Metal-Templated Design: Enantioselective Hydrogen-Bond-Driven Catalysis Requiring only Parts-per-Million Catalyst Loading

Article abstract of DOI:10.1021/jacs.6b02769

Based on a metal-templated approach using a rigid and globular structural scaffold in the form of a bis-cyclometalated octahedral iridium complex, an exceptionally active hydrogen-bond-mediated asymmetric catalyst was developed and its mode of action inve

Full text of DOI:10.1021/jacs.6b02769

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Article
Metal-Templated Design: Enantioselective Hydrogen-Bond-
Driven Catalysis Requiring Only Parts-per-Million Catalyst Loading
Weici Xu, Marcus Arieno, Henrik Löw, Kaifang Huang, Xiulan Xie, Thomas
Cruchter, Qiao Ma, Jianwei Xi, Biao Huang, Olaf Wiest, Lei Gong, and Eric Meggers
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02769 • Publication Date (Web): 23 Jun 2016
Downloaded from http://pubs.acs.org on June 24, 2016
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Metal-Templated Design: Enantioselective Hydrogen-Bond-Driven Catalysis
Requiring Only Parts-per-Million Catalyst Loading
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Weici Xu,1 Marcus Arieno,2 Henrik Löw,3 Kaifang Huang,1 Xiulan Xie,3 Thomas Cruchter,3 Qiao
Ma,1 Jianwei Xi,1 Biao Huang,1 Olaf Wiest,2,4* Lei Gong,1* and Eric Meggers1,3*
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1College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s
Republic of China
2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
USA
3Fachbereich Chemie, PhilippsꢀUniversität Marburg, HansꢀMeerweinꢀStrasse 4, 35043 Marburg,
Germany
4Laboratory of Computational Chemistry and Drug Discovery, Laboratory of Chemical Genomics,
Peking University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of China
*Corresponding authors: owiest@nd.edu, gongl@xmu.edu.cn, meggers@chemie.uniꢀmarburg.de
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Abstract: Based on a metalꢀtemplated approach using a rigid and globular structural scaffold in the
form of a bisꢀcyclometalated octahedral iridium complex, an exceptionally active hydrogenꢀbondꢀ
mediated asymmetric catalyst was developed and its mode of action investigated by crystallography,
NMR, computation, kinetic experiments, comparison with a rhodium congener, and reactions in the
presence of competing Hꢀbond donors and acceptors. Relying exclusively on weak forces, the
enantioselective conjugate reduction of nitroalkenes can be executed at catalyst loadings as low as
0.004 mol% (40 ppm), representing turnover numbers of up to 20250. A rate acceleration by the
catalyst of 2.5 x 105 was determined. The origin of the catalysis is traced to an effective stabilization
of developing charges in the transition state by carefully orchestrated hydrogen bond and van der
Waals interactions between catalyst and substrates. This study demonstrates that the proficiency of
asymmetric catalysis merely driven by hydrogen bond and van der Waals interactions can rival
traditional activation through direct transition metal coordination of the substrate.
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Introduction
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Asymmetric catalysis is considered as one of the most efficient and economical strategies to
access single enantiomers of a chiral molecule since only substoichiometric quantities of the chiral
catalyst are required and remarkable progress has been made with respect to combining high
asymmetric induction with low catalyst loadings. For example, employing a chiral iridium catalyst,
Zhou and coworkers achieved a turnover number (TON) of 4550000 with an enantioselectivity of
98% ee for the enantioselective hydrogenation of acetophenone.1,2 Over the past 10ꢀ15 years, chiral
organic compounds have complemented chiral transition metal complexes as powerful asymmetric
catalysts.3 In one appealing mode of activation, which somewhat mimics enzymatic catalysis, weak
forces such as hydrogen bond formation and van der Waals interactions are exploited to provide both
the required rate acceleration as well as asymmetric induction.4,5 This mild mode of activation is very
attractive because it ensures a high functional group tolerance. However, this comes at the cost of
achieving high turnover numbers with catalyst loadings of 5ꢀ30% (≤ 20 TON) being still standard.6 A
notable exception was recently reported by Song and coworkers for the desilylative kinetic resolution
