A tripodal peptide ligand for asymmetric Rh(ii) catalysis highlights unique features of on-bead catalyst development

Article abstract of DOI:10.1039/c3sc53354a

A tridentate eq-eq-ax peptide ligand for rhodium(ii) complexes, discovered by high-throughput on-bead screening, is an efficient and selective catalyst for asymmetric cyclopropanation reactions. The metallopeptide catalyst is easily prepared and screened on bead. The axial imidazole ligand significantly improves catalyst function over previous mono-peptide Rh(ii) catalysts. Experimental and theoretical investigations shed light on the role of the imidazole ligand and the structural consequences of imidazole ligation. These studies also explain the differential behavior of these metallopeptide catalysts in solution and on bead, and provide insight into the development of immobilized homogeneous catalysts in general.

Full text of DOI:10.1039/c3sc53354a

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A tripodal peptide ligand for asymmetric Rh(II)
catalysis highlights unique features of on-bead
catalyst development†
Cite this: Chem. Sci., 2014, 5, 1401
Ramya Sambasivan,a Wenwei Zheng,a Scott J. Burya,b Brian V. Popp,c Claudia Turro,b
a
a
*
Cecilia Clementi and Zachary T. Ball
A tridentate eq-eq-ax peptide ligand for rhodium(II) complexes, discovered by high-throughput on-bead
screening, is an efficient and selective catalyst for asymmetric cyclopropanation reactions. The
metallopeptide catalyst is easily prepared and screened on bead. The axial imidazole ligand significantly
improves catalyst function over previous mono-peptide Rh(II) catalysts. Experimental and theoretical
investigations shed light on the role of the imidazole ligand and the structural consequences of imidazole
ligation. These studies also explain the differential behavior of these metallopeptide catalysts in solution
and on bead, and provide insight into the development of immobilized homogeneous catalysts in general.
Received 6th December 2013
Accepted 16th January 2014
DOI: 10.1039/c3sc53354a
www.rsc.org/chemicalscience
site isolation behavior prevents assemblies and catalyst–catalyst
interactions in general. On the other hand, catalyst–catalyst
Introduction
interactions are oen detrimental to selective homogeneous
catalysis, and can lead to catalyst-poisoning or decreased
selectivity.5 Ligand design oen must prevent such interactions,
e.g. through steric screening. Because of these disparate catalyst
requirements, it is oen true that soluble catalysts cannot be
effectively adapted to immobilized settings. It is probably less
appreciated, however, that many putative immobilized catalysts
would be wholly unsuitable as soluble catalysts. This would
imply that building immobilized catalysts by adapting soluble
ones will prevent the discovery of many classes of successful
immobilized structures.
Immobilized variants of soluble transition-metal complexes are
an important class of catalysts that exists at the interface between
the two other predominant metal catalyst types: traditional
heterogeneous materials and soluble, molecular transition-metal
complexes. While immobilized catalysts have characteristics of
both soluble and heterogeneous catalysts, they are typically
discovered by adaptation from known soluble catalysts.1 In this
report, we describe efforts to identify immobilized rhodium(II)
metallopeptide catalysts directly through screening on bead, and
we present evidence of the unique opportunities available for the
development of single-site, immobilized catalysts by conducting
screens directly on immobilized species.
