Synthesis and structural analysis of 6-deoxy-6-hydroxyphosphinyl-d- fructopyranose derivatives

Article abstract of DOI:10.1016/j.carres.2004.10.020

3,4-Di-O-benzyl-6-deoxy-6-diethoxyphosphinyl-1,2-O-isopropylidene-β-d- fructofuranose (13) was prepared from the known 1,2-O-isopropylidene-6-O-tosyl- β-d-fructofuranose in five steps. Reduction of 13 with sodium dihydrobis(2-methoxyethoxy)aluminate, foll

Full text of DOI:10.1016/j.carres.2004.10.020

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 31–37
Synthesis and structural analysis of
6-deoxy-6-hydroxyphosphinyl-D-fructopyranose derivatives
Tadashi Hanaya,* Kumiko Imai, YurijV. Prikhod Õko and Hiroshi Yamamoto
Department of Chemistry, Faculty of Science, Okayama University, Tsushima, Okayama 700-8530, Japan
Received 29 June 2004; accepted 13 October 2004
Available online 21 November 2004
Abstract—3,4-Di-O-benzyl-6-deoxy-6-diethoxyphosphinyl-1,2-O-isopropylidene-b-D-fructofuranose (13) was prepared from the
known 1,2-O-isopropylidene-6-O-tosyl-b-D-fructofuranose in five steps. Reduction of 13 with sodium dihydrobis(2-methoxyeth-
oxy)aluminate, followed by the action of hydrochloric acid and then hydrogen peroxide, afforded the 6-deoxy-6-hydroxyphosphin-
yl-D-fructopyranose derivative. This was converted into the 1,2,3,4,5-penta-O-acetyl-6-deoxy-6-methoxyphosphinyl-D-fructo-
1
pyranoses, whose structure and conformation were established by H NMR spectroscopy.
Ó 2004 Elsevier Ltd. All rights reserved.
Keywords: Phospho sugar; 6-Deoxy-6-phosphinyl-D-fructopyranose; Hydroxyphosphinyl group; Acetyl migration; Conformational analysis
Various sugar analogs containing a heteroatom instead
of oxygen in the hemiacetal ring have been prepared be-
cause of the wide interest in their chemical and biochem-
ical properties.1,2 Heteroatom-in-the-ring sugar analogs
of D-fructopyranose, one of the most abundant ketoses
in nature, have also attracted considerable interest,
along with those of aldoses such as D-glucose and D-
mannose. Meanwhile, thio sugar (1)3 and imino sugar
(2)4 analogs of D-fructopyranose have been synthesized
by chemoenzymatic procedures and various antiradia-
tion properties of the former have been reported.5
With the general objective of a chemical modification
by heteroatoms, we have prepared various sugar analogs
having a phosphorus atom in the ring (phospho sugar),6
in the D-glucopyranose (3)7 and D-mannopyranose (4)
analogs.8 As the first example of a P-in-the-ring ketose,
D-fructopyranose having a phenylphosphinyl group (5)9
has been prepared, although the further synthesis, and
characterization of other ketose analogs remained to
be performed. Hydroxyphosphinyl-in-the-ring sugar
analogs are usually more difficult to prepare and to as-
sign than those having alkyl- or phenylphosphinyl group
in the ring, but are expected to be of interest in view of
potential biological activities.6–10 We describe herein a
convenient synthesis and an unambiguous structural
assignment of D-fructopyranose analogs having a
hydroxyphosphinyl group in the ring.
HO
HO
O
P
X
HO
R
OH
OH
OH
OH
HO
HO
OH
1 X = S
3 (R = OH, Ph, Et)
2 X = NH
HO
O
P
HO
O
R
OH
P
HO
Ph
OH
OH
HO
HO
HO
OH
The 6-deoxy-6-phosphinyl-D-fructofuranose deriva-
tives can be perceived as key intermediates in the prep-
aration of the D-fructopyranose-type phospho sugars,
and we chose benzyl group for protection of the 3,4-hydr-
oxy groups, based on the previous study on the synthesis
of various phospho sugars.7–10
4 (R = OH, Me)
5
*
Corresponding author. Fax: +81 86 251 7853; e-mail: hanaya@
cc.okayama-u.ac.jp
0008-6215/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.10.020

32
T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
TsO
TsO
O
HO
O
BnO
O
O
O
O
O
BnBr
+
O
O
O
NaH
DME
HO
BnO
BnO
7 (18%)
8 (75%)
6
O
TsO
I
(EtO)2P
O
AcO
O
AcO
O
AcO
O
O
O
NaI
Ac2O
P(OEt)3
92%
6
O
O
O
pyridine
98%
acetone
96%
AcO
AcO
AcO
10
9
11
O
O
P
1) NaOEt
(EtO)2P
H2P
1) H+
2) H2O2
O
RO
O
BnO
OH
OH
O
O
SDMA
toluene
EtOH
BnO
O
O
2) BnBr
NaH
HO
BnO
OH
RO
BnO
77%
12 R = H
14
15
13 R = Bn
O
O
O
OMe
P
OH
P OMe
BnO
P
AcO
OMe
1) Ac2O, pyridine
2) CH2N2
1) H2, Pd(OH)2
+
AcO
OAc
OAc
OAc
2) Ac2O, pyridine
AcO
BnO
AcO
AcO
OAc
AcO
AcO
OAc
17b',d'
16a–d
17a–d
Scheme 1.
