Design and Synthesis of Building Blocks for PPII-Helix Secondary-Structure Mimetics: A Stereoselective Entry to 4-Substituted 5-Vinylprolines

Article abstract of DOI:10.1002/ejoc.201701584

In the course of our studies towards the synthesis of proline-based secondary-structure mimetics, we developed a straightforward methodology for the diastereoselective preparation of 4-alkyl-5-vinyl-substituted proline derivatives. Starting from N-Boc-protected tert-butyl pyroglutamate, α-alkylation, lactam reduction and acid-catalyzed methanolysis afforded 4-alkyl-5-methoxyproline derivatives. After BF₃-induced formation of an N-acyl-iminium intermediate, the introduction of the 5-vinyl side chain was achieved with high diastereoselectivity by using vinylmagnesium bromide in the presence of AlCl₃ or CuBr·SMe₂ to afford either the cis- or the trans-product, respectively. The utility of the method was demonstrated in the rapid and efficient construction of new diproline mimetics rigidified in a polyproline-type II helix (PPII) conformation.

Full text of DOI:10.1002/ejoc.201701584

A Journal of
Accepted Article
Title: Design and Synthesis of new Building Blocks for PPII-Helix
Secondary Structure Mimetics: A Stereoselective Entry to 4-
Substituted 5-Vinylprolines
Authors: Hans-Günther Schmalz, Slim Chiha, Arne Soicke, Matthias
Barone, Matthias Müller, Judith Bruns, Robert Opitz, Jörg-
Martin Neudörfl, and Ronald Kühne
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701584
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701584
Supported by

10.1002/ejoc.201701584
European Journal of Organic Chemistry
FULL PAPER
Design and Synthesis of new Building Blocks for PPII-Helix
Secondary Structure Mimetics: A Stereoselective Entry to
4-Substituted 5-Vinylprolines
Slim Chiha,[a] Arne Soicke,[a] Matthias Barone,[b] Matthias Müller,[b] Judith Bruns,[a] Robert Opitz,[b] Jörg-
Martin Neudörfl,[a] Ronald Kühne,[b] and Hans-Günther Schmalz*[a]
Abstract: In the course of our studies towards the synthesis of
proline-based secondary structure mimetics we developed
pitch of about 9 Å (three residues per turn) with ψ and ϕ angles
of about 145° and -75°, respectively.[8] As we have recently
shown, such a conformation can be fixed by stereo-defined
introduction of a Z-vinylidene bridge between the two pyrrolidine
rings of a diproline unit (Figure 1).[9] Indeed, the synthetic
tricyclic compound ProM-1 was found to almost perfectly mimic
a Pro-Pro unit in the PPII conformation. ProM-1 and related
scaffolds were then successfully used as modules for the
synthesis of ligands capable of inhibiting PRM-binding domains
(PBDs) such as the EVH1 domain.[2a]
Based on X-ray structural data and subsequent computa-
tional investigations we came to the assumption that the intro-
duction of an additional alkyl substituent at ProM-1 (Figure 1)
should improve the binding strength of the developed EVH1
ligands. Here, we present a reliable and stereoselective entry to
the required 4-alkyl-5-vinyl-substituted proline building blocks
and their use in the synthesis of the new scaffolds ProM-9 and
ProM-13.
a
straightforward methodology for the diastereoselective preparation of
4-alkyl-5-vinyl-substituted proline derivatives. Starting from N-Boc-
protected tert.-butyl pyroglutamate, -alkylation, lactame reduction
and acid-catalyzed methanolysis afforded 4-alkyl-5-methoxyproline
derivatives. After BF3-induced formation of an N-acyl-iminium inter-
mediate, the introduction of the 5-vinyl side chain was achieved with
high diastereoselectivity using vinyl magnesium bromide in the
presence of AlCl3 or CuBr-SMe2 to afford either the cis- or the trans-
product, respectively. The utility of the method was demonstrated in
the rapid and efficient construction of new diproline mimetics
rigidified in a polyproline type II helix (PPII) conformation.
