Postsynthetic modification of peptides: Chemoselective C-arylation of tryptophan residues

Article abstract of DOI:10.1002/chem.200902676

Born to be mild : The general, direct and selective C2 arylation of native Trp-containing peptides can be achieved by palladium-catalyzed C-H activation with aryl iodides in water, under microwave irradiation for a short time (see scheme). Under these mild conditions, the structural and stereochemical integrity of peptides is preserved.

Full text of DOI:10.1002/chem.200902676

DOI: 10.1002/chem.200902676
Postsynthetic Modification of Peptides: Chemoselective C-Arylation of
Tryptophan Residues
Javier Ruiz-Rodrꢀguez,[a] Fernando Albericio,*[a, c, d] and Rodolfo Lavilla*[a, b]
In recent years the model on which the pharmaceutical in-
dustry is based has undergone dramatic changes. Every year,
more biological entities are being accepted by the FDA and
other regulatory agencies. Furthermore, the most recent bio-
logical drugs contain non-natural building blocks, as it has
been shown in peptides, but also in antibodies and pro-
teins.[1] Thus, the development of new methodologies for the
selective and straightforward chemical modification of bio-
molecules is a scientific challenge that has tremendous im-
plications in drug discovery, as well as in chemical biology
and proteomics. The chemical methods to perform these
modifications in native peptides or proteins are normally re-
stricted to a reduced set of reactions which nearly always in-
volve the nucleophilic side chains of amino acids such as
Lys, Cys, Asp or Glu.[2]
promised because of the requirements of having previously
functionalized non-natural residues. Among the synthetic
transformations capable of handling delicate peptides, the
rhodium-catalyzed conjugate addition of aryl siloxanes and
boronates to dehydroalanine residues,[4] the stepwise aryla-
tion of Phe and Tyr side chains in peptides through a iodina-
tion-Suzuki coupling sequence[5] or the site-selective O- and
N-arylation of Tyr and Trp residue[6] are the most illustrative
examples. Particularly demanding is the case of Trp, a key
amino acid for activity–-rarely present in proteins (around
1%)—together with its photo-electronic properties, structur-
al and biological roles make it an ideal site for chemical
modification. Several approaches have been explored and,
although with restrictions, they show the feasibility of these
processes. Francis used rhodium carbenoids for chemoselec-
tive tryptophan labelling,[7] Lindner employed dicarbonyl
compounds, such as malondialdehyde, that react with the
indole nitrogen in Trp residues as reversible tags[8] and Winn
recently described the Pd-catalyzed N-aryl-amination of Trp
residues in small-peptides.[9] However, a general and selec-
tive transformation of the indole ring in Trp residues is still
not available in the synthetic arsenal. Furthermore, the
structures of many natural products, bioactive substances
and drugs display indole rings, and the arylation reaction of
these moieties is crucial from a synthetic point of view.[10]
In this context, the use of transition-metal catalysts to
À
modify biomolecules in a tailored manner through C C
bond formation in aromatic rings could provide an attractive
way to target amino acids that display this structural motif.[3]
Although some remarkable achievements have been dis-
closed recently in this field, their suitability is seriously com-
[a] Dr. J. Ruiz-Rodrꢀguez, Prof. F. Albericio, Prof. R. Lavilla
Institute for Research in Biomedicine, Barcelona Science Park
Baldiri Reixac 10-12, 08028 Barcelona (Spain)
Fax : (+34)93-403-710
À
Reactions leading to the formation of new C C bonds are
E-mail: albericio@pcb.ub.es
pivotal in synthetic organic chemistry, and metal-catalyzed
cross-coupling reactions are the most useful method for
rlavilla@pcb.ub.es
Csp2 Csp2 bond formation.[11] A remarkable breakthrough in
[b] Prof. R. Lavilla
À
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona, Avda. Joan XXII s.n.
08028 Barcelona (Spain)
the field is the “metal-catalyzed direct arylation”, through
[12]
À
C H bond activation. This approach offers the advantage
À
over most aryl aryl coupling methods in that it does not re-
[c] Prof. F. Albericio
quire prefunctionalized organometallic precursors (such as
boronic acids, organostannanes, silanes, etc.).[13] In recent
years, significant advances have been made in direct aryla-
tion involving catalysis by transition metals such as Pd, Rh,
Ru, Ir, Cu or Fe.[14] In many of the protocols developed, ex-
tremely severe conditions (high temperatures around 100–
1508C, long reaction times up to 12–48 h, and strong bases)
are needed,[15] thereby resulting in a reduced range of ap-
CIBER-BBN, Networking Centre on Bioengineering
Biomaterials and Nanomedicine, Barcelona Science Park
Baldiri Reixac 10, 08028 Barcelona (Spain)
[d] Prof. F. Albericio
Department of Organic Chemistry, Faculty of Chemistry
University of Barcelona, Martꢀ i Franquꢁs 1-11
08028 Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902676.
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Chem. Eur. J. 2010, 16, 1124 – 1127

