Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction

Article abstract of DOI:10.1016/S0040-4020(01)01249-2

A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-β-C-ethynyl glycosyl donors in the key Vorbru?ggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield.

Full text of DOI:10.1016/S0040-4020(01)01249-2

TETRAHEDRON
Pergamon
Tetrahedron 58 '2002) 1279±1288
Nucleosides and nucleotides. Part 212: Practical large-scale
synthesis of 1-ꢀ3-C-ethynyl-b-d-ribo-pentofuranosyl)cytosine
ꢀECyd), a potent antitumor nucleoside. Isobutyryloxy group
È
as an ef®cient anomeric leaving group in the Vorbruggen
glycosylation reactionq
Makoto Nomura,a,b Tsutomu Sato,b Masato Washinosu,b Motoaki Tanaka,b Tetsuji Asao,b
Satoshi Shutoa and Akira Matsudaa,p
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
bHanno Research Center, Taiho Pharmaceutical Co Ltd, 1-27 Misugidai, Hanno, Saitama 357-8527, Japan
Received 30 October 2001; accepted 14 December 2001
AbstractÐA practical synthetic route to the antitumor nucleoside, 1-'3-C-ethynyl-b-d-ribo-pentofuranosyl)cytosine 'ECyd, 1) from 1,2-O-
isopropylidene-d-xylofuranose '3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was
prepared without any chromatographic puri®cation in 31% overall yield from compound 3. The isobutyryloxy groupwas found to be an
effective leaving groupat the anomeric position of the 3- b-C-ethynyl glycosyl donors in the key VorbruÈggen glycosylation reaction. Using a
similar procedure without chromatographic puri®cation, the uracil congener EUrd [1-'3-C-ethynyl-b-d-ribo-pentofuranosyl)uracil '2),
which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We previously designed and synthesized the potent anti-
tumor nucleosides 1-'3-C-ethynyl-b-d-ribo-pentofurano-
syl)cytosine 'ECyd, 1) and its uracil congener 'EUrd, 2).1±3
They were converted, via phosphorylation by cellular
uridine/cytidine kinase followed by nucleotide kinases
into the corresponding 50-O-triphosphates, which inhibited
RNA synthesis and demonstrated a potent antitumor effect
both in vitro and in vivo.4
To developECyd and/or EUrd as antitumor drugs, we
planned to investigate their pharmacological, toxicological,
and physicochemical properties. Since a few hundred grams
of the compounds were required, we needed a practical
method for the large-scale preparation of ECyd and EUrd.
The previous route for synthesizing ECyd and EUrd shown
in Scheme 11,2 would be reasonable because: '1) the 1,2-O-
isopropylidene-d-xylofuranose '3) is readily available; '2)
the ethynyl groupcould be introduced highly stereoselec-
tively from the b-face at the 3-position of the keto sugar 5;5
and '3) the nucleobase could be stereoselectively introduced
q See Ref. 19.
Scheme 1. Conditions: 'a) TBSCl, pyridine; 'b) CrO3, pyridine, Ac2O,
CH2Cl2; 'c) TMSCuCH, BuLi, THF, 2788C; 'd) '1) Bu4NF, THF, rt,
Keywords: antitumor compounds; glycosylation; nucleosides; pyrimidines.
Corresponding author. Tel.: 181-11-706-3228; fax: 181-11-706-4980;
e-mail: matuda@pharm.hokudai.ac.jp
'2) BzCl, pyridine, rt; 'e) aqueous 20% HCl, MeOH, rt; 'f) BzCl, DMAP,
pyridine, 1008C; 'g) concentrated H2SO4, Ac2O, AcOH, rt; 'h) 10, SnCl4,
CH3CN; 'i) 11, TMSOTf, CH3CH; 'j) NH3/MeOH.
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)01249-2

1280
M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
Table 1. Oxidation of 14a
Entry
Conditions
Isolated yield '%)a
1
2
DMSO, DCC, H3PO4, rt, 2 h
DMSO, DCC, CF3CO2H, pyridine, rt,
30 min
64
74
3
4
5
6
7
8
9
DMSO, Ac2O, rt, 10 h
NaOCl, AcOH, rt, 8 h
37
0
0
0
0
Ca'OCl)2, AcOH±CH3CN, 08C, 8 h
NBS, Et2O, MeOH, H2O, rt, 8 h
NBS, pyridine, MeOH, H2O, rt, 8 h
NCS, Et2O, MeOH, H2O, rt, 8 h
TEMPO 'cat.), NaOCl, CH2Cl2±aq.
NaHCO3, 08C, 15 min
Figure 1. Structures of ECyd and EUrd.
0
77
via the neighboring 2-O-acetyl group participation by the
VorbruÈggen glycosylation procedure.6 However, it seems to
be inef®cient for the large scale preparation of these
compounds since: '1) each step needs chromatographic
puri®cation because of the non-crystalline compounds, '2)
the toxic CrO3 used for the oxidation of the xylose deriva-
tive 4, and '3) the very expensive Lewis acid TMSOTf used
as the promoter for the glycosylation 'Fig. 1).
10
TEMPO 'cat.), Ca'OCl)2, CH2Cl2±aq.
NaHCO3, 08C, 2.5 h
43
Reactions were carried out in 3 mmol scale.
Compound 15a was isolated without chromatographical separation.
a
yield. Although the 4-MeBz '14b) and the Bz '14d) deriva-
tives were oils, the 4-ClBz '14a) and the 4-NO2Bz '14c)
derivatives were obtained as crystals. Thus, crystalline
14a and 14c were subjected to the next steps. However,
oxidation of 14c with CrO3 proved to be unsuccessful, and
the desired 3-keto derivative 15c was not obtained in pure
form. On the other hand, following the previous method,2
the 4-ClBz derivative 14a was successfully converted into
the corresponding 3-keto derivative 15a and the 3-C-TMS-
ethynyl and 3-C-ethynyl derivatives, 16 and 17, all of which
were obtained as stable crystalline compounds. Therefore,
the 4-ClBz groupwas selected as the protecting groupat the
5-hydroxyl of the sugar moiety.
Considering these facts, we decided to modify the previous
route to developa rpactical method for the large-scale
preparation of ECyd and EUrd.
2. Results and discussion
2.1. Synthesis of the 3b-C-ethynyl sugars
In a large-scale synthesis, crystalline compounds which can
be easily puri®ed without chromatography in each step are
highly desirable. Therefore, we tried to developa crystalline
branched sugar having an ethynyl groupat the 3 b-position
as the sugar unit for synthesizing ECyd and EUrd 'Scheme
2).
Next, reaction conditions for each stepin the large-scale
conversion of 3 to 16 or 17 were investigated. The large-
scale synthesis of 14a was achieved with 1.1 equiv. of
4-ClBzCl and 3 equiv. of Et3N in CH2Cl2. About 200 g
'74%) of the pure 14a was obtained by crystallization with-
out chromatography. Oxidation of the secondary alcohol at
the 3-position of 14a was next examined on a 3 mmol scale
'Table 1). Whereas in the original procedure a CrO3/Ac2O/
pyridine system was used,1±3 here an alternative method
without toxic CrO3 was needed. Therefore, various oxi-
dations of the hydroxyl groupwere examined. Oxidations
using DMSO,7±11 such as the Moffatt oxidation, gave the
desired compound 15a in good yield 'Table 1, entries 1 and
2). However, the reaction produced crystalline dicyclo-
hexylurea, removal of which required troublesome work-
up. Although oxidation with hypochlorite salt,12±14
NBS,15,16 or NCS did not give 15a 'entries 4±8), catalytic
TEMPO-oxidation17,18 successfully furnished the desired
compound. When NaOCl was used as a co-oxidant 'entry
9), the oxidation was complete within 15 min and gave 15a
in excellent yield '3 mmol scale, 77% yield). A similar reac-
tion using Ca'OCl)2, required a longer reaction time, and
resulted in a lower yield 'entry 10). Thus, the reaction
conditions for entry 9 were selected, and 171 g '88%
yield) of 15a was obtained by crystallization without
chromatographic puri®cation in the large scale reaction.
A TBS groupwas used for the protection of the 5-hydroxyl
in the previous route as shown in Scheme 1. However,
O-acyl sugars are often crystallized more easily than the
corresponding O-silyl sugars. To ®nd an effective protecting
groupgiving crystalline comopunds, we ®rst examined
several acyl groups, i.e. 4-chlorobenzoyl '4-ClBz), 4-tolu-
oyl '4-MeBz), 4-nitrobenzoyl '4-NO2Bz), and benzoyl 'Bz)
groups, as the protecting group at the 5-hydroxyl of 1,2-O-
isopropylidene-d-xylofuranose '3). When 3 was treated
with an acyl halide and Et3N in CH2Cl2 at 08C, it gave the
corresponding 5-O-acyl derivatives 14a±d in 73±80%
Introduction of an ethynyl or a TMS-ethynyl groupwas next
examined. When 15a '200 g, 600 mmol) was treated with
TMSCuCMgBr '1.3 equiv.), prepared from EtMgBr and
TMSCuCH in situ, in THF at 48C, a TMS-ethynyl group
Scheme 2.

