A stereoselective synthesis of 9-(3-O-benzyl-5-O-tetrahydropyranyl-β- D-arabinofuranosyl)adenine, a potentially useful intermediate for ribonucleoside synthesis

Article abstract of DOI:10.1016/j.tet.2004.02.033

A novel synthesis for preparing 9-(3-O-benzyl-5-O-tetrahydropyranyl-β- D-arabinofuranosyl)adenine (6) has been developed which does not require sub zero temperatures or exotic reagents. A key step in this synthesis is the selective protection of the 3′-OH of ara-A with a benzyl group. The 5′-OH is then selectively protected with DHP to yield 6, a potentially useful intermediate. A synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo- pentofuranosyl)adenine (1, FddA), an anti-viral compound, is given to illustrate the utility of this new approach.

Full text of DOI:10.1016/j.tet.2004.02.033

Tetrahedron 60 (2004) 3445–3449
A stereoselective synthesis of 9-(3-O-benzyl-5-O-
tetrahydropyranyl-b-D-arabinofuranosyl)adenine, a potentially
useful intermediate for ribonucleoside synthesisq;qq
*
Christopher J. Woltermann, Yuri A. Lapin, Kevin B. Kunnen, David R. Tueting
and Ignacio H. Sanchez
Fine Chemicals, Division of Great Lakes Chemical Corp., 601 E. Kensington Rd., Mt. Prospect, IL 60056, USA
Received 2 December 2003; revised 17 February 2004; accepted 17 February 2004
Abstract—A novel synthesis for preparing 9-(3-O-benzyl-5-O-tetrahydropyranyl-b-D-arabinofuranosyl)adenine (6) has been
d0eveloped which does not require sub zero temperatures or exotic reagents. A key step in this synthesis is the selective protection of the
3 -OH of ara-A with a benzyl group. The 50-OH is then selectively protected with DHP to yield 6, a potentially useful intermediate. A
synthesis of 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine (1, FddA), an anti-viral compound, is given to illustrate the utility of
this new approach.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
intermediate for nucleoside synthesis. This intermediate
was used in a convenient method for preparing 1.
Purine nucleosides bearing fluorine at C20 have been studied
intensely the past few years because of their biological
activity. For example, 9-(2,3-dideoxy-2-fluoro-b-D-threo-
pentofuranosyl)adenine (1, FddA) has been investigated for
its anti-viral activity against HIV.1 Several methods for
synthesizing 1 have been reported,1b,2 all of which take one
of two general approaches: (1) coupling of a fluorinated
sugar with a purine base,1a,2a and (2) fluorination and
transformation of a pre-formed nucleoside derivative.2b–g A
key step in the latter, more attractive synthetic approach is
the selective protection of0 30-OH of the ribonucleosides
prior to0fluorination at the 2 position. The similar reactivity
of the 2 and 30-OH groups of ribonucleosides makes selec-
tive protection of either of these functionalities difficult.
There are a limited number of selective methods for
protecting 30-OH of purine ribonucleosides.3 Herein is
reported a new way to conveniently protect 9-(b-D-
arabinofuranosyl)adenine (2, ara-A) at 30-OH. Once 30-OH
is selectively protected the 50-OH can be easily protected
with a different blocking group to afford a useful
2. Results and discussion
Commercially available 2 is easily converted to 9-(2,3-
anhydro-b-D-lyxofuranosyl)adenine (3) in high yield.4a–c
Nucleophiles such as acetate4c and azide4d preferentially
attack the a-face of 3 at C30 yielding 30-substituted adenine
arabinosides (4a-b, Scheme 1). We have now demonstrated
that when a salt of benzyl alcohol is employed for the
nucleophilic ring-opening, 9-(3-O-benzyl-b-D-arabino-
furanosyl)adenine (4c) is obtained in 74% yield. The
preparation of 4c is performed in benzyl alcohol solvent
with the sodium salt of benzyl alcohol, as generated by NaH
or t-BuONa. The sodium counter ion seems to give the best
results but potassium and magnesium have also been used
successfully. Desired isomer 4c is formed preferentially
over the 20-O-benzyl isomer (5c) in a ratio of ,6:1. This
manipulation effe0ctively provides ara-A that is blocked by a
benzyl group at 3 -OH. The benzyl fragment is an excellent
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found in the
online version at doi: 10.1016/j.tet.2004.02.033
Keywords: Fluororibonucleoside; Ara-A; 9-(3-O-Benzyl-5-O-
tetrahydropyranyl-b-D-arabinofuranosyl)adenine; 9-(2,3-Dideoxy-2-
fluoro-b-D-threo-pentofuranosyl)adenine; FddA.
