Nonlinear effects in asymmetric amino acid catalysis by multiple interconnected stereoselective catalytic networks

Article abstract of DOI:10.1002/chem.201002249

A fine line: The generation of significant positive nonlinear effects in asymmetric amino acid catalysis under homogeneous conditions, which can be explained by the model for cooperative catalytic stereoselective pathways, is reported. The addition of an achiral aldehyde generated the multiple interconnected stereoselective catalytic network.

Full text of DOI:10.1002/chem.201002249

COMMUNICATION
DOI: 10.1002/chem.201002249
Nonlinear Effects in Asymmetric Amino Acid Catalysis by Multiple
Interconnected Stereoselective Catalytic Networks
[
a]
[b, c, e]
[a]
[a, c]
Ramon Rios, Patric Schyman,
Henrik Sundꢀn, Gui-Ling Zhao,
[
a]
[b, c]
[b, c]
[a, c, d]
Farman Ullah, Li-Jun Chen,
Aatto Laaksonen,
and Armando Cꢁrdova*
The generation of positive nonlinear effects in asymmetric
amino acid catalysis by creation of a multiple interconnected
stereoselective catalytic network is presented. Density func-
tional theory calculations together with experimental results
establish a dynamic model for the enantioselective catalytic
network of amino acid catalysis that may have implications
for the origins of homochirality (asymmetric amplification).
The origin of homochirality has intrigued scientists ever
since Pasteurꢀs discovery of optical activity of biomolecules,
work a linear relationship between the ee of the chiral cata-
lyst or auxiliary and the extent of the asymmetric synthesis
was assumed. For a reaction exhibiting this behavior with
scalemic mixtures of catalyst (<0–100% ee) plotting the cat-
alyst ee along the x axis and the corresponding product ee
along the y axis will result in a line. According to Kagan de-
viations from the straight line can be considered as a nonlin-
ear effect. For example, if the ee values of the products ex-
ceeded the calculated values for a linear correlation based
on the ee values of the catalyst, the deviation from the
linear correlation was a positive nonlinear effect. This dis-
covery has inspired researchers to investigate the presence
of nonlinear effects in asymmetric catalysis and its impor-
tance for the origins of homochirality. In this context, Soai
demonstrated a remarkable asymmetric amplification of pyr-
[1]
such as l-amino acids and d-sugars. Several theories of the
origins and evolution of homochirality and its importance
[2]
for the origins of life have been proposed. In pioneering
work, Kagan reported the possibility of achieving asymmet-
ric amplification of products obtained by asymmetric cataly-
[3]
sis (positive nonlinear effects). Preceding this seminal
[4]
imidyl alkanols generated by asymmetric Zn autocatalysis.
[
a] Dr. R. Rios, Dr. H. Sundꢁn, Dr. G.-L. Zhao, Dr. F. Ullah,
Prof. Dr. A. Cꢂrdova
These impressive results could be explained by the Frank
model involving a combination of autocatalytic and inhibi-
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
[2d]
tion processes. In asymmetric amino acid catalysis, nonlin-
ear effects were first observed by Kagan and co-workers
1
06 91 Stockholm (Sweden)
[3,5]
Fax : (+46) 8-154908
E-mail: acordova@organ.su.se
armando.cordova@miun.se
during their investigation of the Hajos–Parrish reaction.
However, they were “re-discovered” by Hanessian in pro-
[6]
line-catalyzed conjugate additions as late as 2000. In 2004,
Blackmond and co-workers reported nonlinear effects in
proline-catalyzed a-aminooxylation of propionaldehyde in
[
b] Dr. P. Schyman, Dr. L.-J. Chen, Prof. Dr. A. Laaksonen
Division of Physical Chemistry
The Arrhenius Laboratory, Stockholm University
[7]
1
06 91 Stockholm (Sweden)
CHCl under heterogeneous conditions. Notably, perform-
3
[
c] Dr. P. Schyman, Dr. G.-L. Zhao, Dr. L.-J. Chen,
Prof. Dr. A. Laaksonen, Prof. Dr. A. Cꢂrdova
Berzelii Center EXSELENT on Porous Materials
The Arrhenius Laboratory, Stockholm University
ing the same a-aminoxylation reaction in DMSO under ho-
mogeneous conditions gives a linear line when plotting the
[7,8]
ee of product against the ee of proline.
These early exam-
ples of nonlinear effects in proline catalysis were independ-
1
06 91 Stockholm (Sweden)
[
9]
[10]
ently explained by Hayashi and Blackmond, to be due
[
d] Prof. Dr. A. Cꢂrdova
[11]
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University, SE-851 70 Sundsvall (Sweden)
to the solid–liquid equilibrium of the amino acid catalyst.
In 2005, our group discovered the first asymmetric amplifi-
[
e] Dr. P. Schyman
cation of sugars generated by asymmetric amino acid cataly-
Current address: Institute of Chemistry and
The Lise Meitner-Minerva Center for
Computational Quantum Chemistry
[12]
sis under homogeneous conditions.
Shortly after, we re-
ported several cases of positive nonlinear effects in proline-
[
13]
catalyzed CÀC bond-forming reactions such as the aldol
The Hebrew University of Jerusalem, 91940, Jerusalem (Israel)
[14]
and the Mannich reaction under homogeneous conditions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002249.
Moreover, we found that racemic proline can catalyze asym-
Chem. Eur. J. 2010, 16, 13935 – 13940
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13935

