Left-Handed Helix of Three-Membered Ring Amino Acid Homopeptide Interrupted by an N-H···Ethereal O-Type Hydrogen Bond

Article abstract of DOI:10.1021/acs.orglett.8b03331

A chiral three-membered ring C^α,α-disubstituted α-amino acid (R,R)-Ac₃c^dMOM, in which the α-carbon is not a chiral center, but two side chain β-carbons are chiral centers, was synthesized from dimethyl l-(+)-tartrate, and its homopeptides were prepared. X-ray crystallographic analysis of (R,R)-Ac₃c^dMOM pentapeptide showed bent left-handed (M) 3₁₀-helical structures with an unusual intramolecular hydrogen bond of the N-H···O (ethereal) type. The left-handedness of the bent helices was exclusively controlled by the side-chain β-carbon chiral centers.

Full text of DOI:10.1021/acs.orglett.8b03331

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Left-Handed Helix of Three-Membered Ring Amino Acid
Homopeptide Interrupted by an N−H···Ethereal O‑Type Hydrogen
Bond
Yurie Koba, Atsushi Ueda, Makoto Oba,† Mitsunobu Doi, Takuma Kato, Yosuke Demizu,§
†
†
‡
‡
,
†
and Masakazu Tanaka*
†
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bukyo-machi, Nagasaki 852-8521, Japan
Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
‡
§
Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki 210-9501, Japan
*
S Supporting Information
α,α
ABSTRACT: A chiral three-membered ring C -disubsti-
dMOM
tuted α-amino acid (R,R)-Ac3c
, in which the α-carbon is
not a chiral center, but two side chain β-carbons are chiral
centers, was synthesized from dimethyl L-(+)-tartrate, and its
homopeptides were prepared. X-ray crystallographic analysis
dMOM
of (R,R)-Ac3c
pentapeptide showed bent left-handed
(
M) 3 -helical structures with an unusual intramolecular
10
hydrogen bond of the N−H···O (ethereal) type. The left-
handedness of the bent helices was exclusively controlled by the side-chain β-carbon chiral centers.
he design of secondary structures of peptides and/or
foldamers is attracting marked attention from organic
ring amino acid (S,S)-Ac5cdOM homopeptides with methoxy
groups formed left-handed (M) 3 - and α-helices without an
1
T
1
0
and medicinal chemists because such structures are invaluable
intramolecular hydrogen bond of the N−H···O (ethereal)
2
3
7
dMOM
for developing chiral catalysts, biological tools, and drug
type, the Ac c
pentapeptide described here shows
3
4
α,α
candidates. C -Disubstituted α-amino acids (dAAs) are
unprecedentedly left-handed (M) 310-helices interrupted by
an N−H···O (ethereal) type intramolecular hydrogen bond.
No such bent helical structures bearing the N−H···O
(ethereal) type intramolecular hydrogen bond have been
reported.
known as one type of building block for the construction of
5
foldamers forming 3 -helix, α-helix, and planar structures.
10
Among dAAs, cyclic dAAs are known to induce helical
6
structures of their peptides.
The three-membered ring dAA, (R,R)-Ac
cdMOM, was
We previously reported the effect of side-chain chiral centers
of cyclic dAAs on their homopeptide conformations.
3
synthesized as follows. At first, dimethyl L-(+)-tartrate was
converted into a chiral diol 3 with two MOM substituents
Homopeptides composed of a chiral five-membered ring
1
1
dOM
dAA (S,S)-Ac5c
with two side chain chiral centers
according to the reported procedures (Scheme 1). Then the
preferentially formed left-handed (M) helical structures
diol 3 was transformed into a cyclic sulfate 4 by treatment with
7
thionyl chloride and subsequent oxidation with RuCl and
without an α-chiral center. Contrary to the one-handed
3
11
helical structure of (S,S)-Ac5cdOM homopeptides, the homo-
NaIO at a quantitative yield. A three-membered ring was
4
constructed by dialkylation of dimethyl malonate with the
peptides composed of a five,six-membered bicyclic ring dAA
12
8
cyclic sulfate 4. At the beginning, the cyclization yield of 5
was 19% using K CO as a base, and then the yield was
(
R,R)-Ab5,6=c with two side-chain chiral centers, a four-
3
BD
membered ring dAA (R,R)-Ac c
with a chiral acetal
2
3
4
9
35dBu
improved to 56% using Cs CO in DMF. Monohydrolysis of
moiety, or a six-membered ring dAA (R,R)-Ac c
two chiral acetal moieties showed uncontrolled right-handed
with
2
3
6
10
cyclic diester 5, followed by Curtius rearrangement with
diphenylphosphoryl azide (DPPA) and workup with BnOH,
(
P) and left-handed (M) helical-screw structures.