The starting material, 1,2-O-isopropylidene-6-O-tos-
yl-b-D-fructofuranose (6)9a was prepared from D-fruc-
tose according to the reported method. Benzylation of
6 with benzyl bromide and sodium hydride in DMF
resulted in formation of mainly a 3,6-anhydro-4-O-benz-
yl derivative 8 (75%), along with the desired 3,4-di-O-
benzyl compound 7 (18%) (Scheme 1). As the location
of 3-hydroxy and 6-tosyloxy groups of 6 appears to
favor an intramolecular substitution reaction, we
employed another approach for the preparation of the
key intermediate 13; namely, introduction of a phosphi-
nyl group at C-6 before 3,4-O-benzylation of 6.
Thus, compound 6 was treated with acetic anhydride–
pyridine to provide the 3,4-di-O-acetyl derivative (9),
which was converted into the 6-iodo compound (10).9a
Michaelis–Arbuzov reaction of 10 with triethyl phos-
phite afforded 6-deoxy-6-diethoxyphosphinyl derivative
(11) in 92% yield. Treatment of 11 with sodium ethoxide
in ethanol gave the deacetylated compound (12), which
was converted into the 3,4-di-O-benzyl derivative (13)
by use of benzyl bromide and sodium hydride in 77%
overall yield from 11.
oxidized with hydrogen peroxide to afford 3,4-di-O-
benzyl-6-deoxy-6-hydroxyphosphinyl-a,b-D-fructopyra-
noses (15).
These products were characterized after having been
converted into the corresponding 6-methoxyphosphin-
yl-1,2,5-triacetates (16) by treatment with acetic anhy-
dride–pyridine and then ethereal diazomethane. By
purification on a silica gel column, the crude product
was separated into two fractions. The faster-eluting frac-
tion gave an inseparable mixture of 6-deoxy-6-[(R)-
methoxyphosphinyl]-a-D-fructopyranose (16a) (4.1%
overall yield from 13) and its 6-[(S)-methoxyphosphinyl]
b-isomer (16d) (10%), whereas the slower-eluting frac-
tion gave an inseparable mixture of the 6-[(R)-methoxy-
phosphinyl] b-isomer (16b) (16%) and the 6-[(S)-meth-
oxyphosphinyl] a-isomer (16c) (11%). The molecular
composition of these compounds was confirmed by
FAB-mass spectra, which gave the (M+1)+ ions at m/z
549 corresponding to C27H34O10P.
The precise structures of 16a–d were established by
1
the analysis of their 600MHz H NMR spectra; for all
5
signals assignments, see Figure 1 and Table 1. The C2
Compound (13) was then reduced with sodium
dihydrobis(2-methoxyethoxy)aluminate (SDMA) to give
the 6-deoxy-6-phosphino derivative (14), whose 6-PH2
group was confirmed on the basis of characteristic values
of 1H NMR (1JP,H = 197.3 and 198.6Hz) and 31P NMR
data (d 1.5). The unstable 14 was immediately treated
with hydrochloric acid at 90°C under argon and then
conformation of 16a–d are assigned from the large
values of J3,P (20–36Hz) and J5,6S (11–13Hz) and the
small values of J5,P (6–14Hz) and J3,4 (5–6Hz).6a,8–10
The presence of a long-range W-coupling (J4,6R = 1.0–
1.5Hz) in 16a–d further supports the C2 conformation
having the equatorial-oriented H-4 and HR-6. It has
5
been reported that b-D-fructopyranose derivatives exist

T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
33
the downfield shift (0.15–0.25ppm) of HS-6 from those
of 16b,d (b anomers) having the equatorial AcO
groups.6a
BnO
HR
O
P
O
P
BnO
OMe
OAc
OMe
AcO
AcO
OAc
Hs
To separate of diastereomeric mixtures 16a,d and
16b,c and for their more detailed characterization,
compounds 16 were converted into the correspond-
ing 1,2,3,4,5-tetraacetates 17. Debenzylation of the
mixture of 16a,d by catalytic hydrogenation over 20%
Pd(OH)2–C, followed by acetylation, afforded 1,2,3,4,
5-penta-O-acetyl-6-deoxy-6-[(R)-methoxyphosphinyl]-a-
D-fructopyranose (17a) (83% from 16a), its 6-[(S)-
phosphinyl]b-isomer (17d) (18% from 16d), and the
corresponding 1,3,4,5-tetra-O-acetyl-6-[(S)-phosphin-
yl]b-analog (17d0) (66% from 16d). Meanwhile, similar
treatment of the other mixture, 16b,c, afforded 1,2,3,4,
5-penta-O-acetyl-6-deoxy-6-[(S)-methoxyphosphinyl]-a-
D-fructopyranose (17c) (81% from 16c), its 6-[(R)-phos-
phinyl] b-isomer (17b) (24% from 16b), and the
corresponding 1,3,4,5-tetra-O-acetyl-6-[(R)-phosphinyl]
b analog (17b0) (59% from 16b).
