Two regioisomers are presented: N-methylimidazole
rings may lie either on cis meso-positions 10 and 15 which
makes the porphyrin asymmetric (1-cis) or on trans
meso-positions 10 and 20 which makes the porphyrin
symmetric (1-tr a n s). The free base porphyrins 1-cis and
-tr a n s share many structural features with our previous
reported models, such as R3â-atropisomerism, two distal
N-methyl-substituted imidazoles, and a proximal CF3Ph-
imidazole tail (1F ) or a nonsubstituted H-tail (1H).4a-c
Herein, we describe the synthesis of 1F -cis, the closest
structural analogue of the metal-free cytochrome c oxi-
dase active site. Its key feature is a phenol-containing
imidazole 2 in the distal area.
The synthesis of 2 starts from the key intermediate 4
which we described previously.3d A new procedure using
the H2WO4/H2O2 couple5 was adopted to desulfurize 4.
This led to 5 with an improved yield and a simple workup
compared with the earlier HNO3/NaNO2 method.3 The
desired phenoxy-substituted imidazole 2 was obtained
after acid hydrolysis of 5 and subsequent formation of
the acid chloride 6. The synthesis of 2 requires nine steps
and gives an 8% overall yield starting from 2-aminophe-
nol (Scheme 1).
Although the synthetic route to 1 appears simple, the
first challenge in its preparation relies on developing
methods to introduce two different imidazoles onto the
R3 face of the porphyrin 3 in good yield. Since the three
distal amines in 3 are not identical, we envisioned that
the introduction of one or two imidazoles would lead to
two regioisomers. The second challenge is separation of
the very polar porphyrin regioisomers.
We developed two synthetic routes to 1 starting from
either of two porphyrin synthons R3AâF3T (3F )4a-c or
R3AâT (3H):4a,b (1) introduction of the phenol substituted
imidazole 2 first and subsequently the two simple imi-
dazoles 7, the “[1 + 2] approach” (route A, Scheme 2);
(2) introduction of the two simple imidazoles 7 first and
subsequently the phenol-substituted imidazole 2, the
“[2 + 1] approach” (route B, Scheme 2).
Syn th esis of Cytoch r om e c Oxid a se Mod els
Bea r in g a Tyr 244 Mim ic
J ames P. Collman,* Richard A. Decre´au, and Chi Zhang
Department of Chemistry, Stanford University,
Stanford, California 94305-5080
jpc@stanford.edu
Received J anuary 5, 2004
Abstr a ct: A close structural analogue of the metal-free
cytochrome c oxidase active site has been synthesized. This
model has a proximal imidazole tail and three distal imi-
dazole pickets attached to a porphyrin. One distal imidazole
is cross-linked to a phenol, mimicking Tyr244. The strategy
behind the successful synthesis of this regioisomerically pure
model involved discovering the best sequence to introduce
the phenol-substituted imidazole and employing a fluori-
nated substituent.
Cytochrome c oxidase is the terminal enzyme in the
respiratory chains of mitochondria and aerobic bacteria.1a-e
One of the three His coordinating CuB in cytochrome c
oxidase (CcO) is cross-linked to a phenol residue from
tyrosine. This phenol that our previous CcO models
lacked is thought to play a key role in the 4H+, 4e-
reduction of O2 to H2O and has been the subject of model
studies.2a-j,3a-c Recently, this Tyr244-His240 moiety has
been studied in some non-heme models,2a-j where other
organic components were missing (heme, proximal imi-
dazole). To obtain a closer analogue of the enzyme active
site, we have designed 1, which has one of the distal
imidazole rings N-substituted with a phenol (Figure 1).
(1) (a) Ferguson-Miller, S.; Babcock, G. T. Chem. Rev. 1996, 96, 2889.
