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

Article abstract of DOI:10.1021/jo0158985

A 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 (9), which was readily obtained from inosine (5), is described. Fluorination at the C2′-β position of the purine 3′-deoxynucleoside with diethylaminosulfur trifluoride was improved by the introduction of a 6-chloro group and proceeded in moderate yield. Purine 3′-deoxynucleoside derivatives were also subjected to nucleophilic reactions with triethylamine trihydrofluoride and gave the desired fluorinated nucleoside in good yield. The safety and yield of the fluorination process were greatly improved by the use of triethylamine trihydrofluoride. The influence of the sugar ring conformation and 6-chloro group on the rate of the nucleophilic reaction against elimination are also discussed.

Full text of DOI:10.1021/jo0158985

J . Org. Chem. 2001, 66, 7469-7477
7469
Syn th esis of
9-(2,3-Did eoxy-2-flu or o-â-D-th r eo-p en tofu r a n osyl)a d en in e (F d d A)
via a P u r in e 3′-Deoxyn u cleosid e
Satoshi Takamatsu,† Tokumi Maruyama,‡ Satoshi Katayama,† Naoko Hirose,†
Masaki Naito,† and Kunisuke Izawa*,†
AminoScience Laboratories, Ajinomoto Co., Inc. 1-1, Suzuki-cho, Kawasaki-ku,
Kawasaki, Kanagawa 210-8681, J apan and Faculty of Pharmaceutical Sciences,
Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, J apan
kunisuke_izawa@ajinomoto.com
Received J uly 6, 2001
A synthesis of 9-(2,3-dideoxy-2-fluoro-â-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-
9-(3-deoxy-â-D-erythro-pentofuranosyl)-9H-purine (9), which was readily obtained from inosine (5),
is described. Fluorination at the C2′-â position of the purine 3′-deoxynucleoside with diethylami-
nosulfur trifluoride was improved by the introduction of a 6-chloro group and proceeded in moderate
yield. Purine 3′-deoxynucleoside derivatives were also subjected to nucleophilic reactions with
triethylamine trihydrofluoride and gave the desired fluorinated nucleoside in good yield. The safety
and yield of the fluorination process were greatly improved by the use of triethylamine trihydrof-
luoride. The influence of the sugar ring conformation and 6-chloro group on the rate of the
nucleophilic reaction against elimination are also discussed.
In tr od u ction
penetrate the blood-brain barrier.8-11 FddA is currently
under clinical trials for the treatment of AIDS.4,12,13
Since the biological activity and chemical or metabolic
stability of FddA have received considerable attention in
antiviral research,2,14 many groups have striven to de-
velop better methods for obtaining C2′-â fluorinated
purine deoxynucleosides. While the condensation of
fluorinated sugar derivatives with a nucleoside base is a
conventional approach to synthesize C2′-â fluorinated
nucleosides,15-17 the synthesis of fluorinated sugar de-
rivatives requires many steps and condensation remains
subject to R-anomer formation.2,18 Consequently, the total
yield of FddA has been limited.
9-(2,3-Dideoxy-2-fluoro-â-D-threo-pentofuranosyl)ade-
nine (1, FddA, lodenosine) is an anti-human immunode-
ficiency virus (HIV) agent characterized by a C2′-â
fluorinated dideoxy nucleoside.1-4 This nucleoside ana-
logue acts as an inhibitor of HIV reverse transcriptase
(RT), like other nucleoside derivatives such as 3′-azido-
3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxyinosine
(3, ddI, didanosine), and 2′,3′-dideoxyadenosine (4, ddA).
This class of nucleoside derivatives is known not only for
its effectiveness, but also for its toxicity and the develop-
ment of resistant strains. However, they are considered
to be effective therapeutic agents based on their success-
ful use in combination with other nucleoside or non-
nucleoside RT inhibitors or with HIV protease inhibitors.5
Among the deoxynucleoside analogues, FddA is impor-
tant due to its effectiveness against strains resistant to
other dideoxy nucleosides,6,7 its improved stability under
acidic conditions1,2 which decompose 2′,3′-dideoxyinosine
(3) and 2′,3′-dideoxyadenosine (4), and its ability to
(7) 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.
(8) Singhal, D.; Morgan, M. E.; Anderson, B. D. Pharm. Res. 1997,
14 786-792.
(9) Driscoll, J . S.; Siddiqui, M. A.; Ford, H., J r.; Kelley, J . A.; Roth,
J . S.; Mitsuya, H.; Tanaka, M.; Marquez, V. E. J . Med. Chem. 1996,
39, 1619-1625.
(10) J ohnson, M. D.; Anderson, B. D. Pharm. Res. 1996, 13 1881-
1886.
* To whom correspondence should be addressed. Phone: +81-44-
245-5066. Fax: +81-44-211-7610. E-mail: kunisuke_izawa@ajinomoto.
com.
(11) Ford, H., J r.; Siddiqui, M. A.; Driscoll, J . S.; Marquez, V. E.;
Kelley, J . A.; Mitsuya, H.; Shirasaka, T. J . Med. Chem. 1995, 38, 1189-
1195.
(12) Maqbool, A. S.; Driscoll, J . S.; Abushanab, E.; Kelley, J . A.;
Barchi, J . J ., J r.; Marquez, V. E. Nucleosides Nucleotides Nucleic Acids
2000, 19, 1-12.
(13) During the preparation of this manuscript, a clinical trial of
FddA was suspended. US Bioscience, Inc.: West Conshohocken, PA,
Press Release, Oct 14, 1999.
† AminoScience Laboratories.
‡ Tokushima Bunri University.
(1) 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.
(2) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.; Kelley,
J . A.; Ford, H., J r.; Roth, J . S.; Broder, S.; J ohns, D. G.; Driscoll, J . S.
J . Med. Chem. 1990, 33, 978-985.
(14) Chu, C. K.; Matulic-Adamic, J .; Huang, J .-T.; Chou, T.-C.;
Burchenal, J . H.; Fox, J . J .; Watanabe, K. A. Chem. Pharm. Bull. 1989,
37, 336-339, and references therein.
(3) Ruxrungtham, K.; Boone, E.; Ford, H., J r.; Driscoll, J . S.; Davey,
R. T., J r.; Lane, H. C. Antimicrob. Agents Chemother. 1996, 40, 2369-
2374, and references therein.
(15) Wysocki, R. J .; Siddiqui, M. A.; Barchi, J . J ., J r.; Driscoll, J . S.;
Marquez, V. E. Synthesis 1991, 1005-1008.
(4) Graul, A.; Silvestre, J . Drugs Future 1998, 23, 1176-1189, and
references therein.
(5) Palmer, S.; Russell, J . D.; Pallansch, L. A.; Driscoll, J . S.;
Buckheit, R. W., J r. Antiviral Res. 1999, 41, LB4.
(6) Driscoll, J . S.; Mayers, D. L.; Bader, J . P.; Weislow, O. S.; J ohns,
D. G.; Buckheit, R. W., J r. Antivir. Chem. Chemother. 1997, 8, 107-
111.
(16) Siddiqui, M. A.; Marquez, V. E.; Driscoll, J . S.; Barchi, J . J .,
J r. Tetrahedron Lett. 1994, 35, 3263-3266.
(17) Chou, T. S.; Becke, L. M.; O’Toole, J . C.; Carr, M. A.; Parker,
B. E. Tetrahedron Lett. 1996, 37, 17-20.
(18) Barchi, J . J ., J r.; Marquez, V. E.; Driscoll, J . S.; Ford, H., J r.;
Mitsuya, H.; Shirasaka, T.; Aoki, S.; Kelley, J . A. J . Med. Chem. 1991,
34, 1647-1655.
10.1021/jo0158985 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/10/2001

7470 J . Org. Chem., Vol. 66, No. 22, 2001
Takamatsu et al.
Ch a r t 1
This is the first report regarding the C2′-â fluorination
of purine 3′-deoxynucleoside in good yield. In addition to
our previous communication,27 we describe fluorination
not only with DAST but also with triethylamine trihy-
drofluoride (Et3N‚3HF), which is more suitable for large-
scale synthesis from a handling safety standpoint. We
also report the details of the synthesis of the 6-chlori-
nated purine 3′-deoxynucleoside. The details of the influ-
ence of the sugar ring conformation and 6-chloro group
on the rate of the nucleophilic displacement reaction
versus elimination are also discussed.
Watanabe, Pankiewicz, and their co-workers re-
ported,19-21 an excellent method for fluorination of ribo-
side at the C2′-â position taking advantage of the control
of conformation to synthesize F-ara-A (2). They found
that C2′-â fluorinated compound was obtained from
O2′,O5′,N6-tritrityladenosine in 30% yield, but an unex-
pected isonucleoside was also obtained in 51% yield.
Recently, Maruyama et al. also reported22 a synthesis of
F-ara-A (2) using 6-chloropurine riboside derivatives with
an excellent fluorination yield. They found that 3′,5′-di-
O-trityl-6-chloropurine riboside gave C2′-â fluorinated
compound in 87% yield. We applied this method to the
synthesis of FddA through protected F-ara-A.23 However,
this F-ara-A route requires deoxygenation of the 3′-
hydroxyl group after the crucial fluorination step, and it
loses a precious fluorinated compound. This method also
requires a multistep synthesis and an expensive reagent
for deoxygenation. Recently, a new synthetic approach
to FddA via deoxygenation of 2′-deoxy-2′-fluoroadenosine
and subsequent hydrogenation of the vinyl intermediate
has been reported.12,24 However, the preparation of 2′-
deoxy-2′-fluoroadenosine from expensive 9-(â-D-arabino-
furanosyl)adenine still requires a multistep synthesis.
