Complete N-1 regiocontrol in the formation of N-arylimidazoles. Synthesis of the active site His-Tyr side chain coupled dipeptide of cytochrome c oxidase.

Article abstract of DOI:10.1021/ol006271w

Under catalysis by copper(II) acetate, complete regiocontrol (N-1 versus N-3) was obtained in the arylation of substituted imidazoles with aryllead(IV) reagents. The mildness of the reaction conditions (rt, no added base) allows for the first synthesis of

Full text of DOI:10.1021/ol006271w

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3055-3057
Complete N-1 Regiocontrol in the
Formation of N-Arylimidazoles.
Synthesis of the Active Site His-Tyr
Side Chain Coupled Dipeptide of
Cytochrome c Oxidase†
,‡
Gregory I. Elliott and Joseph P. Konopelski*
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064
joek@chemistry.ucsc.edu
Received June 28, 2000
ABSTRACT
Under catalysis by copper(II) acetate, complete regiocontrol (N-1 versus N-3) was obtained in the arylation of substituted imidazoles with
aryllead(IV) reagents. The mildness of the reaction conditions (rt, no added base) allows for the first synthesis of the histidine-tyrosine side
chain coupled dipeptide found in the active site of cytochrome c oxidase.
N-Arylimidazoles are important compounds in medicinal
research.1 A significant number of these structures are
therapeutically useful, and many others are in the process
of active study for biomedical applications. Targeted thera-
peutic areas include thromboxane synthase inhibitors,2
AMPA receptor antagonists,3 AMP phosphodiesterase inhibi-
tors,4 cardiotonic agents,5 and antiglaucoma agents.6 Con-
sequently, there is a need for efficient and very mild methods
for their construction.
N-Arylimidazoles have been synthesized by nucleophilic
aromatic substitution2b,3,4b,5a,7 and Ullmann-type couplings.2a,c,d,4,6
Aromatic substitution requires the use of electron-withdraw-
ing substituents, which dampens this methodology. The
Ullmann-type couplings are normally done at high temper-
ature, which limits the use of sensitive compounds. Likewise,
Buchwald8 has demonstrated condensation between aryl-
halides and imidazoles with catalytic amounts of (CuOTf)2‚
benzene/1,10-phenanthroline/dba/Cs2CO3 at temperatures in
the range of 110-125 °C. The necessity of such high
temperatures and base is expected to limit the utility of this
approach with base-sensitive compounds.9 Collman10 re-
† Taken in part from Konopelski, J. P.; Elliott, G. I. Abstracts of Papers,
219th National Meeting of the American Chemical Society, San Francisco,
CA, March 26-30, 2000; American Chemical Society: Washington, DC;
paper ORGN 28.
‡ Phone 831-459-4676, fax 831-459-2935.
(1) Carganio, G.; Cozzi, P. Il Farmaco 1991, 46, 209-231.
(2) (a) Jacobs, C.; Frotscher, M.; Dannhardt, G.; Hartmann, R. W. J.
Med. Chem. 2000, 43, 1841-1851. (b) Cozzi, P.; Carganico, G.; Fusar,
D.; Grossoni, M.; Menichincheri, M.; Pinciroli, V.; Tonani, R.; Vaghi, F.;
Salvati, P. J. Med. Chem. 1993, 36, 2964-2972. (c) Martinez, G. R.; Walker,
K. A. M.; Hirshfield, D. R.; Bruno, J. J.; Yang, D. S.; Maloney, P. J. J.
Med. Chem. 1992, 35, 620-628. (d) Iizuka, K.; Akahane, K.; Momose,
D.; Nakazawa, M.; Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara,
I.; Iguchi, Y.; Okada, T.; Taniguchi, K.; Miyamoto, T.; Hayashi, M. J. Med.
Chem. 1981, 24, 1139-1148.
(3) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J. Med.
Chem. 1996, 39, 3971-3979.
(4) (a) See ref 2c. (b) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.;
Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988, 31, 2136-2145.
