A new and efficient strategy for the synthesis of shimofuridin analogs: 2′-O-(4-O-stearoyl-α-L-fucopyranosyl)thymidine and -uridine

Article abstract of DOI:10.1016/S0008-6215(02)00356-7

Two shimofuridin analogs: 2′-O-(4-O-stearoyl-α-L-fucopyranosyl)thymidine (2) and -uridine (3) have been synthesized using D-arabinose, L-fucose, thymine, uracil, and stearoyl chloride as the starting materials. The synthetic procedures involve the facile preparation of 1-(3,5-di-O-benzyl-β-D-ribofuranosyl)thymine (9) and -uracil (10) by coupling of 1,2-anhydro-3,5-di-O-benzyl-α-D-ribofuranose (8) with silylated thymine and uracil, and then stereoselective formation of the 1,2-cis (α) interglycoside bonds through condensation of the nucleoside derivatives 9 and 10 with 2-(2,3-di-O-benzyl-4-O-stearoyl-β-L-fucopyranosylsulfonyl) pyrimidine (18). The 1,2-anhydro-3,5-di-O-benzyl-α-D-ribofuranose (8) was prepared by an improved procedure from D-arabinose.

Full text of DOI:10.1016/S0008-6215(02)00356-7

Carbohydrate Research 338 (2003) 55–60
www.elsevier.com/locate/carres
A new and efficient strategy for the synthesis of shimofuridin
-fucopyranosyl)thymidine and
analogs: 2%-O-(4-O-stearoyl-a-
L
-uridine
Jun Ning,* Ying Xing, Fanzuo Kong
Research Center for Eco-En6ironmental Sciences, Chinese Academy of Sciences, PO Box 2871, Beijing 100085, PR China
Received 22 July 2002; accepted 9 September 2002
Abstract
Two shimofuridin analogs: 2%-O-(4-O-stearoyl-a-
-arabinose, -fucose, thymine, uracil, and stearoyl chloride as the starting materials. The synthetic procedures involve the facile
preparation of 1-(3,5-di-O-benzyl-b- -ribofuranosyl)thymine (9) and -uracil (10) by coupling of 1,2-anhydro-3,5-di-O-benzyl-a-
ribofuranose (8) with silylated thymine and uracil, and then stereoselective formation of the 1,2-cis (a) interglycoside bonds
through condensation of the nucleoside derivatives 9 and 10 with 2-(2,3-di-O-benzyl-4-O-stearoyl-b- -fucopyranosylsulfonyl)
-ribofuranose (8) was prepared by an improved procedure from -ara-
L-fucopyranosyl)thymidine (2) and -uridine (3) have been synthesized using
D
L
D
D-
L
pyrimidine (18). The 1,2-anhydro-3,5-di-O-benzyl-a-
D
D
binose. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Oligosaccharides; Nucleoside; Synthesis
1. Introduction
Subsequently, six new isomers of 1 (i.e., shimofuridins
B–G) were isolated from the same tunicate.2 Shimofu-
ridins B–E differ from shimofuridin A (1) in the ge-
ometry of the double bonds in the unsaturated acyl
chain moieties, while F–G only differ from A in the
length (i.e., two additional carbon atoms) of the ho-
mologous acyl chains.
So far, a total synthesis of the shimofuridins has not
appeared. Only two shimofuridin nucleoside analogs
were synthesized by van Boom’s and Spencer Knapp’s
groups by using the naturally available inosine as the
starting material.3,4 With the objective to get an insight
into the structure–activity relationships among the shi-
mofuridins, it would be necessary to synthesize shimo-
furidin analogs containing different nucleosides and
side chains. In a preliminary communication, we dis-
closed a new and versatile approach to the preparation
2%-O-[(4¦-O-(9§-O-Octadienoyl)decatrienoyl)-a-L-fuco-
pyranosyl]inosine (1), so-called shimofuridin A (Fig. 1),
was isolated from the extract of the Okinawa marine
tunicate Aplidium multiplicatum Sluiter and identified
by Kobayashi and co-workers in 1993.1 This complex
nucleoside derivative was found to have cytotoxic, an-
timicrobial, and protein kinase C inhibitory activities.
of shimofuridin analogs by using D-arabinose, L-fucose,
activated base, and stearoyl chloride as starting materi-
als.5 In this paper, the synthesis of two shimo-
Fig. 1. Shiofuridin A and its analogs.
furidin analogs: 2%-O-(4-O-stearoyl-a-L-fucopyran-
osyl)thymidine (2) and -uridine (3) (Fig. 1), is presented
in detail.
* Corresponding author. Tel.: +86-10-62923563
E-mail address: fzkong@mail.rcees.ac.cn (J. Ning).
0008-6215/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00356-7

56
J. Ning et al. / Carbohydrate Research 338 (2003) 55–60
1,2-anhydro-3,5-di-O-benzyl-a- -ribofuranose (8) with
D
activated bases in the absence of catalyst.6 In this
report, we use the same strategy to synthesize the free
2%-OH nucleoside derivatives, but the route to com-
pound 8 was slightly improved. Thus, benzoylation of
methyl
selectively afforded methyl 5-O-benzoyl-
oside (5) (60% yield), which was then converted to the
D
-arabinofuranoside7 (4) with BzCl in pyridine
D-arabinofuran-
known 5-O-benzoyl-1,2-O-isopropylidene-b-D-arabino-
furanose (6)8 in acetone containing 1% dry HCl in 75%
yield (Scheme 1). Benzylation of 6 with BnCl in anhy-
drous toluene containing KOH under reflux gave
the known 3,5-di-O-benzyl-1,2-O-isopropylidene-b-D-
Scheme 1. Reagents and conditions: (a) BzCl (1.0 equiv),
pyridine, −5 °C, 3 h, 60%; (b) dry acetone containing 1%
HCl, rt, 24 h, 75%; (c) BnCl, toluene, KOH, reflux, 5 h, 85%;
(d) (i) 30% AcOH, reflux, 3 h; (ii) TsCl (1.5 equiv), K2CO3
(1.5 equiv), pyridine, rt, 12 h; (iii) t-BuOK (1.1 equiv), THF,
rt, 20 min, 55% overall yield; (e) (i) O,O-bis-(trimethylsi-
arabinofuranose9 (7) in 85% yield. The procedure for
the preparation of compound 7 from methyl 5-O-ben-
zoyl-a-
D
-arabinofuranoside (5) instead of from methyl
5-O-tosyl-a-
D
-arabinofuranoside9 is simpler and more
easily operational. Compound 8 was readily obtained
from 7 via removal of the 1,2-O-isopropylidene group
of 7 in 30% AcOH under reflux, followed by 2-O-tosy-
lation with TsCl in pyridine in the presence of K2CO3,
and subsequent treatment of the tosylate with potas-
sium tert-butoxide in dry THF (in 55% overall yield)
according to the procedure developed in our lab.6 Reac-
tion of 8 with trimethylsilylated thymine in the absence
of Lewis acid in dry CH2Cl2 provided a mixture of the
free 2%-OH nucleoside derivative 9 as the major product
along with its 2%-O-trimethylsilylated nucleoside deriva-
tive. The later was converted into 9 by addition of
HCO2H, raising the yield of 9 to 87%. A similar
procedure gave the known compound 106 in 85% yield.
With the glycosyl acceptors 9 and 10 in hand, we
turned our attention to the synthesis of the fucopyran-
osyl donor 18. Treatment of the glycosyl bromide 1110
with 2-mercaptopyrimidine and tetrabutylammonium
hydrogensulfate in a mixture of CH2Cl2 and 1 M aq
Na2CO3 under phase-transfer conditions11 at room tem-
,
lyl)thymine (1.5 equiv), CH2Cl2, 4 A MS, rt, 8 h; (ii) HCO2H,
rt, 10 min, 87% overall yield; (f) (i) O,O-bis-(trimethylsi-
,
lyl)uracil (1.5 equiv), CH2Cl2, 4 A MS, rt, 8 h; (ii) HCO2H, rt,
10 min, 85% overall yield.
Scheme 2. Reagents and conditions: (a) 2-mercaptopyrimidine
(3.0 equiv), tetrabutylammonium hydrogensulfate (1.0 equiv),
1 M aq Na2CO3, CH2Cl2, rt, 24 h, 96%; (b) CH3OH,
NaOCH3 (cat), rt, 3 h, 100%; (c) Me2C(OMe)2, acetone,
TsOH (cat), rt, 20 h, 81%; (d) BnBr, NaH, DMF, reflux, 5 h,
87%; (e) CH3OH, H2SO4 (cat), rt, 20 h, 90%; (f) (i) CH3OH,
dibutyltin oxide, reflux; (ii) toluene, tetrabutylammonium io-
dide, BnBr, 50 °C, 18 h, 71%; (g) C17H35COCl, pyridine, rt, 3
h, 90%; (h) Ac2O, pyridine, rt, 2 h, 97%.
perature afforded the fully acetylated 2-(b-L-fucopyran-
osylsulfanyl)pyrimidine (12) in 96% yield (Scheme 2).
Deacetylation of 12 with a catalytic amount of sodium
methoxide in methanol gave the triol 13. Treatment of
13 with 2,2-dimethoxypropane in the presence of a
catalytic amount of p-toluenesulfonic acid in acetone
gave
2-(3,4-O-isopropylidine-b-L-fucopyranosylsul-
fanyl)pyrimidine (14) in 81% yield. Benzylation of 14
with BnBr and NaH in dry DMF, followed by hydroly-
sis in methanol containing a catalytic amount of
H2SO4, gave 16 in 78% yield for two steps. Selective
2. Results and discussion
In the syntheses of shimofuridin analogs described in
the literature,3,4 the naturally occurring inosine was
used as the starting material, and complex procedures
for the selective protection of 3%-OH and 5%-OH of the
inosine, while leaving 2%-OH free for further coupling
reactions, had to be involved. Earlier, we developed a
special method for the preparation of nucleoside deriva-
tives with 3%-OH and 5%-OH protected, while maintain-
ing the 2%-OH free. This was achieved by coupling
benzylation of 2-(2-O-benzyl-b-L-fucopyranosylsul-
fanyl)pyrimidine (16) with BnBr via its dibutyltin com-
plex gave 17 in 71% yield. The acetylated product 19
further confirms the structure of 17. Stearoylation of 17
with C17H34COCl in pyridine gave the key intermediate
2-(2,3-di-O-benzyl-4-O-stearoyl-1-thio-b-L-fucopyran-
osyl)pyrimidine (18) in 90% yield. Condensation of 9
and 10 with 18 in dry CH2Cl2 at room temperature in

J. Ning et al. / Carbohydrate Research 338 (2003) 55–60
57
the presence of TMSOTf (0.5 equiv) afforded the
3.2. Methyl 5-O-benzoyl-a-D-arabinofuranoside (5)
blocked target compounds 20 and 21 as the sole prod-
ucts in 88 and 90% yields (based on 9 and 10), respec-
tively (Scheme 3). The chemical shift l 5.30 and 5.33
for H-1¦ of 20 and 21, respectively, definitely indicated
the a configuration for the fucosyl linkage.3 The title
compounds 2 and 3 were obtained by debenzylation of
20 and 21 with hydrogen and Pd/C in CH3OH–EtOAc,
respectively.
To a stirred solution of 4 (7.86 g, 47.9 mmol) in dry Py
(100 mL) was added dropwise a solution of BzCl (5.6
mL, 48 mmol) in dry CH2Cl2 (30 mL) at −5 °C over
30 min. After 2.5 h, the mixture was poured into
ice-cold water and extracted with CH2Cl2 (200 mL).
The organic layer was washed with 1N HCl (4×50
mL) and satd aq NaHCO3 (30 mL), and then dried
(Na2SO4). The extract was concentrated, and chro-
matographed on silica gel with 1:1 petroleum ether–
EtOAc to give 5 as a syrup (7.70 g, 60); [h]2D0 +67° (c
In summary, we have successfully developed a new
method for the synthesis of shimofuridin analogs con-
taining different nucleosides.
1
4.1, CHCl3); H NMR (CDCl3): l 8.09–8.00 (m, 2 H,
PhꢀH), 7.60–7.36 (m, 3 H, PhꢀH), 4.90 (s, 1 H, H-1),
4.54 (dd, 1 H, J4,5 4.6, J5,5% 12.4 Hz, H-5), 4.51 (dd, 1 H,
J4%,5% 3.2, J5,5% 12.4 Hz, H-5%), 4.28 (dd, 1 H, J2,3 2.0, J3,4
6.2 Hz, H-3), 4.14 (d, 1 H, J2,3 2.0 Hz, H-2), 4.02 (m, 1
H, H-4), 3.39 (s, 3 H, OCH3). Anal. Calcd for
C13H16O6: C, 58.20; H, 6.01. Found: C, 58.34; H, 5.95.
3. Experimental
3.1. General methods
Optical rotations were determined at 20 °C with a
Perkin–Elmer model 241-Mc automatic polarimeter.
Melting points were determined with a ‘Mel-Temp’
apparatus. 1H and 13C NMR spectra were recorded
3.3. 5-O-Preparation of 5-O-benzoyl-1,2-O-isopropyli-
dene-b-D-arabinofuranose (6)
1
with Bruker ARX 400 spectrometers (400 MHz for H,
100 MHz for 13C) for solutions in CDCl3 or CD3OD as
indicated. Chemical shifts are given in ppm downfield
from internal Me4Si. Thin-layer chromatography (TLC)
was performed on silica gel HF254 with detection by
charring with 30% (v/v) H2SO4 in MeOH or in some
cases by a UV detector. Column chromatography was
conducted by elution of a column (16×240, 18×300,
35×400 mm) of silica gel (100–200 mesh) with
EtOAc–petroleum ether (60–90 °C) as the eluent. Solu-
tions were concentrated at B60 °C under reduced
pressure.
A solution of 5 (5.24 g, 19.5 mmol) in dry C3H6O
containing 1% HCl (100 mL) was stored for 24 h at
room temperature (rt). The mixture was neutralized
with satd aq NaHCO3, extracted with CH2Cl2, dried
(Na2SO4) and concentrated. The residue was crystal-
lized from petroleum ether–EtOAc to give 6 (3.44 g,
60%). The remaining syrup was subjected to column
chromatography with 2:1 petroleum ether–EtOAc as
the eluent to afford additional 6 (0.86 g, 15%); mp
8
147.2–148.7 °C; [h]D20 +22.6° (c 2.1, CHCl3), Lit. mp
147.5–148.5 °C; [h]D +25.25° (c 0.079, CHCl3).
3.4. 3,5-Di-O-benzyl-1,2-O-isopropylidene-b-D-arabino-
furanose (7)
To a solution of 6 (3.8 g, 12.9 mmol) in dry C6H5CH3
(100 mL) was added BnCl (4.5 mL, 50 mmol) and
powdered KOH (4.2 g, 75 mmol) at rt. This mixture
was heated under reflux with stirring for 5 h, at the end
of which time TLC (4:1 petroleum ether–EtOAc) indi-
cated that the reaction was complete. The mixture was
diluted with CH2Cl2, washed with water, dried
(Na2SO4), concentrated and chromatographed on silica
gel with 4:1 petroleum ether–EtOAc to give 7 as a
1
syrup (4.06 g, 85%); [h]2D0 +13.2° (c 1.2, CHCl3); H
NMR (CDCl3): l 7.31 (m, 10 H, 2 PhH), 5.89 (d, 1 H,
J1,2 4.0 Hz, H-1), 4.64 (d, 1 H, J1,2 4.0 Hz, H-2),
4.60–4.54 (m, 4 H, 2 PhCH2), 4.26 (m, 1 H, J3,4 3.0, J4,5
6.3 Hz, H-4), 4.02 (d, 1 H, J3,4 3.0 Hz, H-3), 3.63 (d, 2
H, J4,5 6.3 Hz, H-5), 1.41, 1.33 (2 s, 6 H, 2 CCH3).
Anal. Calcd for C22H26O5: C, 71.33; H, 7.07. Found: C,
71.45; H, 7.01.
Scheme 3. Reagents and conditions: (a) TMSOTf (0.5 equiv),
CH2Cl2, rt, 2 h, 88% for 20, 90% for 21; (b) H2, Pd/C 10%,
1:1 CH3OH–EtOAc, rt, 24 h, 95% for 2, 93% for 3.

58
J. Ning et al. / Carbohydrate Research 338 (2003) 55–60
3.5. 1-(3,5-Di-O-benzyl-b-
D
-ribofuranosyl)thymine (9)
1 H, J1,2 10.3 Hz, H-1), 5.43 (t, 1 H, J1,2 10.3 Hz, J2,3
10.3, H-2), 5.35 (d, 1 H, J3,4 3.4 Hz, H-4), 5.19 (dd, 1
H, J3,4 3.4, J2,3 10.3 Hz, H-3), 4.03 (m, 1 H, J5,6 6.6 Hz,
H-5), 2.23, 2.04, 2.01 (3 s, 9 H, 3 COC H3), 1.22 (d, 3
H, J5.6 6.6 Hz, H-6). Anal. Calcd for C16H20N2O7S: C,
49.99; H, 5.24. Found: C, 50.09; H, 5.23.
To a stirred solution of O,O-bis-(trimethylsilyl)thymine
(0.44 g, 1.44 mmol) in dry CH2Cl2 (10 mL) with
,
molecular sieves (4 A, 0.7 g) was added a solution of
1,2-anhydro-3,5-di-O-benzyl-a-
D
-ribofuranose (8)6 (0.3
g, 0.96 mmol) in dry CH2Cl2 (10 mL) at rt. After 8 h,
HCOOH (0.5 mL) was added. After further 10 min, the
mixture was diluted with CH2Cl2 (80 mL), washed with
satd aq NaHCO3 (10 mL), dried (Na2SO4), and then
concentrated. The residue was chromatographed on
silica gel with 1:2 petroleum ether–EtOAc to give 9 as
white needles (0.37 g, 87%); mp 74–76 °C; [h]2D0 +26.5°
(c 2.4, CHCl3): 1H NMR (CDCl3): l 9.42 (s, 1 H,
NꢀH), 7.52 (s, 1 H, H-6), 7.40–7.21 (m, 10 H, 2 PhH),
5.97 (d, 1 H, J1%,2% 4.0, H-1%), 4.72, 4.59 (2 d, 2 H, J 12.0
Hz, PhCH2), 4.53 (s, 2 H, PhCH2), 4.33–4.23 (m, 2 H,
H-3%, 4%), 4.12 (t, 1 H, J1%,2% 4.0 Hz, J2%,3% 4.0 Hz, H-2%),
3.83 (2 d, 1 H, J4%,5a% 2.4, J5a%,5b% 10.4 Hz, H-5a%), 3.68 (2
d, 1 H, J4%,5b% 1.9, J5a%,5b% 10.4 Hz, H-5b%), 3.15 (bs, 1 H,
OH), 1.52 (s, 3 H, CH3). Anal. Calcd for C24H26N2O6:
C, 65.74; H, 5.98. Found: C, 65.70; H, 6.01.
3.8. 2-(b-L-Fucopyranosylsulfanyl)pyrimidine (13)
To a solution of 12 (4.8 g, 12.5 mmol) in MeOH (50
mL) was added NaOMe (11 mg, 0.2 mmol). After 3 h
at rt, TLC (2:1 petroleum ether–EtOAc) indicated that
the reaction was complete. The solution was concen-
trated to afford 13 as crystals (3.24 g, quant): mp
152–154 °C; [h]2D0 31° (c 4.1, CHCl3); 1H NMR
(CDCl3): l 8.46 (d, 2 H, J 4.7 Hz, PyrH-4, 6), 7.10 (t,
1 H, J 4.7 Hz, PyrH-5), 5.35 (d, 1 H, J1,2 10 Hz, H-1),
3.80 (m, 1 H, J5,6 9.2 Hz, H-5), 3.70–3.55 (m, 3 H, H-2,
3, 4), 1.10 (d, 3 H, J5,6 9.2 Hz, H-6). Anal. Calcd for
C10H14N2O4S: C, 46.50; H, 5.46. Found: C, 46.48; H,
5.41.
3.9. 2-(3,4-O-Isopropylidene-b-L-fucopyran-
osylsulfanyl)pyrimidine (14)
3.6. Preparation of 1-(3,5-di-O-benzyl-b-D-ribofuranos-
yl)uracil (10)
A
mixture of 13 (2.8 g, 10.8 mmol), 2,2-
To a stirred solution of O,O-bis-(trimethylsilyl)uracil
(241 mg, 0.85 mmol) in dry CH2Cl2 (8 mL) with
dimethoxypropane (8 mL), and p-toluenesulfonic acid
monohydrate (20 mg) in C3H6O (8 mL) was stirred for
20 h at rt, at the end of which time TLC (2:1 petroleum
ether–EtOAc) indicated that the reaction was complete.
The solution was diluted with CH2Cl2, neutralized with
satd aq NaHCO3, dried (Na2SO4), and concentrated.
The residue was chromatographed on silica gel with 2:1
petroleum ether–EtOAc to give 14 as crystals (2.62 g,
,
molecular sieves (4 A, 0.8 g) was added a solution of
1,2-anhydro-3,5-di-O-benzyl-a-
D
-ribofuranose (8)6 (185
mg, 0.57 mmol) in dry CH2Cl2 (6 mL) at rt. After 8 h,
HCOOH (0.5 mL) was added. After further 10 min, the
mixture was diluted with CH2Cl2 (60 mL), washed with
satd aq NaHCO3 (10 mL), dried (Na2SO4), and then
concentrated. The residue was chromatographed on
silica gel with 1:2 petroleum ether–EtOAc to give 10 as
white needles (202 mg, 85%); mp 69.8–71.5 °C; [h]D20
1
81%); mp 91–93 °C; [h]2D0 −16.2° (c 3.1, CHCl3); H
NMR (CDCl3): l 8.55 (d, 2 H, J 4.8 Hz, PyrH-4, 6),
7.02 (t, 1 H, J 4.8 Hz, PyrH-5), 5.56 (d, 1 H, J1,2 10.3,
H-1), 4.22–4.01 (m, 3 H, H-3, 4, 5), 3.82 (dd, 1 H, J1,2
10.3 Hz, J2,3 6.6 Hz, H-2), 3.30 (bs, 1 H, OH), 1.60,
1.40 (2 s, 6 H, 2 CCH3), 1.38 (d, 3 H, J5,6 6.0 Hz, H-6).
Anal. Calcd for C13H18N2O4S: C, 52.33; H, 6.08.
Found: C, 52.39; H, 6.01.
+31.2° (c 2.1, CHCl3), Lit.6 mp 70–72 °C; [h]D
31.7° (c 2.1, CHCl3).
+
3.7. 2-(2,3,4-Tri-O-acetyl-b-L-fucopyranosylsulfanyl)-
pyrimidine (12)
To a mixture of glycosl bromide 1110 (5.1 g, 14.4
mmol), 2-mercaptopyridine (4.86 g, 43.3 mmol), and
Bu4HSO4 (4.9 g, 14.4 mmol) in CH2Cl2 (100 mL) was
added 1 M aq Na2CO3 (100 mL). The mixture was
stirred at rt for 1 h, at the end of which time TLC (2:1
petroleum ether–EtOAc) indicated that the reaction
was complete. The mixture was partitioned between
CH2Cl2 and water, the organic layer was concentrated,
and the crude product was chromatographed on silica
gel with 2:1 petroleum ether–EtOAc to give 12 as
crystals (5.3 g, 96%); mp 102–103 °C; [h]2D0 −76° (c
3.10. 2-(2-O-Benzyl-3,4-O-isopropylidene-b-L-fucopy-
ranosylsulfanyl)pyrimidine (15)
To a solution of 14 (2.1 g, 7.04 mmol) in dry DMF (40
mL) was added slowly NaH (0.63 g, 80% in oil, 21
mmol), and then BnBr (0.68 mL, 7.74 mmol) at 0 °C.
The mixture was stirred at rt for 5 h, at the end of
which time TLC (4:1 petroleum ether–EtOAc) indi-
cated that the reaction was complete. The mixture was
poured into water, extracted repeatedly with CH2Cl2,
and then concentrated. The residue was chro-
matographed on silica gel with 4:1 petroleum ether–
EtOAc to afford 15 as crystals (2.4 g, 87%); mp
1
1.2, CHCl3); H NMR (CDCl3): l 8.56 (d, 2 H, J 4.9
Hz, PyrH-4, 6), 7.06 (t, 1 H, J 4.9 Hz, PyrH-5), 5.82 (d,

J. Ning et al. / Carbohydrate Research 338 (2003) 55–60
59
81–82 °C; [h]2D0 −34.6° (c 2.2, CHCl3); 1H NMR
(CDCl3): l 8.52 (d, 2 H, J 4.7 Hz, PyrH-4, 6), 7.40–
7.23 (m, 5 H, PhH), 6.96 (t, 1 H, J 4.6 Hz, PyrH-5),
5.68 (d, 1 H, J1,2 9.3 Hz, H-1), 4.84, 4.78 (2 d, 2 H, J
12.0 Hz, PhCH2), 4.33 (t, 1 H, J2,3 6.2, J3,4 6.2 Hz,
H-3), 4.14–4.0 (m, 2 H, H-4, 5), 3.70 (d, 1 H, J1,2 9.3
Hz, J2,3 6.2 Hz, H-2), 1.52, 1.38 (2 s, 6 H, 2 CCH3),
1.38 (d, 3 H, J5.6 6.1 Hz, H-6). Anal. Calcd for
C20H24N2O4S: C, 61.83; H, 6.23. Found: C, 61.90; H,
6.26.
2.71 (bs, 1 H, OH), 1.36 (d, 3 H, J5.6 6.4 Hz, H-6).
Anal. Calcd for C24H26N2O4S: C, 65.73; H, 5.98.
Found: C, 65.80; H, 5.99.
3.13. 2-(2,3-Di-O-benzyl-4-O-stearoyl-b-L-fucopyran-
osylsulfanyl)pyrimidine (18)
Stearoylation of 17 (0.4 g, 0.91 mmol) with stearoyl
chloride (0.45 g, 1.5 mmol) in Py (8 mL) at rt for 3 h
gave compound 18 as a syrup (0.58 g, 90%); [h]2D0 −46°
1
(c 2.4, CHCl3); H NMR (CDCl3): l 8.52 (d, 2 H, J 4.8
3.11. 2-(2-O-Benzyl-b-
pyrimidine (16)
L
-fucopyranosylsulfanyl)-
Hz, PyrꢀH-4, 6), 7.38–7.20 (m, 10 H, 2 PhH), 6.98 (t,
1 H, J 4.8 Hz, PyrH-5), 5.68 (d, 1 H, J1,2 10.0 Hz, H-1),
5.45 (d, 1 H, J3,4 2.0 Hz, H-4), 4.82 (s, 2 H, PhCH2),
4.76, 4.55 (2 d, 2 H, J 11.2 Hz, PhCH2), 3.95–3.70 (m,
3 H, H-2, 3, 5), 2.48 (t, 2 H, J 6.2 Hz, COCH2C16H33),
1.72–1.60 (m, 2 H, COCH2CH2C15H31), 1.48–1.06 (m,
31 H, COCH2CH2C14H28CH3, H-6), 0.9 (t, 3 H, J 4.5
Hz, COC16H32CH3). Anal. Calcd for C42H60N2O5S: C,
71.55; H, 8.58. Found: C, 71.51; H, 8.50.
To a solution of 15 (1.6 g, 4.1 mmol) in anhyd MeOH
(80 mL) was added a drop of H2SO4. The solution was
stored at rt for 20 h, at the end of which time TLC (2:1
petroleum ether–EtOAc) indicated that the reaction
was complete. The solution was neutralized with satd
aq NaHCO3, and then concentrated. The residue was
chromatographed on silica gel with 1:1 petroleum
ether–EtOAc to give 16 as crystals (1.29 g, 90%); mp
113–115 °C; [h]2D0 −29° (c 3.2, CHCl3); 1H NMR
(CDCl3): l 8.55 (d, 2 H, J 4.8 Hz, PyrH-4, 6), 7.40–
7.22 (m, 5 H, PhH), 7.00 (t, 1 H, J 4.8 Hz, PyrH-5),
5.35 (d, 1 H, J1,2 10.0 Hz, H-1), 4.90, 4.78 (2 d, 2 H, J
12.0 Hz, PhCH2), 3.95–3.70 (m, 4 H, H-2, 3, 4, 5), 1.35
3.14. 2-(4-O-Acetyl-2,3-di-O-benzyl-b-L-fucopyran-
osylsulfanyl)pyrimidine (19)
Acetylation of 17 (100 mg, 0.23 mmol) with Ac2O (4
mL) in Py (5 mL) at rt for 2 h gave 19 as a syrup (106
mg, 97%); [h]2D0 −5° (c 3.7, CHCl3); 1H NMR (CDCl3):
l 8. 52 (d, 2 H, J 4.8 Hz, PyrH-4, 6), 7.40–7.18 (m, 10
H, 2 PhH), 6.98 (t, 1 H, J 4.8 Hz, PyrH-5), 5.70 (d, 1
H, J1,2 10.0 Hz, H-1), 5.44 (d, 1 H, J3,4 1.7 Hz, H-4),
4.83 (s, 2 H, PhCH2), 4.77, 4.55 (2 d, 2 H, J 11.2 Hz,
PhCH2), 3.94–3.75 (m, 3 H, H-2, 3, 5), 2.20 (s, 3 H,
COCH3), 1.22 (d, 3 H, J5,6 6.4 Hz, H-6). Anal. Calcd
for C26H28N2O5S: C, 64.98; H, 5.87. Found: C, 65.09;
H, 5.85.
(d,
3 H, J5,6 6.4 Hz, H-6). Anal. Calcd for
C17H20N2O4S: C, 58.60; H, 5.79. Found: C, 58.70; H,
5.80.
3.12. 2-(2-O-Benzyl-3,4-O-isopropylidene-b-L-fucopy-
ranosylsulfanyl)pyrimidine (17)
To a solution of 16 (1.2 g, 3.4 mmol) in MeOH (50 mL)
was added Bu2SnO (845 mg, 3.4 mmol), and the mix-
ture was heated at reflux. After the mixture became
clear, heating was continued for 1 h, and the stannylene
complex was obtained as a white foamy residue by
evaporation of the MeOH under diminished pressure.
To the residue was added C6H5CH3 (30 mL), tetra-
butylammonium iodide (1.26 g, 3.4 mmol), and BnBr
(0.4 mL, 3.7 mmol). The mixture was stirred at 50 °C
for 18 h, at the end of which time TLC (2:1 petroleum
ether–EtOAc) indicated that the reaction was complete.
The solvent was evaporated under diminished pressure,
and the residue was subjected to column chromatogra-
phy on silica gel with 2:1 petroleum ether–EtOAc as
the eluent to afford 17 as a syrup (1.06 g, 71%); [h]D20
3.15. 3%,5%-Di-O-benzyl-2%-O-(2,3-di-O-benzyl-4-O-
stearoyl-a-L-fucopyranosyl)thymidine (20)
To a stirred solution of 18 (200 mg, 0.28 mmol) and 9
(124.4 mg, 0.28 mmol) in dry CH2Cl2 (15 mL) was
added TMSOTf (27 mL, 0.14 mmol) at rt. After 3 h,
Et3N was added to the solution to quench the reaction.
The solution was concentrated, and chromatographed
on a silica gel column with 1:1 petroleum ether–EtOAc
to give 20 (254 mg, 88%) as a syrup; [h]2D0 −2.1° (c 0.5,
1
CHCl3); H NMR (CDCl3): l 8.30 (s, 1 H, N-H), 7.70
(s, 1 H, H-6), 7.40–7.18 (m, 20 H, 4 PhH), 6.04 (d, 1 H,
J1%,2% 6.7 Hz, H-1%), 5.42 (d, 1 H, J3¦,4¦ 3.0 Hz, H-4¦),
5.30 (d, 1 H, J1¦,2¦ 3.3 Hz, H-1¦), 4.80–4.45 (m, 8 H, 4
PhCH2), 4.40 (t, 1 H, J1%,2% 6.7, J2%,3% 2.7 Hz, H-2%), 4.35
(dd, 1 H, J2%,3% 2.7 Hz, J3%,4% 3.0 Hz, H-3%), 4.25 (q, 1 H,
J5¦,6¦ 6.6 Hz, H-5¦), 4.15 (m, 1 H, J3%,4% 3.0, J4%,5a% 3.0,
J4%,5b% 2.0 Hz, H-4%), 4.0 (dd, 1 H, J2¦,3¦ 10.0 Hz, J3¦,4¦ 3.0
Hz, H-3¦), 3.92 (2 d, 1 H, J4%,5a% 3.0, J5a%,5b% 12.0 Hz,
H-5a%), 3.80 (dd, 1 H, J1¦,2¦ 3.3 Hz, J2¦,3¦ 10.0 Hz, H-2¦),
1
−19° (c 1.7, CHCl3); H NMR (CDCl3): l 8.55 (d, 2
H, J 4.9 Hz, PyrH-4, 6), 7.43–7.21 (m, 10 H, 2 PhH),
7.01 (t, 1 H, J 4.9 Hz, PyrH-5), 5.36 (d, 1 H, J1,2 10.0
Hz, H-1), 4.83 (s, 2 H, PhCH2), 4.78, 7.75 (2 d, 2 H, J
12.2 Hz, PhCH2), 4.08 (t, 1 H, J1,2 10.0, J2,3 10.0 Hz,
H-2), 3.86 (d, 1 H, J3,4 3.9 Hz, H-4), 3.73 (q, 1 H, J5.6
6.4 Hz, H-5), 3.66 (dd, 1 H, J2.3 10.0, J3,4 3.9 Hz, H-3),

60
J. Ning et al. / Carbohydrate Research 338 (2003) 55–60
3.65 (2 d, 1 H, J4%,5b% 2.0, J5a%,5b% 12.0 Hz, H-5b%), 2.36 (t,
2 H, J 6.2 Hz, COCH2C16H33), 1.62 (m, 2 H,
COCH2CH2C15H31), 1.50 (s, 3 H, C5-CH3), 1.36–1.16
(m, 28 H, COCH2CH2C14H28CH3), 1.13 (d, 3 H, J5¦,6¦
6.6 Hz, H-6¦), 0.90 (t, 3 H, J 4.5 Hz, COC16H32CH3).
Anal. Calcd for C62H82N2O11: C, 72.20; H, 8.01.
