London Dispersion Interactions Rather than Steric Hindrance Determine the Enantioselectivity of the Corey–Bakshi–Shibata Reduction

Article abstract of DOI:10.1002/anie.202012760

The well-known Corey–Bakshi–Shibata (CBS) reduction is a powerful method for the asymmetric synthesis of alcohols from prochiral ketones, often featuring high yields and excellent selectivities. While steric repulsion has been regarded as the key director of the observed high enantioselectivity for many years, we show that London dispersion (LD) interactions are at least as important for enantiodiscrimination. We exemplify this through a combination of detailed computational and experimental studies for a series of modified CBS catalysts equipped with dispersion energy donors (DEDs) in the catalysts and the substrates. Our results demonstrate that attractive LD interactions between the catalyst and the substrate, rather than steric repulsion, determine the selectivity. As a key outcome of our study, we were able to improve the catalyst design for some challenging CBS reductions.

Full text of DOI:10.1002/anie.202012760

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Accepted Article
Title: London Dispersion Rather than Steric Hindrance Determines the
Enantioselectivity of the Corey-Bakshi-Shibata Reduction
Authors: Christian Eschmann, Lijuan Song, and Peter Richard
Schreiner
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10.1002/anie.202012760
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RESEARCH ARTICLE
London Dispersion Rather than Steric Hindrance Determines the Enantioselectivity of
the Corey-Bakshi-Shibata Reduction
Christian Eschmann,+ Lijuan Song,+,& and Peter R. Schreiner*
[*]
M. Sc. C. Eschmann, L. Song, PhD, Prof. Dr. P. R. Schreiner, PhD
Institute of Organic Chemistry
Justus Liebig University, 35392 Giessen (Germany)
E-mail: prs@uni-giessen.de
These authors contributed equally to this work.
New Address: Shenzhen Bay Laboratory, Shenzhen 518055, China.
[+]
[&]
Supporting information for this article is given via a link at the end of the document.
Abstract: The well-known Corey-Bakshi-Shibata (CBS) reduction is
a powerful method for the asymmetric synthesis of alcohols from
prochiral ketones, often featuring high yields and excellent
selectivities. While steric repulsion has been regarded as the key
director of the observed high enantioselectivity for many years, here
we show that London dispersion (LD) interactions are at least as
important for enantiodiscrimination. We exemplify this through a
combination of detailed computational and experimental studies for a
series of modified CBS catalysts equipped with dispersion energy
donors (DEDs) in the catalysts and the substrates. Our results
demonstrate that attractive LD interactions between the catalyst and
the substrate rather than steric repulsion determine the selectivity. As
a key outcome of our study, we were able to improve the catalyst
design for some challenging CBS reductions.
predict the enantiofacial discrimination of numerous substrates.
However, this model of steric destabilization does not offer a
satisfying explanation for the selectivity and reactivity of some
substrates. For example, the reduction of trichloroacetophenone
predominantly generates the (R)-enantiomer.[6a] This implies that
the large phenyl group (RL) faces the boron substituent in the
favored transition state, which is in contrast to Corey’s standard
model depicted in Scheme 1. In the reduction of cyclopropyl
isopropyl ketone (1-cyclopropyl-2-methylpropan-1-one) one
would assume poor selectivity, because both substituents are
similar in steric size. Nonetheless, the reduction delivers the (R)-
enantiomer with a selectivity of 91% ee.[5f] Similarly, a high ee
(81%) was also found for p-methoxy-p'-nitrobenzophenone with
two groups of similar size.[5f] In these two cases, the cyclopropyl
substituent and the p-methoxy phenyl group act as RL,
respectively, thereby demonstrating that other factors must also
play an important role in the transition state structure.
