Counterion Enhanced Organocatalysis: A Novel Approach for the Asymmetric Transfer Hydrogenation of Enones

Article abstract of DOI:10.1002/cctc.202000414

We present a novel strategy for organocatalytic transfer hydrogenations relying on an ion-paired catalyst of natural l-amino acids as main source of chirality in combination with racemic, atropisomeric phosphoric acids as counteranion. The combination of a chiral cation with a structurally flexible anion resulted in a novel chiral framework for asymmetric transfer hydrogenations with enhanced selectivity through synergistic effects. The optimized catalytic system, in combination with a Hantzsch ester as hydrogen source for biomimetic transfer hydrogenation, enabled high enantioselectivity and excellent yields for a series of α,β-unsaturated cyclohexenones under mild conditions. Moreover, owing to the use of readily available and chiral pool-derived building blocks, it could be prepared in a straightforward and significantly cheaper way compared to the current state of the art.

Full text of DOI:10.1002/cctc.202000414

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Counterion enhanced organocatalysis: A novel approach for the
asymmetric transfer hydrogenation of enones
Authors: Fabian Scharinger, Adam Mark Palvölgyi, Veronika
Zeindlhofer, Christian Schröder, and Katharina Schröder
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.202000414
Link to VoR: https://doi.org/10.1002/cctc.202000414
01/2020

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
Counterion enhanced organocatalysis: A novel approach for the
asymmetric transfer hydrogenation of enones
Fabian Scharinger,[a],† Ádám Márk Pálvölgyi,[a],† Veronika Zeindlhofer,[b] Michael Schnürch,[a] Christian
Schröder,[b] and Katharina Bica-Schröder*[a]
Dedicated to Prof. Johannes Fröhlich on the occasion of his 60th birthday
Abstract: We present a novel strategy for organocatalytic transfer
hydrogenations relying on an ion-paired catalyst of natural L-amino
acids as main source of chirality in combination with racemic,
atropisomeric phosphoric acids as counteranion. The combination of
a chiral cation with a structurally flexible anion resulted in a novel
chiral framework for asymmetric transfer hydrogenations with
enhanced selectivity through synergistic effects. The optimized
catalytic system, in combination with a Hantzsch ester as hydrogen
source for biomimetic transfer hydrogenation, enabled high
enantioselectivity and excellent yields for a series of α,β-unsaturated
cyclohexenones under mild conditions. Moreover, owing to the use of
readily available and chiral pool derived building blocks, it could be
prepared in a straightforward and significantly cheaper way compared
to the current state of the art.
years later, a new methodology in asymmetric transfer
hydrogenation was reported by Mayer and List as they observed
high catalytic activity and enantioselectivity in the reaction of enals
and enones catalyzed by ammonium salts composed of an achiral
cation and an enantiopure sterically demanding phosphate anion,
TRIP (Figure 1, right).[8,9] Based on the early success of List’s
catalytic system, a new general concept emerged in the field of
organocatalysis, known as Asymmetric Counteranion-Directed
Catalysis (ACDC), which refers to any catalytic reaction, in which
the enantiodiscrimination is induced through the tight ion-pairing
of a cationic intermediate with an enantiomerically pure anion.[10]
The ion-bound nature of this attractive approach for chiral
induction offers considerable flexibility for fine-tuning of the
electronic and steric properties compared to conventional
covalent ligand systems.[11] Since the discovery of ACDC, or in
general, of asymmetric ion-pairing catalysis, several other highly
enantioselective reactions proceeding through cationic
intermediates have been reported.[12–15] While different
asymmetric induction modes can be realized in asymmetric ion-
pairing catalysis, the formation of ion pairs between ammonium
cations and bulky chiral phosphate anions is particularly
prominent.[16–21]
Introduction
Asymmetric transfer hydrogenation has emerged as a powerful
and convenient tool for the reduction of prochiral carbonyl
compounds.[1] The selective reduction of enones is a particularly
challenging task due to the inherent question of regio- and
stereoselectivity.[2] Among many catalytic protocols that have
been described for this particular reaction, the flourishing area of
organocatalysis offers attractive solutions, and iminium-based
asymmetric transfer hydrogenations provide an efficient and
metal-free alternative for the selective reduction of enones via 1,4-
addition.[3–5]
Over the past years, two types of catalysts have emerged as
particularly well suited for organocatalytic transfer hydrogenations
of enals and enones. In 2004, the group of MacMillan reported a
series of imidazolidinone derivatives as powerful benchmark
catalysts for highly asymmetric conjugate hydrogenations of α,β-
unsaturated aldehydes and ketones (Figure 1, left).[5,6] In parallel
List and co-workers described a novel method for the non-
asymmetric transfer hydrogenation of cinnamaldehyde
derivatives using secondary ammonium salts as catalysts.[7] Two
[a]
Fabian Scharinger DI, Ádám Márk Pálvölgyi, MSc., Assoc. Prof. Dr.
