Helical structures of cyclopentenebased α,α-disubstituted a-amino acid homopeptides

Article abstract of DOI:10.2533/chimia.2018.848

The cyclopentene-based α,α-disubstituted a-amino acid Ac5c= and its homopeptides, up to nonapeptides, were synthesized. The side-chain cyclopentene was expected to become symmetric, the Ca-carbon to be puckered, and other Cβ, Cβ', C, C-carbons to be coplanar. As expected, side-chain cyclopentene conformations became symmetric and Ca-carbons were puckered. Conformational studies using FT-IR absorption, 1H NMR spectra, and X-ray crystallographic analyses revealed that Ac5c= homopeptides did not form a planar conformation, but assumed a 310-helical structure, similar to cyclopentane-based α,α-disubstituted a-amino acid homopeptides.

Full text of DOI:10.2533/chimia.2018.848

848 CHIMIA 2018, 72, No. 12
doi:10.2533/chimia.2018.848
Chemistry ties Linking Japan to switzerLand
Chimia 72 (2018) 848–852 © Swiss Chemical Society
Helical Structures of Cyclopentene-
based α,α-Disubstituted α-Amino Acid
Homopeptides
Masakazu Tanaka*a, Haruka Yakabib, Haruki Nakatanib, Atsushi Uedaa, Mitsunobu Doic, and Makoto
Obaa
Abstract: The cyclopentene-based α,α-disubstituted α-amino acid Ac5c= and its homopeptides, up to nona-
peptides, were synthesized. The side-chain cyclopentene was expected to become symmetric, the Cα-carbon
to be puckered, and other Cβ, Cβ', Cγ, Cγ'-carbons to be coplanar. As expected, side-chain cyclopentene con-
formations became symmetric and Cα-carbons were puckered. Conformational studies using FT-IR absorption,
1H NMR spectra, and X-ray crystallographic analyses revealed that Ac5c= homopeptides did not form a planar
conformation, but assumed a 310-helical structure, similar to cyclopentane-based α,α-disubstituted α-amino
acid homopeptides.
Keywords: Conformation · Cyclopentene · α,α-Disubstituted α-amino acid · Helix · Peptide
Masakazu
Chemistry, Japan (1993), the Inoue For example, 1-aminocyclopentanecar-
Tanaka graduated Research Award for Young Scientists boxylic acid (Ac5c) homopeptides were
with a BSc degree (1994), and the Pharmaceutical Society found to preferentially form 310-helical
in Pharmaceutical of Japan Award for Divisional Scientific structures.[10] The side-chain cyclopentane
Sciences
from Promotion (2006). His current research ring formed an envelope conformation,
Kyushu University interests involve foldamers, asymmetric and the puckered carbon was scrambled at
in 1986, and then catalysts, and cell-penetrating peptides.
received an MSc
degree from the
the Cα, Cβ, and Cγ carbons (Fig. 1). On the
other hand, the cyclopentene ring is flatter
than the cyclopentane ring, and four car-
bons may be coplanar in the cyclopentene
ring, while the other carbon is puckered.
same university. He 1. Introduction
became a Research Fellow at the Osaka
Branch of the National Institute of Health
α,α-Disubstituted α-amino acids We designed an achiral 1-aminocyclo-
Sciences Japan in 1988. In 1990, he was ap- (dAAs) are non-coded amino acids that pent-3-enecarboxylic acid (Ac5c=),[11] in
pointed as a Research Associate at Kyushu have an α-alkyl substituent instead of an which the Cα atom may be puckered and
University. After receiving his PhD degree α-hydrogen atom.[1–3] dAA homopeptides four other carbons (Cβ, Cβ', Cγ, Cγ') are
under the supervision of Professor Kiyoshi have been reported to form stable second- coplanar. We anticipated whether Ac5c=
Sakai, he performed postdoctoral work ary structures, such as α-helices, 310-heli- homopeptides, when constructed, form a
with Professor Dieter Seebach’s group in ces, and extended planar structures.[4,5] For symmetric planar conformation because
1994 at ETH in Switzerland. He became
example, α-aminoisobutyric acid (Aib)- the cyclopentene ring may be symmetric
an Associate Professor at the Graduate containing homopeptides preferentially and a rigid structure. In the case that Ac5c=
School of Pharmaceutical Sciences, form 310-helical structures,[6] while diethyl- homopeptides form helical structures, a
Kyushu University (Professor Hiroshi glycine (Deg)-containing homopeptides comparison of helical structures between
Suemune’s group) in 1997. Since 2008, adopt extended planar conformations.[7,8] cyclopentane-amino acid Ac5c and cyclo-
he has been a Professor at the Graduate Furthermore, cyclic 1-aminocycloalkane- pentene-amino acid Ac5c= peptides may
School of Biomedical Sciences, Nagasaki carboxylic acid (Acnc; n = ring size)-con- be of interest because Ac5c-containing
University. He received the Yamanouchi taining homopeptides are known to pref- peptides may be used as cell-penetrating
Seiyaku Award in Synthetic Organic erentially assume 310-helical structures.[9] peptides[12] and helical chiral catalysts.[13]
Fig. 1. Conformational
flexibilities of the
cyclopentane-based
amino acid Ac5c and
cyclopentene-based
amino acid Ac5c=.
