Synthesis of 3,20-disubstituted chlorophyll-a derivatives and reactivity of the substituents

Article abstract of DOI:10.1016/j.tet.2013.07.060

Methyl 20-bromo-pyropheophorbide-a possessing a vinyl group at the 3-position and its analogs having 3-ethyl, 3-(1-hydroxyethyl) and 3-acetyl groups were prepared by modifying naturally occurring chlorophyll(Chl)-a. The 20-bromo-chlorins were cross-coupled with vinyl- and 1-ethoxyvinyl-tributyltins in the presence of a Pd(0) catalyst to afford 20-vinyl- and acetyl-chlorins, respectively. The interconversions among the above four C2-functional groups at the 3-position were readily performed in the semi-synthetic Chl derivatives, but no modification of the 20-vinyl and acetyl groups was observed. The difference of the chemical reactivity is ascribable to the steric factor: the 3 ¹-position was less sterically hindered than the 20 ¹-position. Single hydrogenation and hydration of 3,20-divinyl-chlorin and reduction of 3,20-diacetylchlorin proceeded exclusively at the 3-position. The redmost (Qy) bands in electronic absorption spectra of the semi-synthetic Chl derivatives in a diluted dichloromethane solution were controlled by the 3,20-substituents. The 3-substituent effect on their Qy maxima was determined by the electronic factor (their electronegativity), while the 20-substituent effect was primarily dependent on the steric factor (their local size).

Full text of DOI:10.1016/j.tet.2013.07.060

Tetrahedron 69 (2013) 8412e8421
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3,20-disubstituted chlorophyll-a derivatives and
reactivity of the substituents
,
a
,
,
Hitoshi Tamiaki a , Nobutaka Ariki b, Haruka Sugiyama a b, Yoshichika Taira a,
*
Yusuke Kinoshita a, Tomohiro Miyatake b
a Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
b Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2013
Received in revised form 13 July 2013
Accepted 16 July 2013
Available online 24 July 2013
Methyl 20-bromo-pyropheophorbide-a possessing a vinyl group at the 3-position and its analogs having
3-ethyl, 3-(1-hydroxyethyl) and 3-acetyl groups were prepared by modifying naturally occurring
chlorophyll(Chl)-a. The 20-bromo-chlorins were cross-coupled with vinyl- and 1-ethoxyvinyl-tribu-
tyltins in the presence of a Pd(0) catalyst to afford 20-vinyl- and acetyl-chlorins, respectively. The in-
terconversions among the above four C2-functional groups at the 3-position were readily performed in
the semi-synthetic Chl derivatives, but no modification of the 20-vinyl and acetyl groups was observed.
The difference of the chemical reactivity is ascribable to the steric factor: the 31-position was less ste-
rically hindered than the 201-position. Single hydrogenation and hydration of 3,20-divinyl-chlorin and
reduction of 3,20-diacetylchlorin proceeded exclusively at the 3-position. The redmost (Qy) bands in
electronic absorption spectra of the semi-synthetic Chl derivatives in a diluted dichloromethane solution
were controlled by the 3,20-substituents. The 3-substituent effect on their Qy maxima was determined
by the electronic factor (their electronegativity), while the 20-substituent effect was primarily dependent
on the steric factor (their local size).
Keywords:
Cross-coupling
Pyropheophorbide
Regioselectivity
Substituent effect
Visible absorption spectrum
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Naturally occurring and photosynthetically active chlorophylls
(Chls) have several substituents at the 3-position on the A-ring (see
Fig. 1). The 3-substituents are C2-functional groups except the
formyl group in Chl-d and its 132-epimer Chl-d0, and vinyl, 1-
hydroxyethyl and acetyl groups are available.1,2 At the 20-
position, one of the four meso-positions in cyclic tetrapyrroles
(porphyrinoids), which is connected with the A- and D-rings, no
substituent is usually found, and only a methyl group (C1-group)
was observed for Chls in main light-harvesting antennas of most
green photosynthetic bacteria, bacteriochlorophylls-c and e.1,2
These functional groups affect electronic absorption bands and
singlet excited energy levels,1 and are biosynthetically introduced
in phototrophs: 3-CH]CH2/CH(OH)CH3/COCH3 and 20-
H/CH3.3
Fig. 1. Molecular structures of naturally occurring chlorophylls (M¼Mg, Zn;
E¼COOCH3, H).
functional groups other than natural ones (vide supra) including
ethyl, ethynyl, 2-hydroxyethyl, 1,2-epoxyethyl, and 1,2-
dihydroxyethyl.9,10 Direct substitution at the 20-position was re-
ported and cyanation,11 formylation,12 trifluoromethylation,13
methylthiomethylation,11 nitration,11 trifluoroacetoxylation,14 and
halogenation15 were performed for 20-unsubstituted Chl de-
rivatives. Recently, palladium-catalyzed cross-coupling of 20-
bromo-chlorins with boronic acid (SuzukieMiyaura coupling)7,16,17
and acetylene reagents (Sonogashira coupling)18 afforded 20-aryl-
A variety of Chl derivatives have been prepared for photosyn-
thetic models,4 solar cells,5 photodynamic therapy,6,7 optical sen-
sors,8 and so on. Many functional groups are introduced at their 3-
position by modifying natural Chls,1 and some of them are C2-
* Corresponding author. Fax: þ81 77 561 2659; e-mail address: tamiaki@
fc.ritsumei.ac.jp (H. Tamiaki).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.060

H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
8413
and (aryl-)ethynyl-chlorins, respectively. Except for 20-ethynyl-
chlorin, no Chl derivatives possessing a C2-functional group at the
20-position are available in any literature.
Here we report on the synthesis of Chl derivatives possessing
C2-functional groups at the 3- and 20-positions: 3-ethyl, vinyl, 1-
hydroxyethyl or acetyl group, and 20-vinyl or acetyl group. The
chemical reactivities of their functional moieties in semi-synthetic
Chl derivatives were investigated. Moreover, substituent effects on
their visible absorption spectra in a solution were discussed.
route is preferable to access 2a. Secondary alcohol 2c was dehy-
drated by refluxing in dichloromethane and benzene (1:5) with p-
toluenesulfonic acid (4 equiv) for 1 h (vide supra) to give 2a (62%)
after purification by FCC. The acidic conditions resulted in un-
desired 20-debromination as well as the above dehydration.
Overreacted product 1a (20%) was obtained by the 20-
debromination of 2a and also the starting material 2c (10%) was
recovered from the reaction mixture. Therefore, the total yield of 1a
to 2a via 1c and 2c was estimated to be 50% based on the consumed
starting materials.
2. Results and discussion
The acidic debromination was observed in all the other 20-
bromo-chlorins. The similar treatment of 2b gave 1b in an excel-
lent yield after refluxing for 1 day. By the acidic hydration of 2a
(vide supra), 2c was isolated in 51% yield and 1c was also obtained
in 40% yield. A trace amount of 1a was detected in the reaction
mixture, so 20-debromination occurred before and/or after the
hydration of 2a: 2a/1a/1c and/or 2a/2c/1c. Additionally, no
debromination was found under neutral conditions. Hydrogenation
of 2a to 2b, oxidation of 2c to 2d and reduction of 2d to 2c pro-
ceeded cleanly without the 20-debromination. The isolated yields
in these transformations in 20-bromo-chlorins 2 were comparable
to those in 20-unsubstituted 1. The 20-bromo atom did not disturb
the alteration. The bromination and debromination would thus be
useful for protection of the reactive 20-position of chlorin chro-
mophores, which serves as one of the selective modification pro-
cedures in chlorophyll chemistry.
2.1. Synthesis of methyl 20-unsubstituted pyropheophorbides
1
Methyl pyropheophorbide-a (1a) possessing a reactive vinyl
group at the 3-position and no substituent at the 20-position (see
Scheme 1) was obtained by modifying naturally occurring Chl-
a.10,11 The 3-vinyl group was readily hydrogenated on palla-
diumecharcoal to give methyl mesopyropheophorbide-a (1b).10
The use of acetone as the co-solvent succeeded in reducing selec-
tively the 3-CH]CH2, but not the 13-C]O in a molecule. The 3-
vinyl group was also hydrated by addition of hydrogen bromide
and successive hydrolysis to afford methyl bacteriopheophorbide-
d (1c). As the Markovnikov adduct was initially obtained 3-
CHBrCH3, and the bromide was so reactive that it was quickly
transformed to the secondary alcohol by the action of water. Syn-
thetic secondary alcohol 1c was a 1:1 31-epimeric mixture and no
diastereomerically controlled hydration occurred.19
2.3. Synthesis of methyl 20-substituted pyropheophorbides
by Pd-catalyzed cross-coupling of 2 with Sn reagents
The 1-hydroxyethyl group at the 3-position in 1c was easily
dehydrated under acidic conditions to yield 3-vinyl-chlorin 1a.
