Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers

Article abstract of DOI:10.1002/chem.201905296

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

Full text of DOI:10.1002/chem.201905296

A Journal of
Accepted Article
Title: Mechanism and Origin of Stereoselectivity in Chiral Phosphoric
Acid-Catalysed Aldol-Type Reactions of Azlactones with Vinyl
Ethers
Authors: Kyohei Kanomata, Yuki Nagasawa, Masahiro Yamanaka,
Yukihiro Shibata, Fuyuki Egawa, Jun Kikuchi, and Masahiro
Terada
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To be cited as: Chem. Eur. J. 10.1002/chem.201905296
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Mechanism and Origin of Stereoselectivity in Chiral Phosphoric
Acid-Catalysed Aldol-Type Reactions of Azlactones with Vinyl
Ethers
Kyohei Kanomata,[a],[‡] Yuki Nagasawa,[b] Yukihiro Shibata,[b] Masahiro Yamanaka,*[b] Fuyuki Egawa,[a]
Jun Kikuchi,[a] and Masahiro Terada*[a]
Abstract: The precise mechanism of the chiral phosphoric acid-
catalysed aldol-type reaction of azlactones with vinyl ethers was
investigated. DFT calculations suggested that the reaction proceeds
through a Conia-ene-type transition state consisting of the vinyl ether
and the enol tautomer of the azlactone, in which the catalyst
protonates the nitrogen atom of the azlactone to promote enol
tautomerization. In addition, the phosphoryl oxygen of the catalyst
interacts with the vinyl proton of the vinyl ether. The favorable
transition structure features dicoordinating hydrogen bonds. However,
these hydrogen bonds are not involved in the bond recombination
sequence and hence the catalyst functions as a template for binding
substrates. From the results of theoretical studies and experimental
supports, the high enantioselectivity is induced by the steric repulsion
between the azlactone substituent and the binaphthyl backbone of the
catalyst under the catalyst template effect.
We previously developed the chiral phosphoric acid-catalysed
enantioselective aldol-type reaction of vinyl ethers with
azlactones as nucleophiles (Scheme 1).[7a] When followed by the
ring opening of the azlactone unit, this reaction provides access
to biologically and pharmaceutically intriguing β-hydroxy-α-amino
acid derivatives in enantioenriched forms.[7,8] However, the
precise reaction mechanism and the origin of the high enantio-
and diastereoselectivity have remained unclear. In addition, the
stereoselectivity is intriguingly dependent on substituent Ar at the
2-position of the azlactone,[7a,9] even though the substituent is
introduced at the far side from the reaction site that is the 4-
position of the azlactone.
Two reaction mechanisms have been proposed for the
present aldol-type reaction.[7a,10] We originally proposed
a
stepwise reaction mechanism in which the vinyl ether is
protonated by the catalyst to form oxocarbenium intermediate I,
followed by the stereoselective nucleophilic addition of the
azlactone (Scheme 1).[7a] On the other hand, Tepe and Fisk
proposed Conia-ene-type six-membered cyclic transition state II
for the thermal reaction, namely, without using a catalyst, based
on the fact that the stereospecific syn-addition of the azlactone to
the vinyl ether was observed experimentally (Scheme 2).[10] DFT
studies are a promising approach for clarifying the mechanism of
the present aldol-type reaction. Herein we report detailed DFT
studies of this reaction and disclose that the reaction proceeds via
a six-membered Conia-ene-type cyclic transition state and not
through the stepwise mechanism proposed previously.[7a] Of
Introduction
The development of enantioselective catalysis using a chiral
Brønsted acid has evolved into an active research field over the
past few decades.[1] In particular, BINOL (1,1’-bi-2-naphthol)-
derived chiral phosphoric acids 1, shown in Scheme 1, have
emerged as privileged organocatalysts[2,3] and a broad range of
enantioselective reactions have been established using 1 and its
derivatives. The wide applicability of those acid catalysts has
stimulated mechanistic elucidation not only of stereochemical
control but also of the reaction pathway, and tremendous efforts
have been devoted to identify the chiral Brønsted acid catalysis.
