Direct Access to Highly Enantioenriched α-Branched Acrylonitriles through a One-Pot Sequential Asymmetric Michael Addition/Retro-Dieckmann/Retro-Michael Fragmentation Cascade

Article abstract of DOI:10.1021/acs.orglett.0c02079

A highly enantioselective synthesis of α-branched acrylonitriles is reported featuring a one-pot sequential asymmetric Michael addition/retro-Dieckmann/retro-Michael fragmentation cascade. The method, which relies on a solid, bench-stable, and commercially available acrylonitrile surrogate, is practical, scalable, and highly versatile and provides a direct access to a wide range of enantioenriched nitrile-containing building blocks. Most importantly, the method offers a new tool to incorporate an acrylonitrile moiety in an asymmetric fashion.

Full text of DOI:10.1021/acs.orglett.0c02079

pubs.acs.org/OrgLett
Letter
Direct Access to Highly Enantioenriched α‑Branched Acrylonitriles
through a One-Pot Sequential Asymmetric Michael Addition/Retro-
Dieckmann/Retro-Michael Fragmentation Cascade
Nicolas Duchemin, Martin Cattoen, Oscar Gayraud, Silvia Anselmi, Bilal Siddiq, Roberto Buccafusca,
Marc Daumas, Vincent Ferey, Michael Smietana, and Stellios Arseniyadis*
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ABSTRACT: A highly enantioselective synthesis of α-branched acrylonitriles is reported featuring a one-pot sequential asymmetric
Michael addition/retro-Dieckmann/retro-Michael fragmentation cascade. The method, which relies on a solid, bench-stable, and
commercially available acrylonitrile surrogate, is practical, scalable, and highly versatile and provides a direct access to a wide range of
enantioenriched nitrile-containing building blocks. Most importantly, the method offers a new tool to incorporate an acrylonitrile
moiety in an asymmetric fashion.
hazardous acrylonitrile15 in excess. As such, the development
crylonitrile-containing compounds are particularly attrac-
1
Ative for the pharmaceutical and agrochemical industries. of a general method for the asymmetric synthesis of α-
branched chiral acrylonitriles remains an important unad-
dressed synthetic challenge. To this end, we envisioned a
catalytic enantioselective alternative to the Rauhut−Currier
reaction (Figure 1, B)16,17 using 4-cyano-3-oxotetrahydrothio-
phene (c-THT) as an acrylonitrile surrogate in a one-pot, two-
step sequence featuring an asymmetric Michael addition18 and
a retro-Dieckmann/retro-Michael fragmentation (Figure 1, C).
Although the use of c-THT as an acrylonitrile surrogate has
already been reported in the past,19,20 this is the first time it has
been used in the context of asymmetric catalysis. Moreover,
not only does this strategy allows the introduction of an
acrylonitrile moiety in an asymmetric and unbiased fashion
using an easy to handle, bench-stable, and commercially
available acrylonitrile surrogate, it also provides the first
Indeed, these bis-electrophiles are true launching pads toward
numerous valuable synthons, with the cyano group being a
precursor of amines, alcohols, aldehydes, and carboxylic acids,2
while the polarized alkene offers a plethora of possibilities, such
as 1,4-additions,3 cross-metatheses,4 as well as controlled
radical polymerizations.5 The acrylonitrile moiety can also be
found in a number of biologically active natural products and
other metabolites such as cyanopuupehenone6 and borrelidin.7
Several methods allowing a direct access to this class of
compounds have been reported over the years. The direct
C−H functionalization of alkenes developed independently by
Engle and Cravatt8 and by Studer9 has emerged as a promising
strategy. Alternatively, the hydrocyanation of alkyne precursors
reported by Ritter10 and later by Nakao and Hiyama,11 along
with the α,β-dehydrogenation of activated alkylnitriles,12
represent valuable approaches. Regrettably, however, none of
these strategies have been applied to the synthesis of
enantioenriched α-substituted acrylonitriles. This was even-
tually achieved using an enantioselective Morita−Baylis−
Hillman reaction (Figure 1, A); however, this strategy is
limited to sulfonyl imines13,14 and requires the use of
Received: June 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02079
© XXXX American Chemical Society
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A

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a
Table 1. Systematic Study
b
c
yield
ee
entry ligand
solvent
variations
time
1 h
1 h + 30 s
12 h
12 h
1 h
30 min
30 min
12 h
12 h
12 h
(%)
(%)
d
e
1
L1
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
Toluene
THF
EtOAc
Me-THF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
91
61
49
4
82
83
0
2
3
4
5
8
56
68
62
40
49
59
54
43
60
59
65
60
68
60
38
95
64
37
54
91
87
88
91
94
94
95
95
95
6
7
8
9
10
11
12
13
14
15
16
17
18
2 h
12 h
10 min
12 h
30 °C
1 mol %
2 mmol scale 30 min
f
Figure 1. Development of a catalytic one-pot enantioselective Michael
addition/retro-Dieckmann/retro-Michael fragmentation cascade for
the synthesis of α-substituted acrylonitriles. (A) Asymmetric Baylis−
Hillman of N-sulfonyl imines. (B) Enantioselective cross Rauhut−
Currier reaction. (C) Generalized depiction of the proposed method.