Secondary alcohol 1c was smoothly oxidized by an N-oxide in the
presence of a ruthenium catalyst to give 3-acetyl-chlorin 1d. Al-
though 1d had two keto-carbonyl groups in a molecule, the 3-
acetyl group was more reactive than the 13-C]O and regiose-
lectively reduced by tert-butylamine borane to afford 1c (31R/
31S¼1/1) in a good yield: no stereoselectivity was observed.20 The
difference in the reactivity is due to the fact that the 13-C]O is
20-Bromo-3-ethyl-chlorin 2b was reacted with tributylvinyltin
in refluxing THF by catalytic action of tetrakis(triphenylphosphine)
palladium(0)23 to afford 20-vinyl-chlorin 3b (see Scheme 1) as the
product of Stille reaction and 20-[2-(tributylstanyl)vinyl]chlorin as
the product of Heck reaction. The products in dichloromethane
were treated with silica gel and the complete destanylation of the
Heck product occurred after refluxing overnight to give sole 3b as
the isolable product in a good yield. The similar Pd-catalyzed cross-
coupling of methyl 20-bromo-pyropheophorbides 2a/c/d success-
fully gave the corresponding 20-vinylated products 3a/c/d.
conformationally fixed and conjugated with a chlorin
more than the 3-C]O.
p-system
Under similar conditions, the reaction of 2b with tribu-
tyl(1-ethoxyvinyl)tin24 afforded 20-(1-ethoxyvinyl)chlorin (see
Scheme 2). The resulting ether in dichloromethane was cleaved by
an action of p-toluenesulfonic acid at room temperature and finally
20-acetyl-chlorin 4b was obtained through tautomerization of enol
to ketone. Similar acetylation of 3-substituted chlorins 2a/c/d oc-
curred to afford 4a/c/d. During the mild acidic treatment, no re-
actions at the 3-substituents were observed, especially no
dehydration of 4c to 4a. All coupling products 3/4aed were char-
acterized by their visible, 1H NMR and MS spectra.
2.2. Synthesis of methyl 20-bromopyropheophorbides 2
When 3-ethyl-chlorin 1b was treated with pyridinium bromide
perbromide at room temperature,16 single bromination occurred
quickly at the 20-position (see Scheme 1). The regioselectivity is
explained as follows. In a chlorin
p-system, meso-positions con-
nected with a reduced pyrrole ring are more reactive than the
others: C15/20>C5/10 in the present system. In 1b, the unsub-
stituted carbon-20 was attacked by the brominating reagent rather
than the substituted carbon-15, giving 20-bromo-3-ethyl-chlorin
2b efficiently. Similar 20-bromination of 31-hydroxy analog 1c of 1b
proceeded in an excellent yield. Under the same conditions, bro-
mination of 31-oxo analog 1d of 1b was performed regioselectively
at the 20-position and the yield was slightly lower than those of 1b
and 1c. The small suppression is due to the electron-withdrawing
2.4. Reactivity of 3,20-substituents in methyl
pyropheo-phorbides 1e4
Synthetic chlorin 3a has two vinyl groups at the 3- and 20-
acetyl group, which is directly bound with the chlorin
at the 3-position.
p
-system
positions, which are directly bound with the chlorin p-system.
Hydrogenation of 3a on PdeC in THF and acetone at room tem-
perature gave 3-ethyl-20-vinyl-chlorin 3b in a very good yield (see
Scheme 1), but neither 3-vinyl-20-ethyl-chlorin nor 3,20-diethyl-
chlorin 5b (see also the top of Scheme 3). Use of PtO2 as the catalyst
led to the sole formation of 3b as the hydrogenation product of 3a.
The regioselective reduction indicates that the 3-vinyl group is
reactive in the catalytic hydrogenation, while the 20-vinyl group is
inactive. This is in sharp contrast to the previous report that both
the 3- and 8-vinyl groups in chlorophylls were reduced to the
The similar reaction of 3-vinyl-chlorin 1a afforded a complex
mixture of brominated products,15 from which no 20-bromo-3-
vinyl-chlorin 2a could be isolated. Undesired bromination on the
3-vinyl group was observed as well as the 20-bromination. The
treatment of 1a with N-bromosuccinimide at a lower temperature
(ꢀ60 ꢁC) also gave mixed products, but 2a was successfully isolated
in a low yield by flash column chromatography (FCC) on silica gel.
The reproducibility was so low21 that the following alternative

8414
H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
Scheme 1. Synthesis of methyl 20-vinyl-pyropheophorbides 3aed from methyl pyropheophorbide-a (1a) through cross-coupling of methyl 20-bromo-pyropheophorbides 2aed:
(i) H2, PdeC/THFeacetone; (ii) HBr/AcOH (60 ꢁC), H2O, CH2N2/Et2O; (iii) MeN(O)(CH2CH2)2O, Pr4NRuO4/CH2Cl2; (iv) 4-MeC6H4SO3H∙H2O/CH2Cl2eC6H6 (reflux); (v) tBuNH2BH3/
CH2Cl2; (vi) C6H5NHþBrꢀ3 /CH2Cl2; (vii) (CH2CO)2NBr/CH2Cl2 (ꢀ60 ꢁC); (viii) CH2]CHSnBu3, Pd(PPh3)4/THF (reflux), SiO2/CH2Cl2 (reflux). The isolated yields are shown.

H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
8415
not 3,20-bis(1-hydroxyethyl)chlorin 6c (see the left of Scheme 3).
Furthermore, no hydration of 20-vinyl group in 3b to 6b could be
detected. The 3-substituents in 3a (3-CH]CH2), 3c [3-CH(OH)CH3],
and 3d (3-COCH3) were readily modified and the interconversions
among them were observed (see the right of Scheme 1), but their
20-vinyl groups were not altered in the reduction, oxidation or
hydration.
Two acetyl groups are connected with the chlorin chromophore
in 4d. 3,20-Diacetyl-chlorin 4d was reduced by tBuNH2BH3 in
dichloromethane at room temperature to give 3-(1-hydroxyethyl)-
20-acetyl-chlorin 4c in a good yield (see Scheme 2) and further
reduction to 6c could not be detected (see also the bottom of
Scheme 3). The same treatment of 3-ethyl-20-acetyl-chlorin 4b
gave no reduction product 6b and starting material 4b was re-
covered quantitatively. No reduction of the 20-acetyl group was
observed under the present conditions. The lack in reduction of the
20-acetyl group in 4 is consistent with no hydrogenation of the 20-
vinyl group in 3. Previously, the 3- and 8-acetyl groups in methyl
pyropheophorbides were reported to be reduced to the secondary
alcohols and five-fold more rapid reduction of the 3-COCH3 over 8-
COCH3 was measured in the initial stage.26 The reactivity of these
acetyl groups decreased in the order: 3-Ac>8-Ac>>20-Ac. It is
noteworthy that the 3-substituents in 4a/c/d were reactive in hy-
dration, (de)hydrogenation, oxidation, and reduction to give 4aed
without any change of the 20-acetyl group (see the right of
Scheme 2).
The 3-vinyl and acetyl groups were reactive in hydrogenation/
hydration and reduction, respectively, while the 20-vinyl and acetyl
groups were inactive. The difference in the reactivity is explained
by the steric factor.27 The 3-substituent possesses single methyl
group at the 2-position as its neighboring peripheral moiety, while
the 20-substituent is situated between the 2- and 18-methyl groups
(see Fig. 2). The sterically less hindered 3-vinyl and acetyl groups
are fairly co-planar with a chlorin
p-system, which any reagents
can attack from either side of C]C and C]O. The sterically more
crowded 20-vinyl and acetyl groups are rather perpendicular to
a chlorin
p-plane, so the p-orbitals of the carbon atom at the 20-
position were considerably protected by the two neighboring
methyl groups. As a result, neither hydrogen species nor bromide
could attack the C201 and no more modified compounds on the 20-
substituents were obtained.
