Syntheses of fluorine-containing mucin core 2/core 6 structures using novel fluorinated glucosaminyl donors

Article abstract of DOI:10.1016/j.tet.2009.07.089

Syntheses of fluorinated mucin core 6 disaccharides and core 2 trisaccharides modified at the C-3 or C-4 position of the pertinent glucosamine residue required for mechanistic study of glycosyltransferases and sulfotransferases involved in the biosynthesi

Full text of DOI:10.1016/j.tet.2009.07.089

Tetrahedron 65 (2009) 8325–8335
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of fluorine-containing mucin core 2/core 6 structures using novel
fluorinated glucosaminyl donors
*
Jun Xue, Vipin Kumar, Sirajud D. Khaja, E.V. Chandrasekaran, Robert D. Locke, Khushi L. Matta
Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2009
Received in revised form 28 July 2009
Accepted 29 July 2009
Available online 6 August 2009
Syntheses of fluorinated mucin core 6 disaccharides and core 2 trisaccharides modified at the C-3 or C-4
position of the pertinent glucosamine residue required for mechanistic study of glycosyltransferases and
sulfotransferases involved in the biosynthesis of O-glycans are reported. Novel fluorinated glucosaminyl
donors were synthesized from 2-naphthylmethyl
inversion of the C-3 or C-4 configuration. A one-step
time to afford -O-NAP-GlcNAc in high yield, which constitutes the cornerstone of the synthetic strategy
based on NAP-glycosides in oligosaccharides synthesis.
b
-D
-N-acetylglucosamine (
b-O-NAP-GlcNAc) via double
b-alkylation of GlcNAc was reported for the first
b
Keywords:
NAP-glycosides
Oligosaccharides synthesis
Mucin
Ó 2009 Elsevier Ltd. All rights reserved.
Fluorinated carbohydrates
1. Introduction
Hartman and Coward.4 UDP-5-F-GlcNAc was found to behave as
-Gal-Tacceptor but competed with UDP-GlcNAc for binding to N-
a
b
Glycosyltransferases, sulfotransferases, and sialyltransferases
are widely implicated in regulating the construction of oligosac-
charides, polysaccharides, and glycoconjugates in various cells and
tissues.1 Any undesirable alteration in their basic structure results
in various fundamental changes in their roles in specific cell sig-
naling and recognition events of biological processes,2 such as
chronic inflammation, cancer metastasis, cartilage formation, and
hormone regulation. Thus, it became imperative to study the
mechanistic pathway of these enzyme families in order to un-
derstand their role in various biological processes. Modifications to
the basic enzyme acceptor structures by introduction of fluoro
groups can result in highly specific acceptors or inhibitors for these
individual enzymes. Consequently, this might help in exploring
their catalytic mechanism and in development of therapeutics for
curing the medical complications that occur due to their malfunc-
tion. In this context, several laboratories are engaged in the syn-
thesis of fluoro substituted saccharides and their application as
probes to investigate various enzymes involved in carbohydrate
metabolism has been reported.3 It is now unambiguously accepted
that fluorinated carbohydrates play an important role in in-
vestigating carbohydrates–enzyme and carbohydrate–selectin
interactions. For instance, an efficient route for the synthesis of
UDP-5-F-GlcNAc has been reported via epoxide fluoridolysis by
acetyl glucosaminylphosphotransferase. Feng et al.5 reported the
chemo-enzymatic synthesis of UDP-4-F-GlcNAc and UDP-4-F-Gal-
NAc, which would serve as potential candidates for novel anti-
cancer drugs when acting as glycosyltransferase inhibitors. Blood
group A and B glycosyltransferases were shown to act on C-6 fluoro
substituted Gal whereas a C-3 fluoro substituent on Gal created
competitive inhibitors for both enzymes.3j Berkin et al.6 accom-
plished the synthesis of 4-F-GlcNAc and 4-F-GalNAc, which were
evaluated as inhibitors of hepatic glycosaminoglycan biosynthesis.
3-Fluoro and 4-fluoro analogs of
affinity substrates than -glucose for aldolase reductase while 2-
fluoro and 4-fluoro analogs of -glucitol were inactive substrates
for sorbitol dehydrogenase.3h Esko et al. reported a series of syn-
thetic acetylated analogs of disaccharide peracetylated GlcNAc 1-
3Gal -O-naphthalenemethanol containing –H, –F, –N3, –NH2, or
D-glucose were found to be higher
D
D
b
b
–OCH3 instead of the hydroxyl groups at C-30 and C-40 positions of
the terminal N-acetylglucosamine residue. These compounds were
found to reduce the formation of the glycan sialyl Lewis X in tumor
cells. In addition, the reduction of sLex by the 40-deoxy analog also
results in diminished experimental tumor metastasis by Lewis lung
carcinoma in vivo.7
Interest in the synthesis of fluorine modified acceptors is also
augmented due to the application of the fully acetylated derivatives
of various fluoro sugars as specific decoys/primers for glycosyl-
transferases. Endogenous carboxyesterases present in the cells
remove the acetyl groups from these acetylated fluoro sugars. The
resulting deacetyalted derivatives can act as acceptors for the
* Corresponding author. Tel./fax: þ1 716 845 8768.
E-mail address: khushi.matta@roswellpark.org (K.L. Matta).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.089

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J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
Mucin Core 2
Mucin Core 6
GlcNAc6Sulfo-T
HO
HO
O
β1,4Gal/GalNAc-T
O
GlcNAc6Sulfo-T
HO
HO
O
β1,3Gal/GalNAc-T
α1,3Fuc-T
HO
OH
NHAc
HO
β1,4Gal/GalNAc-T
O
O
β1,3Gal/GalNAc-T
α1,3Fuc-T
HO
NHAc
HO
OBn
NHAc
O
O
α1,4GlcNAc-T
O
OH
HO
HO
OBn
NHAc
β1,3Gal T
β1,3GlcNAc T
α1,2Fuc-T
OH
α2,3Sia-TI or TII
Gal3Sulfo-T4
β1,3GlcNAc-T
Figure 1. Glycosyltransferases and sulfotransferases acting on the mucin core 6 disaccharide and core 2 trisaccharide.
enzymes involved in the biosynthetic pathways of glycans. The
anti-tumor activities of acetylated hexosamines were studied by
Sharma et al.8 and Thomas et al.9 Matta et al. demonstrated the in
vivo inhibition of ovarian tumor cell surface glycoprotein synthesis
by peracetylated 3-F-GlcNAc and 4-F-GlcNAc.10 Dimitroff et al.3f,11
and Zollner et al.12 introduced a new strategy to impede the selectin
ligand production using peracetylated 4-F-GlcNAc as a glycosyla-
tion inhibitor. 4-F-GlcNAc was directly incorporated into native
cutaneous lymphocyte associated antigen (CLA) expressed on hu-
man Tcells, indicating direct inhibition of poly-N-acetyllactosamine
elongation and selectin-binding determinants on PSGL-1 O-gly-
cans. These observations establish a potential treatment approach
for targeting pathologic lymphocyte trafficking to skin and indicate
that 4-F-GlcNAc may be a promising agent for treatment of dermal
tropism associated with malignancies and inflammatory disorder.
In addition to the exhaustive research carried out by other
groups on fluoro analogs of carbohydrates for understanding the
enzyme machinery, over the years our laboratory has been involved
in the synthesis and examination of various fluoro acceptors for
their specificity for these enzymes.9,10,13 In this regard, we first
reported the synthesis of UDP-6-F-GlcNAc and UDP-4-F-GalNAc
used for the biological studies of GalNAc/GlcNAc transferases and
phosphatetransferases.13g In this direction, the first synthesis of
2. Results and discussion
2.1. Retrosynthetic analysis of fluorinated mucin core 2
and core 6 oligosaccharides
Figure 2 outlines the retrosynthetic analysis of fluorinated
mucin core 2 and core 6 structures. Retrosynthetic scission of in-
dicated bond in mucin core 6 disaccharides 1, 2 and core 2 tri-
saccharides 3, 4 provides fluorinated glucosaminyl donors 13, 18
and glycosyl acceptors 19, 24 as potential precursors. It was pro-
jected that C-3 or C-4 fluorinated glucosamine 13 and 18, equipped
with anomeric trichloroacetimidate function, could serve as the
glycosyl donor in a Schmidt coupling reaction15 with the primary
hydroxyl group of the diol acceptor 19 and 24. Based on the pre-
vious reports,16 it was expected that the above coupling reaction
should progress smoothly with the formation of the desired crucial
b-glycosidic bond guided by the C-2 carbamate (N-Troc in 13 or
N-Phth in 18) functionality.
2.2. Retrosynthetic analysis of fluorinated glucosaminyl
donors 13 and 18
The retrosynthetic analysis of key synthetic intermediates 13
and 18 is outlined in Figure 3. The 3-fluoro and 4-fluoro glucos-
aminyldonors could be synthesized fromthe same starting material,
fluorinated mucin core 6 structure (GlcNAcb1, 6GalNAca-OR) using
oxazoline as a 4-F-GlcNAc glycosyl donor was also reported.9 Re-
cently, we described the first effective syntheses and biochemical
evaluation of fluorinated core 2-branched oligosaccharide analogs
modified at the C-3 or C-4 position of the pertinent galactose.13a,b In
continuation of our search for a better fluoro acceptor for various
enzymes involved in biosynthesis of O-glycans, we report herein
a straightforward syntheses of fluorinated mucin core 6 di-
saccharides and core 2 trisaccharides [GlcNAc-beta-1,6-(Gal-beta-
1,3)-GalNAc-alpha-OR] modified at the C-3 or C-4 position of the
glucosamine residue using a novel fluorinated glucosaminyl donor.
These compounds would be used for the investigation of glyco-
syltransferases and sulfotransferases to determine the influence of
enzyme activities resulting from structural modifications (Fig. 1).14
namely b-O-(2-naphthylmethyl)-GlcNAc 6 via double inversion of
the C-3 or C-4 configuration. Use of NAP (2-naphthylmethyl) group
as anomeric protection proved to be highly suitable for our purpose
owing to its stability under a wide range of reaction conditions
required for hydroxyl differentiation, amino protection and fluori-
nation. Also, its chemoselective removal under DDQ oxidative
conditions as required in the later part of our synthetic strategy is
an added advantage.17 The choice of a temporary protecting group
for nitrogen is crucial to both fluorination and
b-glycosylation.
During the course of the synthesis of 4-deoxy-4-fluoro donor 13, it
was expected that the fluorination would advance smoothly in the
presence of C-2 N-acetyl group,5,6 whereas in the case of 3-deoxy-
Figure 2. Retrosynthetic analysis of fluorinated mucin core 2 and core 6 structures.

J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
8327
Figure 3. Retrosynthetic analysis of key synthetic intermediates 13 and 18.
3-fluoro donor 18, the reaction of 4,6-benzylidene protected N-
acetyl allosamine or its corresponding 3-O-mesyl derivative with
DAST and TBAF in acetonitrile would yield only the eliminated
product.18 On the basis of much precedence, the fluorination at C-3
would proceed successfullyonlywhenthe NH2 functional groupwas
protected with a phthaloyl moiety.19 Therefore, N-Phth protection
was employed in the synthesis of 3-deoxy-3-fluoro donor 18.
Furthermore, the N-Phth protecting group in 3-fluorodonor 18 plays
dual roles in both assisting fluorination and guiding stereochemistry
of glycosylation.19 Thus, during the course of the ‘N-protection
Switch,’ the direct hydrolysis of N-acetyl allosamine 15 in refluxing
sodium hydroxide solution would yield the free amine ready to be
protected with the phthaloyl group. But, in the case of the 4-fluoro
donor 13, the N-Troc protecting group would control the stereo-
carried out using NAPBr and NaH in the presence of LiBr in DMF to
afford -O-NAP-GlcNAc (6) in good yield. The compound obtained
b
was with high-purity (NMR) and does not require any un-
economical chromatographic purification. The special insoluble
nature of NAP-glucoside 6, either in water or dichloromethane,
reduced the purification procedures to a simple and fast pre-
cipitation in an aqueous solution, followed by the removal of excess
NAPBr via rinsing with dichloromethane (see Experimental section
for detail). This one-step glycoside synthesis compares well with
the standard peracetylation, selective anomeric deprotection, O-
alkylation at C-1 and deacetylation steps, and the classical four-step
Koenigs–Knorr synthesis20 or its ‘oxazoline’ variant.21 Therefore,
the above
b-alkylation constitutes the cornerstone of our novel
strategy for oligosaccharide synthesis based on NAP-glycoside.
Next, compound 6 was treated with pivaloyl chloride in a mixture
of pyridine and dichloromethane (2:1) at 0 ꢀC to afford 7 in a high
yield of 91%. Exposure of the resulting compound 7 with tri-
fluoromethanesulfonic anhydride (Tf2O) in pyridine–/dichloro-
methane (1:10) afforded the 4-O-triflyl derivative, which was
isolated and immediately treated with sodium nitrite in DMF to
chemical outcome of glycosylation (b-selective) through anchimeric
assistance.16a-d Noteworthy, the N-Troc group is sensitive to basic
conditions and potentially causes problems if carried through
a multi-step sequence such as hydroxyl inversion and fluorination.
