2-(4-Nitrophenyl)ethyl Methylenebis(phosphonate)
J . Org. Chem., Vol. 63, No. 6, 1998 1909
Th ym id in e 5′-Meth ylen ebis(p h osp h on a te) (14a ).
Ta ble 1. 13C NMR of Nu cleosid e
5′-Meth ylen ebis(p h osp h on a te)s
A
yield of 50 mg (82%, as disodium salt) was obtained from the
bis(triethylammonium) salt of 13a (103 mg). 1H NMR (D2O)
δ: 1.91 [d, 3H, CH3(Thy), J ) 1.1 Hz], 2.17 (t, 2H, PCH2P, J
) 19.8 Hz), 2.28-2.45 (m, 2H, H2′, H2′′), 4.09 (m, 2H, H5′,
H5′′), 4.14 (m, 1H, H4′), 4.60 (m, 1H, H3′), 6.32 (t, 1H, H1′, J
) 7.0 Hz), 7.72 [d, 1H, H6 (Thy), J ) 1.1 Hz]. 31P NMR (D2O)
δ: 15.61 (d, 1P, J ) 9.9 Hz) and 18.85 [d, 1P, P(Thy), J ) 9.9
Hz].
purine or
compd C1’ C2’ C3’
C4’
C5’
64.2
PCH2P
27.3
pyrimidine
10a a 90.3 84.0 81.5 85.1
118.7, 140.4,
148.7, 152.5,
155.3
116.2, 137.9,
151.4, 154.0,
158.9
118.8, 137.6,
151.9, 166.7
96.1, 142.9,
154.5, 163.8
118.5, 139.9,
148.5, 152.6,
155.4
J ) 7.8 J ) 4.5 J ) 126
10ba 90.2 83.9 81.5 85.3
J ) 7.9 J ) 5.0 J ) 125
14a b 85.1 38.5 71.1 85.6
64.0 27.5
64.1 27.5
2′-Deoxycytid in e 5′-Meth ylen ebis(p h osp h on a te) (14b).
From 13b [142 mg, bis(triethylammonium salt)] was obtained
14b (46 mg, 76%, as the disodium salt). 1H NMR (D2O) δ:
J ) 7.7 J ) 4.6 J ) 124
86.3 39.3 70.8 86.0 63.7 27.6
J ) 7.7 J ) 5.1 J ) 125
83.7 39.0 71.2 86.0 63.9, 27.6
J ) 7.8 J ) 5.0 J ) 123
14b
14c
2.18 (t, 2H, J ) 19.9 Hz, PCH2P), 2.38 (dt, 1H, H2′′, J 1′,2′′
)
6.6 Hz, J 2′′,3′ ) 3.7 Hz, J 2′,2′′ ) 14.0 Hz), 2.45 (td, 1H, H2′, J 1′,2′
) 6.3 Hz, J 2′,3′ ) 4.1 Hz, J 2′,2′′ ) 14.1 Hz), 4.13 (m, 2H, H5′,
H5′′), 4.21 (m, 1H, H4′), 4.61 (dt, 1H, H3′, J 2′,3′ ) 4.1 Hz, J 2′′,3′
) 3.7 Hz, J 3′,4′ ) 6.0 Hz), 6.18 (d, 1H, J 5,6 ) 7.6 Hz, H6), 6.31
(t, 1H, H1′, J ) 6.6 Hz), 8.10 (d, 1H, J 5,6 ) 7.6 Hz, H5). 31P
NMR (D2O) δ: 15.46 (d, 1P, J ) 9.8 Hz) and 19.05 [d, 1P,
P(Cyt), J ) 9.8 Hz].
14d
83.9 38.8 71.3 85.9
63.9
27.5
115.5, 137.5,
151.2, 154.0,
158.5
J ) 7.4 J ) 5.0 J ) 124
a
Chemical shifts of the carbons of the 2′,3′-O-ispropylidene
group of 10a and 10b are 24.6, 26.3, 115.1; and 24.5, 26.2, 114.9,
2′-Deoxyaden osin e 5′-Meth ylen ebis(ph osph on ate) (14c).
Compound 14c (50 mg, 81%, as disodium salt) was prepared
from the bis(triethylammonium) salt of 13c (101 mg). 1H NMR
(D2O) δ: 2.13 (t, 2H, PCH2P, J ) 19.9 Hz), 2.58 (ddd, 1H, H2′′,
J 1′,2′′ ) 6.5 Hz, J 2′′,3′ ) 4.7 Hz, J 2′,2′′ ) 13.9 Hz), 2.85 (ddd, 1H,
H2′, J 1′,2′ ) 6.5 Hz, J 2′,3′ ) 7.2 Hz, J 2′,2′′ ) 13.9 Hz), 4.00-4.15
(m, 2H, H5′, H5′′), 4.26 (m, 1H, H4′), 4.75 (m, overlapped with
HDO, H3′), 6.49 (t, 1H, H1′, J 1′,2′ ) J 1′,2′′ ) 6.5 Hz), 8.26 (s,
1H, H2), 8.51 (s, 1H, H8). 31P NMR (D2O) δ: 15.68 (d, 1P, J
) 9.2 Hz) and 22.66 [d, 1P, P(Ade), J ) 9.7 Hz].
