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Tetrahedron 60 (2004) 3643–3651

From cyclopentadiene to isoxazoline – carbocyclic nucleosides:


a rapid access to biological molecules through
nitrosocarbonyl chemistry
Paolo Quadrelli,a,* Roberto Scrocchi,a Pierluigi Caramella,a Antonio Rescifinab
and Anna Pipernoc
a
Dipartimento di Chimica Organica, Università degli Studi di Pavia, Viale Taramelli, 10 I-27100 Pavia, Italy
b
Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria, 8 I-95125 Catania, Italy
c
Dipartimento Farmaco-Chimico, Università degli Studi di Messina, Viale S.S. Annunziata I-98168 Messina, Italy
Received 17 November 2003; revised 3 February 2004; accepted 25 February 2004

Abstract—A rapid access to carbocyclic nucleosides containing a fused isoxazoline ring is proposed starting from cyclopentadiene. The
route involves an hetero Diels – Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile
oxides, cleavage of the N– O tether and elaboration of the heterocyclic aminols into nucleosides via linear construction of purine and
pyrimidine heterocycles.
q 2004 Elsevier Ltd. All rights reserved.

1. Introduction mediates affording the HDA adducts 2 (Scheme 1), which


were found to be highly reactive dipolarophiles in the 1,3-
Nucleosides are primary building blocks of biological dipolar cycloaddition of nitrile oxides.10 Detachment of the
systems and are processed into nucleic acids.1 – 3 Many acyl moiety in cycloadducts of type 3 and reductive
efforts have been recently addressed in the search for cleavage of the N – O bond afforded quantitatively the
nucleoside analogues as non-toxic, selective inhibitors of stereodefined anti aminols 410 which could serve as the
kinases and polymerases with increased antiviral power.4 – 6 appropriate precursors of nucleosides through assembly of
In particular, carbocyclic nucleosides, where the sugar purine and pyrimidine rings.
portion of the nucleoside has been replaced with a
cyclopentane ring, have been found to be highly resistant
to host enzymes.7 Even though the exact mechanism of
these antivirals is not fully understood, new inhibitors of a
variety of viral infective agents are extensively proposed by
different research groups.8 The construction of carbocyclic
nucleosides can be achieved mainly through two synthetic
approaches regarding the attachment of the heterocyclic
base: (1) linear construction of the heterocyclic base starting
from an amino substituted carbocycle: (2) convergent
attachment of an intact heterocyclic base to an appropriately
Scheme 1.
substituted carbocyclic ring via nucleophilic substitution.
On pursuing our studies on the synthetic potential of the
We have recently found that the chemistry of nitrosocarbo- nitrosocarbonyl adducts 2, we detail the first synthesis of a
nyls (RCONO) can be applied since these intermediates are class of racemic purine- and pyrimidine – carbocyclic
highly reactive in hetero Diels– Alder (HDA) reactions.9 nucleosides containing a fused isoxazole ring and lacking
Cyclopentadiene 1 efficiently traps these fleeting inter- a methylene (CH2) group in the side chain in the carbocyclic
unit. Nucleosides lacking a methylene group in the side
chain have been reported and in some cases display reduced
Keywords: Carbocyclic nucleosides; Nitrosocarbonyls; Nitrile oxides;
Cycloadditions.
cytotoxicity.11 The paper gives a complete account on the
* Corresponding author. Tel.: þ39-0382-507315; fax: þ39-0382-507323; purine and pyrimidine rings construction and further
e-mail address: paolo.quadrelli@unipv.it functionalization of the purine compounds.

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.057
3644 P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651

2. Results the 1H NMR spectra were unambiguously consistent for the


assigned structures. The spectrum of 6a in CDCl3 showed
2.1. Construction of the purine heterocycles the pyrimidine ring proton as a singlet at d 8.08, the NH2 and
OH protons as a broad singlet at d 3.62 and 3.50, the NH
By adapting known procedures for the construction of the proton as a doublet at d 6.41 (J¼8.6 Hz) and the 5- and
purine nucleus,8b,12 we have converted the stereodefined 4-isoxazoline protons at d 5.16 (d, J¼8.7 Hz) and 4.29 (d,
aminols 4a,b into the pyrimidine derivatives 6a,b by J¼8.7 Hz), respectively, while the cyclopentane protons are
substitution of 5-amino-4,6-dichloropyrimidine 5 and then at d 4.92 (m, CH –N), 4.62 (d, J¼3.2 Hz, CH –O) and 2.00
into the chloropurines 7a,b by condensation with ortho- (m, CH2). The spectrum of the stereoisomeric 6b is
formates (Scheme 2). essentially similar, showing the pyrimidine singlet at d
8.15, the NH2 and OH at d 3.51, the NH at d 6.10 (d,
J¼8.8 Hz) and the 5- and 4-isoxazoline protons d 5.25 (d,
J¼8.8 Hz) and 4.25 (d, J¼8.8 Hz) while the cyclopentane
protons are at d 4.99 (m, CH – N), 4.64 (m, CH –O) and 2.10
(m, CH2).

The conversion of the stereoisomeric pyrimidine 6a,b into


the corresponding chloropurines 7a,b was somewhat
problematic. The results obtained under various conditions
are collected in Table 1. On applying the frequently reported
methods14 using triethyl orthoformate in the presence of
37% HCl at rt no condensation took place and the starting
materials were recovered unchanged after the suggested
work-up (entries 1 and 2). Upon replacing the HCl with
acetic anhydride or acetic acid and performing the reactions
at 100 8C,15 the desired compounds 7a,b (entries 3 and 4)
could be eventually obtained, albeit in poor yields. The use
of diethoxymethyl acetate12a,16 instead of triethyl ortho-
Scheme 2. formate did not improve significantly the yields after
heating for 1 h at 100 8C (entries 5 and 6).
The pyrimidine derivatives 6a,b were obtained in moderate
yields (6a, 52%: 6b, 49%) by refluxing a solution of the The conversion of the stereoisomeric pyrimidines 6a,b into
aminols 4a,b and 5-amino-4,6-dichloropyrimidine 5 the chloropurines 7a,b could finally be achieved in excellent
(2 equiv.) in n-BuOH (bp 117 8C) in the presence of an yield by treatment with triethyl orthoformate in the presence
excess of i-Pr2NEt (5 equiv.) for 48 h. Yields were less of catalytic p-TsOH by keeping the reactions at rt for 8 days
satisfactory in n-PrOH (bp 97 8C) leading to the pyrimidine (entries 7 and 8). Isolation and purification of 7a,b were
derivatives 6a,b in somewhat lower yields (6a, 47%: 6b, secured by evaporation of triethyl orthoformate, addition of
30%). Duplicate experiments in n-BuOH with a larger Et3N to the chloroform solution of the residues, washings
excess of base (i-Pr2NEt, 10 equiv.) led to a decrease in the with water and column chromatography of the organic
reaction yields (6a, 35%: 6b, 32%). From all indications residues.
obtained so far, n-BuOH is the most appropriate solvent for
these reactions while more basic conditions are detrimental The chloropurines 7a,b have been fully characterized
presumably because of the sensitivity of the isoxazoline spectroscopically. Infrared spectra show a single broad
moieties to severe basic conditions, which can often cause band at 3556 cm21 (7a) and 3291 cm21 (7b) corresponding
ring cleavage.13 to the OH absorptions. In the 1H NMR spectra the two
NvCH protons of the purine rings occur as singlets at d
The structures of 6a,b rely upon analytical and spectro- 8.77 and 8.49 for 7a and at d 8.81 and 8.39 for 7b while the
scopic data. While the IR spectra of pyrimidines 6a,b 5- and 4-isoxazolinic protons appear as doublets at d 5.40
exhibit complex series of bands between 3200 and and 4.59 (J¼9 Hz) for 7a and at d 5.59 and 4.55 (J¼8.7 Hz)
3430 cm21 due to the presence of OH, NH and NH2 groups, for 7b. In order to have a firm structural assignment, a single
Table 1. Conversion of pyrimidine derivatives 6a,b into chloropurines 7a,b upon various reaction conditions

