Practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) via a purine 3′-deoxynucleoside

Article abstract of DOI:10.1016/S0040-4039(01)00136-8

A practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-9-(3-deoxy-β-D-erythro-pentofuranosyl)-9H-purine (6) is described. Fluorination at the C2′-β position of the purine 3′-deoxynucleoside was improved

Full text of DOI:10.1016/S0040-4039(01)00136-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2325–2328
Practical synthesis of
9-(2,3-dideoxy-2-fluoro-b- -threo-pentofuranosyl)adenine (FddA)
D
via a purine 3%-deoxynucleoside
Satoshi Takamatsu,a Tokumi Maruyama,b Satoshi Katayama,a Naoko Hirose,a Masaki Naitoa and
Kunisuke Izawaa,*
aAminoScience Laboratories, Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan
bFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 22 January 2001; accepted 24 January 2001
Abstract—A practical synthesis of 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-9-(3-deoxy-
b- -erythro-pentofuranosyl)-9H-purine (6) is described. Fluorination at the C2%-b position of the purine 3%-deoxynucleoside was
D
improved by the introduction of 6-chloro group, and proceeded in moderate yield. The total yield of FddA from readily available
starting material 6 was 35%. © 2001 Elsevier Science Ltd. All rights reserved.
9-(2,3-Dideoxy-2-fluoro-b-
D
-threo-pentofuranosyl)-
anomer formation during condensation with a nucleic
adenine (1, FddA, lodenosine) is an anti-HIV agent,1
and its synthesis has attracted considerable attention.
FddA has significant advantages over a non-fluorinated
dideoxynucleoside such as dideoxyinosine (3, ddI,
didanosine) and dideoxyadenosine (4, ddA) because of
its stability under acidic conditions,1a,b its activity
against dideoxynucleoside-resistant strains of HIV,2
and its ability to permeate the blood–brain barrier
(BBB).3 Compound 1 is currently being tested in clini-
cal trials for the treatment of AIDS.1d,4
base.1b,7 Consequently, the total yield of 1 was limited.
Watanabe, Pankiewicz and their co-workers reported8
an excellent method for fluorination of riboside at the
C2%-b position by conformation control to synthesize
F-ara-A (2). They found that a C2%-b fluorinated com-
pound was obtained from O2%,O5%,N6-tritrityladenosine
in 30% yield, but an unexpected isonucleoside was
obtained in 51% yield as a side product. Recently,
Maruyama et al. also reported9 an F-ara-A synthesis
with 6-chloropurine riboside derivatives with an excel-
lent fluorination yield. They found that 3%,5%-di-O-trityl-
6-chloropurine riboside gave the C2%-b fluorinated
compound in 87% yield. We improved this method in
FddA synthesis.10 However, this riboside route requires
deoxygenation of the 3%-hydroxyl group after the criti-
cal fluorination step, and this results in the loss of
Although 1 has been synthesized by several different
methods,1,4a,5 the introduction of fluorine at C2%-b of
the sugar moiety is still a critical point. The yield of
fluorination at the C-2 (arabino) position of sugar
derivatives has gradually improved,6 but the synthesis
requires many steps and still remains subject to a-
NH2
NH2
R
N
N
N
N
N
N
N
N
N
N
N
N
HO
HO
HO
O
F
O
F
O
HO
3: R=OH (ddI)
1: FddA
2: F-ara-A
4: R=NH2 (ddA)
* Corresponding author. Tel.: +81/44/245.5066; fax: 81/44/211.7610; e-mail: kunisuke izawa@ajinomoto.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00136-8

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S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 2325–2328
precious fluorinated compound. The method also
requires a multi-step synthesis and an expensive reagent
for the deoxygenation.
at 50°C. After conventional work-up and purification
by silica gel chromatography, pure 715 was obtained as
an oil in 89% yield.
Accordingly, direct fluorination at the C2%-b position of
a purine 3%-deoxynucleoside might be a more attractive
approach. Marquez studied1a the fluorination of pro-
tected 3%-deoxy adenosine with tetrabutylammonium
fluoride, however, a fluorinated compound was not
obtained. Herdewijn et al.11 and Shiragami et al.12
reported the fluorination of 5%-O-tritylated and 5%-O-
acetylated 3%-deoxy adenosine, respectively, with diethyl-
aminosulfur trifluoride (DAST), but the yields of the
fluorinated compounds were only 10% in both cases.
