Photochemical synthesis of nucleoside analogues from cyclobutanones: Bicyclic and isonucleosides

Article abstract of DOI:10.3390/molecules15063816

The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from

Full text of DOI:10.3390/molecules15063816

Molecules 2010, 15, 3816-3828; doi:10.3390/molecules15063816
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Photochemical Synthesis of Nucleoside Analogues from
Cyclobutanones: Bicyclic and Isonucleosides
Mileina Jaffer, Abdelaziz Ebead and Edward Lee-Ruff *
Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, M2M 4J4, Canada
* Author to whom correspondence should be addressed; E-Mail: leeruff@yorku.ca;
Tel.: +1-416-736-5443; Fax: +1-416-736-5936.
Received: 8 April 2010; in revised form: 19 May 2010 / Accepted: 24 May 2010 /
Published: 26 May 2010
Abstract: The preparation of two nucleoside analogues are reported. Both syntheses
involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its
subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts
from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an
isonucleoside uses a cyclobutanone with an α-substituted 6-chloropurine. Irradiation of the
latter produces an isonucleoside and acyclic nucleoside analogues.
Keywords: cyclobutanone; oxacarbene; bicyclic nucleosides; isonucleosides; acyclic
nucleoside
1. Introduction
Structurally modified nucleosides represent an important class of medicinal compounds which have
been found to behave as therapeutic agents and are currently used in pharmaceuticals as antitumour,
antiviral, and antibiotic agents [1–4]. Structural modifications include the ribose, as well as the base
moieties. The general synthetic protocols involve the use of monosaccharide chirons which are
coupled to heterocycles employing a key glycosylation step which is often not stereoselective. During
the last decade our group has developed a photochemical glycosylation method based on the
photoisomerization of cyclobutanones to transient 2-tetrahydrofuranylidenes and their insertion into
alcohols [5] or weakly acidic N-H functions (Scheme 1) [6–11,13].

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Scheme 1. N-Glycosylation by Photochemical Ring-expansion of Cyclobutanones.
O
O
O
H-NR2
hν
NR2
The N-glycosylation procedure was exploited for the preparation of modified ribonucleosides
[6–11,13]. Although anomeric mixtures were obtained, some stereoselectivity was observed,
depending on the nature of the ring substituents. The advantages of this method are the mild conditions
for coupling (neutral solutions), the retention of stereochemistry of the cyclobutanone ring substituents
in the photoproducts, and the availability of substituted cyclobutanone precursors with defined
stereochemistry using relatively simple methods [14,15]. These precursors can also be prepared in
chiral modifications for their use in the preparation of chiral nucleosides.
In the current investigation we report the synthesis of two new nucleoside analogues, a bicyclic
(“locked”) derivative and an isonucleoside, from two different cyclobutanone precursors. Furthermore,
photocycloelimination of cyclobutanones results in the stereospecific formation of alkenes as a side
reaction. The extent to which cycloelimination occurs is dependent on the electronic nature of the α-
substituent in the ketone as well as solvent effects. Electron-withdrawing groups promote
cyloelimination over photoisomerization [16]. We also report the stereoselective formation of an
acyclic nucleoside analogue from the photocycloelimination of an α-nucleobase-substituted
cyclobutanone.
2. Results and Discussion
2.1. Photochemical Synthesis of a Bicyclic Nucleoside Analogue
A class of structurally modified nucleosides consists of bicyclic or “locked” derivatives. In this
class of nucleosides, there is an additional ring fused to the sugar moiety [17]. The five membered
sugar rings found in nucleosides exist in a puckered geometry. Figure 1 depicts this geometry in either
the “south” or the “north” conformation. The two conformers are in equilibrium.
Figure 1. Nucleoside Conformations.
C2 Endo (South)
C3 Endo (North)
The specific conformation is crucial for complementary binding with target molecules. An
attractive feature of bicyclic derivatives is their restricted conformational flexibility [17]. Thus, the
nucleoside may be locked in the active conformation (either north or south) required to show activity.
Due to their decreased conformational flexibility, oligonucleotides incorporating these rigid nucleoside
analogues have been observed to display increasing recognition of DNA sequences [17]. The ability of
nucleotides containing locked nucleoside to be able to recognize DNA sequences have rendered these

