Diastereofacial Selective Addition of Ethynylcerium Reagent and Barton-McCombie Reaction as the Key Steps for the Synthesis of C-3′-Ethynylribonucleosides and of C-3′-Ethynyl-2′-deoxyribonucleosides

Article abstract of DOI:10.1021/jo9704568

We describe the preparation of 3′-alkynyluridine 4a and -adenosine 4b and of 3′-alkynyl-2′-deoxyuridine 16a and -adenosine 16b starting from the corresponding nucleosides. The desired stereochemistry of the C-3′ tertiary alcohol was obtained by reaction of an ethynylcerium-lithium reagent on a 3′-ketonucleoside with the hydroxyl group at C-5′ unprotected. The 2′-deoxygenation was performed by a Barton-McCombie reaction under appropriate conditions where the addition of tin hydride to the triple bond was suppressed. Evaluation of the anti-HIV activity of the C-3′ modified nucleosides is reported.

Full text of DOI:10.1021/jo9704568

J . Org. Chem. 1997, 62, 8309-8314
8309
Dia ster eofa cia l Selective Ad d ition of Eth yn ylcer iu m Rea gen t a n d
Ba r ton -McCom bie Rea ction a s th e Key Step s for th e Syn th esis of
C-3′-Eth yn ylr ibon u cleosid es a n d of
C-3′-Eth yn yl-2′-d eoxyr ibon u cleosid es†
Pierre M. J . J ung, Alain Burger,* and J ean-Franc¸ois Biellmann*
Laboratoire de Chimie Organique Biologique URA 31 du CNRS, Faculte´ de Chimie, Universite´ Louis
Pasteur, 1 rue Blaise Pascal, 67008 Strasbourg Cedex, France
Received March 12, 1997X
We describe the preparation of 3′-alkynyluridine 4a and -adenosine 4b and of 3′-alkynyl-2′-
deoxyuridine 16a and -adenosine 16b starting from the corresponding nucleosides. The desired
stereochemistry of the C-3′ tertiary alcohol was obtained by reaction of an ethynylcerium-lithium
reagent on a 3′-ketonucleoside with the hydroxyl group at C-5′ unprotected. The 2′-deoxygenation
was performed by a Barton-McCombie reaction under appropriate conditions where the addition
of tin hydride to the triple bond was suppressed. Evaluation of the anti-HIV activity of the C-3′
modified nucleosides is reported.
AIDS has stimulated the chemist’s interest on the
synthesis of nucleosides and analogues designed as
antiretroviral drugs.1 Numerous modified nucleosides
and 2′-deoxynucleosides show marked activities as an-
tiviral agents. For example, C-3′-methylribonucleosides
and C-3′-methyl-2′-deoxyribonucleosides have shown bio-
logical activities on RNA and DNA polymerases.2 The
substitution of the hydrogen atom in the C-3′ position
with preservation of the natural stereochemistry of the
hydroxyl is an attractive target, since these compounds
could interfere with the biosynthesis of nucleic acids. On
one hand, C-3′-branched deoxynucleotides could act as
slow substrates or inhibitors of HIV reverse transcriptase
during viral DNA chain elongation. On the other hand,
the single strand of viral DNA, where C-3′-branched
deoxynucleosides have been incorporated, could show
anomalous properties.3
prior to the base. Starting from D-glucose, control of
stereochemistry at C-1′ and at C-3′ proved to be easy.4
However, this approach suffered some disadvantages as
the preparation was multistep and the overall yield was
modest. The synthetic route from 2-deoxy-D-ribose suf-
fered from the lack of stereochemical control at the C-3′
and C-1′ positions.3e In the second approach, the C-
nucleophile is added to the corresponding 3′-ketonucleo-
side or 3′-keto-2′-deoxynucleoside. However, previous
studies showed a preferential nucleophilic attack from
the R face giving the tertiary alcohol as the major or as
the sole product with the configuration opposite of the 3′
hydroxyl group of the natural nucleoside.5 Third, taking
advantage of the preference for R attack, one may
introduce the hydroxyl group last as realized by J ør-
gensen et al.6 The 3′-keto-2′-deoxynucleoside was con-
verted into a C-3′-methylidene derivative. Dihydroxyla-
tion of the double bond occurred from the R face and
furnished stereospecifically the desired C-3′-branched-
2′-deoxynucleoside.
The preparation of C-3′-branched nucleosides could be
envisaged essentially in three different approaches.
First, the C-3′ substituent is introduced on the sugar
Initially, we envisioned the use of 2′-deoxynucleosides
as starting materials. The problems associated with this
synthetic route are 2-fold:5 the instability of intermediate
ketone and the stereoselectivity of nucleophilic addition.
The low basicity of the Yamamoto’s reagent7,8 and the
reversal of the stereoselectivity of nucleophilic addition
in its presence should circumvent these problems. How-
ever, with this reagent the desired compound was never
* To whom correspondence should be addressed. Tel: 03-88-41-68-
21. Fax: 03-88-41-15-24. E-mail: aburger@chimie.u-strasbg.fr, jfb@
chimie.u-strasbg.fr.
† Taken from the “These de Doctorat de L’U.L.P.” of P. M. J . J ung,
Strasbourg, France, Dec 1995.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) For reviews, see for instance: (a) Pe´rigaud C.; Gosselin G.;
Imbach J .-L. Nucleosides Nucleotides 1992, 11, 903-945. (b) Herdewijn
P.; Balzarini J .; De Clercq E. In Advances in Antiviral Drug Design;
De Clercq E., Ed. J AI Press, Inc.: Greenwich, 1993; Vol. 1, pp 233-
309.
(2) See, for example: (a) Walton, E.; J enkins, S. R.; Nutt, R. F.;
Zimmerman, M.; Holly, F. W. J . Am. Chem. Soc. 1966, 88, 4524-4525.
(b) Walton, E.; J enkins, S. R.; Nutt, R. F.; Holly, F. W. J . Med. Chem.
1969, 12, 306-309. (c) Mikhailov, S., N. Nucleosides Nucleotides 1988,
7, 679-682. (d) Mikhailov, S. N.; Padyukova, N. S.; Lysov, Y. P.;
Savochkina, L. P. Nucleosides Nucleotides 1991, 10, 339-343. (e)
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) (a) Mikhailov, S. N.; Fomitcheva, M. V. Bioorg. Khim. (Moscow)
1990, 16, 692-700. (b) Beigelman, L. N.; Gurskaya, G. V.; Tsapkina,
E. N.; Mikhailov, S. N. Carbohydr. Res. 1988, 181, 77-88. (c)
Rosenthal, A.; Mikhailov, S. N. Carbohydr. Res. 1980, 79, 235-242.
(d) Fedorov, I. I.; Beztchinsky, Y. E.; Novicov N. A.; Kazmina, E. M.;
Rosenberg, S. G.; Mikhailov, S. N. Bioorg. Khim. (Moscow) 1990, 16,
997-999.
(5) (a) Weeb, T. R. Tetrahedron Lett. 1988, 29, 3769-3772 (b)
Bender, S. L.; Moffett, K. K. J . Org. Chem. 1992, 57, 1646-1647 (c)
Koole, L. H., Buck, H. M.; Vial, J .-M.; Chattopadhyaya, J . Acta Chem.
