W. Gu, S. Martinez, A.K. Singh et al.
European Journal of Medicinal Chemistry 225 (2021) 113785
(
7
(
s), 135.04 (s), 128.36 (s), 127.64 (s), 116.91 (s), 73.65 (s), 73.33 (s),
2H), 1.80 (dd, J ¼ 18.0, 6.0 Hz, 2H), 1.05 (d, J ¼ 6.0 Hz, 12H). 13C NMR
2.37 (d, J ¼ 9.5 Hz), 71.08 (s), 70.11 (t, J ¼ 6.7 Hz), 31.22 (s), 29.35
2
(75 MHz, D O) d 154.77 (s), 151.71 (s), 148.21 (s), 141.92 (s), 117.79
s), 24.10 (s). 31P NMR (121 MHz, CDCl
d
27.18 (s). HRMS: [MþH]þ
(s), 75.21 (d, J ¼ 2.9 Hz), 72.15 (d, J ¼ 6.7 Hz), 66.24 (s), 62.88 (d,
31
3
)
calculated for C19
31
H O
5
P, 371.1982; found 371.1982.
J ¼ 12.0 Hz), 40.73 (s), 29.04 (s), 27.20 (s), 22.90 (d, J ¼ 3.7 Hz).
P
þ
NMR (121 MHz, D
2
O)
d
28.73 (s). HRMS: [MþH] calculated for
4
.1.34. Diisopropyl (3-(benzyloxy)-2-(3-hydroxypropoxy)propyl)
17 30 5 5
C H N O P, 416.2057; found 416.2061.
phosphonate (30b)
To a solution of allyl ether 29 (410 mg, 1.11 mmol) in dry THF
4.1.38. 2-(3-(6-Amino-9H-purin-9-yl)propoxy)-3-
(
1 mL) was added 9-BBN (2.21 mL, 0.5 M in THF). The resulting
(diisopropoxyphosphoryl)propanoic acid (34b)
solution was stirred at room temperature for 12 h. Ethanol (1 mL),
This compound was obtained as a yellow-brown oil (48 mg, 31%)
according to the procedure used for the synthesis of compound
34a, starting from alcohol derivative 33b (150 mg, 0.36 mmol). H
4
0
N NaOH (1 mL) and 30% H
2
O
2
(1 mL) were added sequentially at
ꢀ
1
C. The reaction mixture was stirred at room temperature for 2 h
solution. The
mixture was extracted with ethyl acetate, and the combined
organic layers were dried over anhydrous MgSO and concentrated
and quenched by adding a saturated aqueous NaHCO
3
NMR (300 MHz, DMSO) d 8.24 (s, 1H), 8.12 (s, 1H), 7.21 (s, 1H),
4.62e4.48 (m, 2H), 4.26 (t, J ¼ 6.0 Hz, 2H), 3.83 (t, J ¼ 12.0 Hz, 2H),
4
3.58 (t, J ¼ 6.0 Hz, 1H), 2.29e1.89 (m, 4H), 1.21 (d, J ¼ 6.0 Hz, 12H).
13
in vacuo. The crude residue was further purified by silica gel chro-
C NMR (75 MHz, DMSO) d 174.40 (s), 155.86 (s), 152.25 (s), 149.44
matography (DCM/MeOH, v/v, 100:1 to 60:1 to 30:1) to obtain the
title compound as a colorless oil (0.27 g, 63%). H NMR (300 MHz,
(s), 141.36 (s), 118.81 (s), 75.12 (s), 69.57 (dd, J ¼ 10.0, 6.4 Hz), 66.12
1
(s), 40.22 (s), 31.54 (s), 29.67 (s), 29.43 (s), 23.67 (dd, J ¼ 9.0, 4.0 Hz).
3
1
þ
CDCl
3
)
d
7.40e7.21 (m, 5H), 4.79e4.60 (m, 2H), 4.56 (s, 2H),
P NMR (121 MHz, DMSO)
d
27.09 (s). HRMS: [MþH] calculated
3
2
.89e3.63 (m, 5H), 3.53 (d, J ¼ 5.1 Hz, 2H), 1.98 (dt, J ¼ 15.3, 7.8 Hz,
28 5 6
for C17H N O P, 430.1850; found 430.1852.