BnO
OAc
BnO
OAc
16b
16a
OMe
OMe
BnO
BnO
P
P
O
AcO
O
AcO
OAc
OAc
BnO
OAc
BnO
OAc
16c
16d
Figure 1. Structures and favored conformations for 16a–d.
in the 2C5 conformation, whereas a-D-fructopyranose
derivatives exist mainly in the C2 conformation.11 It
should be noted therefore that 16a–d all exist predomi-
5
5
5
nantly in the C2 conformation. The C2 preference of
16a–d is most likely attributable to avoidance of the
unfavorable 1,2-trans steric repulsion that would arise
if two benzyloxy groups at C-3 and C-4 were oriented
The precise 1H NMR parameters for 17a–d and
17b0,d0 and their favored conformations in CDCl3 are
shown in Table 2 and Figure 2. Compounds 17a,b0,c,d0
exhibit opposite magnitudes of the corresponding cou-
pling constants in comparison with those of 16a–d: that
is, the small values of J3,P (1–10Hz) and J5,6S (5–7Hz)
and the large values of J5,P (26–35Hz) and J3,4 (9–
10Hz), indicating the 2C5 conformation. Compounds
17b,d have moderate or intermediate magnitudes of
J3,P (15Hz), J5,6S (9Hz), and J5,P (19Hz), and J3,4
(7Hz), suggesting an equilibrium mixture of 2C5 and
2
equatorially in the C5 form. Such conformational flips
of the pyranose rings having two bulky substituents at
the 1,2-trans position have been observed; namely, benz-
yloxy,12 tosyloxy,13 tert-butyldimethylsilyloxy groups.14
With regard to the orientation of the ring P@O group,
a downfield shift (0.15–0.25ppm) of H-5 for 16a,b com-
pared with those of 16c,d indicates the axial P@O orient-
ation for the former and the equatorial P@O
orientation for the latter.6a Similarly, the axial orienta-
tions (a anomers) of AcO-2 in 16a,c are established by
1
5C2 conformers in almost equal ratio.15 The H NMR
spectrum of 17b in a polar solvent (Me2SO-d6) exhibited
Table 1. 1H and 31P NMR parameters for compounds (16a–d) in CDCl3
Compound
Chemical shifts/d
H-1
H-10
H-3
H-4
H-5
HR-6
HS-6
POMe
AcO-1,2,5a
CH2O-3b,c
CH2O-4b,c
31P
16a
16b
16c
16d
5.05
4.93
4.92
5.09
4.76
4.50
4.77
4.67
5.00
4.30
4.86
4.75
3.93
3.93
3.87
4.02
5.55
5.56
5.31
5.41
2.14d
2.29
2.08d
2.17
2.67
2.40
2.65
2.51
3.79
3.82
3.80
3.82
2.04, 2.00, 1.70
2.11, 2.02, 1.95
2.08, 2.005, 1.87
2.07, 2.01, 2.005
4.66, 4.62e
4.80, 4.68g
4.68, 4.62g
4.65, 4.61e
4.41, 4.37f
4.49, 4.38e
4.56, 4.50f
4.63, 4.41h
42.5
39.9
40.9
38.7
Coupling constants/Hz
0
0
J1 ,P
J1,1
J1,P
J3,4
J3,P
J4,5
J4,6R
J5,6R
J5,6S
J5,P
J6R,6S
J6R,P
J6S,P
JPOMe
i
16a
16b
16c
16d
12.0
12.9
11.7
12.9
20.8
3.7
6.2
6.6
4.6
5.6
5.9
5.1
27.3
23.7
19.8
22.4
2.5
2.7
2.5
2.7
1.5
1.2
1.0
1.2
3.6
3.9
3.4
3.7
12.7
11.7
10.5
11.4
5.6
9.0
14.1
14.7
14.5
14.6
13.5
13.2
14.5
10.9
11.0
11.1
10.9
10.5
22.7
i
15.4
7.1
10.0
12.5
13.7
8.8
22.3
a The assignment of acetyl signals may be interchanged.
b The assignment of CH2O-3 or -4 may be interchanged.
c Ph: d = 7.16–7.38 (10H, m).
d The chemical shifts were confirmed by 2D-COSY measurement.
e 2J = 11.7Hz.
f 2J = 11.2Hz.
g 2J = 12.0Hz.
h 2J = 10.7Hz.
i Uncertain because of overlapping with other signals.