of racemic alcohols using extremely low catalyst loadings down to 0.0001 mol% (up to 440000
TON).7 The same group also demonstrated an acceleration of hydrogen bond catalysis on water
allowing to reduce the catalyst loading for an enantioselective Michael addition to 0.01 mol% (up to
10000 TON).8
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Nature solves this problem by steering multiple attractive weak interactions between enzyme
catalyst and substrate in a cooperative fashion, thereby lowering the activation barrier through
substrate proximity and electronic activation. This concept has been applied to the design of biꢀ and
multifunctional catalysts.5,9 The activation of both the nucleophile and electrophile within a single
catalyst provides the opportunity to achieve high catalytic activity and high asymmetric induction
through a synergistic electronic activation of the involved substrates together with a control of their
topological arrangement at the active site of the catalyst. However, getting the most out of this concept
poses significant challenges. Firstly, finding the ideal position and orientation of the multiple
functional groups involved in substrate binding and activation is not trivial and requires a versatile
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structural scaffold. Secondly, in cases where only weak forces are at play between the catalyst and the
substrates, entropy must play an important role because the highly ordered ternary complex out of the
two substrates and the catalyst only holds together by weak forces. These two points can rationalize
the often high catalyst loadings that are required by bifunctional thiourea catalysts.5
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In this proof of principle study we demonstrate that a fineꢀtuned cooperativity of hydrogen
bond formation and van der Waals interactions implemented within a rigid template can provide an
extremely active multifunctional asymmetric catalyst achieving remarkable rate accelerations of
kcat/kuncat = 2.5 x 105 with catalyst loadings down to 0.004 mol% and up to 20250 TON while retaining
high enantioselectivity (>90% ee).
Results and Discussion
Catalyst Development. We started this study with ΛꢀIr1,10 a previously developed metalꢀ
templated catalyst containing a structural iridium(III) center,11,12 which was reported to be an effective
asymmetric transfer hydrogenation catalyst. Here, the stereochemical information is provided by the
chiralꢀatꢀmetal iridium, which also positions the catalytic functional group in a precise fashion using is
octahedral coordination environment. However, its performance diminishes at low catalyst loadings.
For example, at a catalyst loading of 0.1 mol%, the conjugate reduction of (E)ꢀ2ꢀmethylꢀ1ꢀnitrostyrene
(1a) to the corresponding nitroalkane (R)ꢀ2a employing the Hantzsch ester 3 as the reducing agent
proceeds sluggishly with an incomplete conversion in the optimal solvent toluene at 20 °C and a low
enantioselectivity of 65% ee (Table 1, entry 1).13ꢀ15 An iterative improvement of this catalyst was
accomplished by replacing the hydroxyl groups with the stronger hydrogen bond acceptor N,Nꢀ
diethylcarboxamide (ΛꢀIr2, entry 2),16ꢀ18 optimizing the substituent at the metalated phenyl moiety
(ΛꢀIr3 and ΛꢀIr4, entries 3ꢀ6),16 replacing the benzoxazole ligands against benzothiazoles (ΛꢀIr5,
entry 7), and by exchanging the pyridylpyrazole ligand with a bisꢀpyrazole (ΛꢀIr6, entries 8ꢀ13). Note
that the final catalyst ΛꢀIr6 is C2ꢀsymmetrical and therefore contains two catalytic sites per iridium
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complex. ΛꢀIr6 displays an atonishing activity, catalyzing the reaction 1a → (R)ꢀ2a with a loading of
only 0.01 mol% while maintaining a high enantioselectivity of 94% ee (entry 9). Using the substrate
(E)ꢀ2ꢀnꢀhexylꢀ1ꢀnitrostyrene (1b), a further reduced catalyst loading of 0.005 mol% is sufficient to
achieve a satisfactory enantioselectivity of 91% ee (entry 11).19 Relevant for aspects of sustainable
chemistry, this reaction can be executed completely devoid of any solvent, even resulting in improved
enantioselectivity.20 For example, substrate 1b is converted into (R)ꢀ2b using 0.005 mol% or 0.004
mol% ΛꢀIr6 with a 94% or 91% ee, respectively (entries 12 and 13). A catalyst loading of 0.004
mol% relates to a substrate/catalyst ratio of 25000 and 20250 TON for a conversion of 81% (entry
13).
