Modification of 3-substituents in (bacterio)chlorophyll derivatives to prepare 3-ethylated, methylated, and unsubstituted (nickel) pyropheophorbides and their optical properties

Article abstract of DOI:10.1021/jo300442t

Methyl mesopyropheophorbide-a possessing an ethyl group at the 3-position, its 3¹-demethyl analogue (3-methyl homologue), and its 3 ¹-deethyl analogue (3-unsubstituted chlorin) were prepared by modifying naturally occurring (bacterio)chlorophylls bearing 3-vinyl, formyl, acetyl, and 1-hydroxyethyl groups. These synthetic 3-(un)substituted chlorophyll derivatives and their nickel complexes are probable intermediates during degradation of (bacterio)chlorophylls to chemically stable porphyrinoids. The optical properties (visible absorption, circular dichroism, and fluorescence emission) of the catabolic candidates in a solution were measured, and the substitution effect was investigated.

Full text of DOI:10.1021/jo300442t

Article
pubs.acs.org/joc
Modification of 3-Substituents in (Bacterio)Chlorophyll Derivatives to
Prepare 3-Ethylated, Methylated, and Unsubstituted (Nickel)
Pyropheophorbides and Their Optical Properties
Hitoshi Tamiaki,* Shinnosuke Machida, and Keisuke Mizutani
Department of Bioscience and Biotechnology, Faculty of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577,
Japan
*
S Supporting Information
ABSTRACT: Methyl mesopyropheophorbide-a possessing an ethyl group at the
1
1
3
-position, its 3 -demethyl analogue (3-methyl homologue), and its 3 -deethyl
analogue (3-unsubstituted chlorin) were prepared by modifying naturally
occurring (bacterio)chlorophylls bearing 3-vinyl, formyl, acetyl, and 1-
hydroxyethyl groups. These synthetic 3-(un)substituted chlorophyll derivatives
and their nickel complexes are probable intermediates during degradation of
(
(
bacterio)chlorophylls to chemically stable porphyrinoids. The optical properties
visible absorption, circular dichroism, and fluorescence emission) of the catabolic
candidates in a solution were measured, and the substitution effect was
investigated.
INTRODUCTION
for development of colorimetric chemosensors for amines and
alcohols.
As degradation products of (B)Chls, various deoxophyllo-
erythroetioporphyrins (DPEPs) were found, and nickel
■
5
Chlorophylls (Chls) are one of the most important pigments in
nature, especially in photosynthetic apparatus. Photosyntheti-
cally active chlorophylls are π-conjugated cyclic tetrapyrroles
1
complexes of DPEP homologues were identified in oil shale
possessing an exo-five-membered ring. A variety of functional
6
(
Scheme 1). Ethyl and methyl groups as well as a hydrogen
groups are found at the peripheral positions of the core π-
system, and the 3-substituents are effective in controlling their
optical and electronic properties. For example, Chl-d possessing
the 3-formyl group (see the left drawing of Figure 1, upper)
gives visible absorption maxima λmax to longer wavelengths than
did Chl-a bearing the 3-vinyl group: λmax = 661/616/430 (Chl-
a) → 686/638/446 nm (Chl-d) in diethyl ether. Since a
formyl group is more electronegative than a vinyl group, Chl-d
is reduced more easily and oxidized less readily than Chl-a: the
atom at the 3-position of Ni-DPEPs would be transformed
from the vinyl, formyl, acetyl, and 1-hydroxyethyl groups at the
3-position of naturally occurring (B)Chls. One of the
7
transformation pathways was proposed as follows. Chl-a is
modified to pyropheophorbide-a through substitution of
magnesium(II) ion at the central position with two protons
2
(
pheophytinization), removal of methoxycarbonyl group at the
3 -position (pyrolysis), and hydrolysis of phytyl ester in the
7-propionate residue. Successive reduction of the 3-vinyl and
2
1
1
1
first reduction/oxidation potentials = −1.12/0.81 (Chl-a) →
0.91/0.88 V (Chl-d) in acetonitrile vs NHE. As a result,
3
−
3-carbonyl groups, aromatization at the D-ring, decarbox-
specific cyanobacteria producing Chl-d can utilize lights in the
region at >700 nm more efficiently than conventional
cyanobacteria biosynthesizing sole Chl-a. A similar substitution
effect is observed in bacteriochlorophyll(BChl)-b possessing
the 3-acetyl group and BChl-g bearing the 3-vinyl group (see
the right drawings of Figure 1): λmax = 767/565/405/3652
2
ylation at the 17 -position, and nickel metalation affords Ni-
DPEP bearing the 3-ethyl group.
Here, we report synthesis of methyl pyropheophorbide-a
derivatives 1−3a possessing ethyl and methyl groups as well as
a hydrogen atom at the 3-position and their nickel complexes
1
−3b as models of degradation intermediates from (B)Chls
(
BChl-g) → 795/579/408/369 nm (BChl-b) in diethyl ether.
The conformation of conjugatable substituents at the 3-
position of (B)Chls affects their electronic absorption bands. In
BChl-a (see the right drawing of Figure 1, upper), typically, the
-acetyl group rotates around the C3−C3 single bond from its
coplanar position with the bacteriochlorin π-system to give a
blue-shifted absorption band. Such a regulation is clearly
(
Figure 2). Modification of the 3-substituents provides possible
pathways for (B)Chl degradation. Effects of the 3-substituents
on the optical properties of synthetic chlorophyll derivatives 1−
3 are also discussed. Investigation of catabolites of (B)Chls is
useful to elucidate mechanisms of natural photosynthesis and
create artificial photosynthetic systems. The present study
1
3
4
observed in the peripheral light-harvesting antenna systems of
purple photosynthetic bacteria. Moreover, (de)conjugation of
the 3-trifluoroacetyl group in chlorophyll derivatives is useful
Received: March 15, 2012
©
XXXX American Chemical Society
A
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Article
provides pathways from all the (B)Chls studied to the same set
of the products with 3-H, CH , or CH CH .
3
2
3
RESULTS AND DISCUSSION
Synthesis of Methyl Pyropheophorbides from Natural
B)Chls. Methyl pyropheophorbide-a (4a) was prepared by
■
(
modifying naturally occurring Chl-a extracted from a
cyanobacterium, Spirulina geitleri, which was commercially
8
available as its dry cell powder (Scheme 2, upper). Chl-a
Scheme 2. Modification of Naturally Occurring (B)Chls
was demetalated to pheophytin(Phe)-a by treatment of an acid
pheophytinization), the phytyl group in Phe-a was trans-
(
esterified to the methyl group in methyl pheophorbide-a (Phe-
a ) by sulfuric acid in cooled methanol, and the methoxy-
M
2
carbonyl moiety at the 13 -position of methyl pheophorbide-a
was removed to 4a by pyrolysis in refluxed 2,4,6-collidine.
Figure 1. Naturally occurring (bacterio)chlorophylls [(B)Chls]
possessing the 7,12-dimethyl and 8-ethyl groups as well as no
substituent at the 20-position.
8,9
BChl-g (C7HC8CHCH ) from a cultured heliobacterium,
3
10
Heliobacterium modesticaldum, was readily isomerized by
action of an acid to give farnesylated Chl-a (Chl-a ; see
Scheme 1. Degradation of Chl-a to Ni-DEPEs
F
11
Scheme 2, lower, right to center) and Phe-a (C7C8
1
2,13
CH CH ),
which were transformed to 4a similarly as
2
3
mentioned above.
Purple photosynthetic bacteria were easily cultivated in an
aqueous media, and BChl-a was extracted from cultured cells of
Rhodobacter sphaeroides, Rhodopseudomonas palustris, and so
14
on. According to the same procedures from Chl-a to 4a,
BChl-a was converted to methyl pyrobacteriopheophorbide-a,
and the resulting bacteriochlorin (7,8,17,18-tetrahydroporphy-
rin) was oxidized through 7,8-dehydrogenation to the
corresponding chlorin (17,18-dihydroporphyrin), methyl 3-
acetyl-3-devinyl-pyropheophorbide-a (8a), by 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (see also Scheme 2, lower, left to
1
5
center). Compound 8a was alternatively prepared by
modification of BChl-b from a cultured purple bacterium,
Blastochloris viridis (formerly named Rhodopseudomonas viridis).
