The synthesis of sugar-decorated hydrophilic porphyrins

Article abstract of DOI:10.1142/S1088424613500703

The synthesis of porphyrins conjugated with sugar moieties is described. meso-Aminophenyl-substituted and β-amino-substituted porphyrin derivatives reacted with benzyl protected glucuronic acid leading to gluco-conjugated hybrids, which after reductive de

Full text of DOI:10.1142/S1088424613500703

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2013; 17: 384–391
DOI: 10.1142/S1088424613500703
Published at http://www.worldscinet.com/jpp/
The synthesis of sugar-decorated hydrophilic porphyrins
Przemysław Wyre˛beka, Anna Osuch-Kwiatkowskab, Zbigniew Pakulskib,
Sławomir Jaroszb and Stanisław Ostrowski*a
a Institute of Chemistry, Uniwersytet Przyrodniczo–Humanistyczny w Siedlcach (formerly University of Podlasie),
ul. 3 Maja 54, 08-110 Siedlce, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland
Received 19 November 2012
Accepted 2 May 2013
ABSTRACT: The synthesis of porphyrins conjugated with sugar moieties is described. meso-
Aminophenyl-substituted and b-amino-substituted porphyrin derivatives reacted with benzyl protected
glucuronic acid leading to gluco-conjugated hybrids, which after reductive deprotection of OH groups
(H2, 10% Pd/C) gave the desired target products of increased hydrophilicity. Alternatively, this type of
similar conjugates were obtained through SNAr reaction of meso-tetrakis(pentafluorophenyl)porphyrin
with aminomethyl sacharides. The substitution took place selectively in para-position of meso-
perfluorophenyl rings, thus giving rise to one, two, or three times substituted products carrying N-linked
glucoside residues.
KEYWORDS: porphyrin derivatives, photodynamic therapy, sugars, glycosides, hydrogenation, DCC,
SNAr substitution.
Among others, glycosylated porphyrin derivatives
INTRODUCTION
have been studied in this field [3, 4]. Undoubtedly, the
In the recent past, a number of investigations
incorporation of sugar residue into porphyrin system
focused on the utilization of porphyrins, chlorins, and
increases hydrophilicity of these compounds and may
bacteriochlorins as sensitizers in photodynamic cancer
improve their bioavailability. Moreover, they can also
therapy (PDT) [1]. Particularly, the hydrophilic moieties
be recognized by cell surface carbohydrate receptors
were sought in this area. Thus, there is the interest of
expressed in malignant tumor cells, and thus enable a
the transformation of porphyrins into their hydrophilic
degree of targeting [3]. Hence, the potentially water-
derivatives which comes from the potential biomedical
soluble glycosylated porphyrins may be used as attractive
application of the latter compounds [2].
PDT drugs, possibly as second-generation PDT drugs
These compounds, as such, being enough soluble in
[5]. These drugs based upon the conjugation of various
the physiological milieu, may be considered as valuable
photosensitizers to a targeting backbone allow for more
photosensitizers in the above mentioned therapy.
efficient light-based therapies.
From a chemistry point of view hydrophilicity under
physiological conditions is particularly important for
the development of highly sensitive agents in order to
RESULTS AND DISCUSSION
prevent aggregation, which has deleterious effects on
In this paper, we present the synthesis of hydrophilic,
singlet oxygen quantum yields [3].
glucose-modifiedmeso-tetraarylporphyrins. meso-Amino-
phenyl-substituted, b-amino-substituted, and meso-penta-
fluorophenyl-substituted porphyrin derivatives were
used as the substrates. Reactions of these porphyrins
with the benzyl protected glucuronic acid or with
*Correspondence to: Stanisław Ostrowski, email: stan@uph.
edu.pl, tel: +48 25-643-1113, fax: +48 25-644-2045
Copyright © 2013 World Scientific Publishing Company

THE SYNTHESIS OF SUGAR-DECORATED HYDROPHILIC PORPHYRINS
385
5-aminomethyl-pyranoside derivative led to gluco-
conjugated moieties.
complexation of the product 3. This protocol allowed us
to isolate the desired glucose-modified porphyrin 4 in
42% yield (calculated for two steps); however, still some
amounts of monobenzylated moiety (5) accompanied the
main product (19%).
In the first goal, the reaction of 5-(4-aminophenyl)-
10,15,20-triphenylporphyrin (1) with protected (1-O-
methyl-2,3,4-tri-O-benzyl) glucuronic acid derivative
(2), in the presence of oxalyl chloride (DMF, NEt3, in dry
CH2Cl2, 0–20 °C, under argon), gave deep purple solid
of the N-linked glyco-conjugated porphyrin (3) in 65%
yield (Scheme 1).
The use in the above reaction of more effective
coupling agent, dicyclohexylcarbodiimide (DCC; rt, 2 h)
allowed us simplify the procedure and increase the yield
of the above amide 3 up to 94%.
Benzyl-deprotection of OH groups, in this case,
were somewhat troublesome. In the first experiments,
hydrogenation on palladium catalyst (10% Pd/C, in ethyl
acetate, rt, overnight) usually led to complicated mixtures
of compounds. Better results were obtained after zinc
A similar coupling procedure was applied to b-amino-
porphyrin derivatives. As we found out that in the next
step metalated glycoconjugated porphyrins could be
debenzylated much easier, leading to moieties with free
OH groups, the nickel complex was used straightaway
as a starting material in this case (Scheme 2). Therefore,
[2-amino-5,10,15,20-tetraphenylporphyrinato]nickel(II)
(6) when reacted in dichloromethane with glucuronic
acid derivative (2), in the presence of DCC at room
temperature, gave the desired porphyrin–sugar hybrid
as a corresponding complex 7. It was purified easily
by column chromatography (eluted with toluene/ethyl
acetate mixture), thus affording purple solid of the pure
Scheme 1.
Scheme 2.
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J. Porphyrins Phthalocyanines 2013; 17: 385–391

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P. WYRE˛BEK ET AL.
Scheme 3.
product in high yield (84%). Reductive deprotection of
OH groups (H2, 10% Pd/C, in ethyl acetate) leads to the
target product 8, bearing hydrophilic glucose residue.
