The Size-Accelerated Kinetic Resolution of Secondary Alcohols

Article abstract of DOI:10.1002/anie.202011687

The factors responsible for the kinetic resolution of alcohols by chiral pyridine derivatives have been elucidated by measurements of relative rates for a set of substrates with systematically growing aromatic side chains using accurate competitive linear regression analysis. Increasing the side chain size from phenyl to pyrenyl results in a rate acceleration of more than 40 for the major enantiomer. Based on this observation a new catalyst with increased steric bulk has been designed that gives enantioselectivity values of up to s=250. Extensive conformational analysis of the relevant transition states indicates that alcohol attack to the more crowded side of the acyl-catalyst intermediate is favoured due to stabilizing CH-π-stacking interactions. Experimental and theoretical results imply that enantioselectivity enhancements result from accelerating the transformation of the major enantiomer through attractive non-covalent interactions (NCIs) rather than retarding the transformation of the minor isomer through repulsive steric forces.

Full text of DOI:10.1002/anie.202011687

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Accepted Article
Title: The Size-Accelerated Kinetic Resolution of Secondary Alcohols
Authors: Hendrik Zipse, Benjamin Pölloth, and Mukund P. Sibi
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10.1002/anie.202011687
Angewandte Chemie International Edition
RESEARCH ARTICLE
The Size-Accelerated Kinetic Resolution of Secondary Alcohols
Benjamin Pölloth,[a] Mukund P. Sibi,[b] and Hendrik Zipse*[a]
[a]
Dr. B. Pölloth, Prof. Dr. H. Zipse
Department of Chemistry
LMU München
Butenandtstr. 5-13, 81377, Munich (Germany)
E-mail: zipse@cup.uni-muenchen.de
Prof. Dr. M. P. Sibi
[b]
Department of Chemistry and Biochemistry
North Dakota State University
Fargo, ND 58108 (USA)
Supporting information for this article is given via a link at the end of the document.
Abstract: The factors responsible for the kinetic resolution of
While the influence of NCIs on ground state properties has
recently been studied thoroughly,[19] most experimental studies
on enantioselective catalysis restrict themselves to the
determination of the stereoselectivity factor s. This latter quantity
is defined as the ratio of rate constants for conversion of the
faster and slower reacting isomer, respectively (s = kmajor/kminor).
However, the s values themselves cannot answer the question
whether selectivity results from the acceleration of the major
enantiomer through attractive NCIs or a deceleration of the
minor enantiomer through repulsive steric interactions.
Surprisingly, kinetic studies on this question are very rare.[20]
This is likely due to the fact that acceleration or deceleration has
to be measured relative to a system with “zero” steric repulsion
or attraction. Elimination of groups that induce steric hindrance
and attraction is, unfortunately, linked to possible changes of
electronic, kinetic and thermodynamic properties. Herein we
present a different approach where the aromatic side chains of
alcohol substrates are increased systematically such that no
additional effective degrees of freedom are introduced.[21] It
should be added that the term "effective" implies that the
conformational space available to all substrates is practically
identical and that the term “size” always refers to the dimensions
of the aromatic side chains. From the rate data measured for
these reactions we can infer how increasing substrate size
impacts kmajor and kminor. This novel approach allows us to
elucidate the origin of enantioselectivity through direct kinetic
measurements. Initial acylation experiments were performed
with fluxionally chiral N,N-dimethylaminopyridine (DMAP)
derivative 3 developed by Sibi et al.[22] This catalyst displays
moderate selectivity for the acylation of 1-phenylethanol 1a
(s = 7) with isobutyric anhydride (2), while a much larger
selectivity was found for the larger substrate 1-(2-
naphthyl)ethanol (1b) with s = 39.
