Concise and efficient synthesis of 2-acetamido-2-deoxy-β-D- hexopyranosides of diverse aminosugars from 2-acetamido-2-deoxy-β-D-glucose

Article abstract of DOI:10.1021/jo801927k

The furanose acetonide derivative 1 is readily prepared from 2-acetamido-2-deoxy-D-glucose on a large scale without the need for chromatography. Mesylation of 1 provides an efficient, concise, synthetic route to rare 2-acetamido-2-deoxy-β-D-hexopyranosides (2 and 3) via the corresponding methyl 2-acetamido-2-deoxy-3-O-methanesulfonyl-β-D- glucopyranoside and subsequent inversion of configuration by direct displacement or formation of a 3,4-epoxide. Opening of this epoxide by azide provided a direct route to methyl 2-acetamido-4-amino-2,4,6-trideoxy-β-D- gulopyranoside 4. Benzylation of 1 followed by ring expansion to the glucopyranoside, deoxygenation at C-6, and subsequent displacement of a C-4 triflate permitted the synthesis of methyl 2-acetamido-4-amino-2,4,6-trideoxy- β-D-galactopyranoside 5. Methyl 2-acetamido-2-deoxy-β-D- glucopyranoside available from 1 in quantitative yield was readily converted to methyl 2-acetamido-2-deoxy-β-D-galactopyranoside 6 (>60%) by inversion of configuration at C-4. Introduction of a lactyl substituent at C-3 of oxazoline 1 also provides a facile synthesis of the biologically important muramic acid β-glycoside 7. An interesting reaction to convert 2-acetamido-2-deoxyhexopyranosides to the corresponding 2-deoxy-2-tetrazole is also reported.

Full text of DOI:10.1021/jo801927k

Concise and Efficient Synthesis of
2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides of Diverse Aminosugars
from 2-Acetamido-2-deoxy-ꢀ-D-glucose
Ye Cai, Chang-Chun Ling,† and David R. Bundle*
Alberta Ingenuity Centre for Carbohydrate Science, Department of Chemistry, UniVersity of Alberta,
Edmonton, AB T6G 2G2 Canada
daVe.bundle@ualberta.ca
ReceiVed September 3, 2008
The furanose acetonide derivative 1 is readily prepared from 2-acetamido-2-deoxy-D-glucose on a large
scale without the need for chromatography. Mesylation of 1 provides an efficient, concise, synthetic
route to rare 2-acetamido-2-deoxy-ꢀ-D-hexopyranosides (2 and 3) via the corresponding methyl
2-acetamido-2-deoxy-3-O-methanesulfonyl-ꢀ-D-glucopyranoside and subsequent inversion of configuration
by direct displacement or formation of a 3,4-epoxide. Opening of this epoxide by azide provided a direct
route to methyl 2-acetamido-4-amino-2,4,6-trideoxy-ꢀ-D-gulopyranoside 4. Benzylation of 1 followed
by ring expansion to the glucopyranoside, deoxygenation at C-6, and subsequent displacement of a C-4
triflate permitted the synthesis of methyl 2-acetamido-4-amino-2,4,6-trideoxy-ꢀ-D-galactopyranoside 5.
Methyl 2-acetamido-2-deoxy-ꢀ-D-glucopyranoside available from 1 in quantitative yield was readily
converted to methyl 2-acetamido-2-deoxy-ꢀ-D-galactopyranoside 6 (>60%) by inversion of configuration
at C-4. Introduction of a lactyl substituent at C-3 of oxazoline 1 also provides a facile synthesis of the
biologically important muramic acid ꢀ-glycoside 7. An interesting reaction to convert 2-acetamido-2-
deoxyhexopyranosides to the corresponding 2-deoxy-2-tetrazole is also reported.
Introduction
mido-2-deoxy-D-gulosamine (D-GulNAc), are also found in
nature. For example, D-AllNAc exists as a component of
allosamidin, a selective and powerful chitinase inhibitor,4 and
D-GulNAc was isolated from the antibiotic streptothricin F and
streptolidin B (Figure 1).5 The L-counterpart of D-GulNAc
constitutes another important nucleoside antibiotic, adenomycin.6
Bacterial glycoconjugates are a source of an even wider number
of aminosugars; two important examples are 2,4-diamino-2,4,6-tri-
deoxyhexoses7-10 and N-acetylmuramic acid (MurNAc).11 2,4-
2-Amino-2-deoxyhexoses are among the most important
modified sugars found in nature.1 2-Acetamido-2-deoxy-D-
glucose (D-GlcNAc) is the most abundant 2-amino-2-deoxy-
hexose found in nature, and together with 2-acetamido-2-deoxy-
D-galactose (D-GalNAc), both constitute essential building
blocks of bioactive oligosaccharides and glycoconjugates that
include glycoproteins, glycopeptides, glycolipids, peptidoglycan,
and glycosaminoglycans.1,2 Other rare aminosugars3 such as
2-acetamido-2-deoxy-D-allosamine (D-AllNAc) and 2-aceta-
(3) Whistler, R. L.; Wolffom, M. L. Methods in Carbohydrate Chemistry II;
Academic Press: New York, 1962; pp 206-257.
(4) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. Tetrahedron Lett. 1986,
27, 2475–2478. Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. J. Antibiot.
1987, 40, 296.
(5) Van Tamelen, E. E.; Dyer, J. R.; Carter, H. E.; Pierce, J. V.; Daniels,
E. E. J. Am. Chem. Soc. 1956, 78, 4817–4818. Jackson, M. D.; Gould, S. J.;
Zabriskie, T. M. J. Org. Chem. 2002, 67, 2934–2941.
† Department of Chemistry, University of Calgary, Calgary AB T2N 1N4,
Canada.
(1) Wittmann, V. In Glycoscience: Chemistry and Chemical Biology; Fraser-
Reid, B., Tatsuta, K. Thiem J., Eds.; Springer-Verlag: Heidelberg, 2001; Vol.
III, pp 2253-2287. Taylor, M. E.; Drickamer, K. Introduction to Glycobiology,
1st ed.; Oxford University Press: Oxford, 2003.
(2) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167–1195.
Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. ReV. 2000, 100, 4495–
4537.
(6) Ogita, T.; Otake, N.; Miyazaki, Y.; Yonehara, H.; Macfarlane, R. D.;
McNeal, C. J. Tetrahedron Lett. 1980, 21, 3203–3206.
(7) Zehavi, U.; Sharon, N. J. Biol. Chem. 1973, 248, 433–438.
580 J. Org. Chem. 2009, 74, 580–589
10.1021/jo801927k CCC: $40.75 2009 American Chemical Society
Published on Web 12/08/2008

Synthesis of 2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides
FIGURE 1. Some naturally occurring 2-amino-2-deoxyhexoses.
FIGURE 2. Amino sugars readily prepared from 1.
Diamino-2,4,6-trideoxyhexoses are frequently found in bacterial
polysaccharides. For instance, 2,4-diamino-2,4,6-trideoxy-D-
glucose (bacillosamine) has been isolated from Bacillus subtilis
polysaccharide7 and from the N-linked glycoprotein of Campy-
lobacter jejuni.8 2,4-Diamino-2,4,6-trideoxy-D-galactose is a
constituent of the capsular polysaccharides of Streptococcus
pneuoniae9 and Shigella sonnei,9 while 2,4-diamino-2,4,6-
trideoxy-D-gulose occurs as a component of the O-antigen of
Pseudomonas aeruginosa.10 Muramic acid (MurNAc) is uni-
versally present in bacterial peptidoglycans as the repeating
disaccharide element ꢀ-D-GlcNAc-(1f4)-ꢀ-D-MurNAc (Figure
1)11 and is an important component of Freund’s complete
adjuvant.12,13 A facile synthesis of a muramic acid glycoside
would provide a convenient route to muramylpeptides. N-
Acetylmuramyl-L-alanyl-D-isoglutamine is one of the smallest
immunoadjuvants capable of replacing whole mycobacteria of
Freund’s adjuvant. Recently, UDP-MurNAc was found to be a
potent inhibitor for MurA enzyme, which plays an important
role in the biosynthesis of bacterial peptidoglycan, an important
target for developing new antibiotics to fight microbial
resistance.14,15
Despite their broad existence in nature, most of the 2-amino-
2-deoxyhexoses are not commercially available. The only
exception is D-GlcNAc, which is inexpensive and can be
purchased in large quantities. The commercial sources of
D-GalNAc are limited and expensive. Conversion of D-GlcNAc
to other 2-amino-2-dexoyhexoses is thus an attractive and
economically viable strategy. However, most of the reported
routesrequireeithertedioustransformationorharshconditions.16-18
The development of concise syntheses of unusual aminosugars
is therefore of practical interest. Here, we extend our recent
report19 of a facile and efficient two-step synthesis of 2-aceta-
mido-2-deoxy-ꢀ-D-glucopyranosides from commercial D-Glc-
NAc via the 5,6-O-isopropylidene furanose derivative 1 to the
synthesis of the aminosugars (2-7) (Figure 2).
Results and Discussion
Oxazoline 1 was prepared from D-GlcNAc20 in one step and
(8) Young, M. N.; Brisson, J.-R.; Kelly, J.; Watson, D. C.; Tessier, L.;
Lanthier, H. P.; Jarrel, H. C.; Cadotte, N.; Michael, F. S.; Aberg, E.; Szymanski,
C. M. J. Bio. Chem. 2002, 277, 42530–42539.
(9) Jennings, H. J.; Lugowski, C.; Young, N. M. Biochemistry 1980, 19,
4712–4719. Kenne, L.; Lindberg, B.; Petersson, K.; Katzenellenbogen, E.;
Romanowska, E. Carbohydr. Res. 1980, 46, 381–385.
in 30 g quantities without the need for chromatography. In our
(10) Knirel, Y. A.; Vinogradov, E. V.; Shashkov, A. S.; Dmitriev, B. A.;
Kochetkov, N. K.; Stanislavsky, E. S.; Mashilova, G. M. Eur. J. Biochem. 1987,
163, 627–637.
(11) Rogers, H. J.; Perkins, H. R.; Ward, J. B. Biosynthesis of Peptidoglycan;
Chapman and Hall: London, 1980.
(12) Lefrancier, P.; Lederer, E. Pure Appl. Chem. 1987, 3, 449–454.
(13) Goldsby, R. A.; Kindt, T. J.; Osborne, B. A. Immunology, 4th ed.; W. H.
Freeman and Company: New York, 2000; pp 66-67.
(14) Bugg, T. D. H.; Walsh, C. T. Nat. Prod. Rep. 1992, 199–215.
Kohlrausch, U.; Holtje, J.-V. FEMS Microbiol. Lett. 1991, 78, 253, and references
cited therein.
(15) Hitchcock, S. A.; Eid, C. N.; Aikins, J. A.; Zia-Ebrahimi, M.; Blaszczak,
L. C. J. Am. Chem. Soc. 1998, 120, 1916–1917. Chu, D. T. W.; Plattner, J. J.;
Katz, L. J. Med. Chem. 1996, 39, 3853. Mizyed, S.; Oddone, A.; Byczynski,
B.; Hughes, D. W.; Berti, P. J. Biochemistry 2005, 44, 4011–4017. Schwartz,
B.; Markwalder, J. A.; Wang, Y. J. Am. Chem. Soc. 2001, 123, 11638–11643.