*
Corresponding author. Tel.: þ704-868-5421; fax: þ704-868-5496;
e-mail address: chris_woltermann@fmc.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.033

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C. J. Woltermann et al. / Tetrahedron 60 (2004) 3445–3449
Scheme 1.
protecting group for preparing 20-fluororibonucleosides
because it will survive fluorination conditions, will not
migrate, as is often seen for acetyl and benzoyl groups, and
can be selectively removed.
accomplished.5 Marquez, et al.2c took advantage of this
behavior in their synthesis of 1 by fluorinating a protected
ara-A derivative from the a-face, eliminating to a vinyl
fluoride intermediate and selectively hydrogenating. By this
sequence, they 0were able to effectively0 invert the stereo-
chemistry at C2 while deoxygenating C3 to produce 1. The
same general approach can be used to transform 6 into 1
(Scheme 2).
With the 30-OH blocked, the primary 50-OH can be protected
easily and selectively to leave only the 20-OH free for
fluorination. A variety of reagents can be used to block
50-OH but dihydropyran (DHP) appears to be the most
amenable to the downstream chemistry for preparing 1. The
resulting tetrahydropyranyl group will not be removed
under the hydrogenation conditions used to remove the
benzyl-protecting group and will not be affected by the
fluorination conditions. Hence, when 4c is reacted with
DHP in DMF at 0 8C, the desired 9-(3-O-benzyl-5-O-
tetrahydropyranyl-b-D-arabinofuranosyl)adenine (6) is
obtained in 85% yield after column chromatography.
Thus, ara-A derivatives bearing different protecting groups
on 30-OH and 50-OH are easily obtainable. The presence of
different protecting groups at 30 and 50 provides synthetic
flexibility because it allows selective removal of either
group.
Fluorination of 6 was accomplished by converting the
20-OH to the triflate and displacing with tetrabutylammo-
nium fluoride in THF to yield 7 in 65% yield after column
chromatography to remove the elimination co-product and
ammonium salts. The benzyl protecting group of 7 can be
removed, without affecting the THP group, by hydro-
genolysis using Pearlman’s catalyst and cyclohexene as a
hydrogen donor.6 Thus, 7 was refluxed in ethanol and
cyclohexene in the presence of 20–40% (based on weight of
7) dry Pearlman’s catalyst to afford 8 in 81% isolated yield.
Interestingly, Pd/C and hydrogen at 150 8C and 180 psi
removed only the THP group. Under these conditions, the
hydrogenation catalyst may behave like a Lewis acid
causing transketalation of the THP group with the ethanol
solvent.
Once the 30- and 50-OH groups have been blocked, the
20-OH can be converted to a leaving group and displaced by
fluoride. Fluorination of purine nucleosides by SN2
displacement at the b-face of C20 is notoriously
difficult1b,2f–g while fluorination from the a-face is readily
Reaction of 8 with Tf2O in the presence of DMAP and
pyridine was rapid and clean. The reaction mixture was
washed with 10% Na2CO3 (aq.) and concentrated to isolate
Scheme 2. Key: (a) Tf2O, DMAP, pyridine, CH2Cl2, 0 8C; (b) TBAF, THF, 0 8C; (c) Pd(OH)2/C (20%), cyclohexene, EtOH, reflux; (d) Tf2O, DMAP, pyridine,
CH2Cl2, 0 8C; (e) t-BuOK, DMSO, rt; (f) H2, Pd/C (10%), THF; (g) pyridinium DOWEX 50, EtOH, MeOH.

