1472 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 10
Nugiel et al.
p h en yl)m eth yl)-2H-1,3-d ia za p in -2-on e (16). Urea 15 (0.13
g, 0.2 mmol) was suspended in butyl formate (2 mL) and
heated to reflux for 1 h. All solids dissolve after 5 min. The
mixture was cooled and the butyl formate removed at reduced
pressure. The residue was chromatographed (silica gel, 5-7%
MeOH/CH2Cl2) to give the desired product (0.12 g, 85%). The
NMR spectrum in MeOH-d4 shows a multiplicity of signals
due to the presence of amide bond rotomers: ESMS m/z 709
(M + H+, 100).
H), 5.0 (d, J ) 14 Hz, 2 H), 4.7 (t, J ) 7.5 Hz, 4 H), 3.7 (bs, 2
H), 3.6 (m, 2 H), 3.3 (m, 6 H), 3.0 (m, 4 H); CIMS m/z 591 (M
+ H+, 100); HRMS calcd for C37H39N2O5 (M + H+) 591.2859,
found 591.2866. Anal. (C37H38N2O5) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(p h en -
ylm eth yl)-4,7-bis((4-m eth yl-3,4-dih ydr o-2H-ben zo[b][1,4]-
oxa zin -6-yl)m et h yl-2H -1,3-d ia za p in -2-on e (24): NMR
(CDCl3) δ 7.33 (m, J ) 7.7 Hz, 1H), 7.17 (d, J ) 4.1), 7.10 (dd,
J ) 7.7, 10.6 Hz, 3 H), 6.80 (d, J ) 3.7 Hz, 1H), 6.80 (d, 8.42,
1H), 6.38 (m, 2H), 4.93 (d, J ) 14.7 Hz, 1H), 4.28 (m, 2H),
3.60 (bs, 1H), 3.49 (m, 1 H), 3.25 (m, 2H), 3.17 (d, J ) 14.2
Hz, 1H), 2.84 (m, 1H), 2.83 (s, 3H), 2.67 (bs, 1H); ESI-MS m/z
874.3 ((M + H)+, 12.1), 424.3 ((M + 2H)2+, 100); HRMS calcd
for C45H46N6O7S2 (M + H+) 847.2939, found 847.2948.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(cyclo-
pr opylm eth yl)-4,7-bis((3,4-(eth ylen edioxy)ph en yl)m eth yl)-
2H-1,3-d ia za p in -2-on e (25): mp 125-130 °C; NMR (CDCl3)
δ 6.7 (d, J ) 9.5 Hz, 2 H), 6.65 (m, 2 H), 6.6 (m, 2 H), 4.25 (s,
8 H), 3.95 (bs, 2 H), 3.55 (m, 2 H), 2.9 (m, 4 H), 2.5 (bs, 2 H),
2.1 (m, 2 H), 0.85 (m, 2 H), 0.35 (m, 4 H), 0.05 (m, 4 H); CIMS
(NH3) m/z 551 (M + H+, 100); HRMS calcd for C31H39N2O7 (M
+ H+) 551.2757, found 551.2749. Anal. (C31H38N2O7) C, H,
N.
(4R,5S,6S,7R)-H exa h yd r o-5,6-d ih yd r oxy-1-((3-a m in o-
p h en yl)m eth yl)-3-((3-(m eth yla m in o)p h en yl)m eth yl)-4,7-
bis((3,4-(eth ylen ed ioxy)p h en yl)m eth yl)-2H-1,3-d ia za p in -
2-on e (17). A solution of compound 16 (0.12 g, 0.17 mmol) in
THF (2 mL) was cooled to 0 °C and treated with BH3‚THF
(0.51 mL, 0.51 mmol, 1.0 M in THF) dropwise over 10 min.
The reaction mixture was allowed to reach room temperature
over 1 h and then heated at reflux for 16 h. The mixture was
cooled and quenched by the addition of MeOH (1 mL).
Concentrated HCL (1 mL) was added, and the mixture was
stirred at room temperature for 30 min. The solvent was
removed at reduced pressure, and the residue was taken up
in EtOAc (10 mL) and washed with saturated NaHCO3 (5 mL),
the organic layer was separated and dried (Na2SO4), and the
solvent was evaporated. Chromatography (silica gel, 5%
MeOH/CH2Cl2) gave a higher running Rf product which
corresponded to the monomethylated product 17 (60 mg, 53%).