J. Org. Chem. Vol. 74, No. 2, 2009 581

Cai et al.
SCHEME 1. Synthesis of Methyl 2-Acetamido-2-deoxy-ꢀ-D-allo- and ꢀ-D-gulopyranosides 2 and 3
previous report, we discovered that furanose 1 can be cleanly
and conveniently converted to the corresponding ꢀ-pyranoside
in quantitative yield on a 20 g scale by reacting 1 with an alcohol
solution under sulfonic acid catalysis.19 Here, we take advantage
of the presence of a single hydroxyl group at C-3 of oxazoline
1 by introducing a protecting group at C-3 prior to the acid-
catalyzed furanose to pyranose ring expansion. We anticipated
that the introduction of groups at C-3 would not interfere with
the rearrangement to give conveniently derivatized ꢀ-pyrano-
sides in high stereoselectivity and in high yield. Manipulation
of methanesulfonyl, benzyl, and lactyl derivatives of 1 provide
access to the ꢀ-glycosides 2-6 and the muramic acid glycoside
7.
group leading to a protonated oxazoline which could be
deprotonated by acetate anion followed by subsequent hydrolysis
of the intermediate oxazoline to afford the target compound 2
(Figure 3).
When mesylate 9 was treated with 2 M NaOMe in methanol
at room temperature, the 3,4-epoxide 10 was obtained in almost
quantitative yield on a 10 g scale (Scheme 2). The 3,4-epoxide
10 underwent acid-catalyzed diaxial ring opening with Amberlite
IR-120 (H+) to the gulopyranoside 3 in 64% yield. The gulo-
1
configuration was confirmed by the characteristic H NMR
coupling constants J2,3 (3.2 Hz), J4,5 (1.4 Hz), and J3,4 (3.5 Hz).
Scheme 1 shows the routes to the ꢀ-pyranosides of D-AllNAc
2 and D-GulNAc 3. Mesylation of oxazoline 1 was carried out
on a 17 g scale and preceded smoothly in almost quantitative
yield as judged by TLC. Purification of crude mesylate 8 was
unnecessary, and subsequent treatment of 8 with methanol in
the presence of 0.1 equiv of p-toluenesulfonic acid afforded the
desired ꢀ-pyranoside 9 in 70% yield over two steps. Mesylate
9 was readily converted to the target methyl 2-acetamido-2-
deoxy-ꢀ-D-allopyranoside 2 in 89% yield under reflux in a
mixture of 2-methoxyethanol, sodium acetate, and saturated
sodium bicarbonate solution.21 The allo-configuration of 2 was
unambiguously established by 1H NMR and the diagnostic J2,3
(2.8 Hz) and J3,4 (2.9 Hz) coupling constants.
FIGURE 3. Intramolecular displacement of 9 by treatment with
NaOAc.
SCHEME 2. Synthesis of Methyl
2-Acetamido-4-amino-2,4,6-trideoxy-ꢀ-D-gulopyranoside 4
from Epoxide 10
The probable mechanism for the inversion of configuration
at C-3 involves the participation by the neighboring acetamido
(16) For examples of the synthesis of D-galactosamine, D-allosamine, and
D-gulosamine derivatives, see: McGeary, R. P.; Wright, K.; Toth, I. J. Org. Chem.
2001, 66, 5102–5105. Ja¨ger, V.; Schro¨ter, D. Synthesis 1990, 556–560. Suami,
T.; Tadano, K.; Iimura, Y.; Tanabe, H. Carbohydr. Res. 1985, 135, 319–323.
Rochepeau-Jobron, L.; Jacquinet, J. C. Carbohydr. Res. 1998, 305, 181–191.
(17) For examples of the synthesis of 2,4-diamino-2,4,6-trideoxy-D-hexopy-
ranosides, see: Medgyes, A.; Farkas, E.; Liptak, A.; Pozsgay, V. Tetrahedron
1997, 12, 4159–4178. Hermans, J. P. G.; Eie, C. J. J.; Vander Marel, G. A.; van
Boon, J. H. J. Carbohydr. Chem. 1987, 6, 451–462. Banaszek, A.; Pakulski, Z.;
Zamojski, A. Carbohydr. Res. 1995, 279, 173–182. Banaszek, A.; Janisz, B.
Tetrahedron: Asymmetry 2000, 11, 4693–4700. Bundle, D. R.; Josephson, S.
Can. J. Chem. 1980, 58, 2679–2685.
(18) For the synthesis of N-acetylmuramic acid derivatives, see: Kubash, N.;
Schmidt, R. R. Eur. J. Org. Chem. 2002, 2710–2726. Hesek, D.; Suvorov, M.;
Morio, K.; Lee, M.; Brown, S.; Vakulenko, S. B.; Mobashery, S. J. Org. Chem.
2004, 69, 778–784. Ueda, T.; Feng, F.; Sadamoto, R.; Niikura, K.; Monde, K.;
Nishimura, S. I. Org. Lett. 2004, 11, 1753–1756.
Adaptation of the ring expansion of 3-O-substituted deriva-
tives of 1 provides an attractive route to methyl 2-acetamido-
4-amino-2,4,6-trideoxy-ꢀ-hexopyranosides 4 and 5. Previously,
syntheses of the corresponding R-glycoside17 and a L-sugar
analogue17 have been achieved. Our improved synthesis of 3,4-
epoxide 10 allowed us to synthesize the ꢀ-glycoside 4 in an
efficient manner, and benzylation of 1 provided a convenient
route to 5. As shown in Scheme 2, treatment of epoxide 10
with NaN3 in the presence of NH4Cl in dry DMF at 90 °C
followed by acetylation gave the target 11 as the major
(19) Cai, Y.; Ling, C.-C.; Bundle, D. R. Org. Lett. 2005, 7, 4021–4024.
(20) Mack, H.; Basabe, J. V.; Brossmer, R. Carbohydr. Res. 1988, 175, 311–
316.
(21) Whistler, R. L.; Wolfrom, M. L. Methods Carbohydr. Chem. 1972, 6,
266–267.
582 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of 2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides
compound (77% yield). Acetylation was necessary in order to
obtain the desired D-gulo-isomer in pure form by removing an
unidentified minor compound, presumably the D-gluco-isomer.
With pure 11 in hand, deacetylation and selective 6-mesylation
gave 12 in 79% yield. Reduction of mesylate of 12 with NaBH4
in DMSO was unsuccessful even at elevated temperature.
NaBH4/NiCl2 in EtOH22 only reduced the azido group to afford
the amino compound 13 in 77% yield. Simultaneous reduction
of the azido and mesylate groups was finally achieved using
the same reagent at 50-60 °C, providing the target compound
4 in 74% yield. The D-gulo configuration of 4 was confirmed
by three small J2,3, J3,4, and J4,5 coupling constants (3.2 Hz, 3.2
Hz, 1.8 Hz).
The formation of the tetrazole functionality (Figure 4)
presumably arose from an excess of triflic anhydride (2 equiv),
which activates the acetamido group to form a triflate imidate
intermediate. This subsequently reacts with excess NaN3 not
only inverting the C-4 position but also converting the activated
imidate to the tetrazole ring. This finding could be used as a
general methodology to synthesize 2-deoxy-2-tetrazole deriva-
tives from 2-acetamido-2-deoxyglycosides. Subsequent hydro-
genation of 18 gave compound 19 in 91% yield without affecting
the 2-tetrazole moiety.
SCHEME 3. Synthesis of 6-Deoxy Derivative 19 from
Oxazoline 1
FIGURE 4. Synthesis of tetrazole-containing derivative 18 via a
proposed triflate imidate.
To avoid the activation of the acetamido group (Scheme 4),
compound 17 was treated with triflic anhydride (1.1 equiv). The
desired product 20 was then obtained in 66% yield. Hydrogena-
tion of 20 over palladium hydroxide afforded the target
compound 5 in excellent yield (93%). Our seven-step route to
5 starting from D-GlcNAc compares favorably with the previ-
ously published 17-step synthesis of 5.17
SCHEME 4. Synthesis of Target Compound 5 from 17
The synthesis of methyl 2-acetamido-4-amino-2,4,6-trideoxy-
ꢀ-D-galactopyranoside 5 was accomplished via the 3-benzylated
oxazoline 14 (Schemes 3 and 4). p-Toluenesulfonic acid
catalyzed methanolysis yielded the desired 3-O-benzyl-ꢀ-D-
glucopyranoside 15 in 70% yield. Selective 6-mesylation gave
compound 16 in 88% yield, and the 6-mesylate was smoothly
reduced by NaBH4 in dry DMSO at elevated temperature to
furnish compound 17 in 83% yield. Compound 17 was
converted to the corresponding triflate using conditions similar
to those employed by Imperialli et al.23 Treatment of alcohol
17 with 2 equiv of triflic anhydride in pyridine at 0 °C afforded
an intermediate which was immediately reacted with NaN3 in
DMF. To our surprise, although we successfully inverted the
configuration at the C-4 position with an azido group, compound
18 also contained a tetrazole functionality at C-2 and was
isolated in 88% yield. The same outcome was observed even
when the temperature was lowered to -30 °C during the
triflation step. The presence of a tetrazole moiety in 18 was
unambiguously confirmed by high resolution mass spectrometry
(HRMS) and elemental analysis. NMR experiments were also
The ease of large-scale synthesis of methyl 2-acetamido-2-
deoxy-ꢀ-D-glucopyranoside 21 in near-quantitative yield from
119 renders its conversion to methyl 2-acetamido-2-deoxy-ꢀ-
D-galactopyranoside 6 an attractive prospect for the facile
synthesis of this otherwise expensive compound (Scheme 5).
Selective pivaloylation16 gave the 3,6-diester 22 in 94% yield
followed by activation at O-4 by triflate and subsequent in situ
displacement of the triflate yielded 23. The reaction mechanism
might follow an intramolecular attack of the intermediate
4-triflate by the 3-O-pivaloyl group to form a cyclic orthoester
which subsequently undergoes hydrolysis to give the 4,6-di-O-
pivalolated 23. Transesterification furnished the desired galac-
topyranoside 6 in 68% overall yield from 22.
SCHEME 5. Synthesis of Methyl
2-Acetamido-2-deoxy-ꢀ-D-galactopyranoside 6
1
consistent with the proposed structure. The H NMR revealed
the absence of a N-H signal, while the 13C NMR spectrum
had a signal at 154.2 ppm correlating with that of a typical
tetrazole carbon (150-160 ppm).24
(22) For examples of NaBH4/NiCl2 reduction, see: Thiem, J.; Meyer, B.
Chem. Ber. 1980, 113, 3067. Paulsen, H.; Schnell, D. Chem. Ber. 1981, 114,
333–345. Weigel, T. M.; Liu, H.-W. Tetrahedron Lett. 1988, 34, 4221–4224.
(23) Weerapana, E.; Glover, K. J.; Chen, M. M.; Imperiali, B. J. Am. Chem.
Soc. 2005, 127, 13766–13767.
(24) Lehnhoff, S.; Ugi, I. Heterocycles 1995, 2, 801–808. Thomas, E. W.
Synthesis 1993, 767–768.
The biological significance of muramic acid prompted us to
apply our methodology to the synthesis of muramic glycosides.18
J. Org. Chem. Vol. 74, No. 2, 2009 583

Cai et al.