Entry Compound Formate and solvent Acid T (8C) Time Product (%)

1 6a CH(OEt)3 HCl 37% 25 14 h 6a


2 6b CH(OEt)3 HCl 37% 25 14 h 6b
3 6a CH(OEt)3 Ac2Oa 100 20 h 7a (39)
4 6b CH(OEt)3 AcOH cat. 100 20 h 7b (20)
5 6a DEMAb / 100 1h 7a (30)
6 6b DEMAb / 100 1h 7b (35)
7 6a CH(OEt)3 p-TsOH cat. 25 8 days 7a (91)
8 6b CH(OEt)3 p-TsOH cat. 25 8 days 7b (89)
a
Ratio 1:1 with respect to triethyl orthoformate.
b
DEMA, diethoxymethyl acetate.
P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651 3645

crystal of 7a was submitted to X-ray analysis which isoxazolinic protons to the adjacent CHO methines is
substantiated the attributed structure.17 negligible in 8Aa and sizeable in 8Ab (J¼3 Hz).

From the chloro-substituted nucleosides 7a,b a variety When fused to an isoxazolinic ring or similar rings19 the
of derivatives can be obtained by nucleophilic substi- cyclopentane moiety usually adopt an envelope confor-
tution.8b,12b,18 On heating MeOH solutions of 7a,b at 50 8C mation with the flap directed toward the isoxazoline ring
in the presence of an excess of NH3 or other differently thus giving a boat-like appearance to the bicyclic system.
substituted primary and secondary amines, the amino The conformation of the bicyclic system with the flap
derivatives 8a,b(A-G) could easily be obtained (Scheme 3). directed away from the isoxazoline ring looks like a chair
and is higher in energy.

Figure 1 shows the B3LYP/6-31Gp20 optimized structure of


the boat-like and chair-like conformations of the parent 2,3-
oxaza[3.3.0]bicyclooct-3-ene. The boat-like conformation
allows for the relief of non-bonded interactions between the
heterocyclic ring and the substituents on the adjacent
cyclopentane carbons and causes the dihedral angles
between the isoxazoline protons and the adjacent trans
cyclopentane protons to be near 908, that is, with a vanishing
coupling constant.

Scheme 3.

Table 2 reports the chemical yields and physical constants


of nucleosides 8a,b(A-G) which have been fully character-
ized through their analytical and spectroscopic data.

Table 2. Yields and physical constants of purine derivatives 8a,b

R R0 Mp (8C) (Solv.) Yields (%)

8aA H H 129 –132 (EtOH) 66


8aB H Me 228 –230 (MeOH) 99
8aC H Et 212 –3 (MeOH) 97
8aD Me Me 205 –8 (MeOH) 98
8aE H CH2Ph 222 –6 (MeOH) 93
8aF H c-Pr 233 –4 (AcOEt) 73
8aG H c-Hept Thick oil 94
8bA H H 223 –5 (MeOH) 74
8bB H Me 260 –2 (MeOH) 98
8bC H Et 196 –200 (MeOH) 96
8bD Me Me 169 –170 (MeOH) 100
8bE H CH2Ph 192 –4 (MeOH) 94
8bF H c-Pr 216 dec. (MeOH) 99
8bG H c-Hept 199 –201 (AcOEt) 92

The IR spectra of the adenine derivatives 8aA and 8bA


showed neat and distictive OH bands (3524 and 3310 cm21,
respectively) and NH2 bands (3269, 3119 and 3288,
3143 cm21, respectively). The 1H NMR spectra showed
the characteristic signals of adenine (CH¼singlets at d 7.78, Figure 1. (a) Boat- and chair-like conformations of 2,3-
8.40 and 8.24, 8.36, respectively). Unlike the previous oxaza[3.3.0]bicyclooct-3-ene, whose numbering system is shown in the
case of the boat conformer. Relative energies are given near the
cases, however, the isoxazolinic protons are no longer neat conformational labels. Curved arrows specify the dihedral angles in
doublets but one or both the isoxazolinic protons occur as degrees between the bridge-head protons and the protons of the adjacent
double doublets, because of an additional coupling with the methylenes. Numbers in parentheses are the ring puckering amplitudes Q
adjacent cyclopentane methines, thus indicating a confor- and phase angles F of the cyclopentane moieties along the 5–4– 4a– 6a–6
perimeter. Structures Aa, Ab and Ua, Ub shown in (b) and (c) are simple
mational change in the cyclopentane ring. The new coupling models lacking the phenyl substituent of the adenine nucleosides 8Aa, 8Ab
constants are sizeable for the isoxazolinic protons adjacent and the uracil nucleosides 11Ua, 11Ub, respectively. Dashed lines indicate
to the CH – N methine (J¼3 – 4 Hz) while the coupling of the hydrogen bonds and the distances are given in Å.
3646 P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651