alcohols by chiral pyridine derivatives have been elucidated by
measurements of relative rates for
a set of substrates with
systematically growing aromatic side chains using accurate
competitive linear regression analysis. Increasing the side chain size
from phenyl to pyrenyl results in a rate acceleration of more than 40
for the major enantiomer. Based on this observation a new catalyst
with increased steric bulk has been designed that gives
enantioselectivity values of up to s = 250. Extensive conformational
analysis of the relevant transition states indicates that alcohol attack
to the more crowded side of the acyl-catalyst intermediate is
favoured due to stabilizing CH-p-stacking interactions. Experimental
and theoretical results imply that enantioselectivity enhancements
result from accelerating the transformation of the major enantiomer
through attractive non-covalent interactions (NCIs) rather than
retarding the transformation of the minor isomer through repulsive
steric forces.
Introduction
Enzymes catalyse a wide variety of reactions with near perfect
enantioselectivity as the results of a precisely tuned network of
attractive non-covalent interactions (NCI) between the substrate
and the enzyme binding pocket.[1] Thus, selectivity is mainly
achieved by selective rate acceleration of the desired
enantiomer whereas the role of repulsive steric interactions to
retard transformation of the minor enantiomer is negligible.[2] In
contrast, steric repulsion traditionally served as a key guiding
principle in the design of asymmetric catalysts,[3] e.g. by using
large “blocking groups”.[4] This does not necessarily exclude the
simultaneous influence of attractive interactions as highlighted in
studies by, for example, Hawkins,[5] Corey,[6] Noyori,[7]
Sharpless,[8] or Fuji.[9] Thus, small-molecule catalysts can induce
enantioselectivity through a combination of several attractive
NCIs[3a, 10] such as aromatic interactions.[11] Accordingly it was
found that the role of attractive London dispersion forces[12] on
chemical reactivity, catalysis and stability was traditionally
underestimated.[13] These analyses were helped by the
development of dispersion-corrected DFT[14] and linear scaling
coupled cluster theories,[15] both of which facilitate the
quantification of NCIs in extended molecular systems.[16] Most of
this progress in elucidating the role of NCIs in asymmetric
catalysis is based on theoretical studies,[16-17] either alone or in
combination with NMR- or X-ray- based structure analyses.[18]
Results and Discussion
Experimental studies
In order to precisely determine relative rates and ensure
absolutely comparable reaction conditions competition
experiments for the acylation of 1 : 1 mixtures of racemic 1b as
reference and racemic 1a,c,d (see Fig. 1) were performed and
monitored by chiral HPLC. Enantioselectivity values
s of
(pseudo)-first order kinetic resolution experiments are commonly
calculated by Kagan’s formulas[23] from the enantiomeric excess
(ee) of products and reactants at a single conversion point. It
1
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10.1002/anie.202011687
Angewandte Chemie International Edition
RESEARCH ARTICLE
(b)
reference:
(a)
12
8
N
12
8
10.1
O
O
k(R)-1a,c,d
k(R)-1b
5.6
3.8
O
O
P
O
O
4
N
4
1.2
1.1
OH
1.0
1.0
1.0
Ar
Np
6
5
O
0
0
(R)-4b
Np
(R)-4a,c,d
k(S)-1a,c,d
k(R)-1a,c,d
1a
1b
1c
1d
1a
(S)-enantiomer
1b
1c
1d
2 (1.5 eq)
1b (0.5 eq)
k(S)-1b
k(R)-1b
catalyst (10 mol%)
(R)-enantiomer
(R)-enantiomer
411
(S)-enantiomer
(S)-enantiomer
(R)-enantiomer
(R)-enantiomer
+
(S)-enantiomer
N
400
O
-50 °C, Et2O
400
300
200
100
0
OH
N
4.6
O
OH
OH
1.7
1.6
2.0
299
N
1.2
Ar
1.0
1.3
N
1.0
300
N
N
Np
N
Ar
1a,c,d (0.5 eq)
N
(S)-1a,c,d
(S)-1b
1a 1b 1c 1d
1a 1b 1c 1d
200
100
0
OH
OH
OH
139
OH
109
62
51
3
7.3
4.6
1.3
1b
s = 39
2.0
9.3
1.0 1.2
1.0
1.7
1.6
7
#
1a
1c
1d
1a
1b
1c
1d
$
1a
1b
1c
1d
! =
#
s = 7.3
s = 53 s = 66
s = 9.2 s = 51 s = 80 s ≈ 250
%
