Sulfoxide-metal exchange for the synthesis of the 2'-tributylstannyl derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4u): a general entry to 2'-carbon-substituted analogues of d4U.

Article abstract of DOI:10.1081/NCN-120006826

Methods are described for the synthesis of the 2'-tributylstannyl derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4U). Two approaches were investigated: radical-mediated desulfonylative stannylation of the 2'-benzenesulfonyl derivative of d4U and sul

Full text of DOI:10.1081/NCN-120006826

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
SULFOXIDE-METAL EXCHANGE FOR THE SYNTHESIS
OF THE 2′-TRIBUTYLSTANNYL DERIVATIVE OF
2′,3′-DIDEHYDRO-2′,3′-DIDEOXYURIDINE (d4U):
A GENERAL ENTRY TO 2′-CARBON-SUBSTITUTED
ANALOGUES OF d4U
Hiroki Kumamoto , Sayoko Onuma , Kumiko Tsuchiya , Yuko Egusa ,
Hiromichi Tanaka & Tsuyoshi Satoh
To cite this article: Hiroki Kumamoto , Sayoko Onuma , Kumiko Tsuchiya , Yuko Egusa ,
Hiromichi Tanaka & Tsuyoshi Satoh (2002) SULFOXIDE-METAL EXCHANGE FOR THE SYNTHESIS
OF THE 2′-TRIBUTYLSTANNYL DERIVATIVE OF 2′,3′-DIDEHYDRO-2′,3′-DIDEOXYURIDINE (d4U): A
GENERAL ENTRY TO 2′-CARBON-SUBSTITUTED ANALOGUES OF d4U, Nucleosides, Nucleotides
and Nucleic Acids, 21:4-5, 275-286, DOI: 10.1081/NCN-120006826
To link to this article: http://dx.doi.org/10.1081/NCN-120006826
Published online: 31 Aug 2006.
Submit your article to this journal
Article views: 27
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lncn20
Download by: [Universite Laval]
Date: 06 November 2015, At: 15:29

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 2104&5), 275±286 02002)
SULFOXIDE-METAL EXCHANGE FOR THE
SYNTHESIS OF THE 20-TRIBUTYLSTANNYL
DERIVATIVE OF 20,30-DIDEHYDRO-20,30-
DIDEOXYURIDINE ꢀd4U): A GENERAL ENTRY
TO 20-CARBON-SUBSTITUTED
ANALOGUES OF d4U
1
Hiroki Kumamoto,1 Sayoko Onuma,1 KumikoTsuchiya,
YukoEgusa, Hiromichi Tanaka,1,* and Tsuyoshi Satoh2
1
1School of Pharmaceutical Sciences, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
2Department of Chemistry, Faculty of Science, Science University
of Tokyo, Kagurazaka, Shinjyuku-ku, Tokyo 162-8601, Japan
ABSTRACT
Methods are described for the synthesis of the 20-tributylstannyl deriva-
tive of 20,30-didehydro-20,30-dideoxyuridine 0d4U). Two approaches were
investigated: radical-mediated desulfonylative stannylation of the 20-
benzenesulfonyl derivative of d4U and sulfoxide-metal exchange reaction
of the 20-benzenesul®nyl derivative. The latter approach was found to
give the desired 20-stannyl derivative in good yield. It was also shown that
manipulations of the stannyl group allowed the introduction of a variety
of carbon-substituents to the 20-position by applying the Stille reaction.
The whole reaction sequence has opened up a highly general entry to 20-
carbon-substituted analogues of d4U.
*Corresponding author.
275
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

276
KUMAMOTO ET AL.
INTRODUCTION
The potent anti-HIV activity of 30-deoxy-20,30-didehydrothymidine
0d4T, 1) has stimulated the synthesis and evaluation of variety of 20,30-
didehydro-20,30-dideoxyribonucleosides 0d4Ns).[1] In spite of the fact that
several d4Ns substituted at the 20- or 30-position possess signi®cant anti-HIV
activity,[2,3] structure-activity relationship studies have been limited to a
narrow range of carbon-substituents.[4,5]
With the aim of developing a general method for the synthesis of 20-
carbon-substituted analogues of 20,30-didehydro-20,30-dideoxyuridine 0d4U,
2), we investigated in this study a radical-mediated desulfonylative stanny-
lation of the 20-benzenesulfonyl derivative 03) as well as a sulfoxide-metal
exchange reaction of the corresponding 20-benzenesul®nyl derivative 04).
RESULTS AND DISCUSSION
Radical Approach to Stannylation at the 20-Position of d4U
Based on organotin chemistry,[6] a variety of manipulations are feasible
to transform a trialkylstannyl group attached to sp2-carbon atom. Therefore,
introduction of a trialkylstannyl group at the 20-position of d4U would
provide diversity for a variety of substituents to be introduced. We recently
reported that reaction between Bu3SnOMe and d4T 01) yielded the trans-
alkoxylation product 5, which underwent an anionic O!C stannyl migration
upon treatment with lithium 2,2,6,6-tetramethylpiperidide 0LTMP) in the
presence of HMPA in THF 0Sch. 1).[7] This approach is, however, not
appropriate for the present purpose, since the migration occurs preferentially
at the 30-position to give 6 as the major product, with only 10% of 7 being
formed. Since a phenylthio group is reported to be readily introduced to the
20-position of uridine by way of its O2,20-anhydro derivative,[8] radical-
mediated desulfonylative stannylation[9] was considered as an alternative
approach.
The starting material 8 was prepared according to the published pro-
cedure by reacting O2,20-anhydrouridine with benzenethiol in DMF.[8]
Compound 8 was selectively silylated with tert-butyldimethylsilyl chloride