dMOM
gave a benzyloxylcarbonyl (Cbz)-protected (R,R)-Ac3c
-
Here, we designed a chiral three-membered ring dAA,
R,R)-1-amino-2,3-bis(methoxymethyl)cyclopropanecarboxylic
OMe 6 at a 71% yield. Hydrogenolysis of 6 using H /5% Pd−
(
2
dMOM
dMOM
C gave an N-terminal free amine 8 at a quantitative yield, and
acid (Ac3c
). The Ac3c
has two methoxymethyl
the reaction in the presence of (Boc) O produced a tert-
(
MOM) substituents at the side-chain β-positions of cyclo-
2
dMOM
butoxylcarbonyl (Boc)-protected Boc-{(R,R)-Ac3c
}-OMe
propane, and the β-carbons become chiral centers without an
dMOM
7 at a 72% yield. Hydrolysis of a methyl (Me) ester in 7 in
α-carbon chiral center. In the Ac3c
peptide, the distance
between side-chain chiral centers and the peptide backbone
become shorter than those of five- and six-membered-ring
amino acids. Although we reported that similar five-membered
Received: October 18, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03331
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of (R,R)-Ac3cdMOM and Its
Homopeptides
The (R,R)-Ac3cdMOM pentapeptide 13 became crystals
suitable for X-ray crystallographic analysis by recrystallization
from MeOH/EtOAc/n-hexane. The structure was solved in a
monoclinic P21 space group, and two crystallographically
independent molecules A and B (both distorted left-handed
310
molecules existed in the asymmetric unit (Figure 1 and
-helices) together with disordered EtOAc and water
15
Table S1). The peptide-backbone structures of molecule A
and B are well-matched, as shown by superimposition of the
structures.
Figure 1. (a) Bent left-handed (M) helices of pentapeptide 13
alkaline solution afforded a C-terminal free Boc-(R,R)-
(
solvents and disordered OMe omitted for clarification). (b)
dMOM
Ac3c
-OH 9 at a quantitative yield.
Superimposed structure of molecules A and B with intramolecular
hydrogen bonds (H bond of N(5)−H···O (3) (ethereal) type in
green).
The N-terminal free H-{(R,R)-Ac3cdMOM}-OMe 8 was
dMOM
coupled with C-terminal free Boc-{(R,R)-Ac3c
}-OH 9
using O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) and 1-hydroxy-7-azabenzotria-
dMOM
zole (HOAt) to give a (R,R)-Ac3c
dipeptide 10 at a 57%
Two intramolecular hydrogen bonds of the N(i+3)−H···O =
C(i) (i = 0 and 1) i ← i+3 type at the N-terminal side,
yield. The peptide chain was elongated in the C- to N-terminal
direction by an iterative sequence of deprotection of a Boc-
protecting group and subsequent coupling with 9 using HATU
and HOAt up to a hexapeptide.
16,17
corresponding to the 3 -helix,
existed in molecules A and
1
0
B. Additionally, one intramolecular hydrogen bond between
the N(5)−H of the peptide backbone and the oxygen of the
MeO substituent at the side-chain cyclopropane of residue (3)
was unprecedentedly observed (Table 1 and Figure 1b).
