A new route for preparation of 2-deoxy-D-ribofuranose phospho sugar

Article abstract of DOI:10.3987/COM-06-S(K)28

The addition reaction of dimethyl phosphonate to (2R,4S)-4-(tert-butyldimethylsilyl)oxymethyl-2-methyl-1,3-dioxan-5-one (11a), followed by dehydroxylation, provided 1-O-(tert-butyldimethylsilyl)-3-deoxy-3-dimethoxy-phosphinoyl-2,4-O-ethylidene-d-erythritol (13a). Elongation of carbon skeleton of the d-erythrose (14) derived from 13a and then acidic methanolysis gave a mixture of methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-α,β-d-erythro-pentopyranosides (7), which was led to 2-deoxy-D-ribofuranose phospho sugar (4) in an appreciably improved total yield compared with the procedures via previously reported route.

Full text of DOI:10.3987/COM-06-S(K)28

HETEROCYCLES, Vol. 72, 2007
411
HETEROCYCLES, Vol. 72, 2007, pp. 411 - 420. © The Japan Institute of Heterocyclic Chemistry
Received, 29th November, 2006, Accepted, 21st December, 2006, Published online, 26th December, 2006. COM-06-S(K)28
A NEW ROUTE FOR PREPARATION OF 2-DEOXY-D-RIBOFURANOSE
PHOSPHO SUGAR
Tadashi Hanaya,* Hiroyuki Tsukui, Naomi Igi, Ayashi Noguchi, 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 – The addition reaction of dimethyl phosphonate to (2R,4S)-4-(tert-
butyldimethylsilyl)oxymethyl-2-methyl-1,3-dioxan-5-one (11a), followed by
dehydroxylation, provided 1-O-(tert-butyldimethylsilyl)-3-deoxy-3-dimethoxy-
phosphinoyl-2,4-O-ethylidene-D-erythritol (13a). Elongation of carbon skeleton
of the D-erythrose (14) derived from 13a and then acidic methanolysis gave a
mixture
of
methyl
2,4-dideoxy-4-dimethoxyphosphinoyl-ꢀ,ꢁ-D-erythro-
pentopyranosides (7), which was led to 2-deoxy-D-ribofuranose phospho sugar
(4) in an appreciably improved total yield compared with the procedures via
previously reported route.
INTRODUCTION
A large number of sugar analogs containing nitrogen,2 sulfur,3 or phosphorus4 as a ring heteroatom have
been prepared due to a wide variety of interest in their chemical and biochemical properties. In view of
such a chemical modification by heteroatoms, synthesis and biological activities of various nucleosides of
imino and thio sugars have been reported;5 e.g., 4’-thiothymidine (1) is a potent inhibitor of leukemia
L1210 cell growth,6 while oligonucleotides containing 4’-acetamido-4’-deoxythymidine (2) show
considerable resistance to degradation by 3’-exonucleases.7 No corresponding nucleosides of phospho
sugars is known. D-Ribofuranose-type (3)8 and 2-deoxy-D-ribofuranose-type phospho sugars (4)9 are
thus considered to be highly of interest as potential precursors for phospho nucleosides.
O
N
O
HN
HN
O
O
N
O
P
HO
HO
HO
S
NAc
OH
OH
HO
HO
HO R
1
2
3 R = OH
4 R = H

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HETEROCYCLES, Vol. 72, 2007
In the first synthesis of 4,9 the introduction of a phosphinoyl group onto the sugar skeleton was
accomplished by the addition of dimethyl phosphonate to the 5,6-dideoxy-6-nitro-hex-5-enofuranose
derivative (5)10 in the presence of triethylamine (TEA) (Scheme 1). Although the desired 5-
phosphinoyl-D-ribo-hexofuranose derivative (6a) was obtained preferentially over the L-lyxo epimer (6b),
the stereoselectivity of the reaction was not so high (66:34). Moreover, the conversion of 6-nitro group
of 6a into its 6-hydroxy derivative and the subsequent conversion into methyl 2,4-dideoxy-4-
dimethoxyphosphinoyl-ꢀ,ꢁ-D-erythro-pentopyranosides (7) required multi-step procedures, thus causing
the overall yield of 7 rather low. We describe herein an improved synthesis of 2-deoxy-D-ribofuranose
phospho sugar (4) by a new route from D-glucose via the 3-phosphinoy-D-erythritol derivative (13a)
obtained by using our alternative procedure;11,12 i.e., addition of phosphonate to the ketone (11a) and the
subsequent deoxygenation.
