From cyclopentadiene to isoxazoline-carbocyclic nucleosides: a rapid access to biological molecules through aza-Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2008.01.124

A rapid access to carbocyclic nucleosides containing a fused isoxazoline ring is proposed through the Grieco cycloaddition of cyclopentadiene to iminium salts. The prolific elaboration of the isoxazoline cycloadducts allowed preparation of the target amin

Full text of DOI:10.1016/j.tet.2008.01.124

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3541e3547
www.elsevier.com/locate/tet
From cyclopentadiene to isoxazoline-carbocyclic nucleosides: a rapid
access to biological molecules through aza-DielseAlder reactions
a,
a
a
b
Paolo Quadrelli *, Andrea Piccanello , Mariella Mella , Antonino Corsaro ,
b
Venerando Pistara`
a
Dipartimento di Chimica Organica, Universit a` degli Studi di Pavia, Viale Taramelli, 10 I-27100-Pavia, Italy
Dipartimento di Scienze Chimiche, Universit a` degli Studi di Catania, Viale A. Doria, 6 I-95125-Catania, Italy
b
Received 19 October 2007; received in revised form 10 January 2008; accepted 31 January 2008
Available online 3 February 2008
Abstract
A rapid access to carbocyclic nucleosides containing a fused isoxazoline ring is proposed through the Grieco cycloaddition of cyclopenta-
diene to iminium salts. The prolific elaboration of the isoxazoline cycloadducts allowed preparation of the target aminols through the unmasking
of the hydroxymethylene group at the C3 level of the azanorbornene structure. The heterocyclic aminols are readily converted into nucleosides
via the linear construction of purine heterocycles.
Ó 2008 Elsevier Ltd. All rights reserved.
3
,5
1
. Introduction
resistance to metabolic enzymes. Ring size modifications
as well as the mono and polycyclic nature of the spacer be-
tween the nucleobases and the hydroxy group affect the con-
formational bias as well as the activity and function of the
Nucleosides are important synthetic targets and the search
for analogues containing significantly altered carbohydrate
moieties is actively pursued because of their potential antiviral
1
and/or antitumor activities. A variety of modifications of the
6
nucleoside analogues, as detailed in various structural studies.
A variety of synthetic approaches are directed to increase the
molecular diversity in nucleosidic compounds, which never-
nucleoside structures have been made and resulted in different
derivatives including di-deoxynucleosides where both hydroxy
7
theless must have the features schematically depicted in 1.
2
groups on the sugar ring are removed, carbocyclic and hetero-
cyclic nucleosides where the sugar moiety is replaced with
Hydroxy group Spacer Nucleobase
3
a carbocyclic or a heterocyclic ring, acyclic-nucleosides as
well as iso-nucleosides, where the nucleobases are transposed
HO
(
CH2)
N
x( )n
x = 0, 1
n = 0, 1, 2, 3
0
0
4
from the 1 -position to the 2 -position of a furanose ring. New
efforts are constantly made to propose attractive synthetic
strategies toward new compounds, with potentially increased
a
c
1
b
The carbocyclic moiety is normally constituted by a cyclo-
pentane ring but four-, six-, and seven-membered ring are
8
often proposed as alternatives. The carbocyclic ring is the
center of the subsequent structural modifications and can be
either saturated or unsaturated and carrying substituents or
fused to carbocyclic or heterocyclic rings. A side arm carrying
a hydroxy group is always present. This last feature discrimi-
nates between the two families of the classical nucleosides
3
biological activities and decreased toxicities.
Among the various modifications, carbocyclic nucleosides
are extensively investigated because the replacement of the
furanose ring oxygen by a methylene group results in the
stabilized glycosyl bond under acidic conditions and higher
(
x¼1) bearing a hydroxymethylene moiety and the nor-nucleo-
*
Corresponding author. Tel.: þ39 0382 987315; fax: þ39 0382 987323.
E-mail address: paolo.quadrelli@unipv.it (P. Quadrelli).
sides (x¼0) having the hydroxy group directly linked to the
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.124

3542
P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
9
5b,15
carbocyclic ring. The nucleobases can be of the purine or pyr-
imidine type and a variety of functionalized structures have
been reported, suitable for various functionalizations.
By adapting the known procedures,
the regioisomeric
aminols 7a,b have been converted into the pyrimidine deriva-
tives 8a,b through condensation with the 5-amino-4,6-di-
chloropyrimidine and then into the chloropurines 9a,b with
orthoformates under HCl catalysis (Scheme 2). The pyrimi-
dine derivatives 8a,b were obtained in good yields (8a, 72%;
8b 75%) by heating a solution of the aminols 7a,b and
In this context, we have prepared a new class of nor-
nucleosides containing a fused isoxazoline ring by the linear
construction of the desired purine and pyrimidine bases on
the aminols obtained from the nitrosocarbonyl adducts with
1
0
cyclopentadiene. Their activity as potential antiviral agents
has been tested against Herpes Simplex virus types 1 and
5-amino-4,6-dichloropyrimidine (2 equiv) in n-BuOH at reflux
(bp 117 C) in the presence of an excess of i-Pr NEt (5 equiv)
ꢀ
2
1
1
0
2
.
In order to evaluate the effect of the elongation of the hy-
for 48 h. The epimeric aminol 7a was also converted into
0
droxy side chain we have recently proposed a novel approach
to useful aminols for the synthesis of carbocyclic nucleosides
starting from a convenient source, the 2-azanorborn-5-enes 3.
These are readily available through the Grieco cycloaddition
the pyrimidine derivatives 8a (79%) and this latter into the
0
chloropurines 9a under the same conditions.
