Helical foldamer-catalyzed enantioselective 1,4-addition reaction of dialkyl malonates to cyclic enones

Article abstract of DOI:10.1016/j.tetlet.2019.151301

The introduction of a five-membered ring α,α-disubstituted α-amino acid into L-Leu-based heptapeptides preferentially induced right-handed (P) helical structures. Using 5 ～ 20 mol% of a single helical foldamers-catalyst, enantioselective 1,4-addition reactions of dialkyl malonates to cycloalk-2-enones (5 ～ 7 rings) proceeded to give chiral 3-substituted cycloalkanones with 94 ～ 99% ee in moderate chemical yields, regardless of the ring size of substrates.

Full text of DOI:10.1016/j.tetlet.2019.151301

Journal Pre-proofs
Helical foldamer-catalyzed enantioselective 1,4-addition reaction of dialkyl
malonates to cyclic enones
Tomohiro Umeno, Atsushi Ueda, Mitsunobu Doi, Takuma Kato, Makoto Oba,
Masakazu Tanaka
PII:
S0040-4039(19)31084-6
DOI:
https://doi.org/10.1016/j.tetlet.2019.151301
TETL 151301
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
11 September 2019
11 October 2019
17 October 2019
Please cite this article as: Umeno, T., Ueda, A., Doi, M., Kato, T., Oba, M., Tanaka, M., Helical foldamer-catalyzed
enantioselective 1,4-addition reaction of dialkyl malonates to cyclic enones, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.151301
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Helical foldamer-catalyzed enantioselective
1,4-addition reaction of dialkyl malonates to
cyclic enones
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Tomohiro Umeno, Atsushi Ueda, Mitsunobu Doi, Takuma Kato, Makoto Oba, and Masakazu Tanaka*
O
O
CH2(CO2R)2
+
CO2R
( )n
( )n
5~20 mol %
H-(L-Leu)2-Ac5c-(L-Leu)4-OMe
R =
Me, Bn, etc.
CO2R
94~99% ee
n = 0~2
40 °C

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Helical foldamer-catalyzed enantioselective 1,4-addition reaction of dialkyl malonates
to cyclic enones
Tomohiro Umeno,a Atsushi Ueda,a Mitsunobu Doi,b Takuma Kato,b Makoto Oba,a and Masakazu Tanakaa*
a Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
b Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The introduction of a five-membered ring -disubstituted -amino acid into L-Leu-based
heptapeptides preferentially induced right-handed (P) helical structures. Using 5~20 mol % of a
single helical foldamers-catalyst, enantioselective 1,4-addition reactions of dialkyl malonates to
cycloalk-2-enones (5~7 rings) proceeded to give chiral 3-substituted cycloalkanones with
94~99% ee in moderate chemical yields, regardless of the ring size of substrates.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Helix
Peptide
Conformation
-disubstituted -amino acid
Chiral organocatalyst
———
*
Corresponding author. Tel. & fax: +81-95-819-2423; e-mail: matanaka@nagasaki-u.ac.jp

2
Tetrahedron Letters
O
1. Introduction
P1
H-(L-Trp)2-{(L-Leu)2-Ac5c}2-OMe (
)
O2N
R1
O
R1
R2
(20 mol %)
R2
Foldamers are “oligomers with specific compact three-
(1)
(2)
+
PhCO2H (100 mol %)
THF (0.2 M), 40 °C, 48-264 h
dimensional structures”.1 Recently, foldamer- and peptide-
catalyzed asymmetric reactions have been increasingly reported
because foldamers are easily tailor-made for specific reactions,
non-toxic, and inert toward oxygen and moisture. For example,
helical urea oligomer-catalyzed 1,4-addition reactions,2 N-
terminal prolylproline-peptide-catalyzed C-C bond forming
up to >99% ee
MeNO2 (20 equiv)
O
O
P1
(20 mol %)
4a
CH2(CO2Bn)2
+
(3 equiv)
CO2Bn
PhCO2H (100 mol %)
THF (0.2 M), 40 °C, 96 h
( )n
( )n
5a 7a
1 3
-
CO2Bn
reactions,3
turn-structure
peptide-catalyzed
asymmetric
n = 0~2
-
: 89~98% ee
reactions,4 -peptide-catalyzed retro-aldol reactions,5 and resin-
bound helical peptide-catalyzed reactions6 have been reported.
