2004 Cyclopentadiene 2004

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, Universita` degli Studi di Pavia, Viale Taramelli, 10 I-27100 Pavia, Italy Dipartimento di Scienze Chimiche, Universita` degli Studi di Catania, Viale A. Doria, 8 I-95125 Catania, Italy c Dipartimento Farmaco-Chimico, Universita` degli Studi di Messina, Viale S.S. Annunziata I-98168 Messina, Italy b

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 Nucleosides are primary building blocks of biological systems and are processed into nucleic acids.1 – 3 Many efforts have been recently addressed in the search for nucleoside analogues as non-toxic, selective inhibitors of kinases and polymerases with increased antiviral power.4 – 6 In particular, carbocyclic nucleosides, where the sugar 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 substituted carbocyclic ring via nucleophilic substitution. We have recently found that the chemistry of nitrosocarbonyls (RCONO) can be applied since these intermediates are highly reactive in hetero Diels– Alder (HDA) reactions.9 Cyclopentadiene 1 efficiently traps these fleeting interKeywords: Carbocyclic nucleosides; Nitrosocarbonyls; Nitrile oxides; Cycloadditions. * Corresponding author. Tel.: þ39-0382-507315; fax: þ39-0382-507323; e-mail address: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.02.057

mediates affording the HDA adducts 2 (Scheme 1), which were found to be highly reactive dipolarophiles in the 1,3dipolar cycloaddition of nitrile oxides.10 Detachment of the acyl moiety in cycloadducts of type 3 and reductive cleavage of the N – O bond afforded quantitatively the stereodefined anti aminols 410 which could serve as the appropriate precursors of nucleosides through assembly of purine and pyrimidine rings.

Scheme 1.

On pursuing our studies on the synthetic potential of the nitrosocarbonyl adducts 2, we detail the first synthesis of a class of racemic purine- and pyrimidine – carbocyclic nucleosides containing a fused isoxazole ring and lacking 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 cytotoxicity.11 The paper gives a complete account on the purine and pyrimidine rings construction and further functionalization of the purine compounds.

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2. Results 2.1. Construction of the purine heterocycles By adapting known procedures for the construction of the purine nucleus,8b,12 we have converted the stereodefined aminols 4a,b into the pyrimidine derivatives 6a,b by substitution of 5-amino-4,6-dichloropyrimidine 5 and then into the chloropurines 7a,b by condensation with orthoformates (Scheme 2).

the 1H NMR spectra were unambiguously consistent for the assigned structures. The spectrum of 6a in CDCl3 showed 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 proton as a doublet at d 6.41 (J¼8.6 Hz) and the 5- and 4-isoxazoline protons at d 5.16 (d, J¼8.7 Hz) and 4.29 (d, J¼8.7 Hz), respectively, while the cyclopentane protons are at d 4.92 (m, CH –N), 4.62 (d, J¼3.2 Hz, CH –O) and 2.00 (m, CH2). The spectrum of the stereoisomeric 6b is 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 orthoformate did not improve significantly the yields after heating for 1 h at 100 8C (entries 5 and 6).

Scheme 2.

The pyrimidine derivatives 6a,b were obtained in moderate yields (6a, 52%: 6b, 49%) by refluxing a solution of the aminols 4a,b and 5-amino-4,6-dichloropyrimidine 5 (2 equiv.) in n-BuOH (bp 117 8C) in the presence of an excess of i-Pr2NEt (5 equiv.) for 48 h. Yields were less satisfactory in n-PrOH (bp 97 8C) leading to the pyrimidine derivatives 6a,b in somewhat lower yields (6a, 47%: 6b, 30%). Duplicate experiments in n-BuOH with a larger excess of base (i-Pr2NEt, 10 equiv.) led to a decrease in the reaction yields (6a, 35%: 6b, 32%). From all indications obtained so far, n-BuOH is the most appropriate solvent for these reactions while more basic conditions are detrimental presumably because of the sensitivity of the isoxazoline moieties to severe basic conditions, which can often cause ring cleavage.13 The structures of 6a,b rely upon analytical and spectroscopic data. While the IR spectra of pyrimidines 6a,b exhibit complex series of bands between 3200 and 3430 cm21 due to the presence of OH, NH and NH2 groups,

The conversion of the stereoisomeric pyrimidines 6a,b into the chloropurines 7a,b could finally be achieved in excellent yield by treatment with triethyl orthoformate in the presence of catalytic p-TsOH by keeping the reactions at rt for 8 days (entries 7 and 8). Isolation and purification of 7a,b were secured by evaporation of triethyl orthoformate, addition of Et3N to the chloroform solution of the residues, washings with water and column chromatography of the organic residues. The chloropurines 7a,b have been fully characterized spectroscopically. Infrared spectra show a single broad band at 3556 cm21 (7a) and 3291 cm21 (7b) corresponding to the OH absorptions. In the 1H NMR spectra the two NvCH protons of the purine rings occur as singlets at d 8.77 and 8.49 for 7a and at d 8.81 and 8.39 for 7b while the 5- and 4-isoxazolinic protons appear as doublets at d 5.40 and 4.59 (J¼9 Hz) for 7a and at d 5.59 and 4.55 (J¼8.7 Hz) 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

1 2 3 4 5 6 7 8

6a 6b 6a 6b 6a 6b 6a 6b

CH(OEt)3 CH(OEt)3 CH(OEt)3 CH(OEt)3 DEMAb DEMAb CH(OEt)3 CH(OEt)3

a b

Ratio 1:1 with respect to triethyl orthoformate. DEMA, diethoxymethyl acetate.