Cl
N
Cl
N
H2N
HN
1
2
N
N
N
b
N
N
N
of cyclopentadiene 2 with iminium salts generated in situ un-
der Mannich-like conditions, in a mild and convenient aqueous
HO
HO
HO
NH2
Ph
a
a
1
aza-DielseAlder (ADA) reaction. They are quite reactive
3
1
4
O
O
O
O
N
N
Ph
Ph
N
Ph
dipolarophiles toward nitrile oxides and afford exclusively
the exo adducts 4. This exclusive exo selectivity of the norbor-
nene-like dipolarophiles has attracted a great deal of attention
and is usually attributed to relief of strain, geometric de-
formation of the double bond (pyramidalization due to p/s
repulsion), and also favorable staggering effects for the exo
attack. The prolific elaboration of the exo isoxazoline cyclo-
adducts 4 allowed the preparation of the target aminols 7
through the intermediates 5 and 6 by using NBS oxidation
and subsequent solvolysis for the unmasking of the hydroxy-
methylene group at the C3 level of the azanorbornene structure
7a
8a
9a
Cl
N
Cl
N
H2N
N
N
N
b
NH2
Ph
HN
H
H
H
HO
HO
O
HO O
N
7a'
N
8a'
N
9a'
Ph
1
0d
Cl
N
Cl
N
H2N
N
b
N
N
HO
Ph
HO
Ph
HO
Ph
NH2
HN
O
a
O
N O
9b
N
7b
N
8b
(
Scheme 1).
Scheme 2. (a) 5-Amino-4,6-dichloropyrimidine (2 equiv), i-Pr
2
NEt (5 equiv),
n-BuOH, D, 48 h; (b) HC(OEt) /HCl, rt, 8 days.
3
1
,3-Dipolar
b c
+
[
R-NH =CH ]
Cycloaddition
Oxidation
2
a
0
The structures of 8a,a ,b rely upon the analytical and spec-
troscopic data. While the IR spectra of pyrimidines 8a,a ,b
ADA
N
Plonovski
N
Cycloaddition
0
R
rearrangement
COR
2
3
4
ꢁ1
exhibit the expected bands between 3200e3500 cm due to
b c
b c
HO
1
the presence of OH, NH, and NH groups, the H NMR spectra
a
Br
Solvolysis
a
Reduction
NH2
2
CHO
N
NH
were unambiguously consistent for the assigned structures.
The spectrum of 8a in CD COCD showed the pyrimidine
a
c
b
COR
COR
5
6
7
3
3
b
N
N
ring proton as a singlet at d 8.03, the NH protons as a broad
2
a
c = R'C
O or O
CR'
singlet at d 4.43 and the OH proton as a triplet at d 4.54
because of the coupling with the methylene at d 3.89 (AB
syst.), while the NH proton is a doublet at d 7.01 (J¼
Scheme 1.
On pursuing our studies on nucleoside syntheses, we detail
6
5
.9 Hz). The 5- and 4-isoxazolinic protons are found at d
.22 (dd, J¼9.6, 3 Hz) and 4.29 (dd, J¼9.6, 3 Hz), respec-
here the first synthesis of a class of racemic purine-carbocyclic
nucleosides containing a fused isoxazole ring and having a
hydroxymethylene (HOeCH ) group in the side chain of the
tively, while the cyclopentane protons are at d 4.85 (m,
CHeN), 2.49 (CHeCH eO), and 2.29, 1.77 (m, CH ).
The spectrum of the regioisomeric 8b is essentially similar,
2
2
2
carbocyclic unit.
showing the pyrimidine singlet at d 7.90, the NH protons as
2
2
. Results and discussion
a broad singlet at d 4.39 and OH proton as a broad singlet at
d 4.77 while the corresponding methylene is at d 3.87 (AB
syst.), the NH at d 6.85 (d, J¼6.4 Hz) and the 5- and 4-isox-
azolinic protons at d 5.11 (d, J¼9 Hz) and 4.24 (dd, J¼9,
3 Hz). The cyclopentane protons are found at d 4.77 (m,
CHeNH), 2.46 (m, CH), and 2.35, 1.77 (m, CH2).
The ADA cycloadduct 3 between cyclopentadiene 2 and the
þ
benzyl-iminium salt [PhCH eNH ]CH ] was transformed
2
2
into the stereodefined regioisomeric anti aminols of type 7
Scheme 1). These syntheses have been performed according
(
1
4
0
to the previously described protocols, which nevertheless
required a proper tuning for the scale-up necessary for the syn-
thesis of nucleosides in the due amount for the biological tests.
Analogously, the spectrum of the stereoisomeric 8a shows
the pyrimidine singlet at d 7.93, the NH protons as a broad
2
singlet at d 4.72, and the NH at d 6.30 (d, J¼5 Hz). The OH

P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
3543
proton appears as a triplet at d 4.65 (J¼6 Hz) while the corre-
Cl
N
R
N
sponding methylene is at d 3.71 (AB syst.). The 5- and 4-iso-
xazolinic protons are shown at d 5.27 (dd, J¼9, 5 Hz) and 4.43
N
N
N
N
N
N
HO
HO
a
a
(
(
d, J¼9 Hz) and the cyclopentane protons are found at d 3.91
2
m, CHeNH), 2.88 (m, CH), and 2.02, 1.56 (m, CH ).
The conversion of the stereoisomeric pyrimidine 8a,a ,b
O
O N
10a
Ph
N
9a
Ph
0
Cl
R
0
N
N
into the corresponding chloropurines 9a,a ,b was performed
using excess triethyl orthoformate in the presence of catalytic
N
N
N
H
N
H
N
N
R
N
N
3
dance with the most frequently reported procedures. The
7% HCl by keeping the reactions at rt for 8 days, in accor-
1
6
HO
O
HO
O N
9a'
N
10a'
Ph
Ph
0
chloropurines 9a,a ,b could finally be isolated in good yields
0
Cl
N
N
N
N
N
(9a, 87%, 9a , 82% and 9b, 84%). Contrary to expectations,
the reactions performed with the method used for the prepara-
N
HO
HO
1
1a
a
tion of the nor-nucleosides, in the presence of excess triethyl
orthoformate and catalytic p-TsOH, did not take place and the
N O
9b
Ph
O
N
10b
Ph
0
pyrimidine derivatives 8a,a ,b were recovered unchanged.