Furthermore, despite bearing bulky groups, there are substrates
that do not deliver high selectivity, e.g., unbranched aliphatic
ketones.[7]
Introduction
The detailed understanding of reaction mechanisms and the
origin of enantioselectivity is essential for successful catalyst
design. Enantioselectivity imparted by chiral, small-molecule
catalysts is rationalized typically by preferential steric
destabilization derived from the repulsive part of the van der
Waals (vdW) potential because it can be readily understood and
taught with hard-sphere classical mechanics models. In contrast,
London Dispersion (LD), the attractive part of the vdW potential,[1]
is often neglected in mechanistic considerations and for catalyst
design.[2] However, for a detailed understanding of a given
catalytic system, all interactions must be considered, even though
we are just learning how to conceptualize this for reaction
planning.[3] Fortunately, modern computational techniques like
dispersion corrected density functional theory (DFT) now allow a
detailed analysis of all factors contributing to transition state
stabilization for a much better understanding of catalyst design.[4]
Here we chose the Corey-Bakshi-Shibata (CBS) reduction, which
is a versatile method for the enantioselective reduction of
prochiral ketones by oxazaborolidines (OXB), achieving high
selectivities and yields[5] to demonstrated that all steric factors,
attraction and repulsion, have to be taken into account to arrive at
a balanced description of the mechanism and to design new,
more selective catalysts.
Scheme 1. CBS reduction of acetophenone and proposed transition structures
for hydride transfer, favoring the (R)-product on the basis of minimizing the steric
repulsion between “R” and “RL”.
There are several reports on the stereoselection of the CBS
reduction trying to shed light on the origin of its enantioselectivity.
In 1993 Liotta et al. used the MNDO semiempirical approach to
suggest that the reduction is more likely to occur via a chair-like
transition state. In addition, the carbinol phenyl substituents of
the catalyst are required to lie parallel to the RL substituent to
minimize steric repulsion.[8] Meyer et al. investigated the role of
steric repulsion in the transition structures of the reduction by
Corey’s widely accepted mechanistic model bases
stereoselection exclusively on steric repulsion between the boron
substituent R on the catalyst and the large RL and small RS
substituents of the ketone in a six-membered boat-like transition
6]
state (Scheme 1).[5f,
With this model, one can qualitatively
1
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determining kinetic isotope effects (KIE), as the C–D bond is
effectively shorter than the C–H bond, resulting in inverse 2H KIEs
for reactions in which steric repulsion increases in the transition
structure.[9] They concluded that Corey’s steric reasoning is too
simplistic, because in the reduction of acetophenone the chair-
like transition state prevails, with the boron substituent only
playing a minor role.[10] In a recent theoretical study, Lachtar et
al. suggest that the origin of the enantioselectivity for the
oxazaborolidine catalyzed reduction of ketimines can be traced
back to noncovalent interactions in the preferred transition
structure.[11] However, by replacing the phenyl groups of the
catalyst by hydrogens, they used a computationally reduced
model that neglects major parts of these key noncovalent
interactions. Furthermore, their B3LYP/6-31G(d,p) computations
do not include dispersion corrections.
Here we aim at bringing together experimental and
computational studies geared towards understanding a reaction
whose stereochemical outcome was classically interpreted as
being derived solely on the basis of steric repulsion. We
demonstrate that a more detailed and hence more powerful
mechanistic reasoning emerges when all interactions are taken
into account and we gauge the role of attractive LD stabilization
in this particular reaction.
coded in black), the relative energies of the transition structures
TS1R and TS1S are notably lower with barriers of only 13.7 kcal
mol–1 and 15.7 kcal mol–1, respectively, which is much more
reasonable for a catalyzed reaction that proceeds quickly at room
temperature. The calculated enantioselectivity of the reduction,
which is expressed in the energy difference between the transition
structures (ΔΔG‡) for hydride transfer, is −2.0 kcal mol–1 and
thereby consistent with previously published experimental results
(−2.2 kcal mol–1).[5b] We computed the TSs in solvent within the
limitations of an SCRF model. The energy difference of TS1R and
TS1S in gas phase is 4.0 kcal mol–1, while it is 2.0 kcal mol–1 in
THF. As expected, the LD interactions are attenuated by the
interaction with the solvent but, more importantly, they do not
vanish. Catalyst regeneration and release of the boronate 7 is
exergonic by –15.1 kcal mol–1. For comparison, we also added
DLPNO-CCSD(T)/cc-pVTZ single-point energies on the DFT-
optimized geometries (and ZPVE corrections) of TS1s and TS1R,
which are 7.7 kcal mol–1 and 10.8 kcal mol–1, respectively. This
indicates the dispersion-corrected energy barrier is more
reasonable and that more complete inclusion of electron
correlation effects emphasize the importance of LD.