C. J. Woltermann et al. / Tetrahedron 60 (2004) 3445–3449
3447
the triflate intermediate, which is quite stable. The crude
triflate was dissolved in DMSO and treated with potassium
tert-butoxide at ambient temperature. The vinyl fluoride, 9,
was isolated in 85% yield. Hydrogenation of 9 was
performed in a non-protic solvent in order to avoid removal
of the THP group at this point. The THP group lends
solubility to the reduced product, 10, which aids in its
removal from the hydrogenation catalyst support. After
filtering and washing the catalyst, the THP group was
removed using the mild deprotection method of Uesugi,
et al.7 The solution is stirred with pyridinium DOWEX 50.
After a few hours, the THP group is removed cleanly. FddA,
1, is thus obtained in 80% yield from 9.
Compound 5c. 1H NMR (300 MHz, Me2SO-d6): d 8.26 (1H,
s, HC8), 8.18 (1H, s, HC2), 7.43 (2H, br.s, H2N), 7.22–7.33
(5H, m, Ph), 6.08 (1H, br.s, HC10 ), 5.99 (1H, br.s, HOC30 ),
4.82 (1H, br.s, HOC50 ), 4.68 (2H, br. s, H2C–Ph), 4.26 (2H,
m, HC30 þHC20 ), 4.13 (1H, m, HC40 ), 3.78 (1H, dd, H00C50 ,
J1¼5.1 Hz, J2¼10.9 Hz), 3.68 (1H, dd, H0C50 , J1¼6.26 Hz,
J2¼10.9 Hz). Signal assignment was made on the basis
of the COSY experiment. 13C NMR (75 MHz, CDCl3): d
155.9, 152.2, 148.5, 139.5, 137.6, 128.3 (2C), 127.7, 127.7
(2C), 118.9, 88.3, 87.6, 84.0, 72.8, 71.0, 59.3. Column
chromatography can be avoided if crude 4c is recrystallized
from 3:1 methanol/water. The yield from two crops is 49%.
4.1.2. 9-(3-O-Benzyl-5-O-tetrahydropyranyl-b-D-arabino-
furanosyl)adenine (6). To a 0 8C solution of 4c (33.0 g,
0.092 mol) and dried p-toluenesulfonic acid (35.3 g,
3. Conclusion
0.205 mol)
in
anhydrous
N,N-dimethylformamide
(500 mL) was added 3,4-dihydro-2H-pyran (77.7 g,
0.923 mol). The reaction progress was monitored by
HPLC. After ,5% 4c remained, the reaction mixture was
treated with 10% NaHCO3 (aq, 300 mL). The mixture was
diluted with water (1.2 L) and extracted with chloroform
(2£1 L). The organic layers were combined, dried over
Na2SO4 and concentrated in vacuo. The residue was
chromatographed through a column of silica gel. Fractions
containing the product were combined and concentrated to
afford 6 as an off-white solid (34.5 g, 85% yield). There are
two diastereomers with a ratio 1:1 due to a non-stereo-
selective attachment of the THP group. 1H NMR (300 MHz,
CDCl3): d 8.23–8.18 (2H, 4 separate s, HC8þHC2), 7.36–
7.26 (5H, m, Ph), 6.36 (1/2H, d, H1C10 , J¼3.7 Hz), 6.34
(1/2H, d, H2C10 , J¼3.7 Hz), 6.30 (2H, H2N), 5.60 (1H, br.s,
HO), 4.77 (1/2H, d, H10 C–Ph, J¼11.6 Hz), 4.76 (1/2H, d,
H20 C–Ph, J¼11.6 Hz), 4.67 (1/2H, m, H1CO2–THP), 4.65
(1H, d, H100C–Ph, J¼11.6 Hz), 4.65 (1H, d, H200C–Ph, J¼
11.6 Hz), 4.59 (1/2H, m, H2CO2–THP), 4.53 (1/2H, dd,
H1C20 , J1¼2.87 Hz, J2¼3.7 Hz), 4.54 (1/2H, dd, H2C20 , J1¼
2.9 Hz, J2¼3.7 Hz), 4.29 (1/2H, m, H1C40 ), 4.28 (1/2H, m,
H2C40 ), 4.25 (1/2H, dd, H1C30 , J1¼2.9 Hz, J2¼3.3 Hz), 4.19
(1/2H, dd, H2C20 , J1¼2.9 Hz, J2¼3.7 Hz), 4.07 (1/2H, dd,
