Nucleosides and Nucleotides. 163. Synthesis of 3′-β-Branched Uridine Derivatives via Intramolecular Reformatsky-Type Reaction Promoted by Samarium Diiodide

Article abstract of DOI:10.1021/jo961665f

A novel efficient method for the synthesis of 3′-β-branched uridines starting from uridine was developed, in which a SmI₂-promoted intramolecular Reformatsky-type reaction was effectively used. 5′-O-(Bromoacetyl)-3′-ketouridine derivatives 12, 26, and 27 were synthesized from uridine and were subjected to an intramolecular Reformatsky-type reaction. When 12, 26, and 27 were treated with 2.0 equiv of SmI₂ in THF at -78°C, intramolecular carbon-carbon bond formation at the 3′-β-position proceeded smoothly to give the corresponding 3′,5′-lactones 14, 28, and 29 in high yields, respectively. Treatment of 28 with NH₃/MeOH gave the 3′-β-branched uridine derivative 32 quantitatively, which was then deprotected to give 3′-C-(carbamoylmethyl)uridine (33).

Full text of DOI:10.1021/jo961665f

1368
J . Org. Chem. 1997, 62, 1368-1375
Nu cleosid es a n d Nu cleotid es. 163. Syn th esis of 3′-â-Br a n ch ed
Ur id in e Der iva tives via In tr a m olecu la r Refor m a tsk y-Typ e
Rea ction P r om oted by Sa m a r iu m Diiod id e1
Satoshi Ichikawa, Satoshi Shuto, Noriaki Minakawa, and Akira Matsuda*
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, J apan
Received August 29, 1996X
A novel efficient method for the synthesis of 3′-â-branched uridines starting from uridine was
developed, in which a SmI2-promoted intramolecular Reformatsky-type reaction was effectively
used. 5′-O-(Bromoacetyl)-3′-ketouridine derivatives 12, 26, and 27 were synthesized from uridine
and were subjected to an intramolecular Reformatsky-type reaction. When 12, 26, and 27 were
treated with 2.0 equiv of SmI2 in THF at -78 °C, intramolecular carbon-carbon bond formation at
the 3′-â-position proceeded smoothly to give the corresponding 3′,5′-lactones 14, 28, and 29 in high
yields, respectively. Treatment of 28 with NH3/MeOH gave the 3′-â-branched uridine derivative
32 quantitatively, which was then deprotected to give 3′-C-(carbamoylmethyl)uridine (33).
In tr od u ction
DAC, 2)2v-z were potent antitumor nucleosides which
significantly inhibited the growth of various human
tumor cells both in vitro and in vivo.
Considerable attention has been focused on branched-
chain sugar nucleosides because of their biological im-
portance. We recently developed stereoselective syn-
thetic methods for 2′-branched-chain sugar nucleosides
and have prepared a variety of 2′-modified nucleoside
analogs.2 We found that 1-(2-deoxy-2-methylene-â-D-
erythro-pentofuranosyl)cytosine (DMDC, 1)2r-u and 1-(2-
C-cyano-2-deoxy-â-D-arabino-pentofuranosyl)cytosine (CN-
Although there have also been several studies on 3′-
branched-chain sugar nucleosides,3 only a few 3′-branched
ribonucleoside analogs (Figure 1, I), with both a hydroxyl
group at the 3′-R-position and a carbon-substituent at the
3′-â-position, have been reported,3a,m,n and their biological
activities have not been investigated in detail. This may
be because efficient synthetic methods for preparing
these 3′-â-branched ribonucleoside analogs have not been
developed. However, it is important to investigate the
biological effects of 3′-branched ribonucleosides, which
may have efficient antitumor and/or antiviral activity,
like 2′-branched-chain sugar nucleosides. On the basis
of these results and considerations, we recently began a
synthetic study of 3′-â-branched ribonucleoside analogs
and found that 1-(3-C-ethynyl-â-D-ribo-pentofuranosyl)-
uracil (EUrd, 3) has a remarkable antitumor activity both
in vitro and in vivo.4
* Author to whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) For part 162 in the series, see: Ueno, Y.; Ogawa, A.; Nakagawa,
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3, 173-182. (b) Ueda, T.; Shuto, S.; Satoh, M.; Inoue, H. Nucleosides
Nucleotides 1985, 4, 401-409. (c) Matsuda, A.; Itoh, H.; Takenuki, K.;
Sasaki, T.; Ueda, T. Chem. Pharm. Bull. 1988, 36, 945-953. (d)
Matsuda, A.; Satoh, M.; Nakashima, H.; Yamamoto, N.; Ueda. T.
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ra, Y.; Takenuki, K. Nucleosides Nucleotides 1989, 8, 743-752. (f)
Takenuki, K.; Itoh, H.; Matsuda, A.; Ueda. T. Chem. Pharm. Bull. 1990,
38, 2947-2952. (g) Matsuda, A.; Takenuki, K.; Sasaki, T.;Ueda. T. J .
Med. Chem. 1991, 34, 234-239. (h) Yoshimura, Y.; Iino, T.; Matsuda.
A. Tetrahedron Lett. 1991, 32, 6003-6006. (i) Matsuda, A.; Azuma,
A.; Nakajima, A.; Takenuki, K.; Dan, A.; Iino, T.; Yoshimura, Y.;
Minakawa, N.; Tanaka, M.; Sasaki. T. In Nucleosides and Nucleotides
as Antitumor and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.;
Plenum Press: New York, 1993; pp 1-22. (i) Kakefuda, A.; Yoshimura,
Y.; Sasaki, T.; Matsuda. A. Tetrahedron 1993, 49, 8513-8528. (j)
Awano, H.; Shuto, S.; Baba, M.; Kira, T.; Shigeta, S.; Matsuda, A.
Bioorg. Med. Chem. Lett. 1994, 4, 367-370. (k) Hassan A. E. A.; Shuto,
S.; Matsuda. A. Tetrahedron 1994, 50, 689-700. (l) Hassan, A. E. A.;
Shuto, S.; Matsuda, A. Nucleosides Nucleotides 1994, 13, 197-211.
(m) Iino, T.; Yoshimura, Y.; Matsuda. A. Tetrahedron 1994, 50, 10397-
10406. (n) Kakefuda, A.; Shuto, S.; Nagahata, T.; Seki, J .; Sasaki, T.;
Matsuda. A. Tetrahedron 1994, 50, 10167-10182. (o) Iino, T.; Shuto,
S.; Matsuda, A. Nucleosides Nucleotides 1996, 15, 169-181. (p) Awano,
H.; Shuto, S.; Miyashita, T.; Ashida, M.; Machida, M.; Kira, T.; Shigeta,
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(q) Hassan, A. E. A.; Nishizono, N.; Minakawa, N.; Shuto, S.; Matsuda,
A. J . Org. Chem. 1996, 61, 6261-6267. (r) Takenuki, K.; Matsuda, A.;
Ueda, T.; Sasaki, T.; Fujii, A.; Yamagami, K. J . Med. Chem. 1988, 31,
1063-1064. (s) Matsuda, A.; Takenuki, K.; Tanaka, M.; Sasaki, T.;
Ueda, T. J . Med. Chem. 1991, 34, 812-819. (t) Yamagami, K.; Fujii,
A.; Arita, M.; Okumoto, T.; Sakata, S.; Matsuda, A.; Ueda, T. Cancer
Res. 1991, 51, 2319-2323. (u) Ono, T.; Fujii, A.; Yamagami, K.; Hosoya,
M.; Okumoto, T.; Sakata, S.; Matsuda, A.; Sasaki, T. Biochem.
Pharmacol. 1996, 52, 1279-1285. (v) Matsuda, A.; Nakajima, Y.;
Azuma, A.; Tanaka, M.; Sasaki, T. J . Med. Chem. 1991, 34, 2917-
2919. (w) Azuma, A.; Nakajima, Y.; Nishizono, N.; Minakawa, N.;
Suzuki, M.; Hanaoka, K.; Kobayashi, T.; Tanaka, M.; Sasaki, T.;
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Matsuda, A.; Terao, T.; Sasaki., T. Cancer Lett. 1992, 64, 67-74. (y)
Azuma, A.; Hanaoka, K.; Kurihara, A.; Kobayashi, T.; Miyauchi, S.;
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38, 3391-3397. (z) Matsuda, A.; Azuma, A. Nucleosides Nucleotides
1995, 14, 461-471.
It has been recognized that addition reactions of carbon
nucleophiles to 3′-keto nucleosides proceed with high
stereoselectivity from the R-face to give the corresponding
3′-R-branched xylonucleoside analogs.3c,e Accordingly, we
synthesized EUrd via glycosylation after constructing the
corresponding 3-ethynyl sugar from D-xylose,4 which
(3) For examples: (a) Nutt, R. F.; Dickinson, M. J .; Holly, F. W.;
Walton, E. J . Org. Chem. 1968, 33, 1789-1795. (b) Shuto, S.; Iwano,
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Hayakawa, H.; Tanaka, J .; Itoh, N.; Nakajima, M.; Miyasaka, T.;
Yamaguchi, K.; Iitaka, Y. Chem. Pharm. Bull. 1987, 35, 2605-2608.
