Synthesis of (S)-(-)-Cucurbitine and Conformation of Its Homopeptides

Article abstract of DOI:10.1021/acs.orglett.1c01291

A chiral cyclic α,α-disubstituted α-amino acid, (S)-(-)-cucurbitine, which has a pyrrolidine ring with a chiral center at the α-position, was synthesized, and its homopeptides were prepared. (S)-(-)-Cucurbitine homopeptides with a Boc-protecting group formed helical structures with slight control of the helical screw sense to the left-handed form. The state of the pyrrolidine ring in (S)-(-)-cucurbitine was important for the control of the helical structures and helical screw sense of its homopeptides.

Full text of DOI:10.1021/acs.orglett.1c01291

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Letter
Synthesis of (S)‑(−)-Cucurbitine and Conformation of Its
Homopeptides
Yuto Yamaberi, Ryo Eto, Tomohiro Umeno, Takuma Kato, Mitsunobu Doi, Hidetomo Yokoo,
Makoto Oba,* and Masakazu Tanaka*
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ABSTRACT: A chiral cyclic α,α-disubstituted α-amino acid, (S)-
(−)-cucurbitine, which has a pyrrolidine ring with a chiral center at
the α-position, was synthesized, and its homopeptides were prepared.
(S)-(−)-Cucurbitine homopeptides with a Boc-protecting group
formed helical structures with slight control of the helical screw sense
to the left-handed form. The state of the pyrrolidine ring in (S)-
(−)-cucurbitine was important for the control of the helical
structures and helical screw sense of its homopeptides.
(S)-(−)-Cucurbitine, a natural product found in the seeds of
several species of Cucurbitaceae, is known to possess
antiparasitic activity against Schistosoma japonicum and
inhibitory activity for the conversion of histidine to histamine.1
Because of its unique biological activities, several asymmetric
syntheses of (S)-(−)-cucurbitine and its derivatives have been
reported.1b,2 (S)-(−)-Cucurbitine is a natural but non-
proteinogenic amino acid categorized as a cyclic α,α-
disubstituted α-amino acid (dAA). An (S)-(−)-cucurbitine
derivative has been used as a building block for a functional
peptide.3 The main structural feature of (S)-(−)-cucurbitine is
a pyrrolidine ring (Figure 1).
cyclic dAA Ac5c3EG, in which the α-carbon atom was a chiral
center.8 The acetal moiety at the γ-position was changeable,
and its bulkiness and hydrogen-bonding donors were
considered to affect the helical screw direction of the peptides.
A conformational analysis of (S)-Ac5c3EG homopeptides
revealed that they formed helical structures without controlling
the helical screw direction for up to hexapeptides and then
with a preference for the left-handed (M) helical-screw
direction for hepta- and octapeptides. This study was the
first report of the conformational analysis of cyclic dAA
homopeptides with chiral centers only at the α-carbon. The
effects of the α-chiral centers of cyclic dAA homopeptides on
the helical screw-sense bias were very weak.
In the current study, we were interested in (S)-
(−)-cucurbitine, in particular, its asymmetric synthesis and
the preferred conformation of its homopeptides (Scheme 1). A
secondary amino group in the side chain of (S)-(−)-cucurbi-
tine can act as a hydrogen bonding donor/acceptor, is easily
converted into an amide or carbamate by a protective group,
and is protonated under acidic conditions. Two substituted
groups (−βCH2−CH2−NH−CH2− and −β′CH2−NH−CH2−
CH2−) at the α-position of (S)-(−)-cucurbitine have similar
steric bulkiness; however, the secondary amino group has
unique properties, which can lead to a change in the
Figure 1. Chemical structure of 1-aminocyclopentane carboxylic acid
(Ac5c) and its derivatives.
