An efficient synthesis of dienic nucleoside analogues via a Mitsunobu reaction

Article abstract of DOI:10.1016/S0040-4020(03)00373-9

Nucleoside analogues 9 and 12 were obtained in good yields from alcohol 7 which, under Mitsunobu conditions, led to the title products after deprotection steps.

Full text of DOI:10.1016/S0040-4020(03)00373-9

Tetrahedron 59 (2003) 3127–3130
An efficient synthesis of dienic nucleoside analogues via a
Mitsunobu reaction
a
Cecile Hubert, Christian Alexandre, Anne-Marie Aubertin and Franc¸ois Huet
a
b
a
,
,
*
*
´
a
` ´ ´
Laboratoire de Synthese Organique, UMR CNRS 6011, Faculte des Sciences, Universite du Maine, Avenue Olivier Messiaen,
F-72085 Le Mans Cedex 9, France
´ ´ ´ ´
Institut de Virologie, INSERM U 544, Faculte de Medecine, Universite Louis Pasteur, 3 Rue Koeberle, F-67000 Strasbourg, France
b
Received 2 December 2002; revised 12 February 2003; accepted 3 March 2003
Abstract—Nucleoside analogues 9 and 12 were obtained in good yields from alcohol 7 which, under Mitsunobu conditions, led to the title
products after deprotection steps. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
account the fact that the replacement of the oxygen atom by
a methylene group increases the stability of the analogue
against phosphorylases and hydrolases. An example in the
field of acyclic compounds is penciclovir 2.7 It is the reason
why we wish to report here the synthesis of carba-acyclic
nucleoside analogues.
Among nucleoside analogues synthesized in recent years,
some of them displayed a significant antiviral activity. In the
search for new compounds, the major modifications were
carried out on the sugar moiety of the nucleoside.1–4 The
interest in the synthesis of acyclic nucleoside compounds
emerged when it appeared that changing the ribose moiety
by an acyclic chain leads to potent anti-viral drugs,2 such as
ganciclovir 1 (Fig. 1),3 which shows anti-herpetic activity.
The acyclic chain may be indeed considered as resulting
from the suppression of a methylene group with respect to a
carbohydrate moiety.5 This means that the total structure of
the glycosyl portion is then not necessarily required for the
biological activity.6 In the course of our research program
towards carbocyclic nucleoside analogues,7 we took into
The structure modifications, which were proposed, tended to
modify the flexibility of the chain between the base and the
hydroxymethylene group. This chain flexibility allowed
the non-natural substrate to improve the interactions with
the enzyme, with respect to the natural one.8 For instance,
Hua et al.6 synthesized a neplanocin A analogue 3. The
introduction of a double bond gave a slight rigidity to the
analogue, which might stabilize the compound in the best
conformation to improve the interactions between the
phosphorylating enzymes and the analogue. In the case of
thymallene9 or adenallene 4,10 the rigidity induced by the
cumulated double bond system is counteracted by the free
rotation of the base and the hydroxymethylene function. In
our concern, we planned to prepare analogues with a dienic
structure (Fig. 2), which could present a compromise
between a flexible saturated chain and a more rigid one as
in adenallene 4.
Figure 2.
Figure 1.
2. Results and discussion
Keywords: cyclobutenes; dienes; Mitsunobu reactions; nucleoside
analogues.
The previously obtained dienic alcohol 511 (Scheme 1) was
protected as a tertiobutyldiphenylsilyl ether to give
compound 6. First attempts of reduction of the ester
*
Tel.: þ33-2-4383-3096; fax: þ33-2-4383-3338;
calexan@univ-lemans.fr; fhuet@univ-lemans.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00373-9

