N-Primary-amine tetrapeptide-catalyzed highly asymmetric Michael addition of aliphatic aldehydes to maleimides

Article abstract of DOI:10.1039/d0ob01457e

The highly asymmetric Michael addition reaction between maleimides and aliphatic aldehydes catalyzed by low-loading β-turn tetrapeptides with excellent yields and enantioselectivities at room temperature was reported. α-Branched and α-unbranched aldehydes both are suitable nucleophiles. N-Aryl, alkyl and hydrogen maleimides all are well tolerated and led to high yields and enantioselectivities. The transformation can be enlarged to the gram scale without decrease in the yield and enantioselectivity. Furthermore, the succinimides were converted into γ-lactams and γ-lactones, showing good practicality of this work. Some reaction intermediates in the proposed reaction mechanism can be captured with the HR-MS method.

Full text of DOI:10.1039/d0ob01457e

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DOI: 10.1039/D0OB01457E
ARTICLE
N-Primary-Amine Tetrapeptide-Catalyzed Highly Asymmetric
Michael Addition of Aliphatic Aldehydes to Maleimides†
Zhi-Hong Du,a Wen-Juan Qin,a Bao-Xiu Tao,a Meng Yuana and Chao-Shan Da*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The highly asymmetric Michael addition reaction between maleimides and aliphatic aldehydes catalyzed by low-
loading β-turn tetrapeptides with excellent yield and enantioselectivity at room temperature was reported. α-Branched
and α-unbranched aldehydes both are suitable nucleophiles. N-aryl, alkyl and hydgogen maleimides all are well tolerated
and obtained high yield and enantioselectivity. The transformation can be enlarged to gram-scale without decrease in the
yield and enantioselectivity. Furthermore, the succinimide were converted into γ-lactam and γ-lactone, showing good
practicality of this work. Some reaction intermediates in the proposed reaction mechanism can be captured with HR-MS
method.
transformations for their readily availability, high stability, easy
modification and well-tolerance to reaction conditions.11
A
Introduction
number of peptide-catalyzed highly enantioselective
transformations have been demonstrated by groups.12,13
Recently, even photocatalytic peptides were developed in
green organic reactions.14 To date, however, only two reports
on catalytic peptides used as artificial enzymes have been
disclosed in this transformation.4a,15 Wennemers and the co-
workers first demonstrated the tripeptide-catalyzed conjugate
addition of linear aldehydes as nucleophiles to maleimides
with high yield, excellent enantioselectivity and good
diastereoselectivity.4a Despite the great success of
Wennemers’s work on this transformation, there is one
Chiral succinimide-bearing compounds display significant
biological activities, such as antibacterial and antitumor
properties.1 In addition, chiral succinimides are also crucial
organic synthetic blocks and can be readily transferred into
various biologically and pharmaceutically active compounds.2
The catalytical asymmetric conjugate addition of nucleophiles
to maleimides is
a main method to synthesize chiral
succinimides.3 Uniquely, the asymmetric Michael addition
reaction of aldehydes with maleimide will produce 1,4-
dicarbonyl motif-bearing succinimides, which can be easily
transformed into pyrrolidines,
γ-lactams and γ-lactones,
limitation that the nucleophiles are only restricted to
α-
showing the great significance of this transformation in the
asymmetric synthesis.4 Therefore, the catalytic asymmetric
conjugated reaction of aldehydes and maleimides has
attracted intense interest to many research groups and
numerous successful catalytic methods have been
demonstrated with excellent results. The catalysts are mainly
organocatalysts, including primary amine-containing thioureas
derived from chiral cyclohexane-diamine and amino acids,5
primary amines,6 guanidines,7 imidazoles,8 squaramide,9 amino
acids and their derivatives.4b,10 Inspite of these excellent
organocatalysts in this asymmetric transformation, other
efficient catalytic method is still rare, and thus interesting and
anticipated.
unbranched aldehydes. The transformation of -branched
α
aldehydes as nucleophiles would produce all-carbon
quaternary center-bearing succinimides. The all-carbon
quaternary center is a common motif in biologically and
pharmaceutically active compounds and has always been in
the research centre of the organic synthesis.16 Juaristi and co-
workers reported the second cases about synthetic short
peptide-catalyzed conjugate addition of aldehydes to
maleimides.15 They employed dendrimeric α,β
-dipeptidic
conjugates as organocatalysts but the enantioselectivity is not
high. Therefore, other synthetic peptides are needed to
efficiently catalyze asymmetric reactions of both
α-branched
and -unbranched aldehydes as nucleophiles with maleimides.