Scand., 1989, 43, 665-669. (d) Hayakawa, H.. Tanaka, H.; Itoh, N.;
Nakajima, M.; Miyasaka, T.; Yamaguchi, K.; Iitaka, Y. Chem. Pharm.
Bull. 1987, 35, 2605-2608. (e) Huss, S.; De las Heras, F. G.; Camarasa,
M. J . Tetrahedron 1991, 47, 1727-1736.
(3) The deletion of the 3′-hydroxyl group is not a sine qua non
condition for anti-HIV activity. Nucleoside triphosphates with
a
remaining 3′-hydroxyl group but where the hydrogen at C-4′ has been
replaced by an azido or an acylated group have been prepared and
their action on HIV-1 RT has been studied; see: (a) Maag, H.;
Rydzewski, R. M.; McRoberts, M. J .; Crawford-Ruth, D.; Verheyden,
J . P. H.; Prisbe, E. J . J . Med. Chem. 1992, 35, 1440-1451. (b) Chen,
M. S.; Suttmann, R. T.; Papp, E.; Cannon, P. D.; McRoberts, M. J .;
Bach, C.; Copeland, W. C.; Wang, T. S.-F. Biochemistry, 1993, 32,
6002-6010. (c) Marx, A.; MacWilliams, M. P.; Bickle, T. A.; Schwitter,
U.; Giese, B. J . Am. Chem. Soc. 1997, 119, 1131-1132.
(6) J ørgensen, P. N.; Stein, P. C.; Wengel, J . J . Am. Chem. Soc. 1994,
116, 2231-2232.
(7) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto,
H. J . Am. Chem. Soc. 1988, 110, 3588-3597.
(8) Power, M. B.; Bott, S. G.; Atwood, J . L., Barron, A. R. J . Am.
Chem. Soc. 1990, 112, 3446-3450.
S0022-3263(97)00456-8 CCC: $14.00 © 1997 American Chemical Society

8310 J . Org. Chem., Vol. 62, No. 24, 1997
J ung et al.
obtained. Only the R,â-unsaturated ketone resulting
from the elimination of the base was observed. As an
alternative, we decided to use the less sensitive 3′-
ketonucleosides as starting material.
acetylide and cerium chloride on a â-hydroxy ketone has
been described by Shibasaki et al.19 in preparation of
phorbol derivates. The reason for stereochemical control
was explained by chelation effects.19 The cerium reagent
R2CeCl reacted first with the hydroxyl group and then
delivered the nucleophile syn to the alkoxy group. Since
we tried a 2/1 ratio of lithium acetylide and cerium
chloride and obtained poorer stereoselectivity than with
a 1/1 ratio, the mechanism proposed by Shibasaki where
a 2/1 ratio was best has been ruled out. However, a 6-fold
excess of reagents was used under our experimental
conditions. Therefore, the preparation of the cerium
reagent does not exclude that a dialkynylcerium species
formed in situ, especially when, as observed by Denmark
et al.,18 cerium salts remained in the precipitate resulting
in its preparation. Therefore, the formulas RCeCl2 and
R2CeCl according to the reagent ratio do not describe
satisfactorily the structure of the reagents.
The ribofuranosyl derivatives 3a and 3b were isolated
in 78 and 72% yields from 1a and 1b, respectively. The
relative configuration of product 3a was determined by
X-ray crystallographic analysis.20 The ribo configuration
of product 3b was established by chemical modification,
NMR experiments,9 and comparison with the ribo deriva-
tive 3a . It confirmed earlier assignments based on NMR
experiments of the xylo and ribo vinyl derivatives.9 The
xylo compounds 5a and 5b have been prepared by
addition of the vinyl Grignard reagent on a appropriate
3′-keto nucleoside. The ribo compounds 6a and 6b have
been obtained after semihydrogenation of the corre-
sponding propargylic alcohol.
In a preliminary publication,9 we have described the
highly stereoselective addition of an alkynylcerium re-
agent to 3′-ketonucleosides, affording the C-3′-alkynyl-
nucleosides with the required stereochemistry. There-
fore, the key advantage of our approach is that the
addition directly affords C-3′-ethynylated nucleosides in
which the 3′-hydroxyl group remains in the natural
configuration. Other organocerium reagents, for ex-
ample, the methyl and vinylcerium reagents, were also
tested on 3′-ketonucleosides, but the stereoselectivity and
the yields were low.10 Since our first publication,9
a
different route to C-3′-ethynyl nucleosides11 and a general
method for the preparation of 1,3-diols by addition of
cerium reagents to sensitive â-hydroxy ketones have been
described.12 Here we present details of the preparation
of C-3′-alkynylnucleosides and their transformation into
the corresponding 2′-deoxyderivatives by Barton-Mc-
Combie reaction.13
The synthesis of C-3′-alkynyluridine 4a and -adenosine
4b started with 2′,5′-bis-O-TBDMS-3′-ketonucleosides 1a
and 1b prepared as reported in the literature.14 Selective
monodeprotection at O-5′ of the disilyl ethers 1a and 1b
was done with trifluoroacetic acid-water (9:1) at 0 °C,
as described for the preparation of ketone 2b.15
The organolithium reagent was prepared by the reac-
tion of 1 equiv of BuLi with (trimethylsilyl)acetylene in
THF at low temperature. The ethynylcerium-lithium
was prepared as described by Imamoto16 by mixing the
lithium acetylide with “dry cerium trichloride”.17 The
effect of the reagent ratio (lithium acetylide/cerium
chloride ) 1/1, 2/1, and 3/1)18 on the yield and the
selectivity of the organocerium addition to hydroxy
ketone 2a and 2b was investigated. The best results in
respect of yield and diastereoselectivity were obtained
with a 1/1 mixture of lithium acetylide and cerium
chloride.9,18 The addition with a 6-fold excess5b of ethy-
nylcerium-lithium reagent to ketones 2a and 2b was
highly stereoselective, and only a trace amount of the
other diastereomer was detected by TLC. A similar
control of addition of alkynylcerium-lithium reagent
prepared with a large excess of a 2/1 mixture of lithium
From the crystallographic structure of product 3a , the
following observations could be made. The pyrimidine
ring was in an anti conformation (-ac) around the
glycosidic bond. The O5′ was in a gauche+ orientation
(+sc). The C-3′-ethynyl uridine 3a showed a south
conformation21 (P ) 169°). The furanose ring was in a
C2′ endo conformation, resulting in the pseudoequatorial
orientation of the alkynyl substituent and the pyrimidine
base. In this case, the conformation in the crystal
corresponded to predominant conformation in solution as
observed by NMR. The large coupling constant J 1′2′ of
C-3′ methyl and ethynyl compounds is indicative of a C2′
endo conformation.5c
(9) J ung, P. M. J .; Burger, A.; Biellmann, J .-F. Tetrahedron Lett.
1995, 36, 1031-1034.
(10) The same lack of selectivity has been observed by others in
cerium-assisted Grignard addition of an allyl group to 3′-ketouridines;
see: Nielsen, P.; Larsen, K.; Wengel, J . Acta Chem. Scand. 1996, 50,
1030-1035.
