98 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1
Ghodousi et al.
(3H, s, 7-methyl); MS (EI mode) m/z 413 (M+), 257 (M+
COC9H7N). Anal. (C23H19N5O3) C, H, N.
P r oced u r e for Cou p lin g 2 to Ca r boxylic Acid s To
-
for 2 h, the solid residue was then filtered off, and the solvent
was removed in vacuo. The solid residue was then reduced,
Fremy-oxidized, and aziridinated as described above.
(3S)-6-Azir idin yl-2,3-dih ydr o-3-(L-lysin ylam in o)-7-m eth -
yl-1H-p yr r olo[1,2-a ]ben zim id a zole-5,8-d ion e (1g): 41 mg
(17% yield); mp 153-155 °C (dec); TLC [dichloromethane/
methanol, (90:10)] Rf ) 0.25; IR (KBr pellet) 3124, 1712, 1642,
1613, 1563, 1467, 1221, 1184 cm-1; 1H NMR (CDCl3) 9.51 (1H,
d, J ) 8.30 Hz, amide proton), 5.28 (1H, m, C(3) proton), 4.31
(1H, m, C(1) methlyene proton), 4.14 (1H, m, C(1) methylene
proton), 3.76 (1H, m, C(4) proton), 2.95 (2H, m, C(2) methylene
protons), 2.74 (2H, q, J ) 8.40 Hz, C(5) methylene protons),
2.29 (4H, s, aziridine protons), 1.92 (3H, s, methyl protons),
1.74 (2H, m, C(8) methylene protons), 1.56 (2H, m, J ) 6.00
Hz, C(6) methylene protons), 1.42 (2H, m, J ) 8.9 Hz, C(7)
methylene protons). Anal. (C19H26N6O3) C, H, N.
(3S)-6-Azir id in yl-2,3-d ih yd r o-(glycin yla m in o)-7-m eth -
yl-3-1H-p yr r olo[1,2-a ]ben zim id a zole-5,8-d ion e (1h ): 38 mg
(19% yield); mp 157-159 °C (dec); TLC [dichloromethane/
methanol (90:10)] Rf ) 0.31; IR (KBr pellet) 3295, 1704, 1685,
1643, 1505, 1289, 1156, 1081 cm-1; 1H NMR (CDCl3) 8.53 (1H,
d, J ) 8.06 Hz, amide proton), 5.19 (1H, t, J ) 7.54 Hz, C(3)
proton), 4.23 (1H, m, C(1) methylene proton), 4.05 (1H, m, C(1)
methylene proton), 3.10 (2H, s, (C4) methylene protons), 2.96
(1H, m, C(2) methylene proton), 2.41 (1H, m, C(2) methylene
proton), 2.28 (4H, s, aziridine protons), 1.93 (3H, s, methyl
protons). Anal. (C15H17N5O3) C, H, N.
(3S)-6-Azir id in yl-2, 3-d ih yd r o-7-m et h yl-3-(L-p r olin yl-
a m in o)-1H-p yr r olo[1,2-a ]ben zim id a zole-5,8-d ion e (1i): 44
mg (20% yield); mp 160-162 °C (dec); TLC [dichloromethane/
methanol (90:10)] Rf ) 0.40; IR (KBr pellet) 3034, 1721, 1675,
1656, 1478, 1239, 1183, 1121 cm-1; 1H NMR (CDCl3) 8.59 (1H,
broad, amide proton), 5.18 (1H, t, J ) 7.85 Hz, C(3) proton),
4.42 (1H, m, C(1) methylene proton), 4.18 (1H, m, C(1)
methylene proton), 3.85 (1H, dd, J ) 2.34 Hz, J ) 7.36 Hz
(C4) proton), 3.18 (2H, m, C(7) methylene protons), 2.91 (1H,
m, C(5) methylene proton), 2.53 (1H, m, C(5) methylene
proton), 2.34 (4H, s, aziridine protons), 2.20 (1H, m, C(2)
methylene proton), 2.05 (3H, s, methyl protons), 1.86 (1H, m,
C(2) methylene proton), 1.75 (2H, q, J ) 8.45 Hz, C(6)
methylene protons). Anal. (C18H21N5O3) C, H, N.