cyclopentane
envelope conformation
R1
R1
R2
R1
H2N
CO2H
*Correspondence: Prof. M. Tanakaa
E-mail: matanaka@nagasaki-u.ac.jp
aGraduate School of Biomedical Sciences
Nagasaki University, 1-14 Bunkyo-machi
Nagasaki 852-8521, Japan
R2
R2
Ac5c
etc
cyclopentene
R1
bSchool of Pharmaceutical Sciences
Nagasaki University, 1-14 Bunkyo-machi
Nagasaki 852-8521, Japan
Conformational flexibility
of the cyclopentene,
may be restricted.
R2
H2N
CO2H
cOsaka University of Pharmaceutical Sciences
Osaka 569-1094, Japan
Ac5c=

Chemistry ties Linking Japan to switzerLand
CHIMIA 2018, 72, No. 12 849
We herein synthesized the cyclopentene- ide hexafluorophosphate (HBTU) and
band to the high-frequency band increased
amino acid Ac5c=, prepared its homopep- 1-hydroxybenzotriazole (HOBt) in 53% as the main-chain length increased (Fig.
tides, up to nonapeptides, and investigated yield. Deprotection of Boc-protecting 2). These FT-IR absorption spectra were
their conformations in solution and in the group in dipeptide 3, and the resulting very similar to those of the saturated Ac5c
crystalline state.
dipeptide amine was coupled with Boc- homopeptides.[10] Ac5c= homopeptides
(Ac5c=)-OH using O-(7-azabenzotriazol- do not have an α-hydrogen atom, and,
1-yl)-1,1,3,3-tetramethyluronium hexa- thus, it was not possible to apply nuclear
2. Synthesis of the Cyclopentene-
based α,α-Disubstituted α-Amino
Acid Ac5c= and its Homopeptides
fluorophosphate (HATU) and 1-hydroxy- Overhauser effect (NOE) correlations us-
7-azabenzotriazole (HOAt) to give a ing α-hydrogen. We measured correlations
tripeptide Boc-(Ac5c=)3-OMe (4) in 75% between N(n)-H and N(n+1)-H in NOESY
yield. Hexapeptide Boc-(Ac5c=)6-OMe (5) NMR spectra. The complete series of se-
ThecyclicaminoacidAc5c= wassynthe-
was prepared by the fragment coupling quential dNN correlations between N(n)-H
sizedas described previously[11,14] (Scheme between tripeptide-carboxylic acid and and N(n+1)-H (n = 1~5) were observed in
1). Dimethyl malonate was dialkylated tripeptide-amine in 75% yield. Similarly, the NOESY NMR spectrum of hexapep-
with cis-1,4-dichloro-2-butene by LiH to nonapeptide Boc-(Ac c=)9-OMe (6) was tide 5, and sequential dNN correlations be-
give the cyclic diester 1 in 71% yield.[14] prepared by the coup5ling between hexa- tween N(n)-H and N(n+1)-H (n = 1~8) in
The monohydrolysis of diester 1 with aque-
peptide-amine and tripeptide carboxylic nonapeptide 6 were observed, except for
ous NaOH, followed by the Curtius rear- acid in 12% yield.
the case of n = 4 at which signals over-
rangement with diphenyl phosphoryl azide
lapped (Fig. 3). These results suggested
(DPPA) and work-up with tBuOH afforded
the formation of a helical conformation.
