A redox-reconfigurable, ambidextrous asymmetric catalyst

Article abstract of DOI:10.1021/ja302283s

A redox-reconfigurable catalyst derived from l-methionine and incorporating catalytic urea groups has been synthesized. This copper complex catalyzes the enantioselective addition of diethyl malonate to trans-β-nitrostyrene. Either enantiomer of the product can be predetermined by selection of the oxidation state of the copper ion. Enantiomeric excesses of up to 72% (S) and 70% (R) were obtained in acetonitrile. The ability of the catalyst to invert enantiomeric preference was reproduced with several different solvents and bases. Facile interconversion between the Cu²⁺ and Cu⁺ redox states allowed easy access to both active helical forms of the complex and, therefore, dial-in enantioselectivity.

Full text of DOI:10.1021/ja302283s

Communication
pubs.acs.org/JACS
A Redox-Reconfigurable, Ambidextrous Asymmetric Catalyst
Shahab Mortezaei, Noelle R. Catarineu, and James W. Canary*
Department of Chemistry, New York University, New York, New York 10003, United States
S
* Supporting Information
of the ligand (see Figure 1). In this communication we report
such a redox-reconfigurable “ambidextrous” chiral catalyst
ABSTRACT: A redox-reconfigurable catalyst derived
from L-methionine and incorporating catalytic urea groups
has been synthesized. This copper complex catalyzes the
enantioselective addition of diethyl malonate to trans-β-
nitrostyrene. Either enantiomer of the product can be
predetermined by selection of the oxidation state of the
copper ion. Enantiomeric excesses of up to 72% (S) and
70% (R) were obtained in acetonitrile. The ability of the
catalyst to invert enantiomeric preference was reproduced
with several different solvents and bases. Facile inter-
conversion between the Cu2+ and Cu+ redox states allowed
easy access to both active helical forms of the complex and,
therefore, dial-in enantioselectivity.
Figure 1. Schematic of redox-inversion of chiral cleft.
capable of delivering either enantiomer of a nitro Michael
addition product dependent on the oxidation state of a single
copper atom. For catalyst Δ/Λ−1 (Figure 2b), urea groups
were selected as reactive components due to their remarkably
robust ability to behave as general acid catalysts via hydrogen
bonding.13
The catalyst ligand was synthesized using commercially
available L-methioninol in five steps with an overall 61% yield
(Supporting Information). Subsequent complexation of the
ligand with Cu(ClO4)2 afforded Δ−1, whereas Λ−1 was
isolated by complexation with Cu(CH3CN)4PF6.
nversion of helicity has long intrigued investigators in a
I
number of fields.1 In synthetic chemistry, interesting studies
have included the employment of single enantiomer ligands
with different solvents,3 counterions,4 metals,5 and temper-
atures6 in an attempt to toggle the enantioselectivity of a
reaction, which has enjoyed varying degrees of success.7 Most
such systems reported to date have been discovered by
serendipity, and rational design of catalysts with ready triggers
to modulate or invert enantioselectivity have been elusive.
Recently, the Feringa group designed a thiourea organocatalyst
employing a phototriggered, helically chiral molecular rotor
scaffold.8 In this system, photoswitching produced thermally
interconverting atropisomers that catalyzed the formation of
enantiomeric products of the addition of a thiophenol to
cyclohexenone. Redox-modulated catalysts have been reported
that provide elements of allosteric reactivity control, but no
redox-based system has been shown to control enantioselec-
tivity.9
Electronic spectra of the copper complexes of Δ/Λ−1
(Figure 2a) are qualitatively similar to those reported for a
similar unsubstituted quinoline derivative of L-methioninol14
but display additional features, most likely due to the presence
of additional aromatic substituents in Δ/Λ−1 that may absorb
in the UV wavelength region of the spectra. The absorption
spectrum of Δ−1 (Cu2+) shows a flattened peak suggesting
transitions of similar intensity near 247 and 258 nm. The
1
transition near 247 nm is likely due to the Bb transition with
Previous studies from this laboratory described redox-
responsive coordination complexes capable of helical inver-
sion.10,11 Complexes derived from methionine or cysteine were
shown to undergo inner sphere ligand rearrangement upon
one-electron oxidation or reduction of copper. The rearrange-
ment was coupled to the orientation of two quinoline rings and
affording right (Δ, Cu2+)- or left (Λ, Cu+)-handed orientations
as evidenced in solution by exciton-coupled circular dichro-
ism.12 In this study, we examine the attachment of catalytic
moieties to the quinoline units of tripodal ligands derived from
L-methioninol for asymmetric catalysis. In such a system, the
copper ion inner coordination sphere would not be involved in
catalysis but would serve to modulate the asymmetric
orientation of the catalytic groups, which in turn could
potentially catalyze organic reactions in both oxidation states
to produce either enantiomer product from a single enantiomer
transition dipole oriented in the longitudinal direction crossing
both rings and giving rise to an exciton couplet in the CD
spectrum with trough at 251 nm, null near 238 nm, and peak
near 230 nm. The latter is likely due to a π−π* transition
involving the quinoline and attached phenyl ring. A possibly
related additional trough appears in the CD spectrum near 260
nm. The Λ−1 (Cu+) compound shows a broad peak near 248
nm and associated peak, null, and trough at 252, 239, and 232
nm, respectively.15 Overall, the CD spectra give significant
mirror image ECCD character for the Δ−1 and Λ−1
complexes, consistent with inversion of the asymmetric
orientation of the chromophores.
Received: March 7, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja302283s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Solvent Dependence of Catalyzed Reaction
Δ−1
b
Λ−1
c
solvent
% ee of (S)-4
% yield of 4
% ee of (R)-4 % yield of 4
toluene
THF
24
48
72
30
46
51
55
33
55
40
44
30
51
57
70
68
74
60
33
78
40
34
43
30
MeCN
CHCl3
CH2Cl2
hexane
a
All reactions were carried out using diethylmalonate 2 (0.68 mmol, 2
equiv), β-nitrosytrene 3 (0.34 mmol, 1 equiv), and NEt3 (0.034 mmol,
0.1 equiv) in solvent (1 mL) with 5 mol % catalyst (Δ−1 or Λ−1) at
b
room temperature for 24 h. Determined by chiral HPLC analysis.
c
Isolated yields
Figure 3. HPLC traces of reaction product when using both forms of
the catalyst in acetonitrile.
Figure 2. Redox-triggered switching between Δ−1 and Λ−1. CD (L
mol−1 cm−1) and UV (L mol−1 cm−1) of Δ/Λ−1 (59 uM,
acetonitrile).
Table 2. Base Screen for Different Complex Oxidation
a
States
Encouraged by spectroscopic evidence indicating helical
chirality inversion, the catalytic behavior of Δ−1 was assessed.
The Michael addition of diethyl malonate (2) to trans-β-
nitrostyrene (3, Scheme 1) has high synthetic utility as such
Δ−1
Λ−1
b
c
base
NEt3
% ee of (S)-4
% yield of 4 % ee of (R)-4 % yield of 4
72
70
66
34
57
55
38
44
40
21
70
56
30
7
40
32
48
34
32
DIPEA
DABCO
DBU
Scheme 1. Asymmetric Conjugate Addition Reaction
DMAP
31
a
All reactions were carried out using diethylmalonate 2 (0.68 mmol, 2
equiv), β-nitrosytrene 3 (0.34 mmol, 1 equiv), and base (0.034 mmol,
0.1 equiv) in MeCN (1 mL) with 5 mol % catalyst (Δ−1 or Λ−1) at
b
room temperature for 24 h. Determined by chiral HPLC analysis.
c
Isolated yields.
Michael adducts16 have previously shown to be amenable to
catalysis by several thio(urea) organocatalysts.17 We envisioned
that the urea moieties of Δ−1 and Λ−1 should lead to nearly
enantiomeric transition states allowing the user to choose
between (S)-4 or (R)-4 simply by choosing the redox state of
the copper ion.
same enantiomer product, with more nucleophilic bases
affording lower yields and ee. This may be due to competitive
catalysis of the competing anionic polymerization of the trans-
β-nitrostyrene starting material.18
To test the catalytic ability of Δ−1, a solvent screen was
performed using 1 mL of solvent, 10 mol % NEt3, and 5 mol %
catalyst Δ−1 at room temperature (Table 1). Of the solvents
tested, acetonitrile provided the highest yield (55%) and ee
(72%) of product (S)-4 (Figure 3). Significantly, in the
presence of Δ−1 all solvents screened yielded product (S)-4.
