Rational Design of 2-Substituted DMAP- N-oxides as Acyl Transfer Catalysts: Dynamic Kinetic Resolution of Azlactones

Article abstract of DOI:10.1021/jacs.0c09075

A novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-N-oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.

Full text of DOI:10.1021/jacs.0c09075

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Article
Rational Design of 2‑Substituted DMAP‑N‑oxides as Acyl Transfer
Catalysts: Dynamic Kinetic Resolution of Azlactones
Ming-Sheng Xie,* Bin Huang, Ning Li, Yin Tian,* Xiao-Xia Wu, Yun Deng, Gui-Rong Qu,
and Hai-Ming Guo*
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ABSTRACT: A novel concept that conversion of chiral 2-
substituted DMAP into its DMAP-N-oxide could significantly
enhance the catalytic activity and still be used as an acyl transfer
catalyst is presented. A new type of chiral 2-substituted DMAP-N-
oxides, derived from L-prolinamides, has been rationally designed,
facilely synthesized, and applied in the dynamic kinetic resolution
of azlactones. Using simple MeOH as the nucleophile, various L-
amino acid derivatives were produced in high yields (up to 98%
yield) and enantioselectivities (up to 96% ee). Furthermore, α-
deuterium labeled L-phenylalanine derivative was also obtained.
Experiments and DFT calculations revealed that in 2-substituted
DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and
the N−H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the
addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical
chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation
results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral
2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.
the conversion of DMAP into DMAP-N-oxide will make the
C2 substituent far from the O-acyl moiety and thus enhance
the activity of the catalyst and the utilization of the C2 position
(Scheme 1b). Meanwhile, challenges can arise due to the
introduction of an additional rotatable O−C bond in the O-
acyl moiety, as well as changing the nucleophilic site from
nitrogen to oxygen (Scheme 1b). However, until now, chiral 2-
substituted DMAP-N-oxide was only developed in the
sulfonylation of 2-substituted indolines and has not been
reported in the enantioselective acyl transfer reaction.11 It must
be emphasized that there is a great difference between
sulfonylation and acylation. In sulfonylation, the nucleophile’s
attack pathway is a SN2 linear trajectory,12 whereas acylation
INTRODUCTION
■
Chiral 4-(dimethylamino)pyridine (DMAP) is recognized as a
classic acyl transfer catalyst in organic synthesis,1 with the
development and generation of diverse DMAP analogues being
an area of tremendous interest (Figure 1).2 The first chiral
DMAP reagent C1 was reported by Vedejs and Chen in 1996
(Figure 1a),3 in which a steering stereocenter was introduced
at the pyridine ring’s C2 position. In this seminal study, the
obvious steric hindrance between the stereocontrol group at
the C2 position and the N-acyl moiety inhibited the catalytic
turnover, and the chiral 2-substituted DMAP reagent C1 must
be employed in stoichiometric amounts, resulting in less
utilization of the C2 position in the further design of chiral
DMAP catalysts as acyl transfer catalysts (Scheme 1a).4−6
Soon afterward, Fu and co-workers developed the 2,3-
disubstituted ferrocene-fused planar chiral DMAP catalyst C2
(Figure 1a) and demonstrated their application in a broad
array of reactions with impressive levels of stereocontrol.4
Since the pioneering studies of Vedejs and Fu, the C3 and C4
positions, which are adequately distant from the nucleophilic
site, have been extensively studied, producing diverse 3-
substituted chiral DMAP,7 4-substituted chiral DMAP,8 and
multiple positions-substituted DMAP (Figure 1b−d).9
follows a Bu
̈
rgi−Dunitz trajectory (Scheme 1c).13 Herein, we
will introduce an L-prolinamide at the C2 position of the
pyridine ring to design a chiral 2-substituted DMAP-N-oxide,
and we hope to achieve asymmetric acylation with the
assistance of the H-bond interaction (Scheme 1c).
Received: August 24, 2020
To reduce or even avoid the steric hindrance influence of the
C2 substituent toward catalytic activity,10 we envisaged that
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Figure 1. Selected chiral DMAP catalysts and their classification via different positions of the chiral group attached to the pyridine ring.
Scheme 1. Design of Chiral 2-Substituted DMAP-N-oxides as Acyl Transfer Catalysts
Figure 2. Chiral acyl transfer catalysts previously used in the DKR of azlactones.
