Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and Electrophile-Catalyst Interaction Revealed by NMR and Computational Studies

Article abstract of DOI:10.1021/jacs.6b04008

Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous example is the dienamine catalysis, for which high ee values are reported despite insufficient shielding of the second double bond. Especially for dienamines with variable Z/E-ratios of the second double bond, no correlations to the ee values are found. Therefore, the structures, thermodynamics, and kinetics of dienamine intermediates in S_N-type reactions are investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation show kinetic preference for the Z-isomer of the second double bond and a slow isomerization toward the thermodynamically preferred E-isomer. Modulations of the rate-determining step, by variation of the concentration of the electrophile, allow the conversion of dienamines to be observed. With electrophiles, a faster reaction of Z- than of E-isomers is observed experimentally. Calculations corroborate these results by correlating ee values of three catalysts with the kinetics of the electrophilic attack and reveal the significance of CH-π and stacking interactions in the transition states. Thus, for the first time a comprehensive understanding of the remote stereocontrol in γ-functionalization reactions of dienamines and an explanation to the Z/E-dilemma are presented. The combination of bulky catalyst subsystems and large electrophiles provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee values.

Full text of DOI:10.1021/jacs.6b04008

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Article
Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and
Electrophile-Catalyst Interaction Revealed by NMR and Computational Studies
Andreas Seegerer, Johnny Hioe, Michael M. Hammer,
Fabio Morana, Patrick J. W. Fuchs, and Ruth M. Gschwind
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04008 • Publication Date (Web): 19 Jul 2016
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Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Prefer-
ences and Electrophile-Catalyst Interaction Revealed by NMR and
Computational Studies
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Andreas Seegerera, Johnny Hioea, Michael M. Hammera, Fabio Moranaa, Patrick J. W. Fuchsb and
Ruth M. Gschwinda*.
a Institut für Organische Chemie, Universität Regensburg, D-93053 Regensburg, Germany
b Institut für Organische Chemie, Universität Leipzig, D-04103, Germany
KEYWORDS: Dienamine catalysis, remote-stereocontrol, enantioselectivity, NMR.
ABSTRACT: Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous
example is the dienamine catalysis, for which high ee-values are reported despite insufficient shielding of the second dou-
ble bond. Especially for dienamines with variable Z/E-ratios of the second double bond no correlations to the ee-values
are found. Therefore, the structures, thermodynamics and kinetics of dienamine intermediates in SN-type reactions are
investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large
electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation
show kinetic preference for the Z-isomer of the second double bond and a slow isomerization towards the thermodynam-
ically preferred E-isomer. Modulations of the rate determining step by variation of the concentration of the electrophile,
allow the conversion of dienamines to be observed. With electrophiles a faster reaction of Z- than of E-isomers is ob-
served experimentally. Calculations corroborate these results by correlating ee-values of three catalysts with the kinetics
of the electrophilic attack and reveal the significance of CH-π and stacking interactions in the transition states. Thus, for
the first time a comprehensive understanding of the remote-stereocontrol in γ-functionalization reactions of dienamines
and an explanation to the “Z/E-dilemma” are presented. The combination of bulky catalyst subsystems and large electro-
philes provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the
other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee-
values.
INTRODUCTION
Remote-stereocontrol is a noble goal in asymmetric catal-
ysis but a challenge in understanding and design. Promi-
nent examples for the application of this remote-
stereocontrol in organocatalysis are found in dienamine,1–
3
trienamine3,4 and tetraenamine3,5 transformations. In
some of these reactions, very high ee-values were reported
and for the sterically demanding Diels-Alder type reac-
tions a plausible reaction mechanism was proposed.2,6
Figure 1. “Z/E-dilemma” in dienamine catalysis, i.e. the cor-
relation between the Z/E-ratio of the second double bond
and the R/S-ratio of the products is in dispute.
However, for SN-type γ-functionalization of dienamines
detailed mechanistic studies and experimental insights
into the underlying mechanism are to our knowledge very
limited. This may obviously hamper the further develop-
ment of the field. The main points under question are the
partial shielding of the catalyst moiety and the “Z/E-
dilemma” of the second double bond in linear aldehydes
(see Figure 1) similar to the “Z/E-dilemma” known for
iminium ion catalysis.7
The dienamine catalysis, which is closely related to the
enamine catalysis, has emerged to one of the most prom-
ising stereoinducing catalytic models in the α- and γ-
functionalization of unsaturated aldehydes.1,2,8–13 This
concept represents a vinylogous version of enamine acti-
vation, magnifies the nucleophilic character of the γ-
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carbon and enables functionalization reactions of conju-
gated aldehydes at their α or γ position (Figure 2).2 The
first selective γ-functionalization of unsaturated alde-
hydes with Jørgensen-Hayashi-type catalysts3,14–16 was
presented by Jørgensen et al. in 2006.2 Later, the principle
of γ-functionalization of dienamines was extended to SN1-
type reactions with bis[4-(dimethylamino)phenyl]-
methanol as electrophile source by Christmann et al. in
2011.12 In their study, mixtures of α- and γ-alkylated prod-
ucts were obtained. For aldehydes, which are disubstitut-
ed at the γ-position, the α-alkylated aldehyde was ob-
served as a major product, in case of mono-substituted
aldehydes the γ:α ratio is inverse. For the γ-alkylation
high to moderate enantioselectivities were achieved (the
longer the chain length of the aldehyde the lower the ee-
values). Later in 2012, Melchiorre et al.11 managed to cir-
cumvent these synthetic limitation associated with the
geometry control and site selectivity by using α-
substituted unsaturated aldehydes. Hence, the formation
of α-product is completely suppressed in this case.
