Synthesis of a 1'-α-phenylselenouridine derivative as a synthetic precursor for various 1'-modified nucleosides, via enolization at the 1'- position of 3',5'-O-TIPDS-2'-ketouridine

Article abstract of DOI:10.1016/S0040-4039(00)00432-9

Synthesis of the 1'-α-phenylselenouridine derivative 1α, a potentially useful precursor for the synthesis of a variety of 1'-modified nucleosides, was achieved via enolization of the 3',5'-O-TIPDS-2'-ketouridine 2. Successive treatment of 2 with LiHMDS and PhSeCl at ≤70°C in THF gave the corresponding 1'-phenylseleno product, which was reduced stereoselectively with NaBH₄/CeCl₃ in MeOH to give the target compound 1α. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00432-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3643–3646
Synthesis of a 10-α-phenylselenouridine derivative as a synthetic
precursor for various 10-modified nucleosides, via enolization at
the 10-position of 30,50-O-TIPDS-20-ketouridine†
Tetsuya Kodama, Satoshi Shuto,∗ Makoto Nomura and Akira Matsuda ∗
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
Received 17 February 2000; revised 6 March 2000; accepted 10 March 2000
Abstract
Synthesis of the 10-α-phenylselenouridine derivative 1α, a potentially useful precursor for the synthesis of a
variety of 10-modified nucleosides, was achieved via enolization of the 30,50-O-TIPDS-20-ketouridine 2. Successive
treatment of 2 with LiHMDS and PhSeCl at ≤70°C in THF gave the corresponding 10-phenylseleno product, which
was reduced stereoselectively with NaBH4/CeCl3 in MeOH to give the target compound 1α. © 2000 Elsevier
Science Ltd. All rights reserved.
In recent years, we have been engaged in the synthetic study of medicinal chemically important
branched-chain sugar nucleosides.1 Although a number of procedures for preparing them have been de-
veloped, examples of newly synthesized 10-branched-chain sugar nucleosides are limited.2 Furthermore,
their biological activities have not yet been investigated in a systematic manner presumably because
efficient synthetic methods for their preparation have not been developed.
We previously demonstrated that 40-phenylselenonucleosides I could be used successfully in preparing
a variety of 40-α-branched-chain sugar nucleosides II via the radical reaction with a temporary con-
necting vinylsilyl tether (Fig. 1).3 Among these, 40-α-ethenyl- and -ethynylthymidines showed potent
antiviral effects.3d Considering the results of the synthetic study of 40-branched-chain sugar nucleosides,
10-phenylselenonucleosides should also be highly useful precursors for the synthesis of 10-α-branched-
chain sugar nucleosides having biological importance. In this communication, we describe the synthesis
of a sugar-protected 10-phenylselenouridine 1 via enolization of the 20-ketouridine derivative followed
by reaction with PhSeCl.
The 30,50-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPDS)-20-ketouridine 2, first prepared by
our group,4 has been widely used for the synthesis of 20-modified nucleosides via nucleophilic addition
reactions at the 20-carbonyl.5 We presumed that treatment of the 20-ketouridine derivative 2 with a strong
∗
†
Corresponding author. Fax: +81-11-706-4980; e-mail: matuda@pharm.hokudai.ac.jp (A. Matsuda)
This paper constitutes Part 199 of Nucleosides and Nucleotides. Part 198: Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.;
Matsuda, A., submitted for publication.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00432-9
tetl 16712

3644
Fig. 1.
base would produce the corresponding 10-enolate 3 (Scheme 1) and that the subsequent reaction with
PhSeCl as an electrophile would give the 10-phenylseleno-20-ketouridine derivative. The stereoselective
hydride reduction of the 20-carbonyl from the β-face would provide the desired 10-α-phenylselenouridine
derivative 1α.
Scheme 1.
We first examined whether enolization at the 10-positon occurred by deuterium-labeling experiments.
A mixture of 2 and LiHMDS (2.1 equiv.) in THF was stirred at ≤70°C for 1 h and quenched with
CD3CO2D/CD3OD. The 20-ketouridine 2D was obtained in about 90% yield,6 of which 54% of the
10-proton was replaced by a deuterium atom. A similar experiment with LDA as the base also gave
the 10-deuterium-labeled product 2D (yield 72%, deuterium-incorporation 50%). Furthermore, when the
reaction mixture of 2 and LiHMDS (2.1 equiv.) in THF was treated with BzCl at ≤70°C, the enol-
O-benzoate 4 was obtained in 73% yield. These experiments clearly show that the 10-enolate 3 was
produced under these conditions, as predicted. As far as we know, this is the first example demonstrating
enolization at the 10-position of a 20-ketonucleoside.7
Introduction of a phenylseleno group at the 10-position was next investigated (Scheme 2), and the
results are summarized in Table 1. The reactions were carried out as follows. A mixture of 2 and a base
in a solvent was stirred at ≤70°C 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 purified by neutral silica
gel column chromatography. The reaction was first performed with 1.5 equivalents of LiHMDS to give
the desired 10-phenylseleno product in 47% yield as an anomeric mixture of 5 and 6 (5:6=2.9:1, entry
1), respectively. It is noteworthy that the 10-β-phenylseleno product 6 was in equilibrium between the 20-
keto-form 6a and its 20-hydrate 6b. The stereochemistries were confirmed by NOE experiments of 6b,
as shown in Fig. 2. When 2.1 or 3.0 equivalents of LiHMDS were used, the yield increased significantly
(entry 2, yield 85%; entry 3, yield 73%).8 However, using 4.0 equivalents of the base resulted in poorer
yield (entry 4).9 In all these reactions, the 10-α-phenylseleno product 5 was selectively obtained as the