The dynamic kinetic resolution (DKR) of azlactones by
alcoholysis is an attractive method of generating enantioen-
riched protected α-amino acid derivatives.14,15 In addition to
alkaloid,22 benzotetramisole,23 phosphoric acid,24 tetrapep-
tide,25 and 1,3-ketoenol.26 Among these organocatalysts, chiral
acyl transfer catalysts are of particular interest because the first
organocatalyst used in DKR of azlactones was a chiral DMAP
(Figure 2).18 In 1998, Fu’s group pioneered the chiral
organocatalytic DKR of azlactones by alcoholysis, by employ-
ing a planar-chiral DMAP derivative C2a.18 Excellent yields
hydrolytic enzymes16 and transition metal complexes,17
a
variety of organocatalysts have been developed for this
transformation, including chiral DMAP,18,5a,19 diketopipera-
zine,20 (thio)urea-based bifunctional catalysts,21 cinchona
B
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a
and moderate enantioselectivities (44−61% ee) were obtained
Table 1. Optimization of the Reaction Conditions
using MeOH as the nucleophile, while higher enantioselectiv-
i
ity (78% ee) was afforded by employing the bulky PrOH
nucleophile, albeit with low reactivity. In 2005, Johannsen’s
group developed ferrocene-based planar chiral DMAP
analogues C16 and C17 and found that 3-substituted DMAP
C16 produced the alcoholysis product in moderate enantio-
selectivities (21−42% ee), while 2-substituted DMAP catalyst
C17 was unreactive.5a In 2010, Birman’s group reported the
benzotetramisole C18 catalyzed highly enantioselective DKR
of azlactones, in which bulky di(1-naphthyl)methanol was
required.23a In 2018, Mandai and Suga’s group described a
highly efficient asymmetric DKR of azlactones using
binaphthyl-based DMAP derivative C19 as the catalyst, in
which bulky iPrOH was employed as the nucleophile.19 On the
basis of the aforementioned reports, it can be determined that
bulky alcohols are often required as nucleophiles to achieve
high enantioselectivities of alcoholysis products in the presence
of chiral acyl transfer catalysts. Therefore, the development of a
chiral acyl transfer catalyst to achieve excellent enantioselectiv-
ities of alcoholysis products, using simple MeOH as the
nucleophile, is desirable. Herein, we described the DKR of
azlactones with MeOH as the nucleophile using chiral 2-
substituted DMAP-N-oxides as the acyl transfer catalysts.27−29
b
c
entry catalyst
x
solvent
y
t (h) yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C23a
C23b
C23c
C23d
C23e
C23f
C23g
C23c
C23c
C23c
C23c
C23c
C23c
C23c
C23c
C23c
C23c
C23c
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CHCl3
EtOAc
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
10
10
10
10
10
10
10
10
10
10
20
1
4
4
4
4
4
4
4
4
4
4
4
3
6
17
8
30
58
24
98
98
98
98
98
98
98
34
97
96
96
98
98
97
98
98
98
98
74
90
92
87
90
70
91
90
92
91
90
90
93
92
93
91
90
94
RESULTS AND DISCUSSION
■
Catalyst Synthesis. Chiral 2-substituted DMAP-N-oxides
C23 were synthesized from 2-chloro-4-nitropyridine N-oxide
and L-prolinamides through 2−3 steps as depicted in Scheme
2. The structure and absolute configuration of chiral 2-
substituted DMAP-N-oxide C23c were determined via single-
crystal X-ray diffraction analysis.
Scheme 2. Synthetic Routes for 2-Substituted DMAP-N-
oxides
0
1
1
1
1
0.5
5
17
d
18
1
a
Unless otherwise noted, the reaction conditions are as follows: 1a
(14.1 mg, 0.05 mmol), 2a (6.1 μL, 3.0 equiv), catalyst (x mol %), and
PhCOOH (y mol %) in solvent (1.0 mL) at room temperature.
b
c
d
Isolated yield. Determined by chiral HPLC analysis. CH2Cl2 (2.0
mL).