Results and Discussion
This section is organized in three parts. First, a comprehensive
computational investigation of the various noncovalent
interactions (NCI) in the transition structures provides
a
contemporary view of the origin of the enantioselectivity in the
CBS reduction. Then we show how these insights help in the
design of new catalysts to improve enantioselectivity, especially
for some challenging substrates. Finally, we provide an
experimental validation of our improved understanding of catalyst
design.
ꢃꢄꢅ
Figure 1. Potential energy surface displaying the free energies (∆ꢀ ) of the
ꢀꢁꢂ
Reconsidering Steric Effects
CBS pathway with (black) and without dispersion (grey) corrections at 2 °C. For
a more detailed PES see Fig. S2. Level of theory: B3LYP-D3(BJ)/6-311+G(d,p)-
SMD(THF)//B3LYP-D3(BJ)/6-311G(d,p). The free energies in brackets are
based on electronic DLPNO-CCSD(T)/cc-pVTZ single-point energy (corrected
for ZPVE).
None of the previously reported computational mechanistic
studies include LD corrections,[8-12] which are needed to strike a
proper balance between repulsive and attractive non-covalent
interactions. As this is the very concept of an “equilibrium
structure”, we set out to determine the role LD plays in the CBS
reduction. We first computed the reaction pathway for the
reduction of acetophenone using a comparison of B3LYP vs.
B3LYP-D3(BJ) with appropriate basis sets and solvent inclusion
(see Computational Details below); the difference should provide
a good estimate of the role dispersion plays (Fig. 1). A detailed
potential energy surface (PES) of the complete reaction pathway
and higher-level single-point energy computations with DLPNO-
CCSD(T)[13] (domain-based local pair natural orbital CCSD(T)) for
the key step are provided in the Supporting Information (Fig. S1).
In this simplified PES, we start with the catalyst, the reducing
agent, and acetophenone as reference 1. The hydride transfer
determining enantioselectivity occurs via two diastereomeric
transition structures. If LD is not taken into account (color-coded
in gray), the transition structures TS1’S and TS1’R are found to be
very high in free energy exhibiting barriers of 29.8 kcal mol–1 and
31.7 kcal mol–1, respectively. These energy barriers are too high
for such a fast reaction at 25 °C. After inclusion of LD (color-
A closer look at the geometries of the transition structures
TS1R and TS1S reveals chair-like conformations (Fig. 2), which
are 3.8 kcal mol–1 lower in energy, than the corresponding boat-
like conformations suggested by Corey (Fig. S1). Thereby, the
catalyst binds to the ketone at the lone pair facing the small
substituent (RS) anti to the electron-rich substituent as it is also
described in Corey’s model. NCI plots indicate some differences
of the non-covalent interactions between catalyst and substrate in
the two transition structure conformations.[14] Contrary to Corey’s
model no steric destabilization (repulsion is color-coded red in the
NCI plot) by hydrogen-hydrogen contacts can be found in less
favored TS1S. In fact, the bond distances of around 2.5 Å in the
preferred transition structure TS1R lead to stabilizing ꢀ − ꢁ LD
interactions[15] between acetophenone and the phenyl groups of
the catalyst, as visualized by the green areas in the NCI plot.
