Photochemical synthesis of novel dideoxynucleosides

Article abstract of DOI:10.1081/NCN-100002080

A series of 2′,3′-dideoxynucleosides based on the apiose family was prepared from photochemical ring-expansion of a common cyclobutanone precursor. The starting ketone, (±) 3-[2′-(benzoyloxy)ethyl]-2,2-dimethylcyclobutanone (12) was prepared from commercially available (±)α-pinene. Since the optically pure antipodes of α-pinene are also commercially available, these nucleosides can be prepared optically pure using the identical procedure.

Full text of DOI:10.1081/NCN-100002080

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PHOTOCHEMICAL SYNTHESIS OF NOVEL
DIDEOXYNUCLEOSIDES
E. Lee-Ruff a & R. Margau a
a Department of Chemistry , York University , Toronto, Ontario, M3J 1P3, Canada
Published online: 17 Aug 2006.
To cite this article: E. Lee-Ruff & R. Margau (2001) PHOTOCHEMICAL SYNTHESIS OF NOVEL DIDEOXYNUCLEOSIDES,
Nucleosides, Nucleotides and Nucleic Acids, 20:3, 185-196, DOI: 10.1081/NCN-100002080
To link to this article: http://dx.doi.org/10.1081/NCN-100002080
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(3), 185–196 (2001)
PHOTOCHEMICAL SYNTHESIS OF NOVEL
DIDEOXYNUCLEOSIDES
E. Lee-Ruff∗ and R. Margau
Department of Chemistry, York University, Toronto,
Ontario, M3J 1P3, Canada
ABSTRACT
A series of 2ꢀ,3ꢀ-dideoxynucleosides based on the apiose family was prepared
from photochemical ring-expansion of a common cyclobutanone precursor. The
starting ketone, ( ) 3-[2ꢀ-(benzoyloxy)ethyl]-2,2-dimethylcyclobutanone (12)
was prepared from commercially available ( )α-pinene. Since the optically
pure antipodes of α-pinene are also commercially available, these nucleosides
can be prepared optically pure using the identical procedure.
INTRODUCTION
The prominent role of nucleosides as antiviral and antitumor agents is well
established (1). Modified nucleosides are known to interfere with DNA (or RNA)
replicationprocesses. Thefactthatmany2ꢀ,3ꢀ-dideoxynucleosides havebeenshown
to act as inhibitors of the human immunodeficiency virus (HIV), responsible for
acquired immune deficiency syndrome (AIDS), is of specific interest. Many of these
phosphorylated derivatives act as DNA chain terminators due to the absence of the
3ꢀ-OHfunction(2). Aninterestingclassofnucleosideanaloguesarethosebelonging
to the apiose family. These nucleosides are related in structure to 9-(β-D-apio-D-
1
furanosyl) adenine (1), a biologically active, relatively non-toxic nucleoside in
which the sugar moiety is based on D-apiose (3,4). This nucleoside analogue is
∗Corresponding author.
1Nucleosides analogues related to natural D-apiose have been shown to inhibit lymphocyte prolifer-
ation and resist enzymatic deamination (3,4).
185
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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LEE-RUFF AND MARGAU
a regioisomer of adenosine via the transposition of the C-4ꢀ hydroxymethyl to the
C-3ꢀ position.
Some of the dideoxygenated apio-adenosine analogues such as (1ꢀ(S), 3ꢀ(R))-
(6-[2,3,4-trideoxy-3-hydroxymethyl]furanosyl) adenine (2) have been shown to
possess potent anti-HIV activity in MT-4 cells with no apparent toxicity (5). Resis-
tance to deamination by adenosine deaminase is exhibited by the isomeric nature
of these compounds. Significant attention has also been directed towards the fu-
ranethanol derivatives (6). The presence of the primary alcohol function as part of
an elongated chain can have interesting effects on cellular phosphorylation and anti-
HIV activity (6). Furthermore, the addition of the methylene carbon adds a degree
of hydrophobicity to the molecule, an important contributing factor in the delivery
of potential prodrugs across cellular membranes. We describe the preparation of
novel dideoxynucleosides based on the apiose family using a simple cyclobutanone
photochemical ring-expansion sequence developed in our laboratory (7). The ad-
vantage of this method over more traditional ones is the availability of substituted
cyclobutanones in both racemic and optically pure modifications (8). The photo-
chemical ring-expansion of these ketones proceeds with stereochemical retention
of the ring substitutents in the product ribosides and allows for the preparation of
several modified nucleosides as potential antiviral and anticancer agents. The spe-
cific nucleosides described in this acticle are the cis and trans isomers of the apiose
derivatives 3–10. The additional two methyl substitutents should impart increased
hydrophobicity rendering these nucleosides even more membrane permeable. Fur-
thermore, the racemic modifications of 3–10 are desirable since both enantiomers
can be screened for HIV inhibition. The employed synthetic procedure allows for
the enantiospecific preparation of each antipode should any biological activity be
observed for a racemic mixture.
RESULTS AND DISCUSSION
Cyclobutanones undergo photochemical ring expansion via an oxacarbene
(7). Insertion of this carbene into OH and NH functional groups give 2-substituted
tetrahydrofurans. The common precursors to nucleosides 3–10 is cyclobutanone
12 which was prepared in racemic form from racemic α-pinene via the known diol
11 (8) as shown in Scheme 1. Since both antipodes of α-pinene are commercially
available, the optically pure enantiomer of cyclobutanone 12 could be prepared
using the identical synthetic sequence as none of the steps involves epimerization
at the stereogenic centers. Diol 11 was mono-benzoylated exclusively at the primary
alcohol group. This mono-protected alcohol was subjected to Swern oxidation to
give cyclobutanone 12 in 76% yield.
In order to assess the photochemical ring-enlargement reaction, ketone 12
was transformed to dihydrofuran 13 in 70% yield on irradiation in methylene
chloride solutions containing methanol. A 1:1 anomeric mixture of the two acetals
was obtained as evident from the acetal signals observed at δ 4.91–5.00 ppm in the
1H-NMR spectrum of 13. The cycloelimination (14) and decarbonylation (15)