20-CARBON-SUBSTITUTED ANALOGUES OF d4U
277
0TBDMSCl) in pyridine to give 9. The 30-O-mesylated derivative 010) was
prepared by a conventional method 0MsCl/pyridine, at 0ꢀC), and then it was
treated with DBN in re¯uxing CH3CN to give the vinyl sul®de 11 080%
overall yield from 8). Oxidation of 11 with 2 equiv of m-CPBA in MeOH
furnished the vinyl sulfone 3 in 79% yield. When the radical reaction of 3
with Bu3SnH 04equiv) was carried out for 6 h in re¯uxing benzene in the
presence of AIBN, the desired 20-stannyl derivative 012)[10] was isolated only
in 35% yield after ¯ash silica gel column chromatography. The starting
material 03) was recovered in 40% yield from this reaction. The fact that no
improvement was seen in the yield of 12 even at higher temperatures
0re¯uxing toluene, 31%; re¯uxing xylene, 32%) led us to investigate an
alternative approach.
Scheme 1.
Sulfoxide-metal Exchange Reaction for the Introduction of
20-Stannyl Group to d4U
Ligand-exchange reaction of sulfoxides with organometallic reagents,
mostly RLi or RMgX, has been known for a long time.[11] It is assumed that
a penta-coordinate sulfrane intermediate would be involved in this reaction
as shown in Sch. 2. As a consequence, a new organometallic species either R1-
Met or R2-Met is generated. Which S-C bond is cleaved is dependent on the
structure of ligands, and it seems likely from several precedents[12,13] that
alkenyl aryl sulfoxides undergo preferential S-alkenyl bond cleavage.

278
KUMAMOTO ET AL.
Scheme 2.
We intended to generate the 20-metallated species of d4U to be reacted
with Bu3SnCl by applying the above sulfoxide-metal exchange reaction. The
sulfoxide 4 was prepared in 81% yield as a mixture of two diastereomers 0ca.
1:1) by oxidation of 11 with 1.1 equiv of m-CPBA in CH2Cl2 at À40ꢀC. For
the exchange reaction of 4, alkyllithiums would not be suitable reagents,
since the generated 20-lithio intermediate is anticipated to give the allene
derivative 13, as reported in our previous study of d4T.[7] Therefore,
Grignard reagent EtMgBr was used in the reaction of 4 0THF at À70ꢀC),
and the extent of generating 14 was veri®ed by deuterium incorporation, the
results of which are summarized in Table 1.
In the reactions shown in entries 1 and 2, the yields of 15[14] were not
high enough due to the presence of the starting material 04). This was
improved either by prolonging the reaction time 0entry 3) or by increasing the
Table 1. Sulfoxide-metal Exchange Reaction of 4 with EtMgBr, and Subsequent Deutera-
tiona
Entry EtMgBr 0equiv) NaH 0equiv) Time 0min)b Yield 0%) of 15 D-incorporation 0%)
1
2
3
2.2
3.0
3.0
±
±
±
0.5
0.5
20
47
72
85
56
68
63
45.0
5
±
0.5
2.0
98
73
2.2
20
98
81
aAll reactions were carried out in THF at À70ꢀC.
bTime required between addition of EtMgBr and quenching with MeOD.

20-CARBON-SUBSTITUTED ANALOGUES OF d4U
279
amount of EtMgBr 0entry 4). Although almost quantitative conversion to 15
was achieved in entry 4, the observed deuterium level was not as high. Also,
the presence of excess Grignard reagent is certainly disadvantageous for the
reaction of 14 with Bu3SnCl in that it has to be carried out in a one-pot
manner. Since the sulfoxide-exchange is reported to be a faster process,[15] it
is conceivable that, in the present case, the generated 20-magnesium inter-
mediate undergoes protonation from the N3H. As shown in entry 5, simply
by pre-treatment of 4 with NaH, the best result was obtained both in terms of
yield of 15 and incorporation level of deuterium.
The preparation of the 20-tributylstannyl derivative 012) was carried out
under the above reaction conditions of entry 5. Reaction of the 20-magnesium
intermediate 14 with Bu3SnCl did not proceed at À70ꢀC, and required stir-
ring for 1 h at room temperature. By this procedure, the desired 12 was
obtained in 62% yield. In addition to Bu3SnCl, some other electrophiles can
also be used in the reaction of 14. Thus, the 20-cyano derivative 016) was
prepared in 48% yield by reacting 14 with p-toluenesulfonyl cyanide at 0ꢀC
for 1 h. Iodination with iodine can be carried out at À70ꢀC, forming 17 in
71% yield after 0.5 h. It would be worthy to mention that, in sulfoxide-metal
exchange reaction of alkenyl aryl sulfoxides, incipient alkenylmetal species
are spontaneously protonated because of its highly basic character.[16] To the
best of our knowledge, there has been only one precedent wherein alke-
nylmetal species derived from a-halovinyl aryl sulfoxides reacted with added
electrophiles.[17]
Finally, the utility of the 20-tributylstannyl derivative 012) as well as the
20-iodo derivative 017) was brie¯y exempli®ed by the preparation of 20-
carbon-substituted analogues. The Stille coupling reaction[18] between 12 and
organic halides 0iodobenzene, b-bromostyrene, allyl bromide, and benzyl
bromide) was carried out in DMF at room temperature using Pd0PPh3)4=CuI
to give the respective products 018^21, yields are given in parentheses).
Compound 17 also serves as a useful substrate especially for cross-coupling
reaction with terminal alkynes.[19] The reaction of 17 with 0trimethylsilyl)ace-
tylene gave 22 in 71% yield.
In conclusion, starting from readily available 20-phenylthiouridine 08),
the 20-tributylstannyl derivative 012) of d4U was synthesized by applying the
sulfoxide-metal exchange reaction to the 20-benzenesul®nyl-d4U 04). Since