should be emphasized, that the reliability of this approach is very
limited for higher s values and neither the internal consistency
Figure 1. (a) Setup of competitive kinetic resolution experiments: 0.01 mmol of catalyst, 0.05 mmol of (rac)-1b and (rac)-1a,c,d were dissolved in 2 mL diethyl
ether. At -50 °C 0.15 mmol of 2 was added. After defined periods of time 0.05 mL of the reaction mixture was quenched and analysed by chiral HPLC. Relative
rates were then determined by linear regression analysis and chemoselectivity calculation (for more details see SI). (b) Relative rates for the acylation of alcohols
1a-1d with catalyst 3 and 5-7. Values are averaged over two independent runs. Experimental reference was (R)-1b, rates are displayed relative to (S)-1a for ease
of discussion. HPLC traces, linear regression analysis, simulations and reliability analysis are provided in the SI.
nor the preconditions for the Kagan equation can be controlled
by a single measurement (for a detailed analysis see Supporting
Information (SI)).[24] Thus, herein all enantioselectivity values
were determined by the more accurate linear regression
analysis method[25] (see Fig. 2). Through simultaneous
determination of chemoselectivity values for the two (R)-
enantiomers relative rates for all four alcohols are obtained as
shown Fig. 1a. The reliability of this approach was validated by
reproducibility measurements and by comparison to literature
data.[22a] In an appropriate model system for measuring the size-
dependence of reaction rates aromatic side chains should be
similar for all four systems. c) Reaction rates for the acylation of
alcohols 1a-d with anhydride 2 are almost identical when using
tri-(n-butyl)phosphine (NBP, 6) as the catalyst (Fig. 1b). This
may be due to the large conformational flexibility of this catalyst,
which is incapable of differentiating the substrate alcohols on the
basis of size (or any other intrinsic property). In sharp contrast,
reaction rates between the largest alcohol 1d and the smallest
alcohol 1a differ by a factor of 10.1 when using DMAP (5) as the
acylation catalyst. These reactivity differences are likely due to
cation-p interactions in the respective transition states.[26-27]
These measurements have been repeated for different DMAP
concentrations in order to verify that there is basically no
uncatalyzed background reactivity of the respective substrates.
With these results in hand, relative rate constants krel for the
acylation of 1a-d with anhydride 2 catalysed by chiral DMAP
derivative 3 were evaluated. Enantioselectivity values for this
reaction increase by a factor of 9 from s = 7 for 1-phenylethanol
(1a) to 66 for 1-(2-pyrenyl)ethanol (1d). Relative rates in Fig. 1
using alcohol (S)-1a as the reference show that the reaction of
both (S)- and (R)-enantiomers is notably accelerated with the
growing aromatic side chain. However, while the rate constant
for (S)-1d increased by a factor of 4.6 relative to (S)-1a, alcohol
(R)-1d reacts 40 times faster than (R)-1a! The size-induced rate
acceleration is thus significantly larger for the (R)- than for the
(S)-alcohols and is also about four times larger for chiral catalyst
3 as compared to DMAP (5). Based on these findings we
explored, whether suitably modified catalysts can further
increase the selectivities obtained with catalyst 3. Sibi et al. have
already reported that enantioselectivity decreases if the naphthyl
moiety in 3 (s = 23 at 0 °C) is replaced by both phenyl (s = 15) or
9-anthracenyl (s = 14).[22a] The first result is in agreement with
the above-mentioned mechanism for size selection. The
comparatively low selectivity for the 9-anthracenyl substituent is
likely due to unfavourable 1,5-interactions that have already
burdened other systematic studies of size effects.[21] We
therefore synthesized 1-pyrenyl-substituted DMAP derivative 7
as a possibly even more size-selective catalyst (see SI).