(11) Hattori, H.; Tanaka, M.; Fukushima, M.; Sasaki, T.; Matsuda,
A. J . Med. Chem. 1996, 39, 5005-5011.
Removal of the silyl ethers of 3a and 3b using Bu4NF
in THF afforded the triols 4a and 4b in good yield.
(12) Bartoli, G.; Bosco, M.; Van Beek, J .; Sambri, L.; Marcantoni,
E. Tetrahedron Lett. 1996, 37, 2293-2296.
(13) For a review, see, for instance: Hartwing, W. Tetrahedron 1983,
39, 2609-2645.
(19) (a) Shigeno, K.; Ohne, K.; Yamaguchi, T.; Sasai, H.; Shibasaki,
M. Heterocycles 1992, 33, 161-171. (b) Shigeno, K.; Sasai, H.; Shiba-
saki, M. Tetrahedron Lett. 1992, 33, 4937-4940. (c) Sugita, K.; Shigeno,
K.; Neville, C. F.; Sasai, H.; Shibasaki, M. Synlett 1994, 325-329.
(20) Crystallography data for 3a : C20H34N2O6Si2, FW ) 454.7,
tetragonal, space groupe P43212, a ) b ) 10.816(3) Å, c ) 43.641(10)
Å, V ) 5105 Å,3 Z ) 8, Dc ) 1.183 g‚cm-3, µ ) 15.497 cm-1. Philips
PW1100/16 diffractometer, 173 K, Cu KR graphite-monochromated
radiation (λ ) 1.5418 Å), colorless crystal of 0.40 × 0.30 × 0.30 mm3,
3° < θ < 52°, 3229 data collected, 2858 observed (I > 3σ(I)). The
structure was determined by direct methods. The correct enantiomorph
was established by comparing x, y, z and -x, -y, -z refinements. Full-
matrix least-squares refinement on XLERI(F). Final results: R ) 0.031,
Rw ) 0.048, GOF ) 1.058.
(14) (a) Samano, V.; Robins, M. J . J . Org. Chem. 1990, 55, 5186-
5188. (b) Hansske, F.; Robins, M. J . Tetrahedron Lett. 1983, 24, 1589-
1592. (c) Hansske, F.; Madej, D.; Robins, M. J . Tetrahedron 1984, 40,
125-135.
(15) (a) Morris, M. J .; Samano, V.; J ohnson, M. D. J . Org. Chem.
1990, 55, 410-412. (b) Samano, V.; Robins, M. J . J . Org. Chem. 1991,
56, 7106-7113. (c) Robins, M. J .; Sarker, S.; Samano, V.; Wnuk, S. F.
Tetrahedron 1997, 53, 447-456.
(16) Imamoto, T. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.: Pergamon Press: New York, 1991; Vol. 1, pp 231-
250.
(17) The usual preparation of the reagent does not lead to anhydrous
CeCl3; see: Evans, W. J .; Feldman, J . D.; Ziller, J . W. J . Am. Chem.
Soc. 1996, 118, 4581-4584.
(18) Demmark, S. E.; Edwards, J . P.; Nicaise, O. J . Org. Chem. 1993,
58, 569-578.
(21) (a) Saenger, W. In Principles of Nucleic Acid Structure; Cantor,
C. R., Ed.; Springer-Verlag, New York, 1983; Chapter 2, pp 8-28. (b)
Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94, 8205-
8212.

Synthesis of C-3′-Ethynylribonucleosides
J . Org. Chem., Vol. 62, No. 24, 1997 8311
Sch em e 1a
Sch em e 3a
a
Key: (i) CF3CO2H‚H2O, 4 °C; (ii) Me3SiCtCLi/CeCl3, THF,
-78 °C; (iii) Bu4NF, THF.
Sch em e 2a
a
Key: (i) TIPSCl, Py, and NEt(iPr)2; (ii) PhOC(S)Cl, DMAP;
(iii) Bu3SnH, AIBN, toluene, 75 °C.
Therefore, it was necessary to protect the 3′ hydroxyl.
The 3′,5′-protected nucleosides 11a and 11b were pre-
pared in 74 and 52% yield, respectively, by reaction of
4a and 4b with 1,3-dichlorotetraisopropyldisiloxane (TIP-
SCl2)24 in pyridine in presence of Hu¨nig’s base. The
reaction of compounds 11a and 11b with phenoxy(thio-
carbonyl) chloride gave thionocarbonates 12a and 12b
in good yield. When 12a was treated under standard
conditions (a solution of 12a , AIBN, and Bu3SnH in
toluene was heated at 75 °C for 3 h) two major com-
pounds 13a and 14a were isolated in 1/1 ratio in a 63%
total yield. Their structure corresponded to the deoxy-
genation at the C-2′ position and to the cis and trans
addition of tin hydride to the triple bond. The addition
of a stannyl radical to a triple bond has been shown to
be a reversible reaction25 and the rather slow reduction
of the vinylic stannylic radical to be dependent on the
concentration of tin hydride.25b By contrast, the reduc-
tion of the thionocarbonate is apparently independent of
the concentration of Bu3SnH.23 A low concentration of
tin hydride might disfavor the addition of the stannyl
hydride on to the triple bond and, therefore, might favor
the formation of deoxy compounds 15a and 15b. Indeed,
treatment of thionocarbonates12a and 12b by a slow
addition of tin hydride and AIBN afforded the deoxy
compounds 15a and 15b in a 40 and 60% yield, respec-
tively (Scheme 4). Under these conditions, none of the
vinyltin adducts were produced. However, reduction of
compound 12a furnished a 1/1 mixture of the desired
compound 15a and unreacted starting material along
with a complex mixture of byproducts as evidenced by
1H NMR of the crude extract. Attempts to improve the
yield of compound 15a failed. The silyl protecting group
a
Key: (i) PhCOCl, Py, -10 °C to rt; (ii) Bu4NF, THF; (iii)
m-CF3PhCOCl, DMAPcat
i-PrOH‚H2O.
, Py; (iv) m-methylcarbazole, hν,
The next important step was the C-2′ deoxygenation
of the 3′-alkynyl nucleosides 4a and 4b to their corre-
sponding 2′-deoxy analogues. In an initial attempt, we
tried to apply the photochemical method to the 2′-
deoxygenation of products 3a and 3b as it has been
described for the deoxygenation of nucleosides.22
Selective benzoylation of the primary alcohol of prod-
ucts 3a and 3b in cold pyridine by reaction with benzoyl
chloride was achieved in good yield. The silyl ether group
at C-2′ of products 7a and 7b was removed by treatment
with Bu4NF. After reaction of the benzoates 8a and 8b
with (trifluoromethyl)benzoyl chloride in the presence of
a catalytic amount of (dimethylamino)pyridine, the pho-
toactive compounds 9a and 9b were obtained in overall
yields of 47% and 74%, respectively. In our hands,
irradiation of compounds 9a and 9b in the presence of
N-methylcarbazole in a mixture of 2-propanol and water
gave no deoxygenated compound and the deoxygenated
compound 10b in a low yield of 25%, respectively. Faced
with the difficulties encountered during the photoreaction
of the uridine derivative, we decided to explore the
13
Barton-McCombie reaction
(Scheme 3) applied ef-
ficiently to the reduction of nucleosides.23
The reaction of 8b with phenoxy(thiocarbonyl) chloride
did not give the expected phenoxy(thiocarbonate), but
instead gave the cyclic O-2′ and O-3′ thiocarbonate.