H20 C50 , J1¼3.6 Hz, J2¼10.8 Hz), 3.97 (1/2H, dd, H10 C50 , J1¼
3.6 Hz, J2¼10.8 Hz), 3.81 (1/2H, m, H20 CO–THP), 3.71
(1/2H, dd, H200C50 , J1¼3.6 Hz, J2¼10.8 Hz), 3.69 (1/2H, m,
H10 CO–THP), 3.58 (1/2H, dd, H200C50 , J1¼3.59 Hz, J2¼
10.8 Hz), 3.49 (1H, m, H2CO–THP), 1.8–1.5 (6H, m,
THP). Signal assignment was made on the basis of the
COSY experiment of a recrystallized sample that has some
enrichment of one stereoisomer. 13C NMR (75 MHz,
CDCl3): d 155.7 (1C), 153.2 (1/2C), 153.1 (1/2C), 150.0
(1/2C), 149.9 (1/2C), 140.9 (1/2C), 140.7 (1/2), 137.6
(1/2C), 137.5 (1/2C), 128.9 (2C), 128.4 (1C), 128.1 (1C),
128.1 (1C), 119.6 (1/2C), 119.5 (1/2C), 99.38 (1/2C), 99.35
(1/2C), 86.1 (1C), 84.06 (1/2C), 83.95 (1/2C), 82.1 (1/2C),
82.0 (1/2C), 74.5 (1/2C), 74.4 (1/2C), 72.3 (1C), 67.24
(1/2C), 67.19 (1/2C), 62.53 (1/2C), 62.49 (1/2C), 30.26
(1/2C), 30.24 (1/2C), 25.4 (1/2C), 25.1 (1/2C), 19.4 (1/2C),
19.3 (1/2C). MS (high res.) actual 442.2072, calculated
442.2090.
We have developed a simple and efficient method to
selectively protect and deprotect 30- and 50-OH of ara-A (2)
which is potentially useful for the synthesis of a variety of
adenosine derivatives. This ability of selective protection of
ara-A with different blocking groups allows great synthetic
flexibility. This methodology has been employed to prepare
FddA (1) from commercially available ara-A (2) by a
relatively short synthetic sequence in 28% overall yield
without the use of expensive protecting groups or undesir-
able fluorinating reagents.
4. Experimental
4.1. General
All new compounds were determined to be .95% pure by
HPLC and NMR.
4.1.1. 9-(3-O-Benzyl-b-D-arabinofuranosyl)adenine (4c).
Fresh sodium tert-butoxide (81.0 g, 0.843 mol) was added
to benzyl alcohol (700 mL). After stirring 10 min., the
yellow solution was cooled to room temperature. Dry
9-(2,3-anhydro-b-D-lyxofuranosyl)adenine (3)4d (70.0 g,
0.281 mol) was added to the solution over a 5 min period.
The tan slurry was heated to 65 8C for 7 h. The resulting
brown solution was cooled to 25 8C and quenched with
acetic acid (51.0 g) and water (200 mL). The upper, organic
layer was separated and concentrated in vacuo. The residue
was purified by silica gel column chromatography to give
4c (74.34 g, 74% yield) and 5c (12.25 g, 12% yield) as
off-white solids.
Compound 4c. 1H NMR (300 MHz, Me2SO-d6): d 8.19 (1H,
s, HC8), 8.12 (1H, s, HC2), 7.25–7.48 (5H, m, Ph), 7.24 (2H,
br.s, H2N), 6.24 (1H, d, HC10 , J¼4.9 Hz), 5.81 (1H, d, HOC20 ,
J¼4.9 Hz), 5.19 (1H, t, HOC50 , J¼5.3 Hz), 4.70 (1H, d,
H0C–Ph, J¼11.8 Hz), 4.62 (1H, d, 0H00C–Ph, J¼11.8 Hz),
4.36 (1H, m, HC20 ), 4.13 (1H, dd, HC3, J1¼J2¼3.8 Hz), 3.98
(1H, ddd, HC40 , J1¼3.8 Hz, J2¼J3¼5.1 Hz), 3.65 (2H, m,
H2C50 ). Signal assignment was made on the basis of the
COSY experiment. 13C NMR (75 MHz, Me2SO-d6): d
155.9, 152.5, 149.3, 140.2, 138.1, 128.3 (2C), 127.6 (3C),
118.2, 83.8, 83.4, 82.4, 73.7, 70.9, 61.2. MS (high res.)
actual 357.1425, calculated 357.1437.