However, in this case a partial optimization was also
necessary. At the beginning, during the hydrogenation
attempts some amounts of chlorin type compounds were
formed. Addition of DDQ to the post-reaction mixture
(dissolved in dichloromethane) and leaving it with
stirring at room temperature for 24 h caused the effective
re-oxidation of saturated chlorin bonds to porphyrin
system, thus yielding product 8 in 64% yield.
The third approach to sugar-modified porphyrins
involved methyl 6-amino-2,3,4-tri-O-benzyl-6-deoxy-
a-D-glucopyranoside (10) and very attractive meso-
tetrakis(pentafluorophenyl)porphyrin system (9a, 9b). In
this case, the above sugar derivative 10 bearing NH2 group
plays a role of nucleophilic agent. It should substitute
fluorine atom in meso-pentafluorophenyl rings, thus
allowing (via SNAr aromatic nucleophilic substitution)
the linking of carbohydrate residues. Indeed, it was a
case. In the reaction carried out in 1,2,4-trichlorobenzene
(reflux, 5 h) we observed the formation of mono-
substituted product, with satisfactory selectivity and
quite good yield (11a, 40%). Some amounts of two
isomers of disubstituted product (12a, 7%; 13a, 14%),
and even trisubstituted derivative (14a, 8%) were isolated
(see Scheme 3). The substitution takes place selectively in
para-position of each meso-perfluorophenyl rings. This
approach allowed us to synthesize more highly decorated
products, and the compounds obtained, carrying two or
three N-linked glucoside units, are even more attractive
because inclusion of several sugar moieties followed by
their deprotection may lead to conjugates of increased
hydrophilicity and solubility in water. Such porphyrins
are sought in PDT therapy and they are potential PDT
agents.
Zinc complex of the above porphyrin, 9b, reacted
similarly, and a new series of the corresponding glucose-
modified porphyrinate derivatives were obtained: 11b
(43%), 12b (4.5%), 13b (8%), and 14b (1%).
Copyright © 2013 World Scientific Publishing Company
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THE SYNTHESIS OF SUGAR-DECORATED HYDROPHILIC PORPHYRINS
387
(5 mL) was added dropwise via a syringe into the
reaction mixture over a period of ca. 10 min. Evolution
of gas was observed again. The mixture was allowed to
stir at room temperature for 1 h. Then, the solvent was
EXPERIMENTAL
General
1H NMR spectra were recorded with a Varian S 500
spectrometer (operating at 500 MHz for 1H and 125 MHz
for 13C) and Varian MR-400 spectrometer (operating
evaporated and the product was purified by column
chromatography (n-hexane/ethyl acetate, from 3:1 to
2:1) to give the amide 3 as a purple solid (129 mg, 65%).
Procedure B. A solution of glucuronic acid derivative
2 (258 mg, 0.540 mmol), DCC (112 mg, 0.543 mmol),
and 5-(4-aminophenyl)-10,15,20-triphenylporphyrin (1;
170 mg, 0.270 mmol) in dry CH2Cl2 (11 mL) was stirred
under argon at room temperature. After 2 h of stirring, the
solvent was evaporated and the product was purified by
column chromatography (toluene/ethyl acetate, 11:1) to
give the amide 3 (278 mg, as a purple solid). Yield: 94%.
Amide 3. 1H NMR (CDCl3, 500 MHz): d, ppm -2.69 (s,
2H, 2 × NH), 3.57 (s, 3H, OCH3), 3.74 (dd, J = 9.7, 3.5
Hz, 1H, H-2s), 3.87 (dd, J = 10.0, 8.9 Hz, 1H, H-4s), 4.22
(apparent t, ‘J’ = 9.3 Hz, 1H, H-3s), 4.44 (d, J = 10.0 Hz,
1H, H-5s), 4.76 (d, J = 12.1 Hz, 1H of CH2), 4.84 (d, J =
3.5 Hz, 1H, H-1s), 4.91 (d, J = 10.6 Hz, 1H of CH2),
4.92 (d, J = 12.1 Hz, 1H of CH2), 5.00 (d, J = 10.8 Hz,
1H of CH2), 5.03 (d, J = 10.6 Hz, 1H of CH2), 5.10 (d,
J = 10.8 Hz, 1H of CH2), 7.32–7.50 (m, 15H, H-Ph of
Bn), 7.76–7.83 (m, 9H, H-Ph), 7.87 (apparent d, J = 8.4
Hz, 2H of C6H4NH), 8.20 (apparent d, J = 8.4 Hz, 2H
of C6H4NH), 8.25–8.30 (m, 6H, H-Ph), 8.89–8.94 (m,
8H, pyrrole-H), CONH — undetected. 13C NMR (CDCl3,
125 MHz): d, ppm 56.0 (OCH3), 71.0 (C-5s),* 73.7
(CH2), 75.6 (CH2), 76.0 (CH2), 79.3 (C-2s), 80.4 (C-3s),
81.7 (C-4s), 98.6 (C-1s), 117.9 (C6H4NH), 119.4, 120.2,
126.7, 127.7, 127.8, 128.0 (two signals), 128.1, 128.2,
128.5 (three signals), 128.6, 134.5, 135.1 (C6H4NH),
137.0, 137.7, 137.9, 138.3, 138.5, 142.1, 167.2; some
of the signals are overlapped. UV-vis (CHCl3): lmax, nm
(log e) 420 (5.70, Soret), 516 (4.26), 551.5 (3.93), 591
(3.70), 647.5 (3.50). MS (FD): m/z (% rel. int.) 1089
(100), 1090 (88), 1091 (43), 1092 (13) (isotope [M]+).
The molecular formula was confirmed by comparing the
theoretical and experimental isotope patterns for the [M]+
ion (C72H59N5O6); it was found to be identical within the
experimental error limits.
1
at 400 MHz for H and 100 MHz for 13C). Bulk of the
signals in the case of sugar moieties was assigned on
the basis of additional COSY and HSQC measurements.