The use of oxazoline 1 to synthesize muramic acid has been
reported by Brossmer’s group25 by reacting oxazoline 1 with
(S)-2-chloropropionic acid; the obtained 3-O-lactyl furanose was
not isolated but subjected to an acid-catalyzed hydrolysis to give
a mixture of anomeric hemiacetals; the reported yield was 73%
for two steps. In order to prepare the glycosides of muramic
acid, 4,6-O-protected N-acetyl-D-glucosamine glycosides were
usually prepared via multiple steps prior to the introduction of
a lactate moiety at C-3. We describe here an extension of
Brossmer’s methodology that achieves the synthesis of ꢀ-gly-
cosides of muramic acid in just two steps from furanosyl
oxazoline 1 (three steps from commercial D-GlcNAc, Scheme
6). Oxazoline 1 was reacted with (S)-2-bromopropionic acid in
the presence of NaH in dry DMF, and crude intermediate 24
was then directly subjected to acid-catalyzed methanolysis using
p-toluenesulfonic acid to furnish the ꢀ-glycoside of muramic
acid 25 in 67% overall yield; the carboxylic acid was simulta-
neously esterified. Hydrolysis of methyl ester 25 using 1.0 M
lithium hydroxide gave MurNAc methyl ꢀ-glycopyranoside 7
in almost quantitative yield. No racemization was observed. It
is noteworthy that we successfully scaled the synthesis to
approximately 3 g.
yield (82%). We decided to re-examine direct glycosylation
using a glycosyl halide donor such as the bromide 2727 (Scheme
7). Glycosylation of 26 with 27 was performed using AgOTf
as a promoter, but unfortunately, a complicated mixture was
obtained most likely due to intramolecular lactonization.26
However, when we carried out the reaction at -60 °C, we found
that the side reactions could be effectively suppressed and the
desired disaccharide 28 was obtained in satisfactory yield (70%).
No lactonized product was isolated. The presence of the ꢀ-(1f4)
linkage in 28 was established by two large anomeric coupling
constants (J1,2 ) 7.8 Hz, J1′,2′ ) 8.4 Hz). This glycosylation
was successfully scaled to 1 g. Disaccharide 28 was subse-
quently treated with dilute hydrazine in EtOH at 35 °C to cleave
the phthalimido group26,28 without affecting the methyl ester
group of the lactate; this could be explained by the unusual
crowding of the methyl ester of the lactate in the molecule
making the nucleophilic attack by hydrazine less accessible.
However, TLC has indeed revealed some partial de-O-acety-
lations. After reacetylations with excess acetic anhydride and
pyridine, the desired compound 29 was isolated in 87% yield
over two steps. The methyl ester of 29 was finally selectively
removed by treatment of 29 with lithium iodide in dry pyridine
at 100 °C to provide the target disaccharide 30 in 85% yield.
Compound 30 could be used directly in the synthesis of bacterial
cell wall peptidoglycan by coupling with suitably protected
peptides (not reported here).
SCHEME 6. Synthesis of Methyl Β-Glycoside of MurNAc 7
In summary, the acid-catalyzed alcoholysis of the furanose
acetonide 1 of D-GlcNAc is an efficient method to synthesize
the ꢀ-pyranosides of a variety of amino sugar derivatives. By
introducing leaving groups or protecting groups at the O-3
position of 1, we have successfully and efficiently synthesized
several biological important amino sugars in large quantities.
The success in applying this methodology to muramic acid
chemistry should provide abundant opportunities to expand and
apply the method for preparation of challenging carbohydrate
targets related to bacterial cell wall research.
Experimental Section
Large-scale synthesis of 7 prompted us to synthesize the
biologically active N-acetyl-ꢀ-D-glycopyranosyl-(1f4)-N-acetyl-
ꢀ-D-muramic acid (NAG-NAM) disaccharide repeating unit of
bacterial cell wall peptidoglycans.26 The synthesis of the NAG-
NAM disaccharide is challenging due to problems associated
with MurNAc chemistry.26 The presence of a lactic acid residue
at O-3 not only introduces steric crowding but also complicates
the chemistry through the potential for lactone formation with
the 4-hydroxyl group. Literature methods to form the ꢀ-(1f4)
glycosydic linkage have employed several kinds of donors
including oxazoline,26 glycosyl halides,26 and glycosyl imidate18,26
and with nitrogen protecting groups such as phthalimido,26
Troc,26 and dimethylmaleoyl (DMM).18,26 In order to minimize
intramolecular lactonization, the lactate residue has to be
orthogonally protected by groups such as phenylsufonylethyl26
or by an alanine residue.15 Thus, MurNAc acceptor 25 was first
selectively protected with 1.1 equiv of pivaloyl chloride in
pyridine at 0 °C to afford the desired acceptor 26 in excellent
2-Methyl-(3-O-methanesulfonyl-1,2-dideoxy-5,6-O-isopropylidene-
r-D-glucofurano)-[2,1-d]-2-oxazoline (8). Mesyl chloride (12 mL,
140 mmol) was added to a solution of oxazoline 119,20 (17 g, 70
mmol) and Et3N (25 mL) in anhydrous dichloromethane (240 mL)
at 0 °C. The mixture was stirred at 0 °C for 2 h and quenched with
water. The resulting mixture was extracted several times with
dichloromethane. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The solvent was evaporated
to afford a yellow oily residue that was used directly in the next
glycosylation step without chromatography. A small amount (258
mg) of the mixture was purified by silica gel chromatography (1:1
toluene-EtOAc) to give the desired product 8 as a white amorphous
solid (196 mg): Rf ) 0.49 (1:3 toluene-EtOAc); [R]D +49.6 (c
1
0.73, CHCl3); H NMR (500 MHz, CDCl3) δ 6.18 (d, 1H, J1,2
5.0 Hz, H-1), 5.10 (d, 1H, J3,4 ) 2.9 Hz, H-3), 4.80 (dd, 1H, J2,3
)
)
1.6 Hz, H-2), 4.25 (ddd, 1H, J5,6a ) 6.0 Hz, J5,6b ) 4.2 Hz, H-5),
4.15 (dd, 1H, J6a,6b ) 9.0 Hz, H-6a), 4.03 (dd, 1H, H-6b), 3.85
(dd, 1H, J4,5 ) 8.5 Hz, H-4), 3.11 (s, 3H, SCH3), 2.08 (s, 3H, N )
CCH3), 1.42, 1.32 (2 × s, 2 × 3H, C(CH3)2); 13C NMR (125 MHz,
CDCl3) δ 109.7, 106.9, 82.4, 80.4, 72.1, 67.3, 38.0, 26.9, 25.1,
14.1; ESI HRMS m/z calcd for C12H20NO7S (M + H+) 322.0955,
found 322.0956. Anal. Calcd for C12H19NO7S: C, 44.85; H, 5.96;
N, 4.36. Found: C, 45.24; H, 5.96; N, 4.60.
(25) Merten, H.; Brossmer, R. Carbohydr. Res. 1989, 191, 144–149.
(26) For examples of previous synthesis of NAG-NAM disaccharide, see:
Kiso, M.; Kaneda, Y.; Shimizu, R.; Hasegawa, A. Carbohydr. Res. 1980, 83,
C8-C11. Kantoci, D.; Keglevic, D. Carbohydr. Res. 1987, 162, 227–235. Saha,
S. L.; VanNieuwenhze, M. S.; Hornback, W. J.; Aikins, J. A.; Blaszczak, L. C.
Org. Lett. 2001, 22, 3575–3577. Frakas, J.; Ledvina, M.; Brokes, J.; Jezek, J.;
Zajick, J.; Zaoral, M. Carbohydr. Res. 1987, 163, 63–72. Hesek, D.; Lee, M.;
Morio, K.; Mobashery, S. J. Org. Chem. 2004, 69, 2137–2146.
(27) Lemieux, R. U.; Takeda, T.; Chung, B. Y. A. C. S. Symp. Ser. 1976,
39, 90–113.
(28) Bundle, D. R.; Josephson, S. Can. J. Chem. 1979, 57, 662–668.
584 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of 2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides
SCHEME 7. Synthesis of a Peptidoglycan Disaccharide Unit 30 from 25
Methyl 2-Acetamido-2-deoxy-3-O-methanesulfonyl-ꢀ-D-glucopy-
ranoside (9). The above crude 8 (22 g, 68.5 mmol) was dissolved
in dry methanol (250 mL), and p-TsOH (1.42 g, 7.5 mmol) was
added. The mixture was stirred at room temperature for 18 h and
quenched by adding the Amberlite IRA-400 basic resin (OH-) to
pH 7. After filtration, the solvent was evaporated, and the residue
was purified by silica gel chromatography (15:1 CH2Cl2-CH3OH)
to afford the desired product 9 as a pale yellow oil (15.3 g, 48.8
mmol, 70% over two steps): Rf ) 0.26 (10:1 CH2Cl2-CH3OH);
[R]D -78.9 (c 0.92, CH3OH); 1H NMR (500 MHz, CD3OD) δ 4.57
(dd, 1H, J3,4 ) 9.1 Hz, H-3), 4.47 (d, 1H, J1,2 ) 8.4 Hz, H-1), 3.88
(dd, 1H, J6a,6b ) 12.0 Hz, H-6a), 3.77 (dd, 1H, J2,3 ) 10.3 Hz,
H-2), 3.72 (dd, 1H, H-6b), 3.57 (dd, 1H, J4,5 ) 9.6 Hz, H-4), 3.47
(s, 3H, SCH3), 3.35 (ddd, 1H, J5,6b ) 5.4 Hz, J5,6a ) 2.6 Hz, H-5),
3.11 (s, 3H, OCH3), 1.95 (s, 3H, NHCOCH3); 13C NMR (125 MHz,
CD3OD) δ 173.7, 102.8, 85.7, 77.6, 69.9, 62.3, 75.2, 55.7, 39.1,
23.0; ESI HRMS m/z calcd for C10H19NO8SNa (M + Na+)
336.0723, found 336.0721. Anal. Calcd for C10H19NO8S: C, 38.33;
H, 6.11; N, 4.47. Found: C, 37.97; H, 6.43; N, 4.14.
