Improved syntheses of d-ribo- and 2-deoxy-d-ribofuranose phospho sugars from methyl β-d-ribopyranoside

Article abstract of DOI:10.3987/COM-07-S(U)34

Abstract - Methyl 4-deoxy-4-dimethoxyphosphinoyl-2,3-O-isopropylidene-13-D-ribopyranoside (12a) and methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-13-D-etythro-pentopyranoside (20) were efficiently prepared respectively from methyl2,3-O-isopropylidene-[3-D-rib

Full text of DOI:10.3987/COM-07-S(U)34

HETEROCYCLES, Vol. 73, 2007
581
HETEROCYCLES, Vol. 73, 2007, pp. 581 - 591. © The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2007, Accepted, 6th August, 2007, Published online, 7th August, 2007. COM-07-S(U)34
IMPROVED
SYNTHESES
OF
D-RIBO-
AND
2-DEOXY-D-
RIBOFURANOSE PHOSPHO SUGARS FROM METHYL β-D-
RIBOPYRANOSIDE
Tadashi Hanaya,* Yuko Koga, Heizan Kawamoto, and Hiroshi Yamamoto1
Department of Chemistry, Faculty of Science, Okayama University, Tsushima-
naka, Okayama 700-8530, Japan. E-mail: hanaya@cc.okayama-u.ac.jp
Abstract – Methyl 4-deoxy-4-dimethoxyphosphinoyl-2,3-O-isopropylidene-β-D-
ribopyranoside (12a) and methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-β-D-
erythro-pentopyranoside (20) were efficiently prepared respectively from methyl
2,3-O-isopropylidene-β-D-ribopyranoside (7a) and its 3,4-O-isopropylidene
isomer (7b) in appreciably improved total yields compared with those via
previously reported routes. Compounds (12a, 20) were led to D-ribofuranose
and 2-deoxy-D-ribofuranose phospho sugars (4, 5).
INTRODUCTION
Sugar analogs having carbon,2 nitrogen,3 sulfur,4 or phosphorus5 in place of the ring oxygen have been
prepared because of the wide interest in their chemical and biochemical properties. In view of such a
chemical modification by carbon and heteroatoms, synthesis and biological activities of various
nucleosides of carba, imino and thio sugars have been reported.6 For examples, aristeromycin (1)
terminates viral growth by inhibiting S-adenosyl-L-homocysteine hydrolase,7 whereas oligonucleotides
containing 4’-acetamido-4’-deoxythymidine (2) show considerable resistance to degradation by 3’-
exonucleases8 and 4’-thiothymidine (3) is a potent inhibitor of leukemia L1210 cell growth.9 Although
no corresponding nucleosides of phospho sugars have been made so far, D-ribofuranose-type (4)10 and 2-
deoxy-D-ribofuranose-type phospho sugars (5)11,12 are considered to be highly of interest as potential
precursors for phospho sugar nucleosides.
NH
O
O
N
2
N
N
N
HN
HN
N
O
N
O
O
P
HO
HO
HO
HO
OH
OH
NAc
S
HO R
HO OH
HO
HO
1
2
3
4 R = OH
5 R = H

582
HETEROCYCLES, Vol. 73, 2007
In the first synthesis of 4,10 the key intermediate 4-deoxy-4-phosphinoyl-D-ribopyranoside derivative
(12a) was prepared by starting with methyl 2,3-O-isopropylidene-β-D-ribopyranoside (7a), a minor
component obtained by acetalization of methyl β-D-ribopyranoside (6) (Scheme 1). In this route, the
introduction of a phosphinoyl group onto sugar skeleton was accomplished by the addition of dimethyl
phosphonate to the 4-tosylhydrazone derivative (9) and the subsequent reductive removal of the
tosylhydrazino group of the addition product (10) with sodium borohydride. Although the desired 4-
phosphinoyl-D-ribopyranoside derivative (12a) was obtained with relatively good diastereoselectivity
(85:15), the total yields of 12a from 9 were rather low due to the simultaneous production of various by-
products. We thus attempted an improved synthesis of D-ribofuranose phospho sugar (4) by using our
alternative procedure of C–P bond formation;13 i.e., addition of phosphonate to the 4-ulose (8) and the
subsequent deoxygenation.
In the mean time, 2-deoxy-D-ribofuranose phospho sugar (5) was prepared by two different routes from
D-glucose by rather long steps including degradation of the sugar skeleton.11,12 We also report herein an
improved synthesis of 5 via a shorter route by an effective use of methyl 3,4-O-isopropylidene-β-D-
ribopyranoside (7b), a major component obtained by acetalization of 6, as the starting material.
O
OMe
(MeO) P
OMe
2
O
O
O
O
previous
route
TsNHN
TsNHNH
O
O
9
10
OMe
OMe
OMe
OMe
O
O
O
O
O
O
present
route
4
O
(MeO) P
HO
2
O
O
O
O
O
OMe
O
12a
7a
8
HO
HO
+
OH
OMe
O
OMe
O
O
6
5
O
(MeO) P
2
O
OH
O
OH
7b
OBn
20
17
Scheme 1
RESULTS AND DISCUSSION
Acetalization of methyl β-D-ribopyranoside (6) with acetone-sulfuric acid has been reported to afford the
2,3-O-isopropylidene derivative (7a) and its 3,4-O-isopropylidene isomer (7b) in 23% and 46% yields,
respectively.14 Attempts to modify the acetalization by use of other reagents brought about improved
yields of 7a and 7b but their ratio remained almost the same. Namely, treatment of 6 with 2,2-
dimethoxypropane in the presence of hydrochloric acid at 20 °C provided 7a in 31% and 7b in 63%,

HETEROCYCLES, Vol. 73, 2007
583
while acetalization of 6 with 2-methoxypropene and p-toluenesulfonic acid in DMF at 0 °C resulted in the
similar formation of the two isomers (7a: 32%, 7b: 62%).
