Synthesis of 2-acetamido-2,5-dideoxy-5-phosphoryl-dglucopyranose derivatives: New phospha-sugar analogs of N-acetyl-D-glucosamine

Article abstract of DOI:10.3987/COM-12-S(N)69

Starting with N-acetyl-D-glucosamine, methyl 2-acetamido-3,6-di-Obenzyl- 2-deoxy-β-D-xylo-hexofuranosid-5-ulose (18) was prepared in 7 steps. The addition reaction of dimethyl phosphonate to 18, followed by deoxygenation of its 5-hydroxy group, provided the 5-deoxy-5-dimethoxyphosphoryl-Dglucofuranoside derivative (21a). The hydride reduction of 21a, followed by the action of hydrochloric acid and then hydrogen peroxide, afforded the first D-glucosamine analog (23) having a phosphoryl group in the hemiacetal ring. This was converted into the per-O-acetylated N-acetyl-D-glucosamine phospha-sugar (25), while the same treatment of the 5-deoxy-5- dimethoxyphosphoryl-L-idose dimethyl acetal derivative (13b) afforded the N-acetyl-L-idosamine phospha-sugar (29).

Full text of DOI:10.3987/COM-12-S(N)69

HETEROCYCLES, Vol. 86, No. 2, 2012
1147
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1147 - 1165. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2012, Accepted, 24th August, 2012, Published online, 3rd September, 2012
DOI: 10.3987/COM-12-S(N)69
SYNTHESIS OF 2-ACETAMIDO-2,5-DIDEOXY-5-PHOSPHORYL-D-
GLUCOPYRANOSE
DERIVATIVES:
NEW
PHOSPHA-SUGAR
ANALOGS OF N-ACETYL-D-GLUCOSAMINE
Tadashi Hanaya,* Masahiro Kawaguchi, Masakazu Sumi, Kazuo Makino,
Keiko Tsukada, and Hiroshi Yamamoto†
Department of Chemistry, Faculty of Science, Okayama University, Tsushima-
naka, Kita-ku, Okayama 700-8530, Japan. E-mail: hanaya@cc.okayama-u.ac.jp
†
School of Pharmacy, Shujitsu University, Nishigawara, Naka-ku, Okayama
703-8516, Japan
Abstract – Starting with N-acetyl-D-glucosamine, methyl 2-acetamido-3,6-di-O-
benzyl-2-deoxy-!-D-xylo-hexofuranosid-5-ulose (18) was prepared in 7 steps.
The addition reaction of dimethyl phosphonate to 18, followed by deoxygenation
of its 5-hydroxy group, provided the 5-deoxy-5-dimethoxyphosphoryl-D-ꢀ
glucofuranoside derivative (21a). The hydride reduction of 21a, followed by the
action of hydrochloric acid and then hydrogen peroxide, afforded the first
D-glucosamine analog (23) having a phosphoryl group in the hemiacetal ring.
This was converted into the per-O-acetylated N-acetyl-D-glucosamine
phospha-sugar (25), while the same treatment of the 5-deoxy-5-
dimethoxyphosphoryl-L-idose dimethyl acetal derivative (13b) afforded the
N-acetyl-L-idosamine phospha-sugar (29).
INTRODUCTION
Various sugar analogs containing nitrogen,1 sulfur,2 or phosphorus3 as a ring heteroatom have been
prepared because of the wide interest in their chemical and biochemical properties.
Heteroatom-in-the-ring sugar analogs of 2-amino- and 2-acetamido-2-deoxyhexopyranoses, which widely
occur as a component of many natural products, have also attracted considerable interest. Azasugar (1)4
and thiasugar analogs (2)5 of N-acetyl-D-glucosamine, for example, have been prepared and N-acetyl-
glucosaminidase inhibitory activity of the former has been reported.
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
In view of such a chemical modification by heteroatoms, we have prepared various sugar analogs having
a phosphorus atom in the ring (phospha-sugar); e.g., D-glucopyranose (3)6 and D-mannopyranose analogs
(4).7 These phospha-sugar analogs are expected to be of interest in view of potential biological activities,
such as glycosidase inhibitory activities8 and antitumor activities against leukemia cells.9 Meanwhile, as
synthetic N-acetyl-D-glucosamine analogs having phosphorus attached to a sugar-carbon atom, the
isosteric phosphonate analog of 1-phosphate (5)10 and the cyclic phosphonate analog (6)11 have been
prepared. We describe herein the first synthetic route to the N-acetyl-D-glucosamine phospha-sugar (25),
by using our effective procedure12 to introduce a phosphoryl group onto a sugar skeleton; namely addition
of a phosphonate to an appropriate hexos-5-ulose derivative and the subsequent deoxygenation.
RESULTS AND DISCUSSION
For the preparation of the key 5-deoxy-5-dimethylphosphoryl-D-glucose precursors (13a and 21a), two
synthetic routes by starting with open-chain and furanose derivatives (7 and 15) of N-acetyl-
D-glucosamine were employed (Scheme 1 and 3).
First, 2-acetamido-2-deoxy-3,4-O-isopropylidene-D-glucose dimethyl acetal (7) (available from N-acetyl-
D-glucosamine in 2 steps)13 served as the starting material for preparation of the 5-ulose intermediate (10)
to introduce a phosphoryl group, as illustrated in Scheme 1. The epoxidation of 7 under Mitsunobu’s
conditions afforded the 5,6-anhydro derivative (8) (91%), which was then treated with benzyl alcohol and
sodium hydride in 1,2-dimethoxyethane (DME) to give the 6-O-benzyl compound (9a) in 87% yield.
As an alternative way for preparation of 9a, the 5,6-diol 7 was treated with dibutyltin oxide in refluxed
toluene to give 5,6-O-stannylene acetal, which was subjected to the benzylation with benzyl bromide in
the presence of tetrabutylammonium iodide in the same solvent,14 providing the 6-O-benzyl derivative
(9a) (90% yield) together with a trace amount of the 5-O-benzyl isomer (9b) (2%). Swern oxidation of
9a with oxalyl chloride-DMSO afforded the D-xylo-hexos-5-ulose dimethyl acetal (10) in 95%.
The addition reaction of dimethyl phosphonate to 10 in the presence of DBU gave the (5R)- and
(5S)-5-C-dimethoxyphosphoryl-D-xylo-hexose derivatives (11) (26% and 54%, respectively).15 The
diastereomeric mixture of 11 was converted to the methoxalyl esters (12) with methoxalyl chloride in the
presence of 4-dimethylaminopyridine (DMAP) in 84% yield and then reduced with tributyltin hydride in
the presence of AIBN, affording a 72:28 mixture of 5-deoxy products. On structural assignment of the

HETEROCYCLES, Vol. 86, No. 2, 2012
1149
1
resulting two separable diastereoisomers by H-NMR, it turned out that the major isomer was not the
expected 5-deoxy-5-dimethoxyphosphoryl-D-glucose derivative (13a) (23%) but the L-idose isomer (13b)
(60%).
Scheme 1
The large J3,4 values (8.5 and 8.2 Hz) of 13a,b indicate an anti relationship of H-3/H-4 for both isomers.
The D-gluco configuration for 13a was assigned on the basis of the small J4,P (9.9 Hz) and J4,5 (4.1 Hz)
4
values and the presence of a long range coupling, J3,P (1.5 Hz)12,16 (Figure 1). Similarly, the L-ido
configuration for 13b was derived from the relatively large J4,P (18.2 Hz) and small J4,5 (5.3 Hz) values.
Figure 1. The most favorable conformations for 13a,b and 21a,b.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Alternatively, methyl 2-acetamido-3-O-benzyl-2-deoxy-D-glucofuranose (15) was prepared from
N-acetyl-D-glucosamine in 4 steps via 14 with a slight modification of reported procedures4,17 (Scheme 2).
The epoxidation of 15 under Mitsunobu’s conditions afforded the 5,6-anhydro derivative (16) (87%),
which was then treated with benzyl alcohol and sodium hydride to give the 6-O-benzyl compound (17a)
in 82% yield. Meanwhile, benzylation of 15 by way of the 5,6-O-stannylene acetal resulted in
production of the 6-O-benzyl derivative (17a) (72% yield) and its 5-O-benzyl isomer (17b) (18%) with
less selectivity than that from 7. Oxidation of 17a with oxalyl chloride-DMSO afforded the
D-xylo-hexofuranosid-5-ulose (18) in 94% yield, while the same reaction with PCC gave 18 in 85%.
Scheme 2
The addition reaction of dimethyl phosphonate to 18 in the presence of DBU provided the (5R)- and
(5S)-5-dimethoxyphosphoryl-D-xylo-hexofuranoside derivatives (19) (69% and 25%, respectively).15
The diastereomeric mixture of 19 was converted to the methoxalyl esters (20) in 85% yield, which were
then reduced with tributyltin hydride, affording the 5-deoxy-5-dimethoxyphosphoryl-D-glucofuranoside
derivative (21a) (43%) and its L-idofuranoside isomer (21b) (18%) together with dephosphorylated
product 18 (12%). The D-gluco configuration for 21a was assigned on the basis of the large J4,5 value