O
O
NO
O
O N
2
CHNO
2
2
O
HO
HO
(MeO) P
P(OMe)
2
2
CH
O
O
8 steps
H P(OMe)
O
2
OH
OH
TEA
O
O
O
O
O
O
OH
+
D-glucose
5
6a
6b
6 steps
O
O
O
O
O
OMe
4
P(OMe)
2
O
(MeO) P
2
O
TBDMSO
TBDMSO
OH
O
11a
13a
7
Scheme 1
RESULTS AND DISCUSSION
D-Glucose served as the starting material for preparation of the key intermediate (11a) to introduce a
phosphinoyl group, as illustrated in Scheme 2. The reported procedures13 for preparation of 2,4-O-
ethylidene-D-erythritol (9) from D-glucose via 4,6-O-ethylidene-D-glucopyranose (8) were slightly
modified to give 8 and 9 in improved yields. The selective protection of 9 with tert-butyldimethylsilyl
(TBDMS) chloride in the presence of TEA and 4-dimethylaminopyridine (DMAP) provided the 1-O-
TBDMS derivative (10)14 in 95% yield. Swern oxidation of 10 with oxalyl chloride-DMSO afforded the
desired ketone (11a) (61%) together with its diastereomer (11b) (30%). As production of 11b can be
perceived as the results of epimerization caused by treatment with TEA, we examined oxidation of 10 to
11a with other conditions. Thus, treatment of 10 with pyridinium chlorochromate (PCC) in
dichloromethane afforded 11a as a sole product (82%), while use of Dess-Martin periodinane as an
oxidizing agent much improved the yield of 11a (95%).

HETEROCYCLES, Vol. 72, 2007
413
1) NaIO
4
O
O
HO
paraldehyde
H SO
rt, 0.5 h
OH 2) NaBH
4
TBDMSCl
O
O
O
OH
D-glucose
TEA, DMAP
2
4
OH
HO
rt, 48 h
92%
rt, 0.5 h
84%
CH Cl , rt, 8 h
2
2
8
9
95%
O
O
O
O
O
O
oxidation
OH
+
O
O
OTBDMS
TBDMSO
TBDMSO
10
11a
11b
DMSO, (COCl) then TEA
2
61%
82%
95%
30%
0%
PCC, MS-3A
Dess-Martin periodinane
0%
Scheme 2
The addition reaction of dimethyl phosphonate to 11a in the presence of DBU gave the (3R)-3-
dimethoxyphosphinoyl-tetritol derivative (12a) and its (3S)-epimer (12b) as an inseparable mixture
(41:59) in 94% yield (Scheme 3). The mixture of 12a,b was converted to the methoxalyl esters with
methoxalyl chloride in the presence of DMAP and then reduced with tributyltin hydride in the presence of
AIBN,15 mainly affording the 3-deoxy-3-phosphinoyl-D-erythritol derivative (13a) (69%) together with a
minor proportion of the L-threitol isomer (13b) (18%).
