From D-Glucose to Biologically Potent L-Hexose Derivatives: Synthesis of α-L-Iduronidase Fluorogenic Detector and the Disaccharide Moieties of Bleomycin A2 and Heparan Sulfate

Article abstract of DOI:10.1002/chem.200305096

A novel and convenient route for the synthesis of biologically potent and rare L-hexose derivatives from D-glucose is described. Conversion of diacetone-α-D-glucose (14) into 1,2:3,5-di-O-isopropylidene-β -L-idofuranose (19) was efficiently carried out in two steps. Orthogonal isopropylidene rearrangement of compound 19 led to 1,2:5,6-di-O-isopropylidene-β-L-idofuranose (27), which underwent regioselective epimerization at the C3 position to give the L-talo- and 3-functionalized L-idofuranosyl derivatives. Hydrolysis of compound 19 under acidic conditions furnished 1,6-anhydro-β-L-idopyranose (35) in excellent yield, which was successfully transformed into the corresponding L-allo, L-altro, L-gulo, and L-ido derivatives via regioselective benzylation, benzoylation, triflation and nucleophilic substitution as the key steps. Applications of these 1,6-anhydro-β-L-hexopyranoses as valuable building blocks to the syntheses of 4-methylcoumarin-7-yl-α-L-iduronic acid and the disaccharide moieties of bleomycin A₂ as well as heparan sulfate are highlighted.

Full text of DOI:10.1002/chem.200305096

FULL PAPER
From d-Glucose to Biologically Potent l-Hexose Derivatives: Synthesis of
a-l-Iduronidase Fluorogenic Detector and the Disaccharide Moieties of
Bleomycin A2 and Heparan Sulfate
Jinq-Chyi Lee,[b] Shu-Wen Chang,[a] Chih-Cheng Liao,[b] Fa-Chen Chi,[b] Chien-
Sheng Chen,[b] Yuh-Sheng Wen,[a] Cheng-Chung Wang,[a] Suvarn S. Kulkarni,[a]
Ramachandra Puranik,[a] Yi-Hung Liu,[c] and Shang-Cheng Hung*[a]
Dedicated to Professor Sunney I. Chan on the occasion of his 67th birthday
Abstract:
A
novel and convenient
to give the l-talo- and 3-functionalized
l-idofuranosyl derivatives. Hydrolysis
of compound 19 under acidic condi-
tions furnished 1,6-anhydro-b-l-idopyr-
anose (35) in excellent yield, which was
successfully transformed into the corre-
sponding l-allo, l-altro, l-gulo, and l-
ido derivatives via regioselective ben-
zylation, benzoylation, triflation and
nucleophilic substitution as the key
steps. Applications of these 1,6-anhy-
dro-b-l-hexopyranoses as valuable
building blocks to the syntheses of 4-
methylcoumarin-7-yl-a-l-iduronic acid
and the disaccharide moieties of bleo-
mycin A2 as well as heparan sulfate are
highlighted.
route for the synthesis of biologically
potent and rare l-hexose derivatives
from d-glucose is described. Conver-
sion of diacetone-a-d-glucose (14) into
1,2:3,5-di-O-isopropylidene-b-l-idofur-
anose (19) was efficiently carried out in
two steps. Orthogonal isopropylidene
rearrangement of compound 19 led to
1,2:5,6-di-O-isopropylidene-b-l-idofur-
anose (27), which underwent regiose-
lective epimerization at the C3 position
Keywords: 1,6-anhydro-b-l-
hexopyranoses
carbohydrates
heparan sulfate
¥
bleomycin A2
glycosides
¥
¥
¥
Introduction
moiety consisting of a a1!2 linked 3-O-carbamoyl-d-man-
nopyranose with l-gulopyranose. Amongst nucleoside anti-
biotics with potential antibacterial properties, adenomycin
(2)[3] is composed of l-gulosamine as a basic subunit where-
The rare l-hexoses are key components of numerous biolog-
ically potent oligosaccharides, antibiotics, glycopeptides, ter-
pene glycosides, as well as steroid glycosides (Figure 1).[1]
A
as capuramycin (3)[4] has
a 3-O-methyl-l-talofuranosyl
remarkable example is presented by bleomycin A2 1,[2] a sig-
nificant antitumor drug exhibiting strong activity through
DNA binding and metal-dependent oxidative cleavage of
nucleotides in the presence of oxygen. It belongs to a family
of glycopeptide antibiotics and contains a disaccharide
sugar. Other notable examples include l-altrose (4), which
is a typical constituent of the extracellular polysaccharides
from Butyrivibrio fibrisolvens strain CF3.[5]
Heparin and heparan sulfate, which are linear sulfated
polysaccharides of glycosaminoglycans comprising of alter-
nating d-glucosamine and hexuronic acid (l-iduronic acid or
d-glucuronic acid) residues with 1!4 linkages, play impor-
tant roles in a diverse set of biological processes, including
blood coagulation, cell growth control, inflammation, wound
healing, virus infection, tumor metastasis and diseases of
nervous system.[6] Heparin, containing the disaccharide re-
peating unit 5 as a major component, can interact with a va-
riety of proteins in many biological events.[7] The rare 3-O-
sulfonated disaccharide residue 6 of cell surface heparan sul-
fate exhibits specific binding site to the glycoprotein gD of
herpes simplex virus type-1 during virus entry.[8] The muco-
polysaccharidosis are a group of heritable lysosomal storage
disorders caused by lack of enzymes catalyzing the stepwise
degradation of glycosaminoglycans.[9] a-l-Iduronidase
[a]S.-W. Chang, Y.-S. Wen, C.-C. Wang, Dr. S. S. Kulkarni,
Dr. R. Puranik, Dr. S.-C. Hung
Institute of Chemistry, Academia Sinica
Taipei 115 (Taiwan)
Fax : (+886)2-2783-1237
E-mail: schung@chem.sinica.edu.tw
[b]J.-C. Lee, C.-C. Liao, F.-C. Chi, C.-S. Chen
Department of Chemistry, National Tsing Hua University
Hsinchu 300 (Taiwan)
[c]Y.-H. Liu
Instrumentation Center, National Taiwan University
Taipei 106 (Taiwan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
399
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FULL PAPER
at the first instance, several
problems still need to be en-
countered, including 1) the ster-
eoselective C5 inversion of
commercially available com-
pounds derived from d-gluco-
pyranose 10 and its furanosyl
form 11, 2) the regioselective
epimerization of the remaining
individual chiral centers in l-
idose, an equilibrating pyrano-
4
syl mixture of the C1 conform-
er 12 and 1C4 conformer 13,
without affecting other func-
tional groups, 3) the control of
regioselective protection in the
d-gluco and l-ido sugars, and
4) the selection of appropriate
protecting groups toward the
synthesis of various l-hexoses
and their related natural prod-
ucts. To tackle these problems,
we have explored a straightfor-
ward route to prepare 1,2:5,6-
di-O-isopropylidene-b-l-furano-
syl and 1,6-anhydro-b-l-pyrano-
syl derivatives of l-idose from
Figure 1. Biologically potent and rare l-hexoses and their related biomolecules.
d-glucose followed by an effi-
(EC 3.2.1.76),[10] a lysosomal hydrolase that cleaves terminal
a-l-iduronic acid unit, is deficient in Hurler and Scheie syn-
dromes. 4-Methylcoumarin-7-yl-a-l-iduronic acid (7) is a
fluorogenic substrate for assay of its activity.[11] Neomycin B
(8), an aminoglycoside antibiotic possessing specific binding
to the A site of the prokaryotic 16S rRNA[12] and inhibition
for the binding of the HIV Rev protein to its viral RNA rec-
ognition site (RRE),[13] has 2,6-diamino-2,6-dideoxy-l-ido-
pyranose as the D ring. Modification of this D ring as the 6-
amino-6-deoxy-l-idopyranosyl derivative 9 also presents
similar antibacterial activity.[14]
cient transformation of these l-ido sugars into the corre-
sponding b-l-hexofuranosyl and 1,6-anhydro-b-l-hexopyra-
nosyl sugars by manipulating the steric and stereoelectronic
factors. Novel approaches toward the synthesis of a-l-iduro-
nidase fluorogenic detector 7 and the disaccharide moieties
of bleomycin A2 and heparan sulfate employing 1,6-anhy-
dro-b-l-hexopyranoses as valuable synthons are also descri-
bed.
Results and Discussion
As most of the structural information of carbohydrate
protein and carbohydrate nucleotide complex at molecular
level remains obscure, homogeneous materials with well-de-
fined configurations are essential for the determination of
biological activity and structure function relationship. These
frequently encountered l-hexoses, however, are not com-
mercially available. This very fact coupled with practical dif-
ficulties in obtaining these rare sugars from nature sources
has urged chemists to develop novel, cost effective, general,
simple, and convenient routes for their syntheses. As a
result, the literature documents an array of methodologies
for this purpose,[15] each one having its own advantages and
disadvantages.
Synthesis of l-idose derivatives: Our idea for the prepara-
tion of the l-ido sugars is based on the model of double
The only difference between the structures of the most
abundant d-glucose and rare l-idose is the stereochemistry
at the C5 position. Our plan (Scheme 1) was to first achieve
the conversion from d-gluco to l-ido configuration in a
shortest possible way and then carry out the specific epime-
rization of the l-ido sugars at C2, C3 and/or C4 to get to the
whole set of l-hexoses.[16] However simple this might appear
Scheme 1.
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Biologically Potent l-Hexose Derivatives
399 415
ketal fixation on the 1,2- and 3,5-hydroxy groups of d-glu-
cose to form a cis anti cis-fused tricyclic d-glucofuranosyl
derivative, which could undergo elimination to form a 5-
exo-double bond followed by electrophilic addition to give
the desired products. An efficient synthesis of 1,2:3,5-di-O-
isopropylidene-b-l-idofuranose (19) from diacetone-a-d-glu-
cose (14) in two steps is outlined in Scheme 2. Consecutive
absolute configuration of compound 19 (see Supporting In-
formation) was unambiguously determined through the
single-crystal X-ray analysis of its 6-O-tosyl derivative 20
(TsCl, pyridine, 88%). The stereo ORTEP drawing illus-
trates that the C4ꢀO4 and C3ꢀC2 bonds are at the axial and
equatorial positions, respectively. Nucleophilic substitution
of 20 with NaN3 gave the corresponding 6-azido derivative
21 (84%). Treatment of the alcohol 19 with diethylamino-
sulfur trifluoride (DAST) provided the 6-fluoro compound
22 in 55% yield.
Apparently, the face selectivity of borane addition in this
case is arising mainly through a combination of complemen-
tary steric factors (Scheme 3). The disposition of the axial
Scheme 3.
C4ꢀO4 bond directs the addition of borane onto the 5-exo
double bond from the less hindered a-face to form the inter-
mediate 25 rather than 23. As a result, the substituted group
(CH2BH2) orients equatorially at the C5 position of 26.
Along with this, the 1,3-diaxial repulsion between the
methyl and CH2BH2 groups in the boron complex 24 also
seems to play a role, resulting in exclusive formation of the
l-ido isomer 19 after oxidative work-up. It is evident that
the transition state required for formation of 24 will be steri-
cally encumbered and hence energetically disfavored.
Scheme 2.
treatment of compound 14 with triphenylphosphine (PPh3),
N-bromosuccinimide (NBS), and freshly distilled 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) in toluene at 808C afford-
ed the enol ether 18 in 63% yield in a one-pot manner.
Mechanistically, PPh3 first reacts with NBS to generate a
phosphonium salt, which is readily attacked by the 3-hy-
droxy group of 14 resulting in the formation of alkoxyphos-
phonium intermediate 15.[17] Due to the rigid cis-5,5-fused
ring conformation, the isopropylidene rearrangement of 15
appears to precede over direct SN2 substitution by bromide
ion owing to the steric hindrance for the a-face attack. In
contrast to this, the transition state in 16 is sterically favored
for a facile nucleophilic displacement by bromide ion, which
ends up in an overall regioselective bromination at C6.
DBU then effects the dehydrobromination of 17 to furnish
the enol ether 18. As expected, hydroboration of compound
18 followed by oxidative work-up led to the desired l-ido-
furanosyl product 19 (92%) as a single diastereoisomer. The
Synthesis of l-talo- and 3-functionalized l-idofuranosyl com-
pounds: As illustrated in Scheme 4, orthogonal isopropyli-
dene rearrangement of compound 19 with a solution of 2,2-
dimethoxypropane and acetone in the presence of catalytic
amount of (ꢁ)-camphorsulfonic acid at room temperature
yielded the 3-alcohol 27[18] as a white solid (42% after re-
crystallization from hexane) and a mixture of unreacted 19
and its 6-O-C(OMe)Me2 derivative in 52% yield. This mix-
ture could be reutilized under the same conditions and simi-
lar results were obtained. Alternatively, regioselective hy-
drolysis of 19 in 60% aq HOAc at 408C followed by 5,6-O-
isopropylidenation furnished the product 27 in 72% overall
yield in two steps. Oxidation of 27 with pyridinium dichro-
mate and acetic anhydride afforded the ketone 28 (98%),
which was subjected to sodium borohydride reduction to
give 1,2:5,6-di-O-isopropylidene-b-l-talofuranose (29) in
92% yield. Its absolute configuration was firmly secured by
401
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S.-C. Hung et al.
FULL PAPER
ic substitution of the 3-triflate derivative of 29. However,
none of the desired products were obtained. Alternatively,
the 3-tosylate 32 (TsCl, Py, 90%), upon treatment with
sodium azide, underwent a facile SN2 reaction to generate
the 3-azido-l-idofuranosyl sugar 33 (69%). In a similar
manner, reaction of compound 29 with DAST gave the cor-
responding 3-fluoro derivative 34 in 47% yield.
Synthesis of 4-methylcoumarin-7-yl-a-l-iduronic acid: The
preparation of the fluorogenic substrate 4-methylcoumarin-
7-yl-a-l-iduronic acid 7 has been reported.[21] However, the
strategy not only involves tedious steps to synthesize the l-
ido sugars but also is low yielding in the glycosylation reac-
tion. In our synthetic plan of compound 7, we needed l-ido-
pyranosyl pentaacetates 36 as the building block. Peracetyla-
tion of l-idose gave a mixture of the corresponding pyrano-
syl and furanosyl pentaacetates together with their anomeric
isomers. The purification of these four compounds was time-
consuming and the furanosyl pentaacetates were not useful
in the context of ongoing synthesis. To obviate these prob-
lems, we have employed 1,6-anhydro-b-l-idopyranose (35)
as a potent synthon, which can undergo one-pot peracetyla-
tion acetolysis to give only the pyranosyl pentaacetates 36.
Scheme 5 depicts our approach toward the synthesis of
target molecule 7. Reflux of compound 19 in a 0.2n ethanol-
ic solution of HCl yielded the triol 35 (88%) as a single
product. One-pot peracetylation acetolysis of 35 (TFA,
Ac2O, 83%) furnished the pentaacetate 36, which was con-
verted to the corresponding a-glycosyl chloride 37 (ZnCl2,
CH3OCHCl2, 93%). An X-ray single-crystal analysis of
compound 37 fully secured its structure (see Supporting In-
formation). Unfortunately, AgOTf-promoted coupling of
the donor 37 with 7-hydroxy-4-methylcoumarin (38) proved
to be a futile exercise due to the formation of the orthoester
39 (30%). So, we opted for an equally concise and even
more promising route. A one-pot synthesis of the alcohol 41
from compound 35 in 90% yield was successfully carried
out via programmable peracetylation, acetolysis, and bromi-
Scheme 4.
the single-crystal X-ray analysis (see Supporting Informa-
tion). Methylation of 29 (NaH, MeI, 93%) led to the corre-
sponding 3-OMe derivative 30 in excellent yield. Regiose-
lective removal of the 5,6-O-isopropylidene group (64%
HOAcaq, 92%) followed by 6-O-silylation (TBDPSCl, cat.
DMAP, Et3N, 77%) fashioned the adduct 31, a key inter-
mediate for the total synthesis of capuramycin.[4]
The anticoagulant activity of heparin via a unique penta-
saccharide sequence binding with antithrombin III (AT-III)
has been an area of intense research directed towards prob-
ing the molecular level details of their interaction.[19] The af-
finity study of the 3-deoxy-l-idose-derived pentasaccharide
with AT-III is reported by Sinay» and co-workers.[20] Since l-
talose is a C3-epimer of l-idose, it was realized that the 3-al-
cohol 29 could be reutilized to prepare differentially 3-func-
tionalized l-ido compounds. We first studied the nucleophil-
1
nation. The reaction, monitored by H NMR and TLC, re-
vealed that the corresponding triacetate was initially formed
in a short period and completely transformed into the pen-
Scheme 5.
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Biologically Potent l-Hexose Derivatives
399 415
taacetate 36 after stirring for 24 h. It is evident from this ob-
servation that acetylation of three hydroxyl groups is faster
than the opening of 1,6-anhydro ring. Addition of HBr into
the reaction mixture in the same pot gave the unstable gly-
cosyl bromide 40, which was hydrolyzed to the correspond-
ing alcohol 41 after neutralization with saturated aqueous
sodium bicarbonate solution. Mitsunobu-type glycosylation
of 41 with the acceptor 38 in the presence of triphenylphos-
phine and diethyl azodicarboxylate led to the desired a-
adduct 42 and its b-isomer in 58 and 24% yield, respectively.
The detailed structure of 42 via the single-crystal X-ray
analysis (see Supporting Information) clearly indicated that
all substituted groups orient toward the axial positions
except the CH2OAc group at C5. Saponification of com-
pound 42 with sodium methoxide in methanol produced the
tetraol 43 (88%), which was identical with the literature
report with respect to 1H NMR spectrum.[21b] This consti-
tutes a more convenient route to 4-methylcoumarin-7-yl-a-
l-iduronic acid 7, since it has been previously obtained from
compound 43 by regioselective C6-oxidation.[21]
ous 1,6-anhydro-b-l-hexopyranoses (Scheme 6). Reaction of
the triol 35 with one equivalents of trifluoromethanesulfonic
anhydride in pyridine led to the 2-OTf derivative 44 as a
single isomer. The high regioselectivity is perhaps a direct
consequence of the inductive effect exerted by two oxygen
atoms at C1 to increase the acidity of O2-proton, forming
the alkoxide at C2 under basic conditions that reacts prefer-
entially with various electrophiles. This result prompted us
to study the one-pot triflation benzoylation and the corre-
sponding ester 45 was successfully isolated in 78% yield.
Treatment of 45 with NaNO2 and NaN3 gave the 1,6-anhy-
dro-b-l-gulopyranosyl sugar 46 (91%) and its 2-azido deriv-
ative 47 (90%), respectively. The single-crystal X-ray analy-
ses of 46 and 47 (see Supporting Information) confirmed
their absolute configurations. Acetolysis of compound 47
using a combination of trifluoroacetic acid, acetic anhydride,
and 1% solution of conc. H2SO4 in acetic anhydride yielded
the corresponding diacetate 48 (89%). It should be noted
that the typical acetolysis conditions failed to deliver the ex-
pected ring-opened product in this case and extra addition
of 1% conc. H2SO4 turned out to be a crucial factor effect-
ing this transformation. The fully protected l-gulosamine
derivative 48 is believed to be a potential precursor in the
synthesis of adenomycin 2.[3]
Towards this end, a highly regioselective 3-O-benzylation
of the potent synthon 35 to the corresponding 2,4-diol 51
(72%) was achieved employing TMSOTf-catalyzed Et3SiH
reductive etherification of its O-trimethylsilylated ether 49
(TMSCl, Et3N, 98%). The high selectivity in this case stems
out from steric interactions. The C2- and C4-trimethylsily-
loxy groups being adjacent to the bridgehead carbon atoms
are less accessible as compared to the C3-OTMS, allow ex-
clusive formation of the TMS-acetal intermediate 50 that
can be further reduced by Et3SiH in the presence of
TMSOTf as an efficient Lewis acid to produce the 3-OBn
compound 51. Triflation (Tf2O, Py) of 51 followed by nucle-
ophilic substitution (NaNO2, HMPA) furnished the corre-
sponding l-allo derivative 52 in 41% overall yield. Regiose-
lective O2-benzoylation of the diol 51 with BzCl in pyridine
Synthesis of 1,6-anhydro-b-l-hexopyranoses: 1,6-Anhydro-b-
hexopyranoses are valuable synthons in the synthesis of oli-
gosaccharides, glycoconjugates as well as natural products.[22]
The advantages of their [3.2.1]bicyclic skeleton in compari-
son with the corresponding pyranoses include 1) the regio-
and stereoselectivities are highly controlled by the rigid con-
formation, 2) the reactivity is affected because of equatorial-
axial conversion of various substituted groups at the C2, C3,
and C4 positions, 3) two less protecting groups at C1 and C6
are needed, and 4) only one anomeric isomer is obtained
which by-passes time-consuming purification and identifica-
tion of two a- and b-epimers. Moreover, once the requisite
functionalities are properly installed, the internal acetal can
be cleaved and the free hydroxyls can be utilized for further
elaboration of sugar by functional group modification or gly-
cosylation.