HETEROCYCLES, Vol. 86, No. 2, 2012
1151
(9.4 Hz) and the presence of a long-range coupling 5J1,P (1.2 Hz), whereas the L-ido configuration for 21b
4
5
was derived from the large J4,5 value (10.6 Hz) and the presence of J3,P (1.2 Hz) and J2,P (1.5 Hz)
(Figure 1).12,16
Although the reduction from the open-chain 5-O-methoxalyl compound (12) preferentially gave the
5-deoxy-L-ido isomer (13b), the same reaction from the furanoside form (20) afforded 5-deoxy-D-gluco
isomer (21a) as a major product. As this reaction proceeds via a radical intermediate formed by a
homolytic cleavage of the O–C-5 bond, ratios of the 5-deoxy products (13a:13b and 21a:21b) are not
correlated to the diastereomeric ratios of the 5-O-methoxalyl precursors.12 As for the predominant
production of the L-ido isomer (13b) from 12, we propose the rotamer A of the radical intermediate from
the viewpoint of electronic factors (Figure 2). Namely, the opposition of the 5-phosphoryl group and
electronegative 4-O atom diminishes their intramolecular electrostatic repulsion.18 Moreover, the
alignment of the "C4–C5 bond with the radical p orbital stabilizes the transition state by hyperconjugation.
Meanwhile, as for the predominant production of the D-gluco isomer (21a) from 20, another possible
rotamer B was proposed, taking into account both the electrostatic repulsion between two electronegative
groups and the steric repulsion between C-6 and the 3-O-benzyl group.19
Figure 2. The most plausible conformations for the radical intermediates A (from 12) and B (from 20)
and directions of the reduction.
The major product (21a) was then reduced with sodium dihydrobis(2-methoxyethoxy)aluminate (SDMA)
to give the 5-phosphino derivative (22), which was immediately treated with hydrochloric acid at 90 °C
and then oxidized with hydrogen peroxide to afford 2-amino-3,6-di-O-benzyl-2,5-dideoxy-5-
hydroxyphosphoryl-#,!-D-glucopyranoses (23) (Scheme 3).
For the purpose of purification and characterization, compounds 23 were converted to the corresponding
1,2,4-triacetyl-5-methoxyphoshoryl derivatives (24) by treatment with acetic anhydride-pyridine and then
trimethylsilyldiazomethane. Debenzylation of 24 by the catalytic hydrogenation over 20% Pd(OH)2-C,
followed by acetylation, afforded the fully acetylated N-acetyl-D-glucosamine phospha-sugar (25). By
purification on a silica gel column, the 5-deoxy-5-[(R)-methoxyphosphoryl]-#-D-glucopyranose (25a)
(7.5% overall yield from 21a), its !-anomer (25b) (2.7%), 5-[(S)-methoxyphosphoryl]-#-D-
glucopyranose (25c) (19%), and its !-anomer (25d) (2.3%) were obtained.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Scheme 3
The similar treatment of the L-idose dimethyl acetal derivative (13b) afforded 2-amino-3,6-di-O-benzyl-ꢀ
2,5-dideoxy-5-hydroxyphosphoryl-#,!-L-idopyranoses (27) via 5-phosphino compound 26. The
L-idopyranose analogs 27 were also converted to N-acetyl-L-idosamine phospha-sugar (29) via 28: the
5-deoxy-5-[(R)-methoxyphosphoryl]-!-L-idopyranose (29a) (3.4% overall yield from 13b), its #-anomer
(29b) (8.3%), 5-[(S)-methoxyphosphoryl]-!-L-glucopyranose (29c) (5.4%), and its #-anomer (29d)
(3.0%).
The precise structures of 25a–d and 29a–d were established by the analysis of their 1H-NMR spectra; for
all the assignments of the signals, see Table 1. The D-glucopyranose configuration of 25a-d are derived
from the large values of J4,5 (11–12 Hz). As for anomeric orientation of C-1, the large J1,2 values (10.5
Hz) of 25b,d indicate the axial H-1 orientation, whereas the small J1,2 values (2.6 Hz) of 25a,c show the
equatorial H-1 configuration.3 With regard to the orientation of the ring P=O group, a downfield shift
(0.2–0.3 ppm) of H-2,4 for 25a,b compared with those of 25c,d indicates the axial P=O orientation for the
former and the equatorial P=O orientation for the latter. In contrast, the small values of J4,5 (5–6 Hz) for
29a–d indicate the L-idopyranose structure and their structural assignments were made by similar
characteristic tendency of the corresponding J1,2 values and H-2,4 chemical shifts for 25a-d.
Present work thus demonstrates a convenient way for preparation of 2-acetamido-2,5-dideoxy-ꢀ
5-phosphoryl-D-glucopyranose from appropriate intermediates. Extension of this work including
applications of these findings in synthesizing other phospha-sugar analogs, as well as biological
evaluation of N-acetyl-D-glucosamine phospha-sugars, is anticipated to be highly of interest.

HETEROCYCLES, Vol. 86, No. 2, 2012
1153
1
31
Table 1. H and P NMR Parameters for Compounds 25a–d and 29a–d in CDCl
3
——————————————————————————————————————————————
Chemical shifts / $
Com- ——————————————————————————————————————————
a
b
31
pound H-1 H-2
H-3
H-4
H-5
H-6
H'-6 POMe HN-2
Ac-1,2,3,4,6,
P
——————————————————————————————————————————————
25a
25b
25c
25d
29a
29b
29c
29d
5.45 4.85 5.19 5.56 2.57 4.43 4.35 3.75 5.68 2.23, 2.08, 2.05, 2.04, 1.91 38.79
5.11 4.79 4.97 5.52 2.42 4.44 4.41 3.85 5.60 2.15, 2.09, 2.07, 2.03, 1.92 37.25
5.58 4.59 5.14 5.39 2.65 4.62 4.24 3.93 5.72 2.25, 2.07, 2.04, 2.04, 1.91 37.29
5.27 4.57 5.00 5.37 2.43 4.59 4.31 3.97 5.65 2.14, 2.08, 2.03, 2.02, 1.92 35.48
5.45 4.67 5.35 5.52 2.98 4.56 4.36 3.84
5.48 4.56 5.31 5.33 2.83 4.43 4.40 3.98 5.48 2.24, 2.15, 2.08, 2.04, 1.92 36.96
5.54 4.67 5.28 5.30 2.91 4.56 4.46 3.90 2.22, 2.10, 2.09, 2.04, 1.96 36.85
5.79 4.45 5.69 5.25 2.59 4.50 4.35 3.97 6.09 2.22, 2.06, 2.01, 1.91, 1.85 36.85
c
2.20, 2.11, 2.08, 2.07, 1.95 37.50
c
——————————————————————————————————————————————
Coupling constants / Hz
——————————————————————————————————————————
J
J
J
J
J
J
J
J
J
J
J
J
J
J
1,2
1,P
2,3
2,P
3,4
4,5
4,P
5,6
5,6'
5,P
6,6'
6,P
6',P
POMe
——————————————————————————————————————————————
25a
25b
25c
25d
29a
29b
29c
29d
2.6 13.2 11.2
0
9.6
9.6
12.2
11.0
11.7
12.0
5.3
1.8
2.0
1.8
2.0
c
5.9 4.7
5.0 6.0
4.4 3.5
5.0 4.1
4.1 7.6
2.9 2.9
4.7 7.3
3.2 4.1
13.8
13.0
13.9
12.5
25.5
25.2
21.4
25.2
12.0
11.8
12.0
11.8
11.7
11.7
11.7
11.5
16.4 12.9
14.5 16.0
22.0 10.0
20.0 11.5
10.9
11.0
10.6
10.6
10.9
10.6
10.9
10.6
10.5
10.5
11.4
11.2
5.6 10.6 2.4
2.6 14.1 11.1
0
9.7
3.0 10.0 2.5
9.8
d
e
5.3 11.2 10.0
c
10.8
8.8
c
10.1
0
4.4 9.5 3.5
5.9
c
9.2
c
3.5 10.8 9.5
c
c
8.5
5.0
c
10.9
7.9
5.0 10.2
10.6
5.9
1.0
c
——————————————————————————————————————————————
a
b
c
J2,NH = 8.5–8.8 Hz.
The assignment of acetyl signals may be interchanged.
Uncertain because of
d
e
overlapping with other signals.
J1,5 = 0.8 Hz.
J1,5 = 1.5 Hz.