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SYNTHESIS OF NOVEL DIDEOXYNUCLEOSIDES
187
X
N
X
N
N
N
N
N
N
N
O
A
A
O
O
O
2′
5
′
HO
3
4' syn to base
4" anti to base
′
OH
OH
OH
RO
RO
1
2
A = adenin-9-yl
3 X = NH2, R = H
5 X = Cl, R = Bz
7 X = O(CH2)5CH3, R = Bz
9 X = O(CH2)5CH3, R = H
4 X = NH2, R = H
6 X = Cl, R = Bz
8 X = O(CH2)5CH3, R = Bz
10 X = O(CH2)5CH3, R = H
OH
(i)
O
O
OCH3
(iii)
(ii)
HO
BzO
BzO
11
12
15
13
OBz
OBz
14
i. BzCl/pyridine; ii. (COCl)2, DMSO, CH2Cl2, (C2H5)3N; iii. hυ/CH3OH, CH2Cl2
products were also formed in 8.3 and 1.1% yields, respectively, and identified
by comparison with authentic samples (9).
Irradiation of a 10−4 M solution of cyclobutanone 12 with 6-chloropurine
(3 eq.) in acetonitrile solution resulted in the formation of the protected nucleo-
sides 5 and 6 (64%) as the major photoproducts. The structures of the separated
individual isomers were assigned based on the 1H-NMR chemical shift values of
the sugar ring and substituent protons (10). These protons are more deshielded in
the cis stereochemistry relative to the purine base component. The more deshielded
H-4ꢀ proton assigned to the syn stereochemistry relative to the purine base is fur-
ther deshielded in the cis isomer 5 relative to the trans isomer 6. This is the re-
sult of the ring current effects associated with both contributions of the purine
and the benzoate groups. The mass spectra of these photoproducts indicated the
characteristic isotope signature pattern in the MH+ and MH− +2 mass fragments
for chlorine (100:37). Deprotection and conversion of the 6-chloropurine unit to
adenosine was accomplished in one step by reacting 5 or 6 in ammonia satu-
rated methanol at 100◦C in a sealed tube in yields of about 80%. The resultant
nucleosides 3 and 4 were characterized individually by spectral and analytical
data and in the case of the cis isomer 3 the X-ray crystal structure was determined

