4736
U. Chiacchio et al. / Tetrahedron 59 (2003) 4733–4738
C12H11N3O3: C, 58.77; H, 4.52; N, 17.13%. Found: C,
58.61; H, 4.53; N, 17.11%.
for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85%. Found: C,
59.52; H, 5.64; N, 13.83%.
3.3. Synthesis of isoxazolidinyluridines 6 and 7
3.3.4. (30RS,50SR)-5-[20-Benzyl-50-hydroxymethyl-10,20-
isoxazolidin-30-yl]uracil (7b). (558 mg, 37% yield,
HPLC: tR 30.4 min; white solid: mp 190–1918C). IR
(KBr) nmax 3450–3250, 3210, 3115, 3025, 2970, 2940,
General procedure. A solution of nitrone 5 (5 mmol) and
allyl alcohol (5.8 g, 6.8 mL, 100 mmol), in dimethylforma-
mide (DMF) (100 mL), was heated, in a sealed tube, for 24 h
at 1208C for 5a and at 1408C for 5b. DMF was evaporated at
reduced pressure and the residue was purified by flash
chromatography column on silica gel (chloroform/metha-
nol, 9:1), followed by preparative HPLC [microsorb silica
1
2895, 1720, 1665, 1430, 1200, 1115, 775 cm–1. H NMR,
0
(DMSOd6, 500 MHz) d 1.83 (dt, 1H, J¼5.5, 12.5 Hz, H4 a),
0
2.73 (dt, 1H, J¼8.0, 12.5 Hz, H4 b), 3.32–3.36 (m, 2H,
CH2OH), 3.87 (d, 1H, J¼13.5 Hz, N-CH2Ph), 3.92 (d, 1H,
0
J¼13.5 Hz, N-CH2Ph), 3.96 (dd, 1H, J¼5.5, 8.0 Hz, H3 ),
˚
0
DYNAMAX-100 A (21£250 mm) column, flow 3.5 mL/
4.23–4.29 (m, 1H, H5 ), 4.69 (t, 1H, J¼5.8 Hz, OH), 7.21–
min] utilising a n-hexane/2-propanol 85:15 eluting mixture
for compounds 6a and 7a while a mixed isocratic and
linear gradient of 2-propanol (10%, 0–15 min, 10–15%,
15–20 min) in n-hexane for compounds 6b and 7b.
7.34 (m, 5H, aromatic protons), 7.30 (s, 1H, H6), 10.73
(bs, 1H, NH), 11.05 (bs, 1H, NH). 13C NMR (DMSOd6,
125 MHz) d 36.9, 59.7, 60.5, 62.8, 77.6, 112.6, 126.9, 128.1,
128.7, 138.0, 138.0, 151.1, 163.8. HRMS (EI) calcd for
[Mþ] C15H17N3O4 303.1219, found: 303.1222. Anal. calcd
for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85%. Found: C,
59.55; H, 5.66; N, 13.81%.
3.3.1. (30RS,50RS)-5-[50-Hydroxymethyl-20-methyl-10,20-
isoxazolidin-30-yl]uracil (6a). (500 mg, 44% yield,
HPLC: tR 37.5 min; sticky oil). IR (KBr) nmax 3450–
3250, 3220, 3105, 2990, 2910, 2840, 1730, 1660, 1450,
3.4. Hydrogenolysis of isoxazolidines 6b and 7b
1
1230, 1050, 770 cm–1. H NMR, (DMSOd6, 500 MHz) d
0
2.03–2.09 (m, 1H, H4 a), 2.22–2.28 (m, 1H, H4 b), 2.49 (s,
3H, N-Me), 3.40–3.43 (m, 2H, CH2OH), 3.53–3.57 (m, 1H,
0
General procedure. Isoxazolidine 6b or 7b (200 mg,
0.66 mmol) was dissolved in anhydrous MeOH (25 mL)
and treated with anhydrous HCO2H (2.3 mL). Palladium
black (700 mg, 6.60 mmol) was added to the rapidly stirring
solution. After 2.5 h TLC analysis revealed that reaction
was completed. The mixture was filtered through Celite,
washed with MeOH (50 mL) and concentrated in vacuo.
The residue was dissolved in MeOH, and stirred with
anhydrous K2CO3 (15 min.). After filtration through
adsorbent cotton, the removal of solvent in vacuo afforded
a residue which was purified by column flash chroma-
tography on silica gel, using methanol as eluant.
0
0
H3 ), 3.93–3.97 (m, 1H, H5 ), 4.75 (bs, 1H, OH), 7.25 (s, 1H,
H6), 10.79 (bs, 1H, NH), 11.10 (bs, 1H, NH). 13C NMR
(DMSOd6, 125 MHz) d 37.3, 44.2, 62.7, 62.9, 77.7, 110.7,
138.6, 151.0, 163.8. HRMS (EI) calcd for [Mþ] C9H13N3O4
227.0906, found: 227.0905. Anal. calcd for C9H13N3O4: C,
47.57; H, 5.77; N, 18.49%. Found: C, 47.43; H, 5.78; N,
18.53%.
3.3.2. (30RS,50SR)-5-[50-Hydroxymethyl-20-methyl-10,20-
isoxazolidin-30-yl]uracil (7a). (386 mg, 34% yield,
HPLC: tR 31.6 min; sticky oil). IR (KBr) nmax 3450–
3250, 3215, 3120, 3030, 2960, 2920, 2880, 1715, 1670,
3.4.1. (30RS,50RS)-5-[50-Hydroxymethyl-10,20-isoxazo-
lidin-30-yl]uracil (8). (130 mg, 93% yield, sticky oil). IR
(KBr) nmax 3500–3300, 3215, 3100, 2985, 2920, 2850,
1420, 1210, 1110, 760 cm–1
.