280
KUMAMOTO ET AL.
the stannyl group of 12 can be transformed into a variety of carbon func-
tionalities, the present study has disclosed a general entry to the 20-carbon-
substituted analogues of d4U.
EXPERIMENTAL SECTION
Melting points are uncorrected. 1H NMR and 13C NMR were measured
at 500 MHz. Chemical shifts are reported relative to Me4Si. Mass spectra
0MS) were taken in FAB mode 0m-nitrobenzyl alcohol as a matrix). Column
chromatography was carried out on silica gel 0Silica Gel 60, Merck). Thin
layer chromatography 0TLC) was performed on silica gel 0precoated silica gel
plate F254, Merck). Where necessary, analytical samples were puri®ed by
high-performance liquid chromatography 0HPLC). HPLC was carried out on
a Shimadzu LC-6AD with a Shim-pack PREP-SIL 0H). KIT column
02625 cm). THF was distilled from benzophenone ketyl.
50- O-ꢀtert-Butyldimethylsilyl)-20-deoxy-20-phenylthiouridine ꢀ9). A mix-
ture of 8 03.0 g, 8.92 mmol) and TBDMSCl 01.61 g, 10.7 mmol) in pyridine
040 mL) was stirred at room temperature for 15 h. The reaction mixture was
evaporated, and then coevaporated with EtOH. The residue was partitioned
between CHCl3 and 0.5 M hydrochloric acid. Column chromatography
0CHCl3=MeOH ˆ 30=1) of the organic layer gave 9 04.01 g, 100%) as a foam:
UV 0MeOH) lmax 256 nm 0e 10,200), lmin 231 nm 0e 2700); 1H NMR 0CDCl3)
d 0.02 and 0.07 06H, each as s, SiMe), 0.83 09H, s, SiBu-t), 2.98 01H, d,
0
J ˆ 2:4Hz, 3 0-OH), 3.72 01H, dd, J ˆ 4:4and 8.8 Hz, H-2 ), 3.79 01H, dd,
J ˆ 2:0 and 11.6 Hz, H-50), 3.92 01H, dd, J ˆ 2:0 and 11.6 Hz, H-50), 4.24±
4.25 01H, m, H-40), 4.27±4.29 01H, m, H-30), 5.65 01H, dd, J ˆ 2:0 and 8.0 Hz,
H-5), 6.29 01H, d, J ˆ 8:8 Hz, H-10), 7.26±7.30 03H, m, Ph), 7.37±7.41 02H, m,
Ph), 7.81 01H, d, J ˆ 8:0, H-6), 8.55 01H, br, NH); FAB-MS m=z 451
‡
0M ‡ H). Anal. Calcd for C21H30N2O5SSi: C, 55.85; H, 6.92; N, 6.16.
Found: C, 55.72; H, 6.75; N, 6.16.
50-O-ꢀtert-Butyldimethylsilyl)-20-deoxy-30-O-methanesulfonyl-20-phenylthio-
uridine ꢀ10). To a solution of 9 033 g, 73 mmol) in pyridine 0300 mL), MsCl
017 mL, 220 mmol) was added at 0ꢀC. After stirring for 12 h at room
temperature, the reaction mixture was poured into ice-water 0ca. 500 mL).
The resulting precipitate was collected and dried under reduced pressure.
This gave 10 030.9 g, 80%) as a solid: mp 145±148ꢀC; UV 0MeOH) lmax
1
255 nm 0e 10,600), lmin 230 nm 0e 2900); H NMR 0CDCl3) d 0.10 and 0.11
06H, each as s, SiMe), 0.88 09H, s, SiBu-t), 3.19 03H, s, SO2Me), 3.7401H, dd,
J ˆ 5:2 and 9.6 Hz, H-20), 3.84±3.91 02H, m, H-50), 4.46±4.47 01H, m, H-40),
5.28 01H, d, J ˆ 5:2 Hz, H-30), 5.49 01H, dd, J ˆ 2:0 and 8.0 Hz, H-5), 6.39
01H, d, J ˆ 9:6 Hz, H-10), 7.23±7.32 03H, m, Ph), 7.39±7.42 02H, m, Ph), 7.49