Introduction
Protein-protein interactions play a key role in many physiological
events and represent important yet particularly challenging
targets for pharmacological intervention. Thus, the search for
synthetic low-molecular weight molecules which are able to
selectively inhibit or modulate relevant protein-protein inter-
actions represents a major task in bio-medicinal research.[1] In
this context, we are aiming at the development of molecules
capable of replacing the natural binding partners of protein
domains specialized in the recognition of so-called proline-rich
motifs (PRM).[2] Particularly abundant, yet so far undruggable,
such specific interactions are involved in a variety of relevant
cellular processes such as tyrosine kinase receptor signaling,[3]
endocytosis,[4] cytoskeletal rearrangements,[5] transcription,[6]
and splicing.[7]
Results and Discussion
Design
As mentioned above, ProM-1 and related scaffolds
mimicking a diproline unit in a PPII helix conformation were
shown to represent powerful structural modules for the develop-
ment of PBD ligands. For instance, the molecule shown in
Figure 1 on the right displays a remarkable affinity and
selectivity towards the Ena/VASP EVH1 domain and reduces
the motility of highly invasive cancer cells.[2a]
H
H
O
R
On binding to their target domains PRMs adopt a left-handed
polyproline type II (PPII) helix secondary structure. Besides an
absence of hydrogen bonding, this type of helix exhibits a helical
H
H
N
O
N
H
HN
H
O
N
N
N
O
O
R
N
H
H
O
CO2H
HO2C
ProM-1 (R = H)
ProM-9 (R = Me)
ProM-13 (R = Et)
Cl
[a]
[b]
M. Sc. S. Chiha, Dr. A. Soicke, B. Sc. J. Bruns, Dr. J.-M. Neudörfl,
Prof. Dr. H.-G. Schmalz
Department of Chemistry, University of Cologne
Greinstrasse 4, 50939 Cologne (Germany)
E-mail: schmalz@uni-koeln.de
EVH1-binding ligands
Figure 1. Design of ProM-1 through the addition of a Z-vinylidene bridge to a
Pro-Pro unit and development of a low-molecular weight EVH1 inhibitor.
http://www.schmalz.uni-koeln.de
To further improve the binding properties of this ligand we
carefully analyzed its interaction with the protein surface. As
illustrated in Figure 2, the crystal structure (PDB code 4MY6)
suggested that the introduction of an additional small alkyl
substituent (R = Me or Et) at the specified position of the ProM-1
substructure (figure 1) should lead to an improved coverage of
M. Sc. M. Barone, Dr. R. Opitz, Dr. M. Müller, Dr. R. Kühne
Leibniz-Institut für Molekulare Pharmakologie (FMP)
Campus Berlin-Buch, Robert-Rössle-Str. 10
13125 Berlin (Germany)
E-mail: kuehne@fmp-berlin.de
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701584
European Journal of Organic Chemistry
FULL PAPER
the hydrophobic protein surface by addressing a lipophilic patch
established by solvent-accessible methionine 14 (M14, Fig. 2)
without sterically affecting proximate amino acid residues.
MgBr
[Al]
R
N
Boc
O
O
MeO
tBuO2C
8 ("cis")
R
R
N
N
Boc
Boc
N
Boc
tBuO2C
tBuO2C
tBuO2C
R
7
5
6
N
Boc
MgBr
[Cu]
tBuO2C
9 ("trans")
Scheme 2. Planned strategy for the synthesis of 4,5-disubstituted proline
derivatives 8 and 9, respectively.
However, we envisioned that the required “cis”-diastereo-
mers (8) could possibly be obtained under modified conditions,
for instance by reacting an in situ-formed N-acyl-iminium
intermediate with a vinyl aluminum reagent.