putational study of a [5+2] cycloaddition using squara-
mide-derived bifunctional organocatalysts (providing a
preorganization of the electrophile by hydrogen bonds)
corroborated the importance of configurational prefer-
ences and π−π interactions within the transition states for
the diastereomeric ratio.33 However, for SN-type reactions
of dienamines it is still unclear how the stereoselectivity is
connected to the Z/E-ratio. Furthermore, in situ reaction
monitoring of dienamine reactions revealing potential
time dependences of the Z/E-ratios or a faster reaction of
E- or Z-dienamine with electrophiles has not been per-
formed so far.
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Therefore, here we present a detailed NMR study of all
structural features of dienamines (including the confor-
mation of the catalyst subsystem) validating our compu-
tational studies of the dienamine ground states. In addi-
tion, theoretical studies of the dienamine reaction path-
way were underpinned and compared with experimental
kinetic studies of the formation and conversion of various
dienamines, which were enabled by intentional shifts of
the rate determining step. With these methods, we gained
detailed insights into the stereoselection mode of SN-type
dienamine reactions and could explain the “Z/E-
dilemma”.
In the field of secondary aminocatalysis, especially in the
fields of enamine17–26 and iminium ion activation7,27–31 re-
cently some mechanistic insights could be gained in
terms of intermediate stabilization, stereoselection modes
and reaction mechanisms. In the first dienamine study2
already structural properties of the diene system (E,s-
trans,E and E,s-trans,Z, including a Z/E-ratio for the se-
cond double bond of 2/1) were solved by NMR. For α-
substituted dienamines, Melchiorre et al. characterized
the diene system using NMR-analysis and theoretical
calculations.11 In contrast to linear dienamines (Z/E=2/1),
α-substituted ones showed exclusively an E configuration
of the second double bond and both isomers (E and Z) of
the first double bond. This inverted structural preference
of the second double bond resulted also in an inversion of
the stereocenter at the γ-position of the major product.
However, neither in cycloadditions nor in SN-type reac-
tions the Z/E-ratios fit to the experimental ee-values, if a
classical shielding model is assumed. Therefore, it became
even more pressing to rationalize the correlation between
the Z/E-ratio of the second double bond and the stereo-
chemical outcome.
A potential explanation to this phenomenon is the differ-
ent stabilization of the transition states towards the two
downstream iminium ion intermediates. Indeed, compu-
tational studies revealed a kinetically controlled [4+2]
Diels-Alder reaction pathway with interactions in the
product iminium ion transition state controlling the ste-
reochemical outcome of the reaction.2,6 In case of DEAD
(diethyl azodicarboxylate) as electrophile a downstream
isomerization of the double bond in the product was
proposed to be responsible for the synthetically observed
γ-functionalized unsaturated aldehydes.2,32 For other [4+2]
cycloadditions of dienamines the higher stabilization of
the zwitterionic endo-iminium intermediate and the cor-
responding reaction pathway was identified to be respon-
sible for the high stereoselectivity.6 Furthermore, a com-
Figure 2. SN-type dienamine reaction (A) Proposed catalytic
cycle based on previous publications.2,11,12 (B) Acid catalyzed
equilibrium between the electrophile source E = Bis(4-
dimethylaminophenyl) methanol (Michler’s hydrol) and the
corresponding electrophile E+.34,35
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RESULTS AND DISCUSSION
Model system and theoretical levels. To investigate
Structure of dienamines. First, the formation and struc-
tures of the dienamine species were investigated by NMR
analysis with samples of 1 equiv. of catalyst and 1 equiv. of
aldehyde in toluene-d8 at 180-300 K (Figure 3).
the structural preferences, intermediates and stereo-
selection modes in SN-type dienamine reactions, we se-
lected as model reaction the γ−alkylation of
α,β-unsaturated aldehydes with bis(4-dimethylamino-
phenyl)methanol E (Figure 2B). As catalysts Jørgensen-
Hayashi prolinolethers15,16,36 A-C (Figure 3B) were chosen,
since they are known in dienamine catalysis to result in
high ee-values and good yields.1,2,11,12 In addition, we were
experienced in the structural elucidation of intermediates
using these catalysts from our enamine studies.22–26 To
reduce the amount of α-substituted product12 γ-methyl
During our investigations, we were able to detect diena-
mines E/Z-1A-C, E/Z-2C, E/Z-3C and 4C. The following
structural analysis was performed for every dienamine.
Generally, all dienamines show the same structural pat-
tern regarding E/Z-configuration and conformation of the
catalyst subsystem. Therefore, for the sake of clarity in the
following discussion only trans-2-pentenal 1 with catalyst
C is described in detail (for other structural analysis see
Supporting Information). For the description of the struc-
tural motif of these isomers, first the diene subsystem is
discussed, then the structure of the catalyst subsystem.