Further elution gave the symmetrical di-N-methylurea 18 (40
mg, 35%). 17: NMR (CD3OD) δ 7.2 (m, 2 H), 6.9-6.5 (m, 12
H), 4.8 (dd, J ) 14.0, 3.7 Hz, 2 H), 4.3 (s, 8 H), 3.6 (m, 6 H),
3.4 (s, 3 H), 3.0 (m, 4 H), 2.8 (s, 3 H); ESMS m/z 667 (M + H+,
100); HRMS calcd for C38H43N4O7 (M + H+) 653.2975, found
653.2979.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1,3-bis(2-n aph -
th ylm eth yl)-4,7-bis((3,4-(eth ylen ed ioxy)p h en yl)m eth yl)-
2H-1,3-d ia za p in -2-on e (26): mp 232-234 °C; NMR (CDCl3)
δ 7.85 (m, 6 H), 7.55 (s, 2 H), 7.5 (m, 6 H), 6.8 (d, J ) 8.1 Hz,
2 H), 6.7 (m, 2 H), 6.6 (dd, J ) 8.1, 1.8 Hz, 2 H), 5.15 (d, J )
14.3 Hz, 2 H), 4.3 (s, 8 H), 3.6 (m, 4 H), 3.4 (d, J ) 14.3 Hz, 2
+
H), 3.0 (m, 4 H), 2.2 (bs, 2 H); CIMS (NH3) m/z 740 (M + NH4
,
100); HRMS calcd for C45H43N2O7 (M + H+) 723.3070, found
723.3051. Anal. (C45H42N2O7) C, H, N.
(4R ,5S ,6S ,7R )-H e xa h yd r o-5,6-d ih yd r oxy-1,3-b is((3-
(m et h yla m in o)p h en yl)m et h yl)-4,7-b is((3,4-(et h ylen ed i-
oxy)p h en yl)m eth yl)-2H-1,3-d ia za p in -2-on e (18). A solu-
tion of compound 16 (0.12 g, 0.17 mmol) in THF (3 mL) was
cooled to 0 °C and treated with a solution of LAH (0.5 mL, 0.5
mmol, 1.0 M in THF) dropwise over 10 min. The cooling bath
was removed and the reaction mixture heated at reflux for 30
min. The reaction mixture was cooled to 0 °C and quenched
with 1 N NaOH (4 drops). After quenching, the reaction was
allowed to reach room temperature and diluted with EtOAc.
Anhydrous sodium sulfate was added directly to the mixture
with continued stirring for 20 min. The reaction was then
filtered (Celite), and the remaining salts were washed with
additional EtOAc. The filtrate was evaporated and the residue
chromatographed (silica gel, 2.5-5% MeOH/CH2Cl2) to give
the desired product (0.11 g, 95%). 18: NMR (CD3OD) δ 7.2
(t, J ) 6.5 Hz, 2 H), 6.9 (d, J ) 7.5 Hz, 2 H), 6.8 (m, 2 H), 6.75
(m, 2 H), 6.6 (m, 2 H), 6.55 (m, 2 H), 6.5 (bs, 2 H), 5.0 (d, J )
14 Hz, 2 H), 4.4 (s, 8 H), 3.8 (bs, 2 H), 3.65 (m, 4 H), 3.2 (d, J
) 14 Hz, 2 H), 3.0 (m, 4 H), 2.8 (s, 6 H), 2.5 (bs, 2 H); ESMS
m/z 681 (M + H+, 100); HRMS calcd for C39H45N4O7 (M + H+)
681.3288, found 681.3289.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(p h en -
ylm eth yl)-4,7-bis((3,5-d im eth oxyp h en yl)m eth yl)-2H-1,3-
d ia za p in -2-on e (20): mp 210-212 °C; NMR (CD3OD) δ 7.3
(m, 4 H), 7.25 (m, 2 H), 7.2 (d, J ) 6 Hz, 4 H), 6.4 (m, 2 H),
6.25 (s, 4 H), 4.75 (d, J ) 14 Hz, 2 H), 3.8 (s, 12 H), 3.6 (m, 4
H), 3.1 (d, J ) 14 Hz, 2 H), 2.95 (d, J ) 8.5 Hz, 2 H), 2.85 (m,
2 H); CIMS m/z 627 (M + H+, 100); HRMS calcd for C37H43N2O7
(M + H+) 627.3070, found 627.3078. Anal. (C37H42N2O7) C,
H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(p h en -
ylm eth yl)-4,7-bis((3,4-d im eth oxyp h en yl)m eth yl)-2H-1,3-
d ia za p in -2-on e (21): mp 204-206 °C; NMR (CD3OD) δ 7.3
(m, 6 H), 7.2 (d, J ) 5.5 Hz, 4 H), 6.9 (d, J ) 5.5 Hz, 2 H), 6.65
(m, 4 H), 4.7 (d, J ) 14 Hz, 2 H), 3.85 (s, 6 H), 3.8 (s, 6 H), 3.6
(m, 4 H), 3.1 (d, J ) 14 Hz, 2 H), 2.95 (m, 2 H), 2.85 (m, 2 H);