With the key molecule 35 in hand, we further studied the
regioselective protection and epimerization to generate vari-
Scheme 6.
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at 08C led to the alcohol 53 as a single isomer (85%). One-
pot benzoylation triflation of 51 provided the 2-OBz,4-OTf
derivative 54 (88%), which was subjected to SN2 substitu-
tions with NaNO2 and NaN3 to afford the corresponding l-
altropyranosyl sugar 55 (84%) and its 4-azido derivative 56
(97%), respectively. The absolute configurations of com-
pounds 51, 53, and 56 were unambiguously assigned through
their single-crystal X-ray analyses (see Supporting Informa-
tion).
Synthesis of the carbohydrate moiety of bleomycin A2: The
construction of the disaccharide subunit in bleomycin A2 re-
quires the coupling of 3-O-carbamoyl-d-mannopyranosyl
donor and l-gulopyranosyl acceptor with a a1!2 linkage.[2]
A d-mannopyranosyl derivative bearing well-distinguished
hydroxy group at C3 should suffice for this purpose. The
rare l-gulose residue, which has to serve a dual function of
a glycosyl acceptor in the disaccharide formation at O2 and
finally as a donor for assembly with the aglycon moiety of
bleomycin A2, is the real key building block for this synthe-
sis.
Our preparation of this carbohydrate moiety is summar-
ized in Scheme 7. Treatment of commercially available 1,6-
anhydro-b-d-mannopyranose (57) with benzoyl chloride in
pyridine gave a mixture of mono-, di- and tri-OBz deriva-
tives without any regioselectivity. Use of benzoyloxybenzo-
triazole (BzOBT) as a mild reagent dramatically enhanced
the simplicity and overall efficiency of the synthetic route,
delivering the expected 2,4-di-OBz adduct 58 in 54% yield.
From this reaction, the corresponding 2-OBz (15%) and
2,3,4-tri-OBz (26%) were also obtained and both com-
pounds could be recycled by removing the benzoyl groups
(cat. NaOMe, MeOH) to recover the starting material 57
back. An X-ray crystal analysis of 58 assured its absolute
structure (See supporting information). The high regioselec-
tivity in this mild benzoylation reaction is perhaps governed
by the 1,3-diaxial repulsion between the C3-OH group and
the C6-methylene group.[22] With the alcohol 58 in hand, it
was successfully converted into the desired carbonate 59 in
89% yield. Ring opening of 59 with TFA and Ac2O gave
the corresponding 1,6-diacetate in low yield. We recently
found that metal trifluoromethanesulfonates are effective
and mild catalysts in acetolysis of 1,6-anhydrohexopyrano-
ses.[23] Consecutive treatment of 59 with Ac2O in the pres-
ence of 5 mol% Cu(OTf)2 followed by addition of 30%
HBr in acetic acid yielded the glycosyl bromide 60 (90%) in
a one-pot manner. AgOTf-promoted coupling of the donor
60 with the alcohol 46 provided the disaccharide 63, albeit
in low yields, along with the orthoester as a major side prod-
uct. Alternatively, Schmidt×s glycosylation method was
thought to be a good solution for our purpose. Hydrolysis of
the crude glycosyl bromide 60 in an acetone/water solution
of AgOTf and 2,6-di-tert-butyl-4-methylpyridine was
smoothly carried out and the alcohol derivative 61 was ob-
tained in excellent yield (93%). Reaction of compound 61
with K2CO3 and CCl3CN led to the corresponding trichlor-
oacetimidate 62 (89%), which was subjected to coupling
with 46 to furnish the a-linked disaccharide 63 (82%), ex-
clusively. Cu(OTf)2-catalyzed acetolysis of 63 afforded the
Scheme 7.
expected diacetate 64 (74%), which upon one-pot nucleo-
philic displacement with ammonia, produced the title com-
pound 65 (77%), a suitable precursor for the total synthesis
of the antibiotic as reported first by Boger[2c] and Hecht.[2f]
Synthesis of a rare and potent disaccharide subunit in hepar-
an sulphate: The 3-O-sulfonated disaccharide moiety 6
found in heparan sulfate chain as a minor component exhib-
its specific binding site during herpes simplex virus entry.[8]
Its mimetics may serve as potential pharmaceutical agents
to block virus entry into target cells. We have explored
herein the synthesis of a disaccharide analogue 77 employ-
ing the 1,6-anhydro-b-l-idopyranosyl sugar 53 as a valuable
building block (Scheme 8).
2-Azido-4,6-O-benzylidene-2-deoxy-d-glucose (66), de-
rived from d-glucosamine hydrochloride in two steps,[24] was
dibenzoylated to furnish the ester 67 (80%), which under-
went ring opening of benzylidene acetal at the O6 position
via a combination of TMSOTf and borane to deliver the pri-
mary alcohol 68 (88%) in very high selectivity. Benzoylation
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Biologically Potent l-Hexose Derivatives
399 415
ditions [NH3, BnNH2, (NH4)2CO3]was low yielding, we de-
cided to convert it into the corresponding glycosyl bromide
via treatment with 30% HBr in acetic acid. When the mix-
ture was quenched with saturated sodium bicarbonate aque-
ous solution, the expected alcohol 72 (82%) was isolated in
a one-pot manner. Transformation of 72 into the corre-
sponding trichloroacetimidate (80%) followed by coupling
with methanol produced the methyl a-glycoside 73 and its
b-isomer in 58 and 17% yield, respectively. Selective deace-
tylation of 73 with HClg in 1,4-dioxane without affecting the
benzoyl groups provided the primary alcohol 74 (85%)
which, upon sequential Jones oxidation and debenzoylation
(NaOMe, MeOH) afforded the triol 75 in 57% overall yield
in two steps. Reaction of 75 with sulfur trioxide/triethyla-
mine complex led to the tri-O-sulfonated carboxylate 76.
One-pot Birch reduction of the azido and two benzyl groups
in compound 76 furnished the amino alcohol, which under-
went selective N-sulfonation with sulfur trioxide/pyridine
complex at pH 9.5 to give the desired target molecule 77 in
37% overall yield from 75.
Conclusion
We have successfully developed a short and convenient
route to prepare the biologically important and rare l-hexo-
ses from the most abundant d-glucose via their correspond-
ing furanosyl and 1,6-anhydropyranosyl derivatives as key
intermediates. In this synthetic endeavor, we have discov-
ered some interesting facets and reactivity patterns exhibit-
ed by these conformationally biased synthons. Applications
of these new developments in the efficient syntheses of the
a-l-iduronidase fluorogenic detector 7 and the disaccharide
moieties of bleomycin A2 and heparan sulfate are demon-
strated.
Experimental Section
General procedures: Solvents were purified and dried from a safe purifi-
cation system.[25] Flash column chromatography[26] was carried out as rec-
ommended with silica gel 60 (230 400 mesh, E. Merck). TLC was per-
formed on pre-coated glass plates of Silica Gel 60 F254 (0.25 mm, E.
Scheme 8.
of 68 (BzCl, Py, 89%) followed by regioselective removal of
Merck); detection was executed by spraying with
a solution of
the anomeric benzoyl group with ammonia gave the alcohol
69 (87%, a/b 3:1, determined by its H NMR spectrum). In-
Ce(NH4)2(NO3)6, (NH4)6Mo7O24, as well as H2SO4 in water and subse-
quent heating on a hot plate. Melting points were determined with a
B¸chi B-540 apparatus and are uncorrected. Optical rotations were meas-
1
terestingly, only the b-form isomer 69 was obtained upon re-
crystallization using vapor diffusion process. Its ORTEP
drawing of X-ray single-crystal diffraction analysis indicates
that the anomeric hydroxy group orients toward the equato-
rial position (see Supporting Information). Compound 69
was treated with CCl3CN and K2CO3 at ꢀ788C to get the
corresponding trichloroacetimidate (84%, a/b 1:4), which
was coupled with the glycosyl acceptor 53 in the presence of
TMSOTf as a catalyst to yield the a-linked disaccharide 70
(58%, J1’,2’ =3.8 Hz) and its b-isomer (16%), respectively.
The 1,6-anhydro ring of 70 was smoothly opened under typi-
cal acetolysis conditions (TFA, Ac2O), generating the diace-
tate derivative 71 in 89% yield. Since regioselective deace-
tylation of 71 at the anomeric position under the basic con-
1
ured with a Jasco DIP-370 polarimeter at ~258C. H and 13C NMR spec-
tra were recorded with Bruker AC300 and AMX400 MHz instruments.
Chemical shifts are in ppm from Me4Si, generated from the CHCl3 lock
signal at d 7.24. Mass spectra were obtained with a VG 70-250S mass
spectrometer in the EI and FAB modes. IR spectra were taken with a
Perkin-Elmer Paragon 1000 FT-IR spectrometer. Elemental analyses
were measured with a Perkin Elmer 2400CHN instrument.
6-Deoxy-1,2:3,5-di-O-isopropylidene-a-d-xylo-hex-5-enofuranose
(18):
N-Bromosuccinimide (5.13 g, 28.8 mmol) was added at room temperature
under nitrogen to a solution of 14 (5.00 g, 19.2 mmol) and triphenylphos-
phine (8.31 g, 31.7 mmol) in anhydrous toluene (50 mL). The reaction
flask was immersed in an oil bath at 908C for 45 min, DBU (20 mL,
134 mmol, freshly distilled from CaH2) was added, and the stirring was
continued at the same temperature for another 2 h. After cooling to
room temperature, the mixture was filtered through Celite followed by
wash with hexane. Water (50 mL) was added to the filtrate, and the aque-
405
Chem. Eur. J. 2004, 10, 399 415
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S.-C. Hung et al.
FULL PAPER
ous phase was extracted with hexane (3î50 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by flash column chromatogra-
phy (EtOAc/Hex 1:15) to afford the enol ether 18 (2.95 g, 63%) as a col-
orless oil. [a]2D5 =+163.7 (c=1.0, CHCl3); IR (CHCl3): n˜ =2988, 1660,
CHCl3); IR (CHCl3): n˜ =2991, 1375, 1204, 1163, 1016 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=5.94 (d, J=3.6 Hz, 1H, H-1), 4.66 (ddd, J=48.2,
9.8, 4.2 Hz, 1H, H-6a), 4.55 (ddd, J=48.2, 7.0, 4.2 Hz, 1H, H-6b), 4.50 (d,
J=3.6 Hz, 1H, H-2), 4.37 4.30 (m, 2H, H-3, H-5), 3.96 (t, J=2.0 Hz, 1H,
H-4), 1.45 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.29 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=111.84(C), 105.30 (CH), 98.21 (C),
83.82 (CH), 83.32 (d, J=251.8 Hz, CH2), 73.74 (CH), 70.61 (d, J=
11.2 Hz, CH), 67.88 (d, J=32.2 Hz, CH), 29.03 (CH3), 26.65 (CH3), 26.09
(CH3), 19.06 (CH3); HRMS (FAB): calcd for C12H20O5F: 263.1295;
found: 263.1288 [M+H+]; elemental analysis calcd (%) for C12H19O5F: C
54.96, H 7.25; found: C 55.03, H 7.40.
1375, 1082, 1017 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.98 (d, J=
;
3.7 Hz, 1H, H-1), 4.76 (d, J=0.6 Hz, 1H, H-6a), 4.69 (d, J=0.6 Hz, 1H,
H-6b), 4.56 (d, J=3.7 Hz, 1H, H-2), 4.37 (d, J=2.3 Hz, 1H, H-3), 4.34
(d, J=2.3 Hz, 1H, H-4), 1.52 (s, 3H, CH3), 1.47 (s, 3H, CH3), 1.40 (s, 3H,
CH3), 1.33 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=150.31 (C),
111.80 (C), 105.20 (CH), 101.37 (CH2), 100.53 (C), 84.27 (CH), 74.66
(CH), 72.34 (CH), 28.01 (CH3), 26.72 (CH3), 26.11 (CH3), 21.90 (CH3);
HRMS (FAB): calcd for C12H18O5: 242.1154; found: 242.1152; elemental
analysis calcd (%) for C12H18O5: C 59.49, H 7.49; found: C 59.19, H 7.38.
1,2:5,6-Di-O-isopropylidene-b-l-idofuranose (27):
A solution of 19
(133 mg, 0.51 mmol) in 60% aq HOAc (1.3 mL) was stirred at 408C for
9 h, and the mixture was coevaporated with toluene (5î5 mL) under re-
duced pressure to furnish the corresponding 3,5,6-triol. This crude triol
was dissolved in anhydrous acetone (0.5 mL) at room temperature under
nitrogen, and 2,2-dimethoxypropane (0.25 mL) and camphorsulfonic acid
(5.0 mg) were consecutive added to the solution. After stirring for 5 min,
the reaction was quenched with aq sat NaHCO3 (5 mL), and the mixture
was extracted with CH2Cl2 (3î5 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The residue was
recrystallized in hexane to afford 27 (95 mg, 72% in two steps) as a
white solid. [a]2D9 =ꢀ21.5 (c=0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d=5.94 (d, J=3.6 Hz, 1H, H-1), 4.45 4.48 (m, 2H), 4.22 (m, 1H, OH),
4.12 4.06 (m, 3H), 3.70 (d, J=3.3 Hz, 1H), 1.47 (s, 3H, CH3), 1.45 (s, 3
H, CH3), 1.42 (s, 3H, CH3), 1.29 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=111.65, 110.38, 104.86, 85.19, 78.02, 76.36, 74.74, 66.09, 26.74,
26.13, 25.83, 25.67; HRMS (FAB): calcd for C12H21O6: 261.1338; found:
261.1335 [M+H+].
1,2:3,5-Di-O-isopropylidene-b-l-idofuranose (19):
A 1m solution of
borane/THF complex in THF (5.53 mL, 5.53 mmol) was added to a mix-
ture of 18 (1.44 g, 5.53 mmol) in THF (15 mL) at room temperature
under nitrogen. After stirring for 3 h, the reaction flask was cooled in an
ice-bath, and a mixed solution of 30% H2O2 (6 mL) and 3n NaOH
(6 mL) was slowly added to the mixture. The aqueous phase was extract-
ed with EtOAc (3î15 mL), and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo to give a liquid residue. Purification of this residue through flash
column chromatography (EtOAc/Hex 1:2) led to the 6-alcohol 19 (1.42 g,
92%) as a colorless oil. [a]D32 =ꢀ3.2 (c=1.0, CHCl3); IR (CHCl3): n˜ =
3491, 2991, 2939, 1653, 1212, 1164, 1090, 1019, 861 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=5.94 (d, J=3.7 Hz, 1H, H-1), 4.49 (d, J=3.7 Hz, 1
H, H-2), 4.31 (d, J=2.2 Hz, 1H, H-3), 4.12 (m, 1H, H-5), 4.01 (t, J=
2.2 Hz, 1H, H-4), 3.88 (dd, J=11.6, 6.9 Hz, 1H, H-6a), 3.78 (dd, J=11.6,
4.6 Hz, 1H, H-6b), 1.48 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.40 (s, 3H,
CH3), 1.31 (s, 3H, CH3); elemental analysis calcd (%) for C12H20O6: C
55.37, H 7.74; found: C 55.01, H 7.69.
1,2:5,6-Di-O-isopropylidene-b-l-lyxo-hex-3-ulose (28): A solution of 27
(1.00 g, 3.84 mmol) in dichloromethane (6 mL) was added to a mixture of
pyridinium dichromate (1.08 g, 2.87 mmol) and acetic anhydride (1.1 mL,
11.6 mmol) in dichloromethane (12 mL) at room temperature under ni-
trogen. The whole mixture was refluxed for 2 h, then cooled to room
temperature, and the solvent was evaporated under reduced pressure.
EtOAc (10 mL) was added to dissolve the solid residue, and the resulting
solution was filtered through Celite. The filtrate was concentrated in
vacuo to obtain ketone 28 (0.97 g, 98%), which could be used for further
reactions. 1H NMR (400 MHz, CDCl3): d=6.10 (d, J=4.2 Hz, 1H, H-1),
4.38 (d, J=4.2 Hz, 1H, H-2), 4.32 (s, 1H, H-4), 4.27 (t, J=7.8 Hz, 1H, H-
5), 4.06 (t, J=7.8 Hz, 1H, H-6a), 4.01 (t, J=7.8 Hz, 1H, H-6b), 1.45 (s, 3
H, CH3), 1.42 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3): d=208.63 (C), 114.18 (C), 109.84 (C),
103.52 (CH), 78.61 (CH), 76.58 (CH), 75.28 (CH), 64.74 (CH2), 27.32
(CH3), 26.86 (CH3), 25.76 (CH3), 25.18 (CH3).
6-Azido-6-deoxy-1,2:3,5-di-O-isopropylidene-b-l-idofuranose (21): Com-
pound 19 (0.15 g, 0.58 mmol) was dissolved in pyridine (1.5 mL) at room
temperature under nitrogen, p-toluenesulfonyl chloride (0.12 g,
0.63 mmol) was added to the reaction solution, and the mixture was kept
stirring for 4 h. The reaction was quenched by addition of water (5 mL),
and the mixture was extracted with EtOAc (3î5 mL). The combined or-
ganic layers were consecutively washed with 1n aq HCl, aq sat NaHCO3,
and brine. The organic phase was dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was recrystallized via vapor diffusion
method to yield the corresponding 6-tosylate 20 (0.20 g, 88%) as color-
1
less crystals. H NMR (300 MHz, CDCl3): d=7.79 (d, J=8.2 Hz, 2H, Ar-
H), 7.33 (d, J=8.2 Hz, 2H, ArH), 5.86 (d, J=3.4 Hz, 1H, H-1), 4.45 (d,
J=3.4 Hz, 1H, H-2), 4.28 4.09 (m, 4H), 3.93 (s, 1H), 2.44 (s, 3H, CH3),
1.46 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.30 (s, 3H, CH3).
1,2:5,6-Di-O-isopropylidene-b-l-talofuranose (29): A solution of sodium
Sodium azide (0.16 g, 2.5 mmol) was added to a solution of compound 20
(0.20 g, 0.51 mmol) in DMF (2 mL), and the mixture was kept stirring at
908C for 3 d. After cooling to room temperature, water (5 mL) was
added to the solution, and the mixture was extracted with EtOAc (3î
5 mL). The combined organic layers were sequentially washed with water
and brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (EtOAc/Hex
1:9) to provide 21 (0.12 g, 84%) as a white solid. [a]2D5 =+7.3 (c=1.1,
borohydride (0.18 g, 4.8 mmol) in water (5 mL) was added at room tem-
perature to
a solution of 28 (0.97 g, 3.8 mmol) in 56% aq EtOH
(4.3 mL). After stirring for 3 h, the mixture was extracted with dichloro-
methane (3î8 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The residue was recrystal-
lized via vapor diffusion method to afford 29 (0.90 g, 92%) as colorless
crystals. [a]2D8 =+20.7 (c=1.0, CHCl3); m.p. 77 788C; IR (CHCl3): n˜ =
453, 2986, 2930, 1210, 1008 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.84
;
CHCl3); IR (neat): n˜ = 2925, 2101,1374, 1088 cmꢀ1
;
1H NMR (400 MHz,
(d, J=4.2, 1H, H-1), 4.58 (dd, J=5.2, 4.2 Hz, 1H, H-2), 4.20 (dt, J=6.8,
8.4 Hz, 1H, H-5), 4.08 (dd, J=8.4, 6.8 Hz, 1H, H-6a), 3.98 (t, J=8.4 Hz,
1H, H-6b), 3.90 (ddd, J=10.4, 8.4, 5.2 Hz, 1H, H-3), 3.75 (dd, J=8.4,
5.2 Hz, 1H, H-4), 2.39 (d, J=10.4 Hz, 1H, 3-OH), 1.54 (s, 3H, CH3), 1.43
(s, 3H, CH3), 1.38 (s, 6H, 2îCH3); 13C NMR (100 MHz, CDCl3): d=
112.75 (C), 109.44 (C), 104.21 (CH), 80.34 (CH), 78.47 (CH), 75.50 (CH),
72.29 (CH), 65.16 (CH2), 26.53 (CH3), 26.45 (CH3), 26.23 (CH3), 25.47
(CH3); HRMS (FAB): calcd for C12H21O6: 261.1338; found: 261.1339
[M+H+]; elemental analysis calcd (%) for C12H20O6: C 55.37, H 7.74;
found: C 55.48, H 7.74.