In the adenine derivatives a conformational change ensues to uracil and thymine nucleosides involves the steps
in order to accommodate a strong intramolecular hydrogen illustrated in Scheme 4 and started with the preparation of
bond between the OH and the basic adenine N3 nitrogen. the appropriate isocyanate 9U,T.
This causes a flattening of the cyclopentane envelope as
well as some twisting around the fused bond of the bicyclic The 3-methoxy-2-propenoyl isocyanate 9U was easily
array toward a half-chair cyclopentane conformation19c obtained starting from the commercially available methyl
with the adenine moiety projecting outside. Figure 1b shows 3-methoxy-2-propenoate through basic hydrolysis to the
the optimized B3LYP/6-31Gp structures of models of the acid,25 conversion to the chloride with thionyl chloride26
adenine derivatives 8aA and 8bA lacking the phenyl ring. and coupling with silver cyanate in benzene.25 The
The relevant dihedral angles around the CH –CHN bonds 3-methoxy-2-methyl-2-propenoyl isocyanate 9T was
increase to 109– 1148 while those around the CH –CHO similarly obtained from the corresponding methyl
bonds show only negligible or modest changes to 958, in 3-methoxy-2-methyl-2-propenoate. The latter is available
agreement with the observed trend in the coupling from the simple methyl methacrylate according to a
constants. The distances involved in the intramolecular convenient reported protocol.27
hydrogen bonding are given in the figure and correspond
well to cases of strong hydrogen bonding.21 The addition reactions of the aminols 4a,b to isocyanates
9U,T were conducted according to the procedure reported in
The ring puckering parameters of the cyclopentane moieties the literature25 by performing the reactions at 220 8C in
(puckering amplitudes Q and phase angle F)22 are also DMF solutions for 12 h. After chromatographic purification,
given in Figure 1. The puckering amplitudes Q demonstrate the urea adducts 10a,b(U,T) were obtained in fair yields
the flattening of the cyclopentane ring in the hydrogen (50%). Their structures rely upon the analytical and
bonded structures while the phase angles indicate their neat spectroscopic data. Table 3 reports the yields, the physical
distortions to the half-chair conformation having the two constants and the significative spectroscopic data. Neat
carbons of the CH2CH(OH) moiety out of plane.23 distinctive bands corresponding to the OH and the two NH
groups were evident in the IR spectra. The NMR spectra
The N-substituted derivatives 8a(B-G) display spectro- showed the signals of the methoxy propenoyl and methyl
scopic patterns essentially similar to the adenine derivatives propenoyl chains as well as those of the carbocyclic moiety
and consistent with the substituents. in the usual ranges.

2.2. Construction of the pyrimidine nucleosides Table 3. Yields, physical constants and significative spectroscopic data of
the ureas 10 and nucleosides 11
The stereoisomeric aminols 4a,b were also converted into Compounds Yield (%) Mp (8C) (EtOH) IR (cm21)
the uracil and thymine nucleosides24 through the linear
construction of these heterocycles.4,6,25 The synthetic route nOH nNH

10Ua 53 245 dec. 3493 3282–3240


10Ta 50 231 dec. 3536 3327–3243
10Ub 52 221–2 3474 3274–3253
10Tb 48 226–7 3485 3237–3343
11Ua 70 143–4 3500 3180
11Ub 65 112–3 3400 3180
11Ta 64 245–6 3461 3153
11Tb 61 218–9 3323 3141

Cyclization of the ureas 10 took place smoothly upon


refluxing in 2 M H2SO4 solution for 3 h. The uracil
nucleosides 11Ua,b and the thymine analogues 11Ta,b
were isolated from these solutions after pH adjustment to 7
and extraction with dichloromethane. The yields of the
cyclization steps were satisfactory (61 – 70%) and the
structures of the nucleosides 11 rely upon their analytical
and spectroscopic data. The IR spectra of nucleosides 11
showed neat and distinct OH and NH bands, which are
reported in Table 3. The 1H NMR spectra of the uracil
nucleoside 11Ua,b showed the characteristic coupled vinyl
protons of the uracil unit as doublets at d 5.68 and 7.85
(J¼8 Hz) while the thymine nucleosides 11Ta,b display the
vinyl proton and the methyl of the thymine unit as singlets at
d 7.7– 7.8 and 1.80, respectively.

Both the isoxazolinic protons occur as double doublets


owing to a conformational change due to a favorable strong
intramolecular hydrogen bond between the OH and the
Scheme 4. uracil and thymine carbonyl as in the case of the adenine
P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651 3647

derivatives. Figure 1c shows the optimized structures of chromatography to separate the excess of amino-pyrimidine
models of the uracil derivatives. 5 from adducts 6a,b which were isolated in 52 and 49%
yield, respectively.

3. Conclusions 4.1.1. Compound 6a. The title compound (1.40 g, 52%) as


white crystals from ethanol, mp 215 – 216 8C: [found C,
The first synthesis of isoxazoline– carbocyclic nucleosides 55.6: H, 4.7: N, 20.3. C16H16N5O2Cl (MW¼345.79)
and a variety of analogues was attained starting from the requires C, 55.58: H, 4.66: N, 20.25%]: nmax (Nujol)
stereodefined heterocyclic aminols 4, which are readily 3424, 3240, 3340, 3200 cm21: dH (300 MHz, CDCl3) 8.10
available through exo selective 1,3-dipolar cycloadditions (2H, m, Ph), 8.08 (1H, s, CHvN), 7.40 (3H, m, Ph), 6.41
of benzonitrile oxide to N-benzoyl-oxazanorbornene 2 (1H, d, J¼8.6 Hz, NH), 5.16 (1H, d, J¼8.7 Hz, H5-isoxaz.),
(R¼Ph) and a simple elaboration of the cycloadducts. The 4.92 (1H, m, CH –NH), 4.62 (1H, d, J¼3.2 Hz, CH – OH),
stereodefined heterocyclic aminols 4 afford the carbocyclic 4.29 (1H, d, J¼8.7 Hz, H4-isoxaz.), 3.62 (3H, bs, OH and
skeleton for the linear construction of the purine, uracil and NH2), 2.00 (2H, m, CH2): dC (75 MHz, CDCl3) 156.6,
thymine moieties. Functionalization of the chloropurines 7 153.3, 149.0, 130.2, 128.6, 128.3, 127.7, 91.5, 79.1, 60.2,
with a variety of amines extended the synthetic potential of 58.3, 56.8, 36.7, 18.3.
this strategy allowing for a fine tuning of their biological
and antiviral activity.18,28 Owing to the availability of the 4.1.2. Compound 6b. The title compound (1.32 g, 49%) as
enantiomerically pure adducts 229 the route described here white crystals from benzene, mp 119 –121 8C: [found C,
lends itself to the synthesis of optically pure nucleoside 55.6: H, 4.6: N, 20.2. C16H16N5O2Cl (MW¼345.79)
derivatives. requires C, 55.58: H, 4.66: N, 20.25%]: nmax (Nujol)
3420, 3230, 3399, 3258 cm21: dH (300 MHz, CDCl3) 8.15
Biological evaluation of the obtained compounds is in (1H, s, CHvN), 7.76 (2H, m, Ph), 7.45 (3H, m, Ph), 6.10
progress. Preliminary data show that compound 7a (1H, d, J¼8.8 Hz, NH), 5.25 (1H, d, J¼8.8 Hz, H5-isoxaz.),
possesses a good inhibitory activity against Herpes Simplex 4.99 (1H, m, CH –NH), 4.64 (1H, m, CH –OH), 4.25 (1H, d,
virus type 1 and 2. J¼8.8 Hz, H4-isoxaz.), 3.51 (2H, bs, NH2), 2.10 (2H, m,
CH2), 2.00 (1H, bs, OH): dC (75 MHz, CDCl3) 156.6, 153.5,
148.9, 130.2, 126.9, 126.7, 122.0, 90.1, 76.9, 61.8, 60.8,
4. Experimental 58.7, 37.4, 18.6.