Acid

T (8C)

Time

Product (%)

HCl 37% HCl 37% Ac2Oa AcOH cat. / / p-TsOH cat. p-TsOH cat.

25 25 100 100 100 100 25 25

14 h 14 h 20 h 20 h 1h 1h 8 days 8 days

6a 6b 7a (39) 7b (20) 7a (30) 7b (35) 7a (91) 7b (89)

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crystal of 7a was submitted to X-ray analysis which substantiated the attributed structure.17

isoxazolinic protons to the adjacent CHO methines is negligible in 8Aa and sizeable in 8Ab (J¼3 Hz).

From the chloro-substituted nucleosides 7a,b a variety of derivatives can be obtained by nucleophilic substitution.8b,12b,18 On heating MeOH solutions of 7a,b at 50 8C in the presence of an excess of NH3 or other differently substituted primary and secondary amines, the amino derivatives 8a,b(A-G) could easily be obtained (Scheme 3).

When fused to an isoxazolinic ring or similar rings19 the cyclopentane moiety usually adopt an envelope conformation with the flap directed toward the isoxazoline ring thus giving a boat-like appearance to the bicyclic system. The conformation of the bicyclic system with the flap 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 2,3oxaza[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 characterized through their analytical and spectroscopic data. Table 2. Yields and physical constants of purine derivatives 8a,b R

R0

Mp (8C) (Solv.)

Yields (%)

8aA 8aB 8aC 8aD 8aE 8aF 8aG

H H H Me H H H

H Me Et Me CH2Ph c-Pr c-Hept

129 –132 (EtOH) 228 –230 (MeOH) 212 –3 (MeOH) 205 –8 (MeOH) 222 –6 (MeOH) 233 –4 (AcOEt) Thick oil

66 99 97 98 93 73 94

8bA 8bB 8bC 8bD 8bE 8bF 8bG

H H H Me H H H

H Me Et Me CH2Ph c-Pr c-Hept

223 –5 (MeOH) 260 –2 (MeOH) 196 –200 (MeOH) 169 –170 (MeOH) 192 –4 (MeOH) 216 dec. (MeOH) 199 –201 (AcOEt)

74 98 96 100 94 99 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, 8.40 and 8.24, 8.36, respectively). Unlike the previous cases, however, the isoxazolinic protons are no longer neat doublets but one or both the isoxazolinic protons occur as double doublets, because of an additional coupling with the adjacent cyclopentane methines, thus indicating a conformational change in the cyclopentane ring. The new coupling constants are sizeable for the isoxazolinic protons adjacent to the CH – N methine (J¼3 – 4 Hz) while the coupling of the

Figure 1. (a) Boat- and chair-like conformations of 2,3oxaza[3.3.0]bicyclooct-3-ene, whose numbering system is shown in the case of the boat conformer. Relative energies are given near the conformational labels. Curved arrows specify the dihedral angles in degrees between the bridge-head protons and the protons of the adjacent methylenes. Numbers in parentheses are the ring puckering amplitudes Q 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 models lacking the phenyl substituent of the adenine nucleosides 8Aa, 8Ab and the uracil nucleosides 11Ua, 11Ub, respectively. Dashed lines indicate ˚. hydrogen bonds and the distances are given in A

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In the adenine derivatives a conformational change ensues in order to accommodate a strong intramolecular hydrogen bond between the OH and the basic adenine N3 nitrogen. This causes a flattening of the cyclopentane envelope as well as some twisting around the fused bond of the bicyclic array toward a half-chair cyclopentane conformation19c with the adenine moiety projecting outside. Figure 1b shows the optimized B3LYP/6-31Gp structures of models of the adenine derivatives 8aA and 8bA lacking the phenyl ring. The relevant dihedral angles around the CH –CHN bonds increase to 109– 1148 while those around the CH –CHO bonds show only negligible or modest changes to 958, in agreement with the observed trend in the coupling constants. The distances involved in the intramolecular hydrogen bonding are given in the figure and correspond well to cases of strong hydrogen bonding.21 The ring puckering parameters of the cyclopentane moieties (puckering amplitudes Q and phase angle F)22 are also given in Figure 1. The puckering amplitudes Q demonstrate the flattening of the cyclopentane ring in the hydrogen bonded structures while the phase angles indicate their neat distortions to the half-chair conformation having the two carbons of the CH2CH(OH) moiety out of plane.23 The N-substituted derivatives 8a(B-G) display spectroscopic patterns essentially similar to the adenine derivatives and consistent with the substituents. 2.2. Construction of the pyrimidine nucleosides The stereoisomeric aminols 4a,b were also converted into the uracil and thymine nucleosides24 through the linear construction of these heterocycles.4,6,25 The synthetic route

to uracil and thymine nucleosides involves the steps illustrated in Scheme 4 and started with the preparation of the appropriate isocyanate 9U,T. The 3-methoxy-2-propenoyl isocyanate 9U was easily obtained starting from the commercially available methyl 3-methoxy-2-propenoate through basic hydrolysis to the acid,25 conversion to the chloride with thionyl chloride26 and coupling with silver cyanate in benzene.25 The 3-methoxy-2-methyl-2-propenoyl isocyanate 9T was similarly obtained from the corresponding methyl 3-methoxy-2-methyl-2-propenoate. The latter is available from the simple methyl methacrylate according to a convenient reported protocol.27 The addition reactions of the aminols 4a,b to isocyanates 9U,T were conducted according to the procedure reported in the literature25 by performing the reactions at 220 8C in DMF solutions for 12 h. After chromatographic purification, the urea adducts 10a,b(U,T) were obtained in fair yields (50%). Their structures rely upon the analytical and spectroscopic data. Table 3 reports the yields, the physical constants and the significative spectroscopic data. Neat distinctive bands corresponding to the OH and the two NH groups were evident in the IR spectra. The NMR spectra showed the signals of the methoxy propenoyl and methyl propenoyl chains as well as those of the carbocyclic moiety in the usual ranges. Table 3. Yields, physical constants and significative spectroscopic data of the ureas 10 and nucleosides 11 Compounds