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47, 1727-1736. (e) Bender, S. L.; Moffett, K. K. J . Org. Chem. 1992,
57, 1646-1647. (f) Valazquez, S.; San-Felix, A.; Perez-Perez, M. J .;
Balzarini, J .; De Clercq, E.; Camarasa, M. J . J . Med. Chem. 1993, 36,
3230-3239. (g) Lee, K.; Wiemer, D. F. J . Org. Chem. 1993, 58, 7808-
7812. (h) J orgensen, P. N.; Stein, P. C.; Wengel, J . J . Am. Chem. Soc.
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Hossain, N.; Plavec, J .; Chattopadhyaya, J . Tetrahedron 1994, 50,
4167-4178. (k) J ohnson, C. R.; Rhumralkar, D. R.; De Clercq, E.
Nucleosides Nucleotides 1995, 14, 185-194. (l) Becouarn, S.; Szernecki,
S.; Valery, J .-M. Tetrahedron Lett. 1995, 36, 873-876. (m) J ung, P.
M. J .; Burger, A.; Biellmann, J .-F. Tetrahedron Lett. 1995, 36, 1031-
1034. (n) Auguste, S. P.; Young, D. W. J . Chem. Soc., Perkin Trans. 1
1995, 395-404.
(4) (a) Matsuda, A.; Hattori, H.; Tanaka, M.; Sasaki, T. Bioorg. Med.
Chem. Lett. 1996, 6, 1887-1892. (b) Tabata, S.; Tanaka, M.; Matsuda,
A.; Fukushima, M.; Sasaki, T. Oncol. Rep. 1996, 3, 1029-1034. (c)
Hattori, H.; Tanaka, M.; Fukushima, M.; Sasaki, T.; Matsuda, A. J .
Med. Chem. 1996, 39, 5005-5011.
S0022-3263(96)01665-9 CCC: $14.00 © 1997 American Chemical Society

SmI2-Promoted Intramolecular Reformatsky-Type Reaction
J . Org. Chem., Vol. 62, No. 5, 1997 1369
in Barbier-type reactions with which highly functional-
ized five- and six-membered carbocycles can be rapidly
constructed in a stereocontrolled fashion.6,9
These results prompted us to explore a new method
for producing 3′-â-branched ribonucleoside analogs via
the SmI2-promoted Reformatsky- or Barbier-type reac-
tions of 3′-keto-nucleoside derivatives. 3′-Keto-nucleo-
sides are known to be unstable, especially under basic
conditions.3e We expected that SmI2 could be effectively
used in a carbon-carbon bond formation reaction with
3′-keto-nucleoside derivatives, since it promotes reactions
under homogeneous neutral conditions. Our synthetic
strategy is outlined in Scheme 1. If the Reformatsky-
type reaction of 5′-O-(bromoacetyl)-3′-keto-nucleosides
(II) or the Barbier-type reactions of 5′-O-(bromopro-
panoyl)- or 5′-O-[(bromomethyl)dimethylsilyl]-3′-keto-
nucleosides (III or IV, respectively) with SmI2 proceed
as we expect, these would give the corresponding 3′,5′-
ring-closure products, V, VI, or VII. Subsequent ring-
cleavage would give the desired 3′-â-branched ribonucle-
oside analogs I.
F igu r e 1. Structures of branched-chain sugar nucleosides
synthesized by us.
needed rather long reaction steps. Therefore, to examine
the biological effects of various 3′-branched ribonucleoside
analogs, the development of more straightforward meth-
ods for their preparation is needed. In this paper, we
describe a novel synthetic method for 3′-â-branched
uridines starting from uridine, using the intramolecular
SmI2-promoted Reformatsky-type reaction as a key step.
Intramolecular Reformatsky-type reactions of haloac-
etates derived from R- or â-hydroxy ketones and alde-
hydes can be used for stereoselective intramolecular
additions to carbonyls to give the corresponding hydroxy
lactones. Intramolecular Barbier-type reactions of ha-
loalkyl ketones or aldehydes are also among the simplest
approaches to the formation of hydroxy carbocyclic ring
structures. However, only limited success has been
realized with both reactions due to low yields and/or
inefficient stereoselectivity, when the reactions have been
performed with zinc (for Reformatsky-type reaction),5 and
lithium or magnesium (for Barbier-type reaction)6 as
reductants. Over the past decade, it has been shown that
samarium diiodide (SmI2) can be used as an efficient
electron-transfer reagent in a variety of transformations
in organic chemistry due to its functional- and stereo-
selectivity.7 This reagent can promote organic reactions
that are difficult to accomplish by any other available
methodologies.7 It has recently been reported that SmI2
also promotes intramolecular Reformatsky-type reactions
to produce medium- and large-ring lactones,8 as well as
â-hydroxy six-membered-lactones as acyclic syn 1,3-diol
equivalents via 1,3-asymmetric induction.5 These reac-
tions were unsuccessful when zinc was used as a pro-
moter.5,8 In addition to serving as a useful replacement
for zinc in Reformatsky-type reactions, SmI2 also provides
advantages over lithium or magnesium as the reductant
Resu lts a n d Discu ssion
First, we used 4-ethoxy-2(1H)-pyrimidone riboside (5)
as a substrate for derivatization: the 4-ethoxy-2-pyrimi-
done moiety is inert under various reaction conditions
compared to the uracil moiety of uridine itself, since it
lacks both the acidic 3-NH and the reactive enone-system
of uracil, and can be converted to either a uracil or
cytosine residue after modification of the sugar moiety.
Compound 5 was conveniently prepared from uridine (4)
using the Mitsunobu reaction. One-pot treatment of
uridine with Ac2O/Et3N/DMAP in MeCN and then with
Ph3P/diethyl azodicarboxylate (DEAD)/EtOH in THF,
followed by removal of the acetyl groups of the sugar
moiety with NaOEt in EtOH, gave 5 in 93% yield. This
method provided 5 in high yield (Scheme 2) and was
clearly superior to the previous method via a 4-chloro-
pyrimidone riboside derivative.2c After the 5′-hydroxyl
of 5 was selectively protected by a dimethoxytrityl
(DMTr) group, it was treated with tert-butyldimethylsilyl
chloride (TBSCl) in pyridine to give the 2′-O-TBS deriva-
tive 7 and the 3′-O-TBS derivative 8 in yields of 51% and
19%, respectively. PDC oxidation of 7 in CH2Cl2 gave
the corresponding ketone 9. The 5′-O-DMTr group was
10
selectively removed by treating 9 with ZnBr2 in CH2Cl2
to give 5′-hydroxy derivative 10, which was too unstable
to be isolated. Therefore, derivative 10 was used in the
next reaction without purification. Crude 10 was treated
with bromoacetyl bromide in the presence of 2,6-lutidine
in CH2Cl2 at -78 °C to give 5′-O-bromoacetyl derivative
12, the substrate of the intramolecular Reformatsky-type
reaction, in 71% yield from 9, after purification by silica
gel column chromatography. 5′-O-Bromopropanoyl de-
rivative 13, the substrate of the intramolecular Barbier-
type reaction, was prepared in a similar manner. Treat-
(5) Molander, G. A., Etter, J . B. J . Am. Chem. Soc. 1987, 109, 6556-
6558, and references cited therein.
(6) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem. Soc.
1987, 109, 453-463, and references cited therein.
(7) (a) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693-2698. (b) Molander, G. A. In Comprehensive Organic
Synthesis; Shereiber, S. L., Ed.; Pergamon Press: New York,; Vol. 1,
pp 251-282. (c) Soderquist, J . A. Aldrichim. Acta 1991, 24, 15-23. (e)
Molander, G. A. Chem. Rev. 1992, 92, 29-68. (f) Molander, G. A.;
Harris, C. R. Chem. Rev. 1996, 96, 307-338.
(8) (a) Tabuchi, T.; Kawamura, K.; Inanaga, J .; Yamaguchi, M.
Tetrahedron Lett. 1986, 27, 3889-3890. (b) Moriya, T.; Handa, Y.;
Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1988, 29, 6947-6948.
(c) Vedejs, E.; Ahmad, S. Tetrahedron Lett. 1988, 29, 2291-2294.
(9) (a) Molander, G. A.; Etter, J . B. J . Org. Chem. 1986, 51, 1778-
1786. (b) Suginome, H.; Yamada, S. Tetrahedron Lett. 1987, 28, 3963-
3966. (c) Otsubo, K.; Kwamura, K.; Inanaga, J .; Yamaguchi, M. Chem.
