A highly stereoselective samarium diiodide-promoted aldol reaction with 1′phenylseleno-2′-keto nucleosides. Synthesis of 1′α-branched uridine derivatives

Article abstract of DOI:10.1021/jo020266j

Since 1′-branched nucleosides are biologically important targets in medicinal chemistry, more efficient methods for preparing them are required. The 1′α-branched uridine derivatives were successfully synthesized via a samarium diiodide (SmI₂)-promoted aldol reaction. Treatment of the 1′α-phenylseleno-2′-ketouridine derivative 6, readily prepared from uridine, with SmI₂ at -78 °C in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO, i-PrCHO, or (CH₂O)_n, to give the corresponding 1′α-1″S-branched products 12a-d. This is the first time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the tandem aldol-Tishchenko reaction proceeded to give the "arabino-type" nucleosides 14a-c, having a 2′-"up" hydroxyl and 1′α-1″S-branched chain. 1′α-Hydroxymethyluridine (21), which is the uracil version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product 10.

Full text of DOI:10.1021/jo020266j

A High ly Ster eoselective Sa m a r iu m Diiod id e-P r om oted Ald ol
Rea ction w ith 1′-P h en ylselen o-2′-k eto Nu cleosid es. Syn th esis of
1′r-Br a n ch ed Ur id in e Der iva tives
Tetsuya Kodama, Satoshi Shuto,* Satoshi Ichikawa, and Akira Matsuda*
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan
shu@pharm.hokudai.ac.jp
Received April 15, 2002
Since 1′-branched nucleosides are biologically important targets in medicinal chemistry, more
efficient methods for preparing them are required. The 1′R-branched uridine derivatives were
successfully synthesized via a samarium diiodide (SmI2)-promoted aldol reaction. Treatment of
the 1′R-phenylseleno-2′-ketouridine derivative 6, readily prepared from uridine, with SmI2 at -78
°C in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium
enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO,
i-PrCHO, or (CH2O)n, to give the corresponding 1′R-1′′S-branched products 12a -d . This is the first
time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective
stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition
state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the
tandem aldol-Tishchenko reaction proceeded to give the “arabino-type” nucleosides 14a -c, having
a 2′-“up” hydroxyl and 1′R-1′′S-branched chain. 1′R-Hydroxymethyluridine (21), which is the uracil
version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product
10.
In tr od u ction
tions.2 Most 1′-branched nucleosides are prepared from
the corresponding ribose derivatives branched at the
1-position via glycosidation or nucleobase construction.6
These methods are not very practical and have draw-
backs: (1) the preparation of the 1′-branched sugars
requires many reaction steps and the overall yields are
low and (2) the stereoselective introduction or construc-
tion of the nucleobase is tedious.
Branched-chain sugar nucleosides are biologically im-
portant targets in medicinal chemistry, and a number of
procedures for preparing them have been developed.2
The antibiotic angustmycin C (1), the structure of
which was identified as the adenosine analogue bearing
a hydroxymethyl group at the 1′R-position, is known to
show antitumor activity.3 2′-Deoxy-1′-pivaloyluridine (2)
proved useful in producing a radical at the 1′-position of
the 2′-deoxyuridine residue in oligonucleotides, which
was effective in studying the mechanism of oxidative
damage of DNA.4 Most recently, the North-form (3′-endo)-
locked 1′-branched nucleoside derivative 3 was effectively
used for investigating the relationship between the DNA/
RNA duplex conformation and the RNase H cleavage
reaction.5 However, despite their biological importance,
syntheses of nucleoside analogues branched at the ano-
meric 1′-position are not as common6-8 as syntheses of
nucleoside derivatives branched at the 2′- and 3′-posi-
1′-Branched nucleosides are considered to be a kind of
C-glycoside having both a nucleobase and a carbon sub-
stituent at the anomeric position of ribose or 2-deoxy-
ribose. C-Glycosides are gaining increasing interest since
they appear as fragments in the structures of a number
of natural products.9 Moreover, because of their resist-
ance to hydrolysis, C-glycosides are expected to be stable
(6) For examples see: (a) Mahmood, K.; Vasella, A.; Bernet, B. Helv.
Chim. Acta 1991, 74, 1555-1584. (b) Elliott, R. D.; Niwas, S.; Riordan,
J . M.; Montgomery J . A.; Secrist, J . A., III Nucleosides Nucleotides
1992, 11, 97-119. (c) Faivre-Buet, V.; Grouiller, A.; Descotes, G.
Nucleosides Nucleotides 1992, 11, 1651-1660. (d) Uteza, V.; Chen, G.-
H.; Toui, J . L.-Q.; Descotes, G.; Fenet, B.; Gouiller, G. Tetrahedron
Lett. 1993, 34, 8579. (e) Hayakawa, H.; Miyazawa, M.; Tanaka, H.;
Miyasaka, T. Nucleosides Nucleotides 1994, 13, 297-308. (f) Ono, A.;
Dan, A.; Matsuda, A. Bioconj. Chem. 1993, 4, 499-508. (g) Yoshimura,
Y.; Otter, B. A.; Ueda, T.; Matsuda, A. Chem. Pharm. Bull. 1992, 40,
1761-1769.
(7) (a) Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. J .
Org. Chem. 1995, 60, 656-662. (b) Yoshimura, Y.; Kano, F.; Miyazaki,
S.; Ashida, N.; Sakata, S.; Haraguchi, K.; Itoh, Y.; Tanaka, H.;
Miyasaka, T. Nucleosides Nucleotides, 1996, 15, 305-324.
(8) (a) Kodama, T.; Shuto, S.; Nomura, M.; Matsuda, A. Tetrahedron
Lett. 2000, 41, 3643-3646. (b) Kodama, T.; Shuto, S.; Nomura, M.;
Matsuda, A. Chem. Eur. J . 2001, 7, 2332-2340.
(1) This report constitutes Part 213 of the series Nucleosides and
Nucleotides: For Part 212 see: Nomura, M.; Sato, T.; Washinosu, M.;
Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A. Tetrahedron 2002, 58,
1279-1288.
(2) Sukeda, M.; Shuto, S.; Sugimoto, I.; Ichikawa, S.; Matsuda, A.
J . Org. Chem. 2000, 65, 8988-8996 and references therein.
(3) Yu¨ntsen, H.; Ohkuma, K.; Ishii, Y. J . Antibiot. 1956, 9A, 195-
201.
(4) Hwang, J .-T.; Greenberg, M. M. J . Am. Chem. Soc. 1999, 121,
4311-4315 and references therein.
(5) Pradeepkumar, P. I.; Zamaratski, E.; Fo¨ldesi, A.; Chatto-
padhyaya, J . Tetrahedron Lett. 2000, 41, 8601-8607.
10.1021/jo020266j CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
7706
J . Org. Chem. 2002, 67, 7706-7715

SmI2-Promoted Aldol Reaction of Nucleosides
SCHEME 1
mimics for natural O-glycosides exhibiting biological
activity.10,11 Although the methods for the synthesis of
C-glycosides have been extensively studied, stereoselec-
tive construction of the desired C-glycosidic linkage is
often difficult.12 These results on C-glycoside synthesis
suggest that the difficulty in synthesizing 1′-branched
nucleosides arises because both the R-C- and the â-N-
glycosidic bonds have to be constructed stereoselectively.
Several years ago, Tanaka and co-workers reported an
efficient method for preparing 1′-branched nucleosides
from common ribonucleosides, such as uridine, via an
electrophilic addition reaction on a 1′,2′-unsaturated
uridine derivative.7 Using this method, they prepared the
antitumor 1′-cyano cytosine nucleoside 4.7b Most recently,
we stereoselectively synthesized 1′-vinyl pyrimidine ribo-
nucleosides starting from uridine, via a novel intra-
molecular radical cyclization reaction with a silyl tether13
as the key step.8 These are the only two practical
examples reported so far that provide 1′-branched nu-
cleosides in rather good overall yield because they use
natural nucleosides as the synthon thereby shortening
the reaction steps. However, the 1′-carbon substituents
to be introduced by these two methods are limited, and
the biological activities of 1′-branched nucleosides have
not been systematically investigated. Consequently, al-
ternative efficient methods, which would allow the
preparation of a variety of 1′-branched nucleosides, are
required.
SCHEME 2
position to generate the enolate II; (3) the substrates,
normally unstable under basic and/or acidic conditions,
can now be used since the reaction proceeds under
neutral conditions at -78 °C; and (4) the reaction is
stereoselective to give the corresponding R-C-glycosides
III as the major product in high yield. We carried out
the first synthesis of the tricyclic-sugar nucleoside anti-
biotic herbicidin B using the SmI2-promoted aldol-type
C-glycosidation reaction as the key step.15b We also
developed an efficient method of preparing 3′-branched
nucleosides using the SmI2-promoted intramolecular
Reformatsky reaction as the key step,16 showing that
SmI2 is particularly effective in nucleoside chemistry.
With these encouraging results in mind, we decided to
investigate the synthesis of 1′-branched nucleosides using
the SmI2-promoted aldol reaction as the key step.
We have already developed a very useful SmI2-
promoted14 aldol-type C-glycosidation reaction (Scheme
1),15 which offers several distinct advantages: (1) the
phenylthio-2-ulose derivatives I, the precursors for gen-
erating the enolates, are stable and easy to prepare; (2)
the regioselective enolization at the anomeric position of
the ulose derivatives can be achieved by SmI2-promoted
reductive cleavage of a C-S bond at the anomeric
(9) (a) Humber, D. C.; Mulholland, K. R.; Stoodley, R. J . J . Chem.
Soc., Perkin Trans. 1 1990, 283-292. (b) Murata, M.; Kumagai, M.;
Lee, J . S.; Yamamoto, T. Tetrahedron Lett. 1987, 28, 5869-5872. (c)
Clayton, J . P.; O’Hanlon, P. J .; Rogers, N. H. Tetrahedron Lett. 1980,
21, 881- 884.
