Rapid synthesis of (±)-r-7-benzyloxymethyl-cyclopenta-cis-[4,5][1,3]-oxazolo[3,2-a] pyrimidinones versatile carbocyclic nucleoside precursors

Article abstract of DOI:10.1016/S0040-4020(02)01531-4

(±)-r-7-Benzyloxymethyl-cyclopenta-cis-[4,5][1,3]-oxazolo[3,2-a] pyrimidinones were synthesized in two steps from 1-hydroxymethyl-3-cyclopentene. These compounds are versatile intermediates for the synthesis of carbocyclic nucleosides. The synthesis has been accomplished by the iodofunctionalization of olefins as a method of coupling the pyrimidine bases and the carbocycle.

Full text of DOI:10.1016/S0040-4020(02)01531-4

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Tetrahedron 59 (2003) 671–676
Rapid synthesis of (6)-r-7-benzyloxymethyl-cyclopenta-cis-
[4,5][1,3]-oxazolo[3,2-a]pyrimidinones versatile carbocyclic
nucleoside precursors
*
´
Nury Perez and Barbara Gordillo
´ ´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
Apartado Postal 14-740, 07000 DF Mexico City, Mexico
Received 17 October 2002; revised 25 November 2002; accepted 26 November 2002
Abstract—(^)-r-7-Benzyloxymethyl-cyclopenta-cis-[4,5][1,3]-oxazolo[3,2-a]pyrimidinones were synthesized in two steps from 1-hydroxy-
methyl-3-cyclopentene. These compounds are versatile intermediates for the synthesis of carbocyclic nucleosides. The synthesis has been
accomplished by the iodofunctionalization of olefins as a method of coupling the pyrimidine bases and the carbocycle. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
to the phosphorylases and hydrolases, enzymes that cleave
the glycosidic bond of parent nucleosides.1 The most active
carbocyclic nucleosides contain in their structure purine
bases, some examples are shown in Figure 1. Carbovir (1)2
and abacavir (2)3 have been approved for their thera-
peutical use against HIV, and entecavir (3)4,5 is currently
in clinical trials for the treatment of HSV infection. On
the other hand, the antiviral activity of carbocyclic
pyrimidine nucleosides have not attracted much attention,
however, their triphosphates display good inhibitory
activities against HIV reverse transcriptase like the
compound 4 (Fig. 1).6
A very active field of research in chemistry since last decade
is the synthesis of nucleoside analogues with antiviral
properties against diseases such as the human virus
immunodeficiency (HIV) syndrome and the Herpes simplex
virus (HSV) infection. Of particular interest are those
nucleoside analogues that are modified in the furanose ring
where the oxygen atom has been changed by a methylene
group, named carbocyclic nucleosides, because they exhibit
biological activities similar to their parent furanose nucleo-
sides with the advantage of having good metabolic stability
Figure 1. Antiviral carbocyclic nucleosides.
Keywords: carbocyclic nucleosides; iodofunctionalization; cyclopenta-oxazolo pyrimidinones.
*
Corresponding author. Tel.: þ52-5557473729; fax: þ52-5557477113; e-mail: ggordill@mail.cinvestav.mx
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01531-4

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N. Perez, B. Gordillo / Tetrahedron 59 (2003) 671–676
672
Figure 2.
Scheme 1. (a) Thymine (TMS)2, NIS, THF, 2158C, 2 h; (b) DBU, CH2Cl2, 08C, 1 h; (c) potassium t-butoxide, THF, 08C, 1 h; (d) CH3OH, 238C, 4 h.
In this paper, we propose an efficient method for the
preparation of (^)-r-7-benzyloxymethyl-cyclopenta-cis-
[4,5][1,3]-oxazolo[3,2-a]pyrimidinones (8–10) as precur-
sors of pyrimidine carbocyclic nucleosides (Fig. 2). The
method is based in a convergent strategy that involves the
coupling of thymine, uracil or cytosine, and the carbocycle
through the nucleophilic opening of a iodonium intermedi-
ate prepared from 1-(hydroxymethyl)-3-cyclopentene.
It is worth of mention that Kim and Misco7 reported,
previously, the direct coupling of a thymine with a cyclic
iodonium furanoid 0 glycal as a key intermediate step0 for
the synthesis of 2 ,30-dideoxy- and 20,30-didehydro-2 ,30-
dideoxy nucleosides; an example is shown in Scheme 1.
2. Results and discussion
1-(Hydroxymethyl)-3-cyclopentene 6 was prepared from
3-cyclopentenecarboxylic acid 5 according to a literature
procedure.8 Reaction of this alcohol with benzyl bromide in
the presence of sodium hydride afforded the benzyl ether
derivative 7 in excellent yield (Scheme 2). In order to prove
if the conditions described by Kim and Misco were suitable
for the coupling of the pyrimidine bases and compound 7,
the reaction between 7, N-iodosuccinimide and the silylated
pyrimidine bases was maintained for 2 h at 2158C.
Scheme 2. (a) LiAlH4, THF, 238C, 30 min; (b) NaH, BnBr, THF, 238C, 8 h.
Scheme 3. Formation of compounds 8, 9 and 10 from 3-hydroxymethyl-3-cyclopentene by iodofunctionalization.

