Nucleophilic ring opening of meso -substituted 5-oxaporphyrin by oxygen, nitrogen, sulfur, and carbon nucleophiles

Article abstract of DOI:10.1021/jo5000412

Nucleophilic ring opening of 23H-[21,23-didehydro-10,15,20-tris(4- methoxycarbonylphenyl)-5-oxaporphyrinato](trifluoroacetato)zinc(II) with various nucleophiles such as alkoxide, amine, thiolate, and enolate gave 19-substituted bilinone zinc complexes, and they were isolated as free base bilinones. An X-ray crystallographic study demonstrated that the product of 5-oxaporphyrin with sodium methoxide was 21H,23H-(4Z,9Z,15Z)-1,21-dihydro-19-methoxy-5,10,15- tris(4-methoxycarbonylphenyl)bilin-1-one with a helicoidal conformation. The structure of the product of 5-oxaporphyrin with an enolate of ethyl acetoacetate was 21H,22H,24H-(4Z,9Z,15Z,19E)-19-(1-ethoxycarbonyl-2-oxopropylidene)-5,10,15- tris(4-methoxycarbonylphenyl)-1,19,21,24-tetrahydrobilin-1-one, with three inner NH groups. The product with SH^- was also the same tautomer, 21H,22H,24H-19-thioxo-bilin-1-one, with three NH groups, while the products with RO^-, RNH₂, and RS^- nucleophiles were 21H,23H-bilin-1-ones with two inner NH groups. The first-order rate constants of the ring opening reaction of 5-oxaporphyrin with 1 M BnOH and BnSH in toluene at 303 K were 3.0 × 10^-4 and 6.1 × 10^-4 s ^-1, respectively. The ratio of the rate of alcohol to thiol was much higher than that with methyl iodide, suggesting that 5-oxaporphyrin reacted as a hard electrophile in comparison to methyl iodide. UV-visible spectra of 19-substituted bilinones in CHCl₃ at 298 K showed that the absorption maximum of the lower energy band was red-shifted in increasing order of O-substituted (645 nm), S-substituted (668 nm), N-substituted (699 nm), and C-substituted bilinones (706 nm).

Full text of DOI:10.1021/jo5000412

Article
pubs.acs.org/joc
Nucleophilic Ring Opening of meso-Substituted 5‑Oxaporphyrin by
Oxygen, Nitrogen, Sulfur, and Carbon Nucleophiles
Kazuhisa Kakeya, Masakatsu Aozasa, Tadashi Mizutani,* Yutaka Hitomi, and Masahito Kodera
Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, and Center for Nanoscience Research,
Doshisha University, Kyotanabe, Kyoto 610-0321, Japan
S
* Supporting Information
ABSTRACT: Nucleophilic ring opening of 23H-[21,23-
didehydro-10,15,20-tris(4-methoxycarbonylphenyl)-5-
oxaporphyrinato](trifluoroacetato)zinc(II) with various nucle-
ophiles such as alkoxide, amine, thiolate, and enolate gave 19-
substituted bilinone zinc complexes, and they were isolated as
free base bilinones. An X-ray crystallographic study demon-
strated that the product of 5-oxaporphyrin with sodium
methoxide was 21H,23H-(4Z,9Z,15Z)-1,21-dihydro-19-me-
thoxy-5,10,15-tris(4-methoxycarbonylphenyl)bilin-1-one with
a helicoidal conformation. The structure of the product of 5-
oxaporphyrin with an enolate of ethyl acetoacetate was 21H,22H,24H-(4Z,9Z,15Z,19E)-19-(1-ethoxycarbonyl-2-oxopropyli-
dene)-5,10,15-tris(4-methoxycarbonylphenyl)-1,19,21,24-tetrahydrobilin-1-one, with three inner NH groups. The product with
SH− was also the same tautomer, 21H,22H,24H-19-thioxo-bilin-1-one, with three NH groups, while the products with RO−,
RNH2, and RS− nucleophiles were 21H,23H-bilin-1-ones with two inner NH groups. The first-order rate constants of the ring
opening reaction of 5-oxaporphyrin with 1 M BnOH and BnSH in toluene at 303 K were 3.0 × 10−4 and 6.1 × 10−4 s−1,
respectively. The ratio of the rate of alcohol to thiol was much higher than that with methyl iodide, suggesting that 5-
oxaporphyrin reacted as a hard electrophile in comparison to methyl iodide. UV−visible spectra of 19-substituted bilinones in
CHCl3 at 298 K showed that the absorption maximum of the lower energy band was red-shifted in increasing order of O-
substituted (645 nm), S-substituted (668 nm), N-substituted (699 nm), and C-substituted bilinones (706 nm).
ization of copper,13 cobalt,14 and iron complexes15 of
INTRODUCTION
■
bilindiones, although bilindione metal complexes are unstable
Linear tetrapyrroles1 are found in nature as the prosthetic
in air. Biliverdin has antivirus activity16 and antioxidant
group of photoreceptor proteins,2 antenna pigments in
action;17 thus, biliverdin not only is an intermediate of heme
photosynthesis,3 and intermediates of heme and chlorophyll
catabolism.4,5 They are π-conjugated dye molecules, and
catabolism but also is applicable to biomaterials and photonic
and electronic materials.
There are two approaches to synthesize linear tetrapyrroles.
absorption maxima are shifted by Z−E isomerization and
intermolecular hydrogen bonding. Upon irradiation of light,
One is chemical oxidation such as coupled oxidation of iron
photochemical Z−E isomerization at the C−D methine linkage
porphyrin18,19 and cobalt porphyrin,14,20 where a reaction
occurs, inducing a hydrogen-bonding rearrangement and
structural changes in the apoprotein.2,6,7 When Z−E isomer-
proceeds analogously to that catalyzed by heme oxygenase, and
the other is stepwise connection of pyrrole units, suitable for
ization occurs, the structure of the photoreceptor protein
the preparation of unsymmetrical linear tetrapyrroles such as
around bilindione is changed through hydrogen bonding
natural biliverdin.21
between the NH proton of bilindione and the apoprotein.8
In addition, the extended π-electron system and the flexible
framework of linear tetrapyrroles have been used as a chirality
sensor9 and an active layer of a molecular switch.10 Bilindione
has helical chirality, and there is dynamic interconversion
between enantiomers.9a,b,11 The dynamic chiral framework was
employed as an element of the chirality amplification
supramolecular system9d,e,12 and as a dopant inducing a chiral
nematic phase in liquid crystals.9f We previously reported that
triarylbilindiones showed solvatochromism through hydrogen
bonding with aprotic amines and amides.6 There have been
several investigations of metal complexes of bilindiones. Ribo’s
and Balch’s groups reported the preparation and character-
There is considerable interest in bilinones bearing a
substituent at the 19-position. Krautler and co-workers and
̈
Tanaka and co-workers demonstrated that 19-formylbilinone is
one of the catabolites of chlorophyll, and elucidation of their
biological roles has just started.22 Bilinones substituted at the
19-position with alkoxy or amino groups have been synthesized
by a ring-opening reaction of 5-oxaporphyrin metal complexes
with alkoxides or amines.23,24 For example, reactions of 5-
oxaporphyrins with various nucleophiles such as alcohol,
Received: January 8, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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a
Scheme 1. Synthesis of 19-Substituted Bilinones 3−10
a
Reagents: (a) Ac2O, Zn(OAc)2, ethanol-free CHCl3, reflux; (b) 0.1% TFA; (c) corresponding nucleophiles; (d) 1 M HCl.
