Effective synthesis of C-nucleosides with 2′,4′-BNA modification

Article abstract of DOI:10.1016/S0040-4020(02)00226-0

The effective synthesis of some C-nucleosides with 2′-O,4′-C-methylene bridged nucleic acid (2′,4′-BNA) modification was accomplished by using the coupling reaction of a tetrahydrofurancarbaldehyde 1 with the magnesium or lithium derivatives of aromatic heterocycles followed by the Mitsunobu cyclization. Moreover, it was clearly shown by ¹H NMR spectra and X-ray crystallography that the sugar conformation in the synthesized C-nucleosides, independent of the nucleobases, was fixed in N-form.

Full text of DOI:10.1016/S0040-4020(02)00226-0

TETRAHEDRON
Pergamon
Tetrahedron 58 +2002) 3051±3063
Effective synthesis of C-nucleosides with 20,40-BNA modi®cation
Yoshiyuki Hari,a Satoshi Obika,a Minako Sakaki,a Ken-ichiro Morio,a Yuriko Yamagatab
and Takeshi Imanishia,p
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
bGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Kumamoto 862-0973, Japan
Received 25 January 2002; accepted 27 February 2002
AbstractÐThe effective synthesis of some C-nucleosides with 20-O,40-C-methylene bridged nucleic acid +20,40-BNA) modi®cation was
accomplished by using the coupling reaction of a tetrahydrofurancarbaldehyde 1 with the magnesium or lithium derivatives of aromatic
heterocycles followed by the Mitsunobu cyclization. Moreover, it was clearly shown by 1H NMR spectra and X-ray crystallography that the
sugar conformation in the synthesized C-nucleosides, independent of the nucleobases, was ®xed in N-form. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
sugar conformation have attracted considerable attention in
view of their property not only as a biologically active
compound but also as a synthon toward development of
practical antisense and/or antigene strategy.3,4 Recently,
we have accomplished the synthesis of 20-O,40-C-methylene
bridged nucleic acids +20,40-BNA/LNA), which have a
locked N-type sugar conformation, by methylene bridging
between the 20-oxygen and 40-carbon atoms +Fig. 1),5,6 and
also found that oligonucleotides containing the 20,40-BNA
monomers showed extremely high binding af®nity not only
to single-stranded RNA but also to double-stranded DNA.7,8
Therefore, application of the C-nucleoside analogues of the
20,40-BNA for antisense and antigene oligonucleotides is
also of great interest.
C-Nucleosides are well known nucleoside analogues that
contain a carbon±carbon linkage between the furanose
and the heterocyclic base, instead of the carbon±nitrogen
linkage in the natural N-nucleosides. They are very
intriguing compounds as an antitumor, antibacterial or anti-
viral agent.1 Recently, several research groups have also
reported that some C-nucleosides were good substrates
in DNA replication.2 Thus, valuable applications of the
C-nucleosides will increasingly spread in the future.
Concerning the sugar puckering, the C-nucleosides were
known to exist in S-type conformation predominantly due
to lack of an anomeric effect. Therefore, restriction of the
sugar puckering of C-nucleosides, especially in N-type
conformation, is thought to contribute towards discovery
of the novel biological activities of C-nucleosides and
clari®cation of the structure±activity relationship.
In this paper, we describe the effective synthesis of 20,40-
BNA modi®ed C-nucleosides containing some unnatural
nucleobases such as oxazole, 2-phenyloxazole, pyridine,
pyrrole and imidazole, and also discuss their conformation.9
On the other hand, nucleoside analogues with a restricted
2. Results and discussion
To synthesize C-nucleosides with 20,40-BNA modi®cation,
we selected a coupling reaction of the aldehyde 1 with
aromatic heterocycles and the following ring-closure reac-
tion as the key steps. The synthesis of the aldehyde 1 was
effectively accomplished as shown in Scheme 1. Methyl
4-hydroxymethyl-2,3-O-isopropylideneribofuranoside +2)10
was monosilylated by a tert-butyldiphenylsilyl group to
Figure 1. Chemical structure of 20,40-BNA/LNA.
²
afford 3 +70%), which was then tosylated to give 4
+98%). Acidic hydrolysis of 4 afforded diol 5 +77%). The
Keywords: nucleosides; nitrogen heterocycles; Grignard reaction; Mitsu-
nobu reaction.
p
²
Corresponding author. Tel.: 181-6-6879-8200; fax: 181-6-6879-8204;
e-mail: imanishi@phs.osaka-u.ac.jp
The stereochemistry of compounds 3, 10 was con®rmed by 1H NMR and
NOE measurements.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+02)00226-0

3052
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
Scheme 1. Reagents and conditions: +a) TBDPSCl, Et3N, CH2Cl2, rt, 13 h, 70%; +b) p-TsCl, Et3N, DMAP, CH2Cl2, rt, 17 h, 98%; +c) TFA, THF, H2O, rt,
20 min, 77%; +d) HMDS, NaNH2, benzene, rt, 30 min, then added 5, THF, further rt, 1 h, 35% +6), 43% +7); +e) TBAF, THF, rt, 0.5 h, quant.; +f) BnBr, NaH,
DMF, 08C, 1 h, 91%; +g) 10% HCl aq., THF, rt, 2 h, quant.; +h) PhCHO, ZnCl2, rt, 2 h, quant.
Table 1. Reductive cleavage of 2,3-O-benzylidene 10
Run
Reagents +equiv.)
Solvent
Temperature
Time +h)
Yield +%)a
11
12
1
2
3
4
5
DIBAH +5.0)
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
08C!rt
6
5
1
2
2
9
56
40
27
24
37
NaBH3CN +5.0), SnCl4 +5.0)
NaBH3CN +5.0), TiCl4 +5.0)
NaBH3CN +1.2), TiCl4 +5.0)
NaBH3CN +5.0), TiCl4 +1.2)
rt
rt
rt
rt
14
67
16
45
a
Isolated yield.
reaction of diol 5 under the alkaline conditions was found to
give the desired product 6 +35%) along with the oxetane
product 7 +43%). After desilylation of 6 +quant.), the
obtained diol 8 was protected by a benzyl group to afford
dibenzyl derivative 9 +90%), which was then treated with
10% HCl aq. to give the desired compound 1 successively
+quant.).11 On the other hand, the selective protection of the
C3-hydroxy group in 5 is thought to lead to convenient
synthesis of 9. The diol 5 was initially treated with
PhCHO and ZnCl2 to give 2,3-O-benzylidene 10 +quant.)
lower selectivity +Table 1, runs 4, 5). Interestingly, 2-O-ben-
zyl compound 12 was yielded as a major product by using
DIBAL or a combination of NaBH3CN and SnCl4 +Table 1,
runs 1, 2). The difference in selectivity of the cleavage was
likely explained as follows: TiCl4 would initially coordinate
with the less hindered 2-oxygen in 10 rather than 3-oxygen,
and then reductive cleavage at the C2±O bond immediately
proceeded owing to its high reactivity. On the other hand,
DIBAL or SnCl4 formed a thermodynamically stable com-
plex with both 3-oxygen and the sulfonyl oxygen in 10;
thereby, the cleavage of the C3±O bond was observed as
a main reaction. Next, on exposure of 11 to NaN+TMS)2,
bicyclic methyl ribofuranoside 13 was obtained +95%) as
shown in Scheme 2. Deprotection at the 5-hydroxy group in
13 +13!14, quant.) followed by substitution by a benzyl
group gave 9 +14!9, 92%).
²
as the sole diastereoisomer. Reductive cleavage of the
benzylidene C±O bond in 10 was examined as shown in
Table 1. As a result, 10 was reduced with NaBH3CN
+5 equiv.) and TiCl4 +5 equiv.) to afford the desired
3-O-benzyl derivative 11 +67%) effectively +Table 1, run
3). A decrease in the amount of NaBH3CN or TiCl4 gave
The aldehyde 1 was coupled with the magnesium and the
lithium derivatives of some aromatic heterocycles +Table 2).
The magnesium derivatives of 2-methylthio-5-oxazole12
and 2-phenyl-5-oxazole13 gave S-15a and S-15b as the
³
main product, respectively. The same stereoselectivity
³
Scheme 2. Reagents and conditions: +a) NaHMDS, THF, rt, 3 h, 95%;
+b) TBAF, THF, rt, 6 h, quant.; +c) BnBr, NaH, DMF, rt, 7 h, 92%.
The stereochemistry of R- and S-16 was determined by NOE measure-
ment after the Mitsunobu reaction.

Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
Table 2. Coupling reaction of aldehyde 1 with some aromatic heterocycles
3053
R
M
Temperature
Time +h)
Product
Yield +%)a
R/Sb
MgBr
Li
rt
2788C
1
13
15a
61
78
15:85
39:61
MgBr
Li
rt
18
2
15b
15c
70
82
8:92
33:67
2788C!308C
MgBr
Li
rt!508C
2788C
3
3
65
56
85:15
22:78
MgBr
Li
rt
2
2
15d
15e
81
56
98:2
50:50
2788C!rt
MgBr
Li
rt
2
2
72
80
90:10
69:31
2788C!rt
a
Isolated yield of the mixture of R- and S-14.
Determined by 1H NMR measurements.
b
was observed when the magnesium derivatives of 2-pyri-
dine,14 N-triisopropylsilyl-3-pyrrole15 and 2-tert-butyldi-
phenylsilyl-1-N,N-dimethylsulfamoyl-5-imidazole16 were
employed. This stereoselectivity would be explained by
the re-face attack of nucleophiles on the carbonyl group
of the chelation model +Fig. 2).17 On the contrary, the
lithium salts of heterocycles also gave the corresponding
products; however, signi®cant stereoselectivities were not
observed.
ditions.18 In the case of 15a, the 2-methylthio group in the
oxazole moiety was removed with Raney Ni +W-2) +Scheme
3), and then the corresponding oxazole derivative 15a0 was
employed for the ring-closure reaction. As shown in Table
3, the b-anomer of C-nucleoside 16a was obtained exclu-
sively by the reaction of S-15a0 with 1,10-azobis+N,N-di-
methylformamide) +TMAD) and n-tributylphosphine +TBP)
in 92% yield.§ b-Anomers of 16b and 16c were similarly
yielded from S-15b and R-15c, respectively, by using
diethyl azodicarboxylate +DEAD) and triphenylphosphine
+TPP). On the contrary, S-15d gave anomeric mixtures of
16d +a/bˆ29:71). This is probably due to the partial
SN1-type reaction caused by the electron-donating feature
of the N-silylated pyrrole ring +Fig. 3). A mixture of R- and
S-15e +R/Sˆ90:10) was also employed for this ring-closure
reaction to afford the desired product 16e +a/bˆ10:90).
After deprotection of the imidazole moiety in 16e by
treatment with 1.5 N HCl aq., each anomer 16e0 was sepa-
rated by silica gel column chromatography +Scheme 4).
a-Anomers of C-nucleosides 16a±d were also obtained by
the cyclization of R-15a0, R-15b, S-15c and S-15d.
After separation of the R- and S-epimers of 15a±d, these
compounds were cyclized under typical Mitsunobu con-
Figure 2. Plausible chelation model.
All attempts +H2/Pd+OH)2±C, cyclohexene/Pd+OH)2±C,
BBr3 etc.) to remove the benzyl group in b-16d failed and
gave only complex mixtures. Although the details are not
clear, this is probably due to the unstable feature of C10 ±O40
bond in b-16d under the debenzylation conditions. On
the other hand, a typical Pd-catalyzed hydrogenolysis of
b-anomers of 16a±c and 16e0 successfully proceeded to
give the desired C-nucleosides 17 +Scheme 5).
The conformation of nucleosides in a solution is readily
1
estimated by their H NMR spectra. The fact that the H10,
H20 and H30 signals of 17a±c and 17e were observed as a
§
Scheme 3. Reagents and conditions: +a) Raney Ni +W-2), EtOH, re¯ux,
30 min, 69% +S-15a0), 50% +R-15a0).
The stereochemistry of a- and b-16 was con®rmed by NOE measure-
ment.

