Efficient Synthesis of a Porphyrin - N-Tripod Conjugate with Covalently Linked Proximal Ligand: Toward New-Generation Active-Site Models of Cytochrome c Oxidase

Article abstract of DOI:10.1021/ol9911730

Matrix Presented A new-generation cytochrome c oxidase active-site model compound (4) featuring both a trisimidazolyl moiety and a proximal base has been designed and efficiently synthesized. During this study, a facile method based on the chemistry of a

Full text of DOI:10.1021/ol9911730

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2121-2124
Efficient Synthesis of a
Porphyrin−N-Tripod Conjugate with
Covalently Linked Proximal Ligand:
Toward New-Generation Active-Site
Models of Cytochrome c Oxidase
James P. Collman,* Min Zhong, Zhong Wang, and Miroslav Rapta
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Eric Rose†
Laboratoire de Synthe`se Organique et Organome´tallique, UMR CNRS 7611, Tour 44,
4, Place Jussieu, 75252 Paris Cedex 05, France
jpc@chem.stanford.edu
Received October 21, 1999
ABSTRACT
A new-generation cytochrome c oxidase active-site model compound (4) featuring both a trisimidazolyl moiety and a proximal base has been
designed and efficiently synthesized. During this study, a facile method based on the chemistry of a 4-magnesioimidazole derivative to synthesize
4-imidazolyl-containing tripodal ligands (7) has been developed.
Cytochrome c oxidase (CcO), the terminal enzyme of the
respiratory chains of mitochondria and aerobic bacteria,
catalyzes the 4e-, 4H+ reduction of O2 to H2O.1 The active
sites of cytochrome c oxidase in bovine heart2 and Para-
coccus denitrificans3 have recently been structurally char-
acterized by X-ray diffraction. These structures demonstrate
that, as previously surmised from indirect evidence, the O2-
binding/activating site in CcO is composed of a myoglobin-
type iron center (heme a3) and a copper atom (CuB)
coordinated with three imidazoles from histidine residues on
the “distal” side. Significant progress has been made in the
construction of covalently linked model compounds which
closely resemble the heme a3/CuB active site to elucidate
the mechanism of O2 reduction. Those previous active-site
models usually contain an ortho-substituted meso-phenylpor-
phyrin connected with imidazolyl,4 pyrazolyl,5 or multipy-
ridyl moieties6 or triazacyclononane-type protocols4c,7 through
a linker on the “distal” side and/or a proximal base, such as
model compounds 1 and 2 (Figure 1). Both 1 with Co(II)
and Cu(I) inside7c and 2 with Fe(II) and Cu(I) inside4f showed
† E-mail: rose@ccr.jussieu.fr.
(1) Ferguson-Miller, S.; Babcock, G. T. Chem. ReV. 1996, 96, 2889.
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S. Science 1995, 269, 1069. (b) Tsukihara, T.; Aoyama, H.; Yamashita, E.;
Tomizaki, T.; Yamaguchi, H.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono,
R.; Yoshikawa, S. Science 1996, 272, 1136.
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660.
10.1021/ol9911730 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1999

