Synthesis of a series of mono-meso-arylmesoporphyrins III of biological interest and their biliverdin derivatives

Article abstract of DOI:10.1055/s-2008-1032203

Synthesis of a series of mono-meso-arylmesoporphyrins III using a MacDonald-type 2+2 condensation is described. In this method, the substituted 1,9-diformyldipyrromethane is treated with a dipyrromethane-1,9-dicarboxylic acid under acidic conditions. The 5-aryldipyrrolic unit was obtained by condensation of tert-butyl, ethyl, or benzyl 4-ethyl-3-methyl-1H-pyrrole-2- carboxylate with different aromatic aldehydes in the presence of 4-toluene-sulfonic acid. In order to obtain the corresponding mesobiliverdins, chemical oxidation of each mesoporphyrin was carried out. Each meso-arylmesoporphyrin rendered two isomeric arylbiliverdins, as the porphyrin meso-aryl bridge is not cleaved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032203

PAPER
875
Synthesis of a Series of Mono-meso-arylmesoporphyrins III of Biological
Interest and Their Biliverdin Derivatives
Synthesis of
M
e
ono-meso
-
r
arylmeso
n
porphyrins
I
a
II ndo Niemevz, Ma. Soledad Vazquez, Graciela Y. Buldain*
Cátedra de Química Orgánica II, Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires,
Junín 956, (C1113AAD) Ciudad Autónoma de Buenos Aires, Argentina
Fax +54(11)49648250; E-mail: gbuldain@ffyb.uba.ar
Received 22 November 2006; revised 30 April 2007
OH
Abstract: Synthesis of a series of mono-meso-arylmesoporphyrins
III using a MacDonald-type 2+2 condensation is described. In this
method, the substituted 1,9-diformyldipyrromethane is treated with
N
N
N
N
N
N
N
N
a dipyrromethane-1,9-dicarboxylic acid under acidic conditions.
The 5-aryldipyrrolic unit was obtained by condensation of tert-bu-
tyl, ethyl, or benzyl 4-ethyl-3-methyl-1H-pyrrole-2-carboxylate
with different aromatic aldehydes in the presence of 4-toluene-
sulfonic acid. In order to obtain the corresponding mesobiliverdins,
chemical oxidation of each mesoporphyrin was carried out. Each
meso-arylmesoporphyrin rendered two isomeric arylbiliverdins, as
the porphyrin meso-aryl bridge is not cleaved.
NADPH
O2
Fe
Fe
PH
PH
PH
PH
heme
α-meso-hydroxyheme
Key words: porphyrin synthesis, mono-meso-arylporphyrin, chem-
ical oxidation, biliverdin
O2
CO
O
O
O
Heme oxygenase, the rate-limiting enzyme in the heme
degradation pathway, oxidizes heme to biliverdin, carbon
monoxide, and free iron1 (Figure 1). In humans and other
mammals, the heme is cleaved exclusively at the a-meso
position to give biliverdin IXa.
NH
N
HN
HN
N
N
N
N
NADPH
O2
Fe
The HO-1-catalyzed oxidation of heme involves sequen-
tial a-meso-hydroxylation, oxygen-dependent fragmenta-
tion of the a-meso-hydroxyheme to verdoheme, and
oxidative cleavage of verdoheme to biliverdin IXa.2
PH
PH
PH
PH
verdoheme
biliverdin IXα
PH = CH2CH2COOH
Figure 1 Enzymatic oxidation of iron–protoporphyrin IX to give bi-
liverdin IXa, carbon monoxide, and free iron.
In 1996, Torpey and Ortiz de Montellano3 attempted the
use of a-meso-methylmesoheme to block a-meso-hydrox-
ylation and thus to inhibit the heme oxygenase reaction.
Surprisingly, this compound was itself oxidized to biliver-
din IXa, albeit without the formation of carbon monoxide.
Equally surprising was the finding that a 15-methyl sub-
stituent caused exclusive cleavage at the g-meso-carbon
rather than at the normal, unsubstituted a-meso-carbon.
No carbon monoxide was formed in these reactions, but
the fragment cleaved from the porphyrin eluded identifi-
cation.
To further characterize the influence of electronic effects
of the meso-substituted heme group on the regioselectivi-
ty of the enzymatic cleavage, we report the synthesis of
four other 5-meso-arylmesoporphyrins bearing electron-
withdrawing or -donating substituents on the aryl moiety.
We also describe the chemical oxidation of the corre-
sponding 5-arylmesoporphyrin–iron complexes, to yield
all biliverdin derivatives. These compounds would be use-
ful references to be compared with products of enzymatic
oxidation, in the same manner as previously described.4
Enzymatic oxidation of synthetic 5-phenyl and 15-phe-
nyl-substituted hemes was then assayed.4 Human heme
oxygenase cleaved 5-phenylheme to give biliverdin IXa
and oxidized 15-phenylheme at the a-meso position to
give 10-phenylbiliverdin IXa. The fragment extruded in
the oxidation of 5-phenylheme was identified as benzoic
acid.4
One of the most efficient approaches to obtain a mono-
meso-substituted porphyrin in a pure form is the use of
MacDonald’s original method5 in its simplified form6–9
consisting of the condensation of a diformyldipyr-
romethane with a dicarboxydipyrromethane.
Accordingly, synthesis of 5-arylporphyrins 1–4 were
achieved via condensation of the 1,9-dicarboxydipyrro-
methanes 5–8 with the known diformyldipyrromethane
9
10 (Scheme 1).
SYNTHESIS 2008, No. 6, pp 0875–0882
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032203; Art ID: M07106SS
© Georg Thieme Verlag Stuttgart · New York

876
F. Niemevz et al.
PAPER
(trifluoromethyl)benzaldehyde] in the presence of 4-tolu-
enesulfonic acid. Hydrogenolysis of benzyl ester groups
in compounds 13, 14, and 15 afforded the corresponding
dicarboxydipyrromethanes 5, 6, and 7 (Scheme 2).
R
CO2H
HO2C
N
N
H
H
Unfortunately, in the hydrogenolysis reaction of com-
pound 16 (3.45 bar H2, 3 h), cleavage of benzyl groups
was accompanied by reduction of acetyl group to give the
ethyl derivative 19. Other attempts to protect the acetyl
group by treatment with ethylene glycol and 4-toluene-
sulfonic acid,12 in the presence of Montmorillonite clay13
failed to afford the desired ketal.
NH
N
N
5 R = OMe
6 R = Me
7 R = CF3
8 R = COMe
R
+
a
HN
PMe PMe
PMe
PMe
We then synthesized the dipyrromethane 1,9-diethyl ester
17, which was able to afford the desired 1,9-unsubstituted
dipyrromethane by saponification with sodium hydroxide
and ethyleneglycol followed by in situ decarboxylation of
the resulting 1,9-dicarboxylic acid. Unluckily, in these
conditions the acetyl group was converted into a 1-hy-
droxyethyl group to give compound 20, a reaction that has
been previously reported for benzophenone and other
ketones14 (Scheme 2).
PMe= CH2CH2CO2Me
CHO
1 R = OMe (39%)
OHC
N
N
2 R = Me
(41%)
H
H
9
3 R = CF3 (30%)
4 R = COMe (32%)
Scheme 1 Synthesis of 5-arylmesoporphyrins III. Reagents and
conditions: (a) (1) PTSA, CH2Cl2, MeOH, (2) Zn(OAc)2, MeOH, (3)
5% H2SO4–MeOH.
