5′-Noraristeromycin derivatives isomeric to aristeromycin and 2′-deoxyaristeromycin

Article abstract of DOI:10.1016/j.tet.2004.12.016

A straightforward synthesis of (1S,2R,3R,4R)-4-(6-aminopurin-9-yl)-2- hydroxymethylcyclopentane-1,3-diol (2), an isomer of aristeromycin, and its 2′-deoxy derivative 3 from readily available disubstituted cyclopentenes is presented. An antiviral analysis

Full text of DOI:10.1016/j.tet.2004.12.016

Tetrahedron 61 (2005) 1839–1843
50-Noraristeromycin derivatives isomeric to aristeromycin
and 20-deoxyaristeromycin
*
Xue-qiang Yin and Stewart W. Schneller
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA
Received 23 October 2004; revised 3 December 2004; accepted 7 December 2004
Available online 12 January 2005
Abstract—A straightforward synthesis of (1S,2R,3R,4R)-4-(6-aminopurin-9-yl)-2-hydroxymethylcyclopentane-1,3-diol (2), an isomer of
aristeromycin, and its 20-deoxy derivative 3 from readily available disubstituted cyclopentenes is presented. An antiviral analysis of 2 showed
it to have significant activity versus Epstein–Barr virus (IC50 0.62 mg/mL in the Elisa assay) and to be free of cytotoxicity effects against the
host cells. In a much less comprehensive antiviral analysis, 3 also was active towards Epstein–Barr (IC50 7.58 mg/mL in the Elisa assay) but
this was accompanied by cellular toxicity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
arise that would be difficult to correlate with the customary
furanose-based oligomers. To develop 50-nor carbanucleo-
sides that would not offer an oligomeric product wit0h
shortened phosphorus to phosphorus distances, 30-homo-5 -
noraristeromycin (2) and its 20-deoxy derivative 3 were
sought. The preparation of 2 and 3 is reported. For
comparative purposes to 1, the antiviral properties of 2 are
given.
Oligonucleotides possessing carbanucleoside monomeric
units have received little attention.1,2 Such derivatives
would be expected to render, among other properties,
nuclease stability3 to the oligos in which they are
incorporated and may have a role to play in nanotech-
nology.4 As an outgrowth of our antiviral studies with 50-nor
carbanucleosides (for example, 50-noraristeromycin, 1)5
(Fig. 1) we became interested in their inclusion in
oligomers.6 However, as a consequence of lacking the
C-50 methylene in the nucleoside monomer, such oligos
would have shortened internucleotide phosphate bonds. As
a consequence, oligomeric structural perturbations would
2. Chemistry
The synthesis of 2 was envisioned as starting with the
readily available chiral hydroxyacetate 47 because of its
facile conversion to 5,8 which possesses functionality
appropriately placed for the cyclopentyl component of 2.
Epoxidation of 5 gave predominantly the a-epoxide 6 (a:b,
10:1), which was based on Henbest’s rule,9 literature
precedence,10a,b and correlation with the confirmed (vide
infra) structure of 8. Epoxide 6 was protected as its benzyl
ether 7. This was followed by reaction with adenine to
provide a mixture of two regioisomers in a 3:1 ratio.
Identification of the two isomers by NMR could not be
achieved due to overlapping signals. However, X-ray
analysis (Fig. 2) revealed 810 as the major component,
possibly arising as a result of the benzyl ether assisting
epoxide ring opening.
Figure 1.
Hydrogenolytic deprotection of the benzyl ether 8 under
various circumstances was unsuccessful. However, treat-
ment of 8 with boron trichloride, followed by addition of
methanol to the reaction mixture and heating gave the
Keywords: 30-Homo carbocylic nucleosides; Epoxide ring opening;
Mitsunobu reaction.