O
O
P2
)
H-(L-Leu)2-{(L-Leu)2-Ac5c}2-OMe (
(20 mol %)
4a
(3 equiv)
Previously, Toniolo group and then we reported that peptides
+
(3)
CO2Bn
PhCO2H (100 mol %)
THF (0.2 M), 40 °C, 96 h
with -disubstituted -amino acids (dAAs) preferentially
formed helical secondary structures.7
Their helical-screw
CO2Bn
1
5a
: 98% ee
directions and the - or 310-helix of peptides were able to be
controlled by the selections of dAAs. Furthermore, we
2. Results and Discussion
demonstrated that helical L-Leu-based peptide-foldamers having
dAAs can be applied to chiral catalyses for enantioselective
First, we examined the 1,4-addition reaction of dibenzyl
malonate 4a to cyclohex-2-enone 1 using 20 mol % L-Leu-based
peptides (P3-P9) with an Ac5c in the presence of benzoic acid in
THF (Table 1). Although it has been reported that peptide-
catalysts having two Ac5c with the sequence -(L-Leu-L-Leu-
Ac5c)2- formed helical structure, the peptides P3-P9 have only
one helicogenic -disubstituted -amino acid Ac5c. The
position of an Ac5c in L-Leu-based heptapeptides only slightly
influenced the enantiomeric excess of 1,4-adduct 5a, except in
the case of N-terminal Ac5c. The N-terminal Ac5c (P3) was
detrimental to the 1,4-addition reaction because the amino group
at the quaternary carbon may be sterically hindered. Among the
heptapeptides (P3-P8) with an Ac5c examined, the peptide P5
with an Ac5c at the third position from the N-terminus exhibited
the greatest enantiomeric excess. Shortened tetrapeptide P9
reduced the enantiomeric excess of the 1,4-adduct to 81% ee,
whereas L-Leu heptapeptide P10 without an Ac5c gave 20% ee.
These low enantiomeric excesses may be due to neither a peptide
P9 nor P10 being able to form stable helical structures (vide
infra). The tetrapeptide P9 is too short to form a helical structure
and L-Leu-homopeptide P10 is too flexible to form a stable
helical secondary conformation.11 Replacement of the two N-
terminal L-Leu with L-Ala (P11) slightly reduced the
enantioselectivity (81% ee). The amount of peptide P5 loading
was reduced to 5 mol % without decreasing the enantiomeric
excess (94% ee); however the use of 1 mol % catalyst P5 reduced
the enantiomeric excess to 75% ee. In the reaction of 1, benzoic
acid was not necessary, and without benzoic acid, the 1,4-
addition reaction using P5 proceeded well to give the 1,4-adduct
5a with 97% ee in a good conversion.
epoxidation8 and 1,4-addition reactions.9
The helical
H-(L-Trp)2-(L-Leu-L-Leu-Ac5c)2-OMe
octapeptide-foldamer
(P1) (Ac5c: 1-aminocyclopentane-1-carboxylic acid) catalyzed
enantioselective 1,4-addition reactions of nitromethane (or
dibenzyl malonate) to -unsaturated ketones to give optically
active 1,4-adducts with up to >99% ee (Scheme 1, eq. 1). Some
chiral organocatalysts with an amino functional group catalyzed
enantioselective 1,4-addition reactions of dialkyl malonates to
cycloalk-2-enones, however; such a small organocatalyst was
unable to be applied to different ring sizes of cycloalk-2-
enones.10 In particular, the enantiomeric excess of 3-substituted
cyclopentanone by small organocatalysts was often
unsatisfactory. On the other hand, helical octapeptide-foldamer
P1-catalyzed 1,4-addition reaction of dibenzyl malonate to cyclic
-unsaturated ketones gave optically active 3-substituted
cycloalkanones (cyclopentanone: 89% ee; cyclohexanone: 93%
ee; cycloheptanone: 98% ee) (eq. 2).
Furthermore, the
octapeptide H-(L-Leu)4-Ac5c-(L-Leu)2-Ac5c-OMe (P2) without
N-terminal L-Trp residues catalyzed the enantioselective 1,4-
addition reaction of dibenzyl malonate to cyclohex-2-enone,
giving 98% ee of the 1,4-adduct (eq. 3).9 These results were
better than those by small organocatalysts,10 but the reaction
required high catalyst loading (20 mol %) and catalysts needed
two dAAs. Thus, there was room to improve the simplicity of
the foldamer-catalyst, the enantiomeric excess, and conversions
of 1,4-adducts. Here, we optimized the structure of peptide-
foldamers and reaction conditions, enabling highly
enantioselective 1,4-addition reactions of dialkyl malonates to
varying cycloalk-2-enones.