M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
1281
Removal of the 1,2-O-isopropylidene group of 16 was
achieved by heating in 50% aqueous HCO2H under re¯ux
to give 19. Using 213 g '500 mmol) of 16, 187 g '97%) of
19 was obtained after crystallization. The same treatment of
17 with aqueous HCO2H also readily gave crystalline 20. A
similar reaction of 16 using AcOH instead of HCO2H
proceeded rather slowly, and the yield of 19 was lower.
Treatment of 19 or 20 with various acyl chlorides in the
presence of Et3N and DMAP in CH2Cl2 provided the glyco-
syl donors 22a, 22b, and 23a±23f, which contained the
same acyl groups at the 1-, 2-, and 3-O-positions, respec-
tively 'Scheme 3).
2.3. The VorbruÈggen glycosidation reaction with the
3-C-TMS-ethynyl and 3-C-ethynyl glycosyl donors
The donors were applied to the VorbruÈggen glycosylation
reaction6 with 2-O,4-N-bis-TMS-cytosine ''TMS)2Cyt, 10)
or bis-TMS-uracil ''TMS)2Ura, 11), which were prepared
by re¯uxing the nucleobase in hexamethyldisilazane
'HMDS) in the presence of 'NH4)2SO4 followed by
evaporation. The reactions were performed with 0.5 mmol
of the glycosyl donor in MeCN, which is an ef®cient solvent
for the VorbruÈggen glycosylation reaction. The results are
summarized in Table 2 'Scheme 4).
Scheme 3. 'a) HCl/H2O±MeOH; 'b) 4-ClBzCl, Et3N, DMAP, CH2Cl2;
'c) HCO2H±H2O; 'd) concentrated H2SO4, Ac2O, AcOH, rt; 'e) acyl-
chloride, Et3N, DMAP, CH2Cl2.
was stereoselectively introduced from the b-side1±3,5 to
afford 16 in 91% yield '238 g), which was obtained as
crystals without column chromatography. Similarly, the
3-C-ethynyl derivative 17 was also prepared from 15a by
treatment with HCuCMgBr in 89% yield.
Although TMSOTf was used effectively as the promoter of
the glycosylation step in the previous synthetic procedure
for ECyd and EUrd,2 it is very expensive. We examined
various cheaper Lewis acids as the promoter for the glyco-
sylation using 'TMS)2Ura and the 1-O-acetyl-3-C-TMS-
ethynyl donor 21 in MeCN. As a result, the rather cheap
Lewis acid, SnCl4, was identi®ed as an effective alternative
promoter for the glycosylation, while other Lewis acids,
such as BF3´OEt2, TiCl4, ZnCl2, or AlCl3, proved ineffective
'data not shown). As seen in entry 1, treatment of the donor
21 with 4 equiv. of 'TMS)2Ura '11) in the presence of
5 equiv. of SnCl4 at room temperature produced the desired
3-C-TMS-ethynyluridine derivative 25a in 83% yield, a
result comparable with that using TMSOTf as the promoter
'entry 2). Therefore, using SnCl4 as the promoter, reactions
with the various donors were next investigated, with the
reaction temperature ®xed at 308C 'entries 3±18).
Thus, a practical synthesis of the 3-C-TMS-ethynyl and
3-C-ethynyl sugars 16 and 17 was developed, which was
applied to the following glycosylation reactions.
2.2. Preparation of glycosyl donors
The potency of the glycosyl donors is probably in¯uenced
by the acyl protecting groups at the hydroxyls. However, it
may be dif®cult to predict the potency of the O-acyl-
protected donors in the glycosylation reaction, since the
effect of the acyl groups is complicated by: '1) an electron
withdrawing acyl groupat the 1-O-opsition making the
donor reactive but also possibly making the donor unstable;
'2) a less electron withdrawing acyl groupat the 2-O-
position, which is desirable for the effective neighboring
group participation to form the b-product highly selectively;
and '3) electron withdrawing protecting groups, e.g. acyl
groups, at the 2, 3, and 5-hydroxyls, which are undesirable
in reducing the reactivity of the donor. Accordingly, glyco-
syl donors having various acyl groups on the hydroxyls, i.e.
21, 22a,b, and 23a±f, were prepared from 16 and 17, as
shown in Scheme 3, to experimentally identify an ef®cient
donor.
When the 3-C-TMS-ethynyl donor 21 was treated with
2 equiv. of 'TMS)2Ura and 3 equiv. of SnCl4 for 3 h,
compound 25a was obtained in 82%-isolated yield 'entry
3). The reactions using the other 3-C-TMS-ethynyl donors
22a and 22b were carried out under the same conditions as
for entries 3 and 4. Although the 1,2,3,5-tetra-O-'4-ClBz)
donor 22a was ineffective 'entry 4, 50%), the reaction of the
1,2,3-tri-O-isobutyryl-5-O-'4-ClBz) donor 22b gave the
desired nucleoside 25b in 89% yield. Similarly, 21 and
22b were effective donors in the reactions with 'TMS)2Cyt
'10) as the acceptor to give the corresponding cytosine
nucleosides 24a and 24b in excellent yields 'entries 6 and
8), while the 1,2,3,5-tetra-O-'4-ClBz) donor 22a was again
ineffective 'entry 7).
The 3-C-TMS-ethynyl sugar 16 was heated under re¯ux
with HCl in aqueous MeOH and gave the corresponding
1-O-methyl sugar, which was acylated with 4-ClBzCl to
afford the tri-O-'4-ClBz)-1-O-methyl sugar 18 '87%).
Treatment of 18 with AcOH/Ac2O/H2SO4 afforded 1-O-
acetyl-2,3,5-tri-O-'4-ClBz)-3-C-[2-'trimethylsilyl)ethynyl]-
d-ribo-pentofuranose '21) in 77% yield.
Next, the 3-C-ethynyl donors 23a±f, having various acyloxy
leaving groups at the 1-position, were examined. They were
treated with 2 equiv. of 'TMS)2Ura and 3 equiv. of SnCl4 for
20 h 'entries 9±14). The reaction with the 1,2,3-tri-O-acetyl

1282
M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
Table 2. Glycosylation reactions of persilylated nucleobase with various acylated sugars in CH3CN
Substrate
R0
'TMS)2 base
Base 'eq).
Lewis acid
'equiv.)
Time
'h)
Temperature
'8C)
Product
Yielda
'%)
Recoverya
'%)
Entry
Number
X
R00
1
2
3
4
5
6
7
8
21
21
21
22a
22b
21
22a
22b
23a
23b
23c
23d
23e
23f
23a
23b
23e
23f
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
H
H
H
H
H
Ac
Ac
Ac
4-ClBz
Isobutyryl
Ac
4-ClBz
Isobutyryl
4-ClBz
Isobutyryl
Ac
Pivaloyl
Bz
4-MeOBz
4-ClBz
Isobutyryl
Bz
4-ClBz
4-ClBz
4-ClBz
4-ClBz
Isobutyryl
4-ClBz
4-ClBz
Isobutyryl
4-ClBz
Isobutyryl
Ac
Pivaloyl
Bz
4-MeOBz
4-ClBz
Isobutyryl
Bz
Ura '4)
Ura '4)
Ura '2)
Ura '2)
Ura '2)
Cyt '2)
Cyt '2)
Cyt '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
Ura '2)
SnCl4 '5)
TMSOTf '5)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
SnCl4 '3)
15
17
3
3
3
3
3
3
20
20
20
20
20
20
3
3
3
3
rt
rt
25a
25a
25a
25a
25b
24a
24a
24b
26a
26b
26c
26d
26e
26f
83
91
82
50
89
73
42
81
62
78
10
0
78
76
17
62
54
65
0
0
4
27
,1
6
48
8
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
9
9
0
0
10
11
12
13
14
15
16
17
18
Quant.
0
0
39
3
24
10
H
H
H
H
26a
26b
26e
26f
H
4-MeOBz
4-MeOBz
a
Entries 1, 2: yield by HPLC analysis. The other entries: isolated yields of the product and the recovered donor.
Scheme 4.
donor 23c gave the desired nucleoside product 26c in poor
yield 'entry 11) and the 1,2,3-tri-O-pyvaloyl donor 23d was
virtually inactive under the same conditions. However,
glycosylation reactions of the 1,2,3-tri-O-isobutyryl, 1,2,3-
tri-O-Bz, and 1,2,3-tri-O-'4-MeOBz) donors, 23b, 23e, and
23f, respectively, proceeded smoothly to give the corre-
sponding 3-C-TMS-ethynyl nucleosides in excellent yields
'entries 10, 13, and 14, 76±78%). The reaction of the 1,2,3-
tri-O-'4-ClBz) donor 23a proceeded rather slowly to give
the nucleoside product 26a in 62% yield 'entry 9) but
when the reaction was stopped after 3 h, compound 26a
was produced in only 17% yield 'entry 15). When the
reactions of the donors 23b, 23e, and 23f, which had effec-
tively produced the desired nucleosides after 20 h, were
stopped after 3 h, their yields decreased somewhat 'entries
16±18).
