Design, synthesis and evaluation of the antioxidant and neuroprotective properties of alkyl- and terpenylphenolchlorin conjugates

Article abstract of DOI:10.1007/s11172-018-2109-4

The new amide conjugates were synthesized from methyl pheophorbide a and its carboxyl derivatives by reactions with aminomethyl derivatives of 2,4-dimethylphenol, 2-isocamphyl-4- methylphenol, 2-bornyl-4-methylphenol, and 2-isobornyl-4-methylphenol. The antioxidant activity of some conjugates was established by investigation of their ability to inhibit the accumulation of secondary products of lipid peroxidation in a brain of laboratory mice in vitro. The neuroprotective properties of porphyrin and terpenylphenol conjugates have been studied on the model of H₂O₂-induced oxidative stress in SH-SY5Y cells (neuroblastoma).

Full text of DOI:10.1007/s11172-018-2109-4

Russian Chemical Bulletin, International Edition, Vol. 67, No. 3, pp. 548—557, March, 2018
548
Design, synthesis and evaluation of the antioxidant and
neuroprotective properties of alkyl- and terpenylphenolchlorin conjugates*
I. Yu. Chukicheva,a E. V. Buravlev,a D. V. Belykh,a I. S. Khudyaeva,a I. V. Fedorova,a O. G. Shevchenko,b
M. A. Maximova,c L. F. Zainullina,c,d Yu. V. Vakhitova,c,d and A. V. Kutchina
aInstitute of Chemistry, Komi Scientific Centre, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomayskaya, 167000 Syktyvkar, Russian Federation.
Fax: +7 (821) 221 9916. E-mail: chukichevaiy@mail.ru
bInstitute of Biology, Komi Scientific Centre, Ural Branch of the Russian Academy of Sciences,
28 ul. Kommunisticheskaya, 167982 Syktyvkar, Russian Federation.
Fax: +7 (821) 221 0163
cInstitute of Biochemistry and Genetics, Ufa Scientific Centre of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6088
dV. V. Zakusov Institute of Pharmacology,
8 ul. Baltiyskaya, 125315 Moscow, Russian Federation.
Fax: +7 (499) 151 1261
The new amide conjugates were synthesized from methyl pheophorbide a and its carboxyl
derivatives by reactions with aminomethyl derivatives of 2,4-dimethylphenol, 2-isocamphyl-4-
methylphenol, 2-bornyl-4-methylphenol, and 2-isobornyl-4-methylphenol. The antioxidant
activity of some conjugates was established by investigation of their ability to inhibit the accu-
mulation of secondary products of lipid peroxidation in a brain of laboratory mice in vitro. The
neuroprotective properties of porphyrin and terpenylphenol conjugates have been studied on
the model of H2O2-induced oxidative stress in SH-SY5Y cells (neuroblastoma).
Key words: conjugates, methyl pheophorbide a, carboxyl derivatives, aminomethyl deriva-
tives, terpenylphenols, antioxidant activity, lipid peroxidation, neuroprotective activity.
It is known that antioxidants of different nature have
ity of the obtained conjugates.6 The next step necessary
to analyze the contribution of structural changes to the
antioxidant activity (AOA) of conjugates was the study of
the terpene substituent and porphyrin cycle effects.
a high neuroprotective activity, which is based on the
inhibition of non-enzymatic free radical oxidation of
lipids and biopolymers, and also on the membrane-
protective action.1 An important requirement for neuro-
protectors is the ability to penetrate through the blood-
brain barrier. Due to this feature, the porphyrin com-
pounds are applied in photodynamic and boron neutron
capture therapies.2—4 Consequently, the synthesis of con-
jugates of phenolic antioxidant and porphyrins is of inter-
est to search for new efficient neuroprotectors.
Results and Discussion
The present work reports on the synthesis of the con-
jugates based on synthetically available terpenylphenols
containing isocamphyl, bornyl, and isobornyl moieties.
2,4-Dimethylphenol (4) was additionally used as the start-
ing material to prove the effect of terpene substituent on
the biological activity of conjugates. The phenolic fragment
was introduced by using the phorbin and chlorin deriva-
tives, which were applied earlier in the synthesis of similar
conjugates.7,8
At the first step, aminomethyl derivatives 10—12 bear-
ing a secondary amino group were synthesized from cresols
4—6 (Scheme 2). Compounds 10—12 were obtained by
aminomethylation of phenols 4—6 followed by transami-
nation of intermediate tertiary amines 7—9.
The amide conjugates based on 2-isobornyl-4-methyl-
phenol 1 and methyl pheophorbide a 2 were previously
synthesized by us (Scheme 1 examplifies the synthesis of
compound 3) and it was shown that their antioxidant and
membrane-protective activities were affected by the length
and nature of the substituent at the nitrogen atom in am-
ide moiety.5 In contrast, the stereochemistry of isobornyl
moiety did not have a significant effect on biological activ-
* Dedicated to Academician of the Russian Academy of Sciences
I. P. Beletskaya.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0548—0557, March, 2018.
1066-5285/18/6703-0548 © 2018 Springer Science+Business Media, Inc.

Alkyl- and terpenylphenolchlorin conjugates
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
549
Scheme 1
Scheme 2*
R = Me (4, 7, 10),
(5, 8, 11 ),
(6, 9, 12)
Reagents and conditions: i. HCHO, Et2NH, benzene, reflux, 6 h; ii. H17C8NH2, reflux, 1 h.
* The numbering of C atoms in Schemes 2 and 3 is used for the interpretation of the NMR spectra and is valid for 4-methylphenolic
derivatives with a terpene moiety, while the numbering of the C atoms is identical for the bornyl and isobornyl structures. The C(1)—C(6)
carbon atoms of the 2,4-dimethylphenolic moiety are numbered according to the IUPAC nomenclature.
1
Subsequent amidation of methyl pheophorbide a 2 and
its carboxyl derivatives (pyropheophorbide a 13 and
13-N-methylamide-15-methyl ester of chlorin e6 14) with
amines 1 and 10—12 provided a series of new alkylphenol-
and terpenylphenolchlorin conjugates 15—25 (Scheme 3).
Racemic secondary amines 1, 11, and enantiomerically
enriched amine 12 obtained from racemic 2-isobornyl-
4-methylphenol, 2-isocamphyl-4-methylphenol 5, and
(+)-enantiomer of 2-bornyl-4-methylphenol 6, respec-
tively, were used in this work.
in the IR spectra. H NMR spectra of the obtained con-
jugates contain signals of the protons of substituted por-
phyrin and aminomethylphenol fragments with the 1 : 1
intensity ratio. H and 13C NMR spectra of compounds
1
16, 17, 19, 21, and 25 contain a double set of signals cor-
responding to the resulting pairs of diastereomers, which
are not equivalent due to different stereochemistry of the
terpene substituent according to our previous work5 de-
scribing diastereomers of compound 3 as the example. In
the case of conjugates 15 and 18, a double set of signals
in the same spectra could represent two atropisomers that
were different in the relative position of substituents at the
amide group, which was previously demonstrated for
conjugates of porphyrin and 2,6-diisobornylphenol.8
Table 1 shows results of the AOA study for starting
porphyrins and their conjugates on a substrate containing
brain lipids of laboratory mice. The significant dependence
of porphyrin AOA on the structure of the macrocycle was
shown. At concentrations of 500 mol L–1, the content of
The chemical structures of the obtained conjugates
1
were confirmed by H and 13C NMR, UV-Vis, and IR
spectroscopy, and mass spectrometry. The peaks corre-
sponding to [M + H]+ or [M]+ molecular ions were ob-
served in the mass spectra for all obtained conjugates.
UV-Vis spectra of the synthesized compounds contain
bands of the corresponding chlorin chromophores. The
bands corresponding to valence vibrations of the C=O
bond of a tertiary amide group (amide I) were observed

550
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
Chukicheva et al.
Scheme 3
R = Me (15, 18, 22),
(16, 19, 23),
(17, 20, 24),
(21, 25)
Reagents and conditions: i. collidine, reflux (see Ref. 9); ii. HCl, acetone, 20 C (see Ref. 10); iii. MeNH2 (aq.), THF, 20 C (see Ref.
11); iv. amine 10—12, toluene, reflux (see Ref. 8); v. amine 1, 10—12, DMAP, 1-methyl-2-chloropyridinium iodide (CMPI), CH2Cl2,
reflux (see Ref. 8).
lipid peroxidation (LPO) secondary products reacting with
2-thiobarbituric acid (TBA-reactive substances, TBA-RS)
in the samples with compounds 13 and 14 was 7.5- and
7.2-times lower than in the samples with porphyrin 2. The
introduction of substituted aminomethylphenol moieties
into the molecules of porphyrins 13 and 14 led to a notice-
able decrease in AOA, which was not observed for conju-
gates 3 and 15–17 obtained from methyl pheophorbide a 2.
It should be noted that the most active compound in each
group of the conjugates was the one containing the iso-
camphyl substituent (16, 19, and 23). Therefore, it was
shown that the terpene fragment structure has a statistically
significant effect on the AOA of the synthesized conjugates.
The effect of compounds 2, 3, and 13—25 on the vi-
ability of the HEK293 (human embryonic kidney) normal
cells and the tumor SH-SY5Y (human neuroblastoma)
cells was evaluated using trypan blue. According to the
data given in Table 2, the starting porphyrins 2, 13, 14, and
conjugates 21 and 22 with IC50 values of 0.5—18 mol L–1
were the most active, while compounds 19 and 25 dem-
onstrated a moderate activity towards the studied cell lines.
The other compounds exerted no negative effect on the
viability of the cells. The insignificant inhibitory effect of
compound 23 in the survival of SH-SY5Y cells (IC50 of
42 mol L–1) without a similar action on HEK293 cells
can be noted.
