An efficient method for the preparation of 1′α-branched-chain sugar pyrimidine ribonucleosides from uridine: The first conversion of a natural nucleoside into 1′-substituted ribonucleosides

Article abstract of DOI:10.1002/1521-3765(20010601)7:11<2332::AID-CHEM23320>3.0.CO;2-W

The 1′α-phenylselenouridine derivative 13 was successfully synthesized by enolization of the 3′,5′-O-TIPDS-2′-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether - an efficient procedure for preparing 1′α-branched-chain sugar p

Full text of DOI:10.1002/1521-3765(20010601)7:11<2332::AID-CHEM23320>3.0.CO;2-W

FULL PAPER
An Efficient Method for the Preparation of 1'a-Branched-Chain Sugar
Pyrimidine Ribonucleosides from Uridine: The First Conversion of
a Natural Nucleoside into 1'-Substituted Ribonucleosides**
Tetsuya Kodama, Satoshi Shuto,* Makoto Nomura, and Akira Matsuda*[a]
Abstract: The 1'a-phenylselenouridine
derivative 13 was successfully synthe-
sized by enolization of the 3',5'-O-
TIPDS-2'-ketouridine 8, and was sub-
jected to a radical reaction with a vinyl-
silyl tetherÐan efficient procedure for
preparing 1'a-branched-chain sugar pyr-
imidine nucleosides. Successive treat-
ment of 8 with LiHMDS and PhSeCl in
THF at < 708C gave the desired 1'-
phenylseleno products in 85% yield as
an anomeric mixture of the 1'a-product
11 and the 1'b-product 12 (11/12 ˆ
2.5:1). Highly stereoselective reduction
at the 2'-carbonyl of the 1'a-product 11
occurred from the b-face by using
NaBH4/CeCl3 in MeOH, and subse-
quent introduction of a dimethylvinyl-
silyl tether at the 2'-hydroxyl gave the
radical reaction substrate 14. The photo-
chemical radical atom-transfer reaction
of 14 by using a high-pressure mercury
lamp proceeded effectively in benzene
to give the exo-cyclized PhSe-transfer-
red product 18, in which (PhSe)2 proved
to be essential as an additive for radical
atom-transfer cyclization reactions. Sub-
sequent phenylseleno-group elimination
of 18 gave the sugar-protected 1'a-vinyl-
uridine. With this procedure, 1'a-vinyl-
uridine (22) and -cytidine (25), designed
to be potential antitumor agents, were
successfully synthesized. This study is
the first example of functionalization at
the anomeric 1'-position of a nucleoside
by starting from a natural nucleoside to
produce a ribo-type 1'-modified nucleo-
side.
Keywords: glycosides ´ nucleosides
´
radical reactions
´ selenium ´
silicon
We are also interested in the biological activity of 1'-
Introduction
branched-chain sugar ribonucleosides I (Scheme 1), since the
antitumor antibiotics angustmycin C (6)[6] and hydantocidin
(7),[7] which have herbicidal and plant-growth regulatory
effects, are included in this class of nucleosides and have been
isolated from bacterial broths. A variety of procedures for
preparing branched-chain sugar nucleosides have been de-
veloped. However, examples of reported 1'-branched-chain
sugar nucleosides are limited,[8] and the biological activities of
these nucleosides have not been systematically investigated;[9]
perhaps because of the lack of efficient synthetic methods for
producing them. The 1'-branched-chain sugar nucleosides
have been synthesized by introduction or construction of a
nucleobase at the 1-position of the corresponding a-C-
glycosidic precursors, the preparation of which required
rather long reaction steps.[10]
In recent years, we have been engaged in the study of
branched-chain sugar nucleosides and have developed stereo-
selective synthetic methods for several of these biologically
important targets in medicinal chemistry.[1] In the course of
these studies, we have prepared a variety of sugar-modified
nucleoside analogs, and have found that 1-(2-deoxy-2-meth-
ylene-b-d-erythro-pentofuranosyl)cytosine (DMDC, 1),[2]
1-(2-C-cyano-2-deoxy-b-d-arabino-pentofuranosyl)cytosine
(CNDAC, 2),[3] and 1-(3-C-ethynyl-b-d-ribo-pentofuranosyl)-
cytosine (ECyd, 3)[4] are potent antitumor nucleosides, which
significantly inhibit the growth of various human solid tumor
cells both in vitro and in vivo. We have also identified 2'-
deoxy-4'-C-ethynylcytidine (4)[5a] and 4'-C-vinylthymidine
(5)[5b] as potent antiviral and/or antitumor agents.
With this in mind, we decided to develop an efficient
method for preparing the 1'a-branched-chain sugar ribonu-
cleosides I, starting from natural nucleosides and using a
radical cyclization reaction, which is a highly versatile method
for forming C C bonds. Since silicon-containing tethers are
very useful for the regio- and stereoselective introduction of a
carbon substituent based on a temporary silicon connection,
there is a growing interest in their use in intramolecular
radical cyclization reactions.[11] We have developed a regio-
[a] Assoc. Prof. Dr. S. Shuto, Prof. Dr. A. Matsuda, T. Kodama,
M. Nomura
Graduate School of Pharmaceutical Sciences
Hokkaido University, Kita-12, Nishi-6, Kita-ku
Sapporo 060-0812 (Japan)
Fax : (‡81)11-706-4980
E-mail: matuda@pharm.hokudai.ac.jp
[**] Nucleosides and Nucleotides, Part 205; for Part 204 see: Y. Ueno, N.
Karino, A. Matsuda, Bioconjugate Chem. 2000, 11, 933 ± 940.
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2332±2340
Scheme 1. Branched-chain nucleosides with biological activity.
Scheme 2. General scheme for the radical cyclization reaction with a vinylsilyl group as a temporary connecting tether.
and stereoselective method for introducing three kinds of C2
substituents, namely 1-hydroxyethyl, 2-hydroxyethyl, and
vinyl groups at the position b to a hydroxyl group in
halohydrins or in a-phenylselenoalkanols a by using an
intramolecular radical cyclization reaction with a dimethyl-
or a diphenylvinylsilyl group as a temporary connecting
radical-acceptor tether (Scheme 2).[12] Thus, the selective
introduction of both 1-hydroxyethyl and 2-hydroxyethyl
groups can be achieved, depending on the concentration of
nBu3SnH in the reaction system, via a 5-exo-cyclization
intermediate g or a 6-endo-cyclization intermediate f, respec-
tively, after oxidative ring-cleavage by reacting the cyclization
of nBu3SnH and at higher reaction temperatures, the radical c
rearranged into the more stable, ring-enlarged 4-oxa-3-
silacyclohexyl radical e via a pentavalent-like silicon radical
transition state d, which was then trapped with nBu3SnH to
give f.[12g]
We recently applied this method to the synthesis of 4'a-
branched-chain sugar nucleosides.[5b, 12a±c] The 4'-phenylsele-
nonucleosides II, which were prepared from natural 2'-
deoxyribonucleosides by the procedure developed by Giese
and co-workers,[14] were used successfully in the synthesis of a
variety of 4'a-branched-chain sugar nucleosides III through a
radical reaction with a temporary connecting vinylsilyl tether
(Scheme 3). Among these, 4'a-ethynyl-2'-deoxycytidine (4)
and 4'a-vinylthymidine (5) showed potent antiviral and/or
antitumor effects.[5] Consequently, the 1'-phenylselenonucleo-
sides should also be highly useful precursors for the synthesis of
the biologically important 1'a-branched-chain sugar nucleosides.