Michael Schnürch, Assoc. Prof. Dr. Katharina Schröder
Institute of Applied Synthetic Chemistry
Figure 1. Iminium-based organocatalytic reduction of enones and different
catalytic systems, including MacMillan’s imidazolidinone catalyst (left), List’s
TRIP phosphate (right) as well as the novel counterion enhanced approach
reported in here (middle).
TU Wien
Getreidemarkt 9/163, 1060 Wien, Austria
E-mail: katharina.schroeder@tuwien.ac.at
Mag. Veronika Zeindlhofer, Assoc. Prof. Dr. Christian Schröder
Department of Computational Biological Chemistry
University of Vienna
[b]
Währinger Str. 17, 1090 Wien, Austria
†
These authors contributed equally to this manuscript
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
While these elegant strategies are certainly among the most
important discoveries in the field of organocatalysis for the last
decades, they still do have some limitations. MacMillan’s
imidazolidinones are excellent catalysts for the asymmetric
transfer hydrogenation of enals; however, the reactivity for
enones is inferior thus requiring higher catalyst loadings.[6] In
contrast, List et al. could successfully reach high reactivity and
selectivity for the asymmetric transfer hydrogenation of enals and
enones even with low catalyst loading based on the chiral TRIP
the presence of biphenyl phosphate 4 (Table 1, entries 4 and 5).
Most importantly, an increase of enantioselectivity to 64 %ee – an
increase by 10 %ee compared to the trifluoroacetate salt - could
be observed, indicating that the troposiomeric and C2-symmetric
biphenyl phosphate anion plays a role in enantiodiscrimination
(Table 1, entries 2 vs. 4). It is worthwhile noticing that this is not
the case with different binaphtyl phosphate anions, as the
observed enantioselectivity with racemic or enantiopure binaphtyl
phosphate was identical to the values obtained for
triflluoroacetate (Table 1, entries 2 vs. 6-8). This clearly shows
that matched/mismatched effects between the chiral amino acid
and the counteranion do not influence the ee of the product.
Further studies showed that this effect is even more pronounced
in MTBE as a solvent, where an enantioselectivity of 74 %ee
compared to 51 %ee obtained with the trifluoroacetate anion was
found (Table 1, entries 3 vs. 5). In fact, when studying the impact
of different solvents in this reaction, we found that the best
selectivity is observed in solvents with low dielectric constants
such as MTBE ( = 4.5) or toluene ( = 2.4), whereas lower
enantioselectivity was found in more polar solvents such as water
( = 80.1), see ESI Table S2, page S24 for details.
counteranion. However, this approach requires
a rather
expensive catalyst, prepared in a five-step synthesis with rather
low overall yields. Moreover, a careful structural optimization is
required for the bulky phosphate anion of the catalyst: while the
TRIP counteranion provides indeed high selectivity in the ATH of
ketones and aldehydes,
a
significant decrease in the
enantiodiscrimination could be observed just with a slight
modification of the phosphate unit, resulting in moderate
selectivity or even close-to-racemic products. Given these
limitations, a straightforward, cheaper and chiral-pool derived
catalytic system that combines high catalytic activity with
excellent enantioselectivity would be highly desirable.
In here, we propose a novel concept of asymmetric ion-paired
organocatalysis with a fixed element of chirality based on ion
aggregation between a chiral amino acid cation and C2-symmetric
atropisomeric phosphate anion. This concept of an ion-paired
catalyst framework offers novel opportunities for ligand design
with unprecedented flexibility compared to conventional ligand
design relying on covalently constructed ligands. Eventually, this
unique approach results in an easily accesible, cheap and chiral
pool-derived a catalytic system that is yet able to reduce a set of
α,β-unsaturated ketones with high yields and selectivity.
