Microwave-assisted stereospecific synthesis of novel tetrahydropyran adenine isonucleosides and crystal structures determination

Article abstract of DOI:10.1016/j.molstruc.2013.08.054

We describe in this article stereospecific syntheses for new isonucleosides analogs of adenine 5-7 from tosyl derivatives 2-4 accessing by microwave irradiations (50-80%). The adenine reacts entirely at the N(9) position. Compounds 2-4 were prepared in two steps from the corresponding alcohols 1, 8 and 9 (81-92%). These tetrahydropyrans alcohols 1, 8 and 9 are achiral (Meso compounds) and were prepared in two steps with complete control of 2,4,6-cis relative configuration by Prins cyclization reaction (60-63%) preceded by the Barbier reaction between allyl bromide with benzaldehyde, 4-fluorobenzaldehyde and 2-naphthaldehyde respectively under Lewis acid conditions (96-98%). The configurations and preferential conformations of 5-7 were determined by crystal structure of 6. These novel isonucleosides 5-7 present in silico potentiality to act as GPCR ligand, kinase inhibitor and enzyme inhibitor, evaluated by Molinspiration program, consistent with the expected antiviral and anticancer bioactivities.

Full text of DOI:10.1016/j.molstruc.2013.08.054

Journal of Molecular Structure 1052 (2013) 189–196
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Microwave-assisted stereospecific synthesis of novel tetrahydropyran
adenine isonucleosides and crystal structures determination
Fábio P.L. Silva a, Marilia L. Cirqueira b, Felipe T. Martins b, Mário L.A.A. Vasconcellos a,
⇑
a Laboratório de Síntese Orgânica Medicinal da Paraíba (LASOM-PB), Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil
b Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
Stereospecific synthesis of novel
adenine isonucleosides analogous.
Determination of crystal structures
and its crystals packing features.
Tetrahydropyran diastereoselectively
prepared by Prins cyclization
reaction.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2013
Received in revised form 5 August 2013
Accepted 27 August 2013
Available online 6 September 2013
We describe in this article stereospecific syntheses for new isonucleosides analogs of adenine 5–7 from
tosyl derivatives 2–4 accessing by microwave irradiations (50–80%). The adenine reacts entirely at the
N(9) position. Compounds 2–4 were prepared in two steps from the corresponding alcohols 1, 8 and 9
(81–92%). These tetrahydropyrans alcohols 1, 8 and 9 are achiral (Meso compounds) and were prepared
in two steps with complete control of 2,4,6-cis relative configuration by Prins cyclization reaction (60–
63%) preceded by the Barbier reaction between allyl bromide with benzaldehyde, 4-fluorobenzaldehyde
and 2-naphthaldehyde respectively under Lewis acid conditions (96–98%). The configurations and pref-
erential conformations of 5–7 were determined by crystal structure of 6. These novel isonucleosides 5–7
present in silico potentiality to act as GPCR ligand, kinase inhibitor and enzyme inhibitor, evaluated by
Molinspiration program, consistent with the expected antiviral and anticancer bioactivities.
Ó 2013 Elsevier B.V. All rights reserved.
Keywords:
Stereospecific synthesis
Prins cyclization reaction
Isonucleosides
Adenine
Tetrahydropyran
Crystal structure determinations
1. Introduction
great interest due to their antiviral and anticancer properties [2–
4]. Natural nucleosides as well as many synthetic nucleosides,
Hundreds of nitrogenous bases and synthetically modified
nucleosides have been prepared, and their effects investigated in
the nucleic acids [1] synthesis. The synthesis and biological evalu-
ation of modified nucleoside analogs have been an area of active
research in Medicinal Chemistry. Nucleoside analogs have drawn
which are from therapeutic use, are quite susceptible to both
hydrolytic and enzymatic cleavage where nucleobases are attached
to the sugar moiety C10 (anomeric carbon). Numerous modifica-
tions have been carried out in the natural nucleosides structure
looking for target specificity, increased stability and decreased tox-
icity [3]. For instance, isonucleosides, in which the heterocyclic
base is linked to a non-anomeric carbon from sugar moiety, in
particular at C20 or C30 from furanose and pyranose at C20, C30 or
⇑
Corresponding author. Tel.: +55 83 3216 7589; fax: +55 3216 7433.
E-mail address: mlaav@quimica.ufpb.br (M.L.A.A. Vasconcellos).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.08.054

190
F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
HO
HO
O
C2'
O
C1'
C2'
C1'
C4'
C3'
C3'
B
B
HO
HO
HO
HO
HO
O
O
O
C3' C2'
C1'
O
C2'
O
C2'
C1'
C1'
C1'
C1'
C4'
C4'
C3'
C3'
B
B
B
B
B
No natural furanose
Natural pyranose
Natural furanose
No natural pyranose
Nucleosides
Isonucleosides
Fig. 1. Nucleosides and Isonucleosides structures. B = Nitrogenous bases.
C40 ring (Fig. 1) have been also reported as promising therapeutic
agents [5–7].