3054
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
Table 3. Cyclization of diols 15 under Mitsunobu conditions
Substrate
R
Methoda
Temperature
Time +h)
Yield +%)
a/b
S-15a0
R-15a0
A
A
rt
rt
2
17
92
77
0:100
100:0
S-15b
R-15b
B
B
08C!rt
08C
6
2
90
72
0:100
100:0
R-15c
S-15c
B
B
08C
08C!rt
3
4
80
64
0:100
100:0
R-15d
S-15d
B
B
rt
rt
12
3
59b
86b
29:71c
78:22c
15e +R/Sˆ90:10)
A
rt
15
90b
10:90c
a
Method A: TMAD, TBP, benzene; Method B: DEAD, TPP, THF.
Isolated yield of the anomeric mixture.
Determined by H NMR measurements.
b
c
1
Figure 3. Cyclization of R-15d.
singlet, supported that the sugar puckering of these 20,40-
BNA modi®ed C-nucleosides was strictly0 restrained in
N-type conformation.19 On the contrary, J1 2 values of the
0
ribo-type C-nucleosides, 2-ribofuranosylpyridine20 and
4-ribofuranosylimidazole21 bearing pyridine and imidazole
as a nucleobase were known to be 5.5 and 6.9 Hz,
Scheme 4. Reagents and conditions: +a) 1.5N HCl aq., THF, re¯ux, 2.5 h,
84%.
Scheme 5. Reagents and conditions: +a) H2 +1 atm), 20% Pd+OH)2±C,
EtOH, rt, 18 h, 82% +17a), 9 h, 46% +17b); 20% Pd+OH)2±C, cyclohexene,
EtOH, re¯ux, 2.5 h, 71% +17c), 5 h, 83% +17e).
Figure 4. ORTEP drawing of 17a.

Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
Table 4. Torsion angles and pseudorotation phase angle +P) of 17a and 18
3055
3.1.1. Methyl 5-O-0tert-butyldiphenylsilyl)-4-0hydroxy-
methyl)-2,3-O-isopropylidene-b-d-ribofuranoside 03).
Under a nitrogen atmosphere, TBDPSCl +4.88 ml, 18.8
mmol), Et3N +2.62 ml, 18.8 mmol) were added to a solution
of compound 210 +2.00 g, 8.54 mmol) in anhydrous CH2Cl2
+40 ml) at 08C and the mixture was stirred at rt for 13 h.
After addition of a saturated aqueous solution of NaHCO3,
the mixture was extracted with AcOEt. The organic phase
was washed with brine and dried over Na2SO4 and concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography [n-hexane/AcOEt +10:1,
v/v)] to give compound 3 +2.82 g, 70%) as a colorless oil.
17a
18
n0+C40 ±O40 ±C10 ±C20)
n1+O40 ±C10 ±C20 ±C30)
n2+C10 ±C20 ±C30 ±C40)
n3+C20 ±C30 ±C40 ±O40)
n4+C30 ±C40 ±O40 ±C10)
P
0.48
237.28
56.08
256.98
36.68
18.08
0.68
236.58
53.98
254.38
34.98
17.48
17
[a]D ˆ216.2 +c 0.52, CHCl3). IR nmax +KBr): 3511, 3061,
2938, 2852, 1465, 1380, 1203, 1103 cm21 1H NMR
.
+CDCl3) d: 1.09 +9H, s), 1.28 +3H, s), 1.49 +3H, s), 3.22
+3H, s), 3.67, 3.76 +2H, AB, Jˆ11 Hz), 3.88, 3.93 +2H,
AB, Jˆ11 Hz), 4.49 +1H, d, Jˆ6 Hz), 4.57 +1H, d, Jˆ
6 Hz), 4.93 +1H, s), 7.38±7.43 +6H, m), 7.67 +4H, d, Jˆ
7 Hz). 13C NMR +CDCl3) d: 19.25, 24.35, 25.93, 26.87,
55.02, 62.86, 64.82, 82.21, 85.95, 88.70, 108.63, 112.63,
127.78, 129.87, 133.03, 135.65. Mass +EI): m/z 457
+M12CH3, 5.9), 129 +100). Anal. calcd for C26H36O6Si´1/
4H2O: C, 65.45; H, 7.71. Found: C, 65.43; H, 7.59.
0
0
respectively. These relatively large J1 2 values mean that
these ribo-type C-nucleosides predominantly existed in
S-type conformation.19 Thus, the 20-O,40-C-methylene
bridging +20,40-BNA modi®cation) is quite effective to
restrict the sugar puckering in N-form not only for
N-nucleosides but also for C-nucleosides.
In addition, X-ray crystallographic analysis22 of 17a was
performed to clarify the detailed structure +Fig. 4 and
Table 4). The endocyclic sugar torsion angles +n0±n4,)
of 17a were almost identical to those of 20,40-BNA modi-
®ed N-nucleoside, 20-O,40-C-methyleneuridine 18.5 The
pseudorotation phase angle +P) of 17a was calculated
to be 18.08, characteristic of the typical C30-endo sugar
puckering.23
3.1.2. Methyl 5-O-0tert-butyldiphenylsilyl)-2,3-O-iso-
propylidene-4-0p-toluenesulfonyloxymethyl)-b-d-ribo-
furanoside 04). Under a nitrogen atmosphere, p-TsCl
+1.34 g, 7.03 mmol), Et3N +3.92 ml, 28.1 mmol), DMAP
+90 mg, 0.74 mmol) were added to a solution of compound
3 +2.13 g, 4.51 mmol) in anhydrous CH2Cl2 +15 ml) at 08C
and the mixture was stirred at rt for 17 h. After addition of a
saturated aqueous solution of NaHCO3, the mixture was
extracted with AcOEt. Usual work-up and puri®cation by
silica gel column chromatography [n-hexane/AcOEt +5:1,
v/v)] gave compound 4 +2.76 g, 98%) as a colorless oil.
Herein, effective synthesis of the 20,40-BNA modi®ed
C-nucleosides with N-type conformation was achieved by
coupling reaction of a metal salt of heteroaromatic
compounds and aldehyde 1 followed by the Mitsunobu
reaction. This synthetic route should be very useful for
preparing the conformationally locked C-nucleosides
having various heteroaromatics, and we also believe that
the C-nucleosides with 20,40-BNA modi®cation will contri-
bute to greater practical use of antisense and/or antigene
strategy.
17
[a]D ˆ23.8 +c 0.56, CHCl3). IR nmax +KBr): 2934, 2852,
1
1369, 1184, 1104 cm21. H NMR +CDCl3) d: 1.02 +9H, s),
1.20 +3H, s), 1.32 +3H, s), 2.41 +3H, s), 3.09 +3H, s), 3.51,
3.77 +2H, AB, Jˆ10 Hz), 4.25, 4.39 +2H, AB, Jˆ9 Hz), 4.34
+1H, d, Jˆ6 Hz), 4.47 +1H, d, Jˆ6 Hz), 4.77 +1H, s), 7.28
+2H, d, Jˆ9 Hz), 7.39±7.46 +6H, m), 7.62±7.65 +4H, m),
7.81 +2H, d, Jˆ9 Hz). 13C NMR +CDCl3) d: 19.16, 21.58,
24.55, 25.81, 26.79, 54.99, 62.73, 68.81, 81.87, 85.64,
87.51, 108.70, 112.78, 127.75, 127.78, 128.21, 129.58,
129.63, 129.87, 132.92, 135.63, 144.42. Mass +EI): m/z
611 +M12CH3, 6.0), 353 +100). Anal. calcd for
C33H42O8SSi: C, 62.99; H, 6.53; S, 5.13. Found: C, 63.23;
H, 6.75; S, 5.11.
3. Experimental
3.1. General
All melting points were measured on a Yanagimoto micro
melting points apparatus and are uncorrected. Optical
rotations were recorded on a JASCO DIP-370 instrument.
IR spectra were recorded on a JASCO FT/IR-200 spectro-
meter. 1H and 13C NMR spectra were recorded on a Varian
VXR-200 +1H, 200 MHz; 13C, 50.3 MHz), JEOL EX-270
+1H, 270 MHz; 13C, 67.8 MHz) or JEOL GX-500 +1H,
500 MHz; 13C, 126 MHz). Mass spectra were recorded on
a JEOL JMS-D300 or JMS-600 mass spectrometer. For
column chromatography, Merck Kieselgel 60 +70±200
mesh) or Fuji Silysia BW-127ZH +100±200 mesh) was
used. For ¯ash column, Fuji Silysia BW-300 +200±400
mesh) was used. For almina column chromatography,
Merck aluminium oxide 90 active, neutral +70±230 mesh)
was used.
3.1.3. Methyl 5-O-0tert-butyldiphenylsilyl)-4-0p-toluene-
sulfonyloxymethyl)-b-d-ribofuranoside 05). TFA +14 ml)
was added to a solution of compound 4 +645 mg,
1.03 mmol) in THF/H2O +8:3, 11 ml) at rt and the mixture
was stirred for 20 min. The mixture was removed under
reduced pressure. The residue was puri®ed by silica gel
column chromatography [n-hexane/AcOEt +2:1, v/v)] to
give compound 5 +464 mg, 77%) as a colorless oil.
17
[a]D ˆ235.8 +c 1.90, CHCl3). IR nmax +KBr): 3499,
1
3051, 2931, 2846, 1596, 1468, 1362, 1176, 1109 cm21. H
NMR +CDCl3) d: 1.02 +9H, s), 2.42 +3H, s), 3.16 +3H, s),
3.54, 3.70 +2H, AB, Jˆ10 Hz), 3.97 +1H, d, Jˆ5 Hz), 4.18
+1H, d, Jˆ5 Hz), 4.26, 4.39 +2H, AB, Jˆ10 Hz), 4.73 +1H,
s), 7.30 +2H, d, Jˆ8 Hz), 7.36±7.44 +6H, m), 7.59±7.66

