Normal and Abnormal Heme Biosynthesis. 1
J . Org. Chem., Vol. 64, No. 2, 1999 475
overlapping triplets), 3.38 (2H, t), 3.68 (3H, s), 3.90 (2H, s),
10.75 (1H, s), 11.15 (1H, s). Anal. Calcd for C23H31N2O6Cl: C,
59.16; H, 6.69; N, 6.00. Found: C, 58.79; H, 6.62; N, 5.88.
5′-(ter t-Bu toxyca r bon yl)-3-eth yl-4′-(2-m eth oxyca r bon -
yleth yl)-3′,4-d im eth yl-2,2′-d ip yr r ylm eth a n e-5-ca r boxyl-
ic Acid (12c). Compound 12c was prepared from 9c by the
procedure detailed above in 97% yield as a pale pink powder:
mp 143 °C dec; 1H NMR (CDCl3) δ 1.23 (3H, t, J ) 7 Hz), 1.53
(9H, s), 2.07 (3H, s), 2.30 (3H, s), 2.45 (2H, t, J ) 7 Hz), 2.95
(4H, m), 3.66 (3H, s), 3.82 (2H, s), 10.80 (1H, br s), 11.58 (1H,
br s). Anal. Calcd for C23H32N2O6: C, 63.87; H, 7.46; N, 6.48.
Found: C, 63.41; H, 7.53; N, 6.08.
8,13-Bis(2-m et h oxyca r b on ylet h yl)-1,2,3,7,12,17,18,19-
octa m eth yl-10,23-d ih yd r obilin Dih yd r obr om id e (13b). 5′-
(tert-Butoxycarbonyl)-3,4′-bis(2-methoxycarbonylethyl)-3′,4-
dimethyl-2,2′-dipyrrylmethane-5-carboxylic acid (12a ; 502 mg)
was treated with trifluoroacetic acid (2 mL) and stirred for 10
min at room temperature. A solution of 3,4,5-trimethylpyrrole-
2-carboxaldehyde (7b; 280 mg; 2.0 equiv) in methanol (8.0 mL)
was added, immediately followed by the addition of a mixture
of aqueous 48% HBr and acetic acid (1:2.33 v/v; 1.6 mL), and
the resulting dark red mixture was stirred at room tempera-
ture for 30 min. Anhydrous ether (40 mL) was added dropwise,
and the resulting mixture was stirred for additional 2 h. The
precipitate was filtered, washed thoroughly with ether, and
dried in vacuo overnight to give the title a,c-biladiene dihy-
drobromide (628 mg; 80%) as a dark red powder: mp 220 °C,
dec; UV-vis (CHCl3) λmax (log ꢀ) 455 (4.45), 525 nm (5.23); 1H
NMR (CDCl3) δ 1.90 (2H, t), 1.95 (3H, s), 1.99 (6H, s), 2.24
(3H, s), 2.27 (3H, s), 2.34 (3H, s), 2.48 (2H, t), 2.68 (6H, s),
2.78 (2H, t, J ) 7 Hz), 2.94 (2H, t, J ) 7 Hz), 3.42 (3H, s), 3.59
(3H, s), 5.19 (2H, s), 7.09 (1H, s), 7.30 (1H, s), 13.22 (2H, br s),
13.25 (1H, br s), 13.30 (1H, br s). Anal. Calcd for C35H46N4O4-
Br2‚H2O: C, 54.98; H, 6.31; N, 7.32. Found: C, 54.59; H, 5.86;
N, 6.98.
2,18-D i e t h y l-8,13-b i s (2-m e t h o x y c a r b o n y le t h y l)-
1,3,7,12,17,19-h exa m et h yl-10,23-d ih yd r ob ilin Dih yd r o-
br om id e (13a ). Compound 13a was prepared from 12a (501
mg) and 4-ethyl-3,5-dimethylpyrrole-2-carboxaldehyde (7a ;
0.308 g; 2.0 equiv) by the procedure detailed above. The bright
red precipitate was filtered, washed thoroughly with ether, and
dried in vacuo overnight to give the title a,c-biladiene dihy-
drobromide (646 g; 82%) as red crystals: mp 194 °C dec; UV-
vis (CHCl3): λmax (log ꢀ) 455 (4.49), 525 nm (5.28); 1H NMR
(CDCl3) δ 1.08 (6H, 2 overlapping triplets), 1.91 (2H, t), 1.94
(3H, s), 2.24 (3H, s), 2.29 (3H, s), 2.34 (3H, s), 2.4-2.5 (6H,
m), 2.69 (6H, s), 2.78 (2H, t, J ) 8 Hz), 2.93 (2H, t, J ) 7 Hz),
3.42 (3H, s), 3.60 (3H, s), 5.20 (2H, s), 7.09 (1H, s), 7.31 (1H,
s), 13.21 (2H, br s), 13.28 (1H, br s), 13.30 (1H, br s). Anal.