COMMUNICATION
plicability, especially when dealing with multifunctionalized,
complex substrates, such as peptides or proteins.
Information) and was used for comparison.[26] In order to
test the stereogenic purity of the C2 aryltryptophans, the re-
action was performed upon both isomers of the parent
amino acid derivative. The resulting arylated products were
purified and analyzed by HPLC on chiral stationary phase,
which showed that racemization occurred in less than 4% in
each case (see Supporting Information).
Excellent yields were obtained in the reaction of Ac-Trp-
OMe (1) with a variety of differently substituted aryl iodides
(Table 1). In this way, both electron-donor (entries 2–4) and
electron-withdrawing (entries 5–7) substituents on the aryl
iodide allowed the reaction, cleanly affording the arylated
compounds in high yields. Remarkably, the reaction was
chemoselective and allowed the differentiation of halogens,
The direct C-functionalization of indoles has been the
subject of extensive research with important consequences
in organic synthesis.[16] The development of new transition-
metal-catalyzed direct arylation methodologies have been
extensively studied for the last decade.[17] Landmarks in the
field include the first methodology that allows direct C2 ary-
lation of indoles based on PdII/IV catalytic cycle using hyper-
valent iodine reagents reported by Sanford.[18] Larrosa re-
ported a remarkably mild related arylation on simple in-
doles using commercial aryl iodides.[19] Shi published a PdII-
catalyzed direct arylation of heteroarenes with phenyl bor-
onic acids using O2 as the final oxidant in acidic media,[20]
and Gaunt described the CuII-catalyzed, direct and site-se-
lective arylation of indoles at C2 or C3 position.[21] These re-
markable processes although synthetically useful on simple
indoles, have the drawbacks of the limited availability of the
arylation partners, substitution pattern and functional group
incompatibilities and/or harsh conditions, which may com-
promise the stereochemical and connectivity patterns of del-
icate substrates, making them potentially problematic for
the functionalization of peptides.
À
maintaining a C Br bond untouched, as shown in entry 5.
This result opens up interesting possibilities for further
transformations, including new metal-catalyzed coupling
processes. Heteroaryl iodides were less reactive, and 2-iodo-
thiophene was coupled to the indole ring of the Trp al-
though with low extension (entry 8), whereas 3-iodopyridine
led to complex mixtures, where the expected compound
could only be detected.
The introduction of aromatic rings into amino acids to
modulate the structure and bioactivity of the ensuing pep-
tides is the subject of active research and constitutes a chal-
lenging synthetic task.[22] Here we report our results on a
Table 1. Scope of C2 arylation of Ac-Trp-OMe (1).
À
general C H arylation of unprotected indole rings in amino
acids and peptides, at position 2 using distinct aryl iodides in
aqueous media, under mild conditions, fully compatible with
a variety of functional groups in a wide array of derivatives.
Inspired by Larrosa findings[19] and after screening several
combinations of silver salts and carboxylic acids, it was
Entry
Peptide
Compound
Yield [%]
1
2
3
4
5
6
7
8
iodobenzene
4-iodotoluene
2a
2b
2c
2d
2e
2 f
2g
2h
89
81
85
76
92
79
86
23
found that the use of phenyl iodide, Pd
N
4-iodo-1,2-dimethylbenzene
1-iodo-4-methoxybenzene
1-bromo-4-iodobenzene
1-iodo-4-(trifluoromethyl)benzene
methyl 4-iodobenzoate
2-iodothiophene
trobenzoic acid in N,N’-dimethylformamide (DMF) at reflux
for 24 h resulted in an efficient arylation of the N-acetyl-
tryptophan methyl ester (Ac-Trp-OMe, 1).[23] However, as
high temperatures and long reaction times often compro-
mise the stereochemical integrity of amino acids, we at-
tempted microwave (MW) irradiation[24] as the heat source.
In this way, the best conditions involved the use of Pd-
The translation of this transformation to more fragile sub-
strates such as peptides poses new challenges and requires a
fine tuning of the reaction parameters. It was determined
that an aqueous medium under milder conditions was con-
venient for peptide arylation. The catalysts and additives
were maintained and the optimized conditions included the
use of a tenfold excess of aryl iodide, in an aqueous phos-
phate buffer (pH 6.0) at 808C for 10 min under MW irradia-
tion. The choice of amino acids in the model peptides cov-
ered the range of functionalities present in the side chains
of the natural proteinogenic derivatives. These models al-
lowed us to establish the practical range of functional
groups that tolerate the arylation reaction under these con-
ditions. All peptides were acetylated at the N-terminus,[27]
while the carboxylic end was left unprotected.
ACHTUNGTRENNUNG
a
(Scheme 1). The NMR spectra of C2-phenylated Trp deriva-
tive 2a match with the reported data for the racemic com-
pound.[25] On the other hand, an N-arylated Trp derivative
(7) was prepared using Buchwald conditions (see Supporting
The methodology for the direct arylation of peptides was
fully compatible with aromatic (entries 2, 3, 5 and 9), acidic
Scheme 1. Arylation of Ac-Trp-OMe (1) under microwave irradiation.
Chem. Eur. J. 2010, 16, 1124 – 1127
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1125

R. Lavilla, F. Albericio and J. Ruiz-Rodrꢀguez
(all entries) and basic amino acids (entries 4–6) (Table 2).
Under these milder conditions, no noticeable racemization
of the peptides was observed, as shown in their respective
HPLC profiles.[28] Peptides that display sulphur-containing
amino acids in their sequence (Met, entry 8)[29] were not
suitably arylated presumably because of selective hydrolysis
of the peptide bond, catalyzed by the palladium complexes
formed in-situ.[30] Interestingly, this hydrolytic cleavage was
also noticed when His was present in the sequence
(entry 5),[31] although it took place at a very reduced extent,
thus allowing the selective Trp arylation of His-containing
peptides. The methodology does not rely on a specific situa-
tion of the Trp along the peptide sequence, as arylation
worked equally well when the Trp residue is located at the
N,C-termini or in inner positions.
Table 2. Pd-catalyzed direct arylation of tryptophan peptides in aqueous
media.
Scheme 2. Selective arylation of a peptide carrying a modified tryptophan
unit.
cess takes place under milder conditions than those needed
for simple indoles, suggesting an active role of the amide
groups in the activation mechanism, presumably by stabiliz-
ing palladium intermediates. Also important for success is
the use of MW irradiation, which allows the process to pro-
ceed rapidly without epimerisation. This protocol guarantees
a convenient and general access to new amino acid derivates
and modified Trp peptides that provide novel and useful ap-
plications in organic synthesis, drug discovery and medicinal
chemistry. In addition it opens up the possibility of prepar-
ing new chemically modified peptides that are potentially
useful in chemical biology (for instance as new fluorescent
probes[32] or substrates for studying electron-transfer events
in complex peptides).[33]
Entry
Peptide
Compound/Yield [%][a]
1
2
3
4
5
6
7
8
9
Ac-Ala-Trp-Ala-OH (3a)
4a/57
4b/68
4c/75
4d/94
4e/51
4 f/95
4g/62
–
Ac-Trp-Leu-Asp-Phe-OH (3b)
Ac-Tyr-Pro-Trp-Phe-OH (3c)
Ac-Arg-Gly-Trp-Ala-OH (3d)
Ac-His-Gly-Trp-Ala-OH (3e)
Ac-Lys-Gly-Trp-Ala-OH (3 f)
Ac-Ser-Gly-Trp-Ala-OH (3g)
Ac-Met-Gly-Trp-Ala-OH (3h)
Ac-Gln-Phe-Ala-Trp-OH (3i)
4i/88
[a] Calculated by integration of HPLC peaks.
In a further experiment, the arylation reaction was suc-
cessfully performed on peptide (5), which contains two Trp
units (one arylated, the other unmodified). This compound
was prepared as described above (Table 1) by introducing
the arylated amino acid through standard solid-phase syn-
thesis using general peptide coupling agents (Scheme 2).
This result demonstrates the feasibility of the protocol,
the synthetic usefulness of the modified amino acids as
building blocks to be introduced in designed sequences, and
the possibility of combining both approaches to prepare
chemically modified peptide sequences simultaneously dis-
playing distinct aryl groups on Trp units. In addition, this ap-
