Synthesis of 2′,3′-dideoxyinosine via radical deoxygenation

Article abstract of DOI:10.1080/15257770701508414

A synthetic method for 2′,3′-dideoxyinosine (ddI) from inosine was established via radical deoxygenation of N1,5′-O-diprotected-2′, 3′-bis-S-methyl dithiocarbonate of inosine derivatives. The radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields using 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of inosine at the N1, 5′-O-positions were effective for the ddI synthesis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701508414

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Synthesis of 2′,3′-Dideoxyinosine via
Radical Deoxygenation
Takayoshi Torii a , Kunisuke Izawa a , Dae Hyan Cho b & Doo Ok Jang b
a AminoScience Laboratories, Ajinomoto Co., Inc. , Kawasaki, Japan
b Department of Chemistry , Yonsei University , Wonju, South Korea
Published online: 10 Dec 2007.
To cite this article: Takayoshi Torii , Kunisuke Izawa , Dae Hyan Cho & Doo Ok Jang (2007) Synthesis
of 2′,3′-Dideoxyinosine via Radical Deoxygenation, Nucleosides, Nucleotides and Nucleic Acids,
26:8-9, 985-988, DOI: 10.1080/15257770701508414
To link to this article: http://dx.doi.org/10.1080/15257770701508414
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Nucleosides, Nucleotides, and Nucleic Acids, 26:985–988, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508414
SYNTHESIS OF 2ꢀ,3ꢀ-DIDEOXYINOSINE VIA RADICAL
DEOXYGENATION
Takayoshi Torii and Kunisuke Izawa
AminoScience Laboratories, Ajinomoto Co.,
2
Inc., Kawasaki, Japan
Dae Hyan Cho and Doo Ok Jang
Department of Chemistry, Yonsei University,
2
Wonju, South Korea
A synthetic method for 2 ꢁ,3 ꢁ-dideoxyinosine (ddI) from inosine was established via radical de-
2
oxygenation of N1,5 ꢁ-O-diprotected-2 ꢁ,3 ꢁ-bis-S-methyl dithiocarbonate of inosine derivatives. The
radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields us-
ing 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of
inosine at the N1, 5 ꢁ-O-positions were effective for the ddI synthesis.
Keywords 2ꢁ,3ꢁ-Dideoxyinosine; radical deoxygenation; 1-ethylpiperidinium hy-
pophosphite; N 1 and 5ꢁ-O-protection; debenzylation
INTRODUCTION
2ꢁ,3ꢁ-Dideoxyinosine (ddI, 1) was developed as a nucleoside reverse tran-
scriptase inhibitor against human immunodeficiency virus for the treatment
of acquired immune deficiency syndrome and was launched in 1991. We
already have reported several synthetic methods of 1.[1] Previously, Chu
et al. reported that 1 is readily obtained by Barton deoxygenation via 2ꢁ,3ꢁ-
bis-S-methyl dithiocarbonate.[2] This is one of the most straightforward
methods to synthesize 1 from 2, requiring only five steps. This method,
however, requires an excess amount of tributyltin hydride for deoxygena-
tion, and therefore purification of the desired product without using silica-
gel chromatography is very difficult. In addition, the toxicity of tributyltin
hydride is not acceptable for large-scale synthesis. Expensive TBDMS-Cl
is also necessary for selective protection of the 5ꢁ-hydroxyl group of in-
osine. We previously reported the use of hypophosphorous acid and 1-
ethylpiperidinium hypophosphite (EPHP) as radical reducing agents in-
stead of tributyltin hydride for the deoxygenation of nucleosides.[3] We
Address correspondence to Kunisuke Izawa, AminoScience Laboratories, Ajinomoto Co., Inc., 1-1,
Suzuki-cho, Kawasaki-ku, Kawasaki, 210-8681, Japan. E-mail: kunisuke izawa@ajinomoto.com
985

986
T. Torii et al.
SCHEME 1 Radical deoxygenation of 4.
SCHEME 2 Deprotection of 5b.
report here an application of this methodology to the synthesis of ddI
(1). We also report efficient processes using more versatile benzyl and p -
methoxybenzyl protection for the N1,5ꢁ-O-groups.
RESULTS AND DISCUSSION
N 1-Benzyl-5ꢁ-O-benzylinosine (3a) was synthesized from 2 through
cyclopentylidene protection, followed by benzylation and deprotection
of ketal.[4] N 1-p -Methoxybenzyl-5ꢁ-O-(p -methoxybenzyl)inosine (3b) was
prepared by the same method as 3a, using p -methoxybenzyl bromide. Com-
pounds 3a and 3b were converted into bis S-methyl dithiocarbonate deriva-
tives 4a and 4b in high yields. Because the N 1 position of 3a and 3b was
protected by benzyl and p -methoxybenzyl, no N 1-methylated byproduct
was formed during the S-methylation.[2] Compounds 4a and 4b were trans-
formed into 2ꢁ,3ꢁ-didehydro-2ꢁ,3ꢁ-dideoxy derivatives 5a and 5b by radical re-
duction using EPHP as a reducing agent and triethylborane as a radical ini-
tiator. The yield of 5a and 5b was 85% and 98%, respectively. In contrast to
the case of tin reduction, the isolation and purification of 5 was easy because
the yields were very high and there was no metal contamination (Scheme 1).
Cleavage of the p -methoxybenzyl groups of 5b with ceric ammonium
nitrate provided 2ꢁ,3ꢁ-didehydro-2ꢁ,3ꢁ-dideoxyinosine (d4I, 6) in 99% yield,
which was eventually transformed into ddI (1) by hydrogenation in 90%
yield (Scheme 2).
On the other hand, cleavage of the benzyl groups of 5a under conven-
tional hydrogenolysis conditions with Pd(OH)2/C did not proceed, and the