3645
major product. The effect of the solvent on the reaction was next examined. Although 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). Although the anomeric ratio did not change in the reactions in DME or Et2O, the facial
selectivity was almost lost in the reaction in THF/HMPA as the solvent (entry 7, yield 75%, 5:6=1.4:1).
Reactions were further carried out with other strong bases. Although the yield decreased in the reaction
with LDA as the base, the 10-phenylseleno products were obtained in excellent yields similar to those
with LiHMDS, when NaHMDS or KHMDS was used as the base (entries 9 and 10). It is interesting to
note that the α-selectivity is lost when the counterion of HMDS is changed to sodium. Furthermore, the
stereoselectivity was reversed to give 10-β-phenylseleno derivative 6 as the major product (5:6=1:3.0)
when potassium was used as the counterion. These results with different counterions, together with the
result in the presence of HMPA (entry 7), suggest that the 10-α-phenylseleno product 5 is probably
produced via a chelation-controlled reaction pathway.10
Scheme 2.
Table 1
The introduction of a phenylseleno group at the 10-position of 2
Fig. 2.
The 10-α-phenyseleno product 5, which was obtained in a pure form after neutral silica gel column
chromatography, was subjected to reduction at the 20-keto moiety. After investigation of various reaction

3646
conditions, we found that the 20-carbonyl group of 5 was functionally- and stereoselectively reduced
from the β-face when it was treated with NaBH4/CeCl3 in MeOH11 at ≤70°C to give the desired sugar-
protected 10-phenylselenouridine 1α in 81% yield as the sole product.12
As far as we know, this is the first example of functionalization at the anomeric 10-position of a
nucleoside, starting from a natural nucleoside, to produce a ribo-type 10-modified nucleoside.13
In summary, we have successfully introduced a phenylseleno group at the 10-position via enolization
of the 20-ketouridine derivative 2. Subsequent functional- and stereoselective reduction of the 20-keto
moiety gave the desired sugar-protected 10-phenylselenouridine 1α (Scheme 3), which should be a highly
useful precursor in the preparation of various 10-α-modified nucleosides of biological interest.14
Scheme 3.
References
1. Ichikawa, S.; Shuto, S.; Minakawa, N.; Matsuda, A. J. Org. Chem. 1997, 62, 1368–1375, and references cited therein.
2. For examples, see: (a) Elliott, R. D.; Niwas, S.; Riordan, J. M.; Montgomery, J. A.; Secrist III, J. A. Nucleosides Nucleotides
1992, 11, 97–119. (b) Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. J. Org. Chem. 1995, 60, 656–662. (c)
Goodman, B. K.; Greenberg, M. M. J. Org. Chem. 1996, 61, 2–3.
3. (a) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 1997, 62, 5676–5677. (b) Shuto, S.; Kanazaki, M.;
Ichikawa, S.; Minakawa, N.; Matsuda, A. J. Org. Chem. 1998, 63, 746–754. (c) Ueno, Y.; Nagasawa, Y.; Sugimoto, I.;
Kojima, N.; Kanazaki, M.; Shuto, S.; Matsuda, A. J. Org. Chem. 1998, 63, 1660–1667. (d) Sugimoto, I.; Shuto, S.; Mori,
S.; Shigeta, S.; Matsuda, A. Bioorg. Med. Chem. Lett. 1999, 9, 385–388. (e) Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org.
Chem. 1999, 64, 7153–7157. (f) Kanazaki, M.; Ueno, Y.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2000, 122, 2422–2432.
4. Ueda, T.; Shuto, S.; Inoue, H. Nucleosides Nucleotides 1984, 3, 173–182.
5. For examples, see: Azuma, A.; Nakajima, Y.; Nishizono, N.; Minakawa, N.; Suzuki, M.; Hanaoka, K.; Kobayashi, T.;
Tanaka, M.; Sasaki, T.; Matsuda, A. J. Med. Chem. 1993, 36, 4183–4189, and references cited therein.
6. It included a trace of an inseparable unknown compound, which might be the corresponding α-anomer.
7. The 30-lithium enolate of 30-deoxy-20-ketouridine derivative has been reported: Haraguchi, K.; Tanaka, H.; Itoh, Y.;
Miyasaka, T. Tetrahedron Lett. 1991, 32, 777–780.
8. When 30,50-bis-O-TBS-20-ketouridine was treated under the conditions identical to those in entry 3, it gave a mixture of
10-α- and 10-β-phenylseleno products in a ratio of ca. 1:1 in 56% yield. Although we also tried to use 30,50-O-di-tert-
butylsilylene-20-ketouridine as the substrate, it was too unstable not to be obtained in a pure form.
9. The 10-phenylseleno group is likely to be replaced by lithium in the presence of an excess of LiHMDS, since the substrate
2 was obtained in 90% yield when 6a was treated again with LiHMDS (4 equiv.) at ≤70°C in THF.
10. While the structure of the chelation intermediate is unclear, a chelation of Li+ between the 20-enol-oxygen and 2-carbonyl-
oxygen of the uracil moiety may be possible.
11. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
12. The reduction of a 10-α-methoxycarbonylethyl-2-ketouridine derivative, synthesized from D-fructose, with NaBH4 has
been reported, in which the corresponding arabino- and ribo-type products were obtained in a ratio of 1:5 in 87% yield:
Yoshimura, Y.; Ueda, T.; Matsuda, A. Tetrahedron Lett. 1991, 32, 4549–4552.
13. 20-Deoxy-10-modified uridines have been synthesized from uridine via electrophilic addition reactions on a 10,20-
unsaturated uridine derivative: Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. J. Org. Chem. 1995, 60, 656–662.
14. After introduction of a vinylsilyl tether at the 20-hydroxy of 1α, its radical reactions successfully gave the corresponding
10-α-branched-chain sugar nucleosides. These results will be reported elsewhere.