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Table 1. Ultra lowꢀloading Hꢀbond catalyst development.a
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entry cat
mol%b TONc
R
conditionsd
t (h)
conv (%)e ee (%)f
1
0.1
470
Me
Me
Me
Me
Me
Me
Me
Me
Me
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
toluene, 20 °C
96
48
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15
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48
24
40
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47
99
98
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94
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64
92
86
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97
90
81
65
93
98
94
98
94
95
97
94
96
91
94
91
ΛꢀIr1
ΛꢀIr2
ΛꢀIr3
ΛꢀIr3
ΛꢀIr4
ΛꢀIr4
ΛꢀIr5
ΛꢀIr6
ΛꢀIr6
ΛꢀIr6
ΛꢀIr6
ΛꢀIr6
ΛꢀIr6
2
0.1
990
3
0.1
980
4
0.05
0.05
0.02
0.02
0.02
0.01
0.01
0.005
0.005
0.004
1120
1880
2800
3200
4600
8600
8800
19400
18000
20250
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a
nHex toluene, 20 °C
nHex toluene, 40 °C
nHex no solvent, rt
nHex no solvent, rt
b
c
BArF = tetrakis[(3,5ꢀdiꢀtrifluoromethyl)phenyl]borate. Catalyst loadings provided in mol%.
Calculated turnover numbers. d Conditions: In anhydrous toluene under stirring with 1.5 eq. 3 (entries
1ꢀ11) or solventꢀfree in a ball mill with 1.1 eq. 3 (entries 12 and 13). e Conversion determined by 1Hꢀ
NMR. f Enantiomeric excess determined by chiral HPLC.
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Substrate Scope and Gram Scale Reactions. As demonstrated by the results in Figure 1,
catalyst ΛꢀIr6 displays an excellent substrate scope and provides for a broad range of β,βꢀ
disubstituted nitroalkenes ee values between 91 and 98% at catalyst loadings between 0.005 and 0.05
mol%. It is also worth noting that the reaction is readily scalable. For example, upon increasing the
scale from milligram to gram scale, the catalytic performance of ΛꢀIr6 even increased slightly:
Dissolved in 13 mL of toluene, 3.0 mg of ΛꢀIr6 (0.005 mol%) converted 6.2 g of 1b into 6.1 g of (R)ꢀ
2b with a high yield of 97% and 92% ee which relates to a TON of 19400 (Figure 1). Under solventꢀ
free conditions, on a gram scale, a yield of 93% with 94% ee was observed (18600 TON).
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(1.1.ꢀ1.5 eq)
R1
R1
toluene or solventꢀfree
NO2
NO2
R2
R2
ꢀIr6 (0.005ꢀ0.05 mol%)
1a l
2a l
ꢀ
ꢀ
1820ꢀ19400 TON
0.005 mol%, 40 °C, 48 h
97% yield, 92% ee
19400 TON
Me
solvent free:
NO2
NO2
93% yield, 94% ee
18600 TON
2a
2c
NO2
0.01 mol%, 20 °C, 60 h
97% yield, 95% ee
9700 TON
0.02 mol%, 20 °C, 36 h
92% yield, 98% ee
4600 TON
2b
Me
Me
NO2
NO2
NO2
2d
2e
2f
Me
MeO
0.02 mol%, 20 °C, 36 h 0.02 mol%, 20 °C, 36 h 0.02 mol%, 20 °C, 36 h
94% yield, 91% ee
4700 TON
93% yield, 96% ee
4650 TON
91% yield, 97% ee
4550 TON
Me
Me
Me
NO2
S
NO2
NO2
2g
2h
2i
Cl
0.02 mol%, 20 °C, 35 h 0.02 mol%, 20 °C, 30 h 0.02 mol%, 20 °C, 36 h
93% yield, 96% ee
4650 TON
94% yield, 97% ee
4700 TON
90% yield, 96% ee
4500 TON
O
O
Me
O
O
NO2
NO2
NO2
2j
2k
2l
0.05 mol%, 0 °C, 36 h 0.05 mol%, 0 °C, 36 h 0.05 mol%, 0 °C, 24 h
91% yield, 95% ee
1820 TON
99% conv., 93% ee
1980 TON
94% yield, 94% ee
1880 TON
Figure 1. Substrate scope of the enantioselective transfer hydrogenation with ΛꢀIr6.