In this report, we describe the synthesis of 1'-phenylsele-
nouridines by enolization of a sugar-protected 2'-ketouri-
dine[15] and its radical reaction with a vinylsilyl tether to
produce 1'a-branched-chain sugar pyrimidine nucleosides.
products together under Tamao oxidation conditions.[13]
A
vinyl group can also be introduced by irradiation of the
vinylsilyl ether in the presence of (nBu3Sn)2, followed by
treatment of the resulting atom-transfer 5-exo-cyclization
product j with the fluoride ion.[12d] The results of our
investigation of the radical cyclization mechanism suggest
that the kinetically favored 5-exo-cyclized radical c, formed
from radical b, was trapped when the concentration of
nBu3SnH was high enough to give g. At lower concentrations
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A. Matsuda, S. Shuto et al.
FULL PAPER
first prepared by our group,[16] has been widely used for the
synthesis of 2'-modified nucleosides by nucleophilic addition
reactions at the 2'-carbonyl.[17] We first examined, by deute-
rium-labeling experiments, whether enolization at the 1'-
position of 8 occurred (Scheme 5). A mixture of 8 and
Scheme 3. Synthesis of 4'-branched 2'-deoxynucleosides by radical cycli-
zation reactions with a vinylsilyl group as a temporary connecting tether.
Results and Discussion
Synthetic plan: Scheme 4 shows our synthetic plan. In order to
provide the substrate for the radical reaction, a method for
introducing a phenylseleno group at the 1'-positon of nucleo-
Scheme 5. Enolization of 3',5'-O-TIPDS-2'-ketouridine (8). a) LiHMDS,
THF. b) CD3CO2D, CD3OD; ca. 90%. c) BzCl; 73%.
lithium hexamethyldisilazide (LiHMDS) (2.1equiv) in THF
was stirred at < 708C for 1 h, then quenched with
CD3CO2D/CD3OD. The 2'-ketouridine 8D was obtained in
about 90% yield,[18] in which 54% of the 1'-protons had been
replaced by deuterium atoms based on the 1H NMR spectrum.
A similar experiment with lithium diisopropylamide (LDA)
as the base also gave the 1'-deuterium-labeled product 8D
(yield 72%, deuterium incorporation 50%). Furthermore,
when the reaction mixture of 8 and LiHMDS (2.1equiv) in
THF was treated with BzCl at < 708C, the enol-O-benzoate
10 was obtained in 73% yield. These experiments clearly
showed that the 1'-enolate 9 was produced under these
conditions, as predicted. As far as we know, this is the first
example demonstrating enolization at the 1'-position of a 2'-
ketonucleoside.[19]
Scheme 4. Strategy for synthesizing 1'a-branched-chain ribonucleosides
via 1'-phenylselenouridine derivatives. a) 1. base, 2. PhSeCl. b) 1. reduc-
ˆ
tion, 2. Me2Si(CH CH2)Cl. c) 1. radical reaction, 2. Tamao oxidation or
elimination.
sides was needed. We assumed that treatment of the 2'-
ketouridine derivative IV, readily prepared from uridine, with
a strong base would produce the corresponding 1'-enolate and
that the subsequent reaction with PhSeCl as electrophile
would give the 1'-phenylseleno-2'-ketouridine derivative V.
The stereoselective hydride reduction of the 2'-carbonyl from
the b-face, followed by introduction of a dimethylvinylsilyl
tether at the 2'-hydroxyl, would provide the desired radical
reaction substrate VI. The radical reaction of VI and
subsequent Tamao oxidation or elimination of the phenyl-
seleno group of the product
Introduction of a phenylseleno group at the 1'-position:
Introduction of a phenylseleno group at the 1'-position of 8
through its enolization was next investigated (Scheme 6), and
the results are summarized in Table 1. The reactions were
carried out as follows. A mixture of 8 and a base in a solvent
was stirred at < 708C for 1 h. Two equivalents of PhSeCl
were added, and the resulting mixture was further stirred at
the same temperature for 1 h. The reaction products were
would afford the corresponding
sugar-protected 1'-branched-
chain sugar nucleosides I'.
Enolization at the 1'-position:
The 3',5'-O-TIPDS-2'-ketouri-
dine 8 (TIPDS ˆ 1,1,3,3-tetra-
Scheme 6. Introduction of a phenylseleno group at the 1'-positon of 3',5'-O-TIPDS-2'-ketouridine (8). a) 1. base,
2. PhSeCl.
isopropyldisiloxane-1,3-diyl),
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1'-Branched-Chain Sugar Pyrimidine Ribonucleosides
2332±2340
Table 1. The introduction of a phenylseleno group at the 1'-position of 8.[a]
NaHMDS or KHMDS was
used (entries 9 and 10). It is
interesting to note that the a-
selectivity is lost when the
counterion of HMDS is
changed to sodium. Further-
more, the stereoselectivity was
reversed to give the 1'b-phenyl-
seleno derivative 12 as the
major product (11/12 ˆ 1:3.0)
when potassium was used as
the counterion.
base (equiv)
solvent
yield (11 ‡ 12 [%])
ratio (11/12)[b]
8 (recovered [%])
1
2
3
4
5
6
7
8
9
LiHMDS (1.5)
LiHMDS (2.1)
LiHMDS (3.0)
LiHMDS (4.0)
LiHMDS (2.1)
LiHMDS (2.1)
LiHMDS (2.1)
LDA (2.1)
THF
THF
THF
THF
DME
Et2O
THF/HMPA (9:1)
THF
THF
47
85
73
5
85
53
75
62
76
79
2.9:1
2.5:1
2.7:1
only 12
2.7:1
2.4:1
1.4:1
2.6:1
1.2:1
1:3.0
47
6
16
57
9
36
3
12
10
6
NaHMDS (2.1)
KHMDS (2.1)
10
THF
[a] solvent at < 708C for 1 h, PhSeCl (2equiv) was added, and the resulting mixture was further stirred at the
same temperature for 1 h. [b] The ratio was obtained from their isolated yield, after purification by neutral silica
gel column chromatography.
These results with different
counterions, together with the
results in the presence of
HMPA (entry 7), suggest that
purified by neutral silica-gel column chromatography. The
reaction was first performed with 1.5 equivalents of LiHMDS
to give the desired 1'-phenylseleno product in 47% yield as an
anomeric mixture of the 1'a-phenylseleno product 11 and the
corresponding b-product 12 (11/12 ˆ 2.9:1, entry 1). It is worth
noting that the 1'b-phenylseleno product 12 was in equilib-
rium between the 2'-keto form 12a and its 2'-hydrate 12b. The
stereochemistry was confirmed by NOE analysis of 12b, as
shown in Figure 1a. When 2.1 or 3.0 equivalents of LiHMDS
were used, the yields increased significantly (entry 2, yield
85%; entry 3, yield 73%).[20] However, when 4.0 equivalents
of the base were used, a poorer yield resulted (entry 4).[21]
In all these reactions, the 1'a-phenylseleno product 11
was obtained selectively as the major product. The
the 1'a-phenylseleno product 11 is probably produced
through a chelation-controlled reaction pathway.[22] While
the structure of the chelation intermediate has not been
elucidated, one might postulate a chelation of Li between the
2'-enol oxygen and 2-carbonyl oxygen of the uracil moiety.
‡
Synthesis of the substrate for the radical reactions: The 1'a-
phenyseleno product 11, obtained in pure form after neutral
silica gel column chromatography, was subjected to reduction
at the 2'-keto moiety with hydride reagents, such as NaBH4,
LiBH4, NaBH3CN, diisobutylaluminum hydride (DIBAL-H),
or LiAl(OEt)3H. We investigated various reaction conditions
and found that the 2'-carbonyl group of 11 was chemo- and
stereoselectively reduced from the b-face when it was treated
with NaBH4 in the presence of CeCl3 in MeOH[23] at < 708C
to give the desired sugar-protected 1'-phenylselenouridine 13
in 90% yield as the sole product.[24] The stereochemistry of 13
was confirmed by NOE experiments, as shown in Figure 1b.
The vinylsilyl tether was introduced at the 2'-hydroxy group
by treating 13 with a dimethylvinylchlorosilane, 4-(dimethyl-
amino) pyridine (DMAP), and Et3N in toluene to give 14, the
substrate for the radical reaction, as shown in Scheme 7.