Cyclic dAAs have been reported to stabilize helical
structures by introduction into peptides4 and have been used
as building blocks for functional helical peptide foldamers.5 In
particular, five-membered ring dAA, 1-aminocyclopentane
carboxylic acid (Ac5c), and its derivatives have been well
studied (Figure 1).6 Homopeptides consisting of Ac5c-based
chiral dAAs, Ac5cdOM having two chiral centers in the side
chain, form helical structures with a preference for right-
handed (P) or left-handed (M) helical screw directions due to
the chiral centers.7 We recently designed and synthesized a
Received: April 15, 2021
Published: May 12, 2021
https://doi.org/10.1021/acs.orglett.1c01291
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4358−4362
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Scheme 1. Synthesis of (S)-(−)-Cucurbitine and Its
Homopeptides
Figure 2. X-ray crystallographic structure of 3.
rearrangement with diphenylphosphoryl azide (DPPA) and
workup with BnOH gave a Cbz-(S)-cucurbitine(Boc)-OEt 6 in
72% yield. 1H and 13C NMR spectra of 6 implied the existence
of rotamers, which was consistent with a previous report of
cucurbitine derivatives.10 The synthesis of the enantiomerically
pure Boc-protected (S)-(−)-cucurbitine derivative 6 was
achieved in seven steps in a total yield of 37%.
The hydrolysis of an ethyl ester in 6 in alkaline solution
afforded a C-terminal free carboxylic acid 7 in quantitative
yield. The hydrogenolysis of 6 using H2/5% Pd−C gave an N-
terminal free amine 8 in quantitative yield. The N-terminal free
amine 8 was coupled to the C-terminal free carboxylic acid 7
using 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminoxy)-
dimethylaminomorpholino)]uronium hexafluorophosphate
(COMU) to give a dipeptide 9 in 65% yield. The peptide
chain was elongated in the C- to N-terminal direction using an
iterative sequence of deprotection of a Cbz-protecting group
and subsequent coupling to 7 using COMU up to an
octapeptide 15. The treatment of Boc-protected heptapeptide
14 with 4 M HCl/dioxane achieved deprotection of Boc
groups and afforded HCl salt heptapeptide 16 in quantitative
yield. The removal of the HCl salt in 16 gave the free amine
(S)-(−)-cucurbitine heptapeptide 17 in 83% yield.
We studied the preferred secondary structures of Boc-
protected peptides 9−15 (n = 2−8) in CDCl3 solution (5
mM) using Fourier transform infrared (FT-IR) absorption
spectroscopy (Figure 3). The FT-IR absorption spectra in the
N−H stretching (amide A) region of peptides 9−15 showed
weak bands in the 3420−3440 cm−1 region (intramolecular
hydrogen bond free N−H) and strong bands in the 3320−
conformational preference of its homopeptides. First, we
developed asymmetric synthesis of an (S)-(−)-cucurbitine
derivative with a Boc-protected group in the side chain and
determined the absolute configuration by X-ray crystallo-
graphic analysis. Then, we synthesized Boc-protected (S)-
(−)-cucurbitine homopeptides up to an octapeptide and
studied their preferred conformation in a solution. The Boc
group was easily deprotected to afford nonprotected (S)-
(−)-cucurbitine homopeptide. Additional conformational
analysis of the (S)-(−)-cucurbitine homopeptide with different
situations revealed that the state of the pyrrolidine ring in (S)-
(−)-cucurbitine strongly affected the preferred conformation,
in particular, for the helical screw direction.
(S)-(−)-Cucurbitine was synthesized using (R)-phenylethyl-
amine as a chiral auxiliary with reference to a previous report9
as follows. Triazinane 1 was first prepared from (R)-
phenylethylamine and aqueous formaldehyde under alkaline
conditions and then reacted with triethyl 1,1,2-ethanetricar-
boxylate in trifluoroacetic acid (TFA) to afford the five-
membered ring compound 2 (98% yield in two steps). The
selective monohydrolysis of 2 was achieved using a porcine
liver esterase (PLE). After recrystallization, the single
1
diastereomer 3 was confirmed using the H NMR spectrum
(67% yield). The stereochemistry of the newly created chiral
center of 3 was unambiguously determined to be R by X-ray
crystallographic analysis (Figure 2, Figure S1, and Table S1).
The carboxylic acid in 3 was converted to a benzyl ester using
BnBr in a quantitative yield. The reduction of the amide
carbonyl group with 9-BBN followed by deprotection of the
benzyl ester, removal of the phenylethyl group on nitrogen,
and protection of a secondary amine using Boc under
conditions with H2 gas, 10% Pd−C, and Boc2O gave a
monocarboxylic acid 5 in 78% yield in two steps. Curtius
Figure 3. FT-IR absorption spectra of Cbz-[(S)-cucurbitine(Boc)]n-
OEt (n = 2 (2 mer, 9), 3 (3 mer, 10), 4 (4 mer, 11), 5 (5 mer, 12), 6
(6 mer, 13), 7 (7 mer, 14), and 8 (8 mer, 15)) in CDCl3 solution.
