Jan-Feb 2001
Synthesis of 5-[2-(Guanin-9-yl)-
49
Anal. Calcd. for C
51.61; H, 6.65.
H
O
: C, 51.43; H, 6.71. Found: C,
mixture was evaporated to dryness under reduced pressure, and
the resulting residue was partitioned between water (50 ml) and
ethyl acetate (50 ml). The aqueous layer was extracted with
ethyl acetate (2 x 50 ml), and the combined extracts were dried
(magnesium sulfate) and evaporated under reduced pressure to
leave a yellow solid, which was purified by column chromatog-
raphy on silica gel using methanol-chloroform (5:95, v/v) as elu-
ent to afford the desired N-9 product 12 or 14 along with N-7
isomer 13 or 15.
18 28 11
cis/trans-5-(2-Bromoethyl)-2-D-ribo-(1',2',3',4'-tetraacetoxy-
butyl)-1,3-dioxane (10) and (11).
To a cooled (0°) and stirred solution of the alcohol 9 (7.57 g,
18.01 mmoles) and carbon tetrabromide (8.96 g, 27.02 mmoles)
in anhydrous N,N-dimethylformamide (60 ml) was added tri-
phenylphosphine (7.08 g, 26.99 mmoles) in one portion, and the
resulting yellow solution was stirred at 0° for 2 hours under a
nitrogen atmosphere. The reaction mixture was quenched by
addition of saturated aqueous sodium bicarbonate solution and
extracted with ethyl acetate (2 x 200 ml). The combined extracts
were dried (magnesium sulfate) and evaporated under reduced
pressure to leave a yellow oil, which was purified by careful col-
umn chromatography on silica gel using ethyl acetate-hexane
(1:2, v/v) as eluent to afford the isomerically pure trans-bromide
10 (2.35 g, 27%) as a solid, cis-isomer 11 (2.70 g, 31%) as a
solid, and a mixture of isomers (3.39 g, 39%) as a colorless oil.
trans-5-[2-(2-Amino-6-chloropurin-9-yl)ethyl]-2-D-ribo-
(1',2',3',4'-tetraacetoxybutyl)-1,3-dioxane (12).
This compound was obtained from 10 in 81% yield as a white
25
foam; [α]
= +18.7 (c = 5.0, methanol); ir (neat): 3474 and
D
−1
1
3373 (NH ), 1754 (C=O) cm ; H nmr (deuteriochloroform): δ
2
1.61 (td, J = 7.5 Hz, J = 6.6 Hz, 2H, CHCH CH N), 2.04-2.14
2
2
(m, 1H, 5-H), 2.04 (s, 3H, COCH ), 2.07 (s, 6H, 2 x COCH ),
3
3
2.12 (s, 3H, COCH ), 3.36 (t, J = 11.1 Hz, 1H, OCH ), 3.39 (t,
3
ax
J = 11.1 Hz, 1H, OCH ), 4.06 (t, J = 7.5 Hz, 2H, CH CH N),
ax
2
2
trans-Isomer (10); mp 75.6-77.1° (diethyl ether-hexane);
4.08-4.22 (m, 3H, 4'-H and 2 x OCH ), 4.42 (dd, J = 12.3
eq
AB
25
[α]
= +15.1 (c = 1.0, methanol); ir (potassium bromide): 1748
D
Hz, J
= 2.1 Hz, 1H, 4'-H), 4.63 (d, J = 4.8 Hz, 1H, 2-H),
3',4'
2,1'
−1
1
(C=O) cm ; H nmr (benzene-d ): δ 0.79 (td, J = 7.5 Hz, J = 6.9
6
5.16 (dd, J = 4.8 Hz, J
= 3.9 Hz, 1H, 1'-H), 5.24 (br s, 2H,
2,1'
1',2'
Hz, 2H, CHCH CH Br), 1.71 (s, 3H, COCH ), 1.72 (s, 3H,
13
2
2
3
NH ), 5.43-5.48 (m, 2H, 2'-H and 3'-H), 7.74 (s, 1H, 8-H);
C
2
COCH ), 1.74 (s, 3H, COCH ), 1.75-1.84 (m, 1H, 5-H), 1.79 (s,
3
3
nmr (deuteriochloroform): δ 20.7 (2C), 20.8, 20.9, 28.5, 31.8,
3H, COCH ), 2.49 (t, J = 7.5 Hz, 1H, CH CH Br), 2.73 (t, J = 11.4
3
2
2
40.9, 62.1, 69.6, 69.8, 70.9, 71.1 (2C), 98.6, 125.2, 141.7, 151.4,
Hz, 1H, OCH ), 2.76 (t, J = 11.4 Hz, 1H, OCH ), 3.63 (ddd,
+
ax
ax
153.7, 159.1, 169.3, 169.5, 169.9, 170.6; ms: m/z (EI) 571 (M ).
