Synthesis of potential antitumor agents, dimeric and trimeric chlorins, from methylpheophorbide a

Article abstract of DOI:10.1007/s11172-011-0112-0

A series of dimeric and trimeric chlorins were synthesized from methylpheophorbide a. They are potential photosensitizers for photodynamic therapy in oncology. The macrocycles were conjugated due to the formation of ester and amide bonds. The carboxy groups were activated and catalytic transesterification was carried out to form the ester bond. The amide bond was formed using carboxy group activation; in several cases, amidation of the ester group in position 13(2) of the exocycle of methylpheophorbide α was carried out, which does not require activation.

Full text of DOI:10.1007/s11172-011-0112-0

Russian Chemical Bulletin, International Edition, Vol. 60, No. 4, pp. 719—728, April, 2011
719
Synthesis of potential antitumor agents, dimeric and trimeric chlorins,
from methylpheophorbide a
D. V. Belykh,a M. V. Mal´shakova,a Yu. A. Yudina,b K. A. Zavadskaya,b V. M. Khudyaev,b and A. V. Kuchina
aInstitute of Chemistry, Komi Research Center, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167982 Syktyvkar, Russian Federation.
Fax: +7 (821) 221 8477. Eꢀmail: belykhꢀdv@mail.ru
bSyktyvkar State University,
55 Oktyabr´sky prosp., 167000 Syktyvkar, Russian Federation
A series of dimeric and trimeric chlorins were synthesized from methylpheophorbide a.
They are potential photosensitizers for photodynamic therapy in oncology. The macrocycles
were conjugated due to the formation of ester and amide bonds. The carboxy groups were
activated and catalytic transesterification was carried out to form the ester bond. The amide
bond was formed using carboxy group activation; in several cases, amidation of the ester group
in position 13(2) of the exocycle of methylpheophorbide а was carried out, which does not
require activation.
Key words: methylpheophorbide a, dimers, trimers, chlorin е6, oligochlorins.
Synthesis of potential photosensitizers (PS) for photoꢀ
dynamic therapy (PDT) in oncology is a topical direction
of the chemistry of tetrapyrrole macrocycles. The known
drug Photofrin II, which exerts a photocytotoxic effect on
cancer cells, is a mixture of porphyrin dimers and triꢀ
mers.1 It is reasonable to expect that natural dimeric and
trimeric porphyrins possess similar biological activity, and
the activity of oligoporphyrin can depend strongly on the
mode of conjugation of macrocycles. Dimeric porphyrins
are also used for modeling various biological processes.2,3
In connection with the aforesaid, it seems interesting to
develop methods for synthesis of dimers and trimers from
chlorophyll derivatives. In the present work, we syntheꢀ
sized a series of chlorin dimers, whose macrocycles are
linked by bridges of various length. The macrocycles were
conjugated due to the formation of the amide or ester
bond. One of the variants of macrocycle conjugation modes
during preparation of dimers was used for the synthesis of
trimeric chlorins.
chlorin with the activated carboxy group of another chlorꢀ
in (activation by formation of mixed anhydride).
In the synthesis of dimers 14—16, the methylproꢀ
pionate substituent of methylpheophorbide а (1) was
hydrolyzed to form the carboxy group, and the correspondꢀ
ing pyro derivative 6 was obtained by reflux of pheophorꢀ
bide а 5 in collidine (see Scheme 1). In the synthesis of
dimer 17, more remote carboxy group was inserted by the
treatment of aminochlorin 3 with succinic anhydride. The
carboxy group of the synthesized chlorins was activated by
the addition of di(tertꢀbutyl) dicarbonate.
1
The Н NMR spectrum of dimer 15 contains signals
of two porphyrin macrocycles. In addition, it exhibits
a broadened multiplet corresponding to protons of two
amide groups, one of which was formed due to the interꢀ
action of pyropheophorbide a (6) with 5,17ꢀdimethyl
chlorin e6 13ꢀNꢀ(6ꢀaminohexyl)amide (4). Similar speꢀ
cific features are observed in the spectra of dimers 14 and
16. The peaks of the corresponding molecular ions are
detected in the mass spectra of dimers 14—16.
Results and Discussion
The MALDI mass spectrum of dimer 17 exhibits peaks
attributed to its molecular ion, protonated molecular ion,
and the adduct of compound 17 with the sodium cation.
In the 1Н NMR spectrum of dimer 17, the signals of two
macrocycles in the molecule coincide due to symmetry of
its structure.
In several cases, the amide bond was formed without
the use of activating agents. It is known that reflux of
methylpheophorbide а (1) with primary and secondary
aliphatic amines results in the amidation of the ester group
In Scheme 1, the synthesis based on methylpheophorꢀ
bide a (1) of analogs of chlorophyll a 2—6, 10, 11, and 13
containing carboxy, hydroxy, and amino groups is shown.
The latter were used for the preparation of ensembles conꢀ
taining two and three chlorin residues: dimeric and triꢀ
meric chlorins. In the synthesis of dimers 14—17 (Scheme 2),
the macrocycles were conjugated by amide bond formaꢀ
tion due to the interaction of the amino group of one
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 704—713, April, 2011.
1066ꢀ5285/11/6004ꢀ719 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Belykh et al.
Scheme 1
Reagents and conditions: a. NaIO4, OsO4, 95% AcOH, THF, 3 h, ~20 °C; b. MeNH2, THF, 1 h, ~20 °C; c. NaBH4, THF, 24 h,
~20 °C; d. HCl, H2O, acetone, 24 h, ~20 °C; e. Collidine, reflux, 40 min; f. Synthesis of 2: ethanolamine, chloroform, 4 h, ~20 °C;
synthesis of 3: ethylenediamine, chloroform, 3 h, ~20 °C; synthesis of 4: hexamethylenediamine, THF, 4 h, ~20 °C; g. ethylenediꢀ
amine (2 mol), 22 h, ~20 °C; h. Succinic anhydride, CH2Cl2, 2 h, ~20 °C.

Oligomers based on methylpheophorbide a
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
721
Scheme 2
R = H: n = 2 (14), 6 (15); R = CO2Me, n = 2 (16)
Reagents and conditions: a. (1) Di(tertꢀbutyl) dicarbonate, dichloromethane—pyridine, 15 min, 0 °C; (2) 3 or 4, 1 h, ~20 °C;
b. (1) Di(tertꢀbutyl) dicarbonate, dichloromethane—pyridine, 15 min, 0 °С; (2) 3, 1 h, ~20 °C.
1
of the exocycle to form the corresponding 13(2)ꢀamides.4
No activation is required for this reaction to occur but can
be used for the conjugation of large fragments.5 This was
accomplished in this work for the synthesis of dimeric and
trimeric chlorins (Scheme 3). In the synthesis of dimeric
chlorins 18 and 19, for amidation it is enough to reflux
compound 1 in toluene with the corresponding aminoꢀ
chlorins 3 or 4 for 1 h. For the synthesis of trimer 21 by the
interaction of diaminochlorin 10 with a twofold molar
excess of compound 1, it is needed to elongate the reacꢀ
tion duration to 10 h. However, despite this, the yield of
trimer 21 (30%) can be considered satisfactory.
The structures of the synthesized oligochlorins were
confirmed by the data of 1Н NMR spectroscopy and mass
spectrometry. The mass spectra of dimers 18 and 19 and
trimer 21 exhibit peaks of the corresponding molecular
ions. The 1Н NMR spectrum of chlorin dimer 18 contains
signals of two porphyrin macrocycles and an additional
broadened triplet appears at δ 7.76, which corresponds to
the proton of the amide group formed by the amidation of
the ester group of methylpheophorbide a (1) with aminoꢀ
chlorin 3. In addition, the singlet signal of the proton in
position 13(2) of the exocycle, which is present in the
1Н NMR spectrum of the initial methylpheophorbide а
(δ 6.17), is also observed in the spectrum of the syntheꢀ
sized dimer 18. This proves that no exocycle opening ocꢀ
curred. No singlet signal at δ 3.80 is observed in the
1Н NMR spectrum of dimer 18, confirming that this was
the ester group of the exocycle to which amidation ocꢀ
curred. Similar changes were observed in the Н NMR
spectra of dimer 19 and trimer 21.