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substituted
(4-methyl-2-pentenal 4)
and
linear
α,β-unsaturated aldehydes ((E)-2-pentenal 1, (E)-2-
heptenal 2, (E)-2-decenal 3) with different chain lengths
were selected. This leads to a modulation of steric and
electronic properties. α-Substituted aldehydes were omit-
ted due to their exclusive E-configuration of the second
double bond. Therefore, they do not allow an insight into
the correlation between Z/E-isomerization of the second
double bond and its influence on the stereoselectivity.11
Bis(4-dimethylaminophenyl)-methanol E (Figure 2B), also
known as Michler’s hydrol was chosen as electrophile
source. It is known to form stabilized carbocations E+
under acidic conditions (Figure 2B).34,35 By varying the
acidity of the additive, the amount of active electrophile
E+ can be controlled (for UV/Vis-spectra see Supporting
Information). In addition, a Diels-Alder pathway is ex-
cluded, since the carbocationic species (E+ see Figure 2B)
reacts as an electrophile with nucleophilic reagents such
as dienamines.11,12,35 As solvent toluene was chosen, be-
cause it is the preferred solvent in synthesis for this reac-
tion type.2,11,12 In this NMR study exclusively dienamines
(E/Z-1A-C, E/Z-2C, E/Z-3C, 4C) (E and Z indicates the
configuration of the second double bond, see next sec-
tion) were detected as intermediates. The iminium ion or
aminol species proposed in the catalytic cycle (see Figure
2A) were below the detection limit. High-level quantum
chemical calculations (SCS-MP2/CBS; see computational
details and Supporting Information) on dienamines were
conducted and compared to the experimental data. In
addition, the potential influence of iminium ion species
on the reactivity and selectivity was investigated by theo-
retical calculations.
Figure 4. Structural preferences of the diene subsystem. The
conformations/configurations detected by NMR and the
corresponding nomenclature are highlighted by boxes. For
details, see text.
In the diene subsystem (Figure 4), the first N-C1 single
bond can principally adopt two conformations (s-trans, s-
cis). However, similar to the structural preferences of
enamines with catalysts A-C,23 exclusively the s-trans
conformation is identified in solution for dienamines.
This can be confirmed by strong NOE signals between H1
and Hα, weak interactions between H1 and Hδ1,2 as well as
3
large JCH couplings between H1 and Cδ (see Supporting
Information). The structural preferences of the C1-C2 dou-
ble bond and the C2-C3 single bond were determined by
3JHH coupling constant analysis. For the C1-C2 double
3
bond, JHH coupling constants of 13.2 to 13.5 Hz were
found. In agreement with previous NMR studies,11 theo-
retical calculations2 and our studies of enamines,22–25 this
indicates E configured C1-C2 double bonds for all diena-
Figure 3. Model systems for structural studies and reaction
monitoring. (A) aldehydes 1-4; (B) Jørgensen-Hayashi type
catalysts A-C.
3
mine systems under investigation (for JHH see Supporting
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Information). The C2-C3 single bond showed smaller JHH
imental error of the NOE in our case does not allow for
couplings in the range of 10.3 to 11.3 Hz (see Supporting
Information). These values are in good agreement with
other literature known examples for s-trans diene systems
(10.4-11.2 Hz).37–39 The first variability within the diene
system of the two isomers is related to the configuration
of the second double bond between C3 and C4 (Figure 4D).
Dependent on the length of the alkyl moiety attached to
the diene system and on the catalyst applied, Z/E-ratios
between 0.88 and 2.16 were detected (Z/E-1A = 1.9/1; Z/E-
1B = 2/1; Z/E-1C =2.16/1; Z/E-2C = 1.04/1; Z/E-3C= 0.88/1;
for details see Supporting Information).
reliable quantification. The related theoretical calcula-
tions predicted almost the same energy for sc-exo and ap
(ꢀGexo-ap = -0.9 kJ/mol for E-1C), which is a second indica-
tion for the presence of the ap conformation in solution.
Subsequently, the shielding of the diene subsystem was
investigated by theoretical structure calculations includ-
ing the experimentally determined preferences discussed
above. The calculated 3D models (Figure 6) showed a
shielded face of the first double bond within the diene
systems (α-position), which hinders an attack of an elec-
trophile comparable to the shielding of the α-position in
enamine catalysis.14 The second double bond (γ-position)
is only partially shielded for this face, leading to the prob-
lem of remote stereocontrol in dienamines. This partial
shielding makes it highly probable that the size of the
electrophile influences the effectiveness of the catalyst
shielding. Thus, for small electrophiles only poor stere-
oselectivities are expected. For bulky electrophiles, the
partial shielding should be much more effective. Indeed,
in dienamine reactions with Michler’s hydrol derivatives
as electrophiles (bulky electrophiles) high ee-values were
reported for α-substituted enals11 and our model system
trans-2-pentenal 1,12 whereas to our knowledge for very
small electrophiles high stereoselectivities have not been
reported so far. This structural analysis is in agreement
with our theoretical calculations of an electrophilic attack
from the shielded face in γ-position. The calculated ener-
gy barriers (approx. 80 kJ/mol) for an attack in γ-position
of both dienamines (E- and Z-1C) on the carbocationic
species E+ is substantially higher than those of the attack
from the unshielded face (44 – 49 kJ/mol). That means,
for large electrophiles such as Michler’s hydrol the par-
tially shielded face of dienamine structures is kinetically
not accessible even in the γ-position (Figure 6).
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Figure 5. Structural preferences of the catalyst subsystem.