Swern oxidation of 7a with oxalyl chloride-DMSO afforded the D-erythro-pentopyranosid-4-ulose (8) in
92% yield (Scheme 2). The addition reaction of dimethyl phosphonate to 8 in the presence of DBU
gave a sole product (in 98% yield), whose structure was assigned to be the (4S)-4-C-dimethoxyphosphinoyl
1
derivative (11) on the basis of H NMR spectra (see below). Compound (11) was converted to the
methoxalyl esters with methoxalyl chloride in the presence of 4-dimethylaminopyridine (DMAP) and the
subsequent reduction with tributyltin hydride in the presence of AIBN15 mainly afforded the desired 4-
deoxy-4-phosphinoyl-D-ribopyranoside derivative (12a) (54%) together with a minor proportion of the L-
lyxopyranoside derivative (12b) (18%).16
The conversion of the major product (12a) into 4-deoxy-4-hydroxyphosphonoyl-D-ribofuranose (4) was
made according to the reported procedures10 with a slight modification: reduction of 12a with sodium
dihydrobis(2-methoxyethoxy)aluminate (SDMA) in toluene at 0 °C, followed by hydrolysis with
hydrochloric acid and then oxidation with hydrogen peroxide, afforded 4. For isolation and
characterization, 4 was converted into the corresponding 4-(methoxyphosphonoyl) tetraacetates (13) by
treatment with acetic anhydride-pyridine and then ethereal diazomethane in improved yields; 4-[(R)-
methoxyphosphonoyl]-α-isomer (13a) (6.3% overall yield from 12a), its β-anomer (13b) (12%), 4-[(S)-
methyoxyphosphonoyl]-α-isomer (13c) (3.2%), and its β-anomer (13d) (5.3%).
O
O
O
1) MeOCOCOCl
DMAP
MeCN, rt
HP OMe
OMe
OMe
(MeO)2P
OMe
OMe (MeO)2P
OMe
O
O
O
O
O
O
O
O
DMSO, (COCl)2
O
+
7a
HO
(MeO)2P
DBU, rt
98%
CH2Cl2, –60 °C
then TEA, 92%
2) Bu3SnH, AIBN
toluene, reflux
O
O
O
O
O
8
11
12a (54%)
12b (18%)
OMe
O
O
MeO
AcO
O
1) SDMA, toluene
0 °C
HO
R2
R1
AcO
R2
P
OH
OH
P
P
1) Ac2O, Py, rt
+
R1
2) HCl, i-PrOH, 90 °C
3) H2O2, rt
2) CH2N2, Et2O, 0 ° C
HO OH
AcO OAc
AcO OAc
13a R1 = OAc, R2 = H
(6.3% from 12a)
13b R1 = H, R2 = OAc (12%)
13c R1 = OAc, R2 = H (3.2%)
13d R1 = H, R2 = OAc (5.3%)
4
Scheme 2
Preparation of 2-deoxy-D-ribofuranose phospho sugar (5) starting with methyl 3,4-O-isopropylidene-β-D-
ribopyranoside (7b) was similarly attempted (Scheme 3). Methyl 2-deoxy-β-D-erythro-pentopyranoside
(15) was prepared from 7b via 14 according to the reported procedures.17 Mono-O-benzylation of 15
was carried out via the 3,4-O-stannylene acetal obtained by treatment of 15 with dibutyltin oxide in
refluxing toluene. The stannylene acetal was then subjected to the benzylation with benzyl bromide in
the presence of tetrabutylammonium bromide in DMF at 100 °C,18 providing the 3-O-benzyl derivative

584
HETEROCYCLES, Vol. 73, 2007
(16a) and the 4-O-benzyl isomer (16b) in 42% and 45% yields, respectively. The yield of desired 16a
was improved by practice of the same reaction in refluxing toluene;19 16a (55%), 16b (40%).