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HETEROCYCLES, Vol. 86, No. 2, 2012
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) AcOEt and (B) 1:9 EtOH-AcOEt]. Column chromatography was performed with Daiso Silica Gel
IR-60/210w. Components were detected by exposing the plates to UV light and/or spraying them with
20% sulfuric acid–ethanol (with subsequent heating). Optical rotations were measured with a Jasco
P-1020 polarimeter in CHCl3. The NMR spectra were measured in CDCl3 with Varian 600-System (600
MHz for 1H, 151 MHz for 13C, 243 MHz for 31P) spectrometer at 23 °C. Chemical shifts are reported as
1
$ values relative to CHCl3 (7.26 ppm as an internal standard for H), CDCl3 (77.0 ppm as an internal
standard for 13C), and 85% phosphoric acid (0 ppm as an external standard for 31P). The assignments of
13C signals were made with the aid of 2D HSQC measurements. The MS spectra were measured on a
VG-70SE instrument.
2-Acetamido-5,6-anhydro-2-deoxy-3,4-O-isopropylidene-D-glucose dimethyl acetal (8).
13
To a solution of 7 (300 mg, 0.976 mmol) and triphenylphosphine (310 mg, 1.18 mmol) in dry toluene
(10 mL) was added DEAD (40% in toluene, 0.470 mL, 1.18 mmol). The mixture was refluxed for 4 h
and evaporated in vacuo. The residue was purified by column chromatography with AcOEt as an eluant
22
to give 8 (257 mg, 91%) as colorless needles: mp 102–103 °C (from AcOEt-hexane): Rf = 0.39 (A); [!]D
+4.55 (c 1.28, CHCl3); 1H-NMR $ = 1.41, 1.42 (3H each, s, CMe2), 2.03 (3H, s, NAc), 2.69 (1H, dd, J6,6’
= 4.7, J5,6’ = 2.6 Hz, H’-6), 2.83 (1H, t, J 5,6 = 4.1 Hz, H-6), 3.79 (1H, td, J4,5 = 4.7 Hz, H-5), 3.36, 3.42
(3H each, 2s, MeO-1), 3.69 (1H, dd, J3,4 = 7.9 Hz, H-4), 4.21 (1H, dd, J2,3 = 2.1 Hz, H-3), 4.26 (1H, ddd,
13
J2,NH = 9.7, J1,2 = 5.9 Hz, H-2), 4.40 (1H, d, H-1), 5.85 (1H, d, HN-2); C NMR $ = 23.36 (CH3CO),
26.66 and 26.85 (CMe2), 45.04 (C-6), 49.46 (C-2), 51.39 (C-5), 53.28 and 55.52 (MeO-1), 75.77 (C-3),
77.10 (C-4), 103.03 (C-1), 109.91 (CMe2), 169.96 (CH3CO). Anal. Calcd for C13H23NO6: C, 53.97; H,
8.01. Found: C, 53.90; H, 8.04.
2-Acetamido-6-O-benzyl-2-deoxy-3,4-O-isopropylidene-D-glucose dimethyl acetal (9a) and its
5-O-benzyl analog (9b).
A. From 8. To a suspension of sodium hydride (60% in mineral oil, 560 mg, 14.0 mmol) and benzyl
alcohol (2.20 mL, 21.3 mmol) in DME (5.0 mL) was added a solution of 8 (2.02 g, 6.98 mmol) in DME
(5.0 mL) at 0 °C. The mixture was stirred at 50 °C for 3 h, diluted with saturated aqueous NH4Cl (20
mL), and extracted with CHCl3 three times. The combined organic layers were washed with water,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography with
3:1 AcOEt-hexane as an eluant to give 9a (2.44 g, 88%) as colorless needles.
B. From 7. To a solution of 7 (1.85 g, 6.02 mmol) in toluene (50 mL) was added dibutyltin oxide (1.80

HETEROCYCLES, Vol. 86, No. 2, 2012
1155
g, 7.23 mmol) and then the suspension was refluxed under Dean-Stark trap for 16 h. After removal of
the trap, benzyl bromide (1.40 mL, 11.8 mmol) and tetrabutylammonium iodide (1.10 g, 2.98 mmol) were
added and the mixture was refluxed for 20 h. The mixture was evaporated in vacuo and the residue was
separated by column chromatography on silica gel to give 9a (2.15 g, 90%) and 9b (45 mg, 2%).
20
1
9a: Colorless needles: 97–99 °C (from AcOEt-hexane); Rf = 0.44 (A); [!]D +13.3 (c 1.23, CHCl3); H
NMR $ = 1.37 (6H, s, CMe2), 2.03 (3H, s, NAc), 3.10 (1H, br s, HO-5), 3.32, 3.39 (3H each, 2s, MeO-1),
3.55 (1H, dd, J6,6’ = 9.8, J5,6’ = 5.8 Hz, H’-6), 3.65 (1H, t, J3,4 = 8.2, J4,5 = 8.0 Hz, H-4), 3.70 (1H, dd, J 5,6
= 2.8 Hz, H-6), 3.79 (1H, ddd, H-5), 4.27 (1H, dd, J2,3 = 1.5 Hz, H-3), 4.42 (1H, d, J1,2 = 6.7 Hz, H-1),
4.47 (1H, ddd, J2,NH = 9.5 Hz, H-2), 4.58 (2H, s, CH2O-6), 5.85 (1H, d, HN-2), 7.27 [1H, t, Jm,p = 7.4 Hz,
Ph(p)], 7.34–7.38 [4H, m, Ph(o,m)]. Anal. Calcd for C20H31NO7: C, 60.44; H, 7.86. Found: C, 60.61;
H, 7.90.
1
9b: Colorless syrup; Rf = 0.41 (A); H NMR $ = 1.38, 1.39 (3H each, s, CMe2), 2.03 (3H, s, NAc), 2.90
(1H, br s, HO-6), 3.28, 3.38 (3H each, 2s, MeO-1), 3.69 (1H, m, H-5), 3.72–3.76 (2H, m, H,H’-6), 3.90
(1H, d, J3,4 = 8.5, J4,5 = 4.4 Hz, H-4), 4.36 (1H, ddd, J2,NH = 9.7, J1,2 = 6.5, J2,3 = 1.2 Hz, H-2), 4.37 (1H,
2
dd, H-3), 4.40 (1H, d, H-1), 4.67, 4.71 (1H each, 2d, J = 11.7 Hz, CH2O-5), 5.88 (1H, d, HN-2), 7.28
[1H, t, Jm,p = 7.5 Hz, Ph(p)], 7.34 [2H, t, Jo,m = 7.5 Hz, Ph(m)], 7.38 [2H, d, Ph(o)].
2-Acetamido-6-O-benzyl-2-deoxy-3,4-O-isopropylidene-D-xylo-hexos-5-ulose dimethyl acetal (10).
To a solution of oxalyl chloride (1.70 mL, 19.5 mmol) in CH2Cl2 (4.0 mL) was added DMSO (2.80 mL,
o
39.4 mmol) in CH2Cl2 (8.0 mL) at –60 C. After stirring for 30 min, a solution of 9a (2.56 g, 6.44
mmol) in CH2Cl2 (8 mL) was added. The mixture was stirred for 16 h and then TEA (9.0 mL, 64.4
mmol) was added. The mixture was stirred for 1 h, diluted with CHCl3, and washed with saturated
aqueous NaCl. The aqueous layer was extracted with CHCl3. The combined organic layers were
washed with water, dried (Na2SO4), and evaporated in vacuo. The residue was purified by column
o
chromatography with AcOEt to give 10 (2.41 g, 95%) as colorless needles: mp 96–97 C (from
AcOEt-hexane); Rf = 0.46 (A); [#]D20 –1.41 (c 1.62, CHCl3); 1H NMR $ = 1.32, 1.43 (3H each, 2s, CMe2),
2.04 (3H, s, NAc), 3.34, 3.40 (3H each, 2s, MeO-1), 4.23 (1H, d, J3,4 = 7.3 Hz, H-4), 4.33, 4.46 (1H each,
2d, J6,6’ = 18.5 Hz, H2-6), 4.38 (1H, d, J1,2 = 5.9 Hz, H-1), 4.45 (1H, dd, J2,3 = 1.8 Hz, H-3), 4.49 (1H, ddd,
J2,NH = 9.7 Hz, H-2), 4.59, 4.63 (1H each, 2d, 2J = 11.7 Hz, CH2O-6), 5.79 (d, 1H, HN-2), 7.27 [1H, t, Jm,p
13
= 7.4 Hz, Ph(p)], 7.34–7.38 [4H, m, Ph(o,m)]; C NMR $ = 23.37 (CH3CO), 25.88 and 26.64 (CMe2),
49.77 (C-2), 53.36 and 55.05 (MeO-1), 72.61 (CH2O-6), 73.28 (C-6), 75.64 (C-3), 80.33 (C-4), 102.87
(C-1), 111.02 (CMe2), 127.99 [Ph(p)], 128.07 [Ph(o)], 128.48 [Ph(m)], 137.04 [Ph(ipso)], 170.15
(CH3CO), 205.67 (C-5). Anal. Calcd for C20H29NO7: C, 60.74; H, 7.39. Found: C, 60.61; H, 7.42.