21, the 1,2,3-tri-O-isobutyryl donors 22b and 23b, the 1,2,3-
tri-O-Bz donor 23e, and the 1,2,3-tri-O-'4-MeOBz) donor
23f appeared to be ef®cient donors in the glycosylation
reaction. In choose the best donor for large-scale synthesis,
we considered many points. The steps for synthesizing 21
from 16 are longer than those for the preparation of other
donors. Among the glycosylated nucleoside products
derived from the candidate donors, the product 26f
'prepared from 23f) was not obtained as crystals but as an
amorphous solid, while the other products 25a, 25b, 24b,
26b and 26e were crystalline. From the viewpoint of safety,
especially in a large-scale synthesis, the 3-C-TMS-ethynyl
sugar 16 is preferable to the 3-C-ethynyl sugar 17, since an
excess of the toxic and explosive acetylene is needed for the
preparation of 17. Based on these considerations and our
experimental results, we selected the 1,2,3-tri-O-iso-
butyryl-5-O-'4-ClBz) donor 22b for the glycosylation
reaction. To our knowledge, this is the ®rst glycosylation
reaction that utilizes the isobutyryloxy groupas a leaving
groupat the anomeric position.
As described above, the potency of the donor is in¯uenced
by the acyl groups on the hydroxyls. Based on the yield and
the reaction rate, the 1-O-acetyl-2,3,5-tri-O-'4-ClBz) donor

M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
1283
2.4. Large scale synthesis of ECyd
and brine, dried over MgSO4, and ®ltrated. The ®ltrate
was evaporated under reduced pressure to give a residue,
which was crystallized from hexane±CHCl3 to give 14a
'196 g, 74% as pale yellow powder): mp 101±1028C;
Treatment of 347 g '900 mmol) of the 3-C-TMS-ethynyl
sugar 19 with isobutyryl chloride, Et3N, and DMAP in tolu-
ene at 25±358C for 6 h gave 544 g of the donor 21b after the
usual water work-upand evaporation. The donor, without
puri®cation, was treated with 'TMS)2Cyt 10, prepared from
120 g '1.08 mol, 1.2 equiv. to 19) of cytosine, and 359 g
'1.35 mol, 1.5 equiv. to 19) of SnCl4 in toluene at 508C
for 3 h. The reaction successfully produced 434 g of the
cytosine nucleoside 24b in 78% yield from 19, after crystal-
lization from isopropyl ether 'IPE) and heptane. We found
that removal of the TMS and the acyl groups of 24b
proceeded more smoothly using DBU/MeOH, compared
with the previous NH3/MeOH system.2 Compound 24b
'430 g, 700 mmol) was deprotected with DBU '41.8 g,
270 mmol) in MeOH at 408C for 3 h to furnish 128 g
'68%) of ECyd '1) after crystallization from aqueous
MeOH. Thus, an ef®cient large-scale synthesis of ECyd
without any column chromatography has been achieved.
EUrd '2) was also synthesized by a similar non-chromato-
graphic procedure.
1
FAB-MS 'NaI), m/z 351 'M1Na)1; H NMR 'CDCl3) d
7.99 'd, 2H, Jˆ8.8 Hz), 7.44 'd, 2H, Jˆ8.8 Hz), 5.96 'd,
1H, Jˆ3.7 Hz), 4.79 'dd, 1H, Jˆ9.3, 13.1 Hz), 4.60 'd, 1H,
Jˆ3.7 Hz), 4.37±4.41 'm, 2H), 4.18 'br, 1H), 3.05 'd, 1H,
Jˆ3.9 Hz, exchanged with D2O), 1.51 's, 3H), 1.33 's, 3H);
Anal. calcd for C15H17ClO6: C, 54.80; H, 5.21. Found: C,
54.80; H, 5.16.
4.1.2. 1,2-O-Isopropylidene-5-O-ꢀ4-toluoyl)-d-xylofura-
nose ꢀ14b). 4-CH3BzCl '727 mL, 5.5 mmol) was added
dropwise to a solution of 3 '950 mg, 5.0 mmol) and Et3N
'2.09 mL, 15 mmol) in CH2Cl2 '9.5 mL) at 08C, and the
mixture was stirred at room temperature for 2 h. Saturated
aqueous NaHCO3 '10 mL) was added and partitioned. The
CH2Cl2 layer was washed with H2O '£2) and brine, dried
over mgSO4, and ®ltrated. The ®ltrate was puri®ed by silica
gel column chromatography to give 14b '1.23 g, 80% as a
colorless hygroscopic oil): FAB-MS, m/z 309 'M1H)1; 1H
NMR 'CDCl3) d 7.94 'd, 2H, Jˆ8.2 Hz), 7.26 'd, 2H, Jˆ
8.2 Hz), 5.96 'd, 1H, Jˆ3.6 Hz), 4.80 'dd, 1H, Jˆ9.6,
12e.5 Hz), 4.60 'd, 1H, Jˆ3.6 Hz), 4.34±4.39 'm, 2H),
4.16 'dd, 1H, Jˆ3.0, 3.3 Hz), 3.38 'd, 1H, Jˆ3.9 Hz,
exchanged with D2O), 2.42 's, 3H), 1.51 's, 3H), 1.32 's,
3H); Anal. calcd for C16H20O6´H2O: C, 58.89; H, 6.79.
Found: C, 59.20; H, 6.76.
3. Conclusion
A practical procedure for the large-scale synthesis of ECyd
and EUrd from 1,2-O-isopropylidene-d-xylofuranose 3 '7
steps, 31 and 39% yield, respectively), without any column
chromatography, was developed. In this study, we found
that the isobutyryloxy groupwas an ef®cient leaving
groupfor the glycosylation reaction with 3- C-ethynyl and
3-C-TMS-ethynyl donors.
4.1.3. 1,2-O-Isopropylidene-5-O-ꢀ4-nitrobenzoyl)-d-xylo-
furanose ꢀ14c). 4-NO2BzCl '1.02 g, 5.5 mmol) was added
to a solution of 3 '950 mg, 5.0 mmol) and Et3N '2.09 mL,
15 mmol) in CH2Cl2 '9.5 mL) at 08C, and the mixture was
stirred at room temperature for 2 h. Saturated aqueous
NaHCO3 '10 mL) was added and partitioned. The CH2Cl2
layer was washed with H2O '£2) and brine, dried over
mgSO4, and ®ltrated. The ®ltrate was puri®ed by silica gel
column chromatography to give a residue, which was
crystallized from Et2O to give 14c '1.23 g, 73% as white
4. Experimental
4.1. General methods
Solvents and reagents are obtained from commercial
sources and are not puri®ed unless speci®ed. Melting points
were measured on a Yanagimoto MP-3 micromelting point
apparatus 'Yanagimoto, Japan) and were not corrected. The
1H NMR spectra were recorded on a JEOL JNM-LA400
'400 MHz) or JEOL JNM-EX270 '270 MHz) spectrometer
with tetramethylsilane '0.00 ppm) as an internal standard.
Chemical shifts were reported in parts per million 'd),
and signals were expressed as a s 'singlet), d 'doublet), t
'triplet), q 'quartet), m 'multiplet), or br 'broad). Coupling
constants 'J) were reported in Hz. Fast atom bombardment
mass spectrometry 'FAB-MS) was done on a JEOL JMS-
SX102A instrument at an ionizing voltage of 70 eV. TLC
was done on Merck Silica gel 60 F254 pre-coated plates. The
silica gel used for column chromatography was Merck
Silica gel 60 '70±230 mesh).
1
crystals): mp104±105 8C; FAB-MS, m/z 340 'M1H)1; H
NMR 'CDCl3) d 8.31 'd, 2H, Jˆ9.2 Hz), 8.24 'd, 2H,
Jˆ9.2 Hz), 5.99 'd, 1H, Jˆ3.6 Hz), 4.81 'dd, 1H, Jˆ6.6,
11.0 Hz), 4.59 'd, 1H, Jˆ3.6 Hz), 4.40±4.53 'm, 2H), 4.24
'dd, 1H, Jˆ2.3, 4.6 Hz), 2.64 'd, 1H, Jˆ4.9 Hz, exchanged
with D2O), 1.52 's, 3H), 1.34 's, 3H); Anal. calcd for
C15H17NO8: C, 53.10; H, 5.05; N, 4.13. Found: C, 53.08;
H, 5.06; N, 4.27.
4.1.4. 5-O-Benzoyl-1,2-O-isopropylidene-d-xylofuranose
ꢀ14d). BzCl '638 mL, 5.5 mmol) was added dropwise to a
solution of 3 '950 mg, 5.0 mmol) and Et3N '2.09 mL,
15 mmol) in CH2Cl2 '9.5 mL) at 08C, and the mixture was
stirred at room temperature for 2 h. Saturated aqueous
NaHCO3 '10 mL) was added and partitioned. The CH2Cl2
layer was washed with H2O '£2) and brine, dried over
MgSO4, and ®ltrated. The ®ltrate was puri®ed by silica
gel column chromatography to give 14d '1.17 g, 79% as a
colorless oil): FAB-MS, m/z 295 'M1H)1; 1H NMR
'CDCl3) d 8.06 'd, 2H, Jˆ7.3 Hz), 7.42±7.63 'm, 3H),
5.96 'd, 1H, Jˆ3.6 Hz), 4.80 'dd, 1H, Jˆ9.2, 12.9 Hz),
4.60 'd, 1H, Jˆ3.6 Hz), 4.35±4.43 'm, 2H), 4.19 'dd, 1H,
Jˆ2.3, 4.0 Hz), 3.32 'br, 1H, exchanged with D2O), 1.51 's,
4.1.1.