Moreover, the C–F bond is unstable under strong basic conditions.
Consequently, the transformation of N-protection from NHAc to
NHTroc functionality should be carried out until the tail-end of
the synthesis of 13. Thus, an indirect route could be followed
where N-deprotection of N-acetyl group via Boc derivative of
NAP-glucosamine 9 underacid conditions would proceed efficiently.
produce the inversion product 8 in 79% yield. Treatment of b-NAP-
galactosamine 8 with diethylaminosulfur trifluride (DAST) in
CH2Cl2 provided 4-fluorine analog 9 in 81% yield.5,6,22 Noteworthy,
the inversion of the configuration of equatorial 4-OH of inexpensive
glucosaminide 7 leads to the expensive galactosamine derivative 8,
which is finally converted (the axial 4-OH of 8) back to the cheap
glucosamine derivative 9. This synthetic sequence maneuver
appeared particularly attractive owing to its economic value. Re-
moval of the pivaloyl group required much stronger basic condi-
tions and a longer time than the conventional deacetylation.
Therefore, compound 9 was treated with 5% NaOMe (1 M) in MeOH
at 45 ꢀC for 20 h. This was followed by exposure of the resultant
product to acetic anhydride and pyridine to afford per-acetate 10.
The cleavage of acetamido is difficult and usually proceeds in harsh
2.3. Preparation of N-Troc-protected 4-deoxy-4-fluoro
glucosaminyl imidate donor 13
Scheme 1 depicts the synthesis of 4-deoxy-4-fluoro imidate
donor 13. The 4-Fluoro analogue of 2-acetamido-2,4-dideoxy-D-
glucose (13) was synthesized by double inversion of the configu-
ration at C-4 of the corresponding 3,6-di-O-pivaloyl glucosamine 7
prepared from NAP-glucoside 6 in a one-step fashion. Thus, a one-
step
b-selective glycosylation of N-acetylglucosamine (5) was
Scheme 1. (a) NaH, NAPBr, LiBr, DMF, rt, 89%; (b) PivCl, py/CH2Cl2 (2:1), 0 ꢀC, 91%; (c) Tf2O, Py/CH2Cl2 (1:10), 0 ꢀC; (d) NaNO2, DMF, rt, 79% over two steps; (e) DAST, CH2Cl2, rt, 81%;
(f) NaOMe, MeOH, 45 ꢀC; (g) Ac2O, py, rt, 93% over two steps; (h) Boc2O, DMAP, THF, 60 ꢀC; (i) NaOMe, MeOH, rt, 94% over two steps; (j) 2 M HCl (aq), CH2Cl2, rt; (k) Troc-Cl, NaHCO3
(satd aq)/ Et2O; (l) Ac2O, py, DMAP, rt, 91% over three steps; (m) DDQ, MeOH/CH2Cl2 (1:4), rt; (n) DBU, CCl3CN, CH2Cl2, 0 ꢀC to ꢁ5 ꢀC, 93% over two steps.

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J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
conditions, such as refluxing in 1 M NaOH aqueous solution over-
night.17a In order to avoid the extreme conditions that may destroy
the frangible C–F bond, acetamide 10 can first be converted to an N-
Boc derivative by an exchange process that relies on the reduced
electrophilicity of the carbamate as well as its increased steric bulk.
Based on this rationality, tert-butoxycarbonyl (Boc) protected car-
bamate 11 was prepared from 10. Thus, treatment of 10 with tert-
butoxycarbonyl anhydride (Boc2O) in the presence of DMAP in THF
at 60 ꢀC followed by careful removal of both the N-acetyl group and
b-O-NAP-GlcNAc 14. Inversion of hydroxyl group at position 3 of
glucosamine 14 was anticipated to be accomplished via a two-step
sequence. Thus, treatment of 14 with MsCl in pyridine, followed by
the direct elimination of the resultant sulfonate with sodium ace-
tate in refluxing MeOCH2CH2OH/H2O mixture afforded the desired
NAP-allosaminide 15. The natural unavailable allosamine derivative
15 was obtained by the inversion of the configuration of axial 3-OH
of the readily available and inexpensive glucosamine precursor 14.
This synthetic sequence, similar to that of 4-F-GlcNAc donor 13, also
appeared attractive owing to its economic value. As a desired
requisite in our synthesis, conversion of acetamido in 15 to N-Phth
was effected successfully in two steps. Hydrolysis of acetamido
group of 15 was carried out by refluxing with 30% KOH in 1,4-di-
oxane and MeOCH2CH2OH. Treatment of the resultant free amine
with phthalic anhydride in the presence of NaHCO3 yielded the
desired N-Phth-protected product 16 in high yield. Fluorination of
16 was carried out using DAST,22 which resulted in the inversion of
configuration at C-3. This was followed by acetolysis of the bezy-
lidene ring and then acetylation, providing the 3-fluorinated N-
phth-protected NAP-glucoside 17 in an overall yield of 93% over
three steps. Removal of NAP using DDQ,17 followed by activation of
the anomeric center as imidate using trichloroacetonitrile and
DBU15 yielded the 3-F-GlcNAc donor 18 in high yield (92% over two
steps).
´
O-acetyl moieties of the resulting compound under Zemplen con-
ditions (cat. 1 M NaOMe solution in MeOH)23 afforded the desired
carbamate 11 in a 94% yield. Removal of the Boc group from the
nitrogen of 11 in 2 M aq HCl in methanol afforded free amine. It is of
some interest that the acid-mediated cleavage of the N-Boc-pro-
tected group is fully compatible with the NAP moiety in compound
11. The anomeric NAP group showed its remarkable stability com-
pared to the other ether protecting group, e.g., the p-methoxy-
benzyl (PMB) group, which was partially cleaved under similar acid
conditions.24 Treatment of the resultant free amine with tri-
chloroethoxycarbonyl chloride (Troc-Cl) in a solution of sodium
bicarbonate (satd aq)/ether (1:1), followed by O-acetylation, fur-
nished the desired N-Troc derivative 12 in 91% yield over three
steps. Removal of the anomeric NAP group in the presence of DDQ
in dichloromethane/methanol (4:1),17 followed by activation of the
resultant hemiacetal with trichloroacetonitrile in the presence of
DBU as a base, afforded the N-Troc-protected 4-fluoro glucosamine
imidate 13 in high yield (93% over two steps).15
2.5. Preparation of fluorinated mucin core 6 disaccacharides
1 and 2
2.4. Preparation of N-Phth-protected 3-deoxy-3-fluoro
glucosaminyl imidate 18
With the required starting material in hand, we turned our at-
tention to the synthesis of fluorinated mucin core 6 disaccacharides
1 and 2 (Scheme 3). Coupling of 4-fluoro N-Troc glycosaminyl donor
13 with the known 4,6-diol galactosamine 1913a mediated by
TMSOTf16 afforded the disacchride 20 in 85% yield. Conversion of
the Troc carbamate into acetamido moiety was carried out with Cd
dust in DMF/HOAc (2:1),25 followed by treatment with acetic an-
hydride in pyridine to afford per-acetate 21. Subsequent deacety-
The 3-fluoro glucosaminyl donor 18 was also synthesized fol-
lowing the same strategy as used for NAP-glycoside 6 (Scheme 2).
The difference lay in the C-2 participating group, introduced to
afford synthesis (of respective donor), which is N-Phth in case of
glycosyl donor 18 and N-Ac in case of 4-F-GlcNAc donor 13. Treat-
ment of 6 with dimethoxyl benzyl acetal in the presence of a cata-
lytic amount of p-TsOH afforded 3-hydroxyl free 4,6-O-benzylidene
lation under Zemplen conditions23 proceeded smoothly, giving the
´
target disaccharide 1, which was precipitated as a white solid in
MeOH. Similarly, glycosylation of diol 19 with 3-fluoro N-phth
glycosaminyl donor 18 under TMSOTf-mediated conditions16
afforded the required disaccharide 22, which was further com-
pletely deprotected to provide the target mucin core 6 disaccharide
2 in good yield.
2.6. Preparation of fluorinated mucin core 2 trisaccharides
3 and 4
Scheme 2. (a) PhC(OMe)2, p-TsOH, MeCN, rt, 94%; (b) MsCl, py; (c) NaOAc/H2O/me-
thoxyethanol, refluxed at 130 ꢀC, 93% over two steps; (d) 30% KOH in 1,4-dioxane/
methoxyethanol (5:3 v/v), refluxed at 120 ꢀC; (e) phthalic anhydride, NaHCO3, 84%
over two steps; (f) DAST, CH2Cl2, rt; (g) 60% AcOH in H2O, 60–65 ꢀC; (h) Ac2O, py, rt,
The synthesis of fluorinated mucin core 2 trisaccacharides 3 and 4
is outlined in Scheme 4. Coupling between 13 and 2413a in the
presence of TMSOTf afforded the trisaccharide 25 in 95% yield. This
compound was converted into per-acetate 26 following same
93% over three steps; (i) DDQ, CH3OH/CH2Cl2 (1:4), rt; (j) Cl3CCN, CH2Cl2, DBU, 0 ꢀ
C
to ꢁ5 ꢀC, 92% over two steps.
Scheme 3. (a) TMSOTf , 4 Å MS, CH2Cl2, N2, ꢁ65 to ꢁ70 ꢀC, 85% for both 20 and 22; (b) Cd, DMF/HOAc, N2, rt; (c) Ac2O, py, rt, 93% over two steps of b and c, 93% over two steps of e
and c; (d) 5% NaOMe (1 M) in MeOH, 45 ꢀC, 95% for 1 and 87% for 2; (e) NH2NH2$H2O/MeOH (1:5), 90 ꢀC.

J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
8329
Scheme 4. (a) TMSOTf, 4 Å MS, CH2Cl2, ꢁ65 to ꢁ70 ꢀC, 95% for 25 and 82% for 27; (b) Cd, DMF/HOAc, N2, rt; (c) Ac2O, py, rt, 93% over two steps of b and c, 89% over two steps of e and
c; (d) 5% NaOMe (1 M) in MeOH, 45 ꢀC, 89% for both 3 and 4; (e) NH2NH2$H2O/MeOH (1:5), 90 ꢀC.
strategy as used for the synthesis of 21. Thus, the reaction with Cd
dust in DMF/HOAc (2:1),25 followed by treatment with acetic anhy-
dride in pyridine, provided the per-acetate 26 in good yield. Sub-
sequent deacetylation gave the target trisaccharide 3, which was
precipitated as a white solid in methanol. Correspondingly, the gly-
cosylation of disaccharide 19 with donor 18 gave the desired tri-
saccharide 27 in 82% yield. Trisaccharide 27 on complete
deprotection provided the target mucin core 2 trisaccharide 4 in
good yield.
fluorine causes a downfield shift of the fluorine-bearing carbon
signal by about 20 ppm. A fluorine atom shields the carbon atom
adjacent to the fluorinated one. The signals of these carbon atoms
are usually shifted upfield by 5 ppm. The 1JC,F values increase with
1
the electronegativity of the geminal substituent. The JC,F of C-6 is
observed as about 175 Hz and that of C-4 or C-3 is about 185 or
2
190 Hz. The JC,F of monodeoxy monofluoro sugars has a constant
value of 18.5ꢂ0.5 Hz when the coupled fluorine atom is gauche to
the oxygen substituent of the coupled carbon atom. Most of the
observed 2JC,F values are in good agreement with this value. Usually,
the typical value observed for 3JC,F is 6.0ꢂ1.0 Hz when the fluorine
atom is gauche with respect to both the carbon atoms concerned
and the ring oxygen atom. However, a carbon atom concerned
having two oxygen atoms and a hydrogen atom as its substituent,
when trans to the fluorine atom, would result in the magnitude of
3JC,F as 11.7 Hz.
2.7. Preparation of peracetylated 6-fluro GlcNAc 30 via
oxazolidinone intermediate
In order to compare the C–F coupling constants with 3-F and 4-
F-GlcNAc, 6-fluoro derivative 30 was readily prepared from the
same starting material 6 via an oxazolidinone intermediate 29
(Scheme 5). Hydrolysis of starting material 6 in refluxing sodium
hydroxide solution, followed by treatment of the resultant free
amine with p-nitro-phenoxycarbonyl chloride (NPCC),26 afforded
oxazolidinone 29 in a high yield of 93%. Selective fluorination of the
primary hydroxyl group followed by hydrolytic ring opening under
mild conditions and acetylation readily afforded the target mono-
saccharide 30 in 91% yield over two steps. It is worth mentioning
here that the application of oxazolidinone-protected 2-amino-2-
The 13C NMR spectrum of compound 17 gives evidence for the
presence of fluorine at C-3 (Table 1). The JC,F values of 17.1 and
17.8 Hz are attributed to the two-bond carbon–fluorine coupling to
C-2 and C-4, respectively. The coupling constants of 8.2 and 9.7 Hz
are attributed to three-bond carbon–fluorine coupling to C-5 and C-
1, respectively. The downfield shift of the 13C NMR signal of C-3 to
d
88.5 and its 1JC,F coupling of 188.1 Hz is the unambiguous evidence
that C-3 is fluorinated in the case of 17. Furthermore, fluorine
coupling at the anomeric carbon atom is a distinctive indication
that C-3 is fluorinated, which is unique in the series of fluorinated
glucosaminyl derivatives.
deoxy-
a
D-glucose derivatives as a glycosyl donor in the formation of
-linked glycosides has attracted wide attention.26,27 Crich et al.28
reported that it also affords a very convenient glycosyl acceptor,
conferring high reactivity on the 4-hydroxy group in glycosylation.