The boxes highlight the experimentally found preferences for
the puckering of the proline ring as well as for the exocyclic
bound moiety of the catalyst. The dashed box indicates a
population of ap conformer predicted by theoretical calcula-
tions.
Next, we investigated the structural and conformational
preferences of the catalyst moiety. The exocyclic bond of
the catalyst can adopt three conformations, namely sc-
endo, sc-exo and ap (see Figure 5B).23 Using similar struc-
tural NMR investigations as previously applied for
enamine intermediates with catalysts A-C,23,40 we found
the same down-puckering of the pyrrolidine ring indicat-
ed by an Hγ2 highfield shift in dienamines in comparison
to the free catalyst (see Figure 5A; ꢀδ (Hγ2) = -0.54 to -0.79
ppm; for details see Supporting Information). This shift is
caused by CH-π-interactions of the aromatic moieties of
the catalyst and Hγ2 in the sc-exo or ap arrangement.
Quantum chemical calculations of the Boltzmann aver-
aged dienamine structures corroborate these experi-
mental data. The Gibbs free energy of sc-endo is about 33
kJ/mol above the global minimum at SCS-MP2/CBS level
of theory and therefore thermally not populated at our
reaction conditions. The NOESY spectra of all investigat-
ed dienamine systems showed interactions between H1
and the protons of the O-protecting group, which is only
plausible in the sc-exo-conformation. Theoretical distance
calculations for E/Z-1C showed an NOE-averaged distance
of H1 to HOTMS of 6.00 Å for ap and 3.47 Å for sc-exo. Using
NOESY measurements, the experimental averaged dis-
tance between these nuclei was calculated to be 3.80 Å
(for equation, see Supporting Information). The detection
of this key NOE proves positively the existence of the sc-
exo conformation. The larger distance is a potential hint
for the coexistence of ap-conformers, however the exper-
One consequence of these combined experimental and
theoretical investigations is that the reported ee-value in
dienamine catalysis with Michler’s hydrol has to originate
from a stereodiscrimination between the attack either on
E-dienamine or Z-dienamine from the unshielded face.
For our catalyst C with trans-2-pentenal 1, a Z/E-ratio of
2/1 was found experimentally. This distribution of isomers
was already observed before by Jørgensen et al.2 In case,
both E- and Z-dienamines would react with the electro-
phile via an isoenergetic barrier, this Z/E-ratio of 2/1
would result in an ee-value of 33%. However, as shown in
our work and also in literature, ee-values of around 92%
are obtained for this reaction (Figure 6).12 In principle,
this deviation between structure related and experimental
ee-values can have two possible causes; first, the experi-
mentally observed Z/E-ratio deviates drastically from that
active in the catalysis (kinetic versus thermodynamic
control) or second, the activation barriers from E-
dienamine and Z-dienamine deviate significantly in their
downstream reactions. Of course, also combinations of
both reasons are highly probable.
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Figure 6. Shielding and remote stereocontrol in dienamines
top: 3D models of dienamine E/Z-1C show a partially shield-
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ed face from the top side. For bulky electrophiles this partial
shielding is sufficient to block electrophilic attacks even in
the γ-position (~35 kJ/mol higher energy barriers); bottom:
kinetically preferred attack of both isomers from the un-
shielded face yielding different enantiomers. Black: expected
ee-value, if both isomers (E/Z = 1/2) react with same rate.
Blue: experimental ee-values.
Enantioselectivity and kinetic control.
Figure 7. Kinetic control of the Z/E-ratio of dienamines; (A)
theoretically predicted barriers of dienamine formation from
iminium ion precursors agree very well with the experi-
mental values, whereas the thermodynamic distribution of
the dienamine E/Z-1C is inverse. All energies are depicted in
kJ/mol. (B) NMR reaction profiles of dienamine formation of
E/Z-1C revealing a slow but significant change of the Z/E-
ratio support the kinetic preference for Z followed by a slow
isomerization to E (1 (1 equiv.) and C (1 equiv.) without acid
at 300 K in toluene-d8).
To examine the origin of the so far unexplained stereose-
lection mode of the electrophilic attack in γ-position of
dienamines from the unshielded face including also the
Z/E-ratio, we investigated the kinetics and thermodynam-
ics of dienamine formation and the conversion with
Michler’s hydrol by NMR and theoretical calculations.41
First, the formation rates of Z-dienamines versus E-
dienamines were addressed. Under experimental condi-
tions typically used in synthesis, the formation of diena-
mines is the rate determining step followed by a fast addi-
tion of the electrophile (see discussion below). In these
setups, dienamines cannot be detected by NMR. There-
fore, our structural investigations of the dienamines were
previously performed exclusively without electrophile. A
kinetically controlled extremely high Z/E-ratio (about 24/1
for an ee-value of 92%) combined with a subsequent fast
isomerization toward the thermodynamic ratio of Z/E
could therefore easily explain the deviation between the
ee-values obtained in synthesis and the Z/E-ratio ob-
served in NMR studies.