All melting points are uncorrected. Elemental analyses were 4.2. Construction of the purine nucleosides 7a,b
done on a C. Erba 1106 elemental analyzer. IR spectra
(nujol mulls) were recorded on an FT-IR Perkin – Elmer To a solution of pyrimidine derivatives 6a,b (0.532 g,
RX-1. 1H- and 13C NMR spectra were recorded on a Bruker 1.54 mmol) in triethyl orthoformate (25 mL), a catalytic
AVANCE 300 in the specified deuterated solvents. amount of p-TsOH was added. The reaction was stirred at rt
Chemical shifts are expressed in ppm from internal for 8 days. After this period of time, the orthoformate was
tetramethylsilane (d). UV – vis spectra were recorded on a evaporated and the residue taken up with chloroform and
UV Perkin –Elmer LAMBDA 16 spectrophotometer using Et3N was added and stirred for several hours. Then the
acetonitrile as solvent. HPLC analyses were carried out by organic phase was washed with water and dried over
means of a WATERS 1525 instrument equipped with an UV anhydrous Na2SO4. After evaporation of the solvent, the
2487 detector (l¼266 nm) both controlled by Breezee residue was taken up with ethyl acetate and finally, after a
software and a RP C-18 Intersil ODS-2 column: a mixture of new evaporation to dryness, submitted to column chomato-
H2O/CH3CN 60:40 was used as eluant. Column chroma- graphy to purify the purine derivatives 7a,b.
tography and TLC: silica gel 60 (0.063 – 0.200 mm)
(Merck): eluant cyclohexane/ethyl acetate from 9:1 to 5:5. 4.2.1. Compound 7a. The title compound (0.50 g, 91%) as
The identification of samples from different experiments white crystals from ethyl acetate, mp 229 –230 8C: [found
was secured by mixed mps and superimposable IR spectra. C, 57.4: H, 4.0: N, 19.7. C17H14N5O2Cl (MW¼355.78)
requires C, 57.39: H, 3.97: N, 19.68%]: nmax (Nujol) 3556,
Materials. Aminols 4a,b were prepared through NaOH/ 1591, 1561 cm21: dH (300 MHz, CDCl3) 8.77 (1H, s,
MeOH hydrolysis and N – O bond hydrogenolysis as CHvN), 8.49 (1H, s, CHvN), 7.58 (2H, m, Ph), 7.40 (3H,
previously reported.10a Methyl 3-methoxy-2-propenoate m, Ph), 5.40 (1H, d, J¼9 Hz, H5-isoxaz.), 5.23 (1H, d,
and silver cyanate were from ACROS ORGANICS. Methyl J¼9.4 Hz, CH – N), 4.78 (1H, d, J¼4.7 Hz, CH – OH), 4.59
methacrilate was from SIGMA-ALDRICH. (1H, d, J¼9 Hz, H4-isoxaz.), 3.50 (1H, bs, OH), 2.3 – 2.7
(2H, m, CH2): dC (75 MHz, CDCl3) 156.9, 151.7, 150.6,
4.1. Synthesis of the pyrimidine derivatives 6a,b 145.6, 130.8, 129.1, 127.4, 127.0, 93.6, 77.1, 60.7, 58.8,
39.4.
To aminols 4a,b (1.70 g, 7.27 mmol) dissolved in n-BuOH
(75 mL), 5-amino-4,6-dichloropyrimidine 5 (2.55 g, 4.2.2. Compound 7b. The title compound (0.49 g, 89%) as
15.5 mmol) and i-Pr2NEt (4.02 g, 31.1 mmol) were added. white crystals from ethyl acetate, mp 234 –236 8C: [found
The mixtures were refluxed at 117 8C with stirring for 48 h. C, 57.4: H, 3.9: N, 19.7. C17H14N5O2Cl (MW¼355.78)
The cooled solutions were evaporated to dryness, taken up requires C, 57.39: H, 3.97: N, 19.68%]: nmax (Nujol) 3291,
in CH2Cl2, washed with water and dried over anhydrous 1596, 1588 cm21: dH (300 MHz, CDCl3) 8.81 (1H, s,
Na2SO4. The crude residues were then submitted to column CHvN), 8.39 (1H, s, CHvN), 7.85 (2H, m, Ph), 7.45 (3H,
3648 P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651