Table 1. Proof of concept in the counterion enhanced asymmetric transfer
hydrogenation of 3-methyl-2-cyclohexenone (1a) using (L)-valine t-butyl ester
as cation source.
Entry[a]
Anion
Conv.[c]/% Yield[c]/ % ee[c] /%
Δee[d]
1
3
<1
78
92
40
75
13
22
20
<1
49
88
27
72
13
13
15
n.d.
54
51
64
74
54
54
54
n.d.
2
3[b]
4
-
-
Results and Discussion
To prove the concept of counterion enhanced asymmetric transfer
hydrogenations, we initially focused on the reduction of 3-methyl-
2-cyclohexenone. The reaction was performed with the common
Hantzsch ethyl ester as mild reductant using standard conditions
that have been previously established by List et al.[5]
4
4
8
8
8
10
23
0
5[b]
6
7
0
Scheme 1. Proof of concept: asymmetric transfer hydrogenation of 3-methyl-2-
cyclohexenone (1a) by using different salts of L-valine t-butyl ester.
8
0
For a first evaluation of the concept, different salts of (L)-valine t-
butyl ester, including the non-chiral trifluoroacetate salt, but also
salts with tropoisomeric biphenyl phosphate as well as
enantiopure or racemic binaphtyl phosphate anions were used as
catalysts (Table 1). While no reaction was observed with the
biphenolate anion 3 due to the lower acidity of 2,2’-biphenol
(Table 1, entry 1), the reaction proceeded with moderate yield in
[a] Performed with 0.18 mmol 3-methyl-2-cyclohexenone (1a), 20 mol% catalyst
and 0.22 mmol Hantzsch ethyl ester in 0.55 mL 1,4-dioxane for 48 hours at 60°C.
[b] MTBE used as solvent. [c] Determined by GC analysis on BGB5 column
using n-dodecane as internal standard and chiral GC analysis using a BGB175
chiral capillary column. [d] ee defined as the difference between the reaction
with phosphate anion 4 and trifluoracetate anion in 1,4-dioxane and MTBE,
respectively.
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
This increase in the enantioselectivity can be attributed to the
solvent’s polarity, resulting in the formation of contact ion pairs in
apolar solvents and hence a stronger interaction between cation
and anion in the catalyst. In contrast to conventional salts that are
defined by a strictly charge-ordered structure of atomic ions
without dipole moment, organic salts, e.g. ionic liquids, possess a
complex network with remarkable structural heterogeneity of the
composing molecular ions.[22] On a supramolecular length scale,
ion pairs, or more precisely ion aggregates exist for a lifetime of a
few picoseconds; however ion pair destabilization occurs as pairs
readily dissociate into individual ions in pure salt melts. This
situation changes drastically when organic salts are dissolved in
molecular solvents: A number of experimental techniques,
including NMR measurements or cyclic voltammetry proved the
existence of long-lived ion pairs, suggesting that the ion pair
formation is insignificant in neat salts but dominant in electrolyte
solutions. Although a key feature of organic salts in solution, ion
aggregation has been scarcely exploited for interionic chirality
transfer. An outstanding example in this regard was published by
Leitner and co-workers in their work on asymmetric
hydrogenations featuring a proline-based chiral ionic liquid as
solvent or additive in combination with atropisomeric phosphine
ligands.[23] Impressive enantioselectivity was obtained through a
complex of [{(R)-binap}Rh{(S)-MeProl}]+, accompanied by N-bis-
(trifluoromethane)sulfonimide anion.
Successively, we performed an extensive screening of the amino
acid as cation source for further optimization of the catalytic
system. Little difference in enantioselectivity (between 72-
80 %ee) were found between (L)-valine, (L)-leucine, (L)-isoleucine
and (L)-t-leucine t-butyl esters, whereas aromatic species such as
(L)-phenylalanine t-butyl ester where less efficient. (L)-Proline t-
butyl ester with a secondary ammonium cation gave also
significantly lower selectivity (see ESI Table S5, page S27 for
details). Finally, modifications on the ester moiety of (L)-valine
revealed that sterically demanding aliphatic groups such as t-butyl,
4-t-butyl cyclohexyl or menthyl are indeed required for reaching
high selectivity, as can be easily seen when comparing the results
with those obtained for methyl or benzyl esters. Eventually, the
best results were obtained when matching (L)-valine with the (+)-
(1S,2R,5S) menthol, as the resulting ester reaching excellent
yields of 98% and an enantioselectivity of 93 %ee. This is in
contrast to the mismatched ester obtained with (−)-(1R,2S,5R)
menthol, which gave only 82 %ee (Scheme 2).