The effects of solvents on the 1,4-addition reaction of
cyclohex-2-enone 1 using 10 mol % of P5 are shown in Table 2.
The reaction slowly proceeded at a concentration of 0.1 M, and
conversions were generally moderate. The use of MeOH was
detrimental to the enantiomeric excess, but other solvents {THF,
EtOAc, 1,4-dioxane, CHCl3, MeCN, and cyclohexane (cHex)}
were suitable for the enantioselective reaction. cHex improved
the conversion, and the use of a mixture of THF and cHex (1 : 9)
at the concentration of 0.4 M greatly improved both the
conversion (>99%) and the enantiomeric excess (97% ee).
Scheme 1

3
Table 1. Peptide-foldamer-catalyzed enantioselective 1,4-addition reaction of dibenzyl malonate to cyclohex-2-enone.
20 mol % peptide
O
O
PhCO2H (1.0 equiv)
4a
CH2(CO2Bn)2
(3 equiv)
+
CO2Bn
CO2Bn
THF (0.2 M)
40 ºC, 20 h
1
5a
P3
P4
P5
O
O
H
O
O
O
H
H
H
H2N
N
OMe
H
N
N
OMe
N
OMe
N
H
N
H2N
H
5
2
4
6
O
O
O
97% ee (94% conv)
96% ee (94% conv)a
94% ee (79% conv)b
2% ee (trace)
96% ee (100% conv)
P6
P7
P8
O
O
O
O
O
H
H
H
H
H
H
H
N
N
OMe
H
N
N
CO2Me
H
N
N
OMe
N
N
N
H
H
H
2
4
3
3
O
5
O
O
93% ee (93% conv)
93% ee (97% conv)
91% ee (92% conv)
P9
P10
P11
O
O
O
H
H
N
H
H
H
N
CO2Me
N
N
OMe
N
H
N
N
H
2
H
H
NH2
H
N
2
2
O
O
O
H
2
O
7
20% ee (60% conv)
81% ee (83% conv)
81% ee (58% conv)
a10 mol % catalyst and PhCO2H (0.50 equiv) were used (48 h).
b 5 mol % catalyst and PhCO2H (0.25 equiv) were used (48 h).
worked as an excellent 1,4-addition acceptor. Using 5 mol %
peptide P5, 1,4-addition reactions with varying dialkyl malonates
proceeded to give 1,4-adducts with excellent enantiomeric
excesses in good isolated yields (entries 1-3). In the case of
diisopropyl malonate 4d, 5 mol % peptide P5 gave a low
chemical yield, and 10 mol % P5 was needed for a good
chemical yield (entry 4). This result may have been due to the
bulkiness of the diisopropyl group because di-tert-butyl malonate
did not react, although the electric properties of 4d may also be
concerned. Although the enantioselective 1,4-addition reaction
of cyclopent-2-enone 2 using small chiral organocatalysts often
gave a low enantiomeric excess of 1,4-adducts,10 the reactions
using 10 mol % peptide P5 with different dialkyl malonates
produced high enantiomeric excesses of 3-substituted
cyclopentanones 6 in moderate chemical yields (entries 5-8).
The 1,4-addition reaction of cyclohept-2-enone 3 using 10 mol %
peptide P5 with dibenzyl malonate also gave a 1,4-addition
product with a high enantiomeric excess, but the chemical yield
was low and the starting material was recovered. The isolated
chemical yield was improved to 61% using 20 mol % peptide P5
in THF. The 1,4-addition reactions of 3 with different dialkyl
Table 2. Effects of solvents.
O
O
P5
10 mol %
4a
CH2(CO2Bn)2
(3 equiv)
+
CO2Bn
CO2Bn
solvent (0.1 M)
40 °C
1
5a
time
(h)
conv
(%)
52
57
52
57
26
30
>99
85
entry
solvent
% ee
1
2
3
4
5
6
7
8
THF
89
97
63
95
94
93
90
92
96
98
98
97
MeOH
EtOAc
1,4-dioxane
CHCl3
MeCN
cHex
THF/cHex (3 : 1)
THF/cHex (1 : 1)
THF/cHex (1 : 3)
89
89
89
89
89
89
72
72
72
23
9
10
11
92
98
>99
malonates using 20 mol
% peptide P5 gave excellent
THF/cHex (1 : 9, 0.4 M)
enantiomeric excesses of 1,4-adducts, but the reaction was very
slow (5 days) and the isolated yields were unsatisfactory.