To examine why there was no reactivity at the C201-position,
20-allyl-chlorin 7b was prepared from Pd-catalyzed cross-coupling
of 2b with allyl(tributyl)tin (see Scheme 4). Catalytic hydrogenation
of 7b on PdeC gave 20-propyl-chlorin 8b in a very good yield. The
C202 in 7b was less sterically crowded than the C201 in 3b, so the
former was readily attacked by a hydrogen atom. Similar reactivity
at the 202-position was also found in the following two cases: (1)
hydrolysis of 20-CH]CHeSnBu3 on silica gel and (2) acidic cleav-
age of 20-C(]CH2)eOEt. In case (1), protonation of the C202 in the
Heck product (vide supra) initially occurred, followed by an attack
of water on the tin center and 20-vinyl-chlorins 3aed were pro-
duced: 20-CH]CHeSnBu3þH2O/20-CH]CH2þHOSnBu3. In case
(2), a proton first attacked the O202 in the ethyl ether, the ethyl
cation was removed and the corresponding vinyl alcohol was
formed to isomerize to 3-acetyl-chlorins 4aed: 20-C(]CH2)e
OEtþHX/20-C(]CH2)eOH[/20-COCH3]þEtX.
Scheme 2. Synthesis of methyl 20-acetyl-pyropheophorbides 4aed by cross-coupling
of methyl 20-bromo-pyropheophorbides 2aed and their interconversion: (i) CH2]
C(OEt)SnBu3, Pd(PPh3)4/THF (reflux), 4-MeC6H4SO3H∙H2O/CH2Cl2; (ii) H2, PdeC/
THFeacetone; (iii) HBr/AcOH (60 ꢁC), H2O, CH2N2/Et2O; (iv) MeN(O)(CH2CH2)2O,
Pr4NRuO4/CH2Cl2; (v) 4-MeC6H4SO3H∙H2O/CH2Cl2eC6H6 (reflux); (vi) tBuNH2BH3/
CH2Cl2. The isolated yields are shown.
2.5. Visible absorption of methyl pyropheophorbides 1e4 in
a solution
corresponding ethyl groups with a slight regioselectivity: the 3-
vinyl was hydrogenated 1.2-fold faster than the 8-vinyl.25
The same regioselectivity was confirmed by the following hy-
dration of vinyl groups. Treatment of 3a with HBr in acetic acid and
successive H2O gave 3-(1-hydroxyethyl)-20-vinyl-chlorin 3c, but
All the synthetic chlorins 1e4 were soluble in dichloromethane
and absorbed visible lights. Their diluted dichloromethane solu-
tions showed similar electronic absorption spectra in the visible
region (see Supplementary data). As shown in Fig. 3, 1a gave one of
the intense bands at 667 nm and the peak position at the longest

8416
H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
Scheme 3. Selective modification of 3-substituents in methyl 3,20-divinyl- and diacetyl-pyropheophorbides-a (3a) and (4d) with no transformation of 20-vinyl and acetyl groups in
3/4bec: (i) H2, PdeC/THFeacetone; (ii) HBr/AcOH (60 ꢁC), H2O, CH2N2/Et2O; (iii) tBuNH2BH3/CH2Cl2.
shifted to a longer wavelength in the order of 3-ethyl (1b)<3-(1-
hydroxyethyl) (1c)<3-vinyl (1a)<3-acetyl (1d). The order is con-
sistent with the electronegativity of the 3-substituents: 2.48 (Et)<
2.60 [CH(OH)Me]<2.79 (CH]CH2)<2.86 (Ac).29 In other 20-
substituted chlorins 2e4, the same substituent effect on the Qy
maxima is observed. The Qy shift dependent on the 3-substituents
is ascribable to their electronic factor.
In 3-ethyl-chlorins nb, the Qy maxima gradually move to the red
side in the order of 20-H (1b)<20-vinyl (3b)<20-Ac (4b)<20-Br
(2b). Similar shifts are measured in other 3-substituted chlorins,
except in 2d. The order seems to be comparable to the local size of
Fig. 2. Partial molecular structure of 3,20-disubstituted chlorin.
substituents: an acetyl group is sterically bulkier than a flat vinyl
wavelength was called Qy maximum.1 The Qy band has two small
vibrational components at 610 and ca. 563 nm. The other intense
band is visible at 414 nm and is called Soret band. The Soret band
also has several vibrational components and two shoulders are
observed at around 397 and 376 nm. Between the Qy and Soret
bands, some small bands are seen and called Qx bands.
The Qy maxima of monomeric chlorins in a diluted solution are
well known to be dependent upon the 3-substituents.1,10,28 Table 1
shows the main Qy maxima of 1e4 in a diluted dichloromethane
(ca. 10ꢀ5 M). The Qy maxima of 20-unsubstituted chlorins 1 are
group and a bromo atom is globular and larger in its local size than
the other two substituents. The shift of Qy maxima dependent upon
the 20-substituents is primarily due to their steric factor. It was
reported that a large 20-substituent disturbs the chlorin
p-plane
and decreases the difference between HOMO and LUMO energy
levels, leading to a bathochromic shift of the longest wavelength
absorption bands (Qy maxima).15 The exception of 2d in the order is
explained by the fact that the 3-acetyl group is less
p-conjugated
with the chlorin moiety due to the remote steric repulsion via the
2-Me between the 3-Ac and large 20-Br.30

H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
8417
Scheme 4. Synthesis of methyl 20-propyl-mesopyropheophorbide-a (8b) by cross-coupling allylation of methyl 20-bromo-mesopyropheophorbide-a (2b) and hydrogenation of
methyl 20-allyl-mesopyropheophorbide-a (7b): (i) CH2]CHCH2SnBu3, Pd(PPh3)4/THF (reflux); (ii) H2, PdeC/THFeacetone. The isolated yields are shown.
spectra were measured with a Hitachi U-3500 spectrophotometer.
1H NMR spectra were recorded on a JEOL ECA-600 (600 MHz)
spectrometer; CHCl3
(
dH¼7.26 ppm) was used as an internal ref-
erence. Time-of-flight (TOF) mass data were obtained using direct
laser desorption/ionization by a Shimadzu AXIMA-CFR plus spec-
trometer. High resolution mass spectra were recorded on a Bruker
micrOTOF II spectrometer; electrospray ionization and positive
mode in an acetonitrile solution. FCC was performed with silica gel
(Merck, Kieselgel 60, 40e63 mm, 230e400 mesh).
All the reactions were done in the dark. Methyl pyropheo-
phorbide-a (1a) was prepared according to reported procedures.11,32
Commercially available acetone, benzene, dichloromethane, meth-
anol, and THF (Nacalai Tesque) were used as the reaction solvents.
Brominating reagents and a palladium catalyst were purchased from
Tokyo Chemical Industry. Other reaction reagents including tin
compounds were obtained from Aldrich. THF for coupling reaction
was passed through an alumina column before use.
Fig. 3. Visible absorption spectrum of 1a (ca. 10ꢀ5 M) in dichloromethane.
Table 1
Qy maxima (nm) of methyl pyropheophorbides 1e4 in dichloromethane (ca.10ꢀ5 M)
Solvents for optical spectroscopy were purchased from Nacalai
Tesque as reagents prepared specially for spectroscopy and used
without further purification.
20-Substituent
3-Substituent
CH2CH3 (b)
CH(OH)CH3 (c)
CH]CH2 (a)
COCH3 (d)
H (1)
656 (1b)
665 (3b)
667 (4b)
668 (2b)
661 (1c)
669 (3c)
671 (4c)
673 (2c)
667 (1a)
672 (3a)
676 (4a)
676 (2a)
683 (1d)
683 (3d)
687 (4d)
682 (2d)
4.2. Modification of peripheral substituents
CH]CH2 (3)
COCH3 (4)
Br (2)
4.2.1. 20-Bromination. To a dichloromethane solution (20 mL) of
methyl 20-unsubstituted pyropheophorbide 1 (0.10 mmol) was
added pyridinium bromide perbromide (42 mg, 0.13 mmol) at room
temperature. The mixture was stirred under nitrogen for about
30 min. After disappearance of the starting chlorin had been
checked by TLC, the reaction mixture was washed with aq 2% HCl
and water, dried over sodium sulfate, and filtered. All the solvent
was evaporated in vacuo and the residue was purified by FCC
(0e10% Et2O and CH2Cl2) and recrystallization (CH2Cl2 and hexane)
to give methyl 20-bromo-pyropheophorbide 2.
20-Bromination of 3-vinyl-chlorin 1a was performed using N-
bromosuccinimide (freshly purified by recrystallization from dis-
tilled water, 23 mg, 0.13 mmol) at ꢀ60 ꢁC instead of pyridinium
bromide perbromide at room temperature. After stirring for 10 min
under argon, the reaction was quenched by addition of acetone
(10 mL) at ꢀ60 ꢁC. All the solvents were evaporated at 0 ꢁC and
similar purification afforded 2a.