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Excluding Direct Metal Involvement. The surprisingly high catalytic activity of the
developed catalysts warrants a confirmation of the role of the involved transition metal, which was
addressed by two sets of experiments using the example of ΛꢀIr4. Firstly, performed with 0.1 mol%
of ΛꢀIr4, the catalyst was reisolated after each catalytic reaction (1a → 2a) in high yields and reused
multiple times without any significant loss of catalytic performance, thereby demonstrating its high
constitutional and configurational stability (Figure 2). Secondly, replacing the central iridium in ΛꢀIr4
for the lighter congener rhodium provides a catalyst (ΛꢀRh4) with almost indistinguishable catalytic
activity (Figure 3a), which can be traced back to highly similar coordination geometries of rhodium
and iridium as demonstrated by crystal structures of the bisꢀcyclometalated “core complexes” (Figure
3b) in which the coordinative bonds to iridium and rhodium vary only in a range from 0.005ꢀ0.025 Å.
Thus, the high inertness of the employed bisꢀcyclometalated iridium(III) complexes together with the
demonstrated insensitivity towards swapping the central metal precludes a direct involvement of the
metal in the catalytic mechanism and confirms that the metal exerts a purely structural role by
providing the essential chirality and serving as a central component of the structural scaffold.21
Furthermore, the observation that the catalyst can be reisolated and reused multiple times without
significantly affecting its catalytic performance reveals the constitutional and configurational stability
of the bisꢀcyclometalated organometallic complex, which is a prerequisite for achieving high turnover
numbers.
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a) Reactions with recycled catalyst
Yields of nitroalkane (%)
Enantioselectivities (%)
99 99
99 99
99 99
98 99
98 98
100
80
60
40
20
0
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1
nd 2
run
rd3
3 run
th4
th5
st
2
4 run
5 run
1 run
b) Catalyst recycling
Yields of recovered catalyst (%)
Enantiomeric excess of recovered catalyst (%)
84 99
81 99
86 99
81 99
100
80
60
40
20
0
1st recovery
2nd recovery
2
3rd recovery 4th recovery
1
3
4
th5
5 run
Figure 2. Catalyst recycling experiments with catalyst ΛꢀIr4 (0.1 mol%) for the conversion 1a → 2a.
(a) Catalytic performance of recovered catalyst. (b) Yields and enantiopurities of the recovered
catalyst after each reaction. Enantiomeric excess of recovered ΛꢀIr4 was determined by HPLC on a
chiral stationary phase.
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a)
BArFꢀ
+
NEt2
O
O
N
N
M
N
Cat
R
Yield (%)
ee (%)
99
N
O
9
ΛꢀRh4
ΛꢀIr4
ΛꢀRh4
ΛꢀIr4
nHex
nHex
Me
96
97
96
93
N
N
H
CONEt2
H
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CF3
99
O
98
Me
98
M = Ir: ꢀIr4, M = Rh: ꢀRh4
b)
Figure 3. Comparison of homologous iridium and rhodium catalysts. (a) Conjugate reduction
catalyzed by ΛꢀIr4 and the lighter congener of ΛꢀRh4. (b) Xꢀray crystal structures of the
corresponding iridium and rhodium “core complexes” racꢀIr7 (CCDC no. 1460846) and racꢀRh7
(CCDC no. 1460844) with the bidentate ligands devoid of any substituents. ORTEP drawings with
50% thermal ellipsoids. The complexes were crystallized as their racemates but only the Λꢀ
enantiomers are shown. The chloride counterions and solvent molecules are omitted for clarity.
Distances of coordinative bonds (Å): Ir1ꢀN1 = 2.045, Rh1ꢀN1 = 2.040, Ir1ꢀN2 = 2.050, Rh1ꢀN2 =
2.042, Ir1ꢀN3 = 2.141, Rh1ꢀN3 = 2.164, Ir1ꢀN4 = 2.113, Rh1ꢀN4 = 2.138, Ir1ꢀC121 = 2.028, Rh1ꢀ
C121 = 2.012, Ir1ꢀC221 = 2.035, Rh1ꢀC221 = 2.013.