The NMR determined Z/E-ratio of the double bond be-
tween C3 and C4 in all investigated dienamines showed an
uncommon high amount of Z-isomer (up to a Z/E-ratio of
2.16:1 for E/Z-1C; for the time of determination see Sup-
porting Information). This deviates clearly from previous2
and our current theoretical calculations of the relative
dienamine ground state energies (here with trans-2-
pentenal 1 as aldehyde), which suggested that the E-
isomer is marginally more stable than the Z-isomer by 0.6
kJ/mol for catalyst B to 2.9 kJ/mol for catalyst C. The
latter (dienamine E/Z-1C) corresponds to a thermody-
namic Z/E-ratio of 24:76 (see Figure 7A). This is in good
agreement with the work of Jørgensen et al. at a lower
level of theory (B3LYP/6-31G(d))2 and indicates a kinetic
preference for Z-dienamines. Our current calculations
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showed that the transition state for the deprotonation of
equals/exceeds the amount of nucleophile (dienamines),
iminium ion precursors with a base catalyst model ((S)-2-
(methoxymethyl)pyrrolidine) leading to Z-dienamine is
lower by 3 kJ/mol than to E-dienamine. A close inspection
of the transition state structures reveals higher steric
hindrance in case of the E-dienamine as the most proba-
ble reason for this energy difference. The lower barrier for
the formation of Z-dienamine is also predicted, when
NMe3 is used as deprotonating agent, which would indi-
cate that the choice of the base is rather insignificant.
According to Eyring theory this energy difference in bar-
rier heights corresponds to a 3.3 fold faster formation of
Z-dienamine compared to E-dienamine, which is similar
to the observed ratio of 2/1 for Z/E (Figure 7A).
the reaction is dependent on the concentration of both
reactants. In the presence of strong acids, the hydrolysis
of the hydrol is accelerated, the thermodynamic equilib-
rium is shifted providing higher concentration of E+, and
the reaction becomes second order. Thus, the reaction
cannot be assigned as a classical “SN1” and the dienamine
formation seems to be the RDS. Due to the very fast con-
version of dienamines, it is not possible to investigate
deviating reaction rates of Z- and E-dienamines experi-
mentally. Therefore, it was crucial for further experiments
to reduce significantly the rate of the electrophilic attack
by lowering the concentration of E+. This has the conse-
quence that now the nucleophile (dienamine) concentra-
tion is significantly higher than the electrophile concen-
tration and the rate determining step is exclusively the
generation of the electrophile (classical SN1). The pKa
dependency of the generation of the electrophile is sche-
matically represented in Figure 8A by the chemical equi-
librium. The amount of active electrophile is varied by
using the different acids (see Supporting Information for
UV/Vis-spectra). Depending on the acid, the reaction
order can be modulated, which leads to a shift of the RDS
to the carbocation formation step. This is proven by the
simultaneous detection of dienamines and products by
NMR (Figure 8C; using AcOH).
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To prove experimentally that the Z/E-ratio is kinetically
driven and that the E-isomer is the thermodynamic prod-
uct, we investigated the isomerization of the second dou-
ble bond towards the thermodynamic equilibrium. For
1
this purpose H kinetic NMR measurements of the reac-
tion of trans-2-pentenal (aldehyde 1) and catalyst C at
different temperatures and under the influence of acid
were carried out. At 300 K and without acidic additive
(Figure 7B) the dienamine formation for E/Z-1C showed a
decrease of Z/E-ratio with time (for identical measure-
ments at higher temperatures and/or with acid, accelerat-
ed both isomerization and polymerization; see Supporting
Information). The final thermodynamic equilibrium was
not reached, due to emerging polymerization after around
9 h, visible on the decay of the sum of signal intensities in
Figure 7B. Nevertheless, the slow but significant change of
the Z/E-ratio towards higher amounts of E during the
initial part of the reaction is in close agreement with the
theoretical predictions. The very slow isomerization pro-
cess lasting for hours in combination with an observed
Z/E-ratio higher than the theoretically predicted one
corroborates a significant kinetic preference of Z followed
by the isomerization toward E, the thermodynamic pref-
erence. In addition, both experiment and calculations
exclude extremely high amounts of Z- dienamines during
the dienamine formation. Thus, an additional factor has
to contribute to reach the high ee-values observed in
synthesis.
Therefore, the downstream reactions of the dienamines
were investigated next and further experimental and
theoretical investigations of the conversion of the diena-
mines with the electrophile were performed. The energy
barriers (black and red lines) for the conversion to the γ-
product (49.6/44.0 kJ/mol) were significantly smaller
than for the dienamine (E/Z-1C) formation (80.2/77.2
kJ/mol) (Figure 8A). The calculated energy barrier differ-
ence translates to several orders of magnitudes in reaction
rates, which means the dienamine species is not detecta-
ble in solution in the presence of a sufficient amount of
electrophile (Figure 8B; using TFA). In an SN1 reaction
(first order by nature), the RDS (rate determining step) is
generally the generation of the carbocation, and therefore
its concentration is significantly lower than the nucleo-
phile. As soon as the amount of electrophile
Figure 8. Energy profiles of dienamine reactions and modu-
lation of the RDS by variation of the electrophile concentra-
tion. (A) Calculated free energy surfaces (ꢀG298) (black E-1C
and red Z-1C line) at SCS-MP2/CBS level of theory, and
schematic acid dependent generation of carbocation E+. (B)
and (C) The NMR reaction profiles show the shift of the RDS;
with TFA no dienamines are detected (B) whereas with acetic
acid both dienamines are observable (C) (aldehyde 1 (2
equiv.), catalyst C (0.2 equiv.) Michler’s hydrol (1 equiv.) and
TFA or acetic acid 0.1 equiv.) at 313 K in toluene-d8.