J
= 11.4 Hz, J
= 6.6 Hz, J = 2.1 Hz, 1H, OCH ), 3.66
gem
eq,5 4,6 eq
Anal. Calcd. for C
H ClN O : C, 48.30; H, 5.29; N, 12.24.
23 30 5 10
(ddd, J
= 11.4 Hz, J
= 6.6 Hz, J = 2.1 Hz, 1H, OCH ),
= 7.5 Hz, 1H, 4'-H), 4.62 (d, J
gem
eq,5 4,6 eq
Found: C, 48.13; H, 5.44; N, 12.05.
4.37 (dd, J = 12.3 Hz, J
=
AB
3',4'
2,1'
trans-5-[2-(2-Amino-6-chloropurin-7-yl)ethyl]-2-D-ribo-
(1',2',3',4'-tetraacetoxybutyl)-1,3-dioxane (13).
5.1 Hz, 1H, 2-H), 4.78 (dd, J = 12.3 Hz, J
= 5.4 Hz, 1H,
AB
3',4'
4'-H), 5.66 (dd, J = 5.1 Hz, J
= 4.2 Hz, 1H, 1'-H), 5.92-5.98
2,1'
1',2'
13
(m, 2H, 2'-H and 3'-H); C nmr (deuteriochloroform): δ 20.7
(2C), 20.8, 20.9, 29.2, 31.3, 33.1, 62.1, 69.6, 69.8, 70.9, 71.0 (2C),
98.6, 169.3, 169.5, 169.8, 170.6; ms: m/z (EI) 483 (M ).
This compound was obtained from 10 in 12% yield as a white
25
solid; mp 184.5−187.0° dec (ethyl acetate); [α]
= +20.8 (c =
D
+
1.0, methanol); ir (potassium bromide): 3407 and 3321 (NH ),
2
-1
1
Anal. Calcd. for C
H BrO : C, 44.73; H, 5.63. Found: C,
18 27 10
1746 and 1736 (C=O) cm ; H nmr (dimethyl sulfoxide-d ): δ
6
44.62; H, 5.80.
1.53 (td, J = 6.6 Hz, J = 6.0 Hz, 2H, CHCH CH N), 1.78-1.95
2
2
(m, 1H, 5-H), 1.98 (s, 3H, COCH ), 2.017 (s, 3H, COCH ),
3
3
cis-Isomer (11); mp 73.1-74.4° (diethyl ether-hexane);
2.021 (s, 3H, COCH ), 2.05 (s, 3H, COCH ), 3.38 (t, J = 11.1
25
3
3
[α]
= +11.5 (c = 1.0, methanol); ir (potassium bromide):
D
Hz, 1H, OCH ), 3.40 (t, J = 11.1 Hz, 1H, OCH ), 4.01-4.13
−1
1
ax
ax
1742 (C=O) cm
; H nmr (benzene-d ): δ 0.99-1.07 (m, 1H,
6
(m, 3H, 4'-H and 2 x OCH ), 4.28 (t, J = 6.6 Hz, 2H,
eq
5-H), 1.68 (s, 3H, COCH ), 1.69 (s, 3H, COCH ), 1.73 (s, 3H,
3
3
CH CH N), 4.31 (dd, J = 12.0 Hz, J = 2.4 Hz, 1H, 4'-H),
COCH ), 1.79 (s, 3H, COCH ), 1.95 (dt, J = 7.2 Hz, J = 6.6 Hz,
2
2
AB
3',4'
3
3
4.64 (d, J = 5.1 Hz, 1H, 2-H), 5.01 (dd, J = 5.1 Hz, J =
2H, CHCH CH Br), 3.04 (t, J = 6.6 Hz, 2H, CH CH Br), 3.27
2,1'
2,1'
1',2'
2
2
2
2
3.3 Hz, 1H, 1'-H), 5.25-5.27 (m, 2H, 2'-H and 3'-H), 6.62 (br s,
(dd, J
= 12.0 Hz, J = 2.7 Hz, 1H, OCH), 3.32 (dd, J