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HETEROCYCLES, Vol. 86, No. 2, 2012
(5R)- and (5S)-2-Acetamido-6-O-benzyl-2-deoxy-5-C-dimethoxyphosphoryl-3,4-O-isopropylidene-
D-xylo-hexose dimethyl acetals (11).
To a solution of 10 (2.10 g, 5.31 mmol) in dimethyl phosphonate (25 mL) was added DBU (1.60 mL,
o
o
10.7 mmol) at 0 C under argon. After stirring for 2 h at 0 C, the mixture was treated with saturated
aqueous NH4Cl at rt for 0.5 h and then extracted with CHCl3 three times. The combined organic layers
were washed with water, dried (Na2SO4), and concentrated in vacuo. The residue was separated by
column chromatography with 1:9 EtOH-AcOEt to give (5R)-11 (958 mg, 36%) and (5S)-11 (1.44 g,
54%).
22
1
(5R)-11: Colorless syrup; Rf = 0.30 (B); [!]D +4.17 (c 1.37, CHCl3); H NMR $ = 1.36, 1.38 (3H each,
2s, CMe2), 2.05 (3H, s, NAc), 3.30, 3.33 (3H each, 2s, MeO-1), 3.80, 3.82 (3H each, 2d, JPOMe = 10.6 Hz,
POMe), 3.85 (1H, dd, J6’,P = 10.9, J6,6’ = 9.9 Hz, H-6’), 3.87 (1H, dd, J6,P = 13.8 Hz, H-6’), 4.02 (1H, t,
J4,P = 8.5, J3,4 = 8.2 Hz, H-4), 4.06 (1H, br s, HO-5), 4.37 (1H, d, J1,2 = 6.5 Hz, H-1), 4.49 (1H, ddd, J2,NH
2
3
= 9.7, J2,3 = 1.1 Hz, H-2), 4.59, 4.66 (1H each, 2d, J = 11.9 Hz, CH2O-6), 4.70 (1H, dt, J3,P = 1.0 Hz,
H-3), 5.84 (1H, d, HN-2), 7.27 [1H, t, Jm,p = 7.6 Hz, Ph(p)], 7.33 [2H, t, Jo,m = 7.5 Hz, Ph(m)], 7.37 [2H, d,
Ph(o)]; 31P NMR $ = 24.77.
(5S)-11: Colorless needles; mp 121–123 oC (from AcOEt); Rf = 0.40 (B); [!]D22 +12.8 (c 0.97, CHCl3); 1H
NMR $ = 1.37, 1.44 (3H each, 2s, CMe2), 1.98 (3H, s, NAc), 3.28, 3.36 (3H each, 2s, MeO-1), 3.72-3.82
(3H, m, H2-6, HO-5), 3.75, 3.80 (3H each, 2d, JPOMe = 10.6 Hz, POMe), 4.03 (1H, dd, J4,P = 19.1, J3,4
=
8.8 Hz, H-4), 4.39 (1H, d, J1,2 = 6.5 Hz, H-1), 4.46 (1H, ddd, J2,NH = 9.7, J2,3 = 1.2 Hz, H-2), 4.57, 4.65
(1H each, 2d, 2J = 12.0 Hz, CH2O-6), 4.79 (1H, dd, H-3), 5.88 (1H, d, HN-2), 7.26 [1H, t, Jm,p = 7.5 Hz,
31
Ph(p)], 7.32 [2H, t, Jo,m = 7.5 Hz, Ph(m)], 7.37 [2H, d, Ph(o)]; P NMR $ = 24.75. Anal. Calcd for
C22H36NO10P: C, 52.27; H, 7.18. Found: C, 52.47; H, 7.13.
(5R)- and (5S)-2-Acetamido-6-O-benzyl-2-deoxy-5-C-dimethoxyphosphoryl-5-O-methoxalyl-3,4-O-
isopropylidene-D-xylo-hexose dimethyl acetals (12).
Methoxalyl chloride (0.330 mL, 3.59 mmol) was added to a solution of 11 (40:60 diastereomeric mixture,
936 mg, 1.79 mmol) and DMAP (608 mg, 4.98 mmol) in dry MeCN (10 mL) at 0 oC. The mixture was
stirred at rt for 5 h under argon and then concentrated in vacuo. The residue was treated with saturated
aqueous NH4Cl and extracted with CHCl3. The combined organic layers were washed with water, dried
(Na2SO4), and evaporated in vacuo. The residue was purified by column chromatography with AcOEt
to give an inseparable mixture (40:60) of (5R)- and (5S)-12 (889 mg, 84%) as a colorless syrup: Rf ꢀ
0.45 (B).
1
(5R)-12: H NMR $ = 1.40, 1.42 (3H each, 2s, CMe2), 2.03 (1H, s, NAc), 3.29, 3.30 (3H each, 2s,
MeO-1), 3.80, 3.81 (3H each, 2d, JPOMe = 11.0 Hz, POMe), 3.89 (3H, s, CO2Me), 4.21 (1H, dd, J6’,P
=

HETEROCYCLES, Vol. 86, No. 2, 2012
1157
15.9, J6,6’ = 9.7 Hz, H’-6), 4.28 (1H, dd, J6,P = 8.2 Hz, H-6), 4.30 (1H, d, J1,2 = 6.5 Hz, H-1), 4.38 (1H, dd,
J3,4 = 8.2, J4,P = 7.4 Hz, H-4), 4.56, 4.60 (1H each, 2d, 2J = 11.7 Hz, CH2O-6), 4.60 (1H, ddd, J2,NH = 10.0,
J2,3 = 1.0 Hz, H-2), 4.80 (1H, dd, H-3), 5.77 (1H, d, HN-2), 7.26 [1H, t, Jm,p = 7.4 Hz, Ph(p)], 7.29–7.34
[4H, m, Ph(o,m)] ; 31P NMR $ = 19.08.
1
(5S)-12: H NMR $ = 1.42, 1.49 (3H each, 2s, CMe2), 2.04 (1H, s, NAc), 3.16, 3.18 (3H each, 2s,
MeO-1), 3.77, 3.80 (3H each, 2d, JPOMe = 10.9 Hz, POMe), 3.89 (3H, s, CO2Me), 4.01 (1H, dd, J6,6’
=
10.6, J6,P = 2.9 Hz, H’-6), 4.16 (1H, dd, J3,4 = 7.9, J4,P = 5.3 Hz, H-4), 4.28 (1H, d, J1,2 = 6,5 Hz, H-1),
4.37 (1H, t, J6,P = 10.2 Hz, H-6), 4.47, 4.63 (1H each, 2d, 2J = 11.7 Hz, CH2O-6), 4.58 (1H, ddd, J2,NH
=
31
10.0, J2,3 = 1.0 Hz, H-2), 4.69 (1H, dd, H-3), 5.79 (1H, d, HN-2), 7.24-7.30 (5H, m, Ph) ; P NMR $ =
19.16. Anal. Calcd for C25H38NO13P: C, 50.76; H, 6.47. Found: C, 50.60; H, 6.51.
2-Acetamido-6-O-benzyl-2,5-dideoxy-5-dimethoxyphosphoryl-3,4-O-isopropylidene-D-glucose
dimethyl acetal (13a) and its L-idose analog (13b).
To a solution of 12 (900 mg, 1.51 mmol) in toluene (6 mL), a solution of AIBN (130 mg, 0.792 mmol)
o
and tributyltin hydride (0.850 mL, 3.16 mmol) in dry toluene (7 ml) was dropwise added at 90 C under
argon. The mixture was stirred at the same temperature for 6 h and then concentrated in vacuo. The
residue was separated by column chromatography with 1:9 EtOH-AcOEt to give 13a (169 mg, 23%) and
13b (442 mg, 60%).
24
1
13a: Colorless syrup; Rf = 0.28 (B); [!]D +1.79 (c 2.47, CHCl3); H NMR $ = 1.33, 1.39 (3H each, 2s,
CMe2), 2.02 (3H, s, NAc), 2.47 (1H, dddd, J5,P = 23.8 Hz, J5,6 = 6.8, J4,5 = 4.1, J5,6’ = 3.2, H-5), 3.30, 3.31
(3H each, 2s, MeO-1), 3.725, 3.73 (3H each, 2d, JPOMe = 10.9 Hz, POMe), 3.79 (1H, ddd, J6’,P = 15.6, J6,6’
= 10.0 Hz, H’-6), 3.89 (1H, ddd, J6,P = 7.6 Hz, H-6), 4.04 (1H, ddd, J4,P = 9.9, J3,4 = 8.5 Hz, H-4), 4.33
4
(1H, d, J1,2 = 5.9 Hz, H-1), 4.35 (1H, ddd, J2,NH = 8.5, J2,3 = 1.5 Hz, H-2), 4.46 (1H, dt, J3,P = 1.5 Hz,
2
H-3), 4.49, 4.55 (1H each, 2d, J = 12.0 Hz, CH2O-6), 5.77 (1H, d, HN-2), 7.26 [1H, t, Jm,p = 7.5 Hz,
13
Ph(p)], 7.34–7.38 [4H, m, Ph(o,m)]; C NMR $ = 23.35 (CH3CO), 26.88 and 27.07 (CMe2), 39.36 (d,
2
1J5,P = 136.9 Hz, C-5), 48.15 (C-2), 52.69 and 52.73 [2d, JC,P = 6.7 Hz, P(OMe)2], 52.95 and 54.93
2
3
(MeO-1), 64.94 (C-6), 73.10 (CH2O-6), 74.32 (d, J4,P = 2.8 Hz, C-4), 76.76 (d, J3,P = 8.4 Hz, C-3),
103.36 (C-1), 108.62 (CMe2), 127.54 [Ph(p)], 127.71 [Ph(o)], 128.25 [Ph(m)], 137.89 [Ph(ipso)], 169.79
(CH3CO); 31P NMR $ = 30.31.
13b: Colorless needles: mp 97–99 oC, Rf = 0.38 (B); [!]D24 +16.6 (c 2.12, CHCl3); 1H NMR $ = 1.38, 1.41
(3H each, 2s, CMe2), 1.99 (3H, s, NAc), 2.52 (1H, dddd, J5,P = 22.0, J5,6’ = 7.6, J4,5 = 5.3, J5,6 = 3.8 Hz,
H-5), 3.28, 3.34 (3H each, 2s, MeO-1), 3.71, 3.72 (3H each, 2d, JPOMe = 11.0 Hz, POMe), 3.75 (1H, ddd,
J6’,P = 15.3, J6,6’ = 10.0 Hz, H’-6), 3.85 (1H, ddd, J6,P = 13.8 Hz, H-6), 4.04 (1H, ddd, J4,P = 18.2, J3,4 = 8.2
Hz, H-4), 4.35 (1H, d, J1,2 = 6.2 Hz, H-1), 4.40 (1H, dd, J2,NH = 9.7, J2,3 = 1.7 Hz, H-2), 4.53 (1H, dd,