5-O-ꢀ4-Chlorobenzoyl)-1,2-O-isopropylidene-d-
xylofuranose ꢀ14a). 4-ClBzCl '113 mL, 891 mmol) was
added dropwise to a solution of 3 '154 g, 810 mmol) and
Et3N '339 mL, 2.43 mol) in CH2Cl2 '1.5 L) at 08C, and the
mixture was stirred at the same temperature for 2 h. Satu-
rated aqueous NaHCO3 '500 mL) was added and par-
titioned. The CH2Cl2 layer was washed with H2O '£2)

1284
M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
3H), 1.32 's, 3H); Anal. calcd for C15H18O6´1/4H2O: C,
60.30; H, 6.24. Found: C, 60.31; H, 6.29.
4.1.8. Methyl 2,3,5-tri-O-ꢀ4-chlorobenzoyl)-3-C-[2-ꢀtri-
methylsilyl)ethynyl]-d-ribo-pentofuranoside ꢀ18). To a
solution of 16 '30.0 g, 70.6 mmol) in a mixture of MeOH
'760 mL) and H2O '35 mL) was added conc HCl '190 mL),
and the resulting mixture was heated at 558C for 30 min.
After cooling the mixture, Et3N '300 mL) was added and
evaporated, and the residue was partitioned between H2O
'450 mL) and EtOAc '500 mL). The organic layer was
washed with H2O '300 mL) and dried over MgSO4, and
evaporated to dryness. To a solution of the residue in
CH2Cl2 '270 mL), Et3N '31.9 mL, 229 mmol) and DMAP
'254 mg, 2.0 mmol), and 4-ClBzCl '35.6 g, 208 mmol) was
added at 08C. After stirring the mixture at room temperature
for 3 h, H2O '200 mL) was added, and the resulting mixture
was partitioned. The organic layer was washed with satu-
rated NaHCO3 solution and H2O, dried over MgSO4, and
evaporated to a half volume to give precipitates. After ®l-
tration of the precipitates, the ®ltrate was evaporated and the
residue was puri®ed by silica gel column chromatography
'20% EtOAc in hexane) to give 18 '40.6 g, 87% as colorless
foam): FAB-MS 'KI) m/z 713 'M1K)1; 1H NMR 'DMSO-
d6) d 7.84 'm, 6H), 7.31±7.46 'm, 6H), 5.97 'd, 0.6H, Jˆ
1.5 Hz), 5.74 'd, 0.4H, Jˆ4.4 Hz), 5.42 'd, 0.4H, Jˆ4.4 Hz),
5.12 'd, 0.6H, Jˆ1.5 Hz), 4.69±4.95 'm, 3H), 3.45 's, 1.8H),
3.42 's, 1.2H), 0.14 's, 5.4H), 0.01 's, 3.6H); a-anomer/
b-anomerˆ4:6; Anal. calcd for C32H29Cl3O8Si: C, 56.85;
H, 4.32. Found: C, 56.87; H, 4.25.
4.1.5.
5-O-ꢀ4-Chlorobenzoyl)-1,2-O-isopropylidene-d-
erythro-pentofuranose-3-urose ꢀ15a). To a solution of
14a '195 g, 593 mmol) and 2,2,6,6-tetramethylpiperidin-1-
oxy '937 mg, 5.93 mmol) in CH2Cl2 '990 mL) was added a
mixture of aqueous sodium hypochlorite solution '336 mL,
8.5±13.5% active chlorine), NaHCO3 '112 g), and H2O
'1.9 L) at 08C, and the mixture was stirred at the same
temperature for 30 min. After addition of 2-propanol
'19.5 mL), the resulting mixture was stirred for 10 min at
room temperature and then partitioned. The CH2Cl2 layer
was washed with H2O '£2), dried over MgSO4, and ®ltrated.
The ®ltrate was evaporated to give a residue, which was
crystallized from hexane±CHCl3 to give 15a '171 g, 88%
as white powder): mp 111±1128C; FAB-MS m/z 327
1
'M1H)1; H NMR 'CDCl3) d 7.89 'd, 2H, Jˆ8.5 Hz),
7.42 'd, 2H, Jˆ8.5 Hz), 6.12 'd, 1H, Jˆ4.4 Hz), 4.68±
4.73 'm, 2H), 4.46 'dd, 1H, Jˆ5.1, 13.1 Hz), 4.41 'd, 1H,
Jˆ4.4 Hz), 1.52 's, 3H), 1.44 's, 3H); Anal. calcd for
C15H15ClO6: C, 55.14; H, 4.63. Found: C, 55.12; H, 4.60.
4.1.6. 5-O-ꢀ4-Chlorobenzoyl)-1,2-O-isopropylidene-3-C-
[2-ꢀtrimethylsilyl)ethynyl]-d-ribo-pentofuranose
ꢀ16).
Tri-methylsilylacetylene '92.0 g, 900 mmol) was added
dropwise to a solution of EtMgBr '0.96 M, 768 g,
770 mmol in THF) at 08C. The mixture was added dropwise
to a solution of 15a '200 g, 600 mmol) in THF '1.2 L) at
48C, and the mixture was stirred for 30 min at 48C. Aqueous
NH4Cl solution '15%, 360 mL) was added to the reaction
mixture, which was then warmed to room temperature.
Following phase separation, the THF layer was washed
with aqueous NaCl solution '25%, 160 mL£2), and then
evaporated. The residue was crystallized from MeOH±
H2O to give 16 '238 g, 91% as white powder): mp 130±
4.1.9.
5-O-ꢀ4-Chlorobenzoyl)-3-C-[2-ꢀtrimethylsilyl)-
ethynyl]-d-ribo-pentofuranose ꢀ19). A suspension of 16
'213 g, 500 mmol) in a mixture of 50% aqueous HCO2H
'2 L) was heated under re¯ux for 45 min, and then cooled.
After addition of H2O '1 L), the resulting mixture was stir-
red for 1 h to give precipitates. The resulting precipitates
were collected by ®ltration and washed with H2O
'500 mL£2), NaHCO3 solution '3%, 250 mL£2), and H2O
'500 mL£2) to give 19 '187 g, 97% as a white powder): mp
130±1328C; FAB-MS m/z 385 'M1H)1; 1H NMR 'CDCl3)
d 7.98 'd, 2H, Jˆ8.5 Hz), 7.43 'd, 2H, Jˆ8.5 Hz), 5.47±
5.51 'dd, 1H, Jˆ4.4, 8.7 Hz), 4.46±4.63 'm, 3H), 4.24 'dd,
1H, Jˆ4.4, 6.8 Hz), 3.58 'd, 1H, Jˆ6.8 Hz), 3.13 's,
1H), 3.07 'd, 1H, Jˆ8.7 Hz), 0.15 's, 9H); Anal. calcd
for C17H21ClO6Si: C, 53.05; H, 5.50. Found: C, 53.09; H,
5.52.
1
1328C; EI-MS m/z 425 'M)1; H NMR 'CDCl3) d 8.02 'd,
2H, Jˆ 8.5 Hz), 7.41 'd, 2H, Jˆ8.5 Hz), 5.95 'd, 1H,
Jˆ3.9 Hz), 4.74 'dd, 1H, Jˆ3.6, 12.0 Hz), 4.17 'd, 1H,
Jˆ3.9 Hz), 4.53 'dd, 1H, Jˆ7.8, 12.0 Hz), 4.17 'dd, 1H,
Jˆ3.6, 7.8 Hz), 2.93 's, 1H, exchanged with D2O), 1.60
's, 3H), 1.39 's, 3H), 0.19 's, 9H); Anal. calcd for
C20H25ClO6Si: C, 56.53; H, 5.93. Found: C, 56.58; H,
5.96.
4.1.7.
5-O-ꢀ4-Chlorobenzoyl)-3-C-ethynyl-1,2-O-iso-
4.1.10. 5-O-ꢀ4-Chlorobenzoyl)-3-C-ethynyl-d-ribo-pento-
furanose ꢀ20). Compound 20 '52.2 g, 81% as white
powder) was obtained from 17 '73 g, 10.2 mmol), according
to the above procedure for preparing 19 from 16: mp116±
117.58C; FAB-MS 'KI), m/z 351 'M1K)1; 1H NMR
'CDCl3) d 7.98 'd, 2H, Jˆ8.8 Hz), 7.43 'd, 2H, Jˆ
8.8 Hz), 5.47±5.51 'm, 1H), 4.50±4.68 'm, 3H), 4.26 't,
1H, Jˆ4.9 Hz), 3.69 'd, 1H, Jˆ8.3 Hz), 3.34 's, 1H), 3.19
'd, 1H, Jˆ4.9 Hz), 2.66 's, 1H); Anal. calcd for C14H13ClO6:
C, 53.77; H, 4.19. Found: C, 53.76; H, 4.05.
