C-3'-branched thymidines as precursors for the selective generation of C-3'-nucleoside radicals

Article abstract of DOI:10.1021/jo982022y

C-3'-nucleoside radicals can be generated via Norrish type I photocleavage of C-3'-acyl nucleoside derivatives. In monomer experiments employing C-3'-acylthymidine derivatives 2 and 3, a 1:1 mixture of isomers of the H-abstraction products was obtained when the photolysis was carried out in the presence of a hydrogen donor. Derivatives 2 were synthesized by an approach which involves the formation of a silyl-protected cyanohydrin, which is subsequently alkylated with organolithium reagents, followed by hydrolysis. Derivatives 3 could be obtained via a multistep synthesis starting from diol 7. Several different methods were attempted to oxidize the unprotected diol to the α-hydroxy aldehyde. Finally, a route was chosen which involves a protection-deprotection sequence followed by oxidation of the free primary alcohol. The resulting modified nucleosides should facilitate the study of C-3'-DNA radicals.

Full text of DOI:10.1021/jo982022y

J . Org. Chem. 1999, 64, 1559-1564
1559
C-3′-Br a n ch ed Th ym id in es a s P r ecu r sor s for th e Selective
Gen er a tion of C-3′-Nu cleosid e Ra d ica ls
Steffi Ko¨rner, Amanda Bryant-Friedrich, and Bernd Giese*
Department of Chemistry, University of Basel, St. J ohanns-Ring 19, CH-4056 Basel, Switzerland
Received October 7, 1998
C-3′-nucleoside radicals can be generated via Norrish type I photocleavage of C-3′-acyl nucleoside
derivatives. In monomer experiments employing C-3′-acylthymidine derivatives 2 and 3, a 1:1
mixture of isomers of the H-abstraction products was obtained when the photolysis was carried
out in the presence of a hydrogen donor. Derivatives 2 were synthesized by an approach which
involves the formation of a silyl-protected cyanohydrin, which is subsequently alkylated with
organolithium reagents, followed by hydrolysis. Derivatives 3 could be obtained via a multistep
synthesis starting from diol 7. Several different methods were attempted to oxidize the unprotected
diol to the R-hydroxy aldehyde. Finally, a route was chosen which involves a protection-deprotection
sequence followed by oxidation of the free primary alcohol. The resulting modified nucleosides should
facilitate the study of C-3′-DNA radicals.
In tr od u ction
enediyne antibiotics.5 Metallointercalators, such as the
phenanthrenequinone diimine complexes of rhodium(III),
have been postulated to also cleave DNA via a radical-
based mechanism similar to that of bleomycin.6 Whereas
the above-mentioned natural products bind to the minor
groove of double-stranded DNA and abstract mainly C-4′
and C-5′ H-atoms from the sugar backbone, these met-
alloorganic compounds intercalate in the major groove
of double-stranded DNA and upon photoactivation ab-
stract C-3′ H-atoms from deoxyribose, generating highly
reactive DNA radicals that lead to strand fragmentation.
The increasing amount of attention focused on the
synthesis of nucleosides and analogues is stimulated by
a variety of factors. Several sugar-modified nucleosides
have been shown to possess the ability to inhibit the
growth of various human tumor cells, whereas others
have shown antiviral activity.1 A great deal of energy has
also been invested into the design of nucleosides suitable
for incorporation into modified oligonucleotides that
hybridize with single-stranded RNA.2 These oligonucleo-
tides are presently under evaluation as novel therapeutic
agents (antisense or ribozyme approach). C-3′-Methyl-
2′-deoxynucleosides, along with other C-3′-substituted 2′-
deoxynucleosides, have shown biological activities on
RNA and DNA polymerases.3
Modified nucleosides have also found their place in the
study of biological processes related to DNA damage.
They have been utilized in the investigation of mecha-
nisms involving radical species, which include ionizing
radiation and the radical-induced cleavage of DNA by
various antitumor agents such as bleomycin4 and the
Here, we introduce the synthesis of a new class of C-3′
branched-chain nucleosides and investigate the feasabil-
ity of their use in the study of the radical-induced DNA
cleavage mechanisms postulated to occur from the major
groove of DNA. We have demonstrated that 2′-deoxy-
nucleotide-4′-radicals can be selectively and indepen-
dently generated by photolysis of ketones 1a -c.7 These
modified nucleosides were incorporated into DNA, and
the mechanism of cleavage of single- and double-stranded
DNA induced by the C-4′ radical has been and continues
to be studied.8 Analogously, C-3′-acyl nucleoside deriva-
tives should generate via photolysis the C-3′-radical
intermediate formed in the photoactivated cleavage of
DNA with metallointercalators, making it possible to
study the mechanisms involved here as well.
(1) See, for example: (a) Maag, H.; Gutierrez, A.; Prisbe, E.;
Rydzweski, R.; Verheyden, J . In Antibiotics and Antiviral Compounds;
Krohn, K., Kirst, H., Maag, H., Eds.; VCH Verlagsgesellschaft:
Weinheim, 1993; pp 421-438. (b) Azuma, A.; Hanaoka, K.; Kurihara,
A.; Kobayashi, T.; Miyauchi, S.; Kamo, N.; Tanaka, M.; Sasaki, T.;
Matsuda, A. J . Med. Chem. 1995, 38, 3391-3397. (c) Drach, J . C. In
Targets for the Design of Antiviral Agents; De Clercq, E., Walker, R.
T., Eds.; Nato Advanced Institutes Series, Series A: Life Sciences;
Plenum Press: New York, 1983; Vol. 33, pp 231-257. (d) Hecht, S. In
Cancer Chemotherapeutic Agents; Foye, W. O., Ed.; American Chemical
Society: Washington, DC 1995; 369-388.
Even though considerable attention has been devoted
to the synthesis of C-3′-branched nucleosides,9 only a few
examples of C-3′-branched deoxynucleoside analogues
(5) (a) Goldberg, I. H.; Kappen, L. S. Enediyne Antibiotics as
Antitumor Agents; Marcel Dekker: New York, 1994; pp 327-362. (b)
Dedon, P. C.; Goldberg, I. H. Chem. Res. Tox. 1992, 5, 311-322.
(6) Sitlani, A.; Long, E. C.; Pyle, A. M.; Barton, J . K. J . Am. Chem.
Soc. 1992, 114, 2303-2312. (b) Hudson, B. P.; Barton, J . K. J . Am.
Chem. Soc. 1998, 120, 6877-6888.
(7) Marx, A.; Erdmann, P.; Senn, M.; Ko¨rner, S.; J ungo, T.; Petretta,
M.; Imwinkelried, P.; Dussy, A.; Kulicke, K.; Macko, L.; Zehnder, M.;
Giese, B. Helv. Chim. Acta 1996, 70, 1980-1994.
(8) (a) Giese, B.; Erdmann, P.; Schaefer, T.; Schwitter, U. Synthesis
1994, 1310-1312. (b) Giese, B.; Dussy, A.; Elie, C.; Erdmann, P.;
Schwitter, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 1861. (c) Giese,
B.; Beyrich-Graf, X.; Erdmann, P.; Petretta, M.; Schwitter, U. Chem.
