Bicyclic nucleoside synthesis - A photochemical approach

Article abstract of DOI:10.1080/15257770802088886

The synthesis of a series of bicyclic nucleosides using photolytic ring-expansion of cyclobutanones is reported. The cyclobutanone precursors were prepared by [2+2] cycloaddition of a series of cyclic alkenes with chlorinated ketenes, derived from dichloro- and trichloroacetyl chloride. The synthesis of the nucleosides was achieved through photolysis of cyclobutanone precursors with 6-chloropurine by UV irradiation. The generality of this method was investigated and the absolute stereochemistry was assigned by NMR spectroscopy. The photoproducts demonstrated a marked preference for the 2′-exo conformation. Copyright Taylor & Francis Group, LLC.

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Bicyclic Nucleoside Synthesis—A
Photochemical Approach
a
a
E. Lee-Ruff & D. Wells
a
Department of Chemistry, York University, Toronto, Ontario,
Canada
Published online: 19 Jun 2008.
To cite this article: E. Lee-Ruff & D. Wells (2008) Bicyclic Nucleoside Synthesis—A Photochemical
Approach, Nucleosides, Nucleotides and Nucleic Acids, 27:5, 484-494
To link to this article: http://dx.doi.org/10.1080/15257770802088886
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Nucleosides, Nucleotides and Nucleic Acids, 27:484–494, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802088886
BICYCLIC NUCLEOSIDE SYNTHESIS—A PHOTOCHEMICAL
APPROACH
E. Lee-Ruff and D. Wells
Department of Chemistry, York University, Toronto, Ontario, Canada
2
The synthesis of a series of bicyclic nucleosides using photolytic ring-expansion of cyclobutanones
is reported. The cyclobutanone precursors were prepared by [2+2] cycloaddition of a series of cyclic
alkenes with chlorinated ketenes, derived from dichloro- and trichloroacetyl chloride. The synthesis of
the nucleosides was achieved through photolysis of cyclobutanone precursors with 6-chloropurine by
UV irradiation. The generality of this method was investigated and the absolute stereochemistry was
ꢁ
assigned by NMR spectroscopy. The photoproducts demonstrated a marked preference for the 2 -exo
conformation.
Keywords Bicyclic nucleosides; synthesis; photolysis; ring-expansion
INTRODUCTION
It has been found that structurally modified DNA and RNA analogues
have a wide range of biological activity, including inhibition of protein
[
1]
synthesis. Such modified nucleosides were found to be effective as anti-
viral agents and have been utilized in the development of drugs used to
combat cancer.[
2]
One form of modification of natural nucleosides involves restricting
its conformational flexibility. Called “bicyclic,” “rigid,” or “locked” nucleo-
sides, these compounds have become some of the most promising in the
antisense approach to gene therapy.[3] Natural ribonucleosides and de-
oxyribonucleosides exist in two distinct puckered conformations—“North”
ꢁ
and “South.” Each of these conformations can also be called 3 -endo and
2
ꢁ
-endo, respectively (Figure 1).[4] The overall conformational flexibility
of the nucleosides is of great importance in the complementary binding
of nucleotides and their interactions with other molecules. A conforma-
tional study demonstrated that the protein Reverse Transcriptase cannot
Received 23 October 2007; accepted 10 March 2008.
Address correspondence to E. Lee Ruff, Department of Chemistry, York University, Toronto,
Ontario M3J 1P3, Canada. E-mail: dawells@gmail.com.
4
84

