Site-selective modification of peptides using rhodium and palladium catalysis: Complementary electrophilic and nucleophilic arylation

Article abstract of DOI:10.1039/b711533d

The site-selective modification of peptides containing dehydroalanine, tyrosine and tryptophan residues has been achieved using rhodium catalysed conjugate additions or palladium catalysed aryl-amination and -etherification reactions. The Royal Society of

Full text of DOI:10.1039/b711533d

Chemical Communications
www.rsc.org/chemcomm
Number 38 | 14 October 2007 | Pages 3877–3968
ISSN 1359-7345
COMMUNICATION
Christopher J. Chapman, Ai Matsuno, Christopher G. Frost and Michael C. Willis
Site-selective modification of peptides using rhodium and palladium catalysis:
complementary electrophilic and nucleophilic arylation

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Site-selective modification of peptides using rhodium and palladium
catalysis: complementary electrophilic and nucleophilic arylation{
Christopher J. Chapman,a Ai Matsuno,b Christopher G. Frost*a and Michael C. Willis*b
Received (in Cambridge, UK) 27th July 2007, Accepted 3rd August 2007
First published as an Advance Article on the web 15th August 2007
DOI: 10.1039/b711533d
The site-selective modification of peptides containing dehy-
droalanine, tyrosine and tryptophan residues has been achieved
using rhodium catalysed conjugate additions or palladium
catalysed aryl-amination and -etherification reactions.
The ability to modify individual residues of peptides or proteins
selectively and reliably opens a number of exciting possibilities in
chemical biology. For example, modification of individual amino
acids has been shown to be responsible for changes in peptide
conformation, allows for bioconjugation to construct diagnostic
arrays and chemical probes, and for the elucidation of an
individual residue’s biological function.1 The majority of methods
used to achieve these modifications are based on biochemical
techniques, however the number of examples of modifications
achieved using small molecule (chemical) reactivity is increasing.2,3
The rhodium catalysed conjugate addition of boronic acids
Scheme 1 Nucleophilic and electrophilic transition metal catalysed
provides an attractive method to effect a nucleophilic arylation of
alkene acceptors.4 Dehydroalanine residues can be revealed by the
arylation of peptide chains.
activation and b-elimination of cysteine or serine derivatives;5
and demonstrate that ester, sulfonamide and trifluoromethyl
conjugate addition to these unsaturated residues represents a
substituents can all be introduced successfully. The efficient
convenient strategy for incorporating unnatural phenylalanine
derivatives.6 In order to develop suitable processes for the selective
arylation of peptide 1 shows that is possible to react selectively
at the indole N–H in preference to the competitive amide and
electrophilic functionalisation of tryptophan and tyrosine units we
carbamate functional groups.
elected to use palladium catalysed hetero-arylation reactions
Our O-arylation study focused on tyrosine derivative 3 (Table 2).
(Scheme 1).7
Our initial reaction conditions employed Pd(OAc)2, ligand 4a and
K3PO4 in toluene at 100 uC,10 and unfortunately provided only
Although the N-arylation of a variety of azoles has been
reported,8 we were attracted to the aryl-amidation conditions
reported by Buchwald as the starting point of our investigation.9
Thus, reaction of indole 1 with 4-bromobenzonitrile using
Pd(OAc)2, the ligand Xantphos, and the weak base Cs2CO3 in
dioxane at 80 uC delivered the N-arylated product 2 in 87% yield
(Table 1, entry1). The reaction temperature could be reduced to
55 uC with little effect on efficiency, however if the reactions were
performed at 50 uC a low yield of the desired product was obtained
(entries 2 and 3). The alternative bases K2CO3 and K3PO4 were
less effective than Cs2CO3 (entries 4 and 5). Entry 6 demonstrates
that toluene is also a suitable solvent for the transformation, with
an 86% yield of the arylated compound being obtained. The final
three entries employ alternative aryl bromide coupling partners
Table 1 N-Arylation of tryptophan derivative 1a
Entry Ar–Br
Base
Time (h) Temp. (uC) Yield (%)b
1
2
3
4
4-CN-Ph
Cs2CO3 18
Cs2CO3 40
Cs2CO3 40
K2CO3 40
K3PO4 40
Cs2CO3 40
80
55
50
55
55
55
60
80
60
87
94
31
27
65
86
54
70
86
4-CN-Ph
4-CN-Ph
4-CN-Ph
4-CN-Ph
4-CN-Ph
4-MeO2C-Ph Cs2CO3 40
4-CF3-Ph Cs2CO3 16
4-R2NSO2-Ph Cs2CO3 40
aDepartment of Chemistry, University of Bath, Claverton Down, Bath,
UK BA2 7AY. E-mail: c.g.frost@bath.ac.uk; Fax: 44 01225 386231;
Tel: 44 01225 386142
5
6c
7d
8d
9d,e
a
bDepartment of Chemistry, University of Oxford, Chemical Research
Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: michael.willis@chem.ox.ac.uk; Fax: 44 1865 285002;
Tel: 44 01865 285 126
Conditions: Ar–Br (1.2 equiv.), Pd(OAc)2 (5 mol%), Xantphos
b
(7.5 mol%), base (1.4 equiv.), dioxane. Isolated yields. Toluene as
c
d
solvent. Ar–Br (2.4 equiv.). R2N = morpholino.
e
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b711533d
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3903–3905 | 3903

Table 2 O-Arylation of tyrosine derivative 3a
Entry Pd-source Ligand Temp. (uC) Time (h) Yield (%)b
1
2
3
4
5
6
7c
a
Pd(OAc)2 4a
Pd(OAc)2 4b
Pd(OAc)2 4c
Pd(OAc)2 4d
Pd2(dba)3 4c
Pd2(dba)3 4c
Pd2(dba)3 4c
100
100
100
100
80
18
18
18
18
18
40
40
,5
6
these two nucleophilic residues to present a significant challenge. In
the event, both N- and O-arylation were achieved with good
selectivity. N-Arylation proceeded under the standard conditions
to deliver an excellent 93% yield of the expected product 9. Under
these conditions no O-arylation was observed. O-Arylation was
less selective but still provided a 63% yield of the desired O-aryl
material 10 along with 11% of an N,O-diarylated peptide.
Dipeptide 7, containing tryptophan and dehydroalanine residues,
was combined with 4-bromobenzonitrile, exposed to the condi-
tions developed in Table 1, and provided the desired N-arylated
peptide 11 in a pleasing 72% yield. The rhodium catalysed
conjugate addition of boronic acids to dehydroalanine derivatives
proceeds in aqueous solvents in the presence of phosphine
ligands.12 These conditions allowed modification of the dehy-
droalanine residue with p-chlorophenyl boronic acid to reveal the
arylated peptide 12 in good isolated yield (as a 1 : 1 mixture of
diastereomers). The tyrosine and dehydroalanine containing
dipeptide 8 was O-arylated using the standard conditions, but at
100 uC, to deliver 55% of the expected product 13; reactions at
lower temperatures were less effective. The conjugate addition to
dipeptide 8 occurred in 86% overall yield to efficiently install a
p-cyanophenylalanine residue 14.
64
22
95
94
91
60
80
Conditions: Ar–Br (1.2 equiv.), Pd source (5 mol%), ligand
b
c
(7.5 mol%), base (2.0 equiv.), toluene. Isolated yields. Dioxane as
solvent.
trace amounts of the desired product (entry 1). Evaluation of
t
alternative electron-rich biphenyl-based ligands showed that Bu-
phosphine derivative 4c was the most successful,11 although this
system still provided only a 64% yield of the O-arylated product 5
(entries 2–4). An improvement in yield to 95% was achieved when
Pd2(dba)3 was used as the Pd source (entry 5). Provided a longer
reaction time was used then the temperature could be reduced to
60 uC and still achieve efficient conversion (entry 6). Finally,
dioxane could also be used successfully in place of toluene (entry 7).
The next stage of our study was to investigate the chemoselec-
tivity of the individual reactions; peptides 6, 7 and 8, each
containing two of the reactive functional groups, were prepared
and reacted under our optimized conditions (Scheme 2). Dipeptide
6 contains both tyrosine and tryptophan residues and we
considered the Pd-catalysed chemoselective functionalisation of
Scheme 3 illustrates our studies using tripeptide 15 that contains
all three reactive functional groups. Chemoselective N-arylation of
Scheme 2 Chemoselective functionalisation of dipeptides 6, 7 and 8.
3904 | Chem. Commun., 2007, 3903–3905
This journal is ß The Royal Society of Chemistry 2007

Scheme 3 Chemoselective functionalisation of tripeptide 15. Reagents and conditions: (i) Pd(OAc)2 (5 mol%), Xantphos (7.5 mol%), K3PO4 (1.4 equiv.),
dioxane, 80 uC, 18 h; (ii) Pd2(dba)3 (5 mol%), 5c (10 mol%), K3PO4 (2.0 equiv.), dioxane, 80 uC, 18 h; (iii) Rh(acac)(C2H4) (6 mol%), rac-BINAP
(6.6 mol%), dioxane : H2O 10 : 1, 100 uC, 18 h.
J. M. McFarland and M. B. Francis, J. Am. Chem. Soc., 2005, 127,
the tryptophan residue was achieved in 71% yield using our
13490; A. Ojida, H. Tsutsumi, N. Kasagi and I. Hamachi, Tetrahedron
standard conditions, with no O-arylated material being observed.
Lett., 2005, 46, 3301; S. D. Tilley and M. B. Francis, J. Am. Chem. Soc.,
2006, 128, 1080.
Attempted O-arylation using the standard conditions was
unsuccessful, however a switch from toluene to dioxane allowed
O-arylation of the tyrosine unit in 48% yield. This was obtained
along with 13% N-arylated material and 10% starting tripeptide.
Pleasingly, the conjugate addition of p-fluorophenyl boronic acid
to the embedded dehydroalanine proceeded under standard
conditions to afford the novel peptide 18 in 54% yield (isolated
as a single diastereomer).
4 For reviews see: T. Hayashi, Synlett, 2001, 879; T. Hayashi and
K. Yamasaki, Chem. Rev., 2003, 103, 2829; K. Fagnou and M. Lautens,
Chem. Rev., 2003, 103, 169.
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6 L. Wang and P. G. Schultz, Angew. Chem., Int. Ed., 2004, 44, 34.
7 For reviews of Pd-catalysed C–N and C–O cross-coupling of aryl
halides, see: (a) J. F. Hartwig, in Handbook of Organopalladium
Chemistry for Organic Synthesis, ed. E. I. Negishi, Wiley-Interscience,
New York, 2002, vol. 1, p. 1051; (b) J. F. Hartwig, in Handbook of
Organopalladium Chemistry for Organic Synthesis, ed. E. I. Negishi,
Wiley-Interscience, New York, 2002, vol. 1, p. 1097; (c) A. R. Muci and
S. L. Buchwald, Top. Curr. Chem., 2002, 219, 131; (d) D. Prim,
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In summary, we have demonstrated that highly selective
arylation of short peptides is possible using complementary Rh-
catalysed conjugate additions and Pd-catalysed N- and O-arylation
reactions. All three processes show excellent chemoselectivity and
good functional group tolerance. The substrates used in this study
represent some of the most complex molecules to be functionalised
using these processes. Success with these small peptide systems
paves the way for application of this methodology to larger, more
complex molecules.
The authors would like to thank the EPSRC for funding. The
EPSRC Mass Spectrometry Service at the University of Wales
Swansea is also thanked for its assistance.
Notes and references
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M. B. Francis, Curr. Opin. Chem. Biol., 2006, 10, 253.
3 H. Dibowski and F. P. Schmidtchen, Angew. Chem., Int. Ed., 1998, 37,
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This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3903–3905 | 3905