Nucleoside Phosphonate Analogues
C10H13N2Na2O8P: C 32.80, H 3.58, N 7.65, P 8.46; found: C 31.55, H
4.41, N 7.22, P 7.20.
67.2 (C-6’, d, J=159.1 Hz), 62.1, 61.4 (OCH2CH3, 2d, J=6.8 Hz), 27.1,
25.3 (C(CH3)2), 16.4, 16.3 ppm (OCH2CH3). (75 MHz, CDCl3): d=
163.3 (C-4), 150.4 (C-2), 142.0 (C-6), 114.6 (C(CH3)2), 102.9 (C-5), 93.4
(C-1’), 86.2 (C-4’, d, J=9.4 Hz), 83.3 (C-2’), 80.6 (C-3’), 70.2 (C-5’, d,
J=4.4 Hz), 68.2 (C-6’, d, J=162.7 Hz), 63.7, 63.0 (OCH2CH3, 2d, J=
7.0 Hz), 27.3, 25.4 (C(CH3)2), 16.5, 16.4 ppm (OCH2CH3); 31P NMR
(100 MHz, [D6]DMSO): d=23.0 ppm. (100 MHz, CDCl3): d=
21.9 ppm; UV/Vis (EtOH 95) lmax(e)=259 nm (9300), lmin (e)=
228 nm (2200); MS (FAB>0, GT): m/z 901 [2M+H]+, 451 [M+H]+,
339 [MꢀB]+; MS (FAB<0, GT): m/z 899 [2MꢀH]ꢀ, 449 [MꢀH]ꢀ, 111
[B]ꢀ; HRMS-FAB: m/z [M+H]+ calcd for C17H28N2O10P: 451.1482;
found: 451.1498; Anal. calcd for C17H27N2O10P: C 45.34, H 6.04, N
6.22, P 6.88; found: C 44.49, H 6.13, N 6.12, P 6.20.
Dihydroxylation procedure: A stirred suspension of AD-mix a or b
(700 mg) in 50% aq t-BuOH (6 mL) was treated with K2OsO4·2H2O
(144 mg, 0.4 mmol) at RT. The yellow mixture was stirred until two
phases were observed (~10–20 min), and then CH3SO2NH2
(448 mg, 0.5 mmol) was added. The mixture was cooled to 08C
and treated with 3 (200 mg, 0.5 mmol). After 2 h, the resulting mix-
ture was allowed to warm to RT and then stirred for 5 h. The solu-
tion was quenched by addition of sodium sulfite (1.5 g, 24 mmol),
and the reaction mixture was stirred for 1 h. The solution was fil-
tered, and the precipitate was washed with EtOAc. The filtrate was
dried over Na2SO4, filtered and concentrated under reduced pres-
1
sure. According to H NMR, AD-mix a gave 83% of the major diol,
1-(6’-Diethylphosphono-b-d-ribo-5’S,6’S-hexofuranosyl)uracil
(19a): Compound 18a (605 mg, 1.34 mmol) was treated using
method A. Column chromatography on reverse phase (H2O/CH3CN,
0!15%) and freeze drying gave the titled compound as a white
solid (525 mg, 93%): Rf =0.4 (CH2Cl2/MeOH, 8:2); ½aꢂ2D0 =ꢀ18.8 (c=
whereas using AD-mix b, the same product was formed in 70%.
Column chromatography on reverse phase (H2O/CH3CN, 10!20%,
v/v; major product eluted first) gave the titled compound (50%
yield of first eluted).
1
1.01 in MeOH); H NMR (300 MHz, [D6]DMSO): d=11.29 (brs, 1H,
1-(2’,3’-O-Isopropylidene-6’-diethylphosphono-b-d-ribo-5’S,6’S-
hexofuranosyl)uracil (18a): Rf =0.3 (CH2Cl2/MeOH, 9:1); ½aꢂ2D0 =+
2.1 (c=0.94 in MeOH); 1H NMR (300 MHz, [D6]DMSO): d=11.20
(brs, 1H, NH), 7.75 (d, J=8.1 Hz, 1H, H-6), 5.77 (d, J=2.3 Hz, 1H,
