Synthesis of a chlorophyll-a derivative fused with an additional exo-five-membered ring and its optical properties

Article abstract of DOI:10.1016/j.tetlet.2019.07.025

A C20-free chlorophyll-a derivative with an additional exo-five-membered ring was successfully prepared using an ethylene linkage at the C3- and C5-positions. A bromination at the C20-position was requisite for the cyclization of a 1-hydroxyethyl or vinyl group at the C3-position of methyl bacteriopheophorbide-d or methyl pyropheophorbide-a, respectively. By comparing optical properties of the cyclized product with those of its 3-ethyl uncyclized analog in a diluted dichloromethane solution, it was shown that the cyclization shifted the Q_x and B_x absorption maxima to longer wavelengths and reduced the Stokes shift.

Full text of DOI:10.1016/j.tetlet.2019.07.025

Tetrahedron Letters 60 (2019) 150934
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a chlorophyll-a derivative fused with an additional
exo-five-membered ring and its optical properties
⇑
Marie Doi, Hitoshi Tamiaki
Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A C20-free chlorophyll-a derivative with an additional exo-five-membered ring was successfully prepared
using an ethylene linkage at the C3- and C5-positions. A bromination at the C20-position was requisite
for the cyclization of a 1-hydroxyethyl or vinyl group at the C3-position of methyl bacteriopheophor-
bide-d or methyl pyropheophorbide-a, respectively. By comparing optical properties of the cyclized pro-
duct with those of its 3-ethyl uncyclized analog in a diluted dichloromethane solution, it was shown that
the cyclization shifted the Qx and Bx absorption maxima to longer wavelengths and reduced the Stokes
shift.
Received 12 June 2019
Revised 8 July 2019
Accepted 12 July 2019
Available online 17 July 2019
Keywords:
Acidic cyclization
Ethylene linkage
Fused ring
Ó 2019 Elsevier Ltd. All rights reserved.
Pyropheophorbide
Plants convert sunlight into chemical energy through photosyn-
thesis. During the initial stage of photosynthesis, chlorophylls
(Chls) play important roles in efficient light-absorbing processes
in light-harvesting antennas, rapid excitation energy-transferring
pathways from the antennas to a reaction center, and successive
charge-separating process in the reaction center [1]. Naturally
occurring Chls are cyclic tetrapyrrole pigments with different
our knowledge, naturally occurring chlorins possessing such two
exo-five-membered rings have not been found yet, and only one
semi-synthetic chlorin molecule with both E- and F-rings has been
reported [7]. Methyl bacteriopheophorbide-c having 3-(1-hydrox-
yethyl) and 20-methyl groups (Fig. 1, middle; M=H2,
R2=R7=R20=R=CH3, R3=CH(OH)CH3, R8=CH2CH3, and E=H) was
refluxed in benzene containing p-toluenesulfonic acid (p-TSA) to
afford a product with the F-ring (Fig. 2, right). Under the same con-
ditions, methyl bacteriopheophorbide-d without the 20-methyl
group did not result in the corresponding cyclized product [7],
and any 20-unsubstituted chlorins with the F-ring have not been
reported yet.
p-conjugated systems and have various substituents at their
peripheral positions (Fig. 1) [2], where the A-, B-, C-, and D-rings
are connected via methine moieties. Chls-a/b/d/f are present in
several oxygenic phototrophs including green plants and
cyanobacteria, which possess a chlorin
partially reduced D-ring (trans-17,18-dihydroporphyrin) [3].
Chls-c, found in chromophytes, have fully -conjugated
p-system containing a
In this communication, a Chl-a derivative with a chlorin
p-
a
p
skeleton possessing the F-ring and lacking the C20-substituent
was first prepared via acidic cyclization of methyl 20-bromobacte-
riopheophorbide-d and subsequent debromination. Its optical
properties in dichloromethane were also discussed, comparing
with those of its 3-ethyl analog lacking the F-ring.
Chl-a was extracted from cyanobacterial cells using methanol
[step (i) in Scheme 1], and was demetalated, transesterified, and
demethoxycarbonylated to convert into methyl pyropheophor-
bide-a (1a) [step (ii)] [8,9]. The 3-vinyl group in 1a was
hydrated to the 3-(1-hydroxyethyl) group in methyl bacterio-
pheophorbide-d (2a) [step (iii)] [9,10], followed by regioselective
bromination at the C20-position to give methyl 20-bromobacterio-
pheophorbide-d (2b) [step (iv)] [11].
porphyrin skeleton (17,18-didehydrochlorin) [4], whereas bacteri-
ochlorophyll(BChl)s-a/b/g, found in purple, green, and heliobacte-
ria, have
a bacteriochlorin p-skeleton possessing partially
reduced B- and D-rings (the C7–C8 single bonded form of a chlorin)
[5]. All photosynthetically active (B)Chls bear an additional
five-membered ring (E-ring) fused to the C-ring with an ethylene
linkage at the C13- and C15-positions. The E-ring always has an
oxo group substituted at the C131-position.
Some fossil porphyrins, observed in sediment and oil shales,
have a different five- membered ring fused to the A-ring by
ethylene linkage at the C3- and C5-positions (Fig. 2, left) [6]. This
five-membered ring is named F-ring in this paper. To the best of
Compound 2b was dissolved in a 1:2 mixture of benzene and
toluene and heated at 80 °C for 10 min under nitrogen, then
p-TSA monohydrate (30 eq.) was added [step (v) in Scheme 2].
⇑
Corresponding author.
E-mail address: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki).
https://doi.org/10.1016/j.tetlet.2019.07.025
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
M. Doi, H. Tamiaki / Tetrahedron Letters 60 (2019) 150934
Therefore, the other product was characterized as methyl 3-devi-
nyl-3,5-ethylene-pyropheophorbide-a (3a), which was yielded by
the ethylene linkage at the C3- and C5-positions and 20-debromi-
nation. The isolated yields of 1a and 3a were 6% and 34%, respec-
tively. Notably, both products were 20-unsubstituted through
acidic debromination at the C20-position as reported previously
[12].
To investigate the cyclization pathway, all products from the
reaction were analyzed. In the first step, methyl 20-bromopy-
ropheophorbide-a (1b) was detected, which was prepared by
dehydration at the 3-(1-hydroxyethyl) group of 2b [step (I) in
Scheme 3] [12]. Subsequently, methyl 20-bromo-3-devinyl-3,5-
ethylene-pyropheophorbide-a (3b) was observed [step (II)]
together with 1a and 3a as the above final products. Under the
aforementioned acidic conditions, 1a gave no product [steps (IX)
and (X)], whereas 1b gave 3a as the cyclized and debrominated
product [steps (II) and (IV)] and 1a as the debrominated product
[step (V)]. Considering that no hydration from 1b to 2b proceeded
under the present reaction conditions [step (VIII)], 1b was directly
cyclized to 3b [step (II)] [13]. However, the direct cyclization of 2b
to 3b has not been ruled out yet [step (III)].
Fig. 1. Naturally occurring (B)Chls with different
skeletons.
p-conjugated cyclic tetrapyrrole
Fig. 2. Porphyrinoids possessing both the E- and F-rings: fossil porphyrins
discovered from geological samples (left) and a synthetic chlorin prepared from
bacteriochlorophyll-c (right).
After further refluxing for 17 h, the starting material disappeared,
which was confirmed by TLC and MS spectral analyses. The reac-
tion mixture was conventionally worked up and purified using sil-
ica gel column chromatography and recrystallization to give two
products. The first eluted product was identified as 1a, which
was produced via dehydration of the C3-substituent and debromi-
nation at the C20-position of 2b [12]. The second eluted product
gave the same parent peak in the mass spectrum as in 1a, but nei-
ther peaks of the vinyl group nor one of the three meso-proton sig-
nals were visible in the 1H NMR spectrum. Two methylene
resonances newly appeared and were correlated with each other,
and the meso-proton at the C5-position (not the C20-position)
was missing from the 2D 1H NMR COSY/NOESY spectral analysis.
Scheme 3. Synthetic route of 2b to 1a and 3a.
Scheme 1. Synthesis of methyl 20-bromobacteriopheophorbide-d (2b): (i) CH3OH; (ii) (a) H2SO4, (b) H2SO4/CH3OH, (c) collidine, reflux; (iii) (a) HBr/AcOH, (b) H2O,
(c) CH2N2/Et2O; (iv) C5H5NH+Br3–/CH2Cl2.
Scheme 2. Acidic dehydration, cyclization, and/or debromination of 2b: (v) p-TSAÁH2O/benzene, toluene, 80 °C.

