Asymmetric 1,4-Addition Reactions Catalyzed by N-Terminal Thiourea-Modified Helical l-Leu Peptide with Cyclic Amino Acids

Article abstract of DOI:10.1002/chem.202101252

N-terminal thiourea-modified l-Leu-based peptide {(3,5-diCF₃Ph)NHC(=S)-(l-Leu-l-Leu-Ac₅c)₂-OMe} with five-membered ring α,α-disubstituted α-amino acids (Ac₅c) catalyzed a highly enantioselective 1,4-addition reaction between β-nitrostyrene and dimethyl malonate. The enantioselective reaction required only 0.5 mol % chiral peptide-catalyst in the presence of ⁱPr₂EtN (2.5 equiv.), and gave a 1,4-adduct with 93 % ee of an 85 % yield. As Michael acceptors, various β-nitrostyrene derivatives such as methyl, p-fluoro, p-bromo, and p-methoxy substituents on the phenyl group, 2-furyl, 2-thiophenyl, and naphthyl β-nitroethylenes could be applied. Furthermore, various alkyl malonates and cyclic β-keto-esters could be used as Michael donors. It became clear that the length of the peptide chain, a right-handed helical structure, amide N?Hs, and the N-terminal thiourea moiety play crucial roles in asymmetric induction.

Full text of DOI:10.1002/chem.202101252

Accepted Article
Accepted Article
Title: Asymmetric 1,4-addition Reactions Catalyzed by N-terminal
Thiourea-modified Helical L-Leu-peptide with Cyclic Amino Acids
Authors: Masakazu Tanaka, Kazuki Sato, Tomohiro Umeno, Atsushi
Ueda, Takuma Kato, and Mitsunobu Doi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202101252
Link to VoR: https://doi.org/10.1002/chem.202101252
01/2020

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Asymmetric 1,4-addition Reactions Catalyzed by N-terminal
Thiourea-modified Helical L-Leu-peptide with Cyclic Amino Acids
Kazuki Sato,[a] Tomohiro Umeno,[a] Atsushi Ueda,[a] Takuma Kato,[b] Mitsunobu Doi,[b] Masakazu
Tanaka*[a]
[a]
K. Sato, Dr. T. Umeno, Dr. A. Ueda, Prof. M. Tanaka*
Graduate School of Biomedical Sciences
Nagasaki University
Nagasaki 852-8521 (Japan)
E-mail: matanaka@nagasaki-u.ac.jp
Dr. T. Kato, Prof. M. Doi
[b]
Osaka Medical and Pharmaceutical University, Osaka 569-8686 (Japan)
Supporting information for this article is given via a link at the end of the document.
Abstract: N-terminal thiourea-modified L-Leu-based peptide {(3,5-
diCF3Ph)NHC(=S)-(L-Leu-L-Leu-Ac5c)2-OMe} with five-membered
ring -disubstituted -amino acids (Ac5c) catalyzed a highly
enantioselective 1,4-addition reaction between -nitrostyrene and
dimethyl malonate. The enantioselective reaction required only 0.5
i
mol % chiral peptide-catalyst in the presence of Pr2EtN (2.5 equiv),
and gave a 1,4-adduct with 93% ee of an 85% yield. As Michael
acceptors, various -nitrostyrene derivatives such as methyl, p-fluoro,
p-bromo, and p-methoxy substituents on the phenyl group, 2-furyl, 2-
thiophenyl, and naphthyl -nitroethylenes could be applied.
Furthermore, various alkyl malonates and cyclic -keto-esters could
be used as Michael donors. It became clear that the length of the
peptide chain, a right-handed helical structure, amide N-Hs, and the
N-terminal thiourea moiety play crucial roles in asymmetric induction.
