Radical deoxygenation and dehalogenation of nucleoside derivatives with hypophosphorous acid and dialkyl phosphites

Article abstract of DOI:10.1016/S0040-4039(01)01617-3

Hypophosphorous acid and dialkyl phosphites are effective radical reducing agents for O-thiocarbonyl groups or halides at the sugar part of nucleoside derivatives and give the corresponding hydrocarbons in high yield.

Full text of DOI:10.1016/S0040-4039(01)01617-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7605–7608
Radical deoxygenation and dehalogenation of nucleoside
derivatives with hypophosphorous acid and dialkyl phosphites
Satoshi Takamatsu, Satoshi Katayama, Naoko Hirose, Masaki Naito and Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan
Received 30 July 2001; accepted 3 September 2001
Abstract—Hypophosphorous acid and dialkyl phosphites are effective radical reducing agents for O-thiocarbonyl groups or
halides at the sugar part of nucleoside derivatives and give the corresponding hydrocarbons in high yield. © 2001 Elsevier Science
Ltd. All rights reserved.
The transformation of functional groups is of consider-
able interest in nucleoside chemistry. Thus far, transfor-
mations such as deoxygenation and dehalogenation of
nucleoside derivatives have been carried out effectively
by free radical reduction (Scheme 1).1 In the original
Barton–McCombie method for deoxygenation, thiocar-
bonates (-OC(ꢀS)-OAr) or xanthates (-OC(ꢀS)-SMe)
were reduced with tri-n-butyltin hydride (nBu3SnH).2
This reaction has been used not only for the reduction
of alcohols at the sugar part of nucleoside derivatives,
but also for general organic synthesis.3
Therefore, various attempts have been made to identify
alternatives. Silanes6 can be used successfully in radical
deoxygenation and dehalogenation. We have also used
various silanes for deoxygenation of the 3%-hydroxyl
group in 5.4a,b However, although they are much less
toxic than tin hydride, they cannot be considered an
inexpensive and easily accessible alternative to tin
hydride.
Barton et al. reported that the commercially available
and inexpensive dialkyl phosphites7 and hypophosphor-
ous acid8 could be used for an efficient radical reaction
In the course of our study4 concerning the synthesis of
instead of Bu3SnH. These phosphorous reagents can
n
an anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-b-
D
-threo-
be considered an almost ideal hydrogen atom source
and chain carrier for a radical reaction because of their
low cost and safety. Since Barton et al. used these
reagents for rather simple substrates, we were interested
in using them for deoxygenation and dehalogenation of
various nucleoside derivatives such as 2, 5, 8, and 10
(Fig. 1).9 All of these compounds require a safe and
economical deoxygenation or dehalogenation for the
synthesis of various nucleoside-related pharmaceuticals.
pentofuranosyl)adenine (1, FddA),5 dehalogenation of
84d (Fig. 1) was carried out by free radical reduction
n
with Bu3SnH. However, this tin reagent is not ideal
from the perspective of pharmaceutical production
because it is toxic, expensive, and produces organotin
waste in large quantities, and more importantly it is
difficult to completely remove tin byproducts and unre-
n
acted Bu3SnH from the reaction product.
base
base
base
base
RO
RO
RO
RO
O
O
O
O
M-H
or
or
radical initiator
R'O
Z
Z
OR'
R'O
OR'
Z = OC(=S)-OAr, OC(=S)-SMe, halogen, ... M = nBu3Sn, R1R2R3Si, (R4O)2P(=O), (HO)2P, ...
base = adenine, hypoxanthine, guanine, ...
radical initiator = azo compound, peroxide, ...
Scheme 1. Radical deoxygenation and dehalogenation of nucleoside derivatives.
Keywords: dehalogenation; deoxygenation; nucleic acid analogues; nucleosides; radicals and radical reactions.
* 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)01617-3

7606
S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 7605–7608
NH2
N
NH2
N
O
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
N
NH
N
N
N
N
N
HO
TrO
AcO
TrO
R'O
O
O
F
O
R
O
O
F
R
OAc
R
R''O R
1: FddA
2: R = OH
3: R = OC(=S)-SMe
4: R = H
5: R = OH
6: R = OC(=S)-SMe
7: R = H
8: R = Br
9: R = H
10: R = OH, R'-R'' = -Si(iPr)2-O-Si(iPr)2-
11: R = OC(=S)-imidazole,
R'-R'' = -Si(iPr)2-O-Si(iPr)2-
12: R = H, R' = R'' = H
Figure 1.
