Cytochrome c oxidases (CcOs), the dinuclear catalytic center
in NORs is FeB-heme-Fe rather than CuB-heme-Fe in CcOs.1
The glutamic acid residues are conserved in NORs, whereas
they are absent in CcOs. Additionally, in most CcOs, a redox
active phenol group from a tyrosine is coupled to one of the
three CuB coordinating histidine moieties.3 The glutamic acid
residues have been reported to be essential for normal levels
of NOR activity.3a Possible functions of these glutamic acids
include increased selective binding of the distal non-heme
FeB over Cu, charge regulation directing to the modulation
of redox potential of the catalytic center, and mediation of
the proton uptake for NO reduction.
Scheme 1. Retrosynthetic Scheme of NOR Model Compound
1
closely replicating the ligand environment of the active site
of native NORs.
The biomimetic approach to studying the structural-
functional relationships of metalloenzyme activities has
proven to be quite successful.3c,4 Simulation and variation
of synthetic models allows for the easy and rapid comparison
of coordination environments, spectroscopic properties, and
functional capabilities of the metalloenzyme active site. Such
information may be difficult to obtain from wild type
enzymes or their mutants due to their restricted availability
and difficulty in handling. Previously, only a few synthetic
models have been developed to study NOR.1a,5 Recently,
Karlin and co-workers reported structural models of NOR
active site featuring a porphyrin covalently linked to a
tetradentate chelate (TMPA, tris(2-pyridylmethyl)amine).5 In
these models, the TMPA moiety was intended to mimic the
trisimidazole ligand environment of FeB site in NORs. A
carboxylic group that mimics the glutamic acid residue was
not included in these models. A more faithful ligand
environment is desirable for modeling of metalloenzymes,
as a more exact mimic should shed light on metal binding
affinity, spectroscopic properties, and redox potential of the
active site of the native enzyme. Our interest on NOR
modeling originates from our long standing effort in CcO
mimicry and investigation of the chemistry occurring at the
bimetallic Fe/Cu active site of CcO using synthetic bioinor-
ganic models.6 Herein we report the syntheses of NOR model
ligands 1 (1a, 1b) featuring a porphyrin bearing trisimidazole
pickets and a carboxylic acid residue (Scheme 1). These
ligands represent the best available NOR model ligands
The retro-synthetic scheme of compounds 1 is shown in
Scheme 1. The four amino groups of RRRR-TAPP (tetrakis-
5,10,15,20-(o-aminophenyl)porphyrin) provide excellent link-
ages for installation of imidazole and carboxylic acid moieties
by forming amide bonds with corresponding imidazolecar-
boxylic acid chloride and glutaric acid chloride.7 One amino
group for introduction of the carboxylic acid residue is
selectively discriminated from other three amino groups for
imidazole moieties by protection with a trityl group.
Preparation of imidazolecarboxylic acid chloride 2 is
shown in Scheme 2. Synthesis of 5-imidazolecarboxylic acids
Scheme 2. Synthetic Scheme of Acid Chlorides 2
8 followed a literature procedure incorporated with our own
modification.8 Diaminomaleonitrile 3 was condensed with
trimethyl orthoformate and trimethyl orthobutyrate to give
dicyanoimidazole 4a and 4b in yields 83-88%, respectively.
4a was methylated with dimethyl sulfate in NaHCO3 aqueous
solution providing 5a in 90% yield. Due to the lower
solubility of 4b in water, an alternative method was employed
for methylation of 4b. Refluxing 4b in trimethyl orthoacetate
provided 1-methylated 4,5-dicyanoimidazole 5b in 84%
yield. The N-methyl group in intermediates 5-8 not only
results in higher solubility of this series of imidazole
intermediates in organic solvents but also leads to stereo
(2) (a) Brudvig, G. W.; Stevens, T. H.; Chan, S. I. Biochemistry, 1980,
19, 5275. (b) Moenne-Loccoz, P.; Vries, S. D. J. Am. Chem. Soc. 1998,
120, 5147.
(3) (a) Butland, G.; Spiro, S.; Watmough, N. J.; Richardson, D. J. J.
Bacteriol. 2001, 183, 189. (b) Silaghi-Dumitrescu, R.; Kurtz, D. M.. Jr.;
Ljungdahl, L. G.; Lanzilotta, W. N. Biochemistry 2005, 44, 6492. (c) Tshuva,
E. Y.; Lippard, S. J. Chem. ReV. 2004, 104, 987.
(4) (a) Holm, R. H.; Solomon, E. I. Chem. ReV. 2004, 104, 347. (b)
Collman, J. P.; Boulatov, R.; Sunderland, C. J.; Fu, L. Chem. ReV. 2004,
104, 561. (c) Solomon, E. I.; Szilagyi, R. K.; George, S. D.; Basumallick,
L. Chem. ReV. 2004, 104, 419. (d) Rao, P. V.; Holm, R. H. Chem. ReV.
2004, 104, 527. (e) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem.
ReV. 2004, 104, 1013
(5) (a) Wasser, I. M.; Huang, H.-W.; Moenne-Loccoz, P.; Karlin, K. D.
J. Am. Chem. Soc. 2005, 127, 3310. (b) Wasser, I. M.; Martens, C. F.;
Verani, C. N.; Rentschler, E.; Huang, H.-W.; Moenne-Loccoz, P.; Zakharov,
L. N.; Rheingold, A. L.; Karlin, K. D. Inorg. Chem. 2004, 43, 651.
(6) (a) Boulatov, R.; Collman, J. P.; Shiryaeva, I. M.; Sunderland, C. J.
J. Am. Chem. Soc. 2002, 124, 11923. (b) Collman, J. P.; Boulatov, R. Angew.
Chem., Int. Ed. 2002, 41, 3487. (c) Collman, J. P.; Sunderland, C. J.;
Boulatov, R. Inorg. Chem. 2002, 41, 2282. (d) Collman, J. P.; Boulatov,
R.; Shiryaeva, I. M.; Sunderland, C. J. Angew. Chem., Int. Ed. 2002, 41,
4139.
(7) For some examples of RRRR-TAPP as a platform in synthesis of
biomimetic models, see: (a) Collman, J. P.; Gagne, R. R.; Reed, C. A.;
Halbert, T. R.; Lang, G.; Robinson, W. T. J. Am. Chem. Soc. 1975, 97,
1427. (b) Wuenschell, G. E.; Tetreau, C.; Lavalette, D.; Reed, C. A. J. Am.
Chem. Soc. 1992, 114, 3346. (c) Collman, J. P.; Yan, Y.-L.; Eberspacher,
T.; Xie, X.; Solomon, E. I. Inorg. Chem. 2005, 44, 9628.
(8) O’Connell, J. F.; Parquette, J.; Yelle, W. E.; Wang, W.; Rapoport,
H. Synthesis 1988, 767.
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Org. Lett., Vol. 8, No. 5, 2006