Biol. 1995, 2, 367. (d) Giese, B.; Dussy, A.; Meggers, E.; Petretta, M.
J . Am. Chem. Soc. 1997, 119, 11130.
(2) (a) Crooke, S. T., Lebleu, B., Eds. Antisense Research and
Applications; CRC Press: Boca Raton, FL, 1993. (b) Wagner, R. W.
Nature, 1994, 372, 333-335. (c) De Mesmaeker, A.; Ha¨ner, R.; Martin,
P.; Moser, H. W. Acc. Chem. Res. 1995, 28, 366-374. (d) Agrawal, S.,
Ed. Antisense Therapeutics; Humana Press: Totowa, NJ , 1996. (e)
Akhtar, S.; Agrawal S. Trends Pharmacol. Sci. 1997, 18, 12-18.
(3) See, for example: (a) Mikhailov, S. N.; Padyukova, N. S.; Lysov,
Y. P.; Savochkina, L. R. Nucleosides Nucleotides 1991, 10, 339-343.
(b) Fedorov, I. I.; Kazmina, E. M.; Novicov, N. A.; Gurskaya, G. V.;
Bochkarev, A. V.; J asko, M. V.; Victorova, L. S.; Kukhanova, M. K.;
Balzarini, J .; De Clercq, E.; Krayevsky, A. A. J . Med. Chem. 1992, 35,
4567-4575.
(4) Stubbe, J .; Kozarich, J . W. Chem. Rev. 1987, 87, 1107-1136.
(b) Burger, R. Chem. Rev. 1998, 98, 1153-1169.
10.1021/jo982022y CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/13/1999

1560 J . Org. Chem., Vol. 64, No. 5, 1999
Ko¨rner et al.
Sch em e 1a
Resu lts a n d Discu ssion
To investigate the relationship between the diastereo-
selectivity of product formation in the reduction of the
C-3′ radical and the stereochemistry of the starting
nucleoside, both the threo and erythro modified nucleo-
sides were synthesized. Taking advantage of the fact that
3′-keto-2′-deoxynucleosides show a preference for nucleo-
philic attack from the R face, we used this method to
synthesize threo-configured C-3′-acyl-substituted 2′-
deoxynucleosides 3a -c. Our approach involved the for-
mation of a trimethylsilyl-protected cyanohydrin that
could then be alkylated and hydrolyzed to give the
desired ketones. Because of the extreme sensitivity of 3′-
keto-2′-deoxynucleosides to acid and base, care was
necessary in the selection of the proper conditions for the
nucleophilic addition of CN- to this ketone. Greenlee et
al.12 reported the addition of trimethylsilyl cyanide to
R-substituted ketones by means of potassium cyanide and
18-crown-6 as catalyst. This method was found to be quite
useful for the synthesis of cyanohydrins from acid-
sensitive ketones. With this method, ketone 413 was
converted to the protected cyanohydrins 5a and 5b, which
were isolated as a 9:1 threo:erythro mixture of isomers
in 63% yield (Scheme 1). The isomers were separated by
repeated flash chromatography. Cyanohydrin 5a was
then subjected to nucleophilic addition of PhLi, MeLi, and
t-BuLi (3-5 equiv of the organolithium reagent and 0.01
equiv of CuI) followed by acid hydrolysis with 1 M HCl
to give the desired ketones 6a -c in high yield. The
absolute configuration of these ketones was unambigu-
ously established by 1H NOE difference experiments
employing ketone 6b . These experiments revealed a
F igu r e 1.
with both a 3′-R-hydroxy group and a 3′-â-carbon sub-
stituent can be found in the literature.10 Via the most
obvious method for the generation of these derivatives,
the addition of a carbon nucleophile to a 3′-ketonucleo-
side, it has been observed that mainly the threo-
configured nucleoside analogues are obtained.11 Wengel
et al.10c used this preference for R attack to generate
nucleoside derivatives with a hydroxymethyl substituent
by bishydroxylation of the corresponding C-3′-meth-
ylidene nucleoside derivatives. This very useful diol was
chosen as a starting point for our synthesis of erythro
C-3′-acyl-substituted 2′-deoxynucleosides.
(9) See, for example: (a) Nutt, R. F.; Dickinson, M. J .; Holly, F. W.;
Walton, E. J . Org. Chem. 1968, 33, 1789-1795. (b) Auguste, S. P.;
Young, D. W. J . Chem. Soc., Perkin Trans. 1 1995, 395-404. (c) J ung,
P. M. J .; Burger, A.; Biellmann, J .-F. Tetrahedron Lett. 1995, 36, 1031-
1034.
(10) (a) J orgensen, P. N.; Stein, P. C.; Wengel, J . J . Am. Chem. Soc.
1994, 116, 2231-2232. (b) Svendsen, M. L.; Wengel, J .; Dahl, O.;
Kirpekar, F.; Roepstorff, R. Tetrahedron 1993, 49, 11341-11352. (c)
J orgensen, P. N. Svendsen, M. L.; Scheuer- Larsen, C.; Wengel, J .
Tetrahedron, 1995, 51, 2155-2164. (d) J ung, P. M. J .; Burger, A.;
Biellmann, J .-F. J . Org. Chem. 1997, 62, 8309-8314. (e) J orgensen,
P. N.; Sorensen, U. S.; Pfundheller, H. M.; Olsen, C. E.; Wengel, J . J .
Chem. Soc., Perkin Trans. 1 1997, 3275-3284. (f) Nielsen, P.; Pfund-
heller, H. M.; Wengel, J . Chem. Commun. 1997, 825-826. (g) Ichikawa,
S.; Shuto, S.; Minakawa, N.; Matsuda, A. J . Org. Chem. 1997, 62,
1368-1375.
(11) Weeb, T. R. Tetrahedron Lett. 1988, 29, 3769-3772. (b) Bender,
S. L.; Moffett, K. K. J . Org. Chem. 1992, 57, 1646-1647. (c) Hayakawa,
H.; Tanaka, J .; Itoh, N.; Nakajimia, M.; Miyuasak, K.; Yamaguchi, Y.;
Iitaka, Y. Chem. Pharm. Bull. 1987, 35, 2605. (d) Koole, L. H.; Buck,
H. M.; Vial, J .-M.; Chattopadhyaya, J . Acta Chem. Scand. 1989, 43,
665-669.
(12) Greenlee, W. J .; Hangauer, D. G. Tetrahedron Lett. 1983, 24,
4559-4560.
(13) Robins, M. J .; Samano, V. J . Org. Chem. 1990, 55, 5186-5188.
J ørgensen et al. Nucleosides Nucleotides 1995, 14, 1465.

