Synthesis of 9-(2,3-dideoxy-2,3-difluoro-β-D-arabinofuranosyl)adenine

Article abstract of DOI:10.1080/15257770701534063

Convergent synthesis of 9-(2,3-dideoxy-2,3-difluoro-β-D- arabinofuranosyl)adenine is described starting from methyl 5-O-benzyl-2-deoxy-2- fluoro-α-D-arabinofuranoside. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701534063

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Synthesis of 9-(2,3-Dideoxy-2,3-
Difluoro-β-D- Arabinofuranosyl)Adenine
Grigorii G. Sivets a , Elena N. Kalinichenko a & Igor A. Mikhailopulo a
b
a Institute of Bioorganic Chemistry, National Academy of Sciences ,
Minsk, Belarus
b Department of Pharmaceutical Chemistry, University of Kuopio ,
Kuopio, Finland
Published online: 05 Dec 2007.
To cite this article: Grigorii G. Sivets , Elena N. Kalinichenko & Igor A. Mikhailopulo (2007) Synthesis
of 9-(2,3-Dideoxy-2,3-Difluoro-β-D- Arabinofuranosyl)Adenine, Nucleosides, Nucleotides and Nucleic
Acids, 26:10-12, 1387-1389, DOI: 10.1080/15257770701534063
To link to this article: http://dx.doi.org/10.1080/15257770701534063
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1387–1389, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701534063
SYNTHESIS OF 9-(2,3-DIDEOXY-2,3-DIFLUORO-β-D-
ARABINOFURANOSYL)ADENINE
Grigorii G. Sivets and Elena N. Kalinichenko
Institute of Bioorganic Chemistry,
2
National Academy of Sciences, Minsk, Belarus
Igor A. Mikhailopulo
Department of Pharmaceutical Chemistry, University of
2
Kuopio, Kuopio, Finland and Institute of Bioorganic Chemistry, National Academy of
Sciences, Minsk, Belarus
Convergent synthesis of 9-(2,3-dideoxy-2,3-difluoro-β-D-arabinofuranosyl)adenine is described
2
starting from methyl 5-O-benzyl-2-deoxy-2-fluoro-α-D-arabinofuranoside.
Keywords Dideoxydifluoro nucleosides; purine; convergent synthesis
INTRODUCTION
The replacement of the hydroxyl group in the sugar moiety of nucle-
osides with a fluorine atom results in nucleoside analogues which have in-
teresting stereoelectronic properties and biological activities. Due to their
broad chemotherapeutic potential, 2ꢁ-β-fluoro nucleosides have been ex-
tensively investigated in recent years.[1] In continuation of our research on
the synthesis of purine 2ꢁ-fluoroarabinonucleosides,[2] we presently report
the synthesis of the adenine nucleoside 9 containing two fluorine atoms in
β-D-arabino-configuration by condensation of the nucleobase and sugar.
RESULTS AND DISCUSSION
We investigated a synthetic route to target nucleoside 9 from methyl
5-O-benzyl-2-deoxy-2-fluoro-α-D-arabinofuranoside (1) that was prepared
by the known method starting from D-xylose.[3] Oxidation of 1 followed
by reduction of intermediate 3-keto derivative gave rise to lyxoside 2 in
This work was supported from Belarus State Program of FOI “Physiological Active Compounds”
(Grant 2.04).
Address correspondence to G. G. Sivets, Laboratory of Nucleotides and Polynucleotides, Institute
of Bioorganic Chemistry, National Academy of Sciences, 220141 Minsk, Acad. Kuprevicha 5/2, Belarus.
E-mail: gsivets@yahoo.com
1387