O
1) MeOCOCOCl
S
H
HP OMe
OMe
DMAP, MeCN
rt, 1 h
4
R
O
H
O
O
1
O
R
O
P(OMe)
2
O
+
O
11a
13a
2
3
2
TBDMSO
P(OMe)
O
DBU, rt, 2 h
94%
2) Bu SnH, AIBN
2
TBDMSO
3
R
TBDMSO
1
toluene
1
2
12a R = P(O)(OMe) , R = OH
2
13a (69%)
13b (18%)
80 °C, 2 h
1
2
12b R = OH, R = P(O)(OMe)
2
–
Cl
O
O
O
+
DMSO, (COCl)
Bu NF
2
4
Ph P CH OMe
3
2
O
P(OMe)
2
O
P(OMe)
2
O
CH Cl , –60 °C
THF, rt, 1 h
96%
2
2
LHMDS, THF
rt, 5 h
HO
CHO
4 h, then TEA
89%
14
15
O
2
1
R
R
O
O
O
HO
P
OH
OH
MeOH
1) SDMA, toluene
2) HCl, i-PrOH
P(OMe)
2
O
+
(MeO) P
2
Amberlite IR-120(H )
OH
O
OMe
reflux, 12 h
3) H O
HO
2
2
1
2
16
7a R = OMe, R = H (22% from 15)
4
1
2
7b R = H, R = OMe (42%)
Scheme 3

414
HETEROCYCLES, Vol. 72, 2007
The D-erythro configuration of 13a was assigned on the basis of the large J2,3 and J3,4S values (10.1 and
11.9 Hz). Similarly, the L-threo configuration of 13b was derived from the large J2,P and J4S,P values
(41.8 and 34.8 Hz). Although compounds (12a,b) have a hydroxy group at C-3, their configurations at
C-3 were assigned by comparison to the corresponding 3-deoxy compounds (13a,b), respectively,
because a similar characteristic tendency of the corresponding coupling constants and the chemical shifts
is expected owing to almost identical conformations. As for the predominant production (79:21) of the
D-erythritol derivative (13a) by the radical reduction of the 3-O-methoxalyl intermediates, we propose a
preferential approach of tin hydride to the radical intermediate16 (A) from the opposite side of the axial H-
2 and HS-4 protons (Figure 1).
S
H
H
O
O
P(OMe)
O
2
TBDMSO
Bu Sn
H
3
A
Figure 1. A plausible conformation for the radical intermediate (A) and the direction of reduction.
The major product (13a) was then oxidized with oxalyl chloride-DMSO to give the 3-deoxy-3-
phosphinoyl-D-erythrose derivative (15), which was treated with (methoxymethyl)triphenylphosphonium
chloride and lithium hexamethyldisilazide (LHMDS) to afford the 4-deoxy-4-phosphinoyl-1-O-methyl-D-
erythro-pent-1-enitol derivative (16). As the purification of 16 by column chromatography was not
successful because of contamination of phosphorus impurities, the product was isolated after having been
converted into methyl pyranoside derivatives. Namely, treatment of crude 16 with methanol in the
presence of an acidic ion-exchange resin, followed by chromatographic separation, provided methyl 2,4-
dideoxy-4-dimethoxyphosphinoyl-ꢀ-D-erythro-pentopyranoside (7a) (22% yield from 15) and its ꢁ-
anomer (7b) (42%). According to the previous procedures,9 these products (7a,b) were reduced with
sodium dihydrobis(2-methoxyethoxy)aluminate (SDMA), followed by hydrolysis with acid and then
oxidation with hydrogen peroxide, to afford 2-deoxy-D-ribofuranose phospho sugar (4).
Thus an improved synthesis of 4 from D-glucose was achieved via a 3-step-shorter route involving
alternative procedures to introduce a phosphinoyl group in a 2.5 times better overall yield. Extension of
this work including applications of these findings in synthesizing other phospho sugars, as well as
derivation of 4 into phospho sugar nucleosides, is in progress.
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) 1:19, (B) 1:9 MeOH-CHCl3, (C) 1:4, (D) 1:1 AcOEt–hexane, and (E) 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

HETEROCYCLES, Vol. 72, 2007
415
heating). Optical rotations were measured with a Jasco P-1020 polarimeter in CHCl3. The NMR
1
13
spectra were measured in CDCl3 with Varian Unity Inova AS600 (600 MHz for H, 151 MHz for C)
31
and Mercury 300 (121 MHz for P) spectrometer at 23 °C. Chemical shifts are reported as ꢀ values
relative to CHCl3 (7.26 ppm as an internal standard for 1H), CDCl3 (77.0 ppm as internal standard for 13C),
13
and 85% phosphoric acid (0 ppm as an external standard for 31P). The assignments of C signals were
made with the aid of 2D C-H COSY measurements.