* Corresponding author. Tel.: C1 334 844 5737; fax: C1 334 844 5748;
e-mail: schnest@auburn.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.016

1840
X. Yin, S. W. Schneller / Tetrahedron 61 (2005) 1839–1843
Figure 2. X-ray structure for compound 8.
desired 2 in a very low yield as a consequence of
purification difficulties.
To improve the yield of 2 an alternative protection of
6 was sought. In this regard, 6 was converted to the
p-methoxybenzyl derivative 9. Opening of epoxide 9 with
adenine provided two isomers (1.5:1). The major isomer 10
was deprotected with 10% trifluoroacetic acid followed by
refluxing in 5 N hydrochloric acid to give 2 in 78% yield
(compared to 10% from 8). The NMR spectra of 2 from both
methods were superimposable.
The synthesis of 3 began with the known11 enone 11. Using
a copper promoted 1,4-addition12 of t-butoxymethyl
lithium, 11 was converted into 12. L-Selectride reduction
of 12 yielded alcohol 13. Mitsunobu coupling of 13 with
6-chlorpurine produced 14, which, upon ammonolysis and
deprotection, provided the desired 3.
Scheme 1. Reagents: a, mCPBA, CH2Cl2, 84.5%; b, BnCl or pMBnCl,
NaH, DMF, 82% for both; c, adenine, NaH, 15-C-5, 56.5% and 34%; d, for
RZBn, BCl3 then MeOH, CH2Cl2, 10%; e, for RZpMBn, 10% TFA then
5 N HCl, CH2Cl2 then MeOH, 78%.
Confirmation of the structure of 14 was achieved via NMR
analysis by, first, carrying-out a proton–proton COSY
determination to assign the cyclopentyl ring protons. In
that direction, the C-1 hydroxyl proton (3.93 ppm and
identified by solvent exchange) correlated only with the H-1
(4.23 ppm). In turn, H-1 correlates with H-5 (H-5a at
2.73 ppm and H-5b at 2.22–2.15 ppm,) and, to a lesser
degree, with H-2 (2.46 ppm). Proton-2 correlated with the
two exocyclic methylene protons and the two H-3 (2.15–
2.08 ppm) while H-4 (5.12 ppm) correlated with all four
H-3 and H-5.
With this information available a NOESY analysis of 14
was performed: major correlations were observed between
(i) H-1, H-5a and H-4; (ii) H-4, H-3a and the exocyclic
methylene protons; and, (iii) H-2 and H-3b.
For the previously stated purposes of this project, the
synthetic methods described to 2 and 3 conveniently lend
themselves to variation of the heterocyclic base unit (step d
of Scheme 1 and step c of Scheme 2).
Scheme 2. Reagents: a, (t-BuOCH2)2CuLi, t-BuOMe, THF, 87%; b,
L-selectride, THF, 79%; c, (i) 6-chloropurine, PPh3, DIAD, THF;
(ii) TBAF, THF, 30.5% overall for 2 steps; d, (i) NH3, MeOH; (ii) TFA,
H2O, 75% overall for two steps.

X. Yin, S. W. Schneller / Tetrahedron 61 (2005) 1839–1843
1841
3. Antiviral results
NMR (CDCl3) d 4.59 (s, 2H), 4.00–3.88 (m, 2H), 3.67–3.50
(m, 3H), 3.38 (s, 3H), 2.65 (dd, JZ7.5 Hz, 1H), 2.21 (m,
1H), 2.10 (brs, 1H), 1.69–1.78 (m, 1H). 13C NMR (CDCl3) d
96.8, 76.9, 62.5, 56.9, 55.73, 54.9, 49.0, 35.1.