Selective Generation of C-3′-Nucleoside Radicals
J . Org. Chem., Vol. 64, No. 5, 1999 1561
Sch em e 2a
Sch em e 3
Ta ble 1. Ir r a d ia tion of C-3′-Br a n ch ed Keton es 2 a n d 3
length of
ratio of products
irradiation yield (%)
14:15
R ) CH3 (2a )
R ) CH3 (3a )
R ) Ph (2c)
3 h
3 h
2 h
2 h
1 h
1 h
20
65
35
33
79
92
1:1
1:1
1:1
1:1
1:1
1:1
R ) Ph (3c)
R ) (CH3)3C (2b)
R ) (CH3)3C (3b)
tory results could be obtained.15 Reaction of MeLi (10
equiv), PhLi (10 equiv), and t-BuLi (14 equiv) along with
an equimolar amount of CeCl3 with 11 in THF delivered
the corresponding alcohols, which were used in the next
step without further purification. Dess-Martin oxidation
of 12a -c in CH2Cl2 and subsequent deprotection of the
3′-hydroxy substituent with TBAF in THF afforded
radical precursors 2a -c.
The structural assignment of ketones 2a -c was done
by comparison of the coupling constants of the H-1′ of
these ketones to the same proton of ketones 3a -c. The
H-1′ signal of ketones 3a -c appears as a doublet of
doublets with a coupling constant of J 1′-2′â ≈ 3.0 Hz,
whereas in the case of 2a -c, this coupling is ≈ 5.5 Hz.
strong NOE effect between the 2′-â-H of the sugar and
the 3′-OH. The 2′-â-H was identified by the NOE effect
observed between this proton and H-6 of the nucleoside
base. These modified nucleosides were then tritylated by
means of standard methods.
With these radical precursors in hand, we then looked
at the selective generation of C-3′-nucleoside radicals by
irradiation of ketones 2 and 3. To probe the efficiency of
radical formation, these ketones were irradiated in the
presence of a hydrogen donor.
When cyanohydrin 5b was subjected to the same
reaction conditions as mentioned above, no ketone could
be isolated. It seems that in this case primarily trimeth-
ylsilyl cleavage occurs and the cyanohydrin then reverts
to the starting ketone. Under these reaction conditions,
this ketone then undergoes base elimination. We then
turned our attention to a different method utilizing diol
8, which was first synthesized by Wengel et al.10c At-
tempts were made to oxidize the primary hydroxy group
to an aldehyde moiety without protection of the tertiary
hydroxy group by employing the Dess-Martin reagent,
TPAP-catalyzed oxidation with NMO, and NIS/tetrabu-
tylammonium iodide. All of these methods led to ring
fragmentation. The diol was then doubly protected by
employing triethylsilyl chloride in the presence of 1H-
imidazole in DMF. Bissilyl ether 9 was isolated in 72%
yield. After selective deprotection of the primary trieth-
ylsilyl ether with HF-pyridine complex in THF, alcohol
10 was obtained in 82% yield (Scheme 2). Through TPAP-
catalyzed oxidation of 10 with NMO in the presence of 4
Å molecular sieve powder in CH2Cl2, aldehyde 11 could
be isolated in 98% yield.14 The next step was the alkyl-
ation of the aldehyde followed by oxidation to give the
desired ketones. When the alkylation was attempted
using organolithium or Grignard reagents, primarily silyl
migration was observed from the tertiary 3′-O of the
sugar to the newly formed secondary OH group of the
side chain. When the alkylation was carried out with
organolithium reagents in the presence of CeCl3, satisfac-
The photolysis of ketones 2a -c and 3a -c (λmax g 320
nm) was carried out in the presence of an excess of nBu3-
SnH in CH3CN (Scheme 3). When the crude reaction
mixture of the photolysis was analyzed directly by
reversed phase HPLC, the reduction products were
detected as a 1:1 mixture of R and â-5′-O-tritylated
thymidine (Table 1). As expected, tert-butyl ketones 2b
and 3b underwent a clean and efficient Norrish type I
cleavage, giving the best results with high yields and only
trace amounts of side products. Methyl ketone 3a also
performs well as a radical precursor; however, in the case
of ketone 2a , side products were detected which caused
a much lower yield. These side products are likely the
result of Norrish type II reaction of the methyl ketone.
In the case of benzoyl ketones 2c and 3c, the reduction
products 14 and 15 were also obtained, however, in low
yield (35% and 33%, respectively). This was not surpris-
ing because of the known complications involved in the
use of aryl ketones as radical precursors.16 The stereo-
chemistry at the 3′-C position of the starting ketone
seems to have no influence on the photocleavage process
or the diastereoselectivity of the reduction, which implies
that the reduction takes place via a free radical process.
(15) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392-4398.
(16) Greenberg, M. M.; Barvian, M. R.; Cook, G. P.; Goodman, B.
K. Matray, T. J .; Tronche, C.; Venkatesan, H. J . Am. Chem. Soc. 1997,
119, 1828-183.
(14) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19.

1562 J . Org. Chem., Vol. 64, No. 5, 1999
Ko¨rner et al.
toluene, nitrile 5b and CuI (0.01 equiv) were dissolved in THF
and cooled to -78 °C. To the solution was then slowly added
the lithium reagent (3-5 equiv). After 5 h of stirring at this
temperature, the reaction was hydrolyzed over 24-72 h at 25
°C with 1 N HCl (20 mL). The reaction mixture was then
extracted with AcOEt and dried over MgSO4, and the solvent
was removed. After flash chromatography, the products were
isolated as white solids.
1-(3-C-Acet yl-2-d eoxy-â-D-th r eo-p en t ofu r a n osyl)t h y-
m in e (6a ). The alkylation of 5a (700 mg, 1.54 mmol) was
performed using 3 equiv of a 5% solution of MeLi in diethyl
ether (4.62 mmol). The intermediate was hydrolyzed over 24
h with 1 N HCl, and ketone 6a was isolated in 78% yield (342
mg) after FC (AcOEt/pentane 2:1 to AcOEt): 1H NMR (CDCl3,
300 MHz) δ 1.94 (d, J ) 1.2 Hz, 3 H), 2.23 (dd, J ) 3.6 Hz,
14.6 Hz, 1 H), 2.42 (s, 3 H), 2.84 (dd, J ) 8.4 Hz, 14.6 Hz, 1
H), 3.97 (m, 2 H), 4.25 (dd, J ) 4.2 Hz, 5.7 Hz, 1 H), 6.26 (dd,
J ) 3.3 Hz, 8.4 Hz, 1 H), 7.82 (d, J ) 1.2 Hz, 1 H); 13C NMR
(DMSO-d6, 75.5 MHz) δ 12.4, 26.4, 44.0, 58.3, 83.2, 83.9, 86.0,
108.8, 136.7, 150.4, 163.8, 210.5; FAB-MS 285 (38, [M + 1]+).
Anal. Calcd for C12H16N2O6 (284.27): C 50.70, H 5.67, N 9.85,
O 33.77. Found C 50.41, H 5.83, N 9.90, O 33.45.
1-(3-C-(1,1-Dim eth ylpr opan oyl)-2-deoxy-â-D-th r eo-pen to-
fu r a n osyl)th ym in e (6b). The alkylation of 5a (1.00 g, 2.20
mmol) was performed using 6 equiv of a 1.5 M solution of
t-BuLi in pentane (13.20 mmol). The intermediate was hydro-
lyzed over 72 h with 1 N HCl, and ketone 6b was isolated in
56% yield (405 mg) after FC (AcOEt/pentane 2:1 to AcOEt).
