R. Csuk – G. Thiede · Synthesis of Spacered Nucleoside
857
= 645.3 (100) [MNa]+, 623.2 (10) [MH]+. – HR-MS: calcd. 1238w, 1195w, 1158w, 1119w, 1033m cm−1. – 1H NMR
3
for C31H48F2N2O5Si2: 622.3069; found: 622.3069. – Anal- (400 MHz, CD3OD): δ = 7.57 (d, JH,H = 7.8 Hz, 1 H,
3
ysis for C31H48F2N2O5Si2 (622.81): calcd. C 59.78, H 7.77, 6’-H), 5.65 (d, JH,H = 7.8 Hz, 1 H, 5’-H), 3.81 and 3.71
N 4.50; found C 59.59, H 7.42, N 4.49.
(AB system, JAB = 10.5 Hz, 4JH,F = 1.9 Hz, 2 H, CH2Ocis),
4
3.79 – 3.74 and 3.66 (AB system, JAB = 11.7 Hz, JH,F
=
( )-1-[(2,2-Bis(tert-butyldimethylsilyloxymethyl)-3,3-di-
fluoro-cyclopropyl-propyl]1,2,3,4-tetrahydro-pyrimidine-
2,4-dione) (( )−7)
1.9 Hz, 2 H, CH2Otrans), 3.79 – 3.74 (m, 2 H, CH2N), 1.82 –
1.74 (m, 2 H, CH2-cyclopropyl), 1.62 – 1.48 (m, 2 H, CH2),
1.39 – 1.29 (m, 1 H, cyclopropyl). – 13C NMR (100 MHz,
CD3OD): δ = 166.70 (s, C-4’), 152.80 (s, C-2’), 147.17 (d,
A solution of 6 (2.69 g, 4.3 mmol) in methanol (45 ml)
was treated with ammonium hydroxide (18 ml, 25%)
overnight. The volatiles were evaporated and the remaining
oil was subjected to column chromatography (silica gel, n-
hexane/ethyl acetate 1:1) to give 7 (2.20 g, 99%) as a white
solid; m.p. 82 – 84 ◦C. – RF (n-hexane/ethyl acetate 1:1)
0.47. – UV/vis (methanol): λmax(lg ε) = 269 nm (3.97). –
IR (KBr): ν = 2957s, 2931s, 2886s, 2858s, 1681s, 1473s,
1430m, 1390m, 1361m, 1257s, 1198m, 1173m, 1081s,
1006m cm−1. – 1H-NMR (400 MHz, CD3OD): δ = 7.55
1
C-6’), 117.52 (dd, JC3,F = 286.2, 293.6 Hz, CF2), 102.30
(d, C-5’), 61.46 (dt, JC,F = 6.9 Hz, CH2Otrans), 56.58
3
(dt, JC,F = 6.9 Hz, CH2Ocis), 40.08 (t, CH2N), 37.18 (t,
2
2JC,F = 9.3 Hz, C-3), 30.20 (dt, JC,F = 10.0 Hz, C-1),
3
19.20 (dt, JC,F = 3.9 Hz, CH2-cyclopropyl). – 19F NMR
2
(188 MHz, CD3OD): δ = −134.21 (dd, JF,F = 162.7 Hz,
3JF,H = 162.7 Hz, 3JF,H = 14.6 Hz, F), −146.69 (d, 2JF,F
=
162.7 Hz, F’). – HPLC-MS (ESI, 4.1 kV, 8 µl/min, methanol,
N2): m/z (%) = 602.8 (36) [M2Na]+, 586.9 (53) [M2Li]+,
313.2 (25) [MNa]+, 297.2 (100) [MLi]+. – HR-MS calcd.
for C12H16F2N2O4: 290.1078; found: 290.1078. – Analysis
for C12H16F2N2O4 (290.27): calcd. C 49.66, H 5.56, N 9.65;
found C 49.51, H 5.29, N 9.42.