Lett. 1987, 1487-1490. (d) Sosnowske, J . J .; Danaher, E. B.; Murray,
R. K. J . Org. Chem. 1985, 50, 2759-2763. (e) Lannoye, G.; Cook, J .
M. Tetrahedron Lett. 1988, 29, 171-174.
(10) Kohli, V.; Blo¨cker, H.; Ko¨ster, H. Tetrahedron Lett. 1980, 21,
2683-3686.

1370 J . Org. Chem., Vol. 62, No. 5, 1997
Ichikawa et al.
Sch em e 1
Sch em e 2a
a
Reagents: (a) (1) Ac2O, Et3N, DMAP, MeCN, (2) Ph3P, DEAD, EtOH, THF, (3) NaOEt, EtOH; (b) DMTrCl, py; (c) TBSCl, py; (d)
PDC,CH2Cl2; (e) ZnBr2, CH2Cl2; (f) BrCH2(CH3)2SiCl, Et3N, imidazole, CH2Cl2; (g) BrCH2COCl or BrCH2CH2COCl, 2,6-lutidine, CH2Cl2;
(h) SmI2, THF; (i) NH3/MeOH; (j) K2CO3, MeOH.
Ta ble 1. In tr a m olecu la r Refor m a tsk y- or Ba r bier -Typ e
ment of crude 10 with (bromomethyl)chlorodimethylsilane
r ea ction s of 3′-Ketou r id in e Der iva tives P r om oted by
a
in the presence of imidazole and Et3N in CH2Cl2 gave
Sm I2
11.11
additive
(equiv)
product
(% isolated yield)
Intramolecular reductive cyclization of 11, 12, and 13
with SmI2 was investigated, and the results are sum-
marized in Table 1. First, the Barbier-type reactions of
11 and 13 were examined. Treatment of 5′-O-bromopro-
pionate 13 with 2.0 equiv of SmI2 in THF at room
temperature resulted in complete recovery of 13 (entry
1). It has been reported that HMPA enhances the
electron-transfer ability of SmI2 and often improves the
yield of the desired products.7a,12 However, when the
reaction was performed in the presence of 5 equiv of
HMPA, it did not give the desired cyclized product, but
rather 4-ethoxy-2-pyrimidone (15) in 72% yield (entry 2).
Similarly, reaction of 5′-O-(bromomethyl)dimethylsilyl
derivative 11 was also unsuccessful. The intramolecular
Reformatsky-type reaction of 5′-bromoacetate 12 was
entry substrate temperature
1
2
3
13
13
11
12
12
12
12
12
12
27
26
26
room temp
room temp
room temp
room temp
room temp
0 °C
none
no reaction
HMPA (5) 15 (72)
HMPA (5) 15 (69)
none
none
none
none
HMPA (5) 14 (76), 15 (11)
t-BuOH (5) 14 (61)
none
none
none
4
14 (71)
16 (22)
14 (75)
14 (90)
5b
6
7
8
9
10
11
12c
-78 °C
-78 °C
-78 °C
-78 °C
29 (85)
28 (65), 31 (18)
28 (85), 31 (trace)
-78 °C
-78 °C
a
Reactions were done in the presence of 2.0 equiv of SmI2 in
b
THF except for entry 5 and 12. Reaction was done with 1.0 equiv
of zinc in toluene. c A soulution of 26 in THF was added slowly
over 2 h to a 2.0 equiv of SmI2 solution in THF.
tried next. When 12 was treated with 2.0 equiv of SmI2
in THF at room temperature, the Reformatsky-type
reaction proceeded effectively to give the desired lactone
14 in 71% yield (entry 4). On the other hand, reaction
of 12 with zinc as a reductant in toluene did not give 14,
(11) Compound 11 was used in the next reaction without purification
because of its instability.
(12) (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485-1486. (b) Handa, Y.; Inanaga, J .; Yamaguchi, M. J . Chem. Soc.,
Chem. Commun. 1989, 298-299. (c) Evans, W. J .; Gummersheimer,
T. S.; Ziller, J . W. J . Am. Chem. Soc. 1995, 117, 8999-9002.

SmI2-Promoted Intramolecular Reformatsky-Type Reaction
J . Org. Chem., Vol. 62, No. 5, 1997 1371
Sch em e 3
3′-ketyl radical, which would result in cleavage of the
glycosidic linkage to give 4-ethoxy-2-pyrimidone (15).
Treatment of 14 with NH3/MeOH at room temperature
gave the desired amide 17 in 45% yield along with 15 in
52% yield.16 When the reaction was performed at -70
°C, 17 was obtained quantitatively. Similar treatment
of 14 with K2CO3 in MeOH gave methyl ester 18 in high
yield. Although removal of the 4-O-ethyl group was
investigated under various acidic and Lewis acidic condi-
tions, cleavage of its glycosidic linkage occurred in
preference to the desired deethylation.
F igu r e 2. The conceivable chelation intermediate of the SmI2-
promoted Reformatsky-type reaction of 12.
Therefore, we next tried the Reformatsky-type reaction
with 3-benzyloxymethyl (BOM) uridine derivative 27 as
a substrate, since the BOM group can be removed by
catalytic hydrogenation. The 3-position was selectively
protected by treating uridine with BOMCl and DBU in
DMF at 0 °C to give 19 quantitatively. Treatment of 19
with TBSCl in the presence of AgNO3 and pyridine in
THF17 gave the 2′,5′-di-O-silylated product 21 in high
yield, which was oxidized as reported elsewhere18 to give
the 3′-keto derivative 23. 5′-Bromoacetate 27, the sub-
strate for the Reformatsky-type reaction, was obtained
by the same procedure as described above for preparing
12. When 27 was treated with 2.0 equiv of SmI2 at -78
°C in THF, the intramolecular Reformatsky-type reaction
proceeded rapidly, as in the case of 12, to give the desired
lactone 29 in 85% yield (Table 1, entry 10). Removal of
the BOM group was achieved at this stage by catalytic
hydrogenation. Although 3-hydroxymethyl derivative 30
was obtained as the major product using Pd-charcoal as
a catalyst, deprotected lactone 28 was obtained quanti-
tatively when the hydrogenation was performed with Pd-
(OH)2 in MeOH.
but only 5′-O-acetate 16 (entry 5). The yield of 14
increased when SmI2-promoted reactions were performed
at lower temperature; 14 was obtained in 75% yield at 0
°C (entry 6) and in 90% yield at -78 °C (entry 7),
respectively. When HMPA was used as an additive, the
yield of 14 was decreased and 15 was isolated in 11%
yield (entry 8). Although t-BuOH has been shown to be
an effective additive for SmI2-promoted reactions,13 it was
ineffective in this reaction system (entry 9).
To obtain insight into the mechanism of cleavage of
the glycosidic linkage during the course of the reaction,
the lactone 14 and 5′-O-acetyl-3′-ketouridine derivative
16 were treated with the SmI2-HMPA system in THF
at room temperature. Although 14 was quantitatively
recovered in the former case, SmI2 cleaved the glycosidic
linkage of 16 to give 15 in 62% yield. This suggests that
the glycosidic linkage is cleaved via electron transfer from
SmI2 to the 3′-carbonyl of 3′-ketouridine derivatives and
subsequent reductive cleavage of the carbon-oxygen
bond14 at the 4′-position, as shown in Scheme 3.
A
similar ring-opening reaction of tetrahydrofuran rings
promoted by SmI2 has been previously reported.15
We also examined the intramolecular Reformatsky-
type reaction of base moiety-unprotected uridine deriva-
tive 26, which was obtained from the known 2′-O-TBS-
3′-ketouridine 24.18 Treatment of 26 with 2.0 equiv of
SmI2 at -78 °C in THF gave lactone 28 in 65% yield and
5′-O-acetyl derivative 31 in 18% yield (Table 1, entry 11).
Lactone 28 was obtained in 85% yield as a sole product
when a solution of 26 in THF was added slowly over 2 h,
using a syringe-pump, to a SmI2 solution in THF at -78
°C (entry 12). These results suggest that the 3-NH of
the uracil moiety acts as a proton source to promote the
reduction of the 5′-ester moiety. Treatment of 28 with
NH3/MeOH at -70 °C gave 2′-O-TBS-3′-C-(carbamoylm-
ethyl)uridine (32) in high yield. Finally, the TBS group
of 32 was removed by heating it with NH4F in MeOH
under reflux to give the target 3′-C-(carbamoylmethyl)-
uridine (33).
In the intramolecular Reformatsky-type reaction with
SmI2, the transfer of two electrons from SmI2 molecules
would occur rapidly at the bromoacetyl moiety to gener-
ate the corresponding enolate. The efficiency of SmI2 as
the promoter of this reaction is due to the chelation of
Sm3+, generated in the reaction process, to the 5′-enolate
of ester and the 3′-carbonyl, as shown in Figure 2, which
can effectively promote the enolate addition reaction to
the carbonyl.5 In the reaction with zinc as a reductant,
while the 5′-enolate would be generated, the subsequent
addition reaction on the 3′-carbonyl did not proceed,
probably due to the inability of Zn2+ to undergo such
chelation. On the other hand, upon treatment of 11 or
13 with the SmI2-HMPA system, electron transfer would
rapidly occur at the 3′-carbonyl to generate an unstable
(13) Yoneda, R.; Harusawa, S.; Kurihara, T. Tetrahedron Lett. 1989,
30, 3681-3684.