CHO
An alternative approach via tert-butyl pyrrole 11, consist-
ing of the treatment of the corresponding dipyrromethane
18 with trifluoroacetic acid, followed with trimethyl
orthoformate to obtain directly the diformyldipyrro-
methane 21 was unsuccessful, because the acetyl group
was reactive in these conditions and the b-formyl enol
ether 22 was obtained (Scheme 2). Similar results were
reported for the reaction of 20-ketosteroids with ortho
esters.15 However, synthesis of 5-(4-acetylphenyl)meso-
porphyrin III (4) was achieved, though with a lower yield
(27%) than the other analogues, by condensation of the di-
formyldipyrromethane 22 with the dicarboxylic acid 2316
(Scheme 3). The b-formyl enol ether group reverted to the
desired acetyl derivative under the acidic conditions of the
MacDonald’s reaction. However, porphyrin 4 was finally
obtained with higher yields (32%) through condensation
of dipyrromethane 8 with 9, the former obtained via selec-
tive hydrogenolysis of benzyl esters of compound 16,
controlling the reaction conditions to prevent the acetyl
group from being reduced (Scheme 1).
R2 = OMe,
+
R1
Me,
N
H
CF3,
COMe
R2
10 R1 = CO2Et
11 R1 = CO2t-Bu
12 R1 = CO2Bn
PTSA/CHCl3
R1
R1
N
N
H
H
13–18
R2
a
a
a
5 R1 = COOH, R2 = OMe
6 R1 = COOH, R2 = Me
7 R1 = COOH, R2 = CF3
19 R1 = COOH, R2 = Et
20 R1 = H, R2 = CHOHMe
21 R1 = CHO, R2 = COMe
13 R1 = CO2Bn, R2 = OMe
14 R1 = CO2Bn, R2 = Me
15 R1 = CO2Bn, R2 = CF3
16 R1 = CO2Bn, R2 = COMe
17 R1 = CO2Et, R2 = COMe
All mesoporphyrins III dimethyl esters were converted
into the corresponding iron complexes17 and coupled oxi-
dation (O2 and ascorbic acid) was carried out, a reaction
that afforded all biliverdin derivatives resulted from
cleavage of all meso bridges. In the case of iron(III)–
mesoporphyrin III dimethyl ester (a compound that we
here synthesized by means of a procedure similar to the
one previously reported),18 three biliverdins were ob-
tained (24a, 24b, and 24g), it is important to observe that
b or d cleavage rendered the same biliverdin isomer
(Scheme 4). Their unequivocal assignment was made on
the basis of chemical shifts of each of the three methine
bridges, and a detailed analysis of the exo or endo b-sub-
stituents, in the same manner as we previously analyzed
protobiliverdins IX.19 It is known that biliverdin b-substit-
uents located at 2 or 8 positions (exo) show a lower chem-
ical shift than that of endo b-substituents.20 In this case,
the two exo-methyl groups of mesobiliverdin 24b show
a
b
18 R1 = CO2t-Bu, R2 = COMe
c
-COMe
22 R1 = CHO, R2 =
CH-CHO
Scheme 2 Synthesis of dipyrromethanes. Reagents and conditions:
(a) H2, Pd/C (3.45 bar), 3 h; (b) ethyleneglycol, NaOH; (c) (1) TFA,
(2) HC(OMe)3.
A very convenient method to synthesize the substrate
dipyrromethanes 13–16 was the treatment of benzyl 4-
ethyl-3-methyl-1H-pyrrole-2-carboxylate (12)11 with the
corresponding aromatic aldehydes [4-methoxybenzalde-
hyde, 4-acetylbenzaldehyde, 4-methylbenzaldehyde, 4-
Synthesis 2008, No. 6, 875–882 © Thieme Stuttgart · New York

PAPER
Synthesis of Mono-meso-arylmesoporphyrins III
877
chemical shifts of d = 1.81 and 1.84 (endo methyl groups
at d = 2.17 and 2.19), while in biliverdins 24a and 24g
there were no exo-methyl groups and the endo ones were
observed at d = 2.07, 2.09; and 2.03, 2.11, respectively. To
differentiate between biliverdins 24a and 24g, the exo- or
endo-methylenes of the ethyl groups gave us the same in-
formation as that mentioned for methyl groups.
COMe
CHO
OHC
N
N
H
H
NH
N
N
C-OMe
a
22
Coupled oxidation of each of the four iron(III)–5-aryl-
mesoporphyrin III dimethyl esters afforded two biliverdin
isomers, by cleavage at each of the three unsubstituted
meso bridges (Scheme 5).
CH-CHO
+
HN
PMe PMe
PMe
By comparison of chemical shifts observed in meso-
biliverdins 24b and 24g with those of arylbiliverdins 25–
28b and 25–28g (Tables 1 and 2), as expected, a diamag-
netic shift of the ethyl groups could be observed.
PMe
4 (27%)
CO2H
HO2C
N
H
N
H
PMe = CH2CH2CO2Me
23
Scheme
3
Synthesis of 5-(4-acetylphenyl)mesoporphyrin III.
Reagents and conditions: (a) (1) PTSA, CH2Cl2, MeOH, (2)
Zn(OAc)2, MeOH, (3) 5% H2SO4–MeOH.
PMe
PMe
N
O
O
N
N
H
N
H
H
α
24α
PMe
PMe
N
N
N
N
δ
Fe3+
β
O
O
N
N
H
N
N
H
H
24β
24γ
γ
PMe
PMe
PMe
PMe
O
Fe(III) mesoporphyrin III
dimethyl ester
O
N
H
N
H
N
N
H
Scheme 4 Chemical oxidation of iron(III)–mesoporphyrin III dimethyl ester. Note that b or d cleavage gives the same biliverdin isomer.
PMe PMe
R
O
O
N
H
N
H
N
N
H
α
β
N
N
N
N
Fe3+
δ
β
R
γ
PMe
PMe
O
PMe
PMe
O
Fe(III) 5-aryl mesoporphyrin III
dimethyl ester
N
N
H
N
N
H
H
25β, 25γ : R = COMe
26β, 26γ : R = OMe
27β, 27γ : R = Me
28β, 28γ : R = CF3
R
γ
Scheme 5 Chemical oxidation of each of the four iron(III)–5-arylmesoporphyrin III dimethyl esters.