Bicyclic Nucleoside Synthesis
485
FIGURE 1 Conformations of ribonucleosides.
ꢁ
ꢁ
distinguish between the North (3 -endo) and South (2 -endo) type of DNA,
but can distinguish between their complementary locked nucleosides, thus
affecting this protein’s function.
Certain rigid nucleosides can be frozen in one of two conformations.
ꢁ
Due to the presence of the pseudoaxially arranged base at carbon-1 and
ꢁ
the steric interactions associated with it and the substituents at carbon-3 , it
ꢁ
is expected that the ‘North’ (3 -endo) conformation would be less favorable
ꢁ
than the “South” (2 -endo) conformation in DNA. Calculations performed
on natural deoxyribonucleosides have confirmed this prediction.
[
3,6]
Different approaches to the synthesis of locked nucleosides have in-
[
7]
cluded fusion of a nitrogen-containing ring to the sugar
rings to different sides of the sugar moiety.
and fusion of
Typically, the procedures
for these syntheses begin with a glycone, followed by the formation of the
[
8–10]
[
1,10]
fused ring through ring-closing metathesis of sugar substituents.
Our
method starts with the fused ring to which a cyclobutanone is annealed.
Cyclobutanones undergo photochemical ring expansion isomerization to
an oxacarbene which can insert into purines at the N(9)-H bond, to give
a photoadduct.[
11]
These ketones serve as glycosyl donors under relatively
mild conditions.
The synthesis of each of these locked nucleosides involved two key
reactions. The first is the [2+2] cycloaddition, generating substituted
cyclobutanones, while the second is the photochemical isomerization of
the ketone to give a furanose. This methodology has been previously
[
11]
developed
and forms the basis for the locked nucleoside preparation.
There are several advantages to using this photochemical ring-
expansion in the synthesis of locked nucleosides. First, it is a simple single-
step reaction involving mild conditions. In addition, the method shown
can be generalized to give consistent yields of ring-expanded products.
This generalization allows for a wide variety of locked nucleosides to be
synthesized with minor alterations of the cyclobutanone substituents.
RESULTS AND DISCUSSION
The cycloaddition was achieved through the reaction of ketene and
a suitable alkene. This reaction has long been known to generate [2 +

4
86
E. Lee-Ruff and D. Wells
2
] cycloaddition products by way of an antarafacial transition state which
[
12]
minimizes steric repulsion of the ketene substituents.
Parent ketene is
conveniently generated by pyrolysis of acetone and cycloadds to alkene
to generate cyclobutanones. However, the relative unreactive nature of
ketene towards [2+2] cycloaddition with non-activated alkenes prompted
us to consider the use of halogenated ketenes. Dichloroketene can be
generated from dehydrochlorination of dichloroacetyl chloride or dechlo-
rination of trichloroacetyl chloride. Cyclic alkenes 1–4 were reacted with
dichloroketene generated in situ to give the dichlorinated ketones 5–8,
respectively (Scheme 1). The NMR spectra of the crude mixtures confirmed
the presence of the bridgehead hydrogens of 5 and 7 at δ 3.4 and 3.6 ppm
and for dichlorinated ketones 6 and 8 at δ 3.6 and 4.2 ppm. Degradation
of these compounds prevented purification and the crude products carried
forward to the next step. Dechlorination with zinc and ammonium chloride
to give 9–12 was confirmed through IR spectroscopy (carbonyl peak shift
−
1
−1
from 1800–1810cm to 1780–1790cm ).
Ketones 9–12 underwent photolytic insertion with 6-chloropurine by
UV excitation (10–14 hours irradiation) in acetonitrile solution, to give
SCHEME 1 [2+2] cycloaddition.

Bicyclic Nucleoside Synthesis
487
the rigid nucleoside analogues 13–16 in yields of 19–24% (Scheme 2).
The nucleosides were isolated and characterized by spectral data and high-
resolution mass spectrometry.
Furanosides 13–15 were present as single stereoisomers. Compound 16
was formed as two stereoisomers in an approximate 2:1 ratio, which were not
SCHEME 2 Photolytic ring expansion.

4
88
E. Lee-Ruff and D. Wells
FIGURE 2 Relative stereochemistry of nucleosides 13–16.
separable. The reason for the presence of a single isomer for furanosides
1
3–15, compared to two isomers of compound 16, is unknown.
1
Stereochemical assignments were based on 1-D H NMR as well as
NOESY. The structures of the four synthesized nucleosides are shown below,
with specific hydrogen atoms labeled accordingly (Figure 2).
The NMR data show the configuration of the synthesized nucleosides.
The NOESY analysis of the two isomers of 16 established a correlation
ꢁ
between H-1 and H-4 in the minor product (‘isomer B ) as seen in Figure 3.
This indicated that the two hydrogen atoms of this isomer (“isomer B”)
are closer in proximity than the H-1 and H-4 atoms of the major product
(
“isomer A”), suggesting that they are on the same side of the ring. In
contrast, H-1 and H-4 of isomer A of 16 are facing in opposite directions
Figure 4). Thus, stereochemistry of the major isomer is assigned the exo
configuration.
Similar results are found for the single stereoisomers of 13–15. 1D slices
(
from 2D NOESY for compounds 13–15 indicated that H-1 and H-4 are
ꢁ
not correlated with the same hydrogen at C-2 (Figure 5). Instead, each of
ꢁ
H-1 and H-4 is correlated to a different hydrogen at C-2 . This indicates
that H-1 and H-4 are in a trans configuration. To correlate these structures
ꢁ
ꢁ
to the 3 -endo and 2 -endo conformations, we can see that in the case of
ꢁ
the 3 -endo conformation, H-1 and H-4 would be closer in proximity to
show a correlation in the NOESY data. Whereas direct comparison of the
stereochemistry between the nucleoside analogues prepared in this study