1H NMR (DMSO-d6, 300 MHz) δ 1.20 (s, 9 H), 1.79 (d, J ) 1.2
Hz, 3 H), 2.22 (dd, J ) 4.1, 14.3 Hz, 1 H), 2.56 (dd, J ) 7.9,
14.3 Hz, 1 H), 3.64 (m, 2 H), 4.14 (dd, J ) 5.4, 4.9 Hz, 1 H),
4.98 (t, J ) 5.5 Hz, 1 H), 5.88 (s, 1 H), 6.00 (dd, J ) 4.0, 7.9
Hz, 1 H), 7.69 (d, J ) 1.2 Hz, 1 H), 11.32 (s, 1 H); 13C NMR
(CDCl3, 75.5 MHz) δ 12.5, 26.4, 45.2, 46.7, 60.8, 83.8, 84.7,
88.2, 110.8, 138.4, 150.5, 164.1, 216.4; FAB-MS 327 (46, [M
+ 1]+). Anal. Calcd for C15H22N2O6 (326.35): C 55.21, H 6.80,
N 8.58. Found C 55.28, H 6.68, N 8.48.
Con clu sion
We have described the synthesis of a new class of C-3′-
R- and â-branched nucleosides. These ketones undergo
Norrish type I photocleavage to give the desired C-3′
radical. This radical is easily reduced in the presence of
a hydrogen donor via a free radical process. The tert-butyl
ketones undergo the most efficient cleavage, delivering
the highest yield of reduction products. These nucleosides
shall be incorporated into oligonucleotides by means of
standard DNA synthesis techniques. The synthesis of
these modified nucleotides will facilitate the study of the
cleavage of DNA by C-3′ radicals. This work is currently
in progress.
Exp er im en ta l Section
Ma ter ia l a n d Meth od s. All quoted temperatures are
uncorrected. All reagents were commercially available and
were used without further purification. Fast atom bombard-
ment (FAB) mass spectra were obtained with m-nitrobenzyl
alcohol as matrix. Combustion analyses were performed by the
Mikroanalytisches Labor, University of Basel. Analytical
HPLC was performed on a Kontron instrument using a Merck
Lichrospher 100 column, RP 18 (5 mm), 250 mm × 4. The
solvents were purified and dried according to standard pro-
cedures. Anhydrous cerium chloride was prepared as described
by Imamoto et al.15: cerium chloride heptahydrate was pulver-
ized and heated to 100 °C for 4 h in vacuo with occasional
swirling. A stir bar was then placed in the flask, and the
temperature was raised to 140 °C. After 3 h at this temper-
ature, the solid was cooled to 0 °C and THF was added. The
suspension was then left to stir under argon at least overnight.
The reactions were carried out in carefully dried apparatus
and under an inert atmosphere.
Gen er a l P r oced u r e for t h e Syn t h esis of Tr im et h yl-
silyl-P r otected Cya n oh yd r in s 5a a n d 5b. After 18-crown-6
(10 mg, 0.03 mmol), KCN (10 mg, 0.20 mmol), and ketone 4
(4.50 g, 12.21 mmol) were coevaporated twice with CH2Cl2,
the mixture was dissolved in 100 mL of CH2Cl2. To the solution
was slowly added, over 10 min, TMSCN (3.05 mL, 24.4 mmol)
at room temperature. After 5 h of stirring, the reaction was
quenched by the addition of H2O (100 mL), and the mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined
organic phases were washed with brine and dried over MgSO4,
and the solvent was evaporated. Flash chromatography (AcOEt/
pentane, 1:3) gave 3.47 g (63%) of 5a and 5b as a mixture of
diastereoisomers (xylo:ribo 9:1).
1-(5-O-(ter t-Bu tyld im eth ylsilyl)-3-O-(tr im eth ylsilyl)-3-
C-cya n o-2-d eoxy-â-D-th r eo-p en tofu r a n osyl)th ym in e (5a ).
1H NMR (CDCl3, 300 MHz) δ 0.13 (s, 6 H), 0.28 (s, 9 H), 0.94
(s, 9 H), 1.92 (s, 3 H), 2.24 (dd, J ) 2.4 Hz, 14.9 Hz, 1 H), 2.95
(dd, J ) 7.8 Hz, 14.9 Hz, 1 H), 3.97 (m, 2 H), 4.08 (m, 1 H),
6.29 (dd, J ) 2.4 Hz, 7.2 Hz, 1 H), 7.31 (d, J ) 1.2 Hz, 1 H),
9.32 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ -5.2, 0.9, 12.6,
18.3, 25.8, 47.8, 59.2, 70.0, 83.8, 87.1, 110.5, 117.8, 135.3, 150.2,
163.7; FAB-MS 454 (18, [M + 1]+). Anal. Calcd for C20H35N3O5-
Si2 (453.69): C 52.95, H 7.78, N 9.26. Found C 52.88, H 7.57,
N 9.10.
1-(5-O-(ter t-Bu tyld im eth ylsilyl)-3-O-(tr im eth ylsilyl)-3-
C-cyan o-2-deoxy-â-D-er yth r o-pen tofu r an osyl)th ym in e (5b).
1H NMR (CDCl3, 300 MHz) δ 0.17 (s, 6 H), 0.31 (s, 9 H), 0.94
(s, 9 H), 1.94 (s, 3 H), 2.40 (dd, J ) 9 Hz, 12.8 Hz, 1 H), 2.67
(dd, J ) 4.8 Hz, 12.8 Hz, 1 H), 4.00 (ddd, J ) 2.4 Hz, 11.7 Hz,
19.2 Hz, 2 H), 4.15 (dd, J ) 2.4 Hz, 12.6 Hz, 1 H), 6.29 (dd, J
) 5.1 Hz, 9.0 Hz, 1 H), 7.52 (d, J ) 1.2 Hz, 1 H), 8.85 (s, 1 H);
13C NMR (CDCl3, 75.5 MHz) δ -5.6, 1.0, 12.5, 18.3, 25.7, 45.7,
62.7, 73.8, 84.1, 88.9, 111.2, 118.0, 134.9, 150.2, 163.8; FAB-
MS 454 (17, [M + 1]+). Anal. Calcd for C20H35N3O5Si2
(453.69): C 52.95, H 7.78, N 9.26. Found C 53.17, H 7.67, N
9.11.