(b) Iwata, S.; Ostermeier, C.; Ludwig, B.; Michel, H. S. Nature 1995,
376, 660. (c) Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.;
Yamaguchi, H.; ShinzawaItoh, K.; Nakashima, R.; Yaono, R.; Yoshika-
wa, S. Science 1996, 272, 1136. (d) Tsukihara, T.; Aoyama, H.;
Yamashita, E.; Tomizaki, T.; Yamagushi, H.; Shinzawaitoh, K.; Na-
kashima, R.; Yaono, R.; Yoshikawa, S. Science, 1995, 269, 1069. (e)
Yoshikawa, S.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Ya-
mashita, E.; Inoue, N.; Yao, M.; Fei, M. J .; Libeu, C. P.; Mizushima,
T.; Yamagushi, H.; Tomizaki, T.; Tsukihara, T. Science, 1998, 280,
1723.
(2) (a) Gennis, R. B. Biophys. Biochim. Acta 1998, 1365, 241. (b)
MacMillan, F.; Kannt, A.; Behr, J .; Prisner, T.; Michel, H. Biochemistry
1999, 38, 9179. (c) Proshlyakov, D. A.; Pressler, M. A.; Babcock, G. T.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8020. (d) Proshlyakov, D. A.;
Pressler, M. A.; DeMaso, C.; Leykam, J . F.; DeWitt, D. L.; Babcock, G.
T. Science 2000, 290, 1588. (e) Sucheta, A.; Szundi, I.; Einarsdottir,
O. Biochemistry 1998, 37, 17905. (f) Collman, J . P.; Zhong, M.;
Constanzo, S.; Zhang, C. J . Org. Chem. 2001, 66, 8252. (g) Collman,
J . P.; Wang, Z.; Zhong, M.; Zeng, L. J . Chem. Soc., Perkin Trans. 1
2000, 8, 1217. (h) Aki, M.; Ogura, T.; Naruta, Y.; Le, TH.; Sato, T.;
Kitagawa, T. J . Phys. Chem. A 2002, 106, 3436. (i) Cappuccio, J . A.;
Ayala, I.; Elliott, G. I.; Szundi, I.; Lewis, J .; Konopelski, J . P.; Barry,
B. A.; Einarsdottir, O. J . Am. Chem. Soc. 2002, 124, 1750. (j) Kamaraj,
K.; Kim, E.; Galliker, B.; Zakharov, L. N.; Rheingold, A. L.; Zuberbu-
hler, A.; Karlin, K. D. J . Am. Chem. Soc. 2003, 125, 6028.
These two strategies have advantages and disadvan-
tages regarding (a) yields of introducing the first imida-
zole leading to 8m on o ([1 + 2] approach) or 9bis ([2 + 1]
approach), (b) byproduct formation and recycling, (c)
yields of introducing the second imidazole, (d) chromato-
graphic separation of polar porphyrin intermediates from
the polar porphyrin starting materials, and (e) chromato-
graphic separation of regioisomers of polar porphyrins.
All of these issues are compared for each approach in
order to determine which offers the best compromise to
these problems and gives an optimum pathway to obtain
1.
(4) (a) Collman, J . P.; Broring, M.; Fu, L.; Rapta, M.; Schwenniger,
R.; Straumanis, A. J . Org. Chem. 1998, 63, 8082. (b) Collman, J . P.;
Broring, M.; Fu, L.; Rapta, M.; Schwenniger, R. J . Org. Chem. 1998,
63, 8084. (c) Collman, J . P.; Sunderland, C.; Boulatov, R. Inorg. Chem.
2002, 41, 2282.
(5) Chang, J . H.; Lee, K. W.; Nam, D. H.; Kim, W. S.; Shin, H. Org.
Process Res. Dev. 2002, 6, 674.
(3) (a) Boulatov, R.; Collman, J . P.; Shiryaeve, 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.; Boulatov,
R.; Sunderland, C. J . In The Porphyrin Handbook; Academic Press:
Boston, 2003; Vol. 11, Chapter 63, pp 1-49. (d). Collman, J . P.;
Fudickar, W. Inorg. Chem. 2003, 42, 3384.
10.1021/jo0499625 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004
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J . Org. Chem. 2004, 69, 3546-3549