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HETEROCYCLES, Vol. 86, No. 2, 2012
H-3), 4.54 (2H, s, CH2O-6), 5.78 (1H, d, HN-2), 7.26 [1H, t, Jm,p = 7.4 Hz, Ph(p)], 7.33 [2H, t, Jo,m = 7.4
Hz, Ph(m)], 7.36 [2H, d, Ph(o)]; 13C NMR $ = 23.36 (CH3CO), 26.89 and 27.06 (CMe2), 40.56 (d, 1J5,P
=
2
138.6 Hz, C-5), 48.58 (C-2), 52.37 and 52.56 [2d, JC,P = 6.7 Hz, P(OMe)2], 52.85 and 55.21 (MeO-1),
66.63 (C-6), 72.93 (CH2O-6), 74.17 (d, 2J4,P = 4.5 Hz, C-4), 77.42 (d, 3J3,P = 7.3 Hz, C-3), 103.50 (C-1),
108.74 (CMe2), 127.52 [Ph(p)], 127.71 [Ph(o)], 128.24 [Ph(m)], 137.87 [Ph(ipso)], 169.72 (CH3CO); 31P
NMR $ = 29.51. Anal. Calcd for C22H36NO9P: C, 53.98; H, 7.41. Found: C, 54.11; H, 7.37.
Methyl 2-acetamido-3-O-benzyl-2-deoxy-!-D-glucofuranoside (15).5
The following modification of the literature procedures4 was made. The oxazoline 14 17 (3.93 g, 11.8
mmol) was dissolved in dry MeOH (40 mL) containing 4M HCl (in dioxane, 0.032 mL). The mixture
was stirred at rt for 5 h and neutralized with Amberlite-IRA96SB at 0 oC. The resin was filtered off and
the filtrate was evaporated in vacuo to give a crude syrup (4.25 g) of methyl 2-acetamido-3-O-benzyl-2-
deoxy-5,6-O-isopropylidene-"-D-glucofuranoside: Rf = 0.59 (A).
o
The above syrup was dissolved in 70% aqueous acetic acid (50 ml) and the mixture was stirred at 40 C
for 6 h. Then the mixture was concentrated in vacuo and the residue was purified by column
chromatography with 1:9 MeOH-CHCl3 to give 15 (3.52 g, 92% from 14) as colorless needles: mp
o
1
121–122 °C (from AcOEt) (lit.,5 mp 123 C, 47% yield); Rf = 0.14 (A); H NMR $ = 2.00 (3H, s, NAc),
2.15, 2.90 (1H each, 2br s, HO-5,6), 3.36 (3H, s, MeO-1), 3.69 (1H, dd, J6,6’ = 11.5, J5,6’ = 5.1 Hz, H’-6),
3.83 (1H, dd, J5,6 = 2.9 Hz, H-6), 4.02 (1H, ddd, J4,5 = 9.3 Hz, H-5), 4.08 (1H, dd, J3,4 = 6.4, J2,3 = 0.9 Hz,
H-3), 4.20 (1H, dd, H-4), 4.50 (1H, d, J2,NH = 7.9, J1,2 = 0 Hz, H-2), 4.62, 4.92 (1H each, 2d, 2J = 11.9 Hz,
13
CH2O-3), 4.80 (1H, s, H-1), 5.68 (1H, d, HN-2), 7.32 [1H, m, Ph(p)], 7.34–7.36 [4H, t, Ph(o,m)]; C
NMR $ = 23.21 (CH3CO), 55.52 (MeO-1), 59.50 (C-2), 64.14 (C-6), 70.62 (C-5), 71.82 (CH2O-3), 79.83
(C-4), 82.63 (C-3), 107.90 (C-1), 128.25 [Ph(p)], 128.25 [Ph(o)], 128.75 [Ph(m)], 137.08 [Ph(ipso)],
169.61 (CH3CO).
Methyl 2-acetamido-5,6-anhydro-3-O-benzyl-2-deoxy-!-D-glucofuranoside (16).
By use of the same procedures described for 8 from 7, compound 15 (2.90 g, 8.91 mmol) was treated with
triphenylphosphine (2.83 g, 10.8 mmol) and DEAD (40% in toluene, 4.30 mL, 10.8 mmol) in toluene (60
mL) to give 16 (2.38 g, 87%) as colorless needles: mp 209–210 oC (from AcOEt-hexane); Rf = 0.36 (A);
1H NMR $ = 1.97 (3H, s, NAc), 2.73 (1H, dd, J6,6’ = 5.0, J5,6’ = 2.6 Hz, H’-6), 2.90 (1H, dd, J5,6 = 4.1 Hz,
H-6), 3.41 (ddt, 1H, J4,5 = 6.7 Hz, H-5), 3.41 (3H, s, MeO-1), 3.84 (1H, t, J3,4 = 6.5, H-4), 4.23 (dd, J2,3 =
2.1 Hz, H-3), 4.40 (dt, 1H, J2,NH = 7.6, J1,2 = 1.2 Hz, H-2), 4.71, 4.81 (1H each, 2d, 2J = 12.3 Hz, CH2O-3),
4.83 (1H, d, H-1), 5.53 (1H, d, HN-2), 7.27 [1H, t, Jm,p = 7.4 Hz, Ph(p)], 7.34 [2H, t, Jo,m = 7.4 Hz, Ph(m)],
7.39 [2H, d, Ph(o)]; 13C NMR $ = 23.24 (CH3CO), 55.79 (MeO-1), 59.12 (C-2), 45.66 (C-6), 49.78 (C-5),

