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Modular Synthesis of Ruthenium-Labeled Diaryl Ether Peptoids.

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Bioinorganic Chemistry
Modular Synthesis of Ruthenium-Labeled Diaryl
Ether Peptoids**
Alexander Schmid and Thomas Lindel*
Dedicated to Professor Wolfgang Steglich
on the occasion of his 70th birthday
Research on peptide-like (“peptoid”[1]) compounds is of basic
relevance to bioorganic and bioinorganic chemistry. Important examples include the fascinating b- and g-peptides.[2]
Radioactive peptide metal complexes constitute a special
case, promising the sensitive, selective detection or perhaps
even the destruction of tumor cells; the biochemical selectivity is efficiently combined with high-energy radiation. The
most prominent example used in nuclear medicine is 111In
radio-labeled octreotide which binds to receptors of the
regulatory hormone somatostatin.[3] Beck et al. have reviewed
the transition-metal complexes of amino acids and peptides as
an emerging area of bioorganometallic chemistry.[4]
Peptides are normally labeled after their assembly, more
recently this has also been possible at specially functionalized
sites.[5] In general, however, the introduction of a large metal
label into a small bioactive peptide may alter or even abolish
its properties. Therefore, it would be desirable to be able to
select from a pool of peptoids all of which are already metal
labeled. Ruthenium isotopes appear to be suitable for labeling, because their half-lives range three days to one year[6] and
because they can be incorporated into peptoids as chemically
inert sandwich complexes. Ruthenium metallopharmaceuticals have recently been reviewed,[7, 8] The potential of
ruthenium isotpes[6] for applications in radiopharmacy had
been recognized early on, but in the peptide area only small
molecules, such as b-ruthenocenylalanine could be characterized.[20] Several research groups, in particular Pearson
et al., used [RuCp]+-(Cp = C5H5) monolabeled peptoid diaryl
ethers as intermediates for the synthesis of natural products.[9]
Sheldrick et al. converted dipeptides and diketopiperazines
into doubly [RuCp*]+-(Cp* = C5Me5) labeled peptoids.[10]
Ruthenium(iii) chloride can directly be used as the source
of radioactive, inert ruthenium sandwich complexes, because
[RuCp*]+ sandwich complexes of benzenoid arenes can be
synthesized in a single step.[13] Herein we report the synthesis
and characterization of a complete initial sequence for the
modular assembly of metal-labeled peptoids with a new
[*] Dipl.-Chem. A. Schmid, Prof. Dr. T. Lindel
Department of Chemistry
Butenandtstrasse 5–13, 81377 Munich (Germany)
Fax: (+ 49) 89-218-077-734
[**] We thank the Degussa AG and Macherey-Nagel GmbH & Co KG for
Supporting information for this article is available on the WWW
under or from the author.
Angew. Chem. Int. Ed. 2004, 43, 1581 –1583
architecture. This method, based on solid-supported processes, has the potential to be used in combinatorial chemistry.
The approach relies on the two-fold use of [RuCp*]+ as both
metal label and as activator of chloroaromates towards
nucleophilic substitution by phenolates.[11] The resulting
[RuCp*]+-complexed diaryl ether partial structures will
enhance the protease stability of the peptoid.[12]
Figure 1 outlines the design of new oligopeptoids with
alternating diaryl ether and amide bonds. Ruthenium labels
Figure 1. Modular architecture of ruthenium-labeled peptoids with
alternating amide and diaryl ether bonds. After the first four building
blocks, repetitive elongation steps are possible.
are incorporated with every second building block, which
allows a high degree of metal-labeling. Unlike the assembly of
regular peptides, four different elongation steps have to be
performed to give a quadruple before repeating the synthetic
cycle. Consequently, the synthesis of the initial tetrapeptoid is
a key goal in developing an automated method for the
modular synthesis of this new type of bioorganometallic
Scheme 1 gives the synthesis of the doubly [RuCp*]+labeled diaryl ether tetrapeptoid 7. As h5-ligand, Cp* was
chosen instead of Cp because [RuCp*(h6-arene)]+ complexes
can be assembled in a one-pot procedure starting from
RuCl3·x H2O,[13] whereas the analogous Cp complexes require
a four-step sequence.[14] As building blocks of the target
tetrapeptoid 7 we used N-Boc-OBn-tyrosine (1), [RuCp*]+complexed p-chlorophenylethylamine (2), tyramine (4), and
the [RuCp*]+ complex of N-Boc-protected p-chlorophenyl
alanine (6). The free carboxylic acid 6 is best synthesized via
its ethyl ester[13b] which is then selectively hydrolyzed using
LiOH in THF:H2O (4:1) at 0 8C for 1 h.