(24) Markiewicz, W. J . Chem. Res., Synop., 1979, 24-25; J . Chem.
Res., Miniprint 1979, 0181-0197.
(25) For a review see: (a) Chatgilialoglu, C.; Ferreri, C. In The
chemistry of triple-bonded functional groups; Patai, S., Ed.; J ohn Wiley
and Sons: 1994; Supplement C2, pp 917-944. (b) Stork, G.; Mook, R.
J . Am. Chem. Soc. 1987, 109, 2829-2831.
(22) Saito, I.; Ikehira, H.; Kasatani, R.; Watanabe, M.; Matsura, T.
J . Am. Chem. Soc. 1986, 108, 3115-3117.
(23) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc.
1983, 105, 4059-4065 and references therein.

8312 J . Org. Chem., Vol. 62, No. 24, 1997
J ung et al.
Sch em e 4a
measured on a Perkin-Elmer 241MC polarimeter. UV spectra
were measured on a Hewlett-Packard 8451A. IR spectra were
recorded on a Perkin-Elmer 881 or a Bruker FT IFS25. NMR
spectra were recorded on a Brucker SY (200 or 400 M Hz)
apparatus. For 1H NMR the residual proton signal of the
deuterated solvent was used as an internal reference: for
CDCl3 (δ ) 7.26 ppm), DMSO-d6 (δ ) 2.50), MeOD-d4 (δ )
3.30), and acetone-d6 (δ ) 2.05). For 13C NMR, the 13C signal
of the deuterated solvent was used as an internal reference;
for CDCl3 (δ ) 76.9 ppm, central signal), DMSO-d6 (39.46),
MeOD-d4 (40.02). The chemical shifts are reported in ppm
downfield from TMS. MS were measured on a LKB 9000S
apparatus by electronic impact (EI, 70 eV), on a Trio 2000
(FISONS, UK) apparatus by chemical ionization (CI), or on a
ZAB (FISONS, UK) apparatus by fast atom bombardment
(FAB, matrix nitrobenzyl alcohol). Microanalyses were per-
formed by the Strasbourg Division or by the Service Central
de Microanalyses of the CNRS at Vernaison.
Unless otherwise indicated, all reagents were obtained from
commercial suppliers and were used without purification. All
experiments sensitive to air and/or to moisture were carried
out under an argon atmosphere in oven-dried (120 °C) glass-
ware assembled under a stream of argon. Anhydrous solvents
were freshly distilled before use: tetrahydrofuran from sodium
benzophenone ketyl radical, pyridine, diisopropylethylamine,
and benzene from CaH2. Analytical thin-layer chromatogra-
phy was performed on silica gel precoated TLC plates (Merck,
60, F254) or on reversed phase C-18 precoated TLC plates
(Merck, HPTLC RP-18, F254S). Products were isolated by
flash chromatography on silica gel (Merck, 60, 230-400 mesh).
Gen er a l P r oced u r e for th e Selective Dep r otection of
2′,5′-O-Bis-TBDMS-k eton u cleosid es. To prepare the un-
stable hydroxy ketones 2a and 2b on 1 g scale, the solvent
evaporation had to be done in a short time since longer times
gave impure products of 2a and 2b. A solution of compound
1a or 1b (2.13 mmol) in a mixture of CF3COOH (15.7 mL) and
of H2O (1.8 mL) was stirred for 30 min at 0 °C. The yellow
solution was poured into a mixture of AcOEt (300 mL),
cyclohexane (200 mL), and an aqueous saturated NaHCO3
solution (250 mL). The phases were separated. The aqueous
phase was extracted with a mixture of AcOEt (300 mL) and
cyclohexane (200 mL). The combined organic phase was
washed with H2O (30 mL), dried over Na2SO4, and filtered.
The solvents were removed in vacuo in a 500 mL flask at 0
°C. When the volume was reduced to about 250 mL, cyclo-
hexane was added, and further evaporation gave a white solid.
The unstable hydroxy ketones were used directly without
further purification.
a
Key: (i) slow addition of Bu3SnH, AIBN, toluene, 75 °C; (ii)
Bu4NF, THF.
was removed with Bu4NF to give the deoxynucleosides
16a and 16b in good yield.
To study the influence of the ethynyl function on the
stability of oligonucleotides26 where C-3′-ethynyluridine
16a has been incorporated, we attempted to prepare the
corresponding phosphoramidite building block. The re-
action of the deoxynucleoside 16a with dimethoxytrityl
chloride gave the corresponding nucleoside protected on
the 5′-position. The reaction of this compound with
chloro(2-cyanoethoxy)(diisopropylamino)phosphane did
not give the corresponding phosphoramidite under stan-
dard conditions.6 Our results were in contrast to the
results of others6,27 who do not mention any problem in
the preparation of the phosphoramidite building blocks
with even more hindered 3′ tertiary alcohols. That this
reaction did not occur was indicative of a lower reactivity
of the tertiary alcohol presumably due to the electronic
nature of the ethynyl group28 at C-3′.
The anti-HIV activity of compounds 4a ,b, 5a ,b, and
16a ,b was evaluated on human T-cells CEM-SS infected
by HIV-1 LAI. IC50 (µM)/CC50 (µM) of 0.0009/0.6 for 4a ,
0.006/0.03 for 4b, 10/100 for 5a , 900/500 for 5b, 90/60
for 16a , 70/80 for 16b, and 0.001/>1 for AZT were
determined. The most potent compound of this series,
C-3′-ethynyluridine 4a , was as active as AZT but with a
lower selectivity index. However, its evaluation on
human T-cells MT4 infected by HIV-1 IIIB showed no
protection whereas cytoxicity was still observed, CC50 of
0.05 µM.29
1-[2-O-(ter t-Bu tyldim eth ylsilyl)-â-D-er yth r o-pen tofu r an -
1
3-u losyl]u r a cil (2a ): IR (KBr) 1788 cm-1; H NMR (CDCl3,
200 MHz) δ 8.17 (s, 1 H), 7.48 (d, J ) 8 Hz, 1 H), 5.84 (dd, J 1
) 2 Hz, J 2 ) 8 Hz, 1 H), 5.72 (d, J ) 8 Hz, 1 H), 4.71 (d, J )
8 Hz, 1 H), 4.26 (m, 1 H), 3.94 (m, 2 H), 0.85 (s, 9 H), 0.13 (s,
3 H), 0.04 (s, 3 H); MS (70 eV) 357 (2), 299 (45), 75 (100).
9-[2-O-(ter t-Bu tyldim eth ylsilyl)-â-D-er yth r o-pen tofu r an -
3-u losyl]a d en in e (2b): IR (KBr) 1782 cm-1; 1H NMR (lit.15c).
1-[2-O-(ter t-Bu t yld im et h ylsilyl)-3-C-[(t r im et h ylsilyl)-
eth yn yl]-â-D-r ibo-p en tofu r a n osyl]u r a cil (3a ). CeCl3‚7H2O
(4.76 g, 12.7 mmol) was dried at 140 °C under vacuum (1
mmHg) for 4 h. The resulting powder was cooled under argon.