H2O
30 min
30 min
30 min
f
EtOH
g
“open air”
example of an enantioselective Rauhut−Currier-type reaction
applied to an acrylonitrile-containing substrate.21
We decided to develop our method around α,β-unsaturated
2-acylimidazoles for their propensity to form strong chelates
with various metals and for their versatility.22 We also chose to
work with scandium triflate for its robustness, practicality, and
unique Lewis acid properties.23−25 To our delight, our first
experiment using chiral PyBOX ligand L1 (Table 1, entry 1) in
CHCl3 showed that the Michael addition proceeded smoothly
at 0 °C to form the corresponding Michael adduct in an
excellent 91% yield. Most importantly, this first attempt led to
an encouraging 82% ee, which prompted us to pursue the
optimization.
As we immediately opted to conduct the cascade in a one-
pot fashion, we kept these initial conditions and turned our
attention to the retro-Dieckmann fragmentation. In the
original work by Baraldi and co-workers,19 treatment with
NaOH in a Et2O/THF mixture triggered the release of the
thioglycolate and the concomitant formation of the corre-
sponding acrylonitrile derivative. Unfortunately, these con-
ditions led to a disappointing 33% yield and a slight erosion of
the enantioselectivity (see Table S1, entry 2). In contrast, the
use of tetrabutylammonium hydroxide (TBAH) promoted the
retro-Dieckmann/retro-Michael fragmentation occurred quasi
instantaneously, affording the desired alkenyl nitrile 3a in 61%
yield and no erosion of the selectivity (Table 1, entry 2). The
rapidity of the fragmentation under these conditions thus
prompted us to continue with TBAH.
a
All reactions were run on a 0.2 mmol scale unless specified.
b
Determined by 1H NMR on the crude reaction mixture using
CH2Br2 as an internal standard. Determined by chiral HPLC. Run
w/o TBAH. Determined on the Michael adduct. Reaction run with
1 equiv of additive. Reaction run in an open air flask and with 1 equiv
of H2O and 1 equiv of EtOH. [TBAH = tetrabutylammonium
hydroxide].
c
d
e
f
g
led to an improved albeit still low 38% ee (Table 1, entry 5).
Interestingly, the use of L526 not only drastically improved the
yield and the enantioselectivity (68% yield, 95% ee), it also
considerably reduced the reaction time (Table 1, entry 6). It is
worth noting that we also investigated various other catalytic
systems, including copper- and indium-based catalysts, but
they generally resulted in lower selectivities (see Table S1 and
substrate scope obtained with the Cu-based system in the
Supporting Information). Interestingly, the use of indium
triflate in combination with L5 led to an inversion of the
selectivity.27 Solvent optimization showed relatively mixed
results (Table 1, entries 6−12), but confirmed the superiority
of CHCl3 (Table 1, entry 6) over the other solvents, including
THF (Table 1, entry 10) which was ruled out due to slow
conversions and lower overall yields. As far as sustainability is
concerned, the reaction could be run in technical grade ethyl
acetate or Me-THF, both considered as green solvents,28 with
a negligible erosion of the selectivity; the resulting acrylonitrile
3a was obtained in 87 and 88% ee respectively (Table 1,
entries 11 and 12). Similarly, the reaction showed a good
temperature tolerance and did not require cryogenic
conditions to reach high levels of enantioselectivity (Table 1,
entry 13). Keeping in mind the possible implementation of the
We next evaluated the influence of the ligand and started by
varying its denticity. PyrOX-L2 (49% yield, 0% ee) and
BipyBOX-L3 (4% yield, 8% ee) performed poorly, affording 3a
in low yields and low selectivities (Table 1, entries 3 and 4).
