A concise synthesis of 3′-α-fluoro-2′,3′-dideoxyguanosine (FddG) via 3′-α-selective fluorination of 8,2′-thioanhydronucleoside

Article abstract of DOI:10.1016/j.tetlet.2006.06.074

The antiviral nucleoside 3′-α-fluoro-2′,3′-dideoxyguanosine (FddG) was synthesized via 3′-α-selective fluorination of 8,2′-thioanhydronucleoside as the key step. Desulfurization of 3′-α-fluoro-3′-deoxy-8,2′-thioanhydronucleoside could be achieved by the treatment with Raney Ni in toluene. This method provides a concise route to 3′-α-fluoro-2′,3′-dideoxynucleosides that avoids the use of explosive and expensive SF₄-related fluorinating reagents.

Full text of DOI:10.1016/j.tetlet.2006.06.074

Tetrahedron Letters 47 (2006) 6139–6141
A concise synthesis of 30-a-fluoro-20,30-dideoxyguanosine
(FddG) via 30-a-selective fluorination of 8,20-thioanhydronucleoside
Takayoshi Torii,a Tomoyuki Onishi,a,* Kunisuke Izawaa and Tokumi Maruyamab
aAminoScience Laboratories, Ajinomoto Co., Inc. 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan
bFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido 1314-1, Sanuki-City,
Kagawa 769-2193, Japan
Received 19 May 2006; revised 5 June 2006; accepted 9 June 2006
Available online 10 July 2006
Abstract—The antiviral nucleoside 30-a-fluoro-20,30-dideoxyguanosine (FddG) was synthesized via 30-a-selective fluorination of 8,20-
thioanhydronucleoside as the key step. Desulfurization of 30-a-fluoro-30-deoxy-8,20-thioanhydronucleoside could be achieved by the
treatment with Raney Ni in toluene. This method provides a concise route to 30-a-fluoro-20,30-dideoxynucleosides that avoids the
use of explosive and expensive SF4-related fluorinating reagents.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
derivative via SN2 inversion suffered from the
generation of 30,40-didehydro-30-deoxy by-products by
trans-elimination, which reduced the yield of the desired
product.1a We report here a concise synthesis of FddG
(1) via 30-a-selective fluorination of 8,20-thioanhydronu-
cleoside, which can be easily prepared from guanosine
(2).
30-a-Fluoro-20,30-dideoxyguanosine (FddG) (1, Fig. 1) is
being developed as a reverse transcriptase inhibitor of
HIV for AIDS1 as well as a potential treatment for hep-
atitis B virus infection.2 We previously reported the syn-
thesis of FddG (1) from guanosine by a 6-step sequence
with bromine rearrangement during fluorination;3 how-
ever, this method required the use of explosive and
expensive SF4-related fluorinating reagents. Although
other methods for the synthesis of FddG (1) have been
reported, they also required SF4-related reagents for
fluorination1a,4,5 and/or rather lengthy reaction steps
to be performed on an industrial scale.6 Notably, con-
ventional 30-a-selective fluorination of 30-b-hydroxy
2. Results and discussion
In contemplating the synthesis of FddG (1), we consid-
ered that 30-a-selective fluorination of a 20-substituted
20-deoxyguanosine derivative could be achieved with
the assistance of the neighboring effect of a hetero atom
located at the 20-b-position. We previously reported that
the fluorination of both 30-b-bromo-30-deoxyadenosine
(3) and 20-b-bromo-20-deoxyadenosine derivatives (4)
with a SF4-related fluorinating agent, which is crucial
for the reaction, gave 30-a-fluorinated compound (5) as
a major product in a ratio of 7:1 (Scheme 1).7 We con-
cluded that selective fluorination of both regioisomers
might proceed via a common bromonium ion intermedi-
ate which is attacked by the fluoride anion from the
a-side of the 30-position. However, the regioselectivity
was not sufficient (2.8:1) in the case of guanine ana-
logues.3 These results prompted us to examine the
fluorination of 8,20-thioanhydronucleoside via a sulfo-
nium ion intermediate, since we anticipated that reten-
tive fluorination might proceed by means of sulfur
O
N
HN
N
H2N
HO
N
O
F
1
Figure 1. Structure of FddG 1.
Keywords: 30-a-Fluoro-20,30-dideoxyguanosine; Stereoselective fluori-
nation; Neighboring effect; Desulfurization.
Corresponding author. Tel.: +81 44 244 7163; fax: +81 44 211
7610; e-mail: tomoyuki_onishi@ajinomoto.com
*
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.074

6140
T. Torii et al. / Tetrahedron Letters 47 (2006) 6139–6141
conditions, in the reaction with NfF/Et3N, the desired
NH2
N
NH2
N
NH2
30-a-fluorinated product 9 was obtained in 63% yield
along with the elimination product 10.10 In this initial
attempt, the ratio of 9:10 was 4:1 and no generation of
20-a-fluorinated product was observed. After we opti-
mized the reaction conditions, we eventually found that
the yield could be improved to 91% by using an excess
amount of NfF in the presence of i-Pr2NEt as a base.11
N
N
N
N
N
N
N
N
N
DAST
DAST
+
N
O
O
O
AcO
AcO
AcO
Br
Br
Br
OH
F
5
F
3
6
6
5:6 = 7:1
NH2
N
N
N
Next, we investigated the reductive desulfurization of
30-a-fluoro-30-deoxy-8,20-thioanhydronucleoside 9. First,
we attempted the desulfurization of 8,20-anhydro-30-a-
fluoro-8-mercapto-30-deoxyguanosine, which can be ob-
tained by treatment of 9 with acetic acid; however, the
reaction with Raney Ni in aq NaOH only gave 20,30-
dideoxyguanosine (ddG). No generation of the desired
FddG (1) was observed in the above reaction. We sus-
pected that fluorine atom might be eliminated by the
nucleophilic attack of the sulfur atom under these highly
basic conditions to give the sulfonium ion again, which
subsequently affords ddG by the reduction with Raney
Ni. Accordingly, we tried to achieve desulfurization of
compound 9 prior to deprotection with the acid. The
reaction of 9 with Raney Ni in EtOH gave a small
amount of the desired Tr2–FddG (11)12 along with
Tr2–ddG (12) as a major product in a ratio of 1:4. The
reaction had to be performed in the presence of Et3N
to avoid the unfavorable removal of trityl groups under
the above reaction conditions. To our delight, when we
used toluene as a solvent in the presence of Et3N,
the preferential formation of Tr2–FddG (11) versus
Tr2–ddG (12) was observed. Eventually, we discovered
that the desulfurization of compound 9 with Raney Ni
in toluene without any additives gave the best ratio of
11:12 (6:1). The use of aprotic solvent such as toluene
may contribute to suppress the unfavorable removal of
trityl groups even in the absence of a base. The desired
+
5
N
O
AcO
Br
5:6 = 7:1
HO
4
Scheme 1. Fluorination of 3 and 4.
facilitating the attack of the fluoride ion8 to the 30a
rather than the 20a position due to possible steric
requirements. In addition, with the assistance of the
neighboring effect of the sulfur atom, elimination might
be suppressed to allow the use of a non-SF4-related
reagent such as perfluorobutanesulfonyl fluoride (NfF)
for fluorination in the presence of a base. If 30-a-selec-
tive fluorination could be accomplished, the sulfur atom
would be removed by treatment with Raney Ni. We
report here a successful realization of this strategy.
0
First, we investigated the fluorination of N2,O5 -ditrityl-
protected compound 8 (Scheme 2). Compound 8 could
be obtained in 60% yield by treatment of 8,20-anhy-
dro-8-mercaptoguanosine (7), which can be easily pre-
pared from guanosine (2) in 3 steps,9 with trityl
chloride in the presence of Et3N. Although the reaction
of 8 with DAST gave a complex mixture due to the
unstable nature of the trityl groups under these reaction
O
O
N
N
N
NfF
TrCl
NH
NH
N NHTr
3 steps
69%
S
S
iPr2NEt
NEt3
Guanosine
N
N
NH2
O
O
2
AcOEt
65 °C
20 h
DMF
40 °C
2 h
HO
TrO
HO
HO
60%
91%
7
8
O
O
O
NfO
S
N
NH
NHTr
N
N
N
HN
NH
S
Raney-Ni
N
N
N
O
O
TrHN
TrO
N
F
N
NHTr
O
TrO
toluene
90 °C
14 h
61%
TrO
F
F
9
11
O
O
O
N
N
N
N
80%
HN
H2N
HN
NH
NHTr
S
AcOH aq
N
N
N
N
F
TrHN
TrO
N
O
O
O
80 °C
2 h
TrO
HO
69%
10
12
FddG, 1
Scheme 2. Synthesis of FddG 1.