1-(3-C-Be n zoyl-2-d e oxy-â-D -t h r eo-p e n t ofu r a n osyl)-
th ym in e (6c). The alkylation of 5a (700 mg, 1.54 mmol) was
performed using 3 equiv of a 2 M solution of PhLi in
cyclohexane/ether (7.95 mmol). The intermediate was hydro-
lyzed over 36 h with 1 N HCl, and ketone 6c was isolated in
61% yield (560 mg) after FC (AcOEt/pentane 2:1 to AcOEt):
1H NMR (CDCl3, 300 MHz) δ 1.81 (s, 3 H), 2.41 (dd, J ) 4.1
Hz, 14.3 Hz, 1 H), 2.88 (dd, J ) 8.4 Hz, 14.3 Hz, 1 H), 3.73 (m,
2 H), 4.33 (dd, J ) 4.2 Hz, 6.3 Hz, 1 H), 4.89 (t, J ) 5.7 Hz, 1
H), 6.14 (dd, J ) 3.9, 8.1 Hz, 1 H), 6.41 (s, 1 H), 7.56 (m, H),
7.84 (s, 1 H), 8.05 (m, H), 11.31 (s, 1 H); 13C NMR (DMSO-d6,
75.5 MHz) δ 12.5, 44.5, 59.7, 83.1, 84.0, 85.6, 109.1, 128.2,
129.8, 132.8, 135.3, 136.8, 150.6, 163.9, 200.8; FAB-MS 347
(8, [M + 1]+). Anal. Calcd for C17H18N2O6 (346.35): C 58.95,
H 5.24, N 8.09, O 27.72. Found C 58.73, H 5.43, N 7.88, O
27.73.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3′-C-Acyl-
5′-O-(4,4′-d im eth oxy-tr ityl)th ym id in es 3. To a solution of
6 in pyridine (40 mL/mmol) at 25 °C was added 4,4′-dimethox-
ytrityl chloride (3 equiv) and DMAP (0.025 equiv). After 15 h
of stirring, the reaction was complete. MeOH was added, and
the reaction mixture was left to stir for 30 min. The solvent
was removed and the residue was dissolved in CH2Cl2 and
washed with NaHCO3 and H2O. The organic phase was
collected and dried over MgSO4, and the solvent was removed.
FC gave 3 as pale yellow foams.
1-(5-O-(4,4′-Dim et h oxyt r it yl)-3-C-a cet yl-2-d eoxy-â-D-
th r eo-p en tofu r a n osyl)th ym in e (3a ). Compound 6a (178 mg,
0.56 mmol) was converted to 3a and after FC was isolated in
83% yield (272 mg): 1H NMR (CDCl3, 300 MHz) δ 1.84 (d, J
) 1.2 Hz, 3 H), 2.19 (dd, J ) 2.7 Hz, 14.7 Hz, 1 H), 2.31 (s, 3
H), 2.86 (dd, J ) 8.4 Hz, 14.7 Hz, 1 H), 3.48 (m, 2 H), 3.79 (s,
6 H), 4.28 (dd, J ) 4.8 Hz, 6.6 Hz, 1 H), 4.79 (s, 1 H), 6.26 (dd,
J ) 2.7 Hz, 8.4 Hz, 1 H), 6.84 (m, 4 H), 7.30 (m, 9 H), 7.59 (d,
J ) 1.2 Hz, 1 H), 9.38 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ
12.5, 25.6, 44.6, 55.2, 60.3, 83.8, 84.4, 84.7, 87.4, 110.5, 113.2,
127.0, 127.9, 127.9, 129.9, 135.2, 136.9, 144.0, 150.6, 158.6,
163.9, 208.4; FAB-MS 587 (2, [M + 1]+). Anal. Calcd for
Gen er a l P r oced u r e for th e Alk yla tion of Cya n oh yd r in
5a w ith Lith iu m Rea gen ts. After coevaporation twice with

Selective Generation of C-3′-Nucleoside Radicals
J . Org. Chem., Vol. 64, No. 5, 1999 1563
C33H34N2O8‚2H2O (622.64): C 63.60, H 6.15, N 4.49. Found C
63.20 H 6.15 N 4.31. HRMS calcd for C33H34N2O8 586.2315,
found 586.2315.
150.9, 159.1, 164.3; FAB-MS 689 (0.8, [M + 1]+). Anal. Calcd
for C38H48N2O8Si (688.90): C 66.25, H 7.02, N 4.07. Found C
66.28, H 7.18, N 4.23.
1-(5-O-(4,4′-Dim e t h oxyt r it yl)-3-C-(1,1-d im e t h ylp r o-
p a n oyl)-2-d eoxy-â-D-th r eo-p en tofu r a n osyl)th ym in e (3b).
Compound 6b (142 mg, 0.40 mmol) was converted to 3b and
after FC was isolated in 88% yield (221 mg): 1H NMR (CDCl3,
300 MHz) δ 1.15 (s, 9 H), 1.92 (d, J ) 1.1 Hz, 3 H), 2.37 (dd,
J ) 3.0 Hz, 14.3 Hz, 1 H), 2.69 (dd, J ) 8.5 Hz, 14.3 Hz, 1 H),
3.24 (dd, J ) 2.5 Hz, 11.3 Hz, 2 H), 3.80 (s, 6 H), 4.45 (m, 1
H), 6.26 (dd, J ) 2.9 Hz, 8.5 Hz, 1 H), 6.84 (m, 4 H), 7.24-
7.41 (m, 9 H), 8.02 (d, J ) 1.1 Hz, 1 H), 9.31 (s, 1 H); 13C NMR
(CDCl3, 75.5 MHz) δ 12.6, 26.3, 45.0, 47.6, 51.8, 55.1, 55.2,
61.6, 83.8, 84.4, 87.6, 110.7, 113.0, 113.1, 113.4, 113.4, 126.6,
127.2, 127.7, 127.7, 128.1, 128.2, 129.1, 129.8, 130.0, 134.4,
134.8, 137.1, 150.5, 158.7, 158.8, 163.9, 215.8; FAB-MS 629
(1, [M + 1]+). HRMS calcd for C36H40N2O8 628.2786, found
628.2786.
1-(5-O-(4,4′-Dim et h oxyt r it yl)-3-O-(t r iet h ylsilyl)-3-C-
for m yl-2-d eoxy-â-D-er yth r o-p en tofu r a n osyl)th ym in e (11).
To a mixture of 10 (200 mg, 0.30 mmol), NMO (520 mg, 0.45
mmol), and 4 Å molecular sieve powder (150 mg) in CH2Cl2 (4
mL) was added TPAP (0.02 mmol, 7.0 mg). After 1 h of stirring,
the reaction mixture was placed directly on a column of silica
gel and eluted with 0.5 L of AcOEt/pentane 2:1 followed by
pure AcOEt. Compound 11 was isolated in 98% yield (196 mg)
as a colorless foam: 1H NMR (CDCl3, 300 MHz) δ 0.58 (q, 6
H), 0.90 (t, 9 H), 1.79 (s, 3 H), 2.33 (dd, J ) 6.9 Hz, 13.9 Hz,
1 H), 2.60 (dd, J ) 6.9 Hz, 13.8 Hz, 1 H), 3.27 (dd, J ) 2.4 Hz,
11.1 Hz, 1 H), 3.49 (dd, J ) 4.5 Hz, 10.9 Hz, 1 H), 3.79 (s, 6
H), 4.03 (m, 1 H), 6.38 (t, J ) 6.9 Hz, 1 H), 6.83 (m, 4 H), 7.31
(m, 9 H), 7.60 (d, J ) 1.2 Hz, 1 H), 9.47 (s, 1 H); 13C NMR
(CDCl3, 75.5 MHz) δ 6.1, 6.5, 6.6, 12.3, 14.1, 21.0, 40.3, 55.1,
59.7, 60.3, 83.0, 84.9., 87.3, 111.1, 113.0, 113.1, 126.9, 127.8,
127.9, 129.9, 135.0, 13.1, 135.6, 144.0, 150.5, 18.6, 163.8, 199.3;
FAB-MS 687 (1, [M + 1]+). Anal. Calcd for C38H46N2O8Si‚
0.5H2O (695.89): C 65.52, H 6.81, N 4.02. Found C 65.65, H
6.96, N 3.88.