(16) The cleavage of the glycosidic linkage thought to proceed via a
3′-keto derivative which could be generated by a retroaldol reaction of
14, because 17 was stable in NH3/MeOH at room temperature.
(17) Hakimelahi, G. H.; Proba, Z. A.; Ogilvie, K. K. Tetrahedron Lett.
1981, 22, 4775-4778.
(18) Robins, M. J .; Samano, V.; J ohnson, M. D. J . Org. Chem. 1990,
55, 410-412.
(14) Deoxygenation of R-oxygenated ketones or esters with SmI2 has
been reported: (a) Molander, G. A.; Harn, G. J . Org. Chem. 1986, 51,
1135-1138. (b) Kusuda, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron
Lett. 1989, 30, 2945-2948.
(15) Enholm, E. J .; Schreier, J . A. J . Org. Chem. 1995, 60, 1110-
1111

1372 J . Org. Chem., Vol. 62, No. 5, 1997
Ichikawa et al.
Sch em e 4a
a
Reagents: (a) BOMCl, DBU, DMF; (b) TBSCl, AgNO3, THF; (c) CrO3, py, molecular seives 4A, Ac2O, CH2Cl2; (d) aqueous TFA (90%);
(e) BrCH2COCl, 2,6-lutidine, CH2Cl2; (f) SmI2, THF; (g) H2, Pd(OH)2, MeOH; (h) NH3/MeOH; (i) NH4F, MeOH.
pressure. The residue was purified by column chromatography
(SiO2, 24% EtOH-CHCl3) to give 5 (25.3 g, 93%) as a white
solid, for which spectral data was in accord with that reported
previously.2c
We have demonstrated that SmI2 effectively promoted
the intramolecular Reformatsky-type reaction of 5′-O-
(bromoacetyl)-3′-ketouridines to give the corresponding
3′,5′-lactones, and subsequent treatment of the lactones
with nucleophiles gave the corresponding 3′-â-branched
uridines. To our knowledge, this is the first example of
the efficient use of a SmI2-mediated carbon-carbon bond
formation reaction in nucleoside chemistry. This method
may be applicable to other pyrimidine and purine nucleo-
sides for synthesizing the corresponding 3′-branched
ribonucleoside analogs.
4-Eth oxy-1-[5-O-(d im eth oxytr ityl)-â-D-r ibofu r a n osyl]-
2(1H)-p yr im id on e (6). A mixture of 5 (13.6 g, 50 mmol) and
dimethoxytrityl chloride (DMTrCl, 20.4 g, 60 mmol) in pyridine
(200 mL) was stirred at room temperature for 2 h. After
MeOH (10 mL) was added, the solution was evaporated under
reduced pressure, and the residue was partitioned between
CHCl3 (500 mL) and H2O (200 mL). The organic layer was
washed with brine (200 mL), dried (Na2SO4), and evaporated
under reduced pressure. The residue was purified by column
chromatography (SiO2, 6% EtOH-CHCl3) to give 6 (27.9 g,
98%) as a white foam: 1H NMR (CDCl3, 500 MHz) δ 7.76 (d,
J ) 8.1 Hz, 1H), 7.36-7.20 (m, 9H), 6.82 (d, 4H), 5.82 (d, J )
3.4 Hz, 1H), 5.50 (d, J ) 8.1 Hz, 1H), 4.44 (br s, 1H), 4.36 (dd,
J ) 3.4, 4.7 Hz, 1H), 4.32 (dd, J ) 2.5, 4.7 Hz, 1H), 4.24 (ddd,
J ) 2.3, 2.5, 3.0 Hz, 1H), 3.89 (q, J ) 6.8 Hz, 2H), 3.78 (s, 6H),
3.49 (dd, J ) 2.3, 10.9 Hz, 1H), 3.41 (dd, J ) 3.0, 10.9 Hz,
1H), 3.19 (br s, 1H), 1.22 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 162.6, 158.9, 144.5, 137.8, 135.5, 135.4, 130.3,
128.0, 128.2, 127.4, 113.5, 102.0, 92.0, 87.3, 84.9, 76.5, 71.2,
62.7, 55.5, 36.5, 13.0; MS (FAB) m/ z 575 (MH+). Anal. Calcd
for C32H34N2O8: C, 66.89; H, 5.96; N, 4.87. Found: C, 67.03;
H, 6.04; N, 4.62.
Derivatization of 33 into various 3′-â-branched-chain
sugar nucleosides and biological evaluations are under
investigation.
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were recorded
at 270 or 500 MHz (1H) and at 125 MHz (13C) and are reported
in ppm downfield from TMS. Mass spectra were obtained by
electron ionization (EI) or fast atom bombardment (FAB)
method. Thin-layer chromatography was done on Merck
coated plate 60F254. Silica gel chromatography was done with
Merck silica gel 5715. SmI2/THF was prepared according to
a reported method.19
4 -E t h o x y -1 -[2 -O -(t e r t -b u t y l d i m e t h y l s i l y l )-5 -O -
(d im eth oxytr ityl)-â-D-r ibofu r a n osyl]-2(1H)-p yr im id on e
(7). A mixture of 6 (6.90 g, 12 mmol) and tert-butyldimeth-
ylsilyl chloride (TBSCl, 19.9 g, 33.0 mmol) in pyridine (100
mL) was stirred at room temperature for 48 h. After MeOH
(5 mL) was added, the solution was evaporated under reduced
pressure, and the residue was partitioned between EtOAc (500
mL) and H2O (200 mL). The organic layer was washed with
saturated aqueous NaHCO3 (200 mL) and brine (200 mL),
dried (Na2SO4), and evaporated under reduced pressure. The
residue was purified by flash column chromatography (SiO2,
25-30% EtOAc-hexane) to give 7 (5.58 g, 51%) and 8 (2.13 g,
19%) as white forms. 7: 1H NMR (CDCl3, 500 MHz) δ 7.73
(d, J ) 8.2 Hz, 1H), 7.27-7.12 (m, 9H), 6.72 (d, 4H), 5.90 (d,
J ) 3.0 Hz, 1H), 5.26 (d, J ) 8.2 Hz, 1H), 4.22 (m, 2H), 4.00
(br s, 1H), 3.87 (q, J ) 7.0 Hz, 2H), 3.77 (s, 6H), 3.40 (dd, J )
2.0, 10.9 Hz, 1H), 3.35 (dd, J ) 2.4, 10.9 Hz, 1H), 2.54 (s, 1H),
1.09 (t, J ) 7.0 Hz, 3H), 0.81 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 162.7, 159.0, 151.0, 144.6, 138.1,
135.5, 135.3, 130.4, 130.3, 128.4, 128.3, 127.4, 113.6, 113.4,
102.3, 89.3, 87.4, 83.8, 70.9, 62.8, 55.5, 36.4, 25.9, 18.2, 13.0,
4-Eth oxy-1-â-D-r ibofu r a n osyl-2(1H)-p yr im id on e (5). A
mixture of uridine (24.4 g, 100 mmol), Et3N (31.2 mL, 330
mmol), Ac2O (29.6 mL, 330 mmol), and DMAP (100 mg) in
MeCN (400 mL) was stirred at room temperature for 30 min.
After MeOH (20 mL) was added, the solution was evaporated
under reduced pressure, and the residue was partitioned
between EtOAc (1 L) and H2O (200 mL). The organic layer
was washed with saturated aqueous NaHCO3 (200 mL × 2)
and brine (200 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue and Ph3P (26.7 g, 105 mmol)
was dissolved in THF (300 mL), to which a solution of diethyl
azodicarboxylate (19.5 mL, 105 mmol) in THF (50 mL) was
added dropwise followed by an addition of EtOH (6.6 mL, 105
mmol) at 0 °C. The mixture was stirred at room temperature
for 20 min and evaporated under reduced pressure. A mixture
of the residue and 1 N NaOEt (2 mL, 2 mmol) in EtOH (500
mL) was stirred at room temperature for 4 h. After neutral-
ization with AcOH, the solvent was removed under reduced
(19) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501-502.