The chloropurine 9a has been fully characterized spectro-
ꢀ
Scheme 3. (a) RNH
2
/MeOH, 50 C, 24 h; R: see Table 1.
scopically. Infrared spectra showed a single broad band at
ꢁ
1
320 cm corresponding to the OH absorptions. In the H
1
3
Table 1
Yields and physical constants of purine derivatives
NMR spectra (CDCl ) the two N]CH protons of the purine
3
rings occur as singlets at d 8.76 and 8.02 while the 5- and
4
ꢀ
R
Mp ( C) (Solvent)
Yield (%)
-isoxazolinic protons appear as double doublets at d 5.47
and 4.82 (JH4H5¼10 Hz). Similarly, the regioisomeric chloro-
9
a
Cl
NH
2
>200 dec (Diisopropyl ether)
224 dec (Diisopropyl ether)
186e188 (Diisopropyl ether)
Oil
87
89
92
90
84
10aA
10aB
ꢁ
1
purine 9b shows a single broad band at 3373 cm corre-
NHMe
NHcPr
OEt
10aC
10aD
sponding to the OH absorptions in the infrared spectrum and
1
in the H NMR spectra the two N]CH protons of the purine
rings occur as singlets at d 8.80 and 8.27. The 5- and 4-isox-
azolinic protons appear as double doublets at d 5.74 and 4.47
130e132 (n-Hexane/benzene)
0
9a
Cl
NH
2
>200 dec (n-Hexane/benzene)
>200 dec (Diisopropyl ether)
191e193 (Diisopropyl ether)
170e175 dec (Diisopropyl ether)
171e173 (Benzene)
82
88
95
80
77
0
0
0
0
1
1
1
1
0a A
0a B
NHMe
NHcPr
OEt
(
JH4H5¼10 Hz).
0a C
0a D
0
The stereoisomeric chloropurine 9a shows a single broad
ꢁ1
band at 3353 cm corresponding to the OH absorptions in
1
the infrared spectrum and in the H NMR spectra the two
9
1
1
b
Cl
NH
2
>200 dec (Diisopropyl ether)
>220 dec (n-Hexane/benzene)
>200 dec (n-Hexane/benzene)
>220 dec (n-Hexane/benzene)
180e182 (Benzene)
84
72
87
80
80
0bA
0bB
N]CH protons of the purine rings occur as singlets at
d 8.80 and 8.13. The 5- and 4-isoxazolinic protons appear at
d 5.67 (dd, J¼9, 5 Hz) and 4.93 (d, J¼9 Hz).
NHMe
NHcPr
OEt
10bC
0bD
1
0
From the chloro-substituted nucleosides 9a,a ,b a variety of
1
derivatives can be obtained by nucleophilic substitution. On
7
between the H4- and H5-isoxazolinic protons while those be-
tween the isoxazolinic protons and the adjacent methines dif-
fer in the two regioisomers (10aA, J¼5 Hz, 10a A, J¼5 Hz,
0
ꢀ
heating MeOH solutions of 9a,a ,b at 50 C in the presence of
an excess of NH or other differently substituted amines, the
0
3
0
amino derivatives 10a,a ,b(AeC) could easily be obtained
0
and 10bA, J¼6 Hz).
0
(
tained from pyrimidine derivatives 9a,a ,b when orthofor-
Scheme 3). Ethoxy derivatives 10a,a ,bD were directly ob-
0
In the amine derivatives 10a,a ,b(B,C) the IR spectra
ꢁ1
showed the NH bands in the range 3257e3394 cm . The
1
þ
mate/H treatment is prolonged for 14 days.
Table 1 reports the chemical yields and physical constants
H NMR spectra showed the characteristic NH signals as
broad singlets at d 6.87, 6.91 for 10aB,C, d 6.83, 6.90 for
0
0
of nucleosides 10a,a ,b(AeD), which have been fully charac-
terized through their analytical and spectroscopic data. The IR
10a B,C, and d 6.82, 6.92 for 10bB,C. In ethoxy derivatives
0
10a,a ,bD the H NMR spectra showed the OCH CH signals,
2 3
1
0
spectra of the adenine derivatives 10aA, 10a A, and 10bA
showed neat and distinctive OH bands (3551, 3399, and
the methylenes as quartets at d 4.72, 4.71, 4.71 and the
methyls as triplets at d 1.57, 1.55, 1.55, respectively.
These compounds, as well as the pyrimidine derivatives
whose synthesis is actually in progress, have been taken as
candidates for the biological evaluation against the same
viruses in order to have a comparison at the SAR level.
ꢁ
1
359 cm , respectively) and NH bands (3311, 3143; 3426,
3
3
2
ꢁ1
1
329, and 3314, 3114 cm , respectively). The H NMR spec-
tra showed the characteristic signals of adenine (CH] singlets
at d 8.16, 8.06; 8.28, 8.15 and 8.22, 8.19 respectively). The
isoxazolinic protons occur as double doublets, because of an
additional coupling with the adjacent cyclopentane methines,
thus indicating the same conformation in the cyclopentane
3. Conclusions
0
ring of the chloro-nucleosides 9a,a ,b. The major coupling
0
The first synthesis of isoxazoline-carbocyclic nucleosides
having a hydroxymethylene side chain and a variety of
constant (J¼10 Hz in 10a,bA and J¼8.5 Hz in 10a A) is

3544
P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
analogues was attained starting from the stereodefined hetero-
0
and the corresponding aldehydes. The 3-bromine derivatives 5
were treated with excess NaHCO in refluxing EtOH for sev-
eral days to promote their solvolysis to the aldehydes of type
6. Reduction of these latters and deprotection of the amino
14
group afforded the desired aminols 7.
cyclic aminols 7a,a ,b, which are readily available through exo
selective 1,3-dipolar cycloadditions of benzonitrile oxide to
3
2
cycloadducts. The stereodefined heterocyclic aminols 7a,a ,b
-azanorborn-5-enes 3 (R¼CH ePh) and elaboration of the
2
0
afford the carbocyclic skeleton for the linear construction of
the purine rings. Functionalization of the chloropurines
0
4.3. Synthesis of the pyrimidine derivatives 8a,a ,b
0
9
a,a ,b with a variety of amines extended the synthetic poten-
0
tial of this strategy allowing for a fine tuning of their biolog-
ical and antiviral activity as well as comparison with the
corresponding nor-nucleosides.
To aminols 7a,a ,b (1.70 g, 7.32 mmol) dissolved in
n-BuOH (75 mL), 5-amino-4,6-dichloropyrimidine (2.55 g,
15.5 mmol) and i-Pr NEt (4.02 g, 31.1 mmol) were added.
2
ꢀ
Biological evaluation of the newly obtained compounds
0
The mixtures were heated at 117 C with stirring for 48 h.
1
4
4
0a,a ,b is actually in progress.