Treatment of the tritylated compound 7 with 2.6 equiv-
alents of diethylaminosulfur trifluoride (DAST) in the
presence of pyridine in dichloromethane under reflux
conditions gave a C2%-b fluorinated compound (8) in
43% yield after purification by preparative silica gel
plate. Almost the same amount of side product was
also formed. This side product was separated and
shown to be an elimination product (9), but was not an
isonucleoside as reported by Watanabe.8a The 1H NMR
spectrum of 816 shows a C2% proton at l=5.25 with a
large geminal coupling constant (J2%,F=53.7 Hz), indi-
cating that a fluorine atom is attached to C2%. This is
also supported by vicinal coupling constants of H1%-F
(J1%,F=19.1 Hz) and H3%-F (J3%,F=35.0, 27.5 Hz). Since
the 1H NMR spectrum shows long-range coupling
between H-8 and the C2% fluorine (J8,F=2.8 Hz), the
fluorine should be in the b configuration.11 Therefore, 8
was confirmed to have a C2%-b fluorinated structure.
We report here a practical synthesis of FddA through
6-chlorinated purine 3%-deoxynucleoside, which was
obtained from inosine (5) in short steps. The method
does not require deoxygenation after fluorination. This
is also the first report regarding the C2%-b fluorination
of purine 3%-deoxynucleoside in moderate yield.
Thus, 6-chloro-9-(3-deoxy-b-D-erythro-pentofuranosyl)-
9H-purine (6)13 was readily synthesized from 5 by a
modification of the method described by Norman and
Reese14 (Scheme 1), without using expensive reagent.
The process was already confirmed with large-scale
production in 3,000 liter scale. The details of this
synthesis will be reported elsewhere. The 5%-hydroxyl
group in 6 was selectively protected with 3.3 equivalents
of trityl chloride (TrCl) in the presence of triethylamine
(Et3N) and 4-dimethylaminopyridine (DMAP) in DMF
After separation and purification, compound 8 was
treated with ammonia in tetrahydrofuran (THF) fol-
lowed by acidic hydrolysis to give FddA (1). Its spec-
troscopic properties were identical in all respects to the
published data.1,10
The 5%-O-acetylated compound (11)17 was also synthe-
sized by selective deprotection of the di-protected com-
pound 10 (Scheme 2), to investigate if the size of
O
Cl
N
Cl
N
N
N
N
N
N
NH
N
N
5steps
50% yield
N
N
TrCl / DMF
Et3N / DMAP
89%
HO
HO
TrO
O
O
O
HO OH
OH
OH
5: inosine
6
7
Cl
N
Cl
NH2
N
N
N
N
N
N
N
N
N
N
N
DAST / pyridine
CH2Cl2
1) NH3 / THF
TrO
TrO
HO
O
F
O
O
F
2) 37% HCl aq.
MeOH
43%
92%
(by 2 steps)
8
9
1
Scheme 1.
Cl
N
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
Et3N / MeOH
34%
MOST / pyridine
CH2Cl2
AcO
AcO
AcO
O
O
O
F
OAc
OH
39%
10
11
12
Scheme 2.

S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 2325–2328
2327
H
H
6-Cl-Purine
6-Cl-Purine
H
H
H
H
O
O
TrO
AcO
H
H
H
H
J1',2' = 2.2 Hz
J1',2' = 2.3 Hz
OH
OH
7: C3'-endo
11: C3'-endo
Figure 1.
5%-hydroxyl protecting group changed the sugar
conformation8 and affected the yield of fluorination.
Although a risk of undesired deprotection during the
fluorination is present, fluorination of 11 was per-
formed by morpholinosulfur trifluoride (MOST), which
is an alternative reagent of DAST and it reacted more
mildly. Thus, treatment of the acetylated compound 11
with MOST in the presence of pyridine in
dichloromethane under reflux conditions gave a C2%-b
fluorinated compound (12)18 in 39% yield after purifica-
tion by silica gel column chromatography. In this
study, it was revealed that the size of 5%-hydroxyl
protecting group did not influence the sugar conforma-
tion and gave a similar yield of the fluorination.
References
1. (a) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.;
Mitsuya, H.; Broder, S.; Roth, J. S.; Driscoll, J. S.
Biochem. Pharmacol. 1987, 36, 2719–2722; (b) Marquez,
V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.; Kelley, J.
A.; Ford, Jr., H.; Roth, J. S.; Broder, S.; Johns, D. G.;
Driscoll, J. S. J. Med. Chem. 1990, 33, 978–985; (c)
Ruxrungtham, K.; Boone, E.; Ford, Jr., H.; Driscoll, J.
S.; Davey, Jr., R. T.; Lane, H. C. Antimicrob. Agents
Chemother. 1996, 40, 2369–2374 and references cited
therein; (d) Graul, A.; Silvestre, J. Drugs of the Future
1998, 23, 1176–1189 and references cited therein.