The radical reaction under reductive conditions: The radical
reactions of the 1'a-phenylselenouridine derivative 14, bear-
ing a dimethylvinylsilyl tether at the 2'-position, were first
performed under reductive conditions with nBu3SnH. How-
ever, the results were undesirable. Treatment of 14 with
nBu3SnH (3.0equiv) in the presence of 2,2'-azobisisobutyro-
nitrile (AIBN, 0.3equiv) in benzene at 608C or 2,2'-azobis-
(2,4-dimethyl-4-methoxyvaleronitrile) (V-70, 0.3equiv) at
08C gave the 1'-reduced product 15 as the major product
(43% at 608C, 33% at 08C). The anomeric configuration
was assigned as a, since this compound was not identical to
the uridine derivative 15b that was prepared by silylation at
the 2'-hydroxyl of 3',5'-O-TIPDS-uridine. The radical reac-
tions with (TMS)3SiH as the reducing agent were also
unsuccessful. For example, when 14 was treated with
(TMS)3SiH (3.0equiv) and AIBN (0.3equiv) in benzene at
608C, a tandem cyclization occurred to give the pentacyclic
product 16 as the major product in 37% yield, along with
5-exo-cyclized 17 (13%) and its atom-transfer product 18
Figure 1. NOE experimental data of compounds 12b, 13, 16, and 17.
effect of the solvent on the reaction was next examined.
Although 1,2-dimethoxyethane (DME) was suitable for this
reaction (entry 5) and gave results similar to the reaction in
THF, the yield decreased when Et2O was used (entry 6). The
anomeric ratio did not change when using DME or Et2O, but
the facial selectivity was almost lost when THF/HMPA
(hexamethylphosphoramide) was the solvent (entry 7, yield
75%, 11/12 ˆ 1.4:1). Although the yield decreased with LDA
as the base, the 1'-phenylseleno products were obtained in
excellent yields similar to those with LiHMDS, when
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A. Matsuda, S. Shuto et al.
FULL PAPER
Table 2. Synthesis of 1'a-vinyluridine derivatives by
transfer reaction of 14.[a]
a
radical atom-
additive (equiv)
elimination
method[b]
products yield [%]
1
2
3
4
5
6
7
8
none
A
A
A
B
B
B
B
B
19 ‡ 20
19 ‡ 20
19 ‡ 20
21
21
21
12
18
47
47
48
70
77
69
(nBu3Sn)2 (0.1)
(PhSe)2 (0.1)
none
(PhSe)2 (0.1)
(PhSe)2 (0.3)
(PhSe)2 (0.7)
(PhSe)2 (1.0)[c]
21
21
[a] A solution of 14 (and an additive) in benzene was irradiated with a high
pressure mercury lamp (300 W) with Pyrex filter at room temperature for
4 h (entry 8, for 24 h). [b] A: The radical atom-transfer cyclization product
was treated with H2O2 in aqueous THFat room temperature. B: The radical
atom-transfer cyclization product was successively treated with TBAF in
THF and with Ac2O/DMAP/Et3N in MeCN at room temperature. [c] After
24 h, a part of the starting material 14 remained was detected by 1H NMR
spectrum of the reaction mixture.
product formed by irradiation without an additive was treated
by method B, the 1'a-vinyl product was isolated in 47% yield
as the tri-O-acetate 21 (entry 4). The photoreaction in the
presence of 0.1equiv of (PhSe)2 and subsequent treatment by
method B gave 21 in 48% yield. When 0.3 or 0.7equiv of
(PhSe)2 was used as an additive in the photoreaction, the yield
increased (entry 6, yield 70%; entry 7, yield 77%). As far as
we know, this is the first example in which (PhSe)2 proved to
be an effective additive for radical atom-transfer cyclization
reactions. However, the use of 1.0equiv of (PhSe)2 resulted in
a slower reaction (entry 8).
Scheme 7. Radical reactions of 1'a-phenylselenouridine derivative 14 with
a vinylsilyl group at the 2'-hydroxyl under reductive conditions. a) NaBH4,
ˆ
CeCl3 ´ 7H2O, MeOH. b) Me2Si(CH CH2)Cl, DMAP, Et3N, toluene.
c) nBu3SnH or (TMS)3SiH, AIBN or V-70, benzene or CH2Cl2.
(3%). The stereochemistries of 16 and 17 were confirmed by
NOE experiments, as shown in Figure 1c and d.
These results suggest the reaction pathways summarized in
Scheme 8. The 5-exo cyclization of the anomeric radical A,
produced by UV irradiation of 14, gives the radical B
(Scheme 9). In the reaction without (PhSe)2, at least three
The introduction of a vinyl group by radical atom-transfer
cyclization: We next investigated the introduction of a vinyl
group at the 1'a-position of uridine by radical atom-transfer
cyclization[25] and subsequent elimination of the phenylseleno
group, which we recently developed.[12d] When the radical
atom-transfer cyclization reaction was performed by irradi-
ation of a solution of 14 in benzene with a high-pressure
mercury lamp through a Pyrex filter at room temperature, the
starting material 14 disappeared within 4 h. The product,
without purification, was immediately treated with aqueous
H2O2 in THF at room temperature (method A) or treated
successively with tetrabutylammonium fluoride (TBAF) in
THF and with Ac2O/DMAP/Et3N in MeCN at room tem-
perature (method B). The results are summarized in
Table 2. The photoreaction was first performed without
an additive, and the product was oxidatively eliminated
by method A to give the desired 1'a-vinyl product in 12%
yield as a mixture of 2'-O-silyl 20 and de-silylated 19
(entry 1).
The effect of additives on the photoreaction was next
examined. Addition of hexabutylditin [(nBu3Sn)2], which
proved effective in our previous study,[12d] did not work in this
system (entry 2). We found that when diphenyldiselenide
[(PhSe)2] was added, the yield of the 1'a-vinyl product
increased (entry 3, yield 47%). We also discovered that b-
elimination with TBAF (method B) was superior to the above
oxidative elimination with H2O2 (method A). When the
Scheme 8. Synthesis of 1'a-vinyluridine (22) by a photochemical radical
atom-transfer cyclization reaction. a) hn, additive, benzene. Method A: aq.
H2O2, THF. Method B: 1. TBAF, THF. 2. Ac2O, DMAP, Et3N, MeCN.
b) Et3N, MeOH.
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1'-Branched-Chain Sugar Pyrimidine Ribonucleosides
2332±2340
chemical radical atom-transfer cyclization with (PhSe)2 as an
additive and for oxidative elimination with H2O2 gave a
mixture of 19 and 20, which, without purification, was further
treated successively with saturated NH3 in MeOH and Ac2O/
DMAP/Et3N in MeCN to give 2'-O-Ac-3',5'-O-TIPDS-1'a-
vinyluridine (23) in 52% overall yield from 14. The 1'a-C-
vinyluridine derivative 23 was treated with 2,4,6-triisopropyl-
benzenesulfonyl chloride (TPSCl)/DMAP/Et3N in MeCN
followed by ammonolysis[26] to give the corresponding cyti-
dine derivative, which was isolated as the tetraacetate 24 in
78% yield. Removal of the acetyl groups of 24 with saturated
NH3 in MeOH afforded the 1'a-C-vinylcytidine (25).
Conclusion
We have successfully introduced a phenylseleno group at the
1'-position of the 2'-ketouridine derivative 8 by its enolization
with LiHMDS. Subsequent chemo- and stereoselective re-
duction of the 2'-keto moiety gave the sugar-protected 1'-
phenylselenouridine 13, which is a highly useful precursor for
the preparation of various 1'a-modified pyrimidine nucleo-
sides of biological interest. After introduction of a dimethyl-
vinylsilyl tether at the 2'-hydroxyl of 13, the photochemical
radical atom-transfer reaction with (PhSe)2 as an effective
additive, followed by elimination of the phenylseleno group
gave the protected 1'a-vinyluridines. 1'a-Vinyluridine (22)
and -cytidine (25) were successfully synthesized by using this
procedure. This study is the first example of functionalization
at the anomeric 1'-position of a nucleoside, starting from a
natural nucleoside, to produce a ribo-type 1'-modified nucleo-
side.