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E/Z-1A-C translated to reaction rate ratios according to the
An experimental setup with weak acid (AcOH) now al-
Eyring equation and the resulting theoretical ee-values. Ex-
perimental ee-values derived from reaction of aldehyde 1 (2
equiv.), catalyst A-C (0.2 equiv.) Michler’s hydrol (1 equiv.)
and acetic acid (0.1 equiv.) at 313 K in toluene-d8 after 24h.
lows for the investigation of the relative reactivity of E-
and Z-dienamines with electrophile. In addition to the
Z/E-ratio, the difference in reactivity towards electrophile
is proposed as a second factor, which affects the observed
ee-values.
Theor.
In the case of a kinetically controlled preference of the Z-
isomer in the electrophilic attack, its amount has to de-
crease faster than E. However, in Figure 8C, both diena-
mines remain constant after reaching a maximum (4 h).
The profile can be explained by the consumption of the
free catalyst, which reduced the rate of the dienamines
formation. After 4 h the rates of dienamines formation
and conversion are comparable leading to a steady state.
To prove the kinetic preference of Z-dienamines towards
electrophile experimentally, kinetic measurements with
higher amount of catalyst (1 equiv.) and acetic acid (1
equiv.) were performed (Figure 9). The adapted stoichio-
metric ratio provides two advantages. First, it increases
the amount of the dienamines and simplifies the detec-
tion. Second and more importantly, both formation and
conversion of dienamines are accelerated. After a short
offset (4 h), the conversion to the γ-product is faster than
the dienamine formation due to the higher concentration
of electrophile E+, which is indicated by the decrease of
both dienamines. Despite the faster formation of Z-
dienamine than E-dienamine, the faster conversion of Z-
dienamine is now observable.42 This reveals a combination
of preferred formation and conversion of Z-dienamines as
origin of the ee-values observed in synthesis.
Z/E-
ratio
(ap-
reac-
tion
rate
ratio Z
vs E
ΔΔG‡
[kJ/m
ol]
experi-
mental
ee
Cata-
lyst
Theor.
ee
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prox.)
A
B
C
2/1
2/1
2/1
1.89
3.13
2.1/1
3.5/2
9.5/1
36%
56%
80%
27%
48%
78%
5.60
From these experimental data, the reason for the pre-
ferred electrophilic attack on Z- compared to E-
dienamines is unclear. Therefore, further theoretical cal-
culations of the electrophilic attack were conducted. For
large electrophiles, the electrophilic attack from the par-
tially shielded face is by far too high in energy (see Figure
6). Considering an exclusive attack from the unshielded
side, the E-dienamine yields the S-enantiomer of the γ-
substituted α,β-unsaturated product, whereas the Z-
dienamine gives the R-enantiomer, which is the major
product. As we have already shown, the higher population
of Z-dienamine (~66%) cannot be solely responsible for
the variation of the ee-values, otherwise similar ee-values
across all investigated systems are expected (Table 1).
Moreover, the NMR kinetic data shown in Figure 9 indi-
cate a kinetically controlled product conversion prefera-
bly from Z-dienamine. Indeed, our current predictions
showed that the transition state for the electrophile at-
tack on the open face of E-1A-C is higher than on Z-1A-C
(Boltzmann averaged 1.90-5.60 kJ/mol; for values of E/Z-
1C see Figure 8A).43
The theoretical calculations showed that the differences
in the free energy barriers (ꢀꢀG‡) between Z and E are the
results of two effects: the higher thermodynamic stability
of E compared to Z and the differences in dienamine-
electrophile interactions in the transition states. Taken
together, the calculations of the transition states corrobo-
rate the faster formation of the major product from Z-
dienamine as shown experimentally.
Figure 9. Reaction profile of dienamines E/Z-1C, the result-
ing Z/E-ratio and simultaneous γ-product formation, show-
ing a faster consumption of Z-dienamine. Aldehyde 1 (1
equiv.), catalyst C (1 equiv.), Michler’s hydrol (1 equiv.) and
AcOH (1 equiv.) at 313 K in toluene-d8.
To confirm the kinetic control of the stereoinduction, we
determined the ee-values of trans-2-pentenal 1 with Mich-
ler’s hydrol using three different catalysts (1 (2 equiv.); A-
C (0.2 equiv.); Michler’s hydrol (1 equiv.); AcOH (0.1
equiv.); 313 K in toluene). Despite of similar Z/E-1A-C
ratios of the dienamines, the ee-values between the cata-
lysts vary strongly, with catalyst C being the most enanti-
oselective and A the least (Table 1). If the kinetic control
is valid, the free energy differences of the transition states
for the iminium ion-electrophile adduct formation will
Table 1. Calculated ΔΔG‡ values [kJ/mol] (Boltzmann aver-
aged) for dienamine electrophile adduct formation step for
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correlate with the ee-values. As shown in Table 1, the
highest ꢀꢀG‡ for E/Z-1C (5.6 kJ/mol) reflects the highest
theoretical ee-value (80%), while the lowest ꢀꢀG‡ for E/Z-
1A (1.90 kJ/mol) reflects the lowest ee-value (36%). This
means these values are in a very good agreement with the
experimental ee-values for the different catalysts.
the general preference of the conversion of Z-dienamines
over E-dienamines seems to originate from stabilizing
CH-π interactions in the transition state between Z-
dienamine and electrophile. The significant differences of
the ee-values depending on the catalyst applied are
caused by structural variations due to interactions be-
tween the aryl-substituents of the catalyst and the elec-
trophile.
