Carbocyclic nucleosides from enantiomeric, α-pinane-based aminodiols

Article abstract of DOI:10.1016/j.tetasy.2010.04.054

Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3. 1.1]heptane-2,2′-oxiran]-3-ol (-)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleosides. The regioselective ring opening of the spiro-oxirane ring of (-)-8 and (+)-8 with NaN₃ resulted in azidodiols (-)-9 and (+)-9. Catalytic reduction of (-)-9 and (+)-9 furnished chiral aminodiols (-)-10 and (+)-10, which were transformed by linear synthesis to purine-type nucleosides 16-18 through pyrimidine intermediates. Regioselective ring opening of the oxirane ring of (-)-8 and (+)-8 resulted in adenine-, cytosine- and uracil-based carbocyclic nucleosides 19-21 in a single-step synthesis.

Full text of DOI:10.1016/j.tetasy.2010.04.054

Tetrahedron: Asymmetry 21 (2010) 831–836
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbocyclic nucleosides from enantiomeric, a-pinane-based aminodiols
Zsolt Szakonyi a, Ferenc Fülöp a,b,
*
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2’-oxiran]-3-ol
(ꢀ)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleo-
sides. The regioselective ring opening of the spiro-oxirane ring of (ꢀ)-8 and (+)-8 with NaN3 resulted in
azidodiols (ꢀ)-9 and (+)-9. Catalytic reduction of (ꢀ)-9 and (+)-9 furnished chiral aminodiols (ꢀ)-10 and
(+)-10, which were transformed by linear synthesis to purine-type nucleosides 16–18 through pyrimi-
dine intermediates. Regioselective ring opening of the oxirane ring of (ꢀ)-8 and (+)-8 resulted in ade-
nine-, cytosine- and uracil-based carbocyclic nucleosides 19–21 in a single-step synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 March 2010
Accepted 21 April 2010
Available online 4 June 2010
1. Introduction
starting from the readily available a
-pinene enantiomers.20 The
resulting aminodiols were successfully applied as chiral catalysts
in the enantioselective addition of diethylzinc to aromatic alde-
hydes and in the regioselective ring closure of aminodiols towards
chiral 1,3-heterocycles.20,21
Our present aim was the comparative synthesis of chiral amino-
diol-based monoterpene nucleosides from pinane-based aminodiol
enantiomers and their starting material epoxy alcohols following
two strategies: linear synthesis of the base component on the
2-aminomethyl substituent of the pinane system and regioselec-
tive ring opening of the spiro-oxirane ring with various purine
and pyrimidine bases.
During the past decade, the discovery of carbocyclic nucleosides
possessing potent antiviral and antitumour activity has led to an
increasing demand for the production of new chiral, alicyclic nucle-
oside analogues.1,2 Bioisosteric replacement of the oxygen in the su-
gar moiety with a methylene unit makes these compounds more
resistant to hydrolysis without a loss of the biological activity. The
first-generation carbocyclic compounds were similar to the adeno-
sine analogue natural aristeomycin 1 and neplanocin A 2, containing
a cyclopentane or cyclopentene ring and two or three hydroxy
groups on the ring, one of them typically as a hydroxymethyl substi-
tuent.1,3–8 In recent years, conformationally locked, bicyclic and
tricyclic analogues have also been successfully prepared.1b,9–12
Some of these compounds possess noteworthy pharmacological
activity, such as the antiviral North-methanocarbathymidine
(N-MCT, 5) or the species-independent A3 receptor-selective agonist
(N)-methanocarba-adenosine 5’-uronamides 6.12–18 The latter com-
pounds clearly show that the primary hydroxy group is not essential
for the biological activity (see Fig. 1).
The synthesis of carbanucleosides may follow different strate-
gies: the convergent attachment of an intact heterocyclic base with
an appropriately functionalized carbocyclic ring by substitution
(e.g., through an activated hydroxy group) or by addition (ring
opening of an epoxy function). Linear construction of the heterocy-
cle from an amine substituent on the carbocycle is also possible,
though often less successful strategy.1,2
As part of our systematic studies on 1,3-difunctional chiral
monoterpenic building blocks,19 we recently reported the synthe-
sis of a (+)- and (ꢀ)-2-aminomethyl-6,6-dimethylbicyclo[3.1.1]
heptane-2,3-diol-type [(+)-10 and (ꢀ)-10)] aminodiol library,
2. Results and discussion
Aminodiols (+)-10 and (ꢀ)-10 were synthesized from commer-
cially available (+)- and (ꢀ)-
a-pinene by modification of literature
methods.20,22–24 Epoxidation of monoterpenes (+)-7 and (ꢀ)-7 with
MCPBA, followed by allylic rearrangement and subsequent epoxi-
dation resulted in the well-known stereohomogeneous epoxy alco-
hols (+)-8 and (ꢀ)-8.22–25 Synthesis of (+)-10 and (ꢀ)-10 was
previously reported by the aminolysis of (+)-8 and (ꢀ)-8 with pri-
mary or secondary amines, followed by reductive debenzylation,
with moderate overall yields.20 In our present work, the reactions
of (+)-8 and (ꢀ)-8 with NaN3 in refluxing EtOH/H2O in the presence
of a catalytic amount of NH4Cl produced azidodiols (+)-9 and (ꢀ)-9
in a regioselective reaction (Scheme 1).26,27 Catalytic reduction of
(+)-9 and (ꢀ)-9 over Pd/C resulted in primary aminodiols (+)-10
and (ꢀ)-10 in excellent yield (78% overall yield from 8).