the cyclopentene-amino acid Boc-(Ac5c=)- 3. Conformational Analysis of
Furthermore, 1H NMR measurements
OMe (2) in 74% yield. The hydrolysis of
Homopeptides in Solution
were performed following the addition of
the strong hydrogen bond acceptor solvent
2 with aqueous NaOH gave the C-terminal
free amino acid Boc-(Ac5c=)-OH in quan-
The FT-IR absorption spectra of Ac5c=
DMSO-d6 or the paramagnetic free radi-
titative yield, and deprotection of Boc- homopeptides Boc-(Ac5c=)m-OMe (m = cal 2,2,6,6-tetramethylpiperidin-1-yloxyl
protecting group in 2 with 2 M metha- 3, 6, 9) in CDCl3 showed weak bands in (TEMPO) to CDCl3 solution. The addi-
nolic HCl gave an N-terminal free amino the 3420~3430 cm−1 region, which were tion of DMSO-d affected chemical shifts
acid H-(Ac5c=)-OMe in quantitative yield. assigned as hydrogen bond-free, solvated in two N–H prot6ons, and two N–H peaks
Dipeptide (3) was prepared by coupling N–H groups, and strong bands in the shifted to lower magnetic fields with an
between Boc-(Ac5c=)-OH and H-(Ac5c=)- 3330~3360 cm−1 region, which were as- increase in DMSO-d6. Furthermore, the
OMe
using
1-[bis(dimethylamino) signed as hydrogen-bonded N–H groups. addition of the TEMPO radical broadened
methylene]-1H-benzotriazolium
3-ox- The relative intensity of the low-frequency the peak width of two N–H protons (Fig.
4). These two N–H protons were solvated,
and not intramolecularly hydrogen-bond-
ed, suggesting the formation of helical
structures in homopeptides 5 and 6.[10]
1) NaOH aq.
Cl Cl
dimethyl
malonate
Boc-HN
Boc-(Ac5c=)-OMe (2)
CO2Me
2) DPPA, Et3N
then tBuOH
MeO2C
CO2Me
LiH
1
71%
74%
2M HCl / MeOH
quant
HCl·H2N
CO2Me
HBTU
HOBt
HCl·H-(Ac5c=)-OMe
iPr2EtN
H
2
N
CO2Me
Boc-HN
53%
O
Boc-(Ac5c=)2-OMe (3)
Fig. 2. FT-IR absorption spectra of Boc-(Ac5c=)m
-OMe 4 (m = 3), 5 (m = 6), and 6 (m = 9) in
CDCl3. A cell with 0.1-mm path length was
used. Peptide concentration: 5.0 mM.
NaOH aq.
MeOH
quant
Boc-HN
CO2H
Boc-(Ac5c=)-OH
4. Secondary Structural Analysis in
the Crystalline State
1) 2M HCl / MeOH
2) Boc-(Ac5c=)3-OH
HATU, HOAt
1) 2M HCl / MeOH
2) Boc-(Ac5c=)-OH
HATU, HOAt
Boc
N
H
OR
3
The Ac5c= tripeptide 4 yielded a suit-
able crystal for X-ray crystallographic
iPr2EtN
Boc
N
H
OMe
m
iPr2EtN
O
O
analysis by the slow evaporation of a mix-
Boc-(Ac5c=)3-OMe (4)
75%
Boc-(Ac5c=)6-OMe (5)
Boc-(Ac5c=)9-OMe (6)
ture of CHCl3 and MeOH.[15] In the asym-
75%
Boc-(Ac5c=)3-OH
12%
NaOH aq.
quant
metric unit, there was a β-turn structure.
The structure was solved in the mono-
clinic centrosymmetric P21/n space group.
Scheme 1. Synthesis of the five-membered ring amino acid Ac5c= and its homopeptides.

850 CHIMIA 2018, 72, No. 12
Chemistry ties Linking Japan to switzerLand
a)
a)
b)
b)
c)
d)
Fig. 3. NOESY NMR spectra of Boc-(Ac5c=)m-
OMe a) 5 (m = 6) and b) 6 (m = 9) in CDCl3.
Fig. 4. Plots of N-H chemical shifts in the 1H NMR spectra of 5 (a) and 6 (c) as a function of an in-
creasing percentage of DMSO-d6 added to the CDCl3 solution, and plots of the bandwidth of the
N-H protons of 5 (b) and 6 (d) as a function of an increasing percentage of TEMPO added to the
CDCl3 solution.