Although intramolecular hydrogen bonds between the oxygen
of the side-chain ethereal functional group and the N−H of the
peptide backbone of the same amino acid residue or of the
The FT-IR absorption spectra in the N−H stretching
dMOM
(
amide A) region of (R,R)-Ac c
homopeptides were
3
measured in CDCl3 solution (Figure S1). Absorptions
−
1
characteristic of the helical structure at 3420−3430 cm
(
intramolecular hydrogen bond free N−H at the N-terminus)
−
1
10,15
and 3320−3370 cm (intramolecular hydrogen bond of the
adjacent amino acid residue have already been reported,
13
N−H···OC type) were observed. The NOESY NMR
no such hydrogen bond between the oxygen of the side-chain
ethereal function of the amino acid and the remote N−H of
the main chain has been reported.
spectrum of 13 in CDCl solution showed d and dN2N3
3
N1N2
correlations but did not show other dNN correlations. The
ROESY NMR spectrum of 14 showed dN1N2, dN2N3, and dN3N4
but neither dN4N5 nor dN5N6 (Figure S2). These FT-IR
absorption and 2D NMR spectra suggest the formation of a
helical secondary structure.
dMOM
Table 2 shows the selected torsion angles of (R,R)-Ac3c
pentapeptide 13. The average ϕ and ψ torsion angles of amino
acid residues (1−3) were +66.2 and +17.2 in molecule A and
+65.8 and +16.8 in molecule B, respectively. These values
1
6
The circular dichroism (CD) spectra of homopeptides (n =
−6) were measured in 2,2,2-trifluoroethanol solution (0.05
match those of the left-handed (M) 3 -helical conformation.
The ψ torsion angles of (R,R)-Ac3c
10
dMOM
4
residues were smaller
mM) (Figure S3). The CD spectra showed a negative
maximum at 222 nm and a positive maximum at 205 nm,
but these CD spectra do not yield valuable information for
secondary structure analysis because the peptide length may be
than the normal ψ torsion angle of 3 -helix. This may be
1
0
dMOM
because the Ac c and (R,R)-Ac c
“bridge” region of the conformational map.
worthy that the ϕ and ψ torsion angles of (R,R)-Ac3c
residues prefer to form
3
3
17,18
It is note-
dMOM
(4)
1
4
too short.
were −94.8 and +17.5 in molecule A and −89.0 and +13.2 in
B
DOI: 10.1021/acs.orglett.8b03331
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Intra- and Intermolecular H-Bond Parameters for
pentapeptide was 115.7°, which is larger than that of the ideal
dMOM
α
Boc-{(R,R)-Ac3c
}5-OMe (13)
tetrahedral angle 109.5° (Table S2). In addition, the N−C
α
and C −C′ bond lengths became shorter than those of normal
donor
dist (Å)
D···A
angle (deg)
D−H···A
symmetry
operations
peptides because of the conjugating ability of the three-
peptide D−H acceptor A
18
membered ring (data not shown).
By calculations using MacroModel, 20000 conformations of
mol A N −H
O0
2.99
3.03
2.94
2.84
161
166
154
154
x, y, z
x, y, z
x, y, z
3
N −H
O1
4
dMOM
hexapeptide Cbz-{(R,R)-Ac3c
}6-OMe were produced
N −H
O3MOM
5
with Monte Carlo methods and minimized with the
N −H
O5
1 − x, 1/2 + y,
1′
20
AMBER* (H O) force field. The left-handed (M) 3 -helix
1
− z
2
10
was obtained as a global minimum energy conformation (0
N −H
O6
2.90
2.81
136
178
1 − x, 1/2 + y,
2′
1
− z
kcal/mol), and the distorted right-handed (P) 3 -helix was
10
O −H
w
O4
1 − x, 1/2 + y,
gained as a local minimum energy conformation (+10.15 kcal/
mol) (Figure S4). These results match the left-handed
structure determined by X-ray crystallographic analysis, but
the calculated left-handed (M) 3 -helix was not bent, and no
1
− z
mol B N −H
O0
O1
O3MOM
O5
3.04
2.89
3.06
2.74
160
163
150
158
x, y, z
x, y, z
x, y, z
3
N −H
4
1
0
N −H
5
intramolecular hydrogen bond with an N−H···O (ethereal)
N −H
−x, 1/2 + y,
1′
type was observed.