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LEE-RUFF AND MARGAU
Figure 1. X-Ray crystal structure of nucleoside 3.
(Figure 1) which confirmed the original stereochemical assignments of nucleosides
5 and 6.
Nucleosides containing the 6-alkoxypurine as the base unit with the alkoxy
substituent having a straight chain length of 6–7 carbon atoms exhibit significant
anti-HIV activity (11). The 6-hexyloxypurine nucleosides 9 and 10 were prepared
using a similar procedure. A solution of cyclobutanone 12 in dichloromethane
containing 6-hexyloxypurine (11) was irradiated giving a mixture consisting of
protected nucleosides 7 and 8 in 59% yield. Some stereoselectivity was observed
with the trans isomer 8 predominating in a 3:2 ratio. The stereochemical assign-
ments were based on relative chemical shifts of the tetrahydrofuran ring and the
α-benzoyloxy methylene protons which are slightly more deshielded in the cis
stereochemistry. The H-4ꢀ (syn to the base) and H-4ꢀꢀ (anti to the base) were as-
signed by 2D-COSY (H, H) spectroscopy for both isomers (see Figure 2 for the
trans isomer 8). The more deshielded H-4ꢀ proton signal absorbed at lower field (δ
2.87 ppm) for one of the isomers which was assigned the cis stereochemistry (vs δ
2.71 ppm for the H-4ꢀ proton in the trans isomer). Further evidence for the stere-
ochemical assignments came from NOE difference spectroscopy which showed a
signal enhancement for the H-3ꢀ proton (3%) upon irradiation of the H-4ꢀ signal only
in the case of isomer assigned the trans stereochemistry. This correlation is also
seen in the NOESY spectrum for 8 (Figure 3) in which the proximity relationships
are observed between the H-5ꢀ (acetal,), H-4ꢀꢀ and the β-methylene protons of the
hydroxyethyl substituents. Deprotection of 7 and 8 was accomplished by stirring
each isomer in methanol saturated with ammonia with a yield of about 80%.
In summary, nucleosides 3–10 based on the apio-series were prepared from
a common cyclobutanone precursor 12 by a photochemical ring-expansion. The
nucleosides were prepared in racemic modification, however since the ketone 12
was ultimately prepared from α-pinene which is also commercially available in both

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SYNTHESIS OF NOVEL DIDEOXYNUCLEOSIDES
189
Figure 2. COSY (H,H) spectrum of nucleoside 8.
enantiomerically pure forms, the identical synthetic sequence could be employed
for the preparation of enantiomerically pure antipodes of nucleosides 3–10. The
racemic modification of nucleosides 3, 4, 9 and 10 are being screened for anti-HIV
activity.
EXPERIMENTAL
Melting points (mp) were determined on a Reichert melting point apparatus
and were uncorrected. Infrared (IR) spectra were recorded on a Pye Unicam SP3-
200 spectrometer as thin films or KBr pellets, and NMR spectra were recorded on
an ARX 400 MHZ superconducting Bruker NMR spectrometer in CDCl3 solutions
unless noted otherwise. The COSY (H, H) and NOESY 2D spectra were obtained
using a Bruker 600 MHz Avance spectrometer. Mass spectra were obtained us-
ing a VG Micromass 16F spectrometer with ionization by electron impact or by
liquid secondary ion MS (Isim) using 3-nitrobenzoic acid (3-NBA) as the matrix.

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LEE-RUFF AND MARGAU
Figure 3. NOESY spectrum of nucleoside 8.
Elemental analyses were performed by Guelph Chemical Laboratories Ltd. Prepar-
ative TLC was conducted using silica gel coated glass plate (750 µm thickness).
Photolyses were performed using a Hanovia 450-W medium pressure mercury
arc lamp in a water-cooled quartz immersion well. Pyrex test tubes containing the
samples were strapped around this well and the assembly immersed in an ice-water
bath. These samples were degassed for 30 minutes with argon prior to irradiation, as
well, argonballoonswereusedtomaintainaninertatmosphereduringthephotolysis
reactions.
All solvents used were dried and distilled according to standard procedures.
Unless otherwise stated, precursor chemicals were obtained from Aldrich Chemical
Company.
( )-cis-3-[2-(Benzoyloxy)ethyl]-2,2-dimethylcyclobutan-1-ol
The racemic diol ( )-11 (8), (9.4 g, 65.2 mmol), was added to a stirred solution
of 118 mL dry pyridine, under argon. This stirred mixture was then cooled to 0◦C