Compounds, which did not demonstrate a cytotoxic
effect on the neuroblastoma SH-SY5Y cells (compounds 3,
15—18, and 24), were tested for their effect on the cell
viability under conditions of oxidative stress simulation

Alkyl- and terpenylphenolchlorin conjugates
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
551
Table 1. Effects of compounds 2, 3, and 13—25 at the concentra-
tion of 500 mol L–1 on the content of secondary LPO products
(TBA-reactive substances, TBA-RS) in the homogenized brain
of laboratory mice*
Table 2. The effect of compounds 2, 3, and 13—25 on the viabil-
ity of HEK293 and SH-SY5Y cells
Compound
IC50/nmol mL–1
HEK293
Methyl pheophorbide a 2 and its conjugates
SH-SYY
Compound
TBA-RS/nmol mL–1
Methyl pheophorbide a 2
and its conjugates
55.29 0.20
2
3
15
16
17
5.5 1.4
>100
3.7 1.5
>100
2
3
15
16
17
>100
>100
55.77 0.49
>100
>100
>100
>100
52.62 0.34
47.45 0.51
Pyropheophorbide a 13 and its conjugates
55.69 0.62
13
18
19
20
21
4.6 1.1
86.7 2.9
22.5 3.9
>100
16.1 6.6
>100
26.1 4.1
≈77.3
8.0 1.1
Pyropheophorbide a 13 and its conjugates
7.36 0.39
13
18
19
20
21
50.55 0.34
17.40 0.33
18.1 2.6
54.42 0.85
Chlorin e6 13-N-methylamide-15-methyl ester
of chlorin e6 14 and its conjugates
36.13 0.30
13-N-methylamide-15-methyl ester
of chlorin e6 14 and its conjugates
7.69 0.26
14
22
23
24
25
0.5 0.0
8.5 0.1
>100
64.2 7.7
44.5 4.6
3.0 0.8
6.5 0.2
42.6 8.1
>100
14
22
23
24
25
44.11 0.47
40.98 0.56
47.4 6.4
57.76 0.20
53.48 0.68
significant effect on AOA of the synthesized conjugates,
and the most active compound was the one bearing the
isocamphylphenol substituent.
* The content of TBA-reactive substances in the control and
intact samples was 63.950.29 and 20.0221.19 nmol mL–1
respectively. The measurements were performed 1 h after the
LPO initiation. For the control sample, LPO was initiated in the
absence of the test compounds; for the intact sample, LPO was
not initiated.
,
The study of the effect of conjugates having a low cyto-
toxicity on cell viability under H2O2-induced oxidative
stress conditions revealed that they can not only cause
the neuroprotective effect on SH-SY5Y cells (methyl
pheophorbide a and 2-isobornyl-4-methyl-6-n-octyl-
aminomethylphenol conjugate 3), but also promote their
death (methyl pheophorbide a and 2,4-dimethyl-6-n-
octylaminomethylphenol conjugate 15). It should be noted
that both compounds are 13(2)-amide derivatives of methyl
pheophorbide a and mechanism of their action is obviously
determined by the structure of the substituent at the posi-
tion 2 in the phenol ring.
(pretreatment of cells with hydrogen peroxide at a con-
centration of 0.75 mol L–1 for 6 h). According to the
acquired data (Table 3), the tested compounds did not
exhibit a protective effect under these experimental condi-
tions except for conjugate 3, which was able to maintain
the viability of neuroblastoma cells after H2O2-induced
oxidative stress to the maximum extent in comparison with
other used compounds.
In summary, this work reports the synthesis of a series
of conjugates based on alkyl- and terpenylphenols with
chlorophyll a fragments, wherein the phenolic and por-
phyrin fragments are connected via an amide linker. The
AOA study of the starting chlorins and their conjugates on
the substrate containing the brain lipids of laboratory mice
revealed that the chlorin macrocycle was involved in the
inhibition of oxidation processes, but its conjugation with
the terpenylphenolic fragment suppressed such properties
in most cases. The acquired data also indicated that the
chlorin macrocycle was specifically responsible for the
cytotoxicity of the most of test compounds towards the
HEK293 and SH-SY5Y cell lines, while the introduction
of terpenylphenolic substituent into the porphyrin mole-
cule led usually to its decrease. The presence and structure
of terpene moiety were shown causing the statistically
Table 3. The effect of compounds 3, 15—18, and 24 on the
viability of SH-SY5Y cells under conditions of oxidative stress
simulation*
Compound
Living cells (%)*
without H2O2
with H2O2
3
92.0 6.2
94.0 2.8
95.0 1.9
92.0 9.3
95.0 7.1
93.0 7.9
77.9 2.7
48.1 9.1
63.9 17.1
63.7 0.3
70.8 2.8
67.1 7.0
15
16
17
18
24
* The percentages of living cells in the control sample in the
absence and in the presence of H2O2 were 95.08.3 and
71.77.6, respectively.

552
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
Chukicheva et al.
periments were presented as the mean values of three measure-
ments for each concentrationstandard deviation with respect to
the control values (0.1% DMSO), which were considered 100%.
To calculate the IC50 values (the concentration of a compound,
which inhibits cell viability by 50%), a non-linear regression of
the logarithm of the compound concentrations and normalized
values for the inhibition percentage of viability (GraphPad Prism
v.5.0, GraphPad Software Inc.) was performed.
Experimental
1H and 13C NMR spectra were recorded on a Bruker Avance
II 300 spectrometer (300.17 and 75.5 MHz) at room temperature.
Diffuse reflectance IR spectra were recorded on a Shimadzu IR
Prestige 21 IR Fourier spectrophotometer in the KBr pellets for
solids and neat for liquids. UV-Vis spectra were obtained
for CH2Cl2 solutions in quartz cells (10 mm) on a Shimadzu
UV-1600 instrument. Mass spectra were obtained on a Thermo
Finnigan LCQ Fleet instrument. Specific rotation values were
measured on an Optical Activity polAAr 3001 polarimeter. The
chemical reaction progress was monitored by TLC on Sorbfil
plates (LLC IMID, Russia); amines were detected by treatment
with KMnO4 solution (15 g of KMnO4, 300 mL of H2O, and
0.5 mL of conc. H2SO4), while colored conjugates did not require
the above detection. 2,4-Dimethylphenol, diethylamine, and
n-octylamine from Alfa Aesar were used for the syntheses. Silica
gel (0.06—0.2 mm) from Alfa Aesar was used for the column
chromatography. Enantiomerically enriched (ee > 99% according
to chiral HPLC) sample of (+)-2-bornyl-4-methylphenol 4
([]D25 of +29.1 (c 0.3, CHCl3)) was used. Methyl pheophorbide
a 2 was obtained from spirulina alga.12 The previously synthesized
conjugate 3,6 porphyrin derivatives 13, 14,10 and 2-isocamphyl-
4-methylphenol 513 were used.
The antioxidant activity of compounds was evaluated in vitro
by their ability to inhibit LPO in a substrate obtained from the
brain of laboratory mice.14,15 After the extraction, the brain was
homogenized (10%) in saline solution (pH 7.4) and centrifuged
for 10 min. Then the supernatant (S1)14,16 containing water,
proteins, DNA, RNA, and lipids (cholesterol, galactolipids,
individual phospholipids, and gangliosides) was taken. The
studied compounds were added to the supernatant as solutions
in acetone (the final concentration 500 mol L–1). After 30 min,
LPO was initiated by addition of a freshly prepared solution of
FeCl2 and ascorbic acid,17 and the test samples were incubated
at 37 C for 1 h under slow stirring. The content of TBA-reactive
substances was determined15,18,19 using the ThermoSpectromic
Genesys 20 spectrophotometer at  = 532 nm. All experiments
were repeated four times.
The effect of compounds 2, 3, and 13—25 on the viability of
HEK293 and SH-SY5Y cells (Russian Collection of Cell Cultures,
Institute of Cytology of the Russian Academy of Sciences,
St. Petersburg) was evaluated by staining cells with trypan blue.
The method is based on the ability of the dye to penetrate into
the interior of the cell through damaged membranes, while living
cells do not stain.20 The cells were seeded in 24-well plates
(1.5•105 cells mL–1) in the DMEM medium (Biolot), containing
10% fetal bovine serum (Invitrogen), 2 mmol L–1 of L-glutamine,
50 g mL–1 of gentamycin sulfate (PanEko, Russia), and cultured
under 5% CO2 atmosphere at 95% humidity. After 24 h from the
reseeding, the test compounds were added to the cells, and the
cells were incubated for 48 h. Immediately before the experiments,
the stock solutions of test compounds (100 mmol L–1 in 100%
DMSO) were diluted with the complete culture medium to the
final concentrations of 1, 10, and 100 mol L–1; the final con-
centration of DMSO was 0.1%. When the incubation was finished,
the cells were trypsinized (0.25% trypsin solution, 0.02% Versene
solution, 3 min, 37 C), and differential counting of live and dead
cells was performed using trypan blue (0.01%) in the Goryaev
chamber. The results were expressed as the percentage of living
cells relative to the total number of cells in the experimental and
control groups. The data obtained from two independent ex-
The neuroprotective properties were evaluated on the
SH-SY5Y cell culture. Immediately before the experiments, the
stock solutions of compounds 3, 15—18, and 24 (50 mmol L–1
in 100% DMSO) were diluted with the complete culture medium
to the final concentration of 50 mol L–1; the final concentration
of DMSO was 0.1%. The cells were seeded in 24-well plates
(2.5•105 cells mL–1) in the DMEM medium (Biolot), containing
10% fetal bovine serum (Invitrogen), 2 mmol L–1 of L-glutamine,
50 g mL–1 of gentamycin sulfate (PanEko), and cultured under
5% CO2 atmosphere at 95% humidity. After 24 h from the reseed-
ing, the damaging agent (hydrogen peroxide) was added to the
cells at the final concentration of 0.75 mmol L–1, the cells were
incubated for 6 h, and the medium was changed to fresh.
Simultaneously, the test compounds were added to the cells, the
cells were incubated for 24 h, and the cell viability was determined
using trypan blue as described above. The results were expressed
as the percentage of living cells relative to the total number of
cells in the experimental and control groups. The data obtained
from two independent experiments were presented as the mean
values of three measurementsstandard deviation with respect to
the control values (0.1% DMSO), which were taken as 100%.
The arithmetic mean value of the total data selection obtained
from two independent experiments and the standard devia-
tion were calculated using the descriptive statistics module in
a Statistica 6.1 program (StatSoft. Inc.). Statistical processing
of the obtained results was performed using the non-parametric
Wilcoxon t-test.
Synthesis of tertiary amines 7—9 (general procedure). Cresol
4, 5, or 6 (1.51 mmol) was dissolved in anhydrous benzene
(10 mL); paraform (54.7 mg, 1.82 mmol) and diethylamine
(0.188 mL, 1.82 mmol) were added, and the reaction mixture was
refluxed for 18 h under stirring. The reaction products were
isolated by column chromatography (eluent was petroleum
ether—Et2O).
6-Diethylaminomethyl-2,4-dimethylphenol (7). Light yellow
oil. Yield 90%. Rf 0.44 (Sorbfil, petroleum ether—Et2O, 5 : 1).
Found (%): C, 75.66; H, 10.09; N, 6.94. C13H21NO. Calculat-
ed (%): C, 75.32; H, 10.21; N, 6.76. IR (neat), /cm–1: 3200
(O—H); 2972, 2922, 2822, 1483, 1385, 1358 (CH3, CH2); 1612
(C=C); 1246, 1161, 1051 (=C–O, C–N); 858, 766 (=C–H).