The cooled solutions were evaporated to dryness, taken up
in CH Cl , washed with brine, and dried over anhydrous
Na SO . The crude residues were then submitted to column
chromatography to separate the excess of amino-pyrimidine
from adducts 8aec, which were isolated in 72, 79, and 75%
yields, respectively.
2
2
. Experimental
2
4
.1. General
All melting points are uncorrected. Elemental analyses
were done on a C. Erba 1106 elemental analyzer. IR spectra
Nujol mulls) were recorded on an FT-IR PerkineElmer
4.3.1. Compound 8a
Yield: 1.90 g, 72% as white crystals from ethanol, mp 175e
(
1
13
ꢀ
RX-1. H and C NMR spectra were recorded on a Bruker
AVANCE 300 in the specified deuterated solvents. Chemical
shifts are expressed in parts per million from internal tetra-
methylsilane (d). UVevis spectra were recorded on a UV
PerkineElmer LAMBDA 16 spectrophotometer using aceto-
nitrile as solvent. HPLC analyses were carried out by means
of a WATERS 1525 instrument equipped with an UV 2487 de-
tector (l¼266 nm) both controlled by BreezeÔ software and a
RP C-18 Intersil ODS-2 column; a mixture of H O/CH CN
180 C; [Found C, 56.6; H, 5.0; N, 19.3. C H N O Cl
7 18 5 2
1
(MW¼359.82) requires C, 56.75; H, 5.04; N, 19.46%]; n
max
ꢁ
1
(Nujol) 3411, 3348, 3303, 3257, 1658 cm ; d (300 MHz,
H
CD COCD ) 8.03 (1H, s, CH]N), 7.91 (2H, m, Ph), 7.39
3
3
(3H, m, Ph), 7.01 (1H, d, J 6.9 Hz, NH), 5.22 (1H, dd, J 9.6,
3 Hz, H5-isoxaz.), 4.85 (1H, m, CHeNH), 4.54 (1H, t, J
4.5 Hz, CH eOH), 4.43 (2H, br s, NH ), 4.29 (1H, dd, J 9.6,
2
2
3 Hz, H4-isoxaz.), 3.89 (2H, m, CH eOH), 1.59 (1H, m, CH),
2
2.29 (1H, m, HeCH), 1.77 (1H, dt, J 13, 5 Hz, HeCH); dC
(75 MHz, CD COCD ) 158.6, 153.7, 148.3, 140.9, 130.9,
130.7, 129.8, 128.5, 124.7, 90.6, 64.3, 61.0, 57.7, 50.7, 36.3.
2
3
5
0:50 was used as eluant. Column chromatography and
3
3
TLC: silica gel 60 (0.063e0.200 mm) (Merck); eluant chloro-
form. The identification of samples from different experiments
was secured by mixed mps and superimposable IR spectra.
0
4.3.2. Compound 8a
Yield: 1.98 g, 75% as white crystals from ethanol,
ꢀ
4
.2. Materials
mp>210 C (dec); [Found C, 56.7; H, 5.0; N, 19.5.
C H N O Cl (MW¼359.82) requires C, 56.75; H, 5.04; N,
1
7
18
5
2
ꢁ
1
(Nujol) 3412, 3368, 3300, 3157, 1646 cm ; d
ADA cycloadduct 3 has been prepared according to
19.46%]; n
max
H
0
12
Grieco s procedure. Benzhydroximoyl chloride was prepared
(300 MHz, CD COCD ) 8.09 (2H, m, Ph), 7.93 (1H, s, CH]
3 3
1
8
according to the reported method. The cycloaddition of BNO
to ADA cycloaddutct 3 was performed according to the proce-
dure described in the previous study, as well as the oxidation
of the regioisomeric 1,3-dipolar cycloadducts with m-CPBA
and the Polonovski rearrangement of the N-oxides with acetic
N), 7.46 (3H, m, Ph), 6.30 (1H, d, J 5 Hz, NH), 5.27 (1H, dd, J
9, 5 Hz, H5-isoxaz.), 4.72 (2H, br s, NH ), 4.65 (1H, t, J 6 Hz,
2
CH eOH), 4.43 (1H, d, J 9 Hz, H4-isoxaz.), 3.91 (1H, m,
2
CHeNH), 3.71 (2H, AB syst., J 13 Hz, CH eOH), 2.88 (1H,
2
m, CH), 2.02 (1H, m, HeCH), 1.56 (1H, m, HeCH); dC
(75 MHz, CD COCD ) 157.9, 153.1, 147.7, 139.9, 130.9,
130.7, 129.9, 128.6, 125.0, 87.8, 62.1, 60.7, 57.6, 49.2, 34.3.
1
4
anhydride.
The N-acetyl derivatives 4 were then dissolved in CCl4
40 mL/g) and 1.5 equiv NBS was added along with
3
3
(
1
5 mol % of AIBN. The mixtures were refluxed at reflux mon-
4.3.3. Compound 8b
Yield: 2.08 g, 79% as white crystals from ethanol, mp 118e
itoring the reaction by TLC until the starting materials have
disappeared (2e3 h). The solutions were cooled down to am-
bient and then to lower temperature in an ice-bath to ensure
the maximum separation of succinimide. From the filtrate or-
ganic phases the solvent was removed upon evaporation and
the crude residues were submitted to chromatographic separa-
tion on silica gel by eluting initially with CHCl and CHCl /
ꢀ
120 C; [Found C, 56.7; H, 5.1; N, 19.5. C H N O Cl
7 18 5 2
1
(MW¼359.82) requires C, 56.75; H, 5.04; N, 19.46%]; n
max
ꢁ
1
(Nujol) 3391, 3327, 3283, 3233, 1654 cm ; d (300 MHz,
H
CD COCD ) 7.90 (1H, s, CH]N), 7.83 (2H, m, Ph), 7.46
3
3
(3H, m, Ph), 6.85 (1H, d, J 6.4 Hz, NH), 5.11 (1H, d, J
9 Hz, H5-isoxaz.), 4.77 (1Hþ1H, m, CHeNHþOH), 4.39 (2H,
3
3
MeOH 9:1 afterward. The bromo-cycloadducts 5 were col-
lected along with the products of their solvolysis, the acetals,
br s, NH ), 4.24 (1H, dd, J 9, 3 Hz, H4-isoxaz.), 3.87 (2H,
2
m, CH eOH), 2.46 (1H, m, CH), 2.35 (1H, m, HeCH),
2

P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
3545
1
1
5
.77 (1H, m, HeCH); d (75 MHz, CD COCD ) 154.3, 147.1,
C
41.3, 130.9, 124.3, 123.6, 123.2, 121.6, 118.0, 87.6, 58.4,
3.2, 47.9, 41.0, 27.9.