3128
C. Hubert et al. / Tetrahedron 59 (2003) 3127–3130
Scheme 1. Conditions (a) tBuPh2SiCl/imidazole/DMF, 14 h; (g) DIBALH/toluene, 2608C, 1 h.
Scheme 2. Conditions (a) PPh3/DEAD/adenine/THE (b) n-TBAF/THE (c) PPh3/DEAD/N-3-benzoylthymine/THF (d) NH4OH/MeOH.
function by aluminium hydride12,13 gave no result, but
alcohol 7 was obtained by reduction of the conjugated ester
6 with diisobutylaluminium hydride14. The alcohol 7 was
treated with adenine, triphenylphosphine and DEAD under
Mitsunobu conditions (Scheme 2). The expected compound
8 was obtained in reasonable yield (48%). It should be
noticed that only the N-9 regioisomer is formed and not
another substitution product (Scheme 3). The cleavage of
the silyl group by tetra-n-butylammonium fluoride provided
the adenine dienic analogue 9. The alcohol 7 reacted with
N-3-benzoylthymine under Mitsunobu conditions to give
compound 10 in 67% yield. This compound was succes-
sively deprotected with NH4OH/MeOH and tetra-n-butyl-
ammonium fluoride to obtain the target thymine dienic
analogue 12.
respectively, in seven steps (21% overall yield from the
cyclobutene anhydride precursor of 5) and in eight steps
(16% overall yield from the same anhydride). These
compounds were evaluated for their anti-HIV activity but
no significant activity was detected.
3. Experimental
3.1. General
NMR spectra were recorded at 400 and 100 MHz for 1H and
13C, respectively. IR spectra were recorded with a FT
infrared spectrophotometer. Melting points are uncorrected.
Elemental analyses were performed by the service of
microanalyses, CNRS ICSN, Gif sur Yvette. The
column chromatography were run on silica gel Gerudan SI
60, 230–400 mesh, under 1–2 bar.
To conclude, in the course of the synthesis of the two new
adenine and thymine dienic analogues 9 and 12, the access
to the key intermediate, the alcohol 7, was allowed by the
use of stereo and chemoselective reactions and by appro-
priate protective steps. The Mitsunobu reaction provided the
expected analogues in an efficient way, leading only to the
N-9 adenine analogue. Finally, the two new adenine and
thymine dienic analogues 9 and 12 were prepared,
3.1.1. Methyl (2Z,4E)-6-([tert-butyl(diphenyl)silyl]oxy)-
hexa-2,4-dienoate 6. To a sample of alcohol 511 (343 mg,
0.85 mmol) in DMF (520 mL) were added tert-butyl-
diphenylsilyl chloride (684 mL) and imidazole (181 mg).
The mixture was stirred 14 h at room temperature and water
(1.2 mL) was added. After extraction with ether
(4£1.4 mL), the combined organic extracts were dried
(MgSO4), the solvent was removed under reduced pressure
and the residue was purified by column chromatography
(cyclohexane/ethyl acetate 95/5) to give 6 (884 mg, 96%) as
an oil. 1H NMR (dppm) (CDCl3): 7.71–7.55 (5H; m); 7.45–
7.34 (6H; m); 6.59 (1H; dd; J¼11.3, 11.6 Hz); 6.09 (1H; dt;
J¼4.4, 15.2 Hz); 5.65 (1H; d; J¼11.3 Hz); 4.34 (2H; dd;
Scheme 3. Relevant 1H/13C HMBC correlations for identification of
compound 9 as the N-9 regioisomer.
J¼1.7, 4.4 Hz); 3.72 (3H; s); 1.09 (9H; s). 13C NMR (dppm
)