SmI2-Promoted Intramolecular Reformatsky-Type Reaction
J . Org. Chem., Vol. 62, No. 5, 1997 1373
-4.4, -4.9; MS (FAB) m/ z 689 (MH+). Anal. Calcd for
C38H48N2O8Si: C, 66.25; H, 7.02; N, 4.07. Found: C, 66.09;
H, 7.11; N, 4.20. 8: 1H NMR (CDCl3, 500 MHz) δ 7.80 (d, J )
8.1 Hz, 1H), 7.30-7.25 (m, 9H), 6.84 (d, 4H), 6.00 (d, J ) 4.0
Hz, 1H), 5.45 (d, J ) 8.1 Hz, 1H), 4.38 (t, J ) 5.2 Hz, 1.0 H),
4.13 (ddd, J ) 4.0, 5.2, 5.8 Hz, 1H), 4.03 (ddd, J ) 2.2, 2.5, 5.2
Hz, 1H), 4.00 (q, J ) 7.0 Hz, 2H), 3.80 (s, 6H), 3.60 (dd, J )
2.2, 10.9 Hz, 1H), 3.30 (dd, J ) 2.5, 10.9 Hz, 1H), 2.83 (d, J )
5.8 Hz, 1H), 1.22 (t, J ) 7.0 Hz, 3H), 0.85 (s, 9H), 0.06 (s, 3H),
-0.04 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.7, 159.0,
151.2, 144.3, 138.1, 135.4, 135.3, 130.4, 130.4, 128.4, 128.2,
127.5, 113.5, 113.4, 102.3, 90.3, 87.3, 83.9, 71.4, 62.3, 55.5, 36.5,
25.9, 18.2, 13.0, -4.6, -4.7.
4 -E t h o x y -1 -[2 -O -(t e r t -b u t y l d i m e t h y l s i l y l )-5 -O -
(d im eth oxytr ityl)-â-D-er yth r o-p en tofr a n -3-u losyl]-2(1H)-
p yr im id on e (9). A mixture of 7 (3.86 g, 5.61 mmol) and PDC
(4.22 g, 11.2 mmol) in CH2Cl2 (50 mL) was stirred at room
temperature for 12 h. The resulting mixture was diluted with
EtOAc and filtered through a Celite pad. The filtrate was
evaporated under reduced pressure, and the residue was
partitioned between EtOAc (200 mL) and H2O (50 mL). The
organic layer was washed with brine (50 mL), dried (Na2SO4),
and evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, 20% EtOAc-
hexane) to give 9 (2.90 g, 76%) as a white foam: 1H NMR
(CDCl3, 500 MHz) δ 7.61 (d, J ) 8.2 Hz, 1H), 7.32-7.16 (m,
9H), 6.83 (d, 4H), 6.29 (d, J ) 7.9 Hz, 1H), 5.49 (d, J ) 8.2 Hz,
1H), 4.53 (d, J ) 7.9 Hz, 1H), 4.27 (br s, 1H), 3.98 (q, J ) 7.0
Hz, 2H), 3.77 (s, 6H), 3.62 (dd, J ) 2.3, 10.5 Hz, 1H), 3.40 (dd,
J ) 2.0, 10.5 Hz, 1H), 1.19 (t, J ) 7.0 Hz, 3H), 0.89 (s, 9H),
0.17 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 208.8,
162.3, 159.1, 151.0, 144.4, 137.4, 135.2, 134.9, 130.3, 130.2,
129.4, 128.3, 128.2, 128.0, 127.5, 113.7, 113.6, 103.4, 87.6, 86.2,
80.8, 63.4, 55.5, 36.7, 25.9, 18.5, 12.9, -4.4, -5.2; MS (FAB)
m/ z 687 (MH+). Anal. Calcd for C38H46N2O8Si: C, 66.45; H,
6.75; N, 4.08. Found: C, 66.22; H, 6.98; N, 3.85.
4-Eth oxy-1-[2-O-(ter t-bu tyld im eth ylsilyl)-â-D-er yth r o-
p en tofr a n -3-u losyl]-2(1H)-p yr im id on e (10). A mixture of
9 (686 mg, 1.00 mmol) and ZnBr2 (4.50 g, 10.0 mmol) in CH2-
Cl2 (10 mL) was stirred at room temperature for 5 min, and
then H2O (20 mL) was added. The organic layer separated
was washed with 1 N HCl (20 mL) and brine (10 mL), dried
(Na2SO4), and evaporated under reduced pressure to give crude
10 (691 mg, quant). The residue was used immediately for
the next reaction without further purification because of its
instability.
4-Eth oxy-1-[5-O-[(br om om eth yl)dim eth ylsilyl]-2-O-(ter t-
bu tyldim eth ylsilyl)-â-D-er yth r o-pen tofr an -3-u losyl]-2(1H)-
p yr im id on e (11). A mixture of crude 10 (prepared from 1.00
mmol of 9), (bromomethyl)dimethylchlorosilane (163 µL, 1.20
mmol), Et3N (104 µL, 1.20 mmol), and imidazole (82 mg, 1.20
mmol) in CH2Cl2 (10 mL) was stirred at room temperature for
10 min. After MeOH (1 mL) was added, the solution was
diluted with CH2Cl2 (30 mL). The resulting solution was
washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL), dried (Na2SO4), and evaporated under reduced
pressure to give crude 11 (863 mg, quant). The residue was
used immediately for the next reaction without further puri-
fication because of its instability.
δ 206.0, 166.1, 161.8, 150.8, 137.9, 103.7, 88.8, 78.5, 75.2, 64.4,
36.5, 25.37, 25.3, 18.1, 12.7, -4.7, -5.4; MS (FAB) m/ z 505,
507 (MH+).
4-E t h oxy-1-[5-O-(b r om op r op ion yl)-2-O-(ter t-b u t yld i-
m et h ylsilyl)-â-D-er yth r o-p en t ofr a n -3-u losyl]-2(1H )-p y-
r im id on e (13). A mixture of crude 10 (prepared from 1.00
mmol of 9), 2,6-lutidine (163 µL, 1.20 mmol), 3-bromopropionyl
chloride (100 µL, 1.20 mmol), and DMAP (10 mg) in CH2Cl2
(10 mL) was stirred at room temperature for 2 h. After MeOH
(1 mL) was added, the solution was diluted with CH2Cl2 (30
mL). The resulting solution was washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4),
and evaporated under reduced pressure. The residue was
purified by flash column chromatography (SiO2, 30% EtOAc-
hexane) to give 13 (343 mg, 69%) as a colorless glass: 1H NMR
(CDCl3, 500 MHz) δ 7.30 (d, J ) 8.0 Hz, 1H), 5.85 (d, J ) 8.0
Hz, 1H), 5.82 (d, J ) 6.2 Hz, 1H), 4.59 (dd, J ) 4.4, 12.4 Hz,
1H), 4.48 (br s, 2H), 4.38 (dd, J ) 5.2, 12.4 Hz, 1H), 3.99 (q, J
) 6.9 Hz, 2H), 3.59 (q, J ) 6.3 Hz, 2H), 2.97 (t, J ) 6.3 Hz,
2H), 1.21 (t, J ) 6.9 Hz, 3H), 0.86 (s, 9H), 0.12 (s, 3H), 0.06 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 206.0, 170.0, 162.1, 151.0,
138.6, 103.6, 90.4, 79.1, 75.0, 63.6, 37.8, 36.7, 25.6, 18.3, 12.9,
-4.4, -5.1; MS (FAB) m/ z 518, 520 (MH+). Anal. Calcd for
C20H31BrN2O7Si: C, 46.24; H, 6.02; N, 5.39. Found: C, 46.49;
H, 6.30; N, 5.11.
4-E t h oxy-1-[2-O-(t er t -b u t yld im e t h ylsilyl)-3-C-(ca r -
b oxym e t h yl)-â-D -r ibo-p e n t ofu r a n osyl]-2(1H )-p yr im i-
d on e 3′,5′-La cton e (14). A solution of 12 (506 mg, 1.00 mmol)
in THF (10 mL) was added to a SmI2 solution in THF (0.1 M,
22.0 mL, 2.20 mmol) at -78 °C. After warming the mixture
to room temperature, EtOAc (50 mL) and 1 N HCl (10 mL)
were added, and the resulting mixture was partitioned. The
organic layer was washed with H2O (20 mL × 2) and brine
(20 mL), dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, 30% EtOAc-hexane) to give 14 (384 mg, 90%) as a
colorless glass: mp 175-177 °C (MeOH-CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.10 (d, J ) 8.1 Hz, 1H, H-6), 6.07 (d, J )
7.6 Hz, 1H, H-1′), 5.87 (d, J ) 8.2 Hz, 1H, H-5), 4.46 (d, J )
12.9 Hz, 1H, H-5′a), 4.40 (br s, 1H, H-4′), 4.37 (dd, J ) 2.3,
12.9 Hz, 1H, H5′b), 4.00 (q, J ) 7.0 Hz, 2H, 4-CH2CH3), 3.65
(d, J ) 7.6 Hz, 1H, H-2′), 3.52 (s, 1H, 3′-OH), 2.78 (d, J ) 15.2
Hz, 1H, H-3′′a), 2.71 (d, J ) 15.2 Hz, 1H, H-3′′b), 1.21 (t, J )
7.0 Hz, 3H, 4-CH2CH3), 0.89 (s, 9H, tert-Bu), 0.10 (s, 3H, Me),
-0.06 (s, 3H, Me); NOE, irradiate H-3′′a, observed H-5′b
(6.0%), H-3′′b (4.3%), and no NOE enhancement was observed
at H-4′; irradiate H-3′′b, observed H-2′ (7.1%), H-3′′a (7.4%),
and no NOE enhancement was observed at H-4′; irradiate H-2′,
observed H-6 (13.1%), H-1′ (2.8%), H-3′b (2.8%), and no NOE
enhancement was observed at 3′-OH; irradiate 3′-OH, observed
H-1′ (4.5%), H-4′ (1.9%), H-2′ (1.3%), H-3′′b (1.9%) and no NOE
enhancement was observed at H-6; 13C NMR (CDCl3, 125 MHz)
δ 169.6, 161.9, 151.0, 136.4, 104.1, 85.6, 81.3, 74.1, 68.4, 40.7,
36.7, 25.7, 18.0, 12.9, -4.5, -4.8; MS (FAB) m/ z 427 (MH+).
