P. Costales et al.
Bioorganic Chemistry 112 (2021) 104859
4
.1.1.6. 2-{3-{[(1R,2S)-2-Aminocyclopentyl]amino}propyl}-1H-benzo
and N-(3-bromopropylnaphthalimide (1.5 mmol) were added and the
mixture was refluxed for 8 h. After this time, potassium carbonate was
removed by filtration and the solvent was evaporated under reduced
pressure. Next, the residue was subjected to flash chromatography (ethyl
acetate–methanol mixtures). The purified compound was stirred with
aqueous HCl (10 mL, 3 M) during 30 min and concentrated to dryness to
yield a white solid. Further crystallization from methanol: tert-butyl
methyl ether provided hydrochloride salts 18 and 19, respectively.
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (11). Global yield: 57%;
2
0
[
α
]
D
+ 11.3 (c 0.10, MeOH) > 99% ee; MS (APCI) m/z (rel. intensity):
+
+
+
2
O ) [(M
3
38.1 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for (C20
H
24
N
3
+
+
H) ] 338.1863; found 338.1859
4
.1.1.7. 2-{3-{[(1S,2R)-2-Aminocyclohexyl]amino}propyl}-1H-benzo
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (12). Global yield: 50%;
2
0
1
[
α
]
D
–7.7 (c 0.10, MeOH) > 99% ee; H NMR (DMSO‑d
6
, 300 MHz): δ
3
1
.20–1.40 (m, 2H). 1.50–2.05 (m, 6H), 2.16 (t, 2H, J = 6.9 Hz), 3.12
4.1.2.1. 2-{3-{[(1R,2R)-2-Hydroxycyclopentyl]amino}propyl}-1H-benzo
(
m, 2H), 3.40 (m, 1H, overlapped by solvent), 3.80 (br s, 1H), 4.11 (t,
[de]isoquinoline-1,3(2H)-dione hydrochloride (18). Global yield: 30%;
3
3
20
1
2
H, J = 6.0 Hz), 7.83 (t, 2H, J = 7.5 Hz), 8.40–8.45 (m, 4H), 8.70 (br s,
[
α]
D
–10.7 (c 0.10, MeOH) > 99%; H NMR (DMSO‑d
6
, 300 MHz): δ
1
3
NH), 9.40 (br s, NH); C NMR (75.5 MHz) δ 18.8 (CH
2
), 23.2 (2 × CH
), 48.0 (CH), 57.9 (CH),
), 131.7 (C),
O); MS (APCI) m/z (rel. intensity): 352.1
2
),
1.70–1.90 (m, 4H), 2.05–2.10 (m, 4H). 3.00 (m, 4H), 3.60 (m, 1H), 3.90
3
3
2
1
1
5.1 (CH
2
), 27.4 (CH
2
), 37.6 (CH
2
), 44.1 (CH
2
(br s, 1H), 4.15 (t, 2H, J = 6.8 Hz), 4.40 (br s, 1H, OH), 7.80 (t, 2H, J =
13
22.4 (2 × C), 127.7 (2 × CH), 127.8 (C), 131.3 (2 × CH
2
7.5 Hz), 8.40–8.55 (m, 4H), 9.60 (br s, NH); C NMR (75.5 MHz) δ 21.5
(CH ), 25.0 (CH ), 28.2 (CH ), 30.5 (CH ), 37.7 (CH ), 44.5 (CH ), 54.3
–
–
34.9 (2 × CH), 164.1 (2 × C
2
2
2
2
2
2
+
+
+
[
(M + H) , 100]; HRMS (ESI , m/z) calcd. for (C21
H
26
N O )
3 2
[(M +
(CH), 73.1 (CH), 122.4 (2 × C), 127.5 (2 × CH), 127.8 (C), 131.0 (2 ×
+
–
H) ] 352.2020; found 352.2044
CH
2
), 131.6 (C), 134.8 (2 × CH), 164.0 (2 × C
–
O); MS (APCI) m/z (rel.