CDCl3): d=5.93 (d, J=3.6 Hz, 1H, H-1), 4.49 (d, J=3.6 Hz, 1H, H-2),
4.31 (d, J=2.2 Hz, 1H, H-3), 4.14 (ddd, J=8.1, 4.5, 2.2 Hz, 1H, H-5),
3.92 (t, J=2.2 Hz, 1H, H-4), 3.58 (dd, J=12.8, 8.1 Hz, 1H, H-6a), 3.36
(dd, J=12.8, 4.5 Hz, 1H, H-6b), 1.48 (s, 3H, CH3), 1.45 (s, 3H, CH3),
1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
111.82, 105.14, 98.31, 83.91, 73.80, 71.33, 68.29, 51.72, 28.98, 26.63,
26.08,19.07; HRMS (FAB): calcd for C12H20O5N3: 286.1402; found:
286.1405 [M+H+].
6-Deoxy-1,2:3,5-di-O-isopropylidene-6-fluoro-b-l-idofuranose (22): N,N-
Diethylaminosulfur trifluoride (0.47 mL, 3.5 mmol) was added at ꢀ408C
under nitrogen to a solution of 19 (150 mg, 0.58 mmol) in dichlorome-
thane (4 mL). The cooling bath was removed, and the mixture was kept
stirring at room temperature for 6 h. Methanol (2 mL) was slowly added
to the reaction mixture at ꢀ108C, the resulting solution was concentrated
in vacuo, and the residue was purified by flash column chromatography
(EtOAc/Hex 1:9) to afford 22 (83 mg, 55%). [a]2D5 =+13.1 (c=1.0,
1,2:5,6-Di-O-isopropylidene-3-O-methyl-b-l-talofuranose (30): Com-
pound 29 (400 mg, 1.46 mmol) was dissolved in THF (4 mL) under nitro-
gen, the reaction flask was immersed in an ice-bath, and 60% sodium hy-
dride in mineral oil (148 mg, 6.17 mmol) was added to the solution. After
30 min, methyl iodide (300 mL, 4.82 mmol) was added to the mixture, the
ice-bath was removed, and the whole solution was gradually warmed up
to room temperature and kept stirring for 2 h. Water (2.4 mL) was added
406
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 399 415

Biologically Potent l-Hexose Derivatives
399 415
to quench the reaction, and the mixture was extracted with EtOAc (3î
5 mL). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc/Hex 1:2) to give the product 30
(390 mg, 93%). [a]2D8 =+84.4 (c=0.6, CHCl3); IR (CHCl3): n˜ =2988,
raphy (EtOAc/Hex 1:5) to give 33 (47 mg, 69%). [a]2D8 =ꢀ80.7 (c=1.0,
CHCl3); m.p. 68 698C; IR (CHCl3): n˜ = 2989, 2937, 2107, 1216, 1076,
1
1022 cmꢀ1; H NMR (400 MHz, CDCl3): d=5.99 (d, J=3.6 Hz, 1H, H-1),
4.71 (d, J=3.6 Hz, 1H, H-2), 4.33 (q, J=7.2 Hz, 1H, H-5), 4.18 (dd, J=
7.2, 4.8 Hz, 1H, H-4), 4.16 (dd, J=8.4, 4.2 Hz, 1H, H-6a), 3.83 (d, J=
3.6 Hz, 1H, H-3), 3.69 (dd, J=8.4, 7.2 Hz, 1H, H-6b), 1.52 (s, 3H, CH3),
1.47 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d=112.43 (C), 110.25 (C), 105.01 (CH), 83.44 (CH),
80.83 (CH), 74.89 (CH), 65.88 (CH), 65.74 (CH2), 26.65 (CH3), 25.64
(CH3), 26.32 (CH3), 25.30 (CH3); HRMS (FAB): calcd for C12H20N3O5:
286.1403; found: 286.1391 [M+H+].
2936, 1372, 1068 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=5.75 (d, J=
;
4.9 Hz, 1H), 4.65 (t, J=4.9 Hz, 1H), 4.18 4.12 (m, 1H), 4.02 3.89 (m, 3
H), 3.60 (dd, J=12.0, 5.6 Hz, 1H), 3.45 (s, 3H), 1.55 (s, 3H), 1.40 (s, 3H),
1.35 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=113.1 (C),
109.4 (C), 104.3 (CH), 81.2 (CH), 77.9 (CH), 76.7 (CH), 75.4 (CH),
65.4(CH2), 58.2 (CH3), 26.8 (CH3), 26.5 (CH3), 26.1 (CH3), 25.8 (CH3); el-
emental analysis calcd (%) for C13H22O6: C 56.92, H 8.08; found: C
56.97, H 8.15.
3-Deoxy-1,2:5,6-di-O-isopropylidene-3-fluoro-b-l-idofuranose (34): Pyri-
dine (0.27 mL, 3.31 mmol) was added at 08C under nitrogen to a solution
of 29 (43 mg, 0.17 mmol) in dichloromethane (0.4 mL). After 10 min,
N,N-diethylaminosulfur trifluoride (0.22 mL, 1.65 mmol) was added drop-
wise to the solution, the ice-bath was removed, and the mixture was kept
stirring at room temperature for 24 h. Methanol (3 mL) was added to
quench the reaction, then the mixture was evaporated under reduced
pressure. Water (5 mL) was added to the residue, and the mixture was
extracted with EtOAc (3î5 mL). The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. Purification of the resulting residue through flash column chroma-
tography (EtOAc/Hex 1:4) provided 34 (20.4 mg, 47%) as a colorless oil.
[a]2D8 =ꢀ37.3 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=6.02 (d,
J=3.8 Hz, 1H, H-1), 4.84 (dd, J=50.7, 2.4 Hz, 1H, H-3), 4.66 (dd, J=
11.6, 3.8 Hz, 1H, H-2), 4.33 (q, J=7.6 Hz, 1H, H-5), 4.17 (ddd, J=30.2,
7.6, 2.4 Hz, 1H, H-4), 4.12 (t, J=7.6 Hz, 1H, H-6a), 3.72 (t, J=7.6 Hz, 1
H, H-6b), 1.47 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.30 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3): d=112.39 (C), 110.13 (C),
105.22 (CH), 94.58 (d, J=182.8 Hz, CH), 82.70 (d, J=31.5 Hz, CH),
81.56 (d, J=18.2 Hz, CH), 74.25 (d, J=8.9 Hz, CH), 65.68 (CH2), 26.71
(CH3), 26.69 (CH3), 26.26 (CH3), 25.31 (CH3).
6-O-tert-Butyldiphenylsilyl-1,2-O-isopropylidene-3-O-methyl-b-l-talofur-
anose (31): A mixture of compound 30 (390 mg, 1.42 mmol) in 64% aq
HOAc (4 mL) was stirred at 408C for 10 h. The solution was cooled in an
ice-bath, and aq sat NaHCO3 was added to neutralize the reaction mix-
ture. The mixture was extracted with chloroform (5î15 mL), and the
combined organic layers were washed by brine, dried over MgSO4, fil-
tered, and concentrated in vacuo to provide the 5,6-diol (306 mg, 92%).
[a]2D8 =+45.3 (c=1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d=5.76 (d,
J=3.8 Hz, 1H), 4.66 (t, J=3.8 Hz, 1H), 3.98 (dd, J=8.8, 1.7 Hz, 1H),
3.79 3.70 (m, 4H), 3.49 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H); 13C NMR
(CDCl3, 75 MHz): d=113.3 (C), 104.3 (CH), 80.2 (CH), 79.7 (CH), 76.6
(CH), 69.9 (CH), 64.8 (CH2), 58.3 (CH3), 26.7 (CH3), 26.4 (CH3).
To a solution of this diol (306 mg, 1.30 mmol) in dichloromethane (3 mL)
was sequentially added triethylamine (219 mL, 1.58 mmol), DMAP (6 mg,
45 mmol), and TBDPSCl (394 mg, 1.44 mmol) at room temperature under
nitrogen atmosphere. After stirring for 16 h, the reaction was diluted by
dichloromethane (10 mL), and the mixture was consecutively washed
with water (2î3 mL) followed by aq sat NH4Cl (2î3 mL). The organic
layer was dried over MgSO4, filtered, and concentrated in vacuo, and res-
idue was purified by flash column chromatography (EtOAc/Hex 1:2) to
furnish the product 31 (472 mg, 77%). [a]2D8 =+35.6 (c=0.5, CHCl3); IR
1,6-Anhydro-b-l-idopyranose (35): A solution of 19 (503 mg, 1.93 mmol)
in 0.2n HClEtOH (15 mL) was heated at 958C for 18 h. After cooling to
room temperature, the reaction was neutralized by Ag2CO3(s) (400 mg),
and the mixture was filtered through Celite to remove AgCl. The filtrate
was concentrated in vacuo, and the residue was purified by flash column
chromatography using EtOAc to give 35 (275 mg, 88%) as a white solid.
[a]3D3 =+106.47 (c=1.0, CHCl3); 1H NMR (400 MHz, CD3COCD3): d=
5.15 (d, J=1.6 Hz, 1H, H-1), 4.42 (d, J=4.2 Hz, 1H, 4-OH), 4.32 (t, J=
4.6 Hz, 1H, H-5), 4.19 (d, J=4.6 Hz, 1H, 3-OH), 4.00 (d, J=6.6 Hz, 1H,
2-OH), 3.96 (d, J=7.4 Hz, 1H, H-6a), 3.66 3.62 (m, 1H. H-4), 3.60 3.56
(m, 1H, H-6b), 3.48 3.45 (m, 1H, H-3), 3.33 (ddd, J=8.2, 6.6, 1.6 Hz, 1
1
(CHCl3): n˜ = 3473, 2931.2, 1428, 1113 cmꢀ1; H NMR (CDCl3, 400 MHz):
d=7.67 7.63 (m, 4H, Ph-H), 7.43 7.33 (m, 6H, Ph-H), 5.75 (d, J=
3.8 Hz, 1H, H-1), 4.65 (t, J=3.8 Hz, 1H, H-2), 4.04 (dd, J=10.0, 1.8 Hz,
1H, H-6a), 3.86 3.83 (m, 1H, H-5), 3.79 (dd, J=6.6, 3.8 Hz, 1H, H-3),
3.77 (dd, J=7.4, 6.6 Hz, 1H, H-4), 3.68 (dd, J=10.0, 5.4 Hz, 1H, H-6b),
3.47 (s, 3H, CH3), 2.29 (d, J=6.4 Hz, 1H, 5-OH), 1.53 (s, 3H, CH3), 1.34
(s, 3H, CH3), 1.04 (s, 9H, tBu); 13C NMR (CDCl3, 75 MHz): d=135.56
(CH), 133.13 (C), 129.74 (CH), 127.74 (CH), 113.08 (C), 104.25 (CH),
79.92 (CH), 77.32 (CH), 76.68 (CH), 69.75 (CH), 65.37 (CH2), 58.42
(CH3), 26.80 (4îCH3), 26.48 (CH3), 19.18 (C); HRMS (FAB): calcd for
C26H37O6Si: 473.2360; found: 473.2354 [M+H+]; elemental analysis calcd
(%) for C26H36O6Si: C 66.07, H 7.68; found: C 65.92, H 7.46.
1
H, H-2); H NMR (400 MHz, CD3COCD3 + 1 drop of D2O): d=5.14 (d,
J=1.7 Hz, 1H, H-1), 4.32 (t, J=4.6 Hz, 1H, H-5), 3.96 (d, J=7.4 Hz, 1H,
H-6a), 3.64 (dd, J=8.2, 4.6 Hz, 1H, H-4), 3.56 (dd, J=7.4, 4.6 Hz, 1H,
H-6b), 3.47 (t, J=8.2 Hz, 1H, H-3), 3.34 (dd, 1H, J=8.2, 1.7 Hz, H-2);
13C NMR (75 MHz, CDCl3): d=102.9 (CH), 76.4 (CH), 76.1 (CH), 72.4
(CH), 65.4 (CH2); elemental analysis calcd (%) for C6H10O5: C 44.45, H
6.22; found: C 44.05, H 6.16.
1,2:5,6-Di-O-isopropylidene-3-O-(p-toluenesulfonyl)-b-l-talofuranose
(32): p-Toluenesulfonyl chloride (422 mg, 2.21 mmol) was added to a sol-
ution of 29 (204 mg, 0.78 mmol) in pyridine (2 mL) at room temperature
under nitrogen. The mixture was stirred for 3 d, and water (0.4 mL) was
added to quench the reaction. After stirring for 20 min, the resulting sol-
ution was poured into ice-water (20 mL), the mixture was filtered, and
the collected solid was recrystallized via vapor diffusion method to yield
32 (292 mg, 90%) as colorless crystals. [a]2D8 =+82.3 (c=1.0, CHCl3);
1,2,3,4,6-Penta-O-acetyl-l-idopyranose (36): Compound 35 (75 mg,
0.46 mmol) was dissolved in acetic anhydride (1.5 mL) under nitrogen,
and the reaction flask was immersed in an ice-bath. Trifluoroacetic acid
(0.38 mL) was added to the reaction solution, the ice-bath was removed,
and the mixture was kept stirring at room temperature for 24 h. After
cooling to 08C, the reaction was quenched by slow addition of methanol
(4 mL), and the mixture was coevaporated with toluene and ethanol in
vacuo. The residue was purified by flash column chromatography
(EtOAc/Hex 1:1) to afford 36 (0.15 g, 83%, a/b 1:1, determined by
1H NMR) as a colorless oil.
m.p. 143 1448C; IR (CHCl3): n˜
= ;
2988, 1623, 1371 cmꢀ1 1H NMR
(400 MHz, CDCl3): d=7.83 (d, J=8.4 Hz, 2H, Ar-H), 7.33 (d, J=8.4 Hz,
2H, Ar-H), 5.73 (d, J=3.2 Hz, 1H, H-1), 4.62 4.56 (m, 2H, H-2, H-3),
4.01 (dd, J=8.0, 2.8 Hz, 1H, H-4), 3.90 3.82 (m, 3H, H-5, H-6a, H-6b),
2.43 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.28 (s, 3H, CH3),
1.21 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=145.27 (C), 132.88
(C), 129.79 (CH), 128.20 (CH), 113.70 (C), 109.48 (C), 104.20 (CH),
77.61 (CH), 76.95 (CH), 76.42 (CH), 73.68 (CH), 65.17 (CH2), 26.66
(CH3), 26.51 (CH3), 25.91 (CH3), 25.61 (CH3), 21.64 (CH3); HRMS
(FAB): calcd for C19H27O8S: 415.1427; found: 415.1460 [M+H+].
Isomer 36a: IR (CHCl3): n˜
= 2990, 2938, 1374, 1204, 1164, 1090,
1016 cmꢀ1; H NMR (400 MHz, CDCl3): d=6.04 (d, J=1.8 Hz, 1H, H-1),
5.05 (ddd, J=3.9, 3.0, 0.5 Hz, 1H, H-3), 4.92 (t, J=3.0 Hz, 1H, H-4), 4.86
(ddd, J=3.9, 1.8, 0.5 Hz, 1H, H-2), 4.17 (ddd, J=9.1, 6.0, 3.0 Hz, 1H, H-
5), 4.26 4.14 (m, 2H, H-6a, H-6b), 2.13 2.01 (m, 15H); 13C NMR
(75 MHz, CDCl3): d=170.47 (C), 169.67 (C), 169.02 (C), 168.79 (C),
168.42 (C), 90.61 (CH), 66.69 (CH), 66.30 (CH), 66.23 (CH), 66.14 (CH),
61.76 (CH2), 20.83 (CH3), 20.69 (CH3); elemental analysis calcd (%) for
C16H22O11: C 49.23, H 5.68; found: C 49.44, H 5.80.
1
3-Azido-3-deoxy-1,2:5,6-di-O-isopropylidene-b-l-idofuranose (33):
A
mixture of 32 (100 mg, 0.24 mmol), [15]crown-5 (96 mL, 0.48 mmol), and
sodium azide (235 mg, 3.62 mmol) in DMF (1 mL) was heated at 1408C
for 14 h. After cooling to room temperature, water (3 mL) was added to
the solution, and the mixture was extracted with chloroform (3î3 mL).
The combined organic layers were dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by flash column chromatog-
407
Chem. Eur. J. 2004, 10, 399 415
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S.-C. Hung et al.
FULL PAPER
Isomer 36b: 1H NMR (400 MHz, CDCl3): d=6.06 (d, J=2.2 Hz, 1H, H-
1), 5.24 (t, J=4.8 Hz, 1H, H-3), 4.99 (dd, J=4.8, 2.2 Hz, 1H, H-2), 4.89
(dd, J=4.8, 2.4 Hz, 1H, H-4), 4.44 (ddd, J=8.8, 6.3, 2.4 Hz, 1H, H-5),
4.23 (d, J=6.3 Hz, 2H, H-6a, H-6b), 2.13 2.01 (m, 15H); 13C NMR
(100 MHz, CDCl3): d=170.33 (C), 169.35 (C), 168.30 (C), 168.53 (C),
168.46 (C), 89.75 (CH), 71.84 (CH), 67.04 (CH), 66.26 (CH), 66.11 (CH),
62.05 (CH2), 20.71 (CH3), 20.58 (CH3), 20.54 (CH3), 20.48 (CH3), 20.44
(CH3).
(CH), 113.00 (CH), 103.74 (CH), 95.36 (CH), 71.67 (CH), 67.37 (CH),
67.04 (CH), 66.73 (CH), 62.49 (CH2), 20.57 (CH3), 20.44 (CH3), 18.52
(CH3); HRMS (FAB): calcd for C24H27O12: 507.1502; found: 507.1517
[M+H+].
4-Methylcoumarin-7-yl-a-l-Idopyranoside (43): A mixture of 42 (0.15 g,
0.31 mmol) and sodium methoxide (2.4 mg, 45 mmol) in methanol
(1.5 mL) was stirred at room temperature for 3 h under nitrogen. The re-
action solution was neutralized with Amberlite-120 acidic resin, and the
mixture was filtered to remove the resin followed by washings with meth-
anol. The filtrate was concentrated in vacuo, and the resulting solid was
recrystallized in a mixed solvent (EtOAc/MeOH/Hex 1:1:10) to furnish
43 (89 mg, 88%) as a white solid. 1H NMR (400 MHz, [D6]acetone): d=
7.69 (d, J=9.4 Hz, 1H, Ar-H), 7.19 7.16 (m, 2H, Ar-H), 6.20 (s, 1H),
5.55 (d, J=3.4 Hz, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.58 (d, J=5.8 Hz, 1H),
4.33 (d, J=4.8 Hz, 1H), 4.20 (ddd, J=5.7, 5.7, 2.3 Hz, 1H), 4.04 (t, J=
5.8 Hz, 1H), 3.95 (q, J=4.6 Hz, 1H), 3.85 3.79 (m, 4H), 2.45 (d, J=
1.2 Hz, 3H); HRMS (FAB): calcd for C16H19O8: 339.1080; found:
339.1084 [M+H+]; elemental analysis calcd (%) for C16H18O8: C 56.80, H
5.36; found: C 56.63, H 5.38.