3. Conclusions
Palladium-catalyzed cross coupling of 3-substituted 20-bromo-
chlorins 2aed with stannyl reagents afforded the corresponding
20-vinyl- and acetyl-chlorins 3aed and 4aed. Interconversions
among their 3-substituents proceeded readily but no reactions of
20-vinyl and acetyl groups were observed. The regioselectivity was
controlled by steric crowdedness at the 31- and 201-positions.
Combination of the present results with previous data25,26 leads to
the following order in the reduction of peripheral substituents: 3-
C]C>8-C]C>>20-C]C and 3-C]O>8-C]O>13-C]O>>20-C]
O.31 Each isolated yield in some modification of 3-substituents was
largely independent of the 20-substitution (H/Br, vinyl, Ac), so
these 20-substituents did not disturb the reactivity of the 3-
substituents. Electronic effect of the 3-substituents and steric ef-
fect of the 20-substituents affected the Qy maxima of 1e4, which is
consistent with previous reports.1
4.2.2. 20-Vinylation. To a THF solution (20 mL) of methyl 20-
bromo-pyropheophorbide
tylvinyltin (44 L, 150 mol) and tetrakis(triphenylphosphine)pal-
ladium (23 mg, 20 mol) under argon. The mixture was refluxed for
2 (30 mmol) were added tribu-
m
m
4. Experimental
4.1. General
m
several hours. After the starting bromide had been consumed (TLC
analysis), the reaction mixture was cooled down to room temper-
ature and the solvent was evaporated in vacuo. The residue was
dissolved in dichloromethane (10 mL), to which silica gel (3 g,
Kieselgel 60) was added under nitrogen. The mixture was refluxed
All melting points were measured with a Yanagimoto micro
melting apparatus and were uncorrected. Visible absorption

8418
H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
overnight, cooled down, and filtered. The silica gel was washed
with dichloromethane containing methanol until the filtrate was
colorless. The combined filtrates were distilled under a reduced
pressure and the residue was purified by FCC (0e5% Et2O and
CH2Cl2) and recrystallization (CH2Cl2 and hexane) to give methyl
20-vinyl-pyropheophorbide 3.
filtered and the solvent was evaporated in vacuo. The residue was
purified by FCC (0e10% Et2O and CH2Cl2) and recrystallization
(CH2Cl2 and hexane) to give methyl 3-acetyl-pyropheophorbide
1e4d.
4.2.7. Dehydration of 1-hydroxyethyl to vinyl group. To a dichloro-
Similar 20-allylation of 2b using allyl(tributyl)tin was performed
without further treatment by silica gel to give 7b.
methane solution (5 mL) of methyl 3-(1-hydroxyethyl)pyropheo-
phorbide 1e4c (20
mmol) was added benzene (25 mL) and p-
toluenesulfonic acid monohydrate (15 mg, 80
mmol) under nitro-
4.2.3. 20-Acetylation. To a THF solution (20 mL) of methyl 20-
gen. The mixture was refluxed for several hours until the starting
alcohol was invisible on a TLC plate, cooled down, washed with
water, aq 4% NaHCO3 and water, dried over sodium sulfate, and
filtered. All the solvents were evaporated in vacuo and the residue
was purified by FCC (4e5% Et2O and CH2Cl2) and recrystallization
(CH2Cl2 and hexane) to give methyl 3-vinyl-pyropheophorbide
1e4a.
bromo-pyropheophorbide 2 (80
ethoxyvinyl)tin (270 L, 800
phosphine)palladium (46 mg, 40
m
m
m
mol) were added tributyl(1-
mol) and tetrakis(tri-phenyl-
mol). The mixture was refluxed
m
overnight under argon. After disappearance of the starting bromide
had been checked by TLC, the reaction mixture was cooled down to
room temperature and the solvent was evaporated in vacuo. The
residue was dissolved in dichloromethane (15 mL), to which p-
toluenesulfonic acid monohydrate (19 mg, 100
mmol) was added
4.2.8. Reduction of acetyl to 1-hydroxyethyl group. To a dichloro-
under nitrogen. The mixture was stirred at room temperature for
several hours until the ether was invisible on a TLC plate, washed
with water, aq 4% NaHCO3 and water, dried over sodium sulfate,
and filtered. All the solvent was evaporated in vacuo and the resi-
due was purified by FCC (0e10% Et2O or 1% MeOH and CH2Cl2) and
recrystallization (CH2Cl2 and hexane) to give methyl 20-acetyl-
pyropheophorbide 4.
methane solution (10 mL) of methyl 3-acetylpyropheophorbide
1e4d (20
mmol) was gradually added borane tert-butylamine
complex (87 mg,1 mmol) at room temperature under nitrogen with
stirring for 1 h. After disappearance of the starting acetyl-chlorin
had been checked by TLC analysis, the reaction mixture was
washed with aq 2% HCl and water, dried over sodium sulfate, and
filtered. The solvent was evaporated in vacuo and the residue was
purified by FCC (5e10% Et2O and CH2Cl2) and recrystallization
(CH2Cl2 and hexane) to give methyl 3-(1-hydroxyethyl)pyropheo-
phorbide 1e4c.
4.2.4. Hydrogenation of vinyl to ethyl group. To methyl 3-vinyl-
pyropheophorbide 1e4a (10
mmol) in a 1:1 mixture of THF and
acetone (10 mL) were added 10% palladium on charcoal (20 mg)
and the mixture was stirred for 2 h under hydrogen at room tem-
perature. After disappearance of the starting vinyl-chlorin had been
checked by TLC, the reaction mixture was filtered on Celite, the
insoluble materials were thoroughly washed with dichloro-
methane and all the solvents were evaporated in vacuo. The residue
was purified by recrystallization (CH2Cl2 and hexane) to give
methyl 3-ethyl-pyropheophorbide 1e4b.
4.3. Data of methyl 20-unsubstituted and 20-bromo-
pyro-pheophorbides 1/2aed
4.3.1. Methyl pyropheophorbide-a (1a). Black solid; mp 217e219 ꢁC
(Ref. 11); vis (CH2Cl2) lmax¼667 (relative absorbance, 0.44), 610
(0.08), 539 (0.10), 508 (0.11), 414 nm (1.00); 1H NMR (CDCl3)
d
¼9.49, 9.38, 8.55 (each 1H, s, 5-, 10-, 20-H), 8.00 (1H, dd, J¼11,
Hydrogenation of the 20-allyl to propyl group (7b/8b) was
done similarly to the above procedures.
18 Hz, 3-CH), 6.26 (1H, dd, J¼2, 18 Hz, 31-CH trans to 3-CeH), 6.16
(1H, dd, J¼2, 11 Hz, 31-CH cis to 3-CeH), 5.25, 5.19 (each 1H, d,
J¼19 Hz, 131-CH2), 4.72 (1H, q, J¼8 Hz, 18-H), 4.21 (1H, br-d,
J¼8 Hz, 17-H), 3.69 (2H, q, J¼8 Hz, 8-CH2), 3.67, 3.62, 3.41, 3.24
(each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3), 2.70e2.56, 2.40e2.29
(each 2H, m, 17-CH2CH2), 1.82 (3H, d, J¼8 Hz, 18-CH3), 1.69 (3H, t,
J¼8 Hz, 81-CH3), 0.46, ꢀ1.69 (each 1H, s, NH ꢂ2); MS (LDI-TOF)
found: m/z¼548. Calcd for C34H36N4O3: Mþ, 548. See also Ref. 11
for its spectral data.
4.2.5. Hydration of vinyl to 1-hydroxyethyl group. Methyl 3-vinyl-
pyropheophorbide 1e4a (30 mmol) was dissolved in 30% hydrogen
bromide in acetic acid (10 mL) and heated for 5 h at 60 ꢁC under
nitrogen. After disappearance of the starting vinyl-chlorin had been
checked by TLC analysis, the ice-chilled reaction mixture was
poured into water (100 mL) and stirred for 30 min. The mixture was
extracted with chloroform several times until the aqueous phase
was colorless. The combined organic phases were washed with
water, aq 4% NaHCO3 and water, dried over sodium sulfate, and
filtered. The solvent was evaporated in vacuo and the residue was
dissolved in dichloromethane (20 mL) and methanol (1 mL). The
mixture was treated with an excess amount of diazomethane in
diethyl ether and stirred for 10 min at room temperature. After
checking the consumption of the carboxylic acid by TLC, all the
solvents were evaporated in vacuo and the residue was purified by
FCC (10% Et2O to 1% MeOH and CH2Cl2) and recrystallization
(CH2Cl2 and hexane) to give methyl 3-(1-hydroxyethyl)pyropheo-
phorbide 1e4c.