metric reactions by the addition
of optically active b-hydroxy al-
dehydes (>95% ee) such as
naturally occurring C-3 and C-4
sugars. This is due to sugar-as-
sisted kinetic resolution of the
amino acid catalysts by forming
covalent oxazolidinone inter-
[13]
mediates. Recently, Tsogoeva
and Mauksch reported asym-
metric amplification due to re-
cycling by denucleation and
nonlinear autocatalytic crystal
[2o]
growth of an amino acid de-
rivative under heterogeneous
[15]
conditions.
Based on the importance of
nonlinear effects in asymmetric
catalysis and its relevance to
the origins of homochirality, we
became curious if it is possible
to generate them by creating a
[16]
dynamic catalytic network of
an amino acid catalyst
Scheme 1). In fact, a dynamic
(
catalytic network such as the
one displayed in Scheme 1 may
also be considered in investiga-
tions of nonlinear effects in
Scheme 1. Possible stereoselective catalytic networks of (S)-proline catalysis under homogeneous reaction con-
ditions. The green pathway is possible when scalemic proline is used as catalyst.
proline-catalyzed asymmetric transformations under homo-
geneous conditions (cycle 1), in which, for example, self-al-
dolization of the donor aldehyde may be present (cycle 2).
Herein, we report the generation of significant positive non-
linear effects in asymmetric amino acid catalysis under ho-
mogeneous conditions, which can be explained by the model
for cooperative catalytic stereoselective pathways.
selective network. It should also be possible to determine
whether this catalytic network can generate nonlinear ef-
fects in asymmetric amino acid catalysis. We decided to in-
vestigate the (S)-proline-catalyzed a-aminooxylation of cy-
clohexanone 3a as the model reaction for the general cata-
lytic cycle 1 using nitrosobenzene as the electrophile. The
advantage of this transformation is that the CÀO bond for-
The generally postulated catalytic mechanism for the (S)-
proline-catalyzed enantioselective additions of ketones or al-
dehydes to different electrophiles involves iminium, enam-
mation is fast and the reaction does not exhibit nonlinear ef-
[8]
fects under homogeneous conditions (Figure 1). This is be-
[17]
ine and oxazolidinone intermediates (Scheme 1, cycle 1).
The main consensus is that the enantioselective CÀC or CÀ
X (X=hetero atom) bond-forming step occurs via a metal-
free six-membered transition state according to the List–
Houk model involving one proline-derived enamine inter-
[17,18]
mediate.
Seebach and Eschenmoser has challenged this
theory by proposing a transition state involving the oxazoli-
dinone intermediate, which can be formed between the
amino acid molecule and the donor carbonyl during the ini-
[19]
tial enamine formation. We envisioned that the addition
of an achiral aldehyde 1 to the general catalytic cycle 1
[20,21]
would initiate and link catalytic cycle 2 to it (Scheme 1).
Simultaneously, the dynamic catalytic pathway involving the
formation of stereoselective oxazolidinone intermediates be-
tween the catalyst and the chiral b-hydroxy aldehyde 2 from
cycle 2 would be created (Scheme 1, red and green path-
Figure 1. Relation between the enantiomeric excess of (S)-proline and
that of the newly formed chiral ketone 4a in the catalytic asymmetric
aminooxylation of cyclohexanone 3a.
: Addition of aldehyde 2a. ^: no
&
[13,22]
ways).
Thus, the simple addition of an achiral aldehyde
additive. The standard deviation for the ee values is Æ0.5% and based
1
would generate a dynamic interconnected catalytic stereo-
on three separate experiments.
13936
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13935 – 13940