The exocycle of the phorbine fragments of the syntheꢀ
sized dimers and trimers can be opened by the action of
amines. This can be used for the transformation of the
phorbine fragments into chlorin moieties. We performed
this transformation by the action of methylamine in aqueous
THF on dimer 19 and trimer 21. The 1Н NMR spectrum
of dimer 20 contains an additional (compared to the specꢀ
trum of the initial compound 19) broadened multiplet
(δ 6.19—6.13) corresponding to the proton of the amide
group, which was formed by opening of the exocycle of
dimer 19 by methylamine. In addition, a doublet assigned
to protons of the methyl group of the methylamide fragꢀ
ment is observed at δ 3.24. The mass spectrum of the
synthesized chlorin—chlorin dimer 20 exhibits peaks corꢀ
responding to its molecular ion and the adduct of comꢀ
pound 20 with the sodium cation. The structure of chlorin
trimer 22 was similarly confirmed.
In the synthesis of dimers 23—25 (Scheme 4), the
ester bond was formed by the catalytic transesterification
of the methoxycarbonyl group in position 13(2) of methylꢀ
pheophorbide а (Nꢀmethylꢀ2ꢀchloropyridinium iodide in
the presence of 4ꢀ(dimethylamino)pyridine as a catalyst).6
The reaction was carried out by reflux in toluene for 3 h.
As a result, dimers 23—25 were obtained, whose macroꢀ
cycles are linked by ester bonds (see Scheme 4). The
1Н NMR spectrum of product 24 exhibits signals of two
macrocycles of the chlorophyll derivatives, indicating

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Belykh et al.
Scheme 3
Reagents and conditions: a. 3 or 4, toluene, reflux, 1 h; b. Methylamine, THF, 1 h, ~20 °C; c. Toluene, reflux, 10 h.

Oligomers based on methylpheophorbide a
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
723
Scheme 4
i. NꢀMethylꢀ2ꢀchloropyridinium iodide, DMAP, reflux, toluene, 3 h.
dimer formation. In addition, no singlet signal correspondꢀ
ing to the methyl group in position 13(2) is observed in the
1Н NMR spectrum of dimer 24. This suggests that the
reaction proceeded at the ester group in position 13. The
mass spectrum of the synthesized compound contains
a peak corresponding to the protonated molecular ion of
dimer 24. The structures of dimers 23 and 25 were conꢀ
firmed analogously.
vation and without activating agents, whereas the formaꢀ
tion of ester bonds involved the catalyst. The synthesized
individual chlorins can be considered as potential
photosensitizers for photodynamic therapy in oncology.
Experimental
Thus, we synthesized dimeric and trimeric chlorins
14—25, whose macrocycles are linked by bridges of various
length due to the formation of amide and ester bonds.
Amide bonds were formed using both carboxy group actiꢀ
1
Н NMR spectra were recorded on a Bruker Avanceꢀ300
instrument (300 MHz) in CDCl3 (except for specially marked
cases). Mass spectra (MALDI) were obtained on a Vision
2000 mass spectrometer. Silica gel 60 (0.060—0.200 mm,

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Belykh et al.
70—230 mesh) was used for column chromatography. Methylꢀ
pheophorbide а (1) was obtained according to the procedure
described earlier.7 15,17ꢀDimethyl chlorin e6 13ꢀNꢀ(2ꢀaminoꢀ
ethyl)amide (3), 15,17ꢀdimethyl chlorin e6 13ꢀNꢀ(6ꢀaminoꢀ
hexyl)amide (4), and 15ꢀmethyl chlorin e6 13,17ꢀN,N´ꢀ(2ꢀ
aminoethyl)diamide (10) were synthesized by the treatment of
methylpheophorbide а with ethylenediamine and hexamethylꢀ
enediamine using our earlier developed procedures8—10; pheoꢀ
phorbide а (5), methylpyropheophorbide а (12), and pyroꢀ
pheophorbide а (6) were synthesized as described in the literaꢀ
ture.11 15,17ꢀDimethyl chlorin e6 13ꢀNꢀ(2ꢀhydroxyethyl)amide (2)
was synthesized by the action of ethanolamine on methylꢀ
phephorbide а using the procedure described earlier.8,9 The hydrꢀ
oxy derivative of chlorin е6 (11) was synthesized by the reaction
of aminochlorin 3 with succinic anhydride as described earlier.12
The spectral characteristics of compounds 1—7, 11, and 12 are
analogous to those presented in the literature. Methylpheoꢀ
phorbide d (7) was obtained by the known procedure.13 In the
assignment of signals of the phorbine macrocycle of dimers
14—16, 18, 19, 23, and 24 and trimer 21 as well as of signals of
the methylpheophorbide macrocycle of dimer 25, the correꢀ
sponding atoms are marked with trait (´).
15,17ꢀDimethyl ester of chlorin е6 3ꢀdevinylꢀ3ꢀformylꢀ13ꢀ
Nꢀmethylamide (8). Methylamine (3 mL) was added to a soluꢀ
tion of methylpheophorbide d (7) (100 mg) in THF (7 mL). The
reaction mixture was magnetically stirred at ~20 °C for 50 min
(TLC: Sorbfil, CCl4—acetone (4 : 1) mixture as eluent). The
mixture was diluted with chloroform (50 mL), and methylamine
excess was washed off with water. The obtained solution was
dried over anhydrous Na2SO4 and evaporated. The mixture was
chromatographed on silica gel (CCl4—acetone (10 : 1) as eluent).
Compound 8 was obtained in a yield of 90 mg (85%). 1Н NMR,
δ: 11.56 (s, 1 H, C(3)СН=О); 10.30 (s, 1 H, H(10)); 9.65 (s, 1 H,
H(5)); 8.98 (s, 1 H, H(20)); 6.42 (q, 1 H, C(13)СОNHMe
(amide), J = 5.14 Hz); 5.58 (d, 1 H, C(15)СН2СО2Me,
J = 18.6 Hz); 5.31 (d, 1 H, C(15)СН2СО2Me, J = 19.2 Hz); 4.51
(q, 1 H, H(18), J = 7.1 Hz); 4.40 (br.d, 1 H, H(17), J = 8.7 Hz);
3.87 (s, 3 H, C(15)СН2СО2Me); 3.81 (s, 3 H, C(12)Me); 3.66
(s, 1 H, C(17)СН2СН2СО2Me); 3.58 (s, 3 H, C(2)Me); 3.34
(s, 3 H, C(7)Me); 3.77 (q, 2 H, C(8)CН2Me, J = 7.7 Hz); 3.32
(d, 3 H, C(13)СОNHMe, J = 4.5 Hz); 2.68—2.20 (m, 4 H,
C(17)CН2CН2СО2Me); 1.74 (d, 3 H, C(18)Me, J = 7.2 Hz);
1.73 (t, 3 H, C(8)СН2Me, J = 7.5 Hz); –1.44 (br.s, 1 H, IꢀNH);
–1.96 (br.s, 1 H, IIIꢀNH).
3.29 (d, 3 H, C(13)СОNHMe, J = 4.8 Hz); 2.66—2.49
(m, 2 H, C(17)CН2СН2СО2Me); 2.28—2.11 (m, 2 H,
C(17)СН2CН2СО2Me); 1.75 (d, 3 H, C(18)Me, J = 7.6 Hz);
1.74 (t, 3 H, C(8)СН2Me, J = 7.6 Hz); –1.68 (br.s, 1 H, IꢀNH);
–1.93 (br.s, 1 H, IIIꢀNH).
13(1)ꢀDeoxoꢀ13(1)ꢀhydroxymethylpyropheophorbide a (13).
NaBH4 (300 mg) was added to a solution of methylpyroꢀ
pheophorbide a (12) (210 mg) in THF (20 mL). The reacꢀ
tion mixture was stirred at ~20 °C for 48 h (TLC: Sorbfil,
CCl4—acetone (4 : 1) as eluent). The mixture was diluted with
chloroform (50 mL), and NaBH4 excess with washed off with
water. The chloroformic solution was dried over anhydrous
Na2SO4 and evaporated. The residue was chromatographed on
silica gel (CCl4—acetone (20 : 1) as eluent). Compound 13 was
obtained as a mixture of diastereomers in a yield of 123 mg
1
(59%). Н NMR, δ: 9.90 (s, 1 H, H(10)); 9.67 (s, 1 H, H(5));
8.93 (s, 1 H, H(20)); 8.26 (dd, 1 H, C(3)СН=СН2, J = 18.0 Hz,
J = 12.0 Hz); 6.49, 6.52 (both d, 1 H each, C(13)C(1)H, J = 6.6 Hz);