4.1.3. 9-(3-O-Benzyl-2-deoxy-2-fluoro-5-O-tetrahydro-
pyranyl-b-D-arabinofuranosyl)adenine (7). 4-Dimethyl-
aminopyridine (21.6 g, 0.177 mol), pyridine (37 mL), and 6
(24.0 g, 0.054 mol) were dissolved in CH2Cl2 (1,440 mL)

3448
C. J. Woltermann et al. / Tetrahedron 60 (2004) 3445–3449
and cooled to 0 8C under nitrogen. Trifluoromethanesul-
fonic acid anhydride (25.1 g, 0.089 mol) was added drop-
wise over 20 min. After 1 h., the reaction mixture was
poured into sat. NaHCO3 (aq., 1.8 L). The organic layer was
removed and the aqueous washed with CH2Cl2 (3£350 mL).
The organic layers were combined, dried over Na2SO4, and
concentrated at below 25 8C. The residue was taken up in
THF (100 mL) and evaporated to remove all traces of
CH2Cl2. The residue was dissolved in THF (550 mL)
and cooled, under nitrogen, to 0 8C. A solution of 1 M
tetrabutylammonium fluoride in THF (109 mL, 0.109 mol)
was added over 30 min. The reaction progress was
monitored by HPLC. After 18 h the reaction was finished.
The solvent was stripped on a rotary evaporator and the
residue was dissolved in CH2Cl2 (500 mL) and washed with
sat. NaCl (aq., 3£250 mL). The organic layer was dried over
Na2SO4 and concentrated. The residue was chromato-
graphed through a column of silica gel. The desired product,
7, was obtained as a pale yellow solid (15.7 g, 65% yield).
1H NMR (300 MHz, CDCl3): d 8.34 (1/2H, s, H1C8), 8.32
(1/2H, s, H2C8), 8.20 (1/2H, s, H1C2), 8.18 (1/2H, s, H2C2),
7.40–7.25 (5H, m, Ph), 6.34 (1/2H, dd, H1C10 , J1¼1.9 Hz,
J2¼11.7 Hz), 6.29 (1/2H, dd, H2C10 , J1¼1.9 Hz, J2¼
11.7 Hz), 5.90 (2H, br.s, H2N), 5.46 (1H, dm, HCF, J¼
51.6 Hz), 4.79 (1H, dd, H0C–Ph, J1¼5.0 Hz, J2¼11.7 Hz),
4.62 (1H, m, H00C–Ph), 4.67–4.38 (3H, m, HC03þHC04þ
HCO2–THP), 4.17 (1/2H, dd, H10 C50 , J1¼2.2 Hz, J2¼
11.5 Hz), 3.98 (1/2H, dd, H20 C50 , J1¼2.9 Hz, J2¼11.5 Hz),
3.82 (1/2H, dd, H200C50 , J1¼2.4 Hz, J2¼11.5 Hz), 3.79 (1/2H,
m, H10 CO–THP), 3.69 (1/2H, m, H20 CO–THP), 3.53 (1/2H,
dd, H100C50 , J1¼3.35 Hz, J2¼11.5 Hz), 3.48 (1H, m, H100CO–
THPþH200CO–THP), 1.80–1.40 (6H, m, THP). Signal
assignment was done on the basis of the COSY experiment.
13C NMR (75 MHz, CDCl3): d 155.64 (1/2C), 155.63
(1/2C), 153.36 (1/2C), 153.31 (1/2C), 149.44 (1/2C), 149.35
(1/2C), 139.4 (1/2C), 139.2 (1/2), 137.17 (1/2C), 137.16
(1/2C), 128.73 (1C), 128.71 (1C), 128.5 (1/2C), 128.4
(1/2C), 128.3 (1C), 128.2 (1C), 120.2 (1/2C), 120.1 (1/2C),
99.3 (1/2C), 99.2 (1/2C), 91.9 (1/2C, d, C20 –F, J¼190.4 Hz),
91.7 (1/2C, d, C200 –F, J¼189.8 Hz), 87.8 (1/2C, d, C10 –F,
J¼33.2 Hz), 87.5 (1/2C, d, C100 –F, J¼32.7 Hz), 81.3 (1/2C),
81.0 (1/2C), 75.2 (1/2C, d, C30 –F, J¼33.0 Hz), 75.0 (1/2C,
d, C300 –F, J¼33.0 Hz), 73.1 (1/2C), 73.0 (1C), 65.7 (1/2C),
65.4 (1/2C), 62.5 (1/2C), 62.3 (1/2C), 30.6 (1/2C), 30.4
(1/2C), 25.4 (1/2C), 25.3 (1/2C), 19.6 (1/2C), 19.4 (1/2C).