Anal. Calcd for C19H30N2O7Si: C, 53.50; H, 7.09; N, 6.57.
Found: C, 53.61; H, 7.18; N, 6.21.
Rea ction of 12 w ith Zin c. A mixture of 12 (47 mg, 0.1
mmol) and zinc (6.5 mg, 0.1 mmol) in toluene (10 mL) was
heated under reflux for 2 h. The resulting mixture was
evaporated under reduced pressure, and the residue was
purified by column chromatography (SiO2, 50% EtOAc-
hexane) to give 16 (9 mg, 22%) as a white foam: 1H NMR
(CDCl3, 500 MHz) δ 8.33 (br s, 1H), 7.34 (d, J ) 8.1 Hz, 1H),
5.78 (d, J ) 7.5 Hz, 1H), 5.84 (d, J ) 8.1 Hz, 1H), 4.44 (m,
3H), 4.34 (dd, J ) 5.1, 13.2 Hz, 1H), 2.10 (s, 3H), 0.87 (s, 9H),
0.10 (s, 3H), 0.07 (s, 3H); MS (EI) m/ z 369 (M+ - Me).
4-E t h oxy-1-[2-O-(ter t-b u t yld im et h ylsilyl)-3-C-[(m et h -
oxyca r bon yl)m eth yl]-â-D-r ibo-p en tofu r a n osyl]-2(1H)-p y-
r im id on e (18). To a solution of 14 (214 mg, 0.500 mmol) in
MeOH (5 mL) was added K2CO3 (62 mg, 0.50 mmol) at -70
°C. The mixture was stirred at the same temperature for 3 h.
The insoluble K2CO3 was filtered off, and the filtrate was
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, 5% MeOH-CHCl3) to give
18 (197 mg, 86%) as a colorless glass: 1H NMR (CDCl3, 500
MHz) δ 7.27 (d, J ) 8.0 Hz, 1H), 5.80 (d, J ) 8.0 Hz, 1H), 5.34
4-Eth oxy-1-[5-O-(br om oa cetyl)-2-O-(ter t-bu tyld im eth -
ylsilyl)-â-D-er yt h r o-p e n t ofr a n -3-u losyl]-2(1H )-p yr im i-
d on e (12). A mixture of crude 10 (prepared from 1.00 mmol
of 9), 2,6-lutidine (163 µL, 1.20 mmol), and bromoacetyl
bromide (104 µL, 1.20 mmol) in CH2Cl2 (10 mL) was stirred
for 5 min at -78 °C. After MeOH (1 mL) was added, the
solution was diluted with CH2Cl2 (30 mL). The resulting
solution was washed with saturated aqueous NaHCO3 (20 mL)
and brine (20 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue was purified by flash column
chromatography (SiO2, 30% EtOAc-hexane) to give 12 (395
mg, 78% from 9) as a yellow foam: 1H NMR (CDCl3, 500 MHz)
δ 7.40 (d, J ) 8.1 Hz, 1H), 5.95 (d, J ) 6.8 Hz, 1H), 5.86 (d, J
) 8.1 Hz, 1H), 4.56 (dd, J ) 5.0, 16.6 Hz, 1H), 4.49 (d, J ) 6.8
Hz, 1H), 4.45 (br s, 1H), 4.44 (dd, J ) 3.9, 16.6 Hz, 1H), 4.00
(q, J ) 7.1 Hz, 2H), 3.90 (s, 2H), 1.21 (t, J ) 7.1 Hz, 3H), 0.86
(s, 9H), 0.17 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 125 MHz)

1374 J . Org. Chem., Vol. 62, No. 5, 1997
Ichikawa et al.
(d, J ) 7.6 Hz, 1H), 4.80 (d, J ) 7.6 Hz, 1H), 4.40 (br s, 1H),
4.00-3.98 (m, 4H), 3.73 (s, 3H), 3.15 (br s, 1H), 3.10 (d, J )
16.1 Hz, 1H), 2.66 (d, J ) 16.1 Hz, 1H), 1.21 (t, J ) 7.1 Hz,
3H), 0.88 (s, 9H), 0.08 (s, 3H), -0.13 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 172.4, 163.6, 152.7, 143.5, 104.3, 96.1, 88.2, 63.8,
53.4, 40.54, 37.9, 27.1, 19.2, 14.2, -3.41; MS (EI) m/ z 458 (M+).
Anal. Calcd for C20H34N2O8Si: C, 52.38; H, 7.47; N, 6.11.
Found: C, 52.70; H, 7.74; N, 5.81.
4-Eth oxy-1-[2-O-(ter t-bu tyld im eth ylsilyl)-3-C-(ca r ba m -
oylm et h yl)-â-D-r ibo-p en t ofu r a n osyl]-2(1H )-p yr im id on e
(17). To a solution of 14 (214 mg, 0.500 mmol) in MeOH (1
mL) was added saturated methanolic ammonia (5 mL) at -70
°C. The mixture was stirred at the same temperature for 3 h
and then evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, 10% MeOH-CHCl3)
to give 17 (217 mg, 98%) as a colorless glass: mp 170-172 °C
(MeOH-CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.51 (d, J )
8.0 Hz, 1H), 6.68 (br s, 1H), 5.81 (d, J ) 8.0 Hz, 1H), 5.66 (d,
J ) 7.6 Hz, 1H), 5.50 (br s, 1H), 4.58 (d, J ) 7.4 Hz, 1H), 4.28
(br s, 1H), 4.00 (q, J ) 7.1 Hz, 2H), 3.90 (dd, J ) 2.2 Hz, 12.7
Hz, 1H), 3.79 (d, J ) 12.7 Hz, 1H), 3.64 (br s, 1H), 2.86 (d, J
) 15.9 Hz, 1H), 2.61 (d, J ) 15.9 Hz, 1H), 1.21 (t, J ) 7.1 Hz,
3H), 0.88 (s, 9H), 0.07 (s, 3H), -0.11 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 172.6, 161.7, 151.1, 140.1, 138.8, 102.1, 86.8, 86.1,
78.0, 77.7, 60.9, 38.3, 35.6, 25.7, 17.8, 12.8, -4.2, -5.0; MS
(FAB) m/ z 443 (M+). Anal. Calcd for C19H33N3O7Si: C, 51.45;
H, 7.50; N, 9.47. Found: C, 51.45; H, 7.77; N, 9.79.
whole was stirred for additional 15 min. Compound 21 (4.72
g, 8.00 mmol) in CH2Cl2 (50 mL) was added to the resulting
mixture, which was stirred at room temperature for 30 min.
The solution was diluted with Et2O (1.5 L) and filtered through
a Celite pad, and the filtrate was evaporated under reduced
pressure. The residue was partitioned between EtOAc (500
mL) and H2O (300 mL). The organic layer was washed with
water (200 mL × 2) and brine (100 mL), dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, 25% EtOAc-hexane) to give
23 (3.77 g, 80%) as a colorless glass: 1H NMR (CDCl3, 500
MHz) δ 7.75 (d, J ) 8.2 Hz, 1H), 7.31-7.18 (m, 5H), 6.24 (d,
J ) 8.0 Hz, 1H), 5.79 (d, J ) 8.2 Hz, 1H), 5.44 (d, J ) 13.4 Hz,
1H), 5.41 (d, J ) 13.4 Hz, 1H), 4.62 (s, 2H), 4.17 (s, 1H), 4.10
(d, J ) 8.0 Hz, 1H), 3.87 (dd, J ) 1.9, 11.3 Hz, 1H), 3.83 (dd,
J ) 1.6, 11.3 Hz, 1H), 0.83 (s, 9H), 0.77 (s, 9H), 0.05 (s, 3H),
0.04 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 208.6, 162.5, 151.4, 138.0, 128.5, 127.9, 103.5, 85.9,
82.2, 72.3, 70.6, 63.1, 26.0, 25.6, 18.5, 18.4, 11.7, -4.6, -5.2,
-5.4, -5.5; MS (FAB) m/ z 591 (MH+). Anal. Calcd for
C29H46N2O7Si2: C, 58.95; H, 7.85; N, 4.74. Found: C, 58.68;
H, 7.71; N, 4.39.