3
3
(d, JH,H = 7.8 Hz, 1 H, 6’-H), 5.63 (d, JH,H = 7.8 Hz,
1 H, 5’-H), 3.92 and 3.68 (AB system, JAB = 10.7 Hz,
4JH,F = 1.9 Hz, 2 H, CH2Ocis), 3.86 and 3.55 (AB sys-
4
tem, JAB = 10.4 Hz, JH,F = 1.8 Hz, 2 H, CH2Otrans),
3
3.76 (t, JH,H = 7.1 Hz, 2 H, CH2N), 1.82 – 1.77 (m, 2
( )-3-Benzoyl-1-[(2,2-bis(tert-butyldimethylsilyloxy-
methyl)-3,3-difluoro-cyclopropyl)propyl]-5-methyl-
1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )−9)
H, CH2-cyclopropyl), 1.58 – 1.54 (m, 2 H, CH2), 1.46 –
1.42 (m, 1 H, cyclopropyl), 0.89 (s, 18 H, CH3C), 0.78 –
0.06 (m, 12 H, CH3Si). – 13C-NMR (100 MHz, CD3OD):
δ = 166.88 (s, C-4’), 152.93 (s, C-2’), 147.23 (d, C-
The reaction was performed under the conditions as de-
scribed for 6 using 5 (2.00 g, 4.7 mmol), TPP (2.41 g,
9.4 mmol), N3-benzoylthymine (2.16 g, 9.4 mmol), 1,4-
dioxane (28 ml) and DIAD (1.91 g, 9.4 mmol) in 1,4-dioxane
(59 ml). After evaporation of the solvents and purification by
column chromatography (silica gel, n-hexane/ethyl acetate
7:3) 9 (2.48 g, 83%) was obtained as a colorless gel, con-
taminated with some impurities that were easily separated in
the next reaction step; an analytical sample was obtained by
column chromatography (silica gel RP-18, methanol/water
10:1). – RF (n-hexane/ethyl acetate = 7:3) 0.27. – UV/vis
(methanol): λmax (lg ε) = 258 nm (4.25). – IR (KBr):
ν = 3436m, 3069m, 2956s, 2930s, 2886m, 2856s, 2363w,
1751s, 1702s, 1660s, 1600m, 1472s, 1463s, 1438s, 1388m,
1352m, 1257s, 1172m, 1082s, 1005m cm−1. – 1H NMR
(400 MHz, CD3OD): δ = 7.91 – 7.52 (m, 6 H, phenyl, 6’-H),
3.92 and 3.68 (AB system, JAB = 10.8 Hz, 4JH,F = 1.6 Hz,
1
6’), 117.61 (dd, JC,F = 286.7, 295.0 Hz, CF2), 102.41
3
(d, C-5’), 62.16 (dt, JC,F = 7.0 Hz, CH2Otrans), 57.09
3
(dt, JC,F = 6.2 Hz, CH2Ocis), 48.95 (t, CH2N), 37.63 (t,
2JC,F = 9.9 Hz, C-2), 29.74 (dt, 2JC,F = 9.9 Hz, C-1), 29.64
(s, CCH3), 26.32 (q, CH3C), 26.31 (q, CH3C), 19.99 (dt,
3JC,F = 3.7 Hz, CH2-cyclopropyl), 19.04 (dt, 4JC,F = 1.7 Hz,
CH2), −5.36 – −5.45 (m, CH3Si). – 19F NMR (188 MHz,
2
3
CD3OD): δ = −134.29 (dd, JF,F = 164.4 Hz, JF,H
=
2
14.7 Hz, F), −146.77 (d, JF,F = 164.4 Hz, F’). – HPLC-
MS (ESI, 4.1 kV, 8 µl/min, methanol, N2): m/z (%) = 541.2
(100) [MNa]+, 519.2 (63) [MH]+. – HR-MS calcd. for
C24H44F2N2O4Si2: 518.2807; found: 518.2807. – Analy-
sis for C24H44F2N2O4Si2 (518.80): calcd. C 55.56, H 8.55,
N 5.40; found C 55.43, H 8.34, N 5.23.
( )-1-[(2,2-Difluoro-3,3-bis(hydroxymethyl)-cyclopropyl)-
propyl]-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )−8)
2 H, CH2Ocis), 3.86 and 3.54 (AB system, JAB = 10.5 Hz,
To a solution of 7 (2.20 g, 4.2 mmol) in THF (40 ml) was 4JH,F = 1.6 Hz, 2 H, CH2Otrans), 3.78 (t, JH,H = 7.2 Hz,
added tetra-n-butylammonium fluoride trihydrate (7.95 g, 2 H, CH2N), 1.84 – 1.82 (m, 2 H, CH2-cyclopropyl), 1.61 –
25.2 mmol). After stirring overnight the solvent was evap- 1.54 (m, 2 H, CH2), 1.48 – 1.43 (m, 1 H, cyclopropyl),
orated and the residue subjected to column chromatography 0.90 – 0.89 (m, 18 H, CH3C), 0.07 – 0.06 (m, 12 H, CH3Si).
3
(silica gel, ethyl acetate/methanol 8:1) to afford 8 (1.00 g,
–
13C NMR (100 MHz, CD3OD): δ = 170.57 (s, CO),
◦
82%) as a white solid; m.p. 136 – 138 C. – RF (ethyl ac- 165.40 (s, C-4’), 151.59 (s, C-2’), 143.47 (d, C-6’), 136.49
etate/methanol 5:1) 0.61. – UV/vis (methanol): λmax (lg ε) = (s, Cq phenyl), 133.16 (d, Cpara phenyl), 131.53(d, Cortho
258 nm (3.93). – IR (KBr): ν = 3462m, 3421m, 2959m, phenyl), 130.56 (d, Cmeta phenyl), 117.66 (dd, 1JC,F = 286.3,
2564w, 1678s, 1467m, 1402w, 1364w, 1351m, 1276m, 294.6 Hz, CF2), 110.91 (d, C-5’), 62.17 (dt, 3JC,F = 6.6 Hz,
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