An improved synthesis of 5′-amino-5′-deoxyguanosine

Article abstract of DOI:10.1081/SCC-120004140

A short and efficient three step synthesis of 5′-amino-5′-deoxyguanosine 1 from guanosine 2 is reported.

Full text of DOI:10.1081/SCC-120004140

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AN IMPROVED SYNTHESIS OF 5′-AMINO-5′-
DEOXYGUANOSINE
a
David K. Dean
a
GlaxoSmithKline, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex,
CM19 5AW, UK
Version of record first published: 12 Dec 2006.
To cite this article: David K. Dean (2002): AN IMPROVED SYNTHESIS OF 5′-AMINO-5′-DEOXYGUANOSINE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:10, 1517-1521
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SYNTHETIC COMMUNICATIONS, 32(10), 1517–1521 (2002)
AN IMPROVED SYNTHESIS OF
-AMINO-5 -DEOXYGUANOSINE
0
0
5
David K. Dean
GlaxoSmithKline, New Frontiers Science Park (North),
Coldharbour Road, Harlow, Essex CM19 5AW, UK
E-mail: David_K_Dean@bphrd.com
ABSTRACT
0
0
A short and efficient three step synthesis of 5 -amino-5 -deoxy-
guanosine 1 from guanosine 2 is reported.
0
During the course of our research we required gram quantities of 5 -
0
0
0
amino-5 -deoxyguanosine 1 for biological studies. Whilst 5 -amino-5 -deoxy-
adenosine and thymidine are well described and commercially available, this
0
0
is not the case for 5 -amino-5 -deoxyguanosine 1. A review of the literature
0
0
1
revealed a handful of syntheses of 5 -amino-5 -deoxyguanosine 1 and its N-
1,2
substituted analogues,
approach.
Schattka and Jastorff reported the synthesis of 5 -amino-5 -deoxygua-
however there are issues associated with each
1
0
0
0
0
nosine 1 in 1972 starting from commercially available 2 ,3 -O-isopropylidene
0
protected guanosine. The route involved activation of the 5 -hydroxyl group
0
ꢀ
0
as a tosylate (TsCl, pyridine, 4 C, 3 days), followed by removal of the 2 ,3 -
diol protecting group (formic acid) and subsequent displacement of the
0
0 0
5
deoxyguanosine 1. The first step in this synthesis was severely hampered by a
-tosyl group with ammonia (bomb, 7 days) to give the target 5 -amino-5 -
1
competing intramolecular cyclisation of N-3 in the guanine unit onto the
1
517
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1
518
DEAN
0
activated C-5 position, leading to the formation of an unwanted cyclonucleo-
,3,4
1
side.
We were unable to suppress the formation of the cyclonucleoside and
purification of the resultant mixture proved difficult on a reasonable scale
which severely compromised the efficiency of this synthetic route. Other
0
0
syntheses of 5 -amino-5 -deoxyguanosine analogues involve N-acylation of
the guanine base prior to incorporation of the amino (or substituted amino)
0
2
group at C-5 . However removal of the guanosine protecting group is gen-
0
erally not trivial and acyl migration onto the newly formed 5 -amino group
leads to complications. These issues prompted us to investigate an alternative
synthesis of 5 -amino-5 -deoxyguanosine 1.
We chose commercially available guanosine 2 as the starting material
for our synthesis of 5 -amino-5 -deoxyguanosine 1 (see scheme). Our syn-
5
thetic strategy was based on the work of McGee and Martin, who reported
0
0
0
0
0
0
the clean conversion of guanosine 2 into 5 -deoxy-5 -iodoguanosine 3
Reagents: (i) Triphenylphosphine, imidazole, iodine, 1-methyl-2-pyrrolidinone, 72%;
(ii) sodium azide, DMF, 69%; (iii) triphenylphosphine pyridine, aqueous ammonium
hydroxide, 78%.
0
0
Scheme. Synthesis of 5 -amino-5 -deoxyguanosine 1.