BChl-b possessing the 8-ethylidene group was readily
demetalated (pheophytinized) and isomerized to the 3-acetyl
analogue of Phe-a by action of an acid (see also Scheme 2,
12,16
lower, right to center) as mentioned in BChl-g to Chl-aF.
The obtained product was transformed to 8a similarly as the
preparation of 4a from Phe-a.
Green sulfur bacteria gave BChl-c, -d, or -e molecules as the
Figure 2. Methyl 3-substituted pyropheophorbides-a 1−14: a for free
base and b for nickel complex.
17
pigment of their main light-harvesting antennae. A strain of
Prosthecochloris vibrioformis (formerly named Chlorobium
vibrioforme) species produced sole BChl-d homologues
B
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Article
possessing various alkylated substituents at the 8- and 12-
Pd(OH) gave no product, and 5a was recovered from the
reaction mixture. Secondary alcohol 5a was esterified with p-
toluic chloride to give the p-toluate (95%), and its trans-
2
1
8
positions. One of them is 8-ethyl-12-methyl-BChl-d ([E,M]-
BChl-d) with a farnesyl ester in the 17-propionate residue (the
left drawing of Figure 1, lower). The separated BChl-d
formation to 1a was unsuccessful under Marko
́
−Lam
deoxygenation conditions (SmI , HMPA/THF). The thio-
2
1
34
molecule as a 3 R-rich diastereomeric mixture was demetalated
and transesterified to afford methyl bacteriopheophorbide-d
carbonate obtained from 5a and PhOCSCl (97%) could not
give 1a under Barton−McCombie deoxygenation conditions
1
9
(
5a), which corresponded to methyl 3-devinyl-3-(1-
35
hydroxyethyl)pyropheophorbide-a. Compound 5a was also
(Bu SnH, AIBN/toluene). After treatment of 5a with thionyl
3
8
,20
synthesized from hydration of the 3-vinyl group in 4a as well
as selective reduction of the 3-acetyl group in 8a (Scheme
chloride, the resulting chloride 6a was hydrogenated on
Pd(OH) to give undesired decomposed products because of
2
1
5,21
22
3
8
).
Reversely, 5a was dehydrated to 4a and oxidized to
its lower chemical stability. The corresponding trifluoroacetate
7a produced from 5a (80%) was successfully reduced to 1a
2
3
a.
(
32%) after hydrogenation on Pd(OH) in acetone−THF. The
2
major isolated byproduct was 5a prepared by hydrolysis of 7a.
Scheme 3. Transformation of 3-Substituents of Methyl
a
When nickel complex 5b in acetone−THF was hydrogenated
Pyropheophorbides
in the presence of Pd(OH) at room temperature for 4 days,
2
direct reduction to 1b was apparently observed (1.7% isolated
yield), and 98% of the starting material 5b was recovered. The
success in the direct hydrogenation of nickel complex (5b →
1b) and the failure in that of free base (5a → 1a) might be
ascribable to the electron-withdrawing effect of the central
nickel.
Synthesis of Methyl 3-Devinyl-3-methyl-pyropheo-
phorbides-a (2). The 3-formyl group of 9a was selectively
3
6
27
30
reduced by NaBH , NaCNBH3, Bu NBH , and t-
4
4
4
2
8,29
BuNH BH3
to give 3-hydroxymethyl-chlorin 10a. Catalytic
hydrogenation of primary alcohol 10a gave a trace amount of
a, and almost all of 10a was recovered. The direct
2
2
hydrogenation (deoxygenation) of primary alcohol 10a but
not secondary alcohol 5a was observed, because the former was
less sterically hindered and more reactive than the latter. Similar
hydrogenation of nickel complex 10b directly afforded 2b in 5%
yield (89% recovery of 10b), which was three times larger than
that in 5b to 1b. The enhancement is due to the higher
reactivity in primary alcohol 10b than in secondary alcohol 5b.
Two other indirect hydrogenation from 10a to 2a proceeded
through chloride 11a and trifluoroacetate 12a as mentioned in
the transformation of secondary alcohol 5a: 10a → 11a (83%)
→ 2a (41%) and 10a → 12a (69%) → 2a (24%). The best way
to access 3-methyl-chlorin 2a was the two-step path through
chloride 11a, and the total yield for deoxygenation of 10a to 2a
was 34%.
a
(
i) H , Pd/C, acetone−THF; (ii) SOCl (for X = Cl), (CF CO) O
2
2
3
2
(
2
for X = OCOCF ), CH Cl ; (iii) H , Pd(OH) , acetone−THF; (iv)
3
2
2
2
2
,4,6-collidine, reflux; (v) CH N /Et O, CH Cl ; (a) hydration; (b)
2 2 2 2 2
dehydration; (c) reduction; (d) oxidation; (e) Wittig reaction; (f)
hydrolysis.
One of the cyanobacteria, Acaryochlorin marina, produced
24
Chl-d as the main chlorophyllous pigment. From its cultured
cells, Chl-d was isolated and transformed to methyl
25
pyropheophorbide-d (9a) similarly as the synthesis of 4a
from Chl-a. Compound 9a is the 3-formyl analogue of 4a,
methyl 3-devinyl-3-formyl-pyropheophorbide-a. The 3-vinyl
group of 4a was oxidatively cleaved to afford 9a possessing
the 3-formyl group by OsO −NaIO (Lemieux−Johnson
Synthesis of Methyl 3-Devinyl-pyropheophorbides-a
(3). The vinyl and formyl groups as the peripheral substituent
of ferric(III) chlorins were reported to be removed by heating
4
4
2
6−29
30
31
37
oxidation),
O (ozonolysis), and O −PhSH. The 3-
in melted resorcinol at 170−200 °C. Heating of vinyl-chlorin
3
2
formyl group was reactive with various reagents. Typically,
4a in resorcinol at a higher temperature than 200 °C gave no
Wittig reaction of the CHO of 9a with CH PPh gave 4a
desired devinyl-chlorin 3a as an isolable product. Decarbon-
2
3
30
38
bearing the 3-CHCH , and its Grignard reaction with
ylation of 3-formyl-chlorin 9a by RhCl(PPh ) in benzonitrile
3 3
2
32
CH MgI afforded 5a bearing 3-CH(OH)CH .
could not be observed. Direct removal of such vinyl and formyl
groups on free base pyropheophorbide chlorin π-systems did
not proceed under the examined conditions.
3
3
Synthesis of Methyl Mesopyropheophorbides-a (1). 3-
Ethyl-chlorin 1a has already been prepared by catalytic
hydrogenation of 4a (Scheme 3). The 3-vinyl group of 4a
was selectively hydrogenated on palladium−charcoal (Pd/C),
and acetone as the solvent was useful to avoid undesired
reduction of the 13-carbonyl group. Treatment of 4a in 1,2-
dichloroethane with nickel acetate in methanol at 80 °C gave
the corresponding nickel complex 4b. Similar hydrogenation of
9
The carboxy groups on some porphyrinoids were removed
39
by pyrolysis in resorcinol as well as biphenyl above 200 °C.
Pyrolysis of 3-carboxy-chlorin 13a was examined. Under
refluxed conditions in 1,2,4-trichlorobenzene (bp = 214 °C)
and quinoline (238 °C), 3-unsubstituted chlorin 3a could not
be detected in the reaction mixture of 13a. Pyrolysis of 13a in
refluxed 2,4,6-collidine (171−172 °C) for 4 days was
performed to successfully give 3a in 9% isolated yield. Starting
material 13a (67%) was recovered, and 3-methoxycarbonyl-
chlorin 14a (3%) was produced as the byproduct. The
formation of 14a would be ascribable to an intramolecular
4
b afforded 1b efficiently, while reduction of 4b on Raney
nickel in ethers had partially led to the additional hydro-
genation of 13-CO to 13-CH and 2C3C to 2CH−3CH.