Additionally, the methyl substituent of the substrate interacts
favorably with the boron substituent of the catalyst. In the less
2
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10.1002/anie.202012760
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Figure 2. Selectivity determining transition structures for hydride transfer in the CBS-reduction of acetophenone with (S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-
c][1,3,2]oxazaborole as the catalyst. Selected bond distances in Å and non-covalent interaction (NCI) plots (s = 0.5 au, –0.01 < r < +0.01 au). Repulsion is color-
coded red, strong attraction is blue, and weak noncovalent interactions are green. The TSs were optimized at B3LYP-D3(BJ)/6-311G(d,p).
favored transition structure TS1S the long distance between
substituents of substrate and catalyst prevent optimal
interactions. These computations suggest LD interactions to be
important for enantiodiscrimination. We additionally employed LD
potential maps developed by Pollice and Chen to visualize these
LD interactions (Fig. S2).[16] These confirm the conclusions drawn
from the qualitative NCI analysis. To examine the general effect
of LD interactions on the enantioselectivity, three literature
examples with various substrates and catalysts were D3(BJ)) are
in better agreement with the experimental ee values (Tab. 1) than
the uncorrected values.
with Corey’s model, in which the larger exchange term should
favor TS1S. Therefore, the selectivity is not determined by steric
repulsion (alone). Although LD is a small part of the total
interaction energy, it decisively contributes. The LD energy
preference for TS1R is 5.9 kcal mol–1, which is in good agreement
with the experimentally observed high selectivity.[5a, 5b] Thus, our
computational results strongly suggest that LD interactions
between catalyst and substrate also determine the
enantioselectivity.
Table 1. Activation free energy (at the temperature of the experiment)
differences in kcal mol–1: experiment vs. theory. Level of theory: B3LYP-
D3(BJ)/6-311+G(d,p)-SMD//B3LYP-D3(BJ)/6-311G(d,p).
R1
H
R1
N
O
B
O
OH
Me
(0.1 equiv.)
Me
BH3.THF (0.6 equiv), THF
R2
R2
R2
Me
R1 / catalyst
structure
config ee
ΔΔꢀꢆ‡ꢇꢈ
ΔΔꢀꢉ‡ꢊꢋ
(without
D3)
ΔΔꢀꢉ‡ꢊꢋ
(with D3)
(%)
Ph
Ph
Ph
Cy
Ph
R 97
R 85
R 67
2.2 (2 °C)
1.3 (–10 °C)
1.0 (23 °C)
1.9
0.9
2.4
2.0
1.1
1.2
Figure 3. SAPT0 analysis of the transition structures TS1R and TS1S in the CBS
reduction of acetophenone. Level of theory: SAPT0/jun-cc-pvdz. See SI for a
plot of relative energies and more information.
-(CH2)4-
SAPT0 (Symmetry Adapted Perturbation Theory) was employed
to analyze the different energetic contributions of the interactions
between substrate and catalyst in the transition structures (Fig.
Improving Catalyst Design with Dispersion Energy
Donors
3).[18]
The components include electrostatics, exchange,
induction, and LD energies. The electrostatic term arises from the
large Coulomb interactions between the Lewis acid and Lewis
base sites (carbonyl and boryl as well as amino and boryl groups).
In the transition structures, electrostatics and induction dominate
the interactions but they are counterbalanced by a large exchange
term (i.e., Pauli repulsion), indicating significant steric repulsion.
However, the larger exchange energy in favored TS1R disagrees
Based on our new understanding of the origin of enantioselectivity
in the CBS reduction, we hypothesized that higher
enantioselectivity can be achieved by modifying the catalyst with
15b]
dispersion energy donors (DEDs)[2c,
that enable favorable
substrate-catalyst interactions through increasing polarizability.
3
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The catalyst modifications involve on the one hand the boron
substituent and the carbinol substituents on the other.
First, we investigated the effect of the substituent at boron
i
t
(Tab. 2); DEDs including Pr, Bu, Cy, CH2Cy, c-C5H9 were
employed. In the reduction of cyclohexyl ketone LD interactions
are the highest using CH2Cy with a ΔΔG‡ of 3.5 kcal mol–1 (entry
1). As expected for large and highly polarizable groups, Cy and
tBu should also deliver significant enantiodiscrimination (entries 2
and 4). For tBu methyl ketone, only the tBu and Me substituents
show high selectivity (entries
8
and 9).
