Alternating asymmetric self-induction in functionalized pyrrolidine oligomers

Article abstract of DOI:10.1002/anie.201302862

Rainbow of pyrrolidines: Red, orange, yellow, green, blue (indigo, violet). Copyright

Full text of DOI:10.1002/anie.201302862

Angewandte
Chemie
DOI: 10.1002/anie.201302862
b-Peptides
Alternating Asymmetric Self-Induction in Functionalized Pyrrolidine
Oligomers**
Konstantin V. Kudryavtsev,* Polina M. Ivantcova, Andrei V. Churakov, Steffen Wiedmann,
Burkhard Luy, Claudia Muhle-Goll, Nikolay S. Zefirov, and Stefan Brꢀse*
Artificial structurally well-defined polymers have excited
interest as functional mimetics of natural biomacromolecules,
exhibiting additional properties not occurring in the living
world.[1] Specific conformational organization of natural and
synthetic polymeric objects leading to unique folding
accounts for the molecular recognition, which is one of the
driving principles in important natural processes. Some non-
natural oligomeric species adopt specific and well-defined
conformations dictated by the structure of monomeric units
and intramolecular interactions and are defined as foldam-
ers.[2] One of the most studied unnatural foldamer types are b-
peptides that adopt stable folded helical, sheet, and turn-like
conformations.[3] b-Peptides are stable towards natural
enzymes, and appropriate design leads to discovery of b-
peptide ligands for complicated pharmaceutical targets, such
as protein–protein interactions.[4] The application of pyrroli-
dine-3-carboxylic acid (Pca) for the construction of b-
polypeptide chain rigidifies the molecular backbone and
provides additional stabilization of the secondary structure of
the oligomer in solution.[5]
The typical synthesis of a b-peptide backbone is based on
the arsenal of peptide chemistry methods, including routine
sequences of amino group protection–deprotection steps and
multiple activations of carboxylic functionality for amide
bond construction. Herein we disclose a fundamentally novel
synthetic method towards well-defined highly functionalized
short b-peptides that avoids protection, deprotection, and
activation procedures and allows to generate efficiently
stereoregular oligomeric pyrrolidine-based molecules. The
developed method, called cycloadditive oligomerization, has
been used for the synthesis of a set of racemic and
enantiopure oligomers containing a Pca backbone. The
realized approach determines highly diverse structural char-
acteristics of b-peptide oligomers, which are characterized by
various physicochemical methods, including X-ray analysis.
The oligomerization utilized azomethine ylide 1,3-dipolar
cycloaddition[6] as a chain-growth approach (Scheme 1). 5-
Arylpyrrolidine-2,4-dicarboxylate units serve both as linked
elements and as auxiliaries to determine stereo- and enantio-
selectivities of the cycloaddition process. The starting 5-
arylpyrrolidine-2,4-dicarboxylic acid diesters 3a (X = H, Br)
for oligomer synthesis were obtained from iminoesters 1 and
tert-butyl acrylate in racemic[7] and enantiopure[8] forms by
1,3-dipolar cycloaddition using Lewis acids for the azome-
thine ylide generation step (Scheme 1, Table 1). Asymmetric
synthesis of the monomer (ꢀ)-3a-H was effectively con-
ducted with the enantiopure ligand 4[8] on a gram scale, and
single recrystallization provided the target compound with
more than 99% ee. Subsequent N-acryloylation of monomers
3a with acryloyl chloride transformed them into dipolaro-
philes 2b with a sterically hindered amide residue connected
to the ethylene fragment. We supposed that these unique
dipolarophiles would induce good diastereo- and enantiose-
lectivities under iterative cycloaddition steps with iminoesters
1 (Scheme 1).