1) CS2, MeI, NaOH
DMSO, rt
1) Bu2SnO
toluene, reflux
OMe
OMe
OMe
OMe
+
OMe
O
O
O
O
O
80% AcOH
rt, 98%
O
O
HO
HO
BnO
2) Bu3SnH, AIBN
toluene, reflux
2) BnBr, Bu4NBr
toluene, reflux
OH
O
O
OH
15
OBn
OH
86%
7b
14
16a (55%)
16b (40%)
O
O
1) MeOCOCOCl
DMAP, MeCN, rt
HP OMe
OMe
OMe
R2
OMe
(MeO)2P
OMe
O
OMe
O
O
O
DMSO, (COCl)2
O
16a
+
DBU, rt
93%
2) Bu3SnH, AIBN
toluene, reflux
R1
OBn
CH2Cl2, –60 °C
then TEA, 90%
(MeO)2P
OBn
OBn
OBn
O
18a R1 = P(O)(OMe)2, R2 = OH
18b R1 = OH, R2 = P(O)(OMe)2
17
19a (53%)
19b (35%)
O
OMe
O
O
1) SDMA
toluene, 0 °C
1) Ac2O
Py, rt
MeO
AcO
HO
R2
R1
AcO
R2
P
OMe
O
P
OH
OH
P
H2/ Pd-C
MeOH, rt
90%
+
19a
2) CH2N2
Et2O
0 ° C
R1
2) HCl, i-PrOH
90 °C
3) H2O2, rt
(MeO)2P
OH
O
HO
AcO
AcO
21a R1 = OAc, R2 = H
(5.2% from 20)
21b R1 = H,
21c R1 = OAc,
R2 = H (6.8%)
21d R1 = H,
R2 = OAc (9.9%)
20
5
R2 = OAc (8.2%)
Scheme 3
The 3-O-benzyl compound (16a) was oxidized with oxalyl chloride-DMSO to give the 4-ulose (17),
which was then treated with dimethyl phosphonate and DBU to provide the (4R)-4-
dimethoxyphosphinoyl derivative (18a) and its (4S)-epimer (18b) as an inseparable mixture (53:47) in
93% yield. By use of same procedures for 12 from 11, deoxygenation of 18a,b afforded the desired 2,4-
dideoxy-4-phosphinoyl-D-erythro-pentopyranoside (19a) and its L-threo-isomer (19b) in 53% and 35%
yields, respectively,16 although its stereoselectivity (60:40) was lower than that of 12 from 11 (75:25).
The C-4 configurations and conformational assignments of the 4-dimethoxyphosphinoyl compounds (11,
1
12a,b and 18a,b, 19a,b) were established by the analysis of their H NMR data (Table 1). The favored
conformations of these compounds in CDCl3 are shown in Figure 1. The D-ribo and D-erythro
4
configurations of 12a and 19a, as well as their C1 conformation, were assigned on the basis of the small
J3,4 (3–4 Hz) and the large J4,5S values (9–12 Hz). Similarly, the L-lyxo and L-threo configurations (with
1C4 conformations) of 12b and 19b were derived from the large J3,4 and J4,5R values (9–10 Hz).
1
Although compounds (11 and 18b) have no H-4 proton, their (4R)-configurations and C4 conformations
were assigned by respective comparison to the corresponding 4-deoxy compounds (12b and 19b),
because a similar characteristic tendency of the corresponding coupling constants and the chemical shifts
is expected owing to almost identical conformations. For example, the presence of long-range couplings
J2,P (for 11, 12b) and J2S,P (for 18b, 19b) indicates all of these compounds exist in the 1C4 conformations

HETEROCYCLES, Vol. 73, 2007
585
and have an equatorial phosphinoyl group, whereas the (4S)-epimer (18a) has the large J3,P and J5R,P
values (20–21 Hz) and thus is considered to exist in the 1C4 conformation.
1
31
Table 1. H and P NMR Parameters for Compounds (11, 12a,b, 18a,b, 19a,b) in CDCl
3
——————————————————————————————————————————————
Chemical shifts / δ
Com- ———————————————————————————————————————————
pound H-1 HR-2 HS-2 a H-3 H-4 HR-5 HS-5 MeO-1 POMe b Me2C
CH2O-3 c
HO-4
P
31
——————————————————————————————————————————————
11
4.89
4.38
4.79
–
–
–
4.09 4.58
–
3.80 3.95 3.42 3.87, 3.83 1.59, 1.40
–
–
–
3.07 23.3
12a
12b
18a
18b
19a
19b
3.92 4.62 2.73 3.92 3.83 3.46 3.77, 3.74 1.53, 1.38
3.96 4.50 2.34 3.80 d 3.78 d 3.39 3.77, 3.765 1.52, 1.35
–
–
27.4
29.6
4.63 2.28 2.05 3.96
4.81 1.96 2.06 4.28
–
–
3.71 4.01 3.38 3.78, 3.735
3.78 3.92 3.33 3.74, 3.72
–
–
–
–
4.70, 4.56 e 3.75 25.7
4.64, 4.61 f 3.75 24.6
4.64, 4.625 e
4.62, 4.56 f
4.71 2.26 1.58 3.96 2.39 3.99 4.01 3.44 3.69, 3.62
–
29.9
4.81 1.60 2.26 4.14 2.29 3.88 3.86 3.32 3.71, 3.655
–
29.7
——————————————————————————————————————————————
Coupling constants / Hz
———————————————————————————————————————————
J
J
J
J
J
J
J
J
J
J
J
J
J
J J J
5R,5S 5R,P 5S,P
1,2R
1,2S
1,5S 2R,2S 2R,3
2R,P
2S,3 2S,P 3,4
3,P
4,5R
4,5S 4,P
——————————————————————————————————————————————
11
–
1.7 1.6
4.9
2.0 2.0
–
–
–
–
–
–
–
0
6.6 2.2
6.3
–
8.3
–
–
–
12.5 4.5 1.0
12a
12b
18a
18b
19a
19b
–
0
–
0
2.9
3.6 5.6 11.8 23.7 11.3 1.2 4.3
–
–
5.2 2.2 8.6 11.3 8.9 5.1 18.8
d
d
d
3.4
3.4
2.7
3.4
4.7 0.8 13.4
8.6
4.6
0
–
–
21.0
4.2
–
–
–
–
–
–
12.0 20.0 6.6
12.9 4.0 1.5
1.5 1.8 12.9 11.2
7.8 13.7 5.1
2.2 2.2 12.9 10.5
1.0 5.1 5.1
4.6 3.2
0.7 4.4 5.6 10.0
0
0
3.7 13.4 4.6 8.8 20.8 11.8 9.5 4.8
8.1 10.3 5.9 17.1 11.7 3.4 4.4
——————————————————————————————————————————————
b
c
a The parameters concerning H-2 of 11 and 12a,b are listed as HS-2.
