(Z), Not (E) – An End to a Century of Confusion about the Double-Bond Stereoisomers of 3-Amino-2-cyanoacrylates

Article abstract of DOI:10.1002/ejoc.201701235

Potent and selective myosin inhibitors are of vast scientific interest in the development of treatments for diseases involving myosin dysfunction or overactivity. A novel fungicide, ethyl 2-cyano-3-amino-3-phenylacrylate (commercialized as “phenamacril”), was recently identified as an inhibitor of myosin-5 in F. graminearum. Although the compound has been known since 1900, a general confusion concerning the stereochemical configuration at the exocyclic double bond persists in the literature, thus restricting further drug development of this compound and derivatives. By using NMR and quantum mechanical calculations, this work establishes the stereoconfiguration as the (Z) form and that the effect of a single hydrogen bond is crucial in keeping these types of molecules in a single configuration.

Full text of DOI:10.1002/ejoc.201701235

A Journal of
Accepted Article
Title: (Z), not (E) - a century of confusion about the double bond
stereoisomers of 3-amino-2-cyano acrylates
Authors: Søren Sejer Donau, Matthias Bechmann, Norbert Müller,
Thorbjørn Terndrup Nielsen, and Reinhard Wimmer
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701235
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701235
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10.1002/ejoc.201701235
European Journal of Organic Chemistry
COMMUNICATION
(Z), not (E) – an end to a century of confusion about the double
bond stereoisomers of 3-amino-2-cyano acrylates
Søren S. Donau, Matthias Bechmann, Norbert Müller, Thorbjørn T. Nielsen, Reinhard Wimmer*
Abstract: Potent and selective myosin inhibitors are of vast scientific
interest in the development of treatments for diseases involving
myosin dysfunction or overactivity. A novel fungicide, Ethyl 2-cyano-
3-amino-3-phenylacrylate (commercialized as “Phenamacril”), was
recently identified as an inhibitor of myosin-5 in F. graminearum.
Although the compound has been known since 1900, a general
confusion concerning the stereochemical configuration at the
exocyclic double bond persists in the literature, thus restricting
further drug development of this compound and derivatives. Using
NMR and quantum mechanical calculations, this work establishes
the stereoconfiguration as always being the (Z)-form and that the
effect of a single hydrogen bond is crucial in keeping these types of
molecules in a single configuration.
sketched the molecular structure.[5,23,24,29] Additionally, to the
best of our knowledge, none of the peer-reviewed fungal activity
related papers include the double bond configuration in the
IUPAC-name of the compound, nor do they provide any data
upon the double bond configuration of the active fungicide.
Judging from the existing drawings of the molecular structure
represented in fungi related literature there is
a
vast
overrepresentation of the (E)-configuration[5,23,24,29] (1b, Scheme
1), seemingly making the (E)-isomer the most widely accepted
stereoisomer of Phenamacril.
Introduction
Ethyl 2-cyano-3-amino-3-phenylacrylate has been known since
1900,[1–3] but it was not until the end 1990´s that the antifungal
properties of this compound were recognized and patented
under the develop-code JS399-19.[4,5] Since 2004 several
scientific papers have dealt with the anti-fungal properties of the
compound[4–30] and recently the compound has been
commercialized as
a
fungicide under the trade name
Phenamacril. In 2015 myosin-5 was identified as a target protein
of Phenamacril.[23] Myosin inhibitors have a vast medical
potential[31] and have been investigated as therapeutical drugs
for cancer.[31,32] Obviously, knowledge of the correct structure is
a
prerequisite for any potential drug development and
pharmacophore modeling.
Although the compound has been known for almost a century
prior to the discovery of its antifungal and myosin inhibiting
properties, vagueness and general discrepancy regarding the
double bond configuration appears in the published literature
(see ESI† S2 - S4 for a complete overview of the structures and
naming of the compound found in peer-reviewed articles,
patents and websites). Excluding non-peer reviewed literature,
only few of the fungicide-related studies of Phenamacril have
Scheme 1. Structures mentioned in the text: Phenamacril is shown both in its
Z (1a) and E (1b) form. The same goes for N,N-dimethyl Phenamacril (2a and
2b). All compounds except 1b were produced synthetically. Structure
verification, NMR spectra and their assignments are given in the ESI S8 – S19.