=
gem
gem
13
2H, NH ), 8.43 (s, 1H, 8-H); C nmr (dimethyl sulfoxide-d ): δ
12.0 Hz, J = 3.0 Hz, 1H, OCH), 3.44 (br d, J
= 12.0 Hz,
2
6
gem
20.38, 20.41, 20.5, 20.6, 29.2, 31.5, 43.5, 61.4, 68.8, 69.0, 70.1,
70.3, 70.4, 97.7, 114.6, 142.1, 149.3, 159.9, 164.3, 169.08,
OCH), 3.50 (br d, J
= 12.0 Hz, OCH), 4.33 (dd, J = 12.0
gem
AB
Hz, J
= 7.5 Hz, 1H, 4'-H), 4.64 (d, J = 5.1 Hz, 1H, 2-H),
3',4'
2,1'
+
169.11, 169.3, 170.0; ms: m/z (EI) 571 (M ).
4.73 (dd, J
= 12.0 Hz, J
= 2.7 Hz, 1H, 4'-H), 5.57 (dd,
3',4'
AB
Anal. Calcd. for C
H ClN O : C, 48.30; H, 5.29; N, 12.24.
J
= 5.1 Hz, J
= 4.5 Hz, 1H, 1'-H), 5.85-5.93 (m, 2H, 2'-H
23 30 5 10
2,1'
1',2'
13
Found: C, 48.18; H, 5.42; N, 12.15.
and 3'-H); C nmr (deuteriochloroform): δ 20.7 (2C), 20.80,
20.84, 31.8, 32.1, 32.4, 62.2, 69.4, 69.48, 69.49, 69.9, 71.1, 99.1,
169.4, 169.5, 169.8, 170.6; ms: m/z (EI) 483 (M ).
cis-5-[2-(2-Amino-6-chloropurin-9-yl)ethyl]-2-D-ribo-
(1',2',3',4'-tetraacetoxybutyl)-1,3-dioxane (14).
+
Anal. Calcd. for C
H BrO : C, 44.73; H, 5.63. Found: C,
18 27 10
This compound was obtained from 11 in 79% yield as a white
44.61; H, 5.77.
25
foam; [α]
= +11.4 (c = 5.0, methanol); ir (neat): 3468, 3369
D
General Procedure for the Synthesis of 2-Amino-6-chloropurine
Derivatives (12-15).
-1
1
and 3334 (NH ), 1756 (C=O) cm ; H nmr (deuteriochloro-
2
form): δ 1.36-1.44 (m, 1H, 5-H), 2.04 (s, 3H, COCH ), 2.06 (s,
3
A suspension of 2-amino-6-chloropurine (0.66 g, 3.89
mmoles), bromide 10 or 11 (1.97 g, 4.08 mmoles), and anhy-
drous potassium carbonate (0.80 g, 5.79 mmoles) in anhydrous
N,N-dimethylformamide (20 ml) was stirred at room tempera-
ture for 24 hours under a nitrogen atmosphere. The reaction
3H, COCH ), 2.07 (s, 3H, COCH ), 2.13 (s, 3H, COCH ), 2.31
3
3
3
(q, J = 7.2 Hz, 2H, CHCH CH N), 3.88 (dd, J = 12.0 Hz, J = 5.4
2
2
Hz, 1H, OCH ), 3.89 (dd, J = 12.0 Hz, J = 5.4 Hz, 1H, OCH ),
eq
eq
4.03 (dd, J = 12.3 Hz, J = 12.0 Hz, 2H, 2 x OCH ), 4.14 (dd,
ax
J
= 12.3 Hz, J
= 6.9 Hz, 1H, 4'-H), 4.21 (t, J = 7.2 Hz, 2H,
AB
3',4'