Transformation of carbonyl to vinylidene groups in the π-conjugated peripheral substituent of chlorophyll derivatives by Tebbe reagent

Article abstract of DOI:10.1016/j.tetlet.2016.01.023

The 13¹-oxo-moiety of chlorophyll-a derivatives including methyl (pyro)pheophorbides-a, mesopyropheophorbide-a, and bacteriopheophorbide-d possessing vinyl, ethyl, and 1-hydroxyethyl groups, respectively, at the 3-position was transformed into the corresponding exo-methylene group by treatment of Tebbe reagent. The synthetic procedures were useful for the regioselective conversion of the carbonyl to vinylidene group at the 3-position and naturally occurring chlorophyll-d (3-CHO) was successfully modified to chlorophyll-a (3-CH=CH₂). Under the methylenation conditions, ester-carbonyl, hydroxy, and allyl groups in the peripheral substituents were tolerant as well as an acid-labile magnesium at the central position of chlorophylls.

Full text of DOI:10.1016/j.tetlet.2016.01.023

Tetrahedron Letters 57 (2016) 788–790
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Tetrahedron Letters
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Transformation of carbonyl to vinylidene groups in the
p-conjugated
peripheral substituent of chlorophyll derivatives by Tebbe reagent
Hitoshi Tamiaki a, , Kazuki Tsuji a,b, Shinnosuke Machida a, Misato Teramura 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
The 131-oxo-moiety of chlorophyll-a derivatives including methyl (pyro)pheophorbides-a,
mesopyropheophorbide-a, and bacteriopheophorbide-d possessing vinyl, ethyl, and 1-hydroxyethyl
groups, respectively, at the 3-position was transformed into the corresponding exo-methylene group
by treatment of Tebbe reagent. The synthetic procedures were useful for the regioselective conversion
of the carbonyl to vinylidene group at the 3-position and naturally occurring chlorophyll-d (3-CHO)
was successfully modified to chlorophyll-a (3-CH@CH2). Under the methylenation conditions,
ester–carbonyl, hydroxy, and allyl groups in the peripheral substituents were tolerant as well as an
acid-labile magnesium at the central position of chlorophylls.
Article history:
Received 7 December 2015
Revised 29 December 2015
Accepted 7 January 2016
Available online 7 January 2016
Keywords:
Carbonyl methylenation
Methylene titanium
Pheophorbide
Ó 2016 Elsevier Ltd. All rights reserved.
Semi-synthetic modification
Chlorophylls are one family of natural porphyrinoids including
hemes and cobalamins.1 Photosynthetically active chlorophylls
are cyclic tetrapyrroles and characterized by a fused and exo-
five-membered ring, called E-ring, bearing an oxo moiety (see
the left drawing of Fig. 1).2 Recently, (bio)chemical modification
of the E-ring has attracted much attention from the viewpoints
of chlorophyll metabolism,3,4 development of novel photoactive
pigments,5–7 and so on. A variety of such semi-synthetic chloro-
phylls are available in the literature.8 We have already reported
that modification of the 131-oxo group of methyl pyropheophor-
bide-a (1, see the right drawing of Fig. 1), one of the chlorophyll-
a derivatives, to the exo-methylene group in 2, caused slight
changes of the optical properties including electronic absorption
bands: redmost (Qy) maximum = 667 (13-C@O) to 666 nm
(13-C@CH2) in CH2Cl2.5 Therefore, such methylene analogs would
be useful for the models of naturally occurring chlorophylls. The
reported chemical transformation involved multi-step processes
(hydrolysis of the 17-propionate residue, methylation of the
13-carbonyl group to 13-CH(OH)Me, re-esterification of the free
carboxylic acid, and acidic dehydration of the resulting 131-methyl
carbinol 3) and the total yield was very low (at most 3%).5,9 Here
we report one-step methylenation of the 131-oxo moiety using
Tebbe reagent, Cp2Ti(AClA)(ACH2A)AlMe2 (Cp = cyclopentadi-
enyl),10 for the efficient transformation. Furthermore, the synthetic
procedures were applied to the transformation of the 3-carbonyl
Figure 1. Molecular structures of natural chlorophylls (left) and their synthetic
derivatives (right).
groups directly conjugated with chlorophyll
responding vinylidene groups.
p-systems to the cor-
First, Wittig reaction of methyl pyropheophorbide-a (1)11,12 was
applied with methylenetriphenylphosphorane,13 but the starting
ketone was recovered. The 13-keto carbonyl group was inactive
with the Wittig reagent, and so was modified to the corresponding
thioketo group. Treatment of more reactive methyl 131-deoxo-
131-thioxopyropheophorbide-a (4)14 with CH2@PPh3 or CH2N3
⇑
Corresponding author. Fax: +81 77 561 3729.
E-mail address: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki).
http://dx.doi.org/10.1016/j.tetlet.2016.01.023
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