4.3.2. Methyl mesopyropheophorbide-a (1b). Black solid; mp
237e238 ꢁC (Ref. 11); vis (CH2Cl2) lmax¼656 (relative absorbance,
0.42), 601 (0.08), 535 (0.08), 504 (0.09), 410 nm (1.00); 1H NMR
(CDCl3)
d
¼9.48, 9.21, 8.45 (each 1H, s, 5-, 10-, 20-H), 5.24, 5.09 (each
1H, d, J¼19 Hz, 131-CH2), 4.88 (1H, q, J¼8 Hz, 18-H), 4.27 (1H, dd,
J¼4, 8 Hz, 17-H), 3.83 (2H, q, J¼8 Hz, 3-CH2), 3.70 (2H, q, J¼8 Hz, 8-
CH2), 3.66, 3.60, 3.29, 3.25 (each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3),
2.70e2.52, 2.33e2.24 (each 2H, m, 17-CH2CH2), 1.80 (3H, d,
J¼7.5 Hz, 18-CH3), 1.73, 1.70 (each 3H, t, J¼8 Hz, 31-, 81-CH3), 0.64,
ꢀ1.59 (each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/z¼550. Calcd for
C
34H38N4O3: Mþ, 550. See also Ref. 11 for its spectral data.
4.2.6. Oxidation of 1-hydroxyethyl to acetyl group. To a dichloro-
methane solution (10 mL) of methyl 3-(1-hydroxyethyl)pyropheo-
4.3.3. Methyl bacteriopheophorbide-d (1c). Black solid; mp 24
5e247 ꢁC (Ref. 12); vis (CH2Cl2) lmax¼661 (relative absorbance,
0.44), 604 (0.07), 536 (0.09), 505 (0.08), 411 nm (1.00); 1H NMR
phorbide 1e4c (20
(12 mg, 100 mol) and the mixture was stirred for 5 min at room
temperature under nitrogen. Tetrapropylammonium perruthenate
(7 mg, 20 mol) and molecular sieves 4A (1 g) were further added
mmol) was added N-methylmorpholine N-oxide
m
(CDCl3)
d
(31R:31S¼1:1)¼9.66/9.64 (1H, s, 5-H), 9.41 (1H, s, 10-H),
8.50/8.49 (1H, s, 20-H), 6.39/6.37 (1H, q, J¼7 Hz, 3-CH), 5.21/5.19,
5.06/5.05 (each 1H, d, J¼20 Hz, 131-CH2), 4.44 (1H, q, J¼7 Hz, 18-
H), 4.15e4.12 (1H, m, 17-H), 3.67 (2H, q, J¼8 Hz, 8-CH2), 3.66,
3.61/3.60, 3.42/3.41, 3.26 (each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3),
m
to the mixture and stirred for less than 1 h. After the starting sec-
ondary alcohol had been consumed (TLC analysis), the mixture was

H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
8419
2.68e2.50, 2.31e2.20 (each 2H, m, 17-CH2CH2), 2.13 (3H, d, J¼7 Hz,
31-CH3), 1.79/1.77 (3H, d, J¼7 Hz, 18-CH3), 1.68 (3H, t, J¼8 Hz, 81-
CH3), 0.24, ꢀ1.88 (each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/
z¼566. Calcd for C34H38N4O4: Mþ, 566. See also Refs. 12 and 32 for
its spectral data.
(3H, d, J¼7 Hz, 18-CH3), 0.74, ꢀ1.98 (each 1H, s, NH ꢂ2); MS (LDI-
TOF) found: m/z¼642. Calcd for C34H35N4O4Br: Mþ, 642. See also
Refs. 30 and 35 for its spectral data.
4.3.4. Methyl 3-acetyl-pyropheophorbide-a (1d). Black solid; mp
264e267 ꢁC (Ref. 33); vis (CH2Cl2) lmax¼683 (relative absorbance,
0.51), 623 (0.07), 548 (0.10), 515 (0.11), 419 (1.00), 385 nm (0.76); 1H
4.4. Data of methyl 3,20-disubstituted pyropheophorbides 3/
4aed and 7/8b
NMR (CDCl3)
d
¼10.01, 9.62, 8.78 (each 1H, s, 5-, 10-, 20-H), 5.33,
4.4.1. Methyl 20-vinyl-pyropheophorbide-a (3a). Black solid; mp
103e105 ꢁC; vis (CH2Cl2) lmax¼672 (relative absorbance, 0.27), 614
5.18 (each 1H, d, J¼20 Hz, 131-CH2), 4.56 (1H, q, J¼7 Hz, 18-H), 4.37
(1H, dd, J¼4, 9 Hz,17-H), 3.73 (2H, q, J¼7 Hz, 8-CH2), 3.72, 3.66, 3.61,
3.30, 3.29 (each 3H, s, 2-, 31-, 7-, 12-CH3, 172-COOCH3), 2.76e2.55,
2.34e2.27 (each 2H, m, 17-CH2CH2), 1.84 (3H, d, J¼7 Hz, 18-CH3),
1.72 (3H, d, J¼7 Hz, 81-CH3), 0.00, ꢀ2.01 (each 1H, s, NH ꢂ2); MS
(LDI-TOF) found: m/z¼564. Calcd for C34H36N4O4: Mþ, 564. See also
Ref. 33 for its spectral data.
(0.14), 521 (0.11), 417 nm (1.00); 1H NMR (CDCl3)
d¼9.46, 9.45
(each 1H, s, 5-, 10-H), 8.30, 7.92 (each 1H, dd, J¼12, 18 Hz, 3-, 20-
CH), 6.23, 6.20 (each 1H, dd, J¼1, 12 Hz, 31-, 201-CH cis to 3-, 20-
CeH), 6.12, 5.68 (each 1H, dd, J¼1, 18 Hz, 31-, 201-CH trans to 3-,
20-CeH), 5.21, 5.19 (each 1H, d, J¼20 Hz, 131-CH2), 4.66 (1H, q,
J¼8 Hz, 18-H), 4.16 (1H, dd, J¼3, 9 Hz, 17-H), 3.85 (2H, q, J¼8 Hz, 8-
CH2), 3.66, 3.58, 3.30, 3.25 (each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3),
2.80e2.56, 2.26e2.17 (each 2H, m, 17-CH2CH2), 1.68 (3H, t, J¼8 Hz,
81-CH3), 1.42 (3H, d, J¼8 Hz, 18-CH3), 0.07, ꢀ0.37 (each 1H, s, NH
ꢂ2); MS (LDI-TOF) found: m/z¼574. Calcd for C36H38N4O3: Mþ,
574; HRMS (ESI-TOF) found: m/z¼574.2944. Calcd for C36H38N4O3:
Mþ, 574.2944.
4.3.5. Methyl 20-bromo-pyropheophorbide-a (2a). Black solid; mp
161e163 ꢁC; vis (CH2Cl2) lmax¼676 (relative absorbance, 0.44), 619
(0.06), 552 (0.14), 520 (0.08), 417 nm (1.00); 1H NMR (CDCl3)
d¼9.58
(1H, s, 5-H), 9.55 (1H, s,10-H), 7.93 (1H, dd, J¼11.5, 18 Hz, 3-CH), 6.29
(1H, dd, J¼1.5, 11.5 Hz, 31-CH cis to 3-CeH), 6.14 (1H, dd, J¼1.5, 18 Hz,
31-CH trans to 3-CeH), 5.25, 5.24 (each 1H, d, J¼19 Hz, 131-CH2), 4.87
(1H, q, J¼7 Hz,18-H), 4.24 (1H, dd, J¼9, 3 Hz,17-H), 3.70 (2H, q, J¼8 Hz,
8-CH2), 3.67 (3H, s, 12-CH3), 3.62 (3H, s, 2-CH3), 3.58 (3H, s, 172-
COOCH3), 3.26 (3H, s, 7-CH3), 2.61e2.50, 2.23e2.17 (each 2H, m, 17-
CH2CH2), 1.70 (3H, t, J¼8 Hz, 81-CH3), 1.59 (3H, d, J¼7 Hz, 18-CH3),
1.04, ꢀ1.78 (each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/z = 626. Calcd.
for C34H35N4O3Br: Mþ, 626; HRMS (ESI-TOF) found: m/z = 626.1982.
Calcd. for C34H35N4O3Br: Mþ, 626.1982. See also Ref. 22 for its spectral
data.