4,6-O-Ethylidene-ꢁ,ꢂ-D-glucopyranoses (8).13
The following modification of the literature procedures13 was made. A mixture of D-glucose (20.0 g,
111 mmol) and paraldehyde (15.0 mL, 111 mmol) containing sulfuric acid (0.12 mL, 2.2 mmol) was
stirred at rt for 30 min and then set under ultrasonic irradiation at 30–35 °C for 48 h. The mixture was
dissolved in hot ethanol (60 mL) and neutralized with 1M ethanolic potassium hydroxide. The mixture
was passed through celite and the filtrate was evaporated in vacuo. The residue was crystallized twice
from ethanol to give 8 (total 21.1 g, 92%) as colorless crystals: mp 176–178 °C (lit.,13 mp 179–181 °C,
70–80% yield); Rf = 0.14 (B).
2,4-O-Ethylidene-D-erythritol (9).13
Modification of the literature procedures13 was made as follows. A solution of 8 (3.01 g, 14.6 mmol) in
water (12 mL) was added dropwise to a solution of sodium periodate (6.30 g, 29.4 mmol) in water (100
mL) at 0–5 °C with keeping the pH value at ca. 4–5 by adding 4M aqueous NaOH. After stirring at
same temperature for 30 min, the pH value was adjusted to ca. 9–10 by adding 4M aqueous NaOH and
then sodium borohydride (1.74 g, 46.0 mmol) was added. The mixture was stirred at rt for 30 min,
neutralized with diluted sulfuric acid, and concentrated in vacuo. The residue was dissolved in hot
CHCl3 and the precipitates were filtered off. The filtrate was evaporated in vacuo and the residue was
purified by column chromatography with 1:9 MeOH-CHCl3 as an eluant to give 9 (1.82 g, 84%) as
colorless plates: mp 98–99 °C (lit.,13 mp 99–100 °C, 78% yield); Rf = 0.32 (B).
1-O-(tert-Butyldimethylsilyl)-2,4-O-ethylidene-D-erythritol (10).14
The following modification of the literature procedures14 was made. tert-Butyldimethylsilyl chloride
(6.60 g, 43.8 mmol) was added to a solution of 9 (5.39 g, 36.4 mmol), TEA (6.10 mL, 43.8 mmol), and
DMAP (200 mg, 1.60 mmol) in dry CH2Cl2 (80 mL). The mixture was stirred at rt for 8 h and diluted
with CHCl3 (80 mL). The mixture was washed with saturated NH4Cl and then water, dried (Na2SO4),
and evaporated in vacuo. The residue purified by column chromatography with 1:4 AcOEt-hexane as an
eluant to give 10 [9.08 g, 95% (lit.,14 95%)] as a colorless syrup: Rf = 0.38 (C); 1H NMR17 ꢀ = 0.10, 0.11
(3H each, 2s, Me2Si), 0.90 (9H, s, Me3C), 1.30 (3H, d, JMe,H = 5.0 Hz, MeCH), 3.35 (1H, br s, HO-3),
3.40 (1H, dd, J4R,4S = 11.0, J3,4S = 10.0 Hz, HS-4), 3.49 (1H, td, J2,3 = 8.8, J1’,2 = 8.3, J1,2 = 4.9 Hz, H-2),
3.73 (1H, ddd, J3,4R = 5.4 Hz, H-3), 3.75 (1H, dd, J1,1’ = 9.8 Hz, H’-1), 3.93 (1H, dd, H-1), 4.13 (1H, dd,
13
HR-4), 4.67 (1H, q, MeCH); C NMR ꢀ = –5.64, –5.59 (Me2Si), 18.14 (Me3C), 20.40 (MeCH), 25.78
(Me3C), 66.16 (C-1), 66.37 (C-3), 70.04 (C-4), 78.44 (C-2), 98.75 (MeCH).

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HETEROCYCLES, Vol. 72, 2007
(2R,4S)-4-(tert-Butyldimethylsilyl)oxymethyl-2-methyl-1,3-dioxan-5-one (11a) and its (2R,4R)-
epimer (11b).