containing tridentate ligands, and its application in the
synthesis of a new-generation model compound (4).
Commercially available 4-iodo-1-tritylimidazole (5)10 can
undergo magnesium-iodine exchange with a Grignard
reagent to give selectively a 4-magnesioimidazole intermedi-
ate (6), which then attacks carbonyl compounds. This
protocol has been used to synthesize not only monoimidazole
compounds of pharmaceutical significance11 but also a wide
range of 4-imidazolyl-containing multidentate ligands for
biomimetic studies.12 To our knowledge there is no previous
study using 5 as a key synthon to make mono-4-imidazolyl-
containing tridentate ligands (7) which can be deprotected
and further functionalized through the N-1 position. As a
part of our active-site model studies, we set forth to study
the reaction of 4-magnesio-1-tritylimidazole (6) with bisimi-
dazolyl and bispyridyl ketones (8)13 (Scheme 1).
Scheme 1
Figure 1.
clean electroreduction of O2 to H2O. Recently, Naruta et al.8
reported a new active-site model compound (3) in which a
trisimidazolylmethane known to give stable complexes with
copper(I) ions9 was combined with a porphyrin through an
amide linkage. However, the synthesis of trisimidazolyl-
methane was inefficient because a tedious protection and a
low-yield Pd(PPh3)4-catalyzed coupling reaction were em-
ployed. Furthermore, there was no built-in proximal base as
in CcO. In our continuing efforts to design and synthesize
more congruent structural models of the CcO active site, we
have focused on developing efficient strategies to construct
fully covalently linked model compounds with both a distal
trisimidazolyl Cu-binding site and a promixal base. Herein
we report a facile method to synthesize mono-4-imidazolyl-
As shown in Table 1, 4-magnesio-1-tritylimidazole (6) (1.2
equiv) which was derived from 5 (1.2 equiv) and EtMgBr
(1.2 equiv) in CH2Cl2 reacted with bis(1-methyl-2-imidazo-
lyl)ketone (8a) (1.0 equiv) to give the trisimidazolylcarbinol
7a in 67% yield. Interestingly, when the more lipophilic
bisimidazolyl ketones 8b and 8c were used, the yield of the
reaction increased to 91% and 99%, respectively. Bispyridyl
ketone (8d) can also react with 6 to form a tridentate ligand
(7d) featuring pyridine donors in 84% yield. However, when
the C-4 or C-5 position on the pyridine rings of 8 was
substituted by methyl group (8e or 8f), the yield of this
reaction decreased dramatically to 55% and 46%, respec-
tively. No desired addition product was obtained when bis-
(3-methyl-2-pyridyl)ketone or bis(6-methyl-2-pyridyl)ketone
was treated with 6, probably because of the interference of
steric hindrance or an acidic methyl group adjacent to
nitrogen in the corresponding ketone. We also found that
the reactivities of the bisimidazolyl ketones (8a-c) are
relatively higher than those of the bispyridyl ketones (8d-
f) in this reaction. All of these tripodal ligands are not only
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2122
Org. Lett., Vol. 1, No. 13, 1999

a chloroacetamide and a proximal base on two sides of the
1
same phenyl ring was desired. In this case, not only the H
Table 1. Synthesis of 4-Imidazolyl-Containing Tripodal
Ligands from 5, EtMgBr, and R2CO (8)a
NMR spectra of all intermediates were simplified but also
the atropisomers were minimized. The chloroacetamide
functional group is a potential linker between the porphyrin
and the tripod on the basis of the well-documented multiple
SN2 reactions.7d,15 As shown in Scheme 3, the bis-faced
Scheme 3a
a Reaction conditions: 5 (1.2 equiv) reacted with EtMgBr (1.2 equiv)
in CH2Cl2 at room temperature for 2 h; then 8 (1.0 equiv) was added and
the resulting mixture was stirred at room temperature for 24-48 h.
important building blocks in CcO active-site model studies
but are also possible carbonic anhydrase (CA) mimics.14
Trisimidazolylcarbinol (7a) was converted to the methy-
lated tripod (9) in a NaH/CH3I/THF system in 93% yield.
Surprisingly, mainly decomposed compounds were obtained
in a NaH/CH3I/DMF system due to retro-aldol condensation.
The trityl groups of the tripodal ligands can be easily
removed in mild acidic conditions. When 9 was stirred in
85% aqueous TFA at room temperature overnight, the free
NH imidazolyl tripod (10) was obtained in 98% yield
(Scheme 2).
a Reagents and conditions: (a) SnCl2‚2H2O, concentrated HCl,
CH2Cl2, 0 °C, 64% for 13a, 28% for 13b; (b) 3-(3′-pyridyl)pro-
pionyl chloride, N,N-diethylaniline, DMF, 68% for 14, 63% for
11; (c) SnCl2‚2H2O, concentrated HCl, CH2Cl2, rt, 86% for 15,
94% for 17; (d) chloroacetyl chloride, Et3N, THF, 0 °C f rt, 84%
for 11, 92% for 16; (e) 10, Cs2CO3, CH3CN, rt, 32%.
dinitroporphyrin (12) was prepared from the mixed conden-
sation16 of mesitaldehyde and 4-tert-butyl-2,6-dinitrobenzal-
dehyde17 with pyrrole in the presence of 3 Å molecular sieves
and BF3‚Et2O in dry CH2Cl2 at room temperature for 1 h
After the free NH imidazolyl tripod (10) was obtained, a
customized bis-faced porphyrin synthon (11) which contains
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Vahrenkamp, H. J. Chem. Soc., Chem. Commun. 1994, 135. (d) Greener,
B.; Moore, M. H.; Walton, P. H. Chem. Commun. 1996, 27. (e) Hannon,
M. J.; Mayers, P. C.; Taylor, P. C. Tetrahedron Lett. 1998, 39, 8509.
(15) (a) Kumazawa, T.; Harakawa, H.; Obase, H.; Oiji, Y.; Tanaka, H.;
Shuto, K.; Ishii, A.; Oka, T.; Nakamizo, N. J. Med. Chem. 1988, 31, 779.
(b) Oshiro, Y.; Sakurai, Y.; Tanaka, T.; Kikuchi, T.; Hirose, T.; Tottori, K.
J. Med. Chem. 1991, 34, 2014. (c) Rezaie, R.; Bremner, J. B.; Blanch, G.
K.; Skelton, B. W.; White, A. H. Heterocycles 1995, 41, 959. (d) Font, M.;
Monge, A.; Cuartero, A.; Elorriaga, A.; Mart´ınez-Irujo, J. J.; Alberdi, E.;
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Scheme 2a
a Reagents and conditions: (a) NaH, CH3I, THF, rt, overnight,
93%; (b) 85% aqueous TFA, rt, overnight, 98%.
Org. Lett., Vol. 1, No. 13, 1999
2123