HETEROCYCLES, Vol. 86, No. 2, 2012
1159
55.69 (MeO-1), 60.55 (C-2), 72.02 (CH2O-3), 81.94 (C-4), 82.68 (C-3), 107.84 (C-1), 127.69 [Ph(p)],
127.79 [Ph(o)], 128.36 [Ph(m)], 137.78 [Ph(ipso)], 169.60 (CH3CO). Anal. Calcd for C16H21NO5: C,
62.53; H, 6.89. Found: C, 62.62; H, 6.93.
Methyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-!-D-glucofuranoside (17a)ꢀ and its 3,5-di-O-benzyl
analog (17b).
A. From 16. By use of the same procedures described for 9a from 8, compound 16 (1.70 g, 5.53 mmol)
was treated with benzyl alcohol (2.0 mL, 19.4 mmol) and sodium hydride (60% in mineral oil, 580 mg,
14.5 mmol) in DME (10 mL) to give 17a (1.88 g, 82%).
B. From 15. To a solution of 15 (1.84 g, 5.65 mmol) in toluene (60 ml) was added dibutyltin oxide
(1.72 g, 6.91 mmol) and then the suspension was refluxed under Dean-Stark trap for 15 h. After
removal of the trap, benzyl bromide (1.35 mL, 11.4 mmol) and tetrabutylammonium iodide (1.05 g, 2.84
mmol) were added and the mixture was refluxed for 22 h. The mixture was evaporated in vacuo and the
residue was separated by column chromatography on silica gel to give 17a (1.70 g, 72%) and 17b (430
mg, 18%).
o
26
17a: Colorless needles; mp 103–105 C (from AcOEt-hexane); Rf = 0.42 (A); [!]D ꢀ –122.6 (c 1.04,
1
CHCl3); H NMR $ = 1.98 (3H, s, NAc), 2.92 (1H, d, J5,OH = 3.5 Hz, HO-5), 3.32 (3H, s, MeO-1), 3.63
(1H, dd, J6,6’ = 10.3, J5,6’ = 5.3 Hz, H’-6), 3.70 (1H, dd, J5,6 = 3.1 Hz, H-6), 4.04 (1H, dd, J3,4 = 6.2, J2,3 =
0.9 Hz, H-3), 4.14 (ddt, 1H, J4,5 = 8.8 Hz, H-5), 4.23 (dd, 1H, H-4), 4.47 (dd, 1H, J2,NH = 7.6, J1,2 = 0 Hz,
2
2
H-2), 4.54, 4.59 (1H each, 2d, J = 12.3 Hz, CH2O-6), 4.59, 4.87 (1H each, 2d, J = 12.3 Hz, CH2O-3),
4.77 (1H, s, H-1), 5.72 (1H, d, HN-2), 7.26–7.36 (10H, m, Ph). Anal. Calcd for C23H29NO6: C, 66.49; H,
7.04. Found: C, 66.60; H, 6.99.
17b: Colorless syrup; Rf = 0.30 (A); 1H NMR $ = 1.99 (3H, s, NAc), 3.05 (1H, br s, HO-6), 3.40 (3H, s,
MeO-1), 3.80 (1H, d, J6,6’ = 12.0, J5,6’ = 3.0 Hz, H’-6), 3.92 (1H, dd, J5,6 = 3.5 Hz, H-6), 3.99 (1H, dt, J4,5
= 8.8 Hz, H-5), 4.03 (1H, dd, J3,4 = 5.0, J2,3 = 0.9 Hz, H-3), 4.28 (dd, 1H, H-4), 4.46, 4.52 (1H each, 2d, 2J
2
= 11.2 Hz, CH2O-5), 4.50 (1H, d, J2,NH = 7.6, J1,2 = 0 Hz, H-2), 4.59, 4.88 (1H each, 2d, J = 12.0 Hz,
CH2O-3), 4.84 (1H, s, H-1), 5.58 (d, 1H, HN-2), 7.26–7.36 (10H, m, Ph). Anal. Calcd for C23H29NO6: C,
66.49; H, 7.04. Found: C, 66.68; H, 7.01.
Methyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-!-D-xylo-hexofuranosid-5-ulose (18).
A. Oxidation with oxalyl chloride-DMSO. By use of the same procedures described for 10 from 9a,
compound 17a (1.54 g, 3.71 mmol) was treated with oxalyl chloride (0.960 mL, 11.2 mmol) and DMSO
(1.60 mL, 22.5 mmol) in CH2Cl2 (20 mL) to give 18 (1.44 g, 94%) as a colorless syrup: Rf = 0.37 (A); 1H
NMR # = 1.99 (1H, s, NAc), 3.44 (3H, s, MeO-1), 4.28 (1H, d, J3,4 = 6.2, J2,3 = 0 Hz, H-3), 4.31, 4.37 (1H

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HETEROCYCLES, Vol. 86, No. 2, 2012
each, 2d, J6,6’ = 17.9 Hz, H2-6), 4.33, 4.49 (1H each, 2d, 2J = 11.7 Hz, CH2O-6), 4.46 (1H, d, J2,NH = 7.3,
2
J1,2 = 0 Hz, H-2), 4.53, 4.77 (1H each, 2d, J = 12.0 Hz, CH2O-3), 4.84 (1H, d, H-4), 4.95 (1H, s, H-1),
5.70 (1H, d, HN-2), 7.22–7.38 (10H, m, Ph); 13C NMR $ = 23.10 (CH3CO), 56.07 (MeO-1), 58.92 (C-2),
71.94 (CH2O-3), 73.19 (CH2O-6), 74.23 (C-6), 83.28 (C-3), 85.89 (C-4), 109.33 (C-1), 127.78 and 127.83
[Ph(p)], 127.86 and 128.09 [Ph(o)], 128.32 and 128.37 [Ph(m)], 137.11 and 137.36 [Ph(ipso)], 169.91
(CH3CO), 205.11 (C-5). Anal. Calcd for C23H27NO6: C, 66.81; H, 6.58. Found: C, 66.54; H, 6.61.
B. Oxidation with PCC. To a suspension of PCC (1.38 g, 6.40 mmol) and finely powdered MS3A (2.0
g) in dry CH2Cl2 (20 mL) was added a solution of 17a (1.10 g, 2.65 mmol) in dry CH2Cl2 (5 mL) at 0 oC.
The mixture was stirred at rt for 6 h and then 2-propanol (5.0 mL) was added at 0 oC. The mixture was
stirred for 30 min, diluted with Et2O, and filtered. The filtrate was evaporated in vacuo and the residue
was purified by column chromatography to give 18 (930 mg, 85%).
Methyl (5R)- and (5S)-2-acetamido-3,6-di-O-benzyl-2-deoxy-5-C-dimethoxyphosphoryl-!-D-xylo-ꢀ
hexofuranosides (19).
By use of the same procedures described for 11 from 10, compound 18 (1.37 g, 3.31 mmol) was treated
with dimethyl phosphonate (15 mL) and DBU (0.75 mL, 5.0 mmol) to give (5R)-19 (1.20 g, 69%) and
(5S)-19 (430 mg, 25%).
26
(5R)-19: Colorless prisms; mp 144–145 oC (from AcOEt); Rf = 0.35 (B); [!]D ꢀ –75.3 (c 1.04, CHCl3); 1H
NMR $ = 2.01 (3H, s, NAc), 3.39 (3H, s, MeO-1), 3.64, 3.68 (3H each, 2d, JPOMe = 10.7 Hz, POMe), 3.75
(1H, dd, J6’,P = 12.5, J6,6’ = 8.9 Hz H’-6), 3.90 (1H, dd, J6,P = 26.2 Hz, H-6), 4.28 (1H, d, J3,4 = 4.9, J2,3 =
2
0 Hz, H-3), 4.48 (1H, d, J2,NH = 7.4, J1,2 = 0 Hz, H-2), 4.56, 4.90 (1H each, 2d, J = 11.0 Hz, CH2O-3),
4.59 (1H, d, J4,P = 0 Hz, H-4), 4.60, 4.63 (1H each, 2d, 2J = 11.9 Hz, CH2O-6), 4.86 (1H, d, 5J1,P = 1.0 Hz,
H-1), 4.99 (1H, s, HO-5), 5.75 (1H, d, HN-2), 7.26-7.39 (10H, m, Ph); 31P NMR $ = 26.21. Anal. Calcd
for C25H34NO9P: C, 57.36; H, 6.55. Found: C, 57.47; H, 6.52.
26
1
(5S)-19: Colorless syrup; Rf = 0.26 (B); [!]D ꢀ –74.0 (c 3.47, CHCl3); H NMR $ = 2.01 (3H, s, NAc),
3.44 (3H, s, MeO-1), 3.55 (2H, dd, J6’,P = 25.9, J6,6’ = 9.2 Hz H’-6), 3.77, 3.85 (3H each, 2d, JP,H = 10.5
Hz, MeOP), 3.79 (2H, dd, J6,P = 10.9 Hz, H-6), 4.05 (1H, d, J3,4 = 4.9, J2,3 = 0 Hz, H-3), 4.26, 4.42 (1H
each, 2d, 2J = 11.9 Hz, CH2O-6), 4.29 (1H, br s, HO-5), 4.30, 4.75 (1H each, 2d, 2J = 11.6 Hz, CH2O-3),
5
4.45 (1H, d, J2,NH = 7.3, J2,P = 1.2, J1,2 = 0 Hz, H-2), 4.66 (1H, t, J4,P = 4.6 Hz, H-4), 4.95 (1H, s, H-1),
6.32 (1H, d, HN-2), 7.24–7.35 (10H, m, Ph); 31P NMR $ = 24.84.
Methyl (5R)- and (5S)-2-acetamido-3,6-di-O-benzyl-2-deoxy-5-C-dimethoxyphosphoryl-5-O-
methoxalyl-"-D-xylo-hexofuranosides (20).
By use of the same procedures described for 12 from 11, compound 19 (74:26 diastereomeric mixture,

HETEROCYCLES, Vol. 86, No. 2, 2012
1161
660 mg, 1.26 mmol) was treated with methoxalyl chloride (0.240 mL, 2.51 mmol) and DMAP (433 mg,
3.54 mmol) to give an inseparable diastereomeric mixture (74:26) of 20 (654 mg, 85%) as a colorless
syrup: Rf = 0.40 (B).
(5R)-20: 1H NMR $ = 1.96 (3H, s, NAc), 3.32 (3H, s, MeO-1), 3.70-3.82 (2H, m, H-6, 6’), 3.73, 3.79 (3H
each, 2d, JPOMe = 11.2 Hz, POMe), 3.81 (3H, s, COOMe), 3.97 (1H, dd, J3,4 = 5.3, J2,3 = 1.2 Hz, H-3),
2
4.48 (1H, dd, J2,NH = 7.9, J1,2 = 0 Hz, H-2), 4.51, 4.73 (1H each, 2d, J = 12.0 Hz, CH2O-3 or 6), 4.54,
2
5
4.75 (1H each, 2d, J = 12.0 Hz, CH2O-3 or 6), 4.85 (1H, d, J1,2 = 1.1 Hz, H-1), 5.25 (1H, dd, J4,P =8.8
Hz, H-4), 5.97 (1H, d, HN-2), 7.25–7.38 (10H, m, Ph). Anal. Calcd for C25H34NO9P: C, 57.36; H, 6.55.
Found: C, 57.47; H, 6.52.
(5S)-20: 1H NMR $ = 1.99 (3H, s, NAc), 3.25 (3H, s, MeO-1), 3.70-3.82 (2H, m, H-6, 6’), 3.70, 3.76 (3H
each, 2d, JPOMe = 11.2 Hz, POMe), 3.87 (3H, s, COOMe), 4.07, 4.64 (1H each, 2d, 2J = 10.9 Hz, CH2O-3
2
or 6), 4.09, 4.68 (1H each, 2d, J = 10.9 Hz, CH2O-3 or 6), 4.13 (1H, dd, J3,4 = 5.0, J2,3 = 1.0 Hz, H-3),
4.45 (1H, dd, J2,NH = 9.4, J1,2 = 0 Hz, H-2), 4.83 (1H, s, H-1), 5.13 (1H, dd, J4,P = 3.5 Hz, H-4), 5.92 (1H,
d, HN-2), 7.25–7.38 (10H, m, Ph).
Methyl 2-acetamido-3,6-di-O-benzyl-2,5-dideoxy-5-dimethoxyphosphoryl-!-D-glucofuranoside
(21a) and its "-L-idofuranoside analog (21b).
To a solution of 20 (695 mg, 1.14 mmol) in toluene (5 mL), a solution of AIBN (101 mg, 0.625 mmol)
o
and tributyltin hydride (0.610 mL, 2.27 mmol) in dry toluene (3 ml) was dropwise added at 90 C under
argon. The mixture was stirred at the same temperature for 6 h and then concentrated in vacuo. The
residue was separated by column chromatography with 1:9 EtOH-AcOEt into three fractions A–C.
Fraction A [Rf = 0.68 (B)] gave a pale yellow syrup which mainly consisted of 18 (53.5 mg, 12%).
o
Fraction B [Rf = 0.30 (B)] gave 21a (249 mg, 43%) as colorless needles: mp 113–115 C (from AcOEt);
[#]D29 –52.0 (c 1.07, CHCl3); 1H NMR $ = 2.00 (3H, s, NAc), 2.89 (1H, dddd, J5,P = 19.5, J4,5 = 9.4, J5,6’
= 5.3, J5,6 = 3.2 Hz, H-5), 3.35 (3H, s, MeO-1), 3.58, 3.64 (3H each, 2d, JPOMe = 10.9 Hz, POMe),
3.90–3.96 (2H, m, H,H’-6), 3.96 (d, 1H, J3,4 = 4.2, J2,3 = 0 Hz, H-3), 4.43 (1H, dd, J2,NH = 7.6, J1,2 = 1.2
2
2
Hz, H-2), 4.50, 4.84 (1H each, 2d, J = 11.7 Hz, CH2O-3), 4.54, 4.58 (1H each, 2d, J = 12.0 Hz,
5
CH2O-6), 4.55 (1H, ddd, J4,P = 7.3 Hz, H-4), 4.79 (1H, d, J1,P = 1.2 Hz, H-1), 5.94 (1H, d, HN-2),
7.25–7.37 (10H, m, Ph); 13C NMR $ = 23.19 (CH3CO), 37.50 (d, 1J5,P = 136.9 Hz, C-5), 52.21 (d, 2JC,P
=
2
2
6.7 Hz, POMe), 52.80 (d, JC,P = 6.2 Hz, POMe), 55.79 (MeO-1), 59.12 (C-2), 66.96 (d, J6,P = 8.4 Hz
2
3
C-6), 71.61 (CH2O-3), 73.35 (CH2O-6), 77.82 (d, J4,P = 5.6 Hz, C-4), 82.30 (d, J3,P = 2.3 Hz, C-3),
108.33 (C-1), 127.44 and 127.48 [Ph(p)], 127.60 and 127.83 [Ph(o)], 128.17 and 128.22 [Ph(m)], 138.02
and 138.19 [Ph(ipso)], 169.75 (CH3CO); 31P NMR $ = 32.25. Anal. Calcd for C25H34NO8P: C, 59.16; H,
6.75. Found: C, 59.04; H, 6.78.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Fraction C [Rf = 0.25 (B)] gave 21b (105 mg, 18%) as a colorless syrup; [#]D29 –92.6 (c 2.79, CHCl3); 1H
NMR $ = 2.01 (3H, s, NAc), 2.70 (1H, dddd, J5,P = 18.2, J4,5 = 10.6, J5,6’ = 3.5, J5,6 = 2.9 Hz, H-5), 3.31
(1H, ddd, J6’,P = 31.7, J6,6’ = 9.7 Hz, H’-6), 3.40 (3H, s, MeO-1), 3.68 (1H, d, J3,4 = 4.4, 4J3,P = 1.2, J2,3 = 0
Hz, H-3), 3.69 (1H, ddd, J6,P = 10.7 Hz, H-6), 3.70, 3.75 (3H each, 2d, JPOMe = 10.9 Hz, POMe), 4.15,
4.29 (1H each, 2d, 2J = 12.0 Hz, CH2O-6), 4.40, 4.80 (1H each, 2d, 2J = 11.7 Hz, CH2O-3), 4.41 (1H, dd,
J2,NH = 7.3, 5J2,P = 1.5, J1,2 = 0 Hz, H-2), 4.48 (1H, ddd, J4,P = 7.0 Hz, H-4), 4.89 (1H, s, H-1), 6.19 (1H, d,
HN-2), 7.20–7.33 (10H, m, Ph); 13C NMR $ = 23.10 (CH3CO), 38.43 (d, 1J5,P = 142.5 Hz, C-5), 52.22 (d,
2JC,P = 7.3 Hz, POMe), 52.80 (d, 2JC,P = 6.2 Hz, POMe), 55.73 (MeO-1), 58.76 (C-2), 66.36 (d, 2J6,P = 7.3
Hz C-6), 70.84 (CH2O-3), 73.07 (CH2O-6), 78.35 (d, 2J4,P = 3.9 Hz, C-4), 80.44 (d, 3J3,P = 11.8 Hz, C-3),
108.38 (C-1), 127.66 and 127.75 [Ph(p)], 127.77 and 128.25 [Ph(o)], 128.25 and 128.60 [Ph(m)], 137.34
and 137.74 [Ph(ipso)], 169.89 (CH3CO); 31P NMR $ = 33.29. Anal. Calcd for C25H34NO8P: C, 59.16; H,
6.75. Found: C, 58.98; H, 6.72.
2-Acetamido-1,3,4,6-tetra-O-acetyl-2,5-dideoxy-5-methoxyphosphoryl-D-glucopyranoses (25a–d).
To a solution of 21a (103 mg, 0.203 mmol) in dry toluene (2.0 mL) was added, with stirring, a solution of
0.34 M SDMA in toluene (2.5 mL, 0.85 mmol) in small portions at –5 °C under argon. The stirring was
continued at this temperature for 1.5 h and diluted with benzene. Then, water (0.10 mL) was added to
decompose excess SDMA and the mixture was centrifuged. The precipitate was extracted with several
portions of benzene. The organic layers were combined and evaporated in vacuo, giving the
5-deoxy-5-phosphino derivative (22) as a colorless syrup: Rf = 0.44 (B).
This syrup was immediately treated with 1:1 2-propanol–0.5 M hydrochloric acid (3.0 mL) at 90 °C for 1
h under argon. After cooling, the mixture was evaporated in vacuo. The residue was dissolved in
MeOH (1.0 mL), treated with 30% hydrogen peroxide (0.6 mL, 5.9 mmol) at rt for 12 h and then
concentrated in vacuo. The residue was dissolved in MeOH (1.0 mL), treated with propylene oxide (0.5
mL) at rt for 2 h, and evaporated in vacuo to give crude 5-deoxy-5-hydroxyphosphoryl-D-glucopyranose
derivatives (23) as a colorless syrup.ꢀ
This was dissolved in dry pyridine (1.5 mL), and acetic anhydride (0.6 mL, 6.3 mmol) was added at 0 °C.
The mixture was stirred at rt for 15 h, diluted with a small amount of cold water, and concentrated in
vacuo. The residue was dissolved in methanol and passed through a column of Amberlite IR-120(H+)
(10 mL).
The eluent was evaporated in vacuo and the residue was methylated with
(trimethylsilyl)diazomethane (2M in ether, 0.40 mL, 0.80 mmol) in dry CH2Cl2 (1.0 mL) at rt for 3 h.
After evaporation of the solvent, the residue was purified by column chromatography with 1:1
EtOH-AcOEt to give an inseparable mixture of the 2-acetamido-3,6-O-dibenzyl-2,5-dideoxy-5-
methoxyphosphoryl derivatives (24) as a colorless syrup: Rf = 0.30–0.25 (B).