Introduction
Incorporation of ,-disubstituted -amino acids (dAAs) into L-
amino acid-based peptides induces stable secondary structures
such as -turn, 310-helix, -helix, and planar conformation. -
Aminoisobutyric acid (Aib), -methylated amino acids, and cyclic
dAAs are known to induce helical structures in their peptides.[1]
We previously reported that -helical L-Leu-based peptides with
cyclic dAAs could be used as chiral catalysts for the epoxidation
of chalcone derivatives (Juliá-Colonna epoxidation) (Figure 1-
1).[2] Furthermore, we reported that -helical L-Leu-based
peptides with cyclic dAAs could catalyze the enantioselective 1,4-
addition reaction of -unsaturated ketones (Figure 1-2).[3]
These results demonstrate that cyclic dAA-containing helical
peptides could be applied to chiral catalysis using the N-terminal
amino group of peptides. The N-terminal amino group would form
an iminium with the carbonyl function of a substrate, and
accelerate the reaction. The two aforementioned reactions
generated products with excellent enantiomeric excesses.
However, the helical peptides can only be applied to catalysis for
limited kinds of asymmetric reactions, and not for the variety of
reactions (Figure 1).[4]
Figure 1. Helical foldamer-catalyzed asymmetric reactions
We hypothesized that N-terminal modification of peptide-
catalysts may change the reaction type, and broaden the
acceptable range of substrates for helical peptide catalysts.
Recently, Guichard, Palomo, and coauthors reported that helical
oligo(thio)urea foldamer at low loadings catalyzed the Michael
addition reaction between nitroolefins and dialkyl malonates to
give 1,4-adducts with excellent enantioselectivities (Figure 1-3).[5]
These results led us to examine the reaction using helical L-Leu-
based peptides with N-terminal (thio)urea modification because
the N-terminal (thio)urea moiety may activate nitroolefins and the
amide N(2)-H, N(3)-H, and N(4)-H of peptides, which might trap
dialkyl malonates by hydrogen bonds. Furthermore, helical L--
1
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amino acid-based peptides were considered to be easily prepared.
Thus, we hypothesized that cyclic dAA-containing the L-Leu-
based peptide with N-terminal (thio)urea may catalyze the
enantioselective 1,4-addition reaction between nitroolefins and
dialkyl malonates, like the helical oligo(thio)urea foldamer does
(Figure 1-4).
7
8
0.5
0.5
iPr2EtN (2.5)
>99
76
93
89
iPr2EtN (0.30)
[a] Conversion % was determined by 1H NMR spectrum. [b] The enantiomeric
excess (ee) was determined by chiral HPLC analysis.
Next, we examined various peptide catalysts, as shown in
Scheme 1. The reaction using catalyst B with the N-terminal urea
also afforded the 1,4-addition product 3aa with an excellent 91%
ee. Contrary to catalysts A and B, catalysts C and D, which are
tripeptides, gave product 3aa with a moderate 57-69% ee. The
length of catalysts C and D may be too short to form helical
structures, and ee of 3aa was unsatisfactory. Catalyst E with
thiourea and urea moieties showed 82% ee, and catalyst F with
two ureas gave a product with 91% ee, which was mostly the
same as catalyst B. The hexapeptide without an N-terminal
(thio)urea gave the product 3aa with a low 7% ee. Thus, the
peptide-catalyst A gave the best result.
Results and Discussion
We constructed a helical structure using L-Leu-based peptides
with 1-aminocyclopentanecarboxylic acid (Ac5c).[6] The peptide
sequence –(L-Leu-L-Leu-Ac5c)n– was selected because the
sequence forming -helix was used as a helical peptide-catalyst
for epoxidation and 1,4-addition reactions of -unsaturated
ketones in our group. We introduced the thiourea or the urea
moiety with the 3,5-bis(trifluoromethyl)phenyl group at the N-
terminal of helical L-Leu-based peptides. Also, we prepared
peptides having an additional (thio)urea moiety at the N-terminal
urea of L-Leu peptide.[7]
Scheme 1. Screening of peptide-catalysts.
