Synthesis and catalytic activity of amino acids and metallopeptides with catalytically active metallocyclic side chains

Article abstract of DOI:10.1021/om300848p

Two approaches to prepare amino acids with catalytically active organometallic side chains are presented. These methods are notable in that they provide access either free or N-protected compounds that are structurally analogous to naturally occurring ami

Full text of DOI:10.1021/om300848p

Communication
pubs.acs.org/Organometallics
Synthesis and Catalytic Activity of Amino Acids and Metallopeptides
with Catalytically Active Metallocyclic Side Chains
Zhihui Zhong, Hao Yang, Chen Zhang, and Jared C. Lewis*
Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States
*
S Supporting Information
ABSTRACT: Two approaches to prepare amino acids with
catalytically active organometallic side chains are presented.
These methods are notable in that they provide access either
free or N-protected compounds that are structurally analogous
to naturally occurring amino acids. The N-protected organo-
metallic amino acids are compatible with standard peptide
coupling conditions and can be used to prepare catalytically
active metallopeptides.
7
he design and synthesis of catalytically active metal-
lopeptides and metalloproteins has received consider-
cally active transition-metal centers, and most protected
1
2
8
T
compounds include extended tethers between the amino
able attention, due to the potential for peptides and proteins to
impart selectivity to metal catalysts using molecular recog-
acid moiety and the organometallic fragment. Because both of
these limitations arise primarily from the well-established metal-
binding ability of the amino acid moiety, protecting group
3
9
nition. Most methods developed thus far involve metal binding
to a peptide backbone or side chains, covalent or noncovalent
bioconjugation of a peptide with a metal-binding ligand or
metal complex, or incorporation of amino acids with metal
binding ligands into a peptide. Using these methods,
researchers have developed a range of catalytically active
metallopeptides and artificial metalloenzymes for synthetic
applications.
4
strategies that would enable installation of a range of metal
centers while still allowing amino acid deprotection without
compromising the activity of the metal center were required.
Particularly attractive in this regard was the 9-borabicyclo-
nonanyl (9-BBN) group, which enables simultaneous protec-
tion of both the amine and carboxylic acid functionalities and
5
6
1
,2
10
can be readily removed using ethylenediamine. The 9-BBN
aducts of p- and m-acetylphenylalanine (1a,b, respectively)
were therefore prepared and purified by washing with hexanes
Herein, we describe two approaches for the synthesis of
organometallic amino acids that enable direct incorporation of
catalytically active metal complexes into peptides (Scheme 1).
(
Scheme 2).
Scheme 1. Approaches To Synthesize Organometallic Amino
Acids for Preparation of Metalloproteins and Peptides
Scheme 2. Amino Acid Protection using 9-BBN
The resulting compounds, 2a,b, were then reacted with a
range of amines and hydrazines to generate imines and
hydrazines 3 (Scheme 3). Reaction of these compounds with
either NaPdCl or [Cp*IrCl ] according to standard literature
Importantly, the organometallic amino acids were designed to
mimic, as closely as possible, natural amino acids in order to
maximize their compatibility with potential in vivo incorpo-
4
2 2
procedures led to the formation of the 9-BBN protected
11
6
organometallic amino acids 4. These were typically isolated as
crude solids, and the free amino acids 5 could then be readily
prepared by simply stirring these complexes in THF solutions
ration efforts. Preserving the native amino acid structure was
also expected to minimize structural perturbations to peptides,
including these amino acids, and to ensure close proximity of
the metal center and the chiral peptide scaffold. Prior to this
work, no general method existed for the preparation of
unprotected amino acids with side chains containing catalyti-
Received: September 1, 2012
©
XXXX American Chemical Society
A
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Organometallics
Communication
Scheme 3
Scheme 4. Synthesis of Hydroxyquinoline- and Lysine-Based
Amino Acids 9 and 13
Table 1. Representative Organometallic Amino Acids
To avoid introducing additional protection steps to the
syntheses outlined above and potential for decomposition of
the metal centers in these compounds, we instead pursued a
monoprotecting group strategy that would mask the amine
functionality with either a Boc or Fmoc group based on recent
work by several groups using tethered amino acid−metal
1
Cumulative yield over metalation and deprotection steps.
10
of ethylenediamine (Table 1). The amino acids precipitated
from solution and could be further purified by precipitation
from methanol/ether solution if necessary. The ethylenedi-
amine was typically observed to displace chloride from the
metal center, binding in either a mono- or bidentate fashion,
depending on the number of coordination sites available.
To demonstrate the generality of the BBN protecting group
for the synthesis of unprotected organometallic amino acids,
two additional compounds were prepared by analogous routes.
Specifically, a 9-BBN-protected hydroxyquinoline-based amino
acid was reacted with [Cp*IrCl ] to provide the corresponding
8
complexes. For in vitro peptide synthesis, enantiopure amino
acids were also required (E. coli only incorporates S amino acids
into proteins; thus, racemic samples can be used for in vivo
6
studies ); therefore, an enzymatic resolution was used to
15
prepare enantiopure acetylphenylalanine 15. This material
was then Boc-protected, converted to the corresponding
methoxyimine, and reacted with either NaPdCl or [Cp*IrCl ]
4
2 2
to yield the Boc-protected metallacyclic amino acids 17 and 18
(
Scheme 5).
To demonstrate the utility of these compounds for the site-
2
2
specific introduction of metal centers into peptide scaffolds,
Cp*Ir−hydroxyquinoline chloride complex, which was depro-
tected to yield amino acid 9 (Scheme 4). In addition, the
known 9-BBN-protected lysine 10 was acylated with 2-
pyridinecarboxylic acid chloride and reacted with [CpRuCO-
14
standard peptide coupling conditions were used to prepare
tetrapeptides 20 and 21 (Scheme 6). The 2-aminoisobutyric
acid (Aib)−proline motif in peptide 19 is known to enforce a β-
(
ACN) ]PF to provide complex 12, which was deprotected to
2 6
12
Scheme 5. Synthesis of Resolved, Protected Pd and Ir Amino
Acids 17 and 18
yield amino acid 13.
Thus, a structurally diverse set of Pd-, Ir-, and Ru-based
amino acids were prepared. The Pd and Ir compounds were
designed to mimic the planar aromatic side chains of
phenylalanine and tyrosine, while the last compound is a
pyrolysine mimic. These compounds are water-soluble and
are readily taken up by E. coli, as judged by their inhibition of
cell growth (see the Supporting Information). While these
compounds are therefore highly promising candidates for
aqueous organometallic catalysis or in vivo incorporation in E.
1
3
6
coli, their potential for use in standard peptide synthesis
procedures required installation of either the Boc or Fmoc
protecting group.
1
4
B
dx.doi.org/10.1021/om300848p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Scheme 6. Peptide Coupling using Amino Acids 17 and 18
In summary, we have described synthetic approaches for the
preparation of a range of unprotected and N-protected
organometallic amino acids. These compounds are structural
analogues of natural amino acids, making them ideal vehicles
for incorporation of organometallic complexes into peptides
and potentially proteins. The compatibility of these amino acids
with standard peptide coupling conditions allowed the facile
preparation of a small set of catalytically active metallopeptides.
The ability of peptide-based catalysts to provide enantiose-
lectivity and site selectivity in a range of organo-catalyzed
16
reactions suggests that metallopeptides analogous to those
prepared hold great promise in similar selectivities in metal-
catalyzed reactions.
turn structure and has been used by many groups, notably
16
Miller and co-workers, to generate highly selective catalysts
for a range of chemical transformations using organic amino
acids. Peptide-based coordination complexes based on β-turn
ASSOCIATED CONTENT
Supporting Information
■
*
S
17
Synthetic procedures and full characterization of all synthetic
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
peptides have also been generated. We hypothesized that
incorporating organometallic catalysts into this platform would
greatly expand the range of catalytic transformations possible
using unique selectivity afforded by peptide catalysts. By using
preformed organometallic complexes as side chains, catalysts
not available via simple coordination of metal ions, such as the
metallacycles described herein, can be selectively introduced
into peptides. NMR and mass spectroscopic analysis of 20 and
AUTHOR INFORMATION
Corresponding Author
*E-mail: jaredlewis@uchicago.edu.
■
Notes
2
1 indicated that the metal centers remained unperturbed by
the peptide coupling conditions. Several analogues of 20 and
1, involving substitution of L-proline with D-proline, variation
The authors declare no competing financial interest.
2
ACKNOWLEDGMENTS
■
of the terminal phenylalanine residue, and addition of an
additional amino acid to form pentapeptides, were also
prepared (data not shown). Attempted removal of the Boc
group from 20 and 21 using TFA led to decomposition of the
metallopeptides, and while these compounds were stable to the
piperidine conditions typically used to remove the Fmoc group,
synthesis of Fmoc-protected amino acids as shown in Scheme 6
was complicated by Fmoc removal during the methoxyamine
condensation.
This work was supported by an NIH Pathways to
Independence Award (5R00GM087551-03) and a Packard
Fellowship in Science and Engineering to J.C.L.
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dx.doi.org/10.1021/om300848p | Organometallics XXXX, XXX, XXX−XXX