10Ua 10Ta 10Ub 10Tb 11Ua 11Ub 11Ta 11Tb

Yield (%)

53 50 52 48 70 65 64 61

IR (cm21)

Mp (8C) (EtOH)

245 dec. 231 dec. 221–2 226–7 143–4 112–3 245–6 218–9

nOH

nNH

3493 3536 3474 3485 3500 3400 3461 3323

3282–3240 3327–3243 3274–3253 3237–3343 3180 3180 3153 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.

Scheme 4.

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 uracil and thymine carbonyl as in the case of the adenine

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derivatives. Figure 1c shows the optimized structures of models of the uracil derivatives.

chromatography to separate the excess of amino-pyrimidine 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, 55.6: H, 4.7: N, 20.3. C16H16N5O2Cl (MW¼345.79) requires C, 55.58: H, 4.66: N, 20.25%]: nmax (Nujol) 3424, 3240, 3340, 3200 cm21: dH (300 MHz, CDCl3) 8.10 (2H, m, Ph), 8.08 (1H, s, CHvN), 7.40 (3H, m, Ph), 6.41 (1H, d, J¼8.6 Hz, NH), 5.16 (1H, d, J¼8.7 Hz, H5-isoxaz.), 4.92 (1H, m, CH –NH), 4.62 (1H, d, J¼3.2 Hz, CH – OH), 4.29 (1H, d, J¼8.7 Hz, H4-isoxaz.), 3.62 (3H, bs, OH and NH2), 2.00 (2H, m, CH2): dC (75 MHz, CDCl3) 156.6, 153.3, 149.0, 130.2, 128.6, 128.3, 127.7, 91.5, 79.1, 60.2, 58.3, 56.8, 36.7, 18.3.

The first synthesis of isoxazoline– carbocyclic nucleosides and a variety of analogues was attained starting from the stereodefined heterocyclic aminols 4, which are readily available through exo selective 1,3-dipolar cycloadditions of benzonitrile oxide to N-benzoyl-oxazanorbornene 2 (R¼Ph) and a simple elaboration of the cycloadducts. The stereodefined heterocyclic aminols 4 afford the carbocyclic skeleton for the linear construction of the purine, uracil and thymine moieties. Functionalization of the chloropurines 7 with a variety of amines extended the synthetic potential of this strategy allowing for a fine tuning of their biological and antiviral activity.18,28 Owing to the availability of the enantiomerically pure adducts 229 the route described here lends itself to the synthesis of optically pure nucleoside derivatives. Biological evaluation of the obtained compounds is in progress. Preliminary data show that compound 7a possesses a good inhibitory activity against Herpes Simplex virus type 1 and 2. 4. Experimental 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 Perkin – Elmer RX-1. 1H- and 13C NMR spectra were recorded on a Bruker AVANCE 300 in the specified deuterated solvents. Chemical shifts are expressed in ppm from internal tetramethylsilane (d). UV – vis spectra were recorded on a UV Perkin –Elmer LAMBDA 16 spectrophotometer using acetonitrile as solvent. HPLC analyses were carried out by means of a WATERS 1525 instrument equipped with an UV 2487 detector (l¼266 nm) both controlled by Breezee software and a RP C-18 Intersil ODS-2 column: a mixture of H2O/CH3CN 60:40 was used as eluant. Column chromatography and TLC: silica gel 60 (0.063 – 0.200 mm) (Merck): eluant cyclohexane/ethyl acetate from 9:1 to 5:5. The identification of samples from different experiments was secured by mixed mps and superimposable IR spectra. Materials. Aminols 4a,b were prepared through NaOH/ MeOH hydrolysis and N – O bond hydrogenolysis as previously reported.10a Methyl 3-methoxy-2-propenoate and silver cyanate were from ACROS ORGANICS. Methyl methacrilate was from SIGMA-ALDRICH. 4.1. Synthesis of the pyrimidine derivatives 6a,b 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, 15.5 mmol) and i-Pr2NEt (4.02 g, 31.1 mmol) were added. The mixtures were refluxed at 117 8C with stirring for 48 h. The cooled solutions were evaporated to dryness, taken up in CH2Cl2, washed with water and dried over anhydrous Na2SO4. The crude residues were then submitted to column