As part of a program aimed at mimicking the properties of
metalloenzymes6–10 for developing asymmetric transition metal
catalysts,11–13 and for rhodium(II) carboxylate complexes in
particular, we have demonstrated that peptides with two
carboxylate side chains (glutamate or aspartate) serve as
chelating ligands12 for rhodium(II), allowing asymmetric catalytic
reactions of diazo compounds.14–17 Polypeptides are readily
optimizable ligands for stereoselective catalysis owing to the
chirality and structural variation present in amino acids.18–20 Our
initial efforts14 developed screening methods that identied bis-
peptide complexes of the type Rh2(peptide)2. In these initial
efforts, we observed efficient chiral induction only for bis-peptide
complexes. These complexes create a dense chiral environment
near the two rhodium active sites, yet are difficult and inefficient
to prepare: Rh2(peptide)2 complexes are formed as two isomers16
with parallel and antiparallel orientations of the peptide ligands,
which were separated by tedious RP-HPLC before use. In addi-
tion, as we have sought to develop more high-throughput, on-
bead screening methods,15 it was clear that Rh2(peptide)2
complexes could not be efficiently synthesized on solid support,
As roughly homogeneous molecular entities, immobilized
catalysts exhibit single-site catalyst behavior and have ligand
structures that can be readily altered and optimized. However,
like heterogenous catalysts, these species resist catalyst
contamination of the product, facilitate reaction workup and
catalyst reuse, and can exhibit larger turnover numbers.2
Immobilized catalysts have distinct requirements that differ
from those of soluble catalysts. For example, homogeneous
catalysts or ligands that act as higher-order assemblies or
aggregates3,4 are not readily amenable to solid support, where
aDepartment of Chemistry, Rice University, MS 60, 6100 Main street, Houston, Texas,
USA. E-mail: zb1@rice.edu; Fax: +1 713 348 5155; Tel: +1 713 348 6159
bDepartment of Chemistry and Biochemistry, The Ohio State University, Columbus,
Ohio, USA. E-mail: turro@chemistry.ohio-state.edu; Tel: +1 614 292 6708
cBennett Department of Chemistry, 100, Prospect street, Morgantown, West Virginia,
USA. E-mail: brian.popp@mail.wvu.edu; Fax: +1 304 293 4904; Tel: +1 304 293 0773
† Electronic supplementary information (ESI) available: Experimental details,
library results, characterization data for cyclopropane products, MD and DFT
renement data. See DOI: 10.1039/c3sc53354a
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so we resorted to screening solid-supported peptides as mono- complexes containing a dissociation-inert NHC ligand in an
peptide, Rh2(peptide)(OAc)2 complexes in 96-well format. The axial site.24,25
best sequences were then re-synthesized to make corresponding
Incorporating a residue designed for axial ligation, such as
soluble Rh2(peptide)2 complexes. We successfully identied a histidine or methionine, was a potentially more attractive
number of useful bis-peptide complexes, but this roundabout means of accomplishing these same goals: it allows design
approach relies on the expeditious—but uncertain—assumption control over which metal center is blocked by axial ligation, and
that optimizing selectivity in Rh2(peptide)(OAc)2 complexes is a it prevents the formation of catalytically dead bis-axial ligation.
reasonable proxy for selectivity of Rh2(peptide)2 complexes. This Furthermore, the intramolecular nature of such tris-chelating
approach was necessary because our initial screens of roughly eq-eq-ax should minimize the involvement of “unbound” cata-
200 sequences did not uncover any mono-peptide complexes lysts with two free axial sites. In this paper, we describe the
yielding the cyclopropane product in >55% ee.15 However, mono- development and exploration of such site-selective mono-
peptide complexes, Rh2(peptide)(OAc)2 are attractive catalysts: peptide catalysts affording high selectivities—up to 97% ee at
they have lower molecular weight, comparing favorably with room temperature (Fig. 1).
traditional small-molecule catalysts. More importantly, because
there is no isomer issue in their formation, they can be prepared
in high yield, without wasting half of the catalyst preparation as
Results
the inferior isomer.
Although straightforward in theory, creating tridentate ligands
that feature a Lewis basic residue chelating to the axial site of
rhodium(II) is experimentally challenging. In contrast to stable
and largely covalent equatorial ligands, axial ligation is weak
and readily reversible in aqueous solution (Kd ꢀ 50 mM).26,27 As a
result, our experience has been that sequences with histidine or
methionine residues, on complexation with Rh(II), form inter-
molecular axial interactions, resulting in ill-dened aggregates
When simple screening failed to uncover effective mono-
peptide catalysts, we decided to change course and modify
our peptide design approach. The lack of symmetry of mono-
peptide complexes, Rh2(peptide)(OAc)2, implies that the two
rhodium atoms should have different chemical environments;
our modeling studies indicated that mono-peptide complexes
provided a robust chiral environment for only one of the two.
One concept we explored was the potential for a third ligating
residue that could bind to one axial position, potentially
blocking the less selective catalytic site (Fig. 1, bottom right).
Two recent reports indicate that external axial ligands can affect
rhodium metallocarbene selectivity, and, intriguingly, both of
these reports involve carboxylate ligands that create different
chemical environments for the two Rh centers.21–23 In one of
these reports, we explored the addition of external phosphites
and found modest increases in enantioselectivity.21 Conceptu-
ally related efforts have examined catalysis with rhodium(II)
Table 1 High ee yielding sequences from libraries 3,4 and 5 for the
formation of product 2a
Ligand
Ligand sequence
% eea
51
% eeb
L2.3615
—
L3.01
L3.02
L3.03
L3.04
L3.05
56
79
56
68
71
—
—
—
—
—
L4.31
L4.28
L4.46
L4.49
L4.52
68
76
76
78
78
—
—
—
—
—
L5.60
L5.64
L5.66
L5.67
L5.75
L5.78
a
84
87
87
89
88
89
95
96
96
97
95
96
Fig. 1 On-bead screening of tripodal peptide ligands for cyclo-
propanation. Reaction conditions: diazo (6 mmol), styrene (60 mmol)
and catalyst (ꢀ0.15 mmol), in CF3CH2OH, overnight at room temper-
ature. All catalysts are attached to the resin at the C-terminus of the
peptide, and the peptide N-terminus is acetylated.
Enantioselectivity of the crude product determined by chiral HPLC
b
analysis. Enantioselectivity of the pure isolated product determined
by chiral HPLC analysis. Gt-Bu ¼ tert-butyl glycine; Z ¼ benzyloxycarbonyl.
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that are challenging to purify and isolate. Proper design of a peptides was not fruitful, but switching to histidine as an axial-
peptide ligand that favors intramolecular axial interactions ligating residue resulted in a number of interesting catalysts. In
might potentially alleviate these issues, but on-bead catalyst L3 screen, ve catalysts—all with histidine in the i + 5 posi-
preparation and screening should render these issues moot, tion—afforded cyclopropanation products in >55% ee (Table 1),
since solid-supported peptides are generally precluded from higher than the selectivity observed with any of ꢀ200 peptides
intermolecular interactions. We previously put into practice in previous screens (L1 or L2).15 Having found a preferred
these ideas: a screen of several resin types and loadings found position for histidine incorporation, this residue was conserved
that so long as loading is kept low (ꢀ0.2 mmol gꢁ1), catalytic predominantly in the i + 5 position for L4 synthesis, which
behavior on resins closely mirrored that in solution.15,17
provided enantioselectivity up to 78%. A nal library (library 5)
We designed and synthesized libraries to assess these ideas incorporating histidine in the i + 5 position and optimal amino
using a parallel synthesis approach in a 96-well-plate format acids from previous libraries in the other positions was
previously developed in our group.15 Starting with 9-mer peptide synthesized. This library screen identied several on-bead
ligands with rhodium-binding aspartate residues at the 3rd and mono-peptide catalysts (L5.xx, see Table 1), varying only in the
7th residues, we chose for variation specic residues, based on 4th or 5th amino acid, that each afforded the product in good
modeling or the results of previous libraries. Variation was (95–97%) enantioselectivity. Scrambling the histidine to other
allowed with a group of two to seven structurally diverse amino positions resulted in inferior catalysts.
acids. We synthesized 95 random members of the theoretical
We tested this class of histidine-containing catalysts with
library (20% of possible sequences). Amino acid positions that various olen substrates in cyclopropanation reactions with
were consistently seen in more selective catalysts were used to tert-butyl a-phenyldiazoacetate. Even at room temperature,
x or heavily bias the next round of library screening (for >90% ee was observed with most olens tested (Table 2), and in
complete details of the libraries and ee values, see ESI†). In this several cases was meaningfully higher than those achieved with
work, three 96-well libraries (L3, L4, and L5) were evolved the previous-generation bis-peptide catalysts. Notably, the
sequentially from the previously reported L1 and L2.15
reaction with a cyclic enol ether yielded the product cyclopro-
When we designed a 96-peptide random library (L3) that pane in 94% ee (Table 2, entry 7) which is signicantly greater
allowed incorporation of histidine and methionine in a subset than the selectivity observed with the solution-phase bis-
of peptides, we found that the histidine- and methionine-con- peptide catalyst derived with the “winning” sequence identied
taining peptides functioned as useful catalysts. Our earlier via on-bead screening in library 2, published previously (80%
on-bead catalyst library (L2)15 screening yielded a methionine- ee, catalyst Rh2(L2.47)2-A).15 We have successfully scaled up the
containing ligand, L2.36 that afforded the product cyclopro- cyclopropanation of an N-vinyl substrate up to 1 mmol without
pane in 51% ee. Optimization of methionine-containing diminishment in yield or selectivity. Interestingly, and quite
importantly, when we prepared catalysts in solution from
puried peptides, signicantly lower enantioselectivity was
observed (81% vs. 37% ee for L5.47, see eqn (1)). To test
Table 2 Asymmetric cyclopropanation with a-diazophenylacetate
the impact of the key histidine residue, we made the catalyst
with a His / Phe substitution. The nearly isosteric phenylala-
nine-containing catalyst (on bead) produced product in 59%
ee (eqn (1)).
Entry Alkene
R1
R2
Prod. ee (%) Yield
Quant.a
98%
(1)
1
2
Me Ph
2a
2b
96
92
tBu Ph
3
tBu OEt
2c
89
Quant.a
4
tBu Ph
2d
99
Quant.a
Discussion
The signicantly better performance of the L5.47 catalyst on
bead, compared to its solution behavior, led us to examine the
reasons for this difference. The catalyst L5.47 contains two
macrocycles formed upon tridentate binding to the rhodium
center, a 12-membered ring and a 24-membered ring. This
feature is somewhat unusual for transition-metal ligands. The
majority of successful asymmetric ligands have small-ring
chelates to the metal center. Strong catalyst preorganization,
favoring chelate structures, is common, especially in cases with
larger, macrocyclic ring sizes formed upon metal binding. In
5
6
tBu (p-Cl)Ph
tBu NMeAc
2e
2f
95
Quant.a
92%b
95b
7
tBu –OCH2CH2– 2g
94
Quant.a
a
b
Yield determined by NMR. Reaction was carried out on a 1 mmol
scale with respect to diazo substrate with Rh2(L5.67)(OAc)2 catalyst.
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solution, small-ring chelates and strong preorganization is
important to prevent bis-metal binding leading to poorly orga-
nized aggregates.28 In immobilized catalysts, this feature is less
important. Because the site isolation afforded by solid support
should generally limit the ability of a metal to bind two different
ligands at once, preorganization should not be an important
criterion for ligand design on solid support. This is especially
true of relatively modest metal–ligand interactions, such as
imidazole–rhodium coordination (Kd ꢀ 50 mM).
The poor enantioselectivity observed in solution with catalyst
L5.47 implies that a different catalyst structure acts in solution.
The supported catalyst L5.47 exhibits a clear blue-shi in visible
absorbance, relative to the isosteric phenylalanine-containing
catalyst, when measured by diffuse reectance spectroscopy
(Fig. 2). A similar shi is observed with the related methionine-
containing catalyst. The blue-shi is indicative of the presence
of a strong donor ligand in the axial position. The blue-shi is
visible to the naked eye as a color shi from blue to green (His)
or pink (Met). We were able to validate the presence of axial
imidazole–rhodium interactions through kinetic means as well.
Within the dirhodium core, coordination of a strong donor
ligand at one axial position is known to result in a decrease in
reaction rate at the other rhodium atom, due to the electronic
effect.21,23 Both histidine and methionine catalyst variants have
signicantly retarded reaction kinetics, with a krel that is 4- to
6-fold lower than the phenylalanine control, in line with
previous work (Fig. 3).29
The behavior in solution is signicantly different. Both
metallopeptides formed from His- or Phe-containing peptides
are cleanly synthesized in high yield within three hours, as
judged by analysis of the reaction mixture by MALDI-MS (see
ESI†), which ionization conditions generally break up aggre-
gates. While the crude Phe-containing metallopeptide exhibits
an expected HPLC with a single major peak (Fig. 4, X ¼ Phe), the
chromatogram for the histidine peptide (X ¼ His) shows a large
number of broad, overlapping peaks, indicative of aggregate
Fig.
3
Kinetics of the cyclopropanation of methyl a-phenyl-
diazoacetate and styrene at rt in CF3CH2OH catalyzed by on-bead
Rh2(IGDNINDXK)(OAc)2.
formation through intermolecular imidazole interactions. We
have observed this aggregation phenomenon previously when
synthesizing rhodium variants of biologically relevant peptides,
a problem solved by substituting for natural methionine and
histidine residues.30
To understand how histidine coordination affects catalyst
selectivity, we conducted a computational study. Molecular
Dynamics (MD) calculations were performed in conjunction
with quantum mechanical modeling using Density Functional
Theory (DFT). The former helps to identify stable peptide-
binding congurations, whereas the latter provides an accurate
structure of the transition metal complex. The sequence
IGDNINDHK was chosen as the model system for MD simula-
tions. The peptide was simulated in implicit solvent with
Generalized Born formalism in GROMACS v4.5.4.31 A total of 18
simulations (each 500 ns long) were performed and the data was
recorded every 100 ps. The free energy prole and stable states
of the free peptide were identied by applying LSDMap and
analyzing the merged data (90 000 frames) from these simula-
tions. LSDMap is a recently developed nonlinear dimensionality
reduction method32 to dene ‘optimal’ reaction coordinates,
Fig. 2 Diffuse reflectance of the on-bead Rh2(IGDNINDXK)(OAc)2
catalysts in Kubelka Munk units (KM). Inset picture shows the wells with
the on-bead catalyst. The l @ lowest reflectance for X ¼ His 590 nm; Fig. 4 HPLC traces of crude reaction mixture during solution-phase
X ¼ Phe 596 nm and X ¼ Met 547 nm.
Rh2(IGDNINDXK)(OAc)2 synthesis.
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that correspond to the slowest collective motions of the system,
and extract them from MD simulation. The free energy pro-
jected onto the rst two diffusion coordinates from the LSDMap
calculation is shown in Fig. 5.
The MD simulations of the free peptide identify a-helix-like
structures (Fig. 5, states A, B, C) to be predominant in solution.
We have previously demonstrated that chelating a rhodium(II)
center to carboxylate side chains with i, i + 4 spacing (as
employed here) signicantly increases this bias in favor of
a-helix structures. Thus, it is reasonable to assume that the
simple bis-carboxylate peptides adopt a helical structure when
bound to rhodium, in line with previous data and assumptions.
The MD simulations indicate that non-helical structures (states
D, E; random or turn-like structures) account for only a small
part of the available energy landscape. The helical structures
constitute nearly 86% of the total number of frames calculated.
To understand the impact of imidazole coordination, we iden-
tied conformations from each state found in MD simulations
that placed the carboxylate and histidine residues closest to the
positions necessary for optimal rhodium-binding geometry.
The chosen conformations were then subjected to steered MD
in GROMACS v4.5.4 with PLUMED plug-in.33 A total of 22
conformations were identied that had the appropriate binding
angles to the arbitrary dirhodium core. Importantly, regardless
of the initial conformation, all computed tridentate metal-
lopeptides exhibited similar non-helical, turn-like structure.
Further renement of the optimal tridentate metallopeptide
structure was achieved using DFT methods (see ESI† for
Fig. 6 (a) Cartoon depiction of preferred secondary structure attained
upon Rh(II) complexation. Left: peptide IGDNINDFK attains an a helix;
right: peptide IGDNINDHK is proposed to attain a hairpin turn (b) DFT
energy minimized model of the Rh2(IGDNINDHK)(OAc)2 catalyst
featuring axial imidazole ligation. The putative catalytic site trans to the
axial-imidazole ligand was occupied by a molecule of water. For
simplicity, formates were used instead of acetates. Hydrogen atoms
have been omitted for clarity.
details), providing a reasonable and representative structure of
tridentate catalysts (Fig. 6b).
The computational results demonstrate that the third ligand
(imidazole) causes a structural switch—from helical to turn-
like—of the peptide backbone (Fig. 6a). The helical structure is
completely inaccessible when the imidazole group is bound to
the axial position. The fact that the ligand itself prefers helical
conformations may explain the complex behavior of the catalyst
in solution: histidine coordination comes at the cost of dis-
rupting the preferred helical secondary structure. Thus, in
solution, intermolecular histidine–rhodium interactions, which
do not require disrupting the helical conformation, out-
compete intramolecular interactions; on bead, intermolecular
interactions are not possible.
Conclusions
This tripodal class of peptide-based ligands allows construction
of mono-peptide catalysts of the type Rh2(peptide)(OAc)2, a
signicant step forward relative to previous, soluble bis-peptide
Rh2(peptide)2 catalysts. In addition to improved enantiose-
lectivity in cyclopropanation reactions, these immobilized
catalysts are trivial to prepare. Standard on-bead peptide
synthesis and rhodium metalation methods deliver active cata-
lysts with no purication beyond simple ltration. In contrast,
our previous bis-peptide catalysts Rh2(peptide)2 required careful
HPLC separation of orientational (parallel and antiparallel)
isomers, wasting half of the material and making the catalysts
inappropriate for preparative work. The catalysts are selective at
Fig. 5 Upper panel: free energy as a function of the first and second
diffusion coordinates with minima marked; lower panel: the typical
configurations in the free energy minima marked in the upper panel.
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room temperature, unlike previous soluble bis-peptide catalysts
that required cryogenic conditions for selectivity, and immobi-
lized metallopeptide catalysts can be easily separated by ltra-
tion. These advances are all made possible by the power of
on-bead catalyst discovery, which enable us to synthesize and
assess catalysts in 96-well-plate format in a matter of days.
Work in metallopeptide design and catalysis is oen moti-
vated by the inspiration of natural metalloenzymes. Metal-
loenzymes use large polypeptide structure to provide steric
screening and to control access to the active site, resulting in
largely site-isolated active sites. Minimalist peptide ligands are
rarely able to replicate this aspect of natural enzymes. Our data
suggest that by employing an on-bead strategy, we are able to
build enzyme-like site isolation into a metallopeptide catalyst,
avoiding destructive intermolecular interactions in the process.
Together with modern analytical tools that can assess structure
of solid-supported materials, it is possible that metalloenzyme
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Acknowledgements
We thank Prof. Angel Marti and Avishek Saha for assistance
with diffuse reectance measurements. We acknowledge 23 For a contradictory analysis of axial ligands in rhodium
nancial and computing resources from West Virginia Univer-
sity (B.V.P.) and nancial support from the Robert A. Welch
Foundation Research Grant C-1680 (Z.T.B.) and Research Grant
metallocarbene chemistry, see: M. C. Pirrung, H. Liu and
A. T. Morehead, J. Am. Chem. Soc., 2002, 124, 1014–
1023.
C-1570 (C.C.). This work was supported by the National Science 24 A. F. Trindade, J. A. S. Coelho, C. A. M. Afonso, L. F. Veiros
Foundation under grant numbers CHE-1055569 (Z.T.B.), CHE- and P. M. P. Gois, ACS Catal., 2012, 2, 370–383.
1152344 (C.C.) and CHE-1265929 (C.C.). C.T. acknowledges 25 P. M. P. Gois, A. F. Trindade, L. F. Veiros, V. Andre,
´
partial support of this work by the Chemical Sciences, Geo-
M. T. Duarte, C. A. M. Afonso, S. Caddick and
sciences and Biosciences Division, Office of Basic Energy
F. G. N. Cloke, Angew. Chem., Int. Ed., 2007, 46, 5750–5753.
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