19F NMR (282.3 MHz, CDCl3): d 2202.58 (F1, ddd, J1¼
16.9 Hz, J2¼18.8 Hz, J3¼52.6 Hz), 2203.30 (F2, ddd, J1¼
15.9 Hz, J2¼18.8 Hz, J3¼55.5 Hz). MS (high res.) actual
444.2042, calculated 444.2047.
foamy solid (0.13 g, 81% yield). The first product fractions
1
contained one stereoisomer: H NMR (300 MHz, Me2SO-
d6): d 8.29 (1H, s, HC8), 8.14 (1H, s, HC2), 7.35 (2H, br.s,
H2N), 6.23 (1H, dd, HC10 , J1¼1.7 Hz, J2¼18.0 Hz), 5.79
(1H, d, HO, J¼6.5 Hz), 5.43 (1H, ddd, HC20 –F, J1¼1.9 Hz,
J2¼4.1 Hz, J¼52.9 Hz), 4.60 (2H, m, HC30 þHCO2–THP),
4.08 (1H, m, HC40 ), 3.79 (1H, dd, H0C50 , J1¼4.1 Hz, J2¼
11.5 Hz), 3.70 (1H, dd, H00C50 , J1¼2.6 Hz, J2¼11.5 Hz), 3.68
(1H, m, H0CO–THP), 3.41 (1H, m, H00CO–THP), 1.73–
1.37 (6H, m, THP). Signal assignment was done on the basis
of the COSY experiment. 13C NMR (75 MHz, Me2SO-d6):
d 156.0, 152.8, 148.8, 139.0, 118.9, 97.7, 93.5 (d, C20 –F,
J¼185.8 Hz), 85.9 (d, C10 –F, J¼33.8 Hz), 79.2, 68.3 (d,
C30 –F, J¼16.1 Hz), 65.1, 61.0, 30.0, 24.9, 18.8. 19F NMR
(282.3 MHz, Me2SO-d6): d 2202.19 (ddd, J1¼17.8 Hz, J2¼
21.7 Hz, J3¼52.5 Hz). The last few main product fractions
1
contained the second stereo-isomer: H NMR (300 MHz,
Me2SO-d6): d 8.32 (1H, s, HC8), 8.14 (1H, s, HC2), 7.35
(2H, br.s, H2N), 6.22 (1H, dd, HC10 , J1¼1.9 Hz, J2¼
18.7 Hz), 5.80 (1H, d, HO, J¼6.2 Hz), 5.42 (1H, ddd,
HC20 –F, J1¼1.9 Hz, J2¼4.5 Hz, J¼55.1 Hz), 4.62 (2H, m,
HC30 þHCO2–THP), 4.10 (1H, m, HC40 ), 3.98 (1H, dd, H0C50 ,
J1¼2.4 Hz, J2¼11.5 Hz), 3.64 (1H, m, H0CO–THP), 3.58
(1H, dd, H00C50 , J1¼5.0 Hz, J2¼11.5 Hz), 3.41 (1H, m,
H00CO–THP), 1.73–1.37 (6H, m, THP). Signal assignment
was done on the basis of the COSY experiment. 13C NMR
(75 MHz, Me2SO-d6): d 156.1, 152.8, 148.8, 139.2, 119.0,
98.1, 93.6 (d, C20 –F, J¼185.6 Hz), 86.0 (d, C10 –F, J¼
33.5 Hz), 81.5, 68.4 (d, C30 –F, J¼16.0 Hz), 66.0, 61.0, 29.9,
24.9, 18.8. 19F NMR (282.3 MHz, Me2SO-d6): d 2201.94
(ddd, J1¼18.9 Hz, J2¼22.0 Hz, J3¼52.5 Hz). MS (high
res.) actual 353.1483, calculated 353.1499.
4.1.5. 9-(2,3-Deoxy-2-fluoro-5-O-tetrahydropyranyl-b-
D-glycero-pent-2-enofuranosyl)adenine (9). 4-Dimethyl-
aminopyridine (0.79 g, 6.5 mmol), pyridine (1.4 mL), and 8
(0.70 g, 2.0 mmol) were dissolved in CH2Cl2 (52 mL) and
cooled to 0 8C under nitrogen. Trifluoromethanesulfonic
acid anhydride (0.92 g, 3.3 mmol) was added dropwise over
5 min. After 2 h, the reaction mixture was poured into
sat. NaHCO3 (aq., 50 mL) and extracted with EtOAc
(3£15 mL). The extracts were combined and dried over
MgSO4. The residual oil was dissolved in DMSO (63 mL)
and treated with potassium tert-butoxide (0.44 g,
4.0 mmol). The solution immediately became dark red.
After 30 min, NH4OAc (0.38 g, 4.0 mmol) was added to
quench the mixture. The DMSO solvent was stripped in
vacuo to leave a yellow oil. The oil was purified by silica gel
column chromatography to yield 9 as a white solid (0.56 g,
1
85% yield). H NMR (300 MHz, CDCl3): d 8.39 (1/2H, s,
4.1.4. 9-(2-Deoxy-2-fluoro-5-O-tetrahydropyranyl-b-D-
arabinofuranosyl)adenine (8). Pearlman’s catalyst
(0.20 g, 20% Pd by wt. on a dry basis, 57% water) was
dried by slurrying in absolute EtOH (25 mL) and concen-
trating to dryness. The dried catalyst was added to a solution
of 7 (0.20 g, 0.45 mmol) in absolute EtOH (14 mL) and
cyclohexene (2 mL). The reaction mixture was refluxed for
18 h at which time 8 was essentially gone. The catalyst was
filtered and washed well with hot EtOH (3£10 mL) and
THF (15 mL). The filtrate was concentrated to dryness and
the residue was passed through a short column of silica gel
eluting with CHCl3/MeOH (15:1). The appropriate fractions
were combined and concentrated to afford 8 as a white,
H1C8), 8.38 (1/2H, s, H2C8), 8.29 (1/2H, d, H1C2, J¼
1.0 Hz), 8.24 (1/2H, d, H2C2, J¼0.7 Hz), 6.95 (1H, m, HC30 ),
6.34 (1H, td, H1C10 , J1¼1.2 Hz, J2¼7.2 Hz), 5.68 (2H, br.s,
H2N), 5.09 (1H, m, HC40 ), 4.62 (1/2H, dd, H1CO–THP,
J1¼2.9 Hz, J2¼3.9 Hz), 4.56 (1/2H, dd, H2CO–THP,
J1¼2.9 Hz, J2¼4.8 Hz), 3.99 (1H, m, H0C50 ), 3.79 (1H, m,
HCO–THP), 3.61 (1H, m, H00C50 ), 3.50 (1H, m, HCO–
THP), 1.92–1.45 (6H, m, THP). Signal assignment was
done on the basis of the COSY experiment. 13C NMR
(75 MHz, CDCl3): d 155.40 (1/2C), 155.37 (1/2C), 153.45
(1/2C, d, C20 –F, J¼283.4 Hz), 153.44 (1C), 152.4 (1/2C, d,
C20 –F, J¼283.4 Hz), 150.7 (1C), 139.4 (1/2C), 139.0 (1/2C),
119.5 (1C), 106.0 (1/2C,d, J¼8.3 Hz), 105.0 (1/2C, d,

C. J. Woltermann et al. / Tetrahedron 60 (2004) 3445–3449
3449
J¼8.3 Hz), 99.6 (1/2C), 99.5 (1/2C), 81.9 (1/2C, d, J¼
28.9 Hz), 81.8 (1/2C), 81.7 (1/2C, d, J¼28.9 Hz), 81.6 (1/
2C), 68.5 (1/2C), 68.1 (1/2C), 62.9 (1/2C), 62.4 (1/2C), 30.4
(1/2C), 30.3 (1/2C), 25.3 (1/2C), 25.1 (1/2C), 19.8 (1/2C),
19.4 (1/2C). 19F NMR (282.3 MHz, CDCl3): d 2136.06 (F1,
ddd, J1¼1.4 Hz, J2¼J3¼5.3 Hz), 2136.29 (F2, ddd, J1¼
2.7 Hz, J2¼J3¼5.1 Hz). MS (high res.) actual 335.1405,
calculated 335.1394.
of Dan Devido (LC, LC/MS) and Dallas Hallberg (NMR).
We gratefully acknowledge US Bioscience, Inc. for
supplying a sizable quantity of ara-A for our studies and
an analytical standard of FddA. Pearlmans catalyst was
generously supplied by Degussa Corp.
References and notes
4.1.6. 9-(2,3-Dideoxy-2-fluoro-b-D-threo-pentofuranosyl)-
adenine (1, FddA). A solution of 9 (1.24 g, 3.7 mmol) in
THF (150 mL) was charged into a shaker bottle with 10%
Pd/C (0.62 g). The mixture was hydrogenated at room
temperature and 70 psi H2 pressure. The reaction was
monitored by LC/MS. After 55 h the reaction was complete
so the catalyst was filtered and washed with THF (25 mL).
The solvent was removed with a rotary evaporator to leave
1.08 g of a pale yellow solid. 1H NMR (300 MHz, CDCl3): d
8.33 (1H, s, HC8), 8.20 (1/2H, d, H1C2, J¼2.6 Hz), 8.17
(1/2H, d, H2C2, J¼2.9 Hz), 6.38 (1/2H, dd, H1C10 , J1¼
3.6 Hz, J3¼17.2 Hz), 6.33 (1/2H, dd, H2C10 , J1¼3.4 Hz, J2¼
18.4 Hz), 6.00 (2H, br.s, H2N), 5.29 (1H, dm, HCF, J¼
53.4 Hz), 4.71 (1H, m, HCO2–THP), 4.45 (1H, m, HC40 ),
3.98 (1H, m, H10 C50 ), 3.88 (1H, m, H0CO–THP), 3.69 (1H, m,
H100C50 ), 3.56 (1H, m, H00CO–THP), 2.48 (2H, m, C30 H2),
1.90–1.50 (6H, m, THP). Signal assignment was done on
the basis of the COSY experiment. 13C NMR (75 MHz,
CDCl3): d 156.0 (1C), 153.5 (1C), 150.2 (1C), 140.5 (1/2C),
140.4 (1/2C0), 119.5 (1C), 99.6 (1/2C), 99.5 (1/2C), 91.2
(1/2C, d, C2–F, J¼190.9 Hz), 91.1 (1/2C, d, C200 –F, J¼
190.2 Hz), 85.1 (1/2C, d, C10 –F, J¼16.6 Hz), 84.9 (1/2C, d,
C100 –F, J¼16.6 Hz), 76.49 (1/2C), 76.48 (1/2C), 69.7 (1/2C),
69.2 (1/2C), 62.8 (1/2C), 62.7 (1/2C), 34.2 (1/2C, d, C30 ,
J¼20.6 Hz), 33.8 (1/2C, d, C300, J¼20.6 Hz), 30.9 (1/2C),
30.8 (1/2C), 25.7 (1C), 19.8 (1/2C), 19.7 (1/2C). 19F NMR
(282.3 MHz, CDCl3): d 2186.8 (F1, m), 2187.4 (F2, m).
MS (high res.) actual 337.1550, calculated 337.1550. The
crude solid was dissolved in 5:1 MeOH/EtOH (42 mL) and
stirred with pyridinium DOWEX 50 W£2–1008 for 2 h.
The resin was filtered and washed with MeOH (25 mL),
1:1:1 pyridine/triethylamine/water (100 mL) and MeOH
(25 mL). The solution was distilled to dryness to leave
0.75 g of 1 (80% from 9). An analytical sample, which is
identical to a standard sample of 1, can be prepared by
recrystallizing from EtOH (50 mL).
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Acknowledgements
8. Prepared by stirring DOWEX 50W£2–100 (2.2 g) with
pyridine (10 mL) for 5 min and decanting the excess pyridine.
The resin was then washed several times with MeOH.
This work was made possible by the hard work and advice