followed by oxidation of the resulting porphyrinogen with
DDQ. The yield of this mixed-condensation reaction is
extremely dependent on not only the ratio of the two
aldehydes but also on the condensation time. The optimized
ratio of mesitaldehyde/4-tert-butyl-2,6-dinitrobenzaldehyde
was 6/1 and the condensation time was 1 h. Interestingly,
compound 12 can be selectively reduced by SnCl2‚2H2O in
the presence of concentrated HCl in CH2Cl2 at 0 °C to give
monoaminoporphyrin (13a) in 64% yield. Thus, selective
acylation could be achieved using 13a instead of diami-
noporphyrin (13b) as a precursor. Acylation of 13a with
3-(3′-pyridyl)propionyl chloride18 using N,N-diethylaniline
as a base in DMF gave 14, followed by reduction to give 15
in 86% yield. Then 15 was acylated with chloroacetyl
chloride while triethylamine served as a base. The reaction
afforded 11 which contains all the functions as described
above in 84% yield. Alternatively, 12 could undergo acy-
lation with chloroacetyl chloride first to give 16, which was
reduced by SnCl2‚2H2O, and then followed by condensation
with the proximal base to give 11. The overall yield of the
latter route is 54%, which is higher than the former one (49%
from 13a).
Subsequently, efforts were made to complete the synthesis
of the new model compound (4). The tripodal ligand (10)
was condensed with porphyrin (11) in the presence of Cs2-
CO3 in CH3CN at room temperature to give 4 in 32% yield
(Scheme 3). In this model compound, the distance between
the center of the tripod and the core of porphyrin can be
controlled by using different linkers between them. Also,
the structures and properties of the building blocks “distal
tridentate ligand” and “proximal base” can be readily varied.
It can be foreseen that a large number of interesting model
compounds of this series can be efficiently synthesized
according to the present method.
In summary, we have developed a general method to
synthesize tripodal ligands (7) containing 4-imidazolyl
moieties based on the reaction of 4-magnesioimidazole
derivative with bisimidazolyl and bispyridyl ketones (8). We
have also designed and efficiently synthesized a new-
generation active-site analogue (4) featuring both a distal
trisimidazolyl moiety and a proximal base. The facile routes
to the new series of tridentate ligands (7) and the modular
approach to construct the model compound (4) will open up
new possibilities in biomimetic heme chemistry.
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Acknowledgment. We thank the NIH and NSF for
financial support. We also thank the Mass Spectrometry
Facility, University of California, San Francisco, supported
by the NIH (Grants RR 04112 and RR 01614).
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 4, 7a-f, 8a-
f, 9-12, 13a-b, and 14-17. This material is available free
of charge via the Internet at http://pubs.acs.org.
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