33
2
Treatment of 3-(1-hydroxyethyl)chlorin 5a in acetone and
THF with hydrogen gas on any catalysts including Pd/C and
C
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disproportionated methylation: two 3-COOH/17 -COOCH
Article
2
2
position generally induce bathochromic shifts of Qy bands.
The substituent constants (σ ) in Hammet rule show that an
3
2
2
(
13a) → 3-COOCH /17 -COOCH (14a) + 3-COOH/17 -
3
3
p
COOH. The production of 3a was indirect transformation of
ethyl group (−0.15) is slightly more electron-withdrawing than
40
4
a/9a to 3a through 13a: 3-CHCH → 3-COOH → 3-H
a methyl group (−0.17).
2
41
and 3-CHO → 3-COOH → 3-H. It is noted that oxidation of
In a diluted dichloromethane solution, the Qy maxima of 3-
unsubstituted chlorin 3a were shifted to a longer wavelength
and/or enhanced with a larger extinction coefficient than those
of 3-alkylated chlorins 1a/2a (see Figure 3A): λmax[Qy(0,0)] =
656/655 → 659 nm and ε[Qy(0,0)] = 51 000/50 000 → 59
5
a (3-CH(OH)CH ) and 8a (3-COCH ) to 13a (3-COOH)
3
3
could not be observed under haloform reaction conditions (KI,
42
I2, NaOH/aq dioxane).
Nickel metalation of 13a to 13b smoothly proceeded under
the conditions slightly modified from the conversion of 4a to
000 M− cm for 1a/2a → 3a. Considering the lack of changes
of Qy band widths and Qx maxima, the red shifts by removal of
such alkyl groups are also ascribable to electron-donating alkyl
1
−1
4
b. In the reaction, methanol as the cosolvent must be replaced
with acetone, to exclude methyl esterification at the 3-carboxy
group of 13a. Nickel complex 13b was pyrolyzed similarly to
afford 3b (4.5%), 14b (0.5%), and 13b (79%) as isolable
compounds after purification with flash column chromatog-
raphy. The conversion yield (21%) in decarboxylation of nickel
complex 13b → 3b (based on consumed 13b) was comparable
to that in free base 13a → 3a (27%).
substituents on the molecular y-axis (the C3−C13 line): the σ -
p
value of H is 0 (see Figure S1, Supporting Information).
Compared with the Soret bands of 1a/2a, the Soret maximum
of 3a was slightly blue-shifted: λmax(Soret) = 410/410 → 408
nm for 1a/2a → 3a. It is noted that all the free bases 1−3a gave
no concentration effect for their visible spectra to be
monomeric in dichloromethane at 1 to 100 μM.
Optical Properties of Synthetic Methyl Pyropheo-
phorbides 1−3. Visible spectrum of 3-ethyl-chlorin 1a in
Circular dichroism (CD) spectra of 1−3a were measured in
dichloromethane (Figure 3B). The spectral shapes were closely
similar, and small shifts were observed as in visible absorption
spectra. Dealkylation at the 3-substituents induces a red-shift of
the CD negative peak at Qy(0,0), no shift of the positive peak
at Qx(0,0) and a blue shift of the most intense positive peak at
the Soret region. In nickel complexes 1−3b, similar substitution
effects were observed in visible and CD spectra (see Figure S2,
Supporting Information). The CD intensities of nickel chlorins
were larger than those of free bases because of the distortion of
dichloromethane gives sharp bands at λ = 656 and 410 nm
max
(black line of Figure 3A), indicating that 1a is monomeric at a
43
π-planes by insertion of nickel at the core position.
Free bases 1−3a are emissive in a diluted dichloromethane
solution. Their fluorescence emission spectra were measured by
excitation at the Soret maxima and gave almost the same shapes
(
Figure 3C). The main emission maxima λ (0,0) were shifted
em
as in Qy(0,0) maxima: λ (0,0) = 658, 657, and 660 nm for 1−
em
−1
3
a. All the Stokes shifts were small to be 40 cm , which was
similar to the values for monomeric chlorophyll derivatives (see
also Figure S1, Supporting Information). The relative
intensities of the vibronic emission band were comparable to
those of the corresponding vibronic Qy absorption bands:
I (1,0)/I (0,0) = 0.16, 0.17, and 0.14, and ε[Qy(0,1)]/
em
em
ε[Qy(0,0)] = 0.18, 0.19, and 0.16 for 1−3a. Quantum yields
and lifetimes of fluorescence emission in 1−3a gradually
increased with a decrease of steric factor in the 3-substituents
Figure 3. Visible absorption (A), circular dichroism (B), and
fluorescence emission spectra (excited at Soret maxima) (C) of
methyl 3-(un)substituted pyropheophorbides-a 1−3a in dichloro-
methane: 1a (3-CH CH , black line), 2a (3-CH , red line) and 3a (3-
(
Table 1).
2
3
3
Table 1. Quantum Yields Φ and Lifetimes τ (ns) of
Fluorescence Emission of 1−3a in Dichloromethane
H, blue line).
a
compound
Φ
τ (ns)
low concentration (ca. 10 μM). The former and latter
absorption bands are called Qy and Soret (B) bands,
respectively. Relatively less intense bands are observed between
the Qy and Soret maxima, which include two vibronic
components of the main Qy band and three vibronic Qx
bands from longer to shorter wavelengths: Qy(0,0), Qy(0,1),
Qy(0,2), Qx(0,0), Qx(0,1), and Qx(0,2) maxima are situated at
1
2
3
a (3-CH CH )
0.20
0.23
0.25
5.7
5.8
6.2
2
3
a (3-CH3)
a (3-H)
a
Excited at Soret maxima at room temperature.
3-Substituted Pyropheophorbides as Proposed Ca-
6
56, 601, ca. 550, 535, 504, ca. 470 nm. Visible spectrum of 3-
tabolites of (B)Chls. 3-Ethylated, 3-methylated, and 3-
unsubstituted porphyrins have been found in nature and are
6
methyl-chlorin 2a in dichloromethane (red line of Figure 3A) is
almost the same as that of 1a, but their close comparison shows
slightly blue shifts (<1 nm) of the maxima in all the Qy bands
by substitution of the 3-ethyl with 3-methyl groups (1a → 2a).
The small substitution effect might be explained by an electron-
withdrawing factor. Electron-withdrawing substituents at the 3-
proposed to be prepared by degradation of naturally occurring
7
(B)Chls. Most of them are metal complexes containing
nickel(II), copper(II), and oxo-vanadium(IV). There are open
questions about their degradation pathways, but pyropheo-
phorbides are probable intermediates (see Scheme 1). Most
D
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The Journal of Organic Chemistry
B)Chls are readily transformed to 3-substituted pyropheo-
Article
reported procedures. H, 13C, and 19F NMR spectra were measured at
00, 150.5, and 564.7 MHz, respectively, and COSY, NOESY, HMBC,
1
(
6
phorbides-a (M = H , R = H in Scheme 4), based on the
2
and HMQC techniques were used to assign the NMR peak. Flash
column chromatography (FCC) was perforemd on silica gel (Merck,
Kieselgel 60, 40−63 μm, 230−400 mesh). Commercially available
dichloromethane, tetrahydrofuran, acetone, methanol, and 1,2-
dichloroethane (Nacalai Tesque, extra pure reagent) were used as
the reaction solvents. Solvents for optical spectroscopy were purchased
from Nacalai Tesque as reagents prepared specially for spectroscopy
and used without further purification. All the optical properties in
Scheme 4. Proposed Degradation Pathways of Natural
(
(
B)Chls to 3-Ethylated, Methylated, and Unsubstituted
Metallo)Pyropheophorbides
4
5
solution were measured as described previously.