Macherey–Nagel pre-coated silica gel plates; detection was by
means of a UV lamp and revelation to vanillin. Flash column chroma-
tography was performed on 300–400 mesh silica gel. Organic layers
were dried over anhydrous MgSO4 or Na2SO4 prior to evaporation on
a rotary evaporator. 1H and 13C NMR spectra were obtained by using
a Varian Mercury Spectra AC 200 (200 MHz for 1H and 50 MHz for
13C) or Varian Inova (500 MHz for 1H and 125 MHz for 13C) in CDCl3
or DMSO-d6. Spectral patterns are designated as s = singlet; d = dou-
blet; dd = doublet of doublets; ddd = double doublet of doublets;
t = triplet; dt = double triplet; q = quartet; m = multiplet. The chem-
icalshifts (d, ppm)were reported in valuesrelative to tetramethylsil-
ane (0 ppm) for 1H NMR and were reported in the scale relative to
CDCl3 (77.00 ppm) for 13C NMR and coupling constants (J) were ex-
pressed in Hz. The Fourier Transform Infrared Spectroscopy spectra
were obtained using a spectrophotometer IR-Prestige-21 (Shima-
dzu). MS data were measured with a Shimadzu GCMS – QP2010
mass spectrometer. The elementary analyses of unpublished com-
pounds were performed in an analyzer organic elementar CHNS-O,
FLASH 2000 of Thermo Scientific.
The Prins cyclization reactions of homoallylic alcohols with
aldehydes under strongly protic acidic or in presence of Brönsted
acid conditions is now emerging as an efficient methodology for
substituted tetrahydropyrans [8–10] preparation. In most in-
stances, 2,4,6-cis equatorial substituted tetrahydropyrans are ob-
tained in high diastereoselectity but some exceptions are being
reported [10].
In connection to our interest in the synthesis of biological activ-
ities compounds via Prins cyclization reaction [11–13] we de-
scribed in a previous paper [14] the diastereoselective synthesis
and determination of crystal structures to alcohol 2,4,6-cis 2,6-di-
phenyl-tetrahydro-2H-pyran-4-ol (1) and the corresponding tosyl-
ate derivative 2 (Fig. 2).
In this article, we describe stereospecific syntheses to the novel
tetrahydropyran adenine isonucleosides derivatives 5–7 (Fig. 2) pre-
pared by reacting adenine with the tosyl precursors 2–4 (which are
diastereoselectively prepared here by Prins cyclization reaction), as-
sisted for microwave irradiation. The configurations and the prefer-
entialconformationsof 3 and 6 were unambiguously determinateby
crystallographic studies that proved the stereospecificity the config-
urational inversion at C30 of these reactions. The adenine isonucleo-
sides 5–7 selection shown in Fig. 2 was based on in silico evaluation
by using Molinspiration Cheminformatics program [15]. The Molin-
spiration Cheminformatics program presents specific activity scores
for each of these six receptor classes (GPCR ligand, ion channel mod-
ulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor
and enzyme inhibitor). Using this program, it is also possible to cal-
culate the Lipinski’s rule of five proprieties [16]. Molinspiration
Cheminformatics virtual screening methodology can efficiently sep-
arate drug-likeness from inactive structures. Compounds 3–5 have
high in silico potentiality to act as GPCR ligand, kinase inhibitor
and enzyme inhibitor, consistent with the expected antiviral and
anticancer bioactivities. Finally, it is important to note that com-
pounds 3–5 are achiral (Meso compounds) which greatly simplifies
these syntheses, since only relative configuration must be
controlled.
2.1.1.1. General procedure for ( )–homoallylic alcohol synthesis. The
( )–homoallylic alcohol synthesis, was performed through a Barbier
reaction. The corresponding aldehyde (8 mmol) was added to water
(40 mL) containing potassium iodide (24 mmol), stannous chloride
dihydrate (12 mmol) and allyl bromide (1 mL). The orange solution
turns white by saturated ammonium chloride addition (20 mL).
The stirring was continued for 2 h at room temperature. After the
end of reaction, the reaction mixture was extracted with CH2Cl2
(2 ꢁ 50 mL) gave an organic phase, washed with water, dried with
sodium sulfate anhydrous, concentrated under reduced pressure
and purified by flash chromatography on silica gel (Ethyl Ace-
tate:Hexane as eluent). The product was concentrated under re-
duced pressure yielding the ( )–homoallylic alcohol, respectively.
2.1.1.1.1. 1-Phenylbut-3-en-1-ol (10) synthesis. This product was
obtained using benzaldehyde. The product was purified by silica
gel column chromatography using Ethyl Acetate/hexane (1:9) as
eluent, resulting in 97% yield. IR (KBr, cmꢂ1): 3371, 3070, 3028,
2904, 1639 e 1492, 1049, 995, 914, 756, 702; 1H NMR (200 MHz,
CDCl3): d = 7.33 (m, 5H), 5.83 (m, 1H), 5.18 (m, 2H), 4.74 (t,
J = 6.0 Hz, 1H), 2.53 (m, 3H); 13C NMR (50 MHz, CDCl3):
d = 144.57, 135.18, 129.09, 128.22, 126.54, 119.02, 74.03, 44.49.
