E. Colacino et al. / Tetrahedron 57 &2001) 8551±8557
8555
4.1.1. -200RS,50RS)-1-[20--Tetrahydropyran-200-yl)-10,20-
isoxaxolidin-50-yl]-uracil -6). Method A. Paraform-
aldehyde 21.91 g, 63.6 mmol), 1-vinyl-uracil 24;2.0 g,
15.9 mmol) and 5-hydroxypentanaloxime 21;4.67 g, 39.8
mmol) were suspended in dry CHCl3 230 mL). The resulting
mixture was re¯uxed for 38 h until complete conversion
of the dipolarophile 2TLC: Et2O/MeOH 95:5, v/v). The
solution was then cooled at room temperature and evapo-
rated to dryness in vacuo. Puri®cation of the recovered
crude material by ¯ash-chromatography afforded the title
compound 6 22.47 g, 65%) as a white powder;[Found: C,
54.01;H, 6.48;N, 15.69. C 12H17N3O4 requires C, 53.92;H,
6.41;N, 15.72]; nmax 2KBr) 3600±3180 2br), 3169, 3046,
2931, 1728 2CvO), 1718 2CvO), 1457, 1265, 1220, 1118,
1034 cm21; dH 2CDCl3) 7.85 21H, d, J8.1 Hz, 6-CH), 7.81
21H, d, J8.1 Hz, 6-CH), 6.18 21H, dd, J7.6, 5.1 Hz,
50-CH), 6.16 21H, dd, J7.5, 5.2 Hz, 50-CH), 5.63 21H, d,
J8.1 Hz, 5-CH), 5.59 21H, d, J8.1 Hz, 5-CH), 4.39 21H,
dd, J10.6, 2.2 Hz, 200-CH), 4.16 21H, dd, J10.0, 2.5 Hz,
200-CH), 4.09±4.01 22H, m, 600-CHaHb), 3.67±3.59 22H, m,
30-CHaHb), 3.52±3.45 22H, m, 600-CHaHb), 3.29±3.22 22H,
m, 40-CHaHb), 3.19±3.12 22H, m, 30-CHaHb), 2.91±2.82
22H, m, 40-CHaHb), 1.91±1.80 24H, m, 500-CH2), 1.68±
1.49 28H, m, 300-CH2 and 400-CH2); m/z 21, NBA) 290
229, MNa1), 268 278, MH1), 184 238), 156 245), 141 241),
139 228), 112 213), 85 2100%).
Removal of the volatiles in vacuo afforded an aqueous
residue which was diluted with distilled water 212 mL)
and extracted twice with CHCl3 230 mL). The organic layers
were dried 2Na2SO4) and evaporated to dryness in vacuo to
give the title compound 9 23.32 mg, 100%) which was
obtained as a white powder and pure enough to be used in
next step without need of puri®cation. [Found: C, 54.26;H,
6.10;N, 25.28. C 15H20N6O3 requires C, 54.21;H, 6.07;N,
25.29]; nmax 2KBr) 3160, 3042, 2950, 1725 2CvO), 1649,
1530, 1462, 1379, 1273, 1122, 1055 cm21; dH 2CDCl3) 8.12
22H, s, 3-CH triazole), 7.95 22H, s, 5-CH triazole), 7.05 22H,
s, 6-CH), 6.16 21H, dd, J7.2, 4.8 Hz, 50-CH), 6.14 21H, dd,
J7.3, 4.7 Hz, 50-CH), 4.40 21H, dd, J11.0, 2.4 Hz,
200-CH), 4.23 21H, dd, J10.5, 2.8 Hz, 200-CH), 4.18±4.12
22H, m, 30-CHaHb), 4.09±4.02 22H, m, 600-CHaHb), 3.49±
3.43 22H, m, 600-CHaHb), 3.41±3.34 22H, m, 30-CHaHb),
3.15±3.10 22H, m, 40-CHaHb), 2.96±2.89 22H, m,
40-CHaHb), 1.85±1.76 24H, m, 500-CH2), 1.62±1.49 28H,
m, 300-CH2 and 400-CH2); m/z 21, NBA) 333 238, MH1),
248 224), 239 222), 178 245), 156 222), 152 229), 85 2100%).
4.1.4. -^)-1--20-H-10,20-Isoxazolidin-50-yl)-4-[1,2,4--1H)-
triazol-1-yl]-5-methyl-pyrimidin-2--1H)-one -10).
A
magnetically stirred solution of 9 2332.3 mg, 1 mmol) in
MeOH/CHCl3 25 mL, 7:3 v/v) was treated with 60%
aqueous HClO4. The acid was added dropwise at room
temperature until complete conversion of the starting
protected cycloadducts 2TLC: Et2O/MeOH 90:10, v/v).