Compound 2 was subjected to antiviral analysis.13 No
activity was found except against Epstein–Barr virus (in
Daudi cells: Elisa assay, IC50 0.62 mg/mL; DNA hybridi-
zation assay, IC50 20 mg/mL; acyclovir IC50 1.7 mg/mL in
both assays).14a Compound 2 was non-toxic to the following
host cells: human foreskin fibroblast, Daudi, MA-104,
MDCK, human embryonic lung, Vero, and human hepato-
blastoma 2.2.15. The promising effects of 2 towards
Epstein–Barr virus prompted a similar assay for 313b (in
Daudi cells: Elisa assay, IC50 7.58 mg/mL; DNA hybridi-
zation assay, IC50 0.1 mg/mL; acyclovir IC50 1.3 mg/mL in
the Elisa assay and 0.4 in the DNA assay).14a However, 3
demonstrated significant toxicity to the Daudi cells (CC50
47.1 mg/mL in both assays). Analog 3 showed no effects
against the other herpes viruses.
To a solution of the above oil (530 mg, 3.06 mmol) in DMF
(10 mL) in an ice-cooled bath were added NaH (88.23 mg,
3.70 mmol) and benzyl bromide (0.409 mL, 3.37 mmol).
This mixture was stirred for 2 h at room temperature and
then evaporated at reduced pressure. The residue was then
diluted with EtOAc (20 mL), washed with H2O (10 mL) and
brine (10 mL) and the organic phase dried (MgSO4). The
drying agent was removed by filtration and the filtrate
evaporated under reduced pressure to give a residue that was
purified by silica gel column chromatography (hexanes–
EtOAc, 10:1 to 3:1) to provide 7 (620 mg, 82%) as white
1
solid, mp 43 8C: H NMR (CDCl3) d 7.36–7.25 (m, 5H),
4.61 (m, 3H), 4.56 (s, 3H), 3.76–3.44 (m, 5H), 3.29 (s, 1H),
2.53 (dd, JZ7.25 Hz, 1H), 2.33 (m, 1H), 1.75 (m, 1H). 13C
NMR (CDCl3) d 138.5, 128.5, 127.8, 127.7, 96.5, 76.7, 73.5,
69.5, 56.9, 55.5, 55.4, 47.3, 34.9. Anal. calcd for C15H20O4:
C, 68.16; H, 7.63; Found: C, 68.19; H, 7.66.
4. Experimental
4.1. General
Melting points were recorded on a Meltemp II melting point
apparatus and are uncorrected. The NMR spectra were
recorded on Bruker AC 250 and AV 400 spectrometers. All
1H chemical shifts are reported in d relative to internal
standard tetramethylsilane (TMS, d 0.00). 13C chemical
shifts are reported in d relative to CDCl3 (center of triplet, d
77.23) or relative to DMSO-d6 (center of septet, d 39.51).
The spin multiplicities are indicated by the symbols s
(singlet), d (doublet), dd (doublet of doublets), t (triplet), q
(quartet), m (multiplet), and br (broad). Coupling constants
(J) are expressed in Hz. The X-ray analysis was conducted
using a Bruker SMART APEX CCD diffractometer. The
optical rotation determinations were carried out on a Jasco
P1010 polarimeter and the ultraviolet spectra recorded using
a Hitachi U2000 spectrophotometer. Atlantic Microlabs,
Atlanta, Georgia, performed the elemental analyses. Reac-
tions were monitored by thin layer chromatography (TLC)
using 0.25 mm Whatman Partisil R Diamond K6F plates
with visualization by irradiation with a Mineral light
UVGL-25 lamp or exposure to iodine vapor. Column
chromatography was performed on Whatman silica gel
4.1.2. (1R,2S,3S,5R)-5-(6-Aminopurin-9-yl)-2-benzyloxy-
methyl-3-methoxymethoxycyclopentanol (8). A suspen-
sion of adenine (686 mg, 5 mmol) and NaH (120 mg,
5 mmol) in DMF (10 mL) was stirred at 135 8C for 15 min.
To this mixture 7 (440 mg, 1.77 mmol) in DMF (10 mL)
and 15-crown-5 (0.1 mL) were added at room temperature.