Synthesis 2008, No. 6, 875–882 © Thieme Stuttgart · New York

878
F. Niemevz et al.
PAPER
Table 1 1H NMR Data of Mesobiliverdin IIIg Dimethyl Esters 24–28
24g
25g
26g
27g
28g
CH2CH3
CH2CH3
CH3 endo
1.14
0.83
0.68
0.72
0.70
2.50–2.56
2.01–2.20
2.01–2.20
2.06–2.21
2.06–2.21
2.07–2.20
2.07–2.20
2.06–2.20
2.06–2.20
2.03
2.11
CH 5 and 15
CH 10
5.85
6.14
–
6.14
6.14
6.14
–
6.56
–
–
CH2CH2CO2Me
2.50–2.56
2.61–2.65
2.61–2.63
2.55–2.70
2.51–2.63
CH2CH2CO2Me
CH2CH2CO2CH3
CH (102)
2.50–2.56
2.49–2.53
3.66
2.51–2.53
3.66
3.66
3.66
3.66
7.34
7.23
2.47
–
–
–
7.59
7.63
7.37
CH (103)
8.08
7.72
6.96
aryl CH3
2.55–2.70
–
3.90
Table 2 1H NMR Data of Mesobiliverdin IIIb Dimethyl Esters 24–28
24b
25b
26b
27b
28b
CH3 exo
CH2CH3
CH2CH3
CH3 endo
1.81
1.84
1.94–2.00
1.89–2.16
1.88–2.02
2.17–2.30
1.86–2.00
1.12
1.21
0.81
0.92
0.75
0.97
0.75
0.94
0.75
0.94
2.48–2.53
1.94–2.00
2.25–2.37
1.89–2.16
2.28
1.88–2.02
2.17–2.30
1.86–2.00
2.10–2.35
2.17
2.19
2.25–2.37
1.89–2.16
2.22
2.17–2.30
2.10–2.35
CH 10
6.68
7.09
6.75
6.77
6.76
CH2CH2CO2Me
2.79
2.84
2.85
2.90
2.77
2.84
2.75–2.86
2.78
2.85
CH2CH2CO2Me
2.48–2.53
2.65
2.50–2.57
2.46
2.58
2.46
2.60
2.46
2.60
CH 5
5.92/ 6.01
6.03
5.93
5.93
5.92
CH2CH2CO2CH3
3.67
3.71
3.65
3.67
3.64
3.69
3.65
3.69
3.64
3.69
CH (152)
CH (153)
aryl CH3
–
–
–
7.64
8.03
2.64
7.50
7.55
–
7.31
6.78
3.78
7.30
7.05
2.10–2.35
Dibenzyl 3,7-Diethyl-2,8-dimethyl-5-(4-methoxyphenyl)dipyr-
romethane-1,9-dicarboxylate (13); Typical Procedure
UV and vis spectra were recorded on Jasco 7850 and Jasco V-570
spectrophotometers. H NMR spectra were determined in CDCl3
1
Pyrrole 1211 (290 mg, 1.20 mmol) was refluxed for 2 h with 4-meth-
oxybenzaldehyde (0.15 mL, 167 mg, 1.20 mmol) and PTSA (114
mg, 0.60 mmol) in CHCl3 (35 mL). The mixture was diluted with
CH2Cl2 (50 mL), washed with 5% NaHCO3 (30 mL), and then with
H2O (30 mL). The soln was dried (anhyd Na2SO4), filtered, and the
solvent was evaporated at reduced pressure (40 °C). The product
and recorded using a Bruker MSL-300 spectrometer. MS-EI were
obtained with a Shimadzu QP 5000-GC 17 and MS-ES-IT (positive
ion mode) in a Finnigan LCQ DUO. HRMS (EI): VG AutoSpec
(Micromass Inst.). Melting points were measured on an Electrother-
mal 9100 and a Ionomex, and are uncorrected. Elemental analysis
were determined in a Carlo Erba EA 1108 analyzer.
Synthesis 2008, No. 6, 875–882 © Thieme Stuttgart · New York

PAPER
Synthesis of Mono-meso-arylmesoporphyrins III
879
was purified by column chromatography (silica gel, 14 × 2.5 cm,
CH2Cl2–hexane, 2:1) to give 13 (290 mg, 80%) as a clear oil.
1H NMR (300 MHz, CDCl3): d = 0.88 [t, J = 7.5 Hz, 6 H, CH3 (32,
72)], 1.52 [s, 18 H, C[CH3]3], 2.23 [s, 6 H, CH3 (21, 81)], 2.28 [q,
J = 7.5 Hz, 4 H, CH2 (31, 71)], 2.58 [s, 3 H, CH3 (56)], 5.58 [s, 1 H,
CH (5)], 7.18 [d, J = 8.4 Hz, 2 H, CH (52)], 7.88 [d, J = 8.4 Hz, 2 H,
CH (53)], 8.28 [br, 2 H, NH].
1H NMR (300 MHz, CDCl3): d = 0.86 [t, J = 7.6 Hz, 6 H, CH3 (32,
72)], 2.27 [m, 10 H, CH2 (31, 71) CH3 (21, 81)], 3.79 [s, 3 H, CH3
(56)], 5.26 [s, 4 H, CH2 (13, 93)], 5.48 [s, 1 H, CH (5)], 6.84 [d,
J = 8.6 Hz, 2 H, CH (53)], 6.99 [d, J = 8.6 Hz, 2 H, CH (52)], 7.29–
7.38 [m, 10 H, CH (15, 16, 17, 95, 96, 97)], 8.24 [br, 2 H, NH].
MS (EI, 20 eV): m/z (%) = 548 (7) [M]+.
Anal. Calcd for C33H44N2O5: C, 72.23; H, 8.08; N, 5.11. Found: C,
72.25; H, 8.09; N, 5.08.
MS (EI, 20 eV): m/z (%) = 604 (5) [M]+, 91 (100).
Dibenzyl 3,7-Diethyl-2,8-dimethyl-5-(4-methylphenyl)dipyrro-
methane-1,9-dicarboxylate (14)
3,7-Diethyl-5-[4-(2-formyl-1-methoxyvinyl)phenyl)-2,8-di-
methyldipyrromethane-1,9-dicarbaldehyde (22)
Following the typical procedure for 13 using 1211 (240 mg, 0.99
mmol), 4-methylbenzaldehyde (0.12 mL, 119 mg, 0.99 mmol), and
PTSA (95 mg, 0.50 mmol) in CHCl3 (30 mL) at reflux for 1 h. Col-
umn chromatography (silica gel, 14 × 2.5 cm, CH2Cl2–hexane, 3:1)
gave 14 (256 mg, 88%) as a clear oil.
Finely, ground dipyrromethane 18 (100 mg, 0.18 mmol) was added
to a flask containing TFA (1 mL) at 20 °C, and after 15 min of stir-
ring HC(OMe)3 (0.5 mL) was added. After a further period of 10
min, the mixture was poured into a cold mixture of H2O–NH3 (4:1,
25 mL). The resulting mixture was extracted with CH2Cl2 (30 mL),
the organic phase was washed with H2O (20 mL), dried (anhyd
Na2SO4), filtered, and evaporated to dryness at reduced pressure (40
°C). The oil thus obtained was purified by column chromatography
(silica gel, 14 × 2.5 cm, CH2Cl2–MeOH, 97:3). The product was
crystallized (CH2Cl2–hexane) to yield 22 (29.5 mg, 37%) as a
cream-colored solid; mp 205–206 °C (dec).
1H NMR (300 MHz, CDCl3): d = 0.96 [t, J = 7.5 Hz, 6 H, CH3 (32,
72)], 2.30 [s, 6 H, CH3 (21, 81)], 2.40 [q, J = 7.5 Hz, 4 H, CH2 (31,
71)], 3.87 [s, 3 H, OCH3], 5.65 [d, J = 7.7 Hz, 1 H, =CHCHO], 5.69
[s, 1 H, CH (5)], 7.14 [d, J = 8.3 Hz, 2 H, CH (52)], 7.43 [d, J = 8.3
Hz, 2 H, CH (53)], 9.42 [d, J = 7.7 Hz, 1 H, =CHCHO], 9.47 [s, 2
H, CHO (11, 91)], 9.70 [br, 2 H, NH].