(5) (a) Gu¨ngo¨r, T.; Fouquet, A.; Teulon, J.-M.; Provost, D.; Cazes, M.;
Cloarec, A. J. Med. Chem. 1992, 35, 4455-4463. (b) Sircar, I.; Weishaar,
R. E.; Kobylarz, D.; Moos, W. H.; Bristol, J. A. J. Med. Chem. 1987, 30,
1955-1962. (c) Sircar, I.; Weishaar, Duell, B. L.; Bobowski, G.; Bristol,
J. A.; Evans, D. B. J. Med. Chem. 1985, 28, 1405-1413.
(6) Lo, Y. S.; Nolan, J. C.; Maren, T. H.; Welstead, W. J., Jr.; Gripshover,
D. F.; Shamblee, D. A. J. Med. Chem. 1992, 35, 4791-4794.
(7) Bambal, R.; Hanzlik, R. B. J. Org. Chem. 1994, 59, 729-732.
(8) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 2657-2660.
10.1021/ol006271w CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000

ported the room-temperature copper-catalyzed condensation
of commercially available arylboronic acids with imidazoles.
While this technology is quite mild, it requires 2 equiv of
the arylboronic acid and is therefore limited by economics.
In addition, both the Collman10 and Buchwald8 procedures
afford mixtures of regioisomers (<5:1 selectivity) when the
reaction is performed on a 4-substituted imidazole.11
Our interest in unusual amino acid synthesis12 directed our
attention to the recent discovery of such a target in the active
site of cytochrome c oxidase. Cytochrome c oxidase is a
heme-copper oxidase and the terminal respiratory enzyme
involved in the reduction of oxygen to water.13,14 The
published amino acid sequence of cytochrome c oxidase was
recently modified, based upon high resolution X-ray data
(Figure 1).15 It was determined that two individual amino
This unprecedented system is expected to afford the
tyrosine-OH unusual physical properties (pKa, redox poten-
tial, etc.) important for the enzymatic event.17 To date, no
detailed information on the spectroscopic or chemical
properties of this cross-linked dipeptide is available,18 and
synthesis of the system is imperative.
Our recent research in organolead reagents19 prompted us
to consider their use in the synthesis of this His-Tyr
dipeptide. The most common use for organolead reagents20
is for the formation of sp2-sp3 quaternary carbon-carbon
bonds.21 Lead reagents are easily handled, and as previously
reported the existence of residual lead is in the background
range after workup.19,22 Organolead reagents also have been
shown to N-arylate when used in conjunction with a copper
catalyst.23 They are easily prepared from the corresponding
tin compound24 or by direct plumbation.25 To date, the
N-arylation of imidazole by a lead reagent has only occurred
with p-tolyllead triacetate26 and was performed at 90 °C in
a mixture of methylene chloride-DMF. Herein we report
the arylation of imidazoles with organolead(IV) reagents. The
reaction proceeds with equimolar ratios of the coupling
substrates at room temperature in the presence of catalytic
amounts of Cu(OAc)2 and results in exclusiVe formation of
the 1,4-disubstituted imidazoles in all cases. The reaction is
mild enough to afford, for the first time, a suitably protected
version of the His-Tyr dipeptide found in the active site of
cytochrome c oxidase.
We initially probed the temperature requirements of the
reaction between p-methoxyphenyllead triacetate (1) and
imidazole (2). Gratifyingly, an 85% yield of coupled material
(3) was obtained within 3 h when the reaction was performed
at room temperature with 10 mol % of copper(II) acetate in
methylene chloride (eq 1).27
Figure 1. Cyclic pentapeptide from active site of cytochrome c
oxidase: (a) PDB structure; (b) standard line drawing, arrow
indicates unusual side chain linkage.
acid residues [histidine (His240) and tyrosine (Tyr244)16]
critical to the active site were cross-linked by a covalent
C-N bond, thus creating a cyclic pentapeptide.
(9) Recently, researchers at Merck observed the loss of optical integrity
in the palladium-catalyzed coupling of vinylogous amides with an aryl halide
derived from phenylalanine. The base and temperature conditions of the
reaction (Cs2CO3, 80 °C) are similar to those employed in the Buchwald
procedure. See: Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org.
Lett. 2000, 2, 1109-1112.