Peptide concentration: 5.0 mM.
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3370 cm−1 region (intramolecular hydrogen bond of N−H···
OC type). The low-frequency band observed at the 3370
cm−1 in tripeptide 10 shifted to a lower wavenumber of 3320
cm−1 in octapeptide 15, and its intensity increased steadily
with peptide elongation. These results were very similar to
those of Ac5c-based peptides, which adopt a helical structure in
solution.4a,e,6b,7b,8a
We then investigated the secondary structures of Boc-
protected peptides 9−15 (n = 2−8) in 2,2,2-trifluoroethanol
(TFE) solution (0.1 mM) using circular dichroism (CD)
spectral measurements (Figure 4). From dipeptide 9 to
Figure 5. 1H NMR spectra (NH region) of Boc-protected
heptapeptide 14 at seven different temperatures (60 to −40 °C) in
CD3CN (600 MHz).
ROESY NMR spectrum of heptapeptide 14 was also measured
at −25 °C (Figure S2c,d) but did not provide information on a
preferred peptide secondary structure. The peptides in this
study have no α-hydrogen, and thus we obtained less available
information about peptide secondary structures. Taken
together, Boc-protected longer peptides adopted several
conformers that were not a complete helical structure. To
evaluate the effect of the state of the pyrrolidine ring on the
peptide secondary structures, CD spectra of three heptapep-
tides including the Boc-protected peptide 14, HCl salt peptide
16, and free amine peptide 17 were measured in TFE solution
(0.1 mM). The CD spectrum of the free amine peptide 17
showed a negative maximum at 195 nm and a positive
maximum at 230 nm, which were not assigned to a specific
peptide secondary structure. In contrast, positive maxima at
206 and 224 nm were observed in the CD spectrum of the HCl
salt peptide 16, and they were stronger than those in the Boc-
protected peptide 14. These results suggested that the order of
the ability for helical conformation or helical screw sense to
one-handedness was HCl salt peptide 16 > Boc-protected
peptide 14 > free amine peptide 17. Note that the ratio of R
implied that the dominant conformation of HCl salt peptide
16 (R = 1.35) was a left-handed (M) α-helical structure. Aida
et al. reported the helical conformation of 4-aminopiperidine-
4-carboxylic acid (Api) oligopeptides.11 The state of the
piperidine ring in Api was very important for the helix-
formation ability of its oligopeptides; the order was protonated
> acylated > free base. Nonprotonated free amines appeared to
hamper the formation of intramolecular hydrogen bonds in the
peptide backbone. (S)-(−)-Cucurbitine had a secondary amine
in a manner similar to Api, and thus protonated (HCl salt)
peptide 16 might form a more stable left-handed (M) helical
structure than Boc-protected peptide 14 and free amine
peptide 17. Furthermore, the conformation of free amine
peptide 17 was analyzed via CD spectroscopy in aqueous
solution (0.1 mM) with various acids (10 mM) including HCl,
HBr, trifluoroacetic acid, acetic acid, propionic acid, and
isobutyric acid. A secondary amine in the pyrrolidine ring was
protonated by additive acids. As shown in Figure S4, different
CD spectra were obtained according to the acids, and the
peptide formed the most stable left-handed (M) helical
structure in the presence of HCl. The order of pKa values of
additive acids is acetic acid ≃ propionic acid ≃ isobutyric acid
> trifluoroacetic acid > HCl > HBr, and thus there is no
correlation between the helical stability of the peptide and the
pKa value of additive acids. The reasons for this helical stability
Figure 4. CD spectra of (a) Cbz-[(S)-cucurbitine(Boc)]n-OEt (n = 2
(2 mer, 9), 3 (3 mer, 10), 4 (4 mer, 11), 5 (5 mer, 12), 6 (6 mer, 13),
7 (7 mer, 14), 8 (8 mer, 15)) and (b) heptapeptides ([Boc-protected
peptide (NBoc, 14), HCl salt peptide (NH·HCl, 16), and free amine
peptide (NH, 17)) in TFE solution. Peptide concentration: 0.1 mM.
hexapeptide 13, the CD spectra did not show characteristic
maxima (208 and 222 nm) for a helical structure. These
peptides might be too short to control the helical screw
direction to one-handedness. On the contrary, heptapeptide 14
and octapeptide 15 showed a negative maximum at 194 nm
and positive maxima at around 208 and 222 nm, which
indicated that the dominant conformation of both peptides in
TFE solution was a left-handed (M) helical structure.
