Synthesis of new porphyrin-containing peptidyl phosphonates

Article abstract of DOI:10.1080/104265090902813

Synthesis of new, porphyrin-containing peptidyl aminophosphonates is described. The products, derived from 5-(4′-carboxyphenyl)-10,15,20-tri-p- tolylporphyrin and some heterocyclic aminophosphonates were obtained in high yield in the reaction of the 5-(4′

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Synthesis of New Porphyrin-
Containing Peptidyl
Phosphonates
Jan Habdas a & Bogdan Boduszek b
a University of Silesia , Katowice, Poland
b Wroclaw University of Technology , Wroclaw,
Poland
Published online: 19 Aug 2006.
To cite this article: Jan Habdas & Bogdan Boduszek (2005) Synthesis of New
Porphyrin-Containing Peptidyl Phosphonates, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:9, 2039-2045, DOI: 10.1080/104265090902813
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Phosphorus, Sulfur, and Silicon, 180:2039–2045, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090902813
Synthesis of New Porphyrin-Containing Peptidyl
Phosphonates
Jan Habdas
University of Silesia, Katowice, Poland
Bogdan Boduszek
Wroclaw University of Technology, Wroclaw, Poland
Synthesis of new, porphyrin-containing peptidyl aminophosphonates is described.
The products, derived from 5-(4ꢀ-carboxyphenyl)-10,15,20-tri-p-tolylporphyrin and
some heterocyclic aminophosphonates were obtained in high yield in the reaction
of the 5-(4ꢀ-carboxyphenyl)-10,15,20-tritolylporphyrin with selected thiophene and
pyridine aminophosphonate diphenyl esters by applying a DCC coupling method
used in the peptide synthesis. The obtained porphyrin aminophosphonate products
were characterized by spectroscopic methods.
Keywords Aminophosphonate derivatives of 5-(4ꢀ-carboxyphenyl)-10,15,20-tri-p-tolyl-
porphyrin; peptide synthesis; porphyrins; tolylporphyrins
Porphyrins play a very important role both in nature and chemistry,
due to their unique properties. The porphyrin structure comprises four
pyrrole rings linked by four methine bridges and shows an aromatic
character because it obeys the Hu¨ckel’s rule of aromaticity. The aro-
matic character of the porphyrins has been shown by some spectroscopic
methods (X-ray, NMR etc.).1
Existence of pyrrole units in the porphyrin structures causes easy
complexation of the most metals by the porphyrins. Such metal-
lic complexes (metalloporphyrins) are well known in nature and
exist as the chlorophyll, hemoglobin, and vitamin B12, containing
Mg, Fe, and Co, atoms, respectively. Metalloporphyrins are principal
species in metabolic processes and in the provision of energy in living
Received September 24, 2004; in final form September 28, 2004.
This work was supported by the Institute of Chemistry, University of Silesia, Katowice,
Poland.
Address correspondence to Bogdan Boduszek, Institute of Organic Chemistry, Bio-
chemistry, and Biotechnology, Wroclaw University, Wroclaw 50-370, Poland. E-mail:
bogdan.boduszek@pwr.wroc.pl
2039

2040
J. Habdas and B. Boduszek
organisms. They are also used for dehalogenation of polychlorinated
hydrocarbons.2
In the past two decades, porphyrins have been the subject of many
researches due to their biological and spectroscopic properties. Mainly,
they are used as so-called Photosensitizers (PS) in the latest-developed
method of diagnostic and therapy of cancer Photodynamic therapy
(PDT).3,4 The first photosensitizer, based on a porphyrin (Photofrin),
was approved for clinic application in Canada, then in the USA and
Japan in 1993. Photofrin is a mixture of about 50 various dimeric deriva-
tives of hematoporphyrins.3
We found that some of the amide-type derivatives of tolylporphy-
rins5−8 showed also the photosensitizing properties. It was found, that
application of the tritolylporphyrin amides7,8 to human melanoma cells
and irradiation with red light (630 nm) causes a 3-fold decrease of the
surviving fraction of the human melanoma cells.9
In 2003, synthesis of some aminophosphonic derivatives of por-
phyrins obtained from the corresponding formylporphyrins of natural
origin was described10 and characterized. The phosphonic moiety was
attached directly to the porphyrin core. These compounds were pro-
jected as a new kind of photosensitizers.10
In this work, we report a first synthesis of some peptidyl, phos-
phonate derivatives of tolylporphyrin, namely, derivatives of the 5-
(4ꢀ-carboxyphenyl)-10,15,20-tri-p-tolylporphyrin. The porphyrin core is
bounded with heterocyclic phosphonate diphenyl ester by a CO NH-
link, in this case. There is expectancy that some of the obtained
porphyrin-phosphonate compounds will show desired biological prop-
erties, that is, photosensitive activity.
RESULTS AND DISCUSSION
The 5-(4ꢀ-carboxyphenyl)-10,15,20-tri-p-tolylporphyrin (1) (Scheme 2)
needed for synthetic work was prepared by a conventional method
of Adler et al.,11 by condensation of 4-methylbenzaldehyde and 4-
carboxybenzaldehyde with pyrrole in boiling propionic acid. The proper
product was isolated from the reaction mixture by column chromatog-
raphy. Amino components, i.e., the thiophene and pyridine diphenyl
aminophosphonates 2a–c, were synthesized according to literature
methods12,13 from the corresponding aldehydes. Structures of the
aminophosphonates 2a–c used for coupling with carboxy-porphyrin 1
are shown in Scheme 1.
Peptidyl aminophosphonic derivatives 3a–c (Scheme 2) of car-
boxyporphyrin
1 were obtained in good yield by a typical
method used in peptide synthesis. Carboxyporphyrin 1 was coupled