1
Chlorination. To 3 -hydroxychlorin 5a/10a (0.1 mmol) in
CH Cl (10 mL) was added dropwise thionyl chloride (15 μL, 0.2
2
2
mmol) at 0 °C, and the mixture was stirred at room temperature under
N2 for 1 h. The reaction was quenched with aqueous saturated
NaHCO3 solution, and the reaction mixture was extracted with
CH Cl , washed with aqueous saturated NaHCO solution, and dried
2
2
3
over Na SO . After evaporation of the solvent, the residue was purified
2
4
1
by FCC (CH Cl −Et O) to give the corresponding 3 -chlorochlorin
1a (5% Et O as an eluent). In the case of 3-(1-chloroethyl)-chlorin
a, the reaction mixture was directly distilled in vacuo, and the crude
2
2
2
1
6
2
product was used for the further reaction without purification because
of its chemical instability.
Trifluoroacetylation. To 3 -hydroxychlorin 5a/10a (0.1 mmol) in
1
CH Cl (6 mL) was added dropwise trifluoroacetic anhydride (56 μL,
2
2
0
.4 mmol) at 0 °C, and the mixture was stirred at room temperature
under N for 1 h. The reaction was quenched with aqueous saturated
2
NaHCO3 solution, and the reaction mixture was extracted with
CH Cl , washed with aqueous saturated NaHCO solution, and dried
2
2
3
over Na SO . After evaporation of the solvent, the residue was purified
2
4
by FCC (CH Cl −Et O) to give the corresponding trifluoroacetate
2
2
2
7
a/12a (5−10% Et O as an eluent).
2
Hydrogenation. To palladium(II) hydroxide (3 mg) in THF (1
1
mL) was added 3 -substituted chlorin 5−7/10−12 (50 μmol) in THF
(2 mL) and acetone (1 mL), and the mixture was stirred at room
temperature under H for 1−4 days. After removal of Pd(OH) by
2
2
filtration, the solvents were evaporated, and the residue was purified by
FCC (CH Cl −Et O) to give the corresponding 3-alkyl-chlorin 1/2 as
2
2
2
the fast-moving band (10% Et O as an eluent) and the starting
2
material as the slow-moving band.
Nickel Metalation. To free base chlorin (0.1 mmol) in 1,2-
dichloroethane (10 mL) was added a methanol solution saturated with
nickel(II) acetate tetrahydrate (5 mL), and the mixture was stirred at
8
0 °C under N for several hours. The reaction mixture was cooled
2
down to room temperature, quenched with aqueous saturated
NaHCO3 solution, extracted with CH Cl , washed with aqueous
2
2
saturated NaHCO solution, and dried over Na SO . After evaporation
3
2
4
present modification of the 3-substituents in methyl pyropheo-
of the solvents, the residue was purified by FCC (CH Cl −Et O) to
2
2
2
phorbides (M = H , Ni, R = CH in Scheme 3). It is not clear
2
3
give the corresponding nickel complex (5−15% Et O as an eluent). In
2
whether such 3-substitution takes place before or after
the case of 3-carboxy-chlorin, acetone instead of methanol was used as
the reaction cosolvent, and methanol (10%) instead of diethyl ether
was necessary for the additional FCC eluent.
1
2
metalation, 13 -deoxygenation, 17 -decarboxylation, and
7,18-dehydrogenation. The 3-vinyl groups of Chls-a/b/c/f
1
and BChl-g, the 3-formyl group of Chl-d, the 3-acetyl group of
BChls-a/b, and the 3-(1-hydroxyethyl) group of BChls-c/d/e
are altered to chemically stable 3-ethyl- and methyl-
porphyrinoids as well as their 3-unsubstituted analogues. The
reactive functional groups at the 3-position of (B)Chls are
converted into less reactive alkyl groups and hydrogen atom
during their degradation. The three types of 3-(un)substituted
pyropheophorbides are more chemically inactive and are
proposed to be catabolites of natural (B)Chls.
Decarboxylation. A solution of 3-carboxychlorin 13 (0.2 mmol)
in 2,4,6-collidine (100 mL) was stirred at 180 °C under N for 4 days.
2
The reaction mixture was cooled to 80 °C, and the solvent was
removed under a reduced pressure. The residue was dissolved in
CH Cl , washed with an aqueous 0.1 M HCl solution, and dried over
2
2
Na SO . After evaporation of the solvent, the residue was purified by
2
4
FCC (CH Cl ) to give the products as the fast-moving band (addition
2
2
of 3−5% Et O as an eluent) and the starting material 13 as the slow-
2
moving band (10% CH OH). The separated products were further
3
purified by FCC (hexane/Et O = 1:2) to afford 3-unsubstituted
2
chlorin 3 as the first fraction and 3-methoxycarbonyl-chlorin 14 as the
second.
EXPERIMENTAL SECTION
■
All the synthetic procedures were done in the dark. Nickel methyl
pyropheophorbide-a (4b), methyl bacteriopheophorbide-d (5a),
The latter methyl ester 14 obtained as a byproduct was alternatively
44
15,20
prepared as follows. To 3-carboxychlorin 13 (50 μmol) in CH
Cl (5
2 2
methyl 3-devinyl-3-hydroxymethyl-pyropheophorbide-a (10a, methyl
mL) and CH OH (5 mL) was added an excess amount of ethereal
diazomethane (10 mL), and the mixture was stirred at room
temperature for a few hours. After evaporation of the solvents, the
3
1
28
3
-demethyl-bacteriopheophorbide-d), and methyl 3-carboxy-3-
41
devinyl-pyropheophoribide-a (13a) were prepared according to
E
dx.doi.org/10.1021/jo300442t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
residue was purified by FCC (CH Cl /Et O = 95:5) to give the
respectively: mp 185−188 °C; VIS (CH Cl ) λ /nm 639 (ε, 6.0 ×
2
2
2
2
2
max
4
4
3
3
corresponding methyl ester 14.
10 ), 595 (1.1 × 10 ), 536 (4.3 × 10 ), 496 (3.3 × 10 ), 417 (5.9 ×
1
4
4
1
Methyl 3 -Trifluoroacetoxy-mesopyropheophorbide-a (7a).
Trifluoroacetylation of 5a (57 mg, 0.10 mmol) gave 7a as dark green
solid (53 mg, 80 μmol, 80%): mp 82−86 °C; VIS (CH Cl ) λmax/nm
10 ), 391 (5.1 × 10 ); H NMR (CDCl ) δ/ppm 9.25 (1H, s, 10-H),
3
8.89 (1H, s, 5-H), 8.09 (1H, s, 20-H), 4.83, 4.78 (each 1H, d, J = 19
Hz, 13 -CH ), 4.25 (1H, dq, J = 1, 7 Hz, 18-H), 3.96 (1H, ddd, J = 1,
4, 8 Hz, 17-H), 3.60 (3H, s, 17 -COOCH ), 3.61−3.50 (each 2H, m,
3-, 8-CH ), 3.46 (3H, s, 12-CH ), 3.12 (3H, s, 7-CH ), 3.02 (3H, s, 2-
1
2
2
2
2
6
65 (relative intensity, 0.50), 608 (0.07), 536 (0.08), 506 (0.09), 410
3
1
1
(
1.00), 319 (0.18); H NMR (CDCl ) δ/ppm (3 R:S = 1:1) 9.60 (1H,
3
2
3
3
1
s, 5-H), 9.55/54 (1H, s, 10-H), 8.64 /63 (1H, s, 20-H), 7.48/46 (1H,
CH ), 2.45−2.40 (1H, m, 17 -CH), 2.28−2.18 (2H, m, 17-CHCH),
2
6
3
1
1 1
q, J = 7 Hz, 3-CH), 5.28 /28 , 5.14 /14 (each 1H, d, J = 19 Hz, 13 -
2.13−2.07 (1H, m, 17-CH), 1.60 , 1.59 (each 3H, t, J = 8 Hz, 3 -, 8 -
4
2
9
8
1
8
1
CH ), 4.52 (1H, dq, J = 2, 8 Hz, 18-H), 4.34−4.31 (1H, m, 17-H),
CH ), 1.54 (3H, d, J = 7 Hz, 18-CH ) [see also the H NMR spectral
2
3
3
3
.72/71 (2H, q, J = 8 Hz, 8-CH ), 3.67/66 (3H, s, 12-CH ), 3.61 /61
data in ref 46]; MS (TOF) found m/z 606, calcd for C H N O Ni
34 36 4 3
2
3
7
4
2
+
(
3H, s, 17 -COOCH ), 3.50 /49 (3H, s, 2-CH ), 3.30/29 (3H, s, 7-
M , 606.