20-CARBON-SUBSTITUTED ANALOGUES OF d4U
281
‡
01H, d, J ˆ 8:0 Hz, H-6), 7.91 01H, br, NH); FAB-MS m=z 529 0M ‡H).
Anal. Calcd for C22H32N2O7S2Si: C, 49.88; H, 6.28; N, 5.29. Found: C, 49.92;
H, 6.09; N, 5.28.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dideoxy-20-phenylthio-
uridine ꢀ11). A mixture of 10 0500 mg, 0.95 mmol) and DBN 0350 mL,
2.84mmol) in CH 3CN 010 mL) was re¯uxed for 2 h. The reaction mixture
was partitioned between 0.5 M hydrochloric acid and CHCl3. Column
chromatography 0hexane=EtOAc ˆ 2=1) of the organic layer gave 11 0420 mg,
100%) as a foam: UV 0MeOH) lmax 259 nm 0e 12,300), lmin 230 nm 0e 7600);
1H NMR 0CDCl3) d 0.05 and 0.06 06H,0each as s, SiMe), 0.90 09H, s, SiBu-t),
3.76 01H, dd, J ˆ 2:4and 11.6 Hz, H-5 ), 3.87 01H, dd, J ˆ 2:8 and 11.6 Hz,
H-50), 4.87±4.89 01H, m, H-40), 5.62 01H, dd, J ˆ 1:6 and 8.0 Hz, H-5), 5.84±
5.85 01H, m, H-30), 6.89±6.90 01H, m, H-10), 7.32±7.37 03H, m, Ph), 7.38±7.46
02H, m, Ph), 7.79 01H, d, J ˆ 8:0, H-6), 8.22 01H, br, NH); FAB-MS m=z 433
‡
0M ‡H). Anal. Calcd for C21H28N2O4SSi: C, 58.30; H, 6.52; N, 6.48. Found:
C, 58.05; H, 6.49; N, 6.28.
20-Benzenesulfonyl-50-O-ꢀtert-butyldimethylsilyl)-20,30-didehydro-20,30-dide-
oxyuridine ꢀ3). A mixture of 11 0500 mg, 1.16 mmol) and m-CPBA 0purity
70698 mg, 2.43 mmol) in MeOH 020 mL) was stirred at room temperature for
3 h. The reaction mixture was neutralized by adding Et3N and partitioned
between saturated aqueous NaHCO3 and CHCl3. Column chromatography
0hexane=
EtOAc ˆ 1=1) of the organic layer gave 3 0425 mg, 79%) as a foam: UV
0MeOH) lmax 230 nm 0e 13,900) and 260 nm 0e 8000), lmin 219 nm 0e 12,300)
1
and 250 nm 0e 7000); H NMR 0CDCl3) d 0.07 and 0.10 06H, eac0h as s,
SiMe), 0.90 09H, s, SiBu-t), 3.9401H, dd, J ˆ 2:4and 12.0 Hz, H-5 ), 3.99
01H, dd, J ˆ 2:0 and 12.0 Hz, H-50), 4.99±5.01 01H, m, H-40), 5.30 01H, dd,
J ˆ 2:4and 8.0 Hz, H-5), 7.15±7.16 01H, m, H-1 0), 7.2401H, t, J ˆ 1:6 Hz, H-
30), 7.51±7.55 02H, m, Ph), 7.57 01H, d, J ˆ 8:0 Hz, H-6), 7.64±7.68 01H, m,
‡
Ph), 7.84±7.87 02H, m, Ph), 8.42 01H, br, NH); FAB-MS m=z 465 0M ‡ H).
Anal. Calcd for C21H28N2O6SSi: C, 54.29; H, 6.07; N, 6.03. Found: C, 54.46;
H, 6.00; N, 5.88.
Radical-mediated desulfonylative stannylation of 3: formation of the 20-
tributylstannyl derivative ꢀ12). A mixture of 3 0400 mg, 0.86 mmol), Bu3SnH
0925 mL, 3.44 mmol), and AIBN 071 mg, 0.43 mmol) in benzene 020 mL) was
heated at 80ꢀC for 6 h. The reaction mixture was evaporated. Flash column
chromatography 0hexane=EtOAc ˆ 3=1) of the residue gave 12 0184mg,
35%) as an oil. Elution with hexane=EtOAc ˆ 2=1 gave the recovered 3
0211 mg, 40%). Physical data for 12 are as follows: UV 0MeOH) lmax 260 nm
1
0e 8400), lmin 232 nm 0e 3000); H NMR 0CDCl3) d 0.07 and 0.08 06H, each
as s, SiMe), 0.85±0.89 09H, m, Sn0CH2)3CH3), 0.90 09H, s, SiBu-t), 0.90±0.95