(10) Collman, J. P.; Zhong, M. Org. Lett. 2000, 9, 1233-1236.
(11) Recently Collman reported that the reaction of 2-iodoanisole and
methylimidazole-4-carboxylate with catalytic CuOTf and Cs2CO3 at 100
°C affords a 40% isolated yield of only the 1,4-disubstituted imidazole.
See: Collman, J. P.; Wang, Z.; Zhong, M.; Zeng, L. J. Chem. Soc., Perkin
Trans. 1 2000, 1217-1221.
(12) (a) Hopkins, S. A.; Ritsema, T. A.; Konopelski, J. P. J. Org. Chem.
1999, 64, 7885-7889. (b) Chu, K. S.; Negrete, G. R.; Konopelski, J. P.;
Lakner, F. J.; Woo, N.-T.; Olmstead, M. M. J. Am. Chem. Soc. 1992, 114,
1800-1812.
(13) Ferguson-Miller, S.; Babcock, G. T. Chem. ReV. 1996, 96, 2889-
2907.
We next chose to investigate the regiocontrol of the
organolead(IV) protocol. The reaction between 4-methyl-
(17) Proshlyakov, D. A.; Pressler, M. A.; Babcock, G. T. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 8020-8025.
(18) A non-peptide mimic of the His-Tyr system has recently appeared.
See: McCauley, K. M.; Vrtis, J. M.; Dupont, J.; van der Donk, W. A. J.
Am. Chem. Soc. 2000, 122, 2403-2404.
(19) Elliott, G. I.; Konopelski, J. P.; Olmstead, M. M. Org. Lett. 1999,
1, 1867-70.
(20) (a) Pinhey, J. T. Pure Appl. Chem. 1996, 68, 819-824. (b) Pinhey,
J. T. Aust. J. Chem. 1991, 44, 1353-1382.
(14) For recent efforts toward understanding the chemistry of the Fe-Cu
reactive center of cytochrome c oxidase, see: (a) Ju, T. D.; Ghiladi, R. A.;
Lee, D.-H.; van Strijdonck, G. P. F.; Woods, A. S.; Cotter, R. J.; Young,
V. G., Jr.; Karlin, K. D. Inorg. Chem. 1999, 38, 2244-2245. (b) Collman,
J. P.; Rapta, M.; Bro¨ring, M.; Raptova, L.; Schwenninger, R.; Boitrel, B.;
Fu, L.; L’Her, M. J. Am. Chem. Soc. 1999, 121, 1387-1388.
(15) Yoshikawa, S.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.;
Yamashita, E.; Inoue, N.; Yao, M.; Fei, M. J.; Libue, C. P.; Mizushima,
T.; Yamaguchi, H.; Tomizaki, T.; Tsukihara, T. Science 1998, 280, 1723-
1729. (b) Ostermeier, C.; Harrenga, A.; Ermler, U. Michel, H. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 10547-10553.
(21) Konopelski, J. P.; Hottenroth, J. M.; Mo´nzo-Oltra, H.; Ve´liz, E.
A.; Yang, Z.-C. Synlett 1996, 609-611.
(22) Paquette has recently disclosed the use of Pb(OAc)4 for the removal
of colored impurities from olefin metathesis reactions and has presented
evidence for very low residual lead in the final product. See: Paquette, L.
A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Me´ndez-Andino, J.;
Yang, J. Org. Lett. 2000, 2, 1259-1261.
(23) (a) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org.
Chem. 1996, 61, 5865-5870. (b) Lo´pez-Alvarado, P.; Avendan˜o, C.;
Mene´ndez, J. C. J. Org. Chem. 1995, 60, 5678-5682. (c) Barton, D. H.
R.; Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J. J. Chem. Soc., Perkin
Trans. 1 1991, 2095-2102.
(16) This numbering scheme is from the bovine sequence.
3056
Org. Lett., Vol. 2, No. 20, 2000

imidazole and phenyllead triacetate 4 could possibly afford
both the 1,4- and 1,5-disubstituted imidazoles, and both
compounds have been reported in the literature.28 In the
event, exclusive formation of the N-1 arylation product was
observed with a yield of 80% (eq 2). When the lead reagent
of the desired product. The coupling of 6 with 1 provided
the desired product as a single N-1 isomer in 68% yield.
