Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates and Trifluoromethyl Ketones by Carbonyl Catalysis

Article abstract of DOI:10.1002/anie.202104031

The direct asymmetric aldol reaction of glycinates represents an intriguing and straightforward strategy to make biologically significant chiral β-hydroxy-α-amino-acid derivatives. But it is not easy to realize the transformation due to the disruption of the reactive NH₂ group of glycinates. Inspired by the enzymatic aldol reaction of glycine, we successfully developed an asymmetric aldol reaction of glycinate 5 and trifluoromethyl ketones 4 with 0.1–0.0033 mol % of chiral N-methyl pyridoxal 7 a as the catalyst, producing chiral β-trifluoromethyl-β-hydroxy-α-amino-acid esters 6 in 55–82 % yields (for the syn-diastereomers) with up to >20:1 dr and 99 % ee under very mild conditions. The reaction proceeds via a catalytic cycle similar to the enzymatic aldol reaction of glycine. Pyridoxal catalyst 7 a activates both reactants at the same time and brings them together in a specific spatial orientation, accounting for the high efficiency as well as excellent diastereo- and enantioselectivities.

Full text of DOI:10.1002/anie.202104031

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Accepted Article
Title: A Highly Efficient Asymmetric Biomimetic Aldol Reaction of
Glycinates and Trifluoromethyl Ketones via Carbonyl Catalysis
Authors: Aolin Cheng, Liangliang Zhang, Qinghai Zhou, Tao Liu,
Jing Cao, Guoqing Zhao, Kun Zhang, Guanshui Song, and
Baoguo Zhao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104031
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10.1002/anie.202104031
Angewandte Chemie International Edition
COMMUNICATION
Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates
and Trifluoromethyl Ketones by Carbonyl Catalysis
Aolin Cheng,† Liangliang Zhang,† Qinghai Zhou,† Tao Liu, Jing Cao, Guoqing Zhao,* Kun Zhang,
Guanshui Song, and Baoguo Zhao*
[a]
The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry, Ministry of Education, and
Shanghai Key Laboratory of Rare Earth Functional Materials, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234,
China. E-mail: gqzhao@shnu.edu.cn; zhaobg2006@shnu.edu.cn
[†]
A. Cheng, L. Zhang and Q. Zhou contributed equally
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Abstract: Direct asymmetric aldol reaction of glycinates represents
an intriguing and straightforward strategy to make biologically
significant
chiral
β-hydroxy-α-amino
acid derivatives. But it is not easy to realize the transformation due to
the disruption of the reactive NH2 group of glycinates. Inspired by
enzymatic aldol reaction of glycine, we successfully developed
asymmetric aldol reaction of glycinate 5 and trifluoromethyl ketones 4
with 0.1-0.0033 mol% of chiral N-methyl pyridoxal 7a as the catalyst,
producing chiral β-trifluoromethyl-β-hydroxy-α-amino acid esters 6 in
55-82% yields (for the syn-diastereomers) with up to >20:1 dr and
99% ee under very mild conditions. The reaction proceeds via a
catalytic cycle similar to the enzymatic aldol reaction of glycine.
Pyridoxal catalyst 7a activates both of the reactants at the same time
and brings them together in a specific spatial orientation, accounting
for the high efficiency, excellent diastereo- and enantioselectivities.
Optically active β-hydroxy-α-amino acids have emerged as an
important structural motif that can be found in numerous bioactive
molecules such as Parkinson drug L-threo-DOPS[1a] and drug
candidate
(2R,3S)-2-amino-3-hydroxy-3-(pyridin-4-yl)-1-
(pyrrolidin-1-yl)propan-1-one[1b,c] (Figure 1).[1,2] Direct asymmetric
aldol condensation of glycinates with aldehydes or ketones may
provide a straightforward and highly attractive method to
construct chiral β-hydroxy-α-amino acid derivatives (Scheme 1a).