2. Experimental
2.1. Chemistry
2.1.1.1.2. 1-(4-Fluorophenyl)but-3-en-1-ol (11) synthesis. This prod-
uct was obtained using 4-Fluorobenzaldehyde. The product was
purified by silica gel column chromatography using Ethyl
Acetate/hexane (3:7) as eluent, resulting in 96% yield. IR (KBr,
cmꢂ1): 3383, 3078, 2981, 2908, 1604, 11508, 1049, 995, 914,
837; 1H NMR (200 MHz, CDCl3): d = 7.41 (m, 2H), 7.14 (m, 2H),
2.1.1. General methods
Commercially available reagents were purchased from Aldrich
and used without further purification. Reactions were monitored
by thin-layer chromatography (TLC) using Silica gel 60 UV254

F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
191
OH
OTs
O
OTs
O
O
F
F
3
2
1
H2N
H2N
N
N
N
N
N
N
N
N
O
OTs
O
O
F
F
4
5
6
H2N
N
N
N
N
O
7
Fig. 2. Some precursors 1–4 and the isonucleosides 5–7 prepared in this work.
5.88 (m, 1H), 5.25 (m, 2H), 4.80 (t, J = 6.0 Hz, 1H), 2.57 (m, 3H); 13
NMR (50 MHz, CDCl3): d = 165.29, 160.42, 140.31, 140.25, 134.96,
C
was purified by column chromatography on silica gel to give 4-hy-
droxy-2,6-disubstituted tetrahydropyran compound.
134.88, 128.29, 128.13, 119.36, 116.13, 115.71, 73.45, 73.33, 44.62.
2.1.1.2.1. 2,6-Diphenyl-tetrahydro-2H-pyran-4-ol (1) synthesis. This
product was obtained using (4.5 mmol) of 1-phenylbut-3-en-1-ol
and (9 mmol) of benzaldehyde. The product was purified by silica
gel column chromatography using Ethyl Acetate/hexane (2.5:7.5)
as eluent, resulting in 60% yield. IR (KBr, cmꢂ1): 3263, 3032,
2947, 2858,1604, 1496, 1319, 1060,752, 694; 1H NMR (200 MHz,
CDCl3): d = 7.37 (m, 10H), 4.57 (d, J = 12 Hz, 2H), 4.10 (m, 1H),
2.27 (dd, J = 12.0, 4.0 Hz, 2H), 2.12 (m, 1H), 1.60 (q, J = 12.0 Hz,
2H); 13C NMR (50 MHz, CDCl3): d = 142.49, 128.85, 128.02,
126.39, 78.32, 69.03, 43.51.
2.1.1.2.2. 2,6-Bis(4-fluorophenyl)-tetrahydro-2H-pyran-4-ol (8) syn-
thesis. This product was obtained using (4.5 mmol) of 1-(4-fluoro-
phenyl)but-3-en-1-ol and (9 mmol) of 4-Fluorobenzaldehyde. The
product was purified by silica gel column chromatography using
Ethyl Acetate/hexane (3:7) as eluent, resulting in 62% yield. IR
(KBr, cmꢂ1): 3329, 3051, 2943, 2854,1604, 1512, 1230, 1068,
821; 1H NMR (200 MHz, CDCl3): d = 7.33 (m, 4H), 7.04 (m, 4H),
4.53 (d, J = 12.0 Hz, 2H), 4.09 (m, 1H), 2.23 (m, 2H), 2.02 (s, 1H),
1.56 (dd, J = 14.0, 12.0 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d = 165.36, 160.48, 138.39, 138.33, 128.41, 128.25, 116.18,
115.75, 78.14, 78.06, 69.09, 43.70.
2.1.1.1.3. 1-(Naphthalen-2-yl)but-3-en-1-ol (12) synthesis. This
product was obtained using 2-naphthaldehyde. The product was
purified by silica gel column chromatography using Ethyl Ace-
tate/hexane (1:9) as eluent, resulting in 98% yield. IR (KBr, cmꢂ1):
3278, 3051, 2947, 2854, 1600, 1508, 1060, 991, 952, 821, 748; 1H
NMR (200 MHz, CDCl3): d = 7.67 (m, 7H), 5.84 (m, 1H), 5.18 (m,
2H), 4.90 (t, J = 6.0 Hz, 1H), 2.60 (m, 2H), 2.34 (s, 1H); 13C NMR
(50 MHz, CDCl3): d = 141.98, 135.11, 133.98, 133.67, 128.94,
128.70, 128.42, 126.86, 126.55, 125.26, 124.75, 119.23, 74.19,
44.45.