(10) (a) Watson, K. A.; Mitchell, E. P.; J ohnson, L. N.; Son, J . C.;
Bichard, C. J . F.; Fleet, G. W. J .; Watkin, D. J .; Oikonomakos, N. G.
J . Chem. Soc., Chem. Commun. 1993, 654-656. (b) Myers, R. W.; Lee,
Y. C. Carbohydr. Res. 1986, 152, 143-158. (c) Martin, J . L.; J ohnson,
L. N.; Withers S. G. Biochemistry 1990, 29, 10745-1057.
Resu lts a n d Discu ssion
(11) Our studies on C-glycosides as stable mimics of biologically
active O-glycosides: (a) Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda,
A. Tetrahedron Lett. 1999, 40, 5527-5531. (b) Shuto, S.; Yahiro, Y.;
Ichikawa, S.; Matsuda, A. J . Org. Chem. 2000, 65, 5547-5557. (c)
Shuto, S.; Terauchi, M.; Yahiro, Y.; Abe, H.; Ichikawa, S.; Matsuda,
A. Tetrahedron Lett. 2000, 41, 4151-4155. (d) Abe, H.; Shuto, S.;
Matsuda, A. Tetrahedron Lett. 2000, 41, 2391-2394. (e) Abe, H.; Shuto,
S.; Matsuda, A. J . Org. Chem. 2000, 65, 4315-4325. (f) Abe, H.; Shuto,
S.; Matsuda, A. J . Am. Chem. Soc. 2001, 123, 11870-11882.
(12) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
J aramillo, C.; Kanapp, S. Synthesis 1994, 1-20. (c) Leavy, D. E.; Tang,
C. The Chemistry of C-Glycosides; Pergamon Press: Oxford, UK, 1995.
(d) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
FL, 1995. (e) Du, Y.; Linhardt, R. J . Tetrahedron 1998, 54, 9913-9959.
(13) Shuto, S.; Sugimoto, I.; Abe, H.; Matsuda, A. J . Am. Chem. Soc.
2000, 122, 1343-1351 and references therein.
(14) SmI2-promoted reactions: (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., Eds.; Pergamon
Press: New York, 1991; 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.
Syn th etic P la n . Our synthetic plan, using the 1′-
phenylseleno-2′-ketouridine derivative IV as the precur-
sor for the 1′-enolate, is summarized in Scheme 2. We
previously reported that a phenylseleno group could be
introduced stereoselectively at the 1′R-position of 2′-
ketouridine derivatives,8 which readily provides the
substrate IV for the SmI2-promoted aldol reaction. We
speculated that if the phenylseleno group at the 1′-
position of VI was reductively cleaved by SmI2 like the
anomeric phenylthio group of the ulose I, the samarium
enolate V would be formed. The condensation reaction
between the resulting enolate V and an aldehyde would
give the corresponding 1′-branched nucleosides VI as the
aldol reaction products. In this reaction, the stereochem-
istry of the product VI could be controlled via a chelation
transition state due to the high affinity of samarium for
(15) (a) Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 1998,
39, 4525-4528. (b) Ichikawa, S.; Shuto, S.; Matsuda, A. J . Am. Chem.
Soc. 1999, 121, 10270-10280.
(16) Ichikawa, S.; Shuto, S.; Minakawa, N.; Matsuda, A. J . Org.
Chem. 1997, 62, 1368-1375.
J . Org. Chem, Vol. 67, No. 22, 2002 7707

Kodama et al.
SCHEME 3
SCHEME 4
F IGURE 1. Examples of biologically important 1′-branched
nucleosides.
phenylseleno group occurred to generate the desired 1′-
enolates.
The aldol reaction was subsequently investigated; the
samarium enolate solution in THF prepared with 2.1
equiv of SmI2 at -78 °C was treated with an aldehyde
as the electrophile. The N-3-unprotected 2′-keto nucleo-
side 5 was first used as the substrate (Scheme 4), and
thus 5 was successively treated with SmI2 and PhCHO
(3 equiv) at -78 °C in THF. Although the aldol reaction
proceeded efficiently to produce the corresponding reac-
tion product 9 in 89% yield, it was nonstereoselective and
1H NMR analysis indicated that the product was a
mixture of the four diastereomers at the 1′- and 1′′-
positions.17,18 When a similar aldol reaction of 5 was
examined with an excess of paraformaldehyde [(CH2O)n]
as the electrophile, the 1′R-hydroxymethyl product 10
was stereoselectively obtained in 52% yield along with
its 1′â-anomer 11 in 13% yield.
The aldol reactions of the N-3-BOM substrate 6 were
next investigated, and the results are summarized in
Table 1 and Scheme 5. When the samarium enolate
prepared from 6 with SmI2 (2.1 equiv) was subjected to
the aldol reaction with PhCHO (3 equiv) as the electro-
phile at -78 °C in THF, the expected 1R′-branched
nucleoside 12a was obtained in 76% yield along with its
anomer 13a in 10% yield (entry 1). Surprisingly, the
reaction was almost completely stereocontrolled at the
1′′-position to produce the 1′′S-product, the stereochem-
istry of which was confirmed as described below. A
F IGURE 2. A possible chelation-controlled reaction pathway
of the SmI2-promoted aldol reaction to stereoselectively pro-
duce the 1′R-branched products.
oxygen.14 We anticipated that the chelation-controlled
reaction would selectively occur from the R-direction at
the 1′-position via the transition states R1 or R2 to give
the corresponding R-product VI because of steric repul-
sion by the tetrahedral 5′-methylene moiety when the
aldehyde approaches from the â-face via transition states
â1 or â2 (Figure 2). Stereoselective reduction of the 2′-
carbonyl of VI would give the “ribo-type” (VII) and the
“arabino-type” (VIII) 1′-branched nucleosides.
Sm I2-P r om oted Ald ol Rea ction of 2′-Keto Ur a cil
Nu cleosid es. First, the SmI2-promoted generation of the
1′-enolate V (Scheme 2) was examined. When 3′,5′-O-
[tetraisopropyldisiloxane-1,3-diyl (TIPDS)]-1′-phenyl-
seleno-2′-ketouridine (5) was treated with 2.5 equiv of
SmI2 at -78 °C in THF, the starting material im-
mediately disappeared on TLC. After the reaction was
quenched with aqueous NH4Cl, the de-phenylselenated
product 7 was obtained in about 90% yield as a mixture
of anomers. The same treatment of the corresponding
N-3-benzyloxymethyl (BOM) derivative 6 also gave the
de-selenated product 8 in high yield. These results
showed that SmI2-promoted reductive removal of the
(17) The numbering used in this paper considers the side-chain
carbon adjacent to the 1′-position as 1′′.
(18) A â-branched product seemed to be in equilibrium between the
2′-keto form and its 2′-hydrate.
7708 J . Org. Chem., Vol. 67, No. 22, 2002

SmI2-Promoted Aldol Reaction of Nucleosides
TABLE 1. Sm I2-P r om oted Ald ol Rea ction betw een 6
a n d Ald eh yd es.
SCHEME 6
electrophile
(equiv)
temp,
°C
1′-branched products
entry
(yield, %)a
R/â
1
2
3
4
5
6
7
PhCHO (3)
PhCHO (1.2) -78
MeCHO (3) -78
-78
12a (76)
12a (60)b
12b (29)
12c (48)b
12c (59)c
13a (10%)
14b (52%)
7.6:1
R
R
R
R
i-PrCHO (3) -78
i-PrCHO (5) -78
t-BuCHO (3) -78frt
d
-
(CH2O)n (3)
-78f0 12d (57%) 13d (12%)d 4.8:1
a
b
Isolated yield. The reduction product 8 was obtained (30%
in entry 2, 33% in entry 4). c Reaction was quenched with TMSCl
(10 equiv). N-3-BOM-uracil (15) was obtained (81% in entry 6,
d
27% in entry 7).
SCHEME 5
been known to reduce other carbon-heteroatom bonds,
such as C-O or C-S bonds, when a carbonyl group is
present at the adjacent position.15,16,19
Sm I2-P r om oted Ta n d em Ald ol-Tish ch en k o Rea c-
tion of th e 2′-Keto Nu cleosid e 6. It is known that in
SmI2-promoted aldol reactions, the resulting aldols are
often further reduced via the Tishchenko reaction.20 Such
reductions stereoselectively afford the corresponding anti-
1,3-diol monoesters through a chelation-controlled path-
way.20 As described above, in this study the Tishchenko-
type reduction of the aldol 12b actually proceeded
to afford the corresponding anti-1,3-diol product, the
“arabino-type” 1′-branched nucleoside 14b, when MeCHO
was used as the electrophile (Table 1, entry 3). The
biological activity of “arabino-type” 1′-branched nucleo-
sides, i.e., nucleosides having 2′-“up” substituent, is
interesting to us since various “arabino-type” nucleoside
analogues are known to show potent antitumor and/or
antiviral effect, as typified by the clinically useful anti-
leukemic drug 1-â-D-arabinofuranosylcytosine (ara-C)
and the antitumor “arabino-type” 1′-cyanocytosine nu-
cleoside 4.7b We therefore decided to investigate the
tandem aldol-Tishchenko reaction of the 2′-keto nucleo-
side 6 (Scheme 6 and Table 2).
similar reaction with 1.2 equiv of PhCHO lowered the
yield of the 1′R-branched nucleoside 12a (60%) and the
1′-reduced product 8 was also formed in 30% yield (entry
2). Other aldehydes were examined as possible electro-
philes. The reaction with 3 equiv of MeCHO instead of
PhCHO under the same conditions as those for entry 1
gave a low yield of the aldol reaction product 12b (29%)
with the 1′R-branched-1′′S-stereochemistry. In this reac-
tion, the Tishchenko reaction of the aldol product 12b
occurred to afford the “arabino-type” 1′-R-branched nu-
cleoside 14b as the major product in 52% yield (entry 4).