H. Tamiaki et al. / Tetrahedron Letters 57 (2016) 788–790
789
left drawing of Fig. 1) isolated from culturing cells of a cyanobac-
terium Acaryochloris marina12,18 was treated with Tebbe reagent
and chlorophyll-a (3-CH@CH2) was successfully detected by HPLC.
Both the central magnesium and the phytyl ester in the propionate
residue remained in the reaction. This is the reverse reaction of
biosynthesis from chlorophyll(ide)-a to chlorophyll(ide)-d.19
In conclusion, Tebbe reagent is useful for the methylenation of
carbonyl groups at the peripheral position of naturally occurring
chlorophyll as well as semi-synthetic chlorophyll derivatives. The
reactivity of carbonyl groups decreased in the order of
3-CHO > 3-COMe > 13-CO ꢁ 132-CO and 172-CO. Alcohol and ester
functional groups as well as acidic labile central magnesium are
tolerant of the present methylenation. Such regioselective trans-
formation of C@O to C@CH2 is promising for the methylenation
of other natural chlorophylls than chlorophyll-d (3-CHO): 2-CHO
in chlorophyll-f, 3-COMe in (zinc) bacteriochlorophylls-a(0)/b and
bacteriopheophytins-a/b, and 7-CHO in (divinyl)chlorophyll-b
and bacteriochlorophylls-e/f.20
Figure 2. Molecular structures of semi-synthetic 131-oxo- and methylene-chlorins
7/9 and 8/10 as well as 31-oxo- and methylene-chlorins 11/13/15 and 12/14.
(Barton–Kellogg reaction)15 gave no desired exo-methylene product. Then,
Tebbe methylenation was examined. Methyl pyropheophorbide-a
(1) was dissolved in dry THF under an argon atmosphere and
cooled down to ꢀ20 °C in the presence of pyridine, to which was
added commercially available Tebbe reagent (10 equiv, 0.5 M in
toluene); the
l-methylene reagent was reacted with pyridine to
Acknowledgments
form CH2@TiCp2 as a transient active species.10 After being stirred
for 10 min in the dark, the reaction was quenched with an aqueous
sodium hydrogen carbonate. The reaction mixture was extracted
with dichloromethane, dried over sodium sulfate, filtered, and
chromatographed with silica gel (0–2% Et2O–CH2Cl2) to successfully
give methyl 131-deoxo-131-methylenepheophorbide-a (2)5,16 in a
35% yield. The yield of one-step methylenation was 10-fold larger
than that of the multi-step transformation reported earlier.5
Reactive Tebbe reagent was useful for methylenation of the less
reactive 13-keto carbonyl group. Under the present reaction
conditions, the ester carbonyl group in the 17-propionate residue
was not modified due to its much lower reactivity. The reactions
for a longer time (>10 min) and/or at a higher temperature
(>ꢀ20 °C) substantially decreased the isolated yield.
We thank Dr. Meiyun Xu, Mr. Masaki Kuno, and Mr. Shoya
Hiraki of Ritsumeikan University for their experimental assistance.
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Artificial Photosynthesis (AnApple)’
(No. 24107002) from the Japan Society for the Promotion of
Science (JSPS).
References and notes
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Methyl pheophorbide-a (5)12 has a similar 13-carbonyl group to
methyl pyropheophorbide-a (1), but the former carbonyl group is
more sterically crowded than the latter due to the neighboring
132-methoxycarbonyl group. In spite of the steric disturbance,
Tebbe reaction of methyl pheophorbide-a (5) afforded the
131-methylene product 6.16 It is noted that the undesired product
methylenated at the 132-methoxycarbonyl group was not
observed from the reaction mixture. Additionally, the 3-ethyl ana-
log of methyl pyropheophorbide-a (7, methyl mesopyropheophor-
bide-a, see Fig. 2) and its 31-hydroxy derivative
9 (methyl
bacteriopheophorbide-d)11,12 were modified by the same Tebbe
reaction to their 131-methylene-chlorins 8 and 10,16 respectively,
in comparable yields to 1 ? 2 (3-vinyl analog). Such substituents
at the diagonally opposite 3-position did not disturb the Tebbe
methylenation at the 131-oxo moiety.
Based on the aforementioned methylenation of keto–carbonyl
groups at the 13-position, the 3-acetyl group was reacted with
Tebbe reagent. 3-Acetyl-131-deoxochlorin 116 was similarly
treated with Tebbe reagent to give desired 31-methylene product
1216 in a 26% yield. Moreover, methyl 3-acetyl-3-devinylpyro-
pheophorbide-a (13)11,12 was methylenated with Tebbe reagent
to afford methyl 31-methylpyropheophorbide-a (14)16 as a major
isolated product (15%). In the reaction mixture, the further
131-methylenated derivative of 14 was observed, but no singly
131-methylenated product of 13 was visible. The regioselectivity
is ascribable to the fact that the 3-C@O is more reactive to
nucleophiles than the 13-C@O.17
Since aldehydes are attacked by nucleophiles more rapidly than
ketones, methyl pyropheophorbide-d (15)12 bearing the 3-formyl
group was reacted with Tebbe reagent to afford the corresponding
3-vinylchlorin 1, methyl pyropheophorbide-a (61% isolated yield).
Under the same reaction conditions, chlorophyll-d (3-CHO, see the

