Screening rhodium metallopeptide libraries "on bead": Asymmetric cyclopropanation and a solution to the enantiomer problem

Article abstract of DOI:10.1002/anie.201202512

Searching with a beady eye: A high-throughput, on-bead screen of rhodium metallopeptide catalysts was developed in a 96-well format for asymmetric cyclopropanation. Different sequences of natural L-amino acids have been identified that produce opposite product enantiomers (see picture). In addition to styrene derivatives, high enantioselectivity is observed for vinyl ether and vinyl amine derivatives.

Full text of DOI:10.1002/anie.201202512

Angewandte
Chemie
DOI: 10.1002/anie.201202512
Catalyst Screening
Screening Rhodium Metallopeptide Libraries “On Bead”: Asymmetric
Cyclopropanation and a Solution to the Enantiomer Problem**
Ramya Sambasivan and Zachary T. Ball*
Peptides are, in many ways, ideal ligands for stereoselective
catalysis. Metalloenzymes use polypeptides to bind transition-
metal centers and to control chemo-, diastereo-, and enantio-
selectivity. For chemists, the allure of peptides is equally
strong: peptides are modular, functional-group-rich struc-
tures that can be easily synthesized in parallel by automated
methods. Efficient screening of ligand diversity is especially
valuable because rational design of chiral ligands remains
a daunting challenge. Furthermore, any single ligand may not
be optimal for a new reaction of interest, and so generating
ligand diversity quickly allows solutions for new selectivity
problems. Herein, we describe an on-bead screen of rhodiu-
m(II) metallopeptides to discover new catalysts for asym-
metric reactions of diazo compounds.[1]
hoped to address with an on-bead library was the “enantio-
mer problem:” Chirality derived from natural sources is
typically available in only one enantiomeric form, requiring
new approaches to access the opposite enantiomer.[13]
We chose to examine rhodium(II) metallopeptide cata-
lysts for asymmetric cyclopropanation reactions. Cyclopropa-
nation of styrene with a-diazophenylacetate was conducted
with bis-peptide complexes from our previous silane-insertion
library. We continued to employ 2,2,2-trifluoroethanol (TFE)
as solvent, because it provided a good combination of
metallopeptide solubility and clean diazo reaction. We
identified a catalyst, Rh2(L16)2-A, affording the cyclopropane
(1S,2R)-2b in 93% ee (Figure 1, see Supporting Information
for details). However, we had absolutely no starting point for
developing catalysts that would afford the opposite enantio-
mer, so a high-throughput approach seemed necessary.
An on-bead screen brings a number of challenges. Fore-
most, in previous studies bis-peptide complexes were signifi-
cantly more selective than mono-peptide complexes [Rh2-
(peptide)(OAc)2]. However, it is not possible to build bis-
peptide complexes on solid support. Therefore, we decided to
screen mono-peptide complexes “on bead”, identify the best
Peptides and peptide-like architectures have become
important catalysts in organocatalytic applications.[2]
A
wide-range of reactions, including aldol and related enolate
couplings,[3] oxidation,[4] and conjugate additions[5] have
proven amenable to peptide catalysis. However, the use of
polypeptides in transition-metal catalysis remains limited, in
part because of the difficulty in creating well-defined metal-
binding sites with natural side chains.[6] Amino acids with
unnatural side chains, such as phosphino[7] or pyridyl[8] groups,
are one solution to this problem. Alternatively, complete
transition-metal complexes have been bound to larger protein
structures.[9] We recently described[10] asymmetric Si H
À
insertion with chelating[11] bis-carboxylate nona-peptides as
ligands for rhodium catalysis.[12]
In initial studies, we synthesized and tested about 40 bis-
peptide complexes {Rh2(peptide)2} over many weeks, arriving
at an efficient catalyst that delivered over 90% ee. Although
this was more efficient than traditional multistep ligand
synthesis, we wanted to increase the ease and speed of
optimization. The synthesis of each bis-peptide catalyst
required preparative HPLC purification of both the peptide
and final metallopeptide, which is a significant commitment of
time and materials. To expand the utility of rhodium metal-
lopeptide catalysts, we decided to develop a new method for
preliminary peptide screening. Among the challenges we
[*] R. Sambasivan, Prof. Z. T. Ball
Department of Chemistry MS 60, Rice University
6100 Main street, Houston, TX 77005 (USA)
E-mail: zb1@rice.edu
Homepage: http://www.ztb.rice.edu
Figure 1. Screening peptide ligands for cyclopropanation. Conditions:
catalyst (ca. 0.15 mmol), diazo (6 mmol), and styrene (60 mmol) in
CF3CH2OH. For structural formula of Rh2(L16)2-A, see Figure 3. All
ligands are linked to resin at the C-terminus and acetylated at the N-
terminus. Lysine side chain amines are capped with the benzyloxycar-
bonyl (Z) group; tfa=trifluoroacetate.
[**] We acknowledge financial support from the Robert A. Welch
Foundation research grant C-1680 and from an NSF CAREER award
(CHE-1055569).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202512.
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Table 1: Amino acid variation incorporated in library 1.
candidates, and then synthesize the corresponding bis-peptide
complexes in solution. This approach assumes that sequences
optimized as mono-peptide complexes will generally be more
selective as bis-peptide complexes, a reasonable but unproven
assumption. This approach also accepts that some possible
catalysts might be passed over in the service of expediency.
We verified that rhodium metallopeptides could be
synthesized on solid support with selectivities similar to
a solution-phase catalyst.[7a] Adapting our solution-phase
method,[10,14] an on-resin peptide was metalated with cis-
[Rh2(tfa)2(OAc)2] and N,N-diisopropylethylamine in TFE.
Among several different resins with varying loading levels,
Novasyn TGR (a polystyrene-polyethylene glycol resin, 0.17–
0.29 mmolgÀ1) afforded catalyst for silane insertion that gave
81% ee, comparable to that obtained for the same
iÀ2
iÀ1
P
W
Y
i
i+1
i+2
i+3
i+4
i+5
i+6
KZ
D
A
I
S
A
P
W
Y
D
W
P
A
KZ
M[a]
M[a]
N
S
T
W
M[a]
P[a]
N
S
T
I
N
M[a]
L
L
I
I
G
G
M[a]
M[a]
[a] This amino acid was constrained to 2% at this position. “KZ” signifies
a lysine residue with the side-chain amine protected as a benzyloxycar-
bonyl (Z) carbamate.
Table 2: Sequences from library 1 that gave over 25% ee for the formation of the si
addition product, (À)-2a.
catalyst in solution[12a] (see Supporting Information
for details). The on-bead catalyst was reused three
times without any diminution in ee value. Other
resins examined, especially those with higher load-
ing, produced inferior results.
Ligand iÀ2 iÀ1
i
i+1 i+2 i+3 i+4 i+5 i+6 ee [%]
L1.03
L1.06
L1.07
L1.09
L1.12
L1.13
L1.15
L1.27
L1.42
L1.47
L1.68
L1.78
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
G
G
G
G
G
I
I
L
P
P
T
D
D
D
D
D
D
D
D
D
D
D
D
I
W
I
A
I
P
W
A
P
A
W
A
A
A
A
A
A
A
A
A
A
A
A
M
G
N
N
P
D
D
D
D
D
D
D
D
D
D
D
D
I
I
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
KZ
27
33
46
27
33
29
44
31
38
28
36
39
W
N
P
P
M
P
A
W
I
Our library design focused on sequences with
rhodium-binding carboxylates (aspartate, D) in i and
i + 4 positions. This spacing induces helical order,[15]
and proved optimal in previous studies.[10] There is
tremendous sequence diversity available in even
these short nona-peptides. We chose to synthesize
libraries in 96-well-plate format. We created a library
with variation focused at the residues immediately
neighboring the rhodium center. We included
a diverse group of 6–10 amino acids at the variable
Y
G
N
P
L
N
N
N
W
A
positions, covering a range of steric demand and polarity
(Table 1). The choice to include significant diversity meant
synthesizing only a small portion of the theoretical library. In
addition, we included a few methionine (which offer potential
ligand–rhodium interactions) residues. As designed, library 1
contains 14400 theoretical members, of which we synthesized
94 unique sequences. Because we severely restricted the
number of methionine residues, the synthetic library was
heavily biased for the 1620-member subset of the theoretical
library that excludes methionine (and proline in position i +
1). Our synthetic library contained 80 members of this subset,
5% of theoretical sequences. Control sequences on Rink
amide resin were found to be over 90% pure by MALDI-
TOF mass spectrometry and HPLC. Following synthesis, the
library was screened against methyl a-phenyldiazoacetate (6-
mmol scale, 1 mg). The entire process of peptide synthesis,
metalation, cyclopropanation, and chiral analysis took about
one week for a single 96-well plate.
Figure 2. Scatter plot of enantioselectivity for amino acids in position
i+3 of Library 1. Positive values indicate the si addition product, (À)-
2a.
Our library screen identified a number of metallopeptides
that furnished, in moderate ee, the “opposite” enantiomer,
(À)-(1R,2S)-2a. The catalysts yielding enantioselectivity
greater than 25% are shown in Table 2 (see Supporting
Information for details). To visualize broad trends, we
prepared “scatter plots” of ee values for each amino acid at
a given position. The scatter plot of the i + 3 position
(Figure 2) shows a predominance of asparagine (Asn; N) in
the best sequences, though the preference is not absolute. The
iÀ1 position (Supporting Information) showed a predomi-
nance of glycine (Gly; G) among high-ee value catalysts.
Table 3: Amino acid variation incorporated in library 2.
iÀ2
KZ
iÀ1
G
A
W
Q
i
i+1
i+2
i+3
i+4
i+5
i+6
D
I
W
L
N
T
A
N
D
W
I
M
Y
L
KZ
Q[a]
M[a]
T
F
[a] This amino acid was constrained to 10% at this position.
2
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Chemie
Scatter plots for other positions did not exhibit clear-cut
“winning” residues (see Supporting Information for details).
We created a second 96-well-plate library (L2.xx, Table 3),
taken from a more focused theoretical set of 420 sequences
and incorporating trends observed in the first library. Scatter
plot analysis of the second library did not identify new
residues that consistently out-performed the others
Figure 3).[17] High ee (> 90%) was observed for a variety of
olefins, including styrene derivatives and ethyl vinyl ether.
Our routine conditions involve 0.25 mol% catalyst, and we
ran the reaction in Table 5 entry 2 at lower loading
(0.1 mol%) with comparable yield and selectivity. In addition,
we found that the metallopeptide catalysts were effective for
(see Supporting Information for details). We did
Table 4: Enantioselectivity of soluble catalysts derived from the best on-bead
identify 10 sequences that gave greater than 45% ee
as mono-peptide catalysts on bead. Previous studies
had indicated that significant improvements in enan-
tioselectivity were often observed upon moving to
bis-peptide catalysts, and so we deemed it likely that
optimal peptides identified in library 2 could form
the basis for selective bis-peptide catalysts.
“Winning” peptide sequences from library 2 were
synthesized, producing two isomeric metallopeptides
(denoted [Rh2(L)2-A] and [Rh2(L)2-B]) as a result of
parallel and antiparallel orientations of the peptide
ligands, which were separated and tested independ-
ently (Table 4, entries 1–4).[16] There was no direct
correlation between on-resin, mono-peptide, and bis-
peptide solution catalysts, but several bis-peptide
sequences.
Entry Ligand Sequence
ee [%]
[Rh2(L)2-A] [Rh2(L)2-B]
[Rh2(L)(OAc)2]
on-bead, RT À358C À358C
À358C
1
2
3
4
5
6
7
8
L2.47
L2.13
L2.63
L2.85
L2.12
L2.89
L2.09
L2.95
KQDNANDTK
KGDLANDIK
KGDLANDWK
KGDNANDYK
KADLANDIK
KGDTANDYK
KQDWAQDFK
KADNAQDYK
54
46
46
42
20
17
6
50
47
44
58
9
13
18
5
83
61
68
49
15
28
3
63
14
43
49
75
22
À27
3
13
À4
catalysts outperformed the corresponding mono- [a] Best value highlighted.
peptide catalysts. The highest
Table 5: Asymmetric cyclopropanation with a-diazophenylacetate.
ee value was obtained with the cat-
alyst [Rh2(L2.47)2-A], which pro-
vided 83% ee for styrene cyclopro-
panation with methyl a-diazophe-
nylacetate (at À358C), and 92% ee
for tert-butyl a-diazophenylacetate
(at À508C). We also synthesized
bis-peptide catalysts from “poor”
sequences from library 2 (Table 4
entries 5—8). The average ee value
of these “poor” sequences as bis-
peptide catalysts was far lower than
that of the “winning” sequences as
bis-peptide catalysts, and no “poor”
sequence reached the level of
ee values seen with the best
sequence, L2.47. One isomer of
the catalyst derived from L2.12 did
Entry
Alkene
R’
Prod.
[Rh2(L16)2-A]
re prod.