4.1.2. Compound 6b. The title compound (1.32 g, 49%) as white crystals from benzene, mp 119 –121 8C: [found C, 55.6: H, 4.6: N, 20.2. C16H16N5O2Cl (MW¼345.79) requires C, 55.58: H, 4.66: N, 20.25%]: nmax (Nujol) 3420, 3230, 3399, 3258 cm21: dH (300 MHz, CDCl3) 8.15 (1H, s, CHvN), 7.76 (2H, m, Ph), 7.45 (3H, m, Ph), 6.10 (1H, d, J¼8.8 Hz, NH), 5.25 (1H, d, J¼8.8 Hz, H5-isoxaz.), 4.99 (1H, m, CH –NH), 4.64 (1H, m, CH –OH), 4.25 (1H, d, 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, 58.7, 37.4, 18.6. 4.2. Construction of the purine nucleosides 7a,b To a solution of pyrimidine derivatives 6a,b (0.532 g, 1.54 mmol) in triethyl orthoformate (25 mL), a catalytic amount of p-TsOH was added. The reaction was stirred at rt for 8 days. After this period of time, the orthoformate was evaporated and the residue taken up with chloroform and Et3N was added and stirred for several hours. Then the organic phase was washed with water and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was taken up with ethyl acetate and finally, after a new evaporation to dryness, submitted to column chomatography to purify the purine derivatives 7a,b. 4.2.1. Compound 7a. The title compound (0.50 g, 91%) as white crystals from ethyl acetate, mp 229 –230 8C: [found 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, 1591, 1561 cm21: dH (300 MHz, CDCl3) 8.77 (1H, s, CHvN), 8.49 (1H, s, CHvN), 7.58 (2H, m, Ph), 7.40 (3H, m, Ph), 5.40 (1H, d, J¼9 Hz, H5-isoxaz.), 5.23 (1H, d, J¼9.4 Hz, CH – N), 4.78 (1H, d, J¼4.7 Hz, CH – OH), 4.59 (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, 145.6, 130.8, 129.1, 127.4, 127.0, 93.6, 77.1, 60.7, 58.8, 39.4. 4.2.2. Compound 7b. The title compound (0.49 g, 89%) as white crystals from ethyl acetate, mp 234 –236 8C: [found C, 57.4: H, 3.9: N, 19.7. C17H14N5O2Cl (MW¼355.78) requires C, 57.39: H, 3.97: N, 19.68%]: nmax (Nujol) 3291, 1596, 1588 cm21: dH (300 MHz, CDCl3) 8.81 (1H, s, CHvN), 8.39 (1H, s, CHvN), 7.85 (2H, m, Ph), 7.45 (3H,

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m, Ph), 5.59 (1H, d, J¼8.7 Hz, H5-isoxaz.), 5.26 (1H, m, CH – N), 4.71 (1H, m, CH – OH), 4.55 (1H, d, J¼8.7 Hz, H4-isoxaz.), 3.50 (1H, bs, OH), 2.74 (1H, m, CH2), 2.44 (1H, m, CH2): dC (75 MHz, CDCl3) 156.9, 155.6, 151.5, 145.4, 130.5, 128.9, 127.7, 127.0, 90.4, 77.0, 63.9, 63.0, 39.5.

(300 MHz, CDCl3) 8.36 (1H, s, CHvN), 7.66 (1H, s, CHvN), 7.3 –7.6 (5H, m, Ph), 5.42 (1H, dd, J¼9, 1 Hz, H5isoxaz.), 4.86 (1H, m, CH – N), 4.69 (1H, m, CH –OH), 4.46 (1H, dd, J¼9, 4 Hz, H4-isoxaz.), 3.60 (6H, b, CH3), 2.87 (1H, m, CH2), 2.25 (1H, m, CH2): dC (75 MHz, CDCl3) 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 General method. Solutions of chloro-nucleosides 7a,b (30 mg, 0.08 mmol) in MeOH (2 mL) were saturated with ammonia or other gaseous amines and kept in a sealed tube at 50 8C for 24 h. In the case of liquid amines, an excess (50 equiv.) was added to the solutions. The solutions are then cooled and in most cases the products crystallize from the methanolic solutions. Otherwise, concentration of the solutions allows the amino derivatives to crystallize (with a single exception, 8aG remains a thick oil). Table 2 reports the physical constants (solvent of crystallization) and yields (determined by HPLC analyses) of the amino nucleosides 8a,b. 4.3.1. Compound 8aA. The title compound (66%) as white crystals from ethanol, mp 129– 132 8C: [found C, 60.8: H, 4.9: N, 24.9. C17H16N6O2 (MW¼336.35) requires C, 60.70: H, 4.80: N, 24.99%]: nmax (Nujol) 3524, 3269, 3119 cm21: dH (300 MHz, CDCl3) 8.40 (1H, s, CHvN), 7.78 (1H, s, CHvN), 7.3– 7.6 (5H, m, Ph), 5.88 (2H, bs, NH2), 5.42 (1H, d, J¼8 Hz, H5-isoxaz.), 4.90 (1H, m, CH – N), 4.71 (1H, m, CH – OH), 4.48 (1H, dd, J¼8, 3.4 Hz, H4-isoxaz.), 2.88 (1H, m, CH2), 2.29 (1H, m, CH2): dC (75 MHz, CDCl3) 157.6, 155.4, 151.9, 150.2, 147.5, 140.6, 130.3, 128.8, 127.5, 126.5, 94.9, 76.8, 61.8, 58.1, 40.4. 4.3.2. Compound 8aB. The title compound (99%) as white crystals from methanol, mp 228 – 230 8C: [found C, 61.7: H, 5.2: N, 24.0. C18H18N6O2 (MW¼350.37) requires C, 61.70: H, 5.18: N, 23.99%]: nmax (Nujol) 3471, 3225 cm21: dH (300 MHz, CDCl3) 8.43 (1H, s, CHvN), 7.76 (1H, s, CHvN), 7.3 –7.6 (5H, m, Ph), 5.96 (1H, bs, NH), 5.52 (1H, d, J¼8 Hz, H5-isoxaz.), 4.85 (1H, m, CH –N), 4.70 (1H, m, CH – OH), 4.46 (1H, dd, J¼8, 4 Hz, H4-isoxaz.), 3.28 (3H, s, CH3 – NH), 2.89 (1H, m, CH2), 2.28 (1H, m, CH2): dC (75 MHz, CDCl3) 200.3, 182.7, 152.4, 140.0, 130.5, 129.1, 127.9, 126.8, 95.5, 62.3, 58.4, 50.7, 40.9. 4.3.3. Compound 8aC. The title compound (97%) as white crystals from methanol, mp 212 – 213 8C: [found C, 62.6: H, 5.6: N, 23.1. C19H20N6O2 (MW¼364.40) requires C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3310, 3230 cm21: dH (300 MHz, CD3COCD3) 8.24 (1H, s, CHvN), 8.20 (1H, s, CHvN), 7.61 (2H, m, Ph), 7.39 (3H, m, Ph), 6.90 (1H, bs, NH), 5.70 (1H, d, J¼6 Hz, OH), 5.32 (1H, d, J¼9.4 Hz, H5isoxaz.), 5.18 (1H, m, CH –OH), 4.88 (1H, dd, J¼9.4, 3 Hz, H4-isoxaz.), 4.53 (1H, m, CH –N), 3.74 (2H, b, CH2 – N), 2.56 (1H, m, CH2), 2.30 (1H, m, CH2), 1.32 (3H, t, CH3): dC (75 MHz, CD3COCD3) 168.1, 162.8, 150.8, 140.6, 139.8, 139.4, 137.7, 104.7, 87.7, 87.6, 69.9, 68.5, 50.3, 45.5, 25.1. 4.3.4. Compound 8aD. The title compound (98%) as white crystals from methanol, mp 205 – 208 8C: [found C, 62.5: H, 5.5: N, 23.0. C19H20N6O2 (MW¼364.40) requires C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3320 cm21; dH