Porphyrin-Containing Peptidyl Phosphonates
2041
SCHEME 1
with aminophosphonate component 2a–c in the presence of 1,3-
dicyclohexylcarbodiimide (DCC), in methylene chloride, at room tem-
perature. 4-(Dimethylamino)pyridine (DMAP) was used as a catalyst
to facilitate the coupling reaction. Phosphonic groups in 2a–c were pro-
tected as the phenyl esters. An outline of the reactions carried out is
shown in Scheme 2.
The obtained porphyrin-phosphonopeptides 3a–c (Scheme 2) were
purified by column chromatography and then characterized by means of
1H, 31P NMR, and ESI+Q1MS spectroscopy. 31P signals from NMR were
observed in the range of 14.8–15.7 ppm for all the obtained porphyrin-
phosphonate products, which is in agreement with the 31P data for
other compounds, similar to phosphonopeptides.13 All of the obtained
products 3a–c were racemic mixtures and no attempts were made to
their resolution.
Results of performed biological tests with the obtained products will
be given in the near future.
EXPERIMENTAL
NMR spectra were recorded on a Bruker Avance TM DRX 300 MHz
in CDCl3 using 300.13 MHz for 1H NMR and 121.51 MHz for 31P
NMR spectra in the Institute of Organic Chemistry, Biochemistry and
Biotechnology, Wroclaw University of Technology. MS analyses were
performed on a Finnigan TSQ 700 Instrument (electrospray ionization)
on mode ESI+Q1MS at the Department of Chemistry, University of
Wroclaw. Melting points were measured on a Digital Melting Point Ap-
paratus Electrothermal 9200. Elemental analyses were done in the Lab-
oratory of Instrumental Analysis in the Institute of Organic Chemistry,
Biochemistry and Biotechnology, Wroclaw. All reagents were purchased
from Sigma Aldrich Company.
Diphenyl thiophene-3-methyl(amino)phosphonate (2a) and diphenyl
2,5-dimethylthiophene-3-methyl(amino)phosphonate(2b) were obtained

2042
J. Habdas and B. Boduszek
SCHEME 2
from thiophene-3-carboxaldehyde and 2,5-dimethylthiophene-3-
carboxaldehyde,14 according to the described method of synthesis of
various thiophene aminophosphonates.12
1
2a: Yield: 93%, Mp. 187–189◦C, H NMR(CDCl3), δ, ppm: 9.30 (bs,
3H, NH3+), 7.70 (s, 1H, thiophene-2), 7.55 (m, 2H, thiophene-4,5),