Methyl 2-Acetamido-2-deoxy-ꢀ-D-allopyranoside (2). Compound
9 (15.1 g, 48.2 mmol) was dissolved in a mixture of 2-methoxy-
ethanol and satd NaHCO3 (250 mL, 9:1, v/v), and NaOAc (20 g,
244 mmol) was added. The mixture was refluxed for 18 h. After
concentration and filtration, the filtrate was concentrated and applied
to a silica gel column (15% CH3OH-CH2Cl2) to afford the desired
product 2 as a white solid (10.1 g, 43.0 mmol, 89%): mp 156-158
°C; Rf ) 0.40 (5:1 CH2Cl2-CH3OH); [R]D -99.7 (c 0.77, CH3OH);
1H NMR (500 MHz, CD3OD) δ 4.59 (d, 1H, J1,2 ) 8.6 Hz, H-1),
3.96 (dd, 1H, J3,4 ) 2.9 Hz, H-3), 3.85 (dd, 1H, J6a,6b ) 11.5 Hz,
H-6a), 3.76 (dd, 1H, J2,3 ) 2.8 Hz, H-2), 3.72 (ddd, 1H, J5,6b ) 5.6
0.93, CH3OH); 1H NMR (600 MHz, CD3OD) δ 4.31 (d, 1H, J1,2
)
7.8 Hz, H-1), 4.13 (dd, 1H, J2,3 ) 2.0 Hz, H-2), 3.92 (dd, 1H, J3,4
) J4,5 ) 5.4 Hz, H-4), 3.78 (dd, 1H, J6a,6b ) 11.5 Hz, J5,6a ) 5.1
Hz, H-6a), 3.75 (dd, 1H, J5,6b ) 5.6 Hz, H-6b), 3.38-3.42 (m, 2H,
H-3 and H-5), 3.39 (s, 3H, OCH3), 1.98 (s, 3H, NHCOCH3); 13C
NMR (125 MHz, CD3OD) δ 173.5, 100.8, 76.2, 63.5, 57.0, 56.7,
56.0, 51.2, 22.5; ESI HRMS m/z calcd for C9H15NO5Na (M + Na+)
240.0842, found 240.0842. Anal. Calcd for C9H15NO5: C, 49.76;
H, 6.96; N, 6.45. Found: C, 49.65; H, 7.01; N, 6.26.
Methyl 2-Acetamido-2-deoxy-ꢀ-D-gulopyranoside (3). Crude ep-
oxide 10 (4 g, 18 mmol) was dissolved in a mixture of acetone
and water (200 mL, 1:1, v/v), and Amberlite IR-120 resin (H+)
(35 g) was added. The mixture was stirred at room temperature
until all of the starting material was consumed or stirred at 70 °C
for 3 h. After filtration, the filtrate was concentrated and chromato-
graphed on silica gel using 10% MeOH in CH2Cl2 as eluent to
yield the target compound 3 as a white amorphous solid (2.7 g,
11.5 mmol, 64%): Rf ) 0.25 (5:1 CH2Cl2-CH3OH); [R]D -108.3
(c 0.66, CH3OH); 1H NMR (600 MHz, CD3OD) δ 4.57 (d, 1H, J1,2
) 8.8 Hz, H-1), 4.10 (dd, 1H, J2,3 ) 3.2 Hz, H-2), 3.92 (ddd, 1H,
J5,6a ) 6.7 Hz, J5,6b ) 5.3 Hz, H-5), 3.88 (dd, 1H, J3,4 ) 3.5 Hz,
H-3), 3.75 (dd, 1H, J6a,6b ) 11.4 Hz, H-6a), 3.71 (dd, 1H, H-6b),
3.63 (dd, 1H, J4,5 ) 1.4 Hz, H-4), 3.45 (s, 3H, OCH3), 1.96 (s, 3H,
NHCOCH3); 13C NMR (125 MHz, CD3OD) δ 173.2, 101.8, 75.1,
71.9, 70.6, 62.8, 56.7, 49.5, 22.8; ESI HRMS m/z calcd for
C9H17NO6Na (M + Na+) 258.0948, found 258.0950. Anal. Calcd
for C9H17NO6: C, 45.95; H, 7.28; N, 5.95. Found: C, 45.55; H,
7.53; N, 5.62.
Methyl 2-Acetamido-3,6-di-O-acetyl-4-azido-2,4-dideoxy-ꢀ-D-gu-
lopyranoside (11). Epoxide 10 (1.09 g, 5 mmol) was dissolved in
dry DMF, and NaN3 (1 g, 15.4 mmol) and NH4Cl (1 g, 18.7 mmol)
were added. The resulting mixture was stirred at 90 °C for 18 h.
The solvent was removed under high vacuum, and the residue was
extracted with methanol; the solid residue was removed by filtration.
The filtrates were combined and evaporated under reduced pressure
to afford a colorless oil. Anhydrous pyridine (50 mL) and acetic
anhydride (5 mL) were added at 0 °C, and the mixture was stirred
at room temperature for 18 h. After concentration, the resulting
mixture was separated by silica gel chromatography using a gradient
eluent of toluene and ethyl acetate (1:1 to 1:2) to provide the pure
compound11(1.32g,3.8mmol,77%):Rf )0.27(1:6toluene-EtOAc);
Hz, J5,6a ) 2.2 Hz, H-5), 3.67 (dd, 1H, H-6b), 3.52 (dd, 1H, J4,5
)
9.6 Hz, H-4), 3.45 (s, 3H, OCH3), 1.97 (s, 3H, NHCOCH3); 13C
NMR (125 MHz, CD3OD) δ 173.0, 101.2, 75.6, 71.4, 68.7, 63.2,
56.9, 54.8, 22.7; ESI HRMS m/z calcd for C9H17NO6Na (M + Na+)
258.0948, found 258.0950. Anal. Calcd for C9H17NO6: C, 45.95;
H, 7.28; N, 5.95. Found: C, 45.72; H, 7.35; N, 5.81.
Methyl 2-Acetamido-3,4-anhydro-2-deoxy-ꢀ-D-allopyranoside
(10). Compound 9 (11.5 g, 3.7 mmol) was dissolved in dry methanol
(90 mL), and a solution of 2 M sodium methoxide in methanol (30
mL) was added. The mixture was stirred at room temperature for
18 h, and a white precipitate was formed. The reaction was
quenched with Amberlite IR-120 resin (H+) to adjust the pH to 7.
The solution was concentrated to afford a crude product as a solid
in quantitative yield. The product could be used directly in the next
step. A small amount of crude product (764 mg) was further purified
by silica gel chromatography using 5% MeOH in CH2Cl2 as eluent
to give the desired product 10 (738 mg) as a white solid: mp
171-173 °C; Rf ) 0.38 (10:1 CH2Cl2-CH3OH); [R]D -183.5 (c
1
[R]D -84.9 (c 0.94, CHCl3); H NMR (500 MHz, CDCl3) δ 5.64
(d, 1H, JNH,H-2 ) 8.2 Hz, NH), 5.33 (dd, 1H, J3,4 ) 3.6 Hz, H-3),
4.54 (d, 1H, J1,2 ) 8.4 Hz, H-1), 4.38 (ddd, 1H, J2,3 ) 3.3 Hz,
H-2), 4.34 (dd, 1H, J6a,6b ) 11.5 Hz, H-6a), 4.20 (dd, 1H, H-6b),
4.06 (ddd, 1H, J5,6a ) J5,6b ) 6.6 Hz, H-5), 3.74 (dd, 1H, J4,5 ) 2.0
Hz, H-4), 3.47 (s, 3H, OCH3), 2.16 (s, 3H, COCH3), 2.10 (s, 3H,
COCH3), 2.01 (s, 3H, NHCOCH3); 13C NMR (125 MHz, CDCl3)
J. Org. Chem. Vol. 74, No. 2, 2009 585

Cai et al.
δ 170.5, 169.7, 169.3, 100.0, 70.9, 70.2, 62.7, 58.4, 55.9, 47.9,
23.3, 20.9, 20.8; ESI HRMS m/z calcd for C13H20N4O7Na (M +
Na+) 367.1224, found 367.1223. Anal. Calcd for C13H20N4O7: C,
45.35; H, 5.85; N, 16.27. Found: C, 44.93; H, 5.86; N, 16.47.
Methyl 2-Acetamido-4-azido-2,4-dideoxy-6-O-methanesulfonyl-
ꢀ-D-gulopyranoside (12). Compound 11 (0.99 g, 2.6 mmol) was
dissolved in anhydrous methanol (50 mL), and a solution of 2 M
sodium methoxide in methanol (0.5 mL) was added. The mixture
was stirred at room temperature for 18 h and quenched with
Amberlite IR-120 resin (H+). After filtration, the organic mixture
was concentrated to give a solid residue. The residue was
redissolved in anhydrous pyridine (15 mL), and the mixture was
cooled to -20 °C; mesyl chloride (0.2 mL, 2.6 mmol) was added,
and the mixture was stirred at -20 °C for 18 h. After concentration,
the residue was purified by silica gel chromatography using 5%
MeOH in CH2Cl2 as eluent to yield the desired product 12 as a
white amorphous solid (695 mg, 2.05 mmol, 79%): Rf ) 0.43 (10:1
was extracted several times with dichloromethane. The combined
extracts were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was dissolved in dichloromethane
and passed through a short silica gel pad. Further purification by
silica gel chromatography (1:1 hexane-ethyl acetate containing 1%
Et3N) afforded compound 14 as a pale yellow oil (5.56 g, 17.1
mmol, 68%): Rf ) 0.47 (1:3 hexane-EtOAc); [R]D -27.6 (c 0.92,
CHCl3) [lit.25 [R]D -36 (c 1.2, CHCl3)]; 1H NMR (600 MHz,
CDCl3) δ 7.34-7.38 (m, 4H, ArH), 7.28-7.32 (m, 1H, ArH), 6.13
(d, 1H, J1,2 ) 5.1 Hz, H-1), 4.73 (d, 1H, J ) 11.8 Hz, PhCH2),
4.66 (d, 1H, J ) 11.8 Hz, PhCH2), 4.53 (dd, 1H, J2,3 ) 1.2 Hz,
H-2), 4.38 (dd, 1H, J5,6a ) J5,6b ) 5.9 Hz, H-5), 4.10 (dd, 1H, J6a,6b
) 8.6 Hz, H-6a), 4.20 (dd, 1H, H-6b), 4.11 (d, 1H, J3,4 ) 3.2 Hz,
H-3), 3.85 (dd, 1H, J4,5 ) 7.1 Hz, H-4), 2.02 (s, 3H, N-CCH3),
1.42, 1.37 (2 × s, 2 × 3H, C(CH3)2); 13C NMR (125 MHz, CDCl3)
δ 167.0, 137.6, 128.4, 127.8, 127.8, 127.8, 127.8, 127.7, 109.0,
107.1, 81.6, 75.4, 72.6, 72.2, 67.0, 26.7, 25.3, 14.2; ESI HRMS
m/z calcd for C18H24NO5Na (M + Na+) 334.1649, found 334.1646.
Methyl 2-Acetamido-3-O-benzyl-2-deoxy-ꢀ-D-glucopyranoside
(15). Compound 14 (5.48 g, 16.4 mmol) was dissolved in dry
methanol (150 mL), and camphor-10-sulfonic acid (1.04 g, 4.5
mmol) was added. The mixture was stirred at room temperature
for 36 h. The acid was removed by adding Amberlite IRA-400
resin (OH-). After filtration, the filtrate was concentrated and the
residue was purified by silica gel chromatography using 5% MeOH
in CH2Cl2 as eluent to afford the desired compound 15 as a white
amorphous solid (3.73 g, 11.5 mmol, 70%): Rf ) 0.29 (10:1
1
CH2Cl2-CH3OH); [R]D -123 (c 0.88, CH3OH); H NMR (600
MHz, CD3OD) δ 4.63 (d, 1H, J1,2 ) 8.7 Hz, H-1), 4.34-4.38 (m,
2H, H-6a and H-6b), 4.30 (d, 1H, J5,6a ) J
) 6.3 Hz, H-5),
5,6b
4.11 (dd, 1H, J3,4 ) 3.3 Hz, H-3), 4.02 (dd, 1H, J2,3 ) 3.1 Hz,
H-2), 3.70 (dd, 1H, J4,5 ) 1.8 Hz, H-4), 3.44 (s, 3H, SCH3), 3.12
(s, 3H, OCH3), 1.97 (s, 3H, NHCOCH3); 13C NMR (125 MHz,
CD3OD) δ 173.2, 101.5, 71.2, 70.0, 69.4, 62.9, 56.9, 51.3, 37.3,
22.7; ESI HRMS m/z calcd for C10H18N4O7SNa (M + Na+)
361.0788, found 361.0788. Anal. Calcd for C10H18N4O7S: C, 35.50;
H, 5.36; N, 16.56. Found: C, 35.15; H, 5.27; N, 16.00.