The reaction with 3 equiv of i-PrCHO at -78 °C was
rather slow but gave the aldol product 12c with the same
1′R-branched-1′′S-stereochemistry in 48% yield accom-
panied by the reduction product 8 (33%). When the
reaction was performed with 5 equiv of i-PrCHO in the
presence of TMSCl, the yield of 12c increased somewhat
(59%, entry 5). The aldol reaction seemed to be sensitive
to the steric hindrance of the electrophile. When the
highly sterically hindered t-BuCHO was used as the
electrophile, the aldol reaction did not proceed at -78
°C, and gradual warming of the reaction mixture to room
temperature resulted in glycosidic bond cleavage to
produce the 3-BOM-uracil (15) (entry 6). Although
paraformaldehyde was also inactive as the electrophile
at -78 °C, the aldol reaction proceeded slowly to give the
R-product 12d as the major product when the reaction
mixture was warmed (entry 7).
The reactions were carried out as follows: To the THF
solution of the samarium enolate of 6, prepared with 2.1
equiv of SmI2, was added 5 equiv of an aldehyde at -78
°C, and the mixture was warmed gradually. The reaction
with PhCHO produced the expected anti-1,3-diol product,
the “arabino-type” 1′-branched nucleosides 14a , in 74%
yield (entry 1). A similar treatment with MeCHO suc-
(19) (a) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135-
1138. (b) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida,
A.; Mikami, K. Tetrahedron Lett. 1997, 38, 2709-2712.
(20) SmI2-promoted tandem aldol-Tishchenko reactions: Lu, L.;
Chen, H.-Y.; Fong, J .-H. J . Org. Chem. 1999, 64, 843-853 and
references therein.
This is the first example that generates an enolate by
reductively cleaving a C-Se bond, although SmI2 has
J . Org. Chem, Vol. 67, No. 22, 2002 7709

Kodama et al.
TABLE 2. Sm I2-P r om oted Ten d em Ald ol-Tish ch en co
Rea ction of 6
SCHEME 8
electrophile
(equiv)
temp
(°C)
1′-branched products
entry
(yield, %)a
1
2
3
PhCHO (5)
MeCHO (5)
i-PrCHO (5)
-78 to rt
-78 to -10
-78 to -10
14a (74)
14b (83)
14c (55)
16 (41)
a
Isolated yield.
SCHEME 7
Compound 17, obtained via the aldol reaction with
PhCHO, was derivatized into the corresponding 2′,3′-O-
isopropylidene derivative 22, which clearly showed its
2′,3′-cis-diol structure. The 1R′-branched-1′′S stereochem-
istry of 17 was successfully determined by the NOESY
spectrum, after its conversion into the corresponding
1′′,2′-O-isopropylidene derivative 23 (Figure 3A). The 1′R-
1′′S-stereochemical result of the aldol reaction with
i-PrCHO was determined based on the structure analysis
of the hemiketal product 16 by its HMBC and NOESY
spectra, as shown in Figure 3B. The 1′′-configuration of
the aldol reaction with MeCHO was also confirmed as S
by the modified Mosher’s method,21 after conversion of
the aldol-Tishchenko reaction product 14b into the
corresponding R- and S-MTPA esters 24R and 24S. Its
2′S-configuration was confirmed by NOE experiments
(Figure 3C). Compound 21 was identified as the uracil
version of angustmycin C from NOE experiments of the
diacetate 25 (Figure 3D).
Therefore, the aldol reactions of 6 were highly stereo-
selective with the major products having the same 1′R-
branched-1′′S-stereochemisty. The reactions with MeCHO
and i-PrCHO as the electrophile, in particular, produced
only the 1′R-branched-1′′S-products (Table 1, entries
2-5). The highly selective formation of the 1′R-branched
products may be explained by the steric repulsion due
to the tetrahedral 5′-methylene moiety when the alde-
hyde approaches from the â-face via the transition states
â1 or â2. The highly selective 1′′S-stereochemical results
suggest that the aldol reaction proceeds via the chelation-
controlled pathway of the transition state R2 rather than
transition state R1 (Figures 2 and 4).22 Dubois and co-
workers reported that the stereochemical results of the
chelation-controlled aldol reaction of 2-substituted cyclo-
pentanones could be dependent upon the bulkiness of the
2-substituent (R), as shown in Figure 5.23 On the other
hand, Tanaka and co-worker reported that in 2′-substi-
tuted 1′,2′-unsaturated uracil nucleosides, the 1′,2′-
unsaturated bond is not conjugated with the uracil base,24
which suggests that in the samarium enolate V (Scheme
2), the enol moiety is not conjugated with the base moiety,
cessfully gave the desired product 14b in 83% yield (entry
2). When i-PrCHO was used as an electrophile, the
reaction also stereoselectively proceeded to give the
corresponding anti-1,3-diol product (entry 3), which was
obtained as the cyclic hemiketal 16 (41%), along with the
usual O-acylated product 14c (55%). These results showed
that the tandem aldol-Tishchenko reaction effectively
proceeded via the six-membered chelation-controlled
pathway as shown in Scheme 6.
Red u ction of th e 2′-Ca r bon yl of th e Ald ol Rea c-
tion P r od u cts by Hyd r id e Rea gen ts. The aldol reac-
tion product 12a was subjected to reduction at the 2′-
keto moiety with hydride reagents. We found that
complete stereochemical reversal of the 2′-carbonyl re-
duction of 12a was possible, depending upon the reducing
reagent, as shown in Scheme 7. Thus, the “ribo-type” 17
was stereoselectively obtained in high yield when 12a
was reduced with NaBH4 in MeOH, where the “arabino-
type” 18 was quantitatively produced by reduction with
NaBH(OAc)3 in MeCN.
On the other hand, although reductions of the 1′-
hydroxymethyl-2′-keto derivatives 10 and 12d with vari-
ous reagents, such as NaBH4, K-selectride, DIBAL-H, or
LiAlH(Ot-Bu)3, were examined, none of these was highly
stereoselective. For example, 10 was reduced with NaBH4
in MeOH to give a mixture of the “arabino-type” 19 and
the “ribo-type” 20 in about 2:3 ratio, which could be
readily separated by the usual silica gel column chro-
matography. Deprotection of 20 with TBAF in THF
furnished the 1′R-hydroxymethyl uridine (21), which is
the uracil version of angustmycin C (Scheme 8).
Ster eoch em istr y of th e Sm I2-P r om oted Ald ol Re-
a ction . The structures of the products including stereo-
chemistry were confirmed by NOE experiments, NOESY
and HMBC spectra, and modified Mosher’s method, as
shown in Figure 3.
(21) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.
(22) It might be that the oxygen of the 2-keto and/or BOM moiety
also interacts with the Sm3+ in the chelation-controlled pathway.
(23) Fellmann, P.; Dubois, J .-E. Tetrahedron 1978, 34, 1349-1357.
7710 J . Org. Chem., Vol. 67, No. 22, 2002

SmI2-Promoted Aldol Reaction of Nucleosides
F IGURE 5. Dubois’ chelation-controlled model.
F IGURE 6.
fact that the stereoselectivity decreased in the reaction
of the N-3-free substrate 5, in which the base moiety is
less bulky compared with that of 6.
We examined the aldol reaction between the lithium
1′-enolate 2625 (Figure 5) and PhCHO under various
conditions. As a result, the reaction was nonstereo-
selective to give a mixture of the aldol reaction product
in low yield. Although we also investigated the Lewis
acid-promoted aldol reaction with 2-O-TMS-enol ether
2726 as the substrate, it produced the enone 28 as the
major product. These experiments clearly demonstrate
the usefulness of the SmI2-promoted aldol reaction with
the 1′R-phenylseleno-2′-ketouridine derivative 6 as the
substrate.
Con clu sion
The 1′-samarium enolate was successfully prepared
from the 1′R-phenylseleno-2′-ketouridine derivative 6 by
treating it with SmI2, which was highly stereoselectively
condensed with aldehydes to give the corresponding 1′R-
1′′S-branched uridine products 12a -d . The excellent
stereochemical results suggest that the aldol reaction
proceeds via a chelation-controlled transition state. The
SmI2-promoted tandem aldol-Tishchenko reaction of 6
also effectively proceeded to produce the “arabino-type”
1′R-1′′S-branched nucleoside products 14a -c, when an
excess of the aldehyde was used. This is the first example
in nucleoside chemistry in which an aldol reaction was
used effectively.
F IGURE 3. Structural determination of the compounds.
F IGURE 4. A possible chelation-controlled reaction pathway
of the SmI2-promoted aldol reaction to stereoselectively pro-
duce the 1′R-branched-1′′S-products.
Exp er im en ta l Section
NMR chemical shifts are reported in ppm downfield from
TMS and J values are given in hertz. The 1H NMR assign-
namely, the two moieties do not lie in the same plane.
Accordingly, the steric repulsion by the base moiety
would be rather significant in the aldol reaction to
produce the 1′′S-product highly stereoselectively via the
R2 transition state, which is similar to Dubois’ cyclo-
pentanone model. This would be in agreement with the
(24) Kumamoto, H.; Shindoh, S.; Tanaka, H.; Itoh, Y.; Haraguchi,
K.; Gen, E.; Kittaka, A.; Miyasaka, T.; Kondo, M.; Nakamura, K. T.
Tetrahedron 2000, 56, 5363-5371.
(25) Prepared from N-3-BOM-3′,5′-O-TIPDS-2′-ketouridine by treat-
ing it with lithium hexamethyldisilazide in THF.
(26) The 1′-lithium enolate of 3′,5′-O-TIPDS-2′-ketouridine (see ref
8) was treated with TMSCl at -78 °C in THF to afford 27.
J . Org. Chem, Vol. 67, No. 22, 2002 7711

Kodama et al.
ments reported for key compounds are in agreement with 2D
NMR spectra. Thin-layer chromatography was done on Merck
coated plates 60F254. Silica gel chromatography was done on
Merck silica gel 5715 or Kanto Chemical silica gel 60 N
(neutral). Reactions were carried out under an argon atmo-
sphere.
