J.A. Mukhlall, W.H. Hersh / Inorganica Chimica Acta 369 (2011) 62–70
69
reaction solution was then diluted further with 15 mL CH2Cl2 and
washed with 5% NaHCO3 (10 mL). The organic layer was removed
and the aqueous layer washed with 3 ꢃ 10 mL CH2Cl2. The com-
bined organic layers were dried with anhydrous MgSO4, filtered,
and evaporated on a vacuum line to give a gum. The crude material
was dissolved in EtOAc/hexanes (2:1) and applied to a short col-
umn of silica gel (ꢁ30 g in a 20 mm diameter column). The mate-
rial was first eluted with 2:1 EtOAc/hexanes, then 4:1 EtOAc/
hexanes, and finally with EtOAc. The appropriate fractions with
Rf = 0.5 (EtOAc) were pooled, and the solvent was evaporated on
a vacuum line to afford SP-17 as a white foam (0.18 g, 82% yield).
1H NMR (400 MHz, CD3CN, peaks assigned by 2D COSY): d 9.23
(br s, NH, 2H), 7.53 (d, J = 1.2 Hz, H-6, 1H), 7.27 (d, J = 1.2 Hz, H-
0.46 (br, BH3, 3H). 13C NMR (100 MHz, CD3CN): d 164.73, 164.71,
151.6, 151.5, 137.1, 136.8, 118.6, 111.64, 111.55, 86.5 (d,
J = 4.6 Hz), 85.8, 85.5, 85.2 (d, J = 6.6 Hz), 79.4 (d, J = 2.6 Hz), 71.3,
67.3 (d, J = 4.8 Hz), 62.9 (d, J = 3.0 Hz), 62.3, 39.9, 39.3 (d,
J = 3.0 Hz), 20.4 (d, J = 6.7 Hz), 12.7, 12.6. 31P NMR (161 Mz,
CD3CN): d 116.21. HRMS (ESI): Calcd for C23H34BN5O11P [M+H]+:
598.2086, found 598.2095.
RP-18 (78 mg, 85% yield from RP-17): 1H NMR (400 MHz,
CD3CN, peaks assigned by 2D COSY): d 9.19 (br s, NH, 2H),
7.53 (d, J = 1.2 Hz, H-6, 1H), 7.28 (d, J = 1.2 Hz, H-6, 1H), 6.20
T1
T2
T1
T2
(m, H-10, H-10, 2H), 5.08 (m, H-30, 1H), 4.35 (m, H-30,
T2
T2
1H), 4.30–420 (m, H-50, H-500, NCCH2CH2OP, 4H), 4.14 (m,
T1H-40, 1H), 3.99 (m, H-40, 1H), 3.72 (m, H-50, H-500, 2H),
T2
T1
T1
T1
T2
T1
6, 1H), 6.20 (m, H-10, H-10, 2H), 5.06 (m, H-30, 1H), 4.44 (m,
3.56 (br s, T2OH), 3.36 (br s, T1OH), 2.79 (t, J = 6.0 Hz, CH2CN,
T2
T2
T1
T1
T2
T2
T2H-30, 1H), 4.29–4.18 (m, H-50, H-500, NCCH2CH2OP, 4H), 4.14
2H), 2.39 (m, H-20, H-200, 2H), 2.20 (m, H-20, H-200, 2H),
T1
T2
T1
T1
(m, H-40, 1H), 3.98 (m, H-40, 1H), 3.71 (m, H-50, H-500, 2H),
1.85 (d, J = 1.2 Hz, CH3C-5, 3H), 1.83 (d, J = 1.2 Hz, CH3C-5, 3H),
3.33 (br t, J = 5.1 Hz, T1OH), 2.79 (t, J = 5.9 Hz, CH2CN, 2H), 2.38
0.46 (br, BH3, 3H). 13C NMR (100 MHz, CD3CN):
d 164.70,
T1
T1
T2
T2
(m, H-20, H-200, 2H), 2.21 (m, H-20, H-200, 2H), 1.85 (d,
J = 1.2 Hz, CH3C-5, 3H), 1.82 (d, J = 1.2 Hz, CH3C-5, 3H), 0.90 (s,
(CH3)3CSi, 9H), 0.46 (br, BH3, 3H), 0.110 (s, CH3Si, 3H), 0.105 (s,
CH3Si, 3H). 13C NMR (100 MHz, CD3CN): d 164.7, 151.54, 151.46,
137.0, 136.9, 118.5, 111.6, 111.5, 86.5 (d, J = 4.4 Hz), 85.8, 85.7,
85.5 (d, J = 6.6 Hz), 79.4 (d, J = 2.2 Hz), 72.4, 67.0 (d, J = 4.8 Hz),
62.9 (d, J = 3.3 Hz), 62.3, 40.3, 39.3 (d, J = 3.0 Hz), 26.1, 20.4 (d,
J = 6.5 Hz), 18.6, 12.7, 12.6, ꢀ4.5, ꢀ4.7. 31P NMR (161 Mz, CD3CN):
164.67, 151.6, 151.5, 137.1, 136.8, 118.5, 111.6, 111.5, 86.50 (d,
J = 4.5 Hz), 85.9, 85.6, 85.3 (d, J = 6.6 Hz), 79.3 (d, J = 3.2 Hz),
71.4, 67.4 (d, J = 4.8 Hz), 63.0 (d, J = 3.0 Hz), 62.3, 39.9, 39.2 (d,
J = 2.9 Hz), 20.4 (d, J = 6.7 Hz), 12.65, 12.60. 31P NMR (161 Mz,
CD3CN):
d 115.90. HRMS (ESI): Calcd for C23H34BN5O11P
[M+H]+: 598.2086, found 598.2099.