282
KUMAMOTO ET AL.
and 1.22±1.48 018H, each as m, Sn0CH2)3 CH3), 3.85 01H, dd, J ˆ 2:4and
0
12.0 Hz, H-50), 3.93 01H, dd, J ˆ 2:4and 12.0 Hz, H-5 ), 4.82±4.85 01H, m,
H-40), 5.6401H, dd, J ˆ 2:0 and 8.4Hz, H-5), 6.17±6.23 01H, m, H-3 0), 7.05±
7.06 01H, m, H-10), 7.8401H, d, J ˆ 8:4Hz, H-6), 8.00 01H, br, NH); FAB-
‡
MS 0120Sn) m=z 653 0M ‡K). Anal. Calcd for C27H50N2OSiSn: C, 52.86; H,
8.22; N, 4.57. Found: C, 52.88; H, 8.37; N, 4.40.
20-Benzenesul®nyl-50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dide-
oxyuridine ꢀ4). Compound 11 0400 mg, 0.92 mmol) in CH2Cl2 010 mL) was
treated with m-CPBA 0293 mg, 1.02 mmol) at À40ꢀC for 0.5 h. After neu-
tralization with Et3N, the reaction mixture was partitioned between saturated
aqueous NaHCO3 and CHCl3. Column chromatograhy 0hexane=AcOEt ˆ
1=1) of the organic layer gave 4 0335 mg, 81%, a mixture of two diaster-
eomers; ca. 1:1) as a foam: UV 0MeOH) lmax 259 nm 0e 8200), lmin 246 nm
0e 6900); 1H NMR 0CDCl3) d 0.08, 0.09, 0.11, and 0.12 06H, each as s, SiMe),
0.91 and 0.92 09H, each as s, SiBu-t), 3.90±4.01 02H, m, H-50), 4.97±5.00 and
5.01±5.03 01H, each as m, H-40), 5.17 00.5H, dd, J ˆ 2:0 and 8.4Hz, H-5),
5.41 00.5 H, dd, J ˆ 2:0 and 8.0 Hz, H-5), 6.93±6.95 01H, m, H-30 and H-10),
7.00±7.02 and 7.06±7.07 01H, each as m, H-30 and H-10), 7.41±7.45 and 7.48±
7.53 03H, each as m, Ph), 7.5400.5 H, d, J ˆ 8:4Hz, H-6), 7.55±7.62 02H, m,
Ph), 7.69 00.5H, d, J ˆ 8:0 Hz, H-6), 8.19 and 8.39 01H, each as br, NH);
‡
FAB-MS m=z 449 0M ‡H). Anal. Calcd for C21H28N2O5SSi: C, 56.22;
H, 6.29; N, 6.24. Found: C, 56.23; H, 6.34; N, 6.14.
Reaction of 4 with EtMgBr and subsequent deuteration: formation of
15. To a solution of 4 0200 mg, 0.45 mmol) in THF 08 mL), NaH 060% oil-
dispersion, 36 mg, 0.9 mmol) was added at room temperature under positive
pressure of dry Ar. After stirring for 20 min, the resulting suspension was
cooled to À70ꢀC, and reacted with EtMgBr 00.9 M in THF, 1.1 mL,
0.99 mmol). After stirring for 20 min at À70ꢀC, the reaction mixture was
quenched by adding MeOD 00.75 mL). The reaction mixture was partitioned
between saturated aqueous NH4Cl and EtOAc. Column chromatography
0hexane=EtOAc ˆ 2=1) of the organic layer gave 15 0144 mg, 98%) as a foam.
The extent of deuterium incorporation 081%) at the 20-position was calcu-
1
lated based on H NMR spectroscopy.
Preparation of the 20-tributylstannyl derivative ꢀ12) by sulfoxide-metal
exchange reaction by using 4. A solution of 4 0300 mg, 0.67 mmol) in THF
08 mL) was treated with NaH followed by EtMgBr by the procedure de-
scribed for the preparation of 15. To the resulting mixture containing 14 was
added Bu3SnCl 0814 mL, 3.0 mmol) at below À70ꢀC. After stirring for 1 h at
room temperature, the reaction mixture was treated with saturated aqueous
NH4Cl. Extraction with CHCl3 followed by ¯ash column chromatography
0hexane=EtOAc ˆ 3=1) gave 12 0253 mg, 62%).

