4
794 J . Org. Chem., Vol. 62, No. 14, 1997
Sobkowska et al.
(
4H, d, J ) 9.0 Hz, 3,3′,5- and 5′-H of DMT), 7.24 -7.39 (9H,
m, ArH of DMT except of 3,3′,5- and 5′-H), 7.57 (1H, m, 6-H),
.6 (1 H, br m, NH, exch. D O) (multiplicity of some signals
due to the presence of the P-diastereomers); HRMS m/ z
86.2606, calcd for C35 PNa 686.2607. Anal. Calcd for
P: C, 63.32; H, 6.38; N, 6.33. Found: C, 63.29; H,
.38; N, 6.16.
′-O-(4,4′-Dim eth oxytr ityl)th ym id in -3′-yl N-isop r op yl-
H-p h osp h on a m id a te (3b): yield 51%; R ) 0.68 (A), 0.15 (B);
) 1.07, 1.14, 1.19 (6H, 3d, J ) 6.3 Hz,
), 1.38, 1.41 (3H, 2s, 5-CH ), 2.43, 2.59 (2H, m 2′,2′′-
), 3.39 (1H, m, CHCH ), 3.37-3.53 (3H, m, 5′,5′′-H and CH
of isopropyl), 3.79 (6H, s, OCH ), 4.26 (1H, m, 4′-H), 5.16 (1H,
m, 3′-H), 6.46 (1H, m, 1′-H), 6.94 and 6.98 (1H, 2d, 1
41.6, 644.0 Hz, PH), 6.83 (4H, d, J ) 8.7 Hz, 3,3′,5- and 5′-H
of DMT), 7.24-7.39 (9H, m, ArH of DMT except of 3,3′,5- and
′-H), 7.58 (1H, m, 6-H), 8.47 (1H, br m, NH, exch. D O)
multiplicity of some signals due to the presence of the
P-diastereomers); HRMS m/ z 672.2449, calcd for C34
PNa 672.2451. Anal. Calcd for C34 P: C, 62.84; H,
.21; N, 6.47. Found: C, 62.76; H, 6.19; N, 6.29.
′-O-(4,4′-Dim eth oxytr ityl)th ym id in -3′-yl N-ter t-bu tyl-
H-p h osp h on a m id a te (3c): yield 60%; R ) 0.70 (A), 0.17 (B);
H NMR δ (CDCl ) 1.25, 1.29 [9H, 2s, C(CH ], 1.37, 1.41 (3H,
), 2.44, 2.61 (2H, 2m, 2′′,2′′-H ), 3.40, 3.52 (2H, 2m,
), 3.79 (6H, s, OCH ), 4.26, 4.29 (1H, 2m, 4′-H), 5.16
1H NMR δ
m, CH CH
(4H, m, NCH
s, OCH ), 4.20, 4.25 (1H, 2m, 4′-H), 5.09 (1H, m, 3′-H), 6.47
(1H, m, 1′-H), 6.72 and 6.76 (1H, 2d, J HP ) 638.3, 649.4 Hz,
PH), 6.83 (4H, d, J ) 8.7, 3,3′,5- and 5′-H of DMT), 7.24-7.39
(9H, m, ArH of DMT except of 3,3′,5- and 5′-H), 7.58 (1H, m,
H
(CDCl
CH CH
, NCH
3
) 1.37, 1.41 (3H, 2s, 5-CH
CH ), 2.42, 2.57 (2H, 2m, 2′,2′′-H
), 3.37, 3.52 (2H, m, 5′,5′′-H ), 3.79 (6H,
3
), 1.35-1.65 (6H,
2
2
2
2
2
2
), 3.00
8
2
2
2
2
3
1
6
H
42
N
3
O
8
35 42 3 8
C H N O
6
5
6-H) and 8.42 (1H, br s, NH, exch. with D
some signals due to the presence of P-diastereomers); HRMS
m/ z 698.2608, calcd for C36 PNa 698.2607. Anal.
Calcd for C36 P: C, 63.97; H, 6.27; N, 6.22. Found: C,
63.62; H, 6,.23; N, 6.22.