The secondary structure of (R,R)-Ac3c
2
− z
dMOM
homochiral
N −H
O6
3.16
132
−x, 1/2 + y,
− z
2
′
2
pentapeptide 13 in the crystalline state was unambiguously
determined to be bent left-handed (M) 3 -helices. The left-
1
0
Table 2. Selected Torsion Angles ω, ϕ, and ψ (deg) for Boc-
handedness of the helix was exclusively controlled by the chiral
centers at the side-chain β-carbons of cyclopropane. These
results are in contrast to those of the uncontrolled helical screw
dMOM
{
(R,R)-Ac3c
} -OMe (13), As Determined by X-ray
5
16,18
Crystallographic Analysis
3
BD
9
8
direction of (R,R)-Ac c
Ac6c homopeptides but are in accordance with the
one-handed helical screw of (S,S)-Ac5c
,
(R,R)-Ab5,6=c, and (R,R)-
4
torsion angle
molecule A
molecule B
10
3
5 dBu
θ0
−176.4
−160.8
73.9
19.6
−173.1
65.5
9.4
−167.9
59.2
−157.8
174.7
70.7
16.3
−172.6
63.0
15.6
−169.1
63.8
dOM
7
homopeptides.
ω0
ϕ1
ψ1
ω1
ϕ2
ψ2
ω2
ϕ3
ψ3
ω3
ϕ4
ψ4
ω4
ϕ5
ψ5
ω5
Two steric factors could be considered as controlling the
helical-screw direction into one-handedness. One is a steric
factor, in which the MOM substituent on the side-chain β-
carbon directly affects the torsion angles of the same amino
acid residue. The cyclopropylcarbonyl parts showed a tendency
21
to form bisected s-cis conformations, and the repulsion
between the oxygen of C′O and the γ-carbon of MOM
might affect the ψ torsion angles. The other is the steric
repulsion between the side-chain MOM substituents of the
amino acid residues (i) and (i+3) in the 3 -helices. The
22.4
18.3
179.1
−94.8
17.5
−179.6
71.0
177.1
−89.0
13.2
179.6
62.7
1
0
repulsion may be different between right- and left-handed
dPh
helices. In the case of the chiral (R,R)-Ac3c
(c diPhe)-
3
containing peptide reported by Toniolo, Cativiela, and co-
22
workers, the steric repulsion between the Ph-substituents of
21.9
178.6
28.1
179.5
the amino acid residues (i) and (i+3) was proposed to be one
of the important factors controlling the helical-screw sense to
one-handedness. However, the MOM substituent of (R,R)-
dMOM
dPh
molecule B, respectively, and thus, the peptide-backbone
structure was largely bent in this residue (4). The twists of ϕ
and ψ torsion angles of the penultimate residue described here
have not been reported. These twisted torsion angles might be
influenced by the intramolecular hydrogen bond of the N(5)−
H···OMe(3) type between the peptide backbone N−H and the
Ac
c
3
is smaller than the Ph substituent of (R,R)-Ac
c
3
,
and the effect of this steric repulsion between the MOM of
amino acid residues (i) and (i+3) may be smaller. Thus, the γ-
carbon of MOM, and additionally, the methoxy of the MOM
dMOM
substituent on the (R,R)-Ac
c
residue would directly
3
influence the same amino acid ψ torsion angles, and the helical-
screw direction might be controlled as left-handed (Figure 2).
Certainly, nonsteric factors such as the hydrophilicity and
electronic density of the methoxy group might also affect the
secondary structure.
15
side-chain ethereal O atom.
Although the reversal of the C-terminal residue ϕ and ψ
torsion angles of dAA homopeptides to those of the preceding
1
9
residues has often been reported
and achiral Ac3c
homopeptides forming a characteristic C-terminal semi-
extended conformation (ϕ 90, ψ 180) have also been
1
8
reported, the C-terminal residue of the chiral (R,R)-
dMOM
Ac3c
pentapeptide formed normal left-handed ϕ and ψ
torsion angles (A: ϕ +71.0, ψ +21.9; B: ϕ +62.7, ψ +28.1), but
α
not a semiextended conformation. The exocyclic τ (N−C −
C′) bond angles of achiral three-membered ring amino acid
Ac c residues in peptides have been reported to become larger
3
18
than that of the regular tetrahedral value. Similarly, the
average τ (N−C −C′) bond angle of the (R,R)-Ac c
Figure 2. Steric repulsion between the γ-carbon of MOM and oxygen
of the C′O group of the same residue.