2,3,4,6-Tetra-O-acetyl-a-l-idopyranosyl chloride (37): Dichloromethyl
methyl ether (2.2 mL) was added to a mixture of 36 (520 mg, 1.33 mmol)
and freshly fused zinc chloride (19 mg, 0.14 mmol) in dichloromethane
(2.2 mL) at room temperature under nitrogen. The mixture was refluxed
for 0.5 h, cooled in an ice-bath, and neutralized by aq sat NaHCO3
(3 mL). The whole mixture was extracted with dichloromethane (3î
3 mL), and the combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by flash
column chromatography (Et3N/EtOAc/Hex 1:8:11), the solid residue was
recrystallized via vapor diffusion method to provide 37 (444 mg, 91%) as
colorless crystals. [a]3D1 =ꢀ114.3 (c=1.3, CHCl3); m.p. 115 1168C; IR
(CHCl3): n˜ = 2973, 1747, 1372, 1218, 1047 cmꢀ1
;
1H NMR (400 MHz,
1,6-Anhydro-3,4-di-O-benzoyl-2-O-trifluoromethanesulfonyl-b-l-idopyra-
nose (45): Trifluoromethanesulfonic anhydride (0.25 mL, 1.48 mmol) was
added to a solution of 35 (201 mg, 1.24 mmol) in pyridine (2 mL) at 08C
under nitrogen. After stirring at the same temperature for 30 min, benzo-
yl chloride (0.58 mL, 5.0 mmol) was added to the mixture, the ice-bath
was removed. The reaction solution was kept stirring for another 16 h,
and methanol (0.4 mL) was added to quench the reaction. The mixture
was coevaporated with toluene under reduced pressure, and the residue
was dissolved in EtOAc (10 mL). The solution was consecutively washed
with aq 2n HCl, aq sat NaHCO3, and brine. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (EtOAc/Hex 1:4) to provide 45 (485 mg,
78%). [a]2D3 =ꢀ29.2 (c=1.0, CHCl3); m.p. 156 1578C; IR (CHCl3): n˜ =
3090, 2922, 2834, 1476, 1412, 1346, 1209, 1141, 1139, 1099, 1017, 963, 890,
CDCl3): d=6.02 (s, 1H, H-1), 5.03 4.99 (m, 2H, H-2, H-3), 4.93 4.92 (m,
1H, H-4), 4.69 4.66 (m, 1H, H-5), 4.27 4.19 (m, 2H, H-6a, H-6b), 2.16
(s, 3H, CH3), 2.14 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.10 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3): d=170.47 (C), 169.54 (C), 168.89 (C),
168.80 (C), 88.23 (CH), 68.46 (CH), 66.35 (CH), 65.87 (CH), 65.60 (CH),
61.74 (CH2), 20.79 (CH3), 20.68 (CH3), 20.59 (CH3); elemental analysis
calcd (%) for C14H19ClO9: C 45.85, H 5.22; found: C 45.85, H 5.26.
2,3,4,6-Tetra-O-acetyl-l-idopyranose (41): Trifluoroacetic acid (0.28 mL)
was added at room temperature under nitrogen to a solution of com-
pound 35 (69 mg, 0.43 mmol) in acetic anhydride (1.4 mL). After stirring
for 24 h, a solution of 30% HBr in acetic acid (1 mL, 4.2 mmol) was
added, and the mixture was kept stirring at room temperature for anoth-
er 6 h. The reaction was quenched with aq sat NaHCO3 at 08C, and the
whole mixture was extracted with EtOAc (3î5 mL). The combined or-
ganic layers were consecutively washed with aq sat NaHCO3 twice fol-
lowed by brine. The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo, and the resulting residue was purified by flash
column chromatography (EtOAc/Hex 2:3) to produce 41 (133 mg, 90%)
as a colorless oil.
754 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.92 (d, J=7.6 Hz, 2H, Bz-
;
H), 7.90 (d, J=7.2 Hz, 2H, Bz-H), 7.49 (dd, J=7.6, 7.2 Hz, 2H, Bz-H),
7.37 (d, J=7.6 Hz, 2H, Bz-H), 7.33 (d, J=7.2 Hz, 2H, Bz-H), 5.92 (t, J=
8.8 Hz, 1H, H-3), 5.63 (s, 1H, H-1), 5.31 (dd, J=8.8, 4.6 Hz, 1H, H-4),
4.87 (d, J=8.8 Hz, 1H, H-2), 4.84 (t, J=4.6, 1H, H-5), 4.32 (d, J=8.0 Hz,
1H, H-6a), 3.86 (dd, J=8.0, 4.6 Hz, 1H, H-6b); 13C NMR (125 MHz,
CDCl3): d=165.25 (C), 165.09 (C), 133.86 (CH), 133.66 (CH), 118.23
(quant, J=253.3 Hz, C), 99.09 (CH), 84.61 (CH), 72.86 (CH2), 71.58
(CH), 69.38 (CH), 65.20 (CH).
4-Methylcoumarin-7-yl-2,3,4,6-tetra-O-acetyl-a-l-idopyranoside (42):
A
solution of diethyl azodicarboxylate (0.16 mL, 1.0 mmol) in THF
(3.6 mL) was added to a mixture of 41 (0.26 g, 0.76 mmol), triphenylphos-
phine (0.25 g, 0.95 mmol), and 7-hydroxy-4-methylcoumarin (38; 0.27 g,
1.5 mmol) in THF (4 mL) at 08C under nitrogen. After stirring for 2 h,
the ice-bath was removed, and the reaction was quenched with aq sat
NaHCO3. The solution was diluted with EtOAc (5 mL), and the mixture
was sequentially washed by aq 0.2n NaOH (3î5 mL), water (2î5 mL),
then brine. The organic layer was dried over MgSO4, filtered and concen-
trated in vacuo. Purification of the residue through flash column chroma-
tography (EtOAc/Hex 3:2) gave 42 (225 mg, 58%) and its b-isomer
(93 mg, 24%).
Compound 42: 1H NMR (400 MHz, CDCl3): d=7.53 (d, J=8.8 Hz, 1H,
Ar-H), 7.08 (d, J=2.4 Hz, 1H, Ar-H), 6.97 (dd, J=8.8, 2.4 Hz, 1H, Ar-
H), 6.20 (d, J=1.2 Hz, 1H), 5.59 (s, 1H), 5.10 (t, J=3.4 Hz, 1H), 5.07
5.06 (m, 1H), 4.95 (t, J=2.6 Hz, 1H), 4.50 (ddd, J=6.3, 6.3, 1.9 Hz, 1H),
4.18 (d, J=6.3 Hz, 2H), 2.42 (d, J=1.2 Hz, 3H, CH3), 2.18 2.14 (m, 9H,
CH3), 1.93 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=169.93 (C),
169.23 (C), 168.79 (C), 168.53 (C), 160.37 (C), 158.13 (C), 154.41 (C),
151.69 (C), 125.157 (CH), 114.76 (C), 113.02 (CH), 112.63 (CH), 104.15
(CH), 95.43 (CH), 66.32 (CH), 66.07 (CH), 65.66 (CH), 65.03 (CH),
61.44 (CH2), 20.36 (CH3), 20.34 (CH3), 20.21 (CH3), 20.08 (CH3), 18.19
(CH3); elemental analysis calcd (%) for C24H26O12: C 55.92, H 5.17;
found: C 55.62, H 5.29.
1,6-Anhydro-3,4-di-O-benzoyl-b-l-gulopyranose (46): Sodium nitrite
(123 mg, 1.8 mmol) and [15]crown-5 (0.36 mL, 1.8 mmol) at room tem-
perature were sequentially added to a solution of 45 (300 mg, 0.60 mmol)
in HMPA (3 mL). After stirring overnight, the reaction was quenched
with H2O (4 mL) and extracted with EtOAc (3î30 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash column chroma-
tography (EtOAc/Hex 1:2) to afford 46 (205 mg, 91%) as a white solid.
[a]2D5 =ꢀ131.3 (c=1.0, CHCl3); m.p. 151 1528C; 1H NMR (400 MHz,
CD3Cl3): d=8.03 (dd, J=8.1, 1.1 Hz, 2H, Bz-H), 7.59 7.52 (m, 2H, Bz-
H), 7.99 (dd, J=8.1, 1.1 Hz, 2H, Bz-H), 7.42 (td, J=8.1, 2.0 Hz, 4H, Bz-
H), 5.65 (ddd, J=9.7, 4.5, 0.8 Hz, 1H, H-4), 5.57 (d, J=2.4 Hz, 1H, H-1),
5.54 (dd, J=9.7, 4.5 Hz, 1H, H-3), 4.83 (t, J=4.5 Hz, 1H, H-5), 4.31
(ddd, J=7.5, 4.5, 2.4 Hz, 1H, H-2), 4.26 (d, J=8.0 Hz, 1H, H-6a), 3.82
(d, J=8.0, 4.5 Hz, 1H, H-6b), 2.16 (d, J=7.5 Hz, 1H, 2-OH); 13C NMR
(100 MHz, CDCl3): d=165.62 (C), 165.59 (C), 133.57 (CH), 133.56 (CH),
129.80 (CH), 129.19 (C), 128.88 (C), 128.50 (CH), 101.53 (CH), 72.57
(CH), 70.30 (CH), 69.72 (CH), 69.49 (CH), 64.26 (CH2); HRMS (FAB):
calcd for C20H17O7: 371.1130; found: 371.1136 [M +]; elemental analysis
calcd (%) for C20H18O7: C 64.86, H 4.90; found: C 64.80, H 4.91.
1,6-Anhydro-2-azido-3,4-di-O-benzoyl-2-deoxy-b-l-gulopyranose (47): A
mixture of 45 (3.04 g, 6.05 mmol), sodium azide (1.97 g, 0.03 mol), and
[15]crown-5 (126 mL, 0.63 mmol) in DMF (30 mL) was stirred at room
temperature for 16 h. Water (25 mL) was added to the reaction solution,
and the mixture was extracted with EtOAc (3î30 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. After purification via flash column chromatogra-
phy (EtOAc/Hex 1:6), the solid residue was recrystallized through vapor
1
Isomer 42b: H NMR (400 MHz, CDCl3): d=7.52 (d, J=8.8 Hz, 1H, Ar-
H), 7.05 (d, J=2.4 Hz, 1H, Ar-H), 6.97 (dd, J=8.8, 2.4 Hz, 1H, Ar-H),
6.19 (d, J=1.2 Hz), 5.59 (d, J=2.4 Hz, 1H), 5.45 (t, J=5.6 Hz, 1H), 5.15
(dd, J=5.6, 2.4 Hz, 1H), 5.03 (dd, J=3.6, 5.6 Hz, 1H), 4.49 4.46 (m, 1
H), 4.32 4.19 (m, 1H), 2.41 (d, J=1.2 Hz, 3H), 2.19 2.07 (m, 9H), 2.01
(s, 3H); 13C NMR (100 MHz, CDCl3): d=170.29 (C), 169.53 (C), 169.39
(C), 168.52 (C), 154. 74 (C), 151.97 (C), 125.48 (CH), 115.16 (C), 113.65
diffusion method to give 47 (2.15 g, 90%) as colorless crystals. [a]D33
=
408
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 399 415

Biologically Potent l-Hexose Derivatives
399 415
ꢀ69.12 (c=1.0, CHCl3); IR (CHCl3): n˜ =2109, 1727, 1272, 1112 cmꢀ1
;
252.0997; found: 252.0992 [M +]; elemental analysis calcd (%) for
C13H16O5: C 61.90, H 6.39; found: C 61.65, H 6.35.
1H NMR (400 MHz, CDCl3): d=8.06 (dd, J=8.0, 1.4 Hz, 2H, Bz-H), 7.98
(dd, J=8.0, 1.4 Hz, 2H, Bz-H), 7.56 7.54 (m, 2H, Bz-H), 7.45 7.40 (m, 4
H, Bz-H), 5.75 (dd, J=9.6, 5.3 Hz, 1H, H-3), 5.65 (dd, J=9.6, 4.2 Hz, 1
H, H-4), 5.56 (d, J=2.2 Hz, 1H, H-1), 4.85 (t, J=4.2 Hz, 1H, H-5), 4.27
(d, J=8.1 Hz, 1H, H-6a), 4.18 (dd, J=5.3, 2.2 Hz, 1H, H-2), 3.82 (dd,
J=8.1, 4.2 Hz, 1H, H-6b); 13C NMR (100 MHz, CDCl3): d=165.59 (C),
165.30 (C), 133.67 (CH), 130.00 (CH), 129.79 (CH), 128.83 (C), 128.55
(CH), 100.58 (CH), 72.59 (CH), 69.69 (CH), 69.44 (CH), 64.84 (CH2),
61.92 (CH); HRMS (FAB): calcd for C20H17N3O6: 396.1196; found:
396.1209 [M +].
1,6-Anhydro-3-O-benzyl-b-l-allopyranose (52): Compound 51 (0.50 g,
1.98 mmol) was dissolved in pyridine (10 mL) at room temperature under
nitrogen, the mixture was cooled to 08C, trifluoromethanesulfonic anhy-
dride (1.0 mL, 5.95 mmol) was added to the solution, and the ice-bath
was removed. After stirring for 16 h, the reaction was quenched with
water (1 mL), and the solvent was coevaporated with toluene under re-
duced pressure. The residue was dissolved in EtOAc (15 mL), and the
mixture was consecutively washed with aq 2n HCl, aq sat NaHCO3, and
brine. The organic phase was dried over MgSO4, filtered, and concentrat-
ed in vacuo to give a residue, which was recrystallized in ethanol to yield
the corresponding 2,4-di-OTf derivative as a white solid (927 mg, 88%).
[a]2D3 =+32.8 (c=1.1, CHCl3); m.p. 117 1188C; IR (CHCl3): n˜ =2974,
6-O-Acetyl-2-azido-3,4-di-O-benzoyl-2-deoxy-l-gulopyranosyl
acetate
(48): Compound 47 (0.10 g, 0.25 mmol) was dissolved in dichloromethane
(1 mL) followed by consecutive addition of acetic anhydride (2 mL), tri-
fluoroacetic acid (0.4 mL), and a solution of 1% H2SO4 in acetic anhy-
dride (0.5 mL) at room temperature under nitrogen. The mixture was
kept stirring for 2 h, the reaction flask was immersed in an ice-bath, and
the reaction was quenched by aq sat NaHCO3 (10 mL). The mixture was
extracted with dichloromethane (3î10 mL), and the combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo to
3076, 1723, 1415, 1274, 1211, 1246, 1241, 1203, 1139, 1100, 927, 702 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.42 7.28 (m, 5H, Ar-H), 5.62 (s, 1H,
H-1), 4.99 (dd, J=8.0, 4.0, H-2), 4.80 (ddd, J=4.8, 4.0, 1.2 Hz, H-5), 4.79
(s, 1H, CH2Ph), 4.78 (s, 1H, CH2Ph), 4.75 (d, J=8.0, 1.2 Hz, H-4), 4.21
(d, J=8.6 Hz, H-6a), 4.13 (t, J=8.0 Hz, H-3), 3.95 (dd, J=8.6, 4.8 Hz, H-
6b); 13C NMR (100 MHz, CDCl3): d = 135.81 (CH), 128.68 (CH), 28.64
(CH), 28.53 (CH), 118.43 (q, J=299.8 Hz, C), 98.97 (CH), 86.35 (CH),
83.06 (CH), 76.39 (CH2), 75.95 (CH), 73.05 (CH), 65.91 (CH2); HRMS
(FAB): calcd for C15H15F6O9S2: 517.00617; found: 517.0233 [M+H+]; ele-
mental analysis calcd (%) for C14H15F6O9S2: C 34.89, H 2.73; found: C
34.89, H 2.69.
1
afford 48 (112 mg, 89%). 48b: H NMR (400 MHz, CDCl3): d=8.10 8.06
(m, 4H, Bz-H), 7.65 7.60 (m, 2H, Bz-H), 7.51 7.47 (m, 4H, Bz-H), 6.12
(d, J=8.6 Hz, 1H, H-1), 5.73 (t, J=4.0 Hz, 1H, H-3), 5.35 (dd, J=4.0,
1.4 Hz, 1H, H-4), 4.48 (dt, J=6.4, 1.4 Hz, 1H, H-5), 4.26 4.18 (m, 2H,
H-6a, H-6b), 4.00 (dd, J=8.6, 4.0 Hz, 1H, H-2), 2.23 (s, 3H, CH3), 1.98
(s, 3H, CH3).
A mixture of this 2,4-di-OTf compound (50 mg, 0.09 mmol), NaNO2
(67 mg, 1.0 mmol), and [15]crown-5 (0.22 mL, 1.0 mmol) in HMPA
(1 mL) was stirred at room temperature for 24 h. Water (3 mL) was
added to the reaction solution, and the mixture was extracted with
EtOAc (2î5 mL). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo, and the residue
was purified by flash column chromatography on silica gel (EtOAc/Hex
2:1) to provide 52 (11.5 mg, 47%) as a colorless oil. [a]2D3 =ꢀ18.6 (c=
0.25, CHCl3); IR (CHCl3): n˜ =3412, 3052, 2949, 1413, 1211, 1138,
1,6-Anhydro-2,3,4-tri-O-trimethylsilyl-b-l-idopyranose (49): Triethyla-
mine (5.5 mL, 40 mmol) at room temperature under nitrogen was added
to a solution of compound 35 (1.28 g, 7.89 mmol) in dichloromethane
(26 mL). The mixture was cooled to 08C, and trimethylsilyl chloride
(4.0 mL, 32 mmol) was slowly added to the reaction solution. The ice-
bath was removed, and the reaction was kept stirring at room tempera-
ture for 3.5 h. The mixture was evaporated under reduced pressure, the
residue was diluted with hexane (20 mL), and the salt was filtered fol-
lowed by washings with hexane. The filtrate was concentrated in vacuo,
and the resulting residue was recrystallized in ethanol to get 49 as a
white solid (2.93 g, 98%). [a]D30 =+43.3 (c=1.0, CHCl3); m.p. 65 668C;
1
946 cmꢀ1; H NMR (400 MHz, CDCl3): d=7.62 7.28 (m, 5H, Ar-H), 5.47
(d, J=1.5 Hz, 1H, H-1), 4.89 (dd, J=8.2, 1.5 Hz, 1H, H-2), 4.76 (d, J=
11.7 Hz, 1H, CH2Ph), 4.60 (dd, J=5.5, 2.5 Hz, 1H, H-4), 4.54 (d, J=
11.7 Hz, 1H, CH2Ph), 3.89 3.82 (m, 3H, H-3, H-5, H-6a), 3.62 (d, J=
8.2 Hz, H-6b), 2.15 1.91 (br, 2H, 2-OH, 4-OH); 13C NMR (100 MHz,
CDCl3): d=137.45 (C), 128.77 (CH), 128.35 (CH), 128.00 (CH), 78.14
(CH), 74.18 (CH), 71.86 (CH2), 68.94 (CH), 67.87 (CH), 63.58 (CH2).
IR (CHCl3): n˜ = 3476, 3303, 2955, 1129, 1062, 1027, 956 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=5.18 (d, J=1.6 Hz, 1H, H-1), 4.26 (t, J=4.6 Hz, 1
H, H-5), 4.08 (d, J=7.5 Hz, 1H, H-6a), 3.69 (dd, J=7.5, 4.6 Hz, 1H, H-
4), 3.68 (dd, J=7.5, 4.6 Hz, 1H, H-6b), 3.56 (t, J=7.5 Hz, 1H, H-3), 3.47
(dd, J=7.5, 1.6 Hz, 1H, H-2), 0.17 (s, 9H, SiMe3), 0.14 (s, 9H, SiMe3),
0.13 (s, 9H, SiMe3); 13C NMR (75 MHz, CDCl3): d=102.06 (CH), 76.35
(CH), 75.72 (CH), 72.91 (CH), 65.07 (CH2), 0.87 (CH3), 0.35 (CH3); ele-
mental analysis calcd (%) for C15H34O5Si3: C 47.62, H 8.99; found: C
47.50, H 9.03.