6.13 (d, 1 H, C(3)СН=CHH (cis), J = 11.1 Hz); 6.09 (d, 1 H,
C(3)СН=СНH (cis), J = 17.7 Hz); 5.27, 5.38 (both dd, 1 H each,
J = 18.0 Hz, J = 6.0 Hz)*; 4.72, 4.59 (both d, 1 H each,
C(13)C(2)СН2, J = 18.0 Hz)*; 4.68 (m, 1 H, H(18)); 4.49,
4.49 (both d, 1 H each, H(17), J = 6.2 Hz)*; 3.88 (q, 2 H,
C(8)СН2Me, J = 6.5 Hz); 3.65 (s, 3 H, C(2)Me); 3.59 (s, 3 H,
C(17)СН2СН2СО2Me); 3.46 (s, 3 H, C(12)Me); 3.44 (s, 3 H,
C(7)Me); 2.88—2.50 (m, 4 H, C(17)СН2СН2СО2Me); 1.88,
1.89 (both d, 3 H each, C(18)Me, J = 6.0 Hz)*; 1.79 (t, 3 H,
C(8)СН2Me, J = 9.0 Hz); –1.31 (br.s, 1 H, IꢀNH); –3.18 (br.s,
1 H, IIIꢀNH).
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[2ꢀ(Nꢀ17(3)ꢀ
pyropheophorbidyl)aminoethyl]amide (14). Di(tertꢀbutyl) diꢀ
carbonate (22 mg, 0.093 mmol) was added to a solution
of pyropheophorbide а (6) (50 mg, 0.093 mmol) in a pyriꢀ
dine—CH2Cl2 (5 : 10) mixture, and the reaction mixture was
stirred at 0 °C for 15 min. Aminochlorin 3 (62 mg, 0.093 mmol)
was added, and the mixture was stirred at ~20 °C for 1 h
(TLC: Sorbfil, CCl4—acetone (2 : 1) as eluent). The reaction
mixture was diluted with chloroform (50 mL), pyridine was
washed off with 7% HCl, and the acid was washed off with water.
The chloroformic solution was dried over anhydrous Na2SO4
and evaporated. The residue was chromatographed on silica gel
(CCl4—acetone (10 : 1) as eluent). Dimer 14 was obtained in
1
a yield of 61 mg (55%). Н NMR, δ: 9.29 (s, 1 H, H(10)); 8.69
(s, 1 H, H(5)); 8.86 (s, 1 H, H(10´)); 8.45 (s, 1 H, H(5´)); 8.16
(s, 1 H, H(20)); 7.79 (s, 1 H, H(20´)); 7.90 (dd, 1 H, C(3)СН=СН2,
J = 18.0 Hz, J = 11.7 Hz); 7.89 (dd, 1 H, C(3´)СН=СН2,
J = 18.0 Hz, J = 11.6 Hz); 7.18 (br.m, 1 H, chlorinꢀ
15,17ꢀDimethyl ester of chlorin е6 3ꢀdevinylꢀ3ꢀhydroxymethylꢀ
13ꢀNꢀmethylamide (9). NaBH4 (100 mg) was added to a solution
of compound 8 (100 mg) in THF (6 mL). The reaction mixꢀ
ture was stored at ~20 °C for 24 h (TLC: CCl4—acetone
(4 : 1) as eluent). The mixture was diluted with chloroform (50 mL),
and NaBH4 excess was washed off with water. The obtained
solution was dried over anhydrous Na2SO4 and evaporated. The
residue was chromatographed on silica gel (CCl4—acetone (5 : 1)
as eluent). Product 9 was obtained in a yield of 106 mg (80%).
1Н NMR, δ: 9.73 (s, 1 H, H(10)); 9.66 (s, 1 H, H(5)); 8.84
(s, 1 H, H(20)); 6.41—6.31 (br.m, 1 H, C(13)СОNHMe);
5.95 (s, 2 H, C(3)СН2ОН); 5.56 (d, 1 H, C(15)СН2СО2Me,
J = 18.9 Hz); 5.29 (d, 1 H, C(15)СН2СО2Me, J = 19.5 Hz); 4.50
(q, 1 H, H(18), J = 7.1 Hz); 4.38 (d, 1 H, H(17), J = 8.7 Hz);
3.85 (s, 3 H, C(15)СН2СО2Me); 3.64 (s, 3 H, C(12)Me);
3.59 (s, 1 H, C(17)СН2СН2СО2Me); 3.50 (s, 3 H, C(2)Me);
3.34 (s, 3 H, C(7)Me); 3.88—3.77 (m, 2 H, C(8)CН2Me);
C(13)СОNHСН2СН2NHСОC(17)ꢀphorbine
(bridge));
6.76 (br.m, 1 H, C(13)СОNHСН2СН2NHСО (bridge));
6.25 (d, 2 H, C(3)СН=СHН (trans), C(3´)СН=СHН (trans),
J = 18.0 Hz); 6.13 (d, 1 H, C(3)СН=СН2 (trans), J = 11.1 Hz);
6.09 (d, 1 H, C(3´)СН=СН2 (trans), J = 11.7 Hz); 5.30
(d, 1 H, C(15)СН2СО2Me, J = 18.9 Hz); 5.15 (d, 1 H,
C(15)СН2СО2Me, J = 19.5 Hz); 4.62 (d, 1 H, C(13)(C(2´))СН2,
J = 19.8 Hz); 4.02 (m, 1 Н, C(13)C(2´)СН2); 4.37 (q, 1 H,
H(18), J = 7.2 Hz); 4.21 (br.d, 1 H, H(17), J = 8.7 Hz);
3.72—3.05 (m, 10 Н, H(18´), H(17´), C(8)СН2Me,
C(8´)СН2Me, C(13)СОNHСН2СН2NHСО (bridge)); 3.60
* Signals of diastereomers differed in chemical shifts are marked
with asterisk (*).

Oligomers based on methylpheophorbide a
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
725
(s, 3 Н), 3.45 (s, 3 Н), 3.42 (s, 3 Н), 3.31 (s, 6 Н), 3.26 (s, 3 Н),
3.08 (br.s, 3 Н), 3.03 (s, 3 Н), 2.33 (br.s, 6 Н) (C(15)СН2СО2Me,
C(17)СН2СН2СО2Me, C(2)Me, C(7)Me, C(12)Me,
C(17)Me, C(2´)Me, C(7´)Me, C(12´)Me); 2.39—2.26 (m, 4 Н,
C(17)СН2СН2СО2Me, C(17´)СН2СН2); 2.25—2.10 (m, 4 Н,
C(17)СН2СН2СО2Me, C(17´)СН2СН2); 1.84—1.69 (m, 6 H,
C(18´)Me, C(8´)СН2Me); 1.44 (d, 3 H, C(18)Me, J = 6.9 Hz);
1.34 (t, 3 H, C(8)СН2Me, J = 7.5 Hz); –0.25 (br.s, 1 H, I´ꢀNH);
–1.94 (br.s, 1 H, III´ꢀNH); –2.06 (br.s, 1 H, IꢀNH); –2.33
(br.s, 1 H, IIIꢀNH). MS (MALDI), m/z: found: 1183.1602.
C71H78N10O7. For [M]+ calculated: 1182.6055.
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[6ꢀ(Nꢀ17(3)ꢀ
pyropheophorbidyl)aminohexyl]amide (15). Di(tertꢀbutyl) diꢀ
carbonate (22 mg, 0.093 mmol) was added to a solution of pyroꢀ
pheophorbide а (6) (50 mg, 0.093 mmol) in a pyridine—CH2Cl2
(1 : 2) mixture, and the reaction mixture was stirred at 0 °C for
15 min. Aminochlorin 4 (68 mg, 0.093 mmol) was added, and the
mixture was stirred at ~20 °C for 1 h (TLC: Sorbfil, CCl4—aceꢀ
tone (2 : 1) as eluent). The reaction mixture was diluted with
chloroform (50 mL), pyridine was washed off with 7% HCl, and
the acid was washed off with water. The chloroformic solution
was dried over anhydrous Na2SO4 and evaporated. The residue
was chromatographed on silica gel (CCl4—acetone (3 : 1) as
eluent). Dimer 15 was obtained in a yield of 33 mg (28%).
1Н NMR, δ: 9.43 (s, 2 H, H(10), H(10´)); 9.41 (s, 1 H, H(5));
9.10 (s, 1 H, H(5´)); 8.80 (s, 1 H, H(20)); 8.49 (s, 1 H,
H(20´)); 8.01 (dd, 2 H, C(3)СН=СН2, C(3´)СН=СН2,
J = 11.9 Hz, J = 17.9 Hz); 6.68—6.57 (br.m, 1 H, chlorinꢀ
tone (2 : 1) as eluent). The reaction mixture was diluted with
chloroform (50 mL), pyridine was washed off with 7% HCl, and
the acid was washed off with water. The chloroformic solution
was dried over anhydrous Na2SO4 and evaporated. The residue
was chromatographed on silica gel (CCl4—acetone (7 : 1) as
eluent). Dimer 16 was obtained in a yield of 46 mg (44%).