20-CARBON-SUBSTITUTED ANALOGUES OF d4U
283
50-O-ꢀtert-Butyldimethylsilyl)-20-cyano-20,30-didehydro-20,30-dideoxyuridine
ꢀ16). A solution of 4 0416 mg, 0.93 mmol) in THF 015 mL) was treated with
NaH followed by EtMgBr by the procedure described for the preparation of
15. To the resulting mixture containing 14 was added p-toluenesulfonyl cy-
anide 0709 mg, 3.91 mmol) at below À70ꢀC. After stirring for 1 h at 0ꢀC, the
reaction mixture was treated with saturated aqueous NH4Cl. Extraction with
CHCl3 followed by column chromatography 0hexane=EtOAc ˆ 1=1) gave 16
0156 mg, 48%) as a foam : UV 0MeOH) lmax 258 nm 0e 8900), lmin 237 nm
0e 5800); 1H NMR 0CDCl3) d 0.10 and 0.11 06H,0each as s, SiMe), 0.91 09H, s,
SiBu-t), 3.93 01H, dd, J ˆ 2:4and 12.0 Hz, H-5 ), 3.99 01H, dd, J ˆ 2:4and
12.0 Hz, H-50), 5.06±5.09 01H, m, H-40), 5.75 01H, dd, J ˆ 2:0 and 8.4Hz,
H-5), 7.07±7.08 01H, m, H-30), 7.13±7.15 01H, m, H-10), 7.76 01H, d,
‡
J ˆ 8:4Hz, H-6), 8.55 01H, br, NH); FAB-MS m=z 350 0M ‡H). Anal.
Calcd for C16H23N3O4Si: C, 54.99; H, 6.63; N, 12.02. Found: C, 55.12; H,
6.65; N, 11.87.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dideoxy-20-iodouridine
ꢀ17). A solution of 4 0300 mg, 0.67 mmol) in THF 015 mL) was treated with
NaH followed by EtMgBr by the procedure described for the preparation of
15. To the resulting mixture containing 14 was added iodine 0766 mg,
3.0 mmol as I2) at below À70ꢀC. After stirring for 0.5 h at below À70ꢀC, the
reaction mixture was treated with saturated aqueous NH4Cl. Extraction with
CHCl3 followed by column chromatography 0hexane=EtOAc ˆ 2=1) gave 17
0213 mg, 71%) as a foam: UV 0MeOH) lmax 259 nm 0e 8900), lmin 234nm
0e 3000); 1H NMR 0CDCl3) d 0.07 and 0.09 06H, each as s, SiMe), 0.90 09H, s,
SiBu-t), 3.8401H, dd, J ˆ 2:8 and 11.6 Hz, H-50), 3.90 01H, dd, J ˆ 2:8 and
11.6 Hz, H-50), 4.85±7.86 01H, m, H-40), 5.72 01H, dd, J ˆ 2:0 and 8.0 Hz, H-
5), 6.54±6.55 01H, m, H-30), 6.92±6.93 01H, m, H-10), 7.7401H, d, J ˆ 8:0 Hz,
‡
H-5), 8.8401H, br, NH); FAB-MS m=z 451 0M ‡H). Anal. Calcd for
C15H23IN2O4Si: C, 40.01; H, 5.15; N, 6.22. Found: C, 40.30; H, 5.06; N, 6.12.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dideoxy-20-phenyluridine
ꢀ18). A mixture of 12 0784mg, 1.28 mmol), PhI 0360 mL, 3.20 mmol),
Pd0Ph3P)4 0150 mg, 0.13 mmol), and CuI 050 mg, 0.26 mmol) in DMF 03 mL)
was stirred at room temperature for 20 h. The resulting suspension was
partitioned between brine and EtOAc. Column chromatography
0hexane=EtOAc ˆ 1=1) of the organic layer gave 18 0407 mg, 80%) as a foam:
UV 0MeOH) lmax 254nm 0 e 21,500), lmin 224nm 0 e 6600); 1H NMR 0CDCl3)
d 0.10 and 0.12 06H, each as s, SiMe), 0.92 09H, s, SiBu-t), 3.91 01H, dd,
J ˆ 2:8 and 11.6 Hz, H-50), 3.97 01H, dd, J ˆ 2:8 and 11.6 Hz, H-50), 5.02±
5.03 01H, m, H-40), 5.56 01H, dd, J ˆ 2:0 and 8.0 Hz, H-5), 6.49±6.50 01H, m,
H-30), 7.32±7.36 05H, m, Ph), 7.48±7.50 01H, m, H-10), 7.79 01H, d,
‡
J ˆ 8:0 Hz, H-6), 8.1401H, br, NH); FAB-MS m=z 401 0M ‡H). Anal.