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Probing Hydrogen Bond Interactions. Having confirmed the absence of any direct metal
coordination to a substrate, we next experimentally probed the involvement of hydrogen bonds during
catalysis. Firstly, the expected hydrogen bond driven mechanism is consistent with an observed high
sensitivity of the catalytic reaction towards competing hydrogen bond donors and acceptors. For
example, the addition of just one equivalent of ethanol or N,Nꢀdimethylacetamide significantly slowed
down the reaction rate with dramatic declines in enantioselectivities to 20% and 8% ee (conversion 1a
→ (R)ꢀ2a with 0.02 mol% ΛꢀIr6), respectively, while the presence of nitrobenzene decreased the
reaction rate significantly (66% instead of 92% conversion after 22 h), apparently by competing with
the substrate for the double hydrogen bond binding site at the catalyst (see Supporting Information for
more details). Secondly, the expected double hydrogen bond between catalyst and nitroalkene lends
further support from temperature dependent downfield chemical shifts of the NꢀH groups of simplified
model catalysts in the presence of a nitroalkene substrate (see Supporting Information for more
details). Thirdly, a coꢀcrystal structure between a simplified model catalyst and a carboxylate
(trifluoroacetate), employed as a structural analog of a nitro compound displays the expected
association of the carboxylate substrate at the catalytic side (Figure 4). In this context it is worth
noting that ΛꢀIr6 represents only a weak Brønsted acid (pKa = 13 in MeCN) and, for example, is not
capable of protonating the weak base pyridine in MeCN (see Supporting Information). A proton
transfer to the nitroalkene substrate in a preꢀequilibrium can therefore be excluded, thus classifying
the mechanism as a real hydrogen bond mediated catalysis (general acid catalysis) and being clearly
distinct from typical Brønsted acid catalysis (specific acid catalysis).
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Figure 4. Coꢀcrystal structure showing a double hydrogen bond interaction between a simplified
model iridium complex (racꢀIr8) and a trifluoroacetate anion used as a structural analog of a nitro
substrate (CCDC no. 1420596). ORTEP drawings with 50% probability thermal ellipsoids.
Probing Van der Waals Interactions. We next probed weak, nonꢀcovalent interactions
between the nitroalkene substrate and the catalyst beyond hydrogen bond formation. This was
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accomplished by employing HꢀNMR titration experiments to determine Kd values for the interaction
of the nitroalkene 1a with simplified model catalysts which only differ in their aromatic moiety
(position R′ in Table 1) (see Supporting Information for more details). As a result, Kd values decrease
in the direction R′ = H > 3,5ꢀMe2Ph > 2,6ꢀMe2Ph, which means that with increasing steric hindrance
the binding affinity improves. Since the hydrogen bond formation of all three model catalysts is
identical, this trend is indicative of attractive van der Waals interactions between the moiety R′ and
the nitroalkene substrate. Indeed, the coꢀcrystal structure displayed in Figure 4 reveals how close one
methyl group of the 2,6ꢀMe2Ph moiety comes to the nitroalkene substrate. These results are consistent
with the observed trend in catalyst performance ΛꢀIr4 (R′ = 2,6ꢀMe2Ph) > ΛꢀIr2 (R′ = 3,5ꢀMe2Ph),
thus supporting our interpretation that our optimized catalyst achieves maximum binding affinity to
the nitroalkene substrate through a combination out of hydrogen bond and van der Waals interactions.
The aromatic and aliphatic moieties of the catalyst ligand sphere generate a hydrophobic cavity, which
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can also be seen in the space filling model of ΛꢀIr6 (Figure 5d) and the model crystal structure in
Figure 4. Since nitro groups are only weak hydrogen bond acceptors,22 the additional van der Waals
interactions are apparently crucial for increasing the binding affinity for the nitroalkene substrate,
thereby being a prerequisite for a sufficient turnover at very low catalyst loadings.
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Kinetics. The reaction rate is an important parameter for achieving a sufficient turnover
frequency at very low catalyst loadings. To determine the rate acceleration achieved by the catalyst Λꢀ
Ir6, we made use of the fact that ΛꢀIr6 displays an almost perfect asymmetric induction. For example,
at a catalyst loading of 0.2 mol% for the reaction 1b → (R)ꢀ2b an enantioselectivity of 99.3% ee is
obtained.23 This means that the formation of the minor enantiomer at lower catalyst loadings must
arise from the uncatalyzed background reaction and therefore allows us to approximate the rate
acceleration of the ΛꢀIr6ꢀcatalyzed (kcat) versus uncatalyzed reaction (kuncat) of kcat/kuncat = 2.5 x 105.