[Rh2(L2.47)2-A]
si prod.
ee[a] [%]
yield[b] [%]
ee[a] [%]
yield[b] [%]
1
2
3
Me
tBu
tBu
2a
2b
2c
75[c]
93
95[c]
96
68[c]
92
84[c]
92
90
87
92
94
4
5
6
tBu
tBu
tBu
2d
2e
2 f
94
90
90
88
92
64
95
97
94
80
94
67
achieve
significant
ee value
(Table 4, entry 5), demonstrating
that some reasonable candidates
are not picked up by this approach.
However, the design of L2.12 (a
member of library 2) would not
have been possible without the
information gleaned from library 1
that informed our design of
library 2, such as the importance of
the i + 3 asparagine residue.
7
8
tBu
tBu
2g
2h
92
90
95
76
55[d]
87[d]
80[d]
93[d]
9
tBu
tBu
2i
2j
87[e]
90
51[e]
98
85[e]
93
42[e]
99
We looked at a variety of olefin
substrates with [Rh2(L2.47)2-A].
We also examined catalyst [Rh2-
(L16)2-A] to access the “normal”
10
[a] The absolute configuration of 2a was established by comparison to published data; that of other
products is assumed by analogy. [b] Yields of isolated pure material. [c] Reaction at room temperature.
(+)-enantiomer
(Table 5, [d] Reaction at À258C. [e] Reaction at 88C in hexafluoroisopropanol:CH2Cl2 (1:22).
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Keywords: homogeneous catalysis · peptides · rhodium ·
.
screening · stereoselectivity
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Figure 3. Optimized ligand structures. L16=KZTDAALDLKZ;
L2.47=KZQDNANDTKZ.
cyclopropanation
of
N-vinyl
compounds
(Table 5,
entries 9,10). Despite their potential value as b-amino acids
or as intermediates for further elaboration, rhodium catalysts
have been little studied for cyclopropanation of N-vinyl
compounds, and then mostly for racemic reactions.[18] One
report describes enantioselective cyclopropanations with
diazoketones,[19] and one paper reported that only moderate
ee (not over 55%) could be achieved for diazoacetate
derivatives with common catalysts for enantioselective cyclo-
propanations.[20] The two metallopeptide catalysts are also
highly diastereoselective, providing only the trans-product
with respect to the ester group.
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In conclusion, the strategy described herein facilitates the
search for new metallopeptide catalysts. At the onset of this
study, despite synthesizing around 40 peptides for our
previous report, we had no lead sequence to begin the
search for catalysts providing “opposite” enantiomer prod-
ucts. In two rounds of screening, the library approach
identified sequence trends that favor formation of the
“opposite” enantiomer and delivered a selective catalyst.
The first (“normal”) class of sequences, providing re-face
addition products, is characterized by bulk (i.e. leucine,
isoleucine, phenylalanine) at the iÀ1 and i + 3 positions. In
contrast, the “enantiomeric” sequences, providing si-face
addition, are characterized by polar carboxamide side chains
(glutamine and asparagine) at these same positions. These
results allow us to infer that the mechanism of stereoinduction
may be different for the two sequence classes identified. Of
particular note, the rhodium-catalyzed cyclopropanation of
N-vinyl species affords b-amino-acid derivatives with high
ee values. This work demonstrates the value of peptides as
asymmetric ligands and provides an example of the benefits of
modular ligands in general.
[10] R. Sambasivan, Z. T. Ball, J. Am. Chem. Soc. 2010, 132, 9289 –
9291.
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6, 920 – 925; d) B. V. Popp, Z. T. Ball, J. Am. Chem. Soc. 2010,
132, 6660 – 6662.
Received: March 31, 2012
Revised: May 8, 2012
Published online: && &&, &&&&
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[17] Interestingly, catalyst L16 is a counter-example to the approach
herein. We subsequently found that the corresponding mono-
peptide complex of L16 is a poor cyclopropanation catalyst (ee <
5%).
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[16] The “A” and “B” designations are based on HPLC run time. We
are unable to determine the tertiary structure of the metal-
lopeptide catalysts.
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Communications
Catalyst Screening
Searching with a beady eye: A high-
throughput, on-bead screen of rhodium
metallopeptide catalysts was developed
in a 96-well format for asymmetric cyclo-
propanation. Different sequences of nat-
ural l-amino acids have been identified
that produce opposite product enantio-
mers (see picture). In addition to styrene
derivatives, high enantioselectivity is
observed for vinyl ether and vinyl amine
derivatives.
R. Sambasivan,
Z. T. Ball*
&&&& — &&&&
Screening Rhodium Metallopeptide
Libraries “On Bead”: Asymmetric
Cyclopropanation and a Solution to the
Enantiomer Problem
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!