When catalyst C23g was employed, product 3aa was produced
in 98% yield and 91% ee (Table 1, entry 7), showing that
changing the pyrrolidinyl group to the dimethylamino group
had no significant influence on the reactivity and selectivity
(Table 1, entries 7 vs 3). Variation of the solvent did not lead
to improved results (Table 1, entries 3, 8−11). Increasing the
amount of benzoic acid from 10 to 20 mol % only slightly
accelerated the reaction but decreased the enantioselectivity
(Table 1, entries 12 vs 3). However, decreasing benzoic acid to
1 mol % gave ester 3aa in 98% yield and 93% ee, albeit with
slightly prolonged reaction time (Table 1, entries 13 vs 3). In
the absence of benzoic acid, the enantioselectivity was
maintained and 97% yield was obtained, while the reaction
rate decreased and a prolonged time of 17 h was needed
(Table 1, entries 14 vs 3). Therefore, the obtained results
Optimization Study. Initially, the DKR reaction of benzyl-
substituted azlactone 1a with MeOH 2a was selected as the
model reaction (Table 1). When catalyst C23a was employed
in CH2Cl2 at room temperature for 4 h with PhCOOH as the
additive,18,23a,b,24 the desired ester 3aa was afforded in 98%
yield and 74% ee (Table 1, entry 1). Several other 2-
substituted DMAP-N-oxides C23b−C23f of varying steric
hindrance and electronic effects were evaluated (Table 1,
entries 2−6). Catalyst C23c, bearing two bulky isopropyl
groups at aniline’s ortho positions, gave the product 3aa with
enhanced enantioselectivity as 92% ee (Table 1, entry 3).
C
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a
Table 2. Substrate Scope of Azlactones
a
Unless otherwise noted, the reaction conditions are as follows: 1 (0.05 mmol), 2a (3.0 equiv), C23c (5 mol %), and PhCOOH (1 mol %) in
b
c
d
e
CH2Cl2 (2.0 mL) at room temperature. Isolated yield. Determined by chiral HPLC analysis. C23c (10 mol %), PhCOOH (10 mol %). C23c
(1 mol %).
implied that the main role of benzoic acid was to accelerate the
reaction (Table 1, entries 3 and 12−14). Screening of the
catalytic loading demonstrated that 5 mol % of C23c was
optimal; however, even 0.5 mol % of C23c still afforded
product 3aa in 98% yield and 90% ee but over prolonged time
(Table 1, entries 13 and 15−17). Further evaluation of the
concentration indicated that 2.0 mL of CH2Cl2 gave an
improved result with 94% ee (Table 1, entry 18).
Scope of the Reaction. Under optimized reaction
conditions (Table 1, entry 18), the substrate scope of
azlactones was explored (Table 2). The DKR of several
C(4)-primary alkyl-substituted azlactones 1b−f afforded α-
amino acid derivatives 3ba−3fa in 91−97% yields and 91−
95% ee (Table 2, entries 2−6). In the case of azlactone 1g
bearing an α-branched alkyl group (iPr), a known challenging
substrate for reported chiral acyl transfer catalysts,19,23a,24 the
corresponding L-valine methyl ester 3ga was obtained in 84%
yield and 91% ee (Table 2, entry 7). Next, methionine-derived
azlactone 1h and α-arylalanine-derived azlactones 1i−l were
evaluated, and they generated protected α-amino acid
derivatives 3ha−3la in 95−98% yields and 92−94% ee
(Table 2, entries 8−12). In the case of N-Me tryptophan-
derived azlactone 1m or tryptophan-derived azlactone 1n
bearing a free N−H bond, the DKR reaction proceeded well
(Table 2, entries 13 and 14). C(4)-Phenyl-substituted
azlactone 1o produced good enantioselectivity for the L-
phenylglycine derivative 3oa, but an increase in catalytic
loading was required (Table 2, entry 15). Variation of C(2)-
aryl-substituted azlactones 1p−u gave the desired protected α-
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amino acid derivatives 3pa−3ua in 88−98% yields and 87−
96% ee (Table 2, entries 16−21).
lective synthesis of α-deuterium labeled L-phenylalanine
derivative was carried out as a representative. By utilizing
low-cost, commercially available CH3OD as the reactant, the
DKR reaction of azlactone 1a afforded the desired α-deuterium
derivative 3aa-d1 in 98% yield, 90% ee, and a 93:7 D/H ratio
(Scheme 3b). On the other hand, this deuterium labeling
experiment also proved that azlactone 1a could be racemized
rapidly. It should be noted that the H/D exchange in the
PhCOOH/CH3OD mixture will lead to the H/D exchange in
unreacted azlactone 1a, but this effect could be ignored when
only 1 mol % PhCOOH was employed (see Table S5 for
details).