In the first amide coupling step, the acid 1 was converted
into its pentafluorophenyl ester with in situ generated tertbutyl pentafluorophenyl carbonate.[15] Reaction with the free
[RuCp*]+-complexed amine 2 provided the dipeptoid 3.
Treatment of 3 with tyramine (4) provided the [RuCp*]+
diaryl ether tripeptoid 5 in good yield. Reaction of 5 with 6 by
the EDCI/HOBt method completed the synthetic cycle and
gave the first tetrapeptoid 7 with two [RuCp*]+-sandwich
labels. The benzyl group currently introduced with the first
building block as a protecting group may later be replaced by
a linker to solid phases.
DOI: 10.1002/anie.200352927
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 2. HPLC elution profile of a comparative mixture of the regioisomeric tripeptoids 5 and 8, and of the tetrapeptoid 7. For conditions
see ref. [18].
mixture of the [RuCp*]+-labeled peptoids 5, 7, and 8 (see
Figure 2).
The new chromatography method allowed us to investigate side products, specifically of the attack of the ambident
nucleophile 4 on the dipeptoid 3. We were able to isolate and
fully characterize the tripeptoid 8 (a regioisomer of 5) with an
Scheme 1. Synthesis of the doubly ruthenium-labeled tetrapeptoid 7
a) 1, pentafluorophenol (1 equiv), Boc2O (1 equiv), pyridine, 23 8C, 4 h;
then 2, 1 day, 23 8C, 1 day, 50 8C, 75 %. b) 4, [18]crown-6, KOtBu,
THF:MeCN (1:1), 30 min, 0 8C; then transfer to precooled solution of
3, 78 8C, 90 min, then 23 8C, 15 min, 64 %. c) 6, HOBt, THF, EDCI,
0 8C, 15 min; then 5 in THF, iPr2NEt, 0 8C to 23 8C, 24 h, 80 %; Boc =
tert-butoxycarbonyl, HOBt = N-hydroxybenzotriazole, EDCI = N-ethylN’-(3-dimethylaminopropyl) carbodiimide.
Larger, permanently charged peptoids, such as the
tripeptoid 5 and the tetrapeptoid 7, require improved
chromatography procedures for analysis and purification.
The use of aminopropyl silica solid phases was already an
important step towards the difficult purification of peptoid
[RuCp]+ complexes.[16] We now discovered that unsurpassed
separation of the cationic [RuCp*]+ sandwich complexes can
be achieved by using the silica-based Nucleosil SA stationary
phase which has both adsorption and ion-exchange properties.[17] Anions and non-charged components of the reaction
mixture eluted easily when using pure methanol as the mobile
phase. The cationic products were then eluted employing a
sodium acetate gradient in methanol.[18] The efficiency of this
approach is shown by the separation of the three-component
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[RuCp*]+ alkylarylamine partial structure. The pronounced
NMR high-field shift of the protons of the benzenoid part of
the sandwich structure of 8 (compared to the diaryl ether 5),
could indicate partial h5 coordination and a double bond to a
deprotonated nitrogen atom, as is observed for the corresponding sandwich complexes of free phenols.[19] However,
the 1H NMR spectrum clearly shows a signal at d =
4.29 ppm,which was assigned to an NH proton by COSY,
HSQC, and HMBC experiments, thus confirming h6 coordination of the C6 ring. The formation of 8 is best avoided by
keeping the reaction mixture at 78 8C for at least 90 min and
using 1.1 equivalents of 4. The [RuCp*]+ sandwich complexes
did not tend to decompose in aqueous solution or on exposure
to air, the exception being the free amine 2 which should be
prepared by deprotection of its Boc-protected precursor
immediately prior to use.
Our approach offers the advantage of full control of the
frequency and positions of [RuCp*]+ complexation. From the
synthesis of the tetrapepoid 7, repetitive steps are envisaged.
The steric bulk of the Cp* unit restricts the number of
possible conformations and we expect to find unusual
secondary structures in the longer chain analogues.
Received: September 22, 2003 [Z52927]
Angew. Chem. Int. Ed. 2004, 43, 1581 –1583
Keywords: bioinorganic chemistry · diaryl ethers ·
metal-labeling · peptoids · sandwich complexes
NaOAc·3 H2O (0.74 m) within 40 min, then MeOH/NaOAc·3 H2O (0.74 m) for 10 min. UV detection at 239 nm.