4.3.5. Compound 8aE. The title compound (93%) as white crystals from methanol, mp 222– 226 8C: [found C, 67.5: H, 5.1: N, 19.8. C24H22N6O2 (MW¼426.46) requires C, 67.59: H, 5.20: N, 19.71%]: nmax (Nujol) 3250, 3198 cm21: dH (300 MHz, CDCl3) 8.45 (s, 1H, CHvN), 7.65 (s, 1H, CHvN), 7.2 –7.6 (m, 10H, Ph), 6.13 (bs, 1H, NH), 5.42 (d, J¼9 Hz, 1H, H5-isoxaz.), 4.92 (b, 2H, CH2 –Ph), 4.80 (m, 1H, CH – N), 4.69 (m, 1H, CH –OH), 4.45 (dd, J¼9, 4 Hz, 1H, H4-isoxaz.), 2.85 (m, 1H, CH2), 2.25 (m, 1H, CH2): dC (75 MHz, CDCl3) 157.8, 154.6, 152.1, 139.9, 137.5, 130.2, 128.8, 128.4, 128.2, 128.1, 127.6, 127.4, 127.3, 126.6, 126.5, 126.4, 95.1, 76.8, 76.4, 61.9, 58.1, 46.1, 44.2, 40.5. 4.3.6. Compound 8aF. The title compound (73%) as white crystals from ethyl acetate, mp 233 –234 8C: [found C, 63.9: H, 5.4: N, 22.4. C20H20N6O2 (MW¼376.40) requires C, 63.82: H, 5.36: N, 22.33%]: nmax (Nujol) 3230, 3225 cm21: dH (300 MHz, CD3COCD3) 8.28 (1H, s, CHvN), 8.23 (1H, s, CHvN), 7.61 (2H, m, Ph), 7.40 (3H, m, Ph), 6.95 (1H, bs, NH), 5.63 (1H, d, J¼6 Hz, OH), 5.33 (1H, d, J¼10 Hz, H5isoxaz.), 5.19 (1H, m, CH –N), 4.90 (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 4.51 (1H, m, CH –OH), 2.51 (1H, m, CH2), 2.26 (1H, m, CH2), 2.20 (1H, m, CH – NH), 0.75 (4H, m, CH2 – CH2): dC (75 MHz, CD3COCD3) 167.0, 166.2, 153.0, 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. 4.3.7. Compound 8aG. The title compound (94%) as thick oil: [found C, 66.3: H, 6.4: N, 19.2. C24H28N6O2 (MW¼432.51) requires C, 66.64: H, 6.53: N, 19.43%]: nmax (Neat) 3340, 3339 cm21: dH (300 MHz, CD3COCD3) 8.26 (1H, s, CHvN), 8.23 (1H, s, CHvN), 7.60 (2H, m, Ph), 7.32 (3H, m, Ph), 6.68 (1H, d, J¼8 Hz, NH), 5.70 (1H, d, J¼6 Hz, OH), 5.30 (1H, d, J¼9.4 Hz, H5-isoxaz.), 5.20 (1H, m, CH – OH), 4.85 (1H, dd, J¼9.4, 3 Hz, H4-isoxaz.), 4.49 (1H, m, CH – N), 2.48 (1H, m, CH2), 2.30 (1H, m, 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, 128.6, 128.5, 127.0, 93.9, 76.7, 60.5, 59.0, 57.9, 39.4, 35.5, 34.6, 28.4, 28.0, 24.3, 23.9. 4.3.8. Compound 8bA. The title compound (74%) as white crystals from methanol, mp 223– 225 8C: [found C, 60.7: H, 4.8: N, 25.0. C17H16N6O2 (MW¼336.35) requires C, 60.70: H, 4.80: N, 24.99%]: nmax (Nujol) 3310, 3288, 3143 cm21: dH (300 MHz, CD3COCD3) 8.36 (1H, s, CHvN), 8.24 (1H, s, CHvN), 7.92 (2H, m, Ph), 7.49 (3H, m, Ph), 6.59 (2H, bs, NH2), 5.56 (1H, m, OH), 5.68 (1H, dd, J¼10, 3 Hz, H5isoxaz.), 5.11 (1H, m, CH – N), 4.50 (1H, m, CH –OH), 4.48 (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, 141.8, 131.3, 130.1, 128.6, 128.4, 91.0, 76.2, 62.8, 40.2, 30.4. 4.3.9. Compound 8bB. The title compound (98%) as white

