Synthesis of 2′,3′-dideoxy-6′,6′- difluorocarbocyclic nucleosides

Article abstract of DOI:10.1021/ol0482947

(Chemical Equation Presented) 2′,3′-Dideoxy-6′,6′- difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring v

Full text of DOI:10.1021/ol0482947

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4257-4259
Synthesis of
,3 -Dideoxy-6
Nucleosides
2′
′
′,6′-difluorocarbocyclic
Yan-Yan Yang,† Wei-Dong Meng,‡ and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and
College of Chemistry and Chemical Engineering, Donghua UniVersity,
1882 West Yanan Lu, Shanghai 200051, China
flq@mail.sioc.ac.cn
Received August 26, 2004
ABSTRACT
2
′ ′-Dideoxy-6′,6′-difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-
,3
1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring via ring-closing metathesis and the incorporation of gem-
difluoromethylene group by way of silicon-induced Reformatskii−Claisen reaction of chlorodifluoroacetic ester 3.
In recent years, attention has been increasingly focused on
structural modifications of carbocyclic nucleosides. Due to
the absence of a glycosidic linkage, carbocyclic nucleosides
are chemically more stable and not subject to the phos-
phorylases that cleave the N-glycosidic linkage in conven-
tional nucleosides. Many carbocyclic nucleosides have now
been identified to exhibit antiviral and antitumor activities.1,2
Abacavir (Figure 1) has been used as an anti-HIV agent.3
Entecavir, a carbocyclic nucleoside with an exocyclic double
bond, is undergoing phase III clinical trials for the treatment
of chronic hepatitis B virus infection.4 6′-Fluorocarbocyclic
nucleoside 1 exhibited moderate activities against herpes
simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro.5
The 2′,3′-dideoxynucleosides (ddNs) have been proved to
be the most effective therapeutic agents against human
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) For reviews, see: (a) Rodriguez, J. B.; Comin, M. J. Mini ReV. Med.
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Figure 1. Rationale for the design of the target nucleosides 2.
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Chemother. 2000, 44, 2052.
10.1021/ol0482947 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/21/2004