The same reaction, using 5 mol % of Λ−1 as the catalyst,
demonstrated a preference for enantiomeric product (R)-4 in
all of the solvents tested. Remarkably, a similar ee (70%) was
obtained in acetonitrile compared to the result with Δ−1.
Several amine bases were examined (Table 2) that gave the
We then set out to test the effects of catalyst loading,
concentration, and temperature (Table 3). Changes in
temperature and concentration appeared to have little effect
on the ee and yield of the reaction. Interestingly, increasing the
loading of the catalyst to 10 mol % (entry 3) caused no change
in enantioselectivity. The catalyst still proved to be effective at
0.5 mol % loading (entry 5) producing (S)-4 at 62% ee. The
yield in this case may benefit from the lower concentration of
base used. Control experiments indicate that the free ligand
catalyzes the reaction (entry 8), which is consistent with
electrophilic catalysis provided by the urea groups and suggests
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dx.doi.org/10.1021/ja302283s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. Effects of Concentration and Loading
Δ−1
b
c
entry
x
y
conc Δ−1 (mM)
% ee
% yield of (S)-4
f
1
2
3
10
10
10
10
2
5
5
17
34
72
70
55 (75)
50
39
52
67
18
<1
44
10
5
34
72
d
4
34
74
5
6
7
0.5
1.7
n/a
17
62
10
0
0
5
5
<1
n/a
20
e
8
10
17
a
All reactions were carried out using diethylmalonate 2 (0.68 mmol, 2
equiv) and β-nitrosytrene 3 (0.34 mmol, 1 equiv) in MeCN (1 mL)
with catalyst (Δ−1 or Λ−1) at room temperature for 24 h unless
b
c
Figure 4. Space filling model of Δ−1 (left) and Λ−1 (right) derived
otherwise noted. Determined by chiral HPLC analysis. Isolated
by modifying X-ray coordinates of related structures.19
d
e
f
yield. Reaction at 0 °C. Reaction carried out with free ligand. NMR
yield.
beneficial by obviating the requirement for a parallel synthesis
of the opposite enantiomer, offering economic or environ-
mental benefit depending on scale, and especially if one
enantiomer is derived from an unnatural chiral source. The
ambidextrous nature of the catalyst is persistent, using several
different solvents and bases. Either complex is available by
simply mixing ligand with the appropriate metal salt, or the
Δ−1 complex can be reduced chemically to the less air stable
Λ−1 complex and used to catalyze the conjugate addition
reaction. The potential for dynamic control of enantioselectivity
offers intriguing possibilities for future applications.
that the copper is not involved directly in catalysis.
Enantioselectivity is poor, however, in the absence of
scaffolding provided by the copper ions.
As reducing agents such as ascorbate are capable of
reconfiguring similar Cu2+ complexes,15 we sought to determine
whether the Δ−1 complex could be reduced in situ to the Λ−1
form and used to catalyze the same reaction. This was
accomplished by stirring a mixture of ascorbate, NEt3, and Δ−1
and isolating the resulting Λ−1 complex after an hour by
precipitation. Nearly the same results (43% yield (R)-4, 71%
ee) were obtained when performing the conjugate addition
(Scheme 1) with the in situ reduced complex. It is of interest
that Et3N significantly solubilizes the Cu2+ complex in the
solvents tested.
The exact mechanism of catalysis in the reaction is not
known. The urea groups are capable of binding both the diethyl
malonate (2) and trans-β-nitrostyrene (3) reactants.20 Whether
one or both urea groups play a role in the transition state is not
yet clear. Molecular models (Figure 4) suggest that the urea
moieties in Δ−1 and Λ−1 form pseudo-enantiomeric clefts,
but the available space may not accommodate simultaneous
hydrogen bonding of both reagents. The ligand alone in the
absence of copper ion is far more flexible than the complex and
likely positions the urea groups further away from one another,
yet the yield of the reaction is similar to that using the complex
(Table 3, entry 8). Monitoring the reaction by 1H NMR
revealed the half-life of the reaction catalyzed by free ligand to
be half that of the Δ−1 complex. This may suggest that both
urea groups do not act in concert in the transition state. Further
mechanistic studies are underway.
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
james.canary@nyu.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Foundation for research (CHE-
0848234) and instrument (CHE-0958457) support.
■
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