The NAP-glycoside could concentrate the bifunctional properties of
oxazolidinone into a versatile intermediate 29. Consequently,
compound 29 would first serve as an active acceptor and then be
converted to an imidate donor capable of introducing 1,2-cis gly-
coside after selective removal of the anomeric NAP group with
DDQ. Further exploration of the versatile chemistry and reaction
pathway of oxazolidinone-protected NAP-glycosamine is in prog-
ress and will be reported in due course.
Table 1
13C-Chemical shifts (ppm) and carbon–fluorine coupling constants (Hz)
Compound
C-1
C-2
C-3
C-4
C-5
C-6
17
97.1
3JF-3,C-1
9.7
55.0
88.5
69.1
71.1
61.8
3-F-GlcNAc
2JF-3,C-2
17.1
1JF-3,C-3
188.1
72.1
2JF-3,C-4
17.8
3JF-3,C-5
8.2
10
99.5
53.4
87.3
71.6
62.6
4-F-GlcNAc
3JF-4,C-2
6.9
2JF-4,C-3
18.8
1JF-4,C-4
186.9
67.8
2JF-4,C-5
23.6
30
98.7
54.1
71.8
72.3
81.1
6-F-GlcNAc
3JF-6,C-4
7.3
2JF-6,C-5
18.2
1JF-6,C-6
174.9
The 13C NMR spectrum of compound 10 provides support for the
existence of fluorine at C-4 (Table 1). The JC,F values of 18.8 and
23.6 Hz are attributed to the two-bond carbon–fluorine coupling to
C-3 and C-5, respectively. The coupling constants of 6.9 Hz are at-
Scheme 5. (a) NaOH aq (1 M), reflux, 110 ꢀC, 92%; (b) NPCC, aq NaHCO3, CH3CN/H2O,
0
over two steps.
ꢀC, 93%; (c) DAST, CH2Cl2, rt, 93%; (d) NaOH, H2O/THF, rt; (e) Ac2O, DMAP, py, rt, 91%
tributed to three-bond carbon–fluorine coupling to C-2. The
1
downfield shift of the 13C NMR signal of C-4 to
d
87.3 and its JC,F
2.8. 13C NMR of fluorinated GlcNAc derivatives
coupling value of 186.9 Hz is clear-cut evidence that C-4 is fluori-
nated in 10. The absence of fluorine coupling at the anomeric car-
bon atom is further evidence that C-3 is not fluorinated in the case
of 10. The coupling pattern of C–F was transferred from
Carbon–fluorine coupling is especially useful for determining
the fluorine position.29 Replacement of a hydroxyl group by

8330
J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
monosaccharide to disaccharide and more complex oligosaccharide
through glycosylation, which is important for structural charac-
terization of the fluorinated carbohydrate.
4.3. 2-Naphthylmethyl 2-acetamido-2-deoxy-3,6-di-O-
pivaloyl- -glucopyranoside (7)
b-D
The 13C NMR spectrum of compound 30 gives evidence for the
presence of fluorine at C-6 (Table 1). The JC,F values of 18.2 Hz is due
to the two-bond carbon–fluorine coupling to C-5. The coupling
constant of 7.3 Hz is owed to the three-bond carbon–fluorine
coupling to C-4. Furthermore, the downfield shift of the 13C NMR
To a solution of compound 6 (4 g, 8 mmol) in dichloromethane
(30 mL) and pyridine (60 mL) was added pivaloyl chloride (4.2 ml,
24 mmol) and stirred for 3 h at 0 ꢀC under an Argon atmosphere.
After 3 h, methanol (5 ml) was added to quench the reaction and
the mixture was diluted with dichloromethane (100 ml). The or-
ganic layer was separated and successively washed with 5% aq HCl,
water, 5% aq NaHCO3, dried over Na2SO4, and concentrated. The
crude product was chromatographed on silica gel with hexanes/
EtOAc (1:2) to furnish 7 as colorless crystals (3.95 g, 91%). 1H NMR
signal of C-6 to
d 81.1 and its coupling with the fluorine atom (JC,F
174.9 Hz) confirms the location of the fluorine atom.
3. Conclusions
(400 MHz, CDCl3) d 7.81–7.72 (m, 4H, ArH), 7.49–7.40 (m, 3H, ArH),
In summary, an efficient access to fluorinated mucin core 6 di-
saccharides (1 and 2) and core 2 trisaccharides (3 and 4) tailored at
the C-3 or C-4 position of the crucial glucosamine residue required
for mechanistic study of enzymes involved in the biosynthesis of
O-glycans has been developed. During the course of our synthesis,
5.67 (br d, 1H, JNH,2¼8.8 Hz, NH), 4.97 (d, Jgem¼12.6 Hz, Abq, 1H,
PhCHAO), 4.96 (t, J3,2¼J3,4¼9.1 Hz, 1H, H-3), 4.95 (dd, J6a,5¼3.5,
Jgem¼12.1 Hz, 2H, H-6), 4.75 (d, Jgem¼12.6 Hz, Abq, 1H, PhCHBO),
4.48 (d, J1,2¼8.3 Hz, 1H, H-1), 4.41 (s, 2H, H-2), 4.07 (t, 1H,
J4,3¼J4,5¼9.0 Hz, H-4), 3.52 (t, J3,4¼9.0 Hz, 1H, H-3), 3.45 (br s, 1H,
OH), 1.83 (s, 3H, NCH3), 1.26 (s, 9H, t-Bu), 1.14 (s, 9H, t-Bu); 13C NMR
a novel one-step
b-alkylation of GlcNAc is reported for the first time
to afford -O-NAP-GlcNAc in high yield, which epitomizes the
b
(100.6 MHz, CDCl3) d 173.0 (NC]O), 167.2 and 167.4 (C]O), 134.9,
foundation of a synthetic strategy based on NAP-glycosides in
oligosaccharides synthesis. The novel fluorinated glucosaminyl
donors 13 and 18 were obtained in high yields from a common
134.0, 128.2, 127.8, 127.7, 126.8, 126.3, 126.1, 125.8, 99.5 (C-1), 74.9
(C-5), 74.3 (C-3), 70.1 (OCH2Ar), 69.4 (C-4), 63.2 (C-6), 53.8 (C-2),
27.2, 27.0, 23.5 (NCOCH3); ESI-MS calcd for C29H39O8NNa (m/z)
[MþNa]þ 552.6, found 552.6. Anal. Calcd for C29H39NO8: C, 65.77;
H, 7.42; N, 2.64. Found: C, 65.71; H, 7.47; N, 2.60.
intermediate, namely b-O-NAP-GlcNAc via double inversion of the
C-3 or C-4 configuration. Further elaboration on this synthetic
sequence and biological evaluation of various target fluorinated
oligosaccharides is ongoing, and the results will be reported in due
course.
4.4. 2-Naphthylmethyl 2-acetamido-2-deoxy-3,6-di-O-
pivaloyl-b-D-galactopyranoside (8)
4. Experimental
4.1. General
To an ice-cold solution of 7 (4.48 g, 8.46 mmol) in CH2Cl2
(50 mL) and pyridine (7.0 mL), trifluoromethanesulfonic anhydride
(4.76 g, 2 equiv) was added dropwise. The solution was stirred for
20 min at 0 ꢀC, diluted with CH2Cl2 (200 mL), and washed succes-
sively with ice-cold aq solutions of KHSO4 (10%), satd NaHCO3,
water, dried (MgSO4), and concentrated under reduced pressure.
The crude triflate was used without further purification. To a stirred
solution of crude triflate in DMF (100 mL) was added NaNO2 (1.75 g,
25.4 mmol), and after 40 h at rt, the mixture was concentrated and
the residue was co-evaporated with toluene under reduced pres-
sure to afford an oil that was subjected to flash chromatography on
silica gel (2:1 EtOAc/hexanes). Compound 8 was isolated as tiny,
TLC was conducted on glass plates precoated with a 0.25 mm
layer of Silica Gel 60 F-254 (Analtech GHLF uniplates). The
compounds were visualized either by exposure to UV light or by
spraying with 5% H2SO4 and 0.2% p-anisaldehyde in a solution of
ethanol and heating, or both. The solutions were concentrated
under reduced pressure at <40 ꢀC. The silica gel used for column
chromatography was Baker Analyzed (60–200 mesh). 1H NMR
spectra were recorded at 30 ꢀC with either a Bruker AM-400
(400 MHz) or an AMX-600 (600 MHz) spectrometer. Chemical
white needles (3.53 g, 79%). 1H NMR (400 MHz, CDCl3)
d 7.81–7.72
shifts are reported as
d
values (ppm) relative to internal standard
(m, 4H, ArH), 7.49–7.47 (m, 3H, ArH), 5.53 (d, JNH,2¼9.2 Hz, 1H, NH),
5.02 (dd, J3,2¼11.5 Hz, J3,4¼3.0 Hz, 1H, H-3), 4.73 (d, Jgem¼12.6 Hz,
1H, OCH2Ar), 4.70 (dq, 2H, J¼11.2 Hz, H-6a, H-6b), 4.65 (d,
J1,2¼8.6 Hz, 1H, H-1), 4.36 and 4.34 (dd, J2,3¼11.1 Hz, 2H, H-2, H-4),
4.30 (d, Jgem¼12.6, 1H, OCH2Ar), 3.93 (s, 1H, OH), 3.77 (dd,
J5,6¼6.3 Hz, 1H, H-5), 1.87 (s, 3H, NCH3), 1.47 (s, 9H, t-Bu), 1.18 (s, 9H,
Me4Si. 13C NMR spectra were recorded at 303.0 K with a Bruker
AM-400 (100.6 MHz) spectrometer using CDCl3 (77.0 ppm) and
CD3OD (49.00 ppm) as references. All samples submitted for
elemental analyses were dried for 48 h under vacuum over P2O5
at rt. Elemental analyses were performed at Robertson Labora-
tory, Madison, NJ. All solvents were purified using standard
procedures.
t-Bu); 13C NMR (100.6 MHz, CDCl3)
d 178.3 (NC]O), 169.7 (C]O),
162.4 (C]O), 134.6, 133.3, 133.1, 128.2, 127.8, 127.7, 126.9, 126.3,
126.1, 125.8, 99.8 (C-1), 77.0, 76.7 (OCH2Ar), 72.4 (C-3), 72.3 (C-5),
70.3 (OCH2Ar), 67.0 (C-4), 62.6 (C-6), 50.8 (C-2), 27.2, 27.0, 23.3
(NCOCH3); ESI-MS calcd for C29H39O8NNa (m/z) [MþNa]þ 552.6,
found 552.7. Anal. Calcd for C29H39NO8: C, 65.77; H, 7.42; N, 2.65.
Found: C, 65.74; H, 7.47; N, 2.67.