Indeed, dimers 3b were effectively synthesized by cyclo-
addition of acrylamides 2b with Schiff bases 1 (X = H, Br) in
presence of AgOAc as a Lewis acid agent for azomethine
ylide generation (Table 1, entries 4–6). Comparison of
1H NMR spectra of the cycloaddition reaction mixtures and
[*] Prof. Dr. K. V. Kudryavtsev, Dipl.-Chem. P. M. Ivantcova,
Prof. Dr. N. S. Zefirov
Prof. Dr. B. Luy
Institute for Biological Interfaces II
Karlsruhe Institute of Technology (KIT)
POB 3640, 76021 Karlsruhe (Germany)
Department of Chemistry
M.V. Lomonosov Moscow State University
Leninskie Gory 1/3, 119991 Moscow (Russian Federation)
E-mail: kudr@org.chem.msu.ru
Prof. Dr. S. Brꢀse
Institute of Toxicology and Genetics (ITG)
Karlsruhe Institute of Technology (KIT)
76344 Eggenstein-Leopoldshafen (Germany)
Prof. Dr. K. V. Kudryavtsev, Prof. Dr. N. S. Zefirov
Institute of Physiologically Active Compounds
Russian Academy of Sciences
[**] Russian Foundation for Basic Research (project Nos. 11-03-00630-
a, 11-03-91375-ST_a and 12-03-92005-NNS_a), RAS Programme
OXHM-3 “Macromolecular compounds”, the State Contract
11.519.11.2032 (the Russian Ministry of Education and Science),
and the Ministry of Science and Art in Baden-Wꢁrttemberg (ZO IV)
are appreciated for generous funding and support. The authors
thank Prof. Dr. Ozdemir Dogan for providing ligand 4. NMR
spectroscopic measurements were performed at the DFG Gerꢀte-
zentrum Pro2NMR.
142432 Chernogolovka, Moscow region (Russian Federation)
Dr. A. V. Churakov
Institute of General and Inorganic Chemistry
Russian Academy of Sciences
Leninskii prosp. 31, 119991 Moscow (Russian Federation)
S. Wiedmann, Prof. Dr. B. Luy, Dr. C. Muhle-Goll, Prof. Dr. S. Brꢀse
Institute of Organic Chemistry (IOC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
E-mail: stefan.braese@kit.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302862.
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Scheme 2. Synthesis of pentamer (ꢀ)-3e-H and its dominant solution
conformation (in box) as determined by NMR spectroscopy (for
details, see Table 1, entry 13, text, and the Supporting Information).
NOE interactions are shown with double-headed arrows.
(Scheme 2) did not rotate polarized light in CH2Cl2 solution
but its methanol solution is characterized by anticlockwise
rotation.
The intriguing issue of the stereochemistry of newly
generated stereogenic centers at the pyrrolidine rings under
developed cycloadditive oligomerization process was under-
pinned by certain structural investigations. We succeeded in
evaluation of several oligomeric molecules 3 by single-crystal
diffraction.[9] The results confirmed without doubt that the
newly formed 5-methoxycarbonyl-2-phenylpyrrolidine frag-
ment has exactly inverse configuration of three new stereo-
genic centers beside the adjacent parent monomer unit, as
shown for the pentamer (ꢀ)-3e-H in Scheme 2. For discussion
purposes, the pyrrolidine rings are numbered with Roman
figures according the order of introducing in an oligomer
chain (Scheme 2). All of the bond lengths and angles of
studied molecules have typical values for organic compounds.
The molecular backbone of racemic dimer 3b-H consists of
two pyrrolidine rings linked by an amide group (see the
Supporting Information).
The central amide fragment O1-C18-N1-C1-C4-C20 of
3b-H is planar to within 0.108(1) ꢀ. Both pyrrolidine cycles in
dimer 3b-H adopt an envelope conformation. Flap atoms C2
and C20 of 3b-H are displaced from the base planes of other
four atoms in pyrrolidine cycles by 0.628(2) and 0.555(3) ꢀ,
respectively. The molecular backbone of racemic trimer 3c-Br
consists of three pyrrolidine rings linked by two amide units
(Figure 1). Bridging amide fragments C18-O5-N1-C1-C4-C20
and C31-O8-N2-C19-C22-C34 are planar within 0.084(2) and
0.081(3) ꢀ, respectively. All three of the pyrrolidine rings
adopt an envelope conformation. The displacements of flap
atoms from the base planes are 0.576(6) ꢀ for C3, 0.557(7) ꢀ
for C21, and 0.536(7) ꢀ for C34. In the crystal, the adjacent
molecules of 3c-Br are combined in chains along the c axis by
weak hydrogen bonds between amino and methoxy groups
Scheme 1. Synthesis of Pca oligomers by cycloadditive self-inductive
oligomerization. Fc=ferrocenyl.
Table 1: Reactions to generate monomers 3a-X and oligomers 3b–e.