2. (a) Driscoll, J. S.; Mayers, D. L.; Bader, J. P.; Weislow,
O. S.; Johns, D. G.; Buckheit, Jr., R. W. Antivir. Chem.
Chemother. 1997, 8, 107–111; (b) Tanaka, M.; Srinivas,
R. V.; Ueno, T.; Kavlick, M. F.; Hui, F. K.; Fridland,
A.; Driscoll, J. S.; Mitsuya, H. Antimicrob. Agents
Chemother. 1997, 41, 1313–1318.
1
In fact, the H NMR spectrum shows that both 715 and
1117 have a C3%-endo conformation (Fig. 1), as indi-
cated by the rather small vicinal coupling constant
between the C1% and C2% protons (J1%,2%=2.2 Hz and 2.3
Hz). Watanabe, Pankiewicz and their co-workers
reported8a that the C3%-endo conformation favors b-
elimination by virtue of a trans diaxial configuration
between the axial hydrogen on C3% and the activated
C2%-hydroxyl group. This argument is supported by
many examples; e.g. the fluorination of N1,O3%,O5%-
tribenzylinosine (J1%,2%=2.5 Hz with 2%-O-triflate)8a and
5%-O-trityl-3%-deoxyadenosine (J1%,2%=1.1 Hz)11 with
DAST gave a poor yield.
3. Dharmendra, S.; Morgan, M. E.; Anderson, B. D.
Pharm. Res. 1997, 14, 786–792.
4. (a) Maqbool, A. S.; Driscoll, J. S.; Abushanab, E.; Kel-
ley, J. A.; Barchi, Jr., J. J.; Marquez, V. E. Nucleosides
Nucleotides Nucleic Acids 2000, 19, 1–12; (b) During the
preparation of this manuscript, a clinical trial of FddA
was suspended. US Bioscience, Inc.: West Conshohocken,
PA, Press Release, Oct. 14, 1999.
5. Maqbool, A. S.; Driscoll, J. S.; Marquez, V. E. Tetra-
hedron Lett. 1998, 39, 1657–1660.
Our 3%-deoxy-6-chloropurine nucleosides gave a moder-
ate yield of fluorination despite the C3%-endo conforma-
tion. The electron-withdrawing 6-chloropurine group
may have affected the yield in our case.
6. (a) Wysocki, R. J.; Siddiqui, M. A.; Barchi, Jr., J. J.;
Driscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005–1008;
(b) Siddiqui, M. A.; Marquez, V. E.; Driscoll, J. S.;
Barchi, Jr., J. J. Tetrahedron Lett. 1994, 35, 3263–3266;
(c) Chou, T. S.; Becke, L. M.; O’Toole, J. C.; Carr, M.
A.; Parker, B. E. Tetrahedron Lett. 1996, 37, 17–20.
7. Barchi, Jr., J. J.; Marquez, V. E.; Driscoll, J. S.; Ford,
Jr., H.; Mitsuya, H.; Shirasaka, T.; Aoki, S.; Kelley, J. A.
J. Med. Chem. 1991, 34, 1647–1655.
8. (a) Pankiewicz, K. W.; Krzeminski, J.; Ciszewski, L. A.;
Ren, W.-Y.; Watanabe, K. A. J. Org. Chem. 1992, 57,
553–559; (b) Pankiewicz, K. W.; Watanabe, K. A. In
Nucleosides and Nucleotides as Antitumor and Antiviral
Agents; Chu, C. K.; Baker, D. C., Eds.; Plenum Press:
New York, 1993; pp. 55–71; (c) Pankiewicz, K. W.;
Watanabe, K. A. J. Fluor. Chem. 1993, 64, 15–36.
9. Maruyama, T.; Sato, Y.; Oto, Y.; Takahashi, Y.; Snoeck,
R.; Andrei, G.; Witvrouw, M.; De Clercq, E. Chem.
Pharm. Bull. 1996, 44, 2331–2334.
In conclusion, FddA (1) was synthesized from readily
available 6-chlorinated purine 3%-deoxynucleoside 6 by
fluorination of the C2%-b position. The electron-with-
drawing 6-chloropurine group suppresses the formation
of elimination product and isonucleoside. Conse-
quently, the yield of fluorination at the C2%-b position
of purine 3%-deoxynucleoside proceeded in moderate
yield (43%). The total yield of FddA from readily
available starting material 6 was 35%. The details of the
reaction are now under investigation in our
laboratories.
