Stereocontrolled de novo synthesis of β-2'-deoxyribonucleosides

Full text of DOI:10.1021/jo960936j

6092
J . Org. Chem. 1996, 61, 6092-6093
Sch em e 1
Ster eocon tr olled d e Novo Syn th esis of
â-2′-Deoxyr ibon u cleosid es
Minnie Park and Carmelo J . Rizzo*
Department of Chemistry, Box 1822, Station B,
Vanderbilt University, Nashville, Tennessee 37235
Received May 21, 1996
General and convenient methods for the synthesis of
nucleosides are of obvious interest. Nucleosides and
nucleoside analogs have long been an important class of
medicinal agents, possessing anticancer and antiviral
activity.1 Recent interest in antiviral nucleosides has
centered around the development of reverse transcriptase
inhibitors as potential AIDS therapies.2 Modified nucleo-
sides have also played a central role in the development
of genetic therapies such as triplex (antigene) and anti-
sense strategies.3
Sch em e 2
The Vorbru¨ggen glycosidation involving the reaction
of ribose tetraacetate (or benzoate) with the appropriate
silylated base under Lewis acid conditions has been used
for the synthesis of nucleosides for over three decades.4
Participation of the neighboring 2′-ester group directs the
glycosidation exclusively from the desired â-face. In the
absence of a directing 2′-group, mixtures of anomers
result which are often difficult to separate.2 If â-2′-
deoxynucleosides are desired, the 2′-hydroxyl is selec-
tively deoxygenated by simultaneous protection of the 5′-
and 3′-hydroxyl groups with an expensive bifunctional
silylating reagent, 1,3-dichloro-1,1,3,3-tetraisopropyl-
disiloxane.5 Derivatization of the 2′-hydroxyl group, tin
hydride mediated deoxygenation and deprotection, pro-
vides the desired 2′-deoxynucleoside.6
Sch em e 3
We are interested in developing more efficient methods
for the deoxygenation of ribonucleosides which would
involve minimum use of protecting groups, thus making
the procedure simpler and more economical. This would
provide a valuable method for the synthesis of natural
and unnatural 2′-deoxynucleosides of biomedical interest.
Our synthetic strategy for the de novo synthesis of 2′-
deoxynucleosides is outlined in Scheme 1. We wished
to prepare a glycosidation precursor in which the 2-O-
ester of ribose is differentiated. The 2-O-ester group
should be capable of directing the glycosidation reaction
as well as be suitable as a precursor for deoxygenation.
We utilized a m-trifluoromethylbenzoyl group as this
directing/deoxygenation precursor. A similar strategy
was employed previously by Benner for the synthesis of
potential antisense nucleosides with modified backbones.7
R-1,3,5-Tribenzoylribose (1) is an ideal starting mate-
rial, since it is differentiated at the 2-position.8 Reaction
of commercially available 1 with m-trifluoromethylben-
zoyl chloride and 2,6-lutidine gave the m-trifluorometh-
ylbenzoate derivative 2 in 97% yield after recrystalliza-
tion (Scheme 2).9 The use of a hindered base is necessary
to prevent migration of the benzoates in 1, consistent
with previous reports.8b We have studied the Vorbru¨ggen
glycosidation of 2 with the five pyrimidine bases shown
in Table 1. Entries a-d utilized silylated uracil deriva-
tives, while entry e used a protected cytosine. In all
cases, glycosidation gave only the desired â-anomer in
greater than 90% yield using either tin tetrachloride or
trimethylsilyl triflate in acetonitrile.
(1) (a) Nucleosides & Nucleotides as Antitumor and Antiviral Agents;
Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993. (b)
Heidelberger, C. Prog. Nucleic Acid Res. Mol. Biol. 1965, 4, 1.
(2) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745. (b)
Wilson, L. W.; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. C. Synthesis
1995, 1465. (c) Hunziker, J .; Leumann, C. Modern Synthetic Methods
1995; Ernst, B., Leumann, C., Eds.; VCH: Basel, Switzerland, 1995;
pp 333-417.
(3) (a) Antisense Research and Applications; Cooke, S. T., Lebleu,
B., Eds.; CRC Press: Boca Raton, FL, 1993. (b) Milligan, J . F.;
Matteucci, M. D.; Martin, J . C. J . Med. Chem. 1993, 36, 1923. (c)
Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543. (d) Bischofberger,
N.; Shea, R. G. Nucleic Acid Targeted Drug Design; Propst, C. L.,
Perun, T. J ., Eds.; Marcel Dekker: New York, 1992; pp 579-612. (e)
Varma, R. S. Synlett 1993, 713. (f) Cohen, J . S.; Hogan, M. E. Sci. Am.
1994, (December issue), 76. (g) DeMesmaeker, A.; Haner, R.; Martin,
P.; Moser, H. E. Acc. Chem. Res. 1995, 28, 366.
Saito showed that benzoyl and m-trifluoromethylben-
zoyl derivatives of secondary alcohols undergo photosen-
sitized electron-transfer deoxygenation with N-methyl-
carbazole (MCZ) as the photosensitizer.10 This processes
(7) Huang, Z.; Schneider, K. C.; Benner, S. A. J . Org. Chem. 1991,
56, 3869.
(8) (a) Brodfuehrer, P. R.; Sapino, C.; Howell, H. G. J . Org. Chem.
1985, 50, 2597. (b) Chavis, C.; Dumont, F.; Wightman, R. H.; Ziegler,
J . C.; Imbach, J . L. J . Org. Chem. 1982, 47, 202.
(9) Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J . Org. Chem.
1993, 58, 1083.
(4) Vorbru¨ggen, H. Acc. Chem. Res. 1995, 28, 509.
(5) (a) Markiewicz, W. T. J . Chem. Res., Synop. 1979, 24. (b) Wada,
T.; Tobe, M.; Naagayama, T.; Furusawa, K.; Sekine, M. Tetrahedron
Lett. 1995, 36, 1683.
(6) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc. 1985,
107, 4059.
(10) Saito, I.; Ikehira, H.; Kasatani, R.; Watanabe, M.; Matsuura,
T. J . Am. Chem. Soc. 1986, 108, 3115.
S0022-3263(96)00936-X CCC: $12.00 © 1996 American Chemical Society