ammonia or other gaseous amines and kept in a sealed tube
ꢀ
3
3
at 50 C for 24 h. In the case of liquid amines, an excess
(50 equiv) was added to the solutions. The solutions are then
cooled and concentration of the solutions afforded oily resi-
dues from which the amino derivatives were crystallized
from the proper solvent. Table 1 reports the physical constants
(solvent of crystallization) and yields (determined by HPLC
0
4
.4. Construction of the purine nucleosides 9a,a ,b
0
To a solution of pyrimidine derivatives 8a,a ,b (0.532 g,
.48 mmol) in triethyl orthoformate (25 mL), a catalytic
0
1
analyses) of the amino nucleosides 10a,a ,b(AeC). Ethoxy
0
amount of HCl was added. The reaction was stirred at rt for
days. After this period of time, the excess orthoformate
was hydrolyzed and the water phase extracted with CH Cl
derivatives 10a,a ,bD were obtained upon extended reaction
with ethyl orthoformate up to 14 days and further addition
of drops of 37% HCl and usual work-up.
8
2
2
and dried over anhydrous Na SO . After evaporation of the
2
4
solvent, the residue was taken up with diisopropyl ether and
0
4.5.1. Compound 10aA
Yield: 25 mg, 89% as white crystals from diisopropyl ether,
the chloropurine derivatives 9a,a ,b crystallized.
ꢀ
mp 224 C (dec); [Found C, 61.3; H, 5.1; N, 23.7. C H N O
6
1
8
18
2
4
.4.1. Compound 9a
Yield: 0.48 g, 87% as white crystals from diisopropyl
(MW¼350.37) requires C, 61.70; H, 5.18; N, 23.99%]; n
max
ꢁ
1
(Nujol) 3551, 3311, 3143, 1666 cm ; d (300 MHz,
H
ꢀ
ether, mp>200 C (dec); [Found C, 58.4; H, 4.4; N, 19.0.
C H N O Cl (MW¼369.82) requires C, 58.46; H, 4.36; N,
CD COCD ) 8.16 (1H, s, CH]N), 8.06 (1H, s, CH]N),
3
3
7.25 (5H, m, Ph), 6.63 (2H, br s, NH ), 5.36 (1H, dd, J 10,
1
8
16
5
2
2
ꢁ1
18.94%]; n
CDCl ) 8.76 (1H, s, CH]N), 8.02 (1H, s, CH]N), 7.29 (5H,
(Nujol) 3320, 1654, 1560 cm ; d (300 MHz,
5 Hz, H5-isoxaz.), 5.02 (2H, m, CHeN and H4-isoxaz.),
4.07 (1H, br s, OH), 3.84 (2H, m, CH eOH), 2.42 (3H, m,
max
H
3
2
m, Ph), 5.47 (1H, dd, J 10, 6 Hz, H5-isoxaz.), 4.97 (1H, m,
CHeN), 4.82 (1H, dd, J 10, 7 Hz, H4-isoxaz.), 4.01 (2H, m,
CH eOH), 2.58 (2H, m, CH ), 2.43 (1H, m, CH); d
C
CH2 and CH); dC (75 MHz, CD COCD ) 165.2, 159.2,
3
153.6, 148.6, 141.4, 138.4, 131.0, 129.9, 129.8, 128.0, 89.4,
63.4, 61.2, 58.3, 50.0, 36.4.
3
2
2
(
75 MHz, CDCl ) 159.3, 156.6, 151.8, 144.5, 144.3, 129.0,
3
1
28.5, 127.6, 126.7, 122.3, 88.0, 62.9, 61.0, 57.9, 48.0, 34.3.
4.5.2. Compound 10aB
Yield: 27 mg, 92% as white crystals from diisopropyl ether,
0
ꢀ
4
.4.2. Compound 9a
Yield: 0.45 g, 82% as white crystals from benzene/n-hex-
mp 186e188 C; [Found C, 62.3; H, 5.5; N, 23.0. C H N O
1
9
20
6
2
(MW¼364.40) requires C, 62.62; H, 5.53; N, 23.06%]; n
max
ꢀ
ꢁ1
ane, mp>200 C (dec); [Found C, 58.5; H, 4.3; N, 18.9.
C H N O Cl (MW¼369.82) requires C, 58.46; H, 4.36; N,
(Nujol) 3402, 3257, 1625 cm ; d (300 MHz, CD COCD )
3
H
3
8.23 (1H, s, CH]N), 8.01 (1H, s, CH]N), 7.31 (5H, m,
Ph), 6.87 (1H, br s, NH), 5.36 (1H, dd, J 10, 5 Hz, H5-isoxaz.),
5.03 (2H, m, CHeN and H4-isoxaz.), 4.11 (1H, br s, OH),
3.83 (2H, m, CH eOH), 2.40 (3H, m, CH and CH), 2.06
1
8
16
5
2
ꢁ
1
1
8.94%];
n
(Nujol) 3353, 1655, 1580 cm
;
d
H
max
(
300 MHz, CDCl ) 8.80 (1H, s, CH]N), 8.13 (1H, s,
3
CH]N), 7.68 (2H, m, Ph), 7.43 (3H, m, Ph), 5.67 (1H, dd,
J 9, 5 Hz, H5-isoxaz.), 5.15 (1H, d, J 6 Hz, CHeN), 4.93
2
2
(3H, d, J 7 Hz, CH ); d (75 MHz, CD COCD ) 159.0,
3
C
3
3
(
(
1H, d, J 9 Hz, H4-isoxaz.), 4.00 (2H, m, CH eOH), 3.13
2
1H, m, CH), 2.24 (2H, m, CH ); dC (75 MHz, CDCl3)
2
153.8, 140.8, 131.0, 130.2, 129.8, 128.5, 128.0, 89.5, 63.3,
61.2, 58.3, 49.9, 36.5, 27.7.