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0
0
5
-AMINO-5 -DEOXYGUANOSINE
1519
using triphenylphosphine, imidazole and iodine in 1-methyl-2-pyrrolidinone
0
0
without the need to protect the 2 ,3 -cis diol. In our hands, this reaction
proceeds cleanly in high yield giving iodide 3 as a stable compound in 72%
isolated yield and none of the corresponding cyclonucleoside byproduct was
detected. This regioselective iodination reaction (2 ! 3) represents a major
0
advance in the synthesis of 5 -functionalised guanosine derivatives.
ꢀ
Treatment of iodide 3 with sodium azide in DMF at 80 C gave the
0
corresponding 5 -azide 4 in 69% yield. Attempts to convert guanosine 2
directly to azide 4 using triphenylphosphine, carbon tetrabromide and
6
sodium or lithium azide were unsuccessful. Azide 4 was subsequently
reduced under mild conditions using triphenylphosphine and pyridine
7
0
0
followed by aqueous ammonium hydroxide to give 5 -amino-5 -deoxy-
guanosine 1 as a colourless solid in 78% yield. Following this straight-
forward three step synthetic scheme (2 ! 3 ! 4 ! 1), we were able to
0
0
prepare gram quantities of 5 -amino-5 -deoxyguanosine 1 in a few days
without recourse to any difficult chromatographic separations.
In summary, we have developed a short and efficient three step
0
0
synthesis of 5 -amino-5 -deoxyguanosine 1 from guanosine which overcomes
the limitations of previous syntheses.
EXPERIMENTAL
0
0
-Azido-5 -deoxyguanosine 4
5
0
0
5
A mixture of 5 -deoxy-5 -iodoguanosine 3 (7.4 g, 19 mmol) and
ꢀ
sodium azide (2.5 g, 38 mmol) in dry DMF (50 ml) was stirred at 80 C
under argon for 20 h [CAUTION! Use of inorganic azide: reaction carried
out behind a safety shield]. After cooling to room temperature, the solvent
was removed under reduced pressure and the residue was stirred in water
(
100 ml) for 30 min. The resultant solid was collected by filtration then
washed successively with water (2 Â 50 ml), cold ethanol (30 ml) and diethyl
0
0
ether (20 ml) before drying in vacuo to give 5 -azido-5 -deoxyguanosine 4
(MeOH):
max
ꢀ
(
4.0 g, 69%) as a colourless solid: [a] þ 52.8 (c0.5, DMSO); l
D
À1
1
2104 cm (azide); H NM R
2
(
55 nm ("12900), 270 nm (sh) ("9100); n
max
0
DMSO-d , 400 MHz): d3.52 (1 H, dd, J ¼ 13.2, 3.6 Hz, H-5 ), 3.67 (1 H,
6
0
0
0
dd, J ¼ 13.2, 7.2 Hz, H-5 ), 3.99 (1 H, m, H-4 ), 4.06 (1 H, m, H-3 ), 4.58
0
(
1 H, m, H-2 ), 5.2–5.7 (2 H, br, exchanged with D O, 2 Â OH ), 5.72 (1 H, d,
2
0
J ¼ 5.6 Hz, H-1 ), 6.50 (2 H, br, exchanged with D O, NH ), 7.90 (1 H, s,
2
2
1
H-8) and 10.3–10.9 (1 H, br, exchanged with D O, NH ) ppm; C NM R
3
2
(
DMSO-d , 100 MHz): d 51.8, 70.9, 72.8, 82.7, 86.8, 116.8, 135.8, 151.3,
6