However, our
experimental results demonstrate that the selectivity does not
change much as compared to the original catalyst when using
CH2Cy and Cy groups (Fig. S3). This implies that the interactions
between substrate and the substituent at boron on the catalyst
only have a subtle effect on the enantioselectivity.
Figure 4. Computed enantioselectivities (expressed through ΔΔG‡) in the
reduction of acetophenone, cyclohexyl methyl ketone, and 2-butanone using
different Ar groups on the catalyst at 25 °C. Level of theory: B3LYP-D3(BJ)/6-
311+G(d,p)-SMD// B3LYP-D3(BJ)/6-311G(d,p).
Table 2. The energy difference between the transition structures for hydride
transfer for computed substrates and catalysts at 25 °C. Level of theory: B3LYP-
D3(BJ)/6-311+G(d,p)-SMD// B3LYP-D3(BJ)/6-311G(d,p).
The intermolecular stabilization by all-meta substitution in
dispersion-driven systems has been demonstrated recently, e.g.,
in the stabilization of molecular dimers[19] and in the catalytic
hydroamination of olefins.[3d] Here we also find that DEDs in
meta-aryl positions provide additional attractive interactions with,
e.g., the ethyl substituent of 2-butanone, as indicated in the NCI
plots (Fig. 5). Again, more stabilizing interactions (–2.8 kcal
mol−1) between aryl groups on the catalyst and the ethyl group in
the substrate are found in the preferred TSR.
ΔΔꢀꢉ‡ꢊꢋ
(without D3)
ΔΔꢀꢉ‡ꢊꢋ
(with D3)
Entry
R1
R2
1
2
3
4
5
6
7
8
9
CH2Cy
Cy
Cy
Cy
Cy
Cy
Cy
tBu
tBu
tBu
tBu
1.0
–0.4
–2.2
0.1
3.5
2.3
c-C5H9
tBu
–0.2
2.0
iPr
1.2
0.9
Cy
–0.5
–0.3
1.7
–1.1
0.1
c-C5H9
tBu
2.3
Me
4.1
4.2
The variation of carbinol substituents of the catalyst leads to
much larger changes of enantioselectivity. Replacing the phenyl
Figure 5. NCI plots (s = 0.5 au, –0.01 < r < +0.01 au) of the transition structures
in the reduction of 2-butanone using 3,5-tBu2Ph as carbinol substituent on the
catalyst. Repulsion is color-coded red, strong attraction is blue, and weak
noncovalent interactions are green. The TSs were optimized at B3LYP-
D3(BJ)/6-311G(d,p).
i
groups with aliphatic DEDs, e.g., Me, Pr, and nBu show
comparable or even reduced selectivity relative to the original
catalyst with its unsubstituted phenyl groups.[6b]
The introduction of DEDs in the meta-positions of the aryl
groups of the catalyst results in comparably high or even slightly
higher enantioselectivities relative to the original catalyst in the
reduction of acetophenone (Fig. 4).
To explore the general potential of aryl-substituted catalysts
computationally, the 3,5- tBu2Ph catalyst was computed in the
reduction of various substrates (Fig. 6). The modified catalyst
shows comparable or improved enantioselectivity, especially for
substrates yielding low enantioselectivity with the original catalyst,
e.g., 2-butanone and cyclohexyl methyl ketone. For 2-butanone,
ΔΔG‡ improves from 0.6 to 2.8 kcal mol–1, implying a theoretical
change in ee from 47% to 98%.
4
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interactions with the substrate. Furthermore, when replacing the
hydrogen at boron with a phenyl group, we observe a decrease in
enantioselectivity. This disagrees with the steric repulsion
hypothesis, where (R)-selectivity should improve with increasing
steric size of the substituent at boron.[6b] Consistent with our
computations (Figs. 2 and 3), we relate this to stabilizing LD
interactions between substrate and the phenyl group at boron in
less favored TSS (Fig. 2). This does not exclude the notion that
catalysts bearing a phenyl group at boron are probably weaker
Lewis acids and less effective, and the lower selectivity might also
be a result of a more prominent unselective background reaction.
Next, we experimentally probed the computationally predicted
effects of the carbinol substituents shown in Fig. 4. We employed
catalysts with aryl groups bearing additional DEDs to check
whether the LD interactions increase and thereby increase
enantioselectivity (Figs. 8 and 9). In all cases, at 50 °C after 1.5 h
the reduction results in near quantitative yields. In the reduction
of cyclohexyl methyl ketone all modified catalysts achieve higher
selectivities due to additional LD stabilizations. As LD through the
meta-substituent seems to be maximized at methyl already, we
decided to test the 4-OMe-3,5-Me2Ph and 4-OMe-3,5-tBu2Ph
catalysts that should be even more polarizable due to electron
donation from the methoxy group. Indeed, the best selectivities
were achieved with the 3,5-Me2Ph- and 4-OMe-3,5-Me2Ph
catalysts. The selectivities with 3,5-iPr2Ph, 3,5-tBu2Ph and 4-
OMe-3,5-tBu2Ph are slightly lower, as the substituents are getting
too bulky for cyclohexylketone; the results are similar for the
reduction of 2-heptanone. While the overall selectivity is lower
due to entropic penalty of the linear alkyl chain,[21] we observed
the best selectivities with 3,5-Me2Ph and 4-OMe-3,5-Me2Ph.
These experimental results fit the qualitative expectation from our
improved model and confirm our computations of Fig. 4, as the
3,5-Me2Ph catalyst was the also the best computed catalyst for
cyclohexyl ketone.
Figure 6. Computed enantioselectivities (expressed as ΔΔG‡ values) for the
reduction of various ketones employing the 3,5-tBu2Ph catalyst compared to the
original CBS catalyst at 25 °C. Level of theory: B3LYP-D3(BJ)/6-311G+(d,p)-
SMD// B3LYP-D3(BJ)/6-311G(d,p).
Experimental Validation
To examine our computational predictions, we performed an
experimental validation employing various catalysts and
substrates. We started with comparing the effects of changing
the substituents in the catalyst at the carbinol and boron positions.
We compared the original CBS catalyst to three modified versions
in the reduction of three ketones bearing aromatic, branched or
unbranched alkyl substituents. We employed Corey’s standard
protocol using 10 mol% of catalyst, 1.1 equiv. of reducing agent
in THF at 50 °C for 1.5 h (Fig. 7).[6b] We chose slightly elevated
temperatures, as for borane reductions there is an increase in
selectivity with increasing temperature up to 30–50 °C (Table
S2).[20] This resulted in nearly quantitative yields. As expected, by
changing the carbinol substituent of the catalyst from hydrogen to
phenyl, the selectivity increases.
Figure 8. CBS Reductions employing modified catalysts with DEDs in the
catalyst’s carbinol position.
Importantly, in the challenging reductions of smaller nalkyl
ketones, we achieve a steady increase in selectivity from 60% up
to 72% ee for 2-butanone and 64% up to 74% ee for 2-pentanone
by increasing DEDs and adding further electron-donor groups (4-
OMe-3,5-Me2Ph, 4-OMe-3,5-tBu2Ph) to the catalyst (Fig. 9).
Figure 7. Reduction of prochiral ketones employing modified CBS catalysts.
These initial findings support our proposal that the carbinol
substituents are key for enantiofacial discrimination due to LD
5
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These results also fit qualitatively to the computations of Fig. 4,
and Fig. 5, as computations suggest the 3,5-iPr2Ph and 3,5-
tBu2Ph derivatives to be the best performing catalysts (the 4-OMe-
3,5-Me2Ph, 4-OMe-3,5-tBu2Ph catalysts have not been
computed). Note that all newly designed catalysts show
improvement over Corey’s original catalyst.
Figure 10. Reductions employing phenyl substituted and fluorinated catalysts
relative to Corey’s original catalyst (Ar = phenyl).