Dry THF (20 mL) was added, and the suspension was stirred
overnight. Independently, a solution of lithium acetylide was
prepared as follows: to a solution of (trimethylsilyl)acetylene
(1.29 g, 13 mmol) at -78 °C in dry THF (20 mL) was added
BuLi (8.24 mL, 13.2 mmol) in hexane (1.6 M). The reaction
temperature was raised to -20 °C over a 1 h period. The
lithium acetylide solution was cooled to -78 °C and added,
via a cannula, to the dry CeCl3 suspension at the same
temperature (prepared above). The mixture was stirred for 1
h, and a cooled solution (-78 °C) of 2a (0.76 g, 2.1 mmol) in
THF (20 mL) was rapidly added via a cannula. After 3 h at
-78 °C, glacial acetic acid (1.8 mL) was added. Over a period
of 1 h, the temperature was raised to 20 °C. The mixture was
poured in an aqueous phosphate buffer solution (2 M, pH 7).
The aqueous phase was extracted with AcOEt (3 × 200 mL).
The combined organic layers were dried over Na2SO4, filtered,
Exp er im en ta l Section
Ma ter ia l a n d Meth od s. Melting points were measured
on a Reichert microscope and were uncorrected. [R]D were
(26) Ikehara, M.; Ohtasaka, E.; Uesugi, S.; Tanaka, T. Chem.
Nucleosides Nucleotides 1988, 1, 283-367.
(27) Tarko¨y, M.; Leumann, C. Angew. Chem., Int. Ed. Engl. 1993,
32, 1432-1434.
(28) One of the reasons we have been interested by the ethynyl
group, relative to alkyl and alkenyl groups, is its high electronegativity,
which is larger than a chloride atom and comparable to a cyano group.
By electron withdrawing, the ethynyl group might lower the nucleo-
philicity of the 3′ tertiary alcohol; see: Wells, P. R. Prog. Phys. Org.
Chem. 1966, 6, 111-145.
(29) Because of its important cytoxicity, compound 4a was retained
for subsequent investigations upon a panel of cultured malignant cells.
Matsuda and his collaborators have described the high potent anti-
tumor activity of compound 4a against human tumor cells in vitro and
in vivo; see ref 11 and: Weltin, D.; J ung, P. M. J .; Holl, V.; Dauvergne,
J .; Burger, A.; Dufour, P.; Aubertin, A. M.; Bischoff, P.; Biellmann J .
F. Submitted for publication.

Synthesis of C-3′-Ethynylribonucleosides
J . Org. Chem., Vol. 62, No. 24, 1997 8313
and evaporated in vacuo. The residue was chromatographed
Hz, 1 H), 4.61 (m, 2 H), 4.33 (m, 1 H), 3.70 (s, 1 H); 13C NMR
(DMSO-d6, 50 MHz) δ 165.0, 156.0, 152.6, 149.5, 139.9, 133.3,
129.1, 129.4, 128.7, 119.1, 85.8, 83.7, 82.0, 77.5, 76.8, 72.3, 64.9.
Anal. Calcd for C19H17O5N5: C, 57.72; H, 4.33; N, 17.71.
Found: C, 57.60; H, 4.41; N, 17.67.
(silica gel: ether-hexane 6:4) to give a white solid 3a (0.74 g,
78% yield in two steps): mp 187-188 °C; [R]25 +47 (c 1,
D
CHCl3); UV (CHCl3) λmax 262 nm (ꢀ 10 300); 1H NMR (CDCl3,
200 MHz) δ 8.38 (s, 1 H), 7.76 (d, J ) 8 Hz, 1 H), 5.88 (d, J )
7 Hz, 1 H), 5.79 (d, J ) 8 Hz, 1H), 4.44 (d, J ) 7 Hz, 1 H), 4.19
(m, 1 H), 3.95 (m, 2 H), 3.31 (s, 1 H), 2.38 (s, 1 H), 0.80 (s, 9
H), 0.14 (s, 3 H), 0.02 (s, 3 H); 13C NMR (DMSO-d6, 50 MHz)
δ 162.7, 150.8, 140.6, 104.4, 102.3, 90.5, 86.8, 85.5, 79.1, 73.0,
61.4, 25.4, 17.6, -0.4, -4.3, -5.3; MS (EI) m/z 397 (100), 342
(8), 285 (34), 255 (26). Anal. Calcd for C20H34O6N2Si2: C,
52.86; H, 7.49; N, 6.17. Found: C, 52.80; H, 7.68; N, 5.94.
9-[2-O-(ter t-Bu t yld im et h ylsilyl)-3-C-[(t r im et h ylsilyl)-
eth yn yl]-â-D-r ibo-p en tofu r a n osyl]a d en in e (3b). Prepara-
tion of 3b from 2b has been achieved using the method as
described for 3a . Chromatography (silica gel: ether-hexane
9-(5-O-Ben zoyl-3-eth yn yl-2-O-[m -(tr iflu or om eth yl)ben -
zoyl]-â-D-r ibo-p en tofu r a n osyl)a d en in e (9b). Product 8b
(0.20 g, 0.51 mmol) and DMAP (2.5 mg, 0.02 mmol) were
dissolved in dry pyridine (10 mL). The solution was cooled to
0 °C, and m-(trifluoromethyl)benzoyl chloride (90 µL, 0.61
mmol) was added. The solution was stirred at rt for 3 h.
Water (4 mL) was then added and the aqueous phase extracted
with ether (3 × 20 mL). The combined organic phases were
dried over Na2SO4, filtered, and evaporated in vacuo. The
residue was chromatographed (silica gel: ethyl acetate-
acetone 99:1) to afford a white solid 9b (0.25 g, 90% yield):
7:3) afforded 3b (72% yield in two steps): mp 204 °C; [R]22
mp 212 °C dec; IR (KBr) 2097, 1733, 1700 cm-1 1H NMR
;
D
-32 (c 1.2, CHCl3); UV (CHCl3) λmax 262 nm (ꢀ 12 300); IR
(KBr) 3348, 2958, 2160, 1642 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 8.38 (s, 1 H), 7.77 (s, 1 H), 6.48 (t, 1 H), 5.74 (d, J ) 8 Hz, 1
H), 5.64 (s, 2 H), 5.16 (d, J ) 8 Hz, 1 H), 4.29 (m, 1 H), 4.98
(m, 2 H), 3.23 (s, 1 H), 0.81 (s, 9 H), 0.2 (s, 9 H), 0.0 (s, 3 H),
-0.48 (s, 3 H); 13C NMR (DMSO-d6, 50 MHz) δ 156.2, 152.3,
148.9, 140.3, 119.5, 104.5, 90.3, 88.0, 86.6, 78.5, 73.1, 61.9, 25.3,
17.4, -0.3, -4.5, -5.7; MS (FAB) m/z 478 (100), 462 (5), 420
(12). Anal. Calcd for C21H35O4N5Si2: C, 52.83; H, 7.34; N,
14.68. Found: C, 52.56; H, 7.35; N, 14.45.
(CDCl3, 200 MHz) δ 8.29 (m, 3 H), 8.01 (m, 3 H), 7.70 (m, 4
H), 7.34 (s, 2 H), 7.17 (s, 1 H), 6.44 (d, J ) 7 Hz, 1 H), 6.36 (d,
J ) 7 Hz, 1 H), 4.76 (m, 2 H), 4.56 (m, 1 H), 3.89 (s, 1 H); 13
C
NMR (DMSO-d6, 50 MHz) δ 165.5, 163.4, 156.0, 152.7, 149.3,
139.3, 133.8, 130.1, 129.2, 128.7, 126.3, 119.0, 84.5, 84.0, 80.2,
78.9, 78.2, 71.8, 64.9. Anal. Calcd for C27H20O6N5F3: C, 57.15;
H, 3.55; N, 12.34. Found: C, 57.01; H, 3.67; N, 12.30.