A. Oxidation with oxalyl chloride-DMSO. 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 10 (1.40 g, 5.34 mmol) in dry CH2Cl2 (5.0 mL) was
slowly added at –60 °C. The mixture was stirred at same temperature for 5 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 separated by column chromatography with
1:5 AcOEt-hexane to give 11a (848 mg, 61%) and 11b (422 mg, 30%).
11a: Colorless syrup: Rf = 0.38 (C); 1H NMR17 ꢀ = 0.06, 0.08 (3H each, 2s, Me2Si), 0.88 (9H, s, Me3C),
2
1.45 (3H, d, J2,Me = 5.1 Hz, Me-2), 3.98 (1H, dd, JH,H’ = 11.3, J4,CH’ = 3.1 Hz, CH’-OSi), 4.00 (1H, dd,
J4,CH = 4.3 Hz, CH-OSi), 4.25 (1H, dd, J6,6’ = 18.0, J4,6’ = 1.2 Hz, H’-6), 4.29 (1H, ddt, J4,6 = 1.0 Hz, H-4),
4.32 (1H, dd, H-6), 5.10 (1H, q, H-2); 13C NMR ꢀ = –5.37, –5.26 (Me2Si), 18.33 (Me3C), 20.49 (Me–C-2),
25.79 (Me3C), 62.89 (CH2OSi), 72.69 (C-6), 83.89 (C-4), 97.18 (C-2), 205.41 (C-5).
1
11b: Colorless syrup; Rf = 0.63 (C); H NMR ꢀ = 0.03, 0.06 (3H each, 2s, Me2Si), 0.88 (9H, s, Me3C),
2
1.41 (3H, d, J2,Me = 5.1 Hz, Me-2), 3.93 (1H, dd, JH,H’ = 10.7, J4,CH’ = 2.4 Hz, CH’-OSi), 4.07 (1H, dd,
J4,CH = 3.1 Hz, CH-OSi), 4.22 (1H, dd, J6,6’ = 18.0, J4,6’ = 1.4 Hz, H’-6), 4.29 (1H, td, H-4), 4.38 (1H, dd,
H-6), 5.56 (1H, q, H-2); 13C NMR ꢀ = –5.71, –5.62 (Me2Si), 18.16 (Me3C), 20.57 (Me–C-2), 25.79
(Me3C), 66.23 (CH2OSi), 73.95 (C-6), 81.14 (C-4), 96.70 (C-2), 206.28 (C-5).
B. Oxidation with PCC. To a suspension of PCC (615 mg, 2.86 mmol) and finely powdered MS3A
(1.0 g) in dry CH2Cl2 (8 mL) was added a solution of 10 (370 mg, 1.42 mmol) in dry CH2Cl2 (4 mL).
The mixture was stirred at rt for 6 h and then 2-propanol (0.5 mL) was added. The mixture was stirred
for 30 min, diluted with ether, and filtered. The filtrate was evaporated in vacuo and the residue was
purified by column chromatography to give 11a (303 mg, 82%) ( lit.,14 75% yield using CrO3-pyridine).
C. Oxidation with Dess-Martin periodinane. To a solution of 10 (200 mg, 0.762 mmol) in dry
CH2Cl2 (5.0 mL) was added a solution of Dess-martin periodinane (420 mg, 0.990 mmol) in dry CH2Cl2
(5.0 mL) at 0 °C. The mixture was stirred at rt for 8 h and then diluted with CHCl3 (20 mL). The
mixture was washed with saturated sodium thiosulfate and then saturated NaHCO3, dried (Na2SO4), and
evaporated in vacuo. The residue was purified by column chromatography to give 11a (188 mg, 95%).
(3R)-1-O-(tert-Butyldimethylsilyl)-3-C-dimethoxyphosphinoyl-2,4-O-ethylidene-D-glycero-tetritol
(12a) and its (3S)-epimer (12b).
DBU (2.30 mL, 15.4 mmol) was dropwise added to a solution of 11a (3.09 g, 11.9 mmol) in dimethyl
phosphonate (25.0 mL, 272 mmol) at 0 °C and the solution was stirred at rt for 2 h under argon. The
mixture was treated with saturated NH4Cl at rt for 30 min and extracted with CHCl3 three times. The
combind organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The residue
was purified by column chromatography with a gradient eluant of 2:1 AcOEt-hexane to AcOEt to give an
inseparable mixture (41:59) of 12a and 12b (4.13 g, 94%) as colorless solid: Rf = 0.42 (E). Anal. Calcd

HETEROCYCLES, Vol. 72, 2007
417
for C14H31O7PSi: C, 45.39; H, 8.43. Found: C, 45.28; H, 8.54.