Although such a rate acceleration cannot match the proficiency of enzyme catalysis, it is remarkable
for a small molecule catalyst that is limited to hydrogen bonding and van der Waals interactions.24
The overall kinetic profile of this reaction, carried out under slightly diluted homogeneous conditions,
was determined to be first order with respect to each substrate and just 0.77 with respect to the catalyst
which is consistent with ΛꢀIr6 displaying two catalytic sites per complex. A determined ꢀH‡ of 34
kJ/mol and ꢀTꢀS‡ of 42 kJ/mol at 20 °C also demonstrates that the entropic penalty for reaching the
highly ordered ternary transition state outperforms the enthalpic part, being consistent with a highly
ordered ternary transition state that is only arranged by a combination of weak forces. This also
supports the notion that the limited flexibility of the employed metal template should be beneficial for
lowering the Gibbs free energy of activation (ꢀG‡).
Computational Study. The overall catalyst design builds on extensive work of bifunctional
thiourea catalysis, including the asymmetric transfer hydrogenation of β,βꢀdisubstituted nitroalkanes
with Hantzsch ester.5,14,15,25 The resulting hypothesis that the amidopyrazole moiety forms a double
hydrogen bond with the nitroalkene while a carboxamide moiety accepts a hydrogen bond from the
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Hantzsch ester was probed using a computational study of the uncatalyzed and catalyzed reactions
summarized in Figure 5.
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The calculated absolute activation enthalpy of 10.6 kJ/mol cannot be directly compared to the
experimental value 34 kJ/mol, due to the differences in the desolvation penalty for the catalyst and
substrates that is not included in the models calculated here. The difference in activation enthalpy
between the catalyzed and the uncatalyzed reaction of 43.6 kJ/mol is a better measure of the catalytic
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effect and is in very good agreement with the experimentally observed rate acceleration of kcat/kuncat
=
2.5 x 105 when using the value of ~5.5 kJ/mol for a tenfold acceleration at room temperature and
considering the differences in ꢀꢀS‡ between reactions through a bimolecular and a termolecular
complex.26 The calculated free energy of reaction is with ꢀ85.7 kJ/mol less exergonic in the catalyzed
compared to the uncatalyzed complex, where a value of ꢀ120.9 kJ/mol was obtained. The lower free
energy of reaction in the termolecular complex is due to the loss of the hydrogen bond between the
Hantzsch ester and the amide C=O as well as the πꢀstacking interactions that were responsible for the
assembly of the complex in the product.
Analysis of the geometry of the transition structures for the uncatalyzed and catalyzed reaction
shown in Figure 5a and 5b, respectively, reveals that the proposed hydrogen bonds in the catalyzed
reaction bring the two substrates into an orientation which perfectly resembles the preferred transition
structure of the uncatalyzed bimolecular reaction. The hydrogen bonds stabilizing the developing
charge in the transition structure are with 1.78 Å much shorter than the corresponding ones in the
reactant complex (1.93 Å) while the hydrogen bond holding the Hantzsch ester in place is with 1.87 Å
and 1.90 Å almost identical in the transition structure and reactant complex, respectively. The πꢀ
systems of the nitroalkene and Hantzsch ester in the substrate complex are stacking against each other
and positioning them for the hydride transfer.
The differences in the lengths of the forming and breaking CꢀH bonds in the uncatalyzed and
catalyzed reaction point to substantial differences in the electronic character of the two transition
structures. While in the uncatalyzed reaction, the breaking CꢀH is with 1.40 Å slightly longer than the
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forming one, the breaking CꢀH bond in the transition structure of the catalyzed reaction is with 1.22 Å
much shorter than the forming CꢀH bond. One approach to rationalize these differences is an analysis
of the partial charges (Figure 5c). In the uncatalyzed reaction, the partial charges of the hydride donor
and acceptor portions almost exactly flip, indicating a minimized charge buildup in the approximately
symmetric position of the hydrogen along the reaction coordinate. In contrast, the charge polarization
for the transition structure of the catalyzed reaction is similar but smaller, indicating that the
developing negative charge in the hydride acceptor portion of this early transition structure is
compensated by the strengthening hydrogen bonds. It should also be mentioned that the charge
analysis indicates an identical partial charge of +0.62 on the central metal in the reactant complex and
the transition structure, thus reemphasizing the structural rather than catalytic role of the metal. These
results are consistent with the hypothesis that the three hydrogen bonds induce a polarization that
increases the electrophilicity of the nitroalkene substrate as well as the hydride donor ability of the
Hantzsch ester in a highly preꢀorganized binding site shown in Figure 5d. This facilitates the hydride
transfer from the Hantzsch ester to the nitroalkene by stabilization of the developing charge in the
transition structure and is followed by a subsequent proton transfer to provide the final nitroalkane.