Porphyrin-Containing Peptidyl Phosphonates
2043
7.36–7.09 (m; 10H, Ph), 5.27(d, 1H, CH P, J = 15.9 Hz). 31P NMR
(CDCl3), δ, ppm: 13.88 (s). Elemental Anal. for 2a: Calc. N, 3.29; P,
7.27; Br, 18.75; Found: N, 3.21; P, 7.25; Br, 18.85.
1
2b: Yield: 44%. Mp. 141–145◦C, H NMR (CDCl3), δ, ppm: 9.21 (bs,
3H, NH3+), 7.23–6.89 (m, 11H, thiophene-4, Ph), 5.25 (d, 1H, CH P, J
= 16.4 Hz), 2.25 (s, 3H, CH3), 2.03 (s, 3H, CH3). 31P NMR (CDCl3), δ,
ppm: 10.40 (s). Elemental Anal. for 2b: Calc. N, 3.08; P, 6.82; Br, 17.59;
Found: N, 3.01; P, 6.91; Br, 17.65.
Diphenyl pyridine-3-methyl(amino)phosphonate (2c) was prepared
as described in the literature.13
Procedure for Preparation of
5-(4ꢀ-Carboxyphenyl)-10,15,20-tri-p-tolylporphyrin (1)
5-(4ꢀ-Carboxyphenyl)-10,15,20-tritolylporphyrin was prepared mainly
according to the Adler method,11 with some modifications. The proce-
dure was the following: In a 1 L round-bottom flask, equipped with
an efficient mechanical stirrer, were placed 600 mL of propionic acid,
4-tolyladehyde (3.6 g, 30 mmol), and 4-carboxybenzaldehyde (1.5 g,
10 mmol). The mixture was heated to 140–2◦C (boiling point) and then
pyrrole (6.7 g, 100 mmol) was added during 30 min. Heating was con-
tinued for 30 min and cooled. The mixture was left for 24 h, the sep-
arated product was filtered off, washed with water several times, and
placed with a mixture of water and methanol (v/v: 8:2). Washing was
continued until the filtrate become colorless and odorless. The obtained
product was dried in air to give a dark solid (the mixture of several
porphyrins; 2.1 g, 30%). The mixture of porphyrins was separated by
column chromatography (silica gel 60–230 mesh, eluent: chloroform-
methanol; v/v 9:1), collecting the second, purple band containing the
desired product 1 after evaporation of the solvent. Yield: 400 mg
(5%). 1H NMR(CDCl3), δ, ppm: 8.90–7.55(m., 24H, Ph’s, pyrroles),
2.71(s, 9H, CH3 × 3), −2.78 (bs, 2H, NH). MS: ESI + Q1MS, 701
(M. + 1).
General Procedure for Preparation of the Aminophosphonate
Derivatives of 5-(4ꢀ-Carboxyphenyl)-10,15,20-tri-
p-tolylporphyrin (3a–c)
To a solution of 5-(4ꢀ-carboxyphenyl)-10,15,20-tritolylporphyrin (70 mg,
0.1 mmol) in dry methylene chloride (10 mL), was added 1,3-
dicyclohexylcarbodiimide (DCC) (21 mg, 0.1 mmol) with stirring. Then
a solution of the hydrobromide of aminophosphonate 2a–c (0.1 mmol)
with triethylamine (11 mg) and 4-(dimethylamino)pyridine (DMAP)

2044
J. Habdas and B. Boduszek
(12 mg) in methylene chloride (10 mL) was added and the mixture
was stirred for 24 h at room temperature. Then the reaction mixture
was evaporated to dryness, treated with ethyl acetate (50 mL), stirred,
and filtered. The filtrate was subsequently washed with 0.1 M. aq. HCl
(15 mL), 1.0 M. aq. NaHCO3, (2 × 15 mL), and water (3 × 20 mL), dried
(anh. Na2SO4), filtered, and evaporated to give the crude porphyrin-
phosphonate product 3a–c as a dark-violet solid. The products 3a–c
were additionally purified by column chromatography (silica gel 70–
210 mesh, eluent CHCl3-MeOH: 20:1 v/v).
3a: Yield, 75 mg (73%), 1H NMR (CDCl3), δ, ppm: 8.73–6.81 (m., 37H,
arom.), 6.52–6.42 (dd, 1H, CH P, J = 9.78 Hz), 3.33 (bs, 2H), 2.69 (s,
9H, CH3). 31P NMR (CDCl3), δ, ppm: 15.04 (s). MS: ESI + Q1MS, 1032.0
(M. + 4).
3b: Yield: 68 mg (64%), 1H NMR (CDCl3), δ, ppm: 8.78–7.03 (m., 35H,
arom.), 6.06 (d, 1H, CH P, J = 9.50 Hz), 2.69 (s, 6H, CH3), 2.63 (m., 3H,
CH3), 2.31 (s, 3H, CH3), 2.26 (s, 3H, CH3), −2.84 (bs, 0.2H, NH). 31P
NMR (CDCl3), δ, ppm: 15.73 (s). IR (KBr), cm−1: 3324.5 (s), 2928, 2849
(s), 1699 (m.), 1626.3 (s), 1572.9 (s), 1489.5 (m.), 1435.9, 1310.7 (m.),
1261.4 (s), 1088.0 (s), 800.7 (s), 640.5 (m.). MS: ESI + Q1MS, 1058.8
(M. + 2).
3c: Yield: 89 mg (87%), 1H NMR (CDCl3), δ, ppm: 9.08–6.79 (m., 38H,
arom.), 5.98–5.88 (dd, 1H, CH P, J = 9.62 Hz), 4.12 (bs, 2H, NH), 2.69
(s, 6H, CH3), 2.63 (s, 3H, CH3), −2.84 (bs, 0.5H, NH). 31P NMR (CDCl3),
δ, ppm: 14.80 (s). MS: ESI+Q1MS, 1025.4 (M. + 2).
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