Scheme 9. A possible reaction mechanism for the radical atom-transfer
cyclization reaction with (PhSe)2 as an additive.
molecules, that is, the desired PhSe-transferred product 18,
the ring-enlarged radical C, and the tandem-cyclized radical
D, can be formed from B, which may explain the poorer yields
of the desired product 18. When (PhSe)2 is present, the 5-exo-
cyclized radical B is likely to be trapped by (PhSe)2; therefore
the side reactions producing the radicals C or D are inhibited
and the yield of the desired 18 increases. However, high
concentrations of (PhSe)2 may also trap the anomeric radical
A to give back the starting material 14, which competes with
the 5-exo-cyclization producing B. This may be why the atom-
transfer reaction (entry 8) proceeded so slowly when 1.0equiv
of (PhSe)2 was used.
Experimental Section
General: NMR Chemical shifts are reported in ppm downfield from TMS
and J values are given in hertz. The 1H NMR assignments reported for key
compounds[27] are in agreement with the COSY spectra. Thin layer
chromatography was done on Merck coated plate 60F254. Silica gel
chromatography was done on Merck silica gel 5715 or Kanto Chemical
silica gel 60N (neutral). Reactions were carried out under an argon
atmosphere.
Deuterium labeling experiment with 8: A solution of LiHMDS (1.0m in
THF, 1.05 mL, 1.05 mmol) was added dropwise to a solution of 8 (242 mg,
0.50 mmol) in THF (5.5 mL) at below 708C, and the mixture was stirred
at the same temperature for 1 h. After dropwise addition of a mixture of
CD3CO2D (120 mL) and CD3OD (120 mL), the resulting mixture was
warmed to room temperature. The whole was partitioned between AcOEt
and H2O, and the organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatography (hexane/
AcOEt 2:1) to give crude 8D as a white solid (233 mg, 96%) containing a
trace amount of an unknown compound, which may be the corresponding
a-isomer. The rate of deuterium incorporation at the 1'-positon was
determined as 54%, based on the 1H NMR spectrum of pure 8D
recrystallized from hexane/AcOEt. M.p. 175 ± 1808C (went yellow and
melted); 1H NMR (CDCl3, 270 MHz) d ˆ 8.15 (brs, D2O exchangeable,
1H), 7.14 (d, J ˆ 7.9 Hz, 1H), 5.75 (dd, J ˆ 7.9, 2.1 Hz, 1H), 5.05 (d, J ˆ
9.0 Hz, 1H), 4.98 (s, 0.46H), 4.13 (dd, J ˆ 12.6, 4.6 Hz, 1H), 4.13 (dd, J ˆ
12.6, 3.3 Hz, 1H), 3.93 (ddd, J ˆ 9.0, 4.6 Hz, 3.3, 1H), 1.13 ± 0.98 (m, 28H);
The synthesis of 1'a-vinyluridine and -cytidine: Removal of
the acetyl groups of 21 with Et3N/MeOH gave the target 1'a-
vinyluridine 22 in high yield. The corresponding cytidine
derivative 25 was synthesized as shown in Scheme 10.
Successive treatment of 14 under the conditions for photo-
‡
FAB-HRMS calcd for C21H36DN2O7Si2 486.2202; found 486.2197 [M‡H] .
Scheme 10. Synthesis of 1'a-vinylcytidine (25) by a photochemical radical
atom-transfer cyclization reaction. a) 1. hn, (PhSe)2, benzene; 2. bq. H2O2,
aq. THF; 3. NH3, MeOH; 4. Ac2O, DMAP, Et3N, MeCN. b) 1. TPSC1,
DMAP, Et3N, MeCN; 2. 25% NH4OH; 3. TBAF, THF; 4. Ac2O, DMAP,
Et3N, MeCN.
2'-O-Enol benzoate 10: A solution of LiHMDS (1.0m in THF, 1.05 mL,
1.05 mmol) was added dropwise to a solution of 8 (242 mg, 0.50 mmol) in
THF (5.5 mL) at below 708C, and the mixture was stirred at the same
temperature for 1 h. After dropwise addition of a solution of BzCl (122 mL,
1.05 mmol) in THF (1.5 mL), the resulting mixture was stirred at the same
Chem. Eur. J. 2001, 7, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0711-2337 $ 17.50+.50/0
2337

A. Matsuda, S. Shuto et al.
FULL PAPER
temperature for 1 h. AcOH (100 mL) was added, and the mixture was
warmed to room temperature. The mixture was partitioned between
AcOEt and H2O, and the organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column chroma-
tography (hexane/AcOEt 4:1, 3:1, 2:1, and 1:1) to give 10 as a white foam.
Yield: 214 mg, 73%; 1H NMR (CDCl3, 500 MHz) d ˆ 8.27 (brs, D2O
exchangeable, 1H), 8.06 (m, 2H), 7.61 (m, 1H), 7.46 (m, 2H), 7.38 (d, J ˆ
8.1 Hz, 1H), 5.77 (dd, J ˆ 8.1, 2.3 Hz, 1H), 5.66 (d, J ˆ 5.1 Hz, 1H), 4.58
(ddd, J ˆ 11.2, 4.8, 5.1 Hz, 1H), 4.19 (dd, J ˆ 11.2, 4.8 Hz, 1H), 3.97 (dd, J ˆ
11.2, 11.2 Hz, 1H), 1.12 ± 0.88 (m, 28H); 13C NMR (CDCl3, 125 MHz) d ˆ
163.54, 162.54, 147.41, 141.49, 136.30, 133.93, 130.28, 130.17, 128.63, 128.38,
126.53, 122.64, 103.28, 86.50, 75.36, 63.91, 17.57, 17.44, 17.40, 17.37, 16.87,
16.81, 16.78, 13.45, 13.42, 13.05, 12.34; FAB-HRMS calcd for C28H41N2O8Si2
28H; isopropyl Â4); NOE (400 MHz, CDCl3): irradiated H6, observed H5'
(1.1%), H3' (1.6%), H2' (0.2%); 13C NMR (CDCl3, 100 MHz) d ˆ 163.18,
148.98, 139.21, 138.53, 129.45, 128.81, 125.86, 106.59, 100.11, 80.16, 75.53,
68.55, 59.75, 17.34, 17.20, 16.98, 16.91, 16.79, 13.39, 13.19, 12.98, 12.62, 12.40;
‡
FAB-HRMS calcd for C27H43N2O7SeSi2 643.1774; found 643.1800 [M‡H] ;
elemental analysis calcd (%) for C27H42N2O7SeSi2 ´ H2O (659.8): C 49.15, H
6.72, N 4.25; found C 49.25, H 6.43, N 4.25.