3-[(Ben zyloxy)m eth yl]-1-[2-O-(ter t-bu tyld im eth ylsilyl)-
â-D-er yth r o-p en tofr a n -3-u losyl]u r a cil (25). A solution of
23 (590 mg, 1.00 mmol) in 90% aqueous TFA (10 mL) was
stirred at 0 °C for 30 min. The mixture was evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, CHCl3) to give 25 (323 mg, 68%) as a yellow
glass: 1H NMR (CDCl3, 500 MHz) δ 7.41 (d, J ) 8.1 Hz, 1H),
7.27-7.16 (m, 5H), 5.77 (d, J ) 8.1 Hz, 1H), 5.70 (d, J ) 7.6
Hz, 1H), 5.40 (d, J ) 13.5 Hz, 1H), 5.37 (d, J ) 13.5 Hz, 1H),
4.58 (s, 2H), 4.57 (d, J ) 7.6 Hz, 1H), 4.16 (br s, 1H), 3.85 (dd,
J ) 2.3, 12.1 Hz, 1H), 3.80 (dd, J ) 2.2, 12.1 Hz, 1H), 0.75 (s,
9H), 0.01 (s, 3H), -0.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
208.6, 162.4, 151.5, 140.6, 137.8, 128.6, 128.1, 127.9, 103.5,
91.0, 82.5, 75.1, 72.5, 70.6, 62.0, 25.9, 25.7, 18.3, -4.41, -5.3;
MS (EI) m/ z 476 (M+).
3-[(Ben zyloxy)m eth yl]-1-[5-O-(br om oa cetyl)-2-O-(ter t-
b u t yld im e t h ylsilyl)-â-D -er yt h r o-p e n t ofr a n -3-u losyl]-
u r a cil (27). Compound 27 was prepared from 25 (323 mg,
0.68 mmol) as described above for the synthesis of 12. After
purification by column chromatography (SiO2, 30% EtOAc-
hexane), 27 was obtained as a yellow foam (348 mg, 86%): 1H
NMR (CDCl3, 500 MHz) δ 7.44 (d, J ) 8.1 Hz, 1H), 7.36-7.20
(m, 5H), 5.96 (d, J ) 6.8 Hz, 1H), 5.88 (d, J ) 8.1 Hz, 1H),
5.48 (d, J ) 11.7 Hz, 1H), 5.47 (d, J ) 11.7 Hz, 1H), 4.68 (s,
2H), 4.56 (dd, J ) 1.0, 11.3 Hz, 1H), 4.49 (d, J ) 6.8 Hz, 1H),
4.46 (br s, 1H), 4.45 (dd, J ) 3.8, 11.3 Hz, 1H), 3.90 (s, 2H),
0.85 (s, 9H), 0.11 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 206.1, 166.3, 162.2, 151.4, 139.0, 137.9, 128.6, 128.0,
127.9, 103.6, 89.1, 75.3, 72.4, 70.65, 64.6, 26.0, 25.6, 25.5, 18.3,
-4.4, -5.0; MS (FAB) m/ z 597, 599 (MH+).
3-[(Ben zyloxy)m eth yl]-1-[2-O-(ter t-bu tyld im eth ylsilyl)-
3-C-(ca r boxym eth yl)-â-D-r ibo-p en tofu r a n osyl]u r a cil 3′,5′-
La cton e (29). Compound 29 was prepared from 27 (338 mg,
0.57 mmol) as described above for the synthesis of 14. After
purification by column chromatography (SiO2, 30% EtOAc-
hexane), 29 was obtained as a yellow glass (236 mg, 80%): mp
114-117 °C (MeOH-CHCl3); 1H NMR (CDCl3, 500 MHz) δ
7.36-7.25 (m, 5H), 7.13 (d, J ) 8.1 Hz, 1H), 6.06 (d, J ) 7.5
Hz, 1H), 5.99 (d, J ) 8.1 Hz, 1H), 5.48 (d, J ) 11.7 Hz, 1H),
5.47 (d, J ) 11.7 Hz, 1H), 4.67 (s, 2H), 4.46 (d, J ) 13.1, 1H),
4.42 (br s, 1H), 4.38 (dd, J ) 1.4, 13.1 Hz, 1H), 3.64 (d, J ) 7.5
Hz, 1H), 3.52 (s, 1H), 2.78 (d, J ) 15.3 Hz, 1H), 2.71 (d, J )
15.3 Hz, 1H), 0.87 (s, 9H), 0.09 (s, 3H), -0.08 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 151.4, 137.3, 128.6, 128.0, 127.9, 104.3,
85.5, 81.3, 74.1, 72.3, 70.6, 68.4, 40.6, 25.7, 17.9, -4.55, -4.68;
MS (FAB) m/ z 519 (MH+). Anal. Calcd for C25H34N2O8Si: C,
57.90; H, 6.61; N, 5.40. Found: C, 57.64; H, 6.64; N, 5.76.
1-[5-O-(Br om oa cetyl)-2-O-(ter t-bu tyld im eth ylsilyl)-â-D-
er yth r o-p en tofr a n -3-u losyl]u r a cil (26). Compound 26 was
prepared from 2418 (4.48 g, 12.6 mmol) as described above for
the synthesis of 12. After purification by column chromatog-
raphy (SiO2, 30% EtOAc-hexane), 26 (4.21 g, 70%) was
obtained as a yellow foam: 1H NMR (CDCl3, 500 MHz) δ 9.69
(br s, 1H), 7.49 (d, J ) 8.2 Hz, 1H), 5.97 (d, J ) 7.1 Hz, 1H),
3-[(Ben zyloxy)m eth yl]-1-(â-D-r ibofu r a n osyl)u r a cil (19).
A mixture of uridine (24.4 g, 100 mmol), DBU (30 mL, 200
mmol), and benzyl chloromethyl ether (20.8 mL, 150 mmol)
in DMF (300 mL) was stirred at 0 °C for 30 min. After MeOH
(10 mL) was added, the solution was evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, 10% EtOH-CHCl3) to give 19 (33.9 g, 93%) as a white
1
crystal: mp 265-268 °C (MeOH-CHCl3); H NMR (DMSO-
d6, 500 MHz) δ 7.98 (d, J ) 8.2 Hz, 1H), 7.35-7.26 (m, 5H),
5.81 (d, J ) 4.8 Hz, 1H), 5.78 (d, J ) 8.2 Hz, 1H), 5.41 (d, J )
5.6 Hz, 1H), 5.33 (d, J ) 12.5 Hz, 1H), 5.30 (d, J ) 12.5 Hz,
1H), 5.12 (t, J ) 5.0 Hz, 1H), 5.09 (d, J ) 5.4 Hz, 1H), 4.59 (s,
2H), 4.03 (ddd, J ) 5.6, 4.8 Hz, 1H), 3.97 (ddd, J ) 5.4, 5.0
Hz, 1H), 3.87 (m, 1H), 3.75 (ddd, J ) 3.2, 5.0, 12.2 Hz, 1H),
3.65 (ddd, J ) 3.2, 5.0, 12.2 Hz, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 172.4, 163.6, 152.7, 143.5, 104.3, 96.1, 88.2, 63.8, 53.4,
40.5, 37.9, 27.1, 19.2, 14.2, -3.41; MS (EI) m/ z 364 (M+). Anal.
Calcd for C17H20N2O7: C, 56.04; H, 5.53; N, 7.69. Found: C,
56.01; H, 5.55; N, 7.50.
3-[(Ben zyloxy)m eth yl]-1-[2,5-O-bis(ter t-bu tyld im eth yl-
silyl)-â-D-r ibofu r a n osyl]u r a cil (21). A mixture of 19 (3.64
g, 10.0 mmol), AgNO3 (3.74 g, 22.0 mmol), pyridine (4.04 mL,
50.0 mmol), and tert-butyldimethylsilyl chloride (3.32 g, 22.0
mmol) in THF (100 mL) was stirred at room temperature for
24 h. After MeOH (5 mL) was added, the precipitate was
filtered off. The filtrate was evaporated under reduced pres-
sure, and the residue was partitioned between EtOAc (1 L)
and H2O (300 mL). The organic layer was washed with water
(200 mL × 3) and brine (200 mL), dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, 30% EtOAc-hexane) to give
21 (5.28 g, 89%) as a white foam: 1H NMR (CDCl3, 500 MHz)
δ 7.87 (d, J ) 8.2 Hz, 1H), 7.27-7.16 (m, 5H), 5.86 (d, J ) 3.7
Hz, 1H), 5.61 (d, J ) 8.2 Hz, 1H), 5.39 (s, 2H), 4.60 (s, 2H),
4.06 (t, J ) 4.0 Hz, 1H), 4.03-4.3.98 (m, 2H), 3.91 (dd, J )
1.3, 11.7 Hz, 1H), 3.73 (dd, J ) 1.2, 11.7 Hz, 1H), 2.48 (br s,
1H), 0.85 (s, 9H), 0.81 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03
(s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.9, 151.2,
138.9, 138.2, 128.6, 128.5, 128.3, 127.8, 102.0, 89.8, 89.5, 84.9,
72.3, 70.4, 70.3, 62.6, 26.1, 25.9, 18.6, 18.2, 11.7, -4.4, -5.0,
-5.3, -5.4; MS (FAB) m/ z 593 (MH+). Anal. Calcd for
C29H48N2O7Si2: C, 58.75; H, 8.16; N, 4.72. Found: C, 58.56;
H, 8.30; N, 4.52.