The desired ortho phenol substituent was introduced with
the coupling of 6 to 5 and 7 in 46% and 49% yields,
respectively. Finally, the target dipeptide was obtained in
48% isolated yield as a single isomer through the reaction
of organolead reagent 8,21 derived from L-tyrosine, with 6.
To our knowledge, this is the first coupling of amino acids
mediated by lead reagents. No racemization is detected by
1H and 13C NMR for this coupling reaction.
was changed to a more electron rich system, such as 1 and
5, no change in selectivity was observed. The yields of these
coupling reactions are 85 and 61% for the isolation of the
respective N-1 aryl product. At the present time we are
uncertain if the lower yield for the ortho-substituent lead
reagent 5 is due to the bulkiness of the ortho-group or to a
poor transfer of the aryl group from lead to copper. A single-
crystal X-ray structure of 5 shows the oxygen atom of the
methoxy group in close proximity to the lead atom with weak
donation of electron density.29 This extra electron density
stabilizes the organolead reagent, which could slow the
transfer of the aromatic group.
In conclusion, our work constitutes the first examples of
an amino acid coupling mediated by organolead reagents.
The reaction conditions are quite mild (room temperature,
no additional base needed) and no racemization occurs. These
reaction conditions provide only N-1 regioselectivity, a
significant improvement over previous methods. Further
studies with the His-Tyr dipeptide reported herein are
underway and will be reported in due course.
With our reaction conditions developed, we moved to the
study of histidine derivatives as the imidazole fragment in
the coupling reaction, with the goal of assessing the level of
regiocontrol and chiral center integrity attendant in this
copper-catalyzed procedure. As the histidine partner we chose
Z-His-OMe (6), which is commercially available and pro-
vides an adequate protection scheme for further elaboration
Acknowledgment. We wish to thank the Petroleum
Research Fund (32051-AC1), administered by the American
Chemical Society, and the American Cancer Society (RPG-
93-017-06-CDD) for support of this work. In addition, we
gratefully acknowledge a Roche Biosciences (Palo Alto, CA)
Fellowship in Synthetic Organic Chemistry for G.I.E. Dis-
cussions with our colleague Professor OÄ lo¨f Einarsdo´ttir were
very important to the success of this project. Purchase of
the 500 MHz NMR used in these studies was supported by
funds from the Elsa U. Pardee Foundation and the National
Science Foundation (BIR-94-19409).
(24) Kozyrod, R. P.; Morgan, J.; Pinhey, J. T. Aust. J. Chem. 1985, 38,
1147-1153.
(25) Kozyrod, R. P.; Pinhey, J. T. Org. Synth. 1984, 62, 24-30.
(26) (a) See ref 23b. (b) Lo´pez-Alvarado, P.; Avenda˜no, C.; Mene´ndez,
J. C. Tetrahedron Lett. 1992, 33, 659-662.
(27) General procedure: Substituted imidazole (1 mmol) is stirred in
10 mL of methylene chloride at room temperature. To this solution is added
copper(II) acetate (0.1 mmol) along with aryllead tricarboxylate (1.4 mmol).
The blue solution, upon completion of time (3-14 h), is quench with 3
mL of a water-sodium sulfide solution. The reaction stirs for an addition
15 min. The black precipitate is passed through Celite. The solution is
extracted with methylene chloride (3 × 5 mL). The organic layer is dried
over sodium sulfate and concentrated in vacuo. Chromatography provides
the substituted arylimidazole.
Supporting Information Available: Experimental pro-
cedures and characterization data for products of the reactions
of 1, 5, 7, and 8 with compound 6 and the reactions of
4-methylimidazole with 1 and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
(28) Pavlik, J. W.; Connors, R. E.; Burns, D. S.; Kurzweil, E. M. J. Am.
Chem. Soc. 1993, 115, 7645-7652.
(29) Buston, J. E. H.; Compton, R. G.; Leech, M. A.; Moloney, M. G.
J. Organomet. Chem. 1997, 585, 326-330.
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