However, the reaction often suffers from the disruption of the NH2
group due to its nucleophilicity and N-H acidity. Thus, in order to
avoid the disruption, protecting group strategy has been
extensively applied for the transformation.[3] The studies include
stoichiometric chiral pyridoxal-promoted biomimetic aldol reaction
of glycine contributed by Kuzahara and Breslow (Scheme 1b),[4]
asymmetric aldol reaction of glycine Schiff base-metal complexes
developed by Belokon and Soloshonok (Scheme 1c),[5] and
asymmetric aldol reaction of protected glycine derivatives
reported by Hayashi, Miller, Maruoka, Dixon, Trost, and others
(Scheme 1d).[6-9] Without protecting group
Scheme 1. Asymmetric aldol reaction to synthesize chiral β-hydroxy-α-amino
acid compounds.
Figure 1. Bioactive β-hydroxy-α-amino acids and derivatives.
1
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10.1002/anie.202104031
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manipulation toward the reactive NH2 group, pyridoxal-dependent
aldolases such as threonine aldolases[10] can promote the
asymmetric aldol reaction of glycine to produce chiral β-hydroxy-
α-amino acids directly.[11] However, for nonenzymatic systems,
direct asymmetric aldol reaction of glycinates still remains a
challenge in organic chemistry.
bonds formed between the phosphinyl O and the imino N of the
imine with the side chain of the chiral pyridoxal catalyst,13 which
orients the imine substrate in a specific spatial arrangement and
thus results in the excellent diastereoselectivity. For the current
aldol reaction, although the trifluoromethyl ketone can also be
activated through a hydrogen bond formed between its carbonyl
O and the side chain of the pyridoxal catalyst, the ketone still can
rotate around the hydrogen bond, leading to a low level of
diastereocontrol. Fortunately and to our surprise, introducing a
catalytic amount of Brønsted acid additive can greatly improve the
diastereoselevity for the reaction with 0.1-0.0033 mol% of N-
methyl chiral pyridoxal[17] 7a as the catalyst, producing various
chiral β-trifluoromethyl-β-hydroxy-α-amino acid esters 6 with
excellent enantiopurities in one step (Scheme 1f). As compared
to similar enzymatic transformations,[18] the reaction displayed
comparable or even higher stereoselectivity (up to > 20:1 dr and
99% ee) and activity (as low as 0.0033 mol% catalyst
loading).[19,20]
Mimicking the enzymatic process, carbonyl catalysis
strategy[12,13] may provide an opportunity to develop chemically
catalyzed direct asymmetric aldol reaction of glycinates.[13-16] By
using chiral pyridoxals as catalysts, we have successfully
developed asymmetric biomimetic Mannich reaction[13] and -C
Michael addition[14] of glycinate, respectively affording chiral α,β-
diamino acid esters and pyroglutamic acid esters with excellent
enantiopurities (Scheme 1e). Herein, we reported the first
catalytic asymmetric aldol reaction of glycinate with
trifluoromethyl ketones (Scheme 1f). In the previously developed
asymmetric Mannich reaction (Scheme 1e), the N-
diphenylphosphinyl imine was activated through double hydrogen
The studies commenced with the reaction of tert-butyl
glycinate 5 with trifluoromethyl ketone 4a in the presence of 0.5
mol % N-methyl chiral pyridoxal (S)-7a as the catalyst (Table 1,
entry 1). The desired aldol products 6a were obtained as a pair
of diastereomers (4:1 syn/anti) in 68% yield with 96% ee for syn-
6a. The structures and absolute configurations for syn-6a and
anti-6a were respectively determined based on X-ray analysis
(Figure 2).[21] The pyridoxal catalyst is crucial for the reaction. No
desired products were observed without catalyst 7a (Table 1,
entry 2). An acid additive such as AcOH resulted in an improved
yield (85% vs. 68%) and an increased diastereoselectivity (7:1 dr)
(Table 1, entry 3). Further screening showed that up to 80% yield
of the diastereomer syn-6a, 9:1 dr, and 98% ee were obtained
when 0.2 equivalent of Tf2NH was used (Table 1, entry 10 vs. 3-
9). Dichloromethane (DCM) was the choice of solvent (Table 1,
entry 11 vs. 3 and 12-15) and catalyst 7a gave the best
performance among the pyridoxals 7a-f examined (Table 1, entry
11 vs. 16-20). To our surprise, the reaction can also proceed
smoothly without losing efficiency and selectivity when lowering
the catalyst loading to 0.1 mol% (Table 1, entry 21 vs. 10).