34
T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
Table 2. 1H and P NMR parameters for compounds (17a–d, 17b0,d0) in CDCl3
31
Compound
Chemical shifts/d
H-1
H-10
H-3
H-4
H-5
HR-6
HS-6
POMe
AcO-1,2,3,4,5a
HO-2
31P
17a
4.51
4.89
4.79
4.52
4.89
4.95
4.81
4.48
4.37
4.59
4.51
4.28
4.50
4.89
4.85
4.44
5.54
5.76
5.61
5.64
6.07
5.97
5.90
5.78
5.40
5.40
5.27
5.38
5.42
5.41
5.29
5.36
5.48
5.51
5.34
5.46
5.35
5.47
5.30
5.42
2.21
2.47
2.59
2.49
2.13d
2.20
2.36
2.34
2.54
2.38
2.57
2.31
2.59
2.56
2.58
2.36
3.91
3.84
3.72
3.82
3.84
3.87
3.77
3.84
2.15, 2.14, 2.13, 2.10, 2.05
2.13, 2.12, 2.10, 2.07, 2.04
2.09, 2.06, 2.05, 2.00, 1.98
2.13, 2.11, 2.10, 1.98c
42.5
38.5
17b
17bb
17b0
17c
5.24
3.26
43.7
39.1
40.2
2.15, 2.14, 2.13, 2.10, 2.04
2.13, 2.11, 2.10, 2.07, 2.065
2.08, 2.07, 2.065, 2.05, 2.00
2.16, 2.14, 2.13, 2.03c
17d
17db
17d0
42.9
Coupling constants/Hz
0
0
J1 ,P
J1,1
J1,P
J3,4
J3,P
J4,5
J4,6R
J5,6R
J5,6S
J5,P
J6R,6S
J6R,P
J6S,P
JPOMe
17a
11.5
12.7
12.5
12.2
11.0
11.7
11.7
12.2
15.4
4.9
9.5
8.1
8.6
7.6
8.8
10.3
9.3
7.1
6.1
9.8
9.6
15.1
9.3
2.7
2.7
2.9
3.2
2.9
2.9
2.9
2.9
0
3.6
3.2
3.9
3.4
3.2
3.7
3.8
3.4
7.1
9.0
6.6
4.9
7.1
9.3
10.0
5.6
25.7
18.6
25.4
34.7
28.1
18.8
16.0
32.7
15.4
14.9
16.1
16.4
15.6
15.6
14.9
15.4
16.0
20.0
16.6
17.1
14.9
15.9
17.0
18.3
15.3
15.1
17.6
10.5
11.2
11.0
10.7
11.2
11.0
11.0
10.7
17b
0.8
0
17bb
17b0
17c
7.6
7.3
7.6
14.2
17.1
11.0
10.3
16.1
1.0
7.1
0
13.7
e
9.0
0
17d
13.0
14.4
4.9
15.4
18.3
3.4
0.8
0.9
0
19.1
19.3
15.4
17db
17d0
a The assignment of acetyl signals may be interchanged.
b In Me2SO-d6.
c AcO-1,3,4,5.
d The chemical shift was confirmed by 2D-COSY measurement.
e Uncertain because of overlapping with other signals.
OAc
mixture in a ratio similar to that observed in CDCl3 (but
5
HR
OH
with a slight increase of the C2 form).
O
O
OAc
HS
The axial P@O orientations (in the 2C5 form) of
17c,d,d0 are confirmed by the downfield shift (0.2–
0.5ppm) of H-3 from those of the corresponding P-epi-
mers 17a,b,b0, respectively. An appreciable downfield
shift of HR-6 is observed for 17b,b0,d,d0 having the axial
AcO-2 (or HO-2), as compared with those of 17a,c hav-
ing the equatorial AcO-2.
OAc
OAc
P
P
OAc
OMe
OAc
OMe
OAc
AcO
AcO
AcO
17b'
17a
O
OAc
AcO
O
P
OAc
P
OMe
OAc
OAc
The tetraacetates (17b0,d0) appear to be formed as the
results of migration of the 2-O-acetyl group to the
debenzylated 3-hydroxy group in the cis-relationship,
and subsequent acetylation. However, the axial 2-hydr-
oxy groups of 6-deoxy-6-phosphinyl-b-D-fructopyra-
OMe
OAc
AcO
AcO
OAc
17b
OAc
OH
MeO
P
MeO
2
OAc
nose derivatives being in the C5 form do not undergo
OAc
OAc
P
OAc
acetylation under such a conditions as acetic anhy-
dride–pyridine in a manner similar to those of b-D-
fructopyranose and 5-thio-b-D-fructopyranose.3c,16 In
contrast, both an axial and an equatorial 2-hydroxy
group of 6-deoxy-6-phosphinyl-b-D-fructopyranose
O
O
OAc
OAc
AcO
AcO
AcO
AcO
17c
17d'
OMe
OAc
AcO
5
MeO
P
derivatives, being in the C2 form, are readily converted
OAc
P
O
OAc
OAc
into the 2-acetates (16a–d). The reactivity of these terti-
ary hydroxy groups, seemingly depending upon their
conformations, remains to be further studied.