Among the approaches endeavored, DFT calculations have
proven to be a powerful tool for elucidating the mechanisms of a
range of reactions catalysed by 1 and its derivatives.[4-6]
[a]
[b]
[‡]
Dr. K. Kanomata, F. Egawa, Dr. J. Kikuchi, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science, Tohoku
University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Y. Nagasawa, Y. Shibata, Prof. Dr. M. Yamanaka
Department of Chemistry and Research Center for Smart
Molecules, Faculty of Science, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
E-mail: myamanak@rikkyo.ac.jp
Present Addresses: Department of Agro-Environmental Sciences,
Graduate School of Bioresource and Bioenvironmental Sciences,
Kyushu University, Fukuoka 819-0395, Japan
Scheme 1. Our previous work: Enantioselective reaction of vinyl ether with
azlactone catalysed by chiral phosphoric acid (R)-1.
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2 Reported by Tepe and Fisk: Stereospecific reaction of vinyl ethers
with azlactones without a catalyst.
Figure 2. Chemical models for computational studies.
Figure 1. Theoretically elucidated Conia-ene-type cyclic transition state of chiral
phosphoric acid-catalysed reaction.
single-point energy calculations for the optimized structures (at
the B3LYP/6-31G* level) were evaluated at the M06-2X/6-31G*
level in the gas phase.[13]
particular interest is that chiral phosphoric acid catalyst is not
involved in the bond recombination sequence of the Conia-ene-
type cyclic transition state and the catalyst functions as a template
for binding both substrates, the vinyl ether and the azlactone,
through hydrogen bonds (Figure 1). In addition, the intriguing
substituent effect of Ar introduced at the 2-position of the
azlactone is well rationalized by a theoretically proposed model,
in which the steric bulkiness of the Ar substituent plays a vital role
in determining the stereochemical outcome. The proposed model
for stereocontrol was also confirmed by further experimental
support.
Investigation of Reaction Pathway Using Simplified Chemical
Model
First, reaction pathways for the present aldol-type reaction
were investigated using the simplified chemical model. After
intensive screening for possible transient configurations, three
reaction pathways were identified in the gas phase and the
solution phase according to the SCRF method based on CPCM
(CH2Cl2) (Figure 3): a pathway involving an oxocarbenium
intermediate (Path A) and pathways proceeding via cyclic
transition structures (Paths B and C).
Path A, which is identical to the reaction mechanism originally
proposed by our group,[7a] involves an oxocarbenium ion as the
key reaction intermediate (Figure 3a). The reaction pathway was
assumed to consist of two steps: (1) protonation of VE by cat to
form an ion-paired complex between the oxocarbenium
intermediate and the chiral phosphate, followed by (2)
nucleophilic addition of the enol tautomer of AZ to the ion-paired
complex. After screening for the possible structural conformations
for the latter step, TS-A was identified as the transition state (TS)
with the lowest relative energy (gas phase: ΔE = 21.7 kcal/mol,
solution phase: ΔE = 16.9 kcal/mol).[14]
Other possible reaction pathways, namely, cyclic TSs, were
also investigated. The transition structure along Path B (TS-B)
features a ten-membered cyclic structure consisting of VE, AZ,
and cat (Figure 3b). In TS-B, cat is embedded into the bond
recombination sequence of the reaction. Accordingly, cat
protonates the double bond of VE and captures another proton
from the enol moiety of AZ, promoting carbon-carbon bond
formation between VE and AZ. Although the transition structure
of Path B has not been located in the solution phase,[15] in the gas
Results and Discussion
Chemical Models and Computational Methods
At the outset of the present study, the reaction mechanism
was investigated using a simplified chemical model in order to
reduce computational costs (Figure 2a). Thus, a biphenol-derived
phosphoric acid (cat) instead of a binaphthol-derived phosphoric
acid, vinyl methyl ether (VE), and
a dimethyl-substituted
azlactone (AZ) were used. Investigations of the steric interactions
and the origin of the stereochemical outcome were then pursued
employing a realistic chemical model (Figure2b) based on the
located transition structures identified using the simplified
chemical model. All of the calculations were performed with the
Gaussian 09 package.[11] The geometries were fully optimized at
the B3LYP/6-31G* level[12] and characterized using frequency
calculations, and the free energies were computed for the gas
phase and the solution phase according to the SCRF method
based on CPCM (CH2Cl2). For the realistic chemical model,
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phase, the relative energy of TS-B (ΔE = 10.3 kcal/mol) is far
lower than that of TS-A (ΔE = 21.7 kcal/mol), and thus the
stepwise pathway via the generation of ionic intermediate I (see
Scheme 1) is unfavorable in the present reaction.