2JPOMe = 10.7–11.0 Hz.
δ = 7.37 [Ph(o)],
e
f
7.34 [Ph(m)], 7.28 [Ph(p)]. d Uncertain because of overlapping with other signals.
2J = 11.5 Hz. 2J = 11.1
Hz.
R
OMe
OMe
H
OMe
O
O
O
O
O
O
O
S
(MeO) P
(MeO) P
O
O
OMe
2
2
OMe
H
(MeO) P
O
(MeO) P
s
2
2
HO
H
O
OBn
OBn
R
BnO
O
R
R
O
(MeO) P
H
2
O
11 R = OH
12b R = H
12a
18a
18b R = OH
19b R = H
19a
Figure 1. Structures and favored conformations for the 4-dimethoxyphosphinoylpyranosides (11, 12a,b,
18a,b, and 19a,b)

586
HETEROCYCLES, Vol. 73, 2007
The hydrogenolysis of the major isomer (19a) in the presence of 10% Pd-C afforded methyl 2,4-dideoxy-
4-dimethoxyphosphinoyl-β-D-erythro-pentopyranoside (20) in 90% yield. By use of same procedures
described for 4 from 12a, compound (20) was converted into 2-deoxy-D-ribofuranose phospho sugar (5),
which was characterized after having been converted into the corresponding 4-methoxyphosphonoyl
1,3,5-tri-O-acetates (21): 4-[(R)-methoxyphosphonoyl]-α-isomer (21a) (5.2% overall yield from 20), its
β-anomer (21b) (8.2%), 4-[(S)-methoxyphosphonoyl]-α-isomer (21c) (6.8%), and its β-anomer (21d)
(9.9%).
Thus, improved syntheses of 4 and 5 from the common starting material (6) were achieved via shorter
routes involving alternative procedures to introduce a phosphinoyl group in better overall yields.
Extension of this work including the improvement of stereoselectivity for C-P bond formation, as well as
derivation of 4 and 5 into the corresponding nucleosides, is in progress.
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) 1:2, (B) 2:1 AcOEt–hexane, and (C) 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 Unity
1
13
31
Inova AS600 (600 MHz for H, 151 MHz for C) and Mercury 300 (121 MHz for P) spectrometer at
23 °C. Chemical shifts are reported as δ values relative to CHCl3 (7.26 ppm as an internal standard for
1H), CDCl3 (77.0 ppm as 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 C-H COSY
measurements.
Methyl 2,3-O-isopropylidene-β-D-ribopyranoside (7a) and its 3,4-O-isopropylidene isomer (7b).14,17
A. Acetalization with 2,2-dimethoxypropane-HCl. To a solution of methyl β-D-ribopyranoside (6)
(5.00 g, 30.3 mmol) in 2,2-dimethoxypropane (50 mL) was added 4M hydrochloric acid in 1,4-dioxane
(1.50 mL). The mixture was stirred at 25 °C for 1 h, neutralized with pyridine, and then concentrated in
vacuo. The residue was separated by column chromatography with 2:1 AcOEt-hexane to give 7a (1.91
g, 31%) and 7b (3.88 g, 63%).
7a: Colorless prisms, mp 70–71 °C (from AcOEt-hexane) (lit.,14 70–71 °C); Rf = 0.41 (B); 1H NMR20 δ =
1.375, 1.55 (3H each, 2s, Me2C), .2.22 (1H, br s, HO-4), 3.44 (3H, s, MeO-1), 3.60 (1H, dd, J5,5’ = 11.2,
J4,5’ = 7.8 Hz, H’-5), 3.80 (1H, dd, J4,5 = 4.6 Hz, H-5), 4.00 (1H, dt, J3,4 = 4.2 Hz, H-4), 4.05 (1H, dd, J2,3
= 6.4, J1,2 = 3.7 Hz, H-2), 4.38 (1H, dd, H-3), 4.57 (1H, d, H-1).
7b: Colorless prisms, mp 65–66 °C (from AcOEt-hexane) (lit.,17 64–65 °C); Rf = 0.29 (B); 1H NMR20 δ =
1.37, 1.55 (3H each, 2s, Me2C), .2.30 (1H, br s, HO-2), 3.46 (3H, s, MeO-1), 3.65 (1H, dd, J1,2 = 5.6, J2,3
= 3.9 Hz, H-2), 3.70 (1H, dd, J5,5’ = 12.9, J4,5’ = 3.2 Hz, H’-5), 3.80 (1H, dd, J4,5 = 3.4 Hz, H-5), 4.27 (1H,
dt, J3,4 = 6.6 Hz, H-4), 4.48 (1H, dd, H-3), 4.62 (1H, d, H-1).