1
CH2Cl2-CH3OH); [R]D -26.6 (c 0.74, CH3OH); H NMR (500
Methyl 2-Acetamido-4-amino-2,4-dideoxy-6-O-methanesulfonyl-
ꢀ-D-gulopyranoside (13). To a solution of compound 12 (20 mg,
0.06 mmol) in ethanol (5 mL) was successively added NaBH4 (15
mg, 0.4 mmol) and a solution of 0.16 M NiCl2 in EtOH (0.2 mL).
The mixture was stirred at room temperature for 18 h and quenched
with acetic acid (1 mL). The mixture was concentrated and purified
by silica gel chromatography (100:10:1 CH2Cl2-CH3OH-NH4OH)
to provide the compound 13 as a colorless oil (14.5 mg, 0.046
mmol, 77%): Rf ) 0.30 (5:1 CH2Cl2-CH3OH); [R]D -72.8 (c 0.28,
MHz, CD3OD) δ 7.20-7.32 (m, 5H, ArH), 4.86 (d, 1H, J ) 11.4
Hz, PhCH2), 4.64 (d, 1H, J ) 11.4 Hz, PhCH2), 4.34 (d, 1H, J1,2
) 8.4 Hz, H-1), 3.89 (dd, 1H, J6a,6b ) 11.9 Hz, H-6a), 3.74 (dd,
1H, J2,3 ) 9.8 Hz, H-2), 3.70 (dd, 1H, H-6b), 3.47-3.52 (m, 2H,
H-4 and H-3), 3.28 (dd, 1H, J5,6b ) 6.0 Hz, J5,6a ) 2.4 Hz, H-5),
3.45 (s, 3H, OCH3), 1.86 (s, 3H, NHCOCH3); 13C NMR (125 MHz,
CD3OD) δ 173.3, 140.3, 129.2, 128.8, 128.5, 103.5, 84.2, 78.0,
75.6, 72.1, 62.7, 57.0, 56.2, 23.0; ESI HRMS m/z calcd for
C16H23NO6Na (M + Na+) 348.1417, found 348.1411. Anal. Calcd
for C16H23NO6: C, 59.06; H, 7.13; N, 4.31. Found: C, 58.85; H,
7.14; N, 4.36.
Methyl 2-Acetamido-3-O-benzyl-2-deoxy-6-O-methanesulfonyl-
ꢀ-D-glucopyranoside (16). Compound 15 (1.2 g, 3.7 mmol) was
dissolved in dry pyridine (30 mL), and the solution was cooled to
-15 °C. Mesyl chloride (1.05 equiv, 0.31 mL, 4 mmol) was added
dropwise, and the mixture was stirred for 4 h until all starting
material was consumed. Methanol (1 mL) was added to quench
the reaction. The solvent was evaporated under reduced pressure,
and the resulting residue was purified by silica gel chromatography
using 2.5% MeOH in CH2Cl2 as eluent to afford the desired
compound 16 as a white amorphous solid (1.32 g, 3.27 mmol, 88%):
Rf ) 0.53 (10:1 CH2Cl2-CH3OH); [R]D +1.8 (c 2.09, CH3OH);
1H NMR (500 MHz, CD3OD) δ 7.22-7.34 (m, 5H, ArH), 4.87 (d,
1H, J ) 11.4 Hz, PhCH2), 4.65 (d, 1H, J ) 11.4 Hz, PhCH2), 4.55
(dd, 1H, J6a,6b ) 11.2 Hz, H-6a), 4.41 (dd, 1H, J6b,5 ) 5.0 Hz,
H-6b), 4.39 (d, 1H, J1,2 ) 8.4 Hz, H-1), 3.73 (dd, 1H, J2,3 ) 8.7
Hz, H-2), 3.48-3.55 (m, 3H, H-3, H-4 and H-5), 3.44 (s, 3H,
SCH3), 3.11 (s, 3H, OCH3), 1.86 (s, 3H, NHCOCH3); 13C NMR
(125 MHz, CD3OD) δ 173.4, 140.1, 129.3, 128.8, 128.6, 103.4,
83.8, 75.8, 75.3, 71.5, 70.4, 57.1, 56.1, 37.5, 23.0; ESI HRMS m/z
calcd for C17H25NO8SNa (M + Na+) 426.1193, found 426.1196.
Anal. Calcd for C17H25NO8S: C, 50.61; H, 6.25; N, 3.47. Found:
C, 50.60; H, 6.22; N, 3.54.
1
CH3OH); H NMR (500 MHz, CD3OD) δ 4.57 (d, 1H, J1,2 ) 8.7
Hz, H-1), 4.40 (dd, 1H, J6a,6b ) 11.1 Hz, H-6a), 4.34 (dd, 1H, H-6b),
4.25 (ddd, 1H, J5,6a ) 7.9 Hz, J5,6b ) 4.1 Hz, H-5), 4.02 (dd, 1H,
J2,3 ) 3.1 Hz, H-2), 3.84 (dd, 1H, J3,4 ) 3.3 Hz, H-3), 3.43 (s, 3H,
SCH3), 3.11 (s, 3H, OCH3), 2.87 (dd, 1H, J4,5 ) 1.8 Hz, H-4),
1.97 (s, 3H, NHCOCH3); 13C NMR (125 MHz, CD3OD) δ 173.1,
102.2, 72.9, 72.4, 71.2, 56.9, 54.0, 50.9, 37.3, 22.7; ESI HRMS
m/z calcd for C10H20N2O7SNa (M + Na+) 335.0889, found
335.0885.
Methyl 2-Acetamido-4-amino-2,4,6-trideoxy-ꢀ-D-gulopyranoside
(4). To a solution of compound 12 (110 mg, 0.32 mmol) in ethanol
(10 mL) were added NaBH4 (100 mg, 2.64 mmol) and 0.16 M
NiCl2 in ethanol (0.2 mL). The mixture was then stirred at 50-60
°C for 18 h and quenched by acetic acid (1 mL). The mixture was
concentrated and purified by silica gel chromatography (100:10:1
CH2Cl2-CH3OH-NH4OH) to afford the desired product 4 as a
colorless oil (52 mg, 0.24 mmol, 74%): Rf ) 0.17 (5:1 CH2Cl2/
CH3OH); [R]D -93.8 (c 0.88, CH3OH); 1H NMR (600 MHz, D2O)
δ 4.72 (d, 1H, J1,2 ) 8.8 Hz, H-1), 4.39 (qd, J5,6 ) 6.6 Hz, H-5),
4.22 (dd, 1H, J3,4 ) 3.3 Hz, H-3), 3.87 (dd, 1H, J2,3 ) 3.2 Hz,
H-2), 3.51 (s, 3H, OCH3), 3.40 (dd, 1H, J4,5 ) 1.8 Hz, H-4), 1.96
(s, 3H, NHCOCH3), 1.30 (d, 3H, H-6 CH3); 13C NMR (125 MHz,
CD3OD) δ 173.1, 102.1, 72.9, 69.6, 56.7, 56.6, 50.9, 22.7, 16.7;
ESI HRMS m/z calcd for C9H18N2O4Na (M + Na+) 241.1159, found
241.1156.
2-Methyl-(3-O-benzyl-1,2-dideoxy-5,6-O-isopropylidene-r-D-glu-
cofurano)-[2,1-d]-2-oxazoline (14). Oxazoline 1 (6 g, 24.7 mmol)
was dissolved in dry DMF (150 mL), and sodium hydride (60%
dispersion of in mineral oil, 5 g) was added. After the mixture was
stirred for 30 min at room temperature, benzyl bromide (5 mL)
was added dropwise at 0 °C. The mixture was stirred for 18 h at
room temperature. The reaction was quenched with methanol (30
mL) and concentrated. Water (100 mL) was added, and the mixture
Methyl 2-Acetamido-3-O-benzyl-2,6-dideoxy-ꢀ-D-glucopyrano-
side (17). Compound 16 (1.1 g, 2.7 mmol) was dissolved in dry
DMSO (20 mL), and NaBH4 (1.0 g, 26.4 mmol) was added. The
mixture was heated at 85-90 °C for 18 h. The reaction was
quenched by adding a 5% acetic acid solution (2 mL) at 0 °C until
it became a clear solution. Next, the solution was diluted with more
H2O and extracted several times with ethyl acetate. The combined
extracts were evaporated under reduced pressure to yield a residue,
586 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of 2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides
which was chromatographed on silica gel using toluene/ethyl acetate
(1:2) as eluent providing the title compound 17 as a white
amorphous solid (0.69 g, 2.23 mmol, 83%): Rf ) 0.28 (1:10
hexane-EtOAc); [R]D -9.6 (c 0.75, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.30-7.40 (m, 5H, ArH), 5.60 (d, 1H, JNH,H-2 ) 7.3 Hz,
NH), 4.76 (d, 1H, J1,2 ) 8.1 Hz, H-1), 4.75 (d, 1H, J ) 12.4 Hz,
filtered, and concentrated under reduced pressure (<20 °C) to afford
an oil. This residue was redissolved in dry DMF (5 mL), and NaN3
(325 mg, 5 mmol) was added. After being stirred at room
temperature for 18 h, the mixture was concentrated. The residue
was dissolved in dichloromethane, washed with water and brine,
and dried over anhydrous Na2SO4. After filtration, the solvent was
removed. The residue was purified by silica gel chromatography
(1:1 toluene-ethyl acetate) to yield compound 20 as a white
amorphous solid (213 mg, 0.64 mmol, 66%): Rf ) 0.20 (1:2
toluene-EtOAc); [R]D +44.5 (c 0.53, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.30-7.40 (m, 5H, ArH), 5.68 (d, 1H, JNH,H-2 ) 7.8 Hz,
NH), 4.91 (d, 1H, J1,2 ) 8.4 Hz, H-1), 4.70 (d, 1H, J ) 11.4 Hz,
PhCH2), 4.62 (dd, 1H, J3,4 ) 3.6 Hz, H-3), 4.56 (d, 1H, J ) 11.4
PhCH2), 4.70 (d, 1H, J ) 11.7 Hz, PhCH2), 3.99 (dd, 1H, J3,4
)
8.8 Hz, H-3), 3.48 (s, 3H, OCH3), 3.42 (qd, 1H, J5,6 ) 6.2 Hz,
H-5), 3.30 (ddd, 1H, J2,3 ) 10.3 Hz, H-2), 3.27 (dd, 1H, J4,5 ) 9.1
Hz, H-4), 1.96 (s, 3H, NHCOCH3), 1.33 (d, 3H, J ) 6.3 Hz, H-6
CH3); 13C NMR (125 MHz, CDCl3) δ 170.6, 138.3, 128.7, 128.1,
128.0, 128.0, 100.5, 80.7, 76.1, 74.1, 71.4, 57.7, 56.7, 23.7, 17.7;
ESI HRMS m/z calcd for C16H23NO5Na (M + Na+) 332.1468, found
332.1465. Anal. Calcd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53.
Found: C, 61.98; H, 7.20; N, 4.50.