4.4.2. Methyl 20-vinyl-mesopyropheophorbide-a (3b). Black solid;
mp 112e115 ꢁC; vis (CH2Cl2) lmax¼665 (relative absorbance, 0.34),
609 (0.07), 547 (0.11), 514 (0.08), 414 nm (1.00); 1H NMR (CDCl3)
d
¼9.44, 9.30 (each 1H, s, 5-, 10-H), 8.27 (1H, dd, J¼11, 18 Hz, 20-
CH), 6.18 (1H, dd, J¼1, 11 Hz, 201-CH cis to 20-CeH), 5.71 (1H,
dd, J¼1, 18 Hz, 201-CH trans to 20-CeH), 5.20, 5.18 (each 1H, d,
J¼20 Hz, 131-CH2), 4.65 (1H, q, J¼8 Hz, 18-H), 4.13 (1H, dd, J¼3,
8 Hz, 17-H), 3.82, 3.67 (each 2H, q, J¼8 Hz, 3-, 8-CH2), 3.65, 3.58,
3.27, 3.26 (each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3), 2.52e2.47,
2.20e2.11 (each 2H, m, 17-CH2CH2), 1.70, 1.68 (each 3H, t, J¼8 Hz,
31-, 81-CH3), 1.40 (3H, d, J¼8 Hz, 18-CH3), 0.01, ꢀ1.47 (each 1H, s,
NH ꢂ2); MS (LDI-TOF) found: m/z¼576. Calcd for C36H40N4O3: Mþ,
576; HRMS (ESI-TOF) found: m/z¼576.3102. Calcd for C36H40N4O3:
Mþ, 576.3100.
4.3.6. Methyl 20-bromo-mesopyropheophorbide-a (2b). Black sol-
id; mp 142e144 ꢁC (Ref. 34); vis (CH2Cl2) lmax¼668 (relative absorb-
ance, 0.42), 613 (0.06), 548 (0.12), 516 (0.07), 415 nm (1.00); 1H NMR
(CDCl3)
d
¼9.53, 9.42 (each 1H, s, 5-, 10-H), 5.23, 5.21 (each 1H, d,
J¼20 Hz,131-CH2), 4.84 (1H, q, J¼7 Hz,18-H), 4.20 (1H, dd, J¼4, 9 Hz,17-
H), 3.93 (2H, q, J¼8 Hz, 3-CH2), 3.68 (2H, q, J¼8 Hz, 8-CH2), 3.64, 3.56,
3.53, 3.26 (each 3H, s, 2-, 7-,12-CH3,172-COOCH3), 2.58e2.47, 2.21e2.15
(each 2H, m,17-CH2CH2),1.70,1.68 (each 3H, t, J¼8 Hz, 31-, 81-CH3),1.57
(3H, d, J¼7 Hz, 18-CH3), 0.64, ꢀ1.59 (each 1H, s, NH ꢂ2); MS (LDI-TOF)
found: m/z¼628. Calcd for C34H37N4O3Br: Mþ,628.SeealsoRefs.34 and
35 for its spectral data.
4.4.3. Methyl 20-vinyl-bacteriopheophorbide-d (3c). Black solid;
mp 132e136 ꢁC; vis (CH2Cl2) lmax¼669 (relative absorbance, 0.34),
613 (0.07), 549 (0.12), 516 (0.08), 414 nm (1.00); 1H NMR (CDCl3)
d
(31R:31S¼1:1)¼9.96/9.89, 9.47 (each 1H, s, 5-, 10-H), 8.30/8.29
(1H, dd, J¼10, 18 Hz, 20-CH), 6.47/6.45 (1H, q, J¼7 Hz, 3-CH), 6.22
(1H, d, J¼10 Hz, 201-CH cis to 20-CeH), 5.69/5.67 (1H, d, J¼18 Hz,
201-CH trans to 20-CeH), 5.25/5.24, 5.18 (each 1H, d, J¼20 Hz, 131-
CH2), 4.66 (1H, q, J¼8 Hz, 18-H), 4.16e4.13 (1H, m, 17-H), 3.67 (2H,
q, J¼8 Hz, 8-CH2), 3.68, 3.66, 3.61, 3.60 (each 3H, s, 2-, 7-, 12-CH3,
172-COOCH3), 2.66e2.62, 2.56e2.53, 2.26e2.05 (1Hþ1Hþ2H, m,
17-CH2CH2), 2.16/2.11 (3H, d, J¼7 Hz, 31-CH3), 1.70 (3H, t, J¼8 Hz,
81-CH3), 1.40 (3H, d, J¼8 Hz, 18-CH3), ꢀ1.63/e1.67 (1H, s, NH)
[another NH and 31-OH were invisible]; MS (LDI-TOF) found: m/
z¼592. Calcd for C36H40N4O4: Mþ, 592; HRMS (ESI-TOF) found: m/
z¼592.3048. Calcd for C36H40N4O4: Mþ, 592.3050.
4.3.7. Methyl 20-bromo-bacteriopheophorbide-d (2c). Black solid;
mp 144e146 ꢁC (Ref. 17); vis (CH2Cl2) lmax¼673 (relative absorb-
ance, 0.45), 616 (0.05), 550 (0.13), 518 (0.07), 415 nm (1.00); 1H NMR
(CDCl3)
d
(31R:31S¼1:1)¼10.11/10.06 (1H, s, 5-H), 9.42 (1H, s, 10-H),
6.48 (1H, q, J¼7 Hz, 3-CH), 5.21, 5.20 (each 1H, d, J¼20 Hz, 131-CH2),
4.83 (1H, q, J¼7 Hz, 18-H), 4.13 (1H, m, 17-H), 3.70 (2H, q, J¼8 Hz, 8-
CH2), 3.62, 3.60, 3.58, 3.28 (each 3H, s, 2-, 7-, 12-CH3, 172-COOCH3),
2.90e2.55, 2.48e2.22 (each 2H, m, 17-CH2CH2), 2.17/2.14 (3H, d,
J¼7 Hz, 31-CH3),1.69 (3H, t, J¼8 Hz, 81-CH3), 1.52 (3H, d, J¼7 Hz,181-
CH3), 0.88, ꢀ2.06 (each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/
z¼644. Calcd for C34H37N4O4Br: Mþ, 644. See also Ref. 17 for its
spectral data.
4.4.4. Methyl 3-acetyl-20-vinyl-pyropheophorbide-a (3d). Black
solid; mp 104e107 ꢁC; vis (CH2Cl2) lmax¼683 (relative absorbance,
0.38), 554 (0.14), 521 (0.11), 417 nm (1.00); 1H NMR (CDCl3)
d
¼9.65,
4.3.8. Methyl 3-acetyl-20-bromo-pyropheophorbide-a (2d). Black
solid; mp 115e116 ꢁC (Ref. 30); vis (CH2Cl2) lmax¼682 (relative
absorbance, 0.48), 626 (0.05), 554 (0.14), 522 (0.09), 416 nm (1.00);
9.54 (each 1H, s, 5-, 10-H), 8.34 (1H, dd, J¼11, 17 Hz, 20-CH), 6.47
(1H, dd, J¼1, 11 Hz, 201-CH cis to 20-CeH), 6.25 (1H, dd, J¼1, 17 Hz,
201-CH trans to 3-CeH), 5.25, 5.24 (each 1H, d, J¼20 Hz, 131-CH2),
4.71 (1H, q, J¼8 Hz, 18-H), 4.21 (1H, dd, J¼4, 9 Hz, 17-H), 3.70 (2H, q,
J¼8 Hz, 8-CH2), 3.65, 3.59, 3.27, 3.24, 3.23 (each 3H, s, 2-, 31-, 7-, 12-
CH3, 172-COOCH3), 2.52e2.42, 2.20e2.10 (each 2H, m, 17-CH2CH2),
1.71 (3H, t, J¼8 Hz, 81-CH3), 1.40 (3H, d, J¼8 Hz, 18-CH3), 0.06, ꢀ1.78
(each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/z¼590. Calcd for
1H NMR (CDCl3)
d¼9.63, 9.61 (each 1H, s, 5-, 10-H), 5.30, 5.29 (each
1H, d, J¼20 Hz, 131-CH2), 4.91 (1H, q, J¼7 Hz, 18-H), 4.29 (1H, dd,
J¼3, 8 Hz,17-H), 3.72, 3.70, 3.59, 3.27, 3.25 (each 3H, s, 2-, 31-, 7-,12-
CH3, 172-COOCH3), 3.69 (2H, q, J¼8 Hz, 8-CH2), 2.65e2.52,
2.27e2.18 (each 2H, m, 17-CH2CH2), 1.71 (3H, t, J¼8 Hz, 81-CH3), 1.61

8420
H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
C36H38N4O4: Mþ, 590; HRMS (ESI-TOF) found: m/z¼590.2890. Calcd
J¼8 Hz, 18-CH3), 0.04, ꢀ1.09 (each 1H, s, NH ꢂ2); MS (LDI-TOF)
found: m/z¼590. Calcd for C37H42N4O3: Mþ, 590; HRMS (ESI-TOF)
found: m/z¼590.3255. Calcd for C37H42N4O3: Mþ, 590.3257.
for C36H38N4O4: Mþ, 590.2893.
