F. Bellany, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115740
−
1
1
20
1
570 (C]C) cm ; H NMR (600 MHz, CDCl
3
) δ 8.32 (1H, s), 7.98 (1H,
[α]
D
+ 54.5 (c 0.1, MeOH); IR νmax (oil) 3320 (NH), 3280 (NH),
s), 7.36–7.29 (5H, m), 5.99 (1H, d, J = 3.4 Hz), 5.91 (2H, br), 5.17 (2H,
apparent s), 5.09 (1H, dd, J = 4.9 and 3.4 Hz), 4.72 (1H, dd, J = 6.4
and 4.9 Hz), 4.53 (1H, dd, J = 12.0 and 3.2 Hz), 4.41 (1H, dd, J = 12.0
and 5.2 Hz), 4.33 (1H, ddd, J = 6.4, 5.2 and 3.2 Hz), 3.46 (2H,
3080 (OH), 2960–2880 (CH), 1730 (C]O), 1640 (C]O) and 1570
−1 1
(C]C) cm ; H NMR (600 MHz, CD OD) δ 8.28 (1H, s), 8.21 (1H, s),
3
6.02 (1H, d, J = 4.5 Hz), 4.72 (1H, t, J = 4.5 Hz), 4.45 (2H, dd,
J = 14.5 and 4.0 Hz), 4.39 (1H, t, J = 5.0 Hz), 4.29–4.26 (1H, m), 4.11
(1H, d, J = 10.5 Hz), 3.95 (1H, d, J = 10.5 Hz), 3.86 (1H, s), 3.50–3.39
(2H, m), 3.10 (2H, t, J = 6.5 Hz), 2.40 (2H, t, J = 6.8 Hz), 1.54–1.45
1
3
apparent s) and 1.10–0.99 (28H, m); C NMR (150 MHz, CDCl
3
) δ
1
1
66.2, 155.7, 153.2, 149.6, 140.2, 135.2, 128.6 (overlapping signals),
20.5, 90.6, 81.7, 75.7, 72.6, 67.5, 64.6, 41.4, 17.4 and 13.5; HRMS
Si expected 686.3041, found 686.3073.
1
3
(2H, m), 0.95 (3H, s) and 0.92–0.88 (6H, m); C NMR (150 MHz,
calc’d for C32
H
48
O
8
N
5
2
CD OD) δ 175.3, 173.6, 168.2, 168.0, 157.6, 153.4, 150.6, 142.0,
3
1
21.0, 90.1, 83.4, 79.3, 75.7, 72.7, 71.7, 65.9, 42.4, 41.6, 39.6, 36.4,
4
.1.2.4. 3-(((5aS,6S,8S,8aS)-8-(6-Amino-9H-purin-9-yl)-2,2,4,4-
23.6, 20.7, 20.6 and 11.7; HRMS calc’d for C25
596.2680, found 596.2684. Note: (CO)CH
NMR as it is exchangeable with NMR solvent.
H
38
N
7
O
10 expected
1
tetraisopropyltetrahydrofuro[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)
2
(CO) signal is not seen in H
methoxy)-3-oxopropanoic acid (16). To protected adenosine analogue
1
5 (1.40 g, 2.04 mmol) and Pd/C (10 wt%, 55 mg, 0.51 mmol) was
added MeOH (5 mL) before evacuating and filling the flask with
4.1.2.7. Benzyl
3-((((3aS,4S,6S,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-
hydrogen. The reaction was stirred at RT under
a
hydrogen
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-3-
oxopropanoate (20). To a solution of amine 19 (3.50 g, 11.4 mmol) and
atmosphere for 5 h. The reaction mixture was filtered through
Celite®, washed with MeOH and the filtrate concentrated in vacuo to
acid 12 (4.42 g, 22.8 mmol) in CH
2
Cl (35 mL) was added DCC (2.96 g,
2
give 16 (860 mg, 71%) as an off-white solid; R
f
0.13 (8% MeOH/
14.8 mmol) and DMAP (347 mg, 2.85 mmol). The reaction was stirred
at RT for 21 h. The insoluble dicyclohexylurea was removed by
2
0
CH
2
Cl
2
); mp 159–161 °C; [α]
D
−17.5 (c 0.2, MeOH); IR νmax (solid)
3
1
1
320 (NH), 3280 (NH), 3170 (OH), 2940–2870 (CH), 1750 (C]O),
filtration, washed with CH
2
Cl and the filtrate concentrated in vacuo.
