4762 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Lebreton et al.
N1-[4-[(3-Am in ob u t yl)a m in o]b u t yl]-N3-[6-[(a m in oim i-
n om eth yl)a m in o]h exyl]p r op a n ed ia m id e, Tr is(tr iflu or o-
a ceta te) (56f). From 55f; translucent white amorphous solid,
yield 47% after purification by MPLC on a RP18 silica gel (CH3-
CN/H2O/TFA, 8/1/1): 1H NMR (DMSO-d6) δ 1.2 (d, 3H), 1.25-
1.7 (m, 15H), 1.7-1.9 (m, 1H), 2.85-3.15 (m, 15H), 4 (s, 2H),
6.87 (m, 5H), 7.7 (t, 1H), 7.85-795 (t, 1H), 7.95-8.2 (m, 3H),
8.7-8.9 (br s, 2H); 13C NMR (D2O) δ 18.02, 23.65, 26.19, 26.28,
26.76, 28.56, 29.93, 31.22, 39.77, 40.59, 41.88, 44.61, 46,11,
48.22, 63.76, 157,54, 158.21, 171.45.
doyl]bis(carbamic acid), bis(1,1-dimethylethyl ester) (1.97 g,
50 mmol) in THF (20 mL) was added. Stirring was maintained
for 0.5 h at -30 °C and then 2 h at room temperature. After
evaporation of the solvent under vacuum, the obtained residue
was purified by flash chromatography on silica gel (EtOAc then
EtOAc/EtOH, 9/1) to afford 59e in the form of a colorless oil
(3.6 g, 81%): [R]D ) -2.3 (c ) 1.0, CHCl3); 1H NMR (CDCl3)
22
δ 1.01 (d, 3H), 1.3-1.8 (m, 41H), 2.3-2.5 (m, 3H), 2.5-2.65
(m, 1H), 3.05-3.2 (m, 2H), 3.2-3.3 (m, 2H), 3.35-3.5 (m, 3H),
3.6 (d, 1H), 3.65-3.8 (m, 1H), 4.5 (s, 2H), 5.35-5.6 (m, 2H),
6.25-6.4 (br s, 1H), 7.2-7.35 (m, 5H), 8.3 (t, 1H), 11.5 (s, 1H).
N1-[4-[(3-Am in ob u t yl)a m in o]b u t yl]-N3-[6-[(a m in oim i-
n om eth yl)a m in o]h exyl]p r op a n ed ia m id e, Tr is(tr iflu or o-
a ceta te) (R) (56h ). From 55h ; translucent white amorphous
solid, yield 46% after purification by MPLC on a RP18 silica
[4-[(3-Am in obu tyl)a m in o]bu tyl]ca r ba m ic Acid , 2-[[6-
[(Am in oim in om eth yl)am in o]h exyl]am in o]-2-oxoeth yl Es-
ter , Tr is(tr iflu or oa ceta te) (R) (60e). This compound was
obtained in the form of a translucent white amorphous solid
(2.48 g, 73%) according to procedure described for 56f and
23
gel (CH3CN/H2O/TFA, 1/8/1): [R]D ) +1.1 (c ) 1, MeOH);
1H NMR (DMSO-d6) δ 1.2 (d, 3H), 1.35-1.7 (m, 12H), 1.75 (m,
1H), 1.9 (m, 1H), 2.85-3.15 (m, 12H), 3.3 (m, 1H), 6.6-7.5 (br
s, 4H), 7.65 (t, 1H), 7.8-8.15 (m, 5H), 8.35-8.7 (2H); 13C NMR
(D2O) δ 18.02, 23.71, 26.18, 26.23, 26.35, 28.56, 28.84, 31.23,
39.50, 40.30, 41.88, 44.30, 44.61, 46,10, 48.15, 158.91, 170.01,
170.33.
22
starting from 59e (3.6 g, 4.5 mmol): [R]D ) +1.1 (c ) 2.0,
CH3OH); ee > 99%; 1H NMR (DMSO-d6) δ 1.18 (d, 3H), 1.25-
1.65 (m, 12H), 1.65-1.85 (m, 1H), 1.85-2.0 (m, 1H), 2.85-
3.15 (m, 10H), 3.2-3.35 (m, 1H), 4.33 (s, 2H), 6.8-7.3 (br s,
3H), 7.32 (t, 1H), 7.62 (t, 1H), 7.86 (t, 1H), 7.9-8.05 (br s, 4H),
8.5-8.7 (br s, 2H); 13C NMR (D2O) δ 18.01, 23.64, 26.19, 26.28,
26.76, 28.56, 28.93, 31.21, 39.77, 40.58, 41.87, 44.60, 46.10,
48.21, 63.75, 157.55, 157.89, 171.44.