Next, the kinetic and thermodynamic terms in the prod-
uct formation step were decomposed to track the origin
of the different energy barriers. As previously described,
the E-1A-C-dienamines are thermodynamically slightly
more stable than the Z-1A-C dienamines (ΔGZ-E(B)= 0.6
kJ/mol; ΔGZ-E(A)= 2.5 kJ/mol; ΔGZ-E(C) = 2.9 kJ/mol). Ex-
cluding the thermodynamics, the highest pure kinetic
effect from the transition states is calculated for catalyst C
(ΔΔG‡-ΔGZ-E= 5.60 – 2.9 = 2.7 kJ/mol), while the lowest is
estimated for catalyst A (ΔΔG‡-ΔGZ-E= 1.9 – 2.5 = -0.6
kJ/mol). The positive value for C means that the transi-
tion state between E-dienamine and the electrophile is
more unstable than the Z-dienamine, and vice versa for A.
At first glance, the altering stability of the transition
states is very puzzling, because both transition states
possess the same conformational preference, (ap-
conformation and down-puckering). Hence a precise
structure analysis was performed.
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From the structure analysis of the transition states, sever-
al distinctive interactions could be identified: (1) Stabiliz-
ing CH-π interactions between C5 bound protons of the
diene system (e.g. methyl group in E/Z-1A-C) and one of
the aromatic rings of the electrophile (Figure 10A high-
lighted in yellow), which are present in all transition
states of Z-dienamines but not in E-dienamines. This CH-
π interaction seems to be a major factor, which stabilizes
the transition state of Z-1A-C. (2) Stabilizing dispersive
interactions (stacking), which extend from the diene
system to the pyrrolidine moiety (Figure 10A). (3) Due to
the dimension of the electrophile, the shielding group of
the catalyst may still interact with the electrophile, either
sterically or electrostatically. The magnitude of the stabi-
lization effects is thus modulated by the arrangement
between the electrophile and the dienamines. Remarka-
bly, both the transition states of E/Z-1C exhibit an elec-
trostatic interaction between the meta-trifloromethyl
group and the aromatic protons of the electrophile (Fig-
ure 10B). This has the consequence that the electrophile is
rotated in the direction of the trifluoromethyl substituent.
The displacement of the electrophile reduces the stacking
interaction between the electrophile and the diene sys-
tem, particularly in the transition state of E-1C. In total,
the TS Z-1C showed better electrophile-dienamines inter-
actions (2.7 kJ/mol) than the TS E-1C.
Figure 10. Transition states of iminium ion product for-
mation and their intermolecular interactions: (A) a closer
distance shows a stronger CH-π interaction in [E+-Z-1C]‡; (B)
The alignment of the two dienamines subsystems (green)
reveals the different arrangements of the electrophile; (B and
C) red dashed arrows show interactions between the CF3
group and the electrophile; (C) catalyst dependent displace-
ment of E+-E-1C compared to E+-E-1A.
The main stereocontrol being the iminium ion product
formation is in principle similar to the stereoselection
mode proposed by Jørgensen et al. for Diels-Alder type
reactions.2 Interestingly, also the barriers for the γ-
functionalization with DEAD are similar. Considering the
variability of potential reaction pathways depending on
the experimental conditions recently also shown for
enamine reactions,44,45 also the nucleophilic addition to
DEAD seems to be possible. In Diels-Alder reactions with
DEAD, the transition state barrier of the product for-
mation is significantly lower than the barrier of the nu-
In contrast, in the transition state of E-1A, such electro-
static interaction between the electrophile and the shield-
ing moiety of the dienamine does not exist and the elec-
trophile is not displaced (Figure 10C). Therefore, the
magnitude of the stacking interaction is considered to be
equal for both E/Z-1A. In this case E-1A is becoming mar-
ginally more stable than Z-1A (-0.6 kJ/mol). In summary,
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cleophilic addition.2 However, in the former reactions a
downstream isomerization of the product is necessary.
Computational Details.
Geometry optimization and frequency analysis were per-
formed with Gaussian09 version D.0146 at DFT level of
theory using hybrid metaGGA functional M06-2X-
D3/def2-SVP in the gas-phase.47–49 Subsequently, single
point calculations were carried out with ORCA 3.0.350 at
SCS-RIMP2/CBS level of theory using two points extrapo-
lation procedure (see Supporting Information for
details).51 Solvent correction in toluene was estimated
using COSMO-SAC52–54as implemented in CRS module of
ADF201455–57with COSMO potential generated by Gaussi-
an09 version D.01.
A recent computational study of [5+2]-cycloaddition reac-
tions using squareamide-derived bifunctional organo-
catalysts with structural preorganization revealed similar
conformational preferences (pyrrolidine puckering, E,s-
trans) and similar non-covalent interactions (e.g.
π−π stacking) with respect to the formation of the stereo-
center at the γ-position of dienamines.33 Thus, independ-
ent of the system weak dispersion interactions seem to be
the key to high stereoselectivities in the dienamine catal-
ysis. However, in our case high stereoselectivities require
additional kinetic preferences to overcome the Z/E-
dilemma.