We examined different ring sizes of cycloalk-2-enones 1~3 as
1,4-addition acceptors and dialkyl malonates 4a~4d as donors
using peptide P5, as shown in Table 3. Cyclohex-2-enone 1
Table 3. Scope of substrates for enantioselective reactions.

4
Tetrahedron Letters
O
O
P5
5~20 mol %
4
CH2(CO2R)2
(3 equiv)
+
CO2R
CO2R
( )n
40 °C, 72~120 h
(0.4 M)
( )n
1 3
-
n = 0~2
5 7
-
isolated
yield
(%)
substrate
(n =)
%
ee
entry
R = mol %
solvent
THF/cHex
(1 : 9)
5a:
86
1
1: (1)
1: (1)
1: (1)
1: (1)
2: (0)
2: (0)
2: (0)
2: (0)
Bn
Me
Et
5
5
97
98
99
99
97
94
96
98
Scheme 2
O
P5
10 mol %
THF/cHex
(1 : 9)
5b:
79
4e
MeCH(CO2Bn)2
(3 equiv)
Me
CO2Bn
2
(1)
(2)
(3)
1
+
THF/cHex (1 : 9)
40 °C, 96 h
CO2Bn
5e
THF/cHex
(1 : 9)
5c:
74
3
5
99% ee, 33% yield
THF/cHex
(1 : 9)
5d:
78
4
iPr
Bn
Me
Et
10
10
10
10
10
O
O
P5
20 mol %
THF/cHex
(1 : 3)
6a:
78
5 a
6 a
7 a
8 a
4a
(3 equiv)
Me
CO2Bn
+
THF/cHex (1 : 9)
40 °C, 144 h
THF/cHex
(1 : 3)
6b:
40
Me
CO2Bn
8
9a
81% ee, 32% yield
THF/cHex
(1 : 3)
6c:
50
O
O
O
THF/cHex
(1 : 3)
6d:
41
P5
10 mol %
iPr
4a
(3 equiv)
+
+
CO2Bn
CO2Bn
Me CO2Bn
THF
THF/cHex
(1 : 9)
7a:
24
Me
rt, 22 h
9
3: (2)
3: (2)
Bn
Bn
10
10
99
97
Me CO2Bn
10
11a
11a
cis-
trans-
7a:
10
THF
THF
THF
THF
THF
11a
trans-
11a
(98% ee) = 2.2 : 1
48% conv
(93% ee) : cis-
37
7a:
11
12
13
14
3: (2)
3: (2)
3: (2)
3: (2)
Bn
Me
Et
20
20
20
20
98
99
99
99
61
7b:
The preferred secondary structures of catalyst P5 in solution
and in the crystalline state were next examined. In the H NMR
1
74
7c:
spectra of P5 in THF-d8, NOE correlations between the N(i)-H
and N(i+1)-H (i = 3~6) protons were observed. These NOE
correlations suggested the formation of a helical conformation by
these residues (3~7), although discrimination of a 310- or -helix
was not possible (Figure S1).12 The FT-IR absorption spectra of
Boc-protected P5 and P5 demonstrated weak absorption at 3430
cm-1 and strong absorption at 3330 cm-1 in Boc-protected P5, and
strong absorption at 3330 cm-1 in P5, suggesting a helical
conformation (Figure S2).13 Although the CD spectra of P6, P7,
and P8 in 2,2,2-trifluoroethanol solution (50 M) exhibited
negative maxima at around 205 nm and 222 nm, characteristic for
right-handed helical structures,14 the CD spectrum of P5 had a
negative maximum at 200 nm and very weak negative maximum
at around 230 nm, suggesting a helical structure together with
other conformations. The CD spectra of P9 and P10 did not
exhibit characteristic maxima for helical structure (Figure S3).
51
7d:
iPr
26
a The reaction was performed at 30ºC.