We reasoned that the catalytic system could be improved by
tuning the steric demand and rotation barrier of the atropisomeric
phosphate anion. For this purpose, a set of biphenyl phosphoric
acids were prepared via microwave-assisted oxidative coupling of
phenols with t-butyl peroxide. This straightforward coupling step,
followed by reaction with POCl3 and successive hydrolysis gave
access to the phosphoric acids (4-7) with variable substituent
pattern in acceptable overall yield, starting from cheap and readily
available phenols (see ESI S10-S13 for details). With this set of
phosphoric acids in hand, the selectivity in asymmetric transfer
hydrogenation could be considerably improved and varied
between 74 and 80 %ee. Best results were obtained with the
isopropyl substituted phosphoric acid 6 as anion source, providing
up to 80%ee with nearly quantitative yield (Figure 2, also see ESI
Table S3, page S25 for details). Furthermore, other acids
traditionally used in organocatalysis have been investigated. The
ee values were below 60% for all cases under the same reaction
conditions, further highlighting the benefits of the atropisomeric
phosphoric acids 4-7 (see ESI Table S4, page S26 for details).
Scheme 2. Optimization of the (L)-valine ester moiety as cations source for. All
reactions were carried out in MTBE at 60°C using phosphate anion 6.
With the ideal cationic and anionic moiety identified, it was also
possible to reduce the catalyst loading to lower amounts: When
studying different catalyst loadings at 25°C, the high selectivity
was maintained even at 5 mol% catalyst, although losses in yield
had to be taken into account. Eventually, a reaction temperature
of 50°C provided an ideal compromise between yield and
selectivity, providing the desired product 2a in 98% yield and
95 %ee (Table 2, entry 9).
Table 2. Optimization of conditions and parameters for the asymmetric transfer
hydrogenation of 3-methyl-2-cyclohexenone (1a) using (L)-valine (+)-
(1R,3R,4S) menthyl ester and the isopropyl substituted phosphoric acid 6 as
anion source.
Entry[a]
T /˚C
60
Catalyst /mol% Hantzsch ester Yield[b] /% ee[c] /%
1
2
3
4
5
6
20
20
20
20
10
5
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
98
98
96
59
43
29
93
95
95
96
96
96
50
40
25
25
Figure 2. Impact of different phosphate anions vs. TFA anion on the
enantioselectivity. All reactions were carried out in MTBE at 60°C using L-valine
t-butyl ester as cation source.
25
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
7
25
50
50
50
25
25
25
25
1
ethyl
ethyl
11
99
98
68
14
17
58
58
96
94
95
93
83
88
69
67
10
11
1j
94 (91)
65 (62)
90 (S)
94 (S)
8
10
5
9
ethyl
ethyl
1k
10
1
11[d]
12[d]
13[d]
14[d]
20
20
20
20
methyl
ethyl
12
1l
89 (86)
70 (S)
i-propyl
t-butyl
[a] Performed with 1.8 mmol ketone, 5 mol% catalyst and 2.2 mmol Hantzsch
ethyl ester in 5.5 mL MTBE at 50°C for 48 hours. [b] 20 mol% catalyst. [c] 10
mol% catalyst. [d] Determined by GC or GC-MS analysis. Isolated yields after
flash column chromatography are given in parenthesis. [e] Determined by chiral
GC analysis using a BGB175 or BGB173 chiral capillary column, or by chiral
HPLC analysis using a Diacel Chiralcel AS-H column. Absolute configurations
have been determined by measuring the optical rotation and comparing with
literature data. [f] Lower isolated yield because of high volatility of the product.
[a] Performed with 0.18 mmol 3-methyl-2-cyclohexenone, 0.009-0.036 mmol
catalyst and 0.22 mmol Hantzsch ester in 0.55 mL MTBE at the given
temperature for 48 hours. [b] Determined by GC analysis on a BGB5 column
using n-dodecane as internal standard. [c] Determined by chiral GC analysis
using a BGB175 chiral capillary column. [d] Performed with (L)-valine t-butyl
ester instead of (L)-valine (+)-(1R,3R,4S) menthyl ester.