′-O-(4,4′-Dim eth oxytr ityl)th ym id in -3′-yl N,N-d iisop r o-
2
O) (multiplicity of
f
1
H NMR δ
CHCH
H
(CDCl
3
42 3 8
H N O
3
3
42 3 8
H N O
H
2
3
2
3
5
J
HP
)
p yl-H-p h osp h on a m id a te (3g). 5′-O-(4,4′-Dimethoxytrityl)-
thymidin-3′-yl H-phosphonate (1) was dried by evaporation of
added pyridine, and after it was dissolved in methylene
chloride containing 10% pyridine (1 mmol/10 mL), diisopro-
6
5
(
2
pylamine (5.0 molar equiv) and 2-chloro-5,5-dimethyl-2-oxo-
H
40
N
3
O
8
-
5
2
λ -1,3,2-dioxaphosphinane (6) (3.0 molar equiv) were added.
40 3 8
H N O
After 1 h, the reaction mixture was diluted with methylene
chloride (5-fold of the initial volume) and washed with
6
5
saturated aqueous NaHCO
and dried over anhydrous Na
3
. The organic layer was separated
SO , and solvents were removed
f
2
4
H
3
3 3
)
by evaporation under reduced pressure. Product 3g was
purified by silica gel column chromatography using a linear
gradient of acetone in methylene chloride (0-20% v/v). Frac-
tions containing the desired product were collected and
evaporated. The H-phosphonamidate 3g was obtained as
2
5
s, 5-CH
′,5′′-H
3
2
2
3
1
(
6
(
6
1H, m, 3′-H), 7.02, 7.08 (1H, 2d, J HP ) 610.7, 642.5 Hz, PH),
.48 (4H, d, J ) 8.7 Hz, 3,3′,5- and 5′-H of DMT), 7.20-7.36
9H, m, ArH of DMT except of 3,3′,5- and 5′-H), 7.58 (1H, m,
-H) and 8.52 (1H, br, NH, exch. D O) (multiplicity of some
signals due to the presence of the P-diastereomers); HRMS
m/ z 686.2599, calcd for C35 PNa 686.2607. Anal.
Calcd for C35 P: C, 63.32; H, 6.38; N, 6.33. Found: C,
3.27; H, 6.47; N, 6.21.
′-O-(4,4′-Dim et h oxyt r it yl)t h ym id in -3′-yl N-b u t yl-N-
m eth yl-H-p h osp h on a m id a te (3d ): yield 56%; R ) 0.76 (A),
) 0.89, 0.93 (3H, 2t, J ) 7.2 Hz,
CH ), 1.38, 1.40 (3H, 2s, 5-Me), 1.48
), 2.44, 2.58 (2H, 2m, 2′,2′′-H ), 2.52, 2.62
3H, 2d, J ) 10.8 Hz, NCH ), 2.93 (2H, m, NCH CH ), 3.38,
), 3.79 (6H, s, OCH ), 4.21, 4.25 (1H,
m, 4′-H), 5.08 (1H, m, 3′-H), 6.44 (1H, m, 1′-H), 6.74 and 6.78
white solid after lyophilization from benzene: yield 69%; R
f
1
2
)
0.74 (A), 0.29 (B); H NMR (CDCl
signals are due to the presence of P-diastereoisomers) δ
of isopropyl) 1.35, 1.39
), 2.46, 2.58 (2H, 2m, 2′,2′′-H ),
and CH of isopropyl), 3.79 (6H, s,
), 4.27 (1H, m, 4′-H), 5.12 (1H, m, 3′-H), 6.46 (1H, m,
′-H), 6.83 (4H, d, J ) 8.9 Hz, 3,3′,5- and 5′-H of DMT), 6.85,
) (multiplicity of some
3
H
1.22,
42 3 8
H N O
1
.23 (12H, 2d, J ) 6.6, 6.9 Hz, CH
3
42 3 8
H N O
(
3
3H, 2d, J ) 1.2, 0.9 Hz, 5-CH
3
2
6
.37-3.54 (4H, m, 5′,5′′-H
2
5
OCH
3
f
1
6
1
0
.24 (B); H NMR δ
CH CH ), 1.27 (2H, m, CH
2H, m, CH CH CH
H
(CDCl
3
1
.93 (1H, 2d, J HP ) 636.8, 637.4 Hz, PH) 7.21-7.39 (9H, m,
2
3
2
3
ArH of DMT except of 3,3′,5- and 5′-H), 7.6 (1H, m, 6-H), 8.3
1H, br s, NH, exch. D O) (multiplicity of some signals due to
the presence of P-diastereomers); P NMR data, see Table 2;
HRMS m/ z 714.2922, calcd for C37 PNa 714.2920.
Anal. Calcd for C37 P: C, 64.23; H, 6.71; N 6.08.