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Molecules 2010, 15
promising as drug candidates for antisense therapy. We have previously reported the photochemical
ring-expansion of a series of bicyclic cyclobutanones and their carbene insertion reactions to 6-chloro-
purine in order to explore this approach for the preparation bicyclic nucleoside analogues [13]. The
earlier report was to demonstrate the proof of concept, but did not incorporate important structural
features associated with substituents necessary for biological functions (i.e. hydroxymethyl, hydroxyl
groups). In the current study we report the preparation of nucleoside analogues 1a and 1b (Figure 2)
with the appropriate hydroxymethyl substituent for binding to the phosphorylating kinase receptor [18]
using the photochemical protocol developed by our group.
Figure 2. Target Bicyclic Derivatives.
N
N
N
R'
R'
O
O
N
N
N
N
N
O
O
OR
1a
OR
1b
R = OBn, H
R' = Cl, NH2
The bicycloheptanone 3 was prepared in two steps from the previously reported 2-
benzyloxymethyl-4,5-dihydrofuran (2) [19] using the standard [2+2] dichloroketene cycloaddition and
dechlorination sequence. Although the overall yield for the two steps is low (~10%) no optimization
was carried out and significant amounts of starting 2 accompanied product formation. The
regioselectivity for the cycloaddition follows previously observed ketene cycloadditions to vinyl ethers
[20]. Irradiation of ketone 3 with 6-chloropurine in acetonitrile solution produced a diastereomeric
mixture of two anomers 1a and 1b in a 2:1 ratio (30%) (Scheme 2).
Scheme 2. Preparation of a Bicyclic Nucleoside Analogue.
N
O
N
Cl
O
Cl
O
N
N
a
b
c
+
N
N
N
N
O
O
O
O
OBn
OBn
1b
OBn
1a
OBn
2
3
(a) DCAC, TEA in hexane or TCAC/Zn-Cu couple, ether, DME ; (b) Zn-Cu couple, NH4Cl
MeOH, (10% overall yield); (c) hν, 6-chloropurine, CH3CN (31%)
The remaining products consisted of polar materials which were not identified. Photocyclo-
elimination is known to accompany ring-expansion, the latter pathway leading to a substituted ketene
which could oligomerize or produce carboxylic acids on work up [16]. The regioselectivity for
insertion of the oxacarbene to the N-9 position has been established from previous studies [6,8–11]
with the predominant presence of the N-9(H) tautomer in solution. The major epimer was shown to

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Molecules 2010, 15
possess the exo stereochemistry on the basis of 1D and 2D (HSQC, COSY and NOESY). For 1a the
NOE correlation was established between the anomeric and the bridgehead protons. For 1b there was
no observable correlation between these respective protons. The cis-fused assignment of both epimers
was established by NOE correlation between the bridgehead and methylene protons. This observation
is consistent with the retention of the ring substituent stereochemistry in these photochemical ring-
expansions of cyclobutanones.
The preference for formation of the exo-adduct is likely due to the less sterically encumbered exo-
approach of the carbene scavenger. The conversion of the chloro-nucleosides to the adenine
derivatives, 1a and 1b (R’ = NH2) as well as deprotection of the alcohol group are straightforward
steps. Our investigations are continuing on extensions to the homologous dihydropyran series,
although these would be more conformationally flexible than the corresponding furan series.
2.2. Synthesis of Acyclic and Isonucleoside Analogues from the same Cyclobutanone Precursor
Isonucleosides are analogues in which the substituents of the ribose moiety are transposed to
different positions in the sugar ring from their natural counterpart [21]. Acyclic nucleosides
incorporate a non cyclic ribose equivalent [22]. Many of these exhibit antiviral activity such as
acyclovir which is used in the treatment of most forms of herpes.
In a separate study involving the preparation of cyclobutane carbocyclic analogues of nucleosides
we synthesized ketone 4 by way of N-alkylation of 2-bromo-3-benzoylxycyclobutanone [10] with 6-
chloropurine [23]. The stereochemistry of 4 was confirmed from the X-ray crystal structure analysis of
one of its derivatives. Photochemical ring-expansion in the presence of water should result in
hemiacetal 5 which on deprotection and aminolysis, carried out in a one pot reaction, would give
isoadenosine 6 (Scheme 3). Regioselectivity would be expected from scission of the more substituted
carbonyl carbon bond.
Scheme 3. Preparation of an Isonucleoside.
N
N
N
N
NH2
N
N
Cl
O
N
HO
HO
O
NH3
hν
O
N
N
N
N
H2O
OH
OBz
OBz
Cl
N
6
5
4
Irradiation of 4 in acetonitrile containing 10 stoichiometric equivalents of water produced, in
addition to 5 (20%), geometric isomers 7 (11%) and 8 (64%) derived from cycloelimination of ketene
Scheme 4). The hemiacetal 5 was formed as a single stereoisomer as was evident by the simple doublet
signal observed for the anomeric proton of the aminoacetal group, although the relative
stereochemistry of the hemiacetal group could not be unambiguously assigned. The formation of the
cis-isomer 8 as the major product was unexpected as the fragmentation of ketene from electronically