4.2. 2-Naphthylmethyl 2-acetamido-2-deoxy-
glucopyranoside (6)
b-D-
N-acetylglucosamine 5 (2 g, 9.04 mmol) was completely dis-
solved in DMF (10 mL) containing LiBr (1.57 g, 18.08 mmol) after
stirring for 1 h, following, which NaH (0.28 g, 11.66 mmol) and
NAPBr (4 g, 18.08 mmol) were added successively in slots. The re-
action mixture was then stirred at rt for 12 h, and, thereafter, was
quenched with MeOH (5 mL) and DMF was evaporated under high
vacuum. The resulting viscous liquid was slowly poured into a
water/CH2Cl2 (1:1) mixture and stirred for 30 min. Compound 6
popped out of the water as a white solid, which was filtered,
washed successively with water (100 mL), and dichloromethane
(100 mL) to obtain pure 6 as a white solid (89%). The spectral data
was consistence with the literature data.30
4.5. 2-Naphthylmethyl 2-acetamido-2,4-dideoxy-4-fluoro-
3,6-di-O-pivaloyl-b-D-glucopyranoside (9)
To a solution of DAST (5.70 g, 35.3 mmol) in CH2Cl2 (20 mL) in
a Teflon Erlenmeyer flask was added dropwise a solution of 8
(2.19 g, 4.16 mmol) in CH2Cl2 (40 mL) at ꢁ5 ꢀC. The reaction mix-
ture was allowed to warm to rt and stirred overnight, after which it
was cooled to ꢁ5 ꢀC and methanol (20 mL) was added dropwise to
destroy the excess DAST. The solution was then concentrated under
reduced pressure to afford a yellowish oil that was subjected to

J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
8331
flash chromatography on silica gel (2:3 hexanes/EtOAc) to obtain
3), 70.6 (ArCH), 60.6 (C-6), 57.2 (3J2,F¼5.8 Hz, C-2), 23.8, 22.7, 20.6
(NHCOCH3); Anal. Calcd C22H33O3NF: C, 69.81; H, 8.79; N, 3.70; F,
5.02. Found: C, 69.78; H, 8.76; N, 3.69; F, 5.04.
pure compound 9 as tiny, white needles (1.77 g, 81%). 1H NMR
(400 MHz, CDCl3)
d 7.85–7.72 (m, 4H, ArH), 7.50–7.26 (m, 3H, ArH),
5.30 (br d, 1H, NH), 5.10 (dd, J3,4¼9.0, J3,F¼13.7 Hz, 1H, H-3), 5.04 (d,
Jgem¼12.6 Hz, 1H, OCH2Ar), 4.76 (d, Jgem¼12.6 Hz, 1H, OCH2Ar), 4.56
(ddd, J4,3¼J4,5¼9.5 Hz, J4,F¼51.0 Hz, 1H, H-4), 4.51 (ddd, J6,F¼1.3,
J6,5¼4.7, Jgem¼12.1 Hz, 2H, H-6), 4.42 (ddd, J2,1¼J2,3¼J2,NH¼9.2 Hz,
1H, H-2), 4.27 (d, J¼8.4 Hz, 1H, H-1), 3.72–3.70 (m, 1H, H-5), 1.87 (s,
3H, NCH3), 1.47 (s, 9H, t-Bu), 1.18 (s, 9H, t-Bu); 13C NMR (100.6 MHz,
4.8. 2-(2,2,2-Trichloroethoxycarbonylamino)-2,4-dideoxy-4-
fluoro-3,6-di-O-acetyl-b-D-glucopyranoside (12)
To a solution of compound 11 (6.12 g 16.2 mmol) in CH2Cl2
(50 mL) at rt, HCl (25 mL) was added and the solution was stirred
for 24 h. The reaction mixture was then cooled in an ice bath,
neutralized with 1 M NaOH, and concentrated to dryness under
vacuum. Purification using a short column of silica gel (7:2:1,
EtOAc/MeOH/H2O) gave free amino alcohol as a white solid. Tri-
chloroethoxycarbonyl chloride (2.23 mL, 16.2 mmol) was added
dropwise at rt to a vigorously stirred solution of free amino alcohol
in Et2O (60 mL) and satd aq NaHCO3 solution (60 mL). The reaction
mixture was allowed to stir for 1.5 h. Et2O was evaporated under
vacuum, and a white solid was precipitated out from the solution,
which was then filtered, washed with distilled water, and dried
under vacuum to obtain an NHTroc-protected compound as a white
solid. The resultant compound was treated with acetic anhydride
(5 mL) and dry pyridine (10 mL) at rt in the presence of a catalytic
amount of DMAP (5 mg) and stirred overnight. The reaction mix-
ture was then concentrated, and the crude reside was purified by
flash chromatography (2:1, hexanes/EtOAc) to afford 12 (8.55 g,
CDCl3)
d 178.0 (NC]O), 169.6 (C]O), 169.4 (C]O), 134.3, 133.2,
133.1, 128.3, 127.8, 127.7, 127.0, 126.3, 126.2, 125.7, 99.5 (C-1), 87.3
(J4,F¼187.3 Hz, C-4), 72.2 (2J3,F¼17.8 Hz, C-3), 71.7 (2J5,F¼21.5 Hz, C-
5), 70.3 (OCH2Ar), 62.6 (C-6), 53.5 (3J2,F¼6.7 Hz, C-2), 27.2, 26.9, 23.2
(NCOCH3); ESI-MS calcd for C29H38O7NFNa m/z [MþNa]þ 554.6,
found: 554.6. Anal. Calcd for C29H38NO7F: C, 65.52; H, 7.21; N, 2.64;
F, 3.57. Found: C, 65.61; H, 7.19; N, 2.67; F, 3.55.
4.6. 2-Naphthylmethyl 2-acetamido-2,4-dideoxy-4-fluoro-
3,6-di-O-acetyl-b-D-glucopyranoside (10)
The compound 9 (14.87 g, 28 mmol) was treated with 1 M
NaOMe/MeOH (1 mL) in MeOH (500 mL) for 8 h at 45 ꢀC and
concentrated. It was then applied to a short silica gel column and
eluted with (CH2Cl2/MeOH, 7:1) to afford a pure compound, which
was treated with acetic anhydride in pyridine/CH2Cl2 (1:1) for 4 h
at rt, after which it was quenched with MeOH (10 mL) and con-
centrated. The residue was dissolved in CH2Cl2 (500 mL), washed
with brine (600 mL), and dried (Na2SO4). The organic extract was
filtered, concentrated in vacuum, and purified by flash chroma-
tography (1:1, hexanes/EtOAc) to afford 10 (9.84 g, 93%) as an
91%) as a syrup. 1H NMR (400 MHz, CDCl3)
d 7.82–7.72 (m, 4H, ArH),
7.48–7.38 (m, 3H, ArH), 5.44 (d, JNH, 2¼9.2 Hz, 1H, NH), 5.31 (ddd,
J3,2¼9.0, J3,4¼10.8, J3,F¼14.2 Hz, 1H, H-3), 5.02 and 4.75 (d, 1H,
Jgem¼12.3 Hz, OCH2Ar, ABq), 4.72 (s, 2H, OCH2CCl3), 4.70 (ddd,
J4,3¼J4,5¼9.5, J4,F¼51.0 Hz, 1H, H-4), 4.57 (d, J1,2¼8.1 Hz, 1H, H-1),
4.45 (ddd, J2,3¼9.9, J2,3¼10.3, J2,1¼8.1 Hz, 1H, H-2), 4.24 (dd, J6,5¼4.5,
J6a,6b¼12.1 Hz, 1H), 3.82 (m, 1H, H-5), 3.65 (br s, 1H), 2.10 and 2.01
amorphous solid. 1H NMR (400 MHz, CDCl3)
d 7.84–7.73 (m, 4H,
ArH), 7.50–7.38 (m, 3H, ArH), 5.53 (d, JNH,2¼9.5 Hz, 1H, NH), 5.22
(ddd, J3,2¼8.9, J3,4¼10.6, J3,F¼14.7 Hz, 1H, H-3), 5.03 (d, J¼12.2 Hz,
1H, OCH2Ar, ABq), 4.76 (d, J¼12.8 Hz, 1H, OCH2Ar, ABq), 4.73 (d,
J1,2¼10.2 Hz, 1H, H-1), 4.60–4.56 (m, 2H, H-6a, H-6b), 4.48 (ddd-dt,
J4,3¼J4,5¼9.5, J4,F¼51.0 Hz, 1H, H-4), 4.27 (ddd, J2,NH¼9.9,
J2,3¼J2,1¼10.3 Hz, 1H, H-2), 4.12–4.10 (m, 1H, H-5), 2.12 and 2.04 (s,
6H, 2ꢃOCH3), 1.89 (s, 3H, NH3); 13C NMR (100.6 MHz, CDCl3)
(s, 6H, 2ꢃCH3); 13C NMR (100.6 MHz, CDCl3)
d 176.5 (NC]O), 170.6
(C]O), 170.1 (C]O), 154.3, 133.9, 133.1, 133.0, 128.2, 127.8, 127.6,
126.8, 126.2, 126.1, 125.6, 99.4 (C-1), 95.8 (OCH2CCl3), 87.0
(J4,F¼187.2 Hz, C-4), 74.5 (OCH2CCl3), 71.9 (2J3,F¼19.1 Hz, C-3), 71.1
(2J5,F¼23.8 Hz, C-5), 70.8 (OCHAr), 62.1 (C-6), 55.9 (3JC,F¼5.8 Hz, C-
2), 20.7 (OCH3), 20.6 (OCH3). ESI-MS calcd for C24H25O8NFCl3Na (m/z)
[MþNa]þ 603.8. Found: 604.2. Anal. Calcd C24H25O8NFCl3: C, 49.63;
H, 4.34; N, 2.41; F, 3.27; Cl, 18.31. Found: C, 49.61; H, 4.36; N, 2.40; F,
3.25; Cl, 18.33.
d
173.5 (NC]O), 170.5 (C]O), 170.1 (C]O), 134.2, 133.1, 133.1,
128.3, 127.8, 127.7, 126.9, 126.3, 125.7, 99.5 (C-1), 87.3
(1J4,F¼186.9 Hz, C-4), 72.1 (2J3,F¼18.8 Hz, C-3), 71.6 (2J5,F¼23.6 Hz,
C-5), 70.8 (ArCH), 62.6 (C-6), 53.4 (3J2,F¼6.9 Hz, C-2), 23.2, 22.7,
20.6 (NCOCH3); ESI-MS calcd for C23H26O7NFNa (m/z) [MþNa]þ
470.5, found 470.4. Anal. Calcd for C23H26O7NF: C, 61.74; H, 5.86; N,
3.13; F, 4.25. Found: C, 61.71; H, 5.90; N, 3.16; F, 4.28.
4.9. 2-(2,2,2-Trichloroethoxycarbonylamino)-2,4-
dideoxy-4-fluoro-3,6-di-O-acetyl-glucopyranosyl
trichloroacetimidate (13)
4.7. 2-Naphthylmethyl 2-(N-tert-butyloxycarbonyl-
acetamido)-2,4-dideoxy-4-fluoro-b-D-glucopyranoside (11)
To a solution of compound 12 (371.2 mg, 0.64 mmol) in
dichloromethane/methanol (10 mL, 4:1) was added DDQ (871 mg,
3.84 mmol) and stirred overnight. The reaction mixture was con-
centrated and taken up in dichloromethane (50 mL), washed with
satd NaHCO3 (3ꢃ50 mL), dried (Na2SO4), and concentrated. The
residue thus obtained was chromatographed using hexane/EtOAc
(2:1) as the eluent to provide alcohol as syrup. The resultant
compound was treated with trichloroacetonitrile (1 mL) and DBU
To a stirred mixture of compound 10 (22.3 g, 50.06 mmol) and
DMAP (0.61 g, 5.01 mmol) in THF (150 mL) was added Boc2O
(54.62 g, 250.3 mmol). Stirring was continued at 60 ꢀC for 3 h, after
which the reaction mixture was concentrated in vacuo and purified
by flash chromatography (3:1, hexanes/EtOAc) to provide com-
pound 11a. ESI-MS: calcd for C28H39O6NFNa (m/z) [MþNa]þ 570.5,
found 570.5. The resultant Boc-protected compound 11a was
treated with methanol (100 mL) containing a catalytic amount of
1 M NaOMe solution and allowed to stir at rt for 1 h to afford
deacetylated compound 11 (17.5 g, 94%). 1H NMR (400 MHz, CDCl3)
7.83–7.82 (m, 4H, ArH), 7.49–7.47 (m, 3H, ArH), 5.10 (d,
Jgem¼12.1 Hz, 1H, OCH2Ar), 4.80 (s, 1H, OCH2Ar), 4.34 (d, J1,2¼8.3 Hz,
1H, H-1), 4.28 (ddd, J4,F¼50.8, J4,3¼J4,5¼8.7 Hz, 1H, H-4), 3.92–3.36
(m, 6H, H-6a, H-6b, H-5, H-3),1.44 (s, 9H, Boc); 13C NMR (100.6 MHz,
(20
m
L) in dry dichloromethane (10 mL) at 0 to ꢁ5 ꢀC for 2 h. The
reaction mixture was then concentrated, and the crude reside was
purified by flash chromatography (3:1, hexanes/EtOAc) to afford 13
(348.2 mg, 93%) as an amorphous solid. 1H NMR (400 MHz, CDCl3)
d
8.95 (s, 1H, OC(NH)CCl3), 6.47 (d, J1,2¼3.1 Hz, 1H, H-1), 5.70 (d,
JNH,2¼9.5 Hz, 1H, NH), 5.40 (ddd, J3,2¼9.0, J3,4¼10.8, J3,F¼14.2 Hz,
1H, H-3), 4.77 (s, 2H, OCH2CCl3), 4.47 (ddd, J4,3¼J4,5¼9.5,
J4,F¼51.0 Hz, 1H, H-4), 4.29–4.31 (m, 2H, H-6a, H-6b), 4.25–4.23 (m,
1H, H-2), 3.90–3.92 (m, 1H, H-5), 2.06 (s, 3H, COCH3), 2.03 (s, 3H,
CDCl3)
d
173.5 (NC]O), 172.4 (C]O), 171.8 (C]O), 134.5, 132.9,
COCH3); 13C NMR (100.6 MHz, CDCl3)
d 176.5 (NC]O),170.3 (C]O),
132.8, 127.8.1, 127.5, 127.3, 126.1, 125.8, 125.7, 125.3, 100.3 (C-1), 89.5
170.1 (C]O), 94.1 (C-1), 95.8 (OCH2CCl3), 86.6 (1JC,F¼187.2 Hz, C-4),
(JC,F¼187.2 Hz, C-4), 73.7 (2J5,F¼23.8 Hz, C-5), 71.9 (2J3,F¼19.1 Hz, C-
73.7 (2J3,F¼18.4 Hz, C-3), 70.9 (OCH2CCl3), 69.5, 68.3, 67.6

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J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
(2J5,F¼23.2 Hz, C-5), 63.2 (C-6), 51.7 (3J2,F¼6.8 Hz, C-2), 20.9 (OCH3),
20.7 (OCH3). ESI-MS calcd for C15H17N2O8Cl6FNa (m/z) [MþNa]þ
608.0, found 607.0. Anal. Calcd for C15H17N2O8Cl6F: C, 30.79; H,
2.93; N, 4.79; F, 3.25; Cl, 36.36. Found: C, 30.76; H, 2.96; N, 4.77; F,
3.27; Cl, 36.31.