C. Hubert et al. / Tetrahedron 59 (2003) 3127–3130
3129
(CDCl3): 166.7; 143.9; 142.2; 135.5; 133.3; 129.7; 127.7;
125.6; 117.0; 63.8; 51.1; 26.8; 19.2. IR (n cm21) (film):
1720; 1644; 1602. Anal. calcd for C23H28SiO3 (þ0.2H2O):
C 71.91; H 7.40. Found: C 71.84; H 7.36.
118.5; 61.1; 40.0. IR (n cm21) (KBr disk): 3401; 3363/3268;
1679; 1600; 1332. Anal. calcd for C11H13N5O: C 57.13; H
5.66; N 30.28. Found: C 56.97; H 5.77; N 30.51.
3.1.5. 1-[(2Z,4E)-6-([tert-Butyl(diphenyl)silyl]oxy)hexa-
2,4-dienyl]-3-benzoyl-5-methylpyrimidine-(1H,3H)-
dione 10. To a solution of alcohol 7 (1.200 g, 3.4 mmol),
triphenylphosphine (1.803 g) and N-3-benzoylthymine
(1.561 g; 6.8 mmol) in THF (21 mL), was added, dropwise
over a period of 2.5 h, a solution of DEAD (1 mL) in THF
(21 mL). The mixture was stirred for 48 h at room
temperature. The solvent was removed under reduced
pressure and the residue was purified by column chroma-
tography (cyclohexane/ethyl acetate 4/1) to give 10
3.1.2. (2Z,4E)-6-([tert-Butyl(diphenyl)silyl]oxy)hexa-2,4-
dien-1-ol 7. To a solution of ester 6 (884 mg, 2.3 mmol) in
toluene (125 mL) at 2608C was added a 1 M solution of
DIBALH in toluene (11.6 mL, 11.6 mmol). After 1 h at
2608C the mixture was hydrolyzed with 10% citric acid
(98 mL). The aqueous layer was extracted with toluene
(2£30 mL) and the combined organic extracts were dried
(MgSO4). The solvent was removed under reduced pressure
and the residue was purified by column chromatography
(cyclohexane/ethyl acetate 95/5) to give 7 (717 mg, 87%) as
an oil. 1H NMR (dppm) (CDCl3): 7.71–7.64 (4H; m); 7.45–
7.35 (6H; m); 6.58 (1H; ddtd; J¼1.2, 1.7, 11.3, 15.1 Hz);
6.11 (1H; ddt; J¼5.5, 11.1, 11.3 Hz); 5.82 (1H; dt; J¼4.7,
15.1 Hz); 5.59 (1H; dtd; J¼1.2, 6.6, 11.1 Hz); 4.30 (2H; dd;
J¼5.5, 6.6 Hz); 4.27 (2H; dd; J¼1.7, 4.7 Hz); 1.6 (1H; s
broad); 1.07 (9H; s).13C NMR (dppm) (CDCl3): 135.5; 134.4;
133.5; 130.1; 129.7; 129.0; 127.7; 124.0; 63.9; 58.8; 26.9;
19.2. IR (n cm21) (film): 3365; 1469; 1110; 1049. Anal.
calcd for C22H28SiO2: C 74.19; H 7.92. Found: C 74.18; H
7.73.
1
(1.293 g, 67%) as a white powder. Mp: 53.6–55.48C. H
NMR (dppm) (CDCl3): 7.93 (2H; dd; J¼1.2, 8.4 Hz); 7.69–
7.63 (5H; m); 7.62 (2H; t; J¼1.5 Hz); 7.52–7.35 (6H; m);
6.99 (1H; q; J¼1.2 Hz); 6.66 (1H; ddtd; J¼0.6, 1.2, 11.3,
14.8 Hz); 6.33 (1H; ddt; J¼5.5, 10.6, 11.3 Hz); 5.96 (1H; dt;
J¼4.3, 15.0 Hz); 5.43 (1H; dtd; J¼0.6, 7.5, 10.6 Hz); 4.49
(2H; dd; J¼5.5, 7.5 Hz); 4.32 (2H; dd; J¼1.2, 4.3 Hz); 1.93
(3H; d; J¼1.2 Hz). 13C NMR (dppm) (CDCl3): 168.1; 162.6;
149.5; 139.0; 136.9; 135.4; 134.9; 133.5; 133.3; 131.6;
130.4; 129.7; 129.0; 127.7; 122.5; 122.2; 110.9; 63.8; 44.4;
26.8; 19.2; 12.4. IR (n cm21) (KBr disk): 1747; 1697; 1646;
1434; 1228; 1110. Anal. calcd for C34H36SiN2O4: C 70.07;
H 6.57; N 4.81. Found: C 70.08; H 6.32; N 4.75.
3.1.3. 9-[(2Z,4E)-6-([tert-Butyl(diphenyl)silyl]oxy)hexa-
2,4-dienyl]-9H-purin-6-amine 8. To a solution of alcohol
7 (612 mg, 1.73 mmol), triphenylphosphine (989 mg) and
adenine (495 mg) in THF (10 mL), was added, dropwise
over a period of 2.5 h, a solution of DEAD (552 mL) in THF
(10 mL). The mixture was stirred for 48 h at room
temperature. The solvent was removed under reduced
pressure and the residue was purified by column chroma-
tography (ethyl acetate/methanol 9/1) to give 8 (398 mg,
48%) as a white powder. Mp: 137.0–138.38C (ether/
methanol 9/1). 1H NMR (dppm) (CDCl3): 8.37 (1H; s);
7.77 (1H; s); 7.73–7.65 (4H; m); 7.48–7.35 (6H; m); 6.75
(1H; ddtd; J¼0.6, 1.8, 4.8, 11.5 Hz); 6.33 (1H; ddt; J¼5.5,
11.1, 11.5 Hz); 5.95 (1H; dt; J¼4.3, 14.8 Hz); 5.94 (2H; s);
5.59 (1H; dtd; J¼0.6, 7.3, 11.1 Hz); 4.91 (2H; dd; J¼5.5,