+
+
intensity): 339.1 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for
+
+
4
.1.1.8. 2-{3-{[(1R,2S)-2-Aminocyclohexyl]amino}propyl}-1H-benzo
(C23
H
30
N
3
O
2
)
[(M + H) ] 339.1703; found 339.1725
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (13).. Global yield: 52%;
2
0
[
α
]
D
+ 11.0 (c 0.10, MeOH) > 99% ee; MS (APCI) m/z (rel. intensity):
4.1.2.2. 2-{3-{[(1S,2S)-2-Hydroxycyclopentyl]amino}propyl}-1H-benzo
+
+
+
2
O ) [(M
3
52.1 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for (C21
H
26
N
3
[de]isoquinoline-1,3(2H)-dione hydrochloride (19). Global yield: 32%;
+
20
+
H) ] 352.2020; found 352.2036
[
α
]
D
+ 8.7 (c 0.10, MeOH) > 99%; MS (APCI) m/z (rel. intensity):
+
+
+
2
O ) [(M
3
39.1 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for (C23
H
30
N
3
+
4
.1.1.9. 2-{4-{[(1R,2R)-2-Aminocyclopentyl]amino}butyl}-1H-benzo[de]
+ H) ] 339.1703; found 339.1740
isoquinoline-1,3(2H)-dione dihydrochloride (14). Global yield: 56%;
2
0
1
[
α
]
D
–20.7 (c 0.10, MeOH) > 99% ee; H NMR (DMSO‑d
6
, 300 MHz): δ
4.1.3. Procedure for the synthesis of 20–21
1
.65–1.90 (m, 8H), 2.05–2.20 (m, 2H). 3.02 (m, 2H), 3.60 (m, 1H), 3.75
To a solution of 6 or 7 (1 mmol) in dry acetonitrile (25 mL), anhy-
drous potassium carbonate (8 mmol) and N-(3-bromopropylnaph-
thalimide (1.5 mmol) were added and the mixture was refluxed for 8 h.
After this time, potassium carbonate was removed by filtration and the
solvent was evaporated under reduced pressure. Next, the residue was
subjected to flash chromatography (ethyl acetate–methanol mixtures).
The purified compound was stirred with aqueous HCl (10 mL, 3 M)
during 30 min and concentrated to dryness to yield a white solid.
Further crystallization from methanol: tert-butyl methyl ether provided
dihydrochloride salts 20 and 21 respectively.
3
(
m, 1H), 4.05 (br s, 2H), 7.85 (t, 2H, J = 7.8 Hz), 8.30–8.45 (m, 4H),
8
.65 (br s, NH), 9.70 (br s, NH); 13C NMR (75.5 MHz) δ 22.4 (CH
CH ), 25.3 (CH ), 28.3 (CH ), 30.2 (CH ), 39.5 (CH ), 46.1 (CH
2
), 24.0
2
), 54.0
(
2
2
2
2
2
(
CH), 62.0 (CH), 122.3 (2 × C), 127.6 (2 × CH), 127.6 (C), 131.2 (2 ×
–
CH
2
), 131.7 (C), 134.8 (2 × CH), 163.8 (2 × C
–
O); MS (APCI) m/z (rel.
+
+
intensity): 352.2 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for
+
+
(
C
21
H
26
N
3
O
2
)
[(M + H) ] 352.2020; found 352.2028
4
.1.1.10. 2-{4-{[(1S,2S)-2-Aminocyclopentyl]amino}butyl}-1H-benzo
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (15). Global yield: 60%;
2
0
′
[
α
]
D
+ 24.7 (c 0.10, MeOH) > 99% ee; MS (APCI) m/z (rel. intensity):
4.1.3.1. 2,2 -{[(1R,2R)-2-Cyclopentane-1,2-diylbis(azanediyl)]bis(pro-
+
+
+
2
O ) [(M
3
52.1 [(M + H) , 100]; HRMS (ESI , m/z) calcd. for (C21
H
26
N
3
pane-3,1-diyl)]}-bis(1H-benzo[de]isoquinoline-1,3(2H)-dione
dihydro-
+ 31.0 (c 0.10, MeOH) > 99%