In general, atropisomerism is a type of axial chirality that may
arise in systems where free rotation about a single covalent bond
is hindered.[24] The isomerization pathways of biphenyls with bulky
ortho-substituents were studied in detail by Masson, showing that
conformers with isomerization barriers > 23 kcal/mol can be
separated at room temperature.[25] Less information is available
for biphenols or biphenyl phosphoric acids. For more insight on
the behavior of the atropisomeric phosphoric acids, we calculated
isomerization barriers for compounds 4-8 (Table 4). The pure
electrostatic barriers were corrected by frequency contributions to
result in the Gibbs free energy barrier (G) at a temperature of
333.15 K. Optimizations, energy evaluations and frequency
calculations were performed on the B3LYP-D3/def2TZVP[26–28]
level of theory with the program package ORCA.[29] Correlation in
the uniform electron gas was modeled according to the Vosko-
Wilk-Nusair VWN5 formalism.[30] A detailed description of the
computational methodology can be found in the ESI (S32-S33).
In general, comparison of the isomerization barriers between
biphenols and biphenyl phosphoric acids is not straightforward. In
case of biphenol, at least five ground state isomers can be
identified, resulting in multiple isomerization pathways.[31]
Sahnoun et al. estimate a value of 11.5 kcal/mol for the lowest
possible pathway.[31]
For further studies on scope and limitation of the newly
established catalytic system, the substrate pool was widened to
investigate the asymmetric transfer hydrogenation of different 3-
substituted cyclohexenones under the previously optimized
reaction conditions. Enantioselectivity exceeded 90% frequently,
thereby demonstrating the versatility and broad application range
of the newly established system.
Table 3. Substrate scope for the counterion enhanced transfer hydrogenation
of enones
Entry[a]
Substrate
Yield [d] /%
ee[e] /%
1
1a 98 (72)f
95 (S)
2
1b 85 (76)f
1c 70 (55)f
92 (S)
91 (S)
93 (S)
86 (S)
88 (S)
92 (S)
89 (S)
82 (S)
3
4
1d
91 (87)
Table 4. Barrier energies for the phosphoric acids on the B3LYP-D3 /def2TZVP
level of theory.
Dihedral angle around
the aryl-aryl bound
5
1e 85 (60)f
Isomerization barrier
G
Biphenol/
Phosphoric acid
Entry
Ground
state
Transition
state
[kcal/mol]
6
1f
75 (68)f
66 (60)
1
2
11.5 [31]
110°
43°
0°
0°
7 [b]
8 [c]
9
1g
4
5
10.0
1h 94 (80)f
3
12.0
49°
0°
1i
86 (84)
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
The most promising catalyst system was investigated further via
non-polarizable molecular dynamics simulations. To model the
ion pair prior to the enantioselective reaction step, we further
investigated the iminium cation formed between (+)-(1S,2R,5S)
menthol-L-valine ester and 3-methyl-2-cyclohexenone, in
combination with phosphate anion 6. Simulations were performed
for one intermediate ion pair at 60°C in methyl butyl ether, a
solvent with a comparable dielectric constant to MTBE (see ESI
S34-S37 for details). To explore any structural difference in the
ion pairs, the (E) and (Z) form of the cation and both enantiomers
of the anion were considered in four different simulations. The ion
pairs incorporating the (R)-enantiomer of the anion are shown in
Figure 4.
6
4
41.2
56°
21°
7
5
6
48.2
61°
75°
29°
26°
42.7 [25]
Due to the additional O-P-O bridge, the phosphoric acids are
restricted in the rotation of the aryl-aryl bond, hence allowing only
one pathway. The phosphoric acids 4 and 5 have similar rotational
barriers of 10 and 12 kcal/mol, indicating that substituents in 3,3’-
position have only a minor impact on the rotation barrier. As
visible from Figure 3 (top), their transition states for the
isomerization are both planar. However, barriers for the acids 6
and 7 increase to 41.2 and 48.2 kcal/mol, respectively, which can
be attributed to the methyl groups in 6,6’-position. Apart from the
steric hindrance of the rotation, this substitution pattern also
forces an out-of-plane transition state (Figure 3, bottom).
Moreover, the optimal dihedral angle of 2,2’-biphenol and
biphenyl phosphoric acid differs significantly due to the
constraints of the phosphate bridge on the rotation of the two
phenyl rings (Table 4). In case of 2,2’-biphenol two hydroxyl
hydrogens are able to form hydrogen bonds to the opposite
oxygen.