m, Ph), 5.59 (1H, d, J¼8.7 Hz, H5-isoxaz.), 5.26 (1H, m, (300 MHz, CDCl3) 8.36 (1H, s, CHvN), 7.66 (1H, s,
CH – N), 4.71 (1H, m, CH – OH), 4.55 (1H, d, J¼8.7 Hz, CHvN), 7.3 –7.6 (5H, m, Ph), 5.42 (1H, dd, J¼9, 1 Hz, H5-
H4-isoxaz.), 3.50 (1H, bs, OH), 2.74 (1H, m, CH2), 2.44 isoxaz.), 4.86 (1H, m, CH – N), 4.69 (1H, m, CH –OH), 4.46
(1H, m, CH2): dC (75 MHz, CDCl3) 156.9, 155.6, 151.5, (1H, dd, J¼9, 4 Hz, H4-isoxaz.), 3.60 (6H, b, CH3), 2.87
145.4, 130.5, 128.9, 127.7, 127.0, 90.4, 77.0, 63.9, 63.0, (1H, m, CH2), 2.25 (1H, m, CH2): dC (75 MHz, CDCl3)
39.5. 158.2, 151.2, 147.9, 138.7, 130.5, 129.1, 127.9, 126.8, 95.5,
77.1, 76.6, 62.2, 58.2, 40.9, 39.0.
4.3. Syntheses of the amino derivatives 8a,b
4.3.5. Compound 8aE. The title compound (93%) as white
General method. Solutions of chloro-nucleosides 7a,b crystals from methanol, mp 222– 226 8C: [found C, 67.5: H,
(30 mg, 0.08 mmol) in MeOH (2 mL) were saturated with 5.1: N, 19.8. C24H22N6O2 (MW¼426.46) requires C, 67.59:
ammonia or other gaseous amines and kept in a sealed tube H, 5.20: N, 19.71%]: nmax (Nujol) 3250, 3198 cm21: dH
at 50 8C for 24 h. In the case of liquid amines, an excess (300 MHz, CDCl3) 8.45 (s, 1H, CHvN), 7.65 (s, 1H,
(50 equiv.) was added to the solutions. The solutions are CHvN), 7.2 –7.6 (m, 10H, Ph), 6.13 (bs, 1H, NH), 5.42 (d,
then cooled and in most cases the products crystallize from J¼9 Hz, 1H, H5-isoxaz.), 4.92 (b, 2H, CH2 –Ph), 4.80 (m,
the methanolic solutions. Otherwise, concentration of the 1H, CH – N), 4.69 (m, 1H, CH –OH), 4.45 (dd, J¼9, 4 Hz,
solutions allows the amino derivatives to crystallize (with a 1H, H4-isoxaz.), 2.85 (m, 1H, CH2), 2.25 (m, 1H, CH2): dC
single exception, 8aG remains a thick oil). Table 2 reports (75 MHz, CDCl3) 157.8, 154.6, 152.1, 139.9, 137.5, 130.2,
the physical constants (solvent of crystallization) and yields 128.8, 128.4, 128.2, 128.1, 127.6, 127.4, 127.3, 126.6,
(determined by HPLC analyses) of the amino nucleosides 126.5, 126.4, 95.1, 76.8, 76.4, 61.9, 58.1, 46.1, 44.2, 40.5.
8a,b.
4.3.6. Compound 8aF. The title compound (73%) as white
4.3.1. Compound 8aA. The title compound (66%) as white crystals from ethyl acetate, mp 233 –234 8C: [found C, 63.9:
crystals from ethanol, mp 129– 132 8C: [found C, 60.8: H, H, 5.4: N, 22.4. C20H20N6O2 (MW¼376.40) requires C,
4.9: N, 24.9. C17H16N6O2 (MW¼336.35) requires C, 60.70: 63.82: H, 5.36: N, 22.33%]: nmax (Nujol) 3230, 3225 cm21:
H, 4.80: N, 24.99%]: nmax (Nujol) 3524, 3269, 3119 cm21: dH (300 MHz, CD3COCD3) 8.28 (1H, s, CHvN), 8.23 (1H,
dH (300 MHz, CDCl3) 8.40 (1H, s, CHvN), 7.78 (1H, s, s, CHvN), 7.61 (2H, m, Ph), 7.40 (3H, m, Ph), 6.95 (1H, bs,
CHvN), 7.3– 7.6 (5H, m, Ph), 5.88 (2H, bs, NH2), 5.42 NH), 5.63 (1H, d, J¼6 Hz, OH), 5.33 (1H, d, J¼10 Hz, H5-
(1H, d, J¼8 Hz, H5-isoxaz.), 4.90 (1H, m, CH – N), 4.71 isoxaz.), 5.19 (1H, m, CH –N), 4.90 (1H, dd, J¼10, 3 Hz,
(1H, m, CH – OH), 4.48 (1H, dd, J¼8, 3.4 Hz, H4-isoxaz.), H4-isoxaz.), 4.51 (1H, m, CH –OH), 2.51 (1H, m, CH2),
2.88 (1H, m, CH2), 2.29 (1H, m, CH2): dC (75 MHz, CDCl3) 2.26 (1H, m, CH2), 2.20 (1H, m, CH – NH), 0.75 (4H, m,
157.6, 155.4, 151.9, 150.2, 147.5, 140.6, 130.3, 128.8, CH2 – CH2): dC (75 MHz, CD3COCD3) 167.0, 166.2, 153.0,
127.5, 126.5, 94.9, 76.8, 61.8, 58.1, 40.4. 140.2, 129.9, 129.6, 128.7, 127.0, 93.9, 77.0, 59.1, 57.8,
39.5, 29.9, 6.2, 3.2.
4.3.2. Compound 8aB. The title compound (99%) as white
crystals from methanol, mp 228 – 230 8C: [found C, 61.7: H, 4.3.7. Compound 8aG. The title compound (94%) as thick
5.2: N, 24.0. C18H18N6O2 (MW¼350.37) requires C, 61.70: oil: [found C, 66.3: H, 6.4: N, 19.2. C24H28N6O2
H, 5.18: N, 23.99%]: nmax (Nujol) 3471, 3225 cm21: dH (MW¼432.51) requires C, 66.64: H, 6.53: N, 19.43%]:
(300 MHz, CDCl3) 8.43 (1H, s, CHvN), 7.76 (1H, s, nmax (Neat) 3340, 3339 cm21: dH (300 MHz, CD3COCD3)
CHvN), 7.3 –7.6 (5H, m, Ph), 5.96 (1H, bs, NH), 5.52 (1H, 8.26 (1H, s, CHvN), 8.23 (1H, s, CHvN), 7.60 (2H, m,
d, J¼8 Hz, H5-isoxaz.), 4.85 (1H, m, CH –N), 4.70 (1H, m, Ph), 7.32 (3H, m, Ph), 6.68 (1H, d, J¼8 Hz, NH), 5.70 (1H,
CH – OH), 4.46 (1H, dd, J¼8, 4 Hz, H4-isoxaz.), 3.28 (3H, d, J¼6 Hz, OH), 5.30 (1H, d, J¼9.4 Hz, H5-isoxaz.), 5.20
s, CH3 – NH), 2.89 (1H, m, CH2), 2.28 (1H, m, CH2): dC (1H, m, CH – OH), 4.85 (1H, dd, J¼9.4, 3 Hz, H4-isoxaz.),
(75 MHz, CDCl3) 200.3, 182.7, 152.4, 140.0, 130.5, 129.1, 4.49 (1H, m, CH – N), 2.48 (1H, m, CH2), 2.30 (1H, m,
127.9, 126.8, 95.5, 62.3, 58.4, 50.7, 40.9. CH2), 2.15 (4H, m, CH2), 1.5 –2.0 (8H, m, CH2): dC
(75 MHz, CD3COCD3) 161.1, 157.3, 152.2, 140.0, 129.9,
4.3.3. Compound 8aC. The title compound (97%) as white 128.6, 128.5, 127.0, 93.9, 76.7, 60.5, 59.0, 57.9, 39.4, 35.5,
crystals from methanol, mp 212 – 213 8C: [found C, 62.6: H, 34.6, 28.4, 28.0, 24.3, 23.9.
5.6: N, 23.1. C19H20N6O2 (MW¼364.40) requires C, 62.62:
H, 5.53: N, 23.06%]: nmax (Nujol) 3310, 3230 cm21: dH 4.3.8. Compound 8bA. The title compound (74%) as white
(300 MHz, CD3COCD3) 8.24 (1H, s, CHvN), 8.20 (1H, s, crystals from methanol, mp 223– 225 8C: [found C, 60.7: H,
CHvN), 7.61 (2H, m, Ph), 7.39 (3H, m, Ph), 6.90 (1H, bs, 4.8: N, 25.0. C17H16N6O2 (MW¼336.35) requires C, 60.70:
NH), 5.70 (1H, d, J¼6 Hz, OH), 5.32 (1H, d, J¼9.4 Hz, H5- H, 4.80: N, 24.99%]: nmax (Nujol) 3310, 3288, 3143 cm21:
isoxaz.), 5.18 (1H, m, CH –OH), 4.88 (1H, dd, J¼9.4, 3 Hz, dH (300 MHz, CD3COCD3) 8.36 (1H, s, CHvN), 8.24 (1H,
H4-isoxaz.), 4.53 (1H, m, CH –N), 3.74 (2H, b, CH2 – N), s, CHvN), 7.92 (2H, m, Ph), 7.49 (3H, m, Ph), 6.59 (2H, bs,
2.56 (1H, m, CH2), 2.30 (1H, m, CH2), 1.32 (3H, t, CH3): dC NH2), 5.56 (1H, m, OH), 5.68 (1H, dd, J¼10, 3 Hz, H5-
(75 MHz, CD3COCD3) 168.1, 162.8, 150.8, 140.6, 139.8, isoxaz.), 5.11 (1H, m, CH – N), 4.50 (1H, m, CH –OH), 4.48
139.4, 137.7, 104.7, 87.7, 87.6, 69.9, 68.5, 50.3, 45.5, 25.1. (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 2.51 (2H, m, CH2): dC
(75 MHz, CD3COCD3) 158.7, 157.3, 153.8, 152.7, 150.8,
4.3.4. Compound 8aD. The title compound (98%) as white 141.8, 131.3, 130.1, 128.6, 128.4, 91.0, 76.2, 62.8, 40.2,
crystals from methanol, mp 205 – 208 8C: [found C, 62.5: H, 30.4.
5.5: N, 23.0. C19H20N6O2 (MW¼364.40) requires C, 62.62:
H, 5.53: N, 23.06%]: nmax (Nujol) 3320 cm21; dH 4.3.9. Compound 8bB. The title compound (98%) as white
P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651 3649