Hz, PhCH2), 3.72 (dd, 1H, J4,5 ) 0.9 Hz, H-4), 3.68 (t, 1H, J5,6
)
6.5 Hz, H-5), 3.20 (ddd, 1H, J2,3 ) 10.6 Hz, H-2), 3.47 (s, 3H,
OCH3), 1.94 (s, 3H, NHCOCH3), 1.33 (d, 3H, H-6 CH3); 13C NMR
(125 MHz, CDCl3) δ 171.0, 137.5, 128.6, 128.2, 128.2, 99.9, 76.4,
72.6, 68.8, 63.4, 56.7, 55.5, 23.8, 17.6; ESI HRMS m/z calcd for
C16H22N4O4Na (M + Na+) 357.1533, found 357.1534. A satisfac-
tory elemental analyses could not be obtained.
Methyl 4-Azido-3-O-benzyl-2,4,6-trideoxy-2-(1H-5-methyltetra-
zol-1-yl)-ꢀ-D-galactopyranoside (18). To a solution of compound
17 (430 mg, 1.4 mmol) in anhydrous dichloromethane (30 mL)
and pyridine (3 mL) was added dropwise trifluoromethanesulfonic
anhydride (0.48 mL, 2.8 mmol) at -10 °C under argon. The mixture
was stirred at -10 °C for 3 h. Dichloromethane (20 mL) was added,
and the mixture was washed successively with 1 M HCl, satd
NaHCO3, and water. The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure (<20
°C bath) to afford a yellow oil. This residue was redissolved in
dry DMF (5 mL)d and NaN3 (450 mg, 7 mmol) was added. The
mixture was stirred for 18 h at room temperature. After concentra-
tion, the residue was dissolved in dichloromethane, washed with
water and brine, and dried over anhydrous Na2SO4. After filtration,
the solvent was removed, and the crude residue was purified by
silica gel chromatography (10:1 toluene-ethyl acetate) to afford
18 as a white solid (438 mg, 1.22 mmol, 87%): mp 104-105 °C;
Methyl 2-Acetamido-4-amino-2,4,6-trideoxy-ꢀ-D-galactopyra-
noside (5). Compound 20 (150 mg, 0.45 mmol) was dissolved in
anhydrous methanol (5 mL), and 20% palladium hydroxide on
carbon (100 mg) was added. The mixture was stirred under a
hydrogen atmosphere for 18 h at room temperature. After filtration,
the solution was concentrated under reduced pressure followed by
silica gel chromatography using dichloromethane/methanol/am-
monium hydroxide (100:10:1) as eluent to afford the target
compound 5 as a white amorphous solid (91 mg, 0.42 mmol, 93%):
Rf ) 0.33 (100:20:1 CH2Cl2-CH3OH-NH4OH); [R]D -10.8 (c
0.91, CH3OH) [lit.17 [R]D -8.7 (c 1.0, CH3OH)]; H NMR (600
1
MHz, D2O) δ 4.43 (d, 1H, J1,2 ) 8.7 Hz, H-1), 4.02-4.07 (m, 2H,
J ) 10.7 Hz, J ) 4.5 Hz, H-3 and H-5), 3.75 (dd, 1H, J2,3 ) 10.9
Hz, H-2), 3.59 (d, 1H, J ) 4.6 Hz, H-4), 3.50 (s, 3H, OCH3), 2.04
(s, 3H, NHCOCH3), 1.34 (d, 3H, J6,5 ) 6.7 Hz, H-6 CH3); 13C
NMR (125 MHz, D2O) δ 176.0, 103.3, 68.8, 68.5, 58.3, 55.7, 52.9,
23.1, 16.5; ESI HRMS m/z calcd for C9H19N2O4 (M + H+)
219.1339, found 219.1336.
1
Rf ) 0.37 (4:1 toluene-EtOAc); [R]D -1.8 (c 1.13, CHCl3); H
NMR (600 MHz, CDCl3) δ 7.28-7.32 (m, 3H, ArH), 7.20-7.25
(m, 2H, ArH), 4.70 (d, 1H, J1,2 ) 8.1 Hz, H-1), 4.45 (d, 1H, J )
11.4 Hz, PhCH2), 4.39 (dd, 1H, J3,4 ) 3.5 Hz, H-3), 4.33 (d, 1H,
J ) 11.2 Hz, PhCH2), 3.78 (qd, 1H, J5,6 ) 6.3 Hz, H-5), 3.76 (dd,
1H, J4,5 ) 1.3 Hz, H-4), 3.34 (s, 3H, OCH3), 2.54 (s, 3H, tetrazole
CH3), 1.41 (d, 3H, H-6 CH3); 13C NMR (125 MHz, CDCl3) δ 154.2,
136.1, 128.7, 128.5, 128.1, 101.6, 78.6, 72.8, 69.4, 62.5, 59.5, 57.2,
17.5, 8.9; ESI HRMS m/z calcd for C16H21N7O3Na (M + Na+)
382.1598, found 382.1598. Anal. Calcd for C16H21N7O3: C, 53.47;
H, 5.89; N, 27.28. Found: C, 53.38; H, 5.81; N, 26.89.
Methyl 2-Acetamido-2-deoxy-3,6-di-O-pivoyl-ꢀ-D-glucopyrano-
side (22). Pivaloyl chloride (13.6 mL, 112 mmol) was added
dropwise to a solution of methyl 2-acetamido-2-deoxy-ꢀ-D-glu-
copyranoside 2119 (9.4 g, 40 mmol) in a mixture of anhydrous
CH2Cl2 (70 mL) and pyridine (170 mL) at 0 °C. The mixture was
stirred at 0 °C for 3 h (after 30 min the solution became cloudy).
CH2Cl2 (300 mL) was added, and the mixture was washed with
satd NaHCO3, water, and brine and dried over anhydrous Na2SO4.
After concentration, the residue was purified by silica gel chroma-
tography (50% AcOEt-hexane) to afford 22 as a white foam (15.2
g, 37.7 mmol, 94%): Rf ) 0.20 (1:1 hexane-EtOAc); [R]D -45.2
(c 0.69, CHCl3); 1H NMR (600 MHz, CDCl3) δ 5.65 (d, 1H, JNH,2
) 9.3 Hz, NH), 5.04 (dd, 1H, J3,4 ) 8.5 Hz, H-3), 4.42 (dd, 1H,
J6a,6b ) 12.1 Hz, H-6a), 4.40 (d, 1H, J1,2 ) 8.2 Hz, H-1), 4.37 (dd,
1H, H-6b), 3.98 (ddd, 1H, J2,3 ) 10.6 Hz, H-2), 3.55 (ddd, 1H,
Methyl 4-Amino-2,4,6-trideoxy-2-(1H-5-methyltetrazol-1-yl)-ꢀ-
D-galactopyranoside (19). To a solution of compound 18 (68 mg,
0.19 mmol) in dry methanol (2 mL) and acetic acid (0.2 mL) was
added 10% palladium on carbon (100 mg). The mixture was stirred
under a hydrogen atmosphere for 18 h at room temperature. After
filtration, the mixture was concentrated, and the crude residue was
purified by silica gel chromatography using 5% methanol in
dichloromethane as eluent to afford 19 as a white solid (42 mg,
0.17 mmol, 91%): mp 202-204 °C; Rf ) 0.39 (5:1 CH2Cl2-
CH3OH); [R]D +12.8 (c 0.69, CH3OH); 1H NMR (400 MHz,
CD3OD): δ 4.78 (d, 1H J1,2 ) 8.1 Hz, H-1), 4.30-3.36 (m, 2H, J
) 10.6 Hz, 8.8 Hz, 2.8 Hz, H-3 and H-2), 3.94 (qt, 1H, J5,6 ) 6.5
J5,6a ) J5,6b ) 2.4 Hz, H-5), 3.51 (ddd, 1H, J4,5 ) 9.7 Hz, J4,OH
)
5.1 Hz, H-4), 3.47 (s, 3H, OCH3), 3.01 (d, 1H, OH at C-4), 1.94
(s, 3H, NHCOCH3), 1.24 (s, 9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3);
13C NMR (125 MHz, CDCl3): δ 179.8, 179.2, 170.0, 102.0, 74.9,
74.3, 69.4, 63.1, 56.4, 53.7, 39.0, 39.0, 27.2, 27.0, 23.3; ESI HRMS
m/z Calcd for C19H33NO8Na (M + Na+) 426.2098, found 426.2102.
Methyl 2-Acetamido-2-deoxy-ꢀ-D-galactopyranoside (6). Trif-
luoromethanesulfonic anhydride (2.9 mL, 17 mmol) was added
dropwise to a solution of compound 22 (6 g, 14.9 mmol) in
anhydrous CH2Cl2 (75 mL) and pyridine (7 mL) at -15 °C under
an atmosphere of argon. The mixture was stirred for several hours
at this temperature until all starting material was consumed
(monitored by TLC) before warming to room temperature. Water
(6 mL) was added, and the resulting mixture was refluxed for 5-6
h. Then the mixture was diluted with dichloromethane (100 mL),
washed with satd NaHCO3, water, and brine, and dried over
Hz, H-5), 3.34 (s, 3H, OCH3), 3.02 (dd, 1H, J4,3 ) 3.4 Hz, J4,5
)
1.7 Hz, H-4), 2.57 (s, 3H, tetrazole CH3), 1.36 (d, 3H, H-6 CH3);
13C NMR (125 MHz, CD3OD) δ 155.8 (tet-C), 103.2(C-1), 71.9,
71.4, 61.9, 57.2, 56.2, 17.1, 8.7 (CH3-CN); ESI HRMS m/z calcd
for C9H18N5O3 (M + H+) 244.1404, found 244.1404.
Methyl 2-Acetamido-4-azido-3-O-benzyl-2,4,6-trideoxy-ꢀ-D-ga-
lactopyranoside (20). Compound 17 (300 mg, 0.97 mmol) was
dissolved in anhydrous dichloromethane (10 mL) and pyridine (1
mL) under argon. After the solution was cooled -30 °C, trifluo-
romethanesulfonic anhydride (0.19 mL, 1.1 mmol) was added
dropwise over approximately 1 min. The mixture was stirred at
-30 °C for 3 h. The reaction was diluted with dichloromethane
(20 mL) and washed successively with 1 M HCl, satd NaHCO3,
and water. The organic layer was dried over anhydrous Na2SO4,
J. Org. Chem. Vol. 74, No. 2, 2009 587

Cai et al.
anhydrous Na2SO4. After filtration, the filtrate was concentrated.
