C-4Ј-Modified (2-Oxabicyclo[3.1.0]hexyl)yrimidine Nucleosides
FULL PAPER
6.5, 9.4 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): H, 5Ј-H), 2.01 (s, 3 H, CH3), 1.18 (t, J = 5.2 Hz, 1 H, 6Јa-H), 1.10
δ = 165.6 (C=O), 162.9 (C-4), 150.2 (C-2), 141.5 (C-6), 133.5–128.8 (dd, J = 5.8, 9.6 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]-
(Car), 102.3 (C-5), 90.6 (C-3Ј), 75.1 (C-1Ј), 67.8 (C-4Ј), 66.3 (C-7Ј), DMSO): δ = 170.7 (COCH3), 163.5 (C-4), 150.5 (C-2), 146.8 (C-
23.6 (C-5Ј), 12.7 (C-6Ј) ppm. FAB-MS: m/z = 345 [M + H]+. 4Ј), 141.5 (C-6), 109.7 (CH=CH2), 102.8 (C-5), 85.5 (C-3Ј), 68.3
HRMS: calcd. for C17H17N2O6 [M+H]+ 345.1087; found 345.1073.
(C-1Ј), 65.8 (C-7Ј), 24.2 (C-5Ј), 20.5 (CH3CO), 19.1 (C-6Ј) ppm.
FAB-MS: m/z = 279 [M + H]+. HRMS: calcd. for C13H15N2O5
[M+H]+ 279.0981; found 279.0969.
[(1S,3R,4R,5S)-4-Hydroxy-3-[5-methyl-2,4-dioxo-3,4-dihydro-
1(2H)-pyrimidinyl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (4):
Yield 505 mg (50%). M.p. 177 °C. [α]2D0 = –97 (c = 1.00, DMSO).
4-Amino-1-[(1S,3R,5S)-1-(hydroxymethyl)-4-methylene-2-oxabi-
1H NMR (300 MHz, [D6]DMSO): δ = 11.36 (br. s, 1 H, NH), 8.04– cyclo[3.1.0]hex-3-yl]-2(1H)-pyrimidinone (8): Yield 50 mg (50%).
7.53 (m, 5 H, C6H5), 7.37 (d, J = 1.1 Hz, 1 H, 6-H), 5.52 (m, 2 H, UV (EtOH 95%): λmax (ε) = 269 nm (9000). [α]2D0 = –94.9 (c = 0.59,
3Ј-H and 4Ј-OH), 4.70 (m, 2 H, 4Ј-H and 7Јa-H), 4.49 (d, J = DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 7.49 (d, J = 7.4 Hz,
12.7 Hz, 1 H, 7Јb-H), 1.94 (m, 1 H, 5Ј-H), 1.62 (s, 3 H, CH3), 1.36 1 H, 6-H), 7.25 (d, J = 13.6 Hz, 2 H, NH2), 6.39 (s, 1 H, 3Ј-H),
(t, J = 6.6 Hz, 1 H, 6Јa-H), 0.94 (dd, J = 6.6, 9.1 Hz, 1 H, 6Јb-H) 5.75 (d, J = 7.4 Hz, 1 H, 5-H), 5.34 (d, J = 1.9 Hz, 1 H, CH=CH2),
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.6 (CO), 163.5 (C-
4), 150.4 (C-2), 136.5 (C-6), 133.5–128.8 (Car), 110.2 (C-5), 89.2 (C-
3Ј), 74.8 (C-4Ј), 67.2 (C-1Ј), 66.1 (C-7Ј), 23.2 (C-5Ј), 12.3 (C-6Ј),
11.7 (CH3) ppm. FAB-MS: m/z = 359 [M + H]+. C18H18N2O6
(358.35): calcd. C 60.33, H 5.06, N 7.82; found C 60.16, H 5.27, N
7.61.
5.04 (t, J = 5.8 Hz, 1 H, 7Ј-OH), 4.65 (s, 1 H, CH=CH2), 3.95 (dd,
J = 6.2, 12.6 Hz, 1 H, 7Јa-H), 3.49 (dd, J = 5.2, 12.6 Hz, 1 H, 7Јb-
H), 2.19 (dd, J = 4.5, 9.3 Hz, 1 H, 5Ј-H), 1.12 (t, J = 5.2 Hz, 1 H,
6Јa-H), 1.07 (dd, J = 5.9, 9.3 Hz, 1 H, 6Јb-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 165.50 (C-4), 155.1 (C-2), 149.9 (C-
4Ј), 142.1 (C-6), 107.3 (CH=CH2), 94.9 (C-5), 85.5 (C-3Ј), 71.4 (C-
1Ј), 61.9 (C-7Ј), 23.6 (C-5Ј), 18.3 (C-6Ј) ppm. FAB-MS: m/z = 471
[2M+H]+, 236 [M+H]+. HRMS: calcd. for C11H14N3O3 [M+H]+
236.1035; found 236.1027.