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H. Tamiaki et al. / Tetrahedron Letters 57 (2016) 788–790
16. Specific spectral data of methylenated chlorins; 2: 1H NMR (CDCl3) d = 6.27
(1H, s, 131=CH cis to C131AC13), 5.84 (1H, s, 131=CH trans to C131AC13) and
HRMS (APCI) m/z = 547.3068 (MH+); 6: d = 6.32, 6.03 (each 1H, s, cis-, trans-
131=CH) and m/z = 605.3110 (MH+); 8: d = 6.24, 5.81 (each 1H, s, cis-, trans-
131=CH) and m/z = 549.3224 (MH+); 10: d = 6.30, 5.84 (each 1H, s, cis-, trans-
131=CH) and m/z = 565.3173 (MH+); 12: d = 6.09 (1H, s, 31=CH cis to C31AC3),
5.64 (1H, s, 31=CH trans to C31AC3) and m/z = 549.3225 (MH+); 14: d = 6.31,
5.89 (each 1H, s, cis-, trans-31=CH) and m/z = 563.3016 (MH+).
17. Tamiaki, H.; Miyatake, T.; Tanikaga, R. Tetrahedron Lett. 1997, 38, 267–270.
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20. Tamiaki, H.; Teramura, M.; Tsukatani, Y. Bull. Chem. Soc. Jpn. 2016, 89, in press.
http://dx.doi.org/10.1246/bcsj.20150307.