3
0
9
3
CH ), 2.73−2.67, 2.60−2.53, 2.33−2.23 (1H+1H+2H, m, 17-
Methyl 3-Chloromethyl-3-devinyl-pyropheophorbide-a
3
1
CH CH ), 2.38 /2.38 (3H, d, J = 7 Hz, 3 -CH ), 1.83 (3H, d, J =
(11a). Chlorination of 10a (55 mg, 0.10 mmol) gave 11a as dark
2
2
3
2
3
1
8
Hz, 18-CH ), 1.71 (3H, t, J = 8 Hz, 8 -CH ), 0.10, −1.89 (each 1H,
purple solid (47 mg, 83 μmol, 83%): mp >300 °C; VIS (CH
2
Cl
)
2
3
3
13
1
1
4
3
4
br, NH × 2); C NMR δ/ppm (3 R:S = 1:1) 196.3 (C13 ), 173.6
λmax/nm 675 (ε, 6.3 × 10 ), 616 (8.0 × 10 ), 540 (1.1 × 10 ), 511 (1.2
3
2
3
4
5
4
1
(
(
(
1
1
5
C17 ), 171.3 (C19), 160.9 (C16), 157.2 (q, J = 43 Hz, C3 ), 154.8
× 10 ), 415 (1.05 × 10 ), 321 (2.2 × 10 ); H NMR (CDCl
) δ/ppm
3
CF
C6), 151.3 (C9), 149.1 (C14), 145.3 (C8), 140.3/140.2 (C1), 138.4
C11), 136.6 (C7), 134.4 /134.4 (C3), 133.9/133.8 (C4), 133.1/
33.0 (C2), 131.0 (C13), 129.2 (C12), 114.8 (q, J = 288 Hz, C3 ),
06.7 (C15), 104.4 (C10), 97.7 (C5), 93.6 (C20), 72.4 /72.4 (C3 ),
1.9, 51.8 (C17, C17 ), 50.1 (C18), 48.2 (C13 ), 31.7/31.0, 30.9/29.9
C17 , C17 ), 23.3 , 23.3 (C3 , C18 ), 19.7 (C8 ), 17.6 (C8 ), 12.2
C12 ), 11.5 /11.5 (C2 ), 11.2 /11.2 (C7 ); F-NMR (CDCl ) δ/
ppm (3 R:S = 1:1) −73.72/73; MS (TOF) found m/z 662, calcd for
C H N O F M , 662; HRMS (FAB) m/z 663.2769, calcd for
9.55(1H, s, 10-H), 9.38 (1H, s, 5-H), 8.61 (1H, s, 20-H), 5.85 (2H, s,
1
3-CH
), 5.28, 5.14 (each 1H, d, J = 19 Hz, 13 -CH ), 4.50 (1H, dq, J =
2
6
3
2
1
4
2, 7 Hz, 18-H), 4.32 (1H, dt, J = 8, 2 Hz, 17-H), 3.71 (2H, q, J = 8 Hz,
CF
1
2
8-CH
s, 2-CH
2.54 (1H, m, 17 -CH), 2.33−2.23 (2H, m, 17-CHCH), 1.82 (3H, d, J
), 3.69 (3H, s, 12-CH
), 3.61 (3H, s, 17 -COOCH
3
), 3.43 (3H,
8
5
2
3
3
5
3
), 3.29 (3H, s, 7-CH
), 2.73−2.68 (1H, m, 17-CH), 2.59−
3
1
2
2
1
1
2
1
(
(
6 2
1
1
1
19
1
= 7 Hz, 18-CH
1H, s, NH × 2); C NMR (CDCl ) δ/ppm 196.3 (C13 ), 173.6
3
), 1.71 (3H, t, J = 8 Hz, 8 -CH ), 0.27, −1.84 (each
3 3
1
3
1
3
2
3
1
13
+
3
(C17 ), 171.4 (C19), 160.7 (C16), 155.0 (C6), 151.3 (C9), 149.0
(C14), 145.3 (C8), 141.6 (C1), 138.4 (C11), 136.5 (C7), 135.2,
3
6
37
4
5 3
+
C H N O F MH , 663.2789.
3
6
38
4
5 3
Methyl Mesopyropheophorbide-a (1a). Hydrogenation of 7a
134.4, 133.6 (C2, C3, C4), 131.0, 129.0 (C12, C13), 106.7 (C15),
5
(
(
1
1
8
33 mg, 50 μmol) gave 1a as black solid (8.8 mg, 16 μmol, 32%): VIS
104.3 (C10), 96.4 (C5), 93.7 (C20), 51.9
2
/51.8
5
(C17, C17 ), 50.0
4
3
2
1
1
2
1
CH Cl ) λ /nm 656 (ε, 5.1 × 10 ), 601 (9.3 × 10 ), 535 (1.0 ×
(C18), 48.2 (C13 ), 36.3 (C3 ), 31.0, 30.0 (C17 , C17 ), 23.3 (C18 ),
19.6 (C8 ), 17.6 (C8 ), 12.2 (C12 ), 11.4 (C7 ), 11.4 (C2 ); HRMS
(FAB) m/z 571.2472, calcd for C33H N O Cl MH , 571.2476.
2
2
max
4
4
5
4
1
2
1
1
1
0 ), 504 (1.0 × 10 ), 410 (1.21 × 10 ), 395 (9.2 × 10 ), 317 (2.4 ×
0 ); H NMR (CDCl ) δ/ppm 9.48 (1H, s, 10-H), 9.21 (1H, s, 5-H),
.45 (1H, s, 20-H), 5.24, 5.09 (each 1H, d, J = 19 Hz, 13 -CH ), 4.45
4
1
+
3
36 4 3
1
Methyl 3-Devinyl-3-trifluoroacetoxymethyl-pyropheophor-
bide-a (12a). Trifluoroacetylation of 10a (55 mg, 0.10 mmol) gave
12a as dark green solid (45 mg, 69 μmol, 69%): mp >300 °C; VIS
2
(
(
1
1H, dq, J = 2, 8 Hz, 18-H), 4.27 (1H, dt, J = 2, 9 Hz, 17-H), 3.83
2H, q, J = 8 Hz, 3-CH ), 3.69 (2H, q, J = 8 Hz, 8-CH ), 3.67 (3H, s,
2
2
2
2-CH ), 3.60 (3H, s, 17 -COOCH ), 3.29 (3H, s, 2-CH ), 3.25 (3H,
(CH
(0.09), 506 (0.10), 411 (1.00), 378 (0.60), 319 (0.19); H NMR
(CDCl ) δ/ppm 9.59 (1H, s, 10-H), 9.42 (1H, s, 5-H), 8.67 (1H, s,
20-H), 6.66 (2H, s, 3-CH
CH ), 4.53 (1H, dq, J = 2, 7 Hz, 18-H), 4.34 (1H, dt, J = 9, 2 Hz, 17-
H), 3.72 (2H, q, J = 8 Hz, 8-CH ), 3.70 (3H, s, 12-CH ), 3.61 (3H, s,
), 3.50 (3H, s, 2-CH ), 3.28 (3H, s, 7-CH ), 2.74−2.68
(1H, m, 17-CH), 2.60−2.54 (1H, m, 17 -CH), 2.34−2.25 (2H, m, 17-
2 2
Cl ) λmax/nm 668 (relative intensity, 0.55), 609 (0.07), 537
3
3
3
1
1
s, 7-CH ), 2.71−2.65 (1H, m, 17 -CH), 2.57−2.50 (1H, m, 17-CH),
3
2
.34−2.23 (2H, m, 17-CHCH), 1.80 (3H, d, J = 8 Hz, 18-CH ), 1.73
3
3
1
1
1
(
3H, t, J = 8 Hz, 3 -CH ), 1.70 (3H, t, J = 8 Hz, 8 -CH ), 0.64, −1.60
), 5.30, 5.16 (each 1H, d, J = 19 Hz, 13 -
2
3
3
1
(
each 1H, s, NH × 2) [see also the H NMR spectral data in ref 9];
2
+
MS (TOF) found m/z 550, calcd for C H N O M , 550.