1
1
56.5, 151.9, 151.3, 144.0, 134.0, 130.7, 129.1, 127.5,
26.9, 88.3, 61.2, 61.0, 58.9, 47.6, 34.0.
4.5.3. Compound 10aC
Yield: 28 mg, 90% as yellowish oil; [Found C, 64.5; H, 5.6;
N, 21.5. C H N O (MW¼390.43) requires C, 64.60; H,
4
.4.3. Compound 9b
Yield: 0.46 g, 84% as white crystals from diisopropyl ether,
2
1
22
6
2
ꢁ
1
(Nujol) 3297, 1622, 1572 cm ; d
5.68; N, 21.53%]; n
max
H
ꢀ
mp>200 C (dec); [Found C, 58.5; H, 4.5; N, 19.1.
C H N O Cl (MW¼369.82) requires C, 58.46; H, 4.36; N,
(300 MHz, CD COCD ) 8.24 (1H, s, CH]N), 8.02 (1H, s,
3 3
CH]N), 7.23 (5H, m, Ph), 6.91 (1H, br s, NH), 5.32 (1H,
dd, J 10, 5 Hz, H5-isoxaz.), 5.03 (2H, m, CHeN and H4-iso-
xaz.), 3.83 (2H, m, CHeNH and CH), 3.73 (2H, m, OeCH2),
2.70 (2H, m, CH ), 0.89 (2H, m, CH ), 0.63 (2H, m, CH ); d
C
1
8
16
5
2
ꢁ
1
1
8.94%];
n
(Nujol) 3373, 1597, 1561 cm
;
d
H
max
(
300 MHz, CDCl ) 8.80 (1H, s, CH]N), 8.27 (1H, s,
3
CH]N), 7.78 (2H, m, Ph), 7.48 (3H, m, Ph), 5.74 (1H, dd,
J 10, 6 Hz, H5-isoxaz.), 4.99 (1H, m, CHeN), 4.47 (1H, dd,
2
2
2
(75 MHz, CD COCD ) 162.0, 152.3, 139.6, 129.6 129.5,
3
3
J 10, 5 Hz, H4-isoxaz.), 3.91 (2H, m, CH eOH), 2.64 (2H,
128.4, 126.6, 122.3, 88.1, 62.0, 59.8, 57.0, 48.6, 35.0, 22.0,
6.2, 5.3.
2
m, CH ), 2.47 (1H, m, CH); dC (75 MHz, CDCl ) 159.9,
3
2
1
6
51.6, 151.4, 144.6, 132.4, 130.5, 128.9, 128.0, 127.3, 89.1,
4.3, 63.9, 53.1, 43.9, 32.9.
4.5.4. Compound 10aD
Yield: 25 mg, 84% as white crystals from n-hexane/
benzene, mp 130e132 C; [Found C, 63.2; H, 5.6; N, 18.5.
0
ꢀ
4
.5. Syntheses of the amino derivatives 10a,a ,b
C H N O (MW¼379.41) requires C, 63.31; H, 5.58; N,
2
0
21
5
3
0
ꢁ1
;
General method: Solutions of chloro-nucleosides 9a,a ,b
30 mg, 0.08 mmol) in MeOH (2 mL) were saturated with
18.46%];
n
(Nujol) 3292, 1598, 1575 cm
d
H
max
(
(300 MHz, CDCl ) 8.52 (1H, s, CH]N), 7.75 (1H, s,
3

3546
P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
CH]N), 7.36 (2H, m, Ph), 7.25 (3H, m, Ph), 5.46 (1H, dd, J
d, J 6 Hz, CHeN), 4.93 (1H, d, J 9 Hz, H4-isoxaz.), 4.71
(2H, q, J 7 Hz, OeCH ), 4.00 (2H, m, CH eOH), 3.15 (1H,
m, CH), 2.18 (2H, m, CH ), 1.55 (3H, t, J 7 Hz, CH ); d
2 3 C
1
1
0, 5 Hz, H5-isoxaz.), 4.88 (1H, m, CHeN), 4.81 (2H, dd, J
2
2
0, 3 Hz, H4-isoxaz.), 4.72 (2H, q, J 7 Hz, OeCH ), 4.00
2
(
2H, br s, CH eOH), 2.63 (2H, m, CH ), 2.48 (1H, m, CH),
(75 MHz, CDCl ) 161.0, 156.8, 152.1, 151.6, 140.7, 130.5
3
2
2
1
1
8
.57 (3H, t, J 7 Hz, CH ); d (75 MHz, CDCl ) 161.1,
58.2, 151.9, 151.1, 141.6, 130.4 128.9, 128.2, 127.8, 126.8,
8.9, 63.4, 63.3, 61.3, 57.8, 47.9, 34.6, 14.4.
129.1, 127.7, 127.0, 122.2, 88.6, 63.2, 61.4, 60.4, 59.0, 47.5,
34.0, 14.4.
3
C
3
4
.5.9. Compound 10bA
0
4
.5.5. Compound 10a A
Yield: 25 mg, 88% as white crystals from diisopropyl ether,
Yield: (20 mg, 72%) as white crystals from n-hexane/benz-
ꢀ
ene, mp>220 C (dec); [Found C, 61.5; H, 5.2; N, 23.7.
C H N O (MW¼350.37) requires C, 61.70; H, 5.18; N,
ꢀ
mp>200 C (dec); [Found C, 61.5; H, 5.2; N, 23.8.
