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Supramolecular Bioinorganic Hybrid Catalysts for Enantioselective Transformations.

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Highlights
DOI: 10.1002/anie.200502907
Asymmetric Catalysis
Supramolecular Bioinorganic Hybrid Catalysts for
Enantioselective Transformations
Roland Krmer*
Keywords:
asymmetric catalysis · DNA · hybrid catalysts · proteins
The efficient preparation of enantiopure compounds is of primary importance for the production of pharmaceuticals, vitamins, agrochemicals, and flavorants and is a major endeavor in
modern organic chemistry. Metal-catalyzed homogeneous enantioselective
transformations (e.g. hydrogenations,
epoxidations, hydroformylations, allylic
substitutions) have proven useful and
versatile, and the achievements in this
field were recognized in 2001 with the
Nobel Prize in Chemistry.[1] Despite
these efforts, it remains difficult to tailor
the second coordination sphere of metal
complexes and predict stereoselectivity,
and the impact of enantioselective catalysis for the production of fine chemicals remains modest.[2]
Biocatalysis has emerged as an alternative tool for the synthesis of enantiopure compounds. The efficiency as well
as chemo-, region-, and stereoselectivity
of enzymatic reactions are often unsurpassed. While specific enzymes have
broad substrate spectra and function in
organic solvents, the substrate scope of
most enzymes is narrower than that of
synthetic metal-complex catalysts. Enzymes are often more useful with polar
substrates in aqueous media where
product isolation can be a serious problem, and their operational stability can
be rather limited.
These problems have been addressed by “genetic” sequence variation
[*] Prof. Dr. R. Kr*mer
Anorganisch-Chemisches Institut
Universit*t Heidelberg
Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
Fax: (+ 49) 6221-548-599
E-mail:
roland.kraemer@urz.uni-heidelberg.de
858
Dedicated to Prof. Gnther Helmchen
on the occasion of his 65th birthday
of the protein.[3] “Directed evolution”
combines the generation of millions of
mutants with efficient high-throughputscreening procedures for enantioselectivity, and is a particular promising
concept for the optimization of protein-based catalysts.[4] Also, a considerable number of interesting transformations has been accomplished by directed
evolution of nucleic acid based biocatalysts (ribozymes, DNAzymes),[5] although their potential for enantioselective reactions has hardly been explored.[6, 7] Despite a great deal of progress, the engineering of biocatalysts for
specific reactions by sequence variation
remains very challenging.
In some respects, metal-complex
catalysts and biocatalysts are complementary. This has prompted chemists to
develop hybrids from inorganic catalysts
and biomacromolecules that provide a
well-defined,
chiral
microenvironment.[8] Both covalent and noncovalent
strategies have been applied successfully
to the site-specific anchoring of a catalytically active metal complex to the
biomolecule.
In view of catalyst optimization, the
noncovalent approach (Figure 1) seems
more appealing since it avoids the
potential complications associated with
chemical modification of the biomacromolecule. Since the host molecule9s
binding pocket was by no means optimized by nature to support the enantioselectivity of a specific metal-catalyzed
reaction, the success of the approach
critically depends on the efficient optimization of catalyst performance. As
early as 1978, Wilson and Whitesides[9]
showed that an achiral rhodium(i) diphosphine complex is converted into an
enantioselective hydrogenation catalyst
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Supramolecular hybrid catalyst of a
metal complex and a biomacromolecule.
(39 % ee) by noncovalent, supramolecular embedding into the protein avidin.
This article highlights two very recent, important contributions to the
field that demonstrate how such bioinorganic hybrid catalysts can be optimized to yield enantioselectivies greater
than or equal to 90 % ee:
[10]
* Ward and co-workers
have substantially improved the performance
of metal-complex/protein hybrids by
a combined chemogenetic approach.
[11]
* Rolfes and Feringa
could for the
first time efficiently transfer the chiral information of the DNA double
helix to a metal-catalyzed, enantioselective reaction.
By structural variations, Ward et al.
have improved the enantioselectivity of
Whiteside9s rhodium–avidin hybrid to
96 % ee.[12] But the strength of the chemogenetic approach is more impressively demonstrated by exploration of a
novel organometallic ruthenium(ii)
Angew. Chem. Int. Ed. 2006, 45, 858 – 860
Angewandte
Chemie
Figure 2. Hydrogenation of acetophenones catalyzed by a supramolecular hybrid composed of a
biotin-modified RuII complex and the protein streptavidin.
complex/streptavidin
hybrid
(Figure 2).[10] The h6-arene complex catalyzes the reduction of acetophenone to 1phenylethanol by transfer hydrogenation, using formate as the hydrogen
source. A biotin conjugate of the complex (Figure 2) forms a 1:1 mixture of
epimers at ruthenium; alone, this catalyst produces a racemic mixture of the
alcohol.
Remarkably, the choice of the capping arene (h6-benzene or h6-p-cymene)
determines which enantiomer of the
product is produced preferentially (Table 1). In addition, several streptavidin
point mutants were screened to “genetically” optimize the performance of the
system. Mutant Pro64Gly (i.e. proline at
position 64 in the wild-type protein is
replaced by glycine) reduces the enantioselectivity of the h6-benzene complex
but increases the R selectivity of the pcymene complex from 66 to 85 %, and
up to 94 % ee with the substrate p-
Table 1: Effect of structural variation of the Ru
complex/streptavidin hybrid on catalyst performance.[10] [a]
Rn
X
Streptavidin Conv. ee
[%]
[%]
H
p-Me(iPr)
H
p-Me(iPr)
p-Me(iPr)
H
H
H
H
CH3
wild type
wild type
Pro64Gly
Pro64Gly
Pro64Gly
30
82
30
90
92
[a] Water, pH 6.3, 1 % catalyst, 45–55 8C.
Angew. Chem. Int. Ed. 2006, 45, 858 – 860
63 (S)
68 (R)
58 (S)
85 (R)
94 (R)
diene and a prochiral dienophile that
binds the metal ion through a pyridyl
group (Scheme 1). Both endo and exo
cycloaddition products are formed, each
as a mixture of two enantiomers. The
CuII complex of the achiral ligand alone
forms the endo product in excess, but
both the endo and exo forms are essentially generated as racemic mixtures. In
the presence of salmon testes DNA, the
complex anchors to the DNA double
helix through the acridine intercalator,
and DNA is expected to create a chiral
“second sphere” and control the enantioselectivity of the reaction. The reactions were performed in water and
followed to > 80 % completion (three
days at 5 8C), and the Cu complex
completed up to 22 turnovers.
Scheme 1. Diels–Alder reaction catalyzed by supramolecular hybrid of a 9-aminoacridinemodified CuII complex and ds-DNA.
methylacetophenone (X = CH3). Chemical and genetic methodologies have
been combined efficiently to optimize
the activity and enantioselectivity of the
hybrid catalyst (Table 1). Very recently,
the substrate specifity of hybrid hydrogenation catalysts could also be tuned in
this way.[13]
In a remarkably simple, supramolecular approach, Roelfes and Feringa
could demonstrate the potential of hybrid DNAzymes in asymmetric catalysis.[11] A catalytically active copper(ii)
complex was attached to DNA through
a 9-aminoacridine unit, a small aromatic
molecule that efficiently intercalates
into the DNA double helix. The copper(ii) complex catalyzes a Diels–Alder
reaction between the diene cyclopenta-
As already observed for the metal–
protein hybrids, variations in the chemical structure of the Cu complex have a
dramatic influence on catalytic selectivity. First, the length of the (CH2)n spacer
between the bidentate chelating ligand
and the aminoacridine moiety is crucial
for both the enantioselectivity and the
enantiopreference (Table 2). Second,
the choice of substitutent R at the
aliphatic N donor of the ligand significantly influences chirality transfer. For
n = 2 the enantioselectivity is improved
significantly from
37 % ee (R = 1naphthylmethyl) to 78 % ee (R = 3,5dimethoxybenzyl). (Positive and negative ee values indicate the two enantiomers.) The highest selectivity ( 90 % ee
for the exo form) was observed for n = 2
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
859
Highlights
Table 2: Effect of structural variation of the CuII complex/DNA hybrid on catalyst performance.[12] [a]
n
ee(exo)[b] [%]
X
DNA
endo/exo
3
2
5
H
H
H
salmon testes
salmon testes
salmon testes
98:2
96:4
97:3
18
37
<5
2
2
2
H
OMe
H
salmon testes
salmon testes
16-mer duplex
92:8
91:9
82:18
78
90
80
R
[5]
[6]
[a] Water, pH 6.5, 5 8C, 3 days, > 80 % conversion. [b] Positive and negative ee values indicate the
two enantiomers.
[7]
and R = 3,5-dimethoxybenzyl with a
methoxy derivative of the dienophile
substrate (Scheme 1, X = OCH3).
The effect of sequence variation of
the DNA host remains to be explored. A
first indication for the influence of DNA
sequence on catalytic selectivity is the
observation that a synthetic 16-mer dsDNA increases the ratio of the exo
product (from 8 % with salmon testes
DNA to 18 % with 16-mer DNA),
although enantioselectivity is nearly unchanged. In contrast to the protein
hybrids discussed above in which the
localization of metal catalyst is well
defined, intercalation of acridine into
DNA is not sequence specific. Using a
selective DNA binding moiety tethered
to the catalyst would open the possibility
to address specific DNA sequences and
create a well-defined second sphere.
In summary, supramolecular hybrid
catalysts of achiral or racemic metal
complexes and biomacromolecules
(proteins, DNA) have recently been
optimized for high enantioselectivity
( 90 % ee for specific reactions) by
860
www.angewandte.org
combined structural variation of both
the chemical and the biological component. It will be interesting to apply the
concept to a broader range of reactions
and to add the potential of directedevolution methods with a more extensive structural variation of the biomolecular part for creating highly enantioselective hybrid catalysts.
[8]
[9]
[10]
Published online: December 22, 2005
[11]
[1] a) W. S. Knowles, Angew. Chem. 2002,
114, 2096 – 2107; Angew. Chem. Int. Ed.
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2022; c) K. B. Sharpless, Angew. Chem.
2002, 114, 2126 – 2135; Angew. Chem.
Int. Ed. 2002, 41, 2024 – 2032.
[2] H.-U. Blaser, Chem. Commun. 2003,
293 – 296.
[3] D. H. Moffet, M. H. Hecht, Chem. Rev.
2001, 101, 3191 – 3203.
[4] a) M. T. Reetz, A. Zonta, K. Schimossek, K. Liebeton, K.-E. Jaeger, Angew.
Chem. 1997, 109, 2961 – 2963; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2830 –
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[12]
[13]
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Sci. USA 2004, 101, 5716 – 5722; Extension of the methodology to the development of hybrid catalysts was proposed:
M. T. Reetz, M. Rentzsch, A. Pletsch,
M. Maywald, Chimia 2002, 56, 721 – 723.
R. R. Breaker, Chem. Rev. 1997, 97,
371 – 390; A. Jenne, M. Famulok, Top.
Curr. Chem. 1999, 202, 101 – 131.
B. Seelig, S. Keiper, F. Stuhlmann, A.
JLschke, Angew. Chem. 2000, 112, 4764 –
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P. Ordukhanian, G. F. Joyce, J. Am.
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D. Qi, C. M. Tann, D. Haring, M. D.
Distefano, Chem. Rev. 2001, 101, 3081;
C. M. Thomas, T. R. Ward, Chem. Soc.
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suggested: M. T. Reetz, Chimia 2002,
56, 721 – 723.
M. E. Wilson, G. M. Whitesides, J. Am.
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J. Am. Chem. Soc. 2004, 126, 14 411 –
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