The mixture was then heated at 135 8C for 3.5 h. The
mixture was evaporated in vacuo and the residue then
diluted with CH2Cl2 (50 mL). The new solution was washed
with brine (20 mL), dried (MgSO4), and evaporated to a
foam (two regioisomers, 3:1 by the NMR). The resulting
foam was purified very carefully by silica gel column
chromatography (MeOH–CH2Cl2, 1:20) to give 310 mg
1
(56.5%) of 8 as a white solid, mp 137–138 8C: H NMR
(CDCl3) d 8.31 (s, 1H), 7.89 (s, 1H), 7.26 (m, 5H), 5.70 (brs,
2H), 4.75–4.50 (m, 7H), 4.25 (q, JZ6.6 Hz, 1H), 3.81 (s,
1H), 3.79 (s, 1H), 3.35 (s, 3H), 2.89 (m, 1H), 2.55 (m, 1H),
2.23 (m, 1H). 13C NMR (CDCl3) d 155.68, 152.7, 150.5,
139.7, 138.0, 128.7, 128.1, 128.0, 120.2, 95.3, 76.5, 73.7,
67.9, 62.1, 55.8, 47.9, 35.8, 18.4. Anal. calcd for
C20H25N5O4$0.25H2O: C, 59.41; H, 6.25; N, 17.12.
Found: C, 59.38; H, 6.34; N, 17.07.
˚
(average particle size 5–25 mm, 60 A) and elution with the
indicated solvent system. Yields refer to chromatographi-
cally and spectroscopically (1H and 13C NMR) homo-
geneous materials. The reactions were generally carried out
in a N2 atmosphere under anhydrous conditions.
4.1.3. (1R,2S,3S,5R)-5-(6-Aminopurin-9-yl)-2-(4-meth-
oxybenzyloxymethyl)-3-(methoxymethoxy)cyclopenta-
nol (10). To a solution of 6 (880 mg, 5.08 mmol) in DMF
(10 mL) cooled in an ice bath was added NaH (134.1 mg,
5.59 mmol). After 10 min, p-methoxybenzyl chloride
(0.68 mL, 5.59 mmol) was added. The mixture was stirred
for 2 h at room temperature and then evaporated under
reduced pressure. The resultant residue was diluted with
EtOAc (20 mL) and this solution washed with H2O (10 mL)
and brine (10 mL), dried (MgSO4), filtered, and the filtrate
concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexanes–EtOAc, 10:1 to 3:1) to
yield 9 (620 mg, 82%) as an oil: 1H NMR (CDCl3) d 7.26 (d,
JZ10 Hz, 2H), 6.86 (d, JZ10 Hz, 2H), 4.54 (s, 2H), 4.51 (s,
2H), 3.80 (s, 3H), 3.70–3.40 (m, 5H), 3.29 (s, 3H), 2.70 (dd,
JZ7.5 Hz, 1H), 2.40 (m, 1H), 1.85 (m, 1H).
4.1.1. (1R,2R,3S,5S)-3-Methoxymethoxy-2-phenethyl-6-
oxabicyclo[3.1.0]hexane (7). To an ice-cold stirring
solution of 58 (600 mg, 3.82 mmol) in 50 mL of CH2Cl2
was added a solution of mCPBA (4.93 g, 77% max.) in
CH2Cl2 (30 mL). The ice bath was removed and the reaction
mixture was kept at rt overnight. The reaction mixture was
washed sequentially with saturated Na2CO3 (3!50 mL)
and brine (50 mL). The organic phase was dried (MgSO4),
filtered and the filtrate concentrated under reduced pressure.
The resultant crude material (NMR analysis indicating two
products in a 10:1 ratio) was purified by silica gel column
chromatography (hexanes–EtOAc, 2:1) to give 6 (the major
1
product) as a colorless, sticky liquid (620 mg, 84.5%): H

1842
X. Yin, S. W. Schneller / Tetrahedron 61 (2005) 1839–1843
A suspension of adenine (1.85 g, 13.5 mmol) and NaH
(240 mg, 10 mmol) in DMF (10 mL) was stirred at 130 8C
for 15 min. To this, 9 (440 mg, 1.77 mmol) in DMF (10 mL)
and 15-crown-5 (0.4 mL) were added at room temperature.