Found: C, 64.19; H, 6.58; N, 5.92.
(
(
2
2
3
2
(
2
31
3
2
2
3
2
.52 (2H, 2m, 5′, 5′′-H
2
3
46 3 8
H N O
46 3 8
H N O
1
(
1H, 2d, J HP ) 646.1, 647.3 Hz, PH), 6.84 (4H, d, J ) 8.7 Hz,
,3′,5- and 5′-H of DMT), 7.24-7.39 (9H, m, ArH of DMT
except of 3,3′,5- and 5′-H), 7.57 (1H, m, 6-H) and 8.24 (1H, br
s, NH, exch. D O) (multiplicity of some signals due to the
presence of the P-diastereomers); HRMS m/ z 700.2763, calcd
for C36 PNa 700.2764. Anal. Calcd for C36 P:
C, 63.78; H, 6.55; N, 6.20. Found: C, 63.63; H, 6.84; N, 6.28.
′-O-(4,4′-Dim eth oxytr ityl)th ym id in -3′-yl N,N-d ibu tyl-
H-p h osp h on a m id a te (3e): yield 60%; R ) 0.79 (A), 0.39 (B);
) 0.89, 0.92 (6H, 2t, J ) 7.2 Hz, CH CH ),
CH CH ), 1.35, 1.39 (3H, 2s, 5-CH ), 1.45 (4H,
), 2.44, 2.57 (2H, 2m, 2, 2′′-H ), 2.95 (4H, m,
), 3.37-3.51 (2H, m, 5′, 5′′-H ), 3.79 (6H, s, OCH ),
.24 (1H, m, 4′-H), 5.12 (1H, m, 3′-H), 6.46 (1H, m, 1′-H), 6.76,
3
5
Rea ction of 2-Ch lor o-5,5-d im eth yl-2-oxo-2λ -1,3,2-d iox-
a p h osp h in a n e (6) w ith Am in es 2a -f. 2-Chloro-5,5-dim-
2
5
ethyl-2-oxo-2λ -1,3,2-dioxaphosphinane (6) (1.0 molar equiv)
2 2
in CH Cl -pyridine (9:1 v/v) (1.0 mmol/10 mL) was allowed
H
44
N
3
O
8
44 3 8
H N O
to react with the appropriate amine 2 (5.0 molar equiv) to
produce the corresponding phosphoramidates. In all instances,
5
31
their P NMR spectra were identical with those of side
f
products of type 7 formed during the condensations of 1 with
1
H NMR δ
.27 (4H, m, CH
m, NCH CH CH
NCH CH
H
(CDCl
3
2
3
31
amines 2a -f mediated by 6; P NMR 7a , δ
P
5.70 ppm (br m);
6.81 ppm (br
P
5.12 ppm (br m).
1
2
2
3
3
7
b, δ
P
4.25 ppm (br m); 7c, δ
P
3.50 (br m); 7d , δ
P
2
2
2
2
m); 7e, δ
P
7.51 ppm (br m); 7f, δ
2
2
2
3
4
6
8
1
Ack n ow led gm en t. We are indebted to Prof. Maciej
Wiewior o´ wski and to Prof. Per J . Garegg for their
interest and helpful discussions. Financial support from
the State Committee for Scientific Research, Republic
of Poland (2 P303 145 07), the Swedish Natural Science
Research Council, and the Swedish Research Council
for Engineering Sciences is gratefully acknowledged.
.82 (1H, 2d, J HP ) 642.2, 630.8 Hz, P-H), 6.84 (4H, d, J )
.7 Hz, 3,3′,5- and 5′-H of DMT), 7.21-7.39 (9H, m, ArH of
DMT except of 3,3′,5- and 5′-H), 7.58 (1H, m, 6-H), 8.48 (1H,
br s, NH, exch. D
presence of the P-diastereomers); HRMS m/ z 742.3227, calcd
for C39 PNa 742.3233. Anal. Calcd for C39 P:
C, 65.06; H, 7.01; N, 5.84. Found: C, 64.82; H, 7.21; N, 5.63.
′-O-(4,4′-Dim eth oxytr ityl)th ym id in -3′-yl N-p ip er id yl-
H-p h osp h on a m id a te (3f): yield 64%; R ) 0.74 (A), 0.18 (B);
2
O) (multiplicity of some signals due to the
H
50
N
3
O
8
50 3 8
H N O
5
f
J O962224Z