M. Doi, H. Tamiaki / Tetrahedron Letters 60 (2019) 150934
3
In the cyclization reaction route, the C32-cationic species was
produced from the 3-vinyl group of 1b (or the 3-(1-hydroxyethyl)
group of 2b) under the acidic conditions, and then the C32-cation
electrophilically attacked the C5-atom, followed by deprotonation
at the C5-position to produce the cyclized product 3b (see
Scheme S1 of SI). Finally, the protonation of 3b at the C20-position
and the removal of the bromonium cation produced 3a. It is noted
that the debromination in the last stage is important for the
desired cyclization.
20-Unsubstituted 1a and 2a gave no cyclized products, whereas
20-brominated 1b and 2b did afford their cyclized products. Con-
sequently, the 20-bromo atom was requisite for the present
cyclization, which is consistent with the previous cyclization in
the 20-methyl analog mentioned above [7]. The presence of the
C20-substituents would direct the C3-substituents toward the
C5-position through their steric interaction with the 2-methyl
group [14,15]. The regioselective 20-bromination of 3-vinyl-chlo-
rin 1a to 1b is problematic owing to the presence of the highly
reactive 3-vinyl group [12,16]; however, 2a bearing the less
reactive 3-(1-hydroxyethyl) group was readily 20-brominated to
2b [11,12]. Therefore, 3a was synthesized as desired from 1a via
2a/b, whose total isolated yield was 27%.
To investigate the effect of ethylene linkage at the C3- and
C5-positions of the F-ring on optical properties, methyl mesopy-
ropheophorbide-a (4), lacking the F-ring by cleavage of the
C32–C5 bond of 3a, was prepared for the hydrogenation of the 3-
vinyl group in 1a as the reference compound [step (vi) in Scheme 4]
[9,12].
The UV–visible absorption spectra of 3a and 4 in dichloro-
methane are shown in Fig. 3A. Compound 3a gave its Qy(0,0)/
(0,1) and Qx(0,0)/(0,1) maxima at 655/600 and 551/517 nm,
respectively, and showed slightly blue-shifted Qy bands and largely
red-shifted Qx bands as compared with those of 4. The main Soret
(B) band of 3a is more intense than that of 4. The enhancement is
ascribed to the large red-shift of the Bx band and the smaller shift
of the By band by the cyclization of 3a to 4. This interpretation is
supported by the difference absorption spectrum (Fig. S1).
Scheme 4. Synthesis of 4: (vi) H2, Pd–C/acetone.
Fig. 4. Normalized visible absorption (dashed line) and fluorescence emission
spectra (excited at Soret maxima, solid line) of 3a (A) and 4 (B) in aerated CH2Cl2 at
room temperature.
Fig. 3. UV–visible absorption (A) and CD spectra (B) of 3a (red line) and 4 (blue line)
in CH2Cl2.