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a) Uncatalyzed transition state
b) Catalyzed transition state
3
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7
hydride
acceptor
1.31 Å
1.78 Å
1.78 Å
1.87 Å
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hydride
donor
1.52 Å
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1.40 Å
1.22 Å
ꢀ85.7
10.6
ꢀ120.9
54.2
ꢀGreact
ꢀH‡
c) Charge distribution
d) Space filling model of ΛꢀIr6
Hydride Hydride
H-bond acceptor
donor
ꢀ0.27
+0.35
ꢀ0.33
ꢀ0.20
acceptor
Reactants
+0.27
double H-bond
donor
Uncatalyzed TS
Reactants/catalyst
Catalyzed TS
ꢀ0.35
binding cavity
+0.38
+0.23
Figure 5. Computational investigations. (a,b) Comparison of the uncatalyzed and catalyzed transition
structure of the hydrogenation, calculated at M06/6ꢀ311+G**+CPCM//6ꢀ31G* and
M06/LANL2DZ/6ꢀ311+G**+CPCM//LANL2DZ/6ꢀ31G* levels of theory, respectively, for a model
complex consisting of nitroethylene, Hantzsch ester bearing methyl instead tertꢀbutyl esters, and a
core structure derived from ΛꢀIr4. (c) Charge distributions based on Mulliken charges at the γꢀC of
the Hantzsch ester (hydride donor) and the βꢀC of the nitroalkene (hydride acceptor). (d) CPK
representation of the M06/LANL2DZ/6ꢀ31G* optimized structure of ΛꢀIr6.
Conclusions
We here demonstrated the power of a metalꢀtemplated catalyst design by developing a
hydrogen bond mediated asymmetric catalyst (ΛꢀIr6) with remarkable performance, reaching
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excellent yields and enantioselectivities at room temperature with turnover numbers as high as 20250
(0.004 mol% catalyst loading), which outperforms all reported organocatalysts and transition metal
catalysts for the conjugate reduction of β,βꢀdisubstituted nitroalkenes for the reaction 1a → (R)ꢀ or
(S)ꢀ2a.14,27 This was accomplished by an iterative improvement of the catalyst through optimization of
hydrogen bond and van der Waals interactions with the involved substrates, limiting the
conformational flexibility of the catalyst, and by rendering the catalyst C2ꢀsymmetrical so that two
catalytic centers are operational per single iridium complex. The versatile globular geometry of the
employed octahedral scaffold gives a large freedom of a tailored arrangement of multiple functional
groups and is combined with a high degree of rigidity which reduces the entropic penalty of the
transition state and allows an acceleration of the asymmetric transfer hydrogenation kcat/kuncat = 2.5 x
105. ΛꢀIr6 apparently mimics somewhat the function of enzymes by perfectly orchestrating hydrogen
bond as well as van der Waals interactions with the substrates within a binding cleft, while
minimizing entropic effects due to a rigid, preorganized catalyst structure. Nitroalkanes are versatile
chiral building blocks and the application of these insights gained for the high performance catalytic
enantioselective conjugate reduction of β,βꢀdisubstituted nitroalkenes to the FriedelꢀCrafts alkylation
of β,βꢀdisubstituted nitroalkenes is ongoing in our laboratory.28
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Experimental Section
Synthesis of enantiomerically pure catalysts. All chiralꢀatꢀmetal iridium complexes were
synthesized following a previously developed auxiliaryꢀmediated strategy.10,29 The iridium complexes
ΛꢀIr1,10 ΛꢀIr2,16a and ΛꢀIr316a have been reported. The new catalysts ΛꢀIr4ꢀ6 were synthesized in a
more economical fashion by employing the readily available amino acid Lꢀproline as the chiral
auxiliary.16b,30 The new rhodium complex ΛꢀRh4 was obtained by resolution of a racemic mixture on
HPLC using a chiral stationary phase. A detailed description of the synthesis and characterization of
these complexes is provided in the Supporting Information.