Found: C, 72.40; H, 7.92.
H28CH3), 1.11 (d, 3 H, J5%%,6%% 6.7 Hz, H-6¦), 0.87 (t, 3 H,
J 7.0 Hz, COC16H32CH3). Anal. Calcd for C61H80-
N2O11: C, 72.02; H, 7.93. Found: C, 72.19; H, 7.90.
3.18. 2%-O-(4-O-Stearoyl-a-L-fucopyranosyl)uridine (3)
Debenzylation of 21 (63 mg, 0.06 mmol) as described
for the debenzylation of 20 gave 3 (37.8 mg, 93%); [h]D20
1
3.16. 2%-O-(4-O-Stearoyl-a-L-fucopyranosyl)thymidine
−6.3° (c 0.4, MeOH); H NMR (CDCl3): l 8.77 (s, 1
(2)
H, NꢀH), 7.88 (d, 1 H, J5,6 8.2 Hz, H-6), 6.08 (d, 1 H,
J1%,2% 6.3, H-1%), 5.18 (d, 1 H, J5,6 8.2 Hz, H-5), 5.13 (d,
1 H, J3%%,4%% 2.8 Hz, H-4¦), 5.03 (d, 1 H, J1%%,2%% 3.2 Hz,
H-1¦), 4.87 (dd, 1 H, J1%,2% 6.3 Hz, J2%,3% 4.5 Hz, H-2%),
4.53 (dd, 1 H, J2%,3% 4.5, J3%,4% 2.8 Hz, H-3%), 4.26 (m, 1 H,
H-4%), 3.91 (dd, 1 H, J2¦,3¦ 9.5, J3¦,4¦ 3.6 Hz, H-3¦), 3.82
(m, 1 H, H-5a%), 3.79 (1 H, m, H-5b%), 3.73 (dd, 1 H,
J1¦,2¦ 3.2 Hz, J2¦,3¦ 9.5 Hz, H-2¦), 3.64 (q, 1 H, J4¦,5¦ 2.8,
J5¦,6¦ 6.6 Hz, H-5¦), 2.37–0.82 (35 H, COC17H35), 0.66
(d, 3 H, J5%%,6%% 6.6 Hz, H-6¦). Anal. Calcd for
C33H56N2O11: C, 60.35; H, 8.59. Found: C, 60.41; H,
8.63.
A suspension of Pd/C (10%, 150 mg) in a solution of 20
(110 mg, 0.107 mmol) in 1:1 CH3OH–EtOAc (15 mL)
was stirred under a flow of H2 at 1 atm and rt for 24 h,
then filtered and concentrated. Column chromatogra-
phy of the residue on Bio-Gel P-4 with CH3OH as the
eluent gave, after freeze drying, 2 (68 mg, 95%); [h]D20
−5.4° (c 0.7, MeOH); 1H NMR (CD3OD): l 8.80 (br s,
1 H, NꢀH), 7.81 (s, 1 H, H-6), 6.15 (d, 1 H, J1%,2% 6.2 Hz,
H-1%), 5.15 (d, 1 H, J3¦,4¦ 3.6 Hz, H-4¦), 5.05 (d, 1 H,
J1¦,2¦ 3.6 Hz, H-1¦), 4.90 (dd, 1 H, J1%,2% 6.2, J%,3% 4.7 Hz,
H-2%), 4.50 (dd, 1 H, J2%,3% 4.7, J3%,4% 2.6 Hz, H-3%), 4.22
(m, 1 H, H-4%), 3.98 (dd, 1 H, J2¦,3¦ 9.9 Hz, J3¦,4¦ 3.5 Hz,
H-3¦), 3.85 (m, 1 H, H-5a%), 3.78 (m, 1 H, H-5b%), 3.76
(dd, 1 H, J1¦,2¦ 3.6, J2¦,3¦ 9.9, H-2¦), 3.68 (q, 1 H, J4¦,5¦
3.0, J5¦,6¦ 6.2 Hz, H-5¦), 2.40–0.8 (35 H, COC17H35),
1.46 (s, 3 H, C5ꢀCH3), 0.68 (d, 3 H, J5¦,6¦ 6.2 Hz, 3
H-6¦). Anal. Calcd for C34H58N2O11: C, 60.88; H, 8.71.
Found: C, 60.85; H, 8.76.
Acknowledgements
This work was supported by the Beijing Natural
Science Foundation (6021004) and National Natural
Science Foundation of China (59973026 and 29905004).
3.17. 3%,5%-Di-O-benzyl-2%-O-(2,3-di-O-benzyl-4-O-
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