1H NMR (300 MHz, CDCl3): d = 0.86 [t, J = 7.6 Hz, 6 H, CH3 (32,
72)], 2.23–2.32 [br, 13 H, CH2 (31, 71), CH3 (21, 81), CH3 (55)], 5.25
[s, 4 H, CH2 (13, 93)], 5.49 [s, 1 H, CH (5)], 6.95 [d, J = 7.9 Hz, 2 H,
CH (53)], 7.10 [d, J = 7.9 Hz, 2 H, CH (52)], 7.26–7.39 [m, 10 H, CH
(15, 16, 17, 95, 96, 97)], 8.26 [br, 2 H, NH].
MS (EI, 20 eV): m/z (%) = 588 (2) [M]+, 318 (5), 91 (100).
Dibenzyl 3,7-Diethyl-2,8-dimethyl-5-[4-(trifluoromethyl)phe-
nyl]dipyrromethane-1,9-dicarboxylate (15)
Following the typical procedure for 13 using 1211 (250 mg, 1.03
mmol), 4-(trifluoromethyl)benzaldehyde (185 mg, 1.04 mmol), and
PTSA (100 mg, 0.53 mmol) in CHCl3 (30 mL) at reflux for 30 min.
Column chromatography (silica gel, 12 × 2 cm, CH2Cl2–hexane,
3:1) gave 15 (284 mg, 85%) as a clear oil.
MS (ES): m/z (%) = 447 (10) [M + H]+, 469 (100) [M + Na]+.
Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77; N, 6.27. Found: C,
72.58; H, 6.79; N, 6.25.
1H NMR (300 MHz, CDCl3): d = 0.87 [t, J = 7.5 Hz, 6 H, CH3 (32,
72)], 2.28 [br, 10 H, CH2 (31, 71), CH3 (21, 81)], 5.26 [s, 4 H, CH2 (13,
93)], 5.60 [s, 1 H, CH (5)], 7.17–7.25 [m, 2 H, CH (52)], 7.27–7.55
[m, 10 H, CH (15, 16, 17, 95, 96, 97)], 7.56–7.60 [d, J = 8.2 Hz, 2 H,
CH (53)], 8.27 [br, 2 H, NH].
Mesoporphyrin III Dimethyl Esters; General Procedure
The corresponding dipyrromethane dibenzyl ester (0.56 mmol) was
dissolved in EtOH (50 mL), 10% Pd/C (300 mg) was added and the
mixture was hydrogenolyzed for 3 h at 3.45 bar. The mixture was
filtered through Celite (which was previously washed with EtOH).
The filtrate was evaporated to dryness (40 °C) and the dipyr-
romethane-1,9-dicarboxylic acid (0.50 mmol, 90%) (as a pale pink
oil) was used without further purification. This compound was then
dissolved in a mixture of anhyd CH2Cl2 (200 mL) and MeOH (30
mL), and the corresponding dipyrromethane-1,9-dicarbaldehyde
(0.50 mmol) was added followed by PTSA (380 mg, 2 mmol). The
mixture was kept at r.t. for 24 h protected from light and sat.
Zn(OAc)2·2H2O in anhyd MeOH (40 mL) was added. After a period
of 72 h under the same conditions, the mixture was concentrated at
reduced pressure (40 °C), and a soln of 5% H2SO4 in MeOH (100
mL) was then added. After a period of 16 h, the mixture was diluted
with CH2Cl2 (150 mL) and the organic phase was washed with H2O
(50 mL), 5% NaHCO3 (50 mL), and H2O (50 mL). The resulting
soln was dried (anhyd Na2SO4), filtered, and evaporated to dryness
at reduce pressure (40 °C). The dark residue was purified by column
chromatography (silica gel, 12 × 2 cm, CH2Cl2–MeOH, 98:2), elut-
ing the red band. The resulting compound was crystallized
(CH2Cl2–hexane) to give a purple powder.
MS (EI, 20 eV): m/z (%) = 642 (3) [M]+, 91 (100).
Dibenzyl 5-(4-Acetylphenyl)-3,7-diethyl-2,8-dimethyldipyrro-
methane-1,9-dicarboxylate (16)
Following the typical procedure for 13 using 1211 (250 mg, 1.03
mmol), p-acetylbenzaldehyde (157 mg, 1.03 mmol), and PTSA (98
mg, 0.52 mmol) in CHCl3 (30 mL) at reflux for 30 min. Column
chromatography (silica gel, 8 × 2 cm) eluting first with CH2Cl2 gave
the excess aldehyde and then with CH2Cl2–MeOH (99:1) gave 16
(260 mg, 82%) as a clear oil.
1H NMR (300 MHz, CDCl3): d = 0.88 [t, J = 7.4 Hz, 6 H, CH3 (32,
72)], 2.27–2.31 [m, 10 H, CH2 (31, 71) CH3 (21, 81)], 2.56 [s, 3 H,
CH3 (56)], 5.23 [s, 4 H, CH2 (13, 93)], 5.60 [s, 1 H, CH (5)], 7.17 [d,
J = 8.4 Hz, 2 H, CH (52)], 7.31–7.36 [m, 10 H, CH (15, 16, 17, 95, 96,
97)], 7.88 [d, J = 8.4 Hz, 2 H, CH (53)], 8.46 [br, 2 H, NH].
MS (EI, 20 eV): m/z (%) = 616 (5) [M]+, 91 (100).
Di-tert-butyl 5-(4-Acetylphenyl)-3,7-diethyl-2,8-dimethyl-
dipyrromethane-1,9-dicarboxylate (18)
Pyrrole 1111 (280 mg, 1.34 mmol), 4-acetylbenzaldehyde (198 mg,
1.34 mmol), and PTSA (127 mg, 0.67 mmol) in CHCl3 (35 mL)
were stirred at r.t. for 3 h. The mixture was diluted with CH2Cl2 (50
mL) and washed with 5% NaHCO3 (30 mL) and H2O (30 mL). The
soln was dried (anhyd Na2SO4), filtered, and the solvent evaporated
at reduced pressure (40 °C). The crude product was subjected to col-
umn chromatography (silica gel, 4 × 4 cm) eluting first with CH2Cl2
gave the excess aldehyde and then with CH2Cl2–MeOH (99:1) gave
18 as a clear oil, which was crystallized (CH2Cl2–hexane) to give a
white powder; yield: 275 mg (76%); mp 132–133 °C.
Mesoporphyrin III Dimethyl Ester
This porphyrin was synthesized in 1965 by Sklyar, Yu. E. et al.18 by
treatment of dipyrrolic units in AcOH–HCl, followed by oxidation
with chloranil. In our case, following the general procedure using
3,7-diethyl-2,8-dimethyldipyrromethane-1,9-dicarboxylic acid21
(230 mg, 0.72 mmol) and 910 (311 mg, 0.77 mmol), with column
chromatography (silica gel, 8 × 2 cm, CH2Cl2–MeOH, 98:2) fol-
lowed by crystallization (CH2Cl2–hexane) yielded the porphyrin
(67 mg, 16%); mp 289–290 °C.
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F. Niemevz et al.
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MS (ES): m/z (%) = 739 (100) [M + H]+, 371 (84) [M + 2 H]2+.