The pH value of the reaction mixture was then adjusted to
neutrality by adding solid NaHCO3. The resulting sus-
pension was ®ltered through a CELITE 545w short pad
2MeOH as eluent) and the mother liquor was evaporated
to dryness in vacuo. Puri®cation by ¯ash-chromatography
of the recovered crude material afforded 10 2228.4 mg,
92%) as a white powder, mp 197±2008C;[Found: C,
48.33;H, 4.80;N, 33.92. C 10H12N6O2 requires C, 48.39;
H, 4.84;N, 33.87]; nmax 2KBr) 3580±3118 2br), 3022,
1721 2CvO), 1648, 1532, 1460, 1379, 1180, 1141,
1010 cm21; dH 2DMSO-d6) 8.12 21H, s, 3-CH triazole),
8.05 21H, s, 5-CH triazole), 7.77 21H, br s, 20-NH), 6.28
21H, dd, J8.9, 6.8 Hz, 50-CH), 6.19 21H, s, 6-CH), 3.28±
3.24 21H, m, 30-CHaHb), 2.79±2.75 21H, m, 30-CHaHb),
2.30±2.26 21H, m, 40-CHaHb), 2.25±2.21 21H, m,
40-CHaHb), 1.97 23H, s, Me); dC 2DMSO-d6) 164.2, 158.1,
127.9, 113.7, 98.9, 52.2, 40.8, 11.8; m/z 21, NBA) 249 234,
MH1), 207 222), 205 219), 178 243), 72 2100%).
4.1.2. -^)-1--20-H-10,20-Isoxazolidin-50-yl)-uracil -8, AdU).
To a magnetically stirred solution of 6 2267.3 mg, 1 mmol),
in MeOH/CHCl3 25 mL, 7:3 v/v), was added dropwise 60%
aqueous HClO4, at room temperature, until complete con-
version of the starting protected cycloadducts 2TLC: Et2O/
MeOH 90:10 v/v). The pH value of the reaction mixture was
then adjusted to neutrality by adding solid NaHCO3. The
resulting suspension was ®ltered through a CELITE 545w
short pad 2MeOH as eluent), and the mother liquor was
evaporated to dryness in vacuo. Puri®cation by ¯ash-
chromatography of the recovered crude material afforded
the title compound 8 2166.7 mg, 91%) as a white powder,
mp 177±1798C;[Found: C, 45.82;H, 5.01;N, 22.88.
C7H9N3O3 requires C, 45.90;H, 4.95;N, 22.94];
nmax
2KBr) 3586±3165 2br), 3026, 1726 2CvO), 1718 2CvO),
1521, 1463, 1332, 1277, 1196, 1014 cm21; dH 2DMSO-d6)
9.32 21H, s, 3-NH), 7.68 21H, br s, 20-NH), 7.12 21H, d,
J8.1 Hz, 6-CH), 6.34 21H, dd, J7.0, 5.3 Hz, 50-CH),
5.63 21H, d, J8.1 Hz, 5-CH), 3.30±3.26 21H, m,
30-CHaHb), 3.06±3.01 21H, m, 30-CHaHb), 2.58±2.53 21H,
m, 40-CHaHb), 2.31±2.26 21H, m, 40-CHaHb); dC 2DMSO-
d6) 164.4, 157.8, 142.6, 100.8, 93.8, 49.5, 42.3; m/z 21, Gly)
206 239, MNa1), 184 268, MH1), 151 237), 141 245), 139
245), 112 220), 72 2100%).
4.1.5.
-^)-1--20-H-10,20-Isoxazolidin-50-yl)-5-methyl-
pyrimidin-2--1H)-one -11; 5-MeAdC). A solution of 10
2248.3 mg, 1 mmol) in dry 1,4-dioxane 210 mL) was treated
with gaseous NH3, under magnetic stirring at room tempera-
ture for 7 h 2TLC: Et2O/MeOH 85:15, v/v). Removal of the
solvent in vacuo gave crude 11 which was puri®ed by ¯ash-
chromatography. Compound 11 was recovered as a white
powder 2186.4 mg, 95%), mp 192±1948C;[Found: C,
48.95;H, 6.08;N, 28.52. C 8H12N4O2 requires C, 48.98;H,
6.12;N, 28.57]; nmax 2KBr) 3590±3130 2br), 3015, 1720
4.1.3. -200RS,50RS)-1-[20--Tetrahydropyran-200-yl)-10,20-
isoxaxolidin-50-yl]-4-[1,2,4--1H)-triazol-1-yl]-5-methyl-
pyrimidin-2--1H)-one -9). Method A. To a magnetically
stirred solution of 5 22.18 g, 10 mmol) in dry CH3CN
240 mL) was added freshly distilled POCl3 21.9 mL, 20
mmol), dry triethylamine 23.22 mL, 25 mmol) and 1,2,4-
21H)-triazole 21.38 g, 20 mmol). The reaction mixture was
maintained at room temperature for 45 min 2TLC: Et2O/
MeOH 95:5, v/v). Triethylamine 27 mL) and distilled
water 23 mL) was then added and the resulting solution
was stirred at room temperature for an additional 10 min.
2CvO), 1530, 1461, 1328, 1282, 1270, 1190, 1084 cm21
;
dH 2DMSO-d6) 7.85 21H, br s, 20-NH), 7.21 22H, br s,
4-NH2), 6.33 21H, dd, J7.9, 6.1 Hz, 50-CH), 6.00 21H, s,
6-CH), 3.36±3.32 21H, m, 30-CHaHb), 2.94±2.89 21H, m,
30-CHaHb), 2.41±2.36 21H, m, 40-CHaHb), 2.28±2.23 21H,
m, 40-CHaHb); dC 2DMSO-d6) 164.8, 158.9, 124.5, 107.8,