1388
G. G. Sivets et al.
SCHEME 1 Reagents and conditions: a,b) Ref.[4]; (ꢀ22%); c) DAST, toluene, rt, 20 hours (45%;
42% of starting 2 was recovered); d) [H]/10% Pd/C, EtOH, rt; e) BzCl/Py, rt (d + e, ꢀ90%); f)
AcOH/Ac2O/concn. H2SO4 (23:6:1, vol), 0◦C, 30 minutes; 4◦C, 18 hours (77%); g) TMS-Br/CDCl3,
3 weeks, 15-16◦C; hours) 4/silylated N6BzAde/SnCl4/MeCN, reflux, 5 hours (7, 9%; 8, 42%; calculated
for consumed methyl glycoside 4, 72% of which was recovered as a mixture of β- and α-anomers); i)
6/Na-salt of N6BzAde/THF, reflux, 5 hours (7, 22%; 8, 3%); k) saturated NH3/MeOH, rt (9, 88%; 10,
81%).
22% isolated yield.[4] Fluorination of the latter with DAST in toluene
at room temperature afforded methyl 5-O-benzyl-2,3-dideoxy-2,3-difluoro-
α-D-arabinofuranoside (3). Using two conventional steps, benzoate 4 was
prepared from 3. The condensation of difluoride 4 with persilylated N6-
benzoyladenine in presence of SnCl4 in acetonitrile resulted in a mixture of
β- and α-nucleosides 7 and 8 (ca. 1:5 according to the 1H NMR data) which
was separated into individual anomers by column chromatography on silica
gel (Scheme 1). It may be noted that α-methyl arabinoside 4 showed signif-
icantly lower reactivity versus the ribo isomer[5] in the glycosylation reaction
of persilylated N 6-benzoyladenine and was mainly recovered from the reac-
tion by column chromatography as a mixture of α- and β-methyl glycosides.
Moreover, we have not detected by TLC the formation of N 7-glycosides that
may be explained by the use of excess SnCl4 in the reaction in order to
minimize their formation (cf., refs.[4,5] and refs. cited therein).
The low yield of desired nucleoside 7 prompted us to study another
approach (Scheme 1). Acetolysis of 4 gave a mixture of acetates 5 after
chromatography on silica gel. Bromination of 5 under mild conditions
(TMSiBr/CDCl3)[6] generated intermediate glycosyl bromide 6 that was re-
acted with the sodium salt of N6-benzoyladenine in tetrahydrofuran[7] to