B. Acetalization with 2-methoxypropene-TsOH. To a solution of 6 (200 mg, 1.21 mmol) in dry DMF

HETEROCYCLES, Vol. 73, 2007
587
(2.0 mL) were added 2-methoxypropene (0.230 mL, 2.40 mmol) and p-toluenesulfonic acid monohydrate
(2.0 mg, 0.011 mmol) at 0 °C. The mixture was stirred at same temperature for 30 min and then worked
up with the same procedures described above, giving 7a (78.9 mg, 32%) and 7b (154 mg, 62%).
Methyl 2,3-O-isopropylidene-β-D-erythro-pentopyranosid-4-ulose (8).10
To a solution of oxalyl chloride (1.15 mL, 13.4 mmol) in dry CH2Cl2 (10 mL) was added a solution of
DMSO (2.00 mL, 27.9 mmol) in dry CH2Cl2 (5.0 mL) at –60 °C. After stirring for 20 min, a solution of
7a (1.09 g, 5.34 mmol) in dry CH2Cl2 (5.0 mL) was slowly added at –60 °C. The mixture was stirred at
same temperature for 6 h and then TEA (4.70 mL, 33.8 mmol) was added. The mixture was stirred at rt
for 30 min, diluted with CHCl3, washed with water, dried (Na2SO4), and evaporated in vacuo. The
residue was purified by column chromatography with 2:1 AcOEt-hexane to give 8 (993 mg, 92%) (lit.,10
94% yield by use of PCC) as a colorless syrup: Rf = 0.64 (B).
Methyl (4S)-4-C-dimethoxyphosphinoyl-2,3-O-isopropylidene-β-D-erythro-pentopyranoside (11).
DBU (1.15 mL, 7.70 mmol) was dropwise added to a solution of 8 (1.50 g, 7.42 mmol) in dimethyl
phosphonate (15.0 mL, 163 mmol) at 0 °C and the solution was stirred at rt for 1 h under argon. The
mixture was treated with saturated NH4Cl at rt for 1 h and extracted with CHCl3 three times. The
combined organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The
residue was recrystallized with AcOEt and hexane to give 11 (2.27 g, 98%) as colorless needles: mp
25
1
31
13
65–66 °C; Rf = 0.48 (C); [α]D –38.9° (c 1.10); H and P NMR, see Table 1; C NMR δ = 24.83 and
26.04 (CMe2), 53.45 and 54.31 [2JC,P = 7.5, 6.3 Hz, P(OMe)2], 55.01 (MeO-1), 60.35 (2J5,P = 9.8 Hz, C-5),
69.27 (1J4,P = 168.1 Hz, C-4), 70.77 (2J3,P = 1.7 Hz, C-3), 73.34 (3J2,P = 9.8 Hz, C-2), 98.53 (C-1), 109.91
(CMe2). Anal. Calcd for C11H21O8P: C, 42.31; H, 6.78. Found: C, 42.19; H, 6.90.
Methyl 4-deoxy-4-dimethoxyphosphinoyl-2,3-O-isopropylidene-β-D-ribo- (12a) and α-L-
lyxopyranoside (12b).10
Methoxalyl chloride (0.800 mL, 8.70 mmol) was added to a solution of 11 (780 mg, 2.50 mmol) and
DMAP (1.06 g, 8.68 mmol) in dry acetonitrile (20 mL) at 0 °C. The mixture was stirred at rt for 1 h
under argon and then poured into water. Most of the solvent was distilled off in vacuo. The residue
was dissolved in CHCl3, washed with saturated NH4Cl and then with water, dried (Na2SO4), and
evaporated in vacuo to give the 4-O-methoxalyl derivative as a pale yellow syrup: Rf = 0.78 (C).
The crude syrup was coevaporated with dry toluene and dissolved in the same solvent (15 mL).
Tributyltin hydride (1.10 mL, 4.09 mmol) and AIBN (70 mg, 0.43 mmol) were added under argon. The
mixture was stirred at 80 °C for 2 h and then concentrated in vacuo. The residue was separated by
column chromatography with a gradient eluant of 2:1 AcOEt–hexane to AcOEt to give 12a and 12b.
1
31
13
12a: Colorless syrup (402 mg, 54%); Rf = 0.26 (C); H and P NMR, see Table 1; C NMR δ = 25.53
and 27.37 (CMe2), 35.45 (1J4,P = 141.1 Hz, C-4), 52.16 and 53.30 [2JC,P = 6.9, 5.8 Hz, P(OMe)2], 56.49
(MeO-1), 59.00 (2J5,P = 4.0 Hz, C-5), 70.47 (2J3,P = 7.5 Hz, C-3), 74.86 (3J2,P = 12.1 Hz, C-2), 101.56 (C-
1), 110.22 (CMe2).

588
HETEROCYCLES, Vol. 73, 2007
1
31
13
12b: Colorless syrup (134 mg, 18%); Rf = 0.30 (C); H and P NMR, see Table 1; C NMR δ = 26.16
and 28.15 (CMe2), 37.74 (1J4,P = 139.3 Hz, C-4), 52.49 and 52.75 [2JC,P = 6.4, 6.3 Hz, P(OMe)2], 55.37
(MeO-1), 56.28 (2J5,P = 1.0 Hz, C-5), 70.35 (2J3,P = 4.0 Hz, C-3), 72.97 (3J2,P = 8.6 Hz, C-2), 99.15 (C-1),
109.28 (CMe2).