Again, deoxygenation and hydrogenation loses a precious
fluorinated compound. We intended to develop a more
direct approach to the synthesis of FddA, which would
be suitable for large-scale synthesis.
Resu lts a n d Discu ssion
6-Chloro-9-(3-deoxy-â-D-erythro-pentofuranosyl)-9H-
purine (9)28 was readily obtained from commercially
available inosine (5) in 50% overall yield, without using
an expensive reagent (Scheme 1). Thus, after treatment
with trimethyl orthoacetate in acetic acid, 5 was deoxy-
genated and brominated simultaneously at the 3′-position
with acetyl bromide by a modified Reese method.29
Although reduction of the acetyl-brominated compound
(6) by palladium-catalyzed hydrogenation predominantly
gave a dideoxy compound,30 the C3′-â bromine of 6 was
selectively reduced by radical reduction.31 Therefore, 6
was treated with 3 equiv of tributyltin hydride and a
catalytic amount of 2,2′-azobisisobutyronitrile (AIBN) in
toluene to obtain 2′,5′-di-O-acetyl-3′-deoxyinosine (7).
Whereas the reaction yield of radical debromination was
92%, separation and purification of the product were
rather difficult because of residual tin reagent. After
separation and purification by recrystallization, the
isolated yield of 7 was 67%. The 6-oxo group of 7 was
substituted with chlorine by reaction with Vilsmeier
reagent or phosphorus oxychloride. As reported,28 cleav-
age of the glycoside bond under standard conditions
during chlorination lead to a low yield of the product.
However, by monitoring the reaction carefully and cooling
the mixture immediately at the end of the reaction,
cleavage of the glycoside bond was decreased to a
negligible level. After deprotection of the 2′- and 5′-O-
acetyl groups with sodium methoxide in methanol,
6-chloropurine 3′-deoxyriboside (9) was crystallized. This
process was shown to be suitable for large-scale produc-
tion on a 3000-L scale. The details of this synthesis will
be reported elsewhere.
Accordingly, direct fluorination at the C2′-â position
of a purine 3′-deoxynucleoside might be a more attractive
approach. Marquez studied1 the fluorination of protected
3′-deoxy adenosine with tetrabutylammonium fluoride;
however, a fluorinated compound was not obtained.
Herdewijn25 and Shiragami26 reported the fluorination
of 5′-O-tritylated and 5′-O-acetylated 3′-deoxy adenosine,
respectively, with diethylaminosulfur trifluoride (DAST),
but the yields of the fluorinated compounds were only
10% in both cases.
In our previous report,27 5′-O-tritylated compound (10)
was obtained as an oil after column separation. To im-
prove this process, the 5′-hydroxyl group in 9 was
selectively protected with 1.1 equiv of trityl chloride
(TrCl) in the presence of 2,4,6-collidine in acetonitrile
(CH3CN) at 45 °C. After quenching with methanol, the
resulting solution was subjected to the usual workup to
give 5′-O-tritylated compound 10 as an oil. Several
different solvents were tested and eventually 10 was
found to be crystallized only from benzotrifluoride (R,R,R-
trifluorotoluene). After crystallization, pure 10 was ob-
In this paper, we report a practical synthesis of FddA
through a 6-chlorinated purine 3′-deoxynucleoside. This
method does not require deoxygenation after fluorination.
(19) Pankiewicz, K. W.; Krzeminski, J .; Ciszewski, L. A.; Ren, W.-
Y.; Watanabe, K. A. J . Org. Chem. 1992, 57, 553-559.
(20) 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.
(21) Pankiewicz, K. W.; Watanabe, K. A. J . Fluorine Chem. 1993,
64, 15-36.
(22) Maruyama, T.; Sato, Y.; Oto, Y.; Takahashi, Y.; Snoeck, R.;
Andrei, G.; Witvrouw, M.; De Clercq, E. Chem. Pharm. Bull. 1996,
44, 2331-2334.
(27) Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.; Naito,
M.; Izawa, K. Tetrahedron Lett. 2001, 42, 2325-2328.
(28) Kumamoto, H.; Hayakawa, H.; Tanaka, H.; Shindoh, S.; Kato,
K.; Miyasaka, T.; Endo, K.; Machida, H.; Matsuda, A. Nucleosides
Nucleotides 1998, 17, 15-27.
(29) Norman, D. G.; Reese, C. B. Synthesis 1983, 304-306.
(30) Shiragami, H.; Amino, Y.; Honda, Y.; Arai, M.; Tanaka, Y.;
Iwagami, H.; Yukawa, T.; Izawa, K. Nucleosides Nucleotides 1996, 15,
31-45, and references therein.
(31) Robins, M. J .; Wilson, J . S.; Madej, D.; Low, N. H.; Hansske,
F.; Wnuk, S. F. J . Org. Chem. 1995, 60, 7902-7908.
(23) Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.; Izawa, K.
Chem. Pharm. Bull. 1999, 47, 966-970.
(24) Siddiqui, M. A.; Driscoll, J . S.; Marquez, V. E. Tetrahedron Lett.
1998, 39, 1657-1660.
(25) Herdewijn, P.; Pauwels, R.; Baba, M.; Balzarini, J .; De Clercq,
E. J . Med. Chem. 1987, 30, 2131-2137.
(26) Shiragami, H.; Tanaka, Y.; Uchida, Y.; Iwagami, H.; Izawa, K.;
Yukawa, T. Nucleosides Nucleotides 1992, 11, 391-400.

Synthesis of FddA via a Purine 3′-Deoxynucleoside
J . Org. Chem., Vol. 66, No. 22, 2001 7471
Sch em e 1a
a
Reagents: (a) MeC(OMe)3, AcOH, 50 °C; (b) AcBr, CH3CN, 10 °C, 80.0%; (c) Bu3SnH, AIBN, toluene, 67.0%; (d) SOCl2, DMF, CH2Cl2,
reflux, 94.1%; (e) POCl3, N,N-dimethylaniline, Et4NCl, CH3CN, reflux, 99.0%; (f) NaOMe, MeOH, r.t., 94.1%.
Sch em e 2a
tained in 85% yield. The pivotal substrate 10 was further
studied for fluorination.
First, we studied diethylaminosulfur trifluoride (DAST)32
as a fluorinating agent. In the laboratory, DAST is useful
for replacing a hydroxyl group with fluorine with an
inversion of configuration. However, it has been re-
ported19 that the C2′-â fluorination of 3′,5′-di-O-protected
nucleoside with DAST is sometimes low yield because
nucleic base migration occurs due to participation of the
nucleophilic purine N3 during the reaction. Therefore,
we prepared 6-chlorinated compound 10, which might
reduce the nucleophilicity of the nucleic base by substitu-
tion of the 6-position of the base with an electron-
withdrawing chlorine.
Thus, 10 was reacted with 2.6 equiv of DAST (Scheme
2) in the presence of pyridine in dichloromethane at
reflux to give a C2′-â fluorinated compound 11 in 43%
yield after purification by preparative silica gel plate. The
6-chloro group was shown to be effective for preventing
purine base migration and improving the yield of fluo-
rination, compared with the 6-aminated compound. The
1H NMR spectrum of 11 shows a C2′ proton at δ ) 5.25
with a large geminal coupling constant (J 2′,F ) 53.7 Hz),
indicating that the fluorine atom is attached to C2′. This
is also supported by vicinal coupling constants of H1′-F
(J 1′,F ) 19.1 Hz) and H3′-F (J 3′,F ) 35.0, 27.5 Hz). Since
the 1H NMR spectrum shows long-range coupling be-
tween H-8 and the C2′ fluorine (J 8,F ) 2.8 Hz), the
fluorine should be in the â configuration. The nuclear
Overhauser effect spectroscopy (NOESY) spectrum also
supported the structure of 11 (Figure 1). Therefore, 11
was confirmed to have a C2′-â fluorinated structure.
During the reaction of 10 with DAST, almost the same
amount of side product was also formed. This side
product was separated and shown to be an elimination
product (12), but was not an isonucleoside as reported
by Watanabe.19-21 The 1H NMR spectrum of 12 shows
the existence of a vinyl proton at δ ) 6.03 (H-2′) and δ )
6.37 (H-3′) with a vicinal coupling constant (J 2′,3′ ) 5.7
Hz).
a
Reagents: (a) TrCl, 2,4,6-collidine, CH3CN, 45 °C, 85.1%; (b)
DAST, pyridine, CH2Cl2, 42.6%; (c) NH3, THF; (d) 37% HCl aq,
MeOH, 91.6% from 11; (e) 37% HCl aq, MeOH, toluene, r.t.; (f)
NH3, MeOH, toluene, 40-60 °C, 72.8% from 11.
After separation and purification, 11 was added to
anhydrous ammonia in tetrahydrofuran (THF) and kept
in a sealed tube at 70 °C for 4 days. The aminated
compound 13 was then deprotected with aqueous hydro-
gen chloride in methanol to give the desired FddA (1).