Subsequently, the substrate scope of alcohols was explored
(Table 3). When straight chain alcohols 2b−e were employed,
a
Table 3. Substrate Scope of Alcohols
b
c
entry
R5
2
3
t (h) yield (%)
ee (%)
1
2
3
Me
Et
Et
nPr
nBu
nPent
iPr
2a
2b
2b
2c
2d
2e
2f
3aa
3ab
3ab
3ac
3ad
3ae
3af
24
48
24
48
48
48
72
48
98
95
97
92
94
96
94
84
94
94
94
95
93
93
94
90
Mechanistic Studies. To gain insight into the reaction’s
mechanism catalyzed by chiral 2-substituted DMAP-N-oxides,
several control experiments were conducted (Figure 3). When
2-substituted DMAP C24c, the reduced product of DMAP-N-
oxide C23c, was employed, product 3aa was obtained in only
9% yield and 80% ee. Through this comparative experiment, it
could be concluded that (i) the proximity of the chiral L-
prolinamide moiety on catalyst C24c was too close to the
nucleophilic site, which had a dramatic influence on reaction
reactivity but only slightly altered the enantioselectivity; and
(ii) the N-oxide group was vital to the chiral induction for
chiral 2-substituted DMAP-N-oxide C23c. Evaluation of
DMAP-N-oxide C23h, the N-Me derivative of C23a, revealed
that product 3aa was obtained in its racemic form (0% ee) and
in lower yield, and this indicated that the N−H proton on the
amide framework was important for reactivity and enantiose-
lectivity. Insertion of the CO double bond between the
pyridine ring and L-prolinamide moiety generated catalyst
C25c, which produced product 3aa in only 5% yield and 10%
ee. Therefore, catalysts C23c and C25c were compared
carefully. In terms of structure, C23c had a donor substituent
at the C2 position, while C25c had an acceptor substituent at
the C2 position. Through natural bond orbital (NBO) theory
analysis, the natural atomic charge (Q) on the oxygen atom in
N-oxide groups of C23c and C25c was −0.722 and −0.692,
respectively (see Scheme S6 for detail). Thus, the oxygen atom
of the N-oxide group in C23c exhibited more negative charge
than that in C25c, and this resulted in a stronger
nucleophilicity and catalytic activity of catalyst C23c. On the
other hand, in C25c, the distance between the L-prolinamide
moiety and the pyridine ring became longer than that in C23c,
which might affect the catalyst configuration and the H-
bonding interaction, thus having an adverse effect on the
reaction selectivity. When 3-substituted DMAP-N-oxide C26c
was used,28g product 3aa was generated in 36% yield and
−15% ee. It was speculated that the L-prolinamide moiety in
C26c was relatively far from the nucleophilic site, which
impeded H-bond formation with the substrate and only
exhibited a steric hindrance effect.
d
4
5
6
e
7
8
1-NpCH2CH2
2g
3ag
a
Unless otherwise noted, the reaction conditions are as follows: 1a
(0.05 mmol), 2 (3.0 equiv), C23c (5 mol %), and PhCOOH (1 mol
b
%) in CH2Cl2 (2.0 mL) at room temperature. Isolated yield.
c
d
e
Determined by chiral HPLC analysis. 2b (5 equiv). C23c (10 mol
%).
the enantioselectivities of the alcoholysis products 3ab−3ae
were 93−95% ee (Table 3, entries 2−6). However, the
reaction rates of these alcohols were slow as compared to that
of MeOH (Table 3, entries 2, 4−6 vs 1). In the case of ethanol,
the DKR reaction activity was enhanced by increasing the
amount of ethanol, while maintaining enantioselectivity (Table
i
3, entries 2 and 3). When bulky PrOH was used, the
enantioselectivity of ester 3af was maintained, but the rate of
reactivity significantly decreased (Table 3, entries 7 vs 1).
Upon using 1-naphthylethanol 2g as the nucleophile, the
enantioselectivity of product 3ag decreased slightly (Table 3,
entries 8 vs 1).
Scale-Up Reaction and Application. To further evaluate
the synthetic utility of the current methodology, gram-scale
synthesis of L-phenylalanine derivative 3aa was performed
(Scheme 3a). Using 1 mol % of catalyst C23c, 4 mmol of
azlactone 1a reacted smoothly with methanol 2a and generated
1.16 g (93% yield) of the desired L-phenylalanine derivative
3aa with 93% ee. After recrystallization, the corresponding 3aa
was obtained as a pure enantiomer (77% yield, 99% ee).
Considering that α-deuterated amino acids are widely used in
mechanistic studies of bioorganic chemistry,22b the enantiose-
Scheme 3. (a) Gram-Scale Synthesis of L-Phenylalanine
Derivative 3aa; and (b) Synthesis of α-Deuterium Labeled
L-Phenylalanine Derivative 3aa-d1
To further probe the mechanism of the reaction, the kinetic
order of each reaction component was determined through
studying initial rates of the reaction (Figure 4). The rate
showed approximately first-order dependence on the concen-
tration of MeOH 2a (Figure 4, top), which indicated that the
alcohol is involved in the rate-determining step and the
nucleophilic attack of alcohol might be the rate-determining
step of the reaction. For catalyst C23c, the rate also showed
approximately first-order dependence on the concentration of
catalyst C23c (Figure 4, top). Meanwhile, azlactone 1a and
PhCOOH exhibited approximately first-order rate dependence
but with saturation at higher concentration (Figure 4, bottom).
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Figure 3. Control experiments.
Figure 4. Kinetic order of each reaction component.
It should be noted that no background reaction occurred in the
absence of catalyst C23c, MeOH 2a, or azlactone 1a. These
kinetic studies suggested that a four-component transition state
including MeOH 2a, catalyst C23c, azlactone 1a, and
PhCOOH might be involved in the rate-determining step of
the reaction. After that, HRMS experiments were carried out to
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Figure 5. Relative energy profiles (in kcal/mol) of nucleophilic addition along the Si face of the azlactone ring plane obtained via the M08-HX/6-
311G(d,p)/CPCM(DCM) method.
shed light on the mechanism of the reaction. In the mixture of
C23c, azlactone 1a, and PhCOOH, a peak at m/z 718.3930
was found, which corresponded to the intermediate [C23c+1a
+H+]+, and confirmed the generation of O-acylated inter-
mediate from catalyst C23c and azlactone 1a (see Figure S11
for details). Afterward, in the reaction mixture of C23c,
azlactone 1a, MeOH 2a, and PhCOOH, an ion at m/z
559.3276 was probed, which might correspond to the
intermediate [C23c+PhCOOH+H+]+, and suggested that
there might be a weak interaction between catalyst C23c and
PhCOOH (see Figure S12 for details). Furthermore, in the
reaction mixture of C23c, azlactone 1g, MeOH, and
PhCOOH, an ion at m/z 824.4600 was observed, which
might correspond to the intermediate [C23c+1g+MeOH
+PhCOOH+H+]+, and suggested a four-component transition
state might be involved in the reaction (see Figure S13 for
details). Subsequently, the relationship between the enantio-
selectivity of the catalyst C23c and the product 3aa was
studied (see Figure S14 for details). There was no nonlinear
effect in this catalytic reaction, which indicated that only one
chiral catalyst might be involved in the rate-determining step of
the reaction.
was utilized to explore and analyze the reaction process. As
described in Figure 5, the mechanism consists of a two-step
process: ring-opening and nucleophilic addition. In step 1, the
reaction starts from the free catalyst C23c and substrate (S)-
1a, followed by the hydrogen-bonded reactant complex (RC)
formed between catalyst C23c and MeOH, and then the
nucleophilic oxygen in the N-oxide group of catalyst C23c
attacks the electrophilic carbonyl carbon of azlactone (S)-1a
from the Si face of the azlactone ring plane. Simultaneously,
the C−O ester single bond of azlactone (S)-1a is broken. In
intermediate IM1, the oxygen anion generated from ring-
opened azlactone is trapped through the H-bond from MeOH
and N−H in the amide framework.
In step 2, in the absence of PhCOOH, relatively stable
intermediate IM2 is formed, in which a less crowded 15-
membered ring H-bond emerges with the release of 2.5 kcal/
mol from IM1. The nucleophilic MeOH molecule, activated by
the N−H bond in the amide framework, then attacks the
carbonyl carbon and allows its labile proton to transfer into the
oxygen anion in the ring-opened azlactone. Simultaneously, the
C−O bond between the carbonyl carbon of the azlactone (S)-
1a and nucleophilic oxygen of catalyst C23c is broken. As
shown in Figure 5, the DFT calculation indicates that the
relative free energy of TS1 (15.4 kcal/mol) is lower than that
of TS2 (19.1 kcal/mol), which suggests that the latter is the
In light of the above experimental findings, to further
elaborate on the nucleophilic addition mechanism and the
origins of stereoselectivity, density functional theory (DFT)
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Figure 6. Optimized structures (bond lengths, Å) and relative free energies (ΔG, kcal/mol) of the enantio-determining transition state along two
attack pathways obtained by the M08-HX/6-311G(d,p)/CPCM(DCM) method. The C23c catalyst was optimized on the basis of the single-crystal
structure, and the crystal conformation of C23c was utilized to explore the catalyzed reaction pathway.
rate-determining step. Finally, the product complex (PC)
releases catalyst C23c and tautomer (S)-3aa-i, which under-
goes exothermic isomerization to generate the corresponding
(S)-3aa with 14.3 kcal/mol. The isomerization mechanism is
described in Scheme S3.
In the presence of PhCOOH (Figure 5), more stable
intermediate IM2-A is formed with the release of up to 12.3
kcal/mol from IM1, in which the PhCOOH participates in the
formation of the H-bond. The relative free energy of the
resulting IM2-A is 9.8 kcal/mol lower than that of IM2, which
can be attributed to the large H-bond bridge contributed by
PhCOOH. In the following nucleophilic substitution step
through TS2-A, due to the high acidity of PhCOOH, which
serves as a bridge to aid hydrogen transfer, the MeOH is
activated by PhCOOH, and the oxygen anion in ring-opened
azlactone also generates a H-bond with PhCOOH. The energy
barrier of this step is 14.3 kcal/mol, which is lower than that of
TS2 and shows that the addition of PhCOOH reduces the
reaction energy barrier, thus accelerating the reaction rate.
Product complex PC-A then is produced and releases the
PhCOOH to give catalyst C23c and tautomer (S)-3aa-i.
When the attack direction of catalyst C23c to reactant (S)-
1a is reversed, as shown in Scheme S4, catalyst C23c attacks
reactant (S)-1a from the Re face of the azlactone ring plane via
transition state TS1. In the following TS2 or TS2-A, whether
PhCOOH is added or not, the energy barriers of the step are
higher than 24 kcal/mol. Therefore, when the attack direction
of the chiral catalyst to reactant is reversed, the energy profiles
might be different, which can be due to the asymmetry of
chiral catalyst C23c and the whole transition state.30
To understand the origin of enantioselectivity, the geometry
information on transition states in the rate-determining step
leading to final product (S)-3aa and its enantiomer was
carefully explored and displayed in Figure 6. In the absence of
H
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Figure 7. Proposed DKR mechanism.
PhCOOH, as shown in Figure 6a and b, the relative free
energy of (Si,S)-TS2 (ΔG = 19.1 kcal/mol, leading to product
(S)-3aa) is 1.6 kcal/mol (ΔΔG⧧) lower than that of (Si,R)-
TS2 (ΔG = 20.7 kcal/mol, leading to product (R)-3aa), which
corresponds to the dominant (S)-configuration alcoholysis
product. In transition state (Si,R)-TS2, enhancement of the
energy barrier is mainly due to the significant steric repulsion
between the Me group in MeOH and the Bn group in ring-
opened azlactone.
When catalyst C23c attacks azlactone 1a from the Re face of
the azlactone ring plane (Figure 6c and d), (Re,R)-TS2
(leading to product (R)-3aa) is energetically more favored
than (Re,S)-TS2, which corresponds to the predominance of
the (R)-configuration alcoholysis product. It should be noted
that the relative free energies of transition states (Re,S)-TS2
and (Re,R)-TS2 are higher than those of (Si,S)-TS2 and
(Si,R)-TS2, leading to that the attack pathway from the Re face
of the azlactone ring plane is not the dominant. In the presence
of PhCOOH, as shown in Figure 6e and f, the transition state
(Si,S)/PhCOOH-TS2, which leads to product (S)-3aa, is
energetically more favored than (Si,R)/PhCOOH-TS2 by 3.8
kcal/mol. As mentioned above, when the catalyst attacks the
azlactone from the Re face of the azlactone ring plane (Figure
6g and h), the relative free energies of (Re,S)/PhCOOH-TS2
and (Re,R)/PhCOOH-TS2 are higher than those of (Si,S)/
PhCOOH-TS2 and (Si,R)/PhCOOH-TS2, which indicate that
the Si face attack is favorable. Therefore, only when the attack
directions of the chiral catalyst are fully considered can the
correct calculation results be obtained.
lowest, which corresponds to the major enantiomer and key
enantio-determining step.
