroperoxybenzoic acid or Camp’s re-
agent (m-CPBA-KF)23 failed.16,17 In the latter case, a
5-fluoro derivative was isolated after extended reaction
times (up to 2 weeks), together with a significant amount
of unreacted glycal. The procedure developed by Goto in
his studies of the synthesis of sialic acid glycosides24 can
be used to generate the epoxides 15a -e in two steps
through an intermediate bromohydrin, as described in
Scheme 2. Thus, treatment of ∆4-uronates 12a -e with
N-bromosuccinimide in aqueous tetrahydrofuran (THF:
H2O, v/v, 2/1) led to the corresponding trans-diaxial
bromohydrins 13a -e in good to excellent yields, together
with a smaller amount of trans-diequatorial bromohy-
drins 14a -e (Table 1). The configuration at C-4 was
deduced from the coupling constants of the vicinal
protons obtained by 1H NMR spectroscopy (Table 2). The
high J 1,2 and J 2,3 values of bromohydrins 13a -e indicate
the axial disposition of H-1, H-2, and H-3, and the smaller
J 3,4 value (<4.0 Hz) indicates a dihedral angle H-3-C-
3-C-4-H-4 between 45° and 135°, while the high J 1,2
,
J 2,3, and J 3,4 values of bromohydrins 14a -e indicate the
axial disposition of H-1, H-2, H-3, and H-4. Treatment
of the trans-diaxial bromohydrins 13a -e with silver
oxide led to the corresponding epoxides 15a -e in high
yield (Scheme 2 and Table 1). The configuration of these
epoxides was determined on the basis of their method of
preparation. Base-catalyzed nucleophilic substitution of
the C-4 bromide by the axial C-5 hydroxyl group led to
the corresponding epoxides with the epoxide oxygen on
the R-side of the pyranosiduronic ring.
Dir ect Red u ction of Ep oxid es 15a -e. The most
common reducing agent for the conversion of epoxide to
alcohol is lithium aluminum hydride, the cleavage usu-
ally occurring so that the more substituted alcohol is
formed. However, the regioselectivity of the ring epoxide
cleavage can be reversed by using borane in tetrahydro-
furan.25 Indeed, we already reported that direct reduction
of the benzyl (benzyl 4-deoxy-2,3-di-O-benzyl-R-L-threo-
hex-4-enopyranosid)uronate by BH3‚HF led to the cor-
responding D-glucopyranosiduronic acid in 84% yield.16,17
Direct reduction of epoxides 15a and 15b with 1 or 2
equiv of BH3‚THF gave no products, even after 24 h at
room temperature. When a large excess of reducing agent
(10 equiv) was added, 15a was slowly converted to a more
polar product while 15b did not react at all. Borane (10
equiv) was added every 8 h until disappearance of the
epoxide. After purification by chromatography on silica
gel, the â-D-glucopyranosiduronic acid 17a was isolated
in 38% yield. The stereoselectivity observed during this
reduction suggests an initial complexation between the
epoxide oxygen and the borane and attack of the hydride
anion from the R-face.17
1
of 12e was confirmed by H NMR spectroscopy, and the
impurity could be removed two steps later, without
affecting any of the subsequent reactions. It should be
noted that the acidic benzylation using p-methoxybenzyl
trichloroacetamidate was successfully performed, while
the benzylation using benzyl trichloroacetamidate failed.
Such a difference in reactivity for the acidic benzylation
of uronic acid residues has been reported.21,22
Con ver sion to th e Ep oxid e. Direct methods for the
conversion of the C-4,5 unsaturated bond to a C-4
(21) J aurand, G.; Tabeur, C.; Petitou, M. Carbohydr. Res. 1994, 255,
295-301.
(22) Rochepeau-J obron, L.; J acquinet, J . C. Carbohydr. Res. 1998,
305, 181-189.
(23) Bellucci, G.; Catelani, G.; Chiappe, C.; d’Andrea, F. Tetrahedron
Lett. 1994, 35, 8433-8436.
(24) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. J pn. 1987,
60, 631-636.
Sodium hydrogentelluride (NaTeH) has also been
reported for the chemo- and regioselective conversion of
(25) Cragg. Organoboranes in Organic Synthesis; Dekker: New
York, 1973; pp 345-348.

Synthesis of Pyranosiduronic Acids from ∆4-Uronates
Ta ble 2. 1H NMR Da ta of Com p ou n d s 13, 14, 16, 17, 19, a n d 20
chemical shifts (ppm)
H-3
J . Org. Chem., Vol. 64, No. 1, 1999 147
coupling constants (Hz)
compounds
H-1
H-2
H-4
H-5
J 1,2
J 2,3
J 3,4
J 4,5
trans-diaxial
bromohydrins
13a
13b
13c
13d
4.95 (d)
5.33 (d)
5.08 (d)
5.27 (d)
5.11 (d)
4.03 (dd)
5.97 (dd)
3.90 (ovl)
4.09 (dd)
5.70 (t)
4.20 (dd)
5.70 (dd)
4.06 (dd)
5.60 (dd)
4.10 (dd)
4.40 (d)
4.82 (d)
4.45 (d)
4.74 (d)
4.51 (d)
7.2
8.1
9.9
9.3
8.8
8.1
3.7
3.7
3.8
3.5
3.7
8.1
7.9
7.8
8.1
13e
trans-diequatorial
bromohydrins
14a
14b
14c
14d
4.98 (d)
5.31 (d)
5.15 (d)
5.27 (d)
3.68 (dd)
5.55 (dd)
3.58 (dd)
3.65 (dd)
4.08 (dd)
5.95 (t)
3.96 (dd)
5.80 (dd)
4.22 (d)
4.60 (d)
4.32 (d)
4.42 (d)
7.7
8.1
8.1
7.9
7.9
9.5
8.5
8.5
10.2
11.0
11.0
8.8
C-5 bromides
16a
16b
16d
4.95 (d)
5.26 (d)
5.24 (d)
3.72 (dd)
5.60 (dd)
3.65 (dd)
3.93 (t)
5.77 (t)
5.62 (t)
3.65 (dd)
4.09 (d)
3.90 (t)
7.9
8.3
8.1
8.1
9.8
9.6
8.7
9.6
9.6
glucuronic acids
17a
17b
17d
4.43 (d)
4.76 (d)
4.71 (d)
3.65 (m)
5.15 (t)
3.65 (dd)
3.65 (m)
5.46 (t)
5.47 (t)
3.91 (bt)
4.09 (bt)
5.30 (bt)
3.85 (d)
4.05 (d)
4.07 (d)
7.3
7.4
7.5
nd
7.5
9.5
8.7
9.6
10.0
9.9
9.5
10.0
iduronic acids
19a
4.98 (d)
4.52 (m)
4.53 (m)
4.94 (m)
5.66 (d)
3.8
<6.3
<6.0
2.8
altruronic acids
20b
20c
20d
20e
5.34 (s)
5.07 (s)
5.21 (s)
5.21 (s)
5.58 (bd)
4.24 (m)
4.21 (bs)
5.58 (bs)
5.95 (dd)
4.25 (t)
5.75 (dd)
4.22 (dd)
4.98 (dd)
4.82 (t)
4.90 (dd)
4.69 (dd)
5.34 (d)
5.54 (d)
5.33 (d)
5.42 (d)
< 1.5
2.4
< 1.5
< 1.5
1.8
5.0
1.8
2.3
5.9
6.4
5.8
5.9
8.5
5.6
8.5
8.0
R,â-epoxy esters to â-hydroxy esters.26 NaTeH was readily
prepared in situ from tellurium and sodium borohydride
in ethanol27 and reacted at 0 °C with 15b. After 30 min,
15b was totally converted to a single, less polar com-
pound. 1H NMR spectroscopy of this new compound
revealed that transesterification of the methyl ester to
the ethyl ester has occurred. No epoxide reduction was
observed, even after extended reaction time.