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Molecules 2010, 15
excited cyclobutanones is known to be a concerted process originating from the singlet state and leads
to alkenes with retention of stereochemistry.
Scheme 4. Photochemical Production of an Isonucleoside and Acyclic Derivatives.
Cl
N
N
N
N
N
N
Cl
O
N
N
N
HO
O
N
+
+
hν/ 3h.
N
N
N
OBz
N
N
CH3CN/H2O
OBz
Cl
OBz
OBz
Cl
N
8
5
7
4
Photocycloelimination of ketene is regioselective, involving cleavage of the more substituted α-
carbon-carbonyl carbon bond similar to the regioselectivity of the ring-expansion reaction. The extent
to which each of these competitive processes occur is influenced by the nature of the α-substituent
with electron-withdrawing groups favouring cycloeliminations and electron-donating groups giving
ring-expansion oxacarbene photoadducts [16]. The distribution of these two competitive pathways is
also affected by solvent polarity, with polar solvents favouring ring-expansion and non-polar solvents
giving rise to cycloeliminations [16]. The solvent effects on the distribution of products is attributed to
reversible formation of the more polar oxacarbene intermediate [16].
In order to maximize the yields of the ring-expansion photoadducts, the photolysis of 4 was carried
out in more polar methanol solutions (Scheme 5). The yield for the ring-expansion photoadduct 9
increased to 40%. Under these conditions a small amount of 8 (13%) was observed with no detectable
presence of 7. However, a new photoadduct 10 was observed in 21% yield.
Scheme 5. Photochemical Production of an Isonucleoside and Acyclic Derivative.
N
N
N
Cl
OBz
N
O
N
N
O
H3CO
Cl
O
hν/ 8h.
+
8
+
N
N
H3CO
N
N
CH3OH
N
OBz
OBz
Cl
N
10
9
4
hν
CH3OH
O
N
N
N
OBz
Cl
N
11
The latter is likely formed from a Norrish Type I reaction involving a transient ketene 11. This
mode for deactivation is unusual for cyclobutanones which yield photoproducts originating from the
singlet state on direct irradiation. Ketene formation from Norrish I reactions normally originate from