(3S)-6-Azir id in yl-2,3-d ih yd r o-3-(N-glycin yl-L-p r olin yl-
am in o)-7-m eth yl-1H-pyr r olo[1,2-a]ben zim idazole-5,8-dion e
(1j): 41 mg (16% yield); mp 169-171 °C (dec); TLC [dichlo-
romethane/methanol (90:10)] Rf ) 0.15; IR (KBr pellet) 3124,
1707, 1686, 1645, 1624, 1511, 1438, 1234, 1091 cm-1; 1H NMR
(CDCl3) 7.29 (1H, broad, amide proton), 4.43 (1H, q, J ) 8.10
Hz, C(3) proton), 4.34 (1H, m, C(1) methlyene proton), 4.13
(1H, m, C(1) methlyene proton), 3.05 (1H, m, (C2) methlyene
proton), 2.40 (1H, m, C(2) methlyene proton), 2.35 (4H, s,
aziridine protons), 2.06 (3H, s, methyl protons), 1.68 (4H, s,
C(6,7) methylene protons), 0.87 (2H, q, J ) 7.80 Hz, C(5)
methylene protons). Anal. (C20H24N6O4) C, H, N.
Affor d 1e,f. To a solution of 0.75 mmol of 2 in 0.5 mL of
distilled pyridine, cooled with an ice-salt bath under
a
nitrogen atmosphere, was added 0.75 mmol of acid chloride.
The mixture was stirred for 20 min with continued cooling.
Water (∼5 mL) was added to the chilled reaction followed by
extraction (3×) with 10-mL portions of chloroform. The
extracts were dried over sodium sulfate and filtered, and the
solvent was removed under reduced pressure. Product was
purified by preparative TLC (1% methanol and chloroform)
and recrystallized from chloroform/hexane.
6-Azir id in yl-2,3-d ih yd r o-7-m eth yl-3-p r op a n a m id o-1H-
p yr r olo[1,2-a ]ben zim id a zole-5,8-d ion e (1d ): 30% yield; mp
190-193 °C dec; TLC [chloroform/methanol (90:10)] Rf ) 0.3;
IR (KBr pellet) 3421, 2926, 2361, 2337, 1674, 1520, 1311 cm-1
;
1H NMR (CDCl3) 2.36 (2H, q, J ) 7.3 Hz, methylene proton),
1.15 (3H, t, J ) 7.3 Hz, methylene proton), 8.63 (1H, d, J )
5.7 Hz, amide proton), 4.36 and 4.14 (2H, 2m, methylene
proton), 5.27 (1H, m, 3-methine), 3.18 and 2.64 (2H, 2m,
methylene proton), 2.34 (4H, s, aziridinyl protons), 1.99 (3H,
s, 7-methyl); MS (EI mode) m/z 314 (M+), 257 (M+ - COCH2-
CH3), 243, 230. Anal. (C16H18N4O3) C, H, N.
3-Va ler yla m id e-6-a zir id in yl-2,3-d ih yd r o-7-m eth yl-1H-
p yr r olo[1,2-a ]ben zim id a zole-5,8-d ion e (1f): 30% yield; mp
179-182 °C dec; TLC [chloroform/methanol (90:10)] Rf ) 0.39;
IR (KBr pellet) 3429, 2958, 2361, 2337, 1683, 1520, 1311 cm-1
;
1H NMR (CDCl3) 2.24 (2H, t, J ) 7.2 Hz, methylene proton),
1.57 (2H, m, methylene proton), 1.33 (2H, m, methylene
proton), 0.90 (3H, t, J ) 7.2 Hz, methylene proton), 6.97 (1H,
d, J ) 5.7 Hz, amide proton), 4.45 and 4.13 (2H, 2m, methylene
proton), 5.21 (1H, m, 3-methine), 3.22 and 2.58 (2H, 2m,
methylene proton), 2.36 (4H, s, aziridinyl protons), 2.02 (3H,
s, 7-methyl); MS (EI mode) m/z 342 (M+), 257 (M+ - COCH2-
CH2CH2CH3), 230. Anal. (C18H22N4O3‚0.55H2O) C, H, N.