1,2,3,5-Tetra-O-acetyl-4-deoxy-4-methoxyphosphonoyl-D-ribofuranose (13a–d).10
The following modification of the literature procedures10 was made. To a solution of 12a (200 mg,
0.675 mmol) in dry toluene (2.0 mL) was added, with stirring, a solution of SDMA (70% in toluene,
0.500 mL, 1.80 mmol) in dry toluene (1.0 mL) in small portions at –5 °C under argon. The stirring was
continued at 0 °C for 1 h. Then, water (0.4 mL) was added to decompose excess SDMA and the mixture
was centrifuged. The precipitate was extracted with several portions of toluene. The organic layers
were combined and evaporated in vacuo, giving the 4-deoxy-4-phosphino derivative as a colorless syrup:
Rf = 0.68 (C).
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 2-
propanol (2.0 mL), treated with 30% hydrogen peroxide (0.6 mL, 5.9 mmol) at rt for 12 h and then
concentrated in vacuo to give crude 4-deoxy-4-hydroxyphosphonoyl-D-ribofuranose (4) as a colorless
syrup.
This was dissolved in dry pyridine (2.0 mL) and then acetic anhydride (1.0 mL, 11 mmol) was added at
0 °C. The mixture was stirred at rt for 12 h, diluted with a small amount of cold water, and concentrated
in vacuo. The residue was dissolved in ethanol and passed through a column of Amberlite IR-120(H+)
(20 mL). The eluent was evaporated in vacuo and the residue was methylated with ethereal
diazomethane in dry CH2Cl2 (2.0 mL) at 0 °C. After evaporation of the solvent, the residue was
separated by column chromatography with a gradient eluent of 2:1 AcOEt-hexane to AcOEt into three
fractions A–C.
Fraction A [Rf = 0.46 (C)] gave the 4-[(R)-methoxyphosphinyl]-β-D-ribofuranose (13b) as colorless syrup
[31.3 mg, 12% from 12a (lit.,10 6.3%)].
Fraction B (Rf = 0.40) gave a colorless syrup (29.8 mg) which consisted of 4-[(R)-P]-α-isomer (13a)
1
[6.3% (lit.,10 3.3%)] and 4-[(S)-P]-β-isomer (13d) [5.3% (lit.,10 2.8%)], the ratio being estimated by H
NMR.
Fraction C (Rf = 0.35) gave 4-[(S)-P]-α-isomer (13a) as a colorless syrup [8.3 mg, 3.2% (lit.,10 1.7%)].
Methyl 3-O-benzyl-2-deoxy-β-D-erythro-pentopyranoside (16a) and its 4-O-benzyl isomer (16b).19
To a solution of 15 (808 mg, 5.45 mmol) in toluene (20 mL) was added dibutyltin oxide (1.40 g, 5.62
mmol) and the suspension was refluxed under a Dean-Stark trap for 12 h. After removal of the trap,
benzyl bromide (0.770 mL, 6.47 mmol) and tetraammonium bromide (1.00 g, 3.10 mmol) were added
and the mixture was refluxed for 24 h. The mixture was evaporated in vacuo and the residue was
separated by column chromatography with 1:2 AcOEt-hexane to give 16a and 16b.
30
27
16a: Colorless syrup (719 mg, 55%); Rf = 0.21 (A); [α]D –98.5° (c 1.22) [lit.,19 [α]D –81.6° (c 15.4,

HETEROCYCLES, Vol. 73, 2007
589
1
CH2Cl2)]; H NMR20 δ = 1.91 (1H, dddd, J2R,2S = 13.2, J2S,3 = 5.0, J1,2S = 2.4, J2S,4 = 1.2 Hz, HS-2), 1.95
(1H, br s, HO-4), 2.04 (1H, ddd, J2R,3 = 11.0, J1,2R = 3.4 Hz, HR-2), 3.34 (3H, s, MeO-1), 3.75 (1H, dd,
J5,5’ = 12.5, J4,5’ = 2.3 Hz, H’-5), 3.765 (1H, dd, J4,5 = 2.3 Hz, H-5), 3.87 (1H, ddd, J3,4 = 3.2 Hz, H-3),
2
3.92 (1H, dtd, H-4), 4.58, 4.60 (1H each, 2d, JH,H = 11.7 Hz, CH2O-3), 4.80 (1H, dd, H-1), 7.30–7.36
(5H, m, Ph).
16b: Colorless syrup (522 mg, 40%) (lit.,19 mp 37–39 °C); Rf = 0.27 (A); [α]D –125.6° (c 1.48) [lit.,19
30
[α]D27 –126.0° (c 7.26, MeOH)];1H NMR20 δ = 1.84 (1H, dddd, J2R,2S = 13.1, J2S,3 = 4.4, J1,2S = 3.4, J2S,4
=
1.0 Hz, HS-2), 1.95 (1H, br s, HO-4), 1.98 (1H, ddd, J2R,3 = 9.6, J1,2R = 3.2 Hz, HR-2), 3.37 (3H, s, MeO-1),
3.60 (1H, dddd, J4,5 = 4.5, J4,5’ = 2.2 Hz, H-4), 3.72 (1H, dd, J5,5’ = 12.5 Hz, H’-5), 3.82 (1H, dd, H-5),
2
4.05 (1H, ddd, J3,4 = 3.4 Hz, H-3), 4.55, 4.73 (1H each, 2d, JH,H = 11.7 Hz, CH2O-3), 4.76 (1H, t, H-1),
7.30–7.36 (5H, m, Ph).