1H NMR (CDCl3), : 1.11 (t, 6 H, NCH2CH3, J = 7.2 Hz); 2.20,
2.22 (both s, 3 H each, C(2)CH3, C(4)CH3); 2.61 (q, 4 H,
NCH2CH3, J = 7.2 Hz); 3.71 (s, 2 H, ArCH2N); 6.63 (s, 1 H,
H(5)); 6.85 (s, 1 H, H(3)). 13C NMR (CDCl3), : 11.20
(NCH2CH3); 15.56 (C(2)—CH3); 20.39 (C(4)–CH3); 46.24
(NCH2CH3); 56.89 (ArCH2N); 121.11 (C(6)); 124.41 (C(4));
126.41; 130.21 (C(3); C(5)); 127.28 (C(2)); 153.93 (C(1)).
2-Diethylaminomethyl-4-methyl-6-(2,2,3-trimethylbicyclo[2.2.1]-
hept-exo-5-yl)phenol (8). Light yellow oil. Yield 92%. Rf 0.75
(Sorbfil, petroleum ether—Et2O, 5 : 1). Found (%): C, 80.35;
H, 10.79; N, 4.02. C22H35NO. Calculated (%): C, 80.19; H, 10.71;
N, 4.25. IR (neat), /cm–1: 3200 (O—H); 2968, 2874, 2822, 1470,
1381, 1369 (CH2, CH3); 1609 (C=C); 1246, 1163, 1049 (=C—O,
C—N); 860, 779 (=C–H). 1H NMR (CDCl3), : 0.81—0.94 (m, 6 H,

Alkyl- and terpenylphenolchlorin conjugates
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
553
C(8)H3, C(10)H3); 1.07 (s, 3 H, C(9)H3); 1.10 (t, 6 H, NCH2CH3,
J = 7.2 Hz); 1.24—1.47 (m, 3 H, 1 H(1); 1 H(6), H(7)); 1.68—1.79
(m, 2 H, 1 H(7), H(3)); 1.92 (s, 1 H, H(4)); 2.24 (s, 3 H,
C(17)H3); 2.21—2.32 (m, 1 H, H(6)); 2.61 (q, 4 H, NCH2CH3,
J = 7.1 Hz); 3.01 (br.t, 1 H, H(5), J = 7.5 Hz); 3.70 (s, 2 H,
ArCH2N); 6.61 (s, 1 H, H(14)); 6.90 (s, 1 H, H(16)). 13C NMR
(CDCl3), : 11.04 (NCH2CH3); 16.31, 24.88 (C(8), C(10)); 20.81
(C(17)); 27.66 (C(9)); 32.90 (C(6)); 33.58 (C(7)); 39.60 (C(2));
40.42 (C(5)); 46.11 (NCH2CH3); 48.78 (C(1)); 49.89 (C(3));
51.28 (C(4)); 56.96 (ArCH2N); 121.21 (C(13)); 125.33 (C(16));
126.05 (C(14)); 126.87 (C(15)); 134.05 (C(11)); 153.57 (C(12)).
2-Diethylaminomethyl-4-methyl-6-{(1R,2R,4S)-1,7,7-tri-
methylbicyclo[2.2.1]hept-2-yl}phenol (9). Colorless semicrystal-
line substance. Yield 81%. []D24 +45.7 (c 0.3, CHCl3). Rf 0.77
(Sorbfil, petroleum ether—Et2O, 5 : 1). Found (%): C, 80.12;
H, 10.96; N, 3.99. Calculated (%): C, 80.19; H, 10.71; N, 4.25.
IR (neat), /cm–1: 3100 (O—H); 2955, 2880, 2810, 1466, 1387,
1369 (CH2, CH3); 1607 (C=C); 1227, 1161, 1049 (=C—O, C—N);
866, 779 (=C—H). 1H NMR (CDCl3), : 0.75 (s, 3 H, C(10)H3);
0.93 (s, 3 H, C(8)H3); 1.09 (t, 3 H, NCH2CH3, J = 7.2 Hz);
1.10 (s, 3 H, C(9)H3); 1.12—1.21 (m, 1 H, 1 H(6)); 1.36—1.45
(m, 2 H, 1 H(3), 1 H(5)); 1.57 (ddd, 1 H, 1 H(6), J = 22.2 Hz,
J = 9.2 Hz, J = 3.8 Hz); 1.69—1.75 (m, 1 H, H(4)); 1.77—1.89
(m, 1 H, 1 H(5)); 2.14 (tt, 1 H, 1 H(3), J = 12.3 Hz, J = 3.9 Hz);
2.28 (s, 3 H, C(17)H3); 2.47—2.71 (m, 4 H, NCH2CH3); 3.62,
3.78 (both d, 1 H each, ArCH2N, J = 13.9 Hz, J = 14.0 Hz);
3.70—3.78 (m, 1 H, H(2)); 6.65 (s, 1 H, H(14)); 6.97 (s, 1 H,
H(16)). 13C NMR (CDCl3), : 11.06 (NCH2CH3); 14.68 (C(10));
18.88 (C(9)); 19.91 (C(8)); 20.99 (C(17)); 28.56 (C(5)); 29.05
(C(6)); 34.77 (C(3)); 40.28 (C(2)); 45.77 (C(4)); 45.99
(NCH2CH3); 50.22 (C(1)); 50.47 (C(7)); 57.10 (ArCH2N); 121.23
(C(13)); 126.41 (C(15)); 126.55 (C(14)); 129.10 (C(16)); 129.28
(C(11)); 154.67 (C(12)).
13 H, 2 H, H(1), 1 H(6), 1 H(7), NCH2C6H12CH3); 1.66—1.81
(m, 2 H, H(3), 1 H(7)); 1.92 (s, 1 H, H(4)), 2.21—2.33 (m, 1 H,
1 H(6)); 2.24 (s, 3 H, C(17)H3); 2.66 (t, 2 H, NCH2C7H15
,
J = 7.1 Hz); 3.02 (br.t, 1 H, H(5), J = 7.4 Hz); 3.92 (s, 2 H,
ArCH2N); 6.64 (s, 1 H, H(14)); 6.91 (s, 1 H, H(16)). 13C NMR
(CDCl3), : 14.08 (NC7H14CH3); 16.31, 24.88 (C(8); C(10)),
20.80 (C(17)); 22.64, 27.12, 29.20, 29.37, 29.43, 31.80
(NCH2C6H12CH3); 27.65 (C(9)); 32.89 (C(6)); 33.59 (C(7));
39.59 (C(2)); 40.41 (C(5)); 48.71 (NCH2C7H15); 48.82 (C(1));
49.87 (C(3)); 51.30 (C(4)); 52.67 (ArCH2N); 121.72 (C(13));
125.59 (C(16)); 125.99 (C(14)); 127.13 (C(15)); 134.53 (C(11));
153.52 (C(12)).
4-Methyl-2-n-octylaminomethyl-6-{(1R,2R,4S)-1,7,7-tri-
methylbicyclo[2.2.1]hept-2-yl}phenol (12). Light yellow oil. Yield
24
66%. []D +56.5 (c 0.3, CHCl3). Rf 0.51 (Sorbfil, petroleum
ether—Et2O—PriOH, 3 : 1 : 0.01). Found (%:) C, 80.85; H, 11.35;
N, 3.35. Calculated (%:) C, 80.98; H, 11.24; N, 3.63. IR (neat),
/cm–1: 3316, 3292 (N—H, O—H); 2953, 2926, 2856, 1466, 1379
(CH2, CH3); 1609 (C=C); 1227, 1152, 1105 (=C—O, C—N);
862, 781, 758 (=C–H). 1H NMR (CDCl3), : 0.76 (s, 3 H, C(10)H3);
0.88 (t, 3 H, NC7H14CH3, J = 6.6 Hz); 0.93 (s, 2 H, C(8)H3);
1.10 (s,
3 H, C(9)H3); 1.26—1.41 (m, 13 H, 1 H(3),
H(6), NC2H4C5H10CH3); 1.43—1.57 (m, 3 H, 1 H(5) and
NCH2CH2C6H13); 1.73 (t, 1 H, H(4), J = 4.2 Hz); 1.80—1.91
(m, 1 H, 1 H(5)); 2.14 (tt, 1 H, 1 H(3), J = 12.4 Hz, J = 3.7 Hz);
2.28 (s, 3 H, C(17)H3), 2.65 (t, 2 H, NCH2C7H15); 3.74 (ddd,
1 H, H(2), J = 11.8 Hz, J = 3.8 Hz, J = 1.8 Hz); 3.89, 3.96 (both
d, 1 H each, ArCH2N, J = 13.6 Hz, J = 13.5 Hz); 6.68 (s, 1 H,
H(14)); 6.98 (s, 1 H, H(16)). 13C NMR (CDCl3), : 14.07
(NC7H14CH3); 14.76 (C(10)); 18.84 (C(9)); 19.90 (C(8)); 20.90
(C(17)); 22.63, 27.13, 29.18, 29.39, 29.49, 31.78 (NCH2C6H12CH3);
28.54 (C(5)); 29.03 (C(6)); 34.87 (C(3)); 40.37 (C(2)); 45.75
(C(4)); 48.59 (NCH2C7H15); 50.25 (C(1)); 50.47 (C(7)); 52.83
(ArCH2N); 121.81 (C(13)); 126.50 (C(14)); 126.63 (C(15)); 129.37
(C(16)); 129.72 (C(11)); 154.68 (C(12)).
Synthesis of secondary amines 10—12 (general procedure).
The mixture of tertiary amine 7, 8, or 9 (1.1 mmol) and n-octyl-
amine (0.45 mL, 2.75 mmol) was refluxed for 1 h under argon
flow and stirring. The reaction products were isolated by column
chromatography (eluent was petroleum ether—Et2O).
Conjugates 15—25 were synthesized according to the known
procedure.8
Methyl pheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3,5-
dimethylbenzyl)amide (15), mixture of diastereomers (dr 1 : 1).
Dark blue-green crystals. Yield 58%. Rf 0.86 (Sorbfil, CCl4—ace-
tone, 4 : 1). MS (ESI), m/z: 838.5 [MH]+. UV-Vis, /nm
(Irel (%)): 668.5 (51); 611.0 (12); 539.0 (14); 508.5 (15); 473.0 (8);
414.0 (100); 328.5 (31); 282.0 (25). IR (KBr), /cm–1: 3391 (NH);
2959, 2926, 2866, 2733 (CH2, CH3); 1732 (C=O, ester); 1695
(C=O, exocycle); 1616 (amide I); 1600 shoulder (chlorin band).