First, we checked the 1,4-addition reaction between -
nitrostyrene 1a (1.0 equiv) and dimethyl malonate 2a (2.0 equiv)
in toluene (1 M) at -20°C using Et3N (0.10 equiv) and 1.0 mol %
peptide-catalyst A {(3,5-diCF3Ph)NHC(=S)-(L-Leu-L-Leu-Ac5c)2-
OMe}, which is a hexapeptide with N-terminal thiourea. Under
these conditions, the reaction was incomplete after 24 h (61%
conv) and the ee of product 3aa was a moderate 75% (entry 1 in
Table 1).[8] Usage of 1.0 equiv Et3N improved the conversion
(>99%), but the ee of the product was still a moderate 73%, and
increase of Et3N (5.0 equiv) improved the ee of 3aa to 90%
(entries 2, 3). The use of iPr2EtN instead of Et3N further improved
the ee of product 3aa to 93% (entry 4). The catalytic amount of A
could be reduced to up to 0.5 mol % without decreasing ee, but
the use of a 0.1 mol % catalyst was detrimental to the high ee,
and ee was decreased to 83% (entries 5, 6). The use of a reduced
i
amount of Pr2EtN (0.30 equiv) decreased the conversion %,
although ee of 3aa was mostly retained (entry 8). Finally, the use
i
of 0.5 mol % peptide A and Pr2EtN (2.5 equiv) was found to be
suitable for the reaction (entry 7).
Table 1. Optimization of 1,4-addition reaction using helical peptide with N-
terminal thiourea.
We studied the generality of Michael acceptors, as shown
in Scheme 2. The 1,4-addition reactions between nitroalkenes
1a-n (1.0 equiv) and dimethyl malonate 2a (2.0 equiv) were
performed using 0.5 mol % peptide-catalyst A in the presence of
iPr2EtN (2.5 equiv) in toluene (1 M) at -20°C. Nitroethylenes 1a-l
with -aryl groups such as o-tolyl, m-tolyl, and p-tolyl groups
smoothly reacted with 2a to give chiral 1,4-adducts 3aa-da with
Entry
Catalyst A
mol %
Base (equiv)
Conv. (%)[a]
Ee (%)[b]
1
2
3
4
5
6
1.0
1.0
1.0
1.0
0.5
0.1
Et3N (0.10)
Et3N (1.0)
61
>99
>99
>99
>99
>99
75
73
90
93
93
83
92-95% ee.
p-Fluoro, p-chloro, p-bromo, and p-methoxy
Et3N (5.0)
substituents on the -phenyl group weakly affected the isolated
yields of 1,4-adducts, but the ee of 3ea-ha remained excellent
(90-92% ee). The reaction of heteroaromatic 2-furyl, and 2-
thiophenyl -nitroethylenes, and 2-naphthyl and 1-naphthyl -
nitroethylenes also proceeded to give 1,4-adducts 3ia-la with an
excellent 90-95% ee. However, nitroethylenes 1m,n with an
iPr2EtN (5.0)
iPr2EtN (5.0)
iPr2EtN (5.0)
2
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aliphatic -substituent gave chiral 1,4-adducts 3ma,na with a
moderate 65-85% ee in low chemical yields. The 1,4-addition
reaction using a gram scale 1a proceeded without problems to
give 3aa with 93% ee.
However, the reaction with di-tert-butyl malonate did not proceed
because the bulky tert-butyl ester may hinder the approach of N-
H of the helical peptide. The 1,4-addition reaction of 1a with
dimethyl 2-methylmalonate 2e gave the 1,4-adduct 3ae (92% ee)
with a quaternary carbon. It should be noted that the reaction of
1a with cyclic -ketoesters 2f and 2g proceeded diastereo- and
enantio-selectively to give 1,4-adducts 3af (88% ee) and 3ag
(96% ee) with a stereogenic quaternary center, respectively.
Scheme 2. Scope of Michael acceptors.
The catalyst
A became crystals suitable for X-ray
crystallographic analysis by recrystallization from DMF/H2O. The
structure was solved in an orthorhombic P212121 space group to
show two crystallographically independent right-handed
(P) helical molecules, a and b, in the asymmetric unit (Figure 2).