The residue was redissolved in anhydrous methanol (80 mL), a
solution of 2 M sodium methoxide in methanol (5 mL) was added,
and the mixture was stirred at room temperature for 18 h. After a
deionizeation with Amberlite IR-120 resin (H+), the mixture was
filtered and the organic solution was concentrated. The residue was
purified by silica gel chromatography (10% methanol in dichlo-
romethane) to provide the target compound 6 as a white amorphous
solid (3.13 g, 13.3 mmol, 89%): Rf ) 0.19 (5:1 CH2Cl2-CH3OH);
[R]D -10.8 (c 0.63, CH3OH); 1H NMR (600 MHz, CD3OD) δ 4.28
(d, 1H, J1,2 ) 8.5 Hz, H-1), 3.90 (dd, 1H, J2,3 ) 10.8 Hz, H-2),
3.82 (dd, 1H, J4,5 ) 0.6 Hz, H-4), 3.77 (dd, 1H, J6a,6b ) 11.4 Hz,
H-6a), 3.73 (dd, 1H, H-6b), 3.56 (dd, 1H, J3,4 ) 3.3 Hz, H-3), 3.48
(ddd, 1H, J5,6a ) 6.7 Hz, J5,6b ) 5.4 Hz, H-5), 1.97 (s, 3H,
NHCOCH3); 13C NMR (125 MHz, CD3OD) δ 174.2, 103.9, 76.7,
73.5, 69.7, 62.5, 56.9, 54.2, 23.0; ESI HRMS m/z calcd for
C9H17NO6Na (M + Na+) 258.0948, found 258.0946. Anal. Calcd
for C9H17NO6: C, 45.95; H, 7.28; N, 5.95. Found: C, 45.59; H,
7.25; N, 5.93.
Methyl 2-Acetamido-2-deoxy-4,6-di-O-pivoyl-ꢀ-D-galactopyra-
noside (23). Compound 23 was prepared from 22 following the
above procedure for compound 6 without carrying out the trans-
esterification. A small amount of crude 23 was purified as a white
solid by silica gel chromatography using 3% CH2Cl2 in MeOH as
eluent: mp 80-81 °C; Rf ) 0.22 (1:1 hexane-EtOAc); [R]D -23.4
(c 1.07, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.84 (bs, 1H, NH),
5.30 (d, 1H, J4,5 ) 3.7 Hz, H-4), 4.42 (d, 1H, J1,2 ) 8.2 Hz, H-1),
4.17 (dd, 1H, J6a,6b ) 11.3 Hz, J6a,5 ) 7.3 Hz, H-6a), 4.09 (dd, 1H,
J6b,5 ) 6.1 Hz, H-6b), 3.99 (dd, 1H, J3,4 ) 3.5 Hz, H-3), 3.89 (dd,
1H, J2,3 ) 10.4 Hz, H-2), 3.69 (m, 1H, H-5), 3.51 (s, 3H, OCH3),
2.06 (s, 3H, NHCOCH3), 1.26 (s, 9H, C(CH3)3), 1.19 (s, 9H,
C(CH3)3); 13C NMR (125 MHz, CDCl3) δ 178.0, 177.8, 173.1,
101.2, 72.0, 72.0, 72.0, 71.4, 68.4, 61.86, 55.7, 55.7, 39.2, 38.7,
27.2, 27.0, 23.4; ESI HRMS m/z calcd for C19H33NO8Na (M +
Na+) 426.2098, found 426.2095.
MHz, CD3OD) δ 4.52 (q, 1H, J ) 6.8 Hz, -CH(CO2CH3,CH3)),
4.32 (d, 1H, J1,2 ) 8.5 Hz, H-1), 3.85 (dd, 1H, J6a,6b ) 11.9 Hz,
H-6a), 3.71 (s, 3H, CO2CH3), 3.66 (dd, 1H, H-6b), 3.59 (dd, 1H,
J2,3 ) 10 Hz, H-2), 3.44 (dd, 1H, J3,4 ) 8.7 Hz, H-3), 3.44 (s, 3H,
OCH3), 3.40 (dd, 1H, J4,5 ) 8.7 Hz, H-4), 3.23 (ddd, 1H, J5,6b
)
5.8 Hz, J5,6a ) 2.3 Hz, H-5), 1.97 (s, 3H, NHCOCH3), 1.35 (d, 3H,
J ) 6.8 Hz, CH3CHCO2CH3)); 13C NMR (125 MHz, CD3OD) δ
175.7, 173.7, 103.5, 83.3, 77.9, 77.0, 72.5, 62.6, 57.0, 56.1, 52.4,
23.2, 19.4; HRMS m/z calcd for C13H23NO8Na (M + Na+)
344.1315, found 344.1313. Anal. Calcd for C13H23NO8: C, 48.59;
H, 7.21; N, 4.36. Found: C, 48.66; H, 7.22; N, 4.31.
Methyl 2-Acetamido-3-O-[(R)-1-carboxyethyl]-2-deoxy-ꢀ-D-glu-
copyranoside (7). To a solution of compound 25 (0.94 g, 2.9 mmol)
in a mixture of dioxane and methanol (60 mL, 1:1, v/v) was added
dropwise an aqueous solution of 1 M lithium hydroxide until the
solution reached pH 10. The mixture was then stirred at room
temperature for 10 h over which period the pH of the mixture was
kept in the range 9.5-10.5 by adding more 1 M LiOH solution as
needed. The mixture was neutralized with Amberlite IR-120 resin
(H+). After filtration, the solvent was removed, and the resulting
residue was applied to a C18 reversed-phase column and eluted
with a gradient of water-methanol (0 f 10%) to afford the desired
compound 7 (0.89 g, 2.9 mmol, 99%): [R]D -8.8 (c 1.3, CH3OH);
1H NMR (600 MHz, D2O) δ 4.42 (d, 1H, J1,2 ) 8.5 Hz, H-1), 4.31
(q, 1H, J ) 6.9 Hz, CH3CHCO2H), 3.92 (dd, 1H, J6a,6b ) 12.4 Hz,
H-6a), 3.74 (dd, 1H, H-6b), 3.70 (dd, 1H, J2,3 ) 10 Hz, H-2), 3.53
(dd, 1H, J3,4 ) 8.6 Hz, H-3), 3.49 (dd, 1H, J4,5 ) 8.6 Hz, H-4),
3.48 (s, 3H, OCH3), 3.45 (ddd, 1H, J5,6b ) 5.7 Hz, J5,6a ) 2.2 Hz,
H-5), 2.0 (s, 3H, NHCOCH3), 1.37 (d, 3H, J ) 6.9 Hz,
CH3CHCO2H); 13C NMR (125 MHz, D2O) δ 179.4, 175.4, 102.9,
83.0, 78.3, 76.5, 70.4, 61.6, 58.0, 55.4, 23.2, 19.5; ESI HRMS m/z
calcd for C12H21NO8Na (M + Na+) 330.1159, found 330.1157.
Methyl 2-Acetamido-2-deoxy-3-O-[(R)-1-(methoxycarbonyl)ethyl]-
6-O-pivaloyl-ꢀ-D-glucopyranoside (26). To a solution of compound
25 (0.44 g, 1.36 mmol) in a mixture of anhydrous dichloromethane
(3 mL) and pyridine (4.5 mL) was added dropwise pivaloyl chloride
(0.17 mL, 1.37 mmol) at 0 °C. The mixture was stirred at 0 °C for
3 h. The mixture was diluted with dichloromethane, washed with
satd NaHCO3, water, and brine, and dried over anhydrous Na2SO4.
After filtration, the solvent was removed, and the residue was
chromatographed using 2.5% MeOH in CH2Cl2 to afford the desired
compound 26 as a white amorphous solid (455 mg, 1.12 mmol,
82%): Rf ) 0.55 (20:1 CH2Cl2-CH3OH); [R]D -20.8 (c 1.14,
2-Methyl-(1,2-dideoxy-5,6-O-isopropylidene-3-O-[(R)-1-carboxy-
ethyl]-r-D-glucofurano)-[2,1-d]-2-oxazoline (24). To a solution of
oxazoline 1 (1.2 g, 5 mmol) in anhydrous DMF (50 mL) was added
a 60% dispersion of NaH in mineral oil (4 g, 0.1 mol) that was
previously washed with hexane. The mixture was stirred at 60 °C
for 20-30 min. A solution of (S)-2-bromoproponic acid (1.35 mL,
15 mmol) in dry DMF (5 mL) was added, and then the mixture
was warmed to 60 °C with stirring for 5 h. After removal of solvent,
the residue was dissolved in a minimum amount of methanol,
filtered through a short pad of silica gel, and eluted with 20% MeOH
in CH2Cl2 containing 1% NH4OH. The filtrate was concentrated
under reduced pressure to give a crude residue that was used in
the next step without further purification. A small amount of the
residue (223 mg) was purified by chromatography on silica gel using
dichloromethane/methanol/NH4OH (100:10:1) as eluent to afford
compound 24 (109 mg): Rf ) 0.22 (100:5:0.5 dichloromethane-
1
CHCl3); H NMR (600 MHz, CDCl3) δ 6.5 (d, 1H, JNH,H-2 ) 7.1
Hz, NH), 4.64 (q, 1H, J ) 7.0 Hz, CH3CHCO2CH3)), 4.56 (dd,
1H, J6a,6b ) 12.1 Hz, H-6a), 4.43 (d, 1H, J1,2 ) 8.0 Hz, H-1), 4.22
(dd, 1H, H-6b), 3.74 (s, 3H, COOCH3), 3.62 (dd, 1H, J3,4 ) 8.2
Hz, H-3), 3.57(dd, 1H, J2,3 ) 10.5 Hz, H-2), 3.48 (s, 3H, OCH3),
3.39 (ddd, 1H, J5,6a ) 4.0 Hz, J5,6b ) 2.4 Hz, H-5), 3.35 (dd, 1H,
J4,5 ) 9.6 Hz, H-4), 2.03 (s, 3H, NHCOCH3), 1.39 (d, 3H, J ) 7.0
Hz, CH3CHCO2CH3), 1.22 (s, 9H, C(CH3)3); 13C NMR (125 MHz,
CDCl3) δ 179.9, 175.4, 171.6, 102.6, 79.7, 74.4, 74.3, 71.4, 63.2,
56.6, 54.9, 52.1, 39.0, 27.2, 23.6, 19.1; HRMS m/z calcd for
C18H31NO9Na (M + Na+) 428.1891, found 428.1893. Anal. Calcd
for C18H31NO9: C, 53.32; H, 7.71; N, 3.45. Found: C, 53.00; H,
7.55; N, 3.44.
1
methanol-NH4OH); H NMR (600 MHz, CDCl3) δ 6.15 (d, 1H,
J1,2 ) 5.2 Hz, H-1), 4.84 (dd, 1H, J2,3 ) 1.0 Hz, H-2), 4.28 (ddd,
1H, J5,6a ) 6.3 Hz, J5,6b ) 5.9 Hz, H-5), 4.14 (q, 1H, J ) 6.8 Hz,
-CH(CO2H, CH3)), 4.10 (dd, 1H, J6a,6b ) 8.6 Hz, H-6a), 4.02 (d,
1H, J3,4 ) 3.1 Hz, H-3), 3.95 (dd, 1H, H-6b), 3.71 (dd, 1H, J4,5
)
7.9 Hz, H-4), 1.98 (s, 3H, NdCCH3), 1.38 (s, 3H, -C(CH3)2), 1.37
(d, 3H, J ) 6.8 Hz, CH3CHCO2H)), 1.33 (s, 3H, -C(CH3)2).