1H NMR (CDCl3), *: –1.55 (br.s, 1 H, HN(III)); 0.61 (br.s,
1 H, HN(I)); 0.82—0.93 (m, 3 H, NC7H14CH3); 0.97—1.62 (m,
12 H, NCH2C6H12CH3); 1.72 (t, 3 H, C(8´(2))H3, J = 8.3 Hz);
1.63 (d, 3 H, C(18´(1))H3, J = 8.3 Hz); 1.95—2.18 (m, 2 H,
C(17´(2))H2); 2.18—2.39 (m, 8 H, NCH2C7H15, C(2)CH3,
C(4)CH3); 2.40—2.60 (m, 2 H, C(17´(1))H2), 3.21/3.23 (s, 3 H,
C(7´(1))H3); 3.40 (s, 3 H, C(2´(1))H3); 3.54 (s, 3 H, C(12´(1))H3);
3.69 (s, 3 H, C(17´(4))H3); 3.59—3.70 (m, 2 H, C(8´(1))H2);
3.72—3.80, 4.60—4.74 (both m, 1 H each, ArCH2N); 4.25—4.54
(m, 2 H, H(17´), H(18´)); 6.19 (d, 1 H, H(3(2)´-cis),
J = 11.0 Hz); 6.30 (d, 1 H, H(3(2)´-trans), J = 18.3 Hz); 6.60/6.70
(s, 1 H, H(13(2)´)); 6.91/6.95 (s, 1 H, H(5)); 7.04 (s, 1 H, H(3));
7.98 (dd, 1 H, H(3(1)´), J = 18.4 Hz, J = 11.9 Hz); 8.51 (s, 1 H,
H(20´)); 9.31/9.34 (s, 1 H, H(5´)); 9.44/9.49 (s, 1 H, H(10´));
2,4-Dimethyl-6-n-octylaminomethylphenol (10). Light yellow
oil. Yield 61%. Rf 0.44 (Sorbfil, petroleum ether—Et2O—PriOH,
3 : 1 : 0.01). Found (%): C, 77.42; H, 10.25; N, 5.44. Calculat-
ed (%): C, 77.51; H, 10.11; N, 5.32. IR (neat), /cm–1: 3316,
3291 (N—H, O—H); 2926, 2855, 1481, 1379 (CH2, CH3); 1612
(C=C); 1246, 1107 (=C—O, C—N); 858, 770 (=C—H). 1H NMR
(CDCl3), : 0.89 (t, 3 H, NC7H14CH3, J = 6.5 Hz); 1.19—1.40,
1.43—1.60 (both m, 10 H, 2 H, NCH2C6H12CH3); 2.21, 2.22
(both s, 3 H each, C(2)H3, C(4)H3); 2.66 (t, 2 H, NCH2C7H15
,
J = 7.1 Hz); 3.92 (s, 2 H, ArCH2N); 6.65 (s, 1 H, H(5)); 6.86
(s, 1 H, H(3)). 13C NMR (CDCl3), : 14.06 (NC7H14CH3); 15.57
(C(2)—CH3); 20.37 (C(4)—CH3); 22.62, 27.12, 29.18, 29.39,
29.59, 31.79 (NCH2C6H12CH3); 48.79 (NCH2C7H15); 52.78
(ArCH2N); 121.72 (C(6)); 124.86 (C(4)); 126.23, 130.34 (C(3),
C(5)); 127.34 (C(2)); 154.01 (C(1)).
4-Methyl-2-n-octylaminomethyl-6-(2,2,3-trimethylbicyclo-
[2.2.1]hept-exo-5-yl)phenol (11). Light yellow oil. Yield 62%.
Rf 0.52 (Sorbfil, petroleum ether—Et2O—PriOH, 3 : 1 : 0.01).
Found (%:) C, 81.19; H, 10.98; N, 3.44. Calculated (%): C, 80.98;
H, 11.24; N, 3.63. IR (neat), /cm–1: 3314, 3292 (N—H, O—H);
2957, 2926, 2859, 1468, 1369 (CH2, CH3); 1609 (C=C); 1246,
1105 (=C—O, C—N); 858, 781 (=C–H). 1H NMR (CDCl3), :
0.88—0.91 (m, 6 H, C(8)H3, C(10)H3); 0.89 (t, 3 H, NC7H14CH3,
J = 6.9 Hz); 1.01 (s, 3 H, C(9)H3); 1.20—1.47, 1.48—1.60 (both m,
* Hereinafter the symbol "/" indicates the signals from dia-
stereomers differing by the chemical shift values.

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Chukicheva et al.
9.62 (br.s, 1 H, OH). 13C NMR (CDCl3), : 11.22 (C(7´(1));
12.04 (C(2´(1))), (C(12´(1))); 14.09 (NC7H14CH3); 16.55
(C(2)—CH3); 17.39 (C(8´(2))); 19.41 (C(8´(1))); 20.39 (C(4)—
CH3); 22.60, 27.08, 28.65, 28.78, 29.15, 29.18 (NCH2C6H12CH3);
22.75 (C(18´(1))); 30.32 (C(17´(2))); 31.73 (C(17´(1))); 50.26
(ArCH2N, NCH2C7H15); 63.22 (C(13´(2))); 51.21 (C(18´));
51.50 (C(17´); C(17´(4))); 93.18 (C(20´)); 97.36 (C(5´)); 104.29
(C(10´)); 106.47 (C(15´)); 122.07 (C(6)); 122.70 (C(3´(2)));
126.51 (C(4)); 127.90 (C(2)); 128.66 (C(13´)); 129.10 (C(5));
129.45 (C(3´(1)), C(12´)); 131.87 (C(3)); 132.11 (C(2´)); 135.83
(C(7´)); 136.11 (C(4´)); 136.22 (C(3´)); 137.94 (C(11´)); 142.05
(C(1´)); 145.19 (C(8´)); 149.55 (C(14´)); 150.96 (C(9´)); 152.12
(C(1)); 155.78 (C(6´)); 161.55 (C(16´)); 170.68 (C(13´(3));
C(19´)); 173.42 (C(17´(3))); 190.70 (C(13´(1))).
exocycle); 1614 (amide I), 1600 shoulder (chlorin band). 1H NMR
(CDCl3), : –1.61 (br.s, 1 H, HN(III)); 0.50 (br.s, 1 H, HN(I));
0.67 (s, 3 H, C(10)H3); 0.70—0.89 (m, 3 H, NC7H14CH3); 0.90
(s, 3 H, C(8)H3); 0.95 (s, 3 H, C(9)H3); 1.11—1.69 (m, 21 H,
1 H(3), C(6)H2, NCH2C6H12CH3, C(5)H2, C(18´(1))H3, H(4)),
1.73 (t, 3 H, C(8´(2))H3, J = 8.3 Hz); 2.00—2.51 (m, 8 H,
C(17´(2))H2, H(2), NCH2C7H15, 1 H(3), C(17´(1))H2); 2.44
(s, 3 H, C(17)H3); 3.25 (s, 3 H, C(7´(1))H3); 3.42 (s, 3 H,
C(2´(1))H3); 3.49 (s, 3 H, C(12´(1))H3); 3.58—3.67 (m, 2 H,
C(8´(1))H2); 3.70 (s, 3 H, C(17´(4))H3); 3.74—3.91 (m, 2 H,
ArCH2N); 4.19—4.38 (m, 2 H, H(17´), H(18´)); 6.20 (d, 1 H,
H(3´(2))-cis, J = 11.9 Hz); 6.31 (d, 1 H, H(3´(2))-trans,
J = 17.4 Hz); 6.58/6.69 (s, 1 H, H(13´(2))); 7.02/7.09 (s, 1 H,
H(14)); 7.19 (s, 1 H, H(16)); 8.01 (dd, 1 H, H(3´(1)), J = 17.4 Hz,
J = 11.9 Hz); 8.54 (s, 1 H, H(20´)); 9.16/9.21 (br.s, 1 H, OH);
9.35/9.37 (s, 1 H, H(5´)); 9.45/9.51 (s, 1 H, H(10´)). 13C NMR
(CDCl3), : 11.13 (C(7´(1))); 12.05 (C(2´(1)), C(12´(1))); 14.16
(NC7H14CH3); 14.69 (C(10)); 17.37 (C(8´(2))); 19.36 (C(8´(1)));
19.89 (C(9)); 20.99 (C(8), C(17)); 22.70, 27.32, 29.08, 29.19,
29.35 (NCH2C6H12CH3); 22.70 (C(18´(1))); 28.67 (C(5)); 29.19
(C(6)); 31.01 (C(17´(2))); 31.87 (C(17´(1))); 35.11 (C(3)); 40.84
(C(2)); 45.82 (C(4)); 47.89 (NCH2C7H15); 50.29 (C(1)); 50.36
(C(7)); 50.64 (C(18´)); 51.28 (C(17´)); 51.48 (ArCH2N); 61.89
(C(13´(2))); 93.11 (C(20´)); 97.24 (C(5´)); 104.08 (C(10´));
106.87 (C(15´)); 122.12 (C(3´(2))); 122.53 (C(13)); 126.96
(C(14)); 128.82 (C(3´(1))); 129.10 (C(13´)); 129.43 (C(16));
130.89 (C(15)); 131.21(C(12´)); 131.71 (C(2´)); 135.91 (C(7´));
136.09 (C(4´)); 136.43 (C(3´)); 137.85 (C(11´)); 141.86 (C(1´));
145.00 (C(8´)); 149.92 (C(14´)); 150.87 (C(9´)); 155.52 (C(12),
C(6´)); 161.38 (C(16´)); 170.88 (C(19´)); 172.00 (C(13´(3)));
173.30 (C(17´(3))); 190.76 (C(13´(1))).
Pyropheophorbide a 17(3)-N-n-octyl-N-(2-hydroxy-3,5-
dimethylbenzyl)amide (18). Dark gray-blue crystals. Yield 56%.
