Synthesis of new strapped porphyrins via a bisdipyrromethane condensation

Article abstract of DOI:10.1055/s-2007-967967

Two new cationic strapped meso-porphyrins were synthesized via a new route, which consists of the condensation of a bisdipyrromethane with an aldehyde under acidic conditions. One of the strapped porphyrins binds to G-quadruplex DNA. Georg Thieme Verlag S

Full text of DOI:10.1055/s-2007-967967

LETTER
591
Synthesis of New Strapped Porphyrins via a Bisdipyrromethane Condensation
Synthesis of
N
ewS
i
trappe
a
d Porphyrins a P. N. Gonçalves, Jeremy K. M. Sanders*
University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336017; E-mail: jkms@cam.ac.uk
Received 25 October 2006
Abstract: Two new cationic strapped meso-porphyrins were syn-
O
O
R2
thesized via a new route, which consists of the condensation of a
bisdipyrromethane with an aldehyde under acidic conditions. One
of the strapped porphyrins binds to G-quadruplex DNA.
R1
R1
O
O
+
O
O
NH
2 equiv
HN
Key words: strapped porphyrins, condensation, synthesis, meso,
bisdipyrromethane
1 equiv
TFA
2 (g)
N
strapped porphyrin
In the past century there have been many reports of
strapped porphyrins in the literature. They presented dif-
ferent structural features for a wide range of applications;
including disulfide-containing strapped porphyrins for
gold surface interactions,1 models for oxidized states of
cytochrome c oxidase,2 building blocks for catenane
synthesis;3 just to name some of the many examples.4
Scheme 1
O
O
R1
R1
O
NH
Herein, we report the synthesis of two new cationic meso-
substituted porphyrins with different strap sizes (Figure 1)
by a new synthetic method.
N
O
+
O
NH
2 equiv
NH
NH
The standard synthesis of strapped meso-porphyrins
consists of the condensation of a dialdehyde with a di-
pyrromethane (Scheme 1).2–5
acid
N2 (g)
1 equiv
strapped porphyrin
In our new synthetic route a bisdipyrromethane is reacted
with an aldehyde (Scheme 2). A related approach for the
synthesis of b-pyrrole-strapped porphyrins has been
previously reported by Wijesekera et al.6
Scheme 2
2 Cl
2 Cl
O
O
O
O
O
O
N
N
O
O
O
O
O
O
NH
N
N
NH
N
N
HN
HN
1
2
N
N
Figure 1
SYNLETT 2007, No. 4, pp 0591–0594
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967967; Art ID: D31506ST
© Georg Thieme Verlag Stuttgart · New York

592
D. P. N. Gonçalves, J. K. M. Sanders
LETTER
A
H
N
O
O
O
O
O
O
O
O
O
(excess)
TFA
N
N
H
H
O
3
4
HN
NH
+
O
1
5
N
anion
exchange
CHCl3
TCA, N2 (g)
2I
O
O
O
O
N
N
O
O
O
O
MeI
DMF
NH
N
N
NH
N
N
HN
HN
7
6
N
N
H
N
B
O
O
O
O
O
O
O
O
O
O
O
O
(excess)
TFA
O
O
NH
NH
O
O
O
N
H
9
O
8
NH
+
O
2
5
N
anion
exchange
CHCl3
TCA, N2 (g)
2I
O
O
O
O
O
O
N
O
O
N
O
O
O
O
MeI
DMF
O
O
O
O
NH
N
N
NH
N
N
HN
HN
11
10
N
N
Scheme 3 Stepwise synthesis of strapped porphyrins 1 (pathway A) and 2 (pathway B), via a new synthetic route
Synlett 2007, No. 4, 591–594 © Thieme Stuttgart · New York

LETTER
Synthesis of New Strapped Porphyrins
593
(5) (a) Ikeda, T.; Asakawa, M.; Miyake, K.; Shimizu, T. Chem.
Lett. 2004, 33, 1418. (b) Anelli, P. L.; Ashton, P. R.;
Ballardini, R.; Balzani, V.; Delgado, M.; Gandolfi, M. T.;
Goodnow, T. T.; Kaifer, A. E.; Philp, D.; Pietraszkiewicz,
M.; Prodi, L.; Reddington, M. V.; Slawin, A. M. Z.; Spencer,
N.; Stoddart, J. F.; Vicent, C.; Williams, D. J. J. Am. Chem.
Soc. 1992, 114, 193.
(6) Wijesekera, T. P.; Paine, J. B. III; Dolphin, D. J. Org. Chem.
1988, 53, 1354.
(7) Preparation of Compound 4.
The synthesis of bisdipyrromethanes 4 and 9 was
achieved in quantitative yields by reacting a large excess
of pyrrole with dialdehydes 3 or 8 in the presence of 1.4
equivalents of TFA, for 15 minutes at room temperature
(Scheme 3).7 The synthesis of dialdehydes 3 and 8 has
been previously reported elsewhere and is suitable for
scale-up.3,5 The condensation of bisdipyrromethanes 4 or
9 with 2 equivalents of aldehyde 5 in the presence of 13
equivalents of trichloroacetic acid (TCA) and under
nitrogen yielded 0.9% and 19% of porphyrins 6 and 10,
respectively, after chromatographic purification.8 The
conventional synthetic pathway exemplified by Scheme 1
yielded 2–4% of porphyrin 10 and a very small amount of
non-quantified residue of porphyrin 6.
To a flask containing 3 (1.5 g, 3.69 mmol) and pyrrole
(118 g, 1.65 mol) was added 1.4 equiv of TFA and the flask
was left to stir in open air for 15 min. The reaction was
quenched with TEA (7.22 g, 71.4 mmol) and then the
unreacted pyrrole was evaporated. The resulting brown oil
was purified by column chromatography on silica gel
(CHCl3–MeOH, 10:1), yielding 4 quantitatively as a light
brown oil. 1H NMR (500 MHz, CDCl3): d = 8.49 (br s, 4 H),
7.21–7.24 (m, 4 H), 6.95–6.92 (m, 2 H), 6.91–6.89 (m, 2 H),
6.87 (s, 4 H), 6.58–6.60 (m, 4 H), 6.06–6.09 (m, 4 H), 5.89–
5.90 (m, 4 H), 5.61 (s, 2 H), 4.21–4.23 (m, 4 H), 4.03–4.05
(m, 4 H) ppm. 13C NMR (500 MHz cryo, CDCl3): d = 155.8,
153.1, 145.7, 132.5, 130.2, 128.2, 121.6, 116.8, 116.6,
112.5, 108.0, 106.4, 67.4, 66.8, 40.4 ppm. HRMS: m/z calcd
639.2971; found: 639.2943 [M + H+].
This new synthetic route appears to be more efficient with
bisdipyrromethane 9 due to its larger ethylene glycol
chain and flexibility, contrasting with the smaller and
more sterically hindered bisdipyrromethane 4.
Quaternization of porphyrins 6 and 10 with iodomethane
in DMF yielded quantitatively porphyrins 7 and 11.9 The
final porphyrins 1 and 2 were obtained quantitatively after
submitting porphyrins 7 and 11 to anion exchange, where
the iodide counter anion was replaced by a chloride.10
Preparation of Compound 9.
To a flask containing 8 (2.4 g, 4.12 mmol) and pyrrole
(236 g, 3.30 mol) was added 1.4 equiv of TFA and the flask
was left to stir in open air for 15 min. The reaction was
quenched with TEA (7.22 g, 71.4 mmol) and then the
unreacted pyrrole was evaporated. The resulting brown oil
was purified by column chromatography on silica gel
(CHCl3–MeOH, 10:1), yielding 9 quantitatively as a light
green oil. 1H NMR (500 MHz, CDCl3): d = 7.24 (dd, J = 1.6,
7.6 Hz, 2 H), 7.18 (dt, J = 1.6, 7.6, 8.0 Hz, 2 H), 6.91 (dt,
J = 0.9, 7.6, 7.6 Hz, 2 H), 6.83 (dd, J = 0.9, 8.0 Hz, 2 H),
6.76 (s, 4 H), 6.62–6.65 (m, 4 H), 6.08–6.10 (m, 4 H), 5.93–
5.94 (m, 4 H), 5.66 (s, 2 H), 4.04–4.06 (m, 4 H), 3.94–3.96
(m, 4 H), 3.77–3.79 (m, 4 H), 3.75–3.76 (m, 4 H), 3.70–3.72
(m, 4 H), 3.65–3.67 (m, 4 H) ppm. 13C NMR (500 MHz cryo,
CDCl3): d = 155.8, 152.9, 132.6, 132.0, 130.1, 128.0, 121.4,
116.5, 115.5, 112.4, 107.8, 106.2, 70.8, 70.7, 69.9, 69.7,
67.8, 67.1, 40.5 ppm. HRMS: m/z calcd: 815.3942; found:
815.4121 [M + H+].
In order to explore the use of bisdipyrromethanes as a
general route to synthesize strapped porphyrins, bisdi-
pyrromethane 9 was reacted with other aldehydes (benzal-
dehyde, tetrafluorobenzaldehyde, 4-methylbenzaldehyde
and 4-nitrobenzaldehyde), but without success. We are
currently investigating this reaction in more detail.
The porphyrin with the longest strap (2) binds to G-qua-
druplex DNA (kD = 18 4 mM), showing some preference
for the antiparallel quadruplex conformation (data not
shown).
In summary, a new synthetic route for the preparation of
two new cationic-strapped meso-porphyrins has been de-
veloped. This new method appears to be specific for the
condensation with 4-pyridinecarboxaldehyde. Porphyrin
2 has been shown to bind to G-quadruplex DNA.
(8) Preparation of Porphyrin 6.
To a stirred solution of 4 (0.50 g, 1.03 mmol) and 4-
pyridinecarboxaldehyde (0.22 g, 2.06 mmol) in CH2Cl2 (500
mL), under nitrogen at r.t. and in the dark, was added TCA
(2.20 g, 13.46 mmol) dissolved in CH2Cl2 (10 mL). After
reacting for 90 min, TEA (7.22 g, 71.4 mmol) was added
followed by DDQ (0.15 g, 0.66 mmol) and the reaction was
stirred for an additional 30 min. The solvent was then
evaporated in vacuo and purified by preparative TLC
(CH2Cl2–MeOH, 10:1), yielding 0.9% of porphyrin 6 (7.5
mg) as a purple solid. UV/Vis: lmax = 418, 518, 556, 602 nm.
1H NMR (500 MHz, CDCl3): d = 8.97 (br s, 4 H), 8.86 (d,
J = 4.8 Hz, 4 H), 8.74 (d, J = 4.8 Hz, 4 H), 7.95 (br s, 4 H),
7.83–7.85 (m, 2 H), 7.77–7.81 (m, 2 H), 7.50–7.55 (m, 2 H),
7.20–7.25 (m, 2 H), 3.87–3.85 (m, 4 H), 3.55 (s, 4 H), 2.82–
2.84 (m, 4 H), –2.74 (br s, 2 H) ppm. 13C NMR (500 MHz
cryo, CDCl3): d = 159.4, 152.3, 148.2, 134.1, 131.8, 130.2,
129.6, 120.4, 113.4, 69.3, 68.6, 58.6 ppm. As is usual in
porphyrin chemistry, many of the quaternary carbon NMR
signals are too weak to be seen. HRMS: m/z calcd: 811.3033;
found: 811.3044 [M + H+].
Acknowledgment
We thank Duncan Howe, Andrew Mason and Brian Crysell for
NMR assistance. The Portuguese Science Foundation (Fundação
para a Ciência e a Tecnologia – FCT – Portugal) SFRH/BD/12414/
2003 (D. P. N. Gonçalves) is gratefully acknowledged for financial
support.
References and Notes
(1) Redman, J. E.; Sanders, J. K. M. Org. Lett. 2000, 2, 4141.
(2) Andrioletti, B.; Ricard, D.; Boitrel, B. New J. Chem. 1999,
23, 1143.
(3) Gunter, M. J.; Hockless, D. C. R.; Johnston, M. R.; Skelton,
B. W. J. Am. Chem. Soc. 1994, 116, 4810.
(4) (a) Osuka, A.; Kobayashi, F.; Nagata, T.; Maruyama, K.
Chem. Lett. 1990, 2, 287. (b) Osuka, A.; Nagata, T.;
Maruyama, K. Chem. Lett. 1991, 10, 1687.
Preparation of Porphyrin 10.
To a stirred solution of 9 (0.59 g, 0.60 mmol) and 4-
pyridinecarboxaldehyde (0.13 g, 1.20 mmol) in CH2Cl2
Synlett 2007, No. 4, 591–594 © Thieme Stuttgart · New York

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D. P. N. Gonçalves, J. K. M. Sanders
LETTER
(500 mL), under nitrogen at r.t. and in the dark, was added
TCA (2.20 g, 13.46 mmol) dissolved in CH2Cl2 (10 mL).
After reacting for 90 min, TEA (7.22 g, 71.4 mmol) was
added followed by DDQ (0.30 g, 1.32 mmol) and the
reaction was stirred for an additional 30 min. The solvent
was then evaporated in vacuo and purified by preparative
TLC (CH2Cl2–MeOH, 10:1), yielding 19% of porphyrin 10
(92.4 mg) as a purple solid. UV/Vis: lmax = 414, 510, 546,
592 nm. 1H NMR (500 MHz, CDCl3): d = 9.00 (br s, 4 H),
8.83 (d, J = 4.6 Hz, 4 H), 8.74 (d, J = 4.6 Hz, 4 H), 8.13 (br
d, 4 H), 7.86 (dd, J = 1.1, 7.9 Hz, 2 H), 7.76 (td, J = 1.6, 7.6,
7.9 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.38 (td, J = 1.1, 7.8,
7.6 Hz, 2 H), 5.79 (s, 4 H), 4.06 (t, J = 5.2 Hz, 4 H), 3.19 (t,
J = 5.2 Hz, 4 H), 2.88–2.90 (m, 4 H), 2.83–2.84 (m, 4 H),
2.79–2.81 (m, 4 H), 2.74–2.77 (m, 4 H) and –2.79 (br s, 2 H)
ppm. 13C NMR (500 MHz cryo, CDCl3): d = 158.4, 152.1,
148.1, 136.1, 130.8, 130.1, 129.3, 119.9, 117.2, 116.5,
115.2, 112.7, 70.2, 70.1, 69.0, 68.6, 67.4 ppm. HRMS:
m/z calcd: 987.4081; found: 987.4041 [M + H+].
the exchange resin for approximately 3 h. The resin was then
filtered off and washed with H2O, giving porphyrin 1 in
quantitative yields and without any further purification.
UV/vis lmax = 424, 518, 556, 602 nm. 1H NMR (500 MHz,
CD3CN 80% CD3OD 20%): d = 9.06 (d, J = 5.3 Hz, 4 H),
9.02–8.72 (br m, 12 H), 8.51 (dd, J = 1.4, 7.1 Hz, 2 H), 8.88–
8.92 (m, 2 H), 7.59 (t, J = 7.1, 8.0 Hz, 2 H), 7.37 (d, J = 8.0
Hz, 2 H), 4.64 (s, 6 H), 3.89–3.91 (m, 4 H), 3.64 (s, 4 H),
2.91–2.90 (m, 4 H) ppm. The NH signals are not present due
to exchange with the solvent. 13C NMR (500 MHz cryo,
CD3CN 80% CD3OD 20%): d = 159.5, 153.2, 144.9, 134.8,
131.9, 121.3, 115.9, 114.4, 69.8, 69.2, 49.2 ppm. HRMS:
m/z calcd: 420.1706 [(M – 2 Cl)/2]; found: 420.1709.
Preparation of Porphyrin 2.
Porphyrin 11 was then submitted to an anion-exchange resin
with Dowex 1X2-200 in the chloride form, by shaking the
dissolved porphyrin in a mixture of acetone–H2O (3:2) with
the exchange resin for approximately 3 h. The resin was then
filtered off and washed with H2O, giving porphyrin 2 in
quantitative yields and without any further purification.
UV/vis lmax = 426, 510, 546, 592 nm. 1H NMR (500 MHz,
CD3NO2): d = 9.19 (d, J = 6.7 Hz, 4 H), 9.03 (br s, 4 H), 8.92
(br s, 4 H), 8.89 (br s, 4 H), 7.86–7.91 (m, 4 H), 7.60 (d,
J = 7.8 Hz, 2 H), 7.41 (td, J = 0.9, 7.0, 7.8 Hz, 2 H), 5.53 (s,
4 H), 4.81 (s, 6 H), 4.18–4.20 (m, 4 H), 3.30–3.32 (m, 4 H),
2.96–2.97 (m, 4 H), 2.87–2.89 (m, 4 H), 2.79–2.81 (m, 4 H),
2.69–2.71 (m, 4 H), –2.82 (br s, 2 H) ppm. 13C NMR (500
MHz cryo, CD3NO2): d = 159.5, 152.8, 144.6, 137.0, 133.8,
131.6, 120.9, 115.9, 113.9, 70.8, 70.7, 69.7, 69.5, 69.4, 69.1
ppm. HRMS: m/z calcd: 508.2231 [(M – 2 Cl)/2]; found:
508.2064.
(9) Preparation of Porphyrin 7.
The quaternization of the pyridyl groups of porphyrin 6 was
achieved by methylation with a large excess of MeI in DMF,
at 40 °C for 5 h, yielding quantitatively porphyrin 7.
Preparation of Porphyrin 11.
The quaternization of the pyridyl groups of porphyrin 10 was
achieved by methylation with a large excess of MeI in DMF,
at 40 °C for 5 h, yielding quantitatively porphyrin 11.
(10) Preparation of Porphyrin 1.
Porphyrin 7 was then submitted to an anion-exchange resin
with Dowex 1X2-200 in the chloride form, by shaking the
dissolved porphyrin in a mixture of acetone–H2O (3:2) with
Synlett 2007, No. 4, 591–594 © Thieme Stuttgart · New York