(32) Middleton, W. J . J . Org. Chem. 1975, 54, 574-578.

7472 J . Org. Chem., Vol. 66, No. 22, 2001
Takamatsu et al.
Sch em e 4a
F igu r e 1. Graphical summary of the NOESY spectrum
observed for C2′-â fluorinated 11.
Sch em e 3a
a
Reagents: (a) Tf2O, pyridine, CH2Cl2, -10 °C; (b) Et3N‚3HF,
Et3N, toluene, 40 °C, 64.5% from 10 on HPLC analysis; (c) 80%
AcOH, toluene; (d) crystallization, 69.5%.
also difficult to handle on a commercial scale due to its
toxicity. Therefore, we examined an alternative fluorina-
tion method for industrial production.
a
Reagents: (a) Et3N, MeOH, 33.5%; (b) MOST, pyridine,
Chou et al. reported33 the large-scale synthesis of C-2
(arabino) fluorinated sugar derivatives with noncorrosive
triethylamine trihydrofluoride (Et3N‚3HF).34,35 However,
the condensation of fluorinated sugar with purine to
synthesize FddA, and its related compounds can still lead
to the formation of undesired R-anomer during the
reaction. Since the application of Et3N‚3HF to fluorinated
nucleoside synthesis has not been well studied,36 we
became interested in using Et3N‚3HF for the synthesis
of FddA (1). In our previous paper,37 we used Et3N‚3HF
for the fluorination of 3′-O-benzoyl-5′-O-tritylriboside
through 2′-O-trifluoromethanesulfonate and 2′-O-imida-
zolesulfonate. We applied our results to the fluorination
of 3′-deoxy-5′-O-tritylriboside (10).
Thus, 10 was fluorinated with Et3N‚3HF in two steps,
as shown in Scheme 4. Prior to the reaction with Et3N‚
3HF, the 2′-hydroxyl group of 10 was converted to
trifluoromethanesulfonate (17). The conditions for the
reaction of Et3N‚3HF with the triflate 17 were examined
as shown in Table 1. The normarized HPLC peak area
ratio in Table 1 was calculated to exclude an influence
of solvent peak from the data comparison. The reaction
proceeded slowly at room temperature (runs 1-3, 7-9).
The results at 70 °C were not as good as expected (runs
4-6), because depurination of starting material and
products occur at the temperature. The reaction had to
CH2Cl2, 38.8%; (c) NH3, THF, 88.2% on HPLC analysis.
The desired FddA was also obtained from 11 by an
alternative procedure, in which the 5′-O-trityl group was
first deprotected by aqueous hydrogen chloride followed
by amination at the 6 position. In both cases, the
spectroscopic properties of 1 were identical in all respects
to the published data.1-3,23
The 5′-O-acetylated compound (15) was also synthe-
sized by partial deacetylation of compound 8 (Scheme 3),
to investigate if the 5′-hydroxyl protecting group changed
the sugar conformation19-21 and affected the yield of
fluorination. Although there is a risk of undesired depro-
tection during fluorination, fluorination of 15 was per-
formed using morpholinosulfur trifluoride (MOST), which
is an alternative to DAST, and the reaction proceeded
more mildly. Thus, treatment of the acetylated compound
15 with MOST in the presence of pyridine in dichlo-
romethane at reflux gave a C2′-â fluorinated compound
(16) in 39% yield after purification by silica gel column
chromatography. Our results showed that the 5′-hydroxyl
protecting group did not influence the sugar conformation
and gave a similar yield of fluorination. Treatment of 16
with anhydrous ammonia in THF gave the desired 1 in
88% yield. To the best of our knowledge, this procedure
may also be the shortest route to FddA by avoiding
sequential deprotection-protection steps from 8 to 10 in
Scheme 1.
(33) Chou, T. S.; Becke, L. M.; O’Toole, J . C.; Carr, M. A.; Parker,
B. E. Tetrahedron Lett. 1996, 37, 17-20.
(34) McClinton, M. A. Aldrichim. Acta 1995, 28, 31-35.
(35) Haufe, G. J . Prakt. Chem. 1996, 338. 99-113.
(36) Its only known use is in the synthesis of 3′-R fluorinated
thymidine: von J anta-Lipinski, M.; Langen, P.; Czech, D. Z. Chem.
1983, 23, 325.
Although the fluorination yield of 6-chloropurine 3′-
deoxyribosides 10 and 15 with dialkylaminosulfur tri-
fluoride (DAST or MOST) were better than that of 3′-
deoxy adenosine derivatives, the fluorination conditions
were corrosive to glass and a stainless steel reactor in
large-scale production. Dialkylaminosulfur trifluoride is
(37) Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.; Izawa,
K. Tetrahedron Lett. 2001, 42, 2321-2324.

Synthesis of FddA via a Purine 3′-Deoxynucleoside
J . Org. Chem., Vol. 66, No. 22, 2001 7473
Ta ble 1. F lu or in a tion of 17 w ith Et3N‚3HF
HPLC peak area ratioa
run
solvent
Et3N‚3HF/equiv
Et3N/equiv
temp/°C
time/days
17
11
12
yield/%b 11
1
2
3
4
5
6
7
8
9
CH3CN
AcOEt
toluene
CH3CN
AcOEt
toluene
CH3CN
AcOEt
toluene
toluene
toluene
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
4.0
-
-
-
-
-
-
r.t.
r.t.
r.t.
70
70
70
r.t.
r.t.
r.t.
40
4.9
4.9
4.9
0.3
0.3
0.9
4.9
4.9
4.9
3.0
1.8
37.3
43.8
82.4
4.3
0.4
0.0
0.6
0.0
8.1
0.0
23.6
24.6
13.8
85.8
57.8
70.4
34.2
38.6
64.4
64.7
66.1
38.7
31.6
3.8
16.2
20.5
11.7
20.3
38.4
34.9
28.6
34.5
57.8
60.3
64.5
9.9
41.7
29.6
65.2
61.3
27.5
35.3
33.4
3.0
3.0
3.0
3.0
2.0
10
11
40
0.5
a
b
The HPLC peak area ratio is normalized to exclude a solvent peak. The yield includes triflation and is calculated from the results
of HPLC analysis.
Sch em e 5a
be carried out in nonpolar solvent to avoid the forma-
tion of elimination product 12. Compared to acetonitrile
(CH3CN) and ethyl acetate (AcOEt), toluene gave the best
ratio of fluorinated compound 11 to elimination product
12 (runs 1-3, 7-9). The addition of half an equivalent
of triethylamine (Et3N) to Et3N‚3HF enhanced the nu-
cleophilicity of the reagent38 and improved the results
(run 9). To shorten the reaction time, the reaction
temperature was moderately increased to 40 °C (runs 10
and 11). At 40 °C, 4 equiv of Et3N‚3HF were enough to
finish the reaction (runs 11). The reaction took ap-
proximately 40-48 h (run 11).
a
Reagents: (a) SO2Cl2, pyridine, CH2Cl2, -35 °C; (b) imidazole,
Therefore, 17 was reacted with 4 equiv of Et3N‚3HF
in toluene in the presence of 2 equiv of Et3N at 40 °C.
HPLC analysis showed that the yield of fluorinated
compound 11 was 65% including trifluoromethanesulfo-
nation. Eliminated product 12 was also formed in around
33% yield. Since Et3N‚3HF is noncorrosive,17,34 the boro-
silicate glassware was not corroded at all even after a
few days under these reaction conditions. The yield of
11 (65%) from 10 in the reaction with Et3N‚3HF was
much greater than that in the reaction with DAST (43%).
The safety and yield of the fluorination process, which
is the key step of the total synthesis, were greatly
improved by the use of triethylamine trihydrofluoride.
Although the fluorination process was improved, the
fluorination still gave a 2:1 mixture of fluorinated
compound 11 and eliminated product 12. For the large-
scale procedure, a purification method without using
column separation was required. One of the advantages
of C2′-â fluorinated nucleoside 1 is its stability in acid1,2
due to its C2′-â fluoride.39 In contrast, 2′,3′-dideoxy-
didehydro nucleoside is acid-labile. Hence, if we treat a
mixture of 11 and 12 with an appropriate acid, there is
a possibility of decomposing only the acid-labile 2′,3′-
dideoxy-didehydro nucleoside (12), while retaining the
acid-stable C2′-â fluorinated nucleoside (11). In fact,
treatment of the mixture of 11 and 12 with 80% acetic
acid in toluene for 6 h at 10 °C led to the recovery of 11
without any loss (Scheme 4). On the other hand, elimina-
tion product 12 was completely decomposed. The in-
creased HPLC peak of 6-chloropurine showed that 12
underwent depurination during acid treatment. The
resulting crude 11 was subjected to crystallization from
the toluene-tetrahydrofuran-cyclohexane mixture to
give pure 11. After amination and deprotection, the
r.t.; (c) Et3N‚3HF, Et3N, toluene, 40 °C, 41.9% from 10 on HPLC
analysis.
overall yield of FddA (1) from inosine was 17%. This
method proceeds without using a corrosive reagent or
column separation. Accordingly, the present method is
suitable for large-scale synthesis of 1.