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Mechanistic investigations. Experimental details of the mechanistic investigations, including
computation, NMR experiments, kinetics, and crystallographic experiments are provided in the
Supporting Information.
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Asymmetric transfer hydrogenations. As a characteristic example for the reaction, to a
solution of catalyst Λ-Ir6 (3.0 mg, 1.340 ꢁmol, 0.005 mol% catalyst loading) in freshly distilled
toluene (13.4 mL), nitroalkene 1b (6.244 g, 26.80 mmol) and tertꢀbutyl Hantzsch ester (9.120 g, 29.48
mmol) were added. The reaction was stirred at 40 °C for 48 hours under an atmosphere of argon.
After cooling to room temperature, the mixture was diluted with nꢀhexane and then directly subjected
to flash silica gel column chromatography with EtOAc/nꢀhexane (1:100 to 1:50) to afford the product
(R)ꢀ2b (6.085 g, 25.89 mmol, 97% yield) with 92% ee as determined by HPLC on a chiral stationary
phase. Complete experimental details of this an all other catalytic reactions are provided in the
Supporting Information.
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Supporting Information. Synthetic details, details of mechanistic experiments, HPLC traces,
crystallographic data, computational study, and NMR study. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgments:
We thank the National Natural Science Foundation of P. R. China (grant nos. 21272192, 21472154
and 21572184), the Program for Changjiang Scholars and Innovative Research Team of P. R. China
(PCSIRT), the National Thousand Talents Program of P. R. China, the Fundamental Research Funds
for the Central Universities (grant no. 20720160027), and the 985 Program of the Chemistry and
Chemical Engineering disciplines of Xiamen University.
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References:
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13 For selected examples of organocatalytic asymmetric transfer hydrogenations with Hantzsch
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14 For the organocatalytic asymmetric transfer hydrogenation of nitroalkenes, see: (a) Martin, N. J.
A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129, 8976–8977. (b) Martin, N. J. A.; Cheng, X.;
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15 For recent reviews on asymmetric transfer hydrogenation with Hantzsch ester, see: (a) You, S.ꢀL.
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18 For selected examples of carboxamides as proposed hydrogen bond acceptors in thiourea
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19 Under our optimized reaction conditions, the reaction mixture is a suspension at the beginning
due to a limited solubility of the Hantzsch ester in toluene and becomes homogeneous over the
course of the reaction.
20 For hydrogen bond mediated catalysis under solventꢀfree conditions, see for example: (a) Wang,
Y.ꢀF.; Chen, R.ꢀX.; Wang, K.; Zhang, B.ꢀB.; Li, Z.ꢀB.; Xu, D.ꢀQ. Green Chem. 2012, 14, 893–
895. (b) Jörres, M.; Mersmann, S.; Raabe, G.; Bolm, C. Green Chem. 2013, 15, 612–616.
21 These two different structural aspects of the metal can be illustrated with two straighforward
experiments: Firstly, as to be expected, ΛꢀIr4 and ꢀꢀIr4 convert the substrate 1b to the mirror
imaged products (R)ꢀ2b and (S)ꢀ2b, respectively. Secondly, the ligands alone, devoid of any
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metal, not only provide the product in a racemic form but also possess an insignificant catalytic
activity. See Supporting Information for more details.
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22 Laurence, C.; Graton, J.; Berthelot, M.; Besseau, F.; Le Questel, J.ꢀY.; Luçon, M.; Ouvrard, C.;
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23 We did not observe any product racemization or decomposition so that the observed
enantioselectivities are a direct consequence of the degree of asymmetric induction and the
background reaction.
24 Zhang, X.; Houk, K. N. Acc. Chem. Res. 2005, 38, 379–385.
25 For an early example of the asymmetric activation of nitroalkenes with a bifunctional thiourea
catalyst, see: Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672–12673.
26 For an overview of the problems with a more quantitative estimate of the entropies of solvation
and activation, see for example: Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137,
3811–3826.
27 For metalꢀcatalyzed asymmetric conjugate reductions of nitroalkenes, see: (a) Czekelius, C.;
Carreira, E. M. Angew. Chem. Int. Ed. 2003, 42, 4793–4795. (b) Czekelius, C.; Carreira, E. M.
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28 Nitro groups can undergo a variety of useful transformations. See: Berner, O. M.; Tedeschi, L.;
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10.1002/ejic.201600260.
TOC graphic:
H-bond acceptor
double H-bond donor
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