C H N O (MW¼350.37) requires C, 61.70; H, 5.18; N,
1
8
18
6
2
ꢁ
1
23.99%]; n
(Nujol) 3359, 3314, 3114, 1673, 1603 cm ;
1
8
18
6
2
max
ꢁ
1
(Nujol) 3426, 3399, 3329, 1654 cm ; d
2
(
3.99%]; n
300 MHz, DMSO) 8.28 (1H, s, CH]N), 8.15 (1H, s,
d (300 MHz, CD COCD ) 8.22 (1H, s, CH]N), 8.19 (1H,
H 3 3
s, CH]N), 7.86 (2H, m, Ph), 7.50 (3H, m, Ph), 6.52 (2, br
s, NH ), 5.84 (1H, dd, J 10, 6 Hz, H5-isoxaz.), 4.98 (1H, m,
CHeN), 4.45 (1H, dd, J 10, 6 Hz, H4-isoxaz.), 4.26 (1H, t,
J 5 Hz, OH), 3.79 (2H, m, CH eOH), 2.53 (2H, m, CH ),
max
H
CH]N), 7.70 (2H, m, Ph), 7.42 (3H, m, Ph), 5.45 (1H, dd,
J 8.5, 5 Hz, H5-isoxaz.), 4.95 (2H, m, CHeN and H4-isoxaz.),
.68 (2H, br, NH ), 3.70 and 3.51 (2H, AB syst., CH eOH),
2 2
2
4
2
2
2
.81 (1H, m, CH), 1.98 and 1.72 (2H, m, CH ); d
2
2.36 (1H, m, CH); dC (75 MHz, CD COCD ) 161.5, 158.9,
3 3
C
(
1
75 MHz, DMSO) 156.5, 155.9, 152.2, 149.2, 139.6, 130.1,
29.0, 128.2, 126.9, 119.1, 87.2, 59.8, 58.5, 57.8, 47.7, 34.6.
157.6, 153.8, 147.6, 141.2, 136.7, 131.2, 130.0, 128.7, 90.3,
64.7, 54.1, 49.3, 34.9, 20.0.
0
4
.5.6. Compound 10a B
Yield: 28 mg, 95% as white crystals from diisopropyl ether,
4.5.10. Compound 10bB
Yield: 25 mg, 87% as white crystals from n-hexane/ben-
ꢀ
ꢀ
mp 191e193 C; [Found C, 62.4; H, 5.4; N, 23.1. C H N O
1
zene, mp>200 C (dec); [Found C, 62.5; H, 5.4; N, 23.2.
C H N O (MW¼364.40) requires C, 62.62; H, 5.53; N,
19 20 6 2
9
20
6
2
(
(
(
MW¼364.40) requires C, 62.62; H, 5.53; N, 23.06%]; n
max
ꢁ
1
Nujol) 3318, 1630 cm ; d (300 MHz, CD COCD ) 8.29
ꢁ1
(Nujol) 3387, 1634, 1576 cm ;
23.06%];
n
d
H
H
3
3
max
1H, s, CH]N), 8.11 (1H, s, CH]N), 7.84 (2H, m, Ph),
(300 MHz, CD COCD ) 8.29 (1H, s, CH]N), 8.14 (1H, s,
3 3
7
5
.44 (3H, m, Ph), 6.83 (1H, br, NH), 5.57 (1H, dd, J 9,
Hz, H5-isoxaz.), 5.13 (1H, d, J 6 Hz, CHeN), 5.03 (1H,
CH]N), 7.87 (2H, m, Ph), 7.49 (3H, m, Ph), 6.82 (1H, br,
NH), 5.84 (1H, dd, J 10, 6 Hz, H5-isoxaz.), 4.99 (1H, m,
CHeN), 4.46 (1H, dd, J 10, 4 Hz, H4-isoxaz.), 4.30 (1H, br,
OH), 3.78 (2H, m, CH eOH), 2.81 (3H, d, J 7 Hz, CH e
dt, J 9, 1 Hz, H4-isoxaz.), 3.94 and 3.74 (1Hþ1H, AB syst.,
CH eOH), 3.16 (1H, br s, OH), 3.05 (1H, m, CH), 2.82
2
2
3
(
d (75 MHz, CD COCD ) 157.9, 153.9, 140.2, 131.2, 130.1,
3H, d, J 8 Hz, NeCH ), 2.25 and 1.95 (1Hþ1H, m, CH );
NH), 2.51 (2H, m, CH ), 2.37 (1H, m, CH); d (75 MHz,
2 C
CD COCD ) 161.0, 153.8, 140.7, 131.2, 130.5, 130.0, 128.7,
3 3
3
2
C
3
3
1
28.3, 89.1, 62.0, 61.9, 60.7, 59.7, 49.6, 35.9.
90.4, 64.7, 64.1, 54.1, 45.8, 35.0, 27.5.
0
4
.5.7. Compound 10a C
Yield: 25 mg, 80% as white crystals from diisopropyl ether,
4.5.11. Compound 10bC
Yield: 25 mg, 80% as white crystals from n-hexane/
ꢀ
ꢀ
mp 170e175 C (dec); [Found C, 64.4; H, 5.5; N, 21.4.
C H N O (MW¼390.43) requires C, 64.60; H, 5.68; N,
benzene, mp>220 C (dec); [Found C, 64.5; H, 5.6; N, 21.5.
C H N O (MW¼390.43) requires C, 64.60; H, 5.68; N,
21 22 6 2
2
1
22
6
2
ꢁ
1
ꢁ1
(Nujol) 3394, 1619, 1572 cm ;
2
1.53%];
n
(Nujol) 3328, 1655, 1618 cm
;
300 MHz, CD COCD ) 8.30 (1H, s, CH]N), 8.13 (1H, s,
d
H
21.53%];
n
d
H
max
max
(
(300 MHz, CD COCD ) 8.30 (1H, s, CH]N), 8.16 (1H, s,
3 3
3
3
CH]N), 7.84 (2H, m, Ph), 7.43 (3H, m, Ph), 6.90 (1H, br s,
NH), 5.57 (1H, dd, J 9, 5 Hz, H5-isoxaz.), 5.13 (1H, d, J
CH]N), 7.86 (2H, m, Ph), 7.47 (3H, m, Ph), 6.92 (1H, br s,
NH), 5.83 (1H, dd, J 10, 6 Hz, H5-isoxaz.), 4.98 (1H, m,
CHeN), 4.45 (1H, dd, J 10, 6 Hz, H4-isoxaz.), 4.29 (1H, br,
OH), 3.77 (2H, m, CH eOH), 2.51 (2H, m, CH ), 2.33 (1H,
6
m, CHeNH), 3.73 (2H, m, OeCH ), 3.16 (1H, br s, OH),
.6 Hz, CHeN), 5.03 (1H, d, J 9 Hz, H4-isoxaz.), 3.95 (1H,
2
2
2
3
m, CH ), 0.72 (2H, m, CH ); d (75 MHz, CD COCD )
.07 (1H, m, CH), 2.08 and 1.92 (2H, m, CH ), 0.83 (2H,
m, CH), 2.10 (1H, m, CHeNH), 0.83 (2H, m, CH ), 0.73
2
2
(2H, m, CH ); d (75 MHz, CD COCD ) 161.0, 153.7,
3
2
2
C
3
3
2
C
3
1
6
53.8, 152.5, 151.2, 140.4, 134.6, 131.2 130.1, 128.4, 89.1,
2.0, 60.7, 59.7, 49.6, 35.9, 25.0, 7.6, 7.3.