1-[(1S,3R,5S)-1-(Hydroxymethyl)-4-methylene-2-oxabicyclo[3.1.0]-
hex-3-yl]-2,4(1H,3H)-pyrimidinedione (5): Yield 140 mg (36% from
3). UV (EtOH 95%): λmax (ε) = 260 nm (9100). [α]2D0 = –28.6 (c =
1
0.14, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 11.39 (br. s,
[(5aR,6aS,7aS,7bS)-2-Oxo-5a,7,7a,7b-tetrahydro-2H,6aH-cyclopro-
pa[4Ј,5Ј]furo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidin-6a-yl]methyl
1 H, NH), 7.50 (d, J = 8.1 Hz, 1 H, 6-H), 6.33 (s, 1 H, 3Ј-H), 5.69
(d, J = 8.1 Hz, 1 H, 5-H), 5.32 (d, J = 1.8 Hz, 1 H, CH=CH2), Benzoate (9): Yield 504 mg (59%). UV (EtOH 95%): λmax (ε) =
5.06 (t, J = 6.1 Hz, 1 H, 7Ј-OH), 4.82 (s, 1 H, CH=CH2), 3.95 (dd, 252 nm (8000). [α]2D0 = –134 (c = 0.94, DMSO). 1H NMR
J = 6.1, 12.7 Hz, 1 H, 7Јa-H), 3.48 (dd, J = 5.1, 12.7 Hz, 1 H, 7Јb- (300 MHz, [D6]DMSO): δ = 7.80 (d, J = 7.4 Hz, 1 H, 6-H), 7.40–
H), 2.22 (dd, J = 4.5, 9.6 Hz, 1 H, 5Ј-H), 1.18 (t, J = 5.2 Hz, 1 H,
6Јa-H), 1.08 (dd, J = 5.9, 9.6 Hz, 1 H, 6Јb-H) ppm. 13C NMR 8.0 Hz, 1 H, 5-H), 5.58 (d, J = 5.5 Hz, 1 H, 4Ј-H), 4.83 (d, J =
(100 MHz, [D6]DMSO): δ = 163.0 (C-4), 150.6 (C-2), 148.6 (C-4Ј), 12.9 Hz, 1 H, 7Јa-H), 4.21 (d, J = 12.9 Hz, 1 H, 7Јb-H), 2.23 (dd,
7.71 (m, 5 H, Car), 6.09 (d, J = 5.5 Hz, 1 H, 3Ј-H), 5.81 (d, J =
141.3 (C-6), 108.3 (CH=CH2), 102.7 (C-5), 84.8 (C-3Ј), 71.9 (C-1Ј), J = 5.6, 10.5 Hz, 1 H, 5Ј-H), 1.29 (dd, J = 5.6, 6.5 Hz, 1 H, 6Јa-
61.8 (C-7Ј), 23.5 (C-5Ј), 18.4 (C-6Ј) ppm. FAB-MS: m/z = 237 H), 1.14 (t, J = 7.2 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz,
[M+H]+. C11H12N2O4 (0.1 dioxane, 254.04): calcd. C 55.88, H
5.27, N 11.43; found C 55.73, H 5.23, N 11.22.
[D6]DMSO): δ = 170.9 (CO), 165.2 (C-4), 159.5 (C-2), 136.7 (C-6),
128.7–133.4 (Car), 108.9 (C-5), 93.2 (C-3Ј), 84.7 (C-4Ј), 70.0 (C-1Ј),
64.4 (C-7Ј), 23.7 (C-5Ј), 17.0 (C-6Ј) ppm. FAB-MS: m/z = 327
[M+H]+. C17H14N2O5 (326.31): calcd. C 62.57, H 4.32, N 8.59;
found C 62.27, H 4.33, N 8.34.