284
KUMAMOTO ET AL.
Calcd for C21H28N2O4Si: C, 62.97; H, 7.05; N, 6.99. Found: C, 62.94; H,
7.23; N, 6.91.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dideoxy-20-styryluridine
ꢀ19). A mixture of 12 0296 mg, 0.48 mmol), b-bromostyrene 0E=Z ˆ 7=1,
154 mL, 1.21 mmol), Pd0Ph3P)4 055 mg, 0.048 mmol), and CuI 018 mg,
0.096 mmol) in DMF 01.5 mL) was stirred at room temperature for 48 h. The
resulting suspension was partitioned between brine and EtOAc. Column
chromatography 0hexane=EtOAc ˆ 1=1) of the organic layer gave 19
0132 mg, 64%, a mixture of two geometrical isomers: E=Z ˆ ca: 8=1) as a
foam: UV 0MeOH) lmax 226 nm 0e 14400) and 277 nm 0e 27800), lmin 238 nm
1
0e 5800); H NMR 0CDCl3) of E-isomer d 0.09 and 0.10 06 H, each as s,
SiMe), 0.91 09H, s, SiBu-t), 3.87 01H, dd, J ˆ 2:8 and 11.6 Hz, H-50), 3.93
01H, dd, J ˆ 2:8 and 11.6 Hz, H-50), 4.92±4.94 01H, m, H-40), 5.6401H, dd,
0
J ˆ 2:4and 8.0 Hz, H-5), 6.24±6.25 01H, m,H-3 ), 6.52 and 6.78 02H, each as
d, J ˆ 16:8 Hz, CHˆCHPh), 7.25±7.39 06H, m, H-10 and Ph), 7.58 01H, d,
1
J ˆ 8:0 Hz, H-6), 8.18 01H, br, NH); H NMR 0CDCl3) of Z-isomer 00.02
and 0.0406H, each as s, SiMe), 0.88 09H, s, SiBu- t), 3.73 01H, dd, J ˆ 3:2 and
12.0 Hz, H-50), 3.79 01H, dd, J ˆ 3:2 and 12.0 Hz, H-50), 4.81±4.82 01H, m,
H-40), 5.59 01H, dd, J ˆ 2:4and 8.0 Hz, H-5), 5.99 and 6.69 02H, each as d,
J ˆ 12:0 Hz, CHˆCHPh), 6.17±6.18 01H, m, H-30), 6.86±6.87 01H, m, H-10),
7.25±7.39 05H, m, Ph), 7.49 01H, d, J ˆ 8:0 Hz, H-6), 7.88 01H, br, NH);
‡
FAB-MS m=z 427 0M ‡H). Anal. Calcd for C23H30N2O4SiÁ1=2H2O: C,
63.42; H, 7.17; N, 6.43. Found: C, 63.04; H, 6.99; N, 6.46.
20-Allyl-50-O-ꢀtert-butyldimethylsilyl)-20,30-didehydro-20,30-dideoxyuridine
ꢀ20). A mixture of 12 0280 mg, 0.62 mmol), allyl bromide 0134 mL,
1.55 mmol), Pd0Ph3P)4 072 mg, 0.062 mmol), and CuI 024mg, 0.124mmol) in
DMF 01.5 mL) was stirred at room temperature for 24h. The resulting sus-
pension was partitioned between brine and EtOAc. Column chromatography
0hexane=EtOAc ˆ 1=1) of the organic layer gave 20 0155 mg, 69%) as a foam:
1
UV 0MeOH) lmax 261 nm 0e 8300), lmin 230 nm 0e 1100); H NMR 0CDCl3)
d 0.07 and 0.08 06H, each as s, SiMe), 0.90 09H, s, SiBu-t), 2.68±2.81 02H, m,
0
CH2CHˆCH2), 3.80 01H, dd, J ˆ 2:4and 11.6 Hz, H-5 ), 3.92 01H, dd,
J ˆ 2:4and 11.6 Hz, H-5 0), 4.84±4.85 01H, m, H-40), 5.07±5.09 and 5.11±5.12
02H, each as m, CH2CHˆCH2), 5.67 01H, dd, J ˆ 2:0 and 8.0 Hz, H-5), 5.69±
5.80 01H, m, CH2CHˆCH2), 5.85±5.86 01H, m, H-30), 6.88±6.89 01H, m, H-
10), 7.89 01H, d, J ˆ 8:0 Hz, H-6), 8.09 01H, br, NH); FAB-MS m=z 365
‡
0M ‡H). Anal. Calcd for C18H28N2O4Si: C, 59.48; H, 7.49; N, 7.71. Found:
C, 59.29; H, 7.88; N, 7.50.
20-Benzyl-50-O-ꢀtert-butyldimethylsilyl)-20,30-didehydro-20,30-dideoxyuridine
ꢀ21). A mixture of 12 02.24g, 3.66 mmol), benzyl bromide 01.3 mL,
10.97 mmol), Pd0Ph3P)4 0422 mg, 0.37 mmol), and CuI 0139 mg, 0.73 mmol) in

20-CARBON-SUBSTITUTED ANALOGUES OF d4U
285
DMF 09 mL) was stirred at room temperature for 40 h. The resulting sus-
pension was partitioned between brine and EtOAc. Column chromatography
0hexane=EtOAc ˆ 1=1) of the organic layer gave 21 0757 mg, 50%) as a foam:
UV 0MeOH) lmax 261 nm 0e 7800), lmin 232 nm 0e 1400); 1H NMR 0CDCl3) d
0.06 and 0.07 06H, each as s, SiMe), 0.90 09H, s, SiBu-t), 3.24and 3.46 02H,
0
each as d, J ˆ 15:6 Hz, CH2Ph), 3.77 01H, dd, J ˆ 2:4and 11.6 Hz, H-5 ),
3.92 01H, dd, J ˆ 2:0 and 11.6 Hz, H-50), 4.83±4.85 01H, m, H-40), 5.44 01H,
0
dd, J ˆ 2:4and 8.0 Hz, H-5), 5.76±5.77 01H, m, H-3 ), 6.90±6.91 01H, m, H-
10), 7.10±7.12 02H, m, Ph), 7.20±7.27 03H, m, Ph), 7.79 01H, d, J ˆ 8:0 Hz, H-
‡
6), 8.01 01H, br, NH); FAB-MS m=z 415 0M ‡H). Anal. Calcd for
C22H30N2O4SiÁ1=5H2O: C, 63.19; H, 7.33; N, 6.70. Found: C, 63.15; H, 7.38;
N, 6.56.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-dideoxy-20-ꢀtrimethyl-
silyl)ethynyluridine ꢀ22). A mixture of 17 0300 mg, 0.67 mmol), 0tri-
methylsilyl)acetylene 0280 mL, 2.0 mmol), Cl2Pd0Ph3P)2 047 mg, 0.067 mmol),
CuI 013 mg, 0.067 mmol), and Et3N 0280 mL, 2.0 mmol) in DMF 03 mL) was
stirred at 80ꢀC for 1 h. The resulting suspension was partitioned between
brine and EtOAc. Column chromatography 0hexane=EtOAc ˆ 2=1) of the
organic layer gave 22 0195 mg, 71%) as a foam: UV 0MeOH) lmax 236 nm
0e 17,300) and 247 nm 0e 18,200), lmin 241 nm 0e 15,200); 1H NMR 0CDCl3) d
0.07 and 0.08 06H, each as s, SiMe2), 0.16 09H, s, SiMe3), 0.90 09H, s, SiBu-t),
0
3.82 01H, dd, J ˆ 2:4and 11.6 Hz, H-5 ), 3.87 01H, dd, J ˆ 2:8 and 11.6 Hz,
H-50), 4.92±4.95 01H, m, H-40), 5.69 01H, dd, J ˆ 2:4and 8.0 Hz, H-5), 6.40±
6.41 01H, m, H-30), 6.91±6.93 01H, m, H-10), 7.69 01H, d, J ˆ 8:0 Hz, H-6),
‡
8.23 01H, br, NH); FAB-MS m=z 421 0M ‡H). Anal. Calcd for
C20H22N2O4Si2: C, 57.05; H, 7.67; N, 6.66. Found: C, 57.25; H, 7.71; N, 6.61.
REFERENCES
1. Krayevsky, A.A.; Watanabe, K.A. Modi¢ed Nucleosides as Anti-AIDS Drugs,
Current Status and Perspectives; Bioinform: Moscow, 1993.
2. Van Aerschot, A.; Herdewijn, P.; Balzarini, J.; Pauwels, R.; De Clercq, E.
J. Med. Chem. 1989, 32, 1743.
3. Koshida, R.; Cox, S.; Harmenberg, J.; Gilljam, G.; Wahren, B. Antimicrob.
Agents Chemother. 1989, 33, 2083.
4. For 30-cyano-d4T analogue: Camarasa, M.J.; Diaz-Ortiz, A.; Calvo-Mateo, A.;
De las Heras, F.G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1989, 32, 1732.
5. For 30-methyl-d4T Analogue: Matsuda, A.; Okajima, H.; Masuda, A.;
Kakefuda, A.; Yoshimura, Y.; Ueda, T. Nucleosides Nucleotides 1992, 11, 197.
6. Pereyre, M.; Quintard, J.-P.; Rahm, A. T|n in Organic Synthesis; Butterworth:
London, 1987.
7. Kumamoto, H.; Tanaka, H. J. Org. Chem. 2002, 67, in press.