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
In the present experiments, apart from 11–13, all of the reactions were carried
out on both enantiomers, although only one of them is presented in the Schemes.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.054

832
Z. Szakonyi, F. Fülöp / Tetrahedron: Asymmetry 21 (2010) 831–836
N
NH2
N
N
N
HO
NH2
NH2
N
N
N
HO
HO
HO
N
N
N
N
N
HO
OH
HO
Cyclobut A 3
HO
OH
aristeomycin 1
neplanocin A 2
N
N
H
N
H
N
O
O
NHR1
NH2
N
HO
NH
MeHN
N
N
N
N
O
HO
OH
HO
OH
HO
R2
F
noraristeomycin 4
N-MCT 5
6
Figure 1. Pharmacologically active nucleoside analogues bearing an aminodiol moiety.
(ꢀ)-11. Azaderivative (+)-12 was then obtained by reaction be-
tween (ꢀ)-11 and 4-chlorobenzenediazonium generated in situ.
Reduction of (+)-12 with Zn in acetic acid gave triaminopyrimidi-
nyl derivative (+)-13. When (+)-13 was treated with triethylortho-
formate in hydrochloric acid, instead of the expected 14, only a
mixture of inseparable products was obtained, probably due to
the inter- or intramolecular reactions of diol and aromatic amino
groups and triethyl orthoformate.
We decided to repeat the above synthesis from 5-amino-4,6-
dichloropyrimidine to reduce the possibility of side-reactions.17
Condensation of (ꢀ)-10 and (+)-10 with 5-amino-4,6-dichloropy-
rimidine in refluxing n-BuOH containing Et3N afforded (ꢀ)-15
and (+)-15. Then, to form the imidazole ring of the purine ana-
logues, (ꢀ)-15 and (+)-15 were treated with triethyl orthoformate
in hydrochloric acid to give (ꢀ)-16 and (+)-16. Besides imidazole
ring formation, cis positioned hydroxy groups reacted with the ex-
cess of orthoformate to afford unique chiral orthoesters (ꢀ)-16 and
(+)-16. Compound (ꢀ)-16 and (+)-16 were converted into the
hydroxy derivatives (ꢀ)-17 and (+)-17 by treatment with 0.25 M
3 steps
O
OH
(-)-8
(-)-7
i
N3
NH2
OH
OH
ii
OH
OH
(-)-10
(-)-9
Scheme 1. Reagents and conditions: (i) 2.0 equiv NaN3, 20% NH4Cl, EtOH/H2O,
reflux, 36 h, 85%; (ii) 10% Pd/C, MeOH, 1 atm H2, rt, 6 h, 92%.
In our first experiment, we attempted the linear synthesis of the
base component from aminodiol (ꢀ)-10 (Scheme 2).17 Condensa-
tion of (ꢀ)-10 with 2-amino-4,6-dichloropyrimidine resulted in
Cl
N
Cl
Cl
N
NH
OH
N
NH
OH
N
NH2
OH
N
N
NH2
NH2
i
ii
OH
(-)-11
OH
(+)-12
OH
(-)-10
iii
Cl
H2N
NH
Cl
N
N
N
N
N
N
OH
OH
OH
NH2
iv
NH2
OH
(+)-13
14
Scheme 2. Reagents and conditions: (i) 2-amino-4,6-dichloropyrimidine, Et3N, n-BuOH, reflux, 24 h, 63%; (ii) 4-chloroaniline, HCl, H2O, NaNO2, NaOAc, HOAc, overnight, 91%;
(iii) Zn powder, HOAc, H2O/EtOH, reflux, 3 h, 73%; (iv) triethyl orthoformate, 12 M HCl, rt, overnight.

Z. Szakonyi, F. Fülöp / Tetrahedron: Asymmetry 21 (2010) 831–836
833
Cl
N
Cl
N
H2N
NH
N
N
O
NH2
OH
N
N
OH
i
ii
OEt
O
OH
OH
(-)-10
(-)-15
(-)-16
iii
N
OH
OH
N
N
N
N
N
O
N . HCl
N
OH
iv
OEt
OH
O
(-)-17
(-)-18
Scheme 3. Reagents and conditions: (i) 5-amino-4,6-dichloropyrimidine, Et3N, n-BuOH, reflux, 24 h, 59%; (ii) triethyl orthoformate, 12 M HCl, rt, 36 h, 82%; (iii) 0.25 M NaOH,
reflux, 6 h, 85%; (iv) 10% HCl, rt, 12 h, 67%.
NaOH at reflux for 6 h. Orthoesters (ꢀ)-17 and (+)-17 were then
successfully hydrolysed to the final nucleoside analogues (ꢀ)-18
and (+)-18 by treatment with hydrochloric acid (Scheme 3).