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Molecules 2010, 15
the triplet state in acyclic and medium size cycloalkanones [24]. Diester 10 would serve as an
important precursor to potential biologically active acyclic nucleosides on reduction-deprotection
and aminolysis.
The purine substituted alkenes 7 and 8 are also important precursors to other acyclic nucleoside as
well as cyclopropane analogues. The effect of less polar solvents such as benzene and acetone on the
photochemistry of ketone 4 was investigated with the objective of maximizing the cycloelimination
pathway. Both solvents yielded alkenes 7 and 8 as the only identifiable products, however the total
yield for 7 and 8 was lower than that obtained in acetonitrile. In benzene trans-7 exceeded cis-8 by a
factor of 2:1. For acetone, a known triplet sensitizer, the distribution of 7 and 8 was about the same.
The unusual non-steroselective photocycloelimination observed in the case of ketone 4 is likely the
result of concurrent photoisomerization between 7 and 8 as was shown by independent experiments
under the conditions of direct or sensitized irradiation.
3. Experimental
3.1. General
Photolyses were carried out using a Hanovia 450-W medium pressure mercury arc lamp in a water-
cooled quartz immersion well. Pyrex tubes containing the samples were strapped around this well, and
the assembly was immersed in an ice-water bath. The samples were purged with argon for 30 min prior
to irradiation. All solvents used were dried and distilled. Proton NMR spectra were obtained on a
Bruker ARX-400 spectrometer and 13C NMR was carried out on a Bruker 300 spectrometer. Mass
Spectra were collected (EI mode) using a Varian Series 4000 GC/MS/MS spectrometer.
3.2. 1-(Benzyloxymethyl)-7,7-dichloro-2-oxabicyclo[3.2.0]heptan-6-one
3.2.1. Method A
Enol ether 2 [20] (2.36 g, 0.0124 mol) was dissolved in hexanes (60 mL) and stirred at room
temperature. Dichloroacetyl chloride (1.92 g, 0.015 mol) was added and the mixture was allowed to
reflux for 20 min. Triethylamine (1.50 g, 0.015 mol) in hexanes (30 mL) was then added dropwise to
the mixture. The reaction was allowed to stir for 1 h and quenched with cold H2O (30 mL). The
organic layer was washed with saturated NaHCO3, dried over Na2SO4, and the solvent was removed
under vacuum to give the title compound in 21% yield. IR (1,805 cm-1) confirmed the presence of the
cyclobutanone carbonyl group. The crude material was used immediately for the dechlorination step
without purification.
3.2.2. Method B
To a solution of alkene 2 (4.022 g, 0.0212 mol) in ether (80 mL) and DME (11 mL) was added
Zn/Cu couple [25] (4.29 g). The mixture was heated to reflux and trichloroacetyl chloride (TCAC)
(10.409 g, 0.05724 mol) was added dropwise to the mixture. The mixture was allowed to reflux
overnight. Zinc precipitate was filtered and the ether was evaporated under reduced pressure. The
residue was dissolved in hexanes and the organic layer was washed twice with saturated NaHCO3

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Molecules 2010, 15
solution. The organic layer was then washed with brine, dried over Na2SO4, and the solvent was
removed under reduced pressure to give the title compound which showed identical spectral properties
as the sample obtained from method A.
3.3. 1-(Benzyloxymethyl)- 2-oxabicyclo[3.2.0]heptan-6-one (3)
3.3.1. Method A
Dichloroketone (0.372 g, 0.00123 mol) obtained above was stirred in MeOH (30 mL) at 0 ºC. To
this solution, zinc powder (0.88 g, 0.013 mol) and ammonium chloride (0.48 g, 0.009 mol) was added.
The mixture was allowed to stir and warm to room temperature overnight. The zinc was filtered and
the solvent was removed under reduced pressure. The residue was dissolved in ether (3 × 20 mL) and
the organic layer was washed with 2 × 15 mL saturated NaHCO3, dried over Na2SO4, and the solvent
removed under reduced pressure to give an oil which was purified by preparative TLC (30% ethyl
1
acetate in hexanes). Yield 10%. IR (cm-1): 1807; H-NMR (CDCl3): δ 7.30–7.38 (m, 5H), 4.66–4.70
(m, 2H), 4.21–4.28 (m, 1H), 3.97-4.03 (m, 1H), 3.82-3.84 (m, 2H), 3.64-3.68 (m, 1H), 3.21-3.29 (dd,
J = 5.4 Hz, 18 Hz, 1H), 2.93-3.00 (dd, J = 2.1 Hz, 18 Hz, 1H), 1.90–2.22 (m, 2H); 13C-NMR
(300 MHz, CDCl3): δ 214 (C=O, C-1), 65.38 (CH, C-2), 29.4 (CH2, C-3), 69.2 (CH2, C-4), 29.9 (C, C-
5), 53.2 (CH2, C-6), 71.7 (CH2, C-7), 73.6 (CH2, C-8) 138 (C, C-9), 127.8-130.6 (CH, C-10); 1H- and
13C-NMR assignments from COSY, HSQC and NOESY data are given in Table 1; MS (EI) m/z 232 (M+).
Table 1. Assignment of 13C and 1H Chemical Shift Values from COSY, HSQC and NOESY Data.
O
1
2
6
3
7
O
4
O
8
9
10
Carbon No.
13C δ (ppm)
214
65.4
29.37
69.20
1H δ (ppm)
1
2
3
4
3.64–3.68 (m, 1H)
1.90–2.22 (m, 2H)
3.97–4.03 (m, 1H)
4.21–4.28 (m, 1H)
5
6
29.9
53.1
3.21–3.29 (dd, J = 5.4 Hz, 18Hz, 1H)
2.93–3.00 (dd, J = 2.1 Hz, 18 Hz, 1H)
3.82–3.89 (m, 2H)
7
71.6
8
73.5
4.66–4.70 (m, 2H)
9
138
10
127.7–130.6
7.30–7.38 (m, 5H)