P. Quadrelli et al. / Tetrahedron 60 (2004) 3643–3651

crystals from methanol, mp 260 –262 8C: [found C, 61.5: H, 5.1: N, 23.8. C18H18N6O2 (MW¼350.37) requires C, 61.70: H, 5.18: N, 23.99%]: nmax (Nujol) 3220, 3223 cm21: dH (300 MHz, CD3COCD3) 8.35 (1H, s, CHvN), 8.20 (1H, s, CHvN), 7.92 (2H, m, Ph), 7.49 (3H, m, Ph), 6.80 (1H, bs, NH), 5.70 (1H, dd, J¼9, 3.3 Hz, H5-isoxaz.), 5.57 (1H, m, OH), 5.11 (1H, m, CH – N), 4.50 (1H, m, CH – OH), 4.48 (1H, dd, J¼9, 3 Hz, H4-isoxaz.), 2.78 (3H, s, CH3), 2.51 (2H, m, CH2): dC (75 MHz, CD3COCD3) 168.1, 151.1, 139.5, 133.6, 132.4, 131.0, 130.7, 97.3, 65.5, 56.0, 40.1. 4.3.10. Compound 8bC. The title compound (96%) as white crystals from methanol, mp 196 – 200 8C: [found C, 62.5: H, 5.5: N, 23.0. C19H20N6O2 (MW¼364.40) requires C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3260, 3220 cm21: dH (300 MHz, CD3COCD3) 8.28 (1H, s, 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, 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, H4-isoxaz.), 3.73 (2H, bs, CH2 – N), 2.81 (2H, m, CH2), 2.56 (2H, m, CH3 – CH2), 1.31 (3H, t, CH3 – CH2): dC (75 MHz, CD3COCD3) 158.7, 153.7, 141.2, 131.3, 130.4, 130.1, 128.4, 91.3, 76.7, 76.6, 63.2, 63.1, 40.6, 36.2, 15.8. 4.3.11. Compound 8bD. The title compound (100%) as white crystals from methanol, mp 169 – 170 8C: [found C, 62.5: H, 5.6: N, 23.1. C19H20N6O2 (MW¼364.40) requires C, 62.62: H, 5.53: N, 23.06%]: nmax (Nujol) 3240 cm21: dH (300 MHz, CD3COCD3) 8.28 (1H, s, CHvN), 8.26 (1H, s, 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, CH –N), 4.55 (1H, m, CH – OH), 4.47 (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 2.85 (3H, s, CH3), 2.69 (3H, s, CH3), 2.51 (2H, m, CH2): dC (75 MHz, CD3COCD3) 158.6, 156.1, 152.9, 151.6, 140.0, 131.2, 130.3, 130.0, 128.4, 91.3, 76.6, 63.1, 62.9, 40.4, 38.9, 38.7, 34.9. 4.3.12. Compound 8bE. The title compound (94%) as white crystals from methanol, mp 192 – 194 8C: [found C, 67.6: H, 5.1: N, 20.0. C24H22N6O2 (MW¼426.46) requires C, 67.59: H, 5.20: N, 19.71%]: nmax (Nujol) 3330, 3380 cm21: dH (300 MHz, CD3COCD3) 8.31 (1H, s, CHvN), 8.26 (1H, s, CHvN), 7.90 (2H, m, Ph), 7.2 –7.6 (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 (2H, b, CH2 – Ph), 4.54 (1H, m, CH –OH), 4.45 (1H, dd, J¼10, 3 Hz, H4-isoxaz.), 2.51 (2H, m, CH2): dC (75 MHz, CD3COCD3) 156.1, 151.1, 139.0, 129.8, 128.7, 127.8, 127.5, 127.0, 126.2, 125.9, 125.5, 88.7, 74.1, 74.0, 60.5, 42.1, 38.0. 4.3.13. Compound 8bF. The title compound (99%) as white crystals from methanol, mp 216 8C dec.: [found C, 63.7: H, 5.4: N, 22.2. C20H20N6O2 (MW¼376.40) requires C, 63.82: H, 5.36: N, 22.33%]: nmax (Nujol) 3260, 3250 cm21: dH (300 MHz, CD3COCD3) 8.30 (1H, s, CHvN), 8.25 (1H, s, CHvN), 7.90 (2H, m, Ph), 7.50 (3H, m, Ph), 6.90 (1H, bs, NH), 5.74 (1H, dd, J¼10, 3.3 Hz, H5-isoxaz.), 5.60 (1H, d, 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), 2.25 (1H, m, CH –NH), 0.75 (4H, m, CH2 – CH2): dC (75 MHz, CD3COCD3) 167.4, 166.2, 152.2, 140.1, 129.9,