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N. Perez, B. Gordillo / Tetrahedron 59 (2003) 671–676
673
was only of 26%. The mass analyses of compounds 8–10
were indicative of the absence of iodine; therefore the
cyclopenta-oxazolo pyrimidinones of Scheme 3 were
proposed, as the products of the reaction.
Indeed the structure of compounds 8–10 was corroborated
by NMR and X-ray diffraction analysis of compound 9. The
ORTEP structure of this compound is shown in Scheme 4,
the syn orientation of the pyrimidine base and the
benzyloxymet0hyl group, which is characteristic of the
groups at C1 and C40 of natural nucleosides, confirms
the stereochemistry assigned to these intermediates.
The cyclopentane ring conformation in the solid state is an
envelope with C-11, C-10, C-9 and C-13 atoms in a plane
and C-12 puckered by 128. The pyrimidine base and the
oxazolo five-membered ring are planar and both are
coplanar and perpendicular to the cyclopentane. Previously
two analogues of 9 were reported as intermediates in the
synthesis of 2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl-
thymine9 and the 20-deoxy-neplanocin,10 however, there are
no report on the X-ray diffraction study of these kinds of
structures in the literature.
Scheme 4. ORTEP projection of the molecular structure of compound 9,
showing the atomic numbering as in the CIF file.
Nevertheless, the reactions did not proceed in any case and
the starting material was recovered. However, when the
reactions were run at room temperature for 72 h in the
presence of iodine, Scheme 3, we observed the formation of
only one product, with good yield, for the thymine and
uracil bases. In the case of the cytosine derivate, the yield
Scheme 5. Synthetic pathway for the obtention of natural nucleosides and carbonucleosides through fused anhydro intermediates.
Scheme 6. (a) 1N NaOH, EtOH, 238C; (b) H2, Pd/C, MeOH, AcOH; (c) t-BuO2Kþ, t-BuOH, 408C, 2 h.