The present work thus demonstrates a convenient
way for preparation and structural assignment of 6-
deoxy-6-hydroxyphosphinyl-D-fructopyranose deriva-
tives. Extension of this work, including applications of
these findings for synthesizing and characterizing
phospho sugar analogs of other ketoses, as well as the
OAc
O
AcO
5C2
OAc
2C5
17d
Figure 2. Structures and favored conformations for 17a–d and 17b0,d0.
2
an equilibrium shift in favor of the C5 form, whereas
17d in Me2SO-d6 was shown to exist as a conformational

T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
35
biological evaluation of D-fructopyranose phospho sug-
ars, is of interest.
10.3Hz, H,H0-1), 4.18 (dd, 1H, J4,5 0.7Hz, H-4), 4.43
(d, 1H, H-5), 4.52, 4.62 (2d, 1H each, 2J 11.7Hz,
CH2O-4), 7.30–7.37 (m, 5H, Ph). Anal. Calcd for
C16H20O5: C, 65.74; H, 6.90. Found: C, 65.81; H, 6.88.
1. Experimental
1.3. 3,4-Di-O-acetyl-6-deoxy-6-diethoxyphosphinyl-1,2-
O-isopropylidene-b-D-fructofuranose (11)
1.1. General methods
All reactions were monitored by TLC (Merck silica gel
60F, 0.25mm) with an appropriate solvent system [(A)
1:2 and (B) 2:1 EtOAc–hexane, (C) EtOAc, (D) 1:19
EtOH–EtOAc]. Column chromatography was per-
formed on Katayama Silica Gel 60K070. Components
were detected by exposing the plates to UV light and/
or spraying them with 20% H2SO4–EtOH (with subse-
quent heating). Optical rotations were measured with a
Jasco P-1020 polarimeter at 28°C in CHCl3. The
NMR spectra were measured in CDCl3 with Varian
Unity Inova AS600 (600 MHz for 1H) and Mercury
300 (121 MHz for 31P) spectrometers at 23°C. Chemical
shifts are reported as d values relative to Me4Si (internal
standard for 1H) and 85% phosphoric acid (external
standard for 31P). The MS spectra were taken on a
VG-70SE instrument and are given in terms of m/z (rela-
tive intensity) compared with the base peak.
A mixture of 109a (620mg, 1.50mmol) and triethyl phos-
phite (3.0mL, 17.5mmol) was heated at 150°C for 18h
with stirring under nitrogen; after 10h, an additional
amount of triethyl phosphite (2.0mL) was added. After
removal of an excess of phosphite in vacuo, the residue
was purified by column chromatography with 3:1
EtOAc–hexane as an eluent to give 11 (585mg, 92%)
as colorless prisms: mp 32–33°C (from 1:4 EtOAc–hex-
28
1
ane); ½aꢀ ꢁ38.3 (c 2.98); Rf 0.51 (C); H NMR: d 1.30,
D
1.31 (2t, 3H each, JEt 7.1Hz, POCCH3), 1.35, 1.49 (2s,
3H each, CMe2), 2.07, 2.11 (2s, 3H each, AcO-3,4),
2.315 (ddd, 1H, J6 ,P 17.8, J6,6 15.4, J5,6 8.1Hz, H-60),
2.36 (ddd, 1H, J6,P 18.8, J5,6 5.6Hz, H-6), 4.05, 4.10
0
0
0
(2d, 1H each, J1,1 9.5Hz, H,H0-1), 4.09, 4.11* (2dq,
0
3
2H each, JH,P 17.1, 14.2*Hz, POCH2), 4.30 (tdd, 1H,
J5,P 8.1, J4,5 4.6Hz, H-5), 5.27 (d, 1H, J3,4 6.4Hz, H-
3), 5.30 (dd, 1H, H-4); 31P NMR: d 27.0. Anal. Calcd
for C17H29O10P: C, 48.11; H, 6.89. Found: C, 48.08;
H, 6.91.
1.2. 3,4-Di-O-benzyl-1,2-O-isopropylidene-6-O-tosyl-b-D-
fructofuranose (7) and 3,6-anhydro-4-O-benzyl-1,2-O-iso-
propylidene-b-D-fructofuranose (8)
1.4. 3,4-Di-O-benzyl-6-deoxy-6-diethoxyphosphinyl-1,2-
O-isopropylidene-b-D-fructofuranose (13)
To a solution of 69a (149mg, 0.398mmol) in dry DMF
(1.0mL) was added, with stirring, sodium hydride
(60% in mineral oil, 35mg, 0.88mmol) and then benzyl
bromide (0.100mL, 0.921mmol) at 0°C. The mixture
was stirred at 0°C for 0.5h. Water (2mL) was added
and then products were extracted with CHCl3 three
times. The combined organic layers were dried (Na2SO4)
and evaporated in vacuo. The residue was separated by
column chromatography with 1:3 EtOAc–hexane as an
eluent to give 7 and 8.