immunodeficiency virus (HIV) and hepatitis B virus (HBV).
Among them, dideoxyinosine (DDI) had been developed into
an anti-HIV drug.6 The gem-difluoromethylene (CF2) group
has been suggested by Blackburn as an isopolar and isosteric
substituent for oxygen.7 Since then, the CF2 group was used
extensively to modify nucleoside analogues. For example,
2′-deoxy-2′,2′-difluorocytidine (gemcitabine) has been ap-
proved as a drug for solid tumor treatment.8 On the basis of
the above consideration and our ongoing efforts to develop
new antiviral and anticancer agents, we designed the 2′,3′-
dideoxycarbocyclic nucleosides 2 (Figure 1), a new type of
analogue of DDI, by replacing the oxygen with difluoro-
methylene group (CF2) based on the bioisosteric rationale.
Herein, an efficient route to synthesize 2′,3′-dideoxycarbo-
cyclic nucleosides 2 is described.
The synthesis of the nucleosides 2 began with (Z)-2-
butene-1,4-diol (Scheme 2). Protection of one of its hydroxy
Scheme 2
As illustrated in Scheme 1, retrosynthetic analysis showed
that the target nucleosides could be synthesized from cyclic
Scheme 1
groups, follwed by esterification of another one with chloro-
difluoroacetic acid catalyzed by sulfonic acid, gave 3 in
multigram quantities.9,10 Then, 3 underwent a silicon-induced
Reformatskii-Claisen reaction11 when a mixture of 3,
chlorotrimethylsilane, and freshly activated zinc dust was
heated for 20 h in dry acetonitrile at 100 °C. The resulting
crude product was esterified with ethanol to give 4 in 84%
yield (two steps). Ester 4 was then transformed into Weinreb
amide 5 in 85% yield. Treatment of 5 with allylmagnesium
bromide resulted in successful conversion into the corre-
sponding â,γ-unsaturated ketone, which was transformed to
6 in 91% yield (two steps) by double-bond isomerization.
With compound 6 in hand, we turned our attention to the
ring-closing metathesis (RCM) of compound 6. Initially, the
RCM of 6 was carried out in the presence of the first-
generation Grubbs’ catalyst, and the reaction did not occur.
Fortunately, when compound 6 was subjected to the second-
generation Grubbs’catalyst12 in refluxing toluene, the reaction
resulted in complete conversion and compound 7 was isolated
in 98% yield. Ketone 7 was transformed to alcohols 8a and
8b via Luche reduction13 in a 2.9:1 cis/trans ratio, which
can be separated easily through column chromatography. The
relative configuration of 8a was confirmed by the structure
of 2a, which was identified by X-ray analysis.
amine 10, which could be used to introduce a base moiety
at the C1 position using a well-known procedure. However,
construction of the special backbone of 10, especially
introduction of gem-difluoromethylene to the C4 position of
10, is very difficult. Although DAST appears to be the most
common reagent for introduction of a gem-difluoromethylene
group, very few sterically hindered five-membered cyclic
ketones have been difluorinated by DAST. We envisioned
that compound 6 could be converted into 10 via ring-closing
metathesis. Compound 6 can be derived from chlorodi-
fluoroacetic ester 3 through Reformatskii-Claisen reaction.
(4) (a) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.;
Zahler, R.; Colonno, R. J. Antimicrob. Agents Chemother. 1997, 41, 1444.
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2525.
(5) Borthwick, A. D.; Kirk, B. E.; Biggadike, K.; Exall, A. M.; Butt, S.;
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Med. Chem. 1991, 34, 907.
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Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Brown, D.; Martin, S.
J. J. Chem. Res., Synop. 1985, 92. (c) Blackburn, G. M.; Eckstein, F.; Kent,
D. E.; Perree, T. D. Nucleosides Nucleotides 1985, 4, 165. (d) Blackburn,
G. M.; Kent, D. E. J. Chem. Soc., Perkin Trans. 1 1986, 913. (e) Blackburn,
G. M.; Peree, T. D.; Rashid, A.; Bisbal, C.; Lebleu, B. Chem. Scr. 1986,
26, 21. (f) Blackburn, G. M.; Brown, D.; Martin, S. J.; Parratt, M. J. J.
Chem. Soc., Perkin Trans. 1 1987, 181.
Hydrogenation of 8a with the catalyst of Pd/C in benzene
for 24 h gave compound 9a in 84% yield (Scheme 3).14
Treatment of alcohol 9a with trifluoromethanesulfonic
(9) Mark, J. K.; Owen, H. W. D. J. Org. Chem. 1985, 50, 5769.
(10) Jack, W. R.; Robert, E. L.; Glen, F. B. J. Am. Chem. Soc. 1963, 28,
3521.
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(12) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783. Also see: (b) Aburel, P. S.; Romming,
C.; Ma, K.; Undheim, K. J. Chem. Soc., Perkins Trans. 1 2001, 1458.
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411.
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Chem. 1988, 5, 3, 2406. (b) Hertel, L. W.; Boder, G. B.; Kroin, J. S.; Rinzel,
S. M.; Poore, G. A.; Todd, G. C.; Grindey, G. B. Cancer Res. 1990, 5, 0,
4417.
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Tetrahedron Lett. 2001, 42, 8323.
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Org. Lett., Vol. 6, No. 23, 2004

Scheme 3
Figure 2. ORTEP drawing of the X-ray crystallographic structure
of 2a.
anhydride and pyridine followed by substitution reaction with
sodium azide in DMF gave the azide compound, which was
directly reduced by hydrogenation to give cyclic amine 10a
in 56% yield (three steps). The construction of pyrimidine
was followed by the reported procedure.15 Condensation of
cyclic amine 10a with 3-ethoxy-2-propenoyl isocyanate in
DMF at -25 °C followed by ring closure with 2 N sulfuric
acid in dioxane successfully produced the nucleoside.
Removal of the benzyl group by hydrogenation gave the
target molecule 2a in 58% yield (three steps). The relative
configuration of racemic 2a was determined by X-ray crystal
structure (Figure 2). With the same synthetic route, isomer
2b was prepared from 8b.
Reformatskii-Claisen rearrangement and ring-closing me-
tathesis are the key steps of the synthesis. The flexibility in
our approach to access these novel nucleosides is noteworthy,
and we are currently investigating enantioselective synthesis
of 2′,3′-dideoxy-6′,6′-difluoro-carbocyclic nucleosides.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, Ministry of Education of China,
and Shanghai Municipal Scientific Committee for funding
this work.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
crystallographic data for compound 2a (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have completed a 14-step synthesis of
racemic 2′,3′-dideoxy-6′,6′-difluorocarbocyclic nucleoside 2a
in 7.6% overall yield and 2b in 1.5% overall yield.
(15) Ferna´ndez, F.; Garc´ıa-Mera, X.; Morales, M.; Rodr´ıguez-Borges,
J. E. Synthesis 2001, 2, 239.
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