α
Synthetic short peptides are often used as artificial
surrogates of natural enzymes in numerous organic
Recently, our group designed and synthesized a series of
tetrapeptides and successfully utilized them to catalyze highly
enantioselective aldol reactions,17 these tetrapeptides are
primary amine N-terminus, different from the proline N-
terminal tripeptides by Wennemers group. Reportedly, proline
and its derivatives are more suitable to catalyze
aldehyde nucleophiles,4a,10b while primary amine-based
organocatalysts are more ideal catalysts for -branched
α-unbranched
α
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aldehyde nucleophiles in this transformations.4b,10a And dipeptidic conjugates is mainly due to the peptide secondary
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DOI: 10.1039/D0OB01457E
compared to the α,β-
dipeptidic conjugates of Juaristi group, structure.15
we proposed that the primary amine N-terminal tetrapeptides
with a β-turn secondary structure should provide a more ideal
sterically restricted chiral environment for this transformation,
possibly resulting in a highly asymmetric induction.18 Intrigued
by this proposal, we have explored the tetrapeptide-catalyzed
Table 1 Optimization of reaction conditions. a
conjugate addition of
α-branched and linear aldehydes to
maleimides for 1,4-dicarbonyl-bearing succinimides. In this
article, we disclose this primary-amine N-terminal and β-turn
secondary structural tetrapeptide-catalyzed conjugate
transformation with high yield and excellent enantioselectivity
under a mild reaction condition for the first time.
Results and discussion
Initially, we screened the tetrapeptide catalysts using N-
phenylmaleimide and isobutyraldehyde as the model reaction,
and found that all tetrapeptides can successfully catalyze the
reaction (table 1, entries 1 to 6). Among them, 1d and 1e
obtained the best results (91% ee) when toluene was used as
the solvent. Next, we optimized the solvent using 1e as the
catalyst because it obtained a higher yield than 1d. Aprotic
solvents such as DCM, MeCN, THF, and EtOAc all obtained
excellent enantioselectivity (97-99% ee), and MeCN is ideal in
view of both yield and enantioselectivity (entry 8).
Dichloromethane obtained the highest enantioselectivity but
with relatively low yield (entry 7). The use of the protic solvent
EtOH caused a significant decrease in enantioselectivity. Next,
we tried to reduce the amount of the tetrapeptide. When the
amount of tetrapeptide 1e was reduced by half, the yield and
enantioselectivity still kept very high (entries 8 vs 13). Further
reducing the amount remarkably deteriorated the yield
although the enantioselectivity was not weakened (entries 13-
15). Finally, we compared the catalytic effects of 1d and 1e
under the optimal reaction conditions again, and found that 1d
entry
1
Peptide (X %)
1a (5%)
1b (5%)
1c (5%)
solvent
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
MeCN
EtOH
yield(%)b
35
Ee(%)c
77
72
41
91
91
85
99
98
88
97
--
2
29
3
38
4
1d (5%)
1e (5%)
43
5
55
6
1f (5%)
43
7
1e (5%)
80
8
1e (5%)
93
9
1e (5%)
91
10
11
12
13
14
15
16
17
18
19
1e (5%)
THF
90
1e (5%)
DMSO
AcOEt
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
--
1e (5%)
90
98
98
98
--
1e (2.5%)
1e (1%)
95
56
1e (0.5%)
1d (2.5%)
1g (2.5%)
1h (2.5%)
1i (2.5%)
trace
98
99
72
97
38
can provide much higher yield and enantioselectivity than 1e
,
90
thus more suitable to this transformation.
91
In order to investigate the origin of the stereoselectivity in
the transformation, tetrapeptides 1g and 1h were prepared
and their catalytic activity and asymmetric induction were
evaluated. The results show that the two peptides obtained
reduced enantioselectivity in comparison with tetrapeptide 1d
(entries 16 vs 17-18). But interesting results were viewed.