2ꢁ,3ꢁ-Dideoxyinosine via Radical Deoxygenation
987
TABLE 1 Debenzylation of 7
Entry
Solvent
Temp.(◦C)
H2(atm)
Additive(eq)
Results
1
2
3
4
5
MeOH
MeOH
MeOH
DMF
rt
1
1
50
1
—
—
—
—
No reaction
No reaction
Complex mixture
9, major product
8, quant
50
50
80
80
DMF
1
NaOH (2.5)
SCHEME 3 Deprotection of 5a.
reaction gave only the protected ddI derivative 7 in 90% yield. It has been re-
ported that the benzyl group at the N 1 of hypoxanthine and guanine,[5] and
the N 3 of uracil and thymine[4,6] is difficult to deprotect under hydrogenol-
ysis conditions: a large amount of Pd catalyst[5a] or high temperature over
100◦C[5b] is required. Therefore, we examined cleavage of the benzyl groups
of 7 under hydrogenolysis conditions using Pd(OH)2/C, whose ratio to 7
was 0.2 by weight (Table 1). Compound 7 remained intact when the reac-
tion temperature was raised to 50◦C (entry 2). Under high H2 pressure,
compound 7 decomposed to give a complex mixture (entry 3). Unexpect-
edly, a benzyl group was deprotected to give 8 with Pd(OH)2/C at 80◦C in
DMF by adding aq. NaOH under 1 atm of H2 (entry 5). In the absence of
NaOH, cleavage of a glycosyl bond of 7 occurred, providing 9 as a major
product (entry 4). The structure of 5ꢁ-O-benzyl-2ꢁ,3ꢁ-dideoxyinosine (8) was
identified by NMR-study.[7] Compound 8 was eventually transformed into
ddI (1) simply by elevating the hydrogenolysis conditions to 100◦C for 6 h
under 1 atm of H2. The isolated yield of 1 from 7 was 70% (Scheme 3).
In conclusion, we established a synthetic method for ddI (1) from in-
osine (2) in 36% overall yield via benzyl-protected compound 3a, and
in 60% overall yield via p -methoxybenzyl protected compound 3b. We
also report that both EPHP/BEt3 reduction and inexpensive benzyl or

988
T. Torii et al.
p -methoxybenzyl protection at the N 1, 5ꢁ-O-position of inosine (2) were ef-
fective for the synthesis of ddI (1).
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7. 1H-NMR (400 MHz, DMSO-d6) of 7: δ 2.07–2.12 (2H, m, H-2ꢁ or H-3ꢁ), 2.42–2.47 (2H, m, H-2ꢁ or
H-3ꢁ), 3.55 (1H, dd, J = 10.6, 5.4 Hz, H-5ꢁa), 3.65 (1H, dd, J = 10.6, 3.6 Hz, H-5ꢁb ), 4.23–4.29 (1H,
m, H-4ꢁ), 4.49 (2H, s, OCH2Ph), 5.23 (2H, s, NCH2Ph), 6.23 (1H, dd, J = 6.8, 3.3 Hz, H-1ꢁ), 7.24–
7.34 (10H, m, aromatic), 8.25 (1H, s, H-8), 8.59 (1H, s, H-2). 1H-NMR (400 MHz, DMSO-d6) of 8:
δ 2.05–2.12 (2H, m, H-2ꢁ or H-3ꢁ), 2.36–2.48 (2H, m, H-2ꢁ or H-3ꢁ), 3.56 (1H, dd, J = 10.5, 5.5 Hz,
H-5ꢁa), 3.65 (1H, dd, J = 10.5, 3.8 Hz, H-5ꢁb), 4.21–4.26 (1H, m, H-4ꢁ), 4.50 (2H, s, OCH2Ph), 6.19
(1H, dd, J = 6.7, 3.8 Hz, H-1ꢁ), 7.24–7.36 (5H, m, aromatic), 8.00 (1H, s, H-8), 8.12 (1H, s, H-2).