Rf 0.90 (Sorbfil, CCl4—acetone, 2 : 1). MS (ESI), m/z: 780.5
[MH]+. UV-Vis, /nm (Irel (%)): 668.0 (40); 610.5 (8); 539.0
(9); 508.0 (10); 414.0 (100); 322.5 (21); 283.0 (20). IR (KBr),
/cm–1: 3391 (NH); 2957, 2924, 2859, 2733 (CH2, CH3); 1694
(C=O, exocycle); 1616 (amide I, chlorin band). 1H NMR
(CDCl3), : –1.68 (br.s, 1 H, HN(III)); 0.49 (br.s, 1 H, HN(I));
0.50—0.62 (m, 3 H, NC7H14CH3); 0.64—1.00, 1.03—1.21
(both m, 10 H, 2 H, NCH2C6H12CH3); 1.73 (t, 3 H, C(8´(2))H3,
J = 7.3 Hz); 1.80 (d, 3 H, C(18´(1))H3, J = 7.3 Hz); 2.17,
2.23 (both s, 3 H, 3 H, C(2)CH3, C(4)CH3), 2.30—2.57 (m, 2 H,
C(17´(1))H2); 2.67 (t, 2 H, NCH2C7H15, J = 7.3 Hz); 2.65—2.85
(m, 2 H, C(17´(2))H2); 3.28 (s, 3 H, C(7´(1))H3); 3.43 (s, 3 H,
C(2´(1))H3); 3.70 (s, 3 H, C(12´(1))H3); 3.67—3.81 (m, 2 H,
C(8´(1))H2); 4.14, 4.22 (both d, 1 H each, ArCH2N, J = 14.7 Hz,
J = 14.7 Hz); 4.39 (m, 2 H, H(17´)); 4.53 (q, 1 H, H(18´),
J = 8.3 Hz); 5.12, 5.26 (both d, 1 H each, H(13´(2)), J = 20.2 Hz,
J = 20.2 Hz); 6.21 (d, 1 H, H(3´(2))-cis, J = 11.9 Hz); 6.32
(d, 1 H, H(3´(2))-trans, J = 18.3 Hz); 6.53 (s, 1 H, H(5)); 6.90
(s, 1 H, H(3)); 8.05 (dd, 1 H, H(3´(1)), J = 17.4 Hz, J = 11.0 Hz);
8.56 (s, 1 H, H(20´)); 9.42 (s, 1 H, H(5´)); 9.53 (s, 2 H, H(10´),
OH). 13C NMR (CDCl3), : 11.28 (C(7´(1))); 12.08 (C(2´(1)));
12.11 (C(12´(1))); 14.05 (NC7H14CH3); 16.46 (C(2)—CH3);
17.46 (C(8´(2))); 19.50 (C(8´(1))); 20.27 (C(4)—CH3); 22.51,
26.11, 27.55, 28.55, 28.75, 28.92 (NCH2C6H12CH3); 23.11
(C(18´(1))); 29.81 (C(17´(2))); 31.45 (C(17´(1))); 46.33
(ArCH2N); 47.11 (NCH2C7H15); 48.05 (C(13´(2))); 49.97
(C(18´)); 51.65 (C(17´)); 92.95 (C(20´)); 97.23 (C(5´)); 104.11
(C(10´)); 106.12 (C(15´)); 121.21 (C(6)); 122.58 (C(3´(2)));
126.26 (C(4)); 127.49 (C(2)); 128.39 (C(13´)); 129.12 (C(5));
Methyl pheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3-
(2,2,3-trimethylbicyclo[2.2.1]hept-exo-5-yl)-5-methylbenzyl)-
amide (16), mixture of diastereomers (dr 1 : 1). Dark blue-green
crystals. Yield 52%. Rf 0.86 (Sorbfil, CCl4—acetone, 4 : 1). MS
(ESI), m/z: 960.5 [MH]+. UV-Vis, /nm (Irel (%)): 668.5 (46);
611.0 (9); 539.0 (10); 509.0 (10); 475.0 (4); 414.0 (100); 330.0
(23); 282.5 (17). IR (KBr), /cm–1: 3392 (NH); 2956, 2926,
2866, 2733 (CH2, CH3); 1738 (C=O, ester); 1699 (C=O, exo-
1
cycle); 1616 (amide I); 1600 shoulder (chlorin band). H NMR
(CDCl3), : –1.54 (br.s, 1 H, HN(III)); 0.61 (br.s, 1 H, HN(I));
0.79—1.11, 1.15—1.54 (both m, 12 H, 17 H, C(8)H3, C(9)H3,
C(10)H3, NC7H14CH3, H(1), 1 H(6), C(7)H2, NCH2C6H12CH3,
H(3)); 1.62 (d, 3 H, C(18´(1))H3, J = 8.3 Hz); 1.73 (t, 3 H,
C(8´(2))H3, J = 8.3 Hz); 1.83—2.60 (m, 12 H, H(4), C(17´(2))H2,
1 H(6), C(17)H3, C(17´(1))H2, NCH2C7H15, H(5)); 3.25
(s, 3 H, C(7´(1))H3); 3.42 (s, 3 H, C(2´(1))H3); 3.51 (s, 3 H,
C(12´(1))H3); 3.61—3.67 (m, 2 H, C(8´(1))H2); 3.70 (s, 3 H,
C(17´(4))H3); 3.76—3.99 (s, 2 H, ArCH2N); 4.24—4.53 (m, 2 H,
H(17´), H(18´)); 6.21 (d, 1 H, H(3´(2))-cis, J = 11.0 Hz); 6.31
(d, 1 H, H(3´(2))-trans, J = 18.3 Hz); 6.59/6.70 (s, 1 H,
H(13´(2))); 6.93/6.99 (s, 1 H, H(14)); 7.08 (s, 1 H, H(16)); 8.01
(dd, 1 H, H(3´(1)), J = 18.3 Hz, J = 11.0 Hz); 8.51/8.53 (s, 1 H,
H(20´)); 9.35/9.37 (s, 1 H, H(5´)); 9.49/9.51 (s, 1 H, H(10´)).
13C NMR (CDCl3), : 11.12 (C(7´(1))); 12.04 (C(2´(1)),
C(12´(1))); 14.09 (NC7H14CH3); 16.30/16.51, 24.86/24.96 (C(8),
C(10)), 17.36 (C(8´(2))); 19.35 (C(8´(1))), 20.84 (C(17));
22.81/22.88, 27.14, 27.68, 29.22, 29.71, 31.76 (NCH2C6H12CH3);
22.62 (C(18´(1))); 27.64 (C(9)); 30.29 (C(17´(2))); 31.08
(C(17´(1))); 33.56 (C(6)); 34.04 (C(7)); 39.57/39.61 (C(2));
40.94/41.09 (C(5)); 48.90 (NCH2C7H15); 49.10 (C(1)); 49.94
(C(3)); 50.32 (C(18´)); 51.18 (ArCH2N); 51.23 (C(4)); 51.49
(C(17´)); 51.96 (C(17´(4))); 67.06 (C(13´(2))); 93.14 (C(20´));
97.27 (C(5´)); 104.18 (C(10´)); 106.50 (C(15´)); 122.03/122.19
(C(13)); 122.60 (C(3´(2))); 127.05 (C(16)); 127.24 (C(14)); 127.52
(C(15)); 128.59/128.66 (C(11)); 128.93 (C(13´)); 129.04
(C(3´(1)), C(12´)); 131.81 (C(2´)); 135.71 (C(7´)); 136.12
(C(4´)); 136.56 (C(3´)); 137.79 (C(11´)); 142.01 (C(1´)); 145.07
(C(8´)); 150.89 (C(14´)); 151.71 (C(9´)); 151.79 (C(12)); 155.65
(C(6´)); 161.62 (C(16´)); 170.56 (C(13´(3))); 172.23 (C(19´));
173.39 (C(17´(3))); 190.70 (C(13´(1))).
Methyl pheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3-
{(1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl}-5-methyl-
benzyl)amide (17), mixture of diastereomers (dr 1 : 1). Dark
blue-green crystals. Yield 50%. Rf 0.86 (Sorbfil, CCl4—acetone,
4 : 1). MS (ESI), m/z: 960.6 [MH]+. UV-Vis, /nm (Irel (%)):
668.5 (45); 611.0 (9); 538.5 (11); 508.5 (12); 473.0 (6); 414.5 (100);
330.0 (24); 283.5 (19). IR (KBr), /cm–1: 3393 (NH); 2955,
2926, 2870, 2731 (CH2, CH3); 1738 (C=O, ester); 1699 (C=O,

Alkyl- and terpenylphenolchlorin conjugates
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
555
129.23 (C(3´(1))); 130.55 (C(12´)); 131.53 (C(3)); 131.99 (C(2´));
135.84 (C(7´)); 136.11 (C(4´)); 136.18 (C(3´)); 137.94 (C(11´));
141.50 (C(1´)); 145.01 (C(8´)); 148.94 (C(14´)); 150.83 (C(9´));
152.01 (C(1)); 155.21 (C(6´)); 160.44 (C(16´)); 171.66 (C(19´));
174.05 (C(17´(3))); 196.121 (C(13´(1))).
NCH2C7H15); 3.29 (s, 3 H, C(7´(1))H3); 3.43 (s, 3 H, C(2´(1))H3);
3.71 (s, 3 H, C(12´(1))H3); 3.74 (q, 2 H, C(8´(1))H2, J = 7.3 Hz);
3.80—3.91 (m, 1 H, H(2)); 3.98 (d, 1 H, ArCH2N, J = 13.7 Hz);
4.35—4.45 (m, 2 H, ArCH2N, H(17´)); 4.51 (q, 1 H, H(18´),
J = 7.3 Hz); 5.09, 5.24 (both d, 1 H each, H(13´(2)), J = 20.2 Hz,
J = 20.2 Hz); 6.21 (d, 1 H, H(3´(2))-cis, J = 11.0 Hz); 6.33
(d, 1 H, H(3´(2))-trans, J = 17.4 Hz); 6.58 (s, 1 H, H(14)); 7.03
(s, 1 H, H(16)); 8.05 (dd, 1 H, H(3´(1)), J = 17.4 Hz, J = 11.9 Hz);
8.55 (s, 1 H, H(20´)); 9.30 (s, 1 H, OH); 9.43 (s, 1 H, H(5´));
9.55 (s, 1 H, H(10´)). 13C NMR (CDCl3), : 11.25 (C(7´(1)));
12.04 (C(2´(1))); 12.10 (C(12´(1))); 14.03 (NC7H14CH3); 14.81
(C(10)); 17.44 (C(8´(2))); 18.85 (C(9)); 19.47 (C(8´(1))); 19.91
(C(8)); 20.80 (C(17)); 22.50, 26.22, 27.65, 28.74, 29.74, 31.46
(NCH2C6H12CH3); 23.06 (C(18´(1))); 28.56 (C(5)); 28.99
(C(6)); 29.91 (C(17´(2))); 31.46 (C(17´(1))); 34.98 (C(3)); 45.73
(C(4)); 46.63 (ArCH2N); 47.26 (NCH2C7H15); 48.03 (C(13´(2)));
49.98 (C(7)); 50.30 (C(1)); 50.52 (C(18´)); 51.65 (C(17´)); 92.95
(C(20´)); 97.18 (C(5´)); 104.05 (C(10´)); 106.04 (C(15´)); 121.46
(C(13)); 122.54 (C(3´(2))); 126.74 (C(14)); 128.30 (C(13´));
129.04 (C(15)); 129.22 (C(3´(1))); 130.53 (C(16)); 130.83
(C(12´)); 131.01 (C(11)); 131.53 (C(2´)); 135.81 (C(7´)); 136.08
(C(4´)); 136.16 (C(3´)); 137.89 (C(11´)); 141.51 (C(1´)); 144.94
(C(8´)); 148.89 (C(14´)); 150.77 (C(9´)); 152.82 (C(12)); 155.19
(C(6´)); 160.31 (C(16´)); 171.12 (C(19´)); 174.05 (C(17´(3)));
196.04 (C(13´(1))).