Protected pyroglutamates have been widely used as chiral
starting materials for the synthesis of substituted proline
derivatives, such as (-)-bulgecinine,[10] (-)-domoic acid,[11] or (-)-
kainic acid.[12] Traditionally, the functionalization at C-4 requires
the generation of the lactam enolate and subsequent reaction
with an electrophile. In most cases, diastereomeric mixtures of
4-substituted pyroglutamates were obtained in moderate
yields.[13-15] However, in certain cases the trans-isomers were
formed with high levels of diastereoselectivity.[14]
In the beginning of our study we deprotonated the pyro-
glutamate 5[2e] with lithium hexamethyldisilazide in THF at -78 °C
for one hour and subsequently reacted the resulting enolate with
different electrophiles (Table 1). In all cases, we obtained a
mixture of mono-substituted products cis-6 and trans-6 together
with minor amounts of the disubstituted product 10. The
formation of the latter could be diminished through the use of
one equivalent of TPPA[16] as a co-solvent. All products could
afterwards be separated through column chromatography and,
moreover, be crystalized. As Table 1 reveals, only low diastereo-
selectivities were generally observed in the alkylation of 5,
except for benzyl bromide which exclusively gave rise to the
trans-4-benzyl substituted product, as previously noticed by
Baldwin.[14] However, base-induced epimerization according to
Young[17] allowed to recycle the undesired cis-isomer. Thus,
refluxing a solution of cis-6 in THF in the presence of 1.1
equivalents of TBAF for 1.5 hours afforded a mixture of epimers
from which the (major) trans-isomer was separated off. This way,
the desired products of type trans-6 were obtained in acceptable
overall yields of typically 40 to 60 % (Table 1).
Figure 2. Cocrystal structure of ENAH EVH1 in complex with the ligand shown
in Fig. 1 (PDB code 4MY6). Solvent-accessible surface is color coded by
hydrophobicity (blue-white-red for hydrophilic-hydrophobic) revealing the
lipophilic patch extending from the main binding groove (Phe77 and Met14), to
be addressed by an additional small alkyl substituent R at the ProM-1 (green)
subunit.
Synthesis
To prepare the required tricyclic scaffolds of type 1 we
decided to follow our established synthetic strategy (Scheme 1)
which utilizes a peptide coupling of two vinyl-proline building
blocks 3 and 4 and subsequent Ru-catalyzed ring-closing
metathesis of the intermediate 2.[2]
R
R
H
H
R
HN
tBuO2C
+
CO2H
N
N
N
N
N
H
O
CO2H
O
CO2tBu
Fmoc
Boc
Boc
1
2
3
4
Scheme 1. Retrosynthetic strategy for the synthesis of compounds of type 1.
While a reliable protocol for the preparation of building block
3 had already been elaborated in our laboratory, [2d] the stereo-
selective synthesis of 4-alkyl-5-vinyl-substituted proline
derivatives of type 4 represented an interesting challenge. As
outlined in Scheme 2, we intended to start from the protected
pyroglutamate 5[2e] and to first introduce the substituent R by -
deprotonation/alkylation. After conversion of the alkylated
product 6 into the 5-methoxy-proline 7 the introduction of the
vinyl unit could be achieved with vinyl-MgBr in the presence of
different additives. In analogy to previous reports[2b] we expected
the “trans”-product (9) being preferentially formed in the
presence of a copper(I) salt.
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10.1002/ejoc.201701584
European Journal of Organic Chemistry
FULL PAPER
Table 2. Diastereoselective vinylation of 5-methoxy-prolines of type 7.
Table 1. -Alkylation of Boc-protected pyroglutamates.
MgBr
[M]
BF3.OEt2
R
R
R
R
i) LiHBEt3
ii) PPTS,
MeOH
MeO
BocN
i) LiHMDS,
TPPA, R-X
R
R
R
CO2tBu
O
CO2tBu
CO2tBu
+
+
O
5
O
trans-6
BocN
BocN
N
N
N
ii) chromatogr.
THF
85-95%
Boc
Boc
cis-6
Boc
tBuO2C
tBuO2C
tBuO2C
trans-6
chromatogr.
10
7
8 ("trans")
9 ("cis")
TBAF
cis/trans-6
Entry
R
Metal additive
Yield[a]
d.r. (8:9)[b]
Yield[a]
Yield[b]
(overall)
trans-6
[c]
1
2
3
4
5
6
H
H
AlCl3
70%
73%
63%
73%
66%
65%
50 : 50
4 : 96
93 : 7
10 : 90
92 : 8
7 : 93
Entry
R-X
trans-6
cis-6
10
[d]
CuBr·SMe2
1
2
3
4
5
6
7
CH3OTf
CH3CH2OTf
31%
32%
5%
6%
7%
3%
4%
9%
5%
47%
42%
59%
51%
-
[c]
Me
Me
Et
AlCl3
24%
34%
41%
47%
24%
19%
47%
35%
25%
-
[d]
CuBr·SMe2
CH2=CHCH2Br
CH2=CCH3CH2Br
C6H5CH2Br
c]
AlCl3
[d]
Et
CuBr·SMe2
[a] Isolated yield. [b] Diastereomeric ratio determined by 1H NMR. [c]
Conditions: Vinyl-MgBr (6.0 eq.), BF3·OEt2 (4.0 eq.), AlCl3 (2.2 eq.), -20 °C,
6 h. [d] Conditions: Vinyl-MgBr (6.0 eq.), BF3·OEt2 (4.0 eq.), CuBr·SMe2 (2.3
eq.), -20 °C, 6 h.