An alternative synthesis of monoterpenic nucleoside analogues
was carried out by a regioselective ring opening of the spiro-oxi-
rane ring of (ꢀ)-8 and (+)-8 with various purine and pyrimidine
bases, resulting in (ꢀ)-19–21 and (+)-19–21.28 Although the yields
of the reactions were moderate, the desired nucleosides were ob-
tained in a single-step reaction. The limitation of this method is
that the yield dropped dramatically when bases with a strong elec-
tron-withdrawing substituent on the heterocyclic ring were ap-
plied, for example, the reaction failed when 5-fluorouracil was
used (Scheme 4).
the synthesis of sterically constrained bicyclic nucleoside ana-
logues. Both epoxy alcohols (ꢀ)-8 and (+)-8 and aminodiols (ꢀ)-
10 and (+)-10 are readily available on a gram scale with high enan-
tiopurity. Synthesis of the desired carbonucleosides has been
successfully performed via two pathways. Aminodiols (ꢀ)-10 and
(+)-10 were transformed by linear synthesis to purine-type nucleo-
sides (ꢀ)-16–18 and (+)-16–18 through pyrimidine intermediates.
Regioselective ring opening of the oxirane ring of (ꢀ)-8 and (+)-
8 resulted in adenine-, cytosine- and uracil-based carbocyclic
nucleosides (ꢀ)-19–21 and (+)-19–21 in single-step syntheses.
The reaction failed when 5-fluorouracil (a nucleoside base with a
strong electron-withdrawing substituent on the heterocyclic ring)
was applied.
3. Conclusions
4. Experimental
Pinane-based chiral epoxy alcohols (ꢀ)-8 and (+)-8 and amin-
odiols (ꢀ)-10 and (+)-10 are highly valuable building blocks for
1H and 13C NMR spectra were recorded on a Bruker Avance DRX
400 spectrometer at 400.13 MHz (1H) and 100.61 MHz (13C) [d = 0
NH2
N
O
NH2
N
N
N
N
N
OH
OH
OH
OH
(-)-20
i
i
(-)-19
O
i
OH
i
(-)-8
OH
OH
F
N
N
O
O
N
N
OH
OH
OH
OH
(-)-21
22
Scheme 4. Reagents and conditions: (i) 1.5 equiv base, 2.0 equiv dry K2CO3, dry DMF, 100 °C, 48 h, 19: adenine (57%), 20: cytosine (60%), 21: uracil (49%), 22: 5-fluorouracil.

834
Z. Szakonyi, F. Fülöp / Tetrahedron: Asymmetry 21 (2010) 831–836
(TMS)] in CDCl3, D2O or DMSO-d6 in a 5-mm tube. Chemical shifts
are expressed in ppm (d) relative to TMS as the internal reference. J
values are given in hertz. Microanalyses were performed on a Per-
kin–Elmer 2400 elemental analyser. Optical rotations were ob-
tained with a Perkin–Elmer 341 polarimeter. Melting points were
determined on a Kofler apparatus and are uncorrected. Chromato-
graphic separations were carried out on Merck Kieselgel 60 (230–
400 mesh ASTM). Reactions were monitored with Merck Kieselgel
60 F254-precoated TLC plates (0.25 mm thickness).
4.3. (1R,2S,3S,5R)-2-[(2-Amino-6-chloropyrimidin-4-
ylamino)methyl]-6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol
(ꢀ)-11
A mixture of aminodiol (ꢀ)-10 (0.370 g, 2.0 mmol) and 2-amino-
4,6-dichloropyrimidine(0.420 g, 2.56 mmol)indryEt3N(2.3 mLand
n-BuOH (11.0 mL) was refluxed under argon for 24 h. The solvent
was then evaporated off under reduced pressure and the residue
was purified by flash chromatography on a silica gel column (tolu-
ene/EtOH = 9/1), resulting in a white crystalline product. Isolated
The enantiomeric purities of the prepared epoxy alcohols and
azidodiols were determined by means of GC measurements involv-
ing direct separation of the enantiomers on a CHIRASIL-DEX CB col-
umn (2500 ꢁ 0.25 mm I.D.) and were found to be >98%.
compound: 0.392 g (63%); mp: 159–162 °C; ½a D20
¼ ꢀ22:0 (c 0.1,
ꢂ
MeOH); 1H NMR (DMSO-d6) d (ppm): 1.05 (3H, s), 1.18 (3H, s), 1.37
(1H, d, J = 10.1 Hz), 1.55 (1H, ddd, J = 2.2, 5.1, 13.8 Hz), 1.78–1.84
(1H, m), 1.96 (1H, t, J = 5.7 Hz), 2.03–2.11 (1H, m), 2.29–2.39 (1H,
m), 3.25 (1H, dd, J = 5.9, 13.4 Hz), 3.36 (1H, dd, J = 5.4, 13.4 Hz),
3.85 (1H, dt, J = 5.8, 9.0 Hz), 4.61 (1H, s), 5.16 (1H, d, J = 5.9 Hz),
5.88 (1H, s), 6.26 (2H, br s), 6.96 (1H, br s); 13C NMR (DMSO-d6)
d (ppm): 24.7, 28.2, 28.5, 38.7, 39.1, 40.9, 49.7, 49.9, 65.7, 75.8,
93.3, 157.6, 163.5, 165.1. Anal. Calcd for C14H21ClN4O2 (312.80): C,
53.76; H, 6.77; N, 17.91. Found: C, 53.52; H, 6.97; N, 17.65.
All thechemicals and solvents wereused assupplied. (ꢀ)-(1S,5S)-
and (+)-(1R,5R)-a-pinene are commercially available; epoxy alco-
hols (ꢀ)-8 and (+)-8 were prepared by a literature method, and were
identical with those reported in the literature.23,25
4.1. (1R,2S,3S,5R)-2-(Azidomethyl)-6,6-dimethylbicyclo-
[3.1.1]heptane-2,3-diol (ꢀ)-9
To a solution of epoxy alcohol (ꢀ)-8 (1.92 g, 11.4 mmol) in EtOH
(50 mL) and water (3.4 mL), NaN3 (1.48 g, 22.8 mmol) and NH4Cl
(0.122 g, 2.3 mmol) were added. The reaction mixture was refluxed
for 36 h, and the EtOH was then evaporated off. The resulting mix-
ture was dissolved in water (100 mL) and extracted with CHCl3
(3 ꢁ 100 mL). The combined organic layer was dried (Na2SO4)
and evaporated, and the yellow oily crude product obtained was
crystallized with n-hexane, resulting in a pale-yellow crystalline
product.29 Isolated compound: 2.05 g (85%); mp: 70–73 °C;
4.4. (1R,2S,3S,5R)-2-[(2-Amino-6-chloro-5-(4-chlorophenyl-
diazenyl)pyrimidin-4-ylamino)methyl]-6,6-dimethyl-
bicyclo[3.1.1]heptane-2,3-diol (+)-12
4-Chloroaniline (0.123 g, 0.96 mmol) in 3 M HCl (0.77 mL)
was treated at 0 °C with NaNO2 (0.069 g, 0.99 mmol) in water
(0.77 mL). The diazonium salt obtained was added to a mixture of
(ꢀ)-11 (0.260 g, 0.83 mmol), NaOAc (1.53 g), AcOH (3.84 mL) and
water (3.84 mL), and was stirred overnight at room temperature.
The resulting precipitate was filtered off and washed with cold
water until neutral, to obtain yellow crystals. Isolated compound:
½
a 2D0
ꢂ
¼ ꢀ11:0 (c 0.5, MeOH); 1H NMR (CDCl3) d (ppm): 0.92 (3H,
s), 1.28 (3H, s), 1.44 (1H, d, J = 10.4 Hz), 1.67 (1H, ddd, J = 2.4, 5.5,
14.1 Hz), 1.91–1.98 (1H, m), 2.10 (1H, t, J = 5.7 Hz), 2.20–2.31
(1H, m), 2.43–2.53 (1H, m), 2.57 (1H, s), 3.27 (1H, d, J = 12.3 Hz),
3.34 (1H, d, J = 12.3 Hz), 3.64 (1H, s), 4.09–4.17 (1H, m); 13C NMR
(CDCl3) d (ppm): 24.5, 28.0, 28.1, 37.5, 39.0, 40.9, 50.4, 61.4, 66.6,
76.0. Anal. Calcd for C10H17N3O2 (211.26): C, 56.85; H, 8.11; N,
19.89. Found: C, 56.98; H, 8.27; N, 19.63.
0.340 g (91%); mp: 249–253 °C; ½a D20
ꢂ
¼ þ24:0 (c 0.1, MeOH); 1H
NMR (DMSO-d6) d (ppm): 1.00 (3H, s), 1.18 (3H, s), 1.40 (1H, d,
J = 10.2 Hz), 1.54–1.63 (1H, m), 1.78–1.87 (1H, m), 1.89–1.95 (1H,
m), 2.05–2.14 (1H, m), 2.31–2.42 (1H, m), 3.48 (1H, dd, J = 4.1,
13.4 Hz), 3.63 (1H, dd, J = 5.9, 13.4 Hz), 3.87–3.95 (1H, m), 4.68
(1H, s), 5.29 (1H, br d, J = 5.4 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.75
(2H, d, J = 8.8 Hz), 10.58 (1H, br t, J = 4.7 Hz); 13C NMR (DMSO-d6)
d (ppm): 24.7, 28.4, 28.6, 38.6, 39.1, 40.9, 50.2, 50.5, 66.1, 74.8,
119.8, 123.7, 130.3, 134.2, 151.6, 156.1, 161.9, 165.5. Anal. Calcd
for C20H24Cl2N6O2 (451.35): C, 53.22; H, 5.36; N, 18.62. Found: C,
53.43; H, 5.62; N, 18.31.