3649

129.6, 128.7, 127.1, 89.9, 75.3, 61.8, 61.7, 39.2, 31.1, 6.2, 3.2. 4.3.14. Compound 8bG. The title compound (92%) as white crystals from ethyl acetate, mp 199 –201 8C: [found C, 66.5: H, 6.5: N, 19.4. C24H28N6O2 (MW¼432.51) requires C, 66.64: H, 6.53: N, 19.43%]: nmax (Nujol) 3340, 3320 cm21: dH (300 MHz, CD3COCD3) 8.26 (1H, s, CHvN), 8.25 (1H, s, CHvN), 7.90 (2H, m, Ph), 7.74 (3H, m, Ph), 6.52 (1H, d, J¼8 Hz, NH), 5.72 (1H, dd, J¼10, 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, bs, OH), 3.30 (1H, m, CH –NH), 2.51 (2H, m, CH2), 2.15 (4H, m, CH2), 1.5 –2.0 (8H, m, CH2): dC (75 MHz, CD3COCD3) 156.0, 151.1, 138.7, 128.7, 127.6, 127.5, 125.9, 88.8, 74.0, 60.6, 60.5, 58.7, 38.0, 33.3, 32.7, 31.3, 26.3, 22.8, 22.7. 4.4. Syntheses of the isocyanate adducts 10a,b(U,T) General method. To solutions of aminols 4a,b (2.29 mmol) in anhydrous DMF (10 mL) at 220 8C, solutions of isocyanates 9U,T (2.52 mmol) in anhydrous benzene were added dropwise with stirring in a nitrogen atmosphere and ˚ . After keeping for one night at rt, in the presence of MS 4 A the solutions were filtered and solvent removed under reduced pressure. The residues were submitted to column chromatography to isolate the compounds 10a,b(U,T). Table 3 reports the physical constants (solvent of crystallization) and the yields of the isocyanate adducts 10a,b(U,T). 4.4.1. Compound 10Ua. The title compound (0.42 g, 53%) as white crystals from ethanol, mp 245 8C dec.: [found C, 59.1: H, 5.6: N, 12.2. C17H19N3O5 (MW¼345.35) requires C, 59.12: H, 5.55: N, 12.17%]: nmax (Nujol) 3493, 3282, 3240, 1700 cm21: dH (300 MHz, DMSO) 10.06 (1H, s, NH), 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, J¼3 Hz, OH), 5.53 (1H, d, J¼12 Hz, vCH – CO), 5.00 (1H, d, J¼9 Hz, H5-isoxaz.), 4.42 (1H, bs, CH – N), 4.26 (1H, s, CH –OH), 4.25 (1H, d, J¼9 Hz, H4-isoxaz.), 3.68 (3H, s, CH3O), 1.71 (2H, m, CH2): dC (75 MHz, DMSO) 166.9, 162.6, 156.5, 152.8, 130.0, 128.7, 128.5, 127.1, 98.0, 91.5, 66.7, 60.0, 57.9, 54.3, 36.9. 4.4.2. Compound 10Ub. The title compound (0.40 g, 50%) as white crystals from ethanol, mp 231 8C dec.: [found C, 59.2: H, 5.7: N, 12.3. C17H19N3O5 (MW¼345.35) requires C, 59.12: H, 5.55: N, 12.17%]: nmax (Nujol) 3536, 3327, 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, J¼12 Hz, vCH –OMe), 7.47 (3H, m, Ph), 5.71 (1H, d, J¼2 Hz, OH), 5.51 (1H, d, J¼12 Hz, vCH – CO), 5.02 (1H, d, J¼9 Hz, H5-isoxaz.), 4.37 (1H, bs, CH – N), 4.24 (1H, s, CH –OH), 4.19 (1H, d, J¼9 Hz, H4-isoxaz.), 3.70 (3H, s, CH3O), 1.74 (2H, m, CH2): dC (75 MHz, DMSO) 167.0, 162.6, 156.2, 152.9, 130.1, 128.9, 128.7, 126.7, 97.9, 91.4, 75.6, 61.0, 57.9, 56.5, 36.8. 4.4.3. Compound 10Ta. The title compound (0.43 g, 52%) as white crystals from ethanol, mp 221– 222 8C: [found C, 60.1: H, 5.9: N, 11.7. C18H21N3O5 (MW¼359.37) requires

3650

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C, 60.16: H, 5.89: N, 11.69%]: nmax (Nujol) 3474, 3274, 3243, 1678 cm21: dH (300 MHz, DMSO) 9.73 (1H, s, NH), 9.36 (1H, d, J¼9 Hz, NH), 7.99 (2H, m, Ph), 7.46 (4H, m, Ph and CHv), 5.61 (1H, d, J¼2 Hz, OH), 5.00 (1H, d, J¼9 Hz, H5-isoxaz.), 4.43 (1H, m, CH –OH), 4.27 (1H, bs, CH – N), 4.22 (1H, d, J¼9 Hz, H4-isoxaz.), 3.80 (3H, s, CH3O), 1.72 (2H, b, CH2), 1.63 (3H, s, CH3): dC (75 MHz, DMSO) 169.3, 158.3, 156.8, 153.3, 130.3, 129.0, 128.9, 127.5, 107.4, 91.9, 77.0, 61.4, 60.4, 54.7, 37.2, 9.2. 4.4.4. Compound 10Tb. The title compound (0.40 g, 48%) as white crystals from ethanol, mp 226– 7 8C: [found C, 60.2: H, 5.8: N, 11.6. C18H21N3O5 (MW¼359.37) requires C, 60.16: H, 5.89: N, 11.69%]: nmax (Nujol) 3485, 3237, 3343, 1689 cm21: dH (300 MHz, DMSO) 9.73 (1H, s, NH), 9.19 (1H, d, J¼9 Hz, NH), 7.76 (2H, m, Ph), 7.48 (4H, m, Ph and CHv), 5.71 (1H, d, J¼1 Hz, OH), 5.01 (1H, d, J¼9 Hz, H5-isoxaz.), 4.38 (1H, m, CH –OH), 4.25 (1H, bs, CH – N), 4.18 (1H, d, J¼9 Hz, H4-isoxaz.), 3.80 (3H, s, CH3O), 1.73 (2H, m, CH2), 1.62 (3H, s, CH3): dC (75 MHz, DMSO) 169.4, 158.3, 156.6, 153.4, 130.4, 129.3, 129.1, 127.0, 107.3, 91.8, 76.0, 61.4, 56.9, 37.1, 9.2.