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SYNTHESIS OF NOVEL DIDEOXYNUCLEOSIDES
191
and 8.2 g (58.7 mmol, 0.9 equivalents) benzoyl chloride was added dropwise over
a 30 min period. The reaction was mixed at ambient temperature for 24 h after
which it was quenched by the addition of 10.0 mL H2O followed by 30 min of
additional stirring. The reaction mixture was concentrated by evaporation and then
diluted with 300 mL CH2Cl2. The organic phase was then washed with successive
portions of 3 × 50 mL H2O, 3 × 50 mL NaHCO3, 3 × 50 mL 1% HCl, and 2 × 50
mL H2O. Evaporation of the solvent followed by flash column chromatography
(6:1 hexane:ethyl acetate) gave 11.31 g, 45.7 mmol (70.0%) of the title compound
as a clear oil. 1H-NMR: δ 8.04-8.02 (d, 2H), 7.57-7.54 (t, 1H), 7.46-7.42 (t, 2H),
4.29-4.22 (m, 2H), 3.75 (dd, 1H), 2.39-2.14 (m, 1H), 1.88-1.50 (m, 5H), 1.09 (s,
3H), 0.99 (s, 3H). 13C-NMR: δ 167, 133, 130, 131, 120, 128, 72, 64, 44, 35, 34, 29,
28, 15. IR (neat):3410 (OH), 2957, 2899, 2866, 1719 (CO benzoyl), 1275 cm−1.
MS m/z 249 (M + 1). Anal. Calculated for C15H20O3.1/4H2O: C, 71.26; H, 7.97.
Found: C, 71.44; H, 8.45.
( )-3-[2-(Benzoyloxy)ethyl]-2,2-dimethylcyclobutanone (12)
The title compound was prepared by a modified Swern oxidation (12). A
solution of 1.25 mL (15 mmol) oxalyl chloride in 63.0 mL of dry CH2Cl2 was
cooled using CHCl3/dry ice, with constant stirring under argon. To this mixture,
2.0 g (25 mmol) DMSO in 12.5 mL dry CH2Cl2 was added over a 5 min pe-
riod. After stirring the reaction for an additional 10 min, 2.5 g (10.1 mmol) of the
mono-protected alcohol, prepared above, in 25.0 mL CH2Cl2, was promptly added
over a 5 min period. After mixing for another 15 min, 7.0 mL TEA was added over
a 5 min period, and the resulting mixture was allowed to warm to ambient temper-
ature. The addition of 30 mL H2O followed by 10 min of stirring allowed for the
separation of the two phases. The organic phase was extracted with 2 × 50 mL por-
tions of CH2Cl2. The CH2Cl2 extracts were combined and washed with successive
portions of 2 × 50 mL 2% HCl, 1 × 50 mL H2O, 1 × 50 mL sat. aq. NaHCO3, and
1 × 50 mL sat. aq. NaCl. The organic phase was then dried over MgSO4 and concen-
trated by evaporation. Purification by flash column chromatography (6.25:1 hex-
ane:ethyl acetate) gave 1.9 g, 7.72 mmol (76.4%) of the title compound as a clear oil.
1H-NMR: δ 8.05-8.03 (d, 2H), 7.58-7.55 (t, 1H), 7.47-7.43 (t, 2H), 4.40-4.35
(m, 2H), 3.24-3.18 (dd, 1H), 2.86-2.80 (dd, 1H), 2.23-2.10 (m, 2H), 1.91-1.85
(m, 1H), 1.22 (s, 3H), 1.15 (s, 3H). 13C-NMR: δ 214, 167, 133, 130, 129.6, 128,
64, 61, 49, 33.6, 30, 23, 17. IR (neat): 2961, 2927, 2868, 1777 (CO), 1719 (CO
benzoyl), 1275 cm−1. MS m/z 246. Anal. Calculated for C15H18O3:C, 73.14; H,
7.37. Found: C, 72.9; H, 7.8.
( )-3-[2-(Benzoyloxy)ethyl]-2,2-dimethyl-5-methoxyoxolane, cis and
trans isomers (13)
A solution consisting of ( )-cyclobutanone 12 (0.070 g, 0.285 mmol) and
6.0 mL methanol (freshly distilled from Na) in 65 mL dry CH2Cl2, was irradiated