1,6-Anhydro-2-O-benzoyl-3-O-benzyl-b-l-idopyranose (53): Pyridine
(3.0 mL, 37.2 mmol) at room temperature under nitrogen was added to a
solution of compound 51 (3.00 g, 11.9 mmol) in dichloromethane
(35 mL). The reaction flask was immersed in an ice-bath, and benzoyl
chloride (1.45 mL, 12.5 mmol) was slowly added to the mixture. After
stirring at the same temperature for 4 h, the reaction was quenched by
methanol (2 mL), and the solvent was evaporated with toluene under re-
duced pressure. The residue was dissolved in EtOAc (30 mL), and the
mixture was sequentially washed with aq 2n HCl, aq sat NaHCO3, water,
and brine. The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo to furnish a solid residue, which was recrystal-
lized via vapor diffusion method to get 53 (3.60 g, 85%) as colorless crys-
1,6-Anhydro-3-O-benzyl-b-l-idopyranose
(51):
TMSOTf
(18 mL,
0.10 mmol) was added to a mixture of compound 49 (0.38 g, 1.0 mmol),
benzaldehyde (0.15 mL, 1.5 mmol), and freshly dried 3 ä molecular
sieves (0.76 g) in dichloromethane (8 mL) at ꢀ788C under nitrogen. The
solution was stirred at the same temperature for 1 h, triethylsilane
(0.24 mL, 1.5 mmol) was added to the mixture, and the reaction was kept
stirring for another 1 h. A 1m solution of tetra-n-butylammonium fluo-
ride in THF (4 mL, 4 mmol) was added to the reaction mixture, and the
resulting solution was further stirred for 1.5 h followed by addition of aq
sat NH4Cl (15 mL). The mixture was extracted with ethyl acetate (3î
15 mL), and the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography on silica gel (EtOAc/Hex 3:2) to
give a white solid, which was further recrystallized via vapor diffusion
method to produce 51 (181 mg, 72%) as colorless crystals. [a]2D7 =+69.2
(c=1.0, MeOH); m.p. 158 1598C; IR (CHCl3): n˜ = 3301, 1128, 1028,
tals. [a]2D7 =+127.5 (c=1.2, CHCl3); m.p. 142 1438C; IR (CHCl3): n˜
3473, 2904, 1722, 1452, 1272, 1113, 1027, 712 cmꢀ1 1H NMR (400 MHz,
=
;
CDCl3): d=8.08 (dd, J=7.6, 1.3 Hz, 2H, Bz-H), 7.59 (tt, J=7.6, 1.3 Hz, 1
H, Bz-H), 7.46 (t, J=7.6 Hz, 2H, Bz-H), 7.29 7.24 (m, 5H, Ar-H), 5.53
(d, J=1.6 Hz, 1H, H-1), 5.07 (dd, J=8.2, 1.6 Hz, 1H, H-2), 4.80 (d, J=
11.6 Hz, 1H, CH2Ph), 4.65 (d, J=11.6 Hz, 1H, CH2Ph), 4.51 (t, J=
4.6 Hz, 1H, H-5), 4.15 (d, J=7.5 Hz, 1H, H-6a), 4.00 (ddd, J=8.2, 4.6,
3.0 Hz, 1H, H-4), 3.87 (t, J=8.2 Hz, 1H, H-3), 3.76 (dd, J=7.5, 4.6 Hz, 1
H, H-6b), 2.22 (d, J=3.0 Hz, 1H, 4-OH); 13C NMR (100 MHz, CDCl3):
d=165.77 (C), 137.94 (C), 133.38 (CH), 129.81 (CH), 129.40 (C), 128.53
(CH), 128.45 (CH), 127.96 (CH), 127.84 (CH), 99.41 (CH), 80.24 (CH),
76.71 (CH), 75.07 (CH), 74.58 (CH2), 71.33 (CH), 65.27 (CH); HRMS
(FAB): calcd for C20H21O6: 357.1338; found: 357.1353 [M+H+]; elemen-
tal analysis calcd (%) for C20H20O6: C 67.41, H 5.61; found: C 67.20, H
5.44.
1
949 cmꢀ1; H NMR (400 MHz, CDCl3): d=7.36 7.28 (m, 5H, Ph-H), 5.27
(d, J=1.8 Hz, 1H, H-1), 4.93 (d, J=11.7 Hz, 1H, CH2Ph), 4.72 (d, J=
11.7 Hz, 1H, CH2Ph), 4.41 (t, J=4.9 Hz, 1H, H-5), 4.01 (d, J=7.8 Hz, 1
H, H-6a), 3.85 (ddd, J=7.8, 4.9, 3.3 Hz, 1H, H-4), 3.71 (dd, J=7.8,
4.9 Hz, 1H, H-6b), 3.64 (dt, J=7.8, 1.8 Hz, 1H, H-2), 3.37 (t, J=7.8 Hz,
1H, H-3), 2.09 (d, J=3.3 Hz, 1H, 4-OH), 1.89 (d, J=7.8 Hz, 1H, 2-OH);
13C NMR (75 MHz, CDCl3): d=138.40 (C), 128.68 (CH), 128.03 (CH),
127.88 (CH), 101.82 (CH), 84.19 (CH), 75.44 (CH), 74.99 (CH), 74.50
(CH2), 71.07 (CH), 65.05 (CH2); HRMS (FAB): calcd for C13H16O5:
1,6-Anhydro-2-O-benzoyl-3-O-benzyl-4-O-trifluoromethanesulfonyl-b-l-
idopyranose (54): A solution of benzoyl chloride (49 mL, 0.42 mmol) in
dichloromethane (0.7 mL) was added to a mixture of compound 51
409
Chem. Eur. J. 2004, 10, 399 415
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S.-C. Hung et al.
FULL PAPER
(0.10 g, 0.40 mmol) in pyridine (0.5 mL) at 08C under nitrogen. After stir-
ring at the same temperature for 4 h, trifluoromethanesulfonic anhydride
(0.20 mL, 1.2 mmol) was added to the reaction solution, the ice-bath was
removed, and the mixture was kept stirring at room temperature for an-
other 1 h. The reaction was quenched by addition of MeOH (0.5 mL),
and the mixture was coevaporated with toluene under reduced pressure.
The solid residue was dissolved in water (4 mL), the mixture was extract-
ed with EtOAc (3î5 mL), and the combined organic layers were washed
with aq 2n HCl, then brine. The organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/Hex 1:4) to furnish a white
solid, which was recrystallized through vapor diffusion method to afford
54 (0.17 g, 88%) as colorless crystals. [a]2D5 =+147.1 (c=1.0, CHCl3);
m.p. 125 1268C; IR (CHCl3): n˜ =1726, 1417, 1270, 1245, 1212, 1142,
74.16 (CH), 72.53 (CH2), 66.32 (CH2), 60.99 (CH); HRMS (FAB): calcd
for C20H20O5N3: 382.1429; found: 382.1439 [M+H+]; elemental analysis
calcd (%) for C20H19N3O5: C 62.98, H 5.02, N 11.01; found: C 63.23, H
5.01, N 11.09.
1,6-Anhydro-2,4-di-O-benzoyl-b-d-mannopyranose (58): N-Benzoyloxy-
benzotriazole (5.31 g, 22.2 mmol) at room temperature under nitrogen
was added to a solution of 57 (3.00 g, 18.5 mmol) in pyridine (60 mL).
The reaction mixture was stirred for 28 h, the same amount of N-benzoyl-
oxybenzotriazole (5.31 g, 22.2 mmol) was added to the solution, and the
mixture was kept stirring for another 48 h. The solvent was coevaporated
with toluene under reduced pressure, water (80 mL) was added to the
solid residue, and the mixture was extracted with EtOAc (2î150 mL).
The combined organic layers were washed with brine, dried over anhy-
drous MgSO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (EtOAc/Hex 1:2!2:1) to furnish a
white solid, which was recrystallized through vapor diffusion method to
afford 58 (3.70 g, 54%) as colorless crystals. IR (CHCl3): n˜ =3552, 2963,
937 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.99 (dd, J=8.4, 1.3 Hz, 2H,
;
Bz-H), 7.58 (tt, J=8.4, 1.3 Hz, 1H, Bz-H), 7.44 (t, J=8.4 Hz, 2H, Bz-H),
7.23 (s, 5H, Ar-H), 5.56 (d, J=1.8 Hz, 1H, H-1), 5.10 (dd, J=8.2, 1.8 Hz,
H-2), 5.01 (dd, J=8.2, 4.6 Hz, H-4), 4.77 (t, J=4.6 Hz, 1H, H-5), 4.73 (d,
J=11.0 Hz, 1H, CH2Ph), 4.66 (d, J=11.0 Hz, 1H, CH2Ph), 4.18 (d, J=
8.1 Hz, 1H, H-6a), 4.12 (t, J=8.2 Hz, H-3), 3.88 (dd, J=8.1, 4.6 Hz, 1H,
H-6b); 13C NMR (75 MHz, CDCl3): d=165.34 (C), 136.65 (C), 133.67
(CH), 129.88 (CH), 128.91 (C), 128.54 (CH), 128.39 (CH), 128.06 (CH),
127.96 (CH), 120.84 (q, J=317.5 Hz, CF3), 99.40 (CH), 83.77 (CH), 76.78
(CH), 76.58 (CH), 75.23 (CH2), 73.03 (CH), 65.42 (CH2); HRMS (FAB):
calcd for C21H20F3O8S: 489.0830; found: 489.0854 [M+H+]; elemental
analysis calcd (%) for C21H19F3O8S: C 51.64, H 3.89; found: C 51.15, H
3.73.
1720, 1601, 1451, 1317, 1266, 1108, 1071, 1028, 986, 710 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=8.08 (d, J=7.8 Hz, 4H, Bz-H), 7.58 (t, J=8.1 Hz,
2H, Bz-H), 7.47 7.43 (m, 4H, Bz-H), 5.66 (s, 1H, H-1), 5.24 (d, J=
1.6 Hz, 1H, H-4), 5.18 (dd, J=5.2, 1.6 Hz, 1H, H-2), 4.78 (d, J=5.4 Hz, 1
H, H-5), 4.44 (d, J=7.6 Hz, 1H, H-6a), 4.37 (t, J=1.6 Hz, 1H, H-3), 3.86
(dd, J=7.6, 5.4 Hz, 1H, H-6b), 3.00 (s, 1H, 3-OH); 13C NMR (100 MHz,
CDCl3): d=165.29 (C), 165.27 (C), 133.67 (CH), 133.57 (CH), 133.52
(CH), 129.31 (C), 128.99 (C), 128.36 (CH), 100.07 (CH), 74.32 (CH), 73.
74 (CH), 69.90 (CH), 68.58 (CH), 65.58 (CH2); HRMS (FAB): calcd for
C20H19O7: 371.1131; found: 371.1154 [M+H+]; elemental analysis calcd
(%) for C20H18O7: C 64.86, H 4.90; found: C 64.98, H 4.78.
1,6-Anhydro-2-O-benzoyl-3-O-benzyl-b-l-altropyranose (55): Compound
54 (50 mg, 0.10 mmol) was dissolved in HMPA (1 mL) at room tempera-
ture, NaNO2 (70 mg, 1.0 mmol) and [15]crown-5 (40 mL, 0.20 mmol) were
consecutively added to the reaction solution, and the mixture was kept
stirring for 3 d. The resulting solution was filtered through Celite, and the
filtrate was diluted with EtOAc (10 mL), which was sequentially washed
by water (4î6 mL) and brine. The organic layer was dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (EtOAc/Hex 1:1) to yield 55
(30.6 mg, 84%) as a white solid. [a]2D5 =+199.5 (c=1.0, CHCl3); m.p. 99
1008C; IR (CHCl3): n˜ =3481, 2918, 1718, 1453, 1273, 1110, 1030,
1,6-Anhydro-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)formyl]-b-d-manno-
pyranose (59): A mixture of compound 58 (90 mg, 0.24 mmol) and
DMAP (0.12 g, 0.97 mmol) in pyridine (0.90 mL) was stirred at room
temperature under nitrogen, p-nitrophenyl chloroformate (0.20 g,
0.97 mmol) was added to the solution, and the reaction was kept stirring
for 48 h. The solvent was coevaporated with toluene under reduced pres-
sure, the residue was partitioned between EtOAc (5 mL) and H2O
(3 mL), and the aqueous phase was extracted with EtOAc (2î5 mL).
The combined organic layers were consecutively washed by aq 2n HCl,
aq 5% K2CO3, and brine. The organic phase was dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc/Hex 2:5) to provide 59 (117 mg, 89%)
as a syrup. 1H NMR (400 MHz, CDCl3): d=8.15 (t, J=9.2, 1.4 Hz, 2H,
Ph-H), 8.08 (dd, J=8.6, 1.2 Hz, 2H, p-NO2Ph-H), 7.64 (dd, J=7.5,
1.4 Hz, 2H, Ph-H), 7.51 (t, J=7.9 Hz, 2H, Ph-H), 7.46 (t, J=7.9 Hz, 2H,
Ph-H), 7.14 (d, J=8.6, 1.2 Hz, 2H, p-NO2Ph-H), 5.71 (d, J=1.7 Hz, 1H,
H-1), 5.51 (ddd, J=5.4, 3.3, 1.0 Hz, 1H, H-3), 5.44 (dd, J=5.4, 1.7 Hz, 1
H, H-2), 5.33 (t, J=3.3 Hz, 1H, H-4), 4.85 (d, J=5.3 Hz, 1H, H-5), 4.41
(dd, J=7.9, 1.0 Hz, 1H, H-6a), 4.01 (dd, J=7.9, 5.3 Hz, 1H, H-6b);
13C NMR (100 MHz, CDCl3): d=165.35 (C), 165.25 (C), 155.25 (C),
151.88 (C), 145.60 (C), 134.07(CH), 133.89 (CH), 130.17(CH), 129.99
(CH),129.12 (CH), 128.74 (CH), 125.34 (CH), 121.70 (CH), 99.50 (CH),
74.11(CH), 72.89 (CH), 72.05 (CH), 67.61 (CH), 65.61 (CH2); HRMS
(FAB): calcd for C27H22O11N: 536.1194; found: 536.1205 [M+H+]; ele-
mental analysis calcd (%) for C27H17O11N: C 60.56, H 4.95, N 3.62;
found: C 60.74, H 4.18, N 5.31.
713 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.01 (dd, J=8.5, 1.1 Hz, 2H,
;
Bz-H), 7.57 (tt, J=8.5, 1.1 Hz, 1H, Bz-H), 7.43 (t, J=8.5 Hz, 2H, Bz-H),
7.23 (s, 5H, Ar-H), 5.53 (d, J=1.7 Hz, 1H, H-1), 5.21 (dd, J=8.6, 1.7 Hz,
H-2), 4.71 (dd, J=5.4, 2.2 Hz, H-5), 4.68 (d, J=12.1 Hz, 1H, CH2Ph),
4.60 (d, J=12.1 Hz, 1H, CH2Ph), 3.98 (dd, J=4.5, 2.2 Hz, 1H, H-4), 3.88
(dd, J=8.6, 4.5, 1H, H-3), 3.80 (dd, J=7.9, 5.4 Hz, 1H, H-6a), 3.71 (d,
J=7.9, 1H, H-6b), 2.98 2.89 (bs, 1H, 4-OH); 13C NMR (100 MHz,
CDCl3): d=165.77 (C), 137.06 (C), 133.30 (CH), 129.85 (CH), 129.50 (C),
128.55 (CH), 128.38 (CH), 128.16 (CH), 127.85 (CH), 99.30 (CH), 75.97
(CH), 74.31 (CH), 74.09 (CH), 72.14 (CH2), 68.41 (CH), 65.46 (CH2);
HRMS (FAB): calcd for C21H20O6: 357.1338; found: 357.1327 [M+H+];
elemental analysis calcd (%) for C20H19O6: C 67.57, H 5.57; found: C
67.40, H 5.66.
1,6-Anhydro-4-azido-2-O-benzoyl-3-O-benzyl-4-deoxy-b-l-altropyranose
(56): A mixture of 54 (60 mg, 0.12 mmol) and NaN3 (33 mg, 0.51 mmol)
in DMF (1 mL) was stirred at 508C for 18 h. The solvent was coevaporat-
ed with toluene under reduced pressure, the syrup was dissolved in water
(3 mL), and the mixture was extracted with EtOAc (3î5 mL). The com-
bined organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/Hex 1:4) to give a white solid, which was re-
crystallized via vapor diffusion method to yield 56 (45.4 mg, 97%) as col-
orless crystals. [a]2D5 =+193.4 (c=1.0, CHCl3); m.p. 132 1338C; IR
6-O-Acetyl-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)fomyl]-a-d-mannopyr-
anosyl bromide (60): Cu(OTf)2 (1.1 mg, 3.0 mmol) was added to a solution
of 59 (32.6 mg, 61 mmol) in acetic anhydride (115 mL) at room tempera-
ture under argon, and the mixture was kept stirring for 24 h. The reaction
flask was immersed in an ice-bath, a 30% solution of HBr in acetic acid
(164 mL, 0.61 mmol) was added to the reaction solution, and the mixture
was gradually warmed up to room temperature and kept stirring over-
night. The whole solution was poured into ice-water (5 mL), the mixture
was extracted with EtOAc (3î10 mL), and the combined organic layers
were washed with aq sat NaHCO3 twice, then brine. The resulting organ-
ic phase was dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication of the residue via flash column chromatography (EtOAc/Hex
1:3) led to the bromide 60 (36.1 mg, 90%). 1H NMR (400 MHz, CDCl3):
d = 8.18 8.07 (m, 6H, Ar-H), 7.65 (t, J=7.4 Hz, 2H, Ar-H), 7.54 7.50
(m, 4H, Ar-H), 7.18 (d, J=9.1 Hz, 2H, Ar-H), 6.54 (d, J=1.4 Hz, 1H, H-
1), 5.99 5.89 (m, 3H, H-2, H-3, H-4), 4.49 (dt, J=7.2, 3.5 Hz, 1H, H-5),
4.40 4.32 (m, 2H, H-6a, H-6b), 2.10 (s, 3H, CH3); 13C NMR (100 MHz,
(CHCl3): n˜ =2904, 2111, 1717, 1453, 1271, 1113, 1030, 980, 715 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=8.01 (dd, J=8.5, 1.4 Hz, 2H, Bz-H), 7.57
(tt, J=8.5, 1.4 Hz, 1H, Bz-H), 7.43 (t, J=8.5 Hz, 2H, Bz-H), 7.28 7.23
(m, 5H, Ar-H), 5.55 (d, J=1.7 Hz, 1H, H-1), 5.23 (dd, J=8.9, 1.7 Hz, H-
2), 4.70 (d, J=12.2 Hz, 1H, CH2Ph), 4.64 (d, J=12.2 Hz, 1H, CH2Ph),
4.62 (dd, J=4.7, 2.1 Hz, H-5), 4.09 (dd, J=8.9, 5.0 Hz, 1H, H-3), 3.80
(dd, J=5.0, 2.1 Hz, 1H, H-4), 3.78 (dd, J=8.1, 4.7 Hz, 1H, H-6a), 3.71
(d, J=8.1 Hz, 1H, H-6b); 13C NMR (100 MHz, CDCl3): d=165.63 (C),
137.15 (C), 133.36 (CH), 129.88 (CH), 129.44 (C), 128.55 (CH), 128.42
(CH), 128.13 (CH), 127.90 (CH), 99.61 (CH), 75.68 (CH), 74.39 (CH),
410
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 399 415

Biologically Potent l-Hexose Derivatives
399 415
CDCl3): d = 170.32 (C), 165.09 (C), 155.05 (C), 151.44 (C), 145.57 (C),
134.16 (CH), 134.07 (CH), 130.03 (CH), 129.99 (CH), 129.02 (CH),
128.75 (C), 125.18 (CH), 121.78 (CH), 82.67 (CH), 73.49 (CH), 72.83
(CH), 72.01 (CH), 65.99 (CH), 61.58 (CH2), 20.57 (CH3); HRMS (FAB):
calcd for C29H24BrO12NNa: 658.0560; found: 658.0563 [M+Na+].