Repeating the acylation reactions of alcohols 1a-d with
anhydride 2 and catalyst 7 under otherwise identical conditions
we find generally increased selectivities for all substrates, the
largest selectivity for alcohol 1d now amounting to approx.
s = 250 (Fig. 1). For a quantitative analysis, the size of the
increased
systematically
without
adding
That alcohols 1a-d
unfavourable
26]
interactions (e.g. 1,5-interactions).[21,
represent a suitable series for such a purpose is supported by
the following characteristics: a) The calculated reaction free
energies for the acylation with anhydride 2 was found to be
almost identical for all four alcohols 1a-d. b) The same
calculations indicate that the partial charge on the alcohol
oxygen atom and the acidity of the hydroxyl group is very
#$ &1 − ))(1 − ,,-./010.
#$ &1 − ))(1 + ,,-./010.
%
2
! =
conditions: 3 (10 mol%),
2 (1.5 eq), -50 °C, Et2O
ln((1-c)(1+eealcohol))
-0.07 -0.04
-0.13
-0.10
-0.01
0.0
y = 39.8x + 0.11
R² = 0.998
-2.0
-4.0
-6.0
y = 67.4x + 0.10
R² = 0.999
y = 64.0x - 0.10
R² = 0.992
y = 37.9x + 0.10
R² = 0.995
Figure 2. Linear regression analysis for the competitive acylation of (rac)-1b
and (rac)-1d with anhydride 2 catalysed by 3. Conversion c was calculated as
(eealcohol)/(eealcohol+eeester)
[23]. Results of two independent measurements are
presented. The slope of the linear correlations corresponds to selectivity value
s.
2
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10.1002/anie.202011687
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RESEARCH ARTICLE
alcohol reagents were calculated as the volume of the van der
Waals cavity used in the SMD solvation model at the B3LYP-
D3/6-31+G(d) level of theory. As shown in Fig. 3, the molecular
volume strongly correlates with ln(krel) for the acylation of (R)-
Furthermore, reagent volume V also correlates positively with
ln(krel) of the minor (S)-enantiomer, which is contrary expectation
if repulsive steric effect were to control the stereoselectivity. The
correlation slope decreases from DMAP (5) to catalyst 3 and
becomes quite flat for catalyst 7. Alternative correlations with
similar trends for the calculated polarizability of the reagents
(see SI) highlight the crucial role of dispersion forces. It can thus
be concluded that enantioselectivity improvements result from a
rate acceleration of the major enantiomer through reinforced
dispersion interactions, if simultaneously the structure of the
loaded catalyst minimizes the rate accelerations for the minor
enantiomer.
3
7
5
N
N
N
O
O
OH
N
N
N
N
N
N
N
(R)-1d
OH
7
6
ln(krel) = 30.0 V - 2.4
R² = 0.96
(R)-1c
OH
ln(krel) = 29.4 V - 2.5
5
R² = 0.96
(R)-1b
Computational studies
The acylation of 1b with anhydride 2 catalysed by DMAP-
OH
4
(R)-1a
ln(krel) = 18.2 V - 2.7
3
derivative
3
was investigated computationally. Geometry
R² = 0.95
optimizations and frequency analyses were performed at
SMD(Et2O)/B3LYP-D3/6-31+G(d)[28] level of theory, followed by
single point calculations at the DLPNO-CCSD(T)/def2-TZVPP
level[15, 29]. In accordance with recent results of Wheeler et al.[30]
the energy profile of the reaction (see SI) implies that loading of
the catalyst 3 through a first transition state TS1 is rate limiting,
followed by the selectivity-determining acylation of alcohol 1b
through transition state TS2. To ensure a comprehensive and
systematic conformational search for TS2, the conformational
space was partitioned into eight geometrical classes as a
function of three criteria (Fig. 4): The Re or Si face attack of the
alcohol substrate; orientation of the pyrazolidinone side chain;
and the relative orientation of the isobutyryl group.