2′-Deoxygu an osin e 5′-Meth ylen ebis(ph osph on ate) (14d).
Starting from 13d [66 mg, bis(triethylammonium) salt] was
prepared 14d (29 mg, 83%, as disodium salt). 1H NMR (D2O)
δ: 2.16 (t, 2H, PCH2P, J ) 19.9 Hz), 2.53 (ddd, 1H, H2′′, J 1′,2′′
) 6.3 Hz, J 2′′,3′ ) 3.6 Hz, J 2′,2′′ ) 14.0 Hz), 2.84 (ddd, 1H, H2′,
J 1′,2′ ) 6.5 Hz, J 2′,3′ ) 7.4 Hz, J 2′,2′′ ) 14.0 Hz), 4.10 (m, 2H,
H5′, H5′′), 4.25 (m, 1H, H4′), 4.75 (m, 1H, H3′, overlapped with
HDO), 6.33 (t, 1H, H1′, J 1′,2′ ) J 1′,2′′ ) 6.4 Hz), 8.20 (s, 1H,
H8). 31P NMR (D2O) δ: 15.68 (d, 1P, J ) 10.0 Hz) and 19.10
[d, 1P, P(Gua), J ) 9.7 Hz].
Ad en osin e 5′-Meth ylen ebis(p h osp h on a te) (11a ). To a
solution of 10a (6 mg, 172 OD260, 0.0115 mmol) in water was
added Dowex50WX8/H+ (1 mL of suspension in water) and the
mixture was left at room temperature for 24 h, with occasional
stirring. Then the mixture was applied on the top of a Dowex
50WX8/Na+ column (1 × 3 cm) and eluted with water. UV-
absorbing fractions were combined and lyophilized to give 11a
(disodium salt, 158 OD260, 5 mg, 0.0105 mmol) in 92% yield.
1H NMR (D2O) δ: 2.17 (t, 2H, PCH2P, J ) 19.8 Hz), 4.16 (two
d, 2H, H5′ and H5′′, J 4′,5′ ) J 4′,5′′ ) 3.4 Hz), 4.37 (m, 1H, H4′),
4.55 (dd, 1H, H3′, J 2′,3′ ) 5.3 Hz, J 3′,4′ ) 3.8 Hz), 4.79 (dd, 1H,
H2′, J 1′,2′ ) 5.6 Hz, J 2′,3′ ) 5.3 Hz), 6.12 (d, 1H, H1′, J 1′,2′ ) 5.6
Hz), 8.25 (s, 1H, H2), 8.52 (s, 1H, H8). 31P NMR (D2O) δ: 15.36
(d, 1P, J ) 9.6 Hz) and 19.57 [d, 1P, P(Ade), J ) 9.6 Hz].
b
respectively. Thymidine CH3 group, 11.8 ppm.
H2 and H8 (Ade)]. 31P NMR (D2O) δ: 17.63 [d, 1P, P(NPE), J
) 11.6 Hz] and 18.16 [d, 1P, P(Ade), J ) 12.0 Hz].
P 1-[2-(4-Nitr op h en yl)eth yl]-P 2-(2′d eoxy-3′-O-a cetyl-N2-
isob u t yr ylgu a n osin -5′-yl) Met h ylen eb is(p h osp h on a t e)
(13d ). Yield: 73 mg [37%, as bis(triethylammonium) salt].
1H NMR (D2O) δ: 1.21 (t, 6H, N2-iBu, J ) 6.5 Hz), 1.26 (t,
18H, Et3N, J ) 7.3 Hz), 2.12 (t, 2H, PCH2P, J ) 20.0 Hz),
2.15 (s, 3H, OAc), 2.54 (ddd, 1H, H2′′, J 1′,2′′ ) 5.9 Hz, J 2′′,3′
)
2.0 Hz, J 2′,2′′ ) 14.5 Hz), 2.81 (t, 2H, CH2CH2PhNO2, J ) 7.0
Hz, overlapped with m, 1H, N2-iBu), 2.98 (ddd, 1H, H2′, J 1′,2′
) 8.5 Hz, J 2′,3′ ) 6.0 Hz, J 2′,2′′ ) 14.5 Hz), 3.18 (q, 12H, Et3N,
J ) 7.3 Hz), 3.99 (q, 2H, CH2CH2PhNO2, J ) 7.0 Hz), 4.16 (m,
2H, H5′,H5′′), 4.39 (m, 1H, H4′), 5.48 (m, 1H, H3′), 6.32 (dd,
1H, H1′, J 1′,2′′ ) 5.9 Hz, J 1′,2′ ) 8.5 Hz), 7.25 [d, 2H, H2, H6
(PhNO2), J ) 8.8 Hz], 7.91 [d, 2H, H3, H5, (PhNO2), J ) 8.8
Hz], 8.24 [s, 1H, H8 (Gua)]. 31P NMR (D2O) δ: 17.53 [d, 1P,
P(NPE), J ) 12.0 Hz] and 18.11 [d, 1P, P(Gua), J ) 12.4 Hz].
DBU Dep r otection of 9a ,b a n d 13a -d . Gen er a l P r o-
ced u r e. The 2-(4-nitrophenyl)ethyl-protected methylenebis-
(phosphonate)s 9a ,b and 13a -d (about 0.2 mmol) were
dissolved in 2 M aqueous DBU (1 mL) and were kept for 4
days at 75-80 °C. The resulting deep orange solutions were
diluted (up to 3 mL) with water, extracted with ethyl acetate,
neutralized with 1 M HCl, and purified by HPLC. Triethyl-
ammonium salts of compounds 10 and 14 were then converted
into corresponding sodium salts by passing through a column
of Dowex 50WX8 (Na+ form). The following compounds were
obtained.
2′,3′-O-Isopr opyliden eaden osin e 5′-Meth ylen ebis(ph os-
p h on a te) (10a ). A yield of 34 mg (91%, as disodium salt) was
obtained from 9a [60 mg, bis(triethylammonium) salt]. 1H
NMR (D2O) δ: 1.45 (s, 3H, CH3C), 1.67 (s, 3H, CH3C), 2.076
and 2.081 (1:1 ratio, t, 2H, PCH2P, J P,H ) 19.9 Hz), 4.09 (m,
2H, H5′,H5′′), 4.66 (m, 1H, H4′), 5.22 (dd, 1H, H3′, J 2′,3′ ) 6.2
Hz, J 3′,4′ ) 2.2 Hz), 5.43 (dd, 1H, H2′, J 2′,3′ ) 6.2 Hz, J 1′,2′ ) 3.3
Hz), 6.27 (d, 1H, H1′, J 1′,2′ ) 3.3 Hz), 8.25 (s, 1H, H2), 8.47 (s,
1H, H8). See Table 1 for 13C NMR data. 31P NMR (D2O) δ:
15.47 (d, 1P, J P,P ) 9.2 Hz), 19.02 [d, 1P, P(Ade), J P,P ) 9.2
Hz].
Gu a n osin e 5′-Meth ylen ebis(p h osp h on a te) (11b). The
compound was obtained in the same manner as 11a , starting
from 14 mg (274 OD253, 0.02 mmol) of 10b. The yield was 10
1
mg (disodium salt, 266 OD253, 0.0194 mmol, 97%). H NMR
(D2O) δ: 2.17 (t, 2H, PCH2P, J ) 19.8 Hz), 4.14 and 4.16 (2d,
1H each, H5′ and H5′′, J 4′,5′ ) J 4′,5′′ ) 3.9 Hz), 4.33 (m, 1H,
H4), 4.53 (dd, 1H, H3′, J 2′,3′ ) 5.5 Hz, J 3′,4′ ) 3.8 Hz), 4.79
(pseudo t, 1H, H2′, J 1′,2′ ) 5.8, J 2′,3′ ) 5.5 Hz), 5.92 (d, 1H, H1′,
J 1′,2′ ) 5.8 Hz), 8.11 (s, 1H, H8). 31P NMR (D2O) δ: 15.53 (d,
1P, J ) 9.2 Hz) and 19.35 [d, 1P, P(Gua), J ) 9.2 Hz].
2′,3′-O-Isopr opyliden egu an osin e 5′-Meth ylen ebis(ph os-
p h on a t e) (10b). A yield of 41 mg [81%, as bis(triethyl-
ammonium) salt] was obtained from 9b [66 mg, bis(triethyl-
ammonium) salt]. 1H NMR (D2O) δ: 1.21 (t, 18H, Et3N, J )
7.3 Hz), 1.39 (s, 3H, CH3C), 1.59 (s, 3H, CH3C), 2.06 (t, 2H,
PCH2P, J P,H ) 19.8 Hz), 3.13 (q, 12H, Et3N, J ) 7.3 Hz), 4.05
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of 11a , 11b, 14a , 14b, 14c, and 14d (6 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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(m, 2H, H5′, H5′′), 4.52 (m, 1H, H4′), 5.16 (dd, 1H, H3′, J 2′,3′
)
6.2 Hz, J 3′,4′ ) 2.4 Hz), 5.31 (dd, 1H, H2′, J 1′,2′ ) 3.0 Hz, J 2′,3′
) 6.2 Hz), 6.00 (d, 1H, H1′, J 1′,2′ ) 3.0 Hz), 7.99 (s, 1H, H8).
31P NMR (D2O) δ: 15.41 (d, 1P, J P,P ) 9.4 Hz), 18.92 [d, 1P,
P(Gua), J P,P ) 9.4 Hz].
J O971859A