This result was, however, not surprising considering the
preferred coordination of scandium for tridentate ligands. We
therefore backtracked to the initial PyBOX core with L4, which
B
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a
Scheme 1. Reaction Scope
a
Conditions: Compounds 1a−x (0.27 mmol), c-THT 2 (0.3 mmol), Sc(OTf)3 (10 mol %), (S,R,R,S)-L5 (11 mol %), TBAH (1 M in MeOH, 0.32
mmol) upon completion of the Michael addition, 0.1 M in CHCl3, 0 °C.
method to large-scale processes, we ran two reactions in
parallel; one on a 0.4 mmol scale using a 10-fold decrease in
catalyst loading and one on a 2 mmol scale using the same
catalyst loading as previously. Both reactions proceeded
smoothly, affording the desired product in roughly 60% yield
and 94% ee (Table 1, entries 14 and 15). We also tested the
robustness of the process by conducting the reaction in the
presence of H2O and/or EtOH in open-air and observed no
noticeable loss in either reactivity or selectivity (Table 1,
entries 16 and 18).
This optimization study shed some light on several aspects
of this reaction sequence. Indeed, although we always observed
complete conversion of the starting material to the
corresponding Michael adduct, the presence of a non-
negligible amount of the α,β-unsaturated 2-acylimidazole
precursor at the end of the process revealed a competition
between the actual retro-Dieckmann fragmentation that leads
to the desired product and a retro-Michael addition that
regenerates the starting material. This side reaction is likely to
arise from the abstraction by TBAH of one of the two protons
adjacent to the carbonyl moiety, whose acidity is exalted by the
presence of the Sc-complex in the reaction mixture. The
transient enolate then naturally expels the THT ring to
regenerate the starting enone 1a through a E1CB-type
elimination. This side reaction could, however, be prevented
by purifying the reaction mixture prior to adding TBAH,
though, for practical purposes, we decided to proceed with the
evaluation of the substrate scope using our one-pot procedure.
It is worth mentioning that all of our attempts to conduct this
reaction using acrylonitrile instead of c-THT were unsuccessful
(see Table S1, entries 27−29).
We initiated the scope assessment with the exploration of
various substrates bearing an aliphatic chain at the β-position
of the enone (Scheme 1). Interestingly, under the optimized
conditions, the desired alkenyl nitriles 3b−f were obtained in
moderate to good yields and excellent enantioselectivities with
ee’s ranging from 93 to 96%. Similarly, substrates bearing
diversely functionalized side chains led to equally high
selectivities. Notably, the presence of an alkene, an alkyne, or
an oxygen-containing moiety did not decrease the selectivity
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Scheme 2. Post-functionalizations
(3g−j). Substrates decorated with an indole (88% ee, 3k) or a
trifluoromethyl (92% ee, 3l) were also obtained with good to
excellent ee’s albeit at lower yields. The selectivity obtained
with the substrate bearing a trifluoromethyl group was
particularly encouraging as it proved that the reaction also
tolerates strong electron-withdrawing groups. We concluded
the scope of the alkyl substituents by screening different
tertiary carbons (3m−3q). Interestingly, the selectivity
decreased quite significantly with ee’s ranging from 68 to
84%. The presence of the tertiary carbon adjacent to the
unsaturation appears to hamper the selectivity as well as the
reactivity as showcased by the longer reaction times.
Following these results, we also evaluated a series of β-aryl-
substituted derivatives and rapidly realized that the presence of
the aromatic group slightly decreased the overall selectivity of
the process as demonstrated by the ee’s obtained with the
phenyl (3r, 80% ee), the biphenyl (3s, 81% ee), and the
naphthyl (3t, 85% ee) derivatives. A similar trend was also
observed with substituted aromatic rings independently of the
nature or the position of the substituent. Hence, a variety of
functional groups including the more electron-withdrawing
halides (3u−y, 70−77% ee), trifluoromethyl (3z, 76% ee),
nitro (3aa, 76% ee), or ester (3ab, 81% ee) and the more
electron-donating ether (3ac, 77% ee) were shown to be
compatible. We eventually pushed the investigation further
with the introduction of heterocycles. Unfortunately, the
presence of a furan ring negatively impacted the enantiose-
lectivity as a clear drop to 42% ee was observed possibly due a
potential alternative coordination of the substrate with the
catalyst.29 This effect was logically attenuated with the
thiophene (3ae, 65% ee). The reaction conditions were
applied to a diene derivative. After slightly adjusting the
reaction conditions (1 equiv of TBAH) to prevent any
racemization or isomerization upon TBAH addition, we were
able to isolate the corresponding acrylonitrile derivative 3af in
50% yield and 84% ee.