UV-vis spectra were measured with a Metertech SP-8001
spectrophotometer. Mass spectra were measured with
a GTC Premier (FD-TOF) Waters spectrometer (FD
method); m/z intensity values for peaks are given as
percentage of relative intensity. Molecular formulas of
the compounds were confirmed by elemental analysis,
HR-MS, and by comparing the isotope molecular patterns
(theoretical and experimental).
TLC analysis was performed on aluminum foil plates
pre-coated with silica gel (60 F-254, Merck AG). All
the products were separated by column chromatography
(silica gel, 230–400 mesh; Merck AG); some compounds
and fractions were rechromatographed on preparative
TLC plates (silica gel, 60 F-254, 0.5 mm; Merck AG).
Starting porphyrins and their complexes were obtained
accordingtostandardliteratureprocedures(appliedearlier
for the same or for similar compounds): 5-(4-amino-
phenyl)-10,15,20-triphenylporphyrin (1) [6]; 2-amino-
5,10,15,20-tetraphenylporphyrin nickel(II) complex (6)
was readily obtained from meso-tetraphenylporphyrin
via complexation and selective nitration in b-position
[7] followed by Sn/HCl reduction of the NO2 group to
the corresponding amine as previously reported [8];
5,10,15,20-tetrakis(pentafluorophenyl)porphyrin(9a)[9];
5,10,15,20-tetrakis(pentafluorophenyl)porphyrin zinc(II)
complex (9b) [10]. Also the sugar substrates 2 and 10
were obtained according to known procedures [11].
Other reagents used were purchased from Aldrich.
Synthesis
Hs and Cs notation stands for protons and carbon atoms
of sugar moiety in the gluco-conjugated hybrids (in the
Experimental section).
Preparation of zinc complex of amide 3 (3-Zn).
A solution of amide 3 (78 mg, 0.072 mmol) and
Zn(OAc)2·2H2O (312 mg, 1.421 mmol) in CHCl3/MeOH
(20 mL, 5:1) was refluxed with a condenser protected at
the top with a CaCl2 tube for 30 min. After cooling, the
solvents were evaporated under reduced pressure and the
residue was diluted with ethyl acetate. Then, the mixture
was filtered through short silica gel column (flushed with
ethyl acetate), and the solution was evaporated to dryness.
The crude zinc complex prepared 3-Zn was directly used
in the next step.
Reaction of 5-(4-aminophenyl)-10,15,20-triphenyl-
porphyrin (1) with glucuronic acid derivative 2.
Procedure A. To a solution of glucuronic acid derivative
2 (369 mg, 0.771 mmol) in dry CH2Cl2 (3 mL) under
argon, dry DMF (100 μL) was added. The solution was
cooled in ice bath and oxalyl chloride (100 μL, 1.182
mmol) was added. An evolution of gas was observed
immediately. The reaction mixture was allowed to stir
on the ice bath for 15 min, then the bath was removed
and the mixture was stirred at room temperature for
additional 1 h. It was cooled again and then a solution
of 5-(4-aminophenyl)-10,15,20-triphenylporphyrin (1;
115 mg, 0.183 mmol) and NEt3 (200 μL) in dry CH2Cl2
Reductive deprotection of zinc complex of amide
3 (3-Zn). A suspension of crude complex of porphyrin-
sugar amide (3-Zn; 75 mg, 0.065 mmol) and palladium
catalyst (10% Pd/C, 60 mg) in ethyl acetate (10 mL) was
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P. WYRE˛BEK ET AL.
stirred under hydrogen at room temperatue overnight.
After this time, the next portion of palladium catalyst
was added and the reaction mixture was stirred for
further 24 h under hydrogen at this temperature. Then,
the reaction mixture was filtered through short silica
gel column and flushed with a mixture of ethyl acetate/
MeOH. The solvents were evaporated and the product
was isolated by column chromatography using mixture of
solvents as eluent (n-hexane/ethyl acetate/MeOH, from
5:3:1 to 10:5:3) to give amide 4 (24.3 mg) as a mojor
product (42%) and amide 5 (11.9 mg, 19%). Amide 4. 1H
NMR (DMSO-d6, 400 MHz): d, ppm 3.38–3.48 (m, 4H)
[inside: 3.45 (s, 3H, OCH3)], 3.49–3.67 (m, 2Hs), 4.19
(d, J = 9.5 Hz, 1H, H-5s), 4.72 (d, J = 3.6 Hz, 1H, H-1s),
4.90–4.97 (m, 1H), 5.06 (broad s, 1H), 5.52 (broad s,
1H), 7.76–7.86 (m, 9H, H-Ph), 8.09–8.22 (m, 10H, H-Ph
and H-C6H4), 8.76 (d, J = 4.7 Hz, 2H, pyrrole-H), 8.77
(s, 4H, pyrrole-H), 8.83 (d, J = 4.7 Hz, 2H, pyrrole-H),
the solvent was evaporated and the product was purified
by column chromatography (toluene/ethyl acetate, from
11:1 to 4:1) to give the amide 7 (189 mg, as a purple
1
solid). Yield: 84%. Amide 7. H NMR (CDCl3, 500
MHz): d, ppm 3.38 (apparent t, ‘J’= 9.5 Hz, 1H, H-4s),
3.39 (s, 3H, OCH3), 3.50 (dd, J = 9.6, 3.8 Hz, 1H, H-2s),
3.75 (d, J = 9.9 Hz, 1H, H-5s), 3.95 (apparent t, J = 9.3
Hz, 1H, H-3s), 4.46 (d, J = 10.5 Hz, 1H of CH2), 4.51
(d, J = 3.8 Hz, 1H, H-1s), 4.65 (d, J = 10.5 Hz, 1H of
CH2), 4.76 (d, J = 12.4 Hz, 1H of CH2), 4.91 (d, J = 12.4
Hz, 1H of CH2), 4.94 and 5.00 (AB system, J = 11.0 Hz,
2H, CH2), 6.64–6.70 (m, 3H, H-Ph of Bn), 7.02–7.06 (m,
2H, H-Ph of Bn), 7.12–7.50 (m, 14H, H-Ph and H-Ph
of Bn), 7.58 (d, J = 7.4 Hz, 1H, H-Ph), 7.62–7.72 (m,
9H, H-Ph), 7.95–8.04 (m, 6H, H-Ph), 8.29 (s, 1H, NH),
8.41 (d, J = 5.0 Hz, 1H, pyrrole-H), 8.64 (d, J = 5.0 Hz,
1H, pyrrole-H), 8.66–8.73 (m, 4H, pyrrole-H), 9.44 (s,
1H, pyrrole-H). 13C NMR (CDCl3, 125 MHz): d, ppm
55.7 (OCH3), 71.5, 73.5, 75.1, 75.9, 78.3, 79.7, 81.8,
98.3, 115.3, 118.5, 119.0, 119.6, 120.8, 126.9, 127.0,
127.5, 127.7, 127.8 (three signals), 127.9 (two signals),
128.0, 128.2, 128.4, 128.5, 128.6, 128.7 (two signals),
131.4, 131.7, 132.0, 132.1, 132.4, 132.5, 132.7, 132.8,
132.9, 133.6, 133.7 (two signals), 137.5, 138.3, 138.6,
138.8, 138.9, 140.6, 141.8, 142.1, 142.5, 142.8, 143.0,
143.1, 165.8; some of the signals are overlapped. UV-vis
(CHCl3): lmax, nm (log e) 420 (5.38, Soret), 535 (4.26),
566 (3.86). MS (FD): m/z (% rel. int.) 1145 (100), 1146
(92), 1147 (87), 1148 (65), 1149 (37), 1150 (14), 1151
(6), 1152 (3) (isotope [M]+). The molecular formula was
confirmed by comparing the theoretical and experimental
isotope patterns for the [M]+ ion (C72H57N5O6Ni); it was
found to be identical within the experimental error limits.
Elemental analysis, calcd. for C72H57N5O6Ni (1146.96):
C 75.40, H 5.01, N 6.11%; found C 75.50, H 5.71, N
5.96%.
13
10.54 (s, 1H, NH). C NMR (DMSO-d6, 100 MHz): d,
ppm 55.2 (OCH3), 71.7, 71.8, 73.1, 73.2, 100.8 (C-1s),
117.5, 120.2 (two signals), 120.3, 126.6, 127.5, 131.4,
131.5, 131.6, 131.7, 134.2, 134.5, 137.8, 138.3, 142.8,
149.2, 149.3, 149.5, 168.1; some of the signals are
overlapped. UV-vis (CHCl3): lmax, nm (log e) 421 (5.82,
Soret), 513 (3.50), 548 (4.39), 586 (3.56). MS (FD): m/z
(% rel. int.) 881 (100), 882 (57), 883 (70), 884 (42), 885
(53), 886 (25), 887 (11), 888 (3) (isotope [M]+). HR-MS
(FD): m/z 881.2173 (calculated for C51H39N5O6Zn [M]+
1
881.2192). Amide 5. H NMR (CDCl3, 400 MHz): d,
ppm -0.45 (broad s, 2H, 2 × OH), -0.12–0.04 (m, 1H,
H-2s), 0.30–0.47 (m, 1H, H-4s), 2.14 (apparent t, J = 8.9
Hz, 1H, H-3s), 2.43 (d, J = 10.1 Hz, 1H of CH2), 3.10
(s, 3H, OCH3), 3.42 (d, J = 10.2 Hz, 1H, H-5s), 3.89 (d,
J = 10.1 Hz, 1H of CH2), 4.17 (d, J = 3.6 Hz, 1H, H-1s),
6.94 (apparent d, J = 8.2 Hz, 2H of H-C6H4), 7.19–7.26
(m, 3H, H-Ph of Bn), 7.72–7.84 (m, 9H, H-Ph), 7.90
(apparent d, J = 8.2 Hz, 2H of H-C6H4), 8.22–8.32 (m,
8H, H-Ph and H-Ph of Bn), 8.98 and 8.99 (AB system,
J = 4.7 Hz, 4H, pyrrole-H), 9.03 and 9.06 (AB system,
J = 4.7 Hz, 4H, pyrrole-H), NH — undetected. NMR-
Reductive deprotection of porphyrin-amide nickel
complex 7. A suspension of amide 7 (98 mg, 0.085
mmol) and palladium catalyst (10% Pd/C, 80 mg) in
ethyl acetate (10 mL) was stirred under hydrogen at
room temperature overnight. The reaction mixture was
then filtered through short silica gel column and flushed
with a mixture of solvents (ethyl acetate/MeOH, 20:2;
33 mL). The solvents were evaporated and the residue
was dissolved in CH2Cl2 (20 mL). To this solution, DDQ
(39 mg, 0.172 mmol) was added and the mixture was
stirred at room temperature for 24 h (to oxidize traces
of the chlorin formed during the hydrogenation). After
evaporation of the solvent, the product was isolated by
preparative thin layer chromatography (eluent: toluene/
MeOH, 25:3) to give the amide 8 (47.9 mg, as a purple
1
COSY (CDCl3, 400 MHz): d, ppm (diagnostic H–1H
correlations): ca.0.38/3.42 (H-4s/H-5s), 2.43/3.89
(CH2-Bn). NMR-HSQC (CDCl3, 400 MHz/100 MHz):
1
d, ppm (diagnostic H-13C correlations): ca.-0.05/68.5
(CH-2s), ca.0.38/78.1 (CH-4s). UV-vis (CHCl3): lmax
,
nm (log e) 421 (5.69, Soret), 512 (2.83), 547 (4.22), 586
(3.13). MS (FD): m/z (% rel. int.) 971 (100), 972 (81),
973 (87), 974 (62), 975 (68), 976 (39), 977 (16), 978
(6), 979 (2) (isotope [M]+). HR-MS (FD): m/z 971.2620
(calculated for C58H45N5O6Zn [M]+ 971.2661).
Reaction of [2-amino-5,10,15,20-tetraphenylpor-
phyrinato]nickel(II) (6) with glucuronic acid deri-
vative 2. A solution of glucuronic acid derivative 2 (380
mg, 0.794 mmol), DCC (165 mg, 0.800 mmol) and
[2-amino-5,10,15,20-tetraphenylporphyrinato]nickel(II)
(6) (135 mg, 0.197 mmol) in CH2Cl2 (8 mL) was stirred
under argon at room temperature. After 70 h of stirring,
1
solid). Yield: 64%. Amide 8. H NMR (CDCl3, 500
MHz): d, ppm 3.43 (s, 3H, OCH3), 3.54 (dd, J = 10.0,
8.8 Hz, 1H, H-4s), 3.58 (dd, J = 9.8, 3.8 Hz, 1H, H-2s),
3.86 (apparent t, J = 9.1 Hz, 1H, H-3s), 4.03 (d, J = 10.0
Hz, 1H, H-5s), 4.45 (s, 1H, OH), 4.76 (d, J = 3.8 Hz, 1H,
H-1s), 7.64–7.83 (m, 12H, H-Ph), 7.92 (d, J = 7.4 Hz,
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THE SYNTHESIS OF SUGAR-DECORATED HYDROPHILIC PORPHYRINS
389
1H, H-Ph), 7.95–8.05 (m, 6H, H-Ph), 8.10 (d, J = 7.1 Hz,
(CH2-Bn), ca.4.80/5.06 (CH2-Bn), 4.96/5.13 (CH2-Bn).
UV-vis (CHCl3): lmax, nm (log e) 416 (5.35, Soret), 509
(4.22), 540 (3.28), 585 (3.70). MS (FD): m/z (% rel. int.)
1417 (100), 1418 (99), 1419 (72), 1420 (32), 1421 (9)
(isotope [M]+). The molecular formula was confirmed
by comparing the theoretical and experimental isotope
patterns for the [M]+ ion (C72H42F19N5O5); it was found
to be identical within the experimental error limits. 12a.
1H NMR (CDCl3, 500 MHz): d, ppm -2.88 (s, 2H, 2 ×
NH), 3.52 (s, 6H, 2 × OCH3), 3.58 (apparent t, J = 9.2
Hz, 2H, 2 × H-4s), 3.66 (dd, J = 9.6, 3.6 Hz, 2H, 2 ×
H-2s), 3.67–3.74 (m, 2H of CH2NH), 4.00–4.17 (m, 6H,
2 × H-3,5s and 2H of CH2NH), 4.56–4.62 (m, 2H, 2 ×
CH2NH), 4.73 (d, J = 3.6 Hz, 2H, 2 × H-1s), 4.74 (d, J =
12.0 Hz, 2H of CH2-Bn), 4.77 (d, J = 11.2 Hz, 2H of
CH2-Bn), 4.89 (d, J = 12.0 Hz, 2H of CH2-Bn), 4.93 (d,
J = 10.8 Hz, 2H of CH2-Bn), 5.03 (d, J = 11.2 Hz, 2H of
CH2-Bn), 5.09 (d, J = 10.8 Hz, 2H of CH2-Bn), 7.29–7.45
(m, 30H, H-Ph), 8.87 (d, J = 4.6 Hz, 4H, pyrrole-H), 8.98
1H, H-Ph), 8.39 (d, J = 5.0 Hz, 1H, pyrrole-H), 8.65 (d,
J = 5.0 Hz, 1H, pyrrole-H), 8.69 and 8.72 (AB system,
J = 5.0 Hz, 2H, pyrrole-H), 8.72 (s, 2H, pyrrole-H), 9.13
(s, 1H, NH), 9.37 (s, 1H, pyrrole-H), 2 × OH groups —
undetected. 13C NMR (CDCl3, 125 MHz): d, ppm 56.1
(OCH3), 69.1, 71.0, 72.5, 73.7, 98.5, 115.5, 118.6, 119.1,
119.7, 121.8, 126.9 (two signals), 127.1, 127.8 (two
signals), 127.9, 128.1, 128.3, 128.9, 131.6, 131.9, 132.2
(two signals), 132.3, 132.5, 132.7, 132.8, 133.3, 133.5,
133.6 (two signals), 137.6, 139.1, 140.5 (two signals),
140.6, 141.2, 142.0, 142.3, 142.7, 142.9, 143.5, 168.6;
some of the signals are overlapped. UV-vis (CHCl3): lmax
,
nm (log e) 420 (5.48, Soret), 534 (4.35), 564.5 (3.96). MS
(FD): m/z (% rel. int.) 875 (100), 876 (96), 877 (94), 878
(73), 879 (38), 880 (15), 881 (5) (isotope [M]+). HR-MS
(FD): m/z 875.2224 (calculated for C51H39N5O6Ni [M]+
875.2254).
Reaction of meso-tetrakis(pentafluorophenyl)por-
phyrin (9a) with methyl 6-amino-2,3,4-tri-O-benzyl-
6-deoxy-a-D-glucopyranoside (10). A solution of meso-
tetrakis(pentafluorophenyl)porphyrin (9a; 150 mg, 0.154
mmol) and glucopyranoside aminomethyl derivative (10;
378 mg, 0.815 mmol) in 1,2,4-trichlorobenzene (8 mL)
was heated to reflux in a flask equipped with a reflux
condenser protected at the top with a CaCl2 tube. After
5 h the reaction mixture was cooled to room temperature
and chromatographed, using initially n-hexane as an
eluent (100 mL, to remove 1,2,4-trichlorobenzene), and
then n-hexane/ethyl acetate (from 7:1 to 2:1), to give
three fractions containing: (a) mono-substituted product,
(b) a mixture of isomers of disubstituted products, and
(c) trisubstituted product, respectively. Each fraction
was rechromatographed by preparative thin layer
chromatography with the use of n-hexane/ethyl acetate
mixture as eluent (from 7:1 to 6:1 for the first fraction
and 4:1 for the second and third one). Yield: 11a, 87 mg
(40%); 12a, 20 mg (7%); 13a, 39 mg (14%); and 14a,
(d, J = 4.6 Hz, 4H, pyrrole-H). UV-vis (CHCl3): lmax
,
nm (log e) 419 (5.65, Soret), 510 (4.51), 542 (3.61),
586 (3.98). MS (FD): m/z (% rel. int.) 1860 (94), 1861
(100), 1862 (59), 1863 (23), 1864 (6) (isotope [M]+).
The molecular formula was confirmed by comparing the
theoretical and experimental isotope patterns for the [M]+
ion (C100H74F18N6O10); it was found to be identical within
the experimental error limits. 13a. 1H NMR (CDCl3, 500
MHz): d, ppm -2.88 (s, 2H, 2 × NH), 3.51 (s, 6H, 2 ×
OCH3), 3.57 (apparent t, ‘J’ = 9.2 Hz, 2H, 2 × H-4s),
3.65 (dd, J = 9.7, 3.6 Hz, 2H, 2 × H-2s), 3.67–3.75 (m,
2H of CH2NH), 3.99–4.16 (m, 6H, 2 × H-3,5s and 2H of
CH2NH), 4.55–4.61 (m, 2H, 2 × CH2NH), 4.73 (d, J = 3.6
Hz, 2H, 2 × H-1s), 4.75 (d, J = 12.1 Hz, 2H of CH2-Bn),
4.77 (d, J = 11.1 Hz, 2H of CH2-Bn), 4.89 (d, J = 12.1
Hz, 2H of CH2-Bn), 4.92 (d, J = 10.8 Hz, 2H of CH2-Bn),
5.02 (d, J = 11.1 Hz, 2H of CH2-Bn), 5.09 (d, J = 10.8
Hz, 2H of CH2-Bn), 7.30–7.45 (m, 30H, H-Ph), 8.86 (d,
J = 4.7 Hz, 2H, pyrrole-H), 8.88 (s, 2H, pyrrole-H), 8.96
(s, 2H, pyrrole-H), 8.98 (d, J = 4.7 Hz, 2H, pyrrole-H).
UV-vis (CHCl3): lmax, nm (log e) 419 (5.41, Soret), 508
(4.25), 541 (3.30), 587 (3.70). MS (FD): m/z (% rel. int.)
1860 (96), 1861 (100), 1862 (60), 1863 (23), 1864 (7)
(isotope [M]+). The molecular formula was confirmed
by comparing the theoretical and experimental isotope
patterns for the [M]+ ion (C100H74F18N6O10); it was found
to be identical within the experimental error limits. 14a.
1H NMR (CDCl3, 500 MHz): d, ppm -2.87 (s, 2H, 2 ×
NH), 3.51 (s, 9H, 3 × OCH3), 3.57 (apparent t, ‘J’ = 9.3
Hz, 3H, 3 × H-4s), 3.65 (dd, J = 9.6, 3.6 Hz, 3H, 3 ×
H-2s), 3.67–3.73 (m, 3H of CH2NH), 3.99–4.09 (m, 6H,
3 × H-5s and 3H of CH2NH), 4.14 (apparent t, J = 9.2
Hz, 3H, 3 × H-3s), 4.54–4.60 (m, 3H, 3 × CH2NH), 4.73
(d, J = 3.6 Hz, 3H, 3 × H-1s), 4.75 (d, J = 12.1 Hz, 3H
of CH2-Bn), 4.77 (d, J = 11.0 Hz, 3H of CH2-Bn), 4.88
(d, J = 12.1 Hz, 3H of CH2-Bn), 4.92 (d, J = 10.7 Hz,
3H of CH2-Bn), 5.02 (d, J = 11.0 Hz, 3H of CH2-Bn),
5.09 (d, J = 10.7 Hz, 3H of CH2-Bn), 7.30–7.47 (m, 45H,
1
28 mg (8%). 11a. H NMR (CDCl3, 500 MHz): d, ppm
-2.90 (s, 2H, 2 × NH), 3.51 (s, 3H, OCH3), 3.57 (apparent
t, ‘J’ = 9.2 Hz, 1H, H-4s), 3.65 (dd, J = 9.8, 3.6 Hz, 1H,
H-2s), 3.67–3.74 (m, 1H of CH2NH), 3.97–4.18 (m, 3H,
H-3,5s and 1H of CH2NH), 4.60 (broad s, 1H, CH2NH),
4.76 (d, J = 3.6 Hz, 1H, H-1s), 4.78 (d, J = 12.2 Hz, 1H of
CH2-Bn), 4.80 (d, J = 11.0 Hz, 1H of CH2-Bn), 4.91 (d,
J = 12.2 Hz, 1H of CH2-Bn), 4.96 (d, J = 10.6 Hz, 1H of
CH2-Bn), 5.06 (d, J = 11.0 Hz, 1H of CH2-Bn), 5.13 (d, J =
10.6 Hz, 1H of CH2-Bn), 7.29–7.45 (m, 15H, H-Ph), 8.90
(d, J = 4.4 Hz, 2H, pyrrole-H), 8.92 (s, 4H, pyrrole-H),
9.01 (d, J = 4.4 Hz, 2H, pyrrole-H). 13C NMR (CDCl3,
125 MHz): d, ppm 46.6 (CH2NH), 55.4 (OCH3), 69.6
(C-5s), 73.6 (CH2), 75.4 (CH2), 75.9 (CH2), 78.9 (C-4s),
80.2 (C-2s), 82.0 (C-3s), 98.3 (C-1s), 127.8, 128.0, 128.1
(three signals), 128.3, 128.5, 128.6, 136.6, 137.8, 138.1,
138.2, 138.3, 138.6, 141.2, 143.3, 145.6, 147.6; some of
the signals are overlapped. NMR-COSY (CDCl3, 400
MHz): d, ppm (diagnostic 1H–1H correlations): 4.78/4.91
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 389–391

390
P. WYRE˛BEK ET AL.
H-Ph), 8.84 (d, J = 4.7 Hz, 2H, pyrrole-H), 8.94 (s, 4H,
pyrrole-H), 8.96 (d, J = 4.7 Hz, 2H, pyrrole-H). UV-vis
(CHCl3): lmax, nm (log e) 421 (5.77, Soret), 511 (4.63),
543 (3.89), 587 (4.11). MS (FD): m/z (% rel. int.) 2303
(76), 2304 (100), 2305 (68), 2306 (35), 2307 (15), 2308
(5) (isotope [M]+). The molecular formula was confirmed
by comparing the theoretical and experimental isotope
patterns for the [M]+ ion (C128H106F17N7O15); it was found
to be identical within the experimental error limits.
545 (4.41), 579 (3.45). MS (FD): m/z (% rel. int.) 1922
(89), 1923 (93), 1924 (100), 1925 (77), 1926 (70), 1927
(48), 1928 (24), 1929 (9), 1930 (3) (isotope [M]+). The
molecular formula was confirmed by comparing the
theoretical and experimental isotope patterns for the [M]+
ion (C100H72F18N6O10Zn); it was found to be identical
1
within the experimental error limits. 13b. H NMR
(CDCl3, 400 MHz): d, ppm 3.41–3.55 (m, 10H) [2 ×
H-4s, 2H of CH2NH; and inside: 3.46 (s, 6H, 2 × OCH3)],
3.60 (dd, J = 9.6, 3.3 Hz, 2H, 2 × H-2s), 3.77–4.13 (m,
6H, 2 × H-3,5s and 2H of CH2NH), 4.19–4.47 (m, 2H,
2 × CH2NH), 4.64–4.75 (m, 6H, 2 × H-1s and 4H of
CH2-Bn), 4.85 (d, J = 12.2 Hz, 2H of CH2–Bn), 4.88 (d,
J = 10.9 Hz, 2H of CH2-Bn), 4.97 (d, J = 10.9 Hz, 2H of
CH2-Bn), 5.05 (d, J = 10.9 Hz, 2H of CH2-Bn), 7.00–7.44
(m, 30H, H-Ph), 8.93 (d, J = 4.6 Hz, 2H, pyrrole-H), 8.96
(s, 2H, pyrrole-H), 9.00 (s, 2H, pyrrole-H), 9.03 (d, J =
4.6 Hz, 2H, pyrrole-H). UV-vis (CHCl3): lmax, nm (log
e) 418 (5.61, Soret), 504 (2.88), 545 (4.35), 578 (3.41).
MS (FD): m/z (% rel. int.) 1922 (93), 1923 (98), 1924
(100), 1925 (82), 1926 (78), 1927 (55), 1928 (26), 1929
(8), 1930 (2) (isotope [M]+). The molecular formula was
confirmed by comparing the theoretical and experimental
isotope patterns for the [M]+ ion (C100H72F18N6O10Zn); it
was found to be identical within the experimental error
Reaction of [meso-tetrakis(pentafluorophenyl)por-
phyrinato]zinc(II) (9b) with methyl 6-amino-2,3,4-tri-
O-benzyl-6-deoxy-a-D-glucopyranoside (10). A solu-
tion of [meso-tetrakis(pentafluorophenyl)porphyrinato]-
zinc(II) (9b; 160 mg, 0.154 mmol) and glucopyranoside
aminomethyl derivative (10; 364 mg, 0.786 mmol) in
1,2,4-trichlorobenzene (6 mL) was heated to reflux in a
flask equipped with a reflux condenser protected at the
top with a CaCl2 tube. After 5 h the reaction mixture
was cooled to room temperature and chromatographed,
using initially n-hexane as an eluent (100 mL, to remove
1,2,4-trichlorobenzene), and then n-hexane/ethyl acetate
(from 6:1 to 3:1), to give two fractions containing: (a)
mono-substituted product, (b) a mixture of isomers of
disubstituted products and trisubstituted product. Each
fraction was rechromatographed by preparative thin layer
chromatography with the use of n-hexane/ethyl acetate
mixture as eluent (6:1 for the first fraction and 4:1 for
the second one). Yield: 11b, 97 mg (43%); 12b, 13 mg
(4.5%); 13b, 24 mg (8%); and 14b, 4 mg (1%). 11b. 1H
NMR (CDCl3, 400 MHz): d, ppm 3.10–3.64 (m, 8H)
[H-4,5s, CH2NH; and inside: 3.32 (s, 3H, OCH3), 3.45 (dd,
J = 9.5, 2.9 Hz, 1H, H-2s)], 3.93 (apparent t, ‘J’= 9.1 Hz,
1H, H-3s), 4.40–4.52 (m, 2H, H-1s and 1H of CH2-Bn),
4.63 (d, J = 12.1 Hz, 1H of CH2-Bn), 4.72–4.83 (m, 3H
of CH2-Bn), 4.97 (d, J = 10.8 Hz, 1H of CH2-Bn), 7.14–
7.38 (m, 15H, H-Ph), 8.95–9.01 (m, 4H, pyrrole-H), 9.01
(s, 4H, pyrrole-H), NH — undetected. UV-vis (CHCl3):
1
limits. 14b. H NMR (CDCl3, 400 MHz): d, ppm 3.29–
3.58 (m, 15H) [3 × H-4s, 3H of CH2NH; and inside: 3.49
(s, 9H, 3 × OCH3)], 3.63 (dd, J = 9.5, 2.9 Hz, 3H, 3 ×
H-2s), 3.92–4.06 (m, 6H, 3 × H-5s and 3H of CH2NH),
4.12 (apparent t, J = 9.1 Hz, 3H, 3 × H-3s), 4.41–4.54 (m,
3H, 3 × CH2NH), 4.67–4.78 (m, 9H, 3 × H-1s and 6H of
CH2-Bn), 4.86 (d, J = 12.4 Hz, 3H of CH2-Bn), 4.90 (d,
J = 10.8 Hz, 3H of CH2-Bn), 5.00 (d, J = 11.3 Hz, 3H of
CH2-Bn), 5.07 (d, J = 10.8 Hz, 3H of CH2-Bn), 7.27–7.45
(m, 45H, H-Ph), 8.92 (d, J = 4.6 Hz, 2H, pyrrole-H), 9.01
(s, 4H, pyrrole-H), 9.03 (d, J = 4.6 Hz, 2H, pyrrole-H).
UV-vis (CHCl3): lmax, nm (log e) 420 (5.43, Soret), 508
(3.11), 546 (4.18), 580 (3.33). MS (FD): m/z (% rel. int.)
2365 (69), 2366 (90), 2367 (100), 2368 (88), 2369 (78),
2370 (57), 2371 (30), 2372 (12), 2373 (5) (isotope [M]+).
The molecular formula was confirmed by comparing the
theoretical and experimental isotope patterns for the [M]+
ion (C128H104F17N7O15Zn); it was found to be identical
within the experimental error limits.
l
max, nm (log e) 416 (5.63, Soret), 502 (2.73), 544 (4.33),
578 (3.53). MS (FD): m/z (% rel. int.) 1479 (100), 1480
(94), 1481 (99), 1482 (84), 1483 (86), 1484 (64), 1485
(25), 1486 (4) (isotope [M]+). The molecular formula was
confirmed by comparing the theoretical and experimental
isotope patterns for the [M]+ ion (C72H40F19N5O5Zn); it
was found to be identical within the experimental error
1
limits. 12b. H NMR (CDCl3, 400 MHz): d, ppm 3.19–
3.52 (m, 10H) [2 × H-4s, 2H of CH2NH; and inside: 3.44
(s, 6H, 2 × OCH3)], 3.57 (dd, J = 9.6, 3.5 Hz, 2H, 2 ×
H-2s), 3.64–3.95 (m, 4H, 2 × H-5s and 2H of CH2NH),
4.06 (apparent t, ‘J’ = 9.2 Hz, 2H, 2 × H-3s), 4.07–4.27
(m, 2H, 2 × CH2NH), 4.62–4.69 (m, 4H, 2 × H-1s and
2H of CH2-Bn), 4.71 (part of AB, J = 12.1 Hz, 2H of
CH2-Bn), 4.83 (part of AB, J = 12.1 Hz, 2H of CH2-Bn),
4.87 (d, J = 10.8 Hz, 2H of CH2-Bn), 4.94 (d, J = 11.0
Hz, 2H of CH2-Bn), 5.04 (d, J = 10.8 Hz, 2H of CH2-Bn),
7.27–7.43 (m, 30H, H-Ph), 8.93 (d, J = 4.7 Hz, 4H,
pyrrole-H), 9.02 (d, J = 4.7 Hz, 4H, pyrrole-H). UV-vis
(CHCl3): lmax, nm (log e) 418 (5.69, Soret), 502 (2.31),
CONCLUSION
We reported herein the synthesis of N-linked
glycoconjugated porphyrins from meso-aminophenyl-
substituted and from b-amino-substituted 5,10,15,20-
tetraphenylporphyrin derivatives, as well as, from
5,10,15,20-tetrakis(pentafluorophenyl)porphyrin.
Selected compounds bearing the 2,3,4-tri-O-benzylated
glucose configured sugar residues were transformed into
OH-deprotected hybrids. Such an inclusion of OH-free
sugar moieties into porphyrin systems increases their
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 390–391

THE SYNTHESIS OF SUGAR-DECORATED HYDROPHILIC PORPHYRINS
391
hydrophilicity. Thus, from the above processes, the
4. For example: a) Pandey RK. J. Porphyrins Phtha-
locyanines 2000; 4: 368–373. b) Silva AMG, Tomé
AC, Neves MGPMS, Silva AMS, Cavaleiro JAS,
Perrone D and Dondoni A. Tetrahedron Lett. 2002;
43: 603–605. c) Silva AMG, Tomé AC, Neves
MGPMS, Cavaleiro JAS, Perrone D and Dondoni
A. Synlett 2005: 857–859. d) Gomes ATPC, Leão
RAC, da Silva FC, Neves MGPMS, Faustino MAF,
Tomé AC, Silva AMS, Pinheiro S, de Souza MCBV,
Ferreira VF and Cavaleiro JAS. J. Porphyrins
Phthalocyanines 2009; 13: 247–255. e) Lv F, He X,
Lu L, Wu L and Liu T. J. Porphyrins Phthalocya-
nines 2011; 15: 217–222. For review see: f) Zheng
X and Pandey RK. Anti-Cancer Agents Med. Chem.
2008; 8: 241–268; and references cited therein.
5. Photodynamic Tumor Therapy: 2nd and 3rd Genera-
tion Photosensitizers, Moser JG. (Ed.) Harwood
Academic Publishers: Amsterdam, 1998.
hydrophobic meso-TPP porphyrin derivatives can be
transformed into the hydrophilic compounds (very fast
and easily). The glycosylated porphyrins, as such, being
potentially enough soluble in the physiological milieu,
may be considered as attractive second-generation PDT
sensitizers and could be used as effective PDT drugs in
the above mentioned photodynamic cancer therapy.
Optimization concerning this porphyrin-carbohydrate
ligation, as well as preparation of higher substituted
meso-tetrakis(pentafluorophenyl)porphyrin derivatives,
is in progress. Currently we are also in the midst of
the studies on the scope and limitation of the presented
derivatization. The results will be published, in
conjunction with biological activity screening of the
products, in due course. It is particularly important for
the development of high quality agents and it should
allow for more efficient light-based therapies.
6. Vögtle F, Ahuis F, Baumann S and Sessler JL.
Liebigs Ann. 1996: 921–926.
Acknowledgements
7. Wyrębek P and Ostrowski S. J. Porphyrins Phthalo-
cyanines 2007; 11: 822–828.
8. Shen D-M, Liu Ch and Chen Q-Y. Eur. J. Org.
Chem. 2007: 1419–1422.
This work was supported by the Ministry of Science
and Higher Education (Poland), Grant N N204 218535
(2008–2012).
9. van der Made AW, Hoppenbrouwer EJH, Nolte
RJM and Drenth W. Recl. Trav. Chim. Pays-Bas
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10. Kashiwagi Y, Imahori H, Araki Y, Ito O, Yamada K,
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11. a) stepwise trityl and benzyl protection of OH
groups, hydrolysis of trityl ether: Goto J, Murao
N, Oohashi J and Ikegawa S. Steroids 1998; 63:
180–185. b) oxidation of CH2OH group: Jarosz
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formation of CH2OH group into CH2N3: Tagmose
TM and Bols M. Chem. Eur. J. 1997: 453–462. d)
reduction of azide to amine derivative: Slättegård
R, Teodorovic P, Hadgu Kinfe H, Ravenscroft N,
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J. Porphyrins Phthalocyanines 2013; 17: 391–391