Bicyclic Nucleoside Synthesis
489
FIGURE 3 NOESY of isomers A and B of nucleoside 16.
and the natural nucleosides cannot be made due to the cis-ring fusion of
ꢁ
the bicyclic ring system, it is only in the 2 -endo conformation where the two
hydrogen atoms H-1 and H-4 are further apart in proximity compared to the
ꢁ
2
-endo conformer. Thus, these analogues serve as stereochemical models for
ꢁ
the 3 -endo conformers of natural nucleosides.
FIGURE 4 Two isolated isomers of nucleoside 16.

4
90
E. Lee-Ruff and D. Wells
FIGURE 5 1D slice of 2D NOESY of nucleoside 13
In summary, bicyclic cyclobutanones can be structurally elaborated to
conformationally rigid nucleoside analogs by photochemical isomerization
to an oxacarbene and insertion to a purine. This novel approach represents
a simple and general scheme for the preparation of these derivatives.
EXPERIMENTAL
All NMR spectra were recorded on Bruker AV300 and AV400 spectrom-
eters. NMR solvents used are as indicated. NOESY spectra were recorded
◦
at 600 MHz at 10 C in CDCl . All IR spectra were recorded on a Genesis
3
II Mattson 3000 FT-IR spectrometer. All thin layer chromatography (TLC)
was done on silica gel 60F 254 alumina sheets. Preparative TLC was done
on Silicycle silica gel 60F 254 precoated glass plates. Mass spectra were run
in electron ionization at made 70 eV on a Micromass/Waters GCT Time-
of-flight mass spectrometer at the McMaster Centre for Mass Spectrometry.
UV spectra were recorded on an Ultrospec 4300 pro UV Spectrophotometer.
All photolysis reactions were carried out using a Hanovia 450 W medium-
pressure mercury arc lamp in a quartz immersion well. All solvents were
distilled and purged with argon for 30 minutes.

Bicyclic Nucleoside Synthesis
491
8,8-Dichlorobicyclo[4.2.0] octan-7-one (5)
Cyclohexene (0.500 g, 6.10 mmol) was stirred with dichloroacetyl
chloride (1.35 g, 9.16 mmol) in dry hexane (20 mL). The solution was
refluxed for 20 minutes, followed by slow addition of TEA (0.930 g, 9.20
mmol) in hexane (10 mL). The mixture was allowed to reflux overnight.
The solid material was removed by filtration and the solvent washed with 2
×
20 mL of saturated NaHCO . After drying over MgSO , the hexane was
removed under vacuum to give 0.934 g of 5 as a colorless liquid. Formation
3 4
of the dichlorocyclobutanone product was confirmed by IR spectroscopy (ν˜
−
1
=
1810 cm ) and immediately carried forward to the next step.
8,8-Dichloro-2-oxabicyclo[4.2.0]octan-7-one (6)
3,4-Dihydropyran (2) (0.500 g, 5.95 mmol) was stirred with DCAC (1.20
g, 8.14 mmol) in dry hexane (20 mL). The solution was refluxed for 20
minutes, followed by the slow addition of TEA (0.85 g, 8.40 mmol) in
hexane (10 mL). The mixture was refluxed for 15 minutes. The solution
was washed with 2 × 20 mL of saturated NaHCO , dried over MgSO , and
3
4
the solvent was subsequently removed under vacuum to give 0.820 g of
−
1
a colorless liquid. Infrared spectroscopy (ν˜ = 1808 cm ) confirmed the
formation of the dichlorocyclobutanone product, which was immediately
carried forward to the next step.
7,7-Dichlorobicyclo[3.2.0]heptan-6-one (7)
Cyclopentene (3) (0.500 g, 7.35 mmol) was dissolved in hexane (30 mL)
and stirred at room temperature. DCAC (1.30 g, 8.82 mmol) was added and
the mixture refluxed for 10 minutes. TEA (0.90 g, 8.89 mmol) in hexane (10
mL) was added and the mixture refluxed for 15 minutes before quenching
with H O (20 mL). The solvent was washed with saturated NaHCO (10
2
3
mL), dried over MgSO , and the solvent removed under vacuum to give 7.
4
−
1
Infrared spectroscopy (ν˜ = 1811 cm ) confirmed the presence of 7, which
was immediately carried forward to the next step.
7,7-Dichloro-2-oxa-bicyclo[3.2.0]heptan-6-one (8)
2,3-Dihydrofuran (4) (0.500 g, 7.14 mmol) was reacted using the same
method as for cyclopentene, described above. Infrared spectroscopy (ν˜ =
−
1
1
807 cm ) confirmed the presence of ketone 8, which was immediately
carried forward to the next step.