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N. Perez, B. Gordillo / Tetrahedron 59 (2003) 671–676
674
In natural nucleosides the formation of the key anhydro
intermediates is through the iodonucleoside (Scheme 5), in
this work we found that the iodocabonucleoside is not stable
enough to be isolated, thus the formation of the cyclopenta-
oxazolo pyrimidinones is straightforward in the only one
step of reaction. The opening of the anhydro intermediates
in alkaline media lead to the nucleoside or carbonucleoside
dihydro analogues in a precise a practical manner
(Scheme 5). In the natural nucleoside the less substituted
alkene is obtained meanwhile in the carbonucleoside the
more substituted is preferred.
of 10.96 g (280 mmol) of LiAlH4 in 100 mL of dry THF,
was added dropwise 7.95 g (70 mmol) of 5 under ice-
cooling. When the addition was completed, the temperature
of the mixture was raised to room temperature and
maintained under stirring for 30 min. To quench the
reaction, a solution of 10% of NaOH and 10 mL of H2O
were added slowly and the mixture was stirred for 1 h.
The mixture was filtered, dried over Na2SO4 (anh.) and
concentrated in a rotary evaporator. Yield 6.81 g (98%). IR
n
max (film) (cm21): 3400 (s), 2930 (s), 1650 (m), 1080 (m),
1
950 (m), 900 (m). H NMR (CDCl3) d (ppm): 5.68 (2H, s,
CHvCH), 3.57 (2H, d, J¼6.2 Hz, CH2O), 2.54 (3H, m,
CHþCH2), 2.15 (2H, m, CH2). 13C NMR (CDCl3), d (ppm):
129.9 (CHvCH), 67.3 (CH2O), 39.5 (CH), 36.0 (2CH2).
The utility of compounds 8 and 9 as intermediates for the
synthesis of carbocyclic nucleosides was also explored in
this work. Summarized in Scheme 6 are the reactions that
were performed with these intermediates. The 20-hydroxy-
20deoxypyrimidin carbonucleosides 13 and 14 are already
known.11,12 In additions we obtained the new carbocyclic
nucleoside analogues 11, 12, 15 and 16.
4.1.2. 4-[(Phenylmethoxy)methyl]-3-cyclopentene 7. To a
solution of 0.55 g (23 mmol) of NaH in dry THF (15 mL)
was added 1.96 g (20 mmol) of alcohol 6. After stirring at
room temperature for 30 min, 2.4 mL (20 mmol) of benzyl
bromide was added to the solution followed by the addition
of a catalytic amount of tetrabutyl iodide resulting a
mixture, which was stirred for 8 h. The mixture was
quenched with H2O (10 mL) and the organic layer was
separated. The aqueous layer was extracted with ethyl
ether (2£20 mL). The combination of extracts were dried
over NaSO4 (anh.), filtered, and concentrated in a rotary
evaporator. The resulting residue was chromatographed
over silica gel in hexanes to afford 3.62 g (97%) of com-
pound 7 as a colorless liquid. IR nmax (film) (cm21): 3055
(m), 2925 (m), 1610 (s), 1490 (w), 1452 (m), 1270 (m), 1100
(s), 1020 (m), 735 (w), 695 (w). 1H NMR (CDCl3), d (ppm):
7.25–7.45 (5H, m, arom.), 5.68 (2H, s, CHvCH), 4.55 (2H,
s, CH2Ph) 3.40 (2H, d, J¼7.1 Hz, CH2O), 2.61 (1H, m, CH),
2.15–2.50 (4H, m, 2CH2). 13C NMR (CDCl3), d (ppm)
139.1 (arom.), 130.0 (CHvCH), 128.8 (arom.), 128.1
(arom.), 128.0 (arom.), 75.2 (CH2Ph), 72.5 (OCH2), 37.3
(CH), 36.5 (2CH2).
3. Conclusions
We have developed a simple and efficient method for the
synthesis of (^)-r-7-benzyloxymethyl-cyclopenta-cis-
[4,5][1,3]-oxazolo[3,2-a]pyrimidinones 8–10 as precursors
of carbocyclic nucleosides using cheap and readily available
reagents, i.e. elemental iodine. Several carbocyclic nucleo-
sides were produced under mild reaction conditions, in high
yields, by using this method.
4. Experimental
4.1. General
Melting points (uncorrected) were recorded using a Mel-
Temp II apparatus. Infrared spectra were recorded in a
Perkin Elmer 16F PC FTIR spectrophotometer and UV
spectra were determined on a Perkin Elmer Lambda 12
spectrophotometer. 1H and 13C NMR spectra were recorded
in a Jeol Eclipse spectrometer at 400 and 100.5 MHz,
respectively. The chemical shifts of the NMR spectra are
given in parts per million (ppm) and constant couplings in
hertz (Hz). Mass spectra were recorded on a Hewlett
Packard 5989A spectrometer using electron impact (EI) at
70 eV. Elemental analysis were performed by Galbraith
Laboratories, Inc., Knoxville, T N. for compounds 8–10,
and were recorded in Thermo Finnigan Flash 1112 analyzer
for compounds 11, 12, 15 and 16. X-Ray diffraction data
were collected in an Enraf-Nonius Kappa CCD. Data
collection: COLLECT software (Nonius BV 1997).13 Cell
refinement and data reduction: Denzo/Scalepack software.14
An integer system of programs was used for the solution,
refinement and analysis of X-ray diffraction data, WinGX
v-1.64.15 The structure was solved by direct methods with
Shelxs-97 (Sheldrick 1997)16 and refined with Shelxs-97
(Sheldrick 1997).17 Molecular graphics with WinGX soft-
ware.15 Florisil was purchased from Merk. All chemicals
used here were of reagent grade and were obtained from
Aldrich Chemical Co.
4.2. General procedure for the coupling of pyrimidine
nucleobases with 4-[(phenylmethoxy)methyl]-3-cyclo-
pentene 7
To a solution of 1.46 g (5 mmol) of iodine in dry CH2Cl2
(10 mL), was added 1 g (5 mmol) of the ether 7 followed by
the addition of the silylated nucleobase (6.25 mmol). The
reaction mixture was stirred for 48 h at room temperature.
The mixture was diluted with CH2Cl2 (20 mL) and a
saturated aqueous solution of sodium thiosulfate was added
vigorously until disappearance of the brown color. The
organic layer was separated, washed with H2O, filtered and
concentrated in a rotary evaporator. The resulting residue
was purified by successive recrystallization from CH2Cl2/
hexanes.
4.2.1. (6)-r-7-Benzyloxymethyl-3-methyl-cyclopenta-
cis-[4,5][1,3]oxazolo[3,2-a]pyrimidin-2-one 8. Yield:
2.50 g (71%). White solid, mp 165–1678C. IR (KBr) n
(cm21): 3504 (m), 2998 (m), 2990 (w), 1774 (s), 1666 (s),
1630 (s), 1546 (s), 1490 (s), 1238 (s), 1194 (s), 1164 (m),
830 (m), 762 (w). UV lmax (MeOH) (nm): 260. MS, m/z
(%): 313 [MþH]þ (13), 312 (17), 206 (35), 174 (70), 148
(100), 122 (55), 91 (57), 85 (27). 1H NMR (CDCl3) d (ppm):
7.27 (5H, m, arom.), 7.06 (1H, d, J¼1.0 Hz, H-4), 5.33 (1H,
4.1.1. 1-Hydroxymethyl-3-cyclopentene 6. To a solution