Palladium(II) pincer complexes of α-amino acids: Towards the synthesis of catalytically active artificial peptides

Article abstract of DOI:10.1016/S0040-4039(02)00656-1

NCN palladium(II) complexes have been covalently attached to the N- and C-termini of L-valine and to the N-terminus of the dipeptide L-Phe-L-Val-OMe. Remarkably, the hydrolysis of the NCN-Pd(II) L-Val-OMe compound afforded the corresponding palladated, fr

Full text of DOI:10.1016/S0040-4039(02)00656-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3895–3898
Palladium(II) pincer complexes of a-amino acids: towards the
synthesis of catalytically active artificial peptides
Gabriela Guillena, Gema Rodr´ıguez and Gerard van Koten*
Debye Institute, Department of Metal-Mediated Synthesis, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Received 28 March 2002; accepted 2 April 2002
Abstract—NCN palladium(II) complexes have been covalently attached to the N- and C-termini of
L-valine and to the N-terminus
of the dipeptide -Phe- -Val-OMe. Remarkably, the hydrolysis of the NCN-Pd(II) -Val-OMe compound afforded the
L
L
L
corresponding palladated, free amino acid without affecting the metal site. This deprotected amino acid could be coupled to any
protein, enzyme or peptidic chain by simple peptide chemistry. These bioorganometallic systems were active as catalysts in the
aldol reaction between methyl isocyanate and benzaldehyde. © 2002 Elsevier Science Ltd. All rights reserved.
The design of peptides that mimic the structural and/or
functional features of naturally occurring proteins has
lately become an area of interest.1 The ability of small
polypeptide chains to fold in secondary structures pro-
vides a unique platform to build man-made enzyme-like
systems for both biological or non biological reactions.
Incorporation of catalytically active transition-metal
complexes to these biomolecules affords the develop-
ment of chiral compounds with unique selectivity and
potential applications in enantioselective synthesis.2
Commonly, this introduction of the metal site at differ-
ent positions of the peptidic chain occurs in the last
step of the synthesis.3 Our approach to the synthesis
of metallated peptides consists of the attachment of
transition-metal complexes of type [MX(NCN)] (NCN
is the monoanionic, para-functionalized ‘pincer’
ligand [C6H2(CH2NMe2)2-2,6]−)4 to amino acids and
peptides.
Herein, we report on the successful binding of NCN
‘pincer’ ligands to the N- and C-termini of a-amino
acids and dipeptides as well as their palladation with
the concomitant creation of biofunctionalized systems
with catalytically active sites. The preliminary results
obtained in the use of these organopalladium(II) com-
plexes as homogeneous catalysts in the aldol condensa-
tion reaction of benzaldehyde and methyl isocyanate
are also described.5
Condensation of the aldehyde 1 with the hydrochloride
form of the methoxy-protected L-valine (L-Val-OMe) in
the presence of MgSO4 led to the formation of a Schiff
Br
Me2N
Br NMe2
Me2N
Pd NMe2
Me2N
Br NMe2
i, ii
iii
NH
NH
O
O
H
O
OMe
OR
1
2
3 R = Me
iv
4 R = H
Scheme 1. Reagents and conditions: (i) (a) L-Val-OMe·HCl, NEt3, MgSO4, rt, 12 h; (b) HOAc, NaBH3CN, MeOH, 10°C, rt, 2 h,
87%; (ii) [Pd2(dba)3·CHCl3], toluene, D, 3 h, 79%; (iii) LiOH, THF/H2O, rt, 12 h, 71%.
* Corresponding author. Tel.: +31-30-2533120; fax: +31-30-2523615; e-mail: g.vankoten@chem.uu.nl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00656-1

3896
G. Guillena et al. / Tetrahedron Letters 43 (2002) 3895–3898
base which could be easily reduced with NaBH3CN
affording the N-terminus pincer functionalized valine 2
(Scheme 1).6
principle the NCN moiety was linked at the N-terminus
of the dipeptide L-Phe-L-Val-OMe affording compound
5 (Scheme 2).
As the [PdXnLm(NCN)] complexes are catalytically
active metallation of 2 with [Pd2(dba)3·CHCl3] was
attempted which indeed resulted in clean formation of
the Pd(II)-valine complex 3. The signals of the NMe2
and ArCH2N moieties were characteristically shifted to
lower field 2.94 and 3.96 ppm (Dl=0.63 and 0.43
ppm), respectively, while the signal corresponding to
the aromatic protons appeared at higher field, 6.75 ppm
(Dl=0.54 ppm).
The palladated dipeptide 6 was obtained by metallation
of the CarylꢀBr bond with [Pd2(dba)3·CHCl3]. The fact
that the 1H NMR spectrum of 6 showed only one
resonance pattern indicated that the coupling of the
pincer ligand 1 occurs with retention of configuration
of Ca of the dipeptide L-Phe-L-Val-OMe.
The incorporation of the organopalladated counterpart
to the C-terminus of an a-amino acid or/and higher
molecular entities like polypeptides, would extend the
application of these systems in catalysis. Therefore, we
decided to attach the ‘pincer’ ligand to the C-terminus
More interesting would be the deprotection of the
N-terminus organopalladated a-amino acids 3, enlarg-
ing the field of application of this system. Deprotected
amino acids could be coupled to any protein, enzyme
or peptidic chain by simple peptide chemistry. Interest-
ingly, the N-terminus palladated compound 3 could be
easily hydrolyzed. Treatment of a THF/H2O solution of
3 with LiOH afforded deprotected 4 without affecting
the Pd-C s-bond. Compound 4 was isolated as a
lithium salt and then converted into the acid form by
ion exchange column chromatography (70% yield,
Scheme 1).
of Boc-protected
L-valine (N-Boc-L-Val). In order to
avoid racemization of the enantiomerically pure start-
ing a-amino acid, standard peptide chemistry was
applied in this synthesis.
Aldehyde 1 was reduced to the required alcohol for the
C-functionalisation of valine. Thus, treatment of a
methanol solution of 1 with NaBH4 at room tempera-
ture afforded the benzylic alcohol 7 in a good yield
(Scheme 3). Further condensation of 7 with Boc-pro-
tected L-valine in the presence of DCC and 4-DMAP
The route developed for 4 should also be applicable to
the attachment of these organometallic units to the
N-termini of peptides or to lateral chains of amino
acids forming part of a peptidic chain. As a proof of
led to C-pincer functionalized valine 8. Oxidative addi-
tion of [Pd2(dba)3·CHCl3] to the CarylꢀBr bond of 8
gave rise to the organometallic a-amino acid ester 9 in
a 76% yield.
Scheme 2. Reagents and conditions: (i) (a) L-Phe-L-Val-OMe·HCl, NEt3, MgSO4, rt, 12 h; (b) HOAc, NaBH3CN, MeOH, 10°C,
rt, 2 h, 58%; (ii) [Pd2(dba)3·CHCl3], toluene, D, 3 h, 40%.
Br
Me2N
Br NMe2
Me2N
Br NMe2
Pd
Me2N
NMe2
O
iii
ii
O
O
H
N
H
N
Boc
R
O
Boc
1 R = CHO
8
9
i
7 R = CH2OH
Scheme 3. Reagents and conditions: (i) NaBH4, MeOH, rt, 2 h, 95%; (ii) DCC, 4-DMAP, Boc-
[Pd2(dba)3·CHCl3], toluene, D, 3 h, 76%.
L-Val-OH, rt, 12 h, 71%; (iii)

G. Guillena et al. / Tetrahedron Letters 43 (2002) 3895–3898
3897
The PdII complexes 3, 4, 6 and 9 were used as catalyst
precursors in the aldol condensation reaction of benz-
aldehyde and methyl isocyanoacetate to form an
oxazoline.
In summary, we have developed a new methodology for
the successful binding of a-amino acids and peptides at
their N- and C-terminus to NCN-palladium(II) com-
plexes. These biometallic systems were active in the
catalytic aldol reaction between methyl isocyanate and
benzaldehyde. The preparation of the free, organopalla-
dated a-amino acids allows the incorporation of these
catalytic units in higher molecular structures such as
peptides or proteins. Their chiral environment should
definitely influence the stereochemistry of the catalytic
reaction.
Consequently, 3, 4, 6 and 9 were converted into their
corresponding cationic analogues by abstracting the
halide anion using AgBF4 in wet acetone.7 After appro-
priate work-up involving a thorough filtration, through
a path of Celite, of the solutions containing the cationic
complexes to remove the insoluble silver salts,† active
catalytic species were isolated and used without further
purification in the aldol condensation reaction.
Acknowledgements
These preliminary experiments were carried out with
i-Pr2EtN (Hunig’s base, 10 mol%) as base, using 1 mol%
of the catalyst, methyl isocyanoacetate (100 mol%) and
benzaldehyde (100 mol%) in dichloromethane at room
temperature.
G. Guillena and G. Rodr´ıguez are Marie Curie fellows
and thank the European Commission for a TMR Grant
(Contract No. HPMF-CT-2000-00472 and HPMF-CT-
1999-00236, respectively). This work was also sup-
ported by the Council for Chemical Sciences from the
Dutch Organisation for Scientific Research (CW–
NWO).
The catalytic results are presented in Table 1, and are
compared with the activity of the corresponding
[PdCl(NCN)] and N-benzyl protected valine (10) as
well as the uncatalyzed reaction.
The catalytic activities of the biofunctionalized Pd(II)
complexes 3, 6 and 9 are similar to the non-functional-
ized [PdCl(NCN)] compound. The best results were
obtained when the palladated free a-amino acid 4 was
used as a catalyst. Most probably the carboxylic moiety
present in 4 interacts with some of the intermediates of
the reaction since the palladium-free analog 10 displays
much lower catalytic activity.
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PdII complex/AgBF4
Ph
CO2Me
Ph
CO2Me
O
OMe
i-Pr2EtN
+
CN
+
O
N
Ph
H
O
N
O
CH2Cl2, RT
cis
trans
Entry
Pd(II) complex
Time (h)
TOF
Conversionc (%)
trans/cisc
1
2
3
4
5
6
7
None
[PdCl(NCN)]
BnValOH (10)
3
4
6
9
5
7
24
7
3
7
0
43
1
52
62
40
30
0
83
18
96
\99
97
–
62:38
80:20
62:38
64:36
68:32
62:38
7
94
a Reaction carried out in CH2Cl2 (4 mL) at rt with ca. 10 mol% Hunig’s base i-Pr2EtN.
b In all catalytic rounds the amount of palladium was kept constant (i.e. ca. 1 mol%).
c Conversion and trans/cis ratio calculated using specific signal integration in 1H NMR spectra.
† This is important to note as the precipitated silver salt can also act as a Lewis acid catalyst.

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