We examined 1,4-addition reactions for the construction of the
quaternary center (Scheme 2). The 1,4-addition reaction of 1
with dibenzyl 2-methylmalonate 4e using 10 mol % P5 gave a
highly enantiomeric excess 1,4-adduct (99% ee) with
a
quaternary carbon at a yield of 33%. On the other hand, the
enantioselective 1,4-addition reaction of 3-methylcyclohex-2-
enone 8 with dibenzyl malonate 4a using 20 mol % P5 slowly
proceeded to give a 1,4-adduct (moderate 81% ee) with a
quaternary stereogenic center at a yield of 32%. The reaction of
racemic 4-methylcyclohex-2-enone 10 with 4a using 10 mol %
P5 proceeded to give 3,4-trans-11a (93% ee) and 3,4-cis-11a
(98% ee) in the ratio of 2.2 to 1, accompanied by the recovery of
10 (48% ee) in a conversion of 48%. The 1,4-addition reaction
enantioselectively proceeded, but the kinetic resolution of
racemate 10 was moderate, and a mixture of the diastereomers
trans-11a and cis-11a was obtained.
Recrystallization of catalyst P5 from MeCN/H2O gave
crystals suitable for X-ray crystallographic analysis (Table S1).
The structure was solved in a triclinic P1 space group to visualize
two crystallographically independent molecules, A and B, in the
asymmetric unit.15 The molecules A and B were right-handed (P)
helical structures, and their peptide backbones were generally
similar (Figure 1). The averaged  and  torsion angles of
residues 2-7 were -78.7° and -31.6° in molecule A, and -79.7°
and -39.9° in molecule B, respectively. These values slightly
differed from those of an ideal right-handed 310-helix (-60°; -30°)
or -helix (-57°; -47°) (Table S2).16 The intramolecular
hydrogen bonds of N(i+3)-H···O=C(i) (i = 1~3) type (310-helix),
and those of N(i+4)-H···O=C(i) (i = 1~3) type (-helix) were
observed in both molecules A and B. Thus, N(5)-H was bound
by bifurcated hydrogen bonds to O(1)=C(1) and O(2)=C(2), and
N(6)-H was bound by bifurcated hydrogen bonds to O(2)=C(2)

5
7.
(a) Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.;
Cavicchioni, G.; Précigoux, G.; Aubry, A.; Kamphuis, J.
Biopolymers 1993, 33, 1061. (b) Toniolo, C.; Crisma, M.;
Formaggio, F.; Peggion, C. Biopolymers 2001, 60, 396. (c)
Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349. (d) Crisma, M.;
and O(3)=C(3), although the distance of N(6)···O(3) was long,
and it was a weak hydrogen bond in both molecules A and B
(Table S3).
Toniolo, C. Biopolymers 2015, 104, 46. (e) Crisma, C.; De Zotti,
M.; Formaggio, F.; Peggion, C.; Moretto, A.; Toniolo, C. J. Pept.
Sci. 2015, 21, 148.
8.
9.
(a) Nagano, M.; Doi, M.; Kurihara, M.; Suemune, H.; Tanaka, M.
Org. Lett. 2010, 12, 3564. (b) Y. Demizu, Y.; Yamagata, N.;
Nagoya, S.; Sato, Y.; Doi, M.; Tanaka, M.; Nagasawa, K.; Okuda,
H.; Kurihara, M. Tetrahedron 2011, 67, 6155.
(a) Ueda, A; Umeno, T.; Doi, M.; Akagawa, K.; Kudo, K.; Tanaka,
M. J. Org. Chem. 2016, 81, 6343. (b) Ueda, A.; Higuchi, M.;
Umeno, T.; Tanaka, M. Heterocycles 2019, 99, 989.
10. (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1176. (b) Yamaguchi, M.; Shiraishi, T.;
Hirama, M. J. Org. Chem. 1996, 61, 3520. (c) Wascholowski,
V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Eur. J.
2008, 14, 6155. (d) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang,
Y.; Liang, X.; Ye, J. Org. Lett. 2009, 11, 753. (e) Yoshida, M.;
Narita, M.; Hara, S. J. Org. Chem. 2011, 76, 8513. (f) Moritaka,
M.; Miyamae, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett
2012, 23, 2554. (g) Yoshida, M.; Kubara, A.; Nagasawa, Y.; Hara,
S.; Yamanaka, M. Asian J. Org. Chem. 2014, 3, 523. (h) Mase,
N.; Fukasawa, M.; Kitagawa, N.; Shibagaki, F.; Noshiro, N.;
Takabe, K. Synlett 2010, 15, 2340.
Figure 1. Superimposed structures of molecules A and B
determined by the X-ray crystallographic analysis of P5.