2.1.1.2. General procedure for 4- hydroxy-2,6-disubstituted tetrahy-
dropyran synthesis. A round bottom flash equipped with a mag-
netic stir bar was charged with 0.81 mL of acetic acid, 7 mL of
benzene, 4.5 mmol of homoallylic alcohol and 9 mmol of aldehyde.
The mixture was cooled to 0 °C and after slow addition of 1.2 mL of
boron trifluoride etherate was stirred in this temperature for 3 h.
To the reaction media was added NaHCO3 sat (10 mL) followed
extraction with Ethyl Acetate (3 ꢁ 10 mL). The combined organic
phase are washed with brine (3 ꢁ 10 mL), dried over Na2SO4, fil-
tered and concentrated under vacuum. The obtained compound
was dissolved in methanol (10 mL) and stirred over potassium car-
bonate (500 mg) for 0.5 h. Then methanol was removed under re-
duced pressure and water (20 mL) was added. The mixture was
extracted with Ethyl Acetate (2 ꢁ 20 mL) and the combined organ-
ic layers were dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. The resulting crude product
2.1.1.2.3. 2,6-Di(naphthalen-2-yl)-tetrahydro-2H-pyran-4-ol (9) syn-
thesis. This product was obtained using (4.5 mmol) of 1-(naphtha-
len-2-yl)but-3-en-1-ol and (9 mmol) of 2-naphthaldehyde. The
product was purified by silica gel column chromatography using
Ethyl Acetate/hexane (1:1) as eluent, resulting in 63% yield. IR
(KBr, cmꢂ1): 3278, 3020, 2947, 2854, 1600, 1508, 1357, 1060,
821, 748; 1H NMR (500 MHz, DMSO): d = 7.92 (m, 8H), 7.63 (dd,
J = 10.0, 5.0 Hz, 2H), 7.50 (m, 4H), 4.82 (d, J = 10.0 Hz, 2H), 4.11

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F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
(m, 1H), 3.82 (s, 1H), 2.29 (dd, J = 10.0, 5.0 Hz, 2H), 1.58 (dd,
J = 25.0, 10.0 Hz, 2H); 13C NMR (125 MHz, DMSO): d = 140.76,
133.40, 132.94, 128.41, 128.30, 128.02, 126.59, 126.28, 125.08,
124.64, 77.81, 67.35, 43.63.
of 2,6-diphenyl-tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfo-
nate. The product was purified by column chromatography on
silica gel using methanol/Ethyl Acetate (1:9) as eluent, resulting
in 80% yield. IR (cmꢂ1): 3267, 3236, 3032, 2916, 2852, 1678,
1608, 1475, 1053, 756, 698; 1H NMR (200 MHz, DMSO-d6):
d = 8.63 (sl, 1H), 8.15 (sl, 1H), 7.36 (m, 10H), 4.91 (m, 3H), 2.64
(m, 3H), 1.94 (s, 1H), 098 (m, 2H); 13C NMR (50 MHz, DMSO-d6):
d = 157.44, 151.29, 143.60, 143.24, 129.59, 128.81, 127.28,
120.46, 75.20, 50.65, 36.89. Anal. calcd for C22H21N5O, C, 71.14;
H, 5.70; N, 18.85 Found C, 71.18; H, 5.79; N, 18.65.
2.2.1.3. General procedure for toluenesulfonates synthesis. A solution
of 4-hydroxy-2,6-disubstituted tetrahydropyran (1 mmol) in dry
CH2Cl2 (1.4 mL). To this solution was added 0.3 mL of triethyl-
amine (Et3N), they were kept under magnetic stirring at 0 °C. To
this solution was added p-toluenesulfonyl chloride (2 mmol). The
solution was stirring at room temperature and the reaction pro-
gress was monitored by thin-layer chromatography (TLC). The
reaction mixture was diluted with HCl-1 N (25 mL) and extracted
with chloroform (30 mL). The organic phase was separated and
washed with 25 mL of saturated NaHCO3 and 25 mL of water, dried
with Na2SO4 and the evaporated under reduced pressure and puri-
fied by flash chromatography on silica gel (Ethyl Acetate:Hexane as
eluent).
2.1.1.3.1. 2,6-Diphenyl-tetrahydro-2H-pyran-4-yl-4-methylbenzene-
sulfonate (2) 2.4. synthesis. This product was obtained using
(1 mmol) of 2,6-diphenyl-tetrahydro-2H-pyran-4-ol. The product
was purified by silica gel column chromatography using Ethyl Ace-
tate/hexane (1.5: 8.5) as eluent, resulting in 82% yield. IR (KBr,
cmꢂ1): 3032, 2927, 2854, 1600, 1496, 1361, 1176, 813, 756, 698;
1H NMR (500 MHz, CDCl3): d = 7.84 (d, J = 10.0 Hz, 2H), 7.36 (m,
10H), 7.28 (d, J = 10.0 Hz, 2H), 4.99 (m, 1H), 4.56 (d, J = 10.0 Hz,
2H), 2.45 (s, 3H), 2.32 (dd, J = 15.0, 5.0 Hz, 2H), 1.86 (dd, J = 25.0,
15.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d = 145.15, 141.38,
134.78, 130.27, 128.78, 128.19, 127.95, 126.22, 78.64, 77.91,
40.43, 21.99.