Other 3-amino cyanoacrylates with various degrees of structural
similarity to Phenamacril have been investigated for their anti-
tumor,[33] antivirus[34] and herbicide[35–40] activities. In these
studies using X-ray single crystal diffraction (XRD) to investigate
the configuration of the compounds one commonly finds the
predominance of the isomer where the amine and the ester
moiety are positioned cis,[33,36–40] with only two exceptions for
compounds containing a large and bulky N-substituent.[34,35]
From the XRD experiments an intramolecular hydrogen bond
between the amino and the ester moiety was also derived and
its formation was thought to be the main reason for the
predominance of the specific stereoconfiguration.[33,36,37]
[*]
S. S. Donau, Dr. T. T. Nielsen, Prof. R. Wimmer
Department of Chemistry and Bioscience
Aalborg University
Frederik Bajers Vej 7H, 9220 Aalborg Ø, Denmark
E-mail: rw@bio.aau.dk
http://www.en.bio.aau.dk/research/biotechnology/nmr-spectroscopy/
Dr. M. Bechmann, Prof. N. Müller
Institute of Organic Chemistry
Johannes Kepler University Linz
Altenbergerstr 69, 4040 Linz, Austria
Prof. N Müller
Faculty of Science
University of South Bohemia
Branišovská 31, 370 05 České Budějovice, Czech Republic
The structures found in the above-mentioned studies differ from
the otherwise sketched (E)-isomer in the studies of Phenamacril
and the most complete information on the structure of
†
Electronic Supporting Information (ESI) for this article (overview of
published Phenamacril structures, experimental methods, NMR and
MS data and DFT-calculations) is given via a link at the end of the
document.
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European Journal of Organic Chemistry
COMMUNICATION
Phenamacril, is found in non-fungicide related literature.[41–43]
Studies of Phenamacril[42] and the closely related methyl ester
derivative,[41] revealed that the stereochemical configuration of
these compounds were independent of the configuration of the
starting materials as only a single stereoisomer was observed
for the product.[41,42]
Albeit not being completely conclusive, Morel and co-workers
deduce the compound to be in the (Z)-configuration, as the IR-
and NMR-data exhibited hydrogen bonding of the amino proton
ascribed to the ester moiety. However, the line of argumentation
for the hydrogen bond of the amino proton connecting to the
ester and not the nitrile, was not clearly described.[41] Similarly,
Jalander and Lönnqvist,[42] reported the stereochemical
configuration to be Z (1a). However, this conclusion was based
on a weak evidence, the absence of an NOE between the ethyl-
and the phenyl- hydrogen atoms in 2D 1H NOESY. While the
findings of Jalander and Lönnqvist do point towards the Z-
isomer, which would fit to the studies of other 3-amino
cyanoacrylates, a complete verification of the structure has still
Figure 1. 1H-spectra of (i) 1a, (ii) 6 and (iii) a mixture of 2a, 2b. Ethyl group
resonances of Phenamacril and the solvent peak are marked by vertical
dashed lines through the spectra.
not been provided.
A
more recent study from 2014,[43]
synthesized compound 1a as a precursor for a N-chloroimine
compound and, while the (Z)-configuration is given in both the
molecular drawing and the IUPAC name, the paper only
includes 1H-NMR data and does not touch upon how the
configuration was derived.
present without dynamic interconversion, as one would expect
these to exhibit signals at different chemical shifts for several of
the hydrogens and carbons.
The 1H-NMR spectrum for Phenamacril shows two distinct broad
signals at 9.41 ppm and 5.75 ppm (in CDCl3). These signals
were unambiguously assigned to the amino protons. Changing
the solvent from CDCl3 to DMSO-d6, one observes a significant
(5.75 to 8.91 ppm) deshielding of one amino proton, but not the
other one(9.41 to 9.23 ppm).
For a range of compounds containing enamine moieties,
interconversion between diastereomeric forms has been shown
to take place in liquid state or solution under different
conditions.[44–49] For these compounds, the ability to rotate
around the partial double bond depends on the substituents of
the amine[44] and the alkene.[47] A correlation between the ability
to form intramolecular hydrogen bonds and the predominance of
one isomer has been observed in several studies.[44–46]
Introducing further complexity, some compounds even
crystallize in only one isomeric form, while an equilibrium
between the isomeric forms exists in liquid state or solution,[44]
excluding solid state methods as a means to determine the
stereochemistry of aminocyanoacrylates in solution.