Asymmetric Catalysis
COMMUNICATION
tween the aldehyde 1a and nitrosobenzene under our reac-
tion conditions supporting that the nonlinear effect was gen-
erated and transferred from catalytic cycle 2 to cycle 1 in
Scheme 1.
To shed more light on “reacted-free” equilibrium for both
(
R)- and (S)-proline (Scheme 2) and on the origin of the
nonlinear effect we performed density functional theory
DFT) calculations (Figure 2). The calculations were per-
(
Scheme 2. The “reacted-free” equilibrium between the two enantiomers
of proline and b-hydroxy aldehydes 2. Products 2 can be obtained by (S)-
proline catalysis.
cause the formation of the bicyclic oxazolidinone intermedi-
ate (Scheme 2, the blue pathway) obtained from the corre-
sponding product 4a and the proline catalyst is not pre-
ferred due to steric constrains and therefore cannot affect a
[13,14]
reaction performed with a scalemic catalyst.
Thus, we
have performed several a-aminooxylation reactions under
homogeneous reaction conditions using (S)-proline
(
50% ee) as the catalyst and different achiral aldehydes 1 as
additives. We found that the addition of propionaldehyde 1a
resulted in asymmetric amplification of product 4a [Eq. (1),
Figure 1].
Plotting the product ee of 4a against the ee of the proline
catalyst gave a significant positive nonlinear relationship
(
Figure 1).
Thus, the addition of aldehyde 1a did initiate the forma-
tion of a catalytic network that synergistically created the
asymmetric amplification of product 4a, which normally ex-
hibits a linear relationship. We also found that b-hydroxy al-
dehyde 2a was formed (Scheme 1, cycle 2). In fact, the pro-
line-catalyzed asymmetric dimerization of aldehyde 1a ex-
hibited nearly the same asymmetric amplification of 2a as
the one of 4a. Moreover, high-resolution mass spectrometry
1
and H NMR analysis revealed the presence of oxazolidi-
[17g]
none intermediates
formed between 2a and proline by
means of the dynamic pathways marked red and green in
Scheme 1. Notably, these pathways have the ability to affect
the two enantiomers of the amino acid differently due to
the inherent diastereomeric interactions with chiral alde-
hyde 2a (Scheme 2). We did not observe any reaction be-
Figure 2. Energy profiles for the parallel reactions. Energies given in the
graph are free energies (kcalmol ) calculated with B3LYP/6-311+G-
AHCTUNGERTNNUNG( 2d,2p) in DMSO. The labels on the energy profiles refer to the corre-
sponding structures that can be found in the Supporting Information
along with all the stationary structures.
À1
Chem. Eur. J. 2010, 16, 13935 – 13940
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13937