3-[(Ben zyloxy)m eth yl]-1-[2,5-O-bis(ter t-bu tyld im eth yl-
silyl)-â-D-er yth r o-pen tofr an -3-u losyl]u r acil (23). To a mix-
ture of molecular sieves 4A (8.00 g) and CrO3 (3.20 g, 32.0
mmol) in CH2Cl2 (100 mL) was added pyridine (5.16 mL, 64.0
mmol) at 0 °C. The mixture was stirred for 30 min, Ac2O (3.04
mL, 32.0 mmol) was added at the same temperature, and the

SmI2-Promoted Intramolecular Reformatsky-Type Reaction
J . Org. Chem., Vol. 62, No. 5, 1997 1375
5.84 (d, J ) 8.1 Hz, 1H), 4.56 (d, J ) 11.9 Hz, 1H), 4.47 (d, J
) 7.1 Hz, 1H), 4.44 (dd, J ) 2.0, 3.5 Hz, 1H), 4.41 (dd, J )
3.6, 11.9 Hz, 1H), 3.91 (s, 2H), 0.83 (s, 9H), 0.09 (s, 3H), 0.02
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 206.2, 166.4, 163.2,
150.6, 140.3, 104.1, 87.9, 78.8, 75.4, 64.5, 25.8, 25.6, 25.5, 18.3,
-4.4, -5.0; MS (FAB) m/ z 477, 479 (MH+).
1-[2-O-(ter t-Bu tyldim eth ylsilyl)-3-C-(car bam oylm eth yl)-
â-D-r ibo-p en t ofu r a n osyl]u r a cil (32). To a solution of 28
(808 mg, 2.03 mmol) in MeOH (5 mL) was added saturated
methanolic ammonia (20 mL) at -70 °C. The mixture was
stirred at the same temperature for 3 h and evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, 10% MeOH-CHCl3) to give 32 (825 mg,
98%) as a colorless glass: mp 242-243 °C (MeOH-CHCl3);
1H NMR (DMSO-d6, 500 MHz) δ 11.3 (br s, 1H), 8.07 (d, J )
8.2 Hz, 1H), 7.45 (br s, 1H), 7.02 (br s, 1H), 5.93 (d, J ) 7.6
Hz, 1H), 5.01 (d, J ) 8.2 Hz, 1H), 4.09 (d, J ) 7.6 Hz, 1H),
4.00 (br s, 1H), 3.71 (d, J ) 10.5 Hz, 1H), 3.57 (d, J ) 10.5 Hz,
1H), 3.64 (br s, 1H), 2.47 (d, J ) 12.5 Hz, 1H), 2.46 (d, J )
12.5 Hz, 1H), 0.79 (s, 9H), 0.00 (s, 3H), -0.07 (s, 3H); 13C NMR
(DMSO-d6, 125 MHz) δ 172.4, 162.9, 151.1, 140.8, 102.6, 86.5,
85.0, 77.5, 60.7, 38.1, 25.6, 17.6; MS (FAB) m/ z 415 (M+). Anal.
Calcd for C17H29N3O7Si: C, 49.14; H, 7.03; N, 10.11. Found:
C, 49.10; H, 7.02; N, 10.13.
1-(2-O-(ter t-Bu tyld im eth ylsilyl)-3-C-(ca r boxym eth yl)-
â-D-r ibo-p en tofu r a n osyl]u r a cil 3′,5′-La cton e (28). A solu-
tion of 26 (477 mg, 1.00 mmol) in THF (10 mL) was added
dropwise over 2 h by a syringe pump to a SmI2 solution in
THF (0.1 M, 22.0 mL, 2.20 mmol) at -78 °C. After warming
the mixture to room temperature, EtOAc (50 mL) and 1 N HCl
(10 mL) were added, and the resulting mixture was parti-
tioned. The organic layer was washed with H2O (20 mL × 2)
and brine (20 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, 50% EtOAc-hexane) to give 28 (337 mg,
85%) as a white solid: mp 243-244 °C (MeOH-CHCl3); 1H
NMR (CDCl3, 500 MHz) δ 8.19 (br s, 1H, NH), 7.16 (d, J ) 8.1
Hz, 1H, H-6), 5.98 (d, J ) 7.5 Hz, 1H, H-1′), 5.84 (d, J ) 8.1
Hz, 1H, H-5), 4.46 (d, J ) 13.1, 1H, H-5′a), 4.41 (br s, 1H, H-4′),
4.37 (dd, J ) 2.4, 13.1 Hz, 1H, H-5′b), 3.66 (d, J ) 7.5 Hz, 1H,
H-2′), 3.49 (s, 1H, 3′-OH), 2.78 (d, J ) 15.3 Hz, 1H, H-3′′a),
2.71 (d, J ) 15.3 Hz, 1H, H-3′′b), 0.91 (s, 9H, tert-Bu), 0.11 (s,
3H, Me), -0.02 (s, 3H, Me); NOE, irradiate H-3′′a, observed
H-5′b (9.5%), H-3′′b (6.1%), and no NOE enhancement was
observed at H-4′; irradiate H-3′′b, observed H-2′ (8.7%), H-3′′a
(5.3%), and no NOE enhancement was observed at H-4′;
irradiate H-2′, observed H-6 (12.6%), H-1′ (2.7%), H-3′′b (2.1%),
and no NOE enhancement was observed at 3′-OH; irradiate
3′-OH, observed H-1′ (4.3%), H-4′ (1.5%), H-2′ (1.2%), H-3′′b
(1.5%), and no NOE enhancement was observed at H-6; 13C
NMR (CDCl3, 125 MHz) δ 169.6, 162.4, 150.3, 131.6, 104.4,
85.0, 81.4, 74.1, 68.4, 40.6, 25.7, 18.0, 11.7, -4.5, -4.6; MS
(FAB) m/ z 399 (MH+). Anal. Calcd for C17H26N2O7Si: C,
51.24; H, 6.58; N, 7.03. Found: C, 51.00; H, 6.67; N, 7.06.
Syn th esis of 28 by Deben zyloxym eth yla tion of 29. A
mixture of 29 (59 mg, 0.10 mmol) and Pd(OH)2 (5 mg) in MeOH
(3 mL) was stirred under atmospheric hydrogen for 30 min.
The resulting mixture was filtered through a Celite pad, and
the filtrate was evaporated under reduced pressure. The
residue was purified by column chromatography (SiO2, CHCl3)
to give 28 (42 mg, 98%) as a white powder.
1-[3-C-(Ca r ba m oylm eth yl)-â-D-r ibo-p en tofu r a n osyl]u -
r a cil (33). A mixture of 32 (281 mg, 0.678 mmol) and NH4F
(502 mg, 13.6 mmol) in MeOH (20 mL) was heated under
reflux for 2 h and evaporated under reduced pressure. The
residue was partitioned between CHCl3 (50 mL) and H2O (50
mL). The aqueous layer was washed with CHCl3 (30 mL × 2)
and evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, 10% MeOH-CHCl3)
to give 33 (205 mg, 99%) as a white powder: mp 242 °C dec
(H2O-MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 9.45 (br s, 1H),
8.05 (d, J ) 8.0 Hz, 1H), 7.47 (br s, 1H), 7.06 (br s, 1H), 5.91
(d, J ) 7.9 Hz, 1H), 5.67 (d, J ) 8.1 Hz, 1H), 5.56 (d, J ) 6.1
Hz, 1H), 5.23 (t, J ) 3.9 Hz, 1H), 5.19 (s, 1H), 3.96 (br s, 1H),
3.94 (dd, J ) 6.3, 7.8 Hz, 1H), 3.71 (ddd, J ) 1.5, 3.4, 12.0 Hz,
1H), 3.59 (ddd, J ) 3.0, 3.4, 12.7 Hz, 1H), 2.57 (d, J ) 15.3
Hz, 1H), 2.50 (d, J ) 15.3 Hz, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 173.0, 163.1, 151.1, 141.0, 102.1, 86.9, 85.6, 77.1, 76.3,
60.7; MS (FAB) m/ z 302 (MH+). Anal. Calcd for
C11H15N3O7: C, 43.86; H, 5.02; N, 13.95. Found: C, 43.97; H,
4.84; N, 13.65.
J O961665F