1-[1-C-Phenylseleno-2-O-dimethylvinylsilyl-3,5-O-(1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl)-b-d-ribo-pentofuranosyl]uracil (14): A mixture of 13
(642 mg, 1.0 mmol), DMAP (25 mg, 0.20 mmol), Et3N (881 mL, 6.3 mmol),
and chlorodimethylvinylsilane (828 mL, 6.0 mmol) in toluene (5 mL) was
stirred at room temperature for 30 min. After addition of MeOH (0.5 mL)
at 08C, the resulting mixture was stirred at room temperature for 10 min
and partitioned between AcOEt and H2O. The organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (CHCl3/AcOEt 8:1 then 4:1) to give 14 as a white
foam. Yield: 705 mg, 97%; 1H NMR (CDCl3, 270 MHz) d ˆ 7.84 (brs, D2O
exchangeable, 1H), 7.51 (d, J ˆ 7.9 Hz, 1H), 7.35 ± 7.17 (m, 5H), 6.34 (dd,
J ˆ 20.4, 14.3 Hz, 1H), 6.08 (dd, J ˆ 14.3, 4.0 Hz, 1H), 5.90 (dd, J ˆ 20.4,
4.0 Hz, 1H), 5.13 (dd, J ˆ 7.9, 2.0 Hz, 1H), 5.06 (d, J ˆ 4.0 Hz, 1H), 4.34 (d,
J ˆ 9.2 Hz, 1H), 4.20 (d, J ˆ 13.8 Hz, 1H), 4.01 ± 3.93 (m, 2H), 1.08 ± 0.81
(m, 28H), 0.40 (s, 3H), 0.39 (s, 3H); 13C NMR (CDCl3, 100 MHz) d ˆ
163.22, 148.18, 139.62, 138.21, 137.28, 133.49, 129.29, 128.66, 126.17, 104.78,
99.51, 80.67, 77.39, 68.32, 58.71, 17.46, 17.32, 17.15, 17.08, 17.06, 16.91, 13.47,
13.05, 12.89, 12.73, 1.16, 1.22; FAB-HRMS calcd for C31H51N2O7SeSi3
‡
589.2402; found 589.2416 [M‡H] .
Introduction of a phenylseleno group at the 1'-position of 8 (General
procedure): A solution of MHMDS in THF (M ˆ Li and Na) or toluene
(M ˆ K) was added dropwise to a solution of 8 (242 mg, 0.50 mmol) in THF
(5.5 mL) at below 708C, and the mixture was stirred at the same
temperature for 1 h. After dropwise addition of a solution of PhSeCl
(192 mg, 1.0 mmol) in THF (1.5 mL), the resulting mixture was stirred at
the same temperature for 1 h. AcOH (ca. 150 mL) was added, and the
mixture was warmed to room temperature. The mixture was partitioned
between AcOEt and H2O, the organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column chroma-
tography (hexane/AcOEt 4:1, 3:1, 2:1, and 1:1) to give 11 (as a pale yellow
foam), a mixture of 12a and 12b (as a yellow solid) and 8 (as a white foam).
11: 1H NMR (CDCl3, 500 MHz) d ˆ 8.51 (d, J ˆ 8.3 Hz, 1H), 8.08 (brs, D2O
exchangeable, 1H), 7.55 (m, 2H), 7.42 (m, 1H), 7.36 (m, 2H), 5.79 (dd, J ˆ
8.3, 2.3 Hz, 1H), 4.95 (d, J ˆ 7.6 Hz, 1H), 4.03 ± 3.99 (m, 3H), 1.13 ± 1.00 (m,
28H); 13C NMR (CDCl3, 100 MHz) d ˆ 197.82, 162.53, 149.09, 143.17,
136.12, 122.99, 129.58, 125.27, 102.43, 96.34, 80.83, 71.47, 63.02, 17.41, 17.29,
17.25, 16.95, 16.89, 16.86, 16.77, 13.37, 13.07, 12.56, 12.51; FAB-HRMS calcd
‡
727.2170; found 727.2187 [M‡H] ; elemental analysis calcd (%) for
C31H50N2O7SeSi3 (726.0): C 51.29, H 6.94, N 3.86; found C 51.24, H 6.98,
N 3.85.
Radical reaction of 14 under reductive conditions: A solution of 14 (44 mg,
0.060 mmol), nBu3SnH or (TMS)3SiH (0.18 mmol), and AIBN (3 mg,
0.015 mmol) or V-70 (6 mg, 0.018 mmol) in benzene or CH2Cl2 (0.6 mL)
was stirred at 608C or at 08C. After 14 had disappeared, as shown by TLC,
the solvent was evaporated, and the residue was purified by column
chromatography (CHCl3/AcOEt 20:1, 10:1, 5:1 then 1:1) to give 15a, 16, 17,
and 18, respectively, in a pure form. 15a: 1H NMR (CDCl3, 500 MHz) d ˆ
9.05 (brs, 1H, D2O exchangeable, N3-H), 7.39 (d, J ˆ 8.1 Hz, 1H; H6), 6.11
‡
for C27H41N2O7SeSi2 641.1618; found 641.1615 [M‡H] ; elemental analysis
calcd (%) for C27H40N2O7SeSi2 (639.8): C 50.69, H 6.30, N 4.38: found: C
50.56, H 6.31, N 4.33.
Purification of 12a and 12b: a mixture of 12a and 12b (740 mg) was treated
with hot AcOEt/hexane to give pure 12b as white crystals (620 mg, M.p.
159.5 ± 160.58C). The filtrate was then evaporated and triturated with
AcOEt/hexane to give pure 12a as a white powder (30 mg). 12a: 1H NMR
(CDCl3, 500 MHz) d ˆ 8.27 (d, J ˆ 8.3 Hz, 1H), 8.08 (brs, D2O exchange-
able, 1H), 7.59 (m, 2H), 7.45 (m, 1H), 7.37 (m, 2H), 5.76 (dd, J ˆ 8.3 Hz, 1.2,
1H), 4.64 (d, J ˆ 9.1 Hz, 1H), 4.52 (ddd, J ˆ 9.1, 4.8, 3.0 Hz, 1H), 3.93 (dd,
J ˆ 12.7, 3.0 Hz, 1H), 3.67 (dd, J ˆ 12.7, 4.8 Hz, 1H), 1.13 ± 0.95 (m, 28H);
FAB-HRMS calcd for C27H41N2O7SeSi2: 641.1618; found 641.1661
ˆ
ˆ
(d, J ˆ 3.1 Hz, 1H; H1'), 6.03 ± 5.95 (m, 2H; CH CH2 and CH CH2), 5.75 ±
ˆ
5.67 (m, 1H; CH CH2), 5.71 (d, J ˆ 8.1 Hz, 1H; H5), 4.43 (dd, J ˆ 3.5,
3.1 Hz, 1H; H2'), 4.34 (dd, J ˆ 9.3, 3.5 Hz, 1H; H3'), 4.15 ± 4.09 (m, H5'a,
2H; H4'), 3.94 (dd, J ˆ 13.2, 2.3 Hz, 1H; H5'b), 1.10 ± 0.96 (m, 28H;
isopropyl Â4), 0.14 (s, 3H; SiCH3), 0.12 (s, 3H; SiCH3); 13C NMR (CDCl3,
125 MHz) d ˆ 163.37, 150.16, 141.83, 136.34, 133.99, 100.52, 85.74, 81.53,
72.70, 70.63, 59.69, 17.39, 17.29, 17.26, 17.14, 17.07, 17.03, 16.89, 13.57, 13.34,
13.03, 12.84, 12.71, 1.79, 1.84; FAB-HRMS calcd for C25H47N2O7Si3
‡
1
‡
[M‡H] . 12b: H NMR (CDCl3, 500 MHz) d ˆ 8.46 (brs, D2O exchange-
able, 1H; N3-H), 7.49 (m, 2H; o-SePh), 7.39 (m, 1H; p-SePh), 7.27 (m, 2H;
m-SePh), 6.95 (d, J ˆ 8.3 Hz, 1H; H6), 6.48 (s, D2O exchangeable, 1H;
2'OH), 5.35 (dd, J ˆ 8.3, 2.3 Hz, 1H; H5), 4.84 (d, J ˆ 7.8 Hz, 1H; H3'), 4.21
(dd, J ˆ 12.9 Hz, 7.0, 1H; H5'a), 4.06 ± 4.04 (m, 2H; H4', H5'b), 3.92 (s, D2O
exchangeable, 1H; O2'H), 1.20 ± 1.01 (m, 28H; isopropyl Â4); NOE
(400 MHz, CDCl3): irradiated H5', observed o-SePh (5.8%), H3' (6.6%);
13C NMR (CDCl3, 125 MHz) d ˆ 162.83, 150.36, 139.66, 138.58, 129.63,
128.84, 125.69, 103.52, 100.49, 100.14, 83.72, 75.64, 62.69, 17.51, 17.47, 17.45,
17.29, 17.01, 17.00, 16.79, 16.76, 13.41, 13.14, 12.82, 12.44; FAB-HRMS calcd
571.2692; found 571.2706 [M‡H] . 16: 1H NMR (CDCl3, 270 MHz) d ˆ
7.25 (brs, D2O exchangeable, 1H; N3-H), 4.95 (dd, J ˆ 8.6, 5.9 Hz, 1H;
H3'), 4.69 (d, J ˆ 5.9 Hz, 1H; H2'), 4.17 ± 4.06 (m, 2H; H5'a, H6), 3.98 (dd,
J ˆ 12.3, 3.0 Hz, 1H; H5'b), 3.68 (m, 1H; H4'), 2.79 (dd, J ˆ 16.5, 4.2 Hz,
1H; H5a), 2.39 (dd, J ˆ 16.5, 13.1 Hz, 1H; H5b), 2.31 (ddd, J ˆ 12.7, 8.6,
5.1 Hz, 1H; H7'a), 1.89 (dd, J ˆ 12.7, 8.6 Hz, 1H; H6'), 1.49 (ddd, J ˆ 12.7,
12.7, 10.5 Hz, 1H; H7'b), 1.14 ± 0.97 (m, 28H; isopropyl Â4), 0.39 (s, 3H;
SiCH3), 0.30 (s, 3H; SiCH3); NOE (400 MHz, CDCl3) irradiated H6',
observed H6 (3.5%), H4' (3.8%); FAB-HRMS calcd for C25H47N2O7Si3:
‡
571.2692; found 571.2702 [M‡H] . 17: 1H NMR (CDCl3, 270 MHz) d ˆ
‡
for C27H42N2O8SeSi2Na: 681.1543; found 681.1567 [M‡Na] .