derivative 16 (13.3 g, 84%). 1H NMR (400 MHz, CDCl3)
d 8.01–7.84
(m, 5H, ArH), 7.81–7.55 (m, 6H, ArH), 7.50–7.30 (m, 5H, ArH), 5.84–
5.82 (m, 1H), 5.01–4.98 (m, 1H), 4.78–4.74 (m, 1H), 4.43–4.40 (m,
1H), 4.21–4.13 (m, 2H), 3.82–3.76 (m, 2H), 2.83 (s, 1H); 13C NMR
(100.6 MHz, CDCl3)
d 167.6, 167.4, 137.3, 135.2, 133.7, 132.4, 132.3,
132.2, 132.1, 131.8, 128.8, 128.7,128.0, 127.9,127.6, 127.3, 127.0, 126.0,
125.1, 101.9, 97.1 (C-1), 86.8 (C-4), 76.2 (C-2), 70.9 (C-6), 68.4 (C-3),
57.9 (C-5). Anal. Calcd for C32H27NO7: C, 71.49; H, 5.06; N, 2.61.
Found: C, 71.52; H, 5.03; N, 2.59.
4.10. 2-Naphthylmethyl 2-acetamido-2-deoxy-4,6-O-
benzylidene-b-D-glucopyranoside (14)
Compound 6 (1.81 g, 3.72 mmol) was suspended in dry CH3CN
(19 mL) and treated with PhCH(OMe)2 (2.64 mL, 17.5 mmol) and p-
TsOH$H2O (33.4 mg, 0.17 mmol) at rt for 2 h. After this time, the
reaction mixture was diluted with CH2Cl2 (20 mL), neutralized with
Et3N, and evaporated to dryness. The residue was chromato-
graphed using hexane/EtOAc (2:1) as the eluent to give 14 (1.56 g,
4.13. 2-Naphthylmethyl 2-phthalimido-2,4-dideoxy-3-fluoro-
4,6-di-O-acetyl-b-D-glucopyranoside (17)
To a solution of DAST (5.70 g, 35.3 mmol) in CH2Cl2 (20 mL) in
a Teflon Erlenmeyer flask was added dropwise a solution of 16
(2.23 g, 4.16 mmol) in CH2Cl2 (40 mL) at ꢁ5 ꢀC. The reaction mix-
ture was warmed to rt and stirred overnight, after which the re-
action mixture was cooled to ꢁ5 ꢀC and methanol (20 mL) was
added dropwise to destroy the excess DAST. The solution was then
concentrated under reduced pressure to afford a yellowish oil that
was subjected to flash chromatography on silica gel (2:3, hexanes/
EtOAc). The resultant compound was taken up in 60% aq acetic acid
and stirred for 1.5 h at 60–65 ꢀC. The solution was then concen-
trated under reduced pressure to obtain a crude residue, which on
column chromatography (silica gel) with dichloromethane/meth-
anol (60:1) afforded a pure compound as an amorphous solid. The
resultant compound was treated with acetic anhydride in pyridine/
CH2Cl2 (1:1) for 4 h at rt, then quenched with MeOH (1 mL). The
reaction mixture was concentrated and taken in CH2Cl2 (50 mL),
then washed with brine (60 mL), dried (Na2SO4), filtered, concen-
trated in vacuum, and purified by flash chromatography (1:1,
hexanes/EtOAc) to afford 17 (1.52 g, 93%). 1H NMR (400 MHz,
94%). 1H NMR (400 MHz, CDCl3)
d 7.84–7.65 (m, 4H, ArH), 7.50–7.24
(m, 8H, ArH), 5.10 (s, 1H, CHPh), 4.80 (d, J1,2¼8.3 Hz, 1H, H-1), 4.50
(m, 1H, H-4), 4.44 (m, 1H, H-2), 4.20–4.17 (m, 2H, H-6, H-3), 3.80 (d,
1H, H-60), 3.60 (m, 1H, H-5), 2.85–2.83 (s, 1H, 3-OH), 1.97 (s, 3H,
NCH3); 13C NMR (100.6 MHz, CDCl3)
d 170.2 (NC]O), 134.7, 134.4,
133.7, 130.2, 128.3, 127.7, 126.8, 126.3, 126.1, 125.8, 103.1 (CHPh),
99.5 (C-1), 73.1 (OCHAr), 70.9 (C-4), 70.1 (C-5), 65.7 (C-3), 63.2 (C-
6), 51.8 (C-2), 23.5 (CH3). Anal. Calcd for C26H27NO6: C, 69.47; H,
6.05; N, 3.12. Found: C, 69.51; H, 6.09; N, 3.18.
4.11. 2-Naphthylmethyl 2-acetamido-2-deoxy-4,6-O-
benzylidene-b-D
-allopyranoside (15)31
To a stirred suspension of 14 (29.9 g, 66.8 mmol) in CH2Cl2
(200 mL) at rt was added pyridine (100 ml). After 10 min, MsCl
(7.50 ml, 96.9 mmol) was added dropwise and stirred for 28 h. The
reaction mixture was then diluted with CH2Cl2 (500 mL), and the
organic layer was washed with H2O (400 mL). The aqueous phase
was extracted with CH2Cl2 (3ꢃ200 mL), and the combined organics
were dried (Na2SO4) and evaporated to give a residue. The residue
was suspended in 2-methoxyethanol/H2O (550 ml, 10:1) and
treated with NaOAc$3H2O (28.0 g, 206 mmol) at 130 ꢀC for 18 h,
after which the reaction mixture was cooled to rt, and the solvents
were evaporated. The residue obtained was dissolved in CH2Cl2
(1000 mL), then washed with brine (1ꢃ600 mL) and dried
(Na2SO4). The organic extract was filtered, concentrated in vacuum,
and purified by flash chromatography (1:1, hexanes/EtOAc) to af-
CDCl3)
d 7.84–7.75 (m, 6H, ArH), 7.60–7.40 (m, 5H, ArH), 5.08–4.93
(m, 2H), 4.78–4.71 (m, 1H), 4.57–4.33 (m, 2H), 4.31–4.23 (m, 1H),
4.15–4.05 (m, 1H), 3.51–3.39 (m, 1H), 2.05, 1.95 (s, 6H, 2ꢃOCH3); 13
C
NMR (100.6 MHz, CDCl3)
d 170.8, 169.3, 134.1, 134.0, 133.0, 132.8,
131.3, 128.2, 127.8, 127.6, 126.9, 126.2, 125.9, 125.5, 97.1 (3J1,F¼9.7 Hz,
C-1), 88.5 (1J3,F¼188.1 Hz, C-3), 71.8 (ArCH), 71.1 (3J5,F¼8.2 Hz, C-5),
69.1 (2J3,F¼17.8 Hz, C-4), 61.8 (C-6), 55.0 (2J2,F¼17.1 Hz, C-2), 20.8,
20.7. Anal. Calcd for C18H18NO8F: C, 54.69; H, 4.59; N, 3.54; F, 4.81.
Found: C, 54.66; H, 4.53; N, 3.56; F, 4.83.
ford 15 (27.8 g, 93%). 1H NMR (400 MHz, CDCl3)
d
7.84–7.65 (m, 8H,
4.14. 2-Phthalimido-2,4-dideoxy-3-fluoro-4,6-di-O-acetyl-
b-
ArH), 7.50–7.24 (m, 8H, ArH), 5.87–5.86 (m, 1H), 5.59 (s, 1H), 4.44–
4.41 (m, 1H), 4.39 (s, 1H), 4.24 (m, 1H), 4.18–4.16 (m, 1H), 3.83–3.79
(m, 1H), 3.75–3.73 (m, 1H), 1.97 (s, 3H, NCH3); 13C NMR (100.6 MHz,
D-glucopyranosyl trichloroacetimidate (18)
Following a similar procedure to that for compound 13, com-
pound 18 (yield 92%) was prepared from compound 17. 1H NMR
(400 MHz, CDCl3) 7.83–7.80 (m, 2H, ArH), 7.73–7.70 (m, 2H, ArH),
CDCl3)
d 135.1, 134.6, 133.5, 130.1, 128.7, 127.5, 126.7, 126.4, 126.0,
125.4, 102.8, 98.4, 76.1, 70.7, 69.5, 63.9, 51.4, 23.7. Anal. Calcd for
C26H27NO6: C, 69.47; H, 6.05; N, 3.12. Found: C, 69.44; H, 6.02; N,
3.10.
d
6.61–6.59 (m, 1H), 5.45–5.42 (m, 1H), 5.23–5.19 (m, 1H), 4.78–4.73
(m, 1H), 4.60–4.55 (m, 1H), 4.45–4.40 (m, 1H), 4.28–4.21 (m, 1H),
3.83–3.77 (m, 1H), 2.05, 2.01 (s, 6H, 2ꢃOCH3); 13C NMR (100.6 MHz,
4.12. 2-Naphthylmethyl 2-phthalimido-2-deoxy-4,6-O-
CDCl3) d 170.3, 167.6, 132.3, 132.1, 127.7, 127.6, 86.9, 86.0 (C-3,
benzylidene-
b-
D
-allopyranoside (16)28
J¼188.0 Hz), 84.1 (C-1, J¼9.7 Hz), 76.7 (C-4, J¼17.8 Hz), 73.9, 65.8,
64.4, 21.0, 20.7. Anal. Calcd for C20H18N2O8Cl3F: C, 44.51; H, 3.36; N,
5.19; Cl, 19.71; F, 3.52. Found: C, 44.53; H, 3.33; N, 5.17; Cl, 19.74; F,
3.55.
Compound 15 (13.3 g, 29.5 mmol) was added to a 30% KOH so-
lution (80 mL) in 1,4-dioxane/methoxyethanol 80 mL (5:3 v/v) and
refluxed at 120 ꢀC for 18 h. The reaction mixture was cooled and
neutralized with 2 N HCl until slightly basic to avoid amine hy-
drochloride formation. The solvents were removed under vacuum,
and the residue obtained was dissolved in water and extracted with
chloroform (4ꢃ100 mL). The combined extracts were then washed
successively with water, brine, and dried over Na2SO4. The chloro-
form layer was then concentrated to give a yellowish-white solid,
which on recrystallization from CHCl3/hexanes afforded the free
amine as a white solid. Reaction of the resultant free amine with
phthalic anhydride in aq sodium bicarbonate gave the phthaloyl
4.15. Benzyl O-[2-(2,2,2-trichloroethoxycarbonylamino)-2,4-
dideoxy-4-fluoro-3,6-di-O-acetyl- -glucopyranosyl]-(1-6)-2-
b
-D
acetamido-2-deoxy-3-O-acetyl-a-D-galactopyranoside (20)
A solution of compound 19 (178 mg, 0.367 mmol) and com-
pound 13 (233.7 mg, 0.385 mmol) in dry dichloromethane (6 mL)
containing 4 Å-MS (2.0 g) was stirred for 2 h at ꢁ65 to ꢁ70 ꢀC under
a N2 atmosphere. After 2 h, TMSOTf (14 mL) in dry dichloromethane
(0.5 mL) was added and stirred at the same temperature for 1 h

J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
8333
under a N2 atmosphere. The reaction was then quenched with a satd
4.18. Benzyl O-[2-phthalimido-2,4-dideoxy-3-fluoro-4,6-di-O-
sodium bicarbonate solution. The solids were filtered off and the
organic layer was washed with satd sodium bicarbonate, dried with
Na2SO4, and concentrated. The crude residue was passed through
a short column of silica gel eluted with hexane/ethyl acetate (1.5:1)
to afford disaccharide 20 (242.0 mg, 85%).1H NMR (400 MHz, CDCl3)
acetyl-
acetyl-
b
-
D
D
-glucopyranosyl]-(1-6)-2-acetamido-2-deoxy- 3-O-
a-
-galactopyranoside (22)
Disaccharide 22 (yield 85%) was prepared from glycosyl donor 18
and acceptor 19 according to the procedure described for the
d
7.33–7.32 (m, 5H, ArH), 6.62 (d, J¼9.4 Hz, 1H), 5.77 (d, J¼9.8 Hz,
preparation of compound 20. 1H NMR (400 MHz, CDCl3)
d 7.83–7.80
1H), 5.30–5.21 (m,1H), 5.11 (dd, J¼2.5, 8.6 Hz,1H), 4.85 (d, J¼3.4 Hz,
1H), 4.79–4.71 (m, 4H), 4.48–4.38 (m, 3H), 4.22 (dd, J¼4.9, 12.1 Hz,
1H), 4.12–4.10 (m, 1H), 4.02–3.98 (m, 3H), 3.93–3.88 (m, 3H), 3.25
(m,1H), 2.10, 2.06, 2.03 (s, 9H, 3ꢃOCH3),1.93 (s, 3H, NCH3); 13C NMR
(m, 2H, ArH), 7.73–7.70 (m, 2H, ArH), 7.33–7.32 (m, 5H, ArH), 6.28–
6.26 (m, 1H), 5.82–5.79 (m, 1H), 5.50–5.45 (m, 1H), 5.25–5.15 (m,
1H), 5.09–4.94 (m, 3H), 4.78–4.75 (m, 2H), 4.58–4.55 (m, 1H), 4.50–
4.43 (m, 1H), 4.32–4.23 (m, 1H), 4.12–3.93 (m, 2H), 3.86–3.78 (m,
1H), 3.55–3.45 (m, 1H), 2.11, 2.07, 2.05 (s, 9H, 3ꢃOCH3), 2.01 (s, 3H,
(100.6 MHz, CDCl3)
d 171.0, 170.8, 170.5, 170.1, 154.60, 136.9, 128.5,
128.4, 128.1, 101.8 (C-1GalNAc), 97.0 (C-1GlcNAc), 88.4 and 86.5 (C-
4GlcNAc, J¼187.3 Hz), 74.1, 72.4 and 72.2 (C-3, J¼18.3 Hz), 71.1, 70.9
and 70.7 (C-5GlcNAc, J¼23.4 Hz), 69.7, 69.6, 69.1, 67.4, 62.3, 55.7, 47.6,
23.1, 20.8, 20.6. Anal. Calcd for C30H38O14N2Cl3F: C, 46.44; H, 4.94; N,
3.61; Cl, 13.71; F, 2.45. Found: C, 46.47; H, 4.93; N, 3.67; Cl, 13.74; F,
2.51.
NCH3); 13C NMR (100.6 MHz, CDCl3)
d 171.2,170.9,170.7,164.4,164.2,
136.6, 132.5, 129.4, 129.2, 128.5, 128.4, 128.1, 102.8, 97.4, 88.9, 86.7,
74.1, 73.5, 72.4, 72.2, 71.1, 70.9, 70.7, 69.6, 69.1, 67.3, 64.3, 63.5, 50.2,
48.6, 47.7, 23.1, 20.8, 20.6. Anal. Calcd for C35H39O14N2F: C, 57.53; H,
5.38; N, 3.83; F, 2.60. Found: C, 57.55; H, 5.43; N, 3.77; F, 2.63.
4.19. Benzyl O-[2-acetamido-2,4-dideoxy-3-fluoro-4,6-di-O-
acetyl-
acetyl-
b
-
D
D
-glucopyranosyl]-(1-6)-2-acetamido-2-deoxy-3-O-
4.16. Benzyl O-(2-acetamido-2,4-dideoxy-4-fluoro-3,6-di-O-
a-
-galactopyranoside (23)
acetyl - -glucopyranosyl)-(1-6)-2-acetamido-2-deoxy-3-O-
b-D
acetyl-a-D-galactopyranoside (21)
A solution of compound 22 (40.8 mg, 0.056 mmol) in dry meth-
anol (10 mL) was treated with NH2–NH2$H2O (2 mL) at 90 ꢀC for 6 h.
The reaction mixture was then concentrated and co-evaporated with
dry toluene to complete dryness. The resulting compound was
acetylated with anhydrous acetic anhydride and dry pyridine (1:1,
6 mL) in the presence of DMAP (5 mg) at rt. After completion of the
reaction (overnight), the reaction mixture was concentrated and
purified by flash chromatography (80:1, dichloromethane/metha-
Cadmium dust (756 mg, 6.73 mmol) was added to a solution of
20 (263.8 mg, 0.34 mmol) in DMF/AcOH (1:1), and the reaction was
stirred at rt under N2. After 12 h, the reaction mixture was filtered
through CeliteÒ, rinsed with DMF (5 mL), and then azeotroped with
toluene (5ꢃ20 mL). The residue was treated with acetic anhydride
in pyridine/CH2Cl2 (1:1) for 4 h at rt, then quenched with MeOH
(1 mL). The reaction mixture was concentrated under vacuum and
the residue redissolved in CH2Cl2 (50 mL), washed with brine
(60 mL), and dried (Na2SO4). The organic extract was filtered, con-
centrated in vacuum, and purified by flash chromatography (1:1,
hexanes/EtOAc) to afford 21 (216.2 mg, 93%). 1H NMR (400 MHz,
nol) to afford 23 (35.5 mg, 93%). 1H NMR (400 MHz, CDCl3)
d 7.84–
7.81 (m, 2H, ArH), 7.75–7.71 (m, 2H, ArH), 7.38–7.26 (m, 5H, ArH),
5.87–5.85 (m, 1H), 5.68–5.66 (m, 1H), 5.38–5.21 (m, 2H), 5.14–5.12
(m, 1H), 4.90–4.88 (s, 1H), 4.70–4.64 (m, 2H), 4.62 (d, J¼8.3 Hz, 1H),
4.52 (ddd, J¼3.7, 9.7, 11.3 Hz, 1H), 4.44–4.42 (m, 2H), 4.35 (m, 2H),
4.52–4.38 (m, 4H), 4.14 (m, 2H), 3.79–3.67 (m, 3H), 2.07, 2.05, 2.04,
1.97 (s, 12H, 4ꢃOCH3), 1.96, 1.87 (s, 6H, 2ꢃNCH3); 13C NMR
CDCl3)
d
7.32–7.24 (m, 5H, ArH), 5.87 (d, J¼8.9 Hz, 1H), 5.65 (d,
J¼9.6 Hz,1H), 5.30–5.21 (m, 2H), 5.11 (dd, J¼3.3,11.3 Hz,1H), 4.91 (d,
J¼3.6 Hz, 1H), 4.68 (d, J¼11.8 Hz, 1H), 4.62 (d, J¼8.3 Hz, 1H), 4.52
(ddd, J¼3.7, 9.7, 11.3 Hz, 1H), 4.44–4.42 (m, 2H), 4.35 (m, 2H), 4.20
(dd, J¼4.9,12.2 Hz,1H), 4.14 (m,1H), 3.79–3.77 (m,1H), 3.76 (m,1H),
3.54–3.51 (m, 1H), 2.09 (s, 3H, OCH3), 2.05 (s, 3H, OCH3), 2.04 (s, 3H,
OCH3), 1.93 (s, 3H, OCH3), 1.86 (6H, NCH3 and OCH3); 13C NMR
(100.6 MHz, CDCl3)
d 170.9, 170.7, 170.6, 169.4, 169.0, 136.7, 128.4,
128.2, 128.1, 101.6, 100.9, 87.8, 86.6, 84.3, 72.4, 72.2, 71.3, 71.2, 68.8,
67.9, 54.5, 23.4, 20.8. Anal. Calcd for C31H41O14N2F: C, 54.38; H, 6.04;
N, 4.09; F, 2.78. Found: C, 54.31; H, 5.99; N, 4.11; F, 2.73.
(100.6 MHz, CDCl3)
d 170.8, 170.7, 170.6, 170.4, 170.3, 170.0, 136.9,
4.20. Benzyl O-[2-acetamido-2,4-dideoxy-3-fluoro-b-D-
128.5, 128.2, 128.1, 100.6 (C-1GalNAc), 96.9 (C-1GlcNAc), 87.6 and 86.4
(C-4GlcNAc, J¼187.3 Hz), 72.2 and 72.1 (C-3, J¼18.3 Hz), 71.3 and 71.2
(C-5GlcNAc, J¼23.4 Hz), 68.7, 67.9, 67.8, 67.5, 62.1, 54.3, 54.3, 47.6, 23.1,
20.7. Anal. Calcd for C31H41O14N2F: C, 54.38; H, 6.04; N, 4.09; F, 2.78.
Found: C, 54.37; H, 5.97; N, 4.05; F, 2.81.
glucopyranosyl]-(1-6)-2-acetamido- 2-deoxy-
a-D-
galactopyranoside (2)
Disaccharide 2 (yield 87%) was prepared from 23 according to the
procedure forpreparation of compound 1.1H NMR(400 MHz, CDOD3)
d
7.36–7.23 (m, 5H, ArH), 4.97 (d, J¼3.2 Hz,1H), 4.76 (d, J¼12.6 Hz, 1H,
4.17. Benzyl O-[2-acetamido-2,4-dideoxy-4-fluoro-
b-D
-
PhCHAO, ABq), 4.50 (d, J¼8.1 Hz, 1H), 4.48 (d, J¼12.6 Hz, 1H, PhCHAO,
ABq), 4.67–4.62 (m,1H), 4.48–4.46 (m,1H), 4.28–3.80 (m,10H), 3.78–
3.64 (m, 2H), 3.54–3.40 (m, 2H), 2.08, 2.05 (s, 6H, 2ꢃNCH3); 13C NMR
glucopyranosyl]-(1-6)-2-acetamido-2-deoxy-
a-D-
galactopyranoside (1)
(100.6 MHz,CDOD3)d173.1,172.4,137.1,128.6,128.3,128.2,104.3,97.2,
The compound 21 (191.5 mg, 0.28 mmol) was treated with 5%
NaOMe (1 M) in MeOH (20
L) in MeOH (10 mL) for 12 h at 45 ꢀC and
concentrated. It was then applied to a short silica gel column and
86.7, 84.5, 74.2, 73.7, 71.370.2, 65.7, 62.3, 62.1, 58.3, 57.9, 23.3, 23.1. ESI-
MS calcd for C23H33O10N2FNa (m/z) [MþNa]þ 539.2, found 539.0.
Anal. Calcd for C23H33O10N2F: C, 53.48; H, 6.44; N, 5.42; F, 3.68. Found:
C, 53.53; H, 6.43; N, 5.37; F, 3.63.
m
eluted with (CH2Cl2/MeOH, 5:1) to give a pure disaccharide 1
(137.2 mg, 95%).1H NMR (400 MHz, CDOD3)
d 7.34–7.26 (m, 5H, ArH),
4.94 (d, J¼3.2 Hz, 1H), 4.76 (d, J¼12.6 Hz, 1H, PhCHAO, ABq), 4.50 (d,
J¼8.1 Hz, 1H), 4.48 (d, J¼12.6 Hz, 1H, PhCHAO, ABq), 4.08–3.95 (m,
3H), 3.92–3.80 (m, 5H), 3.78–3.58 (m, 4H), 2.09, 2.05 (s, 6H,
4.21. Benzyl O-[2-(2,2,2-trichloroethoxycarbonylamino)-2,4-
dideoxy-4-fluoro-3,6-di-O-acetyl-
O-[2,3,4,6-tetra-O-acetyl- -galactopyranosyl-(1-3)]-2-
acetamido-2-deoxy- -galactopyranoside (25)
b-D-glucopyranosyl]-(1-6)-
b-D
2ꢃNCH3); 13C NMR (100.6 MHz, CDOD3)
d
175.8, 174.7, 136.9, 128.5,
a-D
128.2,104.6, 96.7, 87.7, 86.5, 83.4, 72.2, 72.1, 71.3 70.2, 62.3, 62.1, 56.3,
54.3, 23.3 (NCH3), 23.1 (NCH3). ESI-MS calcd for C23H33O10N2FNa
(m/z): 539.2, Found 539.5. Anal. Calcd for C23H33O10N2F: C, 53.48; H,
6.44; N, 5.42; F, 3.68. Found: C, 53.53; H, 6.43; N, 5.37; F, 3.63.
Trisaccharide 25 (yield 95%) was prepared from glycosyl donor
13 and disaccharide acceptor 24 according to the procedure for
preparation of compound 20. 1H NMR (400 MHz, CDCl3)
d 7.33 (m,

8334
J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
5H, ArH), 6.81 (d, J¼8.8 Hz,1H), 5.72 (d, J¼9.3 Hz,1H), 5.33–5.31 (m,
2H), 5.13 (dd, J¼8.1, 4.4 Hz, 1H), 4.95 (dd, J¼3.1, 10.5 Hz, 1H), 4.71–
4.55 (m, 5H), 4.50 (d, J¼11.2 Hz, 1H), 4.30–4.21 (m, 1H), 4.07–4.01
(m, 4H), 3.87 (m, 3H), 3.70–3.66 (m, 1H), 3.51–3.46 (m, 1H), 2.13,
2.10, 2.05, 2.01, 2.00, 1.96 (s, 18H, 6ꢃOCH3), 1.94 (s, 3H, NCH3); 13C
2H, ArH), 7.76–7.70 (m, 2H, ArH), 7.39–7.24 (m, 5H, ArH), 6.78–6.74
(m, 1H), 5.82–5.80 (m, 1H), 5.66–5.63 (m, 1H), 5.50–5.45 (m, 1H),
5.30–5.19 (m, 1H), 5.02–4.90 (m, 5H), 4.78–4.72 (m, 1H), 4.60–4.57
(m, 1H), 4.45–4.40 (m, 1H), 4.31–4.18 (m, 8H), 3.83–3.79 (m, 1H),
3.52–3.47 (s, 1H), 2.12, 2.10, 2.09, 2.07, 2.02, 2.00 (s, 18H, 6ꢃOCH3),
NMR (100.6 MHz, CDCl3)
d
170.5, 170.3, 170.1, 170.0, 169.3, 154.6,
1.96 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3)
d 170.7, 170.4, 170.3,
136.6, 128.8, 128.6, 128.3, 102.2 (C-1Gal), 101.2 (C-1GlcNAc), 96.4 (C-
1GalNAc), 87.9 and 86.1 (C-4GlcNAc, J¼186.8 Hz), 78.6, 73.9, 72.8, 72.7,
70.9, 70.8, 70.6, 69.7, 69.4, 68.9, 68.5, 66.8, 62.1, 61.3, 55.98 and
53.91(C-2GlcNAc, JC,F¼8.0 Hz), 47.6, 23.2, 20.7, 20.6, 20.5, 20.4. 19F
NMR: ꢁ198.37, ꢁ198.42, ꢁ198.51, ꢁ198.55 (dd, 1F); ESI-MS calcd for
C42H54O22N2FCl3Na (m/z) [MþNa]þ 1087.3, found 1087.3. Anal.
Calcd for C42H54O22N2FCl3: C, 47.40; H, 5.11; N, 2.63; F, 1.79; Cl, 9.99.
Found: C, 47.45; H, 5.07; N, 2.68; F, 1.83; Cl, 9.93.
170.2, 170.1, 170.0, 137.1, 128.6, 128.5, 128.4, 128.3, 128.2, 103.1, 98.5,
97.6, 89.7, 86.9, 73.5, 72.3, 72.1, 71.2, 71.1, 71.0, 70.8, 70.7, 69.6, 69.3,
68.7, 68.6, 66.7, 61.8, 61.2, 54.2, 47.8, 23.2, 23.1, 20.6, 20.5, 20.4. Anal.
Calcd for C47H55O22N2F: C, 55.40; H, 5.44; N, 2.75; F, 1.86. Found: C,
55.44; H, 5.46; N, 2.79; F, 1.90.
4.25. Benzyl O-[2-acetamido-2,4-dideoxy-3-fluoro-4,6-O-
benzylidene-b-D-glucopyranosyl]-(1-6)-O-[2,3,4,6-tetra-O-
acetyl-
acetyl-
b
-
D
D
-galactopyranosyl-(1-3)]-2-acetamido-2-deoxy-4-O-
4.22. Benzyl O-(2-acetamido-2,4-dideoxy-4-fluoro-3,6-di-O-
a-
-galactopyranoside (28)
acetyl-
D
b
-
D
-glucopyranosyl)-(1-6)-O-[2,3,4,6-tetra-O-acetyl-
-galactopyranosyl-(1-3)]-2-acetamido-2-deoxy-4-O-acetyl-
-galactopyranoside (26)
b-
a
-
Following a similar procedure to that for compound 23, tri-
saccharide 28 (yield 89%) was prepared from compound 27. 1H
D
NMR (400 MHz, CDCl3) d 7.39–7.24 (m, 5H, ArH), 5.91–5.85 (m, 1H),
Trisaccharide 26 (yield 93%) was prepared from compound 25
according to the procedure for preparation of compound 21.1H NMR
(400 MHz, CDCl3) 7.39–7.34 (m, 5H, ArH), 6.03–6.00 (m,1H), 5.76–
5.66–5.63 (m, 1H), 5.38–5.35 (m, 2H), 5.09–5.04 (m, 2H), 4.97–4.94
(m, 1H), 4.71–4.60 (m, 2H), 4.58–4.37 (m, 6H), 4.20–4.16 (m, 2H),
3.98–3.74 (m, 4H), 3.51–3.41 (m, 1H), 2.11, 2.10, 2.09, 2.08, 2.03,
2.00, 1.96 (s, 21H, 7ꢃOCH3), 1.95, 1.87 (s, 6H, 2ꢃNCH3); 13C NMR
d
5.73 (m, 1H), 5.33–5.11 (m, 4H), 5.08–5.06 (m, 1H), 4.97–4.93 (m,
2H), 4.71–4.68 (m, 1H), 4.59–4.57 (m, 2H), 4.53–4.4.54 (m, 1H),
4.42–4.39 (m, 3H), 4.28–4.25 (m, 2H), 4.13–4.09 (m, 4H), 3.99–3.84
(m, 5H), 3.75–3.73 (m, 1H), 3.51–3.46 (m, 1H), 2.11, 2.10, 2.09, 2.08,
2.03, 2.00,1.96 (s, 21H, 7ꢃOCH3),1.95,1.87 (s, 6H, 2ꢃNCH3); 13C NMR
(100.6 MHz, CDCl3)
d 170.7, 170.5, 170.3, 170.2, 170.1, 170.1, 170.0,
136.9, 128.6, 128.5, 128.5,128.4, 128.3, 128.2, 101.0 (C-1Gal), 100.4 (C-
1GlcNAc), 96.9 (C-1GalNAc), 87.79 and 85.93 (C-4GlcNAc, J¼186.8 Hz),
72.9, 72.3, 72.1, 71.1, 71.2, 71.0, 70.8, 70.7, 69.6, 69.3, 68.7, 68.7, 66.8,
61.9, 61.1, 54.02 and 53.94 (C-2GlcNAc, JC,F¼8.0 Hz), 48.8, 23.2, 23.1,
(100.6 MHz, CDCl3)
d 170.7, 170.5, 170.3, 170.2, 170.1, 170.1, 170.0,
136.9, 128.6, 128.5, 128.5,128.4, 128.3, 128.2, 101.0 (C-1Gal), 100.4 (C-
1GlcNAc), 96.9 (C-1GalNAc), 87.79 and 85.93 (C-4GlcNAc, J¼186.8 Hz),
72.9, 72.3, 72.1, 71.1, 71.2, 71.0, 70.8, 70.7, 69.6, 69.3, 68.7, 68.6, 66.7,
61.9, 61.1, 54.02 and 53.94 (C-2GlcNAc, JC,F¼8.0 Hz), 48.8, 23.2, 23.1,
20.6, 20.6, 20.6, 20.5, 20.4. 19F NMR: ꢁ198.37, ꢁ198.42, ꢁ198.51,
ꢁ198.55 (dd, 1F); ESI-MS calcd for C43H57O22N2FNa (m/z) [MþNa]þ
995.9, found 995.8. Anal. Calcd for C43H57O22N2F: C, 53.09; H, 5.91;
N, 2.88; F, 1.95. Found: C, 53.11; H, 5.94; N, 2.79; F, 1.91.
20.6, 20.6, 20.5, 20.4, 20.4. 19F NMR
d
ꢁ198.37, ꢁ198.42, ꢁ198.51,
ꢁ198.55 (dd, 1F); ESI-MS calcd for C43H57O22N2FNa (m/z) [MþNa]þ
995.9, found 995.8. Anal. Calcd for C43H57O22N2F: C, 53.09; H, 5.91;
N, 2.88; F, 1.95. Found: C, 53.11; H, 5.94; N, 2.79; F, 1.91.
4.26. Benzyl O-[2-acetamido-2,4-dideoxy-3-fluoro-
glucopyranosyl]-(1-6)-O-[ -galactopyranosyl-(1-3)]-2-
acetamido-2-deoxy- -galactopyranoside (4)
b-D-
b-D
a-D
4.23. Benzyl O-[2-acetamido-2,4-dideoxy-4-fluoro-
glucopyranosyl]-(1-6)-O-[ -galactopyranosyl-(1-3)]-2-
acetamido-2-deoxy- -galactopyranoside (3)
b
-
D
-
Following a similar procedure to that for compound 1, tri-
saccharide 4 (yield 89%) was prepared from compound 28. 1H NMR
(400 MHz, CDOD3) d 7.40–7.20 (m, 5H, ArH), 5.05–5.01 (m, 1H),
b-D
a-
D
4.70–4.64 (m, 1H), 4.55–4.52 (m, 1H), 4.40–4.30 (m, 2H), 4.12–4.08
Trisaccharide 3 (yield 89%) was prepared from compound 26
(s, 1H), 4.02–3.20 (m, 15H), 1.98, 1.94 (s, 6H, 2ꢃNCH3); 13C NMR
according to the procedure described for the preparation of com-
(100.6 MHz, CDOD3) d 176.8, 176.6, 138.5, 131.6, 130.5, 129.4, 129.2,
pound 1. 1H NMR (400 MHz, CD3OD)
d
7.56–7.53 (m, 5H, ArH), 5.05
106.1, 102.3, 98.5, 91.2, 90.4, 76.2, 74.8, 71.8, 71.4, 71.2, 64.1, 63.8,
62.3, 61.1, 54.1, 23.5, 21.5. ESI-MS calcd for C29H43O15N2FNa (m/z)
[MþNa]þ 701.7, found 702.1. Anal. Calcd for C29H43O15N2F: C, 51.32;
H, 6.39; N, 4.13; F, 2.80. Found: C, 53.11; H, 5.94; N, 2.79; F, 1.91.
(d, J¼3.6 Hz, 1H), 4.69 (d, J¼8.3 Hz, 1H), 4.59 (d, J¼11.5 Hz, 1H,
PhCHAO, ABq), 4.53 (d, J¼7.9 Hz, 1H), 4.40 (dd, J¼3.8, 10.4 Hz, 1H),
4.25 (dd, J¼2.4, 7.9 Hz, 1H), 4.13 (dd, J¼2.6, 10.9 Hz, 1H), 4.02–3.78
(m, 10H), 3.73–3.70 (m, 1H), 3.68 (d, J¼3.2 Hz, 1H), 3.59 (t, J¼8.0 Hz,
1H), 3.41 (m, 1H), 2.06 (s, 6H, 2ꢃNCH3); 13C NMR (100.6 MHz,
4.27. 2-Naphthylmethyl 2,4,6-trideoxy-4-O-acetyl-6-fluoro-
D-glucopyranoside [2,3-d]-1,3-oxazolidin-2-one (29)
b-
CDOD3, Ref
d
¼49.00)
d
129.7, 129.6, 129.3, 105.6 (C-1Gal), 102.4 (C-
1GlcNAc), 97.2 (C-1GalNAc), 77.9, 75.95, 74.3, 74.1, 73.5, 72.7, 71.6, 70.8,
70.5, 70.3, 69.8, 69.6, 68.2, 61.9, 61.0. 19F NMR (CDOD3)
d
ꢁ198.37,
A solution of 6 (5 g, 13.85 mmol) in 1 M NaOH (500 ml) was
ꢁ198.42, ꢁ198.51, ꢁ198.55 (dd, JF-4,H-4 50.3, JF-4,H-3 14.6 Hz). ESI-MS
calcd for C29H43O15N2FNa (m/z) [MþNa]þ 701.7, found 701.7. Anal.
Calcd for C29H43O15N2F: C, 51.32; H, 6.39; N, 4.13; F, 2.80. Found: C,
53.11; H, 5.94; N, 2.79; F, 1.91.
refluxed at 110 ꢀC for 15 h. The reaction mixture was then cooled to
rt and neutralized with 2 M HCl. A white solid was precipitated
from the solution. Filtration and desiccation under vacuum affor-
ded the pure free amine (4.06 g, 92%). To an ice-cooled stirred so-
lution of p-nitrophenoxycarbonyl chloride (19.50 g, 96.75 mmol) in
acetonitrile (50 mL) was added over several minutes a stirred, ice
bath-cooled mixture of the resultant free amine (18.84 g,
38.7 mmol, 1 equiv) and NaHCO3 (16.25 g, 194 mmol) in 100 mL
water. The mixture was vigorously stirred with ice bath cooling for
1 h after the addition of the final aliquot. After 1 h, the resulting aq
mixture was extracted with ethyl acetate and the combined organic
layers were washed with water, dried over Na2SO4, and concen-
trated in vacuo. Purification over a short column of silica gel with
4.24. Benzyl O-[2-phthalimido-2,4-dideoxy-3-fluoro-4,6-di-O-
acetyl-
-galactopyranosyl-(1-3)]-2-acetamido-2-deoxy-
galactopyranoside (27)
b-D-glucopyranosyl]-(1-6)-O-[2,3,4,6-tetra-O-acetyl-b-
D
a-D-
Following a similar procedure to that for compound 22, tri-
saccharide 27 (yield 82%) was prepared from glycosyl donor 18 and
disaccharide acceptor 24. 1H NMR (400 MHz, CDCl3)
d 7.85–7.80 (m,

J. Xue et al. / Tetrahedron 65 (2009) 8325–8335
2. Bowman, K. G.; Bertozzi, C. R. Chem. Biol. 1999, 6, R9–R22.
8335
ethyl acetate afforded oxazolidinone (9.20 g, 93%). To a solution of
DAST (5.70 g, 35.3 mmol) in CH2Cl2 (20 mL) in a Teflon Erlenmeyer
flask was added dropwise a solution of oxazolidinone (1.61 g,
4.16 mmol) in CH2Cl2 (40 mL) at ꢁ5 ꢀC. The reaction mixture was
allowed to warm to rt and stirred overnight. Thereafter, it was
cooled to ꢁ5 ꢀC and methanol (20 mL) was added dropwise to
destroy the excess DAST and the solution was concentrated under
reduced pressure to afford a yellowish oil that was subjected to
flash chromatography on silica gel (2:3 hexanes/EtOAc) to afford 29
3. (a) Sydnes, L. K.; Valdersnes, S. Pure Appl. Chem. 2007, 79, 2137–2142; (b) Hein,
M.; Miethchen, R. Adv. Org. Synth. 2006, 2, 381–429; (c) Descheny, L.; Gainers,
M. E.; Walcheck, B.; Dimitroff, C. J. J. Invest. Dermatol. 2006, 126, 2065–2073;
(d) Subramamiam, V.; Gurcha, S. S.; Besra, G. S.; Lowary, T. L. Bioorg. Med. Chem.
2005, 13, 1083–1094; (e) Subramamiam, V.; Gurcha, S. S.; Besra, G. S.; Lowary,
T. L. Tetrahedron: Asymmetry 2005, 16, 553–567; (f) Dimitroff, C. J.; Kupper, T.
S.; Sackstein, R. J. Clin. Invest. 2003, 112, 1008–1018; (g) Gudmundsson, K. S.;
Freeman, G. A.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000, 43, 2473–2478;
(h) Scott, M. E.; Viola, R. E. Carbohydr. Res. 1998, 313, 247–253; (i) van Dorst, J.;
van Heusden, C. J.; Tikkanen, J. M.; Kamerling, J. P. Carbohydr. Res. 1997, 297,
209–227; (j) Lowary, T. L.; Hindsgaul, O. Carbohydr. Res. 1993, 249, 163–195.
4. Hartman, M. C. T.; Coward, J. K. J. Am. Chem. Soc. 2002, 124, 10036–10053.
5. Feng, F.; Okuyama, K.; Niikura, K.; Ohta, T.; Sadamoto, R.; Monde, K.; Noguchi,
T.; Nishimura, S. I. Org. Biomol. Chem. 2004, 2, 1617–1623.
(1.50 g, 93%). 1H NMR (400 MHz, CDCl3)
d 7.84–7.76 (m, 4H, ArH),
7.54–7.41 (m, 3H, ArH), 5.25–5.10 (m, 1H), 5.10–5.00 (m, 2H), 4.85–
4.78 (m, 2H), 4.20–4.10 (m, 1H), 4.05–3.96 (m, 1H), 3.80–3.65 (m,
6. Berkin, A.; Szarek, W. A.; Kisilevsky, R. Carbohydr. Res. 2000, 326, 250–263.
7. Brown, J. R.; Yang, F.; Sinha, A.; Ramakrishnan, B.; Tor, Y.; Qasba, P. K.; Esko, J. D.
J. Biol. Chem. 2009, 284, 4952–4959.
8. Sharma, M.; Bernacki, R. J.; Paul, B.; Korytnyk, W. Carbohydr. Res. 1990, 198,
205–221.
1H), 3.50 (m, 1H); 13C NMR (100.6 MHz, CDOD3)
d 158.6, 135.2,
133.7, 131.8, 128.0, 127.6, 127.5, 127.3, 127.0, 126.0, 125, 99.1(C-1),
97.2 (C-3), 83.1 (C-6, J¼174.8 Hz), 76.2 (C-2), 74.2 (C-5, J¼18.1 Hz),
70.4 (C-4, J¼7.2 Hz), 69.5; Anal. Calcd for C20H20O6NF: C, 61.69; H,
5.18; N, 3.60; F, 4.88. Found: C, 61.73; H, 5.14; N, 3.67; F, 4.83.
9. Thomas, R. L.; Abbas, S. A.; Matta, K. L. Carbohydr. Res. 1988, 175, 153–157.
10. (a) Sackstein, R.; Dimitroff, C.J.; Bernacki, R.J.; Sharma, M.; Mata, K.L.;
Paul, B. U.S. Patent. Appl. Publ. US 2003/0148997 A1, Pub. Date: Aug. 7,
2003; (b) Woynarowska, B.; Skrincosky, D. M.; Haag, A.; Sharma, M.;
Matta, K. L.; Bernacki, R. J. J. Biol. Chem. 1994, 269, 22797–22803.
11. Dimitroff, C. J.; Bernacki, R. J.; Sackstein, R. Blood 2003, 101, 602–610.
12. Zollner, T. M.; Asadullah, K. J. Clin. Invest. 2003, 112, 980–983.
13. (a) Xia, J.; Xue, J.; Locke, R. D.; Chandrasekaran, E. V.; Srikrishnan, T.; Matta, K. L.
J. Org. Chem. 2006, 71, 3696–3706; (b) Chandrasekaran, E. V.; Xue, J.; Xia, J.;
Chawda, R.; Piskorz, C.; Locke, R. D.; Neelamegham, S.; Matta, K. L. Biochemistry
2005, 44, 15619–15635; (c) Xia, J.; Alderfer, J. L.; Piskorz, C. F.; Locke, R. D.;
Matta, K. L. Synlett 2003, 1291–1294; (d) Woynarowska, B.; Dimitroff, C. J.;
Sharma, M.; Matta, K. L.; Bernacki, R. J. Glycoconjugate J. 1996, 13, 663–674;
(e) Khan, S. H.; Jain, R. K.; Abbas, S. A.; Matta, K. L. Carbohydr. Res. 1990, 198,
259–273; (f) Thomas, R. L.; Abbas, S. A.; Piskorz, C. F.; Matta, K. L. Carbohydr.
Res. 1988, 175, 158–162; (g) Thomas, R. L.; Abbas, S. A.; Matta, K. L. Carbohydr.
Res. 1988, 184, 77–85.
14. Chandrasekaran, E. V.; Xue, J.; Neelamegham, S.; Matta, K. L. Carbohydr. Res.
2006, 341, 983–994.
15. Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.; Richard, R.; Schmidt, R. R.
Carbohydr. Res. 1996, 296, 135–147.
16. (a) Jackson, T. A.; Robertson, V.; Imberty, A.; Auzanneau, F.-I. Bioorg. Med. Chem.
2009, 17, 1514–1526; (b) Makino, A.; Nagashima, H.; Ohmae, M.; Kobayashi, S.
Biomacromolecules 2007, 8, 188–195; (c) Koeller, K. M.; Smith, M. E. B.; Wong,
C.-H. J. Am. Chem. Soc. 2000, 122, 742–743; (d) Yeung, B. K. S.; Hill, D. C.; Janicka,
M.; Petillo, P. A. Org. Lett. 2000, 2, 1279–1282.
17. (a) Xue, J.; Khaja, S. D.; Locke, R. D.; Matta, K. L. Synlett 2004, 861–865; (b) Xia,
J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta, K. L. Tetrahedron
Lett. 2000, 41, 169–173.
4.28. 2-Naphthylmethyl 2-acetamido-2,4,6-trideoxy-3,4-di-O-
acetyl-6-fluoro-b-D-glucopyranoside (30)
Sodium hydroxide (2 mL, 1 M) was added to a stirred solution of
oxazolidinone 29 (1 g, 2.60 mmol) in THF (10 mL) at rt. The reaction
mixture was stirred for 3 h, poured into H2O (100 mL), and
extracted with ethyl acetate (3ꢃ50 mL). The combined organic
layer was dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was crystallized from Et2O to give free amine, which was
treated with acetic anhydride (5 mL) and dry pyridine (10 mL) in
the presence of a cat. amount of DMAP (5 mg) overnight at rt. After
overnight stirring, the reaction mixture was concentrated and
chromatographed on silica gel with hexanes/EtOAc (2:1) to give
a pure compound 30 as a syrup (1.06 g, 91%). 1H NMR (400 MHz,
CDCl3)
d 7.85–7.75 (m, 4H, ArH), 7.53–7.40 (m, 3H, ArH), 5.45–5.42
(m, 1H), 5.25–5.22 (m, 1H), 5.10–5.00 (m, 2H), 4.80–4.68 (m, 2H),
4.58–4.4 (m, 2H), 4.00–3.96 (m, 1H), 3.80–3.65 (m, 1H), 2.05 (s, 3H,
Ac), 2.04 (s, 3H, OCH3), 1.98 (s, 3H, OCH3); 13C NMR (100.6 MHz,
CDCl3)
d 168.8 (C]O), 135.5, 134.6, 128.6, 128.4, 128.0, 127.9, 127.2,
1
2
98.7, 81.1 (d, JC–F¼174.9 Hz), 72.3 (d, JC–F¼18.2 Hz), 71.8, 67.8 (d,
3JC–F¼7.3 Hz), 54.1, 21.5 (OCH3), 19.5 (OCH3). Anal. Calcd for
C23H26O7NF: C, 61.74; H, 5.86; N, 3.13; F, 4.25. Found: C, 61.71; H,
5.90; N, 3.16; F, 4.28.
18. Sharma, M.; Bernacki, R. J.; Hillman, M. J.; Korytnyk, W. Carbohydr. Res. 1993,
240, 85–93.
19. Kajihara, Y.; Kodama, H.; Endo, T.; Hashimoto, H. Carbohydr. Res. 1998, 306,
361–378.
20. Koenigs, W.; Knorr, E. Chem. Ber. 1901, 34, 957–981.
21. Salo, W. L.; Fletcher, H. G., Jr. J. Org. Chem. 1969, 34, 3189–3191.
22. (a) Rye, C. S.; Withers, S. G. J. Am. Chem. Soc. 2002, 124, 9756–9767; (b) Robins,
M. J.; Wnuk, S. F. J. Org. Chem. 1993, 58, 3800–3801.
Acknowledgements
´
23. (a) Zemple´n, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62, 1613–1614; (b) Agoston,
K.; Dobo´ , A.; Ra´ko´, J.; Kere´kgya´rto´, J.; Szurmai, Z. Carbohydr. Res. 2001, 330,
183–190.
This work was supported by Grant Nos. CA 35329, awarded by
NIH; and DOD W81XWH-06-1-0013 and P30CA16056, awarded by
NCI.
24. (a) Hodgetts, K. J.; Wallace, T. W. Synth. Commun.1994, 24,1151–1155; (b) Misra, A.
K.; Mukherjee, I.;Mukhopadhyay, B.;Roy, N. IndianJ. Chem., Sect. A1999, 38, 90–92.
25. Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett. 1982, 23, 249–252.
26. (a) Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70, 4195; (b) Benakli, K.; Zha, C.;
Kerns, R. J. J. Am. Chem. Soc. 2001, 123, 9461–9462.
References and notes
27. Manabe, S.; Ishii, K.; Ito, Y. J. Am. Chem. Soc. 2006, 128, 10666–10667.
28. Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297–1300.
29. Michalik, M.; Hein, M.; Frank, M. Carbohydr. Res. 2000, 327, 185–218 and
references cited therein.
30. Sarkar, A. K.; Brown, J. R.; Esko, J. D. Carbohydr. Res. 2000, 329, 287–300.
31. Aguilera, B.; Ferna´dez-Mayoralas, A.; Jaramillo, C. Tetrahedron 1997, 53,
5863–5876.
ˇ
ˇ
1. (a) Breton, C.; Snajdrova´, L.; Jeanneau, C.; Koca, J.; Imberty, A. Glycobiology 2006,
16, 29R–37R; (b) Paulson, J. C.; Weinstein, J.; Schauer, A. J. Biol. Chem. 1989, 264,
10931–10934; (c) Honke, K.; Taniguchi, N. Med. Res. Rev. 2002, 22, 637–654;
(d) Buschiazzo, A.; Alzari, P. M. Curr. Opin. Chem. Biol. 2008, 12, 565–572; (e) Lau,
J. T. Y.; Wuensch, S. A. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart,
G. W., Sina¨y, P., Eds.; Wiley-VCH: Weinheim; 2000; Vol. 3, pp 213–226.