Finally, to demonstrate the synthetic utility of the resulting
enantioenriched α-substituted acrylonitriles, several diversifi-
cations were performed (Scheme 2). First, the acylimidazoyl
moiety in 3a was converted to the corresponding ester 4 and
amide 5 using standard conditions (MeOTf, CH2Cl2, 0 °C,
then MeOH or morpholine, DBU, rt).26 Both products were
obtained in good yields and with no erosion of the ee. We also
showed that compounds such as 3a could be readily α-
alkylated under mild phase-transfer catalysis conditions (BnBr
or allylBr, TBAB, CsOH, CH2Cl2, 0 °C).30 The corresponding
α-benzylated and α-allylated products 6 and 7 were obtained
in good yields and satisfying diastereomeric ratios. The latter
was eventually cyclized under ring-closing metathesis con-
ditions [Grubb’s II catalyst (5 mol %), CH2Cl2, 40 °C] to
afford the corresponding cyclopentene derivative 8 in 32%
yield over two steps. The same ring-closing metathesis
conditions applied to alkenyl nitrile 3g led to yet another
five-membered ring derivative (9) in 55% yield and a preserved
95% ee. Compound 3r was eventually converted to the
corresponding β-amino acid precursor 1031 in three steps and
41% overall yield without, once again, any noticeable erosion
of the selectivity.
Finally, to further showcase the synthetic utility of the
method, but also to confirm the absolute configuration of the
D
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Notes
newly formed stereogenic center, we prepared 5-carboxyme-
thylcyclopentene carboxylate 11, a potential key intermediate
in the synthesis of a number of natural products including the
monoterpenes mitsugashiwalactone and dolichodial in three
steps and 57% yield starting from 9.32 Comparison of its
optical rotation with the one reported confirmed the R
The authors declare no competing financial interest.
An early preprint of this work appeared on ChemRxiv
(8091314).33
ACKNOWLEDGMENTS
configuration of the newly formed center {[α]24 +23.9
■
D
(c 0.48, CHCl3) (found), lit.32b [α]26D +30.7 (c 0.6, CHCl3)}.
In summary, we have developed a catalytic one-pot two-step
synthesis of diversely substituted α-branched acrylonitriles
featuring an enantioselective Michael addition/retro-Die-
ckmann/retro-Michael fragmentation cascade using 4-cyano-
3-oxotetrahydrothiophene (c-THT) as an acrylonitrile surro-
gate. Most importantly, the reaction is easy to set up, scalable,
and robust and offers a direct access to interesting chiral
building blocks, which can be readily functionalized. The
concept, through the latent acrylonitrile surrogate (c -THT)
and the retro-Dieckmann/retro-Michael fragmentation, vir-
tually connects the asymmetric Michael addition and the α-
alkylation of acrylonitrile, two reactivities which, at first glance,
appear to be irreconcilable. With this in mind and considering
the importance of the acrylonitrile motif in medicinal,
agrochemical, and polymer chemistry, we believe this method
will become an essential tool in the synthetic chemist’s toolbox.
The authors gratefully acknowledge Sanofi and Queen Mary
University of London for financial support and Prof. Cyril
Bressy (Aix-Marseille University) for fruitful discussions.
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̈
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02079.
́
̂
1
Details of experimental procedures, H and 13C NMR
spectra, HPLC chromatograms (PDF)
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AUTHOR INFORMATION
Corresponding Author
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Silvia Anselmi − Queen Mary University of London, School of
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Bilal Siddiq − Queen Mary University of London, School of
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Marc Daumas − Sanofi Chimie, Route d’Avignon, 30390
Aramon, France
Vincent Ferey − Sanofi R&D, 34080 Montpellier, France
́
Michael Smietana − Institut des Biomolecules Max Mousseron,
́
Universite de Montpellier, 34095 Montpellier, France;
orcid.org/0000-0001-8132-7221
Complete contact information is available at:
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