The imidazolesulfonate (18), obtained from 10, was also
reacted with 6 equiv of Et3N‚3HF in toluene at 50 °C for
2 days. After conventional workup, HPLC analysis
indicated that the fluorinated compound 11 was obtained
in 42% yield in two steps. In the reaction with imida-
zolesulfonate 18, the addition of half an equivalent of
Et3N to Et3N‚3HF was not effective at increasing the
yield of fluorinated compound 11. We tried to fluorinate
the compound with other leaving groups, but without
1
success. The H NMR spectra show that 10, 15, and 17
all have a C3′-endo conformation (Figure 2), as indicated
by the rather small vicinal coupling constant between the
C1′ and C2′ protons (J 1′,2′ ) 2.2, 2.3, and 1.2 Hz,
respectively).
In the course of their studies on 2′-deoxy-2′-fluoro-
arabinofuranosyl purine nucleoside synthesis, Watanabe,
Pankiewicz, and their co-workers have shown19-21 that
if a sugar moiety of a purine nucleoside takes a C3′-endo
conformation, nucleophilic substitution of the C2′-R leav-
ing group does not give a C2′-â fluorinated nucleoside.
This is probably because the hydrogen on C3′ and the
leaving group on C2′ are in almost a trans diaxial
configuration, which favors â-elimination instead of
nucleophilic substitution. Indeed, when N1,O3′,O5′-triben-
zylinosine was treated with DAST, C2′-â fluorinated
arabino nucleoside was not obtained, while elimination
product was obtained exclusively.19 The conformation of
the reaction intermediate of N1,O3′,O5′-tribenzylinosine
is assumed to be C3′-endo by analogy to its 2′-O-triflate
(J 1′,2′ ) 2.5 Hz). This argument is also supported by a
(38) Giudicelli, M. B.; Picq, D.; Veyron, B. Tetrahedron Lett. 1990,
31, 6527-6530.
(39) McAtee, J . J .; Schinazi, R. F.; Liotta, D. C. J . Org. Chem. 1998,
63, 2161-2167.

7474 J . Org. Chem., Vol. 66, No. 22, 2001
Takamatsu et al.
F igu r e 2. The 3′-deoxynucleosides 10, 15, and 17 each have a C3′-endo conformation as indicated by the rather small vicinal
coupling constant between the C1′ and C2′ protons, while in the case of 19, 20, and 21, the two bulky C3′ and C5′ hydroxyl groups
shift the conformation toward C2′-endo, as indicated by the rather large vicinal coupling constant.
report that the fluorination of 5′-O-trityl-3′-deoxyadeno-
sine (J 1′,2′ ) 1.1 Hz)25 with DAST resulted in a poor yield.
On the other hand, when 3′,5′-di-O-trityl-1-benzyli-
nosine (19, J 1′,2′ ) 7.2 Hz) was treated with DAST, C2′-â
fluorinated arabino nucleoside was obtained in 63%
yield,19 since the two bulky trityl groups at the C3′- and
C5′-hydroxyl groups shift the conformation toward C2′-
endo (Figure 2), which favors nucleophilic substitution.
Nevertheless, when 3′,5′-di-O-trityl-inosine (J 1′,2′ ) 7.1
Hz) was treated with DAST, despite its C2′-endo confor-
mation, C2′-â fluorinated arabino nucleoside was ob-
tained in only 30% yield.19 This might be explained by
participation of the hypoxanthine N3 in the sugar moiety
transformation, which results in undesired base migra-
tion. To decrease the influence of the participation of N3,
in previous studies we synthesized 6-chlorinated purine
ribosides such as 3′,5′-di-O-trityl-6-chloropurine riboside
(20, J 1′,2′ ) 4.9 Hz)22 and 3′-O-benzoyl-5′-O-trityl-6-
chloropurine riboside (21, J 1′,2′ ) 6.1 Hz),23 and success-
fully fluorinated these with DAST in good yield (87% and
78%, respectively).
Our present results are quite novel, since this is the
first example in which purine 3′-deoxynucleosides (10,
15, and 17) gave a good C2′-â fluorination yield (up to
65%). These 6-chloropurine 3′-deoxynucleosides were
confirmed to have a C3′-endo conformation favoring
â-elimination. We assume that an electron-withdrawing
6-chloro group might not only suppress nucleic base
migration by reducing the nucleophilicity of the nucleic
base, but may also suppress the formation of elimination
product by reducing the participation of N3 in C3′-â
hydrogen removal.
fluorination process were greatly improved by the use
of Et3N‚3HF. The 2:1 mixture of 11 and 12 was treated
with acetic acid to decompose the acid-sensitive im-
purity 12, while acid-stable C2′-â fluorinated 11 re-
mained and was easily recrystallized to give pure nucleo-
side 11.
Our 6-chloropurine 3′-deoxynucleosides gave a good
fluorination yield despite a C3′-endo conformation. We
assume that the electron-withdrawing 6-chloro group of
the purine moiety might not only suppress base migra-
tion, but may also suppress the formation of elimination
product.
Exp er im en ta l Section
All reagents were purchased and used without further
purification. Preparative layer chromatography (PLC) was
conducted on preparative silica gel plate (layer thickness 2.0
mm). All high-performance liquid chromatography (HPLC)
analyses were carried out with a GL Science ODS-2 column.
All proton NMR spectra were measured in CDCl3 or DMSO-
d6 solvent, and chemical shifts are reported as δ values in parts
per million relative to tetramethylsilane (δ 0.00), CDCl3 (δ
7.26), or DMSO-d6 (δ 2.50) as an internal standard. Data are
reported as follows: chemical shift (integrated intensity or
assignment, multiplicity, coupling constants in hertz, assign-
ment). All carbon NMR spectra were measured in CDCl3 or
DMSO-d6 solvent, and chemical shifts are reported as δ values
in parts per million relative to tetramethylsilane (δ 0.00),
CDCl3 (δ 77.0), or DMSO-d6 (δ 39.5) as an internal standard.
Mass spectra (MS) were obtained with FAB (fast atom
bombardment) ionization.
9-(2,5-Di-O-a cetyl-3-br om o-3-d eoxy-â-D-xylofu r a n osyl)-
1,9-d ih yd r o-6H-p u r in e-6-on e (6). To a suspension of inosine
(20.0 g, 74.6 mmol) in acetic acid (100 mL) was added trimethyl
orthoacetate (11.7 g, 97.4 mmol). After being stirred for 5 h at
50 °C, the reaction mixture was concentrated under reduced
pressure. To this concentrate was added acetic acid (20 mL),
and the reaction mixture was concentrated again under
reduced pressure. To this concentrate was added acetonitrile
(100 mL), and the reaction mixture was cooled to 5 °C. To this
solution was slowly added acetyl bromide (22.0 mL, 298 mmol)
over 2 h. After additional stirring for 4 h at 10 °C, the reaction
mixture was neutralized with aqueous sodium carbonate and
separated into layers. The aqueous layer was extracted with
acetonitrile (50 mL), and the combined organic layers were
dried over sodium sulfate, concentrated in vacuo, and purified
by silica gel column chromatography (CHCl3/MeOH ) 5/1) to
give the desired product (24.8 g, 59.7 mmol, 80.0% yield) as
crystals. An analytical sample was obtained by recrystalliza-
Con clu sion
The pivotal substrate 10, which was obtained from
inosine by a five-step reaction, was treated with DAST
to afford C2′-â fluorinated nucleoside 11. Further ami-
nation and deprotection of 11 gave FddA in good yield.
Another 3′-deoxynucleoside 15 also gave the desired C2′-â
fluorinated derivative 16 under similar treatment with
MOST. To the best of our knowledge, this method is one
of the shortest synthetic route to FddA.
2′-Hydroxyl-activated 3′-deoxynucleoside 17 was also
subjected to the nucleophilic reaction with Et3N‚3HF, to
give the desired C2′-â fluorinated nucleoside 11 along
with elimination product 12. The safety and yield of the
1
tion from acetonitrile: mp 171-172 °C; H NMR (300 MHz,

Synthesis of FddA via a Purine 3′-Deoxynucleoside
J . Org. Chem., Vol. 66, No. 22, 2001 7475
CDCl3) δ 8.34 (1H, s, H-2), 8.24 (1H, s, H-8), 6.20 (1H, bs, H-1′),
5.74 (1H, bs, H-2′), 4.4-4.6 (4H, m, H-3′, H-4′, H-5′ab), 2.20
(3H, s, 5′O-Ac), 2.14 (3H, s, 2′O-Ac); 1H NMR (300 MHz,
DMSO-d6) δ 8.26 (1H, s, H-2), 8.10 (1H, s, H-8), 6.16 (1H, m,
H-1′), 5.82 (1H, m, H-2′), 4.92 (1H, m, H-3′), 4.57 (1H, m, H-4′),
4.36 (2H, m, H-5′), 2.11 (3H, s, 5′O-Ac), 2.06 (3H, s, 2′O-Ac);
13C NMR (75 MHz, CDCl3) δ 170.4, 158.8, 148.4, 146.0, 138.4,
124.2, 87.9, 83.0, 78.6, 64.7, 20.7; IR (KBr) 1750, 1698, 1376,
1226, 1044 cm-1; UV (MeOH) λmax 206, 245 nm; HRMS (FAB+)
calcd for C14H16N4O6Br (M + H)+ 415.0253, found 415.0248.