7.4 Hz); 4.33 (2H; dd; J¼1.8, 4.3 Hz); 1.08 (9H; s). 13C
NMR (dppm) (CDCl3): 156.0; 153.4; 149.5; 140.2; 137.1;
135.9; 133.7; 133.4; 130.2; 128.1; 123.1; 122.7; 119.8; 64.2;
40.8; 27.2; 19.6. IR (n cm21) (KBr disk): 3305; 3126; 1668;
1594; 1301; 1110; 1049. Anal. calcd for C27H31SiN5O: C
69.05; H 6.65; N 14.91. Found: C 69.21; H 6.55; N 14.77.
3.1.6. 1-[(2Z,4E)-6-([tert-Butyl(diphenyl)silyl]oxy)hexa-
2,4-dienyl]-5-methylpyrimidine-(1H,3H)-dione 11. To a
solution of 10 (257 mg, 0.45 mmol) in methanol (11.5 mL)
was added a solution of 20.5% ammonium hydroxide in
water (4.5 mL). The mixture was stirred for 48 h at room
temperature. The solvent was removed under reduced
pressure and the residue was purified by column chroma-
tography (cyclohexane/ethyl acetate 3/1) to give 11
(126 mg, 60%) as a white powder. Mp: 146.3–146.88C
1
(petroleum ether/ether 2/1). H NMR (dppm) (CDCl3): 8.37
(1H; s); 7.71–7.65 (4H; m); 7.47–7.36 (6H; m); 6.90 (1H;
q; J¼1.2 Hz); 6.66 (1H; ddtd; J¼0.6, 1.2, 11.1, 14.8 Hz);
6.30 (1H; ddt; J¼5.5, 10.6, 11.3 Hz); 5.94 (1H; dt; J¼4.3,
14.8 Hz); 5.40 (1H; dtd; J¼0.6, 7.4, 10.6 Hz); 4.44 (2H; dd;
J¼5.5, 7.4 Hz); 4.33 (2H; dd; J¼1.2, 4.3 Hz); 1.89 (3H; d;
J¼1.2 Hz); 1.09 (9H; s). 13C NMR (dppm) (CDCl3): 164.2;
151.0; 139.4; 136.6; 135.5; 133.4; 133.2; 129.8; 127.7;
122.8; 122.7; 63.8; 44.2; 26.8; 19.3; 12.4. IR (n cm21) (KBr
disk): 3438; 3153; 1671; 1652; 1425; 1355; 1218; 1105;
1029. Anal. calcd for C27H32SiN2O3: C 70.40; H 7.00; N
6.08. Found: C 70.65; H 7.01; N 5.91.
3.1.4. 9-[(2Z,4E)-6-Hydroxyhexa-2,4-dienyl]-9H-purin-
6-amine 9. To a solution of protected alcohol 8 (124 mg,
0.26 mmol) in THF was added n-tetrabutylammonium
fluoride (1 M, 532 mL) and the mixture was stirred for 2 h
at room temperature. The solvent was removed under
reduced pressure and the residue was purified by column
chromatography (dichloromethane/methanol 5/1) to give 9
(61 mg, 100%) as a white powder. Mp: 197.7–198.68C
(methanol). 1H NMR (dppm) (DMSO-D6): 8.14 (1H; s); 8.11
(1H; s); 7.21 (2H; s); 6.72 (1H; ddtd; J¼0.6, 1.8, 11.3,
15.0 Hz); 6.20 (1H; ddt; J¼5.5, 10.6, 11.3 Hz); 5.93 (1H; dt;
J¼5.2, 15.0 Hz); 5.56 (1H; dtd; J¼0.6, 7.1, 10.6 Hz); 4.92
(2H; dd; J¼5.5, 7.1 Hz); 4.89 (1H; t; J¼5.4 Hz); 4.06 (2H;
ddd; J¼1.8, 5.2, 5.4 Hz). 13C NMR (dppm) (DMSO-D6):
155.8; 152.4; 149.2; 140.3; 137.5; 131.4; 124.0; 123.3;
3.1.7. 1-[(2Z,4E)-6-Hydroxyhexa-2,4-dienyl]-5-methyl-
pyrimidine-(1H,3H)-dione 12. To a solution of 11
(124 mg, 0.27 mmol) in THF (2.4 mL) was added tetra-n-
butylammonium fluoride (1 M, 539 mL). The mixture was
stirred for 2 h at room temperature. The solvent was
removed under reduced pressure and the residue was
purified by column chromatography (dichloromethane/
methanol 9/1) to give 12 (54 mg, 89%) as a white powder.
1
Mp: 140.1–140.78C. H NMR (dppm) (CD3OD): 7.36 (1H;
q; J¼1.1 Hz); 6.71 (1H; ddtd; J¼0.6, 1.5, 11.3, 15.0 Hz);
6.26 (1H; ddt; J¼5.6, 10.8, 11.3 Hz); 5.94 (1H; dt; J¼5.4,
15.0 Hz); 5.43 (1H; dtd; J¼0.6, 7.1, 10.8 Hz); 4.50 (2H; dd;
J¼5.6, 7.1 Hz); 4.18 (2H; dd; J¼1.5, 5.4 Hz); 1.85 (3H; d;

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C. Hubert et al. / Tetrahedron 59 (2003) 3127–3130
J¼1.1 Hz). 13C NMR (dppm) (CD3OD): 166.8; 152.8; 142.3;
137.4; 133.5; 125.4; 124.8; 111.4; 63.1; 45.7; 12.2. IR (n
cm21) (KBr disk): 3500; 3147; 1695; 1671; 1473; 1355;
1218; 1085. Anal. calcd for C11H14N2O3: C 59.45; H 6.35;
N 12.60. Found: C 59.41; H 6.18; N 12.44.
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Acknowledgements
We thank the local section of Sarthe of the Ligue Nationale
contre le Cancer for a fellowship to C. H.
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