Red u ctive De-p h en ylselen a tion of 5 a n d 6. To a solution
of SmI2 (0.10 M solution in THF, 2.5 mL, 0.25 mmol) was
added dropwise a solution of 5 (64 mg, 0.10 mmol) or 6 (76
mg, 0.10 mmol) in THF (1.5 mL) at -78 °C. After 5 or 6
disappeared on TLC, saturated aqueous NH4Cl was added to
the mixture, and the whole 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 chromatog-
raphy (SiO2, hexane:AcOEt ) 3:1 then 2:1) to give 7 (43 mg,
0.089 mmol, 89%) or 8 (54 mg, 0.090 mmol, 90%).
3-N-Ben zyloxym eth yl-1-[1-p h en ylselen o-3,5-O-(1,1,3,3-
t et r a isop r op yld isiloxa n e-1,3-d iyl)-â-D-er yth r o-2-p en t o-
su lofu r a n osyl]u r a cil (6). A mixture of 5 (2.74 g, 4.28 mmol),
benzyloxymethyl chloride (712 µL, 5.14 mmol), and N,N-
diisopropylethylamine (1.49 mL, 8.56 mmol) in DMF (30 mL)
was stirred at room temperature for 20 min. After addition of
EtOH (1.0 mL), the resulting mixture was stirred at the same
temperature for 5 min and then partitioned between AcOEt
and H2O. The organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column
chromatography (neutral SiO2, 15% AcOEt in hexane) to give
84 (2.93 g, 90% as a pale yellow solid): 1H NMR (CDCl3, 270
MHz) δ 8.47 (d, 1 H, J ) 8.3), 7.56-7.21 (m, 10 H), 5.80 (d, 1
H, J ) 8.3), 5.36, 5.32 (each d, each 1 H, J ) 9.9), 5.00 (d, 1 H,
J ) 7.5), 4.60, 4.59 (each d, each 1 H, J ) 12.3), 4.07-4.01
(m, 3 H), 1.17-1.01 (m, 28 H); 13C NMR (CDCl3, 100 MHz) δ
197.19, 161.74, 150.20, 141.62, 137.27, 135.76, 129.61, 129.21,
127.94, 127.43, 127.33, 125.01, 101.95, 96.78, 80.78, 72.00,
71.11, 70.32, 62.75, 17.39, 17.26, 17.23, 16.95, 16.88, 16.81,
13.39, 13.06, 12.54, 12.48; FAB-HRMS calcd for C35H49N2O8-
SeSi2 761.2192, found 761.2173 (MH+). Anal. Calcd for
each 1 H), 4.32 (ddd, 1H, J ) 8.3, 7.9, 3.6), 3.89 (dd, 1 H, J )
11.5, 3.6), 3.48 (d, 1 H, J ) 10.0), 3.36 (dd, 1 H, J ) 11.5, 7.9),
3.14 (dd, 1 H, J ) 8.3), 1.04-0.85 (m, 28 H, isopropyl × 4);
FAB-HRMS calcd for C36H51N2O9Si2 711.3133, found 711.3123
(MH+).
1-[1-P h en yl-4,6-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-1,3-
d iyl)-er yth r o-2,3-h exod iu lofu r a n osyl]u r a cil (9). Purifica-
tion was accomplished by flash column chromatography (SiO2,
hexane:AcOEt ) 4:1, 3:1. 2:1, then 1:1) to give the diastereo-
meric mixture 9 (53 mg, 0.089 mmol, 89%) as a white foam.
From the mixture 9 (44 mg, ca. 0.074 mmol), the three
diastereomers 9-1 (14 mg, 0.024 mmol), 9-2 (13 mg, 0.022
mmol), and 9-3 (14 mg, 0.024 mmol) were obtained in a pure
form by preparative HPLC separation (YMC D-ODS-5-A, 250
mm × 20 mm; 85% aqueous MeCN, 20 mL/min; 260 nm). The
remaining diastereomer (9-4) could not be isolated. 9-1: 1H
NMR (CDCl3, 500 MHz) δ 8.72 (br s, 1 H), 7.65 (d, 1 H, J )
8.3), 7.33-7.29 (m, 5 H), 5.70 (dd, 1 H, J ) 8.5, 1.8), 5.40 (s,
1 H), 4.82 (d, 1 H, J ) 7.4), 3.99 (dd, 1 H, J ) 11.8, 7.2), 3.94
(dd, 1 H, J ) 11.8, 3.3), 3.35 (ddd, 1 H, J ) 7.4, 7.2, 3.3), 1.07-
0.80 (m, 28 H). 9-2, which was in equilibrium between the keto
and the corresponding hydrate forms: 1H NMR (CDCl3, 500
MHz) δ 8.55 (br s, 1 H), 8.24 (br s, 1 H), 7.66 (d, 1 H, J ) 8.2),
7.38-7.18 (m, 10 H), 6.95 (d, 1 H, J ) 8.4), 5.81 (dd, 1 H, J )
8.2, 1.9), 5.65 (s, 1 H), 5.51 (s, 1 H), 5.36 (dd, 1 H, J ) 8.4,
1.7), 5.22 (s, 1 H), 4.74 (d, 1 H, J ) 8.5), 4.32 (ddd, 1 H, J )
8.3, 8.0, 3.4), 4.24 (dd, 1 H, J ) 12.5, 5.0), 4.15 (br s, 1 H),
4.10 (dd, 1 H, J ) 12.5, 3.0), 3.99-3.88 (m, 2 H), 3.37 (dd, 1
H, J ) 11.7, 8.0), 3.13 (d, 1 H, J ) 8.3), 1.16-0.58 (m, 56 H).
9-3, which was in equilibrium between the keto and the
corresponding hydrate forms: 1H NMR (CDCl3, 500 MHz) δ
9.72 (br s, 0.6 H), 8.59 (br s, 1 H), 8.19 (d, 1 H, J ) 8.4), 7.75
(d, 0.6 H, J ) 8.3), 7.63-7.31 (m, 8 H), 5.74 (d, 1 H, J ) 8.4),
5.70 (d, 0.6 H, J ) 8.3), 5.66 (s, 0.6 H), 5.57 (br s, 0.6 H), 5.21
(s, 1 H), 4.43 (ddd, 1 H, J ) 7.4, 7.3, 3.3), 4.06 (dd, 1 H, J )
11.8, 3.3), 3.96 (dd, 0.6 H, J ) 11.7, 2.8), 3.83-3.78 (m, 1 H),
3.80 (dd, 1 H, J ) 11.8, 7.3), 3.45 (dd, 0.6 H, J ) 11.7, 8.3),
3.21 (d, 0.6 H, J ) 8.5), 3.14 (d, 1 H, J ) 7.4), 1.09-0.70 (m,
45 H).
C
35H48N2O8SeSi2: C, 55.32; H, 6.32; N, 3.69. Found: C, 55.03;
H, 6.23; N, 3.68.
1-[4,6-O-(1,1,3,3-Tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-D-
er yth r o-2,3-h exod iu lofu r a n osyl]u r a cil (10) a n d 1-[4,6-O-
(1,1,3,3-Tet r a isop r op yld isiloxa n e-1,3-d iyl)-r-D-er yth r o-
2,3-hexodiulofuranosyl]uracil(11).Purificationwasaccomplished
by column chromatography (SiO2, hexane:AcOEt ) 2:1 then
1:1) to give 10 (27.7 mg, 0.054 mmol, 54%) as a white foam
and 11 (9 mg, 0.016 mmol, 16%). 10: 1H NMR (CDCl3, 400
MHz) δ 9.10 (br s, 1 H, NH-3), 7.66 (d, 1 H, H-6, J ) 8.2), 5.77
(br d, 1 H, H-5, J ) 8.2), 5.07 (d, 1 H, H-4′, J ) 7.3), 4.07-
3.97 (m, 5 H, H-1′, H-5′, H-6′), 2.83 (br s, 1 H, OH-1′), 1.12-
1.02 (m, 28 H, isopropyl × 4); 13C NMR (CDCl3, 125 MHz) δ
205.46, 162.43, 150.13, 140.83, 102.47, 86.30, 80.86, 72.19,
63.96, 59.92, 17.41, 17.29, 17.26, 17.23, 16.81, 16.78, 16.75,
13.32, 13.06, 12.53, 12.28; FAB-HRMS calcd for C22H39N2-
O8Si2 515.2245, found 515.2216 (MH+). 11: 1H NMR (CDCl3,
400 MHz) δ 8.85 (br s, 1 H), 7.44 (d, 1 H, J ) 8.2), 5.77 (dd, 1
H, J ) 8.5, 2.0), 4.70 (d, 1 H, J ) 9.7), 4.60 (d, 1 H, J ) 9.4),
4.11(br d, 1 H, J ) 13.9), 4.07-4.02 (m, 2 H), 3.81 (dd, 1 H, J
) 8.4, 5.2), 1.14-1.05 (m, 28 H, isopropyl × 4); 13C NMR
(CDCl3, 125 MHz) δ 202.69, 161.63, 151.32, 139.85, 103.01,
88.85, 82.66, 71.58, 62.90, 60.40, 17.24, 17.17, 17.16, 16.88,
16.74, 16.70, 13.60, 12.87, 12.61, 12.44; FAB-HRMS calcd for
Typ ica l P r oced u r e for th e Ald ol Rea ction (Ta ble
1). 3-N-Benzyloxymethyl-1-[(1S)-1-phenyl-4,6-O-(1,1,3,3-tetra-
isop r op yld isiloxa n e-1,3-d iyl)-â-D-er yth r o-2,3-h exod iu lo-
fu r a n osyl]u r a cil (12a ) a n d 3-N-Ben zyloxym eth yl-1-[1-
p h en yl-4,6-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-1,3-d iyl)-
r-D-er yth r o-2,3-h exod iu lofu r a n osyl]u r a cil (13a ). A solu-
tion of 6 (76 mg, 0.10 mmol) in THF (1.0 mL) was added
dropwise to a solution of SmI2 (0.10 M solution in THF, 2.1
mL, 0.21 mmol) at -78 °C. After 6 disappeared on TLC, oxygen
was bubbled into the mixture. To the mixture was added a
solution of PhCHO (2.0 M solution in THF, 150 µL, 0.30 mmol)
at -78 °C, and the resulting mixture was stirred at the same
temperature for 1 h. Saturated aqueous NH4Cl was added to
the mixture, and the whole 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 chromatog-
raphy (SiO2, hexane:AcOEt ) 4:1, 3:1, then 2:1) to give 12a
(55 mg, 0.077 mmol, 76%) as a white foam and 13a (7 mg,
0.010 mmol, 10%, as a colorless oil). 12a : 1H NMR (CDCl3,
500 MHz) δ 7.60 (d, 1 H, H-6, J ) 8.5), 7.36-7.27 (m, 10 H,
Ph × 2), 5.73 (d, 1 H, H-5, J ) 8.5), 5.39 (s, 2 H, NCH2O), 5.36
(d, 1 H, H-1′, J ) 7.6), 4.89 (d, 1 H, H-4′, J ) 7.2), 4.62 (s, 2H,
OCH2Ph), 4.00 (dd, 1 H, H-6′a, J ) 11.7, 7.5), 3.93 (dd, 1 H,
H-6′b, J ) 11.7, 3.4), 3.61 (d, 1 H, OH-1′, J ) 7.6), 3.34 (ddd,
1 H, H-5′, J ) 7.5, 7.2, 3.4), 1.09-0.81 (m, 28 H, isopropyl ×
C
22H39N2O8Si2 515.2245, found 515.2267 (MH+).