Calcd for C37H50N4O4Br2‚0.5H2O: C, 56.71; H, 6.56; N, 7.15.
Found: C, 56.35; H, 6.27; N, 6.89.
vis (CHCl3) λmax (log ꢀ) 455 (4.45), 525 (5.25); 1H NMR (CDCl3)
δ 0.93 (6H, 2 overlapping triplets), 1.40 (8H, m), 1.92 (2H, m),
1.96 (3H, s), 2.24 (3H, s), 2.28 (3H, s), 2.33 (3H, s), 2.42 (4H,
t), 2.48 (2H, t), 2.70 (6H, s), 2.78 (2H, t, J ) 8 Hz), 2.93 (2H,
t, J ) 7 Hz), 3.41 (3H, s), 3.60 (3H, s), 5.20 (2H, s), 7.09 (1H,
s), 7.30 (1H, s), 13.22 (2H, s), 13.28 (1H, s), 13.33 (1H, s). Anal.
Calcd for C41H58N4O4Br2‚0.5H2O: C, 59.28; H, 7.04; N, 6.74.
Found: C, 58.91; H, 6.99; N, 6.62.
2 ,8 ,1 8 -T r i e t h y l -1 3 -( 2 -m e t h o x y c a r b o n y l e t h y l ) -
1,3,7,12,17,19-h exa m et h yl-10,23-d ih yd r ob ilin Dih yd r o-
br om id e (13f). Dipyrrylmethane 12c (602 mg) was dissolved
in TFA (2.8 mL) and the resulting solution stirred at room
temperature for 10 min. A solution of formylpyrrole 7a (420
mg; 2.0 equiv) in methanol (11.1 mL) was added, followed
immediately by 30% HBr in acetic acid (2.1 mL), and the
mixture was stirred for a further 30 min. Anhydrous ether
(40 mL) was added dropwise and the mixture stirred for an
additional 2 h. The precipitate was filtered and washed with
ether to give the a,c-biladiene (521 mg; 52%) as brick red
crystals: mp 210.5-211.5 °C; UV-vis (CHCl3) λmax (log ꢀ) 451
1
(5.05), 525 (4.98); H NMR (CDCl3): δ 0.61 (3H, t, J ) 7 Hz),
1.09 (6H, 2 overlapping triplets), 1.94 (3H, s), 2.23 (3H, s), 2.29
(3H, s), 2.34 (3H, s), 2.2-2.3 (2H, m), 2.4-2.5 (6H, m), 2.70
(6H, s), 2.92 (2H, t), 3.58 (3H, s), 5.18 (2H, s), 7.09 (1H, s),
7.28 (1H, s), 13.18 (1H, br s), 13.26 (2H, br s), 13.35 (1H, br
s). Anal. Calcd for C35H48N4O2Br2‚H2O: C, 57.22; H, 6.86; N,
7.63. Found: C, 57.16; H, 6.26; N, 7.50.
8-(2-Ch lor oeth yl)-2,18-d ieth yl-13-(2-m eth oxyca r bon yl-
eth yl)-1,3,7,12,17,19-h exa m eth yl-10,23-d ih yd r obilin Di-
h yd r obr om id e (13e). Compound 13c was prepared by the
previous procedure from dipyrrole 12b (510 mg) and pyrrole
aldehyde 7a (350 mg). Precipitation with ether gave the a,c-
biladiene (448 mg; 55%) as dark red crystals: mp 223.5-224.5
°C; UV-vis (CH2Cl2) λmax (log ꢀ) 450 (5.22), 521 (5.06); 1H NMR
(CDCl3): δ 1.12 (6H, 2 overlapping triplets), 2.00 (3H, s), 2.31
(3H, s), 2.32 (3H, s), 2.36 (3H, s), 1.95-2.05 (2H, m), 2.45-
2.55 (6H, m), 2.94 (2H, t), 3.03 (2H, t), 3.62 (3H, s), 5.22 (2H,
s), 7.14 (1H, s), 7.33 (1H, s), 13.23 (1H, br s), 13.29 (1H, br s),
13.32 (1H, br s), 13.37 (1H, br s). Anal. Calcd for C35H47N4O2-
Br2Cl: C, 55.97; H, 6.30; N, 7.46. Found: C, 56.09; H, 6.38;
N, 6.96.