2′,5′-Di-O-a cetyl-3′-d eoxyin osin e (7). To a solution of
9-(2,5-di-O-acetyl-3-bromo-3-deoxy-â-D-xylofuranosyl)-1,9-dihy-
dro-6H-purin-6-one (4.31 g, 10.4 mmol) in toluene (77 mL) were
added tributyltin hydride (8.63 mL, 31.1 mmol) and 2,2′-
azobisisobutyronitrile (147 mg, 0.893 mmol). After being
stirred for 2 h at 90 °C, the reaction mixture was immediately
cooled to 0 °C and poured into petroleum ether (41 mL). HPLC
analysis showed that the desired product was obtained in
92.2% yield (3.22 g, 9.57 mmol). The resulting precipitate was
filtered and recrystallized sequentially from ethanol (54 mL)
and acetonitrile/water (5/1, 42 mL). The resulting crystals were
filtered and dried at 40 °C under reduced pressure to give an
analytical sample of the desired product (2.34 g, 6.97 mmol,
67.0% yield) as white crystals: mp 242-244 °C; 1H NMR (300
MHz, CDCl3) δ 8.08 (1H, s, H-2), 8.07 (1H, s, H-8), 6.04 (1H,
d, J ) 1.1 Hz, H-1′), 5.59 (1H, bd, J ) 5.9 Hz, H-2′), 4.60 (1H,
m, H-4′), 4.39 (1H, dd, J ) 12.3, 2.9 Hz, H-5′a), 4.22 (1H, dd,
J ) 12.3, 5.2 Hz, H-5′b), 2.50 (1H, ddd, J ) 14.0, 10.5, 5.9 Hz,
H-3′a), 2.16 (1H, ddd, J ) 14.0, 5.8, 1.1 Hz, H-3′b), 2.09 (3H,
2.01-2.32 (1H, m, H-3′b), 2.13 (3H, s, 5′O-Ac), 1.97 (3H, s, 2′O-
Ac); 13C NMR (75 MHz, DMSO-d6) δ 170.3, 170.1, 152.0, 151.3,
149.6, 146.0, 131.5, 89.2, 78.6, 77.4, 64.5, 32.4, 20.9, 20.6; IR
(neat) 1745, 1674, 1592, 1562, 1387, 1339, 1232, 1094, 1053
cm-1; HRMS (FAB+) calcd for C14H16N4O5Cl (M + H)+
355.0809, found 355.0816.
6-Ch lor o-9-(3-d eoxy-â-D-er yth r o-p en t ofu r a n osyl)-9H -
p u r in e (9). To a solution of 6-chloro-9-(2,5-di-O-acetyl-3-deoxy-
â-D-erythro-pentofuranosyl)-9H-purine (20.8 g, 58.6 mmol) in
methanol (62.3 mL) was added 28% sodium methoxide in
methanol (2.89 mL, 14.2 mmol) at 10 °C. After being stirred
for 3 h at room temperature, this reaction mixture was cooled
to 5 °C. HPLC analysis showed that the desired product was
obtained in quantitative yield. Evaporation of the solvent gave
precipitate which was crystallized from methanol/water to give
the desired product (14.9 g, 55.2 mmol, 94.1% yield) as white
crystals. An analytical sample was obtained by recrystalliza-
tion from methanol/water: mp 180-181 °C; 1H NMR (300
MHz, CDCl3) δ 8.68 (1H, s, H-2), 8.33 (1H, s, H-8), 5.83 (1H,
d, J ) 4.6 Hz, H-1′), 4.92 (1H, ddd, J ) 7.2, 6.5, 4.6 Hz, H-2′),
4.53-4.59 (1H, m, H-4′), 3.98 (1H, dd, J ) 12.5, 2.1 Hz, H5′-
a), 3.60 (1H, dd, J ) 12.5, 2.6 Hz, H5′-b), 2.53 (1H, ddd, J )
12.9, 7.2, 5.7 Hz, H3′-a), 2.18 (1H, ddd, J ) 12.9, 8.0, 6.5 Hz,
H3′-b); 1H NMR (300 MHz, DMSO-d6) δ 8.97 (1H, s, H-2), 8.82
(1H, s, H-8), 6.06 (1H, d, J ) 1.4 Hz, H-1′), 5.80 (1H, s, J )
3.9 Hz, 2′-OH), 5.12 (1H, dd, J ) 5.3, 5.2 Hz, 5′-OH), 4.62-
4.68 (1H, m, H-2′), 4.42-4.50 (1H, m, H-4′), 3.78 (1H, ddd, J
) 12.1, 5.3, 3.2 Hz, H-5′a), 3.59 (1H, ddd, J ) 12.1, 5.2, 3.8
Hz, H-5′b), 2.28 (1H, ddd, J ) 13.3, 9.6, 5.3 Hz, H-3′a), 1.93
(1H, ddd, J ) 13.3, 6.0, 2.2 Hz, H-3′b); 13C NMR (75 MHz,
DMSO-d6) δ 151.8, 151.3, 149.3, 145.4, 131.5, 91.6, 81.9, 75.2,
62.1, 33.6; IR (KBr) 3331, 1596, 1562, 1442, 1405, 1391, 1337,
1207, 1129, 1079, 1068 cm-1; UV (MeOH) λmax 204, 265 nm;
HRMS (FAB+) calcd for C10H12N4O3Cl (M + H)+ 271.0598,
found 271.0584.
6-Ch lor o-9-[3-d eoxy-5-O-(tr ip h en ylm eth yl)-â-D-er yth r o-
p en tofu r a n osyl]-9H-p u r in e (10). To a solution of 6-chloro-
9-(3-deoxy-â-D-erythro-pentofuranosyl)-9H-purine (20.0 g, 98.9%
purity, 73.1 mmol) in acetonitrile (140 mL) were added 2,4,6-
collidine (11.6 mL, 87.8 mmol) and trityl chloride (22.4 g, 80.4
mmol). After being stirred for 3 h at 45 °C, methanol (1.48
mL) was added to the reaction mixture. After additional
stirring for 1 h at room temperature, the reaction mixture was
concentrated under reduced pressure. The residue was dis-
solved in dichloromethane (200 mL) and water (100 mL),
acidified (pH 3.0) with 6 N hydrogen chloride, and separated
into layers. The organic layer was again mixed with water (100
mL), acidified (pH 3.0) with 6 N hydrogen chloride, and
separated into layers. The organic layer was mixed with water
(100 mL), neutralized (pH 7.0) with saturated aqueous sodium
hydrogencarbonate, and separated into layers. The organic
layer was dried over sodium sulfate and concentrated. The
residue was concentrated with benzotrifluoride (220 mL) and
then crystallized from benzotrifluoride (180 mL). The resulting
crystals were filtered and dried at 40 °C under reduced
pressure to give the desired product (31.9 g, 62.2 mmol, 85.1%
yield) as white crystals: mp 205-206 °C; 1H NMR (300 MHz,
CDCl3) δ 8.64 (1H, s, H-2), 8.40 (1H, s H-8), 7.21-7.41 (15H,
m, 5′O-Tr), 6.04 (1H, d, J ) 2.2 Hz, H-1′), 4.85-4.91 (1H, m,
H-2′), 4.68-4.78 (1H, m, H-4′), 3.44 (1H, dd, J ) 10.6, 3.1 Hz,
H-5′a), 3.33 (1H, dd, J ) 10.6, 4.6 Hz, H-5′b), 2.30 (1H, ddd, J
) 13,3. 7.7, 5.6 Hz, H-3′a), 2.17 (1H, ddd, J ) 13.3, 6.5, 3.9
Hz, H-3′b); 13C NMR (75 MHz, CDCl3) δ 151.4, 151.2, 150.4,
146.7, 143.3, 132.4, 128.5, 127.8, 127.2, 93.1, 87.0, 80.7, 76.0,
64.7, 33.9; IR (KBr): 3354, 3059, 1592, 1562, 1491, 1449, 1400,
1338, 1206, 1130, 1078, 1018 cm-1; UV (MeOH) λmax: 207, 265
nm; HRMS (FAB+) calcd for C29H26N4O3Cl (M + H)+ 513.1693,
found 513.1717. Anal. Calcd for C29H25N4O3Cl: C, 67.90; H,
4.91; N, 10.92. Found: C, 67.92; H, 4.95; N, 10.76.
1
s, 5′O-Ac), 2.04 (3H, s, 2′O-Ac); H NMR (300 MHz, DMSO-
d6) δ 8.26 (1H, s, H-2), 8.10 (1H, s H-8), 6.11 (1H, d, J ) 1.4
Hz, H-1′), 5.61 (1H, bd, J ) 6.3 Hz, H-2′), 4.52 (1H, m, H-4′),
4.29 (1H, dd, J ) 12.0, 2.9 Hz, H-5′a), 4.16 (1H, dd, J ) 12.0,
5.8 Hz, H-5′b), 2.60 (1H, ddd, J ) 14.1, 10.3, 6.3 Hz, H-3′a),
2.22 (1H, ddd, J ) 14.1, 5.9, 1.1 Hz, H-3′b), 2.10 (3H, s, 5′O-
Ac), 1.99 (3H, s, 2′O-Ac); 13C NMR (75 MHz, DMSO-d6) δ 170.3,
170.1, 156.7, 147.9, 146.2, 138.9, 124.6, 88.6, 78.2, 77.7, 64.6,
32.6, 20.9, 20.7; IR (KBr) 1746, 1724, 1707, 1419, 1344, 1230,
1205, 1122, 1101 cm-1; UV (MeOH) λmax 203, 245 nm; HRMS
(FAB+) calcd for C14H17N4O6 (M + H)+ 337.1148, found
337.1153.