2
3
34
38
4
3
2
Nickel Methyl Bacteriopheophorbide-d (5b). Nickel metal-
ation of 5a (57 mg, 0.10 mmol) gave 5b as dark green solid (54 mg, 87
μmol, 87%): mp 114−119 °C; VIS (CH Cl ) λmax/nm 642 (relative
17 -COOCH
3
3
3
1
1
CHCH), 1.82 (3H, d, J = 7 Hz, 18-CH
CH
), 1.72 (3H, t, J = 8 Hz, 8 -
2
2
3
13
intensity, 0.87), 598 (0.17), 537 (0.08), 498 (0.07), 417 (1.00), 396
3
), 0.14, −1.90 (each 1H, br, NH × 2); C NMR (CDCl ) δ/ppm
196.3 (C13 ), 173.6 (C17 ), 171.2 (C19), 160.9 (C16), 157.8 (q, JCF
= 43 Hz, C3 ), 154.9 (C6), 151.5 (C9), 149.0 (C14), 145.3 (C8),
3
1
1
1
3
2
(
0.82); H NMR (CDCl ) δ/ppm (3 R:S = 1:1) 9.40/32 (1H, s, 5-H),
3
3
9
7
4
4
3
2
1
1
.11/09 (1H, s, 10-H), 8.08/06 (1H, s, 20-H), 6.16/14 (1H, dq, J = 2,
1
Hz, 3-CH), 4.70/69, 4.61/57 (each 1H, d, J = 19 Hz, 13 -CH ),
140.2 (C1), 138.6 (C11), 136.7 (C7), 136.2 (C2), 135.3 (C3), 131.2
2
1
4
.20/18 (each 1H, dq, J = 1, 8 Hz, 18-H), 3.84 (1H, m, 17-H), 3.51/
(C12), 129.4 (C13), 129.1 (C4), 114.8 (q, JCF = 284 Hz, C3 ), 106.8
2
1
8 (2H, dq, J = 11, 8 Hz, 8-CH ), 3.63/62 (3H, s, 17 -COOCH ),
(C15), 104.3 (C10), 96.8 (C5), 94.0 (C20), 60.9 (C3 ), 52.0 (C17),
2
3
5
2
1
2
.37/36 (3H, s, 12-CH ), 3.16/13, 3.12/11 (each 3H, s, 2-, 7-CH ),
51.9 (C17 ), 50.0 (C18), 48.3 (C13 ), 31.0, 30.0 (C17 , C17 ), 23.4
3
3
1
1
1
2
1
1
1
.72/69 (1H, br, 3 -OH), 2.43−2.38, 2.27−2.21, 2.12−2.02, 2.00−
.88 (each 1H, m, 17-CH CH ), 2.06/03 (3H, d, J = 7 Hz, 3 -CH ),
.57/56 (3H, t, J = 8 Hz, 18-CH ), 1.47/45 (each 3H, d, J = 8 Hz, 8 -
(C18 ), 19.6 (C8 ), 17.6 (C8 ), 12.3 (C12 ), 11.5 (C2 ), 11.3 (C7 );
1
19
F-NMR (CDCl
) δ/ppm −73.54; MS (TOF) found m/z 648, calcd
2
2
3
3
1
+
for C H N O F M , 648; HRMS (FAB) m/z 648.2581, calcd for
3
35 35
4
5 3
13
1
3
+
CH ); C NMR (CDCl ) δ/ppm 195.7 (C13 ), 173.5 (C17 ), 162.0/
C H N O F M , 648.2560.
35 35 4 5 3
3
3
1
61.9 (C19), 156.2 /156.2 (C14), 148.5 (C16), 148.0/147.9 (C1),
44.8/144.7 (C3), 144.2 (C6), 143.7 (C8), 139.8/139.5 (C2), 139.6
Methyl 3-Devinyl-3-methyl-pyropheophorbide-a (2a). Hy-
drogenation of chloride 11a (29 mg, 50 μmol) and trifluoroacetate 12a
(32 mg, 50 μmol) gave 2a (11 mg, 21 μmol and 6.4 mg, 12 μmol) as
black solid in 41 and 24% yield, respectively: mp 237−241 °C; VIS
3
1
1
(
(
(
4
C11), 139.2 (C9), 135.0/134.6 (C4), 134.4 (C12), 133.5 /133.52
C7), 132.5 (C13), 106.3 (C10), 104.8 /104.8 (C15), 100.8/100.3
C5), 93.0/92.9 (C20), 65.8/65.5 (C3 ), 51.9 (C17 ), 49.1 (C17),
8.6/48.5 (C18), 47.1 (C13 ), 30.7, 29.8 (C17 , C17 ), 26.0/25.6
8
8
3
1
5
4
3
(CH Cl ) λ /nm 655 (ε, 5.0 × 10 ), 600 (9.6 × 10 ), 534 (1.0 ×
2 2 max
4 4 5 4
2
1
2
10 ), 503 (1.1 × 10 ), 410 (1.30 × 10 ), 394 (9.7 × 10 ), 316 (2.5 ×
2
1
1
2
4
1
(
(
C3 ), 22.3 /22.3 (C18 ), 19.5 (C8 ), 17.3 (C8 ), 12.5 /12.5
C12 ), 11.6/11.4, 11.2 (C2 , C7 ); MS (TOF) found m/z 623,
10 ); H NMR (CDCl ) δ/ppm 9.40 (1H, s, 10-H), 9.09 (1H, s, 5-H),
5
1
2
0
3
1
1
1
1
8.41 (1H, s, 20-H), 5.22, 5.08 (each 1H, d, J = 19 Hz, 13 -CH ), 4.44
2
+
calcd for C H N O Ni MH , 623; HRMS (FAB) m/z 622.2105,
calcd for C H N O Ni M , 622.2090.