The structures of the two molecules a and b are very similar at
the peptide-backbone, but some differences are observed at the
C-terminal ester, the isobutyl side chain of L-Leu, and the N-
terminal (3,5-diCF3Ph) moiety, as shown by superimposition of
the structures.
In both molecules a and b, three intramolecular hydrogen
bonds of the N(i+3)-H···O=C(i) (i = 1, 2, and 3) i ← i+3 type, which
correspond to the 310-helix, were observed. The N-terminal
thiourea N(0)-H and N(1)-H were intermolecularly hydrogen-
bonded to the carbonyl O(4’)=C(4’) of the neighboring (–1+x,y,z)
molecule, and also an intermolecular hydrogen-bond N(2)-
H···O(5’)=C(5’) (–1+x,y,z) was observed. The mean values of 
and  torsion angles for amino acid residues (1-5) were –64.8°
and –30.2° in molecule a, and –63.7° and –32.6° in molecule b,
respectively. These values are in good accordance with those of
the right-handed (P) 310-helical conformation (–60° and –30°).[9]
The  and  torsion angles of the C-terminal residue (6) in
molecule b were +50° and +31.9°, respectively, which are
opposite signs to those of the preceding residues. Those of the
C-terminal residue (6) in molecule a were distorted (+59.8° and –
144.7°, respectively).
Scheme 3. Generality of Michael donors.
Figure 2. X-ray crystallographic analysis of peptide catalyst A. a) molecule a
(side view); b) molecule a (top view); c) superimposition of molecules a and b.
The circular dichroism (CD) spectra of peptide-catalysts A-
D were measured in 2,2,2-trifluoroethanol solution (0.05 mM).
The CD spectra of A and B showed a positive maximum at 195
nm and negative maxima at 208 and 222 nm, suggesting the
formation of right-handed (P) helices.[10] On the other hand, the
Scheme 3 shows the generality of Michael donors. The
reaction of 1a with diethyl, dibenzyl, and diisopropyl malonates
2b-d gave chiral 1,4-adducts 3ab-ad with an excellent 91-93% ee.
3
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CD spectra of peptide-catalysts C and D did not show
characteristic maxima for the helical structure because the length
of C and D may be too short for the formation of the helical
structure.(Figure S1).
To evaluate the effect of cyclopentyl ring on the reaction,
Ac5c in catalyst A was replaced with Aib to produce catalyst W.
The reaction using catalyst W with Aib gave the 1,4-adduct with
91% ee at >99% conversion. Thus, the side chain structures of
dAAs are of secondary importance, but the induction of helix by
dAA is important.
To examine which N-Hs of the peptide-catalyst plays a
crucial role in the asymmetric 1,4-addition reaction, we examined
the reaction using N-methylated peptides (Scheme 4). Without a
peptide-catalyst, the reaction proceeded to give racemate 3aa at
a 25% conversion. The reaction using 0.5 mol % N(1)-methylated
peptide X gave the 1,4-adduct with 9% ee at a 24% conversion,
and that using N(2)-methylated peptide Y produced the 1,4-
adduct with 18% ee at an 85% conversion. These results suggest
that the N-terminal thiourea N(1)-H is important for the catalytic
reaction because the two N(0)-H and N(1)-H may be used for
activation of -nitrostyrene. On the other hand, N(2)-H may be
used to form a hydrogen bond to dialkyl malonate for asymmetric
induction, and without N(2)-H the reaction itself proceeded to give
the 1,4-adduct with low enantioselectivity. The reaction using
peptide catalyst Z with D-Leu at the N-terminal residue instead of
L-Leu proceeded to give the enantiomeric 1,4-adduct with -26%
ee at >99% conversion, and that using catalyst P with N-terminal
L-Phe afforded the 1,4-adduct with 88% ee at >99% conversion.
Thus, the direction of the side-chain substituent at the N-terminus
as well as helix is important for this asymmetric induction.
Effects of temperature were studied using peptide catalyst
A under the same reaction conditions (Table S4). The reaction at
room temperature gave product 3aa with 84% ee and that at 60 °C
afforded 3aa with 77% ee, both in quantitative conversion. These
results mean that the Ac5c-containing helical peptide secondary
structure might be stable at these elevated temperatures.