propylidene-d-ribo-pentofuranose ꢀ17). To a solution of
15a '6.52 g, 20.0 mmol) in THF '26 mL) was added
HCuCMgBr '0.5 M, 50 mL, 25 mmol in THF) dropwise
at 08C under an argon atmosphere, and the mixture was
stirred at 08C for 40 min. After addition of aqueous
NH4Cl solution '15%, 16 mL), the resulting mixture was
partitioned. The organic layer was washed with aqueous
NaCl solution '25%, 16 mL), and evaporated. A solution
of the residue in 2-propanol '15 mL) was added dropwise
to H2O '15 mL), and the resulting precipitated crystals were
collected by ®ltration to give 17 '6.28 g, 89% as white
crystals): mp136±137 8C; FAB-MS 'KI), m/z 391 'M1
4.1.11. 1-O-Acetyl-2,3,5-tri-O-ꢀ4-chlorobenzoyl)-3-C-[2-
ꢀtrimethylsilyl)ethynyl]-d-ribo-pentofuranose ꢀ21). To a
solution of 18 '20.0 g, 29.6 mmol) in a mixture of AcOH
'93 mL) and Ac2O '12.3 mL, 130 mmol) was added conc
H2SO4 '6.0 mL), and the mixture was stirred at room
temperature for 2.5 h. After slow addition of NaHCO3
'25 g), the resulting mixture was stirred at room temperature
1
K)1; H NMR 'CDCl3) d 8.01 'd, 2H, Jˆ8.6 Hz), 7.41 'd,
2H, Jˆ8.6 Hz), 5.95 'd, 1H, Jˆ3.6 Hz), 4.55±4.76 'm, 3H),
4.15±4.20 'm, 1H), 3.01 'br s, 1H), 2.65 's, 1H), 1.61 's,
3H), 1.46 's, 3H); Anal. calcd for C17H17ClO6: C, 57.88; H,
4.86. Found: C, 57.95; H, 4.82.

M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
1285
for 15 min and then evaporated. A solution of the residue in
EtOAc '150 mL) was washed with H2O '150 mL), saturated
NaHCO3 solution '60 mL£2) and brine '100 mL), dried
over MgSO4, and evaporated. A solution of the residue in
MeOH '110 mL) was poured dropwise into H2O '230 mL).
The resulting precipitates were collected by ®ltration and
dried to give 21 '16.0 g, 77% as an amorphous): FAB-MS
'KI), m/z 741 'M1K)1; 1H NMR 'DMSO-d6) d 7.83±8.08
'm, 6H), 7.31±7.46 'm, 6H), 6.70 'd, 0.35H, Jˆ4.4 Hz),
6.33 'd, 0.65H, Jˆ1.2 Hz), 6.11 'd, 0.65H, Jˆ1.2 Hz),
6.00 'd, 0.35H, Jˆ4.4 Hz), 4.71±5.00 'm, 3H), 2.14
's, 1.95H), 1.98 's, 1.05H), 0.18 's, 5.85H), 0.11 's,
3.15H); a-anomer/b-anomerˆ35:65; Anal. calcd for
C33H29Cl3O9Si: C, 56.30; H, 4.15. Found: C, 56.23; H,
4.08.
4.2. General Procedure for the synthesis of 1,2,3-tri-O-
acyl-5-O-ꢀ4-chlorobenzoyl)-3-C-ethynyl-d-ribo-pento-
furanose ꢀ23a±f)
To a suspension of 20 '1.0 g, 3.2 mmol), Et3N '1.3 g,
12.8 mmol), DMAP '12 mg, 0.098 mmol) in CH2Cl2
'16 mL) was added an acyl chloride '12.8 mmol) at 08C,
and the mixture was stirred at room temperature for 5 h.
After quenching the reaction with MeOH, to the mixture
was added CH2Cl2 '20 mL), the resulting solution was
washed with H2O, 15% aqueous NH4Cl solution, and 25%
aqueous NaCl solution. The organic layer was dried over
MgSO4, evaporated, puri®ed by silica gel column chroma-
tography to give 23a±f.
4.2.1. 1,2,3,5-Tetra-O-ꢀ4-chlorobenzoyl)-3-C-ethynyl-d-
ribo-pentofuranose ꢀ23a). After puri®cation by silica gel
column chromatography 'CH2Cl2), 23a '1.80 g, 77% as
white powder) was obtained: FAB-MS 'KI), m/z 767
4.1.12.
1,2,3,5-Tetra-O-ꢀ4-chlorobenzoyl)-3-C-[2-ꢀtri-
methylsilyl)ethynyl]-d-ribo-pentofuranose ꢀ22a). To a
solution of 19 '22 g, 57.2 mmol), DMAP '210 mg,
1.72 mmol), and Et3N '33.5 mL, 240 mmol) in CH2Cl2
'280 mL) was added 4-ClBzCl '29.1 mL, 229 mmol) at
08C, and then the mixture was stirred at room temperature
for 1 h. After addition of H2O '220 mL), the resulting
mixture was stirred at room temperature for 15 min and
then partitioned. The organic layer was washed with H2O,
saturated NaHCO3 solution, and H2O again, dried over
MgSO4, and evaporated. To the residue was added isopropyl
ether 'IPE) '100 mL) to give precipitates, which were
removed by ®ltration. The ®ltrate was evaporated, and a
solution of the residue in EtOH '800 mL) was poured drop-
wise into H2O '1.1 L) at room temperature under vigorous
stirring. A resulting precipitated powder was collected by
®ltration and dried under reduced pressure to give 22a
'39.9 g, 87% as pale yellow amorphous): FAB-MS 'NaI),
1
'M1K)1; H NMR 'DMSO-d6) d 7.41±8.02 'm, 16H),
6.88 'd, 0.7H, Jˆ4.4 Hz), 6.61 's, 0.3H), 6.12 'm, 1H),
5.30 'dd, 0.7H, Jˆ3.7, 5.6 Hz), 5.20 'dd, 0.3H, Jˆ4.2,
6.8 Hz), 4.7±4.9 'm, 2H), 4.38 's, 0.3H), 4.13 's, 0.7H);
a-anomer/b-anomerˆ7:3; Anal. calcd for C35H22Cl4O9: C,
57.72; H, 3.04. Found: C, 57.83; H, 2.93.
4.2.2.
5-O-ꢀ4-Chlorobenzoyl)-3-C-ethynyl-1,2,3-tri-O-
isobutyryl-d-ribo-pentofuranose ꢀ23b). After puri®cation
by silica gel column chromatography '20% EtOAc in
hexane), 23b '1.37 g, 82% as a pale yellow oil) was
obtained: FAB-MS 'KI), m/z 561 'M1K)1; 1H NMR
'CDCl3) d 8.06±7.99 'm, 2H), 7.41±7.45 'm, 2H), 6.54
'd, 0.7H, Jˆ4.6 Hz), 6.12 'd, 0.3H, Jˆ1.2 Hz), 5.78 'd,
0.3H, Jˆ1.2 Hz), 5.71 'd, 0.7H, Jˆ4.6 Hz), 4.60±4.80 'm,
3H), 2.77 's, 0.3H), 2.69 's, 0.7H), 2.53±2.64 'm, 3H), 1.17±
1.23, 'm, 18H); a-anomer/b-anomerˆ7:3; Anal. calcd for
C26H31ClO9: C, 59.71; H, 5.97. Found: C, 59.69; H, 5.88.
m/z 823 'M1Na)1; H NMR 'DMSO-d6) d 7.75±8.07 'm,
1
8H), 7.20±7.46 'm, 8H), 6.92 'd, 0.55H, Jˆ4.4 Hz), 6.55 's,
0.45H), 6.26 's, 0.45H), 6.11 'd, 0.55H, Jˆ4.4 Hz), 4.73±
5.09 'm, 3 H), 0.17 's, 4.05H), 0.12 's, 4.95H); a-anomer/
b-anomerˆ55:45; Anal. calcd for C38H30Cl4O9Si: C, 57.01;
H, 3.78. Found: C, 56.87; H, 3.72.
4.2.3.
1,2,3-Tri-O-acetyl-5-O-ꢀ4-chlorobenzoyl)-3-C-
ethynyl-d-ribo-pentofuranose ꢀ23c). After puri®cation by
silica gel column chromatography '40% EtOAc in hexane),
23c '1.23 g, 88% as a colorless oil) was obtained: FAB-MS
'KI), m/z 477 'M1K)1; 1H NMR 'CDCl3) d 7.99±8.05 'm,
2H), 7.42±7.99 'm, 2H), 6.52 'd, 0.6H, Jˆ4.6 Hz), 6.14
'0.4H, s), 5.81 '0.4H, s), 5.74 'd, 0.6H, Jˆ4.4 Hz), 4.66±
4.78 'm, 3H), 2.78 's, 0.4H), 2.72 's, 0.6H), 2.04±2.14 'm,
9H); a-anomer/b-anomerˆ6:4; Anal. calcd for C20H19ClO9:
C, 54.74; H, 4.36. Found: C, 54.66; H, 4.34.
4.1.13. 5-O-ꢀ4-Chlorobenzoyl)-1,2,3-tri-O-isobutyryl-3-
C-[2-ꢀtrimethylsilyl)ethynyl]-d-ribo-pentofuranose ꢀ22b).