T. Torii et al. / Tetrahedron Letters 47 (2006) 6139–6141
6141
Jeong, L. S.; Nicklaus, M. C.; George, C.; Marquez, V. E.
Tetrahedron Lett. 1994, 35, 7569.
product 11 could be isolated in 61% yield after column
chromatography. Finally, the Tr2–FddG (11) obtained
was allowed to be deprotected under acidic conditions
to give FddG (1)13 in 69% yield.
9. (a) Kaneko, M.; Shimizu, B. Chem. Pharm. Bull. 1972, 20,
635; (b) Ogilvie, K. K.; Slotin, L.; Westmore, J. B.; Lin, D.
Can. J. Chem. 1972, 50, 2249.
10. The 1H NMR spectrum of 9 shows a C30 proton at d 5.29
In summary, a concise synthesis of FddG (1) using the
30-a-selective fluorination of 8,20-thioanhydronucleoside
8 has been achieved. This synthetic method using reten-
tive fluorination at the C30 position has the advantage of
providing FddG (1) in high yields with a safer fluorina-
tion agent, NfF. Further studies are now in progress.
0
with a large geminal coupling constant ðJ3 -F ¼ 52:1 HzÞ,
indicating that a fluorine atom is attached to C30, not C20.
This is also supported by vicinal coupling constants of
H20-F ðJ2 -F ¼ 20:4 HzÞ and H40-F ðJ4 -F ¼ 22:9 HzÞ.
0
0
0
0
0
0
Since the vicinal coupling constants for J2 –3 and J3 –4
are almost 0 Hz, the C30 proton should be in the b
configuration, and, therefore the fluorine atom at the C30
position should be in the a configuration.
11. Experimental procedure and characterization data: To a
solution of 8 (78.2 mg, 0.1 mmol) in AcOEt (2 mL) was
added NfF (0.224 mL, 1.2 mmol) and i-Pr2NEt (0.216 mL,
1.2 mmol), and the mixture was stirred for 20 h at 65 ꢁC.
After the mixture was cooled to room temperature, AcOEt
(5 mL) and H2O (2 mL) were added and the mixture was
separated. The organic layer was dried over MgSO4. After
the filtrate was concentrated under reduced pressure, the
residue was purified by silica gel column chromatography
(32:1 CH2Cl2–CH3OH) to give 9 (71.8 mg, 91%) as
colorless crystals. Mp 201–203 ꢁC; 1H NMR (400 MHz,
CDCl3) d 3.03–3.09 (1H, m, H-50), 3.18–3.23 (1H, m, H-
50), 4.60 (1H, dt, J = 22.9, 6.9 Hz, H-40), 4.83 (1H, dd,
J = 20.4, 6.5 Hz, H-20), 5.29 (1H, d, J = 52.1 Hz, H-30),
6.34 (1H, d, J = 6.5 Hz, H-10), 6.43 (1H, br, NH), 7.05–
7.40 (31H, m, aromatic and NH); 13C NMR (100 MHz,
CDCl3) d 58.7 (J = 24 Hz), 62.4 (J = 10 Hz), 71.0, 73.3,
85.8 (J = 24 Hz), 87.0, 97.7 (J = 187 Hz), 123.0, 127.3,
127.9, 128.3, 128.4, 128.5, 128.6, 143.0, 143.2, 143.6, 146.8,
150.0, 151.4; HRMS (FAB+) calcd for C48H39FN5O3S
(MH+), 784.2758, found 784.2765.
Acknowledgements
We thank Mr. Daisuke Takahashi for his technical
assistance.
References and notes
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CDCl3) d 2.00–2.30 (2H, m, H-20), 3.20–3.30 (2H, m, H-
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J = 54.7 Hz, H-30), 5.57–5.62 (1H, m, H-10), 7.15–7.45
(33H, m, aromatic, H-8 and NH · 2); 13C NMR
(100 MHz, CDCl3) d 38.7 (J = 30 Hz), 63.3 (J = 9 Hz),
71.1, 81.8, 83.7 (J = 18 Hz), 87.1, 94.1 (J = 177 Hz), 125.1,
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4.9 Hz, H-40), 5.15 (1H, d, J = 5.4 Hz, OH), 5.38 (1H, dd,
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