This mixture was then heated at 130 8C for 6 h. The mixture
was evaporated in vacuo and the residue diluted with EtOAc
(50 mL). The new mixture was washed with brine (20 mL),
dried (MgSO4), and the filtrate evaporated to give a yellow
foam (two regioisomers, 1.5:1 by the NMR). The major
isomer was purified from the residue by silica gel column
chromatography (5% MeOH in CH2Cl2) to give 610 mg
added dropwise to a suspension of potassium tert-butoxide
(4.71 g, 42.0 mmol) in anhydrous tert-butylmethyl ether
(200 mL) at K70 8C over 5 min under N2. After stirring
3.5 h at this temperature, a solution of LiBr (7.27 g,
82.0 mmol) in dry THF (100 mL) was added dropwise at
K70 8C over 10 min. This mixture was then allowed to
warm to K15 8C at which point it was stirred for 30 min.
Upon re-cooling to K70 8C, a solution of CuBr$SMe2
(4.31 g, 20.7 mmol) in diisopropyl sulfide (30 mL) was
added dropwise over 10 min. To this a solution of 1111
(4.32 g, 13.8 mmol) in dry THF (25 mL) was added
dropwise over 5 min. The new reaction mixture was allowed
to cool to K30 8C over 15 min and then stirred at this
temperature for an additional 30 min. The reaction was then
quenched with MeOH/AcOH (1:1, v/v, 25 mL), which was
followed by pouring into NH4Cl/NH4OH solution (25 mL).
After removal of the aqueous layer, the organic phase was
washed with a mixture of saturated NH4Cl and 3% NH4OH
(1:1) and then with brine. The organic layer was dried
(Na2SO4) and then filtered and the filtrate concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (15% EtOAc in hexanes) to
give 12 as a colorless oil (4.81 g, 87%): 1H NMR (CDCl3) d
7.74–7.40 (m, 10H), 4.38 (m, 1H), 3.13 (m, 2H), 2.50–2.06
(m, 5H), 1.09 (s, 9H), 1.03 (s, 9H).
1
(34%) of 1015 as a white solid, mp 136.3 8C: H NMR
(CDCl3) d 8.31 (s, 1H), 7.89 (s, 1H), 7.28 (d, JZ10.0 Hz,
2H), 6.86 (d, JZ10 Hz, 2H), 5.76 (brs, 2H), 4.67–4.60 (m,
4H), 4.55 (d, JZ7.5 Hz, 2H), 4.23 (q, JZ7.5 Hz, 1H), 3.80
(s, 3H), 3.77 (s, 1H), 3.75 (s, 1H), 3.54 (s, 3H), 2.90 (m, 1H),
2.59 (m, 1H), 2.22 (m, 1H), 1.98 (brs, 1H). 13C NMR
(CDCl3) d 154.10, 150.5, 150.24, 147.3, 145.0, 134.26,
124.6, 124.1, 114.7, 108.6, 90.8, 72.0, 71.7, 71.1, 67.9, 62.2,
56.6, 50.3, 50.0, 47.5, 30.40. Anal. calcd for C21H27N5O5:
C, 58.73; H, 6.34; N, 16.31. Found: C, 58.78; H, 6.31; N,
16.39.
4.1.4. (1S,2R,3R,4R)-4-(6-Aminopurin-9-yl)-2-(hydroxy-
methyl)cyclopentane-1,3-diol (2). (a) From 8. To a
solution of 8 (766 mg, 2 mmol) in dry CH2Cl2 (10 mL) at
K78 8C was added BCl3 (7.2 mL, 1.0 M in CH2Cl2). This
mixture was stirred at the same temperature for 2 h and
MeOH (10 mL) was added dropwise. Water (10 mL) was
then added and the mixture refluxed for overnight.