The (1S,2R,3R,5S)-enantiomer (+)-9 was synthesized analo-
gously to (ꢀ)-9; ½a D20
¼ þ11:0 (c 0.5, MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the (1R,2S,3S,5R)-enan-
tiomer. Anal. Calcd for C10H17N3O2 (211.26): C, 56.85; H, 8.11; N,
19.89. Found: C, 57.04; H, 8.19; N, 19.65.
4.2. (1R,2S,3S,5R)-2-Aminomethyl-6,6-dimethylbicyclo[3.1.1]
heptane-2,3-diol (ꢀ)-10
4.5. (1R,2S,3S,5R)-2-[(2,5-Diamino-6-chloropyrimidin-4-
ylamino)methyl]-6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol
(+)-13
To a suspension of palladium-on-carbon (5% Pd/C, 0.40 g) in
MeOH (30 mL) was added azidodiol (ꢀ)-9 (1.05 g, 5.0 mmol) in
MeOH (15 mL), and the resulting mixture was stirred under a H2
atmosphere (1 atm) at room temperature. When the reaction was
complete, as indicated by TLC, the solution was filtered through a
Celite pad and the solvent was removed, affording a colourless oily
product (ꢀ)-10, which crystallized upon standing at ca. 4 °C. The
crystalline product was recrystallized from n-hexane and was
found to be identical with that reported in the literature.20 Isolated
A mixture of (+)-12 (0.433 g, 0.96 mmol), Zn powder (0.530 g,
8.12 mmol), AcOH (0.2 mL), water (6.0 mL) and EtOH (6.0 mL) was
refluxed under argon for 3 h. The reaction mixture was then filtered,
the filtrate was evaporated down under reduced pressure and the
crude reaction mixture was purified by p-TLC (EtOAc), resulting in
(+)-13 as a brown solid. Isolated compound: 0.230 g (73%); mp:
171–174 °C; ½a 2D0
ꢂ
¼ þ19:0 (c 0.5, MeOH); 1H NMR (DMSO-d6) d
compound: 0.85 g (92%); mp 61–63 °C; ½a D20
ꢂ
¼ ꢀ7:5 (c 0.25, EtOH,
(ppm): 1.02 (3H, s), 1.19 (3H, s), 1.37 (1H, d, J = 9.8 Hz), 1.55 (1H,
ddd, J = 2.3, 5.1, 13.7 Hz), 1.77–1.85 (1H, m), 1.94–1.99 (1H, m),
2.02–2.11 (1H, m), 2.30–2.39 (1H, m), 3.39 (2H, d, J = 5.6 Hz), 3.84–
3.92 (1H, m), 4.84 (1H, br s), 4.96 (1H, br d, J = 6.3 Hz), 5.58 (2H, br
s), 6.30 (1H, t, J = 5.5 Hz); 13C NMR (DMSO-d6) d (ppm): 24.1, 27.7,
28.0, 38.3, 38.6, 40.4, 49.3, 50.0, 65.2, 75.3, 113.2, 142.7, 156.1,
157.0. Anal. Calcd for C14H22ClN5O2 (327.81): C, 51.29; H, 6.76; N,
21.36. Found: C, 51.46; H, 6.99; N, 21.01.
lit.:20 ꢀ7.0, c = 0.25, EtOH); Anal. Calcd for C10H19NO2 (185.26): C,
64.83; H, 10.34; N, 7.56. Found: C, 65.01; H, 10.49; N, 7.28.
The (1S,2R,3R,5S)-enantiomer (+)-10 was synthesized analo-
gously to (ꢀ)-10, ½a D20
¼ þ7:0 (c 0.25, EtOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the (1R,2S,3S,5R)-enan-
tiomer. Anal. Calcd for C10H19NO2 (185.26): C, 64.83; H, 10.34; N,
7.56. Found: C, 64.63; H, 10.51; N, 7.22.

Z. Szakonyi, F. Fülöp / Tetrahedron: Asymmetry 21 (2010) 831–836
835
4.6. (1R,2S,3S,5R)-2-[(5-Amino-6-chloropyrimidin-4-ylamino)
methyl]-6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol (ꢀ)-15
(1H, br s); 13C NMR (DMSO-d6) d (ppm): 15.8, 23.9, 25.2, 27.2, 33.4,
38.6, 40.9, 46.1, 51.0, 61.2, 72.7, 86.5, 115.7, 123.5, 141.8, 145.8,
149.4, 157.0. Anal. Calcd for C18H24N4O4 (360.41): C, 59.99; H,
6.71; N, 15.55. Found: C, 60.20; H, 6.86; N, 15.31.
A mixture of aminodiol (ꢀ)-10 (0.370 g, 2.0 mmol) and 5-amino-
4,6-dichloropyrimidine (0.420 g, 2.56 mmol) in dry Et3N (2.3 mL)
and n-BuOH (11.0 mL) was refluxed under argon for 24 h. The sol-
vent was then evaporated off under reduced pressure and the
residue was purified by flash chromatography on a silica gel column
(toluene/EtOH = 9/1), resulting in a white crystalline product.
The (1S,2R,3R,5S)-enantiomer (+)-17 was synthesized analo-
gously to (ꢀ)-17; ½a D20
¼ þ17:0 (c 0.1 MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the (1R,2S,3S,5R)-enan-
tiomer. Anal. Calcd for C18H24N4O4 (360.41): C, 59.99; H, 6.71; N,
15.55. Found: C, 60.17; H, 6.89; N, 15.39.
Isolated compound: 0.388 g (59%); mp: 203–205 °C; ½a D20
¼
ꢂ
ꢀ15:0 (c 0.1, MeOH); 1H NMR (DMSO-d6) d (ppm): 1.05 (3H, s),
1.18 (3H, s), 1.37 (1H, d, J = 10.1 Hz), 1.51–1.60 (1H, m), 1.78–
1.86 (1H, m), 1.93–1.99 (1H, m), 2.03–2.11 (1H, m), 2.31–2.39
(1H, m), 3.47 (1H, dd, J = 5.9, 13.4 Hz), 3.58 (1H, dd, J = 5.4,
13.4 Hz), 3.91 (1H, dt, J = 9.5, 11.2 Hz), 4.56 (1H, s), 5.09 (1H, br
s), 5.16 (1H, d, J = 6.3 Hz), 6.58 (1H, t, J = 5.4 Hz), 7.70 (1H, s); 13C
NMR (DMSO-d6) d (ppm): 24.6, 28.3, 28.5, 38.7, 39.1, 40.9, 49.7,
50.7, 65.6, 75.9, 137.5, 146.3, 153.1, 153.3. Anal. Calcd for
C14H21ClN4O2 (312.80): C, 53.76; H, 6.77; N, 17.91. Found: C,
53.85; H, 6.98; N, 17.61.
4.9. (1R,2S,3S,5R)-2-[(6-Hydroxy-9H-purin-9-yl)methyl]-6,6-
dimethylbicyclo[3.1.1]heptane-2,3-diol hydrochloride (ꢀ)-18
A mixture of (ꢀ)-17 (0.215 g, 0.60 mmol) and 3 M HCl (10.0 mL)
was stirred overnight at room temperature. The reaction mixture
was then concentrated under reduced pressure until dryness,
resulting in (ꢀ)-18 as white crystals in >98% purity (based on
NMR measurement). Isolated compound: 0.136 g (67%); mp:
304–307 °C; ½a 2D0
ꢂ
¼ ꢀ19:0 (c 0.1, MeOH); 1H NMR (DMSO-d6) d
(ppm): 1.18 (3H, s), 1.19 (3H, s), 1.33 (1H, d, J = 9.8 Hz), 1.57 (1H,
dd, J = 5.4, 2.3 Hz), 1.64 (H, t, J = 5.8 Hz), 1.81–1.87 (1H, m), 2.00–
2.08 (1H, m), 2.32–2.42 (1H, m), 4.07 (1H, dd, J = 5.6, 9.7 Hz),
4.20 (2H, dd, J = 14.0, 23.6 Hz), 8.20 (1H, s), 8.62 (1H, s), 12.72
(1H, br s); 13C NMR (DMSO-d6) d (ppm): 24.4, 28.3, 28.4, 38.6,
39.1, 40.9, 49.3, 52.9, 65.0, 74.9, 119.5, 141.5, 147.9, 148.7, 155.4.
Anal. Calcd for C15H21ClN4O3 (340.81): C, 59.20; H, 6.62; N,
18.41. Found: C, 59.36; H, 6.88; N, 18.20.
The (1S,2R,3R,5S)-enantiomer (+)-15 was synthesized analo-
gously to (ꢀ)-15; ½a D20
¼ þ14:5 (c 0.1, MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the 1R,2S,3S,5R enantio-
mer. Anal. Calcd for C14H21ClN4O2 (312.80): C, 53.76; H, 6.77; N,
17.91. Found: C, 53.06; H, 6.94; N, 17.56.
4.7. (1R,2S,6S,8R)-2-[(6-Chloro-9H-purin-9-yl)methyl]-9,9-
dimethyl-4-ethoxy-3,5-dioxatricyclo[6.1.1.02,6]decane (ꢀ)-16
The (1S,2R,3R,5S)-enantiomer (+)-18 was synthesized analo-
gously to (ꢀ)-18; ½a D20
¼ þ17:0 (c 0.1 MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the 1R,2S,3S,5R enantio-
mer. Anal. Calcd for C15H21ClN4O3 (340.81): C, 59.20; H, 6.62; N,
18.41. Found: C, 59.51; H, 6.93; N, 18.26.
A mixture of (ꢀ)-15 (0.20 g, 0.64 mmol), triethyl orthoformate
(3.7 mL) and 12 M HCl (0.19 mL) was stirred overnight under argon
at room temperature. The reaction mixture was then concentrated
under reduced pressure until dryness and the residue was purified
by p-TLC (eluent EtOAc). Compound 16 was isolated as an oil.
4.10. General procedure for the ring opening of epoxy alcohols
(ꢀ)-8 and (+)-8 with nucleoside bases
Isolated compound: 0.195 g (81%); oil; ½a D20
¼ ꢀ124:0 (c 0.155,
ꢂ
MeOH); 1H NMR (DMSO-d6) d (ppm): 1.19–1.24 (9H, m), 1.24
(3H, s), 1.25 (1H, d, J = 10.2 Hz), 1.68 (H, t, J = 5.9 Hz), 1.92–2.12
(4H, m), 2.32–2.41 (1H, m), 3.62 (2H, ddd, J = 2.7, 9.6, 16.6 Hz),
4.39 (1H, d, J = 7.6 Hz), 4.53 (1H, d, J = 14.2 Hz), 4.82 (1H, d,
J = 14.2 Hz), 5.90 (1H, s), 8.39 (1H, s), 8.79 (1H, s); 13C NMR
(DMSO-d6) d (ppm): 15.5, 23.8, 25.2, 26.8, 33.3, 40.2, 45.9, 51.4,
52.5, 61.7, 73.1, 86.6, 116.1, 131.4, 147.5, 148.3, 152.1, 153.1. Anal.