Figure 1. COSY, NOE, and HMBC correlations of bilinones 5 and 8.
alkoxide, amine, and thiolate afforded 19-substituted bili-
nones.24−28 Bilinones can also be obtained by oxidative ring-
cleavage reactions of porphyrins.29 Fuhrhop and co-workers
reported that photooxidation of a β-octaethylporphyrin
magnesium complex gave a 19-formylbilinone magnesium
complex.29 Smith, Cavaleiro, and Latos-Grazynski independ-
ently reported that the magnesium, cadmium, and thallium
complexes of tetraphenylporphyrin, its dianion, or N-confused
tetraphenylporphyrin dianion were photochemically oxidized to
give 19-benzoyl-15-alkoxybilin-1-one.30−32 We previously re-
ported that coupled oxidation of the tetraarylporphyrin iron
complex with dioxygen, ascorbic acid, and pyridine gave
1,15,21,24-tetrahydro-19-benzoyl-15-hydroxybilinone (biladie-
none) as the major product.19 1,15,21,24-Tetrahydro-19-
benzoyl-15-hydroxybilinone was converted to 1,21-dihydro-
19-benzoylbilinone by using acetic acid or mesoporous
silica.19,33 The metal complex of bilinone was more stable
than that of bilindione in protic solvents, and the zinc, cobalt,
and iron complexes of bilinone were reported by Balch and
others.9b,24,27,28
We reported that meso-substituted bilindione reacted with
acetic anhydride and zinc acetate in CHCl3 to give the meso-
substituted 5-oxaporphyrin zinc complex, and it was labile
toward nucleophiles; a solution of meso-substituted 5-
oxaporphyrin in alcohols readily afforded a ring-opened
bilinone at room temperature.24 We report herein that the
ring-opening reactions of meso-tetrakis(methoxycarbonyl-
phenyl)-5-oxaporphyrin with various nucleophiles such as
nitrogen, oxygen, sulfur, and carbon nucleophiles give 19-
substituted bilinones. Tautomeric structures and π-conjugated
electronic structures can be controlled by the substituent
introduced at the 19-position.
RESULTS AND DISCUSSION
■
Synthesis of 19-Substituted Bilinones. meso-Triarylbi-
lindione 1 was prepared from [meso-tetrakis(methoxycarbonyl-
phenyl)porphyrinato]iron(III) chloride by a coupled oxidation
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reaction.19b The meso-substituted 5-oxaporphyrin zinc complex
2 was synthesized in quantitative yield from 1 (Scheme 1).24
19-Substituted bilinones were synthesized from 5-oxaporphyrin
2 by ring-opening reactions with various nucleophiles. Acidic
workup with 1 M HCl afforded the free base bilinones 3−10.
The preparation and characterization of bilindione 1 and 19-
methoxybilinone 3 were reported elsewhere in detail.19b,24
19-Aminobilinone 5 was prepared by the reaction of 2 with
ammonia. The MALDI-TOF mass spectrum of 5 showed a
peak at m/z 731 (M+, M = C43H33N5O7). In the 1H NMR, the
resonances of pyrrole β-protons of bilinone 5 appeared at 6.09,
6.27, 6.40, 6.45, 6.57, 6.85−6.87 (two overlapped doublets),
and 7.05 ppm, the phenyl ortho protons at 7.52 and 7.63−7.65
ppm, and the phenyl meta protons at 8.10−8.16 ppm.
According to the ROESY spectra, the following NOE
correlations were found: the resonances of pyrrole β-protons
at 6.45 and 7.05 ppm (H-7, H-3) with that of the ortho phenyl
protons at 7.52 ppm, the resonances of pyrrole β-protons at
6.57 and 6.85−6.87 ppm (H-8, H-12 or H-13) with that of the
ortho phenyl protons at 7.63−7.65 ppm, and the resonances of
pyrrole β-protons at 6.40 and 6.85−6.87 ppm (H-17 and H-12
or H-13) with that of the ortho phenyl proton at 7.63−7.65
ppm. On the basis of these ROESY correlations, we identified
that bilinone 5 was the 4Z,9Z,15Z geometric isomer (Figure
Figure 2. Tautomeric structures of 19-substituted bilinones.
1
1a). The broad signal at 4.57 ppm (2H) in the H NMR and
or SH stretching in the IR spectra. The resonance of C-19 in
the 13C NMR of 8 appeared at 188.6 ppm, shifted downfield
about 20 ppm in comparison to C-1 or C-19 of 5. The chemical
shift of the CS carbon in 2(1H)-pyridinethione was 180
ppm,36 similar to that of 19-C of 8. Therefore, the tautomeric
equilibrium of 19-surfanylbilinone 8 was shifted to the
the broad peak at 3323 cm−1 in the IR spectrum indicated that
bilinone 5 has an amino group.
The product 8 ring-opened with NaSH was characterized
with 1D and 2D NMR and MALDI-TOF mass spectroscopic
studies. The MALDI-TOF mass spectrum of 8 showed a peak
1
at m/z 748 (M+, M = C43H32N4O7S). In the H NMR, the
1
thioamide form. According to the H NMR, however, the
resonances of pyrrole β-protons of bilinone 8 appeared at 6.08,
6.66, 6.72, 6.82, 7.04−7.06 (two overlapped doublets), 7.16,
and 7.25 ppm, the phenyl ortho protons at 7.50, 7.63, and 7.74
ppm, and the phenyl meta protons at 8.10, 8.13, and 8.22 ppm.
According to the ROESY spectra, following ROESY
correlations were found: the resonances of pyrrole β-protons
at 6.66 and 7.15 ppm (H-7, H-3) with that of the ortho phenyl
protons at 7.50 ppm, the resonances of pyrrole β-protons at
6.82 and 7.04−7.06 ppm (H-12, H-8 or H-13) with that of the
ortho phenyl protons at 7.71 ppm, and the resonances of
pyrrole β-protons at 7.04−7.06 and 7.25 ppm (H-8 or H-13
and H-17) with that of the ortho phenyl protons at 7.71 ppm.
These ROESY correlations suggested that bilinone 8 was the
4Z,9Z,15Z geometric isomer (Figure 1b). The resonance of the
SH proton was not found; alternatively, the resonances of three
NH protons of bilinone 8 appeared at 8.47, 11.63, and 12.17
ppm. The IR spectrum showed that there was no SH stretching
peak. Therefore, 8 was identified as 19-thioxobilin-1-one.
For the ring-opened products with OH−, NH3, and SH−,
there are several tautomers, such as lactam−lactim tautomers,
imine−enamine tautomers, and iminothiol−aminothione tau-
tomers.34 Tautomeric equilibria of bilinones 1, 5, and 8 are
shown in Figure 2. 19-Hydroxybilinone is unstable, and the
tautomeric equilibrium is shifted to bilindione. Generally, the
imine tautomer is more stable than the enamine tautomer,
although 2-aminopyridine is more stable than 2(1H)-
pyridineimine.35 The framework of the enamine in 19-
aminobilinone 5 is similar to that of 2-aminopyridine. 1H
NMR and IR spectra indicated that 19-aminobilinone 5 had an
amino group. Thus, the tautomeric equilibrium of 19-
aminobilinone 5 was shifted to the enamine form. 19-
resonances of other tautomers were also observed and the
signal integration indicates that the fraction of the major
tautomer is about 85%. Other 19-substituted bilinones 4, 6, 7,
9, and 10 were also identified by 1D and 2D NMR and
MALDI-TOF mass spectroscopy. To summarize the tautomeric
structures, 21H,23H tautomers were formed when RO−, RNH2,
and NH3 were employed as nucleophiles (3−7, 9, and 10).
When SH− was employed (8), a mixture of 21H,23H,24H and
21H,22H,24H tautomers was formed.
X-ray Crystallographic Studies of 19-Methoxybilinone
3. Crystals of 3 were obtained by slow diffusion of cyclohexane
into a solution of 3 in dichloromethane. An ORTEP view of 3
is shown in Figure 3 and Figure S21 (Supporting Information).
The crystal structure of 3 demonstrated that it is a
ZZZ,syn,syn,syn keto-methoxy isomer with a helicoidal con-
formation, and NOESY NMR indicated that 3 took this
conformation in solution.24 The phenyl groups were tilted: the
C(pyrrole)−C(meso)−C(phenyl ipso)−C(phenyl ortho) dihe-
dral angles are 47−54°. The A and B rings were almost
coplanar, while the B−C rings and C−D rings were twisted.
The methyl group in the methoxy group at the 19-position was
under the A ring pyrrole and folded into the inside of the
bilinone framework. In the unit cell, there are two bilinone
molecules: one has a P- and the other an M-helix configuration.
Bilinone molecules with the same chirality are stacked to form a
column of helices in the crystal (see Figure S22 in the
Supporting Information). For triphenylbilindione, the NH
group of the A ring is hydrogen-bonded to the D ring carbonyl
group of the neighboring molecule, to form a linear homochiral
column.19a However, 19-methoxybilinone has no NH proton in
the D ring, and there is no hydrogen bonding with the
neighboring molecule. Therefore, 19-methoxybilinone formed a
1
Sulfanylbilinone 8 did not exhibit an SH proton in H NMR
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triphenyl-5-oxaporphyrin24 with 50 mM EtMgBr at −80 °C
gave various colored products, and we failed to isolate 19-
ethylbilinone. When 5-oxaporphyrin 2 was reacted with 20 mM
LiCCTMS, the solution turned from green to brown, and
acidic workup only gave bilindione 1.