1-(5-O-(4,4′-Dim et h oxyt r it yl)-3-O-(t r iet h ylsilyl)-3-C-
(1-h yd r oxyet h yl)-2-d eoxy-â-D-er yth r o-p en t ofu r a n osyl)-
th ym in e (12a ). To a suspension of dry CeCl3 (8.6 mL, 2.60
mmol) and aldehyde 11 (180 mg, 0.26 mmol) in THF at -10
°C was slowly added a 3 M solution of MeMgBr (0.86 mL, 2.6
mmol) in diethyl ether. The reaction stirred at this tempera-
ture for 3 h, after which it was quenched by the addition of
aqueous NH4Cl and allowed to warm to room temperature.
The product was then extracted with CH2Cl2 (3 × 25 mL), the
organic layer was dried over MgSO4, and the solvent was
removed. The mixture of diastereoisomers, which were neither
separated nor further characterized, were used in the next step
without further purification.
1-(5-O-(4,4′-Dim eth oxytr ityl)-3-O-(tr ieth ylsilyl)-3-C-(1-
h yd r oxy-2,2-d im eth ylp r op yl)-2-d eoxy-â-D-er yth r o-p en to-
fu r a n osyl)th ym in e (12b). To a suspension of dry CeCl3 (13.3
mL, 3.92 mmol) in THF at -78 °C was slowly added a 1.6 M
solution of t-butyllithium (2.45 mL, 3.92 mmol) in pentane.
This was allowed to stir for 1.5 h before a solution of 11 (190
mg, 0.28 mmol) in THF (5 mL) was added dropwise at the
same temperature. The reaction stirred at this temperature
for 3 h, after which it was quenched by the addition of aqueous
NH4Cl. The product was then extracted with CH2Cl2 (12 × 25
mL), the organic layer was dried over MgSO4, and the solvent
was removed. As a result, 197 mg (93%) of 12b was isolated
as a single diastereoisomer, which was used in the next step
without further purification: 1H NMR (CDCl3, 300 MHz) δ 0.63
(m, 6 H), 0.88 (t, 9 H), 0.90 (s, 9 H), 1.92 (s, 3 H), 2.22 (dd, J
) 7.2, 14.3, 1 H), 2.88 (dd, J ) 2.7, 14.3, 1 H), 3.15 (d, J ) 5.1,
1 H), 3.26 (dd, J ) 2.7, 10.5, 1 H), 3.47 (d, J ) 5.1, 1 H), 3.71
(dd, J ) 5.1, 10.7, 1 H), 3.80 (s, 6 H), 3.95 (dd, J ) 2.7, 4.8, 1
H), 6.33 (t, J ) 7.2, 1 H), 6.85 (m, 4 H), 7.35 (m, 9 H), 7.84 (s,
1 H), 7.95 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 6.4, 6.9,
12.6, 28.2, 36.1, 40.9, 55.2, 60.3, 78.0, 82.5, 85.4, 87.3, 87.9,
111.1, 113.4, 127.1, 127.9, 128.1, 129.9, 134.8, 135.0, 136.7,
143.8, 150.6, 158.7, 163.9; FAB-MS 745 (0.4, [M + 1]+).
1-(5-O-(4,4′-Dim et h oxyt r it yl)-3-O-(t r iet h ylsilyl)-3-C-
(1-h yd r oxy-1-p h en ylm eth yl)-2-d eoxy-â-D-er yth r o-p en to-
fu r a n osyl)th ym in e (12c). To a suspension of dry CeCl3 (8.6
mL, 2.6 mmol) and aldehyde 11 (180 mg, 0.26 mmol) in THF
at -10 °C was slowly added a 1 M solution of PhMgBr (0.86
mL, 2.6 mmol) in THF. The reaction mixture stirred at this
temperature for 3 h, after which it was quenched by the
addition of aqueous NH4Cl. The product was then extracted
with CH2Cl2, the organic layer was dried over MgSO4, and the
solvent was removed. As a result, 62 mg (31%) of 12c was
isolated as a mixture of diastereoisomers, which were neither
separated nor further characterized and were used in the next
step without further purification.
1-(5-O-(4,4′-Dim eth oxytr ityl)-3-C-(ben zoyl-2-d eoxy-â-D-
th r eo-p en tofu r a n osyl)th ym in e (3c). Compound 6c (106 mg,
0.28 mmol) was converted to 3c (for 3c and 2c, no accurate
combustion analysis or HRMS could be obtained) and after
FC was isolated in 81% yield (148 mg): IR (KBr) 3386, 3058,
2932, 1686, 1607, 1578, 1560, 1542, 1509, 1466, 1448, 1375,
1251, 1177, 1153, 1074, 1033. 1H NMR (CDCl3, 300 MHz) δ
1.90 (d, J ) 1.2 Hz, 3 H), 2.46 (dd, J ) 3.3 Hz, 14.9 Hz, 1 H),
3.03 (dd, J ) 8.7 Hz, 15.2 Hz, 1 H), 3.66 (m, 2 H), 3.72 (s, 6
H), 4.72 (dd, J ) 4.2 Hz, 5.4 Hz, 1 H), 5.05 (s, 1 H), 6.40 (dd,
J ) 3.0 Hz, 8.4 Hz, 1 H), 6.75 (m, 4 H), 7.22 (m, 10 H), 7.46
(m, 2 H), 7.60 (m, 1 H), 7.82 (d, J ) 1.2 Hz, 1 H), 8.02 (m, 2
H), 8.62 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 12.6, 46.4,
55.2, 61.4, 83.4, 83.9, 85.0, 87.6, 111.0, 113.3, 127.1, 127.8,
128.0, 128.4, 129.8, 130.1, 133.4, 134.2, 134.8, 134.9, 143.9,
136.7, 150.5, 158.7, 163.7, 199.3. FAB-MS: 649 (1, [M + 1]+).
