A short route to new cyclobutene nucleoside analogues

Article abstract of DOI:10.1016/S0040-4020(02)00323-X

Nucleoside analogues (+)-4a and (+)-4b were obtained in non-racemic form by a short and efficient way. The key step was a Mitsunobu reaction of alcohol (-)-8 with adenine or protected thymine. The title products were obtained after deprotection steps.

Full text of DOI:10.1016/S0040-4020(02)00323-X

TETRAHEDRON
Pergamon
Tetrahedron 58 %2002) 3775±3778
A short route to new cyclobutene nucleoside analogues
a
Cecile Hubert, Christian Alexandre, Anne-Marie Aubertin and FrancËois Huet
a,p
b
a,p
Â
a
Á Â Â
Laboratoire de Synthese Organique, UMR CNRS 6011, Faculte des Sciences, Universite du Maine, Avenue Olivier Messiaen BP 535,
F-72085 Le Mans Cedex 9, France
   Â
Faculte de Medecine, Institut de Virologie, INSERM U 544, Universite Louis Pasteur, 3 Rue Koeberle, F-67000 Strasbourg, France
b
Received 28 November 2001; revised 11 March 2002; accepted 18 March 2002
AbstractÐNucleoside analogues %1)-4a and %1)-4b were obtained in non-racemic form by a short and ef®cient way. The key step was a
Mitsunobu reaction of alcohol %2)-8 with adenine or protected thymine. The title products were obtained after deprotection steps. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
thereby restored the four atom link between both of them
as in carbovir 2 %Fig. 1).
Unsaturated nucleoside analogues are an interesting class of
biologically active compounds and several of them show a
signi®cant antiviral activity. Among the new structures
synthesized during the past decade, those containing a
carbocycle are particularly promising.1 The advantage of
these analogues, in which the sugar moiety was replaced
by a carbocycle, is their better stability toward the phos-
phorylase enzymes, which cleave the glycosidic linkage.
Many structures were proposed including cyclopropane,2,3
cyclobutane,4 cyclopentane,5 cyclohexane,6 bicyclic7 and
even an acyclic chain.8 Among these, %2)-abacavir 1,9a
and %2)-carbovir 2,9b were reported to be potent inhibitors
of the HIV-1reverse transcriptase. Previous works in our
laboratory led to the synthesis of nor-carbovir 3a10a and of
the analogue 3b.10b These two molecules do not show any
activity against HIV-1. The lack of activity may be due to
the shorter distance than in normal nucleosides between the
50-OH moiety and the base. To check this point we syn-
thesized cyclobutenic derivatives 4 including a methylene
spacer between the carbocycle and the heterocycle. We
We ®rst investigated some synthetic ways in the racemic
series %Scheme 1). They started from diol 5 prepared by
reduction of 3-oxabicyclo[3.2.0]hept-6-en-2,4-dione11with
lithium aluminum hydride %LAH). In the ®rst route, the
monobenzylated derivative12 was converted into mesylate.
The subsequent substitution with the adenine/K2CO3/18-
crown-6 mixture in DMF for 44 h at 308C or with the
thymine/K2CO3/18-crown-6 mixture in DMSO at 308C for
44 h led to the expected products in low yield. Moreover
they were formed together with other regioisomers and
separations were dif®cult. The predominant isomers gave
the target molecules by deprotection with BCl3. An
Scheme 1.
Figure 1.
Keywords: cyclobutenes; asymmetric synthesis; Mitsunobu reactions; nucleoside analogues.
Corresponding authors. Tel.: 133-2-4383-3338/3096; fax: 133-2-4383-3902;
e-mail: calexan@univ-lemans.fr; fhuet@univ-lemans.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020%02)00323-X

3776
C. Hubert et al. / Tetrahedron 58 72002) 3775±3778
Scheme 2. Conditions: %a) PFL/vinyl acetate 2188C 19 h; %b) tBuPh2SiCl/imidazole/DMF; %c) NH3/MeOH %d) PPh3/DEAD/adenine/THF; %e) TBAF/THF;
%f) PPh3/DEAD/N-3-benzoylthymine; %g) NaOH.
alternative way to avoid obtaining of the unwanted regio-
isomers was to build the heterocyclic moiety from an amino
group. Therefore the preceding mesylate was converted to
an azide which was reduced with LAH. Known pro-
cedures13,14 led to the expected purine and pyrimidine
derivatives in poor overall yield %18 and 15%, respectively,
from amine).
This method is interesting because it needs only one step.
Moreover, in these conditions, only the more stable N-9
isomer was obtained probably due to a thermodynamic
control. Deprotection with tetrabutylammonium ¯uoride
led to the nucleoside analogue %1)-4a in good yield.
Similarly alcohol %2)-8 reacted with the protected
thymine to give cyclobutene %1)-10, in very good yield
%94%). This compound was deprotected by treatment with
NaOH/dioxane then tetrabutylammonium ¯uoride to obtain
%1)-4b.
In carbovir only the minus enantiomer is biologically active.
Therefore we tried to synthesize these molecules in enantio-
merically enriched form and with the same con®gurations
%1S,4R) as in carbovir or abacavir. The key intermediate was
one of the two cyclobutenic mono-acetates derived from
alcohol 5 %Scheme 2). The starting material for a non-
racemic route was alcohol %2)-6 obtained by a recently
reported method.15 Unfortunately this alcohol could not be
benzylated and classical conditions led to a mixture of
the corresponding diacetate and dibenzylate. Alternative
methods in acidic media,16,17 led to decomposition of the
starting material. Finally we could obtain alcohol %2)-8 by
protection of the alcohol %2)-6 as a silyl derivative followed
by treatment with NH3/MeOH to remove the acetyl group. A
®rst attempt of introducing adenine base directly under
Mitsunobu conditions %Scheme 2) and in standard con-
ditions gave the desired product but in low yield %Table
1). Fortunately replacement of dioxane by THF as solvent
led to an improvement of the yield of %1)-9 up to 60%
%entry 4).
To conclude, we have synthesized the two non-racemic
nucleoside analogues %1)-4a and %1)-4b, respectively, in
six steps %33% overall yield from the starting anhydride) and
in seven steps %42% overall yield from the starting anhy-
dride). Mitsunobu reaction proved to be ef®cient to intro-
duce purine or pyrimidine bases directly from a primary
alcohol. %1)-4a and %1)-4b were tested against HIV-1but
none of them had a signi®cant antiviral activity.
2. Experimental
2.1. General
NMR spectra were recorded at 400 and 100 MHz for 1H and
13C, respectively. IR spectra were recorded with a FT infra-
red spectrophotometer. Melting points are uncorrected.
Elemental analyses were performed by the service of micro-
analyses, CNRS ICSN, Gif sur Yvette. High-resolution
mass measurements were performed at the CRMPO
%Rennes). The column chromatographies were run on silica
gel Gerudan SI 60, 230±400 mesh, under 1±2 bar.
Table 1.
Entry
Reagents
Solvent
Time
14 h
5 Days
14 h
Yield %%)
1PPh
3/DEAD
PPh3/DEAD
PPh3/DIAD
PPh3/DEAD
PPh3/DEAD
Dioxane
Dioxane
Dioxane
THF
24
37
34
60
38
2
3
4
5
2.1.1. %2)-[%1S,4R)-4-%{[tert-Butyl%diphenyl)silyl]oxy}-
methyl)cyclobut-2-enyl]methyl acetate %2)-7. To
7 Days
5 Days
a
Benzene
sample of alcohol 615 %91.8% ee,1.4 g, 8.97 mmol) in

C. Hubert et al. / Tetrahedron 58 72002) 3775±3778
3777
208C
%68 mg, 98%). [a]D ˆ134.4 %cˆ1.08 DMSO). Mp:
DMF %2.1mL) were added tert-butyldiphenylsilyl chloride
%2.8 mL) and imidazole %737 mg). The mixture was stirred
overnight at room temperature and water %5 mL) was added.
After extraction with ether %4£11 mL), the combined
organic extracts were dried %MgSO4), the solvent was
removed under reduced pressure and the residue puri®ed
by column chromatography %cyclohexane/ethyl acetate 95/
1
126.4±127.48C %methanol). H NMR %dppm) %DMSO-d6):
8.15 %1H; s); 8.12 %1H; s); 7.17 %2H; broad s); 6.19 %1H;
d; Jˆ2.7 Hz); 6.08 %1H; Jˆ2.7 Hz); 4.69 %1H; t; Jˆ4.9 Hz);
4.42 %1H; dd; Jˆ6.0; 13.7 Hz); 4.20 %1H; dd; Jˆ9.8;
13.7 Hz); 3.67±3.51 %2H; m); 3.49±3.40 %1H; m); 3.05
%1H; m). 13C NMR %dppm) %DMSO-d6): 155.9; 152.3;
149.5; 140.8; 138.8; 138.5; 118.7; 60.6; 47.6; 44.8; 43.3.
IR %n cm21) %KBr disc): 3390; 3293; 3118; 1673; 1602.
Anal. calcd for C11H13N5O: C 57.13; H 5.66; N 30.28.
Found: C 57.57; H 5.84; N 30.34.
208C
5) to give %2)-7 %3.35 g, 95%) as an oil. [a]D ˆ24.7
%cˆ1.51 CHCl3). 1H NMR %dppm) %CDCl3): 7.69±7.63
%4H; m); 7.44±7.34 %6H; m); 6.19 %1H; d; Jˆ2.5 Hz); 6.09
%1H; d; Jˆ2.5 Hz); 4.35 %1H; dd; Jˆ6.7; 11.0 Hz); 4.21 %1H;
dd; Jˆ7.3; 11.0 Hz); 3.85 %2H; d; Jˆ6.8 Hz); 3.27±3.11
%2H; m); 1.98 %3H; s); 1.04 %9H; s). 13C NMR %dppm):
171.0; 138.6; 137.9; 135.7; 133.7; 129.7; 127.8; 64.8;
63.9; 47.8; 44.4; 27.0; 20.9; 19.2. Anal. calcd for
C24H30SiO3: C 73.05; H 7.66. Found: C 72.97; H 7.82.
2.1.5. %1)-1-{[%1S,4R)-4-%{[tert-Butyl%diphenyl)silyl]oxy}-
methyl)cyclobut-2-enyl]methyl}-3-benzoyl-5-methyl-
pyrimidine-%1H,3H)-dione %1)-10. To a solution of alco-
hol 8 %662 mg, 1.90 mmol), triphenylphosphine %996 mg)
and N-3-benzoylthymine18 %861mg) in THF %12 mL), was
added dropwise for 2.5 h a solution of DEAD %585 mL) in
THF %12 mL). The mixture was stirred overnight at room
temperature. The solvent was removed under reduced
pressure and the residue was puri®ed by column chroma-
tography %ethyl acetate/methanol 4/1) to give N-benzoyl
%1)-10 %998 mg, 94%) as white needles. Mp: 116.2±
2.1.2.
%2)-[%1S,4R)-4-%{tert-Butyl%diphenyl)silyl]oxy}-
methyl)-cyclobut-2-enyl]methanol %2)-8. To a solution
of acetate 7 %3.35 g, 8.5 mmol) in methanol %80 mL) at
08C, was added a saturated solution of ammonia in methanol
%161 mL). The mixture was stirred for 48 h at room
temperature. After removal of the volatile substances, the
residue was puri®ed by column chromatography %cyclo-
hexane/ethyl acetate 7/1) to give %2)-8 %2.2 g, 74%).
208C
116.88C %ether/petroleum ether 2/1). [a]D ˆ120.8
1
%cˆ1.27 CHCl3). H NMR %dppm) %CDCl3): 7.93 %2H; dd;
208C
1
[a]D ˆ26.5 %cˆ1.32 CHCl3). H NMR %dppm) %CDCl3):
7.67 %4H; dd; Jˆ7.8; 1.5 Hz); 7.47±7.35 %6H; m); 6.01 %1H;
d; Jˆ2.8 Hz); 5.84 %1H; d; Jˆ2.8 Hz); 3.81±3.75 %5H; m);
3.31%1H; ddd; Jˆ3.8; 7.8; 9.2 Hz); 3.15 %1H; ddd; Jˆ3.8;
5.4; 6.6 Hz); 1.04 %9H; s). 13C NMR %dppm): 138.0; 136.6;
135.6; 132.7; 129.9; 127.9; 63.9; 62.2; 48.8; 47.7; 26.9;
19.1. Anal calcd for C22H28SiO2 C 74.99; H 8.00. Found:
C 74.78; H 8.12.
Jˆ0.9; 8.1Hz); 7.68±7.63 %5H; m); 7.62 %2H; dd; Jˆ1.2;
1.2 Hz); 7.52±7.35 %6H; m); 7.07 %1H; dd; Jˆ1.1 Hz); 6.16
%1H; d; Jˆ2.4 Hz); 6.05 %1H; d; Jˆ2.4 Hz); 4.23 %1H; dd;
Jˆ4.8; 13.6 Hz); 3.85 %1H; dd; Jˆ10.3; 13.6 Hz); 3.86 %1H;
dd; Jˆ4.8; 11.1 Hz); 3.77 %1H; dd; Jˆ7.6; 11.1 Hz); 3.33
%1H; ddd; Jˆ4.3; 4.8; 10.3 Hz); 3.20 %1H; ddd; Jˆ4.3; 4.8;
7.6 Hz); 1.92 %3H; d; Jˆ1.1 Hz); 1.07 %9H; s). 13C NMR
%dppm): 168.5; 162.6; 149.2; 140.8; 138.5; 138.3; 135.8;
135.1; 133.5; 131.9; 130.7; 130.1; 129.3; 128.0; 110.8;
63.8; 50.2; 47.2; 44.9; 27.2; 19.5; 12.7. Anal. calcd for
C34H36SiN2O4 %10.25 H2O): C 71.74; H 6.37; N 4.92.
Found C 71.75; H 6.37; N 4.79.
2.1.3. %1)-9-[%1S,4R)-4-%{[tert-Butyl%diphenyl)silyl]oxy}-
methyl)cyclobut-2-enyl]methyl-9H-purin-6-ylamine %1)-9.
To a solution of alcohol 8 %609 mg, 1.73 mmol), triphenyl-
phosphine %987 mg) and adenine %493 mg) in THF %10 mL),
was added dropwise for 2.5 h a solution of DEAD %550 mL)
in THF %10 mL). The mixture was stirred for one week at
room temperature. The solvent was removed under reduced
pressure and the residue was puri®ed by column chroma-
tography %ethyl acetate/methanol 9/1) to give %1)-9
%487 mg, 60%) as white needles. Mp: 134.4±135.28C
2.1.6. %1)-N-1-{[%1S,4R)-4-%{[tert-Butyl%diphenyl)silyl]-
oxy}methyl)cyclobut-2-enyl]methyl}-5-methyl-pyrimidine-
%1H,3H)-dione %1)-11. To a solution of 10 %104 mg,
0.18 mmol) in dioxane %1.5 mL), was added NaOH 8N
%1.5 mL) and the resulting mixture was stirred for 3 days
at room temperature. A 10% solution of hydrochloric acid
was added at 58C to neutralize the base. After extraction
with ethyl acetate %10£4 mL), the combined organic
extracts were dried %MgSO4) and the solvent was removed
under reduced pressure. The residue was puri®ed by column
chromatography %cyclohexane/ethyl acetate 3/1) to give
%1)-11 %72 mg, 85%) as a white powder. Mp: 89.3±
208C
%ether/petroleum ether 3/1). [a]D ˆ10.94 %cˆ1.27
1
CHCl3). H NMR %dppm) %CDCl3): 8.38 %1H; s); 7.80 %1H;
s); 7.67 %4H; m); 7.47±7.37 %6H; m); 6.14 %2H; s); 6.09 %1H;
d; Jˆ2.9 Hz); 6.08 %1H; d; Jˆ2.9 Hz); 4.63 %1H; dd; Jˆ5.9;
13.8 Hz); 4.32 %1H; dd; Jˆ10.3; 13.8 Hz); 3.90 %1H; dd;
Jˆ5.4; 11.0 Hz); 3.85 %1H; dd; Jˆ7.9; 11.0 Hz); 3.51 %1H;
m); 3.24 %1H; m); 1.10 %9H; s). 13C NMR %dppm): 155.5;
152.9; 150.1; 140.5; 138.6; 138.7; 135.6; 135.5; 133.4;
133.3; 129.8; 129.7; 127.7; 119.7; 63.4; 47.5; 45.4; 44.5;
26.9; 19.2. Anal. calcd for C27H31SiN5O: C 69.05; H 6.65; N
14.91. Found: C 68.98; H 6.66; N 14.68.
208C
92.38C %petroleum ether/ether 2/1). [a]D ˆ125.1% cˆ
1.10 CHCl3). 1H NMR %dppm) %CDCl3): 9.42 %1H; s);
7.71±7.65 %4H; m); 7.48±7.36 %6H; m); 6.97 %1H; d;
Jˆ1.2 Hz); 6.14 %1H; d; Jˆ2.8 Hz); 6.05 %1H; d; Jˆ
2.8 Hz); 4.20 %1H; dd; Jˆ4.8; 13.5 Hz); 3.86 %1H; dd;
Jˆ5.0; 11.0 Hz); 3.8 %1H; dd; Jˆ10.5; 13.5 Hz); 3.78 %1H;
dd; Jˆ7.9; 11.0 Hz); 3.31 %2H; ddd; Jˆ4.8; 10.5; 4.5 Hz);
3.19 %2H; ddd; Jˆ4.5; 5.0; 7.9 Hz); 1.89 %3H; d; Jˆ1.2 Hz);
1.08 %9H; s). 13C NMR %dppm): 164.8; 151.3; 141.1; 138.6;
138.5; 135.9; 133.8; 130.2; 128.1; 110.8; 63.8; 49.9; 47.9;
44.9; 27.3; 19.6; 12.7. Anal. calcd for C27H32SiN2O3 %10.15
H2O): C 69.99; H 6.96; N 6.04. Found: C 69.92; H 6.99; N
5.86.
2.1.4. %1)-{%1S,4R)-4-[%6-Amino-9H-purin-9-yl)methyl]-
cyclobut-2-enyl}methanol %1)-4a. Tetrabutylammonium
¯uoride %602 mL of 1M in THF) was added to a solution
of 9 %140 mg, 0.30 mmol) in THF %2.7 mL). After stirring
for 2 h, the volatile substances were removed under reduced
pressure and the residue puri®ed by column chroma-
tography %dichloromethane/methanol 5/1) to give %1)-4a

3778
C. Hubert et al. / Tetrahedron 58 72002) 3775±3778
3. Qiu, Y.-L.; Ksebati, M. B.; Zemlicka, J. Nucleosides Nucleo-
tides Nucl. Acids 2000, 19, 31±37.