crystals from methanol, mp 260 –262 8C: [found C, 61.5: H, 129.6, 128.7, 127.1, 89.9, 75.3, 61.8, 61.7, 39.2, 31.1, 6.2,
5.1: N, 23.8. C18H18N6O2 (MW¼350.37) requires C, 61.70: 3.2.
H, 5.18: N, 23.99%]: nmax (Nujol) 3220, 3223 cm21:
dH (300 MHz, CD3COCD3) 8.35 (1H, s, CHvN), 8.20 4.3.14. Compound 8bG. The title compound (92%) as
(1H, s, CHvN), 7.92 (2H, m, Ph), 7.49 (3H, m, Ph), 6.80 white crystals from ethyl acetate, mp 199 –201 8C: [found
(1H, bs, NH), 5.70 (1H, dd, J¼9, 3.3 Hz, H5-isoxaz.), 5.57 C, 66.5: H, 6.5: N, 19.4. C24H28N6O2 (MW¼432.51)
(1H, m, OH), 5.11 (1H, m, CH – N), 4.50 (1H, m, CH – OH), requires C, 66.64: H, 6.53: N, 19.43%]: nmax (Nujol)
4.48 (1H, dd, J¼9, 3 Hz, H4-isoxaz.), 2.78 (3H, s, CH3), 3340, 3320 cm21: dH (300 MHz, CD3COCD3) 8.26 (1H, s,
2.51 (2H, m, CH2): dC (75 MHz, CD3COCD3) 168.1, CHvN), 8.25 (1H, s, CHvN), 7.90 (2H, m, Ph), 7.74 (3H,
151.1, 139.5, 133.6, 132.4, 131.0, 130.7, 97.3, 65.5, 56.0, m, Ph), 6.52 (1H, d, J¼8 Hz, NH), 5.72 (1H, dd, J¼10,
40.1. 3.3 Hz, H5-isoxaz.), 5.15 (1H, m, CH – N), 4.52 (1H, m,
CH –OH), 4.45 (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 4.74 (1H,
4.3.10. Compound 8bC. The title compound (96%) as bs, OH), 3.30 (1H, m, CH –NH), 2.51 (2H, m, CH2), 2.15
white crystals from methanol, mp 196 – 200 8C: [found C, (4H, m, CH2), 1.5 –2.0 (8H, m, CH2): dC (75 MHz,
62.5: H, 5.5: N, 23.0. C19H20N6O2 (MW¼364.40) requires CD3COCD3) 156.0, 151.1, 138.7, 128.7, 127.6, 127.5,
C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3260, 125.9, 88.8, 74.0, 60.6, 60.5, 58.7, 38.0, 33.3, 32.7, 31.3,
3220 cm21: dH (300 MHz, CD3COCD3) 8.28 (1H, s, 26.3, 22.8, 22.7.
CHvN), 8.23 (1H, s, CHvN), 7.92 (2H, m, Ph), 7.50
(3H, m, Ph), 6.80 (1H, bs, NH), 5.71 (1H, dd, J¼10, 3.4 Hz, 4.4. Syntheses of the isocyanate adducts 10a,b(U,T)
H5-isoxaz.), 5.59 (1H, d, J¼6 Hz, OH), 5.11 (1H, m,
CH –N), 4.54 (1H, m, CH – OH), 4.46 (1H, dd, J¼10, 3 Hz, General method. To solutions of aminols 4a,b (2.29 mmol)
H4-isoxaz.), 3.73 (2H, bs, CH2 – N), 2.81 (2H, m, CH2), 2.56 in anhydrous DMF (10 mL) at 220 8C, solutions of
(2H, m, CH3 – CH2), 1.31 (3H, t, CH3 – CH2): dC (75 MHz, isocyanates 9U,T (2.52 mmol) in anhydrous benzene were
CD3COCD3) 158.7, 153.7, 141.2, 131.3, 130.4, 130.1, added dropwise with stirring in a nitrogen atmosphere and
128.4, 91.3, 76.7, 76.6, 63.2, 63.1, 40.6, 36.2, 15.8. in the presence of MS 4 Å. After keeping for one night at rt,
the solutions were filtered and solvent removed under
4.3.11. Compound 8bD. The title compound (100%) as reduced pressure. The residues were submitted to column
white crystals from methanol, mp 169 – 170 8C: [found C, chromatography to isolate the compounds 10a,b(U,T).
62.5: H, 5.6: N, 23.1. C19H20N6O2 (MW¼364.40) requires Table 3 reports the physical constants (solvent of crystal-
C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3240 cm21: dH lization) and the yields of the isocyanate adducts
(300 MHz, CD3COCD3) 8.28 (1H, s, CHvN), 8.26 (1H, s, 10a,b(U,T).
CHvN), 7.94 (2H, m, Ph), 7.49 (3H, m, Ph), 5.70 (1H, dd,
J¼10, 3 Hz, H5-isoxaz.), 5.62 (1H, bs, OH), 5.14 (1H, m, 4.4.1. Compound 10Ua. The title compound (0.42 g, 53%)
CH –N), 4.55 (1H, m, CH – OH), 4.47 (1H, dd, J¼10, 3 Hz, as white crystals from ethanol, mp 245 8C dec.: [found C,
H4-isoxaz.), 2.85 (3H, s, CH3), 2.69 (3H, s, CH3), 2.51 (2H, 59.1: H, 5.6: N, 12.2. C17H19N3O5 (MW¼345.35) requires
m, CH2): dC (75 MHz, CD3COCD3) 158.6, 156.1, 152.9, C, 59.12: H, 5.55: N, 12.17%]: nmax (Nujol) 3493, 3282,
151.6, 140.0, 131.2, 130.3, 130.0, 128.4, 91.3, 76.6, 63.1, 3240, 1700 cm21: dH (300 MHz, DMSO) 10.06 (1H, s, NH),
62.9, 40.4, 38.9, 38.7, 34.9. 9.27 (1H, d, J¼9 Hz, NH), 7.96 (2H, m, Ph), 7.60 (1H, d,
J¼12 Hz, vCH –OMe), 7.44 (3H, m, Ph), 5.60 (1H, d,
4.3.12. Compound 8bE. The title compound (94%) as J¼3 Hz, OH), 5.53 (1H, d, J¼12 Hz, vCH – CO), 5.00 (1H,
white crystals from methanol, mp 192 – 194 8C: [found C, d, J¼9 Hz, H5-isoxaz.), 4.42 (1H, bs, CH – N), 4.26 (1H, s,
67.6: H, 5.1: N, 20.0. C24H22N6O2 (MW¼426.46) requires CH –OH), 4.25 (1H, d, J¼9 Hz, H4-isoxaz.), 3.68 (3H, s,
C, 67.59: H, 5.20: N, 19.71%]: nmax (Nujol) 3330, CH3O), 1.71 (2H, m, CH2): dC (75 MHz, DMSO) 166.9,
3380 cm21: dH (300 MHz, CD3COCD3) 8.31 (1H, s, 162.6, 156.5, 152.8, 130.0, 128.7, 128.5, 127.1, 98.0, 91.5,
CHvN), 8.26 (1H, s, CHvN), 7.90 (2H, m, Ph), 7.2 –7.6 66.7, 60.0, 57.9, 54.3, 36.9.
(8H, m, Ph), 5.71 (1H, dd, J¼10, 3.4 Hz, H5-isoxaz.), 5.56
(1H, bs, OH), 5.56 (1H, bs, NH), 5.13 (1H, m, CH – N), 4.92 4.4.2. Compound 10Ub. The title compound (0.40 g, 50%)
(2H, b, CH2 – Ph), 4.54 (1H, m, CH –OH), 4.45 (1H, dd, as white crystals from ethanol, mp 231 8C dec.: [found C,
J¼10, 3 Hz, H4-isoxaz.), 2.51 (2H, m, CH2): dC (75 MHz, 59.2: H, 5.7: N, 12.3. C17H19N3O5 (MW¼345.35) requires
CD3COCD3) 156.1, 151.1, 139.0, 129.8, 128.7, 127.8, 127.5, C, 59.12: H, 5.55: N, 12.17%]: nmax (Nujol) 3536, 3327,
127.0, 126.2, 125.9, 125.5, 88.7, 74.1, 74.0, 60.5, 42.1, 38.0. 3243, 1700 cm21: dH (300 MHz, DMSO) 10.11 (1H, s, NH),
9.09 (1H, d, J¼8 Hz, NH), 7.76 (2H, m, Ph), 7.58 (1H, d,
4.3.13. Compound 8bF. The title compound (99%) as white J¼12 Hz, vCH –OMe), 7.47 (3H, m, Ph), 5.71 (1H, d,
crystals from methanol, mp 216 8C dec.: [found C, 63.7: H, J¼2 Hz, OH), 5.51 (1H, d, J¼12 Hz, vCH – CO), 5.02 (1H,
5.4: N, 22.2. C20H20N6O2 (MW¼376.40) requires C, 63.82: d, J¼9 Hz, H5-isoxaz.), 4.37 (1H, bs, CH – N), 4.24 (1H, s,
H, 5.36: N, 22.33%]: nmax (Nujol) 3260, 3250 cm21: dH CH –OH), 4.19 (1H, d, J¼9 Hz, H4-isoxaz.), 3.70 (3H, s,
(300 MHz, CD3COCD3) 8.30 (1H, s, CHvN), 8.25 (1H, s, CH3O), 1.74 (2H, m, CH2): dC (75 MHz, DMSO) 167.0,
CHvN), 7.90 (2H, m, Ph), 7.50 (3H, m, Ph), 6.90 (1H, bs, 162.6, 156.2, 152.9, 130.1, 128.9, 128.7, 126.7, 97.9, 91.4,
NH), 5.74 (1H, dd, J¼10, 3.3 Hz, H5-isoxaz.), 5.60 (1H, d, 75.6, 61.0, 57.9, 56.5, 36.8.
J¼6 Hz, OH), 5.14 (1H, m, CH –N), 4.51 (1H, m, CH – OH),
4.47 (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 2.51 (2H, m, CH2), 4.4.3. Compound 10Ta. The title compound (0.43 g, 52%)
2.25 (1H, m, CH –NH), 0.75 (4H, m, CH2 – CH2): dC as white crystals from ethanol, mp 221– 222 8C: [found C,
(75 MHz, CD3COCD3) 167.4, 166.2, 152.2, 140.1, 129.9, 60.1: H, 5.9: N, 11.7. C18H21N3O5 (MW¼359.37) requires
3650 P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651