500 MHz) d 1.74–2.00 (m, 1H, H4 a), 2.52 (s, 3H, N-Me),
1H NMR, (DMSOd6,
0
2.59–2.65 (m, 1H, H4 b), 3.36–3.40 (m, 2H, CH2OH),
1725, 1665, 1450, 1220, 1040, 760 cm–1 1H NMR,
.
0
0
0
3.63–3.69 (m, 1H, H3 ), 4.15–4.19 (m, 1H, H5 ), 4.71 (bs,
1H, OH), 7.24 (s, 1H, H6), 10.77 (bs, 1H, NH), 11.08 (bs,
1H, NH). 13C NMR (DMSOd6, 125 MHz) d 37.2, 43.7, 62.8,
63.1, 77.1, 111.8, 138.1, 151.0, 163.8. HRMS (EI) calcd for
[Mþ] C9H13N3O4 227.0906, found: 227.0904. Anal. calcd
for C9H13N3O4: C, 47.57; H, 5.77; N, 18.49%. Found: C,
47.47; H, 5.76; N, 18.51%.
(DMSOd6, 500 MHz) d 1.75 (ddd, 1H, J¼5.1, 9.6,
0
0
12.6 Hz, H4 a), 2.06 (dd, 1H, J¼5.9, 12.6 Hz, H4 b), 3.20
00
(bs, 1H, NH), 3.55 (dd, 1H, J¼0.8, 8.8 Hz, H5 a), 3.93 (dd,
00
0
1H, J¼4.4, 8.8 Hz, H5 b), 4.30–4.36 (m, 1H, H5 ), 4.74 (dd,
0
1H, J¼5.9, 9.6 Hz, H3 ), 4.91 (d, 1H, J¼3.3 Hz, OH), 7.21
(s, 1H, H6), 10.80 (bs, 1H, NH), 11.04 (bs, 1H, NH). 13C
NMR (DMSOd6, 125 MHz) d 42.0, 70.9, 73.2, 75.2, 113.2,
137.4, 151.2, 163.4. HRMS (FAB2) calcd for [Mþ]
C8H11N3O4 213.0749, found: 213.0746. Anal. calcd for
C8H11N3O4: C, 45.07; H, 5.20; N, 19.71%. Found: C, 44.86;
H, 5.19; N, 19.76%.
3.3.3. (30RS,50RS)-5-[20-Benzyl-50-hydroxymethyl-10,20-
isoxazolidin-30-yl]uracil (6b). (670 mg, 45% yield,
HPLC: tR 32.7 min; white solid: mp 194–1968C). IR
(KBr) nmax 3450–3250, 3220, 3105, 3030, 2995, 2925,
2855, 1720, 1665, 1440, 1230, 1045, 775 cm–1. H NMR,
3.4.2. (30SR,50SR)-5-[50-Hydroxymethyl-10,20-isoxazo-
lidin-30-yl]uracil (9). (125 mg, 89% yield, sticky oil). IR
(KBr) nmax 3500–3300, 3220, 3115, 3025, 2990, 2920,
1
0
(DMSOd6, 500 MHz) d 2.09 (dt, 1H, J¼7.0, 11.5 Hz, H4 a),
0
2.34 (dt, 1H, J¼8.0, 11.5 Hz, H4 b), 3.34–3.48 (m, 2H,
1
CH2OH), 3.81 (d, 1H, J¼14.0 Hz, N-CH2Ph), 3.86 (dd, 1H,
2850, 1725, 1670, 1450, 1240, 1050, 770 cm–1. H NMR,
0
J¼7.0, 8.0 Hz, H3 ), 3.88 (d, 1H, J¼14.0 Hz, N-CH2Ph),
(DMSOd6, 500 MHz) d 1.62 (ddd, 1H, J¼2.1, 5.8, 13.3 Hz,
0
0
0
3.95–3.99 (m, 1H, H5 ), 4.13 (t, 1H, J¼5.5 Hz, OH), 7.21–
H4 a), 2.35 (ddd, 1H, J¼6.3, 8.5, 13.3 Hz, H4 b), 3.30 (bs,
00
7.32 (m, 5H, aromatic protons), 7.30 (s, 1H, H6), 10.81
(bs, 1H, NH), 11.13 (bs, 1H, NH). 13C NMR (DMSOd6,
125 MHz) d 36.7, 60.7, 61.2, 62.6, 78.1, 111.1, 126.8, 128.0,
128.6, 138.3, 138.5, 151.0, 163.7. HRMS (EI) calcd for
[Mþ] C15H17N3O4 303.1219, found: 303.1221. Anal. calcd
1H, NH), 3.61 (dd, 1H, J¼4.4, 9.2 Hz, H5 a), 3.70 (dd, 1H,
00
0
J¼1.1, 9.2 Hz, H5 b), 4.25–4.33 (m, 1H, H5 ), 4.60 (dd, 1H,
0
J¼5.8, 8.5 Hz, H3 ), 4.96 (d, 1H, J¼4.4 Hz, NH), 7.30 (s,
1H, H6), 10.80 (bs, 1H, NH), 11.10 (bs, 1H, NH). 13C NMR
(DMSOd6, 125 MHz) d 42.1, 70.9, 73.4, 75.3, 114.0, 138.2,