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LEE-RUFF AND MARGAU
for 3 h. Evaporation of the solvent followed by preparative TLC (CH2Cl2:EtOAc,
24:1) gave 0.055 g, 0.198 mmol (69.5%) of the title compound as a ∼1:1 anomeric
mixture. 1H-NMR: δ 8.05-8.03 (d, 2H), 7.57-7.55 (t, 1H), 7.47-7.43 (t, 2H), 5.00-
4.91 (two m, 1H, acetal), 4.37-4.33 (m, 2H, BzOCH2CH2), 3.36-3.33 (two, s, 3H,
methoxy), 2.56-2.28 (two m, 1H), 2.19-2.15, 1.90-1.87 (two m, 2H), 1.78-1.71 (m,
2H, BzOCH2CH2), 1.37, 1.29, 1.20, 1.08 (four s, 6H, methyl). IR (neat): 2972,
2935, 2898, 1720 (CO benzoyl), 1274, 1100, 1038 cm−1. Anal. Calculated for
C16H22O4: C, 69.05; H, 7.97. Found: C, 69.3; H, 8.2.
( )-3-[2-(Benzoyloxy)ethyl]-5-(6-chloropurin-9-yl)-2,2-dimethyloxolane
(cis-5 & trans-6)
A solution of ( )-cyclobutanone 12 (0.070 g, 0.285 mmol) and 6-chloropurine
(0.140 g, 0.906 mmol) in 65 mL dry CH3CN was irradiated for 4 h. Evaporation
of the solvent followed by flash column chromatography (15:1 CH2Cl2: EtOAc to
elute non-polar photoproducts, followed by 15:2 CH2Cl2:EtOAc to elute protected
nucleoside) gave 0.073 g, 0.181 mmol (63.5%) of the title compound as an anomeric
mixture. 0.145 g of this mixture was further purified by preparative TLC (100:5
ether: EtOAc, 3 consecutive elutions) to give 0.074 g of the trans isomer (51%) and
0.071 g of the cis isomer (49%) as clear oils.
( )-cis-isomer (5) 1H-NMR: δ 8.72 (s, 1H), 8.34 (s, 1H), 8.05-8.03 (d, 2H),
7.60-7.57 (t, 1H), 7.47-7.44 (t, 2H), 6.29-6.26 (t, J = 6 Hz, 1H, H-5ꢀ acetal), 4.45-
4.39 (m, 2H, BzOCH2CH2), 3.03-2.98 (m, 1H, H-4ꢀ), 2.48-2.36 (m, 2H, H-4ꢀꢀ and
H-3ꢀ), 2.03-1.99 (m, 1H, BzOCH2CH2), 1.84-1.78, (m, 1H, BzOCH2CH2), 1.45 (s,
3H), 1.32 (s, 3H). IR (neat): 2924, 2852, 1717, 1591, 1559, 1275 cm−1). MS (Isim,
3-NBA) m/z 401 (MH+), 403 (MH++ 2). Anal. Calculated for C20H21N4O3Cl : C,
59.93; H, 5.24; N, 13.98. Found: C, 59.5; H, 5.2; N, 14.2.
( )-trans-isomer (6) 1H-NMR: δ 8.65 (s, 1H), 8.29 (s, 1H), 7.99-7.98 (d,
2H), 7.60-7.56 (t, 1H), 7.46-7.42 (t, 2H), 6.31-6.29 (1H, H-5ꢀ acetal), 4.45-4.33 (m,
2H, BzOCH2CH2), 2.89-2.86 (m, 1H, H-4ꢀ), 2.51-2.40 (m, 2H, H-4ꢀꢀ and H-3ꢀ),
2.00-1.97 (m, 1H, BzOCH2CH2), 1.81-1.76, (m, 1H, BzOCH2CH2), 1.48 (s, 3H),
1.23 (s, 3H). IR (neat): 2925, 2853, 1717, 1591, 1559, 1274 cm−1). MS (sim, 3-
NBA) m/z 401 (MH+), 403 (MH++ 2), ratio 100:36.8 corresponding to 35Cl: 37Cl.
Anal. Calculated for C20H21N4O3Cl: C, 59.93; H, 5.24; N, 13.98. Found: C, 59.8;
H, 5.3; N, 14.1.
( )-cis-9-[2,2-Dimethyl-3-(hydroxyethyl)-oxolan-5-yl]adenine (3)
A solution of ( )-cis-protected nucleoside 5 (0.039 g, 0.974 mmol) and
30.0 mL methanolic ammonia was placed in a thick walled glass tube. The re-
action mixture was frozen with liquid N2 and sealed in the tube under vacuum. The
reaction vessel was then heated to 100◦C for 24 h. After this period of time the tube