proach may overcome the limitation encountered in the
direct arylation of peptide sequences, including Met or Cys
amino acids.
Experimental Section
General procedure for the synthesis of 2-aryltryptophans (2): (S)-N-Ace-
tyltryptophan methyl ester (1; 0.38 mmol), aryl iodide (4 equiv), AgBF4
(1 equiv), 2-nitrobenzoic acid (1.5 equiv) and PdACTHNURGTNEUNG(OAc)2 (5% mol) were
placed in a microwave reactor vessel and dry DMF (300 mL) was added.
The mixture was stirred for 30 min at room temperature and heated
under microwave irradiation (150 W) at 1508C for 5 min. Ethyl acetate
(20 mL) was added and the resulting suspension was filtered through
Celite. The filtrate was successively washed with aqueous saturated solu-
tions of NH4Cl (3ꢃ10 mL), NaHCO3 (3ꢃ10 mL) and brine (3ꢃ10 mL),
then the organic phase was dried over Na2SO4, filtered and the solvent
was removed under vacuum. The crude extract was purified by flash
chromatography on silica gel to obtain 2 as a pure product.
General procedure for the C2 arylation of tryptophan residues in pep-
tides (4): Peptide 3 (100 mg), aryl iodide (10 equiv), AgBF4 (1 equiv), 2-
nitrobenzoic acid (1.5 equiv) and PdACHTUNRGTNEUNG(OAc)2 (5% mol) were placed in a
In summary, here we describe a new route for C2 aryla-
tion of unprotected indoles in Trp derivatives and peptides
microwave reactor vessel and phosphate buffer at pH 6.0 (300 mL) was
added. The mixture was stirred for 30 min at room temperature and
heated under microwave irradiation (80 W) at 808C for 10 min. Water
(10 mL) was added and the resulting suspension was filtered through
Celite. The filtrate was washed with Et2O (3ꢃ10 mL) for remove the
À
through a Pd-catalyzed C H activation protocol with a wide
range of reactivity regarding both the peptide/amino acid
substrates as well as the aryl iodides. Interestingly, the pro-
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Chem. Eur. J. 2010, 16, 1124 – 1127

Postsynthetic Modification of Peptides
COMMUNICATION
excess of aryl iodide and the aqueous phase was lyophilized. The crude
residue was purified by semi-preparative RP-HPLC to obtain 4 as a pure
product.
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Acknowledgements
This work was partially supported by DGICYT (Spain, project BQU
2006-03794), the “Generalitat de Catalunya” (2009SGR 1024), and the
Institute for Research in Biomedicine, and Barcelona Science Park. Lab-
oratorios Almirall and Grupo Ferrer (Barcelona, Spain) are thanked for
financial support. We thank Prof. Cristina Minguillꢄn (IRB Barcelona)
for advice on the chiral HPLC analyses.
À
Keywords: arylation · C H activation · indoles · palladium ·
peptides
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Received: September 29, 2009
Published online: December 10, 2009
Chem. Eur. J. 2010, 16, 1124 – 1127
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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