H-1’), 5.62 (d, J=8.0 Hz, 1H, H-5), 5.41 (t, J=7.0 Hz, 1H, OH-6’),
5.18 (d, J=7.7 Hz, 1H, OH-5’), 5.03 (dd, J=2.5, 6.5 Hz, 1H, H-2’),
4.95 (dd, J=3.1, 6.5 Hz, 1H, H-3’), 4.10–3.90 (m, 5H, H-4’,OCH2CH3),
3.90–3.70 (m, 2H, H-5’, H-6’), 1.47, 1.29 (2 s, 6H, C(CH3)2), 1.21 ppm
(t, J=7.1 Hz, 6H, (OCH2CH3). (300 MHz, CDCl3): d=9.73 (brs, 1H,
NH), 7.32 (d, J=8.1 Hz, 1H, H-6), 5.75 (d, J=8.1 Hz, 1H, H-5), 5.57
(d, J=1.6 Hz, 1H, H-1’), 5.18 (dd, J=2.8, 6.5 Hz, 1H, H-3’), 5.12 (dd,
J=1.6, 6.5 Hz, 1H, H-2’), 4.44 (brs, 1H, OH-5’), 4.30–4.10 (m, 6H, H-
4’, H-5’, OCH2CH3), 4.00 (d, J=10.7 Hz, 1H, H-6’), 3.54 (brs, 1H, OH-
6’), 1.16 (s, 3H, C(CH3)2), 1.34 (m, 9H, C(CH3)2, OCH2CH3); 13C NMR
(75 MHz, [D6]DMSO): d=163.2 (C-4), 150.2 (C-2), 142.9(C-6), 112.6
(C(CH3)2), 101.8 (C-5), 92.2 (C-1’), 85.1 (C-4’, d, J=11.9 Hz), 83.2 (C-
2’), 81.2 (C-3’), 69.7 (C-5’), 66.9 (C-6’, d, J=161.7 Hz), 61.8 (OCH2CH3,
d, J=6.5 Hz), 61.2 (OCH2CH3, d, J=6.8 Hz), 27.0, 25.1 (C(CH3)2), 16.4,
16.3 ppm OCH2CH3). (75 MHz, CDCl3): d=163.0, 150.8 (C-2, C-4),
143.1 (C-6), 114.2 (C(CH3)2), 103.0 (C-5), 96.2 (C-1’), 87.2 (C-4’, d, J=
14.4 Hz), 84.4 (C-2’), 81.8 (C-3’), 69.5 (C-5’), 67.6 (C-6’, d, J=
162.2 Hz), 63.7, 62.7 (OCH2CH3, 2d, J=6.8 Hz), 27.1, 25.2 (C(CH3)2),
16.4 ppm (OCH2CH3); 31P NMR (100 MHz, [D6]DMSO) d=24.1;
(100 MHz, CDCl3): d=22.6 ppm; UV/vis (EtOH 95): lmax(e)=258
(9900), lmin(e)=227 nm (2300); MS (FAB>0, GT): m/z 901 [2M+H]+
, 451 [M+H]+, 339 [MꢀB]+; MS (FAB<0, GT): m/z 899 [2MꢀH]ꢀ,
449 [MꢀH]ꢀ, 111 [B]ꢀ; Anal. calcd for C17H27N2O10P, 0.3H2O: C 44.80,
H 6.10, N 6.15, P 6.80; found: C 44.42, H 6.21, N 6.02, P 6.85.
NH), 7.65 (d, J=8.1 Hz, 1H, H-6), 5.72 (m, 1H, H-1’), 5.57 (d, J=
8.1 Hz, 1H, H-5), 5.40 (brs, 1H, OH-2’), 5.26 (brs, 1H, OH-3’), 5.15
(brs, 1H, OH-5’), 4.98 (brs, 1H, OH-6’), 4.12–4.04 (m, 2H, H-2’, H-3’),
4.04–3.86 (m, 4H, OCH2CH3), 3.86–3.82 (m, 1H, H-4’), 3.82–3.67 (m,
2H, H-5’, H-6’), 1.17, 1.16 ppm (2t, J=7.0 Hz, 6H, OCH2CH3);
13C NMR (75 MHz, [D6]DMSO): d=163.0 (C-4), 150.9 (C-2), 140.9 (C-
6), 102.0 (C-5), 86.6 (C-1’), 84.3 (C-4’, d, J=11.2 Hz), 72.3, 70.0 (3 s,
C-2’, C-3’, C-5’), 66.8 (C-6’, d, J=161.4 Hz), 62.0, 61.2 (OCH2CH3, 2d,
J=6.8 Hz), 16.3, 16.2 ppm (OCH2CH3); 31P NMR (100 MHz,
[D6]DMSO): d=24.1; UV/Vis (EtOH 95): lmax (e)=260 (9700), lmin
(e)=228 nm (2000); MS (FAB>0, GT): m/z 821 [2M+H]+, 411 [M+
H]+, 299 [MꢀB]+; MS (FAB<0, GT): m/z 819 [2MꢀH]ꢀ, 409 [MꢀH]ꢀ,
111 [B]ꢀ; Anal. calcd for C14H23N2O10P 0.3H2O: C 40.45, H 5.72, N
6.74, P 7.45; found: C 40.18, H 5.85, N 6.57, P 7.27.