2
−
1 1
670 (C]O) and 1620 (C]C) cm
;
H NMR (600 MHz, d
6
-DMSO) δ
Purification using flash column chromatography (Gradient: 0–3%
2.91 (1H, br), 8.38 (1H, s), 8.14 (1H, s), 7.36 (1H, br), 6.00 (1H, d,
MeOH/CH
MeOH/CH
2
Cl
2
Cl
2
2
) gave 20 (4.26 g, 78%) as a white gum; R
f
0.63 (10%
−68.2 (c 0.5, MeOH); IR νmax
) 3320 (NH), 3180 (NH), 3060–2920 (CH), 1730
2
0
J = 5.2 Hz), 5.17 (1H, t, J = 5.2 Hz), 4.74 (1H, t, J = 4.7 Hz), 4.39
); mp 77–79 °C; [α]
Cl
D
(
(
1H, dd, J = 11.9 and 4.8 Hz), 4.28 (1H, dd, J = 11.9 and 5.6 Hz), 4.19
(solution in CH
2
2
1
3
−1
1
1H, q, J = 4.8 Hz), 3.40 (2H, apparent s) and 1.09–0.92 (28H, m);
-DMSO) δ 167.9, 166.8, 156.2, 152.8, 149.3, 139.7,
19.1, 81.7, 81.7, 74.8, 72.3, 63.9, 41.4, 17.2 and 12.5; HRMS calc’d
for C25 Si expected 596.2572, found 596.2566
C
(C]O), 1640 (C]O) and 1590 (C]C) cm
; H NMR (600 MHz,
NMR (150 MHz, d
6
CDCl ) δ 8.70 (1H, d, J = 7.9 Hz), 8.26 (1H, s), 7.85 (1H, s), 7.28–7.20
3
1
(5H, m), 6.12 (2H, br), 5.8 (1H, d, J = 4.9 Hz), 5.19 (1H, dd, J = 6.0
H
42
O
8
N
5
2
and 4.9 Hz), 5.13 (1H, d, J = 12.5 Hz), 5.10 (1H, d, J = 12.5 Hz), 4.89
(
1H, dd, J = 6.0 and 2.0 Hz), 4.49 (1H, q, J = 2.0 Hz), 4.17 (1H, ddd,
4
.1.2.5. ((5aS,6S,8S,8aS)-8-(6-Amino-9H-purin-9-yl)-2,2,4,4-
tetraisopropyltetrahydrofuro[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)methyl
(R)-3-hydroxy-2,2-dimethyl-4-oxo-4-((3-oxo-3-(propylamino)propyl)
amino)butyl) malonate (18). To a solution of acid 16 (700 mg,
.17 mmol) and alcohol 17 (337 mg, 1.30 mmol) in CH Cl (30 mL)
at 0 °C was added EDC (271 mg, 1.42 mmol) and DMAP (173 mg,
.42 mmol). The reaction was stirred at RT for 16 h. The reaction
mixture was diluted with CH Cl (20 mL) and washed with 5% citric
acid solution (40 mL), then sat. NaHCO solution (40 mL). The organic
layer was dried (MgSO ), filtered and concentrated in vacuo.
Purification using flash column chromatography (Gradient: 2%, 5%
then 7.5% MeOH/CH Cl ) gave 18 (240 mg, 25%) as an off-white solid;
0.28 (10% MeOH/CH
J = 14.4, 8.8 and 2.5 Hz), 3.48 (2H, apparent s), 3.29 (1H, dt, J = 14.4
13
and 2.5 Hz), 1.62 (3H, s) and 1.36 (3H, d); C NMR (150 MHz, CDCl )
3
(
δ 168.4, 166.0, 156.1, 152.6, 148.8, 140.6, 135.2, 128.6 (overlapping
signals), 121.2, 114.8, 92.8, 83.7, 82.4, 81.7, 67.4, 42.9, 41.4, 27.6 and
1
2
2
25.3; HRMS calc’d for
483.1992.