Communications
Ta ble 1. Yield s for th e Gycosid a tion of 2 a n d
J . Org. Chem., Vol. 61, No. 18, 1996 6093
mM magnesium perchlorate and 1 equiv of photosensi-
tizer. The deoxygenated products 4a -e were isolated in
44-73% yield.10 Of particular interest are entries c and
d which resulted in stereocontrolled syntheses of the
anticancer nucleosides 5-fluoro-2′-deoxyuridine and 5-tri-
fluoromethyl-2′-deoxyuridine (trifluridine).1b The struc-
tures of protected 2′-deoxynucleosides 4a -e were con-
firmed by comparison to authentic samples prepared via
benzoylation of commercially available 2′-deoxynucleo-
sides; deprotection of these compounds to the parent
nucleosides is well established.
Deoxygen a tion of 3
In conclusion, we have developed a short, de novo
synthesis of 2′-deoxynucleosides. The stereochemistry of
the Vorbru¨ggen glycosidation is controlled by a 2-O-m-
trifluoromethylbenzoyl directing group on the ribose unit
2. After the stereocontrolled glycosidation, the m-tri-
fluoromethylbenzoyl group is selectively deoxygenated
via a photosensitized, electron-transfer mechanism. The
overall sequence required just four steps from a com-
mercially available starting material (1) and proceeded
in high overall yield. An advantage of the photodeoxy-
genation over traditional tin hydride based radical
deoxygenations is that toxic tin reagents and byproducts
are avoided.
While pyrimidines undergo stereocontrolled Vorbru¨ggen
glycosidation to give a single product, it is well-known
that purines give regioisomers resulting from gycosida-
tion at N-7 and N-9, the ratio of which is highly
dependent upon the reaction conditions.11 We are cur-
rently investigating the applicability of our sequence to
the synthesis of â-2′-deoxypurines with particular atten-
tion to improving the regiochemistry of Vorbru¨ggen
glycosidation of 2. We are also interested in synthesizing
unnatural 2′-deoxynucleosides of clinical interest as well
as potential antisense nucleosides. A full account of this
work will be reported in due time.
involves an electron transfer from the excited state of
MCZ to the m-trifluoromethylbenzoate (Scheme 3). Pro-
tonation of the radical anion gives radical 7, which
undergoes fragmentation and hydrogen atom abstraction
to give the deoxygenated product. Our examples (3)
possess a benzoate and m-trifluoromethylbenzoate which
are both secondary; while to our knowledge this is the
first example of a direct competition between the two
groups, it has been previously demonstrated that m-
trifluoromethylbenzoates are deoxygenated faster under
these conditions.10 The photolysis of 3 was carried out
through Pyrex using a 450-W medium-pressure mercury
lamp in degassed 9:1 2-propanol/water at 25 °C with 1.4
Ack n ow led gm en t. This work was supported by
Grant DHP-172 from the American Cancer Society.
C.J .R. thanks the American Cancer Society for a J unior
Faculty Research Award.
Su p p or tin g In for m a tion Ava ila ble: Typical experimen-
tal procedures for the preparation of 2-4 and copies of their
1H and 13C NMR spectra (25 pages).
J O960936J
(11) Dudycz, L. W.; Wright, G. E. Nucleosides Nucleotides 1984, 3,
33.