Regioselective Postsynthetic Modification of Phenylalanine Side Chains of Peptides Leading to Uncommon ortho-Iodinated Analogues

Article abstract of DOI:10.1002/anie.200352464

A convenient and direct iodination of Phe residues in peptide sequences was observed upon treatment with IPy₂BF₄. The experimental conditions were optimized (see scheme) and the role of the peptidyl fragment to drive the formation of

Full text of DOI:10.1002/anie.200352464

Angewandte
Chemie
Iodination
Regioselective Postsynthetic Modification of
Phenylalanine Side Chains of Peptides Leading to
Uncommon ortho-Iodinated Analogues**
Gemma Espuæa, Gemma Arsequell, Gregorio Valencia,
JosØ Barluenga,* Julia M. Alvarez-GutiØrrez,
Alfredo Ballesteros, and JosØ M. Gonzµlez
Interest in therapeutic drugs derived from natural peptides
has been steadily increasing as diversity in peptides can be
easily implemented by well-established combinatorial
[*] Prof. Dr. J. Barluenga, Dr. J. M. Alvarez-GutiØrrez, Dr. A. Ballesteros,
Dr. J. M. Gonzµlez
Inst. Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C., Universidad de Oviedo
33071 Oviedo (Spain)
Fax: (+34)98-5103450
E-mail: Barluenga@sauron.quimica.uniovi.es
Dr. G. Espuæa, Dr. G. Arsequell, Dr. G. Valencia
Unit of Glycoconjugate Chemistry, I.I.Q.A.B.-C.S.I.C.
Jordi Girona 18–26, 08034 Barcelona (Spain)
Fax: (+34)93-2045904
[**] This research was partially supportedby the Spanish MCYT (Grant
BQU2001-3853) andthe Fundación la Caixa (Project Reference 00/
010-00 of the IV Program of Grants for Research on Neuro-
degenarative Diseases of the Fundación La Caixa).
Supporting information for this article (experimental procedures
andspectral andchromatographic data for 1–6a, 1–2b, and 7) is
available on the WWW under http://www.angewandte.org or from
the author.
Angew. Chem. Int. Ed. 2004, 43, 325 –329
DOI: 10.1002/anie.200352464
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325

Communications
chemistry techniques[1] and because effective ways to improve
their bioavailability and resistance to metabolic breakdown
by peptidomimetic approaches were found.[2] Among the
different strategies to facilitate entry to new conformationally
restricted peptidomimetic structures and novel ways of
diversity generation,selective and efficient manipulation
methods of either the backbone[3] or the various side-chain
functions[4] of already preformed peptide sequences are being
investigated. These postsynthetic modifications of peptides
avoid the use of preformed amino acid building blocks and a
linear synthesis for every analogue,which has been the basis
of many structure–activity relationship (SAR) studies in
peptide chemistry.[5] Thus,these newer drug-discovery
approaches depart from a single presynthesized peptide
sequence that can be conveniently modified (by applying
different types of reactions or the same reaction with different
substrates) to yield a series of homologous derivatives in a
parallel fashion.
Scheme 1. Postsynthetic modification of a phenylalanine residue in
peptides by sequential iodination/cross-coupling reactions.
To search for suitable solvents,reaction conditions,
peptide/iodonium stoichiometries,and potential acid cata-
lysts,the well-known and readily available dipeptide sweet-
ener aspartame[12] (1) and two closely related analogues were
selected (Scheme 2). The choice was made to check for
possible effects on the iodination reaction of the relative
positions of the functional groups in the proximity of the aryl
group of Phe.
Among the known postsynthetic modifications that could
be applied to implement these techniques,the Suzuki,Heck,
and Stille type of reactions[6] are especially interesting
because Pd0 catalysis does not compromise peptide stability
and is compatible with the multifunctional character of
peptides.[7] A common feature among these methods is the
need for mainly brominated and iodinated aromatic sub-
strates. To date,general reaction conditions for aromatic
electrophilic halogenations of amino acid derivatives and
other simple organic molecules are too harsh and result in
oxidation and degradation when applied to peptides. This is
the main reason for the limited number of methods available
for the halogenation of aromatic side chains of presynthesized
peptides.[8] In the case of iodination,electrophilic aromatic
reagents and milder conditions are only known for the more
activated phenolic moiety of Tyr residues,which can be
performed,for instance,by the chloramine T method [9] or by
the use of the mild and selective iodinating reagent,bis(pyr-
idine) iodonium tetrafluoroborate (IPy2BF4),[10] as reported
by our group.[11] These iodination methods have never been
adapted for the non-activated aromatic side chains of Phe in
peptides and direct iodination reactions of such presynthe-
sized peptides have yet to be described. Alternatively,current
synthetic methods for halogenated peptides make use of
suitable halogenated amino acid building blocks in stepwise
linear synthesis protocols. However,the scope of these
procedures is restricted by the cost and the number of
commercially available halogenated isomeric derivatives of
Tyr and Phe. In fact, ortho-halogenated Phe derivatives are
not commercially available and are also not easy to prepare,
as direct electrophilic substitutions always render the para
derivatives as main reaction products.
Scheme 2. Dipeptide models.
We searched for good reaction media that included
dichloromethane as the solvent. Trifluoroacetic acid,a
broadly used reagent in peptide synthesis,proved to be very
valuable as it not only solubilized the peptides,but also
provided the required acidic conditions to activate the
iodonium reagent. Under these original conditions
(Table 1),the reagent is highly effective,and produces the
monoiodinated peptide derivatives in short reaction times
and preserves peptide integrity. Analysis of crude reaction
Table 1: Monoiodination of model dipeptides promoted by IPy2BF4 in the
presence of TFA (10%) in CH2Cl2.
Herein we report innovative protocols for the use of
IPy2BF4 as the first solution for the direct halogenation
of phenylalanine-containing peptide sequences and the
unusual ortho selectivity accompanying this iodination
reaction. Furthermore,by overcoming the limitations men-
tioned above,these results could provide a solution to
Dipeptide
ortho/para[a]
t [h]
Conversion [%][b]
1
2
3
3:1
3:1
14:1
0.5
0.5
0.5
87
91
90
establish
a
powerful postsynthetic modification of
such peptides with known Pd0 cross-coupling reactions
(Scheme 1).
[a] Determinedby NMR spectroscopic analysis. [b] Conversion deter-
minedby HPLC.
326
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Chemie
products by 1H NMR spectroscopy and analytical HPLC
showed that mixtures of ortho/para-iodinated regioisomers
(3:1) were obtained as the only reaction products of 1 and 2.
In contrast,the protected analogue 3 gave a 14:1 ratio
(Table 1). These results were confirmed by isolation of each
isomer by semipreparative HPLC and characterization by
1H and 13C NMR spectroscopy and MALDI-TOF MS tech-
niques. This ortho selectivity had not been observed previ-
ously in aromatic iodination reactions of simple arene
compounds,[13] or even in different protected derivatives of
phenylalanine.[11a]
The attractiveness of such a simple entry to the elusive
ortho-iodo isomer of a phenylalanine derivative prompted us
to search for more regioselective reaction conditions. We
found that other iodonium-activating acids typically used with
IPy2BF4 improved the selectivity. The best results were found
when we used the same relative amount of TFA (10%) and
added the iodonium reagent along with 2 equivalents of
HBF4. Quantitative conversions were observed and the ortho
isomer was favored over the para congener (20:1 in the case of
2). Most interestingly,the ratio was concentration-dependent:
the ortho/para ratio increased substantially when the reaction
was diluted tenfold (Table 2). The proportion of iodonium to
HBF4 (1:2) was very critical to secure high regioselectivity,but
did not influence the conversion.[14]
Scheme 3. Biologically activity peptides. Nle=norleucine.
b) 5 is a tripeptide that exhibits chemotactic properties,[17] and
c) 6 was chosen as a model pentapeptide sequence. All three
oligopeptides were synthesized by conventional Fmoc solid-
phase protocols. Remarkably,the results observed with these
oligopeptides correspond well to those discussed above for
the dipeptides (Table 3). In all cases,peptide integrity was
Table 3: Monoiodination of biologically active peptides.
Peptides
Method[a]
ortho/para[b]
t [h]
Conversion [%][c]
5
5
4
4
6
6
A
B
A
B
A
B
4:1
7:1
3:1
13:1
1:1
8:1
0.5
3
0.5
3
0.5
0.5
100
100
84
100
84
Table 2: Monoiodination of model dipeptides promoted by IPy2BF4 in
the presence of TFA (10%) in CH2Cl2 andHBF 4 (2 equiv).
90
[a] MethodA: 100 mg in CH 2Cl2/TFA (10:1); IPy2BF4 (1.5 equiv). Method
B: 100 mg in CH2Cl2/TFA (100:10); IPy2BF4/HBF4 (1:2 equiv). [b] Deter-
minedby NMR spectroscopic analysis. [c] Conversion basedon HPLC.
Peptide
ortho/para[a]
t [h]
Conversion [%][b]
1
2
3
20:1
40:1
23:1
0.5
0.5
0.5
100
100
100
preserved,very good conversions were observed,and the
peptides yielded mixtures of iodinated isomers as the main
[a] Determinedby NMR spectroscopic analysis. [b] Conversion deter-
minedby HPLC.
reaction products. Again,addition of HBF (method B) was
4
very significant in increasing the ortho/para ratios. The
reaction has proved successful for peptides presenting a
single Phe residue. More electron-rich arenes,such as those
present in the side chains of Tyr,Trp,and His,are iodinated
under these conditions.
The ortho/para ratio obtained from 2 is twice that
obtained from the closely related peptide 1 and from the
diprotected analogue 3 (Table 2). This is a good indication of
the influence of the structural features surrounding Phe side
chains on the regioselectivity of this process.
As mentioned above, ortho-iodo derivatives of Phe-
containing peptides such as those described herein cannot
be prepared by direct iodination or by conventional stepwise
peptide elongation methods. Therefore,only para analogues
are reported in the literature.[15] Furthermore,the potential of
running the method on a preparative scale has also been
explored. Similar results were observed when the iodination
reaction of 2 was performed on a 1-gram scale under the
reactions conditions outlined in Table 2 (same ratio,86%
yield).
To illustrate possible applications of these iodinated
0
peptide intermediates,a Pd -catalyzed Suzuki-type biphenyl
synthesis was attempted (Scheme 4).[7e] The unsually iodi-
nated ortho isomer 1a of aspartame was treated with a simple
phenyl boronic acid to yield the constrained ortho-phenyl
aspartame derivative 7 in good conversion.[18]
In conclusion,a new peptide postsynthetic modification is
described. The method provides the first iodination protocol
for aromatic side chains of Phe-containing peptides. The
procedure is effected by acid-triggered aromatic electrophilic
substitution with IPy2BF4 to provide ortho/para-monoiodi-
nated mixtures of peptide analogues mostly quantitatively
while preserving peptide integrity. The reaction is sequence-
and acid-dependent,a feature that can be used to access the
otherwise unavailable ortho-iodinated Phe derivatives
Because of these encouraging results,three Phe-contain-
ing peptides were chosen to test the reaction (Scheme 3): a) 4
is a free tetrapeptide used as an opioid peptide precursor,[16]
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Communications
Keywords: amino acids · cross-coupling · iodine ·
.
palladium · peptides
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Experimental Section
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mixture of CH2Cl2 (10 mL) and TFA (1 mL). IPy2BF4 (0.51 mmol)
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RP-HPLC: C18 (Lichrosorb,250 ” 4 mm). Solvents: A = 0.1%
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3
3
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328
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