Thus, 9-(5-O-trityl-2-deoxy-2-fluoro-b-
D
-arabinofura-
while 2%,3%-dideoxy-didehydro nucleoside is acid-labile.
Decomposition of the product, owing to the acidity of
the medium, may have affected the different yield of
non-fluorinated and fluorinated compounds (runs 1 and
2). The yield of product was better when a little excess
amount of base was added (runs 3 and 4). The best
result was obtained when 10 equivalents of H3PO2 and
0.6 equivalents of AIBN were used (run 4);12 however,
the amounts of these reagents can be minimized to 2.5
equivalents and 0.2 equivalents, respectively, without
substantially reducing the yield (run 6). Barton et al.
reported7,8b that benzoyl peroxide must be used as an
initiator when dialkyl phosphite is used as a hydrogen
donor. Interestingly, deoxygenation with dialkyl phos-
phite proceeded well with a catalytic amount of AIBN
in our study, as with H3PO2 (runs 7 and 8).13
nosyl)adenine (5) was synthesized,4a,b which requires
further deoxygenation of the 3%-hydroxyl group to
obtain the anti-HIV nucleoside FddA (1). Since there
was some risk of dehalogenation of the fluorine in 5,
compound 2 was also synthesized and its deoxygena-
tion was examined. Prior to the radical deoxygenation
of 2 and 5, the 3%-hydroxyl group was treated to give
xanthates by sequential reaction with carbon disulfide
(CS2) in the presence of sodium hydroxide, and with
methyl iodide (MeI). The yields of 3 and 6 were 96 and
87%, respectively.10
Xanthates 3 and 6 were then reduced to the corre-
sponding deoxygenated compounds 4 and 7 by the
radical reaction with hypophosphorous acid (H3PO2)
and dialkyl phosphites such as dimethyl phosphite
((MeO)2P(O)H) and diethyl phosphite ((EtO)2P(O)H) in
the presence of a catalytic amount of 2,2%-azobisisobu-
tyronitrile (AIBN) as an initiator (Table 1). Hypophos-
phorous acid is usually available as a 50% aqueous
solution, which can be used as such in water-miscible
solvents like 1,2-dimethoxyethane (DME). The reac-
tions were conducted in the presence of triethylamine
(Et3N) as a base to avoid damaging the acid-labile
substrate and product. High-performance liquid chro-
matography (HPLC) analysis showed that, after the
reaction, the yield of 4 was 79%, while that of 7 varied
from 82 to 93%. Both the non-fluorinated (3) and
Debromination of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-
b- -xylofuranosyl)-1,9-dihydro-6H-purine-6-one (8) to
D
obtain 2%,5%-di-O-acetyl-3%-deoxyinosine (9) was also
examined (Table 2). Compound 9 is also an intermedi-
ate in the synthesis of FddA.4d H3PO2 and sodium
hypophosphite (NaH2PO2) were used as a hydrogen
atom source. Since radical debromination carried out in
aqueous acetonitrile (CH3CN) produce hydrogen bro-
mide, the reaction medium becomes strongly acidic
during the reaction. Prior to the reaction, base was
added to the solution to prevent the decomposition of
acid-labile substrate and product. In the case of the
reaction with H3PO2, triethylamine (Et3N) was used as
a base, while sodium hydroxide (NaOH) was used as a
base in the reaction with NaH2PO2.
fluorinated (6) compounds gave
a deoxygenated
product in good yield (runs 1 and 2). However, C2%-b
fluorinated nucleoside is noted for its stability in acid,11
Table 1. Deoxygenation of xanthate (3 and 6)
Run Substrate
Solvent
MꢁH
PꢁH (equiv.) Et3N (equiv.) AIBN
Temp. (°C)
Time (h)
Yield (%)a
(equiv.)