4.4.5. Methyl 20-acetyl-pyropheophorbide-a (4a). Black solid; mp
285e287 ꢁC; vis (CH2Cl2) lmax¼676 (relative absorbance, 0.39), 618
4.4.10. Methyl
20-propyl-mesopyropheophorbide-a (8b). Black
(0.11), 547 (0.10), 415 nm (1.00); 1H NMR (CDCl3)
d¼9.57, 9.54 (each
solid; mp 150e153 ꢁC; vis (CH2Cl2) lmax¼663 (relative absorbance,
1H, s, 5-, 10-H), 7.88 (1H, dd, J¼12, 18 Hz, 3-CH), 6.30 (1H, dd, J¼1,
12 Hz, 31-CH cis to 3-CeH), 6.12 (1H, dd, J¼1,18 Hz, 31-CH trans to 3-
CeH), 5.25, 5.23 (each 1H, d, J¼20 Hz, 131-CH2), 4.72 (1H, q, J¼8 Hz,
18-H), 4.21 (1H, dd, J¼4, 9 Hz, 17-H), 3.72 (2H, q, J¼8 Hz, 8-CH2),
3.66, 3.57, 3.30, 3.28, 3.26 (each 3H, s, 2-, 7-, 12-, 201-CH3, 172-
COOCH3), 2.60e2.53, 2.30e2.20 (each 2H, m, 17-CH2CH2), 1.71 (3H,
t, J¼8 Hz, 81-CH3), 1.43 (3H, d, J¼8 Hz, 18-CH3), 0.01, ꢀ1.11 (each 1H,
s, NH ꢂ2); MS (LDI-TOF) found: m/z¼590. Calcd for C36H38N4O4:
Mþ, 590; HRMS (ESI-TOF) found: m/z¼590.2890. Calcd for
0.44), 609 (0.08), 539 (0.10), 508 (0.11), 413 nm (1.00); 1H NMR
(CDCl3)
d
¼9.44, 9.31 (each 1H, s, 5-, 10-H), 5.26, 5.24 (each 1H, d,
J¼19 Hz, 131-CH2), 4.47 (1H, q, J¼8 Hz, 18-H), 4.13 (1H, dd, J¼3, 8 Hz,
17-H), 3.86, 3.78 (each 2H, q, J¼8 Hz, 3-, 8-CH2), 3.68 (2H, t, J¼8 Hz,
20-CH2), 3.60, 3.58, 3.34, 3.26 (each 3H, s, 2-, 7-, 12-CH3, 172-
COOCH3), 2.78e2.66, 2.64e2.59, 2.49e2.40, 2.39e2.30 (each 1H, m,
17-CH2CH2), 2.20-2.01 (2H, m, 201-CH2), 1.75, 1.68 (each 3H, t,
J¼8 Hz, 31-, 81-CH3), 1.41 (3H, d, J¼8 Hz, 18-CH3), 1.14 (3H, t, J¼8 Hz,
202-CH3), 0.10, ꢀ1.65 (each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/
z¼592. Calcd for C37H44N4O3: Mþ, 592; HRMS (ESI-TOF) found: m/
z¼592.4313. Calcd for C37H44N4O3: Mþ, 592.4313.
C
36H38N4O4: Mþ, 590.2893.
4.4.6. Methyl 20-acetyl-mesopyropheophorbide-a (4b). Black solid;
mp 245e248 ꢁC; vis (CH2Cl2) lmax¼667 (relative absorbance, 0.34),
613 (0.07), 542 (0.13), 512 (0.07), 413 nm (1.00); 1H NMR (CDCl3)
Acknowledgements
d
¼9.65, 9.54 (each 1H, s, 5-, 10-H), 5.25, 5.23 (each 1H, d, J¼20 Hz,
We thank Mrs. Yuki Kotegawa and Masatoshi Kurioka of Ritsu-
meikan University for their experimental assistance. 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).
131-CH2), 4.72 (1H, q, J¼8 Hz, 18-H), 4.20 (1H, dd, J¼4, 9 Hz, 17-H),
3.72, 3.70 (each 2H, q, J¼8 Hz, 3-, 8-CH2), 3.59, 3.55, 3.26, 3.24, 3.23
(each 3H, s, 2-, 7-, 12-, 201-CH3, 172-COOCH3), 2.52e2.43, 2.20e2.10
(each 2H, m, 17-CH2CH2), 1.71, 1.69 (each 3H, t, J¼8 Hz, 31-, 81-CH3),
1.43 (3H, d, J¼8 Hz,18-CH3), 0.12, ꢀ1.02 (each 1H, s, NH ꢂ2); MS (LDI-
TOF) found: m/z¼592. Calcd for C36H40N4O4: Mþ, 592; HRMS (ESI-
TOF) found: m/z¼592.3048. Calcd for C36H40N4O4: Mþ, 592.3050.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.07.060.
4.4.7. Methyl 20-acetyl-bacteriopheophorbide-d (4c). Black solid;
mp 223e226 ꢁC; vis (CH2Cl2) lmax¼671 (relative absorbance, 0.34),
617 (0.07), 544 (0.12), 512 (0.08), 413 nm (1.00); 1H NMR (CDCl3)
d
(31R:31S¼1:1)¼9.96/9.89, 9.47 (each 1H, s, 5-, 10-H), 6.47/6.45
References and notes
(1H, q, J¼7 Hz, 3-CH), 5.14, 5.12 (each 1H, d, J¼20 Hz, 131-CH2), 4.66
(1H, q, J¼8 Hz, 18-H), 4.16 (1H, dd, J¼3, 8 Hz, 17-H), 3.67 (2H, q,
J¼8 Hz, 8-CH2), 3.68, 3.66, 3.30, 3.24, 3.20 (each 3H, s, 2-, 7-, 12-,
201-CH3, 172-COOCH3), 2.66e2.62, 2.56e2.53, 2.26e2.05
(1Hþ1Hþ2H, m, 17-CH2CH2), 2.16/2.11 (3H, d, J¼7 Hz, 31-CH3), 1.70
(3H, t, J¼8 Hz, 81-CH3), 1.40 (3H, d, J¼8 Hz, 18-CH3), 0.88, ꢀ1.67
(each 1H, s, NH ꢂ2) [31-OH was invisible]; MS (LDI-TOF) found: m/
z¼608. Calcd for C36H40N4O5: Mþ, 608; HRMS (ESI-TOF) found: m/
z¼608.3001. Calcd for C36H40N4O5: Mþ, 608.2999.
1. Tamiaki, H.; Kunieda, M. Handb. Porphyrin Sci. 2011, 11, 223e290.
2. Tamiaki, H.; Shibata, R.; Mizoguchi, T. Photochem. Photobiol. 2007, 83, 152e162;
(a) Niedzwiedzki, D. M.; Blankenship, R. E. Photosynth. Res. 2010, 106, 227e238;
(b) Chen, M.; Scheer, H. J. Porphyrins Phthalocyanines 2013, 17, 1e15.
3. Liu, Z.; Bryant, D. A. Handb. Porphyrin Sci. 2012, 20, 107e140.
4. Kataoka, Y.; Shibata, Y.; Tamiaki, H. Bioorg. Med. Chem. Lett. 2012, 22,
5218e5221; (a) Shoji, S.; Hashishin, T.; Tamiaki, H. Chem.dEur. J. 2012, 18,
13331e13341; (b) Pale, V.; Nikkonen, T.; Vapaavuori, J.; Kostiainen, M.; Ka-
vakka, J.; Selin, J.; Tittonen, I.; Helaja, J. J. Mater. Chem. C 2013, 1, 2166e2173; (c)
Shinozaki, Y.; Richards, G.; Ogawa, K.; Yamano, A.; Ohara, K.; Yamaguchi, K.;
Kawano, S.; Tanaka, K.; Araki, Y.; Wada, T.; Otsuki, J. J. Am. Chem. Soc. 2013, 135,
5262e5265; (d) Sakai, S.; Noji, T.; Kondo, M.; Mizuno, T.; Dewa, T.; Ochiai, T.;
Yamakawa, H.; Ito, S.; Hashimoto, H.; Nango, M. Langmuir 2013, 29, 5104e5109;
(e) Pandit, A.; Ocakoglu, K.; Buda, F.; van Marle, T.; Holzwarth, A. R.; de Groot,
H. J. M. J. Phys. Chem. B 2013, 117, in press.
5. Wang, Y.-W.; Sasaki, S.; Tamiaki, H.; Zhang, J.-P.; Ikeuchi, T.; Hong, Z.; Kido, J.;
Wang, X.-F. Org. Electron. 2013, 14, 1972e1979; (a) Wang, X.-F.; Tamiaki, H.;
Kitao, O.; Ikeuchi, T.; Sasaki, S. J. Power Sources 2013, 242, 860e864.