1
12a: H NMR ꢀ = 0.10, 0.12 (3H each, 2s, Me2Si), 0.91 (9H, s, Me3C), 1.38 (3H, d, JMe,H = 4.9 Hz,
MeCH), 3.82, 3.85 [3H each, 2d, JPOMe = 10.7 Hz, P(OMe)2], 3.84 (1H, m, H-2), 3.89 (1H, dd, J4R,4S
=
11.9, 4J4S,OH = 1.8, J4S,P = 0 Hz, HS-4), 3.99 (1H, ddd, J1,1’ = 11.6, J1’,2 = 2.8, J1’,P = 1.0 Hz, H’-1), 4.01
(1H, dd, J4R,P = 2.7 Hz, HR-4), 4.28 (1H, dd, J1,2 = 3.4 Hz, H-1), 4.75 (1H, q, MeCH), 5.05 (1H, dd, JOH,P
= 5.8 Hz, HO-3); 31P NMR ꢀ = 22.5.
4
1
12b: H NMR ꢀ = 0.10, 0.12 (3H each, 2s, Me2Si), 0.90 (9H, s, Me3C), 1.36 (3H, d, JMe,H = 4.9 Hz,
MeCH), 3.48 (1H, dd, J4S,P = 28.7, J4R,4S = 11.3 Hz, HS-4), 3.72 (1H, ddd, J2,P = 31.1, J1,2 = 9.2, J1’,2 = 5.5
Hz, H-2), 3.84 [6H, d, JPOMe = 10.7 Hz, P(OMe)2], 3.84 (1H, dd, J1,1’ = 9.7 Hz, H’-1), 4.13 (1H, br s, HO-
3), 4.18 (1H, t, H-1), 4.47 (1H, dd, J4R,P = 9.8 Hz, HR-4), 4.75 (1H, q, MeCH); 31P NMR ꢀ = 26.6.
1-O-(tert-Butyldimethylsilyl)-3-deoxy-3-dimethoxyphosphinoyl-2,4-O-ethylidene-D-erythritol (13a)
and its L-threitol epimer (13b).
Methyl oxalyl chloride (0.800 mL, 8.70 mmol) was added to a solution of 12a,b (923 mg, 2.49 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, poured into water and then the most of solvent was distilled off in vacuo. The residue was
dissolved in CHCl3, washed with saturated NH4Cl and then water, dried (Na2SO4), and evaporated in
vacuo to give the 5-methoxalyloxy derivative as a pale yellow syrup: Rf = 0.28 (D).
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 (80 mg, 0.49 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 1:3 to 1:1 AcOEt–hexane to give 13a and 13b.
26
1
13a: Colorless syrup (608 mg, 69%); Rf = 0.24 (D); [ꢁ]D –22.5° (c 2.75); H NMR ꢀ = 0.06, 0.08 (3H
each, 2s, Me2Si), 0.89 (9H, s, Me3C), 1.30 (3H, d, JMe,H = 5.2 Hz, MeCH), 2.52 (1H, dddd, J3,P = 18.0,
J3,4S = 11.9, J2,3 = 10.1, J3,4R = 4.9 Hz, H-3), 3.73, 3.75 [3H each, 2d, JPOMe = 10.7 Hz, P(OMe)2], 3.81
(1H, td, J4R,4S = 11.6, J4S,P = 3.4 Hz, HS-4), 3.83 (2H, m, H’-1, H-2), 3.94 (1H, dd, J1,1’ = 10.1, J1,2 = 0.8
Hz, H-1), 4.24 (1H, ddd, J4R,P = 1.5 Hz, HR-4), 4.66 (1H, q, MeCH); 13C NMR ꢀ = –5.24, –4.97 (Me2Si),
18.46 (Me3C), 20.90 (d, 5JMe,P = 1.7 Hz, MeCH), 25.90 (Me3C), 33.00 (d, J3,P = 34.7 Hz, C-3), 52.43 (d,
JMe,P = 6.9 Hz, POMe), 52.61 (d, JMe,P = 6.3 Hz, POMe), 64.69 (C-1), 65.55 (d, J4,P = 1.7 Hz, C-4), 76.84
31
(d, J2,P = 2.9 Hz, C-2), 98.78 (MeCH); P NMR ꢀ = 27.6. Anal. Calcd for C14H31O6PSi: C, 47.44; H,