9-(5-O-Ben zoyl-3-et h yn yl-2-d eoxy-â-D-er yth r o-p en t o-
fu r a n osyl)a d en in e (10b). To a solution of 9b (0.10 g, 0.17
mmol) under argon in a 1:10 mixture of water and 2-propanol
(152 mL) was added N-methylcarbazol (0.04 g, 0.19 mmol).
The resulting solution was irradiated with a UV lamp (125
W) for 13 h. The solvents were evaporated in vacuo, and the
residue was purified by preparative TLC (silica gel). Elution
with a solution of chloroform and methanol (96:4) afforded the
desired compound 10b (0.016 g, 25% yield): mp 98 °C; IR (KBr)
1-(3-C-E t h yn yl-â-D-r ibo-p en t ofu r a n osyl)u r a cil (4a ).
Bu4NF (1.22 g, 3.9 mmol) was added to a solution of 3a (0.80
g, 1.7 mmol) in THF (32 mL) at 20 °C. After 30 min of stirring,
the solvent was evaporated in vacuo. The crude product was
dissolved in a minimum of acetone and was filtered through a
short column of silica gel with acetone as eluent. The residue
was purified by trituration with ethanol to give pure 4a (0.39
g, 82% yield) with identical spectral data as reported:11 mp
1
2927, 1719, 1642 cm-1; H NMR (CDCl3, 200 MHz) δ 8.35 (s,
1 H), 8.08 (s, 1 H), 8.00 (m, 2 H), 7.57 (m, 1 H), 7.45 (m, 2 H),
6.57 (dd, J 1 ) 7.5 Hz, J 2 ) 6 Hz, 1 H), 5, 70 (s, 2 H), 4.73 (m,
2 H), 4.50 (m, 1 H), 2.98 (m, 1 H), 2.76 (s, 1 H); MS (70 eV)
379 (100), 361 (7), 279 (100).
224 °C (lit.11 mp 226-228 °C); [R]24 +44 (c 1.1, MeOH); UV
D
(MeOH) λmax 262 nm (ꢀ 9600); 13C NMR (DMSO-d6, 50 MHz)
δ 163.0, 150.9, 140.8, 102.0, 86.5, 85.9, 82.7, 77.7, 77.0, 72.6,
61.3. Anal. Calcd for C11H12O6N2: C, 49.25; H, 4.48; N, 10.45.
Found: C, 49.50; H, 4.70; N, 10.23.
1-[3-C-Eth yn yl-3,5-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-
1, 3-d iyl)-â-D-r ibo-p en tofu r a n osyl]u r a cil (11a ). To a solu-
tion of 4a (0.20 g, 0.75 mmol) in dry pyridine (12 mL) was
added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.25 mL,
0.82 mmol). The solution was stirred overnight, and dry
NEt(iPr)2 (0.74 mL, 7.5 mmol) was added. The solution was
stirred further for 2 h, and the solvents were evaporated in
vacuo. The residue was filtered quickly over a short column
of silica gel (silica gel:ether). Evaporation of the solvent gave
a slightly yellow compound (0.28 g, 74% yield). The unstable
compound 11a showed a single spot on TLC and was used
without further purification: mp 98-99 °C; 1H NMR (CDCl3,
200 MHz) δ 8.4 (s, 1 H), 7.46 (d, J ) 8 Hz, 1 H), 5.81 (d, J )
2 Hz, 1 H), 5.71 (d, J ) 8 Hz, 1 H), 4.37 (m, 1 H), 4.17 (m, 3
H), 3.21 (s, 1 H), 2.86 (s, 1 H), 1.08 (m, 28 H); MS (70 eV) 511
(100), 467 (10).
9-(3-C-Eth yn yl-3, 5-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-
1,3-d iyl)-â-D-r ibo-p en tofu r a n osyl)a d en in e (11b). Prepara-
tion of 11b from 4b has been achieved using the method as
described for 11a . The residue was dissolved in a small
volume of ethyl acetate and precipitated by addition of hexane
to give 11b (52% yield). The unstable product was sufficiently
pure to be used directly in the next step: mp 275-279 °C; 1H
NMR (CDCl3, 200 MHz) δ 8.40 (s, 1 H), 8.04 (s, 1 H), 6.08 (d,
J ) 2 Hz, 1 H), 5.57 (s, 2 H), 4.52 (t, J ) 2 Hz, 1 H), 4.42 (m,
1 H), 4.19 (m, 2 H), 3.37 (d, J ) 2 Hz, 1 H), 2.81 (s, 1 H), 1.08
(m, 28 H); MS (CI) 534 (2), 410 (100).
1-[3-C-E t h yn yl-2-O-[p h e n oxy(t h ioca r b on yl)]-3,5-O-
(1,1,3,3-tetr aisopr opyldisiloxan e-1, 3-diyl)-â-D-r ibo-pen to-
fu r a n osyl]u r a cil (12a ). Phenyl thionocarbonate chloride (98
µL, 0.7 mmol) was added to a solution of 11a (0.31 g, 0.6 mmol)
and DMAP (0.16 g, 1.3 mmol) in dry acetonitrile (12 mL) under
argon. The solution was stirred for 2 h, and the solvent was
evaporated in vacuo. The residue was partitioned between
AcOEt (44 mL) and H2O (15 mL). The organic phase and the
aqueous phase were separated, and the aqueous phase was
extracted with AcOEt (3 × 40 mL). The combined organic
phases were dried over Na2SO4 and evaporated in vacuo. The
1-(3-C-Eth yn yl-â-D-r ibo-p en tofu r a n osyl)a d en in e (4b).
Preparation of 4b from 3b has been achieved using the method
as described for 4a . The residue was washed with ethanol to
give 4b (85% yield) with identical spectral data as reported:
11: mp 139-140 °C (lit.11 mp 149-152 °C); [R]24 -31 (c 0.6,
D
H2O); UV(MeOH) λmax 262 nm (ꢀ 16 300); 13C NMR (DMSO-
d6, 50 MHz) δ 156.1, 152.3, 149.1, 140.3, 119.3, 87.8, 86.7, 82.7,
77.5, 76.9, 72.8, 61.9. Anal. Calcd for C12H13O4N5‚H2O: C,
46.60; H, 4.85; N, 22.65. Found: C, 46.97; H, 4.57; N, 22.72.