Methyl 2-Acetamido-2-deoxy-3-O-[(R)-1-(methoxycarbonyl)ethyl]-
ꢀ-D-glucopyranoside (25). Crude residue 24 was dissolved in
anhydrous methanol (80 mL), and p-TsOH (0.95 g, 5 mmol) was
added to adjust the solution to the pH range of 2-3. The mixture
was stirred at room temperature overnight. Amberlite IRA-400 resin
(OH-) was added to the solution to quench the reaction. After
filtration, the solvent was removed, and the resulting residue was
purified by silica gel chromatography using 8% methanol in
dichloromethane as eluent to afford the desired product 25 as a
white solid (1.08 g, 3.36 mmol, 67%): mp 150-151 °C; Rf ) 0.32
(10:1 CH2Cl2-CH3OH); [R]D -4.6 (c 1.69, CH3OH); 1H NMR (600
Methyl 2-Acetamido-4-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthal-
imido-ꢀ-D-glucopyranosyl)-2-deoxy-3-O-[(R)-1-(methoxycarbonyl)-
ethyl]-6-O-pivaloyl-ꢀ-D-glucopyranoside (28). To a solution of
compound 26 (0.55 g, 1.36 mmol) and glycosyl donor 2727 (2.6 g,
5.4 mmol) in dry dichloromethane (14 mL) were added 4 Å
molecular sieves (3 g), and the mixture was stirred at room
temperature for 10 min before cooling to -60 °C. Silver triflate
(1.41 g, 5.4 mmol) was added at -60 °C under argon, and the
mixture was stirred at this temperature for 18 h. The reaction was
slowly warmed to room temperature over 2 h. The solution was
washed with satd NaHCO3, water, and brine and dried over
anhydrous Na2SO4. Upon concentration of the filtrate, the residue
was purified by silica gel chromatography using a gradient of MeOH
588 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of 2-Acetamido-2-deoxy-ꢀ-D-hexopyranosides
in CH2Cl2 (1 f 2%) to yield the target compound 28 as a white
amorphous solid (0.78 g, 0.95 mmol, 70%): Rf ) 0.32 (20:1
CH2Cl2-CH3OH); [R]D -22.8 (c 0.18, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.86 (bs, 2H, ArH), 7.76 (m, 2H, ArH), 6.87 (d, 1H,
JNH,H-2 ) 7.1 Hz, NH), 5.82 (dd, 1H, J3′,4′ ) 9.0 Hz, H-3′), 5.42 (d,
1H, J1′,2′ ) 8.4 Hz, H-1′), 5.18 (dd, 1H, J4′,5′ ) 10.0 Hz, H-4′),
3H, J ) 7.0 Hz, CH3CHCO2CH3)), 1.20 (s, 9H, C(CH3)3); 13C NMR
(125 MHz, CDCl3/CD3OD) δ 179.8, 176.3, 173.9, 173.5, 172.3,
171.9, 171.3, 103.6, 101.6, 79.5, 78.5, 76.7, 74.4, 73.8, 73.0, 70.0,
63.8, 63.8, 63.1, 40.1, 57.3, 56.0, 52.8, 52.8, 28.0, 23.7, 23.7, 23.3,
23.3, 21.3, 21.1, 19.4, 19.4; HRMS m/z calcd for C32H50N2O17Na
(M
+
Na+) 757.3001, found 757.2996. Anal. Calcd for
4.68 (q, 1H, J ) 6.9 Hz, CH3CHCO2CH3)), 4.46 (dd, 1H, J6a’,6b’
)
C32H50N2O17: C, 52.31; H, 6.86; N, 3.81. Found: C, 52.04; H, 6.87;
N, 3.80.
12.4 Hz, H-6a′), 4.36 (dd, 1H, J6a,6b ) 12.2 Hz, H-6a), 4.26 (dd,
1H, J2′,3′ ) 10.5 Hz, H-2′), 4.17 (d, 1H, J1,2 ) 7.8 Hz, H-1), 4.13
(dd, 1H, H-6b′), 3.89 (dd, 1H, J4,5 ) 8.8 Hz, H-4), 3.86 (ddd, J5′,6a′
) 4.6 Hz, J5′,6b′ ) 2.2 Hz, H-5′), 3.77 (s, 3H, COOCH3), 3.67 (ddd,
Methyl 2-Acetamido-4-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-
ꢀ-D-glucopyranosyl)-3-O-[(R)-1-carboxyethyl]-2-deoxy-6-O-pivaloyl-
ꢀ-D-glucopyranoside (30). Anhydrous lithium iodide (240 mg, 1.8
mmol) was added to a solution of compound 29 (120 mg, 0.16
mmol) in anhydrous pyridine (4 mL). The mixture was stirred at
100 °C for 3 days under argon and monitored by TLC. After the
removal of pyridine, the residue was dissolved in a mixture of water/
dichloromethane and acidified with 1 M HCl solution to pH 2.
Extraction with dichloromethane and concentration of the extract
gave a residue which was purified by silica gel chromatography
using 5% methanol in dichloromethane containing 1% acetic acid
to provide the desired compound 30 as a white amorphous solid
(101 mg, 0.14 mmol, 85%): Rf ) 0.36 (100:10:1 CH2Cl2-
CH3OH-AcOH); [R]D -45.5 (c 0.67, CHCl3); 1H NMR (600 MHz,
CD3OD) δ 5.28 (dd, 1H, J3′,4′ ) 10.0 Hz, H-3′), 5.00 (dd, 1H, J4′,5′
) 9.8 Hz, H-4′), 4.74 (d, 1H, J1′,2′ ) 8.4 Hz, H-1′), 4.61 (dd, 1H,
J6a,6b ) 12.0 Hz, H-6a), 4.56 (s, broad, 1H, CH3CHCO2CH3), 4.39
(dd, 1H, J6a′,6b′ ) 12.4 Hz, H-6a′), 4.28 (d, 1H, J1,2 ) 8.0 Hz, H-1),
4.12 (d, broad, H-6b′), 4.04 (dd, 1H, J5,6b ) 6.2 Hz, H-6b), 3.81
1H, J2,3 ) 10.1 Hz, H-2), 3.61 (dd, 1H, H-6b), 3.47 (dd, 1H, J3,4
)
8.5 Hz, H-3), 3.40 (s, 3H, OCH3), 3.24 (ddd, 1H, J5,6b ) 4.5 Hz,
J5,6a ) 2.1 Hz, H-5), 2.08 (s, 3H, COCH3), 2.04 (s, 3H, COCH3),
2.02 (s, 3H, COCH3), 1.85 (s, 3H, COCH3), 1.44 (d, 3H, J ) 6.9
Hz, CH3CHCO2CH3)), 1.20 (s, 9H, C(CH3)3); 13C NMR (125 MHz,
CDCl3) δ 177.3, 171.6, 170.4, 169.9, 169.5, 134.5, 134.4, 131.3,
131.2, 124.0, 123.7, 102.7, 97.3, 74.9, 72.8, 72.0, 70.5, 68.6, 61.9,
61.6, 56.2, 55.1, 54.5, 52.1, 38.8, 27.1, 23.5, 20.6, 20.6, 20.4, 18.6;
ESI HRMS m/z calcd for C38H50N2O18Na (M + Na+) 845.2951,
found 845.2957.
Methyl 2-Acetamido-4-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-
ꢀ-D-glucopyranosyl)-2-deoxy-3-O-[(R)-1-(methoxycarbonyl)ethyl]-
6-O-pivaloyl-ꢀ-D-glucopyranoside (29). To a solution of compound
28 (250 mg, 0.3 mmol) in 95% ethanol (15.5 mL) was added
hydrazine (115 µL), and the mixture was stirred at 35 °C for 2
days. The reaction was quenched with several drops of acetic acid
and evaporated. This residue was dissolved in a mixture of
anhydrous pyridine (3 mL) and acetic anhydride (1 mL) and stirred
at room temperature for several hours. The mixture was diluted
with dichloromethane, washed with water and brine, and dried over
anhydrous Na2SO4. Filtration and concentration of the filtrate gave
a residue, which was purified by silica gel chromatography (2.5%
MeOH in CH2Cl2) to provide the target product 29 as a white
amorphous solid (194 mg, 0.26 mmol, 87%): Rf ) 0.28 (20:1
CH2Cl2-CH3OH); [R]D -36.4 (c 0.11, CHCl3); 1H NMR (600 MHz,
CDCl3/CD3OD) δ 5.16 (dd, 1H, J3′,4′ ) 9.2 Hz, H-3′), 5.02 (dd,
(m, 3H, H-2′, H-2, H-4), 3.76 (ddd, 1H, J5′,6a′ ) 4.0 Hz, J5′,6b′
)
2.2 Hz, H-5′), 3.61 (dd, H, J2,3 ) 9.0 Hz, H-3), 3.54 (m, 1H, H-5),
3.39 (s, 3H, OCH3), 2.02 (s, 3H, COCH3), 1.99 (s, 3H, COCH3),
1.98 (s, 3H, COCH3), 1.96 (s, 3H, COCH3), 1.92 (s, 3H, COCH3),
1.44 (d, 3H, J ) 6.8 Hz, CH3CHCO2CH3)), 1.23 (s, 9H, C(CH3)3);
13C NMR (125 MHz, CD3OD) δ 179.4, 173.7, 172.3, 171.8, 171.3,
103.6, 101.5, 79.9, 78.6, 74.4, 73.7, 73.0, 70.0, 63.7, 62.9, 56.9,
56.2, 56.2, 49.2, 39.9, 27.6, 23.2, 22.9, 20.7, 20.6, 20.5, 19.3; ESI
HRMS m/z calcd for C31H48N2O17Na 743.2845, found 743.2848.
Acknowledgment. We gratefully acknowledge Mr. Jonathan
Cartmell for performing the melting pointing measurement for
compounds 9, 10, 18, 19, 23, and 25.
1H, J4′,5′
) 9.8 Hz, H-4′), 4.63 (q, 1H, J ) 7.0 Hz,
CH3CHCO2CH3)), 4.56 (d, 1H, J1′,2′ ) 8.4 Hz, H-1′), 4.50 (dd, 1H,
J6a,6b ) 11.9 Hz, H-6a), 4.37 (dd, 1H, J6a′,6b′ ) 12.5 Hz, H-6a′),
4.24 (d, 1H, J1,2 ) 7.9 Hz, H-1), 4.06 (dd, 1H, H-6b′), 4.02 (dd,
1H, H-6b), 3.92 (dd, 1H, J2′,3′ ) 10.5 Hz, H-2′), 3.75 (dd, 1H, J4,5
) 8.7 Hz, H-4), 3.72 (s, 3H, COOCH3), 3.69 (ddd, 1H, J5′,6a′ ) 4.3
Hz, J5′,6b′ ) 2.3 Hz, H-5′), 3.66 (dd, 1H, J2,3 ) 10.1 Hz, H-2), 3.54
Supporting Information Available: 1H and 13C NMR
scanned spectra are provided for compounds 2-30. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(dd, 1H, J3,4 ) 8.4 Hz, H-3), 3.48 (ddd, 1H, J5,6b ) 6.0 Hz, J5,6a
)
2.3 Hz, H-5), 3.38 (s, 3H, OCH3), 2.02 (s, 3H, COCH3), 2.00 (s,
3H, COCH3), 1.98 (s, 6H, COCH3), 1.90 (s, 3H, COCH3), 1.37 (d,
JO801927K
J. Org. Chem. Vol. 74, No. 2, 2009 589