8.82. Found: C, 47.60; H, 8.71.
13b: Colorless syrup (160 mg, 18%); Rf = 0.16 (D); [ꢁ]D26 +15.4° (c 2.02); 1H-NMR ꢀ = 0.065, 0.07 (3H
each, 2s, Me2Si), 0.89 (9H, s, Me3C), 1.36 (3H, d, JMe,H = 5.2 Hz, MeCH), 1.99 (1H, dtd, J3,P = 19.5, J3,4S
= 3.4, J2,3 = 3.1, J3,4R = 1.1 Hz, H-3), 3.77, 3.79 [3H each, 2d, JPOMe = 10.7 Hz, P(OMe)2], 3.82–3.86 (2H,
m, H,H’-1), 3.88 (1H, ddd, J4S,P = 34.8, J4R,4S = 11.6 Hz, HS-4), 3.94 (1H, dddd, J2,P = 41.8, J1,2 = 7.1, J1’,2
13
= 5.1 Hz, H-2), 4.56 (1H, ddd, J4R,P = 9.3 Hz, HR-4), 4.73 (1H, q, MeCH); C NMR ꢀ = –5.33, –5.16
(Me2Si), 18.34 (Me3C), 20.95 (MeCH), 25.85 (Me3C), 34.87 (d, J3,P = 39.9 Hz, C-3), 52.08 (d, JMe,P = 6.3
Hz, POMe), 52.58 (d, JMe,P = 5.8 Hz, POMe), 64.60 (d, J1,P = 2.2 Hz, C-1), 67.44 (d, J4,P = 5.2 Hz, C-4),
31
78.90 (d, J2,P = 5.2 Hz, C-2), 100.21 (MeCH); P NMR ꢀ = 31.4. Anal. Calcd for C14H31O6PSi: C,

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47.44; H, 8.82. Found: C, 47.52; H, 8.67.
3-Deoxy-3-dimethoxyphosphinoyl-2,4-O-ethylidene-D-erythritol (14).
Tetrabutylammonium fluoride (1.0 M THF solution, 2.00 mL, 2.00 mmol) was dropwise added to a
solution of 13a (634 mg, 1.79 mmol) in dry THF (2.0 mL) at 0 °C. The mixture was stirred at rt for 1 h,
diluted with water, and extracted with CHCl3 three times. The combined organic layers were dried
(Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography with 1:19
MeOH-CHCl3 as an eluant to give 14 (413 mg, 96%) as a colorless syrup: Rf = 0.28 (A); [ꢀ]D26 –16.9° (c
1.60); 1H NMR ꢁ = 1.33 (3H, d, JMe,H = 5.1 Hz, MeCH), 2.26 (1H, br d, HO-1), 2.46 (1H, dddd, J3,P
=
18.8, J3,4S = 11.7, J2,3 = 10.0, J3,4R = 4.4 Hz, H-3), 3.765, 3.77 [3H each, 2d, JPOMe = 10.7 Hz, P(OMe)2],
3.77 (1H, m, H’-1), 3.80 (1H, td, J4R,4S = 11.7, J4S,P = 2.9 Hz, HS-4), 3.86–3.90 (2H, m, H-1,2), 4.22 (1H,
ddd, J4R,P = 1.9 Hz, HR-4), 4.70 (1H, q, MeCH); 13C NMR ꢁ = 20.89 (d, 5JMe,P = 1.7 Hz, MeCH), 35.24 (d,
J3,P = 35.3 Hz, C-3), 52.74 (d, JMe,P = 6.9 Hz, POMe), 52.79 (d, JMe,P = 6.9 Hz, POMe), 64.50 (C-1),
31
65.59 (d, J4,P = 1.2 Hz, C-4), 76.83 (d, J2,P = 3.0 Hz, C-2), 99.12 (MeCH); P NMR ꢁ = 27.8. Anal.