8.25 (brs, D2O exchangeable, 1H; N3-H), 8.03 (d, J ˆ 8.3 Hz, 1H; H6), 5.69
(dd, J ˆ 8.3, 2.4 Hz, 1H; H5), 5.17 (d, J ˆ 3.3 Hz, 1H; H2'), 4.22 (d, J ˆ
13.7 Hz, 1H; H5'a), 4.17 (dd, J ˆ 9.4, 3.3 Hz, 1H; H3'), 4.00 (dd, J ˆ 9.4,
2.3 Hz, 1H; H4'), 3.93 (dd, J ˆ 13.7, 2.3 Hz, 1H; H5'b), 2.37 (q, J ˆ 7.3 Hz,
1H; H6'), 0.91 (d, J ˆ 7.3 Hz, 3H; H7'), 1.25 ± 0.81 (m, 28H; isopropyl Â4),
0.39 (s, 3H; SiCH3a), 0.26 (s, 3H; SiCH3b); NOE (400 MHz, CDCl3):
irradiated H6', observed H2' (2.4%); FAB-HRMS calcd for C25H47N2O7Si3
1-[1-C-Phenylseleno-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-b-d-
ribo-pentofuranosyl]uracil (13):
A mixture of CeCl3 ´ 7H2O (7.45 g,
20.0 mmol) and NaBH4 (454 mg, 12.0 mmol) in MeOH (40 mL) was stirred
at 708C for 1 h. A solution of 11 (6.40 g, 10.0 mmol) in MeOH (55 mL)
was added to the resulting solution, and the mixture was stirred at the same
temperature for 10 min. After addition of aqueous tartaric acid (5%,
10 mL), the mixture was warmed to room temperature and partitioned
between AcOEt and H2O. The organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column chroma-
tography (hexane/AcOEt 3:1) to give 13 as a white foam. Yield: 5.80 g,
‡
571.2692; found 571.2695 [M‡H] . For 18: 1H NMR (CDCl3, 270 MHz)
d ˆ 8.00 (d, J ˆ 8.5 Hz, 1H), 7.91 (brs, D2O exchangeable, 1H), 7.36 ± 7.22
(m; SePh), 5.70 (dd, J ˆ 8.5, 2.0 Hz, 1H), 5.03 (d, J ˆ 3.3 Hz, 1H), 4.24 (d,
J ˆ 13.6 Hz, 1H), 4.11 (dd, J ˆ 9.2, 3.3 Hz, 1H), 4.03 (dd, J ˆ 9.2, 2.0 Hz,
1H), 3.94 (dd, J ˆ 13.6, 2.0 Hz, 1H), 3.03 (dd, J ˆ 11.8, 7.3 Hz, 1H), 2.95 (dd,
J ˆ 11.8, 8.9 Hz, 1H), 2.76 (dd, J ˆ 8.9, 7.8 Hz, 1H), 1.08 ± 0.97 (m, 28H),
0.44 (s, 3H), 0.32 (s, 3H); FAB-HRMS calcd for C31H51N2O7SeSi3 727.2170;
1
90%; H NMR (CDCl3, 270 MHz) d ˆ 8.39 (brs, D2O exchangeable, 1H;
N3-H), 7.48 (m, 2H; o-SePh), 7.36 (m, 1H; p-SePh), 7.23 (m, 2H; m-SePh),
7.06 (d, J ˆ 8.6 Hz, 1H; H6), 5.20 (d, J ˆ 8.6 Hz, 1H; H5), 4.62 (dd, J ˆ 6.6,
2.0 Hz, 1H; H2'), 4.33 (ddd, J ˆ 8.6, 2.6, 2.6 Hz, 1H; H4'), 4.23 (dd, J ˆ 8.6,
6.6 Hz, 1H; H3'), 4.13 (dd, J ˆ 13.2, 2.6 Hz, 1H; H5'a), 4.11 (dd, J ˆ 13.2,
2.6 Hz, 1H; H5'b), 3.71 (brs, D2O exchangeable, 1H; 2'OH), 1.08 ± 0.85 (m,
‡
found 727.2159 [M‡H] .
1-[2-O-Dimethylvinylsilyl-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-di-
yl)-b-d-ribo-pentofuranosyl]uracil (15b): Compound 15b was obtained as
2338
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0711-2338 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 11

1'-Branched-Chain Sugar Pyrimidine Ribonucleosides
2332±2340
a white foam from 1-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-b-d-
ribofuranosyl]uracil (244 mg, 0.50 mmol, as a foam) as described for the
synthesis of 14, after purification by column chromatography (hexane/
97.61, 83.56, 74.45, 68.65, 59.43; FAB-HRMS calcd for C11H15N2O6
‡
271.0930; found 271.0916 [M‡H] ; elemental analysis calcd (%) for
C11H14N2O6 ´ 0.2H2O (273.9): C 48.25, H,5.30, N 10.23; found C 48.04, H
1
AcOEt 4:1). Yield: 285 mg, quant.; H NMR (CDCl3, 270 MHz) d ˆ 8.83
5.31, N 10.10.