Tetrapeptide 1g, even with an achiral N-terminal glycine, still
realized 90% yield and 72% enantioselectivity, indicating the
enantioselectivity determined by both the chirality of the N-
terminal amino residue and the secondary structure of the
peptide (entry 17). This result is further verified by
tetrapeptide 1h with an N-terminal alanine, the smallest
natural chiral amino acid but with highly increased
enantioselectivity to 97%. Combining these two examples and
the tetrapeptide 1d, we believe that the spatial structure of
the tetrapeptide and the properties of the N-terminal amino
acid cooperatively determine the stereoselectivity for this
asymmetric transformation. We propose that the superior
67
a0.5 mmol of 2a, 1.0 mmol of 3a and 1 mL solvent were used. bIsolated yield was
reported. cee was determined by chiral HPLC. The configuration was assigned by
comparing the optical rotation direction of 4a with its reported datum.5b
To further show the significance of the peptide secondary
structure in the catalytic transformation, tripeptide 1i without
the
D
-proline residue was prepared. The dipeptide -Pro-Gly is
D
a crucial unit to form β-turn and β-hairpin secondary
structures in short peptides.19 Without proline residue,
tripeptide 1i cannot form secondary structure, obviously. Just
as prediction, it only achieved sharply decreased 67% yield and
38% enantioselectivity, strongly showing indispensability of
the proline residue in the peptides and the importance of the
peptide secondary structure in the catalytic asymmetric
reaction.
With the optimized reaction conditions in hand, we explored
scope of maleimides bearing different N-protecting groups
with isobutyraldehyde (Table 2). With a yield up to 98% (4a
, 4f,
enantioselectivity of these tetrapeptides to the reported α,β
-
4l) and ee up to 99% (4a 4b 4e, 4f 4h 4i 4r 4s), The results
,
,
,
,
,
,
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show that succinimides can be obtained always in high yield good to high yield, excellent ee andViewmArtoicdleeOrnalitnee
and excellent enantioselectivity whether the aryl group on N- diastereoselectivity (5f to 5l), showing well-suitability of the
DOI: 10.1039/D0OB01457E
atom is electron-deficient or electron-rich. In addition, tetrapeptide to aliphatic aldehydes. In spite of this, while
unprotected maleimide can directly obtain N-protection-free comparing to the uniformly high yield from
succinimides, which avoids the additional steps to deprotect aldehydes in this transformation, the good to high yield from
the protecting groups and thus represents the economic -unbranched aldehydes shows that N-primary amine terminal
procedure to optically active succinimides.20 In this work, the tetrapeptide is more suitable to
-branched aldehydes.
α-branched
α
α
N-protection-free maleimide also successfully obtained high Therefore, this work is a good supplementary counterpart to
yield and enantioselectivity (4o). Furthermore, N-alkylated Wennemers’ N-prolyl tripeptides in this transformation.4a
maleimides (4p, 4q, 4r, 4s, 4t) can similarly smoothly achieve
Table 3 Michael addition reaction with 2 and 3.a
94-99% excellent enantioselectivity with varied yield from 73-
95%. The sterically-restricted N-terbutyl maleimide resulted
the lowest 73% yield but with high 96% enantioselectivity (4t).
At last, high yield and enantioselectivity enantiomer of
succinimide 4a was also obtained (4a vs. ent-4a) when ent-1d
(the enantiomer of tetrapeptide 1d) was used. Therefore, pairs
of enantiomers can be readily accessible by simply switching a
pair of tetrapeptide enantiomers with each other.
Table 2 Explorer of maleimide with different N-protecting groups.a
a0.5 mmol of 2, 1.0 mmol of 3 and 1 mL MeCN were used. Isolated yield. ee and
dr value were determined by chiral HPLC and the reported ee is anti/syn. b10% 1d
was used. The configuration was assigned by comparing the optical rotation
direction of 5e with its reported datum.4b
a0.5 mmol of 2, 1.0 mmol of 3a and 1 mL MeCN was used. Isolated yield was
reported. ee was determined by chiral HPLC.b ent-1d was used.