We considered the plausible mechanisms of the
enantioselective 1,4-addition reaction, as follows. The helical
peptide N-terminal thiourea N(0)-H and N(1)-H, which were
intermolecularly hydrogen-bonded to the peptide O(4’)=C(4’) by
the X-ray crystallographic structure, may capture the nitroalkene
by hydrogen bonds of type N(0)-H···O=N (nitro) and N(1)-
H···O=N (nitro). Dialkyl malonate may be trapped by hydrogen
bonds with N(2)-H and N(3)-H of the peptide, and be directed to
the enantio-face of nitroalkene.
In conclusion, we demonstrated that N-terminal thiourea-
modified L-Leu-based peptide catalyzed highly enantioselective
1,4-addition reactions between nitroolefins and dialkyl malonates.
The peptide catalyst A formed a right-handed helical structure
because Ac5c induced a helical structure and L-Leu controlled the
helical-screw sense to right-handedness. In comparison with a
Guichard urea-oligomer catalyst, the reaction using peptide A
required a large amount (0.5 mol %) of catalyst loading, but the
chemical yields and enantiomeric excesses of 1,4-products were
very good. Helical structures of peptides composed of L-amino
acids and dAAs have been well-studied, and can be precisely
designed and easily prepared. The N-terminal modification of
helical peptide catalysts would change the applicable reaction
type and broaden the acceptable substrates. Such modification
of peptide catalysts is currently underway in our group.
Scheme 4. Effect of amide N-H, D-Leu, L-Phe, and dAA on enantioselective
reaction.
Experimental Section
General procedure for Michael addition reaction: A solution of -
nitrostyrene (0.50 mmol), dialkyl malonate (1.0 mmol), peptide catalyst A
(2.44 mg, 0.5 mol %), and iPr2EtN (0.21 mL,1.25 mmol) in toluene (0.5 mL)
was stirred at –20°C for 24 h under an Ar atmosphere. Then, the reaction
was quenched with 1 N aqueous HCl, extracted with CHCl3, washed with
brine, and dried over MgSO4. After removal of the solvent, the crude
product was purified by flash chromatography on silica gel to give a 1,4-
adduct.
Reaction on gram scale: A solution of 1a (1.00 g, 6.70 mmol) and peptide
catalyst A (32.5 mg, 0.5 mol %) in dried toluene (6.70 mL, 0.1 M) was
cooled to –20°C, and then dimethyl malonate 2a (1.53 mL, 13.4 mmol) and
iPr2EtN (2.85 mL,16.7 mmol) were added at –20°C under an Ar
atmosphere. After being stirred for 24 h, the reaction mixture was diluted
with 1 N aqueous HCl, extracted with CHCl3, and dried over Na2SO4.
Removal of the solvent afforded a crude 1,4-adduct, which was purified by
column chromatography on silica gel (20% EtOAc in n-hexane) to give 3aa
(1.24 g, 66% yield, 93% ee).
Determination of % ee: The enantiomeric excess (% ee) of products was
determined by HPLC using the chiral column DAICEL CHIRALPAK AD-H,
AS-H, IB N-5, or YMC-SC.
4
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X-ray crystallography: CCDC-2069500 (for peptide-catalyst A) contains
the supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe.
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Acknowledgements
This study was supported by JSPS KAKENHI Grant Number JP-
17K19495 (for M. T.) and 20K06967 (for A. U.).
Keywords: helix • peptide • conformation • organocatalyst • -
disubstituted -amino acid
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5
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N-terminal thiourea-modified helical L-Leu-based peptide (0.5 mol %) catalyzed a highly enantioselective 1,4-addition reaction
between various -nitrostyrenes and dialkyl malonates to give 1,4-adducts with a 65-96% ee. The length of the peptide chain, right-
handed helical structure, amide N-Hs, and the N-terminal thiourea moiety played crucial roles in the asymmetric induction.
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