To a solution of 11 (806mg, 1.90mmol) in dry EtOH
(5.0mL) was added, with stirring, a 21% ethanolic solu-
tion of NaOMe (0.05mL, 0.13mmol) at 0°C. After stir-
ring for 1h, the mixture was diluted with EtOH (10mL)
and neutralized with Amberlite IR-120(H+). The resin
was filtered off and washed with EtOH. The filtrate
was evaporated in vacuo to give 6-deoxy-6-diethoxy-
phosphinyl-1,2-O-isopropylidene-b-D-fructofuranose
1
(12) as a pale yellow syrup (640mg): Rf 0.10 (C); H
NMR: d 1.33, 1.34 (2t, 3H each, JEt 7.1Hz, POCCH3),
Compound 7: colorless needles (39.8mg, 18%); mp
28
D
0
83–84°C (from 1:1 EtOAc–hexane); ½aꢀ ꢁ11.2 (c
1.40, 1.49 (2s, 3H each, CMe2), 2.06 (ddd, 1H, J6 ,P
1
16.8, J6,6 14.7, J5,6 11.0Hz, H0-6), 2.34 (ddd, 1H, J6,P
20.2, J5,6 3.9Hz, H-6), 3.15 (br s, 2H, HO-3,4), 3.94
(ddt, 1H, J4,5 6.6, J5,P 3.7Hz, H-5), 3.97 (d, 1H, J3,4
8.3Hz, H-3), 4.01 (dd, 1H, H-4), 4.035, 4.04 (2d, 1H
0
0
1.44); Rf 0.50 (A); H NMR: d 1.35, 1.40 (2s, 3H each,
Me2C), 2.43 (s, 3H, MeC6–S), 3.89, 3.98 (2d, 1H each,
J1,1 9.5Hz, H,H0-1), 3.95 (d, 1H, J3,4 6.1Hz, H-3),
0
4.03–4.11 (m, 4H, H-4,5,6,60), 4.56, 4.565 (2d, 2H each,
2J 11.7Hz, CH2O-3 or 4), 4.655 (s, 1H, CH2O-3 or 4),
7.28–7.36 (m, 5H, Ph), 7.33, 7.77 (2d, 2H each, J
8.3Hz, C6H4–S). FAB MS: 555 (M+1; 8), 539 (12),
497 (15), 185 (25), 91 (100). Anal. Calcd for
C30H34O8S: C, 64.96; H, 6.18. Found: C, 65.01; H, 6.19.
Compound 8: colorless syrup (87.4mg, 75%);
each, J1,1 9.3Hz, H,H0-1), 4.07–4.17 (m, 4H, POCH2);
0
31P NMR: d 28.5.
This syrup was dissolved in DMF (5.0mL) and, with
stirring, sodium hydride (60% in mineral oil, 230mg,
5.75mmol) and then benzyl bromide (0.700mL,
5.90mmol) was added at 0°C under argon. The mixture
was stirred at 20°C for 2h, diluted with saturated
NH4Cl (20mL), and extracted with CHCl3 three times.
The combined organic layers were washed with water,
dried (Na2SO4), and concentrated in vacuo. The residue
28
D
1
½aꢀ ꢁ6.14 (c 3.42); Rf 0.32 (A); H NMR: d 1.46, 1.52
0
0
(2s, 3H each, CMe2), 3.94 (dd, 1H, J6,6 8.6, J5,6
1.2Hz, H-60), 4.00 (d, 1H, J5,6 0Hz, H-6), 4.01 (d, 1H,
0
J3,4 2.4Hz, H-3), 4.015, 4.065 (2d, 1H each, J1,1

36
T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
was purified by column chromatography with 2:1
EtOAc–hexane as an eluent to give 13 (762mg, 77%
through a column of Amberlite IR-120(H+) (20mL).
The eluent was evaporated in vacuo and the residue
was methylated with ethereal diazomethane in dry
CH2Cl2 (2.0mL) at 0°C. After evaporation of the
solvent, the residue was separated by column chroma-
tography with a gradient eluent of 2:1 EtOAc–hexane
to EtOAc into two fractions.
from 11) as colorless needles: mp 52–53°C (from 2:1
28
EtOAc–hexane); ½aꢀ ꢁ22.5 (c 2.00); Rf 0.28 (B); 1H
D
NMR: d 1.29, 1.30 (2t, 3H each, JEt 7.1Hz, POCCH3),
0
1.46, 1.51 (2s, 3H each, CMe2), 2.18 (ddd, 1H, J6 ,P
0
18.8, J6,6 15.4, J5,6 5.9Hz, H-60), 2.25 (ddd, 1H, J6,P
0
0
17.8, J5,6 7.8Hz, H-6), 3.94, 4.02 (2d, 1H each, J1,1
The faster-eluting fraction [Rf 0.49 (D)] gave a color-
less syrup (29.4mg), which consisted of 6-[(R)-methoxy-
phosphinyl]-a-D-fructopyranose (16a) (4.1% from 13)
and its 6-[(S)-P]-b-isomer (16d) (10%), the ratio being
9.5Hz, H,H0-1), 3.945 (d, 1H, J3,4 5.9Hz, H-3), 4.090,
3
4.091* (2dq, 2H each, JH,P 20.2, 21.9*Hz, POCH2),
4.15 (dd, 1H, J4,5 4.6Hz, H-4), 4.27 (ddd, 1H, J5,P
8.1Hz, H-5), 4.64, 4.65 (2d, 1H each, 2J 12.2Hz,
CH2O-3 or 4), 4.67, 4.72 (2d, 1H each, 2J 11.7Hz,
CH2O-3 or 4), 7.28–7.36 (m, 10H, Ph); 31P NMR: d
27.5. FAB MS: 521 (M+1; 8), 377 (10), 337 (12), 287
(15), 247 (28), 215 (19), 181 (24), 91 (100). Anal. Calcd
for C27H37O8P: C, 62.30; H, 7.16. Found: C, 62.26; H,
7.14.