gel. No furanoside derivatives were detected in the
bromination of 15b and 15d . The hydride reduction was
next performed on the crude bromides with tributyltin
hydride in refluxing toluene for 30 min. Reduction of the
siloxane-protected bromide 16a and purification on silica
gel gave the corresponding â-D-glucopyranosiduronic acid
17a in 54% yield. Reduction of 16b and 16d afforded 17b
and 17d in 26% and 78% yields, respectively. The
configuration of the â-D-glucopyranosiduronic acids 17a ,
Br om in a tion -Red u ction of Ep oxid es. The 1,2,3,4-
tetra-O-acetyl â-D-glucopyranosiduronic acid can be re-
portedly isomerized to the corresponding R-L-idopyrano-
siduronic acid, in 27%28 to 67%29 yield through C-5
bromination of the glucuronic acid, followed by reduction
with tributyltin hydride. Bromination of epoxides 15a ,
15b, and 15d was performed using titanium(IV) bromide
at -78 °C for 30 min and afforded the corresponding C-5
1
17b, and 17d was established by H NMR spectroscopy
from the large vicinal coupling constants J 1,2, J 2,3, and
1
J 3,4 (Table 2). The H NMR spectra of 17a , 17b, and 17d
showed very well resolved doublets or triplets for H-1,
H-2, H-3, and H-5; however, H-4 appeared as a broad
1
triplet, probably the result of a H/2H exchange, suggest-
ing the lability of H-4. The acetates of 17b and 17d could
be isolated in almost quantitative yield following a 1 h
acetylation, while after a 3 h acetylation, the formation
of a less polar compound (21b or 21d ) was observed by
TLC. The 1H NMR spectrum of 21b showed, as expected,
the presence of one benzyl, two benzoyl, and one acetyl
groups as well as a methyl ester function. However, only
three protons corresponding to H-1, H-2, and H-3 were
observed, and H-3 was deshielded. The mass spectrum
of 21b indicated a molecular ion of m/ e 546, consistent
with the presence of only three ring protons. On the basis
of these spectral data and from the partial lability of H-4
observed in 17b, the enolate structure 21b shown in
Scheme 2 was established. The structure of 21d was
similarly assigned. The partial â-elimination observed on
extended acetylation time is similar to the reported
â-elimination of similar derivatives observed under desi-
lylation conditions using n-Bu4NF.30 The glucuronic acids
17a , 17b, and 17d were fully characterized following
their peracetylation. Unexpectedly, the reported R-L-
1
bromides 16a , 16b, and 16d (Scheme 2). The H NMR
spectra of 16a , 16b, and 16d showed four pyranose ring
protons with high vicinal coupling constants and a C-4
hydroxyl indicating the presence of a C-5 bromide (Table
2). While the configuration at C-5 was not determined,
4
the C1 chair conformation of the resulting pyranosidu-
ronic acids suggests an axial bromide. Bromination of the
siloxane epoxide 15a afforded 16a in 46% yield, as well
1
as a second derivative, isolated in 22% yield. H NMR
spectroscopy of this second compound showed four pro-
tons coupled together with smaller coupling constants,
consistent with a furanoside derivative. Although bro-
mination of epoxides 15b and 15d occurred in 80-90%
yield as estimated by TLC, the corresponding bromo
derivatives were isolated in lower yield, 26% for 16b and
54% for 16d , a result of partial decomposition on silica
(26) Osuka, A.; Taka-Oka, K.; Suzuki, H. Chem. Lett. 1984, 271-
272.
(27) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574-1580
(28) Chiba, T.; Sinay¨, P. Carbohydr. Res. 1986, 151, 379-384.
(29) Medakovic, D. Carbohydr. Res. 1994, 253, 299-300.
(30) Coutant, C.; J acquinet, J . C. J . Chem. Soc., Perkin Trans. 1
1995, 1573-1581.

148 J . Org. Chem., Vol. 64, No. 1, 1999
Bazin et al.
4
F igu r e 2. 1C4, C1, and 2S0 conformations of iduronic acid.
of the C-4 ketopyranosides 18b-e. All the vicinal cou-
pling constants J 1,2 and J 2,3 for 18b-e were <1.0 Hz,
suggesting they have the R-L configuration and adopt a
4
1C4 chair conformation. Smaller (1.1 Hz) J 3,5 coupling
constants, between H-3 and H-5 across a carbonyl, have
been reported for similar C-4 ulosides.32 On rearrange-
ment of epoxide 15a with scandium(III) triflate at room
temperature, a mixture of two compounds was obtained
F igu r e 1. Lewis acid-promoted rearrangement of epoxide to
ketone.
1
in a ratio of 2.5:1.0 (as determined by H NMR spectros-
idopyranosiduronic acid formation was not observed in
the reduction of bromo derivatives 16a , 16b, and 16d .
Acid -Ca ta lyzed Rea r r a n gem en t of Ep oxid es to
Keton es a n d Hyd r id e Red u ction . The acid-catalyzed
rearrangement of epoxides to carbonyl compounds is a
well-known synthetic method and has been used for the
synthesis of aldehydes and ketones.31 This transforma-
tion involves the complexation of epoxide ring with a
Lewis acid and its cleavage leading to a rearrangement
involving a hydrogen shift, affording the corresponding
C-4 keto derivative (Figure 1). The acid-catalyzed rear-
rangement of epoxides 15a -e was performed with scan-
dium(III) triflate, for 30 min at room temperature, in
C2HCl3. 1H NMR spectroscopy showed only a single
rearrangement product of 15c, having the four protons
appearing as two doublets and two singlets as expected
copy), which could not be improved by altering the
reaction conditions. Both compounds had similar chemi-
cal shifts and vicinal coupling constants, and at this
stage, it was not possible to differentiate the ketopyra-
noside from the undesired furanoside. The C-4 ketopy-
ranosides 18a -e were reduced without any further
characterization.