Thus, the mirror image, right-handed and
left-handed turn conformers, existed in asymmetric unit (Fig. 6). The space group
residues (3), (4), (5), and (6) in particu5lar
the crystalline state. The φ and ψ torsion P21/n is centrosymmetric, and, thus, right- becoming flatter. The cyclopentene rings
angles were ±60.6 and ±36.3 in residue (1) handed and left-handed helical structures were symmetric, and the Cα-carbons were
structure with two DMF molecules in the the side-chain cyclopentene rings on Ac c=
–
–
and +55.5 and+33.3 in residue (2), respec- (mirror image) both exist. The average
puckered. The superimposed structures of
tively, whereas those of residue (3) had the φ and ψ torsion angles of residues (1~5) Boc-(Ac5c=)6-OMe (5) and Cbz-(Ac5c)6-
opposite signs of ±49.2 and ±43.8, respec- were ±59.0 and ±23.7, accompanied by the OtBu from CCDC-1264125 (X-ray crys-
tively. This kind of reversal of C-terminal
reversal of the C-terminal torsion angles tallographic analysis by C. Toniolo and co-
–
–
torsion angles to those of the preceding (+58.4 and +38.2). The i←i+3 type intra-
workers[10]) is shown in Fig. 7. The peptide
residues was also observed in achiral molecular hydrogen bonds, which corre- backbone structure of Ac c= hexapeptide 5
Ac5c homopeptides.[10] An intramolecular sponded to the 310-helical conformation, matched that of the report5edAc5c hexapep-
hydrogen bond of the i←i+3 type was ob- were formed between the oxygen of car- tide except for C-terminal residue, whereas
served between the oxygen of urethane bonyl C(i)=O(i) and peptide N(i+3)-H (i the conformation of the side-chain cyclo-
C(0)=O(0) and peptide N(3)-H (Fig. 5).
= 0~3). The formyl oxygen of solvents
pentene in Ac5c= differed from that of the
Recrystallization of the Ac5c= hexapep- DMF (A and B) were hydrogen-bonded to cyclopentane in Ac5c. (Tables 1–4)
tide 5 from DMF afforded crystals suitable peptides N(1)-H and N(2)-H, respectively.
for an X-ray crystallographic analysis.[15] Table 4 shows the distance between the
The crystal structure was solved in the
P21/n space group to give a 310-helical Cγ’(i), and Cβ’(i) atoms. These distances
were shorter than those of the cyclopen- Homopeptides composed of cyclopen-
tane-based amino acid (>0.55 Å),[10] with tene-based dAA; Ac5c=, up to nonapep-
Cα(i) atom and plane defined by Cβ(i), Cγ(i), 5. Conclusion
a)
b)
Fig. 5. A β-turn structure of Boc-(Ac5c=)3-OMe
(4) as elucidated by X-ray crystallographic
analysis.
Fig. 6. A 310-helical secondary structure of Boc-(Ac5c=)6-OMe (5) as elucidated by an X-ray crystal-
lographic analysis. a) View perpendicular to the helical axis and b) view along the helical axis.

Chemistry ties Linking Japan to switzerLand
CHIMIA 2018, 72, No. 12 851
Table 1. Crystal and diffraction parameters of Boc-(Ac5c=)3-OMe (4) and Boc-(Ac5c=)6-OMe (5).
Boc-(Ac5c=)3-OMe (4)
C24H33N3O6
Boc-(Ac5c=)6-OMe (5)
C42H54N6O9·2(C3H7NO)
933.10
Empirical formula
Molecular weight Mr
459.53
Crystal dimensions [mm] 0.10 × 0.09 × 0.02
Data collection temp. [K] 93
0.24 × 0.23 × 0.20
93
Fig. 7. Superimposed structures of Boc-
(Ac5c=)6-OMe (5; red) and Cbz-(Ac5c)6-OtBu
(CCDC-1264125; blue) reported by Toniolo
and coworkers.[10]
Crystal system
Lattice parameters
a, b, c (Å)
monoclinic
monoclinic
9.555, 18.267, 14.054
90, 90.266, 90
16.608, 17.917, 17.868
90, 111.743, 90
tides, were synthesized. A conformational
α, β, γ (°)
analysis using FT-IR absorption, and
1H NMR spectra in CDCl3 solution re-
V (Å3)
2453.1
P21/n
4
4938.6
P21/n
4
vealed that Ac5c= homopeptides preferen-
tially formed helical structures. An X-ray
crystallographic analysis unequivocally
showed that the Ac c= hexapeptide formed
a 3 -helical structu5re, but not a planar con-
for1m0 ation, and the side-chain cyclopen-
tene ring in Ac5c= homopeptides became
flatter and Cα-carbons were puckered in
Space group
Z value
D calc [g/cm3]
µ (MoKα) [mm-1]
No. of observations
1.244
0.090
2398
1.255
0.090
7700
the five-membered rings. The olefin in the
cyclopentene-based amino acid Ac5c= and
its peptides may be easily converted into
several functional groups.[16]
No. of variables
R1 (I > 2σ), wR2
Crystallizing solvent
298
604
0.0993, 0.1362
MeOH/CHCl3
0.0877, 0.2342
DMF
Acknowledgments
This work was supported in part by JSPS
KAKENHI Grant Number JP-17H03998
(M. T.).