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193
was cooled to −60.0◦C (CHCL3/dry ice) and cracked open. Solvent removal by
evaporation followed by purification by TLC (1:9 CH3OH:CH2Cl2) gave the target
deprotected nucleoside 0.022 g, 0.0779 mmol (80.0%), as a white solid, mp 172-
173◦C. 1H-NMR (DMSO) δ: 8.34 (s, 1H), 8.13 (s, 1H), 7.23 (s, 2H, amine), 6.14-
6.12 (t, 1H, H-5ꢀ acetal), 4.54-4.52 (t, 1H, OH), 3.52-3.40 (m, 2H, HOCH2CH2),
2.58-2.53 (m, 2H), 2.21-2.17 (m, 1H), 1.64-1.60 (m, 1H, HOCH2CH2), 1.50-1.44
(m, 1H, HOCH2CH2), 1.25 (s, 3H), 1.20 (s, 3H). IR (KBr): 3497, 3366, 3197
(OH), 2971, 2918, 2919 (NH2), 1654, 1598, 1034 cm−1. MS (Isim, 3-NBA) m/z
278 (MH+). Anal. Calculated for C13H19N5O2.2/3H2O: C, 53.98; H, 7.04; N, 24.22.
Found C, 53.9; H, 6.6; N, 23.9.
( )-trans-9-[2,2-Dimethyl-3-(hydroxyethyl)-oxolan-5-yl]adenine (4)
The identical procedure was used as described for the preparation of
the cis-nucleoside ( )-6 giving 0.024 g, 0.0785 mmol (80.5%) of the target
1
trans-nucleoside as a white solid, mp 145-146◦C. H-NMR (DMSO) δ: 8.18
(s, 1H), 8.12 (s, 1H), 7.23 (s, 2H, amine), 6.18-6.16 (d, J = 6.8 Hz, 1H, H-5ꢀ
acetal), 4.53-4.50 (t, 1H, OH), 3.49-3.43 (m, 2H, HOCH2CH2), 2.41-2.29 (m,
2H), 1.61-1.58 (m, 1H, HOCH2CH2), 1.30-1.32 (m, 1H, HOCH2CH2), 1.33 (s,
3H), 1.08 (s, 3H). IR (KBr): 3292, 3115, (OH) 2979, 2932, 2891 (NH2), 1683,
1610, 1536, 1076 cm−1. MS (Isim, 3-NBA) m/z 278 (MH+). Anal. Calculated
for C13N5O2 H19.2/3H2O: C, 53.98, H, 7.04; N, 24.22. Found C, 54.2; H, 7.2; N,
23.8.
6-Hexyloxypurine
In a 250 mL dry round bottom flask, 3.3 g (32 mmol) hexanol and 200 mL dry
THF were cooled to 0◦C under an inert atmosphere. To this stirred solution, 1.44 g
(36 mmol) 60% mineral oil dispersion NaH was added. The resulting mixture was
then heated to reflux for 2 h. After this period of time, the solution was cooled
to 0◦C and 1.0 g (6.47 mmol, 0.2 equivalents) 6-chloropurine was added. The
reactionmixturewasthenheatedtorefluxfor24h. Afterthereactionhadcompleted,
monitoring was accomplished using analytical TLC (2:1 ether: EtOAc), the solution
was cooled to 0◦C and quenched with 10 mL H2O. The product was purified by
adding 200 mL ether and washing the organic phase with successive portions of
1×100 mL 3% HCl, 2×100 mL H2O and 1×100 mL sat. aq. NaCl. The organic
phase was then dried over MgSO4 and the solvent removed under reduced pressure.
Further purification was afforded by recrystallization form CH3CN, yielding 1.27 g,
5.76 mmol (90%) 6-hexyloxypurine as a white solid, mp 149-150 ◦C. The 1H-NMR
of this compound matched that of an authentic sample prepared by a literature
procedure (11).