[19] L. Djakovitch, F. Moulines, D. Astruc, New J. Chem. 1996, 20,
1071 – 1080.
[20] W. H. Soine, C. E. Guyer, F. F. Knapp, Jr., J. Med. Chem. 1984,
27, 803 – 806.
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“picture”) was originally restricted to oligomers of N-substituted
glycines: R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D.
Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg,
C. K. Marlowe, D. C. Spellmeyer, R. Tan, A. D. Frankel, D. V.
Santi, F. E. Cohen, P. A. Bartlett, Proc. Natl. Acad. Sci. USA
1992, 89, 9367 – 9371.
[2] a) D. Seebach, T. Sifferlen, D. J. Bierbaum, M. Rueping, B. Jaun,
B. Schweizer, J. Schaefer, A. K. Mehta, R. D. O'Connor, B. H.
Meier, M. Ernst, A. GlNttli, Helv. Chim. Acta 2002, 85, 2877 –
2917; b) D. Seebach, L. Schaeffer, M. Brenner, D. Hoyer, Angew.
Chem. 2003, 115, 800 – 802; Angew. Chem. Int. Ed. 2003, 42, 776 –
777, and references therein.
[3] a) A. Janecka, M. Zubrzycka, T. Janecki, J. Pept. Res. 2001, 53,
91 – 107; b) A. J. van der Lely, W. W. de Herder, E. P. Krenning,
D. J. Kwekkeboom, Endocrine 2003, 20, 307 – 311.
[4] K. Severin, R. Bergs, W. Beck, Angew. Chem. 1998, 110, 1722 –
1743; Angew. Chem. Int. Ed. 1998, 37, 1635 – 1654.
[5] W. E. P. Greenland, K. Howland, J. Hardy, I. Fogelman, P. J.
Blower, J. Med. Chem. 2003, 46, 1751 – 1757, and references
[6] 97Ru (half-life 2.89 days, electron capture), 103Ru (39.27 days, b ),
and 106Ru (1.02 years, b ); Handbook of Chemistry and Physics,
76th ed. (Ed.: D. R. Lide), CRC, Boca Raton, FL, 1995, pp. 11 –
[7] D. B. Grotjahn, Coord. Chem. Rev. 1999, 190–192, 1125 – 1141.
[8] M. J. Clarke, Coord. Chem. Rev. 2003, 236, 209 – 233.
[9] a) A. J. Pearson, J. G. Park, S. H. Yang, Y. H. Chuang, J. Chem.
Soc. Chem. Commun. 1989, 1363 – 1364; b) A. J. Pearson, S.
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1819 – 1822, and references therein; d) A. Marchetti, J. M.
Ontoria, V. G. Matassa, Synlett 1999, 1, 1000 – 1002; e) S.
Venkatraman, F. G. Njoroge, V. Girijavallabhan, A. T. McPhall,
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[10] a) W. S. Sheldrick, A. Gleichmann, J. Organomet. Chem. 1994,
470, 183 – 187; b) A. J. Gleichmann, J. M. Wolff, W. S. Sheldrick,
J. Chem. Soc. Dalton Trans. 1995, 1549 – 1554.
[11] a) A. N. Nesmeyanov, N. A. Vol'kenau, I. N. Bolesova, L. S.
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[12] H. Eickhoff, G. Jung, A. Rieker, Tetrahedron 2001, 57, 353 – 364.
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197; b) A. Schmid, H. Piotrowski, T. Lindel, Eur. J. Inorg. Chem.
2003, 2255 – 2263.
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b) B. M. Trost, C. M. Older, Organometallics 2002, 21, 2544 –
[15] M. Breslav, N. Doviborov, F. Naider, J. Chem. Res. Synop. 1994,
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3965; b) D. Leone-Stumpf, T. Lindel, Eur. J. Org. Chem. 2003,
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[17] Nucleosil SA (Macherey-Nagel) is functionalized with n-propylbenzenesulfonic acid groups and has mostly been used for the
separation of inorganic cations: M. M. Muenter, K. C. Stokes,
R. T. Obie, J. R. Jezorek, J. Chromatogr. A 1999, 844, 39 – 51, and
references therein.
[18] Stationary phase: Macherey-Nagel EC 250/4 Nucleosil 100-5 SA
(length 25 cm, diameter 0.4 cm, particle size 5 mm). Mobile
phase: MeOH (10 min), then gradient MeOH to MeOH/
Angew. Chem. Int. Ed. 2004, 43, 1581 –1583
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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