1Н NMR (DMFꢀd7), δ: 9.86 (s, 1 H, H(10)); 9.83 (s, 1 H, H(5));
9.76 (s, 1 H, H(10´)); 9.48 (s, 1 H, H(5´)); 9.22 (s, 1 H,
H(20)); 8.99 (s, 1 H, H(20´)); 8.83 (br.t, 1 H, chlorinꢀ
C(13)СОNHСН2СН2NHСОC(17)ꢀphorbine
(bridge),
J = 5.0 Hz); 8.38 (dd, 1 H, C(3)CН=CН2, J = 11.6 Hz,
J = 18.0 Hz); 8.18 (dd, 1 H, C(3´)CН=CН2, J = 11.6 Hz,
J = 18.0 Hz); 7.98 (br.t, 1 H, chlorinꢀC(13)СОNHСН2СН2ꢀ
NHСОC(17)ꢀphorbine (bridge), J = 5.6 Hz); 6.51 (s, 1 H,
C(13)C(2´)Н); 6.49 (d, 1 H, C(3)СН=СНН (trans), J = 18.6 Hz);
6.34 (d, 1 H, C(3´)СН=СНН (trans), J = 17.8 Hz); 6.19 (d, 1 H,
C(3)СН=СНН (cis), J = 11.8 Hz); 6.16 (d, 1 H, C(3´)СН=СНН
(cis), J = 11.6 Hz); 5.62 (d, 1 H, C(15)CН2СО2Me, J = 18.8 Hz);
5.35 (d, 1 H, C(15)CН2СО2Me, J = 19.2 Hz); 4.74—4.65
(m, 2 H, C(18)H, H(18´)); 4.50 (br.d, 1 H, H(17), J = 10.4 Hz);
4.26 (br.d, 1 H, H(17´), J = 7.6 Hz); 3.80 (q, 4 H, C(8)CН2Me,
C(8´)СН2Me, J = 7.6 Hz); 3.76—3.65 (m, 4 H, chlorinꢀ
C(13)СОNHCН2CН2NHСОC(17)ꢀphorbine (bridge)); 3.93
(s, 3 Н), 3.67 (s, 3 Н), 3.62 (s, 3 Н), 3.58 (s, 3 Н), 3.57
(s, 3 Н), 3.44 (s, 3 Н), 3.42 (s, 3 Н), 3.36 (s, 3 Н), 3.22
(s,
3
Н)
(C(15)СН2СО2Me,
C(15´)СН2СО2Me,
C(17)СН2СН2СО2Me, C(2)Me, C(7)Me, C(12)Me, C(7)Me,
C(2´)Me, C(7´)Me, C(12´)Me); 2.82—2.67 (m, 2 Н), 2.58—2.48
(m, 2 Н), 2.37—2.20 (m, 4 Н) (C(17)CН2CН2СО2Me,
C(17)CН´2CН´2); 1.88 (d, 3 H, C(18)Me, J = 7.2); 1.69 (d, 3 H,
C(18´)Me, J = 6.8 Hz); 1.65 (t, 3 H, C(8)СН2Me, J = 7.6 Hz);
1.62 (t, 3 H, C(8´)СН2Me, J = 7.4 Hz); 0.55 (br.s, 1 H, I´ꢀNH);
–1.67 (br.s, 1 H, IꢀNH); –1.69 (br.s, 1 H, III´ꢀNH); –2.00
(br.s, 1 H, IIIꢀNH). MS (MALDI), m/z: found: 1241.4301.
C73H81N10O9. For [MН]+ calculated: 1241.6188.
C(13)СОNH(СН2)6NHСОC(17)ꢀphorbine
(bridge));
5.27—5.18 (br.m, 1 H, chlorinꢀC(13)СОNH(СН2)6NHСОC(17)ꢀ
phorbine (bridge)); 6.34 (d, 1 H, C(3)СН=СНН (trans),
J = 18.0 Hz); 6.29 (d, 1 H, C(3´)СН=СНН (trans),
J = 18.0 Hz); 6.18 (d, 1 H, C(3)СН=СНН (cis), J = 11.7 Hz);
6.14 (d, 1 H, C(3´)СН=СНН (cis), J = 11.7 Hz); 5.51 (d, 1 H,
C(15)СН2СО2Me,
J
=
18.9 Hz); 5.21 (d,
1
H,
C(15)СН2СО2Me, J = 18.9 Hz); 5.03 (d, 1 H, C(13´)C(2)СН2,
J = 19.8 Hz); 4.91 (d, 1 H, C(13´)C(2)СН2, J = 20.1 Hz);
4.50—4.33 (m, 2 H, C(18)H, H(18´)); 4.34 (d, 1 H, H(17),
J = 9.6 Hz); 4.19 (d, 1 H, H(17´)); 3.86—3.75 (m, 4 H,
C(8)СН2Me, C(8´)СН2Me); 3.54—3.41 (m, 4, chlorinꢀ
C(13)СОNHСН2(СН2)4СН2NHСОC(17)ꢀphorbine (bridge));
3.78 (s, 3 Н), 3.58 (s, 3 Н), 3.49 (s, 3 Н), 3.48 (s, 3 Н), 3.38
(s, 3 Н), 3.27 (s, 3 Н), 3.21 (s, 3 Н), 3.07 (s, 3 Н) (C(15)СН2СО2Me,
C(17)СН2СН2СО2Me, C(2)Me, C(7)Me, C(12)Me, C(17)Me,
C(2´)Me, C(7´)Me, C(12´)Me); 2.55—2.30 (m, 4 Н), 2.27—2.15
(m, 4 Н) (C(17)СН2СН2СО2Me, C(17´)СН2СН2); 1.73 (t, 6 H,
C(8´)СН2Me, C(8)СН2Me, J = 7.4 Hz); 1.64 (d, 3 H, C(18´)Me,
J = 7.5 Hz); 1.52 (d, 3 H, C(18)Me, J = 7.5 Hz); 0.96—0.81
(m, 8 H, chlorinꢀC(13)СОNHСН2(СН2)4СН2NHСОC(17)ꢀ
phorbine (bridge)); 0.2 (br.s, 1 H, I´ꢀNH); –1.77 (br.s, 1 H,
III´ꢀNH); –1.8 (br.s, 1 H, IꢀNH); –1.97 (br.s, 1 H, IIIꢀNH).
MS (MALDI), m/z: found: 1238.8230. C75H86N10O7. For [M]+
calculated: 1238.6680. Found: 1239.8325. C75H87N10O7. For
[MН]+ calculated: 1239.6759.
15,17ꢀDimethyl ester of N,N´ꢀbis[13(3)ꢀe6ꢀchlorinylꢀ13ꢀNꢀ
ethylaminosuccine]diamide (17). Di(tertꢀbutyl) dicarbonate
(15 mg, 0.065 mmol) was added to carboxychlorin 11 (50 mg,
0.065 mmol) in a pyridine—CH2Cl2 (1 : 2) mixture. The reacꢀ
tion mixture was stirred at 0 °C for 15 min. Aminochlorin 3
(44 mg, 0.065 mmol) was added, and the reaction mixture was
stirred at ~20 °C for 1 h (TLC: Sorbfil, chloroform—methanol
(9 : 1) as eluent). The mixture was diluted with chloroform
(50 mL), pyridine was washed off with 7% HCl, and the acid was
washed off with water. The chloroformic solution was dried over
anhydrous Na2SO4 and evaporated. After evaporation the resiꢀ
due was chromatographed (CCl4—acetone (3 : 1) as eluent).