6. Savellano, M. D.; Owusu-Brackett, N.; Son, J.; Ganga, T.; Leung, N. L.; Savellano,
D. H. Photochem. Photobiol. 2013, 89, 687e697.
7. Ethirajan, M.; Chen, P.; Ohulchanskyy, T. Y.; Goswami, L. N.; Gupta, A.; Srivatsan, A.;
Dobhal, M. P.; Missert, J. R.; Prasad, P. N.; Kadishi, K. M.; Pandey, R. K. Chem.dEur. J.
2013, 19, 6670e6684.
4.4.8. Methyl 3,20-diacetyl-pyropheophorbide-a (4d). Black solid;
mp 237e240 ꢁC; vis (CH2Cl2) lmax¼687 (relative absorbance, 0.39),
554 (0.11), 518 (0.10), 417 nm (1.00); 1H NMR (CDCl3)
d¼9.65, 9.54
(each 1H, s, 5-, 10-H), 5.25, 5.23 (each 1H, d, J¼20 Hz, 131-CH2), 4.72
(1H, q, J¼8 Hz,18-H), 4.21 (1H, dd, J¼4, 9 Hz,17-H), 3.72 (2H, q, J¼8 Hz,
8-CH2), 3.69, 3.59, 3.27, 3.24, 3.23, 3.11 (each 3H, s, 2-, 31-, 7-,12-, 201-
CH3, 172-COOCH3), 2.52e2.43, 2.20e2.10 (each 2H, m, 17-CH2CH2),
1.71 (3H, t, J¼8 Hz, 81-CH3), 1.43 (3H, d, J¼8 Hz, 18-CH3), 0.08, ꢀ1.78
(each 1H, s, NH ꢂ2); MS (LDI-TOF) found: m/z¼606. Calcd for
8. Tamiaki, H.; Azuma, K.; Kinoshita, Y.; Monobe, R.; Miyatake, T.; Sasaki, S. Tet-
rahedron 2013, 69, 1987e1993.
9. Sasaki, S.; Mizutani, K.; Kunieda, M.; Tamiaki, H. Tetrahedron Lett. 2008, 49,
4113e4115; (a) Machida, S.; Isoda, Y.; Kunieda, M.; Tamiaki, H. Tetrahedron Lett.
2012, 53, 6277e6279.
C
36H38N4O5: Mþ, 606; HRMS (ESI-TOF) found: m/z¼606.2842. Calcd
for C36H38N4O5: Mþ, 606.2842.
4.4.9. Methyl 20-allyl-mesopyropheophorbide-a (7b). Black solid;
mp 190e193 ꢁC; vis (CH2Cl2) lmax¼665 (relative absorbance, 0.40),
608 (0.09), 548 (0.10), 516 (0.11), 414 nm (1.00); 1H NMR (CDCl3)
10. Tamiaki, H.; Machida, S.; Mizutani, K. J. Org. Chem. 2012, 77, 4751e4758.
11. Smith, K. M.; Goff, D. A.; Simpson, D. J. J. Am. Chem. Soc. 1985, 107, 4946e4954.
12. Smith, K. M.; Bisset, G. M. F.; Bushell, M. J. J. Org. Chem. 1980, 45, 2218e2224.
13. Tamiaki, H.; Nagata, Y.; Tsudzuki, S. Eur. J. Org. Chem. 1999, 2471e2473.
14. Iturraspe, J.; Gossauer, A. Photochem. Photobiol. 1991, 54, 43e49.
15. Kureishi, Y.; Tamiaki, H. J. Porphyrins Phthalocyanines 1998, 2, 159e169.
16. Kelley, R. F.; Tauber, M. J.; Wasielewski, M. R. J. Am. Chem. Soc. 2006, 128,
4779e4791.
17. Sasaki, S.; Mizoguchi, T.; Tamiaki, H. J. Org. Chem. 2007,72, 4566e4569;(a)Tamiaki, H.;
Okamoto, Y.; Mikata, Y.; Shoji, S. Photochem. Photobiol. Sci. 2012, 11, 898e907.
18. Kelley, R. F.; Tauber, M. J.; Wasielewski, M. R. Angew. Chem., Int. Ed. 2006, 45,
7979e7982.
d
¼9.44, 9.32 (each 1H, s, 5-, 10-H), 6.71 (1H, ddt, J¼10, 18, 3 Hz, 201-
CH), 5.30 (1H, dd, J¼2,10 Hz, 202-CH cis to 201-CeH), 4.80, 4.71 (each
1H, d, J¼3, 10 Hz, 20-CH2), 4.65 (1H, dd, J¼2, 18 Hz, 202-CH trans to
201-CeH), 5.23, 5.24 (each 1H, d, J¼19 Hz, 131-CH2), 4.17 (1H, q,
J¼8 Hz, 18-H), 3.88 (1H, dd, J¼3, 8 Hz, 17-H), 3.82, 3.81 (each 2H, q,
J¼8 Hz, 3-, 8-CH2), 3.67, 3.62, 3.38, 3.28 (each 3H, s, 2-, 7-, 12-CH3,
172-COOCH3), 2.64e2.56, 2.46e2.37, 2.26e2.18, 2.10e2.01 (each 1H,
m,17-CH2CH2),1.70,1.62 (each 3H, t, J¼8 Hz, 31-, 81-CH3),1.40 (3H, d,
19. No stereoselective hydration of the 3-vinyl group in 1e4a or reduction of the 3-
acetyl group in 1e4a was observed under the present conditions to give a 31-

H. Tamiaki et al. / Tetrahedron 69 (2013) 8412e8421
8421
epimeric mixture (1:1) of the corresponding 1e4c possessing 3-C*H(OH)CH3;
see also Ref. 20.
20. Tamiaki, H.; Monobe, R.; Koizumi, S.; Miyatake, T.; Kinoshita, Y. Tetrahedron:
27. Additional electronic effect could not be ruled out.
28. Tamiaki, H.; Kouraba, M. Tetrahedron 1997, 53, 10677e10688.
29. Inamoto, N.; Matsuda, S. Chem. Lett. 1982, 1003e1006.
Asymmetry 2013, 24, 677e682.
30. Tamiaki, H.; Kotegawa, Y.; Mizutani, K. Bioorg. Med. Chem. Lett. 2008, 18,
6037e6040.
31. The 13-carbonyl group of 4b was reduced with NaBH4 (10 equiv) in CH2Cl2 at
room temperature to give the corresponding 131-hydroxy-chlorin as an isolable
product (see Ref. 20), but no reduction of the 20-acetyl group was observed
under the reaction conditions.
21. The yield of 12% was optimal and 2a was often prepared in a less than 10%
yield. Additionally, 20-bromination of 1a with bromine in carbon tetrachlo-
ride at ꢀ20 ꢁC for 5 min to 2a (35%) was available in Ref. 22, but we were
unable to isolate 2a from the complex reaction mixture by the reported
procedures.
22. Han, G.-F.; Wang, J.-J.; Shim, Y. K. J. Photosci. 2001, 8, 71e73.
23. Sergeeva, N. N.; Scala, A.; Bakar, M. A.; O’Riordan, G.; O’Brien, J.; Grassi, G.;
Senge, M. O. J. Org. Chem. 2009, 74, 7140e7147.
32. Tamiaki, H.; Takeuchi, S.; Tsudzuki, S.; Miyatake, T.; Tanikaga, R. Tetrahedron
1998, 54, 6699e6718.
33. Tamiaki, H.; Yagai, S.; Miyatake, T. Bioorg. Med. Chem. 1998, 6, 2171e2178.
34. Kenner, G. W.; McCombie, S. W.; Smith, K. M. J. Chem. Soc., Perkin Trans. 1 1973,
2517e2523.
24. Muthiah, C.; Lahaye, D.; Taniguchi, M.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem.
2009, 74, 3237e3247.
25. Tamiaki, H.; Takekoshi, D.; Mizoguchi, T. Bioorg. Med. Chem. 2011, 19, 52e57.
26. Tamiaki, H.; Hamada, K.; Kunieda, M. Tetrahedron 2008, 64, 5721e5727.
35. Ethirajan, M.; Joshi, P.; William, W. H., III; Ohkubo, K.; Fukuzumi, S.; Pandey, R.
K. Org. Lett. 2011, 13, 1956e1959.