CIMS m/z 627 (M + H+, 100); HRMS calcd for C37H43N2O7 (M
+ H+) 627.3070, found 627.3080. Anal. (C37H42N2O7) C, H,
N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(p h en -
ylm eth yl)-4,7-bis(2,3-d ih yd r oben zo[b]fu r a n -5ylm eth yl)-
2H-1,3-d ia za p in -2-on e (23): mp 194-196 °C; NMR (CDCl3)
δ 7.4 (m, 6 H), 7.25 (m, 4 H), 6.9 (m, 4 H), 6.8 (d, J ) 7 Hz, 2
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis((4-(h y-
d r oxym et h yl)p h en yl)m et h yl)-4,7-b is((3,4-(et h ylen ed i-
oxy)p h en yl)m eth yl)-2H-1,3-d ia za p in -2-on e (27): mp 127-
130 °C; NMR (CDCl3) δ 7.3 (d, J ) 8.1 Hz, 4 H), 7.2 (d, J ) 8.1
Hz, 4 H), 6.8 (d, J ) 8.3 Hz, 2 H), 6.55 (dd, J ) 8.3, 2.0 Hz, 2
H), 6.4 (m, 2 H), 4.8 (d, J ) 14.1 Hz, 2 H), 4.6 (s, 4 H), 4.25 (s,
8 H), 3.6 (bs, 2 H), 3.5 (m, 2 H), 3.3 (d, J ) 14.1 Hz, 2 H), 2.9
(m, 2 H), 2.8 (m, 2 H); CIMS (NH3) m/z 700 (M + NH4+, 100);
HRMS calcd for C39H43N2O9 (M + H+) 683.2969, found
683.2970. Anal. (C39H42N2O9) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis((4-h y-
dr oxyph en yl)m eth yl)-4,7-bis((3,4-(eth ylen edioxy)ph en yl)-
m eth yl)-2H-1,3-d ia za p in -2-on e (28): mp 228-230 °C; NMR
(CD3OD) δ 7.1 (d, J ) 8.1 Hz, 4 H), 6.8 (m, 6 H), 6.7 (s, 2 H),
6.65 (m, 2 H), 4.75, (d, J ) 14.0 Hz, 2 H), 4.35 (s, 8 H), 3.6 (m,
2 H), 3.55 (bs, 2 H), 3.1 (d, J ) 14.0 Hz, 2 H), 2.95 (m, 2 H),
2.9 (m, 2 H); CIMS (NH3) m/z 672 (M + NH4+, 100); HRMS
calcd for C37H39N2O9 (M + H+) 655.2656, found 655.2662.
Anal. (C37H38N2O9) C, H, N.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1,3-bis(3-acetyl-
4-flu or oben zyl)-4,7-bis((3,4-(eth ylen ed ioxy)p h en yl)m eth -
yl)-2H-1,3-diazapin -2-on e (29): mp 197-199 °C; NMR (CDCl3)
δ 7.7 (m, 2 H), 7.45 (m, 2 H), 7.05 (m, 2 H), 6.8 (d, J ) 8.1 Hz,
2 H), 6.45 (m, 4 H), 4.7 (d, J ) 14.2 Hz, 2 H), 4.25 (s, 8 H),
3.75 (bs, 2 H), 3.5 (m, 4 H), 2.95 (m, 2 H), 2.7 (m, 2 H), 2.6 (d,
J ) 4.6 Hz, 6 H), 2.3 (bs, 2 H); CIMS (NH3) m/z 743 (M + H+,
100); HRMS calcd for C41H41F2N2O9 (M + H+) 743.2780, found
743.2800. Anal. (C41H40N2O9F2) C, H, N.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1,3-bis(3-acetyl-
b en zyl)-4,7-b is(2,3-d ih yd r ob en zo[b]fu r a n -5-ylm et h yl)-
2H-1,3-d ia za p in -2-on e (30): mp 237-240 °C; NMR (DMSO-
d6) δ 7.9 (d, J ) 5 Hz, 2 H), 7.7 (s, 2 H), 7.5 (m, 4 H), 6.6 (m,
6 H), 4.6 (d, J ) 14 Hz, 2 H), 4.5 (t, J ) 7.5 Hz, 4 H), 3.45 (m,
4 H), 3.2 (d, J ) 14 Hz, 2 H), 3.1 (t, J ) 7.5 Hz, 4 H), 2.9 (m,
2 H), 2.7 (m, 2 H), 2.55 (s, 6 H); CIMS m/z 675 (M + H+, 100);
HRMS calcd for C41H43N2O7 (M + H+) 675.3070, found
675.3088. Anal. (C41H42N2O7) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis((3-a m i-
n op h en yl)m eth yl)-4,7-bis(2,3-d ih yd r oben zo[b]fu r a n -5-yl-
m eth yl)-2H-1,3-d ia za p in -2-on e (31): mp 232-235 °C; NMR
(CD3OD) δ 7.0 (t, J ) 6 Hz, 2 H), 6.9 (s, 2 H), 6.85 (m, 2 H),
6.7 (d, J ) 6 Hz, 2 H), 6.6 (m, 2 H), 6.5 (m, 4 H), 4.7 (d, J ) 14
Hz, 2 H), 4.5 (t, J ) 6.5 Hz, 4 H), 3.6 (m, 4 H), 3.3 (d, J ) 14
Hz, 2 H), 3.2 (t, J ) 6.5 Hz, 4 H), 2.9 (m, 4 H); CIMS m/z 621