1
Dimer 17 was obtained in a yield of 37 mg (41%). Н NMR, δ:
9.46 (s, 2 H, H(10)); 9.32 (s, 2 H, H(5)); 8.82 (s, 2 H, H(20));
7.74 (dd, 2 H, C(3)CН=СН2, J = 11.6 Hz, J = 17.3 Hz);
6.20—6.05 (br.m, 2 Н, NH (amide)); 5.72—5.44 (br.m, 2 Н, NH
(amide)); 5.99 (d, 2 H, C(3)СН=СНН (trans), J = 17.7 Hz);
5.82 (d, 1 H, C(3)СН=СНН (cis), J = 11.4 Hz); 4.99 (d, 2 H,
C(15)CН2СО2Me, J = 19.8 Hz); 4.87 (d, 2 H, C(15)CН2СО2Me,
J = 19.4 Hz); 4.54 (q, 2 H, H(18), J = 7.1 Hz); 4.40 (d, 2 H,
H(17), J = 9.3 Hz); 3.84—3.70 (m, 4 H, C(8)CН2Me); 3.68
(s, 6 Н), 3.55 (s, 6 Н), 3.27 (s, 6 Н), 2.85 (s, 6 Н), 2.65 (s, 6 Н)
(C(15)СН2СО2Me, C(17)СН2СН2СО2Me, C(2)Me, C(7)Me,
C(12)Me); 3.65—3.44 (m, 6 H, chlorinꢀC(13)CONH(СН2)2ꢀ
NHCO(CH2)2CONH(СН2)2NHOCC(13)СН2ꢀchlorin
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[2ꢀ(Nꢀ17(3)ꢀ
pheophorbidyl)aminoethyl]amide (16). Di(tertꢀbutyl) dicarbonꢀ
ate (20 mg, 0.084 mmol) was added to a solution of pheophorꢀ
bide а (5) (50 mg, 0.084 mmol) in a pyridine—CH2Cl2 (1 : 2)
mixture, and the reaction mixture was stirred at 0 °C for 15 min.
Then aminochlorin 3 (57 mg, 0.084 mmol) was added, and the
mixture was stirred at ~20 °C for 1 h (TLC: Sorbfil, CCl4—aceꢀ
(bridge)); 2.44—2.24 (m,
8 H, C(17)CН2CН2СО2Me,

726
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Belykh et al.
C(17)CН´2CН´2); 1.75 (t, 6 H, C(8)СН2Me, J = 7.2 Hz); 1.76
(d, 6 H, C(18)Me, J = 7.2 Hz); –1.75 (br.s, 2 H, IꢀNH); –2.06
(br.s, 2 H, IIIꢀNH). MS (MALDI), m/z: found: 1414.8993.
C80H94N12O12. For [M]+ calculated: 1414.7114. Found:
1415.8577. C80H95N12O12. For [MН]+ calculated: 1415.7192.
Found: 1437.8702. C80H94N12O12Na. For [MNa]+ calculated:
1437.7011.
3.22 (s, 3 Н), 3.00 (s, 3 Н) (C(15)СН2СО2Me, C(2)Me, C(7)Me,
C(12)Me, C(17)СН2СН2СО2Me, C(2´)Me, C(7´)Me,
C(12´)Me, C(17´)СН2СН2СО2Me); 3.55—3.26 (m, 4 H, chlorꢀ
inꢀC(13)СОNHCН2(СН2)4CН2NHСОC(17)ꢀphorbine
(bridge)); 2.66—1.99 (m,
8 H, C(17)CН2CН2СО2Me,
C(17´)CН2CН2СО2Me); 1.97—1.69 (m, 12 H, C(8)СН2Me,
C(8´)СН2Me, C(18)Me, C(18´)Me); 0.35 (br.s, 1 H, IꢀNH´);
–1.64 (br.s, 1 H, IIIꢀNH´); –1.69 (br.s, 1 H, IꢀNH); –1.91
(br.s, 1 H, IIIꢀNH). MS (MALDI), m/z: found: 1296.8458.
C77H88N10O9. For [M]+ calculated: 1296.6736. Found: 1297.8123.
C77H89N10O9. For [MН]+ calculated: 1297.6814. Found:
1319.8784. C73H80N10O9Na. For [MNa]+ calculated: 1319.6634.
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[6ꢀ(Nꢀ15(2)ꢀе6ꢀ
chlorinylꢀ13ꢀN´ꢀmethylamideꢀ17ꢀmethyl ester)aminohexylamide]
(20). A 33% aqueous solution of methylamine (1 mL) was added
to a solution of dimer 19 (30 mg) in THF (7 mL), and the
reaction mixture was stirred at ~20 °C for 2 h. The reaction
mixture was diluted with chloroform (50 mL), and methylamine
was washed off with water. The chloroformic solution was dried
over anhydrous Na2SO4 and evaporated. The residue was chroꢀ
matographed on silica gel (CCl4—acetone (1 : 1) as eluent).
The purity of the product was monitored by TLC (Sorbfil,
CHCl3—methanol (9 : 1) as eluent). Product 20 was obtained in
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[2ꢀ(Nꢀ13(2)ꢀ
methylpheophorbidyl)aminoethylamide] (18). Aminochlorin 3
(55 mg, 0.082 mmol) was added to a solution of methylpheophorꢀ
bide а (1) (50 mg, 0.082 mmol) in toluene (10 mL). The mixture
was refluxed for 1 h (TLC: Sorbfil, CCl4—acetone (2 : 1) as
eluent) and then chromatographed (CCl4—acetone (5 : 1) as
eluent). Dimer 18 was obtained in a yield of 63 mg (65%).
1Н NMR, δ: 9.67 (s, 1 H, H(10)); 9.63 (s, 1 H, H(5)); 9.39 (s, 1 H,
H(10´)); 9.36 (s, 1 H, H(5´)); 8.80 (s, 1 H, H(20)); 8.45 (s, 1 H,
H(20´)); 8.13 (dd, 1 H, C(3)CН=СН2, J = 18.0 Hz, J = 11.4 Hz);
7.99 (dd, 1 H, C(3´)CН=СН2, J = 18.0 Hz, J = 11.7 Hz); 7.82
(br.t, 1 H, chlorinꢀC(13)СОNHСН2СН2NHСОC(17)ꢀphorbine
(bridge), J = 4.8 Hz); 7.76 (br.t, 1 H, chlorinꢀC(13)СОꢀ
NHСН2СН2NHСОC(17)ꢀphorbine (bridge), J = 4.5 Hz); 6.39
(d, 1 H, C(3)СН=СНН (trans), J = 17.6 Hz); 6.28 (d, 1 H,
C(3´)СН=СНН (trans), J = 17.6 Hz); 6.18 (d, 2 H,
C(3)СН=СНН (cis), C(3´)СН=СНН (cis), J = 11.0 Hz); 6.17
(s, 1 H, C(13)C(2´)Н); 5.73 (d, 1 H, C(15)CН2СО2Me,
J = 18.8 Hz); 5.31 (d, 1 H, C(15)CН2СО2Me, J = 18.4 Hz);
4.55—4.34 (m, 2 H, H(18), H(18´)); 4.20—3.98 (m, 2 H, H(17),
H(17´)); 3.77—3.43 (m, 4 H, C(8)CН2Me, C(8´)CН2Me); 3.70
(s, 3 Н), 3.57 (s, 3 Н), 3.52 (s, 6 Н), 3.46 (s, 3 Н), 3.34 (s, 6 Н),
3.24 (s, 3 Н), 3.17 (s, 3 Н) (C(15)СН2СО2Me, C(2)Me, C(7)Me,
C(12)Me, C(17)СН2СН2СО2Me, C(2´)Me, C(7´)Me,
C(12´)Me, C(17´)СН2СН2СО2Me); 3.50—3.28 (m, 4 H, chlorinꢀ
C(13)СОNHCН2CН2NHСОC(17)ꢀphorbine (bridge)); 2.70—1.92
(m, 8 H, C(17)CН2CН2СО2Me, C(17´)CН2CН2СО2Me);
1.73—1.62 (m, 12 H, C(8)СН2Me, C(8´)СН2Me, C(18)Me,
C(18´)Me); 0.58 (br.s, 1 H, I´ꢀNH); –1.57 (br.s, 1 H, III´ꢀNH);
–1.52 (br.s, 1 H, IꢀNH); –1.79 (br.s, 1 H, IIIꢀNH). MS (MALDI),
m/z: found: 1240.6321. C73H80N10O9. For [M]+ calculated:
1240.6109. Found 1241.6357. C73H81N10O9. For [MН]+ calcuꢀ
lated: 1241.6188. Found: 1264.6571. C73H80N10O9Na. For
[MNa]+ calculated: 1264.6007.