The reaction mixture obtained on acid-catalyzed rear-
rangement of 15a was reduced using sodium borohydride
in methanol at 0 °C. After acetylation, 1H NMR spec-
troscopy showed the presence of two products in a ratio
of 2.3:1.0. Separation by chromatography on silica gel
afforded the R-L-idopyranosiduronic acid 19a as the major
compound isolated in 53% yield. Characterization of 19a
by 1H NMR spectroscopy showed the H-1 signal downfield
(4.98 ppm) compared to the H-1 of the corresponding
glucuronic acid 17a (4.43 ppm). Although overlapping of
the signals of H-2 and H-3 and long-range coupling in
H-4 did not allow the accurate determination of J 2,3 and
J 3,4, these coupling constants were estimated to be <6.3
Hz and <6.0 Hz, respectively. These values, together with
the very small J 1,2 (3.5 Hz) and J 4,5 (2.8 Hz) coupling
constants, were consistent with the R-L-idopyranosidu-
ronic configuration. The conformation of iduronic acid
residues is highly dependent on the substitution pat-
tern.33 Force field studies34 indicated that the skew boat
form 2S0 is equienergetic with the 1C4 and 4C1 forms
(Figure 2) and showed that the energy barrier between
the three forms is quite high (as large as 9 kcal/mol).
These studies strongly indicated that iduronic acid
residues exist as an equilibrium between the two or three
low-energy conformers. The larger J 2,3 value observed for
19a together with the long-range couplings observed for
H-1 and H-4, usually related to a “W” planar arrange-
ment of the protons, indicate that 19a exists as an
1
for a C-4 ketopyranoside. H NMR spectroscopy of the
Lewis acid-rearrangement products of 15b and 15d
showed the presence of a major C-4 ketopyranoside and
also revealed the presence of a minor compound (<20%)
assigned as a furanoside, formed through a ring contrac-
tion reaction competing with hydrogen migration.16,17
Assignment of the four protons of the C-4 ketopyrano-
1
sides relied on the comparison of the H NMR spectra of
18b-d and 2D COSY NMR spectroscopy. When the
spectrum of the 2-O-benzoylated 18b was compared to
that of 2-O-benzylated 18d , a large shift to low field was
observed for H-2 in 18b. Similarly, comparison of the 3-O-
benzoylated 18d spectrum with that of 3-O-benzylated
18c showed a large downfield shift for H-3 in 18d . On
the basis of these observations, the H-1 and H-2 protons
were assigned as singlets and H-3 and H-5 as doublets.
Decoupling experiments showed that H-3 and H-5 were
4
coupled together with a large J 3,5 coupling constant of
6.5-6.9 Hz, which is surprising for a C-4 ketopyranoside
structure, where H-5 is isolated and expected to be a
singlet. This unexpected coupling led us to perform
additional spectroscopic measurements to confirm the
presence of the ketone functionality. The IR spectrum of
18c displayed two carbonyl stretches at 1763 and 1757
cm-1, indicating an additional carbonyl to that of the
methyl ester. 13C NMR spectroscopy of 18b showed four
carbonyl signals corresponding to the methyl ester at
159.99 ppm, the two benzoyl esters at 164.30 and 164.67
ppm, and a ketone at 187.28 ppm. Mass spectrometry
showed identical molecular ions for 15b and 18b. To-
gether, these spectroscopic data confirmed the structure
1
2
equilibrium between the two conformers, C4 and S0.32
Moreover, 2D ROESY NMR spectroscopy of 19a showed
a substantial nuclear Overhauser enhancement (NOE)
effect between H-2 and H-5, confirming their close
proximity.33 This close spatial relationship can only be
2
observed in the unusual S0 conformation. Reduction of
the reaction mixtures obtained on rearrangement of
epoxides 15b, 15d , and 15e with NaBH4 in methanol at
0 °C, followed by acetylation, led to the corresponding
(32) Mu¨ller, T.; Schmidt, R. R. Liebiegs Ann./ Recueil 1997, 1907-
1914.
(33) Ferro, D. R.; Provosali, A.; Ragazzi, M. Carbohydr. Res. 1990,
195, 157-167.
(31) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H.
Tetrahedron 1994, 50, 3663-3672.
(34) Ragazzi, M.; Ferro, D. R.; Provosali, A. J . Comput. Chem. 1985,
7, 105-112.

Synthesis of Pyranosiduronic Acids from ∆4-Uronates
J . Org. Chem., Vol. 64, No. 1, 1999 149
Ta ble 3. In flu en ce of th e Rea ction Con d ition s on th e
Red u ction of Keton es 18b, 18d , a n d 18ea
temp
(°C)
reducing
agent
entry
solvent
20b
21b
fur.
2.5
Reduction of 18b
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MeOH
EtOH
MeOH
MeOH
EtOH
EtOH
MeOH
MeOHd
EtOH
i-PrOH
THF
NaBH4
NaBH4
NaBH4
Luche’s
NaBH4
Luche’s
Luche’s
Luche’s
Luche’s
Luche’s
NaBH4
Luche’s
LiAlHR3
LiAlHR3
5.8
1.0
1.0
1.0
2.5
1.7
2.8
3.5
1.4
5.8
7.8
12.7
10.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
5.8
6.2
traces
1.3
1.2
1.3
0.5
0.4
0.6
1.7
0.3
1.3
1.2
1.0
1.0
traces
0.3
-40
-40
-40
-40
-78
-78
-78
-78
-40
-40
0
F igu r e 3. B1,4 boat conformation of altruronic and iduronic
acid.
anion can only approach the C-4 carbon from the â-L face,
leading to the formation of an equatorial C-4 hydroxy
product. In the case of 18a , the presence of the bulky
1,1,3,3-tetraisopropylsiloxane substituent hinders the â-L
face, which now becomes more crowded than the R-L face,
forcing the hydride anion to approach from the upper face
and affording an axial C-4 hydroxy product.
THF
EtOH
THF
1.0
1.0
0
Luche’s reagent (sodium borohydride-cerium(III) chlo-
ride)35 has been successfully used for the selective reduc-
tion of ketones from the most hindered face of the
molecule.36,37 The use of this reagent was first investi-
gated with the 4-keto derivative 18b. Reaction of 18b
with NaBH4 in methanol at -40 °C led, after acetylation,
to a mixture of altropyranosiduronic acid 20b and enolate
21b in a ratio of 10.0:1.0 (Table 3, entry 3), as determined
Reduction of 18d
15
16
MeOH
MeOH
0
-78
NaBH4
Luche’s
5.8
1.0
1.0
0.4
1.6
Reduction of 18e
17
18
19
MeOH
MeOH
i-PrOH
0
-78
-78
NaBH4
Luche’s
Luche’s
2.2
1.0
2.1
1.0
1.0
a
MeOHd ) dilute methanolic solution. R ) O-t-Bu. fur. )
furanoside.
1
by H NMR spectroscopy. When 18b was reacted with
Luche’s reagent under the same conditions, a mixture of
20b and 21b was again obtained, in a ratio of 1.0:2.5
(Table 3, entry 4). No idopyranosiduronic acid was
detected in the reaction mixture. Investigation of this
reaction with different solvents and temperatures (Table
3, entries 5-12) always led to a mixture of altropyrano-
siduronic acid and enolate, albeit in different ratios. The
formation of the enolate 21b was favored by low tem-
peratures, alcohol solvents, and CeCl3. Stabilization of
the enolate by chelation with cerium(III) and hydrogen
bonding with the alcohol solvents could be responsible
for the major formation and isolation of 21b. The use of
dilute methanolic solution (Table 3, entry 8) or THF
(Table 3, entries 11-12) for the reaction of 18b with
Luche’s reagent minimized or suppressed the formation
of the enolate. Reduction of 18d and 18e with Luche’s
reagent led to the same observations (Table 3, entries
15-19), although no enolate was formed during the
reduction of 18e (Table 3, entries 17-19).