C
23
H
19
N
6
O
6
expected 483.1992, found
1
2
2
4.1.2.8. Benzyl
3-((((2S,3R,4S,5S)-5-(6-amino-9H-purin-9-yl)-3,4-
3
dihydroxytetrahydrofuran-2-yl)methyl)amino)-3-oxopropanoate (21). To
a cooled suspension of protected adenosine analogue 20 (4.20 g,
4
8.71 mmol) in H O (130 mL) was added TFA (33 mL) and the
2
2
2
reaction stirred at 0 °C for 30 min before warming to RT for 3 h. The
reaction mixture was then concentrated in vacuo. Purification using
flash column chromatography (Gradient: 2%, 5% then 7.5% MeOH/
2
0
R
f
2
Cl
2
); mp 84–86 °C; [α]
D
+ 2.4 (c 0.2,
MeOH); IR νmax (solid) 3310 (NH), 3280 (NH), 2940–2860 (CH), 1730
−
1
1
(
C]O), 1640 (C]O) and 1600 (C]C) cm
;
H NMR (600 MHz,
CH
MeOH/CH
(solid) 3350 (NH), 3290 (NH), 3100 (OH), 3070–2900 (CH), 1710 (C]
2
Cl
2
) gave 21 (3.47 g, 90%) as an off-white solid; R
f
0.39 (10%
2
0
CDCl
3
) δ 8.30 (1H, s), 8.09 (1H, s), 7.52 (1H, t, J = 6.0 Hz), 6.75 (1H,
2
Cl
2
); mp 113–116 °C; [α]
D
−55.2 (c 0.5, MeOH); IR νmax
d, J = 4.5 Hz), 6.07 (2H, br), 6.04 (1H, s). 5.73 (1H, t, J = 5.6 Hz),
−
1 1
4
.97 (1H, d, J = 3.7 Hz), 4.64 (1H, dd, J = 12.4 and 2.3 Hz), 4.49–4.42
O), 1650 (C]O) and 1580 (C]C) cm ; H NMR (600 MHz, d -DMSO)
6
(
2H, m), 4.40–4.35 (2H, m), 4.15 (1H, d, J = 4.9 Hz), 3.84 (1H, d,
δ 8.51 (1H, s), 8.45 (1H, t, J = 5.8 Hz), 8.33 (1H, s), 8.20 (2H, br),
7.37–7.29 (5H, m), 5.90 (1H, d, J = 6.0 Hz), 5.51 (2H, br), 5.11 (2H,
apparent s), 4.64 (1H, t, J = 6.0 Hz), 4.09 (1H, t, J = 4.7 Hz), 3.97 (1H,
dt, J = 5.8 and 4.7 Hz), 3.50–3.38 (2H, m) and 3.35 (2H, apparent s);
J = 10.9 Hz), 3.67–3.59 (1H, m), 3.56–3.49 (1H, m), 3.48 (2H,
apparent s), 3.29–3.16 (2H, m), 2.51–2.37 (2H, m), 1.74–1.56 (2H,
1
3
m) and 1.17–0.89 (37H, m); C NMR (150 MHz, CDCl
3
) δ 172.5, 171.4,
1
3
1
7
1
66.7, 166.0, 155.3, 153.5, 149.0, 138.4, 119.6, 91.0, 81.1, 76.3, 73.8,
1.8, 71.5, 63.0, 41.4, 41.3, 38.5, 35.6, 35.2, 22.9, 21.9, 18.9, 14.5,
3.7 and 13.0; HRMS calc’d for C37 Si expected 838.4202,
C NMR (150 MHz, d -DMSO) δ 167.8, 165.4, 153.9, 149.7, 148.9,
6
141.3, 135.9, 128.4, 128.0, 127.8, 119.2, 87.7, 83.5, 73.0, 71.2, 65.9,
H
64
O
11
N
7
2
42.4 and 41.2; HRMS calc’d for C20
443.1672.
H
23
O
6
N expected 443.1679, found
6
found 838.4238.
4
.1.2.6. ((2S,3R,4S,5S)-5-(6-Amino-9H-purin-9-yl)-3,4-
4.1.2.9. Benzyl 3-((((5aS,6S,8S,8aS)-8-(6-amino-9H-purin-9-yl)-2,2,4,4-
tetraisopropyltetrahydrofuro[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)methyl)
amino)-3-oxopropanoate (22). To adenosine diol 21 (350 mg,
0.79 mmol) in anhydrous DMF (3 mL) was added imidazole (135 mg,
1.98 mmol) and DMAP (24 mg, 0.20 mmol). Then, 1,3-dichloro-1,1,3,3-
triisopropyldisiloxane (303 µL, 0.95 mmol) was added dropwise. The
reaction was stirred at RT for 17 h. The reaction was concentrated in
dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-hydroxy-2,2-dimethyl-4-oxo-
4
-((3-oxo-3-(propylamino)propyl)amino)butyl) malonate (1). To
a
solution of protected CoA analogue 18 (70.0 mg, 0.08 mmol) in
MeOH (2 mL) was added ammonium fluoride (25 mg, 0.68 mmol)
and the reaction was stirred at RT for 1.5 h. The reaction mixture was
concentrated in vacuo. Purification using flash column chromatography
(
Gradient: 5%, 10% then 12.5% MeOH/CH
2
Cl
2
) gave 1 (20 mg, 42%) as
vacuo. The resulting residue was dissolved in CH
2
Cl
2
(10 mL) and
a
colourless oil;
R
f
0.40 (15% MeOH/CH
2
Cl ); mp 96–98 °C;
2
washed with sat. NaHCO
3
solution (10 mL). The aqueous layer was
9