(CH), 68.52 (CH), 66.50 (CH), 64.57 (CH2), 62.62 (CH2), 20.61 (CH3);
HRMS (MALDI): calcd for C49H41NO19Na: 970.2170; found: 970.2168
[M+Na+].
6-O-Acetyl-2-O-{6-O-acetyl-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)form-
yl]-a-d-mannopyranosyl}-3,4-di-O-benzoyl-l-gulopyranosyl acetate (64):
Cu(OTf)2 (0.9 mg, 2.5 mmol) was added to a solution of compound 63
(20.3 mg, 21.4 mmol) in acetic anhydride (203 mL) at room temperature
under argon. After stirring for 4 d, the reaction was quenched with aq sat
NaHCO3 (3 mL), and the mixture was extracted with EtOAc (3î5 mL).
The combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue via flash
column chromatography (EtOAc/Hex 2:5) provided 63 (3.5 mg) and 64
(13.8 mg, 61%, recovery yield=74%). [a]2D8 =ꢀ59.02 (c=0.61, CHCl3);
6-O-Acetyl-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)formyl]-d-mannopyra-
nose (61): Compound 60 (20.3 mg, 30 mmol) was dissolved in 0.5% wet
acetone (0.50 mL) at room temperature. AgOTf (8.7 mg, 30 mmol) and
2,6-di-tert-butyl-4-methylpyridine (3.6 mg, 18 mmol) were consecutively
added to the solution, and the mixture was kept stirring for 1 h followed
by addition of 2,6-di-tert-butyl-4-methylpyridine (3.6 mg, 18 mmol). The
whole reaction mixture was filtered through Celite, and the filtrate was
concentrated in vacuo to give a residue, which was purified by flash
column chromatography (EtOAc/Hex 1:2) to furnish the product 61
(17.1 mg, 93%). 1H NMR (400 MHz, CDCl3): d=8.01 (d, J=9.2 Hz, 2H,
Bz-H), 7.56 (t, J=7.6 Hz, 2H, Ar-H), 7.60 7.42 (m, 4H, Ar-H), 7.05 (d,
J=9.2 Hz, 2H, Ar-H), 5.75 (t, J=10.0 Hz, 1H, H-4), 5.67 (dd, J=3.2,
1.6 Hz, 1H, H-2), 5.58 (dd, J=10.0, 3.2 Hz, 1H, H-3), 5.41 (dd, J=4.1,
1.6 Hz, 1H, H-1), 4.41 (ddd, J=10.0, 7.7, 4.2 Hz, 1H, H-5), 4.30 4.20 (m,
2H, H-6a, H-6b), 3.32 (d, J=4.1 Hz, 1H, 1-OH); 13C NMR (75 MHz,
CDCl3): d=170.84 (C), 165.61 (C), 165.30 (C), 155.16 (C), 151.50 (C),
145.43 (C), 133.83 (CH), 129.89 (CH), 128.90 (C), 128.76 (CH), 128.65
(CH), 128.59 (CH), 125.10 (CH), 121.81 (CH), 92.18 (CH), 74.33 (CH),
69.96 (CH), 68.44 (CH), 66.98 (CH), 62.68 (CH2), 20.62 (CH3); HRMS
(MALDI): calcd for C29H25NO13Na: 618.1224; found: 618.1200 [M+Na+].
IR (CHCl3): n˜ =2919, 1728, 1247, 1087, 708 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=8.22 (dd, J=8.5, 1.4 Hz, 0.9H, Ar-H), 8.15 (dd, J=8.5,
1.4 Hz, 2.3H, Ar-H), 8.13 8.05 (m, 10.4H, Ar-H), 7.96 (dd, J=8.0,
1.4 Hz, 2.1H, Ar-H), 7.67 7.59 (m, 6.4H, Ar-H), 7.53 7.42 (m, 13.1H,
Ar-H), 7.14 7.08 (m, 3.0H, Ar-H), 6.56 (d, J=4,0 Hz, 0.4H), 6.15 (d, J=
8.2 Hz, 1.0H), 5.94 (t, J=3.7 Hz, 1.0H), 5.82 (t, J=3.5 Hz, 0.4H), 5.76
5.70 (m, 1.4H), 5.61 (dd, J=3.2, 1.9 Hz, 1.0H), 5.56 (dd, J=3.2, 1.9 Hz,
0.4H), 5.54 (d, J=3.5 Hz, 0.4H), 5.48 (dd, J=4,0, 1.5 Hz, 1.0H), 5.36
5.33 (m, 2.5H), 5.20 (dd, J=10.1, 3.2 Hz, 0.4H), 4.85 (t, J=6.4 Hz, 0.4
H), 4.68 (dt, J=1.3, 6.4 Hz, 1.0H), 4.47 (t, J=3.9 Hz, 0.4H), 4.39 (m, 9.1
H), 2.23 (s, 3.0H, CH3), 2.09 2.08 (m, 6.0H, CH3), 2.05 (s, 1.5H, CH3),
2.03 (s, 3.0H, CH3); 13C NMR (100 MHz, CDCl3): d=170.44 (C), 170.39
(C), 169.60 (C), 168.71 (C), 165.15 (C), 165.10 (C), 165.04 (C), 165.00
(C), 164.87 (C), 155.25 (C), 155.17 (C), 151.16 (C), 151.10 (C), 145.40
(C), 145.36 (C), 133.97 (CH), 133.89 (CH), 133.76 (CH), 130.12 (CH),
130.02 (CH), 129.97 (CH), 129.93 (CH), 129.78 (CH), 128.84 (C), 128.70
(CH), 128.61 (CH), 128.54 (CH), 125.03 (CH), 121.82 (CH), 95.67 (CH),
95.39 (CH), 90.99 (CH), 89.54 (CH), 74.16 (CH), 71.90 (CH), 70.74
(CH), 69.61 (CH), 69.29 (CH), 68.56 (CH), 68.48 (CH), 68.34 (CH),
68.23 (CH), 67.68 (CH), 66.66 (CH), 66.37 (CH), 66.10 (CH), 64.32
(CH), 62.42 (CH2), 62.33 (CH2), 61.91 (CH2), 61.79 (CH2), 20.97 (CH3),
20.92 (CH3), 20.69 (CH3), 20.65 (CH3), 20.57 (CH3); HRMS (MALDI):
calcd for C53H47NO22Na: 1072.2487; found: 1072.2478 [M+Na+].
6-O-Acetyl-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)formyl]-a-d-mannopyr-
anosyl trichloroacetimidate (62): Potassium carbonate (249 mg,
1.81 mmol) at room temperature under nitrogen was added to a mixture
of 61 (215 mg, 0.36 mmol) and trichloroacetonitrile (362 mL, 3.61 mmol)
in dichloromethane (2 mL). After stirring for 6 h, the reaction mixture
was filtered through Celite, and the organic layer was washed with water
(2 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 62
(238 mg, 89%). [a]2D4 =ꢀ82.0 (c=0.25, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.89 (s, 1H, NH), 8.17 (d, J=9.2 Hz, 2H, Bz-H), 8.15 (d, J=
9.2 Hz, 2H, Ar-H), 8.07 (d, J=7.6 Hz, 2H, Ar-H), 7.65 (dd, J=7.6,
7.2 Hz, 2H, Ar-H), 7.29 (d, J=7.2 Hz, 2H, Ar-H), 7.19 (d, J=9.2 Hz, 2
H, Ar-H), 6.54 (s, 1H, H-1), 5.96 (d, J=3.1 Hz, 1H, H-2), 5.93 (t, J=
10.1 Hz, 1H, H-4), 5.61 (dd, J=10.1, 3.1 Hz, 1H, H-3), 4.45 (ddd, J=
10.1, 6.8, 3.6 Hz, 1H, H-5), 4.33 (dd, J=12.3, 6.8 Hz, 1H, H-6a), 4.32 (dd,
J=12.3, 3.6 Hz, 1H, H-6b), 2.08 (s, 1H, CH3); 13C NMR (100 MHz,
CDCl3): d=170.37 (C), 165.28 (C), 165.12 (C), 159.70 (C), 155.12 (C),
151.56 (C), 145.62 (C), 134.05(CH), 133.95 (CH), 130.04 (CH), 130.00
(CH), 128.69 (CH), 128.59 (C), 125.18 (CH), 121.88 (CH), 94.59 (CH),
74.33 (CH), 71.25 (CH), 67.77 (CH), 66.03 (CH), 62.68 (CH2), 20.54
(CH3).
6-O-Acetyl-2-O-(6-O-acetyl-2,4-di-O-benzoyl-3-O-carbamoyl-a-d-manno-
pyranosyl)-3,4-di-O-benzoyl-l-gulopyranose (65):
A solution of com-
pound 64 (11.2 mg, 10.7 mmol) in THF (3 mL) was saturated with ammo-
nia gas at room temperature, and the mixture was kept stirring for 5 h.
Evaporation of the mixture in vacuo furnished a residue followed by pu-
rification through flash column chromatography (EtOAc/Hex 1:1) to
yield 65 (7.3 mg, 77%). [a]D28 =ꢀ79.4 (c=0.14, CHCl3); IR (CHCl3): n˜ =
3448, 2913, 1723, 1257, 1116, 709 cmꢀ1 1H NMR (400 MHz, CDCl3): d=
;
8.14 8.11 (m, 4.2H, Bz-H), 8.07 (d, J=7.2 Hz, 2.4H, Bz-H), 7.98 (dd, J=
8.4, 1.2 Hz, Bz-H), 7.66 7.58 (m, 3.7H, Bz-H), 7.56 7.52 (m, 3.2H, Bz-
H), 7.51 7.41 (m, 8.1H, Bz-H), 5.85 (t, J=3.6 Hz, 1H), 5.66 (t, J=
10.0 Hz, 0.9H), 5.49 5.43 (m, 3.2H), 5.31 5.27 (m, 2.2H), 4.62 4.58 (m, 1
H), 4.55 (t, J=6.4 Hz, 1.1H), 4.34 4.26 (m, 5.1H), 4.06 (dd, J=7.9,
3.3 Hz, 1.1H), 3.79 (d, J=5.4 Hz, 0.8H), 2.09 (s, 3.4H, CH3), 2.06 (s, 4.5
H, CH3); 13C NMR (100 MHz, CDCl3): d=170.79 (C), 170.57 (C), 165.68
(C), 164.99 (C), 164.95 (C), 164.87 (C), 155.07 (C), 133.83 (CH), 133.65
(CH), 133.46 (CH), 129.96 (CH), 129.87 (CH), 129.42 (C), 129.06 (C),
128.65 (CH), 128.47 (CH), 95.57 (CH), 93.47 (CH), 73.26 (CH), 71.17
(CH), 69.98 (CH), 69.90 (CH), 68.92 (CH), 68.68 (CH), 67.23 (CH),
66.72 (CH), 62.75 (CH2), 20.74 (CH3); HRMS (MALDI): calcd for
C45H43NO18Na: 908.2377; found: 908.2357 [M+Na+].
1,6-Anhydro-2-O-{6-O-acetyl-2,4-di-O-benzoyl-3-O-[(p-nitrophenyl)form-
yl]-a-d-mannopyranosyl}-3,4-di-O-benzoyl-b-l-gulopyranoside (63):
A
mixture of the trichloroacetimidate 62 (26.9 mg, 36.4 mmol), compound
46 (11.2 mg, 30.2 mmol), and freshly dried 4 ä molecular sieves (150 mg)
in dichloromethane (0.5 mL) was stirred at room temperature for 30 min
under nitrogen. The mixture was cooled to ꢀ408C, trimethylsilyl trifluor-
omethanesulfonate (2.7 mL, 14.9 mmol) was added to the reaction mix-
ture, and the resulting solution was gradually warmed up to room tem-
perature. After stirring for 20 h, the reaction was quenched by addition
of triethylamine (6 mL), and the mixture was filtered through Celite fol-
lowed by wash with dichloromethane. The filtrate was concentrated in
vacuo, and the residue was purified by flash column chromatography
(EtOAc/Hex 2:5) to afford 46 (2.7 mg) and 63 (17.8 mg, 62%, recovery
yield: 82%). [a]2D4 =ꢀ237.4 (c=0.15, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 8.15 (d, J=9.2 Hz, 2H, Ar-H), 8.10 7.94 (m, 6H, Ar-H),
7.7 7.38 (m, 10H, Ar-H), 7.32 (t, J=7.4 Hz, Ar-H), 5.82 7.74 (m, 3H, H-
3, H-4, H-3’), 5.72 (dd, J=3.2, 1.8 Hz, 1H, H-2), 5.71~5.69 (m, 2H, H-1’,
H-4), 5.10 (d, J=1.8 Hz, 1H, H-1), 4.91 (dd, J=4.6, 3.4 Hz, 1H, H-5’),
4.56 (ddd, J=8.6, 5.0, 3.2 Hz, 1H, H-5), 4.34 4.31 (m, 2H, H-6a, H-2’),
4.27 (d, J=8.1 Hz, 1H, H-6a’), 4.25 (d, J=10.1, 3.2 Hz, 1H, H-6b), 3.81
(dd, J=8.1, 4.6 Hz, 1H, H-6b’); 13C NMR (125 MHz, CDCl3): d = 170.41
(C), 165.66 (C), 165.52 (C), 165.33 (C), 165.10 (C), 155.30 (C), 151.29
(C), 145.46 (C), 133.87 (CH), 133.78 (CH), 133.64 (CH), 133.46 (CH),
130.13 (CH), 129.90 (CH), 129.84 (CH), 128.88 (C), 128.68 (CH), 128.58
(CH), 128.56 (CH), 125.09 (CH), 121.90 (CH), 100.35 (CH), 99.55 (CH),
77.80 (CH), 74.48 (CH), 72.36 (CH), 70.20 (CH), 69.42 (CH), 69.04
2-Azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-b-d-glucopyranosyl ben-
zoate (67): A mixture of compound 66 (100 mg, 0.34 mmol) and pyridine
(0.19 mL, 2.0 mmol) in dichloromethane (2 mL) was cooled to 08C under
nitrogen. Benzoyl chloride (0.13 mL, 1.1 mmol) was slowly added to the
solution, the ice-bath was removed, and the mixture was kept stirring at
room temperature for 18 h. Methanol (2 mL) was added to quench the
reaction, and the resulting solution was evaporated under reduced pres-
sure. Water (2 mL) was added to the solid residue, the mixture was ex-
tracted with ethyl acetate (3î3 mL), and the combined organic layers
were sequentially washed with aq 1n HCl, aq sat NaHCO3 and brine.
The organic portion was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by flash column chromatog-
raphy (EtOAc/Hex 1:3) to get the 1,3-dibenzoate 67 (137 mg, 80%) as a
white solid. [a]2D9 =ꢀ111.0 (c=1.0, CHCl3); m.p. 129 1308C; IR (CHCl3):
411
Chem. Eur. J. 2004, 10, 399 415
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S.-C. Hung et al.
FULL PAPER
n˜ =2880, 2113, 1746, 1724, 1289 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=
J=5.0, 1H, 1-OH); 13C NMR (100 MHz, CDCl3): d = 166.22 (C), 165.41
(C), 136.61 (C), 133.54 (CH), 133.28 (CH), 129.89 (C), 129.76 (CH),
129.33 (C), 128.58 (CH), 128.45 (CH), 128.24 (CH), 128.12 (CH), 96.35
(CH), 75.72 (CH), 74.88 (CH2), 74.73 (CH), 73.49 (CH), 65.56 (CH),
62.97 (CH2); HRMS (FAB): calcd for C27H25N3O7Na: 526.1593; found:
526.1570 [M+Na+]; elemental analysis calcd (%) for C27H25N3O7: C
64.41, H 5.00, N 8.35; found: C 64.24, H 4.91, N 8.00.
8.11 8.08 (m, 4H, Bz-H), 7.64 7.56 (m, 2H, Bz-H), 7.49 7.44 (m, 4H,
Bz-H), 7.40 7.37 (m, 2H, Ph-H), 7.31 7.28 (m, 3H, Ph-H), 5.98 (d, J=
8.4 Hz, 1H, H-1), 5.58 (t, J=9.6 Hz, 1H, H-3), 5.51 (s, 1H, PhCH), 4.42
(dd, J=15.9, 10.3 Hz, 1H, H-6a), 4.40 (dd, J=9.6, 8.4 Hz, 1H, H-2), 3.88
(dt, J=9.6, 1.7 Hz, 1H, H-4), 3.80 (m, 2H, H-5, H-6b); 13C NMR
(100 MHz, CDCl3): d = 165.17 (C), 164.22 (C), 136.51 (C), 134.07 (CH),
133.44 (CH), 130.09 (CH), 129.90 (CH), 129.24 (C), 129.09 (CH), 128.64
(CH), 128.47 (CH), 128.40 (C), 128.19 (CH), 126.08 (CH), 101.62 (CH),
93.89 (CH), 78.56 (CH), 71.85 (CH), 68.27 (CH2), 67.26 (CH), 64.18
(CH); HRMS (FAB): calcd for C27H23N3O7: 502.1615; found: 502.1624
[M+H+]; elemental analysis calcd (%) for C27H23N3O7: C 64.67, H 4.62,
N 8.38; found: C 64.55, H 4.51, N 8.17.
1,6-Anhydro-4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-a-d-glu-
copyranosyl)-2-O-benzoyl-3-O-benzyl-b-l-idopyranoside (70): A mixture
of 69 (0.47 g, 0.93 mmol) and freshly dried 4 ä molecular sieves (3 g) in
dichloromethane (4.7 mL) was stirred at room temperature for 30 min
under nitrogen. Anhydrous potassium carbonate (0.20 g, 1.4 mmol) and
trichloroacetonitrile (0.93 mL, 9.27 mmol) were sequentially added to the
mixture at ꢀ788C, and the reaction was gradually warmed up to room
temperature. After stirring for 2 h, the resulting mixture was filtered
through Celite, and the filtrate was washed with water, dried over
MgSO4, filtered, and concentrated in vacuo to give the crude trichloroa-
cetimidate derivative (0.51 g, 84%, a/b 1:4 determined by the 1H NMR
spectrum), which was directly used for subsequent reaction without fur-
ther purification.
2-Azido-3-O-benzoyl-4-O-benzyl-2-deoxy-b-d-glucopyranosyl benzoate
(68): A 1m solution of BH3/THF complex in THF (1.6 mL, 1.6 mmol)
was added at 08C under nitrogen to a mixture of 67 (100 mg, 0.20 mmol)
in dichloromethane (2 mL). After 10 min, TMSOTf (18 mL, 0.10 mmol)
was added to the solution, the ice-bath was removed, and the mixture
was kept stirring for 3 h. The reaction was quenched by triethylamine
(50 mL) followed by slow addition of methanol at 08C, till the evolution
of hydrogen gas stopped. The resulting mixture was coevaporated with
methanol, and the residue was purified through flash column chromatog-
raphy (EtOAc/Hex 1:3) to give the 6-alcohol 68 (88.4 mg, 88%) as a
white solid. [a]3D0 =+46.3 (c=1.0, CHCl3); m.p. 137 1388C; IR (CHCl3):
A mixture of this crude trichloroacetimidate (374 mg, 0.58 mmol), com-
pound 53 (138 mg, 0.39 mmol), and freshly dried 4 ä molecular sieves
(1.5 g) in dichloromethane (5 mL) was stirred at room temperature for
30 min under nitrogen. The reaction flask was cooled to ꢀ788C, trime-
thylsilyl trifluoromethanesulfonate (50 mL, 0.30 mmol) was added to the
mixture, and the resulting solution was gradually warmed up to room
temperature and kept stirring overnight. The reaction was quenched with
triethylamine (100 mL), the mixture was filtered through Celite, the fil-
trate was concentrated in vacuo, and the residue was purified by flash
column chromatography (EtOAc/Hex 1:5) to afford 70 (189 mg, 58%)
and its corresponding b-isomer (52 mg, 16%). [a]3D0 =+74.4 (c=0.5,
CHCl3); m.p. 185 1868C; IR (CHCl3): n˜ =3245, 2097, 1690, 1612, 1504,
n˜ =3372, 2950, 2097, 1720, 1646, 1538, 1259, 1082 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=8.09 8.04 (m, 4H, Bz-H), 7.62 7.58 (m, 2H, Bz-
H), 7.48 7.44 (m, 4H, Bz-H), 7.17 7.12 (m, 5H, Ar-H), 5.87 (d, J=
8.4 Hz, 1H, H-1), 5.49 (dd, J=10.2, 9.2 Hz, 1H, H-3), 4.59 (s, 2H,
CH2Ph), 3.95 3.91 (m, 2H, H-4, H-6a), 3.85 (dd, J=9.2, 8.4 Hz, 1H, H-
2), 3.70 (m, 1H, H-5), 3.65 (d, J=8.1 Hz, 1H, H-6b), 1.77 (s, 1H, 6-OH);
13C NMR (100 MHz, CDCl3): d= 137.01 (C), 133.99 (CH), 133.51 (CH),
130.09 (CH), 129.87 (CH),129.11 (C), 128.63 (CH), 128.56 (CH), 128.41
(CH), 128.21 (CH), 128.05 (CH), 93.61 (CH), 76.25 (CH), 74.80 (CH2),
74.70 (CH), 63.39 (CH), 61.01 (CH2).