(1H, dq, J = 2, 8 Hz, 18-H), 4.25 (1H, dt, J = 9, 2 Hz, 17-H), 3.64
3
4
37
4
4
+
2
(2H, q, J = 8 Hz, 8-CH ), 3.63 (3H, s, 12-CH ), 3.62 (3H, s, 17 -
34
36
4
4
2
3
Nickel Methyl Mesopyropheophorbide-a (1b). Hydrogenation
of 5b (31 mg, 50 μmol) gave 1b (0.5 mg, 0.85 mmol, 1.7%) and
starting 5b (31 mg, 49 μmol, 98%). Nickel metalation of 1a and
hydrogenation of 4b over Pd/C in acetone (by the same procedures
as in 4a to 1a) gave 1b as dark green solid in 82 and 90% yield,
COOCH ), 3.30 (3H, s, 3-CH ), 3.25 (3H, s, 2-CH ), 3.20 (3H, s, 7-
3 3 3
1
CH ), 2.71−2.65 (1H, m, 17-CH), 2.58−2.52 (1H, m, 17 -CH),
3
2.32−2.26 (2H, m, 17-CHCH), 1.80 (3H, d, J = 8 Hz, 18-CH ), 1.67
3
9
1
13
(3H, t, J = 8 Hz, 8 -CH ), 0.66, −1.57 (each 1H, br, NH × 2);
NMR (CDCl ) δ/ppm 196.4 (C13 ), 173.7 (C17 ), 172.0 (C19),
C
3
1
3
3
F
dx.doi.org/10.1021/jo300442t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(
1
59.9 (C16), 155.5 (C6), 150.5 (C9), 149.3 (C14), 145.2 (C8), 142.6
C1), 138.2 (C4), 137.5 (C11), 135.7 (C7), 135.5 (C3), 132.0 (C2),
30.2 (C12), 127.9 (C13), 105.9 (C15), 104.3 (C10), 96.0 (C5), 92.4
9 μmol, 4.5%) and 3-methoxycarbonyl-chlorin 14b (0.6 mg, 1 μmol,
0.5%) as well as starting 13b (93 mg, 150 μmol, 75%). Nickel
metalation of 3a (52 mg, 0.10 mmol) gave 3b as dark green solid (46
mg, 79 μmol, 79%): mp 157−161 °C; VIS (CH Cl ) λ /nm 640 (ε,
5
2
(
(
1
C20), 51.8 (C17 ), 51.5 (C17), 50.2 (C18), 48.1 (C13 ), 31.1, 30.0
C17 , C17 ), 23.2 (C18 ), 19.6 (C8 ), 17.6 (C8 ), 12.1 (C12 ), 11.4,
2
2
max
1
2
1
1
2
1
4
3
3
3
5.7 × 10 ), 595 (9.3 × 10 ), 539 (3.8 × 10 ), 496 (3.1 × 10 ), 417 (5.9
1
1
1
4
4
1
1.3, 11.2 (C2 , C3 , C7 ); MS (TOF) found m/z 536, calcd for
× 10 ), 393 (4.5 × 10 ); H NMR (CDCl ) δ/ppm 9.30 (1H, s, 10-
3
+
C H N O M , 536; HRMS (FAB) found m/z 536.2783, calcd for
calcd for C H N O M , 536.2787.
H), 8.90 (1H, s, 5-H), 8.41 (1H, br-q, J = 1 Hz, 3-H), 8.17 (1H, s, 20-
3
3
36
4
3
+
1
33
36
4
3
H), 4.86, 4.81 (each 1H, d, J = 19 Hz, 13 -CH ), 4.29 (1H, dq, J = 1, 7
2
2
Nickel Methyl 3-Devinyl-hydroxymethyl-pyropheophor-
Hz, 18-H), 4.00 (1H, ddd, J = 1, 5, 8 Hz, 17-H), 3.60 (3H, s, 17 -
bide-a (10b). Nickel metalation of 10a (55 mg, 0.10 mmol) gave
1
cited in ref 43.
Nickel 3-Devinyl-3-methyl-pyropheophorbide-a (2b). Hydro-
genation of 10b (30 mg, 50 μmol) gave 2b (1.5 mg, 2.5 μmol, 5%) and
starting 10b (27 mg, 45 μmol, 89%). Nickel metalation of 2a (54 mg,
COOCH ), 3.60, 3.57 (each 1H, dq, J = 14, 7 Hz, 8-CH ), 3.48 (3H, s,
3
2
0b as dark green solid (58 mg, 95 μmol, 95%): its spectral data were
1
2
2-CH ), 3.16 (3H, d, J = 1 Hz, 2-CH ), 3.11 (3H, s, 7-CH ), 2.48−
3
3
3
1
.41 (1H, m, 17 -CH), 2.30−2.20 (2H, m, 17-CHCH), 2.15−2.08
1
(1H, m, 17-CH), 1.60 (3H, t, J = 7 Hz, 8 -CH ), 1.55 (3H, d, J = 7 Hz,
3
13
1
3
1
1
1
8-CH ); C NMR (CDCl ) δ/ppm 195.7 (C13 ), 173.4 (C17 ),
3
3
62.3 (C19), 156.5 (C14), 149.1 (C1), 148.8 (C16), 144.6 (C6),
44.0 (C8), 141.8 (C4), 139.8 (C12), 139.3 (C2, C9), 134.6 (C11),
0
2
1
1
8
.10 mmol) gave 2b as dark green solid (49 mg, 83 μmol, 83%): mp
28−231 °C; VIS (CH Cl ) λ /nm 639 (ε, 5.8 × 10 ), 594 (1.1 ×
4
2
2
max
133.4 (C7), 132.9 (C13), 131.8 (C3), 106.5 (C10), 105.2 (C15),
4
3
3
4
0 ), 536 (4.3 × 10 ), 494 (3.5 × 10 ), 417 (6.1 × 10 ), 391 (5.1 ×
5
1
01.9 (C5), 93.5 (C20), 51.9 (C17 ), 49.2 (C17), 48.8 (C18), 47.4
4
1
0 ); H NMR (CDCl ) δ/ppm 9.21 (1H, s, 10-H), 8.83 (1H, s, 5-H),
2
1
2
1
1
2
3
(C13 ), 30.7, 29.9 (C17 , C17 ), 22.5 (C18 ), 19.6 (C8 ), 17.4 (C8 ),
13.6 (C2 ), 12.7 (C12 ), 11.1 (C7 ); MS (TOF) found m/z 579, calcd
for C H N O Ni MH , 579; HRMS (FAB) found m/z 579.1878,
calcd for calcd for C H N O Ni MH , 579.1901.
1
.05 (1H, s, 20-H), 4.82, 4.76 (each 1H, d, J = 19 Hz, 13 -CH ), 4.24
1
1
1
2
(
(
1H, dq, J = 1, 7 Hz, 18-H), 3.95 (1H, ddd, J = 1, 5, 6 Hz, 17-H), 3.60
3H, s, CH , 17 -COOCH ), 3.54, 3.50 (each 1H, q, J = 14, 7 Hz, 8-
+
32
33
4
3
2
+
3
3
32 33 4 3
CH ), 3.44 (3H, s, 12-CH ), 3.09, 3.08 (each 3H, s, 3-, 7-CH ), 3.00
2
3
3
Nickel Methyl 3-Devinyl-3-methoxycarbonyl-pyropheo-
phorbide-a (14b). Nickel metalation of 14a (58 mg, 0.10 mmol)
gave 14b as dark green solid (58 mg, 91 μmol, 91%), and alternatively,
methyl-esterification of 13b (31 mg, 50 μmol) gave 14b (29 mg, 46
μmol, 92%): mp 203−207 °C; VIS (CH Cl ) λmax/nm 662 (relative
1
(
3H, s, 2-CH ), 2.45−2.40 (1H, m, 17 -CH), 2.29−2.18 (2H, m, 17-
3
1
CHCH), 2.12−2.06 (1H, m, 17-CH), 1.58 (3H, t, J = 7 Hz, 8 -CH ),
1
3
1
13
1
.53 (3H, d, J = 7 Hz, 8 -CH ); C NMR δ/ppm 195.6 (C13 ), 173.5
3
3
(
C17 ), 162.7 (C19), 156.6 (C14), 149.2 (C1), 148.3 (C16), 144.9
2
2
(
C6), 144.0 (C8), 142.8 (C4), 139.4 (C9), 139.1 (C3), 138.9 (C13),
intensity 1.01), 617, (0.17), 551 (0.07), 510 (0.06), 428 (1.00), 409
1
1
35.4 (C2), 134.0 (C11), 132.9 (C7), 132.4 (C12), 106.7 (C10),
1
(
(
1
0.78), 380 (0.65); H NMR (CDCl ) δ/ppm 10.09 (1H, s, 5-H), 9.31
3
5
05.2 (C15), 98.7 (C5), 92.9 (C20), 51.8 (C17 ), 49.0 (C17), 48.9
1H, s, 10-H), 8.34 (1H, s, 20-H), 4.89, 4.81 (each 1H, d, J = 19 Hz,
3 -CH ), 4.32 (1H, dq, J = 1, 7 Hz, 18-H), 4.26 (3H, s, 3-COOCH ),
.03 (1H, ddd, J = 1, 5, 8 Hz, 17-H), 3.61 (3H, s, 17 -COOCH ), 3.58,
2
1
2
1
1
(
C18), 47.3 (C13 ), 30.7, 29.9 (C17 , C17 ), 22.3 (C18 ), 19.5 (C8 ),
1
2
3
2
1
1
1
1
1
7.4 (C8 ), 12.6 (C12 ), 11.4, 11.4, 11.0 (C2 , C3 , C7 ); MS (TOF)
2
4
3
+
found m/z 593, calcd for C H N O Ni MH , 593; HRMS (FAB)
found m/z 592.1958, calcd for C H N O Ni M , 592.1984.