α
dMOM
3
C
DOI: 10.1021/acs.orglett.8b03331
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we synthesized a chiral cyclopropane-based
Towards connecting structure and function. Org. Biomol. Chem. 2010,
dMOM
8
(
, 3101.
2) (a) Becart, D.; Diemer, V.; Salaun, A.; Oiarbide, M.; Nelli, Y. R.;
́
̈
dAA, (R,R)-Ac3c
with two MOM-substituents at the β-
carbons and prepared its homopeptides up to a hexapeptide.
dMOM
Kauffmann, B.; Fischer, L.; Palomo, C.; Guichard, G. Helical
oligourea foldamers as powerful hydrogen bonding catalysts for
enantioselective C−C bond-forming reactions. J. Am. Chem. Soc.
The (R,R)-Ac3c
hexapeptide is the longest homopeptide
constructed from a chiral three-membered ring dAA. The
dMOM
(
R,R)-Ac3c
pentapeptide preferentially formed the bent
2017, 139, 12524. (b) Barrett, K. T.; Miller, S. J. Enantioselective
left-handed (M) 3 -helical structures that were exclusively
10
Synthesis of atropisomeric benzamides through peptide-catalyzed
bromination. J. Am. Chem. Soc. 2013, 135, 2963. (c) Nagano, M.; Doi,
M.; Kurihara, M.; Suemune, H.; Tanaka, M. Stabilized α-helix-
catalyzed enantioselective epoxidation of α,β-unsaturated ketones.
Org. Lett. 2010, 12, 3564. (d) Ueda, A.; Umeno, T.; Doi, M.;
Akagawa, K.; Kudo, K.; Tanaka, M. Helical-peptide-catalyzed
enantioselective Michael addition reactions and their mechanistic
insights. J. Org. Chem. 2016, 81, 6343.
controlled by the side-chain chiral centers. The 3 -helical
1
0
structure of a homopeptide interrupted by an intramolecular
hydrogen bond of the N(5)−H···O (3) (ethereal) type has not
been reported, and the structure would be useful for designing
functional molecules such as chiral peptide catalysts, cell-
penetrating peptides, and protein−protein interaction inhib-
4
itors.
(3) (a) Kato, T.; Oba, M.; Nishida, K.; Tanaka, M. Cell-penetrating
ASSOCIATED CONTENT
Supporting Information
helical peptides having L-arginines and five-membered ring α,α-
disubstituted α-amino acids. Bioconjugate Chem. 2014, 25, 1761.
■
*
S
(b) Yamashita, H.; Demizu, Y.; Shoda, T.; Sato, Y.; Oba, M.; Tanaka,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03331.
M.; Kurihara, M. Amphipathic short helix-stabilized peptides with
cell-membrane penetrating ability. Bioorg. Med. Chem. 2014, 22, 2403.
(c) Oba, M.; Kunitake, M.; Kato, T.; Ueda, A.; Tanaka, M. Enhanced
and prolonged cell-penetrating abilities of arginine-rich peptides by
introducing cyclic α,α-disubstituted α-amino acids with stapling.
Bioconjugate Chem. 2017, 28, 1801. (d) Kato, T.; Oba, M.; Nishida,
K.; Tanaka, M. Cell-penetrating peptides using cyclic nged cell-
penetrating abilities of a basic functional groups. ACS Biomater. Sci.
Eng. 2018, 4, 1368.
Experimental section, spectroscopic data of new
1
compounds, 2D H NMR spectra of 13 and 14, CD
1
spectra of peptides, FT-IR spectra of peptides, H and
1
3
C NMR spectra (PDF)
Calculated structure of the (M)-3 -helix (PDB)
Calculated structure of the (P)-3 -helix (PDB)
1
0
10
(4) Gopalakrishnan, R.; Frolov, A. I.; Knerr, L.; Drury, W. J., III;
Valeur, E. Therapeutic potential of foldamers: From chemical biology
tools to drug candidates? J. Med. Chem. 2016, 59, 9599.