3-N-Ben zyloxym et h yl-1-[(1S)-1-m et h yl-4,6-O-(1,1,3,3-
t et r a isop r op yld isiloxa n e-1,3-d iyl)-â-D-er yth r o-2,3-h exo-
d iu lofu r a n osyl]u r a cil (12b) a n d 3-N-Ben zyloxym eth yl-
1-[(1S)-1-O-a cetyl-1-m eth yl-4,6-O-(1,1,3,3-tetr a isop r op yl-
disiloxan e-1,3-diyl)-â-D-a r a bin o-2-h exu lofu r an osyl]u r acil
(14b). Purification was accomplished by column chromatog-
raphy (SiO2, hexane:AcOEt ) 4:1, 3:1, then 2:1) to give 12b
(18.9 mg, 0.029 mmol, 29%) and 14b (36 mg, 0.052 mmol, 52%)
as a colorless oil. 12b: 1H NMR (CDCl3, 500 MHz) δ 7.70 (d,
1 H, H-6, J ) 8.4), 7.33-7.26 (m, 5 H, Ph), 5.76 (d, 1 H, H-5,
4); FAB-HRMS calcd for
C36H51N2O9Si2 711.3133, found
711.3123 (MH+). Anal. Calcd for C36H50N2O9Si2: C, 60.61; H,
6.96; N, 3.72. Found: C, 60.23; H, 7.24; N, 4.03. 13a : 1H NMR
(CDCl3, 270 MHz) δ 7.58 (d, 1 H, J ) 8.3), 7.38-7.24 (m, 10
H, Ph × 2), 5.81 (d, 1 H, J ) 8.3), 5.47 (d, 1 H, J ) 9.9), 5.40
(d, 1 H, J ) 9.9), 5.20 (d, 1 H, J ) 10.0), 4.70, 4.70 (each s,
7712 J . Org. Chem., Vol. 67, No. 22, 2002

SmI2-Promoted Aldol Reaction of Nucleosides
J ) 8.4), 5.40 (d, 1 H, NCH2O, J ) 9.8), 5.37 (d, 1 H, NCH2O,
J ) 9.8), 5.03 (d, 1 H, H-4′, J ) 5.6), 4.63, 4.64 (each d, each
1 H, OCH2Ph, J ) 12.5), 4.26 (m, 1 H, H-1′), 4.10-4.03 (m, 3
H, H-5′, H-6′), 2.81 (d, 1 H, OH-1′, J ) 9.2), 1.40 (d, 3 H, Me-
1′, J ) 6.6), 1.17-0.99 (m, 28 H, isopropyl × 4); FAB-HRMS
calcd for C31H49N2O9Si2 649.2276, found 649.2296 (MH+).
14b: 1H NMR (CDCl3, 500 MHz) δ 7.98 (d, 1 H, H-6, J ) 8.5),
7.35-7.24 (m, 5 H, Ph), 6.34 (q, 1 H, H-1′, J ) 6.4), 5.76 (d, 1
H, H-5, J ) 8.5), 5.48, 5.46 (each d, each 1 H, NCH2O, J )
9.8), 4.66 (s, 2 H, OCH2Ph), 4.55 (dd, 1 H, H-3′, J ) 7.8, 2.2),
4.15 (dd, 1 H, H-6′a, J ) 13.2, 2.0), 4.10 (dd, 1 H, H-4′, J )
9.2, 7.8), 4.00 (dd, 1 H, H-6′b, J ) 13.2, 2.5), 3.89 (ddd, 1 H,
H-5′, J ) 9.2, 2.5, 2.0), 3.32 (d, 1 H, OH-3′, J ) 2.2), 2.13 (s, 3
H, -CH(OAc)Me), 1.11-0.98 (m, 31 H, isopropyl × 4 and Me-
1′); 13C NMR (CDCl3, 125 MHz) δ 169.79 (COCH3), 162.61 (C-
4), 152.52 (C-2), 139.20 (C-6), 137.78 (OCH2Ph), 128.35
(OCH2Ph), 127.74 (OCH2Ph), 127.71 (OCH2Ph), 101.54 (C-5),
96.64 (C-2′), 82.20 (C-5′), 78.35 (C-3′), 73.32 (C-4′), 72.23
(OCH2Ph), 70.91 (C-1′), 70.55 (NCH2O), 60.14 (C-6′), 21.19
(COCH3), 17.54, 17.39, 17.35, 17.26, 17.06, 16.97, 16.81, 16.76,
13.73, 13.53, 13.04, 12.99, 12.34; FAB-HRMS calcd for
1′), 60.93 (C-6′), 17.38, 17.28, 17.24, 16.98, 16.83, 16.75, 13.61,
12.91, 12.63, and 12.57 (isopropyl carbons); FAB-HRMS calcd
for C30H47N2O9Si2 635.2821, found 635.2823 (MH+).
Typ ica l P r oced u r e for th e Ald ol-Tish ch en k o Rea ction .
3-N-Ben zyloxym et h yl-1-[(1S)-1-O-b en zoyl-1-p h en yl-4,6-
O-(1,1,3,3-tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-D-a r a bin o-
2-h exu lofu r a n osyl]u r a cil (14a ). To a solution of the samar-
ium enolate in THF, which was prepared from 6 (0.10 mmol)
according to the above-mentioned procedure, was added drop-
wise a solution of PhCHO (2.0 M solution in THF) at the same
temperature. The mixture was warmed to room temperature
over 2 h and was stirred further for 1 h. Saturated aqueous
NH4Cl was added to the mixture, and the resulting mixture
was stirred for 5 min at 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 chromatography (SiO2, hexane:
AcOEt ) 9:1, 8:1, then 7:1) to give 14a (60 mg, 0.074 mmol,
74%) as a white foam: 1H NMR (CDCl3, 500 MHz) δ 8.06 (d,
2 H, o-Bz, J ) 7.5), 7.68 (d, 1 H, H-6, J ) 8.5), 7.60-7.11 (m,
14 H, Ar-H and CH(Ph)OBz), 5.53 (d, 1 H, H-5, J ) 8.5), 5.49,
5.46 (each d, each 1 H, NCH2O, J ) 9.8), 4.88 (dd, 1 H, H-3′,
J ) 7.4, 1.8), 4.65, 4.64 (each d, each 1 H, OCH2Ph, J ) 12.1),
4.28-4.19 (m, 3 H, H-4′, H-5′, H-6′a), 4.12 (dd, 1 H, H-6′b, J
) 13.6, 3.2), 3.73 (d, 1 H, OH-3′, J ) 1.8), 1.12-0.96 (m, 28 H,
isopropyl × 4); 13C NMR (CDCl3, 125 MHz) δ 165.13 (COPh),
162.47 (C-4), 152.87 (C-2), 139.04 (C-6), 137.78, 134.64, 133.42,
129.78, 128.98, 128.61, 128.39, 128.23, 128.19, 127.71, and
127.58 (Ph carbons), 101.23 (C-5), 97.32 (C-2′), 82.72 (C-5′),
79.34 (C-3′), 75.45 (C-1′), 73.99 (C-4′), 71.93 (OCH2Ph), 70.42
(NCH2O), 60.55 (C-6′), 17.52, 17.35, 17.23, 17.05, 16.97, 16.83,
16.79, 13.54, 13.24, 13.08, 12.94, and 12.38 (isopropyl carbons);
C
33H52N2O10Si2Na 715.3057, found 715.3060 (MNa+). Anal.
Calcd for C33H52N2O10Si2: C, 57.20; H, 7.56; N, 4.04. Found:
C, 57.60; H, 7.73; N, 3.70.
3-N-Ben zyloxym eth yl-1-[(1S)-1-isop r op yl-4,6-O-(1,1,3,3-
t et r a isop r op yld isiloxa n e-1,3-d iyl)-â-D-er yth r o-2,3-h exo-
d iu lofu r a n osyl]u r a cil (12c). Purification was accomplished
by column chromatography (SiO2, AcOEt in hexane ) 15%,
20%, then 30%) to give 12c (32 mg, 0.048 mmol, 48%) and 8
(20 mg, 0.033 mmol, 33%). 12c: 1H NMR (CDCl3, 400 MHz) δ
7.62 (d, 1 H, H-6, J ) 8.6), 7.26-7.19 (m, 5 H, Ph), 5.71 (d, 1
H, H-5, J ) 8.6), 5.32 (s, 2 H, NCH2O), 4.96 (d, 1 H, H-4′, J )
5.9), 4.57 (s, 2 H, OCH2Ph), 4.08-3.91 (m, 4 H, H-5′, H-6′,
H-1′), 2.63 (br d, 1 H, OH-1′, J ) 8.6), 1.94 (m, 1 H, CHMe2-
1′), 1.07-0.79 (m, 34 H, isopropyl × 4, CHMe2-1′); 13C NMR
(CDCl3, 100 MHz) δ 205.03, 161.48, 151.48, 139.08, 137.26,
127.99, 127.39, 127.31, 101.92, 88.59, 82.61, 75.60, 72.01,
71.51, 70.27, 63.64, 28.25, 22.30, 17.43, 17.26, 16.87, 16.81,
16.76, 16.70, 13.41, 13.04, 12.73, 12.33; FAB-HRMS calcd for
FAB-HRMS calcd for
C43H56N2O10Si2Na 839.3371, found
839.3326 (MNa+). Anal. Calcd for C43H56N2O10Si2: C, 63.21;
H, 6.91; N, 3.43. Found: C, 63.08; H, 6.92; N, 3.50.