To a solution of 19 '2.00 g, 5.20 mmol), Et3N '2.10 g,
20.8 mmol), and DMAP '19 mg, 0.16 mmol) in CH2Cl2
'30 mL) was added isobutyryl chloride '2.17 mL, 20.8
mmol) at 08C, and the mixture was stirred at room tempera-
ture for 5 h. After quenching the reaction with MeOH,
CH2Cl2 '30 mL) and H2O '50 mL) were added and par-
titioned. The aqueous layer was extracted with CH2Cl2
'30 mL), and the organic layers were combined, washed
with H2O, 10% aqueous NaHCO3 solution '£2) and 25%
aqueous NaCl. The organic layer was dried over MgSO4 and
evaporated, and the residue was puri®ed by silica gel
column chromatography 'CH2Cl2) to give 22b '2.68 g,
87% as colorless oil): FAB-MS 'KI), m/z 633 'M1K)1;
1H NMR 'CDCl3) d 8.01±8.05 'm, 2H), 7.41±7.45 'm,
2H), 6.52 'd, 0.5H, Jˆ4.6 Hz), 6.10 's, 0.5H), 5.75 's,
0.5H), 5.71 'd, 0.5H, Jˆ4.6 Hz), 4.57±4.79 'm, 3H),
2.51±2.65 'm, 3H), 1.12±1.22 'm, 18H), 0.15 's, 4.5H),
0.09 's, 4.5H); a-anomer/b-anomerˆ5:5; Anal. calcd
for C29H39ClO9Si: C, 58.52; H, 6.60. Found: C, 58.29; H,
6.67.
4.2.4.
5-O-ꢀ4-Chlorobenzoyl)-3-C-ethynyl-1,2,3-tri-O-
pivaloyl-d-ribo-pentofuranose ꢀ23d). After puri®cation
by silica gel column chromatography '10% EtOAc in
hexane), 23d '1.73 g, 97% as a colorless foam) was
obtained: FAB-MS 'KI), m/z 603 'M1K)1; 1H NMR
'CDCl3) d 8.06±7.99 'm, 2H), 7.41±7.45 'm, 2H), 6.51
'd, 0.6H, Jˆ4.6 Hz), 6.07 'd, 0.4H, Jˆ1.3 Hz), 5.78 'd,
0.4H, Jˆ1.3 Hz), 5.62 'd, 0.6H, Jˆ4.6 Hz), 4.60±4.82 'm,
3H), 2.75 's, 0.4H), 2.64 's, 0.6H), 1.19±1.28 'm, 27H);
a-anomer/b-anomerˆ6:4; Anal. calcd for C29H37ClO9: C,
61.64; H, 6.60. Found: C, 61.55; H, 6.58.
4.2.5. 1,2,3-Tri-O-benzoyl-5-O-ꢀ4-chlorobenzoyl)-3-C-
ethynyl-d-ribo-pentofuranose ꢀ23e). After puri®cation by

1286
M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
silica gel column chromatography '20% EtOAc in hexane),
23e '1.63 g, 82% as a white powder) was obtained: FAB-
MS 'KI), m/z 663 'M1K)1; 1H NMR 'DMSO-d6) d 7.27±
8.08 'm, 19H), 6.91 'd, 0.7H, Jˆ4.6 Hz), 6.61 's, 0.3H),
6.13 's, 0.3H), 6.12 'd, 0.7H, Jˆ4.6 Hz), 5.16±5.27 'm,
1H), 4.70±4.95 'm, 2H), 4.40 's, 0.3H), 4.11 's, 0.7H);
a-anomer/b-anomerˆ7:3; Anal. calcd for C35H25ClO9: C,
67.26; H, 4.03. Found: C, 67.28; H, 3.86.
®cation by silica gel column chromatography 'CHCl3/
MeOH/EtOAc, 19/1/2): mp131±133 8C 'EtOAc-IPE);
1
FAB-MS m/z 754 'M1H)1; H NMR 'DMSO-d6) d 8.05
'd, 2H, Jˆ8.5 Hz), 7.88±7.95 'm, 4H), 7.79 'd, 1H, Jˆ
7.6 Hz), 7.63 'd, 2H, Jˆ8.3 Hz), 7.58 'd, 2H, Jˆ8.3 Hz),
7.53 'd, 2H, Jˆ8.3 Hz), 7.39±7.42 'br, 2H), 6.27 'd, 1H,
Jˆ3.9 Hz), 5.93 'd, 1H, Jˆ3.9 Hz), 5.84 'd, 1H, Jˆ7.6 Hz),
5.04±5.06 'm, 1H), 4.91 'dd, 1H, Jˆ4.1, 12.0 Hz),
4.77±4.81 'm, 1H), 0.11 's, 9H); Anal. calcd for
C35H30Cl3N3O8Si: C, 55.67; H, 4.00; N, 5.57. Found: C,
55.32; H, 3.95; N, 5.56.
4.2.6. 1,2,3-Tri-O-ꢀ4-anisoyl)-5-O-ꢀ4-chlorobenzoyl)-3-
C-ethynyl-d-ribo-pentofuranose ꢀ23f). After puri®cation
by silica gel column chromatography '25% EtOAc in
hexane), 23f '1.97 g, 86% as a colorless oil) was obtained:
4.4.2. 1-{5-O-ꢀ4-Chlorobenzoyl)-2,3-di-O-isobutyryl-3-
C-[2-ꢀtrimethylsilyl)ethynyl]-b-d-ribo-pentofuranosyl}-
cytosine ꢀ24b). The compound was obtained as a colorless
foam after puri®cation by silica gel column chromatography
'CHCl3/MeOH/EtOAc, 14/1/2): mp97±99 8C 'heptane-
1
FAB-MS 'KI), m/z 753 'M1K)1; H NMR 'DMSO-d6) d
7.54±8.07 'm, 10H), 6.82±7.15 'm, 6.8H), 6.50 's, 0.2H),
6.03±6.05 'm, 1H), 5.08±5.22 'm, 1H), 4.65±4.95 'm, 2H),
4.33 's, 0.2H), 4.06 's, 0.8H), 3.87 's, 0.6H), 3.86 's, 2.4H),
3.83 's, 0.6H), 3.82 's, 2.4H), 3.80 's, 0.6H), 3.79 's, 2.4H);
a-anomer/b-anomerˆ8:2; Anal. calcd for C38H31ClO12: C,
63.82; H, 4.37. Found: C, 63.88; H, 4.28.
1
IPE); FAB-MS m/z 618 'M1H)1; H NMR 'DMSO-d6) d
8.03 'd, 2H, Jˆ8.4 Hz), 7.68, 'd, 1H, Jˆ7.6 Hz), 7.63 'd,
2H, Jˆ8.4 Hz), 7.35, 7.33 'each br s, each 1H), 6.08 'd, 1H,
Jˆ5.0 Hz), 5.78 'd, 1H, Jˆ7.6 Hz), 5.61 'd, 1H, Jˆ5.0 Hz),
4.64±4.76 'm, 3H), 2.52±2.67 'm, 2H), 1.08±1.12 'm,
12H), 0.07 's, 9H); Anal. calcd for C29H36ClN3O8Si: C,
56.35; H, 5.87; N, 6.80. Found: C, 56.29; H, 5.83; N, 6.59.
4.3. Glycosylation reactions with the donor 21 ꢀTable 2,
entries 1 and 2)
A suspension of uracil '224 mg, 2.0 mmol) and 'NH4)2SO4
'8 mg), in HMDS '2.0 mL, 9.5 mmol) was heated under
re¯ux under nitrogen atmosphere for 1 h to give a solution.
The solvent was evaporated, and the residue was co-evapo-
rated twice with toluene to give 'TMS)2Ura '11). To a solu-
tion of 11 and 21 '352 mg, 0.50 mmol) in MeCN '3.5 mL)
was added a Lewis acid '2.5 mmol) at 08C, and the mixture
was then stirred at room temperature for 15 or 17 h. The
resulting mixture was poured into saturated aqueous
NaHCO3 '20 mL), and then EtOAc was added and par-
titioned. The extract was diluted with EtOAc to 100 mL,
which was sampled and analyzed by HPLC to determine
the yield of 25a and recovery of 21: column, Puresil 5m
4.4.3. 1-{2,3,5-Tri-O-ꢀ4-Chlorobenzoyl)-3-C-[2-ꢀtrimethyl-
silyl)ethynyl]-b-d-ribo-pentofuranosyl}uracil ꢀ25a). The
compound was obtained as a colorless foam after puri®-
cation by silica gel column chromatography '10% EtOAc
in CHCl3): mp107±109 8C 'EtOAc-IPE); FAB-MS 'KI),
1
m/z 793 'M1K)1; H NMR 'DMSO-d6) d 11.57 's, 1H),
8.05 'd, 2H, Jˆ8.3 Hz), 7.95 'd, 2H, Jˆ8.5 Hz), 7.92 'd, 2H,
Jˆ8.5 Hz), 7.84 'd, 1H, Jˆ8.1 Hz), 7.54±7.65 'm, 6H), 6.25
'd, 1H, Jˆ4.2 Hz), 5.99 'd, 1H, Jˆ4.2 Hz), 5.78 'd, 1H, Jˆ
8.1 Hz), 5.07±5.10 'm, 1H), 4.92 'dd, 1H, Jˆ4.0, 6.0 Hz),
4.87 'dd, 1H, Jˆ6.0, 12.2 Hz), 0.12 's, 9 H); Anal. calcd for
C35H29Cl3N2O9Si: C, 55.60; H, 3.87; N, 3.71. Found: C,
55.46; H, 3.81; N, 3.50.