1H NMR (300 MHz, CDCl3): d = 1.87 [t, J = 7.63 Hz, 6 H, CH3 (32,
72)], 3.30 [t, J = 7.6 Hz, 4 H, CH2 (132, 172)], 4.09 [q, J = 7.63 Hz,
4 H, CH2 (31, 71)], 3.66 [br, 12 H, CH3 (21, 81, 121, 181)], 3.63 [s, 6
H, OCH3 (135, 175)], 4.43 [t, J = 7.6 Hz, 4 H, CH2 (131, 171)], 10.09
and 10.08 [s, s, 1 H, 1 H, CH (5, 15)], 10.10 [s, 2 H, CH (10, 20)].
UV/Vis (CH2Cl2): lmax (log e) = 404 (5.29), 503 (4.25), 537 (3.96),
572 (3.92), 625 nm (3.61).
Anal. Calcd for C43H45F3N4O4: C, 69.90; H, 6.14; N, 7.58. Found:
C, 69.93; H, 6.19; N, 7.54.
MS (ES): m/z (%) = 595 (100) [M + H]+.
MS/MS: m/z (%) = 521 (27) [595 – CH2CO2CH3], 506 (51) [595 –
CH2CH2CO2CH3], 420 (36) [595 – 2 CH2CO2CH3].
5-(4-Acetylphenyl)mesoporphyrin III Dimethyl Ester (4)
Method A: Following the general procedure using 2316 (116 mg,
0.27 mmol) and 22 (112 mg, 0.25 mmol). Column chromatography
(silica gel, 8 × 2 cm, CH2Cl2–MeOH, 98:2) followed by crystalliza-
tion (CH2Cl2–hexane) gave 4 (45 mg, 27%); mp 255–256 °C.
1H NMR (300 MHz, CDCl3): d = –3.2 and –3.1 [br s, br s, 1 H, 1 H,
NH], 1.12 [t, J = 7.4 Hz, 6 H, CH3 (32, 72)], 2.70 [q, J = 7.4 Hz, 4 H,
CH2 (31, 71)], 2.90 [s, 3 H, COCH3 (56)], 3.30 [t, J = 7.7 Hz, 4 H,
CH2 (132, 172)], 3.58 [s, 6 H, OCH3 (135, 175)], 3.66 [br, 12 H, CH3
(21, 81, 121, 181)], 4.40 [t, J = 7.7 Hz, 4 H, CH2 (131, 171)], 8.28 [d,
J = 8.5 Hz, 2 H, CH (52)], 8.33 [d, J = 8.5 Hz, 2 H, CH (53)], 9.95
[s, 1 H, CH (15)], 10.20 [s, 2 H, CH (10, 20)].
UV/Vis (CH2Cl2): lmax (log e) = 398 (5.24), 498 (4.26), 531 (4.13),
567 (4.00), 620 nm (3.89).
Anal. Calcd for C36H42N4O4: C, 72.70; H, 7.12; N, 9.42. Found: C,
72.51; H, 7.15; N, 9.39.
5-(4-Methoxyphenyl)mesoporphyrin III Dimethyl Ester (1)
Following the general procedure using 5 (194 mg, 0.46 mmol) and
9
10 (196 mg, 0.49 mmol). Column chromatography (silica gel, 8 × 2
cm, CH2Cl2–MeOH, 98:2) followed by crystallization (CH2Cl2–
hexane) yielded the porphyrin (123 mg, 39%); mp 269–270 °C.
MS (ES): m/z (%) = 713 (100) [M + H]+.
1H NMR (300 MHz, CDCl3): d = 1.15 [t, J = 7.4 Hz, 6 H, CH3 (32,
72)], 2.80 [q, J = 7.4 Hz, 4 H, CH2 (31, 71)], 3.29 [t, J = 7.8 Hz, 4 H,
CH2 (132, 172)], 3.55 [s, 6 H, OCH3 (135, 175)], 3.66 [br, 12 H, CH3
(21, 81, 121, 181)], 4.12 [s, 3 H, OCH3 (56)], 4.39 [t, J = 7.8 Hz, 4 H,
CH2 (131, 171)], 7.21 [d, J = 7.9 Hz, 2 H, CH (53)], 8.07 [d, J = 7.9
Hz, 2 H, CH (52)], 9.91 [s, 1 H, CH (15)], 10.18 [s, 2 H, CH (10,
20)].
UV/Vis (CH2Cl2): lmax (log e) = 406 (5.23), 503 (4.15), 537 (3.78),
572 (3.77), 625 nm (3.34).
Anal. Calcd for C44H48N4O5: C, 74.13; H, 6.79; N, 7.86. Found: C,
74.08; H, 6.83; N, 7.82.
Method B. Dipyrromethane dibenzyl ester 16 (200 mg, 0.32 mmol)
was dissolved in THF (50 mL) with Et3N (2 drops), 10% Pd/C (40
mg) was added and the mixture was hydrogenolyzed for 3 h at 2.07
bar. The mixture was adjusted to pH 10 with concd NH3 to increase
dicarboxylic acid solubility and the mixture was filtered through
Celite. The filtrate was then acidified with 2 M AcOH to pH 5, and
the dipyrromethane-1,9-dicarboxylic acid 8 precipitate was filtered
at reduced pressure; yield: 121 mg (85%); mp 147–148 °C (with de-
carboxylation).
1H NMR (300 MHz, DMSO-d6): d = 0.96 [t, J = 7.3 Hz, 6 H, CH3
(32, 72)], 2.23 [s, 6 H, CH3 (21, 81)], 2.46–2.49 [m, 7 H, CH2 (31, 71)
COCH3 (56)], 5.68 [s, 1 H, CH (5)], 7.10 [d, J = 7.9 Hz, 2 H, CH
(52)], 7.86 [d, J = 7.9 Hz, 2 H, CH (53)], 11.09 [s, 2 H, COOH (13,
93)].
MS (ES): m/z (%) = 701 (100) [M + H]+.
UV/Vis (CH2Cl2): lmax (log e) = 405 (5.37), 504 (4.28), 537 (3.90),
572 (3.90), 625 nm (3.43).
Anal. Calcd for C43H48N4O5: C, 73.69; H, 6.90; N, 7.99. Found: C,
73.61; H, 7.01; N, 7.93.
5-(4-Methylphenyl)mesoporphyrin III Dimethyl Ester (2)
Following the general procedure using 6 (174 mg, 0.43 mmol) and
9
10 (184 mg, 0.46 mmol). Column chromatography (silica gel, 8 × 2
cm, CH2Cl2–MeOH, 98:2) followed by crystallization (CH2Cl2–
hexane) gave 2 (119 mg, 41%); mp 264–265 °C.
1H NMR (300 MHz, CDCl3): d = –3.2 and –3.1 [br s, br s, 1 H, 1 H,
NH], 1.13 [t, J = 7.4 Hz, 6 H, CH3 (32, 72)], 2.73 [s, 3 H, CH3 (55)],
2.76 [q, J = 7.4 Hz, 4 H, CH2 (31, 71)], 3.29 [t, J = 7.8 Hz, 4 H, CH2
(132, 172)], 3.55 [s, 6 H, OCH3 (135, 175)], 3.66 [br, 12 H, CH3 (21,
81, 121, 181)], 4.39 [t, J = 7.8 Hz, 4 H, CH2 (131, 171)], 7.46 [d,
J = 7.9 Hz, 2 H, CH (53)], 8.04 [d, J = 7.9 Hz, 2 H, CH (52)], 9.91
[s, 1 H, CH (15)], 10.18 [s, 2 H, CH (10, 20)].
Following the general procedure 910 (119 mg, 0.28 mmol) was treat-
ed with 8 (121 mg, 0.28 mmol) to give 4 (63 mg, 32%).