Accession Codes
CCDC 1871355 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing 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.
(
5) (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.;
Cavicchioni, G. Structures of peptides from α-amino acids methylated
at the α-carbon. Biopolymers 1993, 33, 1061. (b) Toniolo, C.; Crisma,
M.; Formaggio, F.; Peggion, C. Control of peptide conformation by
the Thorpe-Ingold effect (C alpha-tetrasubstitution). Biopolymers
2001, 60, 396. (c) Tanaka, M. Design and synthesis of chiral α,α-
disubstituted amino acids and conformational study of their
oligopeptides. Chem. Pharm. Bull. 2007, 55, 349. (d) Crisma, M.;
Toniolo, C. Helical screw-sense preferences of peptides based on
AUTHOR INFORMATION
■
Corresponding Author
α
chiral, C -tetrasubstituted e preferences. Biopolymers 2015, 104, 46.
e) Crisma, C.; De Zotti, M.; Formaggio, F.; Peggion, C.; Moretto, A.;
*E-mail: matanaka@nagasaki-u.ac.jp.
(
ORCID
Toniolo, C. Handedness preference and switching of peptide helices.
Part II: Helices based on noncoded α-amino acids. J. Pept. Sci. 2015,
Atsushi Ueda: 0000-0002-6155-9700
Makoto Oba: 0000-0002-3691-3608
Takuma Kato: 0000-0002-2561-8582
Yosuke Demizu: 0000-0001-7521-4861
Masakazu Tanaka: 0000-0002-6929-4380
Notes
2
(
1, 148.
6) (a) Cativiela, C.; Díaz-de-Villegas, M. D. Stereoselective
synthesis of quaternary α-amino acids. Part 2: Cyclic compounds.
Tetrahedron: Asymmetry 2000, 11, 645. (b) Cativiela, C.; Ordonez, M.
Recent progress on the stereoselective synthesis of cyclic quaternary
α-amino acids. Tetrahedron: Asymmetry 2009, 20, 1.
(7) (a) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
The authors declare no competing financial interest.
Chiral centers in the side chains of α-amino acids control the helical
screw sense of peptides. Angew. Chem., Int. Ed. 2004, 43, 5360.
ACKNOWLEDGMENTS
(b) Demizu, Y.; Doi, M.; Kurihara, M.; Maruyama, T.; Suemune, H.;
■
Tanaka, M. One-handed helical-screw direction of homopeptide-
foldamer exclusively induced by cyclic α-amino acid side-chain chiral
centers. Chem. - Eur. J. 2012, 18, 2430.
This work was supported in part by JSPS KAKENHI Grant
No. JP-17H03998 (M.T.) and by the Sasakawa Scientific
Research Grant from The Japan Science Society (Y. K.).
(8) (a) Tanaka, M.; Anan, K.; Demizu, Y.; Kurihara, M.; Doi, M.;
Suemune, H. Side-chain chiral centers of amino acid and helical-screw
handedness of its peptides. J. Am. Chem. Soc. 2005, 127, 11570.
DEDICATION
■
This paper is dedicated to Professor Dr. Kiyoshi Sakai on the
occasion of his 88th birthday.
(b) Anan, K.; Demizu, Y.; Oba, M.; Kurihara, M.; Doi, M.; Suemune,
H.; Tanaka, M. Helical structures of bicyclic α-amino acid homo-
chiral oligomers with the chiral centers at the side-chain fused-ring
junctions. Helv. Chim. Acta 2012, 95, 1694.
(9) Eto, R.; Oba, M.; Ueda, A.; Uku, T.; Doi, M.; Matsuo, Y.;
Tanaka, T.; Demizu, Y.; Kurihara, M.; Tanaka, M. Diastereomeric
right- and left-handed helical structures with fourteen (R)-chiral
centers. Chem. - Eur. J. 2017, 23, 18120.
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DOI: 10.1021/acs.orglett.8b03331
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b03331
Org. Lett. XXXX, XXX, XXX−XXX