3056
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
+4H, m), 7.78 +2H, d, Jˆ8 Hz). 13C NMR +CDCl3) d: 19.18,
21.60, 26.70, 55.15, 66.52, 69.58, 74.04, 75.22, 84.76,
107.46, 127.75, 128.01, 129.79, 129.85, 132.56, 132.67,
132.81, 135.51, 135.58, 144.87. Mass +EI): m/z 569
+M12OH, 6.4), 199 +100). Anal. calcd for C30H38O8SSi´1/
4H2O: C, 60.94; H, 6.56. Found: C, 60.94; H, 6.43.
tion of compound 8 +406 mg, 2.30 mmol) in anhydrous
DMF +7 ml) was added to a suspension of n-hexane-washed
NaH +60% in mineral oil +w/w), 203 mg, 5.08 mmol) in
anhydrous DMF +8 ml) at 08C and the mixture was stirred
for 1 h at 08C. BnBr +0.60 ml, 5.04 mmol) was added to the
reaction mixture at 08C and the mixture was stirred for 1 h at
rt. After addition of water, the mixture was extracted with
Et2O. Usual work-up and puri®cation by silica gel column
chromatography [n-hexane/AcOEt +6:1, v/v)] gave com-
3.1.4. Methyl 5-O-0tert-butyldiphenylsilyl)-2-O,4-C-
methylene-b-d-ribofuranoside 06) and methyl 5-O-0tert-
butyldiphenylsilyl)-3-O,4-C-methylene-b-d-ribofurano-
side 07). Under a nitrogen atmosphere, +TMS)2NH +0.70 ml,
3.31 mmol) was added to a solution of NaNH2 +129 mg,
3.31 mmol) in anhydrous benzene +1.6 ml) at rt and the
mixture was stirred for 30 min. The mixture was added
to a solution of compound 5 +194 mg, 0.33 mmol) in anhy-
drous THF +4 ml) at rt under a nitrogen atmosphere and the
mixture was stirred for 1 h. After addition of a saturated
aqueous solution of NaHCO3, the mixture was extracted
with CHCl3. Usual work-up and puri®cation by silica gel
column chromatography [n-hexane/AcOEt +5:1, v/v)] gave
compound 6 +48 mg, 35%) and compound 7 +59 mg, 43%)
26
pound 9 +746 mg, 91%) as a colorless oil. [a]D ˆ244.7
+c 1.10, CHCl3). IR nmax +KBr): 2939, 2907, 1454, 1200,
1
1099, 1038 cm21. H NMR +CDCl3) d: 3.39 +3H, s), 3.79,
3.99 +2H, AB, Jˆ8 Hz), 3.77 +2H, s), 4.08 +1H, s), 4.12 +1H,
s), 4.56, 4.67 +2H, AB, Jˆ12 Hz), 4.61 +2H, s), 4.81 +1H, s),
7.27±7.35 +10H, m). 13C NMR +CDCl3) d: 55.28, 66.35,
71.95, 72.13, 73.48, 78.99, 84.93, 104.77, 127.41, 127.50,
127.67, 128.25, 137.47, 137.76. Mass +EI): m/z 356 +M1,
8.8), 91 +100). Anal. calcd for C21H24O5: C, 70.77; H, 6.79.
Found: C, 70.53; H, 6.69.
3.1.7. Methyl 2,3-O-benzylidene-5-O-0tert-butyldiphenyl-
silyl)-4-0p-toluenesulfonyloxymethyl)-b-d-ribofurano-
side 010). Under a nitrogen atmosphere, ZnCl2 +0.15 g,
1.10 mmol) was added to a solution of compound 5
+0.52 g, 0.89 mmol) in PhCHO +4 ml) at rt and the mixture
was stirred for 2 h. After addition of a saturated aqueous
solution of NaHCO3, the mixture was extracted with CHCl3.
The organic phase was washed with a saturated aqueous
solution of NH4Cl and concentrated under reduced pressure.
PhCHO was removed from the residue by steam distillation.
The residue was extracted with AcOEt. Usual work-up
and puri®cation by silica gel column chromatography
[n-hexane/AcOEt +1:1, v/v)] gave compound 10 +0.61 g,
21
each as a colorless oil. Compound 6: [a]D ˆ257.9 +c 1.68,
CHCl3). IR nmax +KBr): 3438, 3064, 2934, 2852, 1468,
1
1103, 1036 cm21. H NMR +CDCl3) d: 1.08 +9H, s), 2.04
+1H, brs), 3.39 +3H, s), 3.65, 3.98 +2H, AB, Jˆ8 Hz), 3.95,
4.02 +2H, AB, Jˆ12 Hz), 4.02 +1H, s), 4.30 +1H, s), 4.79
+1H, s), 7.38±7.46 +6H, m), 7.65±7.69 +4H, m). 13C NMR
+CDCl3) d: 19.25, 26.74, 55.04, 60.72, 71.18, 73.08, 79.88,
85.46, 104.35, 127.80, 129.88, 130.03, 132.88, 135.58,
135.62, 135.71. Mass +EI): m/z 397 +M12OH, 1.6), 383
+M12OCH3, 1.1), 357 +M12C4H9, 49.7), 279 +100).
Anal. calcd for C23H30O5Si´1/4H2O: C, 65.92; H, 7.34.
17
Found: C, 66.07; H, 7.14. Compound 7: [a]D ˆ247.3 +c
24
0.91, CHCl3). IR nmax +KBr): 3457, 3059, 2938, 2852, 1468,
1109 cm21. 1H NMR +CDCl3) d: 1.10 +9H, s), 3.26 +3H, s),
3.71 +2H, s), 4.02 +1H, d, Jˆ6 Hz), 4.35, 4.95 +2H, AB,
Jˆ7 Hz), 5.01 +1H, s), 5.11 +1H, d, Jˆ6 Hz), 7.38±7.44
+6H, m), 7.66 +4H, d, Jˆ7 Hz). 13C NMR +CDCl3) d:
19.28, 26.79, 55.40, 63.70 75.13, 77.20, 77.34, 77.86,
84.48, 86.29, 111.86, 127.78, 128.00, 129.87, 132.90,
132.96, 135.56, 135.81, 135.94. Mass +EI): m/z 357
+M12C4H9, 10.4), 325 +100). Anal. calcd for
C23H30O5Si´1/4H2O: C, 65.92; H, 7.34. Found: C, 65.98;
H, 7.23.
100%) as a colorless oil. [a]D ˆ117.1 +c 1.38, CHCl3).
IR nmax +KBr): 2933, 2864, 1463, 1365, 1179, 1110 cm21
.
1H NMR +CDCl3) d: 1.04 +9H, s), 2.37 +3H, s), 3.13 +3H, s),
3.59, 3.84 +2H, AB, Jˆ10 Hz), 4.30, 4.42 +2H, AB, Jˆ
10 Hz), 4.49 +1H, d, Jˆ6 Hz), 4.80 +1H, d, Jˆ6 Hz), 4.95
+1H, s), 5.67 +1H, s), 7.16±7.43 +13H, m), 7.64±7.73 +6H,
m). 13C NMR +CDCl3) d: 19.16, 21.60, 26.76, 55.06, 62.64,
68.73, 82.61, 86.22, 87.64, 106.29, 108.23, 126.84, 127.76,
127.82, 128.12, 128.39, 129.51, 129.85, 132.63, 132.69,
132.78, 135.29, 135.62, 144.33. Mass +EI): m/z 674 +M1,
0.6), 353 +100). Anal. calcd for C37H42O8SSi: C, 65.85; H,
6.27; S, 4.75. Found: C, 65.94; H, 6.40; S, 4.75.
3.1.5. Methyl 2-O,4-C-methylene-b-d-ribofuranoside 08).
Under a nitrogen atmosphere, TBAF +1 M in THF, 0.45 ml,
0.45 mmol) was added to a solution of compound 6
+157 mg, 0.38 mmol) in anhydrous THF +4 ml) at rt and
the mixture was stirred for 0.5 h at rt. The mixture was
concentrated under reduced pressure. The residue was puri-
®ed by silica gel column chromatography [n-hexane/AcOEt
+1:1, v/v)] to give compound 8 +67 mg, 100%) as a colorless
3.1.8. Methyl 3-O-benzyl-5-O-0tert-butyldiphenylsilyl)-4-
0p-toluenesulfonyloxymethyl)-b-d-ribofuranoside 011)
and methyl 2-O-benzyl-5-O-0tert-butyldiphenylsilyl)-4-
0p-toluenesulfonyloxymethyl)-b-d-ribofuranoside 012).
Under a nitrogen atmosphere, NaBH3CN +23 mg, 0.37
mmol), TiCl4 +40 ml, 0.37 mmol) were added to a solution
of compound 8 +51 mg, 76 mmol) in anhydrous MeCN
+1.2 ml) at 08C and the mixture was stirred for 1 h at rt.
After addition of a saturated aqueous solution of NH4Cl,
the mixture was neutralized by addition of a saturated
aqueous solution of NaHCO3 and ®ltered through Celite
which was subsequently washed with CHCl3. The combined
®ltrate was extracted with CHCl3. Usual work-up and
puri®cation by silica gel column chromatography [n-hex-
ane/AcOEt +5:1, v/v)] gave compound 11 +33 mg, 67%)
and compound 12 +14 mg, 27%) each as a colorless oil.
26
oil. [a]D ˆ2131.0 +c 1.31, CHCl3). IR nmax +KBr): 3373,
1
2947, 1646, 1198, 1035 cm21. H NMR +CDCl3) d: 3.41
+3H, s), 3.64, 3.93 +2H, AB, Jˆ8 Hz), 3.89 +2H, s), 4.05
+1H, s), 4.31 +1H, s), 4.80 +1H, s). 13C NMR +CDCl3) d:
55.63, 58.06, 70.95, 71.65, 79.65, 86.07, 104.74. Mass
+FAB): m/z 177 +MH1). Anal. calcd for C7H12O5´1/4H2O:
C, 46.54; H, 6.97. Found: C, 46.62; H, 7.00.
3.1.6. Methyl 3,5-di-O-benzyl-2-O,4-C-methylene-b-d-
ribofuranoside 09). Under a nitrogen atmosphere, a solu-
23
Compound 11: [a]D ˆ232.8 +c 3.89, CHCl3). IR nmax

Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
3057
+KBr): 3545, 3068, 2932, 2859, 1457, 1362, 1178, 1114,
128.40, 137.56. Mass +FAB): m/z 267 +MH1). Anal. calcd
for C14H18O5´1/6H2O: C, 62.44; H, 6.86. Found: C, 62.48;
H, 6.78.
1
1042 cm21. H NMR +CDCl3) d: 1.03 +9H, s), 2.40 +3H,
s), 2.67 +1H, d, Jˆ5 Hz), 3.11 +3H, s), 3.51, 3.72 +2H,
AB, Jˆ10 Hz), 3.95 +1H, dd, Jˆ5, 5 Hz), 4.10 +1H, d,
Jˆ5 Hz), 4.24, 4.36 +2H, AB, Jˆ10 Hz), 4.52, 4.54 +2H,
AB, Jˆ10 Hz), 4.68 +1H, s), 7.21±7.44 +13H, m),7.60±
7.75 +6H, m). 13C NMR +CDCl3) d: 19.19, 21.58, 26.76,
54.86, 66.64, 69.75, 73.24, 73.66, 81.43, 84.14, 107.64,
127.75, 128.08, 128.20, 128.50, 129.57, 129.81, 129.87,
132.46, 132.64, 132.84, 135.45, 135.60, 136.91, 144.50.
Mass +EI): m/z 619 +M12C4H9, 0.4), 91 +100). Anal.
calcd for C37H44O8SSi: C, 65.65; H, 6.55; S, 4.74. Found:
3.1.11. Methyl 3,5-di-O-benzyl-2-O,4-C-methylene-b-d-
ribofuranoside 09). Under a nitrogen atmosphere, a solu-
tion of compound 14 +46 mg, 0.17 mmol) in anhydrous
DMF +1.5 ml) was added to a suspension of n-hexane-
washed NaH +60% in mineral oil +w/w), 8.0 mg,
0.20 mmol) in anhydrous DMF +1.5 ml) at 08C and the
mixture was stirred for 10 min at 08C. BnBr +24 ml,
0.21 mmol) was added to the reaction mixture at 08C and
the mixture was stirred for 7 h at rt. After addition of water,
the mixture was extracted with AcOEt. Usual work-up
and puri®cation by silica gel column chromatography
[n-hexane/AcOEt +6:1, v/v)] gave compound 9 +56 mg,
92%) as a colorless oil.
23
C, 65.48; H, 6.56; S, 4.36. Compound 12: [a]D ˆ13.2 +c
3.31, CHCl3). IR nmax +KBr): 3534, 3068, 2932, 2858, 1596,
1
1469, 1362, 1178, 1112, 1042 cm21. H NMR +CDCl3) d:
1.00 +9H, s), 2.39 +3H, d, Jˆ6 Hz), 2.59 +1H, s), 3.18 +3H,
s), 3.47, 3.63 +2H, AB, Jˆ10 Hz), 3.80 +1H, dd, Jˆ2, 6 Hz),
4.23 +1H, dd, Jˆ6, 6 Hz), 4.26, 4.41 +2H, AB, Jˆ10 Hz),
4.50, 4.63 +2H, AB, Jˆ12 Hz), 4.77 +1H, d, Jˆ2 Hz), 7.21±
7.44 +13H, m), 7.62±7.76 +6H, m). 13C NMR +CDCl3) d:
19.16, 21.55, 26.69, 55.39, 64.94, 69.48, 73.04, 73.15,
82.41, 85.04, 105.66, 127.72, 127.79, 128.05, 128.19,
128.58, 129.58, 129.76, 132.84, 132.93, 135.59, 136.83,
144.35. Mass +EI): m/z 619 +M12C4H9, 0.3), 91 +100).
Anal. calcd for C37H44O8SSi: C, 65.65; H, 6.55; S, 4.74.
Found: C, 65.50; H, 6.49; S, 4.61.
3.1.12. 3,5-Di-O-benzyl-2-O,4-C-methylene-d-ribofura-
nose 01). HCl +10% in water, 5 drops) was added to a solu-
tion of compound 9 +280 mg, 0.79 mmol) in THF +6 ml) at
08C and the mixture was stirred for 2 h at rt. After addition
of a saturated aqueous solution of NaHCO3, the mixture was
extracted with CHCl3. Usual work-up and puri®cation by
silica gel column chromatography [n-hexane/AcOEt +3:2,
v/v)] gave compound 1 +269 mg, 100%) as a colorless oil.
24
[a]D ˆ155.1 +c 0.85, CHCl3). IR nmax +KBr): 3381, 2869,
1
3.1.9. Methyl 3-O-benzyl-5-O-0tert-butyldiphenylsilyl)-2-
O,4-C-methylene-b-d-ribofuranoside 013). Under
1727, 1454, 1099 cm21. H NMR +CDCl3) d: 3.51, 3.83
a
+2H, AB, Jˆ9 Hz), 3.93, 3.96 +2H, AB, Jˆ9 Hz), 3.94
+1H, s), 4.37 +1H, s), 4.52, 4.67 +2H, AB, Jˆ12 Hz), 4.54,
4.55 +2H, AB, Jˆ12 Hz), 7.26±7.35 +10H, m), 9.65 +1H, s).
13C NMR +CDCl3) d: 67.93, 71.83, 73.68, 75.01, 80.94,
87.01, 87.14, 127.71, 127.76, 127.91, 127.98, 128.43,
128.48, 137.09, 137.29. Mass +EI): m/z 342 +M1, 1.3), 91
+100). Anal. calcd for C20H22O5´1/3H2O: C, 68.95; H, 6.56.
Found: C, 69.09; H, 6.56.
nitrogen atmosphere, NaN+TMS)2 +1 M in THF, 0.92 ml,
0.92 mmol) was added to a solution of compound 11
+0.31 g, 0.46 mmol) in anhydrous THF +6 ml) at 08C and
stirred for 3 h at rt. After addition of a saturated aqueous
solution of sodium NaHCO3, the mixture was extracted with
AcOEt. Usual work-up and puri®cation by silica gel column
chromatography [n-hexane/AcOEt +5:1, v/v)] gave com-
24
pound 13 +0.22 g, 95%) as a colorless oil. [a]D ˆ234.5
+c 1.90, CHCl3). IR nmax +KBr): 2933, 2864, 1195, 1103,
1040 cm21. 1H NMR +CDCl3) d: 1.06 +9H, s), 3.40 +3H, s),
3.67, 3.97 +2H, AB, Jˆ7 Hz), 3.96 +2H, s), 4.13 +1H, s), 4.22
+1H, s), 4.59, 4.67 +2H, AB, Jˆ12 Hz), 4.83 +1H, s), 7.26±
7.42 +11H, m), 7.70±7.72 +4H, m). 13C NMR +CDCl3) d:
19.32, 26.68, 54.84, 60.08, 72.06, 72.15, 77.30, 78.84,
86.19, 104.47, 127.44, 127.67, 128.35, 129.67, 133.16,
133.36, 135.60, 135.65, 137.82. Mass +EI): m/z 504 +M1,
0.2), 91 +100). Anal. calcd for C30H36O5Si: C, 71.39; H,
7.19. Found: C, 71.48; H, 7.22.
3.1.13. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribitol-
1-yl)-2-0methylthio)oxazole 015a). Grignard reaction.
Under a nitrogen atmosphere, MgBr2 +0.494 M in THF,
5 ml, 2.68 mmol) was added to a solution of 5-lithio-2-
+methylthio)oxazole12 [0.148 M in THF/TMEDA +7:4),
11 ml, 1.63 mmol] at rt and the mixture was stirred at
rt for 15 min. A solution of compound 1 +160 mg, 0.47
mmol) in anhydrous THF +3 ml) was added to the mixture
at rt and the mixture was stirred for 1 h at rt. After addition
of water, the mixture was extracted with AcOEt. Usual
work-up and puri®cation by ¯ash silica gel column chroma-
tography [n-hexane/AcOEt +1:1, v/v)] gave a mixture of
compound R-15a and compound S-15a +131 mg, 61%,
R-15a/S-15aˆ15:85). Reaction using organolithium reagent.
Under a nitrogen atmosphere, a solution of compound 1
+233 mg, 0.68 mmol) in anhydrous THF +4 ml) was added
to a solution of 5-lithio-2-+methylthio)oxazole12 [0.171 M in
THF/TMEDA +4:3), 14 ml, 2.39 mmol] at 2788C and the
mixture was stirred at 2788C for 13 h. According to the
Grignard reaction, a mixture of compound R-15a and
compound S-15a +244 mg, 78%, R-15a/S-15aˆ39:61) was
3.1.10. Methyl 3-O-benzyl-2-O,4-C-methylene-b-d-ribo-
furanoside 014). Under a nitrogen atmosphere, TBAF +1 M
in THF, 0.41 ml, 0.41 mmol) was added to a solution of
compound 13 +138 mg, 0.27 mmol) in anhydrous THF
+3 ml) at rt and the mixture was stirred for 6 h at rt. The
mixture was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
[n-hexane/AcOEt +1:1, v/v)] to give compound 14 +72 mg,
24
100%) as a colorless oil. [a]D ˆ252.4 +c 1.74, CHCl3). IR
nmax +KBr): 3442, 2942, 1455, 1197, 1141, 1099, 1037
1
22
cm21. H NMR +CDCl3) d: 1.92 +1H, dd, Jˆ6, 6 Hz), 3.38
given. Compound R-15a. Pale yellow oil. [a]D ˆ170.9 +c
+3H, s), 3.65, 3.99 +2H, AB, Jˆ8 Hz), 3.87±3.88 +2H, m),
4.12 +2H, d, Jˆ6 Hz), 4.60, 4.67 +2H, AB, Jˆ12 Hz), 7.26±
7.37 +5H, m). 13C NMR +CDCl3) d: 55.43, 58.65, 71.72,
72.15, 77.26, 78.47, 85.55, 105.10, 127.52, 127.84,
0.72, CHCl3). IR nmax +KBr): 3372, 2867, 1490, 1104 cm21
.
1H NMR +CDCl3) d: 2.61 +3H, s), 3.29 +2H, brs), 3.58, 3.83
+2H, AB, Jˆ9 Hz), 3.79, 3.91 +2H, AB, Jˆ9 Hz), 4.01 +1H,
s), 4.29, 4.31 +2H, AB, Jˆ12 Hz), 4.30 +1H, d, Jˆ4 Hz),