The use of a sterically hindered hydride can also
reverse the stereoselectivity of the carbonyl reduction by
forcing the hydride to attack from the most crowded face.
However, when 18b was reacted with the bulky tert-
butoxy lithium aluminum hydride LiAl(O-t-Bu)3H at 0
°C and in ethanol, the enolate 21b was the only product
formed, while in THF, a mixture of 20b and 21b was
observed (Table 3, entries 13 and 14).
R-L-altropyranosiduronic acids 20b, 20d , and 20e in 60%,
45%, and 49% yields, respectively. The corresponding
furanosides were also present in the following ratios:
20b:furanoside 3.9:1.0, 20d :furanoside 5.8:1.0, and 20e:
furanoside 2.2:1.0. During the reduction of the dibenzoyl
1
derivative 18b, the enolate 21b was also detected by H
NMR spectroscopy as a minor byproduct (Table 3, entry
1). The configurations of 20b, 20d , and 20e were deter-
mined by 1H and 2D COSY NMR spectroscopy. The
chemical shifts of H-1, 5.21-5.34 ppm, with very small
vicinal coupling constants J 1,2 < 1.0 Hz, the J 2,3 values
varying from 0 to 2.2 Hz and large J 4,5 coupling constants
of 8.0-8.5 Hz, are characteristic of the R-L-altropyrano-
1
siduronic acid in the C4 chair conformation. Reduction
of the methyl ester to the corresponding primary alcohol
was observed when 18b was reacted at room tempera-
ture. Previously, we reported16,17 that Sc(OTf)3-promoted
rearrangement of the benzyl (benzyl 4,5-anhydro-2,3-di-
O-benzyl-â-D-glucopyranosid)uronate, followed by reduc-
tion with NaBH4, afforded the corresponding R-L-idopy-
ranosiduronic acid. This conclusion was based on the
small vicinal coupling constants (<6.0 Hz) observed by
1H NMR spectroscopy, which were similar to those of 20c.
However, the J 4,5 coupling constant in 20c of 5.6 Hz,
higher than the J 4,5 (2.8 Hz) in the iduronic acid 19a and
smaller than the J 4,5 (8.0-8.5 Hz) in the altruronic acids
20b, 20d , and 20e, led us to conduct a more detailed
NMR study and revise our previous conclusion. 2D
ROESY NMR spectroscopy of 20c showed a very strong
NOE effect between the protons H-1 and H-4, indicating
that these protons are spatially close. From this observa-
tion, 20c was assigned as an altruronic acid adopting a
B1,4 boat conformation (Figure 3).
Con clu sion s
A series of glycal monosaccharides 12a -e were pre-
pared as model compounds for ∆4-uronic acid oligosac-
charides obtained enzymatically from glycosaminogly-
cans. The regio- and stereoselective synthesis of â-D-
gluco- and R-L-idopyranosiduronic acids from ∆4-uronate
monosaccharides was successfully demonstrated and
accomplished in four steps. Moreover, a convenient
The complete stereocontrol obtained in the reduction
of 18a to the R-L-idopyranosiduronic acid and 18b-e to
the R-L-altropyranosiduronic acid derivatives is probably
the result of steric effects. Reducing agents such as
NaBH4 react predominantly on the less hindered face.
In compounds 18b-e, the R-L face is extremely crowded
by the presence of three axial substituents. The hydride
(35) Gemal, A. L.; Luche, J . L J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(36) Leclaire, M.; J ean, P. Bull. Soc. Chim. Fr. 1996, 801-803.
(37) Krief, A.; Surleraux, D. Synlett 1991, 273-275.

150 J . Org. Chem., Vol. 64, No. 1, 1999
Bazin et al.
solution of the C-5 bromo derivative in anhydrous toluene and
under nitrogen. After 30 min at reflux, the reaction mixture
was concentrated under vacuum.
Lew is Acid -Ca ta lyzed Rea r r a n gem en t of Ep oxid es. A
catalytic amount of scandium(III) triflate was added to a
solution of epoxide in anhydrous CH2Cl2 and under nitrogen.
After 30 min at room temperature, the reaction mixture was
filtered through a pad of Celite, and the solvent was evapo-
rated.
Red u ction of th e C-4 Ketop yr a n osid es Usin g Sod iu m
Bor oh yd r id e. NaBH4 (1 equiv) was added to a solution of
ketopyranoside in anhydrous alcohol and under nitrogen. After
30 min at a given temperature, the reaction mixture was
quenched by addition of saturated aqueous NH4Cl, stirred for
30 min at room temperature, and extracted with chloroform.
The combined organic extracts were washed with water, dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure.
Red u ction of th e C-4 Ketop yr a n osid es Usin g Lu ch e’s
Rea gen t. CeCl3 (1 equiv) was added to a solution of ketopy-
ranoside in anhydrous alcohol and under nitrogen. After 15
min at room temperature, the reaction mixture was cooled at
the desired temperature and NaBH4 (1 equiv) was added. The
reaction mixture was treated as described above.
synthesis of R-L-altropyranosiduronic acid has also been
developed. The ∆4-uronates were converted, through the
intermediate trans-diaxial bromohydrins, to the corre-
sponding epoxides in high yields. The â-D-glucopyrano-
siduronic acids were obtained in moderate to good yields
through a two-step procedure involving C-5 bromination
of the epoxides, followed by hydride reduction of the
bromo derivatives. These glucopyranosiduronic acids
underwent a partial â-elimination under acetylation
conditions. Lewis acid-catalyzed rearrangement of the
epoxides led to the corresponding R-L C-4 ketopyranosides
adopting the 1C4 chair conformation. This rearrangement
was accompanied by the minor formation of furanosides,
except for the benzyl-protected epoxide. Reduction of the
siloxane ketose led to the corresponding R-L-idopyrano-
siduronic acid in good yield, while reduction of the ester,
ester-ether, or ether-protected 4-keto derivatives led to
the R-L-altropyranosiduronic acids. The use of Luche’s
reagent or a bulky hydride did not reverse the stereose-
lectivity of this reduction. The siloxane group was shown
to be the protection of choice for the conversion of the
∆4-uronate into either â-D-gluco- or R-L-idopyranosidu-
ronic acids. This strategy is currently being applied to
the conversion of the terminal ∆4-uronic acid residue of
larger oligosaccharides obtained by treatment of gly-
cosaminoglycans with lyases.
Acetyla tion . Acetic anhydride (1.5 equiv) was added to a
solution of sugar in anhydrous pyridine cooled at 0 °C and
under nitrogen. After 1 h at room temperature, the reaction
mixture was quenched by addition of methanol, the solvents
were evaporated under vacuum, and the residue was dried by
coevaporation with toluene.
Meth yl (Ben zyl 2-O-ben zoyl-3-O-ter t-bu tyld im eth ylsi-
lyl-4-d eoxy-r-L-th r eo-h ex-4-en op yr a n osid )u r on a t e (10).