1
a yield of 20 mg (59%). Н NMR, δ: 9.67 (s, 1 H, H(10)); 9.66
(s, 1 H, H(5)); 9.61 (s, 1 H, H(10´)); 9.56 (s, 1 H, H(5´)); 8.84
(s, 1 H, H(20)); 8.83 (s, 1 H, H(20´)); 8.12 (dd, 1 H, C(3)CН=СН2,
J = 18.0 Hz, J = 11.4 Hz); 7.94 (dd, 1 H, C(3´)CН=СН2,
J = 17.9 Hz, J = 11.6 Hz); 6.84 (m, 1 H, C(13´)СОNHMe); 6.77
(m, 1 H, chlorinꢀC(13)СОNH(СН2)6NHСОСН2C(15´)ꢀchlorꢀ
in (bridge)); 6.39 (d, 1 H, C(3)СН=СНН (trans), J = 18.3 Hz);
6.24 (d, 1 H, C(3´)СН=СНН (trans), J = 18.0 Hz); 6.17 (d, 1 H,
C(3)СН=СНН (cis), J = 10.8 Hz); 6.01 (d, 1 H, C(3´)СН=СНН
(cis), J = 11.4 Hz); 6.17 (m, 1 H, chlorinꢀC(13)СОNH(СН2)6ꢀ
NHСОСН2C(15´)ꢀchlorin (bridge)); 5.43 (d,
1
H,
C(15)CН2СО2Me, J = 18.9 Hz); 5.18 (d, 1 H, C(15)CН2СО2Me,
J = 19.2 Hz); 5.35 (d, 1 H, C(15´)CН2СО2Me, J = 17.1 Hz); 5.11
(d, 1 H, C(15´)CН2СО2Me, J = 17.7 Hz); 4.69 (d, 1 H, H(17),
J = 9.6 Hz); 4.46 (q, 2 H, H(18), Н(18´), J = 7.1 Hz); 4.39 (d, 1 H,
Н(17´), J = 9.0 Hz); 3.84—3.70 (m, 4 H, C(8)CН2Me,
C(8´)CН2Me); 3.68 (s, 3 Н), 3.61 (s, 3 Н), 3.59 (s, 3 Н), 3.52
(s, 3 Н), 3.43 (s, 3 Н), 3.44 (s, 3 Н), 3.35 (s, 3 Н), 3.34 (s, 3 Н ),
3.19 (s, 3 Н) (C(15)CH2CО2Me, C(15´)CH2CО2Me, C(2)Me,
C(7)Me, C(12)Me, C(17)CH2CH2CО2Me, C(2´)Me, C(7´)Me,
C(12´)Me, C(17´)CH2CH2CО2Me); 3.37—3.26 (m, 4 H, chlorꢀ
inꢀC(13)СОNHCН2(СН2)4CН2NHСОСН2C(15´)ꢀchlorin
(bridge)); 3.24 (d, 3 H, C(13´)СОNHMe, J = 4.8 Hz); 2.56—2.06
(m, 6 H, C(17)CН2CН2СО2Me, C(17´)CН2CН2СО2Me);
1.78—1.62 (m, 12 H, C(18)Me, C(8)СН2Me, C(18´)Me,
C(8´)СН2Me); 1.63—1.40 (m, 4 H, chlorinꢀC(13)СОNHꢀ
СН2(CН2)4СН2NHСОСН2C(15´)ꢀchlorin (bridge)); –1.61
(br.s, 2 H, IꢀNH, I´ꢀNH); –1.86 (br.s, 1 Н), –1.91 (br.s, 1 Н)
(IIIꢀNH, III´ꢀNH). MS (MALDI), m/z: found: 1327.6744.
C78H93N11O9. For [M]+ calculated: 1327.5178. Found:
1328.6770. C78H94N11O9. For [MН]+ calculated: 1328.7236.
Found: 1350.6978. C78H93N11O9Na. For [MNa]+ calculated:
1350.7055.
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[6ꢀ(Nꢀ13(2)ꢀ
methylpheophorbidyl)aminohexylamide] (19). Aminochlorin 4
(59 mg, 0.082 mmol) was added to a solution of methylpheophorꢀ
bide а (1) (50 mg, 0.082 mmol) in toluene (10 mL). The reaction
mixture was refluxed for 1 h (TLC: Sorbfil, CCl4—acetone (2 : 1)
as eluent). The mixture was chromatographed on silica gel
(CCl4—acetone (4 : 1) as eluent). Dimer 19 was obtained in
1
a yield of 36 mg (42%). Н NMR, δ: 9.51 (s, 1 H, H(10)); 9.39
(s, 1 H, H(5)); 9.38 (s, 1 H, H(10´)); 9.20 (s, 1 H, H(5´)); 8.82
(s, 1 H, H(20)); 8.52 (s, 1 H, H(20´)); 8.02 (dd, 2 H, C(3)CН=СН2,
C(3´)CН=СН2, J = 17.2 Hz, J = 11.4 Hz); 7.05 (br.t, 1 H,
chlorinꢀC(13)СОNHСН2СН2NHСОC(17)ꢀphorbine (bridge),
J = 5.0 Hz); 6.68 (br.t, 1 H, chlorinꢀC(13)СОNH(СН2)6NHꢀ
СОC(17)ꢀphorbine (bridge), J = 5.0 Hz); 6.44—6.05 (m, 4 H,
C(3)СН=CН2, C(3´)СН=CН2); 5.94 (s, 1 H, C(13)C(2´)Н);
5.61 (d, 1 H, C(15)CН2СО2Me, J = 19.4 Hz); 5.26 (d, 1 H,
C(15)CН2СО2Me, J = 19.1 Hz); 4.56—4.42 (m, 2 H, H(18),
Н(18´)); 4.42—4.32 (m, 2 H, H(17), Н(17´)); 4.01—3.68 (m, 4 H,
C(8)CН2Me, C(8´)CН2Me); 3.83 (s, 3 Н), 3.60 (s, 3 Н), 3.55
(s, 3 Н), 3.53 (s, 3 Н), 3.52 (s, 3 Н), 3.42 (s, 3 Н), 3.41 (s, 3 Н),
15ꢀMethyl ester of 13,17ꢀbisꢀN,N´ꢀ[2ꢀ(Nꢀ13(2)ꢀmethylꢀ
pheophorbidyl)aminoethylamide]diamideꢀe6ꢀchlorin (21). Methylꢀ
pheophorbide а (1) (92 mg, 0.150 mmol) was added to a solution
of diaminochlorin 10 (50 mg, 0.075 mmol), and the mixture was
refluxed for 10 h (TLC: Sorbfil, CHCl3—MeOH (9 : 1) as eluent).

Oligomers based on methylpheophorbide a
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
727
The reaction mixture was chromatographed on silica gel
(CHCl3—MeOH (15 : 1) as eluent). Product 21 was obtained in
a yield of 42 mg (30%). 1Н NMR, δ: 9.54 (s, 1 Н), 9.49 (s, 1 Н),
9.31 (s, 1 Н), 9.27 (s, 1 Н), 9.09 (s, 1 Н), 9.07 (s, 1 Н), 8.78
(s, 1 Н), 8.44 (s, 1 Н), 8.42 (s, 1 Н) (H(10), H(5), H(10´), H(5´),
H(10´), H(5´), H(20), H(20´), H(20´)); 8.00—7.78 (m, 3 H,
C(3)CН=СН2, C(3´)CН=СН2, C(3´)CН=СН2); 8.00—7.78
(m, 2 Н), 6.90 (m, 1 Н), 6.34 (m, 1 Н) (C(13)СОNHMe, chlorꢀ
inꢀC(13)СОNHСН2СН2NHСОꢀC(13)C(2´)ꢀphorbine
(bridge), chlorinꢀC(17)СОNHСН2СН2NHСОC(13)C(2´)ꢀ
phorbine (bridge)); 6.27—6.10 (m, 5 Н), 5.93 (br.d, 1 H,
J = 11.4 Hz) (C(3)СН=CН2, C(3´)СН=CН2, C(3´)СН=CН2);
6.16 (s, 1 H, C(13´)C(2)Н); 6.13 (s, 1 H, C(13´)C(2)Н); 5.68
(d, 1 H, C(15)CН2СО2Me, J = 18.6 Hz); 5.51—5.47 (m, 1 Н,
C(15)CН2СО2Me); 4.54—4.38 (m, 3 H, H(18), H(18´), Н(18´));
3.28—4.11 (m, 3 H, H(17), H(17´), H(17´)); 4.10—3.96 (m, 6 H,
C(8)CН2Me, C(8´)CН2Me, C(8´)CН2Me); 3.71 (s, 3 Н), 3.52
(s, 3 Н), 3.38 (s, 6 Н), 3.31 (s, 6 Н), 3.29 (s, 3 Н), 3.23 (s, 3 Н),
3.20 (s, 3 Н), 3.17 (s, 6 Н), 3.00 (s, 3 Н) (C(15)CH2CО2Me,
C(2)Me, 7ꢀMe, C(12)Me, C(2´)Me, C(7´)Me, C(12´)Me,
C(17´)CH2CH2CО2Me, C(17´)CH2CH2CО2Me, C(2´)Me,
CН2CН2NHСОC(15´)ꢀchlorin (bridge), chlorinꢀC(17)СОꢀ
NHCН2CН2NHСОC(15´)ꢀchlorin (bridge); 2.78—2.58
(m, 12 H, C(17)CH2CH2CО2Me, C(17´)CH2CH2CО2Me,
C(17´)CH2CH2CО2Me); 1.71—1.60 (m, 18 H, C(18)Me,
C(8)СН2Me,
C(18´)Me,
C(8´)СН2Me,
C(18´)Me,
C(8´)СН2Me); –1.63 (br.s, 3 Н), –1.94 (br.s, 2 H, III´ꢀNH)
(IꢀNH, IIIꢀNH, I´ꢀNH, I´ꢀNH, III´ꢀNH, III´ꢀNH); –2.02
(br.s, 1 H, IꢀNH, IIIꢀNH). MS (MALDI), m/z: found:
1906.5801. C111H129N18O12. For [MН]+ calculated: 1906.0037.
15,17ꢀDimethyl ester of е6ꢀchlorinylꢀ3ꢀdesvinylꢀ3ꢀ(13(2)ꢀ
methylpheophorbidyloxy)methylꢀ13ꢀNꢀmethylamide (23). Comꢀ
pound 9 (22 mg, 0.033 mmol), 4ꢀdimethylaminopyridine (17 mg,
0.132 mmol), and Nꢀmethylꢀ2ꢀchloropyridine iodide (18 mg,
0.066 mmol) were added to a solution of methylpheophorbide а (1)
(20 mg, 0.033 mmol) in toluene (5 mL). The mixture was reꢀ
fluxed for 3 h (TLC: Sorbfil, CCl4—acetone (10 : 1) as eluent).
The mixture was diluted with chloroform (70 mL), pyridine was
washed off with 10% HCl, and HCl excess was washed off with
water. The chloroformic solution was dried over anhydrous
Na2SO4 and evaporated. The residue was chromatographed on
silica gel (CCl4—acetone (7 : 1) as eluent). Dimer 23 was obꢀ
1
C(7´)Me, C(12´)Me); 3.65—3.41 (m,
8
H, chlorinꢀ
tained in a yield of 18 mg (44%). Н NMR, δ: 9.51 (s, 1 H,
C(17)СОNHCН2CН2NHСОC(13)C(2´)ꢀphorbine (bridge),
chlorinꢀC(13)СОNHCН2CН2NHСОC(13)C(2´)ꢀphorbine
(bridge)); 2.55—2.02 (m, 12 H, C(17)CH2CH2CО2Me,
C(17´)CH2CH2CО2Me, C(17´)CH2CH2CО2Me); 1.77—1.51
(m, 18 H, C(18)Me, C(8)СН2Me, C(18´)Me, C(8´)СН2Me,
C(18´)Me, C(8´)СН2Me); 0.38 (br.s, 2 H, I´ꢀNH); –1.55
(br.s, 1 H, IꢀNH); –1.66 (br.s, 1 H, IIIꢀNH); –1.70 (br.s, 2 H,
III´ꢀNH). MS (MALDI), m/z: found: 1844.3300. C109H119N16O12.
For [MН]+ calculated: 1843.9193.
H(10)); 9.46 (s, 1 H, H(5)); 9.34 (s, 1 H, Н(10´)); 9.31 (s, 1 H,
H(5´)); 8.76 (s, 1 H, H(20)); 7.50 (s, 1 H, H(20´)); 7.94 (dd, 1 H,
C(3)CН=СН2, J = 11.7 Hz, J = 17.7 Hz); 6.72 (d, 1 H,
С(3´)СН2, J = 12.9 Hz); 6.61 (d, 1 H, С(3´)СН2, J = 12.3 Hz);
6.52—6.40 (m,
1 H, C(13)СОNHMe); 6.32 (s, 1 H,
C(13)C(2´)Н); 6.23 (d, 1 H, C(3´)СН=СНН (trans), J = 18.0 Hz);
6.15 (d, 1 H, C(3´)СН=СНН (cis), J = 10.5 Hz); 5.58 (d, 1 H,
C(15)CН2СО2Me, J = 18.6 Hz); 5.35 (d, 1 H, C(15)CН2СО2Me,
J = 18.3 Hz); 4.42 (q, 2 H, H(18), H(18´), J = 7.2 Hz); 4.40
(d, 2 H, H(17), H(17´), J = 8.1 Hz); 3.92—3.83 (m, 2 Н), 3.70—3.64
(m, 2 Н) (C(8)CН2Me, C(8´)CН2Me); 3.89 (s, 3 Н), 3.72
(s, 6 Н), 3.60 (s, 3 Н), 3.58 (s, 3 Н), 3.44 (s, 3 Н), 3.24 (s, 3 Н),
3.17 (s, 3 Н), 3.02 (s, 3 Н) (C(2)Me, C(7)Me, C(12)Me,
C(17)CH2CH2CО2Me, C(15)CH2CО2Me, C(2´)Me, C(7´)Me,
15,17ꢀDimethyl ester of 13,17ꢀbisꢀN,N´ꢀ[2ꢀ(Nꢀ15(2)ꢀе6ꢀ
chlorinylꢀ13ꢀN´ꢀmethylamide)aminoethylamide]diamideꢀe6ꢀ
chlorin (22). Methylamine (1 mL) was added to a solution of
trimer 21 (20 mg) in THF (10 mL), and the reaction mixture was
stirred for 3 h (TLC: Sorbfil, CHCl3—MeOH (9 : 1) as eluent).
The mixture was diluted with chloroform (50 mL), methylamine
was washed off with water, and the residue was chromatographed
on silica gel (CHCl3—MeOH (5 : 1) as eluent). Product 22 was
C(12´)Me, C(17´)CH2CH2CО2Me); 3.35 (d,
3
H,
C(13)СОNHMe, J = 4.5 Hz); 2.79—2.70 (m, 1 Н), 2.60—2.41
(m, 3 Н) (C(17)CH2CH2CО2Me, C(17´)CH2CH2CО2Me);
2.29—2.02 (m, 4 Н, C(17)CH2CH2CО2Me, C(17´)CH2ꢀ
CH2CО2Me); 1.72 (t, 3 H, J = 8.1 Hz), 1.42 (t, 3 H, J = 7.33
Hz) (C(8´)СН2Me, C(8)СН2Me); 1.73 (d, 3 H, J = 8.1 Hz),
1.32 (d, 3 H, J = 8.3 Hz) (C(18´)Me, C(18)Me); 0.44 (br.s, 1 H,
I´ꢀNH); –1.82 (br.s, 1 H, IꢀNH); –1.97 (br.s, 1 H, III´ꢀNH);
–2.06 (br.s, 1 H, IIIꢀNH). MS (MALDI), m/z: found: 1216.7580.
C71H77N9O10. For [MН]+ calculated: 1216.5872.