8,12-D i e t h y l-3,17-b i s (2-m e t h o x y c a r b o n y le t h y l)-
1,2,7,13,18,19-h exa m et h yl-20,23-d ih yd r ob ilin Dih yd r o-
br om id e (18). Dipyrrylmethane dicarboxylic acid 16 (150 mg)
was placed in a 50 mL pear-shaped flask and stirred with TFA
(1 mL) at room temperature for 10 min. A solution of aldehyde
17 (197 mg; 2 equiv) in methanol (4 mL) was added, followed
immediately by 0.8 mL of HBr in acetic acid (30%), and the
resulting red solution was stirred for a further 40 min.
Anhydrous diethyl ether (16 mL) was then added and the
mixture stirred for 1 h at room temperature and a further 1 h
while the flask was cooled with an ice bath. The precipitate
was suction filtered and washed with ether to give the title
a,c-biladiene (290 mg; 80%) as a red-brown powder: mp 222-
223 °C; UV-vis (CHCl3) λmax (log ꢀ) 457 (4.40), 529 nm (5.28);
1H NMR (CDCl3) δ 0.67 (6H, t), 2.03 (6H, s), 2.28 (6H, s), 2.56
(8H, m), 2.69 (6H, s), 3.00 (4H, t), 3. 64 (6H, s), 5.22 (2H, s),
7.26 (2H, s), 13.29 (2H, br s), 13.40 (2H, br s). Anal. Calcd for
8,13-Bis(2-m et h oxyca r b on ylet h yl)-1,3,7,12,17,19-h ex-
a m eth yl-2,18-d ip r op yl-10,23-d ih yd r obilin Dih yd r obr o-
m id e (13c). Compound 13c was prepared from 12a (250 mg)
and 4-propyl-3,5-dimethylpyrrole-2-carboxaldehyde (7c; 168
mg; 2.0 equiv) by the preceding method. The precipitate was
filtered, washed well with ether, and dried in vacuo overnight
to give the title a,c-biladiene dihydrobromide (283 mg; 69%)
as a red-orange powder: mp 198 °C dec; UV-vis (CHCl3) λmax
C
37H50N4O4Br2‚0.5H2O: C, 56.71; H, 6.56; N, 7.15. Found: C,
1
(log ꢀ) 456 (4.48), 525 (5.27); H NMR (CDCl3) δ 0.93 (6H, 2
56.04; H, 6.36; N, 7.05.
overlapping triplets), 1.50 (4H, m), 1.90 (2H, t), 1.95 (3H, s),
2.24 (3H, s), 2.28 (3H, s), 2.33 (3H, s), 2.40 (4H, t), 2.48 (2H,
t), 2.70 (6H, s), 2.78 (2H, t, J ) 8 Hz), 2.93 (2H, t, J ) 7 Hz),
3.41 (3H, s), 3.59 (3H, s), 5.20 (2H, s), 7.09 (1H, s), 7.30 (1H,
s), 13.23 (2H, s), 13.29 (1H, s), 13.32 (1H, s). Anal. Calcd for
3,8-Bis(2-m et h oxyca r b on ylet h yl)-2,7,12,13,17,18-h ex-
a m eth ylp or p h yr in (6b). 2,18-Dimethyl-8,13-bis(2-methoxy-
carbonylethyl)-1,3,7,12,17,19-hexamethyl-20,23-dihydrobilin di-
hydrobromide (13b; 620 mg) was added to a stirred solution
of copper(II) chloride (1.89 g) in DMF (325 mL), and the
resulting mixture was stirred in the dark for 2 h. The mixture
was diluted with dichloromethane (350 mL) and washed with
water (3 × 400 mL). The aqueous layers were back-extracted
with dichloromethane, and the combined organic layers were
dried over sodium sulfate and filtered. The solvent was
evaporated on a rotary evaporator under aspirator pressure
and then using a vacuum pump to remove residual DMF. The
solid residue was taken up in 15% v/v sulfuric acid/trifluoro-
acetic acid (60 mL) and stirred in the dark at room tempera-
ture for 45 min. The reaction mixture was diluted with
C
39H54N4O4Br2: C, 58.36; H, 6.78; N, 6.98. Found: C, 58.17;
H, 6.66; N, 6.72.
2,18-D i b u t y l-8,13-b i s (2-m e t h o x y c a r b o n y le t h y l)-
1,3,7,12,17,19-h exa m et h yl-10,23-d ih yd r ob ilin Dih yd r o-
br om id e (13d ). Compound 13d was prepared from 12a (254
mg) and 4-butyl-3,5-dimethylpyrrole-2-carboxaldehyde (7d ;
187 mg; 2.0 equiv) by the procedure reported above. The
bright-red precipitate was filtered, washed thoroughly with
ether, and dried in vacuo overnight to give the title a,c-
biladiene dihydrobromide (284 mg; 66%): mp 210 °C dec; UV-