3. Conclusion
11. (a) Bonora, G. M.; Maglione, A.; Toniolo, C. Polymer 1974, 15,
767. (b) Toniolo, C.; Bonora, G. M. Makromol. Chem. 1974, 175,
1665. (c) Palumbo, M.; Da Rin, S.; Bonora, G. M.; Toniolo, C.
Makromol. Chem. 1976, 177, 1477. (d) Toniolo, C.; Palumbo, M.
Biopolymers 1977, 16, 219. (e) Kelly, M. M.; Pysh, E. S.; Bonora,
G. M.; Toniolo, C. J. Am. Chem. Soc. 1977, 99, 3264.
12. (a) Wagner, G.; Neuhaus, D.; Wörgötter, E.; Vasak, M.; Kägi, J. H.
R.; Wüthrich, K. J. Mol. Biol. 1986, 187, 131. (b) Mammi, S.;
Rainaldi, M.; Bellanda, M.; Schievano, E.; Peggion, E.;
Broxterman, Q. B.; Formaggio, F.; Crisma, M.; Toniolo, C. J. Am.
Chem. Soc. 2000, 122, 11735.
In summary, we demonstrated that an L-Leu-based
heptapeptide having only one cyclic -disubstituted -amino
acid Ac5c preferentially formed a right-handed (P) helical
structure. The peptide-foldamer P5 was able to catalyze the
enantioselective 1,4-addition reaction of varying dialkyl
malonates to cycloalk-2-enones with excellent enantiomeric
excesses, regardless of the ring sizes of substrates.
13. (a) Crisma, M.; Bonora, G. M.; Toniolo, C.; Benedetti, E.; Bavoso,
A.; Di Blasio, B.; Pavone, V.; Pedone, C. Int. J. Biol. Macromol.
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Nagano, M.; Suemune, H.; Tanaka, M. Org. Biomol. Chem. 2011,
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Acknowledgments
This study was supported in part by JSPS KAKENHI Grant
Numbers JP-17H03998 (for M. T.), JP-18K14870 (for A. U.),
and JP- 17J05108 (for T. U.).
Supplementary Material
Supplementary data (Experimental section, spectroscopic data
of new compounds, NOE H NMR spectra of P5, FT-IR spectra
15. CCDC 1923343 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing
1
of Boc-P5 and P5, CD spectra of peptides, X-ray
crystallographic parameters of P5, H and 13C NMR chart, and
1
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
HPLC chart for determination of % ee (PDF)) associated with
this article can be found in the online version, at
http://xxxxxxxxxx.
16. (a) Toniolo, C.; Benedetti, E. Trends Biochem. Sci. 1991, 16, 350.
(b) Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas. 1994, 113, 1.
(c) Pal, L.; Basu, G.; Chakrabarti, P. Proteins: Struct. Funct.
Genet. 2002, 48, 571. (d) Toniolo, C.; Crisma, M.; Formaggio, F.;
Peggion, C.; Broxterman, Q. B.; Kaptein, B. Biopolymers (Pept.
Sci.) 2004, 76, 162.
References and notes
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Huc, I. “Foldamers: Structure, Properties, and Applications”.
Wiley‐VCH Verlag GmbH & Co., 2007. (d) Fischer, L.;
Guichard, G. Org. Biomol. Chem. 2010, 8, 3101.
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Bécart, D.; Diemer, V.; Salaün, A.; Oiarbide, M.; Reddy Nelli,
Y.; Kauffmann, B.; Fischer, L.; Palomo, C.; Guichard, G. J. Am.
Chem. Soc. 2017, 139, 12524.
(a) Wennemers, H. Chem. Commun. 2011, 47, 12036. (b)
Rigling, C.; Kisunzu, J. K.; Duschmalé, J.; Häussinger, D.;
Wiesner, M.; Ebert, M. O.; Wennemers, H. J. Am. Chem. Soc.
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4.
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Metrano, A. J.; Miller, S. J. Acc. Chem. Res. 2019, 52, 199.
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6.

6
Tetrahedron Letters
L-Leu-based helical structure was constructed using
only one cyclic amino acid
Helical peptide catalyzed asymmetric 1,4-addition
reactions to varying cyclic enones
High enantiomeric excesses of 3-substituted
cycloalkanones (5~7 rings) were obtained
Reaction proceeded under mild reaction conditions
(40ºC) and no additive was needed