Gen er a l Syn th esis of 1-Mon op ep tid e. To a solution (1.00
mmol) of tBOC-amino-protected l-amino acid in anhydrous
dichloromethane was added (1.10 mmol) 1,3-dicyclohexylcaro-
diimide (DCC) in 1.2 mL of anhydrous dichloromethane at 0
°C. The resulting mixture was stirred at 5 °C for 5 min. To
this solution was added (0.75 mmol) 3 in 5 mL of anhydrous
dichloromethane, and the resulting mixture was stirred at
room temperature for 1 h. The white solid residue was filtered
off and 4 mL of trifluoroacetic acid was added to the solution
at 5 °C and the mixture stirred at this temperature for 1.2 h.
The solvent was removed and product was purified by reverse
phase chromatography employing H2O/acetonitrile (80:20) as
the eluant (product either capped or converted to dipeptide at
this point). The solid residue was then dissolved in a suspen-
sion of 80 mg of 5% Pd on charcoal in 35 mL of methanol and
hydrogenated under 50 psi for 2 h. The solution was then
filtered through Celite and concentrated to a dry residue
consisting of the nitro-reduced (amino) derivative. A solution
consisting of 80 mL of water and 800 mg of potassium
phosphate monobasic was added to the amino derivative,
followed by addition of 600 mg of Fremy’s salt. The resulting
mixture was stirred at room temperature for 4 h. The solvent
was removed in vacuo, purified by reverse phase chromatog-
raphy employing H2O/acetonitrile (80:20) as the eluant, and
concentrated to the dry quinone derivative. To the quinone
derivative was added 15 mL of anhydrous methanol followed
by addition of 0.4 mL of aziridine. This reaction mixture was
stirred at room temperature for 3 h. The methanol solvent was
evaporated, and the red residue was purified by silica gel flash
chromatography employing chloroform/methanol (91:9) as the
eluant. Recrystallization from ethyl acetate and hexane af-
forded pure amino acid linked 1.
(3S)-6-Azir idin yl-2,3-dih ydr o-7-m eth yl-3-[N-(n icotin yl)-
glycin yla m in o]-1H -p yr r olo[1,2-a ]b en zim id a zole-5,8-d i-
on e (1k ): 42 mg (15% yield); mp 168-170 °C (dec); TLC
[dichloromethane/methanol (90:10)] Rf ) 0.42; IR (KBr pellet)
3220, 1723, 1634, 1612, 1526, 1286, 1186 cm-1 1H NMR
;
(CDCl3) 8.96 (1H, d, J ) 1.50 Hz, aromatic proton), 8.53 (1H,
q, J ) 1.20 Hz, aromatic proton), 8.38 (1H, t, J ) 7.40 Hz,
amide proton), 8.17 (1H, d, J ) 7.80 Hz, aromatic proton), 8.01
(1H, d, J ) 8.70 Hz, amide proton), 7.22 (1H, q, J ) 4.80 Hz,
aromatic proton), 5.49 (1H, m, C(3)), 4.66 (1H, dd, J ) 7.20
Hz, J ) 7.50 Hz, C(4)), 4.24 (1H, m, J ) 4.50 Hz, C(1)
methylene proton), 4.17 (1H, m, J ) 7.20 Hz, C(4) proton),
3.98 (1H, m, J ) 4.70 Hz, C(1)), 3.10 (1H, m, C(2) methylene
proton), 2.69 (1H, m, C(2) methylene proton), 2.21 (4H, t, J )
7.80 Hz, aziridine protons), 2.04 (3H, s, methyl protons). Anal.
(C21H20N6O4) C, H, N.
(3S)-6-Azir id in yl-2,3-d ih yd r o-7-m eth yl-3-(L-p h en yla la -
n yla m in o)-1H-p yr r olo[1,2-a ]ben zim ida zole-5,8-d ion e (1l):
40 mg (18% yield); mp 163-165 °C (dec); TLC [dichlo-
romethane/methanol (90:10)] Rf ) 0.36; IR (KBr pellet) 3387,
1674, 1637, 1518, 1311, 1138, 1031 cm-1; 1H NMR (CDCl3) 8.13
Gen er a l Syn th esis of Ca p p ed 1-Mon op ep tid e a n d
1-Dip ep tid e. The amino acid-linked 3 prepared above was
added to a solution consisting of 1.20 mmol of DCC and 1.10
mmol of the appropriate carboxylic acid or tBOC-amino-
protected L-amino acid, in anhydrous dichloromethane held
at 5 °C. The resulting mixture was stirred at room temperature