1268, 1106 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=8.10 (dd, J=8.5,
1.4 Hz, 2H, Bz-H), 8.05 (dd, J=8.5, 1.4 Hz, 2H, Bz-H), 8.02 (dd, J=8.5,
1.3 Hz, 2H, Bz-H), 7.62 7.55 (m, 3H, Ar-H), 7.49 7.42 (m, 6H, Ar-H),
7.22 7.10 (m, 10H, Ar-H), 5.85 (dd, J=10.8, 9.2 Hz, 1H, H-3’), 5.53 (d,
J=1.7 Hz, 1H, H-1), 5.45 (d, J=3.8 Hz, 1H, H-1’), 5.06 (dd, J=8.0,
1.7 Hz, 1H, H-2), 4.79 (d, J=10.8 Hz, 1H, CH2Ph), 4.74 (d, J=10.8 Hz, 1
H, CH2Ph), 4.64 4.50 (m, 5H, 2îCH2Ph, H-6a, H-6a’, H-6b’), 4.24 (d,
J=7.9 Hz, 1H, H-6b), 4.17 (t, J=8.0 Hz, 1H, H-3), 4.12 4.09 (m, 2H, H-
4, H-5’), 3.81 (dd, J=7.9, 5.0 Hz, 1H, H-5), 3.76 (t, J=9.2, 1H, H-4’),
3.37 (dd, J=10.8, 3.8 Hz, 1H, H-2’); 13C NMR (125 MHz, CDCl3): d =
166.14 (C), 165.71 (C), 165.46 (C), 137.70 (C), 136.47 (C), 133.61 (CH),
133.45 (CH), 133.38 (CH), 129.88 (CH), 129.62 (CH), 129.54 (C), 129.31
(C), 129.25 (C), 128.60 (CH), 128.52 (CH), 128.50 (CH), 128.31 (CH),
127.81 (CH), 127.70 (CH), 99.43 (CH), 99.34 (CH), 79.80 (CH), 77.54
(CH), 77.24 (CH), 76.40 (CH), 75.31 (CH2), 74.90 (CH2), 74.28 (CH),
72.53 (CH), 69.75 (CH), 65.84 (CH2), 63.18 (CH2), 61.42 (CH).
2-Azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-d-glucopyranose
(69):
Benzoyl chloride (54 mL, 0.44 mmol) was slowly added to a solution of 68
(147 mg, 0.29 mmol) in pyridine (1.5 mL) at 08C under nitrogen. The ice-
bath was removed, and the mixture was kept stirring at room tempera-
ture for 1.5 h. Methanol (5 mL) was added to quench the reaction, and
the resulting solution was evaporated under reduced pressure. Water
(2 mL) was added to the solid residue, and the mixture was extracted
with ethyl acetate (3î3 mL). The combined organic layers were sequen-
tially washed with aq 1n HCl, aq sat NaHCO3, and finally with brine.
The organic portion was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo, and the resulting residue was purified by flash
column chromatography (EtOAc/Hex 1:6) to provide the 1,3,6-triben-
zoate (158 mg, 89%). [a]D30 =ꢀ26.1 (c=1.0, CHCl3); IR (CHCl3): n˜ =
2921, 2106, 1725, 1597, 1494, 1259, 1062 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=8.07 8.02 (m, 6H, Bz-H), 7.67 7.54 (m, 3H, Bz-H), 7.44 7.38
(m, 6H, Bz-H), 7.06 7.05 (m, 5H, Ar-H), 5.92 (d, J=8.4 Hz, 1H, H-1),
5.55 (dd, J=10.1, 8.8 Hz, 1H, H-3), 4.63 4.57 (m, 2H, H-6a, H-6b), 4.57
(d, J=10.8, 1H, CH2Ph), 4.52 (d, J=10.8, 1H, CH2Ph), 4.02 3.90 (m, 3
H, H-2, H-4, H-5); 13C NMR (100 MHz, CDCl3): d = 66.03 (C), 165.25
(C), 164.25 (C), 136.51 (C), 133.90 (CH), 133.61 (CH), 133.17 (CH),
130.12 (CH), 129.90 (CH), 129.77 (CH), 129.53 (CH), 129.22 (C), 128.61
(CH), 128.56 (CH), 128.41 (CH), 128.26 (CH), 128.14 (CH), 93.56 (CH),
75.39 (CH), 74.86 (CH2), 74.16 (CH), 63.73 (CH), 62.76 (CH2); HRMS
(FAB): calcd for C36H29N3O8: 608.2034; found: 608.2053 [M+H+].
6-O-Acetyl-4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-a-d-glu-
copyranosyl)-2-O-benzoyl-3-O-benzyl-l-idopyranosyl acetate (71): Tri-
fluoroacetic acid (0.64 mL) at room temperature under nitrogen was
added to a solution of 70 (159 mg, 0.19 mmol) in acetic anhydride
(3.2 mL). After stirring for 24 h, the reaction was quenched by aq sat
NaHCO3 (10 mL), and the mixture was extracted with EtOAc (3î
10 mL). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the residue
via flash column chromatography (EtOAc/Hex 1:3) yielded the diacetate
71 (160 mg, 89%). [a]3D0 =+75.1 (c=1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.11 8.03 (m, 13H, Bz-H), 7.62 7.58 (m, 5H, Bz-H), 7.54
7.41 (m, 16H, Bz-H), 7.32 7.24 (m, 3H, Ar-H), 7.17 7.12 (m, 10H, Ar-
H), 6.36 (d, J=3.3 Hz, 1H, H-1b), 6.23 (d, J=2.8 Hz, 1H, H-1a), 5.80
(dd, J=10.6 Hz, 9.0 Hz, 1H, H-3’b), 5.75 (dd, J=10.6, 9.1 Hz, 1H, H-
3’a), 5.31 (d, J=3.7 Hz, 1H, H-1’b), 5.27 (dd, J=11.1, 3.3 Hz, 1H, H-2b),
5.24 (t, J=3.5 Hz, 1H, H-2a), 5.01 (d, J=3.7 Hz, 1H, H-1’a), 4.87 4.83
(m, 3H), 4.63 4.50 (m, 13H), 4.40 4.33 (m, 2H), 4.26(ddd, J=5.8, 3.6,
2.1 Hz, 1H, H-6’b), 4.21 (ddd, J=6.4, 4.2, 2.2 Hz, 1H, H-6’a), 4.16 (t, J=
3.9 Hz, 1H, H-3), 3.98 (t, J=3.1 Hz, 1H, H-4), 3.94(s, 2H), 3.45 (dd, J=
10.7, 3.7 Hz, 1H, H-2’a), 3.38 (dd, J=10.1, 3.7 Hz, 1H, H-2’b), 2.15 (s, 3
H), 2.15 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3):
d = 170.76 (C), 169.04 (C), 168.95 (C), 166.12 (C), 165.66 (C), 165.23
(C), 137.22 (C), 136.64 (C), 133.52 (CH), 133.42 (CH), 133.33 (CH),
Ammonia gas was passed through a solution of the 1,3,6-tribenzoate
(27 mg, 44 mmol) in a mixed solvent (THF/MeOH 7:3, 1.4 mL) at 08C for
20 min. The reaction was monitored by TLC till the consumption of start-
ing material (ca. 1.5 h). The solvent was concentrated under reduced
pressure, and the residue was purified by flash column chromatography
(EtOAc/Hex 1:3) to afford 69 (19.5 mg, 87%, a/b 3:1). Recrystallization
of the white solid via vapor diffusion method produced 69b as colorless
crystals. [a]2D9 =+46.9 (c=1.0, CHCl3); IR (CHCl3): n˜ =3435, 2901, 2106,
1720, 1601, 1582, 1263, 1091 cmꢀ1 1H NMR (400 MHz,CDCl3): d=8.10
;
8.01 (m, 4H, Bz-H), 7.60 7.56 (m, 2H, Bz-H), 7.49 7.43 (m, 4H, Bz-H),
7.15 7.07 (m, 5H, Ph-H), 5.92 (dd, J=10.3, 9.0 Hz, 1H, H-3), 5.42 (dd,
J=8.0, 5.0 Hz, 1H, H-1), 4.85 4.36 (m, 4H, 2îCH2Ph, H-6a, H-6b),
3.85 3.79 (m, 2H, H-4, H-5), 3.55 (dd, J=10.3, 8.0 Hz, 1H, H-2), 3.41 (d,
412
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 399 415

Biologically Potent l-Hexose Derivatives
399 415
137.22 (CH), 136.64 (CH), 133.52 (CH), 133.42 (CH), 133.33 (CH),
133.25 (CH), 129.85 (CH), 129.73 (CH), 129.66 (CH),129.28 (C), 129.14
(C), 128.56 (CH), 128.51 (CH), 128.41 (CH), 128.31 (CH), 128.25 (CH),
128.13 (CH), 127.90 (CH), 98.55 (CH), 97.43 (CH), 91.48 (CH), 90.16
(CH), 77.35 (CH), 76.13 (CH), 75.00 (CH2), 74.93 (CH2), 74.77 (CH),
73.72 (CH), 73.33 (CH), 73.06 (CH), 72.99 (CH), 72.70 (CH), 70.89
(CH), 70.09 (CH), 68.07 (CH), 63.80 (CH2), 63.04 (CH2), 62.92 (CH2),
61.68 (CH), 61.48 (CH), 21.09 (CH3), 20.95 (CH3), 20.79 (CH3); HRMS
(FAB): calcd for C51H49N3O15: 943.3164; found: 943.3149 [M +].
H-6a, H-6b, H-6a’), 4.41 4.37 (m, 1H, H-5), 4.32 (dd, J=11.4, 4.4 Hz, 1
H, H-6b’), 4.17 4.15 (m, 1H, H-5’), 4.00 (dd, J=4.2, 2.8 Hz, 1H, H-3),
3.89 (t, J=4.2 Hz, 1H, H-4), 3.71 (t, J=8.3 Hz, 1H, H-4’), 3.42 (s, 3H,
CH3), 3.35 (dd, J=8.3, 3.7 Hz, 1H, H-2’), 2.06 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d = 170.51 (C), 166.05 (C), 165.79 (C), 165.04 (C),
137.37 (C), 136.62 (C), 133.40 (CH), 133.21 (CH), 133.05 (CH), 129.78
(CH), 129.66 (CH), 129.44 (C), 129.31 (C), 129.16 (CH), 128.48 (CH),
128.37 (CH), 128.34 (CH), 128.28 (CH), 128.29 (CH), 127.85 (CH),
126.31 (CH), 99.32 (CH), 97.43 (CH), 76.09 (CH), 74.88 (CH2), 73.74
(CH), 73.38 (CH), 73.02 (CH), 72.90 (CH2), 70.21 (CH), 70.04 (CH),
66.58 (CH), 62.99 (CH2), 62.71 (CH2), 61.65 (CH), 55.70 (CH3), 20.80
(CH3); HRMS (FAB): calcd for C50H50N3O14: 916.3294; found: 916.3311
[M+H+].
6-O-Acetyl-4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-a-d-glu-
copyranosyl)-2-O-benzoyl-3-O-benzyl-l-idopyranose (72): Compound 71
(0.41 g, 0.43 mmol) was dissolved in dichloromethane (8.2 mL) at room
temperature under nitrogen, acetic anhydride (83 mL, 0.88 mmol) was
added to the mixture, and the reaction flask was immersed in an ice-
bath. A 30% solution of HBr in acetic acid (0.47 mL) was added to the
mixture, the ice-bath was removed, and the reaction was kept stirring at
room temperature for 0.5 h. The resulting solution was poured into ice-
water (8 mL), and the aqueous phase was extracted with dichlorome-
thane (3î10 mL). The combined organic layers were consecutively
washed by aq sat NaHCO3 (3î15 mL), and finally with brine. The organ-
ic portion was dried over MgSO4, filtered, and concentrated in vacuo,
and the residue was purified by flash column chromatography (EtOAc/
Methyl 4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-a-d-glucopyr-
anosyl)-2-O-benzoyl-3-O-benzyl-b-l-idopyranoside (74): Compound 73
(171 mg, 0.19 mmol) was dissolved in a 0.5% solution of HCl in metha-
nol (3.5 mL) at room temperature under nitrogen. After stirring for 5 h,
the reaction was neutralized by silver carbonate, and the mixture was fil-
tered through Celite. The filtrate was concentrated in vacuo, and the resi-
due was recrystallized in ethanol to provide 74 (139 mg, 85%) as a white
solid. [a]3D2 =+51.4 (c=1.0, CHCl3); m.p. 113 1148C; IR (CHCl3): n˜ =
3400, 3019, 2921, 2108, 1722, 1601, 1316 cmꢀ1 1H NMR (400 MHz,
;
Hex 1:2) to provide 72 (0.32 g, 82%) as
a
colorless oil. 1H NMR
CDCl3): d = 8.06 (dd, J=8.3, 1.7 Hz, 2H, Bz-H), 8.02 7.99 (m, 4H, Bz-
H), 7.59 7.54 (m, 2H, Ar-H), 7.46 7.41 (m, 5H, Ar-H), 7.39 7.32 (m, 3
H, Ar-H), 7.30 7.19 (m, 4H, Ar-H), 7.13 7.07 (m, 5H, Ar-H), 5.71 (dd,
J=10.6, 9.4 Hz, 1H, H-3’), 5.15 (dd, J=3.5, 2.4 Hz, 1H, H-2), 4.88 (d,
J=2.4 Hz, 1H, H-1), 4.85 (d, J=3.8 Hz, 1H, H-1’), 4.80 (d, J=11.6 Hz, 1
H, CH2Ph), 4.67 (d, J=11.6 Hz, 1H, CH2Ph), 4.58 4.46 (m, 4H, 2î
CH2Ph, 2îH-6’), 4.30 4.26 (m, 1H, H-4), 4.16 (ddd, J=9.4, 4.8, 2.4 Hz, 1
H, H-5’), 4.06 4.00 (m, 2H, H-3, H-6a), 3.89 (t, J=3.7 Hz, 1H, H-6b),
3.87 3.82 (m, 1H, H-5), 3.68 (t, J=9.4 Hz, 1H, H-4’), 3.43 (s, 3H, CH3),
3.36 (dd, J=10.6, 3.8 Hz, 1H, H-2’), 1.99 (dd, J=7.8, 4.3 Hz, 1H, 6-OH);
13C NMR (100 MHz, CDCl3): d = 166.14 (C), 165.87 (C), 165.10 (C),
137.47 (C), 136.60 (C), 133.43 (CH), 133.25 (CH), 133.15 (CH), 133.02
(CH), 129.78 (CH), 129.64 (CH), 129.50 (C), 129.30 (C), 128.49 (CH),
128.40 (CH), 128.32 (CH), 128.10 (CH), 127.87 (CH), 127.81 (CH), 99.58
(CH), 97.00 (CH), 76.23 (CH), 74.88 (CH2), 73.45 (CH), 73.07 (CH),
72.85 (CH), 72.62 (CH2), 70.25 (CH), 69.96 (CH), 68.32 (CH), 63.17
(CH2), 61.93 (CH2), 61.69 (CH), 55.66 (CH3).
(400 MHz, CDCl3): d=8.08 7.98 (m, 10H, Bz-H), 7.59 7.52 (m, 4H, Bz-
H), 7.45 7.33 (m, 16H, Bz-H), 7.27 7.26 (m, 8H, Ar-H), 7.13 7.07 (m, 10
H, Ar-H), 5.68 (dd, J=19.5, 9.9 Hz, 2H, H-3’a, H-3’b), 5.31 (dd, J=8.1,
2.4 Hz, 1H), 5.24 (dd, J=8.4, 3.0 Hz, 1H), 5.08 (t, J=4.0 Hz, 1H), 5.06
(t, J=2.5 Hz, 1H, H-1a), 4.98 (d, J=3.6 Hz, 1H, H-1b), 4.94 (d, J=
3.7 Hz), 4.85 4.70 (m, 4H), 4.62 (dd, J=10.4, 5.4 Hz, 2H), 4.31 4.25 (m,
2H), 4.18 4.14 (m, 3H), 3.92 3.89 (m, 1H), 3.86 (t, J=4.8 Hz, 1H), 3.71
(dt, J=13.0, 3.8 Hz, 2H), 3.65 (s, 1H), 3.40 (t, J=3.4 Hz, 1H), 3.38 (t,
J=3.5 Hz, 1H), 2.09 (s, 1H); 13C NMR (100 MHz, CDCl3): d = 171.08
(C), 170.63 (C), 166.28 (C), 166.03 (C), 164.98 (C), 137.24 (C), 136.61
(C), 133.42 (CH), 133.24 (CH), 133.18 (CH), 132.88 (CH), 129.77 (CH),
129.65 (CH), 129.25 (C), 128.47 (CH), 128.37 (CH), 128.29 (CH), 128.26
(CH), 128.19 (CH), 128.09 (CH), 128.00 (CH), 97.64 (CH), 92.78 (CH),
91.93 (CH), 77.22 (CH), 76.03 (CH), 74.90 (CH2), 73.81 (CH2), 73.49
(CH), 73.33 (CH), 73.02 (CH), 72.84 (CH), 71.09 (CH), 70.42 (CH),
70.17 (CH), 66.61 (CH), 64.12 (CH2), 62.89 (CH2), 62.60 (CH2), 61.62
(CH), 20.92 (CH2), 20.87 (C); HRMS (FAB): calcd for C49H47N3O14
:
Methyl
4-O-(2-azido-4-O-benzyl-2-deoxy-a-d-glucopyranosyl)-3-O-
901.3058; found: 901.3044 [M+H+].
benzyl-b-l-idopyranosiduronic acid (75): Jones reagent was slowly added
to a mixture of 74 (361 mg, 0.41 mmol) and Celite (110 mg) in acetone
(4 mL) at 08C. When the solution turned orange color, the reaction was
re-titrated by isopropanol. The whole mixture was filtered through
Celite, and the filtrate evaporated under reduced pressure. Water (8 mL)
was added to the syrup, the mixture was extracted with dichloromethane
(3î8 mL), and the combined organic layers were dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
column chromatography (MeOH/CHCl3 1:10) to afford the correspond-
ing carboxylic acid (315 mg). [a]3D1 =+35.2 (c=1.0, DMSO); IR (CHCl3):
Methyl 6-O-acetyl-4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-benzoyl-a-
d-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-b-l-idopyranoside (73):
A
mixture of 72 (70 mg, 78 mmol) and freshly dried 4 ä molecular sieves
(0.14 g) in dichloromethane (0.7 mL) was stirred at room temperature for
30 min under nitrogen. The reaction flask was cooled to ꢀ788C, anhy-
drous potassium carbonate (23 mg, 0.17 mmol) and trichloroacetonitrile
(83 mL, 0.83 mmol) were sequentially added to the solution, and the
whole mixture was gradually warmed up to room temperature. After 8 h,
the mixture was filtered through Celite followed by wash with dichloro-
methane. The filtrate was concentrated in vacuo to afford the crude tri-
chloroacetimidate derivative (65 mg, 80%), which was directly used for
the ensuing reaction without further purification.
n˜ =3400, 2931, 2104, 1720, 1623, 1268 cmꢀ1 13C NMR (100 MHz, CDCl3):
;
d=166.07 (C), 165.51 (C), 138.64 (C), 137.71 (C), 134.22 (CH), 133.88
(CH), 133.72 (CH), 131.68 (CH), 131.04 (CH), 129.89 (CH), 129.82 (CH),
129.49 (CH), 129.31 (CH), 129.05 (CH), 128.56 (CH), 128.48 (CH),
128.33 (CH), 128.18 (CH), 127.76 (CH), 98.91 (CH), 97.99 (CH), 76.20
(CH), 74.18 (CH2), 73.77 (CH), 73.20 (CH2), 68.98 (CH), 63.60 (CH2),
61.75 (CH), 55.68 (CH3).