9-[5-O-Ben zoyl-2-O-(ter t -b u t yld im et h ylsilyl)-3-[(t r i-
m et h ylsilyl)et h yn yl]-â-D-r ibo-p en t ofu r a n osyl]a d en in e
(7b). Benzoyl chloride (0.24 g, 1.7 mmol) was added to a
solution of 3b (0.75 g, 1.57 mmol) in dry pyridine (14 mL) at
-10 °C. The temperature was allowed to raise to rt, and the
solution was stirred further for 2 h. Water (10 mL) was then
added and the aqueous phase extracted with chloroform (2 ×
20 mL). The combined organic phases were dried over Na2SO4,
filtered, and concentrated in vacuo. Chromatography (silica
gel: ether-hexane 7:3) afforded 7b (0.79 g, 86% yield): mp
1
176-178 °C; IR (KBr) 2960, 2176, 1723, 1651 cm-1; H NMR
(CDCl3, 200 MHz) δ 8.17 (s, 1 H), 8.14 (m, 3 H), 7.53 (m, 3 H),
5.97 (d, J ) 7 Hz, 1 H), 5.51 (s, 2 H), 5.30 (d, J ) 7 Hz, 1 H),
5.73 (m, 2 H), 4.55 (m, 1 H), 3.37 (s, 1 H), 0.78 (s, 9 H), 0.06 (s,
12 H), -0.34 (s, 3 H); MS (70 eV) 581 (10), 566 (45), 524 (100).
9-(5-O-Ben zoyl-3-eth yn yl-â-D-r ibo-p en tofu r a n osyl)a d -
en in e (8b). Bu4NF (0.933 g, 2.9 mmol) was added to a
solution of compound 7b (0.72 g, 1.23 mmol) in THF (29 mL).
The solution was stirred at rt for 30 min, and then the solvent
was evaporated in vacuo. The residue was dissolved in a
minimum of acetone and chromatographed (silica gel: ethyl
acetate-acetone 7:3) to give a white solid (0.46 g, 96% yield):
mp 147-150 °C; [R]24 -28 (c 1.5, DMSO); UV (MeOH) λmax
D
234, 262 nm (ꢀ 14 900, 15 700); IR (KBr) 2100, 1724, 1664,
1604 cm-1; 1H NMR (CDCl3, 200 MHz) δ 8.31 (s, 1 H), 8.07 (s,
1 H), 7.99 (m, 2 H), 7.60 (m, 3 H), 7.30 (s, 2 H), 6.33 (s, 1 H);
6.01 (d, J ) 8 Hz, 1 H), 5.90 (d, J ) 8 Hz, 1 H), 5.10 (t, J ) 8

8314 J . Org. Chem., Vol. 62, No. 24, 1997
J ung et al.
residue was dissolved in the minimum amount of CHCl3 and
chromatographed on silica gel (ether-hexane 4:6) to afford 12a
(0.3 g, 77% yield). The unstable product was sufficiently pure
to be used directly in the next step: mp 73-80 °C; IR (KBr)
139.8, 101.8, 86.8, 83.9, 81.9, 78.9, 73.81, 62.12, 50.6, 17.5, 17.4,
17.3, 17.26, 14.4, 13.4, 12.8; MS (ID) 451 (13), 339 (15), 105
(100).
9-[3-C-Eth yn yl-3,5-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-
1,3-d iyl)-2-d e oxy-â-D-er yth r o-p e n t ofu r a n osyl]a d e n in e
(15b). Preparation of 15b from 12b has been achieved using
the method as described for 15a . Chromatography (silica gel:
chloroform-ethyl acetate 3:7) afforded 15b (60% yield): mp
241-244 °C; IR (KBr) 2940, 2107 cm-1; 1H NMR (CDCl3, 200
2949, 2100, 1691, 1288 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
8.0 (s, 1 H), 7.42 (m, 5 H), 7.13 (m, 1 H), 6.07 (d, J ) 2 Hz, 1
H), 6.04 (d, J ) 2 Hz, 1 H), 5.75 (d, J ) 8 Hz, 1 H), 4.44 (m, 1
H), 4.19 (m, 3 H), 2.92 (s, 1 H), 1.07 (m, 28 H); MS (CI, NH3)
603 (0.5), 573 (0.6).
9-[3-C-E t h yn yl-2-O-[p h e n oxy(t h ioca r b on yl)]-3,5-O-
(1,1,3,3-tetr aisopr opyldisiloxan e-1, 3-diyl)-â-D-r ibo-pen to-
fu r a n osyl]a d en in e (12b). Phenyl thionocarbonate chloride
(22 µL, 0.16 mmol) was added to a solution of 11b (0.08 g,
0.15 mmol) and DMAP (0.04 g, 0.32 mmol) in dry dichlo-
romethane (3 mL). The solution was stirred for 2 h, and water
(30 mL) was added. The aqueous phase was extracted with
dichloromethane (2 × 50 mL). The combined organic phases
were dried over Na2SO4, filtered, and evaporated in vacuo. The
residue was dissolved in dichloromethane and applied on
preparative TLC plates (silica gel: ether-hexane 6:4) to give
12b (0.08 g, 80% yield). The unstable product was sufficiently
pure to be used directly in the next step: mp 218-220 °C; IR
(KBr) 2950, 2109, 1678, 1221 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 8.39 (s, 1 H), 8.16 (s, 1 H), 7.37 (m, 3 H), 7.13 (m, 2 H), 6.39
(d, J ) 2 Hz, 1 H), 6.38 (d, J ) 2 Hz, 1 H), 5.61 (s, 2 H), 4.49
(m, 1 H), 4.23 (m, 2 H), 2.91 (s, 1 H), 1.13 (m, 28 H); MS (CI,
CH4) 698.7 (0.7), 670.4 (9), 136 (4%), 94 (100).
MHz) δ 8.36 (s, 1 H), 8.15 (s, 1 H), 6.39 (dd, J 1 ) 6 Hz, J 2
)
5.5 Hz,1 H), 5.61 (s, 2 H), 4.39 (m, 1 H), 4.11 (m, 2 H), 3.02
(m, 2 H), 2.79 (s, 1 H), 1.05 (m, 28 H); MS (FAB+) 518 (100),
474 (50).