Neutralization of the mixture with NH4OH followed by
evaporation led to a residue that was subjected to silica gel
column chromatography (CH2Cl2–MeOH, 7:1 to 3:1) to
give a white solid. Recrystallization of this material using
MeOH–CH2Cl2 resulted in 2 (50 mg, 10%) as a white solid,
mp 175.5–177 8C; [a]2D3.5ZK20.42 (c 0.10, MeOH); uv
(MeOH) lmax 239 nm (3 453.3); 1H NMR (DMSO) d 8.19 (s,
1H), 8.12 (s, 1H), 7.24 (brs, 2H), 5.22 (d, JZ5 Hz, 1H), 5.13
(d, JZ4.9 Hz, 1H), 4.60–4.51 (m, 2H), 4.31 (t, JZ5.3 Hz,
1H), 4.04 (m, 1H), 3.69 (m, 1H), 3.53 (m, 1H), 2.60 (m, 1H),
2.10–1.95 (m, 2H). 13C NMR (CDCl3) d 155.9, 155.8,
151.9, 140.0, 119.1, 74.9, 70.4, 60.6, 58.4, 42.4, 37.9. Anal.
calcd for C11H15N5O3$0.7H2O: C, 47.50; H, 5.90; N, 25.19.
Found: C, 47.83; H, 5.59; N, 24.96.
To a solution of 12 (1.41 g, 3.5 mmol) in anhydrous THF
(20 mL), was added L-selectride (3.7 mL, 1 M in THF) at
K78 8C. The resulting mixture was stirred at the same
temperature for 40 min and then quenched with sat. aqueous
NH4Cl solution (10 mL). Water (20 mL) was added to this
and the mixture extracted with EtOAc (2!100 mL). The
combined organic layers were dried (MgSO4) and evapo-
rated and the resultant epimeric mixture (3:1 by NMR)
purified by silica gel column chromatography (20% EtOAc
in hexanes) to give, as the major product, 1316 (1.1 g, 79%)
as a colorless oil. Anal. calcd for C26H38O3Si: C, 73.19; H,
8.98; Found: C, 73.36; H, 9.07.
4.1.6. (1S,2R,4S)-4-(6-Aminopurin-9-yl)-2-(tert-butoxy-
methyl)cyclopentanol (14). To a stirring suspension of
6-chloropurine (0.51 g, 3.20 mmol) and triphenylphosphine
(0.72 g, 3.20 mmol) in THF (20 mL) at K78 8C was added,
dropwise, diisopropyl azodicarboxlate (0.70 g, 3.20 mmol).
To this mixture was added a solution of 13 (1.17 g,
2.91 mmol) in dry THF (10 mL). The new mixture was
warmed to room temperature over 2 h and stirred at this
temperature overnight. Following concentration in vacuo,
column chromatography (silica gel) (hexanes–EtOAc, 7:1)
provided a yellow oil (750 mg). This oil (750 mg) was
placed in THF (20 mL) and to this tetrabutylammonium
fluoride (2 mL of 1 M solution in THF) was added. This
mixture was stirred for 2 h at room temperature. This
mixture was then evaporated and the residue carefully
purified by silica gel column chromatography (15% EtOAc
in hexanes) to give 14 (0.2 g, 30.5%, two steps) as a white
(b) From 10. Compound 10 (100 mg, 2.42 mmol) was
stirred in a solution of 10% trifluoroacetic acid (10 mL in
CH2Cl2) for 20 min, during which time it became a clear
pink solution. The mixture was then evaporated and the
residue co-evaporated with anhydrous EtOH (3!20 mL).
The material left from this process was stirred in a solution
of 5 N HCl in MeOH (10 mL) at 50 8C overnight.
Evaporation and then co-evaporation with MeOH (3!