2.1.1.3.2. 2,6-Bis(4-fluorophenyl)tetrahydro-2H-pyran-4-yl-4-methyl-
benzenesulfonate (3) synthesis. This product was obtained using
(1 mmol) of 2,6-bis(4-fluorophenyl)-tetrahydro-2H-pyran-4-ol.
The product was purified by silica gel column chromatography
using Ethyl Acetate/hexane (0.5:9.5) as eluent, resulting in 81%
yield. IR (KBr, cmꢂ1): 3078, 2927, 2858,1600, 1512,1354, 1153,
837; 1H NMR (200 MHz, CDCl3): d = 7.82 (d, J = 8.0 Hz, 2H), 7.33
(m, 6H), 7.02 (t, J = 8.0 Hz, 4H), 4.94 (m, 1H), 4.52 (d, J = 10.0 Hz,
2H), 2.45 (s, 3H), 2.28 (dd, J = 12.0, 4.0 Hz, 2H), 1.81 (dd, J = 24.0,
12.0 Hz, 2H); 13C NMR (50 MHz, CDCl3) d = 164.77, 159.87,
144.93, 136.62, 136.56, 134.11, 129.93, 127.67, 127.59, 127.51,
115.55, 115.13, 76.94, 57.89, 39.97, 21.67.
2.1.1.3.2. 9-(2,6-Bis(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)-9H-
purin-6-amine (6) synthesis. This product was obtained using
(0.1 mmol) of 2,6-bis(4-fluorophenyl)tetrahydro-2H-pyran-4-yl
4-methylbenzenesulfonate. The product was purified by column
chromatography on silica gel using methanol/Ethyl Acetate
(0.5:9.5) as eluent, resulting in 78% yield. IR (cmꢂ1): 3292, 3134,
2958, 2924, 2862, 1672, 1606, 1506, 1062, 831; 1H NMR
(200 MHz, DMSO-d6): d = 8.63 (sl, 1H), 8.19 (sl, 1H), 7.35 (m,
8H), 4.99 (m, 3H), 2.44 (m, 4H); 13C NMR (50 MHz, DMSO-d6):
d = 165.12, 160.29, 157.41, 151.26, 139.77, 129.22, 120.43,
115.98, 74.59, 50.53, 39.52; Anal. calcd. for C22H19F2N5O, C,
64.86; H, 4.70; N, 17.19 Found C, 64.77; H, 4.74; N, 17.20.
2.1.1.3.3. 9-(2,6-Di(naphthalen-2-yl)tetrahydro-2H-pyran-4-yl)-9H-
purin-6-amine (7) synthesis. This product was obtained using
(0.1 mmol) of 2,6-di(naphthalen-2-yl)-tetrahydro-2H-pyran-4-yl
4-methylbenzenesulfonate. The product was purified by column
chromatography on silica gel using methanol/Ethyl Acetate
(0.5:9.5) as eluent, resulting in a 50% yield. IR (cmꢂ1): 3294,
3128, 3055, 2926, 2856, 1668, 1602, 1508, 1064, 817, 748; 1H
NMR (200 MHz, DMSO-d6): d = 8.36 (sl, 1H), 7.25 (m, 15H), 5.33
(s, 1H), 4.76 (m, 2H), 2.16 (m, 4H); 13C NMR (50 MHz, DMSO-d6):
d = 157.48, 151.33, 141.12, 134.07, 133.75, 129.17, 128.83,
127.47, 127.27, 127.22, 125.83, 125.68, 120.50, 75.51, 50.67,
36.87. Anal. calcd. for C30H25N5O, C, 76.41; H, 5.34; N, 14.85 Found
C, 75.41; H, 5.64; N, 14.72.
2.2. Crystallography details
2.1.1.3.3. 2,6-Di(naphthalen-2-yl)-tetrahydro-2H-pyran-4-yl-4-meth-
ylbenzenesulfonate (4) synthesis. This product was obtained using
(1 mmol) of 2,6-di(naphthalen-2-yl)-tetrahydro-2H-pyran-4-ol.
The product was purified by silica gel column chromatography
using Ethyl Acetate/hexane (1:9) as eluent, resulting in 92% yield.
IR (KBr, cmꢂ1): 3055, 2924, 2850, 1597, 1450, 1357, 1180, 817,
748, 667; 1H NMR (200 MHz, CDCl3): d = 7.86 (m, 10H), 7.45 (m,
8H), 5.10 (m, 1H), 4.79 (d, J = 10.0 Hz, 2H), 2.45 (s, 3H), 2.18 (s,
2H), 2.00 (dd, J = 24.0, 12.0 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d = 145.57, 139.03, 135.01, 133.89, 133.74, 130.65, 128.98,
128.73, 128.38, 128.31, 126.89, 126.71, 125.44, 124.74, 79.04,
78.36, 40.67, 40.59.
Room temperature diffraction intensities for well-shaped single
crystals of compounds 3 and 6 were measured employing MoK
a
radiation from an microsource with multilayer optics
IlS
(Bruker-AXS Kappa Duo diffractometer with an APEX II CCD detec-
tor). The diffraction frames were recorded using APEX2 [17], with
u
and x scans. Integration, reduction and scaling of X-ray data
were performed using the programs SAINT and SADABS [17].
Both structures were solved with SIR2004 [18] using direct
methods, in which C, O, N, S, and F were promptly identified from
the Fourier map. The initial model was refined by the full-matrix
least squares method on F2 with SHELXL-97 [19], with anisotropic
atomic displacement parameters for non-hydrogen atoms. Hydro-
gens were not refined and had their positions stereochemically cal-
culated according to the riding model [C–H bond lengths of either
0.93 Å (aromatic), 0.96 Å (methyl), 0.97 Å (methylene) or 0.98 Å
(methine), N–H bond lengths of 0.86 Å] and fixed individual isotro-
pic displacement parameters [Uiso(H) = 1.2Ueq (or 1.5Ueq only in
the case of methyl carbons)]. The programs MERCURY [20] and
ORTEP-3 [21] were used within the WinGX [22] software package
to draw the molecular representations.
2.1.1.3. General procedure for nucleosides analogs synthesis. A tolu-
enesulfonate solution (0.1 mmol), adenine (0.15 mmol), K2CO3
(0.16 mmol) and dry DMF (1 mL) were placed in a glass tube for
specific microwave reactor along with a magnetic stirrer. The reac-
tion was carried out under microwave irradiation at 100 °C for
30 min (‘‘Hold Time’’) under closed vessel conditions (‘‘closed ves-
sel’’). After the reaction is completed, the solvent was evaporated
under reduced pressure. This crude product was then subjected
to flash column chromatography to yield a solid.
The crystallographic information files (abbreviated CIF) loading
the data sets (excluding the structure factors) for compounds 3 and
6 have been deposited with the Cambridge Structural Data Base
under deposit codes CCDC 941558 and 941431.
2.1.1.3.1.
9-(2,6-Diphenyltetrahydro-2H-pyran-4-yl)-9H-purin-
6-amine (5) synthesis. This product was obtained using (0.1 mmol)

F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
193
OH
i
ii
Br
Ar
O
OH
Ar
+
O
Ar
Ar
1, 8 and 9
10, 11 and 12
iii
H2N
N
N
N
OTs
N
iv
O
Ar
Ar
O
Ar
Ar
2, 3 and 4
5, 6 and 7
Scheme 1. Ar = phenyl to 10, 1, 2 and 5; Ar = 4-fluorphenyl to 11, 8, 3 and 6; Ar = 2-naphthyl to 12, 9, 7 and 4. (i) SnCl2, KI, H2O, NH4Cl, 0 °C, r.t., 2 h, 97% of 10, 96% of 11, 98%
of 12; (ii) a)Bz/AcOH, BF3:Et2O,0 °C,3 h. b) K2CO3, MeOH, r.t., 30 min, 60% of 1, 62% of 8, 63% of 9; (iii) Et3N, CH2Cl2, 0 °C, TsCl, r.t., 2 h, 82% of 2, 81% of 3, 92% of 4; (iv) K2CO3,
DMF, MW, 100 °C, 80% of 5, 78% of 6, 50% of 7.
C30 selectivity obtained on this reaction originates from the geom-
3. Results and discussion
etry of the cationic intermediate involved in the reaction. Accord-
ing to Alder‘s interpretation, the interaction between one of n
We started our experimental work by diastereoselective prepa-
ration of alcohols 1, 8 and 9 as shown in Scheme 1. Initially the
( )-alcohols 1-phenylbut-3-en-1-ol (10), 1-(4-fluorophenyl) but-
3-en-1-ol (11) and 1-(naphthalen-1-yl)but-3-en-1-ol (12) were
prepared in very high yields in an aqueous medium from the Bar-
bier reaction [23] respectively between Benzaldehyde, 4-fluor-
benzaldehyde and 2-naphthaldehyde with allyl bromide,
promoted by stannous chloride (96–98%). Subsequently the Meso
alcohol 1 was prepared in total 2,4,6-cis diastereoselectivity from
Prins cyclization reaction between respectively homoallylic alcohol
10, and Benzaldehyde only by changing of Lewis acid, in moderate
yield (60%) and on mild conditions (0 °C) as previously described
by us [14]. The Meso alcohol 8 synthesis was performed here by
reacting homoallylic alcohol 11 with 4-fluorobenzaldehyde (62%,
Scheme 1), and the Meso compound 9 synthesis was made by
reacting homoallylic alcohol 12 with 2-naphthaldehyde (63%,
Scheme 1). It is noteworthy that all reactions occurred with com-
plete control of 2,4,6-cis relative configuration proved previously
by us from crystal structure determination for compound 1 [14].
With the purpose of explain the cis selectivity obtained in 2, 4
and 6 positions of tetrahydropyran rings by Prins cyclization reac-
tion some mechanistic proposals have been described [8,9]. In the
simplest mechanism the reaction involves a homoallylic alcohol,
an aldehyde and a Lewis acid. The latter plays the role of the cata-
lyst and, depending on the experimental conditions, it can act as a
source of nucleophilic anion. In a general mechanism the interme-
diate key, i.e., an oxocarbenium ion, is generated from a hemiacetal
and undergoes 6-endo cyclization to give selectively a secondary
tetrahydropyranyl carbocation 3 that can be trapped by various
nucleophiles. Alder et al. [24] proposed that the favoring equatorial
electrons pair of oxygen with two
of the C–C bonds of the ring cyclic
r
r
electrons pairs (one in each
) and the empty -orbital of
p
carbocation makes particular stability on the system, which can
be classified as a homoaromatic cation. This particular geometry
favors the nucleophilic attack of nucleophilic ion on exo-face lead-
ing the C30-equatorial products (Fig. 3).
After that, the tosyl derivatives of 1, 8 and 9 were easily pre-
pared in high yields (81–92%) reacting these alcohols with tosyl
chloride in dichloromethane as solvent and triethylamine as nucle-
ophilic catalyst [25]. The complete configurational retention in C30
after this reaction was proved by crystallographic studies of tosyl
derivative 2 (which was previously described by us), [14] and also
the tosyl derivative 3, which had its crystal structure determined in
this work. The ORTEP (Oak Ridge Thermal Ellipsoid Plot) graphical
of 3 is shown in Fig. 4.
The crystal structure of compound 3 was solved in the mono-
clinic space group P21 with four crystallographically independent
molecules in the asymmetry unit (Fig. 4). A summary of crystal
data and structure determination statistics is shown in Table 1
for compounds 3 and 6 (see below). These conformers were labeled
with the suffix A to D, and all of them were present with S and R
absolute configurations around their C3 and C11 asymmetry cen-
ters. While a chair conformation is described for the tetrahydropy-
ran moiety of all conformers, with C1 and O1 atoms far away from
the least-squares planes through the other four coplanar atoms
(C2, C3, C10 and C11), the para-fluorophenyl rings are differently
twisted in the crystallographically independent molecules. The
least-squares planes calculated through these rings are bent by
44(1)°, 61(1)°, 18(1)°, and 45(1)° in conformers A, B, C, and D,
respectively. In addition, there is a rotation on the C1–O2 bond axis
responsible for a remarkable conformational difference among the
molecules of 3. Such a rotation results in para-tosyl orientations
variable in the four conformers (Fig. 4). Concerning the conforma-
tion of this moiety, conformers A and D are similar, with, for in-
stance, the dihedral angle C1–O2–S1–C18 measuring 69(1)° and
66(1)°, respectively. On the other hand, the other pair of conform-
ers, namely, those labeled as molecules B and C, differs almost
specularly from conformers A and D in terms of their para-tosyl
Ar
Exo
Ar
o
Nu
o
Nu
C3'
Ar
Ar
H
C3'
H
H
H
H
H
Fig. 3. Nucleophilic (Nu) addition, occurring preferentially by exo face of tetrahy-
dropyran cation.

194
F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
Fig. 4. The ORTEP drawing of the four crystallographically independent molecules of 3. Ellipsoids are at 30% probability level and an arbitrary labeling of atoms is displayed.
Table 1
Crystal data and structure refinement for compounds 3 and 6.