2
Ê
120 A 4.6times;150 mm ; detection, 260 nm; eluent, 90%
MeOH±H2O, 1.0 mL/min; retention time, 21a at 9.8 and
10.2 min, 25a at 6.8 min.
4.4.4. 1-{5-O-ꢀ4-Chlorobenzoyl)-2,3-di-O-isobutyryl-3-
C-[2-ꢀtrimethylsilyl)ethynyl]-b-d-ribo-pentofuranosyl}-
uracil ꢀ25b). The compound was obtained as a colorless
foam after puri®cation by silica gel column chromatography
'25% EtOAc in hexane): mp160±161 8C 'IPE-heptane);
4.4. General procedure for the glycosylation reactions
ꢀTable 2, entries 4±18)
1
FAB-MS m/z 619 'M1H)1; H NMR 'DMSO-d6) d 11.51
A suspension of cytosine '222 mg, 2.0 mmol) or uracil
'224 mg, 2.0 mmol) and 'NH4)2SO4 '8 mg, 0.66 mmol) in
HMDS '2.0 mL, 9.5 mmol) was heated under re¯ux for 1 h
under nitrogen atmosphere to give a solution. The solvent
was evaporated, and the residue was co-evaporated twice
with toluene to give 'TMS)2Cyt '10) or 'TMS)2Ura '11). To
a solution of the silylated base and a glycosyl donor
'1.0 mmol) in MeCN '4.0 mL) was added SnCl4 '354 mL,
3.0 mmol) at 08C, and the mixture was stirred at 308C for 3
or 20 h. After evaporation of the solvent, the residue was
partitioned between toluene '50 mL) and HCl '3 M,
50 mL£2). The organic layer was washed with saturated
NaHCO3 solution '50 mL£2), dried over Na2SO4, and
evaporated. The residue was puri®ed by silica gel column
chromatography.
's, 1H), 8.02 'd, 2H, Jˆ8.5 Hz), 7.75 'd, 1H, Jˆ8.3 Hz),
7.63 'd, 2H, Jˆ8.5 Hz), 6.01 'd, 1H, Jˆ5.4 Hz), 5.72 'd,
1H, Jˆ8.3 Hz), 5.63 'd, 1H, Jˆ5.4 Hz), 4.64±4.76 'm, 3H),
2.60±2.68 'm, 2H), 1.08±1.13 'm, 12H), 0.06 'm, 9H);
Anal. calcd for C29H35ClN2O9Si: C, 56.26; H, 5.70; N,
4.52. Found: C, 56.35; H, 5.60; N, 4.32.
4.4.5. 1-[2,3,5-Tri-O-ꢀ4-chlorobenzoyl)-3-C-ethynyl-b-d-
ribo-pentofuranosyl]uracil ꢀ26a). The compound was
obtained as white crystals after puri®cation by silica gel
column chromatography '50% EtOAc in hexane) followed
by crystallization from IPE: mp115±117 8C; FAB-MS m/z
1
683 'M1H)1; H NMR 'DMSO-d6) d 11.52 'br s, 1H),
7.83±8.04 'm, 7H), 7.56±7.66 'm, 6H), 6.26 'd, 1H, Jˆ
5.1 Hz), 6.00 'd, 1H, Jˆ5.1 Hz), 5.79 'd, 1H, Jˆ8.3 Hz),
5.07 'm, 1H), 4.93 'm, 1H), 4.82 'm, 1H), 4.21 's, 1H); Anal.
calcd for C32H21Cl3N2O9: C, 56.20; H, 3.10; N, 4.10. Found:
C, 56.45; H, 2.87; N, 4.00.
4.4.1. 1-{2,3,5-Tri-O-ꢀ4-chlorobenzoyl)-3-C-[2-ꢀtrimethyl-
silyl)ethynyl]-b-d-ribo-pentofuranosyl}cytosine ꢀ24a).
The compound was obtained as a colorless foam after puri-

M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
1287
4.4.6. 1-[5-O-ꢀ4-Chlorobenzoyl)-2,3-di-O-isobutyryl-3-C-
ethynyl-b-d-ribo-pentofuranosyl]uracil ꢀ26b). The com-
pound was obtained as white crystals after puri®cation by
silica gel column chromatography '3% MeOH in CH2Cl2)
followed by crystallization from EtOAc±heptane: mp 198±
1998C; FAB-MS m/z 547 'M1H)1; 1H NMR 'DMSO-d6) d
11.50 's, 1H), 8.00 'd, 2H, Jˆ8.8 Hz), 7.75 'd, 1H, Jˆ
8.1 Hz), 7.64 'd, 2H, Jˆ8.8 Hz), 6.01 'd, 1H, Jˆ5.6 Hz),
5.74 'd, 1H, Jˆ8.1 Hz), 5.60 'd, 1H, Jˆ5.6 Hz), 4.66±4.80
'm, 3H), 4.06 's, 1H), 2.55±2.69 'm, 2H), 1.08 'm, 12H);
Anal. calcd for C26H27ClN2O9: C, 57.09; H, 4.98; N, 5.12.
Found: C, 57.09; H, 4.97; N, 5.17.
give a solution. The solvent was evaporated, and the residue
was co-evaporated with toluene to give 'TMS)2Cyt '10,
260 g). To a solution of 10 and the crude 22b '544 g) in
toluene '3.6 L) was added SnCl4 '359 g, 1.35 mol) under
nitrogen atmosphere, and the mixture was stirred at 508C
for 3 h. To the mixture was added 98% formic acid '1.8 L),
H2O '0.9 L), and HCl '6 M, 1.9 L), and then the resulting
mixture was partitioned. The organic layer was washed with
HCl '6 M, 1.9 L£2) and aqueous NaCl '25%, 2 L), and then
evaporated. To a solution of the residue in CH3CN '1.8 L)
was added NaHCO3 '757 g), and the resulting mixture was
®ltrated through celite pad and then PTFE membrane ®lter.
The ®ltrate was evaporated to give crystals, which were
recrystallized from IPE±heptane to give crystalline 24b in
a pure form '434 g, 78%).
4.4.7.
1-[2,3-Di-O-acetyl-5-O-ꢀ4-chlorobenzoyl)-3-C-
ethynyl-b-d-ribo-pentofuranosyl]uracil ꢀ26c). The com-
pound was obtained as white crystals after puri®cation by
silica gel column chromatography '3% MeOH in CH2Cl2)
followed by crystallization from IPE: mp218±219 8C; FAB-
MS m/z 491 'M1H)1; 1H NMR 'DMSO-d6) d 11.50 's, 1H),
7.99 'd, 2H, Jˆ6.6 Hz), 7.75 'd, 1H, Jˆ8.3 Hz), 7.63 'd, 2H,
Jˆ6.6 Hz), 6.03 'd, 1H, Jˆ5.8 Hz), 5.73 'd, 1H, Jˆ8.3 Hz),
5.62 'd, 1H, Jˆ5.8 Hz), 4.65±4.78 'm, 3H), 4.07 's, 1H),
2.15 's, 3H), 2.10 's, 3H); Anal. calcd for C22H19ClN2O9: C,
53.83; H, 3.90; N, 5.71. Found: C, 54.04; H, 4.02; N, 5.55.
4.6. Preparation of 25b from 19 without column chroma-
tography
To a solution of 19 '4.23 g, 11.0 mmol), Et3N '4.45 g,
44.0 mmol), and DMAP '40 mg, 0.33 mmol) in CH2Cl2
'63 mL) was added isobutyryl chloride '4.69 g, 44.0
mmol) at 08C, and the mixture was stirred at room tempera-
ture for 4 h. After quenching the reaction with MeOH
'1.35 mL), CH2Cl2 '50 mL) and H2O '50 mL) were added,
and the mixture was partitioned. The organic layer was
washed with H2O '50 mL), aqueous NaHCO3 '10%,
60 mL), and aqueous NaCl solution '25%, 60 mL), dried
over MgSO4, and evaporated to give crude 22b '6.65 g).
4.4.8. 1-[2,3-Di-O-benzoyl-5-O-ꢀ4-chlorobenzoyl)-3-C-
ethynyl-b-d-ribo-pentofuranosyl]uracil ꢀ26e). The com-
pound was obtained as white crystals after puri®cation by
silica gel column chromatography '50% EtOAc in hexane):
mp158±160 8C 'EtOAc±heptane); FAB-MS m/z 615 'M1
Besides,
a mixture of uracil '840 mg, 7.5 mmol),
1
H)1; H NMR 'DMSO-d6) d 11.54 's, 1H), 7.43±8.05 'm,
'NH4)2SO4 '27 mg), and HMDS '5.8 g, 36 mmol) was
heated under re¯ux under nitrogen atmosphere for 1 h to
give a solution. The solvent was evaporated, and the residue
was co-evaporated twice with toluene to give 'TMS)2Ura
'11). To a solution of 11 and the crude 22b '3.02 g) in
CH3CN '20 mL) was added SnCl4 '885 mL, 7.50 mmol) at
08C, and the mixture was stirred for at 508C for 3 h. The
mixture was added dropwise to aqueous NaHCO3 '3%,
40 mL), and then the solvent was evaporated. To the residue
were added CHCl3 '100 mL) and MgSO4 '10 g), and the
mixture was ®ltrated. The ®ltrate was washed with saturated
aqueous NaCl '100 mL), dried over MgSO4, and evapo-
rated. The residue was crystallized from heptane-IPE to
give crystalline 25b in a pure form '2.27 g, 74% from 19).