20 mL) gave a yellow solid that was then dissolved in
MeOH and neutralized with IRA-67 resin. Filtration,
concentration of the filtrate and purification of the residue
by silica gel column chromatography (5% MeOH in
CH2Cl2) gave 2 (50 mg, 78%), whose spectral properties
were identical to 2 obtained from 8.
1
solid, mp 134–136 8C: H NMR (CDCl3, 400 MHz) d 8.74
(s, 1H), 8.34 (s, 1H), 5.12 (m, 1H), 4.23 (m, 1H), 3.93
(d, JZ4.75 Hz, 1H), 3.51 (dd, JZ3.75, 4.25 Hz, 1H), 3.31
(t, JZ4.75 Hz, 1H), 2.73 (ddd, JZ14.4, 6.68, 5.44 Hz, 1H),
2.46 (m, 1H), 2.30 (m, 1H), 2.22–2.15 (m, 1H), 2.15–2.08
(m, 1H) 1.21 (s, 9H). 13C NMR (CDCl3) d 151.5, 151.2,
146.9, 145.1, 132.6, 76.8, 73.4, 64.2, 55.0, 48.1, 36.7, 27.7.
4.1.5. (1R,3S,4R)-3-(tert-Butyldiphenylsilyloxy)-4-(tert-
butoxymethyl)cyclopentanol (13). Under N2 sec-butyl-
lithium solution (1.4 M in hexanes, 30 mL, 42 mmol) was

X. Yin, S. W. Schneller / Tetrahedron 61 (2005) 1839–1843
1843
S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50,
10611–10670.
Anal. calcd for C15H21N4O2Cl: C, 54.47; H, 6.53; N, 10.92;
Cl, 17.25. Found: C, 54.84; H, 6.52; N, 10.55; Cl, 16.92.
4. Wengel, J. Org. Biomol. Chem. 2004, 2, 277–280.
5. For a leading reference, see Rajappan, V. P.; Schneller, S. W.;
Williams, S. L.; Kern, E. R. Bioorg. Med. Chem. 2002, 10,
883–886.
4.1.7. (1S,2R,4S)-4-(6-Aminopurin-9-yl)-2-(hydroxy-
methyl)cyclopentanol (3). A solution of 14 (1.3 g,
4.3 mmol) in dry MeOH (30 mL) saturated with ammonia
was kept at 120 8C for 48 h in a Parr stainless steel, sealed
reaction vessel. The reaction mixture was evaporated and
the resulting white foam stirred overnight in trifluoroacetic
acid (20 mL, 50 v/v% in H2O) at 50 8C. This mixture was
then evaporated and the residue co-evaporated with
anhydrous EtOH (3!20 mL). The new residue was purified
by silica gel column chromatography (50% EtOAc in
MeOH) to give 3 as a white solid (750 mg, 75%, two steps),
mp 184–186 8C: [a]D23.7ZC34.0 (c 0.053, MeOH); uv
(MeOH) lmax 239 nm (3 906.6); 1H NMR (DMSO) d 8.25 (s,
1H), 8.17 (s, 1H), 7.38 (brs, 2H), 4.93 (m, 1H), 4.71 (brs,
1H), 3.99 (q, JZ4.5 Hz, 1H), 3.53–3.34 (m, 2H), 2.41 (m,
1H), 2.22–1.99 (m, 4H), 1.01 (t, JZ7.0 Hz, 1H). 13C NMR
(DMSO) d 155.2, 151.5, 149.1, 140.0, 118.9, 72.0, 62.1,
56.0, 52.3, 49.9, 33.8. Anal. calcd for C11H15N5O2$0.4H2O:
C, 51.47; H, 6.16; N, 27.29; Found: C, 51.71; H, 6.08; N,
27.14.
6. Koga, M.; Abe, K.; Ozaki, S.; Schneller, S. W. Nucleic Acids
Symp. Ser. 1994, 65–66.