13
H), 1.83e1.66 (m, 2H), 1.30 (dd, J ¼ 6.1, 1.8 Hz, 12H). C NMR
138.06 (s), 128.44 (s), 127.73 (s), 74.31 (s), 73.40
(
(
(
75 MHz, CDCl
3
)
d
4.1.39. 2-(3-(6-Amino-9H-purin-9-yl)propoxy)-3-
phosphonopropanoic acid (6)
This compound was obtained as a white solid (14 mg, 36%) ac-
cording to the procedure used for the synthesis of compound 5,
s), 72.29 (d, J ¼ 13.5 Hz), 70.36 (dd, J ¼ 12.0, 6.5 Hz), 67.89 (s), 59.81
31
s), 32.43 (s), 31.30 (s), 29.40 (s), 24.06 (s). P NMR (121 MHz,
þ
CDCl
3
)
d
27.59 (s). HRMS: [MþH] calculated for C19
33 6
H O P,
3
89.2087; found 389.2081.
starting from iso-propyl ester 34b (48 mg, 0.112 mmol). [a]
ꢀ
1
[
20]
D
¼ þ 1.0 (c ¼ 0.2, MeOH). H NMR (300 MHz, D
2
O) d 8.21 (s,
4.1.35. Diisopropyl (3-(benzyloxy)-2-(3-(6-chloro-9H-purin-9-yl)
1H), 8.14 (s, 1H), 4.42e3.25 (m, 2H), 4.01e3.81 (m, 1H), 3.55e3.42
(m, 1H), 3.30e3.20 (m, 2H), 2.16e2.00 (m, 2H), 1.91 (dd, J ¼ 16.4,
propoxy)propyl)phosphonate (31b)
This compound was obtained as a yellow oil (679 mg, 75%) ac-
cording to the procedure used for the synthesis of compound 31a,
1
3
6.8 Hz, 2H). C NMR (75 MHz, D
2
O)
d
180.28 (d, J ¼ 14.6 Hz), 155.28
(s), 152.06 (s), 148.66 (s), 142.87 (s), 118.31 (s), 77.57 (d, J ¼ 5.0 Hz),
31
starting from 6-chloropurine (536 mg, 3.467 mmol) and alcohol
65.80 (s), 40.79 (s), 33.19 (s), 31.44 (s), 29.01 (s). P NMR (121 MHz,
1
-
derivative 30b (670 mg, 1.725 mmol). H NMR (300 MHz, CDCl
3
)
D
2
O)
d
20.49 (s). HRMS: [M ꢁ H] calculated for C11
16 5 6
H N O P,
d
8.72 (s, 1H), 8.42 (s, 1H), 7.39e7.24 (m, 5H), 4.81e4.61 (m, 2H),
.57 (s, 2H), 4.54e4.40 (m, 2H), 3.92e3.76 (m, 1H), 3.66e3.46 (m,
344.0765; found 344.0771.
4
4
13
H), 2.26e2.09 (m, 2H), 2.08e1.88 (m, 2H), 1.38e1.24 (m, 12H).
151.81 (s), 151.48 (s), 150.56 (s), 146.60 (s),
37.80 (s), 131.67 (s),128.30 (s), 127.64 (s), 127.60 (s), 74.36 (s), 73.25
s), 72.17 (d, J ¼ 11.5 Hz), 70.17 (t, J ¼ 7.2 Hz), 65.64 (s), 41.37 (s),
C
4.1.40. Diethyl (R)-(2-((1-hydroxypropan-2-yl)amino)ethyl)
phosphonate (37)
A solution of (R)-2-aminopropan-1-ol 36 (500 mg, 6.66 mmol)
and diethyl vinylphosphonate 35 (625 mg, 3.81 mmol) in H O
2
3
NMR (75 MHz, CDCl ) d
1
(
3
31
1.12 (s), 29.50 (s), 29.23 (s), 23.95 (d, J ¼ 2.9 Hz). P NMR
(10 mL), was stirred for 2 days at room temperature. The solvents
were evaporated in vacuo and the crude residue was purified by
silica gel flash chromatography (DCM/MeOH, 10:1), yielding the
þ
(
121 MHz, CDCl3)
d
26.75 (s). HRMS: [MþH] calculated for
C
24 4 5
H34ClN O P, 525.2028; found 525.2026.
1
title compound as a light-yellow oil (855 mg, 94%). H NMR
4
.1.36. Diisopropyl (2-(3-(6-amino-9H-purin-9-yl)propoxy)-3-
(300 MHz, CDCl
3
)
d
4.11e3.89 (m, 4H), 3.47 (dd, J ¼ 10.8, 3.9 Hz, 1H),
(
benzyloxy)propyl)phosphonate (32b)
3.21 (dd, J ¼ 10.8, 7.3 Hz, 1H), 3.08e2.83 (m, 3H), 2.82e2.61 (m, 2H),
This compound was obtained as a yellowish oil (478 mg, 73%)
1.89 (dt, J ¼ 18.1, 7.2 Hz, 2H), 1.23 (t, J ¼ 7.1 Hz, 6H), 0.94 (d,
13
according to the procedure used for the synthesis of compound
2a, starting from 6-chloropurine derivative 31b (679 mg,
J ¼ 6.5 Hz, 3H). C NMR (75 MHz, CDCl
3
) d 65.39 (s), 61.68 (t,
3
J ¼ 6.0 Hz), 54.28 (s), 40.38 (d, J ¼ 3.6 Hz), 27.47 (s), 25.62 (s), 16.75
1
31
1
7
(
1
(
7
.293 mmol). H NMR (300 MHz, CDCl
.42e7.17 (m, 5H), 6.84 (s, 2H), 4.82e4.63 (m, 2H), 4.55 (s, 2H), 4.37
s, 2H), 3.93e3.78 (m, 1H), 3.67e3.41 (m, 4H), 2.25e1.95 (m, 4H),
.39e1.23 (m, 12H). 13C NMR (75 MHz, CDCl
155.83 (s), 152.64
s), 149.83 (s), 141.24 (s), 137.90 (s), 128.27 (s), 127.58 (s), 119.59 (s),
4.30 (s), 73.21 (s), 72.07 (d, J ¼ 9.9 Hz), 70.12 (t, J ¼ 6.7 Hz), 65.73
3
)
d
8.33 (s, 1H), 7.98 (s, 1H),
(s), 16.37 (d, J ¼ 5.9 Hz). P NMR (121 MHz, CDCl
3
)
d
31.20 (s).
HRMS: [MþH]þ calculated for
9 4
C H22NO P, 240.1359; found
240.1340.
3
) d
4.1.41. Diethyl (R)-(2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-
yl)amino)ethyl)phosphonate (38)
To a solution of alcohol 37 (875 mg, 3.657 mmol) and imidazole
(374 mg, 5.486 mmol) in DMF (10 mL) was added TBDPS-Cl
(1.123 mL, 4.389 mmol). The resulting mixture was stirred at
room temperature overnight and quenched by adding a saturated
31
(
s), 40.68 (s), 31.09 (s), 29.78 (s), 29.21 (s), 23.93 (d, J ¼ 3.7 Hz).
P
þ
NMR (121 MHz, CDCl
3
)
d
26.98 (s). HRMS: [MþH] calculated for
C
24 36
H N
5
O
5
P, 506.2527; found 506.2527.
4
.1.37. Diisopropyl (2-(3-(6-amino-9H-purin-9-yl)propoxy)-3-
aqueous NaHCO
acetate. The combined organic layers were washed with brine,
dried over anhydrous MgSO and concentrated in vacuo. The crude
3
solution. The mixture was extracted with ethyl
hydroxypropyl)phosphonate (33b)
This compound was obtained as a yellowish oil (280 mg, 71%)
4
according to the procedure used for the synthesis of compound
residue was then purified by silica gel chromatography (DCM/
1
3
3a, starting from benzyl derivative 32b (478 mg, 0.946 mmol). H
MeOH, v/v, 60:1 to 30:1) to obtain the title compound as a colorless
1
NMR (300 MHz, D
2
O)
d
7.87 (s, 1H), 7.84 (s, 1H), 4.42 (dq, J ¼ 12.0,
oil (1.397 g, 80%). H NMR (300 MHz, CDCl
3
)
d
7.70e7.57 (m, 4H),
6
.0 Hz, 2H), 4.14e3.98 (m, 2H), 3.57e3.23 (m, 5H), 1.98e1.86 (m,
7.42e7.31 (m, 6H), 4.20e3.98 (m, 4H), 3.61e3.44 (m, 2H), 3.03e2.74
15