Methyl 3-O-benzyl-2-deoxy-β-D-glycero-pentopyranosid-4-ulose (17).
By use of the same procedures described for 8 from 7a, compound (16a) (380 mg, 1.59 mmol) was
treated with oxalyl chloride (0.400 mL, 4.66 mmol) and DMSO (0.650 mL, 9.07 mmol) in dry CH2Cl2
(4.0 ml) to give 17 (339 mg, 90%) as a colorless syrup: Rf = 0.25 (A); [α]D30 –166.6° (c 1.05); 1H NMR δ
= 2.15 (1H, ddd, J2R,2S = 13.0, J2R,3 = 11.7, J1,2R = 3.4 Hz, HR-2), 2.48 (1H, ddd, J2S,3 = 6.8, J1,2S = 2.2 Hz,
HS-2), 3.42 (3H, s, MeO-1), 3.96 (1H, d , 2J5R,5S = 14.9 Hz, HR-5), 4.17 (1H, d, HS-5), 4.37 (1H, dd, H-3),
4.57, 4.88 (1H each, 2d, 2JH,H = 11.7 Hz, CH2O-3), 4.92 (1H, dd, H-1), 7.29 [1H, m, Ph(p)], 7.34 [2H, m,
13
Ph(m)], 7.37 [2H, m, Ph(o)]; C NMR δ = 38.13 (C-2), 55.53 (MeO-1), 67.35 (C-5), 72.65 (CH2O-3),
74.45 (C-3), 98.55 (C-1), 127.80 [Ph(o)], 127.88 [Ph(p)], 128.45 [Ph(m)], 137.60 [Ph(ipso)], 204.98 (C-4).
Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 65.89; H, 6.92.
Methyl (4R)-3-O-benzyl-2-deoxy-4-C-dimethoxyphosphinoyl-β-D-glycero-pentopyranoside (18a)
and its (4S)-epimer (18b).
By use of the same procedures described for 11 from 8, compound (17) (550 mg, 2.33 mmol) was treated
with dimethyl phosphonate (5.0 mL, 54 mmol) and DBU (0.400 mL, 2.68 mmol) to give an inseparable
mixture (53:47) of 18a,b (750 mg, 93%) as a colorless syrup: Rf = 0.40 (C); 1H and 31P NMR, see Table 1.
Anal. Calcd for C15H23O7P: C, 52.02; H, 6.69. Found: C, 52.22; H, 6.51.
Methyl 3-O-benzyl-2,4-dideoxy-4-dimethoxyphosphinoyl-β-D-erythro- (19a) and α-L-threo-
pentopyranoside (19b).
By use of the same procedures described for 12 from 11, compounds (18a,b) (500 mg, 1.44 mmol) was
treated with methoxalyl chloride (0.400 mL, 4.35 mmol) and DMAP (530 mg, 4.34 mmol) in dry
acetonitrile (10 mL). The resulting crude syrup [Rf = 0.67 (C)] of the 4-O-methoxalyl derivatives was
then treated with tributyltin hydride (0.700 mL, 2.60 mmol) and AIBN (45 mg, 0.28 mmol) in dry toluene
(10 mL). The products were separated by column chromatography with a gradient eluant of 2:1 AcOEt-
hexane to AcOEt to give 19a and 19b.
1
19a: Colorless syrup (251 mg, 53%); Rf = 0.30 (C); H and 31P NMR, see Table 1. Anal. Calcd for

590
HETEROCYCLES, Vol. 73, 2007
C15H23O6P: C, 54.54; H, 7.02. Found: C, 54.63; H, 6.90.
1
19b: Colorless syrup (167 mg, 35%); Rf = 0.23 (C); H and 31P NMR, see Table 1. Anal. Calcd for
C15H23O6P: C, 54.54; H, 7.02. Found: C, 54.72; H, 7.11.
Methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-β-D-erythro-pentopyranoside (20).11
To a solution of 19a (200 mg, 0.605 mmol) in methanol (5.0 mL) was added 10% Pd-C (65 mg, 0.061
mmol). The mixture was stirred at rt for 12 h under atmospheric pressure of hydrogen. The catalyst
was filtered off and the filtrate was evaporated in vacuo. The residue was purified by short-path column
chromatography with 1:19 MeOH-CHCl3 to give 20 (131 mg, 90%) as colorless needles: mp 101–102 °C
(lit.,11 101–102 °C); Rf = 0.05 (C).
1,3,5-Tetra-O-acetyl-2,4-dideoxy-4-methoxyphosphonoyl-D-erythro-pentofuranose (21a–d).11
The procedures similar to those for the preparation of 13 from 12a were employed. Thus, compound
(20) (190 mg, 0.781 mmol) were converted into 21 via 2,4-dideoxy-4-hydroxyphosphonoyl-D-erythro-
pentofuranose (5). The crude product (21) was separated by column chromatography into two fractions.