Iron(III) Complexes of Mesoporphyrin Dimethyl Esters
These were obtained according to the described procedures;17 all
hemins were purified by column chromatography (silica gel,
CH2Cl2–MeOH, 95:5) followed by crystallization (CH2Cl2–hex-
ane).
MS (ES): m/z (%) = 685 (100) [M + H]+.
UV/Vis (CH2Cl2): lmax (log e) = 405 (5.37), 503 (4.26), 537 (3.90),
572 (3.90), 625 nm (3.41).
Iron(III)–Mesoporphyrin III
Yield: 87%; mp >300 °C.
MS (ES-IT): m/z (%) = 648 (100) [M]+.
Anal. Calcd for C43H48N4O4: C, 75.41; H, 7.06; N, 8.18. Found: C,
75.35; H, 7.12; N, 8.13.
UV/Vis (CH2Cl2): lmax (log e) = 381 (4.90), 539 nm (3.89).
5-[4-(Trifluoromethyl)phenyl]mesoporphyrin III Dimethyl
Ester (3)
Iron(III)–5-(4-Acetylphenyl)mesoporphyrin III Dimethyl Ester
Yield: 70%; mp >300 °C.
MS (ES-IT): m/z (%) = 766 (100) [M]+.
Following the general procedure using 7 (195 mg, 0.42 mmol) and
9
10 (181 mg, 0.45 mmol). Column chromatography (silica gel, 8 × 2
cm, CH2Cl2–MeOH, 99:1) followed by crystallization (CH2Cl2–
hexane) gave 3 (92 mg, 30%); mp 232–233 °C.
UV/Vis (CH2Cl2): lmax (log e) = 390 (4.60), 556 (3.54), 641 nm
1H NMR (300 MHz, CDCl3): d = –3.2 and –3.1 [br s, br s, 1 H, 1 H,
NH], 1.13 [t, J = 7.4 Hz, 6 H, CH3 (32, 72)], 2.69 [q, J = 7.4 Hz, 4 H,
CH2 (31, 71)], 3.30 [t, J = 7.8 Hz, 4 H, CH2 (132, 172)], 3.55 [s, 6 H,
OCH3 (135, 175)], 3.66 [br, 12 H, CH3 (21, 81, 121, 181)], 4.40 [t,
J = 7.8 Hz, 4 H, CH2 (131, 171)], 7.96 [d, J = 7.9 Hz, 2 H, CH (52)],
8.35 [d, J = 7.9 Hz, 2 H, CH (53)], 9.96 [s, 1 H, CH (15)], 10.20 [s,
2 H, CH (10, 20)].
(2.95).
Iron(III)–5-(4-Methylphenyl)mesoporphyrin III Dimethyl
Ester
Yield: 94%; mp >300 °C.
MS (ES-IT): m/z (%) = 738 (100) [M]+.
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PAPER
Synthesis of Mono-meso-arylmesoporphyrins III
881
UV/Vis (CH2Cl2): lmax (log e) = 385 (4.99), 506 (3.95), 538 (3.87),
633 nm (3.61).
5-(4-Acetylphenyl)mesobiliverdin IIIb Dimethyl Ester (25b)
Yield: 3.0%; mp 139–140 °C.
1H NMR (300 MHz, CDCl3): d = 0.81 and 0.92 [t, t, 3 H, 3 H, CH3
(132, 172)], 1.94–2.00 [m, 8 H, CH3 (21, 181), CH2 (131 ó 171)],
2.25–2.37 [m, 8 H, CH3 (81, 121), CH2 (131 or 171)], 2.50–2.57 [m,
4 H, CH2 (32 or 72)], 2.64 [s, 3 H, CH3 (156)], 2.85 and 2.90 [t, t,
J = 7.2 Hz, J = 7.0 Hz, 2 H, 2 H, CH2 (31 or 71)], 3.65 and 3.67 [s,
s, 3 H, 3 H, OCH3 (35, 75)], 6.03 [s, 1 H, CH (5)], 7.09 [s, 1 H, CH
(10)], 7.64 [d, J = 8.0 Hz, 2 H, CH (152)], 8.03 [d, J = 8.0 Hz, 2 H,
CH (153)].
Iron(III)-5-[4-(Trifluoromethyl)phenyl]mesoporphyrin III
Dimethyl Ester
Yield: 90%; mp >300 °C.
MS (ES-IT): m/z (%) = 792 (100) [M]+.
UV/Vis (CH2Cl2): lmax (log e) = 385 (4.99), 508 (4.02), 539 (3.96),
639 nm (3.70).
Iron(III)-5-(4-Methoxyphenyl)mesoporphyrin III Dimethyl
MS (ES): m/z (%) = 733 (68) [M + H]+, 755 (100) [M + Na]+.
Ester
MS/MS: m/z (%) = 373 (100), 371 (52).
HRMS (ES): m/z [M + H]+ calcd for C43H48N4O7: 732.352300;
found: 732.346852.
Yield: 84%; mp >300 °C.
MS (ES-IT): m/z (%) = 754 (100) [M]+.
UV/Vis (CH2Cl2): lmax (log e) = 386 (4.99), 504 (3.93), 540 (3.86),
631 nm (3.59).
UV/Vis (CH2Cl2): lmax (log e) = 372 (4.30), 319 (4.43), 586 nm
(4.15).
Chemical Oxidation of Iron(III)–Mesoporphyrin Dimethyl
Esters
10-(4-Acetylphenyl)mesobiliverdin IIIg Dimethyl Ester (25g)
Yield: 2.2%; mp 155–156 °C.
Biliverdins were obtained by coupled oxidation with O2 and ascor-
1H NMR (300 MHz, CDCl3): d = 0.83 [t, 6 H, CH3 (82, 122)], 2.01–
2.20 [m, 16 H, CH2 (81, 121), CH3 (31, 71, 131, 171)], 2.55–2.70 [m,
11 H, CH2 (21, 22, 181, 182), CH3 (156)], 3.66 [s, 6 H, OCH3 (25,
185)], 6.14 [s, 2 H, CH (5, 15)], 7.59 [d, J = 7.9 Hz, 2 H, CH (102)],
8.08 [d, J = 7.9 Hz, 2 H, CH (103)].
bic acid according to published procedures.19
Mesobiliverdin IIIa Dimethyl Ester (24a)
Yield: 7.4%; mp 247–248 °C.
1H NMR (300 MHz, CDCl3): d = 1.06 [t, J = 7.5 Hz, 6 H, CH3 (22,
182)], 2.09 and 2.07 [s, s, 6 H, 6 H, CH3 (31, 71, 131, 171)], 2.27 [q,
J = 7.5 Hz, 4 H, CH2 (21, 181)], 2.54 [c, J = 7.6 Hz, 4 H, CH2 (82,
122)], 2.90 [c, J = 7.6 Hz, 4 H, CH2 (81, 121)], 3.67 [s, 6 H, OCH3
(85, 125)], 5.87 [s, 2 H, CH (5, 15)], 6.71 [s, 1 H, CH (10)].
MS (ES): m/z (%) = 733 (14) [M + H]+, 755 (100) [M + Na]+.
MS/MS: m/z (%) = 431 (100).
HRMS (ES): m/z [M + H]+ calcd for C43H48N4O7: 732.352300;
found: 732.349853.