To a solution of 9 (2.08 g, 7.44 mmol) in anhydrous pyridine
(20 mL) and under nitrogen was added TBDMSCl (7.44 mmol,
1.12 g) every 15 h until the starting materiel completely
disappeared. This reaction mixture was directly benzoylated
by addition of benzoyl chloride (14.9 mmol, 1.7 mL). After 5 h
at room temperature, the reaction mixture was quenched by
addition of methanol (20 mL) and concentrated under reduced
pressure to dryness by coevaporation with toluene. Purification
by chromatography on silica gel (ethyl acetate-petroleum
ether, v/v 1:3) afforded 10 as a colorless oil in 88% yield (3.18
Exp er im en ta l Section
Gen er a l Meth od s. Nuclear magnetic resonance (1H NMR)
spectra were recorded at 25 °C, in deuterated chloroform or
methanol. Chemical shifts were recorded in ppm (δ) and
coupling constants in hertz, relative to tetramethylsilane as
internal standard. The 1H NMR spectra were fully assigned
using single frequency decoupling. Melting points are uncor-
rected. Thin-layer chromatography (TLC) was performed using
E. Merck plates of silica gel 60 with fluorescent indicator.
Visualization was effected by spraying plates with Von’s
reagent18 followed by heating at 140 °C. Flash chromatography
was conducted with silica gel (230-430 mesh, E. Merck).
Con ver sion of ∆4-Ur on a tes to Br om oh yd r in s. A solu-
tion of ∆4-uronate in a mixture THF-H2O (v/v 2:1) was reacted
overnight with N-bromosuccinimide (NBS, 1.2 equiv) at room
temperature. The reaction mixture was extracted with chlo-
roform. The combined organic extracts were washed with
water, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo.
1
g). [RD]23 ) -74° (c 1, CHCl3). H NMR (500 MHz, CDCl3): δ
0.72 and 074 (2 s, 3 H each, SiMe2), 0.84 (s, 9 H, t-BuSi), 3.84
(s, 3 H, CO2Me), 4.36 (t, 1 H, J 2,3 ) 3.7 Hz, J 3,4 ) 3.9 Hz, H-3),
4.69 and 4.92 (2 d, 1 H each, J A,B ) 12.3 Hz, CH2Ph), 5.31 (d,
1 H, J 1,2 ) 4.2 Hz, H-1), 5.36 (t, 1 H, H-2), 6.13 (dd, 1 H, H-4),
7.20-7.28, 7.41, 7.60 and 8.00 (m, 10 H, 2 C6H5). Anal. Calcd
for C26H34O7Si (486.6) C 64.17, H 7.04; found C 64.44, H 6.94.
Meth yl (Ben zyl 2-O-ben zoyl-4-d eoxy-r-L-th r eo-h ex-4-
en op yr a n osid )u r on a te (11). Compound 10 (2.08 g, 4.28
mmol) was reacted in anhydrous THF (20 mL) and under
nitrogen with 1 M n-Bu4NF (5.20 mmol, 5.2 mL). After 1 h at
room temperature, the reaction mixture was concentrated
under reduced pressure, and the crude mixture was purified
by chromatography on silica gel (ethyl acetate-petroleum
ether, v/v 1:3) to afford 11 as a colorless oil in 61% yield (1.01
g), and the methyl (benzyl 2-O-benzoyl-4-deoxy-R-L-threo-hex-
Con ver sion of Br om oh yd r in s to Ep oxid es. Silver oxide
(3 equiv) was added to a solution of the trans-diaxial bromo-
hydrin in a mixture of DMF-THF (v/v 2:1) under nitrogen.
After 15 h at room temperature, the reaction mixture was
filtered through
evaporated.
a pad of Celite and the solvents were
Dir ect Red u ction of Ep oxid es Usin g Bor a n e-Tet-
r a h yd r ofu r a n Com p lex. Borane-tetrahydrofuran complex
(1 M in THF, 10 equiv) was added to a solution of epoxide in
anhydrous THF, under nitrogen and at room temperature.
BH3‚THF (10 equiv) was added every 8 h until the starting
material had disappeared, and the reaction mixture was
concentrated under vacuum.
Br om in a tion of Ep oxid es Usin g Tita n iu m (IV) Br o-
m id e. Titanium(IV) bromide (1.5 equiv) was added to a
solution of epoxide in anhydrous CH2Cl2, cooled at -78 °C and
under nitrogen. After 30 min at -78 °C, the reaction mixture
was quenched by addition of saturated aqueous Na2SO4,
stirred 15 min at room temperature, and extracted with
chloroform. The combined organic layers were washed with
saturated aqueous Na2SO4 and water, dried over anhydrous
Na2SO4, filtered ,and concentrated under vacuum.
4-enopyranosid)uronate18 in 30% yield (0.50 g). 11: [RD]23
)
1
-114° (c 1, CHCl3). H NMR (500 MHz, CDCl3): δ 2.87 (d, 1
H, 3-OH), 3.86 (s, 3 H, CO2Me), 4.10 (dd, 1 H, J 2,3 < 1.0 Hz,
J 3,4 ) 5.0 Hz, H-3), 4.70 and 4.84 (2 d, 1 H each, J A,B ) 11.8
Hz, 1 CH2Ph), 5.38 (d, 1 H, J 1,2 < 1.0 Hz, H-1), 5.59 (t, 1 H,
H-2), 6.42 (dd, 1 H, H-4), 7.25-7.32, 7.58, 7.98 (m, 10 H, 2
C6H5). Anal. Calcd for C21H20O7 (384.4) C 65.62, H 5.24; found
C 65.38, H 5.32.
Meth yl (Ben zyl 2,3-d i-O-ben zyl-4-d eoxy-r-L-th r eo-h ex-
4-en opyr an osid)u r on ate (12c). Acetic anhydride (1.53 mmol,
0.15 mL) was added to a solution of 3 (367 mg, 0.77 mmol) in
anhydrous pyridine (10 mL) and under nitrogen. After 3 h at
room temperature, the reaction mixture was quenched by
addition of methanol (5 mL) and concentrated under reduced
pressure. The residue was dissolved in anhydrous CH2Cl2 (10
mL) and reacted, under nitrogen, with DBU (0.77 mmol, 0.12
mL). After 15 h at room temperature, the reaction mixture
R ed u ct ion of t h e C-5 Br om id es Usin g Tr ib u t ylt in
Hyd r id e. Tributyltin hydride (1.05 equiv) was added to a

Synthesis of Pyranosiduronic Acids from ∆4-Uronates
J . Org. Chem., Vol. 64, No. 1, 1999 151
was quenched by addition of saturated aqueous NH4Cl (10 mL)
and extracted with CHCl3 (20 mL × 3). The combined organic
extracts were washed with water (20 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude residue was purified by chromatography on
silica gel (ethyl acetate-petroleum ether, v/v 1:10 f 1:5) to
afford 12c as a white solid in 82% yield (327 mg); mp 96-98
°C; lit. [RD]22 ) -28° (c 1, CHCl3).17 [RD]25 ) -25° (c 1, CHCl3).