1-(6’-Diethylphosphono-b-d-ribo-5’R,6’R-hexofuranosyl)uracil
(19b): Compound 18b (450 mg, 1.0 mmol) was treated using
method A. Column chromatography on reverse phase (H2O/CH3CN,
0 to 15%) and freeze drying gave the titled compound as a white
solid (400 mg, 97%): Rf =0.3 (CH2Cl2/MeOH, 8:2); ½aꢂ2D0 =+13.8 (c=
1
1.09 in MeOH); H NMR (300 MHz, [D6]DMSO): d=11.32 (brs, 1H,
NH), 7.99 (d, J=8.1 Hz, 1H, H-6), 5.78 (d, J=5.3 Hz, 1H, H-1’), 5.78
(brs, 1H, OH-5’ or OH-6’), 5.64 (d, J=8.1 Hz, 1H, H-5), 5.59 (brs,
1H, OH-5’ or OH-6’), 5.36 (d, J=5.4 Hz, 1H, OH-2’), 5.13 (d, J=
4.6 Hz, 1H, OH-3’), 4.15 (m, 1H, H-4’), 4.11–3.96 (m, 6H, H-2’,
OCH2CH3, H-3’), 3.77 (m, 2H, H-5’, H-6’), 1.23 ppm (t, J=7.0 Hz, 6H,
OCH2CH3); 13C NMR (75 MHz, [D6]DMSO): d=163.1 (C-4), 150.7 (C-
2), 140.6 (C-6), 101.7 (C-5), 87.5 (C-1’), 84.0 (C-4’, d, J=2.3 Hz), 73.6
(C-2’), 71.0 (C-3’), 69.7 (C-5’, d, J=11.6 Hz), 67.2 (C-6’, d, J=
159.0 Hz), 62.1, 61.4 (OCH2CH3, 2d, J=6.9 Hz), 16.3, 16.2 ppm
(OCH2CH3, 2d, J=5.6 Hz); 31P NMR (100 MHz, [D6]DMSO) d=
22.9 ppm; UV/Vis (EtOH 95): lmax(e)=260 (9900), lmin(e)=229 nm
(1900); MS (FAB>0, GT): m/z 843 [2M+Na]+, 821 [2M+H]+, 433
[M+Na]+, 411 [M+H]+; MS (FAB<0, GT): m/z 819 [2MꢀH]ꢀ, 409
[MꢀH]ꢀ; HRMS-FAB: m/z [M+H]+ calcd for C14H24N2O10P: 411.1169,
found: 411.1186; Anal. calcd for C14H23N2O10P: C 40.98, H 5.65, N
6.83, P 7.55; found: C 40.55, H 5.85, N 6.69, P 6.70.
1-(2’,3’-O-Isopropylidene-6’-diethylphosphono-b-d-ribo-5’R,6’R-
20
hexofuranosyl)uracil (18b): Rf =0.3 (CH2Cl2/MeOH, 2:1); ½aꢂD
=
ꢀ2.1 (c=0.96 in MeOH); 1H NMR (300 MHz, [D6]DMSO): d=11.40
(brs, 1H, NH), 7.89 (d, J=8.1 Hz, 1H, H-6), 5.90 (d, J=1.1 Hz, 1H,
H-1’), 5.80 (brs, 1H, OH-5’ or OH-6’), 5.60 (brs, 1H, OH-5’ or OH-6’),
5.64 (d, J=8.0 Hz, 1H, H-5), 4.86–4.78 (m, 2H, H-2’, H-3’), 4.32 (t,
J=3.0 Hz, H-4’), 4.12–3.97 (m, 4H, OCH2CH3), 3.9–3.7 (m, 2H, H-5’,
H-6’), 1.49, 1.29 (2 s, 6H, C(CH3)2), 1.23 ppm (t, J=7.0 Hz, 6H,
OCH2CH3). (300 MHz, CDCl3): d=9.60 (brs, 1H, NH), 7.58 (d, J=
8.1 Hz, 1H, H-6), 5.80 (d, J=3.2 Hz, 1H, H-1’), 5.66 (d, J=8.1 Hz,
1H, H-5), 4.91 (dd, J=3.2, 6.3 Hz, 1H, H-3’), 4.80 (dd, J=3.2, 6.2 Hz,
1H, H-2’), 4.39 (t, J=2.8 Hz, H-4’), 4.3–3.9 (m, 8H, (OCH2CH3)2, H-5’,
H-6’, OH-5’, OH-6’), 1.52 (s, 3H, C(CH3)), 1.31–1.25 ppm (m, 9H,
C(CH3), OCH2CH3); 13C NMR (75 MHz, [D6]DMSO): d=163.1 (C-4),
150.4 (C-2), 141.3 (C-6), 113.1 (C(CH3)2), 101.9 (C-5), 89.8 (C-1’), 84.9
(C-4’, d, J=8.1 Hz), 83.3, 80.6 (C-2’, C-3’), 69.7 (C-5’, d, J=9.7 Hz),
1-(6’-Phosphono-b-d-ribo-5’S,6’S-hexofuranosyl)uracil (disodium
salt) (20a): Compound 19a (204 mg, 0.5 mmol) was treated using
method B. Column chromatography on reverse phase (H2O) gave
the corresponding phosphonic acid, and subsequent ion exchange
on DOWEX Na+ and freeze drying gave the titled compound as a
white solid (90 mg, 45%): Rf =0.09 (iPrOH/NH4OH 30%/H2O, 7:1:2);
½aꢂ2D0 =ꢀ15.6 (c=0.90 in H2O); H NMR (300 MHz, D2O): d=7.76 (d,
1
ChemMedChem 2011, 6, 1094 – 1106
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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