Furthermore, the ratios of R (θn→π*/θπ→π*) of heptapeptide
14 and octapeptide 15 were 1.69 and 1.58, respectively,
suggesting that both peptides preferred α-helix to 310-helix.
However, the intensities of these spectra were too low to form
a complete left-handed (M) helical structure. These results
were similar to a previous report on (S)-Ac5c3EG homopep-
tides,8 and thus the helical screw-sense bias by the α-chiral
center of the Boc-protected (S)-(−)-cucurbitine was weak. To
gain further insights into the preferred secondary structures in
solution, detailed 1H NMR spectral measurements of
heptapeptide 14 were performed. The rotating frame Over-
hauser effect spectroscopy nuclear magnetic resonance
(ROESY NMR) spectrum of heptapeptide 14 measured at
60 °C showed no valuable ROE cross-peaks for peptide
secondary structures (Figure S2a,b). A sharp N(1)−H proton
signal at 6.75 ppm suggested that the peptide adopted a single
preferred conformer or several conformers in fast exchange.
Therefore, we measured the 1H NMR spectra of heptapeptide
14 at lowered temperatures. The peak of the N(1)−H proton
first broadened (from 60 to 25 °C) and then was split (from 0
to −40 °C) into at least three peaks, indicating that more than
three conformers existed (Figure 5). Other proton signals also
implied the existence of several conformers (Figure S3). The
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Letter
are unknown, but we conclude that the ability for helical
conformation or helical screw sense to one-handedness of (S)-
(−)-cucurbitine homopeptides was dependent on the type of
acid added.
https://pubs.acs.org/10.1021/acs.orglett.1c01291
Notes
The authors declare no competing financial interest.
In summary, we synthesized a chiral five-membered ring
dAA, Boc-protected (S)-(−)-cucurbitine, and prepared its
homopeptides up to an octapeptide. FT-IR and CD spectra
revealed that Boc-protected (S)-(−)-cucurbitine homopep-
tides formed helical structures with slight control of the helical
screw sense to left-handed. Additional conformational analysis
of heptapeptides with a different state of the pyrrolidine ring
indicated that an HCl salt peptide was the best for control of
the helical structure and helical screw sense. These findings will
be helpful for the design of functional peptides containing
cucurbitine derivatives.
ACKNOWLEDGMENTS
■
This work was financially supported in part by JSPS
KAKENHI grant number 17H03998 (for M.T.) and by the
Asahi Glass Foundation (for M.O.). We thank Dr. Kenji
Kanaori (Kyoto Institute of Technology) for assistance with
NMR spectral measurements.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01291.
Experimental section, spectroscopic data of new
compounds, crystal and diffraction parameters of 3,
1
CD spectra of peptides, and H and 13C NMR spectra
(PDF)
Accession Codes
CCDC 2063691 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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AUTHOR INFORMATION
Corresponding Authors
■
Makoto Oba − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan; Graduate
School of Medical Sciences, Kyoto Prefectural University of
Medicine, Kyoto 606-0823, Japan; orcid.org/0000-0002-
3691-3608; Email: moba@koto.kpu-m.ac.jp
Masakazu Tanaka − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan;
orcid.org/0000-0002-6929-4380; Email: matanaka@
nagasaki-u.ac.jp
Authors
Yuto Yamaberi − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan
Ryo Eto − Graduate School of Biomedical Sciences, Nagasaki
University, Nagasaki 852-8521, Japan
Tomohiro Umeno − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan;
orcid.org/0000-0002-4342-2292
Takuma Kato − Osaka University of Pharmaceutical Sciences,
Osaka 569-1094, Japan; orcid.org/0000-0002-2561-
8582
Mitsunobu Doi − Osaka University of Pharmaceutical
Sciences, Osaka 569-1094, Japan
Hidetomo Yokoo − Graduate School of Medical Sciences,
Kyoto Prefectural University of Medicine, Kyoto 606-0823,
Japan
Complete contact information is available at:
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