Table 2. Selected torsion angles of Boc-(Ac5c=)3-OMe (4) and Boc-(Ac5c=)6-OMe (5).a
Torsion Angle
Boc-(Ac5c=)3-OMe (4)
Boc-(Ac5c=)6-OMe (5)
Received: August 18, 2018
163.9(3)
169.6(2)
ω0
φ1
60.6(5)
36.3(5)
176.1(3)
55.6(5)
33.3(5)
60.6(3)
27.9(4)
175.7(2)
57.7(3)
22.6(4)
ψ1
ω1
φ2
[1] a) F. Ehrlich, A. Wendel, Biochem. Z. 1908, 438;
b) K. Pfister 3rd., W. J. Leanza, J. P. Conbere, H.
J. Becker, A. R. Matzuk, E. F. Rogers, J. Am.
Chem. Soc. 1955, 77, 697; c) G. W. Kenner,
R. C. Sheppard, Nature 1958, 181, 48; d) M.
ψ2
T. Leplawy, D. S. Jones, G. W. Kenner, R. C.
Sheppard, Tetrahedron 1960, 11, 39.
178.4(4)
−49.2(5)
−43.8(5)
179.5(2)
57.7(3)
22.9(4)
ω2
φ3
[2] H. Heimgartner, Angew. Chem., Int. Ed. 1991,
30, 238.
[3] C. Cativiela, M. D. Díaz-de-Villegas,
Tetrahedron: Asymmetry 1998, 9, 3517.
ψ3
[4] M. Tanaka, Chem. Pharm. Bull. 2007, 55, 349.
[5] a) E. Benedetti, Biopolymers (Pept. Sci.) 1996,
178.9(3)
−178.7(2)
ω3
40, 3; b) M. Crisma, M. De Zotti, F. Formaggio,
C. Peggion, A. Moretto, C. Toniolo, J. Pept. Sci.
---
---
---
57.4(3)
24.7(4)
φ4
ψ4
ω4
2015, 21, 148.
[6] I. L. Karle, P. Balaram, Biochemistry 1990,
29, 6747; b) R. Gessmann, H. Brückner, K.
Petratos, J. Pept. Sci. 2003, 9, 753.
−179.4(2)
[7] M. Tanaka, N. Imawaka, M. Kurihara, H.
Suemune, Helv. Chim. Acta 1999, 82, 494.
[8] a) E. Benedetti, V. Barone, A. Bavoso, B.
Di Blasio, F. Lelj, V. Pavone, C. Pedone, G.
---
---
61.8(3)
20.5(4)
φ5
ψ5
M. Bonora, C. Toniolo, M. T. Leplawy, K.
Kaczmarek, A. Redlinski, Biopolymers 1988,
---
179.3(3)
ω5
27, 357; b) C. Toniolo, G. M. Bonora, A.
Bavoso, E. Benedetti, B. Di Blasio, V. Pavone,
---
−58.4(4)
φ6
C. Pedone, V. Barone, F. Lelj, M. T. Leplawy, K.
Kaczmarek, A. Redlinski, Biopolymers 1988,
---
−38.2(3)
ψ6
27, 373; c) C. Peggion, M. Crisma, C. Toniolo,
F. Formaggio, Tetrahedron 2012, 68, 4429; d) F.
Formaggio, M. Crisma, G. Ballano, C. Peggion,
M. Venanzi, C. Toniolo, Org. Biomol. Chem.
2012, 10, 2413.
---
−176.6(3)
ω6
aThe number of amino acid residues begins at the N terminus of the peptide chain.

852 CHIMIA 2018, 72, No. 12
Chemistry ties Linking Japan to switzerLand
Table 3. Intra- and intermolecular H-bond parameters for Boc-(Ac5c=)3-OMe (4) and Boc-(Ac5c=)6-
OMe (5).
[9] C. Toniolo,
M. Crisma, F. Formaggio, E.
Benedetti, A. Santini, R. Iacovino, M. Saviano,
B. Di Blasio, C. Pedone, J. Kamphuis,
Biopolymers 1996, 40, 519.
[10] a) A. Santini, V. Barone, A. Bavoso, E.
Peptide
Donor
D–H
Acceptor Distance
Angle [°] Symmetry
...
...
A
[Å] D A D–H A
operations
Benedetti, B. Di Blasio, F. Fraternali, F. Lelj,
V. Pavone, C. Pedone, M. Crisma, G. M.
Bonora, C. Toniolo, Int. J. Biol. Macromol.
Boc-(Ac5c=)3-OMe (4)
1988, 10, 292; b) M. Crisma, G. M. Bonora, C.
Toniolo, E. Benedetti, A. Bavoso, B. Di Blasio,
V. Pavone, C. Pedone, Int. J. Biol. Macromol.
1988, 10, 300.
N3-H
O0
2.967(4)
2.842(4)
147.4(2)
154.7(2)
x,y,z
N1-H
O2’
−1/2+x,1/2−y,1/2+z
[11] a) C. Cativiela, M. Ordonez, Tetrahedron:
Boc-(Ac5c=)6-OMe (5)
Asymmetry 2009, 20, 1; b) C. Cativiela, M.
D. Díaz-de-Villegas, Tetrahedron: Asymmetry
2000, 11, 645.
N3-H
N4-H
N5-H
N6-H
N1-H
N2-H
O0
3.133(3)
3.037(4)
2.972(4)
2.962(3)
2.924(4)
2.878(4)
168.5(2)
170.2(2)
162.0(2)
166.0(2)
160.5(2)
163.4(2)
x,y,z
x,y,z
x,y,z
x,y,z
x,y,z
x,y,z
[12] T. Kato, M. Oba, K. Nishida, M. Tanaka,
Bioconjugate Chem. 2014, 25, 1761.
[13] a) M. Nagano, M. Doi, M. Kurihara, H.
O1
O2
Suemune, M. Tanaka, Org. Lett. 2010, 12, 3564;
b) A. Ueda, T. Umeno, M. Doi, K. Akagawa,
K. Kudo, M. Tanaka, J. Org. Chem. 2016, 81,
6343.
O3
ODMF-A
ODMF-B
[14] a) D. L. Varie, C. Beck, S. K. Borders, M. D.
Brady, J. S. Cronin, T. K. Ditsworth, D. A. Hay,
D. W. Hoard, R. C. Hoying, R. J. Linder, R. D.
Miller, E. D. Moher, J. R. Remacle, J. A. Rieck,
D. D. Anderson, P. N. Dodson, M. B. Forst, D.
A. Pierson, J. A. Turpin, Org. Proc. Res. Dev.
2007, 11, 546; b) S. Niwayama, H. Cho, C. Lin,
Table 4. Distances between the Cα(i) atom and plane defined by Cβ(i), Cγ(i), Cγ'(i), and Cβ'(i).a
Tetrahedron Lett. 2008, 49, 4434.
[15] CCDC 1855421 and 1855422 contain sup-
Residue number
Residue 1
Residue 2
Residue 3
Residue 4
Residue 5
Residue 6
Boc-(Ac5c=)3-OMe (4) (Å)
Boc-(Ac5c=)6-OMe (5) (Å)
plementary crystallographic data for this
manuscript. These data may be obtained free of
charge via http://www.ccdc.cam.ac.uk/data_re-
quest/cif, by e-mailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
0.404
0.311
0.196
–
0.387
0.372
0.081
0.094
0.147
0.113
[16] a) M. Tanaka, K. Anan,Y. Demizu, M. Kurihara,
–
M. Doi, H. Suemune, J. Am. Chem. Soc. 2005,
127, 11570; b) K. Anan, Y. Demizu, M. Oba,
–
M. Kurihara, M. Doi, H. Suemune, M. Tanaka,
Helv. Chim. Acta 2012, 95, 1694.
aThe number of amino acid residues begins at the N terminus of the peptide chain.