Pyropheophorbide a 17(3)-N-n-octyl-N-(2-hydroxy-3-(1,7,7-
trimethylbicyclo[2.2.1]hept-exo-2-yl)-5-methylbenzyl)amide (21),
mixture of diastereomers (dr 1 : 1). Dark gray-blue crystals.
Yield 62%. Rf 0.90 (Sorbfil, CCl4—acetone, 2 : 1). MS (ESI),
m/z: 902.7 [MH]+. UV-Vis, /nm (Irel (%)): 668.5 (45); 611.0
(8); 540.0 (10); 509.0 (11); 474.5 (5); 414.5 (100); 323.5 (33);
283.5 (29). IR (KBr), /cm–1: 3393 (NH); 2953, 2926, 2870,
2733 (CH2, CH3); 1695 (C=O, exocycle); 1614 (amide I, chlorin
band). 1H NMR (CDCl3), : –1.66 (br.s, 1 H, HN(III)); 0.49
(br.s, 1 H, HN(I)); 0.47—0.71 (m, 4 H, NCH2C2H4C5H11);
0.74 (s, 3 H, C(10)H3); 0.78 (s, 3 H, C(8)H3); 0.82 (t, 3 H,
NC7H14CH3, J = 5.6 Hz); 0.86 (s, 3 H, C(9)H3); 0.89—1.64
(m, 11 H, 1 H(3), C(6)H2, NC3H6C4H8CH3); 1.66—1.91 (m, 7 H,
C(8´(2))H3, H(4), C(18´(1))H3); 1.96—2.18 (m, 5 H, C(17´(2))H2,
C(5)H2, 1 H(3)), 2.20/2.21 (s, 3 H, C(17)H3); 2.26—2.43
(m, 2 H, C(17´(1))H2); 2.61—2.84 (m, 2 H, NCH2C7H15); 3.29
(s, 3 H, C(7´(1))H3); 3.32—3.42 (m, 1 H, H(2)); 3.43/3.45
(s, 3 H, C(2´(1))H3); 3.72 (s, 3 H, C(12´(1))H3); 3.74 (q, 2 H,
C(8´(1))H2, J = 7.3 Hz); 4.04—4.18, 4.26—4.45 (both m, 1 H
and 2 H, ArCH2N, H(17´)); 4.48—4.60 (m, 1 H, H(18´)); 5.14,
5.27 (both d, 1 H each, H(13´(2)), J = 20.2 Hz, J = 20.2 Hz);
6.22 (d, 1 H, H(3´(2))-cis, J = 11.9 Hz); 6.33 (d, 1 H, H(3´(2))-
trans, J = 18.3 Hz); 6.54/6.55 (s, 1 H, H(14)); 7.07 (s, 1 H,
H(16)); 8.05 (dd, 1 H, H(3´(1)), J = 17.4 Hz, J = 11.0 Hz);
8.56/8.57 (s, 1 H, H(20´)); 9.38 (s, 1 H, OH); 9.44/9.47 (s, 1 H,
H(5´)); 9.54 (s, 1 H, H(10´)). 13C NMR (CDCl3), : 11.23
(C(7´(1))); 12.05/12.11 (C(2´(1))); 12.16/12.26 (C(12´(1))); 14.06
(NC7H14CH3); 14.22 (C(10)); 17.44 (C(8´(2))); 19.45 (C(8´(1)));
20.39 (C(9)); 20.78 (C(8)); 20.78 (C(17)); 23.10 (C(18´(1)));
21.47, 22.51/22.54, 23.22, 27.55, 28.52/28.56, 28.93/28.90
(NCH2C6H12CH3); 29.90 (C(17´(3))); 31.45/31.51 (C(17´(3)));
33.98/34.04 (C(3)); 39.45/39.51 (C(2)); 45.79/45.13 (C(4));
46.66/46.76 (ArCH2N); 47.24 (NCH2C7H15); 47.96 (C(1)); 48.06
(C(7)); 49.82/49.92 (C(18´)); 51.72 (C(17´)); 92.98 (C(20´));
97.18 (C(5´)); 104.01 (C(10´)); 106.03/106.13 (C(15´)); 121.18
(C(3´(2))); 122.53 (C(13)); 126.66 (C(14); C(15)); 128.30/128.33
(C(13´)); 129.21 (C(16)); 129.23/129.28 (C(3´(1))); 130.48
Pyropheophorbide a 17(3)-N-n-octyl-N-(2-hydroxy-3-(2,2,3-tri-
methylbicyclo[2.2.1]hept-exo-5-yl)-5-methylbenzyl)amide (19),
mixture of diastereomers (dr 1 : 1). Dark gray-blue crystals.
Yield 59%. Rf 0.90 (Sorbfil, CCl4—acetone, 2 : 1). MS (ESI),
m/z: 902.5 [MH]+. UV-Vis, /nm (Irel (%)): 668.5 (43); 610.5
(8); 540.0 (9); 509.5 (11); 474.5 (5); 414.5 (100); 323.5 (34); 275.5
(33). IR (KBr), /cm–1: 3391 (NH); 2957, 2924, 2859, 2733
(CH2, CH3); 1694 (C=O, exocycle); 1616 (amide I, chlorin band).
1H NMR (CDCl3), : –1.66 (br.s, 1 H, HN(III)); 0.50 (br.s,
1 H, HN(I)); 0.42—0.78 (m, 6 H, NCH2C3H6C4H9); 0.75—0.96
(m, 9 H, C(8)H3, C(10)H3, NC7H14CH3); 1.04/1.05 (s, 3 H,
C(9)H3); 1.07—1.45 (m, 8 H, NC4H8C3H6CH3, C(7)H2);
1.64—1.93 (m, 9 H, 1 H(6), C(18´(1))H3, C(8´(2))H3, H(3),
H(1)); 1.99—2.16 (m, 1 H, H(4)); 2.21 (s, 3 H, C(17)H3);
2.25—2.60 (m, 3 H, 1 H(6), C(17´(1))H2); 2.67 (t, 2 H,
NCH2C7H15, J = 7.3 Hz); 2.71—2.86 (m, 2 H, C(17´(2))H2);
3.07 (br.t, 1 H, H(5), J = 7.3 Hz); 3.28 (s, 3 H, C(7´(1))H3);
3.43/3.45 (s, 3 H, C(2´(1))H3); 3.71 (s, 3 H, C(12´(1))H3); 3.73
(q, 2 H, C(8´(1))H2, J = 7.3 Hz); 4.02—4.24 (m, 2 H, ArCH2N);
4.38 (m, 2 H, H(17´), J = 6.4 Hz); 4.54 (q, 1 H, H(18´),
J = 7.3 Hz); 5.13/5.16, 5.27/5.32 (both d, 1 H each, H(13´(2)),
J = 20.2 Hz, J = 20.2 Hz); 6.21 (d, 1 H, H(3´(2))-cis, J = 11.9 Hz);
6.33 (d, 1 H, H(3´(2))-trans, J = 18.3 Hz); 6.53 (s, 1 H, H(14));
6.94 (s, 1 H, H(16)); 8.05 (dd, 1 H, H(3´(1)), J = 17.4 Hz,
J = 11.0 Hz); 8.56/8.60 (s, 1 H, H(20´)); 9.43 (s, 1 H, H(5´));
9.46 (br.s, 1 H, OH); 9.54 (s, 1 H, H(10´)). 13C NMR (CDCl3),
: 11.27 (C(7´(1))); 12.08 (C(2´(1))); C(12´(1))); 14.03
(NC7H14CH3); 16.28, 24.87 (C(8), C(10)), 17.45 (C(8´(2)));
19.50 (C(8´(1))); 20.66 (C(17)); 22.51, 26.18, 27.49, 28.73, 28.89,
29.77 (NCH2C6H12CH3); 23.14 (C(18´(1))); 27.64 (C(9)); 29.91
(C(17´(2))); 31.46 (C(17´(1))); 32.98/33.19 (C(6)); 33.57 (C(7));
39.56 (C(2)); 40.91 (C(5)); 46.42 (ArCH2N); 48.04 (C(13´(2)));
48.69 (NCH2C7H15); 49.87 (C(1)); 49.93 (C(3)); 49.99 (C(18´));
51.03 (C(4)); 51.66 (C(17´)); 92.97 (C(20´)); 97.22 (C(5´)); 104.11
(C(10´)); 106.10 (C(15´)); 121.32 (C(13)); 122.56 (C(3´(2)));
127.02 (C(16)); 127.13 (C(14)); 127.38 (C(15)); 128.38 (C(13´));
128.56 (C(11)); 129.24 (C(3´(1))); 130.58 (C(12´)); 131.53
(C(2´)); 135.84 (C(7´)); 136.11 (C(4´)); 136.17 (C(3´)); 137.90
(C(11´)); 141.53 (C(1´)); 145.01 (C(8´)); 148.93 (C(14´)); 150.82
(C(9´)); 151.69 (C(12)); 155.20 (C(6´)); 160.39 (C(16´)); 171.73
(C(19´)); 174.03 (C(17´(3))); 196.07 (C(13´(1))).
Pyropheophorbide a 17(3)-N-n-octyl-N-(2-hydroxy-3-
{(1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl}-5-methyl-
benzyl)amide (20). Dark gray-blue crystals. Yield 48%. Rf 0.90
(Sorbfil, CCl4—acetone, 2 : 1). MS (ESI), m/z: 902.6 [MH]+.