286
KUMAMOTO ET AL.
8. 0a) Divakar, K.J.; Reese, C.B. J. Chem. Soc. Perkin I 1982, 1625. 0b) Matsuda,
A.; Miyasaka, T. Heterocycles 1983, 20, 55.
9. Vinyl sulfones are known to undergo radical reaction with Bu3SnH to give vi-
nylstannanes: 0a) Watanabe, Y.; Ueno, Y.; Araki, T.; Endo, T.; Okawara, M.
Tetrahedron Lett. 1986, 27, 215. 0b) Dubois, E.; Beau, J.-M.; Tetrahedron Lett.
1990, 31, 5165. 0c) McCarthy, J.R.; Matthews, D.P.; Stemerick, D.M.; Huber,
E.W.; Bey, P.; Lippert, B.J.; Snyder, R.D.; Sunkara, P.S.J. Am. Chem. Soc.
1991, 113, 7439. 0d) Wnuk, S.F.; Robins, M.J. Can. J. Chem. 1993, 71, 192.
0e) McCarthy, J.R.; Huber, E.W.; Le, T.-B.; Laskovics, F.M.; Matthews,
D.P. Tetrahedron 1996, 52, 45. f) Onuma, S.; Kumamoto, H.; Kawato, M.;
Tanaka, H. Tetrahedron 2002, 58, 2497.
10. The regiochemistry of 12 was determined by comparison of its 13C NMR data
with those of 50-O-0tert-butyldimethylsilyl)-d4U,[14] as shown below.
13C NMR Chemical Shifts 0d ppm) in CDCl3
Compd.
C10
C20
C30
C40
C50
d4U
12
95.0
89.6
141.1
126.6
142.6
134.2
88.1
87.3
64.2
64.1
Ád
.5
5.414 8.40.8
0.1
11. 0a) Oae, S. Rev. Heteroat. Chem. 1991, 4, 195. 0b) Satoh, T. J. Syn. Org. Chem.
Jpn. 1996, 54, 481.
12. Theobald, P.G.; Okamura, W.H. J. Org. Chem. 1990, 55, 741.
13. Cardellicchio, C.; Fiandanese, V.; Naso, F. J. Org. Chem. 1992, 57, 1718.
14. For Physical Data of 50-O-0tert-butyldimethylsilyl)-d4U: Dudycz, L.W.
Nucleosides Nucleotides 1989, 8, 35.
15. The sulfoxide-exchange is reported to be a faster process than halogen-lithium
exchange reaction, see reference 12.
16. For an example: Walkup, R.D.; Boatman, Jr., P.D. Tetrahedron Lett. 1993,
34, 2417.
17. Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.; Koyama, M. Tetra-
hedron 1998, 54, 5557.
18. For a review: Mitchell, T.N. Synthesis 1992, 803.
19. 0a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
0b) Heck, R.F. Acc. Chem. Res. 1979, 12, 146. 0c) Heck, R.F. Org. React.
1982, 27, 345.
Received February 3, 2002
Accepted April 4, 2002