A. Cꢂrdova et al.
[
23]
formed by using the Gaussian 03
software package and
Geometries were optimized with
(d,p) basis set, and characterized with frequency
calculations. Final energies were obtained with the larger
basis set 6-311+G(2d,2p). The effect of solvation in DMSO
was included by using a polarizable continuum model (IEF-
nonlinear effects created from the catalytic network were
due to the unproductive “reacted-free” equilibrium of the
enantiomers of the amino acid with chiral aldehyde 2a, in
which (R)-proline is present a longer time. As a result an
excess of non-bound (S)-proline (ee>eeinitial) was able to cat-
alyze the parallel reaction pathways creating asymmetric
amplification of the corresponding products.
[24,25]
the B3LYP functional.
the 6-31G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[26]
PCM). We have previously proposed that racemic proline
is resolved by the dynamic equilibrium shown in Scheme 2
due to that (R)-proline reacts faster with 2a and as a conse-
quence less “free” (R)-proline would be accessible. Indeed,
our calculations revealed that the initial barrier to form the
proline–aldol intermediate Ic via concerted transition state
Ib, in which both simultaneous CÀN bond formation and
Our results show that observation of nonlinear effects in
amino acid catalysis can be used for giving mechanistic in-
formation on the influence of the different interconnected
catalytic pathways during proline-catalyzed stereoselective
reactions between aldehydes or ketones and different elec-
trophiles (Scheme 1). For example, it explains the absence
of nonlinear effects as for the proline-catalyzed a-aminooxy-
lation of 3a (Figure 1). In this case, the general cycle 1 in
Scheme 1 was the fastest pathway since oxazolidinone for-
mation and self-aldol reactions are very slow due to steric
effects. The mechanistic network displayed in Scheme 1
should also be considered for the proline-catalyzed Mannich
reaction between propionaldehyde 1a and p-methoxyphenyl
(PMP)-protected a-iminoglyoxylate (Scheme 1, 2a=3b:
proton transfer occur for (R)-proline, is larger relative to
the formation of the (S)-proline-derived intermediate IIc
via concerted transition state IIb (Figure 2). However, for
both R and S enantiomers, the most stable intermediates Ig
and IIg, respectively, are formed with barriers of 5.7 and
.0 kcalmol , respectively. The pathway of (R)-proline is in-
À1
5
itiated by a Si-facial attack on the carbonyl group of alde-
hyde 2a via reactant Ia. This is opposite to the Re-facial
attack of (S)-proline on the aldehyde group of 2a via reac-
tant IIa (Figure 2). Other attacks were also considered;
however, only the most favored are shown here (see Sup-
porting Information). The pathways of (R)- and (S)-proline
are energetically different. For example, when (R)-proline
attacks the bulky Si-face of aldehyde 2a, the energies are
higher relative to the reactant Ia during the initial hemiami-
nal bond formation. This is not the case for the Re-facial
attack of (S)-proline on 2a, even though the reactants Ia
and IIa are close in energy. These energy differences be-
tween (R)- and (S)-proline result in different energy
maxima on their energy profiles. Consequently, for (R)-pro-
line the energy maximum Id occurs when the proton is
transferred from the nitrogen of the proline moiety to its
carboxyl group. In the case of (S)-proline, the highest
energy on the potential energy surface is transition state
IIb. The lowest energies in both pathways are the iminium
intermediates Ig and IIg, respectively. The energy barriers
are relative to the respective reactants Ia and IIa. However,
for the purpose of comparing the reactivity between (R)-
and (S)-proline the rate-determining states of the release of
the amino acids are of interest. All intermediates and transi-
tion states can be found in the Supporting Information, as
well as energies calculated at different levels. When compar-
ing the Gibbs free-energy differences (DG) for the two reac-
tion pathways it can be seen that the DG for (R)-proline is
larger compared to (S)-proline. Moreover, as described vide
supra both enantiomers of the amino acid readily enter their
respective pathways. Thus, the major energy difference be-
tween the enantiomers of proline in the reaction with 2a is
in the reversible step. Notably, this energy difference DDG
between the R and S enantiomer was 0.9 kcal, which is in
accordance with the experimental result obtained for the ki-
netic resolution of racemic proline by nearly enantiomeri-
cally pure 2a (66% ee of (S)-proline). Our calculations to-
gether with the experimental results show that the positive
3
[14]
R =H; E=PMPNH=CHCO Et).
2
In this case, both the “reacted-free” equilibrium between
the enantiomers of proline and the chiral aldehyde 2a or 4b
via oxazolidinone intermediates such as IIi and IIIi, respec-
tively, must have cooperatively contributed to the asymmet-
ric amplification of the corresponding product 4b according
[27]
to Scheme 1 (red, green, and blue pathways). The proline-
catalyzed reaction of propionaldehyde 2a to other PMP-
protected imines does not always exhibit nonlinear effects
[28]
under homogeneous conditions.
This study suggests that
for these transformations the catalytic cycle 1 of Scheme 1
must have been the fastest pathway and as a consequence
the dynamic “reacted-free” equilibrium between the corre-
sponding chiral products and the amino acid catalyst does
not have time to affect the whole network. This is in accord-
ance with kinetic measurements for these reactions, which
determined the Mannich reaction to be significantly faster
[29]
than the aldol reaction.
In summary, the generation of positive nonlinear effects
in asymmetric amino acid catalysis by a novel cooperative
catalytic network has been demonstrated. The addition of
an achiral aldehyde generated the multiple interconnected
stereoselective catalytic network. DFT calculations together
with experimental results showed that the asymmetric am-
plification has its origin in the unproductive “reacted-free”
equilibrium of the enantiomers of the amino acid with the
corresponding chiral aldehyde products, in which (R)-pro-
line is present for a longer time as compared to (S)-proline.
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Asymmetric Catalysis
COMMUNICATION
Moreover, important mechanistic information can be gath-
ered on the amino acid catalyzed networks using nonlinear
effects studies. The strategy of addition of achiral aldehydes
to amino acid catalyzed transformations can also be synthet-
ically useful for reactions performed without enantiomeri-
cally pure amino acid catalysts (asymmetric amplification).
The nonlinear effects generated by the possible inherent cat-
alytic network of asymmetric amino acid catalysis may be of
relevance for the evolution of homochirality since they pro-
vide both a model and mechanism for the asymmetric am-
plification of organic molecules such as sugars and amino
acids.
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We gratefully acknowledge the Swedish National Research council and
Wenner-Gren-Foundation for financial support. The Berzelii Center EX-
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Keywords: amino acids · asymmetric catalysis · density
functional calculations · enantioselectivity · nonlinear effects
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Received: August 5, 2010
Published online: November 16, 2010
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Chem. Eur. J. 2010, 16, 13935 – 13940