UV-Vis, /nm (Irel (%)): 668.0 (44); 610.0 (8); 557.5 (3); 539.0
(9); 508.5 (10); 473.0 (4); 413.5 (100); 321.5 (20). IR (KBr),
/cm–1: 3393 (NH); 2955, 2926, 2868, 2731 (CH2, CH3); 1695
(C=O, exocycle); 1614 (amide I, chlorin band). 1H NMR
(CDCl3), : –1.66 (br.s, 1 H, HN(III)); 0.50 (br.s, 1 H, HN(I));
0.41—0.69 (m, 4 H, NCH2C2H4C5H11); 0.73 (s, 3 H, C(10)H3);
0.82 (t, 3 H, NC7H14CH3, J = 7.3 Hz); 0.90 (s, 3 H, C(8)H3);
1.07 (s, 3 H, C(9)H3); 1.09—1.55 (m, 11 H, 1 H(3), C(6)H2,
NC3H6C4H8CH3); 1.69—1.74 (m, 1 H, H(4)); 1.74 (t, 3 H,
C(8´(2))H3, J = 7.3 Hz); 1.81 (d, 3 H, C(18´(1))H3, J = 7.3 Hz);
1.98—2.19 (m, 2 H, C(17´(2))H2); 2.29—2.83 (m, 5 H, C(17´(1))H2,
C(5)H2, 1 H(3)); 2.25 (s, 3 H, C(17)H3); 2.64—2.82 (m, 2 H,

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Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
Chukicheva et al.
(C(15)); 130.54 (C(12´)); 131.49/131.53 (C(2´)); 134.53 (C(7´));
135.80 (C(4´)); 136.02 (C(3´)); 136.11/136.16 (C(11´));
141.53/141.50 (C(1´)); 144.92 (C(8´)); 148.92 (C(14´)); 150.70
(C(9´)); 153.04/153.11 (C(12)); 155.09 (C(6´)); 160.29/160.45
(C(16´)); 171.63/171.67 (C(19´)); 174.06/174.11 (C(17´(3)));
195.99/196.09 (C(13´(1)).
(s, 3 H, C(7´(1))H3); 3.51 (s, 3 H, C(2´(1))H3); 3.58 (s, 3 H,
C(12´(1))H3); 3.82 (q, 2 H, C(8´(1))H2, J = 7.3 Hz); 3.91 (s, 3 H,
C(15´(3))H3); 3.98—4.12 (m, 2 H, ArCH2N); 4.43—4.62 (m, 2 H,
H(17´), H(18´)); 5.46, 5.58 (both d, 1 H each, H(15´(1)),
J = 19.2 Hz, J = 19.2 Hz); 6.18 (d, 1 H, H(3´(2))-cis, J = 11.9 Hz);
6.39 (d, 1 H, H(3´(2))-trans, J = 18.4 Hz); 6.44—6.49 (m, 1 H,
NHCH3); 6.52 (s, 1 H, H(14)); 6.93 (s, 1 H, H(16)); 8.13 (dd, 1 H,
H(3´(1)), J = 18.4 Hz, J = 11.9 Hz); 8.81 (s, 1 H, H(20´)); 9.47
(s, 1 H, OH); 9.67 (s, 1 H, H(5´)); 9.72 (s, 1 H, H(10´)).
13C NMR (CDCl3), : 11.34 (C(7´(1))); 11.95 (C(2´(1))); 12.16
(C(12´(1))); 14.09 (NC7H14CH3); 16.31, 24.87 (C(8), C(10)),
17.72 (C(8´(2))); 19.70 (C(8´(1))); 20.65 (C(17)); 22.59, 26.13,
28.55, 28.71, 28.81, 29.49 (NCH2C6H12CH3); 23.10 (C(18´(1)));
27.29 (C(13´(2))); 27.64 (C(9)); 31.60 (C(17´(2))); 32.97
(C(17´(1))); 33.19 (C(6)); 33.62 (C(7)); 39.57 (C(2)); 40.90
(C(5)); 46.33 (C(1)); 48.79 (NCH2C7H15); 49.45 (C(18´)); 49.88
(C(3)); 51.08 (ArCH2N); 51.23 (C(4)); 52.16 (C(15´(3))); 53.07
(C(17´)); 93.42 (C(20´)); 98.82 (C(5´)); 101.39 (C(10´)); 102.59
(C(15´)); 121.46 (C(3´(2))); 121.56 (C(13)); 126.95 (C(14),
C(16)); 127.10 (C(15)); 128.30 (C(13´)); 128.59 (C(3´(1))); 129.51
(C(12´)); 130.00 (C(2´)); 134.45 (C(7´)); 134.74 (C(4´)); 135.07
(C(3´)); 135.62 (C(11)); 135.65 (C(14´)); 136.06 (C(11´)); 138.77
(C(1´)); 144.73 (C(8´)); 149.14 (C(9´)); 151.69 (C(6´)); 154.15
(C(12)); 166.88 (C(16´)); 169.05 (C(19´)); 170.06 (C(13´(1)));
173.89 (C(17´(3))); 174.49 (C(15´(2))).
Chlorin e6 13-N-methylamide-15-methyl ester 17(3)-N-n-
octyl-N-(2-hydroxy-3-{(1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]
hept-2-yl}-5-methylbenzyl)amide (24). Dark blue-green crystals.
Yield 40%. Rf 0.50 (Sorbfil, CCl4—acetone, 2 : 1). MS (ESI),
m/z: 992.3 [MH]+. UV-Vis, /nm (Irel (%)): 663.5 (31); 607.5
(4); 557.0 (2); 529.0 (3); 500.0 (10); 402.0 (100); 284.0 (16). IR
(KBr), /cm–1: 3304 (NH); 2953, 2926, 2868, 2731 (CH2, CH3);
1736 (C=O, ester); 1659 (amide I, C(O)NHCH3); 1603 (chlorin
band, amide I, C(O)NCH2); 1543 (amide II). 1H NMR (CDCl3),
: –1.80 (br.s, 1 H, HN(III)); –1.57 (br.s, 1 H, HN(I)); 0.30—0.61
(m, 4 H, NCH2C2H4C5H11); 0.75 (s, 3 H, C(10)H3); 0.87 (t, 3 H,
NC7H14CH3, J = 7.3 Hz); 0.93 (s, 3 H, C(8)H3); 0.96—1.53
(m, 12 H, 1 H(3), C(6)H2, 1 H(5), NC3H6C4H8CH3); 1.09
(s, 3 H, C(9)H3); 1.66—1.85 (m, 9 H, C(8´(2))H3, C(18´(1))H3,
H(4), 1 H(5), 1 H(3)); 1.87—2.17 (m, 2 H, C(17´(2))H2); 2.22
(s, 3 H, C(17)H3); 2.23—2.38 (m, 2 H, C(17´(1))H2); 2.43
(m, 2 H, NCH2C7H15); 3.33 (d, 3 H, C(13´(2))H3, J = 4.6 Hz);
3.36 (s, 3 H, C(7´(1))H3); 3.51 (s, 3 H, C(2´(1))H3); 3.59 (s, 3 H,
C(12´(1))H3); 3.54—3.67 (m, 1 H, H(2)); 3.84 (q, 2 H, C(8´(1))H2,
J = 7.3 Hz); 3.90 (s, 3 H, C(15´(3))H3); 3.86—3.91 and 4.13
(m and d, 1 H each, ArCH2N, J = 14.7 Hz); 4.45 (q, 1 H, H(18´),
J = 7.3 Hz); 4.55 (br.d, 1 H, H(17´), J = 7.3 Hz); 5.41, 5.56 (both
d, 1 H each, H(15´(1)), J = 19.2 Hz, J = 19.2 Hz); 6.18 (d, 1 H,
H(3´(2))-cis, J = 11.9 Hz); 6.40 (d, 1 H, H(3´(2))-trans,
J = 17.4 Hz); 6.45—6.55 (m, 2 H, NHCH3, H(14)); 7.01 (s, 1 H,
H(16)); 8.14 (dd, 1 H, H(3´(1)), J = 17.4 Hz, J = 11.9 Hz); 8.80
(s, 1 H, H(20´)); 9.36 (s, 1 H, OH); 9.68 (s, 1 H, H(5´)); 9.72
(s, 1 H, H(10´)). 13C NMR (CDCl3), : 11.35 (C(7´(1))); 11.95
(C(2´(1))); 12.17 (C(12´(1))); 14.10 (NC7H14CH3); 14.78 (C(10));
17.74 (C(8´(2))); 18.87 (C(8´(1))); 19.72 (C(9)); 19.92 (C(8));
20.77 (C(17)); 22.57, 26.07, 28.48, 28.58, 28.80, 29.69
(NCH2C6H12CH3); 23.10 (C(18´(1))); 27.23 (C(13´(2))); 27.30
(C(5)); 29.02 (C(6)); 29.71 (C(17´(2))); 31.60 (C(17´(1))); 35.07
(C(3)); 40.72 (C(2)); 45.75 (C(4)); 46.49 (ArCH2N); 47.23
(NCH2C7H15); 49.59 (C(18´)); 50.32 (C(1)); 50.52 (C(7)); 52.24
(C(15´(3))); 52.98 (C(17´)); 93.39 (C(20´)); 98.85 (C(5´)); 101.39
Chlorin e6 13-N-methylamide-15-methyl ester 17(3)-N-n-
octyl-N-(2-hydroxy-3,5-dimethylbenzyl)amide (22). Dark blue-
green crystals. Yield 33%. Rf 0.50 (Sorbfil, CCl4— acetone, 2 : 1).