TS-C was determined to be the most energetically favorable
transition state (gas phase: ΔE = 3.5 kcal/mol, solution phase: ΔE
= 3.5 kcal/mol). In located transition structure TS-C, the
phosphoric acid (P-OH) of cat protonates the nitrogen atom of AZ,
whereas the phosphoryl oxygen (P=O) of cat interacts with the
vinyl proton of VE. Thus, TS-C features dicoordinating hydrogen
bonds, which are an essential interaction mode observed widely
in chiral phosphoric acid-catalysed reactions and are beneficial
for controlling the stereochemical outcome (Figure 3c).[4-6]
However, it should be emphasized that in the present transition
state, these hydrogen bonds are not involved in the bond
recombination sequence and cat functions as a template for
binding both substrates, AZ and VE, of which relative locations
are fixed. This finding is in stark contrast to the current
understanding of the reaction mechanism under chiral phosphoric
acid catalysis, and thus the dicoordinating hydrogen bonds
effectively participate in the bond recombination sequence and
accelerate the reaction efficiently.[4-6] As discussed above, these
simplified model studies strongly suggest that Path C is the most
favorable of the pathways investigated,[16] presumably because
AZ and VE are well-overlapped in the transient structure of Path
C[17] and hence considerable charge-separation would be avoided
as compared with the other transient structures of Paths A and B.
Reactions via a six-membered cyclic TS (Path C) were also
investigated (Figure 3c). It is noteworthy that the six-membered
ring in TS-C consists of VE and AZ, and thus cat is not involved
in the bond recombination sequence. Instead, cat protonates the
nitrogen atom of AZ, which is the most basic site among the
substrates. The protonation of AZ likely promotes tautomerization
to the enol form and enhances the acidity of the enol proton,
facilitating proton transfer from AZ to VE. A frequency calculation
revealed that TS-C corresponds to the proton transfer step from
AZ to VE. In addition, an intrinsic reaction coordinate (IRC)
calculation suggested that carbon-carbon bond formation
proceeds smoothly without any activation barrier soon after
proton transfer. Transition structures with changing conformations
in Path C ranged in relative energy from 3.5 to 10 kcal/mol,[14] and
Rationalization of Inconsistency between Previous Proposal
and Theoretical Studies
As mentioned in the previous section, the theoretical study of
the simplified chemical model is not consistent with our previous
proposal of a stepwise mechanism as likely shown in Path A
(Figure 3a).[7a] We previously proposed the mechanism on the
basis of experimental evidence, as shown in Scheme 3. The
reaction of (E)- and (Z)-isomers of vinyl ether 2b with azlactone
3a was conducted individually, followed by ring opening of the
azlactone unit, to afford product 6 with exactly the same
diastereo- and enantioselectivities, irrespective of the geometry of
2b. We hence presumed that the common oxocarbenium
intermediate would be generated from (E)- and (Z)-2b through the
double bond protonation.
The experimental evidence shown in Scheme
3 is
alternatively rationalized by the geometrical isomerization of vinyl
ether 2b during the course of the aldol-type reaction. We therefore
monitored the isomerization of 2b by NMR experiment. At the
outset of the monitoring studies, the geometrical isomerization of
2b on its own was monitored by 1H NMR measurement under the
influence of (R)-1 in CD2Cl2 at 20 °C. As shown in Figure 4 (solid
lines), both (E)- and (Z)-2b were isomerized under the influence
of (R)-1. After 9 hours, the (E)/(Z) ratio converged into 42:58,
irrespective of the starting geometry of 2b. This clearly suggests
that (R)-1 facilitates the geometrical isomerization of 2b reversibly
and the isomerization reaches equilibrium after 9 hours. Similarly,
in the aldol-type reaction of 2b with 3a, the geometrical
isomerization of vinyl ether 2b (2 equivalents of 2b to 3a) was
observed, as shown in Figure 4 (dashed lines).[18] It should be
pointed out that after 9 hours, product 6 was formed in around
70% yield in the reaction using either (E)- or (Z)-2b[18] and hence
the reaction was not complete. Accordingly, rate of the
Figure 3. Transition structures located using the simplified chemical model.
Relative energies of the transition state in the gas phase are shown in kcal/mol
with respect to the sum of VE, AZ, and cat. Relative Gibbs free energies are
shown in parentheses. Bond lengths of the transition structures in the gas phase
are indicated in red (angstroms). Relative energies (kcal/mol) of the transition
state in the solution phase were calculated at the same level according to the
SCRF method based on CPCM (CH2Cl2) and are shown in brackets. Similarly,
relative Gibbs free energies are shown in parentheses. Bond lengths in the
solution phase are shown in brackets (angstroms) *In the solution phase, TS-B
has not been located, albeit thorough screening.
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Scheme 3. Reaction of (E)- and (Z)-isomers of vinyl ether 2b with azlactone 3a
catalysed by chiral phosphoric acid (R)-1.
Having identified the most favorable pathway for the present
aldol-type reaction, the origin of stereocontrol was further
explored using the realistic chemical model based on TS-C. As
shown in Scheme 1,[7a] the reaction of 2a with 3a (Ar = 3,5-
(MeO)2C6H3-) at room temperature followed by the ring opening
of the azlactone unit using sodium methoxide afforded syn-5a as
the major diastereomer (syn:anti = 95:5) with high enantiomeric
excess (95% ee for syn-5a at room temperature), preferring
(2S,3R)-5a over (2R,3S)-5a.[19] Transition structures leading to a
pair of enantiomers of the syn-isomer (i.e., TS-sr and TS-rs) were
thoroughly investigated to clarify the origins of the stereochemical
outcome.[20] The experimentally observed enantioselectivities
were qualitatively consistent with the calculated energy
differences. The relative energy difference between TSa-sr and
TSa-rs is sufficient for a high level of enantioselectivity in favor of
TSa-sr (3.5 kcal/mol), where TSa-sr and TSa-rs correspond to
the major and minor enantiomers of syn-5a, respectively (Ar =
3,5-(MeO)2C6H3-) (Figure 5).[21]
(E)-2b (initial E/Z = 91:9)
(Z)-2b (initial E/Z = 3:97)
Detailed analysis of these transition structures revealed that
the observed stereocontrol can be rationalized by the following
repulsive (in minor TSa-rs) and attractive (in major TSa-sr)
interactions (Figures 5 and 6a). Firstly, as highlighted in the red
dashed squares in Figure 5, the sterically bulky t-Bu group of 2a
occupies the empty pocket of catalyst 1 in energetically favored
transition state TSa-sr (Figure 5a), whereas the t-Bu group
engenders a steric repulsion with the 2,4,6-triisopropylphenyl
group of the catalyst in disfavored transition state TSa-rs (Figure
5b). In contrast to the repulsive interaction, the attractive
interaction stabilizes the transition structures efficiently (Figure
6a: also see Figure 7 for schematic model). In fact, energetically
favorable TSa-sr features hydrogen bonds between the
phosphoryl oxygen of 1 with the hydrogen atoms of the inside
vinylic position and the t-Bu group in 2a (Figure 6a: left),[22]
whereas the phosphoryl oxygen in TSa-rs does not form any
hydrogen bonds with vinyl ether 2a (Figure 6a: right).[22] As
discussed in the model studies, in energetically favorable TSa-sr,
phosphoric acid catalyst 1 functions as a template for binding not
only azlactone 3a but also 2a through hydrogen bonding
interaction, although these hydrogen bonds are not involved in the
bond recombination sequence.
As mentioned in the previous section, the NMR monitoring
studies suggest that (Z)-2b is primarily involved in the aldol-type
reaction, although (E)- and (Z)-geometrical mixtures are formed
under the influence of the catalyst because of frequent
isomerization. It is considered that the geometrical isomer of 2b
undergoes efficient resolution under energetically favorable TSa-
sr. As highlighted by the blue dashed circle in Figure 5a, the
introduction of the substituent to the vinyl ether at the (E)-position
would lead to marked steric congestion between the vinyl
substituent and the 2,4,6-triisopropylphenyl substituent of the
catalyst. In contrast, the (Z)-position of the vinyl ether is less
sterically congested and the substituent at the (Z)-position would
not cause any steric repulsions. Consequently, the selective
consumption of (Z)-vinyl ether in the aldol-type reaction well suits
energetically favorable TSa-sr.
3a + (E)-2b (initial E/Z = 91:9)
3a + (Z)-2b (initial E/Z = 3:97)
time (min)
Figure 4. 1H NMR monitoring of (E)/(Z) ratio of 2b [% of (E)-isomer]. Solid lines:
isomerization of (E)- or (Z)-2b (0.2 mmol) in the presence of (R)-1 (0.01 mmol)
in CD2Cl2 (0.5 mL). Dashed lines: the aldol-type reaction of (E)- or (Z)-2b (0.2
mmol: 2 equiv.) with 3a (0.1 mmol) in the presence of (R)-1 (0.01 mmol) in
CD2Cl2 (0.5 mL).
geometrical isomerization is higher than that of the aldol-type
reaction. More interestingly, during the course of the aldol-type
reaction, the (E)-isomer ratio (dashed lines) is higher than that
(solid lines) observed in the simple isomerization of 2b in both
cases using (E)- and (Z)-2b. This observation clearly indicates
that (Z)-2b is consumed faster than (E)-2b in the aldol-type
reaction. Consequently, it is considered that (Z)-2b is primarily
involved in the aldol-type reaction even when (E)-2b is used as
the initial geometrical isomer. On the basis of the rapid
geometrical isomerization, coupled with the efficient resolution of
the generated geometrical isomers, it could be well rationalized
that exactly the same stereoselectivities were observed in the
reaction using either the (E)- or (Z)-isomer of 2b.
Clarification of Origin of Stereoselectivity Using Realistic
Chemical Model
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at room temperature). In order to clarify the substituent effect on
the enantioselectivity, we further conducted theoretical studies on
the realistic chemical model of 2a with 3b. As shown in Figure
6b,[22] the relative energy difference between TSb-sr and TSb-rs,
which are the transition structures that afford each enantiomer of
syn-5b (Ar = Ph), decreased to 1.9 kcal/mol. The relative
relationships of the experimentally observed enantioselectivities
of syn-5a (95% ee) and syn-5b (59% ee) are qualitatively
consistent with the calculated energy differences of these
transition states (TSas: 3.5 kcal/mol, TSbs: 1.9 kcal/mol).
As shown in Figure 6, the template effect of the catalyst
through hydrogen bonds also stabilizes TSb-sr as the favorable
transition state, as has been similarly observed in TSa-sr.
Therefore, the strong dependence of the enantioselectivities on
the substituents of azlactone can be rationalized by steric effects.
In the reaction of azlactone 3a, TSa-rs, which leads to the minor
enantiomer, is destabilized by the steric repulsion between the
binaphthyl backbone of the catalyst and the sterically bulky 3,5-
dimethoxyphenyl group of 3a, whereas in energetically favored
TSa-sr, the 3,5-dimethoxyphenyl group avoids this steric
congestion (Figure 6a). On the other hand, the steric effect of the
corresponding phenyl group in TSb-rs is reduced due to the lack
of methoxy groups at the 3,5-positions (Figure 6b). In fact, the
H···N distance of the O···H···N hydrogen bond formed between
the phosphoric acid and the azlactone is shorter in TSb-rs than in
TSa-rs (1.67 Å vs. 1.70 Å) due to the decreased steric congestion
in TSb-rs. Therefore, the energy difference between TSb-sr and
TSb-rs is reduced because of the stabilization of TSb-rs. These
results suggest that the steric bulkiness of the azlactone
substituent (Ar) plays
stereochemical outcome.
a crucial role in determining the
Next, in order to acquire detailed insights into the origin of the
energy differences between the transition states,
a
distortion/interaction analysis of TSas was conducted (Figure
7).[23] Each transition structure was divided into catalyst and
substrates moieties as separate fragments, and the degree of
distortion (ΔEdist) was estimated by comparing the energies of
each fragment determined using single-point energy calculations
at the M06-2X/6-31G* level. The interaction energies between the
catalyst and the substrates (Eint) were also compared, and Eint
was calculated as follows:
Figure 5. 3D structures of TSa-sr and TSa-rs. Relative energies of the transition
state in the gas phase are shown in kcal/mol. The t-Bu group of 2a is highlighted
in the red dashed squares. CPK model = 2,4,6-(i-Pr)3C6H2 group of catalyst (R)-
1; wire model = binaphthyl backbone of (R)-1; tube model = substrates 2a and
3
Eint = ETS – (Ecat + Esub),
where ETS, Ecat, and Esub represent the energies of the transition
state, the catalyst, and combined substrates 2a and 3,
respectively. Analysis of the highly enantioselective reaction of 3a
revealed that the interaction energy difference is dominant (ΔEint
= +5.6 kcal/mol) in inducing the relative energy difference
between TSa-sr and TSa-rs, whereas the distortion energies are
less significant (ΔEdist = -0.8 and -1.3 kcal/mol). These results
strongly suggest that favorable interactions are realized due to the
formation of hydrogen bonds and the minimization of steric
repulsions in TSa-sr. On the other hand, analysis of the reaction
of 3b indicated that the interaction energy difference (ΔEint) is
decreased to +4.0 kcal/mol (Figure S6b), which is reflected in the
Substituent Effect of Aryl Group at 2-Position of Azlactone
In our previous studies, the stereochemical outcome of the
aldol-type reaction was found to depend markedly on the
substituent (Ar) at the 2-position of azlactone 3. In fact, the
reaction of 3b (Ar = Ph) with 2a followed by the ring opening of
the azlactone unit afforded 5b (Ar = Ph) with moderate
stereoselectivity (syn:anti = 79:21, 59% ee for syn-5b at room
temperature: see section “Experimental Support” and Table 1 for
a detailed discussion of the experimental results), whereas the
reaction of 3a (Ar = 3,5-(MeO)2C6H3-)[7a] afforded corresponding
5a with high stereoselectivity (syn:anti = 95:5, 95% ee for syn-5a
lower enantioselectivity, whereas the distortion energies (ΔEdist
=
-0.8 and -1.3 kcal/mol) remain unchanged compared to those for
the reaction of 3a. It is confirmed again that the steric bulkiness
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Figure 6. 3D structures of (a) TSa-sr and TSa-rs, which result in syn-5a (Ar = 3,5-(MeO)2C6H3-), and (b) TSb-sr and TSb-rs, which result in syn-5b (Ar = Ph). Steric
repulsions are indicated by red curves. Hydrogen bonds are represented by red dashed lines. N···H and O···H distances are indicated in blue and red, respectively
(angstroms). Bond formation/dissociation is indicated by green solid lines.
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Figure 7. Distortion/interaction analysis for TSa-sr and TSa-rs. Hydrogen bonds are represented by red dashed lines, and bond formation/dissociation is indicated
by green dashed lines. Bond lengths are indicated in red (angstroms).
of the azlactone substituent (Ar) plays a vital role in determining
the stereochemical outcome.
present effect stems from that the binaphthyl backbone of the
catalyst locates in close proximity, particularly in less favorable
TSx-rss (TSx = TSa–TSd), to the Ar substituent introduced at
the 2-position of azlactone, because the catalyst protonates the
nitrogen atom next to the carbon atom substituted by the Ar
substituent. Otherwise, the present substituent effect would not
be expected.
As the steric repulsion between azlactone 3 and the
backbone of catalyst 1 is the dominant factor influencing the
enantioselection, replacement of the Ar group of the azlactone
with another bulky group should maintain the relative energy
difference between the transition states. Indeed, the calculation
for the reaction of azlactone 3c (Ar = 3,5-Me2C6H3-) predicted a
sufficient relative energy difference between corresponding TSc-
sr and TSc-rs (3.3 kcal/mol, Figure S7a), although the value was
slightly lower than that for the reaction of 3a (3.5 kcal/mol,
Figures 5 and 6a). On the other hand, replacement of 3a in the
transition structures with sterically less hindered 3d (Ar = 4-
ClC6H4-) considerably reduced the relative energy difference
between corresponding TSd-sr and TSd-rs, as expected (1.7
kcal/mol, Figure S7b). As mentioned above, the marked
substituent effect was pointed out by the theoretical studies. The
Experimental Support
In order to confirm the model for stereocontrol as proposed
above, the reactions of 2a with 3a–3d were performed using (R)-
1 as the catalyst under the same conditions (room temperature
in dichloromethane).[7a,24] The reaction proceeded in moderate to
good yields in a syn-selective fashion (Table 1). As expected, the
reaction using 3c afforded corresponding product 5c with
relatively high enantiomeric excess (Table 1, entry 3). On the
other hand, the use of 3d dramatically decreased the
enantioselectivity (Table 1, entry 4). The experimentally
observed results were in good agreement with the
computationally predicted stereochemical outcomes, thus
confirming the above proposed model for stereocontrol in the
phosphoric acid-catalysed reaction of azlactones with vinyl
ethers.