2ꢁ,3ꢁ-Dideoxy-2ꢁ,3ꢁ-Difluoro-ara-A
1389
afford a mixture of β- and α-nucleosides 7 and 8 (ca. 7:1 according to the 1H
NMR data), the β-nucleoside 7 being the main product which was isolated
by chromatography in moderate yield (22%). TLC of the reaction mixture
displays some additional spots of lower intensity compared to that of nucle-
osides 7 and 8 but the corresponding compounds have not been isolated
(cf. ref.[7]).
Standard deprotection of individual blocked nucleosides 7 and 8 with
methanolic ammonia gave pure amorphous 9-(2,3-dideoxy-2,3-difluoro-β-
D-arabinofuranosyl)adenine (9) and its α-anomer 10, respectively. Thus,
we have complemented a set of known 2ꢁ,3ꢁ-dideoxy-2ꢁ,3ꢁ-difluoro-β-D-
arabinofuranosyl pyrimidine nucleosides[8] with the first purine nucleoside
of this class.
The structure of all compounds was verified by 1H[9] and 13C NMR spec-
troscopy, and by UV and mass spectroscopy in the case of nucleosides 9 and
10.
REFERENCES
1. Pankiewicz, K.W. Fluorinated nucleosides. Carbohydr. Res. 2000, 327, 87–105.
2. Sivets, G.G.; Kalinichenko, E.N.; Mikhailopulo, I.A. Synthesis of C2ꢁ-β-fluoro-substituted adenine nu-
cleosides via pivaloyl derivatives of adenosine and 3ꢁ-deoxyadenosine. Letters Org. Chem. 2006, 5, 402–
408.
3. Wright, J.A.; Taylor, N.F.; Fox, J.J. Nucleosides. LX. Fluorocarbohydrates. XXII. Synthesis of 2-deoxy-
2-fluoro-D-arabinose and 9-(2-deoxy-2-fluoro-α- and β-arabinofuranosyl)adenines. J. Org. Chem. 1969,
34, 2632–2636.
4. Mikhailopulo, I.A.; Sivets, G.G.; Poopeiko, N.E.; Khripach, N.B. Oxidation-reduction sequence for
the synthesis of peracylated fluorodeoxy pentofuranosides. Carbohydr. Res. 1995, 278, 71–89.
5. Mikhailopulo, I.A.; Pricota, T.I.; Sivets, G.G.; Altona, C. 2ꢁ-Chloro-2ꢁ,3ꢁ-dideoxy-3ꢁ-fluoro-D-
ribofuranosides: Synthesis, stereospecificity, some chemical transformations, and conformational
analysis. J. Org. Chem. 2003, 68, 5897–5908.
6. Gillard, J.W.; Israel, M. Trimethylsilyl bromide as a mild, stereoselective anomeric brominating agent.
Tetrahedron Lett. 1981, 22, 513–516.
7. Jin, F.; Wang, D.; Confalone, P.N.; Pierce, M.E.; Wang, Z.; Xu, G.; Choudhury, A.; Nguyen,
D. (2R,3S,5S)-2-Acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran: A key intermediate for the
practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranofuranosyl)adenine (FddA). Tetra-
hedron Lett. 2001, 42, 4787–4789.
8. Martin, J.A.; Busnell, D.J.; Duncan, I.B.; Dunsdon, S.J.; Hall, M.J.; Machin, P.J.; Merret, J.H.; Parkes,
K.E.B.; Roberts, N.A.; Thomas, G.J.; Galpin, S.A.; Kinchington, D. Synthesis and antiviral activity of
monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunod-
eficiency virus (HIV-1). J. Med. Chem. 1990, 33, 2137–2145.
9. 1H NMR (CD3OD; δTMS, ppm; J, Hz); compound 9–8.30 (d, 1H, J8,2 F = 2.3; H-8); 8.21 (s, 1H; H-2);
ꢁ
4
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
6.53 (ddd, 1H, J1 ,2 = 3.97; J1 ,2 F = 17.67; J1 ,3 F = 1.86; H-1’); 5.50 (dddd, 1H, J2 ,3 = 2.17; J2 ,3 F
gem
gem
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J
= 12.82;
J
= 50.52; H-2’); 5.46 (dddd, 1H, J3 ,4 = 3.76; J3 ,2 F = 15.29;
J
= 51.24; H-
2 ,2 F
3 ,3 F
gem
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
3’); 4.30 (dm, 1H, J4 ,5 = 4.27; J4 ,5 = 4.85; J4 ,3 ,F = 24.80; H-4’); 3.89 (ddd, 1H,
= 12.80;
5 ,5
ꢁ
ꢁ
ꢁ
J5 ,3 F (2 F) ≈ 1.0; H-5’); 3.85 (m, 1H; H-5”). Compound 10: 8.40 & 8.39 (2s, 2H; H-8 & H-2); 6.53 (dd,
gem
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
1H, J1 ,2 = 2.42; J1 ,2 F = 15.90; H-1’); 6.04 (ddt, 1H, J2 ,3 = 2.74; J2 ,3 F = 14.00;
J
= 49.70;
2 ,2 F
gem
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-2’); 5.47 (dddd, 1H, J3 ,4 = 3.90; J3 ,2 F = 15.90;
J
= 51.70; H-3’); 4.81 (ddt 1H, J4 ,5
=
3 ,3 F
gem
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
5.04; J4 ,5 = 4.98; J4 ,3 ,F = 21.16; H-4’); 3.83 (dd, 1H,
J
= 12.85; H-5’); 3.79 (ddd, 1H; J5 ,3 F
5 ,5
= 1.15; H-5”).