4
92
E. Lee-Ruff and D. Wells
Bicyclo[4.2.0]octan-7-one (9)
Ketone 5 (0.400 g, 2.07 mmol) was stirred in MeOH (20 mL) at 0 C. To
◦
this solution was added zinc powder (2.00 g, 30.6 mmol) and ammonium
chloride (0.90 g, 16.8 mmol). The mixture was allowed to stir and warm
to room temperature overnight. The zinc was then filtered and the solvent
removed under vacuum. The residue was washed with 3 × 15 mL of ether
and the organic layer was washed with 2 × 10 mL saturated NaHCO , dried
3
over MgSO , the solvent removed under vacuum, and the residue purified
4
by column chromatography (20% ethyl acetate in hexane) to provide 9
1
(
1
0.21 g, 80%). H NMR (CDCl ) δ 3.30–3.49 (m, 2H), 2.51–2.60 (m, 2H),
3
−
1
.37–2.05 (m, 8H). IR (liquid film) 1779 cm . The physical data were
consistent with those previously reported (13).
2-Oxabicyclo[4.2.0]octan-7-one (10)
Ketone 6 (0.300 g, 1.54 mmol) was reacted in the same manner as
compound 5, described above. The dechlorinated product 10 was isolated
(
0.150 g, 79%) after purification by column chromatography (20% ethyl
1
acetate in hexane). H NMR (CDCl ) δ 4.50 (m, 1H), 3.95 (m, 2H),
2
physical data were consistent with those previously reported.
3
−
1
.83–3.33 (m, 3H), 1.41–2.03 (m, 4H). IR (liquid film) 1780 cm . The
[
14]
Bicyclo[3.2.0]heptan-6-one (11)
Dichloroketone 7 (0.500 g, 2.79 mmol) was stirred in MeOH (20 mL)
◦
at 0 C. To this solution was added zinc powder (2.0 g, 30.58 mmol) and
ammonium chloride (1.10 g, 20.56 mmol). The mixture was allowed to stir
and warm to room temperature overnight. The zinc was then filtered and
the solvent removed under vacuum. The residue was washed with 3 × 15
mL of ether and the organic layer was washed with 2 × 10 mL saturated
NaHCO , dried over MgSO , and the solvent removed under vacuum which
3
4
was purified by column chromatography (20% ethyl acetate in hexane) to
1
provide 11 (0.20 g, 66%). H NMR (CDCl ) δ 3.04–3.35 (m, 3H), 2.49–2.60
3
−
1
(
m, 1H), 1.37–1.85 (m, 6H). IR (liquid film) 1785 cm . The physical data
were consistent with those previously reported.
[
15]
2-Oxa-bicyclo[3.2.0]heptan-6-one (12)
Ketone 8 (0.250 g, 1.38 mmol) was reacted using the same method as
for compound 7, described above. Purification by column chromatography
1
(
20% ethyl acetate in hexane) provided 12 (1.11 g, 72% yield). H NMR
(
CDCl ) δ 4.92 (m, 1H), 3.72–3.95 (m, 3H), 3.01–3.28 (m, 2H), 2.01–2.22
3