(brs, D2O exchangeable, 1H; N3-H), 7.95 (d, J ˆ 7.9 Hz, 1H; H6), 6.19 (dd,
1-[2-O-Acetyl-1-C-ethenyl-3,5,-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-di-
yl)-b-d-ribo-pentofuranosyl]uracil (23): A stirring solution of 14 (1.02 g,
1.4 mmol) and (PhSe)2 (306 mg, 0.98 mmol) in benzene (14 mL) was
irradiated with a high-pressure mercury lamp (300 W) at room temperature
for 4 h, and then the solvent was evaporated. A mixture of the residue and
H2O2 (30% in H2O, 630 mL, 5.6 mmol) in THF (14 mL) was stirred at room
temperature for 15 min, and then aqueous saturated Na2S2O3 (1 mL) was
added. The resulting mixture was partitioned between AcOEt and H2O,
and the organic layer was washed with brine, dried (Na2SO4), and
evaporated. Saturated NH3 in MeOH (10 mL) was added to a solution of
the residue in MeOH (5 mL), and the mixture was stirred at room
temperature for 1 h. After the solvent was evaporated, a mixture of the
residue, DMAP (17 mg), Et3N (390 mL, 2.8 mmol), and Ac2O (264 mL,
2.8 mmol) was stirred at room temperature for 2.5 h. After addition of
MeOH (0.3 mL), the resulting mixture was partitioned between AcOEt
and H2O, and the organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatography (hexane/
AcOEt 3:1) to give 23 as a pale brown foam. Yield: 402 mg, 52%; 1H NMR
(CDCl3, 270 MHz) d ˆ 8.40 (brs, D2O exchangeable, 1H), 7.97 (d, J ˆ
9.2 Hz, 1H), 6.43 (dd, J ˆ 17.2, 10.6 Hz, 1H), 6.17 (d, J ˆ 4.6 Hz, 1H),
5.68 (d, J ˆ 9.2 Hz, 1H), 5.53 (d, J ˆ 17.2 Hz, 1H), 5.33 (d, J ˆ 10.6 Hz, 1H),
4.33 (dd, J ˆ 9.9, 4.6 Hz, 1H), 4.26 (d, J ˆ 13.2 Hz, 1H), 4.08 (brd, J ˆ
9.9 Hz, 1H), 3.98 (dd, J ˆ 13.2, 2.0 Hz, 1H), 2.12 (s, 3H), 1.08 ± 0.92 (m,
28H); FAB-HRMS calcd for C25H43N2O8Si2 555.2558; found 555.2557
ˆ
ˆ
J ˆ 19.8, 15.2 Hz, 1H; CH CH2), 6.03 (dd, J ˆ 15.2, 4.6 Hz, 1H; CH CH2),
ˆ
5.85 (dd, J ˆ 19.8, 4.6 Hz, 1H; CH CH2), 5.66 (dd, J ˆ 7.9, 2.0 Hz, 1H; H5),
5.61 (s, 1H; H1'), 4.25 (dd, J ˆ 13.9 Hz, ca. 0, 1H; H5'a), 4.23 ± 4.14 (m, 2H;
H2', H4'), 4.08 (dd, J ˆ 9.2, 4.0 Hz, 1H; H3'), 3.97 (dd, J ˆ 13.9, 2.0 Hz, 1H;
H5'b), 1.10 ± 1.00 (m, 28H; isopropyl Â4), 0.28 (s, 3H; SiCH3), 0.27 (s, 3H;
SiCH3).
Radical atom-transfer cyclization and subsequent elimination:
Method A: A stirring solution of 14 (44 mg, 0.060 mmol) and an additive
(0.006 mmol) in benzene (0.6 mL) was irradiated with a high-pressure
mercury lamp (300 W) at room temperature for 4 h. The solvent was
evaporated, and a mixture of the residue and H2O2 (30% in H2O, 27 mL,
0.24 mmol) in THF (7 mL) was stirred at room temperature for 35 min.
After addition of aqueous saturated Na2S2O3 (100 mL), the mixture was
partitioned between AcOEt and H2O. The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was purified by column
chromatography (CHCl3/AcOEt 2:1, 1:1, 1:2, and AcOEt) to give a mixture
of 19 and 20 (19/20 ˆ 1:5 based on the 1H NMR). 1H NMR (CDCl3,
270 MHz) of the mixture. For 19, d ˆ 8.45 (brs, D2O exchangeable, 1H),
7.99 (d, J ˆ 8.6 Hz, 1H), 6.11 (dd, J ˆ 17.2, 10.6 Hz, 1H), 5.68 (dd, J ˆ 8.6,
2.0 Hz, 1H), 5.52 (dd, J ˆ 17.2, 1.3 Hz, 1H), 5.38 (dd, J ˆ 10.6, 1.3 Hz, 1H),
4.80 (d, J ˆ 4.0 Hz, 1H), 4.29 (dd, J ˆ 9.2, 4.6 Hz, 1H), 4.25 (d, J ˆ 13.2 Hz,
1H), 4.16 (d, J ˆ 9.2 Hz, 1H), 3.99 (dd, J ˆ 13.2, 2.6 Hz, 1H), 2.79 (brs, 1H),
1.08 ± 0.98 (m, 28H). For 20, d ˆ 9.55 (brs, D2O exchangeable, 1H), 8.05 (d,
J ˆ 7.9 Hz, 1H), 6.52 (dd, J ˆ 17.2, 10.6 Hz, 1H), 5.70 (dd, J ˆ 7.9, 2.0 Hz,
1H), 5.40 (d, J ˆ 17.2 Hz, 1H), 5.29 (d, J ˆ 10.6 Hz, 1H), 5.04 (d, J ˆ 2.6 Hz,
1H), 4.26 (dd, J ˆ 13.9, 0.7 Hz, 1H), 4.16 ± 4.15 (m, 2H), 3.96 (dd, J ˆ 13.9,
2.0 Hz, 1H), 3.72 (brs, D2O exchangeable, 1H), 1.08 ± 0.96 (m, 28H), 0.24
(s, 3H), 0.20 (s 3H); FAB-HRMS of the mixture: calcd for C23H41N2O7Si2
‡
[M‡H] .
N4-Acetyl-1-(2,3,5-tri-O-acetyl-1-C-ethenyl-b-d-ribo-pentofuranosyl)cyto-
sine (24): A mixture of 23 (361 mg, 0.65 mmol), TPSCl (395 mg, 1.3 mmol),
DMAP (159 mg, 1.3 mmol), and Et3N (182 mL, 1.3 mmol) in MeCN (6 mL)
was stirred at room temperature for 5 h. After addition of NH3 (25% in
H2O, 6 mL), the resulting mixture was stirred at room temperature for 2.5 h
and then partitioned between AcOEt and H2O, and the organic layer was
washed with brine, dried (Na2SO4), and evaporated. A mixture of the
residue and TBAF (1.3 mL, 1.3 mmol, 1m) in THF (4 mL) was stirred at
room temperature for 1 h, and then the solvent was evaporated. A mixture
of the residue, DMAP (16 mg), Et3N (906 mL, 6.5 mmol), and Ac2O
(613 mL, 6.5 mmol) in MeCN (6 mL) was stirred at room temperature for
12 h. After addition of MeOH (0.3 mL), the resulting mixture was
partitioned between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (CHCl3, CHCl3/MeOH 20:1 then 10:1) to give 24
as a white foam. Yield: 200 mg, 78%; 1H NMR (CDCl3, 400 MHz) d ˆ 9.49
(brs, D2O exchangeable, 1H), 8.20 (d, J ˆ 7.7 Hz, 1H), 7.40 (d, J ˆ 7.7 Hz,
1H), 6.47 (dd, J ˆ 17.1, 10.8 Hz, 1H), 6.32 (d, J ˆ 4.8 Hz, 1H), 5.51 (d, J ˆ
17.1 Hz, 1H), 5.33 (d, J ˆ 10.8 Hz, 1H), 5.23 (dd, J ˆ 7.7, 4.8 Hz, 1H), 4.50
(m, 1H), 4.39 (dd, J ˆ 13.0, 2.4 Hz, 1H), 4.29 (dd, J ˆ 13.0, 3.7 Hz, 1H), 2.27,
2.13 (each s, each 3H), 2.07 (s, 3H), 2.02 (s, 3H); FAB-HRMS calcd for
‡
513.2452; found 513.2447 ([M‡H] for 19); calcd for C25H47N2O8Si3
‡
587.2640; found 587.2639 ([M‡H] for 20).
Method B: A stirring solution of 14 (1.02 g, 1.4 mmol) and (PhSe)2 (0 ±
1.4 mmol) in benzene (14 mL) was irradiated with a high-pressure mercury
lamp (300 W) at room temperature for 4 h (Table 2 entry 8, 24 h). The
solvent was evaporated, and a mixture of the residue and TBAF (1.0m in
THF, 7.0 mL, 7.0 mmol) was stirred at room temperature for 1 h. After the
solvent was evaporated,
a mixture of the residue, DMAP (32 mg,
0.26 mmol), Et3N (1.95 mL, 14 mmol), and Ac2O (1.32 mL, 14 mmol) in
MeCN (10 mL) was stirred at room temperature for 70 min. After addition
of MeOH (0.5 mL), the resulting solution was partitioned between AcOEt
and H2O. The organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatography (hexane/
AcOEt 1:1, 1:2, then 1:4) to give 21 as a white foam. 1H NMR (CDCl3,
270 MHz) d ˆ 8.25 (brs, D2O exchangeable, 1H), 7.78 (d, J ˆ 8.6 Hz, 1H),
6.28 (d, J ˆ 4.6 Hz, 1H), 6.26 (dd, J ˆ 17.2, 11.2 Hz, 1H), 5.70 (dd, J ˆ
8.6 Hz, ca. 0, 1H), 5.53 (dd, J ˆ 17.2, 1.3 Hz, 1H), 5.37 (dd, J ˆ 11.2,
1.3 Hz, 1H), 5.33 (dd, J ˆ 7.3, 4.6 Hz, 1H), 4.49 (m, 1H), 4.38 (dd, J ˆ 12.4,
2.6 Hz, 1H), 4.27 (dd, J ˆ 12.4, 4.0 Hz, 1H), 2.13 (s, 3H), 2.06 (s, 3H), 2.05
(s, 3H); 13C NMR (CDCl3, 100 MHz) d ˆ 170.03, 169.22, 168.63, 162.75,
149.62, 139.49, 131.78, 118.00, 101.61, 97.36, 79.81, 74.29, 69.76, 61.75, 20.79,
20.59, 20.47; FAB-HRMS calcd for C17H21N2O9: 397.1247; found 397.1252
‡
C19H24N3O9 438.1512; found 438.1487 [M‡H] .
1-(1-C-Ethenyl-b-d-ribo-pentofuranosyl)cytosine (25): Saturated NH3 in
MeOH (2.5 mL) was added to a solution of 24 (198 mg, 0.5 mmol) in
MeOH (3 mL) at 08C, and the resulting mixture was stirred at the same
temperature for 30 min and at room temperature for 15 h. The solvent was
evaporated, and the residue was purified by column chromatography
(CHCl3/MeOH 5:1, then 3:1) to give a solid. This solid was dissolved in
H2O, and the resulting solution was freeze-dried to give 25 as a white
cotton. Yield: 76 mg, 80%; 1H NMR ([D6]DMSO, 400 MHz) d ˆ 8.00 (d,
J ˆ 7.3 Hz, 1H, H6), 7.08 (brs, D2O exchangeable, 1H; NH4), 7.02 (brs,
‡
[M‡H] ; elemental analysis calcd (%) for C17H20N2O9 ´ 0.8H2O (410.8): C
49.71, H 5.30, N 6.82; found C 49.67, H 5.02, N 6.77.
1-(1-C-Ethenyl-b-d-ribo-pentofuranosyl)uracil (22):
A mixture of 21
(198 mg, 0.50 mmol), Et3N (2 mL, 15 mmol), and MeOH (3 mL) was
stirred at room temperature for 90 h. The solvent was evaporated, and the
residue was purified by column chromatography (CHCl3/MeOH 15:1, 10:1
then 5:1) to give a solid. The solid was dissolved in H2O, which was freeze-
ˆ
D2O exchangeable, 1H; NH4), 6.43 (dd, J ˆ 17.2, 10.6 Hz, 1H; CH CH2),
dried to give 22 as
a
white cotton. Yield: 84 mg, 62%; 1H NMR
5.65 (d, J ˆ 7.3 Hz, 1H; H5), 5.55 (brs, 1H; OH), 5.07 (dd, J ˆ 10.6, 1.8 Hz,
ˆ
ˆ
([D6]DMSO, 400 MHz) d ˆ 11.13 (brs, D2O exchangeable, 1H; N3-H),
1H; CH CH2), 5.04 (dd, J ˆ 17.2, 1.8 Hz, 1H; CH CH2), 4.88 (brs, total
2H; OH), 4.53 (d', J ˆ 4.0 Hz, 1H; H2), 3.95 (m, 1H; H4'), 3.86 (dd, J ˆ 5.9,
4.0 Hz, 1H; H3'), 3.61 (dd, J ˆ 11.9, 3.3 Hz, 1H; H5'a), 3.45 (dd, J ˆ 11.9,
4.0 Hz, 1H; H5'b); 13C NMR ([D6]DMSO, 100 MHz) d ˆ 165.62, 155.57,
141.35, 135.95, 114.59, 97.64, 92.78, 84.38, 75.44, 69.78, 60.21; FAB-HRMS
ˆ
8.08 (d, J ˆ 8.2 Hz, 1H; H6), 6.40 (dd, J ˆ 17.5, 10.6 Hz, 1H; CH CH2), 5.51
(d, J ˆ 4.9 Hz, 1H; 2'OH), 5.50 (d, J ˆ 8.2 Hz, 1H; H5), 5.18 (dd, J ˆ 17.5,
ˆ
ˆ
1.3 Hz, 1H; CH CH2), 5.18 (dd, J ˆ 10.6, 1.3 Hz, 1H; CH CH2), 4.98 (t,
J ˆ 5.5 Hz, 1H; 5'-OH), 4.87 (d, J ˆ 6.6 Hz, 1H; 3'-OH), 4.63 (dd, J ˆ 4.9,
4.5 Hz, 1H; H2'), 3.95 ± 3.84 (m, H4', 2H; H3'), 3.73 (ddd, J ˆ 12.5, 5.5,
2.3 Hz, 1H; H5'a), 3.50 (ddd, J ˆ 12.5, 5.5, 4.6 Hz, 1H; H5'b); 13C NMR
([D6]DMSO, 100 MHz) d ˆ 163.45, 150.32, 140.64, 134.77, 115.68, 99.90,
‡
calcd for C11H16N3O5 270.1090; found 271.1095 [M‡H] ; elemental analysis
calcd (%) for C11H15N3O5 ´ 0.8H2O (283.7): C 46.58, H 5.90, N 14.81; found
C 46.35, H 5.46, N 14.85.
Chem. Eur. J. 2001, 7, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0711-2339 $ 17.50+.50/0
2339

A. Matsuda, S. Shuto et al.
FULL PAPER
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Acknowledgement
This investigation was supported in part by a grant from the Ministry of
Education, Science, Sports, and Culture of Japan. We are grateful to H.
Matsumoto, A. Maeda, S. Oka, and N. Hazama (Center for Instrumental
Analysis, Hokkaido University) for technical assistance with NMR, MS,
and elemental analyses.
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[20] When 3',5'-bis-O-TBS-2'-ketouridine was treated under conditions
identical to those in entry 3, it gave a mixture of 1'a- and 1'b-
phenylseleno products in a ratio of about 1:1 in 56% yield. Although
we also tried to use 3',5'-O-di-tert-butylsilene-2'-ketouridine as the
substrate, it was too unstable to be obtained in pure form.
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presence of an excess of LiHMDS, since the substrate 8 was obtained
in 90% yield when 11 was treated again with LiHMDS (4equiv) at
<
708C in THF.
[22] Introduction of carbon substituents at the 1'-position via the enolate 9
was examined, but it was unsuccessful.
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which the corresponding arabino- and ribo-type products were obtained
in a ratio of 1:5 in 87% yield: a) Y. Yoshimura, T. Ueda, A. Matsuda,
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Received: October 20, 2000 [F2813]
2340
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0947-6539/01/0711-2340 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 11