N1-[4-[(3-Am in ob u t yl)a m in o]b u t yl]-N3-[6-[(a m in oim i-
n om eth yl)a m in o]h exyl]p r op a n ed ia m id e, Tr is(tr iflu or o-
a ceta te) (S) (56i). From 55i; colorless oil, yield 61% after
purification by MPLC on a RP18 silica gel (CH3CN/H2O/TFA,
[4-[(3-Am in obu tyl)a m in o]bu tyl]ca r ba m ic Acid , 2-[[6-
[(Am in oim in om eth yl)am in o]h exyl]am in o]-2-oxoeth yl Es-
ter , Tr is(tr iflu or oa ceta te) (60a ). From 59a ; colorless oil,
yield 89% after purification by MPLC on a RP18 silica gel (CH3-
CN/H2O/TFA, 2/7.5/0.5): 1H NMR (DMSO-d6) δ 1.2 (d, 3H),
1.25-1.7 (m, 12H), 1.8 (m, 1H), 1.95 (m, 1H), 2.80-3.15 (m,
10H), 3.3 (m, 1H), 4.3 (s, 2H), 6.9-7.5 (m, 5H), 7.7 (t, 1H),
7.75-8.3 (m, 4H), 8.8 (br s, 2H); 13C NMR (D2O) δ 18.02, 23.65,
26.19, 26.28, 26.76, 28.56, 28.93, 31.22, 39.77, 40.59, 41.88,
44.61, 46.11, 48.22, 63.76, 157.54, 158.21, 171.45.
[4-[(3-Am in op en tyl)a m in o]bu tyl]ca r ba m ic Acid , 2-[[6-
[(Am in oim in om eth yl)am in o]h exyl]am in o]-2-oxoeth yl Es-
ter , Tr is(tr iflu or oa ceta te) (60b). From 59b; translucent
white amorphous solid, yield 76% after purification by MPLC
on a RP18 silica gel (CH3CN/H2O/TFA, 1/8/1): 1H NMR
(DMSO-d6) δ 0.9 (t, 3H), 1.2-1.65 (m, 14H), 1.85 (m, 2H),
2.85-3.25 (m, 11H), 4.3 (s, 2H), 6.7-7.35 (m, 5H), 7.6 (t, 1H),
7.8-8.1 (m, 4H), 8.55 (br s, 2H); 13C NMR (D2O) δ 9.06, 23.65,
25.39, 26.20, 26.30, 26.77, 28.57, 28.94, 29.01, 39.78, 40.58,
41.88, 44.53, 48.19, 51.24, 52.08, 63.75, 158.44, 158.51, 198.17.
[4-[(3-Am in o-3-p h en ylp r op yl)a m in o]b u t yl]ca r b a m ic
Acid , 2-[[6-[(Am in oim in om eth yl)a m in o]h exyl]a m in o]-2-
oxoeth yl Ester , Tr is(tr iflu or oa ceta te) (60c). From 59c;
colorless oil, yield 96% after purification by MPLC on a RP18
silica gel (CH3CN/H2O/TFA, 2/7.5/0.5): 1H NMR (DMSO-d6)
δ 1.2-1.6 (m, 12H), 2.1-2.35 (m, 2H), 2.8-3.15 (m, 10H),
4.25-4.45 (m, 3H), 6.6-7.7 (m, 11H), 7.9 (m, 1H), 8.4-8.8 (m,
6H); 13C NMR (D2O) δ 23.58, 26.27, 26.36, 26.78, 28.64, 29.01,
30.56, 39.85, 40.62, 41.96, 44.60, 48.16, 51.74, 51.76, 53.71,
63.84, 128.14, 130.60, 131.01, 135.04, 158.26, 158.60, 171.52.
[4-[(3-Am in o-4,4,4-t r iflu or ob u t yl)a m in o]b u t yl]ca r -
b a m ic Acid , 2-[[6-[(Am in oim in om et h yl)a m in o]h exyl]-
a m in o]-2-oxoeth yl Ester , Tr is(tr iflu or oa ceta te) (60d ).
From 59d ; colorless oil, yield 94% after purification by MPLC
on a RP18 silica gel (CH3CN/H2O/TFA, 2/7.5/0.5): 1H NMR
(DMSO-d6) δ 1.25-1.65 (m, 12H), 1.9 (m, 1H), 2.05 (m, 1H),
2.9-3.2 (m, 10H), 4.05 (m, 1H), 4.35 (s, 2H), 6.6-7.4 (m, 5H),
7.6 (t, 1H), 7.9 (t, 1H), 8.0-8.8 (m, 5H); 13C NMR (D2O) δ 23.63,
24.48, 26.20, 26.29, 26.75, 28.57, 28.94, 39.77, 40.55, 41.86,
43.83,48.27, 50.86, 63.74, 115.24, 119.10, 122.44, 126.15,
157.91, 158.24, 171.47.