6-Ch lor o-9-(2,5-d i-O-a cetyl-3-d eoxy-â-D-er yth r o-p en to-
fu r a n osyl)-9H-p u r in e (8). Rea ction w ith Vilsm eier Re-
a gen t. To a suspension of 2′,5′-di-O-acetyl-3′-deoxyinosine
(2.89 g, 8.60 mmol) in dichloromethane (40 mL) were added
dimethylformamide (1.92 mL, 24.8 mmol) and thionyl chloride
(1.81 mL, 24.8 mmol). After being stirred for 6 h at reflux, the
reaction mixture was cooled to 10 °C and poured into ice-
water (500 mL). The reaction mixture was separated into
layers, and the organic layer was washed with aqueous
saturated sodium hydrogencarbonate (× 2). The organic layer
was concentrated in vacuo to give the desired product (2.87 g,
8.09 mmol, 94.1% yield) as a colorless foam.
Rea ction w ith P OCl3 a n d P h a se-Tr a n sfer Ca ta lyst. To
a suspension of 2′,5′-di-O-acetyl-3′-deoxyinosine (1.00 g, 2.97
mmol) in acetonitrile (4.5 mL) were added N,N-dimethylaniline
(0.81 mL, 6.4 mmol), tetraethylammonium chloride (736 mg,
4.44 mmol), and phosphorus oxychloride (0.62 mL, 6.7 mmol).
After being stirred for 2 h at reflux, the reaction mixture was
cooled to room temperature and poured into dichloromethane/
ice-water. The reaction mixture was separated into layers,
and the organic layer was washed with aqueous saturated
sodium hydrogencarbonate and water. The organic layer was
dried over sodium sulfate and concentrated in vacuo to give
the desired product (1.04 g, 2.94 mmol, 99.0% yield) as a
colorless foam: 1H NMR (300 MHz, CDCl3) δ 8.77 (1H, s, H-2),
8.32 (1H, s, H-8), 6.15 (1H, d, J ) 1.3 Hz, H-1′), 5.74 (1H, d, J
) 5.8 Hz, H-2′), 4.63-4.74 (1H, m, H-4′), 4.46 (1H, dd, J )
12.3, 2.8 Hz, H-5′a), 4.30 (1H, dd, J ) 12.3, 5.1 Hz, H-5′b),
2.65 (1H, ddd, J ) 14.1, 10.6, 6.0 Hz, H-3′a), 2.27 (1H, ddd, J
) 14.1, 5.6, 1.3 Hz, H-3′b), 2.17 (3H, s, 5′O-Ac), 2.08 (3H, s,
2′O-Ac); 1H NMR (300 MHz, DMSO-d6) δ 8.85 (2H, s, H-2, H-8),
6.31 (1H, s, H-1′), 5.76 (1H, s, H-2′), 4.55-4.64 (1H, m, H-4′),
4.32 (1H, dd, J ) 12.1, 2.8 Hz, H-5′a), 4.22 (1H, dd, J ) 12.1,
5.8 Hz, H-5′b), 2.67 (1H, ddd, J ) 14.2, 10.3, 6.1 Hz, H-3′a),
6-Ch lor o-9-[2,3-dideoxy-2-flu or o-5-O-(tr iph en ylm eth yl)-
â-D-th r eo-p en tofu r a n osyl]-9H-p u r in e (11) a n d 6-Ch lor o-
9-[2,3-d id eoxy-2,3-d id eh yd r o-5-O-(tr ip h en ylm eth yl)-â-D-
er yth r o-p en tofu r a n osyl]-9H-p u r in e (12). Rea ction w ith
DAST. To a solution of 6-chloro-9-[3-deoxy-5-O-(triphenyl-
methyl)-â-D-erythro-pentofuranosyl]-9H-purine (104 mg, 0.202

7476 J . Org. Chem., Vol. 66, No. 22, 2001
Takamatsu et al.
mmol) in dichloromethane (10 mL) was added pyridine (0.120
mL, 1.48 mmol) at 0 °C. At this temperature, to this solution
was added diethylaminosulfur trifluoride (70.0 µL, 0.530
mmol) dropwise with vigorous stirring. After stirring for 4 h
at reflux, this reaction mixture was recooled to room temper-
ature and then poured into aqueous saturated sodium hydro-
gencarbonate (20 mL) and dichloromethane (10 mL) with
vigorous stirring. After additional stirring for 20 min, the
reaction mixture was separated into layers. The organic layer
was concentrated azeotropically with toluene under reduced
pressure. The residue was purified by preparative silica gel
plate (hexane/ethyl acetate ) 1/1) to give the desired product
(44.3 mg, yield 42.6%) as a white solid. An analytical sample
was obtained by recrystallization from hexane/ethyl acetate:
mp 191-192 °C; 1H NMR (300 MHz, CDCl3) δ 8.73 (1H, s, H-2),
8.34 (1H, d, J ) 2.8 Hz, H-8), 7.22-7.52 (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′), 4.42-4.50 (1H, m, H-4′), 3.48 (1H, dd, J )
9.9, 6.6 Hz, H-5′a), 3.30 (1H, dd, J ) 9.9, 3.8 Hz, H-5′b), 2.57
(1H, dddd, J ) 35.0, 14.8, 9.0, 5.6 Hz, H-3′a), 2.36 (1H, dddd,
J ) 27.5, 15.1, 5.1, 1.7 Hz, H-3′b); 13C NMR (75 MHz, CDCl3)
δ 152.0, 151.2 (d, J ) 16.8 Hz), 144.7 (d, J ) 5.8 Hz), 143.6,
128.6, 127.9, 127.2, 90.6 (d, J ) 188.9 Hz), 86.9, 85.0 (d, J )
16.4 Hz), 76.8, 65.7, 33.8 (d, J ) 20.5 Hz); IR (KBr): 1593,
1567, 1492, 1220, 1206, 1079 cm-1; UV (MeOH) λmax: 206, 264
(pH 1.8) with 37% aqueous hydrogen chloride and separated
into layers. The aqueous layer was washed with ethyl acetate
(2 × 17 mL), neutralized (pH 7.5) with 25% aqueous ammonia,
and cooled to 6 °C. After stirring for 1 h, the resulting crystals
were filtered, washed with water, and dried at 50 °C under
reduced pressure to obtain the desired product (7.97 g, 31.5
mmol, 91.6% yield) as white crystals: mp 226-227 °C (lit.2
227 °C); 1H NMR (300 MHz, DMSO-d6) δ 8.27 (1H, d, J ) 2.3
Hz, H-8), 8.16 (1H, s, H-2), 7.33 (2H, bs, 6-NH2), 6.32 (1H, dd,
J ) 16.1, 3.9 Hz, H-1′), 5.43 (1H, dm, J ) 54.4 Hz, H-2′), 5.07
(1H, t, J ) 5.9 Hz, 5′-OH), 4.13-4.23 (1H, m, H-4′), 3.54-3.69
(2H, m, H-5′ab), 2.47-2.68 (1H, m, H-3′a), 2.17-2.36 (1H, m,
H-3′b); 13C NMR (75 MHz, DMSO-d6) δ 156.2, 152.9, 149.3,
139.7 (d, J ) 4.7 Hz), 118.4, 91.5 (d, J ) 185.9 Hz), 83.8 (d, J
) 16.1 Hz), 77.9, 63.1, 32.6 (d, J ) 19.3 Hz); IR (KBr): 3328,
3208, 3136, 1661, 1076, 1061 cm-1; UV (MeOH) λmax: 259, 204
nm; HRMS (FAB+) calcd for C10H13N5O2F (M + H)+ 254.1053,
found 254.1048. Anal. Calcd for C10H12N5O2F: C, 47.43; H,
4.78; N, 27.66; F, 7.50. Found: C, 47.45; H, 4.84; N, 27.46; F,
7.13.
