Synthesis study of 3′-α-fluoro-2′,3′- dideoxyguanosine

Article abstract of DOI:10.1081/NCN-200060053

A synthetic method was established for 3′-α-fluoro-2′, 3′-dideoxyguanosine 1 from guanosine 2 in 27% overall yield and 6 steps. A byproduct 6a of fluorination was identified by NMR studies, its presence strongly supporting our supposition that the fluorination itself proceeded via a bromonium cation. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200060053

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SYNTHETIC STUDY OF 3′-α-FLUORO-2′,3′-
DIDEOXYGUANOSINE
Takayoshi Torii a , Tomoyuki Onishi a , Shigehisa Tanji a & Kunisuke Izawa a
a AminoScience Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan
Version of record first published: 15 Nov 2011.
To cite this article: Takayoshi Torii , Tomoyuki Onishi , Shigehisa Tanji & Kunisuke Izawa (2005): SYNTHETIC STUDY OF 3′-α-
FLUORO-2′,3′-DIDEOXYGUANOSINE, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 1051-1054
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):1051–1054, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060053
SYNTHESIS STUDY OF 3’-a-FLUORO-2’,3’-DIDEOXYGUANOSINE
Takayoshi Torii, Tomoyuki Onishi, Shigehisa Tanji, and Kunisuke Izawa
5
AminoScience Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan
5
A synthetic method was established for 3’-a-fluoro-2’,3’-dideoxyguanosine 1 from guanosine 2
in 27% overall yield and 6 steps. A byproduct 6a of fluorination was identified by NMR
studies, its presence strongly supporting our supposition that the fluorination itself proceeded via a
bromonium cation.
Keywords 3’-a-Fluoro-2’,3’-dideoxyguanosine
INTRODUCTION
3’-a-Fluoro-2’,3’-dideoxyguanosine 1 is now being developed as a reverse
transcriptase inhibitor for HIV as well as a potential treatment for hepatitis B
virus.[1,2] There have only been a few reports describing the preparation of 1,[3–6]
(notably that by Herdewijn’s group) probably because guanosine derivatives are
normally difficult to synthesize and also because of the necessity of introducing a
fluorine atom with appropriate stereo- and regioselectivity. Previously, we reported
a synthetic method for a 3’-a-fluorinated 2’,3’-dideoxyadenosine derivative in-
volving a novel rearrangement.[7,8] We wish to disclose herein that the same
method can be applied to the synthesis of 1.
RESULTS AND DISCUSSION
N2,5’-O-Diacetyl-3’-b-bromo-3’-deoxyguanosine 4a was synthesized by the
selective 2’-O deacetylation of N2,2’,5’-O-triacetyl-3’-b-bromo-3’-deoxyguanosine 3
in 77% yield—this was easily prepared from guanosine.[9,10] The 3’-a-fluorinated
compound 5a was successfully obtained by treating 4a with DAST* in 59% yield.
The reaction proceeded via a rearrangement of the bromine atom from the 3’-b to
We wish to thank Mr. Paul Goddard for assistance in proofreading the manuscript.
*A similar result was obtained when MOST was used as the fluorinating reagent. The yield of 5a was 58%,
the ratio of 5a/6a was 2.7.
Address correspondence to Kunisuke Izawa, AminoScience Laboratories, Ajinomoto Co., Inc., 1-1, Suzuki-
cho, Kawasaki-ku, Kawasaki 210-8681, Japan; E-mail: kunisuke_izawa@ajinomoto.com
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T. Torii et al.
SCHEME 1 Synthesis of 3’-a-fluoro-2’,3’-dideoxyguanosine 1.
the 2’-b position, 3’-a fluorination taking place simultaneously.[7,8] In this reaction,
the 2’-a fluorinated compounds 6a and 7 were also obtained as byproducts,
although these were not observed in the case of adenosine. The ratio of 5a/6a
was 2.8.
1
We identified the structure of byproduct 6a by NMR-study.y The H-NMR
spectrum of 6a shows a C2’ proton at d = 5.56 with a large geminal coupling
constant (J2’-F = 50.3 Hz), indicating that a fluorine atom is attached to C2’. This is
also supported by a vicinal coupling constant of H1’-F (J1’-F = 21.3 Hz). Since the
1H-NMR spectrum does not show long-range coupling between H-8 and the C2’
fluorine, the fluorine should be in the a configuration.[11] The generation of 6a as a
result of the fluorination of 4a strongly supported our supposition that the
fluorination itself proceeded via a bromonium cation[7,8] and fluoride attack at C3’
or C2’ from the a side.
In the case of 4b, which is the N-deacetylated compound of 4a, the ratio of
fluorination at C3’/C2’ was improved from 2.8 to 4.1. Variations in C3’/C2’ ratio
were nucleic base dependent between N-acetylguanine, guanine, and adenine.
Although the reason for this is not clear, we may speculate it is related to the
electronic properties of each respective base.
yH NMR (400 MHz, DMSO-d6) of 6a: d 11.79 (1H, s), 8.15 (1H, s, H-8), 6.04 (1H, d, J = 21.3 Hz, H-1’), 5.56
(1H, d, J = 50.3 Hz, H-2’), 4.64–4.45 (4H, m, H-3’, 4’, 5’), 2.20 (3H, s, NAc), 2.08 (3H, s, OAc).

T. Torii et al.
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SCHEME 2 Putative fluorination mechanism.
SCHEME 3 Fluorination of 4b.
The structure of byproduct 7 was identified by NMR-studyz as an N3-C2’
cyclized compound. The yield of 7 was less than 10%. Similar cyclizations have
already been reported by several groups,[11,12] one, in particular, describing an N3
attack of the aglycon on the C2’ of an adenosine derivative.[13] We considered that
7 was formed in a similar manner to that reported by Herdewijn et al.[11] We note
with interest, however, that no such cyclized product was observed in the case of
the adenosine derivative.[7,8]
5a was isolated by chromatography. The debromination of 5a proceeded by
means of radical reduction, using hypophosphorus acid and triethylamine,[14,15] to
give N2,5’-O-diacetyl-3’-a-fluoro-2’,3’-dideoxyguanosine 8 in 98% yield. Acetyl
groups were deprotected using ammonia-methanol to obtain the target nucleoside
1 in 82% yield. Structural confirmation was obtained by a comparison with
analytical data.[3–6]
In conclusion, we established a synthetic method for 1 from 2 in 27% overall
yield in 6 steps. To the best of our knowledge, this is the highest overall yield of 1
starting from guanosine that has yet been reported.
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zH NMR (400 MHz, DMSO-d6) of 7: d 8.13 (1H, s, H-8), 6.56 (1H, d, J = 3.9 Hz, H-1’), 5.68 (1H, t, J = 3.6
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J = 12.5, 4.8 Hz, H-5’b), 2.15 (3H, s, NAc), 1.76 (3H, s, OAc).

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