Table 1. Optimization of the reaction conditions[a]
entry
1
catalyst
(S)-7a
none
additive
-
solvent yield (%) syn/anti ee (%)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
DCM
DCM
dioxane
DMF
MeCN
THF
68
0
4:1
-
96
-
2
-
3
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S,R)-7b
(R,S)-7c
(R,S)-7d
(R,S)-7e
(S,S)-7f
(S)-7a
AcOH
PhCO2H
PhOH
CF3CO2H
TfOH
TsOH
Tf2NH
Tf2NH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Tf2NH
85
87
68
73
42
67
50[b]
80[b]
88
39
55
63
58
56
64
93
41
95
80[b]
7:1
7:1
4:1
7:1
7:1
9:1
9:1
9:1
7:1
6:1
3:1
3:1
6:1
5:1
4:1
5:1
4:1
5:1
9:1
96
92
93
96
95
96
97
98
96
93
71
92
96
98
-97
-96
-97
92
98
4
5
6
7
8
9
10[c]
11
12
13
14
15
16
17
18
19
20
21[d]
DCM
DCM
DCM
DCM
DCM
DCM
Figure 2. X-ray structures of syn-6a and anti-6a-S
[a] All reactions were carried out with 4a (0.20 mmol), 5 (0.30 mmol), catalyst
(0.0010 mmol, 0.5 mol%), and additive (0.10 mmol) in solvent (1.0 mL) at -10
oC for 24 h unless otherwise stated. Isolated yields of 6a were based on 4a. The
dr (syn:anti) values were determined by 1H NMR analysis of the crude reaction
mixture. The ee values of syn-6a were determined by chiral HPLC analysis. The
absolute configurations of syn-6a and anti-6a were respectively determined as
(2S,3R) and (2S,3S) based on X-ray analysis. [b] Isolated yield of syn-6a based
on 4a. [c] Tf2NH (0.040 mmol). [d] 4a (1.0 mmol), 5 (1.5 mmol), 7a (0.0010
mmol, 0.10 mol%), and Tf2NH (0.20 mmol) in DCM (4.0 mL) at -10 oC for 48 h.
Under the optimized reaction conditions, substrate scope
was then investigated for the asymmetric biomimetic aldol
reaction with 0.1 mol% of (S)-7a as the catalyst (Table 2). Various
alkyl trifluoromethyl ketones 4 underwent the transformation
smoothly to give the corresponding chiral β-trifluoromethyl-β-
hydroxy-α-amino acid esters 6a-aa in good yields (55-82% for
syn-6) with high diastereoselectivities (up to >20:1) and excellent
2
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Table 2. Substrate scope investigation[a]
such as 4ab was applied to the reaction, the corresponding chiral
β-hydroxy-α-amino acid ester 6ab was produced with high
diastereoselectivity. Trichloroacetaldehyde was also reactive for
the transformation, to produce β-hydroxy-α-amino acid ester 6ac
with low diastereoselectivity. Under the standard conditions,
aldehydes such as benzaldehyde and dec-9-enal and
perfluorinated ketones such as hexafluoroacetone and
1,1,1,3,4,4,4-heptafluoro-3-(trifluoromethyl)butan-2-one are both
ineffective for the reaction. Methyl pyruvate can autocatalyze its
reaction with glycinate. And the reaction of ethyl glyoxylate with
glycinate is very messy.