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3.3.2. Method B
To a stirring mixture of 1-(benzyloxymethyl)-7,7-dichloro-2-oxabicyclo[3.2.0]heptan-6-one
obtained above (1.75 g, 0.0096 mol) and ammonium chloride (2.59 g, 0.048 mol) in methanol (41 mL)
was added zinc-copper couple (1.90 g) at room temperature. The reaction mixture was stirred for 1 h.
The zinc precipitate was filtered and the filtrate was concentrated. The residue was dissolved in DCM,
and the solution was washed with brine, dried over anhydrous sodium sulphate, filtered, and
concentrated. The residue was purified by preparative TLC (30% ethyl acetate-hexanes). Yield 10%.
The sample obtained showed identical spectral properties with those of the sample obtained from
method A.
3.4. 9-(3a-(Benzyloxymethyl)dihydrofuro[3,2-b]furan-2-yl)-6-chloro-9H-purine (1a and 1b)
A solution of ketone 3 (0.085 g, 0.00037 mol) and 6-chloropurine (0.085 g, 0.0006 mol) in
acetonitrile (80 mL) was irradiated for 6 h in a pyrex tube. The solvent was removed under reduced
pressure and the residue dissolved in chloroform. The photolysate were purified by preparative TLC
(70% ethyl acetate-hexanes) giving 1a (20%) and 1b (10%) as oils.
1
Nucleoside 1a: H-NMR (CDCl3, 400 MHz): δ 8.70 (s, 1H), 8.45 (s, 1H), 7.25–7.37 (m, 5H),
6.53–6.55 (dd, J = 5.2 Hz, 7.2 Hz, 1H), 4.90 (d, J = 4.4 Hz, 1H), 4.5 (AB q, J = 12 Hz, 2H), 4.04–4.14
(m, 2H), 3.66 (d, J = 9.6 Hz, 1H), 3.53 (d, J = 9.6 Hz, 1H), 3.02 (dd, J =5.2 Hz, 14.4 Hz, 1H), 2.81
(dd, J = 7.2 Hz, 14.4 Hz, 1H), 2.12–2.23 (m, 2H); 13C-NMR (CDCl3, 300 MHz): δ 92.2 (CH, C-1),
33.2 (CH2, C-2), 73.6 (CH2, C-3), 70.7 (CH2, C-5), 67.9 (CH2, C-4), 76.6 (C, C-7), 41.914 (CH2, C-8),
86.1 (CH, C-9), 126.0-127.8 (CH, C-6), 143.5 (CH, C-10), 151.9 (CH, C-11); MS (EI) m/z 388 (M+,
13
37Cl), 386 (M+, 35Cl); 1H- and C-NMR assignments from COSY, HSQC and NOESY data are given
in Table 2.
Nucleoside 1b: 1H-NMR (CDCl3, 300 MHz): δ 8.59 (s, 1H), 8.79 (s, 1H), 7.28–7.40 (m, 5H), 6.47–6.49
(dxd, J = 3.9 Hz, 7.8 Hz, 1H), 4.73 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H), 4.09 (m, 2H), 3.63 (d, J = 9.6 Hz,
1H), 3.54 (d, J = 9.6 Hz, 1H), 2.99 (dd, J =7.8 Hz, 14.7 Hz, 1H), 2.76 (dd, J = 3.6 Hz, 14.7 Hz, 1H),
2.13-2.19 (m, 2H); 13C NMR (CDCl3, 300 MHz): δ 87.266 (CH, C-1), 32.777 (CH2, C-2), 73.738
(CH2, C-3), 68.196 (CH2, C-4), 70.931 (CH2, C-5), 76.00 (C, C-7), 40.108 (CH2, C-8), 84.240 (CH, C-
9), 143.981 (CH, C-10), 127.304-128.577 (CH, C-6), 152.214 (CH, C-11); MS (EI) m/z 388 (M+,
13
37Cl), 386 (M+, 35Cl); 1H- and C-NMR assignments from COSY, HSQC and NOESY data are given
in Table 2.
Table 2. Assignment of 13C and 1H Chemical Shift Values from COSY, HSQC and NOESY Data.
Major nucleoside 1a

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Molecules 2010, 15
Cl
10
N
1
H
9
N
N
O
N
11
2
7
8
O
O
3
4
5
6
Table 2. Cont.
Carbon No.
13C δ (ppm)
92.2
33.2
73.6
67.9
70.7
126.0-127.8
76.6
1H δ (ppm)
4.90 (d, J = 4.4 Hz, 1H)
2.12–2.23 (m, 2H)
1
2
3
4
5
6
7
8
4.04–4.14 (m, 2H)
3.66 (d, J = 9.6 Hz, 1H), 3.53 (d, J = 9.6 Hz, 1H)
4.5 (AB q, J = 12 Hz, 2H)
7.25–7.37 (m, 5H)
41.9
2.81 (dd, J = 7.2 Hz, 14.4 Hz, 1H)
3.02 (dd, J = 5.2 Hz, 14.8 Hz, 1H)
6.53–6.55 (dd, J = 5.2 Hz, 7.2 Hz, 1H)
8.45 (s, 1H)
9
10
11
86.1
143.5
151.9
8.70 (s, 1H)
Minor nucleoside 1b:
Cl
10 N
9 N
N
O
1
7
H
N
11
8
2
O
O
3
4
5
6
Carbon No.
13C δ (ppm)
87.3
1H δ (ppm)
1
2
3
4
5
6
7
8
4.73 (d, J =2.4 Hz, 1H)
2.13–2.19 (m, 2H)
32.8
73.7
4.09 (m, 2H)
68.2
3.63 (d, J = 9.6 Hz, 1H), 3.54 (d, J = 9.6 Hz, 1H)
4.63 (s, 2H)
70.9
127.3–128.6
76.0
7.28–7.40 (m, 5H)
40.1
2.99 (dd, J =7.8 Hz, 14.7 Hz, 1H)
2.76 (dd, J = 3.6 Hz, 14.7 Hz, 1H)
6.47–6.49 (dxd, J = 3.9 Hz, 7.8 Hz, 1H)
8.59 (s, 1H)
9
84.2
10
11
144.0
152.2
8.79 (s, 1H)
3.5. Cyclobutanone 4
This ketone was prepared by a two step sequence involving α-bromination followed by N-
alkylation with 6-chloropurine [23]. Regioisomers of the N-7 and N-9 (compound 9) alkylated