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( )-3-[2-(Benzoyloxy)ethyl]-5-(6-hexyloxypurin-9-yl)-2,2-
dimethyloxolane (cis-7 & trans-8)
A solution of ( )-cyclobutanone 12 (0.070 g, 0.285 mmol) and 6-hexyloxy-
purine (0.126 g, 0.57 mmol) in 65 mL dry dichloromethane was placed in a Pyrex
photolysis tube and irradiated for 4 h. Prior to the irradiation, this mixture was
purged with argon for 0.5 h. After the photolysis, evaporation of the solvent fol-
lowed by flash column chromatography (15:2 CH2Cl2: EtOAc) gave 0.078 g, 0.0165
mmol (58%) of the title compound as an anomeric mixture. A 0.154 g sample of
this mixture was further purified by preparative TLC (100% diethyl ether) to give
0.098 g (64%) of the trans isomer and 0.055 g (36%) of the cis isomer as clear oils.
( )-cis-isomer (7) 1H-NMR (CDCl3) δ:8.42 (s, 1H), 8.08 (s, 1H), 7.97-
7.95 (d, 2H), 7.52-7.48 (t, 1H), 7.39-7.35 (t, 2H), 6.21-6.18 (t, 1H, H-5ꢀ,
acetal), 4.53-4.49 (t, 2H,OCH2CH2CH2CH2CH2CH3), 4.34-4.21 (t, 2H, BzOCH2-
CH2), 2.90-2.84 (m, 1H, H-4ꢀ), 2.35-2.29 (m, 2H, H-3ꢀ and H-4ꢀꢀ), 1.93-1.90
(m, 1H, BzOCH2CH2), 1.84-1.80 (m, 2H, OCH2CH2CH2 CH2CH2CH3) 1.76-1.73
(m, 1H, BzOCH2CH2), 1.44-1.40 (m, 2H, OCH2CH2CH2CH2CH2CH3), 1.36 (m,
3H, methyl), 1.29-1.25 (m, 4H, OCH2CH2CH2CH2CH2CH3), 1.24 (s, 3H, methyl)
0.83–0.80 (t, 3H, OCH2CH2CH2CH2CH2CH3); IR (neat): 1717 (CO) cm−1. MS
(lsim, 3-NBA) m/z 467 (MH+). Anal. Calculated for C26H34O4N4: C, 66.93; H,
7.35; N, 12.02. Found C, 67.2; H; 7.5, N, 11.9.
( )-trans-isomer (8) 1H-NMR (CDCL3) δ: 8.35 (s, 1H), 8.00 (s, 1H),
7.92-7.90 (d, 2H), 7.47-7.44 (t, 1H), 7.34-7.31 (t, 2H), 6.20-6.19 (d, 1H, H-5ꢀ,
acetal), 4.49-4.46 (t, 2H, OCH2CH2CH2CH2CH2CH3), 4.30-4.25 (t, 2H, BzOCH2
CH2), 2.72-2.71 (m, 1H, H-4ꢀ), 2.35-2.32 (m, 2H, H-3ꢀand H-4ꢀꢀ), 1.89-1.86 (m, 1H,
BzOCH2CH2), 1.82-1.76 (m, 2H, OCH2CH2CH2CH2CH2CH3) 1.69-1.66
(m, 1H, BzOCH2CH2), 1.37 (m, 2H, OCH2CH2CH2CH2CH3, and 3H, methyl),
1.25-1.22 (m, 4H, OCH2CH2CH2CH2CH2CH3), 1.11 (s, 3H, methyl), 0.8–0.77
(t, 3H,OCH2 CH2CH2CH2CH2CH3). IR (neat): 2959, 2933, 2871, 1718 (CO)
1599, 1456, 1274 cm−1. MS (lsim, 3-NBA) m/z 467 (MH+). Anal. Calculated
for C26H34O4N4: C, 66.93; H, 7.35; N, 12.02. Found C, 67.3; H; 7.6, N, 11.7.
( )-cis-9-[2,2-Dimethyl-3-(hydroxyethyl)-
oxolan-5-yl]-6-hexyloxypurine (9)
A solution of the ( )-cis-protected nucleoside 7 (0.040 g, 0.086 mmol) and
30 mL methanolic ammonia was stirred at room temperature for 24 h. Solvent
removal under reduced pressure followed by purification by TLC (1:15 CH3OH:
CH2Cl2) gave the target nucleoside, 0.023 g, 0.069 mmol (81%) as a clear oil. 1H-
NMR: δ: 8.49 (s, 1H), 8.12 (s, 1H), 6.25 (t, H-5,ꢀ acetal), 4.58 (t, 2H, OCH2CH2CH2
CH2CH3), 3.73 (m, 2H, OCH2CH2), 2.86 (m, 1H, H-4ꢀ), 2.32 (m, 2H, H-3ꢀ and
H-4ꢀꢀ), 1.89 (m, 2H), 1.76–1.39 (m, 9H), 1.41 s, 3H), 1.28 (s 3H), 0.90 (t, 3H);
IR (neat): 3450, 3310, (OH) cm−1. MS (Isim, 3-NBA) m/z 363 (MH+). Anal.