5-Oxaporphyrin 2 reacted with the enolate monoanions of
ethyl acetoacetate, acetylacetone, and (E)-6-phenyl-5-hexene-
2,4-dione to yield enolate-appended bilinones 11−13,
respectively (Scheme 2). The MALDI-TOF mass spectrum of
11 showed a peak at 845 (M + H+, M = C49H40N4O10). In the
1H NMR, the resonances of pyrrole β-protons of bilinone 11
appeared at 6.18, 6.65, 6.70, 6.85−6.89 (two overlapped
doublets), 6.97, 7.07, and 7.48 ppm, the phenyl ortho protons
at 7.54, 7.60, and 7.77 ppm, the phenyl meta protons at 8.03,
8.12, and 8.19 ppm, and the NH protons at 8.28, 11.61, and
11.89 ppm. The resonances at 1.24 (3H), 2.00 (3H), and 4.19
(2H) ppm indicate that 11 has an ethyl acetoacetate group. The
signals at 1.24 and 4.19 ppm were assigned to the ethoxy group,
and the singlet signal at 2.00 ppm was assigned to the acetyl
group. The characteristic resonances in the 13C NMR of 11
appeared at 103.9, 166.9, 167.9, 171.1, and 195.5 ppm. In order
to identify the structure, COSY, HMBC, HMQC and ROESY
experiments were carried out. The signal at 166.9 ppm in the
13C NMR spectrum was correlated with the methyl ester
protons in the phenyl groups at 3.88−3.96 ppm in the HMBC
experiment; therefore, this signal was assigned to the ester
carbonyl carbons in the phenyl groups. The signal at 167.9 ppm
was correlated with methylene protons in the ethoxy group at
4.19 ppm in the HMBC experiment; therefore, this signal was
assigned to the ester carbonyl carbons in the ethyl acetoacetate
group. The signals at 195.5 and 103.9 ppm were correlated with
the acetyl protons at 2.00 ppm in the HMBC experiment;
therefore, the signal at 195.5 ppm was assigned to the acetyl
carbonyl carbon in the ethyl acetoacetate group and the signal
at 103.9 ppm was assigned to the methylene carbon between
the two carbonyl carbons in the ethyl acetoacetate group.
Furthermore, the HMBC experiments indicated that there was
a long-range coupling between the resonances at 6.18 and 7.07
Figure 3. ORTEP view of 19-methoxybilinone 3.
slant column in the crystal without intermolecular hydrogen
bonding. In comparison to the bilinone with alkyl substituents
at the β-positions of pyrrole,37 3 has a narrower helix with a
larger helix pitch. The distance between C5 and C15 is 7.03 Å,
longer than that of β-substituted bilinone (6.82 Å), and the
distance between the CO oxygen and the methoxy oxygen is
4.14 Å, longer than that of β-substituted bilinone (3.94 Å).
Moreover, introduction of phenyl groups at the meso positions
makes the C4−C5−C6, C9−C10−C11, and C14−C15−C16
bond angles smaller than those of β-substituted bilinone,
leading to a better spatial overlap of the terminal A, D pyrroles.
The average of the three bond angles around the meso carbons
of 3 was 122.4°, while that of β-substituted bilinone was 126.7°.
Therefore, the helical pitch of 3 is larger than that of β-
substituted bilinone.
Reaction of 5-Oxaporphyrin 2 with Carbon Nucleo-
philes. A pyrylium salt reacts with cyanide,38 Grignard
reagents,39 and enolates.39a Balch and co-workers reported
that the zinc complex of β-octaethyl-5-oxaporphyrin reacted
with tetrabutylammonium cyanide to give 19-cyanobilinone
along with dicyanobilinones such as 10,19-dicyanobilinone and
15,19-dicyanobilinone.40 We investigated the reaction of 5-
oxaporphyrin 2 with carbon nucleophiles such as a Grignard
reagent, acetylide, and enolates. The reaction of 10,15,20-
1
ppm in the H NMR and the resonance at 171.1 ppm in the
13C NMR. The signal at 171.1 ppm was assigned to the lactam
carbonyl carbon; therefore, the signals at 6.18 and 7.07 ppm
were assigned to the pyrrole β-protons at H-2 and H-3.
According to the ROESY spectra, the following NOE
correlations were found: the resonances of pyrrole β-protons
at 6.70 and 7.07 ppm (H-7, H-3) with that of the ortho phenyl
a
Scheme 2. Synthetic Route to Enolate-Appended Bilinones
a
Reagents: (a) corresponding enolates; (b) 1 M HCl.
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protons at 7.54 ppm, the resonances of pyrrole β-protons at
6.65 and 6.58−6.89 ppm (H-12, H-8 or H-17) with that of the
ortho phenyl protons at 7.60 ppm, and the resonances of
pyrrole β-protons at 6.58−6.89 and 6.97 ppm (H-8 or H-17
and H-13) with that of the ortho phenyl proton at 7.77 ppm. In
addition, the resonance of acetyl protons at 2.0 ppm showed an
NOE correlation with the resonance of phenyl protons at 7.54
ppm (5-phenylene H-2′) in the ROESY spectrum. On the basis
of these ROESY correlations, we concluded that bilinone 11
was a 4Z,9Z,15Z,19E geometric isomer. Scheme S2 (Support-
ing Information) shows possible tautomeric structures of
enolate-appended bilinone 11. The resonance of the methylene
carbon between two carbonyl groups at 104 ppm was not
correlated with any protons in the HMQC experiment;
therefore, this carbon was a quaternary carbon. At this point,
tautomers having a proton at the methylene carbon such as
(RS)-β-diketo and O-alkylated products were excluded.
Furthermore, according to the COSY experiment, the following
COSY correlations were found: the resonances of β-protons at
6.18 and 7.07 ppm (H-2 and H-3) with that of the NH proton
at 8.28 ppm, the resonances of β-protons at 6.70 and 6.85−6.89
ppm (H-7 and H-8) with that of the NH proton at 11.89 ppm,
and the resonances of β-protons at 6.85−6.89 and 7.48 ppm
(H-17 and H-18) with that of the NH proton at 11.61 ppm.
Therefore, the major tautomer of enolate-appended bilinone 11
had the structure shown in Figure 4. Molecular modeling with
ab initio B3LYP/6-31G(D) suggested that hydrogen bonding
between the acetyl group and the D ring NH stabilized the
conformation. In this conformation, the methyl group of the
acetyl group was close to the ortho proton of the 5-phenyl
1
group, consistent with the observed NOE. In the H NMR,
however, the resonances of other tautomers were also present
in a fraction of about 10%. The other 19-enolate-substituted
bilinones 12 and 13 were also identified by 1D and 2D NMR
and MALDI-TOF mass spectra. Bilinone 11 had a 1-acetyl-2-
oxopropylidene group at the 19-position. For bilinone 13, we
did not determine whether the 19E or 19Z form is the major
1
isomer, owing to the complex H NMR spectrum.
Kinetic Studies on Nucleophilic Ring Opening of
meso-Substituted 5-Oxaporphyrin. We previously reported
that meso-substituted 5-oxaporphyrins had higher reactivity
than β-substituted species: meso-substituted 5-oxaporphyrins
reacted with weak nucleophiles such as methanol, ethanol, and
2-propanol to give 19-alkoxybilinone zinc complexes, and the
rate of this nucleophilic ring-opening reaction depended on the
steric hindrance of the nucleophiles.24 We compared the rates
of the nucleophilic ring opening of 5-oxaporphyrin 2 with
various nucleophiles such as BnOH, PhOH, BnNH2, PhNH2,
BnSH, and PhSH. As a representative example, the UV−visible
spectral changes of 2 in 1 M BnOH in toluene at 30 °C are
shown in Figure 5. When 2 was dissolved in 1 M BnOH in
toluene, the absorption of 2 at 398 and 645 nm decreased and
new peaks developed at 324 and 800 nm. The spectral changes
followed a first-order kinetic equation. The first-order rate
constants of the ring-opening reaction with other nucleophiles
were also determined at a concentration of 1 M in toluene
except for BnNH2, for which a concentration of 1 mM in
toluene was employed due to its high reactivity. Table 1
Table 1. First-Order Rate Constants of Nucleophilic Ring
Opening of 5-Oxaporphyrin 2 in 1 M BnOH, BnSH, PhOH,
PhNH2, and PhSH and in 1 mM BnNH2 in Toluene at 30 °C
nucleophile
k/s−1
nucleophile
k/s−1
BnOH
BnNH2
BnSH
(3.0 0.2) × 10−4
(3.6 0.4) × 10−4
(6.1 0.6) × 10−4
PhOH
PhNH2
PhSH
(2.6 0.2) × 10−4
(1.2 0.2) × 10−3
(5.2 0.1) × 10−3
summarizes the rate constants of the nucleophilic ring-opening
reaction of 2 by BnOH, PhOH, BnNH2, PhNH2, BnSH, and
PhSH at 30 °C. The reactivity of 2 toward nucleophiles
decreases in the order BnNH2 ≫ PhSH > PhNH2 > BnSH >
Figure 4. COSY and NOE correlations of enolate-appended bilinone
11.