Calcd for C18H23ClN4O3 (378.85): C, 57.07; H, 6.12; N, 14.79. Found:
C, 57.40; H, 6.35; N, 14.51.
A mixture of the corresponding base (1.4 mmol, (ꢀ)-19 and (+)-
19: adenine, (ꢀ)-20 and (+)-20: cytosine, (ꢀ)-21 and (+)-21: uracil),
K2CO3 (0.260 g, 1.89 mmol), and 18-crown-6 (0.150 g, 0.55 mmol)
was suspended in anhydrous DMF (5.0 mL). A solution of (ꢀ)-8 or
(+)-8 (0.160 g, 0.94 mmol) in anhydrous DMF was added to the mix-
ture under argon at room temperature. After stirring for 0.5 h, the
mixture was heated at 100 °C for 48 h. After filtration and evapora-
tion, the crude product was purified by flash chromatography on a
silica gel column (CHCl3/MeOH = 9/1), which resulted in a white
crystalline product.
The (1S,2R,3R,5S)-enantiomer (+)-16 was synthesized analo-
gously to (ꢀ)-16; ½a D20
¼ þ119:0 (c 0.155, MeOH); all the spectro-
ꢂ
scopic data and the mp were similar to those for the 1R,2S,3S,5R
enantiomer. Anal. Calcd for C18H23ClN4O3 (378.85): C, 57.07; H,
6.12; N, 14.79. Found: C, 57.39; H, 6.28; N, 14.68.
4.10.1. (1R,2S,3S,5R)-2-[(6-Amino-9H-purin-9-yl)methyl]-6,6-
dimethylbicyclo[3.1.1]heptane-2,3-diol (ꢀ)-19
Isolated compound: 0.165 g (57%); mp: 236–239 °C; ½a D20
¼
ꢂ
4.8. (1R,2S,6S,8R)-2-[(6-Hydroxy-9H-purin-9-yl)methyl]-9,9-
dimethyl-4-ethoxy-3,5-dioxatricyclo[6.1.1.02,6]decane (ꢀ)-17
ꢀ19:0 (c 0.125, MeOH ee 98%); 1H NMR (DMSO-d6) d (ppm): 1.15
(3H, s), 1.22 (3H, s), 1.30 (1H, d, J = 9.9 Hz), 1.50–1.61 (2H, m),
1.77–1.86 (1H, m), 1.95–2.05 (1H, m), 2.31–2.43 (1H, m), 4.05
(1H, dt, J = 5.9, 11.8 Hz), 4.12 (1H, dd, J = 14.4, 16.1 Hz), 4.62 (1H,
s), 5.29 (1H, d, J = 6.4 Hz), 7.14 (2H, s), 8.05 (1H, s), 8.13 (1H, s);
13C NMR (DMSO-d6) d (ppm): 23.7, 27.4, 27.5, 37.8, 38.3, 40.0,
48.3, 51.1, 64.3, 74.3, 118.0, 142.2, 150.4, 152.2, 155.8. Anal. Calcd
for C15H21N5O2 (303.36): C, 59.39; H, 6.98; N, 23.09. Found: C,
59.61; H, 7.23; N, 22.87.
A mixture of (ꢀ)-16 (0.15 g, 0.164 mmol) and 0.25 M NaOH
(5.1 mL) was refluxed for 5 h, whereafter the reaction mixture was
cooled and the solvent was removed under reduced pressure until
dryness, and the residue was purified by p-TLC (eluent EtOAc) to
afford (ꢀ)-17 as white crystals. Isolated compound: 0.121 g (85%);
mp: 280–284 °C; ½a D20
ꢂ
¼ ꢀ18:0 (c 0.1, MeOH); 1H NMR (DMSO-d6)
d (ppm): 1.19 (6H, s overlapped with t), 1.24 (3H, s), 1.25 (1H, d,
J = 10.2 Hz), 1.69 (H, t, J = 5.4 Hz), 1.83–1.95 (3H, m), 2.03–2.13
(1H, m), 2.29–2.38 (1H, m), 3.58 (2H, ddd, J = 2.1, 7.1, 14.2 Hz),
4.41 (1H, d, J = 14.4 Hz), 4.53 (1H, d, J = 7.7 Hz), 4.61 (1H, d,
J = 14.4 Hz), 6.00 (1H, s), 7.88 (1H, s), 8.09 (1H, d, J = 3.8 Hz), 12.29
The (1S,2R,3R,5S)-enantiomer (+)-19 was synthesized analo-
gously to (ꢀ)-19; ½a D20
¼ þ21:0 (c 0.1, MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the (1R,2S,3S,5R)-enan-
tiomer. Anal. Calcd for C15H21N5O2 (303.36): C, 59.39; H, 6.98; N,
23.09. Found: C, 59.53; H, 7.17; N, 22.78.

836
Z. Szakonyi, F. Fülöp / Tetrahedron: Asymmetry 21 (2010) 831–836
4.10.2. 4-Amino-1-[((1R,2S,3S,5R)-2,3-dihydroxy-6,6-
dimethylbicyclo[3.1.1]heptan-2-yl)methyl]pyrimidin-2(1H)-
one (ꢀ)-20
References
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49, 1140–1148.
Isolated compound: 0.160 g (60%); mp: 259–260 °C; ½a D20
¼
ꢂ
ꢀ17:0 (c 0.125, MeOH); 1H NMR (DMSO-d6) d (ppm): 1.07 (3H, s),
1.18 (3H, s), 1.31 (1H, d, J = 9.9 Hz), 1.51 (1H, ddd, J = 2.2, 5.5,
13.8 Hz), 1.75–1.85 (2H, m), 1.98–2.07 (1H, m), 2.27–2.38 (1H, m),
3.70 (2H, dd, J = 14.1, 15.5 Hz), 4.00 (1H, dt, J = 5.7, 9.5 Hz), 4.64
(1H, s), 5.11 (1H, d, J = 6.6 Hz), 5.59 (1H, d, J = 7.1 Hz), 6.91 (2H, br
d, J = 24.7 Hz), 7.52 (1H, d, J = 7.4 Hz); 13C NMR (DMSO-d6) d
(ppm): 23.2, 27.4, 27.5, 37.8, 38.3, 40.0, 48.8, 55.5, 64.0, 75.3, 92.3,
147.8, 157.0, 165.7. Anal. Calcd for C14H21N3O3 (279.33): C, 60.20;
H, 7.58; N, 15.04. Found: C, 60.33; H, 7.87; N, 15.86.
The (1S,2R,3R,5S)-enantiomer (+)-20 was synthesized analo-
gously to (ꢀ)-20; ½a D20
¼ þ20:0 (c 0.1, MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the 1R,2S,3S,5R enantio-
mer. Anal. Calcd for C14H21N3O3 (279.33): C, 60.20; H, 7.58; N,
15.04. Found: C, 60.42; H, 7.77; N, 14.79.
ˇ
´
ˇ
´
9. Sa˘la, M.; Hrebabecky, H.; Dracínsky, M.; Masojídková, M.; De Palma, A. M.;
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15. Kojima, H.; Kozaki, A.; Iwata, M.; Ando, T.; Kitade, Y. Bioorg. Med. Chem. 2008,
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4.10.3. 1-[((1R,2S,3S,5R)-2,3-Dihydroxy-6,6-dimethylbicyclo[3.1.1]-
heptan-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione (ꢀ)-21
Isolated compound: 0.131 g (49%); mp: 235–237 °C; ½a D20
¼
ꢂ
ꢀ28:0 (c 0.125, MeOH ee >98%); 1H NMR (DMSO-d6) d (ppm):
1.05 (3H, s), 1.19 (3H, s), 1.32 (1H, d, J = 10.1 Hz), 1.51 (1H, dd,
J = 5.0, 13.3 Hz), 1.76–1.85 (2H, m), 2.02–2.11 (1H, m), 2.29–2.40
(1H, m), 3.62 (1H, d, J = 13.8 Hz), 3.73 (1H, d, J = 13.8 Hz), 3.98
(1H, dt, J = 5.7, 9.9 Hz), 4.43 (1H, s), 5.35 (1H, d, J = 6.4 Hz), 5.46
(1H, dd, J = 2.1, 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz), 11.12 (1H, s); 13C
NMR (DMSO-d6) d (ppm): 23.2, 27.4, 27.5, 37.7, 38.2, 39.9, 48.7,
54.2, 64.0, 75.0, 99.6, 147.6, 151.8, 163.7. Anal. Calcd for
C14H20N1O4 (280.32): C, 59.99; H, 7.19; N, 9.99. Found: C, 60.28;
H, 7.51; N, 9.82.
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Tanaka, H. Tetrahedron 2009, 65, 8007–8013.
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24. Scheidl, F. Synthesis 1982, 728.
The (1S,2R,3R,5S)-enantiomer (+)-21 was synthesized analo-
gously to (ꢀ)-21; ½a D20
¼ þ22:0 (c 0.1, MeOH); all the spectroscopic
ꢂ
data and the mp were similar to those for the (1R,2S,3S,5R)-enan-
tiomer. Anal. Calcd for C14H20N1O4 (280.32): C, 59.99; H, 7.19; N,
9.99. Found: C, 60.36; H, 7.41; N, 9.73.
25. Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.; Staab, E.; Willt, B. J. Am. Chem.
Soc. 1989, 111, 203–212.
26. Griesbeck, A. G.; Lex, J.; Saygin, K. M.; Steinwascher, J. Chem. Commun. 2000,
2205–2206.
Acknowledgements
27. Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. J. Org. Chem. 2007, 72, 8786–8790.
28. Wang, F.; Yang, Z.-J.; Jin, H.-W.; Zhang, L.-R.; Zhang, L.-H. Tetrahedron:
Asymmetry 2007, 18, 2139–2146.
We are grateful to the Hungarian Research Foundation (OTKA
No. NF69316 and NK81371) for the financial support. We thank
E. Bakos for her assistance in the experimental work.
29. Compound
9 was first reported in Ref. 26, but no physical or analytical
characterization was given.