C, 60.16: H, 5.89: N, 11.69%]: nmax (Nujol) 3474, 3274, 62.4: H, 5.2: N, 12.9. C17H17N3O4 (MW¼327.33) requires
3243, 1678 cm21: dH (300 MHz, DMSO) 9.73 (1H, s, NH), C, 62.37: H, 5.24: N, 12.84%]: nmax (Nujol) 3461, 3153,
9.36 (1H, d, J¼9 Hz, NH), 7.99 (2H, m, Ph), 7.46 (4H, m, 1680 cm21: dH (300 MHz, DMSO) 11.25 (1H, s, NH), 7.75
Ph and CHv), 5.61 (1H, d, J¼2 Hz, OH), 5.00 (1H, d, (1H, s, CHv), 7.48 (2H, m, Ph), 7.32 (3H, m, Ph), 5.63 (1H,
J¼9 Hz, H5-isoxaz.), 4.43 (1H, m, CH –OH), 4.27 (1H, bs, d, J¼3.8 Hz, OH), 5.08 (1H, dd, J¼10.2, 2.8 Hz, H5-
CH – N), 4.22 (1H, d, J¼9 Hz, H4-isoxaz.), 3.80 (3H, s, isoxaz.), 4.81 (1H, dt, J¼11.9, 4.8 Hz, CH –N), 4.58 (1H,
CH3O), 1.72 (2H, b, CH2), 1.63 (3H, s, CH3): dC (75 MHz, dd, J¼10.2, 4.8 Hz, H4-isoxaz.), 4.18 (1H, m, CH –O), 2.15
DMSO) 169.3, 158.3, 156.8, 153.3, 130.3, 129.0, 128.9, (1H, m, CH2), 1.90 (1H, m, CH2), 1.81 (3H, s, CH3): dC
127.5, 107.4, 91.9, 77.0, 61.4, 60.4, 54.7, 37.2, 9.2. (75 MHz, DMSO) 163.8, 157.7, 150.7, 138.8, 130.2, 128.9,
128.1, 126.9, 109.2, 92.8, 75.8, 58.3, 55.4, 38.6, 12.4.
4.4.4. Compound 10Tb. The title compound (0.40 g, 48%)
as white crystals from ethanol, mp 226– 7 8C: [found C, 4.5.4. Compound 11Tb. The title compound (28 mg, 61%)
60.2: H, 5.8: N, 11.6. C18H21N3O5 (MW¼359.37) requires as white crystals from ethanol, mp 218 –219 8C: [found C,
C, 60.16: H, 5.89: N, 11.69%]: nmax (Nujol) 3485, 3237, 61.9: H, 5.0: N, 12.6. C17H17N3O4 (MW¼327.33) requires
3343, 1689 cm21: dH (300 MHz, DMSO) 9.73 (1H, s, NH), C, 62.37: H, 5.24: N, 12.84%]: nmax (Nujol) 3323, 3141,
9.19 (1H, d, J¼9 Hz, NH), 7.76 (2H, m, Ph), 7.48 (4H, m, 1695 cm21: dH (300 MHz, DMSO) 11.35 (1H, s, NH), 7.90
Ph and CHv), 5.71 (1H, d, J¼1 Hz, OH), 5.01 (1H, d, (2H, m, Ph), 7.80 (1H, s, CHv), 7.51 (3H, m, Ph), 5.85 (1H,
J¼9 Hz, H5-isoxaz.), 4.38 (1H, m, CH –OH), 4.25 (1H, bs, bs, OH), 5.41 (1H, dd, J¼10.2, 5 Hz, H5-isoxaz.), 4.71 (1H,
CH – N), 4.18 (1H, d, J¼9 Hz, H4-isoxaz.), 3.80 (3H, s, m, CH –N), 4.15 (2H, m, CH – O and H4-isoxaz.), 2.10 (2H,
CH3O), 1.73 (2H, m, CH2), 1.62 (3H, s, CH3): dC (75 MHz, m, CH2), 1.80 (3H, s, CH3): dC (75 MHz, DMSO) 163.7,
DMSO) 169.4, 158.3, 156.6, 153.4, 130.4, 129.3, 129.1, 157.7, 150.9, 139.0, 130.1, 128.9, 128.4, 127.1, 109.1, 87.8,
127.0, 107.3, 91.8, 76.0, 61.4, 56.9, 37.1, 9.2. 73.2, 61.4, 60.3, 38.3, 12.1.