Figure 5. UV−visible spectral changes of 5 × 10−6 M 5-oxaporphyrin 2 in 1 M BnOH in toluene at 30 °C. Spectra were recorded every 5 min.
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BnOH > PhOH. The reaction of 2 with BnNH2 was about
1000 times faster than those for other nucleophiles. Aniline,
thiol, and alcohols reacted at a similar rate.
with phenoxide, ammonia, butylamine, aniline, sodium hydro-
gensulfide, butanethiolate, benzenethiolate, enolate anions of
ethyl acetoacetate, acetylacetone, and 6-phenyl-5-hexene-2,4-
dione to give bilinone zinc complexes, and they were isolated as
free base bilinones by acid treatment in yields ranging from 53
to 87%. An X-ray crystallographic study demonstrated that 19-
methoxybilinone 3 is a ZZZ,syn,syn,syn keto-methoxy isomer
with a helicoidal conformation. When RONa, NH3, RNH2, and
RSNa were used as nucleophiles, 21H,23H tautomers were
formed. When NaSH was used as a nucleophile, a
21H,22H,24H tautomer was formed. 1D and 2D NMR
demonstrated that enolate-appended bilinone 11 is a ZZZE,
β-diketo tautomer. 5-Oxaporphyrin 2 reacted with BnOH and
BnSH at similar rates and with BnNH2 1000 times faster. The
higher reactivity of 2 toward alcohol and amine relative to
methyl iodide suggested that 5-oxaporphyrin 2 was a hard
electrophile. UV−visible spectra of 19-substituted bilinones in
CHCl3 at 298 K showed that the higher energy band of the
absorption maximum of bilinones was red-shifted in the
increasing order of methoxybilinone 3, butylaminobilinone 6,
butylsulfanylbilinone 9, and enolate-appended bilinone 11,
while their lower energy bands were red-shifted in the
increasing order of 3, 9, 6, and 11. The absorption maximum
of enolate-appended bilinone 13 was red-shifted by 17 nm with
respect to 11. Finally, various meso-substituted bilinones having
near-infrared absorption and helicity were easily obtained in
good yields from meso-substituted 5-oxaporphyrin zinc
complexes.
Pearson and co-workers compared the rate constants of
methyl iodide with various nucleophiles.41 The ratio of the rate
constant of the reaction of methyl iodide with PhSH to that
with methanol was 50000, and the ratio of the rate constant of
reaction of methyl iodide with PhSH to that with PhNH2 was
1.2. In contrast, the ratio of the rate constant of the reaction of
2 with PhSH to that with BnOH was 16 and the ratio of the
rate constant of reaction of 2 with PhSH to that with PhNH2
was 4.3. These comparisons indicate that the reaction of 2 with
alcohol was notably faster in comparison to that for methyl
iodide. According to the HSAB theory, BnOH and BnNH2 are
hard nucleophiles and BnSH is a soft nucleophile.42 The
relatively fast reaction of 2 toward alcohols in comparison with
methyl iodide thus implies that 5-oxaporphyrin 2 is a harder
electrophile than methyl iodide. The ring-opening reaction is a
multistep reaction, much more complex than nucleophilic
substitution of methyl iodide. Nucleophilic ring opening of 5-
oxaporphyrin was proposed to proceed through a tetrahedral
intermediate initially formed by nucleophilic attack of the
nucleophiles to the carbon neighboring the oxygen atom, C4,
and it was then directly converted to a helical ring-opened zinc
complex.40,43
UV−Visible Spectra of 19-Substituted Bilinones.
Figure 6 shows the UV−visible spectra of 19-substituted
EXPERIMENTAL SECTION
■
Commercially available reagents were used as received. Chromato-
graphic separation of 19-substituted bilinones was performed using
silica gel 60N, spherical neutral with particle size 40−50 μm. The
preparations of bilindione 1, 5-oxaporphyrin 2, and 19-methoxybili-
none 3 were reported elsewhere.19b,24 Tetramethylsilane was used as
1
1
an internal standard for H and 13C NMR spectra. H NMR and 13C
1
NMR signals were assigned using H−1H COSY, ROESY, HMBC,
and HMQC spectra. High-resolution mass spectral data were obtained
from a double-focusing, magnetic sector, high-resolution mass
spectrometer. A blue needle crystal of methoxybilinone 3 was obtained
by slow diffusion of cyclohexane into a solution of 3 in dichloro-
methane. Crystal data and data collection parameters are given in
Table S1 (Supporting Information).
Figure 6. UV−visible spectra of 3 × 10−5 M 19-substituted bilinones
in CHCl3 at 25 °C.
21H,23H-(4Z,9Z,15Z)-1,21-Dihydro-5,10,15-tris(4-methoxy-
carbonylphenyl)-19-phenoxybilin-1-one (4). 5-Oxaporphyrin 2
(122 mg, 0.137 mmol) was placed in a 100 mL three-necked flask, and
dry THF (50 mL) was added. Phenol (129 mg, 1.37 mmol) and
sodium hydride (60% oil dispersion, 60 mg, 1.50 mmol) were added to
dry THF (10 mL). The phenoxide solution (2 mL) was added
dropwise to the 5-oxaporphyrin solution, and the reaction mixture was
stirred at room temperature for 5 min. Then chloroform (50 mL) was
added to the reaction mixture, the chloroform solution was washed
once with water, twice with 1 M HCl, and once again with water. The
organic layer was dried over Na2SO4. Evaporation of the solvent under
reduced pressure gave a blue-green solid. The product was purified on
silica gel chromatography using dichloromethane/acetone (10/1) as
eluent. Further purification by silica gel chromatography using
chloroform yielded 89.7 mg of 4 (81%).
bilinones in CHCl3 at 25 °C. The absorption maximum of the
higher energy band of bilinones with a 21H, 23H tautomeric
structure was red-shifted in the order of O-substituted, N-
substituted, and S-substituted, while their lower energy bands
were red-shifted in the order of O-substituted, S-substituted,
and N-substituted. Enolate-appended bilinone 11 was a
21H,22H,24H tautomer, and its tautomeric structure was
identical with that of bilindione 1. The π-conjugated system of
bilinone 11 was extended via the ethyl acetoacetate group. In
comparison to bilindione 1, the higher energy band and the
lower energy band of the UV−visible spectrum of bilinone 11
were red-shifted by 64 nm from 399 to 463 nm and by 80 nm
from 626 to 706 nm, respectively. The absorption maximum of
bilinone 13, in which the π-conjugated system was more
extended via the phenylethenyl group, was red-shifted by 17 nm
with respect to bilinone 11.
1H NMR (500 MHz, CDCl3): δ 3.95 (s, 3H; COOCH3), 3.96 (s,
3H; COOCH3), 3.97 (s, 3H; COOCH3), 6.17 (two overlapped
doublets, 2H; pyrrole H-2 and H-18), 6.32 (m, 1H; pyrrole H-12 or
H-13), 6.38 (m, 1H; pyrrole H-12 or H-13), 6.41 (d, J = 4.60 Hz, 1H;
pyrrole H-7), 6.83 (three overlapped doublets, 3H; pyrrole H-3, H-8,
and H-17), 7.05 (m, 1H; phenyl), 7.15 (m, 4H; phenyl), 7.34 (d, J =
8.45 Hz, 2H; 5-phenylene H-2′), 7.60 (d, J = 8.45 Hz, 2H; 10 or 15-
phenylene H-2′), 7.66 (d, J = 8.40 Hz, 2H; 10 and 15-phenylene H-
CONCLUSIONS
■
[21,23-Didehydro-10,15,20-tris(4-methoxycarbonylphenyl)-
23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) (2) reacted
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2′), 8.09 (d, J = 8.45 Hz, 2H; 5-phenylene H-3′), 8.15 (m, 4H; 10 or
15-phenylene H-3′), 10.5 (s, 1H; NH), 13.1 (s, 1H; NH). 13C NMR
(125 MHz, CDCl3): δ 52.3 (COOCH3), 52.4 (COOCH3), 117.7,
118.5 (pyrrole C-2 or C-8), 120.0 (phenoxy), 120.3 (pyrrole C-12 or
C-13), 123.0 (pyrrole C-12 or C-13), 125.0 (phenoxy), 125.4 (pyrrole
C-2 or C-18), 128.3 (pyrrole C-7), 129.06, 129.11, 129.3 (phenoxy),
129.7, 130.4, 131.0, 131.3, 131.4, 132.1, 132.2, 135.0 (pyrrole C-3 or
C-8 or C-17), 136.8 (pyrrole C-3 or C-8 or C-17), 137.5 (pyrrole C-11
or C-14), 137.9 (pyrrole C-3 or C-8 or C-17), 138.3, 140.6 (pyrrole C-
11 or C-14), 141.1, 141.2, 142.0, 142.3 (pyrrole C-4 or C-16), 148.3
(pyrrole C-4 or C-16), 152.6 (phenoxy), 154.1 (pyrrole C-9), 166.6
(COOCH3), 166.8 (COOCH3), 167.9 (pyrrole C-6), 170.9 (pyrrole
C-1), 174.6 (pyrrole C-19). MS (MALDI-TOF): m/z 809 [M + H]+.