(Z)-cation/(R)-anion
(E)-cation/(R)-anion
Figure 4. Snapshots of the (Z)-cation/(R)-anion (top) and (E)-cation/(R)-anion
(bottom) pairs from the simulations. All solvent molecules as well as all
hydrogens except the nitrogen-bound hydrogen were omitted for clarity.
From the average interionic distance calculated respective to
center of mass, it can be seen that the ions form stable pairs
throughout the simulation. In all systems, the hydrogen bond
between cation and anion (see Figure 4 and Table 5) is present
for more than 85% of the simulation time. This hydrogen bond
promotes a certain orientation of the ion pair, with the phosphate
group of the anion oriented towards the nitrogen of the cation.
This also affects the average distance between the prochiral C3-
atom of the cation and the P-atom of the anion. In the unfavored
(Z)-form, the methyl group bound to the prochiral C3 points on the
opposite side of the nitrogen-bound hydrogen, resulting in an
interionic distance of approx. 6.5 Å away. In contrast, the C3-P
distance is shorter by about 1 Å in the favored (E)-form, providing
a closer ion pair and thus might be ideal for chiral induction.
Figure 3. Optimized geometry of the transition states of compounds 4-7
The rotational barrier itself cannot explain the different
enantioselectivity observed in the ATH reaction (Table 1). For
example, anions arising from phosphoric acid 5 and 7 gave similar
enantioselectivity, despite a considerable difference in their
rotational barriers. Additionally, the rotational barrier of the
binaphtyl phosphate is considerably higher compared to biphenyl
phosphate. However, the latter has a considerably higher
rotational barrier, indicating that a complex interplay of the steric
demand, anion geometry and rotation barrier is responsible for
the different performance in the ATH reaction.
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
Acknowledgements
Table 5. Average number of hydrogen bonds and interionic distances obtained
from molecular dynamics simulations.
Financial support by the Austrian Science Fund (project P29146-
N34) is gratefully acknowledged.
Average interionic
distance (center of
mass) [Å]
Average number of
hydrogen bonds
Average distance
C3-P [Å]
Ion pair
Keywords: organocatalysis • asymmetric synthesis • transfer
hydrogenation• ion aggregation • phosphoric acid
Z-cat/R-an
Z-cat/S-an
E-cat/R-an
E-cat/S-an
0.90 ± 0.04
0.85 ± 0.07
0.90 ± 0.05
0.87 ± 0.03
7.2 ± 0.8
6.9 ± 0.9
7.1 ± 0.9
6.8 ± 0.9
6.7 ± 0.5
6.6 ± 0.6
5.5 ± 0.4
5.2 ± 0.4
[1]
[2]
D. Wang, D. Astruc, Chem. Rev. 2015, 115, 6621–6686.
W. S. Mahoney, J. M. Stryker, J. Am. Chem. Soc. 1989, 111, 8818–
8823.
[3]
A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107, 5416–
5470.
[4]
[5]
R. P. Herrera, Top. Curr. Chem. 2016, 374, 29.
S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem. Soc.
2005, 127, 32–33.
[6]
[7]
J. B. Tuttle, S. G. Ouellet, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 12662–12663.
J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew. Chem. Int.
Ed. 2004, 43, 6660–6662.
Conclusion
[8]
[9]
[10]
[11]
[12]
S. Mayer, B. List, Angew. Chem. Int. Ed. 2006, 45, 4193–4195.
N. J. A. Martin, B. List, J. Am. Chem. Soc. 2006, 128, 13368–13369.
M. Mahlau, B. List, Angew. Chem. Int. Ed. 2013, 52, 518–533.
K. Brak, E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534–561.
G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317,
496–499.
In here, we reported a novel concept of counterion catalysis for
organocatalytic asymmetric transfer hydrogenations. The ion-
paired catalysts, based on cheap amino acid-derived cations and
flexible phosphate anions could be readily synthetized from
natural compounds, providing a significantly cheaper alternative
to the current start-of-art ACDC methodology. After careful
parameter optimization, a series of different enones could be
reduced with high yields and enantioselectivity under mild
conditions even with low catalyst loadings.