4.7. Synthesis of 2-cyanoethyl thymidin-30-yl thymidin-50-yl phosphite
(SP-19 and RP-19)
d
116.47. HRMS (ESI): Calcd for
C
29H48BN5O11PSi [M+H]+:
712.2950, found 712.2962.
RP-17 (0.12 g, 87% yield from RP-16): 1H NMR (400 MHz, CD3CN,
peaks assigned by 2D COSY): d 9.27 (br s, NH, 1H), 9.26 (br s, NH,
1H), 7.54 (d, J = 1.2 Hz, H-6, 1H), 7.27 (d, J = 1.2 Hz, H-6, 1H), 6.20
In the glove box, a solution of SP-18 (0.115 g, 0.192 mmol) in
2 mL of pyridine was stirred for 36 h at rt. The solution was then
evaporated over 1 g of silica gel on a vacuum line. The material
was applied to a short column of silica gel (ꢁ10 g in a coarse frit)
and then eluted with 5% MeOH/EtOAc followed by 5% MeOH/
THF. All fractions with Rf = 0.54 (5% MeOH/THF) were combined
and the solvent evaporated on a vacuum line to afford SP-19 as a
white foam (0.10 g, 90% yield). 1H NMR (400 MHz, CD3CN): d
9.04 (br s, NH, 2H), 7.53 (d, J = 1.2 Hz, H-6, 1H), 7.40 (d,
J = 1.2 Hz, H-6, 1H), 6.22–6.16 (m, H-10, 2H), 4.87 (m, H-30, 1H),
4.35 (m, H-30, 1H), 4.09–4.00 (m, H-50 (2H), H-40 (1H),
NCCH2CH2OP, 5H), 3.95 (m, H-40, 1H), 3.70 (m, H-50, 2H), 3.50 (br
s, OH, 1H), 3.27 (br s, OH, 1H), 2.70 (t, J = 5.9 Hz, CH2CN, 2H),
2.37–2.23 (m, H-20, 2H), 2.20–2.14 (m, H-20, 2H), 1.84 (d,
J = 1.2 Hz, CH3-C-5, 3H), 1.82 (d, J = 1.2 Hz, CH3-C-5, 3H). 31P NMR
(161 Mz, CD3CN): d 140.78.
T1
T2
T1
T2
(m, H-10, H-10, 2H), 5.08 (m, H-30, 1H), 4.43 (m, H-30, 1H),
T2
T2
T1
4.27–4.17 (m, H-50, H-500, NCCH2CH2OP, 4H), 4.13 (m, H-40,
T2
T1
T1
1H), 3.98 (m, H-40, 1H), 3.71 (m, H-50, H-500, 2H), 3.35 (br t,
J = 5.1 Hz, T1OH), 2.79 (t, J = 5.9 Hz, CH2CN, 2H), 2.38 (m, H-20,
T1
T1H-200, 2H), 2.20 (m, H-20, H-200, 2H), 1.85 (d, J = 1.2 Hz, CH3C-
5, 3H), 1.82 (d, J = 1.2 Hz, CH3C-5, 3H), 0.90 (s, (CH3)3CSi, 9H),
0.49 (br, BH3, 3H), 0.111 (s, CH3Si, 3H), 0.104 (s, CH3Si, 3H). 13C
NMR (100 MHz, CD3CN): d 164.74, 164.71, 151.6, 151.5, 137.1,
137.0, 118.5, 111.6, 111.5, 86.5 (d, J = 4.4 Hz), 85.8, 85.7, 85.5 (d,
J = 6.3 Hz), 79.2 (d, J = 3.6 Hz), 72.5, 67.1 (d, J = 4.4 Hz), 63.1 (d,
J = 2.9 Hz), 62.3, 40.4, 39.3 (d, J = 3.0 Hz), 26.1, 20.4 (d, J = 6.5 Hz),
18.6, 12.64, 12.62, ꢀ4.5, ꢀ4.7. 31P NMR (161 Mz, CD3CN): d 116.25.
HRMS (ESI): Calcd for C29H48BN5O11PSi [M+H]+: 712.2950, found
712.2957.
T2
T2
RP-19 (90 mg, 80% yield from RP-18): 1H NMR (400 MHz,
CD3CN): d 9.03 (br s, NH, 2H), 7.53 (s, H-6, 1H), 7.39 (s, H-6, 1H),
6.21–6.17 (m, H-10, 2H), 4.91 (m, H-30, 1H), 4.34 (m, H-30, 1H),
4.04–4.01 (m, H-50 (2H), H-40 (1H), NCCH2CH2OP, 5H), 3.94 (m,
H-40, 1H), 3.71 (m, H-50, 2H), 3.48 (br s, OH, 1H), 3.26 (br s, OH,
1H), 2.70 (t, J = 5.9 Hz, CH2CN, 2H), 2.37–2.26 (m, H-20, 2H), 2.19–
2.14 (m, H-20, 2H), 1.84 (s, CH3-C-5, 3H), 1.82 (s, CH3-C-5, 3H).
31P NMR (161 Mz, CD3CN): d 140.37.
4.6. Synthesis of 2-cyanoethyl thymidin-30-yl thymidin-50-yl
boranophosphate (SP-18 and RP-18)
Compound SP-17 (0.17 g, 0.24 mmol) was dissolved in 8 mL THF
and HF pyridine (0.54 mL, 5.99 mmol) was added to the magneti-
cally stirred solution. After ꢁ20 h at rt, TLC indicated complete
conversion to the product. The reaction solution was evaporated
on a vacuum line to dryness, then redissolved in 10 mL MeOH
and evaporated on 1 g silica gel. The material was applied to a silica
gel column (ꢁ20 g in a 20 mm diameter column) and eluted with
10% MeOH/EtOAc. The appropriate fractions with Rf = 0.42 (10%
MeOH/EtOAc) were combined and the solvent evaporated on a vac-
uum line to afford SP-18 as a white foam (0.123 g, 87% yield). 1H
NMR (400 MHz, CD3CN, peaks assigned by 2D COSY): d 9.27 (br s,
NH, 2H), 7.54 (d, J = 1.2 Hz, H-6, 1H), 7.28 (d, J = 1.2 Hz, H-6, 1H),
4.8. Synthesis of 2-cyanoethyl 50-O-(acetyl)thymidin-30-yl 30-O-
(acetyl)thymidin-50-yl phosphite (SP-20 and RP-20)
In the glove box, a solution of SP-18 (80.3 mg, 0.138 mmol) and
acetic anhydride (2.089 mg, 0.2133 mmol) in 4 mL of pyridine, was
stirred for 24 h at rt. Approximately 0.5 g silica gel was then added
to the flask and then the excess pyridine was evaporated on a vac-
uum line. The silica gel containing the crude product was applied
to a short column of silica gel (ꢁ10 g in a 15 mL coarse frit), then
eluted with EtOAc followed by 2:1 EtOAc/THF and then THF. The
fractions with Rf = 0.41 (2:1 EtOAc/THF) were combined and the
solvent evaporated on a vacuum line to afford SP-20 as a white
foam (76.3 mg, 83% yield). 1H NMR (400 MHz, CD3CN, peaks as-
signed by 2D COSY): d 9.30 (br s, NH, 2H), 7.42 (d, J = 1.2 Hz, H-6,
T1
T2
T1
T2
6.21 (m, H-10, H-10, 2H), 5.07 (m, H-30, 1H), 4.36 (m, H-30,
T2
T2
1H), 4.31–4.20 (m, H-50, H-500, NCCH2CH2OP, 4H), 4.14 (m,
T1H-40, 1H), 3.99 (m, H-40, 1H), 3.71 (m, H-50, H-500, 2H), 3.60
T2
T1
T1
(br s, T2OH), 3.36 (br t, J = 4.7 Hz, T1OH), 2.79 (t, J = 6.0 Hz, CH2CN,
T1
T1
T2
T2
2H), 2.37 (m, H-20, H-200, 2H), 2.18 (m, H-20, H-200, 2H),
1.85 (d, J = 1.2 Hz, CH3C-5, 3H), 1.82 (d, J = 1.2 Hz, CH3C-5, 3H),