HRMS (FAB): calcd for C49H36O8N4 m/z 808.2533, found 808.2551.
UV−vis (CHCl3, 25 °C): λmax (εmax) 328 (3.84 × 104), 409 (5.05 ×
104), 651 nm (1.52 × 104 M−1 cm−1).
21H,23H-(4Z,9Z,15Z)-19-Amino-1,21-dihydro-5,10,15-tris(4-
methoxycarbonylphenyl)bilin-1-one (5). 5-Oxaporphyrin 2 (25.0
mg, 0.0280 mmol) was placed in a 200 mL three-necked flask. Dry
acetone (60 mL) was added, and NH3 gas was bubbled at room
temperature for 5 min. NH3 gas was generated by heating 28%
ammonia solution. Then chloroform (50 mL) was added to the
reaction mixture, and the chloroform solution was washed twice with
water, once with 1 M HCl, once with saturated aqueous sodium
hydrogen carbonate, and once with brine. The organic layer was dried
over Na2SO4. Evaporation of the solvent under reduced pressure gave
a green solid. The product was purified by silica gel chromatography
using chloroform as eluent to yield 16.0 mg of 5 (78%).
166.97, 167.03, 167.1, 169.9, 170.7. MS (MALDI-TOF): m/z 788 [M
+ H]+. HRMS (FAB): calcd for C47H42O7N5 m/z 788.3054, found
788.3084. UV−vis (CHCl3, 25 °C): λmax (εmax) 336 (3.72 × 104), 420
(4.21 × 104), 699 nm (1.67 × 104 M−1 cm−1).
21H,23H-(4Z,9Z,15Z)-1,21-Dihydro-5,10,15-tris(4-methoxy-
carbonylphenyl)-19-N-phenylaminobilin-1-one (7). 5-Oxapor-
phyrin 2 (27.0 mg, 0.0303 mmol) was placed in a 200 mL three-
necked flask, and dry dichloromethane (100 mL) was added. Distilled
aniline (9.15 mL, 0.100 mol) was added into the three-necked flask,
and the reaction mixture was refluxed for 10 h. After it was cooled to
room temperature, the reaction mixture was washed twice with 1 M
HCl and twice with brine. The organic layer was dried over Na2SO4.
Evaporation of the solvent under reduced pressure gave a green solid.
The product was purified by silica gel chromatography using
chloroform/acetone (17/3) as eluent. Further purification by silica
gel column chromatography using chloroform yielded 20.8 mg of 7
(85%).
1H NMR (500 MHz, CDCl3): δ 3.97 (three overlapped singlets,
9H; COOCH3), 6.07 (d, J = 5.70 Hz, 1H), 6.42 (three overlapped
doublets, 2H), 6.50 (d, J = 4.60 Hz 1H), 6.56 (d, J = 4.00 Hz, 1H),
6.85 (d, J = 5.70 Hz, 1H), 6.91 (three overlapped doublets, 3H), 7.05
(m, 2H), 7.12 (m, 4H), 7.68 (m, 4H), 8.01 (d, J = 8.00 Hz, 2H), 8.14
(m, 4H), 9.89 (s, 1H; NH), 13.0 (s, 1H; NH). 13C NMR (125 MHz,
CDCl3): δ 52.26, 52.30, 52.4, 117.9, 119.2, 119.4, 123.4, 124.3, 124.6,
126.0, 127.7, 128.8, 129.0, 129.12, 129.16, 129.6, 129.9, 131, 131.5,
131.6, 132.4, 134.2, 136.4, 136.6, 137.8, 138.1, 139.1, 140.5, 141.3,
142.0, 142.5, 142.8, 151.5, 164.4, 165.7, 166.68, 166.77, 166.90, 170.2.
MS (MALDI-TOF): m/z 808.0 [M + H]+. HRMS (FAB): calcd for
C49H38O7N5 m/z 808.2766, found 808.2766. UV−vis (CHCl3, 25 °C):
λmax (εmax) 366 (4.09 × 104), 433 (4.46 × 104), 706 nm (1.23 × 104
M−1 cm−1).
(21H,23H,24H)-(4Z,9Z,15Z)-5,10,15-Tris(4-methoxycarbonyl-
phenyl)-19-thioxo-1,19,21,24-tetrahydrobilin-1-one (8). 5-Ox-
aporphyrin 2 (25.0 mg, 0.0280 mmol) was placed in a 200 mL three-
necked flask, and acetone (100 mL) was added. An aqueous solution
of 2.6 M of sodium hydrogen sulfide (200 μL) was added to the
solution of 2, and the reaction mixture was stirred at room
temperature for 30 s. Then chloroform (50 mL) was added to the
reaction mixture, and the chloroform solution was washed with 1 M
HCl and with brine. The organic layer was dried over Na2SO4.
Evaporation of the solvent under reduced pressure gave a green solid.
The product was purified by silica gel chromatography using
chloroform as eluent. Thioxobilinone eluted in the latter fraction
was further purified by silica gel column chromatography using
dichloromethane/methanol (30/1). The thioxobilinone fraction was
further purified by preparative silica gel TLC using dichloromethane/
ethyl acetate (20/1) to yield 11.3 mg (54%) of 8.
1H NMR (500 MHz, CDCl3): δ 3.96−3.98 (three overlapped
singlets, 9H; COOCH3), 4.57 (s, 2H; NH2), 6.09 (d, J = 5.75 Hz, 1H;
pyrrole H-2), 6.27 (d, J = 4.60 Hz, 1H; pyrrole H-18), 6.40 (d, J = 4.00
Hz, 1H; pyrrole H-13), 6.45 (d, J = 4.00 Hz, 1H; pyrrole H-7), 6.57 (s,
1H; pyrrole H-12), 6.85−6.87 (two overlapped doublets, 2H; pyrrole
H-8 and H-17), 7.05 (d, J = 5.75 Hz, 1H; pyrrole H-3), 7.52 (d, J =
8.05 Hz, 2H; 5-phenylene H-2′), 7.63−7.65 (two overlapped doublets,
2H; 10,15-phenylene H-2′), 8.10−8.16 (three overlapped doublets,
6H; 5,10,15-phenylene H-3′), 9.89 (s, 1H; NH), 13.16 ppm (s, 1H;
NH). 13C NMR (125 MHz, CDCl3): δ 52.1 (COOCH3), 52.2
(COOCH3), 118.1, 118.8 (pyrrole C-13), 121.2 (pyrrole C-18), 124.4
(pyrrole C-12), 124.7 (pyrrole C-2), 127.0 (pyrrole C-7), 128.8, 128.9,
129.4, 129.7, 129.8, 130.7, 131.4, 132.0, 134.4 (pyrrole C-8), 135.7,
136.1 (pyrrole C-3), 138.5, 138.7 (pyrrole C-17), 139.7 (pyrrole C-4),
141.4, 141.7, 142.4, 143.2, 151.0 (pyrrole C-9), 153.3 (pyrrole C-16),
165.2 (pyrrole C-6), 166.6 (COOCH3), 166.8 (COOCH3), 167.6
(pyrrole C-19), 170.6 (pyrrole C-1). MS (MALDI-TOF): m/z 731
[M]+. HRMS (FAB): calcd for C43H33O7N5 m/z 731.2380, found
731.2398. UV−vis (CHCl3, 25 °C): λmax (εmax) 331 (3.57 × 104), 408
(4.51 × 104), 673 nm (1.59 × 104 M−1 cm−1). IR (KBr): 3323, 2950,
2883, 1716, 1697, 1635, 1427, 1278, 1114, 962 cm−1.