Furthermore, other possible transition states are also
proposed and calculated in Scheme S5. In the transition
state (Si,S)-TS, as shown in Scheme S5a, the CO double
bond in O-acylated pyridinium cation is locked by the N−H in
the amide framework through the H-bond. The H atom in OH
group of MeOH is activated by the oxygen anion in ring-
opened azlactone. The energy barrier for this transition state is
21.9 kcal/mol, which is higher than that mentioned in Figure
6a. Similarly, the attack direction of the chiral catalyst and
steric repulsion factors can also affect the energy barrier of
these transition states (Scheme S5b−d).
On the basis of the experiments and DFT calculations, a
possible DKR mechanism was proposed in Figure 7. First,
azlactone 1a could be racemized rapidly due to their
configurational lability.31 For azlactone (S)-1a, in the presence
of catalyst C23c and PhCOOH, the alcoholysis of MeOH
underwent a four-component transition state with a low
relative free energy of 14.3 kcal/mol. The ring-opened
tautomer (S)-3aa-i then was produced, which underwent
exothermic isomerization to generate the corresponding (S)-
3aa. For azlactone (R)-1a, due to the significant steric
repulsion between the Me group in MeOH and the Bn
group in the ring-opened azlactone, the corresponding
transition state exhibited a higher relative free energy with
18.1 kcal/mol. As a result, the rate of alcoholysis step became
slow and (R)-3aa was a minor enantiomer. Finally, most (R)-
1a converted into (S)-1a through in situ racemization and
participated in the alcoholysis step, and this made (S)-3aa a
major enantiomer.
More delicately, as shown in Figure 6i, for the chiral catalyst
to interact with the reactant through the Si face and Re face,
the reverse attack direction and asymmetry of chiral catalyst
directly lead to differences in the chemical microenvironment
between transition state Si-TS2 and Re-TS2. More importantly,
the relative free energy of transition state (Si,S)-TS2 is the
In conclusion, we present a novel concept in that conversion
of chiral 2-substituted DMAP into its DMAP-N-oxide could
significantly enhance the catalytic activity and still be used as
an acyl transfer catalyst. A new type of chiral 2-substituted
DMAP-N-oxides has been rationally designed, facilely
I
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synthesized, and applied as acyl transfer catalysts in the DKR
of azlactones with MeOH. Using simple MeOH as the
nucleophile, a variety of L-protected amino acid derivatives
were obtained in 88−98% yields and 87−96% ee. Other
alcohols were also suitable nucleophiles. In the presence of 1
mol % of catalyst loading, the DKR reaction was performed on
the gram-scale with excellent results. The mechanism experi-
ments and DFT calculations revealed that in 2-substituted
DMAP-N-oxide C23c, the oxygen atom was the nucleophilic
site and the N−H bond in L-prolinamide moiety was the H-
bond donor. The high enantioselectivity of the reaction is
governed by steric factors, and the addition of benzoic acid
reduces the activation energy by participating in the
construction of the H-bond bridge. The theoretical calculation
study shows that only when the attack directions of chiral
catalyst are fully considered can the correct calculation results
be obtained. This work will open the door for the utilization of
the C2 position of the pyridine ring and the development of
chiral 2-substituted DMAP-N-oxides as efficient acyl transfer
organocatalysts.
Ning Li − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Xiao-Xia Wu − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Yun Deng − School of Pharmacy, Chengdu University of
Traditional Chinese Medicine, Chengdu 611137, China
Gui-Rong Qu − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09075.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09075
Experimental procedures, catalyst synthesis and charac-
terization, mechanism experiments, computational data,
and copies of NMR and HPLC spectra (PDF)
Notes
The authors declare no competing financial interest.
Crystallographic data for 1a (CIF)
Crystallographic data for C22c (CIF)
Crystallographic data for C23c (CIF)
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC (Nos.
U1604283, 21778014, and 21971056), the Natural Science
Foundation of Henan Province (202300410224), the Program
for Science & Technology Innovation Talents in Universities
of Henan Province (19HASTIT036), and the 111 Project (no.
D17007).
AUTHOR INFORMATION
Corresponding Authors
■
Ming-Sheng Xie − Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China; orcid.org/0000-0003-4113-2168;
Email: xiemingsheng@htu.edu.cn
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Authors
Bin Huang − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
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