1-[(1S,3R,5S)-1-(Hydroxymethyl)-4-methylene-2-oxabicyclo[3.1.0]-
hex-3-yl]-5-methyl-2,4(1H,3H)-pyrimidinedione (6): Yield 120 mg
(36% from 3). UV (EtOH 95%): λmax (ε) = 263 nm (8900). [α]2D0
= –100.0 (c = 0.6, DMSO).1H NMR (300 MHz, [D6]DMSO): δ = [(5aR,6aS,7aS,7bS)-3-Methyl-2-oxo-5a,7,7a,7b-tetrahydro-2H,6aH-
11.38 (br. s, 1 H, NH), 7.38 (d, J = 1.2 Hz, 1 H, 6-H), 6.33 (s, 1 H, cyclopropa[4Ј,5Ј]furo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidin-6a-yl]-
3Ј-H), 5.31 (d, J = 1.9 Hz, 1 H, CH=CH2), 5.09 (t, J = 6.4 Hz, 1
H, 7Ј-OH), 4.79 (d, J = 0.9 Hz, 1 H, CH=CH2), 3.96 (dd, J = 5.8,
methyl Benzoate (10): Yield 475 mg (60%). M.p. 238 °C. UV (EtOH
95%): λmax (ε) = 263 nm (7000). [α]2D0 = –97 (c = 1.00, DMSO). 1H
12.7 Hz, 1 H, 7Јa-H), 3.49 (dd, J = 5.0, 12.7 Hz, 1 H, 7Јb-H), 2.22 NMR (300 MHz, [D6]DMSO): δ = 7.50–7.40 (m, 6 H, C6H5 and
(dd, J = 4.5, 9.6 Hz, 1 H, 5Ј-H), 1.75 (d, J = 1.2 Hz, 3 H, CH3),
1.17 (t, J = 5.2 Hz, 1 H, 6Јa-H), 1.08 (dd, J = 5.8, 9.6 Hz, 1 H,
6-H), 6.08 (d, J = 5.1 Hz, 1 H, H-3Ј), 5.55 (d, J = 5.1 Hz, 1 H, 4Ј-
H), 4.87 (d, J = 12.9 Hz, 1 H, 7Јa-H), 4.18 (d, J = 12.9 Hz, 1 H,
6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.8 (C-4), 7Јb-H), 2.22 (dd, JH5Ј–H6Јa = 5.5, 10.2 Hz, 1 H, 5Ј-H), 1.65 (s, 3 H,
149.7 (C-2), 147.8 (C-4Ј), 135.9 (C-6), 109.2 (C-5), 107.3 CH3), 1.28 (dd, J = 6.4, 10.2 Hz, 1 H, 6Јb-H), 1.12 (t, J = 5.8 Hz,
(CH=CH2), 83.7 (C-3Ј), 70.9 (C-1Ј), 60.9 (C-7Ј), 22.7 (C-5Ј), 17.6
(C-6Ј), 11.3 (CH3 ) ppm. FAB-MS: m/z = 251 [M + H]+ .
C12H14N2O4 (0.3 H2O, 255.66): calcd. C 56.38, H 5.76, N 10.96;
found C 56.20, H 5.48, N 10.91.
1 H, 6Јa-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.3
(CO), 165.2 (C-4), 159.0 (C-2), 128.6–133.3 (C-6 and Car), 117.1
(C-5), 93.7 (C-3Ј), 84.2 (C-4Ј), 69.8 (C-1Ј), 64.2 (C-7Ј), 23.9 (C-
5Ј), 17.0 (C-6Ј), 13.3 (CH3) ppm. FAB-MS: m/z = 341 [M+H]+.
C18H16N2O5 (340.33): calcd. C 63.52, H 4.74, N 8.23; found C
63.37, H 4.40, N 8.48.
[(1S,3R,5S)-3-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-methyl-
ene-2-oxabicyclo[3.1.0]hex-1-yl]methyl Acetate (7): To a solution of
compound 5 (150 mg, 0.635 mmol) in pyridine (4 mL) was added
acetic anhydride (0.9 mL, 9.5 mmol). After 12 h, the solution was
evaporated, co-evaporated with toluene, and the residue was puri-
fied by silica gel column chromatography (CH2Cl2/methanol, 97:3)
[(1S,3R,4R,5S)-4-Azido-3-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidin-
yl]-2-oxabicyclo[3.1.0]hex-1-yl]methyl Benzoate (11): Yield 50 mg
(44 %). UV (EtOH 95 %): λmax (ε) = 260 (10500). 1H NMR
(300 MHz, [D6]DMSO): δ = 11.45 (br. s, 1 H, NH), 8.00–7.63 (m,
J = 8.0 Hz, 6 H, C6H5 and 6-H), 5.62 (d, J = 5.2 Hz, 1 H, 3Ј-H),
to give compound 7 (170 mg, 96%) as a colourless syrup. [α]2D0
=
–163 (c = 0.92, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 5.53 (d, J = 8.0 Hz, 1 H, H-5), 5.00 (t, J = 5.6 Hz, 1 H, 4Ј-H), 4.67
11.41 (br. s, 1 H, NH), 7.35 (d, J = 8.1 Hz, 1 H, 6-H), 6.28 (s, 1 H, (d, J = 12.7 Hz, 1 H, 7Јa-H), 4.63 (d, J = 12.7 Hz, 1 H, 7Јb-H),
3Ј-H), 5.74 (d, J = 8.1 Hz, 1 H, 5-H), 5.38 (d, J = 1.9 Hz, 1 H,
2.20 (m, 1 H, 5Ј-H), 1.38 (t, J = 5.5 Hz, 1 H, 6Јa-H), 1.11 (dd, J =
CH=CH2), 4.86 (s, 1 H, CH=CH2), 4.47 (d, J = 12.8 Hz, 1 H, 7Јa- 6.8, 9.1 Hz, 1 H, 6Јb-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
H), 4.20 (d, J = 12.8 Hz, 1 H, 7Јb-H), 2.36 (dd, J = 5.1, 9.2 Hz, 1 δ = 165.5 (C=O), 162.8 (C-4), 149.9 (C-2), 140.9 (C-6), 133.5–128.8
Eur. J. Org. Chem. 2006, 4891–4897
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