21H,23H-(4Z,9Z,15Z)-19-N-Butylamino-1,21-dihydro-
5,10,15-tris(4-methoxycarbonylphenyl)bilin-1-one (6). 5-Oxa-
porphyrin 2 (26.2 mg, 0.0293 mmol) was placed in a 200 mL three-
necked flask, and dry dichloromethane (100 mL) was added.
Butylamine (1 mL) was added into the three-necked flask, and the
reaction mixture was stirred at room temperature for 2 h. Then the
dichloromethane solution was washed with 1 M HCl and with brine.
The organic layer was dried over K2CO3. Evaporation of the solvent
under reduced pressure gave a green solid. The product was purified
by silica gel chromatography using chloroform as eluent to yield 20.1
mg of 6 (87%).
1H NMR (500 MHz, CDCl3): δ 3.92 (s, 3H; COOCH3), 3.95 (s,
3H; COOCH3), 4.00 (s, 3H; COOCH3), 6.08 (d, J = 5.20 Hz, 1H;
pyrrole H-2), 6.66 (d, J = 4.60 Hz, 1H; pyrrole H-7), 6.72 (d, J = 5.15
Hz, 1H; pyrrole H-18), 6.82 (d, J = 4.60 Hz, 1H; pyrrole H-12), 7.04−
7.06 (two overlapped doublets, 2H; pyrrole H-8 and H-13), 7.16 (d, J
= 5.20 Hz, 1H; pyrrole H-3), 7.26 (1H; pyrrole H-17, overlapped with
CHCl3), 7.51 (d, J = 8.00 Hz, 2H; 5-phenylene H-2′), 7.64 (d, J = 8.00
Hz, 2H; 10-phenylene H-2′), 7.74 (d, J = 8.60 Hz, 2H; 15-phenylene
H-2′), 8.10 (d, J = 8.00 Hz, 2H; 5-phenylene H-3′), 8.14 (d, J = 8.00
Hz, 2H; 10-phenylene H-3′), 8.23 (d, J = 8.60 Hz, 2H; 15-phenylene
H-3′), 11.05 (s, 1H; NH). 13C NMR (125 MHz, CDCl3): δ 52.3
(COOCH3), 52.4 (COOCH3), 117.3, 118.2 (pyrrole C-13), 123.25
(pyrrole C-2 or C-17), 123.31 (pyrrole C-2 or C-17), 124.6 (pyrrole
C-12), 126.7, 129.4, 129.5, 129.6, 130.2, 130.4, 130.5, 130.6, 131.2,
131.8, 132.1 (pyrrole C-8), 134.4 (pyrrole C-17), 136.2, 138.1 (pyrrole
C-3 or C-4), 138.2 (pyrrole C-3 or C-4), 140.6, 141.1, 142.9 (pyrrole
C-9), 144.1(pyrrole C-16), 145.1 (pyrrole C-11 or C-14), 152.0
(pyrrole C-6), 152.9(pyrrole C-14), 166.5 (COOCH3), 166.6
(COOCH3), 170.6 (pyrrole C-1), 188.6 (pyrrole C-19). MS
(MALDI-TOF): m/z 749 [M + H]+. HRMS (FAB): calcd for
C43H33O7N4S m/z 749.2070, found 749.2059. UV−vis (CHCl3, 25
°C): λmax (εmax) 332 (2.78 × 104), 360 (3.34 × 104), 444 (4.75 × 104),
1H NMR (500 MHz, acetone-d6): δ 0.71 (t, J = 6.85 Hz, 3H), 1.12
(q, J = 6.85 Hz, 2H), 1.40 (m, 2H), 3.23 (bm, 1H), 3.94−3.95 (m,
9H), 6.13 (d, J = 5.70 Hz, 1H), 6.31 (d, J = 4.60 Hz, 1H), 6.36 (s, 1H),
6.54 (d, J = 4.00 Hz, 1H), 6.61 (bs, 1H), 6.74 (d, J = 4.55 Hz, 1H),
6.87 (d, J = 4.60 Hz, 1H), 6.98 (bs, 1H), 7.04 (d, J = 5.70 Hz, 1H),
7.57−7.75 (m, 6H), 8.11−8.18 (m, 6H), 10.38 (s, 1H; NH), 13.62 (s,
1H). 13C NMR (125 MHz, acetone-d6): δ 13.9, 20.7, 32.3, 43.0, 52.49,
52.56, 52.64, 117.4, 118.1, 121.1, 124.2, 125.3, 125.8, 127.5, 129.7,
129.9, 130.2, 130.5, 130.6, 131.9, 132.5, 133.3, 134.5, 135.8, 137.6,
138.1, 139.2, 142.4, 142.6, 143.6, 143.7, 145.1, 151.9, 156.0, 166.0,
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676 nm (1.62 × 104 M−1 cm−1). IR (KBr): 3124, 2954, 2881, 1722,
1608, 1540, 1508, 1435, 1278, 1191, 1145, 1113, 966 cm−1.
4), 152.8 (pyrrole C-16), 152.9 (pyrrole C-9), 166.7 (COOCH3),
166.8 (COOCH3), 168.0 (pyrrole C-6), 170.8 (pyrrole C-1), 173.5
(pyrrole C-19). MS (MALDI-TOF): m/z 825 [M + H]+. HRMS
(FAB): calcd for C49H37O7N4S m/z 825.2377, found 825.2389. UV−
vis (CHCl3, 25 °C): λmax (εmax) 342 (3.74 × 104), 430 (5.47 × 104),
667 nm (1.23 × 104 M−1 cm−1).
21H,22H,24H-(4Z,9Z,15Z,19E)-19-(1-Ethoxycarbonyl-2-oxo-
propylidene)-5,10,15-tris(4-methoxycarbonylphenyl)-
1,19,21,24-tetrahydrobilin-1-one (11). 5-Oxaporphyrin 2 (30.4
mg, 0.0341 mmol) was placed in a 100 mL three-necked flask, and dry
THF (20 mL) was added. Ethyl acetoacetate (100 μL, 0.785 mmol)
and sodium hydride (60% oil dispersion, 33.3 mg, 0.833 mmol) were
added to dry THF (1 mL). The enolate suspension was added
dropwise to the 5-oxaporphyrin solution, and the reaction mixture was
stirred at room temperature for 10 min. Then chloroform (50 mL)
was added to the reaction mixture, and the chloroform solution was
washed with 1 M HCl and with water. The organic layer was dried
over Na2SO4. Evaporation of the solvent under reduced pressure gave
a green solid. The product was purified by silica gel chromatography
using chloroform as eluent to yield 18.7 mg of 11 (66%).
21H,23H-(4Z,9Z,15Z)-19-Butylsulfanyl-1,21-dihydro-5,10,15-
tris(4-methoxycarbonylphenyl)bilin-1-one (9). 5-Oxaporphyrin 2
(25.2 mg, 0.0283 mmol) was placed in a 100 mL three-necked flask,
and dry dichloromethane (20 mL) was added. Butanethiol (30 μL,
0.274 mmol) and sodium hydride (60% oil dispersion, 40 mg, 1.00
mmol) were added to dry THF (10 mL). The thiolate solution (2 mL)
was added dropwise to the 5-oxaporphyrin solution, and the reaction
mixture was stirred at room temperature for 1 min. Then the
dichloromethane solution was washed with water, with 1 M HCl, and
with brine. The organic layer was dried over Na2SO4. Evaporation of
the solvent under reduced pressure gave a green solid. The product
was purified on silica gel chromatography using chloroform as eluent
to yield 14.3 mg of 9 (63%).