6-Ch lor o-9-(2,3-d id eoxy-2-flu or o-â-D-th r eo-p en tofu r a -
n osyl)-9H-p u r in e (14) a n d 9-(2,3-Did eoxy-2-flu or o-â-D-
th r eo-p en tofu r a n osyl)a d en in e (1, F d d A). To a suspension
of 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl)-â-D-
threo-pentofuranosyl]-9H-purine (3.65 g, 7.09 mmol) in metha-
nol (18 mL) and toluene (18 mL) was added 0.5 equiv of 37%
aqueous hydrogen chloride (0.30 mL, 3.5 mmol). After being
stirred for 4 h at room temperature, the reaction mixture was
treated with 2 equiv of poly (4-vinylpyridine) and filtered. The
filtrate was concentrated under reduced pressure. An analyti-
cal sample was obtained by recrystallization from dichlo-
romethane/methanol: mp 154-155 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.89 (1H, d, J ) 1.4 Hz, H-8), 8.84 (1H, s, H-2),
6.52 (1H, dd, J ) 14.1, 4.0 Hz, H-1′), 5.55 (1H, ddd, J ) 54.2,
9.9, 4.3 Hz, H-2′), 5.11 (3H, t, J ) 5.8 Hz, 5′OH), 4.20-4.31
(1H, m, H-4′), 3.59-3.75 (2H, m, H-5′ab), 2.50-2.72 (1H, m
H-3′a), 2.22-2.42 (1H, m, H-3′b); 13C NMR (75 MHz, CDCl3)
δ 151.9, 151.3, 149.3, 145.8 (d, J ) 3.4 Hz), 130.7, 91.4 (d, J )
186.9 Hz), 84.2 (d, J ) 16.2 Hz), 78.5, 62.6, 32.0 (d, J ) 19.3
Hz); IR (KBr) 3397, 1592, 1564, 1494, 1452, 1343, 1214, 1144,
1059 cm-1; HRMS (FAB+) calcd for C10H11N4O2FCl (M + H)+
273.0555, found 273.0555. The resulting residue was dissolved
in methanol (200 mL) and toluene (200 mL). After stirring for
5 days at 40-60 °C under a 3-5 bar ammonia atmosphere,
the pressure was reduced to ambient pressure, and the
temperature was allowed to fall to room temperature. The
resulting mixture was concentrated in vacuo, and the residue
was triturated with 80% aqueous acetone. The resulting
crystals were filtered to give the desired product (1.60 g, 81.7%
purity, 72.8% yield) as pale yellow crystals. An analytical
sample was obtained by recrystallization from acetone/water
and ethanol/water.
nm; HRMS (FAB+) calcd for
C
29H25N4O2FCl (M + H)+
515.1650, found 515.1658; Anal. Calcd for C29H24N4O2FCl: C,
67.64; H, 4.70; N, 10.88; Cl, 6.88. Found: C, 67.34; H, 4.81;
N, 10.61; Cl, 6.98.
The side product 12 was also purified by preparative silica
gel plate (hexane/ethyl acetate ) 1/1). An analytical sample
was obtained by recrystallization from hexane/ethyl acetate:
1
mp 156 °C (decomp); H NMR (300 MHz, CDCl3) δ 8.68 (1H,
s, H-2), 8.15 (1H, s H-8), 7.14-7.41 (15H, m, 5′O-Tr), 7.09 (1H,
bs, H-1′), 6.37 (1H, bd, J ) 5.7 Hz, H-3′), 6.03 (1H, bd, J ) 5.7
Hz, H-2′), 5.10 (1H, bs, H-4′), 3.40 (1H, dd, J ) 10.2, 5.5 Hz,
H-5′a), 3.27 (1H, dd, J ) 10.2, 3.9 Hz, H-5′b); 13C NMR (75
MHz, CDCl3) δ 151.7, 151.1, 150.5, 143.3, 143.0, 134.9, 131.6,
128.2, 127.5, 126.9, 124.3, 88.8, 86.6, 86.4, 65.0; IR (KBr):
3058, 1591, 1558, 1335, 1195, 1075 cm-1; UV (MeOH) λmax
:
212, 265 nm; HRMS (FAB+) calcd for C29H24N4O2Cl (M + H)+
495.1588, found 495.1583. Anal. Calcd for C29H23N4O2Cl: C,
70.37; H, 4.68; N, 11.32. Found: C, 70.20; H, 4.81; N, 11.19.
9-[2,3-Dideoxy-2-flu or o-5-O-(tr iph en ylm eth yl)-â-D-th r eo-
p en tofu r a n osyl]a d en in e (13) a n d 9-(2,3-d id eoxy-2-flu or o-
â-D-th r eo-p en tofu r a n osyl)a d en in e (1, F d d A). 6-Chloro-9-
[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl)-â-D-threo-pento-
furanosyl]-9H-purine (17.7 g, 34.4 mmol) was dissolved in
tetrahydrofuran (270 mL). After stirring for 4 days at 70 °C
under a 5.6-6.0 bar ammonia atmosphere, the pressure was
reduced to ambient pressure, and the temperature was allowed
to fall to room temperature. The resulting mixture was
concentrated in vacuo to give the desired product. An analyti-
cal sample was obtained by recrystallization from ethyl ace-
9-(5-O-Acet yl-3-d eoxy-â-D-er yth r o-p en t ofu r a n osyl)-6-
ch lor o-9H-p u r in e (15). To a solution of 6-chloro-9-(2,5-di-O-
acetyl-3-deoxy-â-D-erythro-pentofuranosyl)-9H-purine (5.00 g,
14.1 mmol) in methanol (25 mL) was added triethylamine (2.00
mL, 14.3 mmol). After additional stirring for 66 h, the reaction
mixture was neutralized (pH 7.0) with 1 N hydrogen chloride.
The reaction mixture was concentrated under reduced pres-
sure and purified by silica gel column chromatography (hex-
ane/ethyl acetate ) 1/3) to give the desired product (1.48 g,
4.73 mmol, 33.5% yield). An analytical sample was obtained
by recrystallization from hexane/ethyl acetate: mp 161-164
1
tate/methanol: mp 235-236 °C; H NMR (300 MHz, CDCl3)
δ 8.33 (1H, s, H-2), 8.06 (1H, d, J ) 3.0 Hz, H-8), 7.20-7.52
(15H, m, 5′O-Tr), 6.33 (1H, dd, J ) 19.9, 2.9 Hz, H-1′), 6.18
(2H, bs, 6-NH2), 5.20 (1H, dm, J ) 53.8 Hz, H-2′), 4.35-4.45
(1H, m, H-4′), 3.46 (1H, dd, J ) 10.0, 6.5 Hz, H-5′a), 3.27 (1H,
dd, J ) 10.0, 4.1 Hz, H-5′b), 2.50 (1H, dddd, J ) 35.5, 14.9,
9.0, 5.4 Hz, H-3′a), 2.31 (1H, dddd, J ) 27.5, 14.9, 4.8, 1.4 Hz,
H-3′b); 13C NMR (75 MHz, CDCl3) δ 155.4, 152.9, 149.6, 143.6,
140.1 (d, J ) 6.9 Hz), 128.6, 127.9, 127.1, 119.0, 90.6 (d, J )
188.6 Hz), 86.7, 84.7 (d, J ) 16.7 Hz), 76.2, 65.8, 33.9 (d, J )
1
°C; H NMR (300 MHz, CDCl3) δ 8.75 (1H, s, H-2), 8.43 (1H,
20.6 Hz); IR (KBr): 3151, 1649, 1599, 1578, 1403, 1063 cm-1
UV (MeOH) λmax 208, 259 nm; HRMS (FAB+) calcd for
29H27N5O2F (M + H)+ 496.2149, found 496.2141.
To a solution of the resulting 9-[2,3-dideoxy-2-fluoro-5-O-
;
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); 13C NMR (75 MHz, DMSO-d6) δ
170.4, 151.9, 151.4, 149.4, 145.6, 131.6, 91.7, 78.5, 74.5, 65.0,
:
C
(triphenylmethyl)-â-D-threo-pentofuranosyl]adenine in metha-
nol (173 mL) was added 37% aqueous hydrogen chloride (11.6
mL, 139 mmol). After being stirred for 1 h at room tempera-
ture, the reaction mixture was quenched (pH 4.5) with 25%
aqueous ammonia. After concentration in vacuo at 18 °C, the
residue was dissolved in water (52 mL) and ethyl acetate (52
mL). After vigorous stirring, the reaction mixture was acidified
34.6, 20.7; IR (KBr): 3230, 1752, 1593, 1569, 1241, 1134 cm-1
;
HRMS (FAB+) calcd for C12H14N4O4Cl (M + H)+ 313.0704,
found 313.0690. Anal. Calcd for C12H13N4O4Cl: C, 46.09; H,
4.19; N, 17.92. Found: C, 46.13; H, 4.24; N, 17.96.
9-(5-O-Acetyl-2,3-d id eoxy-2-flu or o-â-D-th r eo-p en tofu r a -
n osyl)-6-ch lor o-9H -p u r in e (16) a n d 9-(2,3-Did eoxy-2-

Synthesis of FddA via a Purine 3′-Deoxynucleoside
J . Org. Chem., Vol. 66, No. 22, 2001 7477
flu or o-â-D-th r eo-p en tofu r a n osyl)a d en in e (1, F d d A). To a
solution of 9-(5-O-acetyl-3-deoxy-â-D-erythro-pentofuranosyl)-
6-chloro-9H-purine (100 mg, 0.320 mmol) in dichloromethane
(3.2 mL) was added pyridine (0.16 mL, 1.9 mmol) at 5 °C. At
this temperature, to this solution was added morpholinosulfur
trifluoride (98 µL, 0.80 mmol) dropwise with vigorous stirring.