140.9, 131.2, 130.5, 130.0, 128.7, 90.3, 64.8, 64.1, 54.1,
45.8, 34.9, 23.6, 7.6, 6.7.
0
4
.5.8. Compound 10a D
Yield: 23 mg, 77% as white crystals from benzene, mp
4.5.12. Compound 10bD
Yield: 24 mg, 80% as white crystals from benzene, mp
ꢀ
ꢀ
1
71e173 C; [Found C, 63.1; H, 5.5; N, 18.4. C H N O
2
180e182 C; [Found C, 63.2; H, 5.6; N, 18.5. C H N O
20 21
0
21
5
3
5
3
(
(
MW¼379.41) requires C, 63.31; H, 5.58; N, 18.46%]; n
(MW¼379.41) requires C, 63.31; H, 5.58; N, 18.46%]; n
max
max
ꢁ
1
Nujol) 3348, 1596 cm ; d (300 MHz, CDCl ) 8.55 (1H,
ꢁ1
(Nujol) 3294, 1597, 1575 cm ; d (300 MHz, CDCl ) 8.55
H
H
3
3
s, CH]N), 7.88 (1H, s, CH]N), 7.72 (2H, m, Ph), 7.44
3H, m, Ph), 5.66 (1H, dd, J 9, 5 Hz, H5-isoxaz.), 5.11 (1H,
(1H, s, CH]N), 8.01 (1H, s, CH]N), 7.77 (2H, m, Ph),
7.48 (3H, m, Ph), 5.71 (1H, dd, J 10, 5 Hz, H5-isoxaz.),
(

P. Quadrelli et al. / Tetrahedron 64 (2008) 3541e3547
3547
4
.96 (1H, m, CHeN), 4.71 (2H, q, J 7 Hz, OeCH ), 4.47 (1H,
8. (a) Bodnar, B. S.; Miller, M. J. J. Org. Chem. 2007, 72, 3929e3932; (b)
Wang, J.; Froeyen, M.; Herdewijn, P. Adv. Antiviral Drug Des. 2004, 4,
2
dd, J 10, 5 Hz, H4-isoxaz.), 3.90 (2H, m, CH eOH), 2.94 (1H,
br, OH), 2.67 (2H, m, CH ), 2.49 (1H, m, CH), 1.55 (3H, t,
2
J 7 Hz, CH ); d (75 MHz, CDCl ) 160.0, 151.7, 141.6,
1
3
2
1
19e145; (c) Miller, M. J. Proceedings of the International Symposium
on Advances in Synthetic, Combinatorial and Medicinal Chemistry,
Moscow, Russia, May 5e8, 2004; T14 and P140. (d) Vogt, P. F.; Miller,
M. J. Tetrahedron 1998, 54, 1317e1348; (e) Boger, L.; Weinreb, S. M.
Hetero DielseAlder Methodology in Organic Synthesis; Academic: San
Diego, CA, 1987.
3
C
3
30.3, 128.8, 128.2, 127.3, 89.8, 64.6, 63.2, 53.5, 44.2, 33.1,
0.8, 14.4.
9
. (a) Sato, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839e3842; (b)
Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579e3582; (c)
Flower, K. R.; Lightfoot, A. P.; Wan, H.; Whiting, A. J. Chem. Soc.,
Perkin Trans. 1 2002, 2058e2064; (d) Iwasa, S.; Fakhruddin, A.;
Tsukamoto, Y.; Kameyama, M.; Nishiyama, H. Tetrahedron Lett. 2002,
Acknowledgements
Financial support by University of Pavia (FAR) and MIUR
PRIN 2005) is gratefully acknowledged.
(
4
3, 6159e6161; (e) Ware, R. W., Jr.; Day, C. S.; King, S. B. J. Org.
Chem. 2002, 67, 6174e6180; (f) Chow, C. P.; Shea, K. J.; Sparks,
S. M. Org. Lett. 2002, 4, 2637e2640; (g) Surman, M. D.; Mulvihill,
M. J.; Miller, M. J. Tetrahedron Lett. 2002, 43, 1131e1134; (h) Surman,
M. D.; Mulvihill, M. J.; Miller, M. J. J. Org. Chem. 2002, 67, 4115e4121;
(i) Iwasa, S.; Tajima, K.; Tsushima, S.; Nishiyama, H. Tetrahedron Lett.
2001, 42, 5897e5899.
References and notes
1
. (a) Hnang, W.; Miller, M. J.; De Clercq, E.; Balzarini, J. Org. Biomol.
Chem. 2007, 5, 1164e1166 and references therein; (b) Mizuno, Y. The
Organic Chemistry of Nucleic Acids; Kadansha: Tokyo, 1986; (c) Ueda,
T. Chemistry of Nucleosides and Nucleotides; Townsend, Ed.; Plenum:
New York, NY, 1988; Vol. 1, Chapter 1; (d) Srivasta, P. C.; Robins,
R. K.; Meyer, R. B., Jr. Chemistry of Nucleosides and Nucleotides; Town-
send, Ed.; Plenum: New York, NY, 1988; Vol. 1, Chapter 2; (e) Revenkar,
G. R.; Robins, R. K. Chemistry of Nucleosides and Nucleotides;
Townsend, Ed.; Plenum: New York, NY, 1988; Vol. 2, Chapter 4; (f)
Bloomfield, V. A.; Crothers, D. M.; Tinoco, I., Jr. Nucleic Acids; Univer-
sity Science Books: Sausalito, CA, 2000; pp 13e43.
10. (a) Quadrelli, P.; Gamba Invernizzi, A.; Caramella, P. Tetrahedron Lett.
1996, 37, 1909e1996; (b) Quadrelli, P.; Mella, M.; Gamba Invernizzi,
A.; Caramella, P. Tetrahedron 1999, 55, 10497e10510; (c) Quadrelli,
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