1H NMR (500 MHz, CDCl3): δ 3.80 (m, 4 H, H-2 and CO2Me),
4.13 (dd, 1 H, J 2,3 ) 4.1 Hz, J 3,4 ) 3.6 Hz, H-3), 4.62, 4.63,
4.64, 4.70, 4.75 and 4.97 (6 d, 1 H each, J A,B ) 12.3 Hz, 3 CH2-
Ph), 5.14 (d, 1 H, J 1,2 ) 5.4 Hz, H-1), 6.18 (d, 1 H, H-4), 7.20-
7.40 (m, 15 H, 3 C6H5).
Meth yl [Ben zyl 4,5-a n h yd r o-2,3-O-(1,1,3,3-tetr a isop r o-
p ylsiloxa n e-1,3-d iyl)-â-D-glu cop yr a n osid ]u r on a te (15a ).
trans-Diaxial bromohydrin 13a (1.03 g, 1.67 mmol) in solution
in DMF:THF (20 mL:10 mL) was reacted with Ag2O (5.01
mmol, 1.16 g). Flash chromatography on silica gel (ethyl
acetate-petroleum ether, v/v 1:40 f 1:9) afforded the corre-
sponding epoxide 15a as a colorless oil in 92% (735 mg) yield.
[RD]25 ) -2.5° (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ
0.97-1.17 (m, 28 H, 4 i-Pr), 3.51 (s, 1 H, J 3,4 < 1.0 Hz, H-4),
3.67 (dd, 1 H, J 1,2 ) 7.8 Hz, J 2,3 ) 7.5 Hz, H-2), 3.86 (s, 3 H,
CO2Me), 4.11 (dd, 1 H, H-3), 4.71 and 4.97 (2 d, 1 H each, J A,B
) 12.6 Hz, CH2Ph), 4.77 (d, 1 H, H-1), 7.20-7.40 (m, 5 H,
C6H5). Anal. Calcd for C26H42O8Si2 (538.8) C 57.96, H 7.86;
found C 57.74, H 8.00.
Meth yl (Ben zyl 3-O-ben zoyl-2-O-ben zyl-4-d eoxy-r-L-
th r eo-h ex-4-en op yr a n osid )u r on a te (12d ). Compound 8
(850 mg, 2.36 mmol) in anhydrous pyridine (15 mL) and under
nitrogen was benzoylated by addition of benzoyl chloride (7.1
mmol, 0.82 mL). After 5 h at room temperature, the reaction
mixture was quenched by addition of methanol (15 mL) and
concentrated under reduced pressure. The residue was dis-
solved in anhydrous CH2Cl2 (10 mL) and reacted, under
nitrogen, with DBU (2.83 mmol, 0.5 mL). After 15 h at room
temperature, the reaction mixture was treated as described
for 12c. The crude residue was purified by chromatography
on silica gel (ethyl acetate-petroleum ether, v/v 1:10 f 1:5)
to afford 12d as an amorphous white solid in 85% yield (951
Meth yl (Ben zyl 4,5-a n h yd r o-2,3-d i-O-ben zoyl-â-D-glu -
cop yr a n osid )u r on a te (15b). trans-Diaxial bromohydrin 13b
(2.11 g, 3.61 mmol) in solution in DMF:THF (30 mL:15 mL)
was reacted with Ag2O (10.83 mmol, 2.51 g). Flash chroma-
tography on silica gel (ethyl acetate-petroleum ether, v/v 1:9)
afforded the corresponding epoxide 15b as a colorless oil in
1
81% (1.48 g) yield. [RD]25 ) -14° (c 1, CHCl3). H NMR (500
MHz, CDCl3): δ 3.51 (s, 1 H, J 3,4 < 1.0 Hz, H-4), 3.85 (s, 3 H,
CO2Me), 4.71 and 5.19 (2 d, 1 H each, J A,B ) 12.0 Hz, CH2Ph),
5.21 (d, 1 H, J 1,2 < 1.0 Hz, H-1), 5.30 (dd, 1 H, J 2,3 ) 1.5 Hz,
H-2), 5.68 (dd, 1 H, H-3), 7.36-8.08 (m, 15 H, 3 C6H5). Anal.
Calcd for C28H24O9 (504.5) C 66.66, H 4.80; found C 66.12, H
4.91.
1
mg). [RD]25 ) -5° (c 1, CHCl3). H NMR (500 MHz, CDCl3): δ
Meth yl (Ben zyl 4,5-a n h yd r o-2,3-d i-O-ben zyl-â-D-glu -
cop yr a n osid )u r on a te (15c). trans-Diaxial bromohydrin 13c
(121 mg, 0.217 mmol) in solution in DMF:THF (8 mL:4 mL)
was reacted with Ag2O (0.652 mmol, 151 mg). Purification by
chromatography on silica gel (ethyl acetate-petroleum ether,
v/v 1:20 f 1:5) afforded 15c as a colorless oil in 92% (95 mg)
3.82 (s, 3 H, CO2Me), 3.29 (dd, 1 H, J 1,2 ) 2.9 Hz, J 2,3 ) 3.8,
H-2), 4.64, 4.76, 4.82 and 4.94 (4 d, 1H each, J A,B ) 11.8 Hz,
2 CH2Ph), 5.36 (d, 1 H, H-1), 6.00 (dd, 1 H, J 3,4 ) 4.8 Hz, H-3),
6.28 (d, 1 H, H-4), 7.30-7.40, 7.60 and 7.96 (m, 15 H, 3 C6H5).
Anal. Calcd for C28H26O7 (474.5) C 70.87, H 5.52; found C 70.54,
H 5.58.
1
yield. [RD]25 ) -64° (c 1, CHCl3). H NMR (500 MHz, CDCl3):
Meth yl [Ben zyl 4-br om o-5-deh ydr o-4-deoxy-5-h ydr oxy-
2,3-O-(1,1,3,3-tetr a isop r op ylsiloxa n e-1,3-d iyl)-â-D-ga la c-
top yr a n osid ]u r on a te (13a ) a n d Meth yl [Ben zyl 4-br om o-
-5-dehydro-4-deoxy-5-hydroxy-2,3-O-(1,1,3,3-tetraisopropyl-
siloxa n e-1,3-d iyl)-r-L-id op yr a n osid ]u r on a te (14a ). Reac-
tion of 12a (1.19 g, 2.27 mmol) with NBS (2.73 mmol, 485 mg)
in THF:H2O (20 mL:10 mL) and purification by chromatog-
raphy on silica gel (ethyl acetate-petroleum ether, v/v 1:30
f 1:6) afforded the trans-diequatorial isomer 14a in 9% (127
δ 3.55 (t, 1 H, J 1,2 ) 5.7 Hz, J 2,3 ) 5.8 Hz, H-2), 3.62 (s, 1 H,
J 3,4 < 1.0 Hz, H-4), 3.82 (s, 3 H, CO2Me), 5.94 (d, 1 H, H-3),
4.59, 4.65, 4.67, 4.70, 4.72 and 5.03 (6 d, 1 H each, J A,B ) 12.1
Hz, 3 CH2Ph), 4.90 (s, 1 H, H-1), 7.22-7.37 (m, 15 H, 3 C6H5).