3058
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
4.58 +2H, s), 4.99 +1H, d, Jˆ4 Hz), 7.01 +1H, s), 7.12±7.32
+10H, m). 13C NMR +CDCl3) d: 14.79, 66.82, 68.86, 72.00,
73.83, 74.95, 81.38, 83.32, 87.08, 125.51, 127.39, 127.70,
127.80, 127.93, 128.28, 128.43, 137.17, 137.27, 152.18,
161.10. Mass +EI): m/z 457 +M1, 6.8), 91 +100). Anal.
calcd for C24H27NO6S´1/5H2O: C, 62.51; H, 5.99; N, 3.04;
S, 6.95. Found: C, 62.54; H, 5.99; N, 2.95; S, 6.67.
130.35, 137.14, 137.30, 150.66, 161.64. Mass +EI):
m/z 487 +M1, 2.4), 91 +100). Anal. calcd for C29H29NO6:
C, 71.44; H, 6.00; N, 2.87. Found: C, 71.12; H, 6.06; N,
2.84.
3.1.15. 2-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribitol-
1-yl)pyridine 015c). Grignard reaction. Under a nitrogen
atmosphere, a solution of compound 1 +205 mg, 0.60 mmol)
in anhydrous THF +2.5 ml) was added to a solution of
2-pyridylmagnesium bromide14 +0.233 M in THF, 9.0 ml,
2.10 mmol) at rt and the mixture was stirred at rt for 2 h
and stirring was continued at 508C for 1 h. After addition of
a saturated aqueous solution of NH4Cl, the mixture was
extracted with AcOEt. Usual work-up and puri®cation by
¯ash silica gel column chromatography [n-hexane/AcOEt
+9:8, v/v)] gave a mixture of compound R-15c and
compound S-15c +163 mg, 0.39 mmol, 65%, R-15c/S-15cˆ
85:15). Reaction using organolithium reagent. Under a
nitrogen atmosphere, n-BuLi +1.60 M in THF, 1.47 ml,
2.35 mmol) was added to a solution of 2-bromopyridine
+0.224 ml, 2.34 mmol) in THF +10 ml) at 2788C and the
mixture was stirred at 2788C for 40 min. A solution of
compound 1 +161 mg, 0.47 mmol) in anhydrous THF
+3 ml) was added to the mixture at 2788C and the mixture
was stirred at 2788C for 3 h. According to the Grignard
reaction, a mixture of compound R-15c and compound
S-15c +111 mg, 0.26 mmol, 56%, R-15c/S-15cˆ22:78)
was given. Compound R-15c. Colorless crystals. Mp 103±
22
Compound S-15a. Pale yellow oil. [a]D ˆ130.9 +c 0.91,
1
CHCl3). IR nmax +KBr): 3383, 2868, 1489, 1102 cm21. H
NMR +CDCl3) d: 2.61 +3H, s), 3.01 +2H, brs), 3.57, 3.82
+2H, AB, Jˆ9 Hz), 3.81 +1H, d, Jˆ2 Hz), 3.85, 3.90 +2H,
AB, Jˆ10 Hz), 4.25 +1H, dd, Jˆ2, 5 Hz), 4.46 +2H, s), 4.58
+2H, s), 4.76 +1H, d, Jˆ5 Hz), 7.00 +1H, s), 7.17±7.34 +10H,
m). 13C NMR +CDCl3) d: 14.77, 66.67, 69.11, 72.36, 73.81,
75.21, 81.60, 84.90, 85.71, 125.86, 127.58, 127.78, 127.87,
127.94, 128.37, 128.43, 137.11, 137.18, 152.00, 161.10.
Mass +EI): m/z 457 +M1, 1.7), 91 +100). Anal. calcd for
C24H27NO6S: C, 63.00; H, 5.95; N, 3.06. Found: C, 62.91;
H, 5.90; N, 3.10.
3.1.14. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribitol-
1-yl)-2-phenyloxazole 015b). Grignard reaction. Under a
nitrogen atmosphere, MgBr2 +0.428 M in THF, 40 ml,
17.1 mmol) was added to a solution of 5-+2-phenyloxazo-
lyl)lithium13 +0.137 M in THF, 100 ml, 13.7 mmol) at 308C
and the mixture was stirred at 308C for 15 min. A solution of
compound 1 +1.17 g, 3.42 mmol) in anhydrous THF +20 ml)
was added to the mixture at 308C and the mixture was stirred
for 18 h at rt. After addition of a saturated aqueous solution
of NH4Cl, the mixture was extracted with AcOEt. Usual
work-up and puri®cation by ¯ash silica gel column chroma-
tography [n-hexane/AcOEt +3:2, v/v)] gave a mixture of
compound R-15b and compound S-15b +1.16 g, 70%,
R-15b/S-15bˆ8:92). Reaction using organolithium reagent.
Under a nitrogen atmosphere, a solution of compound 1
+198 mg, 0.58 mmol) in anhydrous THF +4 ml) was added
to a solution of 5-+2-phenyloxazolyl)lithium13 +0.191 M in
THF, 14 ml, 2.67 mmol) at 2788C and the mixture was
stirred at 308C for 2 h. According to the Grignard reaction,
a mixture of compound R-15b and compound S-15b
+230 mg, 82%, R-15b/S-15bˆ33:67) was given. Compound
25
1048C +n-hexane±AcOEt). [a]D ˆ150.5 +c 0.53, CHCl3).
1
IR nmax +KBr): 3370, 2865, 1593, 1449, 1057 cm21. H
NMR +CDCl3) d: 3.61, 3.77 +2H, AB, Jˆ10 Hz), 3.80,
3.94 +2H, AB, Jˆ9 Hz), 3.86 +1H, d, Jˆ2 Hz), 3.99 +2H,
s), 4.15 +1H, brs),4.28 +1H, dd, Jˆ2, 4 Hz), 4.58 +2H, s),
5.04 +1H, d, Jˆ4 Hz), 5.13 +1H, brs), 6.94±6.99 +2H, m),
7.18±7.32 +9H, m), 7.47 +1H, d, Jˆ8 Hz), 7.71 +1H, ddd, Jˆ
2, 8, 8 Hz), 8.56 +1H, ddd, Jˆ2, 8, 8 Hz). 13C NMR +CDCl3)
d: 69.35, 71.48, 72.60, 73.78, 75.28, 81.46, 83.51, 89.29,
121.60, 122.86, 127.40, 127.53, 127.75, 127.80, 128.18,
128.39, 136.80, 137.66, 137.77, 148.32, 158.36. Mass
+EI): m/z 421 +M1, 2.9), 91 +100). Anal. calcd for
C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.00;
H, 6.42; N, 3.26. Compound S-15c. Colorless crystals. Mp
23
R-15b. Pale yellow oil. [a]D ˆ1104.9 +c 0.74, CHCl3). IR
1
25
nmax +KBr): 3360, 2918, 2866, 1100, 1062 cm21. H NMR
84±858C +n-hexane±AcOEt). [a]D ˆ116.2 +c 0.51,
+CDCl3) d: 3.33 +1H, brs), 3.60, 3.85 +2H, AB, Jˆ9 Hz),
3.84, 3.95 +2H, AB, Jˆ10 Hz), 3.89 +1H, d, Jˆ3 Hz), 4.05
+1H, d, Jˆ2 Hz), 4.24, 4.26 +2H, AB, Jˆ12 Hz), 4.43 +1H,
dd, Jˆ2, 4 Hz), 4.59 +2H, s), 5.14 +1H, m), 6.99±7.45 +14H,
m), 8.00±8.02 +2H, m). 13C NMR +CDCl3) d: 67.21, 68.86,
71.97, 73.84, 75.04, 81.41, 83.25, 87.31, 125.66, 126.18,
127.08, 127.25, 127.62, 127.81, 127.95, 128.19, 128.44,
128.69, 130.31, 137.06, 137.18, 150.82, 161.45. Mass
+EI): m/z 487 +M1, 5.5), 91 +100). Anal. calcd for
C29H29NO6: C, 71.44; H, 6.00; N, 2.87. Found: C, 71.36;
H, 6.14; N, 2.93. Compound S-15b. Pale yellow oil.
CHCl3). IR nmax +KBr): 3372, 2867, 1594, 1449, 1096
.
cm21
1H NMR +CDCl3) d: 3.64, 3.83 +2H, AB, Jˆ
10 Hz), 3.76, 3.84 +2H, AB, Jˆ9 Hz), 4.08 +1H, brs), 4.13
+1H, d, Jˆ3 Hz), 4.33 +1H, dd, Jˆ3, 3 Hz), 4.58, 4.59 +2H,
AB, Jˆ12 Hz), 4.61 +2H, s), 4.79 +1H, d, Jˆ3 Hz), 4.96
+1H, brs), 7.19±7.22 +1H, m), 7.27±7.35 +11H, m), 7.70
+1H, ddd, Jˆ2, 8, 8 Hz), 8.53 +1H, m). 13C NMR +CDCl3)
d: 69.49, 72.58, 73.10, 73.82, 75.60, 81.49, 85.41, 87.98,
120.83, 122.61, 127.75, 127.82, 128.43, 136.84, 137.83,
148.10, 158.80. Mass +EI): m/z 421 +M1, 26.4), 91 +100).
Anal. calcd for C25H27NO5: C, 71.24; H, 6.46; N, 3.32.
Found: C, 71.05; H, 6.41; N, 3.30.
21
[a]D ˆ140.0 +c 1.24, CHCl3). IR nmax +KBr): 3340,
3063, 3031, 2928, 2866, 1452, 1097 cm21 1H NMR
.
+CDCl3) d: 3.30 +1H, brs), 3.59, 3.84 +2H, AB, Jˆ9 Hz),
3.66 +1H, brs), 3.87 +1H, d, Jˆ2 Hz), 3.88, 3.93 +2H,
AB, Jˆ10 Hz), 4.35 +1H, dd, Jˆ2, 4 Hz), 4.46 +2H, s),
4.59 +2H, s), 4.88 +1H, m), 7.12±7.43 +14H, m), 8.00±
8.02 +2H, m). 13C NMR +CDCl3) d: 66.81, 69.13, 72.40,
73.80, 75.22, 81.65, 84.91, 85.93, 126.24, 126.34, 127.28,
127.64, 127.89, 127.92, 128.03, 128.43, 128.54, 128.70,
3.1.16. 3-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribitol-
1-yl)-1-0triisopropylsilyl)pyrrole 015d). Grignard reaction.
Under a nitrogen atmosphere, 3-bromo-1-+triisopropyl-
silyl)pyrrole +3.36 g, 11.1 mmol) was added to a solution
of MrBr2 +0.494 M in THF, 45 ml, 22.2 mmol) at rt and
the mixture was stirred at rt for 1 h. A solution of compound
1 +952 mg, 2.78 mmol) in anhydrous THF +15 ml) was

Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
3059
added to the mixture at rt and the mixture was stirred at rt for
2 h. After addition of water, the mixture was extracted with
AcOEt. Usual work-up and puri®cation by ¯ash silica gel
column chromatography [n-hexane/AcOEt +3:1, v/v)] gave
a mixture of compound R-15d and compound S-15d +1.28 g,
2.26 mmol, 81%, R-15d/S-15dˆ98:2). Reaction using orga-
nolithium reagent. Under a nitrogen atmosphere, a solution
of compound 1 +195 mg, 0.57 mmol) in anhydrous THF
+3 ml) was added to a solution of 3-lithio-1-+triisopropylsi-
lyl)pyrrole15 +0.221 M in THF, 9.0 ml, 1.99 mmol) at
2788C and the mixture was stirred at 2788C for 1 h and
continued stirring at rt for 1 h. According to the Grignard
reaction, a mixture of compound R-15d and compound S-
15d +182 mg, 0.32 mmol, 56%, R-15d/S-15dˆ 50:50) was
in THF, 10 ml, 3.49 mmol) at 2788C and the mixture was
stirred at rt for 2 h. According to the Grignard reaction, a
mixture of compound R-15e and compound S-15e +448 mg,
80%, R-15e/S-15eˆ69:31) was given. A pale yellow oil. IR
nmax +KBr): 3401, 2932, 2864, 1460, 1374, 1101 cm21
.
Mass +EI): m/z 631 +M1, 1.3), 91 +100). Anal. calcd for
C31H45N3O7SSi: C, 58.93; H, 7.18; N, 6.65; S, 5.07.
Found: C, 58.64; H, 7.10; N, 6.42; S, 4.98. +Compound
1
R-15e): H NMR +CDCl3) d: 0.37 +6H, s), 0.95 +9H, s),
2.84 +6H, s), 3.33 +1H, s), 3.56, 3.82 +2H, AB, Jˆ9 Hz),
3.80, 3.87 +2H, AB, Jˆ9 Hz), 3.92 +1H, brs), 4.05 +1H, s),
4.16, 4.24 +2H, AB, Jˆ12 Hz), 4.20 +1H, d, Jˆ4 Hz), 4.56
+2H, s), 5.22 +1H, dd, Jˆ2, 4 Hz), 7.19±7.20 +2H, m),
7.27±7.36 +8H, m), 7.38 +1H, s). +Compound S-15e):
1H NMR +CDCl3) d: 0.40 +3H, s), 0.41 +3H, s), 1.01
+9H, s), 2.84 +6H, s), 3.27 +1H, s), 3.50 +1H, brs), 3.57,
3.82 +2H, AB, Jˆ10 Hz), 3.80 +1H, d, Jˆ2 Hz), 3.86,
3.93 +2H, AB, Jˆ9 Hz), 4.26 +1H, dd, Jˆ2, 4 Hz),
4.42, 4.47 +2H, AB, Jˆ12 Hz), 4.59 +2H, s), 5.08 +1H, dd,
Jˆ4, 4 Hz), 7.15±7.17 +2H, m), 7.27±7.36 +8H, m), 7.44
+1H, s).
21
given. Compound R-15d. Pale yellow oil. [a]D ˆ119.9 +c
0.84, CHCl3). IR nmax +KBr): 3327, 2947, 2867, 1464,
1
1102 cm21. H NMR +CDCl3) d: 1.05, 1.08 +both 9H, d,
Jˆ7 Hz), 1.42 +3H, hept, Jˆ7 Hz) 3.17 +1H, brs), 3.62,
3.80 +2H, AB, Jˆ10 Hz), 3.80, 3.93 +2H, AB, Jˆ9 Hz),
3.89 +1H, brs), 3.92, 3.99 +2H, AB, Jˆ12 Hz), 3.97 +1H,
d, Jˆ2 Hz), 4.20 +1H, dd, Jˆ2, 2 Hz), 4.58 +2H, s), 5.12
+1H, m), 6.29 +1H, m), 6.77 +1H, m), 6.83 +1H, m), 7.05±
7.06 +2H, m), 7.23±7.29 +8H, m). 13C NMR +CDCl3) d:
11.56, 17.77, 69.49, 69.63, 71.41, 73.73, 75.31, 81.19,
83.24, 90.76, 108.57, 121.10, 124.89, 125.79, 127.24,
127.39, 127.71, 128.14, 128.37, 137.88, 138.08. Mass
+EI): m/z 565 +M1, 0.7), 252 +100). Anal. calcd for
C33H47NO5Si: C, 70.05; H, 8.37; N, 2.48. Found: C,
69.99; H, 8.32; N, 2.59. Compound S-15d. Pale yellow
3.1.18. 5-[01R)-3,5-Di-O-benzyl-2-O-4-C-methylene-d-
ribitol-1-yl]oxazole 0R-15a0). Raney Ni +W-2) +ca. 1.8 g)
was added to a solution of compound R-15a +304 mg,
0.66 mmol) in EtOH +8 ml) and the mixture was re¯uxed
for 30 min. The reaction mixture was ®ltered and the
combined ®ltrate was concentrated under reduced pressure.
The residue was puri®ed by ¯ash silica gel column chroma-
tography [n-hexane/AcOEt +1:1, v/v)] to give a mixture of
compound R-15a0 +136 mg, 0.33 mmol, 50%) as a colorless
25
oil. [a]D ˆ123.9 +c 0.80, C6H6). IR nmax +KBr): 3434,
2867, 1461, 1096 cm21 1H NMR +DMSO-d6) d: 1.01,
.
25
1.02 +both 9H, d, Jˆ7 Hz), 1.43 +3H, hept, Jˆ7 Hz), 3.53,
3.57 +2H, AB, Jˆ10 Hz), 3.63 +1H, d, Jˆ3 Hz), 3.70 +2H,
s), 3.83 +1H, dd, Jˆ3, 8 Hz), 4.00, 4.02 +2H, AB, Jˆ12 Hz),
4.50 +2H, s), 4.59 +1H, dd, Jˆ5, 8 Hz), 4.83 +1H, d, Jˆ
5 Hz), 5.10 +1H, s), 6.26 +1H, m), 6.75±6.77 +2H, m),
7.05±7.08 +2H, m), 7.23±7.32 +8H, m). 13C NMR
+DMSO-d6) d: 10.93, 17.66, 68.52, 70.95, 71.03, 72.58,
74.22, 80.78, 86.48, 89.12, 109.92, 121.64, 123.75,
126.85, 127.03, 127.16, 127.26, 127.92, 127.99, 138.05,
138.33. Mass +EI): m/z 565 +M1, 0.3), 252 +100). Anal.
calcd for C33H47NO5Si: C, 70.05; H, 8.37; N, 2.48. Found:
C, 69.73; H, 8.31; N, 2.47.
oil. [a]D ˆ145.4 +c 0.72, CHCl3). IR nmax +KBr): 3341,
1
2868, 1503, 1455, 1103 cm21. H NMR +CDCl3) d: 3.21
+2H, brs), 3.58, 3.87 +2H, AB, Jˆ9 Hz), 3.80, 3.92 +2H,
AB, Jˆ10 Hz), 4.00 +1H, s), 4.24 +2H, s), 4.32 +1H, s),
4.58 +2H, s), 5.07 +1H, s), 7.08 +3H, m), 7.27±7.32 +8H,
m), 8.00 +1H, s). 13C NMR +CDCl3) d: 66.96, 68.79,
71.89, 73.85, 74.93, 81.39, 83.15, 87.22, 123.92, 127.39,
127.76, 127.81, 127.97, 128.31, 128.46, 137.13, 137.16,
150.70, 151.18. Mass +EI): m/z 411 +M1, 13.6), 91 +100).
Anal. calcd for C23H25NO6´1/10H2O: C, 66.85; H, 6.15; N,
3.39. Found: C, 66.54; H, 6.20; N, 3.27.
3.1.19.
5-[01S)-3,5-Di-O-benzyl-2-O-4-C-methylene-d-
3.1.17. 2-0tert-Butyldimethylsilyl)-5-03,5-di-O-benzyl-2-
O-4-C-methylene-d-ribitol-1-yl)-1-0N,N-dimethylsulfa-
moyl)imidazole 015e). Grignard reaction. Under a nitrogen
atmosphere, MgBr2 +0.521 M in THF, 30 ml, 15.6 mmol)
was added to a solution of 2-+tert-butyldimethylsilyl)-1-
N,N-dimethylsulfamoyl-5-lithio-imidazole16 +0.396 M in
THF, 30 ml, 11.9 mmol) at rt and the mixture was stirred
at rt for 10 min. A solution of compound 1 +1.02 g, 2.98
mmol) in anhydrous THF +15 ml) was added to the reaction
mixture at rt and the mixture was stirred for 2 h at rt. After
addition of water, the mixture was extracted with AcOEt.
Usual work-up and puri®cation by ¯ash silica gel column
chromatography [n-hexane/AcOEt +10:7, v/v)] gave a
mixture of compound R-15e and compound S-15e +1.35 g,
72%, R-15e/S-15eˆ90:10). Reaction using organolithium
reagent. Under a nitrogen atmosphere, a solution of
compound 1 +298 mg, 0.87 mmol) in anhydrous THF
+5 ml) was added to a solution of 2-+tert-butyldimethyl-
silyl)-1-N,N-dimethylsulfamoyl-5-lithio-imidazole16 +0.349 M
ribitol-1-yl]oxazole 0S-15a0). Raney Ni +W-2) +ca. 2.4 g)
was added to a solution of compound S-15a +360 mg,
0.79 mmol) in EtOH +8 ml) and the mixture was re¯uxed
for 30 min. The reaction mixture was ®ltered and the
combined ®ltrate was concentrated under reduced pressure.
The residue was puri®ed by ¯ash silica gel column chroma-
tography [n-hexane/AcOEt +2:3, v/v)] to give a mixture of
compound S-15a0 +223 mg, 0.54 mmol, 69%) as a colorless
22
oil. [a]D ˆ113.8 +c 0.82, CHCl3). IR nmax +KBr): 3345,
2868, 1099 cm21. 1H NMR +CDCl3) d: 3.11 +2H, brs), 3.57,
3.84 +2H, AB, Jˆ9 Hz), 3.84, 3.92 +2H, AB, Jˆ9 Hz), 3.86
+1H, d, Jˆ2 Hz), 4.26 +1H, dd, Jˆ2, 4 Hz), 4.47 +2H, s),
4.59 +2H, s), 4.81 +1H, d, Jˆ4 Hz), 7.05 +1H, s), 7.20±7.33
+10H, m), 7.81 +1H, s). 13C NMR +CDCl3) d: 66.60, 69.04,
72.41, 73.82, 75.21, 81.60, 84.80, 86.00, 124.09, 127.62,
127.81, 127.92, 127.96, 128.41, 128.44, 137.08, 137.14,
150.73, 151.06. Mass +EI): m/z 411 +M1, 23.3), 91 +100).
Anal. calcd for C23H25NO6´1/5H2O: C, 66.56; H, 6.17; N,
3.37. Found: C, 66.26; H, 6.21; N, 3.19.