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Molecules 2010, 15
products were formed and their structures determined by X-ray single crystal diffraction [23]. m.p.
60–62 ºC; IR (cm-1) 1799 (C=O of cyclobutanone); 1715 (C=O of ester); 1H-NMR (CDCl3): δ 8.65 (s,
1H), 8.17 (s, 1H), 7.90–7.88 (d, J = 8.0 Hz, 2H), 7.58–7.55 (t, J = 7.0 Hz, 1H), 7.42–7.38 (t,
J = 7.8 Hz, 2H), 5.78–5.76 (d, J = 7.6 Hz, 1H), 4.77–4.76 (d, J = 5.2 Hz, 2H), 3.60–3.54 (m, 1H),
3.47-3.40 (m, 1H), 3.26–3.19 (dd, J = 8.8 Hz, 17.6 Hz, 1H); 13C-NMR (CDCl3): δ 196.9, 166.6, 152.3,
151.6, 151.5, 144.0, 133.8, 131.6, 129.7, 129.2, 128.8, 68.9, 65.0, 45.3, 33.3.
3.6. Photolysis of Ketone 4 in Acetonitrile spiked with Water
A solution of ketone 4 (71 mg, 0.2 mmol) in 45 mL of acetonitrile and 0.036 mL (2.0 mmol) of
water was irradiated for 3 h. The solvent was removed under vacuum and the residue purified by
preparative TLC (60% ethyl acetate-hexane) to give 15 mg (20.2%) of diastereomeric mixture of
hemiacetal 5, 7 mg (11.1%) of trans-alkene 7 and 40 mg (63.5%) of the cis-alkene 8.
Benzoic acid 2-(6-chloro-purin-9-yl)-5-hydroxy-tetrahydro-furan-3-ylmethyl ester (5). 1H-NMR
(CDCl3): δ 8.76 (s, 1H), 8.29 (s, 1H), 8.13–8.11 (d, J = 8.0 Hz, 2H), 7.64–7.59 (t, J = 6.4 Hz, 1H),
7.48–7.44 (t, J = 8.0 Hz, 3H), 6.56–6.55 (d, J = 4.0 Hz, 1H), 4.70–4.68 (dd, J = 4.0 Hz, 12.0 Hz, 1H),
4.55–4.50 (dd, J = 6.4 Hz, 11.6 Hz, 1H), 3.80–3.78 (m, 1H), 3.66–3.59 (dd, J = 10.0 Hz, 18.0 Hz, 1H),
2.80–2.74 (m, 1H); MS: m/z 361 (M+-OH, 37Cl), 386 (M+-OH, 35Cl).
1
E-1’-(6-Chloropurin-9-yl)-2’-benzoyloxyethene (7). H NMR (CDCl3): δ 8.82 (s, 1H), 8.32 (s, 1H),
8.10-8.08 (d, J = 8.0 Hz, 2H), 7.61-7.58 (t, J = 7.0 Hz, 1H), 7.49-7.45 (t, J = 7.6 Hz, 2H), 7.41–7.38 (d,
J = 14.4 Hz, 1H), 6.94-6.88 (ddd, J = 6.4, 14.4, 20.8 Hz, 1H), 5.08-5.07 (d, J = 6.0 Hz, 2H); 13C NMR
(CDCl3): δ 166.3, 152.8, 151.8, 151.0, 143.0, 133.5, 132.4, 130.3, 129.9, 128.7, 124.0, 117.1, 62.7;
MS: m/z 316 (M+, 37Cl), 314 (M+, 35Cl).
1
Z-1’-(6-Chloropurin-9-yl)-2’-benzoyloxyethene (8). H-NMR (CDCl3): δ 8.80 (s, 1H), 8.41 (s, 1H),
7.97-7.96 (d, J = 7.8 Hz, 2H), 7.59-7.56 (t, J = 7.5 Hz, 1H), 7.45-7.42 (t, J = 7.8 Hz, 2H), 7.11-7.10 (d,
J = 9.0 Hz, 1H), 6.16-6.12 (q, J = 7.6, 15.6 Hz, 1H), 5.03-5.02 (d, J = 6.6 Hz, 2H); 13C-NMR (CDCl3):
δ 166.2, 152.9, 151.9, 151.8, 144.4, 133.7, 131.4, 129.8, 129.4, 128.7, 123.0, 122.1, 59.8; MS: m/z 316
(M+, 37Cl), 314 (M+, 35Cl).
3.7. Photolysis of Ketone 4 in Methanol
A solution of ketone 4 (60 mg, 0.17 mmol) in methanol (50 mL) was irradiated for 8 h. Evaporation
of the solvent under vacuum followed by chromatographic purification (gradient solvent mixture from
40% ethyl acetate-hexane to 60% ethyl acetate-hexane) yielded 7 mg (13.2%) of cis-alkene 8, 14 mg
(21.2%) of diester 10, and 26 mg (39.3%) methoxyacetal 9 as a diastereomeric mixture which was
further separated by preparative TLC (40% ethyl acetate-hexane).
Benzoic acid 2-(6-chloro-purin-9-yl)-5-methoxy-tetrahydro-furan-3-ylmethyl ester (9) (less polar
1
anomer). H-NMR (CDCl3) :δ 8.59 (s, 1H), 8.47 (s, 1H), 7.64-7.62 (d, J = 7.6 Hz, 2H), 7.53–7.49 (t,
J = 7.4 Hz, 1H), 7.31–7.27 (t, J = 7.2 Hz, 2H), 6.57–6.55 (d, J = 5.6 Hz, 1H), 5.30-5.27 (m, 1H),