Anal. Calcd for C28H28O7 (476.5) C 70.58, H 5.92; found C 70.18,
H 5.87.
Meth yl [Ben zyl 5-br om o-5-d eh yd r o-2,3-O-(1,1,3,3-tet-
r a isop r op ylsiloxa n e)-â-D-glu cop yr a n osid ]u r on a te (16a ).
Epoxide 15a (33 mg, 0.061 mmol) in CH2Cl2 (3 mL) was reacted
with TiBr4 (0.092 mmol, 34 mg). Flash chromatography on
silica gel (ethyl acetate-petroleum ether, v/v 1:40 f 1:15)
mg) yield ([RD]24 ) -4.4° (c 0.1, CHCl3). Anal. Calcd for C26H43
-
BrO8 (619.7) C 50.40, H 6.99; found C 50.00, H 7.09) and the
trans-diaxial isomer 13a as a crystalline solid in 87% (1.23 g)
yield: mp 124-126 °C; [RD]24 ) -0.5° (c 0.1, CHCl3). Anal.
Calcd for C26H43BrO8 (619.7) C 50.40, H 6.99; found C 50.73,
H 7.11.
afforded 16a as a colorless oil in 41% (16 mg) yield. [RD]25
)
-138° (c 0.5, CHCl3). Anal. Calcd for C26H43BrO8Si2 (619.7) C
50.39, H 6.99; found C 50.86, H 7.06.
Meth yl (Ben zyl 2,3-d i-O-ben zoyl-5-br om o-5-d eh yd r o-
â-D-glu cop yr a n osid ) u r on a te (16b). Epoxide 15b (30 mg,
0.060 mmol) in CH2Cl2 (3 mL) was reacted with TiBr4 (0.090
mmol, 33 mg). Flash chromatography on silica gel (ethyl
acetate-petroleum ether, v/v 1:8 f 1:3) afforded 16b as a
colorless oil in 26% (9 mg) yield. [RD]24 ) -39° (c 1, CHCl3).
Anal. Calcd for C28H25BrO9 (585.4) C 57.45, H 4.30; found C
56.98, H 4.73.
Meth yl (Ben zyl 2,3-d i-O-ben zoyl-4-br om o-5-d eh yd r o-
4-deoxy-5-h ydr oxy-â-D-galactoyr an osid)u r on ate (13b) an d
Met h yl (Ben zyl 2,3-d i-O-b en zoyl-4-b r om o-5-d eh yd r o-4-
d eoxy-5-h yd r oxy-r-L-id op yr a n osid )u r on a te (14b). Reac-
tion of 12b (3.46 g, 7.09 mmol) with NBS (8.50 mmol, 1.52 g)
in THF:H2O (30 mL:15 mL) and flash chromatography on silica
gel (ethyl acetate-petroleum ether, v/v 1:5 f 1:3) afforded the
trans-diequatorial isomer 14b as a colorless glass in 21% (0.87
Meth yl [Ben zyl 2,3-O-(1,1,3,3-tetr a isop r op ylsiloxa n e)-
â-D-glu cop yr a n osid ]u r on a te (17a ). Red u ction of 15a w ith
BH3‚THF . Compound 15a (26 mg, 0.048 mmol) in solution in
THF (2.5 mL) was reduced with BH3‚THF (1 M in THF, 4 ×
0.48 mL). Flash chromatography on silica gel (ethyl acetate-
petroleum ether, v/v 1:20) afforded 17a in 38% (10 mg) yield.
Br om in a tion -Red u ction of 15a . Compound 15a (38 mg,
0.071 mmol) in CH2Cl2 (3.5 mL) was reacted with TiBr4 (0.107
mmol, 39 mg). The crude bromide 16a was reduced with Bu3-
SnH (0.075 mmol, 20 µL) in toluene (3 mL). Purification by
chromatography on silica gel (ethyl acetate-petroleum ether,
v/v 1:20) afforded 17a in 54% (21 mg) yield. Acetylated 17a :
[RD]25 ) -64° (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.98-
g) yield ([RD]25 ) -14° (c 1, CHCl3). Anal. Calcd for C28H25
-
BrO9 (585.4) C 57.45, H 4.30; found C 57.80, H 4.47) and the
trans-diaxial isomer 13b in 56% (2.32 g) yield, isolated as a
colorless glass: [RD]25 ) +35° (c 1, CHCl3). Anal. Calcd for
C
28H25BrO9 (585.4) C 57.45, H 4.30; found C 57.23, H 4.63.
Meth yl (Ben zyl 2,3-d i-O-ben zyl-4-br om o-5-d eh yd r o-4-
deoxy-5-h ydr oxy-â-D-galactopyr an osid)u r on ate (13c) an d
Met h yl (Ben zyl 2,3-d i-O-b en zyl-4-b r om o-5-d eh yd r o-4-
d eoxy-5-h yd r oxy-r-L-id op yr a n osid )u r on a te (14c). Reac-
tion of 12c (180 mg, 0.39 mmol) with NBS (0.47 mmol, 84 mg)
in THF:H2O (4 mL:2 mL) and flash chromatography on silica
gel (ethyl acetate-petroleum ether, v/v 1:5 f 1:3) afforded the
trans-diequatorial isomer 14c as a colorless glass in 22% (48
mg) yield (lit.17 [RD]22 ) -73° (c 1, CHCl3); [RD]25 ) -76° (c 1,
CHCl3)) and the trans-diaxial isomer 13c in 67% (146 mg)
yield, isolated as a colorless glass: [RD]26 ) -18° (c 0.5, CHCl3).
HRFABMAS (positive): calcd for C28H29O7Br1 [M + Li]+
563.1257; found 563.1255.17
1.20 (m, 28 H, 4 i-Pr), 2.03 (s, 3H, OAc), 3.71 (dd, 1 H, J 1,2
)
7.4 Hz, J 2,3 ) 8.4 Hz, H-2), 3.77 (t, 1 H, J 3,4 ) 8.9 Hz, H-3),
3.76 (s, 3 H, CO2Me), 3.89 (d, 1 H, J 4,5 ) 10.1 Hz, H-5), 4.42 (d,
1 H, H-1), 4.68 and 4.94 (2 d, 1 H each, J A,B ) 12.5 Hz, CH2-
Ph), 5.10 (t, 1 H, H-4), 7.24-7.40 (m, 5 H, C6H5). Anal. Calcd
for C28H46O9Si2 (582.5) C 57.70, H 7.96; found C 57.82, H 8.16.

152 J . Org. Chem., Vol. 64, No. 1, 1999
Bazin et al.
Meth yl (Ben zyl 2,3-d i-O-ben zoyl-â-D-glu cop yr a n osid )-
u r on a te (17b). Epoxide 15b (38 mg, 0.075 mmol) in CH2Cl2
(3.5 mL) was reacted with TiBr4 (0.112 mmol, 41 mg) and the
crude bromide reduced with Bu3SnH (0.078 mmol, 21 µL) in
toluene (3 mL). Flash chromatography on silica gel (ethyl
acetate-petroleum ether, v/v 1:10 f 1:3) afforded 17b in 26%
19a as a colorless oil in 53% (52 mg) yield. [RD]24 ) -32° (c 1,
CHCl3). Anal. Calcd for C28H46O9Si2 (582.5): C 57.70, H 7.96;
found C 57.72, H 8.27.
Meth yl (Ben zyl 4-O-a cetyl-2,3-d i-O-ben zoyl-r-L-a ltr o-
p yr a n osid )u r on a t e (20b). Rearrangement of 15b (60 mg,
0.119 mmol) followed by reduction with NaBH4 (0.119 mmol,
4.5 mg) in MeOH (3 mL) and at 0 °C afforded, after acetylation
and purification by chromatography on silica gel (ethyl acetate-
petroleum ether, v/v 1:20), 20b as a white solid, in 60% (39
mg) yield: mp 100-102 °C. [RD]25 ) +28° (c 1, CHCl3). FABMS
(positive): [M + H - H2]- 547.6. Anal. Calcd for C30H28O10
(548.5) C 65.69, H 5.14; found C 65.27, H 5.16.
Meth yl (Ben zyl 4-O-a cetyl-2,3-d i-O-ben zyl-r-L-a ltr op y-
r a n osid )u r on a te (20c). Rearrangement of 15c (24 mg, 0.05
mmol) followed by reduction with NaBH4 (0.05 mmol, 1.9 mg)
in MeOH (2.5 mL) and at 0 °C afforded, after acetylation and
purification by chromatography on silica gel (ethyl acetate-
petroleum ether, v/v 1:20), 20c as a colorless oil in 82% (21
mg) yield. [RD]25 ) -59° (c 0.5, CHCl3). Anal. Calcd for C30H32O8
(520.6) C 69.22, H 6.20; found C 69.20, H 6.24.
Meth yl (Ben zyl 4-O-a cetyl-2,3-d i-O-ben zoyl-r-L-th r eo-
h ex-4-en op yr a n osid )u r on a te (21b). [RD]24 ) +57° (c 1,
CHCl3). FABMS (positive): [M + Na]+ 569.3, [M + H]+ 547.3.
1H NMR (500 MHz, CDCl3): δ 2.31 (s, 3 H, OAc), 3.66 (s, 3 H,
CO2Me), 4.69 and 4.94 (2 d, 1 H each, J A,B ) 11.5 Hz, CH2Ph),
5.44 (s, 1 H, H-1), 5.65 (s, 1 H, H-2), 6.64 (s, 1 H, H-3), 7.32-
7.49, 7.54-7.62, 8.00 and 8.18 (m, 15 H, 3 C6H5). Anal. Calcd
for C30H26O10 (546.5) C 65.93, H 4.79; found C 65.37, H 4.96.
1
(10 mg) yield. Acetylated 17b: [RD]25 ) +19° (c 1, CHCl3). H
NMR (500 MHz, CDCl3): δ 1.94 (s, 3 H, OAc), 3.79 (s, 3 H,
CO2Me), 4.18 (d, 1 H, J 4,5 ) 9.7 Hz, H-5), 4.68 and 4.94 (2 d,
2 H, J A,B ) 12.5 Hz, CH2Ph), 4.78 (d, 1 H, J 1,2 ) 7.4 Hz, H-1),
5.50 (t, 1 H, J 3,4 ) 9.4 Hz, H-4), 5.52 (t, 1 H, J 2,3 ) 9.3 Hz,
H-2), 5.64 (t, 1 H, H-3), 7.18-7.60, 7.80 and 8.05 (m, 15 H, 3
C6H5). Anal. Calcd for C30H28O10 (548.5) C 65.69, H 5.15; found
C 65.00, H 5.23.
Meth yl [Ben zyl 2,3-O-(1,1,3,3-tetr a isop r op ylsiloxa n e)-
r-L-th r eo-h exop yr a n osid -4-u lose]u r on a te (18a ). 1H NMR
(500 MHz, CDCl3): δ 0.96-1.16 (m, 28 H, 4 i-Pr), 3.83 (s, 3 H,
CO2Me), 4.24 (dd, 1 H, J 1,2 ) 4.3 Hz, J 2,3 ) 7.2 Hz, H-2), 4.65
and 4.82 (2 d, 1 H each, J A,B ) 12.9 Hz, CH2Ph), 5.01 (t, 1 H,
J 3,5 ) 8.7 Hz, H-3), 5.18 (d, 1 H, H-1), 5.67 (d, 1 H, H-5), 7.28-
7.40 (m, 5H, C6H5).
Meth yl (Ben zyl 2,3-d i-O-ben zoyl-r-L-th r eo-h exop yr a -
n osid -4-u lose)u r on a te (18b). FABMS (positive): [M + Na]+
527. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 3 H, CO2Me), 4.65
and 5.23 (2 d, 2 H, J A,B ) 11.0 Hz, CH2Ph), 5.45 and 5.46 (2 s,
1H each, H-1 and H-2), 5.85 (d, 1 H, J 3,5 ) 6.5 Hz, H-5), 6.21
(d, 1 H, H-3), 7.18-7.62, 7.80 and 8.10 (m, 15 H, 3 C6H5). 13C
NMR (125.8 MHz, CDCl3): δ 52.89 (CO2Me), 69.29, 75.97,
79.74 and 84.12 (C-2, C-3, C-5 and CH2Ph), 105.17 (C-1),
127.61-136.98 (C6H5), 159.99 (CO2Me), 164.30 and 164.67 (2
COPh), 187.28 (C-4).
Met h yl (Ben zyl 2,3-d i-O-b en zyl-r-L-th r eo-h exop yr a -
n osid -4-u lose)u r on a te (18c). 1H NMR (500 MHz, CDCl3):
δ 3.65 (s, 3 H, CO2Me), 4.04 (s, 1 H, J 1,2, J 2,3 < 1.0 Hz, H-2),
4.34, 4.47, 4.50, 4.52, 4.57 and 5.13 (6 d, 1 H each, J A,B ) 11.3
Hz, 3 CH2Ph), 4.65 (d, 1 H, J 3,5 ) 6.9 Hz, H-3), 5.29 (s, 1 H,
H-1), 5.66 (d, 1 H, H-5), 7.22-7.38 (m, 15 H, 3 C6H5).
Meth yl [Ben zyl 4-O-a cetyl-2,3-O-(1,1,3,3-tetr a isop r o-
p ylsiloxa n e-1,3-d iyl)-r-L-id op yr a n osid ]u r on a te (19a ). Re-
arrangement of 15a (90 mg, 0.17 mmol) followed by reduction
with NaBH4 (0.17 mmol, 6.3 mg) in MeOH (3 mL) at 0 °C
afforded, after acetylation and purification by chromatography
on silica gel (ethyl acetate-petroleum ether, v/v 1:40 f 1:15),
Ack n ow led gm en t. The authors thank Professor
Toshihiko Toida for his assistance in interpreting the
NMR experiments, Dr. Robert Kerns and Dr. Iontcho
Vlahov for helpful discussions during the early stages
of this work, and the National Institutes of Health (GM
38060) for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of 1-8, 12e, 13d -e, 14d , 15d -e,
16d , 17d , 18d -e, 20d -e, and 21d and supporting analytical
data (10 pages). See any current masthead page for ordering
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