33
35
4
3
3.55 (each 1H, dq, J = 15, 8 Hz, 8-CH ), 3.48 (3H, s, 12-CH ), 3.44
2
3
+
33
34
4
3
(3H, s, 2-CH ), 3.14 (3H, s, 7-CH ), 2.48−2.43, 2.32−2.27 (each 1H,
1
3
3
Methyl 3-Devinyl-pyropheophorbide-a (3a). Pyrolysis of 13a
m, 17 -CH), 2.26−2.20, 2.13−2.07 (each 1H, m, 17-CH), 1.59 (3H, t,
(
113 mg, 0.20 mmol) gave 3-unsubstituted chlorin 3a (9.4 mg, 18
1
13
J = 8 Hz, 8 -CH ), 1.54 (3H, d, J = 7 Hz, 18-CH ); C NMR
3
3
μmol, 9%) and 3-methoxycarbonyl-chlorin 14a (3.5 mg, 6 μmol, 3%)
as well as starting 13a (76 mg, 134 μmol, 67%). 3a: black solid; mp
1
3
1
(
(
CDCl ) δ/ppm 195.5 (C13 ), 173.4 (C17 ), 166.2 (C3 ), 160.8
C19), 156.2 (C14), 150.0 (C16), 145.5 (C6), 144.3 (C1), 143.85,
3
3
7
1
×
05−109 °C (lit., 172−173 °C); VIS (CH Cl ) λ /nm 659 (ε, 5.9
2
2
max
1
1
1
43.8 (C3, C8), 141.0, (C12), 140.4 (C9), 139.3 (C2), 135.9 (C11),
4
3
4
4
1
10 ), 603 (9.4 × 10 ), 535 (1.2 × 10 ), 504 (1.1 × 10 ), 408 (1.24 ×
0 ), 316 (2.6 × 10 ); H NMR (CDCl ) δ/ppm 9.49 (1H, s, 10-H),
35.4 (C7), 133.8 (C13), 128.9 (C4), 105.9 (C10), 105.4 (C15),
5
4
1
1
9
5
1
3
5
3
03.1 (C5), 94.5 (C20), 52.1 (C3 ), 51.9 (C17 ), 49.6 (C17), 48.6
.21 (1H, br-d, J = 1 Hz, 5-H), 8.71 (1H, br, 3-H), 8.54 (1H, s, 20-H),
.28, 5.13 (each 1H, d, J = 19 Hz, 13 -CH ), 4.49 (1H, dq, J = 2, 8 Hz,
8-H), 4.31 (1H, dt, J = 8, 2 Hz, 17-H), 3.67 (2H, q, J = 8 Hz, 8-
2
1
2
2
1
(C18), 47.4 (C13 ), 30.7, 29.7 (C17 , C17 ), 22.4 (C18 ), 19.5 (C8 ),
1
2
2
1
1
1
1
7.3 (C8 ), 13.6 (C2 ), 12.7 (C12 ), 11.2 (C7 ); MS (TOF) found m/
3
+
z 636, calcd for C H N O Ni M , 636; HRMS (FAB) found m/z
2
34 34
4
5
CH ), 3.66 (3H, s, 12-CH ), 3.62 (3H, s, 17 -COOCH ), 3.41 (3H,
d, J = 1 Hz, 2-CH ), 3.22 (3H, s, 7-CH ), 2.73−2.67 (1H, m, 17-CH),
2
+
2
6
3
3
6
37.1974, calcd for calcd for C H N O Ni MH , 637.1956.
34 35 4 5
3
3
1
.59−2.54 (1H, m, 17 -CH), 2.33−2.25 (2H, m, 17-CHCH), 1.82
1
(
(
1
3H, d, J = 8 Hz, 18-CH ), 1.69 (3H, t, J = 8 Hz, 8 -CH ), 0.31, −1.80
ASSOCIATED CONTENT
Supporting Information
3
3
■
13
1
each 1H, br, NH × 2); C NMR (CDCl ) δ/ppm 196.4 (C13 ),
3
3
*
S
73.7 (C17 ), 171.4 (C19), 160.2 (C16), 155.4 (C6), 150.9 (C9),
48.9 (C14), 145.1 (C8), 142.6 (C1), 138.0 (C11), 137.3 (C4), 136.1
Relation of σ with λ [Qy(0,0)] and λ (0,0) of 1−3a, visible
1
p
abs
em
13
1
(
(
5
C7), 135.7 (C2), 130.6 (C13), 128.4 (C3), 128.1 (C12), 106.1
C15), 104.0 (C10), 99.5 (C5), 93.1 (C20), 51.8 , 51.8 (C17, C17 ),
and CD spectra of 1−3b, as well as H/ C NMR spectra of 1−
3a/b and their synthetic intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
5
5
3
2
1
2
1
0.0 (C18), 48.2 (C13 ), 31.0 (C17 ), 30.4 (C17 ), 23.2 (C18 ), 19.6
1
2
1
1
1
(
C8 ), 17.6 (C8 ), 13.4 (C2 ), 12.2 (C12 ), 11.3 (C7 ); HRMS (FAB)
+
found m/z 522.2630, calcd for C H N O M , 522.2631.
32
34
4
3
AUTHOR INFORMATION
Methyl 3-Devinyl-3-methoxycarbonyl-pyropheophorbide-a
■
(14a). Methyl-esterification of 13a (28 mg, 50 μmol) gave 14a as dark
Corresponding Author
brown solid (21 mg, 36 μmol, 71%): its spectral data were cited in ref
1.
Nickel Methyl 3-Carboxy-3-devinyl-pyropheophorbide-a
13b). Nickel metalation of 13a (57 mg, 0.10 mmol) gave 13b as
*
Fax: 81-77-561-2659. E-mail: tamiaki@fc.ritsumei.ac.jp.
4
Notes
(
The authors declare no competing financial interest.
dark green solid (51 mg, 82 μmol, 82%): mp 187−192 °C; VIS
(
(
CH Cl ) λ /nm 664 (relative intensity 0.97), 618 (0.19, sh), 554,
0.09), 506 (0.08), 429 (1.00), 408 (0.80), 381 (0.71); H NMR gave
2 2 max
1
ACKNOWLEDGMENTS
■
broad peaks in usual deuterated solvents; HRMS (TOF) found m/z
6
6
+
We thank Dr. Yuichiro Kashiyama of Ritsumeikan University
for useful discussion. This work was partially supported by a
Grant-in-Aid for Scientific Research (A) (No. 22245030) from
the Japan Society for the Promotion of Science (JSPS).
22, calcd for C H N O Ni M , 622; HRMS (FAB) found m/z
33 32 4 5
+
23.1797, calcd for C H N O Ni MH , 623.1799.
33
33
4
5
Nickel Methyl 3-Devinyl-pyropheophorbide-a (3b). Pyrolysis
of 13b (125 mg, 0.20 mmol) gave 3-unsubstituted chlorin 3b (5.2 mg,
G
dx.doi.org/10.1021/jo300442t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
32) Tamiaki, H.; Shimono, Y.; Rattray, A. G. M.; Tanikaga, R.
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H
dx.doi.org/10.1021/jo300442t | J. Org. Chem. XXXX, XXX, XXX−XXX