30/65/5): [R]D ) -0.9 (c ) 2, MeOH); 1H NMR (DMSO-d6) δ
23
1.2-1.65 (m, 12H), 1.8 (m, 1H), 1.95 (m, 1H), 2.8-3.15 (m,
12H), 3.3 (m, 1H), 6.8-7.6 (br s, 4H), 7.75 (t, 1H), 7.9-8.15
(m, 5H), 8.5-8.7 (m, 2H).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
60a -g. Compounds of the general structure 60a -g (Scheme
9) were synthesized from the N-Protected R-alkylated sper-
midine intermediates (8a -d and 54a ,b) or mono-N-Boc-
protected 1,4-diaminobutane with methyl 2-[(phenoxycarbonyl)-
oxy]acetate and [(6-aminohexyl)carbonimidoyl]bis(carbamic
acid), bis(1,1-dimethylethyl ester) (B), the syntheses of which
were described in a previous paper.3 The syntheses of com-
pounds 60a -g were performed according to the representative
procedure illustrated for 60e.
[3-[[4-(2,4-Dioxo-3-oxa zolid in yl)bu tyl](p h en ylm eth yl)-
a m in o]-1-m eth ylp r op yl]ca r ba m ic Acid , 1,1-Dim eth yleth -
yl Ester (R) (57e). To a solution of methyl 2-[(phenoxycar-
bonyl)oxy]acetate (1.57 g, 7.5 mmol) and triethylamine (0.8 g,
8 mmol) in toluene (100 mL) was added a solution of 54a (1.8
g, 5.15 mmol) in toluene (50 mL). The reaction mixture was
stirred at 80 °C for 15 h. The solvent was evaporated off under
reduced pressure and the obtained residue was purified by
flash chromatography on silica gel (methylcyclohexane/EtOAc,
7/3, then EtOAc) to afford 57e (4.5 g, 90%) as an oil which
22
crystallized as white needles: [R]D ) -1.0, (c ) 1.0, CHCl3);
1H NMR (CDCl3) δ 1.04 (d, 3H), 1.4-1.7 (m, 15H), 2.3-2.6
(m, 4H), 3.4-3.75 (m, 5H), 4.66 (s, 1H), 5.3 (br s, 1H), 5.3 (br
s, 1H), 7.2-7.4 (m, 5H).
2,2,6-Tr im eth yl-4,15-dioxo-9-(ph en ylm eth yl)-3,16-dioxa-
5,9,14-tr ia za octa d eca n -18-oic Acid (R) (58e). 57e (2 g, 4.62
mmol) was dissolved in a mixture of 1 N NaOH (20 mL) and
DME (20 mL). The reaction mixture was stirred for 15 h at
room temperature, concentrated to one-third of its volume,
and then acidified to pH 2 with 1 N HCl. The aqueous solu-
tion was then lyophilized to give 58e (2.5 g) as a white pasty
solid which contained sodium chloride but which can be used
22
without further purification in the next step: [R]D ) -3.9 (c
1
) 1.0, CHCl3); H NMR (CDCl3) δ 1.17 (d, 3H), 1.25-2.1 (m,
15H), 2.35-3.3 (m, 8H), 3.45-3.7 (m, 1H), 4.0-4.35 (m, 2H),
4.8-5.2 (m, 1H), 7.15-7.8 (m, 6H), 12.1-12.7 (br s, 1H).
[4-[[3-[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]b u t yl]-
(p h en ylm et h yl)a m in o]b u t yl]ca r b a m ic Acid , 11-[[(1,1-
Dim et h ylet h oxy)ca r b on yl]a m in o]-15,15-d im et h yl-2,13-
d ioxo-14-oxa -3,4,12-tr ia za -11-h exa d ecen -1-yl Ester (R)
(59e). A solution of isobutyl chloroformate (0.68 g, 5.0 mmol)
in THF (5 mL) was added dropwise to a solution, cooled to
-30 °C, of 58e (2.5 g, 5.6 mmol) and N-methylmorpholine (1.51
g, 15.0 mmol) in THF (50 mL). The reaction mixture was
stirred for 0.5 h and a solution of [(6-aminohexyl)carbonimi-
[4-[(3-Am in obu tyl)a m in o]bu tyl]ca r ba m ic Acid , 2-[[6-
[(Am in oim in om eth yl)am in o]h exyl]am in o]-2-oxoeth yl Es-
ter , Tr is(tr iflu or oa ceta te) (S) (60f). From 59f; translucent
white amorphous solid, yield 82% after purification by MPLC
23
on a RP18 silica gel (CH3CN/H2O/TFA, 1.5/8/0.5): [R]D
)
1
-0.95 (c ) 2, CH3OH); ee > 99%; H NMR (DMSO-d6) δ 1.2
(d, 3H), 1.25-1.7 (m, 12H), 1.75 (m, 1H), 1.9 (m, 1H), 2.85-
3.10 (m, 10H), 3.30 (m, 1H), 4.35 (s, 2H), 6.8-7.4 (m, 5H), 7.6
(t, 1H), 7.75-8.1 (m, 4H), 8.4-8.6 (m, 2H); 13C NMR (D2O) δ