HETEROCYCLES, Vol. 86, No. 2, 2012
1163
The compounds 24 dissolved in 1:1 EtOH-AcOEt (2.0 mL) was hydrogenated in the presence of 20%
Pd(OH)2-C (3.0 mg) at rt under atmospheric pressure of hydrogen. After 24 h, the catalyst was filtered
off and the filtrate was evaporated in vacuo. The residue was acetylated again with dry pyridine (1.0
mL) and acetic anhydride (0.20 mL). The mixture was evaporated in vacuo and the residue was
sepalated by column chromatography with a gradient eluent of AcOEt to 1:9 EtOH-AcOEt into two
fractions.
The faster-elutiong fraction [Rf = 0.36–0.32 (B)] gave a colorless syrup (17.5 mg), which consisted of the
5-[(R)-methoxyphosphoryl]-#-D-glucopyranose (25a) (7.5% from 21a) and its 5-[(S)-P]-#-isomer (25c)
(11.6%), the ratio being estimated by 1H NMR: 1H and 31P NMR, see Table 1. HRMS (FAB): m/z calcd
for C17H27NO11P [M + H]+ 452.1322, found 452.1333.
The slower-eluting fraction [Rf = 0.34–0.30 (B)] gave a colorless syrup (11.2 mg) which consisted of 25c
(7.2% from 21a), 5-[(R)-P]-!-isomer (25b) (2.7%), and its 5-[(S)-P]-!-isomer (25d) (2.3%), the ratio
being estimated by 1H NMR: 1H and 31P NMR, see Table 1.
2-Acetamido-1,3,4,6-tetra-O-acetyl-2,5-dideoxy-5-methoxyphosphoryl-L-idopyranoses (29a–d).
The procederes similar to those for preparation of compounds 25 from 21a were employed. Thus,
compound 13b (101 mg, 0.206 mmol) were converted into the diasteromeric L-idopyranoses (29) via
intermediates 26, 27, and 28. The crude product 29 was separated by column chromatography into two
fractions.
The faster-eluting fraction [Rf = 0.26–0.22 (B)] gave a colorless syrup (10.2 mg), which consisted of the
5-[(R)-methoxyphosphoryl]-!-L-idopyranose (29a) (3.4% from 13a), its 5-[(R)-P]-#-isomer (29b) (4.3%),
and 5-[(S)-P]-!-isomer (29c) (3.2%), the ratio being estimated by 1H NMR: 1H and 31P NMR, see Table 1.
HRMS (FAB): m/z calcd for C17H27NO11P [M + H]+ 452.1322, found 452.1311.
The slower-eluting fraction [Rf = 0.24–0.20 (B)] gave a colorless syrup (8.5 mg) which consisted of 29b
(4.0% from 13b), its 5-[(S)-P]-!-isomer (29c) (2.2%), and 5-[(S)-P]-#-isomer (29d) (3.0%), the ratio
being estimated by 1H NMR: 1H and 31P NMR, see Table 1.
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
REFERENCES AND NOTES
1. (a) H. Paulsen, Angew. Chem., Int. Ed. Engl., 1966, 5, 495; G. Legler and E. Jülich, Carbohydr. Res.,
1984, 128, 61; (b) T. Niwa, T. Tsuruoka, H. Gori, Y. Kodama, J. Itoh, S. Inoue, Y. Yamada, T. Niida,
M. Nobe, and Y. Ogawa, J. Antibiot., 1984, 37, 1579.

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2. (a) B. Hellman, A. Lernmark, J. Sehlin, I.-B. Taljedal, and R. L. Whistler, Biochem. Pharmacol.,
1973, 22, 29; (b) M. J. Pitts, M. Chmielewski, M. S. Chen, M. M. A. Abd El-Rahman, and R. L.
Whistler, Arch. Biochem. Biophys., 1975, 169, 384; (c) H. Yuasa, M. Izumi, and H. Hashimoto, Yuki
Gosei Kagaku Kyokai Shi, 2002, 60, 774.
3. (a) T. Hanaya and H. Yamamoto, Trends in Heterocyclic Chemistry, 2003, 9, 1; (b) H. Yamamoto
and T. Hanaya, Studies in Natural Products Chemistry, ed. by Atta-ur-Rahman; Elsevier:
Amsterdam, 1990, Vol. 6, pp. 351–384; (c) T. Hanaya and H. Yamamoto, Yuki Gosei Kagaku
Kyokai Shi, 1993, 51, 377.
4. E. Kappes and G. Legler, J. Carbohydr. Chem., 1989, 8, 371.
5. (a) R. Bognar, P. Herczegh, R. L. Whistler, and E. B. Madumelu, Carbohydr. Chem., 1981, 90, 138;
(b) R. D. Guthrie and K. O’Shea, Aust. J. Chem., 1981, 34, 2225; (c) E. Tanahashi, M. Kiso, and A.
Hasegawa, Carbohydr. Res., 1983, 117, 304.
6. (a) H. Yamamoto, T. Hanaya, H. Kawamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T.
Nakashima, J. Org. Chem., 1985, 50, 3516; (b) T. Richter, P. Luger, T. Hanaya, and H. Yamamoto,
Carbohydr. Res., 1989, 193, 9; (c) T. Hanaya, Y. Fujii, S. Ikejiri, and H. Yamamoto, Heterocycles,
1999, 50, 323.
7. (a) T. Hanaya, K. Hirose, and H. Yamamoto, Heterocycles, 1993, 36, 2557; (b) T. Hanaya and H.
Yamamoto, Helv. Chim. Acta, 2002, 85, 2608.
8. (a) S. Hanessian, N. Galeotti, P. Rosen, G. Oliva, and S. Babu, Bioorg. Med. Chem. Lett., 1994, 4,
2763; (b) J. W. Darrow and D. G. Drueckhammer, Bioorg. Med. Chem., 1996, 4, 1341.
9. (a) S. Ito, M. Yamashita, T. Niimi, M. Fujie, K. R. Valluru, H. Totsuka, B. Harutha, K. Maddali, S.
Nakamura, K. Asai, T. Suyama, J. Yamashita, Y. Iguchi, G. Yu, and T. Oshikawa, Heterocycl.
Commun., 2009, 15, 23; (b) M. Yamada, M. Yamashita, T. Suyama, J. Yamashita, K. Asai, T. Niimi,
N. Ozaki, M. Fujie, K. Maddali, S. Nakamura, and K. Ohnishi, Bioorg, Med. Chem. Lett., 2010, 20,
5943.
10. F. Casero, L. Cipolla, L. Lay, F. Nicotra, L. Panza, and G. Russo, J. Org. Chem., 1996, 61, 3428.
11. S. Hanessian and O. Rogel, J. Org. Chem., 2000, 65, 2667.
12. T. Hanaya, K. Sugiyama, and H. Yamamoto, Carbohydr. Res., 2003, 338, 1641.
13. A. Hasegawa and M. Kiso, Carbohydr. Res., 1980, 79, 265.
14. E. A. Mash, S. K. Nimkar, and S. M. DeMoss, J. Carbohydr. Chem., 1995, 14, 1369.
15. Although (5R)- and (5S)-5-hydroxy compounds (11, 19) have no hydrogen atom at C-5 position,
their C-5 configurations were assigned by comparing with the corresponding 5-deoxy compounds
(13a,b and 21a,b) because the similar characteristic tendency of the corresponding coupling
constants and the chemical shifts is expected due to almost identical conformations.

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16. (a) T. Hanaya, H. Yamamoto, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1992, 65, 1154; (b) T.
Hanaya, K. Yasuda, H. Yamamoto, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1993, 66, 2315.
17. H. Mack, J. V. Basabe, and R. Brossmer, Carbohydr. Res., 1988, 175, 311.
18. Y. Guindon, C. Yoakim, V. Gorys, W. W. Ogilvie, D. Delorme, J. Renaud, G. Robinson, J.-F.
Lavallée, A. Slassi, G. Jung, J. Rancourt, K. Durkin, and D. Liotta, J. Org. Chem., 1994, 59, 1166.
19. Y. Guindon, A. Slassi, J. Rancourt, G. Bantle, M. Bencheqroun, L. Murtagh, É. Ghiro, and G. Jung,
J. Org. Chem., 1995, 60, 288.