1
1
estimated by H NMR: H and 31P NMR, see Table
1. FAB MS m/z 549 (M+1; 20), 507 (18), 521 (11), 181
(12), 91 (100). Found: m/z 549.1871. Calcd for
C27H34O10P: M+1, 549.1890.
The slower-eluting fraction [Rf 0.42 (D)] gave a color-
less syrup (53.9mg), which consisted of 6-[(R)-methoxy-
phosphinyl]-b-D-fructopyranose (16b) (16% from 13)
and its 6-[(S)-P]-a-isomer (16c) (11%), the ratio being
1
1
1.5. 1,2,5-Tri-O-acetyl-3,4-di-O-benzyl-6-deoxy-6-meth-
oxyphosphinyl-D-fructopyranose (16a–d)
estimated by H NMR: H and 31P NMR, see Table
1. FAB MS m/z 549 (M+1; 22), 507 (15), 521 (13), 181
(24), 91 (100). Found: m/z 549.1878. Calcd for
C27H34O10P: M+1, 549.1890.
To a solution of 13 (192mg, 0.369mmol) in dry toluene
(2.0mL) was added, with stirring, a solution of SDMA
(70% in toluene, 0.25mL, 0.90mmol) in small portions
at ꢁ10°C under argon. The mixture was stirred at this
temperature for 1h. Then, water (0.2mL) was added
to decompose excess SDMA and the mixture was centri-
fuged. The precipitate was extracted with several por-
tions of toluene. The organic layers were combined
and evaporated in vacuo, giving 3,4-di-O-benzyl-6-
deoxy-1,2-O-isopropylidene-6-phosphino-b-D-fructofura-
1.6. 1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-methoxyphos-
phinyl-D-fructopyranose (17a–d) and 1,3,4,5-tetra-O-
acetyl-6-deoxy-6-methoxyphosphinyl-D-fructopyranose
(17b0,d0)
A 28:72 mixture of 16a and 16d (22.0mg, 0.0401mmol)
dissolved in EtOH (1.0mL) was hydrogenated in the
presence of 20% Pd(OH)2–C (8.0mg) at 25°C under
an atmospheric pressure of H2. After 10h, the catalyst
was filtered off and the filtrate was evaporated in vacuo.
The residue was separated by column chromatography
with a gradient eluent of 3:1 EtOAc–hexane to EtOAc
into two fractions.
1
nose (14) as a colorless syrup: Rf 0.78 (B); H NMR: d
0
1.47, 1.51 (2s, 3H each, CMe2), 1.82 (ddq, 1H, J6,6
0
3
14.5, J6 ,PH 10.0, J6 ,P 5.7, J5,6 5.9, J6 ,PH 4.7Hz,
H-60), 1.95 (dddt, 1H, J6 ,PH 9.7, J6,P 7.9, J6,PH 5.5,
2
3
0
0
0
0
3
2
3
0
0
1
2
J5,6 5.3Hz, H-6), 2.63 (dddd, 1H, JP,H 197.3, JH,H
0
0
1
12.1Hz, H0–P), 2.74 (dddd, 1H, JP,H 198.6Hz, H–P),
3.91 (dq, 1H, J5,P 8.3, J4,5 5.1Hz, H-5), 3.97, 4.03 (2d,
1H each, J1,1 9.4Hz, H,H0-1), 4.00 (d, 1H, J3,4 6.4Hz,
The faster-eluting fraction [Rf 0.45 (D)] gave 6-[(S)-
methoxyphosphinyl]-b-D-fructopyranose pentaacetate
1
0
(17d) (2.4mg, 18% from 16d) as a colorless syrup: H
2
H-3), 4.06 (dd, 1H, H-4), 4.62, 4.70 (2d, 1H each, J
and 31P NMR, see Table 2. FAB MS m/z 453 (M+1;
100), 411 (84), 393 (37), 381 (30), 369 (41), 248 (53),
219 (62), 189 (49). Found: m/z 453.1151. Calcd for
C17H26O12P: M+1, 453.1162.
11.7Hz, CH2O-3 or 4), 4.66, 4.74 (2d, 1H each, 2J
11.7Hz, CH2O-3 or 4), 7.27–7.37 (m, 10H, Ph); 31P
NMR: d 1.5.