1
obtained in a yield of 12 mg (48%). Н NMR, δ: 9.64 (s, 1 Н),
9.62 (s, 2 Н), 9.60 (s, 1 Н), 9.53 (s, 1 Н), 8.87 (s, 1 Н), 8.77 (s, 1 Н),
8.75 (s, 1 Н), 8.53 (s, 1 Н), 8.15 (s, 1 Н) (H(10), H(5), H(10´),
H(5´), H(10´), H(5´), H(20), H(20´), H(20´)); 8.05 (dd, 3 H,
C(3)CН=СН2, C(3´)CН=СН2, C(3´)CН=СН2, J = 16.9 Hz,
J = 11.7 Hz); 6.74—6.46 (m, 3 Н), 6.43—6.52 (m, 2 Н), 5.79
(m, 1 Н) (C(13´)СОNHMe, C(13´)СОNHMe, chlorinꢀ
C(13)СОNHСН2СН2NHСОC(15´)ꢀchlorin (bridge), chlorinꢀ
C(17)СОNHСН2СН2NHСОC(15´)ꢀchlorin (bridge)); 6.33
(br.d, 3 H, C(3)СН=СНН (trans), C(3´)СН=СНН (trans),
C(3´)СН=СНН (trans), J = 16.2 Hz); 6.13 (br.d, 3 H,
C(3)СН=СНН (cis), C(3´)СН=СНН (cis), C(3´)СН=СНН
(cis), J = 11.4 Hz); 5.27—4.59 (m, 6 Н, C(15)CН2СО2Me,
C(15´)CН2СО2Me, C(15´)CН2СО2Me); 4.30—4.21 (m, 3 H,
H(18), H(18´), H(18´)); 4.50—4.35 (m, 3 H, H(17), H(17´),
H(17´)); 3.82—3.66 (m, 6 H, C(8)CН2Me, C(8´)CН2Me,
C(8´)CН2Me); 3.47 (s, 6 Н), 3.45 (s, 3 Н), 3.39 (s, 6 Н), 3.36
(s, 6 Н), 3.27 (s, 6 Н), 3.19 (s, 6 Н), 3.14 (s, 3 Н) (C(15)CH2CО2Me,
C(2)Me, C(7)Me, C(12)Me, C(2´)Me, C(7´)Me, C(12´)Me,
C(17´)CH2CH2CО2Me, C(2´)Me, C(7´)Me, C(12´)Me,
C(17´)CH2CH2CО2Me); 3.23—3.20 (m, 6 H, C(13´)СОNHMe,
C(13´)СОNHMe); 3.69—3.46 (m, 8 H, chlorinꢀC(13)СОNHꢀ
15,17ꢀDimethyl ester of e6ꢀchlorinylꢀ13ꢀNꢀ[2ꢀ(13(2)ꢀmethylꢀ
pheophorbidyloxy)ethylamide] (24). 15ꢀ17ꢀDimethyl chlorin е6
13ꢀNꢀ(2ꢀhydroxyethyl)amide (2) (60 mg, 0.066 mmol), 4ꢀdiꢀ
methylaminopyridine (34 mg, 0.264 mmol), and Nꢀmethylꢀ2ꢀ
chloropyridine iodide (35 mg, 0.132 mmol) were added to
a solution of methylpheophorbide а (1) (40 mg, 0.066 mmol) in
toluene (10 mL). The reaction mixture was refluxed for 3 h
(TLC: Sorbfil, CCl4—acetone (5 : 1) as eluent). The mixture was
diluted with chloroform (70 mL), pyridine was washed off with
10% HCl, and HCl excess was washed with water. The chloroꢀ
formic solution was dried over anhydrous Na2SO4 and evaporated,
and the residue was chromatographed on silica gel (CCl4—aceꢀ
tone (7 : 1) as eluent). Dimer 24 was obtained in a yield of 53 mg
1
(63%). Н NMR, δ: 9.73 (s, 1 H, H(10)); 9.61 (s, 1 H, H(5));
9.35 (s, 1 H, Н(10´)); 9.22 (s, 1 H, H(5´)); 8.85 (s, 1 H, H(20));

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Belykh et al.
8.52 (s, 1 H, H(20´)); 8.17 (dd, 1 H, C(3)CН=СН2, J = 11.9 Hz,
J = 17.9 Hz); 7.98 (dd, 1 H, C(3´)CН=СН2, J = 12.5 Hz,
J = 18.2 Hz); 7.94—7.86 (m, 1 H, chlorinꢀC(13)СОNНСН2ꢀ
C(12)Me, C(17)СН2СН2СО2Me, C(2´)Me, C(7´)Me, C(12´)Me,
C(17´)СН2СН2СО2Me); 2.42—2.28 (m, 4 Н), 2.22—2.00
(m, 4 Н) (C(17)CН2CН2СО2Me, C(17´)CН2CН2СО2Me);
1.84—1.72 (m, 12 H, C(18)Me, C(18´)Me, C(8)СН2Me,
C(8´)СН2Me); 0.21 (br.s, 1 H, I´ꢀNH); –1.38 (m, 1 H, IꢀNH),
–1.74 (br.s, 1 H, IIIꢀNH´); –3.30 (br.s, 1 H, IIIꢀNH). MS
(MALDI), m/z: found: 1126.5572. C69H74N8O7. For [MН]+
calculated: 1126.5681.
СН2ООСC(13)C(2)ꢀphorbine (bridge)); 6.43 (d,
1 H,
C(3)СН=СНН (trans), J = 17.7 Hz); 6.32 (s, 1 H, C(13)C(2´)Н);
6.29 (d, 1 H, 3´ꢀСН=СНН (trans), J = 18.6 Hz); 6.20 (d, 2 H,
C(3)СН=СНН (cis), C(3´)СН=СНН (cis), J = 11.7 Hz); 5.68
(d, 1 H, C(15)CН2СО2Me, J = 18.9 Hz); 5.26 (d, 1 H,
C(15)CН2СО2Me, J = 18.0 Hz); 4.53—4.26 (m, 4 H, H(17),
H(17´), H(18), H(18´)); 3.86—3.68 (m, 4 Н, C(8)CН2Me,
C(8´)CН2Me); 3.66—3.50 (m, 4 H, chlorinꢀC(13)СОNНꢀ
CН2CН2ООСC(13)C(2)ꢀphorbine (bridge)); 3.80 (s, 3 Н),
3.56 (s, 6 Н), 3.43 (s, 3 Н), 3.40 (s, 3 Н), 3.38 (s, 3 Н), 3.31
(s, 3 Н), 3.23 (s, 3 Н), 2.93 (s, 3 Н) (C(2)Me, C(7)Me,
C(12)Me, C(15)СН2СО2Me, C(17)CH2СН2СО2Me, C(2´)Me,
C(7´)Me, C(12´)Me, C(17´)CH2СН2СО2Me); 2.72—2.37
(m, 4 Н), 2.33—1.97 (m, 4 Н) (C(17)CH2CН2СО2Me,
C(17´)CH2CН2СО2Me); 1.84 (d, 3 H, J = 6.6 Hz), 1.77—1.57
(m, 9 H, J = 7.5 Hz) (C(18)Me, C(18´)Me, C(8)СН2Me,
C(8´)СН2Me); 0.64 (br.s, 1 H, I´ꢀNH); –1.53 (br.s, 1 H,
III´ꢀNH); –1.58 (br.s, 1 H, IꢀNH); –1.76 (br.s, 1 H, IIIꢀNH).
MS (MALDI), m/z: found: 1242.6704. C73H80N9O10. For [MН]+
calculated: 1242.6028.
References
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13(1)ꢀDeoxoꢀ13(1)ꢀ(13(2)ꢀmethylpheophorbidyloxy)methylꢀ
pyropheophorbide а (25). 13(1)ꢀHydroxymethylpyropheophorꢀ
bide а (13) (19 mg, 0.033 mmol), 4ꢀdimethylaminopyridine
(17 mg, 0.132 mmol), and Nꢀmethylꢀ2ꢀchloropyridine iodide
(18 mg, 0.066 mmol) were added to a solution of methylꢀ
pheophorbide а 1 (20 mg, 0.033 mmol) in toluene (5 mL).
The reaction mixture was refluxed for 3 h (TLC: Sorbfil,
CCl4—acetone (10 : 1) as eluent). The mixture was diluted with
chloroform (70 mL), pyridine was washed off with 10% HCl,
and HCl excess was washed off with water. The chloroformic
solution was dried over anhydrous Na2SO4 and evaporated. The
residue was chromatographed on silica gel (CCl4—acetone
(80 : 1) as eluent). Dimer 25 was obtained in a yield of 13 mg (34%).
1Н NMR, δ: 9.99 (s, 1 H, H(10´)); 9.66 (s, 1 H, H(10)); 9.64 (s, 1 H,
H(5)); 9.35 (s, 1 H, Н(5´)); 8.76 (s, 1 H, H(20)); 7.79 (s, 1 H,
Н(20´)); 8.30 (dd, 1 H, C(3)CН=СН2, J = 11.6 Hz, J = 17.9 Hz);
7.92 (dd, 1 H, J = 11.6 Hz, C(3´)CН=СН2, J = 17.9 Hz); 6.54
(s, 1 H, C(13)C(2´)СН); 6.38 (d, 2 H, C(3)СН=СНН (trans),
C(3´)СН=СНН (trans), J = 17.6 Hz); 6.21 (m, 3 H, phorbineꢀ
C(13)C(1)CНОСОC(17´)ꢀphorbine, C(13)C(2)СН2); 6.12
(d, 2 H, C(3)СН=СНН (cis), C(3´)СН=СНН (cis), J = 11.4 Hz);
4.41 (d, 1 H, J = 17.0 Hz); 4.26 (q, 1 H, J = 7.3 Hz), 3.95—3.85
(m, 3 Н) (H(17), H(17´), H(18), H(18´)); 4.00—3.82 (m, 2 Н,
C(8)CН2Me, C(8´)CН2Me); 3.80—3.68 (m, 2 Н, C(8)CН2Me,
C(8´)CН2Me); 3.75 (s, 3 Н), 3.54 (s, 3 Н), 3.50 (s, 3 Н), 3.49
(s, 6 Н), 3.30 (s, 3 Н), 3.27 (s, 3 Н), 3.08 (s, 3 Н) (C(2)Me, C(7)Me,
5. E. V. Buravlev, I. Yu. Chukicheva, D. V. Belykh, A. V.
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Received June 8, 2010;
in revised form October 18, 2010