Moreover, this is consistent with the reduction of special
substrates like pentafluorobenzophenone and p-methoxy-p-nitro-
benzophenone (Tab. 3). In all cases, the enantiomer maximizing
the attractive ꢀ − ꢁ interactions in the TS is favored. Also, the
ꢀ − ꢁ interaction of a C6F5 substituent to a phenyl ring is lower
than the ꢀ − ꢁ of two phenyl groups (entry 1).[15c] For p-methoxy-
p-nitro-benzophenone the electron-rich aryl group (4-OMe-C6H4)
provides the stronger interaction with the catalyst (entries 2 and
3). In the case of cyclopropyl isopropyl ketone (entry 4), the
catalyst interacts with the more ꢁ -electron rich cyclopropyl
Figure 9. CBS Reductions employing modified catalysts with DEDs in the
catalyst’s carbinol position for challenging substrates. Corey’s original catalyst
is the first entry (Ar = phenyl).
The trend of increasing selectivities in the experiments is
consistent with our computational results but the absolute
selectivities differ. While computations suggest an increase of
selectivity of up to 98% ee by introducing DEDs, the
experimentally observed improvement is more moderate. There
may be several reasons for this. First, the mechanism is more
complex than accounted for in the computations. Second, the
reduction features also a non-negligible background reaction with
BH3, which could have a larger impact on the modified catalysts,
as the activity of these is lower compared to the original catalyst,
because the EDG in the carbinol position reduces the Lewis
acidity at boron.[22] Third, the computations are not accurate
enough as compared to highest-level ab initio computations. This
is certainly true but we are pleased to see trends with predictability
leading to improved catalyst performance, in particular, for the
most challenging of substrates.
substituent
favoring
the
R
enantiomer.
With
trichloroacetophenone (entries 5 and 6), the more attractive ꢀ − ꢁ
interaction results in R selectivity, as chloromethanes strongly
interact with aryl rings due to LD (Tab. S4).[23a]
Table 3. Reductions employing some challenging ketones. See SI for more
details.
H
Ar
Ar
catalyst (0.1 equiv.)
BH3.SMe2 (1.1 equiv.)
O
OH
N
O
B
R1 R2
R1 R2
THF, 50 °C, 1.5 h
H
Entry
R1
R2
cat. Ar
config[a] ee
(%)
In order to also provide some counter examples, we included
catalysts with 3,5-(CF3)2Ph and C6F5 carbinol substituents and
found that the fluorinated catalysts are much less selective (Fig.
10), despite their high steric demand and significant activation of
the boron Lewis acid. These results are in accord with the
computed values (Tab. S1) and suggest weakened LD
interactions between the fluorinated aryl groups and the
substrates, as we decrease attractive ꢀ − ꢁ interactions through
the strongly electron withdrawing fluorine substituents.[15c, 23]
1
2
3
Ph
C6F5
Ph
Ph
S 92
R 56
R 62
4-OMe-C6H4
4-OMe-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-OMe-3,5-
Me2Ph
4
5
6
c-Pr
CCl3
CCl3
iPr
Ph
Ph
Ph
Ph
R 91[b]
R 27
4-OMe-3,5-
Me2Ph
R 45
[a] Abs. configuration is based upon measurement of rotation and comparison
with literature or computed values (see SI) [b] Reaction as reported by Corey et
al. with 15 mol% of catalyst and catecholborane as reducing agent at –78 °C.[5f]
6
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10.1002/anie.202012760
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RESEARCH ARTICLE
Figure 11 summarizes the results for the reductions of a variety of
ketones with our best modified catalyst. These data also indicate
that enantioselectivities increase with the computed
polarizabilities per volume ꢂ/V, resulting in a higher interaction
energy of the substituent with the catalyst (Fig. 12).[15a]
LD interactions in the TS are at work, because the rate of the
sterically more demanding substrate is higher.
t
Figure 13. Ketone to alcohol ratios in the competitive reduction of Bu ketone
and 2-pentanone after the given reaction times.