3-N-Ben zyloxym eth yl-1-[(1S)-1-O-a cetyl-1-m eth yl-4,6-
O-(1,1,3,3-tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-D-a r a bin o-
2-h exu lofu r a n osyl]u r a cil (14b). Purification was accom-
plished by column chromatography (SiO2, hexane:AcOEt ) 9:1,
7:1, then 4:1) to give 14b (58 mg, 0.083 mmol, 83%) as a
colorless oil, the physical data of which was ubi supra.
C
33H53N2O9Si2 677.3289, found 677.3250 (MH+). Anal. Calcd
for C33H52N2O9Si2: C, 58.55; H, 7.74; N, 4.14. Found: C, 58.68;
H, 7.85; N, 4.05.
3-N-Ben zyloxym et h yl-1-[(1S)-1-isop r op yl-1-O-isob u -
tyr yl-4,6-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-
D-a r a bin o-2-h exu lofu r a n osyl]u r a cil (14c) a n d Cyclic
Hem ik eta l 16. Purification was accomplished by column
chromatography (SiO2, AcOEt in hexane ) 5%, 10%, then 15%)
to give 14c (41.8 mg, 0.056 mmol, 55%) as a clorless glass and
16 (30.7 mg, 0.041 mmol, 41%). 14c: 1H NMR (CDCl3, 500
MHz) δ 8.04 (d, 1 H, H-6, J ) 8.6), 7.34-7.24 (m, 5 H, Ph),
6.37 (d, 1 H, H-1′, J ) 2.9), 5.78 (d, 1 H, H-5, J ) 8.6), 5.51,
5.47 (each d, each 1 H, NCH2O, J ) 9.8), 4.66 (each d, each 1
H, OCH2Ph, J ) 12.6), 4.37 (d, 1 H, H-3′, J ) 8.2), 4.16 (dd, 1
H, H-6′a, J ) 13.5, 1.2), 4.02 (dd, 1 H, H-4′, J ) 9.4, 8.2), 3.99
(dd, 1 H, H-6′b, J ) 13.5, 2.5), 3.85 (ddd, 1 H, H-5′, J ) 9.4,
2.5, 1.2), 3.24 (br s, 1 H, OH-3′), 2.67 (qq, 1 H, CHMe2-1′, J )
7.0, 7.0), 1.80 (dqq, 1 H, -OCOCHMe2, J ) 6.8, 6.8, 2.9), 1.26,
1.25 (each d, each 3 H, OCOCHMe2, J ) 7.0), 1.10-0.92
(m, 28 H, isopropyl × 4), 0.88, 0.84 (each d, each 3 H,
-CH(OCOCHMe2)CHMe2, J ) 6.8); 13C NMR (CDCl3, 125
MHz) δ 176.54, 162.71, 152.72, 139.08, 137.80, 128.33, 127.71,
127.68, 101.56, 97.56, 82.16, 79.37, 75.75, 72.37, 72.13, 70.52,
60.01, 34.43, 28.73, 20.88, 19.39, 19.13, 17.53, 17.39, 17.35,
17.24, 17.08, 17.05, 16.99, 16.77, 13.53, 13.02, 13.00, 12.39;
3-N-Ben zyloxym eth yl-1-[4,6-O-(1,1,3,3-tetr a isop r op yl-
d isiloxa n e-1,3-d iyl)-â-D-er yth r o-2,3-h exod iu lofu r a n osyl]-
u r a cil (12d ) a n d 3-N-Ben zyloxym eth yl-1-[4,6-O-(1,1,3,3-
tetr a isop r op yld isiloxa n e-1,3-d iyl)-r-D-er yth r o-2,3-h exo-
d iu lofu r a n osyl]u r a cil (13d ). Purification was accomplished
by column chromatography (SiO2, hexane:AcOEt ) 3:1, 2:1,
1:1, then 1:2) to give 12d (36 mg, 0.057 mmol, 57%) as a white
foam, 13d (8 mg, 0.012 mmol, 12%) as a white glass, and 15
(6 mg, 0.027 mmol, 27%) as a white solid. 12d : 1H NMR
(CDCl3, 500 MHz) δ 7.57 (d, 1 H, H-6, J ) 8.3), 7.32-7.26 (m,
5 H, Ph), 5.77 (d, 1 H, H-5, J ) 8.3), 5.38 (s, 2 H, NCH2Ph),
5.14 (d, 1 H, H-3′, J ) 7.3), 4.63 (s, 2 H, OCH2Ph), 4.13-3.96
(m, 5 H, H-5′, H-6′, and H-1′), 2.69 (br s, 1 H, OH-1′), 1.16-
0.98 (m, 28 H, isopropyl × 4); 13C NMR (CDCl3, 125 MHz) δ
205.82 (C-3′), 161.89 (C-4), 151.94 (C-2), 139.59 (C-6), 137.72
(OCH2Ph), 128.36 (OCH2Ph), 127.75 (OCH2Ph), 127.72 (OCH2-
Ph), 102.66 (C-5), 87.04 (C-2′), 81.42 (C-5′), 72.28 (OCH2Ph),
72.26 (C-4′), 70.51 (NCH2O), 64.15 (C-1′), 60.30 (C-6′), 17.47,
17.36, 17.29, 16.91, 16.87, 16.86, 13.48, 13.16, 12.68, 12.42;
FAB-HRMS calcd for C30H47N2O9Si2 635.2821, found 635.2853
(MH+). 13d : 1H NMR (CDCl3, 500 MHz) δ 7.38-7.26 (m, 6 H,
H-6, Ph), 5.78 (d, 1 H, H-5, J ) 8.3), 5.45, 5.39 (each d, each
1 H, NCH2O, J ) 9.8), 4.70-4.63 (m, 4 H, H-4′, H-5′, OCH2Ph),
4.07 (dd, 1 H, H-6′a, J ) 13.5, 1.3), 4.03 (dd, 1 H, H-6′b, J )
13.5, 2.5), 3.90, 3.88 (each d, each 1 H, H-1′, J ) 12.2), 2.65
(br s, 1 H, OH-1′), 1.14-1.02 (m, 28 H, isopropyl × 4); 13C NMR
(CDCl3, 125 MHz) δ 202.63 (C-3′), 161.86 (C-4), 152.69 (C-2),
138.88 (C-6), 137.73 (OCH2Ph), 128.33 (OCH2Ph), 127.83
(OCH2Ph), 127.73 (OCH2Ph), 102.83 (C-5), 88.97 (C-2′), 82.95
(C-5′), 72.30 (OCH2Ph), 71.66 (C-4′), 70.49 (NCH2O), 63.45 (C-
FAB-HRMS calcd for
C37H60N2O10Si2Na 711.3684, found
711.3688 (MNa+). 16: 1H NMR (CDCl3, 500 MHz) δ 8.23 (d, 1
H, H-6, J ) 8.5), 7.35-7.27 (m, 5 H, Ph), 6.36 (s, 1 H, OH-3′),
5.85 (d, 1 H, H-5, J ) 8.5), 5.55, 5.47 (each d, each 1 H, NCH2O,
J ) 9.9), 4.86 (d, 1 H, OCH(CHMe2)O, J ) 4.5), 4.78 (d, 1 H,
H-1′, J ) 7.4), 4.63 (s, 2 H, OCH2Ph), 4.24 (d, 1 H, H-6′a, J )
13.8), 4.10 (dd, 1 H, H-5′, J ) 9.6, 1.9), 4.05 (d, 1 H, H-4′, J )
9.6), 4.00 (dd, 1 H, H-6′b, J ) 13.8, 1.9), 1.98-1.92 (m, 2 H,
CHMe2), 1.10-0.90 (m, 37 H,Si(CHMe2) × 4 and CHMe2 × 3),
J . Org. Chem, Vol. 67, No. 22, 2002 7713

Kodama et al.
0.69 (d, 3 H, CHMe2, J ) 6.8); NOE (400 MHz, CDCl3)
irradiated H-6, observed H-4′ (1.2%), H-6′(6.3%); irradiated
H-1′, observed OH-3′ (4.4%), OCH(CHMe2)O (12.9%); irradi-
ated OCH(CHMe2)O, observed H-1′ (14.1%), OH-3′ (9.5%);
irradiated OH-3′, observed H-4′ (1.9%); 13C NMR (CDCl3, 125
MHz) δ 162.23, 154.31, 139.87, 137.49, 128.37, 127.81, 102.33,
101.30, 98.61, 93.80, 82.78, 78.80, 72.10, 71.30, 70.57, 59.47,
32.47, 28.11, 19.71, 19.31, 17.62, 17.47, 17.40, 17.22, 17.09,
16.99, 16.80, 16.69, 16.04, 13.52, 13.27, 12.93, 12.65, 12.34;
FAB-HRMS calcd for C37H61N2O10Si2 749.3865, found 749.3888
(MH+).