1H NMR (500 MHz, CDCl3): δ 0.62 (t, J = 7.60 Hz, 3H; CH3),
0.99 (septet, J = 7.60 Hz, 2H; CH2), 1.37 (sextet, J = 7.60 Hz, 2H;
CH2), 2.57 (bs, 2H; SCH2), 3.98−3.99 (three overlapped singlets, 9H;
COOCH3), 6.09 (d, J = 5.50 Hz, 1H; pyrrole H-2), 6.52 (d, J = 4.80
Hz, 1H; pyrrole H-18), 6.53 (m, 1H; pyrrole H-13), 6.59 (m, 1H;
pyrrole H-12), 6.65 (d, J = 4.80 Hz, 1H; pyrrole H-7), 6.95 (d, J = 4.80
Hz, 1H; pyrrole H-17), 6.98 (d, J = 4.80 Hz, 1H; pyrrole H-8), 7.04
(d, J = 5.50 Hz, 1H; pyrrole H-3), 7.53 (d, J = 8.25 Hz, 2H; 5-
phenylene H-2′), 7.68 (d, J = 8.95 Hz, 2H; 10-phenylene H-2′), 7.72
(d, J = 8.25 Hz, 2H; 15-phenylene H-2′), 8.15−8.18 (m, 6H; 5,10,15-
phenylene H-3′), 9.63 (s, 1H; NH), 12.51 (s, 1H; NH). 13C NMR
(125 MHz, CDCl3): δ 13.3 (CH3), 22.2 (CH2), 30.7 (CH2) 31.2
(SCH2), 52.31 (COOCH3), 52.37 (COOCH3), 52.42 (COOCH3),
116.8, 120.6 (pyrrole C-13), 123.7 (pyrrole C-12), 124.9 (pyrrole C-
2), 126.9 (pyrrole C-18), 128.3 (pyrrole C-7), 129.09, 129.12, 129.5,
129.9, 130.3, 131.1, 131.6, 132.5, 135.0 (pyrrole C-8), 136.4 (pyrrole
C-17), 136.8 (pyrrole C-3), 137.4, 137.5 (pyrrole C-11 or C-14),
141.1, 141.3, 141.6 (pyrrole C-11 or C-14), 142.3 (pyrrole C-4), 152.2
(pyrrole C-9), 152.9 (pyrrole C-16), 166.6 (COOCH3), 166.7
(COOCH3), 166.8 (COOCH3), 167.0 (pyrrole C-6), 170.1 (pyrrole
C-1), 172.7 (pyrrole C-19). MS (MALDI-TOF): m/z 805 [M + H]+.
HRMS (FAB): calcd for C47H41O7N4S m/z 805.2696, found 805.2721.
UV−vis (CHCl3, 25 °C): λmax (εmax) 346 (3.45 × 104), 427 (4.17 ×
104), 668 nm (1.07 × 104 M−1 cm−1).
21H,23H-(4Z,9Z,15Z)-1,21-Dihydro-5,10,15-tris(4-methoxy-
carbonylphenyl)-19-phenylsulfanylbilin-1-one (10). 5-Oxapor-
phyrin 2 (25.2 mg, 0.0283 mmol) was placed in a 100 mL three-
necked flask, and dry dichloromethane (20 mL) was added.
Thiophenol (28.8 μL, 0.281 mmol) and sodium hydride (60% oil
dispersion, 40 mg, 1.00 mmol) were added to dry THF (10 mL). The
thiolate solution (8 mL) was added dropwise to the 5-oxaporphyrin
solution, and the reaction mixture was stirred at room temperature for
5 min. Then the dichloromethane solution was washed twice with
water, twice with 1 M HCl, and once with water. The organic layer was
dried over Na2SO4. Evaporation of the solvent under reduced pressure
gave a green solid. The product was purified by silica gel
chromatography using chloroform as eluent. Further purification by
preparative silica gel TLC using dichloromethane/ethyl acetate (40/1)
yielded 12.5 mg of 10 (53%).
1H NMR (500 MHz, acetone-d6): δ 1.24 (t, J = 6.90 Hz, 3H; CH3),
2.00 (s, 3H; COCH3), 3.88 (s, 3H; COOCH3), 3.93 (s, 3H;
COOCH3), 3.96 (s, 3H; COOCH3), 4.19 (q, J = 6.90 Hz, 3H;
COOCH2), 6.18 (d, J = 5.40 Hz, 1H; pyrrole H-2), 6.65 (d, J = 4.30
Hz, 1H; pyrrole H-12), 6.69−6.71 (m, 1H; pyrrole H-7), 6.85−6.89
(two overlapped doublets, 2H; pyrrole H-8 and H-17), 6.97 (d, J =
4.350 Hz, 1H; pyrrole H-13), 7.07 (d, J = 5.40 Hz, 1H; pyrrole H-3),
7.48 (d, J = 5.75 Hz, 1H; pyrrole H-18), 7.54 (d, J = 8.60 Hz, 2H; 5-
phenylene H-2′), 7.60 (d, J = 8.60 Hz, 2H; 10-phenylene H-2′), 7.77
(d, J = 8.60 Hz, 2H; 15-phenylene H-2′), 8.03 (d, J = 8.60 Hz, 2H; 5-
phenylene H-3′), 8.12 (d, J = 8.60 Hz, 2H; 10-phenylene H-3′), 8.19
(d, J = 8.60 Hz, 2H; 15-phenylene H-3′), 8.28 (s, 1H; NH), 11.61 (s,
1H; NH), 11.89 (s, 1H; NH). 13C NMR (125 MHz, acetone-d6): δ
14.6 (CH3), 31.0 (COCH3), 52.5 (COOCH3), 52.6 (COOCH3), 60.8
(COOCH2), 103.9 (methylene), 116.6, 120.7 (pyrrole C-7), 122.5,
124.2 (pyrrole C-2), 127.2 (pyrrole C-8 and C12), 129.8, 129.9, 130.0,
130.9 (pyrrole C-18), 131.0, 131.8, 132.6 (pyrrole C-17), 132.8, 133.3,
134.2 (pyrrole C-13), 137.9, 138.2 (pyrrole C-3), 138.8 (pyrrole C-6
or C-9), 139.7 (pyrrole C-4), 142.5, 142.6, 143.0 (pyrrole C-16), 146.4
(pyrrole C-6 or C-9), 150.4 (pyrrole C-11), 157.8 (pyrrole C-19),
161.2 (pyrrole C-14), 166.9 (COOCH3), 167.9 (COOCH2), 171.1
(pyrrole C-1), 195.5 (COCH3). MS (MALDI-TOF): m/z 845 [M +
H]+. HRMS (FAB): calcd for C49H41O10N4 m/z 845.2823, found
845.2824. UV−vis (CHCl3, 25 °C): λmax (εmax) 371 (4.19 × 104), 463
(4.82 × 104), 706 nm (1.75 × 104 M−1 cm−1).
21H,22H,24H-(4Z,9Z,15Z)-19-(1-Acetyl-2-oxopropylidene)-
5,10,15-tris(4-methoxycarbonylphenyl)-1,19,21,24-tetrahy-
drobilin-1-one (12). 5-Oxaporphyrin 2 (20.7 mg, 0.0232 mmol) was
placed in a 100 mL three-necked flask, and dry THF (20 mL) was
added. Acetylacetone (100 μL, 0.984 mmol) and sodium hydride (60%
oil dispersion, 40 mg, 1.00 mmol) were added to dry THF (1 mL).
The enolate suspension was added dropwise to the 5-oxaporphyrin
solution, and the reaction mixture was stirred at room temperature for
10 min. Then chloroform (50 mL) was added to the reaction mixture,
and the chloroform solution was washed with 1 M HCl and then with
water. The organic layer was dried over Na2SO4. Evaporation of the
solvent under reduced pressure gave a green solid. The product was
purified by silica gel chromatography using chloroform as eluent to
yield 12.3 mg of 12 (65%).