Calcd for C8H17O6P: C, 40.00; H, 7.13. Found: C, 39.96; H, 7.22.
3-Deoxy-3-dimethoxyphosphinoyl-2,4-O-ethylidene-D-erythrose (15).
To a solution of oxalyl chloride (0.63 mL, 7.2 mmol) in dry CH2Cl2 (2.0 mL) was added a solution of
DMSO (1.00 mL, 14.0 mmol) in dry CH2Cl2 (4.0 mL) at –60 °C. After stirring for 15 min, a solution of
14 (310 mg, 1.29 mmol) in dry CH2Cl2 (2.0 mL) was slowly added at –60 °C. The mixture was stirred
at same temperature for 4 h and then TEA (2.20 mL, 15.8 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 1:19 MeOH-CHCl3 as an eluant to give 15 (273 mg,
89%) as a colorless syrup: Rf = 0.35 (A); [ꢀ]D23 –14.8° (c 4.75); 1H-NMR ꢁ = 1.39 (3H, d, JMe,H = 5.1 Hz,
MeCH), 2.54 (1H, dddd, J3,P = 18.3, J3,4S = 11.6, J2,3 = 11.0, J3,4R = 4.9 Hz, H-3), 3.77, 3.79 [3H each, 2d,
JPOMe = 11.0 Hz, P(OMe)2], 3.91 (1H, td, J4R,4S = 11.7, J4S,P = 3.1 Hz, HS-4), 4.31 (1H, ddd, J4R,P = 3.1 Hz,
HR-4), 4.41 (1H, ddd, J2,P = 3.3, J1,2 = 1.3 Hz, H-2), 4.75 (1H, q, MeCH), 9.63 (1H, d, H-1). Anal. Calcd
for C8H15O6P: C, 40.34; H, 6.35. Found: C, 40.12; H, 6.48.
Methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-ꢀ-D-erythro-pentopyranoside (7a) and its ꢂ-anomer
(7b).9
To a solution of (methoxymethyl)triphenylphosphonium chloride (476 mg, 1.39 mmol) in dry THF (5.0
mL) was added LHMDS (1.0 M THF solution, 1.40 mL, 1.40 mmol) at 0 °C under argon. After stirring
for 15 min, a solution of 15 (250 mg, 1.05 mmol) in THF (1.0 mL) was added at 0 °C. The mixture was
stirred at rt for 5 h, treated with saturated NH4Cl, and extracted with CHCl3 three times. The combined
organic layers were dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed with
1:19 MeOH-CHCl3 as an eluant to give 2,4-dideoxy-4-dimethoxyphosphinoyl-3,5-O-ethylidene-1-O-
methyl-D-erythro-pent-1-enitol (16) (280 mg) as a colorless syrup which contained considerable amount
of phosphorus impurities: Rf = 0.35–0.30 (A).

HETEROCYCLES, Vol. 72, 2007
419
The crude 16 was dissolved in dry MeOH (20 mL) and Amberlite IR-120(H+) (ca. 4 mL) was added.
The mixture was refluxed for 12 h and then the resin was filtered off. The filtrate was evaporated in
vacuo and the residue was separated by column chromatography with 1:19 MeOH-CHCl3 as an eluant to
give 7a and 7b.
26
7a: Colorless needles (55.6 mg, 22% from 15); mp 107–108 °C (lit.,9 106–107 °C); Rf = 0.33 (A); [ꢀ]D
+133.8° (c 1.39).
26
7b: Colorless needles (106 mg, 42% from 15); mp 101–102 °C (lit.,9 101–102 °C); Rf = 0.23 (A); [ꢀ]D
–50.8° (c 1.80).
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
REFERENCES AND NOTES
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Med. Chem., 1988, 31, 1729.
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1
17. The complete parameters for 10 and 11a obtained in the present study are shown here, because H
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