(ddd, 1 H, J ) 8.8, 2.3, 2.3), 3.73 (br d, 1 H, J ) 3.5), 3.11 (br
s, 1 H), 1.11-0.96 (m, 28 H); 13C NMR (CDCl3, 100 MHz) δ
163.30, 151.62, 141.27, 101.56, 96.81, 80.78, 77.50, 72.49,
65.20, 59.91, 17.47, 17.34, 17.30, 17.19, 17.00, 16.90, 16.76,
16.73, 13.43, 12.96, 12.92, 12.24; FAB-HRMS calcd for
C
22H41N2O8Si2 517.2402, found 517.2369 (MH+). 20: 1H NMR
(CDCl3, 400 MHz) δ 8.84 (br s, 1 H), 7.97 (d, 1 H, J ) 8.2),
5.69 (dd, 1 H, J ) 8.2, 2.3), 4.78 (br s, 1 H), 4.27-4.22 (m, 5
H), 3.99 (br d, 1 H, J ) 13.5), 3.36 (br s, 1 H), 2.90 (br s, 1 H),
1.28-0.86 (m, 28 H, isopropyl × 4); 13C NMR (CDCl3, 100 MHz)
δ 163.28, 150.08, 140.83, 101.04, 97.76, 81.92, 75.09, 68.58,
63.33, 59.41, 17.39, 17.29, 17.20, 17.07, 16.95, 16.92, 16.86,
16.76, 13.39, 12.88, 12.76, 12.39; FAB-HRMS calcd for
3-N-Ben zyloxym et h yl-1-[(1S)-1-p h en yl-4,6-O-(1,1,3,3-
tetr aisopr opyldisiloxan e-1,3-diyl)-â-D-r ibo-2-h exu lofu r an -
osyl]u r a cil (17). A solution of 12a (7.1 mg, 10 µmol) and
NaBH4 (1.0 mg, 0.03 mmol) in MeOH (0.2 mL) was stirred at
0 °C for 30 min. After AcOEt (1 mL) and saturated aqueous
NH4Cl (1 mL) were added to the solution, the mixture was
warmed to room temperature and was partitioned between
AcOEt and H2O. The organic layer was washed with brine,
dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (SiO2, 10%, 15%, then 20% AcOEt in
hexane) to give 17 (6.6 mg, 9.3 µmol, 93%, as a colorless glass)
C
22H41N2O8Si2 517.2402, found 517.2369 (MH+).
1-(â-D-r ibo-2-Hexu lofu r a n osyl)u r a cil (21). A solution of
TBAF (1.0 M in THF, 50 µL, 50 µmol) was added to a solution
of 20 (12 mg, 24 µmol) in THF at room temperature, and the
mixture was stirred at the same temperature for 20 min. The
solvent was evaporated, and the residue was purified by
column chromatography (SiO2, 10%, 15%, 20%, then 25%
MeOH in CHCl3) to give 21 (6 mg, 22 µmol, 91%), the spectrum
data of which were in accord with those reported previously.6g
1
along with a trace of 18; H NMR (CDCl3, 400 MHz) δ 7.41-
1-[(1S)-1-P h en yl-3,4-O-isopr opyliden e-â-D-r ibo-2-h exu lo-
fu r a n osyl]u r a cil (22). A mixture of 17 (108.0 mg, 0.15 mmol)
and Pd (10% on carbon, 300 mg) in MeOH (3 mL) was
vigorously stirred under atmospheric pressure of hydrogen at
room temperature for 40 h. After the insoluble material was
filterd off on Celite, the filtrate was evaporated. The residue
was purified by column chromatography (SiO2, hexane:AcOEt
) 2:1) to give the corresponding N-3-free product as a colorless
glass (91 mg, 0.15 mmol, 100%). A mixture of the product (59
mg, 100 µmol) and TBAF (1.0 M in THF, 200 µL, 0.2 µmol) in
THF (1.0 mL) was stirred at 0 °C for 20 min. The solvent was
evaporated, and the residue was purified by column chroma-
tography (SiO2, 5% then 10% MeOH in AcOEt) to give the
corresponding TIPDS-deprotected product as a white glass (26
mg, 74 µmol, 74%). A mixture of the product (7 mg, 20 µmol),
PPTS (1 mg, 4 µmol), 2,2-dimethoxypropane (88 µL, 1.0 mmol),
and CuSO4 (100 mg) in acetone (1 mL) was stirred at room
temperature for 72 h. After K2CO3 (10 mg) was added to the
solution, the insoluble material was filterd off on Celite, the
filtrate was evaporated. The residue was purified by column
chromatography (SiO2, 5%, 7%, then 10% MeOH in CHCl3) to
give 22 a colorless glass (1 mg, 2.7 µmol, 13%): 1H NMR
(CDCl3, 500 MHz) δ 7.29-7.24 (m, 5 H, Ph), 7.02 (d, 1 H, H-6,
J ) 8.3), 5.64 (d, 1 H, H-1′, J ) 3.3), 5.46 (d, 1 H, H-3′, J )
6.8), 5.14 (d, 1 H, H-5, J ) 8.3), 4.86 (ddd, 1 H, H-4′, J ) 6.8,
3.7, 3.1), 4.73 (dd, 1 H, H-5′, J ) 6.5, 3.1), 3.89 (dd, 1 H, H-6′a,
J ) 11.7, 3.1), 3.77 (dd, 1 H, H-6′b, J ) 11.7, 3.7), 3.64 (s, 1 H,
OH-6′), 3.45 (d, 1 H, OH-1′, J ) 3.3), 1.91, 1.46 (each s, each
3 H, Me × 2); FAB-HRMS calcd for C19H23N2O7 391.1505,
found 391.1506 (MH+).
1-[(1S)-4,6-Di-O-a cetyl-1,3-O-isop r op ylid en e-1-p h en yl-
â-D-r ibo-2-h exu lofu r a n osyl]u r a cil (23). Compoud 17 (108
mg, 0.15 mmol), hydrogenated as described above, gave the
corresponding N-3-free product (90.5 mg, 0.15 mmol, 100%).
To a stirring solution of the product (30 mg, 50 µmol), 2,2-
dimethoxypropane (88 µL, 1.0 mmol), and PPTS (2.5 mg, 10
µmol) in DMF (1.0 mL) was added 2-methoxypropene (20 µL,
0.20 mmol) at room temperature 5 times (total 100 µL, 2.0
mmol). The resulting mixture was stirred further at the same
temperature for 12 h, then was poured into aqueous saturated
NaHCO3. The mixture was extracted with Et2O (×5), and the
organic layer was dried (Na2SO4) and evaporated. The residue
was purified by column chromatography (SiO2, 5%, 10%, then
20% AcOEt in hexane) to give the corresponding acetonide (27
mg, 43 µmol, 86%). A solution of the acetonide and TBAF (1.0
M in THF, 100 µL, 0.1 mmol) was stirred at room temperature
for 30 min. The mixture was evaporated and then purified by
column chromatography (SiO2, hexane:AcOEt:MeOH ) 1:1:0,
20:80:1, 10:40:1, then 10:40:2) to give the desilylated product
(7 mg). A mixture of the product, Ac2O (3.8 µL, 0.04 mmol),
7.12 (m, 11 H, H-6, Ph × 2), 5.95 (d, 1 H, H-1′, J ) 2.4), 5.49
and 5.44 (each d, each 1 H, NCH2O, J ) 9.8), 5.31 (d, 1 H,
H-5, J ) 8.4), 4.97 (d, 1 H, H-3′, J ) 5.2), 4.67 and 4.66 (each
d, each 1 H, OCH2Ph, J ) 12.0), 4.40 (ddd, 1 H, H-5′, J ) 8.9,
2.2, 2.1), 4.27-4.25 (m, 2 H, H-4′, H-6′a), 4.04-4.01 (m, 2 H,
H-6′b, OH-1′), 3.44 (br s, 1 H, 2′-OH), 1.10-0.93 (m, 28 H,
isopropyl × 4); 13C NMR (CDCl3, 125 MHz) δ 165.78, 162.55,
151.29, 138.36, 137.79, 136.94, 128.52, 128.36, 12.09, 127.71,
127.57, 112.78, 100.39, 97.87, 84.18, 73.24, 71.93, 70.11, 69.10,
60.03, 17.38, 17.22, 17.19, 17.09, 17.01, 16.98, 16.88, 16.84,
13.46, 12.98, 12.78, 12.57; FAB-LRMS m/z 735 (MNa+). Anal.
Calcd for C36H52N2O9: C, 60.65; H, 7.35; N, 3.93. Found: C,
60.76; H, 7.12; N, 4.10.
3-N-Ben zyloxym et h yl-1-[(1S)-1-p h en yl-4,6-O-(1,1,3,3-
tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-D-a r a bin o-2-h exu lo-
fu r a n osyl]u r a cil (18). NaBH(OAc)3 (11 mg, 50 µmol) was
added to a solution of 12a (7 mg, 10 µmol) in 5% AcOH/MeCN
(0.5 mL) at 0 °C. After the resulting mixture was stirred at
the same temperature for 3 h, AcOEt (2 mL) and saturated
aqueous NH4Cl (1 mL) were added to the mixture. The whole
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 chromatography (SiO2, 10%f15%f20% AcOEt in
1
hexane) to give 18 (7 mg, 10 µmol, 100%); H NMR (CDCl3,
400 MHz) δ 7.73 (d, 1 H, H-6, J ) 8.5), 7.35-7.12 (m, 10 H,
Ph × 2), 5.92 (br s, 1 H, H-1′), 5.49 (d, 1 H, H-5, J ) 8.5), 5.42
and 5.38 (each d, each 1 H, NCH2O, J ) 10.0), 5.10 (br d, 1 H,
H-3′, J ) 7.6), 4.54 (s, 2 H, OCH2Ph), 4,20-4.14 (m, 2 H, H-4′,
H-6′a), 4.09 (ddd, 1 H, H-5′, J ) 9.4, 2.4, 2.1), 4.02 (dd, 1 H,
H-6′b, J ) 13.5, 2.4), 3.62 (br s, 1 H, OH-1′), 2.75 (br s, 1 H,
OH-3′), 1.10-0.96 (m, 28 H, isopropyl × 4); FAB-LRMS m/z
735 (MNa+). Anal. Calcd for C36H52N2O9: C, 60.65; H, 7.35;
N, 3.93. Found: C, 60.76; H, 7.12; N, 4.10.