1H NMR (500 MHz, CDCl3): δ 3.96−3.98 (three overlapped
singlets, 9H; COOCH3), 6.11−6.13 (two overlapped doublets, 2H;
pyrrole H-2 and H-18), 6.52−6.54 (two overlapped doublets, 2H;
pyrrole H-7 and H-13), 6.57 (d, J = 3.45 Hz, 1H), 6.85 (d, J = 4.15 Hz,
1H; pyrrole H-17), 6.94 (d, J = 4.15 Hz; pyrrole H-8), 7.09 (d, J = 6.20
Hz, 1H; pyrrole H-3), 7.38−7.47 (m, 3H; phenyl), 7.43 (d, J = 7.60
Hz, 2H; phenyl), 7.54 (d, J = 8.25 Hz, 2H; 15-phenylene H-2′), 7.67
(d, J = 8.25 Hz, 2H; 10-phenylene H-2′), 7.69 (d, J = 8.25 Hz, 2H; 5-
phenylene H-2′), 8.12−8.16 (m, 6H; 5,10,15-phenylene H-3′), 9.79 (s,
1H; NH), 12.76 (s, 1H; NH). 13C NMR (125 MHz, chloroform-d): δ
52.3 (COOCH3), 52.4 (COOCH3), 117.8, 121.4 (pyrrole C-7 or C-
13), 123.1 (pyrrole C-12), 124.8 (pyrrole C-18), 125.2 (pyrrole C-2),
128.8 (pyrrole C-7 or C-13), 129.07, 129.10, 129.2, 129.5, 129.8,
130.3, 130.4, 131.0, 131.4, 131.5, 131.7, 132.3, 134.4, 135.2 (pyrrole C-
8), 135.8 (pyrrole C-17), 137.2 (pyrrole C-3), 138.2 (pyrrole C-11 or
C-14), 140.5 (pyrrole C-11 or C-14), 141.3, 141.6, 142.3 (pyrrole C-
1H NMR (500 MHz, acetone-d6): δ 1.99 (s, 3H; COCH3), 2.34 (s,
3H; COCH3), 3.93 (s, 3H; COOCH3), 3.95 (s, 3H; COOCH3), 3.96
(s, 3H; COOCH3), 6.19 (d, J = 5.70 Hz, 1H; pyrrole H-2), 6.61 (d, J =
4.60 Hz, 1H; pyrrole H-12), 6.68−6.71 (m, 1H; pyrrole H-7), 6.84−
6.89 (two overlapped doublets, 2H; pyrrole H-8 and H-17), 6.94 (d, J
= 4.60 Hz, 1H; pyrrole H-13), 7.11 (d, J = 5.75 Hz, 1H; pyrrole H-3),
7.19 (d, J = 5.70 Hz, 1H; pyrrole H-18), 7.55 (d, J = 8.60 Hz, 2H; 5-
phenylene H-2′), 7.60 (d, J = 8.60 Hz, 2H; 10-phenylene H-2′), 7.77
(d, J = 8.60 Hz, 2H; 15-phenylene H-2′), 8.04 (d, J = 8.60 Hz, 2H; 5-
phenylene H-3′), 8.12 (d, J = 8.60 Hz, 2H; 10-phenylene H-3′), 8.19
(d, J = 8.60 Hz, 2H; 15-phenylene H-3′), 8.47 (s, 1H; NH), 11.63 (s,
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Article
1H; NH), 12.17 (s, 1H; NH). 13C NMR (125 MHz, acetone-d6): δ
31.3 (COCH3), 52.4 (COOCH3), 52.5 (COOCH3), 115.2 (methyl-
ene), 116.7, 120.4 (pyrrole C-12), 121.9, 124.4, 126.8 (pyrrole C-8),
127.2 (pyrrole C-12), 128.9 (pyrrole C-18), 129.9, 130.0, 130.9, 131.8,
132.6, 132.7, 132.9 (pyrrole C-17), 133.2, 134.3 (pyrrole C-13), 137.8,
138.2 (pyrrole C-3), 138.7 (pyrrole C-6 or C-9), 139.5, 139.6 (pyrrole
C-4), 142.5, 143.0, 144.1 (pyrrole C-16), 146.2 (pyrrole C-6 or C-9),
150.6 (pyrrole C-11), 155.8 (pyrrole C-19), 161.9 (pyrrole C-14),
166.9 (COOCH3), 171.3 (pyrrole C-1), 194.7 (COCH3), 199.6
(COCH3). MS (MALDI-TOF): m/z 814 [M]+. HRMS (FAB): calcd
for C48H38O9N4 m/z 814.2639, found 814.2657. UV−vis (CHCl3, 25
°C): λmax (εmax) 331 (2.94 × 104), 371 (3.55 × 104), 459 (4.09 × 104),
706 nm (1.49 × 104 M−1 cm−1).
21H,22H,24H-(4Z,9Z,15Z,19E)-19-((E)-1-Acetyl-2-oxo-4-phe-
nyl-3-butenylidene)-5,10,15-tris(4-methoxycarbonylphenyl)-
1,19,21,24-tetrahydrobilin-1-one (13). 5-Oxaporphyrin 2 (25.2
mg, 0.0283 mmol) was placed in a 100 mL three-necked flask, and dry
THF (15 mL) was added. (E)-6-Phenyl-5-hexene-2,4-dione (56 mg,
0.298 mmol) and sodium hydride (60% oil dispersion, 40 mg, 1.00
mmol) were added to dry THF (5 mL). (E)-6-Phenyl-5-hexene-2,4-
dione was synthesized according to the literature.44 The enolate
suspension was added dropwise to the 5-oxaporphyrin solution, and
the reaction mixture was stirred at room temperature for 5 min. Then
chloroform (50 mL) was added to the reaction mixture, and the
chloroform solution was washed with 1 M HCl and with water. The
organic layer was dried over Na2SO4. Evaporation of the solvent under
reduced pressure gave a green solid. The product was purified by silica
gel chromatography using chloroform/acetone (20/1) as eluent.
Further purification by preparative silica gel TLC using dichloro-
methane/acetone (20/1) yielded 18.3 mg of 13 (72%).
AUTHOR INFORMATION
■
Corresponding Author
*T.M.: tel, +81-774-65-6623; fax, +81-774-65-6794; e-mail,
tmizutan@mail.doshisha.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by “Creating Research Center for
Advanced Molecular Biochemistry”, Strategic Development of
Research Infrastructure for Private Universities, the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
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1H NMR (500 MHz, CDCl3): δ 2.07 (s, 3H; COCH3), 3.92 (s, 3H;
COOCH3), 3.96 (s, 3H; COOCH3), 4.00 (s, 3H; COOCH3), 6.17
(dd, J = 5.50, 1.35 Hz, 1H; pyrrole H-2), 6.55 (d, J = 4.80 Hz, 1H;
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6.79 (d, J = 15.8 Hz, 1H; CCH), 6.87−6.88 (two overlapped
doublets, 2H; pyrrole H-8 and H-17), 6.95 (d, J = 4.80 Hz, 1H;
pyrrole H-13), 7.06 (d, J = 5.50 Hz, 1H; pyrrole H-3), 7.13 (d, J = 5.75
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Hz, 1H; CCH), 7.54 (d, J = 8.25 Hz, 2H; 5-phenylene H-2′), 7.59
(d, J = 8.25 Hz, 2H; 10-phenylene H-2′), 7.73 (d, J = 8.25 Hz, 2H; 15-
phenylene H-2′), 8.01 (d, J = 8.25 Hz, 2H; 5-phenylene H-3′), 8.13 (d,
J = 8.25 Hz, 2H; 10-phenylene H-3′), 8.21 (d, J = 8.25 Hz, 2H; 15-
phenylene H-3′), 11.36 (s, 1H; NH), 11.95 (s, 1H; NH). 13C NMR
(125 MHz, CDCl3): δ 29.9 (COCH3), 52.28 (COOCH3), 52.34
(COOCH3), 52.4 (COOCH3), 113.0, 117.4, 121.3, 122.7 (pyrrole C-
7), 123.7 (pyrrole C-2), 124.5 (pyrrole C-12), 127.5 (pyrrole C18),
128.1, 128.3, 128.5, 128.9, 129.0, 129.2 (pyrrole C-8 or C-17), 129.4,
130.21, 130.24, 130.6, 130.6, 131.0 (pyrrole C-13), 131.2, 131.7, 131.8,
132.0, 132.1, 132.4, 134.5 (pyrrole C-8 or C-17), 136.8, 137.1 (pyrrole
C-3), 137.4 (pyrrole C-4), 141.1, 141.4, 141.7, 142.7 (pyrrole C-9),
143.1 (PhCH), 145.8, (pyrrole C-10 or C-14), 151.5 (pyrrole C-6),
155.6 (pyrrole C-10 or C-14), 156.6 (pyrrole C-19), 166.53
(COOCH3), 166.56 (COOCH3), 155.60 (COOCH3), 170.0 (pyrrole
C-1), 191.7 (COCH), 194.9 (COCH3). MS (MALDI-TOF): m/z
903 [M + H]+. HRMS (FAB): calcd for C55H43O9N4 m/z 903.3030,
found 903.3039. UV−vis (CHCl3, 25 °C): λmax (εmax) = 372 (4.54 ×
104), 480 (5.18 × 104), 723 nm (2.12 × 104 M−1 cm−1).
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ASSOCIATED CONTENT
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S
* Supporting Information
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An X-ray crystallographic file for 3 in CIF format, the
1
numbering scheme of 1−13, H NMR and 13C NMR spectra
of 4−13, UV−visible spectra of 1, 4, 5, 7, 8, 10, and 12,
tautomeric structures of 11, and crystallographic data for 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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