Entry
1
2
Conditions[a] 3-X
Yield [%] Conf.[b]
1
2
3
4
5
6
7
8
1-H 2a
1-H 2a
1-Br 2a
A
B
A
C
C
C
C
C
C
C
C
C
C
C
rac-3a-H
65
81
67
70
90
82
94
87
82
83
85
81
93
85
S(R)
S
S(R)
R(S)
R
R(S)
S(R)
S
S(R)
R(S)
R
(ꢀ)-3a-H
rac-3a-Br
rac-3b-H
(ꢀ)-3b-H
rac-3b-Br
rac-3c-H
(+)-3c-H
rac-3c-Br
rac-3d-H
(ꢀ)-3d-H
rac-3d-Br
(ꢀ)-3e-H
rac-3e-Br
1-H rac-2b-H
1-H (ꢀ)-2b-H
1-Br rac-2b-Br
1-H rac-2c-H
1-H (ꢀ)-2c-H
1-Br rac-2c-Br
1-H rac-2d-H
1-H (+)-2d-H
1-Br rac-2d-Br
1-H (ꢀ)-2e-H
1-Br rac-2e-Br
9
10
11
12
13
14
R(S)
S
S(R)
[a] Conditions: A) LiBr (1.5 equiv), Et3N (1.2 equiv), THF, 08C; B) Cata-
lyst 4 (0.1 equiv), Zn(OTf)2 (0.1 equiv), Et3N (0.1 equiv), THF, ꢀ208C;
C) AgOAc (1.5 equiv), Et3N (1.5 equiv), toluene, RT. [b] Configuration at
the newly generated C5(2) center (see Scheme 1).
ꢀ
corresponding pure dimers 3b indicated more than 95%
cycloaddition diastereoselectivity. Compound (ꢀ)-3b-H has
an enantiomeric purity of 97% ee. The racemic analogue 3b-
H was characterized by X-ray crystallographic analysis.
Repetition of the acroylation/cycloaddition processes gave
access to oligomers 3c–e with up to five pyrrolidine units in
good yields (Table 1, entries 7–14 and the Supporting Infor-
mation). The enantiomerically pure pentamer (ꢀ)-3e-H
N3 H1···O3(1ꢀx, 1ꢀy, 0.5 + z) with N···O distances equal to
3.576 ꢀ. There are wide, solvent-accessible channels passing
along the a axis with an approximate diameter of 5.2 ꢀ (see
the Supporting Information).
The molecular geometry of chiral trimer (+)-3c-H was
also determined by X-ray studies and is very similar to the
bromophenyl trimer 3c-Br (Figure 1). The only noticeable
differences were observed in rotations of methoxycarbonyl
2
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Figure 1. Molecular structures of trimers 3c-Br (left) and (+)-3c-H
(right).
Figure 2. Relevant NOE contacts in the trimer rac-3c-H. Part of a 1H–
ꢀ
ꢀ
groups along C4 C16 and C32 C42 single bonds. However,
the crystal packing of (+)-3c-H is completely different. In
(+)-3c-H, amino hydrogen atom H1 does not participate in
any hydrogen bonding and the crystal is built by van der
Waals interactions only. In contrast to 3c-Br, in the structure
of (+)-3c-H no solvent-accessible voids are observed.
1H-NOESY with 400 ms mixing time showing the pyrrolidine proton
region. The assignment is indicated in the 1D-spectrum above (?
indicates residual CHDCl2). Characteristic NOEs between the rings are
boxed (cyan), with the assignment given in the spectrum. Peaks
arising from chemical exchange between major and minor conforma-
tions appear with opposite sign. Exemplified are exchange peaks
between H6(I) (major conformation) and H6(I)’ (1st minor) or H6(I)
major and H6(I)’’ (2nd minor; green boxes).
An NMR study of well-ordered oligomers 3 of the phenyl
series (X = H, Scheme 1) elucidated their structural prefer-
ences in solution. Assignment of the 1H and 13C NMR signals
can be found in the Supporting Information, Table S1. Based
on pyrrolidine ring-proton spin couplings, the dihedral angles
were calculated[10] and correlated with the corresponding X-
ray data for the racemic dimer 3b-H and the trimer (+)-3c-H.
This demonstrated almost full consistency between the main
conformations in solution and the crystal structures (Support-
ing Information, Table S2). Further study of conformational
modes of the racemic trimer 3c-H in CD2Cl2 solution was
formation for oligomers rac-3b-H, rac-3c-H, and (ꢀ)-3d-H is
characterized by NOEs between the pyrrolidine rings protons
H6(i)/H6(i+1) and H4(i)/H6(i+1) corresponding to cis b-
peptide bond with an alternating arrangement of the phenyl
substituents, as observed in the crystalline state for trimers
rac-3c-Br and (+)-3c-H. Increasing the number of pyrroli-
dine units in oligomers leads to an increase in cis/trans amide
bond isomerization cases and complication of conformational
balance. The dominant conformer of pentamer (ꢀ)-3e-H in
CD2Cl2 solution deviates from all cis b-peptide bond con-
formation and shows a trans b-peptide bond between the
second and third pyrrolidine ring (Scheme 2). Using the
described method, we performed conformational analysis of
the phenyl series of oligomers 3 (Scheme 3; Supporting
Information, Table S3). Tenfold dilution of CD2Cl2 solution of
pentamer (ꢀ)-3e-H did not change the 1H NMR (see the
Supporting Information), indicating negligible influence of
intermolecular interactions on conformer population. We also
performed atomic force microscopy studies of tetramers rac-
3d-H, (ꢀ)-3d-H, and rac-3d-Br to detect supramolecular
organization in solid state, but no ordering was observed (see
the Supporting Information). At the current stage it is
difficult to make a statement about the definite type of
folding of the Pca oligomers 3 synthesized herein. Undoubt-
edly an appropriate selection of aryl substituents and
carboxylic functions (for example, COOH instead of
COOMe) would be a powerful way to design intra- and
intermolecular interactions in Pca oligomers 3.
1
assessed by correlating 2D H NMR experiments (Figure 2).
In the trimer rac-3c-H we observed at least three stable
conformations with relative intensities of 89.7/7.2/2.7. The
minor conformations were in dynamic exchange with the
main conformation, as demonstrated by exchange peaks with
opposite intensity than the conventional NOEs. Within
a temperature range from 08C to 408C the relative intensities
of the observed rac-3c-H conformations did not change. The
spatial arrangement of pyrrolidine units in the minor con-
formers was determined by a detailed analysis of the
corresponding NOEs (Figure 2, Scheme 3). Cis/trans amide
bond isomerization[5d,11] is an evident reason of the detected
conformational exchange. The major regular solution con-
The enantiopure set of polypyrrolidines 3 was studied by
CD spectroscopy. CD spectra were recorded in the far UV
area from 300 nm to 190 nm, a region of essential absorbance
Scheme 3. Conformers of the trimer rac-3c-H in CD2Cl2 solution as
determined by NMR spectroscopy.
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(ꢀ)-2c-H was purified by column chromatography on silica gel
(eluent CH2Cl2/MeOH 100:1) and isolated as yellowish crystals in
78% yield (for spectroscopic data, see the Supporting Information).
(ꢀ)-2c-H (1.100 g, 1.86 mmol) was dissolved in anhydrous toluene
(20 mL) under an argon atmosphere. The reaction flask was protected
from the light with aluminum foil. A solution of 1-H (0.395 g,
2.23 mmol) in anhydrous toluene (20 mL) and AgOAc (500 mg,
2.79 mmol) were added sequentially. Et3N (0.283 g, 390 mL,
2.79 mmol) was added dropwise to the reaction mixture and stirred
at the ambient temperature for 24 h. The volatiles were removed
under vacuum and the residue was redissolved in CH2Cl2 (50 mL) and
filtered. The organic phase was washed with water (25 mL), brine
(25 mL), and then dried over Na2SO4. The residue after solvent
evaporation was subjected to purification by column chromatography
on silica gel (eluent CH2Cl2/MeOH 100:1). Trimer (+)-3c-H was
isolated as yellowish crystals, 1.241 g, yield 87%; m.p. 144–1468C;
95% ee (Chiralpack IB column, heptane/iPrOH 75:25, 0.7 mLminꢀ1
,
26
tR(major) = 18.99 min); [a]D + 22.078 (c 0.97, CH2Cl2). H NMR
(300 MHz, CDCl3, 293 K, dominant conformer signals): d = 1.17 (s,
9H), 1.58–1.69 (m, 1H), 1.94–1.97 (m, 1H), 2.16–2.24 (m, 1H), 2.25–
2.35 (m, 3H), 2.71–2.74 (m, 1H), 2.97–3.00 (m, 1H), 3.07–3.11 (m,
1H), 3.66–3.81 (m, 13H), 4.33 (d, J = 7.4 Hz, 1H), 4.66 (d, J = 8.9 Hz,
1H), 5.01 (d, J = 8.5 Hz, 1H), 7.32–7.46 (m, 13H, HAr), 7.60 ppm (d,
J = 6.4 Hz, 2H, HAr). 13C NMR (100 MHz, CDCl3, 293 K, dominant
conformer signals): d = 27.69, 28.44, 29.56, 34.62, 47.40, 47.83, 50.63,
52.11, 52.15, 52.24, 59.09, 59.17, 60.12, 62.65, 62.76, 66.55, 82.07,
127.03, 127.06, 128.04, 128.24, 128.55, 128.65, 128.96, 137.53, 138.61,
138.93, 167.45, 167.45, 167.99, 177.65, 171.72, 172.77 ppm. HRMS
(FAB): [M + H]+ calculated for C43H50N3O10 768.3496, found
768.3497.
Figure 3. CD spectra of monomer (ꢀ)-3a-H (no symbol) and oligo-
~
*
^
mers (ꢀ)-3b-H ( ), (+)-3c-H ( ), (ꢀ)-3d-H (&), and (ꢀ)-3e-H ( ).
of the amide and ester groups and to a lesser extent of
aromatic groups. The CD spectrum of the dimer (ꢀ)-3b-H
shows a maximum at 190 nm and two minima at 201 and
217 nm (Figure 3). By analogy to other peptoids and peptides,
the band at 217 nm was assigned to the n!p* transition[11b] of
the amide and ester chromophores and the other two bands to
the exciton-split p* transition. In the higher oligomers, the
position of these bands change and the relative intensities
vary considerably. In the trimer (+)-3c-H, the absorption is
mainly positive, in the tetramer (ꢀ)-3d-H it is negative, and in
the pentamer (ꢀ)-3e-H it was found that any true extrema
can no longer be distinguished (Figure 3). In contrast to
peptoids and peptides with uniform chirality, the alternating
R/S configurations in adjacent pyrrolidine units of enantio-
merically pure oligomers 3 seemingly lead to bands of
opposite intensities, which partially compensate each other
and thus cause the flattening of the curves.
In conclusion, a unique set of racemic and chiral
oligomers based on the Pca scaffold was efficiently synthe-
sized by an efficient cycloadditive oligomerization approach.
A specific feature of the developed synthetic method is the
self-generation of new stereogenic centers with a high degree
of stereoselectivity. Owing to the rigidity of poly(5-arylpyr-
rolidine-2-carboxylic acid) systems, we aim to produce well-
organized oligomeric nanosized objects having various func-
tional groups in a confined spatial arrangement for biological,
catalytic, and materials applications. Theoretical studies of
the stereochemical course of the observed reversal under
chain growth will be also performed.
Received: April 6, 2013
Revised: July 24, 2013
Published online: && &&, &&&&
Keywords: asymmetric synthesis · azomethine ylide ·
.
b-peptides · 1,3-dipolar cycloaddition · foldamer
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Experimental Section
The general procedure for the synthesis of oligomers is illustrated by
example of trimer (+)-3c-H: Et3N (0.423 g, 583 mL, 4.18 mmol) was
added to a solution of (ꢀ)-3b-H (1.400 g, 2.61 mmol) in CH2Cl2
(50 mL) at 08C. Acryloyl chloride (353 mg, 310 mL, 3.92 mmol) was
added dropwise to the reaction mixture under an argon atmosphere at
08C. After 15 min, the reaction mixture was allowed to warm to
ambient temperature and stirred for 24 h. After washing with water
(25 mL), saturated NaHCO3 solution (25 mL), and brine (25 mL), an
organic phase was dried over Na2SO4 and evaporated. Acrylamide
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4
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[9] CCDC 911207 (rac-3b-H), 911208 (rac-3c-Br), and 911209
((+)-3c-H) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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Communications
b-Peptides
K. V. Kudryavtsev,* P. M. Ivantcova,
A. V. Churakov, S. Wiedmann, B. Luy,
C. Muhle-Goll, N. S. Zefirov,
S. Brꢁse*
&&&& — &&&&
Alternating Asymmetric Self-Induction in
Functionalized Pyrrolidine Oligomers
Rainbow of pyrrolidines: Red, orange, yellow, green, blue (indigo, violet).
6
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