[13]
[14]
S. Liao, B. List, Angew. Chem. Int. Ed. 2010, 49, 628–631.
P. García-García, F. Lay, C. Rabalakos, B. List, Angew. Chem. Int.
Ed. 2009, 48, 4363 – 4366.
V. Rauniyar, Z. J. Wang, H. E. Burks, F. D. Toste, J. Am. Chem.
Soc. 2011, 133, 8486–8489.
D. Qian, J. Sun, Chem. – A Eur. J. 2019, 25, 3740–3751.
G. B. Rowland, E. B. Rowland, Y. Liang, J. A. Perman, J. C. Antilla,
Org. Lett. 2007, 9, 2609–2611.
[15]
[16]
[17]
From the simulation data, we can conclude that interionic
interactions are strong enough to form a stable ion pair in apolar
solvents such as MTBE, and that the hydrogen bond both favors
a certain arrangement of the ion pair, with the C3 atom relatively
close to the anion. The exact interplay between the ions, and the
mechanism of a possible chirality transfer remains unclear, and it
will be further evaluated in future studies addressing the influence
of aggregate formation rather than a single ion pair.
Current investigations focus on the exploration of the reaction
scope for counterion enhanced organocatalysis with chiral amino
acid derived cations and atropisomeric phosphate anions. Overall,
we expect that the concept of counterion enhanced catalysis
relying on chiral cations and atropisomeric anions will find broad
utility in organocatalysis, but also in transition metal catalyzed
process.
[18]
[19]
L. Ren, T. Lei, L.-Z. Gong, Chem. Commun. 2011, 47, 11683.
X. Cheng, S. Vellalath, R. Goddard, B. List, J. Am. Chem. Soc.
2008, 130, 15786–15787.
M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte, Org.
Lett. 2005, 7, 3781–3783.
R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 84–86.
R. Hayes, G. G. Warr, R. Atkin, Chem. Rev. 2015, 115, 6357–6426.
D. Chen, M. Schmitkamp, G. Franciò, J. Klankermayer, W. Leitner,
Angew. Chem. Int. Ed. 2008, 47, 7339–7341.
J. Chandrasekhar, R. Dick, J. Van Veldhuizen, D. Koditek, E.-I.
Lepist, M. E. McGrath, L. Patel, G. Phillips, K. Sedillo, J. R.
Somoza, et al., J. Med. Chem. 2018, 61, 6858–6868.
E. Masson, Org. Biomol. Chem. 2013, 11, 2859.
A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010,
132, 154104.
F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297.
F. Neese, Wiley Interdiscip. Rev.-Comput. Mol. Sci. 2012, 2, 73–78.
S. H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200–1211.
R. Sahnoun, S. Koseki, Y. Fujimura, J. Phys. Chem. A 2006, 110,
2440–2447.
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
Experimental Section
Representative procedure for the asymmetric transfer hydrogenation
A glass vial equipped with a magnetic stir bar was charged with ketone
(1.8 mmol, 1.0 equiv.) in MTBE (5.5 mL, 0.33 M), followed by the addition
of the catalyst (55.4 mg, 0,09 mmol, 5 mol%) and Hantzsch ester (552 mg,
2.2 mmol, 1.2 equiv.). The reaction mixture was stirred at 50°C for 48 h.
After cooling to room temperature, diethyl ether (5 mL) and 4 M HCl (10
mL) was added and the mixture was stirred until the phases were
transparent (30 min). The phases were separated and the organic phase
was washed with 4 M HCl (3 × 20 mL). The organic phase was dried over
Na2SO4 and concentrated under reduced pressure. Purification by column
chromatography (15
% Et2O: PE, vanillin staining agent or UV
visualization) gave the 3-substituted cyclohexanones.
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000414
ChemCatChem
RESEARCH ARTICLE
Entry for the Table of Contents (Please choose one layout)
Layout 1:
RESEARCH ARTICLE
We present a novel strategy for
organocatalytic transfer
hydrogenations relying on an
ion-paired catalyst of natural L-
amino acids as main source of
chirality in combination with
racemic, atropisomeric
Fabian Scharinger, Ádám Márk
Pálvölgyi, Veronika Zeindlhofer,
Michael Schnürch, Christian
Schröder and Katharina Bica-
Schröder*
Page No. – Page No.
Counterion enhanced
organocatalysis: A novel
approach for the asymmetric
transfer hydrogenation of
enones
phosphoric acids as
counteranion.
This article is protected by copyright. All rights reserved.