4.5. Construction of the uracil and thymine nucleosides


11a,b(U,T)
Acknowledgements
General method. 0.14 mmol adducts 10a,b(U,T) are
suspended in 2 M H2SO4 (10 mL) solutions and refluxed Financial support by University of Pavia (FAR), MIUR
for 3 h. After cooling, the pH is adjusted to 7 with NaHCO3 (PRIN 2002 and FIRB 2001) and CNR 2000 is gratefully
and the water phase extracted with dichloromethane. acknowledged. Thanks are due to Prof. Giovanni Romeo for
Evaporation of the dried organic phase afforded the uracil fruitful discussions on nucleoside chemistry. We also thank
or thymine nucleosides which were purified by Prof. L. Toma for invaluable aid in determining the
crystallization. puckering parameters.

4.5.1. Compound 11Ua. The title compound (30 mg, 70%)


as white crystals from ethanol, mp 143– 144 8C: [found C,
61.4: H, 4.9: N, 13.5. C16H15N3O4 (MW¼313.30) requires References and notes
C, 61.33: H, 4.83: N, 13.41%]: nmax (Nujol) 3500, 3181,
1695 cm21: dH (300 MHz, DMSO) 11.20 (1H, bs, NH), 7.87 1. (a) Mizuno, Y. The organic chemistry of nucleic acids;
(1H, d, J¼8 Hz, vCH), 7.53 (2H, m, Ph), 7.43 (3H, m, Ph), Kadansha: Tokyo, 1986. (b) Ueda, T. Chemistry of nucleosides
5.68 (1H, d, J¼8 Hz, vCH – CO), 5.66 (1H, d, J¼3.7 Hz, and nucleotides; Townsend, L. B., Ed.; Plenum: New York,
OH), 5.07 (1H, dd, J¼10, 3 Hz, H5-isoxaz.), 4.81 (1H, m, 1988; Vol. 1. Chapter 1.
CH – N), 4.62 (1H, dd, J¼10, 4.4 Hz, H4-isoxaz.), 4.19 (1H, 2. (a) Srivasta, P. C.; Robins, R. K.; Meyer, R. B., Jr. Chemistry
m, CH – O), 2.11 (1H, m, CH2), 1.90 (1H, m, CH2): dC of nucleosides and nucleotides; Townsend, L. B., Ed.; Plenum:
(75 MHz, DMSO) 163.2, 157.6, 150.7, 143.3, 130.2, 128.9, New York, 1988; Vol. 1, Chapter 2. (b) Revenkar, G. R.;
128.0, 126.9, 101.5, 92.8, 75.8, 59.0, 55.5, 38.4. Robins, R. K. Chemistry of nucleosides and nucleotides;
Townsend, L. B., Ed.; Plenum: New York, 1988; Vol. 2,
4.5.2. Compound 11Ub. The title compound (28 mg, 65%) Chapter 4.
as white crystals from benzene/ligroin, mp 112 –113 8C: 3. Bloomfield, V. A.; Crothers, D. M.; Tinoco, I., Jr. Nucleic
[found C, 61.3: H, 4.8: N, 13.4. C16H15N3O4 (MW¼313.30) acids; University Science Books: Sausalito, CA, 2000;
requires C, 61.33: H, 4.83: N, 13.41%]: nmax (Nujol) 3400, pp 13 – 43.
3180, 1701 cm21: dH (300 MHz, DMSO) 10.09 (1H, bs, 4. Crimmins, M. T. Tetrahedron 1998, 54, 9229– 9272.
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