Scheme 1 Transformations of the Michael Addition Product 4a
Next, the scope of the aldehydes was explored and the results
To display the practicality of this work, the model reaction of
isobutyraldehyde and N-phenylmaleimide was successfully
enlarged to gram scale without reducing yield and
enantioselectivity (i, Scheme 1). Furthermore, succinimide 4a
are shown in Table 3. First, symmetrical
were observed; high yield and uniformly excellent 99%
enantioselectivity were obtained (Table 3, 5a 5b and 5c).
Second, asymmetric -branched aldehydes were evaluated
α-branched aldehydes
,
α
can be readily oxidized to acid
6
with oxone (ii), reduced into
with
and all of them obtained succinimides 5d and 5e of exocyclic
linear all-carbon quaternary stereocenter with high yield,
excellent enantioselectivity and moderate diastereoselectivity
(up to 3:1). Finally, a series of linear aldehydes were
investigated and they also smoothly obtained succinimides in
lactone with NaBH4 (iii), and transferred into lactam
7
8
NaBH(OAc)3 and BnNH2 by reductive amination (iv). These
derivatives all are crucial intermediates for biological active
molecule synthesis.1,2
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DOI: 10.1039/D0OB01457E
Figure 1 Intermediate captured by HR-MS
realeasing (S)-succinimide 4a. The special spatial conformation
and steric effect of β-turn tetrapeptide 1d well determines the
attacking direction and thus leads to high yield and excellent
enantioselectivity of the conjugate reaction.
Conclusions
In summary, we have developed the first N-primary amine
terminal β-turn tetrapeptide-catalyzed highly enantioselective
conjugate addition aliphatic aldehydes to maleimide with high
yield and excellent enantioselectivity. N-arylated and alkylated
maleimides all are suitable substrates and achieved high yield
and excellent enantioselectivity. Even the N-protection-free
maleimide is well-tolerated with no reduction of the yield and
enantioselectivity.
both compatible to the tetrapeptide although the
α
-Branched and unbranched aldehydes are
-branched
Scheme 2 Proposed activation and reaction mechanism
α
aldehydes obtained higher yield in some cases. Compared to
the reported organocatalysts, less amount of the tetrapeptide
can achieve high yield and excellent enantioselectivity in this
work. The reaction can be successfully enlarged into gram-
scale and the yield and enantioselectivity are not deteriorated.
The yielded succinimide can be transformed into some crucial
synthetic intermediates for bioactive compounds. The reaction
possibly follows the enamine-based mechanism and the key
intermediates can be investigated using HR-MS method.
To explore the reaction mechanism, we tried to capture the
intermediates of the transformation in situ by using the HR-MS
method. Figure 1 shows that the reaction mixture includes the
intermediate
I or its enamine form generated from
tetrapeptide 1d with isobutyraldehyde, intermediate III
formed by tetrapeptide 1d with succinimide 4a, the product
succinimide (S)-4a and tetrapeptide 1d. This result clearly
indicates that the reaction undergoes possibly following the
enamine intermediate process. Based on such an investigation
and previous reports,6a we speculate that the possible reaction
process in Scheme 2. Tetrapeptide 1d first combines
Conflicts of interest
There are no conflicts to declare.
isobutyraldehyde in situ to form imine I. Imine I can reversibly
change into reactive and nucleophilic enamine II. Enamine II
then reacts with maleimide, which is activated by the terminal
-COOH group of the tetrapeptide via H-bond formation
between H-atom of the -COOH from the peptide and the O-
atom of the carbonyl group from maleimide. The attack of the
enamine to maleimide occurs in the Si-face of maleimide,
Acknowledgements
This work is financially supported by Hangzhou Xinfu Science &
Tech Co. Ltd. We thank engineer Hong-Yu Wang at Lanzhou
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01457E
Table of Contents Entry
O
O
O
O
peptide
( 2.5 mol%)
O
O
N
R2
+
N
R1
N
R1
H
H
N
HN
-O
H
i-Bu
MeCN, r.t
O
R3
R2 R3
O
O
Ph
+
NH3
1d
O
up to 99% ee
up to 98%yield
up to 88:12 dr
R1 = H, alkyl, Aryl
The highly asymmetric Michael addition reaction between maleimides and aldehydes catalyzed by
N-Primary-Amine β-turn tetrapeptides with excellent yield and enantioselectivity was reported.