A mixture of the crude trichloroacetimidate (100 mg, 0.10 mmol), metha-
nol (80 mL, 1.98 mmol), and freshly dried 4 ä molecular sieves (200 mg)
in dichloromethane (1 mL) was stirred at room temperature for 30 min
under nitrogen. Trimethylsilyl trifluoromethanesulfonate (3.6 mL,
0.02 mmol) was added to the reaction solution at ꢀ788C, the reaction
flask was gradually warmed up to room temperature, and the mixture
was kept stirring overnight. Triethylamine (8 mL) was added to quench
the reaction, the whole mixture was filtered through Celite, the filtrate
was concentrated in vacuo, and the residue was purified by flash column
chromatography (EtOAc/Hex 1:5) to give 73 (51 mg, 58%) and its corre-
sponding b-isomer (15 mg, 17%). [a]3D2 =+47.8 (c=1.0, CHCl3); m.p.
117 1188C; IR (CHCl3): n˜ =3029, 2918, 2108, 1724, 1452, 1268, 1094,
The above carboxylic acid (315 mg, 0.35 mmol) was dissolved in metha-
nol (3.4 mL) at room temperature under nitrogen, sodium methoxide
(41 mg, 0.93 mmol) was added to the reaction solution, and the mixture
was kept stirring overnight. The reaction was acidified by Amberlite IR-
120 acidic resin to pH 2, then the whole mixture was filtered through
paper. The filtrate was concentrated in vacuo, and the residue was puri-
fied by flash column chromatography (MeOH/CHCl3 1:10) to yield 75
(133 mg, 56% in two steps) as a colorless oil. [a]3D1 =+6.8 (c=1.0,
MeOH); 1H NMR (400 MHz, CD3OD): d = 7.40 7.26 (m, 10H, Ar-H),
5.13 (s, 1H, H-1), 4.99 (d, J=3.8 Hz, 1H, H-1’), 4.93 (d, J=10.9 Hz, 1H,
CH2Ph), 4.72 4.58 (m, 4H, 3îCH2Ph, H-5), 4.24 (s, 1H, H-4), 4.00 (t,
J=9.8 Hz, 1H, H-3’), 3.89 3.86 (m, 2H, H-5’, H-6a’), 3.81 (s, 1H, H-3),
3.73 3.69 (m, 2H, H-2, H-6b’), 3.52 (dd, J=9.8, 3.8 Hz, 1H, H-2’), 3.40 (s,
3H, CH3), 3.40 3.32 (m, 1H, H-4’); 13C NMR (100 MHz, MeOH): d=
1069 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.05 (d, J=7.6 Hz, 2H, Bz-
;
H), 8.00 (d, J=7.6 Hz, 4H, Bz-H), 7.59 7.54 (m, 2H, Ar-H), 7.44 7.33
(m, 8H, Ar-H), 7.29 7.19 (m, 5H, A-H), 7.11 7.09 (m, 4H, Ar-H), 5.71
(t, J=8.3 Hz, 1H, H-3’), 5.14 (t, J=2.8 Hz, 1H, H-2), 4.89 (d, J=3.7 Hz,
1H, H-1’), 4.84 (d, J=2.8 Hz, 1H, H-1), 4.80 (d, J=11.6 Hz, 1H,
CH2Ph), 4.67 (d, J=11.6 Hz, 1H, CH2Ph), 4.58 4.47 (m, 5H, 2îCH2Ph,
413
Chem. Eur. J. 2004, 10, 399 415
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S.-C. Hung et al.
FULL PAPER
176.64 (C), 139.99 (C), 139.55 (C), 129.69 (CH), 129.53 (CH), 129.41
(CH), 129.34 (CH), 129.15 (CH), 128.95 (CH), 128.86 (CH), 103.64 (CH),
97.03 (CH), 80.10 (CH), 76.19 (CH2), 74.68 (CH), 74.57 (CH), 74.35
(CH), 73.13 (CH), 72.79 (CH2), 69.84 (CH), 67.90 (CH), 66.31 (CH),
62.83 (CH2), 56.31 (CH3); HRMS (MALDI): calcd for C27H33N3O11Na:
598.2013; found: 598.2015 [M+Na+].
m) M. V. Keck, R. A. Manderville, S. M. Hecht, J. Am. Chem. Soc.
2001, 123, 8690 8700; n) Y. Zou, E. Fahmi, C. Vialas, G. M. Miller,
S. M. Hecht, J. Am. Chem. Soc. 2002, 124, 9476 9488.
[3]T. Ogita, N. Otake, Y. Miyazaki, H. Yonehara, R. D. Macfarlane,
C. J. McNeal, Tetrahedron Lett. 1980, 21, 3203 3206.
[4]a) H. Yamaguchi, S. Sato, S. Yoshida, K. Takada, M. Itoh, H. Seto,
N. Otake, J. Antibiot. 1986, 39, 1047 1053; b) S. Knapp, S. R.
Nandan, J. Org. Chem. 1994, 59, 281 283.
Methyl 4-O-(2-azido-4-O-benzyl-2-deoxy-3,6-di-O-sulfonato-a-d-gluco-
pyranosyl)-3-O-benzyl-2-O-sulfonato-b-l-idopyranosiduronic acid (76):
Sulfur trioxide-triethylamine complex (470 mg, 2.60 mmol) was added at
[5]R. J. Stack, FEMS Microbiol. Lett. 1987, 48, 83 87.
[6]a) U. Lindahl, Pure Appl. Chem. 1997, 69, 1897 1902; b) R. V.
Iozzo, Annu. Rev. Biochem. 1998, 67, 609 652; c) D. L. Rabenstein,
Nat. Prod. Rep. 2002, 19, 312 331.
[7]a) D. A. Lane, U. Lindahl, Heparin: Chemical and Biological Prop-
erties, Clinical Applications, CRC Press, Boca Raton, FL, 1989;
b) H. E. Conrad, Heparin-Binding Proteins, Academic Press, San
Diego, 1998; c) R. J. Linhardt, I. Capila, Angew. Chem. 2002, 114,
426 450; Angew. Chem. Int. Ed. 2002, 41, 390 412.
[8]D. Shukla, J. Liu, P. Blaiklock, N. W. Shworak, X. Bai, J. D. Esko,
G. H. Cohen, R. J. Eisenberg, R. D. Rosenberg, P. G. Spear, Cell
1999, 99, 13 22.
[9]E. F. Neufeld, J. Muenzer, The Metabolic and Molecular Bases of In-
herited Disease (Eds.: C. R. Scriver, A. L. Beaudet, W. S. Sly, D.
Valle), McGraw-Hill, New York, 1995, pp. 2465 2494.
room temperature under nitrogen to
a solution of 75 (33.2 mg,
56.3 mmol) in DMF (0.66 mL). The mixture was gradually warmed up to
508C, then kept stirring overnight. After cooling to room temperature, a
solution of sodium bicarbonate (874 mg) in water (10.4 mL) was added
to the reaction solution, and the mixture was stirred for another 16 h.
The solvent was removed in vacuo, and the residue was dissolved in a
mixed solvent (CH2Cl2/MeOH 1:1, 2 mL). The mixture was filtered
through paper, and the filtrate was concentrated in vacuo. The residue
was again dissolved in a mixed solvent (CH2Cl2/MeOH 4:1, 1 mL), the
mixture was filtered, and the filtrate was concentrated in vacuo to furnish
the crude 76 (46.8 mg) as a white powder. MS-ESI (negative mode):
calcd for C27H32N3O20S3: 814.07, found 813.94 [MꢀH]ꢀ1
.
Methyl 4-O-(2-deoxy-3,6-di-O-sulfonato-2-N-sulfonato-a-d-glucopyrano-
syl)-2-O-sulfonato-b-l-idopyranosiduronate, pentasodium salt (77): Am-
monia gas was condensed in a reaction flask containing a mixture of
sodium (60.0 mg, 2.61 mmol) in tetrahydrofuran (3 mL), and a solution of
the crude 76 (46.8 mg, 57.7 mmol) in a mixed solvent (EtOH/THF 1:1,
3 mL) was added. When the deep blue color was disappeared, the mix-
ture was gradually warmed up to room temperature followed by concen-
tration in vacuo.
[10]K.-W. Zhao, K. F. Faull, E. D. Kakkis, E. F. Neufeld, J. Biol. Chem.
1997, 272, 22758 22765.
[11]a) B. Weissmann, Methods Enzymol. 1978, 50, 141 150; b) L. H.
Roma, Methods Enzymol. 1982, 83, 578 582.
[12]a) D. Fourmy, M. I. Recht, S. C. Blanchard, J. D. Puglisi, Science
1996, 274, 1367 1371; b) W. A. Greenberg, E. S. Priestley, P. Sears,
P. B. Alper, C. Rosenbohm, M. Hendrix, S.-C. Hung, C.-H. Wong, J.
Am. Chem. Soc. 1999, 121, 6527 6541; c) F. Walter, Q. Vicens, E.
Westhof, Curr. Opin. Chem. Biol. 1999, 3, 694 704; d) S. J. Sucheck,
C.-H. Wong, Curr. Opin. Chem. Biol. 2000, 4, 678 686; e) S. J. Su-
check, A. L. Wong, K. M. Koeller, D. D. Boehr, K.-A. Draker, P.
Sears, G. D. Wright, C.-H. Wong, J. Am. Chem. Soc. 2000, 122,
5230 5231; f) L. P. Kotra, S. Mobashery, Curr. Org. Chem. 2001, 5,
193 205.
[13]a) M. L. Zapp, S. Stern, M. R. Green, Cell 1993, 74, 969 978;
b) W. K. C. Park, M. Auer, H. Jaksche, C.-H. Wong, J. Am. Chem.
Soc. 1996, 118, 10150 10155; c) Y. Tor, Angew. Chem. 1999, 111,
1681 1685; Angew. Chem. Int. Ed. 1999, 38, 1579 1582; d) S. R.
Kirk, N. W. Luedtke, Y. Tor, J. Am. Chem. Soc. 2000, 122, 980 981;
e) T. Hermann, Angew. Chem. 2000, 112, 1962 1979; Angew. Chem.
Int. Ed. 2000, 39, 1890 1905.
The above residue was dissolved in water (5 mL) at room temperature,
and aq 2n NaOH was slowly added to the solution till pH 9.5. Sulfur tri-
oxide/pyridine complex (29.3 mg, 18.4 mmol) was added to the mixture,
and the pH value was maintained at 9.5 by addition of aq 2n NaOH.
After 1 h, the same amount of sulfur trioxide/pyridine complex (29.3 mg,
18.4 mmol) was added to the reaction solution, and the mixture was kept
stirring for another 5 h. The mixture was concentrated in vacuo, and the
residue was purified by column chromatography on Sephadex G-25 (0.2n
aq NaCl). Desalting through a Sephadex G-25 column eluted with water
gave compound 77 (14.6 mg, 37% in three steps). MS-ESI (negative
mode): calcd for C13H23NO23S4: 686.93; found: 686.76 [Mꢀ2H]2ꢀ
.
Acknowledgement
[14]P. B. Alper, M. Hendrix, P. Sears, C.-H. Wong, J. Am. Chem. Soc.
1998, 120, 1965 1978.
We thank Professor Chun-Chen Liao for his helpful discussions. This
work was supported by the National Science Council of Taiwan (NSC 91-
2113M-001-004 and NSC 91-2323-B-001-006).
[15]Some selected recent papers and reviews: a) S. Y. Ko, A. W. M. Lee,
S. Masamune, L. A. Reed III, K. B. Sharpless, F. J. Walker, Science
1983, 220, 949 951; b) Y. Auberson, P. Vogel, Helv. Chim. Acta
1989, 72, 278 286; c) S. Y. Ko, A. W. M. Lee, S. Masamune, L. A.
Reed III, K. B. Sharpless, F. J. Walker, Tetrahedron 1990, 46, 245
264; d) P. H¸nenberger, S. Allemann, P. Vogel, Carbohydr. Res.
1994, 257, 175 187; e) L. M. Lerner, G. Mennitt, Carbohydr. Res.
1994, 259, 191 200; f) A. Medgyes, E. Farkas, A. Liptµk, V. Pozsgay,
Tetrahedron 1997, 53, 4159 4178; g) A. Dondoni, A. Marra, A.
Massi, J. Org. Chem. 1997, 62, 6261 6267; h) M. Adinolfi, G.
Barone, F. De Lorenzo, A. Iadonisi, Synlett 1999, 336 338; i) M.
Takeuchi, T. Taniguchi, K. Ogasawara, Synthesis 1999, 341 354;
j) J. M. Harris, M. D. Keranen, G. A. O’Doherty, J. Org. Chem. 1999,
64, 2982 2983; k) A. TÛth, A. Medgyes, I. Bajza, A. Liptµk, G.
Batta, T. Kontrohr, K. Pÿterffy, V. Pozsgay, Bioorg. Med. Chem.
Lett. 2000, 10, 19 21; l) H. Takahashi, Y. Hitomi, Y. Iwai, S. Ikega-
mi, J. Am. Chem. Soc. 2000, 122, 2995 3000; m) L. Ermolenko, A.
Sasaki, P. Potier, J. Chem. Soc. Perkin Trans. 1 2000, 2465 2473;
n) H. Pellissier, Org. Prep. Proced. Int. 2002, 34, 441 465, and refer-
ences therein.
[1]P. M. Collins, Dictionary of Carbohydrates, Chapman
London, 1998.
& Hall,
[2]a) T. Takita, Y. Umezawa, S. Saito, H. Morishima, H. Naganawa, H.
Umezawa, T. Tsuchiya, T. Miyake, S. Kageyama, S. Umezawa, Y.
Muraoka, M. Suzuki, M. Otsuka, M. Narita, S. Kobayashi, M. Ohno,
Tetrahedron Lett. 1982, 23, 521 524; b) Y. Aoyagi, K. Katano, H.
Suguna, J. Primeau, L.-H. Chang, S. M. Hecht, J. Am. Chem. Soc.
1982, 104, 5537 5538; c) D. L. Boger, T. Honda, J. Am. Chem. Soc.
1994, 116, 5647 5656; d) R. M. Burger, Chem. Rev. 1998, 98, 1153
1169; e) D. L. Boger, T. M. Ramsey, H. Cai, S. T. Hoehn, J. Stubbe,
J. Am. Chem. Soc. 1998, 120, 9139 9158; f) K. Katano, H. An, Y.
Aoyagi, M. Overhand, S. J. Sucheck, W. C. Stevens, C. D. Hess, X.
Zhou, S. M. Hecht, J. Am. Chem. Soc. 1998, 120, 11285 11296;
g) D. L. Boger, H. Cai, Angew. Chem. 1999, 111, 470 500; Angew.
Chem. Int. Ed. 1999, 38, 448 476; h) A. T. Abraham, X. Zhou, S. M.
Hecht, J. Am. Chem. Soc. 1999, 121, 1982 1983; i) C. A. Claussen,
E. C. Long, Chem. Rev. 1999, 99, 2797 2816; j) S. M. Hecht, J. Nat.
Prod. 2000, 63, 158 168; k) A. T. Abraham, X. Zhou, S. M. Hecht,
J. Am. Chem. Soc. 2001, 123, 5167 5175; l) S. E. Hashimoto, B. X.
Wang, S. M. Hecht, J. Am. Chem. Soc. 2001, 123, 7437 7438;
[16]a) S.-C. Hung, R. Puranik, F.-C. Chi, Tetrahedron Lett. 2000, 41, 77
80; b) S.-C. Hung, S. R. Thopate, F.-C. Chi, S.-W. Chang, J.-C. Lee,
C.-C. Wang, Y.-S. Wen, J. Am. Chem. Soc. 2001, 123, 3153 3154.
[17]G. Hodosi, B. Podµnyi, J. Kuszmann, Carbohydr. Res. 1992, 230,
327 342.
414
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 399 415

Biologically Potent l-Hexose Derivatives
399 415
[18]N. A. Hughes, N. M. Munkombwe, Carbohydr. Res. 1982, 101, 221
229.
Driguez, P. Duchaussoy, P. Sizun, J.-P. Hÿrault, J.-M. Herbert, M. Pe-
titou, P. Sinay», Angew. Chem. 2001, 113, 1723 1726; Angew. Chem.
Int. Ed. 2001, 40, 1670 1673.
[19]a) P. Sinay», J.-C. Jacquinet, M. Petitou, P. Duchaussoy, I. Lederman,
J. Choay, G. Torri, Carbohydr. Res. 1984, 132, C5-C9; b) C. A. A.
van Boeckel, T. Beetz, J. N. Vos, A. J. M. de Jong, S. F. van Aelst,
R. H. van den Bosch, J. M. R. Mertens, F. A. van der Vlugt, J. Car-
bohydr. Chem. 1985, 4, 293 321; c) Y. Ichikawa, R. Monden, H. Ku-
zuhara, Carbohydr. Res. 1988, 172, 37 64; d) H. P. Wessel, L.
Labler, T. B. Tschopp, Helv. Chim. Acta 1989, 72, 1268 1276;
e) C. A. A. van Boeckel, M. Petitou, Angew. Chem. 1993, 105,
1741 1761; Angew. Chem. Int. Ed. Engl. 1993, 32, 1671 1690; f) M.
Petitou, C. A. A. van Boeckel, Pure Appl. Chem. 1997, 69, 1839
1846; g) M. Petitou, J.-P. Hÿrault, A. Bernat, P-A. Driguez, P. Duch-
aussoy, J.-C. Lormeau, J.-M. Herbert, Nature 1999, 398, 417 422;
h) P. Sinay», Nature 1999, 398, 377 378; i) R. C. Buijsman, J. E. M.
Basten, C. M. Dreef-Tromp, G. A. van der Marel, C. A. A. van
Boeckel, J. H. van Boom, Bioorg. Med. Chem. 1999, 7, 1881 1890;
j) R. C. Buijsman, J. E. M. Basten, T. G. van Dinther, G. A. van der
Marel, C. A. A. van Boeckel, J. H. van Boom, Bioorg. Med. Chem.
Lett. 1999, 9, 2013 2018; k) S. K. Das, J.-M. Mallet, J. Esnault, P.-A.
[20]P.-S. Lei, P. Duchaussoy, P. Sizun, J.-M. Mallet, M. Petitou, P. Sinay»,
Bioorg. Med. Chem. 1998, 6, 1337 1346.
[21]a) R. M. Srivastava, N. Hudson, F. R. Seymour, B. Weiddmann, Car-
bohydr. Res. 1978, 60, 315 326; b) N. Baggett, A. Samra, A. Smith-
son, Carbohydr. Res. 1983, 124, 63 74.
œ
¬
œ
[22]M. C erny, J. Stanek, Adv. Carbohydr. Chem. Biochem. 1977, 34, 23
177.
[23]J.-C. Lee, C.-A. Tai, S.-C. Hung, Tetrahedron Lett. 2002, 43, 851
855.
[24]S.-C. Hung, S. R. Thopate, C.-C. Wang, Carbohydr. Res. 2001, 330,
177 182.
[25]A. B. Pangborn, A. Giardello, R. H. Grubbs, R. K. Rosen, F. J.
Timmers, Organometallics 1996, 15, 1518 1520.
[26]W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923 2925.
Received: May 3, 2003
Revised: July 11, 2003 [F5096]
415
Chem. Eur. J. 2004, 10, 399 415
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim