Synthesis of 5-fluoro N-acetylglucosamine glycosides and pyrophosphates via epoxide fluoridolysis: Versatile reagents for the study of glycoconjugate biochemistry

Article abstract of DOI:10.1021/ja0127234

Numerous carbohydrate-processing enzymes facilitate catalysis via stabilization of positive charges on or near the C-1, C-4, C-5, or C-6 positions. Substrate analogues differing only in the substitution of a fluorine for the axial C-5 hydrogen would possess reduced electron density at these positions and could be useful mechanistic probes of these enzymes. Introduction of this 5-fluoro substituent after radical halogenation was problematic because of the incompatibility of many protecting groups to the radical halogenation and the instability of the subsequent 5-fluoro hexosamines. Thus, to allow easy access to a wide variety of 5-fluoro glycosides and glycosyl phosphates, a versatile method for the introduction of the 5-fluoro group has been developed, the key step being the fluoridolysis of C-5, 6 epoxides. By use of this method, two fluorinated carbohydrates, uridine 5′-diphospho-5-fluoro-N-acetylglucosamine and octyl 5-fluoro-N-acetylglucosamine, have been synthesized. Initial biochemical investigations of these compounds show that 5-fluoro analogues are useful probes of transition-state charge development in several enzyme-catalyzed reactions.

Full text of DOI:10.1021/ja0127234

Published on Web 07/30/2002
Synthesis of 5-Fluoro N-Acetylglucosamine Glycosides and
Pyrophosphates via Epoxide Fluoridolysis: Versatile
Reagents for the Study of Glycoconjugate Biochemistry
Matthew C. T. Hartman and James K. Coward*
Contribution from the Departments of Chemistry and Medicinal Chemistry, UniVersity of
Michigan, Ann Arbor, Michigan 48109-1055
Received December 18, 2001
Abstract: Numerous carbohydrate-processing enzymes facilitate catalysis via stabilization of positive
charges on or near the C-1, C-4, C-5, or C-6 positions. Substrate analogues differing only in the substitution
of a fluorine for the axial C-5 hydrogen would possess reduced electron density at these positions and
could be useful mechanistic probes of these enzymes. Introduction of this 5-fluoro substituent after radical
halogenation was problematic because of the incompatibility of many protecting groups to the radical
halogenation and the instability of the subsequent 5-fluoro hexosamines. Thus, to allow easy access to a
wide variety of 5-fluoro glycosides and glycosyl phosphates, a versatile method for the introduction of the
5-fluoro group has been developed, the key step being the fluoridolysis of C-5, 6 epoxides. By use of this
method, two fluorinated carbohydrates, uridine 5′-diphospho-5-fluoro-N-acetylglucosamine and octyl 5-fluoro-
N-acetylglucosamine, have been synthesized. Initial biochemical investigations of these compounds show
that 5-fluoro analogues are useful probes of transition-state charge development in several enzyme-catalyzed
reactions.
Introduction
Carbohydrates are a functionally and structurally diverse class
of biological macromolecules.1 Enzymes that catalyze biosyn-
thetic reactions to create this diversity include the following:
Glycosyltransferases2 assemble carbohydrate monomers into
oligomers and polymers or glycosylate proteins.3-5 Glyco-
sidases6-8 hydrolyze inter-saccharidic linkages. Dehydrogenases,
dehydratases, and epimerases modify carbohydrate monomers.9
While the reactions catalyzed by these enzymes are diverse,
many of the chemical transformations during catalysis occur at
the C-1, C-4, C-5, and C-6 positions (Figure 1).
Incorporation of a 5-fluoro group would provide a useful
probe for many of these enzyme-catalyzed reactions (Table 1).
For example, glycosyltransferases utilize nucleotide diphospho
sugars such as uridine 5′-diphospho-N-acetylglucosamine (UDP-
GlcNAc) as glycosyl donors. Evidence from crystal structures10-15
Figure 1. Sites of possible charge buildup during specified enzyme-
catalyzed reactions.
and substrate analogues16-18 points to formation of a glycosyl
oxocarbenium ion during catalysis. Epimerization at C-2 (UDP-
GlcNAc f UDP-N-acetylmannosamine) also involves formation
of a transient oxocarbenium ion followed by reprotonation from
the opposite face of the proposed glycal intermediate.19 An
electron-withdrawing 5-fluoro substituent would be expected
* Address correspondence to this author. E-mail: jkcoward@umich.edu.
(1) Science 2001, 291, 2263-2502.
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10036
J. AM. CHEM. SOC. 2002, 124, 10036-10053
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5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
Table 1. UDP-GlcNAc Utilizing Enzymes That May Be Affected by 5-Fluoro Substrate Analogs
to destabilize the putative oxocarbenium ion in either case. This,
in turn, should lead to slower turnover than in the natural
substrate if these hypotheses are correct.
prevent the H-5 deprotonation step required for this elimination.
C-6 dehydrogenases, which lead to the corresponding uronic
acids, proceed via two oxidations (with a thiohemiacetal
intermediate)21 that should be affected in a similar manner.
Epimerase-catalyzed reactions at C-4 proceed via a different
mechanism that involves C-4 oxidation followed by reduction
of the opposite face of the ketone.9 Partial carbocationic
character at C-4 is expected to develop along the reaction
coordinate for these oxidation reactions, and the 5-fluoro
substituent should, therefore, slow this reaction. Dehydratase-
catalyzed reactions also involve oxidation at C-4 followed by
elimination of water across the C-5,6 bond.20 In addition to
retarding the oxidation reaction, the 5-fluoro substituent would
Returning to the glycosyltransferases, glycosylation often
involves the 4-OH or 6-OH groups of the glycosyl acceptor. A
5-fluoro analogue of the natural acceptor could be a useful
mechanistic probe because the pKa of each neighboring hydroxyl
group and nucleophilicity of the conjugate base would be
lowered by the presence of the electron-withdrawing fluorine
atom.22 Finally, glycosidases have been extensively studied using
5-fluoro glycosyl fluorides.23 The affinity of these reagents could
(20) Creuzenet, C.; Schur, M. J.; Lin, J. J.; Wakarchuk, W. W.; Lam, J. S. J.
Biol. Chem. 2000, 275, 34873-34880.
(21) Campbell, R. E.; Tanner, M. E. J. Org. Chem. 1999, 64, 9487-9492.
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10037

A R T I C L E S
Hartman and Coward
Table 2. Synthesis of 5-Fluoro Glucosamine Compounds Subsequent to Radical Halogenation
% yield
entry
R
2
X
Y
3 f 4
4f 5
5f 6
a
b
c
d
e
f
Ac2
H
OAc
H
H
OAc
H
H
a
<5
43
52
35
66
nd
nd
55
56
43
52
nd
nd
nd
25
nd
75
TCP
TCP
TCP
TCP
Pht
OC6H4OMe(p)
OCH2CCl3
H
OAc
OAc
a Inseparable 5-Br and 1-Br regioisomers.
be improved by incorporation of the natural aglycon.24 Alter-
natively, incorporation of a 5-fluoro substituent on the aglycon
would be useful for investigating the effect of the leaving group
pKa in C-4 or C-6 linked oligosaccharides. With these multiple
applications in mind, the synthesis of 5-fluoro GlcNAc deriva-
tives 1 and 2 (Figure 2) has been investigated.
are typically limited to monosaccharides; only one 5-bromo
disaccharide has been described.26 Finally, the only application
of this method to nitrogen-containing monosaccharides gave
very low yields.27 Thus, we sought to either circumvent these
limitations or create a new and more versatile method to
incorporate the 5-fluoro moiety. GlcNAc-based carbohydrates
were selected as the first synthetic targets because working with
amino sugars provides a rigorous test of any new methodology.
Results
Introduction of the 5-Fluoro Moiety after Radical Halo-
genation. Our initial work centered on improving the yields
and the scope of the radical halogenation method. A series of
N-substituted, tri-O-acetyl glucosamine derivatives, 3, were
synthesized as described in the literature (3b,d-f) or in the
Experimental Section (3a,c). These substrates were then sub-
jected to radical bromination, halide exchange (Br f F), and
epimerization conditions. The results are summarized in Table
2.
It was initially observed that amide NH groups were
incompatible with the N-bromosuccinimide (NBS) reaction,
likely due to bromine transfer from NBS to the carbohydrate
amide. Thus, imide protecting groups such as N,N-diacetyl (entry
a), tetrachlorophthaloyl (TCP) (entries b-e), and phthaloyl (Pht)
(entry f) were investigated. The N,N-diacetyl compound 4a gave
a mixture of 5-bromo and 1-bromo isomers during the NBS
reaction. The tetrachlorophthaloyl protecting group was compat-
ible with these reaction conditions, leading to the desired
5-bromo derivatives, 4, but yields were consistently lower as
compared to the phthaloyl series (compare 4e and 4f).
Since 5-fluoro glycosyl pyrophosphates (1) were desired, we
decided to investigate alternative C-1 hydroxyl protecting groups
that might survive the bromination and fluorination steps yet
would be amenable to selective deprotection in the presence of
O-acetyl protecting groups. For this purpose, the p-methox-
yphenyl28 and trichloroethyl29 groups (entries b and c), prepared
by BF3‚OEt2-mediated glycosylation of the corresponding
glycosyl acetates,30,31 were chosen. Unfortunately, these protect-
Figure 2. 5-Fluoro synthetic targets.
The wide variety of substrates for these diverse enzymes
requires a flexible synthetic route for incorporation of the
5-fluoro substituent. Other than the synthesis of 5-fluoro
glycosyl fluorides by Withers and co-workers,23 no methods
(flexible or otherwise) for introducing fluorine at C-5 have been
developed. In prior syntheses, the key step was introduction of
a 5-bromo moiety via radical halogenation.25 Although this step
allows introduction of the 5-fluoro group concisely, the types
of substrates compatible with this reaction are limited, and the
yields are usually only modest. In particular, C-1 electron-
withdrawing groups are required to prevent competing bromi-
nation at that position. Common carbohydrate protecting groups
containing a radical-stabilizing functionality such as benzyl or
allyl groups are also incompatible. Furthermore, because of
competing bromination at other C-5 positions, these reactions
(26) Blattner, R.; Ferrier, R. J.; Petpiboon, P. J. Chem. Soc., Chem. Commun.
1980, 20, 944-945.
(22) Jencks, W. P.; Regenstein, J. In Handbook of Biochemistry and Molecular
Biology; Fasman, G. D., Ed.; CRC Press: Boca Raton, FL, 1985.
(23) Williams, S. J.; Withers, S. G. Carbohydr. Res. 2000, 327, 27-46.
(24) McCarter, J. D.; Yeung, W.; Chow, J.; Dolphin, D.; Withers, S. G. J. Am.
Chem. Soc. 1997, 119, 5792-5797.
(25) Somsak, L.; Ferrier, R. J. In AdVances in Carbohydrate Chemistry and
Biochemistry; Horton, D., Ed.; Academic Press: San Diego, 1991; Vol.
49, pp 37-92.
(27) Vocadlo, D. J.; Mayer, C.; He, S.; Withers, S. G. Biochemistry 2000, 39,
117-126.
(28) Zhang, Z.; Magnusson, G. Carbohydr. Res. 1996, 295, 41-55.
(29) Lemieux, R. U.; Driguez, H. J. Am. Chem. Soc. 1975, 97, 4063-4068.
(30) Dahmen, J.; Frejd, T.; Magnusson, G.; Noori, G. Carbohydr. Res. 1983,
114, 328-330.
(31) Ellervik, U.; Magnusson, G. J. Org. Chem. 1998, 63, 9314-9322.
9
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5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
Scheme 2. Synthesis of 5-F Octyl Glycoside 2
Figure 3. Rationale for instability of 5-fluoro reducing sugars.
ing groups proved unsatisfactory in the NBS reaction, leading
to competing bromination at C-1. Thus the reaction seems
limited to C-1 ester protecting groups.
The N-phthaloyl â-acetate (entry f) compound proved to be
the best substrate for the series of reactions. Bromination
proceeded in good yield; silver fluoride displacement yielded
only the L-ido configured compound 5f. The final inversion
reaction was accomplished with BF3‚OEt2 in the presence of
molecular sieves to prevent hydrolytic attack of the carbocationic
intermediate. Unfortunately, deprotection of the 5-fluoro product
6f gave only decomposition, likely due to a postulated ring
opening resulting in a keto aldehyde (Figure 3) with concomitant
loss of fluoride as observed by 19F NMR.
Synthesis of 5-Fluoro Glycosides via Epoxide Fluoridoly-
sis. The demonstrated instability of these 5-fluoro hexosamines
necessitated development of a new method to introduce the
5-fluoro group (Scheme 1). We envisioned that a C-5,6 epoxy
group could be opened in the presence of fluoride, thus giving
the desired 5-fluoro product. The C-5,6 epoxide could be
prepared from a C-5,6 alkene which should be readily available
from a C-6 selenide after oxidation and elimination.32 The C-6
selenide should be inert to several transformations, allowing
introduction of the fluorine late in the synthesis.33-35
selenoxide elimination in dihydropyran. Dihydropyran was used
as the solvent to trap the postulated electrophilic selenium
products,37 thereby preventing electrophilic addition onto the
electron-rich olefin of 10. Surprisingly, epoxidation gave only
one of the two possible diastereomeric epoxides, 11. This
epoxide was opened with HF‚pyridine and acetylated. The
desired D-gluco isomer 12a was formed in excellent yield and
was easily separable from a small amount of the C-5 epimer,
12b. Deprotection of the acetates of 12a with methanolic
ammonia provided the desired octyl 5-fluoro GlcNAc 2 in good
yield. The overall yield from 7 in the 10-step synthesis was
34%.
Scheme 1. Retrosynthetic Analysis for Introduction of the 5-Fluoro
Group
Synthesis of Glycosyl Phosphates via Epoxide Fluoridoly-
sis. Inspired by this success, we now turned to the second
challenge, namely, to introduce the 5-fluoro substituent into
glycosyl phosphates. Because some methods for synthesizing
glycosyl phosphates require a reducing sugar,38 a functionality
previously shown to be incompatible with the 5-fluoro sub-
stituent (Figure 3), introduction of the glycosyl phosphate prior
to the fluorine atom would be advantageous. This presented a
different problem, however, because the unstable GlcNAc
phosphate triesters39 would have to be carried through multiple
steps as the fluorine was introduced. Thus, the N-trifluoroacetyl
(TFA) group was utilized because of its ability to stabilize C-1
phosphotriesters.40 With these constraints in mind, three routes
to phosphate introduction were envisioned (Scheme 3). A
reducing sugar could serve as a phosphorylation substrate either
via the phosphite41 (route A) or direct phosphorylation with
tetrabenzylpyrophosphate (route B).39 The oxazoline method40,42
(route C) could also be utilized.
Synthesis of 5-F-GlcNAc Glycosides via Epoxide Fluori-
dolysis: Development of the Method. To explore the proposed
new methodology, â-octyl 5-F-GlcNAc, 2, was selected as the
initial synthetic target. 4,6-Benzylidene glucosamine derivative
736 served as the starting material (Scheme 2). NBS bromination
gave the corresponding 6-bromo, 4-O-benzoyl compound,
following which the selenide was introduced in high yield by
nucleophilic displacement with PhSeH to give 8. Cleavage of
the base-labile protecting groups with ethanolic hydrazine at
80 °C followed by acetylation gave N-acetyl glycoside 9. After
one-pot oxidation (m-chloroperoxybenzoic acid (mCPBA)) and
elimination (Et3N, reflux)32 failed, the desired alkene 10 was
prepared by oxidation of 9 with NaIO4 followed by thermal
(32) Myers, A. G.; Gin, D. Y.; Rogers, D. H. J. Am. Chem. Soc. 1994, 116,
4697-4718.
(37) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.; Wenderborn, D. F. J.
Org. Chem. 1978, 43, 1697-1705.
(33) While this work was in progress, Murphy and co-workers (refs 34 and 35)
described the synthesis of 5-ketohexoses via hydrolysis of a C-5,6 epoxy
intermediate derived from appropriately protected 6-deoxyhex-5-enopyra-
nosides.
(38) Shibaev, V. N.; Danilov, L. L. In Glycoproteins and Related Compounds;
Large, D. G., Warren, C. D., Eds.; Marcel Dekker: New York, 1997; pp
456-487.
(34) Enright, P. M.; O’Boyle, K. M.; Murphy, P. V. Org. Lett. 2000, 2, 3929-
(39) Lee, J.; Coward, J. K. J. Org. Chem. 1992, 57, 4126-4135.
(40) Busca, P.; Martin, O. R. Tetrahedron Lett. 1998, 39, 8101-8104.
(41) Sim, M. M.; Kondo, H.; Wong, C.-H. J. Am. Chem. Soc. 1993, 115, 2260-
2267.
3932.
(35) O’Brien, J. L.; Tosin, M.; Murphy, P. V. Org. Lett. 2001, 3, 3353-3356.
(36) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447-1465.
9
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A R T I C L E S
Hartman and Coward
Scheme 3. Three Possibilities for Phosphate Introduction
Scheme 4. Synthesis of TBS Glycoside 16b
20 in excellent yield. Trifluoroacetylation with trifluoroacetic
anhydride (TFAA) in pyridine followed by acetylation of the
C-4 hydroxyl gave trifluoroacetamides 21 which contained the
suitable protecting groups for C-1 phosphorylation.
Two anomeric protecting groups that should be easily
removed to allow introduction of the phosphate, the p-
methoxyphenyl (PMP) and tert-butyldimethylsilyl (TBS), were
investigated. PMP glycosides in particular are stable to a wide
variety of conditions yet can be cleaved to give glycosyl
bromides, thiophenyl glycosides, and reducing glycosides.28 The
PMP glycoside, 16a, was prepared according to a literature
procedure,43 and the corresponding TBS glycoside, 16b, was
synthesized as shown in Scheme 4. Selective anomeric deacety-
lation of 13 proceeded smoothly using the method of Zhang
and Kovac.44 After silylation to give 15, deprotection and
benzylidenation gave 4,6-benzylidene 16b in good yield.
The selenide and N-TFA groups on both the PMP and TBS
glycosides were then introduced (Scheme 5). Treatment with
NBS gave the 6-bromo compounds, 17. In the context of
ultimately employing this new methodology in the synthesis of
5-F-GlcNAc-containing oligosaccharides, it was desirable to
protect the 3-hydroxyl so that it could be selectively unmasked
in the presence of the 4-O-benzoyl protecting group and vice
versa. Therefore, the benzyloxymethyl (BOM) group was chosen
for 3-hydroxyl protection. Benzyloxymethylation with BOMCl
gave the selectively protected compounds 18 in good yield. With
the PMP glycoside, the BnOH byproduct was difficult to
remove, and the isolated yield of pure 18a was therefore
reduced. Formation of the C-6 selenide 19 proceeded in good
yield for both glycosides. With the selenide in place, the TFA
group could be introduced in three steps. First, cleavage of the
phthaloyl and benzoate groups with hydrazine in EtOH gave
Introduction of the C-1 Phosphate Starting from the PMP
Glycoside. Attempted oxidative cleavage of the PMP group
failed to give the reducing sugar, probably as a result of
competing oxidation of the selenide. Thus an alternate route to
the reducing sugar was developed (Scheme 6). Treatment of
28
21a with AcBr and BF3‚OEt2 did not give the glycosyl
bromide as expected. Instead, the BOM group was cleaved and
acetylated to give 22. Treatment of 22 with AcBr, BF3‚OEt2,
and catalytic ZnI2 gave glycosyl bromide 23. The glycosyl
phosphate could be introduced via two routes from this
intermediate. Conversion of 23 to the trifluoromethyl oxazoline
24 using Bu4NBr and 2,6-lutidine proceeded smoothly. Bu4-
NBr was required to suppress glycal formation.45 Unfortunately,
phosphorolysis of the oxazoline to give 2640 was difficult to
reproduce in good yield. The reaction was highly sensitive to
the presence of water, and even when water was rigorously
excluded, the extended reaction times required for larger scale
reactions led to decomposition. As evidenced by thin-layer
chromatography (TLC), the â-phosphate formed rapidly; de-
composition occurred only during subsequent heating to obtain
the desired R-glycosyl phosphate, 26, as the thermodynamic
product. Because this reaction proceeded smoothly on the
corresponding 6-OAc compound,40 the 6-seleno substituent
likely decreased the thermal stability of this glycosyl phosphate,
resulting in decomposition. An alternative route, however,
Scheme 5. Preparation of the PMP and TBS Glycosides 21a and 21b
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5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
Scheme 6. Introduction of the Phosphate from the PMP Glycoside 21a
Scheme 7. Introduction of the Phosphate from the TBS Glycoside
21b
Scheme 8. Preparation of Protected 5-F Glucosamine Phosphate
30a
proved to be more successful. Conversion of 23 to the reducing
sugar 25 using Ag2CO3 in wet acetone followed by lithium
alkoxide formation and phosphorylation with tetrabenzylpyro-
phosphate39 gave glycosyl phosphate 26 in satisfactory yields.
Compound 26 proved to be stable to chromatography.
one-pot mCPBA oxidation/elimination method led only to
decomposition during the selenoxide elimination, probably due
to the basic conditions required to prevent electrophilic addition
of the “PhSeOH” onto the alkene product.37 Oxidation with an
excess of dimethyldioxirane (DMDO) led to some overoxidation
to the selenone. In contrast, oxidation of 28 with NaIO4 followed
by thermal selenoxide elimination in dihydropyran (see also
Scheme 2) gave alkene 29 in good yield. Treatment of 29 with
DMDO provided a 3:2 mixture of epoxides. Fluoridolysis with
HF‚pyridine followed by acetylation of the resulting fluorohy-
drins led to a mixture of separable 5-fluoro epimers, 30, in good
overall yield. The epimers could be partially separated by flash
chromatography and completely separated by preparative high-
performance liquid chromatography (HPLC). Thus, the newly
developed fluorination strategy was useful for the preparation
of glycosyl phosphates. To utilize this 5-fluoro glycosyl
phosphate, 30a, in the synthesis of 1, deprotection of 30a was
required (Scheme 9). Hydrogenation of the BOM and benzyl
groups gave free phosphate 31. Deacetylation with methanolic
ammonia proceeded smoothly to give an unstable amine that
was immediately acetylated with Ac2O/Et3N to give the desired
GlcNAc phosphate, 32. Purification of 32 was difficult as a
result of pH-dependent instability. Anion-exchange chromatog-
raphy could, however, be performed at pH 4.5 to give 32 in
good yield. UMP-morpholidate was treated with 32 and 1H-
tetrazole47 in pyridine, giving the desired sugar nucleotide 1 in
moderate yield.
Introduction of the C-1 Phosphate Starting from the TBS
Glycoside. The deprotection of 21b proceeded most easily using
HF‚pyridine in THF,46 giving intermediate 27 as a mixture of
R/â-isomers (10:1) (Scheme 7). Phosphitylation41 gave a mixture
of R/â-phosphites in a 3:2 ratio and was not pursued further.
Phosphorylation using lithium diisopropylamide (LDA) and
tetrabenzylpyrophosphate,39 however, proceeded smoothly to
give stable glycosyl phosphate 28 in the desired R-configuration
and in high yield. During the reaction, the â-phosphotriester
was also formed but was converted in situ to the 1,2-oxazoline,
which was easily separated from 28 by flash chromatography.
Comparing the number of steps, reaction conditions, and overall
yields (Scheme 6 vs Scheme 7) the preferred method for
synthesis of the desired N-TFA, 6-seleno glucosamine R-1-
phosphate, is via the TBS glycoside, 21b. This synthetic route
offers the additional advantage of maintaining the differential
protection at C-3 and C-4.
With 28 in hand, the main challenge remaining was the
introduction of the 5-fluoro group (Scheme 8). The standard
(42) Warren, C. D.; Herscovics, A.; Jeanloz, R. W. Carbohydr. Res. 1978, 61,
181.
(43) Nakano, T.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1993, 243, 43-69.
(44) Zhang, J.; Kovac, P. J. Carbohydr. Chem. 1999, 18, 461-469.
(45) Blatter, G.; Beau, J.-M.; Jacquinet, J.-C. Carbohydr. Res. 1994, 260, 189-
202.
Biochemical Studies. Biochemical evaluation of compounds
1, 2, and 32 has focused on the enzyme-catalyzed reactions
shown in Scheme 10.
(46) Debenham, J.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1997, 62,
4591-4600.
9
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A R T I C L E S
Hartman and Coward
Scheme 9. Deprotection and Synthesis of UDP-5F-GlcNAc 1
To assess the effect of a 5-fluoro substituent on the nucleo-
philicity of a hydroxyl group at C-4 or C-6, the ability of the
5-F-GlcNAc glycoside, 2, to act as a glycosyltransferase
acceptor was investigated. Thus, in the reaction catalyzed by
â-1,4-galactosyltransferase (GalT, Scheme 10, reaction f),
compound 2 shows an 8-fold reduction in kcat/Km when
compared with GlcNAc â-octyl glycoside (Figure 5). Again,
these results are in accord with the predicted effect of fluorine
on the acidity of adjacent hydroxyl groups22 and the resulting
attenuated reactivity of compounds such as 2 in glycosyltrans-
ferase-catalyzed reactions (Table 1). Interestingly, the major
effect of the 5-F substituent appears to be in Km (ca. 6-fold
increase) rather than kcat (ca. 30% decrease). The magnitude of
this kcat effect is consistent with the small value of ânuc calculated
for an analogous system, the deglycosylation of the galactosyl
enzyme intermediate in â-galactosidase.48 A more complete
investigation of the GalT reaction kinetics is currently in
progress in our laboratory.
Preliminary results indicate that 32 is an alternate substrate
for the phosphotransferase, glmU (Scheme 10, reaction a, data
not shown), consistent with the expected minimal electronic
effect of the fluorine on the nucleophilicity of the distal glycosyl
phosphate. Similarly, compound 1 competes with UDP-GlcNAc
in binding to N-acetyl glucosaminylphosphotransferase (reaction
b, data not shown) as would be expected for an alternate
substrate; however, turnover of compound 1 has not yet been
evaluated. Biochemical studies of GlcNAc transferases (reac-
tions c and d) are currently underway. Complete details of these
biochemical investigations will be published in due course.
To investigate the effect of fluorine on hydride transfer at an
adjacent carbon, the epimerization reaction catalyzed by UDP-
GlcNAc 4-epimerase (reaction e) was studied. This enzyme,
encoded by the WbgU gene from Plesiomonas shigelloides (P.
Kowal and P. G. Wang, unpublished results), catalyzes the
epimerization of UDP-GlcNAc to UDP-N-acetylgalactosamine
(UDP-GalNAc) (Figure 4a). Under the reaction conditions
described in Figure 4b, the electron-withdrawing fluorine at C-5
completely blocks the corresponding epimerization of UDP-
5FGlcNAc (1). Inhibition of UDP-GlcNAc epimerization in the
presence of 1 (Figure 4c) indicates that 1 binds to the enzyme.
Thus, the strongly electron-withdrawing fluorine at C-5 mark-
edly retards an epimerization reaction that, by analogy to UDP-
galactose 4-epimerase,9 is expected to involve sequential
NADH-mediated oxidation and reduction at C-4 via a 4-keto
intermediate. These preliminary results with 1 are in accord with
the underlying hypothesis that a 5-fluoro substituent should
destabilize developing positive charge associated with hydride
transfer at C-4 (Table 1).
Discussion
Because of the ability of the 5-F group to effect large
electronic changes with only small steric alterations, 5-F
glycosides and phosphates can be useful reagents in enzymology
(Table 1). Initial attempts to create a versatile strategy for the
Scheme 10. Initial Biochemical Evaluations of 5-FGlcNAc Derivatives (1, 2, and 32)a
a (a) UDP N-acetylglucosamine pyrophosphorylase, glmU, EC 2.7.7.23; (b) UDP-N-acetylglucosamine dolichyl/polyisoprenyl phosphate N-acetylglu-
cosaminephosphotransferase, EC 2.7.8.15; (c) N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase, EC 2.4.1.141; (d) â-1,3-N-
acetylglucosaminyltransferase, lgtA; (e) UDP-N-acetylglucosamine 4-epimerase EC 5.1.3.7; (f) â-1,4-galactosyltransferase from bovine milk, EC 2.4.1.38.
9
10042 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
Figure 5. Comparison of octyl 5-F-GlcNAc, 2 (open circles), and octyl
GlcNAc (closed circles) in a Sep-Pak assay (ref 49) with â-1,4-galacto-
syltransferase from bovine milk (Sigma).
Scheme 11. Summary of the New Methdology
Figure 4. Comparison of capillary electrophoretic analysis of UDP-GlcNAc
and UDP-5-F-GlcNAc, 1, in the reactions catalyzed by UDP-GlcNAc
4-epimerase, WbgU. In addition to the substrate, each reaction mixture
contained 20 mM Tris‚HCl, pH ) 8.5, 10 mM BME, and 150 ng of enzyme
in a total volume of 40 µL. (a) Incubation of UDP-GlcNAc (200 µM) with
epimerase (3 min). (b) Incubation of 1 (200 µM) with epimerase (3 min).
The arrow shows the expected location of UDP-5-F-GalNAc. (c) Incubation
of both 1 (200 µM) and UDP-GlcNAc (200 µM) with epimerase (3 min),
clearly showing inhibition of epimerization of UDP-GlcNAc by 1. The arrow
shows the smaller UDP-GalNAc peak.
cessfully. Even 5-fluoro glycosyl phosphate triesters can be
prepared with this methodology provided a suitable C-2 electron-
withdrawing protecting group (such as the N-TFA) is employed.
The fluorination step itself is accomplished under mild
conditions (HF‚pyridine) compatible with numerous functional
groups. Fluorination favors the D-configured pyranoses, and
selectivity is good to excellent. Configuration of the 5-F
compounds can be readily determined by a comparison of 19F
synthesis of these reagents via fluorination after radical halo-
genation failed, as a result of incompatibility of various
protecting groups in the bromination reaction (Scheme 11).
Deprotection of 6f, derived from the best substrate for the
halogenation and isomerization reactions, 3f, led only to
decomposition.
Epoxide fluoridolysis, on the other hand, is much more
general, simply requiring the synthesis of a suitable C-6 seleno
precursor. As long as the chosen protecting groups are stable
to the oxidation conditions required for the two-step conversion
of the selenide to an epoxide, the fluoridolysis should succeed
on stable glycosides. A variety of protecting groups on the C-1
through C-4 oxygen or nitrogen groups can be utilized suc-
1
chemical shift data and J4,5 coupling constants from H NMR
spectral data. As shown in Table 3, 19F ppm values for the
D-gluco-configured compounds were consistently shifted upfield
relative to the L-ido-configured compounds. In addition, the
H-4-F-5 coupling constants for the L-ido compounds were
typically severalfold less. This is reasonable because the trans-
diaxial character of the D-gluco compounds places H-4 and F-5
at a 180° dihedral angle. These trends are in accord with a recent
review of NMR spectral data for fluorinated carbohydrates.50
(47) Wittmann, V.; Wong, C.-H. J. Org. Chem. 1997, 62, 2144-2147.
(48) Richard, J. P.; Westerfield, J. G.; Lin, S.; Beard, J. Biochemistry 1995, 34,
11713-11724.
(49) Palcic, M. M.; Heerze, L. D.; Pierce, M.; Hindsgaul, O. Glycoconjugate J.
1988, 5, 49-63.
(50) Michalik, M.; Hein, M.; Frank, M. Carbohydr. Res. 2000, 327, 185-218.
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10043

A R T I C L E S
Hartman and Coward
mmol)57 in dry THF in an atmosphere of N2 was added diisopropyl-
ethylamine (1.38 mL, 7.94 mmol) and freshly distilled acetyl chloride
(0.456 mL, 6.42 mmol). Within 5 min, a white solid began to precipitate.
After stirring for 2.5 days at room temperature, the solid was filtered
and the solvent was evaporated in vacuo, leaving a brown oil (1.1 g).
The oil was dissolved in 40 mL of EtOAc and washed with saturated
NaHCO3 (3 × 40 mL), water (40 mL), and saturated NaCl (40 mL).
The organic extract was evaporated, leaving a brown oil (670 mg) which
was purified by flash chromatography (hexanes/EtOAc 3:2-2:3). The
resulting yellow oil crystallized upon standing and was triturated with
anhydrous ether, giving the title compound as white needles (229 mg,
Table 3. NMR Spectral Characteristics of D-Gluco and L-Ido
Isomers
D-gluco
L-ido
compound
19F, ppm
J4,5, Hz
compound
19F, ppm
J4,5, Hz
5c
5e
5d
5f
12b
30b
-30.06
-30.94
-29.24
-30.80
-26.35
-42.08
4.8
5.1
6.2
6.1
12.7
a
6d
6f
-47.86
-55.96
-52.46
-48.32
-47.28
-54.57
-54.11
-61.64
22.4
23.0
22.7
22.8
22.8
a
12a
30a
31
32
1
1
42%). mp 111-113 °C. H NMR (300 MHz, CDCl3): δ 6.24 (d, 1H,
a
a
J ) 3.3 Hz), 6.10 (dd, 1H, J ) 9.0, 11.4 Hz), 5.10 (dd, 1H, J ) 9.0,
10.0 Hz), 4.68 (dd, 1H, J ) 3.3, 11.4 Hz), 4.35 (dd, 1H, J ) 4.0, 12.4
Hz), 4.23 (m, 1H), 4.09 (dd, 1H, J ) 1.9, 12.4 Hz), 2.35 (s, 6H), 2.11-
1.98 (m, 12H). 13C NMR (75 MHz, CHCl3): δ 173.73, 170.55, 169.71,
169.51, 169.18, 90.60, 70.10, 69.42, 68.93, 61.41, 57.47, 26.64, 20.92,
20.67, 20.56. FAB-MS m/z (rel intensity): 454.2 ([M + Na]+ 100.0),
394.1 (44.8), 372.1 (48.5), 330.1 (75.9), 176.0 (70.4), 136.1 (90.1).
FAB-HRMS calcd for C18H25NO11Na [M + Na]+, 454.1325; obsd,
454.1318.
2
a H-4 was obscured by other protons, and the coupling constant could
not be determined.
In addition to providing access to a new class of fluorinated
carbohydrates, this research provides evidence that 5-F GlcNAc
glycosides and phosphates are useful mechanistic probes for a
wide variety of enzyme-catalyzed reactions (Figure 1 and Table
1). Preliminary results from several enzyme-mediated transfor-
mations (Scheme 10) illustrate the useful mechanistic data that
can be gathered about transition state charge buildup using the
5-F GlcNAc derivatives, 1 and 2. In conclusion, an efficient
and versatile route for the synthesis of 5-fluoro glycosides and
phosphates has been accomplished via epoxide fluoridolysis.
These reagents show considerable promise for mechanistic
studies of various carbohydrate-utilizing enzymes.
2,2,2-Trichloroethyl 3,4,6-Tri-O-acetyl-2-deoxy-2-tetrachlorophthal-
imido-â-D-glucopyranose (3c). A mixture of 3d and 3e (1:4) (250 mg,
0.41 mmol) and 2,2,2-trichloroethanol (47 µL, 0.49 mmol) were
dissolved in dry CH2Cl2 (2.5 mL), and the solution was cooled to 0
°C. BF3‚OEt2 (300 µL, 2.36 mmol) was added dropwise over 2 min,
and the reaction was allowed to warm to room temperature after 1.25
h. After 24 h, the reaction was diluted with CH2Cl2 (10 mL), extracted
with saturated NaHCO3 (10 mL) and saturated NaCl (10 mL), dried
over MgSO4, filtered, and evaporated, leaving a dark brown oil (340
mg). The oil was purified by flash chromatography (CHCl3/EtOAc
60:1-5:1), giving the title compound as a white solid (40%, 117 mg).
Experimental Section
General. All chemicals were purchased from Aldrich or Acros with
the exception of BOM-Cl which was purchased from TCI America.
Solvents were purified by distillation as follows: tetrahydrofuran (THF)
from sodium benzophenone ketyl; MeOH, Et3N, DMF, CH2Cl2, and
pyridine from CaH2; CCl4 from CaCl2. CHCl3 was purified by passing
through a column of activated Al2O3. Flash chromatography was carried
out using 230-400 mesh Whatman SiO2. TLC analyses were performed
on SiO2 60 F254 Whatman plates, and compounds were visualized with
UV light, by staining with cerium molybdate followed by heating, or
by phosphorus stain.51,52 Preparative TLC utilized Whatman plates (250
µm). Cation exchange was performed on DOWEX 50WX8-100
(Aldrich). Anion exchange was performed with AG 1-X8 (Bio-Rad
Laboratories) converted to the appropriate form prior to use. Size-
exclusion chromatography was performed on Bio-Gel P-2, fine (Bio-
Rad Laboratories). NMR spectra were recorded on Bruker AVANCE
1
mp 212-214 °C. H NMR (500 MHz, CDCl3): δ 5.84 (dd, 1H, J )
9.3, 10.7 Hz), 5.59 (d, 1H, J ) 8.5 Hz), 5.23 (dd, 1H, J ) 9.3, 10.3
Hz), 4.43 (dd, 1H, J ) 8.4, 10.7 Hz), 4.38 (d, 1H, J ) 12.1 Hz), 4.35
(dd, 1H, J ) 4.4, 12.2 Hz), 4.20 (dd, 1H, J ) 2.4, 12.2 Hz), 4.12 (d,
1H, J ) 12.1 Hz), 3.89 (ddd, 1H, J ) 2.4, 4.4, 10.3 Hz), 2.14 (s, 3H),
2.05 (s, 3H), 1.93 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.62,
170.40, 169.34, 140.67, 129.94, 126.84, 98.52, 95.82, 80.43, 72.08,
70.20, 68.37, 61.59, 55.02, 20.75, 20.57, 20.51. The TCP CdO peak
was presumably broad and not observed. EIMS m/z (rel intensity):
703.0 ([M]+, 0.6), 393.0 (11.8), 326.9 (17.1), 43.4 (100.00). EI-HRMS
calcd for C22H18NO10Cl7 [M]+, 700.8750; obsd, 700.8779.
2,2,2-Trichloroethyl 5-Bromo-3,4,6-tri-O-acetyl-2-deoxy-2-tetra-
chlorophthalimido-â-D-glucopyranose (4c). N-Bromosuccinimide (130
mg, 0.73 mmol) and 3c (117 mg, 0.17 mmol) were suspended in CCl4
(10 mL). The mixture was illuminated with a 150 W flood lamp placed
ca. 0.25 in. from the flask, and the reaction gradually turned bright
orange. After 1.5 h, the mixture was cooled on ice, the white solid
was filtered off, and the filtrate was washed with water, saturated
NaHCO3 (10 mL), and saturated NaCl (10 mL). The organic layer was
dried over MgSO4, filtered, and evaporated in vacuo, leaving a yellow
oil (184 mg) which was purified by flash chromatography (hexanes/
EtOAc 4:1-2:1), giving the title compound as a colorless oil (56 mg,
43%). 1H NMR (500 MHz, CDCl3): δ 6.10 (d, 1H, J ) 8.5 Hz), 6.06
(dd, 1H, J ) 9.3, 10.5 Hz), 5.35 (d, 1H, J ) 9.3 Hz), 4.57-4.53 (m,
2H), 4.44 (d, 1H, J ) 12.2 Hz), 4.39 (d, 1H, J ) 12.0 Hz), 4.10 (dd,
1H, J ) 12.1 Hz), 2.17 (s, 3H), 2.10 (s, 3H), 1.93 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 170.02, 169.81, 168.99, 162.05, 140.79, 130.04,
126.76, 98.89 (1), 95.38, 95.38, 80.82 (2), 69.02 (1), 68.91 (1), 65.75
(2), 54.03 (1), 20.65 (3), 20.52 (3), 20.40 (3).
1
DRX-500 or DPX-300 spectrometers as indicated. H NMR chemical
shifts in CDCl3 and MeOH are reported relative to tetramethylsilane
at 0.00 ppm. Spectra obtained in D2O are reported referenced to HOD
at 4.79 ppm. 13C NMR chemical shifts are reported relative to the center
solvent peak, CDCl3 (77.00), and CD3OD (49.00). The number of
attached protons (1, 2, or 3) is indicated and was determined by DEPT
NMR. 19F NMR chemical shifts are referenced to an external standard
of TFA in CDCl3. 31P NMR chemical shifts are referenced to a capillary
containing 0.85% H3PO4 in H2O. Compounds 3b,31 3d,53 3e,31 3f,54
7,36 13,54,55 and 16a43 and tetrabenzylpyrophosphate56 were prepared
as described.
N,N-Diacetyl-1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-r-D-glu-
copyranose (3a). To a stirred solution of R-(AcO)4GlcNAc (0.5 g, 1.28
(51) Ryu, E. K.; MacCoss, M. J. Lipid Res. 1979, 20, 561-563.
(52) Ditmer, J. C.; Lester, R. L. J. Lipid Res. 1964, 5, 126-127.
(53) Debenham, J. S.; Debenham, S. D.; Fraser-Reid, B. Bioorg. Med. Chem.
1996, 4, 1909-1918.
2,2,2-Trichloroethyl 5-Fluoro-3,4,6-tri-O-acetyl-2-deoxy-2-tetra-
chlorophthalimido-r-L-idopyranose (5c). To a stirred solution of 4c
(54) Medgyes, A.; Farkas, E.; Liptak, A.; Pozsgay, V. Tetrahedron 1997, 53,
4159-4178.
(55) Bergmann, M.; Zervas, L. Chem. Ber. 1931, 64, 973-980.
(56) Khorana, H. G.; Todd, A. R. J. Am. Chem. Soc. 1953, 75, 2257-2260.
(57) Chaplin, D.; Crout, D. H. G.; Bornemann, S.; Hutchinson, D. W.; Khan,
R. J. Chem. Soc., Perkin Trans. 1 1992, 2, 235-237.
9
10044 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
in dry CH3CN (1.0 mL) under an Ar atmosphere was added AgF (18
mg, 0.142 mmol). The flask was immediately covered with foil and
stirred. After 5 h, the suspension was filtered through SiO2/Celite,
washing with EtOAc (30 mL). The filtrate was evaporated and then
purified on a plug of SiO2, eluting with CHCl3/EtOAc (20:1), giving
the title compound as an oil (28 mg, 55%). 1H NMR (300 MHz,
CDCl3): δ 5.91 (dd, 1H, J ) 5.1, 8.0 Hz), 5.72 (dd, 1H, J ) 3.5, 10.0
Hz), 5.37 (dd, 1H, J ) 3.5, 4.8 Hz), 4.88 (ddd, 1H, J ) 2.0, 8.0, 10.0
Hz), 4.48-4.24 (m, 3H), 4.16 (d, 1H, J ) 12.0 Hz), 2.20 (s, 3H), 2.15
(s, 3H), 1.93 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.18, 169.88,
168.74, 162.84, 140.76, 129.99, 126.86, 110.76 (d, J ) 226 Hz), 96.74,
95.75, 79.80, 70.14 (d, J ) 44 Hz), 68.56, 62.24 (d, J ) 29 Hz), 54.39
(d, J ) 162 Hz), 20.66, 20.61, 20.58. 19F NMR (282 MHz, CDCl3): δ
-30.06 (m). FAB-MS m/z (rel intensity): 743.9 ([M + Na]+, 100.00).
FAB-HRMS calcd for C22H17NO10FNaCl7, 741.8554; obsd, 741.8545.
(5 mL) and saturated NaCl (5 mL). The organic extract was dried over
MgSO4, filtered, and evaporated, leaving a yellow oil (15 mg) which
was purified by preparative TLC (CHCl3/EtOAc 10:1). The Rf 0.41
band was removed, and the product was extracted with 4% MeOH in
CH2Cl2 and evaporated, leaving the product as a white solid (5 mg,
1
25%). H NMR (300 MHz, CDCl3): δ 6.74 (dd, 1H, J ) 9.7, 11.6
Hz), 6.31 (d, 1H, J ) 3.7 Hz), 5.31 (dd, 1H, J ) 9.7, 22.4 Hz), 4.83
(dd, 1H, J ) 3.7, 11.6 Hz), 4.36 (dd, 1H, J ) 5.5, 12.0 Hz), 4.03 (dd,
1H, J ) 3.6, 12.0 Hz), 2.15 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 1.93 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 169.77, 169.74, 169.56, 168.75,
162.51, 140.95, 130.28, 126.57, 110.54 (d, J ) 235 Hz), 89.71, 69.17
(d, J ) 23 Hz), 63.52, 61.87 (d, J ) 40 Hz), 52.47, 21.01, 20.60, 20.47,
20.47. 19F NMR (282 MHz, CDCl3, 1H decoupled): δ -47.86. CI-MS
(NH3) m/z (rel intensity): 651.6 (M + NH4+, 100.00), 614.5 (38.59),
554.5 (31.53). CI-HRMS (NH3) calcd for C22H22N2O11FCl4 [M +
NH4]+, 648.9961; obsd, 648.9977.
5-Bromo-1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-
r-D-glucopyranose (4d). To a stirred solution of 3d (0.359 g, 0.58
mmol) in dry CCl4 (35 mL) was added N-bromosuccinimide (0.457 g,
2.57 mmol). The mixture was illuminated with a 150 W flood lamp
placed ca. 0.25 in. from the flask, and the reaction gradually turned
bright orange. After 7 h, the orange suspension was cooled, the white
solid was filtered off, and the filtrate was washed with water (50 mL),
saturated NaHCO3 (50 mL) (a disappearance of the orange color was
observed), and saturated NaCl (50 mL). The organic layer was dried
over MgSO4, filtered, and evaporated in vacuo, leaving an off-white
foam (423 mg) which was purified by flash chromatography (hexanes/
EtOAc 2:1), giving the title compound as a white powder (209 mg,
5-Bromo-1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-
â-D-glucopyranose (4e). Compound 3e (1.0 g, 1.63 mmol) and
N-bromosuccinimide (1.27 g, 7.15 mmol) were suspended in dry CCl4
(100 mL) in a flask flushed with Ar and fitted with a condenser and
drying tube (CaCl2). The mixture was illuminated with a 150 W flood
lamp placed at a distance of 0.5 in. from the flask. Over the first 0.5
h, the reaction mixture became deep orange. After 9 h, the reaction
was cooled on ice and filtered. The filtrate was washed with sat.
NaHCO3 (120 mL) and sat. NaCl (120 mL), dried over MgSO4, filtered,
and evaporated in vacuo, leaving a white foam/oil (2.23 g). The oil
was purified by flash chromatography, eluting with CHCl3/EtOAc
(400:1-12.5:1), giving the title compound as a foam (395 mg, 35%).
1H NMR (300 MHz, CDCl3): δ 6.98 (d, 1H, J ) 9.1 Hz), 6.06 (dd,
1H, J ) 9.3, 10.4 Hz), 5.35 (d, 1H, J ) 9.3 Hz), 4.65 (d, 1H, J ) 12.3
Hz), 4.57 (dd, 1H, J ) 9.2, 10.3 Hz), 4.35 (d, 1H, J ) 12.3 Hz), 2.16
(s, 3H), 2.13 (s, 3H), 2.05 (s, 3H), 1.91 (s, 3H). 13C NMR (75 MHz,
CHCl3): δ 170.13, 169.75, 169.01, 168.04, 162.54, 140.86, 130.23,
126.75, 94.75, 89.51 (1), 69.32 (1), 68.59 (1), 65.70 (2), 53.34 (1),
20.65 (3), 20.61 (3), 20.49 (3), 20.31 (3).
1
52%). mp 175 °C dec. H NMR (500 MHz, CDCl3): δ 6.81 (dd, 1H,
J ) 9.6, 11.4 Hz), 6.39 (d, 1H, J ) 4.1 Hz), 5.21 (d, 1H, J ) 9.6, Hz),
4.85 (dd, 1H, J ) 4.1, 11.7 Hz), 4.52 (d, 1H, J ) 12.2 Hz), 4.33 (d,
1H, J ) 12.2 Hz), 2.16-1.91 (m, 12H). 13C NMR (126 MHz, CDCl3):
δ 169.75, 169.39, 169.02, 168.46, 161.96, 140.95, 130.28, 126.58,
93.46, 90.34 (1), 70.18 (1), 66.47 (2), 64.91 (1), 52.36 (1), 21.20 (3),
20.61 (3), 20.53 (3), 20.53 (3). FAB-MS m/z (rel intensity): [M +
Na]+ 715.8. FAB-HRMS calcd for C22H18NO11NaCl4Br [M + Na]+,
713.8715; obsd, 713.8720.
5-Fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-
â-L-idopyranose (5e). Compound 4e (396 mg, 0.57 mmol) was
dissolved in dry CH3CN (10 mL) under an Ar atmosphere (the solution
remained slightly cloudy). AgF (146 mg, 1.15 mmol) was added, and
the flask was immediately covered with foil. After 43 h, the reaction
was filtered twice through a Celite/SiO2 plug, eluting with 30:1 CHCl3/
EtOAc. The filtrate was extracted with sat. NaHCO3, H2O, and sat.
NaCl. The organic extracts were dried over MgSO4, filtered, and
evaporated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 3:1), giving the title compound as a
light yellow film (155 mg, 43%). 1H NMR (300 MHz, CDCl3): δ 6.73
(dd, 1H, J ) 8.2, 4.4 Hz), 5.69 (ddd, 1H, J ) 3.5, 6.1, 9.6 Hz), 5.35
(dd, 1H, J ) 3.5, 5.1 Hz), 4.51 (ddd, 1H, J ) 2.3, 8.2, 9.6 Hz), 4.47-
5-Fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-
â-L-idopyranose (5d). To a stirred solution of 4d (50 mg, 0.72 mmol)
in freshly distilled CH3CN under a N2 atmosphere was added AgF (21
mg, 0.146 mmol). The flask was immediately covered with foil, and
the reaction was stirred for 39 h. The black/brown suspension was
filtered through SiO2/Celite, washing with EtOAc (10 mL). The yellow
filtrate was washed with saturated NaHCO3 (6 mL), water (6 mL), and
saturated NaCl (6 mL). After drying over MgSO4, filtering, and
evaporating, the resulting oil (39 mg) was purified by preparative TLC
(CHCl3/EtOAc 10:1), giving a white solid (25 mg, 56%). mp 157-
1
159.5 °C. H NMR (300 MHz, CDCl3): δ 6.33 (dd, 1H, J ) 0.7, 3.4
Hz), 6.27 (ddd, 1H, J ) 1.1, 2.7, 9.8 Hz), 5.39 (dd, 1H, J ) 2.7, 6.2
Hz), 5.10 (dd, 1H, J ) 3.4, 9.7 Hz), 4.49 (dd, 1H, J ) 12.3, 22.1 Hz),
4.22 (dd, 1H, J ) 12.5, 12.5 Hz), 2.19-2.03 (m, 12H). 13C NMR (75
MHz, CHCl3): δ 169.84, 169.60, 169.22, 168.59, 162.73, 140.81,
130.16, 126.66, 110.22 (d, J ) 223 Hz), 88.28, 69.97 (d, J ) 44 Hz),
66.11, 62.44 (d, J ) 27 Hz), 60.36, 21.02, 20.95, 20.60, 20.56. 19F
NMR (282 MHz, CDCl3): δ -29.24 (ddd, J ) 20.3, 12.7, 6.2 Hz).
FAB-MS m/z (rel intensity): 656.0 ([M + Na]+, 6.5), 329.1 (28.6),
289.1 (17.0), 176.0 (100.0). FAB-HRMS calcd for C22H18NO11FNaCl4
[M + Na]+, 656.9516; obsd, 656.9519.
4.25 (m, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H). 13
C
NMR (75 MHz, CDCl3): δ 170.14, 169.70, 169.02, 168.93, 162.69,
140.85, 130.20, 126.77, 111.09 (d, J ) 228 Hz), 88.29 (1), 70.17 (d,
J ) 45 Hz) (1), 68.59 (1), 62.17 (d, J ) 28 Hz) (2), 52.44 (d, J ) 3.0
Hz) (1), 20.86 (3), 20.63 (3), 20.53 (3), 20.49 (3). 19F NMR (282 MHz,
CDCl3): δ -30.94 (m). FAB-MS m/z (rel intensity): 656.0 ([M +
Na]+, 37.8), 513.9 (100.0), 411.9 (54.7), 107.0 (100.0). FAB-HRMS
calcd for C22H18NO11FNaCl4 [M + Na]+, 653.9516; obsd, 653.9540.
5-Bromo-1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-â-D-glu-
copyranose (4f). Compound 3f (300 mg, 0.628 mmol) and N-
bromosuccinimide (492 mg, 2.76 mmol) were suspended in dry CCl4
(30 mL). The mixture was illuminated with a 150 W flood lamp placed
at a distance of 0.5 in. from the flask with a piece of filter paper
positioned to reflect some of the incident light. The mixture gradually
turned bright orange. After 3.5 h, the reaction was cooled on ice, and
the insoluble succinimide was filtered and washed with cold CCl4. The
filtrate (∼40 mL) was washed with sat. NaHCO3 (40 mL), H2O (40
5-Fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-
r-D-glucopyranose (6d). To a 0 °C solution of 5d (25 mg, 0.039 mmol)
in CH2Cl2 (0.5 mL) in an NMR tube were added 3 Å molecular sieves
and BF3‚OEt2 (3.0 µL, 0.023 mmol). The reaction was monitored by
19F NMR over 4 h. Gradual disappearance of the starting material peak
at -30.13 ppm and appearance of a peak at -48.76 ppm were observed.
A number of other smaller peaks at -70 to -80 ppm were also observed
(along with BF3‚OEt2). After 4 h, the reaction was worked up by diluting
with EtOAc, filtering, and washing the filtrate with saturated NaHCO3
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10045

A R T I C L E S
Hartman and Coward
mL), and sat. NaCl (40 mL). The organic extracts were dried over
MgSO4, filtered, and evaporated in vacuo, leaving a white oil (480
mg) which was purified by flash chromatography (hexanes/EtOAc 4:1-
1:1), giving the title compound as a white solid (229 mg, 66%). mp
heated to reflux temperature. As the reaction progressed, the solution
turned deep orange; the disappearance of color signified termination
of the reaction. After 75 min, the colorless suspension was cooled and
filtered. The solid was washed with CHCl3 (85 mL), and the filtrate
was evaporated, leaving a white powder (1.89 g) which was dissolved
in CHCl3 (60 mL) and washed with H2O (3 × 100 mL) and sat.
NaCHO3 (60 mL). The organic layer was dried over MgSO4, filtered,
and evaporated, leaving the 6-bromo, 4-O-benzoyl compound as a white
powder sufficiently pure for further transformations (1.25 g, 96% crude
recovery). 1H NMR (300 MHz, CDCl3): δ 8.06-8.03 (m, 2H), 7.86-
7.83 (m, 2H), 7.73-7.70 (m, 2H), 7.62-7.58 (m, 1H), 7.48-7.43 (m,
2H), 5.32 (d, 1H, J ) 8.4 Hz), 5.15 (dd, 1H, J ) 9.1, 9.7 Hz), 4.62
(dd, 1H, J ) 9.1, 10.8 Hz), 4.31 (dd, 1H, J ) 8.4, 10.8 Hz), 3.99 (ddd,
1H, J ) 2.6, 7.4, 9.7 Hz), 3.88 (ddd, 1H, J ) 6.3, 6.3, 9.8 Hz), 3.60
(dd, 1H, J ) 2.6, 11.2 Hz), 3.55-3.45 (m, 2H), 1.49-1.38 (m, 2H),
1.25-1.00 (m, 10H), 0.84-0.80 (m, 3H). 13C NMR (75 MHz,
CDCl3): δ 168.26, 166.41, 134.14, 133.77, 131.59, 129.93, 128.84,
128.58, 123.46, 98.24, 75.39, 73.47, 70.29, 70.07, 57.16, 31.63, 31.40,
29.22, 29.10, 29.10, 25.77, 22.57, 14.03. In addition, 1H and 13C NMR
spectra indicated the presence of succinimide as a contaminant.
1
158 °C dec. H NMR (300 MHz, CDCl3): δ 7.82 (m, 2H), 7.72 (m,
2H), 6.94 (d, 1H, J ) 9.2 Hz), 6.09 (dd, 1H, J ) 9.4, 10.5 Hz), 5.27
(d, 1H, J ) 9.4 Hz), 4.58 (d, 1H, J ) 12.3 Hz), 4.51 (dd, 1H, J ) 9.3,
10.5 Hz), 4.27 (d, 1H, J ) 12.3 Hz), 2.07 (s, 3H), 2.01 (s, 3H), 1.96
(s, 3H), 1.80 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.74, 169.61,
169.13, 168.03, 167.14, 134.57 (1), 131.14, 123.85 (1), 95.16, 89.74
(1), 69.09 (1), 68.96 (1), 65.79 (2), 52.62 (1), 20.63 (3), 20.63 (3),
20.55 (3), 20.28 (3). FAB-MS m/z (rel intensity): 580.1 ([M + H]+,
6.5), 289.1 (42.4), 106.1 (98.5), 89.0 (96.6), 77.0 (100.0). FAB-HRMS
calcd for C22H22NO11NaBr [M + Na]+, 578.0274; obsd, 578.0261.
5-Fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-r-L-idopy-
ranose (5f). Compound 4f (1.56 g, 2.8 mmol) was dissolved in freshly
distilled CH3CN (20 mL) under a N2 atmosphere. AgF (0.685 g, 5.5
mmol) was added, and the flask was immediately covered with foil.
After 2.5 h, the reaction mixture was filtered through SiO2/Celite and
washed with EtOAc (∼80 mL). The filtrate was washed with sat.
NaHCO3 (100 mL), H2O (100 mL), and sat. NaCl (100 mL). The
organic extracts were dried over MgSO4, filtered, and evaporated in
vacuo, leaving a brown oil (1.33 g) which was purified by flash
chromatography (hexanes/EtOAc 4:1-3:2), giving the title compound
as a white solid (720 mg, 52%). mp 129 °C dec. 1H NMR (300 MHz,
CDCl3): δ 7.80 (m, 2H), 7.71 (m, 2H), 6.72 (dd, 1H, J ) 4.1, 8.3 Hz),
5.72 (dd, 1H, J ) 3.9, 9.9 Hz), 5.27 (dd, 1H, J ) 3.9, 6.1 Hz), 4.51
(ddd, 1H, J ) 2.3, 8.3, 9.9 Hz), 4.38-4.20 (m, 2H), 2.10 (s, 3H), 2.05
(s, 3H), 1.97 (s, 3H), 1.89 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
169.67, 168.98, 168.87, 167.22, 134.49, 131.11, 123.74, 111.20 (d, J
) 229 Hz), 88.57, 70.70 (d, J ) 44.4 Hz), 68.53, 62.29 (d, J ) 27.8
Hz), 51.29, 20.75, 20.54, 20.45, 20.36. On the basis of peak intensity,
two of the acetate carbonyl carbons were indistinguishable. 19F NMR
(282 MHz, CDCl3): δ -30.80 (m). FAB-MS m/z (rel intensity): 518.1
([M + Na]+, 29.0), 376.1 (15.9), 289.1 (45.7), 107.0 (100.0), 89.0
(94.1), 77.0 (96.5). FAB-HRMS calcd for C22H22NO11FNa [M + Na]+,
518.1075; obsd, 518.1074.
To a stirred solution of crude product (1.25 g, 2.12 mmol) in freshly
distilled THF (5.4 mL) under an Ar atmosphere were added phenylse-
lenol (700 µL, 6.64 mmol) and triethylamine (1.87 mL, 13.3 mmol).
A voluminous white precipitate formed, and freshly distilled THF (20
mL) was added to permit stirring. The yellow suspension was heated
to reflux temperature. After 12 h, the brown suspension was diluted
with CH2Cl2 (200 mL) and washed with sat. NaHCO3 (200 mL). The
aqueous layer was back-extracted with CH2Cl2 (100 mL), and the
combined organic layers were washed with sat. NaCl (75 mL), dried
over MgSO4, filtered, and evaporated, leaving a yellow powder (2.13
g). The crude solid was purified by flash chromatography (hexanes/
EtOAc 2:1), giving the title compound as a white powder (610 mg)
together with mixed fractions which were further purified by flash
chromatography (hexanes/EtOAc 9:4), giving an additional 495 mg of
the title compound. Total yield: 1.11 g, 79% over two steps. mp 160-
1
164 °C. H NMR (500 MHz, CDCl3): δ 8.04-7.97 (m, 2H), 7.86-
7.84 (m, 2H), 7.75-7.70 (m, 2H), 7.61-7.57 (m, 1H) 7.53-7.42 (m,
4H), 7.22-7.19 (m, 3H), 5.26 (d, 1H, J ) 8.4 Hz), 5.12 (dd, 1H, J )
9.2, 9.7 Hz), 4.60-4.52 (m, 1H), 4.29 (dd, 1H, J ) 8.4, 10.8 Hz), 3.98
(ddd, 1H, J ) 3.4, 7.8, 9.7 Hz), 3.77 (ddd, 1H, J ) 6.2, 6.2, 9.7 Hz),
3.42 (ddd, 1H, J ) 6.6, 6.6, 9.6 Hz), 3.22-3.10 (m, 2H), 2.71 (d, 1H,
J ) 6.6 Hz), 1.43-1.42 (m, 2H), 1.19-1.01 (m, 10H), 0.82 (t, 3H, J
) 7.0 Hz).13C NMR (75 MHz, CDCl3): δ 168.23, 166.65, 134.09,
133.67, 132.50, 131.67, 130.48, 129.91, 129.05, 128.96, 128.52, 126.95,
123.43, 98.18, 76.92, 74.00, 70.47, 69.84, 57.31, 31.66, 29.48, 29.24,
29.14, 29.14, 25.81, 22.59, 14.06. EIMS m/z (rel intensity): 665.2 (M+,
3.3), 228.0 (15.1), 189.0 (10.9), 105.0 (100.0). EI-HRMS calcd for
C35H39NO7Se [M]+, 665.1891; obsd, 665.1897.
5-Fluoro-1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-â-D-glu-
copyranose (6f). Compound 5f (200 mg, 0.40 mmol) was dissolved
in freshly distilled CH2Cl2 (4 mL). Molecular sieves (4 Å) were added,
and the solution was cooled to 0 °C. BF3‚OEt2 (4 µL, 0.036 mmol)
was added, and the flask was removed from the ice bath. The reaction
was followed by 19F NMR. After all of the starting material had been
consumed (60 min), the solution was diluted with CH2Cl2 and washed
with sat. NaHCO3 (10 mL), H2O (10 mL), and sat. NaCl (10 mL). The
organic extracts were dried over MgSO4, filtered, and evaporated in
vacuo, leaving an oil (230 mg) which was dissolved in CHCl3 and
purified by flash chromatography (hexanes/EtOAc 1:1), giving the title
compound as an off-white foam (149 mg, 75%). 1H NMR (300 MHz,
CDCl3): δ 7.89 (m, 2H), 7.79 (m, 2H), 6.94 (d, 1H, J ) 9.1 Hz), 6.12
(dd, 1H, J ) 9.7, 10.7 Hz), 5.40 (dd, 1H, J ) 9.7, 23.0 Hz), 4.51 (dd,
1H, J ) 9.1, 10.7 Hz), 4.45 (dd, 1H, J ) 4.4, 12.0 Hz), 4.16 (dd, 1H,
J ) 4.0, 12.0 Hz), 2.18 (s, 3H), 2.14 (s, 3H), 1.97 (s, 3H), 1.87 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 169.64, 169.50, 169.32, 168.02,
167.03, 134.51, 130.97, 123.75, 109.49 (d, J ) 230 Hz), 86.66 (d, J )
4.9 Hz), 68.37, 67.14, 61.54 (d, J ) 37.7 Hz), 52.73, 20.52, 20.44,
20.32, 20.16. 19F NMR (282 MHz, CDCl3): δ -55.96 (ddd, J ) 4.5,
4.5, 22.6 Hz). FAB-MS m/z (rel intensity): 518.1 (M + Na+, 100.00),
476.3 (54.43), 436.3 (35.83), 376.2 (88.85), 274.2 (31.93), 272.2
(25.18), 254.2 (29.79), 226.2 (73.66), 214.2 (20.80). FAB-HRMS calcd
for C22H22N2O11FNa [M + Na]+, 518.1075; obsd, 518.1098.
Octyl 3,4-Di-O-acetyl-2,6-dideoxy-2-acetamido-6-phenylseleno-
â-D-glucopyranoside (9). To a suspension of 8 (50 mg, 0.078 mmol)
in EtOH (1.8 mL) in a sealed tube was added hydrazine hydrate (200
µL, 4.1 mmol). The tube was placed under vacuum and sealed, and
the suspension was heated to 80 °C. Upon heating, the suspension
became clear, and as the reaction progressed, a white solid precipitated.
After 15.5 h, the reaction mixture was cooled and evaporated under
high vacuum, leaving a white solid (57 mg). Pyridine (0.50 mL) and
acetic anhydride (0.50 mL, 5.2 mmol) were added. After 26 h, DMAP
(8 mg, 0.065 mmol) was added. After 44 h, the reaction was diluted
with CH2Cl2 (5 mL) and washed with cold HCl (1.0 M, 3 × 5 mL)
and sat. NaHCO3 (5 mL). The organic layer was dried over MgSO4,
filtered, and evaporated, leaving an oil (105 mg) which was purified
by preparative TLC (hexanes/EtOAc 1:2), giving the title compound
as a white solid (35 mg, 80% over two steps). For larger scale reactions,
the product could be purified by crystallization from EtOH/H2O. In
Octyl 4-O-Benzoyl-2,6-dideoxy-6-phenylseleno-2-phthalimido-â-
D-glucopyranoside (8). N-Bromosuccinimide (433 mg, 2.43 mmol),
barium carbonate (1.31 g, 6.63 mmol), and compound 7 (1.13 g, 2.21
mmol) were suspended in CCl4 (56 mL) under an Ar atmosphere. The
flask was fitted with a drying tube (CaCl2), and the suspension was
1
each case, similar yields were obtained. mp 116-121 °C. H NMR
(300 MHz, CDCl3): δ 7.51-7.48 (m, 2H), 7.27-7.24 (m, 3H), 5.53
9
10046 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
(d, J ) 8.8 Hz), 5.26 (dd, 1H, J ) 9.2, 10.6 Hz), 4.96 (dd, 1H, J ) 9.2,
10.5 Hz), 4.62 (d, 1H, J ) 8.3 Hz), 3.84 (ddd, 1H, J ) 8.3, 8.8, 10.5
Hz), 3.78-3.69 (m, 2H), 3.42 (ddd, 1H, J ) 6.9, 6.9, 9.6 Hz), 3.06-
3.03 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.54-1.52 (m,
2H), 1.26 (m, 10H), 0.88 (m, 3H). 13C NMR (75 MHz, CDCl3): δ
170.92, 170.09, 169.63, 132.44 (1), 130.42, 129.04 (1), 126.98 (1),
100.51 (1), 73.68 (1), 72.60 (1), 72.30 (1), 69.77 (2), 54.93 (1), 31.78
(2), 29.37 (2), 29.27 (2), 29.25 (2), 29.17 (2), 25.84 (2), 23.30 (3),
22.62 (2), 20.73 (3), 20.71 (3), 14.08 (3). FAB-MS m/z (rel intensity):
580.2 ([M + Na]+, 72.8), 558.2 (53.2) 428.1 (100.00). FAB-HRMS
calcd for C26H39NO7NaSe [M + Na]+, 580.1789; obsd, 580.1785.
Octyl 3,4-Di-O-acetyl-2,6-dideoxy-5,6-didehydro-2-acetamido-â-
D-glucopyranoside (10). To a stirred suspension of 9 (195 mg, 0.350
mmol) in MeOH/H2O (6:1, 10 mL) at room temperature were added
NaHCO3 (32 mg, 0.385 mmol) and NaIO4 (97 mg, 0.455 mmol). As
the reaction progressed, a white precipitate formed. After 30 min, the
MeOH was evaporated and the resulting aqueous suspension was
partitioned between H2O (75 mL) and CH2Cl2 (75 mL). The aqueous
layer was re-extracted with CH2Cl2 (2 × 30 mL). The organic layers
were combined, dried over Na2SO4, filtered, and evaporated, leaving
the diastereomeric selenoxides (3:1 ratio) as a white powder (193 mg,
96%) which was used directly in the following step without purification.
1H NMR (300 MHz, CDCl3): δ 7.76-7.71 (m, 2H), 7.58-7.53 (m),
5.37-5.34 (m), 5.06-4.98 (m), 4.83 (d, J ) 8.5 Hz), 4.60 (d, J ) 8.4
Hz), 4.26-4.12 (m), 3.98-3.90 (m), 3.66-3.55 (m), 3.30 (ddd), 3.16-
3.02 (m), 2.06 (s), 2.04 (s), 2.03 (s), 2.02 (s), 1.98 (s), 1.82 (s), 1.63-
1.61 (m), 1.25 (m), 0.88-0.83 (m).
A stirred cloudy suspension of the diastereomeric selenoxides (193
mg, 0.337 mmol) in dry dihydropyran (6.5 mL) was heated to reflux
temperature. After 40 min, the yellow solution was cooled and diluted
with CH2Cl2 (65 mL). This solution was washed with H2O (150 mL),
sat. NaHCO3 (65 mL), and sat. NaCl (65 mL). The organic extracts
were dried over Na2SO4, filtered, and evaporated. The resulting yellow
residue (500 mg) was purified by flash chromatography (hexanes/EtOAc
2:3), giving the title compound as a white solid (126 mg, 90% over
two steps). mp 133-136 °C. 1H NMR (300 MHz, CDCl3): δ 5.91 (d,
1H, J ) 8.8 Hz), 5.63 (d, 1H, J ) 7.4 Hz), 4.96 (dd, 1H, J ) 6.0, 7.4
Hz), 4.76-4.75 (m, 2H), 4.55 (dd, 1H, J ) 1.3, 1.3 Hz), 4.22 (ddd,
1H, J ) 4.0, 6.0, 8.8 Hz), 3.81 (ddd, 1H, J ) 6.6, 6.6, 9.4 Hz), 3.42
(ddd, 1H, J ) 6.4, 6.4, 9.4 Hz), 2.13 (s, 3H), 2.07 (s, 3H), 1.99 (s,
3H), 1.60-1.56 (m, 2H), 1.36-1.26 (m, 10H), 0.88 (t, 3H, J ) 6.5
Hz). 13C NMR (75 MHz, CDCl3): δ 170.30, 169.69, 168.97, 150.70,
101.12 (1), 96.52 (2), 71.37 (1), 69.03 (2), 68.61 (1), 52.50 (1), 31.70
(2), 29.26 (2), 29.18 (2), 29.13 (2), 25.84 (2), 23.09 (3), 22.53 (2),
20.73 (3), 20.68 (3), 13.99 (3). CI-MS (NH3) m/z (rel intensity): 400.3
([M + H]+, 100.00), 340.3 (22.94), 270.2 (11.42), 139.1 (11.79). CI-
HRMS (NH3) calcd for C20H34NO7 [M + H]+, 400.2335; obsd,
400.2329.
To a stirred -78 °C solution of the epoxide 11 (212 mg, 0.510 mmol)
(previously dried under vacuum for 45 min) in CH2Cl2 (7 mL) under
an atmosphere of Ar was added dropwise HF‚pyridine (150 µL). After
0.5 h, the solution was diluted with CH2Cl2 (30 mL) and washed with
H2O (30 mL) and sat. NaHCO3 (30 mL). The organic layer was dried
over Na2SO4, filtered, and evaporated, leaving a white powder (223
mg). The white powder was dissolved in pyridine (1.5 mL), and acetic
anhydride (1.5 mL, 15.8 mmol) was added. After 2 h, the reaction was
diluted with CH2Cl2 (30 mL) and washed with sat. NaHCO3 (3 × 30
mL) and sat. NaCl (30 mL). The organic layer was dried over Na2SO4,
filtered through a plug of SiO2, and evaporated, leaving a white powder
(230 mg). The white powder was purified by flash chromatography
(hexanes/EtOAc 1:2), giving the title compound as a white powder
(174 mg, 72%) along with 25 mg (10%) of the C-5 epimer.
1
(a) D-Gluco Isomer, 12a (Major Product). mp 136-138 °C. H
NMR (500 MHz, CDCl3): δ 5.61 (d, J ) 9.4 Hz), 5.38 (dd, 1H, J )
9.7, 22.7 Hz), 5.32 (ddd, 1H, J ) 9.6, 9.7 Hz), 4.94 (d, 1H, J ) 7.9
Hz), 4.33 (dd, 1H, J ) 6.9, 11.8 Hz), 4.27 (ddd, 1H, J ) 7.9, 9.4, 9.6
Hz), 4.02 (dd, 1H, J ) 4.9, 11.8 Hz), 3.86 (ddd, 1H, J ) 6.4, 6.4, 9.5
Hz), 3.49 (ddd, 1H, J ) 6.8, 6.8, 9.5 Hz), 2.10 (s, 3H), 2.08 (s, 3H),
2.04 (s, 3H), 1.96 (s, 3H), 1.58-1.57 (m, 2H), 1.30-1.26 (m, 10H),
0.88 (t, 3H, J ) 6.8 Hz). 13C NMR (75 MHz, CDCl3): δ 170.87, 169.90,
169.82, 169.25, 109.64 (d, J ) 228 Hz), 98.54 (d, J ) 4 Hz), 70.21,
69.62, 68.36 (d, J ) 25 Hz), 62.09 (d, J ) 39 Hz), 53.25, 31.77, 29.28,
29.24, 25.79, 23.21, 22.62, 20.62, 20.58, 20.46, 14.06. On the basis of
peak intensity, two carbons of the octyl side chain (∼29 ppm) were
indistinguishable. 19F NMR (282 MHz CDCl3): δ -52.46 (ddd, J )
5.1, 5.1, 21.7 Hz). FAB-MS m/z (rel intensity): 500.0 ([M + Na]+,
100.0), 478.1 (26.2), 458.1 (56.6), 180.0 (64.9), 175.9 (74.9). FAB-
HRMS calcd for C22H36NO9FNa [M + Na]+, 500.2272; obsd, 500.2274.
1
(b) L-Ido Isomer, 12b (Minor Product). mp 94-96 °C. H NMR
(300 MHz, CDCl3): δ 6.09 (d, J ) 8.4 Hz), 5.80 (dd, 1H, J ) 8.4,
12.7 Hz), 5.07 (dd, 1H, J ) 5.5, 8.4 Hz), 4.91 (dd, 1H, J ) 1.3, 2.3
Hz), 4.54 (dd, 1H, J ) 11.9, 12.1 Hz), 4.30 (m, 1H), 4.10 (dd, 1H, J
) 10.4, 11.8 Hz), 3.86 (ddd, 1H, J ) 6.8, 6.8, 9.2 Hz), 3.46 (ddd, 1H,
J ) 6.5, 6.5, 9.2 Hz), 2.16 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.00 (s,
3H), 1.60-1.58 (m, 2H), 1.27-1.25 (m, 10H), 0.88 (t, 3H, J ) 6.5
Hz). 13C NMR (75 MHz, CDCl3): δ 170.49, 170.08, 169.69, 168.59,
110.03 (d, J ) 226 Hz), 101.39 (1), 71.07 (d, J ) 7 Hz, 1), 70.12 (d,
J ) 37 Hz, 1), 69.23 (2), 63.46 (d, J ) 39 Hz, 2), 53.94 (1), 31.79 (2),
29.27 (2), 29.18 (2), 29.18 (2), 25.85 (2), 23.18 (3), 22.62 (2), 20.74
(3), 20.74 (3), 20.56 (3), 14.07 (3). 19F NMR (282 MHz CDCl3): δ
-26.35 (ddd, J ) 12.1, 12.1, 12.1 Hz). FAB-MS m/z (rel intensity):
500.0 ([M + Na]+, 88.4), 478.3 (100.00), 458.3 (39.9), 180.1 (37.6),
176.0 (74.3). FAB-HRMS calcd for C22H36NO9FNa [M + Na]+,
500.2272; obsd, 500.2281
Octyl 5-Fluoro-2-deoxy-2-acetamido-â-D-glucopyranoside (2).
NH3 was bubbled through a stirred methanolic (2.0 mL) solution of
12a (50 mg, 0.105 mmol) cooled to ca. -10 °C. After 10 min, the
flask was sealed and allowed to warm to ambient temperature. After
70 min, the solvent and NH3 were removed with a stream of nitrogen.
The resulting white solid (41 mg) was purified by flash chromatography
(EtOAc/MeOH 5:1), giving the title compound as a white powder (30
Octyl 5-Fluoro-3,4,6-tri-O-acetyl-2-deoxy-2-acetamido-â-D-glu-
copyranoside (12a). To a stirred 0 °C solution of 10 (202 mg, 0.506
mmol) in freshly distilled CH2Cl2 (3.5 mL) was added excess
dimethyldioxirane in acetone (7.0 mL). After 4.5 h, the solvent was
evaporated, leaving 11 as a white powder (212 mg, 95%). The product
1
contained only one of the two possible diastereomers. H NMR (300
1
mg, 83%). mp 95-96 °C. H NMR (500 MHz, CD3OD): δ 4.82 (m,
MHz, CDCl3): δ 5.73 (d, 1H, J ) 9.5 Hz), 5.63 (d, 1H, J ) 9.6 Hz),
5.28 (dd, 1H, J ) 9.6, 9.6 Hz), 4.77 (d, 1H, J ) 7.9 Hz), 4.33 (ddd,
1H, J ) 7.9, 9.5, 9.6 Hz), 3.77 (ddd, 1H, J ) 6.4, 6.4, 9.6 Hz), 3.42
(ddd, 1H, J ) 6.6, 6.6, 9.6 Hz), 3.06 (d, 1H, J ) 4.0 Hz), 2.73 (d, 1H,
J ) 4.0 Hz), 2.06 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 1.55-1.52 (m,
2H), 1.26 (m, 10H), 0.87 (t, 3H, J ) 6.3 Hz). 13C NMR (75 MHz,
CDCl3): δ 170.79, 169.83, 169.54, 99.87 (1), 79.41, 70.75 (1), 70.03
(2), 66.59 (1), 53.43 (1), 49.54 (2), 31.77 (2), 29.31 (2), 29.23 (2),
25.78 (2), 23.23 (3), 22.61 (2), 20.65 (3), 20.49 (3), 14.05 (3). On the
basis of peak intensity, two carbons of the octyl side chain (∼29 ppm)
were indistinguishable.
H-1), 3.86 (ddd, 1H, J ) 6.1, 6.1, 9.6 Hz), 3.79-3.76 (m, 3H), 3.65
(m, 1H), 3.63 (dd, 1H, J ) 4.6, 11.8 Hz), 3.46 (ddd, 1H, J ) 6.7, 6.7,
9.5 Hz), 1.98 (s, 3H) 1.55-1.54 (m, 2H), 1.36-1.29 (m, 10H), 0.90
(t, 3H, J ) 6.2 Hz). 13C NMR (75 MHz, CD3OD): δ 173.58, 113.57
(d, J ) 224 Hz), 99.94 (d, J ) 4 Hz) (1), 72.09 (d, J ) 26 Hz) (1),
71.60 (1), 70.92 (2), 63.11 (d, J ) 34 Hz) (2), 56.72 (1), 33.01 (2),
30.57 (2), 30.47 (2), 27.08 (2), 23.73 (2), 22.96 (3), 14.43 (3). On the
basis of peak intensity, two carbons (∼30 ppm) were indistinguishable.
19F NMR (282 MHz CD3OD): δ -61.64 (m). CI-MS (NH3) m/z (rel
intensity): 352.2 ([M + H]+, 3.18), 332.2 (64.40), 314.4 (26.06), 272.2
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10047

A R T I C L E S
Hartman and Coward
(18.89), 242.2 (68.23), 202.1 (100.00), 184.1 (30.47), 102.01 (46.05).
CI-HRMS (NH3) calcd for C16H31NO6F [M + H]+, 352.2135; obsd,
352.2127.
2.77 (d, 1H, J ) 3.6 Hz), 0.69 (s, 9H), 0.04 (m, 3H), -0.09 (m, 3H).
13C NMR (75 MHz, CDCl3): δ 168.16, 136.98, 134.07 (1), 131.53,
129.28 (1), 128.32 (1), 126.30 (1), 123.29 (1), 101.87 (1), 93.83 (1),
82.28 (1), 68.65 (2), 68.22 (1), 66.14 (1), 58.68 (1), 25.20 (3), 17.43,
-4.32 (3), -5.66 (3). FAB-MS m/z (rel intensity): 534.3 ([M + Na]+,
35.4), 454.2 (63.5), 380.1 (66.0), 274.1 (32.8), 256.0 (37.7), 246.0
(42.8), 136.0 (100.00), 105.0 (90.9). FAB-HRMS calcd for C27H33-
NO7NaSi [M + Na]+, 534.1924; obsd, 534.1946.
3,4,6-Tri-O-acetyl-2-deoxy-2-phthalimido-â-D-glucopyranoside (14).
Under an atmosphere of Ar, ethylenediamine (840 µL, 12.6 mmol) and
acetic acid (840 µL, 14.7 mmol) were added to THF (250 mL). To
this suspension was added 13 (5.00 g, 10.4 mmol). After 6 h, the
suspension was diluted with water (100 mL) and was extracted with
CH2Cl2 (1.0 L). The organic layer was washed with 0.1 M HCl (1.0
L), sat. NaHCO3 (1.0 L), and sat. NaCl (1.0 L). The organic layer was
dried over MgSO4, filtered, and evaporated, leaving a white solid which
was purified through a short column of SiO2 eluting with (hexanes/
EtOAc 1:1), giving the product as a white powder (4.41 g, 97%), R/â
10:1. 1H NMR (300 MHz, CDCl3): δ 7.88-7.86 (m, 2H), 7.76-7.73
(m, 2H), 5.87 (dd, 1H, J ) 9.1, 10.8 Hz), 5.64 (dd, 1H, J ) 7.3, 8.3
Hz), 5.18 (dd, 1H, J ) 9.1, 10.1 Hz), 4.36-4.18 (m, 3H), 3.94 (ddd,
1H, J ) 2.2, 4.7, 10.1 Hz), 3.16 (d, 1H, J ) 7.3 Hz), 2.13 (s, 3H),
p-Methoxyphenyl 4-O-Benzoyl-2,6-dideoxy-6-bromo-2-phthal-
imido-â-D-glucopyranose (17a). Compound 16a (4.09 g, 8.12 mmol),
NBS (1.59 g, 8.94 mmol), and BaCO3 (4.81 g, 24.36 mmol) were
suspended in dry CCl4 (200 mL) in a flask fitted with a reflux condenser
and drying tube (CaCl2). The colorless suspension was heated to reflux
temperature and turned orange after ∼2 min. After 50 min, additional
NBS (60 mg, 0.34 mmol) was added. After 60 min total reaction time,
the reaction mixture was cooled on ice and filtered. The solid was
washed with CHCl3, and the filtrate was evaporated, leaving a solid
(25 g). The solid was dissolved in CHCl3 (400 mL), and the resulting
solution was washed with H2O (3 × 400 mL) and sat. NaCl (400 mL).
The organic layer was evaporated in vacuo, giving a white solid (7.69
g) which was purified by flash chromatography (EtOAc/toluene 1:4.5),
giving the title compound as a white powder (4.43 g, 94%). mp 237-
1
2.05 (s, 3H), 1.88 (s, 3H). The literature provides H NMR spectral
data for this compound but only for the carbohydrate protons.58
tert-Butyldimethylsilyl 3,4,6-Tri-O-acetyl-2-deoxy-2-phthalimido-
â-D-glucopyranoside (15). To a stirred 0 °C solution of 14 (846 mg,
1.94 mmol) in dry dimethylformamide (DMF) (4 mL) was added
imidazole (264 mg, 3.89 mmol). After stirring for 10 min, TBDMSCl
(381 mg, 2.53 mmol) was added. The solution was gradually warmed
to room temperature (RT) over 2 h. After 45 h, sat. NaHCO3 (0.5 mL)
was added to the light yellow solution. Following stirring for 10 min,
most of the solvent was removed in vacuo. The resulting oily solid
was equilibrated between CHCl3 (20 mL) and sat. NaHCO3 (200 mL).
The organic layer was drained and the aqueous layer was extracted
with CHCl3 (2 × 100 mL). The combined organic layers were washed
with sat. NaCl (200 mL), dried over MgSO4, filtered, and evaporated,
leaving an oil (1.1 g) which was purified by flash chromatography
(hexanes/EtOAc 1:1), giving the title compound as a white powder,
881 mg (82%). mp 139-140 °C. 1H NMR (300 MHz, CDCl3): δ 7.88-
7.84 (m, 2H), 7.76-7.73 (m, 2H), 5.85 (dd, 1H, J ) 9.0, 10.8 Hz),
5.56 (d, 1H, J ) 8.0 Hz), 5.13 (dd, 1H, J ) 9.0, 10.1 Hz), 4.30-4.24
(m, 2H), 4.16 (dd, 1H, J ) 2.4, 12.0 Hz), 3.89 (ddd, 1H, J ) 2.4, 4.8,
10.1 Hz), 2.10 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H), 0.69 (s, 9H), 0.06 (s,
3H), -0.05 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.66, 170.17,
169.57, 167.91 (broad), 134.26 (1), 131.34, 123.46 (1), 93.16 (1), 71.80
(1), 70.26 (1), 69.47 (1), 62.42 (2), 56.68 (1), 25.25 (3), 20.73 (3),
20.65 (3), 20.51 (3), 17.51, -4.38 (3), -5.58 (3).
1
240 °C. H NMR (300 MHz, CDCl3): δ 8.07-8.03 (m, 2H), 7.87-
7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.64-7.59 (m, 1H), 7.49-7.44 (m,
2H), 7.28-7.13 (m, 2H), 6.98-6.90 (m, 2H), 6.79-6.71 (m, 2H), 5.80
(d, J ) 8.3 Hz, H-1), 5.21 (dd, 1H, J ) 8.9, 10.0 Hz), 4.71 (ddd, 1H,
J ) 6.9, 8.9, 10.7 Hz), 4.57 (dd, 1H, J ) 8.3, 10.7 Hz), 4.10 (ddd, 1H,
J ) 2.5, 7.6, 10.0 Hz), 3.73 (s, 3H), 3.62 (dd, 1H, J ) 2.5, 11.2 Hz),
4.18 (dd, 1H, J ) 7.6, 11.2 Hz), 2.81 (d, 1H, J ) 6.9 Hz). 13C NMR
(75 MHz, CDCl3): δ 168.17, 166.43, 155.60, 150.67, 134.29 (1), 133.90
(1), 131.53, 129.96 (1), 128.70, 128.64 (1), 123.63 (1), 118.73 (1),
114.43 (1), 97.57 (1), 75.20 (1), 73.92 (1), 70.25 (1), 56.98 (1), 55.58
(3), 31.08 (2). FAB-MS m/z (rel intensity): 606.1 ([M + Na]+, 6.8),
329.2 (100.00). FAB-HRMS m/z calcd for C28H24NO8NaBr [M + Na]+,
604.0582; obsd, 604.0610.
p-Methoxyphenyl 4-O-Benzoyl-3-O-[(benzyloxy)methyl]-2,6-di-
deoxy-6-bromo-2-phthalimido-â-D-glucopyranoside (18a). To a stirred
solution of 17a (4.43 g, 7.61 mmol) in THF (45 mL) under Ar in a
flask fitted with a reflux condenser and drying tube were added benzyl
chloromethyl ether (4.5 mL, 32.7 mmol) and diisopropylethylamine
(6.2 mL, 36 mmol). The resulting light yellow solution was heated to
reflux temperature. After 27 h, the reaction was cooled and diluted
with CH2Cl2 (400 mL). This solution was washed with sat. NaHCO3
(400 mL). The aqueous layer was back-extracted with CH2Cl2 (400
mL). The organic layers were each washed with sat. NaCl (400 mL)
and were dried over MgSO4, filtered, and evaporated, leaving a brown
oil. The oil was purified by flash chromatography (CHCl3/EtOAc 40:
1), giving the product contaminated with BnOH (4.37 g). To remove
the BnOH, the mixture was repeatedly crystallized from hexanes, giving
white needles (3.03 g). The mother liquor of the final crystallization
was concentrated in vacuo and the resulting residue triturated with cold
95% EtOH, giving additional product as a white powder (184 mg).
Total yield: 3.21 g, 61%. A small sample was recrystallized from
hexanes, giving colorless needles. mp 121-122 °C. 1H NMR (500
MHz, CDCl3): δ 8.08-8.02 (m, 2H), 7.74 (broad m, 2H), 7.62-7.57
(m, 3H), 7.47-7.43 (m, 2H), 7.12-7.06 (m, 3H), 6.93-6.90 (m, 2H),
6.82-6.81 (m, 2H), 6.76-6.73 (m, 2H), 5.75 (d, 1H, J ) 8.5 Hz),
5.36 (dd, 1H, J ) 8.9, 9.9 Hz), 4.85 (dd, 1H, J ) 8.9, 10.6 Hz), 4.65
(d, 1H, J ) 7.2 Hz), 4.65 (dd, 1H, J ) 8.5, 10.6 Hz), 4.55 (d, 1H, J )
7.2 Hz), 4.11-4.02 (m, 3H), 3.72 (s, 3H), 3.69 (m, 2H).13C NMR (75
MHz, CDCl3): δ 165.16, 155.24, 150.75, 136.87, 134.12 (1), 133.74
(1), 131.36, 129.81 (1), 128.75, 128.66 (1), 128.05 (1), 127.21 (1),
126.86 (1), 123.41 (1), 118.47 (1), 114.41 (1), 97.67 (1), 96.18 (2),
77.35 (1), 74.54 (1), 73.21 (1), 69.67 (2), 55.63 (1), 55.55 (3), 43.51
(2). The N-Pht CdO peak was presumably very broad and not observed.
CI-MS m/z (rel intensity): 721.4 ([M + NH4]+, 74.08), 675.5 (100.00),
tert-Butyldimethylsilyl 4,6-O-Benzylidene-2-deoxy-2-phthalimido-
â-D-glucopyranoside (16b). To a stirred solution of 15 (3.67 g, 6.68
mmol) in dry MeOH (30 mL) under an atmosphere of Ar was added
1.0 M NaOMe (625 µL, 0.625 mmol, prepared by adding Na (23 mg)
to MeOH (1.0 mL) under Ar). After stirring at RT for 2.5 h, DOWEX
50WX8-100 (H+ form) (945 mg) was added, and the suspension was
stirred gently for 105 min. The resin was removed by filtration, and
the filtrate was evaporated and then coevaporated with pentane, leaving
a white powder (2.96 g). The powder was suspended in dry CH3CN
(58 mL) under an Ar atmosphere, and benzaldehyde dimethyl acetal
(1.6 mL, 11.6 mmol) and TsOH‚H2O (13 mg, 0.068 mmol) were added.
After 11 h, the pink solution was placed under a gentle vacuum. After
13.5 h total reaction time, K2CO3 (378 mg, 2.73 mmol) was added and
the mixture was stirred for 0.5 h. The mixture was filtered and
evaporated, leaving a white solid/oil (4.24 g) which was purified by
flash chromatography (hexanes/EtOAc 3:1), giving the title compound
1
as a white foam (3.03 g, 89% over two steps). H NMR (300 MHz,
CDCl3): δ 7.84-7.80 (m, 2H), 7.72-7.67 (m, 2H), 7.52-4.47 (m,
2H), 7.39-7.35 (m, 3H), 5.56 (s, 1H), 5.45 (d, 1H, J ) 8.0 Hz), 4.64
(ddd, 1H, J ) 3.4, 8.5, 11.0 Hz), 4.32 (dd, 1H, J ) 3.4, 9.8 Hz), 4.19
(dd, 1H, J ) 8.0, 10.7 Hz), 3.86-3.79 (m, 1H), 3.63-3.56 (m, 2H),
(58) Classon, B.; Garegg, P. J.; Samuelsson, B. Acta Chem. Scand., Ser. B 1984,
38, 419-422.
9
10048 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
414.2 (51.87), 396.2 (36.95), 274.1 (48.29), 240.2 (54.87), 124.1
(30.11), 121.1 (65.34), 105.1 (66.23), 91.1 (52.98). CI-HRMS calcd
for C36H36N2O9Br [M + Na]+, 719.1604; obsd, 719.1636.
(broad d, 1H, J ) 6.6 Hz), 5.11 (d, 1H, J ) 7.9 Hz), 4.92 (d, 1H, J )
7.2 Hz), 4.76 (d, 1H, J ) 11.8 Hz), 4.70 (d, 1H, J ) 7.2 Hz), 4.57 (d,
1H, J ) 11.7 Hz), 4.39 (s, 1H), 3.90-3.85 (m, 2H), 3.75 (s, 3H), 3.62
(ddd, 1H, J ) 2.4, 8.5, 9.1 Hz), 3.51-3.45 (m, 2H), 3.09 (dd, 1H, J )
8.5, 13.0 Hz). 13C NMR (75 MHz, CDCl3): δ 157.48 (q, J ) 37 Hz),
155.64, 150.96, 136.08, 132.12 (1), 130.52, 129.07 (1), 128.67 (1),
128.34 (1), 128.06 (1), 126.76 (1), 118.73 (1), 115.56 (q, J ) 288 Hz),
114.54 (1), 99.18 (1), 96.04 (2), 83.54 (1), 75.48 (1), 73.32 (1), 70.63
(2), 56.44 (1), 55.59 (3), 29.38 (2).
p-Methoxyphenyl 4-O-Benzoyl-3-O-[(benzyloxy)methyl]-2,6-di-
deoxy-6-phenylseleno-2-phthalimido-â-D-glucopyranoside (19a). To
a stirred solution of 18a (0.775 g, 1.1 mmol) in THF (8.0 mL) under
an Ar atmosphere in a flask fitted with a reflux condenser and drying
tube were added phenylselenol (0.35 mL, 3.3 mmol) and triethylamine
(0.928 mL, 6.6 mmol). The solution was heated to reflux temperature.
After ∼5 min, a white precipitate began to appear, and the reflux was
maintained for 24 h. The suspension was then cooled and equilibrated
between sat. NaHCO3 (70 mL) and CH2Cl2 (70 mL). The aqueous layer
was back-extracted with CH2Cl2 (70 mL), and the organic layers were
combined and washed with sat. NaCl, dried over MgSO4, filtered, and
evaporated, leaving a yellow oil (1.51 g). The oil was purified by flash
chromatography (hexanes/EtOAc 2:1), giving the title compound as a
To the crude N-TFA compound (1.36 g, 2.12 mmol) in pyridine (7
mL) was added Ac2O (7.0 mL, 74 mmol). The reaction was allowed
to stir at ambient temperature overnight. The solution was diluted with
EtOAc and washed with an equal volume of sat. NaHCO3 (3×), sat.
CuSO4, and sat. NaCl. The organic layer was dried over MgSO4,
filtered, and evaporated, leaving an off-white solid which was purified
on a plug of SiO2, giving the title compound as a white powder (1.18
g, 84% over two steps). mp 171-174 °C. 1H NMR (300 MHz,
CDCl3): δ 7.49-7.46 (m, 2H), 7.36-7.21 (m, 8H), 7.00-6.97 (m,
2H), 6.92 (broad d, 1H, J ) 7.7 Hz), 6.82-6.76 (m, 2H), 5.21 (d, 1H,
J ) 8.2 Hz), 5.03 (dd, 1H, J ) 9.0, 9.6 Hz), 4.72 (s, 2H), 4.55 (s, 2H),
4.18 (dd, 1H, J ) 9.0, 10.3 Hz), 3.91 (ddd, J ) 7.7, 8.1, 10.2 Hz),
3.75 (s, 3H), 3.71 (ddd, 1H, J ) 4.4, 7.8, 9.6 Hz), 3.10-3.01 (m, 2H),
1.98 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.84, 157.56 (q, J )
37 Hz), 155.71, 150.97, 136.89, 132.59, 130.13, 129.13, 128.44, 127.90,
127.77, 127.15, 118.85, 115.55 (q, J ) 288 Hz), 114.52, 99.42, 95.32,
77.35, 73.94, 73.93, 69.91, 56.85, 55.56, 29.11, 20.87. FAB-MS m/z
(rel intensity): 706.1 ([M + Na]+, 8.7), 560.1 (9.3), 91.0 (100.00).
FAB-HRMS calcd for C31H32NO8F3NaSe [M + Na]+, 706.1143; obsd,
706.1147.
1
white foam (780 mg, 91%). H NMR (300 MHz, CDCl3): δ 8.01-
7.98 (m, 2H), 7.72 (broad m, 2H), 7.64-7.55 (m, 3H), 7.46-7.41 (m,
4H), 7.18-7.13 (m, 3H), 7.09-7.04 (m, 3H), 6.93-6.90 (m, 2H), 6.81-
6.79 (m, 2H), 6.75-6.71 (m, 2H), 5.73 (d, 1H, J ) 8.3 Hz), 5.39 (dd,
1H, J ) 9.1, 9.2 Hz), 4.81 (dd, 1H, J ) 9.1, 10.5 Hz), 4.65 (dd, 1H,
J ) 8.3, 10.6 Hz), 4.62 (d, 1H, J ) 7.2 Hz), 4.53 (d, 1H J ) 7.2 Hz),
4.06-3.96 (m, 3H), 3.71 (s, 3H), 3.13 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 167.53, 165.20, 155.42, 150.74, 136.91, 134.06 (1), 133.59
(1), 132.39 (1), 131.37, 130.21, 129.77 (1), 129.06 (1), 128.97, 128.59
(1), 128.02 (1), 127.16 (1), 126.96 (1), 126.82 (1), 123.40 (1), 118.55
(1), 114.34 (1), 97.67 (1), 96.09 (2), 77.31 (1), 75.19 (1), 74.17 (1),
69.60 (2), 55.76 (1), 55.56 (3), 29.02 (2).
p-Methoxyphenyl 3-O-[(Benzyloxy)methyl]-2,6-dideoxy-6-phenyl-
seleno-2-amino-â-D-glucopyranoside (20a). To a suspension of 19a
(1.71 mg, 2.20 mmol) in EtOH (40 mL) in a glass tube was added
hydrazine hydrate (5.0 mL, 160 mmol). The suspension was placed
under a gentle vacuum, and the tube was sealed. The suspension was
heated, and the temperature was maintained between 95 and 110 °C.
Upon heating, the suspension gradually became clear. After 17 h, the
reaction was cooled and the solution was equilibrated between EtOAc
(400 mL) and water (400 mL). The EtOAc layer was washed with sat.
NaHCO3 (400 mL) and sat. NaCl (400 mL). After drying over Na2-
SO4, the organic layer was filtered and evaporated, leaving an oil which
was purified by flash chromatography (EtOAc). The product eluted as
a colorless oil (1.15 g, 96.0%). 1H NMR (300 MHz, CDCl3): δ 7.53-
7.48 (m, 2H), 7.37-7.32 (m, 5H), 7.22-7.19 (m, 3H), 7.09-7.07 (m,
2H), 6.85-6.79 (m, 2H), 5.01 (d, 1H, J ) 7.2 Hz), 4.82 (d, 1H, J )
7.3 Hz), 4.81 (d, 1H, J ) 11.7 Hz), 4.67 (d, 1H, J ) 7.3 Hz), 4.61 (d,
1H, J ) 11.7 Hz), 3.76 (s, 3H), 3.57-3.42 (m, 3H), 3.27 (dd, 1H, J )
9.6, 9.6 Hz), 3.15-3.06 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
155.25, 151.19, 136.20, 132.02 (1), 130.77, 128.97 (1), 128.62 (1),
128.25 (1), 128.05 (1), 126.57 (1), 118.36 (1), 114.39 (1), 102.86 (1),
96.46 (2), 89.08 (1), 75.61 (1), 72.60 (1), 70.54 (2), 55.86 (1), 55.56
(3), 29.66 (2). CI-MS (NH3) m/z (rel intensity): 546.1 (M + H+,
100.00), 422.0 (63.46), 390.1 (29.64), 284.2 (25.48), 124.0 (42.45),
110.0 (38.96), 108.1 (44.40), 91.0 (36.17). CI-HRMS (NH3) m/z calcd
for C27H32NO6Se [M + H]+, 546.1395; obsd, 546.1398.
p-Methoxyphenyl 4-O-Acetyl-3-O-[(benzyloxy)methyl]-2,6-dideoxy-
6-phenylseleno-2-trifluoroacetamido-â-D-glucopyranoside (21a). To
a stirred solution of 20a (1.12 g, 2.06 mmol) in pyridine (11 mL) at 0
°C was added trifluoroacetic anhydride (1.45 mL, 10.3 mmol). After
30 min, the solution was diluted with CH2Cl2 (200 mL) and washed
with sat. NaHCO3 (200 mL), 0.1 M HCl (2 × 180 mL), sat. NaHCO3
(150 mL), and sat. NaCl (150 mL). The organic layer was stirred over
SiO2 (10 g) overnight. The suspension was filtered, and the filtrate
was evaporated, leaving p-methoxyphenyl 3-O-[(benzyloxy)methyl]-
2,6-dideoxy-6-phenylseleno-2-trifluoroacetamido-â-D-glucopyrano-
side contaminated with a small amount of pyridine (1.36 g, 103%). 1H
NMR (300 MHz, CDCl3): δ 7.53-7.49 (m, 2H), 7.38-7.32 (m, 5H),
7.23-7.19 (m, 3H), 7.00-6.96 (m, 2H), 6.82-6.77 (m, 2H), 6.71
tert-Butyldimethylsilyl 4-O-Benzoyl-3-O-[(benzyloxy)methyl]-2,6-
dideoxy-6-bromo-2-phthalimido-â-D-glucopyranoside (18b). N-Bro-
mosuccinimide (1.16 g, 6.52 mmol), barium carbonate (3.50 g, 17.7
mmol), and 16b (3.01 g, 5.87 mmol) were suspended in dry CCl4 (110
mL) under an Ar atmosphere. The suspension was heated to reflux
temperature. As the reaction progressed, the solution turned deep
orange; the disappearance of color signified completion of the reaction.
After 1 h, the colorless suspension was cooled and filtered. The solid
was washed with CHCl3, and the filtrate was evaporated, leaving a
white powder which was dissolved in CHCl3 (300 mL) and washed
with H2O (3 × 100 mL) and sat. NaCHO3 (100 mL). The solvent was
dried over MgSO4, filtered, and evaporated, leaving 17b as a white
powder sufficiently pure for further transformations, 3.40 g (98% crude
recovery). 1H NMR (300 MHz, CDCl3): δ 8.08-8.04 (m, 2H), 7.85-
7.81 (m, 2H), 7.73-7.69 (m, 2H), 7.62-7.57 (m, 1H), 7.48-7.43 (m,
2H), 5.53 (d, 1H, J ) 8.0 Hz), 5.14 (dd, 1H, J ) 9.0, 10.2 Hz), 4.70
(dd, 1H, J ) 9.0, 10.9 Hz), 4.29 (dd, 1H, J ) 8.0, 10.9 Hz), 4.01 (ddd,
1H, J ) 2.5, 8.0, 10.2 Hz), 3.56 (dd, 1H, J ) 2.5, 11.2 Hz), 3.48 (dd,
1H, J ) 8.0, 11.2 Hz), 0.71 (s, 9H), 0.15 (m, 3H), 0.01 (m, 3H). 13C
NMR (75 MHz, CDCl3): δ 168.35, 166.35, 134.16 (1), 133.73 (1),
131.45, 129.89 (1), 128.82, 128.55 (1), 123.34 (1), 93.35 (1), 75.45
(1), 73.91 (1), 69.74 (1), 59.18 (1), 31.22 (2), 25.27 (3), 17.44, -4.12
(3), -5.72 (3).
To a stirred solution of crude 17b (3.40 g, 5.74 mmol) in freshly
distilled THF (50 mL) under Ar were added DIEA (5.5 mL, 31.5 mmol)
and benzyl chloromethyl ether (3.89 mL, 28.0 mmol). The solution
was heated to reflux temperature. After 27.5 h, the reaction was cooled
and diluted with CH2Cl2 (500 mL). This solution was washed with sat.
NaCHO3 (500 mL). After back-extracting the aqueous layer with CH2-
Cl2 (500 mL), the organic extracts were combined and washed with
sat. NaCl (500 mL), dried over MgSO4, filtered, and evaporated. The
resulting brown oil was purified by flash chromatography (hexanes/
EtOAc 6:1-5:1), giving pure product as a white foam (2.61 g) along
with product contaminated with BOMCl (1.85 g). The contaminated
product was purified a second time by flash chromatography (hexanes/
EtOAc 6:1-5:1), giving the product as a foam (630 mg). Total yield:
1
3.24 g (78% over two steps). H NMR (300 MHz, CDCl3): δ 8.05-
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10049

A R T I C L E S
Hartman and Coward
8.03 (m, 2H), 7.74 (broad m, 2H), 7.67-7.57 (m, 3H), 7.48-7.44 (m,
2H), 7.13-7.04 (m, 3H), 6.84-6.82 (m, 2H), 5.51 (d, 1H, J ) 8.1
Hz), 5.28 (dd, 1H, J ) 8.9, 10.4 Hz), 4.82 (dd, 1H, J ) 8.9, 10.7 Hz),
4.67 (d, 1H, J ) 7.2 Hz), 4.55 (d, 1H, J ) 7.2 Hz), 4.36 (dd, 1H, J )
8.1, 10.7 Hz), 4.09 (s, 2H), 3.94 (ddd, 1H, J ) 4.6, 6.8, 10.4 Hz),
3.65-3.47 (m, 2H), 0.74 (s, 9H), 0.17 (m, 3H), 0.01 (m, 3H). 13C NMR
(75 MHz, CDCl3): δ 168.71, 165.25, 136.95, 134.00 (1), 133.65 (1),
131.40, 129.78 (1), 128.88, 128.62 (1), 128.00 (1), 127.14 (1), 126.85
(1), 123.08 (1), 96.03 (2), 93.48 (1), 77.08 (1), 74.42 (1), 74.34 (1),
69.55 (1), 57.92 (1), 31.10 (2), 25.26 (3), 17.43, -4.02 (3), -5.77 (3).
FAB-MS m/z (rel intensity): 734.2 ([M + Na]+, 6.0), 176.0 (43.0),
105.0 (100.0), 91.0 (70.8). FAB-HRMS calcd for C35H40NO8NaSeBr
[M + Na]+, 732.1604; obsd, 732.1622.
solution was diluted with CH2Cl2 (300 mL) and washed with sat.
NaHCO3 (300 mL), 0.1 M HCl (2 × 300 mL), NaHCO3 (300 mL),
and sat. NaCl (300 mL). The organic extracts were dried over MgSO4
and filtered, and the filtrate was stirred overnight with SiO2 (50 g).
After filtering the suspension, the filtrate was evaporated, leaving the
title compound contaminated with pyridine. To remove the pyridine,
the oil was dissolved in CH2Cl2 (300 mL) and washed with sat. CuSO4
(2 × 300 mL), H2O (300 mL), and sat. NaCl (300 mL). The organic
extracts were dried over MgSO4, filtered, and evaporated, leaving the
2-N-TFA derivative as a white powder sufficiently pure for further
transformations (2.54 g, 91%). mp 106-109 °C. 1H NMR (300 MHz,
CDCl3): δ 7.50-7.47 (m, 2H), 7.35-7.15 (m, 8H), 6.85 (broad d, 1H),
4.89 (d, 1H, J ) 7.2 Hz), 4.88 (d, 1H, J ) 7.4 Hz), 4.73 (d, 1H, J )
11.8 Hz), 4.67 (d, 1H, J ) 7.2 Hz), 4.53 (d, 1H, J ) 11.8 Hz), 4.31 (s,
1H), 3.73-3.65 (m, 2H), 3.54 (ddd, 1H, J ) 2.3, 8.6, 9.0 Hz), 3.45-
3.41 (m, 2H), 3.08 (dd, 1H, J ) 8.6, 12.6 Hz), 0.87 (s, 9H), 0.14 (s,
3H), 0.12 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 157.50 (q, J ) 37
Hz), 136.20, 131.84 (1), 130.97, 129.01 (1), 128.59 (1), 128.21 (1),
127.97 (1), 126.53 (1), 115.68 (q, J ) 288 Hz), 95.06 (2), 94.89 (1),
83.87 (1), 75.33 (1), 73.54 (1), 70.52 (2), 58.11 (1), 29.64 (2), 25.41
(3), 17.66, -4.04 (3), -5.69 (3).
tert-Butyldimethylsilyl 4-O-Benzoyl-3-O-[(benzyloxy)methyl]-2,6-
dideoxy-6-phenylseleno-2-phthalimido-â-D-glucopyranoside (19b).
To a stirred solution of 18b (3.23 g, 4.54 mmol) in freshly distilled
THF (30 mL) under an Ar atmosphere were added phenylselenol (1.4
mL, 14 mmol) and triethylamine (3.8 mL, 27.2 mmol). The yellow
suspension was heated to reflux temperature. After 4.5 days, the reaction
was diluted with CH2Cl2 (300 mL) and washed with sat. NaHCO3 (300
mL) and sat. NaCl (75 mL). The organic layer was dried over MgSO4,
filtered, and evaporated. Purification by flash chromatography (hexanes/
EtOAc 5:1) gave the title compound as a white powder (3.50 g, 98%).
To this crude product (1.50 g, 0.52 mmol) in pyridine (7.5 mL) was
added Ac2O (7.5 mL, 79.5 mmol). After 18 h, the solution was diluted
with CH2Cl2 (80 mL) and washed with sat. CuSO4 (2 × 150 mL),
H2O (150 mL), sat. NaHCO3 (2 × 150 mL), and sat. NaCl (150 mL).
The organic layer was dried over MgSO4, filtered, and evaporated,
leaving the title compound as an off-white powder (1.55 g, 97%). mp
1
mp 131.5-132 °C. H NMR (300 MHz, CDCl3): δ 8.02-7.99 (m,
2H), 7.73 (broad m, 2H), 7.65-7.60 (m, 3H), 7.46-7.41 (m, 4H), 7.20-
7.18 (m, 3H), 7.08-7.06 (m, 3H), 6.82-6.80 (m, 2H), 5.50 (d, 1H, J
) 8.1 Hz), 5.32 (dd, 1H, J ) 8.9, 9.4 Hz), 4.78 (dd, 1H, J ) 8.9, 10.7
Hz), 4.62 (d, 1H, J ) 7.2 Hz), 4.53 (d, 1H, J ) 7.2 Hz), 4.38 (dd, 1H,
J ) 8.1, 10.7 Hz), 4.08 (s, 2H), 3.94 (ddd, 1H, J ) 2.9, 9.4, 9.4 Hz),
3.20-3.06 (m, 2H), 0.71 (s, 9H), 0.14 (s, 3H), 0.00 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 168.64 (broad d), 165.23, 136.96, 133.93 (1),
133.45 (1), 133.45 (1), 132.07 (1), 131.37, 130.51, 129.69 (1), 129.08,
129.02 (1), 128.50 (1), 127.93 (1), 127.05 (1), 126.77 (1), 123.07 (broad
d) (1), 95.93 (2), 93.49 (1), 77.08 (1), 75.60 (1), 73.93 (1), 69.47 (2),
57.93 (1), 29.16 (2), 25.22 (3), 17.36, -4.12 (3), -5.82 (3). FAB-MS
m/z (rel intensity): 810.3 ([M + Na]+, 87.6), 758.3 (64.2), 730.2
(100.0), 680.2 (25.7), 656.1 (29.5). FAB-HRMS calcd for C41H45NO8-
NaSiSe [M + Na]+, 810.1977; obsd, 810.2005.
1
161-162 °C. H NMR (300 MHz, CDCl3): δ 7.49-7.43 (m, 2H),
7.38-7.21 (m, 8H), 6.90 (broad d, 1H, J ) 8.2 Hz), 4.98-4.92 (m,
2H), 4.70 (s, 2H), 4.54 (s, 2H), 4.08 (dd, J ) 9.2, 10.4 Hz), 3.74-3.61
(m, 2H), 3.09-2.94 (m, 2H), 1.96 (s, 3H), 0.87 (s, 9H), 0.12 (s, 3H),
0.08 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.93, 157.35 (q, J )
38 Hz), 137.00, 132.24 (1), 130.55, 129.09 (1), 128.39 (1), 127.81 (1),
127.72 (1), 126.93 (1), 115.61 (q, J ) 288 Hz), 95.20 (2), 94.89 (1),
77.42 (1), 74.50 (1), 73.74 (1), 69.75 (2), 58.81 (1), 29.20 (2), 25.38
(3), 20.89 (3), 17.63, -4.10 (3), -5.76 (3). FAB-MS m/z (rel
intensity): 714.0 ([M + Na]+, 8.0), 662.0 (2.2), 90.9 (100.0). EI-HRMS
calcd for C26H31NO7F3SiSe [M - C4H9]+, 634.0987; obsd, 634.0956.
tert-Butyldimethylsilyl 3-O-[(Benzyloxy)methyl]-2,6-dideoxy-6-
phenylseleno-2-amino-â-D-glucopyranoside (20b). To a suspension
of 19b (3.50 g, 4.44 mmol) in EtOH (3.2 mL) in a glass tube was
added hydrazine hydrate (2.0 mL, 416 mmol). The tube was placed
under vacuum and sealed, and the suspension was heated to 100 °C.
Upon heating, the suspension gradually became clear. After 15 h, the
reaction was cooled and the solution was equilibrated between EtOAc
(900 mL) and water (900 mL). The EtOAc layer was washed with sat.
NaHCO3 (900 mL) and sat. NaCl (900 mL). After drying over MgSO4,
the organic layer was filtered and evaporated, leaving an oil which
was purified by flash chromatography using EtOAc as the eluant. The
p-Methoxyphenyl 3,4-Di-O-acetyl-2,6-dideoxy-6-phenylseleno-2-
trifluoroacetamido-â-D-glucopyranoside (22). To a stirred 0 °C
solution of 21a (1.17 g, 1.71 mmol) in dry CHCl3 (24 mL) under an
atmosphere of Ar was added AcBr (250 µL, 3.38 mmol) and BF3‚
OEt2 (21 µL, 0.17 mmol). After 2 h, additional BF3‚OEt2 (84 µL, 0.66
mmol) was added. After a further 30 min, additional AcBr (250 µL,
3.38 mmol) was added. After 7 h total reaction time, the solution was
diluted with CH2Cl2 (200 mL) and washed with sat. NaHCO3 (200
mL), H2O (200 mL), and sat. NaCl (200 mL). The organic extracts
were dried over MgSO4, filtered, and evaporated, leaving an off-white
powder (1.49 g). The powder was purified by flash chromatography
(hexanes/EtOAc 2:1), giving the title compound as a white powder
1
title compound eluted as a colorless oil (2.38 g, 97%). H NMR (300
1
MHz, CDCl3): δ 7.55-7.48 (m, 2H), 7.38-7.29 (m, 5H), 7.25-7.16
(m, 3H), 4.97 (d, 1H, J ) 7.1 Hz), 4.79 (d, 1H, J ) 7.1 Hz), 4.78 (d,
1H, J ) 11.8 Hz), 4.59 (d, 1H, J ) 11.8 Hz), 4.47 (d, 1H, J ) 7.6
Hz), 3.53-3.37 (m, 3H), 3.20 (dd, 1H, J ) 9.5, 9.5 Hz), 3.10 (dd, 1H,
J ) 8.9, 12.8 Hz), 2.83 (m, 1H), 0.92, (s, 9H), 0.18 (s, 6H). 13C NMR
(75 MHz, CDCl3): δ 136.26, 131.84 (1), 131.16, 128.90 (1), 127.55
(1), 128.14 (1), 127.97 (1), 126.37 (1), 98.49 (1), 96.37 (2), 89.06 (1),
75.48 (1), 72.97 (1), 70.37 (2), 57.70 (1), 29.94 (2), 25.73 (3), 17.88,
-3.89 (3), -5.42 (3). CI-MS (NH3) m/z (rel intensity): 554.4 (M +
H+, 100.00), 398.4 (22.71), 242.3 (10.81). CI-HRMS (NH3) calcd for
C26H40NO5SiSe [M + H]+, 554.1841; obsd, 554.1826.
tert-Butyldimethylsilyl 4-O-Acetyl-3-O-[(benzyloxy)methyl]-2,6-
dideoxy-6-phenylseleno-2-trifluoroacetamido-â-D-glucopyrano-
side (21b). To a stirred 0 °C solution of 20b (2.38 g, 4.29 mmol) in
pyridine (30 mL) under an atmosphere of Ar was added dropwise
trifluoroacetic anhydride (3.1 mL, 22.0 mmol). After 45 min, the
(920 mg, 88%). mp 194-195 °C. H NMR (300 MHz, CDCl3): δ
7.51-7.47 (m, 2H), 7.37-7.23 (m, 3H), 7.00-6.95 (m, 2H), 6.83-
6.78 (m, 2H), 6.54 (broad d, 1H, J ) 8.9 Hz), 5.28 (dd, 1H, J ) 9.4,
10.4 Hz), 5.08 (dd, 1H, J ) 8.7, 9.4 Hz), 4.99 (d, 1H, J ) 8.3 Hz),
4.26 (ddd, 1H, J ) 8.3, 8.9, 9.4 Hz), 3.83-3.76 (m, 4H), 3.11-3.01
(m, 2H), 2.05 (s, 3H), 2.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
171.39, 169.54, 157.46 (q, J ) 37 Hz), 155.84, 150.89, 132.51 (1),
130.01, 129.20 (1), 127.27 (1), 118.85 (1), 115.56 (q, J ) 288 Hz),
114.52 (1), 100.20 (1), 74.02 (1), 72.12 (1), 71.60 (1), 55.61 (3), 54.76
(1), 28.85 (2), 20.62 (3), 20.42 (3). FAB-MS m/z (rel intensity): 628.0
([M + Na]+, 13.5) 482.0 (27.0), 329.1 (23.5), 176.0 (81.5), 124.1
(100.00). FAB-HRMS calcd for C25H26NO8F3NaSe [M + Na]+,
628.0673; obsd, 628.0685.
3,4-Di-O-acetyl-2,6-dideoxy-6-phenylseleno-2-trifluoroacetamido-
â-D-glucopyranosyl bromide (23). To a stirred 0 °C solution of 22
(100 mg, 0.165 mmol) in dry CHCl3 (2.0 mL) under an atmosphere of
9
10050 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
Ar was added dropwise AcBr (77 µL, 1.04 mmol) and BF3‚OEt2 (33
µL, 0.265 mmol), followed by ZnI2 (5 mg, 0.016 mmol). The reaction
was gradually warmed to RT. After 11.5 h, the reaction mixture was
warmed to 40 °C. After 16.5 h total reaction time, the reaction was
diluted with CH2Cl2 (20 mL) and washed with sat. NaHCO3 (containing
6 crystals of Na2S2O3) (20 mL), H2O (20 mL), and sat. NaCl (20 mL).
The organic layer was dried with MgSO4, filtered, and evaporated,
leaving a brown oil (114 mg) which contained product contaminated
with p-methoxyphenyl acetate. The oil was used in the subsequent
reactions without prior purification.
(m). EIMS m/z (rel intensity): 759.3 ([M]+, 0.88), 481.1 (20.03), 264.1
(10.95), 222.1 (19.01), 157.0 (11.37), 91.1 (50.17), 43.0 (100.00). EI-
HRMS calcd for C32H33NO10F3PSe [M]+, 759.0959; obsd, 759.0925.
4-O-Acetyl-3-O-[(benzyloxy)methyl]-2,6-dideoxy-6-phenylseleno-
2-trifluoroacetamido-â-D-glucopyranoside (27). To a stirred 0 °C
solution of 21b (202 mg, 0.292 mmol) and pyridine (1.1 mL) in freshly
distilled THF (4.5 mL) was added dropwise HF‚pyridine (400 µL).
After 2.75 h, the reaction was removed from the ice bath and allowed
to warm to RT. After 6.5 h total reaction time, the reaction was diluted
with CH2Cl2 (80 mL), and the organic layer was washed with sat.
NaHCO3 (80 mL) and sat. NaCl (80 mL). The organic layer was dried
over MgSO4, filtered, and evaporated, leaving a yellow oil (230 mg)
which was purified by flash chromatography (hexanes/EtOAc 2:1),
giving the desired product as a white powder (153 mg), 91% (R/â
2-Trifluoromethyl-(3,4-di-O-acetyl-1,2,6-trideoxy-6-phenylseleno-
r-D-glycopyrano)[2,1-d]-2-oxazoline (24). To a stirred solution of
crude 23 (115 mg) in dry CH3CN (2 mL) under an atmosphere of Ar
was added Bu4NBr (53 mg, 0.165 mmol) and 2,6-lutidine (29 µL, 0.249
mmol). After 20 min, the reaction was diluted with CH2Cl2 (20 mL)
and washed with pH ) 7 K2PO4 buffer (20 mL), H2O (20 mL), and
sat. NaCl (20 mL). The organic extracts were dried with Na2SO4,
filtered, and evaporated, leaving a brown oil (168 mg). The oil was
purified by flash chromatography (hexanes/EtOAc/Et3N 3:1:0.04),
giving the product as a light brown oil (70 mg, 89% over two steps).
1H NMR (300 MHz, C6D6): δ 7.43-7.39 (m, 2H), 6.95-6.86 (m, 3H),
5.44 (dd, 1H, J ) 1.5, 2.1 Hz), 5.43 (d, 1H J ) 7.6 Hz), 5.10 (ddd,
1H, J ) 1.5, 2.1, 8.2 Hz), 3.68 (ddd, 1H, J ) 3.9, 6.8, 8.2 Hz), 3.58
(ddd, 1H, J ) 2.1, 2.1, 7.6 Hz), 2.95 (dd, 1H, J ) 3.9, 13.0 Hz), 2.81
(dd, 1H, J ) 6.8, 13.0 Hz), 1.57 (s, 3H), 1.35 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 169.45, 169.05, 133.37, 129.20, 128.15, 127.51,
102.25, 71.13, 69.90, 68.84, 63.86, 30.83, 20.85, 20.73. The sample
was too dilute to observe the oxazoline CF3 and NdC peaks. 19F NMR
(282 MHz, CDCl3, machine standard): δ 5.85.
1
10:1). mp 165-166 °C. H NMR (300 MHz, CDCl3) (R anomer): δ
7.52-7.47 (m, 2H), 7.38-7.23 (m, 8H), 7.17 (broad d, 1H, J ) 7.1
Hz), 5.47 (dd, 1H, J ) 3.0, 3.4 Hz), 4.99 (dd, 1H, J ) 9.0, 9.8 Hz),
4.74 (d, 1H, J ) 6.6 Hz), 4.67 (d, 1H, J ) 6.6 Hz), 4.59 (d, 1H, J )
12.3 Hz), 4.54 (d, 1H, J ) 12.3 Hz), 4.17 (ddd, 1H, J ) 5.9, 5.9, 9.8
Hz), 4.11 (ddd, 1H, J ) 3.0, 7.1, 10.6 Hz), 3.98 (dd, 1H, J ) 9.0, 10.3
Hz) 3.57 (d, 1H, J ) 3.4 Hz), 3.03-2.99 (m, 2H), 2.00 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 169.68, 157.32 (q, J ) 37 Hz), 136.61,
132.75, 130.24, 129.10, 128.53, 128.05, 127.80, 127.18, 119.46 (q, J
) 288 Hz), 95.54, 90.39, 74.00, 69.87, 69.65, 53.63, 29.30, 20.86. One
carbon was obscured by the CDCl3 solvent peak. EIMS m/z (rel
intensity): 577.1 ([M]+, 7.2), 120.1 (18.5), 91.1 (100.00), 43.4 (43.0).
EI-HRMS calcd for C24H26NO7F3Se [M]+, 577.0827; obsd, 577.0837.
4-O-Acetyl-3-O-[(benzyloxy)methyl]-2,6-dideoxy-6-phenylseleno-
2-trifluoroacetamido-r-D-glucopyranosyl 1-Dibenzyl Phosphate (28).
To a stirred -78 °C solution of 27 (1.09 g, 1.89 mmol) in freshly
distilled THF (57 mL) was added dropwise freshly prepared LDA (0.49
M in THF/hexanes, 5.4 mL). After 15 min, a -78 °C solution of
tetrabenzylpyrophosphate (1.27 g, 2.36 mmol) in freshly distilled THF
(27 mL) was added. The solution was stirred for 20 min at -78 °C
and was then warmed to 0 °C via an ice bath. After an additional 2 h,
the solution was diluted with CH2Cl2 (800 mL) and was washed with
sat. NaHCO3 (2 × 800 mL) and sat. NaCl (800 mL). The organic layer
was dried over Na2SO4, filtered, and evaporated, leaving a colorless
oil which was purified by flash chromatography (hexanes/EtOAc 2:1),
giving the title compound as a low-melting solid (1.33 g, 84%). In a
separate fraction, a small amount of the 1,2-oxazoline was obtained.
3,4-Di-O-acetyl-2,6-dideoxy-6-phenylseleno-2-trifluoroacetamido-
â-D-glucopyranose (25). To a stirred solution of crude glycosyl bromide
23 (49 mg, 0.079 mmol) in acetone/H2O 2:1 (3.6 mL) was added Ag2-
CO3 (44 mg, 0.16 mmol). The flask was immediately covered with
foil. After 45 min, the reaction was filtered through Celite which was
washed with EtOAc. The filtrate was washed with sat. NaHCO3 (30
mL) and sat. NaCl (30 mL). The organic layer was dried over MgSO4,
filtered, and evaporated, leaving a residue (42 mg) which was purified
by preparative TLC (hexanes/EtOAc 2:1), giving the product as a
1
powder (25 mg, 64% over two steps) (R/â 8:1). H NMR (R-anomer)
(300 MHz, CDCl3): δ 7.52-7.49 (m, 2H), 7.27-7.25 (m, 3H), 6.69
(d, 1H, J ) 9.5 Hz), 5.35-5.28 (m, 2H), 5.06 (dd, 1H, J ) 9.7, 9.7
Hz), 4.44-4.22 (m, 2H), 3.38 (d, 1H, J ) 2.1 Hz), 3.06 (dd, 1H, J )
3.5, 12.9 Hz), 2.99 (dd, 1H, J ) 8.0, 12.9 Hz), 2.01 (s, 6H).
1
mp 59-62 °C. H NMR (300 MHz, CDCl3): δ 7.46-7.44 (m, 2H),
7.37-7.19 (m, 19H), 5.92 (dd, 1H, J ) 3.0, 6.5 Hz), 5.07-5.00 (m,
5H), 4.72 (d, 1H, J ) 6.4 Hz), 4.60 (d, 1H, J ) 6.4 Hz), 4.57 (d, 1H,
J ) 12.4 Hz), 4.52 (d, 1H, J ) 12.4 Hz), 4.16-4.08 (m, 2H), 3.84
(dd, 1H, J ) 9.3, 10.5 Hz), 3.00-2.91 (m, 2H), 1.99 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 169.39, 157.54 (q, J ) 38 Hz), 136.45, 135.26
(d, J ) 6.5 Hz), 135.09 (d, J ) 6.2 Hz), 132.72, 130.34, 129.12, 128.77,
128.74, 128.62, 128.62, 128.57, 128.30, 128.15, 128.08, 127.85, 127.17,
115.77 (q, J ) 288 Hz), 95.48, 94.57 (d, J ) 6.4 Hz), 76.00, 73.01,
71.71, 69.99 (d, J ) 5.7 Hz), 69.88 (d, J ) 5.7 Hz), 69.85, 53.46 (d,
J ) 7.4 Hz), 29.67, 20.78. 31P NMR (121 MHz, CDCl3): δ -2.57
(m). FAB-MS m/z (rel intensity): 860.0 ([M + Na]+, 59.46), 837.0
([M]+, 21.15), 560.0 (100.00), 530.0 (30.39), 482.0 (18.60), 460.1
(25.54). FAB-HRMS calcd for C38H39NO10F3PSe [M]+, 837.1429; obsd,
837.1429.
3,4-Di-O-acetyl-2,6-dideoxy-6-phenylseleno-2-trifluoroacetamido-
r-D-glucopyranosyl 1-Dibenzyl Phosphate (26). To a stirred -78 °C
solution of 25 (25 mg, 0.050 mmol) in freshly distilled THF (1.25 mL)
was added 0.49 M LDA in hexanes (143 µL). After 15 min, a -78 °C
solution of tetrabenzylpyrophosphate (33 mg, 0.063 mmol) in freshly
distilled THF (750 µL) was added. After a further 20 min, the yellow
solution was warmed to 0 °C. Seventy minutes later, the suspension
was diluted with CH2Cl2 (20 mL) and washed with sat. NaHCO3 (2 ×
20 mL) and sat. NaCl (20 mL). The CH2Cl2 layer was dried over Na2-
SO4, filtered, and evaporated, leaving an oil which was purified by
preparative TLC (hexanes/EtOAc 2:1), giving the product as an oil
1
(25 mg, 66%). H NMR (300 MHz, C6D6): δ 8.95 (d, 1H, J ) 8.7
Hz), 7.57-7.54 (m, 2H), 7.35-7.03 (m, 13H), 5.72 (dd, 1H, J ) 9.4,
10.8 Hz), 5.68 (dd, 1H, J ) 3.4, 7.1 Hz), 5.36 (dd, 1H, J ) 9.4, 10.0
Hz), 5.20 (d, 2H, J ) 8.3 Hz), 5.06-5.02 (m, 2H), 4.66 (dddd, 1H, J
) 2.6, 3.4, 8.7, 10.8 Hz), 4.58 (ddd, 1H, J ) 3.2, 6.9, 10.0 Hz), 3.23
(dd, 1H, J ) 3.2, 13.2 Hz), 2.98 (dd, 1H, J ) 6.9, 13.2 Hz), 1.78 (s,
3H), 1.67 (s, 3H). 13C NMR (75 MHz, C6D6): δ 170.74, 168.93, 158.00
(q, J ) 38 Hz), 136.09 (d, J ) 6.9 Hz), 135.62 (d, J ) 6.3 Hz), 133.24,
131.29, 129.33, 128.85, 128.78, 128.64, 127.27, 116.65 (q, J ) 288
Hz), 95.45 (d, J ) 6.3 Hz), 72.02, 71.42, 70.18-70.11 (m, 2C), 52.94
(d, J ) 7.2 Hz), 29.83, 20.16, 20.04. Several expected 13C peaks were
obscured by the solvent peak. 31P NMR (121 MHz, CDCl3): δ -2.47
4-O-Acetyl-3-O-[(benzyloxy)methyl]-2,6-dideoxy-5,6-didehydro-
2-trifluoroacetamido-r-D-glucopyranosyl 1-Dibenzyl Phosphate (29).
