Cyclic α,α-Disubstituted α-Amino Acids with Menthone in Their Side-Chains Linked through an Acetal Moiety and Helical Structures of Their Peptides

Article abstract of DOI:10.1002/ejoc.201600241

The chiral cyclic α,α-disubstituted α-amino acids, Hms[(–)-Men] and Hms[(+)-Men] with (–)- and (+)-menthones in their side-chains, respectively, were designed and synthesized. Hms[(–)-Men] homopeptides and Hms[(–)/(+)-Men]-containing l-Leu-based peptides were prepared in order to investigate the conformational properties of Hms[(–)/(+)-Men]. The preferred conformations of the Hms[(–)/(+)-Men]-containing peptides were determined by FTIR,¹H NMR, and CD spectroscopy in solution, and by X-ray crystallographic analysis in the crystal state. Conformational analysis in solution revealed similar right-handed (P) 3₁₀-helical structures for the Hms[(–)/(+)-Men]-containing octapeptides. In the solid state of the hexapeptides, the peptide main-chain structures were mostly similar; however, some differences were observed in the side-chains. The Hms[(–)/(+)-Men] may function as helical inducers, but their side-chain chiralities had only a negligible effect on their helical-screw control of l-Leu-based peptides.

Full text of DOI:10.1002/ejoc.201600241

DOI: 10.1002/ejoc.201600241
Full Paper
Secondary Structures
Cyclic α,α-Disubstituted α-Amino Acids with Menthone in Their
Side-Chains Linked through an Acetal Moiety and Helical
Structures of Their Peptides
Kaori Furukawa,[a] Makoto Oba,*[a] George Ouma Opiyo,[a] Mitsunobu Doi,[b] and
Masakazu Tanaka*[a]
Abstract: The chiral cyclic α,α-disubstituted α-amino acids, Conformational analysis in solution revealed similar right-
Hms[(–)-Men] and Hms[(+)-Men] with (–)- and (+)-menthones in handed (P) 310-helical structures for the Hms[(–)/(+)-Men]-con-
their side-chains, respectively, were designed and synthesized. taining octapeptides. In the solid state of the hexapeptides, the
Hms[(–)-Men] homopeptides and Hms[(–)/(+)-Men]-containing peptide main-chain structures were mostly similar; however,
L-Leu-based peptides were prepared in order to investigate the some differences were observed in the side-chains. The
conformational properties of Hms[(–)/(+)-Men]. The preferred Hms[(–)/(+)-Men] may function as helical inducers, but their
conformations of the Hms[(–)/(+)-Men]-containing peptides side-chain chiralities had only a negligible effect on their heli-
were determined by FTIR, 1H NMR, and CD spectroscopy in solu- cal-screw control of
tion, and by X-ray crystallographic analysis in the crystal state.
L-Leu-based peptides.
Introduction
same amino-acid residues, and was not capable of controlling
the helical-screw sense regardless of its twelve chiral centers.
Therefore, extensive efforts have been devoted to designing
and synthesizing new cyclic dAAs, and carrying out conforma-
tional analysis of their dAA-containing peptides.[5]
Peptides composed of cyclic α,α-disubstituted α-amino acids
(dAAs) are known to adopt helical structures;[1] they may be
used as helical foldamers in functional peptides.[2] The helical-
screw sense of homopeptides is in some cases controllable by
the chiral centers in their side-chains. The number of chiral cen-
ters in the peptides and also their environments are important
for controlling the helical-screw sense.[3] The presence of het-
eroatoms, such as oxygen, in the side-chains of dAAs also has
a significant influence on the secondary structure; heteroatoms
are capable of cleaving intramolecular hydrogen bonds be-
tween the amide N–H and carbonyl O=C in the peptide back-
bone, and forming new hydrogen bonds with the amide N–H.[4]
Leplawy, Toniolo, and coworkers described O,O-isopropylidene-
α-(hydroxymethyl)serine [Hms(Ipr)] (Figure 1), the peptides of
which formed destabilized 310-helical structures as a result of
newly observed intramolecular hydrogen bonds between the
ether oxygen and the amide N–H.[4b] We recently synthesized a
cyclic dAA with two chiral acetals [(R,R)-Ac6c35dBu], and analyzed
the conformation of its peptides (Figure 1).[4d] The (R,R)-
Ac6c35dBu tripeptide had intramolecular hydrogen bonds be-
tween the side-chain acetal oxygen and the amide N–H in the
Figure 1. Structures of Hms(Ipr), (R,R)-Ac6c35dBu, Hms[(–)-Men], and Hms[(+)-
Men].
In the work described in this paper, a cyclic dAA {Hms[(–)/
(+)-Men]} with (–)- or (+)-menthone in the side-chain, attached
through an acetal moiety, was designed and synthesized (Fig-
ure 1). We synthesized Hms[(–)/(+)-Men] homopeptides and
heteropeptides in L-leucine (Leu) sequences, and were inter-
ested in the conformational properties of Hms[(–)/(+)-Men]
from two points of view. One was whether Hms[(–)/(+)-Men]-
containing peptides would adopt a helical structure in spite of
the bulky menthone moiety and acetal oxygens in the side-
chain. The other was whether the helical screw-sense of the
peptides would be affected by the chirality of the (–)- or (+)-
menthone moiety. Conformational analysis of Hms[(–)/(+)-Men]
[a] Graduate School of Biomedical Sciences, Nagasaki University,
Nagasaki 852-8521, Japan
E-mail: moba@nagasaki-u.ac.jp
matanaka@nagasaki-u.ac.jp
http://www.ph.nagasaki-u.ac.jp/lab/biomimic/index-j.html
[b] Osaka University of Pharmaceutical Sciences,
Osaka 569-1094, Japan
1
heteropeptides was carried out in solution using FTIR, H NMR,
and CD spectroscopic measurements, and in the crystal state
by X-ray crystallographic analysis.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600241.
Eur. J. Org. Chem. 2016, 2988–2998
2988
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Results and Discussion
determined by NOESY NMR spectroscopy (Figure S1). The
NOESY NMR spectrum of 7a showed a correlation between the
amide proton and the iPr methine proton, suggesting that the
Cbz-amino group at the α position and the C-2 carbon in the
iPr group derived from (–)-menthone had a syn relationship.
The stereochemistry of the major product (i.e., 7a) was unam-
biguously confirmed by X-ray crystallographic analysis of its
peptide derivatives (vide infra). Acetalization between diol Cbz-
Hms-OMe 6 and (+)-menthone gave enantiomer Cbz-Hms[(+)-
Men]-OMe 7b.
Synthesis of Chiral Hms[(–)/(+)-Men] with Menthone in the
Side-Chain
A chiral dAA Hms[(–)-Men] was synthesized starting from 2-
amino-2-hydroxymethyl-1,3-propanediol (Scheme 1). Treatment
of 2-amino-2-hydroxy-1,3-propanediol with 2,2-dimethoxyprop-
ane and pTsOH·H2O gave O,O-isopropylidene derivative 1 as a
pTsOH salt in 94 % yield. Cbz (benzyloxycarbonyl) protection of
the amino group was carried out using benzyl chloroformate
to give 2. Swern oxidation of alcohol 2 followed by Pinnick
oxidation of the resulting aldehyde 3 gave Cbz-Hms(Ipr)-OH 4
in an excellent yield. Treatment of 4 with (trimethylsilyl)diazo-
methane quantitatively gave ester Cbz-Hms(Ipr)-OMe 5, which
was converted into diol Cbz-Hms-OMe 6 by acidic hydrolysis.
Diol Cbz-Hms-OMe 6 was also obtained from Cbz-Hms(Ipr)-OH
4 by methyl esterification and O,O-isopropylidene deprotection
by treatment with acidic MeOH. Acetalization using (–)-menth-
one was initially attempted by heating in refluxing toluene in
the presence of pTsOH (Table 1, entry 1). Unfortunately, these
acetalization conditions resulted in a low yield (20 %) and a
moderate diastereomeric ratio (7a/7a′ = 83:17). The ratios of
diastereomeric mixtures were determined based on the peak
Table 1. Acetalization of the side-chain of Cbz-Hms-OMe 6 using (–)-menth-
one.
Entry
Conditions
Yield
[%]
dr (7a/7a′)[a]
1
2
(–)-menthone, pTsOH, toluene, reflux
i. HMDS, TMSOTf, THF, 0 °C
20
41
83:17
93:7
ii. (–)-menthone, TMSOTf, CH2Cl2, –40 °C
i. HMDS, TMSOTf, THF, 0 °C
1
intensity ratio of the methyl ester protons in the H NMR spec-
3
84
98:2
ii. (–)-menthone, TMSOTf, CH2Cl2, –78 °C
tra (δ = 3.75 ppm for major product 7a, and δ = 3.80 ppm for
minor product 7a′). The diastereomers were separated by col-
umn chromatography on silica gel (n-hexane/acetone). To im-
prove the yield and diastereometic ratio, Noyori's conditions
[a] dr was determined by 1H NMR spectroscopy.
were examined.[6] Treatment of Cbz-Hms-OMe
6
with
Preparation of Peptides
1,1,1,3,3,3-hexamemethyldisiazane (HMDS) and trimethylsilyl
trifluoromethanesulfonate (TMSOTf) gave a bis(trimethylsilyl)
ether, which was used in a subsequent reaction without purifi-
cation. The crude bis(trimethylsilyl) ether was treated with (–)-
menthone and TMSOTf at –40 °C, giving Cbz-Hms[(–)-Men]-
OMe 7 in a moderate yield (41 %) with a good diastereomeric
ratio (7a/7a' = 93:7; Table 1, entry 2). Furthermore, at a lower
temperature (–78 °C), the acetalization gave a good yield (84 %)
and an excellent diastereomeric ratio (7a/7a′ = 98:2; Table 1,
entry 3). The stereochemistry of the major product (i.e., 7a) was
We initially attempted to synthesize Hms[(–)-Men] homopept-
ides (Scheme 2). The alkaline hydrolysis and hydrogenolysis of
Cbz-Hms[(–)-Men]-OMe 7a gave C-terminal-free carboxylic acid
8a and N-terminal-free amine 9a, respectively. Dipeptide 10a
was easily prepared in 91 % yield by coupling 8a and 9a by
Scheme 2. Synthesis of Hms[(–)-Men] homopeptides; DIPEA = diisopropyleth-
ylamine.
Scheme 1. Synthesis of Cbz-Hms-OMe 6; TFA = trifluoroacetic acid.
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2989
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
treatment with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl- a), and Hms[(+)-Men]-containing peptides 13b, 14b, and 15b′
uronium hexafluorophosphate (HATU) and 1-hydroxy-7-aza- (Figure 2, b) in the 3250–3500 cm–1 region (CDCl3). The weak
bands in the 3420–3440 cm–1 region were assigned to free
(solvated) peptide NH groups, the weak bands in the 3370–
3400 cm–1 region were assigned to peptide NH groups with
intramolecular hydrogen bonds to the acetal oxygens, and the
strong bands in the 3300–3370 cm–1 region were assigned to
peptide NH groups with intramolecular hydrogen bonds to the
peptide O=C groups.[4b] The low-frequency band observed at
3340 cm–1 in pentapeptides 13a and 13b shifted to a lower
wavenumber of 3320 cm–1 in octapeptides 15a, 15a′, and
15b′, and its intensity increased with elongation of the peptide
length. These shifts in wavelength and increases in intensity are
similar to those observed for Acnc homopeptides.[1c] Hexa-
peptides 14a and 14b showed bands assigned to peptide NH
groups intramolecularly hydrogen bonded to the acetal oxy-
gens, and weak bands assigned to free peptide NH groups. The
α-helical and 310-helical peptides have three and two intramo-
lecular-hydrogen-bond-free peptide NH groups at the N-termi-
nus, respectively. Accordingly, hexapeptides 14a and 14b did
not form a complete and typical helical structure. The presence
of Hms[(–)/(+)-Men] at the N-terminus of the hexapeptide af-
fected the formation of hydrogen bonds between the N-termi-
nal peptide N–H and the acetal oxygens.
benzotriazole (HOAt). Hydrogenolysis of 10a followed by cou-
pling with 8a using HATU or (1-cyano-2-ethoxy-2-oxoethyl-
idenaminoxy)dimethylaminomorpholinocarbenium hexafluoro-
phosphate (COMU) as a coupling reagent gave tripeptide 11a
in 27 or 44 % yield. After deprotection of the Cbz group in 11a,
coupling between the amine derived from 11a and carboxylic
acid 8a was attempted using HATU or COMU. However, no tet-
rapeptide was isolated, which may have been due to the steric
hindrance of the (–)-menthone moiety and the unfavorable
conformation masking the N-terminal amine.
We subsequently synthesized heteropeptides having Hms-
[(–)-Men] or Hms[(+)-Men] in L-Leu sequences (Scheme 3). The
synthesis of octapeptides 15a, 15a′, and 15b′ was achieved
using solution-phase methods with HATU and HOAt as the cou-
pling reagents. Elongation of the peptide chain proceeded well
by fragment coupling using an N-terminal-protected L-Leu di-
peptide, or by stepwise addition of C-terminal-free carboxylic
acid 8a or 8b.
The NOESY NMR spectra of hexapeptides 14a and 14b and
octapepetides 15a, 15a′, and 15b′ were measured in CDCl3 so-
lution (Figure 3 and Figure S2) in order to investigate the effects
of the chiralities of methone (14a and 14b; 15a′ and 15b′)
and the N-terminal-protecting groups (15a and 15a′) on the
preferred conformation of peptides. Sequential NH (i→i+1) di-
polar interactions [dNN (i→i+1)] are generally used to diagnose
helical structures, and the NOE constraints dαN (i→i+2) and dαN
(i→i+4) are characteristics of 310-helical and α-helical structures,
respectively.[7] The NOESY NMR spectrum of Hms[(–)-Men]-con-
taining hexapeptide 14a showed a complete series of sequen-
tial NH (i→i+1) dipolar interactions from the N-terminal NH to
C-terminal NH, together with the NOE constraint dαN (2→4),
suggesting the existence of a partial 310-helical structure (Fig-
ure S2a). In the NOESY spectrum of Hms[(+)-Men]-containing
hexapeptide 14b, four NH (i→i+1) dipolar interactions [dNN
(i→i+1); i = 1, 3, 4, and 5] were observed (Figure S2b); however,
none of the NOE constraints dαN useful for determining the
types of helical structures were observed. The NOESY NMR
spectra of Hms[(–)-Men]-containing octapeptides 15a and 15a′
showed a series of sequential NH (i→i+1) dipolar interactions
from the N-terminal N(1)–H to N(7)–H, but did not show the
dipolar interaction dNN (7→8) (Figure S2c and Figure 3). Neither
NOE constraints dαN (i→i+2) nor dαN (i→i+4) were observed.
The preferred conformation of Hms[(–)-Men]-containing octa-
peptides 15a and 15a′ in CDCl3 may be similar, regardless of
the N-terminal protecting groups. The NOESY spectrum of
Hms[(+)-Men]-containing octapeptide 15b′ showed partial di-
polar interactions [dNN (i→i+1); i = 1, 3–7], but not the dipolar
interaction dNN (2→3) (Figure S2d). However, neither NOE con-
straints dαN (i→i+2) nor dαN (i→i+4) were analyzed due to over-
lap of the proton signals. Most sequential NH (i→i+1) dipolar
interactions [dNN (i→i+1)] were observed in all of the peptides,
Scheme 3. Synthesis of heteropeptides having Hms[(–)-Men] or Hms[(+)-Men]
in L-Leu sequences. Only the structures of Hms[(–)-Men] and its peptides are
shown.
Conformational Analysis in Solution
Figure 2 shows the FTIR absorption spectra of the Hms[(–)-
Men]-containing peptides 13a, 14a, 15a, and 15a′ (Figure 2,
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2990
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 2. FTIR absorption spectra of a) Hms[(–)-Men]-containing peptides 13a, 14a, 15a, and 15a′, and b) Hms[(+)-Men]-containing peptides 13b, 14b, and
15b′. The peptide concentration was 5 mM in CDCl3.
Figure 3. NOESY NMR spectra of Hms[(–)-Men]-containing octapepetide 15a′.
which implies the existence of helical structures; however, it is 14b, and 15b′ were measured in 2,2,2-trifluoroethanol (TFE) so-
difficult to deduce the preferred conformations based on these lution (Figure 4). Negative maxima at 205–209 nm (π→π*) and
results alone.
222–225 nm (n→π*) are diagnostic of right-handed (P) helical
structures.[8] The ratio of R (θn→π*/θπ→π*) has been used as a
The CD spectra of Hms[(–)-Men]-containing peptides 13a,
14a, 15a, and 15a′ and Hms[(+)-Men]-containing peptides 13b, parameter to distinguish α-helical from 310-helical structures
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2991
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 4. CD spectra of a) Hms[(–)-Men]-containing peptides 13a, 14a, 15a, and 15a′, b) Hms[(+)-Men]-containing peptides 13b, 14b, and 15b′, and c) octapep-
tides 15a′ and 15b′. The peptide concentration was 0.1 mM in TFE.
(i.e., R ≈ 1: α-helix; R ≤ 0.4: 310-helix). Hms[(–)-Men]-containing affect the ratio R (Cbz 15a: 0.222; Boc 15a′: 0.173) (Boc = tert-
pentapeptide 13a showed a negative maximum at 193– butoxycarbonyl). Comparisons between (–)- and (+)-menthone
200 nm, and positive maximum at 220 nm, which is similar in the side-chains of dAAs in octapeptides 15a′ and 15b′ re-
to a random structure. The spectra of pentapeptide 13b and vealed that the values obtained at 222 nm were similar (Fig-
hexapeptides 14a and 14b did not show the maxima character- ure 4, c). The CD spectrum of homotripeptide 11 was also
istic of a helical structure. These results imply that shorter pept- measured, but it did not show the characteristic maxima of a
ides such as pentapeptides and hexapeptides do not have the one-handed helical-screw structure (data not shown).
ability to form complete helical structures and/or control the
helical screw-sense in TFE solution. Although the existence of
Conformational Analysis in the Crystal State
partial 310-helical structures was suggested from the NOESY
Hms[(–)-Men]-containing pentapeptide 13a, hexapeptide 14a,
NMR spectrum of hexapeptide 14a, the CD spectrum of 14a
and octapeptide 15a′, and Hms[(+)-Men]-containing hexapept-
ide 14b formed good crystals for X-ray crystallographic analysis
through slow evaporation of the solvent (13a: EtOH/MeOH;
did not indicate a one-handed helical-screw sense. However,
the different solvents used for the measurements (CDCl3 for
NMR spectroscopy, and TFE for CD spectroscopy) may affect
the preferred conformation in solution. Furthermore, the results
obtained from the different methods were not completely con-
sistent with each other for other peptides; this may be due not
only to the different solvents used, but also to direct informa-
14a: DMF; 14b: DMF; 15a′: EtOAc/n-hexane) at room tempera-
ture.[9] The crystal and diffraction parameters of 13a, 14a, 14b,
and 15a′ are summarized in Table S1. The molecular structures
of 13a, 14a, 14b, and 15a′ are given in Figures 5, 6, 7, 8, and
tion about peptide secondary structures not being obtained
(FTIR: free or hydrogen-bonded N–H; NOESY spectrum: distance
between hydrogen atoms). Octapeptides 15a, 15a′, and 15b′
showed negative maxima at approximately 208 nm and
222 nm, and a positive maximum at 192 nm; this shows the
presence of right-handed (P) helical structures. The ratio of R
(θn→π*/θπ→π*) suggested that the dominant secondary struc-
ture of the octapeptides 15a (R = 0.222), 15a′ (R = 0.173), and
15b′ (R = 0.270) was a 310-helix. However, the intensities of
negative maxima at 205–209 nm (π→π*) and 222–225 nm
(n→π*) were too weak for ideal helices. These results imply that
the helical secondary structures and/or helical screw-sense of
the octapeptides were not completely controlled. Figure 4 (a)
indicates that N-terminal protecting groups do not markedly
Figure 5. X-ray crystallographic structure of pentapeptide 13a as viewed
a) perpendicular to and b) along the helical axis.
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2992
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
9. The relevant backbone and side-chain torsion angles as well
as intra- and intermolecular hydrogen-bond parameters are
listed in Tables 2, 3, and S2.
Table 2. Average values of torsion angles φ and ψ [°] for pentapeptide 13a,
hexapeptides 14a and 14b, and octapeptide 15a′, as determined by X-ray
crystallographic analysis.
Peptide
φ [°]
ψ [°]
Secondary structure
pentapeptide 13a
hexapeptide 14a[a]
hexapeptide 14b[a]
octapeptide 15a[b]
–61.8
–60.2
–62.4
–63.5
–32.6
–25.6
–30.3
–25.3
(P) 310-helix
distorted (P) 310-helix
distorted (P) 310-helix
distorted (P) 310-helix
[a] Torsion angles of Leu(5) and Leu(6) were omitted. [b] Torsion angles of
Leu(1) were omitted.
Table 3. Intra- and intermolecular hydrogen-bond parameters for penta-
peptide 13a, hexapeptides 14a and 14b, and octapeptide 15a′.
Peptide[a]
Donor
D–H
Acceptor Distance [Å] Angle [°] Symmetry
Figure 6. X-ray crystallographic structure of hexapeptide 14a as viewed
a) perpendicular to and b) along the helical axis. In a), the DMF molecule has
been omitted.
A
D···A
D–H···A operation
Pentapeptide 13a
N(3)–H O(0)
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
N(2)–H O(5′)
3.20
3.07
3.04
2.92
2.93
135
156
142
162
146
x, y, z
x, y, z
x, y, z
–1 + x, y, z
–1 + x, y, z
Hexapeptide 14a
N(3)–H O(0)
N(4)–H O(1)
N(5)–H O(2)
N(6)–H O(3)
N(2)–H O(DMF)
N(1)–H O(5′)
2.98
3.05
2.96
3.08
2.80
2.87
160
140
154
161
159
169
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
3/2 – x, 1 – y,
–1/2 + z
Figure 7. X-ray crystallographic structure of hexapeptide 14b as viewed
a) perpendicular to and b) along the helical axis.
Hexapeptide 14b
N(3)–H O(0)
N(4)–H O(1)
N(5)–H O(2)
N(6)–H O(3)
N(1)–H O(6′)
3.02
3.44[b]
2.95
3.04
2.95
141
128
152
162
142
x, y, z
x, y, z
x, y, z
x, y, z
– × , –1/2 + y,
1/2 – z
N(2)–H O(5′)
2.98
137
–x, –1/2 + y,
1/2 – z
Octapeptide 15a′
N(4)–H O(1)
N(5)–H O(2)
N(6)–H O(3)
N(7)–H O(4)
N(8)–H O(5)
N(1)–H O(6′)
3.00
3.01
3.00
3.02
2.92
2.74
158
156
146
165
156
135
x, y, z
x, y, z
x, y, z
x, y, z
Figure 8. Overlaid structures of hexapepetides 14a (blue) and 14b (green),
as viewed a) perpendicular to and b) along the helical axis.
x, y, z
1/2 – x, 2 – y,
–1/2 + z
1/2 – x, 2 – y,
–1/2 + z
N(3)–H O(7′)
2.98
176
[a] The number of amino acid residues begins at the N-terminus of the pept-
ide chain. [b] The distance of N(4)–H···O(1) (3.44 Å) in 14b is too long for an
intramolecular hydrogen bond.
for the φ and ψ torsion angles from the N-terminal residue to
the C-terminal residue. The mean values of the φ and ψ torsion
angles of the amino acid residues (1–5) were –61.8° and –32.6°,
which are close to the ideal values for a right-handed (P) 310-
helix (–60° and –30°). Three intramolecular hydrogen bonds
were observed in the crystal state, with each hydrogen bond
Figure 9. X-ray crystallographic structure of octapeptide 15a′ as viewed
a) perpendicular to and b) along the helical axis. The EtOAc molecule has
been omitted.
Pentapeptide 13a was folded into a right-handed (P) 310- forming a 10-membered (atom) pseudoring of the i←i+3 type
helical structure (Figure 5). The molecule showed negative signs corresponding to a 310-helical conformation (Table 3). In the
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2993
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
packing mode, the molecule was connected by intermolecular slightly different structures. Nevertheless, the lack of a marked
hydrogen bonds between H–N(1) and C(4′)=O(4′), and between difference in the peptide main-chain structures between hexa-
H–N(2) and C(5′)=O(5′) of a symmetry-related molecule (–1 + x, peptides 14a and 14b may be due to the chiral centers being
y, z), thereby forming a head-to-tail alignment of 310-helical far from the α-carbon atoms[4c,4d] and/or the low flexibility of
chains. These results are different from those seen for the CD the side-chain structures.[3c,3e] Hydrogen bonds between the
spectrum (random structure). This may be due to the fact that peptide N–H and acetal oxygens were not detected in the crys-
the single crystal for X-ray analysis was obtained by recrystalli- tal state.
zation from EtOH/MeOH, and that the CD spectrum was meas-
ured in TFE, or alternatively a minor right-handed (P) 310-helical
structure existing in solution could be preferentially induced in
the crystal state as a result of nucleation events.
The X-ray crystallographic results for hexapeptides 14a and
14b were different from those from the CD spectra; this may
be due to the different solvents used for recrystallization and
for the CD measurements. Alternatively, several random struc-
tures were present in solution, and the helical structures were
formed preferentially in the crystal state as a result of the nucle-
ation events.
The crystal structure of hexapeptide 14a containing two (–)-
menthone units was solved; this molecule crystallized together
with a DMF molecule in the space group P212121. The structure
showed a distorted right-handed (P) 310-helix (Figure 6). The
mean values of the φ and ψ torsion angles of the amino acid
residues (1–4) were –60.2° and –25.6°, respectively, which are
close to those of an ideal right-handed 310-helical structure.
However, the torsion angles of Leu(5) (φ = –92.8°; ψ = –7.4°)
and Leu(6) (φ = –69.1°; ψ = +142.8°) were different from the
ideal helical values. Four consecutive intramolecular hydrogen
bonds of the i←i+3 type were present (Table 3). In the packing
mode, two intermolecular hydrogen bonds were observed be-
tween H–N(2) and ODMF of DMF, and between H–N(1) and C(5)=
O(5′) of a symmetry-related molecule (3/2 – x, 1 – y, –1/2 + z).
The helical molecules were connected by intermolecular
hydrogen bonds forming a head-to-tail alignment of chains.
Conformational analysis of hexapeptide 14a by NOESY NMR
spectroscopy revealed the existence of a partial 310-helical
structure, which is consistent with the results of the X-ray crys-
tallographic analysis.
The structure of octapeptide 15a′, with two (–)-menthone
units, was solved in the space group P212121 to give a distorted
right-handed (P) 310-helical structure, along with an EtOAc mol-
ecule in an asymmetric unit (Figure 9). The Boc protecting
group, the side-chain of the Leu(4) residue, and the methyl es-
ter group were disordered. The mean values of the torsion an-
gles φ and ψ of amino acid residues 2–8 were –63.5° and –25.3°,
respectively, and are close to the ideal values for a right-handed
(P) 310-helical structure. However, the torsion angles φ and ψ
for the Leu(1) residue were +74.5° and +13.8°, respectively,
which are different from those expected for a right-handed (P)
helix, and closer to the values expected for a left-handed (M)
helix. Five successive intramolecular hydrogen bonds of the
i←i+3 type, corresponding to a 310-helical conformation, were
observed (Table 3). However, an intramolecular hydrogen bond
was not observed between H–N(3) and C(0)=O(0). In the pack-
ing mode, two intermolecular hydrogen bonds were observed
between H–N(1) and C(6′)=O(6′) and between H–N(3) and
C(7′)=O(7′) of a symmetry-related molecule (1/2 – x, 2 – y, –1/2
+ z). The 310-helical structures were packed to form a head-to-
tail alignment in a chain. The distorted right-handed (P) 310-
helical structure in the crystal state is consistent with the results
of the CD spectrum, which suggest a right-handed (P) 310-
helical conformation in solution.
In the crystal structure of hexapeptide 14b, two enantio-
meric (+)-menthones exclusively crystallized into a distorted
right-handed (P) 310-helical structure (Figure 7); however, com-
pound 14b did not show the characteristic CD spectrum of a
helical structure (Figure 4, b). The mean values of the torsion
angles φ and ψ of amino acid residues 1–4 were –62.4° and
–30.3°, respectively, which are close to the ideal values for a
right-handed (P) 310-helix; however, the torsion angles for
Leu(5) (φ = –102.5°; ψ = +14.3°) and Leu(6) (φ = –50.2°; ψ =
–42.9°) residues were different from the helical values. Three
intramolecular hydrogen bonds of the i←i+3 type were ob-
served (Table 3). The distance between H–N(4) and C(1)=O(1)
(3.44 Å) was too long for an intramolecular hydrogen bond. In
the packing mode, two intermolecular hydrogen bonds be-
tween H–N(1) and C(6′)=O(6′), and between H–N(2) and C(5′)=
O(5′) of a symmetry-related molecule (–x, –1/2 + y, 1/2 – z)
were observed. The 310-helical structures were packed to form
a head-to-tail alignment of chains.
Conclusions
We synthesized the chiral cyclic dAAs Hms[(–)-Men] and
Hms[(+)-Men] with high diastereomeric excesses, and prepared
Hms[(–)-Men]- and Hms[(+)-Men]-containing
ides. The dominant conformations of the Hms[(–)-Men]- and
Hms[(+)-Men]-containing peptides with -Leu sequences in so-
L-Leu-based pept-
L
1
lution appeared to be helical structures, based on FTIR and H
NMR spectra. Furthermore, CD spectra suggested that the dom-
inant secondary structures were similar for Hms[(–)-Men]- and
Hms[(+)-Men]-containing peptides, and demonstrated the exis-
tence of a right-handed (P) 310-helical structure for the octapept-
ides. The preferred conformations of Hms[(–)-Men]-containing
peptides 13a, 14a, and 15a′ and Hms[(+)-Men]-containing
peptide 14b were determined to be a complete or partial right-
The peptide main-chain structure of hexapeptide 14a was
similar to that of hexapeptide 14b, as shown by the superimpo-
sitions in Figure 8; however, some differences in the side-chains
and protecting groups were observed. We identified marked
differences, particularly in the acetal moieties derived from
(–)- and (+)-menthones. Each isopropyl substituent occupied an handed (P) 310-helical structure by X-ray crystallographic analy-
equatorial position on a cyclohexane ring (in a chair conforma- sis. All the cyclohexane rings of the methone moieties occupied
tion); this may have resulted in the the acetal moieties having chair structures with the methyl and isopropyl substituents in
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2994
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5-Benzyloxycarbonylamino-2,2-dimethyl-1,3-dioxan-5-carbal-
dehyde (3): DMSO (3.6 mL, 51 mmol) was added to a stirred solu-
tion of oxalyl chloride (2.1 mL, 25 mmol) in CH2Cl2 (40 mL) at –78 °C,
and the mixture was stirred at –78 °C for 30 min. Compound 2
(2.5 g, 8.4 mmol) was then added, and stirring was continued for a
further 30 min. Triethylamine (13 mL, 93 mmol) was added, and the
mixture was stirred at –78 °C for 10 min, and then at room tempera-
ture for 30 min. The solution was diluted with water, and extracted
with CH2Cl2. The combined organic layers were washed with NaH-
SO4 (saturated aq.), NaHCO3 (5 % aq.), brine, and dried with MgSO4.
equatorial positions. A comparison between hexapeptides 14a
and 14b in order to evaluate the effect of menthone chirality
on the peptide secondary structures revealed that the peptide
main-chain structures were similar; however, some differences
in the side-chains and protecting groups, particularly in the
acetal moieties, were observed. These results imply that the
influence of Hms[(–)/(+)-Men] residues on the secondary struc-
tures of
L-Leu-based peptides incorporating such residues is
weak, because the chiral centers are far from the α-carbon at-
oms, and/or because of the rigid inflexible nature of the side- The solvent was removed, and the residue was purified by column
chromatography on silica gel (20 % EtOAc in hexane) to give alde-
hyde 3 (1.48 g, 98 %) as colorless crystals, m.p. 86–89 °C. IR
chain structures. The acetal moiety in the dAAs designed here
can be changed, and our results may be beneficial for the de-
sign of functional helical peptides.
(KBr): ν = 3332, 2993, 1728, 1712, 1520, 1454, 1381, 1246, 1204,
˜
1130 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.69 (s, 1 H), 7.32–7.38
(m, 5 H), 5.81 (br. s, 1 H), 5.13 (s, 2 H), 4.00–4.15 (m, 4 H), 1.48 (m,
3 H), 1.18 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 199.2, 155.9,
135.7, 128.6, 128.4, 128.2, 98.8, 67.4, 62.5, 60.1, 27.0, 19.7 ppm.
HRMS (FAB+): calcd. for C15H20NO5 [M + H]+ 294.1341; found
294.1386.
Experimental Section
General Remarks: Optical rotations [α]rD.t. were measured with a
Jasco DIP-370 polarimeter using a 0.5 dm cell. Infrared spectra (IR)
were recorded with a Shimadzu IR Affinity-1 spectrometer for con-
ventional measurement (KBr), or using the solution (CDCl3) method
N-α-(Benzyloxycarbonyl)-O,O-isopropylidine-α-hydroxymethyl-
serine [Cbz-Hms(Ipr)-OH 4]. A solution of aldehyde 3 (2.6 g,
8.9 mmol) in tBuOH (80 mL) and 2-methyl-2-butene (20 mL) was
added to a stirred solution of NaCl2O (7.8 g, 86 mmol) and NaH2PO3
(10 g, 74 mmol) in water over 10 min. The mixture was stirred at
room temperature for 24 h. The solvent was removed, the residue
was diluted with water, and the mixture was washed with n-hexane.
The aqueous layer was acidfied with NaHSO4, and extracted with
EtOAc, and the organic extract was dried with MgSO4. Removal of
the solvent gave 4 (6.3 g, 95 %) as colorless crystals. This compound
was used for the next reaction without further purification, m.p.
with a 0.1 mm path-length NaCl cell. H and 13C NMR spectra were
1
determined with JEOL AL 400 (400 MHz) and Varian NMR System
500PS SN type (500 MHz) spectrometers. FAB-MS spectra and DART-
MS spectra were recorded with JEOL JMS-700N and JEOL JMS-
T1000TD spectrometers, respectively. X-ray crystallographic analy-
ses were measured with Rigaku Varimax Saturn/1200S and XtaLAB
P200 MM007HF-DW instruments.
(5-Amino-2,2-dimethyl-1,3-dioxan-5-yl)methanol p-Tosylate (1):
2,2-Dimethoxypropane (5.0 mL, 40 mmol) and 2-amino-2-hydroxy-
methyl-1,3-propanediol (1.0 g, 8.2 mmol) were added to a stirred
solution of p-toluenesulfonic acid monohydrate (2.9 g, 15 mmol) in
acetone (30 mL), and the mixture was stirred at room temperature
overnight. The resulting precipitate was collected by filtration,
washed with acetone and Et2O, and then dried to give 1 (2.6 g,
94 %) as colorless crystals. This was used for the next reaction with-
165–167 °C. IR (KBr): ν = 3433, 3321, 3020, 1735, 1539, 1334,
˜
1
1215 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.38 (m, 5 H), 5.79
(br. s, 1 H), 5.13 (s, 2 H), 4.17 (s, 4 H), 1.80 (br. s, 1 H), 1.49 (s, 3 H),
1.48 (s, 3 H) ppm. HRMS (FAB+): calcd. for C15H20NO6 [M + H]+
310.1290; found 310.1241.
N-α-(Benzyloxycarbonyl)-O,O-isopropylidine-α-hydroxymethyl-
serine Methyl Ester [Cbz-Hms(Ipr)-OMe 5]. A solution of (trimeth-
ylsilyl)diazomethane (9.3 mL, 16.5 mmol) in toluene (10 mL) was
added to a stirred solution of 5 (1.27 g, 4.1 mmol) in toluene (15 mL)
and MeOH (10 mL). The mixture was stirred at room temperature
for 15 min. The solvent was then removed. The residue was purified
by column chromatography on silica gel (20 % EtOAc in hexane) to
give methyl ester 5 (1.34 g, quant.) as colorless crystals, m.p. 78–
out further purification, m.p. 161–162 °C. IR (KBr): ν = 3306, 3148,
˜
2990, 1616, 1524, 1454, 1373, 1226, 1165, 1123 cm–1
.
1H NMR
(400 MHz, [D6]DMSO): δ = 7.99 (br. s, 3 H), 7.48 (d, J = 16 Hz, 2 H),
7.12 (d, J = 16 Hz, 2 H), 5.47 (t, J = 9.5 Hz, 1 H), 3.89 (d, J = 25 Hz,
2 H), 3.65 (d, J = 25 Hz, 2 H), 3.49 (d, J = 8.8 Hz, 2 H), 2.29 (s, 3 H),
1.38 (s, 6 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 145.7, 137.8,
125.9, 125.3, 98.7, 61.8, 59.7, 53.3, 26.3, 20.7, 19.7 ppm. HRMS (FAB+):
calcd. for C7H16NO3 [M + H]+ 162.1130; found 162.1133.
1
79 °C. H NMR (400 MHz, CDCl3): δ = 7.32–7.36 (m, 5 H), 5.72 (br. s,
1 H), 5.11 (s, 2 H), 4.23 (d, J = 12 Hz, 2 H), 3.96 (d, J = 12 Hz, 2 H),
3.75 (s, 3 H), 1.48 (s, 3 H), 1.42 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.0, 155.1, 136.0, 128.5, 128.2, 98.8, 67.1, 63.8, 60.4,
56.3, 52.7, 28.5, 18.2, 14.2, 4.3 ppm. HRMS (DART+): calcd. for
C16H22NO6 [M + H]+ 324.1447; found 324.1464.
(5-Benzyloxycarbonylamino-2,2-dimethyl-1,3-dioxan-5-yl)meth-
anol (2): NaHCO3 solution (5 % aq.; 120 mL) was added to a suspen-
sion of compound 1 (4.0 g, 12 mmol) in dioxane (60 mL). A solution
of benzyl chloroformate (6.0 mL, 42 mmol) in dioxane (8 mL) was
then added dropwise with stirring, and the mixture was kept at
room temperature for 24 h. The dioxane was evaporated, and the
residual mixture was diluted with Et2O, washed with NaHCO3 (5 %
aq.), and brine, and dried with MgSO4. The solvent was removed,
and the residue was purified by column chromatography on silica
gel (80 % EtOAc in hexane) to give compound 2 (3.5 g, 98 %) as
N-α-(Benzylxycarbonyl)-α-hydroxymethylserine Methyl Ester
(Cbz-Hms-OMe 6)
Method 1: Compound 5 (2.0 g, 6.3 mmol) was added to a mixture
of trifluoroacetic acid (1.8 mL) and H2O (0.2 mL) at 0 °C, and the
resulting mixture was stirred at 0 °C for 1 h. The solvent was then
removed. The residue was purified by column chromatography
(50 % EtOAc in hexane) to give 6 (910 mg, 99 %) as colorless crys-
tals.
colorless crystals, m.p. 64–66 °C. IR (KBr): ν = 3399, 3287, 2943, 1686,
˜
1
1547, 1454, 1373, 1296, 1261, 1134, 1084 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.32–7.40 (m, 5 H), 5.62 (br. s, 1 H), 5.09 (s, 2 H), 3.75–
3.91 (m, 6 H), 1.84 (br. s, 1 H), 1.44 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.4, 135.9, 128.5, 127.5, 98.7, 67.0, 64.1, 64.0, 53.5,
Method 2: SOCl2 (0.92 mL, 13 mmol) was added to a stirred solu-
26.0, 20.4 ppm. HRMS (DART+): calcd. for C15H22NO5 [M + H]+ tion of compound 4 (2.6 g, 8.5 mmol) in MeOH (320 mL). The mix-
296.1498; found 296.1519.
ture was stirred at 60 °C for 10 h. The reaction mixture was neutral-
2995 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org

Full Paper
ized with NaHCO3 (5 % aq.), and then the MeOH was removed un-
der vacuum. The residual mixture was extracted with CHCl3 and
dried with Na2SO4. The solvent was then removed. The residue was
purified by column chromatography on silica gel (50 % EtOAc in
hexane) to give 6 (2.2 g, 93 %) as colorless crystals, m.p. 65–67 °C.
22.2, 21.7, 18.4 ppm. HRMS (DART+): calcd. for C23H34NO6 [M + H]+
420.2386; found 420.2386.
Data for 7b: [α]2D9 = +17.9 (c = 1.0, CHCl3).
Cbz-Hms[(–)-Men]-OH (8a): NaOH solution (1
M aq.; 1.5 mL,
1.5 mmol) was added dropwise to a stirred solution of Cbz-Hms-
[(–)-Men]-OMe (7a) (0.63 g, 1.5 mmol) in MeOH (20 mL). The mixture
was stirred at room temperature overnight. The MeOH was re-
moved, and the aqueous layer was acidfied with citric acid to pH 3,
and extracted with CHCl3. The organic extract was dried with
MgSO4. Removal of the solvent gave crude carboxylic acid 8a
(0.60 mg, quant.) as a colorless oil, which was used in the next
reaction without further purification. 1H NMR (400 MHz, CDCl3): δ =
8.31 (br. s, 1 H), 7.33–7.35 (m, 5 H), 5.72 (br. s, 1 H), 5.15 (s, 2 H),
4.35 (d, J = 12 Hz, 1 H), 4.18 (d, J = 12 Hz, 1 H), 4.01 (d, J = 12 Hz,
1 H), 3.96 (d, J = 12 Hz, 1 H), 2.71 (d, J = 13 Hz, 1 H), 2.36–2.39 (m,
1 H), 1.74 (d, J = 12 Hz, 1 H), 1.36–1.54 (m, 3 H), 1.25–1.27 (m, 1 H),
0.86–0.93 (m, 10 H), 0.72 (t, J = 13 Hz, 1 H) ppm. MS (DART): m/z =
406 [M + H]+.
IR (KBr): ν = 3399, 3349, 3067, 2893, 2855, 2754, 2646, 2592, 2461,
˜
2164, 1794, 1748, 1674, 1639, 1524, 1439, 1385, 1331, 1254, 1234,
1
1204, 1126, 1084, 1065, 1011 cm–1. H NMR (400 MHz, CDCl3): δ =
7.32–7.38 (m, 5 H), 5.91 (br. s, 1 H), 5.13 (s, 2 H), 4.04 (d, J = 12 Hz,
2 H), 3.94 (d, J = 12 Hz, 2 H), 3.80 (s, 3 H), 2.15 (br. s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 171.6, 135.9, 128.6, 128.3, 128.1, 67.3,
64.1, 53.1 ppm. HRMS (DART+): calcd. for C13H18NO6 [M + H]+
284.1134; found 284.1128.
Cbz-Hms[(–)-Men]-OMe (7a)
Method 1: A mixture of p-toluenesulfonic acid monohydrate
(0.10 g, 0.53 mmol), 6 (0.80 g, 2.9 mmol), and (–)-menthone
(0.70 mL, 4.1 mmol) in toluene was heated at reflux for 24 h. The
mixture was then diluted with diethyl ether, washed with NaHCO3
(5 % aq.), and dried with MgSO4. The solvent was removed, and the
residue was purified by column chromatography (90 % EtOAc in n-
hexane) to give Cbz-Hms[(–)-Men]-OMe 7 (0.24 g, 20 %) as a color-
less oil.
H-Hms[(–)-Men]-OMe (9a): A mixture of Cbz-Hms[(–)-Men]-OMe
(7a) (0.62 g, 1.5 mmol) and Pd/C (5 %; 300 mg) in MeOH (30 mL)
was vigorously stirred under a hydrogen atmosphere at room tem-
perature. After 2 h, the Pd/C catalyst was removed by filtration, and
the filtrate was concentrated in vacuo to give a crude amine 9a
(405 mg, 97 %), which was used for next reaction without further
Method 2: 1,1,1,3,3,3-Hexamethyldisilazane (HMDS; 1.2 mL,
18 mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf;
101 μL, 1.8 mmol) were added to a stirred solution of 6 (0.80 g,
9.1 mmol) in THF (30 mL). The reaction mixture was stirred at 0 °C
for 90 min. The mixture was then diluted with Et2O, washed with
ice-cold water, and dried with MgSO4. The solvent was removed to
give crude TMS-6 (1.2 g, 96 %), which was used in the next reaction
without further purification.
1
purification. H NMR (400 MHz, CDCl3): δ = 4.40 (d, J = 12 Hz, 1 H),
4.18 (d, J = 12 Hz, 1 H), 3.76 (s, 3 H), 3.57–3.62 (m, 2 H), 2.72–2.75
(m, 1 H), 2.44–2.49 (m, 1 H), 1.99 (br. s, 2 H), 1.71–1.77 (m, 1 H),
1.43–1.53 (m, 3 H), 1.25–1.30 (m, 1 H), 0.85–0.96 (m, 10 H), 0.72 (t,
J = 12 Hz, 1 H) ppm. MS (DART): m/z = 286 [M + H]+.
Cbz-{Hms[(–)-Men]}2-OMe (10a): Crude amine 8a (0.30 g,
1.2 mmol) was added to a stirred solution of crude carboxylic acid
9a (0.4 g, 0.98 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethy-
luronium hexafluorophosphate (HATU; 0.64 g, 1.3 mmol), 1-hydroxy-
7-azabenzotriazole (HOAt; 0.40 g, 1.3 mmol), and diisopropylethyl-
amine (162 μL, 1.3 mmol) in CH2Cl2 (5 mL). The mixture was stirred
at 40 °C for 48 h, then the solvent was evaporated. EtOAc was
added, and the mixture was washed with NaHCO3 (5 % aq.), and
brine, and dried with MgSO4. The solvent was removed to give a
white solid, which was purified by column chromatography on silica
gel (10 % EtOAc in hexane) to give dipeptide 10a (604 mg, 91 %)
as colorless crystals, m.p. 168–170 °C. [α]2D7 = –32.2 (c = 1.0, CHCl3).
TMSOTf (10 μL, 0.18 mmol) was added to a stirred solution of TMS-
6 (0.76 g, 1.8 mmol) and (–)-menthone (0.62 mL, 3.4 mmol) in
CH2Cl2 (15 mL) at –40 or –78 °C, and the mixture was stirred at –40
or 78 °C for 24 h. NaOH (2 % in MeOH; 3 mL) was then added, and
the mixture was stirred at room temperature for 1 h. The mixture
was diluted with ice-cold water, and extracted with Et2O. The com-
bined organic extracts were washed with H2O and dried with
MgSO4. The solvent was removed, and the residue was purified by
column chromatography (90 % EtOAc in hexane) to give Cbz-
Hms[(–)-Men]-OMe (7) (0.63 g, 84 %) as a colorless oil.
IR (KBr): ν = 3421, 2951, 2873, 1744, 1667, 1554, 1504, 1381, 1304,
Data for 7a: [α]2D7 = –16.8 (c = 1.0, CHCl3). IR (neat): ν = 3437, 2955,
˜
˜
1
1269, 1153, 1118 cm–1. H NMR (400 MHz, CDCl3): δ = 7.73 (br. s, 1
1717, 1497, 1458, 1381, 1273, 1234, 1123, 1072 cm–1
.
1H NMR
H), 7.31–7.36 (m, 5 H), 5.44 (br. s, 1 H), 5.16 (s, 2 H), 4.32–4.37 (m, 2
H), 4.24 (d, J = 12 Hz, 1 H), 4.01–4.13 (m, 2 H), 3.85–3.95 (m, 3 H),
3.72 (s, 3 H), 2.73 (t, J = 12 Hz, 2 H), 2.35–2.41 (m, 2 H), 1.69–1.77
(m, 2 H), 1.37–1.55 (m, 6 H), 1.26 (t, J = 8 Hz, 2 H), 0.82–0.94 (m, 20
H), 0.65–0.73 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4,
169.3, 156.2, 135.8, 128.5, 128.2, 128.0, 101.4, 101.1, 67.3, 63.0, 62.8,
62.7, 61.7, 57.4, 55.8, 52.5, 50.7, 35.8, 35.6, 34.7, 29.0, 24.3, 24.1, 23.8,
23.7, 22.1, 22.0, 21.62, 21.55, 18.9, 18.5 ppm. HRMS (DART+): calcd.
for C37H57N2O9 [M + H]+ 673.4064; found 673.4064.
(400 MHz, CDCl3): δ = 7.31–7.37 (m, 5 H), 5.06 (s, 2 H), 4.96 (br. s, 1
H), 4.29–4.37 (m, 2 H), 4.04–4.09 (m, 1 H), 3.87–3.92 (m, 1 H), 3.80
(br. s, 3 H), 2.69 (d, J = 12 Hz, 1 H), 2.38–2.48 (m, 1 H), 1.71–1.74 (m,
1 H), 1.33–1.55 (m, 3 H), 1.27 (d, J = 12 Hz, 1 H), 0.84–0.93 (m, 10
H), 0.72 (t, J = 11 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.9, 155.1, 136.3, 128.44, 128.42, 128.0, 127.7, 101.2, 67.8, 63.0,
2.4, 58.4, 56.5, 52.6, 50.8, 35.7, 34.7, 29.0, 24.3, 23.7, 22.1, 21.5,
18.4 ppm. HRMS (DART+): calcd. for C23H34NO6 [M + H]+ 420.2386;
found 420.2386.
Cbz-{Hms[(–)-Men]}3-OMe (11a):
A mixture of Cbz-{Hms[(–)-
Data for 7a′: [α]2D1 = –10.1 (c = 0.23, CHCl3). IR (neat): ν = 3341,
˜
Men]}2-OMe 10a (0.14 g, 0.21 mmol) and Pd/C (20 %; 30 mg) in
MeOH (30 mL) was vigorously stirred under a hydrogen atmosphere
at room temperature. After 17 h, the Pd/C catalyst was removed by
filtration, and the filtrate was evaporated in vacuo to give crude
10a-amine (0.11 g, quant.).
2956, 1735, 1506, 1459, 1279, 1229, 1161, 1074 cm–1
.
1H NMR
(400 MHz, CDCl3): δ = 7.31–7.36 (m, 5 H), 5.06 (s, 2 H), 4.98 (br. s, 1
H), 4.36 (d, J = 12 Hz, 1 H), 4.32 (d, J = 12 Hz, 1 H), 4.06–4.10 (m, 1
H), 3.85–3.93 (m, 1 H), 3.80 (s, 3 H), 2.68 (d, J = 12 Hz, 1 H), 2.32–
2.35 (m, 1 H), 1.71–1.74 (m, 1 H), 1.38–1.57 (m, 3 H), 1.24–1.26 (m,
1 H), 0.83–0.92 (m, 10 H), 0.75 (t, J = 12 Hz, 1 H) ppm. 13C NMR The crude 10a-amine (41 mg, 76 μmol) was added to a stirred solu-
(100 MHz, CDCl3): δ = 164.6, 154.8, 135.7, 128.6, 128.4, 128.2, 101.0,
tion of crude carboxylic acid 9a (38 mg, 93 μmol), COMU (49 mg,
77.2, 67.2, 63.3, 62.9, 54.9, 52.7, 50.9, 36.4, 34.7, 29.2, 23.9, 23.7, 0.11 mmol), and diisopropylethylamine (16 μL, 0.11 mmol) in CH2Cl2
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2996
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(15 mL). The mixture was stirred at 40 °C for 48 h, then the solvent The crude 12a-amine (0.20 g, 0.38 mmol) was added to a stirred
was evaporated. EtOAc was added, and the mixture was washed
with NaHCO3 (5 % aq.), and brine, and dried with MgSO4. Removal
of the solvent gave a white solid, which was purified by column
chromatography on silica gel (10 % EtOAc in hexane) to give dipep-
solution of carboxylic acid Cbz-(L-Leu)2-OH (0.10 g, 0.38 mmol),
HATU (0.18 g, 0.46 mmol), HOAt (64 mg, 0.46 mmol), and diisopro-
pylethylamine (80 μL, 0.46 mmol) in CH2Cl2 (30 mL). The mixture
was stirred at room temperature for 48 h, then the solvent was
evaporated. EtOAc was added, and the mixture was washed with
tide 11a (31 mg, 44 %) as colorless crystals, m.p. 115–117 °C. [α]D19
=
–13.9 (c = 1.4, CHCl3). IR (KBr): ν = 3348, 2954, 1716, 1693, 1519, NaHCO3 (5 % aq.), and brine, and dried with MgSO4. Removal of
˜
1
1496, 1296, 1246 cm–1. H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H), the solvent gave a white solid, which was purified by column chro-
7.35–7.36 (m, 5 H), 6.88 (s, 1 H), 5.81 (s, 1 H), 5.26 (d, J = 12 Hz, 1
H), 5.11 (d, J = 12 Hz, 1 H), 4.06–4.41 (m, 9 H), 3.80–3.94 (m, 3 H),
3.71 (s, 3 H), 2.74–2.78 (m, 3 H), 2.46–2.49 (m, 1 H), 2.33–2.39 (m, 2
H), 1.25–1.74 (m, 15 H), 0.83–0.93 (m, 30 H), 0.66–0.74 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.1, 169.8, 168.0, 156.7, 135.7,
128.6, 128.4, 128.0, 101.5, 101.2, 100.6, 67.7, 63.8, 63.4, 62.4, 61.8,
61.6, 61.2, 57.8, 56.6, 52.3, 50.9, 50.71, 50.67, 35.9, 35.8, 35.7, 34.8,
34.7, 29.1, 29.04, 29.00, 24.5, 24.3, 24.0, 23.83, 23.81, 23.7, 22.2, 22.0,
21.72, 21.70, 21.5, 19.2, 19.1, 18.5 ppm. HRMS (FAB+): calcd. for
matography on silica gel (60 % EtOAc in hexane) to give dipeptide
13a (179 mg, 53 %) as colorless crystals, m.p. 230–231 °C. [α]D26
=
–35.2 (c = 1.2, CHCl3). IR (CDCl3): ν = 3363, 2958, 2360, 1716, 1670,
˜
1
1508, 1269 cm–1. H NMR (400 MHz, CDCl3): δ = 7.31–7.41 (m, 7 H),
6.87 (s, 1 H), 6.71 (d, J = 2.6 Hz, 1 H), 5.39 (d, J = 2.8 Hz, 1 H), 5.25
(d, J = 9.7 Hz, 1 H), 4.97 (d, J = 9.8 Hz, 1 H), 4.64 (d, J = 9.6 Hz, 1
H), 4.46–4.51 (m, 2 H), 4.31–4.39 (m, 1 H), 4.19 (d, J = 9.8 Hz, 1 H),
3.92–3.97 (m, 3 H), 3.66 (s, 3 H), 2.85 (d, J = 10 Hz, 1 H), 2.42–2.49
(m, 1 H), 1.49–1.88 (m, 14 H), 1.35–1.41 (m, 1 H), 1.28 (d, J = 12 Hz,
1 H), 0.89–1.10 (m, 35 H), 0.73 (t, J = 12 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.1, 173.2, 172.6, 169.0, 157.0, 135.5, 128.6,
128.5, 128.3, 100.9, 67.9, 64.0, 61.0, 58.4, 55.0, 54.9, 52.4, 52.0, 51.0,
50.8, 40.23, 40.17, 39.8, 39.5, 35.9, 34.8, 29.0, 25.1, 25.0, 24.5, 24.4,
24.0, 23.4, 23.1, 22.8, 22.7, 22.1, 21.82, 21.76, 21.53, 21.47, 20.9,
19.4 ppm. HRMS (FAB+): calcd. for C47H78N5O10 [M + H]+ 872.5749;
found 872.5741.
C
51H80N3O12 [M + H]+ 925.5742; found 925.5755.
Cbz-Hms[(–)-Men]-( -Leu)2-OMe (12a): The amine H-(L-Leu)2-OMe
L
(0.44 g, 1.8 mmol) was added to a stirred solution of crude carb-
oxylic acid 8a (0.47 g, 1.1 mmol), HATU (0.78 g, 1.8 mmol), HOAt
(0.28 g, 1.8 mmol), and diisopropylethylamine (358 μL, 1.8 mmol)
in CH2Cl2 (100 mL). The mixture was stirred at room temperature
for 48 h, then the solvent was evaporated. EtOAc was added, and
the mixture was washed with NaHCO3 (5 % aq.), and brine, and
dried with MgSO4. Removal of the solvent gave a white solid, which
was purified by column chromatography on silica gel (30 % EtOAc
Cbz-(L-Leu)2-Hms[(+)-Men]-(L-Leu)2-OMe (13b): Pentapeptide
13b was prepared from tripeptide 12b and Cbz-(
L-Leu)2-OH in a
manner similar to that described for the preparation of tripeptide
in hexane) to give tripeptide 12a (665 mg, 94 %) as a colorless oil. 12a: 46 % yield, colorless crystals, m.p. 220–221 °C. [α]2D6 = –0.29
[α]1D9 = –11.4 (c = 0.43, CHCl3). IR (KBr): ν = 3441, 3020, 2918, 2350, (c = 1.0, CHCl3). IR (CDCl3): ν = 3422, 3340, 2958, 1716, 1670, 1508,
˜
˜
1753, 1678, 1577, 1539, 1384, 1215 cm–1. 1H NMR (400 MHz, CDCl3): 1263 cm–1. H NMR (400 MHz, CDCl3): δ = 7.27–7.41 (m, 7 H), 6.88
1
δ = 7.29–7.38 (m, 5 H), 7.08 (s, 1 H), 6.66 (d, J = 2.8 Hz, 1 H), 5.27–
5.29 (m, 2 H), 5.01 (d, J = 14 Hz, 1 H), 4.48–4.51 (m, 2 H), 4.34–4.48
(m, 2 H), 3.93–4.03 (m, 1 H), 3.91–3.95 (m, 1 H), 3.68 (s, 3 H), 2.88
(J = 14 Hz, 1 H), 2.38–2.42 (m, 1 H), 1.51–1.75 (m, 12 H), 1.24–1.26
(s, 1 H), 6.73 (d, J = 3.4 Hz, 1 H), 5.44 (d, J = 2.9 Hz, 1 H), 5.24 (d,
J = 12 Hz, 1 H), 4.97 (d, J = 12 Hz, 1 H), 4.63 (d, J = 12 Hz, 1 H),
4.42–4.51 (m, 2 H), 4.35–4.40 (m, 1 H), 4.19 (d, J = 10 Hz, 1 H), 3.92–
4.00 (m, 3 H), 3.65 (s, 3 H), 2.87 (d, J = 12.5 Hz, 1 H), 2.48 (q, J =
(m, 1 H), 0.85–1.01 (m, 20 H), 0.70 (t, J = 12 Hz, 1 H) ppm. 13C NMR 14 Hz, 1 H), 1.50–1.83 (m, 14 H), 1.31–1.42 (m, 1 H), 1.26–1.29 (m, 1
(100 MHz, CDCl3): δ = 174.0, 173.2, 172.6, 169.0, 135.5, 128.7, 128.6,
128.3, 100.9, 67.9, 64.1, 58.4, 55.0, 52.4, 52.0, 50.8, 40.2, 39.9, 39.5,
35.9, 34.8, 29.0, 25.1, 24.5, 24.0, 23.4, 23.1, 22.8, 22.1, 21.8, 21.5, 20.9,
19.5 ppm. HRMS (FAB+): calcd. for C35H55N3O8Na [M + Na]+
668.3887; found 668.3898.
H), 0.73–1.02 (m, 35 H), 0.73 (t, J = 12 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.4, 173.2, 172.8, 172.5, 168.8, 157.0, 135.6,
128.6, 128.5, 128.2, 100.6, 67.8, 64.5, 60.4, 58.4, 55.3, 52.3, 52.0, 51.0,
50.8, 40.4, 40.0, 39.9, 39.7, 36.0, 34.8, 29.1, 25.0, 24.9, 24.4, 23.8, 23.5,
23.4, 23.1, 22.6, 22.5, 22.0, 21.9, 21.8, 21.5, 21.4, 20.9, 19.1 ppm.
HRMS (FAB+): calcd. for C47H78N5O10 [M + H]+ 872.5749; found
872.5751.
Cbz-Hms[(+)-Men]-(
pared from 8b and H-(
scribed for the preparation of tripeptide 12a: 82 % yield, colorless
crystals, m.p. 60–61 °C. [α]1D7 = –2.0 (c = 1.1, CHCl3). IR (KBr): ν = Hexapeptide 14a was prepared from pentapeptide 13a and carb-
L-Leu)2-OMe (12b): Tripeptide 12b was pre-
L-Leu)2-OMe in a manner similar to that de-
Cbz-Hms[(–)-Men]-(L-Leu)2-Hms[(–)-Men]-(L-Leu)2-OMe
(14a):
˜
3325, 2955, 1732, 1651, 1535, 1454, 1269, 1157 cm–1
.
1H NMR
oxylic acid 8a in a manner similar to that described for the prepara-
tion of pentapeptide 13a: 54 % yield, colorless crystals, m.p. 236–
(400 MHz, CDCl3): δ = 7.27–7.37 (m, 5 H), 6.96 (d, J = 7.1 Hz, 1 H),
6.78 (d, J = 8.1 Hz, 1 H), 5.63 (s, 1 H), 5.23 (d, J = 12 Hz, 1 H), 5.09
(d, J = 13 Hz, 1 H), 4.46–4.56 (m, 2 H), 4.38–4.42 (m, 1 H), 4.26 (d,
J = 12 Hz, 1 H), 3.97 (d, J = 12 Hz, 1 H), 3.84 (d, J = 13 Hz, 1 H), 3.71
(s, 3 H), 2.78 (d, J = 13 Hz, 1 H), 2.37–2.41 (m, 1 H), 1.24–1.79 (m,
13 H), 0.87–0.95 (m, 20 H), 0.69 (t, J = 12 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.9, 171.4, 169.0, 156.2, 135.6, 128.5, 128.3,
127.8, 101.4, 67.3, 62.9, 62.0, 60.3, 57.9, 52.1, 51.8, 50.8, 50.6, 40.7,
40.0, 35.8, 34.6, 29.6, 28.9, 24.8, 24.1, 23.6, 23.0, 21.9, 21.6, 20.9, 18.6,
14.1 ppm. HRMS (FAB+): calcd. for C35H56N3O8 [M + H]+ 646.4067;
found 646.4062.
237 °C. [α]2D5 = +7.9 (c = 1.0, CHCl3). IR (CDCl3): ν = 3337, 2959, 1712,
˜
1
1670, 1523, 1269 cm–1. H NMR (400 MHz, CDCl3): δ = 7.67 (d, J =
4.3 Hz, 1 H), 7.33–7.38 (m, 7 H), 6.81 (s, 1 H), 6.52 (d, J = 4.9 Hz, 1
H), 5.97 (s, 1 H), 5.14–5.23 (m, 2 H), 4.48–4.56 (m, 3 H), 4.31–4.41
(m, 4 H), 3.91–4.11 (m, 4 H), 3.69 (s, 3 H), 3.48–3.51 (m, 1 H), 2.94
(d, J = 13 Hz, 1 H), 2.73 (d, J = 12 Hz, 1 H), 2.41–2.45 (m, 1 H), 2.28–
2.32 (m, 1 H), 1.15–1.81 (m, 23 H), 0.65–1.01 (m, 45 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.9, 173.2, 172.9, 170.6, 169.2, 157.0,
135.2, 128.7, 128.5, 127.8, 101.8, 100.7, 67.9, 64.7, 64.4, 60.7, 60.4,
60.2, 58.7, 57.8, 55.7, 54.1, 52.3, 52.0, 51.0, 50.7, 40.1, 40.0, 39.6, 39.1,
36.0, 35.8, 34.9, 34.6, 29.1, 29.0, 25.2, 25.1, 25.0, 24.8, 24.5, 23.9, 23.6,
23.1, 23.0, 22.8, 22.1, 21.54, 21.45, 21.0, 20.9, 19.3, 18.2 ppm. HRMS
(FAB+): calcd. for C61H100N6O13Na [M + Na]+ 1147.7246; found
1148.7339.
Cbz-(L-Leu)2-Hms[(–)-Men]-(L-Leu)2-OMe (13a): A mixture of Cbz-
Hms[(–)-Men]-(
L-Leu)2-OMe (12a) (0.31 g, 0.48 mmol) and Pd/C
(20 %; 75 mg) in MeOH (50 mL) was vigorously stirred under a
hydrogen atmosphere at room temperature. After being stirred for
17 h, the Pd/C catalyst was removed by filtration, and the filtrate
was evaporated in vacuo to give crude 12a-amine (0.23 g, quant.).
Cbz-Hms[(+)-Men]-(L-Leu)2-Hms[(+)-Men]-(L-Leu)2-OMe
(14b):
Hexapeptide 14b was prepared from pentapeptide 13b and carb-
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2997
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
oxylic acid 8b in a manner similar to that described for the prepara-
tion of pentapeptide 13a: 79 % yield, colorless crystals, m.p. 239–
Acknowledgments
This work was financially supported by Japan Society for the
Promotion of Science (JSPS), KAKENHI, grant number 25713008
(grant to M. O.), 25560226 (grant to M. O.), and 26105745 (grant
to M. T.). The authors thank the Rigaku Corporation for the X-
ray crystallographic analysis of octapeptide 15a′.
240 °C. [α]2D6 = –52.8 (c = 1.0, CHCl3). IR (CDCl3): ν = 3333, 2958,
˜
1716, 1670, 1523, 1265 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79
(d, J = 3.4 Hz, 1 H), 7.56 (dd, J = 7.8, 11.6 Hz, 1 H), 7.30–7.35 (m, 5
H), 7.15 (d, J = 3.9 Hz, 1 H), 6.61 (s, 1 H), 6.07 (s, 1 H), 5.70 (s, 1 H),
5.28 (d, J = 13 Hz, 1 H), 5.08–5.12 (m, 2 H), 4.67 (d, J = 12 Hz, 1 H),
4.17–4.40 (m, 4 H), 3.85–4.12 (m, 8 H), 3.83 (d, J = 12 Hz, 1 H), 3.70
(s, 3 H), 2.99 (d, J = 12 Hz, 1 H), 2.72 (d, J = 13 Hz, 1 H), 2.20–2.48
(m, 2 H), 0.73–1.81 (m, 65 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.1, 173.6, 173.1, 173.0, 170.3, 169.1, 165.7, 156.6, 135.5, 128.5,
128.3, 128.2, 128.0, 127.5, 127.0, 101.3, 100.9, 100.5, 67.1, 64.4, 61.0,
58.4, 57.3, 55.9, 53.2, 52.2, 51.8, 51.1, 50.9, 50.6, 39.8, 39.4, 39.1, 38.4,
35.6, 34.8, 34.6, 28.8, 28.7, 24.9, 24.5, 24.2, 24.0, 23.6, 23.4, 22.9, 22.8,
22.4, 22.3, 21.9, 21.6, 21.4, 21.3, 20.9, 20.7, 19.7, 18.8, 18.3 ppm.
HRMS (FAB+): calcd. for C61H101N6O13 [M + H]+ 1125.7227; found
1125.7440.
Keywords: Peptides · Peptidomimetics · Amino acids ·
Conformation analysis · Helical structures · Acetals
[1] a) P. K. C. Paul, M. Sukumar, R. Bardi, A. M. Piazzesi, G. Valle, C. Toniolo,
P. Balaram, J. Am. Chem. Soc. 1986, 108, 6363–6370; b) E. Benedetti, B.
Di Blasio, V. Pavone, C. Pedone, A. Santini, M. Crisma, G. Valle, C. Toniolo,
Biopolymers 1989, 28, 175–184; c) M. Gatos, F. Formaggio, M. Crisma, C.
Toniolo, G. Bonora, Z. Benedetti, B. Di Blasio, R. Iacovino, A. Santini, M.
Saviano, J. Kamphuis, J. Pept. Sci. 1997, 3, 110–122; d) M. Tanaka, Chem.
Pharm. Bull. 2007, 349–358; e) M. Crisma, C. Toniolo, Biopolymers 2015,
104, 46–64.
[2] a) M. Nagano, M. Doi, M. Kurihara, H. Suemune, M. Tanaka, Org. Lett.
2010, 12, 3564–3566; b) K. Akagawa, J. Sen, K. Kudo, Angew. Chem. Int.
Ed. 2013, 52, 11585–11588; Angew. Chem. 2013, 125, 11799–11802; c) T.
Kato, M. Oba, K. Nishida, M. Tanaka, Bioconjugate Chem. 2014, 25, 1761–
1768.
Cbz-(
(15a): Octapeptide 15a was prepared from hexapeptide 14a and
Cbz-( -Leu)2-OH in a manner similar to that described for the prepa-
L-Leu)2-Hms[(–)-Men]-(L-Leu)2-Hms[(–)-Men]-(L-Leu)2-OMe
L
ration of pentapeptide 13a: 20 % yield, colorless crystals, m.p. 241–
242 °C. [α]2D4 = –3.5 (c = 1.3, CHCl3). IR (CDCl3): ν = 3321, 2985, 1708,
˜
1
1223 cm–1. H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 3.1 Hz, 1 H),
[3] a) M. Tanaka, Y. Demizu, M. Doi, M. Kurihara, H. Suemune, Angew. Chem.
Int. Ed. 2004, 43, 5360–5363; Angew. Chem. 2004, 116, 5474–5477; b) S.
Royo, W. M. De Borggraeve, C. Peggin, F. Formaggio, M. Crisma, A. I.
Jimenez, C. Cativiela, C. Toniolo, J. Am. Chem. Soc. 2005, 127, 2036–2037;
c) M. Tanaka, K. Anan, Y. Demizu, M. Kurihara, M. Doi, H. Suemune, J. Am.
Chem. Soc. 2005, 127, 11570–11571; d) Y. Demizu, M. Doi, M. Kurihara,
T. Maruyama, H. Suemune, M. Tanaka, Chem. Eur. J. 2012, 18, 2430–2439;
e) K. Anan, Y. Demizu, M. Oba, M. Kurihara, M. Doi, H. Suemune, M.
Tanaka, Helv. Chim. Acta 2012, 95, 1694–1713.
7.58 (d, J = 4.6 Hz, 1 H), 7.50 (d, J = 9.9 Hz, 1 H), 7.49 (d, J = 8.3 Hz,
1 H), 7.38 (m, 6 H), 6.90 (s, 1 H), 6, 77 (s, 1 H), 5.42 (s, 1 H), 5.35 (d,
J = 12 Hz, 1 H), 5.00 (d, J = 12 Hz, 1 H), 4.48–4.61 (m, 3 H), 4.30–
4.42 (m, 4 H), 4.12–4.18 (m, 1 H), 3.92–4.08 (m, 5 H), 3.68–3.74 (m,
1 H), 3.67 (s, 3 H), 2.98 (d, J = 14 Hz, 1 H), 2.80–2.85 (m, 1 H), 2.42–
2.50 (m, 2 H), 0.77–1.86 (m, 86 H) ppm. HRMS (FAB+): calcd. for
C
73H123N8O15 [M + H]+ 1351.9108; found 1351.9097.
[4] a) M. Stasiak, W. M. Wolf, M. T. Leplawy, J. Pept. Sci. 1998, 4, 46–57; b)
W. M. Wolf, M. Stasiak, M. T. Leplawy, A. Bianco, F. Formaggio, M. Crisma,
C. Toniolo, J. Am. Chem. Soc. 1998, 120, 11558–11566; c) M. Oba, N.
Ishikawa, Y. Demizu, M. Kurihara, H. Suemune, M. Tanaka, Eur. J. Org.
Chem. 2013, 7679–7682; d) K. Tanda, R. Eto, K. Kato, M. Oba, A. Ueda, H.
Suemune, M. Doi, Y. Demizu, M. Kurihara, M. Tanaka, Tetrahedron 2015,
71, 3909–3914.
[5] a) C. Cativiela, M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry 2000, 11,
645–732; b) C. Cativiela, M. Ordonez, Tetrahedron: Asymmetry 2009, 20,
1–63; c) M. Oba, H. Takasaki, N. Kawabe, M. Doi, Y. Demizu, M. Kurihara,
H. Kawakubo, M. Nagano, H. Suemune, M. Tanaka, J. Org. Chem. 2014,
79, 9125–9140; d) M. Oba, N. Kawabe, H. Takasaki, Y. Demizu, M. Doi, M.
Kurihara, H. Suemune, M. Tanaka, Tetrahedron 2014, 70, 8900–8907; e) T.
Hirata, A. Ueda, M. Oba, M. Doi, Y. Demizu, M. Kurihara, M. Nagano, H.
Suemune, M. Tanaka, Tetrahedron 2015, 71, 2409–2420.
[6] T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980, 21, 1357–1358.
[7] a) K. Wuthrich, NMR of Proteins and Nucleic Acids, Wiley, New York, 1986;
b) G. Wagner, D. Neuhaus, E. Worgotter, M. Vasak, J. H. R. Kagl, K. Wu-
thrich, J. Mol. Biol. 1986, 187, 131–135.
[8] a) C. T. Chang, C. S. C. Wu, J. T. Yang, Anal. Biochem. 1978, 91, 13–31; b)
S. Brahms, J. Brahms, J. Mol. Biol. 1980, 138, 149–178; c) M. C. Manning,
R. W. Woody, Biopolymers 1991, 31, 569–586; d) T. S. Yokum, T. J. Gau-
thier, R. P. Hammer, M. L. McLaughlin, J. Am. Chem. Soc. 1997, 119, 1167–
1168.
Boc-(
(15a′): Octapeptide 15a′ was prepared from hexapeptide 14a and
Boc-( -Leu)2-OH in a manner similar to that described for the prepa-
L-Leu)2-Hms[(–)-Men]-(L-Leu)2-Hms[(–)-Men]-(L-Leu)2-OMe
L
ration of pentapeptide 13a: 20 % yield, colorless crystals, m.p. 250–
251 °C. [α]2D7 = –9.5 (c = 0.38, CHCl3). IR (CDCl3): ν = 3341, 2885,
˜
1
1717, 1258 cm–1. H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 4.2 Hz,
1 H), 7.62 (d, J = 4.2 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.44 (d, J =
8.8 Hz, 1 H), 7.05 (s, 1 H), 6.83 (s, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 4.83
(d, J = 4.9 Hz, 1 H), 4.52–4.59 (m, 5 H), 4.32–4.41 (m, 2 H), 4.13 (d,
J = 12 Hz, 1 H), 3.90–4.01 (m, 5 H), 3.72–3.78 (m, 1 H), 3.68 (s, 3 H),
2.95 (d, J = 12 Hz, 1 H), 2.80 (d, J = 12 Hz, 1 H), 2.45 (ddd, J = 6.7,
14, 20 Hz, 1 H), 2.31 (ddd, J = 6.7, 14, 21 Hz, 1 H), 1.49 (s, 9 H), 1.15–
1.89 (m, 23 H), 0.62–1.03 (m, 63 H) ppm. HRMS (FAB+): calcd. for
C70H125N8O15 [M + H]+ 1317.9264; found 1317.9276.
Boc-(
(15b′): Octapeptide 15b′ was prepared from hexapeptide 14b and
Boc-( -Leu)2-OH in a manner similar to that described for the prepa-
L-Leu)2-Hms[(+)-Men]-(L-Leu)2-Hms[(+)-Men]-(L-Leu)2-OMe
L
ration of pentapeptide 13a: 20 % yield, colorless crystals, m.p. 250–
251 °C. [α]2D3 = +27.7 (c = 0.29, CHCl3). IR (CDCl3): ν = 3321, 2958,
˜
1708, 1670, 1532, 1223 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.81
(d, J = 3.4 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1
H), 7.32 (d, J = 5.9 Hz, 1 H), 6.86 (s, 1 H), 6.74 (s, 1 H), 6.55 (s, 1 H),
4.78 (d, J = 4.9 Hz, 1 H), 4.28–4.49 (m, 5 H), 3.80–4.18 (m, 8 H), 3.68
(s, 3 H), 3.55–3.61 (m, 1 H), 2.83 (d, J = 14 Hz, 1 H), 2.58 (d, J =
14 Hz, 1 H), 2.18–2.34 (m, 2 H), 1.21–1.86 (m, 32 H), 0.72–1.04 (m,
63 H) ppm. HRMS (FAB+): calcd. for C70H125N8O15[M + H]+
1317.9264; found 1317.9277.
[9] CCDC 1453020 (for 13a), 1453021 (for 14a), 1453022 (for 14b), and
1453023 (for 15a′) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
Received: March 2, 2016
Published Online: May 30, 2016
Eur. J. Org. Chem. 2016, 2988–2998
www.eurjoc.org
2998
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim