Efficient and versatile synthesis of new porphyrins bearing an N3O moiety: Ligands for mimicking cytochrome c oxidase

Article abstract of DOI:10.1021/ol800731t

(Chemical Equation Presented) Two new generations of ligands for cytochrome c oxidase mimicking have been designed and synthesized via an efficient, convergent, and versatile synthesis. These porphyrins are functionalized with both an internal nitrogen ba

Full text of DOI:10.1021/ol800731t

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2673-2676
Efficient and Versatile Synthesis of New
Porphyrins Bearing an N3O Moiety:
Ligands for Mimicking Cytochrome c
Oxidase
Christian Ruzie´, Pascale Even-Hernandez, and Bernard Boitrel*
UniVersite´ de Rennes1, Sciences Chimiques de Rennes, Inge´nierie Chimique et
Mole´cules du ViVant, UMR CNRS 6226, 35042 Rennes Cedex, France
bernard.boitrel@uniV-rennes1.fr
Received April 3, 2008
ABSTRACT
Two new generations of ligands for cytochrome c oxidase mimicking have been designed and synthesized via an efficient, convergent, and
versatile synthesis. These porphyrins are functionalized with both an internal nitrogen base on one side and a triaza (N3) or a triaza-phenol
(N3O) moiety on the other side, attached to the macrocycle by various spacers. Unlike tailed porphyrins, the triaza motif as well as the
nitrogen base are linked by two points.
Dioxygen binding and activation are obviously two of the
most important phenomena in aerobic biological systems.1
Theses two reactions are illustrated in the activity of a
paramount enzyme, cytochrome c-dioxygen oxido-reductase,
commonly named cytochrome c oxidase (CcO).2 The latter
catalyzes the four-electron/four-proton reduction of dioxygen
in water producing a proton gradient across the mitochondrial
membrane.3 The resulting electrochemical potential gradient
provides the driving force needed by ATP synthase for the
synthesis of ATP from ADP.
Indeed, dioxygen binding and reduction occur at a heter-
obinuclear site that is comprised of a heme a3 and CuB in
Figure 1. Cytochrome c oxidase active site (left) and subsequent
design of a copper complex (right).
(1) Lippard, S. J.; Berg, J. M. Principles of Bioinorganic Chemistry;
University Science Books: Mill Valley, USA, 1994.
(2) Ferguson-Miller, S.; Babcock, G. T. Chem. ReV. 1996, 96, 2889–
2907.
close proximity (Figure 1, left).4 Additionally, one copper-
ligated histidine ligand (His240) is covalently linked to a
(3) Ludwig, B.; Bender, E.; Arnold, S.; Hu¨ttemann, M.; Lee, I.;
Kadenbach, B. Chembiochem 2001, 2, 392–403.
10.1021/ol800731t CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

tyrosine side chain (Tyr244) according to a posttranslational
modification.5 This cross-linking is believed to decrease the
pKa value of the tyrosine residue around physiological pH,
therefore allowing the transfer of a proton to the bound
superoxo complex or the transfer of an electron via the
formation of a tyrosyl radical or both. Since dioxygen
reactivity of heme-copper complexes has attracted many
synthetic modeling chemists, numbers of synthetic model
compounds have been described to understand the key step
of the reductive cleavage of the O-O bond.6 For instance,
Naruta et al. have described the first X-ray structure of an
iron-η2-copper-η1-peroxo complex in which the copper ligand
is based on a tetraza motif (TMPA).7 However, Karlin et al.
clearly demonstrated the influence of denticity (tetradentate
versus tridentate) of the copper coordination sphere on the
binding mode of dioxygen.8 Nevertheless, few models
incorporate all the structural features of the active site: (1) a
heme possessing an intramolecular fifth ligand; (2) a flexible
triaza ligand for copper I/II coordination, and finally (3) a
mimic of Tyr244. On one hand, Collman et al. have reported
the synthesis of such molecules,9 one of them existing as a
mixture of two isomers,10 and on the other hand, Karlin et
al. studied the reactivity of dioxygen on a model in which
both entities, the heme and the phenol cross-linked tetraza
complex, are not covalently linked.11
tetrakis-o-aminophenyl porphyrin12 (TAPP) RRꢀꢀ as this
atropisomer allows the attachment of two different residues
on the opposite sides of the porphyrin. For instance, we have
already shown with an X-ray structure that a diethyl malonate
group attached on each side of porphyrin 1 was oriented
toward the center of the porphyrin.13
Furthermore, a commercially available compound such as
C-pyridin-3-yl-methylamine can be bis-linked on the second
face of the porphyrin, delivering a fifth ligand to the iron in
future steps.14 The syntheses of the desired compounds were
achieved by using one-pot procedures in which two different
nucleophiles were mixed with porphyrin 115 in THF at 70 °C
overnight (Scheme 1).
Scheme 1. Synthetic Route to Porphyrins 2a,b
This observation prompted us to synthesize a new triaza
ligand bearing a Tyr244 mimic which could be attached by
two linkers on a tetraaryl-porphyrin. Observing the active
site of CcO, we have designed the molecule depicted in
Figure 1 (right) in which a nitro-phenol is attached to a triaza
ligand. Indeed, this nitro-phenol, with a pKa of 7.5, represents
a simple way to probe if the transfer of a proton to the
superoxo complex is an important process for the catalytic
activity. Moreover, this N3O ligand can be easily linked on
a porphyrin. The properties of the phenol can also be
modulated by varying the nature of the substituent in para
position as well as the position itself of the OH group on
the aromatic ring. Accordingly, we chose to functionalize
(4) (a) Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.;
Yamaguchi, H.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yoshikawa,
S. Science 1995, 269, 1069–1074. (b) Iwata, S.; Ostermeier, C.; Ludwig,
B.; Michel, H. Nature 1995, 376, 660–669.
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Fei, M. J.; Libeu, C. P.; Mizushima, T.; Yamaguchi, H.; Tomizaki, T.;
Tsukihara, T. Science 1998, 280, 1723–1729.
(6) (a) Collman, J. P.; Boulatov, R.; Sunderland, C. J.; Fu, L. Chem.
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K. D. Chem. ReV. 2004, 104, 1077–1133.
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For instance, to obtain 2a (11%), C-pyridin-3-yl-methy-
lamine and compound 3a were used to obtain both a nitrogen
base and an N3O coordination sphere for copper, respec-
(10) Collman, J. P.; Decre´au, R. A.; Zhang, C. J. Org. Chem. 2004, 69,
3546–3549.
(11) Kim, E.; Kamaraj, K.; Galliker, B.; Rubie, N. D.; Moe1nne-Loccoz,
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2674
Org. Lett., Vol. 10, No. 13, 2008

tively. But, obviously, two minor compounds were also
formed as porphyrins 4a (7%) and 5 (4%), leading to a global
yield of 22%. For comparison purposes, the analogous
compound of 2a bearing a benzyl group instead of the benzyl
nitro phenol residue, namely, 2b (11%), has also been
synthesized. Actually, as the synthesis of the tripods is
convergent, it implies only one new step (Scheme 2). Briefly,
analogous compounds exhibiting less preorganization, we
applied the same synthesis to 9 (Scheme 3) that possesses
Scheme 3. Sequential Synthesis of Model Compound 8
Scheme 2. Synthesis of New N3O and N3 Moieties
two acrylamide pickets per side and that should react
according to a Michael addition.18
However, porphyrin 9 reacts differently from porphyrin
1. For the former, we were able to isolate porphyrin 10 in
which only one side of the porphyrin was functionalized by
C-pyridin-3-yl-methylamine with a decent yield of 32%. This
peculiar reactivity allowed us to graft the N3O synthon onto
10 in a final step to isolate with 50% yield the expected
compound 11.
3a or 3b was prepared starting from (2-amino-ethyl)-
carbamic acid tert-butyl ester 6.16 In a first step, the third
nitrogen atom of the future triaza compound is introduced
by reductive amination of the primary amine of 6 to afford
7 (74%). A second alkylation of the same nitrogen atom leads
to either 8a (94%) or 8b (93%) using either 5-hydroxy-2-
nitro-benzaldehyde or bromomethyl-benzene. Exposure of
the latters to TFA resulted in 3a (68%) or 3b (87%).
It should be mentioned that this convergent synthesis is
efficient using various electrophilic picket porphyrins. We
have tuned it for porphyrin 1 in which the pickets are quite
rigid and preorganized (U-shaped pickets) as we wanted the
resulting models to exhibit some preorganization both for
the iron and the copper. For instance, Chang et al. were the
first to demonstrate that such a 1,3-chloromethyl benzoyl link
was properly preorganized to deliver an imidazole residue
close to the iron of a porphyrin.17 We reasoned that any
structure delivered by two such linkers would be firmly
maintained over the porphyrin. However, to dispose of
As both series of porphyrins feature an internal nitrogen
base as the fifth ligand of the metal in the porphyrin, it was
crucial to verify that these new structures allow the coordina-
tion of their intramolecular fifth ligand. In the case of the
series built-up with the acrylamide pickets, this coordination
was verified on porphyrins 10Zn and 11Zn by the actual
1
coordination of the pyridine derivative monitored by H
NMR spectroscopy (see Supporting Information for further
details, S4-S5, S18). In the series prepared from porphyrin
1 bearing “U-shaped” pickets, the coordination of the internal
nitrogen base was evidenced for both zinc complexes of
porphyrin 5 in which the two sides of the macrocycle are
equivalent and porphyrin 2b bearing a pyridinyl base and a
benzyl N3 ligand (Figure 2). With the proton NMR data of
2b and 2bZn, the coordination of the axial ligand on zinc is
characterized by the upfield shift of the protons from the
pyridinyl cycle but also by the deshielding of proton H2′
located in the position 2 of the “U-shaped” picket. In
comparison, on the NMR spectra of porphyrins 5 and 5Zn
(Supporting Information, S3), proton H2′ is shifted from 3.81
(13) Halime, Z.; Balieu, S.; Lachkar, M.; Roisnel, T.; Richard, P.; Boitrel,
B. Eur. J. Org. Chem. 2006, 1207-1215.
(14) Even, P.; Ruzie´, C.; Ricard, D.; Boitrel, B. Org. Lett. 2005, 7, 4325–
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(15) Didier, A.; Michaudet, L.; Ricard, D.; Baveux Chambenoit, V.;
Richard, P.; Boitrel, B. Eur. J. Org. Chem. 2001, 1917-1926.
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Org. Lett., Vol. 10, No. 13, 2008
2675