To a stirred RT suspension of 28 (670 mg, 0.816 mmol) in MeOH/
H2O (6:1, 175 mL) were added NaHCO3 (75 mg, 0.90 mmol) and NaIO4
(261 mg, 1.22 mmol). As the reaction progressed, a white precipitate
formed. After 1.5 h, the suspension was filtered and washed with CH2-
Cl2. The organic portion of the filtrate was evaporated, and the resulting
aqueous suspension was partitioned between H2O (135 mL) and CH2-
Cl2 (135 mL). The aqueous layer was washed with CH2Cl2 (2 × 70
mL). The organic layers were combined, dried over Na2SO4, filtered,
9
J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10051

A R T I C L E S
Hartman and Coward
and evaporated, leaving the product selenoxides (2:1 ratio) as a white
powder (690 mg), 101%. 1H NMR (only nonoverlapping assigned
peaks) (300 MHz, CDCl3): δ 7.77-7.73 (m, 2H, SePh), 7.68-7.65
(m, 2H, SePh), 5.98 (dd, J ) 3.1, 6.5 Hz), 5.89 (dd, J ) 3.1, 6.3 Hz).
(d, J ) 7.1 Hz), 135.02 (d, J ) 7.2 Hz), 128.68 (1), 128.56 (1), 128.56
(1), 128.53 (1), 128.09 (1), 127.94 (1), 127.86 (1), 127.76 (1), 115.47
(q, J ) 288 Hz), 110.79 (d, J ) 233 Hz), 95.65 (2), 94.04 (d, J ) 6.4
Hz) (1), 71.97 (1), 69.93 (2), 69.78 (2, d, J ) 5.3 Hz), 69.74 (2, d, J
) 5.4 Hz), 69.34 (1, d, J ) 23 Hz), 62.02 (2, d, J ) 39 Hz), 52.84 (1,
d, J ) 7.6 Hz), 20.46 (3), 20.42 (3). 19F NMR (282 MHz, CDCl3): δ
0.12, -48.32 (ddd, J ) 5.6, 5.6, 22.8 Hz). 31P NMR (121 MHz,
CDCl3): δ -3.40 (ddddd, J ) 7.0 Hz) FAB-MS m/z (rel intensity):
780.3 ([M + Na]+, 100.00), 758.4 ([M + H]+, 31.60). FAB-HRMS
calcd for C34H36NO12F4NaP [M + Na]+, 780.1809; obsd, 780.1834.
(b) L-Ido Isomer, 30b (Minor Product). 1H NMR (300 MHz,
CDCl3): δ 7.36-7.35 (m, 15H), 6.90 (d, 1H, J ) 8.8 Hz), 6.04 (dd,
1H, J ) 1.0, 7.6 Hz), 5.22 (m, 1H), 5.09-5.01 (m, 4H), 4.90 (d, 1H,
J ) 7.2 Hz), 4.83 (d, 1H, J ) 7.2 Hz), 4.69-4.58 (m, 2H), 4.50-4.37
(m, 2H), 4.01-3.92 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 169.68, 167.79, 156.84 (q, J ) 38 Hz), 136.80,
135.10 (d, J ) 6.9 Hz), 134.98 (d, J ) 7.1 Hz), 128.81, 128.76, 128.62,
128.46, 128.02, 127.95, 127.90, 111.41 (d, J ) 230 Hz), 94.30, 90.92
(dd, J ) 3.5, 4.5 Hz), 72.54, 70.03 (d, J ) 7.7 Hz), 69.95 (d, J ) 7.8
Hz), 64.59 (d, J ) 43 Hz), 64.76 (d, J ) 23 Hz), 49.05 (d, J ) 7.0
Hz), 20.37, 20.28. Several carbons overlapped in the aromatic region.
Also, the sample was too dilute to observe the CF3.19F NMR (282 MHz,
CDCl3): δ 0.10, -42.08 (s, broad). 31P NMR (121 MHz, CDCl3): δ
-3.15 (ddddd, J ) 8.4 Hz). FAB-MS m/z (rel intensity): 780.2 ([M +
Na]+, 100.00), 758.2 ([M + H]+, 49.05), 650.2 (13.98). FAB-HRMS
calcd for C34H36NO12F4NaP [M + H]+, 780.1809; obsd, 780.1838.
A stirred clear, colorless suspension of the selenoxides (690 mg) in
freshly distilled dihydropyran (30 mL) was heated to reflux temperature.
Upon heating, the residual solid dissolved. After 4.75 h, the yellow
solution was cooled and diluted with CH2Cl2 (200 mL). This solution
was washed with H2O (200 mL), sat. NaHCO3 (200 mL), and sat. NaCl
(200 mL). The organic extracts were dried over Na2SO4, filtered, and
evaporated, leaving a yellow oil (900 mg) which was purified by flash
chromatography (hexanes/EtOAc 2:1), giving the title compound as a
1
white solid (480 mg, 89% over two steps). mp 97-98 °C. H NMR
(500 MHz, CDCl3): δ 7.52 (broad d, 1H, J ) 6.9 Hz), 7.37-7.26 (m,
15H), 5.94 (dd, 1H, J ) 3.0, 6.8 Hz), 5.42 (dd, 1H, J ) 1.8, 1.8, 8.8
Hz), 5.04 (m, 4H), 4.78-4.77 (m, 2H), 4.69 (d, 1H, J ) 6.5 Hz), 4.58
(d, 1H, J ) 12.4 Hz), 4.55 (d, 1H, J ) 12.4 Hz), 4.55 (dd, 1H, J )
1.8, 2.0 Hz), 4.28 (dddd, 1H, J ) 2.6, 3.0, 6.9, 9.8 Hz), 3.94 (dd, 1H,
J ) 8.8, 9.8 Hz), 2.09 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 168.93,
157.51 (q, J ) 38 Hz), 149.73, 136.49, 135.79 (d, J ) 6.7 Hz), 135.04
(d, J ) 6.2 Hz), 128.77 (1), 128.75 (1), 128.61 (1), 128.54 (1), 128.08
(1), 128.03 (1), 127.94 (1), 127.79 (1), 115.50 (q, J ) 288 Hz), 99.25
(2), 95.29 (2), 94.14 (1, d, J ) 5.9 Hz), 75.20 (1), 70.39 (1), 60.96-
60.85 (2, m, 2C), 52.94 (1, d, J ) 7.9 Hz), 20.64 (3). 31P NMR (121
MHz, CDCl3): δ -2.86 (m). FAB-MS m/z (rel intensity): 702.2 ([M
+ Na]+, 11.3), 176.0 (53.1), 91.0 (100.0). FAB-HRMS calcd for C32H33-
NO10F3NaP [M + Na]+, 702.1692; obsd, 702.1688.
4,6-Di-O-acetyl-5-fluoro-3-O-[(benzyloxy)methyl]-2-deoxy-2-tri-
fluoroacetamido-r-D-glucopyranosyl 1-Dibenzyl Phosphate (30a).
To a solution of 29 (410 mg, 0.622 mmol) in freshly distilled CH2Cl2
(9 mL) was added excess dimethyldioxirane (20 mL in acetone). After
14.5 h, an additional aliquot of dimethyldioxirane (freshly prepared,
3.0 mL in acetone) was added. After 17.5 h total reaction time, the
colorless solution was dried over Na2SO4, filtered, and evaporated,
leaving a white foam/oil (417 mg). 1H NMR (C6D6) confirmed the
presence of diastereomeric epoxides (1.5:1 ratio). The product was
transferred to a Schlenk tube and was placed under vacuum for 30
min. The flask was purged with Ar (3×), and the residue was dissolved
in freshly distilled CH2Cl2 (6.5 mL). The solution was cooled to -78
°C, and HF‚pyridine (150 µL) was added. After 3.5 h, HF‚pyridine
(50 µL) was added. After 4.5 h total reaction time, HF‚pyridine (50
µL) was added. After 17 h, a final aliquot of HF‚pyridine (150 µL)
was added. Since no further reaction was observed, the reaction was
quenched with Et3N until pH ) 7 (2.75 mL). The solution was warmed
to ambient temperature, diluted with CH2Cl2 (40 mL), and extracted
with H2O (40 mL) and sat. NaHCO3 (40 mL). The organic layer was
dried over Na2SO4 and filtered, and the filtrate along with heptane (10
mL) was evaporated, leaving an oil (610 mg). The oil was dissolved
in pyridine (2 mL), and Ac2O (1.5 mL, 21 mmol) was added. After
stirring for 1 h, the solution was partially evaporated and then diluted
with CH2Cl2 (30 mL) and washed with sat. NaHCO3 (3 × 30 mL) and
sat. NaCl (30 mL). The organic layer was dried over MgSO4, filtered,
and evaporated, leaving a green/yellow oil (472 mg). The oil was
purified by flash chromatography (CH2Cl2/MeOH 200:1-100:1), giving
mixed fractions (310 mg). The mixed fractions were further purified
by preparative HPLC (Dynamax normal phase column 40% EtOAc in
hexanes), giving the D-gluco title compound (125 mg, 30%) as a
colorless oil along with the L-ido configured compound (59 mg 19%)
as a colorless oil, as well as the 3-OAc D-gluco compound (11 mg
2.5%) as a colorless oil. Total of the 5-fluoro products: 195 mg, 52%.
Triethylammonium 4,6-Di-O-acetyl-5-fluoro-2-deoxy-2-trifluoro-
acetamido-r-D-glucopyranosyl Phosphate (31). Compound 30a (41
mg, 0.054 mmol) was dissolved in 3:1 CH2Cl2/MeOH (3.0 mL). Pd-
(OH)2/C (15 mg) was added, and the reaction was fitted with a balloon
containing H2. After 4.5 h, Et3N (15.8 µL, 0.114 mmol) was added
and the reaction was filtered through Celite, washing with MeOH. The
filtrate was concentrated in vacuo to give the title compound as a light
1
yellow oil (34 mg, 100%). NMR showed 1.7 equiv Et3N. H NMR
(300 MHz, CD3OD): δ 5.69 (dd, 1H, J ) 2.1, 8.4 Hz), 5.43 (dd, 1H,
J ) 8.0, 22.8 Hz), 4.30-4.24 (m, 2H), 4.19 (dd, 1H, J ) 5.5, 11.7
Hz), 4.01 (dd, 1H, J ) 5.4, 11.7 Hz), 3.12 (q, 12H, J ) 7.2 Hz), 2.11
(s, 3H), 2.06 (s, 3H), 1.28 (t, 18H, J ) 7.2 Hz). 13C NMR (75 MHz,
CD3OD): δ 171.67, 171.60, 159.70 (q, J ) 37 Hz), 111.49 (d, J )
232 Hz), 94.94 (d, J ) 5.2 Hz), 72.93 (d, J ) 24 Hz), 66.10, 63.50 (d,
J ) 41 Hz), 55.81 (d, J ) 6.4 Hz), 47.26, 20.68, 20.55, 9.32. The
sample was too dilute to observe the CF3 carbon. 19F NMR (282 MHz,
CD3OD): δ 0.67 (s), -47.28 (ddd, J ) 5.6, 5.6, 22.6 Hz). 31P NMR
(121 MHz, CD3OD): δ 0.57 (d, J ) 8.2 Hz). FAB-MS m/z (rel
intensity): 456.0 (M-, 96.0), 199.0 (100.0).
Pyridinium 5-Fluoro-2-deoxy-2-acetamido-r-D-glucopyranosyl
Phosphate (32). NH3 was bubbled through a stirred -10 °C solution
of 31 (34 mg, 0.054 mmol) in MeOH. The flask was sealed, and the
reaction was allowed to warm to room temperature. After 1.75 h, the
solvent was evaporated, giving a white powder which was dissolved
in MeOH (2 mL). Acetic anhydride (100 µL, 1.07 mmol) and
triethylamine (38 µL, 0.27 mmol) were added. Additional aliquots of
Ac2O (550 µL total) were added to push the reaction to completion.
After 25 h, the solvent was evaporated. The resulting mixture was
dissolved in MeOH and slowly added to Ac2O (500 µL). After 2 h, the
reaction was evaporated, dissolved in MeOH (4 mL), and treated for
0.5 h with NH3 in a sealed tube. The solvent was evaporated, and the
residue was dissolved in MeOH (4 mL) and treated with DOWEX
50WX8 (H+ form) (100 mg) for 0.5 h. The resin was removed by
filtration, and Et3N (20 µL) was added to the filtrate. The filtrate was
evaporated, leaving a brown oil (51 mg). The oil was dissolved in
MeOH and purified by anion exchange chromatography (BioRad AG
1 × 8 resin, AcO- form) by washing with first H2O (30 mL) and then
0.5 M aqueous pyridine/AcOH, pH ) 4.5 (30 mL). The buffered wash
was collected as one fraction and lyophilized, giving the title compound
1
(a) D-Gluco Isomer, 30a (Major Product). H NMR (300 MHz,
CDCl3): δ 7.37-7.26 (m, 16H), 6.04 (dd, 1H, J ) 3.2, 7.6 Hz), 5.42
(dd, 1H, J ) 9.3, 22.8 Hz), 5.12-4.99 (m, 5H), 4.76 (d, 1H, J ) 6.3
Hz), 4.66 (d, 1H, J ) 6.3 Hz), 4.57 (m, 2H), 4.30-4.17 (m, 2H), 3.92
(dd, 1H, J ) 4.3, 12.0 Hz), 2.07 (s, 3H), 2.06 (s, 3H).13C NMR (126
MHz, CDCl3): δ 169.66, 169.17, 157.63 (q, J ) 38 Hz), 136.40, 135.17
1
as a light brown hygroscopic solid (17 mg, 82% over two steps). H
9
10052 J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002

5-Fluoro GlcNAc Glycosides and Pyrophosphates
A R T I C L E S
NMR (300 MHz, D2O): δ 8.75 (m, 2H), 8.60 (m, 1H), 8.05 (m, 2H),
5.49 (dd, 1H, J ) 3.0, 8.3 Hz), 4.08-3.98 (m, 2H), 3.73-3.63 (m,
3H), 2.01 (s, 3H). 13C NMR (126 MHz, CD3OD): δ 173.98, 145.45,
144.71, 127.68, 114.33 (d, J ) 231 Hz), 95.53 (d, J ) 4.4 Hz), 72.12
(d, J ) 25 Hz), 67.69, 63.18 (d, J ) 36 Hz), 54.86 (d, J ) 5.1 Hz),
22.69. 19F NMR (282 MHz, D2O): δ -54.57 (ddd, J ) 4.5, 7.9, 23.2
Hz). 31P NMR (121 MHz, D2O): δ -1.47 (broad m). FAB-MS m/z
(rel intensity): 318.1 (M-, 100.00), 96.9 (71.93), 78.9 (69.08). A trace
amount of the N-TFA O-deacetylated precursor of 32 was observed as
indicated by a peak at 372.
Pyridinium 5-Fluoro-2-deoxy-2-acetamido-r-D-glucopyranosyl
Uridine 5′-Diphosphate (1). UMP-morpholidate (8.0 mg, 0.012 mmol)
and 32 (3.0 mg, 0.0078 mmol) were dissolved in dry pyridine (1.0
mL). The resulting solution was evaporated under high vacuum, and
the flask was purged with Ar. This was repeated two times, and the
flask was placed under high vacuum for 1.5 h. The resulting foam was
dissolved in dry pyridine (500 µL), and 1H-tetrazole (1.6 mg, 0.024
mmol) was added. The reaction was stirred under an Ar atmosphere
for 4 days. H2O (1.0 mL) was added, and the solution was evaporated.
The resulting oil was dissolved in 50 mM pyridine/AcOH buffer (pH
) 4.5) and was purified via size exclusion chromatography (Biogel
P-2, 1.5 cm × 67 cm), eluting with 50 mM pyridine/AcOH, pH ) 4.5.
Fractions (100 drops) containing the desired product as detected by
TLC (3:1 CH3CN/H2O) were collected and lyophilized, giving the title
compound as a white powder (monopyridinium salt) (2.5 mg, 45%).
1H NMR (500 MHz, D2O): δ 8.63 (m, 1H), 8.35 (m, 0.5H), 7.84-
7.83 (m, 2H), 5.87-5.86 (m, 2H), 5.50 (dd, 1H, J ) 3.4, 8.0 Hz),
4.26-4.25 (m, 2H), 4.16-4.03 (m, 4H), 3.95 (dd, 1H, J ) 9.8, 9.8
Hz), 3.68-3.60 (m, 3H), 1.97 (s, 3H). 19F NMR (282 MHz, D2O): δ
-54.11 (m). 31P NMR (121 MHz, D2O): δ -11.05 (broad m), -12.92
(broad m). FAB-MS m/z (rel intensity): 624.2 ([M]-, 100.0).
Acknowledgment. This research was supported in part by
funds from the Department of Chemistry and the College of
Pharmacy, University of Michigan. M.C.T.H. is the recipient
of a Regents’ Fellowship from the University of Michigan and
a Lilly Fellowship from the Department of Chemistry. We also
thank Przemek Kowal, Jun Shao, and Professor P. G. Wang
(Wayne State University), Dr. Songmin Jiang and Professor C.
J. Waechter (University of Kentucky) for assistance with the
initial biochemical evaluations of 1. We are grateful to Mr.
Kevin Jane (Indiana Wesleyan University, NSF-REU, 1999) for
assistance with the preparation of 2.
Supporting Information Available: 1H spectral data for all
new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA0127234
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J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10053