To further evaluate the efficiency of the biomimetic aldol
reaction, a lower catalyst loading such as 0.02 mol% or even
0.0033 mol% was tested with the reaction of glycinate 5 and
trifluoromethyl ketone 4i (Scheme 2a). The aldol product 6i was
obtained in moderate to good yields with comparable diastereo-
and enantioselectivities. The reaction became obviously slow
during the late stage probably due to the partial deactivation of
the catalyst. At -10 oC, almost only product 4i and unreacted
1
starting materials were observed from the H NMR spectrum of
the crude reaction mixture (Scheme 2a, entry 1). For the reaction
at 10 oC in the presence of 0.0033 mol% of catalyst loading, small
amount of unidentified byproducts appeared and product 6i was
obatined in 59% yield along with 18% of 4i recovered (Scheme
2a, entry 3).
The synthetic transformations of the aldol products have
been demonstrated with β-trifluoromethyl-β-hydroxy-α-amino
acid ester 6b (Scheme 2b). Deprotection of the tert-butyl group by
treatment of 6b with aqueous HCl gave enantiopure β-hydroxy-α-
amino acid 8 in 80% yield. Reduction of 6b with LiAlH4 formed
chiral 2-amino-1,3-diol 9 in 64% yield with 98% ee (Scheme 2b).
[a] All reactions were carried out with 4 (1.0 mmol), 5 (1.5 mmol), catalyst (S)-
7a (0.0010 mmol, 0.1 mol%), and Tf2NH (0.20 mmol) in DCM (4.0 mL) at -10 oC
for 48 h unless otherwise stated. For 6ac, reaction was 67 h. For 6a-ab, isolated
yields of syn-6 (major isomer) based on 4 were collected. For 6ac, isolated yield
of syn- and anti-6ac based on 4 was collected. The dr (syn:anti) values were
determined by 1H NMR analysis of the crude reaction mixtures. The ee values
were determined by chiral HPLC analysis. The absolute configuration of syn-6a
were determined as (2S,3R) by X-ray analysis. The absolute configurations of
the two newly-generated chiral centers for syn-6b-ab were tentatively assigned
as (2S,3R) by analogy. [b] The reaction was performed at 0 oC for 72 h.
Scheme 2. (a) Investigation of catalyst efficiency. (b) Synthetic transformations.
The reaction was proposed to proceed via a mechanistic
pathway similar to the biological aldol process[22] (Scheme 3a).
Condensation of N-methyl pyridoxal catalyst 7a with glycinate 5
forms imine 10. Deprotonation of the CH of 10 generates
active delocalized carbanion 11,[23] which then undergoes
electrophilic addition to trifluoromethyl ketone 4 and subsequent
hydrolysis to produce β-hydroxy-α-amino acid eater 6 and
regenerate catalyst 7a. The main species of the catalytic cycle,
including catalyst 7a, imines 10 and 13, can be detected
according to the HRMS spectroscopy (Scheme 3 and SI).
enantioselectivities (96-99% ee). The substituents on the alkyl
chain of the ketones, such as heterocyclic (for 6d), aromatic (for
6e-t), heteroaromatic (for 6u-w), silyl (for 6aa) groups, and C-C
double bond (for 6x-y) had little impact on the reaction in terms of
yield and selectivity. When a chiral alkyl trifluoromethyl ketone
3
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An acid additive such as AcOH and Tf2NH led to obviously-
increased diastereoselectivity and slightly-improved reaction yield
(Table 1, entries 3, 10 and 11 vs. 1). The acid effect was also
observed during the investigation of the impact of Tf2NH amount
on the reaction (Scheme 5). Introducing 0.1~0.2 equivalent of
Tf2NH can obviously improve the yield and the dr value of product
6x. Further increasing the amount of Tf2NH to 0.4 equivalent led
to a slight decrease in yield likely due to low pH conditions
disfavoring the deprotonation of 10 to 11, but with similar diastero-
and enantioselectivities.
Scheme 5. Impact of Tf2NH amount.