Deshielding indicates formation of intermolecular hydrogen
1
bonds with the solvent. Additionally, data from several H-NMR
spectra recorded at different concentrations of Phenamacril in
CDCl3, showed no significant changes in the chemical shifts of
the amino protons (data not shown). Altogether, these
observations consistently indicate that the high chemical shift of
one amino-H signal of Phenamacril is a result of a strong
intramolecular hydrogen bond formed between this amino-H and
either the nitrile or the ester H-bond acceptor moiety. Comparing
the 1H-NMR spectra of Phenamacril to those of 5 (ESI S16), the
nitrile group does not seem to be capable of causing a high-
frequency shift of the same magnitude as observed in
Phenamacril (chemical shift of the amino protons of 5 in CDCl3:
5.56 and 6.27 ppm), whereas the chemical shifts of the lower-
frequency amino proton of 3 (chemical shift of the amino protons
of 3 in CDCl3: 5.10 and 8.98 ppm (ESI S12)), exhibit a higher
similarity to the chemical shifts of the amino protons of
Phenamacril, indicating that the ester moiety in Phenamacril is
Results and Discussion
1
The 1D H- and 13C-spectra of Phenamacril (Figure 1 (i)) show
only one set of signals suggesting that either (i) only one
isomeric form is present, or (ii) fast interconversion between the
two isomeric forms occurs under the experimental conditions,
hence the measured NMR-signals are averaged between the
two isomers. It is highly unlikely that both isomers should be
13
Figure 2. 13C-2D-J-resolved NMR spectra of the C7 resonance of
C
-
15N5-Phenamacril in CDCl3 with 1H broadband decoupling without (panel A) and with
1,2,4
selective decoupling of C2 (73 ppm, panel B), C4 (118.4 ppm, panel C) and C1 (168.3 ppm, panel D) during the evolution time.
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10.1002/ejoc.201701235
European Journal of Organic Chemistry
COMMUNICATION
positioned cis to the amine, hence suggesting the (Z)-
configuration. Our DFT calculations corroborate the (Z)-
configuration as it leads to the lowest energies after geometry
optimization (ESI S22). Moreover, the (Z)-configuration also
yields the best agreement between experimental and calculated
chemical shieldings. (ESI S23 – S29).
formation of both the (E)- and (Z)-isomer[41] and likewise
observed by Jalander and Lönnqvist, who explained the
phenomenon by restricted rotation.[42]
The 1H-NMR spectrum of 2 (Figure 1 (iii)) clearly shows two sets
of signals for the aromatic and ethyl group resonances and four
sets of signals (with different line broadening at room
temperature, but not at 240 K) for the N6-methyls, indicative of
two intramolecular exchange processes going on; one of them
being a rotation around the C3-N6 partial double bond. The
other process could be a rotation around the C2-C3 or C1-C2
bond, both being represented as double bonds in some
mesomeric forms and as single bonds in others. To find out,
about which bond the rotation occurs, compounds 3 and 4 were
synthesized (Scheme 1) and their 1H and 13C-NMR spectra
compared. The methylations caused the two sets of ethyl-ester
signals observed in 3 to collapse to a single set of signals in 4,
hence appearing “chemically equivalent”, albeit broadened (ESI
S12 – S15). For these ethyl-ester signals to coalesce, the
rotation must take place around the C2-C3 bond. We therefore
deduced that the second chemical exchange process, which
To determine the diastereomeric configuration of Phenamacril in
solution once and for all, the vicinal J(C,C) couplings between
3
C7 and C1 and C4, respectively (numbering shown in Scheme
1) were exploited. The use of 3J(C,H) coupling constants to
distinguish (E)- and (Z)-geometries is not unusual.[50,51] However,
the use of 13C-13C couplings is much less common, due to the
low natural abundance of 13C.[52] Vicinal coupling constants (3J)
depend on the dihedral angle between the coupling partners
around the central bond in a manner described by the Karplus
equation.[53] This is also the case for substituents of a C=C
double bond, where 3J(C,C) generally is smaller for cis couplings
(θ=0°) than trans couplings (θ=180°) as e.g. shown for 3,3-
dimethylacrylic and cinnamic acids,[52] compounds sharing some
structural similarity with Phenamacril. For the Z-configuration of
Phenamacril (1a), we therefore expect 3J(C7,C1) > 3J(C7,C4)
and the opposite for the E-configuration (1b).
1
causes the splitting of the H- and 13C-signals in the spectra (2)
also takes place around the C2-C3 bond.
To obtain experimental values for these coupling constants, a
selectively 1,2,4-13C,5-15N-labelled isotopomer of 2-cyano-3-
amino-3-phenylacrylate was synthesized from ethyl cyano-13C,
15N-acetate-1,2-13C2, from which we determined the 3JCC of C7 to
C4 and C1 (Figure 2) through a series of selectively 13C
decoupled 13C-13C J-resolved NMR experiments.
C7 displayed the expected coupling pattern of ddd (doublet of
doublet of doublet). In order to assign the three observed
couplings to the respective coupling partners (C1, C2 and C4;
other C are at natural isotope abundance of 98.9% 12C and can
thus be ignored), we repeated the experiment with selective
decoupling of each coupling partner during evolution. The
experimentally determined coupling constant from C7 to the
carbonyl C1 is 4.5 Hz, larger than the coupling constant to the
nitrile C4 which is 1.9 Hz.
To confirm the coupling constant argument used in the structure
elucidation DFT-calculations were performed (ESI S29). These
computations of the vicinal coupling constants for both (E)- and
(Z)-2-cyano-3-amino-3-phenylacrylate showed that in all cases
3J(C7,C)cis was significantly lower than 3J(C7,C)trans. For the
geometry-optimized structure of (Z)-Phenamacril, calculated
coupling constants coincided within ±0.1 Hz with the
experimental values. Thus, we conclude that the ester
functionality is positioned opposite (trans) to the phenyl ring and
the compound therefore assumes the (Z)-configuration (1a) in
solution. Two different (Z)-configurations were considered, with
the H-bond acceptor alternatively being the carbonyl or ester
oxygen atom. The form with the carbonyl oxygen atom as H-
bond acceptor (referred to as Z2) turns out to yield better
matches for both the coupling constants and the calculated
chemical shifts and is also the configuration with the lowest force
field energy. To assess the importance of the intramolecular
hydrogen bond for the structure of Phenamacril, N6-mono- and
Exchange rates between the (Z) and (E) forms were investigated
by Saturation Transfer NMR experiments. The signal intensities
obtained in the saturation transfer experiment were converted to
chemical exchange rates as described earlier.[54] Exchange rates
determined at different temperature (ESI S20) yielded a molar
activation enthalpy for the rotation around the C2-C3 bond of
ΔHa = 53.9 ± 0.2 kJ mol-1.
In previous studies of bioactive 3-amino-2-cyanoacrylates the
appearance of only one diastereomeric configuration during the
synthesis of the compound was assumed to be owed to the
reaction mechanism, where the nucleophilic amine moiety is
being “guided” towards the substrate by hydrogen bond
formation, thus resulting in the amine and ester moieties being
positioned cis to each other.[33,35,39,40] However, our findings
rather indicate that the predominance of one isomeric
configuration is not a result of the reaction mechanism, but
rather reflects thermodynamic stability. There is considerable
rotational freedom around the C2-C3 partial double bond, and, if
one configuration is energetically favored (e.g. because of
hydrogen-bond formation), the equilibrium will be shifted towards
that conformation, regardless of the initially formed diastereomer.
Conclusion
In summary, using homonuclear 13C-13C J-resolved NMR and
DFT-calculations of vicinal coupling constants, the correct
stereochemical configuration of Phenamacril was finally
determined as the (Z)-isomer and not the previously most often
sketched (E)-isomer. Furthermore, this study showed the
importance of the intramolecular hydrogen bonds in relation to
the structures and dynamic properties of Phenamacril and its
derivatives.
N6,N6-dimethylated
derivatives
of
Phenamacril
were
The findings are of huge interest to researchers in the field of
fungicides in particular, as well as for research involving
applications relaying on myosin inhibition, like the investigation
of myosin inhibitors as anti-cancer drugs. The validity of results
obtained from virtual screening/docking simulations of
cyanoacrylates and myosin relies heavily on the knowledge of
the stereochemically correct molecular structure of the small
molecule ligands.
synthesized. While the 1H and 13C-NMR spectra of the N6-
mono-methylated derivative (6) do not differ much from the
Phenamacril spectra, the N6,N6-dimethyl derivative (2b) shows
a complete set of extra signals in both the 13C (ESI S10 – S11)
and 1H-NMR spectra (Figure 1).
For N,N-dialkylated derivates, similar signal splitting was
reported by Morel and co.-workers who ascribed it to the
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Acknowledgements
This work was supported by the Independent Research Fund
Denmark|Technology and Production Sciences (grant no 4005-
00204B). The NMR laboratory at Aalborg University is supported
by the Obel, SparNord and Carlsberg foundations. We thank
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Entry for the Table of Contents
COMMUNICATION
More than a century after the
discovery of 3-amino-2-cyano-
acrylates, their correct
Stereochemistry of 3-Amino-2-
cyanoacrylates
Søren S. Donau, Matthias Bechmann,
Norbert Müller, Thorbjørn T. Nielsen and
Reinhard Wimmer*
stereochemistry is finally proven.
Page No. – Page No.
(Z), not (E) – an end to a century of
confusion about the double bond
stereoisomers of 3-amino-2-cyano
acrylates
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