Figure 3.
1H NMR of compounds (a) 12Fe and (b) 12FeCO (500
MHz, CDCl3, 298 K).
Figure 2
.
1H NMR of compounds 2b and 2bZn (500 MHz, CDCl3,
323 K): pyr refers to the aminomethyl pyridyl residues.
complexes leads to a six-coordinate diamagnetic complex
for which a regular spectrum is observed (Figure 3, top).
In summary, owing to a versatile synthesis, we have
prepared three porphyrins, 2a, 2b, and 11, that exhibit
important structural features for future CcO modeling, as a
built-in nitrogen base and a flexible triaza-benzyl residue or
a triaza-benzylphenol residue both suspended over the center
of the porphyrin via a strap attached on adjacent meso
positions. This particular geometry is expected to allow some
flexibility to the linked structures. Porphyrin 11 possesses
the same functions on both sides of porphyrin 2a but without
preorganization, due to aliphatic spacers instead of 1,3-
aromatic linkers. The phenol residue of the distal structure
can easily be substituted by different groups. The reactivity
toward dioxygen as well as spectroscopic characterization
of these models are currently under investigation.
ppm downfield to 4.78 ppm. Moreover, the signal due to
H2′ and those from the pyridine cycle are sharp for the free-
base porphyrin and become large and unresolved for the zinc
porphyrin. These observations are consistent with the fact
that the strap has to be moved away from the center of the
porphyrin to allow the coordination of the axial base.
Additionally, the coordination of this internal nitrogen base
was also observed in this series with iron inside the
porphyrin. For this purpose, we have studied the behavior
of the iron complex of porphyrin 12 (Figure 3), the analogue
of porphyrins 2a or 2b, but resulting from the addition of
C-pyridin-3-yl-methylamine on one side and (2-amino-ethyl)-
carbamic acid tert-butyl ester 6 on the other one. As this
type of porphyrin will be further studied as bimetallic
iron-copper complexes, in a first step, it is crucial to verify
first that the iron-only complex can form a five-coordinate
complex with the built-in nitrogen base and second that the
former can coordinate a small molecule as dioxygen or
carbon monoxide in the sixth coordination site of iron(II).
Again, these two phenomena can be easily probed by proton
NMR spectroscopy. Indeed, it is well established that five-
coordinate high-spin (S ) 2) iron(II) complexes exhibit a
typical proton pattern on NMR spectra with ꢀ-pyrrolic
protons downfield-shifted at around 50-60 ppm14,19 (Figure
3, bottom) and that coordination of carbon monoxide on such
Acknowledgment. We are indebted to CNRS and Re´gion
Bretagne for their financial support.
Supporting Information Available: Experimental section
and spectral data for selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800731T
(19) (a) Goff, H; Ma Mar, G. N. J. Am. Chem. Soc. 1977, 99, 6599–
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