7. (a) Laumen, K.; Reimerdes, E. H.; Schneider, M. Tetrahedron
Lett. 1985, 26, 407–410. (b) Laumen, K.; Schneider, M.
Tetrahedron Lett. 1984, 25, 5875–5878. (c) Seley, K. L.;
Schneller, S. W.; Rattendi, D.; Bacchi, C. J. J. Med. Chem.
1997, 40, 622–624.
8. Matsuumi, M.; Ito, M.; Kobayashi, Y. Synlett 2002,
1508–1510.
9. Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957,
1958–1965.
10. This result is consistent with related cyclopentyl epoxide ring
openings using adenine and thymine reported by
(a) Madhavan, G. V. B.; McGee, D. P. C.; Rydzewski,
R. M.; Boehme, R.; Martin, J. C.; Prisbe, E. J. J. Med. Chem.
1988, 31, 1798–1804. (b) Biggadike, K.; Borthwick, A. D.;
Exall, A. M. J. Chem. Soc., Chem. Commun. 1990, 458–459.
(c) Cyrstallographic data (excluding structure factors) for 8
have been deposited with Cambridge Crystallographic Data
Centre as supplementary number CCDC 253434.
11. Borthwick, A. D.; Crame, A. J.; Exall, A. M.; Weingarten,
G. G. Tetrahedron Lett. 1994, 35, 7677–7680.
Acknowledgements
This research was supported by funds from the Department
of Health and Human Services (AI 48495 and AI 56540),
which is appreciated. We are also indebted to the following
individuals for providing the antiviral data13,14 following
their standard procedures: Dr. Erik De Clercq, the Rega
Institute, Leuven Belgium; Dr. Earl Kern, University of
Alabama at Birmingham, Birmingham, AL; Dr. Brent
Korba, Georgetown University, Washington, DC; and, Dr.
Robert Sidwell, Utah State University, Logan, UT. The
assistance of Dr. Lyle Castle of the Idaho State University,
Pocatello, Idaho, in using NMR to determine the structure of
14 is gratefully acknowledged. We thank Dr. Thomas
Albrecht-Schmitt, Auburn University, for securing the
X-ray data for 8.
´
12. Marino, J. P.; Fernandez, R.; de la Pradilla, R.; Laborde, E.
J. Org. Chem. 1987, 52, 4898–4913.
13. (a) Viruses subjected to 2 were herpes simplex 1 and 2, human
cytomegalo, varicella zoster, Epstein–Barr, hepatitis B,
vaccinia, cowpox, influenza A (H3N2), respiratory syncytial,
and yellow fever. The antiviral and cytotoxicity assays were
performed following procedures previously reported.14
(b) Derivative 3 was only assayed against the herpes viruses.
14. For leading references on the procedures used for the assays
see (a) Ref. 5. (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W.;
Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; de Clercq, E.
J. Med. Chem. 1994, 37, 551–554. (c) Seley, K. L.; Schneller,
S. W.; Korba, B. Nucleosides Nucleotides 1997, 16,
2095–2099. (d) http://www.usu.edu/iar/Brochure/brochure.
html (October 14, 2004).
15. Confirmation of 10 as the regioisomeric form shown in
Scheme 1 was achieved by its conversion to 2 whose structure
was related to the X-ray analysis of 8.
References and notes
16. Compound 13 was identified as the major product based on its
reaction with 6-chloropurine under Mitsunobu reaction
conditions17 to produce 14, a structure assigned by NMR
analysis (see text).
1. Marquez, V. E. Advan. Antiviral Drug Design 1996, 2,
89–146.
2. For leading references on oligomers possessing carbacyclic
monomers see Ref. 1 and Xu, Y.; Kino, K.; Sugiyama, H.
J. Biomol. Struct. Dyn. 2002, 20, 437–446.
17. Inversion of configuration in the Mitsunobu reaction is
well documented (a) Mitsunobu, O. Synthesis 1981, 1–28.
(b) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127–164.
3. Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand,