Enantioselective epoxidation of α,β-unsaturated ketones catalyzed by stapled helical l-Leu-based peptides

Article abstract of DOI:10.1016/j.tet.2011.06.075

Stapled helical l-leucine-based heptapeptides were synthesized and used as catalysts for the enantioselective epoxidation of α,β-unsaturated ketones. All N-terminal free stapled peptides were successfully used as chiral catalysts. Among them, the use of H-hS₃,₇hS-10 gave epoxide products with high enantioselectivities of up to 99% ee. Furthermore, the dominant conformations of the N-terminal protected stapled peptides R ₃,₇R-10 and hS₃,₇hS-10 were investigated by ¹H NMR, IR, CD spectra, and X-ray crystallographic analysis. The peptide R₃,₇R-10 formed a right-handed (P) α-helix in solution and in the crystalline state, while hS ₃,₇hS-10 formed a right-handed (P) 3₁₀-helix in solution.

Full text of DOI:10.1016/j.tet.2011.06.075

Tetrahedron 67 (2011) 6155e6165
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective epoxidation of a,b-unsaturated ketones catalyzed by stapled
helical
L-Leu-based peptides
,
a,
Yosuke Demizu a , Nanako Yamagata b, Saori Nagoya a, Yukiko Sato a, Mitsunobu Doi c,
*
Masakazu Tanaka d, Kazuo Nagasawa b, Haruhiro Okuda a, Masaaki Kurihara a
,
*
a Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan
b Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
c Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
d Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2011
Received in revised form 21 June 2011
Accepted 22 June 2011
Available online 29 June 2011
Stapled helical
selective epoxidation of
L
-leucine-based heptapeptides were synthesized and used as catalysts for the enantio-
a,b
-unsaturated ketones. All N-terminal free stapled peptides were successfully
used as chiral catalysts. Among them, the use of H-hS3,7hS-10 gave epoxide products with high enan-
tioselectivities of up to 99% ee. Furthermore, the dominant conformations of the N-terminal protected
stapled peptides R3,7R-10 and hS3,7hS-10 were investigated by 1H NMR, IR, CD spectra, and X-ray crys-
tallographic analysis. The peptide R3,7R-10 formed a right-handed (P)
crystalline state, while hS3,7hS-10 formed a right-handed (P) 310-helix in solution.
a-helix in solution and in the
Keywords:
Stapled peptide
Helix
Ó 2011 Elsevier Ltd. All rights reserved.
Organocatalyst
Enantioselective epoxidation
a,b-Unsaturated ketones
1. Introduction
The de novo design of peptides and proteins is of extraordinary
importance in the fields of organic chemistry, nanotechnology, and
medicinal chemistry. A variety of approaches to controlling the
conformations of peptides have been investigated,1 and the in-
O
O
O
O
O
H
N
H
N
H
N
Boc
N
H
N
H
N
H
N
H
CO2Me
R
R
corporation of a,a-disubstituted a
-amino acids2 and cross-linked
O
O
O
side chains3 into peptide sequences is of vital importance for con-
structing stable helical structures. Recently, we have reported that
residue
1
2
3
4
5
6
7
numbering
the
contains an
a helical promoter and
seventh (7R) positions as a cross-linked subunit,5 formed a stable
right-handed (P)
-helix (Fig. 1).6 Furthermore, its N-terminal free
L
-leucine (
-aminoisobutyric acid (Aib)4 at its fourth position as
-serine derivatives at its third (R3) and
L
-Leu) rich stapled heptapeptide R3,7R-10, which
a
stapled heptapeptide R3,7R-10
D
Fig. 1. Chemical structure of the stapled heptapeptide R3,7R-10. The nomenclature
R3,7R refers to a peptide with an R configuration at its third position and an R con-
figuration at its seventh position.
a
H-R3,7R-10 was successfully used as a chiral catalyst for the enan-
tioselective epoxidation of (E)-chalcone.7 However, the enantioface
discrimination by H-R3,7R-10 was not so succesful.6 As part of our
ongoing research, we prepared stapled peptides with different
side-chain lengths at the third and seventh positions and used
2. Results and discussion
Stapled peptides were synthesized as follows (Scheme 1). First,
the hydroxy group of Boc-L/D-Ser or Boc-L-homoserine (Boc-L-Hse)
was allylated, and then treatment with 1 M HCl in MeOH afforded
the amino acid esters (S)-3, (R)-3, and (S)-4. The linear heptapep-
tides S3,7S-9, S3,7R-9, R3,7S-9, R3,7R-9, hS3,7S-9, hS3,7R-9, and
hS3,7hS-9 were prepared by conventional solution-phase methods
them for the catalytic enantioselective epoxidation of
saturated ketones.
a,b-un-
* Corresponding authors. Tel.: þ81 3 3700 1141; fax: þ81 3 3707 6950; e-mail
addresses: demizu@nihs.go.jp (Y. Demizu), masaaki@nihs.go.jp (M. Kurihara).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.075

6156
Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
OH
n
O
O
n
n
1M HCl in MeOH
NaH, allyl bromide
DMF, rt
Boc
Boc
N
H
CO2H
HCl H2N
CO2Me
N
H
CO2H
Boc-
L
/
D
-Ser (n = 1)
(S)-1, (R)-1 (n = 1)
(S)-3, (R)-3 (n = 1)
Boc-
L
-Hse (n = 2)
(S)-2
(n = 2)
(S)-4
(n = 2)
O
O
Boc-(
L
-Leu)2-OH
O
H
O
1) TFA, CH2Cl2
EDC, HOBt, DIPEA
n
n
H
N
N
Boc
Boc
N
H
CO2Me
N
H
N
CO2Me
CH2Cl2, rt
2) Boc-Aib-OH, EDC,
HOBt, DIPEA
H
2
O
2
(S)-7, (R)-7 (n = 1)
(S)-8 (n = 2)
(S)-5, (R)-5 (n = 1)
(S)-6
(n = 2)
1) deprotection
2) coupling
O
n
O
1) 2nd Grubbs cat.
2) H2, Pd-C
O
O
O
n
H
N
H
N
H
N
Boc
N
H
N
H
N
H
N
CO2Me
H
O
O
O
S3,7S-9, S3,7R-9, R3,7S-9, R3,7R-9, hS3,7S-9, hS3,7R-9, hS3,7hS-9
O
n
O
S
: L-Ser derivative
O
O
O
H
N
H
N
H
N
n
R
D
:
-Ser derivative
L-Hse derivative
Boc
hS :
N
H
N
H
N
H
N
CO2Me
H
O
O
O
S , S-10 S , R-10 R , S-10 R , R-10 hS , S-10 hS , R-10 hS , hS-10
,
,
,
,
,
,
3 7
3 7
3 7
3 7
3 7
3 7
3 7
Scheme 1. Synthesis of the stapled heptapeptides S3,7S-10, S3,7R-10, R3,7S-10, R3,7R-10, hS3,7S-10, hS3,7R-10, and hS3,7hS-10. The nomenclature hS indicates an L-homoserine (L-Hse)
derivative.
with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
1-hydroxybenzotriazole (HOBt) as coupling reagents. Then, intra-
molecular ruthenium-catalyzed ring-closing metathesis reactions
involving the linear peptides gave stapled peptides as a mixture of
olefin isomers (the E/Z ratio of isomers was not determined). The
subsequent hydrogenation of the olefin mixtures afforded the
saturated stapled peptides S3,7S-10, S3,7R-10, R3,7S-10, R3,7R-10,
hS3,7S-10, hS3,7R-10, and hS3,7hS-10.
We examined the enantioselective epoxidation of (E)-chalcone
(11a) using N-terminal free peptides (Table 1).8,9 The epoxidation of
11a using 5 mol % of peptides was carried out in THF containing
urea-H2O2 (UHP) and DBU under aerobic conditions with the
temperature gradually increasing from 0 ꢀC to room temperature
over 24 h. In all cases, the epoxidation proceeded smoothly to af-
ford the (2R,3S)-epoxidated chalcone 12a in high yield. The use of
the stapled peptides gave (2R,3S)-12a with higher enantiose-
lectivity than those produced using the linear peptides (entries
1e14). Among the stapled peptides H-S3,7S-10, H-S3,7R-10, H-R3,7S-
10, and H-R3,7R-10 (entries 2, 4, 6, 8) with the same-length linker,
the reaction by H-R3,7R-10 proceeded with the most enantiose-
lective efficiency.6 Among H-S3,7S-10, H-hS3,7S-10, and H-hS3,7hS-
10 (entries 2, 10, 14), which have the different side-chain lengths,
the use of H-hS3,7hS-10 afforded (2R,3S)-12a with the highest en-
antiomeric excess (87% ee). Furthermore, using 10 mol % H-hS3,7hS-
10 (entry 15), (2R,3S)-12a was obtained in almost complete enan-
tioselectivity (99% ee).

Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
6157
Table 1
spectra of both R3,7R-10 and hS3,7hS-10 were very similar to those
of helical peptides in solution.12
Asymmetric epoxidation of (E)-chalcone (11a) using the N-terminal free peptides
Peptide (5 mol %)
Next, the preferred conformations of R3,7R-10 and hS3,7hS-10
were studied in CDCl3 solution using 1H NMR spectroscopy. Fig. 3
shows a solvent perturbation experiment involving the addition
of the strong H-bond acceptor solvent DMSO (0e10% (v/v)). Three
NH [N(1)eH, N(2)eH, and N(3)eH] chemical shifts in R3,7R-10 were
sensitive to the addition of the perturbing reagent DMSO (Fig. 3A).
These results demonstrate that the three NH protons are solvent-
exposed, suggesting that they are not intramolecularly hydrogen-
UHP (1.1 Eq.)
DBU (5.6 Eq.)
O
O
O
S
Ph
Ph
11a
Ph
Ph
THF,0° C to rt, 24h
R
12a
(E)-chalcone (
)
(2R,3S)-
Entry
Peptide
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
H-S3,7S-9
H-S3,7S-10
H-S3,7R-9
H-S3,7R-10
H-R3,7S-9
H-R3,7S-10
H-R3,7R-9
H-R3,7R-10
H-hS3,7S-9
H-hS3,7S-10
H-hS3,7R-9
H-hS3,7R-10
H-hS3,7hS-9
H-hS3,7hS-10
H-hS3,7hS-10
90
89
91
89
82
86
93
89
94
96
96
95
97
93
99
58
65
57
64
35
37
30
69
77
79
71
75
79
87
>99
bonded and are in accord with an a-helical structure. In the pep-
tide hS3,7hS-10, two NH [N(1)eH and N(2)eH] chemical shifts were
sensitive to the addition of the perturbing reagent DMSO (Fig. 3B),
indicating a 310-helical structure.4d
The CD spectra of the N-terminal protected linear peptides
R3,7R-9 and hS3,7hS-9 and the stapled peptides R3,7R-10 and
hS3,7hS-10 were measured in 2,2,2-trifluoroethanol (TFE) solution.
The CD spectra of all four peptides showed negative maxima at
around 204 and 222 nm, indicating a right-handed helical-screw
9
10
11
12
13
14
15a
sense (P) (Fig. 4).13 The R ratio (q222
/q204) suggested that the dom-
inant secondary structure of the linear R3,7R-9 peptide was a 310
-
helix (R¼0.3)13,14 and that of the corresponding stapled R3,7R-10
-helix (R¼0.8, Fig. 4A).13 The dominant secondary
a
Catalyst (10 mol %) was used.
peptide was an
a
structures of both the linear peptide hS3,7hS-9 and the stapled
peptide hS3,7hS-10 were 310-helices (R¼0.3, Fig. 4B).14 The intensity
of the CD spectrum for the stapled peptide hS3,7hS-10 was in-
creased compared with that of the linear peptide hS3,7hS-9, in-
dicating that the stapled peptide hS3,7hS-10 formed a more helical
structure than the linear peptide hS3,7hS-9.14
Next, we examined the asymmetric epoxidation of several
acyclic -unsaturated ketones (11aeh) using 10 mol % H-hS3,7hS-
a,b
10 (Table 2).10,11 The substrates were converted to the corre-
sponding epoxides in high yield (87e99%; entries 1, 5e8) although
the yields of the substrates containing an alkyl substituent as the R2
were low (entries 2e4). The epoxide in which R1¼Ph and R2¼2-
furanyl was obtained with excellent enantiomeric excess (99% ee,
entry 5), while the enantioselectivities of other epoxides were
moderate to high (72e88% ee, entries 2e4, 6e8).
The stapled peptide R3,7R-10 formed good crystals for X-ray
crystallographic analysis by slow evaporation of the solvent CHCl3/
n-hexane at room temperature. The crystal and diffraction pa-
rameters of R3,7R-10 are summarized in Table 3, and the relevant
Table 2
Asymmetric epoxidation of
a,
b
-unsaturated ketones (11aeh) using H-hS3,7hS-10
O
O
O
O
O
H
H
N
H
N
N
H2N
N
H
N
H
N
H
CO2Me
O
O
O
O
O
H-hS , hS-10
3 7
O
(10 mol %), UHP (1.1 Eq.), DBU (5.6 Eq.)
S
R1
R2
11a 11h
R1
R2
R
THF,0° C to rt, 24h
12a 12h
-
-
Entry
Substrate
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
11a: R1¼Ph, R2¼Ph
98
49
78
60
99
99
99
87
99
72
86
88
99
72
85
74
11b: R1¼Ph, R2¼Me
11c: R1¼Ph, R2¼iPr
11d: R1¼Ph, R2¼tBu
11e: R1¼Ph, R2¼2-furanyl
11f: R1¼Me, R2¼Ph
11g: R1¼4-ClePh, R2¼Ph
11h: R1¼4-MeOePh, R2¼Ph
To obtain information on the preferred conformations of the N-
terminal protected stapled peptides R3,7R-10 and hS3,7hS-10, the
FT-IR spectra of the NH-stretching region (amide A:
3250e3500 cmꢁ1) were measured in CDCl3 solution (Fig. 2, peptide
concentration: 1.0 mM). The weak bands around the 3430 cmꢁ1
region were assigned to free (solvated) peptide NH groups, and the
strong bands around the 3330 cmꢁ1 region were assigned to pep-
tide NH groups with NeH/O]C intramolecular H-bonds. The IR
backbone and side-chain torsion angles, and intra- and in-
termolecular hydrogen-bond parameters are listed in Tables 4 and
5, respectively. Data collection was performed on Bruker AXS
SMART APEX imaging plate diffractometers using graphite-
monochromated Mo Ka radiation. All crystals remained stable
during the X-ray-data collection. The structure of R3,7R-10 was
solved using the SHELXS 97 direct method15 and expanded by the
Fourier technique.16 All non-H-atoms were given anisotropic

6158
Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
Fig. 2. FT-IR spectra (3250e3500 cmꢁ1 region) of (A) R3,7R-10 and (B) hS3,7hS-10 in CDCl3 solution. Peptide concentration: 1.0 mM.
Fig. 3. 1H NMR experiment involving the addition of DMSO to the CDCl3 solution of (A) R3,7R-10 and (B) hS3,7hS-10. Plots of NH chemical shifts in the 1H NMR spectra of R3,7R-10
and hS3,7hS-10 as a function of increasing concentrations of DMSO (v/v) being added to the CDCl3 solution. Peptide concentration: 1.0 mM.
Fig. 4. 190e260 nm Region of the CD spectra of (A) the linear peptide R3,7R-9 (solid line) and the stapled peptide R3,7R-10 (dashed line), and (B) the linear peptide hS3,7hS-9 (solid
line) and the stapled peptide hS3,7hS-10 (dashed line) in TFE solution. Peptide concentration: 0.5 mM.
thermal parameters, some H-atoms were refined isotropically, and
the remaining H-atoms were placed at the calculated positions. The
final cycle of full-matrix least-squares refinement of R3,7R-10 gave
and ꢁ46.9ꢀ, respectively, which are close to the values for an ideal
right-handed (P)
a
-helix (ꢁ60ꢀ and ꢁ45ꢀ), and the torsion angles of
D
-Ser (7) were distorted (
f
¼65.0ꢀ,
j
¼ꢁ170.5ꢀ). Fig. 5 shows the
an R1 factor of 0.0719 on the basis of 4202 (I>2
s
(I)) reflections and
X-ray structure of the (P) a-helical wheel as viewed from positions
an Rw factor of 0.2165 for all data.17
perpendicular to and along the helical axis. Three intramolecular
hydrogen bonds, which formed a 13-membered (atoms) pseudo
ring of the i)iþ4 type, were observed between the HeN(4) and
In the asymmetric unit of the stapled peptide R3,7R-10, only one
right-handed (P) -helical conformer of the peptide molecule was
a
ꢀ
detected, together with a chloroform molecule. The mean values of
C(0)]O(0) [N(4)/O(0)¼2.92 A], the HeN(5) and C(1)]O(1)
torsion angles of amino acid residues (1e6) were ꢁ67.2ꢀ
[N(5)/O(1)¼3.17 A], and the HeN(7) and C(3)]O(3) groups
ꢀ
the
f
and
j

Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
6159
Table 3
molecules were connected by intermolecular hydrogen bonds,
forming head-to-tail aligned chains, as shown in Fig. 6.
Crystal and diffraction parameters for R3,7R-10
Formula
C44H79O12N7, CHCl3
Mr
1017.51
Crystal dimensions [mm]
T [K]
0.40ꢂ0.30ꢂ0.01
240
Crystal system
Monoclinic
10.728, 18.340, 14.943
90, 105.782, 90
2829.3
P21
ꢀ
a, b, c [A]
a
,
b
,
g
[ꢀ]
3
ꢀ
V [A ]
Spacer group
Z
2
D calcd [g/cm3]
1.194
0.22
m
(Mo Ka ]
) [cmꢁ1
Fig. 6. Packing of R3,7R-10 in the crystalline state. The intramolecular (blue) and in-
termolecular (red) hydrogen bonds are indicated as dashed lines.
No. of observations
No. of variables
R1, Rw
4202 (I>2s(I))
604
0.0719, 0.2165
Solvent
CHCl3/n-hexane
The dominant conformations of the stapled heptapeptides
R3,7R-10 and hS3,7hS-10 in solution were found to be helical
structures. Judging from R values of their CD spectra in TFE solution,
Table 4
Selected torsion angles (
u, f, j, and c
[ꢀ]) for R3,7R-10
the peptide hS3,7hS-10, which contained cross-linked L-homoserine
derivatives at its third and seventh positions, formed a stable right-
Residue
Torsion angle
handed (P) 310-helix, as reported by O’Leary and Grubbs.5 On the
f
j
u
c
other hand, the peptide R3,7R-10, which is tethered by
derivatives at the third and seventh positions, formed a (P)
D
-serine
-helix.
L
L
-Leu(1)
-Leu(2)
-Ser(3)
ꢁ75.2
ꢁ62.2
ꢁ52.6
ꢁ57.7
ꢁ67.8
ꢁ87.9
65.0
ꢁ50.5
ꢁ38.5
ꢁ52.3
ꢁ37.4
ꢁ28.7
ꢁ74.2
176.3
176.5
ꢁ177.9
ꢁ178.9
179.1
ꢁ70.0
ꢁ172.9
165.6
d
a
These results might be attributed to the fact that the R configura-
tions of the third and seventh -serine residues and the length of
CeC tether stabilize -helices more than 310-helices.
The N-terminal free stapled peptides catalyzed the enantio-
selective epoxidation of -unsaturated ketones to afford epox-
D
Aib(4)
L
L
D
-Leu(5)
-Leu(6)
-Ser(7)
ꢁ62.7
ꢁ65.5
ꢁ69.9
a
ꢁ176.7
D
ꢁ170.5
ꢁ176.1
a,b
ides with higher enantioselectivities than those produced using
the linear peptides. Among the stapled peptides, the use of H-
hS3,7hS-10 gave epoxides with the highest enantioselectivity,
even though the corresponding N-terminal protected peptide
hS3,7hS-10 formed a 310-helix. According to Roberts’ model, the
Table 5
Intra- and intermolecular H-bond parameters for R3,7R-10a
Donor DeH
Acceptor A
Distance D/A
Angle [ꢀ]
Symmetry
operations
DeH/A
three N-terminal protons in a-helical peptides without an N-ter-
N4eH
N5eH
N6eH
N7eH
N1eH
N2eH
N3eH
CCl3eH
O0
O1
O2
O3
2.92
3.17
3.26b
2.92
3.04
3.03
2.96
3.12
158.2
150.7
143.0
140.3
161.7
151.3
154.6
172.9
x, y, z
x, y, z
x, y, z
x, y, z
1þx, y, z
1þx, y, z
1þx, y, z
1þx, y, z
minal N(1)eH proton, N(2)eH, N(3)eH, and N(4)eH, are crucial
for asymmetric induction.9b,19 In addition, 310-helical peptides
possess less catalytic activity than
these points into account, N-terminal free H-hS3,7hS-10 might
form a mixture of
/310-helices under our reaction conditions.21
Although R3,7R-10 was folded into a right-handed (P) -helix,
a
-helical peptides.9e,20 Taking
0
O4
0
O5
a
0
O6
0
O5
a
a
the enantioselectivity of the epoxychalcone 11a produced using
N-terminal free H-R3,7R-10 was lower than that produced using
H-hS3,7hS-10. This can be attributed to the fact that having a third
The amino acid numbering begins at the N-terminus of the peptide chain.
The distance is a bit long for a hydrogen bond.
b
D
-serine residue with an R configuration, which results in the
formation of a hydrogen bond with the chalcone peroxide enolate,
is less favorable than the S configuration produced by a third
L
-
homoserine residue.9b,19
3. Conclusion
We have synthesized
serine, -serine, and
L-Leu-rich peptides that are tethered by
-homoserine derivatives at their third and
L
-
D
L
seventh positions. All N-terminal free stapled peptides were suc-
cessfully used as chiral catalysts for the enantioselective epoxida-
tion of (E)-chalcone. In addition, the use of H-hS3,7hS-10 gave
Fig. 5. X-ray diffraction structure of R3,7R-10, (A) as viewed perpendicular to the he-
lical axis and (B) an ORTEP drawing as viewed along the helical axis.
epoxide products of
a,b-unsaturated ketones with high enantio-
selectivities. Our results provide valuable information for the de-
sign of stabilized short helical peptides, which can be applied to
asymmetric reactions.
ꢀ
[N(7)/O(3)¼2.92 A], and one weak intramolecular hydrogen bond
was detected between the HeN(6) and C(2)]O(2) groups [N(6)/
ꢀ
O(2)¼3.26 A]. In packing mode, three intermolecular hydrogen
4. Experimental
bonds were formed between the HeN(1) and O(40) [N(1)/O(40)¼
0
0
ꢀ
ꢀ
3.04 A], the HeN(2) and O(50) [N(2)/O(5 )¼3.03 A], and the
4.1. General methods
0
ꢀ
HeN(3) and O(6 ) [N(3)/O(6 )¼2.96 A] groups. Furthermore,
the chloroform molecule was 0held in plac0e by a weak hydrogen
Optical rotations [
a] were measured with JASCO P-2200 po-
D
bond between HeCCl3 and O(5 ) [Cl3C/O(5 )¼3.12 A].18 The helical
larimeter using a 1.0 dm cell in CHCl3. 1H NMR spectra were
ꢀ

6160
Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
recorded on a Varian AS 400 spectrometer in CDCl3 with tetrame-
thylsilane used as an internal standard. FT-IR spectra were recorded
on a JASCO FT-IR-4100 spectrometer at 1 cmꢁ1 resolution, with an
average of 128 scans used for the solution (CDCl3) method and
a 0.1 mM path length for NaCl cells. ESI-MS spectra were taken on
a SHIMADZU LCMS-IT-TOF spectrometer. CD spectra were recorded
with a Jasco J-720 W spectropolarimeter using a 1.0 mm path
length cell. 2,2,2-Trifluoroethanol (TFE) was used as a solvent.
(S)-1, (R)-1, and(S)-2weresynthesizedinaccordancewithRef. 22.
d 172.6, 171.6, 170.4, 134.0, 117.6, 117.5, 72.2, 72.2, 69.3, 52.6, 52.5,
51.6, 41.2, 40.9, 40.7, 28.2, 24.8, 24.7, 24.6, 23.0, 22.8, 22.0, 21.9, 21.8;
[HR-ESI(þ)]: m/z calcd for C24H43N3O7Na [MþNa]þ 508.2999:
found 508.2996.
4.1.6. Boc-L-Leu-L-Leu-L-Hse(O-allyl)-OMe [(S)-6]. Tripeptide (S)-6
was prepared using a similar method to that described for the
preparation of (S)-5. 63% yield; Colorless crystals; mp 113e115 ꢀC;
½
a 2D4
ꢃ
ꢁ39.5 (c 0.50, CHCl3); IR (in CDCl3)
n
3326, 2960, 2872, 1676,
1502 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.96 (d, J¼7.2 Hz, 1H), 6.50
4.1.1. O-Allyl-
L
-serine methyl ester (
L
-Ser(O-allyl)-OMe) hydrochlo-
(d, J¼7.6 Hz,1H), 5.90 (m,1H), 5.20e5.31 (m, 2H), 4.85 (br s,1H), 4.65
(m, 1H), 4.46 (m, 1H), 4.11 (br s, 1H), 3.94 (d, J¼5.6 Hz, 2H), 3.73 (s,
3H), 3.72 (m, 1H), 3.49e3.57 (m, 3H), 2.06e2.19 (m, 2H), 1.64e1.70
(m, 4H),1.46 (s, 9H), 0.92e0.95 (m,12H); 13C NMR (100 MHz, CDCl3)
ride [(S)-3]. Compound (S)-1 (24 mmol, 5.9 g) in 1 M HCl in MeOH
(100 mL) was stirred at room temperature for 12 h. The solution
was then evaporated to give (S)-3 (4.7 g, quant.) as colorless crys-
tals, which were used next reaction without further purification.
d
172.4,172.0,171.5,134.3,117.3, 72.1, 66.6, 66.4, 52.3, 51.5, 50.9, 41.5,
Colorless crystals; mp 99e101 ꢀC; ½a D24
ꢃ
þ14.8 (c 0.30, MeOH); 1H
40.9, 31.2, 28.3, 24.7, 24.6, 22.9, 22.0; [HR-ESI(þ)]: m/z calcd for
NMR (400 MHz, CD3OD) d 5.91 (m, 1H), 5.21e5.35 (m, 2H), 4.30 (m,
C25H45N3O7Na [MþNa]þ 522.3155: found 522.3152.
1H), 4.04e4.08 (m, 2H), 3.93 (d, J¼4.4 Hz,1H), 3.91 (d, J¼4.8 Hz,1H),
3.85 (s, 3H), 13C NMR (100 MHz, CD3OD)
d
169.0, 135.1, 118.3, 73.3,
4.1.7. Boc-Aib-L-Leu-L-Leu-L-Ser(O-allyl)-OMe [(S)-7]. Trifluoroacetic
67.9, 54.4; [HR-ESI(þ)]: m/z calcd for C7H13NO3Na [MþNa]þ
acid (15 mL) was added to a solution of (S)-5 (6.2 g, 12.7 mmol) in
CH2Cl2 (15 mL) at 0 ꢀC, and the whole was stirred at room tem-
perature for 1 h. Removal of the solvent afforded a crude amine,
which was used without further purification. A mixture of EDC
(11.3 g, 59 mmol), HOBt (8.0 g, 59 mmol), and Boc-Aib (10.0 g,
49.2 mmol) in CH2Cl2 (280 mL) was stirred at 0 ꢀC for 30 min, then,
a solution of amine in CH2Cl2 (50 mL) and DIPEA (14.7 mL,
84.4 mmol) was added. After being stirred at room temperature for
12 h, the solution was diluted with EtOAc, washed with 3% aqueous
HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. After re-
moval of the solvent, the residue was purified by column chroma-
tography on silica gel (n-hexane/AcOEt¼1:1) to give tetrapeptide
182.0793: found 182.0794.
4.1.2. O-Allyl-D-serine methyl ester (D-Ser(O-allyl)-OMe) hydrochlo-
ride [(R)-3]. Compound (R)-3 was prepared using a similar method
to that described for the preparation of (S)-3. ½a D24
ꢃ
ꢁ14.2 (c 0.30,
MeOH).
4.1.3. O-Allyl-
L
-homoserine methyl ester (
L
-Hse(O-allyl)-OMe) hy-
drochloride [(S)-4]. Compound (S)-4 was prepared using a similar
method to that described for the preparation of (S)-3. Yellow oil;
½
a 2D4
ꢃ
þ24.8 (c 0.1, MeOH); 1H NMR (400 MHz, CD3OD)
d 5.91 (m,
1H), 5.19e5.30 (m, 2H), 4.17 (m, 1H), 4.00 (d, J¼1.2 Hz, 1H), 3.94 (d,
(S)-7 (5.8 g, 81%). Foam; ½a D24
ꢃ
ꢁ24.3 (c 0.50, CHCl3); IR (in CDCl3):
n
J¼1.2 Hz, 1H), 3.83 (s, 3H), 3.70e3.74 (m, 2H), 2.17e2.24 (m, 2H), 13C
3439, 3335, 2961, 2874, 1677, 1516 cmꢁ1; 1H NMR (400 MHz, CDCl3)
NMR (100 MHz, CD3OD)
d
170.7, 135.8, 117.5, 73.0, 66.7, 53.7, 52.5,
d
7.18 (br s, 1H) 7.10 (d, J¼7.2 Hz, 1H), 6.56 (d, J¼6.4 Hz, 1H), 5.85 (m,
31.2; [HR-ESI(þ)]: m/z calcd for C8H15NO3Na [MþNa]þ 196.0950:
1H), 5.14e5.26 (m, 2H), 4.92 (br s, 1H), 4.85 (m, 1H), 4.52 (m, 1H),
4.31 (m, 1H), 3.95e3.99 (m, 2H), 3.83 (m, 1H), 3.75 (s, 3H), 3.71 (m,
1H), 1.48e1.83 (m, 6H), 1.48 (s, 6H), 1.44 (s, 9H), 0.87e0.99 (m, 12H);
found 196.0948.
4.1.4. Boc-
L
-Leu-
L
-Leu-
L
-Ser(O-allyl)-OMe [(S)-5]. A mixture of Boc-
13C NMR (100 MHz, CDCl3)
d 174.8, 172.1, 172.0, 170.6, 155.2, 134.3,
(
L
-Leu)2-OH (12.2 g, 35.5 mmol), (S)-3 (6.9 g, 35.5 mmol), EDC
117.1, 80.9, 72.0, 69.3, 56.9, 52.8, 52.6, 52.4, 51.7, 40.2, 40.1, 28.2, 28.2,
26.4, 25.0, 24.7, 23.1, 23.0, 21.5, 21.4; [HR-ESI(þ)]: m/z calcd for
C28H50N4O8Na [MþNa]þ 593.3526: found 593.3519.
(8.2 g, 42.6 mmol), HOBt (5.8 g, 42.6 mmol), and DIPEA (13.6 mL,
78.1 mmol) in CH2Cl2 (300 mL) was stirred at room temperature for
12 h. The solution was then evaporated, diluted with AcOEt
(300 mL), washed with 3% aqueous HCl, 5% NaHCO3, and brine, and
dried over anhydrous MgSO4. Evaporation of the solvent gave
a white solid, which was purified by column chromatography on
silica gel (n-hexane/AcOEt¼2:1) to give (S)-5 (16.4 g, 95%) as col-
4.1.8. Boc-Aib-L-Leu-L-Leu-D-Ser(O-allyl)-OMe [(R)-7]. Tetrapeptide
(R)-7 was prepared using a similar method to that described for the
preparation of (S)-7. 85% yield; Colorless crystals; mp 132e133 ꢀC;
½
a 2D4
ꢃ
ꢁ33.3 (c 0.50, CHCl3); IR (in CDCl3):
n
3429, 3334, 2961, 2874,
7.26 (br s, 1H), 7.16 (d,
orless crystals. Mp 120e121 ꢀC; ½a D24
ꢃ
ꢁ23.8 (c 0.80, CHCl3); IR (in
1673, 1513 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
CDCl3):
n
3432, 3342, 2960, 2872, 1672, 1506 cmꢁ1
;
1H NMR
J¼7.2 Hz,1H), 6.56 (d, J¼6.4 Hz,1H), 5.86 (m, 1H), 5.15e5.27 (m, 2H),
4.87 (br s, 1H), 4.69 (m, 1H), 4.49 (m, 1H), 4.27 (m, 1H), 4.00 (d,
J¼6.4 Hz, 2H), 3.85 (m, 1H), 3.74 (m, 1H), 3.72 (s, 3H), 1.65e1.83 (m,
6H),1.51 (s, 6H),1.45 (s, 9H), 0.88e0.97 (m,12H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
6.70 (d, J¼8.8 Hz, 1H), 6.48 (d, J¼8.8 Hz, 1H),
5.83 (m, 1H), 5.18e5.26 (m, 2H), 4.84 (br s, 1H), 4.69 (m, 1H), 4.50
(m, 1H), 4.11 (m, 1H), 3.98 (m, 2H), 3.87 (m, 1H), 3.76 (s, 3H), 3.63 (q,
J¼4.4 Hz, 1H), 1.66e1.71 (m, 6H), 1.44 (s, 9H), 0.90e0.94 (m, 12H);
CDCl3)
d 175.0, 172.3, 172.1, 170.7, 155.3, 134.4, 117.1, 81.1, 72.2, 72.1,
13C NMR (100 MHz, CDCl3)
d
172.5, 171.7, 170.4, 134.0, 117.6, 117.4,
69.1, 57.0, 53.1, 52.8, 52.6, 52.4, 52.2, 52.1, 51.9, 40.3, 40.0, 28.3, 28.2,
26.6, 25.1, 25.0, 24.8, 24.4, 24.2, 23.1, 23.0, 22.9, 21.6, 21.2; [HR-
ESI(þ)]: m/z calcd for C28H50N4O8Na [MþNa]þ 593.3526: found
593.3520.
72.3, 72.2, 69.3, 52.9, 52.6, 51.5, 41.1, 41.0, 40.9, 28.3, 24.8, 24.7, 24.6,
23.0, 22.8, 22.0, 21.9, 21.8; [HR-ESI(þ)]: m/z calcd for C24H43N3O7Na
[MþNa]þ 508.2999: found 508.2991.
4.1.5. Boc-
L
-Leu-
L
-Leu-
D-Ser(O-allyl)-OMe [(R)-5]. Tripeptide (R)-5
4.1.9. Boc-Aib-L-Leu-L-Leu-L-Hse(O-allyl)-OMe [(S)-8]. Tetrapeptide
was prepared using a similar method to that described for the
(S)-8 was prepared using a similar method to that described for the
preparation of (S)-5. 57% yield; Colorless crystals; mp 121e122 ꢀC;
preparation of (S)-7. 60% yield; Colorless crystals; mp 108e110 ꢀC;
½
a 2D4
ꢃ
ꢁ59.3 (c 0.20, CHCl3); IR (in CDCl3)
n
3431, 3344, 2960, 2874,
6.83 (d, J¼8.8 Hz,1H),
½
a 2D4
ꢃ
ꢁ29.0 (c 1.00, CHCl3); IR (in CDCl3):
n
3427, 3340, 2961, 2875,
7.21 (br s, 1H), 7.19 (br
1678,1501 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1675, 1516 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.46 (d, J¼8.8 Hz, 1H), 5.82 (m, 1H), 5.26e5.17 (m, 2H), 4.83 (br s,
1H), 4.69 (m, 1H), 4.51 (m, 1H), 4.10 (br s, 1H), 3.96 (d, J¼8.8 Hz, 2H),
3.84 (d, J¼8.8 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J¼8.8 Hz, 1H) 1.55e1.71
(m, 6H), 1.44 (s, 9H), 0.91e0.96 (m, 12H); 13C NMR (100 MHz, CDCl3)
s, 1H), 6.52 (d, J¼6.0 Hz, 1H), 5.88 (m, 1H), 5.13e5.26 (m, 2H), 4.95
(br s, 1H), 4.62 (m, 1H), 4.52 (m, 1H), 4.30 (m, 1H), 3.93e3.95 (m,
2H), 3.71 (s, 3H), 3.49 (t, J¼7.2 Hz, 2H), 2.06e2.17 (m, 2H), 1.53e1.86
(m, 6H), 1.48 (s, 6H), 1.47 (s, 9H), 0.89e0.98 (m, 12H); 13C NMR

Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
6161
(100 MHz, CDCl3)
d
174.8, 172.2, 171.8, 155.4, 134.9, 116.8, 81.2, 71.9,
CDCl3):
n
3427, 3328, 2960, 2872, 1666, 1529 cmꢁ1
;
1H NMR
66.5, 57.0, 53.2, 52.2, 51.7, 50.1, 40.3, 40.1, 31.6, 28.2, 26.8, 25.2, 24.8,
23.2, 23.1, 21.5, 21.3; [HR-ESI(þ)]: m/z calcd for C29H52N4O8Na
[MþNa]þ 607.3683: found 607.3684.
(400 MHz, CDCl3)
d
7.67 (d, J¼4.4 Hz, 1H), 7.47 (d, J¼4.8 Hz, 1H),
7.38 (br s, 1H), 7.36 (d, J¼6.0 Hz, 1H), 7.18 (d, J¼6.4 Hz, 1H), 6.90 (br
s, 1H), 5.81e5.91 (m, 2H), 5.11e5.27 (m, 4H), 5.07 (br s, 1H), 4.71
(m, 1H), 4.45 (m, 1H), 4.23 (m, 1H), 3.91e4.00 (m, 6H), 3.77 (d,
J¼5.2 Hz, 1H), 3.74 (s, 3H), 3.47e3.60 (m, 4H), 2.12 (m, 1H), 1.96 (m,
1H), 1.46e1.86 (m, 27H), 0.86e0.99 (m, 24H); 13C NMR (100 MHz,
Linear heptapeptides S3,7S-9, S3,7R-9, R3,7S-9, R3,7R-9, hS3,7S-9,
hS3,7R-9, and hS3,7hS-9 were synthesized by conventional solution-
phase methods by EDC and HOBt as coupling reagents.
CDCl3)
d 175.5, 174.1, 173.4, 173.1, 173.0, 172.3, 170.8, 156.7, 134.7,
OMe (S3,7S-9). Foam; ½LaꢃD24 ꢁ32.5 (c 0.50, CHCl3); IR (in CDCl3):
4.1.10. Boc-
L
-Leu-
L
-Leu- -Ser(O-allyl)-Aib-
L
-Leu-
L
-Leu-
L
-Ser(O-allyl)-
134.3, 117.6, 116.9, 81.4, 72.0, 71.9, 69.5, 67.4, 57.1, 55.2, 54.3, 53.8,
53.5, 52.7, 52.3, 51.9, 40.1, 39.7, 39.6, 39.4, 30.4, 28.3, 28.2, 27.3,
25.2, 24.9, 24.8, 23.4, 23.3, 23.2, 22.9, 22.8, 21.8, 21.4, 21.1, 20.7;
[HR-ESI(þ)]: m/z calcd for C47H84N7O12 [MþH]þ 938.6178: found
938.6168.
n
3432, 3327, 2960, 2872, 1666, 1530 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 7.45 (br s, 1H), 7.43 (br s, 1H), 7.36 (br s, 1H), 7.34 (br s, 1H),
7.10 (d, J¼5.6 Hz, 1H), 6.74 (d, J¼4.4 Hz, 1H), 5.77e5.92 (m, 2H),
5.11e5.27 (m, 4H), 4.87 (d, J¼4.0 Hz, 1H), 4.72 (m, 1H), 4.46 (m, 1H),
4.25(m,1H), 4.07 (m,1H), 3.92e4.03 (m, 7H), 3.76e3.83 (m, 2H), 3.74
(s, 3H), 3.69 (m, 1H), 1.44e1.84 (m, 27H), 0.87e1.00 (m, 24H); 13C
4.1.15. Boc-
L
-Leu-
L
-Leu-
L
-Hse(O-allyl)-Aib-
L
-Leu-
ꢁ27.0 (c 0.50, CHCl3); IR (in CDCl3):
;
3431, 3327, 2960, 2871, 1666, 1529 cmꢁ1 1H NMR (400 MHz,
L-Leu-D-Ser(O-al-
lyl)-OMe (hS3,7R-9). Foam; ½a D24
ꢃ
NMR (100 MHz, CDCl3)
d
175.5, 174.2,173.5,173.1, 173.0, 170.8, 170.5,
n
156.7, 134.7, 133.9, 117.1, 116.9, 81.4, 72.3, 72.1, 69.5, 67.9, 57.3, 56.9,
54.1, 53.5, 52.7, 52.3, 52.0, 40.2, 39.9, 39.6, 39.5, 28.2, 27.2, 25.3, 24.9,
24.8, 23.4, 23.2, 22.9, 22.8, 22.6, 21.8, 21.5, 21.1, 20.8; [HR-ESI(þ)]: m/z
calcd for C46H81N7O12Na [MþNa]þ 946.5841: found 946.5834.
CDCl3)
d
7.69 (d, J¼4.4 Hz, 1H), 7.51 (d, J¼6.0 Hz, 1H), 7.34 (d,
J¼7.2 Hz, 1H), 7.20 (d, J¼7.2 Hz, 1H), 6.83 (br s, 1H), 5.84e5.93 (m,
2H), 5.12e5.29 (m, 4H), 4.89 (br s, 1H), 4.69 (m, 1H), 4.41 (m, 1H),
4.18 (m, 1H), 3.93e4.04 (m, 6H), 3.78e3.85 (m, 2H), 3.70 (s, 3H),
3.49e3.64 (m, 4H), 1.61e2.14 (m, 14H), 1.45e1.55 (m, 15H),
4.1.11. Boc-
L
-Leu-
L
-Leu-
L
-Ser(O-allyl)-Aib-
L
-Leu-
L
-Leu-
D
-Ser(O-allyl)-
0.87e1.00 (m, 24H) 13C NMR (100 MHz, CDCl3)
d 175.8, 174.4, 173.7,
OMe (S3,7R-9). Foam; ½a D24
ꢃ
ꢁ32.6 (c 0.50, CHCl3); IR (in CDCl3):
n
173.5, 173.3, 172.5, 171.0, 156.7, 134.6, 134.4, 117.5, 116.9, 81.3, 72.1,
72.0, 69.1, 67.2, 57.1, 55.0, 54.4, 54.1, 53.7, 52.9, 52.5, 52.0, 40.1, 39.7,
39.4, 30.5, 28.3, 28.2, 27.2, 25.2, 24.9, 24.8, 24.7, 23.5, 23.3, 23.1 22.9,
22.7, 21.8, 21.4, 21.1, 29.8; [HR-ESI(þ)]: m/z calcd for C47H83N7O12Na
[MþNa]þ 938.6178: found 938.6177.
3430, 3327, 2960, 2871,1665,1529 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.51 (d, J¼6.0 Hz, 1H), 7.48 (d, J¼4.8 Hz, 1H), 7.38 (br s, 1H), 7.34 (d,
J¼5.6 Hz,1H), 7.15 (d, J¼6.0 Hz,1H), 6.78 (d, J¼4.0 Hz,1H), 5.77e5.93
(m, 2H), 5.12e5.30 (m, 4H), 4.96 (d, J¼4.0 Hz, 1H), 4.69 (m, 1H), 4.41
(m, 1H), 4.18 (m, 1H), 3.93e4.13 (m, 9H), 3.79e3.86 (m, 2H), 3.70 (s,
3H), 1.47e1.89 (m, 27H), 0.87e1.00 (m, 24H); 13C NMR (100 MHz,
4.1.16. Boc-
L
-Leu-
L
-Leu-
L
-Hse(O-allyl)-Aib-
L
-Leu-
ꢁ32.9 (c 0.50, CHCl3); IR (in
CDCl3): n ;
3426, 3327, 2960, 2871, 1665, 1529 cmꢁ1 1H NMR
L-Leu-L-Hse(O-al-
CDCl3)
d
1.75.7, 174.2, 173.6, 173.3, 173.2, 171.1, 170.5, 134.7, 133.9,
lyl)-OMe (hS3,7hS-9). Foam; ½a D24
ꢃ
117.1,116.9, 81.5, 72.1, 71.8, 69.2, 67.9, 57.3, 56.9, 54.1, 53.7, 52.8, 52.4,
52.0, 40.2, 39.8, 39.7, 39.5, 28.3, 28.2, 27.3, 25.3, 25.0, 24.9, 24.8, 23.3,
23.1, 22.9, 22.8, 22.7, 21.8, 21.4, 21.0, 20.8; [HR-ESI(þ)]: m/z calcd for
C46H81N7O12Na [MþNa]þ 946.5841: found 946.5830.
(400 MHz, CDCl3)
d
7.68 (d, J¼4.4 Hz, 1H), 7.48 (br s, 1H), 7.46 (br s,
1H), 7.32 (d, J¼7.2 Hz, 1H), 7.23 (d, J¼6.0 Hz, 1H), 7.06 (br s, 1H),
5.80e5.91 (m, 2H), 5.42 (br s, 1H), 5.08e5.25 (m, 4H), 4.62 (m, 1H),
4.40 (m, 1H), 4.18 (m, 1H), 3.89e4.03 (m, 7H), 3.69 (s, 3H),
3.48e3.58 (m, 4H), 1.96e2.21 (m, 4H), 1.53e1.84 (m, 12H), 1.48 (s,
6H), 1.45 (s, 9H), 0.85e0.97 (s, 24H); 13C NMR (100 MHz, CDCl3)
OMe (R3,7S-9). Foam; ½DaꢃD24 ꢁ6.3 (c 0.50, CHCl3); IR (in CDCl3):
n
4.1.12. Boc-L-Leu-L-Leu- -Ser(O-allyl)-Aib-L-Leu-L-Leu-L-Ser(O-allyl)-
3429, 3327, 2960, 2872,1667,1525 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 176.0, 174.5, 173.7, 173.2, 173.0, 172.7, 172.5, 135.0, 134.3, 117.4, 16.6,
d
7.51 (br s, 1H), 7.38 (d, J¼7.3 Hz, 1H), 7.33 (d, J¼6.0 Hz, 1H), 7.21 (br
81.3, 72.0, 71.8, 67.1, 66.3, 57.0, 54.9, 54.4, 54.2, 53.7, 52.2, 52.1, 49.8,
40.1, 39.7, 39.6, 39.3, 31.6, 39.5, 28.2, 27.2, 25.2, 24.8, 24.7, 23.4, 23.3,
23.0, 22.9, 22.7, 21.8, 21.5, 21.0, 20.7; [HR-ESI(þ)]: m/z calcd for
C48H86N7O12 [MþH]þ 952.6334: found 952.6333.
s, 1H), 7.03 (br s, 1H), 5.76e5.91 (m, 2H), 5.13e5.26 (m, 4H), 4.94 (br
s, 1H), 4.72 (m, 1H), 4.50 (m, 1H), 4.24 (m, 1H), 4.08 (m, 1H),
3.94e4.05 (m, 9H), 3.56 (m, 2H), 3.74 (s, 3H), 1.44e1.83 (m, 27H),
0.88e1.00 (m, 24H); 13C NMR (100 MHz, CDCl3)
d 175.2, 174.0, 172.9,
172.8, 172.7, 170.7, 169.8, 156.7, 134.6, 134.1, 117.4, 117.0, 81.5, 72.2,
72.0, 69.4, 68.0, 57.2, 54.6, 54.4, 53.7, 53.6, 52.7, 52.3, 51.8, 40.3, 40.0,
39.8, 39.6, 29.7, 28.3, 28.2, 27.0, 25.2, 24.9, 24.8, 24.7, 23.4, 23.3,
22.8, 21,8, 21.7, 21.2, 21.0; [HR-ESI(þ)]: m/z calcd for C46H81N7O12Na
[MþNa]þ 946.5841: found 946.5837.
4.1.17. Stapled heptapeptide S3,7S-10. Under inert atmosphere,
a solution of S3,7S-9 (73 mg, 0.08 mmol) and Grubbs catalyst second
generation (24 mg, 0.03 mmol) in CH2Cl2 (20 mL) was stirred at
room temperature for 20 h. The solution was poured in water and
extracted with CH2Cl2. The combined organic layer was dried over
MgSO4 and the solvent was removed under reduced pressure to
afford a stapled peptide, which was used for the next reaction
without further purification. A solution of above peptide and
Pd(OH)2 (5 mg) in MeOH (4 mL) was vigorously stirred under an H2
atmosphere for 2 h. The Pd-catalyst was filtered off, and the filtrate
was concentrated in vacuo, which was purified by silica gel column
chromatography (n-hexane/AcOEt¼1:3) to afford a S3,7S-10 (54 mg,
4.1.13. Boc-
L
-Leu-
L
-Leu-
D
-Ser(O-allyl)-Aib-
L
-Leu-
þ1.0 (c 0.50, CHCl3); IR (in CDCl3):
1H NMR (400 MHz,
L-Leu-D-Ser(O-al-
lyl)-OMe (R3,7R-9). Foam; ½a D24
ꢃ
n
3432, 3327, 2960, 2872, 1666, 1530 cmꢁ1
;
CDCl3)
d
7.55 (br s, 1H), 7.45 (d, J¼6.4 Hz, 1H), 7.34 (d, J¼7.6 Hz, 1H),
7.22 (br s, 1H), 7.14 (br s, 1H), 6.61 (d, J¼4.8 Hz, 1H), 5.76e5.93 (m,
2H), 5.11e5.30 (m, 4H), 4.96 (br s, 1H), 4.69 (m, 1H), 4.46 (m, 1H),
4.21 (m, 1H), 4.09 (m, 1H), 3.80e4.04 (m, 10H), 3.70 (s, 3H),
1.44e1.82 (m, 27H), 0.91e0.99 (m, 24H); 13C NMR (100 MHz, CDCl3)
76% yield). Foam; ½a D24
ꢃ
ꢁ19.5 (c 0.50, CHCl3); IR (in CDCl3):
n
3429,
7.73
3321, 2959, 2874,1666,1528 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
d
175.6, 174.1, 173.2, 172.8, 171.0, 169.8, 134.6, 134.2, 117.3, 117.0, 81.6,
(d, J¼9.2 Hz, 1H), 7.43 (d, J¼8.0 Hz, 1H), 7.37 (d, J¼7.6 Hz, 1H), 7.32
(br s, 1H), 6.81 (d, J¼3.6 Hz, 1H), 6.69 (d, J¼6.8 Hz, 1H), 5.06 (d,
J¼4.4 Hz, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 4.34 (m, 1H), 4.03 (m, 1H),
3.84 (m, 1H), 3.78 (s, 3H), 3.66e3.76 (m, 5H), 3.36e3.56 (m, 4H),
1.45e1.83 (m, 31H), 0.86e1.00 (m, 24H); 13C (100 MHz, CDCl3)
72.1, 72.0, 69.1, 57.1, 54.6, 54.4, 53.8, 53.7, 52.9, 52.1, 40.2, 39.9, 39.8,
39.5, 28.3, 25.2, 24.9, 24.8, 24.7, 23.4, 23.3, 23.3 22.8, 21.8, 21.7, 21.0,
20.9; [HR-ESI(þ)]: m/z calcd for C46H81N7O12Na [MþNa]þ
946.5841: found 946.5834.
d
174.5, 174.4, 173.2, 172.9, 171.1, 170.4, 156.9, 81.3, 71.3, 70.3, 70.1,
4.1.14. Boc-
L
-Leu-
L
-Leu-
L
-Hse(O-allyl)-Aib-
L
-Leu-
L
-Leu-
L
-Ser(O-al-
68.2, 57.4, 55.4, 54.5, 54.1, 53.3, 53.2, 52.5, 52.4, 41.3, 40.1, 40.0, 39.9,
28.3, 28.2, 26.6, 25.4, 25.3, 25.2, 24.9, 24.8, 24.6, 23.9, 23.3, 22.8,
lyl)-OMe (hS3,7S-9). Foam; ½a D24
ꢃ
ꢁ33.2 (c 0.50, CHCl3); IR (in

6162
Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
22.7, 21.9, 21.5, 21.3, 21.0, 19.1; [HR-ESI(þ)]: m/z calcd for
C44H79N7O12Na [MþNa]þ 920.5684: found 920.5681.
J¼7.6 Hz, 1H), 7.52 (br s, 1H), 7.11 (d, J¼7.2 Hz, 1H), 6.66 (d, J¼4.8 Hz,
1H), 5.17 (br s, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 4.01e4.09 (m, 2H),
3.97 (m, 1H), 3.88 (d, J¼4.4 Hz, 1H), 3.79 (m, 1H), 3.71 (s, 3H),
3.60e3.63 (m, 3H), 3.46e3.51 (m, 2H), 3.33e3.39 (m, 2H),1.43e2.18
4.1.18. Stapled heptapeptide S3,7R-10. Stapled peptide S3,7R-10 was
prepared using a similar method to that described for the prepara-
(m, 33H), 0.88e1.00 (m, 24H) 13C NMR (100 MHz, CDCl3)
d 175.2,
tion of S3,7S-10. 62%; Foam; ½a D24
ꢃ
ꢁ29.1 (c 0.50, CHCl3); IR (in CDCl3):
174.4, 174.0, 173.7, 173.5, 173.3, 170.5, 157.3, 80.6, 72.1, 69.8, 69.3,
65.5, 57.0, 55.4, 55.2, 54.3, 54.0, 53.3, 53.1, 52.0, 40.9, 40.2, 39.8,
39.6, 31.2, 28.3, 28.2, 27.1, 26.8, 25.1, 24.8, 24.6, 24.3, 23.4, 23.3, 23.2,
23.1, 23.0, 22.8, 22.6, 21.7, 21.6, 21.4, 20.8; [HR-ESI(þ)]: m/z calcd for
C45H81N7O12Na [MþNa]þ 912.6021: found 912.6013.
n
d
3439, 3327, 2961, 2872,1665,1529 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.87 (d, J¼7.2 Hz,1H), 7.65 (d, J¼8.8 Hz,1H), 7.41 (br s,1H), 7.28 (br s,
1H), 6.97 (br s,1H), 6.63 (d, J¼8.0 Hz,1H), 5.01 (d, J¼5.6 Hz,1H), 4.61
(m,1H), 4.37 (m,1H), 4.32 (m,1H), 4.06e4.16 (m, 1H), 3.74e3.86 (m,
4H), 3.70 (s, 3H), 3.40e3.49 (m, 6H), 1.44e1.86 (m, 31H), 0.87e1.00
(m, 24H); 13C NMR (100 MHz, CDCl3)
d
174.5,174.1,173.5,172.9,172.4,
4.1.23. Stapled heptapeptide hS3,7hS-10. Stapled peptide hS3,7hS-10
170.8, 70.9, 69.6, 66.9, 57.5, 54.2, 53.7, 53.0, 52.9, 52.1, 40.2, 40.1, 39.9,
39.4, 28.2, 26.4, 25.2, 25.0, 24.9, 24.8, 24.6, 24.5, 24.1, 23.3, 23.2, 22.9,
22.7, 22.2, 21.7, 21.3, 21.1, 20.8; [HR-ESI(þ)]: m/z calcd for
C44H79N7O12Na [MþNa]þ 920.5684: found 920.5681.
was prepared using a similar method to that described for the
preparation of S3,7S-10. 87%; Colorless crystals; mp 105e107 ꢀC; ½a D24
ꢃ
ꢁ16.1 (c 0.50, CHCl3); IR (in CDCl3):
n 3430, 3326, 2960, 2871, 1665,
d
1530cmꢁ1; 1HNMR(400 MHz, CDCl3)
7.59(d, J¼2.4Hz,1H), 7.56(br
s,1H), 7.31 (d, J¼9.2 Hz,1H), 7.22 (br s,1H), 7.16 (d, J¼6.8 Hz,1H), 6.55
(d, J¼4.4 Hz, 1H), 5.09 (br s, 1H), 4.73 (m, 1H), 4.53 (m, 1H), 4.23 (m,
1H), 3.05 (m, 1H), 4.00 (m, 1H), 3.94 (m, 1H), 3.74 (s, 3H), 3.61e3.67
(m, 2H), 3.47e3.57 (m, 2H), 3.35e3.44 (m, 4H), 1.65e2.26 (m, 20H),
1.48e1.60 (m, 15H), 0.87e1.00 (m, 24H); 13C NMR (100 MHz, CDCl3)
4.1.19. Stapled heptapeptide R3,7S-10. Stapled peptide R3,7S-10 was
prepared using a similar method to that described for the prepara-
tion of S3,7S-10. 58%; Foam; ½a D24
ꢃ
ꢁ35.0 (c 0.50, CHCl3); IR (in CDCl3):
n
3439, 3328, 2960, 2873, 1667, 1529 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
7.41 (d, J¼8.4 Hz, 1H), 7.33 (br s, 1H), 7.23 (d, J¼7.3 Hz, 1H),
d 176.0, 174.4, 173.7, 173.4, 173.3, 172.6, 172.3, 157.1, 81.3, 70.5, 70.3,
7.10 (br s, 1H), 6.69 (br s, 1H), 6.63 (d, J¼6.0 Hz, 1H), 4.92 (br s, 1H),
4.70 (m, 1H), 4.33 (m, 1H), 4.21 (m, 1H), 4.03 (m, 1H), 3.52e3.81 (m,
9H), 3.40e3.51 (m, 4H),1.45e1.90 (m, 31H), 0.85e0.10 (m, 24H); 13C
66.8, 66.0, 56.9, 55.3, 54.9, 54.1, 53.7, 52.4, 52.1, 49.3, 40.3, 40.2, 40.0,
39.5, 32.2, 31.2, 28.3, 28.2, 27.2, 25.4, 25.3, 25.1, 24.9, 24.8, 24.6, 23.5,
23.4, 23.1, 22.8, 22.7, 21.7, 21.6, 21.0, 20.9, 20.7; [HR-ESI(þ)]: m/z calcd
for C46H84N7O12 [MþH]þ 926.6178: found 926.6171.
NMR (100 MHz, CDCl3) d 174.7, 174.5, 173.9, 173.1, 170.3, 170.2, 157.2,
80.6, 74.1, 71.3, 71.2, 70.5, 57.3, 57.0, 54.9, 54.2, 53.8, 53.1, 52.9, 52.5,
40.1, 39.7, 28.2, 26.8, 26.5, 25.4, 25.1, 24.7, 24.3, 23.5, 23.3, 23.2, 23.1,
22.7, 22.6, 22.5, 21.9, 21.6, 21.3, 21.0, 20.8; [HR-ESI(þ)]: m/z calcd for
C44H79N7O12Na [MþNa]þ 920.5684: found 920.5673.
4.1.24. H-L-Leu-L-Leu-L-Ser(O-allyl)-Aib-L-Leu-L-Leu-L-Ser(O-allyl)-
OMe (H-S3,7S-9). Trifluoroacetic acid (0.2 mL) was added to a so-
lution of S3,7S-9 (448 mg, 0.5 mmol) in CH2Cl2 (5 mL) at 0 ꢀC and the
solution was stirred at room temperature for 1 h. Then, the solution
was neutralized with saturated aqueous NaHCO3, extracted with
CH2Cl2 and dried over MgSO4. After removal of the solvent, N-ter-
minal free peptide H-S3,7S-9 (358 mg, 90%) was obtained, which
was used as catalyst for enantioselective epoxidation without fur-
4.1.20. Stapled heptapeptide R3,7R-10. Stapled peptide R3,7R-10 was
prepared using a similar method to that described for the prepa-
ration of S3,7S-10. 62%; Colorless crystals; mp 206e208 ꢀC (recryst
from CHCl3/n-hexane); ½a D24
ꢃ
ꢁ11.4 (c 0.50, CHCl3); IR (in CDCl3):
n
3421, 3326, 2960, 2872, 1699, 1508 cmꢁ1
;
1H NMR (400 MHz,
ther purification. Foam; ½a D24
ꢃ
ꢁ30.1 (c 0.50, CHCl3); IR (in CDCl3):
n
CDCl3)
d
7.88 (br s, 1H), 7.64 (d, J¼7.6 Hz, 1H), 7.33 (br s, 1H), 6.54 (d,
3427, 3329, 2959, 2872, 1666, 1527 cmꢁ1 1H NMR (400 MHz,
;
J¼5.6 Hz, 1H), 6.35 (br s, 1H), 4.92 (br s, 1H), 4.67 (m, 1H), 4.50 (m,
1H), 4.35 (m, 1H), 4.22 (m, 1H), 4.13 (m, 1H), 3.91e4.00 (m, 2H),
3.67e3.79 (m, 4H), 3.36e3.57 (m, 4H), 2.24 (t, J¼7.2 Hz,1H), 2.13 (m,
1H), 1.91 (m, 1H), 1.45e1.80 (m, 31H), 0.87e1.00 (m, 24H); 13C NMR
CDCl3)
d
8.01 (d, J¼3.6 Hz, 1H), 7.47 (br s, 1H), 7.40 (d, J¼8.0 Hz, 1H),
7.33 (d, J¼8.0 Hz, 1H), 7.02 (d, J¼6.8 Hz, 1H), 6.97 (d, J¼5.2 Hz, 1H),
5.80e5.92 (m, 2H), 5.12e5.30 (m, 4H), 4.72 (m, 1H), 4.45 (m, 1H),
4.24 (m, 1H), 3.96e4.09 (m, 6H), 3.58e3.84 (m, 9H), 3.42 (m, 1H),
1.24e1.85 (m, 18H), 0.87e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 174.1, 173.5, 173.4, 173.1, 171.9, 170.6, 80.6, 70.9,
69.9, 68.4, 57.0, 54.7, 53.3, 53.0, 52.9, 52.6, 52.5, 52.3, 40.4, 40.3,
40.0, 38.6, 28.2, 25.8, 25.0, 25.2, 24.9, 24.7, 24.6, 24.5, 24.4, 23.3,
23.2, 22.9, 22.8, 21.7, 21.1, 21.0; [HR-ESI(þ)]: m/z calcd for
C44H79N7O12Na [MþNa]þ 920.5684: found 920.5671.
d 175.4, 173.5, 173.1, 173.0, 170.9, 170.5, 134.6, 133.8, 117.1, 117.0, 72.0,
71.9, 69.4, 67.8, 57.3, 56.0, 53.9, 53.5, 53.2, 52.7, 52.4, 52.0, 43.3, 39.9,
39.6, 39.5, 29.7, 27.1, 25.2, 25.1, 24.8, 24.7, 23.4, 23.3, 23.2, 22.9, 21.4,
21.3, 21.1, 20.8; [HR-ESI(þ)]: m/z calcd for C41H74N7O10 [MþH]þ
824.5497: found 824.5482.
4.1.21. Stapled heptapeptide hS3,7S-10. Stapled peptide hS3,7S-10
was prepared using a similar method to that described for the
4.1.25. H-L-Leu-L-Leu-L-Ser(O-allyl)-Aib-L-Leu-L-Leu-D-Ser(O-allyl)-
preparation of S3,7S-10. 79%; Foam; ½a D24
ꢃ
ꢁ14.5 (c 0.50, CHCl3); IR
OMe (H-S3,7R-9). N-Terminal free peptide H-S3,7R-9 was prepared
using a similar method to that described for the preparation of H-
(in CDCl3):
n
3428, 3327, 2960, 2871, 1665, 1530 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
7.67 (d, J¼8.4 Hz, 1H), 7.58 (d, J¼4.8 Hz, 1H), 7.41
S3,7S-9. 99%; Foam; ½a D24
ꢃ
ꢁ35.4 (c 0.50, CHCl3); IR (in CDCl3):
n 3428,
(d, J¼8.0 Hz, 1H), 7.19 (br s, 1H), 7.11 (d, J¼7.6 Hz, 1H), 6.64 (d,
J¼4.0 Hz, 1H), 5.23 (br s, 1H), 4.87 (m, 1H), 4.53 (m, 1H), 4.36 (m,
1H), 4.03e4.08 (m, 2H), 3.91e3.98 (m, 2H), 3.78 (s, 3H), 3.51e3.56
(m, 2H), 3.36e3.49 (m, 4H), 2.43 (t, J¼7.6 Hz, 1H), 2.02 (m, 1H),
1.44e1.87 (m, 32H), 0.87e1.00 (m, 24H); 13C NMR (100 MHz, CDCl3)
3328, 2960, 2872, 1666, 1524 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
8.02 (d, J¼4.0 Hz, 1H), 7.49 (br s, 1H), 7.47 (d, J¼8.0 Hz, 1H), 7.32 (d,
J¼4.8 Hz, 1H), 7.04 (d, J¼5.6 Hz, 1H), 7.00 (br s, 1H), 5.80e5.92 (m,
2H), 5.14e5.28 (m, 4H), 4.70 (m, 1H), 4.42 (m, 1H), 4.19 (m, 1H), 4.08
(m, 1H), 3.98e4.04 (m, 6H), 3.81e3.86 (m, 2H), 3.69e3.80 (m, 5H),
3.40e3.43 (m, 2H), 1.50e1.87 (m, 18H), 0.87e1.02 (m, 24H); 13C
d
174.9, 174.2, 173.7, 173.3, 172.8, 170.2, 157.1, 81.5, 70.5, 70.3, 69.9,
65.7, 57.1, 55.4, 54.8, 54.1, 53.0, 52.8, 52.5, 41.2, 40.3, 40.1, 40.0, 31.5,
28.3, 27.3, 25.9, 25.6, 25.2, 25.0, 24.8, 24.4, 23.5, 23.4, 23.1, 22.9,
22.7, 22.6, 21.8, 21.6, 21.1, 20.9; [HR-ESI(þ)]: m/z calcd for
C45H82N7O12 [MþH]þ 912.6021: found 912.6014.
NMR (100 MHz, CDCl3) d 177.4, 175.6, 173.6, 173.3, 173.1, 171.1, 170.5,
134.6, 133.8, 117.3, 117.0, 72.1, 71.8, 69.1, 67.8, 57.2, 55.8, 53.9, 53.7,
53.1, 52.8, 52.3, 52.1, 43.4, 40.0, 39.7, 39.5, 29.7, 27.0, 25.2, 25.1, 24.8,
24.7, 23.3, 23.2, 23.1, 22.9, 21.4, 21.2, 21.0, 20.8; [HR-ESI(þ)]: m/z
calcd for C41H74N7O10 [MþH]þ 824.5497: found 824.5592.
4.1.22. Stapled heptapeptide hS3,7R-10. Foam; ½a D24
ꢁ11.9 (c 0.50,
ꢃ
CHCl3); IR (in CDCl3):
n
3430, 3328, 2960, 2871, 1665, 1530 cmꢁ1; 1H
4.1.26. H-
L-Leu-L-Leu-D-Ser(O-allyl)-Aib-L-Leu-L-Leu-L-Ser(O-allyl)-
NMR (400 MHz, CDCl3)
d 7.70 (br s, 1H), 7.66 (br s, 1H), 7.51 (d,
OMe (H-R3,7S-9). N-Terminal free peptide H-R3,7S-9 was prepared

Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
6163
using a similar method to that described for the preparation of H-
prepared using a similar method to that described for the prepa-
S3,7S-9. 76%; Foam; ½a D24
ꢃ
ꢁ7.9 (c 0.50, CHCl3); IR (in CDCl3):
n
3425,
ration of H-S3,7S-9. 89%; Foam; ½a D24
ꢃ
ꢁ31.6 (c 1.00, CHCl3); IR (in
3326, 2960, 2872, 1664, 1522 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
CDCl3):
CDCl3)
n ;
d
3329, 2959, 2872, 1663, 1528 cmꢁ1 1H NMR (400 MHz,
d
7.97 (d, J¼4.8 Hz,1H), 7.56 (br s, 1H), 7.40 (d, J¼8.4 Hz, 1H), 7.25 (br
8.01 (d, J¼3.6 Hz, 1H), 7.67 (br s, 1H), 7.63 (d, J¼4.8 Hz, 1H),
s, 1H), 7.04 (br s, 1H), 6.63 (br s, 1H), 5.80e5.88 (m, 2H), 5.14e5.30
(m, 4H), 4.71 (m, 1H), 4.44 (m, 1H), 4.36 (m, 1H), 4.27 (m, 1H),
3.92e4.04 (m, 6H), 3.82 (m, 1H), 3.74 (s, 3H), 3.70e3.73 (m, 3H),
3.60 (m, 1H), 3.38 (m, 1H), 1.25e1.79 (m, 18H), 0.89e1.01 (m, 24H);
7.40 (d, J¼8.4 Hz, 1H), 7.30 (d, J¼8.8 Hz, 1H), 7.19 (d, J¼5.6 Hz, 1H),
5.83e5.95 (m, 2H), 5.10e5.34 (m, 4H), 4.62 (m, 1H), 4.46 (m, 1H),
4.21 (m, 1H), 4.08 (m, 1H), 3.96e4.01 (m, 5H), 3.93 (d, J¼5.6 Hz, 2H),
3.71 (s, 3H), 3.59 (m, 1H), 3.51 (t, J¼6.8 Hz, 3H), 3.41 (m, 1H),
2.16e2.23 (m, 2H), 2.03e2.12 (m, 2H), 1.25e1.84 (m, 18H),
13C NMR (100 MHz, CDCl3)
d 172.9, 172.8, 170.8, 170.2, 134.3, 133.6,
118.3, 117.2, 72.3, 72.0, 69.2, 68.7, 57.2, 54.1, 53.6, 53.3, 53.1, 52.7,
52.4, 52.0, 43.5, 39.9, 39.6, 29.7, 26.3, 25.0, 24.8, 24.7, 24.6, 23.8,
23.3, 23.2, 22.5, 22.1, 21.4, 21.2, 21.1; [HR-ESI(þ)]: m/z calcd for
C41H74N7O10 [MþH]þ 824.5497: found 824.5576.
0.87e1.02 (m, 24H); 13C NMR (100 MHz, CDCl3)
d 176.0, 173.7, 173.4,
173.2, 172.6, 172.2, 135.0, 134.1, 117.8, 116.6, 72.3, 71.8, 68.0, 66.3,
57.1, 55.9, 54.3, 53.8, 53.0, 52.2, 49.8, 43.0, 40.1, 39.7, 39.4, 31.5, 29.7,
27.1, 25.1, 25.0, 24.8, 24.7, 23.4, 23.3, 23.1, 23.0, 22.8, 21.4, 21.3, 20.9,
20.7; [HR-ESI(þ)]: m/z calcd for C43H78N7O10 [MþH]þ 852.5810:
found 852.5809.
4.1.27. H-L-Leu-L-Leu-D-Ser(O-allyl)-Aib-L-Leu-L-Leu-D-Ser(O-allyl)-
OMe (H-R3,7R-9). N-Terminal free peptide H-R3,7R-9 was prepared
usingasimilarmethodtothatdescribedforthepreparationofH-S3,7S-
4.1.31. N-Terminal free stapled peptide H-S3,7S-10. N-Terminal free
stapled peptide H-S3,7S-10 was prepared using a similar method to
9. 99%; Colorlesscrystals;mp 186e188 ꢀC;½a D24
ꢃ
ꢁ4.5 (c1.00, CHCl3); IR
(in CDCl3):
n
3424, 3326, 2960, 2872, 1666, 1521 cmꢁ1
;
1H NMR
that described for the preparation of H-S3,7S-9. 88%; Foam; ½a D24
ꢃ
(400 MHz, CDCl3)
d
7.97 (d, J¼4.8 Hz, 1H), 7.56 (br s, 1H), 7.45 (d,
ꢁ25.8 (c 0.20, CHCl3); IR (in CDCl3):
n 3422, 3326, 2960, 2872, 1667,
J¼8.0 Hz, 1H), 7.28 (d, J¼6.8 Hz, 1H), 6.92 (d, J¼6.8 Hz, 1H), 6.61 (d,
J¼6.4 Hz,1H), 5.79e5.92 (m, 2H), 5.14e5.30 (m, 4H), 4.68 (m,1H), 4.45
(m, 1H), 4.39 (m, 1H), 4.21 (m, 1H), 3.94e4.06 (m, 6H), 3.74e3.86 (m,
4H), 3.71 (s, 3H), 3.59 (m, 1H), 3.39 (m, 1H), 1.25e1.84 (m, 18H),
1521 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼4.4 Hz, 1H), 7.49
(br s,1H), 7.38 (br s,1H), 7.32 (d, J¼7.6 Hz,1H), 7.20 (d, J¼8.0 Hz,1H),
6.54 (d, J¼6.8 Hz, 1H), 4.75 (m, 1H), 4.46e4.52 (m, 2H), 4.36 (m, 1H),
4.16 (m, 1H), 4.00e4.07 (m, 3H), 3.67e3.82 (m, 5H), 3.38e3.51 (m,
5H), 3.34 (m, 1H), 1.26e2.05 (m, 22H), 0.85e1.02 (m, 24H); 13C NMR
0.89e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3)
d 175.4, 173.0, 172.9,
172.8, 170.9, 170.2, 134.4, 133.7, 118.2, 117.2, 72.3, 72.1, 69.0, 68.7, 57.2,
54.1, 53.7, 53.5, 53.2, 52.8, 52.3, 52.2, 43.1, 39.9, 39.8, 39.6, 29.7, 26.4,
25.0, 24.9, 24.8, 24.7, 23.7, 23.3, 23.2, 23.1 22.6, 22.0, 21.5, 21.1; [HR-
ESI(þ)]: m/zcalcdfor C41H74N7O10 [MþH]þ 824.5497:found825.4487.
(100 MHz, CDCl3) d 178.9, 173.5, 173.2, 173.1, 171.2, 171.1, 171.0, 71.2,
70.4, 69.8, 68.2, 57.1, 55.1, 54.6, 53.7, 53.6, 53.3, 53.0, 52.7, 41.7, 40.7,
40.2, 39.8, 29.7, 29.3, 25.8, 25.5, 25.4, 24.9, 24.7, 24.4, 24.3, 23.1,
22.6, 22.5, 21.9, 21.6, 21.4, 21.3; [HR-ESI(þ)]: m/z calcd for
C39H72N7O10 [MþH]þ 798.5341: found 798.5329.
4.1.28. H-L-Leu-L-Leu-L-Hse(O-allyl)-Aib-L-Leu-L-Leu-L-Ser(O-allyl)-
OMe (H-hS3,7S-9). N-Terminal free peptide H-hS3,7S-9 was pre-
4.1.32. N-Terminal free stapled peptide H-S3,7R-10. N-Terminal free
peptide H-S3,7R-10 was prepared using a similar method to that
pared using a similar method to that described for the preparation
of H-S3,7S-9. 99%; Foam; ½a D24
ꢃ
ꢁ24.1 (c 0.70, CHCl3); IR (in CDCl3):
n
described for the preparation of H-S3,7S-9. 93%; Foam; ½a D24
ꢁ50.9 (c
ꢃ
3330, 2959, 2872, 1663, 1527 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
0.25, CHCl3); IR (in CDCl3): n 3424, 3330, 2960, 2872, 1666,
d
8.01 (d, J¼4.0 Hz, 1H), 7.64 (d, J¼4.8 Hz, 1H), 7.62 (br s, 1H), 7.44 (d,
1523 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.92 (d, J¼4.8Hz,1H), 7.53(br
J¼8.4 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.16 (d, J¼6.0 Hz, 1H),
5.82e5.95 (m, 2H), 5.11e5.33 (m, 4H), 4.72 (m, 1H), 4.46 (m, 1H),
4.24 (m, 1H), 4.07 (m, 1H), 3.94e4.02 (m, 7H), 3.76e3.81 (m, 2H),
3.74 (s, 3H), 3.57 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 2.05e2.08 (m,
2H), 1.24e1.83 (m, 18H), 0.87e1.01 (m, 24H); 13C NMR (100 MHz,
s, 1H), 7.50 (br s, 1H), 7.44 (br s, 1H), 7.12 (d, J¼8.0 Hz, 1H), 6.52 (d,
J¼7.2 Hz, 1H), 4.48e4.55 (m, 2H), 4.33e4.40 (m, 2H), 4.21 (m, 1H),
4.04 (m,1H), 3.85 (m,1H), 3.75 (d, J¼6.0 Hz, 2H), 3.71 (s, 3H), 3.55 (m,
1H), 3.43e3.51 (m, 4H), 3.32e3.37 (m, 2H), 1.24e1.86 (m, 22H),
0.86e1.02 (m, 24H); 13C NMR (100 MHz, CDCl3)
d 174.7, 173.6, 173.2,
CDCl3)
d
175.9, 173.8, 173.7, 173.6, 173.4, 172.4, 171.2, 134.4, 134.2,
173.1,171.1,171.0,170.8, 71.1, 70.1, 69.6, 67.5, 57.2, 54.9, 54.1, 53.6, 53.4,
53.3, 53.1, 52.3, 42.4, 41.2, 40.4, 39.8, 29.7, 25.7, 25.3, 25.1, 25.0, 24.9,
24.7, 24.5, 23.2, 23.1, 22.8, 22.7, 21.7, 21.5, 21.2, 20.9; [HR-ESI(þ)]: m/z
calcd for C39H72N7O10 [MþH]þ 798.5341: found 798.5311.
117.7, 117.1, 72.2, 72.0, 69.1, 67.7, 57.0, 55.7, 54.6, 53.9, 53.2, 52.9,
52.5, 52.4, 42.2, 40.0, 39.8, 39.6, 29.9, 26.9, 25.2, 25.1, 24.9, 24.8,
24.7, 24.6, 23.3, 23.2, 22.8, 22.7, 21.6, 21.0, 20.9; [HR-ESI(þ)]: m/z
calcd for C42H76N7O10 [MþH]þ 838.5654: found 838.5668.
4.1.33. N-Terminal free stapled peptide H-R3,7S-10. N-Terminal free
peptide H-R3,7S-10 was prepared using a similar method to that
4.1.29. H-L-Leu-L-Leu-L-Hse(O-allyl)-Aib-L-Leu-L-Leu-D-Ser(O-allyl)-
OMe (H-hS3,7R-9). N-Terminal free peptide H-hS3,7R-9 was pre-
described for the preparation of H-S3,7S-9. 82%; Foam; ½a D24
ꢁ18.8 (c
ꢃ
pared using a similar method to that described for the preparation
1.00, CHCl3); IR (in CDCl3): n 3425, 3324, 2960, 2872, 1665,
of H-S3,7S-9. 79%; Foam; ½a D24
ꢃ
ꢁ20.2 (c 1.30, CHCl3); IR (in CDCl3):
n
1520 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼5.6 Hz, 1H), 7.53
3330, 2959, 2874, 1664, 1525 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
(d, J¼6.8 Hz, 1H), 7.52 (br s, 1H), 7.38 (d, J¼13.2 Hz, 1H), 7.16 (d,
J¼8.8 Hz, 1H), 6.53 (br s, 1H), 4.66 (m, 1H), 4.50 (m, 1H), 4.34 (m,
1H), 4.15 (m, 1H), 4.04 (m, 1H), 3.90 (m, 1H), 3.78e3.84 (m, 2H), 3.74
(s, 3H), 3.57e3.72 (m, 2H), 3.34e3.52 (m, 6H), 1.24e1.96 (m, 22H),
d
8.05 (d, J¼3.2 Hz, 1H), 7.70 (d, J¼4.8 Hz, 1H), 7.65 (br s, 1H), 7.53 (d,
J¼8.0 Hz, 1H), 7.38 (d, J¼7.6 Hz, 1H), 7.23 (d, J¼6.0 Hz, 1H),
5.81e5.95 (m, 2H), 5.14e5.33 (m, 4H), 4.69 (m, 1H), 4.40 (m, 1H),
4.18 (m, 1H), 4.11 (m, 1H), 4.03 (d, J¼5.6 Hz, 2H), 3.95e4.01 (m, 5H),
3.80e3.86 (m, 2H), 3.71 (s, 3H), 3.58 (m, 1H), 3.52 (m, 1H), 3.41 (m,
1H), 2.05 (m, 2H), 1.26e1.88 (m, 18H), 0.87e1.01 (m, 24H) 13C NMR
0.87e1.02 (m, 24H); 13C NMR (100 MHz, CDCl3)
d 174.9, 174.1, 173.6,
173.4, 173.1, 171.0, 170.7, 71.5, 71.4, 70.5, 70.3, 57.5, 57.3, 53.9, 53.6,
53.4, 53.2, 52.8, 52.6, 43.8, 40.2, 40.0, 39.4, 26.5, 26.2, 25.3, 25.1,
25.0, 24.6, 23.5, 23.4, 23.1, 22.8, 22.7, 22.2, 21.8, 21.6, 21.5, 21.4; [HR-
ESI(þ)]: m/z calcd for C39H72N7O10 [MþH]þ 798.5341: found
798.5338.
(100 MHz, CDCl3) d 175.9, 173.7, 173.5, 173.4, 172.1, 171.1, 134.5, 134.1,
117.8, 117.1, 72.3, 72.1, 69.0, 68.0, 57.1, 55.7, 54.2, 53.8, 52.8, 52.5,
52.3, 43.1, 40.1, 39.7, 39.5, 29.6, 27.0, 25.1, 25.0, 24.8, 24.7, 23.3, 23.1,
22.9, 22.8, 21.4, 21.3, 21.0, 20.8; [HR-ESI(þ)]: m/z calcd for
C42H76N7O10 [MþH]þ 838.5654: found 838.5640.
4.1.34. N-Terminal free stapled peptide H-R3,7R-10. N-Terminal free
peptide H-R3,7R-10 was prepared using a similar method to that
4.1.30. H-
L
-Leu-
L
-Leu-
L
-Hse(O-allyl)-Aib-
L
-Leu-
L
-Leu-
L
-Hse(O-allyl)-
described for the preparation of H-S3,7S-9. 96%; Foam; ½a D24
ꢁ22.0
ꢃ
OMe (H-hS3,7hS-9). N-Terminal free peptide H-hS3,7hS-9 was
(c 0.50, CHCl3); IR (in CDCl3):
n 3423, 3330, 2960, 2872, 1668,

6164
Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
1521 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.87 (d, J¼6.8 Hz, 1H), 7.78
temperature. After being stirred for 24 h, the reaction mixture was
diluted with AcOEt, and washed with saturated aqueous Na2S2O3.
Then, organic layer was evaporated to give an oily residue, which
was purified by silica gel column chromatography (n-hexane/
AcOEt¼20:1) to afford a (2R,3S)-12a (60 mg, 89% yield, 69% ee).
(d, J¼8.0 Hz, 1H), 7.52 (br s, 1H), 7.06 (d, J¼7.2 Hz, 1H), 6.41 (d,
J¼7.6 Hz,1H), 6.10 (d, J¼7.2 Hz,1H), 4.63 (m,1H), 4.46e4.54 (m, 2H),
4.28e4.37 (m, 2H), 4.11e4.22 (m, 2H), 4.00 (m, 1H), 3.78e3.86 (m,
2H), 3.70 (s, 3H), 3.44e3.52 (m, 5H), 3.33 (m, 1H), 1.24e2.19 (m,
22H), 0.90e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3)
d
174.9, 173.9,
Colorless crystals; ½a D23
ꢃ
ꢁ183.6 (c 1.00, CHCl3); 1H NMR (400 MHz,
173.6, 173.3, 172.8, 171.2, 171.0, 71.3, 70.6, 70.5, 69.9, 57.5, 56.8, 54.7,
53.8, 53.5, 53.3, 52.7, 52.5, 40.4, 40.1, 29.9, 29.8, 25.4, 25.3, 25.1, 25.0,
23.6, 23.5, 23.4, 23.3, 23.2, 23.0, 22.0, 21.8, 21.7, 21.4, 21.3, 21.2; [HR-
ESI(þ)]: m/z calcd for C39H71N7O10Na [MþNa]þ 820.5160: found
820.5152.
CDCl3)
d
8.00e8.02 (m, 2H), 7.36e7.62 (m, 8H), 4.29 (d, J¼1.6 Hz,
1H), 4.08 (d, J¼1.6 Hz, 1H). HPLC (DAICEL Chiralpak AD column,
4.6 mm
f
ꢂ250 mm; 10% EtOH in hexane; flow rate, 1.0 mL/min):
retention time (tR)¼19.1 min (2R,3S-enantiomer, major), 26.4 min
(2S,3R-enantiomer, minor).9e
4.1.35. N-Terminal free stapled peptide H-hS3,7S-10. N-Terminal free
peptide H-hS3,7S-10 was prepared using a similar method to that
4.2.1. (3R,4S)-trans-Epoxy-4-phenylbutan-2-one
(12b). Colorless
oil: ½a 2D6
ꢃ
ꢁ56.7 (c 1.00, CDCl3) [lit.,23 ꢁ73.3ꢀ(c 1.00, CHCl3)]; 1H NMR
described for the preparation of H-S3,7S-9. 99%; Foam; ½a D24
ꢃ
ꢁ19.1 (c
(400 MHz, CDCl3) d 7.35e7.40 (m, 3H), 7.27e7.29 (m, 2H), 4.00 (d,
1.00, CHCl3); IR (in CDCl3):
n
3322, 2958, 2874, 1663, 1529 cmꢁ1; 1H
J¼1.6 Hz, 1H), 3.49 (d, J¼1.6 Hz, 1H), 2.19 (s, 3H). HPLC (DAICEL
i
NMR (400 MHz, CDCl3)
d
8.14 (br s, 1H), 7.78 (br s, 1H), 7.55 (br s,
Chiralpak IA 4.6 mm
f
ꢂ250 mm, 1% PrOH in hexane, flow rate is
1H), 7.41 (br s, 1H), 7.24 (br s, 1H), 7.21 (br s, 1H), 4.83 (m, 1H), 4.41
(m, 1H), 4.26 (m, 1H), 4.15 (m, 1H), 4.08 (m, 1H), 3.86 (m, 1H), 3.77
(s, 3H), 3.75 (d, J¼6.8 Hz, 2H), 3.56e3.58 (m, 2H), 3.39e3.50 (m,
6H), 2.02e2.05 (m, 2H), 1.26e1.92 (m, 22H), 0.86e1.01 (m, 24H);
0.5 mL/min): tR¼14.9 min (2S,3R-enantiomer, minor), 16.7 min
(2R,3S-enantiomer, major).
4.2.2. (4R,5S)-trans-Epoxy-2-methyl-5-phenylpentan-3-one
a 26
13C NMR (100 MHz, CDCl3)
d
175.9, 174.9, 174.7, 174.1, 173.5, 173.4,
(12c). Colorless crystals: ½ ꢃD ꢁ141.4 (c 1.00, CDCl3) [lit.,24 ꢁ208ꢀ (c
170.9, 70.5, 69.8, 69.4, 65.8, 56.6, 54.7, 54.1, 53.7, 53.4, 53.0, 52.7,
52.4, 43.1, 43.0, 40.8, 40.0, 26.5, 25.7, 25.6, 24.9, 24.8, 24.7, 24.6, 24.4,
23.2, 23.1, 22.9, 22.5, 21.8, 21.7, 21.2, 21.1; [HR-ESI(þ)]: m/z calcd for
C40H74N7O10 [MþH]þ 812.5497: found 812.5496.
1.00, CHCl3)]; 1H NMR (400 MHz, CDCl3)
d 7.28e7.40 (m, 5H), 3.92
(d, J¼2.0 Hz, 1H), 3.60 (d, J¼2.0 Hz, 1H), 1.17 (q, J¼5.2 Hz, 6H). HPLC
(DAICEL Chiralcal OD-H 4.6 mm
flow rate is 1.0 mL/min): tR¼5.34 min (2R,3S-enantiomer, major),
5.65 min (2S,3R-enantiomer, minor).
f
ꢂ250 mm, 5% EtOH in hexane,
4.1.36. N-Terminal free stapled peptide H-hS3,7R-10. N-Terminal free
peptide H-hS3,7R-10 was prepared using a similar method to that
4.2.3. (1S,2R)-trans-Epoxy-4,4-dimethyl-1-phenylpentan-3-one
described for the preparation of H-S3,7S-9. 61%; Foam; ½a D24
ꢃ
ꢁ34.8
(12d). Colorless crystals: ½a D26
ꢃ
ꢁ150.9 (c 1.0, CDCl3) [lit.,25 ꢁ194ꢀ (c
(c 0.50, CHCl3); IR (in CDCl3):
n
3328, 2959, 2874, 1664, 1527 cmꢁ1
;
1.00, CHCl3)]; 1H NMR (400 MHz, CDCl3)
d 7.30e7.39 (m, 5H), 3.86 (s,
1H NMR (400 MHz, CDCl3)
d
8.00 (d, J¼4.4 Hz, 1H), 7.75 (d, J¼8.0 Hz,
2H), 1.24 (s, 9H). HPLC (DAICEL Chiralcal OD-H 4.6 mm
f
ꢂ250 mm,
1H), 7.52 (br s, 1H), 7.41 (br s, 1H), 7.22 (br s, 1H), 6.57 (br s, 1H), 4.42
(m, 1H), 4.34 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 3.88 (m, 1H), 3.79
(m, 1H), 3.71 (s, 3H), 3.60 (m, 1H), 3.55 (m, 1H), 3.41e3.51 (m, 7H),
3.35 (m, 1H), 1.93e2.14 (m, 2H), 1.25e1.88 (m, 22H), 0.87e1.02 (m,
5% EtOH in hexane, flow rate is 1.0 mL/min): tR¼5.5 min (2R,3S-
enantiomer, major), 5.9 min (2S,3R-enantiomer, minor).
4.2.4. (2R,3S)-trans-Epoxy-3-phenyl-1-(2-furyl)propan-1-one
24H), 13C NMR (100 MHz, CDCl3)
d
176.0, 174.3, 174.3, 173.8, 173.3,
(12e). Colorless crystals: ½a D26
ꢃ
ꢁ191.9 (c 1.00, CDCl3) [lit.,26 ꢁ200ꢀ (c
171.5, 171.0, 71.7, 70.4, 69.0, 66.4, 57.4, 56.8, 54.7, 54.3, 54.1, 53.9,
53.8, 52.6, 43.1, 40.5, 40.2, 40.1, 31.1, 26.7, 26.2, 25.6, 25.1, 24.9, 24.8,
24.0, 23.5, 23.4, 23.3, 23.2, 22.9, 21.9, 21.8, 21.6, 21.5; [HR-ESI(þ)]:
m/z calcd for C40H74N7O10 [MþH]þ 812.5497: found 812.5478.
1.00, CHCl3)]; 1H NMR (400 MHz, CDCl3)
d 7.67 (m, 1H), 7.46 (d,
J¼4.0 Hz, 1H), 6.59e6.60 (m, 5H), 4.20 (m, 2H). HPLC (DAICEL
Chiralcal OD-H 4.6 mm
f
ꢂ250 mm, 5% EtOH in hexane, flow rate is
1.0 mL/min): tR¼59.5 min (2R,3S-enantiomer, major), 39.1 min
(2S,3R-enantiomer, minor).
4.1.37. N-Terminal free stapled peptide H-hS3,7hS-10. N-Terminal
free peptide H-hS3,7hS-10 was prepared using a similar method to
4.2.5. (2R,3S)-trans-Epoxy-3-methyl-1-phenylpropan-1-one
that described for the preparation of H-S3,7S-9. 74%; Foam; ½a D24
ꢃ
(12f). Colorless crystals: ½a D26
ꢃ
ꢁ5.0 (c 1.00, CDCl3) [lit.,27 ꢁ10.0ꢀ (c
ꢁ33.8 (c 0.82, CHCl3); IR (in CDCl3):
n
3329, 2958, 2874, 1664,
0.60, CHCl3)]; 1H NMR (400 MHz, CDCl3)
d 8.01e8.26 (m, 2H), 7.61
1528 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
8.00 (d, J¼4.4 Hz, 1H), 7.69
(m, 1H), 7.48e7.52 (m, 1H), 3.97 (s, 1H), 3.23 (m, 1H), 1.52 (d,
(d, J¼8.4 Hz, 1H), 7.30 (d, J¼6.8 Hz, 1H), 7.28 (br s, 1H), 7.09 (d,
J¼4.8 Hz, 1H), 6.82 (d, J¼7.2 Hz, 1H), 4.66 (m, 1H), 4.49 (m, 1H), 4.26
(m, 1H), 4.17 (m, 1H), 4.09 (m, 1H), 3.73 (s, 3H), 3.57 (m, 1H),
3.37e3.54 (m, 10H), 2.18e2.25 (m, 2H), 1.91e2.11 (m, 2H), 1.25e1.85
J¼4.4 Hz, 3H). HPLC (DAICEL Chiralcal OD-H 4.6 mm ꢂ250 mm, 1%
f
iPrOH in hexane, flow rate is 1.0 mL/min): tR¼15.2 min (2R,3S-en-
antiomer, major), 17.1 min (2S,3R-enantiomer, minor).
(m, 22H), 0.87e1.02 (m, 24H); 13C NMR (100 MHz, CDCl3)
d
176.5,
4.2.6. (2R,3S)-trans-Epoxy-3-(4-chlorophenyl)-1-phenylpropan-1-
174.6, 174.4, 173.8, 173.1, 173.0, 70.7, 70.6, 66.8, 66.4, 56.9, 55.0, 54.8,
54.3, 53.6, 52.9, 52.7, 49.9, 42.9, 40.4, 40.1, 40.0, 31.9, 31.4, 26.8, 25.7,
25.6, 25.2, 25.1, 24.9, 24.8, 23.6, 23.5, 23.4, 23.2, 22.9, 21.9, 21.8, 21.2,
21.1; [HR-ESI(þ)]: m/z calcd for C41H76N7O10 [MþH]þ 826.5654:
found 826.5651.
one (12g). Thin yellow crystals: ½a D26
ꢃ
ꢁ202.4 (c 1.00, CDCl3) [lit.,26
ꢁ233ꢀ (c 1.00, CH2Cl2)]; 1H NMR (400 MHz, CDCl3)
d 7.99e8.01
(m, 2H), 7.61e7.65 (m, 2H), 7.48e7.52 (m, 2H), 7.38 (d, J¼8.4 Hz,
2H), 7.31 (d, J¼8.4 Hz, 2H), 4.24 (d, J¼1.6 Hz, 1H), 4.06 (d, J¼1.6 Hz,
1H). HPLC (DAICEL Chiralcal OD-H 4.6 mm
f
ꢂ250 mm, 1% iPrOH in
hexane, flow rate is 1.0 mL/min): tR¼30.0 min (2S,3R-enantiomer,
4.2. General procedure for peptide-catalyzed asymmetric
epoxidation of chalcone
minor), 32.3 min (2R,3S-enantiomer, major).
4.2.7. (2R,3S)-trans-Epoxy-3-(4-methoxyphenyl)-1-phenylpropan-
THF (2 mL) was added to the mixture of peptide H-R3,7R-2
(12 mg, 0.015 mmol) and (E)-chalcone (11a) (63 mg, 0.3 mmol) in
a screw vial equipped with a magnetic stirring bar. Urea hydrogen
1-one (12h). Thin yellow crystals: ½a D26
ꢃ
ꢁ169.1 (c 1.00, CDCl3) [lit.,28
another 2S,3R-enantiomer, þ131ꢀ (c 0.70, CHCl3)]; 1H NMR
(400 MHz, CDCl3)
d
8.01 (d, J¼7.2 Hz, 2H), 7.61 (m, 1H), 7.47e7.52
peroxide (31 mg, 0.33 mmol) and DBU (11.3
mL, 1.68 mmol) were
(m, 2H), 7.30 (d, J¼8.8 Hz, 2H), 6.92e6.94 (m, 2H), 4.28 (d, J¼1.6 Hz,
1H), 4.03 (d, J¼1.6 Hz, 1H), 3.83 (s, 3H). HPLC (DAICEL Chiralcal OD-
added at 0 ꢀC, and the mixture was gradually warmed to room

Y. Demizu et al. / Tetrahedron 67 (2011) 6155e6165
6165
ꢂ250 mm, 1% iPrOH in hexane, flow rate is 0.5 mL/min):
8. See the Experimental section.
H 4.6 mm
f
9. (a) Berkessel, A.; Koch, B.; Toniolo, C.; Rainaldi, M.; Broxterman, Q. B.; Kaptein,
B. Biopolymers (Pept. Sci.) 2006, 84, 90e96; (b) Carrea, G.; Colonna, S.; Kelly, D.
R.; Lazcano, A.; Ottolina, G.; Roberts, S. M. Trends Biotechnol. 2005, 23, 507e513;
(c) Kelly, D. R.; Bui, T. T. T.; Caroff, E.; Drake, A. F.; Roberts, S. M. Tetrahedron Lett.
2004, 45, 3885e3888; (d) Takagi, R.; Shiraki, A.; Manabe, T.; Kojima, S.; Ohkata,
K. Chem. Lett. 2000, 366e367; (e) Nagano, M.; Doi, M.; Kurihara, M.; Suemune,
H.; Tanaka, M. Org. Lett. 2010, 12, 3564e3566.
tR¼27.1 min (2R,3S-enantiomer, major), 29.0 min (2S,3R-enantio-
mer, minor).
Acknowledgements
This work was supported, in part, by a Grant-in-Aid for Scientific
Research (C) (22590114) from the Japan Society for the Promotion
of Science, and also by a Kaneka Award in Synthetic Organic
Chemistry, Japan.
10. It has already been known that (Z)-chalcone is isomerised under hydroperoxide
conditions to an equimolar mixture of the (Z)- and (E)-isomers prior to epox-
idation. See reference: Kelly, D. R.; Caroff, E.; Flood, R. W.; Heal, W.; Roberts, S.
M. Chem. Commun. 2004, 2016e2017 Therefore, the authors did not attempt to
examine the epoxidation to (Z)-chalcone.
11. The asymmetric epoxidation of 2-cyclohexen-1-one as an aliphatic ketone gave
(1S,6S)-7-oxabicyclo[4.1.0]heptan-2-one with moderate yield (62%) and low
enantioselectivity (18% ee).
References and notes
12. (a) Kennedy, D. F.; Crisma, M.; Toniolo, C.; Chapman, D. Biochemistry 1991, 30,
6541e6548; (b) Demizu, Y.; Tanaka, M.; Doi, M.; Kurihara, M.; Okuda, H.; Su-
emune, H. J. Pept. Sci. 2010, 16, 621e626.
1. (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.; Broxterman, Q. B.;
Kaptein, B. J. Inclusion Phenom. Macrocyclic Chem. 2005, 51, 121e136; (b) Kaul, R.;
Balaram, P. Bioorg. Med. Chem. 1999, 7, 105e117; (c) Gellman, S. H. Acc. Chem. Res.
1998, 31,173e180; (d) Wysong, C. L.; Yokum, T. S.; MacLaughlin, M. L.; Hammer, R.
P. Chemtech 1997, 27, 26e33.
13. Demizu, Y.; Tanaka, M.; Nagano, M.; Kurihara, M.; Doi, M.; Maruyama, T.; Su-
emune, H. Chem. Pharm. Bull. 2007, 55, 840e842.
14. (a) Formaggio, F.; Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman, Q.
B.; Kamphuis, J.; Toniolo, C. Chem.dEur. J. 2000, 6, 4498e4504; (b) Toniolo, C.;
Polese, A.; Formaggio, F.; Crisma, M.; Kamphuis, J. J. Am. Chem. Soc. 1996, 118,
2744e2745.
2. (a) Crisma, M.; Formaggio, F.; Moretto, A.; Toniolo, C. Biopolymers (Pept. Sci.)
2006, 84, 3e12; (b) Royo, S.; Borggraeve, W. M. D.; Peggion, C.; Formaggio, F.;
ꢁ
Crisma, M.; Jimenez, A. I.; Cativiela, C.; Toniolo, C. J. Am. Chem. Soc. 2005, 127,
2036e2037; (c) Dehner, A.; Planker, E.; Gemmecker, G.; Broxterman, Q. B.;
Bisson, W.; Formaggio, F.; Crisma, M.; Toniolo, C.; Kessler, H. J. Am. Chem. Soc.
2001, 123, 6678e6686; (d) Demizu, Y.; Doi, M.; Kurihara, M.; Okuda, H.; Na-
gano, M.; Suemune, H.; Tanaka, M. Org. Biomol. Chem. 2011, 9, 3303e3312; (e)
Demizu, Y.; Doi, M.; Sato, Y.; Tanaka, M.; Okuda, H.; Kurihara, M. J. Org. Chem.
2010, 75, 5234e5239; (f) Nagano, N.; Tanaka, M.; Doi, M.; Demizu, Y.; Kurihara,
M.; Suemune, H. Org. Lett. 2009, 11, 1135e1137; (g) Tanaka, M.; Anan, K.;
Demizu, Y.; Kurihara, M.; Doi, M.; Suemune, H. J. Am. Chem. Soc. 2005, 127,
11570e11571; (h) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
Angew. Chem., Int. Ed. 2004, 43, 5360e5363.
15. Sheldrick, G. M. Program for Crystal Structure Refinement (SHELXL 97); University
€
€
of Gottingen: Gottingen, 1997.
16. Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; Gelder, R. D.; Israel,
R.; Smits, J. M. M. The DIRDIF-99 Program System, Technical Report of the Crys-
tallography Laboratory; University of Nijmegen: The Netherlands, 1994.
17. CCDC-797487 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/re-
trieving.html (or from the Cambridge Crystallographic Data Center, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: (þ44) 1223-336-033; or deposit@ccdc.cam.
ac.uk).
3. (a) Kim, Y.-W.; Kutchukian, P. S.; Verdine, G. L. Org. Lett. 2010, 12, 3046e3049;
(b) Ousaka, N.; Inai, Y.; Kuroda, R. J. Am. Chem. Soc. 2008, 130, 12266e12267; (c)
Wang, D.; Liao, W.; Arora, P. S. Angew. Chem., Int. Ed. 2005, 44, 6525e6529; (d)
Chapman, R. N.; Dimartino, G.; Arora, P. S. J. Am. Chem. Soc. 2004, 126,
12252e12253; (e) Schafmeister, C. E.; Po, J.; Verdine, G. L. J. Am. Chem. Soc.
2000, 122, 5891e5892; (f) Phelan, J. C.; Skelton, N. J.; Braisted, A. C.; McDowell,
R. S. J. Am. Chem. Soc. 1997, 119, 455e466; (g) Jackson, D. Y.; King, D. S.;
Chmielewski, J.; Singh, S.; Schultz, P. G. J. Am. Chem. Soc. 1991, 113, 9391e9392.
4. (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.; Broxterman, Q. B.; Kap-
tein, B. Biopolymers (Pept. Sci.) 2004, 76, 162e176; (b) Karle, I. L. Biopolymers
(Pept. Sci.) 2001, 60, 351e365; (c) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. Rev. 2001, 101, 3131e3152; (d) Demizu, Y.; Yamagata, N.; Sato,
Y.; Doi, M.; Tanaka, M.; Okuda, H.; Kurihara, M. J. Pept. Sci. 2010, 16, 153e158;
(e) Oba, M.; Demizu, Y.; Yamagata, N.; Sato, Y.; Doi, M.; Tanaka, M.; Suemune, H.;
Okuda, H.; Kurihara, M. Tetrahedron 2010, 66, 2293e2296.
18. (a) Steiner, T. New J. Chem. 1998, 22, 1099e1103; (b) Desiraju, G. R. Acc. Chem.
Res. 1991, 24, 290e296; (c) Demizu, Y.; Doi, M.; Sato, Y.; Tanaka, M.; Okuda, H.;
Kurihara, M. J. Pept. Sci. 2011, 17, 420e426.
19. Kelly, D. R.; Roberts, S. M. Chem. Commun. 2004, 2018e2020.
20. Licini, G.; Bonchio, M.; Broxterman, Q. B.; Kaptein, B.; Moretto, A.; Toniolo, C.;
Scrimin, P. Biopolymers (Pept. Sci.) 2006, 84, 97e104.
21. It was difficult to measure the CD spectra (range from 190 to 260 nm) of N-
terminal free peptides H-R3,7R-10 and H-hS3,7hS-10 in THF because of the
background noise.
22. Glenn, M. P.; Pattenden, L. K.; Reid, R. C.; Tyssen, D. P.; Tyndall, J. D. A.; Birch, C.
J.; Fairlie, D. P. J. Med. Chem. 2002, 45, 371e381.
23. Adger, B. M.; Barkley, J. V.; Bergeron, S.; Cappi, M. W.; Flowerdew, B. E.; Jackson,
M. P.; MacCague, R.; Nugent, T. C.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1
1997, 3501e3507.
24. Bickley, J. F.; Roberts, S. M.; Runhui, Y.; Skidmore, J.; Smith, C. B. Tetrahedron
2003, 59, 5731e5736.
25. Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2725e2726.
26. Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.; Mahendar, K.; Sreedhar, B. J.
Am. Chem. Soc. 2004, 126, 3396e3397.
5. Blackwell, H. E.; Sadowsky, J. D.; Howard, R. J.; Sampson, J. N.; Chao, J. A.;
Steinmetz, W. E.; O’Leary, D. J.; Grubbs, R. H. J. Org. Chem. 2001, 66, 5291e5302.
6. Preliminary communication of this paper was published. See; Yamagata, N.;
Demizu, Y.; Sato, Y.; Doi, M.; Tanaka, M.; Nagasawa, K.; Okuda, H.; Kurihara, M.
Tetrahedron Lett. 2011, 52, 798e801.
ꢁ
7. (a) Julia, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.; Annuziata, R.; Molinari,
27. Lattanzi, A. Org. Lett. 2005, 7, 2579e2582.
28. Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289e6300.
ꢁ
H. J. Chem. Soc., Perkin Trans. 1 1982, 1317e1324; (b) Julia, S.; Masana, J.; Vega, J.
C. Angew. Chem., Int. Ed. Engl. 1980, 19, 929e931.