Unusual β-elimination of carbocyclic ketonucleosides catalyzed by silica gel

Article abstract of DOI:10.1080/15257770601052273

β-elimination reactions occurred when carbocyclic ketonucleosides were treated with silica gel and α,β-unsaturated ketonucleosides were obtained. The positions of ketone groups did not affect the occurrance of the elimination reaction. The yields of the r

Full text of DOI:10.1080/15257770601052273

Nucleosides, Nucleotides, and Nucleic Acids, 26:45–49, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770601052273
UNUSUAL β-ELIMINATION OF CARBOCYCLIC KETONUCLEOSIDES
CATALYZED BY SILICA GEL
Xiaozhen Liu, Xin Guo, Fei Wang, and Guangqing Lei
Beijing Institute of
2
Pharmaceutical Chemistry, Beijing, China
Dongdong Luo
College of Chemistry and Materials Science, SCUFN,
2
Wuhan, China
β-elimination reactions occurred when carbocyclic ketonucleosides were treated with silica gel
2
and α,β-unsaturated ketonucleosides were obtained. The positions of ketone groups did not affect
the occurrance of the elimination reaction. The yields of the reaction were influenced by the properties
of leaving groups.
Keywords Carbocyclic nucleosides; elimination; silica gel
INTRODUCTION
Carbocyclic analogues of nucleosides have been of interest because
these compounds sometimes had higher antiviral activities compared with
the nucleosides with a “sugar” moieties and could usually avoid enzymatic
degradation.[1] The analogues of carbocyclic nucleosides with a double
bond inside or outside cyclopentane rings, such as Neplanocin A, Abcavir,
and Entacavir, showed potent antiviral activities and low toxicities.[2] In
some cases the antiviral activities of the carbocyclic nucleosides could be
improved by the incorporation of such a double bond.
As a part of our program focused on the synthesis of carbocyclic
nucleosides with a double bond outside the cyclopentane ring, 2a, b were
required as key intermediates. These two compounds were synthesized as
shown in Scheme 1. The starting materials, 1c and 1b, were prepared by
the known procedures.[3–5] N -Acetylation of 1c produced 1a. Compound
1a and 1b were oxidized with Dess-Martin reagents to obtain 2a, b.[4,5]
Surprisingly, when 2a and 2b were purified by column chromatography
Received 5 April 2006; accepted 21 June 2006.
The authors are very grateful to Professor Ming Zhang for reviewing the manuscript for grammar
and spelling.
Address correspondence to Guangqing Lei, P.O. Box 1044-401, Beijing 102205, China. E-mail:
lxzwxylym@126. com
45

46
X. Liu et al.
SCHEME 1 i, Dess-Martin reagent; ii, CHCl3, silica gel.
with silica gel, compounds 3a, and 3b were isolated in 87% and 73% yields
respectively. The same transformation could also be completed within one
hour when compounds 2 a, b were stirred with silica gel in CHCl3.
The β-elimination of carbocyclic nucleosides in which the ketone
groups were at the other positions was investigated as they were treated with
silica gel. Compound 7 was designed and synthesized as shown in Scheme 2.
SCHEME 2 i, acetic anhydride, toluene, reflux; ii, DDQ, CH2Cl2, H2 O; iii, Dess-Martin reagent,
CH2Cl2, rt; iv, CHCl3, silica gel.
Compound 4 was prepared by epoxide-opened reaction with O-
benzylguanine.[6] After acetylating hydroxyl and amino groups, 5 was
obtained. Compound 6 was synthesized by removal of the p-methoxybenzyl
group of 5 with DDQ. Then 6 was oxidized with Dess-Martin reagent and 7
formed. Stirring 7 with silica gel in CHCl3 for one hour produced 8 in 98%
yield.
These results showed that the β-elimination could occur though the
ketone groups at different positions in carbocyclic nucleoside. The proper-
ties of the leaving groups influenced the yields in this transformation. The
easier the leaving groups removed, the higher the yields were. The reaction
proceeded in high yield when the leaving group was acetoxy, but the yield
became lower for the benzyloxy group because of its reduced leaving activity.
There were some examples for β-elimination reactions of ketonucle-
osides, the eliminated groups at β-position of ketone included fluoro[7]
and acetoxy,[8] all occurring under alkaline or enzymatic conditions. No

Unusual β-Elimination of Ketonucleosides
47
report was found that β-elimination of carbocyclic ketonucleosides could
be catalyzed by silica gel.
In this program, it was speculated at first that the acidity of silica
gel induced the β-elimination reactions, but no change occurred when
compound 2a was treated for 24 hours with acetic acid or trifluoroacetic
acid respectively. It seemed that the absorption on silica gel was important
for this transformation. But the mechanism of this reaction was still unclear.
EXPERIMENTAL
Dess-Martin reagents was purchased from J&K Chemical Ltd. (Beijing,
1
China). The H-NMR spectra were recorded on a Varian Inova 600 (600
MHz) spectrometer. FT-ICR and FAB mass spectral data were measured
with Bruker Daltonics. Inc. (National Center of Biomedical Analysis,
Beijing, China). Apex II mass spectrometer and ZabSped mass spectrometer
(National Center of Biomedical Analysis, Beijing, China).
[1 S-(1α, 2β, 3α, 5β)]-5-[(2-Acetylamido)-6-(phenylmethoxy)-9 H-purin-
yl]-3-(phenyl- methoxy)-2-[(phenylmethoxy)methyl]cyclopentanol (1a). To
the stirred solution of [1S-(1α, 2β, 3α, 5β)]-5-[2-amino-6-(pheny-
lmethoxy)-9H-purin-yl]-3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]
cyclopentanol (1c)[3–5] (1 g, 1.81 mmol) in dry toluene (60 ml) at 60◦C was
added acetic anhydride (5 ml, 54.3 mmol) and the mixture was refluxed
for 2 hours. The solvent was evaporated and the residue was dissolved in
MeOH (100 ml). The solution was cooled in an ice-water bath and KOH
(0.3 g, 4.39 mmol) was added. The mixture was stirred for 3 hours at
0–5◦C, then the solvent was evaporated and the residue was extracted with
water (100 ml)/ethyl acetate (200 ml) system. Organic phase was separated
and dried with magnesium sulfate. After evaporating, 1a (1.05 g, 99%)
1
was obtained as a pale yellow gum. H-NMR(CDCl3) δ 8.04–8.03 (d, 1H),
7.73 (s, 1H),7.46–7.24 (m, 15H), 5.58–5.51 (m, 2H),4.74–4.70 (m, 1H),
4.58–4.49 (m, 4H), 4.38–4.35 (t, 1H), 4.04–4.02 (t, 1H), 3.70–3.63 (m, 2H),
2.57–2.51 (m, 2H), 2.34–2.30 (m, 4H). Maldi-tof-MS m/z: M+H+, 594.3.
C34H35N5O5 requires M+H+, 594.6.
5S-5-[(2-Acetylamido)-6-(phenylmethoxy)-9H-purin-yl]-2-en-2-[(phenyl-
methoxy)methyl]cyclopentanone (3a). Dess-Martin reagent (15% by weight,
3.9 ml, 2.04 mmol) was added to dry CH2Cl2 (15 ml) under N2, and then
dry t-butanol (0.19 ml, 2.04 mmol) was injected to the solution and stirred
for 15 minutes at room temperature. A solution of 1a (0.93 g, 1.57 mmol) in
dry CH2Cl2 (15 ml) was added via cannula. The mixture was stirred under
N2 at rt for 1 hour and TLC showed 1a was consumed. The mixture was
diluted with 100 ml CHCl3 and stirred vigorously with 10% sodium sulfite
solution-saturated sodium bicarbonate solution (1:1, 150 ml) for 1 hour.
The organic phase was separated and treated with silica gel (10 g) for
2 hours, and TLC showed that 2a was disappeared. The mixture was filtered

48
X. Liu et al.
and the filtrate was concentrated to about 10 ml, then it was separated by
column chromatography (chloroform-methanol, 100:1) and 3a (0.66 g,
20
87%) was obtained as a pale yellow gum. [α]
= +8.4◦ (c 1.0, CHCl3);
D
1H-NMR(CDCl3,) δ 8.01 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.47–7.26 (m,
10H), 5.55 (s, 2H), 4.98–4.97 (q, 1H), 4.61 (s, 2H), 4.29–4.23 (m, 2H),
13
3.29–3.25 (q, 1H), 3.09–3.06 (d, 1H), 2.40 (s, 3H);
C-NMR(CDCl3) δ
200.1, 160.8, 156.5, 152.3, 151.9, 142.3, 141.2, 137.5, 135.7, 128.4, 128.4,
128.1, 128.1, 127.9, 127.7, 117.9, 73.4, 68.7, 63.8, 57.5, 33.8, 24.9; FT-ICRMS
m/z M+H+, 484.1983. Calc. for C27H26N5O4.
1S-1-[2-oxo-3-en-3-[(Phenylmethoxy)methyl]cyclopentyl]-2,4(1H, 3H)-
pyrimidinedion (3b). [1 S-(1α, 2β, 3α, 4β)]-1-[2-Hydroxy-4-(pheny-
methoxy)-3-[(phenylmethoxy)methyl] cyclopentyl]-2,4(1H,3H)-pyrimid-
inedion (1b)[3,4] was treated with Dess-Martin reagent and silica gel
successfully as 1a was treated, 3b was obtained in 73% yield as amorphous
20
1
solid; [α]
= +5.8◦ (c 1.0, CHCl3); H-NMR(CDCl3,) δ 8.37 (br, 1H),
D
7.62 (s, 1H), 7.37–7.29 (m, 5H), 6.97–6.96 (d, 1H), 5.74–5.73 (q, 1H),
4.61–4.59 (t, 3H), 4.26–4.25 (m, 2H), 3.18–3.13 (m, 1H), 2.84–2.79 (m,
1H); FAB-MS m/z calcd for M+H+ 313.3, found 313.0.
[1S-(1α, 2β, 3α, β)]-N-Acetyl-6-(phenylmethoxy)-9-[2-acetoxy-4-(4-
methoxybenzyloxy)-3-[(phenylmethoxy)methyl]cyclopentyl]-9H-purin-
2-amine (5). To a stirred solution of [1S-(1α, 2β, 3α, 5β)]-5-[2-amino-6-
(phenylmethoxy)-9H-purin-yl]-3-(4-methoxybenzyloxy)-2-[(phenylmetho-
xy)methyl]cyclopentanol (4) (1 g, 1.72 mmol) in pyridine (20 ml), DMAP
(0.05 g) and acetyl chloride (0.5 ml, 6.88 mmol) were added, then the
mixture was stirred for 2 hours at rt and stood overnight. Pyridine was
evaporated in vacuo. The residue was dissolved in chloroform (200 ml) and
washed successively with saturated aqueous sodium bicarbonate solution
(100 ml) and brine (250 ml). After dried with magnesium sulfate and
evaporated, 5 (1.12 g, 96%) was obtained as a white amorphous solid.
[1S-(1α, 2β, 3α, 4β)]-4-[(2-Acetylamido)-6-(phenylmethoxy)-9H-purin-
yl]-3-acetoxy-2-[(phenylmethoxy)methyl]cyclopentanol (6). To a stirred so-
lution of 5 (1.1 g, 1.65 mmol) in dichloromethane-H2O (19:1, 40 ml),
DDQ (0.56 g, 2.48 mmol) was added. The mixture was stirred vigorously
for 14 hours, then was diluted with CH2Cl2 (100 ml) and washed with
saturated aqueous sodium bicarbonate solution (100 ml). The aqueous
solution was extracted with CH2Cl2 (100 ml), the combined organic phase
was dried by magnesium sulfate. After evaporated, a dark oily residue was
produced, which was purified by column chromatography (chloroform-
methanol, 20:1) and 6 (0.72 g, 80%) was obtained as a yellow amorphous
solid. 1H-NMR(CDCl3)δ 7.83 (br, 1H), 7.77 (s, 1H), 7.48–7.26(m, 10H), 5.58
(s, 2H), 5.56–5.54 (t, 1H), 5.04–5.00 (q, 1H), 4.56 (s, 2H), 4.52–4.50 (q,
1H), 3.77–3.75 (q, 1H), 3.68–3.65 (t, 1H), 2.70–2.65 (m, 1H), 2.54 (s, 3H),
2.34–2.27 (m, 2H), 1.95 (s, 3H). FAB-MS m/z M+H+, 546.2. C29H31N5O6
requires M+H+, 546.6.

Unusual β-Elimination of Ketonucleosides
49
4S-4-[(2-Acetylamido)-6-(phenylmethoxy)-9H-purin-yl]-2-en-2-[(phenyl-
methoxy)methyl]cyclopentanone (8). Compound 6 (0.4 g, 0.74 mmol) was
oxidized with the same procedure as 1a, then treated with silica gel (10 g).
Compound 8 (0.35 g, 98%) was obtained as a yellow gum. [α] 20 = +6.5◦
D
1
(c 1.0, CHCl3); H-NMR(CDCl3,) δ 8.03 (br, 1H), 7.76 (s, 1H), 7.51–7.26
(m, 10H), 5.72–5.71 (m, 1H), 5.60 (s, 2H), 4.62 (s, 2H), 4.32–4.32 (t, 2H),
3.17–3.13 (q, 1H),2.76–2.72 (dd, 1H), 2.49 (s, 3H), 2.09 (s, 1H); FAB-MS
m/z calcd for M+H+ 484.2, found 484.5.
REFERENCES
1. Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.R.; Earl, R.A.; Guedj, R. Synthesis of
carbocyclic nucleosides. Tetrahedron 1994, 50, 10611–10670.
2. Huryn, D.M.; Okabe, M. AIDS-driven nucleoside chemistry. Chem. Rev. 1992, 92, 1745–1768.
3. Biggadike, K.; Borthwick, A.D.; Exall, A.M.; Kirk, B.E.; Roberts, S.M.; Youds, P. Short convergent route
to homochiral carbcyclic 2ꢁ-deoxynucleosides and carbocyclic ribonucleosides. J. Chem. Soc., Chem.
Commun. 1987, 1083–1085.
4. Pennington, R.Z.; Skillman, W.A.S. Hydroxymethyl(methylene-cyclopentyl)purines and pyrimidines.
US Pat. No. 5340816.
5. Bisacchi, G. S.; Sundeen, J.E. Improved process for preparing the antiviral agent [1 S-(1α, 3α, 4β)]-2-
amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2- methylene- cyclopentyl] 6 H-purin-6-one. WO
9809964, 1998.
6. Jones, M.F.; Myers, P.L.; Robertson, C.A.; Storer, R.; Williamson, C. Synthesis of (-)-carbovir. J. Chem.
Soc., Perkin Trans I. 1991, 2479–2484.
7. Egron, M.-J.; Komiotis, D.; Dorange, I.; Herscovici, J.; Ollapally, A.P.; Antonakis, K. New short route to
unsaturated fluoroketonnucleosides: case of 5-fluoro-1-(6-O-acetyl-3,4-di-deoxy-3-fluoro-β-D-glycero-
hex-3-eno-pyranos-2-ulosyl) uracil. Nucleosides, Nucleotides and Nucleic Acids 2005, 24, 243–246.
8. Madhavan, G.V.B.; McGee, D.P.C.; Rydzewski, R.M.; Boehme, R.; Martin, J.C.; Prisbe, E.J. Synthesis
and antiviral evaluation of 6ꢁ-substituted aristeromycins: potential mechanism-based inhibitors of S-
adenosylhomocysteine hydrolase. J. Med. Chem. 1988, 31, 1798–1804.