1-(3-C-Eth yn yl-2-d eoxy-â-D-er yth r o-p en tofu r a n osyl)u -
r a cil (16a ). Bu4NF (0.04 g, 0.13 mmol) was added to a
solution of 15a (0.03 g, 0.06 mmol) in THF (3 mL). The
solution was stirred for 2 h, and the solvent was evaporated
in vacuo. The crude product, dissolved in a minimum of
acetone, was filtered through a short column of silica gel
(acetone). After evaporation of the solvent, the residue was
purified by trituration with acetone to give 16a (0.01 g, 85%
yield): mp 205-207 °C; IR (KBr) 2940, 2113, 1653 cm-1; [R]24
D
+79 (c 0.7, MeOH); UV (MeOH) λmax 262 nm (ꢀ 9600); 1H NMR
(acetone-d6, 200 MHz) δ 9.95 (s, 1 H), 8.15 (d, J ) 8 Hz, 1 H),
6.35 (dd, J 1 ) 8 Hz, J 2 ) 6 Hz, 1 H), 5.61 (d, J ) 8 Hz, 1 H),
5.24 (s, 1 H), 4.20 (dd, J 1 ) J 2 ) 5 Hz,1 H), 4.06 (m, 1 H), 3.91
(m, 2 H), 3.20 (s, 1 H), 2.52 (m, 2 H); 1H NMR (MeOD-d4, 200
MHz) δ 9.89 (s, 1 H), 8.10 (d, J ) 8 Hz, 1 H), 6.26 (dd, J 1 ) 8
Hz, J 2 ) 6 Hz,1 H), 5.70 (d, J ) 8 Hz, 1 H), 3.98 (m, 1 H), 3.87
(m, 2 H), 3.12 (s, 1 H), 2.45 (m, 2 H); 13C NMR (MeOD-d4, 100
MHz) δ 166.2, 152.2, 142.6, 102.6, 90.0, 85.8, 76.8, 73.4, 63.4,
47.5; MS (FAB) 505.1 (15), 275.1 (35), 253 (100). Anal. Calcd
for C11H12N2O5‚1/3H2O: C, 51.16; H, 4.90; N, 10.85. Found:
C, 51.37; H, 4.90; N, 10.92.
(E)- a n d (Z)-1-[3,5-O-(1,1,3,3-Tetr a isop r op yld isiloxa n e-
1,3-d iyl)-3-[(t r ib u t ylst a n n yl)vin yl]-2-d eoxy-â-D-er yth r o-
p en tofu r a n osyl]u r a cil (13a ) a n d (14a ). A degassed solu-
tion of 12a (0.12 g, 0.18 mmol), Bu3SnH (0.1 mL, 0.39 mmol),
and AIBN (0.01 g, 0.05 mmol) in toluene (5 mL) under argon
was heated for 3 h. After evaporation of the solvent, the crude
product was chromatographed on analytical TLC plates (silica
gel: chloroform-ethanol 99:1) to afford 13a (32% yield) and
14a (31% yield).
9-(3-C-Eth yn yl-2-d eoxy-â-D-er yth r o-p en tofu r a n osyl)a d -
en in e (16b). Preparation of 16b from 15b has been achieved
using the method as described for 16a . The residue was
washed with chloroform to give 16b (89% yield): mp 131-
(E)-Olefin ic d er iva tive 13a : oil; 1H NMR (CDCl3, 200
MHz) δ 8.63 (s, 1 H), 7.31 (d, J ) 8 Hz, 1 H), 6.36 (d, J ) 19
Hz, 1 H), 6.07 (m, 2 H), 5.70 (bd, J ) 8 Hz, 1 H), 4.16 (m, 2 H),
3.83 (m, 1 H), 2.55 (m, 2 H), 1.36-1.03 (m, 55 H); MS (FAB)
809 (17), 787 (18), 729 (100).
133 °C; IR (KBr) 2095, 1645 cm-1; [R]24 -8 (c 1.3, MeOH);
D
1
UV (MeOH) λmax 262 nm (ꢀ 15 400); H NMR (acetone-d6, 200
MHz) δ 8.25 (s, 1 H), 8.18 (s, 1 H), 6.71 (s, 2 H), 6.44 (dd, J 1
)
(Z)-Olefin ic d er iva tive 14a : mp 145-185 °C; 1H NMR
(CDCl3, 200 MHz) δ 8.49 (s, 1 H), 7.43 (d, J ) 8 Hz, 1 H), 6.00
(dd, J 1 ) 8 Hz, J 2 ) 4 Hz, 1 H), 5.75 (dd, J 1 ) 8 Hz, J 2 ) 2 Hz,
1 H), 5.62 (d, J ) 11 Hz, 1 H), 5.29 (d, J ) 11 Hz, 1 H), 4.00
(m, 3 H), 2.81 (m, 1 H), 2.21 (m, 1 H), 1.03 (m, 55 H); 13C NMR
(CDCl3, 50 MHz) δ 163.1, 150.1, 140.1, 138.9, 126.9, 102.2,
86.3, 82.7, 79.9, 60.9, 48.9, 25.7, 29.9, 17.2, 16.6, 13.6, 13.1,
12.3; MS (FAB) 809 (20), 729 (100).
9.5 Hz, J 2 ) 5 Hz, 1 H), 5.66 (dd, J 1 ) 8.5 Hz, J 2 ) 4 Hz, 1 H),
5.26 (s, 1 H), 4.13 (m, 1 H), 3.90 (m, 2 H), 3.18 (dd, J 1 ) 12.5
Hz, J 2 ) 9.5 Hz, 1 H), 3.17 (s, 1 H), 2.59 (dd, J 1 ) 12.5 Hz, J 2
) 5 Hz, 1 H). Anal. Calcd for C12H13O3N5‚1/2H2O: C, 50.70;
H, 4.60; N, 24.65. Found: C, 50.41; H, 4.66; N, 24.48.
Ack n ow led gm en t. The Agence Nationale de Re-
cherches sur le Sida (ANRS) is gratefully acknowledged
for financial support. The authors are grateful to Dr.
A. De Cian and to Dr. J . Fischer for the X-ray experi-
ments (service commun de Rayons-X from our Univer-
sity) and to Dr. A. M. Aubertin for the anti-HIV
evaluation of our compounds (Institut de Virologie from
our University).
1-[3-C-Eth yn yl-3,5-O-(1,1,3,3-tetr a isop r op yld isiloxa n e-
1,3-diyl)-2-deoxy-â-D-er yth r o-p en tofu r a n osyl]u r a cil (15a ).
A degassed solution of Bu3SnH (83 µL, 0.31 mmol) and AIBN
(0.01 g, 0.08 mmol) in toluene (1 mL) under argon was added
with a syringe pump over a 4 h period to a degassed solution
of 12a (0.18 g, 0.28 mmol) in toluene (6 mL) under argon. After
evaporation of the solvent, the residue was filtered through a
short column of silica gel (ether). The resulting mixture of
products was further purified by C-18 HPLC (acetonitrile-
water 9:1) to give 15a (0.06 g, 40% yield). Alternatively, the
mixture of products was treated with Bu4NF in THF, and the
resulting crude product was chromatographed on analytical
TLC plates (silica gel: acetone-ethyl acetate 1:9) to furnish
the final compound 16a in a comparable yield: mp 163 °C; 1H
NMR (CDCl3, 400 MHz) δ 9.23 (s, 1 H), 7.54 (d, J ) 4 Hz, 1
H), 6.13 (dd, J 1 ) 8 Hz, J 2 ) 3 Hz, 1 H), 5.71 (d, J ) 4 Hz, 1
H), 4.36 (m, 1 H), 4.00 (m, 2 H), 2.82 (s, 1 H), 2.77 (m, 2 H),
1.08 (m, 28 H); 13C NMR (CDCl3, 100 MHz) δ 163.3, 150.3,
Su p p or tin g In for m a tion Ava ila ble: Ortep plot of one
molecule of 3a with the labeling scheme used. Experimental
details and spectroscopic characteristics of 5a , 5b, 6a , 6b and
of the intermediates for their preparation and of 7a , 8a , and
9a (7 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9704568