Bicyclic Nucleoside Synthesis
493
−
1
(
m, 2H). IR (liquid film) 1782 cm . The physical data were consistent with
[
14]
those previously reported.
6-Chloro-9-(octahydrobenzofuran-2-yl)-9H-purine (13)
6-Chloropurine (0.300 g, 1.94 mmol) was dissolved in argon-purged
CH CN (350 mL) and placed in a pyrex glass immersion well. To this was
3
added 9 (0.200 g, 1.61 mmol) and the solution was placed in ice-water bath
and irradiated for 10 h. The solvent was removed under vacuum and the
residue washed with CH Cl (3 × 50 mL). The product was purified by
2
2
column chromatography (65% ethyl acetate in hexane) to give 13 (0.90 g,
1
2
1
2
0%) as a clear oil. H NMR (CDCl ) δ 8.75 (s, 1H), 8.27 (s, 1H), 6.45 (t,
3
H, J = 6.31), 4.58 (m, 1H), 2.45 (m, 2H), 1.21–2.10 (m, 9H). MS 280 (1),
78 (M+), 181 (20), 154 (20), 125 (40), 81 (100), 71 (75), 49 (60). HRMS
(
EI) calc. for C H N OCl 278.0934, found 278.0924. UV (λ
= 268.7
13
15
4
max
3
nm) ε = 1.75 × 10 L/mol cm.
6-Chloro-9-(hexahydro-2H-furo[3.2-b]pyran-2-yl)-9H-purine (14)
Ketone 10 (0.200 g, 1.59 mmol) was reacted in the same way as 9,
described above. The solvent was removed under vacuum and the residue
washed with CH Cl (3 × 50 mL). The product was purified by column
2
2
chromatography (70% ethyl acetate in hexane) to give 14 (0.98g, 22%) as
1
a clear oil. H NMR (CDCl ) δ 8.75 (s, 1H), 8.27 (s, 1H), 6.81 (m, 1H),
3
4
.21 (m, 1H), 3.70–3.98 (m, 3H), 2.51–2.62 (m, 2H), 1.41–1.91 (m, 4H).
MS 282 (1), 280 (M+), 238 (8), 210 (10), 154 (100), 119 (90), 85 (100), 67
(
2
25), 55 (30), 41 (50). HRMS (EI) calc. for C H N O Cl 280.0727, found
80.0717. UV (λmax = 268.8 nm) ε = 3.16 × 10 L/mol cm.
12 13 4 2
3
6-Chloro-9-(hexahydro-cyclopenta[b]furan-2-yl)-9H-purine (15)
6-Chloropurine (0.300 g, 1.94 mmol) was dissolved in argon-purged
CH CN (350 mL) and placed in a pyrex glass immersion well. To this was
3
added 11 (0.200 g, 1.82 mmol) and the solution was placed in ice-water bath
during irradiation (10 hours). The solvent was removed under vacuum and
the residue washed with CH Cl (3 × 50 mL). The product was purified by
2
2
column chromatography (65% ethyl acetate in hexane) to give 15 (0.11 g,
1
2
3%) as a clear oil. H NMR (CDCl ) δ 8.79 (s, 1H), 8.27 (s, 1H), 6.41 (d,
3
1
H, J = 5.81), 4.82 (m, 1H), 2.25–2.40 (m, 2H), 1.21–2.10 (m, 7H). MS 266
(
(
1), 264 (M+), 181 (13), 154 (70), 119 (45), 111 (100), 81 (80), 67 (100), 53
25), 43 (70). HRMS (EI) calc. for C H N OCl 264.0778, found 264.0765.
12
13
4
3
UV (λmax = 271.2 nm) ε = 8.73 × 10 L/mol cm.

4
94
E. Lee-Ruff and D. Wells
6-Chloro-9-(hexahydro-furo[3,2-b]furan-2-yl)-9H-purine (16)
Ketone 12 (0.200 g, 1.78 mmol) was reacted using the same method as
for compound 11, described above. Product 16 (0.090 g, 19%) was isolated
1
as a mixture of two isomers. H NMR (CDCl ) δ 8.78 (s, 1H), 8.24 (s, 1H),
3
6.52 (m, 1H) 6.43 (m, 1H), 5.10 (m, 1H), 4.98 (m, 1H), 3.90–4.10 (m, 4H),
2
.70–3.02 (m, 2H), 0.90–2.2 (m, 6H). MS 268 (1), 266 (M+), 244 (10), 223
(30), 188 (70), 154 (90), 140 (90), 119 (100), 113 (100), 95 (55), 81 (40),
6
9 (80). HRMS (EI) calc. for C H N O Cl 266.0571, found 266.0577. UV
11 11 4 2
3
(
λ
= 268.6 nm) ε = 3.12 × 10 L/mol cm.
max
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