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1
520
DEAN
þ
1
53.8 and 156.9 ppm; MS: (FAB, positive ion þ Na) m/e 309 [M þ H] , 331
þ
[M þ Na] .
0
0
-Amino-5 -deoxyguanosine 1
5
0
0
A stirred solution of 5 -azido-5 -deoxyguanosine 4 (3.1 g, 10 mmol) in
ꢀ
dry pyridine (50 ml) at 0 C was treated with triphenylphosphine (5.2 g,
20 mmol). After stirring at room temperature for 3 h, the resulting thick
ꢀ
suspension was re-cooled to 0 C, treated with ammonium hydroxide
solution (0.880 ammonia, 15 ml) and water (50 ml), then stirred at room
temperature for 18 h. The solvent was removed under reduced pressure,
and the residue was suspended in ethyl acetate (300 ml) and stirred at
room temperature for 15 min. The resultant solid was collected by filtration,
washed with ethyl acetate (50 ml), cold ethyl acetate/methanol (1 : 1, 50 ml)
ꢀ
0
0
and water (50 ml), then dried at 50 C under vacuum to give 5 -amino-5 -
ꢀ
1
deoxyguanosine 1 (2.2 g, 78%) as a colourless solid: m.p. 219–220 C (from
ꢀ
1
ꢀ
water) [m.p. 221 C ]; [a] À 41.6 (c 0.5, DMSO); l (MeOH): 254 nm
" 12600), 268 nm (sh) (" 9100); (0.01 N HCl); 254 nm (" 12000), 270 nm (sh)
8500); (0.01 N KOH): 264 nm (" 10600); H NMR (DMSO-d , 400 MHz):
6
D
max
(
"
1
0
0
d 2.72 (1 H, dd, J ¼ 13.6, 5.4 Hz, H-5 ), 2.79 (1 H, dd, J ¼ 13.6, 4.8 Hz, H-5 ),
0
0
0
3
.78 (1 H, m, H-4 ), 4.08 (1 H, m, H-3 ), 4.44 (1 H, m, H-2 ), 4.5–5.6 (5 H,
0
br, exchanged with D O), 5.66 (1 H, d, J ¼ 6.0 Hz, H-1 ), 6.47 (2 H,
2
1
br, exchanged with D O, NH ) and 7.93 (1 H, s, H-8) ppm; C NM R
3
2
2
(
1
DMSO-d , 100 MHz): d 43.5, 70.6, 73.2, 85.6, 86.2, 116.7, 135.7, 151.3,
6
þ
53.6 and 156.7 ppm; MS: (FAB positive ion) m/e 283 [M þ H] . Found:
C, 39.8, H, 5.3, N, 27.5%. C H N O ꢁH O requires C, 40.0, H, 5.33,
1
0
14
6
4
2
N, 28.0%.
REFERENCES
. Schattka, K.; Jastorff, B. Chem. Ber. 1972, 105, 3824–3832.
. Schattka, K.; Jastorff, B. Chem. Ber. 1974, 107, 3043–3052; Shuman,
D.A.; Bloch, A.; Robins, R.K.; Robins, M.J. J. Med. Chem. 1969, 12,
1
2
653–657; Elloumi, B.; Moreau, B.; Aguiar, L.; Jaziri, N.; Sauvage, M.;
Hulen, C.; Capman, M.L. Eur. J. Med. Chem. 1992, 27, 149–154;
Heskamp, B.M.; Veeneman, G.H.; van de Marel, G.A.; van Boeckel,
C.A.A.; van Boom, J.H. Tetrahedron. 1995, 51, 8397–8406; Li, H.;
Miller, M.J. J. Org. Chem. 1999, 64, 9289–9293.
3. Holmes, R.E.; Robins, R.K. J. Org. Chem. 1963, 28, 3483–3486.

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0
0
5
-AMINO-5 -DEOXYGUANOSINE
1521
4. Unwanted cyclonucleoside formation (from Reference 1).
5
6
. McGee, D.P.C.; Martin, J.C. Can. J. Chem. 1986, 64, 1885–1889.
. Yamamoto, I.; Sekine, M.; Hata, T. J. Chem. Soc., Perkin 1 1980,
06–310.
3
7
. Mungall, W.S.; Greene, G.L.; Heavner, G.A.; Letsinger, R.L. J. Org.
Chem. 1975, 40, 1659–1662; Kvasyuk, E.I.; Mikhailopulo, I.A.; Homan,
J.W.; Iacono, K.T.; Muto, N.F.; Suhadolnik, R.J.; Pfeiderer, W.; Helv.
Chim. Acta 1999, 82, 19–29.
Received in the UK February 12, 2001

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