4
M. Doi, H. Tamiaki / Tetrahedron Letters 60 (2019) 150934
Table 1
Optical properties of 3a and 4 in CH2Cl2.a
Compound
kabs/nm
kem/nm
D
/cmÀ1
Uem/%
kem/ns
Soret
Bx/By
Qx
Qy
main/minor
(0,1)/(0,0)
(0,1)/(0,0)
3a
4
411.8b
394.8/410.2
516.6/551.2
504.4/535.6
600.2/655.0
601.6/656.8
657.2/705.3
660.1/709.0
50
80
16
18
8.4
6.1
a
kabs, absorption maximum; kem, fluorescence emission maximum (excited at Soret maximum);
D
, Stokes shift = [1/kabs(Qy(0,0)) À 1/kem(main)] Â 107; Uem, fluorescence
quantum yield (excited at Soret maxima); kem, fluorescence emission lifetime (excited at 403 nm).
b
Not resolved.
From the CD spectra of 3a and 4 (Fig. 3B), the cyclization moved
the negative peak at the Qy(0,0) region to a slightly shorter wave-
length and the positive peak at the Qx(0,0) region to a much longer
wavelength, which are consistent with the aforementioned
UV–visible absorption spectral shifts. Thus, we inferred that the
electronic transition moment along the molecular x-axis (see
Scheme 4) was considerably perturbed via the cyclization, result-
ing in significantly bathochromic shifts of Qx and Bx bands.
Upon excitation at the Soret maxima, both 3a and 4 strongly
emitted red light in aerated dichloromethane at room temperature.
Their fluorescence emission spectra were obtained with mirror
images of the Qy bands (Fig. 4). Both emission spectra were similar,
which was also comparable to their Qy absorption spectra. The
Stokes shift of 3a was smaller than that of 4 (see also Table 1).
The suppression indicates that the molecular structural difference
between the ground and excited states of 3a is smaller than that of
4 because of a limited molecular distortion in the chlorin skeleton
by the cyclization. Additionally, the cyclization slightly reduced the
fluorescence quantum yield and increased the fluorescence
lifetime (Table 1).
Scientific Research on Innovative Areas ‘‘Innovation for Light-
Energy Conversion (I4LEC)”.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.07.025.
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In summary, the hydration of 1a, regioselective bromination at
the C20-position, and heating in a mixture of benzene and toluene
containing an excess amount of p-TSA successfully gave
a
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20-bromo atom was critical. Cyclization by the linkage at the
C3- and C5-positions, as in 4 to 3a, red-shifted Qx and Bx bands
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Acknowledgments
[15] An electronic factor of the 20-substituent might contribute to the cyclization,
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group [7] and the electron-withdrawing 20-bromo atom gave their cyclized
compounds.
We would like to thank Mr. Nobutaka Ariki of Ritsumeikan
University for experimental assistance. This work was partially
supported by JSPS KAKENHI Grant Number JP17H06436 in
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