MS (ESI), m/z: 869.6 [MH]+. UV-Vis, /nm (Irel (%)): 663.0
(30); 607.5 (4); 528.0 (4); 500.5 (10); 402.0 (100); 284.0 (18). IR
(KBr), /cm–1: 3304 (NH); 2957, 2924, 2860, 2733 (CH2, CH3);
1736 (C=O, ester); 1657 (amide I, C(O)NHCH3); 1601 (chlorin
band, amide I, C(O)NCH2); 1545 (amide II). 1H NMR (CDCl3),
: –1.77 (br.s, 1 H, HN(III)); –1.54 (br.s, 1 H, HN(I));
0.41—0.85, 0.96—1.34 (both m, 6 H each, NCH2C6H12CH3);
0.89 (t, 3 H, NC7H14CH3, J = 6.4 Hz); 1.68—1.80 (m, 6 H,
C(8´(2))H3, C(18´(1))H3); 1.83—1.95, 2.41—2.25 (both m, 2 H
each, C(17´(1))H2, C(17´(2))H2); 2.17, 2.22 (both s, 3 H each,
C(2)CH3, C(4)CH3); 2.60 (t, 2 H, NCH2C7H15, J = 8.2 Hz);
3.33 (d, 2 H, C(13´(2)H3), J = 3.7 Hz); 3.36 (s, 3 H, C(7´(1))H3);
3.51 (s, 3 H, C(2´(1))H3); 3.59 (s, 3 H, C(12´(1))H3); 3.89
(s, 3 H, C(15´(3))H3); 3.84 (q, 2 H, C(8´(1))H2, J = 7.3 Hz);
4.11 (s, 2 H, ArCH2N); 4.42—4.56 (m, 2 H, H(17´), H(18´));
5.44, 5.57 (both d, 1 H each, H(15´(1)), J = 19.2 Hz, J = 19.2 Hz);
6.18 (d, 1 H, H(3´(2))-cis, J = 11.0 Hz); 6.40 (d, 1 H, H(3´(2))-
trans, J = 18.3 Hz); 6.42 (m, 1 H, NHCH3); 6.54 (s, 1 H, H(5));
6.89 (s, 1 H, H(3)); 8.13 (dd, 1 H, H(3´(1)), J = 18.3 Hz,
J = 11.9 Hz); 8.81 (s, 1 H, H(20´)); 9.53 (s, 1 H, OH); 9.67
(s, 1 H, H(5´)); 9.73 (s, 1 H, H(10´)). 13C NMR (CDCl3), :
11.35 (C(7´(1))); 11.94 (C(2´(1))); 12.16 (C(12´(1))); 14.10
(N(CH2)7CH3); 16.46 (C(2)—CH3); 17.72 (C(8´(2))); 19.70
(C(8´(1))); 20.24 (C(4)—CH3); 22.59, 26.18, 27.36, 28.59, 28.78,
28.83 (NCH2C6H12CH3); 23.04 (C(18´(1))); 27.26 (C(13´(2)));
29.50 (C(17´(2))); 31.61 (C(17´(1))); 46.32 (NCH2C7C15); 47.11
(ArCH2N); 49.45 (C(18´)); 52.16 (C(15´(3))); 53.06 (C(17´));
93.46 (C(20´)); 98.82 (C(5´)); 101.40 (C(10´)); 102.57 (C(15´));
121.57 (C(3´(2))); 121.35 (C(6)); 126.25 (C(4)); 127.45, 129.13
(C(3), C(5)); 128.28 (C(13´)); 129.51(C(12´)); 130.01 (C(2));
131.90 (C(2´)); 134.46 (C(7´)); 134.74 (C(4´)); 135.11 (C(3´));
136.05 (C(11´)); 138.82 (C(1´)); 144.70 (C(8´)); 149.00 (C(14´));
149.06 (C(9´)); 152.09 (C(6´)); 153.99 (C(1)); 166.96 (C(16´));
169.07 (C(19´)); 170.03 (C(13´(1))); 174.00 (C(17´(3))); 174.49
(C(15´(2))).
Chlorin e6 13-N-methylamide-15-methyl ester 17(3)-N-n-
octyl-N-(2-hydroxy-3-(2,2,3-trimethylbicyclo[2.2.1]hept-exo-5-
yl)-5-methylbenzyl)amide (23). Dark blue-green crystals. Yield
39%. Rf 0.50 (Sorbfil, CCl4—acetone, 2 : 1). MS (ESI), m/z:
991.7 [MH]+. UV-Vis, /nm (Irel (%)): 663.5 (35); 608.0 (4);
556.5 (2); 528.5 (4); 500.5 (11); 402.5 (100); 287.0 (17). IR (KBr),
/cm–1: 3304 (NH); 2957, 2926, 2868, 2733 (CH2, CH3); 1736
(C=O, ester); 1649, 1654 (amide I, C(O)NHCH3): 1603 (chlorin
band, amide I, C(O)NCH2); 1545 (amide II). 1H NMR (CDCl3),
: –1.77 (br.s, 1 H, HN(III)); –1.54 (br.s, 1 H, HN(I));
0.42—0.64 (m, 4 H, NCH2C2H4C5H11); 0.84—0.97 (m, 9 H,
C(8)H3, C(10)H3, NC7H14CH3); 1.06 (s, 3 H, C(9)H3); 1.14—1.48
(m, 8 H, NC3H6C4H8CH3); 1.65—1.82 (m, 10 H, C(8´(2))H3,
C(18´(1))H3, H(3), C(7)H2, H(1)); 1.84—2.02 (m, 3 H, C(17´(2))H2,
H(4)); 2.20 (s, 3 H, C(17)H3); 2.24—2.45 (m, 4 H, C(17´(1))H2,
C(6)H2); 2.48—2.60 (m, 2 H, NCH2C7H15); 3.02—3.11
(m, 1 H, H(5)); 3.32 (d, 3 H, C(13´(2))H3, J = 3.7 Hz); 3.34

Alkyl- and terpenylphenolchlorin conjugates
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
557
(C(10´)); 102.62 (C(15´)); 121.57 (C(3´(2))); 121.63 (C(13));
126.69 (C(14)); 128.30 (C(13´)); 129.02 (C(16)); 129.53
(C(3´(1))); 130.01 (C(15)); 130.73 (C(12´)); 131.04 (C(2´));
134.45 (C(7´)); 134.73 (C(4´)); 135.04 (C(3´)); 135.12 (C(14´));
136.09 (C(11´)); 138.79 (C(1´)); 144.73 (C(8´)); 149.14 (C(9´));
152.82 (C(6´)); 154.14 (C(12)); 166.84 (C(16´)); 169.04 (C(19´));
170.03 (C(13´(1))); 173.83 (C(17´(3))); 174.43 (C(15´(2))).
Chlorin e6 13-N-methylamide-15-methyl ester 17(3)-N-n-
octyl-N-(2-hydroxy-3-(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-
yl)-5-methylbenzyl)amide (25), mixture of diastereomers (dr 1 : 1).
Dark blue-green crystals. Yield 40%. Rf 0.50 (Sorbfil, CCl4—acet-
one, 2 : 1). MS (ESI), m/z: 992.3 [MH]+. UV-Vis, /nm (Irel (%)):
664.0 (32); 608.0 (3); 557.0 (1); 529.0 (2); 501.0 (8); 403.5 (100).
IR (KBr), /cm–1: 3304 (NH); 2953, 2926, 2870, 2733 (CH2,
CH3); 1736 (C=O, ester); 1659 (amide I, C(O)NHCH3); 1603
(chlorin band, amide I, C(O)NCH2); 1543 (amide II). 1H NMR
(CDCl3), : –1.76 (br.s, 1 H, HN(III)); –1.54 (br.s, 1 H, HN(I));
0.40—0.78 (m, 6 H, NC4H8C3H6CH3); 0.84—0.93 (m, 9 H, C(8)H3,
C(10)H3, NC7H14CH3); 0.97—1.44 (m, 10 H, 1 H(3), C(6)H2,
1 H(5), NCH2C3H6C4H9); 1.05 (s, 3 H, C(9)H3); 1.67—1.81
(m, 8 H, C(8´(2))H3, C(18´(1))H3, H(4), 1 H(3)); 1.87—1.93
(m, 1 H, 1 H(5)); 2.20 (s, 3 H, C(17)H3); 2.22—2.44 (m, 4 H,
C(17´(1))H2, C(17´(2))H2); 2.47—2.59 (m, 2 H, NCH2C7H15);
3.00—3.14 (m, 1 H, H(2)); 3.33 (d, 3 H, C(13´(2))H3, J = 5.5 Hz);
3.36 (s, 3 H, C(7´(1))H3); 3.51 (s, 3 H, C(2´(1))H3); 3.59 (s, 3 H,
C(12´(1))H3); 3.84 (q, 2 H, C(8´(1))H2, J = 7.3 Hz); 3.91 (s, 3 H,
C(15´(3))H3); 4.04 (s, 2 H, ArCH2N); 4.41—4.60 (m, 2 H,
H(18´), H(17´)); 5.45, 5.58 (both d, 1 H each, H(15´(1)),
J = 19.2 Hz, J = 19.2 Hz); 6.18 (d, 1 H, H(3´(2))-cis, J = 11.9 Hz);
6.40 (d, 1 H, H(3´(2))-trans, J = 18.3 Hz); 6.42—6.56 (m, 2 H,
NHCH3, H(14)); 6.93 (s, 1 H, H(16)); 8.13 (dd, 1 H, H(3´(1)),
J = 17.4 Hz, J = 11.9 Hz); 8.80 (s, 1 H, H(20´)); 9.44/9.46 (s, 1 H,
OH); 9.67 (s, 1 H, H(5´)); 9.72 (s, 1 H, H(10´)). 13C NMR
(CDCl3), : 11.35 (C(7´(1))); 11.97 (C(2´(1))); 12.16 (C(12´(1)));
12.24, 14.10 (NC7H14CH3, C(10)); 17.72 (C(8´(2))); 19.72
(C(8´(1))); 21.47 (C(8)); 20.74 (C(17)); 21.47 (C(9)); 22.59,
26.03/26.13, 28.45, 28.56, 28.77, 29.40 (NCH2C6H12CH3); 23.13
(C(18´(1))); 27.29 (C(13´(2))); 27.54 (C(5)); 28.83 (C(6)); 29.72
(C(17´(2))); 31.60 (C(17´(1))); 34.03/34.10 (C(3)); 39.49 (C(2));
45.12 (C(4)); 47.96 (NCH2C7H15); 49.42 (C(1)); 49.57 (C(18´));
49.82 (C(7)); 52.19/52.22 (C(15´(3))); 53.00 (C(17´)); 53.15
(ArCH2N); 93.45 (C(20´)); 98.84 (C(5´)); 101.43 (C(10´));
102.59 (C(15´)); 121.60 (C(3´(2))); 121.25/121.31 (C(13)); 126.60
(C(14)); 128.28 (C(13´)); 128.63 (C(15)); 129.19 (C(16)); 129.51
(C(3´(1))); 129.97/130.06 (C(11)); 131.87 (C(12´)); 132.00
(C(2´)); 134.49 (C(7´)); 134.77 (C(4´)); 135.09 (C(14´));
136.05 (C(3´), C(11´)); 138.83 (C(1´)); 144.73 (C(8´), C(9´));
153.03 (C(6´)); 153.08 (C(12)); 166.81 (C(16´)); 169.10 (C(19´));
170.05 (C(13´(1))); 173.93/173.89 (C(17´(3))); 174.49/174.40
(C(15´(2))).
tained from the scientific collection of experimental ani-
mals at the Institute of Biology of Komi Scientific Centre,
Ural Branch of the Russian Academy of Sciences (http://
www.ckp-rf.ru/usu/471933/).
This work was financially supported by the Russian
Science Foundation (Project No. 16-13-10367).
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The synthesized compounds were analysed using the
equipment of the "Chemistry" Center for Collective Use
at the Institute of Chemistry of Komi Scientific Centre,
Ural Branch of the Russian Academy of Sciences. The
evaluation of antioxidant activity of compounds was per-
formed using the equipment of the "Molecular Biology"
Center for Collective Use at the Institute of Biology of
Komi Scientific Centre, Ural Branch of the Russian
Academy of Sciences. The laboratory animals were ob-
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Received December 8, 2017;
in revised form January 10, 2018;
accepted January 16, 2018