After stirring for 3 h at reflux, the reaction mixture was
recooled to room temperature and then poured into aqueous
saturated sodium hydrogencarbonate (20 mL) and dichlo-
romethane (20 mL) with vigorous stirring. After additional
stirring for 30 min, the reaction mixture was separated into
layers. The organic layer was washed with 0.5 N hydrogen
chloride (20 mL) and saturated aqueous sodium hydrogencar-
bonate (20 mL), dried over sodium sulfite, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography (dichloromethane/methanol ) 10/1) to give
the desired product (38.9 mg, 0.124 mmol, 38.8% yield) as a
foam. An analytical sample was obtained by recrystallization
from hexane/ethyl acetate.Mp 201 °C (decomp); 1H NMR (300
MHz, CDCl3) δ 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); 13C NMR (75 MHz,
CDCl3) δ 170.7, 152.1, 151.4, 144.6 (d, J ) 5.6 Hz), 90.5 (d, J
) 189.2 Hz), 85.4 (d, J ) 16.7 Hz), 75.7, 65.3, 33.7 (d, J )
312 mmol) and triethylamine (15.8 g, 21.8 mL, 156 mmol) at
32 °C. After being stirred for 43 h at 40 °C, the reaction
mixture was treated with water (400 mL) and separated into
layers. The organic layer was washed with water (2 × 400 mL),
aqueous sodium hydrogencarbonate (400 mL), and aqueous
sodium carbonate (2 × 400 mL). After concentration, HPLC
analysis showed that 25.9 g of desired product was obtained
(64.5% yield in two steps). The side product 12 was also
obtained in 32.6% yield.
P u r ification an d Separ ation of 6-Ch lor o-9-[2,3-dideoxy-
2-flu or o-5-O-(tr iph en ylm eth yl)-â-D-th r eo-pen tofu r an osyl]-
9H-p u r in e (11). To part of the resulting concentrated toluene
solution (260 mL) of the mixture of 6-chloro-9-[2,3-dideoxy-2-
fluoro-5-O-(triphenylmethyl)-â-D-threo-pentofuranosyl]-9H-pu-
rine (15.7 g, 30.5 mmol) and 12 was added 80% acetic acid
(120 mL). After vigorous stirring for 6 h at 10 °C, the reaction
mixture was separated into layers. The aqueous layer was
extracted with toluene (24 mL), and the combined organic
layers were washed with water (2 × 24 mL). The organic layers
were treated with tetrahydrofuran (48 mL) and 80% acetic acid
(3 mL) and again separated into layers. The organic layer was
concentrated to 50 mL under reduced pressure at 20 °C and
treated with cyclohexane (72 mL). The resulting crystals were
filtered, washed with cyclohexane (2 × 24 mL), and dried
under reduced pressure to give the pure desired product (10.9
g, 21.2 mmol, 69.5% yield) as white crystals.
6-Ch lor o-9-[2,3-dideoxy-2-flu or o-5-O-(tr iph en ylm eth yl)-
â-D-th r eo-p en tofu r a n osyl]-9H-p u r in e (11). Rea ction w ith
Et3N‚3HF th r ou gh 6-Ch lor o-9-[3-d eoxy-2-O-(su lfu r ylim i-
d a zolyl)-5-O-(tr ip h en ylm eth yl)-â-D-er yth r o-p en tofu r a n o-
syl]-9H-p u r in e (18). To a solution of 6-chloro-9-[3-deoxy-5-
O-(triphenylmethyl)-â-D-erythro-pentofuranosyl]-9H-purine (590
mg, 1.15 mmol) in dichloromethane (11 mL) were added
pyridine (0.17 mL, 2.05 mmol) and sulfuryl chloride (0.11 mL,
1.37 mmol) at -35 °C. After being stirred for 30 min at -35
°C, the reaction mixture was treated with imidazole (360 mg,
5.13 mmol) and stirred for 16 h at room temperature. To this
reaction mixture was added imidazole (800 mg, 1.14 mmol),
and the result was stirred for 4.5 h at room temperature. The
reaction mixture was treated with water and separated into
layers. The aqueous layer was extracted with dichloromethane,
and the combined organic layers were dried over sodium
sulfate, concentrated in vacuo, and purified by silica gel column
chromatography to give the desired product (790 mg) as an
oil.
To a solution of 6-chloro-9-[3-deoxy-2-O-(sulfurylimidazolyl)-
5-O-(triphenylmethyl)-â-D-erythro-pentofuranosyl]-9H-pu-
rine (110 mg, 0.18 mmol) in toluene (1.8 mL) was added
triethylamine trihydrofluoride (0.18 mL, 1.1 mmol) at 50 °C.
After being stirred for 2 days at 50 °C, the reaction mixture
was cooled to room temperature and treated with ethyl acetate
and aqueous sodium hydrogencarbonate. The reaction mixture
was separated into layers and dried over sodium sulfate. After
concentration, HPLC analysis showed that 38.0 mg of the
desired product was obtained (41.9% yield in two steps).
20.7 Hz), 20.9; IR (KBr): 1731, 1595, 1565, 1271, 1222 cm-1
;
HRMS (FAB+) calcd for C12H13N4O3ClF (M + H)+ 315.0660,
found 315.0651; Anal. Calcd for C12H12N4O3ClF: C, 45.80; H,
3.84; N, 17.80. Found: C, 46.05; H, 3.90; N, 17.79. The
resulting 9-(5-O-acetyl-2,3-dideoxy-2-fluoro-â-D-threo-pento-
furanosyl)-6-chloro-9H-purine (32.4 mg, 0.103 mmol) was
dissolved in tetrahydrofuran (0.5 mL). After stirring for 4 days
at 60 °C under a 2.8 bar ammonia atmosphere, the pressure
was reduced to ambient pressure, and the temperature was
allowed to fall to room temperature. HPLC analysis showed
that the desired product was obtained in 88.2% yield (23.0 mg,
0.0908 mmol).
6-Ch lor o-9-[3-d eoxy-2-O-[(tr iflu or om eth yl)su lfon yl]-5-
O-(tr ip h en ylm eth yl)-â-D-er yth r o-p en tofu r a n osyl]-9H-p u -
r in e (17). To a solution of 6-chloro-9-[3-deoxy-5-O-(triphenyl-
methyl)-â-D-erythro-pentofuranosyl]-9H-purine (40.0 g, 78.0
mmol) in dichloromethane (400 mL) were added pyridine (18.9
mL, 234 mmol) and trifluoromethanesulfonic anhydride (14.4
mL, 85.8 mmol) at -10 °C. After being stirred for 4 h at -10
°C, the reaction mixture was treated with ice (220 g) and water
(100 g), acidified (pH 3.0) with 2 M sulfuric acid, and separated
into layers. The organic layer was washed with water (320 mL)
and aqueous sodium hydrogencarbonate (320 mL) and con-
centrated in vacuo. The residue was concentrated azeotropi-
cally with toluene to give the desired product quantitatively
as a foam which was used without further purification. An
analytical sample was purified by silica gel column chroma-
tography (hexane/ethyl acetate ) 3/1): mp 108-112 °C (de-
comp); 1H NMR (300 MHz, CDCl3) δ 8.67 (1H, s, H-2), 8.30
(1H, s H-8), 7.21-7.40 (15H, m, 5′O-Tr), 6.32 (1H, d, J ) 1.2
Hz, H-1′), 6.18 (1H, bd, J ) 5.2 Hz, H-2′), 4.62-4.73 (1H, m,
H-4′), 3.50 (1H, dd, J ) 10.8, 3.1 Hz, H-5′a), 3.40 (1H, dd, J )
10.8, 4.5 Hz, H-5′b), 2.87 (1H, ddd, J ) 15.0. 9.7, 5.4 Hz, H-3′a),
2.44 (1H, ddd, J ) 14.7, 5.6, 1.4 Hz, H-3′b); 13C NMR (75 MHz,
CDCl3) δ 152.0, 151.4, 150.4, 143.7, 143.0, 132.2, 128.4, 127.8,
127.2, 118.3 (q, J ) 318.1 Hz), 89.6, 88.9, 87.1, 80.2, 63.5, 33.1;
Ack n ow led gm en t. The authors thank Dr. Kyoichi
A. Watanabe for valuable suggestions and comments,
and Dr. Etienne De Cock and Mr. Geert Schelkens
(OmniChem N.V.) for their assistance during this work.
We are also grateful to Mr. Hideo Takeda, Mr. Shigekat-
su Tsuchiya, and Mr. Mitsuhiko Kojima for their
technical assistance and to the staff members of the
Analytical Department of Ajinomoto Co., Inc. for mea-
suring spectral data.
IR (KBr): 1593, 1564, 1419, 1248, 1211, 1143, 1081 cm-1
;
HRMS (FAB+) calcd for C30H25N4O5ClF3S (M + H)+ 645.1186,
found 645.1179; Anal. Calcd for C30H24N4O5ClF3S: C, 55.86;
H, 3.75; N, 8.69. Found: C, 55.40; H, 4.04; N, 8.46.
6-Ch lor o-9-[2,3-dideoxy-2-flu or o-5-O-(tr iph en ylm eth yl)-
â-D-th r eo-p en tofu r a n osyl]-9H-p u r in e (11). Rea ction w ith
Et3N‚3HF . To a solution of 6-chloro-9-[3-deoxy-2-O-[(trifluo-
romethyl)sulfonyl]-5-O-(triphenylmethyl)-â-D-erythro-pento-
furanosyl]-9H-purine (50.3 g, 78.0 mmol) in toluene (2000 mL)
were added triethylamine trihydrofluoride (50.3 g, 50.9 mL,
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra for compounds 1 and 6-17 and NOESY
data for 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0158985