ORDER
REPRINTS
SYNTHESIS OF NOVEL DIDEOXYNUCLEOSIDES
195
Calculated for C19H30O3N4 · 1/2H2O: 61.46: H, 8.09; N, 15.09. Found C, 61.5; H,
8.5; N, 15.1.
( )-trans-9-[2,2-Dimethyl-3-(hydroxyethyl)-oxolan-5-yl]-6-
hexyloxypurine (10)
A solution of the ( )-trans-protected nucleoside 8 (0.060 g, 0.129 mmol) and
30 mL methanolic ammonia was stirred at room temperature for 24 h. Solvent re-
moval under reduced pressure followed by purification by TLC (1:15 CH3OH:CH2
1
Cl2) gave the target nucleoside, 0.036 g, 0.103 mmol (80%) as a clear oil. H-
NMR: δ: 8.51 (s, 1H), 8.22 (s, 1H), 6.30 (t, H-5ꢀ, acetal), 4.58 (t, 2H), 3.75 (m,
2H), 2.80 (m, 1H, H-4ꢀ), 2.52 (br.s, 1H, OH) 2.37 (m, 2H), 1.90 (m, 2H), 1.45–1.30
(m, 8H), 1.50 (s, 3H), 1.27 (s, 3H), 0.90 (t, 3H); IR (neat): 3300 cm−1 (OH); MS
(lsim, 3-NBA) m/z 363 (MH+). Anal. Calculated for C19H30O3N4 · 1/2H2O: C,
61.46; H, 8.09; N, 15.09. Found C, 61.6; H, 8.6; N, 15.0.
X-ray Crystallography
Crystalsofcis-( )-9-[2,2-dimethyl-3-(hydroxyethyl)-oxolan-5-yl]adenine(3)
were grown by evaporation from methanol under anhydrous conditions. X-ray
diffraction data was collected on a Siemens R3/v diffractometer. The cis nucleo-
side ( ) 3 was refined in triclinic Pi using 637 out of 1396 observed reflections.
The structure was solved by Direct Methods followed by Fourier Synthesis. Fi-
nal refinement was done using full-matrix least-squared procedures with isotropic
thermal parameters on all non-hydrogen atoms. The hydrogen atoms were placed
❛
in idealized positions and refined isotropically using a riding model (C-H, 0.96 A,
❛
U11 = 0.08 A2). This refinement gave a data/par ratio of 637/81 and an R value of
0.200.
The software used for the structural determination was the SHELX Plus (PC)
Package (13). Prior to the application of Direct Methods, the default on TREF (i.e.
in the initial instruction file) was changed to TREF 2000.
ACKNOWLEDGMENTS
We are grateful to the Ontario HIV Treatment Network (OHTN) and the Nat-
ural Science and Engineering Research Council of Canada (NSERC) for financial
support of this investigation.
REFERENCES
1. Nucleosides and Nucleotides as Antitumor and Antiviral Agents. C.K. Chu and D.C.
Baker (Eds). Plemum Press, N.Y. 1933.

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196
LEE-RUFF AND MARGAU
2. DNA Replication, Second Edition, Kornberg, A.; Baker, T.A., Eds. W.H. Freeman and
Co., 1992.
3. Tronchet, J.M.; Tronchet, J. J. Med. Chem., 1974, 17, 1055.
4. (a). Parikh, D.K.; Watson, R. J. Med. Chem., 1978, 21, 706. (b). Sells, T.B.; Nair, V.
Tetrahedron Letters, 1992, 33, 7639. (c). Sells, T.B.; Nair, V. Tetrahedron. 1994, 50,
117. (d). Nair, V.; Jahnke, T.S. Antimicrob. Agent Chemother. 1995, 39, 1017.
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Jahnke, T.S. Tetrahedron 1995, 51, 10443. (c). Nair, V.; St. Clair, M.H.; Reardon, J.E.;
Krasney, H.C.; Hazen, R.J.; Paff, M.T.; Boone, L.R.; Tisdale, M.; Najera, I.; Dornsife,
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E.; Xi, F.-D.; Qie, J.H. J. Org. Chem., 1996, 61, 1547. (e) Lee-Ruff, E.; Ostrowski,
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Tamm, C. Helv. Chim. Acta. 1972, 55, 1996. (c). Okabe, M.; Sun, R.-C.; Tam, Y.K.;
Todaro, J.L.; Coffen, D.L. J. Org. Chem. 1988, 53, 4780.
11. Burns, C.L.; St. Clair, M.H.; Frick, L. W.; Spector, T; Averett, D.R.; English, M.L.;
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13. Sheldrick, G.M. SHELX TL PC version 4.1. Siemens Analytical X-ray Instruments
Inc. Madison, WI.
Received April 20, 2000
Accepted October 27, 2000

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