3
C
6
Molecular formula
Formula weight (g molꢂ1
Temperature (K)
Wavelength (Å)
24H22F2O4S
C22H19F2N5O1
407.42
296(2)
)
444.49
296(2)
0.71073
0.71073
Crystal system
Space group
Monoclinic
P21
Triclinic
P-1
Unit cell parameters
a = 15.400(4) Å
b = 13.804(4) Å
c = 20.076(5) Å
a = 7.8524(16) Å
b = 14.220(3) Å
c = 18.205(4) Å
a
= 90°
b = 96.109(5)°
= 90°
a
= 94.447(9)°
b = 102.46(1)°
= 90.00(1)°
c
c
Volume (Å3)
4244(2)
1978.7(7)
Z
8
4
Density calculated (Mg/m3)
Absorption coefficient (mmꢂ1
Crystal size (mm3)
1.391
0.199
0.173 ꢁ 0.101 ꢁ 0.094
1.31–25.77
1856
1.368
0.101
0.305 ꢁ 0.193 ꢁ 0.060
1.91–26.43
848
)
h-range for data collection (°)
F(000)
Index ranges
ꢂ18 6 h 6 18
–16 6 k 6 16
–24 6 l 6 11
23677
ꢂ9 6 h 6 9
–17 6 k 6 17
–22 6 l 6 22
18560
Reflections collected
Independent reflections
15,222
7358
[R(int) = 0.1430]
99.2
1117
[R(int) = 0.0731]
95.4
487
Completeness to hmax
Parameters refined
Goodness-of-fit on F2
1.093
1.389
R1 for I > 2
wR2 for all data
Largest diff. peak/hole (e Åꢂ3)
r
(I)
0.0687
0.2418
0.41/ꢂ0.42
0.0701
0.2043
0.47/ꢂ0.40

F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
195
Several procedures have been described to introduce adenine
moiety in sugar analogs [3]. For example, the use of adenine/
K2CO3 in 18-crown-6 as solvent is one of the best method [26]. It
has not been described reactions using microwave irradiation
accelerating this reaction. It can note that in our protocol (step
iv, Scheme 1) we do not use 18-crown-6 as solvent (that is very
expensive). Tautomeric forms for adenine have been measured cal-
culated but N(7)H and N(9)H tautomers (Fig. 5) are the most abun-
dant species. Fluorescence experiments conclude that adenine in
2-butanol at 170 K consists of 6% N(7)H and 94% N(9)H forms
[27]. In fact, in most cases the adenine reactivity occurs preferen-
tially on N(9)H but some regioisomer is produced in minor propor-
tion. Based on the determined crystal structure for 6 (ORTEP
model, see Fig. 7) we can note that the steps of adenine insertion
were stereospecific performed (total configurational inversion at
C30, via SN2 mechanism, Fig. 6), and also were selective in adenine
reactivity only at 9 position (Fig 6).
NH2
6
NH2
6
H
5
4
7
N
5
4
7
N1
N
N
N1
8
8
2
2
9 N
N
N
9 H
3
3
94% N(9)H
6% N(7)H
Fig. 5. Tautomeric forms for adenine: N(9)H and N(7)H.
orientation (the corresponding dihedral angles are ꢂ70(1)° and
ꢂ73(1)° in molecules B and C). All conformational features of 3,
besides Z0 content and space group, were reported for the related
compound having hydrogen instead of fluorine in para position
of both phenyl rings [3].
NH2
5
NH2
5
N7
N9
6
6
N 7
N9
NH2
5
1
N
6
1
N
2
N 7
N
8
8
Ar
1
N
2
8
TsO
+
4
4
N
N
δ
O
2
3
3
4
slow step
N
9
Ar
3
Ar
H
Ar
O
O
+
Ar
Ar
OTs
TsO
Fig. 6. SN2 proposal mechanism for the complete configuration inversion at C30 carbon. Ar = Benzaldehyde; 4-fluorobenzaldehyde or 2-naphthaldehyde.
Fig. 7. The ORTEP drawing of isonucleoside 6. For more drawing details, please see Fig. 4 caption.
Fig. 8. The hydrogen-bonded pair of molecules A and B in the crystal structure of 6.

196
F.P.L. Silva et al. / Journal of Molecular Structure 1052 (2013) 189–196
Compound 6 crystallizes in the triclinic space group P-1 with
Acknowledgement
two crystallographically independent molecules in the asymmet-
ric unit (Fig. 7). These molecules were set apart by adding the suf-
This work has been supported by CNPq, CAPES and FAPESQ-PB.
Chemistry Institute of Federal University of Goiás (UFG) by CHNS
analysis.
fixes
A and B and they are conformationally similar. It is
important to note that the mirror symmetry of the molecule is
responsible for the opposite configuration of its chiral carbons.
These carbons named as C3 and C11 have R and S configurations
in both crystallographically independent molecules A and B of
compound 6 so that the inversion center in the unit cell gives rise
to the corresponding mirror image of each one of the two mole-
cules with C3 and C11 with S and R configurations as opposite to
those of the chosen asymmetric unit, but in these inversion-re-
lated molecules C3 and C11 do look like C11 and C3 of the iden-
tity molecules, respectively, keeping the relative configuration of
the enantiomer. Both molecules are present with their tetrahy-
dropyran ring in a chair conformation, as described above for
the conformers of 3. The 4-fluorobenzene moieties are also
twisted similarly in these molecules. The least-squares planes
through the 4-fluorophenyl rings form angles of 52.1(4)° and
53.4(5)° in molecules A and B, respectively. Adenine adopts sim-
ilar conformation in both crystallographically independent mole-
cules. In molecules A and B of 6, torsions around the C1–N1 bond
do not differ much (for instance, C18–N1–C1–C10 dihedral angle
measures 33(2)° and 35(2)° in molecules A and B, respectively).
Indeed, the occurrence of two crystallographically independent
molecules in the crystal structure of isonucleoside 6 is mainly re-
lated to the formation of a Wobble base pair of molecules A and B
hydrogen bonded through their adenine moieties, which can be
interpreted as the asymmetry supramolecular entity of this com-
pound (Fig. 8).
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.
2013.08.054.
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4. Conclusions
Finally, in this article we are able to prepare three new isonu-
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SN2 reactions on tosyl derivatives accessing by microwave irradi-
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corresponding Meso tetrahydropyrans alcohols, and were pre-
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