The impact of an acid additive on diastereoselectivity implied
the Brønsted acid likely participated in the asymmetric addition of
intermediate 11 toward trifluoromethyl ketone 4 (Scheme 3a). In
order to understand the role of Tf2NH and the origin of the chiral
induction, computational studies has been carried out for the step
(see SI). As shown in the optimized transition state 12 (Scheme
3b), the ketone 4 was well activated through double hydrogen
bonds, respectively, with the N‒H group of the amide side chain
of 7a and with Tf2NH.[24] The CF3 group of 4 pointed to the
direction parallel to the amide side chain of 7a, which avoided the
steric repulsion with the bulky Tf2N group. The enolated glycinate
approached to the trifluoromethyl ketone 4 from beneath,
resulting in the formation of chiral β-hydroxy-α-amino acid ester 6
with (2S,3R) configuration from (S)-7a.
Scheme 3. Proposed mechanism for the reaction.
The proposed transition state got supported from the control
experiments on catalyst comparison (Scheme 6). Methylation of
the N-H group of the side amide chain of 7a led to obvious
decreases in activity and stereoselectivity (7a vs. 7h), implying
the N-H group likely participated in the catalysis via hydrogen
bonding with the carbonyl group of ketone 4 as proposed in the
transition state 12 (Scheme 3). In addition, the strong electron-
withdrawing ability of the N-quaternized pyridine ring of 7a is also
a necessary requirement for its high activity. Pyridoxal 7g without
methylation of the pyridine nitrogen was almost inactive for the
reaction (Scheme 6).
Scheme 4. Kinetic isotope effect studies.
Kinetic isotope effect studies were carried out with equimolar
amounts of 5 and 5-d2 (Scheme 4). Compound syn-6i and the
deuterated syn-6i-d were obtained with a ratio of 3.3:1. The
obvious KIE indicated the deprotonation of imine 10 to form active
intermediate 11 is the rate-determining step for the reaction.
Considering the very low amount (0.1 mol%) of catalyst 7a in the
reaction and the high tendency of pyridoxals to form imines with
amines, the imine 10 should be the resting-state of the catalyst
7a. Kinetic studies have shown that the reaction was first order in
glycinate 5, zero order in trifluoromethyl ketone 4 and first order
in catalyst 7a (see SI), suggesting that glycinate 5 was involved
in the rate-determining step and the addition of intermediate 11 to
trifluoromethyl ketone 4 was a quick step. In the rate-determining
step from imine 10 to intermediate 11, glycinate served as a base
to deprotonate the CH of 10.
Scheme 6. Comparison of catalysts.
4
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In summary, with 0.1-0.0033 mol% of chiral N-methyl
pyridoxal 7a as the catalyst, we have developed a highly efficient
asymmetric biomimetic aldol reaction of glycinate and
trifluoromethyl ketones, producing various chiral β-trifluoromethyl-
β-hydroxy-α-amino acid esters 6 in good yields (55-82% for syn-
6) with high distereoselectivities (7:1 ‒ >20:1 dr) and excellent
enantioselectivities (96-99% ee) under very mild conditions. The
reaction proceeds without any protecting manipulations toward
the active NH2 group, representing a straightforward and atom-
economic method for the synthesis of chiral β-trifluoromethyl-β-
hydroxy-α-amino acid esters.
[7]
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We are grateful for the generous financial support from the
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Chem. 2019, 131, 3250-3255.
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6
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Entry for the Table of Contents
An extremely efficient biomimetic aldol reaction of glycinate and trifluoromethyl ketones was developed with 0.1-0.0033 mol% of
chiral pyridoxal 7a as catalyst, producing β-hydroxy-α-amino acid esters 6 in 55-82% yields with excellent distereo- and
enantioselectivities (up to >20:1 dr and 99% ee) without protection to the active NH2 group. The reaction proceeds via a bifunctional
catalysis pathway similar to enzymatic aldol reaction of glycine.
7
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