3060
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
3.1.20. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-b-d-ribo-
furanosyl)oxazole 0b-16a). Under a nitrogen atmosphere,
TBP +0.47 ml, 1.89 mmol) and TMAD +323 mg, 1.88
mmol) were added to a solution of compound S-15a0
+515 mg, 1.25 mmol) in anhydrous benzene +12 ml) at 08C
and the mixture was stirred for 2 h at rt. After the solvent
was ®ltered through Celite, the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed by ¯ash
silica gel column chromatography [n-hexane/AcOEt +12:5,
v/v)] to give compound b-16a +452 mg, 92%) as a colorless
469 +M1, 2.9), 91 +100). Anal. calcd for C29H27NO5: C,
74.18; H, 5.80; N, 2.98. Found: C, 73.86; H, 5.83; N, 2.98.
3.1.23. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-a-d-ribo-
furanosyl)-2-phenyloxazole 0a-16b). Under a nitrogen
atmosphere, TPP +71 mg, 0.27 mmol) and DEAD +40% in
toluene, 0.12 ml, 0.28 mmol) were added to a solution of
compound R-15b +88 mg, 0.18 mmol) in anhydrous THF
+4 ml) at 08C and the mixture was stirred for 2 h at 08C.
The solvent was concentrated under reduced pressure. The
residue was puri®ed by alumina column chromatography
[n-hexane/AcOEt +5:1, v/v)] to give compound a-16b
22
oil. [a]D ˆ212.2 +c 0.89, CHCl3). IR nmax +KBr): 2951,
1
2878, 1501, 1456, 1102, 1030 cm21. H NMR +CDCl3) d:
24
3.80 +2H, s), 4.09, 4.12 +2H, AB, Jˆ8 Hz), 4.27 +2H, s),
4.57, 4.64 +2H, AB, Jˆ12 Hz), 4.60 +2H, s), 5.10 +1H, s),
6.95 +1H, s), 7.31±7.33 +10H, m), 7.81 +1H, s). 13C NMR
+CDCl3) d: 66.35, 72.26, 73.45, 73.69, 75.95, 78.54, 78.95,
85.85, 124.79, 127.48, 127.60, 127.66, 127.92, 128.28,
128.35, 137.14, 137.65, 148.55, 150.97. Mass +EI): m/z
393 +M1, 9.1), 91 +100). Anal. calcd for C23H23NO5: C,
70.21; H, 5.89; N, 3.56. Found: C, 70.09; H, 5.88; N, 3.51.
+61 mg, 72%) as a colorless oil. [a]D ˆ29.4 +c 0.78,
CHCl3). IR nmax +KBr): 3033, 2939, 2876, 1454, 1362,
1
1119, 1062, 1005 cm21. H NMR +CDCl3) d: 3.78 +2H, s),
4.07, 4.11 +2H, AB, Jˆ7 Hz), 4.26 +1H, s), 4.46 +1H, s),
4.61, 4.65 +2H, AB, Jˆ13 Hz), 4.66, 4.72 +2H, AB, Jˆ
12 Hz), 5.17 +1H, s), 7.32±7.44 +14H, m), 8.01 +2H, m).
13C NMR +CDCl3) d: 65.77, 72.09, 73.77, 73.99, 74.61,
77.68, 80.48, 87.39, 126.22, 126.97, 127.30, 127.56,
127.65, 127.68, 127.92, 128.32, 128.41, 128.59, 130.18,
137.23, 137.56, 148.66, 161.54. Mass +EI): m/z 469 +M1,
6.6), 91 +100). Anal. calcd for C29H27NO5: C, 74.18; H,
5.80; N, 2.98. Found: C, 74.28; H, 5.92; N, 3.00.
3.1.21. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-a-d-ribo-
furanosyl)oxazole 0a-16a). Under a nitrogen atmosphere,
TBP +74 ml, 0.30 mmol) and TMAD +38 ml, 0.30 mmol)
were added to a solution of compound R-15a0 +81 mg,
0.20 mmol) in anhydrous benzene +3 ml) at 08C and the
mixture was stirred for 17 h at rt. After the mixture was
®ltered through Celite, the ®ltrate was concentrated under
reduced pressure. The residue was puri®ed by ¯ash silica gel
column chromatography [n-hexane/AcOEt +2:1, v/v)] to
give compound a-16a +60 mg, 77%) as a colorless oil.
3.1.24. 2-03,5-Di-O-benzyl-2-O-4-C-methylene-b-d-ribo-
furanosyl)pyridine 0b-16c). Under a nitrogen atmosphere,
TPP +64 mg, 0.24 mmol) and DEAD +40% in toluene, 88 ml,
0.20 mmol) were added to a solution of compound R-15c
+43 mg, 0.10 mmol) in anhydrous THF +2 ml) at 08C and the
mixture was stirred for 3 h at 08C. The solvent was concen-
trated under reduced pressure. The residue was puri®ed by
alumina column chromatography [n-hexane/AcOEt +5:1,
v/v)] to give compound b-16c +33 mg, 80%) as a colorless
24
[a]D ˆ227.6 +c 0.71, CHCl3). IR nmax +KBr): 3030,
1
2877, 1500, 1455, 1102 cm21. H NMR +CDCl3) d: 3.76
+2H, s), 4.01, 4.07 +2H, AB, Jˆ8 Hz), 4.23 +1H, s), 4.40
+1H, s), 4.59, 4.63 +2H, AB, Jˆ12 Hz), 4.64, 4.70 +2H,
AB, Jˆ12 Hz), 5.11 +1H, s), 7.23 +1H, s), 7.31±7.34
+10H, m), 7.87 +1H, s). 13C NMR +CDCl3) d: 65.70,
72.10, 73.75, 74.53, 77.63, 80.40, 87.37, 125.07, 127.54,
127.62, 127.68, 127.92, 128.32, 128.41, 137.18, 137.52,
149.04, 150.84. Mass +EI): m/z 393 +M1, 2.0), 91 +100).
Anal. calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56.
Found: C, 69.84; H, 6.01; N, 3.51.
24
oil. [a]D ˆ134.5 +c 0.71, CHCl3). IR nmax +KBr): 3030,
1
2939, 2878, 1589, 1455, 1148, 1096, 1037 cm21. H NMR
+CDCl3) d: 3.85 +2H, s), 4.02 +1H, s), 4.12, 4.13 +2H, AB,
Jˆ8 Hz), 4.43, 4.58 +2H, AB, Jˆ12 Hz), 4.61 +1H, s), 4.66
+1H, s), 5.18 +1H, s), 7.14±7.36 +11H, m), 7.51 +1H, d,
Jˆ8 Hz), 7.65 +1H, ddd, Jˆ2, 8, 8 Hz), 8.54 +1H, m). 13C
NMR +CDCl3) d: 66.58, 71.88, 73.53, 73.66, 77.49, 79.82,
84.64, 86.27, 120.85, 122.30, 127.51, 127.64, 127.71,
128.27, 128.36, 136.68, 137.48, 138.08, 149.02, 158.78.
Mass +EI): m/z 403 +M1, 1.2), 91 +100). Anal. calcd for
C25H25NO4: C, 74.42; H, 6.25; N, 3.47. Found: C, 74.23;
H, 6.34; N, 3.47.
3.1.22. 5-03,5-Di-O-benzyl-2-O-4-C-methylene-b-d-ribo-
furanosyl)-2-phenyloxazole 0b-16b). Under a nitrogen
atmosphere, TPP +306 mg, 1.17 mmol) and DEAD +40%
in toluene, 0.51 ml, 1.17 mmol) were added to a solution
of compound S-15b +379 mg, 0.78 mmol) in anhydrous
THF +10 ml) at 08C and the mixture was stirred for 3 h at
08C and stirring was continued for 3 h at rt. The solvent was
concentrated under reduced pressure. The residue was
puri®ed by alumina column chromatography [n-hexane/
AcOEt +5:1, v/v)] to give compound b-16b +329 mg,
3.1.25. 2-03,5-Di-O-benzyl-2-O-4-C-methylene-a-d-ribo-
furanosyl)pyridine 0a-16c). Under a nitrogen atmosphere,
TPP +148 mg, 0.56 mmol) and DEAD +40% in toluene,
0.25 ml, 0.57 mmol) were added to a solution of compound
S-15c +95 mg, 0.23 mmol) in anhydrous THF +3 ml) at 08C
and the mixture was stirred for 2 h at 08C and stirring was
continued for 2 h at rt. The solvent was concentrated under
reduced pressure. The residue was puri®ed by alumina
column chromatography [n-hexane/AcOEt +7:2, v/v)] to
give compound a-16c +58 mg, 64%) as a colorless oil.
22
90%) as a colorless oil. [a]D ˆ17.2 +c 1.41, CHCl3). IR
nmax +KBr): 3031, 2943, 2879, 1484, 1451, 1364, 1112,
1
1028 cm21. H NMR +CDCl3) d: 3.86 +2H, s), 4.12, 4.16
+2H, AB, Jˆ8 Hz), 4.35 +1H, s), 4.41 +1H, s), 4.62, 4.71
+2H, AB, Jˆ12 Hz), 4.62 +2H, s), 5.13 +1H, s), 7.02 +1H,
s), 7.31±7.32 +10H, m), 7.43±7.46 +3H, m), 7.86 +2H, d,
Jˆ7 Hz). 13C NMR +CDCl3) d: 66.45, 72.06, 73.46,
73.73, 76.07, 78.67, 78.74, 85.90, 126.33, 126.83, 126.99,
127.57, 127.66, 127.71, 128.01, 128.37, 128.52, 128.77,
130.57, 137.27, 137.83, 148.07, 162.05. Mass +EI): m/z
23
[a]D ˆ277.6 +c 1.43, CHCl3). IR nmax +KBr): 3028,
1
2939, 2877, 1584, 1462, 1099, 1056, 1010 cm21. H NMR
+CDCl3) d: 3.85, 3.86 +2H, AB, Jˆ11 Hz), 3.95, 4.05 +2H,
AB, Jˆ8 Hz), 4.32 +1H, s), 4.61±4.73 +5H, m), 5.22 +1H, s),
7.18±7.21 +1H, m), 7.32±7.37 +10H, m), 7.63 +1H, d,
Jˆ8 Hz), 7.73 +1H, ddd, Jˆ2, 8, 8 Hz), 8.54 +1H, m). 13C

Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
3061
NMR +CDCl3) d: 66.23, 71.83, 73.72, 73.77, 78.97, 80.55,
83.36, 87.61, 120.60, 122.13, 127.53, 127.58, 127.61,
127.78, 128.29, 128.35, 136.35, 137.35, 137.73, 148.74,
158.67. Mass +EI): m/z 403 +M1, 0.8), 91 +100). Anal.
calcd for C25H25NO4: C, 74.42; H, 6.25; N, 3.47. Found:
C, 74.10; H, 6.31; N, 3.61.
AcOEt +4:1, v/v)] to give compound a-16e, b-16e +1.05 g,
90%, a-16e/b-16eˆ10:90). Compound a-16e. Colorless
1459, 1370, 1254, 1187, 1144 cm21. H NMR +CDCl3) d:
23
oil. [a]D ˆ228.3 +c 0.86, CHCl3). IR nmax +KBr): 2934,
1
0.38 +3H, s), 0.39 +3H, s), 0.99 +9H, s), 2.75 +6H, s), 3.75
+2H, s), 3.96, 4.04 +2H, AB, Jˆ8 Hz), 4.22 +1H, s), 4.51
+1H, s), 4.59, 4.60 +2H, AB, Jˆ12 Hz), 4.64, 4.71 +2H,
AB, Jˆ12 Hz), 5.24 +1H, s), 7.27±7.34 +10H, m), 7.56
+1H, s). 13C NMR +CDCl3) d: 23.57, 23.49, 18.50,
27.27, 37.54, 65.96, 72.01, 73.61, 73.65, 74.72, 78.25,
80.69, 87.05, 127.48, 127.52, 127.65, 127.83, 128.30,
128.37, 131.41, 132.29, 137.36, 137.66, 156.10. Mass
+EI): m/z 556 +M12C4H9, 100), 91 +59.6). Anal. calcd for
C31H43N3O6SSi´1/3H2O: C, 60.07; H, 7.10; N, 6.78; S, 5.17.
Found: C, 60.06; H, 6.92; N, 6.64; S, 5.00. Compound
3.1.26.
3-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribo-
furanosyl)-1-0triisopropylsilyl)pyrrole 016d). Mitsunobu
reaction of R-15d. Under nitrogen atmosphere, TPP
+0.79 g, 3.01 mmol) and DEAD +40% in toluene, 1.3 ml,
2.99 mmol) were added to a solution of compound R-15d
+1.13 g, 2.00 mmol) in anhydrous THF +30 ml) at 08C and
the mixture was stirred for 12 h at rt. The solvent was
concentrated under reduced pressure. The residue was
puri®ed by alumina column chromatography [n-hexane/
AcOEt +10:1, v/v)] to give compounds a-16d, b-16d
+0.64 g, 59%, a-16d/b-16dˆ29:71). Mitsunobu reaction
of S-15d. Under a nitrogen atmosphere, TPP +38 mg,
0.14 mmol) and DEAD +40% in toluene, 63 ml, 0.14
mmol) were added to a solution of compound S-15d
+55 mg, 0.10 mmol) in anhydrous THF +2 ml) at 08C and
the mixture was stirred for 3 h at rt. The solvent was concen-
trated under reduced pressure. The residue was puri®ed by
alumina column chromatography [n-hexane/AcOEt +10:1,
v/v)] to give compounds a-16d, b-16d +46 mg, 86%,
a-16d/b-16dˆ78:22). Compound a-16d. Colorless oil.
25
b-16e. Colorless oil. [a]D ˆ120.4 +c 0.59, CHCl3). IR
1
nmax +KBr): 2936, 2852, 1373, 1184, 1146, 1031 cm21. H
NMR +CDCl3) d: 0.39 +6H, s), 1.01 +9H, s), 2.83 +6H, s),
3.77 +2H, s), 4.02, 4.09 +2H, AB, Jˆ8 Hz), 4.13 +1H, s), 4.37
+1H, s), 4.54, 4.59 +2H, AB, Jˆ12 Hz), 4.60 +2H, s), 5.20
+1H, s), 7.15 +1H, s), 7.28±7.32 +10H, m). 13C NMR
+CDCl3) d: 23.59, 23.48, 18.50, 27.30, 37.70, 66.21,
72.20, 73.31, 73.62, 77.15, 78.23, 79.12, 85.46, 127.48,
127.58, 127.63, 127.85, 128.33, 131.52, 131.90, 137.25,
137.68, 156.36. Mass +EI): m/z 556 +M12C4H9, 100), 91
+93.7). Anal. calcd for C31H43N3O6SSi: C, 60.65; H, 7.06; N,
6.85; S, 5.22. Found: C, 60.30; H, 6.84; N, 6.75; S, 5.08.
25
[a]D ˆ226.8 +c 0.85, C6H6). IR nmax +KBr): 2951, 2868,
1460, 1096, 1014 cm21. 1H NMR +DMSO-d6) d: 1.04, 1.04
+both 9H, d, Jˆ7 Hz), 1.44 +3H, hept, Jˆ7 Hz), 3.70 +2H, s),
3.83, 3.91 +2H, AB, Jˆ7 Hz), 4.19 +1H, s), 4.36 +1H, s), 4.53
+2H, s), 4.60, 4.67 +2H, AB, Jˆ12 Hz), 4.98 +1H, s), 6.28
+1H, m), 6.75 +1H, m), 6.81 +1H, m), 7.28±7.35 +10H, m).
13C NMR +DMSO-d6) d: 10.96, 17.65, 66.55, 70.64, 72.48,
73.41, 76.47, 78.36, 80.81, 85.79, 110.36, 122.83, 123.17,
123.89, 127.29, 127.32, 127.35, 128.07, 128.10, 137.94,
138.01. Mass +EI): m/z 547 +M1, 22.7), 91 +100). Anal.
calcd for C33H45NO4Si: C, 72.35; H, 8.28; N, 2.56. Found:
C, 72.28; H, 8.25; N, 2.64. Compound b-16d. Colorless oil.
3.1.28.
4-03,5-Di-O-benzyl-2-O-4-C-methylene-d-ribo-
furanosyl)imidazole 016e0). A solution of compounds
a-16e, b-16e +1.04 g, 1.69 mmol, a-16e/b-16eˆ10:90) in
THF +23 ml) was re¯uxed with HCl +1.5 N in water, 37 ml)
for 2.5 h. After neutralization by addition of ammonium
hydroxide +28% in water), the solvent was extracted with
AcOEt. Usual work-up and puri®cation by silica gel column
chromatography [CHCl3/MeOH +30:1, v/v)] gave com-
pounds a-16e0, b-16e0 +561 mg, 84%, a-16e0/b-16e0ˆ
25
29:71). Compound a-16e0. Colorless oil. [a]D ˆ224.8 +c
0.94, CHCl3). IR nmax +KBr): 3113, 2875, 1455, 1096 cm21
.
[a]D ˆ21.3 +c 1.20, C6H6). IR nmax +KBr): 2945, 2874,
1H NMR +CDCl3) d: 3.76, 3.76 +2H, AB, Jˆ12 Hz), 3.98,
4.12 +2H, AB, Jˆ8 Hz), 4.26 +1H, s), 4.43 +1H, s), 4.58, 4.62
+2H, AB, Jˆ12 Hz), 4.64, 4.69 +2H, AB, Jˆ12 Hz), 5.13
+1H, s), 5.46 +1H, brs), 7.11 +1H, s), 7.29±7.35 +10H, m),
7.64 +1H, s). 13C NMR +CDCl3) d: 66.16, 72.03, 73.73,
74.18, 76.14, 78.46, 80.74, 86.79, 120.42, 127.54, 127.63,
127.85, 128.29, 128.36, 133.80, 135.24, 137.27, 137.54.
Mass +EI): m/z 392 +M1, 3.2), 91 +100). Anal. calcd for
C23H24N2O4´1/4H2O: C, 69.59; H, 6.22; N, 7.06. Found:
C, 69.36; H, 6.20; N, 7.02. Compound b-16e0. Colorless
21
1462, 1097, 1031 cm21. 1H NMR +DMSO-d6) d: 0.96, 0.97
+both 9H, d, Jˆ7 Hz), 1.35 +3H, hept, Jˆ7 Hz), 3.76 +2H, s),
3.80, 3.90 +2H, AB, Jˆ8 Hz), 4.11 +1H, s), 4.27 +1H, s),
4.50, 4.58 +2H, AB, Jˆ12 Hz), 4.54, 4.58 +2H, AB, Jˆ
12 Hz), 4.90 +1H, s), 6.08 +1H, m), 6.62 +1H, m), 6.71
+1H, m), 7.29±7.31 +10H, m). 13C NMR +DMSO-d6) d:
11.04, 17.77, 66.42, 70.84, 72.69, 77.93, 79.48, 79.77,
84.80, 108.81, 121.48, 124.48, 124.58, 127.27, 127.40,
127.54, 128.20, 128.25, 137.89, 138.35. Mass +EI): m/z
547 +M1, 77.5), 91 +100). Anal. calcd for C33H45NO4Si:
C, 72.35; H, 8.28; N, 2.56. Found: C, 72.35; H, 8.27; N,
2.66.
25
oil. [a]D ˆ13.0 +c 0.76, CHCl3). IR nmax +KBr): 3124,
1
2878, 1455, 1097, 1032 cm21. H NMR +CDCl3) d: 3.82,
3.84 +2H, AB, Jˆ11 Hz), 4.06, 4.11 +2H, AB, Jˆ8 Hz), 4.33
+1H, s), 4.38 +1H, s), 4.54, 4.64 +2H, AB, Jˆ12 Hz), 4.59
+2H, s), 5.13 +1H, s), 6.89 +1H, s), 7.27±7.33 +10H, m), 7.66
+1H, s). 13C NMR +CDCl3) d: 66.84, 72.03, 73.44, 73.69,
79.08, 79.20, 79.45, 85.33, 115.69, 127.55, 127.66, 128.24,
128.32, 135.07, 137.16, 137.53, 137.67. Mass +EI): m/z 392
+M1, 3.9), 91 +100). Anal. calcd for C23H24N2O4: C, 70.39;
H, 6.16; N, 7.14. Found: C, 70.10; H, 6.22; N, 7.09.
3.1.27. 2-0tert-Butyldimethylsilyl)-5-03,5-di-O-benzyl-2-
O-4-C-methylene-d-ribofuranosyl)-1-0N,N-dimethylsul-
famoyl)imidazole 016e). Under a nitrogen atmosphere,
TBP +0.71 ml, 2.85 mmol) and TMAD +0.49 g, 2.85
mmol) were added to a solution of compound 15e +1.20 g,
1.90 mmol, R-15e/S-15eˆ90:10) in anhydrous benzene
+40 ml) at 08C and the mixture was stirred for 15 h at rt.
After the solvent was ®ltered through Celite, the ®ltrate was
concentrated under reduced pressure. The residue was puri-
®ed by ¯ash silica gel column chromatography [n-hexane/
3.1.29. 5-02-O-4-C-Methylene-b-d-ribofuranosyl)oxazole
017a). Under a hydrogen atmosphere, a solution of com-
pound b-16a +452 mg, 1.15 mmol) and 20% Pd+OH)2±C