This syrup was immediately dissolved in 1:1 2-propa-
nol–0.5M HCl (3.0mL) and solution was stirred at
90°C for 2h under argon. After cooling, the mixture
was evaporated in vacuo. The residue was dissolved in
2-propanol (2.0mL), treated with 30% H2O2 (0.6mL,
5.9mmol) at rt for 12h and then concentrated in vacuo
to give crude 3,4-di-O-benzyl-6-deoxy-6-hydroxyphos-
phinyl-a,b-D-fructopyranoses (15) as a colorless syrup:
Rf 0 (C). This was dissolved in dry pyridine (1.5mL),
and Ac2O (0.70mL, 7.4mmol) was added at 0°C. The
mixture was stirred at rt for 24h and concentrated
in vacuo. The residue was dissolved in EtOH and passed
The slower-eluting fraction [Rf 0.36 (D)] gave a color-
less syrup (12.2mg), which consisted of 6-[(R)-P]-a-D-
fructopyranose pentaacetate (17a) (4.2mg, 83% from
16a) and 6-[(S)-P]-b-D-fructopyranose tetraacetate
(17d0) (8.0mg, 66% from 16d), the ratio being estimated
by 1H NMR:1H and 31P NMR, see Table 2. Compound
17d0 was crystallized from EtOAc: mp 91–92°C. Anal.
Calcd for C15H23O11P: C, 43.91; H, 5.65. Found: C,
43.86; H, 5.66.
By use of the same procedures described above, a
60:40 mixture of 16b and 16c (33.0mg, 0.0602mmol)
was converted into the corresponding acetyl derivatives,

T. Hanaya et al. / Carbohydrate Research 340 (2005) 31–37
37
4. Page, P.; Blonski, C.; Perie, J. Tetrahedron 1996, 52, 1557–
1572.
5. Whistler, R. L. U.S. Patent 4,420,489, 1983; Chem. Abstr.
1984, 100, 117256n.
which were separated by column chromatography into
two fractions.
The faster-eluting fraction [Rf 0.49 (D)] gave 6-[(S)-
methoxyphosphinyl]-a-D-fructopyranose pentaacetate
6. (a) Hanaya, T.; Yamamoto, H. Trends Heterocycl. Chem.
2003, 9, 1–18; (b) Yamamoto, H.; Hanaya, T. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Else-
vier: Amsterdam, 1990; Vol. 6, pp 351–384; (c) Hanaya,
T.; Yamamoto, H. Yuki Gosei Kagaku Kyokai Shi 1993,
51, 377–387.
7. (a) Yamamoto, H.; Hanaya, T.; Kawamoto, H.; Inokawa,
S.; Yamashita, M.; Armour, M.-A.; Nakashima, T. T. J.
Org. Chem. 1985, 50, 3516–3521; (b) Richter, T.; Luger,
P.; Hanaya, T.; Yamamoto, H. Carbohydr. Res. 1989, 193,
9–21; (c) Hanaya, T.; Fujii, Y.; Ikejiri, S.; Yamamoto, H.
Heterocycles 1999, 50, 323–332; (d) Yamamoto, H.;
Yamamoto, K.; Kawamoto, H.; Inokawa, S.; Armour,
M.-A.; Nakashima, T. T. J. Org. Chem. 1982, 47, 191–193;
(e) Hanaya, T.; Akamatsu, A.; Isono, T.; Yamamoto, H.
J. Chem. Res. (S) 1994, 434–435.
1
(17c) (8.8mg, 81% from 16c) as a colorless syrup: H
and 31P NMR, see Table 2. FAB MS m/z 453 (M+1;
100), 411 (78), 393 (30), 381 (32), 369 (26), 248 (45),
219 (44), 189 (32). Found: m/z 453.1140. Calcd for
C17H26O12P: M+1, 453.1162.
The slower-eluting fraction [Rf 0.41 (D)] gave a color-
less syrup (12.6mg), which consisted of 6-[(R)-P]-b-D-
fructopyranose pentaacetate (17b) (24% from 16b) and
6-[(R)-P]-b-D-fructopyranose tetraacetate (17b0) (59%
1
from 16b), the ratio being estimated by H NMR:1H
and 31P NMR, see Table 2.
8. (a) Hanaya, T.; Hirose, K.; Yamamoto, H. Heterocycles
1993, 36, 2557–2564; (b) Hanaya, T.; Yamamoto, H. Helv.
Chim. Acta 2002, 85, 2608–2618; (c) Hanaya, T.; Ohmori,
K.; Yamamoto, H.; Armour, M.-A.; Hogg, A. M. Bull.
Chem. Soc. Jpn. 1990, 63, 1174–1179.
Acknowledgements
We are grateful to the SC–NMR Laboratory of Okay-
ama University for the NMR measurements.
9. (a) Hanaya, T.; Okamoto, R.; PrikhodÕko, Y. V.; Armour,
M.-A.; Hogg, A. M.; Yamamoto, H. J. Chem. Soc., Perkin
Trans. 1 1993, 1663–1671; (b) Hanaya, T.; Okamoto, R.;
PrikhodÕko, Y. V.; Yamamoto, H. Chem. Lett. 1991,
1438–1442.
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