1-(5-O-(4,4′-Dim eth oxytr ityl)-3-O-(tr ieth ylsilyl)-3-C-(tr i-
eth ylsilyl-oxym eth yl)-2-d eoxy-â-D-er yth r o-p en tofu r a n o-
syl)th ym in e (9). A solution of diol 810c (945 mg, 1.64 mmol)
and imidazole (535 mg, 7.78 mmol) in DMF (8 mL) was stirred
at 25 °C for 5 min, after which TESCl (0.66 mL, 3.94 mmol)
was added. After 24 h of stirring, the mixture was poured onto
saturated NaHCO3, extracted with CH2Cl2 (3 × 100 mL), and
dried (MgSO4), and the solvent was evaporated. After FC
(AcOEt/pentane 1:2), 9 was isolated as a colorless foam in 72%
yield (946 mg): IR (KBr) 3412, 3186, 3058, 2955, 2911, 2875,
2836, 1698, 1608, 1582, 1509, 1464, 1414, 1375, 1252, 1209,
1176, 1150, 1112, 1034; 1H NMR (CDCl3, 300 MHz) δ 0.49 (q,
6 H), 0.61 (t, 6 H), 0.90 (m, 18 H), 1.44 (d, J ) 1.2 Hz, 1 H),
2.08 (dd, J ) 8.7 Hz, 12.9 Hz, 1 H), 2.41 (dd, J ) 5.7 Hz, 12.9
Hz, 1 H), 3.17 (dd, J ) 4.5 Hz, 10.8 Hz, 1 H), 3.41 (d, J ) 10.2
Hz, 1 H), 3.53 (dd, J ) 3.6 Hz, 10.8 Hz, 1 H), 3.60 (d, J ) 10.2
Hz, 1 H), 3.80 (s, 6 H), 4.10 (m, 1 H), 6.36 (dd, J ) 5.7 Hz, 8.7
Hz, 1 H), 6.83 (m, 4 H), 7.34 (m, 9 H), 7.67 (d, J ) 1.2 Hz, 1
H), 7.90 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 4.1, 6.3, 6.8,
7.0, 11.7, 42.8, 55.2, 62.3, 65.6, 77.2, 83.7, 84.2, 87.0, 87.7,
110.8, 113.2, 113.2, 127.1, 127.9, 128.3, 130.2, 135.3, 135.4,
144.1, 135.9, 150.0, 158.7, 163.4; FAB-MS 804 (0.5, [M + 1]+).
Anal. Calcd for C44H62N2O8Si2 (803.15): C 65.80, H 7.78, N
3.49. Found C 65.87, H 7.77, N 3.39. HRMS calcd for
C
44H62O8N2Si2 802.4045, found 802.4042.
1-(5-O-(4,4′-Dim et h oxyt r it yl)-3-O-(t r iet h ylsilyl)-3-C-
(h yd r oxym et h yl)-2-d eoxy-â-D-er yth r o-p en t ofu r a n osyl)-
th ym in e (10). A solution of 9 (150 mg, 0.19 mmol) in THF (4
mL) and pyridine (0.2 mL) was cooled to 0 °C and HF-pyridine
(0.3 mL, 0.95 mmol) was added dropwise. After 7 h of stirring,
the reaction mixture was placed directly on a column of silica
gel and eluted with AcOEt/pentane 2:1 to AcOEt. Alcohol 10
was isolated in 77% yield (98 mg) as a colorless foam: 1H NMR
(CDCl3, 300 MHz) δ 0.60 (q, 6 H), 0.93 (t, 9 H), 1.60 (s, 3 H),
2.18 (dd, J ) 8.6 Hz, 13.4 Hz, 1 H), 2.36 (dd, J ) 6.0 Hz, 13.4
Hz, 1 H), 3.25 (dd, J ) 2.6 Hz, 10.8 Hz, 1 H), 3.54 (m, 2 H),
3.79 (s, 6 H), 4.07 (dd, J ) 2.5 Hz, 4.7 Hz, 1 H), 6.40 (dd, J )
6.0 Hz, 8.5 Hz, 1 H), 6.85 (m, 4 H), 7.33 (m, 9 H), 7.70 (s, 1 H),
8.62 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 6.6, 7.2, 12.3, 42.5,
55.5, 62.0, 65.9, 83.6, 83,7, 86.8, 87.9, 111.4, 113.6, 124.0, 127.5,
128.3, 128.4, 130.3, 134.9, 135.3, 136.2, 144.0, 149.8, 136.4,
Gen er a l P r oced u r e for th e Syn th esis of Keton es 13.
To a solution of the alcohol in CH2Cl2 and pyridine at room
temperature was added the Dess-Martin reagent in one

1564 J . Org. Chem., Vol. 64, No. 5, 1999
Ko¨rner et al.
portion. After 2 h of stirring, the reaction was quenched by
the addition of a solution of Na2S2O3. The mixture was diluted
with ether and washed with NaHCO3. The organic layer was
collected and dried over MgSO4, and the solvent was removed.
The residue was then chromatographed on silica gel with
AcOEt:pentane 1:2 as eluent.
5′-O-(4,4′-Dim eth oxytr ityl)-3′-C-(a cetyl)th ym id in e (2a ).
Compound 13a (15.9 mg, 0.02 mmol) was converted to 11.1
mg (95%) of 2a : 1H NMR (CDCl3, 300 MHz) δ 1.69 (s, 3 H),
2.12 (s, 3 H), 2.36 (dd, J ) 6.0 Hz, 13.8 Hz, 1 H), 2.53 (dd, J
) 8.4 Hz, 13.8 Hz, 1 H), 3.29 (dd, J ) 6.6 Hz, 10.7 Hz, 1 H),
3.38 (dd, J ) 4.4 Hz, 10.7 Hz, 1 H), 3.80 (s, 6 H), 4.06 (dd, J
) 4.5 Hz, 6.7 Hz, 1 H), 6.37 (dd, J ) 6.3 Hz, 8.4 Hz, 1 H), 6.84
(m, 4 H), 7.30 (m, 9 H), 7.52 (d, J ) 0.9 Hz, 1 H); 13C NMR
(CDCl3, 75.5 MHz) δ 12.2, 15.3, 26.8, 42.7, 55.2, 61.9, 65.8,
83.6, 85.4, 86.4, 87.6, 111.5, 113.3, 127.2, 127.9, 128.0, 128.1,
129.9, 130.0, 130.1, 134.9, 135.6, 143.8, 150.1, 158.8, 163.2,
208.2; HRMS calcd for C33H34N2O8 586.2135, found 586.2135.
5′-O-(4,4′-Dim e t h oxyt r it yl)-3′-O-(t r ie t h ylsilyl)-3′-C-
(a cetyl)th ym id in e (13a ). Alcohol 12a was converted to 13a
and isolated as an off-white foam in 15% yield (25 mg): 1H
NMR (CDCl3, 300 MHz) δ 0.66 (q, 6 H), 0.95 (t, 9 H), 1.67 (s,
3 H), 1.96 (s, 3 H), 2.37 (dd, J ) 6.6 Hz, 14.1 Hz, 1 H), 2.68
(dd, J ) 7.8 Hz, 14.1 Hz, 1 H), 3.22 (dd, J ) 4.2 Hz, 10.8 Hz,
1 H), 3.34 (dd, J ) 4.2 Hz, 10.7 Hz, 1 H), 3.79 (s, 6 H), 4.05
(m, 1 H), 6.38 (m, 1 H), 6.80 (m, 4 H), 7.10 (m, 9 H), 7.72 (s, 1
H), 8.21 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 6.2, 6.9, 12.1,
26.7, 42.1, 55.2, 61.4, 82.9, 87.2, 87.5, 111.0, 113.1, 127.1, 127.9,
128.3, 130.1, 130.2, 135.1, 135.1, 136.3, 143.8, 150.4, 158.7,
163.4, 163.4, 208.9. Anal. Calcd for C39H48N2O8Si (700.91): C
66.83, H 6.09, N 4.00. Found C 66.68, H 7.17, N 3.75.