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4.67–4.57 (dd, J = 4.6, 11.0 Hz, 1H), 4.47–4.42 (m, 1H), 3.48-3.42 (m with overlapping s, 4H),
2.47–2.44 (dd, J = 7.6, 12.8 Hz, 1H), 2.20-2.13 (m, 1H); MS: m/z 390 (M+, 37Cl), 388 (M+, 35Cl).
Benzoic acid 2-(6-chloro-purin-9-yl)-5-methoxy-tetrahydro-furan-3-ylmethyl ester (9) (more polar
1
anomer). H- NMR (CDCl3): δ 8.59 (s, 1H), 8.26 (s, 1H), 7.84–7.82 (d, J = 7.6 Hz, 2H), 7.50–7.45 (t,
J = 7.8 Hz, 1H), 7.40–7.35 (t, J = 7.8 Hz, 2H), 6.40–6.39 (d, J = 4.0 Hz, 1H), 5.44–5.43 (d, J = 4.8 Hz,
1H), 4.59–4.57 (d, J = 7.6 Hz, 2H), 3.48-3.42 (m with overlapping s, 4H), 2.80–2.73 (m, 1H),
2.03–1.99 (dd, J = 3.6, 14.0 Hz, 1H); MS: m/z 390 (M+, 37Cl), 388 (M+, 35Cl).
Benzoic acid 2-(6-chloro-purin-9-ylmethyl)-3-methoxycarbonyl-propyl ester (10). 1H-NMR (CDCl3): δ
8.70 (s, 1H), 8.23 (s, 1H), 7.91–7.90 (d, J = 7.6 Hz, 2H), 7.60–7.57 (t, J = 7.0 Hz, 1H), 7.46–7.43 (t,
13
J = 7.8 Hz, 2H), 4.58–4.47 (m, 2H), 4.41-4.31 (m, 2H), 3.12–3.03 (m, 1H), 2.59–2.47 (m, 2H); C-
NMR (CDCl3): δ 171.7, 166.2, 152.3, 151.4, 145.7, 133.7, 131.6, 130.2, 129.6, 129.4, 128.7, 64.7,
52.3, 45.4, 35.9, 33.7; MS: m/z 390 (M+, 37Cl), 388 (M+, 35Cl).
3.8. Photolysis of Ketone 4 in Acetone
A solution containing 100 mg (0.28 mmol) of ketone 4 in 90 mL of acetone was irradiated for 6 h.
The solvent was removed and the residue purified by preparative TLC (30% ethyl acetate-hexane) to
give 18 mg (20.4%) of trans-alkene 7, and 21 mg (23.9%) of cis-alkene 8. The spectral properties for
each of these fractions were identical for the corresponding derivatives reported above.
3.9. Photolysis of Ketone 4 in Benzene
A solution of ketone 4 (120 mg, 0.34 mmol) in 80 mL of benzene was irradiated for 3 h. Removing
of the solvent under vacuum followed by chromatographic purification (30% ethyl acetate-hexane)
yielded 20 mg (18.7%) of cis-alkene 8 and 35 mg (32.7%) of trans-alkene 7 with identical spectral
properties as reported above.
4. Conclusions
The direct irradiation of the bicyclic cyclobutanone 3 proceeds by isomerisation to a transient
oxacarbene which can insert into the N-9 N-H bond of 6-chloropurine to give the corresponding
bicyclic nucleoside analogues. The choice of 6-chloropurine was based on its solubility in common
organic solvents such as acetonitrile or THF, ensuring homogeneity in order to maximize
photochemical efficiency. Furthermore, nucleophilic aryl substitution of the C(6)-Cl function by NH2
has been shown to occur under mild conditions in order to access the adenine derivatives [6]. While
yields are quite modest, this approach represents one of the most simple routes to these derivatives.
Another cyclobutanone 4 in which the purine nucleobase is attached undergoes photochemical ring-
expansion with water or methanol to give photoadducts which represent the isonucleoside class of
derivatives. A competing side reaction involving cycloelimination yields purinyl base substituted
alkenes, the distribution of which is solvent dependent. These compounds are of interest as
intermediates in the synthesis of cyclopropane carbocyclic nucleosides. The photolysis of 4 in
methanol produced an unexpected Norrish I photoadduct 10 which on hydride reduction would

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generate the corresponding diol representing an acyclic nucleoside analogue. These latter studies are
currently being extended to include pyrimidine nucleobases as part of a general program for the
preparation of cyclobutane based nucleoside analogues.
Acknowledgements
We would like to thank NSERC for funding this project. AE would like to acknowledge the support
in the form of a graduate scholarship from the Government of Egypt.
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