2.1.7. %1)-N-1-{[%1S,4R)-4-%hydroxymethyl)cyclobut-2-
enyl]methyl}-5-methyl-pyrimidine-%1H,3H)-dione 4b.
4. Guan, H.-P.; Ksebati, M. B.; Kern, E. R.; Zemlicka, J. J. Org.
Chem. 2000, 65, 5177±5184.
To a solution of protected alcohol 11 %222 mg, 0.46
mmol) in THF %4.2 mL), was added tetrabutylammonium
¯uoride %1M, 920 mL) and the mixture was stirred for 2 h
at room temperature. The solvent was removed in vacuum
and the residue was puri®ed by column chromatography
%dichloromethane/methanol 9/1) to give %1)-4b %96 mg,
5. Besada, P.; Teran, C.; Santana, L.; Teijeira, M.; Uriarte, E.
Nucleosides Nucleotides 1999, 18, 725±726.
6. Wang, J.; Busson, R.; Blaton, N.; Rozenski, J.; Herdewijn, P.
J. Org. Chem. 1996, 61, 3051±3058.
208C
7. Demaison, C.; Hourioux, C.; Roingeard, P.; Agrofoglio, L.
Tetrahedron Lett. 1998, 39, 9175±9178.
94%). [a]D ˆ161.9 %cˆ1.01 methanol). Mp: 132.8±
1
133.98C %ether /methanol 6/1). H NMR %dppm) %CDCl3):
8. Gao, H.; Mitra, A. K. Synthesis 2000, 329±351.
9. %a) Hughes, W.; McDowell, J. A.; Shenep, J.; Flynn, P.; Kline,
M. W.; Yogey, R.; Symonds, W.; Lou, H.; Hetherington, S.
Antimicrob. Agents Chemother. 1999, 43, 609±615.
%b) Coates, J. A.; Inggall, H. J.; Pearson, B. A.; Penn, C. R.;
Storer, R.; Williamson, C.; Cameron, J. M. Antiviral Res.
1991, 15, 161. %c) Ray, A. S.; Anderson, K. S. Nucleosides
Nucleotides Nucl. Acids 2001, 20, 1247±1250.
7.45 %1H; q; Jˆ1.2 Hz); 6.18±6.15 %2H; m); 4.07 %1H; dd;
Jˆ5.7; 13.8 Hz); 3.81 %1H; dd; Jˆ10.1; 13.8 Hz); 3.74 %1H;
dd; Jˆ5.9; 11.0 Hz); 3.7 %1H; dd; Jˆ8.4; 11.0 Hz); 3.33±
3.24 %1H; m); 3.20±3.12 %1H; m); 1.87 %3H; d; Jˆ1.2 Hz).
13C NMR %dppm) %CD3OD): 166.8 153.0; 143.3; 139.7;
139.1; 111.0; 62.6; 49.8; 48.8; 45.9; 12.2. IR %n cm21
)
%KBr disc): 3463, 3160, 3027, 1691. Anal. calcd for
C11H14N2O3: C 59.45; H 6.35; N 12.60. Found: C 59.38;
H 6.26; N 12.67.
10. %a) Gourdel-Martin, M.-E.; Huet, F. Nucleosides Nucleotides
1999, 18, 645±648. %b) Gourdel-Martin, M.-E.; Huet, F.
J. Org. Chem. 1997, 62, 2166±2172.
11. Comoy, C.; Lescop, C.; Gauvry, N.; Huet, F. Synthesis 1999,
574±576.
Acknowledgements
Â
12. Mevellec, L.; Evers, M.; Huet, F. Tetrahedron 1996, 52,
15103±15116.
We thank the local section of Sarthe of the Ligue Nationale
contre le Cancer for a fellowship to C. H.
13. Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.;
Sham, H.; Herrin, T.; Plattner, J. J.; Erickson, J.; Clement,
J.; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh, K.; Arnett,
G.; Shannon, W.; Broder, S.; Mitsuya, H. J. Med. Chem. 1990,
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