15H), 6.26 'd, 1H, Jˆ4.9 Hz), 5.98 'd, 1H, Jˆ4.9 Hz), 5.80
'd, 1H, Jˆ8.3 Hz), 4.79±5.07 'm, 3H), 4.21 's, 1H); Anal.
calcd for C32H23ClN2O9: C, 62.50; H, 3.77; N, 4.56. Found:
C, 62.42; H, 3.57; N, 4.52.
4.4.9. 1-[2,3-Di-O-ꢀ4-anisoyl)-5-O-ꢀ4-chlorobenzoyl)-3-
C-ethynyl-b-d-ribo-pentofuranosyl]uracil ꢀ26f). The
compound was obtained as a colorless foam after puri®-
cation by silica gel column chromatography '60% EtOAc
in hexane): FAB-MS m/z 675 'M1H)1; 1H NMR 'DMSO-
d6) d 11.53 's, 1H), 7.65±7.80 'm, 9H), 6.95±7.10 'm, 4H),
6.21 'd, 1H, Jˆ4.9 Hz), 5.92 'd, 1H, Jˆ4.9 Hz), 5.79 'd, 1H,
Jˆ8.3 Hz), 4.75±5.10 'm, 3H), 4.16 's, 1H), 3.85 's, 3H),
3.81 's, 3H); Anal. calcd for C34H27ClN2O11: C, 60.49; H,
4.03; N, 4.15. Found: C, 60.60; H, 4.19; N, 3.77.
4.6.1. 1-ꢀ3-C-Ethynyl-b-d-ribo-pentofuranosyl)cytosine
ꢀECyd, 1). A solution of 24b '430 g, 0.70 mol) and DBU
'41.8 g, 270 mmol) in MeOH '2.8 L) was stirred at 408C for
3 h. AcOH '19.4 g, 320 mmol) and toluene '2.8 L) were
added, and the resulting mixture was stirred at 10±208C
for 1 h. The resulting crystals were collected by ®ltration,
which were recrystallized from H2O±MeOH to afford pure
ECyd '1, 128 g, 68%): mp233±235 8C; FAB-MS 'negative)
4.5. Large-scale preparation of 1-{5-O-ꢀ4-Chlorobenzoyl)-
2,3-di-O-isobutyryl-3-C-[2-ꢀtrimethylsilyl)ethynyl]-b-d-
ribo-pentofuranosyl}cytosine ꢀ24b) from 19
To a mixture of 19 '347 g, 900 mmol) and DMAP '3.3 g,
27 mmol) in toluene '3.5 L) were added Et3N '365 g,
3.6 mol) and isobutyryl chloride '341 g, 3.2 mol) at 08C,
and the mixture was stirred at 25±358C for 6 h. After
quenching the reaction with MeOH '88 g), H2O '1.25 L)
was added, and the resulting mixture was partitioned. The
organic layer was washed with HCl '1 M, 1.25 L), aqueous
NaHCO3 '3%, 1.25 L), and aqueous NaCl '25%, 1.25 L),
dried over MgSO4, and evaporated to give crude 22b
'544 g). Besides, a mixture of cytosine '120 g, 1.08 mol),
'NH4)2SO4 '400 mg), and HMDS '870 g, 5.40 mol) was
heated under re¯ux under nitrogen atmosphere for 1 h to
1
m/z266 'M2H)2; H NMR 'DMSO-d6) d 7.81 'd, 1H,
Jˆ7.6 Hz), 7.21 'br s, 1H), 7.17 'br s, 1H), 5.83 'd, 1H,
Jˆ6.6 Hz), 5.73±5.79 'm, 3H), 5.02 't, 1H, Jˆ4.9 Hz),
4.11 't, 1H, Jˆ6.6 Hz), 3.85±3.87 'm, 1H), 3.65±3.69 'm,
2H) 3.51 's, 1H); Anal. calcd for C11H13N3O5: C, 49.44; H,
4.90; N, 15.72. Found: C, 49.58; H, 4.91; N, 15.71.
4.6.2. 1-ꢀ3-C-Ethynyl-b-d-ribo-pentofuranosyl)uracil
ꢀEUrd, 2). A solution of 25b '2.0 g, 3.2 mmol) and DBU
'2.0 g, 13 mmol) in MeOH '16 mL) was stirred at room

1288
M. Nomura et al. / Tetrahedron 58 12002) 1279±1288
Ohshimo, H.; Kato, T.; Matsuda, A.; Sasaki, T.; Fukushima,
M. Jpn. J. Cancer Res. 2001, 92, 343±351. 'g) Azuma, A.;
Matsuda, A.; Sasaki, T.; Fukushima, M. Nucleosides, Nucleo-
tides, Nucleic Acids 2001, 20, 609±619.
temperature for 1.5 h. After addition of AcOH '2.0 g), the
resulting mixture was evaporated, and a solution of the resi-
due in MeOH '4.4 mL) and CHCl3 '44 mL) was stirred at
room temperature for 1 h. The resulting crystals was
collected by ®ltration to afford pure EUrd '802 mg, 92%):
5. Nakatani, K.; Arai, K.; Terashima, S. J. Chem. Soc., Chem.
Commun. 1992, 289±291.
1
FAB-MS 'negative) m/z 267 'M2H)2; H NMR 'DMSO-
6. Niedballa, U.; VorbruÈggen, H. J. Org. Chem. 1974, 39, 3654±
3660.
d6) d 11.24 'br s, 1H), 7.87 'd, 1H, Jˆ8.3 Hz), 5.91 's, 1H),
5.82±5.86 'm, 2H), 5.68 'd, 1H, Jˆ8.3 Hz), 5.10 't, 1H,
Jˆ4.4 Hz), 4.17 't, 1H, Jˆ6.1 Hz), 3.88±3.90 'm, 1H),
3.63±3.73 'm, 2H), 3.54 's, 1H); Anal. calcd for
C11H12N2O6: C, 49.26; H, 4.51; N, 10.44. Found: C,
19.16; H, 4.60; N, 10.31.
7. P®tzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85,
3027±3028.
8. P®tzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87,
5661±5670.
9. Trummlitz, G.; Moffatt, J. G. J. Org. Chem. 1973, 38, 1841±
1845.
References
10. Onodera, K.; Hirano, S.; Kashimura, K. J. Am. Chem. Soc.
1965, 87, 4651±4652.
1. Matsuda, A.; Hattori, H.; Tanaka, M.; Sasaki, T. Bioorg. Med.
Chem. Lett. 1996, 6, 1887±1892.
11. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87,
4214±4216.
2. Hattori, H.; Tanaka, M.; Fukushima, M.; Sasaki, T.; Matsuda,
A. J. Med. Chem. 1996, 39, 5005±5011.
12. Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23,
35±38.
3. Hattori, H.; Nozawa, E.; Iino, T.; Yoshimura, Y.; Shuto, S.;
Shimamoto, Y.; Nomura, M.; Fukushima, M.; Tanaka, M.;
Sasaki, T.; Matsuda, A. J. Med. Chem. 1998, 41, 2892±2902.
4. 'a) Tabata, S.; Tanaka, M.; Matsuda, A.; Fukushima, M.;
Sasaki, T. Oncol. Rep. 1996, 3, 1029±1034. 'b) Tabata, S.;
Tanaka, M.; Endo, Y.; Obata, T.; Matsuda, A.; Sasaki, T.
Cancer Lett. 1997, 116, 225±231. 'c) Takatori, S.; Tsutsumi,
S.; Hidaka, M.; Kanda, H.; Matsuda, A.; Fukushima, M.;
Wataya, Y. Nucleosides Nucleotides 1998, 17, 1309±1317.
'd) Matsuda, A.; Fukushima, M.; Wataya, Y.; Sasaki, T.
Nucleosides Nucleotides 1999, 18, 811±814. 'e) Takatori,
S.; Kanda, H.; Takenaka, K.; Wataya, Y.; Matsuda, A.;
Fukushima, M.; Shimamoto, Y.; Tanaka, M.; Sasaki, T.
Cancer Chemother. Pharmacol. 1999, 44, 97±104.
'f) Shimamoto, Y.; Fujioka, A.; Kazuno, H.; Murakami, Y.;
13. Stevens, R. V.; Chapman, K. T.; Weller, H. N. J. Org. Chem.
1980, 45, 2030±2032.
14. Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.;
Albizati, K. F. Tetrahedron Lett. 1982, 23, 4647±4650.
15. Jones, R. E.; Kocher, F. W. J. Am. Chem. Soc. 1954, 76, 3682±
3683.
16. Fieser, L. F.; Rajagopalan, S. J. Am. Chem. Soc. 1949, 71,
3938±3941.
17. Anelli, P. L.; Bif®, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559±2562.
18. Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org.
Chem. 1990, 55, 462±466.
19. Part 211 in this series: Shuto, S., Niizuma, S., Minakawa, N.,
Kim, H-S., Wataya, Y., Matsuda, J. Med. Chem. in press.