Table 1. Enantioselective Direct Aldol-Type Reaction of Vinyl Ether 2a with
Azlactones 3 Catalyzed by (R)-1.[a]
Conclusions
The mechanism for the enantioselective aldol-type reaction
of vinyl ethers with azlactones catalysed by chiral phosphoric
acid was investigated. DFT studies using a simplified chemical
model revealed that the reaction proceeds via a six-membered
cyclic transition state. In the favorable transition state,
phosphoric acid (P-OH) protonates the nitrogen atom of
azlactone, whereas the phosphoryl oxygen (P=O) of the catalyst
interacts with the vinyl proton of vinyl ether. It is noteworthy that
these hydrogen bonds are not involved in the bond
recombination sequence and the catalyst functions as a template
for binding both substrates, azlactone and vinyl ether, of which
relative locations are fixed. Therefore, the present template
effect is beneficial not only for stabilizing the transition structures
but also for controlling the stereochemical outcome. Further
analysis of the realistic chemical model, coupled with
experimental support, clarified that the steric repulsion between
ee [%][c,d]
for syn-5
entry
3
5
Time [h]
Yield
[%][b]
syn:anti[c]
95 (3.5)
59 (1.9)
73 (3.3)
46 (1.7)
1
2
3
4
3a
3b
3c
3d
5a
5b
5c
5d
4
85
69
60
79
95:5
79:21
81:19
75:25
24
24
24
[a] All reactions were performed using 0.01 mmol of (R)-1 (5 mol %), 0.4
mmol of 2a (2.0 equiv), 0.2 mmol of 3, and 100 mg of MS4A in 0.4 mL of
CH2Cl2 at room temperature. [b] Combined yield of syn/anti-5. [c]
Determined by chiral stationary phase HPLC analysis. [d] The relative
energy differences of the transition states, ΔE = ETSx-rs - ETSx-sr (kcal/mol)
(TSx = TSa–TSd), are shown in parentheses.
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the substituent (Ar) of the azlactone and the binaphthyl backbone
of the catalyst is also crucial for the enantioselection. The
present finding, namely, the template effect, is regarded as one
of the key stereocontrolling systems in chiral phosphoric acid
catalysis and hence, expands the scope of enantioselective
reactions catalysed by chiral phosphoric acids and their
derivatives. Further studies on the development of
enantioselective reactions using the present intriguing effect are
in due course in our laboratory.
[7]
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT, Japan (No.
23105002 & 23105005) and a Grant in Aid for Scientific
Research on Innovative Areas “Hybrid Catalysis for Enabling
Molecular Synthesis on Demand” from MEXT, Japan (No.
JP17H06447 & JP18H04660). We also thank the Japan Society
for the Promotion of Sciences for the JSPS Research Fellowship
for Young Scientists (K. K.).
[8]
[9]
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Mosey, J. J. Tepe, Chem. Soc. Rev. 2007, 36, 1432-1440; b) N. M.
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Keywords: Asymmetric Synthesis • Enantioselectivity • DFT •
Organocatalysis • Reaction Mechanism
For 3,5-dimethoxyphenyl substituted azlactones as an efficient
substrate for enantioselective transformations, see; G. Lu, V. B. Birman,
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[2]
For comprehensive reviews on organocatalysts, see; a) Science of
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215-241.
[14] See SI for less stable other tansition structures (Figures S1 and S2).
[15] No transition structure of Path B could be located in the solution phase
even by thorough screening for initial structures and optimization
methods. However, during the course of this investigation, other
transition state TS-B’ was identified in the solution phase, which affords
an acetal product in the reaction of vinyl ether with phosphoric acid
(Figure S2). The relative energy for TS-B’ (ΔE = 8.9 kcal/mol [ΔG = 28.9
kcal/mol]) is higher than that for TS-C (ΔE = 3.5 kcal/mol [ΔG = 25.6
kcal/mol]) but lower than that for TS-A (ΔE = 16.9 kcal/mol [ΔG = 45.0
kcal/mol]). Although the transition structure of the acetal formation
reaction, instead of Path B, was identified in the solution phase, Path C
is the most favorable among the pathways investigated.
[3]
For seminal works of chiral phosphoric acid catalysts, see; a) T.
Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem., Int. Ed. 2004,
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K. Moriyama, T. Maki, K. Ishihara, Angew. Chem. Int. Ed. 2010, 49,
3823-3826; d) M. Terada, K. Kanomata, Synlett 2011, 1255-1258.
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P. H.-Y. Cheong, C. Y. Legault, J. M. Um, N. Çelebi-Ölçüm, K. N. Houk,
Chem. Rev. 2011, 111, 5042-5137.
[4]
[5]
[6]
For a review of computational studies of chiral Brønsted acid catalysis,
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1142-1158.
[16] Single-point energy calculations of the optimized transition states
were conducted at the same level in the solution phase according to
the SCRF method based on CPCM (CH2Cl2). As the result, relative
energies of the transition state were calculated to be: Path A: +18.4
kcal/mol, Path B: +12.1 kcal/mol, Path C: +8.2 kcal/mol. See SI for
details (Figure S1).
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Sci. 2014, 5, 3515-3523; h) M. Terada, T. Komuro, Y. Toda, T.
[17] The effective electron delocalization through attractive non-covalent
interaction between AZ and VE in TS-C was confirmed by NCIPLOT.
See SI for details (Figure S3).
[18] See SI for 1H NMR monitoring in details (Figures S8-S11).
[19] The relative stereochemistry of the product was determined by X-ray
crystrallographic analysis, and the absolute stereochemistry at the C3
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position of the product was determined by modified Mosher’s method.
See Ref. 7a for details.
[23] The distortion/interaction analysis was performed by means of the
counterpoise method. The computational details are shown in SI. For
the original distortion/interaction analysis, see: a) K. Morokuma, K.
Kitaura in Chemical Applications of Atomic and Molecular Electrostatic
Potentials (Eds.: P. Politzer, D. G. Truhlar), Plenum, New York, 1981.
For selected examples using the distortion/interaction analysis, see: b)
D. N. Ess, K. N. Houk, J. Am. Chem. Soc. 2007, 129, 10646-10647; c)
D. H. Ess, K. N. Houk, J. Am. Chem. Soc. 2008, 130, 10187-10198; d)
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R. S. Paton, S. Kim, A. G. Ross, S. J. Danishefsky, K. N. Houk, Angew.
Chem., Int. Ed. 2011, 50, 10366-10368. f) A. G. Green, P. Liu, C. A.
Merlic, K. N. Houk, J. Am. Chem. Soc. 2014, 136, 4575-4583; g) M.
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Nagasawa, J. Am. Chem. Soc. 2015, 137, 1909-1915.
[20] See SI for the structures of TSa-rr and TSa-ss, both of which afford
enantiomers of the anti-isomer (Figure S4).
[21] The geometrical optimization of transition states TSa-sr and TSa-rs
was also conducted at the B3LYP-D/6-31G* level. Single-point energy
calculations of the optimized structures were performed at the same
level with the SCRF method based on CPCM (CH2Cl2). Relative energy
difference in the solution phase was calculated to be 3.2 kcal/mol in
favor of TSa-sr (Figure S5). Similarly, identification of transition states
TSa-sr and TSa-rs using the M06-2X/6-31G* level, followed by single-
point energy calculations of the optimized structures at the same level
with the SCRF method based on CPCM (CH2Cl2), was also conducted.
Relative energy difference in the solution phase was calculated to be
2.4 kcal/mol in favor of TSa-sr (Figure S5).
[22] 3D representations were prepared using CYLview. C. Y. Legault,
[24] Molecular sieves 4A was added to improve the reproducibility of the
reaction outcomes.
CYLview,
1.0b;
Université
de
Sherbrooke,
2009
(http://www.cylview.org).
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Entry for the Table of Contents (Please choose one layout)
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The mechanism of chiral phosphoric
acid-catalyzed aldol-type reaction of
azlactones with vinyl ethers was
investigated. A Conia-ene-type
transition state consisting of the vinyl
ether and the enol tautomer of the
azlactone was identified on the basis
of DFT calculations. Although
Dr. Kyohei Kanomata, Yuki Nagasawa,
Yukihiro Shibata, Prof. Dr. Masahiro
Yamanaka,* Fuyuki Egawa, Dr. Jun
Kikuchi, and Prof. Dr. Masahiro Terada*
Page No. – Page No.
hydrogen bonds are formed between
the catalyst and the substrates, these
are not involved in the bond
recombination sequence and hence
the catalyst functions as a template for
binding the substrates.
Mechanism and Origin of
Stereoselectivity in Chiral Phosphoric
Acid-Catalysed Aldol-Type Reactions
of Azlactones with Vinyl Ethers
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Author(s), Corresponding Author(s)*
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Title
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