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Figure 11. Schematic overview of all investigated reaction features: kinetic preference of Z-dienamine formation, effective shield-
ing of the top side and catalyst dependent reaction barriers (ꢀꢀG‡) for electrophile-adduct formation including a kinetically
controlled conversion of Z-dienamines and the resulting ee-values.
CONCLUSION
plained (i.e. the missing clear correlation between the Z/E
ratio and the ee-values). In case of large electrophiles, the
partial shielding of the double bond by the catalyst is
sufficient to effectively block attacks even in γ-position.
As a result, the ee-values for γ-functionalization has to
correlate directly with the reaction profiles of the corre-
sponding Z- and E-dienamines. Here, three aspects inter-
twine, the kinetic preference for the formation of Z-
dienamines, the higher thermodynamic energy level of Z-
dienamines and the lower activation barrier for electro-
phile attacks from Z-dienamines. Theoretical studies
corroborate for the first time a similar kinetic preference
of Z-dienamine formation observed in experiments for all
catalysts investigated. The main stereodiscrimination is
effective in the second step, the electrophile adduct for-
mation. Advantageous CH-π interactions between Z-
dienamines and the electrophile in the transition state of
product iminium ion formation seem to cause faster con-
versions of Z-dienamines in general. Depending on the
To summarize, for the first time the conformational pref-
erences of dienamine intermediates with Jørgensen-
Hayashi prolinol ether catalysts were fully characterized
by NMR spectroscopy. Similar to enamines, dienamines
exhibit in the catalyst moiety down-puckering of the pyr-
rolidine ring and a preference for sc-exo conformations.
For linear aldehydes, the first double bond is connected
via an s-trans conformation and is E configured. For the
second double bond, connected via s-trans conformations
the preference for Z configurations was confirmed. These
structural studies were underpinned by theoretical calcu-
lations of the whole reaction pathway, kinetic NMR stud-
ies and a shift of the rate determining step by variation of
the electrophile concentration. For the first time both the
stereoinduction mode of dienamines in SN-reactions and
the “Z/E-dilemma of the second double bond” were ex-
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Halskov, K. S.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2015, 54, 13860.
Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.; Yin,
X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am.
Chem. Soc. 2011, 133, 5053.
structure of the catalyst different interactions between its
aryl moieties and the electrophile are observed modulat-
ing the stacking between the pyrrolidine/diene and the
electrophile. These structural modulations determine the
level of the ee.
(4)
(5)
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(7)
Zhou, Q.-Q.; Xiao, Y.-C.; Yuan, X.; Chen, Y.-C. Asian J.
Org. Chem. 2014, 3, 545.
The secret of the highly effective remote stereocontrol in
dienamines with Z/E variability of the second double
bond is thus a delicate interplay of substrate, catalyst and
electrophile structure. Two factors promote high ee-
values, a high Z/E dienamine ratio and an effective ste-
reodiscrimination in the product iminium ion formation.
From our studies the Z/E-ratio can be enhanced by em-
ploying short unsaturated aldehydes. Large electrophiles
in combination with bulky interacting catalyst structures
support an effective catalyst shielding and high stereodis-
crimination for attacks from the unshielded face.
In Diels-Alder- as well as SN-type reactions, the key to
high stereoselectivity in the γ-functionalization is the
intermolecular interaction in the “product iminium ion
transition state”. In the case of DEAD as electrophile, an
alternative pathway via nucleophilic addition, which is
energetically comparable to SN-type reactions, would
allow γ−functionalization without downstream isomeriza-
tion of the product.
Johansen, T. K.; Gómez, C. V.; Bak, J. R.; Davis, R. L.;
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ASSOCIATED CONTENT
Supporting Information. Assignments of all dienamine
species and products. NMR and HPLC parameters and sam-
ple preparation procedure. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ruth.gschwind@ur.de
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
ACKNOWLEDGMENT
Thanks to the DFG for financial support (grant GS 13/4-1).
We thank Dr. Markus Schmid for the initial NMR investiga-
tions on the structure of enamines. Many thanks to the
working group of Prof. Dr. Kirsten Zeitler in Leipzig for using
the HPLC.
Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Org. Chem.
2011, 76, 3005.
Lelais, G.; MacMillan, D. W. C. In Enantioselective
Organocatalysis; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2007; Vol. 107, pp 95–120.
Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chemie
2011, 123, 12062.
Holland, M. C.; Metternich, J. B.; Mück-Lichtenfeld, C.;
Gilmour, R. Chem. Commun. 2015, 51, 5322.
Holland, M. C.; Metternich, J. B.; Daniliuc, C.;
Schweizer, W. B.; Gilmour, R. Chem. Eur. J. 2015, 21,
10031.
ABBREVIATIONS
(28)
(29)
(30)
AcOH, acetic acid; DEAD, diethyl azodicarboxylate; equiv.,
equivalent; NMR, nuclear magnetic resonance; NOE, nuclear
overhauser effect; RDS, rate determining step ; TFA, tri-
fluoroacetic acid.
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During our investigations, it was not possible to assign
any α-alkylated product for our model system, because
of
a
low signal to noise ratio. However, the
stereoselection mode of the α-alkylation product is
expected to be identical to the enamine catalysis, and
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The initial increase of the Z/E-ratio (Figure 9) is most
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concentration of E-isomer.
Note that structural analysis revealed that the most
stable transition state of the product iminium ion
formation exhibits an antiperiplanar arrangement (ap-
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