, 600 MHz): δ 1.80 (m, 2H), 1.95 (m, 2H),
.05–2.15 (m, 6H). 3.04 (m, 2H), 3.12 (m, 2H), 3.78 (br s, 2H), 4.15 (t,
+
20
+
H) ] 352.2020; found 352.2041
chloride (20). Global yield: 40%; [ ]
D
α
1
ee; H NMR (DMSO‑d
6
2
4
4
.1.1.11. 2-{3-{[(1R,2R)-2-Aminocyclopentyl]amino}hexyl}-1H-benzo
3
3
3
H, J = 6.6 Hz), 7.83 (t, 4H, J = 7.2 Hz), 8.44 (d, 4H, J = 7.2 Hz), 8.51
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (16). Global yield: 48%;
13
2
0
1
(
d, 4H, 3J = 7.2 Hz), 9.70 (br s, NH), 10.02 (br s, NH); C NMR (150
[
α]
D
–8.5 (c 0.10, MeOH) > 99% ee; H NMR (DMSO‑d
6
, 300 MHz): δ
MHz) δ 22.7 (CH
2 × CH
31.2 (4 × CH
2
), 25.4 (2 × CH
2
), 28.1 (2 × CH
2
), 37.8 (2 × CH
2
), 44.5
1
3
4
2
3
.50–1.90 (m, 12H), 2.05–2.15 (m, 2H). 2.95 (m, 2H), 3.65 (m, 1H),
3
(
2
), 61.3 (2 × CH), 122.6 (4 × C), 127.6 (4 × CH), 128.0 (2 × C),
.75 (m, 1H), 4.10 (br s, 2H), 7.70 (t, 2H, J = 7.6 Hz), 8.35–8.45 (m,
H), 8.70 (br s, NH), 9.50 (br s, NH); 1 C NMR (75.5 MHz) δ 19.5 (CH
3
–
–
O); MS
1
2
), 131.8 (2 × C), 134.8 (4 × CH), 164.1 (4 × C
2
2
),
),
+
+
(
APCI) m/z (rel. intensity): 575.2 [(M + H) , 70]; HRMS (ESI , m/z)
1.0 (CH
2
), 22.4 (CH
2
2 2 2
), 24.0 (CH ), 25.3 (CH ), 28.3 (CH ), 30.2 (CH
+
+
calcd. for (C35
H
35
4
N O
4
)
[(M + H) ] 575.2653; found 575.2675
9.5 (CH
2
), 46.1 (CH
2
), 53.7 (CH), 61.5 (CH), 122.3 (2 × C), 127.6 (2 ×
CH), 127.6 (C), 131.2 (2 × CH
2
), 131.7 (C), 134.8 (2 × CH), 163.8 (2 ×
+
′
–
–
4.1.3.2. 2,2 -{[(1S,2S)-2-Cyclopentane-1,2-diylbis(azanediyl)]bis(pro-
C
O); MS (APCI) m/z (rel. intensity): 380.2 [(M + H) , 35]; HRMS
+
+
+
(
ESI , m/z) calcd. for (C23
H
30
N
3
O
2
)
[(M + H) ] 380.2333; found
pane-3,1-diyl)]}-bis(1H-benzo[de]isoquinoline-1,3(2H)-dione
dihydro-
2
0
3
80.2350
chloride (21). Global yield: 35%; [ ]
D
α
–26.7 (c 0.10, MeOH) > 99% ee;
+
+
MS (APCI) m/z (rel. intensity): 575.2 [(M + H) , 40]; HRMS (ESI , m/z)
+
+
calcd. for (C35
H
35
4
N O
4
)
[(M + H) ] 575.2653; found 575.2659
4
.1.1.12. 2-{3-{[(1S,2S)-2-Aminocyclopentyl]amino}hexyl}-1H-benzo
[
de]isoquinoline-1,3(2H)-dione dihydrochloride (17).. Global yield: 50%;
2
0
4
.1.4. Procedure for the synthesis of 22–23
The synthesis of compounds 22 and 23 was accomplished following
[
α]
D
+ 13.6 (c 0.10, MeOH) > 99% ee; MS (APCI) m/z (rel. intensity):
+
+
+
2
O ) [(M
3
80.2 [(M + H) , 40]; HRMS (ESI , m/z) calcd. for (C23
H
30
N
3
+
an identical procedure to that described in the section 4.1.1 for com-
pounds 6–17, but using 3-nitro-1,8-naphthalic anhydride as precursor.
Thus, the pair of enantiomers 22–23 was isolated as dihydrochloride
salts.
+
H) ] 380.2333; found 380.2338
4
.1.2. General procedure for the synthesis of 18–19
To a solution of (R,R)- or (S,S)-trans-2-aminocyclopentanol (1 mmol)
in dry acetonitrile (25 mL), anhydrous potassium carbonate (8 mmol)
6