MS (ES): m/z (%) = 615 (64) [M + H]+, 637 (19) [M + Na]+.
UV/Vis (CH2Cl2): lmax (log e) = 383 (4.31), 307 (3.94), 653 nm
(3.57).
MS/MS: m/z (%) = 313 (100).
HRMS (ES): m/z [M + H]+ calcd for C35H42N4O6: 614.310435;
found: 614.309862.
5-(4-Methoxyphenyl)mesobiliverdin IIIb Dimethyl Ester (26b)
Yield: 10.8%; mp 184–185 °C.
UV/Vis (CH2Cl2): lmax (log e) = 366 (4.73), 629 nm (4.12).
1H NMR (300 MHz, CDCl3): d = 0.75 and 0.94 [t, t, J = 7.4 Hz,
J = 7.4 Hz, 3 H, 3 H, CH3 (132, 172)], 1.88–2.02 [m, 8 H, CH3 (21,
181), CH2 (131 or 171)], 2.17–2.30 [m, 8 H, CH3 (81, 121), CH2 (131
or 171)], 2.46 and 2.60 [t, t, J = 7.6 Hz, J = 7.6 Hz, 2 H, 2 H, CH2
(32, 72)], 2.77 and 2.84 [t, t, J = 7.6 Hz, J = 7.6 Hz, 2 H, 2 H, CH2
(31, 71)], 3.65 and 3.69 [s, s, 3 H, 3 H, OCH3 (35, 75)], 3.78 [s, 3 H,
OCH3 (155)], 5.93 [s, 1 H, CH (5)], 6.77 [s, 1 H, CH (10)], 6.78 [d,
J = 8.7 Hz, 2 H, CH (153)], 7.31 [d, J = 8.7 Hz, 2 H, CH (152)].
Mesobiliverdin IIIb Dimethyl Ester (24b)
Yield: 9.2%; mp 229–230 °C.
1H NMR (300 MHz, CDCl3): d = 1.12 and 1.21 [t, t, J = 7.5 Hz, 3
H, 3 H, CH3 (132, 172)], 1.81 and 1.84 [s, s, 3 H, 3 H, CH3 (21, 181)],
2.17 and 2.19 [s, s, 3 H, 3 H, CH3 (81, 121)], 2.48–2.53 [m, 6 H, CH2
(131, 171, 32 or 72)], 2.65 [t, J = 7.6, 2 H, CH2 (32 or 72)], 2.79–2.84
[m, 4 H, CH2 (31, 71)], 3.67 and 3.71 [s, s, 3 H, 3 H, OCH3 (35, 75)],
5.92 and 6.01 [s, s, 1 H, 1 H, CH (5, 15)], 6.68 [s, 1 H, CH (10)].
MS (ES): m/z (%) = 721 (94) [M + H]+, 743 (100) [M + Na]+.
MS (ES): m/z (%) = 615 (100) [M + H]+, 637 (90) [M + Na]+.
MS/MS: m/z (%) = 371 (43), 361 (55).
HRMS (ES): m/z [M + H+] calcd for C42H48N4O7: 720.352300;
found: 720.358775.
MS/MS: m/z (%) = 371 (25).
HRMS (ES): m/z [M + H]+ calcd for C35H42N4O6: 614.310435;
found: 614.310198.
UV/Vis (CH2Cl2): lmax (log e) = 377 (4.37), 322 (4.43), 596 nm
(4.23).
UV/Vis (CH2Cl2): lmax (log e) = 367 (4.78), 642 nm (4.22).
10-(4-Methoxyphenyl)mesobiliverdin IIIg Dimethyl Ester (26g)
Mesobiliverdin IIIg Dimethyl Ester (24g)
Yield: 10.8%; mp 208–209 °C.
Yield: 9.0%; mp 234–235 °C.
1H NMR (300 MHz, CDCl3): d = 0.72 [t, 6 H, CH3 (82, 122)], 2.07–
2.20 [m, 16 H, CH2 (81, 121), CH3 (31, 71, 131, 171)], 2.51–2.53 [m,
4 H, CH2 (122, 182)], 2.61–2.63 [m, 4 H, CH2 (21, 181)], 3.66 [s, 6
H, OCH3 (25, 185)], 3.90 [s, 3 H, OCH3 (105)], 6.14 [s, 2 H, CH (5,
15)], 6.96 [d, J = 8.7 Hz, 2 H, CH (103)], 7.37 [d, J = 8.7 Hz, 2 H,
CH (102)].
1H NMR (300 MHz, CDCl3): d = 1.14 [t, J = 7.5 Hz, 6 H, CH3 (82,
122)], 2.03 and 2.11 [s, s, 6 H, 6 H, CH3 (31, 71, 131, 171)], 2.50–2.56
[m, 12 H, CH2 (81, 121, 21, 22, 181, 182)], 3.66 [s, 6 H, OCH3 (25,
185)], 5.85 [s, 2 H, CH (5, 15)], 6.56 [s, 1 H, CH (10)].
MS (ES): m/z (%) = 615 (97) [M + H]+, 637 (100) [M + Na]+.
MS/MS: m/z (%) = 313 (100).
MS (ES): m/z (%) = 721 (78) [M + H]+, 743 (100) [M + Na]+.
HRMS (ES): m/z [M + H]+ calcd for C35H42N4O6: 614.310435;
MS/MS: m/z (%) = 419 (100).
found: 614.310006.
HRMS (ES): m/z [M + H]+ calcd for C42H48N4O7: 720.352300;
UV/Vis (CH2Cl2): lmax (log e) = 370 (4.92), 636 nm (4.26).
found: 720.357951.
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F. Niemevz et al.
PAPER
UV/Vis (CH2Cl2): lmax (log e) = 388 (4.63), 310 (4.30), 651 nm
(3.90).
4 H, CH2 (122, 182)], 2.61–2.65 [m, 4 H, CH2 (21, 181)], 3.66 [s, 6
H, OCH3 (25, 185)], 6.14 [s, 2 H, CH (5, 15)], 7.63 [d, J = 8.2 Hz, 2
H, CH (102)], 7.72 [d, J = 8.2 Hz, 2 H, CH (103)].
5-(4-Methylphenyl)mesobiliverdin IIIb Dimethyl Ester (27b)
MS (ES): m/z (%) = 759 (56) [M + H]+, 781 (100) [M + Na]+.
Yield: 13.1%; mp 215–216 °C.
MS/MS: m/z (%) = 457 (100).
HRMS (ES): m/z [M + H]+ calcd for C42H45F3N4O6: 758.329120;
found: 758.328547.
1H NMR (300 MHz, CDCl3): d = 0.75 and 0.94 [t, t, J = 7.4 Hz,
J = 7.4 Hz, 3 H, 3 H, CH3 (132, 172)], 1.86–2.00 [m, 8 H, CH3 (21,
181), CH2 (131 or 171)], 2.10–2.35 [m, 11 H, CH3 (81, 121, 154), CH2
(131 or 171)], 2.46 and 2.60 [t, t, J = 7.6 Hz, J = 7.6 Hz, 2 H, 2 H,
CH2 (32, 72)], 2.78 and 2.85 [t, t, J = 7.6 Hz, J = 7.6 Hz, 2 H, 2 H,
CH2 (31, 71)], 3.64 and 3.69 [s, s, 3 H, 3 H, OCH3 (35, 75)], 5.92 [s,
1 H, CH (5)], 6.76 [s, 1 H, CH (10)], 7.05 [d, J = 7.6, 2 H, CH (153)],
7.30 [d, J = 7.6 Hz, 2 H, CH (152)].