The faster-eluting fraction [Rf = 0.44 (C)] gave a colorless syrup (33.7 mg) which consisted of 4-[(R)-P]-
α-isomer (21a) [5.2% (lit.,11 3.9%)] and 4-[(R)-P]-β-isomer (21b) [8.2% (lit.,11 6.1%)], the ratio being
estimated by 1H NMR.
The slower-eluting fraction (Rf = 0.39) gave a colorless syrup (42.0 mg) which consisted of 4-[(S)-P]-α-
isomer (21c) [6.8% (lit.,11 5.2%)] and 4-[(S)-P]-β-isomer (21d) [9.9% (lit.,11 7.5%)], the ratio being
estimated by 1H NMR.
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
REFERENCES AND NOTES
1. Present address: School of Pharmacy, Shujitsu University, Okayama 703-8516, Japan.
2. S. Ogawa, Yuki Gosei Kagaku Kyokaishi, 1985, 43, 26; T. Suami and S. Ogawa, Adv. Carbohydr.
Chem. Biochem., 1990, 48, 21.
3. H. Paulsen, Angew. Chem., Int. Ed. Engl., 1966, 5, 495; G. Legler and E. Jülich, Carbohydr. Res.,
1984, 128, 61; 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.
4. B. Hellman, A. Lernmark, J. Sehlin, I.-B. Taljedal, and R. L. Whistler, Biochem. Pharmacol., 1973,
22, 29; M. J. Pitts, M. Chmielewski, M. S. Chen, M. M. A. Abd El-Rahman, and R. L. Whistler,
Arch. Biochem. Biophys., 1975, 169, 384; H. Yuasa, M. Izumi, and H. Hashimoto, Yuki Gosei
Kagaku Kyokai Shi, 2002, 60, 774.
5. T. Hanaya and H. Yamamoto, Trends in Heterocyclic Chemistry, 2003, 9, 1; H. Yamamoto and T.
Hanaya, Studies in Natural Products Chemistry, ed. by Atta-ur-Rahman; Elsevier: Amsterdam, 1990,

HETEROCYCLES, Vol. 73, 2007
591
Vol. 6, pp. 351–384; T. Hanaya and H. Yamamoto, Yuki Gosei Kagaku Kyokai Shi, 1993, 51, 377.
6. V. E. Marquez and M.-U. Lim, Med. Res. Rev., 1986, 6, 1; M. Yokoyama and A. Momotake,
Synthesis, 1999, 1541; M. Yokoyama, Synthesis, 2000, 1637.
7. E. De Clercq, Biochem. Pharmacol., 1987, 36, 2567.
8. K.-H. Altman, S. M. Freier, U. Pieles, and T. Winkler, Angew. Chem., Int. Ed. Engl., 1994, 33, 1654.
9. W. B. Parker, S. C. Shaddix, L. M. Rose, K. N. Tiwari, J. A. Montgomery, J. A. Secrist III, and L. L.
Bennett, Jr., Biochem. Pharmacol., 1995, 50, 687.
10. T. Hanaya and H. Yamamoto, Bull. Chem. Soc. Jpn., 1989, 62, 2320.
11. T. Hanaya, A. Noguchi, M.-A. Armour, A. M. Hogg, and H. Yamamoto, J. Chem. Soc., Perkin
Trans. 1, 1992, 295.
12. T. Hanaya, H. Tsukui, N. Igi, A. Noguchi, H. Kawamoto, and H. Yamamoto, Heterocycles, 2007, 72,
411.
13. T. Hanaya, K. Sugiyama, H. Kawamoto, and H. Yamamoto, Carbohydr. Res., 2003, 338, 1641; T.
Hanaya and H. Yamamoto, Helv. Chim. Acta, 2002, 85, 2608; T. Hanaya, K. Sugiyama, Y. Fujii, A.
Akamatsu, and H. Yamamoto, Heterocycles, 2001, 55, 1301.
14. N. A. Hughes and C. D. Maycock, Carbohydr. Res., 1974, 35, 247.
15. S. C. Dolan and J. MacMillan, J. Chem. Soc., Chem. Commun., 1985, 1588.
16. As the reduction of the 4-O-methoxalyl derivatives proceeds via a radical intermediate formed by a
homolytic cleavage of the O—C-4 bond, the ratios of 4-deoxy products (12a:12b and 19a:19b) are
not correlated to the C-4 configuration of their corresponding 4-hydroxy precursors (11 and 18a,b).
The predominant production of 12a (from 11) and 19a (from 18a,b) seems to be ascribed to a
preferential approach of tin hydride to the radical C-4 from the less hindered upper side of the ring.
The mechanistic proposals for the radical-mediated reduction of α-methoxalyloxyphosphonates have
been reported in Ref. 13.
17. S. Inokawa, T. Mitsuyoshi, H. Kawamoto, H. Yamamoto, and M. Yamashita, Carbohydr. Res., 1985,
142, 321.
18. I. I. Cubero, M. T. P. López-Espinosa, R. R. Díaz, and F. F. Montalbán, Carbohydr. Res., 2001, 330,
401; M. N. Nashed, Carbohydr. Res., 1978, 60, 200.
19. E. A. Mash, S. K. Nimkar, and S. M. DeMoss, J. Carbohydr. Res., 1995, 14, 1369.
20. The complete parameters for 7a,b and 16a,b obtained in the present study are shown here, because
1H NMR data for these compounds including insufficient assignments were reported in Ref. 14 and
19.