62.4: H, 5.2: N, 12.9. C17H17N3O4 (MW¼327.33) requires C, 62.37: H, 5.24: N, 12.84%]: nmax (Nujol) 3461, 3153, 1680 cm21: dH (300 MHz, DMSO) 11.25 (1H, s, NH), 7.75 (1H, s, CHv), 7.48 (2H, m, Ph), 7.32 (3H, m, Ph), 5.63 (1H, d, J¼3.8 Hz, OH), 5.08 (1H, dd, J¼10.2, 2.8 Hz, H5isoxaz.), 4.81 (1H, dt, J¼11.9, 4.8 Hz, CH –N), 4.58 (1H, dd, J¼10.2, 4.8 Hz, H4-isoxaz.), 4.18 (1H, m, CH –O), 2.15 (1H, m, CH2), 1.90 (1H, m, CH2), 1.81 (3H, s, CH3): dC (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. 4.5.4. Compound 11Tb. The title compound (28 mg, 61%) as white crystals from ethanol, mp 218 –219 8C: [found C, 61.9: H, 5.0: N, 12.6. C17H17N3O4 (MW¼327.33) requires C, 62.37: H, 5.24: N, 12.84%]: nmax (Nujol) 3323, 3141, 1695 cm21: dH (300 MHz, DMSO) 11.35 (1H, s, NH), 7.90 (2H, m, Ph), 7.80 (1H, s, CHv), 7.51 (3H, m, Ph), 5.85 (1H, bs, OH), 5.41 (1H, dd, J¼10.2, 5 Hz, H5-isoxaz.), 4.71 (1H, m, CH –N), 4.15 (2H, m, CH – O and H4-isoxaz.), 2.10 (2H, m, CH2), 1.80 (3H, s, CH3): dC (75 MHz, DMSO) 163.7, 157.7, 150.9, 139.0, 130.1, 128.9, 128.4, 127.1, 109.1, 87.8, 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 for 3 h. After cooling, the pH is adjusted to 7 with NaHCO3 and the water phase extracted with dichloromethane. Evaporation of the dried organic phase afforded the uracil or thymine nucleosides which were purified by crystallization. 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 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 (1H, d, J¼8 Hz, vCH), 7.53 (2H, m, Ph), 7.43 (3H, m, Ph), 5.68 (1H, d, J¼8 Hz, vCH – CO), 5.66 (1H, d, J¼3.7 Hz, OH), 5.07 (1H, dd, J¼10, 3 Hz, H5-isoxaz.), 4.81 (1H, m, CH – N), 4.62 (1H, dd, J¼10, 4.4 Hz, H4-isoxaz.), 4.19 (1H, m, CH – O), 2.11 (1H, m, CH2), 1.90 (1H, m, CH2): dC (75 MHz, DMSO) 163.2, 157.6, 150.7, 143.3, 130.2, 128.9, 128.0, 126.9, 101.5, 92.8, 75.8, 59.0, 55.5, 38.4. 4.5.2. Compound 11Ub. The title compound (28 mg, 65%) as white crystals from benzene/ligroin, mp 112 –113 8C: [found C, 61.3: H, 4.8: N, 13.4. C16H15N3O4 (MW¼313.30) requires C, 61.33: H, 4.83: N, 13.41%]: nmax (Nujol) 3400, 3180, 1701 cm21: dH (300 MHz, DMSO) 10.09 (1H, bs, NH), 7.87 (1H, d, J¼8 Hz, vCH), 7.54 (2H, m, Ph), 7.44 (3H, m, Ph), 5.67 (1H, d, J¼8 Hz, vCH – CO), 5.64 (1H, d, J¼3.8 Hz, OH), 5.08 (1H, dd, J¼9, 2.4 Hz, H5-isoxaz.), 4.83 (1H, m, CH – N), 4.62 (1H, dd, J¼10, 4 Hz, H4isoxaz.), 4.19 (1H, m, CH – O), 2.15 (1H, m, CH2), 1.90 (1H, m, CH2): dC (75 MHz, DMSO) 163.1, 157.5, 150.7, 143.3, 130.2, 128.9, 128.0, 126.8, 101.4, 92.8, 75.8, 59.0, 55.4, 38.4. 4.5.3. Compound 11Ta. The title compound (29 mg, 64%) as white crystals from ethanol, mp 245– 246 8C: [found C,

Financial support by University of Pavia (FAR), MIUR (PRIN 2002 and FIRB 2001) and CNR 2000 is gratefully acknowledged. Thanks are due to Prof. Giovanni Romeo for fruitful discussions on nucleoside chemistry. We also thank Prof. L. Toma for invaluable aid in determining the puckering parameters.

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