UV/Vis (CH2Cl2): lmax (log e) = 380 (4.64), 304 (4.28), 655 nm
(3.91).
Acknowledgment
MS (ES): m/z (%) = 705 (100) [M + H]+, 727 (56) [M + Na]+.
This work was supported by a grant from Universidad de Buenos
Aires, UBACyT B005. We thank Dr. Fernando Lafont Déniz (Uni-
versidad de Córdoba, Spain) for performing mass spectra.
MS/MS: m/z (%) = 371 (6).
HRMS (ES): m/z [M + H]+ calcd for C42H48N4O6: 704.357385;
found: 704.356624.
References
UV/Vis (CH2Cl2): lmax (log e) = 375 (4.23), 320 (4.44), 611 nm
(4.23).
(1) Tenhunen, R.; Marver, H. S.; Schmid, R. J. Biol. Chem.
1969, 244, 6388.
(2) Ortiz de Montellano, P. R. Curr. Opin. Chem. Biol. 2000, 4,
221; and references therein.
(3) Torpey, J.; Ortiz de Montellano, P. R. J. Biol. Chem. 1996,
271, 26067.
(4) Wang, J.; Niemevz, F.; Lad, L.; Huang, L.; Alvarez, D. E.;
Buldain, G. Y.; Poulos, T. L.; Ortiz de Montellano, P. R.
J. Biol. Chem. 2004, 279, 42593.
10-(4-Methylphenyl)mesobiliverdin IIIg Dimethyl Ester (27g)
Yield: 9.3%; mp 193–194 °C.
1H NMR (300 MHz, CDCl3): d = 0.70 [t, 6 H, CH3 (82, 122)], 2.06–
2.20 [m, 16 H, CH2 (81, 121), CH3 (31, 71, 131, 171)], 2.47 [s, 3 H,
CH3 (104)], 2.51–2.63 [m, 8 H, CH2 (21, 181, 122, 182)], 3.66 [s, 6 H,
OCH3 (25, 185)], 6.14 [s, 2 H, CH (5, 15)], 7.34 [d, J = 7.6 Hz, 2 H,
CH (102)], 7.23 [d, J = 7.6 Hz, 2 H, CH (103)].
MS (ES): m/z (%) = 705 (100) [M + H]+, 727 (96) [M + Na]+.
(5) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am.
Chem. Soc. 1960, 82, 4384.
(6) Valasinas, A. L.; Frydman, B. J. Org. Chem. 1976, 41, 2991.
(7) Robinsohn, A. E.; Buldain, G. Y. J. Heterocycl. Chem. 1995,
32, 1567.
MS/MS: m/z (%) = 403 (87).
HRMS (ES): m/z [M + H]+ calcd for C42H48N4O6: 704.357385;
found: 704.352486.
(8) Robinsohn, A. E.; Maier, M. S.; Buldain, G. Y. Heterocycles
2000, 53, 2127.
(9) Niemevz, F.; Lázaro Martínez, J. M.; Carballo, R.; Rezzano,
I.; Buldain, G. Y. Synthesis 2006, 870.
(10) Chen, Q.; Huggins, M. T.; Lightner, D. A.; Norona, W.;
McDonagh, A. F. J. Am. Chem. Soc. 1999, 121, 9253.
(11) Awruch, J.; Frydman, B. Tetrahedron 1986, 42, 4137.
(12) Daignault, R. A.; Eliel, E. L. Org. Synth. Coll. Vol. V; John
Wiley & Sons: London, 1973, 303.
(13) Li, T.-S.; Li, S.-H.; Li, J.-T.; Li, H.-Z. J. Chem. Res., Synop.
1997, 26.
(14) Kleinfelter, D. C. J. Org. Chem. 1967, 32, 840.
(15) Dusza, J. P.; Joseph, J. P.; Bernstein, S. J. Am. Chem. Soc.
1964, 86, 3908.
(16) Mironov, A. F.; Ovsepyan, T. R.; Evstigneeva, R. P.;
Preobrazhenskii, N. A. Zh. Obshch. Khim. 1965, 35, 324.
(17) Fuhrhop, J.-H.; Smith, K. M. In Laboratory Methods in
Porphyrin and Metalloporphyrin Research; Elsevier:
Amsterdam, 1975, 44.
UV/Vis (CH2Cl2): lmax (log e) = 385 (4.79), 308 (4.41), 655 nm
(4.10).
5-[4-(Trifluoromethyl)phenyl]mesobiliverdin IIIb Dimethyl
Ester (28b)
Yield: 14.3%; mp 125–126 °C.
1H NMR (300 MHz, CDCl3): d = 0.75 and 0.97 [t, t, J = 7.4 Hz,
J = 7.4 Hz, 3 H, 3 H, CH3 (132, 172)], 1.89–2.16 [m, 11 H, CH3 (21,
181, 81 or 121), CH2 (131 or 171)], 2.22 [s, 3 H, CH3 (81 or 121)], 2.28
[c, J = 7.4 Hz, 2 H, CH2 (131 or 171)], 2.46 and 2.58 [t, t, J = 7.6 Hz,
J = 7.6 Hz, 2 H, 2 H, CH2 (32, 72)], 2.77 and 2.84 [t, t, J = 7.6 Hz,
J = 7.6 Hz, 2 H, 2 H, CH2 (31, 71)], 3.64 and 3.69 [s, s, 3 H, 3 H,
OCH3 (35, 75)], 5.93 [s, 1 H, CH (5)], 6.75 [s, 1 H, CH (10)], 7.50
[d, J = 8.5 Hz, 2 H, CH (152)], 7.55 [d, J = 8.5 Hz, 2 H, CH (153)].
MS (ES): m/z (%) = 759 (89) [M + H]+, 781 (100) [M + Na]+.
MS/MS: m/z (%) = 373 (100).
HRMS (ES): m/z [M + H]+ calcd for C42H45F3N4O6: 758.329120;
(18) Sklyar Yu, E.; Evstigneeva, R. P.; Preobrazhenskii, N. A.
Khim. Geterotsikl. Soedin. 1965, 4, 633.
(19) (a) Niemevz, F.; Alvarez, D. E.; Buldain, G. Y. Heterocycles
2002, 57, 697. (b) Niemevz, F.; Buldain, G. Y.
J. Porphyrins Phthalocyanines 2004, 8, 989.
(20) Bonnett, R.; McDonagh, A. F. J. Chem. Soc., Perkin Trans.
1 1973, 881.
found: 758.335458.
UV/Vis (CH2Cl2): lmax (log e) = 373 (4.28), 320 (4.35), 583 nm
(4.13).
10-[4-(Trifluoromethyl)phenyl]mesobiliverdin IIIg Dimethyl
Ester (28g)
Yield: 8.9%; mp 191–192 °C.
(21) Abraham, R. J.; Jackson, A. H.; Kenner, G. W.; Warburton,
G. J. J. Chem. Soc. 1963, 863.
1H NMR (300 MHz, CDCl3): d = 0.68 [t, 6 H, CH3 (82, 122)], 2.06–
2.21 [m, 16 H, CH2 (81, 121), CH3 (31, 71, 131, 171)], 2.49–2.53 [m,
Synthesis 2008, No. 6, 875–882 © Thieme Stuttgart · New York