2
ln(krel) = 11.6 V – 2.0
R² = 0.83
1
ln(krel) = 4.8 V - 0.8
R² = 0.94
0
0.15
0.2
0.25OH
OH
OH
OH
-1
(S)-1c
(S)-1a
(S)-1b
(S)-1d
molecular volume V alcohol reagent (10-30 m3 )
Figure 3. Correlation of ln(krel) for the different catalysts and alcohols with the
molecular volume of the reagents calculated at the B3LYP-D3/6-31+G(d) level
of theory.
Due to its absolute configuration alcohol (R)-1b attacks the acyl-
catalyst intermediate preferentially from the (Si) face, while
alcohol (S)-1b shows the opposite preference. For both alcohols
we find a preference for a trans-conformation of isobutyryl and
pyrazolidinone side chain. Thus, all conformations populated by
more than 1% are either in class I ((R)-1b) or in class III ((S)-1b).
Conformations for (S)-TS2 are best described as “triple-
sandwich” structures of the aromatic alcohol side chain, catalyst
pyridinium core, and catalyst sidechain. Wheeler et al. found
geometrically similar conformations governing the kinetic
resolution of biaryl substrates by catalyst 3.[30] In the best (R)-
TS2, in contrast, attack occurs from the crowded side of the
catalyst resulting in a cage structure of the three aromatic rings.
A similar structure for (S)-1b is strongly disfavoured by the
absolute configuration of the tert-butyl group of 3. The difference
in free energy (∆∆G‡223 = +8.6 kJ mol-1) on single point level for
the energetically best conformers of each enantiomer (R)-TS2_1
and (S)-TS2_1 is in good accordance with the experimental
enantioselectivity value. In order to identify the origin of this
alcohols with catalysts 3, 7, and DMAP (5). The slope of the
correlations is notably higher for the chiral catalysts 3 and 7 than
in the case of DMAP (5). Thus, the bulky substituents in 3 and 7
further increase the size-acceleration of the reaction rates.
80
(S)-1b
(R)-1b
60
40
20
0
class
I
II
III
IV
V
VI
(Re)
(P)
VII
(Si)
(M)
cis
VII
(Si)
(P)
cis
Attack 1b
Orientation
Geometry
(Si)
(M)
(Si)
(P)
(Re)
(M)
(Re)
(P)
(Re)
(M)
cis
trans trans
trans
trans
cis
selectivity the respective free energy difference ∆∆G‡
(black
223
bar in Fig. 5) was decomposed into its contributors. Surprisingly,
the solvation energy (blue bar in Fig. 5) stabilizes all of the
relevant (S) conformers relative to (R)-TS2_1. Thus, solvation is
a counterplayer of enantioselectivity. Hence, we also found a
very good negative correlation of experimental ln(s) values and
solvent polarity parameter ET(30)[31] (see SI). To further
distinguish the impact of NCIs involving the aromatic moiety of
the alcohol, relative single point energies were calculated for
TS2_HC structures, wherein the naphthyl moiety of 1b was
replaced by a hydrogen atom (see Fig. 5).[32] While almost no
energy difference is found for the H-capped structures TS2_HC
(green bars in Fig. 5), the NCI energy contribution (yellow bar in
(R)-TS2_1 (class I)
(S)-TS2_1 (class III
)
Figure 4. Relative free energies at the SMD(Et2O)/B3LYP-D3/6-31+G(d) level
of theory for TS2 of (S)-1b (red circles) and (R)-1b (blue crosses). TS
conformers are categorized by Re/Si face attack of 1b, pyrazolidinone side
chain orientation and relative position of the isobutyryl group (see bottom left).
Structures of the best conformers for (R)- and (S)-1b are presented (for others
see SI).
3
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10.1002/anie.202011687
Angewandte Chemie International Edition
RESEARCH ARTICLE
Fig. 5) is very significant at -10.9 kJ mol-1 and thus the dominant
component for the preference of the (R)-TS2_1. Similar trends
were found for all of the other relevant conformers (see SI). A
local energy decomposition analysis[33] confirmed that the
intermolecular dispersion energy of alcohol (R)-TS2_1 and
loaded catalyst is -6.7 kJ mol-1 more stabilizing as compared to
(S)-TS2_1. Thus, stronger dispersive interactions of catalyst and
alcohol are indeed the crucial factors in determining the
Conclusion
The enantioselectivity of acylation reactions catalysed by chiral
DMAP derivates increases systematically with increasing size of
the aromatic side chains in the alcohol substrates. Rate
measurements for alcohols with different-sized aromatic side
chains reveal that reaction rates for the major enantiomer are
increased more than 40 times by substitution of phenyl by
pyrenyl. These rate acceleration correlate with the polarizability
and volume of the reagents. When also increasing the size of
the catalyst side chain in a similar manner, enantioselectivity
values of up to s = 250 have been obtained. Computational
studies show that alcohol attack from the more crowded side of
the loaded catalyst is most favourable and stabilized by CH-p-
stacking interactions. In combination with the results of kinetic
measurements this implies that the selectivity values obtained
result from a targeted rate acceleration of the transformation of
the major enantiomer through dispersive interactions and not
from steric hindrance of the minor enantiomer. The approach for
elucidating the origins of enantioselectivity described in this
study should also be useful for the analysis and systematic
improvement of catalyst performance in other cases.
(S)-TS2_1
+10.9+8.6
N
N
8
6
R
R
H
N
N
O
C
O
C
O
O
4
H
H
-OOCiPr
-OOCiPr
2
TS2
TS2_HC
(R)-TS2_1
∆∆"‡ $%2 = ∆∆"‡ TS2_HC + ∆"./0
0
∆∆Esolvation
∆∆Ethermal
∆∆E‡ (TS2_HC)
∆ENCI
+2.4
-2
-4
-0.5
∆∆G‡
-4.3
223
Figure 5. Energy decomposition scheme for (S)-TS2_1 relative to (R)-TS2_1.
Solvation energies and thermal corrections were calculated at the
SMD(Et2O)/B3LYP-D3/6-31+G(d) level of theory. The differences between
DLPNO-CCSD(T)/def2-TZVPP single point energies for TS2 and TS2_HC
yield NCI energies.
Acknowledgements
This work was financially supported by the Deutsche For-
schungsgemeinschaft (DFG) through the Priority Program
‘Control of London Dispersion Interactions in Molecular
Chemistry’ (SPP 1807). We thank Dr. Peter Mayer for measuring
and resolving X-ray crystal structures,[37] and the Leibniz-
Rechenzentrum (LRZ) for generous allocation of computational
resources.
236
236
333
283
288
325
Keywords: Asymmetric catalysis • Acylation • Kinetic resolution
312
• Noncovalent interactions • Molecular recognition
(R)-TS2_1
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Figure 6. Non-covalent bond paths between alcohol 1b and loaded catalyst
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RESEARCH ARTICLE
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10.1002/anie.202011687
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
fast
O
NMe2
+
high selectivity
N
N
Ar
N
Ar
CO
O
H
slow
+
low selectivity
=
Steric bulk increases selectivity through rate acceleration: The kinetic resolution of secondary alcohols by fluxionally chiral
pyridine catalysts is increasingly selective with increasingly bulky substrates. Detailed kinetic and computational studies show that
this is mainly provoked by a selective reaction rate acceleration for the major isomer through non-covalent interactions. More bulky
catalysts further increase reaction rate AND selectivity.
6
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