1-[4,6-O-(1,1,3,3-Tetr a isop r op yld isiloxa n e-1,3-d iyl)-â-D-
a r a bin o-2-h exu lofu r an osyl]u r acil (19) an d 1-[4,6-O-(1,1,3,3-
Tetr aisopr opyldisiloxan e-1,3-diyl)-â-D-r ibo-2-h exu lofu r an -
osyl]u r a cil (20). A solution of 10 (18 mg, 0.035 mmol) and
NaBH4 (4 mg, 0.1 mmol) in MeOH (1 mL) was stirred at 0 °C
for 30 min. After addition of saturated aqueous NH4Cl (5 mL),
the mixture was warmed to room temperature and extracted
with AcOEt (10 mL × 3). The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (SiO2, 50%, 60%, then 70%
AcOEt in hexane) to give 19 (7 mg, 14 µmol, 39%) as a white
powder and 20 (11 mg, 21 µmol, 59%) as a colorless glass. 19:
1H NMR (CDCl3, 400 MHz) δ 9.27 (br s, 1 H, NH-3, D2O
exchangeable), 8.04 (d, 1 H, J ) 7.6), 5.72 (dd, 1 H, J ) 7.6,
3.8), 4.24-4.09 (m, 4 H), 4.01 (dd, 1 H, J ) 13.5, 2.6), 3.80
7714 J . Org. Chem., Vol. 67, No. 22, 2002

SmI2-Promoted Aldol Reaction of Nucleosides
Et3N (5.6 µL, 0.04 mmol), and DMAP (0.5 mg, 0.004 mmol) in
MeCN (0.5 mL) was stirred at room temperature. After 30 min,
MeOH was added to the solution, and the resulting mixture
was partitioned between Et2O and aqueous saturated NaH-
CO3, H2O, and then brine. The organic layer was dried
(Na2SO4) and evaporated. The residue was purified by column
chromatography (SiO2, hexane:AcOEt ) 4:1, 3:1, then 2:1) to
give 23 (6 mg, 82%) as a white glass: 1H NMR (CDCl3, 500
MHz) δ 9.09 (br s, 1 H, NH-3), 7.31-7.21 (m, 5 H, Ph), 7.07
(d, 1 H, H-6, J ) 8.3), 5.79 (d, 1 H, H-3′, J ) 3.5), 5.60 (s, 1 H,
H-1′), 5.42 (dd, 1 H, H-5, J ) 8.3, 2.0), 4.97 (dd, 1 H, H-4′, J )
9.5, 3.5), 4.74 (ddd, 1 H, H-5′, J ) 9.5, 3.0, 2.2), 4.28 (dd, 1 H,
H-6′a, J ) 13.1, 3.0), 4.25 (dd, 1 H, H-6′b, J ) 13.1, 2.2), 2.13,
1.95 (each s, each 3 H, Ac × 2), 1.87, 1.57 (each s, each 3 H,
Me × 2).13C NMR (CDCl3, 125 MHz) δ 170.19, 169.97. 163.29,
150.27, 141.55, 133.40, 128.94, 128.87, 128.02, 100.59, 99.78,
92.01, 79.18, 71.43, 70.86, 70.09, 61.13, 29.02, 20.74, 20.70,
(d, 3 H, 1′-Me, J ) 6.2), 1.09-0.95 (m, 28 H, isopropyl × 4).
24R: 1H NMR (CDCl3, 500 MHz) δ 8.52 (br s, 1 H, NH-3),
7.892(5) (d, 1 H, H-6, J ) 8.5), 7.56-7.39 (m, 5 H, Ph), 6.442
(q, 3 H, H-1′, J ) 6.3), 5.655(5) (dd, 1 H, H-5, J ) 8.5, 2.0),
4.203(5) (dd, 1 H, H-3′, J ) 8.0, 3.3), 4.034 (d, 1 H, H-6′a, J )
13.5, 1.4), 3.949 (dd, 1 H, H-4′, J ) 9.2, 8.0), 3.818 (dd, 1 H,
H-6′b, J ) 13.5, 2.5), 3.559 (s, 3 H, OMe), 3.483 (ddd, 1 H,
H-5′, J ) 9.2, 2.5, 1.4), 3.446 (br s, 1 H, OH-3′), 1.268 (d, 3 H,
1′-Me, J ) 6.3), 1.09-0.93 (m, 28 H, isopropyl × 4).
1-[1,3-Di-O-a cetyl-4,6-O-(1,1,3,3-tetr a isop r op yld isilox-
a n e-1,3-d iyl)-â-D-r ibo-2-h exu lofu r a n osyl]u r a cil (25). A
mixture of 20 (9 mg, 0.018 mmol), Ac2O (8 µL, 0.090 mmol),
Et3N (13 µL, 0.090 mmol), and DMAP (1 mg, 0.08 mmol) in
MeCN (1.0 mL) was stirred at room temperature for 10 min.
After addition of AcOEt (5 mL) and EtOH (0.1 mL), the
resulting mixture was further stirred for 10 min at room
temperature and then partitioned between AcOEt and satu-
rated aqueous NaHCO3. The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (SiO2, hexane:AcOEt )
4:1) to give 25 (11 mg, 0.027 mmol, 91%) as a colorless glass:
1H NMR (CDCl3, 400 MHz) δ 8.39 (d, 1 H, H-6, J ) 8.5), 7.93
(d, 1 H, H-6, J ) 8.2), 6.08 (d, 1 H, H-2′, J ) 5.0), 5.71 (dd, 1
H, H-5, J ) 8.5, 2.3), 4.76, 4.65 (each d, each 1 H, CH2OAc, J
) 12.0), 4.26 (dd, 1 H, H-3′, J ) 9.7, 5.0), 4.21 (d, 1 H, H-5′a,
J ) 13.5), 4.06 (m 1 H, H-4′), 3.95 (dd, 1 H, H-5′, J ) 13.5,
2.5), 2.17, 2.01 (each s, each 3 H, Ac), 1.07-0.88 (m, 28 H,
isoproryl × 4); NOE (400 MHz, CDCl3) irradiated H-6,
observed H-3′ (2.6%); irradiated H-2′, observed H-3′ (10.3%);
13C NMR (CDCl3, 100 MHz) δ 169.64, 167.89, 162.67, 149.18,
140.10, 100.95, 94.96, 74.77, 67.33, 62.52, 58.76, 20.60, 20.51,
17.36, 17.20, 17.15, 17.04 16.89, 16.81, 16.72, 16.69, 13.43,
12.87, 12.70, 12.58; FAB-HRMS calcd for C26H45N2O10Si2
601.2613, found 601.2627 (MH+).
20.62; FAB-HRMS calcd for
C23H27N2O9 475.1717, found
475.1730 (MH+).
MTP A Ester s 24R a n d 24S. A mixture of 14b (171.6 mg,
0.30 mmol) and Pd (10% on carbon, 300 mg) in AcOEt-EtOH-
AcOH (95:95:10, 2 mL) was vigorously stirred at room tem-
perature under atmospheric pressure of hydrogen for 4 days.
After the insoluble material was filtered off on Celite, the
filtrate was evaporated. The residue was purified by column
chromatography (SiO2, hexane:AcOEt ) 2:1) to give the
corresponding N-3-free product. A mixture of the product and
K2CO3 (41 mg, 0.30 mmol) in MeOH-THF (3:1, 4 mL) was
vigorously stirred at 4 °C for 5 h. The reaction was quenched
with saturated aqueous NH4Cl, and the resulting 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 (SiO2, hexane:
AcOEt ) 2:1 then 1:1) to give the diol derivative (90 mg, 0.17
mmol) as a white solid. A solution of (S)- or (R)-MTPA acid
(3.5 mg, 15 µmol) and EDC (2.9 mg, 15 µmol) in CH2Cl2 (100
µL) was stirred at room temperature for 10 min. To the
resulting mixture was added a solution of the diol (5.3 mg, 10
µmol) in THF (100 µL), and the mixture was stirred at room
temperature. After 2 h, DMAP (1 mg) was added to the
mixture. The resulting mixture was stirred further at the same
temperature for 10 h, then partitioned between AcOEt and
H2O. The organic layer was washed with brine, dried (Na2SO4),
and evaporated. The residue was purified by column chroma-
tography (SiO2, hexane:AcOEt ) 2:1 then 1:1) to give 24S (2.8
mg, 3.7 µmol, 37%) or 24R (3.3 mg, 4.4 µmol, 44%). 24R: 1H
NMR (CDCl3, 500 MHz) δ 8.70 (br s, 1 H, NH-3), 7.960 (d, 1
H, H-6, J ) 8.5), 7.53-7.46 (m, 5 H, Ph), 6.441(5) (q, 3 H, H-1′,
J ) 6.2), 5.679(5) (d, 1 H, H-5, J ) 8.5), 4.451(5) (dd, 1 H,
H-3′, J ) 8.1, 3.3), 4.005 (d, 1 H, H-4′, J ) 8.1), 3.984(5) (br d,
1 H, H-6′a), 3.809 (dd, 1 H, H-6′b, J ) 13.5, 2.5), 3.668 (br s,
1 H, OH-3′), 3.534 (m, 1 H, H-5′), 3.503 (s, 3 H, OMe), 1.179
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) from the J apan Society for Pro-
motion of Science. We are also grateful to Ms. H.
Matsumoto, A. Maeda, S. Oka, and N. Hazama (Center
for Instrumental Analysis, Hokkaido University) for
technical assistance with NMR, MS, and elemental
analyses.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectral
charts of 9-1, 9-2, 9-3, 10, 11, 12a , 12b, 12c, 12d , 13d , 14a ,
14b, 14c, 16, 17, 18, 19, 20, 21, 22, 23, 24R, 24S, and 25.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O020266J
J . Org. Chem, Vol. 67, No. 22, 2002 7715