CH≡CCH2Br
CH3C≡CCH2Br
21%
18%
32%
29%
[a] Isolated yields after initial -alkylation of 5. [b] Overall yield of trans-6 after
one recycling step (epimerization of cis-6 and subsequent separation).
In the case of the Al-mediated vinylations it appears that the
observed diastereoselectivity results mainly from a repulsive
interaction of the in situ-generated vinyl Al organyl
(Al(vinyl)3)[21,22] with the substituent R (in the case of substrates
with R ≠ H).
By means of chiral stationary phase HPLC (using a racemic
sample as a control) we could ensure that no racemization (at C-
2) occurs under the base-mediated epimerization conditions.
According to the chosen strategy (Scheme 2) the synthesis
of ProM-9/13 proceeded with the selective reduction of both the
methyl- and the ethyl-substituted pyroglutamates of type trans-6
to the corresponding hemi-aminals by treatment with lithium
triethylborohydride at -78 °C.[18] The use of DIBAL-H at -78 °C
afforded lower yields.[2e] The conversion of the reduction
O
O
Boc
N
R
tBu
[Al]
[Al]
BocN
H
tBuO2C
R
R
BF3
I
8
BocN
7
MgBr
tBuO2C
products to the 5-methoxy-prolines of type
7 proceeded
[Cu]
O
O
Boc
N
R
11
tBu
[Cu]
smoothly upon dissolution in anhydrous methanol in the
presence of catalytic amounts of pyridinium tosylate (PPTS).
A key challenge of the present study was the stereoselective
introduction of the vinyl side-chain by substitution of the 5-
methoxy group in 7 using a vinyl Grignard reagent. As
summarized in Table 2 we indeed succeeded to prepare either
the cis- (8) or the trans-isomers (9) in dependence on the
reaction conditions.
In all cases, the reactions were performed in the presence of
an excess (4.0 equiv.) of BF3·OEt2 to ensure the in situ formation
of an acyl-iminium cation intermediate (11). Using AlCl3 as an
additive the substituted substrates (R = Me, Et) afforded the “cis”
products of type 8 with very good diastereoselectivity (≥ 92:8)
while a 1:1 mixture of diastereomers was obtained with the
“unsubstituted” substrate (R = H). In contrast, the use of
CuBr·SMe2 as an additive delivered the “trans” products of type
8 as the main products with even higher diastereoselectivity in
all three cases. The latter result is in accordance to literature
reports,[19] where the stereoselectivity had been explained by
assuming an intermediate Cu-carbonyl-iminium chelate which
effectively shields the “upper” face during the attack of the vinyl
cuprate nucleophile to give the “trans”-product 9 (Scheme 3).[20]
BocN
H
[Cu]
R
tBuO2C
II
9
Scheme 3. Divergent diastereoselectivity in the Al- and the Cu-mediated
vinylation of 5-methoxy-prolines of type 7.
To prepare for the peptide coupling, the selective mono-
deprotection[23] of 8 (cleavage of the N-Boc group) was achieved
through treatment with TMSOTf in CH2Cl2. After chromate-
graphic purification the desired building blocks of type 4 were
obtained in pure form. In the case of 4 (R = Me) the relative
configuration was unambiguously confirmed by X-ray crystal
structure analysis of its hydrochloride salt (cf. supporting
information).
The synthesis of the novel scaffolds ProM-9 (R = Me) and
ProM-13 (R = Et) was then performed as shown in Scheme 4 in
analogy to the synthesis of ProM-1 (R = H).[2d] Employing the
known 3-vinylproline 3 as an acid building block the peptide
coupling with amines of type 4 proceeded smoothly under the
established conditions (PyBOP, DIPEA)[2d] to afford the desired
coupling products 2a-c.
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10.1002/ejoc.201701584
European Journal of Organic Chemistry
FULL PAPER
R
R
R
H
H
H
H
a
b
c
3 + 4
N
N
N
N
N
N
H
H
O
CO2tBu
O
CO2tBu
O
CO2H
Boc
Boc
Fmoc
a: R = H
b: R = Me
c: R = Et
2a (87%)
2b (87%)
2c (82%)
12a (82%)
12b (82%)
12c (88%)
1a (97%)
1b (92%)
1c (93%)
Scheme 4. a) PyBOP, DIPEA, MeCN, 16 h; b) Grubbs II cat. (6 mol%), CuI (9
mol%), Et2O, reflux, 6 h; c) TFA/CH2Cl2, 1:1, 1 h; then Fmoc-Cl, NaHCO3,
H2O/THF, 15 h.
Initially, the subsequent ring-closing metathesis step was
carried out according to our previous study in the presence of 10
mol% of the Grubbs II catalyst in CH2Cl2 to afford the cyclized
products of type 12 in moderate yield (60-70%). However, we
were able to improve the metathesis step by performing the
reaction in Et2O in the presence of 6 mol% of Grubbs II catalyst
and 9 mol% of CuI according to a protocol reported by Lipshutz
et al.[24] Exploiting this “CuI effect” the metathesis yields went up
to 82-88%. Global deprotection (TFA in CH2Cl2) and subsequent
Fmoc (re-) protection of the amine under previously reported
conditions[2d] finally delivered the novel scaffolds Fmoc-ProM-9
(1b) and Fmoc-ProM-13 (1c) in high overall yield. The
configuration of ProM-9 was confirmed by X-ray single crystal
structure analysis (Figure 3) at the stage of 12b. The molecular
structure illustrates the expected tendency of this compound to
adopt an almost perfect PPII-type conformation.
Figure 4. Structure of the tricyclic compound 14 in the crystalline state.[25]
Conclusions
Taking the rational designed scaffolds ProM-9 and ProM-13 as
target molecules we have elaborated a useful methodology for
the preparation of 4-substituted 5-vinylproline derivatives of type
8 and 9, respectively. Furthermore, we could demonstrate that
building blocks of type 4 (derived from 8) can be efficiently
employed in the synthesis of the tricyclic target structures
through (1) peptide coupling, (2) Ru-catalyzed ring-closing
metathesis and (3) protecting group adjustment. X-ray crystal
structure analysis confirmed the expected geometry of the new
scaffolds. These will be used in future studies as modules for the
development of PPII helix secondary structure mimetics, for
instance as inhibitors of protein-protein interactions involving the
Ena/VASP EVH1 domain.
Acknowledgements
The authors thank the Deutsche Forschungsgemeinschaft (DFG
FOR 806), the Schering Stiftung (fellowship to A. S.) and the
German Federal Ministry of Education and Research (VIP-0351)
for financial support. Valuable gifts of chemicals from EVONIK
and BASF SE are gratefully acknowledged. We also thank
Andreas Adler for support in HPLC analyses.
Figure 3. Structure of the tricyclic compound 12b (Boc-ProM-9-OtBu) in the
crystalline state.
Unable to crystalize the ProM-13-derived compound 12c we
managed to obtain a crystal structure of compound 14 (Figure 4),
which is a diastereomer of 12c prepared through peptide
coupling of the “cis”-amine 4c with the enantiomeric building
block ent-3 and subsequent ring closing metathesis (Scheme 5).
Keywords: amino acids
•
protein-protein interactions
•
peptidomimetics • ring-closing metathesis.
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10.1002/ejoc.201701584
European Journal of Organic Chemistry
FULL PAPER
Secondary Structure Mimetics
R
H
R
H
O
HN
HN
N
N
H
t
O
CO2H
CO2H
CO2 Bu
H
R = Me: ProM-9
R = Et: ProM-13
Starting from pyroglutamic acid, 4-substituted-5-vinylprolines were stereoselectively prepared and used as building blocks for the
synthesis of conformationally well-defined diproline analogs, which are of interest as proline-derived modules (ProMs) for the
construction of PPII-helix secondary structure mimetics acting as inhibitors of relevant protein-protein interactions.
This article is protected by copyright. All rights reserved.