A New and Versatile Synthesis of 1,3-Dioxan-5-yl-pyrimidine and Purine Nucleoside Analogues

Article abstract of DOI:10.1055/s-0034-1380112

1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new and versatile synthetic strategy. These analogues were synthesized via nucleophilic addition of the selected nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving group in position 5. In particular cis and trans isomers of purine/pyrimidine nucleosides and their halogenated homologues were obtained. NMR experiments, carried out on the cis isomers, led to assignment of an equatorial orientation to the 2-hydroxymethyl group and axial orientation to the nucleobase in position 5 of the 1,3-dioxane. The trans isomers showed a diequatorial orientation of these groups. These assignments were confirmed by X-ray crystallographic studies.

Full text of DOI:10.1055/s-0034-1380112

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 625–630
letter
625
C. Sorbi et al.
Letter
Synlett
A New and Versatile Synthesis of 1,3-Dioxan-5-yl-pyrimidine and
Purine Nucleoside Analogues
Claudia Sorbia
O
Adolfo Prandia
O
O
OEt
OEt
HO
O
O
O
Br
+
base
Umberto M. Battistia
Silvia Franchinia
Andrea Corniab
Jan Balzarinic
O
ONa
OTs
- all 1,3-dioxane based nucleoside analogues were obtained
- both trans and cis diastereoisomers were isolated and structurally characterized
Lak Shin Jeongd
Sang Kook Leed
Jayoung Songd
Livio Brasili*a
a Department of Life Sciences, University of Modena & Reggio Emilia, Via G. Campi 183, 41125 Modena, Italy
livio.brasili@unimore.it
b Department of Chemical and Geological Sciences, University of Modena & Reggio Emilia, Via G. Campi 183, 41125 Modena, Italy
c Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium
d College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
HO
base
Received: 14.11.2014
Accepted after revision: 22.12.2014
Published online: 22.01.2015
HO
base HO
base
O
O
O
O
S
O
DOI: 10.1055/s-0034-1380112; Art ID: st-2014-d0944-l
1,3-oxathiolane-
based nucleosides
1,3-dioxolane-
based nucleosides
1,3-dioxane-
based nucleosides
Abstract 1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues
were prepared following a new and versatile synthetic strategy. These
analogues were synthesized via nucleophilic addition of the selected
nucleobase to a 1,3-dioxane scaffold that presents an appropriate leav-
ing group in position 5. In particular cis and trans isomers of purine/py-
rimidine nucleosides and their halogenated homologues were ob-
tained. NMR experiments, carried out on the cis isomers, led to
assignment of an equatorial orientation to the 2-hydroxymethyl group
and axial orientation to the nucleobase in position 5 of the 1,3-dioxane.
The trans isomers showed a diequatorial orientation of these groups.
These assignments were confirmed by X-ray crystallographic studies.
Figure 1
pletely revealed when all nucleoside analogues were pro-
duced and evaluated. This consideration is supported by the
case of 1,3-oxathiolane-based nucleosides in which only
the cytosine analogue showed a good antiviral (i.e., HIV,
HBV) potency and selectivity.5 Supported by this evidence,
we developed a novel synthetic approach to obtain the cor-
responding purine derivatives. Unlike the previously re-
ported methods, the synthetic strategy presented herein al-
lowed us to isolate and fully characterize both cis and trans
isomers of all targeted derivatives. The 1,3-dioxane-based
nucleosides were obtained by reacting each purine and py-
rimidine base with a key intermediate in the last step of the
synthetic pathway. This strategy avoids the expensive and
time-consuming Mitsunobu-type condensation of bis-1,3-
trityloxy-2-propanol with each nucleobase in the first step
of the synthetic path.7,8 In addition, it overcomes the de-
manding separation of the cis/trans diastereoisomers to be
performed on the precious and hard-to-handle nucleoside
mixture. Moreover, the Mitsunobu reaction cannot be ap-
plied in the case of purines due to their poor solubility in
the suitable reaction solvents. At present, 1,3-dioxan-5-yl-
purine nucleosides have never been isolated and character-
ized. In this work we developed a different synthetic ap-
proach in order to obtain a large variety of cis- and trans-
pyrimidine/purine nucleoside analogues by using a com-
Key words nucleosides, 1,3-dioxane, purines, pyrimidines, antiviral
The synthesis and biological evaluation of nucleoside
analogues have been a very active research area for a num-
ber of years.1,2 Among them, a well-known class of mole-
cules endowed with antiviral or anticancer activity was ob-
tained by replacing the 2-deoxyribose moiety with a 1,3-di-
oxolane3,4 or 1,3-oxathiolane ring.5,6 Based on the results
reported, we focused part of our research on the synthesis
of nucleoside analogues having these novel sugar-replacing
rings. Furthermore, with the aim to investigate the proper-
ties of higher homologues of the 1,3-dioxolane-based nu-
cleosides, 1,3-dioxane analogues were also considered (Fig-
ure 1).
Although 1,3-dioxan-5-yl pyrimidines were previously
reported as potential anti-HIV nucleoside alike com-
pounds,7,8 we felt that the true value of a structural modifi-
cation concerning the sugar portion would only be com-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

626
C. Sorbi et al.
Letter
Synlett
Figure 2 Upper: trans isomers of 1,3-dioxane-based nucleoside analogues 14a–23a and 1H NMR signal of H-5′. Lower: cis isomers 14b–23b and 1H
NMR signal of H-5′.
mon intermediate (Scheme 1). Diethyl acetal 1,17 required
as starting material, was prepared from sodium benzoate
and bromoacetaldehyde diethyl acetal. Synthesis of the 1,3-
dioxane ring was accomplished by Lewis acid mediated
condensation of 1 with glycerol to give compound 2.9,18 The
reaction proceeds without stereoselectivity and regioselec-
tivity preferences, giving cis (2a)19 and trans (2b)20 isomers
in comparable yields as well as their corresponding 1,3-di-
oxolane isomers. The molar ratio of 1,3-dioxane/1,3-dioxol-
ane cis,trans-diastereoisomeric mixture was 55:45. Howev-
er, due to the marked difference in polarity, the single dias-
tereoisomers of 2 were easily separated by flash column
chromatography and obtained in high purity free from their
lower homologues (1,3-dioxolanes). Treatment of 2a and 2b
with p-toluenesulfonyl chloride gave the key intermediates
3a and 3b,21 respectively. Nucleophilic displacement of the
tosyl group by the selected nucleobase produced an inver-
sion of the configuration at C-5 of the 1,3-dioxane and fur-
nished trans (4a–13a) and cis isomers (4b–13b),22–24 re-
spectively, of the desired nucleosides. Deprotection of the
hydroxyl group in position 2 of the 1,3-dioxane with NH3–
H2O and the subsequent crystallization gave the final
pyrimidine nucleosides as pure trans (14a–21a) or cis dia-
stereoisomers (14b–21b; Scheme 1,Table 1).25
Stereochemical and conformational assignments were
based on NMR studies. The relative chemical shifts of the H-
5′ (1,3-dioxane) and H-6 (pyrimidine) or H-8 (purine) were
Table 1 Synthesized Compounds28
Nucleoside
Nucleobase
Nucleobase abbreviation
14a
14b
15a
15b
16a
16b
17a
17b
18a
18b
19a
19b
20a
20b
21a
21b
22a
22b
23a
23b
uracil
U
uracil
U
5-chlorouracil
5-chlorouracil
5-fluorouracil
5-fluorouracil
5-bromouracil
5-bromouracil
5-iodouracil
5-iodouracil
thymine
5ClU
5ClU
5FU
5FU
5BrU
5BrU
5IU
5IU
T
thymine
T
cytosine
C
cytosine
C
The desired adenine analogues 22a and 22b26 were ob-
tained by treatment of the parent compounds 12a and 12b
with saturated NH3–H2O, in a reactor at 100 °C. Compounds
13a and 13b were transformed into the final guanine nu-
cleosides 23a and 23b27 by heating at 100 °C in the pres-
ence of aqueous NaOH–methanol solution (Scheme 1).
5-fluorocytosine
5-fluorocytosine
adenine
5FC
5FC
A
adenine
A
guanine
G
guanine
G
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

627
C. Sorbi et al.
Letter
Synlett
O
taken into account to assign the cis/trans configurations to
all final compounds 14–23 (Figure 2 and Table 2). In partic-
ular, the H-5′ signal of the trans isomers appears downfield
with respect to that of the corresponding cis isomers. This
result is probably due to the deshielding effect of the 1,3-
dioxane oxygen atoms, suggesting an axial orientation of H-
5′. Alternatively, in the cis isomers the H-5′ proton is ar-
ranged equatorially so that the nucleobase presents an axial
orientation. The deshielding effect of the oxygen atoms is
exerted also on H-6 of the pyrimidine or on H-8 of the pu-
rine. In particular, when the base is axially oriented, as in
the cis isomers, the signal of these protons falls at lower
field with respect to that of the corresponding trans isomer.
Moreover, the pattern of all H-5′ protons unambiguously
confirmed that in all cis isomers the nucleobase is axially
oriented while in trans isomers the base has equatorial ori-
entation (Figure 2). In fact, for the cis isomers, the H-5′ peak
is a broadened singlet with two small coupling constants.
This evidence is in good agreement with an equatorial ori-
entation of this proton when 2′,5′-disubstituted 1,3-diox-
anes show a C-2′,C-5′ cis configuration. By contrast, the H-5′
signal of the trans isomers appears as a defined multiplet,
with two large coupling constants that indicate its axial ori-
O
OEt
OEt
i)
OEt
OEt
Br
O
O
+
ONa
1
ii)
O
O
O
O
O
+
O
O
OH
OH
55:45
iii)
2
2c
O
O
O
O
O
O
O
O
OH
OH
2a
2b
3b
iv)
iv)
O
O
O
O
O
O
O
O
OTs
OTs
3a
v)
O
v)
O
O
Table 2 1H NMR Chemical Shifts (multiplicity) of H-5′, H-6, or H-8 of
the 1,3-Dioxane-Based Nucleoside Analogues 14–23a
O
O
O
O
O
base
base
Compound
Base
Isomer
H-5′
4.32–4.51 (m)
H-6b or H-8c
4a–13a
4b–13b
14a
14b
15a
15b
16a
16b
17a
17b
18a
18b
19a
19b
20a
20b
21a
21b
22a
22b
23a
23b
U
U
trans
cis
7.72 (d)
8.15 (d)
8.16 (s)
8.47 (s)
8.11 (d)
8.37 (d)
8.20 (s)
8.45 (s)
8.22 (s)
8.61 (s)
7.62 (s)
8.04 (s)
7.61 (d)
8.11 (d)
8.03 (d)
8.28 (d)
8.21 (s)
8.40 (s)
7.63 (s)
7.88 (s)
vi)
vi)
4.29 (br s)
5ClU
trans
cis
4.41–4.52 (m)
4.31 (br s)
O
O
O
O
HO
HO
5ClU
5FU
5FU
5BrU
5BrU
5IU
5IU
T
base
base
trans
cis
4.39–4.49(m)
4.30 (br s)
14a–23a
14b–23b
NH2
base:
O
O
N
trans
cis
4.39–4.49 (m)
4.32 (br s)
R
R
NH
NH
N
trans
cis
4.42–4.58 (m)
4.33 (br s)
N
O
O
N
O
trans
cis
4.41–4.58 (m)
4.31 (br s)
4, 14 R = H
10, 20 R = H
11, 21 R = F
9, 19
5, 15 R = Cl
6, 16 R = F
7, 17 R = Br
8, 18 R = I
T
C
trans
cis
4.43–4.59 (m)
4.30 (br s)
R
R
N
C
N
N
N
N
N
5FC
5FC
A
trans
cis
4.45–4.61 (m)
4.30 (br s)
N
N
NH2
trans
cis
4.61–4.82 (m)
4.51 (br s)
12 R = Cl
22 R = NH2
13 R = Cl
23 R = OH
A
G
trans
cis
4.31–4.50 (m)
4.29 (br s)
Scheme 1 Reagents and conditions: i) 18-crown-6, DMF, 160 °C, 6 h; (ii)
CoCl2, TMSCl, glycerol, MeCN, r.t., 0.1 h; iii) flash column chromatogra-
phy (cyclohexane–EtOAc, 70:30); iv) TsCl, Et3N, CH2Cl2, 0 °C to r.t., 12 h;
v) K2CO3, selected pyrimidine or purine, 18-crown-6, DMF, 160 °C, 24 h;
vi) NH3–H2O, r.t., 5 h (4a–11a and 4b–11b) or NH3–H2O, 100 °C, 12 h
(12a,b) or 40% NaOH–MeOH, 100 °C, 5 h (13a,b).
G
a 1H NMR: 400 MHz, DMSO-d6 as solvent, TMS as internal reference.
b Pyrimidine derivatives.
c Purine derivatives.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

628
C. Sorbi et al.
Letter
Synlett
1
entation. These results were confirmed by H NMR studies
on 2′,5′-disubstituted 1,3-dioxane analogues.7,8,10 The NMR
structural elucidations were further supported by X-ray
crystallographic studies. The crystals of 22b, obtained from
aqueous solution, were analyzed by single-crystal X-ray dif-
fraction at room temperature. The crystals were monoclinic
(space group P21/c) with four molecules per unit cell. Bond
lengths and angles are unexceptional, as compared with
those found in cyclohexyl11 and pyranosyl12 derivatives of
adenine. The 1,3-dioxane ring adopts a chair conformation,
with the adenine and hydroxymethyl groups in axial and
equatorial positions, respectively (Figure 3).
(for HIV) or HEL (other viruses) cell cultures. Moreover no
microscopically visible cytotoxicity was observed at the
highest concentrations tested (i.e., 200 μM) of all com-
pounds. The compounds were also evaluated for cytotoxic
effects towards several human cancer cell lines such as
HCT116 (colon), A549 (lung), SNU638 (stomach), PC3 (pros-
tate), SK-Hep-1 (liver), using sulforhodamine B (SRB) pro-
tein staining method.16 None of the tested compounds
showed significant antitumor activity, with an EC50 value
> 100 μM.
In summary, a new and versatile synthesis of achiral
1,3-dioxan-5-yl-based nucleosides (pyrimidin-1-yl/purin-
9-yl) has been developed. This synthetic strategy allows
both cis and trans diastereoisomers of all purine and pyrim-
idine analogues to be obtained. Furthermore, 1,3-dioxan-5-
yl purines were isolated and structurally characterized for
the first time. None of the compounds possesses significant
antiviral and antitumor activity in the biological assays
performed. Further or different modifications have to be in-
troduced to unlock the antiviral/antitumor activity. Howev-
er, this synthetic approach may represent a valuable tool for
obtaining new analogues of this class of compounds.
Acknowledgment
The antiviral and cytostatic evaluations were performed by Leentje
Persoons, Frieda De Meyer, Kristien Erven, Kris Uyttersprot, and Liz-
ette van Berckelaer and supported by a grant of the KU Leuven (GOA
10/14).
Figure 3 Partially labeled ORTEP-3 plot of 22b, with displacement el-
lipsoids at 40% probability level and H atoms drawn as spheres with ar-
bitrary radius.14 Only H atoms bound to heteroatoms are labeled.
The purine base is in the anti orientation with respect
to the 1,3-dioxane ring, as shown by the torsion angle C7–
C6–N1–C5, –151.31(7)°. The molecular structure is remark-
ably similar to that of trans-9-(2-ethoxy-1,3-dioxan-5-
yl)adenine, which, however, features the ethoxy substituent
in axial position.13
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380112.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
In the crystal lattice, complementary donor–acceptor
interactions link molecules in chains that run parallel to the
c axis. The hydroxyl oxygen atom O3 is hydrogen-bonded to
the imidazole nitrogen atom N2 of a neighboring molecule
[O3–HO3···N2 2.7759(11) Å]. In turn, the exocyclic amino
group of the latter acts as a hydrogen donor towards one of
the 1,3-dioxane ring oxygens [N5–HN5a···O2 3.0265(11) Å].
These chains are connected to each other via a third hydro-
gen bond that involves the remaining amino hydrogen and
the pyrimidine nitrogen atom N3 [N5–HN5b···N3
3.0645(10) Å]. The crystal structure is further stabilized by
short C–H···O contacts and base-stacking interactions.
All synthesized nucleosides 14–23 were evaluated for
their potential activity against a variety of viruses following
the previously described procedures.15 None of the com-
pounds showed significant antiviral activity against human
immunodeficiency virus type 1 and 2 (HIV-1, HIV-2), her-
pes simplex virus type 1 and 2 (HSV-1, HSV-2), vaccinia vi-
rus and vescicular stomatitis virus (VSV) in infected MT-4
(1) Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Nat. Rev.
Drug Discov. 2013, 12, 447.
(2) Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev.
2010, 110, 3337.
(3) (a) Norbeck, D. W.; Spanton, S.; Broder, S.; Mitsuya, H. Tetrahe-
dron Lett. 1989, 30, 6263. (b) Kim, H. O.; Ahn, S. K.; Alves, A. J.;
Beach, J. W.; Jeong, L. S.; Choi, B. G.; Van Roey, P.; Schinazi, R. F.;
Chu, C. K. J. Med. Chem. 1992, 35, 1987. (c) Kim, H. O.; Schinazi,
R. F.; Shanmuganathan, K.; Jeon, L. S.; Beach, J. W.; Nampalli, S.;
Cannon, D. L.; Chu, C. K. J. Med. Chem. 1993, 36, 519.
(4) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C.
Cancer Res. 1995, 55, 3008.
(5) (a) Soudeyns, H.; Yao, X.-J.; Gao, Q.; Belleau, B.; Kraus, J.-L.;
Nguyen-Ba, N.; Spira, B.; Wainberg, M. A. Antimicrob. Agents
Chemother. 1991, 35, 1386. (b) Schinazi, R. F.; Chu, C. K.; Peck,
A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L.-S.; Beach, J.
W.; Choi, W.-B.; Yeola, S.; Liotta, D. C. Antimicrob. Agents
Chemother. 1992, 36, 672. (c) Beach, J. W.; Jeong, L.-S.; Alves, A.
J.; Pohl, D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.;
Cheng, Y.-C.; Chu, C. K. J. Org. Chem. 1992, 57, 2217. (d) Jin, H.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

629
C. Sorbi et al.
Letter
Synlett
Siddiqui, M. A.; Evans, C. A.; Tse, H. L. A.; Mansour, T. S.;
Goodyear, M. D.; Ravenscroft, P.; Beels, C. D. J. Org. Chem. 1995,
60, 2621.
with NaHCO3 (5%). The organic layer was dried (Na2SO4), fil-
tered, and the solvent was evaporated under vacuum to give an
oily residue. Purification and separation of two diastereoiso-
mers 2a and 2b was achieved by flash column chromatography
(cyclohexane–ethyl acetate, 70:30): 5.00 g of cis isomer 2a (21.0
mmol, 15%), 5.34 g of trans isomer 2b (22.4 mmol, 16%), and
10.0 g of [4-(hydroxymethyl)-1,3-dioxolan-2-yl]methyl benzo-
ate (2c, 42.0 mmol, 30%) as an inseparable cis/trans diastereo-
isomeric mixture (50:50) were obtained. Molar ratio 1,3-diox-
anes/1,3-dioxolanes = 55:45.
(6) (a) Chang, C.-N.; Doong, S.-L.; Zhou, J. H.; Beach, J. W.; Jeong,
L.-S.; Chu, C. K.; Tsai, C.-H.; Cheng, Y.-C.; Liotta, D.; Schinazi, R.
J. Biol. Chem. 1992, 267 13938. (b) Schinazi, R. F.; McMillan, A.;
Cannon, D.; Mathis, R.; Lloyd, R. M.; Peck, A.; Sommadossi, J. P.;
St Clair, M.; Wilson, J.; Furman, P. A.; Painter, G.; Choi, W. B.;
Liotta, D. C. Antimicrob. Agents Chemother. 1992, 36, 2423.
(7) Capaldi, D. C.; Eleuteri, A.; Chen, Q.; Schinazi, R. F. Nucleosides
Nucleotides 1997, 16, 403.