5′-O-(4,4′-Dim eth oxytr ityl)-3′-O-(tr ieth ylsilyl)-3′-C-(1,1-
d im eth ylp r op a n oyl)th ym id in e (13b). Alcohol 12b was
converted to 13b and isolated as an off-white foam in 94% yield
(20 mg): 1H NMR (CDCl3, 300 MHz) δ 0.77 (q, 6 H), 0.96 (s,
9H), 0.98 (t, 9 H), 1.77 (s, 3 H), 2.47 (d, J ) 7.5 Hz, 2 H), 2.93
(dd, J ) 1.5 Hz, 10.5 Hz, 1 H), 3.16 (dd, J ) 7.5 Hz, 10.5 Hz,
1 H), 4.22 (dd, J ) 1.5 Hz, 7.2 Hz, 1 H), 6.44 (m, 1 H), 6.81 (m,
4 H), 7.29 (m, 9 H), 7.76 (s, 1 H), 8.79 (s, 1 H); 13C NMR (CDCl3,
75.5 MHz) δ 6.2, 6.8, 12.2, 27.0, 28.9, 45.0, 55.0, 63.9, 82.9,
88.8, 89.8, 111.9, 113.2, 127.1, 127.9, 128.3, 130.1, 135.1, 135.2,
136.3, 144.1, 150.2, 158.4, 164.0, 216.0. Anal. Calcd for
5′-O-(4,4′-Dim eth oxytr ityl)-3′-C-(2,2-dim eth ylpr opan oyl)-
th ym id in e 2b. Compound 13b (20 mg, 0.03 mmol) was
converted to 16 mg (84%) 2b: 1H NMR (CDCl3, 300 MHz) δ
1.01 (s, 9 H), 2.17, (s, 3 H), 2.33 (dd, J ) 5.0 Hz, 13.5 Hz, 1 H),
2.74 (dd, J ) 9.9 Hz, 13.5 Hz, 1 H), 3.07 (dd, J ) 5.2 Hz, 10.8
Hz, 1 H), 3.19 (dd, J ) 3.3 Hz, 10.8 Hz, 1 H), 3.78 (s, 6 H),
4.25 (m, 1 H), 6.50 (dd, 5.2 Hz, 9.5 Hz, 1 H), 6.82 (m, 4 H),
7.32 (m, 9 H), 7.63 (s, 1 H), 8.01 (s, 1 H); 13C NMR (CDCl3,
75.5 MHz) d 11.8, 26.9, 44.5, 55.3, 76.6, 76.8, 87.2, 87.4, 88.4,
111.1, 113.2, 127.2, 127.9, 128.6, 130.4, 135.9, 150.6, 158.8,
202.6; HRMS calcd for C36H40O8N2 628.2786, found 628.2786.
5′-O-(4,4′-Dim eth oxytr ityl)-3′-C-(ben zoyl)th ym id in e 2c.
Compound 13c (55 mg, 0.07 mmol) was converted to 25 mg
(54%) of 2c: 1H NMR (CDCl3, 300 MHz) δ 1.20 (s, 3 H), 2.43
(dd, J ) 4.8 Hz, 13.7 Hz, 1 H), 2.63 (m, 1 H), 3.12 (m, 1 H),
3.49 (dd, J ) 2.8 Hz, 7.1 Hz, 1 H), 3.75 (s, 6 H), 4.50 (m, 1 H),
6.63 (dd, J ) 5.1 Hz, 9.9 Hz, 1 H), 6.68 (m, 4 H), 7.05 (m, 4 H),
7.15 (m, 4 H), 7.28 (m, 3 H), 7.46 (m, 1 H), 7.71 (s, 1 H), 7.85
(m, 2 H), 8.68 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 11.3,
42.9, 55.2, 62.1, 83.2, 86.7, 87.2, 87.6, 111.9, 113.0, 127.2, 127.8,
128.3, 128.5, 130.2, 130.3, 130.4, 133.0, 134.2, 134.4, 134.6,
136.1, 143.5, 150.7, 158.6, 158.7, 163.6, 195.9.
C
42H54N2O8Si‚H2O (760.99): C 66.21, H 7.42, N 3.68. Found
C 65.81, H 7.73, N 3.92.
5′-O-(4,4′-Dim e t h oxyt r it yl)-3′-O-(Tr ie t h ylsilyl)-3′-C-
(ben zoyl)th ym id in e (13c). Alcohol 12c (62.2 mg, 0.08 mmol)
was converted to 13c and isolated as an off-white foam in 35%
yield (60 mg): 1H NMR (CDCl3, 300 MHz) δ 0.51 (tq, 6 H),
0.84 (t, 9 H), 1.19 (s, 3 H), 2.47 (dd, J ) 4.8 Hz, 13.8 Hz, 1 H),
3.07 (dd, J ) 2.4 Hz, 11.0 Hz, 1 H), 3.18 (dd, J ) 10.2 Hz, 13.8
Hz, 1 H), 3.45 (dd, J ) 3.0 Hz, 11.0 Hz, 1 H), 3.75 (s, 6 H),
4.55 (m, 1 H), 6.59 (dd, J ) 4.8 Hz, 10.4 Hz, 1 H), 6.68 (m, 4
H), 7.06 (m, 4 H), 7.32 (m, 8 H), 7.76 (d, J ) 0.9 Hz), 7.80 (m,
2 H), 8.37 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ 6.0, 6.8,
11.2, 42.1, 55.2, 62.1, 83.3, 87.5, 89.1, 89.3, 111.5, 112.9, 113.0,
127.2, 127.8, 128.2, 128.5, 130.3, 130.5, 133.1, 133.8, 134.3,
134.6, 136.1, 143.5, 150.4, 158.6, 163.6, 195.3; HRMS calcd
for C44H50N2O8Si 762.3334, found 762.3334.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3′-C-Acyl-
5′-O-(4,4′-d im eth oxytr ityl)th ym id in es 2. To a solution of
the protected alcohol in THF at O °C was added dropwise
TBAF (1.5 equiv). The solution was then allowed to warm to
room temperature and was stirred at this temperature for 15
min. The reaction mixture was placed directly on a column of
silica gel and was chromatographed with 2:1 AcOEt:Pentane
to AcOEt as eluent.
Gen er a l P h otolysis Con d ititon s. Photolyses were carried
out in quartz glass cells (1 cm path length) in 2 mL of
acetonitrile in the presence of 3 equiv of nBu3SnH. A 500 W
Hg high-pressure lamp with a 320 nm cut-off filter was
employed. The cells were maintained at 20 °C. After photolysis,
the solutions were analyzed, and the yields were determined
by reverse-phase HPLC. Products were identified by compari-
son with authentic samples.
Ack n ow led gm en t. This work was supported by the
Swiss National Science Foundation.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 2c and 3c. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O982022Y