1
2
3
4
5
6
7
8
3
6
6
6
6
6
6
6
DME
DME
DME
DME
DME
DME
DME
DME
H3PO2
H3PO2
H3PO2
H3PO2
H3PO2
H3PO2
5.0
5.0
10
10
5.0
2.5
10
10
20
11
5.5
2.8
–
0.3
0.3
0.6
0.6
0.1
0.2
0.6
0.6
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
1.0
1.0
1.8
1.8
1.2
1.3
2.0
2.0
79
84
86
93
90
90
84
82
(MeO)2P(O)H 10
(EtO)2P(O)H 10
–
a The yield is calculated from the results of HPLC analysis.

S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 7605–7608
Table 2. Dehalogenation of brominated nucleoside derivative (8)
7607
Run Solvent
PꢁH (equiv.)
Base (pHa)
Initiator (equiv.)
Temp. (°C)
Time (h)
Yield (%)b
1c
2
3
4
5
6
7
8
Toluene
(nBu3SnH) (3.0)
H3PO2 (4.0)
NaH2PO2 (4.0)
H3PO2 (3.0)
NaH2PO2 (2.0)
H3PO2 (3.0)
NaH2PO2 (2.0)
NaH2PO2 (2.0)
None (–)
AIBN (0.1)
AIBN (0.1)
AIBN (0.1)
V-50 (0.1)
90
70
70
60
60
50
60
60
2.0
1.0
2.0
3.0
2.0
2.0
1.0
1.0
92
97
76
82
70
99
89
85
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
Et3N (pH 7.0)
NaOH (pH 7.0)
Et3N (pH 8.0)
NaOH (pH 8.5)
Et3N (pH 8.0)
NaOH (pH 8.5)
NaOH (pH 8.5)
V-50 (0.1)
VA-044 (0.1)
VA-044 (0.1)
VA-046B (0.1)
a pH of the medium when the reaction was started.
b The yield is calculated from the results of HPLC analysis.
c Ref. 4d.
Although the reaction of brominated compound 8 with
nBu3SnH in toluene in the presence of AIBN gave 9 in
92% yield (Table 2, run 1),4d the reaction with H3PO2
or NaH2PO2 also gave the product in high yield (runs
2–8). When we used H3PO2 in the reaction, the yield
was always higher than that with NaH2PO2 (runs 2–3,
4–5, 6–7). We assume that decomposition of the
product decreased the yield because the pH of the
medium after the reaction with NaH2PO2 was always
much lower than in the reaction with H3PO2. Since the
reaction was implemented in aqueous medium, the
contamination of obtained crystals with hydrophobic
AIBN (runs 2–3) was a problem due to its toxicity.
Therefore, hydrophilic azoamidine compounds were
tested as a radical initiator (runs 4–8) to facilitate the
purificationoftheproduct. 2,2%-Azobis(2-methylpropion-
amide) dihydrochloride (V-50™), 2,2%-azobis[2-(2-imi-
dazolin-2-yl)propane] dihydrochloride (VA-044™), and
2,2%-azobis[2-(2-imidazolin-2-yl)propane] disulfate dihy-
drate (VA-046B™) are all known as azo polymerization
initiators, and are available from Wako Pure Chemical
Industries, Ltd. When hydrophilic azoamidine com-
pounds were used (runs 4–8), the initiators did not
remain in separated crystals, while the yield of the
product was at least as high as that with AIBN (runs
2–3). The reaction with a combination of H3PO2 and
VA-044 gave the product in almost quantitative yield
(run 6).14
and pharmaceuticals such as antisense oligonucleotides.
Although chemical transformation from the corre-
sponding ribose to 2%-deoxynucleoside by radical deoxy-
genation is known,1 toxic tin reagents are required for
this reaction. To demonstrate the further applicability
of this system, an economical synthesis of 2%-deoxy-
nucleoside from readily available ribonucleoside by radi-
cal deoxygenation with H3PO2 was attempted.
The 3%- and 5%-hydroxyl groups of adenosine were pro-
tected by
a 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl
(TIPDS) group to give the corresponding nucleoside 10
in good yield.15 Deoxygenation of the 2%-hydroxyl
group of 10 was explored to obtain the 2%-deoxy-
nucleoside 12 (Scheme 2), using conditions similar to
those mentioned above. First, conversion of the 2%-
hydroxyl to its thiocarbonylimidazolyl derivative was
accomplished by treatment of 10 with thiocarbonyl-
diimidazole in DMF, to give 11 in 82% yield. Deoxygena-
tion of 11 in DME with aqueous H3PO2 in the presence
of Et3N and a catalytic amount of AIBN gave the
2%-deoxyadenosine 12 after deprotection of the TIPDS
group by tetra-n-butylammonium fluoride (nBu4NF).
The yield was rather low under the above conditions,
which might be due to hydrolysis of the thiocar-
bonylimidazolyl derivative 11 back to 10. This is partly
because of the liberation of imidazole in the reaction
mixture. This argument is supported by the finding that
27% of adenosine was recovered after the reduction and
deprotection of 11. If we exclude this hydrolysis, the
yield of the 2%-deoxyadenosine 12 from 11 was 45%.
Radical deoxygenation with more stable O-thiocar-
bonyl derivatives is now under investigation in our
laboratories.
2%-Deoxynucleosides, including 2%-deoxyadenosine and
2%-deoxyguanosine, are currently produced in limited
amounts from salmon milt, and it is difficult to satisfy
the growing need for these compounds in the produc-
tion of new diagnostic reagents such as a DNA chip
1) 50% H3PO2 aq. / AIBN
NH2
NH2
N
NH2
N
Et3N / DME / 100 °C
2) AcOEt / H2O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
3) Phase separation
4) nBu4NF / THF / 70 °C
O
O
HO
O
O
O
(iPr)2Si
(iPr)2Si
S
O
O
(iPr)2Si
(iPr)2Si
DMF
r.t. -> 70 °C
N
O OH
O O
N
HO
S
10
11
12
Scheme 2.

7608
S. Takamatsu et al. / Tetrahedron Letters 42 (2001) 7605–7608
In conclusion, hypophosphorous acid and dialkyl phos-
phites are effective radical reducing agents for O-thio-
carbonyl groups, as in xanthates and thiocarbonates, or
halides at the sugar part of nucleoside derivatives to
give the corresponding hydrocarbons in high yields.
The present method is useful for the synthesis of vari-
ous 2%-deoxy or 3%-deoxynucleoside derivatives, includ-
ing FddA and 2%-deoxyadenosine.
9. (a) Takamatsu, S.; Katayama, S.; Hirose, N.; Izawa, K.
European Patent Application EP0999218, 2000; (b) Taka-
matsu, S.; Katayama, S.; Hirose, N.; Izawa, K. Japanese
Patent Application JP2000-198796, 2000.
10. A representative experimental procedure is as follows: 5
(6.60 g, 12.9 mmol) was dissolved in DMSO (52.4 ml) and
cooled to 12°C. To this were added 5M sodium hydroxide
(2.84 ml, 14.2 mmol) and carbon disulfide (3.09 ml, 51.6
mmol) at 15°C. After stirring for 15 min at 15°C, methyl
iodide (1.60 ml, 25.7 mmol) was added to the mixture. The
resulting mixture was poured into water (80 ml) and ethyl
acetate (80 ml) with vigorous stirring. The reaction mixture
was separated into layers, and the organic layer was
washed with water (80 ml). The organic layer was concen-
trated under reduced pressure to give an oily residue. The
residue was crystallized from acetonitrile (50 ml). The
resulting crystals were filtered and dried at 50°C under
reduced pressure to give the desired product (7.32 g, 91.8%
purity, 11.2 mmol, 86.6% yield).
Acknowledgements
The authors thank Professor Tokumi Maruyama of
Tokushima Bunri University for scientific discussion
and help in preparation of the manuscript. We are also
grateful to Mr. Hideo Takeda and Mr. Shigekatsu
Tsuchiya of Ajinomoto Co., Inc. for their technical
assistance.
11. McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem.
1998, 63, 2161–2167.
References
12. A representative experimental procedure is as follows: To
a solution of 6 (102 mg, 98.0% purity, 0.166 mmol) in
DME (0.83 ml) were added Et3N (0.255 ml, 1.83 mmol)
and 50% aqueous H3PO2 (0.172 ml, 1.66 mmol). This
mixture was heated until reflux and AIBN (16.4 mg, 0.0997
mmol) dissolved in DME (0.49 ml) was added in three
portions. After stirring for 1.8 h at reflux, the reaction
mixture was cooled to room temperature, treated with
dichloromethane (5 ml) and water (5 ml), and separated
into layers. The organic layer was concentrated under
reduced pressure to give a solid residue. HPLC analysis
showed that the desired product was obtained in 93.0%
yield (76.5 mg, 0.154 mmol).
13. A representative experimental procedure is as follows: To
a solution of 6 (61.4 mg, 98.0% purity, 0.100 mmol) in
DME (1.0 ml) was added (MeO)2P(O)H (110 mg, 1.00
mmol). This mixture was heated until reflux, and AIBN
(10.0 mg, 0.0600 mmol) dissolved in DME (0.60 ml) was
added in three portions. After stirring for 2 h at reflux, the
reaction mixture was cooled to rt and concentrated under
reduced pressure to give a solid residue. HPLC analysis
showed that the desired product was obtained in 84.1%
yield (41.7 mg, 0.0841 mmol).
14. A representative experimental procedure is as follows: To
a solution of 50% aqueous H3PO2 (15.5 ml, 150 mmol) in
water (104 ml) was added Et3N (21.0 ml, 151 mmol) at
16°C. The resulting solution was added to a solution of 8
(20.8 g, 50.0 mmol) in CH3CN (38.7 ml). This mixture was
heated to 43°C, and added Et3N (3.82 ml, 27.4 mmol) to
raise the pH value from 3.8 to 8.0. This mixture was heated
to 50°C and VA-044™ (1.62 g, 5.00 mmol) dissolved in
water (8.3 ml) was added. After stirring for 30 min at 50°C,
the reaction mixture was neutralized to pH 4.0 with 25%
aqueous sodium hydroxide (3.54 g, 22.1 mmol). After
additional stirring for 1.5 h at 50°C, the reaction mixture
was cooled to 10°C, and neutralized to pH 6.0 with 25%
aqueous sodium hydroxide (5.94 g, 37.1 mmol). HPLC
analysis showed that the desired product was obtained in
99.2% yield (16.7 g, 49.6 mmol).
1. (a) Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc. 1981,
103, 932–933; (b) Robins, M. J.; Wilson, J. S.; Hansske,
F. J. Am. Chem. Soc. 1983, 105, 4059–4065.
2. Barton, D. H. R.; McCombie, S. W. J. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574–1585.
3. (a) Hartwig, W. Tetrahedron 1983, 39, 2609–2645; (b)
Ramaiah, M. Tetrahedron 1987, 43, 3541–3676; (c) Moth-
erwell, W. B.; Crich, D. Free Radical Chain Reactions in
Organic Synthesis; Academic Press: London, 1992; Chap-
ter 3, pp. 29–129.
4. (a) Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.;
Izawa, K. Chem. Pharm. Bull. 1999, 47, 966–970; (b)
Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.;
Izawa, K. Tetrahedron Lett. 2001, 42, 2321–2324; (c)
Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.;
Naito, M.; Izawa, K. Tetrahedron Lett. 2001, 42, 2325–
2328; (d) Takamatsu, S.; Maruyama, T.; Katayama, S.;
Hirose, N.; Naito, M.; Izawa, K. J. Org. Chem., accepted.
5. (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) Herdewijn,
P.; Pauwels, R.; Baba, M.; Balzarini, J.; De Clercq, E. J.
Med. Chem. 1987, 30, 2131–2137; (c) 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; (d) 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; (e) Graul, A.;
Silvestre, J. Drugs Future 1998, 23, 1176–1189 and refer-
ences cited therein.
6. (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188–194;
(b) Chatgilialoglu, C.; Ferreri, C. Res. Chem. Intermed.
1993, 19, 755–775.
7. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetra-
hedron Lett. 1992, 33, 2311–2314.
8. (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs.
Tetrahedron Lett. 1992, 33, 5709–5712; (b) Barton, D. H.
R.; Jang, D. O.; Jaszberenyi, J. Cs. J. Org. Chem. 1993, 58,
6838–6842.
15. Markiewicz, W. T. J. Chem. Res. (S) 1979, 24–25.