(8) Cadet, G.; Chan, C.-S.; Daniel, R. Y. Davis C. P.; Guaideen, D.;
Rodriguez, G.; Thomas, T.; Walcott, S.; Scheiner, P. J. Org. Chem.
1998, 63, 4574.
(9) Battisti, U. M.; Sorbi, C.; Franchini, S.; Tait, A.; Brasili, L. Synthesis
2014, 46, 943.
(10) (a) Eliel, E. L.; Hutchins, R. O. J. Am. Chem. Soc. 1969, 91, 2703.
(b) Eliel, E. L.; Kandasamy, D.; Sechrest, R. C. J. Org. Chem. 1977,
42, 1533. (c) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S.
A.; Alcudia, F.; Eliel, E. L. J. Am. Chem. Soc. 1976, 98, 956.
(11) Van der Helm, D. J. Cryst. Mol. Struct. 1973, 3, 249 (CSD entry
CHXADI10).
(19) cis-(5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2a)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 3.10 (br s, 1 H, OH),
3.52–3.61 (m, 1 H, CH-5 diox), 3.90–4.01 (m, 2 H, CH-4ax, CH-6ax
diox), 4.04–4.13 (m, 2 H, CH-4eq, CH-6eq diox), 4.40 (d, J = 4.6 Hz,
2 H, CH2O), 4.96 (t, J = 4.6 Hz, 1 H, CH-2 diox), 7.44 (dd, 2 H, J =
7.4, 7.8 Hz, CH-3, CH-5 Ph), 7.57 (t, 1 H, J = 7.4 Hz, CH-4 Ph), 8.01
(d, 2 H, J = 7.8 Hz, CH-2, CH-6 Ph). 13C NMR (100 MHz, CDCl3): δ
= 64.0 (C-5 diox), 64.9 (CH2OCO), 71.9 (C-4, C-6 diox), 98.9 (C-2
diox), 128.5 (C-3, C-5 Ph), 129.6 (C-1 Ph), 129.7 (C-2, C-6 Ph),
+
133.2 (C-4 Ph), 166.2 (CO). HRMS-APCI: m/z calcd for C12H15O5
[M + H]+: 239.0914; found: 239.0917.
(20) trans-(5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2b)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 3.02 (br s, 1 H, OH),
3.42 (dd, J = 10.4, 10.8 Hz, 2 H, CH-4ax, CH-6ax diox), 3.81–3.91
(m, 1 H, CH-5 diox), 4.22 (dd, J = 4.9, 10.4 Hz, 2 H, CH-4eq, CH-6eq
diox), 4.35 (d, J = 4.6 Hz, 2 H, CH2O), 4.78 (t, J = 4.6 Hz, 1 H, CH-2
diox), 7.43 (dd, 2 H, J = 7.2, 7.8 Hz, CH-3, CH-5 Ph), 7.55 (t, 1 H, J
= 7.2 Hz, CH-4 Ph), 8.04 (d, 2 H, J = 7.8 Hz, CH-2, CH-6 Ph). 13C
NMR (100 MHz, CDCl3): δ = 60.7 (C-5 diox), 64.4 (CH2OCO), 70.8
(C-4, C-6 diox), 97.8 (C-2 diox), 128.2 (C-3, C-5 Ph), 129.2 (C-1
Ph), 129.5 (C-2, C-6 Ph), 133.1 (C-4 Ph), 166.1 (CO). HRMS-APCI:
m/z calcd for C12H15O5+ [M +H]+: 239.0914; found: 239.0915.
(21) trans-[5-(Tosyloxy)-1,3-dioxan-2-yl]methyl Benzoate (3b)
p-Toluenesulfonyl chloride (1.20 g, 6.3 mmol) was added at 0 °C
to a solution of 2b (1.0 g, 4.2 mmol), Et3N (8.4 mmol, 1.17 mL) in
anhydrous CH2Cl2 (20 mL). The mixture was stirred at r.t. for 12
h. Ice and H2O were added, and the mixture was extracted with
CH2Cl2. The organic extracts were collected and dried (Na2SO4).
Crystallization from EtOAc–cyclohexane afforded the desired
compound (0.86 g, 2.2 mmol, 52%).
(12) Böhringer, M.; Roth, H.-J.; Hunziker, J.; Gobel, M.; Krishnan, R.;
Giger, A.; Schweizer, B.; Schreiber, J.; Leumann, C.;
Eschenmoser, A. Helv. Chim. Acta 1992, 75, 1416 (CSD entry
PAKWON).
(13) Mishnev, A. F.; Bleidelis, Y. Y.; Goncharova, I. N.; Ramzaeva, N. P.
Latv. PSR Zinat. Akad. Vestis Khim. Ser. 1979, 736 (CSD entry
EXOADN).
(14) Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565.
(15) (a) Pertusati, F.; Hinsinger, K.; Flynn, Á. S.; Powell, N.; Tristram,
A.; Balzarini, J.; McGuigan, C. Eur. J. Med. Chem. 2014, 78, 259.
(b) Meng, G.; Liu, Y.; Zheng, A.; Chen, F.; Chen, W.; De Clercq, E.;
Pannecouque, C.; Balzarini, J. Eur. J. Med. Chem. 2014, 82, 600.
(16) Lee, S. K.; Heo, Y. H.; Steele, V. E.; Pezzuto, J. M. Anticancer Res.
2002, 22, 97.
(17) Benzoyloxyacetaldehyde Diethyl Acetal (1)
Potassium benzoate (125.2 mmol, 20.0 g) was added to a solu-
tion of bromoacetaldehyde diethyl acetal (160.0 mmol, 24.4 mL)
and 18-crown-6 ether (catalytic amount) in anhydrous DMF (25
mL), and the mixture was refluxed for 6 h. Then, after cooling to
r.t., H2O was added, and the mixture was extracted three times
with EtOAc. The combined extracts were washed with H2O,
dried (Na2SO4), and concentrated under vacuum. The residue
was dried azeotropically with toluene to give benzoyloxyacetal-
dehyde diethyl acetal (24.72 g, 104.0 mmol, 83%). This product
was used in the next step without further purification.
Dark oil. 1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 6 H, 2
× CH3), 3.54–3.68 (m, 2 H, CH2CH3), 3.68–3.80 (m, 2 H, CH2CH3),
4.35 (d, J = 5.4 Hz, 2 H, CH2OCO), 4.84 (t, J = 5.4 Hz, 1 H, CH), 7.43
(dd, J = 7.6, 7.7 Hz, 2 H, CH-3, CH-5 Ph), 7.55 (t, J = 7.6 Hz, 1 H,
CH-4 Ph), 8.05 (d, J = 7.7 Hz, 2 H, CH-2, CH-6 Ph). 13C NMR (100
MHz, CDCl3): δ = 15.0 (2 CH3), 62.2 (2 CH2), 64.1 (CH2OCO), 99.4
(CH), 128.1 (C-3, C-5 Ph), 129.4 (C-2, C-6 Ph), 129.7 (C-1 Ph),
1
White solid; mp 83–85 °C. H NMR (400 MHz, CDCl3): δ = 2.46
(s, 3 H, CH3), 3.57 (dd, J = 10.4, 11.3 Hz, 2 H, CH-4ax, CH-6ax diox),
4.14 (dd, J = 5.3, 11.3 Hz, 2 H, CH-4eq, CH-6eq diox), 4.32 (d, J =
4.6 Hz, 2 H, CH2O), 4.45–4.58 (m, 1 H, CH-5 diox), 4.78 (t, J = 4.5
Hz, 1 H, CH-2 diox), 7.31–7.45 (m, 2 H, CH-2, CH-6 Ph), 7.43–
7.56 (m, 2 H, CH-3, CH-5 Ph), 7.58–7.64 (m, 1 H, CH-4 Ph), 7.81
(d, J = 8.4 Hz, 2 H, CH-3, CH-5 Ts), 8.04 (d, J = 8.4 Hz, 2 H, CH-2,
CH-6 Ts). 13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 63.9
(CH2OCO), 67.5 (C-5 diox), 67.9 (C-4, C-6 diox), 98.1 (C-2 diox),
127.6 (C-3, C-5 Ts), 128.1 (C-3, C-5 Ph), 129.5 (C-2, C-6 Ts), 129.2
(C-1 Ph), 129.9 (C-2, C-6 Ph), 133.4 (C-4 Ph), 133.7 (C-1 Ts),
145.3 (C-4 Ts), (165.8 (CO). HRMS-APCI: m/z calcd for
C
19H21O7S+ [M + H]+: 393.1003; found: 393.1006.
(22) cis-{5-[5-Chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-
1,3-dioxan-2-yl}methyl Benzoate (5b)
+
132.8 (C-4 Ph), 166.0 (CO). HRMS-APCI: m/z calcd for C13H19O4
[M + H]+: 239.1278; found: 239.1280.
To a suspension of 5-chlorouracil (1.2 mmol) and K2CO3 (1.2
mmol), in anhydrous DMF (10 mL), was added portionwise,
under nitrogen, the tosylated compound 3b (1 mmol) and 18-
crown-6 (catalytic amount). The resulting mixture was stirred
and heated to reflux for 24 h. After cooling to r.t. the mixture
was concentrated under vacuum. The residue was partitioned
between EtOAc and H2O. The organic layer was separated, and
the aqueous phase was extracted with EtOAc. The extracts were
(18) (5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2)
To a solution of CoCl2 (9.7 g, 75.0 mmol) in anhydrous MeCN
(100 mL), benzoyloxyacetaldehyde diethyl acetal (1, 33.3 g,
140.0 mmol), TMSCl (19.0 mL, 149.0 mmol), and glycerol (19.3
mL, 265.0 mmol) were added at r.t. under stirring. After 12 h
the reaction was stopped, the mixture was extracted three
times with EtOAc, and the extracts were collected and washed
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

630
C. Sorbi et al.
Letter
Synlett
combined, washed with H2O, and dried (Na2SO4). The suspen-
sion was filtered and the solvent evaporated under vacuum. The
residue obtained was purified by flash chromatography to yield
the desired compound (0.046 g, 0.125 mmol, 12%).
compound (0.026 g, 0.099 mmol, 79%).
White solid; mp 207–209 °C. 1H NMR (400 MHz, DMSO): δ =
3.34–3.47 (m, 2 H, CH2OH), 4.01–4.12 (m, 2 H, CH-4ax, CH-6ax
diox), 4.13–4.21 (m, 2 H, CH-4eq, CH-6eq diox), 4.31 (br s, 1 H,
CH-5 diox), 4.71 (t, J = 4.1 Hz, 1 H, CH-2 diox), 4.95 (t, J = 6.0 Hz,
1 H, OH), 8.47 (s, 1 H, CH-6 uracil), 11.30 (br s, 1 H, NH). 13C
NMR (100 MHz, DMSO): δ = 47.5 (C-5 diox), 62.4 (CH2OH), 68.0
(C-4, C-6 diox), 100.6 (C-2 diox), 108.3 (C-5 uracil), 141.2 (C-6
uracil), 160.3 (C-2 uracil), 163.4 (C-4 uracil). Anal. Calcd for
C9H11ClN2O5: C, 41.16; H, 4.22; N, 10.67. Found: C, 41.05; H,
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 4.19–4.37 (m, 4 H,
CH2-4, CH2-6 diox), 4.50 (br s, 1 H, CH-5 diox), 4.53 (d, J = 3.8 Hz,
2 H, CH2O), 5.11 (t, J = 3.8 Hz, CH-2 diox), 7.53 (dd, J = 7.5, 8.0
Hz, 2 H, CH-3, CH-5 Ph), 7.69 (dd, J = 1.3, 7.5 Hz, 1 H, CH-4 Ph),
7.94 (dd, J = 1.3, 8.0 Hz, 2 H, CH-2, CH-6 Ph), 8.65 (s, 1 H, CH-6
uracil). 13C NMR (100 MHz, CDCl3): δ = 48.5 (C-5 diox), 64.0
(CH2OCO), 68.5 (C-4, C-6 diox), 99.0 (C-2 diox), 108.7 (C-5 ura-
cil), 128.3 (C-3, C-5 Ph), 129.6 (C-2, C-6 Ph), 129.9 (C-1 Ph),
133.2 (C-4 Ph), 139.6 (C-6 uracil), 149.2 (C-2 uracil), 157.8 (C-4
uracil), 166.1 (CO). ESI-HRMS: m/z calcd for C16H16ClN2O6+ [M +
H]+: 367.0691; found: 367.0692.
+
4.14; N, 10.41. ESI-HRMS: m/z calcd for C9H12ClN2O5 [M + H]+:
263.0429; found: 263.0428..
(26) cis-[5-(6-Amino-9H-purin-9-yl)-1,3-dioxan-2-yl]methanol
(22b)
Compound 12b (0.055 g, 0.147 mmol) was dissolved in concen-
trated aq NH3 (15 mL) and placed in a reactor at 100 °C for 12 h.
After solvent evaporation under vacuum, the residue was crys-
tallized from MeOH–Et2O to give the desired compound (0.025
g, 0.100 mmol, 68%).
(23) cis-[5-(6-Chloro-9H-purin-9-yl)-1,3-dioxan-2-yl]methyl Ben-
zoate (12b)
The compound was obtained from 3b and 6-chloropurine, fol-
lowing the procedure described for 5b (0.059 g, 0.158 mmol,
15%).
Yellow solid; mp 255–257 °C. 1H NMR (400 MHz, DMSO): δ =
Dark-brown oil. 1H NMR (400 MHz, CDCl3): δ = 4.30–4.38 (m, 2
H, CH-4ax, CH-6ax diox), 4.39–4.46 (m, 2 H, CH-4eq, CH-6eq diox),
4.49 (d, J = 4.3 Hz, 2 H, CH2O), 4.82 (br s, 1 H, CH-5 diox), 5.21 (t,
J = 4.3 Hz, 1 H, CH-2 diox), 7.48 (dd, J = 7.5, 7.8 Hz, 2 H, CH-3,
CH-5 Ph), 7.60 (dd, J = 1.2, 7.5 Hz, 1 H, CH-4 Ph), 8.07 (dd, J = 1.2,
7.8 Hz, 2 H, CH-2, CH-6 Ph), 8.73 (s, 1 H, CH-2 purine), 8.92 (s, 1
H, CH-8 purine). 13C NMR (100 MHz, CDCl3): δ = 48.5 (C-5 diox),
64.6 (CH2OCO), 69.0 (C-4, C-6 diox), 99.4 (C-2 diox), 128.5 (C-3,
C-5 Ph), 129.3 (C-1 Ph), 129.8 (C-2, C-6 Ph), 131.0 (C-5 purine),
133.5 (C-4 Ph), 145.4 (C-8 purine), 151.1 (C-4 purine), 151.5 (C-
6 purine), 151.8 (C-2 purine), 166.1 (CO). ESI-HRMS: m/z calcd
for C17H16ClN4O4+ [M + H]+: 375.0855; found: 375.0862.
(24) cis-[5-(2-Amino-6-chloro-9H-purin-9-yl)-1,3-dioxan-2-
yl]methyl Benzoate (13b)
3.47 (dd, 2 H, J = 4.0, 6.2 Hz, CH2O), 4.02–4.16 (m, 2 H, CH-4ax,
CH-6ax diox), 4.18–4.32 (m, 2 H, CH-4eq, CH-6eq diox), 4.51 (br s,
1 H, CH-5 diox), 4.69 (t, J = 4.0 Hz, 1 H, CH-2 diox), 4.90 (t, J = 6.2
Hz, 1 H, OH), 7.17 (br s, 2 H, NH2), 8.08 (s, 1 H, CH-2 purine),
8.40 (s, 1 H, CH-8 purine). 13C NMR (100 MHz, DMSO): δ = 49.3
(C-5 diox), 62.5 (CH2OH), 67.9 (C-4, C-6 diox), 101.3 (C-2 diox),
118.9 (C-5 purine), 139.4 (C-8 purine), 149.5 (C-4 purine), 153.0
(C-2 purine), 156.3 (C-6 purine). Anal. Calcd for C10H13N5O3: C,
47.81; H, 5.22; N, 27.87. Found: C, 47.86; H, 5.44; N, 28.03. ESI-
+
HRMS: m/z calcd for C10H14N5O3 [M + H]+: 252.1091; found:
252.1093.
(27) cis-2-Amino-9-[2-(hydroxymethyl)-1,3-dioxan-5-yl]-1H-
purin-6(9H)-one (23b)
Compound 13b (0.060 g, 0.154 mmol) was dissolved in MeOH
and 40% NaOH aq solution was added. The reaction mixture
was heated to reflux at 100 °C for 5 h, after which the solvent
was removed under vacuum. The solid residue was then dis-
solved in DMF, and insoluble material was removed by filtra-
tion. The DMF was evaporated under vacuum to give a black oil.
Crystallization from MeOH–Et2O afforded the desired com-
pound (0.035 g, 0.131 mmol, 85%).
The compound was obtained from 3b and 6-chloro-2-amino-
purine, following the procedure described for 5b (0.063 g, 0.162
mmol, 16%).
Dark-brown oil. 1H NMR (400 MHz, CDCl3): δ = 4.30–4.44 (m, 4
H, CH2-4, CH2-6 diox), 4.50 (d, J = 4.2 Hz, 2 H, CH2O), 4.69 (br s, 1
H, CH-5 diox), 5.05 (br s, 2 H, NH2), 5.18 (t, J = 4.2 Hz, 1 H, CH-2
diox), 7.51 (dd, J = 7.4, 7.8 Hz, 2 H, CH-3, CH-5 Ph), 7.62 (t, J = 7.4
Hz, 1 H, CH-4 Ph), 8.09 (d, J = 7.8 Hz, 2 H, CH-2, CH-6 Ph), 8.77 (s,
1 H, CH-8 purine). 13C NMR (100 MHz, CDCl3): δ = 48.8 (C-5
diox), 64.4 (CH2OCO), 68.8 (C-4, C-6 diox), 99.5 (C-2 diox), 128.9
(C-3, C-5 Ph), 129.4 (C-1 Ph), 129.9 (C-2, C-6 Ph), 130.8 (C-5
purine), 133.5 (C-4 Ph), 139.6 (C-8 purine), 151.5 (C-6 purine),
Yellow solid; mp 280–282 °C. 1H NMR (400 MHz, DMSO): δ =
3.41–3.49 (m, 2 H, CH2OH), 4.01–4.13 (m, 2 H, CH-4ax, CH-6ax
diox), 4.19–4.31 (m, 3 H, CH-5, CH-4eq, CH-6eq diox), 4.69 (t, J =
4.2 Hz, 1 H, CH-2 diox), 4.81–4.92 (m, 1 H, OH), 6.52 (br s, 2 H,
NH2), 7.88 (s, 1 H, CH-8 purine). 13C NMR (100 MHz, DMSO): δ =
49.3 (C-5 diox), 62.5 (CH2OH), 67.9 (C-4, C-6 diox), 101.3 (C-2
diox), 116.6 (C-5 purine), 134.9 (C-8 purine), 151.3 (C-4
purine), 155.8 (C-6 purine), 158.6 (C-2 purine). Anal. Calcd for
152.7 (C-4 purine), 159.1 (C-2 purine), 166.0 (CO). ESI-HRMS:
+
m/z calcd for
C
17H17ClN5O4 [M
+
H]+: 390.0964; found:
390.0969.
(25) cis-5-Chloro-1-[2-(hydroxymethyl)-1,3-dioxan-5-yl]pyrimi-
dine-2,4(1H,3H)-dione (15b)
C
10H13N5O4: C, 44.94; H, 4.90; N, 26.21. Found: C, 44.97; H, 5.16;
+
N, 26.49. ESI-HRMS: m/z calcd for C10H14N5O4 [M + H]+:
Compound 5b (0.046 g, 0.125 mmol) was dissolved in concen-
trated aq NH3 (15 mL) and stirred for 5 h in a Pyrex pressure
tube. After evaporation of the solvent under vacuum, the
residue was crystallized from MeOH–Et2O to give the desired
268.1040; found: 268.1041.
(28) Experimental procedures and analytical data of all compounds
reported in this work can be found in the Supporting Informa-
tion.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 625–630

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.