Acknowledgements
10. Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.;
Izawa, K. Chem. Pharm. Bull. 1999, 47, 966–970.
11. Herdewijn, P.; Pauwels, R.; Baba, M.; Balzarini, J.; De
Clercq, E. J. Med. Chem. 1987, 30, 2131–2137.
The authors thank Mr. Hideo Takeda and Mr.
Shigekatsu Tsuchiya of Ajinomoto Co., Inc. for their
help in this research.

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S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 2325–2328
12. Shiragami, H.; Tanaka, Y.; Uchida, Y.; Iwagami, H.;
Izawa, K.; Yukawa, T. Nucleosides Nucleotides 1992, 11,
391–400.
Hb-5%), 2.57 (1H, dddd, J=35.0, 14.8, 9.0, 5.6 Hz, Ha-3%),
2.36 (1H, dddd, J=27.5, 15.1, 5.1, 1.7 Hz, Hb-3%); UV
(MeOH) umax: 206 nm (logm 2.24), 264 nm (logm 0.37);
HRMS (FAB+) calcd for C29H25ClFN4O2 (M+H)+
515.1650, found 515.1658.
13. Kumamoto, H.; Hayakawa, H.; Tanaka, H.; Shindoh, S.;
Kato, K.; Miyasaka, T.; Endo, K.; Machida, H.; Mat-
suda, A. Nucleosides Nucleotides 1998, 17, 15–27.
14. Norman, D. G.; Reese, C. B. Synthesis 1983, 304–306.
15. 1H NMR (300 MHz, CDCl3): l 8.64 (1H, s, H-2), 8.40
(1H, s, H-8), 7.41–7.21 (15H, m, 5%O-Tr), 6.04 (1H, d,
J=2.2 Hz, H-1%), 4.87 (1H, m, H-2%), 4.73 (1H, m, H-4%),
3.44 (1H, dd, J=10.6, 3.1 Hz, Ha-5%), 3.33 (1H, dd,
J=10.6, 4.6 Hz, Hb-5%), 2.30 (1H, ddd, J=13.3, 7.7, 5.6
Hz, Ha-3%), 2.17 (1H, ddd, J=13.3, 6.5, 3.9 Hz, Hb-3%);
UV (MeOH) umax 207 nm (logm 2.27), 265 nm (logm 0.31);
HRMS (FAB+) calcd for C29H26ClN4O3 (M+H)+
513.1693, found 513.1717.
17. 1H NMR (300 MHz, CDCl3): l 8.75 (1H, s, H-2), 8.43
(1H, s, H-8), 6.04 (1H, d, J=2.3 Hz, H-1%), 4.84–4.90
(1H, m, H-2%), 4.77–4.84 (1H, m, H-4%), 4.42 (1H, dd,
J=12.4, 3.0 Hz, H-5%a), 4.31 (1H, dd, J=12.4, 4.4 Hz,
H-5%b), 2.18–2.31 (2H, m, H-3%ab), 2.07 (3H, s, 5%O-Ac);
HRMS (FAB+) calcd for C12H14ClN4O4 (M+H)+
313.0704, found 313.0690.
18. 1H NMR (300 MHz, CDCl3): l 8.74 (1H, s, H-2), 8.45
(1H, d, J=2.7 Hz, H-8), 6.43 (1H, dd, J=18.9, 3.1 Hz,
H-1%), 5.32 (1H, dddd, J=53.4, 5.1, 3.1, 1.8 Hz, H-2%),
4.50–4.59 (1H, m, H-4%), 4.43 (1H, dd, J=11.9, 6.4 Hz,
H-5%a), 4.32 (1H, dd, J=11.9, 3.7 Hz, H-5%b), 2.68
(1H, dddd, J=36.0, 15.2, 8.8, 5.2 Hz, H-3%a), 2.43 (1H,
dddd, J=25.7, 15.2, 4.5, 1.7 Hz, H-3%b); HRMS (FAB+)
calcd for C12H13ClFN4O3 (M+H)+ 315.0660, found
315.0651.
16. 1H NMR (300 MHz, CDCl3): l 8.73 (1H, s, H-2), 8.34
(1H, d, J=2.8 Hz, H-8), 7.52–7.22 (15H, m, 5%O-Tr), 6.41
(1H, dd, J=19.1, 3.1 Hz, H-1%), 5.25 (1H, dddd, J=53.7,
5.2, 3.1, 2.0 Hz, H-2%), 4.46 (1H, m, H-4%), 3.48 (1H, dd,
J=9.9, 6.6 Hz, Ha-5%), 3.30 (1H, dd, J=9.9, 3.8 Hz,
.