Conclusions
Figure 11. Reductions of various substrates employing our new modified CBS
catalyst.
We present
a combined computational and experimental
exploration of the origin of the enantioselectivities in CBS
reductions. Contrary to the current hypothesis that makes steric
repulsion solely responsible for enantioselection, our
computations reveal the presence of stabilizing noncovalent
interactions in the hydride transfer transition structure. NCI plots
qualitatively aided in visualizing these intermolecular interactions
particularly between the substrate and the phenyl substituents of
the catalyst. A quantitative SAPT analysis suggests that LD
interactions tip the balance in favor of attractive non-covalent
steric interactions to achieve high enantioselectivity.
Catalysts bearing DEDs in the meta-positions of the aryl
groups increase the enantioselectivity for different substrates, as
confirmed in both computations and experiment.
More
polarizable substrates lead to stronger LD interactions with the
catalyst and therefore to higher enantioselectivities as well as
faster reaction rates. If steric repulsion was the chief selector, the
rates would diminish with increasing selectivity – the opposite is
Figure 12. Increasing polarizability per Volume ꢁ/V of the substrates typically
leads to higher enantioselectivites in the reduction with a given catalyst (here:
4-OMe-3,5-Me2Ph). Computed values of polarizability ꢁ and volume V of the
corresponding substituent. Level of theory: PBE0/aug-cc-pVDZ//B3LYP-
D3(BJ)/6-311G(d,p).[24]
the case.
Even though the overall positive effect on
enantioselectivity through the addition of DEDs is moderate, it
provides strong evidence that the success of the CBS reduction
is due to an excellent balance of attractive and repulsive steric
interactions, with LD interactions being key to rationalizing the
experimental findings. Our study therefore emphasizes that
attractive LD interactions can and should be used as a modern
catalyst design principle.
These findings are confirmed by a competitive rate analysis in
the reduction of 2-pentanone and tBu methyl ketone in the same
reaction flask (Fig. 13). After the given reaction times, we took a
small sample of the reaction mixture, quenched it in citric acid,
and analyzed the conversion after work up. We chose tBu methyl
ketone and 2-pentanone, as they are reduced with quite different
t
selectivities (Fig. 11). While Bu methyl ketone is reduced in
excellent selectivity, the reaction should proceed slowly because
the neopentyl position is traditionally viewed as highly sterically
encumbered, thereby hampering the attack of nucleophiles.[25]
Computational Methods
All computations were performed with the Gaussian16 or
t
Remarkably, the consumption of Bu methyl ketone occurs at a
ORCA[26] program suite.
Geometries were optimized with
higher reaction rate than that of 2-pentanone. Computations show
dispersion corrections [DFT-D3[4a](BJ)[4b]] and without dispersion
corrections in conjunction with the B3LYP functional combining a
6-311G(d,p) basis set. Vibrational frequencies were computed for
each optimized structure to verify the stationary structures as
minima or saddle points. Solvent effects were included by single-
t
that the complex of the catalyst with Bu methyl ketone has a
similar energy as that with 2-pentanone (Fig. S6). This implies
that electrostatic interactions with catalyst are similar, and
electronic effects are not significant. We conclude, that stabilizing
7
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10.1002/anie.202012760
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RESEARCH ARTICLE
point energy computations with the SMD model[27] at the same
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orbital CCSD(T) (labeled DLPNO-CCSD(T)) method with a cc-
pVTZ basis set. The SAPT analysis was performed at the
SAPT0/jun-cc-pvdz level of theory on the optimized geometries[28]
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RESEARCH ARTICLE
Entry for the Table of Contents
London dispersion rules and facilitates the enantioselectivity in the Corey-Bakshi-Shibata (CBS) reduction. Employing a
combination of computational and experimental studies, we provide a modern view on the origin of enantioselectivity in this powerful
organocatalyzed reaction. Our results demonstrate that attractive LD interactions between the catalyst and the substrate rather than
steric repulsion determine the selectivity.
Institute and/or researcher Twitter usernames: @prsgroupjlu
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