3062
Y. Hari et al. / Tetrahedron 58 .2002) 3051±3063
+317 mg) in EtOH +9 ml) was stirred for 18 h at rt. After the
mixture was ®ltered, SiO2 +1 g) was added to the ®ltrate.
The mixture was concentrated under reduced pressure. The
residue was puri®ed by ¯ash silica gel column chroma-
tography [AcOEt/MeOH +20:1, v/v)] to give compound
17a +201 mg, 82%). One crystallization from AcOEt gave
the analytical specimen, colorless crystals. Mp 148±1498C
chromatography [CHCl3/MeOH +4:1, v/v)] to give com-
pound 17e +145 mg, 83%). One reprecipitation from
AcOEt±MeOH gave the analytical specimen. A white
21
powder. Mp 168±1708C +AcOEt±MeOH). [a]D ˆ229.2
+c 0.96, MeOH). IR nmax +KBr): 3165, 2951, 2885, 2744,
1
1033 cm21. H NMR +CD3OD) d: 3.86, 3.87 +2H, AB, Jˆ
12 Hz), 3.91, 4.02 +2H, AB, Jˆ8 Hz), 4.12 +1H, s), 4.26
+1H, s), 4.98 +1H, s), 7.06 +1H, s), 7.64 +1H, s). 13C NMR
+CD3OD) d: 59.59, 72.47, 73.48, 80.49, 83.57, 88.04,
116.50, 136.54. Mass +EI): m/z 212 +M1, 13.1), 97 +100).
HRMS +EI) calcd for C9H12N2O4 +M1) 212.0797, found
212.0826. Anal. calcd for C9H12N2O4´1/5AcOEt: C, 51.22;
H, 5.96; N, 12.19. Found: C, 51.03; H, 5.86; N, 11.89.
25
+AcOEt). [a]D ˆ229.7 +c 0.84, MeOH). IR nmax +KBr):
1
3147, 1507, 1338, 1130 cm21. H NMR +CD3OD) d: 3.86
+2H, s), 3.93, 4.04 +2H, AB, Jˆ8 Hz), 4.19 +1H, s), 4.36
+1H, s), 5.04 +1H, s), 7.14 +1H, s), 8.18 +1H, s). 13C NMR
+CD3OD) d: 59.43, 73.22, 73.54, 76.89, 82.46, 88.47,
125.19, 151.05, 153.49. Mass +EI): m/z 213 +M1, 4.4), 96
+100). Anal. calcd for C9H11NO5: C, 50.70; H, 5.20; N, 6.57.
Found: C, 50.68; H, 5.14; N, 6.59.
3.2. X-Ray crystallographic data of 17a
Ê
3.1.30.
5-02-O-4-C-Methylene-b-d-ribofuranosyl)-2-
C9H11NO5, Mˆ213.19, orthorhombic, aˆ10.9079 +6) A,
Ê
Ê
Ê 3
phenyloxazole 017b). Under a hydrogen atmosphere, a
solution of compound b-16b +39 mg, 83 mmol) and 20%
Pd+OH)2±C +46 mg) in EtOH +8 ml) was stirred for 9 h at
rt. After the mixture was ®ltered, the ®ltrate was concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography [CHCl3/MeOH +20:1,
v/v)] to give compound 17b +11 mg, 46%). One crystalli-
zation from AcOEt gave the analytical specimen, colorless
bˆ13.9320 +8) A, cˆ6.2584 +6) A, Vˆ951.1 +1) A , Tˆ
283 K, space group P212121 +no. 19), Zˆ4, Dcalc
ˆ
1.489 g cm23, F000ˆ448.00, m+Cu Ka)ˆ10.59 cm21, 918
re¯ections measured. The ®nal R+F) and Rw+F) were
0.033 and 0.031 for 816 observed re¯ections [F2.3s+F2)]
used in all calculations.
24
crystals. Mp 148±1498C +AcOEt). [a]D ˆ121.5 +c 1.16,
Acknowledgements
MeOH). IR nmax +KBr): 3438, 3048, 2936, 2820,
2711 cm21. H NMR +CD3OD) d: 3.88, 3.89 +2H, AB,
1
Part of this work was supported by a Grant for Research on
Health Sciences focusing on Drug Innovation from The
Japan Health Sciences Foundation, Industrial Technology
Research Grant Program in '00 from New Energy and
Industrial Technology Development Organization +NEDO)
of Japan, a Grant-in-Aid from Japan Society for the Promo-
tion of Science, and a Grant-in-Aid from the Ministry of
Education, Science, and Culture, Japan. We thank JSPS
Research Fellowships for Young Scientists +Y. H.).
Jˆ12 Hz), 3.95, 4.06 +2H, AB, Jˆ8 Hz), 4.27 +1H, s),
4.49 +1H, s), 5.09 +1H, s), 7.23 +1H, s), 7.51 +3H, m), 8.00
+2H, m). 13C NMR +CD3OD) d: 59.31, 73.24, 73.49, 76.90,
82.52, 88.38, 127.00, 127.20, 127.86, 129.95, 131.92,
150.56, 163.19. Mass +EI): m/z 289 +M1, 73.2), 174 +100).
Anal. calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84.
Found: C, 61.98; H, 5.23; N, 4.79.
3.1.31. 2-02-O-4-C-Methylene-b-d-ribofuranosyl)pyri-
dine 017c). A solution of compound b-16c +510 mg,
1.26 mmol), 20% Pd+OH)2±C +230 mg) and cyclohexene
+6.4 ml, 63 mmol) in EtOH +20 ml) was re¯uxed for 2.5 h.
After the mixture was ®ltered, SiO2 +1 g) was added to
the ®ltrate. The mixture was concentrated under reduced
pressure. The residue was puri®ed by ¯ash silica gel column
chromatography [AcOEt/MeOH +20:1, v/v)] to give com-
pound 17c +201 mg, 71%) as a white powder. Mp 123±
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3363, 2930, 1043 cm21. H NMR +CD3OD) d: 3.91, 3.92
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