Metallopeptides for asymmetric dirhodium catalysis

Article abstract of DOI:10.1021/ja103747h

Natural peptide sequences ligate to dirhodium centers through two bridging aspartate side chains, creating a macromolecular ligand framework with helical structure. The generation of a small peptide library allowed optimization of peptide sequence and produced an efficient catalyst for enantioselective carbenoid insertion into Si-H bonds. Analysis of the library indicates that the i-1 and i+3 positions of nonapeptides have the most significant effect on enantioselectivity, though the structural basis for selectivity is different at each of the positions.

Full text of DOI:10.1021/ja103747h

Published on Web 06/02/2010
Metallopeptides for Asymmetric Dirhodium Catalysis
Ramya Sambasivan and Zachary T. Ball*
Department of Chemistry, Rice UniVersity, MS 60, 6100 Main Street, Houston, Texas
Received May 2, 2010; E-mail: zb1@rice.edu
Abstract: Natural peptide sequences ligate to dirhodium centers
through two bridging aspartate side chains, creating a macro-
molecular ligand framework with helical structure. The generation
of a small peptide library allowed optimization of peptide sequence
and produced an efficient catalyst for enantioselective carbenoid
insertion into Si-H bonds. Analysis of the library indicates that
the i-1 and i+3 positions of nonapeptides have the most
significant effect on enantioselectivity, though the structural basis
for selectivity is different at each of the positions.
Polypeptides are the predominant biological solution to chemo-
and stereoselective ligand design. They are modular structures
allowing facile side-chain variation and have been developed as
useful asymmetric catalysts.1 Chiral ligand design remains a largely
empirical exercise, so straightforward access to large ligand libraries
is often critical to successful reaction development. Despite the
obvious attraction of peptide ligands, extending the example of
natural metalloenzymes to synthetic capabilities has been limited.2
In this paper, we describe the use of carboxylate-containing peptides
as ligands for asymmetric dirhodium catalysis. The few examples
of stereoselective organometallic catalysis with peptide ligands have
typically employed non-natural amino acids containing phosphine3
or pyridine4 groups or attachment of whole coordination complexes
to proteins by covalent5 or supramolecular6 means.
Rh2(L1)2-isoB relative to the mono-peptide complex led us to pursue
a broader screen of bis-peptide complexes (Figure 1).
Dirhodium tetracarboxylates are important catalysts for asym-
metric synthesis,7 catalyzing useful reactions of diazo compounds
that are compatible with diverse functional groups. We have recently
demonstrated that the side-chain carboxylates of a peptide can be
used as bidentate ligands for dirhodium,8 affording metallopeptides
that retain catalytic activity in diazo decomposition reactions.8c We
chose the insertion of PhMe2SiH into methyl R-diazophenylacetate9
as a model reaction to explore the selectivity of dirhodium
metallopeptide catalysts.
Our ligand design began with the notion that peptides with
defined secondary structure would be good candidates for asym-
metric induction. We examined nonapeptide ligands such as
KADAALDAK (L1) that feature carboxylate-containing residues
(glutamate, E or aspartate, D) with i, i+4 spacing to induce R-helical
structure.8b The complex Rh2(OAc)2(L1), with a chelating bis-
carboxylate peptide ligand,10 was accessed8a by treatment of the
peptide ligand with Rh2(OAc)2(tfa)2 and provided a modest 32%
ee (eq 1). In an attempt to improve chiral recognition, we turned
to the bis-peptide complex Rh2(L1)2, accessible by reaction of the
peptide with Rh2(tfa)4. The bis-peptide complexes are formed as
mixtures of parallel and antiparallel isomers (eq 1), which are
separable by HPLC.11 The two isomers of Rh2(L1)2 provided
different levels of enantioinduction (20% vs 45%), and the ee
afforded by Rh2(L1)2-isoB could be improved to 58% by dropping
the reaction temperature to -35 °C and changing the solvent to
pure CF3CH2OH.12 The improved enantioselectivity afforded by
Figure 1. Optimization of a peptide ligand for eq 1. Reaction conditions:
0.5 mol % Rh2(L)2 catalyst at -35 °C in CF3CH2OH. All ligands are
C-terminal -NH2 amides and N-terminal acetyls. Lysine side chains are
capped as Cbz carbamates to improve solubility.
Circular dichroism studies indicated that even very short peptides
with i, i+4 carboxylate spacing become strongly helical upon metal
binding (see the Supporting Information).8a Based on computed
structures of the helical metallopeptides,8b we identified the residues
in positions i-1 and i+3 as positioning side chains in proximity
to the metal center and thus as likely to impact stereoselectivity
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J. AM. CHEM. SOC. 2010, 132, 9289–9291 9289

C O M M U N I C A T I O N S
on enantioselectivity, even when compared to the other residues
adjacent to aspartate ligation sites, i+1 and i+5 (Figure 1, L14,
L16).
Although the enantioselectivity of the complex Rh2(L1)2 was
modest, our peptide screen soon arrived at a new peptide, L21,
that provides the silane product in 92% ee (Figure 1). Several trends
emerge from the peptide screen. At the i+3 position, steric size
correlates with product enantioselectivity: the best ligands contain
bulky residues at this position (e.g., L7, L8, L20, L21). The
structural basis for selectivity at the i-1 position is less obvious.
The best residues at the i-1 position include threonine, asparagine,
and tryptophan, but selectivity drops significantly with the sterically
demanding isoleucine (e.g., L5). Brief explorations of glutamate
linkages (L2, L17, L18) or alternative carboxylate spacing (L19,
L22) produced inferior catalysts. An intriguing aspect of this work
is the variability in enantioselectivity between isomeric versions
of a given bis-peptide catalyst. In certain cases both isomers of the
bis-peptide catalysts exhibit comparable ee (e.g., 79% and 81%
for L8), while for other ligands a pronounced difference is observed
(7% and 80% for L7). Several R-diazoesters were examined for
Si-H insertion using the optimized catalyst, Rh2(L21)2-isoB. All
3- and 4-substituted aryl substrates reacted to form the product with
90-99% ee (Table 1). Ortho substitution has a deleterious effect
on selectivity (entries 8-9). Allylsilanes are important chiral
intermediates, and we were gratified to find that a vinyl-substituted
diazo substrate could also be efficiently transformed into the
corresponding allyl silane (entry 7). Selectivity was lower for an
alkyl-substituted substrate (entry 10).
Figure 2. Tube and space-filling models for L21 bound to a dirhodium
center. The key i-1 and i+3 residues are shown in blue. For clarity, Cbz
groups, hydrogen atoms, and the second peptide chain are not shown.
(Figure 2). We synthesized a small peptide library and found that
the predicted i-1 and i+3 positions have the most significant effect
Table 1. Asymmetric Insertion of Diazoacetates into Si-H Bonds
In conclusion, we demonstrate a strategy to utilize natural
polypeptide ligands in the development of chiral dirhodium
catalysts. Starting from a relatively poor initial “hit” of 45% ee,
the power of parallel automated peptide synthesis allowed us to
quickly arrive at an effective catalyst. The combined efficiency of
peptide libraries and facile dirhodium complexation should prove
valuable in the discovery of selective catalytic transformations.
Acknowledgment. We thank Prof. Jeffrey Hartgerink and Erika
Bakota for assistance with peptide synthesis and Dr. Brian V. Popp
and Alexander N. Zaykov for helpful discussions. We acknowledge
financial support from the Robert A. Welch Foundation Research
Grant C-1680 and Rice University.
Supporting Information Available: Experimental details, spectral
data for insertion products, and characterization data for metallopeptides.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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